electrophilic amination of carbanions, enolates, …6 organic reactions there is only one previous...

CHAPTER 1

ELECTROPHILIC AMINATION OF CARBANIONS, ENOLATES,AND THEIR SURROGATES

ENGELBERT CIGANEK

121 Spring House Way, Kennett Square, PA, 19348, USA

CONTENTSPAGE

ACKNOWLEDGEMENTS . . . . . . . . . . . . . 4INTRODUCTION . . . . . . . . . . . . . . 5REAGENTS AND MECHANISMS . . . . . . . . . . . 6

Preparation of Carbanions, Enolates, and Their Surrogates . . . . . 6Aminating Reagents . . . . . . . . . . . . 6

Metal Amides . . . . . . . . . . . . . 6Haloamines . . . . . . . . . . . . . 7Hydroxylamines . . . . . . . . . . . . 8

N-Unsubstituted O-Alkylhydroxylamines . . . . . . . 8N-Unsubstituted O-Arylhydroxylamines . . . . . . . . 8N-Monosubstituted O-Alkylhydroxylamines . . . . . . . 8N,N-Disubstituted O-Alkylhydroxylamines . . . . . . . 9O-Acyl Hydroxylamines . . . . . . . . . . 10N-Unsubstituted O-Sulfonylhydroxylamines . . . . . . . 10N-Monosubstituted O-Sulfonylhydroxylamines . . . . . . 10N,N-Disubstituted O-Sulfonylhydroxylamines . . . . . . 11O-Phosphinoylhydroxylamines . . . . . . . . . 11

Oxaziridines . . . . . . . . . . . . . 12Imines . . . . . . . . . . . . . . 13(N -Arenesulfonylimino)phenyliodinanes . . . . . . . . 14Oximes . . . . . . . . . . . . . . 15Diazonium Salts . . . . . . . . . . . . 15Diazo Compounds . . . . . . . . . . . . 16Azo Compounds . . . . . . . . . . . . 16

Alkyl Azo Compounds . . . . . . . . . . . 16Aryl Azo Compounds . . . . . . . . . . . 16Esters of Azodicarboxylic Acid . . . . . . . . . 16Other Acyl Azo Compounds . . . . . . . . . . 18Sulfonyl Azo Compounds . . . . . . . . . . 18

Azides . . . . . . . . . . . . . . 18Alkyl Azides . . . . . . . . . . . . . 18

[email protected] Reactions, Vol. 72, Edited by Scott E. Denmark et al. 2008 Organic Reactions, Inc. Published by John Wiley & Sons, Inc.

1

COPYRIG

HTED M

ATERIAL

2 ORGANIC REACTIONS

Vinyl Azides . . . . . . . . . . . . . 20Aryl Azides . . . . . . . . . . . . . 20Acyl Azides . . . . . . . . . . . . . 21Sulfonyl Azides . . . . . . . . . . . . 21Sodium Azide/Ammonium Cerium(IV) Nitrate . . . . . . 23Diphenyl Phosphorazidate . . . . . . . . . . 23Miscellaneous Azides . . . . . . . . . . . 23

Miscellaneous Reagents . . . . . . . . . . . 24Chloramine-T/Osmium Tetroxide . . . . . . . . . 24N -Chlorocarbamate/Chromium(II) Chloride . . . . . . . 24Bis[N -p-Toluenesulfonyl)]selenodiimide . . . . . . . 24Nitridomanganese Complexes . . . . . . . . . 24

SCOPE AND LIMITATIONS . . . . . . . . . . . . 24Amination of Aliphatic Carbanions . . . . . . . . . 24

Preparation of Alkyl Amines . . . . . . . . . . 24Preparation of Alkyl Hydrazines . . . . . . . . . 26Preparation of Alkyl Azides . . . . . . . . . . 28

Amination of Allylic and Propargylic Carbanions . . . . . . . 28Amination of Arylmethyl and Heteroarylmethyl Carbanions . . . . . 28Amination of Vinyl and Allenyl Carbanions . . . . . . . . 29Amination of Ethynyl Carbanions . . . . . . . . . . 30Amination of Aryl Carbanions . . . . . . . . . . 30

Preparation of Arylamines . . . . . . . . . . . 30Preparation of Aryl Hydrazines . . . . . . . . . . 32Preparation of Aryl Azides . . . . . . . . . . 32

Amination of Heterocyclic Carbanions . . . . . . . . . 32Amination of Aldehyde Enolates, Enol Ethers, and Enamines . . . . 33Amination of Ketone Enolates, Enol Ethers, and Enamines . . . . . 35Amination of Imine and Hydrazone Anions . . . . . . . . 39Amination of Carboxylic Acid Dianions . . . . . . . . 40Amination of Ester Enolates and Ketene Acetals . . . . . . . 41Amination of Thioester Enolates and Ketene Thioacetals . . . . . 44Amination of Lactone Enolates . . . . . . . . . . 44Amination of Amide Enolates and Ketene Aminals . . . . . . 45Amination of N -Acyloxazolidinone Enolates . . . . . . . . 46Amination of Lactam Enolates . . . . . . . . . . 50Amination of Nitrile-Stabilized Carbanions . . . . . . . . 51Amination of Nitronates . . . . . . . . . . . 52Amination of Sulfone-Stabilized Carbanions . . . . . . . . 52Amination of Phosphorus-Stabilized Carbanions . . . . . . . 52Amination of Enolates of α,β-Unsaturated Carbonyl Compounds . . . . 54Amination of Enolates of α-Cyanocarbonyl and β-Dicarbonyl Compounds . . 56Intramolecular Aminations . . . . . . . . . . . 58

Formation of Aziridines . . . . . . . . . . . 58Formation of Higher-Membered Rings . . . . . . . . 59

COMPARISON WITH OTHER METHODS . . . . . . . . . . 60Amination with Nitrogen Oxides . . . . . . . . . . 60Amination with Nitrosyl Chloride, Nitryl Chloride, and Nitronium Tetrafluoroborate 60Amination with Alkyl Nitrites . . . . . . . . . . 61Amination with Alkyl Nitrates . . . . . . . . . . 61Amination with Nitroso Compounds . . . . . . . . . 62Amination With Nitro Compounds . . . . . . . . . 63Amination of Enolates with Diazonium Salts . . . . . . . . 65

ELECTROPHILIC AMINATION OF CARBANIONS 3

The Diazo Transfer Reaction . . . . . . . . . . . 65Amination of Boranes . . . . . . . . . . . . 65The Neber Rearrangement . . . . . . . . . . . 66

EXPERIMENTAL CONDITIONS . . . . . . . . . . . 66Preparation of Electrophilic Aminating Reagents . . . . . . . 66Conversions of Amination Products . . . . . . . . . 66

EXPERIMENTAL PROCEDURES . . . . . . . . . . . 68N ,N -Diisopropylaniline (Amination of an Arylcopper Reagent with a Lithium

Dialkylamide) . . . . . . . . . . . . . 69Diethyl Aminomalonate (Amination of a β-Dicarbonyl Compound with

Chloramine) . . . . . . . . . . . . . 70N -tert-Butylbenzylamine (Amination of an Alkyllithium Compound with a Lithium

Nitrenoid) . . . . . . . . . . . . . . 71tert-Butyl 4-Fluorophenylcarbamate (Amination of an Arylcopper Reagent with

Lithium tert-Butyl N -Tosyloxycarbamate) . . . . . . . . 72N -Phenylmorpholine (Amination of an Arylzinc Derivative with an

O-Acylhydroxylamine) . . . . . . . . . . . 72N ,N -Diethyl-5,10-dihydroindeno[1,2-b]indol-10-amine (Amination of a Benzylic

Anion with an N ,N -Disubstituted O-Arenesulfonylhydroxylamine) . . . 73Ethyl (N -Acetylamino)phenylacetate (Amination of an Ester Enolate with an

O-Phosphinoylhydroxylamine) . . . . . . . . . . 73Diamino-N ,N ′-diphenylmalonamide and Imino-N ,N ′-diphenylmalonamide

(Diamination of a Malonamide with 1-Oxa-2-azaspiro[2.5]octane and Conversion ofthe Product into an Imine) . . . . . . . . . . 74

Ethyl tert-Butoxycarbonylamino(cyano)phenylacetate (Amination of a CyanoaceticEster Enolate with an N -Acyloxaziridine) . . . . . . . . 74

N -Isopropyl-p-anisidine (Amination of a Grignard Reagent with an Imine) . 752-[N -(p-Toluenesulfonyl)amino]acetophenone (Amination of a Ketone Silyl Enol Ether

with [N -(p-tolylsulfonyl)imino] phenyliodinane) . . . . . . 751-Aminoadamantane Hydrochloride (Amination of a Grignard Reagent with an

O-Arenesulfonyloxime) . . . . . . . . . . . 75E-(tert-Butyl)(4-chlorophenyl)diazene (Reaction of a Grignard Reagent with an

Aryldiazonium Salt) . . . . . . . . . . . . 761,2-Diphenyl-1-(1-p-tolylpentyl)hydrazine (Amination of a Benzotriazolylmethyl

Anion with an Azo Compound Followed by Displacement of the BenzotriazoleFunctionality by a Grignard Reagent) . . . . . . . . 76

tert-Butyl N -(3-Bromo-1-methylpropyl)-N ′-(tert-butoxycarbonyl)hydrazinecarboxylicAcid (Catalyzed Hydrohydrazination of an Olefin with an Azo Ester) . . 77

2-[N ,N ′-bis(tert-Butoxycarbonyl)hydrazino]thiophene (Amination of a HeterocyclicZinc Reagent with an Azo Ester) . . . . . . . . . 77

(R)-Dibenzyl 1-(1-Hydroxyhexan-2-yl)hydrazine-1,2-dicarboxylate (CatalyticAsymmetric Amination of an Aldehyde with an Azo Ester) . . . . 78

(S)-Dibenzyl 1-(1-Oxo-1,2,3,4-tetrahydronaphthalen-2-yl)hydrazine-1,2-dicarboxylate(Catalyzed Asymmetric Amination of a Ketone Silyl Enol Ether with anAzo Ester) . . . . . . . . . . . . . 78

Methyl 2-(Naphthalen-2-ylamino)methylacrylate (Amination of an Allylindium Specieswith an Azide) . . . . . . . . . . . . . 79

N -Ethylaniline (Preparation of an N -Substituted Aniline by Reaction of a GrignardReagent with an Aromatic Azide) . . . . . . . . . 79

2,4-Dimethylaniline (Preparation of Trimethylsilylmethyl Azide and Its Reaction withan Arylmagnesium Reagent to Give an Aniline) . . . . . . 80

2-Aminobenzothiazole (Preparation of Azidomethyl Phenyl Sulfide and Its Reactionwith a Heterocyclic Grignard Reagent to Give a Heterocyclic Amine) . . 80

4 ORGANIC REACTIONS

(4R)-3{(Z,2R)-2-Azido-6-[(4R)-3-tert-butoxycarbonyl-2,2-dimethyl-1,3-oxazolidin-4-yl]-1-oxohex-5-enyl}-4-phenylmethyl-1,3-oxazolidinone and(4R)-4[(1Z,5R)-5-Azido-5-carboxypent-1-enyl]-3-tert-butoxycarbonyl-2,2-dimethyl-1,3-oxazolidine (Diastereoselective Azidation of an N -Acyloxazolidinone with TrisylAzide and Removal of the Chiral Auxiliary) . . . . . . . 81

2-Azido-1,3,5-trimethylbenzene (Preparation of an Azide from a Grignard Reagent andTosyl Azide) . . . . . . . . . . . . . 82

α-[(tert-Butoxycarbonyl)amino]-N -methyl-N -phenyl-2-thiopheneacetamide (Aminationof an Amide Enolate with Diphenyl Phosphorazidate) . . . . . 83

2-Azido-2-methylcyclohexanone (Preparation of an α-Azido Ketone by Reaction of aKetone Triisopropylsilyl Enol Ether with Sodium Azide and Ammonium Cerium(IV)Nitrate) . . . . . . . . . . . . . . 83

2,2,2-Trichloroethyl 2-Oxocyclohexylcarbamate (Amination of a Ketone Enol Etherwith the Chromium(II) Chloride/Chlorocarbamate Reagent) . . . . 83

TABULAR SURVEY . . . . . . . . . . . . . 84Chart 1. Structures of Reagents and Catalysts . . . . . . . 87Table 1A. Acyclic Aliphatic Carbanions . . . . . . . . 88Table 1B. Cyclic Aliphatic Carbanions . . . . . . . . . 118Table 1C. Allylic and Propargylic Carbanions . . . . . . . 126Table 1D. Arylmethyl and Heteroarylmethyl Carbanions . . . . . 132Table 2. Vinyl and Allenyl Carbanions . . . . . . . . . 143Table 3. Ethynyl Carbanions . . . . . . . . . . . 146Table 4. Aryl Carbanions . . . . . . . . . . . 147Table 5. Heterocyclic Carbanions . . . . . . . . . . 186Table 6. Aldehyde Enolates . . . . . . . . . . . 194Table 7A. Acyclic Ketone Enolates . . . . . . . . . 207Table 7B. Cyclic Ketone Enolates . . . . . . . . . . 216Table 8. Imine and Hydrazone Anions . . . . . . . . . 235Table 9. Carboxylic Acid Dianions . . . . . . . . . 238Table 10A. Ester Enolates . . . . . . . . . . . 240Table 10B. Thioester Enolates . . . . . . . . . . 258Table 11. Lactone Enolates . . . . . . . . . . . 260Table 12. Amide Enolates . . . . . . . . . . . 264Table 13. N -Acyloxazolidinone Enolates . . . . . . . . 267Table 14. Lactam Enolates . . . . . . . . . . . 286Table 15. Cyano-Stabilized Carbanions . . . . . . . . . 290Table 16. Nitronates . . . . . . . . . . . . 295Table 17. Sulfone-Stabilized Carbanions . . . . . . . . 296Table 18. Phoshorus-Stabilized Carbanions . . . . . . . . 297Table 19. Enolates of α,β-Unsaturated Carbonyl Compounds . . . . . 303Table 20. Enolates of α-Cyanocarbonyl and β-Dicarbonyl Compounds . . . 307Table 21. Intramolecular Aminations . . . . . . . . . 336

REFERENCES . . . . . . . . . . . . . . 345

ACKNOWLEDGEMENTS

I am indebted to E. I. du Pont de Nemours & Co., Inc. and Dr. Pat Confalonefor permission to use the company libraries and especially to Ms. Susan Titterof the Agricultural Products Department for valuable assistance. Professor ScottDenmark and Ms. Donna Whitehill of the University of Illinois and Professor


Peter Wipf and Ms. Michelle Woodring of the University of Pittsburgh graciouslyprovided copies of less common journals. I also thank the many colleagues whoanswered questions or provided copies of their papers. My editor, Dr. StuartMcCombie, is thanked for his guidance and advice and for painstakingly proof-reading the manuscript. Last, but not least, I owe a large debt of gratitude toDr. Linda Press for valuable help during the preparation of this chapter andfor patiently answering my many questions regarding the mysteries of computersoftware.

INTRODUCTION

Nitrogen-containing organic compounds are ubiquitous in nature and essentialto life. They are also important intermediates and products of the chemical andpharmaceutical industries. As a consequence, chemists have developed a plethoraof methods for their generation, starting with the first organic synthesis, Wohler’spreparation of urea from ammonium cyanate in 1828.1 There are many reports ofthe formation of carbon-nitrogen bonds by electrophilic amination of carbanionsand enolates in the early literature, but development of this method as a usefulsynthetic tool, especially for asymmetric synthesis, is of more recent date.

Most electrophilic aminations can be divided into two types: substitutions(e.g. Eq. 1) and additions (e.g. Eq. 2) to give products that in many cases arenot amines. A detailed discussion of the conversion of these intermediates intoamines is beyond the scope of this chapter, but references to relevant methodsare given in the section on Experimental Conditions.

R1M + (R2)2NX

R1M = Grignard or organolithium reagent, etc.

R1N(R2)2 + MX (Eq. 1)

MO

R1 R3

R21. R4N=NR5

2. H2O R1 NO

NHR2 R3

R4

R5

M = metal

(Eq. 2)

The initial intent to cover the subject exhaustively had to be abandoned becauseof the overwhelming amount of relevant literature. The following reactions arenot covered but are briefly discussed, with references to reviews and seminalpapers, in the section on Comparison with Other Methods: reactions of carbanionsand enolates and their surrogates with nitrogen oxides, nitrite and nitrate esters,and nitroso and nitro compounds; reactions of enolates with diazonium salts,including the Japp-Klingemann reaction; the diazo transfer reaction except as itinterferes with the synthesis of azides; the amination of boranes; and the Neberrearrangement.

The large number of reagents that are available for amination necessitated adeviation from the standard Organic Reactions format. The section on Reagentsand Mechanisms includes discussion and exemplification of each reagent orreagent class as well as comments on mechanism, particularly in context ofreagent-substrate combinations that can lead to more than one product. Stereo-chemistry is discussed in the relevant sections of Scope and Limitations.

6 ORGANIC REACTIONS

There is only one previous comprehensive review of the electrophilicamination of carbanions;2 shorter reviews3 – 9 and reviews limited to particularreagents, substrates, or products have appeared: amination with haloamines,10

sulfonylhydroxylamines,11 oxaziridines,12 oximes,13 diazonium salts,14,15 diazocompounds,16 activated azo compounds,17 azides,18 – 23 and nitridomanganese(V)reagents;24,25 amination of enolates;26 – 30 and the preparation of α-amino acidsby electrophilic amination.31 – 34

REAGENTS AND MECHANISMS

Preparation of Carbanions, Enolates, and Their Surrogates

The preparation of carbanions,35 organolithium reagents,36,37 Grignardreagents,38,39 and organozinc reagents40,41 has been reviewed. For reviews onthe generation of enolates see refs. 42–45. The synthesis of silyl enol ethersis reviewed in refs. 46–49, that of silyl ketene acetals in ref. 50. The term“carbanion” is used loosely without regard to aggregation or solvation.

Aminating Reagents

All aminating reagents dealt with in this chapter are listed here; references totheir preparation are found in the section on Experimental Conditions. Stereo-chemistry is discussed in the relevant sections of Scope and Limitations. Theterm amination refers to the formation of a carbon-nitrogen bond, not just to theintroduction of an amine group. For a quantum Monte Carlo study of electrophilicamination reagents see ref. 51.

Metal Amides. Amidocuprates, when treated with molecular oxygen at lowtemperatures, give secondary or tertiary amines (Eq. 3). The substrates may begenerated from disubstituted lithium cuprates and a primary or secondary amine(method A);52 one equivalent of the cuprate may be used but yields are higherwith three to five equivalents. Only one of the two R1 groups enters into theproduct; it may be, among others, an aryl or tert-butyl group. Acyl and hydroxygroups in the amine are tolerated. Method B involves the reaction of an organo-lithium reagent with an excess of a copper amide, which in turn is generated froma lithium amide with copper(II) iodide.52 The copper amide may be replaced byan anilido cuprate ArN(R3)Cu(X)Li where X is Cl or CN.53 The third method(C) employs a lower-order cuprate and a lithium amide. R1 may be alkyl, aryl,heteroaryl, or styryl. Yields in the three methods are moderate to good. Sub-stituted hydrazines are obtained by replacing the lithium amides in method Cwith a lithium hydrazide, but yields are only in the 20–40% range.54 THF is thepreferred solvent in these reactions, which fail with Grignard or organolithiumreagents. An eight-membered planar complex has been suggested54 as the inter-mediate, which reacts with oxygen to give the product via an aminyl radical.


Yields are improved in method C when zinc cyanocuprates and co-oxidants (o-dinitrobenzene or copper(II) nitrate) are employed.55

R1Cu(CN)Li + R2R3NLi

O2

A

B

C

(R1)2CuLi + R2R3NH

R1Li + R2R3NCu amidocuprate R1NR2R3 (Eq. 3)

Haloamines. Chloramine was one of the earliest reagents investigated for theamination of Grignard reagents and organolithium compounds.56 – 59 An excessof the latter is usually required because of the acidic nature of the haloaminehydrogens. Replacement of one of these by lithium to give a nitrenoid hasbeen suggested as the first step (Eq. 4).60 Bromamine offers no advantage overchloramine.61 In the reactions of haloamines with Grignard reagents, yieldsdecrease in the order of RMgCl > RMgBr > RMgI.61 Chloramine aminates sodiomalonates.62 – 64 With sodium phenolates, ring-expanded products are obtained.65

The mechanism of these reactions is unknown62 but a nitrenoid intermediateis unlikely because of the lower basicity of the substrates. No reaction occursbetween 2-lithio N -methylimidazole and chloramine.66

H2O RLi

–LiClRLi + ClNH2 ClNHLi RNHLi RNH2

(Eq. 4)

Monosubstituted chloramines have not received much attention. The reactionof N -chloro-tert-butylamine with di(tert-butyl)magnesium gives di(tert-butyl)amine in 10% yield.67 Butylmagnesium chloride and N -chloromethylamine pro-duce mostly methylamine by reduction and only 14% of N -methylbutylamine.68

Disubstituted chloramines are claimed to not react with phenylmagnesiumbromide69 and with only very poor yields with n-butyl- or benzylmagnesiumchloride.68 N -Chlorodiisopropylamine reacts with isopropylpotassium to give tri-isopropylamine in 3% yield.70 Similar low yields are obtained in the reactionsof phenylethynyllithium,71 phenylethynylmagnesium bromide,71 or diethylzinc72

with N -chlorodiethylamine. Chloramines of type ClNRCHRAr, prepared fromthe secondary amines with N -chlorosuccinimide, react with arylmagnesium chlo-rides to give the corresponding tertiary amines (see Eq. 62).73 N,N-DisubstitutedN -chloroamines react with enamines to give mixtures of α-amino aldehydesin moderate to excellent yields where the α-amino group is derived from thechloro amine in one product and from the enamine in the other (see Eq. 86). Amechanism involving aziridinium intermediates has been suggested.74

N ,N -Dibromoamine,75 N ,N -dichloroalkylamines,68,72,76 and even trichloro-amine58,77 react with Grignard or dialkylzinc reagents to give amines by reductionof the excess halogen. Yields are low and these reagents are currently of no valuein synthesis.

Chloramine-T, the sodium salt of N -chloro-p-toluenesulfonamide, tosylami-nates a number of in situ generated enamines of α-substituted propionaldehydes(see Eq. 78), α-substituted arylacetaldehydes, and methyl arylmethyl ketones.78

8 ORGANIC REACTIONS

Hydroxylamines. A number of O-substituted hydroxylamines are electrophi-lic aminating reagents for introduction of unsubstituted as well as mono- anddisubstituted amino groups.

N-Unsubstituted O-Alkylhydroxylamines. The most widely used in this cat-egory are O-methylhydroxylamine, and, to a lesser extent, O-benzylhydroxyl-amine. In the amination of the dianion of 3-methylbutanoic acid with RONH2,79

yields decrease in the order R = Me > Et = i-Pr > t-Bu > Bn and range from34% for MeONH2 to a trace for BnONH2. However, the latter aminates organo-lithium and Grignard reagents (two equivalents) in fair to good yields.80 Themechanism of the amination of organolithium reagents with O-alkylhydroxylami-nes involves the nitrenoid intermediate 1 (Eq. 5) and eventual displacement ofthe methoxy group by R in a counterintuitive reaction between two negativelycharged species that is sterically akin to an SN2 reaction. The mechanism is basedon extensive experimental81 – 85 and computational work60,86 – 90 and also appliesto Grignard, organozinc, and organocopper reagents.91 However, it should be keptin mind that other mechanisms are, at least in principle, available, in view of thefact that N,N-disusbstituted O-alkylhydroxylamines are also aminating reagentseven though a process involving a nitrenoid is impossible with these reagents.By generating the nitrenoid 1 with methyllithium only one equivalent of RLi isrequired. Application of this method to aminations with O-alkylhydroxylaminesreported in the earlier literature should increase the efficiency of these reactions.An excess of the nitrenoid MeONHLi is recommended; in the reaction with n-butyllithium the yields of n-butylamine are 51% with one equivalent, 71% withtwo (see also Eq. 63), and 85% with four.92

MeLi + MeONH2

RLi

1

R OMeNH

2–

RNHLi– LiOMe

RNH2

H2O

RLi

NLi H

OMeMeONHLi

2 Li+

(Eq. 5)

N-Unsubstituted O-Arylhydroxylamines. Amination of malonic and cyano-acetic ester enolates93 and of methyl 9-fluorenecarboxylate94 may be carried outin fair to good yields with O-(2,4-dinitrophenyl)hydroxylamine. Yields are lowwith the more basic phenylacetic ester enolates and the anion of phenylacetoni-trile, both of which partially decompose the reagent with formation of diimide.93

This reagent provides much poorer yields than Ph2P(O)ONH2 in the aminationof the anion of tetraethyl methylenebis(phosphonate).95 The corresponding N -methyl derivative is unreactive in an N-amination.94 Various analogs of the highlyexplosive O-(2,4-dinitrophenyl)hydroxylamine have been tested in N-aminationsonly 94,96 and O-(4-nitrophenyl)hydroxylamine was found to provide the highestyields and to have the highest onset temperature of explosive decomposition.96

N-Monosubstituted O-Alkylhydroxylamines. Various O-methylhydroxyl-amine derivatives (MeONHR) aminate aliphatic and aromatic organolithium com-pounds: R = Me,82,83,97 n-Pr and i-Pr,83 benzyl,83,85 α-methylbenzyl,82,83,85,97


and 2-phenylethyl.83 The order of reactivity of BnNLiOMe toward butyl-lithium reagents is n-Bu < s-Bu < t-Bu.85 BnNLiOMe reacts much morerapidly with these three alkyllithium reagents than its α-methyl derivativePhCHMeNLiOMe;85 the latter is about equal in reactivity to MeNLiOMe.97

Reagents of type RCH2NLiOBn may be prepared by addition of an organolithiumreagent RLi to formaldehyde O-benzyl oxime (Eq. 6).98 A nitrenoid of this classis also formed in the reaction of phenyllithium with nitrosobenzene (Eq. 7),99 butit reacts so rapidly with unreacted phenyllithium that the possibility of trappingit with another organolithium reagent seems remote.

CH2 NOBn n-BuLi, THF

–40°

1. PhLi, 0-40°

2. 4-PhC6H4COCl

(47%)

n-Bu NOBn

Lin-Bu N

PhPh

O

(Eq. 6)

PhNOPhLi (1.1 eq), THF

–100°, 70 minPhN(Li)OPh Ph2NLi + PhOLi

H2OPh2NH + PhOH(41%) (41%)

PhLi

(Eq. 7)

O-Trimethylsilylhydroxylamine reagents (RNHOTMS where R is TMS oralkyl), aminate organocuprates of type R1

2Cu(CN)Li2 (see Eqs. 64 and 73), butnot organolithium reagents.100 – 102 Small amounts of alcohols R1OH are formedin some reactions as a consequence of the nitrenoid 2/oxenoid 3 equilibrium(Eq. 8), with the latter acting as a hydroxylating agent.60,103

TMSNOTMS

2 3

(TMS)2NO– M+

M+–

(Eq. 8)

Amination with an N-monosubstituted cyclic hydroxylamine is shown inEq. 9.104

NHO

O

O NHPhOH

O

OPhMgBr (3 eq), –78° to 0°, 1 h

(~100%)

(Eq. 9)

N,N-Disubstituted O-Alkylhydroxylamines. In the amination with a series ofN,N-disubstituted O-methylhydroxylamines, more bulky alkyllithium compoundsreact more readily (product 4, Eq. 10).85 The small amounts of products 5 are theresult of elimination of methanol from the substrate to give the imine followedby addition of R1Li to the latter. Reagents where R2, R2 is H, Me or Me, Medo not react. A single-electron-transfer process involving a nitrogen radical has

10 ORGANIC REACTIONS

been proposed,85 but no cyclized product is formed when R3 is a dimethylvinylgroup.

BnNOMe

R3

R2 R2R1Li, –78°, 3 h

rt, 1-2 dBn

NH

R3

R2 R2

+R1

5

R1

n-Bus-But-But-Bu

BnNR1

R3

R2 R2

R2

HHHH

R3

PhPhPhCH=CMe2

4

4(5%)

(47%)(72%)(67%)

5(5%)(5%)(5%)(—)

(Eq. 10)

Silyl ketene acetals are aminated by the ethoxycarbonylnitrene precursorEtO2CN(TMS)OTMS to give α-ethoxycarbonylamino esters via aziridines in fairto good yields (see Eq. 124).105

O-Acyl Hydroxylamines. O-Acyl N-unsubstituted hydroxylamines have beenused occasionally in the amination of enolates.79,106 In the amination of thesodium salt of diethyl phenylmalonate, O-(4-nitrobenzoyl)hydroxylamine issomewhat more efficient than (4-MeOC6H4)2P(O)ONH2 (99% vs 92% yields).106

This reagent also gives the highest yield in the N-amination of oxazolidinoneanions.107 A series of N,N-disubstituted O-benzoylhydroxylamines is used in theamination of alkyl- and arylzinc chlorides in the presence of a catalytic amountof (Ph3P)2NiCl2108 and of dialkyl-, diaryl-, and di(heteroaryl)zinc reagents inthe presence of a catalytic amount of a copper(II) salt (see Eq. 36).109 – 112 Thedisubstituted zinc reagents may be prepared in situ by reaction of Grignardreagents with a catalytic amount of zinc chloride because transmetalation isfaster than the reaction of the Grignard reagent with O-benzoylhydroxylamine.Functional groups on the aryl ring, such as NO2, CO2R, and CN are toleratedand 0.6 equivalent of the disubstituted zinc reagent may be employed with aslight reduction of the yield. Arylmagnesium reagents may be aminated in thisway without the intervention of the corresponding zinc reagents.113 An SN2mechanism has been advanced.113

N-Unsubstituted O-Sulfonylhydroxylamines. The acidic nature of hydroxy-lamine O-sulfonic acid makes it essentially useless in electrophilic aminations ofcarbanions. One of the few exceptions is shown in Eq. 161. The explosive114,115

O-(mesitylenesulfonyl)hydroxylamine aminates alkylzirconium complexes (seeEqs. 41 and 51),116 acid dianions,115 and ester enolates.117 O-Arenesulfonylhy-droxylamines with no ortho substituents are thermally unstable at room tempe-rature.11

N-Monosubstituted O-Sulfonylhydroxylamines. N -Ethoxycarbonyl-O-(p-tol-uenesulfonyl)hydroxylamine (6) is used in the amination of enamines.118,119

The more reactive N -ethoxycarbonyl-O-(4-nitrobenzenesulfonyl)hydroxylamine


(7) aminates enamines120,121 and enol ethers122 derived from ketones (seeEq. 96), as well as metalloimines,123 enolates of β-dicarbonyl compounds,124

and enamines derived from β-dicarbonyl compounds.125 The lithium saltof N -(tert-butoxycarbonyl)-O-(p-toluenesulfonyl)hydroxylamine (8) aminatesalkyl- and aryllithium and -copper reagents (see Eq. 69),126 – 128 estersand N -acyloxazolidinone enolates,126 and α-alkylphosphonamides.129 Theallyloxycarbonyl analogs 10 and 11 are similarly used.130 The structure ofthe mesityl analog 9 (dimer, crystallizing with three molecules of THF) hasbeen determined by single crystal X-ray crystallography.131 Because this classof reagents offers a much better leaving group, the possibility exists thatthe nitrenoids lose the elements of ArSO3M to give nitrenes NCO2R.60 Theinvolvement of these reactive intermediates has been proposed in a number ofexamples.

6 R = Me7 R = O2N

10 R = Me11 R = 4-MeC6H4

8 R1 = Me R2 = H9 R1, R2 = Me

R

O2S

O

LiN O

O

O2S

O

R2

R1 R2R

O2S

O

HN

CO2EtLiN

CO2Bu-t

N,N-Disubstituted O-Sulfonylhydroxylamines. Compounds of typeR1SO2ON(R2)2 (R1 = Me, Ph, p-tolyl, mesityl; R2 = Me, Et) are versatile ami-nating reagents for a wide variety of substrates: aliphatic (see Eq. 35),132,133

allylic,133,134 olefinic (see Eq. 56),133 acetylenic (see Eq. 60),135 benzylic(see Eq. 53),133,136 and aromatic132,133 metal derivatives and enolates (seeEq. 89).133,134 Reactions of MeSO2ONMe2 (and probably other similar reagents)with RMgI should be avoided because iodide reduces the reagent.137 Both anelectron-transfer and an SN2-type substitution mechanism have been consideredfor these transformations.136

O-Phosphinoylhydroxylamines. The non-explosive138 O-diphenylphosphi-noylhydroxylamine, Ph2P(O)ONH2, aminates alkyl,139,140 aryl,139 ethynyl (seeEq. 60),135 cyanomethyl, and phosphinoylmethyl (see Eq. 152)95,141 metalderivatives and enolates of esters,139,142 lactams (see Eq. 137),143 α,β-unsaturatedcarbonyl compounds (see Eq. 153),144 and β-dicarbonyl compounds.139

The equally stable methoxy analog (4-MeOC6H4)2P(O)ONH2 has beenrecommended106 as a better reagent because of its increased solubility in organicsolvents at low temperatures but there is a report of a low yield and formation ofa hydroxylation product in the amination of a malonic ester enolate.145 Aminationwith the disubstituted analog Ph2P(O)ONMe2

146 and the chiral, non-racemiccyclic derivative 12 (see Eqs. 109 and 143)147 has also been reported. Thereappear to be no mechanistic studies of these reagents but it is relevant thatequimolar amounts of the substrate and the reagent or a slight excess of the latterare usually employed.


NMe

POPh

ONMe2

12

O

HN

13a

ONCOY

ArY = t-Bu, NEt2, (–)-menthoxide

14

O

Oxaziridines. The readily synthesized 1-oxa-2-azaspiro[2,5]octane (13a)148

aminates12 enolates of β-dicarbonyl compounds,149,150 α-cyano carbonylcompounds,149,150 and anions derived from cyanomethyl derivatives furtheractivated by aryl or heteroaryl groups.150 The products are either amines, N -cyclohexylidene derivatives, or more complex structures (see Eq. 162). Thecamphor-derived oxaziridine 13b aminates enolates of esters, β-dicarbonyl andα-cyano carbonyl compounds,151 and anions derived from various cyanomethylcompounds.151 Esters are aminated only if they carry an additional aryl group.151

The products resulting from β-dicarbonyl and α-cyano carbonyl compounds arecamphorimines that have lost the ester group by hydrolysis and decarboxylation.Camphorimines derived from aminations of esters retain the ester group. Thecyano group in all substrates is converted into an amide group and the mechanismshown in Eq. 11 has been proposed. The first step is analogous to that of themechanistically fairly well-established hydroxylation of enolates with N -sulfonyloxaziridines152 except that attack by the anion is on nitrogen rather than oxygen.When R is methyl or ethyl, only rearrangement products of the aminating reagentare isolated.151

13bO

NHR

CNO–

HN

R

N

ONH

R

N–

N–O

NHR

NO

NH2

R

H2O

–

R = CH=CH2, Ar (45-80%)

R = Me, Et (0%)

(Eq. 11)

Oxaziridines 14 transfer the NCOY group to enolates of ketones (seeEq. 90),153 – 156 esters (see Eq. 110),153,155,157,158 amides,158 N -acyloxazolidino-nes,153,157 and β-dicarbonyl compounds,155 anions stabilized by cyano (seeEq. 141),155 sulfonyl (see Eq. 145),158 and phosphinoyl154 groups, and ketoneenol ethers.155 Yields are in the 20–60% range. The first step in these reactions ispresumably attack of the enolate on nitrogen as in Eq. 11, followed by eliminationof an aldehyde ArCHO and formation of the amination product. With esters,


the aldehyde may undergo an aldol reaction with the substrate enolate whenLiHMDS, KHMDS, LDA, or t-BuLi are used as the bases to generate theenolates. This undesired side reaction is not observed with NaHMDS providedthat two equivalents of the reagent are used, but yields are low.155

Imines. Organometallic compounds normally attack imines at the carbonatom. Predominant or exclusive attack on nitrogen may be forced by attachingone or two electron-withdrawing groups to the imine carbon atom.159 – 167 Inthe examples of Eq. 12161 involving a substrate with a fairly bulky group onnitrogen, the ratios of product 15 to 16 demonstrate that only the tert-butyl andallyl Grignard reagents attack on carbon, the former presumably for steric reasons.All cadmium reagents RCdX tested (R = Me, n-Pr, i-Pr, Bn) add normally oncarbon.

N CO2R1

PhH

R2MX (X not specified)

Et2O

R1 =

NR2

CO2R1

PhH

NH

CO2R1

PhH

R2

+

15 16

MMgMgMgMgMgMgMgCd

15 + 16(45-55%)(44-55%)(44-55%)(45-55%)(45-55%)(45-55%)(45-55%)(55-70%)

15:1695:596:4

60:400:10096:4

0:100100:00:100

R2

Etn-Pri-PrCH2CH=CH2

i-But-BuBnBn

(Eq. 12)

A second method of favoring attack on nitrogen involves systems where theimine carbon is surrounded by fairly bulky substituents and where placing anegative charge on this carbon is favored by formation of a cyclopentadienylanion (Eq. 13).168 A phenyl group on nitrogen reverses this trend, with product18 now predominating over 17.

NR1

R2Li, THF, hexane

–78°, 2 h; to rt

R1R2N H R1NH R2

+

R1

Men-BuPh

R2

n-BuEtn-Bu

17(71%)(65%)(15%)

17 18

18(0%)(5%)(50%)

(Eq. 13)

Attack of isopropylmagnesium bromide on the hindered imine in Eq. 14 sur-prisingly occurs on nitrogen whereas the less bulky ethylmagnesium bromide addsto the carbonyl group.169 Organozinc reagents react with anthranil under Ni(acac)2

catalysis to give α-aminobenzaldehyde derivatives by a proposed single-electron


transfer mechanism (Eq. 15).170 Diethyl zinc adds to 1,4-diaza-1,3-butadienes ina net 1,4-fashion (Eq. 16).171

HN O

t-Bu

t-Bu

i-PrNH O

t-Bu

t-Bu

i-PrMgBr, Et2O

(35%)

(Eq. 14)

RZnCl +N

ONi(acac)2, THF, 0° to rt, 2 h CHO

NHRR = Me, 2-thienyl, Ph, 2-, 3-, and 4-MeOC6H4

(4-86%)

(Eq. 15)

NN

Bu-tt-Bu Et2Zn, toluene

–70° NBu-t

ZnEt2

Bu-tN –50°

NBu-t

ZnEtN

t-Bu Et

t-BuOH, pentane, rtN NHBu-t

t-BuEt N NBu-t

t-BuEt+

(76%) (12%)

(Eq. 16)

(N -Arenesulfonylimino)phenyliodinanes. [N -(p-tolylsulfonyl)imino]phe-nyliodinane (TsN=IPh) and its pentafluoro analog C6F5SO2N=IPh react read-ily on warming in acetonitrile with silyl enol ethers derived from acetophe-nones to give the α-tosylamino derivatives in high yields. The reaction isless efficient in methylene chloride, gives low yields with the trimethylsilylether of 3-pentanone and with 1-trimethylsilyloxybutadiene, and fails com-pletely with 1-trimethylsilyloxycyclohexene and a ketene acetal, 1-phenoxy-1-(trimethylsilyloxy)ethylene.172 The latter two types of substrates do reactwhen a copper catalyst is employed, but yields do not exceed 50% (see alsoEq. 92).173 With chiral (ligand 19 or 20) copper catalysts, modest to fair enan-tiomeric excesses are achieved (Eq. 17).174 The proposed mechanism involves aslightly favored front-side attack of the enol derivative on the initially formedligand–copper nitrene complex with formation of an aziridine, which is con-verted directly into the α-tosylamino product during isolation when methyl ortrimethylsilyl enol ethers are used.

Ph

AcO+ TsN=IPh

[Cu(MeCN)4]PF6, 19 or 20

CH2Cl2, –40° Ph

AcONTs

HCl, MeOH

PhNHTs

O

Ligand1920

Conversion a

(>95%)(61%)

ee28% R52% RN N

Ar Ar19 Ar = C6H3Cl2-2,6

N

O

N

O

Ph Ph20

a based on TsN=IPh reacted

(Eq. 17)


Oximes. Reaction of alkyl- or arylmagnesium reagents with two equivalentsof acetone oxime in toluene gives alkyl or arylamines, respectively, in low yields.The yields are improved by converting the oxime into the salt with ethylmagne-sium halide followed by addition of the desired Grignard reagent. A mechanisminvolving a four-membered cyclic transition state is postulated (Eq. 18).174a Sim-ilar reactions with the lithium salt or methyl ether of benzaldoxime have alsobeen reported.175 Among the O-sulfonyloxime derivatives 21176 – 178 (see Eq. 61),22178,179 (see Eq. 40), 23,180 24,181 and 25,181,182 the dioxolane 25b combinesthe advantages of high product yields in reactions with alkyl-, vinyl-, aryl-, andheteroarylmagnesium reagents with ease of hydrolysis of the initially formedimine to the amine (see Eq. 37).182 Reactions with other types of anions donot seem to have been investigated except that phenolates (Eq. 176) and eno-lates of β-dicarbonyl (Eq. 175) and α-sulfonyl carbonyl compounds undergo anintramolecular version of this amination reaction. The mechanism is believed toinvolve direct SN2 substitution on the sp2 nitrogen of the oxime13,183 rather thanaddition/elimination or electron transfer.

EtMgX Ph(CH2)2MgX (2 eq)

N

CH2

MgX

MgXO

Bn

NOH NO– MgX+

N

Ph

H2N

Ph

(48%)

(Eq. 18)

NR OSO2C6H2Me3-2,4,6

21 R = Me, Ph

N

PhPh

PhPh23

EtO

EtON

OTs

OSO2Ph

Z

YN

OSO2Ph

24

25a25b25c25d25e

YOONMeONMe

ZOOONMeNMe

R1

R1

R1

R1

R1

HMeHHH

NAr

Ar OSO2R

22 Ar = Ph, 4-CF3C6H4, 3,5-(CF3)2C6H3

R = Me, 4-MeC6H4

Diazonium Salts. Diazonium salts are potentially explosive. See the caution-ary note in Experimental Conditions. Aryldiazonium salts 26 react with alkyl- andarylmagnesium reagents,184 – 191 arylzinc,190,192,193 and aryltin reagents194 to giveazo compounds. Yields vary considerably; the best are achieved with the diazo-nium salt 26e191 (see Eq. 48). Aryldiazonium salts also react with enolates, enolderivatives, or enamines of aldehydes (see Eq. 85),195 ketones (see Eq. 95),185

and with silyl ketene acetals (see Eq. 121).196,197


ArN2+ X–

26a26b26c26d

26e X =SO2

N

O2S

XClZnCl3BF4

Zn(BF4)Cl2

Diazo Compounds.198 Alkyl- and arylmagnesium199 – 204 and alkyllithiumreagents205 add to diazo compounds in a little-used reaction to give hydrazones.Diazo compounds add to enolates to give azines.206 With enamines, diazo com-pounds give hydrazones of α-diketones.207

Azo Compounds. Alkyl Azo Compounds. The only aminations with alkylazo compounds found in the literature involve the cyclic derivatives 27,208 28,209

and 29.210 Reaction of 29 with phenyllithium followed by in situ arylation of theanion (Eq. 19)210 is one of the few examples of tandem reactions in aminationsreported thus far. Azo compounds 27 add to cyclohexyl- and phenylmagnesiumreagents at −78◦ with fair to excellent yields,208 and the bicyclic azo compound28 gives an adduct with t-BuLi at −78◦ in almost quantitative yield.209 Reliefof strain no doubt is one of the driving forces for these reactions but the lowtemperatures involved may indicate that they could be extended to acyclic alkylazo compounds.

NNR

R

R, RMe, Men-Pr, n-Pr—(CH2)5—27

NN

28

NN

29

1. PhLi, MeO(CH2)2OMe, Et2O, –35° to –20°

NC6H4NO2-4

NPh

(34%)

2. 4-FC6H4NO2, –20° to rt (Eq. 19)

Aryl Azo Compounds. Alkyl- (including tert-butyl) and aryllithium reagentsadd to azo benzene to give trisubstituted hydrazines in fair to excellent yields(see Eqs. 44 and 45); alkylation of the intermediate anion in situ leads to tetra-substituted hydrazines.211 Benzyl and heteroarylmethyl (see Eq. 54) anions andthe enolate of phenylacetamide add to azo benzene in fair to excellent yields.212

Aromatic Grignard reagents are reported to reduce azo benzene and its deriva-tives to the hydrazo compounds (cf. also Eq. 20).213 The only other aryl azocompound investigated in aminations appears to be benzo[c]cinnoline.214

Esters of Azodicarboxylic Acid. These compounds are versatile aminatingreagents for alkyl- (see Eq. 46), allenyl- (see Eq. 59), aryl- and heteroarylmetal(see Eq. 75) derivatives, and especially enolates (see Eqs. 87, 88, 115–117, and


119) and metalloimines (see Eqs. 104–106). An important new reaction involvesaddition of azo esters to alkenes,215 dienes,216 and enynes216 in the presence ofsilanes catalyzed by cobalt and manganese complexes to give the more highlysubstituted hydrazino esters (see Eqs. 49, 52, and 55). Based on preliminarymechanistic studies of this hydrohydrazination reaction, rate-limiting addition ofa metal hydride species to the double bond is followed by a fast amination step.215

Benzyl and tert-butyl esters are widely used because of their ready conver-sion into the hydrazines after the amination step and the presence of an aromaticchromophore in the former. Addition of the organometallic species to the estercarbonyl group does not appear to be a problem, although tert-butyl esters oftenprovide higher yields. Formation of substantial amounts of an α,β-unsaturatedcarbonyl compound by elimination of the hydrazino ester from the desired prod-uct has been reported in the reaction of dibenzyl azodicarboxylate with the enolateof a sugar ketone.217 Esters derived from azodicarboxylic acid and chiral alcoholshave been prepared218,219 and a chiral amide has been used in the amination of anachiral enolate (see Eq. 134).219 The failure of a secondary Grignard reagent toadd to diisopropyl azodicarboxylate is shown in Eq. 20.220 The asymmetric ami-nation of aldehydes (see Eqs. 76 and 77)221 – 227 and ketones (see Eq. 91)228,229 byazo esters is catalyzed by proline and its derivatives. The proposed mechanisminvolving a hydrogen bond from the catalyst to the N=N double bond in the tran-sition structure is shown in Eq. 21221 (see also ref. 224). The amination of β-ketoesters by azo esters proceeds at room temperature neat or in polar solvents suchas alcohols230,231 or, as with β-aminocrotonic ester, even in petroleum ether.230

The former reaction may be carried out enantioselectively with catalysts such ascinchona alkaloids (see Eq. 163),231,232 chiral urea and thiourea derivatives,233

chiral copper(bis)oxazoline complexes234 (see Eqs. 103, 151, and 164),235 – 237

and chiral palladium BINAP complexes (see Eqs. 150 and 165).238,239

PhMgCl

Ph

(82%)(82%)

i-PrO2CN

NCO2Pr-i+ i-PrO2C

HN

NH

CO2Pr-i+

(Eq. 20)

R1 CHONH

CO2HN CO2H

OH–N CO2H

R1 R1

R2O2CN=NCO2R2

N CO2–

NH

CO2H+N

R1

O

OHN

N

R2O2C

CO2R2R1 N

H

NHCO2R2

CO2R2

CHO

R1 N

H

NHCO2R2

CO2R2

(Eq. 21)


Azo esters also aminate enol ethers (see Eq. 82),240 – 245 enamines (seeEq. 147),118,246 – 250 ketene acetals (see Eqs. 112 and 113),251 ketene aminals (seeEqs. 125 and 126),251,252 and ketene thioacetals.253

Other Acyl Azo Compounds. Various azo derivatives [R1N=NCOR2: R1 =aryl, R2 = CO2R, CONR2, or COAryl; and R1CON=NCOR2: R1 = R3O, (R3)2 N,Ar, R2 = (R3)2N, Ar] have been used as aminating agents. The site selectivityis governed by the degree to which a substituent stabilizes the negative chargeon nitrogen, which increases in the order Aryl < CONR2 < CO2R < COAr.N -Phenyltriazolinedione has been used to aminate acetone254 and a silyl enolether.245

Sulfonyl Azo Compounds. Aryl and cyclopropyl Grignard reagents add toArN=NTs to give diaryl or cyclopropylarylamines after allylation and reduction(Eq. 22).255 For a similar reaction involving organozinc reagents see Eq. 38.

Ar1Ii-PrMgCl, THF

–20°Ar1MgI

1. Ar2N=NTs, THF, –20°

2. ICH2CH=CH2, N-methylpyrrolidinone, rt, 2 h

Ar1

NN

Ar2

Ts1. Remove solvents

2. Zn, HOAc, CF3CO2H, 75°Ar1NHAr2

(63-86%)

(Eq. 22)

Azides. Alkyl Azides. A variety of alkyl azides react with alkyl- and aryl-metal species to give triazenes (Eq. 23) (see cautionary note with regard to bothazides and triazenes in Experimental Conditions): methyl azide,256 – 258 ethylazide,258 isopropyl azide,259 n-butyl azide,260 – 262 cyclopropylmethyl azide,262

allyl azide,263 trimethylsilylmethyl azide,264 – 267 a protected 2-hydroxyethylazide,268 n-hexyl and cyclohexyl azide,269 benzyl azide,261,269,270 and polymethy-lene diazides N3(CH2)nN3 (n = 2,3).271,272 Protolysis of the intermediate metalsalts of the triazenes may give rise to two different triazenes (Eq. 23) and theirstructures have not always been determined with certainty. The product of thereaction of benzyl azide with phenylmagnesium bromide is identical to thatobtained from phenyl azide and benzylmagnesium chloride and was assignedstructure 30 with the extended conjugation (Eq. 24)270 on the basis of the prod-uct obtained with phenyl cyanate. Protolysis of triazene 30 with 1 N HCl givesaniline hydrochloride and benzyl chloride (Eq. 24);270 similarly, N -methyl- andN -ethyl-N ′-phenyltriazenes, on treatment with HCl, give aniline hydrochlorideand methyl or ethyl chloride, respectively.270 The intermediate triazenes obtainedfrom trimethylsilylmethyl azide and aryllithium or arylmagnesium reagents de-compose to arylamines on aqueous workup.264 Triazenes are also not isolatedfrom the reaction of allylindium species, generated in situ from the bromides andindium metal, with alkyl and aryl azides in DMF; however, N -alkyl and N -arylallylamines, respectively, are obtained (Eq. 25).269 This example appears to beone of only two instances where, in a reaction of an organometallic species withan azide, both substituents on the intermediate triazene appear in the product. Theother is the addition of alkylmagnesium species to aryl azides mentioned below.


By contrast, allyl azide, and aryllithium or arylmagnesium species react to givearylamines after acidic workup (Eq. 26).263 The triazene intermediate should bethe same, except for the counter ion and the solvent, as the one in Eq. 25. Noexplanation for these differing results has been advanced.

R1M + R2N3H2O R1

NH

NN

R2 R1

NN

NH

R2

and/orNN

NR1 R2 M+

(Eq. 23)

BnMgCl + PhN3

PhMgBr + BnN3

HClBnCl + PhNH3

+ Cl– + N2(—) (—)

30 ("good yield")

BnNH

NN

Ph(Eq. 24)

N3Br+

In, NaI, DMF

rt, 2 h

NN

N NH4Cl

H2O

HN

(90%)

N

(5-8%)

+

(Eq. 25)

MgBrN3+

Et2O

–78° to rt

H3O+ NH2

(83%)

NN

N

(Eq. 26)

Both N ,N ′-di(n-butyl) and N ,N ′-di(cyclopropylmethyl)triazenes react differ-ently with dilute HCl (0.1% in acetone) to give nitrogen gas and nitrogen-freeproducts (n-BuOH, s-BuOH, 1-butene, and 2-butene with the former triazene)via alkyldiazonium species.262

Reaction of the α-heteroatom-substituted azides 31 and 32 with 2-phenethyl-magnesium bromide proceeds with equal rates at −78◦; analog 33 only reacts at0◦, whereas both azides 34 and 35 are essentially unreactive at this temperature.273

Both aliphatic (see Eq. 40) and aromatic Grignard reagents, but not aromaticlithium reagents, may be used with azide 32, which has a low steric requirement asevidenced by its reaction with the exo and endo isomers of 2-norbornylmagnesiumbromide at about equal rates274 (see also Eq. 39).

31 R = MeO

32 R = H

TMSO N3

i-Pr

33 3435

MeS N3 MeO N3S

R

N3

Hydrolysis of the triazenes so obtained from aromatic Grignard reagents togive aromatic amines may be carried out with either aqueous formic acid or


aqueous potassium hydroxide.275 Triazene anions derived from aliphatic Grignardreagents are quenched with acetic anhydride (or benzoyl chloride) and the acetates36 are then converted into the aliphatic amines using the conditions shown inEq. 27.273 The scope of this method is somewhat limited, however: the unstabletriazenes, obtained in almost quantitative yields from tert-butylmagnesium chlo-ride and n-octylmagnesium bromide, could not be converted into the amines andquenching the triazene anion obtained from azide 32 and 1-octenylmagnesiumbromide with acetic anhydride gives the regioisomer of acetate 36, which isunsuitable for further manipulation.274 The 2-anions of furan, thiophene, N -methylpyrrole, and N -methylindole do not react with azide 32.274

MgBr+Ac2O

–60° to –30°, 1.5 h

RNAc

NN SPh

n-Bu4NH+ HCO2–, DMF, 45°

or: KOH, Me2SO, 0°RNH2

36

RN

NN

CH2SPh

(Eq. 27)

Azide 32 aminates ester enolates (see Eq. 114)275 and a sugar-derived azideaminates the anion derived from cyanoacetamide276 (see Eq. 167).

Vinyl Azides. Vinyl azides such as 37 or 38 react with alkyl-, aryl-, andheteroaryllithium reagents like other azides to give the corresponding triazenes.Hydrolysis of the latter leads to nitrogen-free carbonyl compounds when aliphaticlithium reagents are used (path A, Eq. 28),277 but when benzyl, aromatic, andheteroaromatic lithium reagents are used, amines are formed in fair to good yields(path B).278

Ph

N3 N3

Bu-t37

1. RLi, THF –78°

2. H2OR N

N NH

Bu-t

HClA

BRNH2

38 (45-70%)

t-Bu CHO

R

or

(Eq. 28)

Aryl Azides. The triazenes formed by addition of alkylmagnesium halidesto aryl azides lose nitrogen and give N -alkylaniline derivatives on workup withaqueous ammonium chloride (Eq. 29).279 This is unusual in two respects: earlierreports270,280 – 283 state that triazenes are isolated under these conditions (see alsoEq. 58) and that anilines, rather than N -alkylanilines, are formed on treatmentwith acid at room temperature (see discussion under Alkyl Azides, above).

F

N3 c-C6H11MgBr

Et2O, rt, 1 h

NH4Cl, H2O

F

NHC6H11-c

(85%)

F

NC6H11-c

MgBr+

– N2NN

NC6H11-c

F

MgBr+–

(Eq. 29)


Aromatic Grignard reagents react normally with aryl azides to givetriazenes280,281,284,285 as do vinylmagnesium halides.286 – 288 Grignard reagentsalso add to a variety of aromatic diazides to give the correspondingbis(triazenes).272,289,290 Phenylmagnesium bromide adds preferentially to anazide group in the presence of a diaryl azo group.290 Addition of N-protectedimidazole anions to phenyl azide gives the corresponding 2-amino derivativesafter acid hydrolysis.66 Addition of phenyl azide to ketene dimethyl acetalsand decomposition of the intermediate triazolines gives α-anilino esters in lowyields.291 The formation of diazomalonamide in addition to aniline from theenolate of malonamide and phenyl azide is the earliest example of a diazotransfer reaction.292 Aryl azides undergo net reduction to arylamines and N -formyl arylamines on reaction with the enolate of acetaldehyde.293

Acyl Azides. The only additions of a Grignard reagent to acyl azides appear tobe those of phenylmagnesium bromide to carbonyl azide (N3CON3) and methyland ethyl azidoformates (N3CO2R) to give triazenes in low or unstated yieldswith retention of the carbonyl group.284 However, the same Grignard reagentreacts faster with the carbonyl than the azide group in azido acetone.294 Ethyland tert-butyl azidoformates aminate tetrahydropyrans,295 ketone silyl enol ethers(see Eq. 98),296,297 ketene acetals,298 – 301 and enamines.302,303 A camphorsulfone-derived acyl azide has also been used.304 Either irradiation or thermolysis or acombination of the two is used and the reactions proceed either via the triazolineand aziridine or directly via the latter. Yields vary widely from poor to good.

Sulfonyl Azides. Alkyl- and arylmagnesium halides,305,306 as well as alkyl-307,aryl- (see Eq. 70),308 – 312 and heteroaryllithium313 reagents add to sulfonyl azidesto give triazene salts which may be reduced to amines 305,310 – 312 or convertedinto azides. The latter reaction has been accomplished by an aqueous workup withthe highly hindered 2,6-dimesitylphenyl azide,314 whereas quenching with aque-ous potassium hydroxide (see Eq. 72)305,315 sodium bicarbonate,313 or sodiumpyrophosphate305,316 (see Eqs. 67 and 74) is necessary with other arenesulfonylazide adducts. Thermolysis of the dry triazene salts also leads to azides,307,308

but because of the hazards involved, this procedure is not recommended.Azidations of certain phosphorus-stabilized anions with 2,4,6-triisopropylben-

zenesulfonyl azide (“trisyl azide,” 41a) may be reversible.317

The most widely used application of sulfonyl azides is in the azidation ofenolates and other stabilized carbanions. The main challenge here is the avoid-ance of the diazo transfer reaction, which leads to diazo compounds and thusmakes a diastereoselective amination impossible. Addition of the enolates to thesulfonyl azide proceeds rapidly at low temperatures (−78◦ or lower) to give themesomeric ion 42 (Eq. 30).318 Reagents 41, the counter ion M+, the solvent,and the quenching reagent all influence the subsequent partition between azideand diazo compound. For enolates of esters (39) and N -acyloxazolidinones (40)the preferred reagent is trisyl azide (41a); 4-nitrobenzenesulfonyl azide (41c)promotes diazo transfer, and tosyl azide (41b) usually leads to mixtures of thetwo types of products. For ester enolates 39, either lithium or potassium as the


counter ion in combination with trisyl azide favors azidation (see Eqs. 118, 120,122, and 123), whereas for N -acyloxazolidinone enolates 40 the potassium eno-lates are usually employed. Diazidation may occur with ester enolates (but notwith N -acyloxazolidinone enolates) as a consequence of proton transfer from theinitial adduct 42 to the enolate 39 (see Eq. 122); it can be avoided or minimizedby use of the lithium enolate or by inverse addition of the enolate to the sulfonylazide. Quenching agents are added after short reaction times (about one minute).Acetic acid is the reagent of choice for azidation, whereas trifluoroacetic acidpromotes diazo transfer.318 In the triethylamine-promoted reaction of a β-ketoester with trisyl azide, use of THF or acetonitrile as the solvent leads to the azideexclusively, whereas in methylene chloride only diazo transfer and other prod-ucts are formed.319 The use of TMSCl as the quenching agent gives considerablyhigher yields than acetic acid in the azidation of a lactone enolate.320 The reasonsfor the above experimental observations do not appear to be clear. In the azida-tion of cyclic β-keto esters, where trisyl azide also promotes azidation,319,321 thebulky and less electrophilic trisyl azide may inhibit formation of the triazolineprecursor to the diazo compound. However, trisyl azide is the only reagent thatpromotes diazo transfer to a number of simple ketone enolates, which do not nor-mally react with sulfonyl azides.322 – 324 One of the few exceptions is the azidationof a taxane-derived ketone enolate where reaction with tosyl azide followed byquenching with acetic acid gives the diazo compound, whereas quenching withaqueous ammonium chloride leads to the azide.325 In another example, a lactonelithium enolate reacts with 4-nitrobenzenesulfonyl azide (41c) to give exclu-sively the azide.326 These examples underscore the fact that exceptions exist tothe above-mentioned rules. Other factors that affect yields and azide/diazo com-pound partitioning in specific reactions are discussed in the relevant sections ofScope and Limitations. A reaction in which the N -arenesulfonylamide rather thanthe azide is obtained on quenching with aqueous ammonium chloride is shownin Eq. 106.327

R1

R2

O–M+

39 R2 = OR3

40 R2 = ON

O

R4

ArSO2N3

R1

R2

O

NNN

SO2Ar41a Ar = 2,4,6-(i-Pr)3C6H2

41b Ar = 4-MeC6H4

41c Ar = 4-O2NC6H4

R1

R2

O

NNN

SO2ArM+ M+

42

R1

R2

O

N3

R1

R2

O

N2

A

B

+ ArSO2H

+ ArSO2NH2

quench

(Eq. 30)


Trifluoromethanesulfonyl azide, prepared in situ from trifluoromethanesulfonylchloride and sodium azide in dimethylformamide, is reported to azidate phospho-noacetic esters and β-dicarbonyl compounds in the presence of triethylamine,309

whereas the same, but preformed, reagent gives the diazo compounds with α-nitro328 and α-cyano329 carbonyl compounds in the presence of pyridine. Thereason for this dichotomy is not clear but because the former reaction was car-ried out under typical diazo transfer conditions the products may have beenmisidentified.330

Sodium Azide/Ammonium Cerium(IV) Nitrate. Silyl enol ethers give α-azidoketones on treament with sodium azide and anhydrous ammonium cerium(IV)nitrate in anhydrous acetonitrile (see Eq. 97).297,325,331 With a glycal, the 2-azido-1-hydroxy nitrate derivative is formed.332 Low yields due to hydrolysis of the silylenol ether may be improved by use of the triisopropylsilyl (TIPS) derivatives,331

although with a sterically encumbered taxane-derived enol ether the TMS deriva-tive gives higher yields than the TIPS derivative.325 The mechanism is believedto involve addition of an azide radical to the double bond.

Diphenyl Phosphorazidate. (PhO)2P(O)N3, reacts with aromatic Grignardand lithium reagents to give aromatic amines after in situ reduction of the initiallyformed triazene salt.333,334 Reaction of a lithiated poly(phenylsulfone) with thisreagent is not as clean as the corresponding reaction with tosyl azide.335 Addi-tion of lithium amide enolates to (PhO)2P(O)N3 at low temperature and trappingthe triazene salt with di-tert-butyl dicarbonate gives protected α-amino amides inhigh yields (Eq. 31).336 When the initial addition is carried out at 0◦, the α-diazoamides are formed exclusively.337 Similarly, reaction of (PhO)2P(O)N3 with anester enolate gives exclusively the diazo ester whereas azidation only occurs withtrisyl azide.338

RN(Me)Ph

O

NNN

(PhO)2PO– Li+

RN(Me)Ph

O

N– Li+NN

(PhO)2P

(t-BuO2C)2O

–78°

RN(Me)Ph

O

NCO2Bu-tNN

(PhO)2P

RN(Me)Ph

O

NCO2Bu-tNN

(PhO)2POHO H

H2O RN(Me)Ph

O

NHCO2Bu-t

OO(Eq. 31)

Miscellaneous Azides. Ethyl (N -methanesulfonyl)azidoformimidate[N3C (OEt)=NSO2Me] has been used to aminate chiral cyclopentanone enaminesbut the yields are low and the reaction could not be extended to the correspond-ing cyclohexanone enamines.303 Trimethylsilyl azide (TMSN3) transfers the TMSrather than the azide group to a lactam enolate.339


Miscellaneous Reagents. Chloramine-T/Osmium Tetroxide. The Sharplessasymmetric aminohydroxylation system for olefins (4-MeC6H4SO2N(Na)Cl/OsO4/cinchona alkaloid derived catalysts)340,341 converts silyl enol ethers intoα-(p-tosylamino) ketones in 34–40% yield and 76–92% ee (see Eq. 99).342

N-Chlorocarbamate/Chromium(II) Chloride. Enol ethers (see Eq. 80) andglycals (see Eq. 84) react with N-chlorocarbamates in the presence of chromouschloride to produce α-amino carbonyl derivatives.343 Trimethylsilyl enol ethersgive low yields because of their ease of hydrolysis. A radical chain mechanismhas been proposed with the N-haloamide acting as the transfer agent (Eq. 32).344

OR1

R2R4

R3

ClNHCOR5 + CrCl2 NHCOR5 + CrCl3

NHCOR5 +OR1

R2R4

R3

R5CONH

OR1

R2R4

R3

R5CONH ClNHCOR5+OR1

R2R4

R3

R5CONH Cl NHCOR5+

R2R4

R3

R5CONHOOR1

R2R4

R3

R5CONH ClH3O+

(Eq. 32)

Bis[N-(p-Toluenesulfonyl)]selenodiimide. The reagent obtained from thereaction of chloramine-T with selenium metal, proposed to have structureTsN=Se=NTs, reacts with TIPS enol ethers in an ene-like reaction to give thecorresponding α-tosylamino enol ethers (see Eq. 100).345 – 349

Nitridomanganese Complexes. Stoichiometric amounts of chiral complexesof type 43 react with silyl enol ethers in the presence of trifluoroacetic orp-toluenesulfonic anhydride to give α-(N -trifluroacetyl)amino- and α-(N -p-tosylamino) ketones, respectively (see Eq. 160).350 – 353 With glycals, the 1-hydroxy-2-(N -trifluoroacetyl)amino derivatives are formed (see Eq. 83).354 Amechanism involving approach of the enol ether from the least hindered sideof the 43•TFA complex has been proposed.353

N N

O O

R2

R1

R2

R1

R3R3

43

N

Mn

SCOPE AND LIMITATIONS

Amination of Aliphatic CarbanionsPreparation of Alkyl Amines. The main application of the electrophilic

amination of aliphatic carbanions is in the preparation of hindered amines. These


are not usually accessible by nucleophilic displacement involving an alkyl halideand ammonia or an amine and have been prepared by alternate methods such asthe Curtius rearrangement or the Ritter reaction. Examples are shown in Eqs. 10,12, 33,52 34,355 35,133 36,112 37,182 and 38.356

t-BuCuMeLi +

NH21. Et2O, –20°, 2 h

2. O2, –20°

NHBu-t

(35%) (Eq. 33)

ClNH2, Et2O, sonication(67%)

Ph

PhPh Li

Ph

PhPh NH2 (Eq. 34)

Li2,4,6-Me3C6H2SO2ONMe2, Et2O

–10° to –15°; to rt, 15 h

NMe2

(54%) (Eq. 35)

(t-Bu)2Zn + Bn2NOBzTHF, (CuOTf)2•C6H6 (1 mol%)

15-60 mint-BuNBn2 (98%) (Eq. 36)

O O

NOSO2Ph

+1. Et2O, CH2Cl2, 0°, 30 min

2. HCl, EtOH, H2O, reflux, 10 hMgBr NH2(89%)

(Eq. 37)

Zn2

EtO2C

N=NTs

+1. THF, –20°, 30 min

2. RaNi, EtOH, reflux, 90 min NH

CO2Et

(50%)

(Eq. 38)

Preparation of N -alkylanilines from aliphatic Grignard reagents and aryl azideswas discussed previously (Eq. 29). The net insertion of a methylene groupbetween the alkyl or aryl group of an organolithium reagent and the nitrogenas part of an amination was also mentioned earlier (Eq. 6).

Both lithium and Grignard reagents are aminated with retention of configu-ration (Eqs. 39274 and 40220). On the other hand, preparation of an organozincreagent from a chiral, non-racemic bromide with highly reactive zinc, subse-quent amination with an azo ester, and reduction of the adduct gives the racemicamine; racemization is believed to have occurred during preparation of the zincreagent.357

NH2

H

1. t-BuLi (2 eq), pentane, –78°, 30 min; to rt2. PhSCH2N3, THF, pentane, –78°; to rt, 1.5 h

(45%)Br

H

H

H

H

H3. NH4Cl, H2O4. KOH, DMSO, rt, 1 h

(Eq. 39)


PhS

Cl

PhNHAc

A: 1. [3,5-(CF3)2C6H3]2C=NOTs, toluene, Et2O, –70°, 10 d 2. Ac2O, Et3NB: 1. PhSCH2N3, THF, –78°, 1 h 2. Ac2O, –60° to –30° 3. KOH, DMSO, 0° to rt, 3 h

(25%) 90% ee

(82%) 92-95% ee

O

Cl

THF, –78° to –30° PhMgCl A or BEtMgCl (5 eq)

(Eq. 40)

Zirconium complexes, generated in situ by addition of HZrCp2Cl to alkenes,can be aminated with O-(mesitylenesulfonyl)hydroxylamine; an example isshown in Eq. 41.116 When the initial hydrozirconation is not regioselective, aswith styrene, mixtures of amines are formed. A reaction that permits aminationat the tertiary carbon in a similar substrate is discussed below (Eq. 49).

1. HZrCp2Cl (inverse addition), THF, rt

2. 2,4,6-Me3C6H2SO2ONH2, 0°, 10 minNH2

(88%) (Eq. 41)

Chiral ligands of type 44 may be prepared from chiral amines via ami-docuprates (Eq. 42).54

n-BuCu(CN)Li +1. THF, –40°, 15 min

2. O2, –78°, 20 min; to rt

NHLi NHBu-n

44 (60%)

(Eq. 42)

Preparation of Alkyl Hydrazines. As mentioned previously (Eq. 19), addi-tions of aliphatic carbanions to unactivated azo compounds are rare. Anotherexample is shown in Eq. 43.208 On the other hand, additions to diaryl azocompounds (Eq. 44)211 and esters of azodicarboxylic acids (Eq. 46)358 are welldocumented. The intermediate anion in Eq. 44 can be trapped with alkyl halidesto give tetrasubstituted hydrazines. An extension of the reaction of Eq. 44 exploitsthe ready displacement of the benzotriazole functionality by Grignard reagents(Eq. 45).359 Because of the instability of the intermediate 45, the Grignard reagentis added before the azobenzene in the actual experiments.

MgBr NN

+Et2O, 0° to rt, 1 h

HNN

(86%) (Eq. 43)

t-BuLi + PhN

NPh

hexane, THF, –78°, 2 h

rt, 10 h

PhN

HN

Pht-Bu

(47%) (Eq. 44)


NNN

1. n-BuLi, THF, –78°

2. PhN=NPh NHNn-BuPh

PhNLi

NNPh

Ph

NN

2. NH4Cl

(54%)45Ph PhPh

1. n-BuMgBr, –78° to rt

(Eq. 45)

ZnBr

+ t-BuO2CN

NCO2Bu-t THF, 0°, 1 h t-BuO2C

HN

NCO2Bu-t

(75%)

(Eq. 46)

Hydrazines may also be obtained via amidocuprates (Eq. 47)54 but the yieldsare low. Addition of Grignard reagents to diazonium salts provides azo com-pounds, which may be reduced to hydrazines. Yields in the former reaction areoften low and the requirement to use dry diazonium salts adds a potential hazard.The best yields are obtained with o-benzenedisulfonimide salts (Eq. 48).191

t-BuCu(CN)Li1. Ph2NNHLi, THF, –40°, 30 min

2. O2, –78°, 30 mint-Bu

NH

NPh

Ph

(30%) (Eq. 47)

Cl

N2+ O2

SN

SO2

–t-BuMgX +THF, –78°, 1 h

to rtCl

NN

Bu-t

(83%)

(Eq. 48)

A wide variety of N -alkyl hydrazinedicarboxylic esters may be obtained inexcellent yields by the hydrohydrazination reaction depicted in Eq. 49.215 Useof cobalt complexes results in more highly regioselective reactions at the cost oflower reaction rates as compared to additions where manganese complexes areemployed. Di(tert-butyl) azodicarboxylate is the preferred azo ester; reduction ofthe N=N double bond becomes more prominent when less hindered azo esters areused. Alcoholic solvents are essential; the reaction fails when methylene chlorideor THF is used.

PhSiH3, t-BuO2CN=NCO2Bu-t

cobalt complex (5 mol%), EtOH, rt, 5 h

L = MeOH

NCO2Bu-t

NHCO2Bu-t(90%)

NCo

O

OO

O

NH2O

L

cobalt complex

(Eq. 49)


Preparation of Alkyl Azides. A hydroazidation reaction similar to the reac-tion of Eq. 49 permits preparation of alkyl azides (Eq. 50).215

3. TsN3, t-BuO2H, rt, 5 min4. (Me2SiH)2O, rt, 10 h

t-Bu OH

N

PhPh

OK

O

ligandBu-t

BnO

OBnO

O

N3

(77%)

1. Co(BF4)3•6 H2O (6 mol%), ligand (6 mol%), EtOH, rt, 10 min2. Substrate

(Eq. 50)

Amination of Allylic and Propargylic CarbanionsThe literature in this area is fairly sparse, presumably because of the ease of

preparation of allyl- and propargylamines by nucleophilic amination. The reactionof allylindium species with aryl azides to give N -allylarylamines was mentionedearlier (Eq. 25). It has also been applied to the indium species derived frommethyl 2-(bromomethyl)acrylate.269 The amination of alkylzirconium speciesmentioned above (Eq. 41) can also be applied to allenes (Eq. 51).116

1. HZrCp2Cl (inverse addition), THF, rt

2. 2,4,6-Me3C6H2SO2ONH2, 0°, 10 min•

NH2(62%) (Eq. 51)

Application of the hydrohydrazination mentioned above (Eq. 49) to dienes andenynes gives N -allyl- and N -propargyl- (Eq. 52)216 hydrazinedicarboxylic estersin generally good yields. Serious competition from the Diels-Alder reaction is aproblem only with very reactive dienes such as cyclopentadiene.

PhPh(Me2SiH)2O, t-BuO2CN=NCO2Bu-t

cobalt complex (5 mol%), EtOH, rt, 2 hNNHCO2Bu-t

CO2Bu-t(56%)

L = MeOH

NCo

O

OO

O

NH2O

L

cobalt complex

(Eq. 52)

Amination of Arylmethyl and Heteroarylmethyl CarbanionsArylmethyl carbanions such as benzyl carbanions in general undergo most of

the amination reactions discussed for aliphatic carbanions. The difference is that


they may often be generated directly by metalation of the arylmethyl compoundsas shown in Eq. 53.136 Heteroarylmethyl carbanions frequently are also accessibleby direct metalation but they have been used in electrophilic aminations muchless frequently, although the method shown in Eq. 54212 should be applicable toother aminating reagents.

HN 1. n-BuLi (2.1 eq), THF, hexane, 0°

HN

NEt2

(43%)2. 2,4,6-Me3C6H2SO2ONEt2, –78°, to rt; rt, overnight

(Eq. 53)

NN

1. LDA (2 eq), THF, hexane, 1 h

2. PhN=NPh, –78°, 10 min(77%)

PhN

NH

Ph

(Eq. 54)

Catalytic hydrohydrazination of vinylarenes and vinylheteroarenes proceedsregioselectively and with often excellent yields (Eq. 55).215

3. substrate, 0°, 5 h

N

NMe

N

NMe

NNHCO2Bu-t

CO2Bu-t

1. manganese complex (1 mol%), i-PrOH, rt to 0°2. PhSiH3, t-BuO2CN=NCO2Bu-t, 0°

(88%)

manganese complex

Mn

OO

O

O

OO

Bu-t

t-But-Bu

t-But-Bu

Bu-t(Eq. 55)

Amination of Vinyl and Allenyl CarbanionsAmination of vinyl carbanions gives enamines (Eqs. 56133 and 5755) or their

derivatives (Eq. 58).286 Only arylamines are isolated when products of type 46are hydrolyzed with acid.

Li2,4,6-Me3C6H2SO2ONEt2, Et2O or Et2O/THF

–10° to –20°; to rt, 14 h(28%)NEt2 (Eq. 56)

1. (i-Pr)2NLi, THF, –78° to –40°, 40 min2. 1,2-(O2N)2C6H4, THF, –78°

PhN(Pr-i)2

(60%)

PhCu(CN)ZnCl 3. O2, –78°, 30 min

(Eq. 57)

PhMgBr

Ph

N3

OMe

+THF, rt, 2 h

Ph

PhN

N

HN

OMe46 (55%)

(Eq. 58)


In situ generated allenyltitanium complexes of type 47 are aminated byazodicarboxylic esters and the products may be degraded to α-hydrazino acids(Eq. 59).360 High α-symmetric induction is achieved only when R is a methylgroup; when it is n-butyl or isobutyl, the enantiomeric excess in the productdecreases to 55% and 27%, respectively.

TMSOP(O)(OEt)2

R+ Ti(OPr-i)4

i-PrMgBr (3 eq), Et2O

–50°, 2 h•

TMS

(i-PrO)2TiOP(O)(OEt)2

R

t-BuO2CN=NCO2Bu-t

–78°; to 0°, 1 h

TMSNCO2Bu-t

R

(77%) 81% ee

R = Me (94% ee)47

HNCO2Bu-t

HO2CNCO2Bu-t

R

HNCO2Bu-t

(80-83%)

RuCl3

NaIO4

(Eq. 59)

Amination of Ethynyl Carbanions

Amination of alkynylcuprates gives ynamines (Eq. 60);135 the yields are basedon two of the three ethynyl groups reacting. Yields are very low with organo-lithium and Grignard reagents.135 Amination of lithium bis(phenylethynyl)cupratewith Ph2P(O)ONH2 gives phenylacetonitrile by rearrangement of the initiallyformed primary ynamine.139 Imines of primary ynamines, however, can be iso-lated (Eq. 61).178 Phenylethynylsodium and tosyl azide react to give the triazolineby cycloaddition rather than the ethynyl azide.361

(RC C)3CuLi2Me2NX, Et2O

RC CNMe2

Rt-BuPh

XPh2P(O)OMsO

(71%)(52%)

(Eq. 60)

(PhC C)3CuLi2 NOSO2PhPh

Et2O, rt, 20 hN

Ph(39%)Ph+ (Eq. 61)

Amination of Aryl Carbanions

Preparation of Arylamines. Many methods to prepare arylamines by elec-trophilic amination are available. Some have been mentioned previously (Eqs. 13,15, 22, 24, 25, 26, 28, and 29) and some of the methods described for thepreparation of alkylamines (Eqs. 33, 35–37) can also be used to synthesize ary-lamines. Additional methods are shown in Eqs. 62,73 63,82 64,101 65264 66,333,334

and 67.305 The recently developed direct catalytic amination of aryl halides andaryl sulfonates,362 – 373 and arylboronic acids,374 however, has the advantage overthese methods of requiring one or more fewer steps. The approach that meritsconsideration will need to be decided based on each individual objective.


NC MgCl•LiClNMe

Br

Cl

THF, –45°, 15 minNC

MeN

Br

(70%)(Eq. 62)

MeONHLi (2 eq)Li

+1. Et2O, hexane, –78° to –15°, 2 h

2. BzCl

NHBz

(96%)

(Eq. 63)

Cu(CN)Li2+

F

2t-BuNHOTMS

THF, –50° to rt, 2 h

F

NHBu-t

(45%)

(Eq. 64)

MgBr+ TMSCH2N3

1. Et2O, rt, 3 h

2. H2O

NH2(79%) (Eq. 65)

MgBr+ (PhO)2P(O)N3

1. Et2O, –73° to –69°, 2 h NH2

(67%)

2. NaAlH2(OCH2CH2OMe)2, toluene, –70° to 0°, 1 h

(Eq. 66)

MgBr

Bn

1. TsN3, THF, 0°

2. Na4P2O7, H2O

2. RaNi, NaOH

3. HCl

N3

Bn

NH3+ Cl–

Bn

(49%)

(71%)

(Eq. 67)

The situation is more favorable when the aryl carbanion can be prepareddirectly from the arene by ortho lithiation. Examples are shown in Eqs. 68,53

69 (the copper reagent gives higher yields than the lithium reagent),128 and70.311 Phenylthiomethyl azide (32) does not react with aryllithium reagentsbut this failure can be remedied by converting them into magnesium reagents(Eq. 71).274,275,375 Trimethylsilylmethyl azide (Eq. 65) aminates aryllithiumreagents but the yields are lower than for Grignard reagents. On the other hand,the reactions of diphenyl phosphorazidate, illustrated in Eq. 66, work equallywell with organolithium reagents.

OMeCONEt2

1. s-BuLi, TMEDA, THF, –78°, 50 min2. PhNHCu(CN)Li, –78°, 2 h

OMeCONEt2

NHPh

(63%)3. O2, –78°, 30 min

(Eq. 68)

O

O1. n-BuLi, THF, Et2O, 0°, 2 h; rt, 22 h2. CuI, 0°, 15 min

O

O

NHCO2Bu-t

(45%)

3. TsON(Li)CO2Bu-t, –78°, 30 min; 0°, 2 h(Eq. 69)


O

N1. s-BuLi, TMEDA, THF, –78°, 1 h2. TsN3

O

N

NH2(50%)

3. NaBH4, n-Bu4N+ HSO4– (Eq. 70)

O

O

CONEt2

1. s-BuLi, THF, hexane2. MgBr2

3. PhSCH2N3, –78° to 0°; 0°, 1 hO

O

CONEt2

NH2

(71%)

4. NH4Cl, H2O5. 50% KOH in H2O, MeOH, THF, rt, 16 h

(Eq. 71)

The direct amination of arenes with chloramines in the presence of redoxcatalysts is another alternative that usually proceeds with good yields.376

Preparation of Aryl Hydrazines. All methods mentioned above for thehydrazination of alkyl carbanions may also be applied to aryl carbanions. Addi-tion of phenyllithium to a cyclic azo compound followed by in situ arylationto give a tetrasubstituted hydrazine was mentioned earlier (Eq. 19). An alternatehydrazination method, not involving aryl anions, is the reaction of electron-richarenes with azodicarboxylic esters and aroylazocarboxylic esters under the influ-ence of various catalysts.230,377 – 384

Preparation of Aryl Azides. Aryl azides may be prepared by reaction ofaryl carbanions with tosyl azide followed by treatment of the triazene salt withsodium pyrophosphate (Eq. 67)305 or aqueous base (Eq. 72).315

1. n-BuLi (5.4 eq), Et2O, rt, 5 h2. TsN3, rt, overnight

(28%) (6%)

Fe Fe FeN3 N3

N3

+3. 10% KOH in H2O

(Eq. 72)

Amination of Heterocyclic Carbanions

Aminations in this area involve anions of both π-excessive and π-deficientheterocycles, which are generated from the halo compounds or by directmetalation. Most of the aminating reagents seem to be applicable except thatphenylthiomethyl azide (32) fails with the 2-lithium or 2-copper derivatives offuran, thiophene, N -methylpyrrole, and N -methylindole.274 Similarly, chloramineand O-methylhydroxylamine, but not phenyl azide, fail to aminate 2-lithio-1-methylimidazole 66 and the MeN(Li)OMe nitrenoid does not react with 2-lithiothiophene.97 The reactions that appear to be most widely applicable toheterocyclic carbanions are shown in Eqs. 73,100,101 74,316 and 75.358


1. CuCN, THF, –40°, 20 min

2. R2NHOTMS, –50° to rt, 2 hR1Li R1NHR2

R1

2-thienyl3-pyridyl2-benzo[b]thienyl

R2

i-PrTMSTMS

(65%)(58%)(58%)

R2 = H after hydrolytic workup

(Eq. 73)

S

Li

O

O1. TsN3, Et2O, –78°

2. Na4P2O7, H2O, rt, overnight S

N3

O

O (65%) (Eq. 74)

S ZnBr

t-BuO2CN=NCO2Bu-t

THF, 0°, 1 h S NCO2Bu-t

NHCO2Bu-t(80%) (Eq. 75)

Amination of Aldehyde Enolates, Enol Ethers, and Enamines

There appear to be no reports of aminations of aldehyde enolates in the lit-erature, presumably because of their instability and their tendency to undergoaldol self-condensations. Since electrophilic hydroxylations of sterically hinderedaldehyde enolates have been reported,152 these should also be amenable to elec-trophilic amination. α-Amino aldehydes or their derivatives, however, can be gen-erated by the use of aldehyde enol ethers or enamines, either as substrates, or as insitu generated intermediates. An example of the latter is shown in Eq. 76223 wherethe aldehyde product is isolated.222,226,229,385 The mechanism of this reactionwas discussed earlier (Eq. 21). D-Proline gives the enantiomeric product.224,227

Derivatives of proline385,386 and L-azetidinecarboxylic acid222,223,229 are also usedas catalysts. In other applications of this method the products are reduced in situ tothe α-amino alcohols221,223,227 or their cyclization products.222 – 225,386 An exampleof the latter reaction sequence involves a diastereoselctive Michael addition to anα,β-unsaturated aldehyde to generate the precursor aldehyde enolate (Eq. 77).225

L-Proline in this reaction gives lower diastereo- and enantioselectivities. Reactionof α-branched aldehydes with chloramine-T in the presence of L-proline gives theracemic α-tosylamino aldehydes in high yield (Eq. 78).78 A similar reaction withsulfonyl azides also produces α-tosylamino aldehydes, but with modest yieldsand enantioselectivities (Eq. 79).386a

CHO

1. L-proline (0.5 eq), CH2Cl2, 0°; rt, 1 h2. EtO2CN=NCO2Et, rt, 2.5 d

CHO

N NHCO2EtCO2Et

(54%) 86% ee

3. H2O

(Eq. 76)


CHO

(1.5 eq)+ BnSH

NH

ArAr

OTMS(0.1 eq)

BzOH, toluene, –15°, 16 h CHOSBn

EtO2CN=NCO2Et

–15°, 16 h

CHOSBn

NHN

CO2EtCO2Et

1. NaBH4, MeOH, 0°, 10 min

2. NaOH ON

ONH

EtO2C

SBn

(63%) 90% de, >99% ee

Ar = 3,5-(CF3)2C6H3

(Eq. 77)

TsN(Cl)Na•x H2O, L-proline (2 mol%),

MeCN, rt, 2 d

CHO CHO

NHTs (86%) (Eq. 78)

CHO

CHO

NHSO2C6H4NO2-44-O2NC6H4SO2N3, L-proline (1 eq),

EtOH, rt, 1 d

OMe OMe (49%) 69% ee

(Eq. 79)

Examples where enol ethers of aldehydes are used as starting materials areshown in Eqs. 80,343 81,387 and 82.241 Glycals may also serve as substrates(Eqs. 83354 and 84343).

OEt + ClNHCO2Bn

1. CHCl3, MeOH, –78°2. CrCl2, –78°

OEt

OMeBnO2CHN

(81%)3. NaOMe, –78° to rt

(Eq. 80)

OBu-nO2N

N3

+ CHCl3, 40°, 70 h

n-BuO

OAc HN

NO2

NNN

OBu-n

NO2

(96%)

AcOH, PhH

50°, 10 minN

OBu-n

NO2

H

+(88%)

(Eq. 81)

O1. MeO2CN=NCO2Me

2. HCl, MeOH

O

OMeN

MeO2CNH

MeO2C

(85%) (Eq. 82)


+1. 2,6-(t-Bu)2-4-Me-pyridine, CH2Cl2

2. (CF3CO)2O, –78° to rt, 5-6 h(2 eq)

(80%) C2 de 86%

O

BnO

BnO

O

BnO

BnO

OHNHCOCF3

2

N N

O O

N

Mn

(Eq. 83)

O

AcO

OAc

AcO 1. ClNHCO2CH2CH2Cl, CHCl3, MeOH, –78°

(55%)O

AcO

OAc

AcO

NHCO2CH2CH2Cl

OMe

2. CrCl23. MeOH, AgNO3

(Eq. 84)

Enamines may serve as precursors as well (Eqs. 85195 and 8674). The latterreaction is of interest for the formation of rearrangement product 48, whichapparently has not been followed up as a means of preparing α-amino aldehydes.A mechanism involving an aziridinium intermediate has been proposed.74

PhNEt2

HO2C

N2+ Cl–

+NaOAc, H2O

pH 5-6

Ph CHO

NNH

CO2H

(89%)

(Eq. 85)

NMe2NCl+

dioxane, Et2O, 0°, 2 h

rt, overnight; reflux, 5 h NMe2

CHO NCHO

+

(53%) 48 (24%)

(Eq. 86)

Amination of Ketone Enolates, Enol Ethers, and EnaminesWith ketone enolates, issues of site selectivity arise. Generation of enolates

under conditions of kinetic control results in preferential amination at the less sub-stituted α-carbon (product 49, Eq. 87;388 Eq. 88217) unless one of the α-positionsis benzylic (Eq. 89).134 Trialkylsilyl groups may also be used to direct aminations(Eq. 90).156 On the other hand, in reactions involving ketone enamine interme-diates under thermodynamic control, amination at the more highly substitutedα-carbon predominates, but as the bulk at that position increases, reaction timesincrease and selectivity decreases (products 51 and 52, Eq. 91).228 A potentialsolution to this problem that apparently has not been explored extensively is toselectively generate silyl enol ethers and treat them with one of the reagents thatare known to aminate these derivatives. The lone example of this approach isshown in Eq. 92.173


R1 R2O

1. Ph(n-Bu)NMnMe•4 LiBr,THF, rt, 1 h

2. R4O2CN=NCO2R4, –30°; rt, 2.5 h

E = N(CO2R4)NHCO2R4

R1

Hn-C5H11

Et

R2

HMeEt

R3

MeMeBn

R4

Ett-BuEt

49

49 + 50(50%)(60%)(93%)

49:501:1

98:298:2

R3

R1 R2O

R3E

R1 R2O

R3 E

50

49 dr——3:1

+

(Eq. 87)

O

TBSO

OOBu-t

O

TBSO

OOBu-tNBnO2CN

H CO2Bn

1. LDA, THF, –78°

2. BnO2CN=NCO2Bn, –78°

(74%)

(Eq. 88)

O 1. unspecified Li base, Et2O or THF

2. Me2NOMs, –30° to 0°

O

NMe2

(52%) (Eq. 89)

OPr-i

i-Pr

OPr-i

i-PrNHCO2Bu-tNCO2Bu-t

O

4-O2NC6H4

1. LDA, THF, 0°

2. , –100° to rt

(29%) 88% de

t-BuMe2Si t-BuMe2Si

(Eq. 90)

OR

EtO2CN=NCO2Et, L-proline (0.1 eq)

MeCN, rt, time

OR

OR+

E = N(CO2Et)NHCO2Et

51 52Time10 h20 h95 h

51 + 52(80%)(77%)(69%)

51:5210:14:13:1

51 ee95%98%99%

RMeEti-Pr

EE(Eq. 91)

OTMS TsN=IPh (0.67 eq),

CuClO4 (8 mol%)

MeCN, 0°, 1.5 h

ONHTs

(53%)

(Eq. 92)

Ketone silyl enol ethers react with derivatives of diacyl azo compounds atroom temperature245 or on heating242,243 (see also Eq. 82) as well as enantio-selectively under the influence of silver trifluoromethanesulfonate and BINAP(Eq. 93)244 or copper bis(oxazoline) complexes (Eq. 94). The latter is proposed toproceed via a formal hetero Diels-Alder adduct.252 Ketones themselves react withazodicarboxylic esters either thermally246,389,390 or in the presence of potassiumcarbonate390 but yields are low. Higher yields can be achieved with LDA,391 – 394

(see also Eq. 88), LiHMDS,395,396 or KOBu-t325 as the bases. Aryl diazonium


salts also aminate lithium enolates (Eq. 95) but yields can be low.185 Better yieldscould potentially be achieved with arenediazonium o-benzenedisulfonimides(26d), which are very efficient in the amination of Grignard reagents (seeEq. 48).191

OTMS1. BnO2CN=NCO2Bn, AgOTf, (R)-BINAP (12 mol%), THF, 2,4,6-Me3C6H3, –45°, 1 h

O

NNH CO2Bn

(95%) 86% ee

2. HF, THFBnO2C (Eq. 93)

copper complex (10 mol%),CF3CH2OH (1 eq), THF, –78°, overnight

(94%) 99% ee

TMSO

ON NH

CO2CH2CCl3

ON

OO

N

OO

N

t-Bu t-BuCu

(OTf)2

NNN

Cl3CCH2O2C

O

OO

2+

N

NN CO2CH2CCl3

O

O

OCuL2

TMSO

CF3CH2OH

copper complex (Eq. 94)

OLi

+ PhN2+ BF4

–THF, –78°

O

N NPh

(72%) (Eq. 95)

Hypervalent iodine reagents aminate ketone enol ethers.172 – 174 Yields areoften high but enantioselectivities in catalyzed reactions are generally consid-erably lower than the 52% achieved in Eq. 17.174 Other reagents that aminateketone enol ethers include N -arenesulfonyloxy carbamates119,122,397 (Eq. 96),122

the sodium azide/ammonium cerium(IV) nitrate reagent297,331 (Eq. 97),297 ethylazidoformate,296,397 (Eq. 98),296 the N -chlorocarbamate/chromium(II) chloridereagent (Eq. 32),343 the chloramine-T/osmium tetroxide system (Eq. 99),342 andbis[N -(p-toluenesulfonyl)]selenodiimide (Eq. 100).345 Nitridomanganese comp-lexes (cf. Eq. 83) can also be applied to the amination of silyl enol ethers.352,353,398

OTMS

+ 4-O2NC6H4SO2ONHCO2EtCH2Cl2, CaO

rt, 3.5 h

ONHCO2Et

(67%)

(Eq. 96)


OO

OOTBS

NaN3, Ce(NH4)2(NO3)6

MeCN, –15°, 2 h; to rt

OO

OO

N3

H

(70%) (Eq. 97)

OTMS

+ EtO2CN3

1. 100°, 15 h

2. SiO2

O

NHCO2Et (40%) (Eq. 98)

OTMS

t-Bu

rt, 15 min

a see List of Abbreviations

O

t-Bu

NHTs

+ TsN(Cl)Na

(34%) 76% ee

(DHQD)2CLBa (0.008 eq),OsO4 (0.004 eq), t-BuOH/H2O (1:1)

(Eq. 99)

OSi(Pr-i)3

+ "TsN=Se=NTs"CH2Cl2, 0°

OSi(Pr-i)3

TsNH(62%) (Eq. 100)

Enamines derived from ketones undergo some of the same reactionsdescribed for enol ethers, for example with arenesulfonyloxy carbamates as inEq. 96120,121,399 and with ethyl azidoformate as in Eq. 98.302,303 The reactionwith activated azo compounds occurs readily at room temperature or belowand diamination often cannot be avoided with the more electrophilic reagents(Eq. 101).400,401 The proline-catalyzed reaction of ketones with azodicarboxylicesters, which proceeds by way of the enamines, has been mentioned above(Eq. 91).

N

1. PhN=NCOPh, Et2O, 0°, 15 min

2. HCl, Me2CO, 0°, few min

O

N

1. PhCON=NCO2Me (1 eq), Et2O, –30°, 3 h

2. HCl, Me2CO, 5°, 48 h

O

E

O

EE+

E = C(CO2Me)NHCOPh

(20%) (26%)

(55%)NHCOPh

Ph

(Eq. 101)

In the Morita-Baylis-Hillman reaction, enolate intermediates are formed byaddition of a nucleophilic catalyst to an α,β-unsaturated carbonyl compound.These intermediates can be trapped with a variety of electrophiles,402 includingazodicarboxylic esters (Eq. 102).403 The reaction fails with ethyl acrylate.


C7H13-n

OC7H13-n

O

NNHCO2EtEtO2C

1,4-diazabicyclo[2.2.2]octane (cat)

THF, rt, 8 h

(61%)

EtO2CN

NCO2Et+

(Eq. 102)

α-Keto esters can be aminated enantioselectively with azodicarboxylic estersunder the influence of copper bis(oxazoline) catalysts (Eq. 103);404 the initialproducts were not isolated but were reduced and cyclized to give derivatives ofsyn-β-amino-α-hydroxy esters.

CO2Et

O

N

OO

NCu

(OTf)2Ph Ph

Ph Ph

BnO2CN

NCO2Bn

CO2Et

O

NBnO2C NHCO2Bn

L-selectride, THF

–78°, 1 h; to rtCO2Et

NBnO2C NHCO2Bn

OH

1. NaOH, H2O, rt, 2 h

2. TMSCH2N2, MeOH, 15 minON

O

CO2Me

BnO2CNH(62%) 93% ee

(10 mol%)

CH2Cl2, rt, 16 h+

(Eq. 103)

Enamines derived from cyclohexane-1,2-dione react readily with azodicar-boxylic esters but the enamine products are very resistant to hydrolysis.249

Amination of Imine and Hydrazone Anions

Imines have the advantage over ketones of permitting the introduction of achiral auxiliary on the imine nitrogen, which is then removed when the imine ishydrolyzed to the ketone. An example involving a manganese enamine is shownin Eq. 104.388 Amination occurs selectively at the less substituted α-carbon, asshown by the distribution of products 53 and 54; the configuration at the newlycreated stereogenic center was not reported. Reaction of imines with azodi-carboxylic esters proceeds slowly at room temperature (Eq. 105a), and yieldsand diastereoselectivities are comparable to those achieved via the aza enolate(Eq. 105b).405


R1 R3N

t-BuS(O)

R2

R1 R3NMnN(Me)Ph

t-BuS(O)

R2

Ph(Me)NMnMe•4 LiBr

THF, rt, 1 h

1. R4O2CN=NCO2R4, –30°; rt, 2.5 h

2. HClR1 R3

O

R2

R1 R3O

R2EE

+

53 54

E = N(CO2R4)NHCO2R4

R1

Men-C5H11

Et

R2

MeMeEt

R3

MeMeBn

R4

Ett-But-Bu

53 + 54(50%)(65%)(50%)

*

*RRR,S

53 ee40%68%—

53:5490:1098:299:1

*

(Eq. 104)

N

MeO Bu-i

H

1. LDA, hexane, THF, –45°, 75 min

2. t-BuO2CN=NCO2Bu-t, –78°, 5 min

t-BuO2CN=NCO2Bu-t, rt, 24 h

(85%) 64% eeN

MeO Bu-i

HE

E = N(CO2Bu-t)NHCO2Bu-t(82%) 76% ee

(Eq. 105a)

(Eq. 105b)

Hydrazone anions have also been subjected to electrophilic amination. Theyreact very rapidly at −78◦ but the overall yields of the α-aminated ketones areonly fair (Eq. 106).327 Interestingly, the N -arylsulfonamides rather than the azidesare obtained in the attempted azidations.

Ph

NMe2N

1. LDA, THF

0°, 4-6 h

Ph

NMe2N

2. t-BuO2CN=NCO2Bu-t

–78°, 2-5 min

2. 2,4,6-(i-Pr)3C6H2SO2N3

Ph

NMe2N

Ph

O

Ph

O

O3, CH2Cl2

–30°

O3, CH2Cl2

–30°

(66%) (65%)E = N(CO2Bu-t)NHCO2Bu-t

(69%) (48%)R = SO2C6H2(Pr-i)3-2,4,6

E E

NHR NHR–78°, 2-5 min

3. NH4Cl, H2O

(Eq. 106)

Amination of Carboxylic Acid Dianions406

Although electrophilic amination of carboxylic acid dianions is potentiallya very short route to α-amino acids and their derivatives, little work has beenpublished and yields achieved so far, with few exceptions (Eq. 107),407 are low.Aminations of the dianions of α,β-unsaturated acids are discussed in the sectionon α,β-unsaturated carbonyl compounds (see below).


Ph CO2H1. LDA (2.2 eq), THF, HMPA

2. MeONH2, –15° to –10°, 2 h, rt, overnight Ph CO2H

NH2(55%) (Eq. 107)

Amination of Ester Enolates and Ketene AcetalsEfforts to introduce the amino or substituted amino group directly into

ester enolates by electrophilic amination have met with limited success. O-[Di(p-methoxyphenyl)]phosphinoylhydroxylamine aminates the enolate of ethylphenylacetate (Eq.108),106 but the reaction has not been applied to enolatesthat do not contain a second activating group such as phenyl or carbonyl. Thechiral phosphinoyl reagent 12 also has been applied only to phenylacetatesand the products are obtained with low diastereoselectivities (Eq. 109).147 O-Mesitylenesulfonylhydroxylamine aminates a simple ester in low yield117 andN ,N -dimethyl-O-methanesulfonylhydroxylamine converts the lithium enolate ofethyl phenylacetate into ethyl (α-dimethylamino)phenylacetate in 48% yield.134

The amination with oxaziridines,151,154,155,157,158 including chiral, non-racemicones such as 55 (Eq. 110),154 is often plagued by low yields and generally poordiastereoselectivities and sometimes154 side reactions involving the aldehyde thatis a product of the reaction.

Ph CO2Et

1. KOBu-t, –78°, 15 min2. (4-MeOC6H4)2P(O)ONH2, –78°, 6 h; to rt

Ph CO2Et

NHAc(76%)

3. Ac2O, Et3N

(Eq. 108)

Ph CO2Et

PPh

ONMe2

Ph CO2Et

NMe2(50%) 23% ee

O

Li 12

THF, –15°

(Eq. 109)

CO2Et

ON

NC

O

O

i-Pr

1. LDA, THF, –78°, 1 h

2. 55, –78°; to rt, 2-3 h

CO2Et

HN O

O

i-Pr

+

NC

CHO

(49%) 17% de

55

(Eq. 110)

Silyl ketene acetals are aminated by the hypervalent iodine reagent TsN=IPh(Eq. 111),173 and by EtO2CN(TMS)(OTMS) (see Eq. 124 in the section on ami-nation of lactones).105

+ TsN=IPh (0.67 eq)MeCN, –20°

OTMS

OPhOPh

O

NHTs(50%)

(Eq. 111)


Aminations of ester enolates with azodicarboxylic esters and arenesulfonylazides are more successful but the most widely used method for the prepara-tion of chiral, non-racemic α-amino acids involves N -acyloxazolidinones whichare discussed in a separate section (see below). Ester enolates in general reactrapidly with azodicarboxylic esters at low temperature as illustrated below inconnection with β-substituted ester enolates (Eqs. 115–117 and 119). Esters ofazodicarboxylic acid derived from borneol, menthol, and isoborneol aminateester enolates with no or low diastereoselectivity.408 Similarly, an ester eno-late where the alcohol portion is derived from a camphorsulfonamide reactswith di(tert-butyl) azodicarboxylate with only moderate diastereoselectivity.409

Ketene acetals react with azodicarboxylic esters either slowly at room temperature(Eq. 112),251 or at low temperatures catalyzed by TiCl4,410,411 Ti(OPr-i)4,409,412

AgOTf,244 or AgClO4. The latter catalyst together with (R)-BINAP furnishes theamination product with moderate enantioselectivity.244 Much higher diastereos-electivities are achieved with enol ethers derived from chiral alcohols409,411,412

(Eq. 113).409,412

OMe

OMePh+ EtO2CN=NCO2Et

PhH, rt, 6 dOMe

OMePh

NEtO2CNHCO2Et

(86%)

(Eq. 112)

O

OTMsSO2N(C6H11-c)2

1. Ti(OPr-i)4, CH2Cl2, –78°2. t-BuO2CN=NCO2Bu-t, –78°, 5 min O

OSO2N(C6H11-c)2

NH

NHCO2Bu-t

CO2Bu-t

(65%) >99.5% de

3. TiCl44. Add substrate, –78°, 1 h

(Eq. 113)

Reaction of ester enolates with trisyl azide and short reaction times at −78◦

gives the α-azido esters in 50–70% yields;318,413,414 with 4-nitrobenzenesulfonylazide, the diazo esters are formed almost exclusively.318 Azidomethyl phenylsulfide and ester enolates give α-amino amides274,275 (Eq. 114),274 but the scopeof this reaction has not been determined.

CO2Me

NN

NOSPh

NH2

ONH

SPh1. LDA, THF, –78° 1. NH4Cl, H2O

(79%)

2. PhSCH2N3, –78° to –20°, 45 min

2. NH4OH, THF, rt, 12-24 h

(Eq. 114)

Ketene dimethyl acetals react with phenyl azide to give α-anilido esters afteracid hydrolysis of the intermediate triazolines, but yields are low.291 The reac-tion of ketene acetals with arenesulfonyl azides does not appear to have beeninvestigated.


A considerable amount of work has been carried out on the amination withazodicarboxylic esters of β-hydroxy esters, a class of compounds where bothenantiomers are readily available by asymmetric reduction of β-keto esters. Yieldsare in the range of 50-70% for lithium115,415 – 417 (Eq. 115),417 magnesium,416

zinc,416,418 – 424 and titanium enolates,416 but diastereoselectivities are highest withzinc enolates (Eq. 116).416 Attack from the less hindered side of zinc enolate 57accounts for the observed anti selectivity. Similar results are obtained with theother enantiomer.416 The lithium enolate of the rigidized derivative of ester 56gives higher yields with a somewhat reduced anti selectivity (Eq. 117). 416

MeO

MeOCO2Et

OH 1. LDA (4 eq), THF, –78°

2. t-BuO2CN=NCO2Bu-tMeO

MeOCO2Et

OH

Nt-BuO2C NHCO2Bu-t

(55%) 89% de (Eq. 115)

OEt

OH O1. MeZnBr (1.1 eq), THF, Et2O, 0°

OEt

O OZn

1. t-BuO2CN=NCO2Bu-t –78°, 10 min

OEt

OH O

Nt-BuO2C NHCO2Bu-t

(63%) >90% de

57562. LDA (2.2 eq), –78°, 1 h 2. NH4Cl, H2O

(Eq. 116)

OO

O

1. LDA

2. t-BuO2CN=NCO2Bu-t, –78°

OO

ON

NHCO2Bu-tt-BuO2C

(90%), 90% de

(Eq. 117)

Reaction of the lithium enolate of ethyl β-hydroxybutyrate with trisyl azidefurnishes the azide in 77% yield but with only 64% anti diastereomeric excess;the diazo ester (10%) and the diazide (1%) are also formed.318

Other β-substituents also promote anti selectivity with both azo esters andtrisyl azide. Examples are given in Eqs. 118,425 and 119.426 Use of trisyl azidein the latter reaction gives the two diastereomeric azides as a 1 : 1 mixture in 90%yield.426 More remote substituents, however, may reverse the trend (Eq. 120).427

CO2MeSiMe2Ph

CO2MeSiMe2Ph

1. LDA, THF, –78°

2. 2,4,6-(i-Pr)3C6H2SO2N3,

–78° to rt, 10 h

N3

(73%) 95% de

(Eq. 118)


PhHN

CO2EtEtO2C 1. LiHMDS (1.2 eq), THF,

HMPA, –78°; –55°, 1 hPhHN

CO2EtEtO2C

Nt-BuO2CNH CO2Bu-t

(80%) 93.5% de

2. t-BuO2CN=NCO2Bu-t, –78°, 4.5 min3. HOAc

(Eq. 119)

TBDPSOCO2Me

BOMO1. KHMDS, THF, –78°, 30 min

TBDPSOCO2Me

BOMO N3

(70%)

2. 2,4,6-(i-Pr)3C6H2SO2N3, –78°, 20 min

(Eq. 120)

Reaction of silyl ketene acetals with aryldiazonium salts produces α-ketoester hydrazones196,197 by rearrangement of the initially formed azo compounds(Eq. 121). The latter are obtained with disubstituted ketene acetals.197

Ph

OMe

OTMS

PhN2+ BF4

–, pyridine

0°, 2 hCO2Me

Ph

NCO2Me

Ph

NPhNHPhN

(70%)

(Eq. 121)

Amination of Thioester Enolates and Ketene Thioacetals

Only a few examples in this category were found in the literature and azodi-carboxylic esters are the only aminating reagents that have been used. Thereactivities appear to be similar to those described above for ester enolates andketene acetals. The catalyzed enantioselective amination of ketone silyl enolethers described in Eq. 94 has also been applied to ketene thioacetals.252

Amination of Lactone Enolates

Lactone enolates behave similarly to ester enolates in electrophilic aminations.Examples are shown in Eqs. 122428 and 123;429 attack on the less-hindered sideto give the equatorial azide is illustrated by the distribution of products 58 and59 in Eq. 123.

O

O

OO

1. KHMDS, THF, –80°; rt, 50 min

O

O

OO O

O

OO

H

N3

N3

N3+

(79%) (6%)

2. 2,4,6-(i-Pr)3C6H2SO2N3, –80°, 10 min

(Eq. 122)


OO

BnO

R1

R2

OBnO

O

BnO

R1

R2

OBnO

O

BnO

R1

R2

OBnN3

N3

58 59

1. KHMDS, toluene, THF, –90°, 15 min

2. 2,4,6-(i-Pr)3C6H3SO2N3, –90°, 2 min

O

BnOBnO

OBn

R1

BnO

H

H

R2

H

BnO

58

(0%)

(50%)

(0%)

59

(70%)

(0%)

(60%)OBn

+

(Eq. 123)

Ester- and lactone-derived silyl enol ethers are aminated by theEt2OCN(TMS) OTMS reagent (Eq. 124).105

O

OTMS90°, 5 d

O

O

NHCO2EtEtO2C NTMS

OTMS+ (44%) (Eq. 124)

Amination of Amide Enolates and Ketene Aminals

Amide enolates mirror ester enolates in their amination reactions. Secondaryamides can be used by employing two equivalents of the base, but yields inthe only example found in the literature are low to fair.212 Ketene aminals reactwith azodicarboxylic esters at room temperature, but yields are low (Eq. 125).251

Eq. 126 shows the application of the copper-catalyzed enantioselective additionof mixed ketene acetal/aminals to azodicarboxylic esters previously described forsilyl enol ethers in Eq. 94.252 Increasing bulk of the R substituent in the substratecauses partial or complete amination on the pyrrole, as evidenced by the yieldsof products 60 and 61 as R is varied.

N

N

Y

Y

+ RO2CN

NCO2R PhH, rt, 3 d

RO2CN

NH

CO2R

YOCH2

(18%)(41%)

REtMe

NO

Y

(Eq. 125)


copper complex (5 mol%),THF, CF3CH2OH

NNN

Cl3CCH2O2C

O

OOR OTMS

N

R

N

O

E

R

N

O

E

+

RMet-Bu

60 61

NNH

NE = Cl3CCH2O2C

O

OO

Temp–78°–20°

Time30 min5 min

60(96%) 99% ee

(0%)

61(0%)(80%)

N

OO

N

t-Bu t-BuCu

(OTf)2

copper complex

(Eq. 126)

Amination of N -Acyloxazolidinone Enolates

This reaction is arguably the most useful and certainly the most widely usedapplication of the electrophilic C-amination of enolates in organic synthesis. Anumber of 4- and 4,5-substituted 2-oxazolidinones are commercially available inboth enantiomeric forms and the chiral auxiliary is easily recovered.430 Reactionsof N -acyloxazolidinone enolates with azo esters431,432 and arenesulfonyl azides433

are rapid even at very low temperatures (−100◦) and the diastereochemical out-

come is reliably predictable. The facile removal of the chiral auxiliary and readyconversion of the azide or hydrazino ester functionalities into amines makes thesereactions a standard method for the preparation of D- and L-α-amino acids.

The optimum conditions have been thoroughly worked out,318,431 although adirect comparison of the diastereodirecting efficiency of various oxazolidinonesdoes not appear to have been made for aminations. However, they all direct theincoming electrophile to the less hindered side of the Z-enolate as illustratedin Eqs. 127431 and 128.434 The diastereomer with the opposite configuration atthe amination site can be obtained using the enantiomeric chiral auxiliary orfrom the same N -acyloxazolidinone by a bromination/SN2 displacement sequence(Eq. 129)431 or a hydroxylation/Mitsunobu reaction protocol.427

Ph N

O

O

O

Bn

LDA, THF, –78°

30 min Ph N

O

O

O

Bn

Li

t-BuO2CN=NCO2Bu-t

CH2Cl2, –78°, 0.5 to 3 min

Ph N

O

O

O

BnNR

NCO2Bu-t

Li+ –

HOAc Ph N

O

O

O

BnNR

HNCO2Bu-t

62 R = CO2Bu-t

(91%) 94% de

(Eq. 127)


N

O

O

O

Ph

i-Pr

MeO2. 2,4,6-(i-Pr)3C6H2SO2N3, –78°, 15 min3. HOAc

N

O

O

Oi-Pr

MeON3

Ph

(85%) >90% de

1. KHMDS, THF, –78°, 30 min

(Eq. 128)

Ph N

O

O

O

Bn

1. i-Pr2NEt, CH2Cl2, rt2. (n-Bu)2BOTf, –78°; to rt, 1 h

Ph N

O

O

O

BnBr

(98%) 80% deMe2N

Me2NNH2

+ N3–1. , CH2Cl2, 0°, 3 h

2. NaHCO3, H2OPh N

O

O

O

BnN3

(85%) >98% de

3. Add to NBS, CH2Cl2, –78°, 3 h4. NaHSO3, H2O

(Eq. 129)

Lithium diisopropylamide (LDA) or KHMDS is used as the base althoughthe former seems to be preferred for reactions with azodicarboxylic esters andthe latter with trisyl azide. In one report435 a mixture of KHMDS and sodiumhydride (one equivalent of each) gave much-improved yields in an azidation.As little as 5 mol% of sodium tert-butoxide, lanthanum tri(tert-butoxide), or theconjugate base 62 (Eq. 127) effect the amination, indicating that the externalbase serves as initiator whereas anion 62 is the base in the catalytic cycle.436 Noyields were reported in this investigation. Most procedures call for slightly morethan one equivalent of the base except when other acidic protons are present inthe molecule (see below). In one azidation, 1.2 equivalents of KHMDS gave amixture of the diazo compound and the azide in low yields, whereas the latterwas formed exclusively in 78% yield with 1.5 equivalents of the base.437 Trisylazide is the electrophile of choice for the azidation; 4-nitrobenzenesulfonyl azideand tosyl azide lead to the diazo compounds either exclusively or in admixturewith the azides. The benzyl and tert-butyl esters of azodicarboxylic acid are themost widely used members of that class of electrophiles because the products areeasily cleaved to the hydrazines and the former has an aromatic chromophore forUV detection in chromatography. Azo esters and trisyl azide usually work equallywell although there is one report where the former gives a cleaner product,438

and one instance involving an N -acyloxazolidinone with a sugar attached tothe γ-position where di(tert-butyl) azodicarboxylate reacted (Eq. 135), but trisylazide did not.439 Addition of the pre-cooled electrophile solution to the enolate(or vice versa) is often carried out by means of a cooled or insulated cannulaalthough one report finds that addition of the solid trisyl azide to the cold enolatesolution gives the highest yield.440 The reaction is usually quenched with aceticacid after a short period. The effect of other quenching reagents was discussedin the section on Reagents and Mechanisms.

The following functional groups are tolerated in electrophilic aminations of N -acyloxazolidinones: Br 441 – 443 (but see below), CH2CO2Bu-t (with one equivalent


of base),444 NH (with two equivalents of base),445,446 NRCO2Bu-t (with twoequivalents of base when R = H),440,447 – 452 NHAc (with two equivalents ofbase),453 RNCO2Bn,454 aliphatic alcohols protected by trialkylsilyl or tosyl,455

protected phenols, phenylselenyl,456 (t-BuO)2P(O)CH2 (with one equivalent ofbase),457 and Ph2P(S)CH2 (the amount of base was not reported).458

A few problems have been reported. Cleavage of the N -acyloxazolidinoneoccurs to a considerable extent in the reaction of Eq. 130.445,446 A bromine atomat a distance of five carbons from the carbonyl group causes the enolate to cyclizeunder normal procedures (product 64, Eq. 131); azide 63 (n = 3) is obtainedin 40% yield only by adding an excess of trisyl azide early in the enolizationstep.443 The α,β-unsaturated N -acyloxazolidinone 65 does not undergo aminationunder conditions where its isomer 66 does (Eq. 132).453 However, product 67epimerized on attempted removal of the auxiliary.

HN

N5

O

O

O

Bn

1. KHMDS (2.3 eq), THF, –78°, 30 min2. 2,4,6-(i-Pr)3C6H2SO2N3, –78°, 3 min

HN

N5

O

O

O

Bn(34%)

HN

NH25

O

(24%)

+N3 N3

3. HOAc, –78° to rt, overnight4. NaHCO3, H2O

(Eq. 130)

BrN

O

OO

Bn

n1. KHMDS, THF, –78°, 30 min

2. 2,4,6-(i-Pr)3C6H2SO2N3

BrN

O

OO

Bn

NO

OO

Bn

+N3

63 64

n234

63(60-70%)

(0%)(60-70%)

64(—)

only product(—)

n

(Eq. 131)

N

O

O

O

AcNH Bn65

N

O

O

O

AcNH Bn

66


N

O

O

O

AcNH Bn

67 (53%) E = N(CO2Bu-t)NHCO2Bu-t

E2. t-BuO2CN=NCO2Bu-t, CH2Cl2, –78°, 3 min

(Eq. 132)


In the attempted double diastereoselection shown in Eq. 133, amination of apair of enantiomeric N -acyloxazolidinones with (−)-diisobornyl azodicarboxy-late furnishes a single product for each. The same reactions with dibenzyl azodi-carboxylate as the electrophile proceed with only 9:1 diasteromeric ratio. Theseexperiments indicate that the only effect of the bulky isobornyl group is toenhance the diastereoselectivity, which is controlled by the enolate geometry.408

N

O

O

O

i-Pr

1. LDA, THF, –78°, 40 min

2. RO2CN=NCO2R, –78°, 4 minN

O

O

O

i-PrE

RBn(–)-isobornylBn(–)-isobornyl

Yield(—)

(56%)(—)

(88%)

% de80 (S)

100 (S)80 (R)

100 (R)

E = N(CO2R)NHCO2R

C4 Config.SSRR

4 4

(Eq. 133)

Alternate routes to chiral α-amino acids and α-amino alcohols that apparentlyproceed with somewhat higher diasteroselectivity involve the reactions of achi-ral α-chloronitroso compounds with chiral enolates or of chiral α-chloronitrosocompounds with achiral enolates (see section on the amination with nitroso com-pounds in Comparison with Other Methods), but they have not been appliednearly as frequently as the aminations described above.

Chiral azo amide 68 reacts with an achiral oxazolidinone enolate to givea single product with the configuration indicated in Eq. 134, but the hydrazinoamide could not be hydrolyzed.219 A remote chiral group attached to an achiral N -acyloxazolidinone directs a diastereoselctive amination as shown in Eq. 135.459

HNN

MeN

NMe

O

O

N

O

O

O

NN

MeN

NMe

O

O

N

O

O

O 1. LDA, THF, –78°, 20 min

2. 68, CH2Cl2, –78°, 7 min

(85%)

68 (Eq. 134)

O

RR

R R

O

N O

O

O

RR

R R

O

N O

O

R = OBn

1. LDA, THF, –78°, 30 minN

CO2Bu-tHNCO2Bu-t

(70%) 73% de

2. t-BuO2CN=NCO2Bu-t, –78°, 5 min

(Eq. 135)


The amination of an achiral N -acyloxazolidinone with azo esters may also becarried out catalytically with magnesium complex 69 as the base (Eq. 136).436

The role of N -methyl-p-toluenesulfonamide, which accelerates the reaction, isnot clear. Enantiomeric excesses are in the range of 82–90% but the catalyticamination has only been carried out with N -arylmethylcarbonyloxazolidinones.

N -acyloxazolidinones are cleaved to the acid salts by lithium hydroxide/hydro-gen peroxide.318 The chiral auxiliary is recovered by extraction into an organicsolvent; the acid is obtained by acidification of the aqueous phase.

O

N O

OF

N N

PhPh

SO2O2SMg

69

t-BuO2CN=NCO2Bu-t, 69 (10 mol%), TsNHMe (20 mol%)

O

N O

OF

Nt-BuO2C NHCO2Bu-t

(97%) 90% ee

Et2O, CH2Cl2, –65°, 2 d

(Eq. 136)

Amination of Lactam Enolates

O-(Diphenylphosphinoyl)hydroxylamine (Eq. 137),143 azo esters (Eq. 138),460

and arenesulfonyl azides (Eq. 139)339 have been used to aminate lactam enolates.In the azidation of the lactam 70,461 the diazo compound 73 predominates overazide 72 even though trisyl azide is used as the aminating agent; amination withdi(tert-butyl) azodicarboxylate was unsuccessful. The closely related lactam 71462

reacts normally with trisyl azide (Eq. 140).

Nt-BuO2C

H

O

1. LiHMDS, THF, –78°

2. (Ph2P(O)ONH2

Nt-BuO2C

H

O

NH2

(47%) >82% de

(Eq. 137)

MeN

MeN

O1. LDA, THF, hexane, –78°, 2 h MeN

MeN

ON

(67%) >98% de

2. t-BuO2CN=NCO2Bu-t, –78°, 6 h; to rt, 3-6 h

CO2Bu-t

NHCO2Bu-t(Eq. 138)

N

S

MeO2C CO2MeO

1. LiHMDS, THF, –78°, 4 h2. TsN3, –70°

N

S

MeO2C CO2MeO

H N3

(68%)3. TMSCl

(Eq. 139)


N

H

RO

mn

O

1. LDA, THF, –78°, 20 minN

H

RO

mn

O

N

H

RO

mn

O

R = TBDPS70 or 71

N3 N2+

m21

n12

72 73

72(20%)(43%)

73(64%)(0%)

Time10 min3 h

7071

2. 2,4,6-(i-Pr)3C6H2SO2N3, –78°, time

(Eq. 140)

Amination of Nitrile-Stabilized CarbanionsLittle work could be found on the electrophilic amination of simple nitrile-

stabilized carbanions. The lithium anion of propionitrile reacts normally with anN-substituted oxaziridine (Eq. 141).158 The amination of nitriles with a camphor-derived N-unsubstituted oxaziridine was discussed earlier (Eq. 11).151 Aminoma-lononitrile is formed from malononitrile anion and O-(mesitylenesulfonyl)hydro-xylamine (Eq. 142).463

CN

1. n-BuLi, hexane, THF, 0°, 30 min

NCONEt2 ,O

2-NCC6H4

CN

NHCONEt2(56%)

2.

–78°, 3 h; to rt, 1.5 h

(Eq. 141)

NC CN2. 2,4,6-Me3C6H2SO2ONH2, THF, 0°, 2.5 h3. TsOH

NC CN

NH3+ TsO–

(55%)1. unspecified Na base

(Eq. 142)

The anion of phenylacetonitrile has been aminated with a variety of reagents;examples are shown in Eq. 143.106,147 In the reaction involving the chiral O-phosphinoylhydroxylamine, epimerization is believed to have occurred duringisolation of the product.

Ph CN

2. (4-MeOC6H4)2P(O)NH2, –78° to rt; rt, overnight3. Ac2O, Et3N

Ph CN

NMe2NMe

POPh

ONMe2

1. unspecified Li base, THF

2. , –15°

Ph CN

NHAc(67%)

(62%) 8% ee

O

1. KOBu-t, THF, –78°, 15 min

3. H3O+ (pH 4.5)(Eq. 143)


Amination of NitronatesOnly one example involving a number of substituted nitromethane anions was

found in the literature and the reaction with p-toluenesulfonyl azide proceedswith loss of the nitro group (Eq. 144). Nitromethane itself failed to react underthese conditions.464

NO2

1. KH, THF, rt; 40°, 15 min

2. TsN3, –10° to 0°; 0°, 1 h

Ts N3

(56%)(Eq. 144)

Amination of Sulfone-Stabilized CarbanionsThe few examples indicate that sulfone-stabilized carbanions should react nor-

mally with electrophilic aminating reagents (Eqs. 145158 and 146465) with thecaveat that free α-amino sulfones are unstable.158,465 The β,γ-unsaturated sulfone74 is aminated at the γ-position (Eq. 147),250 presumably by an ene reaction. Thepreparation of α-tosyl azides from nitronates was shown above in Eq. 144. Thescope of this reaction does not seem to have been determined. Reaction of theanions of nitrobenzyl aryl sulfones with 1-oxa-2-azaspiro[2.5]octane (13a) givesnitrobenzaldehydes by cleavage of the initially formed amination products.466

Similarly, reaction of the lithium salt of benzyl phenyl sulfone with phenyl azidegives benzilydeneaniline and phenyl sulfinate.467 No reports on aminations ofsulfoxide-stabilized carbanions were found.

O2S

Me

O2S1. n-BuLi, THF, hexane, 0°, 30 min NHCONEt2

(43%)

NCONEt2 ,O

2-NCC6H42.

–78°, 3 h; to rt, 1.5 h

(Eq. 145)

SO2

N

H

BnOR

SO2

N

H

OR

1. n-BuLi, THF, pentane, –78°, 55 min

Bn

N3

R = TBDPS

SO2

N

H

OR

N3

Bn+

(24%)(40%)

2. 2,4,6-Me3C6H2SO2N3, –78°, 6 h

(Eq. 146)

SO2

NHBu-n

EtO2CN=NCO2Et, MeCN

reflux, 3 h

SO2

NHBu-nN

EtO2CNH

EtO2C

(65%)

74

(Eq. 147)

Amination of Phosphorus-Stabilized CarbanionsOnly one report on the amination of a phosphine oxide anion (Eq. 148) is

known;467 the product is claimed to have the structure shown but no spectral


data excluding the isomer where the N=N double bond is conjugated with thephenyl group were provided.

PP

1. LiNEt2, PhH, rt, 1 h2. PhN3, rt, 18 h

NNNHPh

(26%)O

O

3. H2O(Eq. 148)

All other reactions involve derivatives of methanephosphonic acid and a rangeof aminating reagents has been applied, including hydroxylamine derivatives,oxaziridines, azo esters, and sulfonyl azides. The products are α-amino phospho-nic acids or derivatives that can be converted into these biologically interestinganalogs of α-amino acids. The best results with methanephosphonic acid deriva-tives not containing an additional activating group have been obtained so farwith phosphorinanes of type 75 (Eq. 149).317 The diastereoselectivity using thestandard acetic acid quench to generate the azide is disappointing, and yieldsfrom analogous compounds are low, possibly because here the addition of trisylazide is reversible. Trapping the triazene salt with acetic anhydride resolves theproblem. Cleavage of the product and removal of the chiral auxiliary gives thephosphono analog of (S)-phenylglycine.

NPO Ph

t-Bu

O

75 (2S,6S)

1. LDA, Et2O, –78°, 30 min2. 2,4,6-Me3C6H2SO2N3, –78°, 5 h N

PO Ph

t-Bu

O

AcNNN

C6H2(Pr-i)3-2,4,6

(75%) 86% de

3. Ac2O

(Eq. 149)

Two catalytic enantioselective methods have been developed for β-keto phos-phonic acid derivatives (Eqs. 150238 and 151468).

O

P(O)(OEt)2

P(C6H3Me2-3,5)2

P(C6H3Me2-3,5)2

P

P

P

PPd

O

OPd

+2

EtO2CN=NCO2Et

2 BF4– (2.5 mol%),

Me2CO, rt, 20 h

O

P(O)(OEt)2

N CO2EtNHCO2Et

(91%) 99% ee

P

P=

(Eq. 150)


1. (10 mol%), CH2Cl2

2. add substrate, then BnO2CN=NCO2Bn, rt, 140 h

OP(O)(OEt)2

OP(O)(OEt)2

N CO2Bn

NHCO2Bn

(85%) 98% ee

NZn

N

OO

Ph Ph(OTf)2

(Eq. 151)

Standard amination methods may be used for the synthesis of racemic α-phosphono α-amino carboxylic esters (Eq. 152).141 No diastereo- or enantiose-lective syntheses appear to have been reported.

1. NaH, THF, rt, 1 h2. Ph2P(O)ONH2, THF, –78°, 2 h

(60%)

(EtO)2P CO2Bn

O

(EtO)2P CO2Bn

O NH3+ –O2CCO2H

3. HO2CCO2H(Eq. 152)

Amination of Enolates of α,β-Unsaturated Carbonyl Compounds

Enolates of α,β-unsaturated carbonyl compounds can react at either the α- orγ-position and α,β-unsaturated ketones can react at the α′-position as well. On thebasis of limited evidence, NH2

+ synthons react at the α-position,64,144 whereasazo esters aminate preferentially at the γ-position144,469 (Eq. 153),144 both bykinetic control, although there are exceptions (product 77 vs. 76, Eq. 154).469

With an α,β-unsaturated N -acyloxazolidinone, the two constitutiona isomers areformed in equal amounts (Eq. 155).431 The catalytic method shown in Eq. 156470

is believed to involve a hetero Diels-Alder reaction of the intermediate dienamine.Allyltin and allylgermanium reagents give mostly or exclusively the productsof an SE2′ reaction (Eqs. 157 and 158).469 The substrates for these reactionsare prepared by addition of tin tetrachloride and trimethylgermanium chloride,respectively, to the lithium enolates of the corresponding α,β-unsaturated esters.The generation of the tin substrate can be carried out in situ. Silyl ketene acetal78, the only example of this type of derivative whose amination was found inthe literature, reacts predominantly at the γ-position (Eq. 159).469

CO2H

1. LiNEt2 (2.0 eq), THF, –70°, 15 min

2. Ph2P(O)ONH2, –70°, 25 min; rt, 2 h

1. LiNEt2 (2.2 eq), THF, –70°, 30 min

2. EtO2CN=NCO2Et, –70°, 55 min

CO2HNH2

(64%)

CO2H

N(50%)

EtO2CNHCO2Et

(Eq. 153)


CO2Et

1. LDA, HMPA, THF, –78°, 70 min2. EtO2CN=NCO2Et, –78°, 3 min

CO2EtCO2Et

EE

n n n+

76 77

n12

76(22%)(55%)

77(65%)(14%)

77 E:Z1:2

1:1.5

E = N(CO2Et)NHCO2Et

3. MeOH

(Eq. 154)

NO

OO

Bn

1. LDA, THF, –78°, 30 minN

O

OO

Bn

NO

OO

Bn

E

E+

(51%) 96% de(42%) E:Z = 3:2

E = N(CO2Bu-t)NHCO2Bu-t

2. t-BuO2CN=NCO2Bu-t, CH2Cl2, –78°, 0.5 to 3 min

(Eq. 155)

CHOCHO

NEtO2C NHCO2Et

MeSMeS

(43%), 88% ee

1. (10 mol%),

toluene, rt, 15 min

NH

OTMSAr

Ar

2. EtO2CN=NCO2Et, 1.5 h

(Eq. 156)

Cl3Sn CO2Me

1. EtO2CN=NCO2Et, THF, –10°, 30 min

CO2MeE CO2Me

E+

(53%) (5%)

E = N(CO2Et)NHCO2Et

2. to –78°; MeOH, –78° to rt

(Eq. 157)

CO2Me

GeMe31. EtO2CN=NCO2Et, ZnCl2, CH2Cl2, –78°

CO2Me

NEtO2C NHCO2Et

(55%) E:Z = 6:1

2. add substrate, –78° to 0°, 30 min3. MeOH

(Eq. 158)

OMe

OTMS

1. EtO2CN=NCO2Et, TiCl4, CH2Cl2, –78°

E CO2MeCO2Me

E+

(68%) (17%)

E = N(CO2Et)NHCO2Et78

2. add substrate, –78°, 30 min3. MeOH

(Eq. 159)

The dianion of trans,trans-hepta-2,4-dienoic acid (sorbic acid) is aminated inthe α-position by Ph2P(O)ONH2 and in the γ-position by diethyl azodicarbo-xylate.144

The amination of the only derivative of an α,β-unsaturated ketone is shownin Eq. 160.471


OTMS

CH2Cl2, TFAA, pyridine, –78° to rt, 3-4 h

ONHCOCF3

(50%)

N N

O O

N

Mn(Eq. 160)

Amination of Enolates of α-Cyanocarbonyl and β-Dicarbonyl CompoundsThe electrophilic amination of the sodium salts of α-unsubstituted β-dicarbonyl compounds is one of the few examples of an amination wherehydroxylamine O-sulfonic acid gives useful yields (Eq. 161);472 with twoequivalents of the substrate, pyrroles are formed.472,473 Chloramine,62,64 O-arylhydroxylamines,93,124,474 O-sulfonylhydroxylamines,134 and O-(diarylphos-phinoyl)hydroxylamines106,139,475 have also been employed, although a low yieldand formation of the hydroxylation product as a side product have been reportedin one instance with (4-MeOC6H4)2P(O)ONH2.145 Some of these aminations usechiral auxiliaries in the substrates with modest diastereoselectivities,124,475,476 butthese have been superseded by the catalytic methods discussed below.

OO

NH2OSO3H, NaOH, H2O

rt, few minutesOO

NH2

(100%) (Eq. 161)

The oxaziridine 13a reacts with a variety of β-dicarbonyl and α-cyanocarbonylcompounds under base catalysis (Eq. 162).149

O

HN

13a

NCN

O

OR+

R = H; toluene, NaOH

H2O, 0°, 10 min

R = C6H4OMe-4

N

O

ONH2

NHHN

OR

NO

O

+

(48%) (39%)

N

O

OR NH2

(56%)

EtOH, reflux, 5 min

(95%)

H2N

O

O

H2N

toluene, NaOH, H2O, rt, 12 h

(Eq. 162)

Lithium477 and potassium478 enolates of β-dicarbonyl compounds are aminatedby azodicarboxylic esters in good to excellent yields. Diethyl malonate, ethylacetoacetate, N ,N -diethyl acetoacetamide, and acetylacetone have also been ami-nated with diethyl azodicarboxylate under nickel acetylacetonate catalysis,479 andnickel salicylideneimine complexes catalyze the analogous amination of acetyl-acetone and its 2-methyl derivative.480


A number of catalytic, enantioselective reactions of azodicarboxylic esterswith β-dicarbonyl and α-cyanocarbonyl compounds have been recently devel-oped, using cinchona alkaloids or their derivatives,231,232,481 BINAP-derived pal-ladium complexes,239 chiral copper bis(oxazoline) complexes,235,237 and chiralamidines and amines233 as catalysts. With cinchona alkaloid-derived catalysts,cyanoacetic esters carrying aryl substituents in the α-position give higher selec-tivities than those with alkyl groups in that position232,481 (Eq. 163).232 Withthe quinidine-derived catalyst 79, the newly created stereogenic center has theS-configuration; the quinine-derived enantiomer furnishes the R-isomer. Cin-chonine and cinchonidine catalyze the reaction of dibenzyl azodicarboxylatewith ethyl α-ethylacetoacetate but the enantioselectivity is low (47 and 27%ee, respectively).231 However, α-fluoro-237 and α-alkyl 235 acyl and aroylacetatesrespond well to catalysis by chiral copper bis(oxazoline) complexes (Eq. 164).235

The reaction of ethyl α-methylacetoacetate with dibenzyl azodicarboxylate is alsocatalyzed by a BINAP-derived palladium complex (95% ee).239 This catalystalso induces good enantioselectivity in the amination of two cyclic β-dicarbonylcompounds (Eq. 165).239

NC CO2Et

RBnO2C

NN

CO2Bn+

N

NC CO2Et

R NNHCO2Bn

CO2Bn

RMe4-BrC6H4

Time30 min1 min

(75%)(86%)

ee35%91%

N

OH

BnO

79 (10 mol%)

toluene, –78°

79

(Eq. 163)

CO2Bu-tO

t-BuO2CN

NCO2Bu-t

+

CH2Cl2, rt, 16 h

CO2Bu-tO

N CO2Bu-tNHCO2Bu-t

(89%) 98% ee

NCu

N

OO

Ph Ph(OTf)2

(0.5 mol %)

(Eq. 164)

PPh2

PPh2

P

PPd

OH2

NCMe

+2

i-PrO2CN=NCO2Pr-i

2 PF6– (5 mol%), MeOH, rt

P

P

=

Y O

COR

Y O

RMeOEt

YOCH2

Time9 h

31 h(93%)(89%)

ee93%97%

CORN

CO2Pr-i

NHCO2Pr-i

(Eq. 165)


Enolates of β-dicarbonyl and α-cyanocarbonyl compounds have a strongtendency to form diazo compounds with arenesulfonyl azides. α-Substitutedsubstrates react normally to give azides482,483 but even then a diazo transfer(Eq. 166)484 or other transformations319,321,484 may occur as side reactions.

O TsN3, Et3N, Et2O

rt, 140 h

OCO2Et

N3

NHTsO

CO2EtN2

+

(74%)

(20%)

CO2Et (Eq. 166)

An interesting addition of a sugar azide to the enolate of cyanoacetamide isshown in Eq. 167.276

OR

R

R

N3

R = OBn

OR

R

R

N+ NC CONH2

KOH, DMF, H2O, rt

NN

NH2

CONH2(85%)

(Eq. 167)

Intramolecular AminationsFormation of Aziridines. The addition of O-methylhydroxylamine to α,β-

unsaturated carbonyl compounds gives β-methoxyamino derivatives which ontreatment with sodium methoxide at elevated temperatures give aziridines(Eq. 168).485,486 The products were initially considered to be the isomeric primaryenamines.485 The reaction has been carried out with other leaving groups:benzyloxy,487 – 489 OCOBu-t ,490 TMSO,491 arenesulfonyloxy492,493 (Eq. 169),492

and trimethylammonium (with formation of an azirine; Eq. 170).494 An exampleinvolving a chiral auxiliary is shown in Eq. 171.487,488

Ph Ph

OMeONH2, EtOH

80°, 3 h Ph Ph

O

Ph

O

MeONHNaOMe, MeOH

60°, 10 min

HN

(64%)

(94%)Ph

ONHMeO

Ph Ph

(Eq. 168)

MeO2CCO2Me

CO2Me 2,4,6-Me3C6H2SO2ONH2

BF3•Et2O, Et2O, rt, 48 hMeO2C

CO2Me

CO2Me

NHOSO2C6H2Me3-2,4,6

Et3N, CH2Cl2, rt

MeO2CCO2Me

CO2MeNH

(50%)

(100%)(Eq. 169)


NNMe3 I–+

NaOPr-i, i-PrOH, 40°, 1 h

Ph(80%)

N

Ph (Eq. 170)

N NMe

O O

Ph

N NMe

O O

Ph

HN1. AlMe2Cl, CH2Cl2

(71%)

BnONH

2. add to Et3N (2 eq), CH2Cl2, rt, 30 min

(Eq. 171)

Hydroxylamine derivatives add to activated double bonds in the presence of abase to give aziridines where intermediates of the type illustrated above have notbeen isolated or observed. These reactions may proceed via stereospecific additionof nitrenoid intermediates to the double bonds. However, in some instances,both isomeric aziridines are produced and these are included in Table 21 of theTabular Survey since the possibility exists that they are formed by a Michaeladdition/cyclization process. An example is shown in Eq. 172.495

O

H

O

4-O2NC6H4SO2ONHCO2Et (3 eq)

CaO, CH2Cl2, rtO

H

O

EtO2CN

O

H

O

EtO2CH2N+

(42%) (39%)

(Eq. 172)

Formation of Higher-Membered Rings. Intramolecular displacement of amethoxy group by an aryl carbanion by way of a nitrenoid intermediate (Eq. 5)produces 4- (Eq. 173),83 5-,82 6-,83 and 7-membered83 benzannulated ring sys-tems. The 8-membered benzazocine cannot be prepared by this method.83 Thediphenylphosphinoyloxy functionality has also been employed as the leavinggroup (Eq. 174).496 Five-, 6-, and 7-membered unsaturated nitrogen-containingrings are obtained from substituted oximes (Eqs. 175497 and 176498,499). The for-mer reaction is postulated to proceed by an SN2 displacement on sp2 nitrogenrather than an addition/elimination process. The intermediate 80 in the latter reac-tion is air sensitive and is either reduced to the tetrahydroquinoline or oxidized tothe quinoline. The cyclization in this case is believed to involve a single-electrontransfer.

Br

NHOMe1. MeLi, hexane, –78°2. n-BuLi, –78°, 30 min; to –15°

NAc(21%)

3. AcCl

(Eq. 173)

NCO2Et

CO2EtPh2P(O)O Me

t-BuOKNMe

CO2Et

CO2Et (95%) (Eq. 174)

NOSO2Me

CO2BnCO2Bn

N

CO2BnCO2Bn

DBU, CH2Cl2, 0°, 30 min(87%) (Eq. 175)


OHNOC6H3(NO2)2-2,4

OHNH

OHN

OHN

NaH

dioxane

Na(CN)BH3

50°, 10 h(78%)

(70%)DDQ, HOAc

reflux, 2 h80

(Eq. 176)

COMPARISON WITH OTHER METHODS

The number of methods for the formation of carbon-nitrogen bonds500 – 505

is too large to permit a meaningful comparison. A few other methods werementioned where appropriate in Scope and Limitations. The following is a briefdiscussion of the reagents for electrophilic amination that were excluded fromthe scope of this chapter.

Amination with Nitrogen Oxides

Nitrous oxide (N2O) reacts with phenyllithium to give complex mixturescontaining azobenzene, hydrazobenzene, and biphenyl, among others.506 With 9-fluorenyllithium, fluorenone azine is formed in 60% yield; the analogous productis obtained with the sodium salt of phenylacetonitrile.506 With n-butyllithium, theN -butylhydrazone of butyraldehyde is formed in low yield.507 Nitric oxide (NO)reacts with alkyl- and arylmagnesium reagents to give N -nitrosohydroxylaminesin low to fair yields.508,509 α,β-Unsaturated amides react with nitric oxide andtriethylsilane in the presence of cobalt complexes to give α-nitroso amides.510

Dinitrogen tetroxide (N2O4) and ethylmagnesium bromide511 or triethylaluminumetherate512 give N ,N -diethylhydroxylamine.

Amination with Nitrosyl Chloride, Nitryl Chloride, and NitroniumTetrafluoroborate

Combination of arylmagnesium halides and nitrosyl chloride (NOCl) givesmixtures of arylnitroso compounds and diarylamines.513 – 515 With alkylmagne-sium halides, N -nitrosohydroxylamines509 or dialkylhydroxylamines516,517 areformed. Aldehyde and ketone trimethylsilyl enol ethers and ketene acetals reactwith nitrosyl chloride to give the α-oximino aldehydes, ketones, or esters, respec-tively, by rearrangement of the intermediate nitroso compounds (Eq. 177).518 Thelatter are isolated from enol ethers of α, α-disubstituted aldehydes. α-Nitro alde-hydes and α-nitro ketones are formed in low yields by reaction of enol acetateswith nitryl chloride (NO2Cl).519 Alkyl- and allylsilanes react with nitroniumtetrafluoroborate (NO2

+ BF4−) to give the corresponding nitro compounds.520

The reaction of ketone enol ethers with nitronium tetrafluoroborate gives α-nitroketones.521,522


OTMS 1. NOCl (excess), CH2Cl2, –10° to –15°, 30 s

O

NO

O

NOH

(82%)

2. 0°, vacuum(Eq. 177)

Amination with Alkyl Nitrites

Alkyl nitrites, of which the most commonly used representative is isopentylnitrite,523 react with a wide variety of compounds containing active methylenegroups to give oximes.524 – 526 Activating functionalities include carbonyl, cyano,nitro, and aryl. For the latter, the presence of two aryl groups is usually requiredbut by using chromium-complexed arenes, one aryl group suffices (Eq. 178).527

The oximes can then be reduced to hydroxylamines or amines.528,529 Alkyl nitritesreact with dialkylzinc530 and alkylmagnesium516 reagents to give dialkylhydrox-ylamines, whereas with arylmagnesium reagents, diarylnitroxyls are formed.531

Activated olefins react with triphenylsilane and n-butyl nitrite in the presence ofcobalt complexes to give the corresponding α-hydroxyimino derivatives.532,533 Asimilar reaction of unactivated olefins in the presence of iron complexes givesnitrosoalkane dimers.534

MeO

(CO)3Cr1. t-BuONO, DMSO, rt

2. KOBu-t, 30 minMeO

(CO)3CrNOH

(60%) (Eq. 178)

Amination with Alkyl Nitrates

Alkyl nitrates535 give N ,N -dialkylhydroxylamines with alkylmagnesium rea-gents.536,537 The reaction of 9-fluorenylpotassium with isopentyl nitrate forms the9-nitro derivative in unspecified yield.538 The main application of alkyl nitrates,however, has been in the nitration of ketone enolates539 – 544 to give mono- ordinitro ketones. Many steroid nitro ketones have been prepared in this waybut yields are variable.542,545 – 548 α-Nitro amides,549 α-nitro lactams,540 and α-nitro nitriles550 may also be prepared in this manner. Aza enolates give nitroenamines551,552 (Eq. 179).552 Acetyl nitrate, prepared in situ from acetic anhy-dride and nitric acid, nitrates enol acetates.522,553 – 555 Similarly, α-nitro ketonesare formed from the reaction of enol ethers and esters with trifluoroacetyl nitrate,prepared in situ from ammonium nitrate and trifluoroacetic anhydride.522,548,556,557

Cyclohexanone triisopropylsilyl enol ethers and a mixture of tetra-n-butylammo-nium nitrate and trifluoroacetic anhydride give α-nitro enol ethers.558

N 1. KNH2, NH3 (liq), –33°, 1 h

2. n-PrONO2, <–40°; –33°, 25 min

HN

NO2

(50%)

(Eq. 179)


Amination with Nitroso CompoundsNitroso compounds559 – 561 are versatile electrophiles that undergo a num-

ber of different amination reactions. Arylnitroso compounds and aryl Grig-nard reagents are variously reported to give diarylhydroxylamines,99,562 – 568

diarylamines,99,514,569 or diaryl azo compounds.567 The reaction has beendeveloped into a general diarylamine synthesis (Eq. 180).570 Nitrosotrifluo-romethane undergoes a nitroso aldol reaction with the anions of pentane-2,4-dione(Eq. 181)571 and bis(trifluoromethyl)acetonitrile572 as does nitrosobenzene withketone lithium and tin enolates573 and with aldehydes in the presence of a proline-derived catalyst.574 The reaction of tin enolates with nitrosobenzene catalyzed byLewis acids gives mostly the hydroxylation products.575 Ketone trimethylsilylenol ethers react with nitrosobenzene to give adducts of type 81,242,243,576,577

which on reaction with triethylamine give imines of α-keto aldehydes.576 Oxi-dation of intermediates 81 leads to nitrones,577 and reduction to amino alco-hol derivatives (Eq. 182).578 Similarly, ketene bis(trimethylsilyl)acetals give N -phenyl α-amino acids on reduction of the intermediate adducts.578 Enamines reactwith nitroso arenes to give α-(N -arylhydroxylamino) ketones.579,580

Me2N

NO ClMg

CO2Et

+1. THF, –20°, 1 h

2. FeCl2, NaBH4, rt, 2 h

HN

CO2EtMe2N

(72%)

(Eq. 180)

O OO O

+ CF3NOEt3N, Et2O

–10°

NCF3 OH

(65%) (Eq. 181)

TMSO

Ph PhNO, CHCl3

rt, 4-6 h PhN

O OTMS

PhN

O

Ph

Et3N, CHCl3

rt, 1 d

81 (80%)

(100%)

PhN

O

Ph(80%)

1. HCl, THF, rt

2. Ag2O, C6H6, rt

Ph

HN

Ph(75-78%)

OHLiAlH4, Et2O, rt

or Pd/C, H2, THF, rt

Ph

O

(Eq. 182)

α-Chloronitroso compounds581 react with alkyl- and arylmagnesium rea-gents582,583 and with trialkylaluminum reagents584 to give nitrones. In


contrast, allylzinc reagents and α-chloronitroso compounds furnish mostly O-allyloximes.585 An important application of these reagents is in the aminationof enolates586 – 594 (Eqs. 183587 and 184595). Using these methods, the reactionsapparently proceed with somewhat higher diastereoselectivity than aminationsof N -acyloxazolidinones. However, amination of a β-lactam enolate withchloronitroso reagent 82, while completely trans selective, occurs with poordiscrimination between the two enantiomers of the enolate (products 83 and 84,Eq. 185).592 A mannose-derived α-chloronitroso compound has been prepared596

but apparently not yet applied in amination reactions.

N

SO2


2. , –78°, 30 minCl NO

O

N

SO2

O

NO

+

–

Ph Ph

N

SO2

O

PhNHOHHCl, H2O

rtO

PhNH2

1. Zn, HCl, HOAc, rt

2. LiOH

(78%) >99% de(87%) >99% ee

HO

(Eq. 183)

R

Cl

NO

Ph

O1. LiHMDS2. ZnCl2

Ph

O

NO

+–

R

82 R = SO2N(C6H11-c)2

1. HCl2. NaBH4, MeOH

Ph

OH

NH2

(68%) 90% de, 96% ee

3. 82 3. Zn, HCl, HOAc

(Eq. 184)

NO Ar

HPh

1. LDA, –78°, 10 min2. 82, –78° to –30°, 2 h

NO Ar

NO Ar

+

Ar = C6H4OMe-483 84(58%) 83:84 = 3:2

HONH PhPh HONH

3. HCl (Eq. 185)

Amination With Nitro CompoundsThe reaction of Grignard reagents with nitro compounds is complex and the

products depend on the nature of both reactants, but a number of useful syn-thetic schemes have been developed in recent years. Alkylmagnesium reagentsundergo 1,2- or 1,4-addition to aromatic nitro compounds to give ring-alkylatedintermediates that may be converted into ring-alkylated arylnitro compounds oranilines.597 The less basic organocerium reagents react with nitroalkanes to giveN,N-disusbstituted hydroxylamines.598 N -Allyl-599 and N -allenylmagnesium600


halides react with nitroalkanes and nitroarenes to give N -allyl- and N -propargyl-,N -alkyl- and N -arylhydroxylamines after reduction of the intermediate hydrox-ylamine N -oxides. Nitrones can be isolated from the reaction of allyl- andbenzylmagnesium reagents with nitroalkanes601 – 603 (Eq. 186).603 Arylmagnesiumreagents react with nitroarenes to give nitroso arenes which rapidly react withanother molecule of the arylmagnesium halide to give diarylhydroxylamines inlow to good yields;604 the formation of diarylamines has also been reported.605 Byreducing the unstable diarylhydroxylamines in situ, diarylamines are accessiblein good yields (compare to Eq. 180).606

O2NTHF, –78°

20 min

Ph NO–

+Ph N

O–

++

Ph MgCl +

(29%) (46%)

Ph N–O OMgCl

+

(Eq. 186)

Reactions of nitroarenes with vinylmagnesium halides give indoles (the Bartolireaction).607 Site selectivity problems may be avoided by temporarily installinga bromine ortho to the nitro group (Eq. 187).608

BrNO2

MgBr+

3 eq

THF, –40°, 1 h

BrNO

BrN

O

MgBr BrNMgBr

O

Br

N OMgBr

Br

NH

(67%)NH

(91%) Bu3SnH, AIBN

toluene, 110°, 12 h

(Eq. 187)

Reaction of the highly explosive fluorotrinitromethane with the anion of 2,4,6-trinitrotoluene, prepared with potassium hydroxide, gives the highly explosiveα,2,4,6-tetranitrotoluene in 89% yield.609 Ketone enol silyl ethers and the equallyhighly explosive tetranitromethane react to give α-nitro ketones in low to veryhigh yields (Eq. 188).610

OTMS

Ph

1. C(NO2)4, pentane, –30°, 6 h

2. KF, H2O, 30 min

O

PhNO2

(55%)

(Eq. 188)


N,N-Disubstituted nitroxides are formed in the reaction of tert-butylmagnesiumchloride with 1,1-dimethylnitroethane611 and nitroarenes,612,613 and by reactionof 1,1-dimethylnitroethane with arylsodium or aryllithium reagents.614

Amination of Enolates with Diazonium Salts

Enolates of β-dicarbonyl and similar doubly activated compounds are aminatedby aryldiazonium salts to give hydrazones by rearrangement of the intermediateazo compounds.14,15,615,616 The Japp-Klingemann reaction617,618 is a variation inwhich either acyl cleavage or decarboxylation occurs in situ after the amination.The hydrazones may be reduced to amines.619

The Diazo Transfer Reaction

Stabilized carbanions react with certain azides to give diazo compounds(Eq. 30, path A)620 – 624 Substrates include enolates with one additional activatinggroup and cyclopentadienide anions.625 Simple ketones only rarely322,324 undergothe diazo transfer reaction unless a formyl group is installed temporarily in theα-position. Only one example of an alkylcarbanion leading to a diazo compoundwas found in the literature.626 The most widely used azide is tosyl azide but lessdangerous sulfonyl azides have been proposed as alternatives.627 – 629 The vastmajority of diazo compounds preparared in this manner is used as precursors tocarbenes or carbenoids although methods exist for their reduction to hydrazones,hydrazines, or amines.198,205,630 Diastereo- or enantioselective reductions of thiskind do not seem to have been reported although the carbenoid NH insertion631

reaction shown in Eq. 189632 indicates that they may be feasible.

NMe

POPh O

N2

PhBnOCONH2, Rh2(OAc)4 (cat)

toluene, 80°, 5 h NMe

POPh O

Ph

NHCO2Bn

(56%) 15% de

(Eq. 189)

Amination of Boranes

Organoboranes, which are readily accessible by hydroboration of olefins,633

undergo many of the amination reactions also observed with alkyl carbanions butoften afford higher yields with fewer complications.634 Thus organoboranes giveamines by reaction with chloramine635 and its dialkyl derivatives, N -chloro O-(2,4-dinitrophenyl)hydroxylamine,636 hydroxylamine O-sulfonic acid,635,637,638

O-(2,4-dinitrophenyl)hydroxylamine,639 the lithium or potassium salts of tert-butyl N -tosyloxycarbamate,640 chloramine-T,641 and azides.642 – 644 Enantiomer-ically enriched amines are formed using chiral, non-racemic borane645,646 orboronic esters.220,647,648 Reaction of triphenylborane with hydroxylamine O-sulfonic acid gives aniline.649


The Neber RearrangementThe Neber rearrangement650 – 653 is a method for preparing α-amino ketones

by base-catalyzed intramolecular rearrangement of ketoxime O-sulfonates. Theintermediate azirine,654 – 656 which can be isolated, can also lead to aziridinederivatives when the base is lithium aluminum hydride657 or a Grignard reagent(the Hoch-Campbell reaction)658,659 (Eq. 190).

R1 R2N

OY– HOY

pyridine

or RO–

LiAlH4

R3MgX

R1 R2O

NH2

N

R1

R2

NH

R1

R2

NH

R1

R2

R3

(Eq. 190)

EXPERIMENTAL CONDITIONS

A number of reagent and product classes discussed in this chapterrequire special handling. Haloamines are toxic and explosive; the exper-imental hazards are eliminated or greatly reduced by using solutionsin inert solvents.10 Some O-sulfonylhydroxylamines are explosive: O-(2,4-dinitrobenzenesulfonyl)hydroxylamine is flammable, highly toxic, and highlyexplosive; an explosion occurred when brought in contact with potassiumhydride.93 An explosion of O-mesitylenesulfonylhydroxylamine occurred on stor-age below 0 ◦.114 Dry aryldiazonium salts are explosive. Hydrazoic acid and itssalts are toxic. Organic azides are explosive. Distillation should be avoided or car-ried out at low temperatures behind a shield. Tosyl azide has the exposive powerof TNT.627,660,661 Triazenes, the products of the reaction of azides with carbanions,are potent chemical carcinogens 258 and vesicants.259 Low-molecular-weight tri-azenes have high vapor pressures. Some are explosive and cause headaches.662

Chromium and cadmium salts are toxic.The great variey of reagents and substrates dealt with in this chapter does

not permit a detailed discussion of conditions for each experiment. Most ofthe reactions require flame-dried glassware, anhydrous solvents, and an inertatmosphere of nitrogen or argon.

Preparation of Electrophilic Aminating ReagentsReferences to the preparation of electrophilic aminating reagents are given in

Table A.


Table A

References to the Preparation of Amination Reagents

1. Haloamines. Reviews: refs.10, 663. ClNH2: refs. 664-668; method of analysis: ref. 64. BrNH2: ref. 669. Cl2NH: refs. 663, 667. Cl3N: ref. 670. RNHCl, R2NCl, RNCl2; R = alkyl: ref. 68. R2NCl from R2NH and N-chlorosuccinimide: refs. 671-673. ClNHCO2R: ref. 674.2. O-Substituted Hydroxylamines: review ref. 675. a. O-Alkyl-Substituted Hydroxylamines: refs. 676-680. MeONH2: refs. 681-683. EtONH2: ref. 682. BnONH2: refs. 85, 680, 684, 685. MeONHR [R = Bn, 2-MeC6H4, Ph(CH2)3]: ref. 85. MeONR2 (R = alkyl): ref. 85. RONMe2 (R = alkyl): ref. 677. b. O-Arylhydroxylamines PhONH2: ref. 686. 2-O2NC6H4ONH2: ref. 94. 4-O2NC6H4ONH2: refs. 94, 96, 107. 2,4-(O2N)2C6H3ONH2: refs. 93, 94, 96, 687-689. various substituted 2-O2NC6H3ONH2 and 5-O2NC6H3ONH2: ref. 96. 2,4,6-(O2N)3C6H4ONH2: ref. 94. c. O-Acylhydroxylamines: refs. 679, 699. Me3CCO2NH2: ref. 690. BzONH2: refs. 690, 691. 3-ClC6H4CO2NH2: ref. 690. 4-O2NC6H4CO2NH2: ref. 690. 2,4,6-Me3C6H2CO2NH2: refs. 690, 692, 693. BzONHR ( R = alkyl): ref. 694. RCO2NHCO2Bu-t (R = t-Bu, aryl: ref. 690. BzONR2: refs. 109, 695.

d. O-Sulfonylhydroxylamines HSO3ONH2: refs. 696-698. MeSO2ONH2: ref. 137. PhSO2ONH2: ref. 133. 4-MeC6H4SO2ONH2: refs. 132, 699. 2,4,6-Me2C6H2SO2ONH : refs. 700 (review), 116, 133, 693, 699-703. 2

Hazards: refs. 114, 116, 395, 703, 704. 2-O2NC6H4SO2ONH2: ref. 705. 2,4-(O2N)2C6H3SO2ONH2: ref. 705. 2,4,6-(O2N)3C6H2SO2ONH2: ref. 705. ArSO2ONEt2 (Ar = Ph, 2,4,6-Me3C6H2): ref. 133. ArSO2ONR2 (Ar = Ph, 2,4,6-Me3C6H2; NR2 = 1-piperidinyl): ref. 134. TsONHCO2Et: ref. 119. TsON(M)CO2Bu-t (M = Li, MgCl): refs. 127. ArSO2ON(Li)CO2CH2CH=CH2 (Ar = 4-MeC6H4; 2,4,6-Me3C6H2): ref. 130. 4-O2NC6H4SO2ONHP(O)NHSO2C6H4NO2-4: ref. 706.


SO2ONH2O

Brref. 534

NP

O O

ONMe2

Ph

ref. 147

O

O

NHOSO2C6H4-NO2-4

NC6H3Me2-3,5

SO2Ph

ref. 707

NOSO2CF3

ref. 708

e. OSi-Substituted Hydroxylamines TMSONHOTMS: refs. 699, 709. TMSONHR (R = alkyl): refs. 101, 709. TMSONHBn: ref. 709.f. O-Phosphinylhydroxylamines Ph2P(O)ONH2: refs 138, 141, 710-713. (4-MeOC6H4)2P(O)ONH2: refs. 106, 141, 712, 713. (4-MeC6H4)2P(O)ONH2: refs. 141, 712, 713. Ph2P(O)ONMe2: refs. 85, 714. Ph2P(O)ONR1R2 (R1 = alkyl; R2 = alkyl, allyl, Bn): ref. 715. Ph2P(O)ONR1R2 (R1R2 = (CH2)4, CH=CH-CH=CH): ref. 715. Ph2P(O)ONR2 (R = alkyl, c-C6H11, Bn): ref. 716.

3. Oxaziridines

O

HN

ONH N

H

O

ref. 718 ref. 718ref. 148

O

HN

ref. 717

ONR3R1

R2

R2

HMeCO2EtPhCF3

HHHH

HPh

R3

CO2Bu-tCOMe (chiral)CO2Bu-tCO2Bu-tCO2Bu-tCO2MeCO2Bu-tCONEt2

CONHCH(Me)CH(ODBDPS)Ph (derived from pseudoephedrine) 9-fluorenylmethoxycarbonylCO2Me

Refs.719717155155155153

157, 720158155

720153

R1

CCl3MeCO2EtCO2MePhArArArAr

ArPh

4. Imines

NEtO2C

EtO2C

C6H4OMe-4

ref. 167

NArCF3

EtO2C

ref. 721

5. (N-Arylsulfonylimino)phenyliodinanes TsN=IPh: ref. 722.


6. OximesN

R1

R2

OR3

R1

HMePh4-CF3C6H4

4-CF3C6H4

3,5-(CF3)2C6H3

R2

HMeMe, Ph4-CF3C6H4

4-CF3C6H4

3,5-(CF3)2C6H3

R3

Bn (see Eq. 6)SO2C6H2Me3-2,4,6SO2Ph, 4-BrC6H4SO2, 4-MeC6H4SO2

SO2MeSO2C6H4Me-4SO2C6H4Me-4

Refs.723724725179, 726179179

7. Diazonium Salts

SO2

–N

O2S

ref. 728

8. Azo Compounds

R1

PhPhArArArNHCO

R2

CO2RCOPhSO2C6H4Me-4COArCO2R

Refs.401, 729, 730729255389, 729383, 731

R1N=NR2

Z

YN

OSO2Ar

YOONMeONMe

ZOOONMeNMe

R1

R1

R1

R1

R1

HMeHHH

refs. 181, 182 NTsO

Ph

PhPh

Ph

ref. 727

ArN2+

R1

EtCl3CCH2

Cl3CCH2

allylt-BuPhBn(+)-menthyl(–)-menthyl(–)-bornyl(–)-isobornyl

R2

EtCl3CCH2

(CH2)2TMSallylt-But-BuBn(+)-menthyl(–)-menthyl(–)-bornyl(–)-isobornyl

Refs.732733, 734380735736410737408218406408

R1O2CN=NCO2R2

O

O

N

O

(CH2)n N

OO

n = 1, 2 ref. 738

NN

MeN

NMe

O

O

ref. 219


10. "TSN=Se=NTs": refs. 348, 349, 754.11. Nitridomanganese complexes reviews: 24, 25

refs. 471, 755, 756

RSO2N3

RTMSTMSCH2

EtO2Ct-BuCH=CHPhSCH2

(PhO)2P(O)

Refs.739see Experimental Procedures302, 740741see Experimental Procedures742

RN3

RMeCF3

4-MeC6H4

RPh R = H, 2-I, 2-NO2

2,4,6-(i-Pr)3C6H2

4-AcNHCOC6H4

polymer-bound

Refs.743309, 744, 745335, 746, 747hazards: 627, 660, 661safer analogs: 627-629, 748 448, 748-750751752, 753NCON3

SO2

ref. 304

9. Azides

N N

O O

R2

R1

R2

R1

N

Mn

R3 R3

Conversions of Amination ProductsThe following is a selection of procedures for the conversion of non-amine

amination products into amines and other nitrogen-containing compounds. Rele-vant information may also be found in reviews of protecting groups.757,758

N -Tosylamines into Amines: Bu3SnH,349 Na/liquid ammonia.348

N -Tosylamines into N -Tosylimines: SeO2.345

Azo Compounds into Hydrazines: Al/Hg.205

Azo Compounds into Amines:759 H2/Pd.196,197,415

Hydrazides into Amides or Amines:759 TFA-SmI2;233,481,760 peracids;761

Raney nickel;405,432,460,762−765 sodium in liquid ammonia;762,766 N2O3 orNaNO2/HOAc;767,768 H2/Pt.411,769,770

Triazene Salts into Amines: NaBH4;311 Ac2O-Al/Hg;317 sodium bis(2-methoxyethoxy)aluminum hydride.333

Azides into Amines:20,23,771,772 H2/Pd or H2/Pt;317,318,339,450,773 H2/Pd-(Boc)2Oin N -acyloxazolidinones to prevent reaction of the amine with the chiralauxiliary;774 Raney nickel;444 SnCl2;444,450,458,775,776 Zn;777 Al/Hg;777 sodiumborohydride under phase-transfer conditions;778 lithium aluminum hydride;779

H2S;780 triphenylphosphine.325,781,782

Azides into Imines: base.783 – 785

Azides into Enamines: NaReO4.331


EXPERIMENTAL PROCEDURES

Procedures are listed by type of reagent in the same order as in the section onReagents and Mechanisms.

+ CuCNTHF, –40°

PhCu(CN)Li1. i-Pr2NLi, –40°

2. O2, –78°, 20 min

Li N(Pr-i)2

(60%)

N ,N -Diisopropylaniline (Amination of an Arylcopper Reagent with a Li-thium Dialkylamide).54 Copper(I) cyanide (2 mmol) was added at −40◦ to asolution of phenyllithium (2 mmol) in THF (10 mL) and the mixture was stirredfor 20 minutes. A THF solution of LDA was added and after 15 minutes at −40◦

the mixture was cooled to −78◦ and a vigorous stream of oxygen was introducedfor 20 minutes. The mixture was allowed to warm to room temperature andpassed through a pad of celite. Concentration and kugelrohr distillation of theresidue (100◦ bath temperature, 20 mmHg) gave 0.21 g (60%) of the title productas an oil: 1H NMR (CDCl3) δ 7.69–7.33 (m, 5H), 3.80 (m. 2H) and 1.24 (d,J = 6.8 Hz, 12H). Anal. Calcd for C12H19N: C, 81.29; H, 10.81; N, 7.90. Found:C, 82.00; H, 10.81; N, 8.92.

EtO2C CO2Et1. NaH, benzene EtO2C CO2Et

NH2(89%)

2. ClNH2, morpholine, Et2O, rt, overnight; reflux, 5 h

Diethyl Aminomalonate (Amination of a β-Dicarbonyl Compound withChloramine).62 Diethyl malonate was converted into the sodium salt withsodium hydride in benzene and the solvent was removed. To a suspension ofthe salt (11.3 g, 0.06 mol) in Et2O (100 mL) was added with cooling a solutionof chloramine in Et2O (0.12 mol) followed by morpholine (5.22 g, 0.06 mol).The mixture was stirred with cooling for 2 hours and at room temperature overnight and then refluxed for 5 hours. The filtered mixture was concentrated and theresidue was distilled to give 10.9 g (89%) of the title compound, bp 116–117◦

(18 mmHg). The product gave the correct elemental analysis and the physicalproperties were those reported in the literature.

MeLi +

HN

MeO ether, hexanes

–78°

LiN

MeO t-BuLi, pentane

–78° to –10°

HN

t-Bu(99%)

N-tert-Butylbenzylamine (Amination of an Alkyllithium Compound witha Lithium Nitrenoid).85 To a solution of MeLi in Et2O (1.40 mL, 1.54 mmol)was added at −78◦ a solution of N -benzyl-O-methylhydroxylamine (0.21 g,1.53 mmol) in hexanes (5 mL). After stirring for 5 minutes, a solution of t-BuLiin pentane (1.2 mL, 1.28 M, 1.53 mmol) was added, the mixture was allowed towarm to −10◦ and kept at that temperature for 2 hours. Water and Et2O were


added and the dried (Na2SO4) Et2O solution was concentrated. The residue wasdistilled (kugelrohr) to give 0.28 g (99%) of the title product, bp 70◦ (0.5 mmHg):1H NMR (CDCl3) δ 7.33 (s, 5H), 3.73 (s, 2H) and 1.18 (s, 9H); 13C NMR δ

141.4, 128.4, 128.2, 126.7, 50.6, 47.2, 29.1. Anal. Calcd for C11H17N: C, 80.93;H, 10.50; N, 8.58. Found: C, 80.59; H, 10.91; N. 8.67.

Br

F

1. n-BuLi, hexanes, –78°2. CuBr•Me2S

NHCO2Bu-t

F

(50%)3. TsON(Li)CO2Bu-t, THF, –78°

tert-Butyl 4-Fluorophenylcarbamate (Amination of an Arylcopper Rea-gent with Lithium tert-Butyl N -Tosyloxycarbamate).127 A solution of n-BuLiin hexane (0.4 mL, 2.5 M, 1 mmol) was added dropwise at −78◦ to a solutionof tert-butyl N -tosyloxycarbamate (0.287 g, 1 mmol) in THF. The mixture wasstirred at −78◦ for one hour. In a separate vessel, a solution of 4-fluoro-1-bromobenzene (1 mmol) was treated with one equivalent of n-BuLi in hexaneat −78◦ for 30 minutes and then cannulated into a suspension of CuBr•Me2S(1 mmol) in THF (2 mL). The mixture was stirred at −60◦ to −78◦ for onehour, cooled to −78◦, treated dropwise with the solution of lithium tert-butylN -tosyloxycarbamate, and stirred at −78◦ for 30 minutes. A saturated aqueoussolution of NH4Cl and ammonia (5 mL) was added and the aqueous phase wasextracted with Et2O. The combined organic phases were washed with brine,dried (MgSO4), and concentrated. Flash chromatography of the residue (1:5EtOAc/cyclohexane) gave 0.105 g (50%) of the title product, mp. 111◦: IR (KBr)2255, 1690 cm−1; 1H NMR (CDCl3) δ 7.31 (m, 2H), 6.97 (m, 2H), 6.6 (s, 1H);1.51 (s, 9H); 13C NMR δ 158.6, 156.2, 134.2, 120.2, 115.4, 80.5, 28.2. Anal.Calcd for C11H14FO2N: C, 62.55; H, 6.68; N, 6.62. Found: C, 62.45; H, 6.69;N, 6.47.

Ph2Zn +

O

NO

Bz

CuCl2 (2.5 mol%)

THF, 0-5°, 90 minO

NPh

(67%)

N -Phenylmorpholine (Amination of an Arylzinc Derivative with an O-Acylhydroxylamine). This procedure is found in Organic Syntheses.111

NH

1. n-BuLi (2.1 eq), THF, hexane, TMEDA, 0°

NH

Et2N

(43%)2. 2,4,6-Me3C6H2SO2ONEt2, –78°; to rt, overnight


N,N-Diethyl-5,10-dihydroindeno[1,2-b]indol-10-amine (Amination of aBenzylic Anion with an N,N-Disubstituted O-Arenesulfonylhydroxyl-amine).136 A solution of n-BuLi (30 mL, 2.25 M in hexane, 67.5 mmol) wasadded with ice cooling to a solution of 5,10-dihydroindeno[1,2-b]indol (6.6 g,32.1 mmol) and TMEDA (20 mL) in THF (200 mL), the mixture was stirredat room temperature for 45 minutes, and cooled to −78◦. Solid N,N-diethyl O-mesitylenesulfonylhydroxylamine (8.7 g, 39.7 mmol) (caution, the N,N-unsubsti-tuted analog is explosive) was added in one portion and the mixture was leftto warm to room temperature and stirred overnight. Et2O (150 mL) was addedand the organic phase was washed with water (2 × 100 mL) and then extractedwith 2 N HCl (2 × 60 mL). The precipitate that formed in the acid extracts wascollected by filtration and suspended in 2 N NaOH solution (100 mL). The mix-ture was extracted with Et2O (150 mL), which was then washed with water (3 ×100 mL). Concentration of the dried (MgSO4) Et2O solution gave 3.8 g (43%)of the title product as a brownish-pink solid, mp 126.0−126.5◦, unchanged oncrystallization from petrol ether: 1H NMR (CDCl3) δ 8.2 (br s, 1H), 7.91–7.03(m, 8H), 4.87 (s, 1H), 2.58 (q, J = 7 Hz, 4H), 1.08 (t, J = 7 Hz, 6H). Anal.Calcd for C19H20N2: C, 82.56; H, 7.28; N, 10.13. Found: C, 82.81; H, 7.29;N, 9.93.

CO2Et

1. KOBu-t, THF, –78°2. (4-MeOC6H4)2P(O)ONH2, –78° to rt

CO2Et

NHAc

(67%)3. Ac2O, Et3N

Ethyl (N -Acetylamino)phenylacetate (Amination of an Ester Enolate withan O-Phosphinoylhydroxylamine).106 A freshly prepared solution of KOBu-t(31 mg, 0.28 mmol) in THF (2 mL) was added slowly to a solution of ethylphenylacetate (41 mg; 0.25 mmol) in THF (3 mL) cooled to −78◦ and the mix-ture was stirred at −78◦ for 15 minutes. O-[Di(p-methoxyphenyl)]phosphinoyl-hydroxylamine (caution, related hydroxylamine derivatives are explosive) (81 mg,0.28 mmol) was added as a solid in one portion, and the mixture was left to warmto room temperature and stirred overnight. Acetic anhydride (71 µL, 0.75 mmol)and triethylamine (210 µL, 1.5 mmol) were added and the mixture was stirredat room temperature for one hour. Et2O (20 mL) and saturated aqueous NH4Clsolution (30 mL) were added, and the aqueous layer was extracted with Et2O (2x 30 mL). The dried (MgSO4) extracts were concentrated and the residue waspurified by flash chromatography (1:1 EtOAc:cyclohexane) to give 37 mg (67%)of the title product as a colorless oil, Rf 0.20 (1:1 EtOAc:cyclohexane). No otherdata were reported.

NH (2.5 eq)O

DABCO, toluene,rt, 12 h

CONHPh

CONHPh

CONHPh

CONHPh

H2N

H2N

CONHPh

CONHPh

EtOH, refluxHN

(91%) (96%)


Diamino-N ,N ′-diphenylmalonamide and Imino-N ,N ′-diphenylmalona-mide (Diamination of a Malonamide with 1-Oxa-2-azaspiro[2.5]octane andConversion of the Product into an Imine).149 A suspension of N ,N ′-diphen-ylmalonamide in a mixture of toluene and 2.2–2.5 equivalents of 1-oxa-2-azaspi-ro[2.5]octane was treated with a solution of 1,4-diazabicyclo[2.2.2]octane (5–10mol%) in toluene (1 mL). The solid was collected by filtration after 12 hoursat room temperature, washed with a small amount of EtOH, and air dried togive diamino-N ,N ′-diphenylmalonamide in 91% yield, mp 130−132◦: 1H NMR(DMSO-d6) δ 6.9-7.9 (m, 10H), 3.2–3.6 (br, 6H); 13C NMR (DMSO-d6) δ 170.6,138.3, 128.6, 123.6, 119.4, 73.9. Anal. Calcd for C15H16N4O2: C, 63.37; H, 5.67;N, 19.71. Found: C, 62.60; H, 5.85; N, 19.74.

A 10% solution of diamino-N ,N ′-diphenylmalonamide in EtOH was heatedunder reflux for 15 minutes. The solid was collected after 12 hours at roomtemperature and air-dried to give imino-N ,N ′-diphenylmalonamide in 96% yield,mp 158−162◦. 1H NMR (DMSO-d6) δ 12.33 (br, 1H), 10.5 (br, 2H), 6.9–7.9 (m,10H); 13C NMR (DMSO-d6) δ 159.8, 162.3, 164.1, 137.3, 137.3, 119.7, 120.4,128.6, 128.9, 124.3, 124.4. Anal. Calcd. for C15H13N3O2: C, 67.40; H, 4.90; N,15.72. Found: C, 66.70; H, 5.05; N, 16.34.

CO2Et

CN

ONCO2Bu-t

EtO2C

EtO2C

1. LiHMDS, THF, –78°CN

CO2EtNHCO2Bu-t

(70%)2. , –78°, 20 h

Ethyl tert-Butoxycarbonylamino(cyano)phenylacetate (Amination of aCyanoacetic Ester Enolate with an N -Acyloxaziridine).155 Ethyl phenyl-cyanoacetate (0.22 mmol) was added to a solution of LiHMDS (0.22 mL, 1.0M in hexane, 0.22 mmol) at −78◦. After 30 minutes, a solution of N-tert-butoxycarbonyl-3,3-bis(ethoxycarbonyl)oxaziridine (95 mg, 0.33 mmol) in THF(1 mL) was added, the mixture was stirred at −78◦ for 12 hours and then left towarm to room temperature. CH2Cl2 and saturated aqueous NH4Cl were added,and the organic layer was washed twice with saturated NH4Cl. Removal ofthe solvent from the dried (Na2SO4) solution and flash chromatography of theresidue (10:1 petrol ether/EtOAc) gave 47 mg (70%) of the title product as anoil: IR (film) 2253, 1754, 1721 cm−1; 1H NMR (CDCl3) δ 7.67 (br 2H), 7.46-7.45 (m, 3H), 5.75 (br, 1H), 4.25 (q, J = 7.2 Hz, 2H), 1.46 (s, 9H), 1.25 (d,J = 7.2 Hz, 3H). MS-CI (m/z): [M + H]+ calcd for C16H20N2O4: 305.1501;found: 305.1511.

i-PrMgBrN

MeO

CO2Me

CO2Me

THF, –95°Pr-iN

MeO

CO2Me

CO2Me

KOH, EtOH

air, rt, 48 h

NHPr-i

MeO(57%)

+


N -Isopropyl-p-anisidine (Amination of a Grignard Reagent with anImine).167 Isopropylmagnesium bromide (0.83 M in THF, 0.54 mL, 0.45 mmol)was added slowly to a solution of diethyl 2-[N -(p-methoxyphenyl)imino]malo-nate (84 mg, 0.30 mmol) in THF (5 mL) at −95◦. After 30 minutes saturatedaqueous NaHCO3 was added and the mixture was extracted with EtOAc (3 ×10 mL). The combined extracts were washed with brine, dried (Na2SO4), and thesolvent was removed. The residue was stirred vigorously with 1 M aqueous KOH(0.11 mL) and EtOH (3.3 mL) at room temperature for 48 hours. The EtOH wasremoved after addition of aqueous Na2SO3 and the residue was extracted withEtOAc (3 × 10 mL). The extracts were washed with brine, dried (Na2SO4),and the solvent was removed. Preparative TLC of the residue (silica gel, 1:15EtOAc:hexane) gave 28 mg (57%) of the title product: 1H NMR (CDCl3) δ 6.57(d, J = 8.9 Hz, 2H), 6.77 (d, J = 8.9 Hz, 2H), 1.19 (d, J = 6.3 Hz, 6H), 3.74(s, 3H), 3.61–3.48 (m, 1H); 13C NMR (CDCl3) δ 23.07, 45.24, 55.79, 114.93,141.73, 151.95.

OTMS

+ TsN=IPhMeCN, warm

ONHTs

(95%)

2-[N -(p-Toluenesulfonyl)amino]acetophenone (Amination of a Ketone SilylEnol Ether with [N -(p-tolylsulfonyl)imino] phenyliodinane).172 A solution of1-(trimethylsilyloxy)styrene (0.5 mmol) in dry MeCN (7 mL) was treated withTsN=IPh (0.6 mmol). The mixture was warmed and the solvent was removedafter the reagent had dissolved. The residue was purified by chromatography onsilica gel followed by crystallization from Et2O to give the title product in 95%yield. No analytical or spectroscopic data were reported.

MgBrOO

NO

SO2Ph

+N

O O

PhCl, 0° HCl, EtOH

reflux, 6 h NH3+ Cl–

(89%)

1-Aminoadamantane Hydrochloride (Amination of a Grignard Reagentwith an O-Arenesulfonyloxime).182 To a solution of 4,4,5,5-tetramethyl-1,3-dioxolane-2-one O-benzenesulfonyloxime (602 mg, 2.01 mmol) in chloroben-zene (14 mL) was added dropwise at 0◦ 1-adamantylmagnesium bromide (0.63M in Et2O, 3.5 mL, 2.2 mmol) and the mixture was stirred at 0◦ for 30 minutes.The reaction was quenched with pH 9 buffer at 0◦ and the mixture was extractedthree times with EtOAc. The combined extracts were washed with brine, dried(Na2SO4), and concentrated. The crude imine was refluxed with 10 mL of EtOHand 1.3 mL of 6 M HCl for 10 hours. The ethanol was removed, the residue wasmade basic with 5 mL of 5 M NaOH, and the mixture was extracted three timeswith CH2Cl2. The combined extracts were washed with brine, dried (Na2SO4),


and concentrated. The residue was dissolved in MeOH, HCl in Et2O was added,and all volatiles were removed under vacuum. The residue was stirred with Et2Oand the solids were collected by filtration and dried to give 334 mg (89%) of thetitle product: 1H NMR (DMSO-d6) δ 8.18 (br, 3H), 2.05 (s, 3H), 1.79 (s, 6H),1.62 (d, J = 12.2 Hz, 3H), 1.54 (d, J = 12.2 Hz, 3H); 13C NMR (DMSO-d6)δ 51.1, 40.1, 35.4, 28.5.

t-BuMgCl +

O2S

NSO2

–N2

+

Cl

N

Cl

NBu-tTHF, –78°(86%)

E -(tert-Butyl)(4-chlorophenyl)diazene (Reaction of a Grignard Reagentwith an Aryldiazonium Salt).191 A suspension of 4-chlorobenzenediazoniumo-benzenedisulfonimide (1.77 g, 5 mmol) in anhydrous THF (15 mL) was stirredvigorously at −78◦, a solution of t-BuMgCl (5 mmol) was added over a periodof 10 minutes, and stirring at −78◦ was continued for one hour. The mixture waspoured into 30 mL of water and extracted with Et2O (2 × 30 mL). The washed(H2O, 30 mL) and dried (Na2SO4) extracts were heated in a 70◦ water bath toremove the Et2O and heating was continued for 1 hour to ensure conversionof any Z into the E isomer. Purification by column chromatography gave thetitle product in 83% yield, bp 57–58◦/0.25 mm: 1H NMR (CDCl3) δ 7.60 (d,J = 8.9 Hz, 2H), 7.38 (d, J = 8.9 Hz, 2H), 1.32 (s, 9H); 13C NMR (CDCl3)δ 150.5, 135.5, 128.8, 122.9, 67.5, 26.4.

NN

N

1. n-BuLi, THF, –78°

2. PhN=NPh

NHNn-BuPh

PhNLi

NNPh

Ph

NN

1. n-BuMgBr, –78° to rt

(57%)

2. NH4Cl

1,2-Diphenyl-1-(1-p-tolylpentyl)hydrazine (Amination of a Benzotriazolyl-methyl Anion with an Azo Compound Followed by Displacement of theBenzotriazole Functionality by a Grignard Reagent).359 To a solution of1-(4-methylbenzyl)benzotriazole (2 mmol) in THF (7 mL) was added n-BuLi(2 mmol) at −78◦ and the mixture was stirred at −78◦ for 10 minutes. n-BuMgBr(4 mmol) in Et2O was added followed by the azobenzene (2 mmol), and the mix-ture was left to warm to room temperature overnight. It was washed with 30 mLof 10% NH4Cl solution and the washing was extracted with EtOAc (2 × 10 mL).Removal of the solvents from the dried (MgSO4) organic phase and column chro-matography of the residue (SiO2, 1:1 toluene/hexane) gave the title product in57% yield, mp 97–99◦: 1H NMR δ 7.20–7.04 (m, 8H), 6.93 (d, J = 8 Hz,2H), 6.81–6.68 (m, 4H), 5.07 (br, s, 1H), 4.94 (t, J = 7 Hz, 1H), 2.28 (s, 3H),2.18–2.06 (m, 1H), 2.01–1.86 (m, 1H), 1.57–1.26 (m, 4H), 0.88 (t, J = 7 Hz,


3H); 13C NMR δ 150.3, 148.5, 137.1, 129.1, 128.9, 128.1, 119.5, 115.2, 112.2,66.0, 31.2, 29.4, 22.7, 21.1, 14.1. Anal. Calcd for C24H28N2: C, 83.68; H, 7.93;N, 8.48. Found: C, 83.68; H, 8.06; N, 8.48.

PhSiH3, t-BuO2CN=NCO2Bu-t,

cobalt complex, EtOH, rt, 5 hBr

Br

NNHCO2Bu-tt-BuO2C

(90%)

L = MeOH

NCo

O

OO

O

NH2O

L

cobalt complex

tert-Butyl N -(3-Bromo-1-methylpropyl)-N ′-(tert-butoxycarbonyl)hydra-zinecarboxylic Acid (Catalyzed Hydrohydrazination of an Olefin with anAzo Ester).215 The Co catalyst (10 mg, 0.025 mmol) was dissolved in EtOH(2.5 mL) at room temperature under argon. To the brown-red solution were added4-bromo-1-butene (68 mg, 0.50 mmol) and phenylsilane (65 µL, 0.52 mmol),followed by di(tert-butyl) azodicarboxylate (0.17 g, 0.75 mmol) in one portion.The resulting solution was stirred at room temperature for 5 hours. Water (1 mL)and brine (5 mL) were added and the reaction mixture was extracted with EtOAc(3 × 10 mL). The combined organic layers were dried over Na2SO4, filtered, andthe solvents were removed under reduced pressure. The residue was purified bycolumn chromatography (1:15 EtOAc:hexane) to give 166 mg (90%) of the titleproduct, mp 88−90◦: 1H NMR (CDCl3, 300 MHz, 52◦

) δ 6.06 (br s, 1H), 4.38(m, 1H), 3.45 (m, 2H), 2.13 (m, 1H), 1.82 (m, 1H), 1.46 (s, 18H), 1.12 (d,J = 6.5 Hz, 3H); 13C NMR (CDCl3, 75 MHz, 52◦

) δ 156.0, 154.7, 81.3, 52.2,37.5, 30.5, 28.3, 28.2, 18.0. Anal. Calcd for C14H27N2O4Br: C, 45.78; H, 7.41;N, 7.63. Found: C, 45.98; H, 7.48; N, 7.63.

S Br1. Zn*, THF, rt

2. t-BuO2CN=NCO2Bu-t, 0° to rt S NNHCO2Bu-t

CO2Bu-t(80%)

2-[N ,N ′-bis(tert-Butoxycarbonyl)hydrazino]thiophene (Amination of aHeterocyclic Zinc Reagent with an Azo Ester).358 To 1.5 equivalents of activezinc in THF, contained in a 50-mL centrifuge tube, was added 2-bromothiophene(0.163 g, 1 mmol) with stirring at room temperature. The mixture was stirred for30 minutes, then centrifuged. The supernatant was cannulated into another flaskand di(tert-butyl) azodicarboxylate (1 mmol in THF) was added over 5 minutes at0◦. After stirring for one hour the reaction was quenched with saturated aqueousNaHCO3, the mixture was extracted with Et2O, the solvent was removed, andthe residue was purified by flash chromatography (silica, hexanes/EtOAc) to give


1.2 g (80%) of the title product, mp. 82–84◦ (Et2O): 1H NMR (DMSO-d6, 100◦)δ 9.54 (br s, 1H), 7.03 (dd, J = 5.5, 1.6 Hz, 1H), 6.82 (dd, J = 5.5, 3.8 Hz,1H), 6.70 (dd, J = 3.8, 1.6 Hz, 1H), 1.47 (s, 9H), 1.44 (s, 9H). Anal. Calcd forC14H22N2O4S: C, 53.43; H, 7.05; N, 8.91; S, 10.20. Found: C, 53.8; H, 7.0; N,8.7; S, 10.2.

1. BnO2CN=NCO2Bn, L-proline, MeCN, 0° to rt, 3 h

BnO2CNH

NOH

CO2Bn

CHO

(94%) 97% ee

2. NaBH4, EtOH3. NaOH

(R)-Dibenzyl 1-(1-Hydroxyhexan-2-yl)hydrazine-1,2-dicarboxylate (Cata-lytic Asymmetric Amination of an Aldehyde with an Azo Ester).221 Hex-anal (1.5 mmol) was added to a solution of dibenzyl azodicarboxylate (330 mg,1 mmol) and L-proline (12 mg, 0.1 mmol) in MeCN (10 mL) at 0◦. The mixturewas stirred at 0◦ for 2 hours, warmed to room temperature during one hour, andcooled back to 0◦. EtOH (10 mL) and NaBH4 (40 mg) were added and the mix-ture was stirred at 0◦ for 5 minutes. Addition of aqueous NH4Cl and EtOAc andremoval of the solvent from the dried (MgSO4) organic phase gave the crude titleproduct, which was purified by column chromatography (EtOAc/hexanes) to give376 mg (94%) of the title compound as a colorless solid: 1H NMR (CDCl3) δ 7.35(m, 10H), 6.45 (s, 1H), 5.10 (m, 4H), 4.60–3.90 (m, 2H), 3.34 (m, 2H), 1.25(m, 6H), 0.83 (m, 3H); 13C NMR (CDCl3) δ 136.2, 135.8, 129.5, 129.1, 128.7,128.5, 69.1, 68.9, 62.9, 61.2, 28.8, 28.2, 22.3, 14.3; HRMS-MALDI (m/z): [M +Na]+ calcd for C22H28N2O5, 423.1890; found 423.1889. The enantiomeric excess(97%) was determined by conversion into the oxazolidinone (K2CO3, toluene,reflux, 1 hour) and HPLC on a Chiralpak AD-RH column.

OSiMe3 ON

NHCO2Bn

CO2Bn1. AgClO4, (R)-BINAP, BnO2CN=NCO2Bn, THF, –45°

(82%) 65% ee

2. add substrate, –45°, 5 h

(S )-Dibenzyl 1-(1-Oxo-1,2,3,4-tetrahydronaphthalen-2-yl)hydrazine-1,2-dicarboxylate (Catalyzed Asymmetric Amination of a Ketone Silyl EnolEther with an Azo Ester).244 A solution of silver perchlorate (0.040 mmol)and (R)-BINAP (0.048 mmol, 12 mol%) in THF (1 mL) was stirred at roomtemperature for 30 minutes, cooled to −45◦, and treated with dibenzyl azodicar-boxylate (0.44 mmol). After stirring for 10 minutes, (3,4-dihydronaphthalen-1-yloxy)trimethylsilane (0.4 mmol) in THF (0.5 mL) was added and the mixturewas stirred at −45◦ for 5 hours. Aqueous HF (20%) and THF (1:1) were addedand the mixture was stirred at room temperature for one hour after which timeit was made basic with aqueous NaHCO3 solution and extracted with CH2Cl2.


Removal of the solvent from the dried (MgSO4) extracts and preparative thin-layer chromatography of the residue gave the title product in 82% yield, mp141◦. 1H NMR (DMSO-d6, 70◦) δ 2.2–2.4 (m, 2 H), 2.9–3.5 (m, 2 H), 4.92 (brs, 1 H), 5.09 (s, 2 H), 5.13 (s, 2 H), 7.2–7.5 (m, 12 H), 7.56 (t, J = 7.5 Hz, 1H), 7.89 (d, J = 7.9 Hz, 1 H), 9.35 (br s, 1 H). Anal. Calcd for C26H24N2O5:C, 70.26; H, 5.44; N, 6.30. Found: C, 70.52; H, 5.57; N, 6.13. The enantiomericexcess (65%) was determined by HPLC analysis (DAICEL, CHIRALCEL ODor AS).

N3

CO2Me

Br+

In, NaI, DMF

rt, 3.5 h

HN

CO2Me (75%)

Methyl 2-(Naphthalen-2-ylamino)methylacrylate (Amination of an Allylin-dium Species with an Azide).269 A mixture of 2-azidonaphthalene (5 mmol),methyl 2-(bromomethyl)acrylate (7.5 mmol), indium powder (7.5 mmol), sodiumiodide, (7.5 mmol), and DMF (15 mL) was stirred at room temperature for3.5 hours. Saturated aqueous NH4Cl (15 mL) was added and the mixture wasextracted with Et2O (2 × 15 mL). The solvent was removed from the extractsand the residue was purified by silica gel chromatography (0.5:9.5 EtOAc/hexane)to give the title product in 75% yield: IR (KBr) 1605 cm−1; NMR (CDCl3)δ 7.87–7.80 (m, 2H), 7.50–7.43 (m, 2H), 7.30 (d, J = 8 Hz, 1H), 7.25 (d,J = 8.0 Hz, 1H), 6.58 (d, J = 7.8 Hz, 1H), 6.35 (s, 1H), 5.85 (s, 1H), 4.25 (s,2H), 3.83 (s, 3H); EIMS (m/z): 241 (M+), 209, 180.

N3

+ EtMgBrEt2O, rt, 30 min NHEt

(90%)

N -Ethylaniline (Preparation of an N -Substituted Aniline by Reaction ofa Grignard Reagent with an Aromatic Azide).279 A solution of ethylmag-nesium bromide (15 mmol) in Et2O (20 mL) was added to a solution of phenylazide (1.19 g, 10 mmol) in Et2O (5 mL) at room temperature and the mixturewas stirred another 30 minutes. Saturated aqueous NH4Cl (15 mL) was addedand the mixture was extracted with ethyl acetate (2 × 25 mL). The extracts werewashed with water and brine, dried (Na2SO4), and concentrated. The residuewas purified by column chromatography (silica, 1:9 EtOAc:hexane) to give 1.09g (90%) of the title product as a pale yellow liquid. 1H NMR δ 6.8-6.5 (m, 5H),3.25 (br s, 1H), 3.15 (q, J = 8.0 Hz, 2H), 1.25 (t, J = 8.0 Hz, 3H); 13C NMRδ 148.2, 128.9, 116.8, 112.5, 38.1, 14.5; MS (m/z): 121 (M+), 106, 77, 51.

MgBr

TMS ClNaN3, DMF

80°, 44 hTMS N3 Et2O, rt, 3 h

NH2

(98%)(79%)


2,4-Dimethylaniline (Preparation of Trimethylsilylmethyl Azide and ItsReaction with an Arylmagnesium Reagent to Give an Aniline).264 A mix-ture of trimethylsilylmethyl chloride (0.2 mol), sodium azide (0.24 mol), and dryDMF was heated at 80◦ for 44 hours. Distillation gave trimethylsilylmethyl azide,bp 43◦ (43 mmHg) in 97% yield. 1H NMR δ 2.75 (s, 2H), 0.12 (s, 9H). Theproduct is stable and can be stored in a refrigerator for at least 6 months but likeall azides it is potentially explosive and should be handled with care.

Trimethylsilylmethyl azide (1.2 eq) was added dropwise at room temperatureto a solution of 2,4-dimethylphenylmagnesium bromide (1 eq) in ether and themixture was stirred at room temperature for 3 hours. After conventional workupthe low-boiling substances were removed under reduced pressure, leaving thetitle product in 79% yield. It was identified by comparison of its properties withthose of an authentic sample.

S Cl NaN3, NaI (cat)

MeCN, reflux, 4.4 h

S N3(99%)

S

N1. n-BuLi, –75°2. MgBr, CuI, 0°

S

NNH2 (59%)

3. PhSCH2N3, 0° to rt4. KOH, MeOH, rt

2-Aminobenzothiazole (Preparation of Azidomethyl Phenyl Sulfide andIts Reaction with a Heterocyclic Grignard Reagent to Give a HeterocyclicAmine).274 A mixture of chloromethyl phenyl sulfide (40.0 g, 0.25 mol),sodium azide (32.5 g, 0.50 mol), dry MeCN (167 mL), and sodium iodide (100mg) was stirred and heated under reflux for 4.4 hours, cooled, diluted with Et2O,and filtered through celite. Removal of the solvents and distillation of the residuegave 40.8 g (99%) of azidomethyl phenyl sulfide as a colorless oil, bp 55–58◦

(0.23 mmHg): 1H NMR (CDCl3) δ 7.64–7.34 (m, 5H), 4.58 (s, 2H); 13C NMR(acetone-d6) δ 134.5, 131.2, 129.8, 128.0, 55.9.

A solution of benzothiazole (75 mg, 0.55 mmol) in Et2O (0.75 mL) was addedto a solution of n-BuLi in hexane (0.32 mL, 1.75 M, 0.55 mmol) and Et2O(0.75 mL) at −75◦. After 10 minutes, a solution of MgBr2 (0.26 mL, 2.24 M inbenzene/Et2O, 0.58 mmol) was added, followed by THF (0.75 mL). Azidomethylphenyl sulfide (96 mg, 0.58 mmol) was added and the solution was warmedto 0◦. Cuprous iodide (5.0 mg, 0.026 mmol) was added and after 1 hour themixture was warmed to room temperature, stirred for another 2 hours, and pouredinto saturated aqueous NH4Cl. The mixture was extracted twice with Et2O, theextracts were washed with brine, dried (Na2SO4), and concentrated. The residuewas stirred with THF (1 mL), methanol (1 mL), and 50% KOH in H2O (0.25 mL)at room temperature for 3 hours and the mixture was poured into water andextracted three times with Et2O. Acid-base purification and crystallization ofthe crude product from water gave 49 mg (59%) of 2-aminobenzothiazole, mp129–131◦ (lit. mp 129◦

): 1H NMR (CDCl3) δ 7.55 (t, J = 9.0 Hz, 2H), 7.30 (dt,J = 7.6, 1.2 Hz, 1H), 7.11 (dt, J = 7.6, 1.2 Hz), 5.35 (br s, 2H).


NO

O

Bn

O

O

NBoc

1. KHMDS, THF, –78°2. 2,4,6-(i-Pr)3C6H4SO2N3, N

O

O

Bn

O

O

NBocN3

LiOH, rt

O

O

NBocN3

OH

(92%)

(97%)

–78°, 3 min3. HOAc

(4R)-3{(Z ,2R)-2-Azido-6-[(4R)-3-tert-butoxycarbonyl-2,2-dimethyl-1,3-oxazolidin-4-yl]-1-oxohex-5-enyl}-4-phenylmethyl-1,3-oxazolidinone and(4R)-4[(1Z ,5R)-5-Azido-5-carboxypent-1-enyl]-3-tert-butoxycarbonyl-2,2-dimethyl-1,3-oxazolidine (Diastereoselective Azidation of an N -Acyloxazoli-dinone with Trisyl Azide and Removal of the Chiral Auxiliary).440 KHMDSin toluene (2.85 mL, 0.5 M, 1.43 mmol) was added at −78◦ to THF (7.5 mL)followed by a pre-cooled (−78◦

) solution of the substrate (601 mg, 1.27 mmol;E/Z = 1:13) in THF (9.5 mL) by insulated steel cannula. The mixture was stirredat −78◦ for 80 minutes. Solid 2,4,6-triisopropylbenzenesulfonyl azide (591 mg,1.91 mmol) was added in one portion with vigorous stirring and the reaction wasquenched with AcOH/THF (1:1, 0.7 mL) after 3 minutes. The flask was imme-diately placed in a 28◦ water bath, the mixture was stirred for 30 minutes, andthen partitioned between 50 mL of half-saturated aqueous NH4Cl and 50 mLof EtOAc, and the aqueous phase was extracted with 2 × 50 mL of EtOAc.The combined extracts were dried (MgSO4) and concentrated, and the residuewas purified by flash chromatography (EtOAc/hexane) to give 602 mg (92%)of the title product as an oil, E/Z = 1:13. Crystallization (Et2O/hexane) gavethe pure Z-isomer, mp 87–88◦: [α]22

D −6.3◦ (c 1.15, CHCl3); IR (CHCl3)2108,1783, 1690 cm−1; 1H NMR (CDCl3) δ 7.12-6.82 (m, 5H), 5.51 (ddt, J = 10.7,9.2, 1.4 Hz, 1H), 5.38 (br dt, J = 10.7, 7.5 Hz, 1H), 5.18 (br q, 1H), 4.62 (m,1H), 4.15 (ddt, J = 9.2, 8.2, 3.2 Hz, 1H), 3.85 (dd, J = 8.6, 6.3 Hz, 1H), 3.54(dd, J = 8.6, 3.1 Hz, 1H), 3.35 (t, J = 9.1 Hz, 1H), 2.93 (dd, J = 13.6, 3.2 Hz,1H), 2.44–2.28 (m, 2H), 2.33 (dd, J = 13.6, 9.2 Hz, 1H), 2.08–1.94 (m, 1H),1.92–1.78 (m, 1H), 1.67 (s, 3H), 1.56 (s, 3H), 1.43 (s, 9H). Anal. Calcd forC26H35N5O6: C, 60.80; H, 6.87; N, 13.64. Found: C, 60.8; H, 6.9; N. 13.0.

A solution of the above product (150 mg, 0.29 mmol) in 3:1 THF/water wastreated at 0◦ with lithium hydroxide hydrate (25 mg, 0.59 mmol) and the mixturewas stirred at 0−2◦ for 45 minutes. Aqueous NaHCO3 (2 mL, 0.5 M) was addedat 0−2◦ and the THF was removed under reduced pressure. The aqueous phasewas extracted with CH2Cl2 (4 × 30 mL) to recover the chiral auxiliary (51 mg,98%). The aqueous phase and aqueous back-extracts were acidified (2 mL of2 N HCl) and the product was extracted into EtOAc (4 × 40 mL). The dried(MgSO4) extracts were concentrated to give 101 mg (97%) of the title acid, mp95.5–96.5◦: [α]22

D + 54.5◦ (c 0.53, CHCl3); IR (CHCl3) 2109, 1719, 1698 cm−1;


1H NMR (C6D6) δ 1.3–1.9 (m, 2 H), 1.41 (s, 9 H), 1.53 (s, 3 H), 1.63 (s, 3H), 2.07–2.33 (m, 2 H), 3.48 (dd, J = 8.7, 3.3 Hz, 1 H), 3.80 (br m, 1 H), 5.22(dt, J = 10.2, 7.5 Hz, 1 H), 5.45 (dd, J = 10.7, 9.2 Hz, 1 H), 8.49 (br s 1 H).Anal. Calcd for C16H26N4O5: C, 54.22; H, 7.39; N, 15.81. Found, C, 54.0; H,7.3; N, 15.8.

MgBr

4-MeC6H4SO2N3

Et2O, 0°

NN N

SO2C6H4Me-4 – MgBr+

Na4P2O7, H2O

Et2O, rt, overnight

N3

(63%)

2-Azido-1,3,5-trimethylbenzene (Preparation of an Azide from a GrignardReagent and Tosyl Azide).305 A solution of 2,4,6-trimethylphenylmagnesiumbromide in Et2O, prepared from 39.8 g (0.2 mol) of 2-bromo-1,3,5-trimethylben-zene, was added with ice cooling to a solution of 19.7 g (0.1 mol) of tosylazide (caution; tosyl azide has the explosive power of TNT ) in Et2O (500 mL).The mixture was stirred for 30 minutes and the tan precipitate was collected byfiltration, washed with Et2O and petrol ether, and dried to give 50.8 g of thetriazene salt (caution: triazenes are potential carcinogens). It was suspended in250 mL of Et2O and a solution of tetrasodium pyrophosphate decahydrate (44.6g) in H2O (500 mL) was added dropwise with ice cooling. The mixture wasstirred overnight, the layers were separated, and the aqueous layer was extractedwith petrol ether (2 × 100 mL). The solvents were removed from the dried(CaCl2) organic phases to leave 16.7 g of a red oil, which was passed through acolumn of 300 g of alumina and eluted with petrol ether to give 10.16 g (63%)of the title product as a colorless oil. An analytical sample was distilled at 65◦

(0.2 mm): IR (neat) 2130 cm−1; 1H NMR (CCl4) δ 6.60 (s, 2H), 2.21 (s, 6H),2.17 (s, 3H). Anal. Calcd for C9H11N3: C, 67.05; H, 6.88; N, 26.07. Found: C,66.98; H, 6.82; N, 26.03.

S NMePh

O1. LDA, THF, –78°, 1 h2. (PhO)2P(O)N3, –78°, 5 min

S NMePh

O

NHCO2Bu-t

(70%)3. (t-BuO2C)2O, –78° to rt, 6 h

α-[(tert-Butoxycarbonyl)amino]-N -methyl-N -phenyl-2-thiopheneaceta-mide (Amination of an Amide Enolate with Diphenyl Phosphorazidate).336

To a solution of N -methyl-N -phenyl-2-thiopheneacetamide (3 mmol) in THF(6 mL) was added LDA (1.5 M in cyclohexane, 3.3 mmol) at −78◦ and the mix-ture was stirred at −78◦ for one hour. Diphenyl phosphorazidate (3.3 mmol) wasadded, the mixture was stirred for 5 minutes, (t-BuO2C)2O (6 mmol) in THF


(3 mL) was added, and the mixture left to warm to room temperature during6 hours. The solvents were removed and the residue was purified by chromatog-raphy (SiO2, hexane/EtOAc) to give 725 mg (70%) of the title product as yellowcrystals, mp 104−106◦: IR 1705, 1655 cm−1; 1H NMR δ 7.45−7.40 (m, 3H),7.35–7.25 (d-like, 1H), 7.20–7.00 (m, 2H), 6.85–6.80 (t-like, 1H), 6.70-6.65(d-like, 1H), 5.74 (d, J = 8 Hz, 1H), 3.30 (s, 3H), 1.40 (s, 3H); MS–CI (m/z):[M + 1]+ 293.

OSi(Pr-i)3NaN3, (NH4)2Ce(NO2)6

MeCN, –20°

ON3

(49%)

2-Azido-2-methylcyclohexanone (Preparation of an α-Azido Ketone byReaction of a Ketone Triisopropylsilyl Enol Ether with Sodium Azide andAmmonium Cerium(IV) Nitrate).331 To a solution of 1-methyl-2-(triisopro-pylsilyloxy)cyclohexene in MeCN (0.4M, 1.99 mmol) was added at −20◦ sodiumazide (8.86 mmol, 4.5 eq) followed dropwise by a solution of ammonium cerium-(IV) nitrate in MeCN (0.4M, 5.90 mmol, 3 eq). When the reaction was complete(TLC), ice-cold water was added and the mixture was extracted with ice-coldEt2O. The combined extracts were washed with ice-cold water, dried (Na2SO4),and concentrated. The residue was purified by silica gel chromatography (1:3ether/pentanes) to give the title product in 49% yield as a pale yellow oil: IR(CHCl3) 2102, 1722 cm−1; 1H NMR (CDCl3) δ 2.61–2.51 (m, 1H); 2.37–2.28(m, 1H), 1.91-1.56 (m, 6H), 1.35 (s, 3H); 13C NMR δ 207.7, 67.9, 39.1, 36.2,26.9, 21.1, 20.2; HRMS (m/z): calcd for C7H11NO, 153.090; found, 153.090.

OMe 1. ClNHCO2CH2CCl3 (inverse addition), CHCl3, MeOH, –78°

ONHCO2CH2CCl3 (86%)

2. CrO2, MeOH, –78° to rt

2,2,2-Trichloroethyl 2-Oxocyclohexylcarbamate (Amination of a KetoneEnol Ether with the Chromium(II) Chloride/Chlorocarbamate Reagent).343

A solution of N -chloro 2,2,2-trichloroethyl carbamate (1.33 g, 5.74 mmol) inCHCl3 (4 mL) and MeOH (1 mL) was cooled to −78◦ and treated with a pre-cooled solution of 1-methoxycyclohexene (1.5 mL, 12 mmol) in CHCl3 (2 mL).During 1 hour, a 1 M solution of CrCl2 (about 5 mL, 5 mmol) in MeOH wasadded dropwise until a starch-iodide paper test was negative. The cooling bathwas removed and air was admitted. Sulfuric acid (1 mL of a 1 N solution) wasadded and the mixture was stirred at room temperature for 4 hours, poured into50 mL of water, and extracted with CH2Cl2 (3 × 100 mL). The combined extractswere washed twice with water, dried, and concentrated. The residue was sepa-rated by chromatography (1:4 ether/hexane) into 2,2,2-trichloroethyl carbamate


(0.185 g) and the less polar title product (1.302 g, 86%), mp 75−78◦. Crystal-lization from hexane gave an analytical sample, mp 80−80.5◦: IR (CCl4)1745,1720 cm−1; 1H NMR (CCl4) δ 5.92 (m, 1H), 4.63 (s, 2H), 4.22 (dt, J = 6, 12 Hz;dd, J = 6, 11.5 Hz after D2O exchange, 1H). Anal. Calcd for C9H12Cl3NO3: C,37.44; H, 4.19; Cl, 36.89; N, 4.85. Found: C, 37.43, H, 4.17; Cl, 37.10; N, 5.02.

TABULAR SURVEY

An effort was made to include all relevant reactions that appeared in the liter-ature up to the middle of 2007. However, in view of the difficulties in searchingthe subject, omissions are inevitable. The tables are arranged according to sub-strates and follow the organization of the section on Scope and Limitations. Thetitles of the individual tables are listed in the Table of Contents and are notrepeated here.

Substrates are listed in the order of increasing carbon count. To group similarsubstrates together, protecting groups and chiral auxiliaries are not counted norare groups on heteroatoms such as N, O, S, and P. This includes alcohol por-tions of esters and groups such as methyl or ethyl in ethers, amides, and amines.Ligands in metal complexes are excluded from the count but ferrocene is listedin Table 4 (Aromatic Carbanions) under C10. However, all ring carbons in hete-rocycles are included in the carbon count. Within each carbon count or range ofcarbon counts entries are listed in the order in which reagents are discussed inthe section on Reagents and Mechanisms: amines, haloamines, hydroxylamines,oxaziridines, imines, oximes, diazonium salts, diazo compounds, azo compounds,azides, and miscellaneous other reagents. This order is not followed in Table 5(Heterocyclic Anions) where like heterocycles are grouped together. Only sub-strates where the carbanionic center is in the heterocyclic ring are listed here.Heterocyclic substrates where the carbanionic center is on a side chain are listedin Table 1A (Arylmethyl and Heteroarylmethyl Carbanions). Substrates wherethe carbanionic center is on an aromatic ring fused to, or attached to, a hetero-cycle are listed Table 4 (Aryl Carbanions). Table 10A (Esters) does not includelactones and Table 12 (amides) does not include lactams which are in separatetables (11 and 14, respectively) and which are not listed in Table 5 (HeterocyclicCarbanions). Surrogates of carbonyl compounds, such as enol ethers or enamines,are listed together with their parent carbonyl compounds.

A dash enclosed in parentheses [(−)] next to a product signifies that theproduct was isolated but no yield was reported. When a reaction involving thesame aminating reagent has been reported in more than one publication, theconditions producing the highest yield are shown and the reference to that paperis given first. Extensive variations of catalysts, solvents, and conditions are notincluded in the tables; instead, one or two sets of conditions that produce thehighest yield and best selectivity are given.


The following abbreviations are used in the tables:

Ac acetylacac 2,4-pentadionato (acetylacetonato)BINAP 2,2-bis(diphenylphosphino)-1-binaphthyl[bmim][BF4] N -butyl-N ′-methylimidazolium tetrafluoroborateBn benzylBoc tert-butoxycarbonylBOM benzyloxymethylBu butylBz benzoyl[capemim][BF4] N -5-carboxypentyl-N ′-methylimidazolium

tetrafluoroborateCbz benzyloxycarbonylCp η5-cyclopentadienylDABCO 1,4-diazabicyclo[2.2.2]octaneDBU 1,8-diazabicyclo[5.4.0]undec-7-eneDDQ 2,3-dichloro-5,6-dicyanobenzoquinone(DHQD)2CLB dihydroquinidinyl p-chlorobenzoate (see Chart 1)(DHQD)2PYR dihydroquinidinyl pyrimidine (see Chart 1)DMF dimethylformamideDME dimethoxyethaneDMPU 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinoneDMSO dimethylsulfoxideEt ethylFmoc 9-fluorenylmethoxycarbonylHMPA hexamethylphosphoric triamideia inverse additionKHMDS potassium hexamethyldisilazideLDA lithium diisopropylamideLiHMDS lithium hexamethyldisilazideMe methylMEM (2-methoxyethoxy)methylMs methanesulfonylNaHMDS sodium hexamethyldisilazidePh phenylPiv pivaloylPMB p-methoxybenzylPr propylPy pyridine(saltmen)Mn(N) nitrido[N ,N ′-(1,1,2,2-tetramethyl)

bis(salicylideneaminato)]manganese (see Chart 1)TMS trimethylsilylTBS tert-butyldimethylsilylTBDPS tert-butyldiphenylsilyl


TEMPO 2,2,6,6-tetramethylpiperidinyl-1-oxylTf trifluoromethanesulfonylTFA trifluoroacetic acidTFAA trifluoroacetic anhydrideTHF tetrahydrofuranTMEDA tetramethylethylenediamineTr triphenylmethylTs tosyl; 4-methylbenzenesulfonyl

NN

OO

N Mn

CH

AR

T 1

. ST

RU

CT

UR

ES

OF

RE

AG

EN

TS

AN

D C

AT

AL

YST

S

(sal

tmen

)Mn(

N)

Nitr

ido[

N,N

'-(1,

1,2,

2-te

tram

ethy

l)bi

s(sa

licyl

iden

eam

inat

o)]m

anga

nese N

N

OO

NN

OM

eM

eOH

H

N

H

Et

NE

t

(DH

QD

) 2PY

R

N

MeO

HO

O

Cl

Et

H

(DH

QD

) 2C

LB

cata

lyst

A

L =

MeO

H, 2

:1 m

ixtu

re o

f is

omer

s

cata

lyst

B

N

Co

O

OO

O

NH

2O

LM

n

OO O

O

OO

Bu-

t

t-B

u

t-B

u

t-B

u

t-B

u

Bu-

t

87

Subs

trat

eR

efs.

Con

ditio

nsPr

oduc

t(s)

and

Yie

ld(s

) (%

)

TA

BL

E 1

A. A

CY

CL

IC A

LIP

HA

TIC

CA

RB

AN

ION

S

R1 M

(1-

5 eq

)1.

R2 R

3 NH

, sol

vent

, tem

p 1,

2 h

2. O

2, te

mp

2, ti

me

R1 N

R2 R

352

R1

Me

Me

Me

Me

Me

n-B

u

n-B

u

n-B

u

n-B

u

n-B

u

t-B

u

t-B

u

t-B

u

t-B

u

t-B

u

t-B

u

M CuM

eLi

Cu

CuM

eLi

Cu

CuM

eLi

CuM

eLi

CuM

eLi

CuM

eLi

CuM

eLi

CuM

eLi

CuM

eLi

CuM

eLi

CuM

eLi

CuM

eLi

CuM

eLi

CuM

eLi

R2

Ph Ph n-C

7H15

n-C

7H15

(CH

2)2P

h

Ph Ph n-C

7H15

c-C

6H11

(CH

2)2P

h

Ph 3-A

cC6H

4

3-(M

eCH

OH

)C6H

4

1-na

phth

yl

n-C

10H

21

(CH

2)2P

h

R3

Me

Me

n-B

u

n-B

u

(CH

2)2P

h

Me

(CH

2)2O

H

n-B

u

c-C

6H11

(CH

2)2P

h

H H H H H (CH

2)2P

h

Solv

ent

tolu

ene

TH

F, H

MPA

Et 2

O

TH

F

Et 2

O

Et 2

O

Et 2

O

Et 2

O

Et 2

O

Et 2

O

TH

F

Et 2

O

Et 2

O

TH

F

TH

F

TH

F

Tem

p 1

0° rt rt rt rt

–20°

–20°

–20°

–20°

–20°

–20°

–20°

–20°

–20°

–20°

–20°

Tem

p 2

–78° rt rt rt rt

–20°

–20°

–20°

–20°

–20°

–20°

–20°

–20°

–20°

–20°

–20°

Tim

e

— — — — — — —

3 m

in

— — — — — — — —

(33)

(46)

(39)

(52)

(76)

(57)

(37)

(73)

(38)

(62)

(46)

(32)

(39)

(35)

(23)

(26)

C1-

4

R1 C

u(C

N)L

iR

1 NR

2 R3

54

R1

Me

n-B

u

n-B

u

n-B

u

n-B

u

R2

Ph Me

i-Pr

Ph (R)-

1-(1

-nap

hthy

l)et

hyl

R3

Bn

Bn

i-Pr

H H

(50)

(45)

(50)

(62)

(60)

1. R

2 R3 N

Li,

TH

F, –

40°,

15 m

in

2. O

2, –

78°.

20 m

in; t

o rt

88

R1 C

u(C

N)X

1. R

2 R3 N

Li,

TH

F, te

mp,

tim

e

2. A

dden

d, T

HF,

–78

°3.

O2,

–78

°, 30

min

R1 N

R2 R

3

R1

Me

n-B

u

n-B

u

n-B

u

n-B

u

R2

Ph H Me

i-Pr

Ph

R2

Bn

Ph Bn

i-Pr

Ph

Add

end

1,2-

(O2N

) 2C

6H4

none

1,2-

(O2N

) 2C

6H4

none

Cu(

NO

3)2

Tem

p

–78°

to –

40°

–78°

to –

40°

–78°

to –

40°

–78°

to –

40°

–40°

Tim

e

40 m

in

40 m

in

40 m

in

40 m

in

20 m

in

(60)

(70)

(57)

(85)

(60)

55

C1-

4

RM

(x

eq)

See

tabl

e.R

NH

2 +

R2N

H

C1-

8

R Me

Me

Et

Et

Et

Et

n-Pr

n-Pr

n-Pr

i-Pr

i-Pr

n-B

u

n-B

u

n-B

u

n-B

u

n-B

u

n-B

u

s-B

u

s-B

u

M Li

MgB

r

MgC

l

MgC

l

ZnE

t

ZnE

t

MgC

l

ZnP

r-n

ZnP

r-n

MgC

l

MgC

l

Li

MgC

l

MgB

u-n

MgC

l

MgC

l

MgC

l

MgC

l

MgC

l

x 1

exce

ss

exce

ss

4

exce

ss

exce

ss

exce

ss

exce

ss

exce

ss

exce

ss

4 3 1

3 or

mor

e

4

exce

ss

exce

ss

exce

ss

4

Rea

gent

NH

2Cl

NH

2Cl

NH

2Cl

NC

l 3

NH

2Cl

NC

l 3

NH

2Cl

NH

2Cl

NC

l 3

NH

2Cl

NC

l 3

NH

2Cl

NH

2Cl

NH

2Cl

NC

l 3

NH

2Br

NH

Br 2

NH

2Cl

NC

l 3

Con

ditio

ns

Et 2

O, 0

°E

t 2O

, 0°

Et 2

O, 0

°E

t 2O

petr

ol e

ther

, –30

°; r

t, ov

erni

ght

petr

ol e

ther

, –30

°; r

t, ov

erni

ght

Et 2

O, 0

°pe

trol

eth

er, –

30°;

rt,

over

nigh

t

petr

ol e

ther

, –30

°; r

t, ov

erni

ght

Et 2

O, 0

°E

t 2O

Et 2

O, –

50°

petr

ol e

ther

, 0°;

rt,

over

nigh

t

Et 2

O, d

ioxa

ne, –

60°

Et 2

O

E2O

, 2-3

°E

t 2O

, 0°

Et 2

O, 0

°E

t 2O

(4)

(26)

(57)

(29)

(46)

(17)

(58)

(57)

(8)

(66)

(23)

(39)

(57)

(97)

(37)

(29)

(15)

(70)

(23)

(—)

(—)

(—)

(6)

(—)

(—)

(—)

(—)

(—)

(—)

(2)

(—)

(—)

(—)

(5)

(—)

(5)

(—)

(3)

58 56 56, 5

8

77, 5

8

58 58 58,5

6

58

58 57 77 58 59, 5

6, 5

8

59 77, 5

8

61 75 57 77

X ZnC

l

ZnC

l

ZnC

l

ZnC

l

Li

89

Subs

trat

eR

efs.

Con

ditio

nsPr

oduc

t(s)

and

Yie

ld(s

) (%

)

TA

BL

E 1

A. A

CY

CL

IC A

LIP

HA

TIC

CA

RB

AN

ION

S (C

onti

nued

)

R s-B

u

s-B

u

t-B

u

t-B

u

t-B

u

n-C

5H11

i-C

5H11

s-C

5H11

t-C

5H11

Ph(C

H2)

2

Ph(C

H2)

2

Ph(C

H2)

2

M MgC

l

MgC

l

MgC

l

MgC

l

MgC

l

MgC

l

MgC

l

MgC

l

MgC

l

MgC

l

MgC

l

MgC

l

x

exce

ss

exce

ss

exce

ss

4

exce

ss

4

exce

ss

exce

ss

exce

ss

exce

ss

4

exce

ss

Rea

gent

NH

2Br

NH

Br 2

NH

2Cl

NC

l 3

NH

2Br

NC

l 3

NH

2Cl

NH

2Cl

NH

2Cl

NH

2Cl

NC

l 3

NH

Br 2

Con

ditio

ns

Et 2

O, 2-

3°E

t 2O

, 2-3

°E

t 2O

, 0°

Et 2

O

Et 2

O, 2

-3°

Et 2

O

Et 2

O, 0

°E

t 2O

, 0°

Et 2

O, 0

°E

t 2O

, 0°

Et 2

O

Et 2

O, 2

-3°

(46)

(21)

(60)

(30)

(45)

(21)

(55)

(72)

(66)

(74)

(20)

(18)

(—)

(5)

(—)

(2)

(—)

(5)

(—)

(—)

(—)

(—)

(2)

(3)

61 75 57 77 61 77 56 57 57 56 77 75

R1 N

HB

zR

1 M1.

R2 O

NH

Li (

2 eq

, ia)

, Et 2

O, –

78° t

o –1

5°, 2

h

2. B

zCl

R1

Me

Et

n-B

u

n-B

u

n-B

u

i-B

u

s-B

u

s-B

u

s-B

u

s-B

u

t-B

u

(80)

(78)

(77)

a

(95)

(16)

(67)

(71)

(19)

(58)

(18)

(80)

82, 7

86

82, 7

86

82, 7

86

82 83, 7

86

82, 7

86

82, 8

3

83 83 83 82, 7

86

M Li

Li

Li

Li

MgB

r

Li

Li

MgB

r

CuL

i

Me 2

ZnL

i

Li

R2

Me

Me

Me

CH

2CH

=C

H2

Me

Me

Me

Me

Me

Me

Me

C1-

8

C1-

4

RM

x e

q

See

tabl

e.R

NH

2 +

R2N

H

90

C1-

4

RM

1T

sON

CO

2Bu-

t (M

2 )+R

NH

CO

2Bu-

t

R Me

n-B

u

n-B

u

n-B

u

s-B

u

s-B

u

s-B

u

M2

Li

Li

Li

MgC

l

Li

Li

MgC

l

M1

Li

Li

(CuL

i)0.

5

(CuL

i)0.

5

Li

(CuL

i)0.

5

(CuL

i)0.

5

Tim

e

2 h

3 h

1.5

h

1.5

h

3 h

1.5

h

1.5

h

Tem

p

–78°

to –

30°

–78°

to –

40°

–78°

–78° 0° –78°

–78°

(60)

(71)

(62)

(70)

(42)

(32)

(57)

126

127,

126

127

127

127,

126

127

127

R1 M

2 SO2O

N(R

R3 ) 2

(ia)

, Et 2

O o

r E

t 2O

/TH

FR

1 N(R

3 ) 2

R1

Me

Me

n-B

u

Ph(C

H2)

2

R3

Me

Et

Me

Me

R2

2,4,

6-M

e 3C

6H2

Ph Ph Me

RM

X

X n

ot s

peci

fied

(ia)

, Et 2

OC

O2

R Me

Et

n-Pr

n-Pr

i-Pr

i-Pr

i-B

u

t-B

u

M Cd

Mg

Mg

Cd

Mg

Cd

Mg

MgC

O2

N

PhH

RC

O2

N H

PhH

R

III

+16

1

I +

II

(55-

70)

(45-

55)

(45-

55)

(55-

70)

(45-

55)

(55-

70)

(45-

55)

(45-

55)

I:II

0:10

0b

95:5

96:4

0:10

0b

60:4

0

0:1

00b

96:4

0:10

0

(45)

(39)

(47)

(70)

M Li

Li

Li

MgB

r

Tem

p, T

ime

–10°

to –

20°;

to r

t, 15

h

–10°

to –

20°;

to r

t, 15

h

–10°

to –

20°;

to r

t, 15

h

–30°

to 0

°

133

133

133

134

C1-

8

C1-

4

– N

PhH

Pr-i

91

Subs

trat

eR

efs.

Con

ditio

nsPr

oduc

t(s)

and

Yie

ld(s

) (%

)

TA

BL

E 1

A. A

CY

CL

IC A

LIP

HA

TIC

CA

RB

AN

ION

S (C

onti

nued

)

C1-

14

RM

gBr

4-M

eOC

6H4N

(R)C

H(C

O2E

t)2

I

4-M

eOC

6H4N

HR

II

167,

166

R Me

Et

n-Pr

i-Pr

n-B

u

t-B

u

c-C

6H11

CH

2

Ph(C

H2)

2

n-C

10H

21

n-C

12H

25

n-C

14H

29

Tem

p

–78°

–78°

–78°

–95°

–78°

–95°

–78°

–78°

–78°

–78°

–78°

I

(98)

c

(91)

c

(81)

c

(86)

c

(98)

c

(56)

(93)

c

(86)

c

(78)

c

(94)

c

(79)

c

IId

(63)

(93)

(79)

(68)

(98)

(0)

(91)

(89)

(79)

(84)

(71)

R1 M

gIR

2 R3 C

=N

2, E

t 2O

R1

Me

Me

Me

Me

Et

R2

EtO

2C

CN

Ph Ph EtO

2C

R3

H CN

Ph Bz

H

(30)

(60)

(84)

(—)

(—)

C1-

2

R2 R

3 C=

NN

HR

1

C1

MeL

i1.

ZnC

l 2, T

HF,

0° t

o rt

2.

(ia

), N

i(ac

ac) 2

(ca

t), 2

h

NO

CH

O

NH

Me

(70)

170

199

203

202

201

199

1. 4

-MeO

C6H

4N=

C(C

O2E

t)2,

TH

F, te

mp,

30

min

(fo

rms

I)

2. A

ir, K

OH

, H2O

, EtO

H (

form

s II

)

92

Fe

MeL

iN

2

O

, Et 2

O, c

oolin

gN

NH

Me

O

(—)

201

C1

MeL

i

N2

1.

(

ia),

Et 2

O

2. F

eCl 3

N=

NM

e

N=

NM

e

787

(—)

RM

X1

ArN

2+ (X

2 )–Ph

N=

NR

C1-

6

X1

I I I Br

Br

Br

Cl

— — — Cl

Br

Solv

ent

Et 2

O

Et 2

O

Et 2

O

Et 2

O

Et 2

O

Et 2

O

E2O

TH

F

TH

F

TH

F

TH

F

TH

F

Tem

p

refl

ux

refl

ux

refl

ux

refl

ux

refl

ux

refl

ux

–10°

–78°

–78°

–78°

–78° 0°

(15)

e

(7)e

(5)e

(15)

e

(5)e

(10)

e

(40)

(71)

(83)

(78)

(40)

(0)

184

184

184

184

184

184

192

191

191

191

185

190

X2

Cl

Cl

Cl

Cl

Cl

Cl

BF 4

f f f BF 4

BF 4

M Mg

Mg

Mg

Mg

Mg

Mg

Zn

Mg

Mg

Mg

Mg

Zn(

C6H

11-n

) 2

Ar

Ph 1-na

phth

yl

2-na

phth

yl

Ph 1-na

phth

yl

2-na

phth

yl

Ph Ph 4-C

lC6H

4

4-M

eOC

6H4

Ph Ph

R Me

Me

Me

Et

Et

Et

t-B

u

t-B

u

t-B

u

t-B

u

t-B

u

n-C

6H11

Tim

e

15 m

in

15 m

in

15 m

in

15 m

in

15 m

in

15 m

in

22 h

1 hg

1 hg

1 hg

— 1 h

93

Subs

trat

eR

efs.

Con

ditio

nsPr

oduc

t(s)

and

Yie

ld(s

) (%

)

TA

BL

E 1

A. A

CY

CL

IC A

LIP

HA

TIC

CA

RB

AN

ION

S (C

onti

nued

)

R1 M

N3

R1 N

HN

=N

R2

an

d/or

h R

1 N=

N-N

HR

2

R1

Me

Me

Me

Me

Me

Me

Me

Me

Me

Me

M Li

MgC

l

MgB

r

MgI

MgB

r

Li

MgI

MgI

MgI

MgI

R2

R2

Me

Me

Me

Me

n-B

u

(CH

2)2O

TB

DM

S (i

a)

4-B

rC6H

4

Ph 4-M

eC6H

4

4-E

tC6H

4

Solv

ent

pent

ane

Et 2

O

Et 2

O

Et 2

O

Et 2

O

Et 2

O

Et 2

O

Et 2

O

Et 2

O

Et 2

O

Tem

p, T

ime

0°, 1

h

–40°

; –10

°, 30

min

; to

rt

–40°

; 0°,

30 m

in; t

o rt

–20°

; to

rt; r

eflu

x, 2

0 m

in

0° to

rt,

2 h

–20°

; to

rt, 2

h

refl

ux, 0

.5 h

refl

ux, 0

.5 h

refl

ux, 3

0 m

in

refl

ux, 3

0 m

in

(60)

(—)

(—)

(—)

(85)

(70)

(—)

(75)

(—)

(—)

258,

256

257

257

257

261

268

280

270,

285

280

280

C1-

10

94

R1

Me

Me

Me

Et

Et

Et

Et

Et

n-Pr

i-Pr

n-B

u

n-B

u

n-B

u

t-B

u

t-B

u

c-C

3H5C

H2

i-C

5H11

i-C

5H11

n-C

6H13

4-cy

cloh

exen

ylm

ethy

l

n-C

8H17

Ph(C

H2)

2

Ph(C

H2)

2

Ph(C

H2)

2

Ph(C

H2)

2

4-M

eOC

6H4(

CH

2)2

PhC

(Me)

2CH

2

M MgB

r

MgB

r

MgI

MgB

r

Al 1

/3

Al 1

/3

MgI

MgB

r

MgB

r

MgB

r

Li

Li

MgB

r

MgC

l

MgC

l

Li

MgB

r

MgB

r

MgB

r

MgB

r

MgB

r

MgB

r

MgB

r

MgB

r

MgB

r

MgB

r

MgB

r

R2

Bn

1-na

phth

yl

PhSO

2 (i

a)

Et

n-B

u

Ph Ph 1-na

phth

yl

1-na

phth

yl

i-Pr

n-B

u

Bn

1-na

phth

yl

PhSO

2 (i

a)

PhSC

H2

(ia)

c-C

3H5C

H2

(ia)

Ph 1-na

phth

yl

PhSO

2 (i

a)

PhSC

H2

(ia)

PhSC

H2

(ia)

MeS

CH

2 (i

a)

PhSC

H2

(ia)

4-M

eOC

6H4S

CH

2 (i

a)

4-M

eC6H

4SO

2

PhSC

H2

4-M

eC6H

4SO

2

Solv

ent

Et 2

O

Et 2

O

Et 2

O

Et 2

O

petr

ol e

ther

petr

ol e

ther

Et 2

O

Et 2

O

Et 2

O

pent

ane

TH

F

pent

ane

Et 2

O

Et 2

O

TH

F

pent

ane

Et 2

O

Et 2

O

Et 2

O

TH

F

TH

F

TH

F

TH

F

TH

F

TH

F

Et 2

O

TH

F

Tem

p, T

ime

refl

ux, 2

5 m

in

0° to

rt,

2 h

—

0°, 1

h

40°,

10 h

rt, 1

d

refl

ux, 3

0 m

in

refl

ux, 2

5 m

in

refl

ux, 2

5 m

in

0° to

rt,

2 h

0°, 1

h

0° to

rt,

2 h

refl

ux, 2

5 m

in

—

–78°

; to

–20°

, 2.5

h

–70°

, 30

min

refl

ux, 2

5 m

in

refl

ux, 2

5 m

in

— –78°

–78°

, 1 h

; to

rt

0°, 2

h

–78°

, 1.7

5 h;

to 0

°, 30

min

–78°

, 1.7

5 h;

to 0

°, 30

min

0°–7

8°, 2

h

0°

(95)

(80)

(—)

(45)

(60)

(50)

(55)

(53)

(54)

(12)

(>88

)

(91)

(65)

(—)

(96)

(>55

)

(—)

(50-

55)

(—)

(86)

(100

)

(>86

)

(>90

)

(90)

(25)

i

(>73

)j

(25)

i

261,

270

281

306

258

260

260

270

281

281

259

262

261

281

306

274

262

281

281

306

273

274

274

274,

273

274

305

274,

273

305

95

Subs

trat

eR

efs.

Con

ditio

nsPr

oduc

t(s)

and

Yie

ld(s

) (%

)

TA

BL

E 1

A. A

CY

CL

IC A

LIP

HA

TIC

CA

RB

AN

ION

S (C

onti

nued

)

C1

SS

Li

N3

Ph1.

,

TH

F, –

78°;

rt,

2 h

2. H

Cl

SS

NH

2(6

4)27

8

RL

i27

7N

3B

u-t

RH

NN

NB

u-t

R Me

Et

n-B

u

t-B

u

(91)

(—)

(—)

(—)

, E

t 2O

, –78

°; to

rt,

2-12

h

C1-

4

RM

gX X

= C

l or

Br

N

YN

N3

N3

N3

N

YN

N=

NN

HR

N=

NN

HR

RN

HN

=N

, Et 2

O, 1

h

R Me

Et

n-B

u

n-B

u

(60)

(70)

(52)

(—)

788

RM

gBr

PhC

OC

H2N

3, E

t 2O

789

RN

NN

HR

PhH

OR M

e

Et

n-B

u

(93)

(95)

(64)

C1

MeL

iY

N3

N3

, Et 2

OY

RR

Y =

O, C

H2

; R =

N=

NN

HM

e

(—)

290

Y CH

CH

CH

N

96

C1-

5

RM

gXN

3–Y

–N3,

Et 2

O27

2

R Me

Me

Et

Et

n-Pr

n-Pr

i-Pr

i-Pr

n-B

u

n-B

u

n-B

u

n-B

u

i-C

5H11

i-C

5H11

Y (CH

2)2

(CH

2)2

(CH

2)2

(CH

2)2

CH

2CH

Me

(CH

2)3

(CH

2)2

X I I Br

Br

Br

Br

Br

Br

Br

Br

Br

Br

Br

Br

(92)

(80)

(41)

(80)

(—)

(76)

(72)

(70)

(71)

(87)

(65)

(72)

(61)

(78)

NY

NN

NH

Rh

NR

HN

97

Subs

trat

eR

efs.

Con

ditio

nsPr

oduc

t(s)

and

Yie

ld(s

) (%

)

TA

BL

E 1

A. A

CY

CL

IC A

LIP

HA

TIC

CA

RB

AN

ION

S (C

onti

nued

)

RM

gX

X

not

spe

cifi

edNS

N3

NSR

HN

N=

N

, Et 2

O, 1

0-12

h

R Me

Et

n-Pr

i-Pr

n-B

u

i-B

u

n-C

5H11

i-C

5H11

(78)

(68)

(23)

(57)

(28)

(40)

(38)

(62)

790

C1-

5

C2-

3

(R1 ) 2

Zn

R2 N

Cl 2

, pet

rol e

ther

, col

d

R2

Me

Et

n-B

u

i-C

5H11

n-B

u

(46)

(42)

(43)

(42)

(24)

R2 N

H2

+

R

2 NH

R1

R1

Et

Et

Et

Et

n-Pr

72

(44)

(49)

(57)

(52)

(61)

C2

Et 2

Zn

EtN

Cl 2

, Et 2

O, 0

°E

t

Et3N

(35

)

+

EtN

H2

(—)

76

Et 2

NC

l, pe

trol

eth

er, c

old

2NH

(70

)

+

Et 3

N (

2)72

98

R1 M

gX1

1. R

2 ON

H2,

sol

vent

, tem

p (f

orm

s I)

2. H

X2

(for

ms

II)

R1 N

H2

I

R1 N

H3X

2 II

R1

Et

Et

n-Pr

n-B

u

n-B

u

i-B

u

s-B

u

t-B

u

n-C

5H11

i-C

5H11

i-C

5H11

i-C

5H11

i-C

5H11

t-C

5H11

4-(1

-pen

teny

l)

Ph(C

H2)

2

X1

Br

Br

Br

Cl

Br

Br

Cl

Cl

Br

Cl

Br

I Br

Br

Cl

Cl

R2

Me

Bn

Me

Me

Me

Me

Me

Me

Me

Me

Me

Me

Bn

Me

Me

Me

X2

Cl

Cl

Cl

— — — Cl

Cl

— Cl

Cl

Cl

Cl

— — —

I

(—)

(—)

(—)

(58)

(63)

(90)

(—)

(—)

(65)

(—)

(—)

(—)

(—)

(48)

(—)

(68)

II (81)

(46)

(85)

(—)

(—)

(—)

(73)

(74)

(—)

(80)

(71)

(5)

(61)

(—)

(—)

(—)

791,

792

80 791

791

791

791

792

791,

792

791

791

791

792

80 791

793

791

C2-

8

Solv

ent

Et 2

O

Et 2

O

Et 2

O

Et 2

O

Et 2

O

Et 2

O

Et 2

O

Et 2

O

Et 2

O

Et 2

O

Et 2

O

Et 2

O

Et 2

O

Et 2

O

— Et 2

O

Tem

p

–10

° to

–15°

–10

° to

–15°

–10

° to

–15°

–10

° to

–15°

–10°

to –

15°

–10°

to –

15°

–10°

to –

15°

–10°

to –

15°

–10°

to –

15°

–10°

to –

15°

–10°

to –

15°

–10°

to –

15°

–10°

to –

15°

–10°

to –

15°

—

–10°

to –

15°

R1

ZrC

pCl

k2,

4,6-

Me 3

C6H

2SO

2ON

H2,

Et 2

O, 0

°, 10

min

116

C2-

10

R1

TM

S

TM

SCH

2

Cl(

CH

2)3

Et

n-C

6H13

Ph Ph(C

H2)

2

R2

R1

NH

2

R2

R2

H H H i-Pr

H H H

(81)

(76)

(78)

(85)

(77)

(60)

l

(80)

99

Subs

trat

eR

efs.

Con

ditio

nsPr

oduc

t(s)

and

Yie

ld(s

) (%

)

TA

BL

E 1

A. A

CY

CL

IC A

LIP

HA

TIC

CA

RB

AN

ION

S (C

onti

nued

)

Bn 2

NO

Bz

+ C

uCl 2

(2.

5 m

ol%

, ia,

slo

w a

dditi

on),

TH

F, r

t, 15

min

RN

Bn 2

113

R Et

t-B

u

C2-

4

(95)

(88)

X Br

Cl

RM

gX

(R1 ) 2

Zn

1.1

eq

R2 R

3 NO

Bz,

cat

alys

t, T

HF,

rt

R1 R

2 R3 N

R1

Et

i-Pr

t-B

u

t-B

u

t-B

u

R2

Bn

Bn

t-B

uCH

2CM

e 2

Bn

Bn

Cat

alys

t

(CuO

Tf)

2•Ph

H

(CuO

Tf)

2•Ph

H

CuC

l 2

CuC

l 2

(CuO

Tf)

2•Ph

H

R3

Bn

Bn

H Bn

Bn

Tim

e

1 h

1 h

15-6

0 m

in

15 m

in

1 h

(91)

(77)

(43)

(99)

(98)

109,

112

109,

112

112

109

109,

112

C2

Et 2

Zn

R1 N

=C

HC

O2R

2 , pen

tane

, –80

° to

rt

R1 =

i-Pr

, t-B

u; R

2 = M

e, E

tN

R1

NC

O2R

2

OR1

Et

(80-

90)

163

1. t-

BuN

=C

HC

OM

e, h

exan

e, –

100°

2. C

H2C

l 2, H

2Ot-

Bu

NC

OM

e

Et

(80)

162

R1 N

NR

1R

2

R3

1.

, hex

ane,

rt

2. t-

BuO

H

NE

tR1

R1 E

tN R2

R3

171

R1

i-Pr

i-Pr

t-B

u

t-B

uCH

2

c-C

6H11

c-C

6H11

(i-P

r)2C

H

R2

H H H H H Me

H

R3

H Me

H H H Me

H

(—)

(—)

(88)

(—)

(—)

(—)

(—)

100

C2-

4

R1 M

165

R2 C

F 2N

R3

CO

2Et

NR

1 R3

CO

2Et

R2

FC

F 3

CO

2Et

NH

R3

R1

NR

1 R3

CO

2Et

+

R1

Et

Et

Et

Et

Et

Et

Et

Et

n-B

u

M MgB

r

ZnE

t

ZnE

t

ZnE

t

ZnE

t

ZnE

t

ZnE

t

ZnE

t

Li

R2

F F F F F F F C2F

5

F

R3

4-M

eOC

6H4

4-M

eOC

6H4

Ph 4-C

lC6H

4

2-E

tC6H

4

2,6-

Me 2

C6H

3

PhC

HM

e

4-M

eOC

6H4

4-M

eOC

6H4

Solv

ent

Et 2

O

tolu

ene

tolu

ene

tolu

ene

tolu

ene

tolu

ene

tolu

ene

tolu

ene

tolu

ene

Tim

e

30 s

30 s

30 s

30 s

30 s

30 s

30 s

2 m

in

30 s

R1

F

+

III

III

I

(50)

(88)

(80)

(84)

(65)

(1)

(85)

(77)

(0)

II (0)

(1)

(—)

(—)

(—)

(—)

(—)

(—)

(80)

III

(15)

(0)

(—)

(—)

(—)

(—)

(—)

(—)

(0)

R1 L

i, T

HF,

hex

ane,

–78

°, 2

h; to

rt

168

NR

2

R3

R3

R3

R2 H

NR

1R

1 R2 N

H

+

R1

Et

n-B

u

n-B

u

n-B

u

n-B

u

n-B

u

n-B

u

n-B

u

n-B

u

n-B

u

R2

n-B

u

Me

n-B

u

n-B

u

i-B

u

Ph 4-M

eC6H

4

4-M

eOC

6H4

Ph(C

H2)

2

Ph(C

H2)

4

R3

H H H Me

H H H H H H

(65)

(71)

(70)

(0)

(41)

(15)

(17)

(19)

(80)

(62)

(5)

(0)

(0)

(—)

(16)

(50)

(52)

(47)

(5)

(15)

Tem

p

rt rt rt rt rt rt rt

100°

80°

101

Subs

trat

eR

efs.

Con

ditio

nsPr

oduc

t(s)

and

Yie

ld(s

) (%

)

TA

BL

E 1

A. A

CY

CL

IC A

LIP

HA

TIC

CA

RB

AN

ION

S (C

onti

nued

)

RM

gX

1. [

3,5-

(CF 3

) 2C

6H3]

2C=

NO

Ts

(ia)

, Et 2

O, t

olue

ne, r

t, 0.

5 h

2. H

Cl,

Me 2

CO

3. B

zCl,

Et 3

N

RN

HB

z17

9

R Et

t-B

u

Ph(C

H2)

3

X Br

Cl

Br

(87)

(35)

(96)

m

C2-

9

R1 M

Br

R2 C

ON

=N

R3

NN

R1

R3

H

R2 C

O

R1

Et

Et

n-Pr

i-Pr

i-B

u

t-B

u

i-C

5H11

Me 2

(Et)

C

MeC

O2(

CH

2)4

5-C

l(C

H2)

2

4-N

C(C

H2)

4

EtO

2C(C

H2)

5

2-oc

tyl

M Mg

Mg

Mg

Mg

Mg

Mgn

Mg

Zn

Mg

Zn

Zn

Zn

Zn

Zn

R2

Ph Ph Ph Ph Ph t-B

uO

Ph t-B

uO

CH

2=C

HC

H2O

t-B

uO

t-B

uO

t-B

uO

t-B

uO

t-B

uO

R3

Ph Bz

Bz

Bz

Bz

CO

2Bu-

t (ia

)

Bz

CO

2Bu-

t

CO

2CH

2CH

=C

H2

(ia)

CO

2Bu-

t

CO

2Bu-

t

CO

2Bu-

t

CO

2Bu-

t

CO

2Bu-

t

(25)

(—)

(—)

(poo

r)

(—)

(26)

(40)

(75)

(55)

(90)

(81)

(90)

(90)

(94)

Solv

ent

Et 2

O

Et 2

O

Et 2

O

Et 2

O

Et 2

O

Et 2

O

Et 2

O

TH

F

TH

F

TH

F

TH

F

TH

F

TH

F

TH

F

794

794

794

794

794

795

794

358

735

358

358

358

358

358

Tem

p, T

ime

rt rt rt rt rt

0°, 1

5 m

in; r

t, 10

h

rt

rt, 3

0 m

in

–78°

to r

t

rt, 3

h

rt, 3

h

rt, 1

h

rt, 3

h

rt, 3

h

C2-

8

TM

SCC

(CH

2)2

RM

t-B

uO2C

NN

CO

NN

NH

CO

N

t-B

uO2C

NH

N

R

t-B

uO2C

I

+

II

410

CO

R

N

C2-

4

, –78

°, so

lven

t, 1

h

102

RM

Et 2

AlC

l

Et 2

Zn•

TiC

l 4

n-B

uLi

Solv

ent

CH

2Cl 2

CH

2Cl 2

Et 2

O

I

(100

)

(—)

(65)

II (0)

(64)

(23)

RM

gX

X n

ot s

peci

fied

ArN

3 (i

a), E

t 2O

, rt

ArN

HR

279

R Et

Et

n-Pr

n-Pr

i-Pr

i-Pr

i-Pr

i-Pr

n-B

u

n-C

5H11

n-C

7H15

n-C

8H17

n-C

10H

21

n-C

12H

25

Ar

Ph MeC

6H4

4-FC

6H4

(3-O

CH

2-4)

C6H

3

3,4-

Cl 2

C6H

3

4-M

eOC

6H4

3,4-

(MeO

) 2C

6H3

2-na

phth

yl

MeC

6H4

2-na

phth

yl

4-C

lC6H

4

4-M

eOC

6H4

2-na

phth

yl

4-C

lC6H

4

(90)

(89)

(82)

(88)

(85)

(88)

(87)

(88)

(87)

(87)

(84)

(90)

(88)

(85)

C2-

12

Tim

e

30 m

in

30 m

in

1 h

30 m

in

1 h

1 h

30 m

in

1 h

30 m

in

1 h

1 h

30 m

in

1 h

1.5

h

EtM

gBr

4-N

3C6H

4CO

Me,

Et 2

O(—

)28

3

N3

N3 , E

t 2O

, –20

°(5

8)

EtN

HN

=N

N=

NN

HE

th

289

C2

OH

Et

EtN

HN

=N

103

Subs

trat

eR

efs.

Con

ditio

nsPr

oduc

t(s)

and

Yie

ld(s

) (%

)

TA

BL

E 1

A. A

CY

CL

IC A

LIP

HA

TIC

CA

RB

AN

ION

S (C

onti

nued

)

R1 M

gCl

R1 R

2 NH

+ (

R1 ) 2

NR

2 + R

2 NH

2

R1

n-Pr

n-B

u

n-B

u

n-C

5H11

R2

Et

Me

Et

Et

(12)

(22)

(11)

(12)

(8)

(5)

(9)

(8)

(52)

(43)

(36)

(34)

68R

2 NC

l 2, E

t 2O

, 5°,

1 h

C3-

5

C3-

4

R1 M

(R2 ) 2

NC

l(R

2 ) 2N

H +

R1 (R

2 ) 2N

+ (

R2 ) 2

NN

(R2 ) 2

R1

i-Pr

n-B

u

R2

i-Pr

n-B

u

(—)

(85)

Solv

ent

petr

ol e

ther

Et 2

O

(3)

(4)

(4.5

)

(0)

70 68

C3-

8

Ph2P

(O)O

NH

2, T

HF

RN

H2

C3

i-Pr

MgC

l

NH

O

t-B

ut-

Bu

, Et 2

O

NPr

-i

O

t-B

ut-

Bu

(35)

169

R i-Pr

n-B

u

Ph(C

H2)

2

X Cl o

r B

r

Cl o

r B

r

Br

RM

gX

Tem

p

–78°

; to

rt

–78°

; to

rt

–20°

; rt,

12 h

(36)

m

(50)

m

(40)

140

140

139

Tem

p

rt,

then

ref

lux

5°

M K MgC

l

Tim

e

— 1 h

104

C3-

10

RZ

nX1.

ArN

=N

Ts,

TH

F, –

20°

2. R

aney

Ni,

EtO

H, r

eflu

x

ArN

HR

356

R EtO

2C(C

H2)

2

n-C

5H11

n-C

8H17

PhC

(Me)

2CH

2

PhC

(Me)

2CH

2

X EtO

2C(C

H2)

2

I I Br

Br

(45)

(55)

(52)

(79)

(0)q

Ar

4-M

eOC

6H4

4-E

tO2C

C6H

4

4-E

tO2C

C6H

4

4-E

tO2C

C6H

4

3,5-

(CF 3

) 2C

6H3

C3-

8

RM

gX

1. (

4-C

F 3C

6H4)

2C=

NO

Ms

+ C

uCN

•2 L

iCl (

ia),

TH

F, H

MPA

, 0°,

30 m

in

2. H

3O+

RN

H2

179,

726

R i-Pr

n-B

u

t-B

u

3,4-

(TB

SO) 2

C6H

3(C

H2)

2

(93)

o

(96)

o

(61)

o

(87)

p

X Br

Cl

Cl

Br

105

Subs

trat

eR

efs.

Con

ditio

nsPr

oduc

t(s)

and

Yie

ld(s

) (%

)

TA

BL

E 1

A. A

CY

CL

IC A

LIP

HA

TIC

CA

RB

AN

ION

S (C

onti

nued

)

R2

R1

R3

R2

R1

R3 E

R5

R4

R4

R5

R2

R1

R3

R4

R5

E+

III

E =

N(C

O2B

u-t)

NH

CO

2Bu-

t

HH

Con

ditio

ns 1

: 1. C

atal

yst A

(se

e C

hart

1; 5

mol

%),

EtO

H, r

t

2

. Sub

stra

te, t

hen

PhSi

H3

3

. t-B

uO2C

N=

NC

O2B

u-t,

rt, t

ime

Con

ditio

ns 2

: 1. C

atal

yst B

(se

e C

hart

1; 2

mol

%),

i-Pr

OH

, 0°

2

. Sub

stra

te, t

hen

PhSi

H3,

0°

3

. t-B

uO2C

N=

NC

O2B

u-t,

0°, t

ime

C3-

10

R1

H H H H H Me

H H Me

Et

Et

H Me

Me

H H H

R2

H H H H H H H H Me

H H H Me

Me

H H H

R3

H H H H H H H H H H H Me

Me

Me

H H H

R4

OH

OB

n

OM

e

CH

2OH

CH

2OH

OH

OH

CH

2Br

OH

Me

Me

Et

H H CH

2CO

Me

CH

2Ph

CH

2Ph

R5

H H OM

e

H H H Me

H H H H H H H H H H

Con

ditio

ns

1 1 1 1 2 2 1 1 1 1 2 1 1 2 1 1 2

I

(78)

(76)

(70)

(22)

(72)

(32)

(73)

dr

1:1

(90)

(—)

(16)

(66)

(88)

(14)

(78)

(76)

(85)

(76)

215

215

215

796

215

215

215

215

215

796

215

215

215

215

215

215

215

II (—)

(—)

(—)

(—)

(—)

(58)

(—)

(—)

(70)

(—)

(—)

(—)

(—)

(—)

(—)

(—)

(18)

Tim

e

3 h

3 h

7 h

12 h

2.5

h

2 h

5 h

5 h

8 h

10 h

3 h

5 h

10 h

3 h

3 h

4 h

2.5

106

R2

R1

R3

R4

R1

H H H H H H H H H H H H H H H H H CH

2OT

BD

PS

CH

2OT

BD

PS

CH

2OT

BD

PS

CH

2OT

BD

PS

R2

H H H H H H H H H H H H H H H H H H H H H

R5

4-M

eC6H

4

4-M

eC6H

4

2-M

eO-5

-MeC

6H3

2-M

eO2C

C6H

4

4-M

eC6H

4

4-M

eC6H

4

2-M

eO-5

-MeC

6H3

2-M

eO2C

C6H

4

4-M

eC6H

4

4-M

eC6H

4

4-M

eC6H

4

4-M

eC6H

4

2-M

eO-5

-MeC

6H3

2-M

eO2C

C6H

4

4-M

eC6H

4

2-M

eO-5

-MeC

6H3

2-M

eO2C

C6H

4

4-M

eC6H

4

4-M

eC6H

4

2-M

eO-5

-MeC

6H3

2-M

eO2C

C6H

4

Sila

ne

PhSi

H3

(Me 2

SiH

) 2O

(Me 2

SiH

) 2O

(Me 2

SiH

) 2O

PhSi

H3

(Me 2

SiH

) 2O

(Me 2

SiH

) 2O

(Me 2

SiH

) 2O

PhSi

H3

(Me 2

SiH

) 2O

PhSi

H3

(Me 2

SiH

) 2O

(Me 2

SiH

) 2O

(Me 2

SiH

) 2O

(Me 2

SiH

) 2O

(Me 2

SiH

) 2O

(Me 2

SiH

) 2O

PhSi

H3

(Me 2

SiH

) 2O

(Me 2

SiH

) 2O

(Me 2

SiH

) 2O

Tim

e

48 h

48 h

— 48 h

2 h

18 h

18 h

18 h

3 h

3 h

— — — — — — — — — — —

I

(35)

(39)

(<20

)

(28)

(55)

(67)

(19)

(44)

(73)

(85)

(73)

(58)

(89)

(91)

(40)

(64)

(76)

(63)

(48)

(83)

(79)

I:II — — — — — — — — — — — — — — — — — — — —

89:1

1

R3

H H H H H H H H H H Me

Me

Me

Me

Me

Me

Me

Me

Me

Me

Me

C3-

14

1. C

o(B

F 4) 3

•6 H

2O (

6 m

ol%

), li

gand

(6

mol

%),

EtO

H, r

t, 10

min

2. S

ubst

rate

3. R

5 SO2N

3, t-

BuO

2H, r

t, 5

min

4. S

ilane

, rt,

time

t-B

uO

H

N

PhPh

OK

O

Lig

and:

215

Bu-

t

R4

CH

2OB

n

CH

2OB

n

CH

2OB

n

CH

2OB

n

CH

2OT

BD

PS

CH

2OT

BD

PS

CH

2OT

BD

PS

CH

2OT

BD

PS

(CH

2)2O

TB

DPS

(CH

2)2O

TB

DPS

CH

2OT

BD

PS

CH

2OT

BD

PS

CH

2OT

BD

PS

CH

2OT

BD

PS

CH

2OB

n

CH

2OB

n

CH

2OB

n

Me

Me

Me

Me

+

III

R2

N3

R1

R4R

3

R2

R1

R4

R3

107

Subs

trat

eR

efs.

Con

ditio

nsPr

oduc

t(s)

and

Yie

ld(s

) (%

)

TA

BL

E 1

A. A

CY

CL

IC A

LIP

HA

TIC

CA

RB

AN

ION

S (C

onti

nued

)

R2

R1

R3

R4

C3-

14

R1

H H H H H H H H H H H H H H Me

Me

H H

R2

H H H H H H H H H H H H H H H H H H

R5

4-M

eC6H

4

4-M

eC6H

4

4-M

eC6H

4

4-M

eC6H

4

4-M

eC6H

4

4-M

eC6H

4

2-M

eO-5

-MeC

6H3

2-M

eO2C

C6H

4

Et

Ph 4-M

eC6H

4

4-M

eC6H

4

4-M

eC6H

4

4-M

eC6H

4

4-M

eC6H

4

4-M

eC6H

4

4-M

eC6H

4

4-M

eC6H

4

R4

(CH

2)2C

O2B

n

(CH

2)2C

O2B

n

CH

2C6H

3-3-

CH

2OC

H2-

4

CH

2C6H

3-3-

CH

2OC

H2-

4

(CH

2)2P

h

(CH

2)2P

h

(CH

2)2P

h

(CH

2)2P

h

(CH

2)2P

h

(CH

2)2P

h

(CH

2)2P

h

(CH

2)2P

h

(CH

2)2C

OPh

(CH

2)2C

OPh

(CH

2)2P

h

(CH

2)2P

h

(CH

2)2-

2-na

phth

yl

(CH

2)2-

2-na

phth

yl

Sila

ne

PhSi

H3

(Me 2

SiH

) 2O

PhSi

H3

(Me 2

SiH

) 2O

PhSi

H3

(Me 2

SiH

) 2O

(Me 2

SiH

) 2O

(Me 2

SiH

) 2O

PhSi

H3

PhSi

H3

PhSi

H3

(Me 2

SiH

) 2O

PhSi

H3

(Me 2

SiH

) 2O

PhSi

H3

(Me 2

SiH

) 2O

PhSi

H3

(Me 2

SiH

) 2O

Tim

e

10 h

10 h

20 h

20 h

2 h

3 h

5 h

4 h

2 h

10 h

3 h

12 h

24 h

24 h

30 h

30 h

8 h

12 h

I

(75)

(77)

(65)

(62)

(90)

(86)

(94)

(91)

(>75

)

(90)

(86)

(90)

(49)

(46)

(66)

(48)

(72)

(69)

I:II

96:4

— — —

89:1

1

— — —

77:2

3

90:1

0

— — — — — — — —

R3

H H H H H H H H H H Me

Me

H H Me

Me

H H

(Tab

le c

onti

nued

from

pre

viou

s pa

ge.)

+

III

215

n-B

uMgC

lM

eNH

Cl,

Et 2

O, 5

°, 1

hn-

BuN

HM

e (1

4) +

MeN

H2

(72

)68

(t-B

u)2M

gt-

BuN

HC

l, di

oxan

e, E

t 2O

, 5°,

2 h;

rt o

vern

ight

(t-B

u)2N

H (

10)

67

C4

R2

N3

R1

R4R

3

R2

R1

R4

R3

108

RL

i

R n-B

u

s-B

u

t-B

u

(0)

(35.

5)

(29.

2)

(71)

(25)

(7.3

)

PhN L

i

OM

e (

ia),

hex

ane,

–78

°; to

rt,

2 h

PhN H

RPh

NH

2

R+

85C

4

R1 L

i1.

R2 N

(Li)

OR

3 (ia

), te

mp,

tim

e

2. A

rCO

Cl

R1 R

2 NC

OA

r

R1

n-B

u

n-B

u

n-B

u

n-B

u

n-B

u

n-B

u

n-B

u

n-B

u

s-B

u

s-B

u

s-B

u

t-B

u

t-B

u

t-B

u

R2

Me

n-Pr

i-Pr

n-C

5H11

i-C

5H11

Bn

PhC

HM

es

Ph(C

H2)

2

Me

Bn

Ph(C

H2)

3

Me

Bn

Ph(C

H2)

3

Ar

Ph Ph Ph Phr

4-M

eOC

6H4r

— — Ph Ph Ph — Ph — —

Solv

ent(

s)

Et 2

O, h

exan

e

Et 2

O, h

exan

e

Et 2

O, h

exan

e

TH

F

TH

F

hexa

ne

Et 2

O, h

exan

e

Et 2

O, h

exan

e

— hexa

ne

hexa

ne

— hexa

ne

hexa

ne

R3

Me

Me

Me

Bn

Bn

Me

Me

Me

Me

Me

Me

Me

Me

Me

(63)

(64)

(47)

(70)

(50)

(68)

t

(68)

t

(68)

(62)

(60)

(66)

t

(30)

(99)

t

(61)

t

83, 8

2, 9

7

83 83 98 98 85 82, 9

7

83 97, 8

2

85, 8

3

85 82 85 85

Tem

p, T

ime

–78

°; to

rt,

3 h

–78

°; to

–15

°, 3

h

–78

°; to

rt,

18 h

0° t

o 40

°, 1-

3 h

0° t

o 40

°, 1-

3 h

–78

°; to

–10

°, 2

h

rt t

o 40

°, 2

h

–78

°; to

rt

—

–78

°; to

–10

°, 2

h

–78

°; to

–10

°, 2

h

—

–78

°; to

–10

°, 2

h

–78

°; to

–10

°, 2

h

RL

i R

= n

-Bu,

s-B

u, t-

Bu

BnN

(Li)

OM

e +

PhC

HM

eN(L

i)O

Me

(1:1

9, ia

), h

exan

e, –

78° t

o –1

0°R

NH

Bn

(—)

85

R1 L

i +

R2 L

iB

nN(L

i)O

Me

(ia)

, hex

ane,

–78

° to

–10°

, 2 h

R1 N

HB

n +

R

2 NH

Bn

85

R1

s-B

u

t-B

u

t-B

u

R2

n-B

u

n-B

u

s-B

u

R1 L

i:R2 L

i

1:9.

8

1:12

.3

1:11

.7

(27)

(29)

(19)

(47)

(50)

(60)

109

Subs

trat

eR

efs.

Con

ditio

nsPr

oduc

t(s)

and

Yie

ld(s

) (%

)

TA

BL

E 1

A. A

CY

CL

IC A

LIP

HA

TIC

CA

RB

AN

ION

S (C

onti

nued

)

R1 L

i(i

a), h

exan

e, –

78°,

3 h;

rt,

1-2

dR

2N O

Me

R3

R4

R5

R2

N R1

R3

R4

R5

R2

N H

R3

R4

R5

+II

85

R1

n-B

u

s-B

u

s-B

u

t-B

u

t-B

u

t-B

u

t-B

u

t-B

u

R2

Ph Ph c-C

6H11

Ph Ph c-C

6H11

Ph Ph

R3

H H H H H H Me

Me

R4

H H H H H H H Me

R5

Ph Ph c-C

6H11

CH

=C

Me 2

Ph c-C

6H11

Ph Ph

I (5)

(47)

(9.5

)

(67)

(72)

(45)

(tra

ce)

(tra

ce)

II

III(5

)

(5)

(—)

(—)

(5)

(—)

(—)

(—)

R1

R2C

u(C

N)L

i 21.

TM

SNH

OT

MS,

TH

F, –

50° t

o rt

, 1 h

2. B

zCl,

pyri

dine

RN

HB

z I

+ R

OH

II

100

(48)

(60)

(80)

(18)

(5)

(10)

R n-B

u

s-B

u

t-B

u

C4

I

RM

gX (

x eq

)

X

not

spe

cifi

ed

Me 2

C=

NO

M, t

olue

neR

NH

217

4a

R n-B

u

Ph(C

H2)

2

Ph(C

H2)

2

(15)

(25)

(48)

x 2 2 1

M H H MgB

ru

C4-

10

RM

gBr

(ia)

, tol

uene

, Et 2

O, –

78°,

15 m

in18

1N

Me

MeN

NO

Ts

NM

eM

eN

NR

vR t-

Bu

Ph(C

H2)

2

Ph(C

H2)

2CH

Me

(<8)

(94)

(96)

110

C4

"4-C

l(C

H2)

4Zn

reag

ents

"M

e 2C

=N

OSO

2C6H

3Me 3

-2,4

,6, C

uCN

(ca

t), T

HF,

rt,

3 h

4-C

l(C

H2)

4NH

2(0

)17

7

RC

u1.

(4-

CF 3

C6H

4)2C

=N

OM

s, T

HF,

HM

PA, t

emp,

tim

e

2. B

zCl,

Et 3

N

RN

HB

z17

9

R n-B

u

s-B

u

t-B

u

Tem

p

–23°

–45°

–23°

(92)

(79)

(60)

Tim

e

30 m

in

1 h

1 h

Bn

RO

2CN

2

Bn

RO

2CN

NH

Bu-

n1.

, T

HF,

–78

°, 20

min

(fo

rms

I)

2. M

eI, –

78°,

3 h;

to r

t, 18

h (

form

s II

)

N=

NB

u-n

Bn

RO

2C

205

III

R Me

Bu

I

(56)

(—)

II (—)

(52)

n-B

uLi

CH

2=N

2, E

t 2O

, rt

(53)

202

1. Z

nCl 2

, TH

F, –

78°,

10 m

in

2. C

uCN

, –30

°3.

Ph 2

NN

HL

i, 30

min

4. O

2, –

78°

(18)

54

t-B

uLi

NN

(ia)

, TH

F, –

78°

N H

NB

u-t

(>90

)20

9

RL

iPh

N=

NPh

, hex

ane

or c

yclo

hexa

ne/T

HF,

–78

°, 2

h; r

t, 10

h

R n-B

u

s-B

u

t-B

u

(88)

(73)

(47)

211,

797

211

211,

798

Me

H NN H

Bu-

n

n-B

u

H NN

Ph2

Ph

R NN H

Ph

111

Subs

trat

eR

efs.

Con

ditio

nsPr

oduc

t(s)

and

Yie

ld(s

) (%

)

TA

BL

E 1

A. A

CY

CL

IC A

LIP

HA

TIC

CA

RB

AN

ION

S (C

onti

nued

)

R1 M

2 O2C

N=

NC

O2R

2

R1

CH

2=C

H(C

H2)

2

CH

2=C

H(C

H2)

3

t-C

5H11

MeC

O2(

CH

2)4

(Z)-

TM

SCH

2CH

=C

H(C

H2)

2

(Z)-

EtC

H=

CH

(CH

2)2

Cl(

CH

2)5

NC

(CH

2)4

EtO

2C(C

H2)

5

2-oc

tyl

M MgX

w

MgX

w

MgX

w

ZnB

r

ZnB

r

MgX

w

MgX

w

ZnB

r

ZnB

r

ZnB

r

ZnB

r

Solv

ent

Et 2

O o

r T

HF

Et 2

O o

r T

HF

Et 2

O o

r T

HF

TH

F

TH

F

Et 2

O o

r T

HF

Et 2

O o

r T

HF

TH

F

TH

F

TH

F

TH

F

Tem

p

–78°

–78°

–78° rt rt

–78°

–78° 0° rt rt rt

(>47

)

(>42

)

(>46

)

(75)

(90)

(>23

)

(>35

)

(81)

(90)

(90)

(94)

799

799

799

358

358

799

799

358

358

358

358

R2

Me

Me

Me

t-B

u

t-B

u

Me

Me

t-B

u

t-B

u

t-B

u

t-B

u

Tim

e

— — —

30 m

in

3 h

— — 3 h

1 h

3 h

3 h

C4-

8

C4

R1 C

u(C

N)M

1. (

R2 ) 2

NN

HL

i, T

HF,

tem

p 1,

tim

e 1

2. A

dden

d

3. O

2, te

mp

2, 3

0 m

in

R1 N

HN

(R2 ) 2

R1

n-B

u

n-B

u

t-B

u

t-B

u

M ZnC

l

ZnC

l

ZnC

l

Li

R2

Me

Ph Ph Ph

Tem

p 1

–78°

to –

40°

–78°

to –

40°

–78°

to –

40°

–40°

Tim

e 1

— — —

30 m

in

Add

end

1,2-

(O2N

) 2C

6H4

1,2-

(O2N

) 2C

6H4

1,2-

(O2N

) 2C

6H4

—

Tem

p 2

— — — –78°

(50)

(34)

(60)

(30)

55 55 55 55, 5

4

n-B

uMgB

r80

0NS

Cl

N3

NS

Cl

NH

2(9

5)1.

,

Et 2

O, r

t, 30

min

2. N

H4C

l, H

2O

CH

C(C

H) 2

R2 O

2CN

N H

CO

2R2

R1

R

112

C5-

10

BrM

g(C

H2)

nMgB

rM

eON

H2,

Et 2

O, –

10° t

o –1

5°, 3

0 m

in2N

(CH

2)nN

H2

791

n 5 6 10

(68)

(51)

(53)

n-B

uM(i

a)80

0NS

PhN

NNNS

PhM L

i

MgB

r

Solv

ent

PhH

Et 2

O

Con

ditio

ns

–10°

to r

t, 1

h; th

en H

2O

rt, 3

0 m

in; r

eflu

x, 3

0 m

in;

then

NH

4Cl,

H2

H

O, N

H3

(—)

(54)

N=

NN

HB

u-n

NN

N CH

2Li

n-B

uMgB

r1.

(ia)

, TH

F, –

78°

2. P

hN=

NPh

, –78

°; to

rt

Ph(n

-C5H

11)N

NH

Ph(3

4)35

9

C5

C6

Mg,

Me 2

NO

SO2C

6H2M

e 3-2

,4,6

, Mg,

TH

F, r

t, 2

h80

1

1. M

g, M

e 2C

=N

OSO

2C6H

2Me 3

-2,4

,6, T

HF,

ref

lux,

3 h

2. B

zCl

(<15

)80

2

E+

1. C

atal

yst A

(se

e C

hart

1; 5

mol

%),

EtO

H, r

t

2. S

ubst

rate

, the

n Ph

SiH

3

3. t-

BuO

2CN

=N

CO

2Bu-

t, rt

, 5 h

(59%

)(<

5%)

215

E =

N(C

O2B

u-t)

NH

CO

2Bu-

t

E

Br

NM

e 2(5

4)

NH

Bz

113

Subs

trat

eR

efs.

Con

ditio

nsPr

oduc

t(s)

and

Yie

ld(s

) (%

)

TA

BL

E 1

A. A

CY

CL

IC A

LIP

HA

TIC

CA

RB

AN

ION

S (C

onti

nued

)

RM

gBr

OO

NO

SO2P

h

1.

,

Et 2

O, C

H2C

l 2, t

emp,

tim

e

2. H

Cl,

EtO

H, H

2O, r

eflu

x, 2

-6 h

RN

H3+

Cl–

182

(90)

(89)

(92)

R Ph(C

H2)

2

PhC

H2C

HM

e

PhC

HM

eCH

2

C8-

9

C8

NO

Bz

O, (

Ph3P

) 2N

iCl 2

(ca

t), T

HF,

rt,

10 m

in to

6 h

(58)

108

Tim

e

15 m

in

1 h

30 m

in

Tem

p

rt 0° 0°

C6-

9

YY

E

Y

EE

Y

E

+

+E

= N

(CO

2Bu-

t)N

HC

O2B

u-t

Con

ditio

ns 1

: 1. C

atal

yst A

(se

e C

hart

1; 5

mol

%),

EtO

H, r

t

2

. Sub

stra

te, t

hen

PhSi

H3

3

. t-B

uO2C

N=

NC

O2B

u-t,

rt, t

ime

Con

ditio

ns 2

: 1. C

atal

yst B

(se

e C

hart

1; 2

mol

%),

i-Pr

OH

, 0°

2

. Sub

stra

te, t

hen

PhSi

H3,

0°

3

. t-B

uO2C

N=

NC

O2B

u-t,

0°, t

ime

III

III

215

Y O O CH

2

CH

2

C(C

O2E

t)2

C(C

O2E

t)2

Con

ditio

ns

1 2 1 2 1 2

Tim

e

15 h

24 h

20 h

15 h

15 h

4 h

I

(<5)

(<5)

(40)

(34)

(<5)

(<5)

II (—)

(—)

(24)

(30)

(—)

(—)

III

(68)

(88)

(8)

(6)

(62)

(93)

III

dr

1.6:

1

2.5:

1

1.4:

1

5:1

7:1

9:1

ZnC

l4

N4

O

114

C8

1. P

hSC

H2N

3 (i

a), T

HF,

–78

°, 1-

4 h

2. A

cyla

ting

reag

ent,

tem

p, 1

h

3. N

H4C

l, H

2O

4. H

ydro

lysi

s

274

Acy

latin

g R

eage

nt

Ac 2

O

BzC

l

Hyd

roly

sis

n-B

u 4N

+ H

CO

2– , DM

F,

45°

, 4 h

50%

KO

H in

H2O

, TH

F,

MeO

H, 0

°, 40

min

(82)

R =

Me

(75)

R =

Ph

1. R

SCH

2N3

(ia)

, TH

F, te

mp,

tim

e

2. N

H4C

l, H

2O

274

R Me

Ph 4-M

eOC

6H4

Tem

p, T

ime

0°, 2

hx

–78°

, 1.7

5 h;

to 0

°, 30

min

–78°

, 2 h

(>86

)

(>90

)

(90)

C10

MgC

l

i-Pr

O2C

N=

NC

O2P

r-iaa

Ph+

i-P

rO2C

NH

NH

CO

2Pr-

i

(82)

(82)

220

1. [

3,5-

(CF 3

) 2C

6H3]

C=

NO

Ts,

tolu

ene,

Et 2

O, –

70°,

10 d

2. A

c 2O

, Et 3

NPh

NH

Ac

220

(25)

90%

ee

1. Z

n, T

HF,

0°

2. t-

BuO

2CN

=N

CO

2Bu-

t, 0°

(94)

z35

7

Ph

2,4,

6-M

e 3C

6H2S

O2O

NH

2, E

t 2O

, 0°,

10 m

in(8

8)11

6

1. P

hSC

H2N

3, T

HF,

–60

°, 1

h

2. A

c 2O

, –60

° to

–30°

3. K

OH

, DM

SO, 0

° to

rt, 3

hPh

NH

Ac

220

(82)

92-

95%

ee

PhM

gBr

PhN

HC

OR

Tem

p

–78°

to –

20°

–78°

to 0

°

Ph

H NN

NR

h

n-C

8H17

Br

n-C

8H17

Nt-

BuO

2CN

HC

O2B

u-t

ZrC

p 2C

l yN

H2

115

Subs

trat

eR

efs.

Con

ditio

nsPr

oduc

t(s)

and

Yie

ld(s

) (%

)

TA

BL

E 1

A. A

CY

CL

IC A

LIP

HA

TIC

CA

RB

AN

ION

S (C

onti

nued

)

C10

1. Z

nCl 2

, TH

F, –

78°,

80 m

in

2. B

n 2N

OB

z, C

uCl 2

(ca

t), –

78° t

o rt

, 2 h

3. H

2, P

d

3. A

c 2O

, Et 3

N

Ph

NH

Ac

(18)

75%

ee

113

MgC

l

Ph(c

a. 8

4% e

e)

aA

fter

30

min

utes

at –

15° t

he m

ixtu

re w

as r

eflu

xed

for

one

hour

.b

The

rea

ctio

n w

as c

arri

ed o

ut w

ith b

oth

R a

nd S

ena

ntio

mer

s (C

MeP

h); t

he o

ptic

al y

ield

s w

ere

5-46

%.

cT

he p

rodu

ct is

uns

tabl

e; th

e yi

eld

was

det

erm

ined

by

NM

R s

pect

rosc

opy.

d T

reat

men

t of

prod

ucts

II

with

BnO

CO

Cl f

ollo

wed

by

ceri

um a

mm

oniu

m n

itrat

e ga

ve R

NH

CO

2Bn.

eT

he y

ield

was

est

imat

ed b

y re

duct

ion

with

Zn/

HC

l and

titr

atio

n w

ith N

aNO

2.f X

2 was

.

gH

eatin

g to

70°

con

vert

ed a

ny Z

-azo

com

poun

ds in

to th

e E

isom

ers.

hSo

me

of th

e tr

iaze

nes

are

isol

ated

as

mix

ture

s of

dou

ble-

bond

isom

ers.

iT

he y

ield

is th

at o

f th

e am

ine

hydr

ochl

orid

e af

ter

redu

ctio

n of

the

tria

zene

with

RaN

i.J

The

pro

duct

was

con

vert

ed in

situ

into

the

(N-4

-met

hoxy

phen

ylet

hyl)

pipe

rony

lcar

boxa

mid

e.k

The

sub

stra

te w

as p

repa

red

in s

itu b

y re

actio

n of

the

alke

neR

1 R2 C

=C

H2

with

HZ

rCp 2

Cl i

n T

HF

at r

oom

tem

pera

ture

.l

PhC

HM

eNH

2(2

1%)

was

als

o fo

rmed

by

addi

tion

of th

e zi

rcon

ium

rea

gent

toC

1 of

sty

rene

.m

The

yie

ld is

that

of

the

hydr

ochl

orid

e.n

The

sub

stra

te w

as t-

BuM

gCl.

oT

he y

ield

is th

at o

f th

e N

-ben

zoyl

der

ivat

ive.

pT

he y

ield

is th

at o

f th

e fu

mar

ate.

qT

he in

itial

unc

leav

ed a

dduc

t was

isol

ated

in 4

1% y

ield

.r

The

rea

gent

R2 C

H2N

(Li)

OB

n w

as p

repa

red

in s

itu b

y ad

ditio

n of

R2 L

i to

CH

2=N

OB

n.s

The

rea

gent

was

pre

pare

d ei

ther

by

reac

tion

of P

hCH

MeN

HO

Me

with

MeL

i or

of P

hCH

MeN

(OM

e)C

O2(

CH

2)2B

r w

ith tw

o eq

uiva

lent

s of

t-B

uLi.

The

yie

ld in

the

latte

r re

actio

n w

as 6

4%.

tT

he y

ield

is th

at o

f th

e un

benz

oyla

ted

amin

e.u

The

rea

gent

was

pre

pare

d in

situ

by

reac

tion

of th

e ox

ime

with

one

equ

ival

ent o

f E

tMgB

r.

S O2N

O2

S

116

v T

he p

rodu

cts

wer

e co

nver

ted

into

RN

H2

with

CsO

H in

eth

ylen

e gl

ycol

at 1

50° o

r in

to R

NH

Me

with

LiA

lH4.

w X

was

not

spe

cifi

ed.

x N

o re

actio

n oc

curr

ed a

t –7

8°.

y T

he s

ubst

rate

was

pre

pare

d in

situ

by

reac

tion

of (

1S)-

(–)-

β-pi

nene

with

HZ

rCp 2

Cl i

n T

HF

at r

oom

tem

pera

ture

.

z T

reat

men

t with

TFA

fol

low

ed b

y re

duct

ion

with

RaN

i/H2

gave

the

race

mic

am

ine.

Rac

emiz

atio

n m

ost l

ikel

y oc

curr

ed d

urin

g fo

rmat

ion

of th

e or

gano

zinc

rea

gent

.aa

The

sub

stra

te w

as r

acem

ic.

117

Subs

trat

eR

efs.

Con

ditio

nsPr

oduc

t(s)

and

Yie

ld(s

) (%

)

TA

BL

E 1

B. C

YC

LIC

AL

IPH

AT

IC C

AR

BA

NIO

NS

R1 M

gBr

(R2 ) 2

NO

Bz

+ C

uCl 2

(x

mol

%, i

a, s

low

add

ition

), T

HF,

rt,

15 m

inR

1 N(R

2 ) 211

3

R1

c-C

3H5

c-C

6H11

c-C

6H11

C3-

6R

2

Bn

CH

2CH

=C

H2

Bn

x 15 2.5

2.5

(59)

(84)

(88)

C5-

10

RZ

nX1.

ArN

=N

Ts,

TH

F, –

20°,

30 m

in

2. R

aney

Ni,

EtO

H, r

eflu

x, 1

.5 h

ArN

HR

356

R c-C

5H9

c-C

5H9

c-C

6H11

c-C

6H11

exo-

1-no

rbor

nyl

exo-

1-no

rbor

nyl

X I I I c-C

6H11

exo-

1-no

rbor

nyl

exo-

1-no

rbor

nyl

Ar

4-E

tO2C

C6H

4

3,5-

Me 2

C6H

3

4-FC

6H4

4-E

tO2C

C6H

4

4-M

eOC

6H4

3-qu

inol

yl

4-M

eOC

6H4

4-E

tO2C

C6H

4

(71)

(76)

(75)

(62)

(71)

exo

:end

o =

4:1

(62)

exo

:end

o =

4:1

(67)

(50)

C3

1. 4

-RC

6H4N

=N

Ts,

TH

F, –

28°,

1 h

2. C

H2=

CH

CH

2I, N

-met

hylp

yrro

lidin

one,

rt,

3 h

3. Z

n, A

cOH

, TFA

, 75°

, 10

min

255

R Br

CO

2Et

(67)

(62)

MgB

rN

HC

6H4R

-4

C5-

12

Con

ditio

ns 1

: 1. C

atal

yst A

(se

e C

hart

1; 5

mol

%),

EtO

H, r

t

2

. Sub

stra

te, t

hen

PhSi

H3

3

. t-B

uO2C

N=

NC

O2B

u-t,

rt, t

ime

Con

ditio

ns 2

: 1. C

atal

yst B

(se

e C

hart

1; 2

mol

%),

i-Pr

OH

, 0°

2

. Sub

stra

te, t

hen

PhSi

H3,

0°

3

. t-B

uO2C

N=

NC

O2B

u-t,

0°, t

ime

n

R1

R2

n

R1

R2

NC

O2B

u-t

NH

CO

2Bu-

t

215

118

R1

H H H H H H Me

—(C

H2)

4—

—(C

H2)

4—

H

n 1 1 2 2 4 4 2 2 2 2

R2

H H H H H H Me

Ph

Con

ditio

ns

1 2 1 2 1 2 2 1 2 1

(74)

(94)

(24)

(90)

(62)

(95)

(79)

, dr

= 1

:1

(78)

(74)

(80)

Tim

e

8 h

2 h

24 h

2 h

24 h

2.5

h

3 h

18 h

18 h

8 h

C6

1. B

nON

H2,

Et 2

O, –

10° t

o –1

5°2.

HC

l

X Cl

Br

(79)

(62)

80

2,4,

6-M

e 3C

6H2S

O2O

NH

2, E

t 2O

, 0°,

10 m

in11

6(7

5)

1. T

sON

Me 2

, Et 2

O, r

t, 10

min

2. H

Cl

(13)

132

1. P

h 2P(

O)O

NH

2, T

HF,

–78

°; to

rt

2. H

O2C

CO

2H

(24)

140

Me 2

C=

NO

H, t

olue

ne(1

2)17

4a

MgX

NH

3+ C

l–

ZrC

p 2C

laN

H2

MgX

NM

e 2

exce

ss

X =

Br

NH

3+ H

O2C

CO

2–

X =

Cl o

r B

r

MgX

b

2 eq

NH

2

1. M

g, M

e 2C

=N

OSO

2C6H

2Me 3

-2,4

,6, T

HF,

ref

lux,

3 h

2. B

zCl

(<15

)80

2

NH

Bz

Br

119

Subs

trat

eR

efs.

Con

ditio

nsPr

oduc

t(s)

and

Yie

ld(s

) (%

)

TA

BL

E 1

B. C

YC

LIC

AL

IPH

AT

IC C

AR

BA

NIO

NS

(Con

tinu

ed)

1.M

e 2C

=N

OSO

2C6H

2Me 3

-2,4

,6, E

t 2O

, tol

uene

, 0°,

2 h

2. H

ydro

lysi

s

(40)

c80

3

C6

MgB

rN

H2

RM

gBr

1.

, E

t 2O

, CH

2Cl 2

, tem

p, ti

me

1

2. H

Cl,

EtO

H, H

2O, r

eflu

x, ti

me

2

OO

NO

SO2P

h

RN

H3+

Cl–

182

R c-C

6H11

1-no

rbor

nyl

1-ad

aman

tyl

C6-

10

Tem

p

0° rt 0°

Tim

e 1

30 m

in

12 m

in

30 m

in

Tim

e 2

6 h

10 h

10 h

(92)

d

(64)

(89)

1. M

e 2C

=N

OSO

2C6H

2Me 3

-2,4

,6, C

uCN

(0.

2 eq

), T

HF,

rt,

3 h

2. H

Cl

(20)

177

[Ar 2

C=

NO

R2

+ a

dden

d] (

ia),

30

min

R1 N

H2

R1

c-C

6H11

c-C

6H11

1-no

rbor

nyl

1-ad

aman

tyl

Ar

4-C

F 3C

6H4

3,5-

(CF 3

) 2C

6H3

4-C

F 3C

6H4

4-C

F 3C

6H4

R2

Ms

Ts

Ms

Ms

Add

end

CuC

N +

2 L

iCl (

0.2

eq)

— CuC

N +

2 L

iCl (

0.2

eq)

CuC

N +

2 L

iCl (

0.2

eq)

Solv

ent

TH

F, H

MPA

Et 2

O, t

olue

ne

TH

F, H

MPA

TH

F, H

MPA

Tem

p

0° rt 0° 0°

(80)

d

(87)

d

(96)

e

(82)

e

X Cl

Cl

Cl

Br

179,

726

179

179

179,

726

R1 M

gX

ZnC

l

exce

ss

NH

3+C

l–

C6

(EtO

2C) 2

C=

NC

6H4O

Me-

4 (i

a), T

HF,

–95

°, 30

min

(48)

167

PhN

2+ B

F 4– , T

HF,

0°,

1 h

(0)

190

MgB

rN

OM

e

C6H

11-c

EtO

2C EtO

2C

PhN

N

ZnM

gBr

3

120

, Et 2

O, 0

° to

rt, 1

hN

H

NC

6H11

-cR

1

R2

208

R1

Me

i-Pr

—(C

H2)

5—R2

Me

i-Pr

(62)

(40)

f

(86)

NNR

1

R2

MgB

r

RM

gX

1. P

hSC

H2N

3, T

HF,

Et 2

O, –

78°

2. A

c 2O

, –78

°3.

n-B

u 4N

+ H

CO

2– , DM

F, r

t, 1.

5 h;

45°

, 2 h

RN

HA

c27

3, 2

74,

275

R c-C

6H11

2-no

rbor

nylg

(93)

(70)

C6-

7

PhSO

2N3

(ia)

, Et 2

O30

6

N3

N3

, Et 2

O(7

9)27

2

2

4-FC

6H4N

3 (i

a), E

t 2O

, rt,

1 h

(85)

279

(—)

C6

C7

MgB

r

MgX

b

MgC

lH N

NN

SO2P

h

H N

FH N

NN

MgB

rN

Bn 2

1. Z

nCl 2

(50

mol

%),

Et 2

O, T

HF,

rt,

1 h

2. B

n 2N

OB

z, C

uCl 2

(ca

t), T

HF,

rt,

2 h

(57)

, end

o:ex

o =

65:

3511

3

exo:

endo

= 6

0:40

MgB

rN

Bn 2

1. Z

nCl 2

(50

mol

%),

Et 2

O, T

HF,

–78

°, 1

h

2. B

n 2N

OB

z, C

uCl 2

(ca

t), T

HF,

–78

° to

rt, 2

h

(56)

, end

o:ex

o >

95:

511

3H

H

Li

NM

e 2

2,4,

6-M

e 3C

6H2S

O2O

NM

e 2, E

t 2O

or

Et 2

O/T

HF,

–10

° to

–15°

; to

rt, 1

5 h

(54)

133

121

Subs

trat

eR

efs.

Con

ditio

nsPr

oduc

t(s)

and

Yie

ld(s

) (%

)

TA

BL

E 1

B. C

YC

LIC

AL

IPH

AT

IC C

AR

BA

NIO

NS

(Con

tinu

ed)

Li

NH

2

(39)

355

ClN

H2,

Et 2

O, s

onic

atio

n

NCO

2Bu-

t

NH

CO

2Bu-

t21

5

Con

ditio

ns

1 2

(66)

(98)

Con

ditio

ns 1

: 1. C

atal

yst A

(se

e C

hart

1; 5

mol

%),

EtO

H, r

t

2

. Sub

stra

te, t

hen

PhSi

H3

3

. t-B

uO2C

N=

NC

O2B

u-t,

rt, 7

h

Con

ditio

ns 2

: 1. C

atal

yst B

(se

e C

hart

1; 2

mol

%),

i-Pr

OH

, 0°

2

. Sub

stra

te, t

hen

PhSi

H3,

0°

3

. t-B

uO2C

N=

NC

O2B

u-t,

0°, 7

h

C7

NC

O2B

u-t

NH

CO

2Bu-

t

1. C

atal

yst A

(se

e C

hart

1; 5

mol

%),

EtO

H, r

t

2. S

ubst

rate

, the

n Ph

SiH

3

3. t-

BuO

2CN

=N

CO

2Bu-

t, rt

, 5 h

(90)

215

(27)

307

Cl

H2N

1. L

i, cy

cloh

exan

e, 9

0°2.

TsN

3, E

t 2O

, pen

tane

, –15

°, 30

min

3. I

sola

te tr

iaze

ne s

alt a

nd h

eat t

o 75

°/0.

1 m

m f

or 5

hh

N3

1. C

o(B

F 4) 3

•6H

2O, l

igan

d, E

tOH

, rt,

10 m

in

2. S

ubst

rate

3. 4

-MeC

6H4S

O2N

3, t-

BuO

2H, r

t, 5

min

4. P

hSiH

3, r

t, 12

h

t-B

uO

H

t-B

uN

PhPh

OK

O

Lig

and:

(56)

215

C8

122

Li

H

NH

2

H

1. P

hSC

H2N

3, T

HF,

pen

tane

, –78

°; to

rt,

1.5

h

2. N

H4C

l, H

2O

3. K

OH

, DM

SO, r

t, 1

h

C9

(45)

274

H H

H H

C10

-12

R

Br

1. L

i, E

t 2O

, son

icat

ion

2. C

lNH

2, E

t 2O

, son

icat

ion

R H Me

(54)

(48)

355

R

R

NH

2

R

1. C

atal

yst A

(se

e C

hart

1; 5

mol

%),

EtO

H, r

t

2. S

ubst

rate

, the

n Ph

SiH

3

3. t-

BuO

2CN

=N

CO

2Bu-

t, rt

, 4 h

215

(94)

NCO

2Bu-

t

NH

CO

2Bu-

t

PhN

2+ B

F 4– , T

HF,

–78

°N

(low

)18

5N

Ph

MgB

rN

NM

e

MeN

NM

eM

eN

NO

Ts

(ia)

, tol

uene

, Et 2

O, 0

°, 15

min

(55)

i18

1

NN

HC

O2B

u-t

NH

CO

2Bu-

t

1. C

atal

yst A

(se

e C

hart

1; 5

mol

%),

EtO

H, r

t

2. S

ubst

rate

, the

n Ph

SiH

3

3. t-

BuO

2CN

=N

CO

2Bu-

t, rt

, 5 h

(70)

, dr

= 5

:121

5

C10

1. C

atal

yst A

(se

e C

hart

1; 5

mol

%),

EtO

H, r

t

2. S

ubst

rate

, the

n Ph

SiH

3

3. t-

BuO

2CN

=N

CO

2Bu-

t, rt

, 5 h

N NH

CO

2Bu-

t

CO

2Bu-

t(8

4), d

r =

1:2

-1:3

215

123

Subs

trat

eR

efs.

Con

ditio

nsPr

oduc

t(s)

and

Yie

ld(s

) (%

)

TA

BL

E 1

B. C

YC

LIC

AL

IPH

AT

IC C

AR

BA

NIO

NS

(Con

tinu

ed)

C11

OM

e

ZnP

r-i

OM

e

NH

C6H

4CO

2Et-

4

1. 4

-EtO

2CC

6H4N

=N

Ts,

TH

F, –

20°

2. R

aney

Ni,

EtO

H, r

eflu

x, 1

2 h

(40)

88%

ee;

tran

s:ci

s =

98:

235

6

chir

al n

on-r

acem

ic

N3

1. C

o(B

F 4) 3

•6H

2O, l

igan

d, E

tOH

, rt,

10 m

in

2. S

ubst

rate

3. 4

-MeC

6H4S

O2N

3, t-

BuO

2H, r

t, 5

min

4. S

ilane

, rt,

12 h

t-B

uO

H

t-B

uN

PhPh

OK

O

Lig

and:

Sila

ne

PhSi

H3

(Me 2

SiH

) 2O

(89)

(76)

dr 4:1

4:1

215

C10

C15

Ph

Ph

MgB

r

2,4,

6-M

e 3C

6H2S

O2O

NM

e 2, E

t 2O

or

Et 2

O/T

HF,

–10

° to

–15°

; to

rt, 1

5 h

Ph

Ph

NM

e 213

3, 1

34(4

7)

C20

Li

ClN

H2,

Et 2

O, s

onic

atio

n

NH

2

(41)

355

124

N

(48)

CO

2Bu-

t

t-B

uO2C

N=

NC

O2B

u-t,

Et 2

O, s

onic

atio

n35

5

a The

sub

stra

te w

as p

repa

red

in s

itu b

y ad

ditio

n of

HZ

rCp 2

Cl t

o cy

cloh

exen

e.b X

was

not

spe

cifi

ed.

c The

yie

ld w

as d

eter

min

ed b

y ga

s ch

rom

atog

raph

y.d T

he p

rodu

ct w

as is

olat

ed a

s th

e N

-ben

zoyl

der

ivat

ive.

e T

he p

rodu

ct w

as is

olat

ed a

s th

e hy

droc

hlor

ide.

f The

pro

duct

was

isol

ated

as

the

oxal

ate.

g T

he s

ubst

rate

was

a m

ixtu

re o

f ex

o an

d en

do is

omer

s.

h C

auti

on!

Exp

losi

ons

and

spon

tane

ous

igni

tion

wer

e en

coun

tere

d in

this

ste

p.

i The

pro

duct

was

con

vert

ed in

to a

min

oada

man

tane

with

CsO

H in

eth

ylen

e gl

ycol

at 1

50° (

71%

yie

ld)

or

into

N-m

ethy

lam

inoa

dam

anta

ne w

ith L

iAlH

4 (5

5% y

ield

).

NH

t-B

uO2C

125

Subs

trat

eR

efs.

Con

ditio

nsPr

oduc

t(s)

and

Yie

ld(s

) (%

)

TA

BL

E 1

C. A

LL

YL

IC A

ND

PR

OPA

RG

YL

IC C

AR

BA

NIO

NS

C3

Li

1. M

eON

HL

i (2

eq, i

a), E

t 2O

, –78

° to

rt, 2

h

2. B

zCl

NH

Bz

82(7

8)

NC

O2

PhH

N HC

O2

PhH

(0)

(44-

55)

+16

1M

gX

MgX

R

C3-

4

N

RM

eO2C

N=

NC

O2M

e, E

t 2O

or

TH

F, –

78°

R H Me

(>23

)

(>60

)

799

MgX

RN

3, E

t 2O

NH

N=

NR

R Ph PhSO

2

1-na

phth

yl

Tem

p

— —

refl

ux

(48)

(—)a

(60)

282

306

281

In b

R1

R2 N

3, D

MF,

rt

NH

R2

R1

269

NR

2

R1

+2

C3

C3-

4

MeO

NH

2, E

t 2O

, –10

° to

–15°

, 30

min

791

(40)

MgB

rN

H2

X Br

Cl

Br

III

X n

ot s

peci

fied

2 eq

X n

ot s

peci

fied

Tim

e

— —

25 m

in

(ia)

, Et 2

ON

CO

2

PhH

CO

2Me

NH

CO

2Me

i-Pr

i-Pr

126

R1

H H H H H H CO

2Me

CO

2Me

CO

2Me

CO

2Me

CO

2Me

CO

2Me

CO

2Me

CO

2Me

CO

2Me

CO

2Me

R2

Ph c-C

6H11

n-C

6H11

4-C

lC6H

4

4-M

eC6H

4

Bn

Ph 3-C

lC6H

4

3,4-

Cl 2

C6H

3

4-M

eOC

6H4

4-C

l-2-

MeO

C6H

3

3,4-

(MeO

) 2C

6H3

2-M

eC6H

4

2-B

r-4-

MeC

6H3

Bn

2-na

phth

yl

Tim

e

2.0

h

2.5

h

3.0

h

3.0

h

1.5

h

2.0

h

1.5

h

2.5

h

2.5

h

1.0

h

2.5

h

3.0

h

3.0

h

2.0

h

2.5

h

3.5

h

I

(90)

(73)

(70)

(85)

(88)

(80)

(80)

(81)

(80)

(87)

(80)

(89)

(84)

(85)

(84)

(75)

II

(5-8

)

(5-8

)

(5-8

)

(5-8

)

(5-8

)

(—)

(—)

(—)

(—)

(—)

(—)

(—)

(—)

(—)

(—)

(—)

C4

2t-

BuO

2CN

(M)O

Ts,

TH

F, –

78°,

1.5

hN

HC

O2B

u-t

127

M Li

MgC

l

(66)

(72)

CN

1. L

iHM

DS

(ia)

, TH

F, –

78°

2.

(

+),

–78

°; to

rt,

26.5

h

N H

ON

CO

NH

2

151

(45)

CuM

gCl

SnB

u 3t-

BuO

2CN

NC

ON

ZnC

l 2•O

Et 2

, CH

2Cl 2

, –78

° to

rt, 2

hN

CO

N

(73)

410

t-B

uO2C

NH

Nt-

BuO

2CH

NC

ON

+

(7)

,

127

Subs

trat

eR

efs.

Con

ditio

nsPr

oduc

t(s)

and

Yie

ld(s

) (%

)

TA

BL

E 1

C. A

LL

YL

IC A

ND

PR

OPA

RG

YL

IC C

AR

BA

NIO

NS

(Con

tinu

ed)

C4-

10

R1

R3

R4

R1

R3

R4

NN

HC

O2R

5R

5 O2C

1. C

atal

yst A

(1-

5 m

ol%

), E

tOH

, rt

2. S

ubst

rate

, the

n si

lane

3. R

5 O2C

N=

NC

O2R

5 , rt,

time

R1

TM

S

TM

S

TM

S

TM

S

TM

S

TM

S

TM

S

TM

S

TM

S

TM

S

TM

S

n-B

u

n-B

u

Ph Ph (4-M

eOC

6H4C

O2)

CM

e 2

(4-M

eOC

6H4C

O2)

CM

e 2

R2

H H H H Me

Me

H H H Me

Me

H H H H H H

R2

R2

R3

H H Me

(H)

Me

(H)

H H CH

2OH

CH

2OT

BD

MS

CO

2Me

H H H H H H H H

R4

H H H (

Me)

H (

Me)

H H H H H CH

2OH

CH

2OH

H H H H H H

R5

Et

t-B

u

Et

t-B

u

Et

t-B

u

t-B

u

t-B

u

t-B

u

Et

t-B

u

Et

t-B

u

Et

t-B

u

Et

t-B

u

Sila

ne

PhSi

H3

PhSi

H3

PhSi

H3

PhSi

H3

PhSi

H3

PhSi

H3

PhSi

H3

PhSi

H3

PhSi

H3

PhSi

H3

(Me 2

SiH

) 2O

PhSi

H3

PhSi

H3

PhSi

H3

(Me 2

SiH

) 2O

PhSi

H3

PhSi

H3

Tim

e

1 h

2 h

1.5

h

3 h

2 h

4 h

2 h

2 h

4 h

3 h

4 h

1.5

h

45 m

in

1.5

2 h

1 h

1.5

h

(73)

(83)

(45)

(55)

(67)

(42)

(77)

(63)

(47)

(66)

(27)

(72)

(78)

(46)

(56)

(75)

(61)

216

C5

Me 2

N

Me 2

NO

Ms,

TH

F, –

20°,

30 m

in(4

7)80

4L

i+

ZrC

p 2C

l cN

H2

2,4,

6-M

e 3C

6H2S

O2O

NH

2, E

t 2O

, 0°,

10 m

in(6

2)d

116

128

C6

EE

+

III

I +

II

(60)

, I:I

I =

4:1

E =

N(C

O2B

u-t)

NH

CO

2Bu-

t

1. C

atal

yst A

(se

e C

hart

1; 2

.5 m

ol%

), E

tOH

, rt

2. (

Me 2

SiH

) 2O

, the

n su

bstr

ate

3. t-

BuO

2CN

=N

CO

2Bu-

t, rt

, 12

h

216

C5-

8

n

N

NC

O2B

u-t

CO

2Bu-

t

n

+

1. C

atal

yst A

(se

e C

hart

1; 2

.5 m

ol%

), E

tOH

, rt

2. (

Me 2

SiH

) 2O

, the

n su

bstr

ate

3. t-

BuO

2CN

=N

CO

2Bu-

t, rt

, tim

e

n 1 2 3 4

Tim

e

12 h

12 h

12 h

6 h

I

(45)

(73)

(84)

(81)

II (23)

(0)

(0)

(0)

216

NN

HC

O2B

u-t

CO

2Bu-

t

1. C

atal

yst A

(se

e C

hart

1; 2

.5 m

ol%

), E

tOH

, rt

2. (

Me 2

SiH

) 2O

, the

n su

bstr

ate

3. t-

BuO

2CN

=N

CO

2Bu-

t, rt

, 12

h

(83)

216

C5

Y

C6-

9

Y

E

Y

+

1. C

atal

yst A

(se

e C

hart

1; 2

.5 m

ol%

), E

tOH

, rt

2. (

Me 2

SiH

) 2O

, the

n su

bstr

ate

3. t-

BuO

2CN

=N

CO

2Bu-

t, rt

, tim

eI

IIE

= N

(CO

2Bu-

t)N

HC

O2B

u-t

Y NT

s

C(C

O2E

t)2

I

(90)

(60)

II (0)

(15)

216

Tim

e

7 h

2 h

NN

N CH

(Li)

CH

=C

H2

n-B

uMgB

r

1.

(

ia),

TH

F, –

78°

2. P

hN=

NPh

, –78

°; to

rt

359

C7

n-B

uN

(32)

E

NC

O2B

u-t

NH

CO

2Bu-

t

n

NH

Ph

Ph

129

Subs

trat

eR

efs.

Con

ditio

nsPr

oduc

t(s)

and

Yie

ld(s

) (%

)

TA

BL

E 1

C. A

LL

YL

IC A

ND

PR

OPA

RG

YL

IC C

AR

BA

NIO

NS

(Con

tinu

ed)

C8

1. C

atal

yst A

(se

e C

hart

1; 2

.5 m

ol%

), E

tOH

, rt

2. (

Me 2

SiH

) 2O

, the

n su

bstr

ate

3. t-

BuO

2CN

=N

CO

2Bu-

t, rt

, 12

hE

E

+I

II

E =

N(C

O2B

u- t)N

HC

O2B

u- t

I +

II

(71)

, I:I

I =

7:1

216

C9

NH

2Ph

MgC

lPh

ClN

H2,

Et 2

O, –

20°

(14)

805

(PhO

) 2P(

O)O

NM

e 2, T

HF,

–30

° to

0°(—

)14

6

Li+

(PhO

) 2P(

O)O

NM

e 2, T

HF,

–30

° to

0°(4

0)14

6

H H

NM

e 2

H

HN

Me 2

Li+

2,4,

6-M

e 3C

6H2S

O2O

NM

e 2, E

t 2O

or

Et 2

O/T

HF,

–10

° to

–15°

; to

rt, 1

5 h

NM

e 2

(69)

133

Li

2,4,

6-M

e 3C

6H2S

O2O

NM

e 2, E

t 2O

or

Et 2

O/T

HF,

–10

° to

–15°

; to

rt, 1

5 h

NM

e 2

133

+

NM

e 2

III

I +

II

(57)

, I:I

I —

Li+

C10

(37)

NH

2

Ph2P

(O)O

NH

2, T

HF,

–20

°; r

t, 12

h13

9

130

ON

Ph

Li

MeO

C11

t-B

uO2C

N=

NC

O2B

u-t,

TH

F, –

78°;

to r

t, 15

h

ON

Ph

MeO

(34)

806

C15

-21

PhPh

Li

C15

PhPh

Ph2P

(O)O

NH

2, T

HF,

–20

°; r

t, 12

hO

(31)

139

a Pyr

olys

is o

f th

e tr

iaze

ne s

alt g

ave

ally

l azi

de in

13%

yie

ld.

b The

sub

stra

tes

wer

e pr

epar

ed c

oncu

rren

tly f

rom

the

brom

ide

with

indi

um m

etal

in th

e pr

esen

ce o

f on

e eq

uiva

lent

of

NaI

.c T

he s

ubst

rate

was

pre

pare

d in

situ

by

addi

tion

of H

ZrC

p 2C

l to

3-m

ethy

l-1,

2-bu

tadi

ene.

d The

pro

duct

was

cha

ract

eriz

ed a

s th

e N

-ben

zoyl

der

ivat

ive.

PhPh

R1

Li

PhPh

R1

2,4,

6-M

e 3C

6H2S

O2O

N(R

2 ) 2, E

t 2O

or

Et 2

O/T

HF,

–10

° to

–15°

; to

rt, 1

5 h

R1

H t-B

u

Ph Ph

(37)

(31)

(38)

(39)

133

R2

Me

Me

Me

Et

(R2 ) 2

N

C10

1. C

atal

yst A

(se

e C

hart

1; 1

.5 m

ol%

), E

tOH

, rt

2. (

Me 2

SiH

) 2O

, the

n su

bstr

ate

3. t-

BuO

2CN

=N

CO

2Bu-

t, rt

, 12

h

NC

O2B

u-t

NH

CO

2Bu-

t

(65)

216

NN

CO

2Bu-

t

CO

2Bu-

t

+

(3)

NN

HC

O2B

u-t

t-B

uO2C

131

Subs

trat

eR

efs.

Con

ditio

nsPr

oduc

t(s)

and

Yie

ld(s

) (%

)

TA

BL

E 1

D. A

RY

LM

ET

HY

L A

ND

HE

TE

RO

AR

YL

ME

TH

YL

CA

RB

AN

ION

S

C5

NN

NN

1. K

NH

2, N

H3

(liq

uid)

, Et 2

O

2. P

hN=

NPh

(39)

212

N1.

Bas

e (x

eq)

, TH

F, h

exan

e, c

ondi

tions

2. A

rN=

NA

r, –

78°,

10 m

in

212

R H H 4-M

e

6-M

e

4,6-

Me 2

Bas

e

LD

A

LD

A

n-B

uLi

LD

A

n-B

uLi

Con

ditio

ns

rt, 1

h

rt, 1

h

—

rt, 1

h

—

(69)

(36)

(47)

(83)

(63)

Ar

Ph 4-C

lC6H

4

Ph Ph Ph

x 2 1 1 2 1

C6-

8

R

C5-

6

Y

N R

Y

N R

Con

ditio

ns 1

: 1. C

atal

yst A

(se

e C

hart

1; 2

.5 m

ol%

), E

tOH

, rt

2

. PhS

iH3,

t-B

uO2C

N=

NC

O2B

u-t,

rt

3

. Sub

stra

te, r

t, tim

e

Con

ditio

ns 2

: 1. C

atal

yst B

(se

e C

hart

1; 1

mol

%),

i-Pr

OH

, rt t

o 0°

2

. PhS

iH3,

t-B

uO2C

N=

NC

O2B

u-t,

0°

3. S

ubst

rate

, 0°,

time

215

Y N N CH

CH

CH

R Me

Me

H Boc

Ts

Con

ditio

ns

1 2 1 1 1

(60)

(88)

(<5)

(67)

(74)

Tim

e

8 h

5 h

— 11 h

11 h

Nt-

BuO

2CN

HC

O2B

u-t

N

RNA

r

NH

Ar

NN

HPh

Ph

132

C6-

7

YR

Y

Y O S S

R H H Me

(68)

(84)

(58)

215

1. C

atal

yst A

(se

e C

hart

1; 2

.5 m

ol%

), E

tOH

, rt

2. P

hSiH

3, t-

BuO

2CN

=N

CO

2Bu-

t, rt

3. S

ubst

rate

, rt,

time

Tim

e

12 h

18 h

7 h

Nt-

BuO

2CN

HC

O2B

u-t

R

C6

O

O

Nt-

BuO

2CN

HC

O2B

u-t (7

5)21

5

1. C

atal

yst A

(se

e C

hart

1; 2

.5 m

ol%

), E

tOH

, rt

2. P

hSiH

3, t-

BuO

2CN

=N

CO

2Bu-

t, rt

3. S

ubst

rate

, rt,

18 h

C6-

8

NY

NY

Nt-

BuO

2CN

HC

O2B

u-t

R1

R2

R2

R1 Y N C

H

CH

CH

R1

H H Me

H

R2

H H H Me

(63)

(77)

(60)

(54)

215

1. C

atal

yst A

(se

e C

hart

1; 2

.5 m

ol%

), E

tOH

, rt

2. P

hSiH

3, t-

BuO

2CN

=N

CO

2Bu-

t, rt

3. S

ubst

rate

, rt,

time

Tim

e

24 h

4 h

5 h

5 h

N

1. L

DA

(2

eq),

TH

F, h

exan

e, 1

h

2. A

rN=

NA

r, –

78°,

10 m

in

Ar

Ph 2-C

lC6H

4

4-C

lC6H

4

Ph Ph

(97)

(53)

(44)

(82)

(77)

R21

2

212

212

212

212,

807

R H H H 2-M

e

2,6-

Me 2

N

R

NA

r

NH

Ar

133

Subs

trat

eR

efs.

Con

ditio

nsPr

oduc

t(s)

and

Yie

ld(s

) (%

)

TA

BL

E 1

D. A

RY

LM

ET

HY

L A

ND

HE

TE

RO

AR

YL

ME

TH

YL

CA

RB

AN

ION

S (C

onti

nued

)

C7

NC

l 3, E

t 2O

77

Br 2

NH

, Et 2

O, 2

-3°

75

RN

HC

l, E

t 2O

, 5°,

1 h

68

R Me

Et

I

(14)

(12)

II (70)

(75)

NH

2Cl,

Et 2

O, 0

°(9

2)80

5, 5

6

RN

Cl 2

, Et 2

O, 5

°, 1

h68

2 eq

1. B

nON

H2,

Et 2

O, –

10° t

o –1

5°2.

HC

l

80

1. M

eON

HL

i (2

eq, i

a), E

t 2O

2. B

zCl

(97)

82, 7

86

I

(25)

(19)

III

(3)

(6)

II (43)

(28)

R Me

Et

III

R2N

Cl,

Et 2

O, 5

°, 1

hR

2NH

III

R Me

Et

n-Pr

I (5)

(5)

(5)

II (95)

(89)

(78)

68

PhM

gCl

exce

ss

4 eq

exce

ss

PhN

H2

PhN H

PhI

(32)

+

II (

7)

I (3

4) +

II

(6)

PhN

HR

+R

NH

2

I III

I +

II

+Ph

N RPh

PhN

R2

+

PhL

iPh

N HPh

O

PhN

H3+

Cl–

(79)

134

Me 2

NO

Ms,

Et 2

O o

r T

HF,

–30

° to

0°13

4

Mg,

Me 2

NO

SO2C

6H2M

e 3-2

,4,6

, Mg,

TH

F, r

t, 2

h80

1

R1 R

2 NO

Bz,

(Ph

3P) 2

NiC

l 2 (

cat)

, TH

F, r

t, 10

min

to 6

h10

8

R1

—

(CH

2)5—

—(C

H2)

2O(C

H2)

2—R2

(68)

(85)

R1 R

2 NO

Bz,

(C

uOT

f)2•

PhH

(ca

t), T

HF,

rt,

1 h

R1

Bn

—(C

H2)

2O(C

H2)

2—

R2

Bn

109

112,

109

(91)

(80)

PhM

gCl

PhN

Me 2

(43)

I

I (1

0)Ph

Br

PhZ

nCl

PhN

R1 R

2

PhZ

n

I

IPh

Ph2P

(O)O

NH

2, T

HF,

–20

°; r

t, 12

h13

9

M Li

MgC

l

MgB

r

(30)

(70)

(51)

, TH

F, –

78°;

to r

t, ov

erni

ght

PhN

CO

2Bu-

n

PhN

BnC

O2B

u-n

M MgC

l

MgC

l•E

t 3A

l

Cu

Cu•

BF 3

Ti(

OPr

-i) 3

(95)

(78)

(22)

(50)

(55)

164

PhM

PhN

H2

X n

ot s

peci

fied

M Mg

CdN

CO

2

PhH

Bn

N HC

O2

PhH

Bn

I

II

+

161

I +

II

(45-

55)

(55-

70)

I:II

100:

0

0:10

0a

PhM

X(i

a), E

t 2O

NC

O2

PhH

i-Pr

i-Pr

135

Subs

trat

eR

efs.

Con

ditio

nsPr

oduc

t(s)

and

Yie

ld(s

) (%

)

TA

BL

E 1

D. A

RY

LM

ET

HY

L A

ND

HE

TE

RO

AR

YL

ME

TH

YL

CA

RB

AN

ION

S (C

onti

nued

)

4-M

eOC

6H4N

CO

2Et

CO

2Et

(80)

167,

166

Me 2

C=

NO

SO2C

6H2M

e 3-2

,4,6

, CuC

N (

cat)

, TH

F, r

t, 3

h(5

6)17

7

1. C

H2=

N2,

Et 2

O, r

t

2. H

Cl

202,

199

(ia)

, TH

F, –

95°,

30 m

inPh

MgB

r

PhZ

nPh

exce

ssPh

NH

2

PhM

gCl

Me

H NN H

Bn

•HC

l(4

1)

C7

NC

O2E

t

CO

2Et

Bn

MeO

Ph2C

=N

2, E

t 2O

, rt

(73)

202

(0)

PhN

2+ B

F 4– , T

HF,

0°,

1 h

190

RC

ON

=N

CO

R

R MeO

t-B

uO

Ph

Solv

ent

Et 2

O o

r T

HF

TH

F

Et 2

O

(>70

)

(90)

(30)

Tim

e

—

30 m

in

—

M MgX

b

ZnB

r

MgB

r

799

358

794

Tem

p

–78° rt rt

RN

3, E

t 2O

R Ph PhSO

2 (i

a)

Tem

p

refl

ux

—

(goo

d)

(98)

270

306

PhM

gBr

PhN

H NB

n

Ph

PhM

PhN

NPh

RN

H N

O

Bn

R

O

PhM

gCl

Tim

e

30 m

in

—

N

H NN H

Bn

cR

N

136

N3

Ph

1.

, TH

F, –

78°;

to r

t, 2

h

2. H

Cl,

then

bas

e

278

790

NSN

3

(43)

, Et 2

O, 1

0-12

h

PhL

iPh

NH

2(6

0) NSN

BnH

NN

PhM

gXb

C8

, TH

F, –

15°

N MeP

O

ON

Me 2

Ph

147

X Cl

Br

(63)

30%

ee

(40)

44%

ee

O

1. L

DA

, TH

F, h

exan

e, 1

h

2. A

rN=

NA

r, –

78°,

5 m

in21

2

Ar

Ph 2-C

lC6H

4

(73)

(68)

PhM

gXPh

NM

e 2

NC

NC

N

H N

Ar

Ar

NN

N CH

(R2 )L

i

R1 M

gBr

1.

(ia)

, TH

F, –

78°

2. A

rN=

NA

r, –

78°;

to r

t

359

C8-

13

R1

Ar

NN

HA

r

R2 R

1

Me

n-B

u

n-B

u

n-B

u

n-B

u

Ph

R2

Ph Ph Ph Ph 4-M

eC6H

4

Ph

Ar

Ph Ph 4-C

lC6H

4

4-M

eC6H

4

Ph Ph

(40)

(54)

(51)

(48)

(57)

(52)

137

Subs

trat

eR

efs.

Con

ditio

nsPr

oduc

t(s)

and

Yie

ld(s

) (%

)

TA

BL

E 1

D. A

RY

LM

ET

HY

L A

ND

HE

TE

RO

AR

YL

ME

TH

YL

CA

RB

AN

ION

S (C

onti

nued

)

Con

ditio

ns 1

: 1. C

atal

yst A

(se

e C

hart

1; 5

mol

%),

EtO

H, r

t

2

. Sub

stra

te a

nd P

hSiH

3

3

. t-B

uO2C

N=

NC

O2B

u-t,

rt, t

ime

Con

ditio

ns 2

: 1. C

atal

yst A

(se

e C

hart

1; 5

mol

%),

EtO

H, r

t

2

. PhS

iH3,

t-B

uO2C

N=

NC

O2B

u-t,

rt

3

. Sub

stra

te, r

t, tim

e

Con

ditio

ns 3

: 1. C

atal

yst B

(se

e C

hart

1; 5

mol

%),

i-

PrO

H, r

t to

0°

2. S

ubst

rate

, PhS

iH3

3

. t-B

uO2C

N=

NC

O2B

u-t,

0°, t

ime

Con

ditio

ns 4

: 1. C

atal

yst B

(se

e C

hart

1; 1

mol

%),

i-

PrO

H, r

t to

0°

2

. PhS

iH3,

t-B

uO2C

N=

NC

O2B

u-t,

0°

3. S

ubst

rate

, 0°,

time

C8-

15

R1

Ar

R3

R2

R3

R2

N

Ar

R1

t-B

uO2C

NH

CO

2Bu-

t

Ar

Ph 4-H

2NC

6H4

4-H

2NC

6H4

4-Fm

ocN

HC

6H4

Ph Ph Ph Ph Ph

R1

H H H H Me

H H Me

Me

R2

H H H H H Me

CH

2OH

Me

Me

R1

H H H H H H H H Me

Con

ditio

ns

2 2 4 2 2 1 1 1 3

(86)

(20-

40)

(66)

(98)

(88)

(88)

(91)

(13)

(51)

215

Tim

e

5 h

20 h

4 h

4 h

2 h

3 h

1 h

20 h

4 h

C8

N

1. B

uLi,

hexa

ne, T

HF,

–78

°2.

PhN

=N

Ph(6

5-77

)21

2

N

NN

HPh

Ph

138

Li

2,4,

6-M

e 3C

6H2S

O2O

NM

e 2, E

t 2O

or

Et 2

O/T

HF,

–10

° to

–15°

; to

rt, 1

5 h

NM

e 2

133

NM

e 2

+(5

7)

C10

NN

212

1. B

ase,

sol

vent

, tem

p, ti

me

2. A

rN=

NA

r Bas

e

KN

H2,

NH

3 (l

iq)

LD

A

Solv

ent

Et 2

O

TH

F, h

exan

e

Tem

p, T

ime

30 m

in

rt, 1

h, t

hen

–78°

Ar

Ph 2-C

lC6H

4

(50)

(7)

C9

1. C

atal

yst A

(se

e C

hart

1; 5

mol

%),

EtO

H, r

t

2. S

ubst

rate

, the

n Ph

SiH

3

3. t-

BuO

2CN

=N

CO

2Bu-

t, rt

, 4 h

215

(94)

NCO

2Bu-

t

NH

CO

2Bu-

t

NS1.

Cat

alys

t A (

see

Cha

rt 1

; 5 m

ol%

), E

tOH

, rt

2. S

ubst

rate

, the

n Ph

SiH

3

3. R

O2C

N=

NC

O2R

, rt,

4 h

215

NS

N CO

2RNH

CO

2RR E

t

t-B

u

(54)

(<14

)

N HN H

N NH

CO

2Bu-

t

CO

2Bu-

t1.

Cat

alys

t A (

see

Cha

rt 1

; 2.5

mol

%),

EtO

H, r

t

2. P

hSiH

3, t-

BuO

2CN

=N

CO

2Bu-

t

3. S

ubst

rate

, rt,

5 h

(82)

215

N RN RN

t-B

uO2C

NH

CO

2Bu-

t

1. C

atal

yst A

(se

e C

hart

1; 2

.5 m

ol%

), E

tOH

, rt

2. P

hSiH

3, t-

BuO

2CN

=N

CO

2Bu-

t

3. S

ubst

rate

, rt,

11 h

R Boc

Ts

(76)

(85)

215

NAr

NH

Ar

139

Subs

trat

eR

efs.

Con

ditio

nsPr

oduc

t(s)

and

Yie

ld(s

) (%

)

TA

BL

E 1

D. A

RY

LM

ET

HY

L A

ND

HE

TE

RO

AR

YL

ME

TH

YL

CA

RB

AN

ION

S (C

onti

nued

)

C11

NH

2

ClN

H2

(47)

805

MgC

l

MsO

NM

e 2, E

t 2O

or

TH

F, –

30° t

o 0°

(84)

134

R Me

2,4,

6-M

e 3C

6H2

Solv

ent(

s)

Et 2

O o

r T

HF

Et 2

O o

r E

t 2O

/TH

F

(61)

(95)

134

133

C13

RSO

2ON

Me 2

Tem

p, T

ime

–30°

to 0

°–1

0° to

–20

° to

rt; r

t, 15

h

Li

NM

e 2

PhPh

N NH

CO

2Bu-

t

CO

2Bu-

t

Con

ditio

ns 1

: 1. C

atal

yst A

(se

e C

hart

1; 5

mol

%),

EtO

H, r

t

2

. Sub

stra

te, t

hen

PhSi

H3

3

. t-B

uO2C

N=

NC

O2B

u-t,

rt, 5

h

Con

ditio

ns 2

: 1. C

atal

yst B

(se

e C

hart

1; 2

mol

%),

i-Pr

OH

, 0°

2

. Sub

stra

te, t

hen

PhSi

H3,

0°

3

. t-B

uO2C

N=

NC

O2B

u-t,

0°, 4

h

Con

ditio

ns

1 2

(48)

(60)

215

C12

PhPh N N

HC

O2B

u-t

CO

2Bu-

t1.

Cat

alys

t A (

see

Cha

rt 1

; 5 m

ol%

), E

tOH

, rt

2. S

ubst

rate

, the

n Ph

SiH

3

3. t-

BuO

2CN

=N

CO

2Bu-

t, rt

, 4 h

(80)

215

PhL

i

Ph

PhN

Me 2

Ph

140

Ph2P

(O)O

NH

2, T

HF,

–20

°; r

t, 12

h(4

1)13

9

NH

2

Ph2P

(O)O

NH

2, T

HF,

–20

°; r

t, 12

h13

9(3

0)

1. L

DA

, TH

F, h

exan

e, 1

h

2. A

rN=

NA

r, –

78°,

10 m

in

212

Ar

Ph 2-C

lC6H

4

(92)

(20)

PhL

i

Ph

PhN

H2

Ph

PhN

Ph

Ar

NH

Ar

PhPh

R1

Li

C15

-21

PhPh

R1

2,4,

6-M

e 3C

6H2S

O2O

N(R

2 ) 2, E

t 2O

or

Et 2

O/T

HF,

–10

° to

–15°

; to

rt, 1

5 h

R1

H t-B

u

Ph Ph

(37)

(31)

(38)

(39)

133

R2

Me

Me

Me

Et

(R2 ) 2

N

H N

H N Et 2

N

(43)

1. n

-BuL

i (2.

1 eq

), T

HF,

hex

ane,

0°

2. 2

,4,6

-Me 3

C6H

2SO

2ON

Et 2

, –78

° to

rt; r

t, ov

erni

ght

136

C15

O PhOC

14

1. K

NH

2, N

H3

(liq

), E

t 2O

2. P

hN=

NPh

OO

PhN

(30)

212

NH

Ph

Ph

141

Subs

trat

eR

efs.

Con

ditio

nsPr

oduc

t(s)

and

Yie

ld(s

) (%

)

TA

BL

E 1

D. A

RY

LM

ET

HY

L A

ND

HE

TE

RO

AR

YL

ME

TH

YL

CA

RB

AN

ION

S (C

onti

nued

)

C19

ClN

H2,

Et 2

O, s

onic

atio

n

(67)

355

R Me

2,4,

6-M

e 3C

6H2

Solv

ent(

s)

Et 2

O o

r T

HF

Et 2

O o

r E

t 2O

/TH

F

(60)

(30)

134

133

Tem

p, T

ime

–30°

to 0

°–1

0° to

–20

°; r

t, 15

h

RSO

2ON

Me 2

Cn

Ph Li

n

Ph NH

2n

1. M

eON

HL

i, T

HF,

Et 2

O, h

exan

e, –

78° t

o –1

5°, 2

h

2. M

eOH

(93)

808

d

a The

rea

ctio

n w

as c

arri

ed o

ut w

ith b

oth

R a

nd S

ena

ntio

mer

s (C

MeP

h); t

he o

ptic

al y

ield

s w

ere

5-46

%.

b X w

as n

ot s

peci

fied

.c S

ome

of th

e tr

iaze

nes

are

isol

ated

as

mix

ture

s of

dou

ble-

bond

isom

ers.

d The

sub

stra

te w

as p

repa

red

by a

dditi

on o

f se

c-bu

tylli

thiu

m to

sty

rene

in b

enze

ne/T

HF

at r

oom

tem

pera

ture

.

PhL

i

PhPh

PhN

H2

PhPh

PhN

Me 2

PhPh

142

Subs

trat

eR

efs.

Con

ditio

nsPr

oduc

t(s)

and

Yie

ld(s

) (%

)

TA

BL

E 2

. VIN

YL

AN

D A

LL

EN

YL

CA

RB

AN

ION

S

C2-

3

R

MgB

rR

= H

, Me

PhN

2+ B

F 4– , T

HF

R

N(0

)18

5

C3

2,4,

6-M

e 3C

6H2S

O2O

NE

t 2, E

t 2O

or

Et 2

O/T

HF,

–10

° to

–20°

; to

rt, 1

4 h

(28)

133

C3-

8

OO

NO

SO2P

h

1.

,

Et 2

O, P

hCl,

0°; r

t 2 h

2. p

H 9

buf

fer

N

R2

R1

OO18

2

R1

H Ph

R2

Me

H

(93)

a

(100

)

MgB

rN

(0)

185

C6

MgB

r

R2

R1

PhN

2+ B

F 4– , T

HF

E:Z — 1:1

NPh

NPh

Li

NE

t 2

R2

MgB

r

R1

C4-

14

ArN

3, T

HF,

2 h

R2

N

R1

NN

HA

r

R1

Me

H H H Ph Ph Ph Ph

Ar

Ph Ph 4-M

eC6H

4

2-na

phth

yl

Ph 4-B

rC6H

4

4-M

eC6H

4

4-M

eOC

6H4

(—)

(55)

(72)

(48)

(63)

(31)

(56)

(55)

286

R2

Me

Ph Ph Ph Ph Ph Ph Ph

143

Subs

trat

eR

efs.

Con

ditio

nsPr

oduc

t(s)

and

Yie

ld(s

) (%

)

TA

BL

E 2

. VIN

YL

AN

D A

LL

EN

YL

CA

RB

AN

ION

S (C

onti

nued

)

C8

1. R

1 R2 N

Li,

TH

F, –

78° t

o –

40°,

40 m

in

2. 1

,2-(

O2N

) 2C

6H4,

TH

F, –

78°

3. O

2, –

78°,

30 m

in; t

o rt

55, 5

4

n-C

6H13

MgB

r1.

PhS

CH

2N3

(ia)

, pen

tane

, ben

zene

, TH

F, E

t 2O

,

–

75° t

o 0°

, 1 h

; 0°,

1 h

2. A

c 2O

, 30

min

n-C

6H13

NN

Ac

NSP

h(4

1)27

4

R1 Ti

•R

2

R3

X(i

-PrO

) 2R

4 O2C

N=

NC

O2R

4 , Et 2

O, –

78° t

o rt

, 1 h

b

R1

R2

R3

R4 O

2CN

NH

CO

2R4

360

R1

TM

S

n-C

5H11

TM

S

TM

S

Me

n-B

u

TM

S

TM

S

TM

S

TM

S

TM

S

R2

H H i-B

u

i-B

u

i-B

u

Me

Me

Me

Me

n-B

u

i-B

u

R3

H H H H H H (CH

2)3P

r-i

(CH

2)3P

r-i

H H H

R4

t-B

u

t-B

u

t-B

u

Et

t-B

u

t-B

u

t-B

u

Et

t-B

u (S

) 94

% e

e

t-B

uc 9

6% e

e

t-B

uc 96

% e

e

(49)

(51)

(75)

(52)

(62)

(61)

(61)

(50)

(77)

81%

ee

(S)

(73)

53%

eea

(74)

27%

eea

X =

OC

O2E

t or

OP(

O)(

OE

t)2

C7-

12

R1

i-Pr

i-Pr

R2

Me

Bn

(60)

(56)

PhC

u(C

N)L

iPh

NR

1 R2

144

Ar

MgB

rA

r

Ar

C20

Ar

N=

NN

HPh

Ar

Ar

PhN

3

(59)

(50

)d

(35)

d

287,

288

288

Ar

Ph 4-M

eOC

6H4

Solv

ent

Et 2

O

TH

F

a The

con

figu

ratio

n w

as n

ot r

epor

ted.

b T

he s

ubst

rate

was

pre

pare

d by

rea

ctio

n of

[X

= O

CO

2Et o

r O

P(O

)(O

Et)

2] w

ith T

i(O

Pr-i

)4

and

two

equi

vale

nts

of i-

PrM

gBr.

c T

he s

ubst

rate

was

a s

ingl

e en

antio

mer

of

unsp

ecif

ied

conf

igur

atio

n.

d The

sub

stra

te h

ad 14

C in

the

2-po

sitio

n.

R1 C

CC

R2 R

3 X

Tem

p

rt 0°

Tim

e

3 h

1 h

145

Subs

trat

eR

efs.

Con

ditio

nsPr

oduc

t(s)

and

Yie

ld(s

) (%

)

TA

BL

E 3

. ET

HY

NY

L C

AR

BA

NIO

NS

C2-

8

Me 2

NX

, Et 2

O

R TM

S

n-Pr

n-B

u

t-B

u

c-C

6H11

Phc

PhS

X Ph2P

(O)O

Ph2P

(O)O

Ph2P

(O)O

Ph2P

(O)O

Ph2P

(O)O

MsO

Ph2P

(O)O

(67)

(87)

b

(78)

(71)

(75)

(52)

(45)

PhN

3, E

t 2O

, 10

d28

9, 8

09C

2

C2-

81.

TsN

3, E

t 2O

, 0°

2. 2

-C10

H7O

H, r

t

3. H

+N

NN

H

RN

=NH

O

R H n-B

u

Ph

(tra

ce)

(31)

(10)

810

135

C3

N3

N3, E

t 2O

(90)

272

C8

ClN

Et 2

M Li

MgB

r

Solv

ent

diox

ane

Et 2

O

(2.3

)e

(1.7

)

71

Ph2P

(O)O

NH

2, T

HF,

–20

°; r

t, 12

h13

9

Ph RN

OSO

2Ar,

Et 2

O, 2

0°, 2

0 h

PhN

R Me

Ph

Ar

Ph 4-M

eC6H

4

(39)

(45)

178

R

MgB

rB

rMg

R3

RN

Me 2

a

NH

N=

NPh

d (1

-2)

PhN

=N

HN

Li

R

MgB

rN

HN

=N

2

PhM

PhN

Et 2

Ph2

Ph3

CuL

i 2Ph

a The

yie

lds

of th

is p

rodu

ct a

re b

ased

on

two

of th

e th

ree

acet

ylen

ic g

roup

s re

actin

g.b T

he y

ield

was

det

erm

ined

by

NM

R s

pect

rosc

opy.

c (Ph

enyl

ethy

nyl)

lithi

um u

nder

thes

e co

nditi

ons

prod

uced

no

ethy

nyla

min

e; th

e co

rres

pond

ing

Gri

gnar

d re

agen

t gav

e on

ly tr

aces

.

d The

pro

duct

was

a m

ixtu

re o

f tw

o is

omer

s.e T

he y

ield

rep

orte

d is

that

of

the

crud

e pr

oduc

t.f 2

-Phe

nyle

thyn

amin

e w

as f

orm

ed a

s an

inte

rmed

iate

.

CuL

i 2

CuL

iPh

CN

f(3

8)

Tem

p

50°;

rt

rt

Tim

e

—; 3

d

12 h

146

Subs

trat

eR

efs.

Con

ditio

nsPr

oduc

t(s)

and

Yie

ld(s

) (%

)

TA

BL

E 4

. AR

YL

CA

RB

AN

ION

S

PhM

gCl

PhN

H2

58, 5

6(2

7)

ArL

i (3

eq)

ClN

H2,

Et 2

OA

rNH

258

PhC

u(C

N)Z

nCl

1. R

1 R2 N

Li,

TH

F, –

78° t

o –9

0°, 4

0 m

in

2. 1

,2-(

O2N

) 2C

6H4,

TH

F, –

78°

3. O

2, –

78°,

30 m

in

PhN

R1 R

255

R1

H i-Pr

Ph Ph

R2

Ph i-Pr

Ph Bn

(69)

(70)

(76)

(68)

OE

t

Li

OE

t

Ph2C

uLi

1. R

1 R2 N

H, s

olve

nt, r

eflu

x, 6

h

2. O

2, –

78°

PhN

R1 R

252

R1

Me

n-B

u

Ph

R2

Ph n-C

7H15

Ph

(72)

(64)

(94)

1.

(

5 eq

), T

HF,

hex

ane,

ref

lux,

2 h

2. O

2

OE

t

N OE

t

(51)

52

C6

NC

u

ClN

H2,

pet

rol e

ther

, 0°;

rt,

over

nigh

t

Solv

ent

TH

F

Et 2

O

Et 2

O

ArC

u(C

N)L

i

NH

Li

R

1.

,

TH

F, –

40°,

15 m

in

2. O

2, –

78°,

20 m

in; t

o rt

NH

Ar

Ar

Ph 2-M

eOC

6H4

2-B

nOC

6H4

(48)

(55)

(46)

54

Ar

Ph 4-M

eC6H

4

Tem

p

–50° 0°

(33)

(16)

147

Subs

trat

eR

efs.

Con

ditio

nsPr

oduc

t(s)

and

Yie

ld(s

) (%

)

TA

BL

E 4

. AR

YL

CA

RB

AN

ION

S (C

onti

nued

)

Ar1 M

gCl•

LiC

l, T

HF,

–45

°, 15

min

73C

lN

Ar2

R1

R2

Ar1

NA

r2

R1

R2

Ar1

Ph 4-IC

6H4

3-N

CC

6H4

3-N

CC

6H4

4-N

CC

6H4

2-E

tO2C

C6H

4

2-E

tO2C

C6H

4

4-M

eO2C

C6H

4

4-M

eO2C

C6H

4

4-M

eO2C

C6H

4

1-na

phth

yl

Ar2

Ph Ph 4-B

rC6H

4

1-na

phth

yl

Ph Ph Ph Ph 4-B

rC6H

4

Ph Ph

R1

H H H Me

Me

(R)

H Me

(R)

H H Me

(S)

H

R2

Me

Et

Me

Me

Me

Et

Me

Me

Me

n-C

6H13

Me

(57)

(33)

(70)

(65)

(70)

99%

ee

(67)

(67)

99%

ee

(64)

(73)

(34)

98%

ee

(56)

C6-

7

PhM

gBr

R1 R

2 NC

l, E

t 2O

, 0°;

rt,

12 h

R1 , R

2 = M

e, M

e; E

t, E

t; —

(CH

2)5—

PhN

R1 R

2 (0)

69

PhM

gBr

H2N

OH

, Et 2

O, 0

°, 30

min

; rt,

15 m

inPh

NH

2 (

4)81

1

M =

MgB

r, (

CuM

gBr)

0.5,

Zn 0

.5C

uCN

Ar

= P

h, 3

-BrC

6H4,

4-B

rC6H

4, 3

-MeC

6H4,

4-M

eC6H

4, 3

-MeO

C6H

4, 4

-MeO

C6H

4H2N

OM

e (2

eq)

, TH

F, –

15°

ArN

H2

(—

)a91

PhM

gCl (

4 eq

)N

Cl 3

, Et 2

OPh

NH

2 (4

) +

Ph 2

NH

(1)

77

C6

ArM

148

C6-

10

ArM

RO

NH

2A

rNH

2

M Li

Li

MgB

r

MgI

MgB

r

MgI

Zn 0

.5

ZnC

l

Ph2Z

nLi

MgB

r

MgB

r

ZnC

l

Zn(

C6H

4OM

e-4)

MgB

r

R Me

Bn

Me

Me

Bn

Bn

Me

Me

Me

Me

Bn

Me

Me

Bn

Add

end

— — — — — — — CuC

N

CuC

N

— — CuC

N

CuC

N

—

Solv

ent

Et 2

O

Et 2

O

Et 2

O

Et 2

O

Et 2

O

Et 2

O

TH

F

TH

F

TH

F

Et 2

O

Et 2

O

TH

F

TH

F

Et 2

O

Tem

p

–10°

to –

15°

–10°

to –

15°

–10°

to –

15°

–10°

to –

15°

–10°

to –

15°

–10°

to –

15°

rt rt rt

–10°

to –

15°

–10°

to –

15°

rt rt

–10°

to –

15°

Ar

Ph Ph Ph Ph Ph Ph Ph Ph Ph 4-B

rC6H

4

4-B

rC6H

4

4-M

eC6H

4

4-M

eOC

6H4

1-na

phth

yl

792

80 792

792

80 80 177

176

176

792

80 176

176

80

(63)

b

(72)

b

(67)

b

(0.3

)b

(57)

b

(7)b

(41)

c

(70)

(92)

(73)

b

(58)

b

(65)

c

(65)

c

(25)

b

Tim

e

— — — — — — 3 h

3 h

3 h

— — 3 h

3 h

—

C6-

8

ArL

i

1. M

eON

HL

i (2

eq, i

a), E

t 2O

, hex

ane,

–7

8° to

–15

°, 2

h

2. B

zCl

ArN

HB

z(9

0)d

(46)

(98)

(73)

(28)

(96)

(93)

(14)

e

(78)

82, 8

3,

177,

786

83 83, 7

86

83 83 82 83 82 83

Ar

Ph 3-C

lC6H

4

2-M

eOC

6H4

3-M

eOC

6H4

4-M

eOC

6H4

2-M

eC6H

4

4-M

eC6H

4

2-(i

-Pr)

2NC

OC

6H4

2-E

tC6H

4

149

Subs

trat

eR

efs.

Con

ditio

nsPr

oduc

t(s)

and

Yie

ld(s

) (%

)

TA

BL

E 4

. AR

YL

CA

RB

AN

ION

S (C

onti

nued

)

Ar1 L

i1.

R1 N

(Li)

OR

2 (ia

), s

olve

nt(s

), te

mp,

tim

e

2. A

r2 CO

Cl

Ar1 N

R1 C

OA

r2

Ar1

Ph Ph Ph Ph 2-(i

-Pr)

2NC

OC

6H4

R1

Me

n-C

5H11

f

Bnf

PhC

HM

e

Me

Solv

ent(

s)

Et 2

O, h

exan

e

TH

F

TH

F

Et 2

O, h

exan

e

Et 2

O, h

exan

e

Tem

p, T

ime

–78°

to –

15°,

3 h

0° to

40°

, 1-3

h

0° to

40°

, 1-3

h

78° t

o –1

5°, 3

h; t

o 40

°78

° to

–15°

, 3 h

Ar2

Ph 4-Ph

C6H

4

4-M

eOC

6H4

Ph Ph

(67)

(47)

(37)

(44)

(0)

97, 8

2

98 98 97 97

R2

Me

Bn

Bn

Me

Me

C6

Ar

Ph Ph Ph Ph 4-FC

6H4

4-FC

6H4

3-M

eOC

6H4

3-M

eOC

6H4

4-M

eOC

6H4

4-M

eOC

6H4

4-M

eOC

6H4

4-M

eC6H

4

4-M

eC6H

4

4-M

eC6H

4

R TM

S

Me

i-Pr

t-B

u

i-Pr

t-B

u

Me

t-B

u

TM

S

Me

i-Pr

Me

i-Pr

t-B

u

100

101

101

101

101

101

101

101

100

101

101

101

101

101

C6-

7

Tem

p

–50°

–50°

to r

t

–50°

to r

t

–50°

to r

t

–50°

to r

t

–50°

to r

t

–50°

to r

t

–50°

to r

t

–50°

–50°

to r

t

–50°

to r

t

–50°

to r

t

–50°

to r

t

–50°

to r

t

Ar 2

Cu(

CN

)Li 2

1. R

NH

OT

MS,

TH

F, te

mp,

tim

e

2. H

Cl,

then

bas

e

ArN

HR

(90)

R =

Hb

(58)

(64)

(53)

(45)

(45)

(59)

(73)

(70)

R =

Hb

(88)

(73)

(57)

(67)

(65)

Tim

e

1 h

2 h

2 h

2 h

2 h

2 h

2 h

2 h

1 h

2 h

2 h

2 h

2 h

2 h

150

C6

PhM

gBr

1. M

e 2N

OT

s, E

t 2O

, rt,

10 m

in

2. H

Cl

PhN

HM

e 2+ C

l– (50

)13

2

ArC

uC

H2=

CH

CH

2O2C

N(L

i)O

R,

TH

F, –

78°

130

Ar

Ph Ph 3-FC

6H4

4-M

eOC

6H4

4-M

eOC

6H4

1-na

phth

yl

R Ms

Ts

Ts

Ms

Ts

Ts

Tim

e

1 h

1 h

3 h

3 h

3 h

4 h

(51)

(51)

(44)

(52)

(68)

(57)

C6-

10

ArM

t-B

uO2C

N(L

i)O

Ts,

TH

F

Ar

Ph Ph 4-FC

6H4

2-M

eOC

6H4

M Li

Cu

Cu

Cu

Tem

p

–78°

to 0

°0° –78°

–78°

to 0

°

Tim

e

2 h

2 h

30 m

in

2 h

(10)

(51)

(50)

(73)

127

127,

126

127

127

C6

OO1.

n-B

uLi,

TH

F, E

t 2O

, hex

ane,

0°,

2 h;

rt,

22 h

2. C

uI, 0

°, 15

min

3. t-

BuO

2CN

(Li)

OT

s, –

78°,

30 m

in; 0

°, 2

hOO

NH

CO

2Bu-

t

(45)

128

PhM

gBr

1. M

e 2N

OT

s, E

t 2O

, rt,

10 m

in

2. H

Cl

PhN

HM

e 2+ C

l– (50

)13

2

C6-

10

2,4,

6-M

e 3C

6H2S

O2O

NR

2, E

t 2O

or

Et 2

O/T

HF,

–10

° to

–15°

; to

rt, 1

5 h

ArM

gBr

ArN

R2

133

Ar

Ph 1-na

phth

yl

R Et

Me

(42)

(69)

OH N

O

Ar

OB

u-t

H N

O

Ar

151

Subs

trat

eR

efs.

Con

ditio

nsPr

oduc

t(s)

and

Yie

ld(s

) (%

)

TA

BL

E 4

. AR

YL

CA

RB

AN

ION

S (C

onti

nued

)

C6-

7A

rBr

ArN

Me 2

801

Mg,

Me 2

NO

SO2C

6H2M

e 3-2

,4,6

,

Mg,

TH

F, r

t, 2

h

Ar

Ph 2-M

eC6H

4

3-M

eC6H

4

4-M

eC6H

4

3-M

eOC

6H4

4-M

eOC

6H4

(81)

(60)

(83)

(79)

(78)

(80)

C6-

9

ArM

gBr

R1 R

2 NO

Bz

+ C

uCl 2

(x

mol

%, i

a, s

low

add

ition

),

T

HF,

rt,

15 m

in

ArN

R1 R

211

3

Ar

Ph Ph Ph Ph Ph Ph Ph 4-FC

6H4

2-M

eC6H

4

2-M

eC6H

4

2-M

eC6H

4

4-M

eOC

6H4

4-M

eOC

6H4

4-M

eOC

6H4

4-M

eOC

6H4

2,4,

6-M

e 3C

6H2

2,4,

6-M

e 3C

6H2

R1

s-B

u

—(C

H2)

2O(C

H2)

2—

—(C

H2)

2O(C

H2)

2—

—

(CH

2)5—

—

(CH

2)5—

Bn

Bn

Bn

Et

—(C

H2)

2O(C

H2)

2—

—

(CH

2)5—

Et

Et

Et

Et

Et

—

(CH

2)5—

R2

H Bn

Bn

Bn

Et

Et

Et

Et

Et

Et

Et

x 5 2.5

10 2.5

10 5 10 10 2.5

2.5

2.5 5 10 25 50 2.5

2.5

(tra

ce)

(37)

(68)

(52)

(64)

(20)

(92)

(58)

(61)

(7)

(75)

(65)

(75)

(26)

(8)

(80)

(61)

152

PhM

gBr

x e

q

Et 2

NO

CO

R (

slow

ia d

urin

g 7

min

),

CuC

l 2 (

3 m

ol%

), Z

nCl 2

(y

eq),

TH

F, r

t; rt

, 15

min

PhN

Et 2

R EtO

t-B

u

Ph Ph Ph 4-M

eOC

6H4

4-M

eOC

6H4

4-M

e 2N

C6H

4

4-M

e 2N

C6H

4

2-M

eC6H

4

2-M

eC6H

4

2,4,

6-M

e 3C

6H2

2,4,

6-M

e 3C

6H2

(27)

(83)

(89)

(87)

(84)

(79)

(62)

(79)

(81)

(89)

(74)

(82)

(75)

x 2.2

2.2

1.1

2.2

2.2

2.2

2.2

2.2

2.2

2.2

2.2

2.2

2.2

y 0 0 0 0 0.1 0 0.1 0 0.1 0 0.1 0 0.1

113

N OB

zN Ph

(ia)

, CuC

l 2 (

2.5

mol

%),

TH

F, r

t(0

)11

3

ArZ

nCl

R1 R

2 NO

Bz,

(Ph

3P) 2

NiC

l 2 (

cat)

,

TH

F, r

t, 10

min

to 6

h

ArN

R1 R

210

8

Ar

Ph Ph Ph 4-C

lC6H

4

4-M

eOC

6H4

4-M

eOC

6H4

4-M

eOC

6H4

2-M

eC6H

4

4-C

F 3C

6H4

4-N

CC

6H4

4-E

tO2C

C6H

4

R1

Et

—(C

H2)

5—

—(C

H2)

2O(C

H2)

2—

—(C

H2)

2O(C

H2)

2—

Et

—(C

H2)

5—

—(C

H2)

2O(C

H2)

2—

—(C

H2)

2O(C

H2)

2—

—(C

H2)

2O(C

H2)

2—

—(C

H2)

2O(C

H2)

2—

—(C

H2)

2O(C

H2)

2—R2

Et

Et

(71)

(77)

(89)

(84)

(92)

(92)

(89)

(73)

(82)

(56)

(59)

C6-

7

153

Subs

trat

eR

efs.

Con

ditio

nsPr

oduc

t(s)

and

Yie

ld(s

) (%

)

TA

BL

E 4

. AR

YL

CA

RB

AN

ION

S (C

onti

nued

)

Ph2Z

n1.

(67)

111

2. S

ubst

rate

, TH

F, 0

-5°,

1.5

hO

NPh

C6

NO

Bz,

CuC

l 2 (

2.5

mol

%),

TH

F, 0

-5°

O

PhM

x e

q

NO

Bz,

Cu

sour

ce (

y eq

), T

HF

NPh

113

M Li

Li

Li

MgB

r

MgB

r

ZnB

r

ZnB

r

ZnP

h

x 1 2 2 1 1 2 2 1.1

y 1 1 1 1 1 1 1

0.05

Cu

sour

ce

CuB

r•M

e 2S

CuB

r•M

e 2S

Li 2

CuC

l 3

CuB

r•M

e 2S

Li 2

CuC

l 3

CuB

r•M

e 2S

Li 2

CuC

l 3

CuC

l

(55)

(68)

(72)

(56)

(68)

(68)

(78)

(88)

Et 2

NO

CO

R, T

HF

PhN

Et 2

113

M MgB

r

MgB

r

MgB

r

MgB

r

MgB

r

MgB

r

MgB

r

MgB

r

MgB

r

Li

Li

Li

x 2.2

2.2

2.2

2.2

1.1

1.1

1.1

1.1

1.1

2.2

2.2

2.2

R EtO

t-B

u

t-B

u

t-B

u

Ph 2-M

eC6H

4

4-M

eOC

6H4

4-M

e 2N

C6H

4

2,4,

6-M

e 3C

6H2

2,4,

6-M

e 3C

6H2

2,4,

6-M

e 3C

6H2

2,4,

6-M

e 3C

6H2

Tem

p

rt 0° rt 44°

rt rt rt rt rt

–30° 0° rt

(14)

(37)

(54)

(57)

(9)

(18)

(17)

(21)

(85)

(50)

(46)

(36)

154

Ar 2

Zn

1.1

eqg

R1 R

2 NO

Bz

(ia)

, (C

uOT

f)2•

PhH

(ca

t),

TH

F, r

t, 15

to 6

0 m

in

ArN

R1 R

2

Ar

Ph Ph Ph Ph Ph Ph Ph Ph Ph 2-M

eOC

H2O

C6H

4h

2-E

t 2N

CO

C6H

4h

3-FC

6H4

4-FC

6H4

4-C

lC6H

4

4-C

lC6H

4

4-M

eOC

6H4

4-M

eOC

6H4

4-M

eOC

6H4

4-A

cOC

6H4

4-T

fOC

6H4

2-O

2NC

6H4

2-O

2NC

6H4

2,4-

(O2N

) 2C

6H3

2-M

eC6H

4

2-M

eC6H

4

2-M

eC6H

4

2-M

eC6H

4

3-C

F 3C

6H4

R1

s-B

u

i-B

u

Et

—(C

H2)

2O(C

H2)

2—

—

(CH

2)5—

i-Pr

CH

2CH

=C

H2

t-B

uCH

2CM

e 2

Bn

—(C

H2)

2O(C

H2)

2—

—(C

H2)

2O(C

H2)

2—

—(C

H2)

2O(C

H2)

2—

—(C

H2)

2O(C

H2)

2—

—(C

H2)

2O(C

H2)

2—

Bn

—(C

H2)

2O(C

H2)

2—

—

(CH

2)5—

Bn

—(C

H2)

2O(C

H2)

2—

—(C

H2)

2O(C

H2)

2—

—(C

H2)

2O(C

H2)

2—

Bn

—(C

H2)

2O(C

H2)

2—

Et

—(C

H2)

2O(C

H2)

2—

—

(CH

2)5—

i-Pr

—(C

H2)

2O(C

H2)

2—R2

H H Et

i-Pr

CH

2CH

=C

H2

H Bn

Bn

Bn

Bn

Et

i-Pr

(80)

(71)

(69)

(91)

(91)

(72)

(96)

(74)

(94)

(95)

(62)

(74)

(71)

(74

)i

(93)

(88)

(93)

(71

)i

(95)

(87)

(76)

(95)

(83

)i

(83)

(97)

(59)

(70)

(94)

(86)

i

(62)

(74)

C6-

10

112,

109

,

111

155

Subs

trat

eR

efs.

Con

ditio

nsPr

oduc

t(s)

and

Yie

ld(s

) (%

)

TA

BL

E 4

. AR

YL

CA

RB

AN

ION

S (C

onti

nued

)

Ar 2

Zn

1.1

eqg

(T

able

con

tinu

ed fr

om p

revi

ous

page

.)

ArN

R1 R

2

Ar

2-(4

,4-d

imet

hyl-

4,5

-dih

ydro

oxaz

ol-2

-yl)

]phe

nylh

4-N

CC

6H4

4-N

CC

6H4

4-E

tO2C

C6H

4

4-E

tO2C

C6H

4

4-(i

-Pr)

2NC

OC

6H4h

4-(2

-met

hyl-

1,3

-dio

xola

n-2-

yl)p

heny

l

2,4,

6-M

e 3C

6H2

1-na

phth

yl

R1

—(C

H2)

2O(C

H2)

2—

—(C

H2)

2O(C

H2)

2—

Bn

—(C

H2)

2O(C

H2)

2—

Bn

—(C

H2)

2O(C

H2)

2—

—(C

H2)

2O(C

H2)

2—

i-Pr

—(C

H2)

2O(C

H2)

2—

R2

Bn

Bn

i-Pr

(55)

(76)

(74

)i

(95)

(77)

(99)

(88)

(79)

(76)

(90)

C6-

10

112,

109

,

111

X Cl

Br

Br

(35)

(22)

(31)

ArM

gXPh

2P(O

)ON

H2,

TH

F, –

20°;

rt,

12 h

ArN

H2

139

Ar

Ph Ph 1-na

phth

yl

PhM

gBr

4-M

eOC

6H4N

=C

(CO

2Et)

2 (i

a),

TH

F, –

95°,

30 m

in

167,

166

PhN

CH

(CO

2Et)

2

4-M

eOC

6H4

(59)

PhM

gBr

2

eq

1. P

hCH

=N

OR

, Et 2

O,

heat

2. H

Cl

175

R H Me

Bn

(—)

(—)

(68)

PhM

gBr

3

eqN

HOO

O, –

78° t

o 0°

, 1 h

NH

Ph

OH

O

O(~

100)

C6

104

PhN H

Ph

Ph •HC

l

156

C6-

7

ArM

gXj

x

eqM

e 2C

=N

OR

, tol

uene

ArN

H2

174a

Ar

Ph Ph 4-C

lC6H

4

2-M

eOC

6H4

4-M

eOC

6H4

4-M

eC6H

4

4-M

eC6H

4

x 1 2 2 2 2 1 2

(62)

(35)

(20)

(18)

(12)

(70)

(31)

C6

PhL

i

3

eq

Me 2

C=

NO

HI

+

P

hNH

2 I

I

I +

II

(—),

I:I

I =

4:1

174a

ArL

i

NO

1. Z

nCl 2

, TH

F, 0

°; to

rt

2.

, N

i(ac

ac) 2

(ca

t), 2

h

CH

O

NH

Ar

Ar

Ph 2-M

eOC

6H4

3-M

eOC

6H4

4-M

eOC

6H4

(86)

(61)

(70)

(79)

170

R MgB

r

H H H H MgB

r

H

PhN

HPh

ArM

gBr

NM

eM

eN

NO

Ts

(ia)

, tol

uene

, Et 2

O

NM

eM

eN

NA

r18

1

Ar

Ph 2-M

eOC

6H4

2,4-

(MeO

) 2C

6H3

2-M

eC6H

4

4-C

F 3C

6H4

2,6-

Me 2

C6H

3

1-na

phth

yl

Tem

p

0°0°

to r

t

0° to

rt

0° 0°0°

to r

t

0°

Tim

e

15 m

in

30 m

in

30 m

in

15 m

in

15 m

in

30 m

in

30 m

in

(98)

k

(99)

k

(96)

k

(96)

k

(88)

l

(85)

m

(>99

)k

C6-

10

157

Subs

trat

eR

efs.

Con

ditio

nsPr

oduc

t(s)

and

Yie

ld(s

) (%

)

TA

BL

E 4

. AR

YL

CA

RB

AN

ION

S (C

onti

nued

)

PhM

gBr

181

R1

—

O(C

H2)

2O—

EtO

—N

Me(

CH

2)2O

—

—O

(CH

2)2N

Me—

—N

Me(

CH

2)2N

Me—R2

EtO

Solv

ent

tolu

ene

tolu

ene

tolu

ene

CH

2Cl 2

tolu

ene

(66)

(<10

)

(97)

(0)n

(98)

R1

R2

NO

Ts

R1

R2

NPh

(ia)

Tem

p

0°–3

0° to

rt

rt 0° 0°

ArM

gBr

R2C

=N

OSO

2C6H

2Me 3

-2,4

,6 (

0.6-

0.8

eq),

cat

alys

t, E

t 2O

, tol

uene

, 60°

ArN

H2p

803

Ar

Ph Ph Ph Ph 4-M

eC6H

4

4-M

eC6H

4

1-na

phth

yl

(58)

(59)

(56)

(59)

(36)

(58)

(0)

R Me

Me

Me

Ph Me

Me

Me

Cat

alys

t

— CuI

MgC

l 2

CuI

— MgC

l 2

—

Tim

e

40 h

11 h

22h

2.5

h

46 h

20 h

—

C6

Tim

e

1 h

12 h

30 m

in

30 m

in

15 m

in

C6-

10

ArN

H3+

Cl–

182

OO

NO

SO2R

1.

(i

a), E

t 2O

, cos

olve

nt, t

emp,

tim

e 1

2. M

etho

d A

: HC

l, M

eOH

, Et 2

O, r

t, tim

e 2

or

M

etho

d B

: HC

l, E

tOH

, H2O

, ref

lux,

tim

e 2

158

Ar

Ph 4-FC

6H4

2-M

eOC

6H4

3-M

eOC

6H4

4-M

eOC

6H4

2,4-

(MeO

) 2C

6H3

4-M

eC6H

4

4-M

eC6H

4

4-M

eC6H

4

4-M

eC6H

4

4-C

F 3C

6H4

2,6-

Me 2

C6H

3

1-na

phth

yl

R Ph Ph Ph Ph Ph Ph Meo

Ph 4-M

eC6H

4

2,4,

6-M

e 3C

6H2

Ph Ph Ph

Cos

olve

nt

PhC

l

CH

2Cl 2

CH

2Cl 2

CH

2Cl 2

PhC

l

CH

2Cl 2

CH

2Cl 2

PhC

l

CH

2Cl 2

CH

2Cl 2

PhC

l

PhC

l

CH

2Cl 2

Tem

p

0° rt rt rt 0° rt — 0° — — 0° 0° rt

Tim

e 1

0.5

h

1 h

0.5

h

0.5

h

0.5

h

1 h

— 0.5

h

— — 1 h

1 h

0.5

h

Met

hod

A A A A A A A A A A A B A

Tim

e 2

1.5

h

1.5

h

2 h

2.5

h

2.5

h

6.5

h

— 1.5

h

— — 0.5

h

3 h

1 h

(93)

(90)

(96)

(90)

(96)

(91)

(86)

(97)

(90)

(80)

(94)

(90)

(93)

ArZ

nCl

1. M

e 2C

=N

OSO

2C6H

2Me 3

-2,4

,6 (

2 eq

),

C

uCN

(10

mol

%),

DM

PU (

2 eq

), r

t, 3

h

2. c

onc.

HC

l, th

en b

ase

3. B

zCl

ArN

HB

z81

2

Ar

Ph 3-B

rC6H

4

4-M

eOC

6H4

4-M

eC6H

4

1-na

phth

yl

(78)

(70)

(75)

(72)

(79)

159

Subs

trat

eR

efs.

Con

ditio

nsPr

oduc

t(s)

and

Yie

ld(s

) (%

)

TA

BL

E 4

. AR

YL

CA

RB

AN

ION

S (C

onti

nued

)

ArM

Me 2

C=

NO

SO2C

6H2M

e 3-2

,4,6

,

CuC

N (

cat)

, TH

F

ArN

H2

R Ph Ph Ph Ph Ph Ph 4-B

rC6H

4

4-M

eOC

6H4

4-M

eC6H

4

4-E

tO2C

C6H

4

M ZnC

l

Ph2Z

nLi

PhZ

n

Cu(

CN

)Li

Cu(

CN

)ZnC

l

Ph2Z

nMgB

r

ZnC

l

ZnC

l

ZnC

l

ZnC

l

Tem

p

rt rt rt rt 0° rt rt rt rt rt

Tim

e

3 h

3 h

3 h

3 h

1 h

3 h

3 h

3 h

3 h

3 h

(70)

(79)

(44)

(76)

c

(57)

(85)

(33)

(54)

c

(49)

c

(51)

176,

177

176

176

177

176

177

177

176,

177

176,

177

177

C6-

7

Me 2

C=

NO

SO2C

6H2M

e 3-2

,4,6

,

TH

F, r

eflu

x, 1

-2 h

ArN

H2

(—)a

183

ArB

r

1. M

g, M

e 2C

=N

OSO

2C6H

4Me 3

-2,4

,6,

T

HF,

ref

lux,

3 h

2. B

zCl

ArN

HB

z80

2

Ar

Ph 4-M

eOC

6H4

4-M

eC6H

4

1-na

phth

yl

(52)

(40)

(53)

(40)

ArM

gBr

1. [

3,5-

(CF 3

) 2C

6H3]

2C=

NO

Ts

(ia)

,

E

t 2O

, tol

uene

, rt,

30 m

in

2. B

zCl,

Et 3

N

ArN

HB

z17

9

Ar

Ph 4-FC

6H4

2-M

eOC

6H4

3-M

eOC

6H4

4-M

eOC

6H4

4-C

F 3C

6H4

2,4-

Me 2

C6H

3

1-na

phth

yl

(96)

(86)

(72)

(94)

(98)

(71)

b

(98)

(91)

C6-

10

ArM A

r =

Ph,

3-B

rC6H

4, 4

-BrC

6H4,

4-M

eOC

6H4,

3-M

eC6H

4, 4

-MeC

6H4;

M =

MgB

r or

Cu(

CN

)ZnC

l

160

C6-

14

ArM

gBr

NO

Ts

Ph

PhPh

Ph(i

a), T

HF,

–78

°, 45

-90

min

NA

r

Ph

PhPh

Ph18

0

Ar

Ph 2,3,

5,6-

Me 4

C6H

1-na

phth

yl

2-na

phth

yl

9-ph

enan

thry

l

(95)

(65-

68)

(70)

(78)

(83)

PhM

gBr

N2

PhL

i, F

eCl 3

(—)

787

CH

2=N

2, E

t 2O

, 0°

(8)

200

CH

2=N

2, E

t 2O

, rt

(48)

b20

2

EtO

2CC

H=

N2,

Et 2

O, c

oolin

g(—

)19

9

(NC

) 2C

=N

2, E

t 2O

, coo

ling

(66)

203

PhC

u(C

N)L

i1.

Me 2

NN

HL

i, T

HF,

–40

°, 40

min

2. O

2, –

78°,

30 m

in

(40)

54

C6

Ph2C

=N

2, E

t 2O

, rt,

30 m

in(7

0)20

2

(PhS

O2)

2C=

N2

(ia)

, Et 2

O, 3

0 m

in(5

4)20

4

PhM

gBr

O

N2

O

NN

HPh

, Et 2

O, c

oolin

g20

1(—

)

Ph

H NN

Me 2

NN

HPh

Ph

H NN

HPh

Ph

NN

HPh

Ph Ph

OH

NC

NN

HPh

CN

Fe

NN

Ph

NN

Ph

NN

HPh

Ph

Ph

NN

HPh

PhSO

2 PhSO

2

161

Subs

trat

eR

efs.

Con

ditio

nsPr

oduc

t(s)

and

Yie

ld(s

) (%

)

TA

BL

E 4

. AR

YL

CA

RB

AN

ION

S (C

onti

nued

)

C6-

7

Ar 3

ZnM

gBr

PhN

2+ B

F 4– , T

HF,

0°,

1 h

190

Ar

Ph 4-B

rC6H

4

4-M

eOC

6H4

4-M

eC6H

4

(87)

(74)

(72)

(88)

ArM

1. P

hN2+

BF 4

– , TH

F, a

dden

d, te

mp,

tim

e

2. H

Cl

3. N

aBH

4, N

iCl 3

•6 H

2O, M

eOH

, 0°,

1 h

ArN

H2

190

Ar

Ph Ph (4-M

eC6H

4)3

M MgB

r

MgB

r

ZnB

r

Add

end

— TM

ED

A (

0.3

eq)

—

Tem

p

–78°

–15°

–15°

Tim

e

3 h

3 h

1 h

(53)

p

(57)

p

(67)

p

Ar1 M

gBr

Ar2 N

2+ Z

nCl 3

– (i

a), E

t 2O

, ref

lux;

rt,

60 m

inC

6-10

Ar1

Ph Ph Ph Ph Ph 2-B

rC6H

4

2-B

rC6H

4

3-B

rC6H

4

3-B

rC6H

4

3-B

rC6H

4

4-B

rC6H

4

4-B

rC6H

4

Ar2

2-E

tO2C

C6H

4

3-E

tO2C

C6H

4

4-E

tO2C

C6H

4

1-na

phth

yl

2-na

phth

yl

1-na

phth

yl

2-na

phth

yl

3-M

eOC

6H4

1-na

phth

yl

2-na

phth

yl

1-na

phth

yl

2-na

phth

yl

(poo

r)

(43)

(42)

(22)

(11)

(3.5

)

(12)

(17)

(4)

(12)

(11)

(13)

187

187

187

188

188

188

188

189

188

188

188

188

Ar

NN

Ph

Ar1

NN

Ar2

162

2-M

eOC

6H4

2-M

eOC

6H4

2-M

eOC

6H4

2-M

eOC

6H4

2-M

eOC

6H4

3-M

eOC

6H4

3-M

eOC

6H4

3-M

eOC

6H4

3-M

eOC

6H4

3-M

eOC

6H4

3-M

eOC

6H4

4-M

eOC

6H4

4-M

eOC

6H4

4-M

eOC

6H4

4-M

eOC

6H4

4-M

eOC

6H4

4-M

eOC

6H4

2-M

eC6H

4

2-M

eC6H

4

2-M

eC6H

4

2-M

eC6H

4

2-M

eC6H

4

2-M

eC6H

4

2-M

eC6H

4

2-M

eC6H

4

2-M

eC6H

4

2-M

eC6H

4

2-M

eC6H

4

3-M

eC6H

4

3-M

eC6H

4

3-M

eC6H

4

3-M

eC6H

4

4-B

rC6H

4

2-M

eOC

6H4

3-B

rC6H

4

1-na

phth

yl

2-na

phth

yl

4-B

rC6H

4

2-M

eOC

6H4

3-M

eOC

6H4

4-M

eOC

6H4

1-na

phth

yl

2-na

phth

yl

3-B

rC6H

4

4-B

rC6H

4

2-M

eOC

6H4

4-M

eOC

6H4

1-na

phth

yl

2-na

phth

yl

2-B

rC6H

4

3-B

rC6H

4

4-B

rC6H

4

2-M

eOC

6H4

3-M

eOC

6H4

4-M

eOC

6H4

2-E

tO2C

C6H

4

3-E

tO2C

C6H

4

4-E

tO2C

C6H

4

1-na

phth

yl

2-na

phth

yl

2-B

rC6H

4

3-B

rC6H

4

4-B

rC6H

4

2-M

eOC

6H4

(2)

(1.4

)

(9)

(12)

(11)

(1)

(11)

(8)

(34)

(12)

(6)

(10)

(14)

(7)

(7)

(9)

(11)

(64)

(61)

(42)

(18)

(29)

(9)

(36)

(56)

(63)

(7)

(12)

(40)

(52)

(68)

(11)

189

189

189

188

188

189

189

189

189

188

188

189

189

189

189

188

188

186

186

186

189

189

189

187

187

187

188

188

186

186

186

189

163

Subs

trat

eR

efs.

Con

ditio

nsPr

oduc

t(s)

and

Yie

ld(s

) (%

)

TA

BL

E 4

. AR

YL

CA

RB

AN

ION

S (C

onti

nued

)

Ar1

3-M

eC6H

4

3-M

eC6H

4

3-M

eC6H

4

3-M

eC6H

4

3-M

eC6H

4

3-M

eC6H

4

3-M

eC6H

4

4-M

eC6H

4

4-M

eC6H

4

4-M

eC6H

4

4-M

eC6H

4

4-M

eC6H

4

4-M

eC6H

4

4-M

eC6H

4

4-M

eC6H

4

4-M

eC6H

4

4-M

eC6H

4

4-M

eC6H

4

1-na

phth

yl

1-na

phth

yl

1-na

phth

yl

2-na

phth

yl

2-na

phth

yl

2-na

phth

yl

Ar2

3-M

eOC

6H4

4-M

eOC

6H4

2-E

tO2C

C6H

4

3-E

tO2C

C6H

4

4-E

tO2C

C6H

4

1-na

phth

yl

2-na

phth

yl

2-B

rC6H

4

3-B

rC6H

4

4-B

rC6H

4

2-M

eOC

6H4

3-M

eOC

6H4

4-M

eOC

6H4

2-E

tO2C

C6H

4

3-E

tO2C

C6H

4

4-E

tO2C

C6H

4

1-na

phth

yl

2-na

phth

yl

2-E

tO2C

C6H

4

3-E

tO2C

C6H

4

4-E

tO2C

C6H

4

2-E

tO2C

C6H

4

3-E

tO2C

C6H

4

4-E

tO2C

C6H

4

(20)

(4)

(45)

(53)

(42)

(23)

(6)

(60)

(68)

(68)

(11)

(14)

(13)

(49)

(48)

(45)

(20)

(7)

(tra

ce)

(25)

(4)

(1)

(1)

(tra

ce)

189

189

187

187

187

188

188

186

186

186

189

189

189

187

187

187

188

188

188

188

188

188

188

188

Ar1 M

gBr

(T

able

con

tinu

ed fr

om p

revi

ous

page

.)

C6-

10

Ar1

NN

Ar2

164

Ar1 Z

nCl

Ar2 N

2+ B

F 4– , E

t 2O

, –10

°19

2

Ar1

Ph Ph Ph 4-C

lC6H

4

4-M

eOC

6H4

2,4,

6-M

e 3C

6H2

Ar2

4-C

lC6H

4

4-M

eOC

6H4

2,4,

6-M

e 3C

6H2

Ph Ph Ph

Tim

e

18 h

22 h

24 h

6 h

18 h

22 h

(10)

(2)

(0)

(35)

(20)

(8)

C6-

9

Ar1

NN

Ar2

165

Subs

trat

eR

efs.

Con

ditio

nsPr

oduc

t(s)

and

Yie

ld(s

) (%

)

TA

BL

E 4

. AR

YL

CA

RB

AN

ION

S (C

onti

nued

)

Ar1 M

gX1

Ar2 N

2+ (

X2 )– (

ia)

Ar1

Ph Ph Ph Ph Ph Ph Ph Ph Ph 4-C

lC6H

4

4-C

lC6H

4

4-C

lC6H

4

4-C

lC6H

4

4-C

lC6H

4

4-C

lC6H

4

4-C

lC6H

4

4-M

eOC

6H4

2-M

eC6H

4

4-M

eC6H

4

4-M

eC6H

4

4-M

eC6H

4

4-M

eC6H

4

4-M

eC6H

4

4-M

eC6H

4

4-M

eC6H

4

X1

— Br

— — — — — — Br

— — — — — — — Br

Br

— — — — — — —

Ar2

Ph Ph 2-C

lC6H

4

4-C

lC6H

4

3-B

rC6H

4

4-B

rC6H

4

3-M

eOC

6H4

4-M

eOC

6H4

1-na

phth

yl

Ph 2-C

lC6H

4

4-C

lC6H

4

3-B

rC6H

4

4-B

rC6H

4

3-M

eOC

6H4

4-M

eOC

6H4

Ph Ph Ph 2-C

lC6H

4

4-C

lC6H

4

3-B

rC6H

4

4-B

rC6H

4

3-M

eOC

6H4

4-M

eOC

6H4

X2

q BF 4

q q q q q q Cl

q q q q q q q BF 4

BF 4

q q q q q q q

Solv

ent

TH

F

TH

F

TH

F

TH

F

TH

F

TH

F

TH

F

TH

F

Et 2

O

TH

F

TH

F

TH

F

TH

F

TH

F

TH

F

TH

F

TH

F

TH

F

TH

F

TH

F

TH

F

TH

F

TH

F

TH

F

TH

F

(71)

(66)

(52)

(80)

(82)

(85)

(81)

(91)

(5)

(69)

(45)

(79)

(80)

(86)

(86)

(85)

(74)

(87)

(66)

(45)

(84)

(89)

(83)

(84)

(84)

191

185,

184

191

191

191

191

191

191

184

191

191

191

191

191

191

191

185

185

191

191

191

191

191

191

191

Con

ditio

ns

–78°

, 1 h

; 70°

, 1 h

r

–78°

–78°

, 1 h

; 70°

, 1 h

r

–78°

, 1 h

; 70°

, 1 h

r

–78°

, 1 h

; 70°

, 1 h

r

–78°

, 1 h

; 70°

, 1 h

r

–78°

, 1 h

; 70°

, 1 h

r

–78°

, 1 h

; 70°

, 1 h

r

ZnC

l 2, r

eflu

x, 1

5 m

in

–78°

, 1 h

; 70°

, 1 h

r

–78°

, 1 h

; 70°

, 1 h

r

–78°

, 1 h

; 70°

, 1 h

r

–78°

, 1 h

; 70°

, 1 h

r

–78°

, 1 h

; 70°

, 1 h

r

–78°

, 1 h

; 70°

, 1 h

r

–78°

, 1 h

; 70°

, 1 h

r

–78°

–78°

–78°

, 1 h

; 70°

, 1 h

r

–78°

, 1 h

; 70°

, 1 h

r

–78°

, 1 h

; 70°

, 1 h

r

–78°

, 1 h

; 70°

, 1 h

r

–78°

, 1 h

; 70°

, 1 h

r

–78°

, 1 h

; 70°

, 1 h

r

–78°

, 1 h

; 70°

, 1 h

r

C6-

7

Ar1

NN

Ar2

166

C6

Ph2Z

nA

rN2+

BF 4

– , DM

F, 0

°19

3

Ar

Ph 4-C

lC6H

4

4-O

2NC

6H4

4-M

eOC

6H4

Tim

e

2.5

h

15 m

in

15 m

in

15 m

in

(95)

(96)

(57)

(72)

ArS

n(R

1 ) 3(i

a), M

eCN

, rt

N2+

BF 4

–

O2N

R2

N=

NA

r

O2N

R2

813

Ar

Ph 4-C

lC6H

4

2-M

eOC

6H4

2-M

eOC

6H4

4-M

eOC

6H4

4-M

eOC

6H4

3-C

H2O

CH

2-4-

C6H

3

4-T

MSC

6H4

2-M

eC6H

4

3-M

eC6H

4

4-M

eC6H

4

4-E

tC6H

4

2,4,

6-M

e 3C

6H2

R2

NO

2

NO

2

H NO

2

H NO

2

NO

2

NO

2

NO

2

NO

2

NO

2

NO

2

NO

2

R1

n-B

u

Me

Me

n-B

u

Me

Me

Me

Me

Me

Me

Me

Me

n-B

u

Tim

e

18 h

18 h

27 h

1.5

h

7 h

2 m

in

2 m

in

20 h

16 h

16 h

16 h

18 h

6 h

(31)

(14)

(16)

(66)

(57)

(83)

(78)

(36)

(53)

(67)

(62)

(54)

(65)

C6-

9

C6

PhM

gBr

PhN

HN

(62)

s20

8, E

t 2O

, 0°;

to r

t, 1

h

PhL

iN

N

4-O

2NC

6H4NPh

N(3

4)21

01.

,

DM

E, E

t 2O

, –35

° to

–20°

2. F

C6H

4NO

2-4,

–20

° to

rt

N N

PhN

NA

r

167

Subs

trat

eR

efs.

Con

ditio

nsPr

oduc

t(s)

and

Yie

ld(s

) (%

)

TA

BL

E 4

. AR

YL

CA

RB

AN

ION

S (C

onti

nued

)

PhM

PhN

=N

Ph

NN

, Et 2

O, 1

5 m

in

PhN

NH

(—)

214

PhL

i

M Li

K CaI

Solv

ent(

s)

hexa

ne o

r cy

cloh

exan

e, T

HF

PhH

Et 2

O

Tem

p

–78°

; rt

0°re

flux

(90)

(38)

(18)

211,

214

,

506,

814

815

815

C6

ArM

gBr

C6-

9

NN

Ts

R1.

, T

HF,

–20

°, 1

h

NH

Ar

R25

5

Ar

4-IC

6H4

3-T

fOC

6H4

3-T

fOC

6H4

3-T

fOC

6H4

R 4-E

tO2C

t

4-B

r

4-M

eO

3-T

fO

(63)

(70)

(81)

(76)

3-T

fOC

6H4

2-E

tO2C

C6H

4

4-E

tO2C

C6H

4

4-E

tO2C

C6H

4

4-E

tO2C

C6H

4

4-E

tO2C

C6H

4

2,4,

6-M

e 2C

6H2

2,4,

6-M

e 2C

6H2

4-E

tO2C

t

4-B

r

2-B

r

4-B

r

4-I

4-N

C

4-B

r

4-M

eO

(80)

(80)

(65)

(83)

(71)

(64)

(69)

(83)

Ph

H NN

Ph2

2. C

H2=

CH

CH

2I, N

-met

hylp

yrro

lidin

one,

rt,

3 h

3. Z

n, A

cOH

, TFA

, 75°

, 2.5

h

Tim

e

2 h;

10

h

8 h

12 h

168

ArM

R1 O

CN

=N

R2

C6-

10

Ar

Ph Ph Ph Ph Ph Ph 4-M

eOC

6H4

4-M

eSC

6H4

3,4-

(MeO

) 2C

6H3

4-(n

-C5H

11O

)C6H

4

4-(C

F 3C

H2O

)C6H

4

2-C

F 3C

6H4

4-N

CC

6H4

4-E

tO2C

C6H

4

6-M

eO-2

-nap

hthy

l

R1

EtO

t-B

uO

MeO

EtO

Ph Ph t-B

uO

t-B

uO

Et

t-B

uO

t-B

uO

t-B

uO

t-B

uO

t-B

uO

t-B

uO

M Li

Li

MgB

r

MgB

r

MgB

r

MgB

r

ZnI

MgB

r

MgB

r

MgB

r

Li

MgB

r

ZnB

r

ZnB

r

MgB

r

R2

CO

2Et

CO

2Bu-

t

CO

2Me

CO

2Et

Ph CO

Ph

CO

2Bu-

t

CO

2Bu-

t

CO

2Et

CO

2Bu-

t

CO

2Bu-

t

CO

2Bu-

t

CO

2Bu-

t

CO

2Bu-

t

CO

2Bu-

t

Solv

ent

TH

F

TH

F

— TH

F

Et 2

O

Et 2

O

TH

F

TH

F

TH

F

TH

F

TH

F

TH

F

TH

F

TH

F

TH

F

Tem

p

–78°

–78° — –78° rt rt rt

–78°

–78°

–78°

–78°

–78°

70°

70°

–78°

(100

)

(60)

(poo

r)

(100

)

(50)

(30)

(55)

u

(>75

)

(96)

(>60

)

(61)

(81)

(66)

(40)

(47)

816

816

794

816

794

794

358

816

816

816

816

816

358

358

816

ArM

TM

SCH

2N3

ArN

H2

Ar

Ph 4-C

lC6H

4

2-M

eOC

6H4

2-M

eOC

6H4

4-M

eOC

6H4

2-M

e 2N

CH

2C6H

4

2,3-

(MeO

) 2C

6H3

2,6-

Me 2

C6H

3

M MgB

r

MgB

r

Li

MgB

r

MgB

r

Li

Li

MgB

r

Solv

ent

Et 2

O

Et 2

O

— Et 2

O

Et 2

O

— Et 2

O

Et 2

O

Con

ditio

ns

rt, 3

h, t

hen

H2O

rt, 3

h, t

hen

H2O

—

rt, 3

h, t

hen

H2O

rt, 3

h, t

hen

H2O

—

0° to

rt,

then

HC

l, N

aOH

rt, 3

h, t

hen

H2O

(72)

(92)

(35)

(73)

(69)

(41)

(78)

(79)

264

264

264

264

264

264

265

264

C6-

7

C6

PhM

gBr

2

eq

N3(

CH

2)nN

3, E

t 2O

n 2 5

(72)

(—)

271

290

Tim

e

— — — — — — 3 h

310

min

— — — — 3 h

3 h

—

PhN

N

H NH N

NN

Phn

Tem

p

rt —

Tim

e

10 m

in

—

NN

HR

2

O

R1

Ar

169

Subs

trat

eR

efs.

Con

ditio

nsPr

oduc

t(s)

and

Yie

ld(s

) (%

)

TA

BL

E 4

. AR

YL

CA

RB

AN

ION

S (C

onti

nued

)

C6-

10A

rMC

H2=

CH

CH

2N3,

sol

vent

, –78

° to

rt; t

hen

H3O

+A

rNH

226

3

Ar

Ph Ph 3-C

lC6H

4

4-C

lC6H

4

2-M

eOC

6H4

3-M

eOC

6H4

4-M

eOC

6H4

2-M

e-5 -

FC6H

3

2-na

phth

yl

M Li

MgB

r

MgB

r

MgB

r

MgB

r

MgB

r

MgB

r

MgB

r

MgB

r

Solv

ent

n-he

xane

Et 2

O

Et 2

O

Et 2

O

Et 2

O

Et 2

O

Et 2

O

Et 2

O

Et 2

O

(61)

(76)

(68)

(52)

(71)

(55)

(75)

(66)

(77)

ArL

i1.

CH

2=C

(N3)

R1 , T

HF,

–78

°; to

rt,

2 h

2. K

OH

ArN

H2

278

Ar

Ph 2,3-

(MeO

) 2C

6H3

2,6-

(MeO

) 2C

6H3

2-R

2 NH

CO

C6H

4w

(68)

(60)

(70)

(52)

R1

—v

Ph —v

—v

C6-

7

Ar1 M

gBr

Ar2 N

3, E

t 2O

Ar1

Ph Ph Ph Ph Ph 4-E

tOC

6H4

4-M

eC6H

4

1-na

phth

yl

Ar2

Ph 4-E

tOC

6H4

4-M

eC6H

4

Bn

1-na

phth

yl

Ph Ph Ph

Tem

p

0°re

flux

refl

ux

refl

ux

refl

ux

refl

ux

refl

ux

refl

ux

(71)

(—)

(—)

("go

od")

(64)

(—)

(—)

(—)

285,

284

280

280

270

281,

280

280

280

280

C6-

10

Ar1

H NN

NA

r2 x

Tim

e

—

30 m

in

30 m

in

30 m

in

25 m

in

30 m

in

30 m

in

30 m

in

170

1. P

hSC

H2N

3, T

HF,

hex

ane,

tem

p, ti

me

1

2. N

H4C

l, H

2O

3. 5

0% K

OH

in H

2O, M

eOH

, TH

F, r

t, tim

e 2

275,

274

R H 2-M

eO

4-M

eO

2,6-

(MeO

) 2

2-M

e 2N

CH

2

2-(t

-BuO

2CN

H)-

5

-5

-5

-Cl

2-(E

t 2N

CO

)-(

OC

H2)

-6

2-M

eO-P

h

MgB

r

R

Me

N N Me

2-C

H2

Tem

p, T

ime

1

–78°

, 3 h

; rt,

2 h

–78°

, 1.5

h; 0

°, 2

h

–78°

, 2 h

; 0°,

1 h

–78°

, 45

min

; to

0°, 3

h

–78°

, 15

min

; 0°,

3 h

–78°

, 1.5

h; 0

°, 2

h

–78°

to 0

°; 0

°, 1

h

–78°

, 1.5

h; t

o 0°

, 1.5

h

0°, 2

h

Tim

e 2

3 h

2 h

24 h

3 h

2 h

19 m

in

over

nigh

t

36 h

24 h

(66)

(78)

(50)

(67)

y

(85)

(66)

(71)

(60)

z

(84)

C6-

12N

H2

R

PhM

gBr

RC

OC

H2N

3, E

t 2O

, coo

ling;

rt,

over

nigh

t81

7

R Me

Ph

(40)

(50)

C6

C6-

7

ArM

gBr

PhC

OC

H2N

3, E

t 2O

789

Ar

4-M

eOC

6H4

4-M

eC6H

4

(71)

(35)

PhM

gBr

4-N

3C6H

4CO

Me,

Et 2

O(8

4)28

3

ArN

=N

C6H

4N3-

4, E

t 2O

Ar

Ph 4-M

eC6H

4

(91)

(—)

290

C6

Ph

H NN

NPh

RO

H

Ph

H NN

NA

rA

rO

H

NA

rN

NN

NH

Ph

N H

N

Ph

PhN

OH

171

Subs

trat

eR

efs.

Con

ditio

nsPr

oduc

t(s)

and

Yie

ld(s

) (%

)

TA

BL

E 4

. AR

YL

CA

RB

AN

ION

S (C

onti

nued

)

PhM

gXj

2

eq

, Et 2

O, 1

0-12

h79

0(7

8)x

NSN

3

NSPh

NH

N=

NC

6

PhM

800

NSN

3

Cl

(ia)

NSN

HN

=N

Phx

Cl

M Li

MgB

r

Solv

ent

— Et 2

O

Tem

p

–10°

to r

t

rt

(63)

(100

)

PhM

gBr

NS

NNN

, tol

uene

, 100

°, 30

min

NSN

=N

NH

Ph x

(70)

818

, Et 2

O, 0

°28

9N

3N

3Ph

NH

N=

NN

=N

NH

Ph x

(65)

N

YN

N3

N3

N3

, Et 2

O, 1

h

N

YN

PhN

HN

=N

N=

NN

HPh

N=

NN

HPh

788

Y CH

N

(47)

(90)

PhM

gX(i

a)NS

NNN

NSN

HN

=N

Ph x

X Br

Cl

Br

Br

Br

Solv

ent

tolu

ene

tolu

ene

tolu

ene

tolu

ene

Et 2

O

RR

R H 6-C

l

6-M

eO

6-M

e

4-Ph

(80)

(—)

(85)

(—)

(65)

818

819

818

818

800

4

6

x

Tim

e

1 h

10 h

Tem

p

100°

100°

100°

100°

rt; r

eflu

x

Tim

e

30 m

in

30 m

in

30 m

in

30 m

in

30 m

in; 3

0 m

in

172

(CH

2)n

N3

N3, E

t 2O

(CH

2)n

RR

R =

PhN

HN

=N

— x

n 0 1

PhM

gBr

(79)

(—)

272

290

RC

ON

3, E

t 2O

, coo

ling;

ref

lux,

15

min

R H2N

MeO

EtO

Ph PhN

H

(14-

18)

(11-

14)

(—)

(8)

(0)

N3C

ON

3, E

t 2O

, coo

ling

284

820

820,

284

820

820

820

(18)

aa

ArM

gBr

1. P

h 3Si

N3,

sol

vent

, tem

p, ti

me

2. H

Cl,

refl

ux

ArN

H2

821

Ar

Ph 2,4,

6-M

e 3C

6H2

Solv

ent

Et 2

O

tolu

ene

Tim

e

6 h

4 h

(56)

(26)

PhM

Ph3S

iN3,

Et 2

O, 1

00°,

24 h

821

M MgB

r

MgP

h

(61)

(—)

ArM

gBr

1. (

PhO

) 2P(

O)N

3 (i

a), E

t 2O

, –73

° to

–69°

, 2 h

2. 1

0% H

Cl,

MeO

H, r

t, 20

0 m

in

ArN

H3+

Cl–

334

Ar

Ph 4-C

lC6H

4

2-M

eC6H

4

4-M

eC6H

4

1-na

phth

yl

(51)

(63)

(33)

(33)

(28)

e

C6-

9

C6

C6-

10

RN

NN

HPh

O

NH

2N H

NPh

N

O

PhSi

NPhPh

M

Ph

Tem

p

100°

120°

173

Subs

trat

eR

efs.

Con

ditio

nsPr

oduc

t(s)

and

Yie

ld(s

) (%

)

TA

BL

E 4

. AR

YL

CA

RB

AN

ION

S (C

onti

nued

)

ArM

1. (

PhO

) 2P(

O)N

3 (i

a), s

olve

nt, –

73° t

o –6

9°, 2

h

2. N

aAlH

2(O

CH

2CH

2OM

e)2,

tolu

ene,

–7

0°; t

o 0°

, 1 h

ArN

H2

Ar

Ph 4-C

lC6H

4

4-M

eOC

6H4

2,6-

(MeO

) 2C

6H3

2,5-

(MeO

CH

2O) 2

C6H

3

4-M

eC6H

4

2,4,

6-M

e 3C

6H2

1-na

phth

yl

M MgB

r

MgB

r

Li

Li

Li

MgB

r

MgB

r

MgB

r

Solv

ent

Et 2

O

Et 2

O

TH

F

TH

F

TH

F

Et 2

O

Et 2

O

Et 2

O

(73)

b

(79)

b

(84)

(72)

(47)

(88)

b

(67)

(89)

333,

334

C6-

10

PhM

gBr

1. T

sN3

(ia)

, Et 2

O, –

18° t

o –1

5°, 3

0 m

in

2. I

sola

te P

hN=

NN

(MgB

r)T

s

3. 1

20-1

30° (

0.1-

3.0

mm

Hg)

PhN

330

8(8

2)

ArM

gBr

1. T

sN3,

TH

F, 0

°2.

Rea

gent

s

ArN

330

5

Ar

Ph 4-C

lC6H

4

4-M

eOC

6H4

4-M

eC6H

4

2,4,

6-M

e 3C

6H2

2-t-

BuC

6H4

4-Ph

C6H

4

2-B

nC6H

4

Rea

gent

s

NaO

H, H

2O

Na 4

P 2O

7, K

OH

, H2O

Na 4

P 2O

7, H

2O

Na 4

P 2O

7, K

OH

, H2O

Na 4

P 2O

7, H

2O

Na 4

P 2O

7, H

2O

NH

4Cl,

H2O

Na 4

P 2O

7, H

2O

(50)

(70)

(55)

(73)

(63)

(42)

(68-

79)

(49)

C6-

13

174

ArM

gBr

1. T

sN3,

TH

F, 0

°2.

RaN

i, N

aOH

3. H

Cl

ArN

H3+

Cl–

305

(41)

(49)

(63)

(51)

(82)

(79)

(66)

(76)

(19)

(62)

e

(71)

C6-

13

R1

Li

R2

R1

NH

2

R2

1. T

sN3,

Et 2

O, 0

°2.

RaN

i, 50

% K

OH

, 0° t

o rt

, 2 h

310

R1

H MeO

CH

2NM

e 2

CO

NH

Me

CO

NH

Me

R2

H H H H MeO

(80-

85)

(75-

80)

(52-

55)

(37-

40)

(34-

38)

C6-

7

Ar

3-C

lC6H

4

4-C

lC6H

4

2-M

eOC

6H4

4-M

eOC

6H4

2-M

eC6H

4

3-M

eC6H

4

4-M

eC6H

4

2,4-

Me 2

C6H

3

2-t-

BuC

6H4

4-Ph

C6H

4

2-B

nC6H

4

175

Subs

trat

eR

efs.

Con

ditio

nsPr

oduc

t(s)

and

Yie

ld(s

) (%

)

TA

BL

E 4

. AR

YL

CA

RB

AN

ION

S (C

onti

nued

)

OM

e

CO

NM

e 2

Li

OM

e

CO

NM

e 2

N

NC

u(C

N)L

i1.

(

5 eq

), T

HF,

78°

, 2 h

2. O

2, –

78°

(33)

53

C7

R1

Li

R2

R1

NH

2

R2

1. T

sN3

(ia)

, Et 2

O, –

70°;

–70

°, 5

h; to

–10

°2.

NaB

H4,

Bn 4

N+

HSO

4– , H2O

C6-

8

3

R1

OC

H2O

Me

OC

H2O

Me

OC

ON

Et 2

CO

NE

t 2

CO

NE

t 2

CO

NE

t 2

CO

NE

t 2

CO

NE

t 2

CO

NE

t 2

CO

NE

t 2

CO

NE

t 2

CO

NE

t 2

ON

R2

H 3-M

e

H H H 3-C

l

3-M

eO

4-M

eO

6-M

eO

5-M

eO-6

-TM

S

5-M

eO-6

-CH

(TM

S)2

4-M

e

3-M

eO-4

-Me

(67)

(72)

bb

(94)

(50)

(40)

(31)

(55)

(34)

(66)

(69)

(47)

(82)

(69)

311

312

311

311

311

311

311

311

311

311

311

311

311

176

CO

N(R

2 ) 2

Li

R1

NR

4 Cu(

X)L

iR

31.

(5

eq)

, TH

F, –

78°,

2 h

2. O

2, –

78°

CO

N(R

2 ) 2

N

R1

R4

R3

53

C7-

11

R1

H H 3-M

eO

3-M

eO

3-M

eO

3-M

eO

6-M

eO

3,5-

(MeO

) 2

3-M

eO-4

-OC

H2O

-5

3-(C

H=

CH

) 2-4

3

R2

Et

Et

Et

Me

Et

Me

Me

Me

Me

Et

R3

H 2-M

eO

H H H 3-M

eO

H H H H

R4

Me

H H Me

TM

S

H Me

Me

Me

Me

X Cl

CN

CN

CN

CN

CN

CN

Cl

Cl

CN

(46)

(50)

(63)

(33)

(54)

(R

4 = H

)

(36)

(26)

(43)

(48)

(61)

1. M

eLi,

t-B

uLi

2. A

cCl

C7-

9

ON

HM

e

Li

n

OA

c

NM

eAc

n

n 1 2 3

(13)

cc

(7)cc

(12)

cc

81 82 83

C7

MgC

l

CO

2Me

NB

n 2

CO

2Me

1. Z

nCl 2

, TH

F, –

78°,

15 m

in

2. B

n 2N

OB

z, C

uCl 2

(ca

t), T

HF,

–35

° to

rt, 1

h

(81)

113

CO

2N(C

H2A

r)2

MgC

l

CO

2Me

N(C

H2A

r)2

1:1

mix

ture

of

Ar

= P

h, R

= H

and

and

Ar

= C

6D5,

R =

D

1. Z

nCl 2

(1

eq),

TH

F, –

78°,

–3

5°, 4

0 m

in

2. C

uCl 2

(0.

0015

mol

%),

–35

° to

rt

3. T

MSC

HN

2, M

eOH

, Et 2

O

(50)

d0:

d 4:d

10:d

14 =

100

:100

:97:

94cc

R R

R

R

113

177

Subs

trat

eR

efs.

Con

ditio

nsPr

oduc

t(s)

and

Yie

ld(s

) (%

)

TA

BL

E 4

. AR

YL

CA

RB

AN

ION

S (C

onti

nued

)

1. T

MSC

H2N

3

2. H

3O+

(39)

267

C10

RO

NH

2, E

t 2O

R Me

Bn

Con

ditio

ns

–20°

to r

t, 4

h

–18°

to –

20°,

15 m

in; t

o rt

, 30

min

(8)

(21)

822

823,

684

,

822

RR

RLi

RR

RNH

2

R =

CH

(TM

S)2

C9

R1

R2

C10

-11

R1

R2

1.

, t-

BuO

K, D

MSO

, rt,

4 h

2. A

c 2O

, pyr

idin

e

NN

NH

2NN

HA

c

R1

H H Cl

R2

H CN

Cl

(38)

(64)

(60)

824

C10

MgB

rN

H2

PhC

H=

NO

H o

r Ph

CH

=N

OM

e, E

t 2O

, ref

lux

(15)

175

(2 e

q)

ArM

gBr

Ar

= 1

-nap

hthy

lB

zCH

=N

2, E

t 2O

, rt,

seve

ral h

Ar

N H

NO

H

Ar

Ph

Ar

N H

NPh

O

+82

5

(7)

(8-1

6)

Fe

Li

Fe

NH

2

178

SnR

3N

=N

C6H

3(N

O2)

2-2,

4

2,4-

(O2N

) 2C

6H3N

2+ B

F 4– , M

eCN

, rt

R Me

n-B

u

Tim

e

6 h

1 h

(55)

(71)

813

2,4-

(O2N

) 2C

6H3N

2+ B

F 4– , M

eCN

, rt

SnM

e 3N

=N

C6H

3(N

O2)

2-2,

4

(76)

813

1. 4

-BrC

6H4N

=N

Ts,

TH

F, –

20°,

1 h

2. C

H2=

CH

CH

2I, N

-met

hylp

yrro

lidin

one,

rt,

3 h

3. Z

n, A

cOH

, TFA

, 75°

, 15

min

(58)

255

R1

R2

R2

OH

R1

R2

R2

OH

NC

O2B

u-t

t-B

uO2C

N=

NC

O2B

u-t,

cata

lyst

(20

mol

%)

N

Et

HH

OE

CO

2Bu-

t

826

HO

Cat

alys

t

IA IB IC

E H N(C

O2B

u-t)

NH

N(C

O2B

u-t)

NH

CO

2Bu-

t

I

N

Et

HH

O

HO II

t-B

uO2C

NH

Fe

MgB

r

Fe

NH

C6H

4Br-

4

179

Subs

trat

eR

efs.

Con

ditio

nsPr

oduc

t(s)

and

Yie

ld(s

) (%

)

TA

BL

E 4

. AR

YL

CA

RB

AN

ION

S (C

onti

nued

)

R1

R2

R2

OH

(Ent

ry c

onti

nued

from

pre

viou

s pa

ge.)

C10

1. n

-BuL

i (5.

4 eq

), E

t 2O

, rt,

5 h

2. T

sN3

(ia)

, rt,

30 m

in; r

t, ov

erni

ght

3. 1

0% K

OH

in H

2O

+(2

8)(6

)31

5

1. n

-BuL

i (1.

3 eq

), T

HF,

pen

tane

, rt,

2 h

2. T

sN3,

0°;

rt,

4 h

3. N

aBH

4, n

-Bu 4

+ I

– , H2O

, rt,

48 h

(64)

, >

98%

de

(R,R

)82

7

(85)

(90)

(85)

(87)

(91)

(95)

(91)

(94)

(98)

(95)

(98)

(98)

(98)

(80)

(96)

(85)

(95)

% e

edd

16 88 –61

87 –96

33 93 –96

78 94 –94

48 92 –98

80 98 –96

R1

NH

2

NH

2

NH

2

NH

2

NH

2

NH

Me

NH

Me

NH

Me

NH

C5H

11-n

NH

C5H

11-n

NH

C5H

11-n

NH

Bn

NH

Bn

NH

Bn

NH

2

NH

2

NH

2

R2

H H H H H H H H H H H H H H Br

Br

Br

Cat

alys

t

quin

ine

IA II IB IC IA IB IC IA IB IC IA IB IC IA IB IC

Solv

ent

tolu

ene

ClC

H2C

H2C

l

ClC

H2C

H2C

l

ClC

H2C

H2C

l

ClC

H2C

H2C

l

ClC

H2C

H2C

l

ClC

H2C

H2C

l

ClC

H2C

H2C

l

ClC

H2C

H2C

l

ClC

H2C

H2C

l

ClC

H2C

H2C

l

ClC

H2C

H2C

l

ClC

H2C

H2C

l

ClC

H2C

H2C

l

ClC

H2C

H2C

l

ClC

H2C

H2C

l

ClC

H2C

H2C

l

Tem

p

rt

–20° rt

–20°

–20°

–20°

–20°

–20°

–20°

–20°

–20°

–20°

–20°

–20°

–20°

–20°

–20°

Fe Fe

SR

O

t-B

u

Fe

N3

N3

Fe

N3

Fe

SO

t-B

u

NH

2

180

C10

SS Y

YB

rMg

SS Y

YH

2N

1. P

hSC

H2N

3, E

t 2O

, TH

F, h

exan

e, –

78° t

o 0°

, 1 h

2. 5

0% K

OH

in H

2O, M

eOH

, TH

F, 3

0 m

in

Y O NM

e

(88)

(—)ee

274

C11

MeO

Li

OL

i

MeO

NH

2O

H

1. P

hSC

H2N

3, T

HF,

pen

tane

, –78

° to

rt, 1

.5 h

2. K

OH

, DM

SO, r

t, 1

h

("po

or")

274

1. L

DA

, TH

F, –

78°,

40 m

in

2. T

sN3,

–78

°, 4

h; to

rt

3. N

aBH

4, n

-Bu 4

+ I

– , H2O

, rt,

48 h

(67)

>99

% d

e (S

,S)

827

OM

e

MgB

r

OM

e

OM

e

MO

MO

375

1. P

hSC

H2N

3 (i

a), T

HF,

hex

ane,

–7

8°; t

o 0°

; 0°,

1h; r

t, 1

h

2. N

H4C

l, H

2O

3. 5

0% a

q. K

OH

, MeO

H, T

HF,

rt,

2.5

h

OM

e

NH

2

OM

e

OM

e

MO

MO

(71)

TM

SNH

OT

MS,

Et 2

O, T

HF,

–50

°, 1

h;

to

rt, o

vern

ight

R =

2-t

hien

yl

(56)

102

C12

SL

iS

NH

2

MeO

NH

Li,

Et 2

O, h

exan

e, –

15°,

30

min

; ref

lux

1 h

(55)

786

Fe

SS

C6H

4Me-

2

O

Fe

SC

6H4M

e-2

O

NH

2

Fe

O

O

OM

e

CuR

Li

Fe

O

O

OM

e

NH

2

181

Subs

trat

eR

efs.

Con

ditio

nsPr

oduc

t(s)

and

Yie

ld(s

) (%

)

TA

BL

E 4

. AR

YL

CA

RB

AN

ION

S (C

onti

nued

)

YL

iY

NH

2

NH

2OM

e, –

20°,

2 h

Y O S

(78)

(28)

828,

829

830

1. (

PhO

) 2P(

O)N

3, T

HF,

–78

°, 2

h; to

–20

°, 30

min

2. N

aAlH

2(O

CH

2CH

2OM

e)2,

tolu

ene,

–7

8°; 0

°, 1

h; r

t, 30

min

I

I33

3, 3

34

Y O S

(58)

(62)

O S

(58)

(62)

OO

OM

e

NH

2OM

e, E

t 2O

, 0°,

then

HC

l(2

4)83

1

BrM

gO

Me

H3N

Cl–

SS

MeO

NH

Li (

ia),

Et 2

O, –

78° t

o –1

5°, 2

h(5

5)82

OO

NH

2OM

e(3

3)82

8

OO

Li

NH

21.

(Ph

O) 2

P(O

)N3,

TH

F, –

78°,

2 h;

to –

20°,

30 m

in

2. N

aAlH

2(O

CH

2CH

2OM

e)2,

tolu

ene,

–7

8°; 0

°, 1

h; r

t, 30

min

(71)

333,

334

MgB

rN

H2

Li

NH

2

YS

Li

YS

NH

2

NH

2OM

e, E

t 2O

Y O S

832

833,

834

(59)

(26)

Tem

p

–20°

; ref

lux

0-5°

; rt

Tim

e

—; "

seve

ral"

h

15 m

in; 1

h

C12

182

C24

R!

R!

R2

Li

R1

R1

R2

N3

TsN

3

R1

2,4,

6-M

e 3C

6H2

2,4,

6-M

e 3C

6H2

R2

H Me

Solv

ent(

s)

Et 2

O, h

exan

es

TH

F

(96)

(95)

314

835

Cn

Poly

sulf

oneff

1. n

-BuL

i, T

HF,

hex

ane,

–70

°2.

MeO

NH

2

Am

inat

ed p

olys

ulfo

ne(—

)83

6

OO

2S

On

1. n

-BuL

i (2.

15 e

q), T

HF,

–78

°

15

min

2. T

sN3

(3 e

q), t

o –5

0°, 1

h

335

OO

2S

On

N3

N3

(95)

gg

OO

2S

O

n

1. n

-BuL

i (1.

2 eq

), T

HF,

–78

°2.

MeO

NH

Li,

–78°

OO

2S

O

n

NH

2

(17)

837

OO

2S

O

n

N3

1. n

-BuL

i (2.

5 eq

), T

HF,

–78

°2.

TsN

3 (3

eq)

, –78

°, 15

min

;

t

o –5

0°, 9

0 m

in

335

Tem

p

0° —

Tim

e

2 h

—

(95)

N3

183

Subs

trat

eR

efs.

Con

ditio

nsPr

oduc

t(s)

and

Yie

ld(s

) (%

)

TA

BL

E 4

. AR

YL

CA

RB

AN

ION

S (C

onti

nued

)

OO

2S

YO

n

1. n

-BuL

i (2.

1 eq

), T

HF,

–65

°2.

4-A

cNH

C6H

4SO

2N3,

to –

50°,

15 m

in

3. H

2O, E

tOH

OO

2S

YO

n

(—)

837

N3

N3

Y =

bon

d or

CM

e 2

a Thi

s is

a c

ompe

titiv

e ki

netic

stu

dy. N

o yi

elds

wer

e re

port

ed.

b The

pro

duct

was

isol

ated

as

the

hydr

ochl

orid

e.c T

he p

rodu

ct w

as is

olat

ed a

s th

e N

-ben

zoyl

der

ivat

ive.

d With

PhM

gBr

at r

eflu

x th

e yi

eld

was

37%

and

with

PhC

uLi t

he y

ield

was

83%

.e T

he y

ield

is th

at o

f th

e am

ine.

f The

rea

gent

was

pre

pare

d in

situ

by

addi

tion

of n

-BuL

i or

PhL

i, re

spec

tivel

y, to

CH

2=N

OB

n.g U

nles

s ot

herw

ise

note

d, th

e su

bstr

ates

wer

e pr

epar

ed f

rom

the

Gri

gnar

d re

agen

ts a

nd Z

nCl 2

.h T

he s

ubst

rate

was

pre

pare

d by

ort

holit

hiat

ion

follo

wed

by

reac

tion

with

ZnC

l 2. T

he c

atal

yst i

n th

e su

bseq

uent

am

inat

ion

was

CuC

l 2.

i Thi

s w

as th

e yi

eld

whe

n 0.

6 eq

uiva

lent

s of

Ar 2

Zn

wer

e us

ed.

j X w

as n

ot s

peci

fied

.k T

he p

rodu

ct w

as c

onve

rted

into

the

aryl

amin

e w

ith C

sOH

in e

thyl

ene

glyc

ol a

t 150

° or

into

the

N-m

ethy

lary

lam

ine

with

LiA

lH4.

l Hyd

roly

sis

with

CsO

H in

eth

ylen

e gl

ycol

at 1

50° g

ave

met

hyl 4

-am

inob

enzo

ate;

with

LiA

lH4,

par

tial l

oss

of th

e fl

uori

ne a

nd th

e m

ethy

l gro

up w

as o

bser

ved.

m N

o re

actio

n oc

curr

ed u

nder

the

cond

ition

s of

foo

tnot

e k.

n PhC

(=N

Ts)

NM

e(C

H2)

2OH

was

for

med

in 7

0% y

ield

.o T

his

reag

ent i

s hy

gros

copi

c an

d re

prod

ucib

le r

esul

ts w

ere

obta

ined

onl

y w

ith f

resh

ly p

repa

red

mat

eria

l.p T

he y

ield

s w

ere

dete

rmin

ed b

y ga

s ch

rom

atog

raph

y.

q X2 w

as

.

S O2N

O2

S

Cn

184

r Hea

ting

to 7

0° f

or o

ne h

our

conv

erte

d an

y Z

-azo

com

poun

d in

to th

e E

isom

er.

s The

yie

ld w

as d

eter

min

ed b

y io

dom

etry

.t T

hese

are

cor

rect

ed e

ntri

es; K

noch

el, P

.; K

ofin

k, C

. Uni

vers

ity o

f M

unic

h, G

erm

any.

Per

sona

l com

mun

icat

ion,

200

5.u T

he y

ield

was

det

erm

ined

by

NM

R s

pect

rosc

opy.

v R1 w

as n

ot s

peci

fied

but

it w

as e

ither

Ph

or t-

Bu.

w R

2 was

not

spe

cifi

ed.

x So

me

of th

e tr

iaze

nes

are

isol

ated

as

mix

ture

s of

dou

ble-

bond

isom

ers.

y 2,6

-Dim

etho

xy-4

-(ph

enyl

thio

met

hyl)

anili

ne w

as a

lso

form

ed in

16%

yie

ld.

z The

pro

duct

was

indo

le a

fter

trea

tmen

t of

the

amin

e w

ith o

xalic

aci

d.aa

A la

ter

publ

icat

ion

(ref

. 820

) re

port

ed a

0%

yie

ld f

or th

is r

eact

ion.

bb T

he p

rodu

ct w

as is

olat

ed a

s th

e N

-ter

t-bu

toxy

carb

onyl

der

ivat

ive.

cc D

eute

rium

labe

ling

indi

cate

s th

at th

e re

actio

n is

inte

rmol

ecul

ar.

dd C

atal

ysts

IA

, IB

, and

IC

, II

gave

atr

opis

omer

s w

ith th

e op

posi

te a

bsol

ute

conf

igur

atio

ns.

ee A

mix

ture

of

tria

zene

s w

as o

btai

ned

in lo

w y

ield

.ff T

he ty

pe o

f po

lysu

lfon

e w

as n

ot s

peci

fied

.gg

A m

ono-

azid

e w

as o

btai

ned

in 9

5% y

ield

with

1.1

eq

of n

-BuL

i and

1.5

eq

of T

sN3.

The

cor

resp

ondi

ng r

eact

ions

with

(Ph

O) 2

P(O

)N3

wer

e no

t as

clea

n.

185

Subs

trat

eR

efs.

Con

ditio

nsPr

oduc

t(s)

and

Yie

ld(s

) (%

)

TA

BL

E 5

. HE

TE

RO

CY

CL

IC C

AR

BA

NIO

NS

C3

N

N Me

Li

N

N Me

NH

2C

lNH

2 or

MeO

NH

2(0

)66

PhN3

1.

o

r

, T

HF,

–78

° to

rt, 2

h

2. H

Cl,

then

bas

e

I (

45)

278

N3

Bu-

t

N

N R

Li

N

N R

NH

3+ C

l–

1. P

hN3,

rt,

1.5

h

2. H

OA

c, H

2O

3. H

Cl,

80-9

0°

R Me

Ph Bn

(70)

(43)

(64)

66

C4

NN B

nO

HO

NN B

nO

HO

NH

2

NN B

nO

HO

H N

(90)

+

(4)

149

O

H N, t

olue

ne, N

aOH

, H2O

, 0°,

10 m

in

1. P

hSC

H2N

3 (i

a), T

HF,

–75

° to

0°2.

CuI

, 0°,

1 h

3. K

OH

(50

% a

q.),

MeO

H, T

HF,

rt,

3 h

N RL

iN R

NH

2R

= M

e or

SO

2Ph

(0)

274

NN Ph

ON

N Ph

OC

(CN

) 2, p

yrid

ine,

0°,

1 h

TsO

N

NC

(CN

) 2

PyH

+(5

0)83

8

N

N

HO

OH

OH

N

N

HO

OH

O

C(C

N) 2

, pyr

idin

e, –

30° t

o rt

TsO

NN

C(C

N) 2

PyH

+(5

0)83

8

I

N

186

OO

MgB

rN

PhPh Ph

PhN

OT

s

PhPh

PhPh

180

(ia)

, TH

F, –

78°,

10 m

in(8

1)

1. P

hSC

H2N

3 (i

a), T

HF,

–75

° to

0°2.

CuI

, 0°,

1 h

3. K

OH

(50

% a

q.),

MeO

H, T

HF,

rt,

3 h

OM

ON

H2

M =

Li o

r M

gBr

(0)

274

C4

O

ON

OT

s

PhPh

PhPh

180

(ia)

, TH

F, –

78°,

10 m

in(7

8)

MgB

r

NPh Ph

Ph

Ph

SC

u(C

N)M

SN

PhR

1. P

hRN

Li,

TH

F, te

mp

1, ti

me

1

2. A

dden

d, T

HF,

–78

°3.

O2,

tem

p 2,

tim

e 2

M Li

Li

ZnC

l

R Me

Me

Bn

Add

end

— Cu(

NO

3)2

1,2-

(O2N

) 2C

6H4

(52)

(70)

(75)

54 55 55

OO

t-B

uO2C

N(L

i)O

Ts,

TH

F,

–78

° to

–40°

, 2 h

(48)

127

Cu

NH

CO

2Bu-

t

SL

iS

NH

Me

MeN

(Li)

OM

e, E

t 2O

, hex

ane,

–78

° to

–15°

, 3 h

(0)

97

OO

Nt-

BuO

2CN

HC

O2B

u-t

1. C

atal

yst B

(se

e C

hart

1; 2

mol

%),

i-

PrO

H, r

t to

0°2.

Add

sub

stra

te, t

hen

PhSi

H3,

0°

3. t-

BuO

2CN

=N

CO

2Bu-

t, 0°

, 4 h

(81)

215

Tem

p 1

–40°

–40°

–78°

to –

40°

Tem

p 2

–78°

; to

rt

–78°

–78°

Tim

e 1

15 m

in

20 m

in

40 m

in

Tim

e 2

—

30 m

in

30 m

in

187

Subs

trat

eR

efs.

Con

ditio

nsPr

oduc

t(s)

and

Yie

ld(s

) (%

)

TA

BL

E 5

. HE

TE

RO

CY

CL

IC C

AR

BA

NIO

NS

(Con

tinu

ed)

SC

u(C

N)L

i 2S

NH

RR

NH

OT

MS,

TH

F2

R TM

S

Me

i-Pr

Tim

e

1 h;

—

2 h

2 h

(72)

(60)

(65)

100

101

101

SM

gBr

SN

N Me

MeN

NM

eM

eN

NO

Ts

(ia)

, tol

uene

, Et 2

O,

(84)

a18

1

SL

i

NO

1. Z

nCl 2

, TH

F, 0

°; to

rt

2.

(ia

), N

i(ac

ac) 2

(ca

t), T

HF,

2 h

SN H

OH

C

(4-1

5)17

0

SZ

nBr

(80)

358

t-B

uO2C

N=

NC

O2B

u-t,

TH

F, r

t, 30

min

1. T

sN3,

Et 2

O, –

70°

2. N

a 4P 2

O7,

H2O

, rt,

over

nigh

tS

Li

SN

3

316

R H 1,3-

diox

olan

-2-y

l

C4-

5

(10)

(0)

S

R

S

R1.

TsN

3, E

t 2O

, –70

°2.

Na 4

P 2O

7, H

2O, r

t, ov

erni

ght

Li

N3

316

R H 2-M

e

4-M

e

2-(1

,3-d

ioxo

lan-

2-yl

)

4-(1

,3-d

ioxo

lan-

2-yl

)

(85)

(68)

(70)

(65)

(70)

RR

SC

uS

NH

CO

2Bu-

tt-

BuO

2CN

(Li)

Ts,

TH

F, –

78° t

o –4

0°, 2

h12

7(5

2)

C4

0°, 1

5 m

in

Tem

p

–50°

; to

rt

–50°

to r

t

–50°

to r

t

SN

H N

CO

2Bu-

t

CO

2Bu-

t

188

SS

Li

N3

Ph1.

, T

HF,

–78

°; r

t, 2

h

2. H

Cl

SS

NH

2(6

4)27

8

NZ

n2

NN

O

ON

OB

z (i

a), (

CuO

Tf)

2•Ph

H (

cat)

,(7

1)11

2, 1

09

N

C4

C5

Cu

NN

HC

O2B

u-t

t-B

uO2C

N(L

i)O

Ts,

TH

F, 0

°, 2.

5 h

(53)

127

RN

HO

TM

S, T

HF

NC

u(C

N)L

i 22

NN

HR

R TM

S

Me

i-Pr

t-B

u

Tim

e

— 2 h

2 h

2 h

(60)

R =

H b

(65)

(68)

(70)

100

101

101

101

NC

uN

N H

TsO

N(L

i)C

O2C

H2C

H=

CH

2, T

HF,

–78

°, 3

h(2

6)13

0

NL

iN

NH

2

N3

PhB

u-t

N3

o

r

, T

HF,

–78

°;

to

rt, 2

h, t

hen

HC

l, or

KO

H

(45)

278

1. P

hN3,

Et 2

O

2. H

OA

c, H

2O

3. H

Cl,

80-9

0°N

NH

3+ C

l–(3

8)66

1. P

hSC

H2N

3 (i

a), T

HF,

–75

° to

0°2.

CuI

, 0°,

1 h

3. K

OH

(50

% a

q.),

MeO

H, T

HF,

rt,

3 h

SL

iS

NH

2(0

)27

4

TH

F, r

t, 15

-60

min

Tem

p

–60°

to r

t

–50°

to r

t

–50°

to r

t

–50°

to r

t

O

O

189

Subs

trat

eR

efs.

Con

ditio

nsPr

oduc

t(s)

and

Yie

ld(s

) (%

)

TA

BL

E 5

. HE

TE

RO

CY

CL

IC C

AR

BA

NIO

NS

(Con

tinu

ed)

NN

N RN

NN

N RNN

3

NN

N RN

2

1. L

DA

, tol

uene

, TH

F, –

78°,

20 m

in

2. A

rSO

2N3,

–78

°; to

rt,

1-2

h

3. N

aHC

O3,

H2O

R MeO

CH

2

BnO

CH

2

—

Ar

4-M

eC6H

4

4-M

eC6H

4

2,4,

6-M

e 2C

6H2

(57)

(69)

(0)

(16)

c

(11)

(—)

313

SN

H2

SL

i(5

8)27

8

N

N Me

NH

CO

2Bu-

t

N

N Me

NH

CO

2Bu-

t

C5

N3

1. n

-BuL

i (2.

1 eq

), T

HF,

–75

°2.

TsN

3, 1

0 m

in

(60)

840

SNM

gBr

SNN

H2

1. P

hSC

H2N

3 (i

a), T

HF,

–75

° to

0°2.

CuI

, 0°,

1 h

3. K

OH

(50

% a

q.),

MeO

H, T

HF,

rt,

3 h

(59)

274

SNL

iSN

NH

2(5

3)27

8

1. P

hN3,

Et 2

O

2. H

OA

c, H

2O

3. H

Cl,

80-9

0°SN

NH

3+ C

l–66

(52)

C7

Boc

NS

MeO

2CN

=N

CO

2Me,

105

°, 2

d83

9

MeO

2C

Boc

NS

MeO

2CN

(CO

2Me)

NH

CO

2Me

(—)

1. T

MSN

HO

TM

S, T

HF,

–60

° to

rt

2. "

Hyd

roly

tic w

orku

p" b

N2

N

Cu(

CN

)Li 2

NH

2

(58)

100

N3

PhB

u-t

N3

o

r

, T

HF,

–78

°; to

rt,

2 h

N3

PhB

u-t

N3

o

r

, T

HF,

–78

°; to

rt,

2 h

C6

190

N HN H

N H

NE

750

4-R

C6H

4SO

2N3

R O2N

MeO

Me

Solv

ent

EtO

H

diox

ane

diox

ane

Tem

p

refl

ux

80°

75-8

0°

I +

II

(61)

(22)

(46)N

HE

E =

SO

2C6H

4R-4

N Me

N Me

N Me

NE

NH

ER

C6H

4SO

2N3,

dio

xane

, 75-

80°,

18-2

4 h

750

+

III

R H 4-C

l

4-B

r

3,4-

Cl 2

4-A

cNH

2-O

2N

3-O

2N

4-O

2N

3-O

2N,4

-Cl

4-M

eO

4-M

e

2,4,

6-M

e 3

2,4,

6-(i

-Pr)

3

I

(54)

(60)

(49)

(63)

(67)

(75)

(74)

(72)

(82)

(44)

(47)

(34)

(32)

II (22)

(16)

(12)

(14)

(5)

(14)

(6)

(21)

(8)

(22)

(24)

(15)

(24)

E =

SO

2C6H

4R

NN

Et

Li

NN

Et

NH

N=

NPh

PhN

3, E

t 2O

, –20

°, 1

h(6

1)84

1

C8

+

III Tim

e

6 h

26 h

48 h

d

191

Subs

trat

eR

efs.

Con

ditio

nsPr

oduc

t(s)

and

Yie

ld(s

) (%

)

TA

BL

E 5

. HE

TE

RO

CY

CL

IC C

AR

BA

NIO

NS

(Con

tinu

ed)

O2

Cu(

CN

)Li 2

ON

TM

S1.

TM

SNH

OT

MS,

TH

F, –

30° t

o rt

, 18

h

2. T

MSC

l

(70)

100

S2

Cu(

CN

)Li 2

ST

MSN

HO

TM

S, T

HF,

–50

°, 1

h; to

rt

(58)

100

NH

2

OC

u(C

N)L

iO

NM

ePh

1. P

hMeN

Li,

TH

F, –

40°,

20 m

in

2. C

u(N

O3)

2, T

HF,

–78

°3.

O2,

–78

°, 30

min

(76)

55, 5

4

SL

iS

N3

1. T

sN3,

Et 2

O, –

70°,

5 h

2. N

a 4P 2

O7,

H2O

(7)

316

SS

1. T

sN3,

Et 2

O, –

70°,

5 h

2. N

a 4P 2

O7,

H2O

(83)

316

Li

N3

SL

i

R

SN

3

R

TsN

3, E

t 2O

, hex

ane,

–70

°, 5

h; to

–10

°R 2-

thie

nyl

3-th

ieny

l

(33)

(41)

779

SR

Li

SR

N3

TsN

3, E

t 2O

, hex

ane,

–70

°, 5

h; to

–10

°R 2-

thie

nyl

3-th

ieny

l

(72)

(73)

779

S

Li

S

N3

TsN

3, E

t 2O

, hex

ane,

–70

°, 5

h; to

–10

°R 2-

thie

nyl

3-th

ieny

l

(75)

(77)

779

RR

N R

MgB

rN R

NH

2

1. P

hSC

H2N

3 (i

a), T

HF,

–75

° to

0°2.

CuI

, 0°,

1 h

3. K

OH

(50

% a

q.),

MeO

H, T

HF,

rt,

3 h

(0)

274

R =

Me,

PhS

O2

C8

192

O PhO

1. K

NH

2, N

H3

(liq

), E

t 2O

2. P

hN=

NPh

OO

PhN

(Ph)

NH

Ph

(30)

212

C14

a The

pro

duct

was

con

vert

ed in

to N

-met

hyl-

2-th

ieny

lam

ine

with

LiA

lH4

but i

t cou

ld n

ot b

e hy

drol

yzed

to th

e am

ine.

b A

hyd

roly

tic w

orku

p w

as m

entio

ned

in th

e te

xt b

ut n

o de

tails

wer

e gi

ven

in th

e E

xper

imen

tal S

ectio

n.

c With

KH

MD

S, o

nly

the

dim

er I

I w

as o

btai

ned

in 7

0% y

ield

.d I

som

ers

I an

d II

exi

st in

equ

ilibr

ium

.

C9

N Bn

CO

2Et

MgC

l

N Bn

CO

2Et

NH

C6H

4R-4

1. 4

-RC

6H4N

=N

Ts,

TH

F, –

20°,

1 h

2. C

H2=

CH

CH

2I, N

-met

hylp

yrro

ldin

one,

rt

, 3 h

3. Z

n, A

cOH

, TFA

, 75°

, 2.5

h

R Br

CO

2Et

(58)

(71)

255

193

Subs

trat

eR

efs.

Con

ditio

nsPr

oduc

t(s)

and

Yie

ld(s

) (%

)

TA

BL

E 6

. AL

DE

HY

DE

EN

OL

AT

ES

C2

OE

t1.

ClN

HC

O2B

n, C

HC

l 3, M

eOH

, –78

°2.

CrC

l 2

3. M

eON

aB

nO2C

NH

OE

t

OM

e(8

1)34

3

4-O

2NC

6H4N

2+ C

l– , H2O

, 0-1

0°(—

)84

2

OR

1. M

eO2C

N=

NC

O2M

e, r

t

2. H

Cl (

3% in

MeO

H),

rt

MeO

2CN

HN

OM

e

OM

eM

eO2C

(—)

843

R =

Et,

i-B

u, n

-C18

H37

SR

R =

Et,

Ph, 4

-ClC

6H4

1. E

tO2C

N=

NC

O2E

t, Ph

H, r

t

2. M

eOH

EtO

2CN

HN

SR

OM

eE

tO2C

(—)

844

OB

u-n

1. 4

-O2N

C6H

4N3,

CH

Cl 3

, 40°

, 7 h

2. A

cOH

, PhH

, 50°

, 10

min

4-O

2NC

6H4N

HO

Ac

OB

u-n

(84)

387

N1.

MeO

2CN

=N

CO

2Me,

Et 2

O,

rt

2. H

Cl (

3% in

MeO

H),

rt

MeO

2CN

HN

N

OM

eM

eO2C

(—)

843

OO

OPh

1. R

CO

N=

NC

OR

, rt

2. H

Cl,

MeO

H

RC

ON

HN

OPh

OM

e(—

)R

CO

240

OA

r1.

MeO

2CN

=N

CO

2Me,

rt

2. H

Cl,

MeO

H

MeO

2CN

HN

OA

r

OM

eM

eO2C

240

Ar

4-C

lC6H

4

4-M

eOC

6H4

4-M

eC6H

4

(56)

(82)

(85)

4-O

2NC

6H4N

2+ C

l– , H2O

, 0-1

0°84

2O

Et

(—)

C3

N H

NC

HO

O2N

N H

NC

HO

O2N

R =

MeO

, EtO

, Cl 3

CC

H2O

, Ph

194

1. R

2 O2C

N=

NC

O2R

2 ,

L

-pro

line

(0.1

eq)

, MeC

N

2. N

aBH

4, E

tOH

221

CO

2R2

NO

H

R1

R2 O

2CN

H

R1

Me

n-Pr

i-Pr

i-Pr

n-B

u

Bn

(97)

(93)

(97)

(99)

(94)

(95)

R2

Bn

Bn

t-B

u

Bn

Bn

Bn

Tem

p

0° to

rt

0° to

rt

20°

0° to

rt

0° to

rt

0° to

rt

Tim

e

3 h

3 h

— 3 h

3 h

3 h

% e

e

>95

>95 92 96 97 >95

1. E

tO2C

N=

NC

O2E

t, D

-pro

line

, 5°

2. N

aBH

4

OE

tO2C

NH

N

C3

O

224

(—)

92-9

3% e

e

C3-

9

C3-

7

R2 O

2CN

=N

CO

2R2 , c

atal

yst (

x eq

), r

t

CO

2R2

NC

HO

R2 O

2CN

H

R1

Me

Me

Me

Me

Me

Me

Me

Et

i-Pr

n-C

5H11

n-C

5H11

R2

Et

— Et

i-Pr

t-B

u

Bn

t-B

u

Et

Bn

Bn

Bn

x 0.5

— 0.02 0.1

0.1

0.2

0.2

0,1

0.1

0.2

0.2

Solv

ent

CH

2Cl 2

neat

CH

2Cl 2

CH

2Cl 2

CH

2Cl 2

CH

2Cl 2

CH

2Cl 2

CH

2Cl 2

CH

2Cl 2

CH

2Cl 2

CH

2Cl 2

Tim

e

45 m

in

2 m

in

5 h

105

min

205

min

3.5

h

22 h

2 h

4 h

1.25

h

15 h

(93)

(100

)

(92)

(91)

(99)

(62)

(60)

(77)

(>90

)

(62)

(69)

% e

e

92 77 84 88 89 54 74 90 >90 91 72

R1

Cat

alys

t

L-p

rolin

e

L-p

rolin

e

L-p

rolin

e

L-p

rolin

e

L-p

rolin

e

L-p

rolin

e

L-a

zetid

inec

arbo

xylic

aci

d

L-p

rolin

e

L-p

rolin

e

L-p

rolin

e

L-a

zetid

inec

arbo

xylic

aci

d

222

222

222

222

222

229

229

222

229

229

229

HR

1

O

1.5

eq H

O

195

Subs

trat

eR

efs.

Con

ditio

nsPr

oduc

t(s)

and

Yie

ld(s

) (%

)

TA

BL

E 6

. AL

DE

HY

DE

EN

OL

AT

ES

(Con

tinu

ed)

1. R

2 O2C

N=

NC

O2R

2 ,

L

-pro

line

(0.1

eq)

, CH

2Cl 2

, rt

2. N

aBH

4, M

eOH

, the

n 0.

5 N

NaO

HO

R2 O

2CN

HN

O

R1

R1

Me

Et

CH

2=C

HC

H2

i-Pr

i-Pr

t-B

u

Bn

R2

Et

Et

Et

Et

Bn

Et

Et

(67)

(77)

(92)

(83)

(70)

(57)

(68)

% e

e

93 95 93 93 91 91 89C

4

222,

224

,

845

222

222

222

222

222

222

C3-

9

NR

1 R2

NR

3 R4

CH

O

NR

1 R2

CH

O+

R3 R

4 NC

l, O

2, d

ioxa

ne,

0°, 2

h;

rt,

over

nigh

t; re

flux

, 5 h

74

R1

Me

Me

Et

—(C

H2)

4—

—(C

H2)

2O(C

H2)

2—

—(C

H2)

5—

—(C

H2)

5—

t-B

u

R2

Me

Me

Et

MgB

r

R3

Me

Me

Et

Me

Me

Me

—(C

H2)

5—

Me

R4

Me

Me

Et

Me

Me

Me

Me

R1

CH

O

R2

R1

R2

CH

O

NH

Ts

4-M

eC6H

4SO

2N(C

l)N

a•x

H2O

,

L-p

rolin

e (2

mol

%),

MeC

N, r

t

78

R1

Me

Me

Et

H —(C

H2)

5—R2

Me

Et

Et

i-Pr

Tim

e

1 d

1 d

1 d

1 d

2 d

(83)

(81)

(78)

(86)

(86)

% e

e

0 0 0 0 0

C4-

7

R1

CH

O

III

I

(—)

(7)

(32)

(53)

(42)

(53)

(—)

(88)

I +

II

(61)

(—)

(—)

(—)

(—)

(—)

(42)

(—)

II (—)

(32)

(7)

(36)

(15)

(24)

(—)

(0)

196

C4

1. [

BnO

2CN

=N

CO

2Bn,

D-p

rolin

e, M

eCN

] (i

a),

0°

, 2 h

; to

rt, 1

h; r

t

2. N

aBH

4, E

tOH

, 0°,

5 m

in

CO

2Bn

NO

HB

nO2C

NH

Et

(92)

, 96%

ee

227

OT

MS

CH

O

NH

Ts

PhI=

NT

s, M

eCN

172

(52)

4-O

2NC

6H4N

2+ C

l– , H2O

, 0-1

0°84

2(—

)O

ArN

HN

R1

CH

O

ArN

2+ C

l– , H2O

, NaO

Ac,

pH

5-6

195

R1

Et

Et

Et

Ph Ph Ph Ph

C4-

8

R2

—(C

H2)

5—

—(C

H2)

5—

—(C

H2)

5—

Et

Et

Et

Et

R3

Et

Et

Et

Et

Ar

4-C

lC6H

4

4-O

2NC

6H4

4-H

O2C

C6H

4

4-C

lC6H

4

4-O

2NC

6H4

4-M

eOC

6H4

4-H

O2C

C6H

4

(65)

(41)

(53)

(90)

(94)

(76)

(89)

C4

S

S

i-Pr

4-O

2NC

6H4N

2+ B

F 4– , C

H2C

l 2, r

t, 1

h(8

5)84

6

C4-

6

1.

(10

mol

%),

R

2 O2C

N=

NC

O2R

2 , CH

2Cl 2

, rt,

15 m

inO

N

O

NH

CO

2R2

R1

R1

Et

i-Pr

i-Pr

ally

l

t-B

u

R2

Et

Et

i-Pr

Et

Et

(79)

(88)

(73)

(81)

(83)

% e

e

90 97 92 92 97

386

CH

O

Ar

= 3

,5-(

CF 3

) 2C

6H3

S

S

i-Pr

NN

O2N

R1

NR

2 R3

HO

CH

O

N

H N

NO

2

N H

Ar A

rO

TM

S

2. N

aBH

4, M

eOH

, 0°

O

R1

H

197

Subs

trat

eR

efs.

Con

ditio

nsPr

oduc

t(s)

and

Yie

ld(s

) (%

)

TA

BL

E 6

. AL

DE

HY

DE

EN

OL

AT

ES

(Con

tinu

ed)

C4-

15Fo

r I:

1. C

atal

yst (

0.5

eq),

sol

vent

, rt,

30 m

in

2. S

ubst

rate

, 0°;

rt,

1 h

3. R

3 O2C

N=

NC

O2R

3 , rt,

time

For

II f

rom

I:

NaB

H4,

CH

2Cl 2

, EtO

H, 0

°, 30

min

CH

O

R2

R1

R2

R1

N NH

CO

2R3

O

OR

2

R1

CH

O

E

R1

Me

Me

Me

Me

Me

Me

Et

Et

—(C

H2)

5—

Et

Me

Me

Me

Me

Me

Me

Me

Me

Me

Me

Me

R2

Me

Me

Et

Et

n-Pr

n-Pr

Et

Et

n-B

u

2-th

ieny

l

Ph Ph Ph Ph Ph 4-FC

6H4

4-FC

6H4

4-C

lC6H

4

4-B

rC6H

4

4-O

2NC

6H4

Cat

alys

t

L-p

rolin

e

L-p

rolin

e

L-p

rolin

e

L-2

-aze

tidin

ecar

boxy

lic a

cid

L-p

rolin

e

L-p

rolin

e

L-p

rolin

e

L-p

rolin

e

L-p

rolin

e

L-p

rolin

e

L-p

rolin

e

L-p

rolin

e

L-p

rolin

e

L-2

-aze

tidin

ecar

boxy

lic a

cid

L-p

rolin

e

L-2

-aze

tidin

ecar

boxy

lic a

cid

L-p

rolin

e

L-p

rolin

e

L-p

rolin

e

L-p

rolin

e

L-p

rolin

e

R3

Et

Bn

Et

Et

Et

Bn

Et

Bn

Et

Et

Bn

Et

Et

Et

Bn

Bn

Et

Bn

Bn

Bn

Et

Tim

e

3 d

3 d

— — 3 d

3d 4 d

4 d

4 d

9 d

3 d

3 d

3 d

— 3 d

— 5 d

5 d

3 d

3 d

2 d

I

(83)

(85)

(—)

(—)

(60)

(60)

(55)

(51)

(—)

(—)

(60)

(62)

(—)

(—)

(—)

(—)

(26)

(29)

(86)

(70)

(85)

223

223

847,

223

847

223

223

223

223

847,

223

847,

223

223

223,

847

847

847

847,

223

847

223

223

223

223

223

% e

e

— — 28 6 — — — — — 4 — — 81 51 81 52 — — — — —

II (—)

(—)

(52)

(—)

(—)

(—)

(—)

(—)

(26)

(35)

(—)

(—)

(17)

(—)

(83)

(—)

(—)

(—)

(—)

(—)

(—)

% e

e

— — — — — 39 — — — — 70 80 — — — — 68 35 61 79 36

III

E: N

(CO

2R3 )N

HC

O2R

3

198

Me

Me

Me

Me

Me

Me

Me

Me

Me

Me

Et

Et

Me

Me

4-O

2NC

6H4

3-M

eOC

6H4

4-M

eOC

6H4

3,5-

(MeO

) 2C

6H3

3,4-

(BnO

) 2C

6H3

4-N

CC

6H4

4-C

F 3C

6H4

4-C

F 3C

6H4

4-M

eO2C

C6H

4

4-Ph

C6H

4

Ph Ph 2-na

phth

yl

2-na

phth

yl

L-p

rolin

e

L-p

rolin

e

L-p

rolin

e

L-p

rolin

e

L-p

rolin

e

L-p

rolin

e

L-p

rolin

e

L-p

rolin

e

L-p

rolin

e

L-p

rolin

e

L-p

rolin

e

L-2

-aze

tidin

ecar

boxy

lic a

cid

L-p

rolin

e

L-2

-aze

tidin

ecar

boxy

lic a

cid

Bn

Et

Et

Et

Bn

Bn

Et

Bn

Et

Bn

Et

Et

Et

Et

2 d

3 d

5 d

6 d

7 d

3 d

5 d

3 d

6 d

3 d

3 d

— 2.5

d

—

(99)

(62)

(87)

(63)

(58)

(62)

(19)

(40)

(50)

(53)

(59)

(—)

(54)

(—)

223

223

223,

847

223,

847

223

223

223

223

223,

847

223

223,

847

847

223,

847

847

— — — — — — — — — — — — — —

(—)

(—)

(—)

(—)

(—)

(—)

(—)

(—)

(—)

(—)

(—)

(—)

(—)

(—)

56 83 76 85 73 53 — — 82 84 80 49 86 56

R1

CH

OR

2 SO

R3 O

2CN

HN

R1

O

225

1.5

eq

C4-

5

R1

Me

Me

Me

Et

Et

R2

Et

Bn

Bn

Bn

Et

R3

Bn

Et

Bn

Et

Bn

Tim

e

16 h

3.5

h

16 h

16 h

16 h

(51)

(57)

(44)

(42)

(38)

dr

88:1

2

95:5

89:1

1

96:4

95:5

ee %

>99

>99

a

>99

>99 97

1.

(cat

), R

2 SH (

1 eq

),

to

luen

e

Ar

= 3

,5-(

CF 3

) 2C

6H3

N H

Ar A

rO

TM

S

2. R

3 O2C

N=

NC

O2R

3 (1.

3 eq

), ti

me

3. N

aBH

4

4. N

aOH

199

Subs

trat

eR

efs.

Con

ditio

nsPr

oduc

t(s)

and

Yie

ld(s

) (%

)

TA

BL

E 6

. AL

DE

HY

DE

EN

OL

AT

ES

(Con

tinu

ed)

CH

O

R1

R2

CH

O

NH

SO2R

3

R1

R2

R3 SO

2N3,

(1

eq),

rt

N H

R4

386a

C4-

14

R2

Ph Me

Et

n-Pr

Et

n-B

u

Ph Ph Ph Ph Ph Ph Ph Ph Ph Ph Ph Ph Ph Ph Ph Ph Ph

R3

4-M

eC6H

4

4-M

eC6H

4

4-M

eC6H

4

4-M

eC6H

4

4-M

eC6H

4

4-M

eC6H

4

2-O

2NC

6H4

Me

n-C

4F9

5-ch

loro

-3-t

hien

yl

2,5-

dich

loro

-3-t

hien

yl

6-ch

loro

-5-b

rom

o-2-

pyri

dyl

2-O

2NC

6H4

4-O

2NC

6H4

2,4-

(O2N

) 2C

6H3

3,4-

(MeO

) 2C

6H3

4-M

eC6H

4

2-M

eO2C

C6H

4

1-na

phth

yl

2-na

phth

yl

2,4,

6-(i

-Pr)

3C6H

2

4-M

eC6H

4

4-M

eC6H

4

4-M

eC6H

4

R4

CO

2H

CO

2H

CO

2H

CO

2H

CO

2H

CO

2H

CO

2H

CO

2H

CO

2H

CO

2H

CO

2H

CO

2H

CO

2H

CO

2H

CO

2H

CO

2H

CO

2H

CO

2H

CO

2H

CO

2H

CO

2H

H tetr

azol

yl

CO

NH

Ts

Solv

ent

EtO

H

EtO

H

EtO

H

EtO

H

EtO

H

EtO

H

EtO

H

EtO

H

EtO

H

EtO

H

EtO

H

EtO

H

EtO

H

EtO

H

EtO

H

EtO

H

EtO

H

EtO

H

EtO

H

EtO

H

EtO

H

EtO

H

EtO

H

DM

SO

Tim

e

1 d

1 d

1 d

1 d

1 d

1 d

1 d

1 d

1 d

1 d

1 d

1 d

1 d

1 d

1 d

1 d

1 d

1 d

1 d

1 d

1 d

1 d

1 d

1 d

(26)

(42)

(49)

(51)

(47)

(52)

(54)

(33)

(24)

(36)

(27)

(24)

(44)

(52)

(27)

(43)

(35)

(39)

(36)

(42)

(33)

(36)

(24)

(25)

% e

e

— — 5 12 — — 28 71 29 54 47 46 56 82 45 67 59 8 65 63 50 — 66 66

R1

H Me

Me

Me

Et

—(C

H2)

5—

Et

Me

Me

Me

Me

Me

Me

Me

Me

Me

Me

Me

Me

Me

Me

Me

Me

Me

200

Ph Ph Ph Ph Ph Ph Ph Ph Ph Ph Ph Ph Ph Ph Ph 2-M

eOC

6H4

2-M

eOC

6H4

3-M

eOC

6H4

3-M

eOC

6H4

4-M

eOC

6H4

4-M

eOC

6H4

2,4-

(MeO

) 2C

6H3

2,5-

(MeO

) 2)C

6H3

3,5-

(BnO

) 2C

6H3

4-(t

-Bu)

C6H

4

Ph

4-M

eC6H

4

2-O

2NC

6H4

4-M

eC6H

4

4-M

eC6H

4

2-O

2NC

6H4

2-O

2NC

6H4

2-O

2NC

6H4

4-M

eC6H

4

4-M

eC6H

4

4-M

eC6H

4

4-M

eC6H

4

4-M

eC6H

4

4-M

eC6H

4

2-O

2NC

6H4

4-M

eC6H

4

2-O

2NC

6H4

4-O

2NC

6H4

2-O

2NC

6H4

4-O

2NC

6H4

2-O

2NC

6H4

4-O

2NC

6H4

2-O

2NC

6H4

2-O

2NC

6H4

2-O

2NC

6H4

2-O

2NC

6H4

4-M

eC6H

4

(1-p

yrro

lidin

yl)m

ethy

l•C

F 3C

O2H

(1-p

yrro

lidin

yl)m

ethy

l•C

F 3C

O2H

CH

2OH

C(P

h)2O

H

C(P

h)2O

TM

S

C(C

10H

7)2O

TM

S

C(P

h)2C

Me

CO

2Hc

CO

2Hc

CO

2Hc

CO

2H

CO

2H

CO

2H

CO

2H

CO

2H

CO

2H

CO

2H

CO

2H

CO

2H

CO

2H

CO

2H

CO

2H

CO

2H

CO

2H

CO

2H

CO

2H

DM

SO

DM

SO

EtO

H

EtO

H

EtO

H

EtO

H

EtO

H

TH

F

MeC

N

CH

2Cl 2

t-B

uOH

DM

SO

[bm

im][

BF 4

]

[bm

im][

BF 4

]

[cap

emim

][B

F 4]

EtO

H

EtO

H

EtO

H

EtO

H

EtO

H

EtO

H

EtO

H

EtO

H

EtO

H

EtO

H

EtO

H

70 m

in

1 d

4 d

1 d

1 d

1 d

1 d

7d 4d 4d 1 d

2 h

1 d

1 d

1 d

1 d

1 d

1 d

1 d

1 d

1 d

1 d

1 d

1 d

1 d

1 d

(23)

(26)

(<10

)

(0)

(26)

b

(38)

b

(52)

(21)

(14)

(0)

(25)

(28)

(38)

(55)

(53)

(21)

(21)

(47)

(49)

(53)

(44)

(34)

(32)

(31)

(55)

(36)

45 57 — — — 64 55 53 54 — 54 60 72 66 20 72 59 84 69 86 76 45 54 72 61 —

Me

Me

Me

Me

Me

Me

Me

Me

Me

Me

Me

Me

Me

Me

Me

Me

Me

Me

Me

Me

Me

Me

Me

Me

Me

Ph

C5

OO

OM

e

NH

CO

2Et

1. C

lNH

CO

2Et,

CH

Cl 3

, MeO

H, –

78°

2. C

rCl 3

3. H

2SO

4

(77)

343

201

Subs

trat

eR

efs.

Con

ditio

nsPr

oduc

t(s)

and

Yie

ld(s

) (%

)

TA

BL

E 6

. AL

DE

HY

DE

EN

OL

AT

ES

(Con

tinu

ed)

C5-

6

O

R1 R2

EtO

2CN

3, R

3 OH

, hν

O

R1 R2

NH

CO

2Et

OR

3O

R1 R2

NH

CO

2Et

OR

3

O

R1 R2

NH

CO

2Et

OR

3O

R1 R2

NH

CO

2Et

OR

3

III

III

IV

R1

H H AcO

CH

2

AcO

CH

2

H

R2

H H H H MeO

R3

Me

t-B

u

Me

t-B

u

t-B

u

I (0)

(0)

(31)

(36)

(51)

II (53)

(69)

(25)

(20)

(0)

III

(0)

(0)

(0)

(0)

(18)

IV (10)

(7)

(11)

(tra

ce)

(11)

295

1. (

Saltm

en)M

n(N

) (2

eq)

,

2,

6-(t

-Bu)

2,4-

Me-

pyri

dine

, CH

2Cl 2

2. T

FFA

, –78

°; to

rt,

5-6

h

(80)

, C2

de 8

6%35

4

1. (

Saltm

en)M

n(N

) (2

eq)

,

2,

6-(t

-Bu)

2,4-

Me-

pyri

dine

, CH

2Cl 2

2. T

FFA

, –78

°; to

rt,

5-6

h

(80)

, C2

de 8

2%35

4

O

BnO

OB

n

OH

NH

CO

CF 3

O

BnO

OB

n2

OO

DPT

PS

OO

OO

DPT

PS

OO

NH

CO

CF 3

OH

2

C5

202

C6

OO

Ac

AcO R

1 R2

OO

Ac

AcO R

1 R2

OM

e

NH

CO

2Et

OO

Ac

AcO R

1 R2

NH

CO

2Et

OM

e

OO

Ac

AcO R

1

III

III

R1

H AcO

R2

AcO

H

I (5)

(4)

II (26)

(4)

III

(11)

(34)

N3C

O2E

t, M

eOH

, hν

295

R2

OM

eN

HC

O2E

t

OO

Ac

AcO

AcO

NaN

3, C

e(N

H4)

2(N

O3)

6,

MeC

N, c

oolin

g, 8

-10

h

OO

Ac

AcO

AcO

N3

ON

O2

OO

Ac

AcO

AcO

N3

OO

Ac

AcO

AcO

OO

Ac

AcO

AcO

ON

O2

ON

O2

N3

NH

Ac

(53)

(22)

(8)

(10)

332

N3

O

O

OA

c

OO

O

OA

c

OO

Me

NH

CO

2Et(1

2)34

3

1. C

lNH

CO

2Et,

CH

Cl 3

,

M

eOH

, –78

°2.

CrC

l 2

3. M

eOH

, AgN

O3

O

AcO

OA

cO

AcO

OA

c NH

CO

2CH

2CH

2Cl

OM

e

AcO

AcO

1. C

lNH

CO

2CH

2CH

2Cl,

C

HC

l 3, M

eOH

, –78

°2.

CrC

l 2

3. M

eOH

, AgN

O3

(55)

343

PhPh

203

Subs

trat

eR

efs.

Con

ditio

nsPr

oduc

t(s)

and

Yie

ld(s

) (%

)

TA

BL

E 6

. AL

DE

HY

DE

EN

OL

AT

ES

(Con

tinu

ed)

O

OO

O

AcO

1. C

lNH

CO

2CH

2CC

l 3,

C

HC

l 3, M

eOH

, –78

°2.

CrC

l 2

3. M

eOH

, AgN

O3

4. A

cOH

, the

n A

c 2O

(65)

343

OA

cO

Ac

NH

CO

2CH

2CC

l 3

AcO

OM

e

Ph

1. T

FAA

, CH

2Cl 2

2. (

Saltm

en)M

n(N

) (1

eq)

, CH

2Cl 2

;

ad

ditio

n ov

er 7

h

O

OO

PhO

OO

PhO

H

NH

CO

CF 3

2(7

0), C

2 de

0%

354

1. T

FAA

, CH

2Cl 2

2. (

Saltm

en)M

n(N

) (1

eq)

, CH

2Cl 2

;

ad

ditio

n ov

er 7

h

O

O

OR

O

R =

TB

S

O

O

OR

O

PhO

H

NH

CO

CF 3

2(7

5), C

2 de

75%

354

Ph

O

PMB

O

PMB

O1.

TFA

A, C

H2C

l 2

2. (

Saltm

en)M

n(N

) (1

eq)

, CH

2Cl 2

;

ad

ditio

n ov

er 7

h

O

PMB

O

PMB

ON

HC

OC

F 3O

H(6

0), C

2 de

75%

354

2

O

OO

OPM

B

1. T

FAA

, CH

2Cl 2

2. (

Saltm

en)M

n(N

) (1

eq)

, CH

2Cl 2

;

ad

ditio

n ov

er 7

h

O

OO

OPM

B

NH

CO

CF 3

OH

235

4Ph

PhR PM

B

TB

S

(66)

(68)C

2 %

de

71

75

C6

1. T

FAA

, CH

2Cl 2

2. (

Saltm

en)M

n(N

) (1

eq)

, CH

2Cl 2

;

ad

ditio

n ov

er 7

h

354

R Bn

TB

DPS

(62)

(64)

C2

de %

87.5

87.5

O

OO

RO

O

OO

RO

NH

CO

CF 3

HO

(Sal

tmen

)Mn(

N),

TFA

A,

2,

6-(t

-Bu)

2,4-

Me-

pyri

dine

, –78

° to

rt

O

OO

O

OO

NH

CO

CF 3

HO

(69)

351

2

2

204

SSH H

PhSS

H H

N Ph

SSH H

N Ph

4-O

2NC

6H4N

2+ B

F 4– , C

H2C

l 2, r

t

EtO

2CN

=N

CO

2Et,

CH

2Cl 2

, rt,

6 h

(79)(5

8)84

6

846

PhN

PhC

HO

N1.

MeO

2CN

=N

CO

2Me

2. H

3O+, H

2O(—

)24

7

C8

PhC

HO

Ph

NH

Ts

CH

O

4-M

eC6H

4SO

2N(C

l)N

a•x

H2O

,

pyr

rolid

ine

(10

mol

%),

PhN

Me 3

+ B

r 3– (

10 m

ol%

), M

eCN

, rt,

1 d

(70)

78

C9

NC

6H4N

O2-

4

NH C

O2E

t

CO

2Et

NH

CO

2Me

MeO

2C

R1

CH

O

R2

R1

R2

CH

O

NH

Ts

4-M

eC6H

4SO

2N(C

l)N

a•x

H2O

,

L-p

rolin

e (2

mol

%),

MeC

N, m

icro

wav

e ir

radi

atio

n (y

W)

0% e

e78

R2

Ph Ph Ph Ph 4-FC

6H4

4-O

2NC

6H4

4-M

eC6H

4

4-C

F 3C

6H4

4-N

CC

6H4

Ph naph

thyl

4-(i

-Pr)

C6H

4CH

2

R1

Me

Me

Me

Me

Me

Me

Me

Me

Me

Ph Me

Me

Tem

p

90°

50°

50°

60°

60°

60°

60°

60°

60°

60°

60°

rt

Tim

e

30 m

in

30 m

in

40 m

in

30 m

in

30 m

in

30 m

in

30 m

in

30 m

in

30 m

in

30 m

in

30 m

in

1 d

(50)

(66)

(90)

(90)

(85)

(89)

(73)

(79)

(86)

(88)

(91)

(83)

C9-

13

y 100

150

200

200

200

200

200

200

200

200

200

200

205

Subs

trat

eR

efs.

Con

ditio

nsPr

oduc

t(s)

and

Yie

ld(s

) (%

)

TA

BL

E 6

. AL

DE

HY

DE

EN

OL

AT

ES

(Con

tinu

ed)

CH

O

R

OH

CN

BnO

2CN

=N

CO

2Bn,

L-p

rolin

e (3

0 m

ol%

),

MeC

N, r

t, 1

h

226

(99%

), >

99%

ee

Br

C10

N HH

NNN

N1.

(

15 m

ol%

), M

eCN

2. A

dd B

nO2C

N=

NC

O2B

n,

th

en s

ubst

rate

, rt,

3 h

(95)

, 80

% e

e38

5

OH

C

Br

OH

CN

CH

O

R

C10

-11

R

EC

HO

R Br

CO

2Me

(75)

(96)

% e

e

>99

>99

1. D

-Pro

line

(15

mol

%),

MeC

N,

B

nO2C

N=

NC

O2B

n

2. A

dd s

ubst

rate

, rt,

4 h

226

E =

N(C

O2B

n)N

HC

O2B

n

a With

L-p

rolin

e as

the

cata

lyst

, bot

h dr

and

ee

valu

es w

ere

cons

ider

ably

low

er.

b The

pro

duct

was

red

uced

with

NaB

H4

prio

r to

isol

atio

n.c T

he c

atal

yst l

oadi

ng w

as 4

0 m

ol%

.

NH

CO

2Bn

CO

2BnN

HC

O2B

n

CO

2Bn

206

Subs

trat

eR

efs.

Con

ditio

nsPr

oduc

t(s)

and

Yie

ld(s

) (%

)

TA

BL

E 7

A. A

CY

CL

IC K

ET

ON

E E

NO

LA

TE

S

C3

OE

t4-

O2N

C6H

4N2+

Cl– , H

2O, 0

–10°

(—)

842

N

N Ph

N

OO

, ref

lux

HN

N Ph

NC

H2C

OM

e

OO

(~10

0)25

4

C4-

14

R2

O

R3

R1

R2

O

R3

R1

R2

O

R3

R1

1. P

hR4 N

MnM

e•4

LiB

r (i

a), T

HF,

rt,

1 h

2. R

5 O2C

N=

NC

O2R

5 , –30

°; r

t, 2.

5 h

NI

IIR

1

H Me

Et

n-Pr

n-Pr

n-C

5H11

Et

Et

R2

H Me

H H H Me

Et

Et

R3

Me

Me

Et

n-Pr

n-Pr

Me

Bn

Bn

R4

n-B

u

n-B

u

Me

Me

Me

n-B

u

n-B

u

n-B

u

R5

Et

Et

t-B

u

Et

t-B

u

t-B

u

Et

t-B

u

I +

II

(50)

(72)

(60)

(90)

(60)

(60)

(93)

(75)

I:II

50:5

0

90:1

0

— — — 98:2

98:2

90:1

0

I dr

— — — — — — 3:1

3:1

388

R1

O40

3R

2 O2C

N=

NC

O2R

2 , DA

BC

O (

cat)

, TH

F

R1

Me

Me

Et

Et

n-C

6H13

n-C

7H15

PhC

H=

CH

PhC

H=

CH

C4-

11

R2

Et

t-B

u

Et

t-B

u

Et

Et

Et

t-B

u

Tem

p

rt 40°

rt 40°

rt rt rt 40°

Tim

e

8 h

24 h

24 h

24 h

24 h

8 h

8 h

24 h

(83)

(63)

(78)

(34)

(79)

(61)

(90)

(52)

O

H NN

Ac

O2N

E =

CO

2R5

NN H

EE

E

NH

E

+

R1

O

NR

2 O2C

NH

CO

2R2

207

Subs

trat

eR

efs.

Con

ditio

nsPr

oduc

t(s)

and

Yie

ld(s

) (%

)

TA

BL

E 7

A. A

CY

CL

IC K

ET

ON

E E

NO

LA

TE

S (C

onti

nued

)

C4-

10O

R1

R2

O

R1

R3 O

2CN

=N

CO

2R3 , c

atal

yst (

x eq

), r

t

O

R1

N

R2

R2

I

R1

H H H H H Me

H H H

R2

Me

Me

Me

Me

Me

Me

Et

i-Pr

Bn

R3

Et

Et

Et

t-B

u

t-B

u

Et

Et

Et

Et

x 0.2

0.05 0.1

0.2

0.1

0.1

0.1

0.1

0.1

Tim

e

52 h

65 h

10 h

114

h

114

h

60 h

20 h

96 h

24 h

I

(—)

(—)

(73)

(49)

(54)

(79)

(62)

(52)

(75)

I %

eea

96 93 95 94 90 94 98 99 98

II

(<10

)

(<10

)

(7)

— — — (15)

(17)

(17)

Cat

alys

t

L-p

rolin

e

L-p

rolin

e

L-p

rolin

e

L-p

rolin

e

L-a

zetid

inec

arbo

xylic

aci

d

L-p

rolin

e

L-p

rolin

e

L-p

rolin

e

L-p

rolin

e

228

228

228

229

229

228

228

228

228

Solv

ent

MeC

N

neat

MeC

N

CH

2Cl 2

CH

2Cl 2

MeC

N

MeC

N

MeC

N

MeC

N

R1

CO

2Et

O

N

OO

NR3

R3

R4

R5

R4

R5

Cu

(OT

f)2

1.

(

10 m

ol%

), s

olve

ntN

OO

NH

CO

2R2

MeO

2C

R1

404

R1

Me

Me

i-Pr

i-Pr

CH

2CH

=C

H2

CH

2CH

=C

H2

i-B

u

i-B

u

(CH

2)2C

H=

CH

2

(CH

2)2C

H=

CH

2

R2

Bn

Bn

Bn

Bn

Bn

Bn

Bn

Bn

Bn

Bn

R3

H Me

H H H H H H H H

R4

Ph Ph Ph Ph Ph Ph Ph Ph Ph Ph

R5

Ph Ph Ph Ph Ph Ph Ph Ph Ph Ph

Solv

ent

CH

2Cl 2

TH

F

CH

2Cl 2

TH

F

CH

2Cl 2

TH

F

CH

2Cl 2

TH

F

CH

2Cl 2

TH

F

(45)

(44)

(78)

(60)

(62)

(38)

(53)

(51)

(52)

(36)

% e

e

90 92 95 95 93 90 96 95 92 94

E =

CO

2R3

NH

E

E

II

+

NE

EH

N

2. A

dd s

ubst

rate

, the

n R

2 O2C

N=

NC

O2R

2 ,

rt

, 16

h

3. L

-Sel

ectr

ide,

TH

F, –

78°,

1 h;

to r

t

4. N

aOH

, H2O

, rt,

2 h

5. T

MSC

HN

2, M

eOH

, tol

uene

, hex

ane,

15

min

208

n-C

5H11

n-C

5H11

c-C

6H11

CH

2

c-C

6H11

CH

2

Bn

Bn

Bn

Bn

Bn

Bn

Bn

Bn

Bn

Bn

Bn

Et

Et

Bn

Bn

Bn

Bn

Bn

H H H H Me

Me

Me

Me

Me

H Me

Ph Ph Ph Ph H H H H H Ph Ph

Ph Ph Ph Ph Ph Ph Ph Ph t-B

u

Ph Ph

CH

2Cl 2

TH

F

CH

2Cl 2

TH

F

CH

2Cl 2

TH

F

CH

2Cl 2

TH

F

TH

F

TH

F

TH

F

(63)

(48)

(54)

(72)

(55)

(47)

(39)

(60)

(31)

(57)

(58)

93 97 96 96 68 35 90 82 7 89 88

OT

MS

O

NH

Ts

PhI=

NT

s, M

eCN

(53)

172

C5

R1

R2

R3 M

e 2Si

R1

R2

R3 M

e 2Si

NH

CO

2Bu-

t

1. L

DA

, TH

F, 0

°2.

, tem

p; to

rt

R1

Me

Et

n-Pr

Me

Bn

R2

Me

Et

n-Pr

Bn

Me

R3

t-B

u

t-B

u

t-B

u

t-B

u

t-C

6H13

Tem

p

–100

°–1

00°

–100

°–7

8°–7

8°

(27)

(37)

(29)

(19)

(20)

% d

e

80 87 88 41 83

156

OO

ON

4-O

2NC

6H4

CO

2Bu-

t

C5-

11

209

Subs

trat

eR

efs.

Con

ditio

nsPr

oduc

t(s)

and

Yie

ld(s

) (%

)

TA

BL

E 7

A. A

CY

CL

IC K

ET

ON

E E

NO

LA

TE

S (C

onti

nued

)

S

SR

1

R2

OC

5-12

OS

SR

1

R2

OO

S

SR

1

R2

OO

NC

O2B

u-t

NC

O2B

u-t

NH

CO

2Bu-

tN

HC

O2B

u-t

III

R1

Me

Et

Et

Et

Et

Ph Et

Et

R2

Me

H Me

i-Pr

t-B

u

Me

Ph Bn

Ena

ntio

mer

+/–

+/–

+/– + + +/– + +

1. L

iHM

DS,

TH

F, –

78°

2. t-

BuO

2CN

=N

CO

2Bu-

t, –7

8°, 1

5 m

in

3. H

OA

c, –

78° b

I +

II

(69)

(72)

(48)

(89)

(91)

(37)

(85)

(93)

I:II

2:1

—

>99

:1

— — 2:1

— —

% d

e

— — — 72c

— — — 69c

848

S

SR

1

R2

O

C5-

6

OS

SR

1

R2

OO

S

SR

1

R2

OO

NC

O2B

u-t

NC

O2B

u-t

NH

CO

2Bu-

tN

HC

O2B

u-t

III

1. L

iHM

DS,

TH

F, –

78°

2. t-

BuO

2CN

=N

CO

2Bu-

t, –7

8°, 1

5 m

in

3. H

OA

c, –

78° b

848

(+/–

)

R1

Me

Et

Et

R2

Me

H Me

I +

II

(76)

(89)

(42)

I:II

3:1

— 12:1

C5

OSi

(Pr-

i)3

O

N3

NaN

3, C

e(N

H4)

2(N

O3)

6, M

eCN

, –20

°(3

0)33

1

+ +

210

C6-

9

R1

R2

OT

MS

R1

NH

Ts

O

R2

PhI=

NT

s (0

.67

eq),

CuC

lO4

(3-6

mol

%),

MeC

N

173

R1

n-B

u

Ph Ph

R2

H H Me

Tem

p

0° –20° 0°

Tim

e

1.5

h

3 h

15 m

in

(53)

(76)

(58)

OO

TM

S

C6

EtO

2CN

=N

CO

2Et,

PhH

, 80°

, 8 h

(73)

243,

242

R1

OT

MS

R1

NH

CO

2Et

O

R2

1. E

tO2N

3, 1

00°

2. S

iO2

296

R2

R1

t-B

u

n-Pr

Ph

C6-

8

R2

H Et

H

(65)

(56)

(35)

C7

OL

iO

N=

NPh

PhN

2+ B

F 4– (

ia),

TH

F, –

78°

(72)

185

1. L

iHM

DS

(ia)

, TH

F, –

78°,

30 m

in

2.

,

–78°

, 20

h; to

rt

ON

CO

2Bu-

tE

tO2C

EtO

2C

R H Me

Ph

(21)

(31)

(15)

155

C8-

14

C8-

9

C8

OM

eN

HC

O2E

t

O1.

ClN

HC

O2E

t, C

HC

l 3, M

eOH

, –78

°2.

CrC

l 2

3. H

2SO

4

(59)

343

ON

CO

2R2

4-N

CC

6H4

i-Pr

1. L

DA

(ia

), T

HF,

–78

°, 1

h

2.

, –

78°;

to r

t, 2-

3 h

NH

O

OR

2Ph

O

154

R1

R1

H Me

(59)

(62)

% d

e

— 5

R2 =

OO

NN

HC

O2E

t

CO

2Et

Ph

H NC

O2B

u-t

R

O

Ph

R

O

Ph

R1

O

211

Subs

trat

eR

efs.

Con

ditio

nsPr

oduc

t(s)

and

Yie

ld(s

) (%

)

TA

BL

E 7

A. A

CY

CL

IC K

ET

ON

E E

NO

LA

TE

S (C

onti

nued

)

C8-

9

Ar

OT

MS

Ar

O

PhI=

NT

s, M

eCN

, rt

172

Ar

Ph 4-C

lC6H

4

4-O

2NC

6H4

4-M

eOC

6H4

2-M

eC6H

4

3-M

eC6H

4

4-M

eC6H

4

Ph

Tim

e

4.5

h

>24

h

6 h

3.5

h

18 h

11 h

1 h

—

(95)

(99)

(85)

(97)

(51)

(96)

(97)

(94)

Ph

OT

MS

C8

ON

CO

NE

t 2,

4-C

lC6H

4

155

TsN

H

H NPh

O

Et 2

N

OPh

O

HO

III

+I

+ I

I (—

), I

:II

= 1

:5

RR

R H H H H H H H Me

RPh

OT

MS

C8-

9

RPh

O

N

1. B

nO2C

N=

NC

O2B

n +

AgO

Tf

(ia)

,

C

H2C

l 2, –

45°,

30 m

in

2. H

F, T

HF

244

R H Me

(91)

(84)

Ph

O1.

BnO

2CN

=N

CO

2Bn

+ A

gOT

f +

(R

)-B

INA

P (i

a),

T

HF,

cos

olve

nt, –

45°,

time

2. H

F, T

HF

244

N

BnO

2CR M

e

Et

Cos

olve

nt

2,4,

6-M

e 3C

6H3

—

(95)

(93)

% e

e

86 59R

Ph

OT

MS

Ph

O

N

EtO

2C

N H

1. E

tO2C

N=

NC

O2E

t, C

H2C

l 2,

0-

5°, 3

h; r

t, 2

h

2. H

2O, r

t, 2

h

(56)

245

C8

Tim

e

18 h

3 h

1.

, C

H2C

l 2,

0-

5°, 3

h; r

t, 2

h

N

N Ph

N

OO

HN

N Ph

N

OO

PhO

(50)

245

EtO

H, H

2O (

3:1)

, rt,

44 h

2. H

2O, r

t, 2

h

EtO

2C

NH

CO

2Bn

BnO

2C

BnO

2CH

N

212

Ph

OT

MS

C8

(Sal

tmen

)Mn(

N),

CH

2Cl 2

, pyr

idin

e,

TFF

A, –

78° t

o rt

, 3-4

hPh

O

CF 3

CO

NH

(69)

471

1. L

i bas

e, E

t 2O

or

TH

F

2. M

e 2N

OM

s, –

30° t

o 0°

(52)

134

C9

Ph

OR

Ph

O

PhI=

NT

s, C

uPF 6

, lig

and

(5.5

-6 m

ol%

),

C

H2C

l 2, –

40°

NN

2,6-

Cl 2

C6H

4C

6H3C

l 2-2

,6

R Me

Me

Ac

Ac

TM

S

TM

S

TB

DM

S

TB

DM

S

Tim

e

3 h

3 h

5 h

5 h

5 h

4 h

3 h

16 h

(87)

(76)

(>95

)

(61)

(>95

)

(90)

(>95

)

(92)

% e

e

9 (R

)

10 (

S)

28 (

R)

52 (

R)

18 (

S)

16 (

S)

12 (

S)

13 (

S)

174

Lig

and

1 2 1 2 1 2 1 2N

OO

N

PhPh

1 2

NH

Ts

1. L

DA

(ia

), T

HF,

–78

°, 1

h

2.

,

ON

CO

NE

t 22-

NC

C6H

415

8

1. L

iHM

DS,

TH

F, –

78°,

30 m

in

2.

, –78

°, 30

min

153,

157

ON

CO

2Bu-

t4-

NC

C6H

4Ph

O

Ph

O

NH

CO

2Bu-

tPh

OO

H

C6H

4CN

-4+

(36)

(25)

Ph

O

NH

CO

NE

t 2

(60)

Ar

O

Ar

O

NH

Ts

4-M

eC6H

4SO

2N(C

l)N

a•x

H2O

,

L-p

rolin

e (2

mol

%),

MeC

N, r

t

0% e

e

Ar

Ph 4-FC

6H4

3-M

eOC

6H4

4-M

eOC

6H4

3-C

F 3C

6H4

Tim

e

1 d

2 d

1 d

1 d

2 d

(83)

(82)

(74)

(71)

(83)

78

Ph

OPh

O

NM

e 2

–78°

, 3 h

; to

rt, 1

.5 h

213

Subs

trat

eR

efs.

Con

ditio

nsPr

oduc

t(s)

and

Yie

ld(s

) (%

)

TA

BL

E 7

A. A

CY

CL

IC K

ET

ON

E E

NO

LA

TE

S (C

onti

nued

)

(43)

849

EtO

2CN

=N

CO

2Et,

AlC

l 3, d

ioxa

ne, r

t, 48

hPh

O

PhN

OC

O2E

t

NH

CO

2Et

Ph

OR

Ph

O

NH

Ts

PhI=

NT

s, C

uPF 6

, 1 o

r 2

(str

uctu

res

on

pre

viou

s pa

ge, 6

mol

%),

CH

2Cl 2

, –40

°, 4

h

R TM

S

TB

DM

S

TM

S

TB

DM

S

(89)

(91)

(92)

(>95

)

174

Lig

and

1 1 2 2

% e

e

20 (

R)

27 (

R)

19 (

S)

21 (

S)

Ar

R

OT

MS

Ar

R

O

Cl 3

CC

H2O

2CN

N HN

OOO

252

Ar

Ph 4-M

eOC

6H4

Ph Ph Ph Ph 4-M

eOC

6H4

6-M

eO-2

-nap

hthy

l

4-M

eOC

6H4

4-M

eOC

6H4

R Me

Me

Et

CH

2CH

=C

H2

i-Pr

i-B

u

t-B

u

Me

Ph Bn

Tem

p

–20°

–20°

–20°

–20°

–20°

–20°

–20°

–20°

–50°

–78°

(95)

(96)

(93)

(92)

(86)

(92)

(84)

(96)

(94)

(94)

% e

e

99 99 98 97 99 98 98 99 97

99

Tim

e

2 m

in

<1

min

30 m

in

2 h

3 h

2 h

6 h

1 m

in

13 h

12 h

Ph

OT

MS

TsN

(Cl)

Na

+ O

sO4

(0.0

04 e

q) +

(D

HQ

D) 2

PYR

(0.

008

eq)

(ia)

,

t-B

uOH

/H2O

(1:

1), r

t, 2

hPh

O

NH

Ts

(45)

, 85%

ee

342

C9-

13

C9

C9

ON

Cl 3

CC

H2O

2CN

=N

OO

CF 3

CH

2OH

(1

eq),

3 (

5 m

ol%

), T

HF

,

NC

u(O

Tf)

2

N

OO

t-B

uB

u-t

3

214

a The

ee

valu

es a

re th

ose

of th

e cr

ude

prod

ucts

; som

e ra

cem

izat

ion

occu

rred

on

silic

a ch

rom

atog

raph

y.b S

ome

equi

libra

tion

appe

ars

to o

ccur

eve

n at

–78

°.c T

he e

e va

lue

was

det

erm

ined

in a

deg

rada

tion

prod

uct.

OT

MS

PhI=

NT

s, M

eCN

O

NH

Ts

(70)

172

C15

215

Subs

trat

eR

efs.

Con

ditio

nsPr

oduc

t(s)

and

Yie

ld(s

) (%

)

TA

BL

E 7

B. C

YC

LIC

KE

TO

NE

EN

OL

AT

ES

C5

NN

NC

O2E

tN N

HC

O2E

t(1

2)

(10)

(8)

4-O

2NC

6H4S

O2O

NH

CO

2Et,

Et 3

N, C

H2C

l 2, r

t, 2

h

399

C5-

10O

Si(P

r-i)

3

R1

R2

R1

R2

OSi

(Pr-

i)3

N3

N3

nn

PhIO

(1.

5 eq

), T

MSN

3 (3

eq)

,

TE

MPO

a (0.

1 eq

), s

olve

nt, –

45°,

16 h

R1

H H —

OC

H2O

—

t-B

u

R2

H H H

n 0 1 1 1 1

Solv

ent

tolu

ene

CH

2Cl 2

CH

2Cl 2

CH

2Cl 2

CH

2Cl 2

(60)

sin

gle

isom

er

(91)

sin

gle

isom

er

(82)

3:1

mix

ture

of

isom

ers

(71)

sin

gle

isom

er

(67)

4:2

:1 m

ixtu

re o

f is

omer

s

850

C5

NO

O

NN

HC

H2C

O2M

e1.

MeO

2CC

H=

N2,

rt,

7 d

2. S

iO2,

H2O

(—)

207

(MeO

2C) 2

C=

N2,

Et 2

O, –

30°

207

NO

NN

HC

H(C

O2M

e)2

(65)

OO

EtO

2CC

O2E

t

O

NH

CO

2Et

++

216

OT

MS n

O

N1.

EtO

2CN

=N

CO

2Et,

Et 2

O, 0

-5°,

3 h;

rt,

2 h

2. H

2O, r

t, 2

h

245

n 0 1

(68)

(>72

)

C5-

6C

O2E

t

NH

CO

2Et

NYC

5

O

NH

PhNY

NPh

NH

CO

2Me

1. P

hN=

NC

O2M

e, E

t 2O

, dar

k,

rt

, 96

h (f

orm

s I)

2. H

Cl (

5% in

Me 2

CO

), 5

°, 48

h (

form

s II

)

III

401

Y — CH

2

NPh

O

I

(—)

(—)

(—)

(46)

II (70)

(71)

(40)

(71)

1. B

zN=

NC

O2M

e (1

eq)

, Et 2

O,

–3

0°, 3

h (

form

s I,

II,

and

III

)

2. H

Cl (

10%

in M

e 2C

O),

5°,

48 h

(f

orm

s IV

fro

m I

and

II;

V f

rom

III

)

NY

NY

EE

NY

EE

III

O

E

O

EE

E =

N(C

O2M

e)N

HB

z

IVV

Y — CH

2

NPh

O

I

(—)

(—)

(—)

(—)

II (—)

(—)

(—)

(40)

III

(—)

(—)

(—)

(—)

IV (20)

(30)

(32)

(40)

V (26)

(23)

(8)

(23)

401

N

N Ph

N

O, C

H2C

l 2, 0

-5°,

4 h;

O

O

nNN

PhH

N

O

n 0 1

(62)

(60)

245

n

rt,

over

nigh

t

III

++

+

O

217

Subs

trat

eR

efs.

Con

ditio

nsPr

oduc

t(s)

and

Yie

ld(s

) (%

)

TA

BL

E 7

B. C

YC

LIC

KE

TO

NE

EN

OL

AT

ES

(Con

tinu

ed)

NO

NO

NN

PhNH

HN

N

O

O

+Ph

N=

NC

ON

H2,

MeO

H, 0

°; 5

°, 2

h85

1

NH

CO

NH

2

Ph

C5

(25)

(25-

35)

1. A

r1 N=

NC

OA

r2 , sol

vent

, 0°,

time

1

2. 1

0% H

Cl,

Me 2

CO

, tem

p, ti

me

2

400

Ar1

Ph 4-O

2NC

6H4

Ph

Ar2

Ph Ph C6H

4NO

2-4

Solv

ent

Et 2

O

PhH

PhH

Tim

e 1

10-1

5 m

in

2 d

2 d

Tem

p

0° rt rt

Tim

e 2

few

min

24-4

8 h

24-4

8 h

(55)

(64)

(63)

O2S

NO

1. E

tO2C

N=

NC

O2E

t, Ph

H, r

t, 72

h

2. H

Cl,

EtO

H, H

2O, r

t, 24

h

(86)

248

O2S

NH

Bu-

n

O2S

n-B

uHN

NE

tO2C

N=

NC

OR

, MeC

N, r

eflu

x, 3

h25

0

R OE

t

Ph

(65)

(65)

YOT

MS

n1.

EtO

2CN

3, 1

00°,

15 h

2. S

iO2

296

Y CH

2

CH

2

CH

Bu-

t

n 0 1 1

(40)

(49)

(36)

C5-

9

YO nN

HC

O2E

t

O

NN

HC

OA

r2

Ar1

O2S

O

NN

HC

O2E

t

CO

2Et

NH

CO

R

CO

2Et

218

YOT

MS

YO

N3

NaN

3, C

e(N

H4)

2(N

O3)

6, M

eCN

, –20

°Y — O

(65)

(47)

331

C5

NM

eOO

NH

CO

2Et

1. E

tO2C

N3,

CH

2Cl 2

, ref

lux

2. h

ν, rt

, 4 h

(18)

, 24%

ee

303

OH N

, C

H2C

l 2, r

t, 30

min

(25)

, 18%

ee

303

MsN EtO

N3

NM

s

OE

t

NM

eOO

Me

, C

H2C

l 2, r

t, 30

min

MsN EtO

N3

NM

eOO

Me

H NN

Ms

OE

t

OH N

NM

e

OE

t

I (

18),

>95

% d

eII

20%

ee

303

NO

NH

CO

R

NSO

2

RC

ON

3, C

H2C

l 2, 3

0 m

in

R =

NC

OR

N(5

), 4

5% d

e(2

2), >

95%

de

304

1. 2. r

t ; I

con

vert

s sl

owly

into

II

+

C6

OM

eO

NH

CO

2CH

2CC

l 31.

ClN

HC

O2C

H2C

Cl 3

, CH

Cl 3

, MeO

H, –

78°

2. C

rCl 2

3. M

eON

a

(86)

343

OR

1O

NH

CO

2Et

4-R

2 C6H

4SO

2ON

HC

O2E

t, ad

dend

,

C

H2C

l 2, r

t

R1

TM

S

TM

S

O(C

H2)

2OT

MS

Tim

e

24 h

3.5

h

2 h

(51)

(67)

(33)

R2

Me

O2N

O2N

Add

end

Cs 2

CO

3

CaO

CaO

119

122

122

219

Subs

trat

eR

efs.

Con

ditio

nsPr

oduc

t(s)

and

Yie

ld(s

) (%

)

TA

BL

E 7

B. C

YC

LIC

KE

TO

NE

EN

OL

AT

ES

(Con

tinu

ed)

NR

O

NH

CO

2Et

4-O

2NC

6H4S

O2O

NH

CO

2Et,

Et 3

N,

C

H2C

l 2, r

t, 3

hN N

HC

O2E

t

R

III

(—)

R CO

2Bu-

t (S)

CH

2OT

MS

(S)

CH

2OM

e (S

)

CH

2OM

e (R

)

I

(14)

(12)

(18)

(21)

% e

e

5 52 77 50

121

C6

NR

1R

1O

NH

CO

2Et

N NH

CO

2Et

III

ArS

O2O

NH

CO

2Et,

adde

nd,

C

H2C

l 2, r

t

R2

R2

R1

H H H Me

H H

R2

H H H H Me

t-B

u

Add

end

— Cs 2

CO

3

Cs 2

CO

3

Et 3

N

Et 3

N

Et 3

N

Tim

e

2 h

24 h

24 h

3 h

3 h

3 h

I

(—)

(38)

(35)

(15)

(19)

(24)

II (—)

(0)

(34)

(0)

(0)

(0)

I:II

49:5

1

— — — — —

399

118

118

120

120

120

OO

TM

S

RR

O

NH

CH

O2E

t4-

O2N

C6H

4SO

2ON

HC

O2E

t, E

t 3N

,

C

H2C

l 2, r

t, 3

h

ON

CO

2Et

OT

MS

R

R

III

R Me

(R,R

)

MeO

CH

2 (R

,R)

Ph (

S,S)

BnO

CH

2 (S

,S)

I

(24)

(27)

(36)

(28)

% e

e

68 63 75 60

II (0)

(0)

(19)

(0)

% d

e

— — >95 —

397

Ar

4-O

2NC

6H4

4-M

eC6H

4

4-O

2NC

6H4

4-O

2NC

6H4

4-O

2NC

6H4

4-O

2NC

6H4

NN

CO

2Et

III

III

(0)

(tra

ce)

(31)

(0)

(0)

(0)

+

+

++

220

OR

O

NH

Ts

PhI=

NT

s (0

.67

eq),

MeC

N, –

20°,

1.5

h(6

4-65

)R

= T

MS,

TB

S17

2, 1

73

NN

2,6-

Cl 2

C6H

4C

6H3C

l 2-2

,6

OT

MS

PhI=

NT

s, C

uPF 6

, 1 (

cat)

,

CH

2Cl 2

, –40

°, 5

h

O

NH

Ts

(45)

, 19%

ee

174

OL

i

PhN

2+ B

F 4– (

ia),

TH

F, –

78°

O

N=

NPh

(10-

30)

com

plex

mix

ture

185

N

O

N-N

HA

r1.

ArN

2+ C

l– , con

c. H

Cl,

H2O

, –3°

to 0

°2.

NaO

Ac

to p

H 5

-6

852

Ar

Ph 2-O

2NC

6H4

4-O

2NC

6H4

2-M

eOC

6H4

4-M

eOC

6H4

2-M

eC6H

4

4-M

eC6H

4

(75)

(74)

(77)

(61)

(55)

(82)

(85)

C6-

10

RNY

RO

N1.

ArN

=N

CO

2Et,

0°2.

HC

l, H

2O, E

tOH

R H H H H t-B

u

Y — — O O —

Ar

Ph 4-O

2NC

6H4

Ph 4-O

2NC

6H4

Ph

(45)

(50)

(10)

(45)

(39)

853

NH

CO

2Et

Ar

1

221

Subs

trat

eR

efs.

Con

ditio

nsPr

oduc

t(s)

and

Yie

ld(s

) (%

)

TA

BL

E 7

B. C

YC

LIC

KE

TO

NE

EN

OL

AT

ES

(Con

tinu

ed)

C6-

10

RNY

RO

N

1. E

tO2C

N=

NC

OA

r, E

t 2O

, 0°,

48 h

2. H

Cl,

Me 2

CO

, H2O

, 48

h

R H H t-B

u

t-B

u

t-B

u

t-B

u

Y O O O O — —

Ar

Ph 4-O

2NC

6H4

Ph 4-O

2NC

6H4

Ph 4-O

2NC

6H4

(84)

b

(36)

b

(41)

b

(55)

b

(50)

b

(37)

b

853

R1

NO

R1

NO

N

R1

H H H t-B

u

t-B

u

t-B

u

R2

H H O2N

H H O2N

R3

H O2N

H H O2N

H

Solv

ent

Et 2

O

PhH

PhH

Et 2

O

PhH

PhH

(23)

(20)

(80)

(41)

(21)

(74)

4-(R

2 )C6H

4N=

NC

OC

6H4(

R3 )-

4,

sol

vent

, 0°,

48 h

854

NC

OC

6H4(

R3 )-

4

C6H

4(R

2 )-4

RO

RO

N

BzN

=N

Bz,

100

-110

°, 20

hR

= H

, t-B

u(2

0-25

)38

9

RNY

Y — CH

2

O O O

R H H H H t-B

u

Ar

Ph Ph Ph 4-M

eC6H

4

Ph

(79)

(87)

(80)

(81)

(74)

389,

855

ArC

ON

=N

CO

Ar,

PhH

, 7-8

°; r

t, 24

h

NH

CO

Ar

CO

2Et

NH

Bz

Bz

RO

NN

HC

OA

r

CO

Ar

222

O

EtO

2CN

=N

CO

2Et,

K2C

O3

or K

OA

c, 1

00°,

4 h

(28-

32)

390

RO

2CN

=N

CO

2R, 1

00°,

24 h

R Me

Et

(20)

(48)

246

390,

246

OT

MS

1. B

nO2C

N=

NC

O2B

n +

AgO

Tf

(ia)

,

C

H2C

l 2, 0

°, 30

min

2. H

F, T

HF

(91)

244

C6

O

NN

HC

O2E

t

CO

2Et

O

NN

HC

O2R

CO

2R

O

NN

HC

O2B

n

CO

2Bn

RO

2CN

=N

CO

2R, c

atal

yst (

x eq

)

O

E

R Et

Et

Et

i-Pr

t-B

u

Bn

Bn

Bn

Bn

x 0.1

0.2

0.2

0.2

0.2

0.2

0.2

0.2

0.2

Solv

ent

Cl(

CH

2)2C

l

Cl(

CH

2)2C

l

CH

2Cl 2

MeC

N

MeC

N

CH

2Cl 2

CH

2Cl 2

CH

2Cl 2

CH

2Cl 2

Tim

e

23 h

44 h

— 6 h

52 h

24 h

24 h

— 24 h

I

(67)

(—)

(46)

(—)

(—)

(—)

(56)

(—)

60)

% e

ec

84 84 — 59 59 — 61 6 90

O

EE

II (0)

(0)

— (10)

(10)

(—)

(—)

(—)

(—)

E =

N(C

O2R

)NH

CO

2R

228

228

229

228

228

229

229

229

229

Cat

alys

t

L-p

rolin

e

L-p

rolin

e

L-p

rolin

e

L-p

rolin

e

L-p

rolin

e

DL

-pro

line

L-p

rolin

e

L-a

zetid

inec

arbo

xylic

aci

d

L-a

zetid

inec

arbo

xylic

aci

d

Tem

p

rt rt rt rt rt rt rt 40°

rt

III

O

+

223

Subs

trat

eR

efs.

Con

ditio

nsPr

oduc

t(s)

and

Yie

ld(s

) (%

)

TA

BL

E 7

B. C

YC

LIC

KE

TO

NE

EN

OL

AT

ES

(Con

tinu

ed)

NY

R1

NY

R1

E

O

R1

ENY

EE

EE

O

III

III

IV

1. R

2 O2C

N=

NC

O2R

2 (1

eq),

sol

vent

,

te

mp,

tim

e

2. H

Cl R

1

H H H H Me

H H

R2

Me

Et

Me

Et

Et

Me

Et

Y — — O O O CH

2

CH

2

Solv

ent

Et 2

O

Et 2

O

Et 2

O

Et 2

O

PhH

Et 2

O

Et 2

O

Tem

p, T

ime

rt, 2

0 h

rt, 1

5 h

rt, 4

8 h

ice

bath

, the

n rt

, 24

h

refl

ux, 4

h

ice

bath

, the

n rt

, 15

h

ice

bath

, the

n rt

, 15

h

I (0)

(0)

(0)

(45)

(0)

(56)

(0)

II (53)

(38)

(67)

(18)

(79)

(35)

(86)

e

dd

III

(12)

(48)

(0)

(0)

(0)

(0)

(0)

IV (16)

(0)

(19)

(28)

(0)

(0)

(0)

E =

N(C

O2R

2 )NH

CO

2R2

246

C6-

7

++

+

1. P

hR2 N

MnM

e (i

a), T

HF,

rt,

time

2. t-

BuO

2CN

=N

CO

2Bu-

t

O

R1

O

E

O

E

R1

E

R1

H Me

Me

Me

Mee

R2

Me

Me

n-B

u

n-B

u

—

Tim

e

1 h

1 h

0.5

h

1 h

—

I +

II

(25)

(52)

(96)

(84)

(52)

I:II —

40:6

0

88:1

2

91:9

12:8

8

I

388

E =

N(C

O2B

u-t)

NH

CO

2Bu-

t

II

I dr — 3:1

3:1

3:1

3:1

O

Nt-

BuO

2CN

=N

CO

2Bu-

t, Ph

H, r

t, 24

h(6

6),

38%

ee

(S)

NM

eO

+

NH

CO

2Bu-

t

CO

2Bu-

t

224

O

NH

R1

O

NH

R1

N

O

N

N

ON

NH

CO

R2

R1 N

O

III

III

EtO

2CN

=N

CO

R2 , E

t 2O

, –20

°

R1

n-B

u

n-B

u

t-B

u

t-B

u

Ph Ph

R2

EtO

Ph EtO

Ph EtO

Ph

Tim

e

2 h

2 h

2 h

48 h

2 h

15 m

in

I

(—)

(—)

(90)

(—)

(90)

(25)

II (35)

(35)

(0)

(60)

(—)

(—)

III

(30)

(35)

(0)

(—)

(—)

(—)

856

NH

CO

R2

CO

2Et

CO

2Et

R1

CO

2Et

NH

CO

R2

+

+

C6

O

NY

O

NY

NR

1 N=

NC

OR

2 , PhH

Y — — O O O O

(100

)f

(58)

f

(100

)f

(100

)f

(100

)f

(95)

R2

OE

t

Ph OE

t

Ph C6H

4NO

2-4

C6H

4NO

2-4

R1

EtO

2C

EtO

2C

EtO

2C

EtO

2C

EtO

2C

4-O

2NC

6H4

249

249

249

249

249

857

Tem

p, T

ime

0°, 4

8-72

h; t

o rt

0°, 4

8-72

h; t

o rt

0°, 4

8-72

h; t

o rt

0°, 4

8-72

h; t

o rt

0°, 4

8-72

h; t

o rt

refl

ux

NH

CO

R2

R1

225

Subs

trat

eR

efs.

Con

ditio

nsPr

oduc

t(s)

and

Yie

ld(s

) (%

)

TA

BL

E 7

B. C

YC

LIC

KE

TO

NE

EN

OL

AT

ES

(Con

tinu

ed)

R4

R5

R2

OR

1

R3

R4

R5

R2

OR

3 N3

R1

SiM

e 3

Si(P

r-i)

3

Si(P

r-i)

3

Si(P

r-i)

3

Si(P

r-i)

3

Si(P

r-i)

3

Si(P

r-i)

3

R2

H H Me

H H H H

R3

H H H Me

H H t-B

u

R4

H H H H Me

—O

(CH

2)2O

—

H

R5

H H H H H H

(38)

(72)

(56)

g

(49)

(81)

g

(59)

(65)

g

NaN

3, C

e(N

H4)

2(N

O3)

6, M

eCN

, –20

°33

1

OO

OO

TB

S

C6-

10

C6

OO

OO

N3

NaN

3, C

e(N

H4)

2(N

O3)

6,

MeC

N, –

15°,

2 h;

to r

t

(70)

297

H

NR

O

NH

CO

2Et

1. E

tO2C

N3,

CH

2Cl 2

, ref

lux

2. h

ν3.

SiO

2

R CO

2Bu-

t

CH

2OT

MS

CH

2OM

e

(48)

(51)

(40)

% e

e

3 (S

)

35 (

S)

18 (

S)

302

302

302,

303

OO

O

OO

O

1. t-

BuO

2CN

3, 6

0°, 3

6 h

(for

ms

I)

For

II f

rom

I:

1. h

ν, M

eCN

, 0°,

30 m

in

2. A

cOH

, the

n n-

Bu 4

N+ F

–

297

N N CO

2Bu-

t

N

OT

BS

OT

BS

OO

O

O

NH

CO

2Bu-

t

I (

85)

II (

88)

OO

TM

S

RR

O

NH

CO

2Et

EtO

2CN

3, C

H2C

l 2, 1

20°,

4 h

III

397

OO

NH

CO

2Et

RR

+

226

R Me

(R,R

)

CH

2OM

e (R

,R)

CH

2OB

n (S

,S)

Ph (

S,S)

I

(—)

(—)

(10)

(—)

% e

e

— — 76 —

II (14)

(14)

(—)

(13)

% d

e

69 63 — 62

OR

NC

ON

3

S O2

, CH

2Cl 2

, hν,

7 h

NC

ON

S O2

HO

R TM

S

Me

(61)

(53)

% d

e

60 60

304

OT

MS

C6-

10

R

O R

NH

Ts

[TsN

(Cl)

Na

+ O

sO4

(0.0

04 e

q) +

cat

alys

t (0.

008

eq)]

(ia)

,

t-B

uOH

/H2O

(1:

1), r

t, 15

min

342

R H Me

t-B

u

Cat

alys

t

(DH

QD

) 2C

LB

(DH

QD

) 2PY

R

(DH

QD

) 2C

LB

(35)

(40)

(34)

% e

e

92 86 76

OSi

(Pr-

i)3

h

R

OR N

HT

s"T

sN=

Se=

NT

s"(i

a), C

H2C

l 2, 0

° to

rt, 3

h

nn

n 0 1 1

R Me

Me

Ph

(23)

(39)

(36)

348,

347

C6-

8O

Si(P

r-i)

3 h

R1

R2

R3

OSi

(Pr-

i)3

R1

R3

R4

"TsN

=Se

=N

Ts"

(ia)

, CH

2Cl 2

, 0° t

o rt

, 3 h

n

R1

Me

H Me

H H

n 0 1 1 1 1

R2

H H H H Me

R3

H H H Me

Me

NH

Ts

OSi

(Pr-

i)3

TsN

H I

(38)

(39)

(49)

(51)

(37)

II (0)

(11)

(0)

(0)

(0)

348,

347

III

n+

C6-

12

227

Subs

trat

eR

efs.

Con

ditio

nsPr

oduc

t(s)

and

Yie

ld(s

) (%

)

TA

BL

E 7

B. C

YC

LIC

KE

TO

NE

EN

OL

AT

ES

(Con

tinu

ed)

C7

OT

MS

O

NH

CO

2Bn

1. C

lNH

CO

2Bn,

MeO

H, C

HC

l 3, –

78°

2. C

rCl 2

3. M

eOH

(19)

343

OT

MS

ON

=N

PhPh

N2+

BF 4

– (ia

), T

HF,

–78

°(6

1)18

5

Me

N

O

Me

N

O

1. L

DA

, TH

F, –

78°,

45 m

in

2. E

tO2C

N=

NC

O2E

t, –7

8°, 3

0 m

in

(80)

391

N H

O

O

O

O

O

O

O

O

N1.

LD

A, T

HF,

hex

ane,

–78

°, 1

h

2. t-

BuO

2CN

=N

CO

2Bu-

t,

C

H2C

l 2, –

78°,

30 m

in

(66)

349

H

OO

O

O

O

O

O

NH

Ts

"TsN

=Se

=N

Ts"

, CH

2Cl 2

, rt,

2 h

(81)

349

OSi

(Pr-

i)3

H

NH

CO

2Et

CO

2Et

NH

CO

2Bu-

t

CO

2Bu-

t

O

TB

SO

O

OB

u-t

O

TB

SO

O

OB

u-t

NB

nO2C

N HC

O2B

n

1. L

DA

, TH

F, –

78°

2. B

nO2C

N=

NC

O2B

n, –

78°

(74)

217

O

TB

SO

O

OB

u-t

O

TB

SO

O

OB

u-t

NB

nO2C

N HC

O2B

n

1. L

DA

, TH

F, –

78°

2. B

nO2C

N=

NC

O2B

n, –

78°

(—)

217

O

TB

SO

O

OB

u-t

("su

bsta

ntia

l am

ount

s")

+

228

O

TB

SO

OB

u-t

O

O

TB

SO

OB

u-t

O

E1.

t-B

uOK

,i TH

F, –

78° t

o 0°

2. B

nO2C

N=

NC

O2B

n, –

78°,

10 m

in

(94)

E =

N(C

O2B

n)N

HC

O2B

n85

8, 2

17

PivO

PivO

ON R

NN

HO

1. L

DA

(ia

), T

HF,

–78

°, 1

h

2. R

N3,

–78

°, 30

min

; to

rt

859

R n-C

6H11

c-C

6H11

Bn

(93)

(69)

(67)

j

OSi

(Pr-

i)3

R1

R2

R3

OSi

(Pr-

i)3

R1

R2

R3

TsN

H

"TsN

=Se

=N

Ts"

345

R1

H Me

R2

H CH

2=C

(Me)

R3

Me

H

Solv

ent

— CH

2Cl 2

Tem

p

rt 0°

C7-

10

(51)

(62)

C8-

10

ClN

H2,

2,6

-(R

1 ) 2-4

-R2 C

6H2O

H, 1

00-1

40°;

rt

, ove

rnig

ht

R1

Me

Me

Et

R2

H Me

H

(55)

(51)

(33)

65

O– N

a+ R1

R1

R2

NH

OR

1

R2

R1

C9

OOT

MS

OO

NH

Ts

NN

2,6-

Cl 2

C6H

3C

6H3C

l 2-2

,6

PhI=

NT

s, C

uPF 6

, 1 (

cat)

, CH

2Cl 2

, –40

°, 3

h(1

6), 6

% e

e17

4

1

k

229

Subs

trat

eR

efs.

Con

ditio

nsPr

oduc

t(s)

and

Yie

ld(s

) (%

)

TA

BL

E 7

B. C

YC

LIC

KE

TO

NE

EN

OL

AT

ES

(Con

tinu

ed)

n

R

OT

MS

C9-

11

nO

N

R H Me

H H

n 1 1 2 3

Tem

p

–78°

–78°

–20°

–78°

(90)

(88)

(51)

(94)

% e

e

21 96 90 99

CO

2CH

2CC

l 3

H N

O N

O

O

ON

Cl 3

CC

H2O

2CN

=N

OO

CF 3

CH

2OH

(1

eq),

2 (

10 m

ol%

), T

HF

252

C10

OO

NH

CO

NE

t 2

O

NC

ON

Et 2

2-N

CC

6H4

1. n

-BuL

i, he

xane

, TH

F, 0

°, 30

min

2.

, –78

°, 3

h;

to

rt,

1.5

h

(59)

158

OT

MS

O

NH

Ts

PhI=

NT

s (0

.67

eq),

CuC

lO4

(3-6

mol

%),

M

eCN

, 0°,

90 m

in

(53)

173

R

O

R

O

R1.

LD

A, T

HF,

hex

ane,

–78

°2.

BnO

2CN

=N

CO

2Bn,

–78

°, 3

min

393,

392

R H MeO

(87)

(57)

N

,

NH

CO

2Bn

CO

2Bn

O

NB

n 2

O

NB

n 2

EO

H

E1.

LD

A, T

HF,

HM

PA, –

78°,

30 m

in

2. B

nO2C

N=

NC

O2B

n, –

78°,

1 h;

rt,

24 h

(45-

60)

(11-

28)

860

E =

N(C

O2B

n)N

HC

O2B

n

+

NC

u(O

Tf)

2

N

OO

t-B

uB

u-t

2

Tim

e

12 h

6 h

0.5

h

over

nigh

t

230

OT

MS

O

N1.

BnO

2CN

=N

CO

2Bn

+ A

gClO

4 +

(R

) -B

INA

P +

TH

F (i

a), –

45°,

5 h

2. H

F, T

HF

(82)

, 65%

ee

244

NN

O

NN

O

N

1. L

iHM

DS,

TH

F, –

78°,

30 m

in

2. B

nO2C

N=

NC

O2B

n, –

78°,

3 m

in

(52)

395,

396

OSi

(Pr-

i)3

N3

N3

Si(P

r-i)

3

PhIO

(1.

5 eq

), T

MSN

3 (3

eq)

, TE

MPO

a ,

CH

2Cl 2

, –45

°, 16

h

(41)

, 4:1

mix

ture

of

isom

ers

850

OT

MS

O

NH

Ts

TsN

(Cl)

Na,

(D

HQ

D) 2

CL

B (

0.00

8 eq

),

OsO

4 (0

.004

eq)

, t-B

uOH

/H2O

(1:

1), 1

0 m

in

(28)

, 76%

ee

342

OSi

(Pr-

i) 3

R

C10

-13

OSi

(Pr-

i)3

R

NH

Ts

TsN

=Se

=N

Ts,

CH

2Cl 2

, 0° t

o rt

, 40

h34

8, 3

46

R H CH

2=C

HC

H2

(71)

(59)

OT

MS

C10

(Sal

tmen

)Mn(

N),

CH

2Cl 2

, pyr

idin

e, T

FFA

,

–78

° to

rt, 3

-4 h

O

NH

CO

CF 3

(78)

471

OM

eO

Me

NH

CO

2Bn

CO

2Bn

BnO

2CN

HC

O2B

n

231

Subs

trat

eR

efs.

Con

ditio

nsPr

oduc

t(s)

and

Yie

ld(s

) (%

)

TA

BL

E 7

B. C

YC

LIC

KE

TO

NE

EN

OL

AT

ES

(Con

tinu

ed)

C10

OT

MS

R1

R1

O

NH

CO

CF 3

235

3

R1

H H MeO

MeO

R2

—(C

H2)

4—

Ph —(C

H2)

4—

Ph

Mn

NN

OO

N

R3

Ph Ph

(R,R

)

(S,S

)

(R,R

)

(S,S

)

R4

H t-B

u

H H

(83)

(74)

(58)

(55)

% e

e C

2

75 (

R)

65 (

S)

62 (

R)

41 (

S)

OT

MS

H

4 (y

eq)

, R2O

, pyr

idin

e, C

H2C

l 2, a

dden

d

x eq

O

NH

R

x 10 1

y 1 2

R Ts

CF 3

CO

Add

end

pyri

dine

N-o

xide

—

Tim

e

6 h

3 h

(76)

(58)

% e

e

48 79

352

Mn

NN

OO

NO

TM

S

1. 5

(2

eq)

+ p

yrid

ine

(ia)

, CH

2Cl 2

, –78

°2.

TFF

A, –

78° t

o rt

, 3-4

hO

NH

CO

CF 3

H(5

5)47

1

C11

O

OH

OSi

(Pr-

i)3

O

OH

O

N3

NaN

3, C

e(N

H4)

2(N

O3)

6, M

eCN

, –20

°(6

0)33

1

H

Mn

NN

OO

NR

2R

3

R4

R4

1. 3

(2.

2 eq

), p

yrid

ine,

CH

2Cl 2

, –78

°2.

TFF

A, –

78°,

6 h;

to r

t

3 4

Tem

p

0°–7

8° to

rt

5

232

C12

O

Ph

OPh N

Me 2

1. L

i bas

e, E

t 2O

or

TH

F

2. M

e 2N

OSO

2Me,

–30

° to

0°(5

0)13

4

OSi

(Pr-

i)3

Ph(i

-Pr)

3SiO

N3

N3

PhPh

IO, T

MSN

3 (3

eq)

, TE

MPO

a ,

CH

2Cl 2

, –45

°, 16

h

(59)

, 67%

de

850

N

O

O

CH

(OE

t)2

CH

(OE

t)2

N

O

O

CH

(OE

t)2

CH

(OE

t)2

N(C

O2B

n)N

HC

O2B

n

1. L

DA

, TH

F, –

78°

2. B

nO2C

N=

NC

O2B

n, –

78°,

3 m

in

(75)

394,

392

O

OA

cOO

R1

OH

OA

cH

OB

zO

C20

O

OA

cOO

R1

OH

OA

cH

OB

zO

1. K

OB

u-t (

ia),

TH

F, D

MPU

, –72

°, tim

e 1

2. R

2 O2C

N=

NC

O2R

2 , tem

p, ti

me

2

325

R1

SiE

t 3

CO

2Bu-

t

CO

2Bu-

t

R2

Bn

Bn

t-B

u

Tim

e 1

45 m

in

15 m

in

15 m

in

Tem

p

–65°

–68°

to –

50°

–68°

Tim

e 2

3 h

3 h

1 h

(76)

(65)

(72)

R2 O

2CN

HN C

O2R

2

O

OA

cOO

R

OH

OA

cH

OB

zO

O

OA

cOO

R

OH

OA

cH

OB

zO

1. K

OB

u-t (

ia),

TH

F, D

MPU

, –72

°, 10

min

2. T

sN3,

–72

° to

–50°

, 2 h

3. N

H4C

l, H

2Ol

325

N3

R SiE

t 3

CO

2Bu-

t

(92)

(85)

233

Subs

trat

eR

efs.

Con

ditio

nsPr

oduc

t(s)

and

Yie

ld(s

) (%

)

TA

BL

E 7

B. C

YC

LIC

KE

TO

NE

EN

OL

AT

ES

(Con

tinu

ed)

OA

cOO

SiE

t 3 OH

OA

cH

OB

zO

O

OA

cOO

SiE

t 3 OH

OA

cH

OB

zO

NaN

3, C

e(N

H4)

2(N

O3)

6, M

eCN

, 0°

N3

RO

325

R Me 3

Si

(i-P

r)3S

i

(95)

(55)

a TE

MPO

was

add

ed to

sup

pres

s fo

rmat

ion

of th

e β-

azid

o en

ol e

ther

by

a ra

dica

l mec

hani

sm.

b T

he y

ield

is th

at o

f th

e pr

oduc

t bef

ore

acid

hyd

roly

sis;

the

latte

r is

rep

orte

d to

pro

ceed

in a

lmos

t qua

ntita

tive

yiel

d.c

The

ee

valu

es a

re th

ose

of th

e cr

ude

prod

ucts

; som

e ra

cem

izat

ion

occu

rred

dur

ing

chro

mat

ogra

phy

on s

ilica

.d

Thi

s pr

oduc

t was

isol

ated

bef

ore

acid

trea

tmen

t. e

The

sub

stra

te w

as th

e lit

hium

eno

late

pre

pare

d w

ith L

DA

at 0

° to

roo

m te

mpe

ratu

re f

or o

ne h

our.

f The

pro

duct

is v

ery

resi

stan

t to

acid

hyd

roly

sis.

g The

pro

duct

is a

mix

ture

of

cis

and

tran

s is

omer

s.h T

MS

and

TB

DM

S en

ol e

ther

s ga

ve n

eglig

ible

am

ount

s of

pro

duct

s.i W

ith L

DA

, lith

ium

tetr

amet

hylp

iper

idid

e, o

r L

iHM

DS,

red

uctio

n of

the

keto

ne o

ccur

red.

j With

die

thyl

ket

one,

cyc

lohe

xano

ne, a

nd v

ario

us c

yclo

hexe

none

s, e

limin

atio

n of

wat

er o

ccur

red

to g

ive

the

tria

zole

der

ivat

ives

.k T

he in

term

edia

te a

min

atio

n pr

oduc

t rin

g ex

pand

s to

the

trop

olon

e pr

oduc

t und

er th

e re

actio

n co

nditi

ons.

l The

dia

zo c

ompo

unds

wer

e fo

rmed

whe

n th

e re

actio

ns w

ere

quen

ched

with

ace

tic a

cid.

Tim

e

1 h

1 d

C20

234

Subs

trat

eR

efs.

Con

ditio

nsPr

oduc

t(s)

and

Yie

ld(s

) (%

)

TA

BL

E 8

. IM

INE

AN

D H

YD

RA

ZO

NE

AN

ION

S

C5-

15

R1

R2

NR

1R

2

N

N

1. L

DA

, TH

F, 0

°, 4-

6 h

2. t-

BuO

2CN

=N

CO

2Bu-

t, –7

8°, 2

-5 m

in

R1

Et

n-Pr

—(C

H2)

4—

Ph Bn

R2

Me

Et

Me

Ph

(85)

(75)

(78)

(66)

(63)

327

R1

R2

N

NH

SO2C

6H2(

Pr-i

) 3-2

,4,6

1. L

DA

, TH

F, 0

°, 4-

6 h

2. 2

,4,6

-(i-

Pr) 3

C6H

2SO

2N3,

–

78°,

2-5

min

3. N

H4C

l, H

2O

R1

Et

n-Pr

—(C

H2)

4—

Ph Bn

R2

Me

Et

Me

Ph

(84)

(78)

(66)

(69)

(65)

327

C6

NR1

H a

R2

O1.

Uns

peci

fied

K b

ase,

DM

E,

C

H2C

l 2, r

t, 1.

5 h

2. 4

-O2N

C6H

4SO

2ON

HC

O2E

t (3

eq),

L

iOH

(10

eq)

, –70

°, 3

h; to

rt

3. H

3O+

NH

CO

2Et

O

NCO

2Et

123

R1

Ph Me

MeO

CH

2

I

(32)

(25)

(10)

% e

e

— 34 36

II — (10)

(5)

% e

e

— 8 9

III

R2

H Ph Bn

1. t-

BuO

2CN

=N

CO

2Bu-

t, to

luen

e,

re

flux

, 2-

5 h

2. H

O2C

CO

2H

O

NR

1

Ph Me

MeO

CH

2

R2

H Ph Bn

(45)

(30)

(—)

% e

e

— — 5

123

Me 2

NM

e 2N

Me 2

N

+

NH

CO

2Bu-

tt-

BuO

2C

NH

CO

2Bu-

t

CO

2Bu-

t

NH

CO

2Et

235

Subs

trat

eR

efs.

Con

ditio

nsPr

oduc

t(s)

and

Yie

ld(s

) (%

)

TA

BL

E 8

. IM

INE

AN

D H

YD

RA

ZO

NE

AN

ION

S (C

onti

nued

)

C6-

13

R1

R3

R2

Nt-

BuS

(O)

R1

R3

R2

O

N

R1

R3

R2

O

N

1. P

hMeN

MnM

e•4

LiB

r, T

HF,

rt,

1 h

2. R

4 O2C

N=

NC

O2R

4 , –30

°; r

t, 2.

5 h

3. H

Cl

388

R1

Me

n-Pr

n-C

5H11

n-C

5H11

Et

R2

Me

H Me

Me

Et

R3

Me

n-Pr

Me

Me

Bn

R4

Et

Et

t-B

u

t-B

u

t-B

u

* R R R,S

R R,S

*

III

I

(50)

(50)

(65)

(65)

(50)

I:II

90:1

0

— 98:2

98:2

99:1

I %

ee

40 65 — 68 —

C6

NR1

H a

R2

O1.

LD

A, H

MPA

, TH

F, 0

°, 90

min

2. t-

BuO

2CN

=N

CO

2Bu-

t, 0°

; to

rt, t

ime

3. H

O2C

CO

2H

N12

3

R1

Ph Me

MeO

CH

2

R2

H Ph Bn

Tim

e

3 h

4 h

8 h

(23)

(19)

(28)

% d

e

— 29 33

C9-

10

PhR

1

NR

2

PhR

1

NR

2 N

EtO

2CN

=N

CO

2Et,

hexa

ne, r

t, 2

h84

9

R1

Me

Me

Et

Et

Et

R2

Ph 4-M

eC6H

4

Ph 2-M

eC6H

4

4-M

eC6H

4

(59)

(—)

(—)

(—)

(—)

NH

CO

2Bu-

t

CO

2Bu-

t

R4 O

2C

NH

CO

2R4

NH

CO

2R4

R4 O

2C

+

NH

CO

2Et

EtO

2C

236

C10

N

MeO

R2

HR

1

N

MeO

R2

HR

1E

N

MeO

R2

HR

1E

III

E =

N(C

O2R

3 )NH

CO

2R3

R1

H H MeO

H

R2

Bn

i-B

u

i-Pr

Bn

1. L

DA

, TH

F, h

exan

e, –

45°,

1.25

h

2. R

3 O2C

N=

NC

O2R

3 , –78

°, 3

min

R3

t-B

u

t-B

u

t-B

u

Bn

I +

II

(86)

(82)

(—)

(65)

I %

de

72 76 38 40

405

R3 O

2CN

=N

CO

2R3 , T

HF

I +

II

R1

H H H H MeO

H

R2

Bn

i-B

u

i-Pr

t-B

u

i-Pr

Bn

R3

t-B

u

t-B

u

t-B

u

t-B

u

t-B

u

Bn

Tem

p

rt rt rt rt rt 0°

Tim

e

24 h

24 h

24 h

48 h

20 h

1 h

I +

II

(84)

(85)

(85)

(85)

(77)

(72)

I %

de

74 64 58 74 — 40

405

a Thi

s is

a c

orre

cted

str

uctu

re; p

erso

nal c

omm

unic

atio

n fr

om L

. Pel

laca

ni, D

ipar

timen

to d

i Chi

mic

a, U

nive

rsitá

"L

a Sa

pien

za",

Rom

e, I

taly

.

+

237

Subs

trat

eR

efs.

Con

ditio

nsPr

oduc

t(s)

and

Yie

ld(s

) (%

)

TA

BL

E 9

. CA

RB

OX

YL

IC A

CID

DIA

NIO

NS

C4-

101.

LD

A (

2.2

eq),

TH

F, 0

°2.

R2 N

H2,

–10

° to

rt, 1

h; r

t to

30°,

2-5

h

R1

MeS

CH

2CH

2

i-Pr

i-Pr

i-Pr

i-Pr

i-Pr

i-Pr

i-Pr

i-Pr

i-Pr

i-B

u

Ph Ph(C

H2)

2

R2

MeO

Cl

HO

SO2O

MeO

EtO

i-Pr

O

t-B

uO

BnO

2,4,

6-M

e 3C

6H2C

O2

2,4,

6-M

e 3-3

,5-(

O2N

)C6C

O2

MeO

MeO

MeO

(—)

(8)

(tra

ce)

(34)

(22)

(25)

(13)

(tra

ce)

(4)

(5)

(—)

(56)

(24)

861

79 79 79 79 79 79 79 79 79 861

79, 8

61

861

1. L

DA

(2.

2 eq

), T

HF,

HM

PA, –

15°,

15 m

in

2. M

eON

H2a

(3 e

q), t

emp,

tim

e

R1

MeS

CH

2CH

2

i-Pr

CH

2Pr-

i

Ph Bn

407

Tim

e

2 h;

ove

rnig

ht

2 h;

ove

rnig

ht

2 h;

ove

rnig

ht

2 h

2 h;

ove

rnig

ht

(9)b

(27)

(11)

b

(55)

(70b

C4-

11

R1

CO

2HR

1C

O2H

NH

2

R1

CO

2H

NH

2

Tem

p

–15°

to –

10°;

rt

–15°

to –

10°;

rt

–15°

to –

10°;

rt

–15°

to –

10°

–15°

to –

10°;

rt

238

HO

2CC

O2H

R

HO

2CC

O2H

R

1. n

-BuL

i (3

eq),

TH

F, h

exan

e, te

mp

1, ti

me

1

2. C

lNH

2, E

t 2O

, tem

p 2,

tim

e 2

668

R H PhS

Tim

e 2

—; 1

h

—; 4

5 m

in

(8)

(3.7

)

NH

2

C6

a Oth

er a

min

atin

g ag

ents

gav

e lo

wer

yie

lds.

b The

yie

ld w

as d

eter

min

ed b

y an

am

ino

acid

ana

lyze

r.

C7

1. L

DA

(2.

4 eq

), T

HF,

–10

°, 30

min

2. H

MPA

, –5°

, 30

min

3. 2

,4,6

-Me 3

C6H

2SO

2ON

H2,

–5°

; 0°,

3 h

(27)

668

1. n

-BuL

i (3.

3 eq

), T

HF,

hex

ane,

–5

0° to

0°,

1 h

2. C

lNH

2, E

t 2O

, –50

° to

–10°

; 0°,

45 m

in

+66

8

III

I +

II

(19)

, I:I

I =

1:3

NO

MeO

CO

2HN

O

MeO

CO

2H

H2N

(19)

115

1. n

-BuL

i (3.

3 eq

), T

HF,

hex

ane,

–5

0° to

0°,

1 h

2. C

lNH

2, E

t 2O

, –50

° to

–10°

; 0°,

45 m

in

HO

2CC

O2H

HO

2CC

O2H

HO

2CC

O2H

NH

2

HO

2CN

H2

CO

2HH

O2C

NH

2

CO

2H

Tem

p 1

–50°

; –40

°; 0

°–5

0° to

0°

Tim

e 1

—; 0

.5 h

; 1.5

h

1 h

Tem

p 2

–50°

; to

rt

–50°

to –

10°;

0°

239

Subs

trat

eR

efs.

Con

ditio

nsPr

oduc

t(s)

and

Yie

ld(s

) (%

)

TA

BL

E 1

0A. E

STE

R E

NO

LA

TE

S

C2

(0)

932,

4-(O

2N) 2

C6H

3ON

H2,

TH

F

153,

157

1. L

iHM

DS,

TH

F, –

78°,

30 m

in

2.

, –7

8°, 3

0 m

in

O

NC

O2B

u-t

4-N

CC

6H4

1. B

ase

(ia)

, TH

F, –

78°,

1 h

2.

,

–78

°, 3

h; to

rt,

1.5

h

O

NC

ON

Et 2

Ar

Ar

2-C

lC6H

4

4-C

lC6H

4

4-C

lC6H

4

2,6-

Cl 2

C6H

3

2-N

CC

6H4

2-N

CC

6H4

4-N

CC

6H4

I (0)

(31)

(30)

(0)

(55)

(33)

(39)

Bas

e

LD

A

LD

A

NaH

MD

Sa

LD

A

LD

A

NaH

MD

S

LD

A

II (0)

(10)

(0)

(0)

(7)

(23)

(20)

158

158

155

158

158

155

158

R1

CO

2R2

R1

CO

2R2

HN

Oi-

Pr

1. L

DA

(ia

), T

HF,

–78

°, 1

h

2. 1

, –78

° to

rt, 2

-3 h

C2-

5

ON

4-N

CC

6H4

O

O

i-Pr

R1

H Me

Me

Me

i-Pr

R2

Bu-

t

Me

Et

t-B

u

Et

(60)

(57)

(52)

(51)

(49)

% d

e

— 5 8 7 17

154

O

OB

u-t

O

OB

u-t

OH N

t-B

uO2C

(35)

OB

u-t

OH N

Et 2

NC

OO

Bu-

t

O

Ar

OH

+

III

BrZ

nC

O2E

tH

2NC

O2E

t

1

240

C2-

81.

LiH

MD

S, T

HF,

–78

°

2.

, –78

°, 3-

7 h;

to r

t

ON

H

RC

O2E

t

NC

O2E

t

RH

NC

O2E

t

RH

R H n-Pr

PhI

II

151

I (0)

(0)

(25)

II (0)

(0)

(25)

+

OPh

OT

MS

PhI=

NT

s, M

eCN

(0)

172

OM

e

OM

eR

O2C

N=

NC

O2R

, PhH

, rt

251

C2

R Me

Et

Tim

e

2 d

shor

t

(74)

(52)

C3-

4

OT

MS

OR

3

R1

R2

CO

2R3

NH

CO

2Et

R2

R1

EtO

2CN

(OT

MS)

(TM

S), 9

0°, 5

d

R1

Me

H H

R2

Me

Me

Et

R3

Me

Et

Et

(25)

(70)

(48)

105

C3

CO

2Et

CO

2Et

NH

CO

NE

t 2O

NC

ON

Et 2

Ar

1. L

DA

2.(<

10)

155

R2C

HC

O2E

t

R2C

HC

O2E

t

HN

1. L

DA

(ia

), T

HF,

–78

°2.

2,

–78°

, 4 h

; to

rt

155

C3-

5

R H Me

(low

)

(<10

)

dr —

5:1

(S:R

)

TsH

NC

O2P

h

RO

2CN

CO

2Me

NH

CO

2R+

tw

o 2:

1 ad

duct

s (—

)

Na

CO

2Et

NC

O2E

t

Pn

EtO

2CN

H

PhN

=N

CO

2Et

(—)

159

Ar

= 2

-NC

C6H

4 or

4-N

CC

6H4

ON

4-C

lC6H

4

O

NM

e

OT

BD

PS

Ph

2

O

Me

N

Ph

OT

BD

PS

241

Subs

trat

eR

efs.

Con

ditio

nsPr

oduc

t(s)

and

Yie

ld(s

) (%

)

TA

BL

E 1

0A. E

STE

R E

NO

LA

TE

S (C

onti

nued

)

C3

OL

i

OB

u-t

PhN

2+ B

F 4– (

ia),

TH

F, –

78°

PhN

=N

CO

2Bu-

t(1

0-30

) co

mpl

ex m

ixtu

re18

5

OM

e

OT

MS

RR

CO

2Me

NPh

NH

RC

O2M

e

NN

HPh

PhN

2+ B

F 4– ,

pyri

dine

, 0°,

2 h

R Me

2-th

ieny

l

Ph Bn

I +

II

(59)

(72)

(83)

(76)

I:II

100:

0

90:1

0

88:1

2

100:

0

197,

196

C3-

9

C3

CO

2Me

CO

2Me

EtO

2CN

NH

CO

2Et

EtO

2CN

=N

CO

2Et,

DA

BC

O, T

HF,

rt,

120

h40

3

R1

R2

OR

3

OM

e

1. B

nO2C

N=

NC

O2B

n +

AgO

Tf

(ia)

,

C

H2C

l 2, –

45°,

0.5

h

2. H

F, T

HF

R1

H Me

Me

R2

Meb

Me

Me

R3

TM

S

TM

S

TB

DM

S

(91)

(97)

(95)

244

C3-

4

OT

MS

OPh

NC

O2P

h

CO

2Bn

1. B

nO2C

N=

NC

O2B

n +

AgC

lO4

+

(

R)-

BIN

AP

(cat

) (i

a), t

olue

ne, T

HF,

–

45°,

3 h

2. H

F, T

HF

(73)

, 51%

ee

244

C3

C3-

9

OR

2R

1

OT

MS

R2 =

Ph

NM

e 2

HH

R1

Me

Et

i-Pr

n-B

u

i-B

u

Bn

(70)

(65)

(35)

(45)

(70)

(45)

% d

e

90 84 — 78 81 91

t-B

uO2C

N=

NC

O2B

u-t,

TiC

l 4, C

H2C

l 2, –

80°

411

(0)

+

R2

NN

HC

O2B

nR

1C

O2M

e

CO

2Bn

BnO

2CH

N

t-B

uO2C

HN

NC

O2R

2

CO

2Bu-

t

HR

1

242

O

OT

MS

SO2N

(C6H

11-c

) 2

C3-

13

O

OSO

2N(C

6H11

-c) 2

RE

H

R1.

Ti(

OPr

-i) 4

, CH

2Cl 2

, –78

°2.

t-B

uO2C

N=

NC

O2B

u-t,

–78°

, 5 m

in

3. T

iCl 4

4. S

ubst

rate

, –78

°, 1

h

R Me

Et

n-Pr

i-Pr

n-B

uc

i-B

u

n-C

6H11

Bn

1-ad

aman

tylm

ethy

l

(81)

(84)

(72)

(73)

(85)

(71)

(69)

(76)

(65)

% d

ed

93.8

96.2

96.4

95.2

92.6

93.2

96.0

96.4

64.0

412,

409

E =

N(C

O2B

u-t)

NH

CO

2Bu-

t

C3

R1

R2

OT

MS

OR

3

C3-

4

EtO

2CN

3R

2C

O2R

3

R1

NH

CO

2Et

R2

CO

2R3

R1

O

NT

MS

OE

tR

2C

ON

HC

O2E

t

R1

OR

3

III

III

R1

H H Me

Me

H H H

R2

Me

Me

Me

Me

Et

Et

Et

R3

Et

Et

Me

Me

Et

Et

Et

Con

ditio

ns

110°

, 30

min

hν, 0

°, 5

h

110°

, 30

min

hν, r

t, 5

h

110°

, 30

min

hν, 0

°, 5

h

CH

2Cl 2

, hν,

0°,

5 h

I (1)

(21)

(7)

(30)

(4)

(38)

(82)

II (42)

(1)

(9)

(1)

(42)

(2)

(—)

III

(4)

(4)

(35)

(7)

(13)

(4)

(—)

299

299

299

299

299

299

300

O

OSi

Me 2

RSO

2N(C

6H11

-c) 2

O

OSO

2N(C

6H11

-c) 2

NH

CO

2Et

HE

tO2C

N3,

pen

tane

, hν,

Ar

R Me

(1S,

2R)

Me

(1R

,2S)

t-B

u (1

S,2R

)

(14)

(38)

(77)

% d

e

50 (

S)

53 (

R)

70 (

S)

300

++

243

Subs

trat

eR

efs.

Con

ditio

nsPr

oduc

t(s)

and

Yie

ld(s

) (%

)

TA

BL

E 1

0A. E

STE

R E

NO

LA

TE

S (C

onti

nued

)

OE

t

OT

MS

TM

SOC

O2E

t

TM

SO

N=

NPh

PhN

2+ B

F 4– , p

yrid

ine,

–35

°, 18

h(2

2), d

r >

95:5

415

OM

e

OT

MS

N=

NPhCO

2Me

PhN

2+ B

F 4– , p

yrid

ine,

0°,

2 h

(90)

196

C4-

10

OR

3

OT

MS

R1

R2

R1

N=

NA

r

R2

CO

2R3

ArN

2+ B

F 4– , p

yrid

ine,

0°,

2 h

197

R1

Me

Me

Me

Et

Ph

R2

Me

Me

Me

Ph Et

R3

Me

Me

Me

Ph Me

Ar

Ph 4-C

lC6H

4

4-M

eOC

6H4

Ph Ph

(90-

92)

(72)

(84)

(90)

(90)

C4

R1

CO

2R2

R1

CO

2R2

Nt-

BuO

2CN

HC

O2B

u-t

Con

ditio

ns 1

: 1. C

atal

yst A

(se

e C

hart

1; 5

mol

%),

E

tOH

, rt

2

. Sub

stra

te, t

hen

PhSi

H3

3

. t-B

uO2C

N=

NC

O2B

u-t,

rt,

tim

e

Con

ditio

ns 2

: 1. C

atal

yst B

(se

e C

hart

1; 2

mol

%),

i-

PrO

H, 0

°

2. S

ubst

rate

, the

n Ph

SiH

3, 0

°

3. t

-BuO

2CN

=N

CO

2Bu-

t, 0°

, tim

e

R1

Me

Me

Me

Me

OOR

2

Et

Et

Con

ditio

ns

1 2 1 2

Tim

e

12 h

6 h

20 h

3 h

(66)

(88)

(75)

(74)

dr — — 78:2

61:9

215

215

215

215

PhE

t1

—(8

7)9:

179

6

C4-

9

EtO

2CC

O2E

tE

tO2C

CO

2Et

N1.

LiH

MD

S, T

HF,

–78

°, 15

min

2. R

O2C

N=

NC

O2R

, –78

°, 7

min

408

R (–)-

men

thyl

(–)-

born

yl

(–)-

isob

orny

l

(13)

(49)

(41)

2S:2

R

1:1

1:1

1:1

C4

NH

CO

2RR

O2C

244

R1

CO

2R2

OH

R1

CO

2R2

OH

N

1. L

DA

(x

eq),

TH

F, h

exan

e, te

mp

1, ti

me

1

2. t-

BuO

2CN

=N

CO

2Bu-

t, te

mp

2, ti

me

2

x 4.2

4.2

2.5

4.2 3 4.2

4.2

Tim

e 2

1 h

10 m

in

15 m

in

3 m

in

—

3 m

in

3 m

in

R1

Me

Me

Me

CF 3

Ph3C

OC

H2

n-C

6H13

c-C

6H11

R1

CO

2R2

OH

N

III

I +

II

(56)

(75)

(62-

66)

(62)

(48)

(74)

(81)

I:II

94:6

84:1

6

—

87:1

3

96:4

90:1

0

85:1

5

415

415

769

415,

862

769

415

415

R2

Et

Et

t-B

u

Et

t-B

u

Et

Et

C4-

9

RC

O2M

e

NB

n 2

RC

O2M

e

NB

n 2

E

RC

O2M

e

NB

n 2 E

E =

N(C

O2B

u-t)

NH

CO

2Bu-

t

+

III

R CH

2OB

n

Ph Bn

I +

II

(90)

(92)

(90)

I:II

94:6

93:7

97:3

863

C4-

10

1. K

HM

DS,

TH

F, to

luen

e, –

78°,

1 h

2. t-

BuO

2CN

=N

CO

2Bu-

t (so

lid),

–78

°, 1

h

R1

CO

2Me

OH

R1

CO

2Me

OH

N

1. M

eZnB

r, T

HF,

0°,

time

1

2. L

DA

(2

eq),

–78

°, 1

h

3. R

2 O2C

N=

NC

O2R

2 (2 e

q), –

78°,

time

3

C4-

8

R1

CH

(OM

e)2

Et

n-C

5H11

Tim

e 1

30 m

in

1 h

1 h

R2

Bn

t-B

u

t-B

u

Tim

e 3

—

10 m

in

10 m

in

(66)

(60)

(63)

% d

e

>95

>90

>90

421

416

416

Tem

p 1

–60°

; –20

°–6

0°; –

20°

–60°

to –

20°

–60°

; –20

°–4

0°; 0

°–6

0°; –

20°

–60°

; –20

°

Tim

e 1

—; 3

0 m

in

—; 3

0 m

in

30 m

in

—; 3

0 m

in

5 m

in; 3

0 m

in

—; 3

0 m

in

—; 3

0 m

in

Tem

p 2

–25°

–50°

–50°

–78°

–20°

to 0

°–7

8°–7

8°

+

NH

CO

2R2

R2 O

2C

NH

CO

2Bu-

tt-

BuO

2CN

HC

O2B

u-t

t-B

uO2C

245

Subs

trat

eR

efs.

Con

ditio

nsPr

oduc

t(s)

and

Yie

ld(s

) (%

)

TA

BL

E 1

0A. E

STE

R E

NO

LA

TE

S (C

onti

nued

)

R1

Me

(MeO

) 2C

H

(i-P

r)3S

iOC

H2

Et

n-C

5H11

Ph

R2

Et

Me

Me

Me

Me

Et

R3

t-B

u

Bn

Bn

t-B

u

t-B

u

t-B

u

Tim

e 1

1 h

30 m

in

1 h

1 h

1 h

1 h

Tim

e 3

10 m

in

30 m

in

90 m

in

10 m

in

10 m

in

10 m

in

(63)

(66)

(52)

(58)

(66)

(69)

416

422

423

416

416

416

% d

e

>90

>95

>95

>90

>90

>90

C4-

9

R1

CO

2R2

OH

R1

CO

2R2

OH

N

1. M

eZnB

r, T

HF,

0°,

time

1

2. L

DA

(2

eq),

–78

°, 1

h

3. R

3 O2C

N=

NC

O2R

3 (2

eq)

, –78

°, tim

e 3

R1

CO

2R2

OH

R1

CO

2R2

OH

N1.

LD

A (

2 eq

), T

HF

2. t-

BuO

2CN

=N

CO

2Bu-

t, –7

8°, 3

min

R1

H H

R2

Me

Et

(58)

(57)

% d

e

(64)

(54)

864

C4

NH

CO

2R3

R3 O

2C

NH

CO

2Bu-

tt-

BuO

2C

OO

OR

OO

OR

N

1. L

DA

2. t-

BuO

2CN

=N

CO

2Bu-

t, –7

8°

R Me

n-C

5H11

(74)

(66)

% d

e

>90

>90

416

NH

CO

2Bu-

tt-

BuO

2C

OO

O

R3

R2 R1

OO

O

R3

R2 R1

N

1. B

ase,

TH

F, te

mp

1

2. t-

BuO

2CN

=N

CO

2Bu-

t, te

mp

2, ti

me

2

C4-

14

NH

CO

2Bu-

tt-

BuO

2C

246

R1

Me

Me

CF 3

CF 3

CF 3

CF 3

R2

H H H Me

n-B

u

Ph

R3

H (CH

2)2P

h

t-B

u

t-B

u

t-B

u

t-B

u

Tem

p 1

— — –75°

–75°

–75°

–75°

Tem

p 2

–78°

–78°

–75°

–75°

–75°

–75°

Bas

e

LD

A

LD

A

t-B

uLi

t-B

uLi

t-B

uLi

t-B

uLi

(90)

(95)

(97)

(86)

(80)

(71)

% d

e

90 99 >96

>96

>96

>96

416

864

865,

866

865

865

865

C4

NH

O OC

O2E

t

NH

O OC

O2E

t

Ni-

PrO

2C

NH

CO

2Pr-

i

1. U

nspe

cifi

ed b

ase

2. i-

PrO

2CN

=N

CO

2Pr-

i

(52)

sin

gle

isom

er86

7

HN

Ph

CO

2Et

EtO

2C

HN

Ph

CO

2Et

EtO

2C1.

LiH

MD

S (1

.2 e

q, ia

), T

HF,

HM

PA,

–7

8°; –

55°,

1 h

2. R

O2C

N=

NC

O2R

, –78

°, 4.

5 m

in

HN

Ph

CO

2Et

EtO

2C

N

III

R t-B

u

Bn

I +

II

(80)

(75)

I:II

e

30:1

18:1

N

426

Tim

e 2

—

3 m

in

40 m

in

40 m

in

40 m

in

40 m

in

+

OM

e

OM

e

R1

R2

C4-

6

R1

NH

CO

2Et

R2

CO

2Me

1. E

tO2C

N3

(0.5

eq)

, 35°

, tim

e

2. H

Cl,

Me 2

CO

, 30

min

R1

Me

—(C

H2)

4—R2

Me

(10)

(34)

298

Tim

e

14 d

4 d

RO

2CN

HC

O2R

RO

2CN

HC

O2R

247

Subs

trat

eR

efs.

Con

ditio

nsPr

oduc

t(s)

and

Yie

ld(s

) (%

)

TA

BL

E 1

0A. E

STE

R E

NO

LA

TE

S (C

onti

nued

)

R1

CO

2Me

R2

NNN

R3

R1

R2

O

R2

R1

NH

2CO

NH

R3

For

I:

1. L

DA

, TH

F, –

78°

2. R

3 N3

(ia)

, tem

p, ti

me

For

II f

rom

I:

1. N

H4C

l, H

2O

2. N

H4O

H, T

HF,

rt,

12-2

4 h

R1

Me

Me

—

(CH

2)5—

—C

H2C

H=

CH

(CH

2)2—R

2

Me

Me

R3

PhSC

H2

1-ad

aman

tyl

PhSC

H2

PhSC

H2

Tem

p, T

ime

–78°

, 20

min

; to

–10°

, 90

min

–78°

; rt,

3 h

–78°

to –

20°,

45 m

in

–78°

; rt,

3 h

I

(85)

(70)

(—)

(—)

II (78)

(—)

(79)

(83)

274,

275

867a

274

274,

275

C4-

7

III

RC

O2E

t

SiM

e 2Ph

RC

O2E

t

SiM

e 2Ph

N3

1. L

DA

, –78

°2.

2,4

,6-(

i-Pr

)C6H

2SO

2N3,

–78

°, 2

h

R Me

Ph

(58)

(64)

% d

e

>96

>96

868

C4-

9

C4-

6

R1

R2

OM

e

OM

e

PhN

NN

OM

e OM

eR

1

R2

R1

NH

Ph

R2

CO

2Me

1. P

hN3

(0.6

eq)

, 70°

, 4 h

; 100

°, 20

h (

form

s I)

2. H

OA

c, M

e 2C

O, r

t, 24

h (

form

s II

)

III

291

R1

Me

—(C

H2)

4—R2

Me

I

(44)

(38)

II (11)

f

(7)f

CO

2Bu-

t

NB

nPh

CO

2Bu-

t

NB

nPh

N3

CO

2Bu-

t

NB

nPh

N2

1. L

DA

(ia

), T

HF,

–78

°, 1

h

2. R

eage

nt, –

78°,

2 m

in

Rea

gent

2,4,

6-(i

-Pr)

3C6H

2SO

2N3

Ph2P

(O)N

3

III

I

(32)

(0)

% d

e

>95 —

II (9)

(64)

338

+

C4

248

NH

O OC

O2E

t

NH

O OC

O2E

tN

3

NH

O OC

O2E

tN

3

1. M

HM

DS

(2 e

q), T

HF,

–78

°2.

ArS

O2N

3

III

M Li

Li

Na

Na

K K

Ar

4-M

eC6H

4

2,4,

6-(i

-Pr)

3C6H

2

4-M

eC6H

4

2,4,

6-(i

-Pr)

3C6H

2

4-M

eC6H

4

2,4,

6-(i

-Pr)

3C6H

2

I +

II

(90)

(80)

(86)

(89)

(84)

(84)

I:II

5:1

3:1

7:1

7:1

5:1

4:1

867

HN

Ph

CO

2Et

EtO

2C

HN

Ph

CO

2Et

EtO

2C

HN

Ph

CO

2Et

EtO

2C

N3

N3

+1.

KH

MD

S (1

.3 e

q, ia

), T

HF,

–78

°; –

55°,

1 h

2. 2

,4,6

-(i-

Pr) 3

C6H

2SO

2N3,

–78

°, 6

min

(45)

426

(45)

CO

2Et

OH

CO

2Et

OH

1. L

DA

(2.

2 eq

), T

HF,

–78

° to

–20°

, 10

min

2. H

MPA

3. 2

,4,6

-(i-

Pr) 3

C6H

2SO

2N3,

–78

°, 30

s

318

N3

(77)

, 64%

de

CO

2Et

1. N

aHM

DS,

TH

F, –

80°,

5 m

in

2. t-

BuO

2CN

=N

CO

2Bu-

t, –8

0°, 3

min

869

O

O

CO

2Et

O

O

N

(87)

CO

2Et

OH

MeOM

eO

CO

2Et

OH

MeOM

eO1.

LD

A (

4 eq

), T

HF,

–78

°2.

t-B

uO2C

N=

NC

O2B

u-t

(55)

, 89%

de

417

C5

+

NH

CO

2Bu-

tt-

BuO

2C

249

Subs

trat

eR

efs.

Con

ditio

nsPr

oduc

t(s)

and

Yie

ld(s

) (%

)

TA

BL

E 1

0A. E

STE

R E

NO

LA

TE

S (C

onti

nued

)

CO

2Me

OH

MeOM

eOC

O2M

e

OH

MeOM

eO

N

1. L

DA

, MeZ

nBr

2. B

nO2C

N=

NC

O2B

n, –

78°

(66)

, >98

% d

e42

4

N H

H N

O

CO

2Bu-

i

C5

1. L

DA

, TH

F

2. B

nO2C

N=

NC

O2B

n, –

78°

870

O

O

CO

2Bu-

i

O

O

N

(61)

, 89%

de

OH

OH

CO

2Et

3N H

H N

O

CO

2Et

3N3

1. L

DA

, TH

F, –

30°

2. 2

,4,6

-(i-

Pr) 3

C6H

2SO

2N3,

HM

PA, –

78°

(70)

414

C6

OR

1

OR

2n-

Bu

PhI=

NT

s (0

.8 e

q), C

u(M

eCN

) 4C

lO4

(cat

)

R1

TM

S

TM

S

TB

DM

S

PhM

e 2Si

R2

Me

Ph Ph Ph

Tim

e

— — 1 h

—

(27)

(50)

(50)

(0)

173

O

SO2N

(C6H

11-c

) 2

O

OSO

2N(C

6H11

-c) 2

E

Bu

1. L

DA

, TH

F, –

78°,

adde

nd

2. t-

BuO

2CN

=N

CO

2Bu-

t

409

O

Bu

E =

N(C

O2B

u-t)

NH

CO

2Bu-

tO

OSO

2N(C

6H11

-c) 2

E

Bu

+

I (—

)II

(—

)A

dden

d

— HM

PA

I:II

81:1

9

27:7

3

OT

MS

OM

et-

Bu

t-B

uC

O2M

e

–78;

to r

t, 12

.5 h

NN

HC

O2B

u-t

CO

N(1

5)41

0N

CO

N=

NC

O2B

u-t,

TiC

l 4, C

H2C

l 2,

Tem

p

rt

–20°

–20° rt

n-B

uN

HT

s

CO

2R2

BnO

2CN

HC

O2B

n

BnO

2CN

HC

O2B

n

250

SiM

e 2Ph

SiM

e 2PhC

O2M

eC

O2M

e

N3

1. L

DA

, TH

F, –

78°

2. 2

,4,6

-Me 3

C6H

2SO

2N3,

–78

° to

rt, 1

0 h

(73)

, 95%

de

425

1. L

iHM

DS,

g T

HF,

–78

°2.

2,4

,6-M

e 3C

6H2S

O2N

3, –

78°

R Me

Et

MeO

CH

2

BnO

CH

2

(66)

, (71

)h

(74)

, (85

)h

(83)

, (65

h)h

(84)

, (61

)h

dr

>19

:1

>19

:1

>19

:1

>19

:1

784

TB

DPS

OC

O2M

e

OB

OM

TB

DPS

OC

O2M

e

BO

MO

N3

1. K

HM

DS,

TH

F, –

78°,

30 m

in

2. 2

,4,6

-Me 3

C6H

2SO

2N3,

–78

°, 20

min

(70)

427

CO

2Me

NO

CO

2Bu-

t

CO

2Me

NO

CO

2Bu-

t

CO

2Me

NO

CO

2Bu-

tN

3N

3+

1. K

HM

DS,

TH

F, –

78°,

30 m

in

2. 2

,4,6

-Me 3

C6H

2SO

2N3,

–78

°, 20

min

427

III

I +

II

(72)

, I:I

I=

6:1

C6

C6-

7

NC

O2M

e

O

O

Ph

Ph

R

N3

NC

O2M

e

O

O

Ph

Ph

R

EtO

2CC

O2E

tE

tO2C

CO

2Et

NH

2

1. B

ase

2. P

h 2P(

O)N

3

(0)

668

C7

i-Pr

O2C

CO

2Et

HO

2CC

O2H

NH

2

1. L

DA

, TH

F, –

40° t

o –5

°2.

ClN

H2,

Et 2

O, –

40°;

to r

t

3. H

Cl,

HO

Ac,

ref

lux,

2.4

h

HO

2CH

2C

O2H

NH

2

+

III

I +

II

(27)

, I:I

I =

1:2

668

O

OO

MeO

CO

2Me

O

OO

MeO

CO

2Me

R1

R1

R2

R2

R1

OH

H

R2

H OH

(56)

(59)

1. M

eZnB

r, T

HF,

0°,

30 m

in

2. L

DA

(2.

2 eq

), –

78°,

1 h

3. B

nO2C

N=

NC

O2B

n (2

eq)

, –78

°42

1R

4R

3

R3

H E

R4

E H

% d

e

>95

>95

E =

N(C

O2B

n)N

HC

O2B

n

251

Subs

trat

eR

efs.

Con

ditio

nsPr

oduc

t(s)

and

Yie

ld(s

) (%

)

TA

BL

E 1

0A. E

STE

R E

NO

LA

TE

S (C

onti

nued

)

N R

TB

SO

CO

2Me

N R

TB

SO

N R

TB

SO

1. K

HM

DS,

tolu

ene,

TH

F, –

78°,

30 m

in

2. 2

,4,6

-Me 3

C6H

2SO

2N3,

–78

°, 3

min

III

R Cbz

CO

2Me

I +

II

(>80

)

(91)

I:II

90:1

0

>95

:5

872

873

N R1

R2

CO

2Me

N R1

R2

N R1

R2

1. K

HM

DS,

tolu

ene,

TH

F, –

78°,

30 m

in

2. 2

,4,6

-Me 3

C6H

2SO

2N3,

–78

°, 3-

5 m

in

R1

H Cbz

Cbz

R2

H H TB

S

III

I +

II

(—)

(>80

)

(>80

)

I:II

90:1

0

80:2

0

95:5

871

872,

454

872

C8

1. n

-BuL

i, T

HF,

–70

°2.

MeO

NH

2, –

20° t

o –1

5°, 2

h; r

t, ov

erni

ght

(0)

874

PhC

O2E

t

R1.

NaH

, –70

° to

0°, 2

5 m

in

2. 2

,4-(

O2N

) 2C

6H3O

NH

2, 0

°, 35

min

R H Me

(8)

(31)

93

Me 2

NO

SO2M

e, E

t 2O

or

TH

F, –

30° t

o 0°

(48)

134

C8-

9

PhO

TM

S

OE

t

C8

2,4-

(O2N

) 2C

6H3O

NH

2, T

HF,

ref

lux,

4 h

(0)

93H

2NC

O2E

t

PhNH

2

CO

2Et

Ph

R

PhC

O2E

t

NM

e 2

PhC

O2B

u-t

NH

2

PhC

O2E

t

Li

PhC

O2B

u-t

+

+

N3

CO

2Me

CO

2Me

N3

N3

CO

2Me

CO

2Me

N3

HH

HH

252

PhC

HO

ZnM

e

OPr

-i

PhC

O2P

r-i

NH

CO

2Bu-

tT

sON

(Li)

CO

2Bu-

t, T

HF,

–78

° to

0°, 3

h(3

5)12

6

C8

PhC

HO

Li

OE

t

PhC

O2E

t

NH

2

Ph2P

(O)O

NH

2, T

HF,

–20

°; r

t, 12

h (

45)

139

1. B

ase,

TH

F, –

78°,

15 m

in

2. (

4-M

eOC

6H4)

2P(O

)ON

H2,

tem

p, ti

me

3. A

c 2O

, Et 3

N

PhC

O2E

t

NH

Ac

106

PhC

O2E

t

R

PhC

O2E

t

RN

Me 2

1. L

i bas

e

2.

, T

HF,

–15

°

N MeP

OPh

ON

Me 2

R H Me

(50)

(56)

% e

e

23 21

147

PhC

O2B

u-t

NH

CO

NE

t 2O

NC

ON

Et 2

4-C

lC6H

4

1. N

aHM

DS

2.(t

race

)15

5

C8

C8-

9

Bas

e

LiH

MD

S

LD

A

NaH

MD

S

KO

Bu-

t

KO

Bu-

t

(22)

i

(31)

i

(46)

i

(67)

i

(76)

i

(25)

i

Tim

e

over

nigh

t

over

nigh

t

over

nigh

t

over

nigh

t

6 h;

—

over

nigh

t

PhC

HO

Li

OPr

-iT

sON

(Li)

CO

2Bu-

t, T

HF,

–78

° to

rt, 1

6 h

126

PhC

O2P

r-i

NH

2

(0)

+

t-B

uO2C

NH

2 (3

5)

O

PhC

O2E

t

PhC

O2B

u-t

Tem

p

–78°

to r

t

–78°

to r

t

–78°

to r

t

–78°

to r

t

–78°

; to

rt

–78°

to r

t

MeS

CO

2Me

MeS

CO

2Me

NH

2

1. L

DA

(ia

), T

HF,

HM

PA, –

78°,

3 h

2. 2

,4,6

-Me 3

C6H

2SO

2ON

H2,

–78

°, 2

h;

r

t, ov

erni

ght

(38)

117

(Me 2

N) 3

PN P(

NM

e 2) 2

t-B

uN

253

Subs

trat

eR

efs.

Con

ditio

nsPr

oduc

t(s)

and

Yie

ld(s

) (%

)

TA

BL

E 1

0A. E

STE

R E

NO

LA

TE

S (C

onti

nued

)

1. L

iHM

DS

(ia)

, TH

F, –

78°,

15 m

in

2. R

O2C

N=

NC

O2R

, –78

°, 7

min

PhC

O2E

t

N

R (–)-

men

thyl

(–)-

born

yl

(–)-

isob

orny

l

(59)

(57)

(42)

22S

:2R

2:1

1:1

1:1

408

CO

2Me

OH

Et

CO

2Me

OH

Et

N

1. M

eZnB

r, T

HF,

0°,

1 h

2. L

DA

, TH

F, –

78°,

1 h

3. t-

BuO

2CN

=N

CO

2Bu-

t, –7

8°, 1

0 m

in

(53)

, >98

% d

e41

8

PhO

R1

OR

2R

3 O2C

N=

NC

O2R

3 , PhH

, rt

PhO

R1

OR

2R

3 O2C

NH

N CO

2R3

R1

Me

Me

—(C

H2)

2—R1

Me

Me

R3

Me

Et

Et

(42)

(86)

(42)

251

C9

PhC

O2B

nPh

CO

2Bn

N1.

LD

A, T

HF,

–78

°, 30

min

2. t-

BuO

2CN

=N

CO

2Bu-

t, C

H2C

l 2, –

70°

(60)

431,

848

BnOC

lC

O2M

e

OH

420

1. M

eZnB

r, 0

°2.

LD

A (

2 eq

), –

78°

3. t-

BuO

2CN

=N

CO

2Bu-

t (2

eq),

–78

°B

nOCl

CO

2Me

OH

N(6

5),

>98

% d

e

CO

2Bn

1. M

eZnB

r

2. L

DA

3. t-

BuO

2CN

=N

CO

2Bu-

t

875

MeO

OH

CO

2Bn

MeO

OH

N(5

0), >

95%

de

CO

2Me

OH

CO

2Me

OH

N

1. M

eZnB

r, T

HF,

0°,

1 h

2. L

DA

(2.

2 eq

), –

78°,

1 h

3. t-

BuO

2CN

=N

CO

2Bu-

t, –7

8°, 3

0 m

in

(66)

, >95

% d

e87

6, 4

19

C8

PhC

O2E

t

Tim

e

4 d

6 d

2 d

t-B

uO2C

NH

CO

2Bu-

t

t-B

uO2C

NH

CO

2Bu-

t

t-B

uO2C

NH

CO

2Bu-

t

t-B

uO2C

NH

CO

2Bu-

t

t-B

uO2C

NH

CO

2Bu-

t

RO

2CN

HC

O2R

BnO

BnO

254

CO

2Me

OH

CO

2Me

OH

N

1. M

eZnB

r, 0

°2.

LD

A (

2 eq

), –

78°

3. t-

BuO

2CN

=N

CO

2Bu-

t, –7

8°(5

5), >

98%

de

419

PhC

O2B

nPh

CO

2Bn

PhC

O2B

nPh

CO

2Bn

N3

N3

N3

N2

1. B

ase,

TH

F, –

78°,

30 m

in

2. A

rSO

2N3,

TH

F, –

78°,

time

III

III

Bas

e

LD

A

LD

A

LD

A

KH

MD

S

KH

MD

S

Ar

2,4,

6-(i

-Pr)

3C6H

2

4-M

eC6H

4

4-O

2NC

6H4

2,4,

6-(i

-Pr)

3C6H

2

2,4,

6-(i

-Pr)

3C6H

2

Tim

e

2 m

in

0.5

min

15 m

in

1 m

in

1 m

in j

I

(73)

(48)

(5)

(48)

(72)

II (—)

(—)

(—)

(20)

(8)

III

(1)

(24)

(68)

(—)

(—)

318

++

R1

R2

CO

2Et

413

R1

R2

CO

2Et

N3

1. L

DA

(ia

), T

HF,

–78

° to

–30°

, 1 h

2. H

MPA

, –78

°3.

2,4

,6-(

i-Pr

) 3C

6H2S

O2N

3, –

78°,

1 h

R1

H H H —C

H2O

CH

2—R2

H MeO

MO

MO

(60)

(58)

(51)

(52)

t-B

uO2C

NH

CO

2Bu-

t

PhC

O2B

u-t

NB

nPh

PhC

O2B

u-t

NB

nPh

PhC

O2B

u-t

NB

nPh

N3

1. B

ase

(ia)

, TH

F, –

78°,

1 h

2. 2

,4,6

-Me 3

C6H

2SO

2N3,

–78

°, 2

min

III

338

Bas

e

LD

A

KN

(Pr-

i)2

I

(57)

(64)

de 85 55

II (17)

(<2)

N2

+

255

Subs

trat

eR

efs.

Con

ditio

nsPr

oduc

t(s)

and

Yie

ld(s

) (%

)

TA

BL

E 1

0A. E

STE

R E

NO

LA

TE

S (C

onti

nued

)

NB

ocO

CO

2Me

OR

NB

ocO

CO

2Me

OR

N3

R =

MO

M

1. K

HM

DS,

TH

F, –

78°,

30 m

in

2. 2

,4,6

-Me 3

C6H

2SO

2N3,

–78

°, 20

min

(65)

427

C9

SO2N

R2

O

O

OT

BS

Ph

Ph

OT

BS

SO2N

R2

EtO

2CN

3, p

enta

ne, h

ν, 0

°, 8

h

SO2N

R2

O

O

NH

CO

2Et

Ph

SO2N

R2

O

O

NH

CO

2Et

Ph

III

301

I +

II

(84)

, I:I

I =

88:

12

EtO

2CN

3, p

enta

ne, h

ν, 0

°, 8

h30

1O

SO2N

R2

O

NH

CO

2Et

Ph

O

SO2N

R2

O

NH

CO

2Et

Ph

III

I +

II

(89)

, I:I

I =

77:

23

R =

c-C

6H11

R =

c-C

6H11

C10

OT

BS

OM

e

HPh

EtO

2CN

3, p

enta

ne, h

ν, 0

°, 8

h

III

I +

II

(61)

, I:I

I =

7:3

301

C12

FC

O2B

u-t

Bn

F

FC

O2B

u-t

Bn

NH

2

F

1. L

DA

, TH

F, –

78°,

30 m

in

2. P

h 2P(

O)O

NH

2, –

78°,

30 m

in

142

(20)

FC

O2B

u-t

Bn

N

F

1. L

DA

, TH

F, –

78°,

30 m

in

2. E

tO2C

N=

NC

O2E

, –78

°, 3

min

142

(44)

CO

2Me

Ph

NH

CO

2Et

CO

2Me

Ph

NH

CO

2Et

+

+ +

EtO

2C

NH

CO

2Et

C14

(34)

134

Me 2

NO

SO2M

e, E

t 2O

or

TH

F, –

30° t

o 0°

PhC

O2E

t

PhL

i

PhC

O2E

t

PhN

Me 2

256

CO

2Me

H2N

CO

2Me

1. K

OM

e, M

eOH

, PhH

2. 2

,4-(

O2N

) 2C

6H3O

NH

2, r

t, ov

erni

ght

(50

)

Me 2

NC

O2M

eN

aC

O2M

e

Me 2

NO

SO2M

e, E

t 2O

or

TH

F, –

30° t

o 0°

(54)

134

94,8

77

1. L

i bas

e

2. P

h 2P(

O)O

NH

2, T

HF,

–20

°; r

t, ov

erni

ght

139

CO

2RH

2NC

O2R

R Me

Bu-

t

(47)

(78)

1. N

aH, g

lym

e, r

t

2. T

sN3,

rt;

35-4

0°, 1

h

483

CO

2Me

N3

CO

2R

(57)

CO

2Me

OH

11

CO

2Me

OH

11

N

1. M

eZnB

r, 0

°, 1

h

2. L

DA

(2

eq),

–78

°, 1

h

3. t-

BuO

2CN

=N

CO

2Bu-

t, –7

8°, 2

h

(72)

, >95

% d

e87

8

C17

t-B

uO2C

NH

CO

2Bu-

t

a Am

ong

a ra

nge

of b

ases

(L

iHM

DS,

NaH

MD

S, K

HM

DS,

BuL

i, N

aH, a

nd N

aOB

u-t)

, NaH

MD

S ga

ve th

e hi

ghes

t yie

ld.

b The

sub

stra

te c

onta

ined

6%

of

the

Z is

omer

.c R

eact

ion

of th

e ki

netic

lith

ium

eno

late

with

t-B

uO2C

N=

NC

O2B

u-t g

ave

the

prod

uct i

n 62

% y

ield

and

62%

de.

d T

he v

alue

s ar

e fo

r th

e cr

ude

prod

ucts

.e

Use

of

LiH

MD

S w

ithou

t HM

PA, n

-BuL

i-L

iHM

DS,

or

KH

MD

S re

sulte

d in

I:I

I ra

tios

of 1

:1 to

2.5

:1.

f The

num

ber

is th

e ov

er-a

ll yi

eld

from

the

subs

trat

e ke

tene

ace

tal.

g With

KH

MD

S as

the

base

, the

yie

lds

wer

e hi

gher

but

the

dias

tere

omer

ic r

atio

s w

ere

low

er.

h The

yie

lds

are

from

the

two

dias

tere

omer

s of

the

subs

trat

e, r

espe

ctiv

ely.

i The

num

ber

is th

e pe

rcen

t con

vers

ion.

j The

eno

late

was

add

ed to

the

azid

e.

257

Subs

trat

eR

efs.

Con

ditio

nsPr

oduc

t(s)

and

Yie

ld(s

) (%

)

TA

BL

E 1

0B. T

HIO

EST

ER

EN

OL

AT

ES

OT

MS

SEt

1. t-

BuO

2CN

=N

CO

2Bu-

t + A

gOT

f (i

a),

C

H2C

l 2, 0

°, 3

h

2. H

F, T

HF

(92)

244

R1

YR

2

S

C2-

8

R1

YR

2

S

N

1. B

uLi (

ia),

TH

F, –

70°,

20 m

in

2. R

3 O2C

N=

NC

O2R

3 , –70°

‚ to

rt

R1

H H H H Ph

R2

Me

Me

Et

Et

Et

R3

Et

t-B

u

Et

Et

Et

Y S S O S S

(54)

(57)

(57)

(57)

(0)

477

RSE

t

SEt

RSE

t

SEt

MeO

2CN

=N

CO

2Me,

PhH

, rt,

time

N NH

CO

2Me

R H Ph

Tim

e

3 d

2 d

(56)

(90)

251

R1

STM

S

SMe

R2

1. t-

BuO

2CN

=N

CO

2Bu-

t, C

H2C

l 2, r

t, tim

e

2. H

OA

c, H

2O

R1

H Me

Me

n-C

5H11

Ph Bn

n-C

8H17

R2

H H Me

H H H H

Tim

e

3 h

1 h

3 h

1 h

2 h

1 h

1 h

(37)

(72)

(90)

(75)

(69)

(76)

(80)

253

C3

R3 O

2CN

HC

O2R

3

MeO

2C

R1

SMe

S

R2

N

t-B

uO2C

NH

CO

2Bu-

t

CO

SEt

Nt-

BuO

2CN

HC

O2B

u-t

258

OT

MS

SBu-

t25

2

ON

O

NN

Cl 3

CC

H2O

CO

O

1, 2

(0.

1 m

ol%

), T

HF,

CF 3

CH

2OH

,

–78

°, ov

erni

ght

ON

O

N H

O(8

9), 8

4% e

eN

CO

SBu-

t

Cl 3

CC

H2O

O

NC

u(O

Tf)

2

N

OO

t-B

uB

u-t

21

252

ON

O

N H

O

(85)

, 96%

ee

N

CO

SBu-

t

Cl 3

CC

H2O

O

1, 2

(0.

1 m

ol%

), T

HF,

CF 3

CH

2OH

,

–20

°, 20

h

OT

MS

SBu-

t

259

Subs

trat

eR

efs.

Con

ditio

nsPr

oduc

t(s)

and

Yie

ld(s

) (%

)

TA

BL

E 1

1. L

AC

TO

NE

EN

OL

AT

ES

OO

OR

OO

OR

N

1. L

DA

2. t-

BuO

2CN

=N

CO

2Bu-

t, –7

8°

R Me

n-C

5H11

(74)

(66)

% d

e

>90

>90

416

C5

OO

O

R3

R2 R1

OO

O

R3

R2 R1

N

1. B

ase,

TH

F, te

mp

1

2. t-

BuO

2CN

=N

CO

2Bu-

t,

te

mp

2, ti

me

2

R1

Me

Me

CF 3

CF 3

CF 3

CF 3

R2

H H H Me

n-B

u

Ph

R3

H (CH

2)2P

h

t-B

u

t-B

u

t-B

u

t-B

u

Tem

p 1

— — –75°

–75°

–75°

–75°

Tem

p 2

–78°

–78°

–75°

–75°

–75°

–75°

Bas

e

LD

A

LD

A

t-B

uLi

t-B

uLi

t-B

uLi

t-B

uLi

(90)

(95)

(97)

(86)

(80)

(71)

% d

e

90 99 >96

>96

>96

>96

416

864

865,

866

865

865

865

Boc

NH

OO

Boc

NH

N3

1. L

DA

(2.

1 eq

), T

HF,

–7

8° to

–20

°, 1

h

2. T

sN3,

–78

°, 1

h

3. T

MSC

l, –7

8° to

0°

(58)

, 100

% d

e87

9

OO

RN

H

OO

RN

HN

31.

LiH

MD

S (2

eq,

ia),

TH

F,

–7

8°, 3

0 m

in

2. T

sN3,

TH

F, –

78°,

5 m

in

(55)

a88

0

R =

Boc

or

Cbz

OO

C4

OO

TM

SE

tO2C

N(T

MS)

OT

MS,

90°

, 5 d

(44)

OO

NH

CO

2Et

105

Tim

e 2

—

3 m

in

40 m

in

40 m

in

40 m

in

40 m

in

t-B

uO2C

NH

CO

2Bu-

t

t-B

uO2C

NH

CO

2Bu-

t

260

O

O

OO

C7

O

O

OO

O

O

OO

N3

N3 N

3+

1. K

HM

DS

(ia)

, TH

F, –

80°;

to r

t, 50

min

2. 2

,4,6

-(i-

Pr) 3

C6H

2SO

2N3,

–80

°, 10

min

86%

ee

(79)

(6)

428

H

OO

1. B

ase,

TH

F, –

78°

2. 2

,4,6

-(i-

Pr) 3

C6H

3SO

2N3

882

Bas

e

LiH

MD

S

NaH

MD

S

KH

MD

S

I

(45)

(20)

(26)

SMe

OO

SMe

OO

SMe

OO

SMe

N2

N3

N3

II (7)

(4)

(4)

III

(0)

(9)

(28)

III

III

OO

BnO

R1

R2

OB

n

C6

OO

BnO

R1

R2

OB

nO

O

BnO

R1

R2

OB

nN

3

N3

III

1. K

HM

DS,

tolu

ene,

TH

F, –

90°,

15 m

in

2. 2

,4,6

-(i-

Pr) 3

C6H

3SO

2N3,

–90

°, 2

min

R1

BnO

H

R2

H BnO

429,

881

I (0)

(50)

II (70)

(0)

C5

OO

RO

OO

RO

OO

RO

N3

N3

+

III

1. B

ase,

TH

F, –

78°,

30 m

in

2. 2

,4,6

-(i-

Pr) 3

C6H

2SO

2N3,

–78

°, 30

min

3. Q

uenc

hing

age

nt

320

R TB

DPS

TB

DPS

Tr

Tr

Tr

Bas

e

LiH

MD

S

LiH

MD

S

LiH

MD

S

NaH

MD

S

KH

MD

S

Que

nchi

ng A

gent

HO

Ac

TM

SCl

HO

Ac

HO

Ac

HO

Ac

I

(33)

(53)

(37)

(25)

(11)

II (13)

(28)

(12)

(tra

ce)

(tra

ce)

+

++

261

Subs

trat

eR

efs.

Con

ditio

nsPr

oduc

t(s)

and

Yie

ld(s

) (%

)

TA

BL

E 1

1. L

AC

TO

NE

EN

OL

AT

ES

(Con

tinu

ed)

C9

O

O OT

BS

O

O OT

BS

N3

1. K

HM

DS

(ia)

, tol

uene

, TH

F,

–7

8°, 3

0 m

in

2. 2

,4,6

-(i-

Pr) 3

C6H

2SO

2N3,

–78

°, 1-

2 m

in

(63)

883

OO

i-B

u

OO

i-B

u

OO

i-B

uN

3N

3

+(6

9)(2

6)1.

LiH

MD

S (i

a), T

HF,

–78

°, 60

min

2. 2

,4,6

-(i-

Pr) 3

C6H

2SO

2N3,

–78

°, 30

min

884

TB

DPS

OT

BD

PSO

TB

DPS

O

OO

Ar

ArC

H2O

OO

Ar

ArC

H2O

OO

Ar

ArC

H2O

N3

N2

C11

1. L

DA

2. 4

-O2N

C6H

4SO

2N3

3. p

H 7

buf

fer

1. L

iHM

DS,

TH

F, –

78°,

45 m

in

2. 4

-O2N

C6H

4SO

2N3,

–78

°, 10

min

3. Q

uenc

h co

nditi

ons

III

Ar

Ph 3,4-

(OC

H2O

)C6H

3

Que

nch

cond

ition

s

AcO

H, t

o rt

AcC

l, to

rt;

then

DM

AP,

TH

F, r

t, 16

h

I

(58)

(27)

II (0)

(40)

OO

Ph

BnO

OO

Ph

BnO

OO

Ph

BnO

N3

N2

326

(45)

(6)

O

O

OT

BS

O

O

OT

BS

N3

1. L

DA

(ia

), T

HF,

–78

°, 30

min

2. 2

,4,6

-(i-

Pr) 3

C6H

2SO

2N3,

–78

°, 15

min

(89)

885

326,

886

326

++

262

1. L

iHM

DS,

TH

F, –

78°,

45 m

in

2. 4

-O2N

C6H

4SO

2N3,

–78

°, 10

min

3. A

cCl,

–78°

; to

rt

OO

Ph

BnO

N

OO

Ph

BnO

N+

326

III

Ar

= C

6H4N

O2-

4

I +

II

(100

)b

R =

TB

DPS

1. n

-BuL

i, T

HF

2. 2

,4,6

-(i-

Pr) 3

C6H

2SO

2N3,

–78

°(7

2)88

7

C18

OO

BnO

R

OB

nO

O

BnO

R

OB

nO

O

BnO

R

OB

nN

3

N2

1. K

HM

DS,

tolu

ene,

TH

F, –

78°,

15 m

in

2. 2

,4,6

-(i-

Pr) 3

C6H

2SO

2N3,

–78

°, 2

min

429

(60)

(15)

O

BnO BnO

R =

C12

OB

n

a The

use

of

KH

MD

S or

2,4

,6-(

i-Pr

) 3C

6H2S

O2N

3 ga

ve lo

wer

yie

lds.

b The

rat

io I

:II

was

not

rep

orte

d. O

n tr

eatm

ent w

ith D

MA

P in

TH

F, th

e 3-

R a

zide

and

the

diaz

o co

mpo

und

wer

e ob

tain

ed in

48%

and

51%

yie

lds,

res

pect

ivel

y.

C22

N Boc

OPh Ph

Bn

O1.

KH

MD

S, T

HF,

–78

° to

rt

2. B

nO2C

N=

NC

O2B

n or

2,

4,6-

(i-P

r)3C

6H2S

O2N

3, –

78°,

30 m

inN B

oc

OPh Ph

O Bn

E =

N(C

O2B

n)N

HC

O2B

n or

N3

(0)

888

E

+

N Boc

HEt

OR

O

H

ON B

ocHE

t

OR

O

H

ON3

N

N

Ac

SO2A

rN

Ac

NA

r

OB

n

263

Subs

trat

eR

efs.

Con

ditio

nsPr

oduc

t(s)

and

Yie

ld(s

) (%

)

TA

BL

E 1

2. A

MID

E E

NO

LA

TE

S

C2

1. L

DA

(ia

), T

HF,

–78

°, 1

h

2. 1

, –78

°; to

rt,

2-3

h

ON

4-N

CC

6H4

O

Oi-

Pr

i-Pr

ON H

O(5

6)15

4, 1

58

N N

Y Y

1. L

DA

, TH

F, h

exan

e, –

78°,

40 m

in

2. R

2 O2C

N=

NC

O2R

2 , –78

°, 4

min

Y CH

2

O

R Me

Et

(41)

(18)

251

C3-

9

RN

O

O

RN

O

Ot-

BuO

2CN

H

1. n

-BuL

i, T

HF,

–78

°2.

CuC

N, –

78° t

o –5

°3.

TsO

N(L

i)C

O2B

u-t,

–78°

, 30

min

889

R Me

i-Pr

n-B

u

i-B

u

t-B

u

Ph Bn

(63)

(67)

(68)

(72)

(52)

(51)

(77)

% d

e

99 99 96 99 99 99 99

R1

CO

NM

e 2

C3-

5

R1

CO

NM

e 2

N40

8

R1

Me

i-Pr

(72)

(87)

% d

e

(0)

(0)

RC

ON

MeP

hR

CO

NM

ePh

NH

CO

2Bu-

t

1. L

DA

, TH

F, –

78°,

60 m

in

2. (

PhO

) 2P(

O)N

3, –

78°,

5 m

in

3. (

t-B

uO2C

) 2O

, –78

° to

rt, 6

h

C3-

8

336

R Me

Et

2-th

ieny

l

Ph

(74)

(76)

(70)

(80)

RO

2CN

=N

CO

2R, P

hH, r

t, 3

dN O

Y

NR

O2C

HN

CO

2R

1

NM

e 2

O

NM

e 2

O

NH

CO

2R2

R2 O

2C R

2 = is

obor

nyl

264

R1

O

R2

R1

O

R2

N

1. T

ris(

dipi

valo

ylm

etha

nato

)man

gane

se(I

II)

(

5 m

ol%

) +

i-Pr

OH

(ia

), 0

°2.

R3 O

2CN

=N

CO

2R3 , i

-PrO

H

3. P

h 3Si

H, 0

°, tim

e

890

R1

H Me

MeS

(CH

2)2

n-Pr

n-Pr

n-Pr

n-Pr

n-Pr

i-Pr

n-C

7H15

Ph(C

H2)

2

R2

III

III

III

I II III

III

III

III

III

III

R3

t-B

u

t-B

u

t-B

u

t-B

u

t-B

u

Et

i-Pr

t-B

u

t-B

u

t-B

u

t-B

u

Tim

e

1 h

1 h

1 h

1.5

h

1.5

h

1.5

h

1.5

h

1.5

h

1.5

h

1.5

h

1.5

h

(56)

(84)

(72)

(—)a

(78)

(—)a

(47)

(81)

(78)

(80)

(68)

dr 91:1

98:2

96:4

—

89:1

1

—

90:1

0

96:4

99:1

96:4

97:3

I R

2 =N

Ph

Ph

II R

2 =N

Ph

Ph

NS O

2

III

R2 =

C3-

11

OT

MS

NR

N

O

E

RN

O E

R Me

CH

2=C

H-C

H2

i-Pr

t-B

u

Tem

p

–78°

–20°

–20°

–20°

I

(96)

(73)

(65)

(0)

% e

e

(99)

(98)

(99)

(—)

II (0)

(18)

(23)

(80)

III

252

C3-

6

NH

CO

2R3

R3 O

2C

ON

O

NN

Cl 3

CC

H2O

CO

O

1, 2

(5

mol

%),

TH

F, C

F 3C

H2O

H

1

+

ON

O

N H

NC

l 3C

CH

2OC

O

OE

=

Tim

e

30 m

in

5 m

in

5 m

in

5 m

in

NC

u(O

Tf)

2

N

OO

t-B

uB

u-t

2

C5-

9

NS O

2

R

Ot-

Bu

NS O

2

R

Ot-

Bu

N3

1. N

aHM

DS,

TH

F, –

78°,

30 m

in

2. 2

,4,6

-(i-

Pr) 3

C6H

2SO

2N3,

–78

°, 2

min

891

R CH

2CH

=C

H2

Bn

(96)

(85)

% d

e

>96 98

265

Subs

trat

eR

efs.

Con

ditio

nsPr

oduc

t(s)

and

Yie

ld(s

) (%

)

TA

BL

E 1

2. A

MID

E E

NO

LA

TE

S (C

onti

nued

)

C7

N S O2

O

R

R =

O

R

N3

1. K

HM

DS,

TH

F, –

78°,

30 m

in

2. 2

,4,6

-(i-

Pr) 3

C6H

2SO

2N3,

–78

°, 1-

2 m

in

(78)

776

Bn 2

N

O

Bn 2

N

O

PhN

R1 R

2

OPh

NR

1 R2

O

NH

2

1. B

ase

(x e

q), T

HF,

–70

°2.

MeO

NH

2, te

mp,

2 h

;

rt

, ove

rnig

ht

874

R1

H H Et

R2

H t-B

u

Et

Bas

e

n-B

uLi

LD

A

LD

A

x 2 2 1

(0)

(49)

(15)

Tem

p

–20°

to –

15°

–20°

to –

15°

–20°

C8

PhN

HR

OPh

NH

R

O

N

1. B

ase

(2 e

q), T

HF,

1 h

2. A

rN=

NA

r, –

78°,

5 m

in

R H Ph Ph

Ar

Ph Ph 2-C

lC6H

4

Bas

e

NaN

H2

NaN

H2

LD

A

(29)

(49)

(6)

212

R1

R2

R3

Me

N

O

Ph

OH

R1

R2

R3

Me

N

O

Ph

OH

1. L

DA

(2

eq),

TH

F, 7

8°, 1

h;

0°

, 15

min

; rt,

5 m

in

2. t-

BuO

2CN

=N

CO

2Bu-

t, –1

05°,

1 h;

to r

t

NR

1

MeO

—O

CH

2O—

MeO

BnO

R2

MeO

MeO

MeO

R3

H H MeO

BnO

(89)

(91)

(90)

(86)

% d

e

>90

>90

>90

>90

764,

892

,

765

NH

Ar

Ar

t-B

uO2C

NH

CO

2Bu-

t

a The

rea

ctio

n pr

oduc

ts w

ere

a co

mpl

ex m

ixtu

re.

C8-

12

S O2N

R

t-B

uO

S O2N

R

t-B

uO

N3

1. N

aHM

DS

(ia)

, TH

F, –

78°,

30 m

in

2. 2

,4,6

-(i-

Pr) 3

C6H

2N3,

–78

°, 2

min

R 3-T

MSO

C6H

4

1-na

phth

yl

(92)

(96)

893

266

Subs

trat

eR

efs.

Con

ditio

nsPr

oduc

t(s)

and

Yie

ld(s

) (%

)

TA

BL

E 1

3. N

-AC

YL

OX

AZ

OL

IDIN

ON

E E

NO

LA

TE

S

C3-

9

NO

OO

R1.

LD

A, T

HF,

–78

°, 20

min

2. 1

, C

H2C

l 2, –

78°,

7 m

in

R Me

Bn

(85)

a

(92)

a

219

HN N

Me

N N Me

O OR

N

O

O

O

N N

Me

N N Me

O O

NO

OO

R1

i-Pr

NO

OO

i-Pr

1. L

DA

, TH

F, –

78°,

15-4

0 m

in

2. R

2 O2C

N=

NC

O2R

2 , –78

°3.

HC

l, tim

e (q

uenc

h; f

or

R

2 = is

obor

nyl:

HO

Ac)

R1

Me

Me

Me

t-B

u

Bn

R2

t-B

u

Bn

(–)-

isob

orny

l

Bn

Bn

Tim

e

0 m

in

0 m

in

4 m

in

0 m

in

0 m

in

(92)

(91)

(56)

(85)

(90)

% d

e

— 80b

100

94b

88b

432

432,

408

408

432

432

NO

OO

i-Pr

C3

1. L

DA

, TH

F, –

78°,

40 m

in

2. R

O2C

N=

NC

O2R

, –78

°, 4

min

R Bn

(–)-

isob

orny

l

(—)

(88)

% d

e

80 100

408

1

E =

N(C

O2R

2 )NH

CO

2R2

R1

E

NO

OO

i-Pr

E

E =

N(C

O2R

)NH

CO

2R

267

Subs

trat

eR

efs.

Con

ditio

nsPr

oduc

t(s)

and

Yie

ld(s

) (%

)

TA

BL

E 1

3. N

-AC

YL

OX

AZ

OL

IDIN

ON

E E

NO

LA

TE

S (C

onti

nued

)

NO

OO

R

Bn

1. L

DA

, TH

F, –

78°,

30 m

in

2. t-

BuO

2CN

=N

CO

2Bu-

t, C

H2C

l 2,

3

0-18

0 s

R Me

i-Pr

CH

2CH

=C

H2

t-B

u

MeO

2C(C

H2)

2c

Ph Bn

(92)

(95)

(94)

(96)

(51)

(96)

(91)

2S:2

R

98:2

98:2

98:2

>99

:1

>95

:5

97:3

97:3

431

C3-

8

NO

OO

R

Bn N

O

OO

R

Bn

1. B

ase,

TH

F, –

78°,

30 m

in

2. A

rSO

2N3,

–78

°, tim

e 2

3. A

cid,

tem

p 3,

tim

e 3

(que

nch)

C3-

9

N3

NO

OO

R

Bn

N2

+

III

R Me

i-Pr

CH

2CH

=C

H2

t-B

u

Ph Bn

Bn

Bn

Bn

Bn

Bn

Bn

Ar

2,4,

6-(i

-Pr)

3C6H

2

2,4,

6-(i

-Pr)

3C6H

2

2,4,

6-(i

-Pr)

3C6H

2

2,4,

6-(i

-Pr)

3C6H

2

2,4,

6-(i

-Pr)

3C6H

2

4-O

2NC

6H4

4-O

2NC

6H4

4-M

eC6H

4

4-M

eC6H

4

2,4,

6-(i

-Pr)

3C6H

2

2,4,

6-(i

-Pr)

3C6H

2

2,4,

6-(i

-Pr)

3C6H

2

Bas

e

KH

MD

S

KH

MD

S

KH

MD

S

KH

MD

S

KH

MD

S

NaH

MD

S

KH

MD

S

KH

MD

S

KH

MD

S

LD

A

NaH

MD

S

KH

MD

S

Tim

e 2

1-2

min

1-2

min

1-2

min

1-2

min

1-2

min

1 h

— — —

1 m

in

30 s

1-2

min

I

(74)

d

(77)

d

(78)

d

(90)

d

(82)

d

(0)

(15)

(51)

(0)

(74)

(59)

(92)

I %

de

94 96 94 >98 82 — — — — — — 94

II (0)

(0)

(0)

(0)

(0)

(85)

(70)

(26)

(57)

(0)

(0)

(0)

318,

433

Aci

d

HO

Ac

HO

Ac

HO

Ac

HO

Ac

HO

Ac

TM

SCl

HO

Ac

HO

Ac

TFA

HO

Ac

HO

Ac

HO

Ac

Tem

p 3

— — — — — –78° — — —

–78°

to r

t

–78°

to r

t

–78°

to r

t

Tim

e 3

— — — — — 1 h

— — — 12 h

3 h

3 h

E

E =

N(C

O2B

u-t)

NH

CO

2Bu-

t

268

C3-

4

NO

OO

(EtO

) 2P(

O)

1. N

aHM

DS,

TH

F, –

78°,

30 m

in

2. 2

,4,6

-(i-

Pr) 3

C6H

2SO

2N3,

T

HF

(pre

cool

ed),

–78

°, 30

min

894

n 1 2

(66)

(64)

de

>98

%

—

nN

O

OO

(EtO

) 2P(

O)

n N3

NO

OO

Bn

Ph2P

(S)

NO

OO

Bn

Ph2P

(S)

N3

1. K

HM

DS

(ia)

, TH

F, –

78°,

30 m

in

2. 2

,4,6

-(i-

Pr) 3

C6H

2SO

2N3,

–78

°, 2

min

458

(85)

, 94%

de

C3

1. N

aHM

DS,

TH

F, –

78°,

30 m

in

2. H

MPA

, –78

°, 15

min

3. t-

BuO

2CN

=N

CO

2Bu-

t, –7

8°, 1

h

I (

61)

+

II

(21

)89

5

C4

NO

OO

Bn

NO

OO

Bn

NO

OO

Bn

NO

OO

Bn

1. L

DA

, TH

F, –

78°,

30 m

in

2. H

MPA

, –78

°, 15

min

3. t-

BuO

2CN

=N

CO

2Bu-

t, –7

8°, 1

hE

E

E

I (

44)

+

+

II (

18)

(7)

(i-P

r)2N

E =

N(C

O2B

u-t)

NH

CO

2Bu-

t

895

269

Subs

trat

eR

efs.

Con

ditio

nsPr

oduc

t(s)

and

Yie

ld(s

) (%

)

TA

BL

E 1

3. N

-AC

YL

OX

AZ

OL

IDIN

ON

E E

NO

LA

TE

S (C

onti

nued

)

C4-

5

C4

N

OO

R1

N

OO

N

OO

ER

1R

1E

+

E =

N(C

O2R

2 )NH

CO

2R2

R2 O

2CN

=N

CO

2R2 , c

atal

yst (

10 m

ol%

),

ClC

H2C

H2C

l

896

R1

H H H H H H Me

R2

Et

Et

Bn

Bn

Bn

Bn

Et

Cat

alys

t

A B A B B B B

Tem

p

rt rt 0° rt 0° 50°

50°

Tim

e

18 h

12 h

4 d

17 h

72 h

17 h

—

I +

II

(94)

(97)

(100

)

(100

)

(100

)

(100

)

(0)

I:II

73:2

7

74:2

6

89:1

1

70:3

0

69:3

1

63:2

7

—

ON

iO

OO

ON

iO

OO

Cat

alys

t A

III

O

O

Bn

OO

OO

Bn

Bn

NO

OO

Bn

RO

NO

OO

Bn

RO

R =

TB

DM

SE

(71)

, 80%

de

1. N

aHM

DS,

TH

F. –

78°,

30 m

in

2. t-

BuO

2CN

=N

CO

2Bu-

t, –7

8°, 1

h

895

Cat

alys

t B

E =

N(C

O2B

u-t)

NH

CO

2Bu-

t

NO

OO

Bn

1. L

DA

, TH

F, –

78°,

30 m

in

2. A

dden

d

3. t-

BuO

2CN

=N

CO

2Bu-

t, –7

8°, 1

h

NO

OO

Bn

E

NO

OO

Bn

E+

III

Add

end

— HM

PA (

1 eq

)

HM

PA (

5 eq

)

I

(51)

(61)

(52)

II (33)

(21)

(11)

E =

N(C

O2B

u-t)

NH

CO

2Bu-

t

895

270

NO

OO

R2

R1

Bn

NO

OO

R2

Bn

1. B

ase,

TH

F, te

mp

1, ti

me

1

2. t-

BuO

2CN

=N

CO

2Bu-

t,

te

mp

2, ti

me

2

R1

MeO

—O

(CH

2)2O

—R2

MeO

Bas

e

LD

A

NaH

MD

S

(93)

(67)

897

896,

898

NO

OO B

n

Br

1. L

DA

(ia

), T

HF,

–78

°, 45

min

2. t-

BuO

2CN

=N

CO

2Bu-

t, C

H2C

l 2,

–

78°,

15 m

in

NO

OO

Br

Bn

(84)

441

R1

NO

OO

Bn

NO

OO

Bn

1. L

DA

, TH

F, –

78°,

30 m

in

2. t-

BuO

2CN

=N

CO

2Bu-

t, –7

8°, 3

min

E

(86)

, 98%

de

895

C5

E =

N(C

O2B

u-t)

NH

CO

2Bu-

t

NO

OO

Br

Ph

NO

OO

PhN

Boc

N Boc

(70)

441

1. L

DA

(ia

), T

HF,

hex

ane,

–78

°, 80

min

2. t-

BuO

2CN

=N

CO

2Bu-

t, –7

8°, 1

h

3. D

MPU

, –78

° to

rt

E E

E =

N(C

O2B

u-t)

NH

CO

2Bu-

t

E =

N(C

O2B

u-t)

NH

CO

2Bu-

t

Tem

p 1

–78°

–80°

Tim

e 1

—

30 m

in

Tem

p 2

–78°

–80°

Tim

e 2

—

3 m

in

NO

OO B

n

Br

1. L

DA

(ia

), T

HF,

–78

°, 2

h

2. t-

BuO

2CN

=N

CO

2Bu-

t, C

H2C

l 2,

< –

70°,

15 m

in

3. B

u 4N

I (0

.15

eq),

e –78

°, 15

min

;

–

20°,

18 h

NO

OO B

n

(91)

, 94%

de

442,

441

NB

ocN B

oc

1. K

HM

DS,

TH

F, –

78°,

30 m

in

2. 2

,4,6

-(i-

Pr) 3

C6H

2SO

2N3

NO

OO B

n

Br

C5-

7

N

OO B

n

Br

O

N3

n 2 3 4

(60-

70)

(40)

f

(60-

70)

% d

e

95 95 95

443

nn

271

Subs

trat

eR

efs.

Con

ditio

nsPr

oduc

t(s)

and

Yie

ld(s

) (%

)

TA

BL

E 1

3. N

-AC

YL

OX

AZ

OL

IDIN

ON

E E

NO

LA

TE

S (C

onti

nued

)

NO

OO

N3

Bn

R1

R2

NO

OO

N3

Bn

R1

R2

N3

1. K

HM

DS

(ia)

, TH

F, –

78°,

30 m

in

2. 2

,4,6

-(i-

Pr) 3

C6H

2SO

2N3,

TH

F,

–

78°,

1-2

min

(46)

, 82.

5% d

e89

9

mix

ture

of

R1 =

T; R

2 = H

and

R1 =

H a

nd R

2 = T

C5

PhSe

NO

OO B

n

PhSe

NO

OO B

n

1. K

HM

DS

(ia)

, tol

uene

, TH

F,

–

78°,

40 m

in

2. 2

,4,6

-(i-

Pr) 3

C6H

2SO

2N3,

TH

F,

–

78°,

4 m

in

N3

(80)

456

NO

OO B

n

OT

BD

PS

MeN

CO

2Bu-

t

NO

OO B

n

OT

BD

PS

MeN

CO

2Bu-

tN

3

1. K

HM

DS,

TH

F, –

78°,

30 m

in

2. 2

,4,6

-(i-

Pr) 3

C6H

2SO

2N3,

–78

°, 1

min

(>40

), 9

3% d

e44

7

1. T

ris(

dipi

valo

ylm

etha

nato

)man

gane

se(I

II)

(

5 m

ol%

), i-

PrO

H (

ia),

0°

2. t-

BuO

2CN

=N

CO

2Bu-

t, i-

PrO

H

3. P

h 3Si

H, 0

°, 90

min

NOO

RR

O Ph

NOO

RR

O PhE

C6

E =

N(C

O2B

u-t)

NH

CO

2Bu-

t

R H Ph

(75)

(51)

dr

68:3

2

65:3

5

890,

900

NO

OO

R2

NO

OO

R2

N3

1. B

ase

(x e

q), T

HF,

–78

°2.

2,4

,6-(

i-Pr

) 3C

6H2S

O2N

3, –

78°,

time

R1

R1

C6-

7

NO

OO

R1

N2

+

III

272

R1

TB

DPS

O

BzO

Me

Me

R2

Ph Bn

Bn

Bn

Bas

e

KH

MD

S

NaH

MD

S

KH

MD

S

KH

MD

S

x — 1.2

1.2

1.5

I

(82)

(73)

(10)

(76)

II (—)

(—)

(20)

(—)

901,

902

903

437

437

C6

Tim

e

2 m

in

3 m

in

— —

TB

DPS

ON

O

OO B

n

TB

DPS

ON

O

OO B

n

*1.

KH

MD

S, T

HF,

–78

°, 30

min

2. 2

,4,6

-(i-

Pr) 3

C6H

2SO

2N3,

–78

°, 2

min

* C

onfi

g.

R S

(86)

(80)

904

NO

OO B

n

O

NO

OO B

n

O

N3

1. K

HM

DS,

TH

F, –

78°,

30 m

in

2. 2

,4,6

-(i-

Pr) 3

C6H

2SO

2N3,

–78

°, 2

min

(84)

905

NO

OO i-

Pr

RN

O

OO i-

Pr

R

N3

1. K

HM

DS

(ia)

, TH

F, –

78°,

45 m

in

2. 2

,4,6

-(i-

Pr) 3

C6H

2SO

2N3,

–78

°, 5

min

R CM

e 2C

O2B

n

1-ad

aman

tyl

(55)

(27)

906

C6-

12

C7

NO

OO

Bn

NO

OO

Bn

N3

1. K

HM

DS,

TH

F, –

78°

2. 2

,4,6

-(i-

Pr) 3

C6H

2SO

2N3,

–78

°(6

7)90

7

N3

NO

OO

Bn

NO

OO

Bn

N3

1. K

HM

DS,

TH

F, –

78°

2. 2

,4,6

-(i-

Pr) 3

C6H

2SO

2N3,

–78

°(—

)90

8

*

273

Subs

trat

eR

efs.

Con

ditio

nsPr

oduc

t(s)

and

Yie

ld(s

) (%

)

TA

BL

E 1

3. N

-AC

YL

OX

AZ

OL

IDIN

ON

E E

NO

LA

TE

S (C

onti

nued

)

NO

OO

Bn

R1

NR

2 CO

2Bu-

t

NO

OO

Bn

R1

NR

2 CO

2Bu-

t

N3

R1 , R

2 = H

, H; H

, Me;

Me,

H; M

e,M

e

1. K

HM

DS,

TH

F, –

78°

2. 2

,4,6

-(i-

Pr) 3

C6H

2SO

2N3,

–78

°(4

0-50

), d

e >

95%

451

NO

OO

Ph

N N Bn

NO

OO

Ph

N N Bn

1. K

HM

DS

(ia)

, TH

F, –

50°,

45 m

in

2. 2

,4,6

-(i-

Pr) 3

C6H

2SO

2N3,

–78

° 2 m

inN

3

(72)

909

NO

OO

R1

N Cbz

H

R2

NO

OO

R1

N Cbz

H

R2

N3

1. K

HM

DS,

TH

F, –

78°,

30 m

in

2. 2

,4,6

-(i-

Pr) 3

C6H

2SO

2N3,

–78

°, 5

min

R1

H Me

R2

H Ph

(—)

(68)

thre

o:er

ythr

o

1:2

100:

0

871

454

NO

Bn

O

N

O

O

Bn

OO

NO

Bn

O

N

O

O

Bn

OO

1. K

HM

DS

(2 e

q, ia

), T

HF,

–78

°, 30

min

2. 2

,4,6

-(i-

Pr) 3

C6H

2SO

2N3

(2 e

q),

–

78°,

30 m

inN

3N

3

OO

N3

N3

+

(35)

(8)

910

NO

Bn

O

N

O

O

Bn

OO

1. K

HM

DS

(2 e

q, ia

), T

HF,

–78

°, 30

min

2. 2

,4,6

-(i-

Pr) 3

C6H

2SO

2N3

(2 e

q),

–

78°,

30 m

in

N

O

O

Bn

O

2,4,

6-(i

-Pr)

3C6H

2SO

2NH

O

(—)

910

C7-

8

C7

H

274

NO

OO

Ar

C8-

12

NO

OO

Ar

t-B

uO2C

N=

NC

O2B

u-t,

TsN

HM

e (0

.2 e

q), C

H2C

l 2

RN

MgN

R

PhPh

(0.1

eq)

,

Ar

Ph 4-FC

6H4

4-M

eOC

6H4

3,4-

(OC

H2O

)C6H

3

3-C

l-4 -

MeO

C6H

3

2-na

phth

yl

Tem

p

–75°

–65°

–65°

–75°

–75°

–65°

Tim

e

48 h

48 h

48 h

72 h

60 h

48 h

(92)

d

(97)

d

(93)

d

(85)

d

(84)

d

(87)

d

% e

e

86 90 86 82 80 82

436

R =

SO

2C6H

3Me 2

-2,5

E

E =

N(C

O2B

u-t)

NH

CO

2Bu-

t

NO

OO

Bn

Ph

C8

1. B

ase

(x e

q)

2. t-

BuO

2CN

=N

CO

2Bu-

tN

O

OO

Bn

Ph(—

)

Bas

e

LiN

Et 2

NaO

Bu-

t

La(

OB

u-t)

3

1

x 1.0

0.05

0.05

0.05

436

2S:2

R

97:3

95:5

97:3

95:5

NO

OO

Ar

Bn

1. K

HM

DS,

TH

F, –

78°,

time

1

2. 2

,4,6

-(i-

Pr) 3

C6H

2SO

2N3,

–78

°, tim

e 2

NO

OO

Ar

Bn

N3

Ar

3,5-

(MeO

) 2C

6H3

4-(M

eO)-3

,5-(

i-Pr

O) 2

C6H

2

4-(M

eO)-

3,5-

(BnO

) 2C

6H2

Tim

e 1

—

30 m

in

30 m

in

Tim

e 2

—

5 m

in

2 m

in

(—)

(71)

(82)

% d

e

>60

>85 80

911

892,

912

913

E =

N(C

O2B

u-t)

NH

CO

2Bu-

tE

E =

N(C

O2B

u-t)

NC

O2B

u-t

NO

OO B

n

Ph

E

–Na+

1

275

Subs

trat

eR

efs.

Con

ditio

nsPr

oduc

t(s)

and

Yie

ld(s

) (%

)

TA

BL

E 1

3. N

-AC

YL

OX

AZ

OL

IDIN

ON

E E

NO

LA

TE

S (C

onti

nued

)

NO

OO

Ar

Ph

NO

OO

Ar

PhN

3

C8-

9

1. K

HM

DS,

TH

F, –

78°,

time

2. 2

,4,6

-(i-

Pr) 3

C6H

2SO

2N3,

–78

°, 2

min

Ar

3-B

nOC

6H4

3-B

nO-4

-MeO

C6H

3

4-C

lC6H

4CH

2

Tim

e

30 m

in

23 m

in

30 m

in

(30-

50)

(90)

(68)

% d

e

— 92 >98

914

915

914

C8

NO

OO B

n

O

O

H

HN

O

OO B

n

O

O

H

HN

O

OO B

n

O

O

H

HN

3N

3

+1.

KH

MD

S, T

HF,

–78

°, 30

min

2. 2

,4,6

-(i-

Pr) 3

C6H

2SO

2N3,

–78

°, 2

min

(26)

(26)

916

NO

OO

Ar

Bn

NO

OO

Ar

Bn

N3

1. K

HM

DS,

TH

F, –

78°,

time

1

2. 2

,4,6

-(i-

Pr) 3

C6H

2SO

2N3,

–78

°, tim

e 2

Ar

Ph 4-FC

6H4

4-C

lC6H

4

3,5-

(MeO

) 2C

6H3

3-T

BSO

-4-M

eOC

6H3

3,5-

(BnO

) 2C

6H3

3,5-

(BnO

) 2-4

-MeC

6H2

3-(C

H2=

CH

CH

2O)-

4-M

e-5-

BnO

C6H

2

3,5-

(3,4

-Cl 2

C6H

3CH

2)2C

6H3

Tim

e 1

15-4

5 m

in

30 m

in

20 m

in

15-4

5 m

in

20 m

in

—

15-4

5 m

in

15-4

5 m

in

15-4

5 m

in

Tim

e 2

1-2

min

2 m

in

5 m

in

1-2

min

5 m

in

—

1-2

min

1-2

min

1-2

min

(82)

(67)

(—)

(78)

(75)

(81)

(81)

(75)

(76)

% d

e

82 — — 80 — — 76 80 76

450

917

918

450

918

919

450

450

450

C8-

22

276

NO

OO B

n

NR

CO

2Bu-

t

NO

OO B

n

NR

CO

2Bu-

t

N3

1. K

HM

DS

(2 e

q), T

HF,

–78

°, 20

min

2. 2

,4,6

-(i-

Pr) 3

C6H

2SO

2N3,

–78

°, 1

min

R H Me

(54)

(51)

452

NO

OO B

n

R

C8-

11

NO

OO B

n

R

N3

1. K

HM

DS

(ia)

, TH

F, –

78°,

30 m

in

2. 2

,4,6

-(i-

Pr) 3

C6H

2SO

2N3,

–78

°, 1-

2 m

in

R i-Pr

(R

,S)

Ph (

R)

Ph (

S)

920

(63)

(68)

(68)

NO

OO B

n

NO

OO B

n

R

N3

1. K

HM

DS

(ia)

, TH

F, –

78°,

60 m

in

2. 2

,4,6

-(i-

Pr) 3

C6H

2SO

2N3,

–78

°, 60

min

R c-C

5H9

c-C

6H11

CH

2

c-C

8H15

t-B

u

(—)

(61)

(—)

(—)

(—)

R

C8-

13

438

C8

NO

OO B

nO

NB

oc

NO

OO B

nO

NB

ocN

3

1. K

HM

DS

(ia)

, TH

F, –

78°,

80 m

in

2. 2

,4,6

-(i-

Pr) 3

C6H

2SO

2N3

(m

ode

of a

dditi

on),

tem

p, ti

me

Mod

e of

Add

ition

azid

e so

lutio

n pr

ecoo

led

to –

78°

azid

e so

lutio

n pr

ecoo

led

to –

95°,

ins

ulat

ed c

annu

la

azid

e ad

ded

as a

sol

id

Tem

p

–78°

–95°

to –

100°

–78°

Tim

e

220

sec

220

sec

200

sec

(20-

40)

(45-

82)

(75-

95)

440

277

Subs

trat

eR

efs.

Con

ditio

nsPr

oduc

t(s)

and

Yie

ld(s

) (%

)

TA

BL

E 1

3. N

-AC

YL

OX

AZ

OL

IDIN

ON

E E

NO

LA

TE

S (C

onti

nued

)

C9

NO

OO

Bn

NO

OO

Bn

1. L

i bas

e, C

uI, T

HF

2. T

osO

N(L

i)C

O2B

u-t,

–50°

, 1 h

NH

2

(55)

126

O

NC

O2B

u-t,

4-N

CC

6H4

1. L

iHM

DS

(ia)

, TH

F, –

78°,

60 m

in

2.

–

78°,

30 m

in

NO

OO

Bn

(33)

153,

157

14C

NO

OO B

n

Bn

14C

NO

OO B

n

Bn

1. L

DA

(ia

), T

HF,

–78

°, 1.

5 h

2. t-

BuO

2CN

=N

CO

2Bu-

t, T

HF,

–

78°,

30 m

in

(46)

921

NO

OO B

nA

cNH

NO

OO B

nA

cNH

1. K

HM

DS

(1.9

eq)

, TH

F, –

78°,

30 m

in

2. t-

BuO

2CN

=N

CO

2Bu-

t (ia

),

C

H2C

l 2, –

78°,

3 m

in

(53)

h45

3

E =

N(C

O2B

u-t)

NH

CO

2Bu-

t

E

EE

= N

(CO

2Bu-

t)N

HC

O2B

u-t

NH

t-B

uO2C

NO

OO B

n

Ar

NO

OO B

n

Ar

N3

1. K

HM

DS,

TH

F, –

78°,

time

1

2. 2

,4,6

-(i-

Pr) 3

C6H

2SO

2N3,

–78

°, tim

e 2

Ar

Ph 3-B

nOC

6H4

3-(i

-PrO

)-4-

MeO

C6H

3

Tim

e 1

15 m

in

—

30 m

in

Tim

e 2

2 m

in

—

2 m

in

(—)

(59)

(83)

dr — 95:5

—

444

774,

922

923

278

NO

OO i-

Pr

Ph

C6H

4Me-

4

C6H

4Me-

4

1. K

HM

DS

(ia)

, TH

F, –

78°,

30 m

in

2. 2

,4,6

-(i-

Pr) 3

C6H

2SO

2N3,

–78

°, 2

min

NO

OO i-

Pr

Ph

C6H

4Me-

4

C6H

4Me-

4

N3

924

(65)

, 92%

de

NO

OO

R2

O

OR

1O

R1

R1 O

OR

1N

O

OO

R2

E

1. B

ase,

TH

F, –

78°,

30 m

in

2. t-

BuO

2CN

=N

CO

2Bu-

t (ia

),

–

78°,

5 m

in*

R1

Me

Bn

Bn

Bn

Bn

* α β α β β

n 1 1 1 1 2

Bas

e

KH

MD

S

LD

A

KH

MD

S

KH

MD

S

LD

A

(61)

(70)

(72)

(68)

(65)

C10

-11

% d

e

92 73i

72 98 98

R2

i-Pr

H i-Pr

i-Pr

i-Pr

439

459

439

439

459

NO

OO B

n

C10

N

O

O

O

Bn

NO

OO B

n

N

O

O

O

Bn

N3

N3

1. K

HM

DS

(2.1

eq)

(ia

), T

HF,

–

78°,

30 m

in

2. 2

,4,6

-(i-

Pr) 3

C6H

2SO

2N3

(2.2

eq)

,

–

78°,

10 m

in

Con

nect

ion

1,3

1,4

(73)

(65)

% d

e

>95 60

925

NO

OO B

n

BnN

N CO

2Bn

NH

CO

2Bu-

t

NO

OO B

n

BnN

N CO

2Bn

NH

CO

2Bu-

tN3

1. K

HM

DS

2. 2

,4,6

-(i-

Pr) 3

C6H

2SO

2N3

(>62

), 5

2% d

e44

9

nn

E =

N(C

O2B

u-t)

NH

CO

2Bu-

t

279

Subs

trat

eR

efs.

Con

ditio

nsPr

oduc

t(s)

and

Yie

ld(s

) (%

)

TA

BL

E 1

3. N

-AC

YL

OX

AZ

OL

IDIN

ON

E E

NO

LA

TE

S (C

onti

nued

)

NO

OO B

n

OO

OT

s

NO

OO B

n

OO

OT

s

1. K

HM

DS,

TH

F, –

78°,

30 m

in

2. 2

,4,6

-(i-

Pr) 3

C6H

2SO

2N3,

–78

°, 3

min

N3

(73)

455

C11

NO

OO

PhPM

BO

TM

S

NO

OO

PhPM

BO

TM

S N3

1. K

HM

DS,

TH

F, –

100°

, 30

min

2. 2

,4,6

-(i-

Pr) 3

C6H

2SO

2N3

(3 e

q),

–

78°,

5 m

in

(50)

, 80%

de

782

NO

OO Ph

N R

NO

OO Ph

N R

N3

1. K

HM

DS,

TH

F, –

78°,

30 m

in

2. 2

,4,6

-(i-

Pr) 3

C6H

2SO

2N3,

–78

°, 5

min

R CO

2Bu-

t

2,4,

6-M

e 3C

6H2S

O2

(40)

(59)

928

929,

930

C12

NO

OO Ph

N R

NO

OO Ph

N R

N3

1. K

HM

DS

(ia)

, TH

F, –

78°,

30 m

in

2. 2

,4,6

-(i-

Pr) 3

C6H

2SO

2N3

(ia)

, –78

°, 5

min

R =

2,4

,6-M

e 3C

6H2S

O2

(62)

929,

930

C10

C11

-13

NO

OO Ph

1. K

HM

DS,

TH

F

2. 2

,4,6

-(i-

Pr) 3

C6H

2SO

2N3,

–78

°

R

Ar

NO

OO Ph

R

Ar

Ar

2,6-

Me 2

-4-M

eOC

6H2

2-na

phth

yl

R i-Pr

Me

(80)

(94)

% d

e

>95

>95

N3

926

927

280

NO

OO B

n

RO

NO

OO Ph

RO

1. K

HM

DS

(ia)

, TH

F, –

78°,

40 m

in

2. 2

,4,6

-(i-

Pr) 3

C6H

2SO

2N3,

–78

°, 2

min

N3

R TB

S

Bn

(95)

(73)

931

O

NO

O

Bn

O

NO

O

Bn

E1.

LD

A, T

HF,

–78

°, 30

min

2. t-

BuO

2CN

=N

CO

2Bu-

t, –7

8°, 1

h

(82)

C13

438

NO

OO i-

PrN M

e

NO

OO i-

PrN M

e

N3

1. K

HM

DS

(ia)

, TH

F, –

78°

2. 2

,4,6

-(i-

Pr) 3

C6H

2SO

2N3,

–78

°, 1

min

(70)

, >

98%

de

932

NO

OO B

n

TB

SO

R

NO

OO B

n

TB

SO

R

1. K

HM

DS

(1.2

eq,

ia),

TH

F, –

78°,

40 m

in

2. 2

,4,6

-(i-

Pr) 3

C6H

2SO

2N3,

–78

°, 2

min

N3

(35)

457

C15

NO

OO

Ph

Ph

Ph

NO

OO

Ph

Ph

Ph

1. K

HM

DS,

TH

F, –

78°

2. 2

,4,6

-(i-

Pr) 3

C6H

2SO

2N3,

–78

°N

3

(94)

933

R =

(t-

BuO

) 2P(

O)

NO

OO Ph

MeO

i-Pr

NO

OO Ph

MeO

i-Pr

N3

1. K

HM

DS

(ia)

, TH

F, –

78°,

30 m

in

2. 2

,4,6

-(i-

Pr) 3

C6H

2SO

2N3,

–78

°, 15

min

(85)

, >

90 d

e43

4

E =

N(C

O2B

u-t)

NH

CO

2Bu-

t

NO

OO

Ph

Ph

NO

OO

Ph

Ph

Ph1.

KH

MD

S, T

HF,

–78

°2.

2,4

,6-(

i-Pr

) 3C

6H2S

O2N

3, –

78°

N3

(—)

933

Ph

R =

P(O

)(O

Bu-

t)2

281

Subs

trat

eR

efs.

Con

ditio

nsPr

oduc

t(s)

and

Yie

ld(s

) (%

)

TA

BL

E 1

3. N

-AC

YL

OX

AZ

OL

IDIN

ON

E E

NO

LA

TE

S (C

onti

nued

)

NO

OO i-

Pr

N

N

OE

t

OE

t

i-Pr

NO

OO i-

Pr

N

N

OE

t

OE

t

i-Pr

N3

1. K

HM

DS

(ia)

, TH

F, –

78°,

30 m

in

2. 2

,4,6

-(i-

Pr) 3

C6H

2SO

2N3,

–78

°, 2

min

(84)

934

NO

OO

Ph

NO

OO

Ph

C17

1. K

HM

DS,

TH

F, –

78°

2. 2

,4,6

-(i-

Pr) 3

C6H

2SO

2N3,

–78

°N

3

(85)

935

C15

NO

OO

Ph

NO

OO

Ph

1. K

HM

DS,

TH

F, –

78°

2. 2

,4,6

-(i-

Pr) 3

C6H

2SO

2N3,

–78

°N

3

(—)

935

NO

OO B

n

NH N

NO

OO B

n

NH N

N3

O

N3

NH

2

1. K

HM

DS

(2.3

eq)

, TH

F, –

78°,

30 m

in

2. 2

,4,6

-(i-

Pr) 3

C6H

2SO

2N3,

–78

°, 3

min

3. H

OA

c, –

78° t

o rt

, ove

rnig

ht

4. N

aHC

O3,

H2O

+44

5, 4

46

(34)

(24)

NO

OO B

n

R

Cl

R

R

NO

OO B

n

R

Cl

R

R

R =

BnO

N3

1. K

HM

DS,

TH

F, –

78°,

15-4

5 m

in

2. 2

,4,6

-(i-

Pr) 3

C6H

2SO

2N3,

–78

°, 1-

2 m

in

(77)

, >90

% d

e45

0

55

5

55

282

C17

NO

OO B

nO

NO

OO B

nO

N3

1. K

HM

DS,

TH

F, –

78°,

30 m

in

2. 2

,4,6

-(i-

Pr) 3

C6H

2SO

2N3,

–78

°, 2

min

(85)

448

OBoc

N

OBoc

N

NO

Bn

(83-

86),

d 95%

deg

OO

O

MeO

CO

2Bu-

t

C18

NO

Bn

OO

O

MeO

CO

2Bu-

tN3

1. K

HM

DS,

TH

F, –

78°,

15 m

in

2. 2

,4,6

-(i-

Pr) 3

C6H

2SO

2N3,

–78

°, 2

min

444

NO

Bn

(85)

OO

1. K

HM

DS

(2.2

eq)

, TH

F, –

78°,

15 m

in

2. 2

,4,6

-(i-

Pr) 3

C6H

2SO

2N3,

–78

°, 1-

2 m

in

433

MeO

O

CO

2Bn

NH

Boc

NO

Bn

OO

MeO

O

CO

2Bn

NH

Boc

N3

NO

Bn

OO

BnO

OB

n

BnO

R

NH

Boc

NO

Bn

OO

BnO

OB

n

BnO

R

NH

Boc

R =

TM

S(C

H2)

2O2C

1:1

mix

ture

of

2 at

ropi

som

ers

N3

1. K

HM

DS

(2.2

eq)

, TH

F, –

78°,

15 m

in

2. 2

,4,6

-(i-

Pr) 3

C6H

2SO

2N3,

–78

°, 1

min

(60)

, 86%

dej

450

283

Subs

trat

eR

efs.

Con

ditio

nsPr

oduc

t(s)

and

Yie

ld(s

) (%

)

TA

BL

E 1

3. N

-AC

YL

OX

AZ

OL

IDIN

ON

E E

NO

LA

TE

S (C

onti

nued

)

NO

PhOO

R

1. K

HM

DS

(1 e

q), N

aH (

1 eq

), T

HF,

–

78°,

30 m

in

2. 2

,4,6

-(i-

Pr) 3

C6H

2SO

2N3,

–78

°, 15

min

NO

PhOO

R

R t-B

u

Ph

(54)

(73)

435,

936

NO

PhOO

R

1. K

HM

DS

(1 e

q), N

aH (

1 eq

), T

HF,

–

78°,

30 m

in

2. 2

,4,6

-(i-

Pr) 3

C6H

2SO

2N3,

–78

°, 15

min

NO

PhOO

R

R t-B

u

Ph

(51)

(60)

435,

936

N3

N3

ME

MO

ME

MO

ME

MO

ME

MO

C19

-21

NO

Bn

OO

BnO

O

O CN

NO

Bn

OO

BnO

O

O CN

N3

1. K

HM

DS

(2.2

eq)

, TH

F, –

78°,

15

-45

min

2. 2

,4,6

-(i-

Pr) 3

C6H

2SO

2N3,

–78

°, 1-

2 m

in

(61)

, 84%

de

450

C24

284

a The

chi

ral a

uxili

ary

coul

d no

t be

clea

ved

to g

ive

the

hydr

azin

e de

riva

tive.

b Rea

gent

s w

here

R1 =

Me

or E

t gav

e pr

oduc

ts w

ith p

oore

r dr

val

ues.

c The

trea

tmen

t tim

e w

ith L

DA

was

5 m

inut

es.

d The

num

ber

is th

e yi

eld

of p

ure

maj

or p

rodu

ct.

e Add

ition

of

Bu 4

NI

prev

ents

the

reve

rse

reac

tion

of th

e in

itial

ly f

orm

ed a

dduc

t; oc

curr

ence

of

a re

vers

e re

actio

n ha

s be

en d

ispu

ted

(Ref

. 441

).f E

xces

s 2,

4,6-

(i-P

r)3C

6H2S

O2N

3 w

as a

dded

ear

ly in

the

enol

izat

ion

step

to p

artia

lly c

ount

erac

t cyc

lizat

ion

of th

e en

olat

e.g T

he v

alue

s ar

e th

ose

of th

e cr

ude

prod

uct.

h The

pro

duct

epi

mer

ized

on

atte

mpt

ed r

emov

al o

f th

e ch

iral

aux

iliar

y.i N

o co

nfig

urat

ions

wer

e as

sign

ed to

the

two

dias

tere

omer

s.j T

he n

umbe

rs a

re th

e fo

r th

e tw

o at

ropi

som

ers.

285

Subs

trat

eR

efs.

Con

ditio

nsPr

oduc

t(s)

and

Yie

ld(s

) (%

)

TA

BL

E 1

4. L

AC

TA

M E

NO

LA

TE

S

C3-

4

MeN

O

R

MeN

O

R1.

LD

A, E

t 2O

, –70

°2.

TsN

3, –

78° t

o –5

0°, 1

h

3. T

MSC

l, re

flux

, 6 h

N3

R EtS

Me

(52)

(39)

339

TB

SNO

PhS

H

TB

SNO

PhS

H

1. L

DA

2. 2

-C10

H7S

O2N

3

(66)

780

TB

SNO

PhS

H

TB

SNO

PhS

HN

31.

LD

A

2. 2

-C10

H7S

O2N

3

3. T

MSC

l

(56)

780

N3

C4-

10

NN

O

R

Me

Bn

NN

OM

e

Bn

N R1.

LD

A, T

HF,

hex

ane,

–78

°, 2

h

2. t-

BuO

2CN

=N

CO

2Bu-

t, –7

8°, 6

h; r

t, 3-

6 h

R Me

Et

Bn

(45)

(67)

(73)

% d

e

>98

>98

>98

460

NNO

R

Me Bn

NNO

Me

Bn

N R1.

LD

A, T

HF,

hex

ane,

–78

°, 2

h

2. t-

BuO

2CN

=N

CO

2Bu-

t, –7

8°, 6

h; r

t, 3-

6 h

R Me

Et

Bn

(41)

(37)

(25)

% d

e

>98

>98

>98

460

RN

OR

NON

31.

LD

A, T

HF,

–78

°, 2

h

2. T

sN3,

–78

°, 1

h

3. T

MSC

l, rt

. 1 h

R =

C(C

O2M

e)2C

6H4O

Bn-

4

(76)

777

MeN

OM

eNO

1. L

DA

, Et 2

O, –

70°

2. T

MSN

3, –

78° t

o –5

0°, 1

h

3. T

MSC

l, re

flux

, 6 h

TM

S

339

(64)

C4

C3

CO

2Bu-

t

NH

CO

2Bu-

t

CO

2Bu-

t

NH

CO

2Bu-

t

286

Nt-

BuO

2CO

H

C7

1. L

iHM

DS,

TH

F, –

78°

2. P

h 2P(

O)O

NH

2

Nt-

BuO

2CO

H

NH

2(4

7)14

3

C9

N Boc

ON B

oc

ON3

1. K

HM

DS

(ia)

, TH

F, –

78°,

80 m

in

2. 2

,4,6

-(i-

Pr) 3

C6H

2SO

2N3

(pre

cool

ed to

–9

5°, i

nsul

ated

can

nula

)

(36)

, 17%

de

440

N

S

MeO

2CC

O2M

eON

S

MeO

2CC

O2M

eON3

H1.

LiH

MD

S, T

HF,

–70

°, 4

h

2. T

sN3,

–70

°3.

TM

SCl,

to r

t

(68)

339

N

O

H

TB

DPS

O

N

O

H

TB

DPS

O

1. L

DA

(ia

), T

HF,

–78

°, 20

min

2. 2

,4,6

-(i-

Pr) 3

C6H

2SO

2N3,

–78

°, 3

hN

3

(65)

, 72%

de

462

NH

TB

DPS

OO

NH

TB

DPS

OO

1. L

DA

(ia

), T

HF,

–78

°, 20

min

2. 2

,4,6

-(i-

Pr) 3

C6H

2SO

2N3,

a –78

°, 10

min

N3

NH

TB

DPS

OO

N2

(20)

(64)

461

Boc

OB

ocO

C8

1. K

OB

u-t,

TH

F, –

78°,

30 m

in

2. 2

,4,6

-(i-

Pr) 3

C6H

2SO

2N3,

TH

F, –

78°,

30 m

inN

R N

Cl

O

N

R N

Cl

O

N3

R Me

PMB

(57)

(92)

938

+

C5

Cbz

NO

t-B

uO2C

Cbz

NO

t-B

uO2C

Cbz

NO

t-B

uO2C

EE

1. L

iHM

DS,

–78

°2.

t-B

uO2C

N=

NC

O2B

u-t

I+

II

I +

II

(76)

, I:I

I =

10:

1

937

E =

N(C

O2B

u-t)

NH

CO

2Bu-

t

287

Subs

trat

eR

efs.

Con

ditio

nsPr

oduc

t(s)

and

Yie

ld(s

) (%

)

TA

BL

E 1

4. L

AC

TA

M E

NO

LA

TE

S (C

onti

nued

)

N

O

H

TB

DPS

O

N

O

H

TB

DPS

O

1. t-

BuL

i, T

HF,

–78

°, 1

h

2. 2

,4,6

-(i-

Pr) 3

C6H

2SO

2N3,

–78

°, 3

h

(63)

940

OM

e

N3

OM

eC

10

C9

NM

e

NPr

-i

O

O

NM

e

NPr

-i

O

ON

3

1. K

HM

DS,

TH

F, –

78°

2. 2

,4,6

-(i-

Pr) 3

C6H

2SO

2N3,

–78

°(—

)93

9

C10

N N

O

OHN N

O

OHN N

O

ON3

R

HN

3N

3

RR

1. K

HM

DS,

TH

F, –

78°

2. 2

,4,6

-(i-

Pr) 3

C6H

2SO

2N3,

–78

°

R H OT

BD

MS

I

(42)

(22)

II (0)

(22)

941

C11

-21

N

N R2

OR

1

N

N R2

OR

1

N3

R1

Me

Me

Me

Me

Me

CH

2CF 3

CH

2CF 3

CH

2CF 3

i-Pr

4-M

eOC

6H4C

H2

4-M

eOC

6H4C

H2

R2

Et

n-Pr

i-Pr

MeO

(CH

2)2O

CM

e 2

Ph i-Pr

i-Pr

Ph Ph i-Pr

Ph

(83)

(76)

(86)

(81)

(88)

(50)

(94)

b

(77)

(89)

(84)

(89)

942

1. K

HM

DS,

TH

F, –

78°,

5 m

in

2. 2

,4,6

-(i-

Pr) 3

C6H

2SO

2N3,

–78

°, 5

min

III

+

288

N N

O

OHN N

O

ON3

MeO

2CM

eO2C

1. K

HM

DS,

TH

F, –

78°

2. 2

,4,6

-(i-

Pr) 3

C6H

2SO

2N3,

–78

°94

1(7

9)

C11

C12

NO

ON(B

n)O

Bn

H

Ph

NO

ON(B

n)O

Bn

H

Ph

1. L

DA

(ia

), T

HF,

–78

°, 30

min

2. R

O2C

N=

NC

O2R

, –78

°, 8

h

NR t-

Bu

Bn

(70)

(85)

943,

944

C15

-18

N

OOM

eH

TB

DPS

O

Et

RN

OOM

eH

TB

DPS

O

Et

1. t-

BuL

i, T

HF

2. 2

,4,6

-(i-

Pr) 3

C6H

2SO

2N3,

–78

°88

7N

3

R

R CM

e=C

H2

1-cy

cloh

exen

yl

Ph

(72)

(78)

(60)

N

O

H

Bn

TB

DPS

O

N

O

H

TB

DPS

O

N

O

H

TB

DPS

O

Bn

N3

N3

Bn

1. t-

BuL

i, T

HF,

pen

tane

, –78

°, 50

min

2. 2

,4,6

-(i-

Pr) 3

C6H

2SO

2N3,

–78

°, 6

h

C16

(27)

(15)

462

NN

N

MeO

O

Ph

NN

N

MeO

O

Ph

N3

1. t-

BuO

K, T

HF

2. 2

,4,6

-(i-

Pr) 3

C6H

2SO

2N3,

–78

°

(26)

945

N

O4-

MeO

C6H

4

R

TB

SO

N

O4-

MeO

C6H

4

R

TB

SO

N3

N

O4-

MeO

C6H

4

R

TB

SO

N3

1. L

DA

(ia

), T

HF,

–78

°; to

0°,

30 m

in

2. 2

,4,6

-(i-

Pr) 3

C6H

2SO

2N3,

–78

°, 5

min

C18

(59)

(24)

946

R =

OSi

Et 3

a No

reac

tion

occu

rred

with

t-B

uO2C

N=

NC

O2B

u-t.

b The

bas

e w

as K

OB

u-t (

2 eq

).

+ +

NH

CO

2R

CO

2R

289

Subs

trat

eR

efs.

Con

ditio

nsPr

oduc

t(s)

and

Yie

ld(s

) (%

)

TA

BL

E 1

5. C

YA

NO

-ST

AB

ILIZ

ED

CA

RB

AN

ION

S

C3

NC

NC

Na+

1. 2

,4,6

-Me 3

C6H

2SO

2ON

H2,

TH

F, 0

°, 2.

5 h

2. T

sOH

NC

NC

NH

3+ T

sO–

(55)

463

CN

NC

ON

Et 2

O

2-N

CC

6H4

1. n

-BuL

i, he

xane

, TH

F, 0

°, 30

min

2.

,

–78°

, 3 h

; to

rt, 1

.5 h

CN

NH

CO

NE

t 2(5

6)15

8

NC

NC

HN

O

1. L

iHM

DS

(ia)

, TH

F, –

78°,

1 h

2.

(–)

, –78

°, 7

h; to

rt

N

CN C

ON

H2(5

7), 2

3% d

e15

1

N

CN C

ON

H2

(82)

, dr

1:1

151

(NC

) 2C

=N

OT

s, p

yrid

ine,

Et 2

O, 0

°N

C

NC

NC

N

CN

(55)

838

C3-

4

RC

N

1. L

iHM

DS

(ia)

, TH

F, –

78°,

1 h

2.

(

+)

, –78

°, tim

e; to

rt

ON

H

CO

NH

2

N

OI

II

R Me

Et

Tim

e

4.5

h

6.5

h

I

(36)

(83)

II (0)

(17)

151

C3

H

1. L

iHM

DS

(ia)

, TH

F, –

78°,

1 h

2.

(

+)

, –78

°, 6

h; to

rt

ON

H

+

C4

CN

NC

ON

H2

(45)

151

1. L

iHM

DS

(ia)

, TH

F, –

78°,

1 h

2.

(

+)

, –78

°, 26

.5 h

; to

rt

ON

H

PyH

+

290

Con

ditio

ns 1

: 1. C

atal

yst A

(se

e C

hart

1; 5

mol

%),

E

tOH

, rt

2

. Sub

stra

te, t

hen

PhSi

H3

3

. t-B

uO2C

N=

NC

O2B

u-t,

rt, t

ime

Con

ditio

ns 2

: 1. C

atal

yst B

(se

e C

hart

1; 2

mol

%),

i-

PrO

H, 0

°

2. S

ubst

rate

, the

n Ph

SiH

3, 0

°

3. t

-BuO

2CN

=N

CO

2Bu-

t, 0°

, tim

e

CN

CN

NN

HC

O2B

u-t

t-B

uO2C

Con

ditio

ns

1 2

Tim

e

18 h

2.5

h

(46)

(45)

215

TM

SO NC

R1.

LD

A

2. P

h 2P(

O)O

NM

e 2, –

78° t

o 20

°, 5

h

947

C6-

15

R 2-fu

ryl

2-th

ieny

l

2-(1

-met

hylp

yrro

lyl)

2-py

ridi

nyl

Ph 2-C

lC6H

4

4-C

lC6H

4

4-B

rC6H

4

4-M

eOC

6H4

4-M

e 2N

C6H

4

2,4-

(HO

) 2C

6H3

E-P

hCH

=C

H

1-na

phth

yl

2-na

phth

yl

4-B

zC6H

4

(77)

(80)

(68)

(96)

(76)

(92)

(95)

(91)

(75)

(98)

(67)

(35)

(80)

(90)

(51)

RN

Me 2

O

Ph NC

1. n

-BuL

i

2. 2

,4-(

O2N

) 2C

6H4O

NH

2

Ph NC

NH

2 (

7)93

C8

1. B

ase,

TH

F, –

78°,

15 m

in

2. (

4-M

eOC

6H4)

2P(O

)ON

H2,

–78

° to

rt;

rt

, ove

rnig

ht

3. A

c 2O

, Et 3

N

Ph NC

NH

Ac

106

Bas

e

LiH

MD

S

NaH

MD

S

KO

Bu-

t

(59)

(64)

(67)

291

Subs

trat

eR

efs.

Con

ditio

nsPr

oduc

t(s)

and

Yie

ld(s

) (%

)

TA

BL

E 1

5. C

YA

NO

-ST

AB

ILIZ

ED

CA

RB

AN

ION

S (C

onti

nued

)

Ph NC

C8

1. L

i bas

e, T

HF

or e

ther

2. M

eSO

2ON

Me 2

, –30

° to

0°

Ph NC

NM

e 2

I (

69)

134

LD

A, P

h 2P(

O18

)ON

Me 2

84

NPO

PhO

NM

e 2

Me

I (6

5)

I (6

2), 8

% e

ea14

7O

NC

ON

H2

151

Ar

NC

ON

H2

Ar

+

CO

NH

2

III

III

+

Ar

Ph 4-C

lC6H

4

4-O

2NC

6H4

4-M

eOC

6H4

1-na

phth

yl

2-na

phth

yl

Tim

e

4.5

h

5 h

6 h

9 h

4.5

h

4.5

h

I +

II

(78)

b

(80)

(0)

(75)

(80)

(73)

% d

e

25 16 — 5 33 33

III

(0)

(0)

(21)

(0)

(0)

(0)

C8-

12

Ar

NC

1. L

iHM

DS

(ia)

, TH

F, –

78°,

1 h

2.

(

+)

, –78

°, tim

e; to

rt

ON

H

1. L

i bas

e, T

HF

2.

, –15

°

NA

r

CO

NH

2

Ar

Ph 1-na

phth

yl

2-na

phth

yl

(55)

(48)

(31)

% d

e

50 33 52

151

HN

O

1. L

iHM

DS

(ia)

, TH

F, –

78°,

1 h

2.

(–)

, –78

°; to

rt

292

1. L

iHM

DS

(ia)

, TH

F, –

78°

2.

,

–78°

, 20

h; to

rt

ON

CO

2Bu-

tE

tO2C

EtO

2C

Ar

NC

NH

CO

2Bu-

t

Ar

Ph 4-C

lC6H

4

4-M

eOC

6H4

(45)

(46)

(20)

155

N HNC

N

NH

O, D

AB

CO

(ca

t), t

olue

ne, r

tN HN

CO

NH

2

N(—

)15

0

C14

Ph PhC

N1.

Li b

ase,

TH

F

2. P

h 2P(

O)O

NH

2, –

20°,

rt, 2

0 h

Ph Ph

CN

NH

2

I (

67)

139

4-O

2NC

6H4

NC

4-O

2NC

6H4

NC

N

CN

CN

–Py

H+ (

85)

NC

NC

NT

s, p

yrid

ine,

rt,

1 h

838

C8

C9

CN

TM

SO

C10

OT

MS

NC

Me 2

N

NM

e 2O

O

1. L

DA

2. P

h 2P(

O)N

Me 2

, –78

° to

rt, 5

h

(36)

947

1. N

aH, T

HF,

rt,

15 m

in

2. R

eage

nt, r

t, ov

erni

ght

106

Rea

gent

Ph2P

(O)O

NH

2c

(4-M

eOC

6H4)

2P(O

)ON

H2

4-O

2NC

6H4C

O2N

H2

(67)

(85)

(66)

I

293

Subs

trat

eR

efs.

Con

ditio

nsPr

oduc

t(s)

and

Yie

ld(s

) (%

)

TA

BL

E 1

5. C

YA

NO

-ST

AB

ILIZ

ED

CA

RB

AN

ION

S (C

onti

nued

)

N H

HN

Ph Ph

O

(82)

150

1. L

i bas

e, E

t 2O

or

TH

F

2. M

eSO

2ON

Me 2

, –30

° to

0°

Ph Ph

CN

NM

e 2(6

7)13

4

1. N

aH, g

lym

e, r

t

2. T

sN3,

rt;

35-4

0°, 1

h

Ph Ph

CN

N3

(18)

d48

3

a R

acem

izat

ion

prob

ably

occ

urre

d du

ring

isol

atio

n by

trea

tmen

t with

aci

d (p

H 4

.5).

b I is

the

maj

or is

omer

.c L

iHM

DS

was

use

d as

the

base

.d T

he r

epor

ted

yiel

d is

that

of

the

crud

e pr

oduc

t.

C14

Ph PhC

NN

HO

, DA

BC

O (

cat)

, tol

uene

, rt

294

Subs

trat

eR

efs.

Con

ditio

nsPr

oduc

t(s)

and

Yie

ld(s

) (%

)

TA

BL

E 1

6. N

ITR

ON

AT

ES

C1-

6

R1

R2

NO

2

R1

R2

N3

Ts

1. K

H, T

HF,

rt;

40°,

15 m

in

2. T

sN3,

–10

° to

0°; 0

°, 1

h

464

R1

H Me

Me

—(C

H2)

5—

Me

R2

H H Me

(0)

(37)

(49)

(56)

(35)

OO

(CH

2)2

295

Subs

trat

eR

efs.

Con

ditio

nsPr

oduc

t(s)

and

Yie

ld(s

) (%

)

TA

BL

E 1

7. S

UL

FON

E-S

TA

BIL

IZE

D C

AR

BA

NIO

NS

PhSO

2C

uLi

PhSO

2N

Me 2

Me 2

NO

SO2R

, Et 2

O o

r T

HF,

0°

R =

Me,

Ph,

4-M

eC6H

4, o

r 2,

4,6-

Me 3

C6H

2

134

(22)

PhO

2SC

uLi

PhO

2S13

4(2

8)

C7

PhPh

Ph

NM

e 2

PhO

2SN

Me 2

PhC

13

PhSO

2Me

ON

CO

NE

t 2,

2-N

CC

6H4

1. n

-BuL

i, T

HF,

hex

ane,

0°,

30 m

in

2.

–

78°,

3 h;

to r

t, 90

min

(43)

158

C15

S O2

NH

OT

BD

PSB

nS O

2

NH

OT

BD

PSS O

2

NH

OT

BD

PS

Bn

N3

N3

Bn

(40)

(33)

1. t-

BuL

i, T

HF,

pen

tane

, –78

°, 55

min

2. 2

,4,6

-(i-

Pr) 3

C6H

2SO

2N3,

–78

°, 6

h

465

PhO

2SC

uLi

Ph

SO2

NH

Bu-

n

C5

SO2

NH

Bu-

n

EtO

2CN

RC

ON

H

EtO

2CN

=N

CO

R, M

eCN

, ref

lux,

3 h

(60)

(60)

R OE

t

Ph

250

1. M

e 2N

OSO

2R, E

t 2O

or

TH

F, 0

° (fo

rms

I as

inte

rm.)

2.

(fo

rms

II)

R =

Me,

Ph,

4-M

eC6H

4, o

r 2,

4,6-

Me 3

C6H

2I

II

(—)

+

H NC

ON

Et 2

PhSO

2

296

Subs

trat

eR

efs.

Con

ditio

nsPr

oduc

t(s)

and

Yie

ld(s

) (%)

TA

BL

E 1

8. P

HO

SPH

OR

US-

STA

BIL

IZE

D C

AR

BA

NIO

NS

C1

1. N

aH, T

HF,

rt,

15 m

in

2. S

ee ta

ble.

95

Rea

gent

2,4-

(O2N

) 2C

6H3O

NH

2

Ph2P

(O)O

NH

2

Tem

p

rt

–70°

; rt

(15)

(50)

(51)

158

C1-

8R H M

e

i-Pr

t-B

u

Ph Bn

(53)

(65)

(65)

(71)

(75)

(50)

770

C2

1. N

aH, D

ME

2. 2

,4,6

-Me 3

C6H

2SO

2ON

H2,

30°

, 30

min

(47)

704

1. N

aH, T

HF,

rt,

1 h

2. P

h 2P(

O)O

NH

2, T

HF,

–78

°, 2

h

3. H

O2C

CO

2H

(60)

141

MsO

N(L

i)C

O2C

H2C

H=

CH

2, T

HF,

–78

° to

–60°

, 1.5

h

(58)

130

1. n

-BuL

i, T

HF,

–78

°2.

t-B

uO2C

N=

NC

O2B

u-t,

–78°

, few

min

EtO

PP

O

EtO

O

OE

tO

Et

EtO

PM

e

O

EtO

EtO

PO

EtO

R

EtO

PO

EtO

CO

2Me

EtO

PO

EtO

CO

2Bn

EtO

PO

EtO

–C

u+

EtO

PP

O

EtO

O

OE

tO

Et

NH

2

Tim

e

12 h

2 h;

10

h

ON

CO

NE

t 2,

2-N

CC

6H4

1. n

-BuL

i, T

HF,

hex

ane,

0°,

30 m

in

2.

–

78°,

3 h;

to r

t, 1.

5 h

EtO

PO

EtO

H NC

ON

Et 2

EtO

PO

EtO

R

Nt-

BuO

2CN

HC

O2B

u-t

EtO

PO

EtO

CO

2Me

NH

2

EtO

PO

EtO

CO

2Bn

NH

3+ H

O2C

CO

2–

EtO

PO

EtO

HN

O

O

297

Subs

trat

eR

efs.

Con

ditio

nsPr

oduc

t(s)

and

Yie

ld(s

) (%

)

TA

BL

E 1

8. P

HO

SPH

OR

US-

STA

BIL

IZE

D C

AR

BA

NIO

NS

(Con

tinu

ed)

TsO

N(L

i)C

O2B

u-t

R Me

Ph

(80)

(50)

126

EtO

PO

EtO

R–

Cu+

C2-

7

EtO

PO

EtO

R

NH

CO

2Bu-

t

Me

N N MeP

Ph Ph

C2-

8M

eN N M

eP

Ph PhN

HC

O2B

u-t

1. n

-BuL

i, T

HF,

–78

°2.

CuB

r. Me 2

S

3. T

sON

(Li)

CO

2Bu-

t, T

HF,

–78

°

R Me

Ph

(59)

(49)

% d

e

30 35

129

1. n

-BuL

i, T

HF,

–78

°2.

t-B

uO2C

N=

NC

O2B

u-t,

–78°

, few

min

Me

N N MeP

Me

N N Me

(33)

mix

ture

of

two

dias

tere

omer

s

770

Me

N N MeP

Ph Bn

Me

N N MeP

Ph Bn

N

1. L

DA

, TH

F, –

30°

2. t-

BuO

2CN

=N

CO

2Bu-

t, –3

0°, 5

min

(41)

, 52%

de

948

Me

N N MeP

Ph Bn

Me

N N MeP

Ph Bn

1. L

DA

, TH

F, –

30°

2. t-

BuO

2CN

=N

CO

2Bu-

t, –3

0°, 5

min

(46)

, 83%

de

948

R N OP

R2

R1

C2

1. L

DA

, TH

F, –

78°

2. t-

BuO

2CN

=N

CO

2Bu-

t, –7

8°, 3

0 m

in

R1

H Ph Ph

R2

Ph H H

R3

Me

Me

i-Pr

(55)

(58)

(65)

dr 2:1

1.5:

1

1:4

949

OO

OO

OO

OO

O

RR

PN

NH

CO

2Bu-

t

CO

2Bu-

t

t-B

uO2C

NH

CO

2Bu-

t

Nt-

BuO

2CN

HC

O2B

u-t

3R N O

P

R2

R1

O Nt-

BuO

2CN

HC

O2B

u-t

3

298

N OP

R2

R1

1. L

DA

, TH

F, –

78°

2. t-

BuO

2CN

=N

CO

2Bu-

t, –7

8°, 3

0 m

in

R1

H Ph Ph

R2

Ph H H

R3

R3

Me

Me

i-Pr

(50)

(54)

(62)

dr 1:1

1.5:

1

1:3

949

O

R N OP

R2

R1

O Nt-

BuO

2CN

HC

O2B

u-t

3

C2-

9

1. n

-BuL

i, he

xane

, cos

olve

nt,

–7

8°, 3

0 m

in

2. 2

,4,6

-(i-

Pr) 3

C6H

2SO

2N3,

–78

°, 5

h

3. A

c 2O

, –78

° to

rtR

1

H H H Me

H H Me

Me

R2

Bu-

t

Bu-

t

Bu-

t

Bu-

t

Bu-

t

CE

t 3Ph

CH

Me

(S)

isob

orny

l

R3

Me

Ph Ph Ph Bn

Ph Phc

Phd

(72)

(56-

79)

(75)

(70-

93)

(63)

(79)

(52)

(74)

dra

4:1

11:1

13:1

b

>20

:1

2:1

3:1

>20

:1

5.3:

1

317

N R2P

O

R1

R3

N R2P

O

R1

R3

NN

NSO

2C6H

2(Pr

-i) 3

-2,4

,6

Ac

OO

Cos

olve

nt

TH

F

TH

F

Et 2

O

TH

F

TH

F

TH

F

TH

F

TH

FC

3

PO

OE

t1.

LD

A, T

HF,

–78

°2.

2,4

,6-(

i-Pr

) 3C

6H4S

O2N

3, –

78°

Com

plex

mix

ture

895

C4-

13

R1

P(O

)(O

R3 ) 2

O

R2

R1

P(O

)(O

R3 ) 2

O R2

N

1. 1

(10

mol

%),

CH

2Cl 2

2. S

ubst

rate

,

th

en B

nO2C

N=

NC

O2B

n, r

t, tim

e

R1

Me

—

(CH

2)3—

—

(CH

2)4—

Ph Ph Bn

Ph 2-na

phth

yl

R2

Me

Me

Me

Me

CH

2CH

=C

H2

Me

R3

Et

Et

Et

Me

Et

Et

Et

Et

Tim

e

48 h

48 h

48 h

48 h

48 h

48 h

140

h

48 h

(75)

(98)

(98)

(97)

(85)

(60)

(85)

(93)

% e

e

85 95 94 94 92 95 98 92

468

NZ

n(O

Tf)

2

N

OO

PhPh

1

NH

CO

2Bn

CO

2Bn

299

Subs

trat

eR

efs.

Con

ditio

nsPr

oduc

t(s)

and

Yie

ld(s

) (%

)

TA

BL

E 1

8. P

HO

SPH

OR

US-

STA

BIL

IZE

D C

AR

BA

NIO

NS

(Con

tinu

ed)

C4-

6

1. n

-BuL

i, T

HF,

–78

°, 30

min

2. 2

,4,6

-(i-

Pr) 3

C6H

2SO

2N3,

–78

°, 1

h

n 1 1 2 2 3 3

R Et

i-Pr

Et

i-Pr

Et

i-Pr

(74)

(77)

(76)

(69)

(69)

(72)

773

C7

N MeP

Me

NPh

N MeP

Me

NPh

NH

CO

2Bu-

t

1. n

-BuL

i, T

HF,

–78

°2.

CuB

r•M

e 2S

3. T

sNO

(Li)

CO

2Bu-

t, T

HF,

–78

°(4

9), 5

2% d

e12

9

1. L

iN(E

t)2,

PhH

, rt,

1 h

2. P

hN3,

rt,

18 h

(26)

467

OO

NP(O

)(O

Pr-i

) 21.

n-B

uLi o

r L

DA

, TH

F, –

78°

2. E

tO2C

N=

NC

O2E

t

(35)

773

C4

P(O

)(O

R) 2

nn

P(O

)(O

R) 2

N3

N MeP

OPh

PhN M

ePO

Ph

Ph

N3

N MeP

OPh

Ph

N2

1. L

DA

, TH

F, –

78°,

30 m

in

2. 4

-O2N

C6H

4SO

2N3,

–78

°; to

rt

(—)

(19)

632

+

OO

O

N MeP

Me

N

Ph

O

N MeP

Me

N

Ph

O

N MeP

Me

N

Ph

O

N3

+(—

)(3

3)1.

n-B

uLi,

TH

F, –

78°,

30 m

in

2. 4

-O2N

C6H

4SO

2N3,

–78

°, 4

h

632

NH

CO

2Et

CO

2Et

P(O

)(O

Pr-i

) 2

PhP

PhPh

OPh

PPh

PhO

NN

NH

Ph

N2

300

1. K

HM

DS,

TH

F, –

78°,

30 m

in

2. 2

,4,6

-(i-

Pr) 3

C6H

2SO

2N3,

–78

°, 3

h

3. A

cOH

(34-

53),

dr

>20

:1a

317

N Bu-

t

PO

Ph

N Bu-

t

PO

PhN

3H

H

OO

R1

H Me

Me

R2

Bu-

t

Bu-

t

PhC

HM

e (S

)

(52-

70)

(52-

68)

(70)

dra

1.3:

1

>20

:1

2:1

317

1. n

-BuL

i, he

xane

, sol

vent

, –78

°, 30

min

2. 2

,4,6

-(i-

Pr) 3

C6H

2SO

2N3,

–78

°, 5

h

3. A

c 2O

, –78

° to

rt

R1

H Me

R2

H Me

(47-

60)

(56)

dra

3:1

>20

:1

317

ON

PPh

ON

PPh

t-B

u

N3

1. K

HM

DS,

TH

F, –

78°,

30 m

in

2. 2

,4,6

-(i-

Pr) 3

C6H

2SO

2N3,

–78

°, 3

h

3. A

cOH

(30)

, dr

>20

:1a

317

Solv

ent

TH

F

Et 2

O

N R2P

O

R1

1. K

HM

DS,

TH

F, –

78°,

30 m

in

2. 2

,4,6

-(i-

Pr) 3

C6H

2SO

2N3,

–78

°, 3

h

3. A

cOH

N Bu-

t

PO

R1

Ph

R2

H

PhN R

2PO

R1

Ph

N3

O

OO

O

N Bu-

t

PO

R1

Ph

R2

H

O

AcNN

NSO2C

6H2(

Pr-i

) 3-2

,4,6

1. n

-BuL

i, he

xane

, TH

F, –

78°,

30 m

in

2. 2

,4,6

-(i-

Pr) 3

C6H

2SO

2N3,

–78

°, 5

h

3. A

c 2O

, –78

° to

rt

ON

PPh

N(6

2), d

r 2.

5:1a

317

O

t-B

u

t-B

u

NN

SO2C

6H2(

Pr-i

) 3-2

,4,6

Ac

ON

P

Ph

ON

P

Ph

N

1. n

-BuL

i, he

xane

, TH

F, –

78°,

30 m

in

2. 2

,4,6

-(i-

Pr) 3

C6H

2SO

2N3,

–78

°, 5

h

3. A

c 2O

, –78

° to

rt

(81)

, dr

4.3:

1a31

7O

O

N

Ac

N

SO2C

6H2(

Pr-i

) 3-2

,4,6

t-B

u

t-B

u

301

Subs

trat

eR

efs.

Con

ditio

nsPr

oduc

t(s)

and

Yie

ld(s

) (%

)

TA

BL

E 1

8. P

HO

SPH

OR

US-

STA

BIL

IZE

D C

AR

BA

NIO

NS

(Con

tinu

ed)

Bu-

tN

P

R

PhB

u-t

NP

R

Ph

N1.

n-B

uLi,

hexa

ne, T

HF,

–78

°, 30

min

2. 2

,4,6

-(i-

Pr) 3

C6H

2SO

2N3,

–78

°, 5

h

3. A

c 2O

, –78

° to

rt

R H Me

(70)

(85)

dra

6:1

9:1

317

HO

HO

OO

NA

cN

SO2C

6H2(

Pr-i

) 3-2

,4,6

C7

N Pr-iP

Pr-i

NPh Ph

PhN Pr

-iP

Pr-i

NPh Ph

Ph

N3

1. n

-BuL

i, he

xane

, TH

F, –

78°,

30 m

in

2. 2

,4,6

-(i-

Pr) 3

C6H

2SO

2N3,

–78

°, 3

h

3. H

2O

(100

)e , dr

2:1a

317

C9

O

P(O

)(O

R) 2

O

N(C

O2E

t)N

HC

O2E

t

P(O

)(O

R) 2

H OPd

O H

PdP P

P P=

P(C

6H3M

e 2-3

,5) 2

P(C

6H3M

e 2-3

,5) 2

EtO

2CN

=N

CO

2Et,

2 (2

.5 m

ol%

),

Me 2

CO

, rt

R Me

Et

i-Pr

Tim

e

35 h

20 h

60 h

(81)

(92)

(68)

% e

e

99 99 99

238

2+

OO

2

P P

2 B

F 4–

a The

val

ues

are

for

the

dias

tere

omer

ic r

atio

s in

the

crud

e pr

oduc

ts.

b Cle

avag

e of

the

prod

uct f

ollo

wed

by

hydr

olys

is g

ave

(S)-

phos

phon

o gl

ycin

e.c T

he c

onfi

gura

tion

on p

hosp

horu

s w

as n

ot e

stab

lishe

d.d T

he s

ubst

rate

was

a m

ixtu

re o

f ci

s an

d tr

ans

isom

ers.

e The

rep

orte

d yi

eld

is th

at o

f cr

ude

prod

uct.

302

Subs

trat

eR

efs.

Con

ditio

nsPr

oduc

t(s)

and

Yie

ld(s

) (%

)

TA

BL

E 1

9. E

NO

LA

TE

S O

F α,

β-U

NSA

TU

RA

TE

D C

AR

BO

NY

L C

OM

POU

ND

S

C4-

10

R3

CO

2H

R2

R1

R3

CO

2H

R2

R1

NH

2

1. L

iNE

t 2 (

2.2

eq,a ia

),

T

HF,

–70

°; 0

°, 15

min

2. P

h 2P(

O)O

NH

2, –

70°,

25 m

in; r

t, 2

h

R1

H Me

Me

H H

R2

H H H t-B

u

Ph

R3

H H Me

H H

(14)

(45)

(64)

(28)

(45)

144

1. L

iNE

t 2 (

2.2

eq,a ia

),

T

HF,

–70

°, 30

min

2. E

tO2C

N=

NC

O2E

t, –7

0°, 1

5 m

in

R3

CO

2H

R2

R1

N

R3

CO

2H

R2

R1

NN

HC

O2E

tI

R1

H Me

H H Me

H H

R2

H H Me

H H H Ph

R3

H H H Me

Me

Et

H

I

(69)

(65)

(68)

(51)

(50)

(62)

(74)

II

II

(0)

(3)

(0)

(0)

(0)

(0)

(0)

144

C4-

11

CO

2R3

R1

R2

CO

2R3

I

R1

R2

N

CO

2R3

II

R1

R2

N1.

LD

A, T

HF,

add

end,

–78

°, 70

min

2. E

tO2C

N=

NC

O2E

t, –7

8°‚

3 m

in

3. M

eOH

, –78

°; to

rt

469,

950

R1

H H H H Bn

R3

Me

Et

Et

Et

Me

R2

H Me

Me

Me

H

Add

end

HM

PA

HM

PA

— ZnC

l 2b

HM

PA

I

(64)

(63)

(71)

(61)

(71)

I E

:Z

>99

:1

2:1

1:1

1:1

>99

:1

II (0)

(12)

(7)

(25)

(0)

EtO

2CN

HC

O2E

t

NH

CO

2Et

EtO

2CE

tO2C

NH

CO

2Et

EtO

2C

+ +

303

Subs

trat

eR

efs.

Con

ditio

nsPr

oduc

t(s)

and

Yie

ld(s

) (%

)

TA

BL

E 1

9. E

NO

LA

TE

S O

F α,

β-U

NSA

TU

RA

TE

D C

AR

BO

NY

L C

OM

POU

ND

S (C

onti

nued

)

OM

e

OT

MS

CO

2Me

NNH

CO

2Et

CO

2Me

N(6

8)(1

7)

1. E

tO2C

N=

NC

O2E

t, T

iCl 4

,

C

H2C

l 2, –

78°

2. S

ubst

rate

, –78

°, 30

min

469,

950

C4-

5

RC

O2E

t c

Cl 3

Sn

CO

2Et

E

R1.

EtO

2CN

=N

CO

2Et,

TH

F,

–

10°,

time;

to –

78°

2. M

eOH

, –78

° to

rt

RC

O2E

t

E

R H Me

II (5)

(3)

Tim

e

30 m

in

100

min

I

(53)

(26)

E =

N(C

O2E

t)N

HC

O2E

t

469

III

C5

CO

2Et

Bu 3

Sn

CO

2Et

CO

2Et

NN

(75)

(5)

469,

950

R1

CO

2R3

GeM

e 3 d

R2

1. E

tO2C

N=

NC

O2E

t, Z

nCl 2

,

C

H2C

l 2, –

78°

2. S

ubst

rate

, –78

° to

tem

p, ti

me

R1

CO

2R3

R2

N

469

R1

H —(C

H2)

3—

—(C

H2)

4—R2

Me

R3

Et

Et

Me

Tem

p

rt 5° 0°

(71)

(88)

(55)

E:Z

3:1

8:1

6:1

1. E

tO2C

N=

NC

O2E

t, Z

nCl 2

,

C

H2C

l 2, –

78°

2. S

ubst

rate

, –78

° to

0°, 4

0 m

in

NO

OO

Bn

1. L

DA

, TH

F, –

78°,

30 m

in

2. A

dden

d

3. t-

BuO

2CN

=N

CO

2Bu-

t, –7

8°, 1

h

NO

OO

Bn

E

NO

OO

Bn

E+

I

Add

end

— HM

PA (

1 eq

)

HM

PA (

5 eq

)

I

I

(51)

(61)

(52)

II

II

(33)

(21)

(11)

E =

N(C

O2B

u-t)

NH

CO

2Bu-

t

895

C4

Tim

e

2 h

40 m

in

30 m

in

+

+

+

EtO

2CN

HC

O2E

tE

tO2C

EtO

2CN

HC

O2E

t

NH

CO

2Et

CO

2Et

EtO

2CN

HC

O2E

t

304

ON

O Bn

O

ON

O Bn

O

EO

N

O Bn

OE

+

1. L

DA

, TH

F, –

78°,

30 m

in

2. t-

BuO

2CN

=N

CO

2Bu-

t, C

H2C

l 2, –

78°‚

30

-180

s

431

E =

N(C

O2B

u-t)

NH

CO

2Bu-

t(5

1), >

96%

de

(42)

, E:Z

= 3

:2

1. N

aH, E

t 2O

, 0°,

3 h

2. C

lNH

2, –

78°;

to 0

°

C6

CO

2Et

CO

2Et

EtO

2C2

(74)

+

(1.5

)64

C5-

11

RC

HO

RC

HO

NE

tO2C

NH

CO

2Et

1.

(10

mol

%),

s

olve

nt, r

t, 15

min

2. E

tO2C

N=

NC

O2E

t, tim

e

Ar

= 3

,5-(

CF 3

) 2C

6H3

N H

OT

MS

Ar

Ar

R Me

Me

Et

MeS

CH

2

n-Pr

i-Pr

CH

2CH

=C

HE

t

n-C

6H13

Bn

% e

e

97 89 89 88 88 89 89 88 93

(46)

(56)

(58)

(43)

(56)

(40)

(54)

(49)

(52)

Tim

e

— 3 h

6 h

1.5

h

5 h

56 h

4.5

h

8 h

4 h

Solv

ent

CH

2Cl 2

tolu

ene

tolu

ene

tolu

ene

tolu

ene

tolu

ene

tolu

ene

tolu

ene

tolu

ene

470

CO

2H1.

LiN

Et 2

(2.

2 eq

,a ia),

TH

F, –

70°;

0°

, 15

min

2. P

h 2P(

O)O

NH

2, –

70°,

25 m

in; r

t, 2

h

CO

2H

NH

2

(50)

144

1. L

iNE

t 2 (

ia),

TH

F, –

70°,

30 m

in

2. E

tO2C

N=

NC

O2E

t, –7

0°, 1

5 m

inC

O2H

(81)

144

NE

tO2C

NH

CO

2Et

EtO

2CN

H2

EtO

2CC

O2E

t

EtO

2CN

H

EtO

2CC

O2E

t

305

Subs

trat

eR

efs.

Con

ditio

nsPr

oduc

t(s)

and

Yie

ld(s

) (%

)

TA

BL

E 1

9. E

NO

LA

TE

S O

F α,

β-U

NSA

TU

RA

TE

D C

AR

BO

NY

L C

OM

POU

ND

S (C

onti

nued

)

CO

2Rn

CO

2Rn

CO

2Rn

1. L

DA

, HM

PA, T

HF,

–78

°, 70

min

2. E

tO2C

N=

NC

O2E

t, –7

8°, 3

min

3. M

eOH

, –78

°

EE

III

R Et

Me

Me

n 1 2 2E

= N

(CO

2Et)

NH

CO

2Et

I

(65)

(14)

(13)

E:Z 1:2

1:1.

5

10:1

II (22)

(55)

(38)

e

469

C7-

8

NOO

O Bn

NOO

O Bn

E1.

LiH

MD

S, T

HF,

78°

2. t-

BuO

2CN

=N

CO

2Bu-

t

(0)

453

E =

N(C

O2B

u-t)

NH

CO

2Bu-

t

C8

OT

MS

O

NH

CO

CF 3

(50)

471

RR

R =

NH

Ac

(Sal

tmen

)Mn(

N),

CH

2Cl 2

, pyr

idin

e,

TFF

A, –

78° t

o rt

, 3-4

h

C8-

10

ClN

H2,

2,6

-(R

1 ) 2-4

-R2 C

6H2O

H,

100

-140

°; r

t, ov

erni

ght

R1

Me

Me

Et

R2

H Me

H

(55)

(51)

(33)

65

Na+

O

R1

R1

R2

NH

OR

1

R2

R1

+

a T

his

is a

cor

rect

ed v

alue

; per

sona

l com

mun

icat

ion

from

R. M

estr

es, D

epar

tmen

t of

Che

mis

try,

Uni

vers

ity o

f V

alen

cia,

Spa

in, 2

006.

b

The

ZnC

l 2 w

as a

dded

aft

er th

e fo

rmat

ion

of th

e lit

hium

die

nola

te.

c The

sub

stra

te w

as g

ener

ated

in s

itu f

rom

the

lithi

um d

ieno

late

and

SnC

l 4.

d The

sub

stra

te w

as g

ener

ated

in s

itu f

rom

the

lithi

um d

ieno

late

and

ClG

eMe 3

.e P

roto

natio

n w

as c

arri

ed o

ut a

t 0°.

f The

inte

rmed

iate

for

med

upo

n am

inat

ion

of th

e en

olat

e un

derg

oes

subs

eque

nt r

ing

expa

nsio

n to

giv

e th

e pr

oduc

t sho

wn.

f

306

Subs

trat

eR

efs.

Con

ditio

nsPr

oduc

t(s)

and

Yie

ld(s

) (%

)

TA

BL

E 2

0. E

NO

LA

TE

S O

F α−

CY

AN

O C

AR

BO

NY

L A

ND

β−D

ICA

RB

ON

YL

CO

MPO

UN

DS

C3-

10

ClN

H2

(ia)

, Et 2

O, m

orph

olin

e, 0

°, 2

h;

rt,

over

nigh

t; re

flux

, 5 h

62

R H Me

Et

i-Pr

s-B

u

Ph Bn

(92)

(85)

(89)

(71)

(83)

(70)

(72)

1. N

aH, T

HF,

rt,

25 m

in

2. 2

,4-(

O2N

) 2C

6H3O

NH

2, r

t, ov

erni

ght

3. 6

N H

Cl,

refl

ux

4. E

t 3N

R Me

Et

Et 2

OC

CH

2

n-B

u

Bn

(98)

(74)

(61)

(46-

57)

(73)

93

1. N

aH, T

HF,

rt,

25 m

in

2. 2

,4-(

O2N

) 2C

6H3O

NH

2, r

t, ov

erni

ght

C3-

10

C3-

9R H M

e

Ph

(55)

a

(31)

b

(65)

93

C3-

9

1. N

aH, T

HF,

rt,

15 m

in

2. R

eage

nt, r

t, ov

erni

ght

R H H H Ph Ph Ph

Rea

gent

Ph2P

(O)O

NH

2

(4-M

eOC

6H4)

2P(O

)ON

H2

4-O

2NC

6H4C

O2N

H2

Ph2P

(O)O

NH

2

(4-M

eOC

6H4)

2P(O

)ON

H2

4-O

2NC

6H4C

O2N

H2

(57)

b

(41)

(52)

(31)

b

(92)

(99)

106

RC

O2E

t

CO

2Et

RC

O2E

t

CO

2Et

RC

O2E

t

CO

2Et

R

CO

2Et

EtO

2C

NH

2

R

CO

2Et

EtO

2C

NH

2

RN

H2

CO

2H

CO

2Et

CO

2Et

RN

a+

–

R

CO

2Et

EtO

2C

NH

2

307

Subs

trat

eR

efs.

Con

ditio

nsPr

oduc

t(s)

and

Yie

ld(s

) (%

)

TA

BL

E 2

0. E

NO

LA

TE

S O

F α−

CY

AN

O C

AR

BO

NY

L A

ND

β−D

ICA

RB

ON

YL

CO

MPO

UN

DS

(Con

tinu

ed)

C3

NH

HN

Y

OO

NH

HN

Y

OO

NH

2

150

Y O S

(78)

(82)

NH

HN

O

OO

HN

HN

N

NH

NH

O O

O

OO

O– N

H4+

(88)

149

NH

HN

OO

HN

HN

N

O O

(79)

149

NC

NR

1 R2

O

NR

1 R2

O

NH

2

NH

O

, NaO

H, t

olue

ne

NH

O

, tol

uene

, H2O

, N

H4O

H, r

t, 30

min

NH

O

, tol

uene

, DA

BC

O, r

t, 12

h

NH

O

, tol

uene

, NaO

H, H

2O, 0

°, 10

min

O

H2N

NR

1 R2

OO

H2N

H2N

NH

2I

R1

H Me

H

—(C

H2)

4—

—(C

H2)

2O(C

H2)

2—

—(C

H2)

5—

H

R2

Me

Me

n-Pr

Bn

I

I

(62)

(81)

(18)

(59)

(56)

(61)

(17)

II

II

III(0

)

(0)

(0)

(0)

(0)

(0)

(74)

149

+

NH

R

O

NH

O

NH

R

OO

RH

N H2N

NH

2

149

O

RH

NN

HR

OO

RH

N

NH I

1.(2

eq)

, tol

uene

, DA

BC

O, r

t, 12

h (

form

s I)

2.E

tOH

, ref

lux,

15

min

; rt,

12 h

(fo

rms

II)

308

R n-Pr

Ph 3-C

lC6H

4

4-B

rC6H

4

2-E

tO2C

C6H

4

Bn

n-C

8H17

I

(47)

(91)

(73)

(52)

(93)

(83)

(39)

II (—)

(96)

(—)

(73)

(90)

(—)

(—)

I

NC

O2E

t

R2

NC

O2E

t

R2

ON

H

151

C3-

9

1. L

iHM

DS

(ia)

, TH

F, –

78°,

30 m

in

2.

,

78°,

20 h

; to

rt

R1

EtO

Me

EtO

EtO

EtO

R2

H H Me

Bu

Ph

I +

II

(50)

(43)

(20)

(14)

(0)

Tim

e

6 h

48 h

56 h

49 h

60 h

NC

O2B

u-t

EtO

2CR

1

H H Ph

R2

Et

Bu-

t

Et

(33)

(20)

(50)

155

1. L

iHM

DS

(1.1

eq,

ia),

TH

F, –

78°,

1 h

2.

, –

78° t

o rt

, 2 h

; rt,

time

OE

tO2C

R1

CO

2Et

R2

O

NC

CO

2R2

R1

C3-

4

NC

O2E

t

R

NC

O2E

t

R

ON

H1.

NaO

Et (

2.9

eq),

, E

tOH

, rt

2. S

ubst

rate

, rt,

time

R H Me

Tim

e

3 h

4 h

I

I

(—)

(45)

II (—)

(45)

151

EtO

2CC

O2E

t

R

NC

NH

CO

2Bu-

t

R1

CO

2R2

+ +

I +

II

II

III(6

8)

(—)

309

Subs

trat

eR

efs.

Con

ditio

nsPr

oduc

t(s)

and

Yie

ld(s

) (%

)

TA

BL

E 2

0. E

NO

LA

TE

S O

F α−

CY

AN

O C

AR

BO

NY

L A

ND

β−D

ICA

RB

ON

YL

CO

MPO

UN

DS

(Con

tinu

ed)

NO

Ts

NC

NC

, pyr

idin

e, E

t 2O

NC

NC

N

CN

CO

R

PyH

+R N

H2

OM

e

OE

t

Tem

p

refl

ux

— —

(45)

(51)

(46)

838

C3

NC

CO

R

Tim

e

10 h

— —C

3-4

1. N

a ba

se

2. P

hNH

N=

C(C

O2E

t)2

PhN

HN

CO

2Et

R

CH

(CO

2Et)

2

159

RC

O2E

t

C3-

5

1. N

a ba

se

2. R

3 N=

NC

O2E

t

R1

NC

NC

Ac

Ac

R2

EtO

EtO

EtO

Me

159

R2 O

2CN

=N

CO

2R2 , K

OA

c

R1

NC

EtO

2C

EtO

2C

R2

Et

Me

Et

Tem

p

60°

rt rt

(25)

(>90

)

(80-

90)

478

C3

R3

EtO

2C

Ph Ph Ph

R1

CO

R2

R1

CO

R2

NR

3N

HC

O2E

t

R1

CO

2Et

N NH

HNN

R2 O

2CC

O2R

2

R1

CO

2Et

R2 O

2CC

O2R

2

R =

CN

, CO

2Et,

Ac

(—)

("ve

ry p

oor"

)

R1

R1

YY

R1

R1

YY

N

1. n

-BuL

i (ia

), T

HF,

–70

°, 20

min

2. R

2 CO

N=

NC

OR

2 , –78

°; to

rt

R1

MeO

MeO

MeO

MeO

MeO

Me 2

N

Me 2

N

Me 2

N

Me 2

N

Me 2

N

Y O O O S S O O O O S

R2

EtO

i-Pr

O

t-B

uO

EtO

t-B

uO

EtO

i-Pr

O

t-B

uO

N-m

orph

olin

yl

t-B

uO

(88)

(83)

(80)

(62)

(54)

(85)

(76)

(82)

(76)

(57)

b

477

R2 O

CN

HC

OR

2

310

Me 2

NN

Me 2

SS

Me 2

NN

Me 2

SS

1. L

DA

, TH

F, –

70°,

1 h

2. E

tO2C

N=

NC

O2E

t, –7

8°; t

o rt

, 2 h

NC

O2E

t

(52)

477

R2

EtO

EtO

NE

t 2

Me

Tem

p

rt rt rt 50°

Tim

e

2 h

2 h

17 h

1 h

EtO

2CN

=N

CO

2Et,

Ni(

acac

) 2, C

H2C

l 2R

1R

2

O

N47

9

R1

EtO

Me

Me

Me

(71)

(87)

(95)

(78)

R1

R2

OO

C3-

5

R MeO

EtO

Me

(34)

(30)

(28)

C3

O

RN

3

R

R

R =

BnO

, KO

H, D

MF,

H2O

, rt

O

RN

R

RN N

CO

NH

2

NH

2

O

R

R

R

NN

NC

ON

H2

NH

2+

(5)

O

R

R

R

R =

BnO

, KO

H, D

MF,

H2O

, rt

N3

I (

85)

276

276

C4-

5

1. H

2NSO

3H, K

2CO

3, H

2O, r

t, ov

erni

ght

2. A

cCH

2CO

RN H

CO

R

RC

O47

3

C4-

9

1. L

i bas

e

2. M

e 2N

OSO

2Me,

Et 2

O o

r T

HF,

–30

° to

0°

R Me

Ph

(50)

(52)

134

NC

CO

NH

2

Ac

CO

R

RC

O2E

t

CO

2Et

EtO

2CN

HC

O2E

t

I

(72)

RN

Me 2

EtO

2CC

O2E

t

C4-

5

N

S O2

OO

R

N

S O2

OO

4-O

2NC

6H4S

O2O

NH

CO

2Et,

CaO

,

CH

2Cl 2

, rt,

6 h

RN

HC

O2E

t

124

R H Me

(54)

(0)

% d

e

40 —

O

c

311

Subs

trat

eR

efs.

Con

ditio

nsPr

oduc

t(s)

and

Yie

ld(s

) (%

)

TA

BL

E 2

0. E

NO

LA

TE

S O

F α−

CY

AN

O C

AR

BO

NY

L A

ND

β−D

ICA

RB

ON

YL

CO

MPO

UN

DS

(Con

tinu

ed)

C4-

7

4-O

2NC

6H4S

O2O

NH

CO

2Et (

y eq

), C

aO (

z eq

),

CH

2Cl 2

, rt

124

R H H Me

i-Pr

x — 5 5 1

y — 1 1 3

z 3 2 1 6d

III

III

I (2)

(58)

(58)

(28)

II (41)

(8)

(0)

(0)

III

(0)

(0)

(4)

(5)

Tim

e

3 h

— 1 h

5 h

C4-

6

N

CO

2Et

R1

R2

R1

R2

NH

CO

2Et

CO

2Et

O

4-O

2NC

6H4S

O2O

NH

CO

2Et,

CH

2Cl 2

, rt

R1

H H CH

2OM

e

R2

H Me

H

Tim

e

45 h

2 h

2 h

(40)

(33)

(36)

% d

e

—

— (

R)

80 (

S)

125

C4-

10

R1

CO

2R2

CN

SO2N

(C6H

11-c

) 2

OR

2 =

1. L

iHM

DS,

TH

F, h

exan

e, –

78°,

1 h

2. P

h 2P(

O)O

NH

2, –

78°;

rt,

12 h

CN

H2N

CO

2R2

R1

R1

Me

n-Pr

i-Pr

i-B

u

Bn

(87)

(84)

(78)

(84)

(91)

% d

e

56 52 40 44 60

475

NN B

nO

HO

C4

NN B

nO

HO

NH

2

NN B

nO

HO

NH

N

(90)

+(4

)14

9O

H N, t

olue

ne, N

aOH

, H2O

, 0°,

10 m

in

RO

2CC

O2R

RO

2CC

O2R

NH

CO

2Bu-

t1.

LiH

MD

S (i

a), T

HF,

–78

°, 30

min

2.

,

–78°

, 20

h; to

rt

ON

CO

2Bu-

tE

tO2C

EtO

2C

R Me

Et

(30)

(22)

155

Ac

CO

2Et

R

Ac

CO

2Et

R

NH

CO

2Et

EtO

2CH

N

CO

2Et

Ac

NH

CO

2Et

Ac

CO

2Et

R

NC

O2E

t

NH

CO

2Et

++

x eq

312

N

OH

N

OH

Et

EtO

2CC

O2P

ht-

BuO

2CN

=N

CO

2Bu-

t, 1

(5 m

ol%

),

tol

uene

, rt,

16 h

EtO

2CC

O2P

h

N(C

O2B

u-t)

NH

CO

2Bu-

t(9

9), 9

0% e

e (R

)48

1

C4

C4-

6

R3

O

R1

O

R2

R3

O

R1

O

N

Ar Ar

NH

NH

2

t-B

uO2C

N=

NC

O2B

u-t,

2 (

2 m

ol%

), T

HF,

–60

°

2

Bu-

t

Bu-

t

951

R1

H Me

Me

Me

Et

R2

Me

Me

Me

Et

Me

R3

OB

u-t

OE

t

OB

u-t

OB

u-t

OB

u-t

Tim

e

0.5

h

0.5

h

3 h

24 h

24 h

(99)

(99)

(>99

)

(54)

(90)

% e

e

83

85 (

S)

88 62 86

R2

NC

O2B

u-t

NH

CO

2Bu-

t

Ar

=

1

313

Subs

trat

eR

efs.

Con

ditio

nsPr

oduc

t(s)

and

Yie

ld(s

) (%

)

TA

BL

E 2

0. E

NO

LA

TE

S O

F α−

CY

AN

O C

AR

BO

NY

L A

ND

β−D

ICA

RB

ON

YL

CO

MPO

UN

DS

(Con

tinu

ed)

R2

OO

R1

R2

OO

R2

OO

ER

1R

1E

+

E =

N(C

O2R

3 )NH

CO

2R3

R3 O

2CN

=N

CO

2R3 , c

atal

yst (

10 m

ol%

),

ClC

H2C

H2C

l89

6

R1

H H H H H H Me

Me

Me

NO

Bn

O

R2

Y Y Y Y Y Y Me

OE

t

Y

R3

Et

Et

Bn

Bn

Bn

Bn

Et

Et

Et

Cat

alys

t

A B A B B B B B B

Tem

p

rt rt 0° rt 0° 50°

50°

50°

50°

Tim

e

18 h

12 h

4 d

17 h

72 h

17 h

20 h

23 h

—

I +

II

(94)

(97)

(100

)

(100

)

(100

)

(100

)

(96)

(73)

(0)

I:II

73:2

7

74:2

6

89:1

1

70:3

0

69:3

1

63:2

7

— — —

Y =

ON

iO

OO

ON

iO

OO

Cat

alys

t A

III

Cat

alys

t B

C4-

6

C4-

13

NC

CO

2Bu-

t

R1

NC

CO

2Bu-

t

R1

N48

1

N

OH

N

OH

Et

R2 O

2CN

=N

CO

2R2 , 1

(5

mol

%),

tolu

ene

1

NH

CO

2R2

R2 O

2C

314

R1

Me

i-B

u

2-th

ieny

l

Ph Ph Ph Ph Ph 2-FC

6H4

4-C

lC6H

4

4-O

2NC

6H4

4-M

eOC

6H4

3-M

eC6H

4

2-na

phth

yl

R2

t-B

u

t-B

u

t-B

u

Et

Cl 3

CC

H2

t-B

u

t-B

u

Bn

t-B

u

t-B

u

t-B

u

t-B

u

t-B

u

t-B

u

Tem

p

— — –78°

–78°

–78°

–78° rt

–78°

–50°

–78°

–50°

–78°

–78°

–78°

Tim

e

— —

16-2

0 h

30 s

30 s

4 h

45 m

in

30 s

16-2

0 h

16-2

0 h

16-2

0 h

16-2

0 h

16-2

0 h

16-2

0 h

("ex

celle

nt")

("ex

celle

nt")

(99)

(>95

)

(>95

)

(>95

)

(>95

)

(>95

)

(99)

(99)

(99)

(95)

(99)

(99)

% e

e

("lo

wer

")

("lo

wer

")

97 84 7 >98 90 64 98

98 (

S)

91 89 97 98C

4

BnO

2CN

=N

CO

2Bn,

cat

alys

t (10

mol

%),

tol

uene

, –78

°, 30

min N

NOH

BnO

N

OB

n

NOH

Cat

alys

t AC

atal

yst B

NC

CO

2Et

NC

CO

2Et

NC

atal

yst

A B

(75)

(74)

% e

e

35 23

232

NH

CO

2Bn

BnO

2C

315

Subs

trat

eR

efs.

Con

ditio

nsPr

oduc

t(s)

and

Yie

ld(s

) (%

)

TA

BL

E 2

0. E

NO

LA

TE

S O

F α−

CY

AN

O C

AR

BO

NY

L A

ND

β−D

ICA

RB

ON

YL

CO

MPO

UN

DS

(Con

tinu

ed)

C4-

9

R1 C

OC

OR

2

F

R1 C

OC

OR

2

FN

1.

[S

,S (

A)

or R

,R (

B),

5 m

ol%

],N

OO

N

PhPh

237

R1

Me

Me

Me

Me

Me

Me

Me

Me

Me

Me

Me

Me

Me

t-B

u

t-B

u

Ph Ph

R2

OM

e

OM

e

OM

e

OE

t

OE

t

OE

t

OE

t

OE

t

OE

t

(2S,

3R)-

men

thyl

oxy

(2S,

3R)-

men

thyl

oxy

(2S,

3R)-

men

thyl

oxy

NPh

2

OE

t

OE

t

OE

t

OE

t

R3

Et

Et

Bn

Et

Et

Et

Et

Bn

Bn

Bn

Bn

Bn

Bn

Et

Bn

Et

Bn

Solv

ent

CH

2Cl 2

hexa

ne

CH

2Cl 2

CH

2Cl 2

hexa

ne

tolu

ene

MeC

N

CH

2Cl 2

hexa

ne

CH

2Cl 2

CH

2Cl 2

CH

2Cl 2

CH

2Cl 2

CH

2Cl 2

CH

2Cl 2

CH

2Cl 2

CH

2Cl 2

(94)

(90)

(95)

(90)

(84)

(95)

(82)

(73)

(—)

(31)

(75)

(95)

(88)

(84)

(84)

(85)

(78)

% e

e or

dr

94 86 92 93 90 85 20 91 88

43:5

7

87.5

:12.

5

1.5:

98.5

92 93 93 87 81

Cat

alys

t or

Add

end

A A A A A A A A A

TM

ED

A

A B A A A A A

CO

2Et

NH

2N

NH

2CO

2Et

RO

2CN

=N

CO

2R, s

olve

nt23

0

R Me

Et

(—)

(96)

e

Solv

ent

Et 2

O

MeO

H

C4

NH

CO

2R3

CO

2R3

C

u(O

Tf)

2 (5

mol

%),

sol

vent

, rt,

3 h

2. S

ubst

rate

and

R3 O

2CN

=N

CO

2R3 , r

t, 2

d

CO

2R

NH

CO

2R

316

C4

N

S O2

OO

N

S O2

OO

N

S O2

OO

HE

HE

BnO

2CN

=N

CO

2Bn,

cat

alys

t (0.

06 e

q), M

eCN

,

ref

lux,

24

h

+

I m

ajor

pro

duct

II

476

Cat

alys

t

RuH

2(PP

h 3) 4

RuC

l 2(P

Ph3)

3

PPh 3

I +

II

(100

)

(100

)

(86)

% d

e

81 79 22

C5-

7

R1

R2

OO

R1

R2

OO

NH

2

1. H

2NSO

3H, N

aOH

, H2O

, rt,

few

min

utes

(f

orm

s I)

2. R

1 C(O

)CH

2C(O

)R2 (

form

s II

)

472

x eq

N H

R2 O

C

CO

R2

R1

R1

III

I

(100

)

(—)

(—)

(—)

(—)

II (0)

(—)

(—)

(30)

(47)

OO

R

C5-

6

OO

RN

1.

(

cat)

, tol

uene

, BrC

8F17

, 60°

2.E

tO2C

N=

NC

O2E

t, re

flux

, 3 d

480

R H Me

(96)

(40)

f

E =

N(C

O2B

n)N

HC

O2B

n

R1

Me

Me

Et

Me

Me

R2

Me

Me

Et

OE

t

NH

Ph

x 1 2 2 2 2

Ar

= 4

- (n-

C10

F 21)

C6H

4

NN

i/ 2O

Ar

NH

CO

2Et

CO

2Et

317

Subs

trat

eR

efs.

Con

ditio

nsPr

oduc

t(s)

and

Yie

ld(s

) (%

)

TA

BL

E 2

0. E

NO

LA

TE

S O

F α−

CY

AN

O C

AR

BO

NY

L A

ND

β−D

ICA

RB

ON

YL

CO

MPO

UN

DS

(Con

tinu

ed)

C5-

15

R1

R2

OO

R1

R2

OO

N

R3 N

HC

ON

=N

CO

2R4 , Z

nCl 2

, CH

2Cl 2

(fo

rms

I, th

en I

I)N N

HC

O2R

4

NR

3

O

R1

R2 C

OI

952

R1

Me

Me

Me

Me

Me

Me

Me

Me

Ph Ph Ph Ph Ph Ph Ph

R2

Me

Me

Me

OE

t

Ph Ph Ph Ph OE

t

OE

t

OE

t

Ph Ph Ph Ph

R3

Cl(

CH

2)2

c-C

6H11

4-M

eOC

6H4

Cl(

CH

2)2

Cl(

CH

2)2

Ph 2,4-

F 2C

6H3

4-FC

6H4

Cl(

CH

2)2

4-FC

6H4

c-C

6H11

Cl(

CH

2)2

c-C

6H11

2,4-

F 2C

6H3

3-C

lC6H

4

R4

Me

Me

Me

Me

Me

Et

Et

Et

Me

Et

Me

Me

Me

Et

Et

Tem

p

rt rt 0° rt rt 0° 0° 0° rt 0° rt rt rt 0° 0°

Tim

e

4 h

4 h

5 h

4 h

23 h

2.5

h

5 h

2 h

3 h

2 h

2 h

10 h

4 h

5 h

2 h

I

I

>73

>86

(—)

(—)

(—)

(—)

(—)

(—)

(—)

(—)

(>92

)

(—)

(>90

)

(—)

(—)

II

II

(—)

(—)

(47)

(69)

(68)

(77)

(90)

(86)

(65)

(88)

(—)

(93)

(—)

(57)

(72)

CO

2Et

OC

5

CO

2Et

ON

(57)

, 95%

ee

(R)

239

OH

2Pd

NC

Me

P P=

PPh 2

PPh 2

2+

3

P P

2 PF

6–

BnO

2CN

=N

CO

2Bn,

3 (

5 m

ol%

),

MeO

H, r

t, 62

h

NH

CO

2R4

R3 H

NO

C

NH

CO

2Bn

CO

2Bn

318

CO

2Et

O

Ar

N HN H

S

NM

e 2

tol

uene

, rt,

"slo

w"

(10

mol

%),

t-B

uO2C

N=

NC

O2B

u-t,

N(7

6) 1

5% e

e23

3C

O2E

t

O

C5

R1

CO

2R3

O

R2

C5-

11

R1

N

O R2

CO

2R3

1.

(S,

S) (

x m

ol%

),N

OO

N

PhPh

235

R1

Me

Me

Me

—(C

H2)

3—

—(C

H2)

3—

Et

—(C

H2)

4—

Me

i-Pr

i-Pr

—(C

H2)

5—

Ph Ph Bn

Bn

R2

Me

Me

Me

Me

CH

2CH

=C

H2

Me

Me

Me

Me

Me

Me

R3

Et

Et

t-B

u

Et

Et

Et

Et

t-B

u

t-B

u

t-B

u

Et

Et

Et

t-B

u

t-B

u

x 0.2

10 10 0.5

10 0.5

0.5

0.5

0.5

10 0.5

0.5

10 0.5

10

(91)

(98)

(86)

(96)

(98)

(98)

(96)

(80)

(89)

(96)

(70)

(81)

(85)

(79)

(84)

% e

e

96 98 98 99 99 98 99 98 98 98 99 87 95 98 98

Ar

= 3

,5-(

CF 3

) 2C

6H3

t-B

uO2C

NH

CO

2Bu-

t

NH

CO

2Bn

CO

2Bn

C

u(O

Tf)

2, C

H2C

l 2

2. S

ubst

rate

, the

n B

nO2C

N=

NC

O2B

n, r

t, 16

h

319

Subs

trat

eR

efs.

Con

ditio

nsPr

oduc

t(s)

and

Yie

ld(s

) (%

)

TA

BL

E 2

0. E

NO

LA

TE

S O

F α−

CY

AN

O C

AR

BO

NY

L A

ND

β−D

ICA

RB

ON

YL

CO

MPO

UN

DS

(Con

tinu

ed)

O

OO

O

OO

OO

OO

O

OO

O

EO

OO

E

+

I m

ajor

isom

erII

E =

N(C

O2R

)NH

CO

2R

RO

2CN

=N

CO

2R, c

atal

yst (

x eq

),

MeC

N, r

t, 24

h

R Et

Et

Et

i-Pr

t-B

u

t-B

u

Bn

Bn

Bn

Cat

alys

t

RuC

l 2(P

Ph3)

3

RuH

2(PP

h 3) 4

PPh 3

RuH

2(PP

h 3) 4

RuC

l 3(P

Ph3)

3

RuH

2(PP

h 3) 4

RuC

l 2(P

Ph3)

3

RuH

2(PP

h 3) 4

PPh 3

x

0.03

0.03

0.09

0.03

0.09

0.09

0.03

0.03

0.09

I +

II

(92)

(72)

(83)

(69)

(75)

(55)

(98)

(64)

(65)

% d

e

13 33 48 40 0 19 5 34 0

476

C5

CO

2Et

EtO

2C

CO

2Et

C6

1. N

aH, E

t 2O

, 0°,

3 h

2. N

H2C

l, –7

8°; t

o 0°

(74)

+

(1.5

)

CO

2Et

EtO

2C

CO

2Et

1. N

aH, E

t 2O

, 0°,

3 h

2. N

H2C

l, –7

8°; t

o 0°

64(—

)

64

CO

2Et

EtO

2C

CO

2Et

1. N

aH, P

hH, 0

°; r

t, 1

h

2. A

dd s

uspe

nsio

n of

Na

salt

in E

t 2O

to C

lNH

2

at

0°;

rt,

2 h

I (

65)

63

EtO

2CN

H2

EtO

2CC

O2E

t

EtO

2CN

H2

EtO

2CC

O2E

t

I

EtO

2C

H N

EE

CO

2Et

EE

E =

CO

2Et

320

C6-

10

NC

NH

R2

O

R1

NH

HN

OR

1

CO

NH

R2

NR

2

N HO

R1

H2N

CH

2ON

H, t

olue

ne, N

aOH

, H2O

, rt,

12 h

O

149

R1

i-Pr

c-C

6H11

4-C

lC6H

4CH

2

4-O

2NC

6H4C

H2

2-M

eOC

6H4C

H2

4-M

eOC

6H4C

H2

4-M

eOC

6H4C

H2

4-M

eOC

6H4C

H2

4-M

e 2N

C6H

4CH

2

R2

2,6-

Me 2

C6H

3

PhC

H2C

H2

Me

3,4-

(MeO

) 2C

6H3(

CH

2)2

Me

i-Pr

Ph 2,6-

Me 2

C6H

3

i-Pr

I

(—)

(62)

(47)

(35)

(81)

(—)

(—)

(52)

II (81)

(—)

(—)

(—)

(—)

(58)

(98)

(—)

CO

2Et

Et

OC

O2E

t

O

BnO

2CN

=N

CO

2Bn,

cat

alys

t, C

H2C

l 2, –

25°,

7 d

Et

N

Cat

alys

t

cinc

honi

ne

cinc

honi

dine

(72)

(72)

% e

e

47g

27g

231

C6

O

CO

2Et

O

CO

2Et

NR i-

Pr

Bn

Tim

e

31 h

1 h

(89)

(73)

% e

e

97

93 (

R)

239

RO

2CN

=N

CO

2R, 3

(5

mol

%),

MeO

H, r

t

+

I +

II

(54)

NH

CO

2Bn

CO

2Bn

CO

2R NH

CO

2R

C6-

7O

CO

2Et

O

CO

2Et

O

CO

2Et

NC

O2E

tN

HC

O2E

t4-

O2N

C6H

4SO

2ON

HC

O2E

t (1

eq),

CaO

(2

eq),

CH

2Cl 2

, rt

5 eq

n 1 2

Tim

e

1 h

3 h

I

(49)

(40)

II (4)

(10)

+12

4

nn

nI

I

II

II

OH

2Pd

NC

Me

P P=

PPh 2

PPh 2

2+

3

P P

2 PF

6–

321

Subs

trat

eR

efs.

Con

ditio

nsPr

oduc

t(s)

and

Yie

ld(s

) (%

)

TA

BL

E 2

0. E

NO

LA

TE

S O

F α−

CY

AN

O C

AR

BO

NY

L A

ND

β−D

ICA

RB

ON

YL

CO

MPO

UN

DS

(Con

tinu

ed)

O

CO

2Et

EtO

2CN

=N

CO

2Et,

4 (c

at),

tolu

ene,

rt

OC

uO

OOt-

Bu

Bu-

t

(95)

953

O

CO

2Et

N

C6

O

CO

2R1

O

CO

2R1

N

1. 5

(12

.5 m

ol%

), M

(OT

f)3

(9 m

ol%

), 4

Å M

S,

so

lven

t, rt

, ove

rnig

ht

2. S

ubst

rate

3. t-

BuO

2CN

=N

CO

2Bu-

t, te

mp

NN

OO

N

R2

R2

954

4

5

CO

2Bu-

t

NH

CO

2Bu-

t

CO

2Et

NH

CO

2Et

322

R1

Et

Et

Et

Et

Et

Et

t-B

u

t-B

u

t-B

u

t-B

u

t-B

u

t-B

u

t-B

u

t-B

u

1-ad

aman

tyl

1-ad

aman

tyl

1-ad

aman

tyl

1-ad

aman

tyl

1-ad

aman

tyl

1-ad

aman

tyl

1-ad

aman

tyl

1-ad

aman

tyl

1-ad

aman

tyl

1-ad

aman

tyl

R2

i-Pr

1-ad

aman

tyl

i-Pr

1-ad

aman

tyl

i-Pr

1-ad

aman

tyl

i-Pr

i-Pr

1-ad

aman

tyl

i-Pr

i-Pr

1-ad

aman

tyl

i-Pr

1-ad

aman

tyl

i-Pr

i-Pr

i-Pr

i-Pr

i-Pr

i-Pr

i-Pr

i-Pr

i-Pr

i-Pr

M Yb

Yb

Eu

Eu

La

La

Sc Yb

Yb

Eu

Eu

Eu

La

La

Yb

La

Eu

Eu

Eu

Eu

Eu

Eu

Eu

Eu

Solv

ent

CH

2Cl 2

CH

2Cl 2

CH

2Cl 2

CH

2Cl 2

CH

2Cl 2

CH

2Cl 2

CH

2Cl 2

CH

2Cl 2

CH

2Cl 2

CH

2Cl 2

CH

2Cl 2

CH

2Cl 2

CH

2Cl 2

CH

2Cl 2

CH

2Cl 2

MeC

N

MeC

N

MeC

N

MeC

N

ClC

H2C

H2C

l

CH

2Cl 2

DM

E

TH

F

cycl

ohex

ane

Tem

p

rt rt 0° 0° 0° 0° rt

–41°

to 0

°rt rt

–41°

to 0

°–4

1° 0° –41°

0° rt rt 0° –41° 0° 0° 0° 0° 0°

(85)

(74)

(82)

(88)

(84)

(79)

(0)

(70)

(31)

(55)

(81)

(66)

(78)

(71)

(62)

(—)

(—)

(—)

(—)

(—)

(—)

(—)

(—)

(—)

% e

e

68 0 62 12 52 18 — 70 66 67 >95 86 22 84 55 89 93 95 100

73 71 30 50 0

Con

fig.

R — R S R R — R S R R S R S R R R R R R R R R —

323

Subs

trat

eR

efs.

Con

ditio

nsPr

oduc

t(s)

and

Yie

ld(s

) (%

)

TA

BL

E 2

0. E

NO

LA

TE

S O

F α−

CY

AN

O C

AR

BO

NY

L A

ND

β−D

ICA

RB

ON

YL

CO

MPO

UN

DS

(Con

tinu

ed)

n 1 1 1 1 1 1 1 2 2

R Et

Et

Et

Et

Et

Bn

Bn

Et

Et

Cat

alys

t

KO

Ac

quin

ine

quin

idin

e

cinc

honi

ne

cinc

honi

dine

cinc

honi

ne

cinc

honi

dine

cinc

honi

ne

cinc

honi

dine

Tim

e

15 m

in

2 m

in

1 m

in

5 m

in

5 m

in

2 m

in

10 m

in

48 h

24 h

% e

e

— 26h

38h

88 (

R)

87 (

S)

54i

76i

84 (

R)

77 (

S)

C6-

7O

CO

2R

O

CO

R

NB

nO2C

N=

NC

O2B

n, C

H2C

l 2, c

atal

yst,

–25°

231

nn

(>80

)

(—)

(—)

(95)

(95)

(99)

(99)

(92)

(81)

NH

CO

2Bn

CO

2Bn

t-B

uO2C

N=

NC

O2B

u-t,

2 (

x m

ol%

), T

HF,

–60

°95

1

n 1 1 2

x

0.05 2 2

Tim

e

4 h

5 m

in

24 h

(100

)

(100

)

(>99

)

% e

e

97 (

R)

97 (

R)

98

O

CO

2Et

n

O

CO

2Et

nN N

HC

O2B

u-t

CO

2Bu-

t

N

Ar Ar

NH

NH

2

2

Bu-

t

Bu-

t

Ar

=

Con

fig.

— — — R S — — R S

Con

fig.

R R —

324

YO

CO

Me

YON

CO

2Bu-

t

NH

CO

2Bu-

tt-

BuO

2CN

=N

CO

2Bu-

t, 2

(cat

, 2 m

ol%

), T

HF,

–60

°Y O C

H2

Tim

e

24 h

5 h

(>99

)

(99)

% e

e

15 91

951

CO

Me

N

Ar Ar

NH

NH

2

2

Bu-

t

Bu-

t

Ar

=

C6-

7

C6-

11

R OB

u-t

Et

CH

2Bu-

t

Tem

p

–52° rt

–50°

(99)

(86)

(90)

Tim

e

66 h

143

h

91 h

% e

e

89 83 83

481

n 1 2 1

O

CO

Me

O

C6

O

CO

Me

OE(9

3), 9

3% e

e23

9

O

CO

R

n

OC

OR

nN N

HC

O2B

u-t

CO

2Bu-

t

E =

N(C

O2P

r-i)

NH

CO

2Pr-

i

N

OH

N

OH

Et

t-B

uO2C

N=

NC

O2B

u-t,

1 (5

mol

%),

tolu

ene

1

i-Pr

O2C

N=

NC

O2P

r-i,

3 (5

mol

%),

MeO

H, r

t, 9

h

OH

2Pd

NC

Me

P P=

PPh 2

PPh 2

2+

3

P P

2 B

F 4–

325

Subs

trat

eR

efs.

Con

ditio

nsPr

oduc

t(s)

and

Yie

ld(s

) (%

)

TA

BL

E 2

0. E

NO

LA

TE

S O

F α−

CY

AN

O C

AR

BO

NY

L A

ND

β−D

ICA

RB

ON

YL

CO

MPO

UN

DS

(Con

tinu

ed)

O

NY

O

NY

E

OE

OH

1. E

tO2C

N=

NC

OA

r, P

hH, 0

°, 2-

3 d

(for

ms

I)

2. H

3O+, r

t, 30

d (

form

s II

)

249

I

(59)

(50)

(67)

(65)

II (40)

(45)

(—)

(—)

Ar

Ph 4-O

2NC

6H4

Ph 4-O

2NC

6H4

Y — — O O

III

E =

N(C

O2E

t)N

HC

OA

r

C6

NH

R1

O

NH

R1

ONR

2 CO

N=

NC

OR

2 , MeC

N, r

eflu

x, 3

h

R1

n-B

u

n-B

u

t-B

u

t-B

u

Ph Ph

250

R2

EtO

Ph EtO

Ph EtO

Ph

(46)

(67)

(50)

(40)

(65)

(65)

CO

R2

NH

CO

R2

O

CO

R OO

CO

R

ONB

nO2C

N=

NC

O2B

n, C

H2C

l 2, c

atal

yst,

–25°

Cat

alys

t

cinc

honi

ne

cinc

honi

dine

cinc

honi

ne

cinc

honi

dine

cinc

honi

ne

cinc

honi

dine

Tim

e

2 m

in

2 m

in

25 m

in

40 m

in

4 d

4 d

(91)

(96)

(91)

(91)

(68)

(51)

% e

ei

49 42 60 64 51 57

R Me

Me

i-Pr

i-Pr

t-B

u

t-B

u

231

NY

OR

R

NY

OR

R

N95

5

R H H Me

Me

Y — O — O

(100

)

(100

)

(—)

(—)

EtO

2CN

=N

CO

2Et

CO

2Bn

NH

CO

2Bn

CO

2Et

NH

CO

2Et

C6-

9

C6-

8

326

C7

CO

2Et

NH

ON

HC

O2E

t

CO

2Et

4-O

2NC

6H4S

O2O

NH

CO

2Et,

CH

2Cl 2

, rt

(49)

, 60%

de

125

Ph

BnO

2CN

=N

CO

2Bn,

CH

2Cl 2

(100

)23

6•

Ac

CO

2Et

•A

c

EtO

2CN

NH

CO

2Bn

CO

2Bn

C7-

8

CO

R1

OO

N

CO

R1

R2 O

2CN

=N

CO

2R2 , c

atal

yst (

10 m

ol%

), to

luen

e

3,5-

(CF 3

) 2C

6H3

N HN H

Y

NM

e 2ca

taly

st A

: Y =

S B

: Y =

O

NM

e 2

BzN

H

cata

lyst

C

233

R1

OM

e

OM

e

OM

e

OM

e

OM

e

OM

e

OPr

-i

OB

u-t

Me

OM

e

OB

u-t

R2

Et

i-Pr

t-B

u

t-B

u

t-B

u

Bn

t-B

u

t-B

u

t-B

u

t-B

u

t-B

u

Cat

alys

t

B B A B C B B B B B B

Tem

p

–78°

–78° rt

–78°

–78°

–78°

–78°

–78°

–78° rt

–40°

Tim

e

2 h

2.5

h

1 h

3 h

15 h

2 h

10 h

15 h

3 h

96 h

48 h

n 1 1 1 1 1 1 1 1 1 2 3

(96)

(94)

(91)

(96)

(90)

(92)

(98)

(96)

(97)

(52)

(90)

% d

e

51 72 75 83 60 50 91 91 80 87 90

nn

CO

2R2

NH

CO

2R2

C8-

11

CN

H2N

O

HN

NH

O

R

CO

NH

2

R14

9

R c-C

5H9

2-fu

rylm

ethy

l

4-(1

-ben

zyl)

pipe

ridy

l

c-C

6H11

n-C

8H17

(94)

(87)

(81)

(99)

(76)

NH

, DA

BC

O (

cat)

, tol

uene

, rt,

12 h

O

327

Subs

trat

eR

efs.

Con

ditio

nsPr

oduc

t(s)

and

Yie

ld(s

) (%

)

TA

BL

E 2

0. E

NO

LA

TE

S O

F α−

CY

AN

O C

AR

BO

NY

L A

ND

β−D

ICA

RB

ON

YL

CO

MPO

UN

DS

(Con

tinu

ed)

NHC

O2E

t

ONH

CO

2Et

N3

O

1. L

DA

, TH

F

2. T

sN3

3. T

MSC

l

(—)

482

C9

(53)

1. N

aH, D

MF

2. 2

,4-(

O2N

) 2C

6H3O

NH

287

7

1. L

i bas

e, T

HF

2. P

h 2P(

O)O

NH

2, –

20°;

rt,

12 h

I (

31)

139

Ph

CO

2Et

CO

2Et

Ph

CO

2Et

CO

2Et

H2N

I

C8

O

CO

R1

n

O nNC

OR

2

NH

CO

2R2

n 1 1 2 2 2 2 2 2 2 2 3 3

R1

s-B

u

s-B

u

Me

Me

Et

i-Pr

s-B

u

s-B

u

Ph Ph s-B

u

s-B

u

R2

Bn

Bn

Bn

Bn

Bn

Bn

Bn

Bn

Et

Bn

Bn

Bn

x 10 10 1 10 10 10 1 10 10 10 10 10

Tem

p

rt

–24° rt rt rt rt rt rt rt rt rt

–24°

Tim

e

18 h

18 h

18 h

18 h

18 h

18 h

18 h

18 h

40 h

18 h

18 h

18 h

(60)

(60)

(94)

(82)

(83)

(86)

(76)

(76)

(74)

(87)

(90)

(89)

% e

e

89 94 80 84 94 94 94 95 77 91 83 85

956

C8-

13

1.

(S,

S) (

x m

ol%

),N

OO

N

PhPh

C

u(O

Tf)

2 (x

mol

%),

CH

2Cl 2

, rt,

2 h

2. S

ubst

rate

, the

n R

2 O2C

N=

NC

O2R

2 ,

te

mp,

tim

e

CO

2R2

328

1. N

aH, T

HF,

rt,

15 m

in

2. R

eage

nt, r

t, ov

erni

ght

Rea

gent

Ph2P

(O)O

NH

2

(4-M

eOC

6H4)

2P(O

)ON

H2

4-O

2NC

6H4C

O2N

H2

(96)

b

(75)

(85)

106

1. L

iHM

DS

or N

aHM

DS

2.(0

)15

5

1. L

i bas

e, T

HF

2. P

h 2P(

O)O

NH

2, –

20°;

rt,

12 h

139

I (

>96

)

O

NC

ON

Et 2

4-C

lC6H

4

CO

NH

Ph

CO

NH

PhN

H, D

AB

CO

, tol

uene

, rt,

12 h

O(7

2)14

9Ph

CO

2Et

CN

1. L

iHM

DS

(ia)

, TH

F, –

78°,

1 h

2.

(+

), –

78°,

31 h

; to

rt

ON

HN

NN

PhH

HPh

CN

CN

CO

NH

2

Ph

(34)

(34)

(9)

151

Ph+

+

1. L

i bas

e

2. 2

,4,6

-Me 3

C6H

2SO

2ON

Me 2

, Et 2

O o

r T

HF,

–10°

to –

20° ;

rt,

15 h

(95)

133

Ar

N HN H

S

NM

e 2(10

mol

%),

tolu

ene,

–78

°

t-B

uO2C

N=

NC

O2B

u-t,

233

(93)

, 73%

ee

CO

2Et

CN

Ph

Ph

CNCO

2Et

Me 2

N

Ar

= 3

,5-(

CF 3

) 2C

6H3

Ph

CNCO

2Et

H2N

I

Ph

NH

CO

NE

t 2

CO

2Et

NC

Ph

CO

NH

Ph

CO

NH

Ph

NH

2

Ph

NCO

2Et

NC

NH

CO

2Bu-

t

CO

2Bu-

t

PhC

O2E

t

CN

1. N

aH, T

HF

2. 2

,4-(

O2N

) 2C

6H3O

NH

2

(54)

93Ph

CNCO

2Et

H2N

329

Subs

trat

eR

efs.

Con

ditio

nsPr

oduc

t(s)

and

Yie

ld(s

) (%

)

TA

BL

E 2

0. E

NO

LA

TE

S O

F α−

CY

AN

O C

AR

BO

NY

L A

ND

β−D

ICA

RB

ON

YL

CO

MPO

UN

DS

(Con

tinu

ed)

C9-

13A

rC

O2E

t

CN

RO

2CN

=N

CO

2R, c

atal

yst (

x m

ol%

),

so

lven

t, –7

8°

N

NOH

BnO

N

OB

n

NOH

cata

lyst

A

cata

lyst

B

232

Ar

Ph Ph Ph Ph Ph Ph Ph Ph 4-FC

6H4

4-FC

6H4

4-C

lC6H

4

4-C

lC6H

4

4-B

rC6H

4

4-B

rC6H

4

4-B

rC6H

4

4-B

rC6H

4

4-M

eOC

6H4

4-M

eOC

6H4

2-M

eC6H

4

2-M

eC6H

4

4-M

eC6H

4

4-M

eC6H

4

1-na

phth

yl

1-na

phth

yl

R Et

i-Pr

t-B

u

t-B

u

t-B

u

t-B

u

t-B

u

Bn

t-B

u

t-B

u

t-B

u

t-B

u

t-B

u

t-B

u

Bn

Bn

t-B

u

t-B

u

Bn

Bn

t-B

u

t-B

u

t-B

u

t-B

u

Cat

alys

t

A A A A A A B A A B A B A B A B A B A B A B A B

x 10 10 10 10 10 5 5 10 5 5 5 5 5 5 5 5 10 10 5 5 5 5 10 10

Solv

ent

tolu

ene

tolu

ene

Et 2

O

TH

F

CH

2Cl 2

tolu

ene

tolu

ene

tolu

ene

tolu

ene

tolu

ene

tolu

ene

tolu

ene

tolu

ene

tolu

ene

tolu

ene

tolu

ene

tolu

ene

tolu

ene

tolu

ene

tolu

ene

tolu

ene

tolu

ene

tolu

ene

tolu

ene

Tim

e

1 m

in

45 m

in

3 h

12 h

11 h

2 h

4 h

1 m

in

1 h

2 h

30 m

in

30 m

in

1 h

2 h

1 m

in

1 m

in

5 m

in

10 m

in

1 h

3.5

h

8 h

8 h

8 h

12 h

(—)

(—)

(—)

(—)

(—)

(92)

(92)

(—)

(97)

(95)

(96)

(94)

(99)

(97)

(86)

(83)

(96)

(96)

(71)

(72)

(96)

(96)

(99)

(98)

% e

e

85 44 70 10 77 95 97 89 94 96

93 (

S)

97 93 96 91 92 94 97 82 87 94 96 93 99

Ar

NCO

2Et

NC

NH

CO

2R

CO

2R

330

C9-

10R

CO

2Et

CO

2Et

1. N

aH, g

lym

e, r

t

2. T

sN3,

rt;

35° t

o 40

°, 1

h

483

R Ph 7-cy

cloh

epta

trie

nyl

(71)

j

(65)

j

4-B

nOC

6H4

CO

2Et

CO

2Et

1. N

aH, T

HF,

HM

PA, r

t, 2

h

2. T

sN3,

50°

, 2.5

h

(76)

777,

957

C9

O CO

2Et

O CO

2Et

N3

TsN

HC

O2E

t

N2

O

TsN

3, E

t 3N

, Et 2

O, r

t, 14

0 h

+

(74)

k(2

0)

NC

NR

2 R3

O

R1

NH

HN

OR

1 CO

NR

2 R3

H2N

CH

2ON

R2 R

3

O

R1

N

III

NH

, NaO

H, t

olue

ne, H

2O, r

t, 12

hO

149

+

H2N

OC

NR

2 R3

O

R1

H2N

III

R1

4-M

eOC

6H4C

H2

4-C

lC6H

4CH

2

2-M

eOC

6H4C

H2

4-M

eOC

6H4C

H2

R2

—(C

H2)

2O(C

H2)

2—

—(C

H2)

5—

—(C

H2)

5—

Ph

R3

Me

I

(48)

+ 3

9% I

II

(62)

I +

III

(—)

(—)

II (—)

(—)

(32)

(43)

Add

end

— — HC

l

HC

l

III

(95)

(82)

(90)

a

(98)

a

C10

O

CO

2R

C10

-11

O

CO

2R

E23

3

n 1 2

R t-B

u

Me

Tem

p

–78°

–40°

Tim

e

4 h

5 h

(93)

(99)

% e

e

90 97

E =

N(C

O2B

u-t)

NH

CO

2Bu-

t

319

n

(for

ms

I +

II)

1. 2. I

or

II, E

tOH

, add

end,

ref

lux,

5 m

in

(f

orm

s II

I)

R

CO

2Et

CO

2Et

N3

4-B

nOC

6H4

CO

2Et

CO

2Et

N3

Ar

N HN H

S

NM

e 2(10

mol

%),

tolu

ene

t-B

uO2C

N=

NC

O2B

u-t,

Ar

= 3

,5-(

CF 3

) 2C

6H3

n

331

Subs

trat

eR

efs.

Con

ditio

nsPr

oduc

t(s)

and

Yie

ld(s

) (%

)

TA

BL

E 2

0. E

NO

LA

TE

S O

F α−

CY

AN

O C

AR

BO

NY

L A

ND

β−D

ICA

RB

ON

YL

CO

MPO

UN

DS

(Con

tinu

ed)

O

CO

2R3

O

CO

2R3

E

R1

R2

n 1 1 1 1 2 2 2

R1

H H H MeO

H H H

R2

H H H MeO

H H MeO

R3

Et

Et

Bn

Et

Me

Et

Et

R4

Et

i-Pr

i-Pr

i-Pr

t-B

u

Et

t-B

u

X PF6

PF6

PF6

PF6

BF 4

PF6

SbF 6

Solv

ent

MeO

H

MeO

H

MeO

H

Me 2

CO

MeO

H

MeO

H

MeO

H

Tim

e

30 m

in

30 m

in

30 m

in

170

h

106

h

1 h

144

h

(94)

(98)

(99)

(71)

(56)

(75)

(66)

% e

e

94 97 94 95 95 91 91

239

C10

-11

O

CO

2Et

RO

2CN

=N

CO

2R, 3

(5

mol

%),

ion

ic li

quid

[bm

im]Y

, rt

O

CO

2Et

E

239

C10

R Et

Et

Et

Et

Et

Et

i-Pr

i-Pr

i-Pr

X BF 4

PF6

SbF 6

PF6

SbF 6

PF6

SbF 6

PF6

SbF 6

Y BF 4

BF 4

SbF 6

SbF 6

PF6

PF6

PF6

PF6

SbF 6

Tim

e

30 m

in

1 h

30 m

in

1 h

1 h

1 h

12 h

18 h

12 h

(88)

(90)

(91)

(89)

(96)

(93)

(96)

(81)

(92)

% e

e

0 0 87 79 97 85 91 71 89

OH

2Pd

NC

Me

P P=

PPh 2

PPh 2

2+

3

P P

2 X

–

E =

N(C

O2R

)NH

CO

2R

R4 O

2CN

=N

CO

2R4 , 3

(as

abo

ve, 5

mol

%),

sol

vent

, rt

E =

N(C

O2R

4 )NH

CO

2R4

nn

332

C10

S

NOC

O2M

e

EtO

2CC

O2E

t

1. L

iHM

DS,

TH

F, –

70°,

5 m

in

2. T

sN3,

–70

°3.

TM

SCl,

–70°

; to

rt,

2 h

S

NO

EtO

2CC

O2E

tN3

CO

2Me

339

(43)

C10

-12

O

CO

2Et

O

CO

2Et

N3

RSO

2N3,

Et 3

N, s

olve

nt

+

prod

ucts

of

diaz

o tr

ansf

er I

II

I

n 1 1 2 2 3 3 3 3 3 3 3 3 3

R 4-O

2NC

6H4

4-M

eC6H

4

4-O

2NC

6H4

4-M

eC6H

4

4-O

2NC

6H4

4-M

eC6H

4

4-M

eC6H

4

4-M

eC6H

4

Me

Me

2,4,

6-(i

-Pr)

3C6H

2

2,4,

6-(i

-Pr)

3C6H

2

2,4,

6-(i

-Pr)

3C6H

2

Solv

ent

TH

F

TH

F

TH

F

TH

F

TH

F

TH

F

MeC

N

DM

F

TH

F

MeC

N

TH

F

MeC

N

CH

2Cl 2

Tim

e

30 m

in; 2

h

6 d

20 h

4 d

6 d

5 d

1 d

10 h

3 d

15 h

10 d

4 d

1 h

I (0)

(16)

(21)

(75)

(31)

(31)

(20)

(32)

(24)

(19)

(72)

(80)

(0)

II (0)

(0)

(47)

(0)

(34)

(0)

(56)

(18)

(30)

(60)

(0)

(0)

(71)

EtO

2CC

ON

HSO

2R

II

III

(94)

(80)

(0)

(tra

ce)

(14)

(66)

(18)

(10)

(28)

(8)

(0)

(0)

(15)

321

321

321

321

319

321

319

319

319

319

319

319

319

TsN

3, E

t 3N

, Et 2

O, r

t, 19

0 h

O

CO

2Me

O

CO

2Me

CO

NH

Ts

N2

CO

2Me

+(2

0)(5

6)31

9

C11

N3

nn

n−1

+

Tem

p

0°; r

t

rt rt rt rt rt rt rt rt rt rt rt 0°

333

Subs

trat

eR

efs.

Con

ditio

nsPr

oduc

t(s)

and

Yie

ld(s

) (%

)

TA

BL

E 2

0. E

NO

LA

TE

S O

F α−

CY

AN

O C

AR

BO

NY

L A

ND

β−D

ICA

RB

ON

YL

CO

MPO

UN

DS

(Con

tinu

ed)

C17

PhC

O2E

t

CO

2Et

Ph

CO

2Et

CO

2Et

NH

21.

NaH

, TH

F, r

t, 25

min

2. 2

,4-(

O2N

) 2C

6H3O

NH

2, r

t, 20

h(6

2)47

4

PhPh

OO

Et

C13

PhPh

OO

Et

NE

tO2C

N=

NC

O2E

t, ca

taly

st (

x eq

), M

eCN

,

rt

, 24

h

476

N CO

2EtC

O2M

e

CO

2Me

i-Pr

N CO

2EtCO

2Me

CO

2Me

i-Pr

1. N

aH, T

HF,

HM

PA, r

t, 2

h

2. T

sN3,

rt;

refl

ux, 2

h

(62)

958

N3Cat

alys

t

Ph3P

RuC

l 2(P

Ph3)

3

x 1

0.06

(100

)

(83)

C11

O

CO

2Et

OC

O2E

t

N NH

CO

2Bu-

t

(>99

), 9

7% e

e95

1

N

Ar Ar

NH

NH

2

t-B

uO2C

N=

NC

O2B

u-t,

2 (

2 m

ol%

), T

HF,

–60

°, 1

h

2

Bu-

t

Bu-

t

Ar

=

CO

2Bu-

t

NH

CO

2Et

CO

2Et

334

C19

(4-M

eOC

6H4)

2P(O

)ON

H2,

NaH

, TH

F, r

t14

5

CO

2Et

CO

2Et

n-C

6H13 N

O2

CO

2Et

CO

2Et

n-C

6H13 N

O2

+

NH

2

CO

2Et

CO

2Et

n-C

6H13 N

O2 O

H

(31)

(15)

a The

pro

duct

was

isol

ated

as

the

hydr

ochl

orid

e.b

The

bas

e us

ed w

as L

DA

.c T

he a

min

ated

pro

duct

is f

orm

ed a

s an

inte

rmed

iate

, whi

ch th

en r

eact

s w

ith a

noth

er m

olec

ule

of th

e st

artin

g di

keto

ne to

yie

ld th

e py

rrol

e de

riva

tive.

d Lith

ium

hyd

roxi

de (

6 eq

) w

as a

lso

adde

d.e T

he n

umbe

r is

the

yiel

d of

cru

de p

rodu

ct.

f With

cat

alys

t rec

over

ed f

rom

the

BrC

8F17

pha

se, t

he y

ield

was

92%

.g T

he a

bsol

ute

conf

igur

atio

n w

as n

ot d

eter

min

ed b

ut it

was

opp

osite

to th

at o

btai

ned

with

the

othe

r ca

taly

st.

h Qui

nine

and

qui

nidi

ne g

ave

the

oppo

site

ena

ntio

mer

s as

the

maj

or p

rodu

cts.

i In e

ach

exam

ple,

cin

chon

ine

and

cinc

honi

dine

gav

e th

e op

posi

te e

nant

iom

ers

as th

e m

ajor

pro

duct

s.j T

he n

umbe

r is

the

yiel

d of

unp

urif

ied

prod

uct.

k With

the

corr

espo

ndin

g 5-

, 6-,

and

7-m

embe

red

keto

est

ers,

onl

y th

e ri

ng-o

pene

d di

azo

este

rs w

ere

obta

ined

.l T

he is

omer

ic 1

-car

beth

oxy-

2-ke

to a

nalo

gs (

n =

1, 2

) on

ly g

ave

the

prod

ucts

of

diaz

o tr

ansf

er a

nd/o

r ri

ng c

ontr

actio

n.

335

Subs

trat

eR

efs.

Con

ditio

nsPr

oduc

t(s)

and

Yie

ld(s

) (%

)

TA

BL

E 2

1. I

NT

RA

MO

LE

CU

LA

R A

MIN

AT

ION

S

NC

O2M

ePh

OC

OB

u-t

C3

NaH

, KH

, or

LD

A, T

HF,

–80

° to

15°

(0)

490

NN

Me

OO

Ph

NN

Me

OO

Ph

NH

1. T

iCl 4

, CH

2Cl 2

, rt,

15 m

in

2. A

dd to

Et 3

N (

2 eq

), C

H2C

l 2, r

t, 30

min

488

NN

Me

OO

Ph

NH

+

NN

Me

O

R

O

Ph

NN

Me

O

R

O

Ph

NH

1. M

X, C

H2C

l 22.

Add

to E

t 3N

(2

eq),

CH

2Cl 2

, rt,

30 m

in

487,

488

BnO

NH

C4-

6R M

e

Me

Et

n-Pr

MX

TiC

l 4

AlM

e 2C

l

AlM

e 2C

l

AlM

e 2C

l

(97)

(80)

(67)

(70)

C4-

12

R2

NO

2

R1

R2NO

2

R1

NO

2

R2

R1

CO

2Et

NC

O2E

tN

+4-

O2N

C6H

4SO

2ON

HC

O2E

t,

CaO

, nea

t, rt

, 20

min

III

959

R1

Me

Et

i-Pr

—

(CH

2)4—

c-C

6H11

n-C

6H13

Z-E

tCH

=C

H(C

H2)

2

Ph(C

H2)

2

Ph(C

H2)

2

R2

Me

Me

Me

Me

(CH

2)2C

H=

CH

2

Me

Me

Et

I

(38)

(58)

(63)

(89)

(70)

(71)

(70)

(70)

(72)

II (5)

(6)

(12)

(0)

(8)

(4)

(7)

(16)

(13)

NPh

CO

2Me

BnO

NH

(81)

(14)

336

C4

F F

CF 3

CF 3

F F

CF 3

CF 3

NCO

Ph

Y NH

Cl

NH

OK

NN

Me 3

Pyri

dine

, DM

F, 0

° to

rt; r

t, 1

h

MeC

N, 0

°; r

t, 14

h

MeC

N, h

eat

(66)

(62)

(5)

960

F F

CF 3

R1

F F

CF 3

R1

NR2

R2 N

HO

SO2C

6H4N

O2-

4, E

t 3N

, sol

vent

R1

CF 3

CF 3

CO

2Me

CO

NM

e 2

R2

CO

2Et

SO2P

h

CO

2Et

CO

2Et

Solv

ent

Et 2

O

MeC

N

Et 2

O

CH

2Cl 2

961

NN

Me

O

R

O

Ph

NN

Me

O

R

O

Ph

NH

1. M

X, C

H2C

l 22.

Add

to E

t 3N

(2

eq),

CH

2Cl 2

, rt,

30 m

in

487,

488

BnO

NH

R Me

Me

Et

n-Pr

MX

TiC

l 4

AlM

e 2C

l

AlM

e 2C

l

AlM

e 2C

l

(96)

(77)

(71)

(70)

C4-

6

Ar1

NC

O2R

CF 3

Et 2

OC

NaH

, TH

F49

3

R Et

Bn

Ph

NA

r2

NA

r2

PhO

2S

(67)

(47)

(88)

(52)

PhC

OY

CF 3

CO

2R

NCO

2Et

Ar1 =

4-O

2NC

6H4S

O2O

(100

)

(100

)

(100

)

(100

)

(—)

— —

de 1

8-19

%

de 6

8-72

%

sing

le d

iast

ereo

mer

Ar2 =

3,5

-Me 2

C6H

3— — —

mix

ture

of

dias

tere

omer

s

sing

le d

iast

ereo

mer

PhO

2S

337

Subs

trat

eR

efs.

Con

ditio

nsPr

oduc

t(s)

and

Yie

ld(s

) (%

)

TA

BL

E 2

1. I

NT

RA

MO

LE

CU

LA

R A

MIN

AT

ION

S (C

onti

nued

)

4-O

2NC

6H4S

O2O

NH

CO

2Et (

5-6

eq),

CaO

, CH

2Cl 2

495

R1

H H MeO

R2

H Me

H

(tra

ce)

(30)

(tra

ce)

C4-

5

OO

R1

R2

OO

R1

R2

N

R4

R3

R2

R1

C5-

10

Et 3

N, E

t 2O

, rt

N H

R2

R1

R4

R3

R1

H H H Me

H

R2

CO

2Me

CO

2Me

CN

CO

2Me

4-O

2NC

6H4

R3

CO

2Me

CN

CO

2Et

CN

CO

2Me

R4

CO

2Me

CO

2Me

CO

2Et

CO

2Me

CN

(100

)a

(80)

b

(90)

b

(76)

b

(32)

b

492

OOR

2R

1

C5-

11

4-O

2NC

6H4S

O2O

NH

CO

2Et (

x eq

), C

aO, C

H2C

l 2,

w

ater

bat

h

OOR

2R

1

OOR

1R

2

EtO

2CN

EtO

2CN

+

III

R1

H Me

H Me

n-C

5H11

H Ph

R2

H H Me

Me

H n-C

5H11

H

x 2 3 3 3 5 5 5

I

(39)

(45)

(42)

(52)

(47)

(28)

(60)

II (0)

(0)

(39)

(0)

(0)

(24)

(0)

495

Ar

= 2

,4,6

-Me 3

C6H

2SO

2O

NH

Ar

CO

2Et

338

N

CO

2Et

R2

Ph2P

(O)O

R1

C6-

13

N H

CO

2Et

R2

Bas

e

R1

Me

Me

CH

2CH

=C

H2

Bn

Bn

CH

MeP

h

CM

e 2Ph

R2

H CO

2Et

H H CO

2Et

H H

Bas

e

LD

A

t-B

uOK

LD

A

LD

A

t-B

uOK

LD

A

LD

A

I

(75)

(95)

(20)

(47)

(81)

(10)

(0)

YN

+

III

II (0)

(0)

(0)

(40)

(0)

("al

mos

t exc

lusi

vely

")

(0)

496

C7-

10

CO

2Me

R

TM

SON

CO

2Me

t-B

uOK

(0.

25 e

q), C

H2C

l 2, T

HF,

rt,

4 h

N HH

RC

O2M

e

CO

2Me

R n-Pr

i-Pr

i-B

u

Ph n-C

7H15

(57)

(78)

(65)

(0)

(54)

491

•

CF 3

CF 3

CF 3

CF 3

EtO

2CN

HO

SO2C

6H4N

O2-

4, E

t 3N

, CH

2Cl 2

,

Fr

eon®

113

, rt,

3 h

CF 3

CF 3

CF 3CF 3

CO

2Et

N(7

0)96

1

C7

CO

2Et

C7-

11

Br

NH

OM

eN C

OM

e

1. M

eLi,

adde

nd, E

t 2O

, –78

°, 30

min

;

to

–15

°, 3

h

2. A

cCl,

pyri

dine

n 0 1 2 3 4

Add

end

n-B

uLi

n-B

uLi

t-B

uLi

t-B

uLi

—

(21)

(43)

(64)

(24)

(0)

n83 82

, 97

83 83 83

n

Y — — — PhC

H

— PhM

eC

—

339

Subs

trat

eR

efs.

Con

ditio

nsPr

oduc

t(s)

and

Yie

ld(s

) (%

)

TA

BL

E 2

1. I

NT

RA

MO

LE

CU

LA

R A

MIN

AT

ION

S (C

onti

nued

)

R1 O

2CR

4

NO

R5

R3

R2

R1 O

2C

DB

U, C

H2C

l 2, 0

°, 30

min

NR4

R1 O

2CC

O2R

1

R2R

3

R1

Bn

Bn

Bn

Bn

Me

Me

Me

Me

Me

R2

H H i-Pr

n-C

5H11

Ph Ph Ph

R3

H Me

H H H H H H H

R4

Me

Me

Me

Me

H Me

Me

Me

CO

2Me

Ph Ph Ph

R5

Ms

Ms

Ms

Ms

Ms

Ac

CO

CF 3

Ms

Ms

(87)

(96

)c

(87)

(79

)c

(96)

(79

)c

(83)

(0)d

(0)

(57)

(99)

(83)

(80

)c

497

C8

NO

Ms

BnO

2C

CO

2Bn

DB

U, D

MF,

rt,

5 d

N

BnO

2CC

O2B

n

(83)

497

NM

eN

Ph

O

Ph

NH

OB

nO

NM

eN

Ph

O

Ph

OH N

C9

AlM

e 2C

l, E

t 3N

, CH

2Cl 2

, 0°

489

NM

eN

Ph

O

Ph

NH

OB

nO

NM

eN

Ph

OO

H N

AlM

e 2C

l, E

t 3N

, CH

2Cl 2

, 0°

489

(75)

, 100

% d

e

(75)

, 100

% d

ePh

C7-

11

340

N

PhPh

NN

Me 3

I–

C9-

10R

1R

1R

1

H Me

Tem

p

50°

—

(29%

)

(85%

)

494

962

R3

N

R1

OH

OC

6H3(

NO

2)2-

2,4

R2

R4

R3

N H

R1

OH

R2

R4

NaH

+ N

a(C

N)B

H3

(ia)

, dio

xane

, rt;

50°

, 10

h

R1

H Br

H H H H H

R2

H H H Me

H H H

R3

H H H H H Me

H

R4

H Me

Me

Me

i-Pr

Et

CH

=C

HPh

(0)

(92)

(78)

(83)

(83)

(70)

(64)

C9-

17

498

499

499

499

499

499

499

C10

-17

R3

N

R1

OH

OC

6H3(

NO

2)2-

2,4

R2

R4

R3

N

R1

OH

R2

R4

1. N

aH, d

ioxa

ne, 5

0°, 2

0 h

2. D

DQ

, HO

Ac,

ref

lux,

2 h

499

R1

Br

H H H H H H H

R2

H H H Me

H H H H

R3

H H H H H Me

—O

CM

e 2O

—

H

R4

Me

Me

Et

Me

i-Pr

Et

CH

=C

HPh

(90)

(80)

(75)

(74)

(84)

(72)

(62)

(60)

cis:

tran

s

— — — 5:1

— 5:1

—

NaO

R2 , R

2 OH

Tim

e

1 h

—

R2

t-B

u

i-Pr

+

341

Subs

trat

eR

efs.

Con

ditio

nsPr

oduc

t(s)

and

Yie

ld(s

) (%

)

TA

BL

E 2

1. I

NT

RA

MO

LE

CU

LA

R A

MIN

AT

ION

S (C

onti

nued

)

C10

O

OC

ON

3

OH N

O

O

OH

(20)

, 95%

de

963

1. h

ν, C

H2C

l 2, r

t, 4

h

2. B

F 3•E

t 2O

, MeO

H, r

eflu

x, 2

h

N

OH

OSO

2Me

OH

N

OH

N

+(2

0)(6

)N

aH, d

ioxa

ne, r

eflu

x49

8

NPh

O2S

CO

2Et

OM

s

C12

N H

EtO

2CD

BU

, CH

2Cl 2

, 0°,

30 m

in(4

8)49

7

C12

-14

N H

NO

H

R2

R3

R1

N CO

C6F

5

N

R1

R2

R3

OH

R1

H Me

H

R2

H H Me

R3

H H Me

(63)

sin

gle

dias

tere

omer

(72)

mix

ture

of

two

dias

tere

omer

s

(74)

sin

gle

dias

tere

omer

1. M

sCl,

Et 3

N, C

H2C

l 2, 0

°, 1

h

2. C

6F5C

OC

l, rt

, 4 h

3. N

aHC

O3,

H2O

, Me 2

CO

, rt,

20 h

964

Ph

NN

Me 3

I–

NaO

Pr-i

, i-P

rOH

, 40°

, 1 h

(80)

494

C13

N

Ph

+

342

N HN

NM

sCl,

Et 3

N, C

H2C

l 2, 0

°96

4

R1

NO

HR

2R

2

R1

R1

H CO

2Bu-

t

R2

Me

H

Tim

e

1 h

6 h

(95)

(68)

mix

ture

of

two

isom

ers

C13

NPh

CO

CO

2Et

OM

sN H

DB

U, C

H2C

l 2, 0

°, 30

min

(80)

497

PhC

O

EtO

2C

C13

Y N OC

6H3(

NO

2)2-

2,4

R

OH

nY N H

R

OH

nH

H

H

HN

aH, N

a(C

N)B

H3,

dio

xane

, rt,

5 h

Y CH

2

CH

2

NB

oc

R Me

Me

n-B

u

n 1 2 1

Y N HR

OH

nH

H+

III

I

(65)

(80)

(93)

II (28)

(0)

(0)

499

C13

-16

N OC

6H3(

NO

2)2-

2,4

OH

H

H

N HO

H

H

H

N

OH

NaH

, Na(

CN

)BH

3, d

ioxa

ne, r

t, 17

h+

(52)

(12)

499

C14

343

Subs

trat

eR

efs.

Con

ditio

nsPr

oduc

t(s)

and

Yie

ld(s

) (%

)

TA

BL

E 2

1. I

NT

RA

MO

LE

CU

LA

R A

MIN

AT

ION

S (C

onti

nued

)

N OC

6H3(

NO

2)2-

2,4

OH

NaH

, dio

xane

, rt,

4 h

N

OH

(98)

499,

498

C15

-16

4-R

1 C6H

4C

6H4R

2 -4

ON

HO

Me

4-R

1 C6H

4C

6H4R

2 -4

ON

NaO

Me,

MeO

H, 6

0°, 1

0 m

in; r

t, ov

erni

ght

R1

H H Cl

Br

H Me

R2

H Cl

H H Br

H

(94)

(80)

(66)

(83)

(90)

(64)

485e

485e

485e

485e

485e

485e , 4

86

C20

O

PO

NM

e 2O

Ph

1. L

DA

, TH

F, –

10°,

1 h;

rt,

36 h

2. C

H2N

2

85(7

)f

a The

rea

ctio

n w

as c

arri

ed o

ut in

CH

2Cl 2

.b T

he y

ield

incl

udes

that

of

the

prep

arat

ion

of th

e su

bstr

ate.

c The

yie

ld is

that

of

the

one-

pot r

eact

ion

of th

e ox

ime

with

MsC

l and

Et 3

N f

ollo

wed

by

addi

tion

of D

BU

.d B

eckm

ann

frag

men

tatio

n oc

curr

ed e

xclu

sive

ly.

e The

pro

duct

s w

ere

initi

ally

con

side

red

to b

e th

e pr

imar

y en

amin

es. T

he c

orre

ct a

ssig

nmen

t was

mad

e in

a la

ter

publ

icat

ion.

486

f The

yie

ld w

as 1

0% w

ith th

e su

bstr

ate

labe

led

with

13C

at t

he c

yano

car

bon

and

one

deut

eriu

m in

one

of

the

met

hyl g

roup

s. T

he is

otop

ic la

belin

g co

nfir

med

the

intr

amol

ecul

arity

of

the

reac

tion.

H

O3

CN

O

PO

Me

OPh

O3

CN

Me 2

N

MeO

H, r

eflu

x, 1

5 m

in(6

5)96

54-

MeO

C6H

4Ph

ON

HO

Me

4-M

eOC

6H4

Ph

ONH

C14

C16

344


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