organic reaction mechanisms 2000...organic reaction mechanisms · 2000 an annual survey covering the...

ORGANIC REACTIONMECHANISMS · 2000

An annual survey covering the literaturedated December 1999 to December 2000

Edited by

A. C. KnipeUniversity of Ulster

Northern Ireland

An Interscience Publication

Innodata0470021152.jpg

ORGANIC REACTION MECHANISMS · 2000

ORGANIC REACTIONMECHANISMS · 2000

An annual survey covering the literaturedated December 1999 to December 2000

Edited by

A. C. KnipeUniversity of Ulster

Northern Ireland

An Interscience Publication

Copyright 2004 John Wiley & Sons Ltd, The Atrium, Southern Gate, Chichester,West Sussex PO19 8SQ, England

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Contributors

C. T. BEDFORD Department of Chemistry, University College, London,W1M 8JS

D. C. BRADDOCK Department of Chemistry, Imperial College London,South Kensington, London, SW7 2AZ

M. CHRISTLIEB Inorganic Chemistry Laboratory, University of Oxford,South Parks Road, Oxford, OX1 3QY

A. J. CLARK Department of Chemistry, University of Warwick,Coventry, CV4 7AL

R. G. COOMBES Department of Biological Sciences, Brunel University,Uxbridge, Middlesex, UB8 3PH

M. R. CRAMPTON Chemistry Department, The University, Durham,DH1 3LE

N. DENNIS University of Queensland, PO Box 6382, St Lucia,Queensland 4067, Australia

A. DOBBS School of Chemistry, University of Exeter, StockerRoad, Exeter, EX4 4QD

J. V. GEDEN Department of Chemistry, University of Warwick,Coventry, CV4 7AL

E. GRAS Laboratoire de Synthese et Physico-Chimie desMolecules d’Interet Biologique, Universite Toulouse,III-Paul Sabatier, Toulouse, France

T. C. T. HO GlaxoSmith Kline, Old Powder Mills, Leigh, Tonbridge,Kent TN11 9AN

D. M. HODGSON Dyson Perrins Laboratory, University of Oxford, SouthParks Road, Oxford, OX1 3QY

A. C. KNIPE School of BMS, The University of Ulster, Coleraine, Co.Londonderry, BT52 1SA

P. KOČOVSKÝ Department of Chemistry, The Joseph Black Building,The University of Glasgow, Glasgow, G12 8QQ

R. A. McCLELLAND Department of Chemistry, University of Toronto, 80 StGeorge Street, Toronto, Ontario M5S 1A1, Canada

N. P. MURPHY Department of Chemistry, University of Warwick,Coventry, CV4 7AL

A. W. MURRAY Chemistry Department, The University, Perth Road,Dundee, DD1 4HN

B. MURRAY Department of Applied Science, IT Tallaght, Dublin24, Ireland

J. SHORTER 29 Esk Terrace, Whitby, North Yorkshire, Y021 1 PA

v

Preface

The present volume, the thirty-sixth in the series, surveys research on organic reactionmechanisms described in the literature dated December 1999 to December 2000. Inorder to limit the size of the volume, it is necessary to exclude or restrict overlapwith other publications which review specialist areas (e.g. photochemical reactions,biosynthesis, electrochemistry, organometallic chemistry, surface chemistry and het-erogeneous catalysis). In order to minimize duplication, while ensuring a compre-hensive coverage, the editor conducts a survey of all relevant literature and allocatespublications to appropriate chapters. While a particular reference may be allocatedto more than one chapter, it is assumed that readers will be aware of the alternativechapters to which a borderline topic of interest may have been preferentially assigned.

There have been several changes of authorship since last year, with the welcomeaddition of co-authors (Drs J. V. Geden, A. W. Murphy, and T. C. T. Ho) and thereplacement of two authors who have made a major contribution to the series: DrsR. A. McClelland and D. C. Braddock take over from R. A. Cox and B. Davis asauthors of ‘Carbocations’ and ‘Oxidation and Reduction’, respectively.

However, the most notable change to the team is the departure of my erstwhileco-editor Prof W. E. Watts. We assumed joint editorship of the series in 1977, fromTony Butler and John Perkins, and as colleagues at the University of Ulster werewell placed to share the editorial demands. Throughout this period it was a pleasureto work with Bill, who displayed his characteristic prompt, thorough, and exactingapproach combined with sociable good humour at all times. Bill first contributed toORM in 1974 and his departure marks a 25 year period of unrivalled dedication tothe series.

Once again I wish to thank the production staff of John Wiley and Sons and theteam of experienced contributors for their efforts to ensure that the review standardsof this publication are sustained.

A.C.K.

vii

CONTENTS

1. Reactions of Aldehydes and Ketones and their Derivatives byB. A. Murray . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1

2. Reactions of Carboxylic, Phosphoric, and Sulfonic Acids and theirDerivatives by C. T. Bedford . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45

3. Radical Reactions: Part 1 by A. J. Clark, J. V. Geden, and N. P. Murphy 1154. Radical Reactions: Part 2 by A. P. Dobbs and T. C. T. Ho . . . . . . . . . . . . . 1495. Oxidation and Reduction by D. C. Braddock . . . . . . . . . . . . . . . . . . . . . . . . . . 1796. Carbenes and Nitrenes by D. M. Hodgson, M. Christlieb and E. Gras . . . 2097. Nucleophilic Aromatic Substitution by M. R. Crampton . . . . . . . . . . . . . . . 2298. Electrophilic Aromatic Substitution by R. G. Coombes . . . . . . . . . . . . . . . . 2399. Carbocations by R. A. McClelland . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 249

10. Nucleophilic Aliphatic Substitution by J. Shorter . . . . . . . . . . . . . . . . . . . . . . 27711. Carbanions and Electrophilic Aliphatic Substitution by A. C. Knipe . . . 30712. Elimination Reactions by A. C. Knipe . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35113. Addition Reactions: Polar Addition by P. Kočovský . . . . . . . . . . . . . . . . . . . 37514. Addition Reactions: Cycloaddition by N. Dennis . . . . . . . . . . . . . . . . . . . . . . 42715. Molecular Rearrangements by A. W. Murray . . . . . . . . . . . . . . . . . . . . . . . . . 475

Author index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 601Subject index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 643

ix

CHAPTER 1

Reactions of Aldehydes and Ketones and their Derivatives

B. A. MURRAY

Department of Applied Sciences, Institute of Technology Tallaght, Dublin, Ireland

Formation and Reactions of Acetals and Related Species . . . . . . . . . . . . . . . 1Reactions of Glucosides and Nucleosides . . . . . . . . . . . . . . . . . . . . . . . . . . . 3Reactions of Ketenes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4Formation and Reactions of Nitrogen Derivatives . . . . . . . . . . . . . . . . . . . . 5

Imines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5Iminium Ions and Related Species . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8Oximes, Hydrazones, and Related Species . . . . . . . . . . . . . . . . . . . . . . . . . 8

C−C Bond Formation and Fission: Aldol and Related Reactions . . . . . . . . . 10Regio-, Enantio-, and Diastereo-selective Aldol Reactions . . . . . . . . . . . . . . . 10The Mukaiyama Aldol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11Other Aldol-type Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12Allylations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14

Other Addition Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15General and Theoretical . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15Protonation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16Hydration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16Addition of Zinc Reagents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17Addition of Other Organometallics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18The Wittig Reaction, and Variants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19Addition of Other Carbon Nucleophiles . . . . . . . . . . . . . . . . . . . . . . . . . . . 22Miscellaneous Additions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24

Enolization and Related Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25Enolates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27

Oxidation and Reduction of Carbonyl Compounds . . . . . . . . . . . . . . . . . . . 27Oxidation Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27Regio-, Enantio-, and Diastereo-selective Reductions . . . . . . . . . . . . . . . . . . 28Other Reduction Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31

Atmospheric Chemistry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32Other Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35

Formation and Reactions of Acetals and Related Species

A simple hemiacetal has been stabilized by pressure.1 Acetone and propanol react togive 2,2-dimethoxypropane: if the reaction is carried out with 1 : 1 dilute reactantsin THF, the hemiacetal is formed quantitatively at pressures above 2 GPa (20 atm).

Organic Reaction Mechanisms 2000. Edited by A. C. Knipe 2004 John Wiley & Sons, Ltd ISBN 0-470-85439-1

1

2 Organic Reaction Mechanisms 2000

All thermodynamic functions have been reported for the reaction, as functions oftemperature and pressure.

3-(Hydroxymethyl)-5-methylsalicylaldehyde (1, or its acetonide) undergoes a stereo-selective cyclotetramerization to yield the S4-symmetric (R,S,R,S)-tetraacetal (2), themost thermodynamically stable of the four possible diastereomers.2 �de

OHOH

Me

H

O

MeO

O

OO

MeO

O

OO

H

HH

H

Me

Me

(2)

(1)

9-Phenyl-1-thia-5-oxaspiro[5.5]undecane, a spiro-1,3-oxathiane prepared from 4-phenylcyclohexanone and 3-mercaptopropan-1-ol, exists as a mixture of diastereomers,(3-cis) and (3-trans), with the phenyl acting as a ‘holding group’ on the cyclohexanering.3 Rate and equilibrium data have been reported for the isomerization in CDCl3solution via an open-chain form, i.e. a ring–chain tautomeric equilibrium.

O

S

S

O

Ph Ph(3-cis) (3-trans)

Formaldehyde acetals, R1OCH2OR2, are increasingly employed as fuel additives.

Their fate in the atmosphere has been investigated in studies of the rate of reactionwith hydroxyl radicals.4 They show higher reactivity than ethers or alcohols, with themain degradation pathway being initiated by OH attack at the α-carbon of one orother R group.

The relative rates of hydrolysis of a range of aldehyde- and ketone-derived acetals,orthoesters, and orthocarbonates have been compared with each other and with therelated six-membered cyclic and six, six-membered spiro analogues, with a view toseparating out steric, inductive, and stereoelectronic effects.5

The roles of solvent, catalyst, and sonication have been studied in the acetalizationof D-gluconolactones with long-chain aldehydes.6

For selective hydrolysis of hydrazones without affecting acetals, see Hydrazonesbelow.

1 Reactions of Aldehydes and Ketones and their Derivatives 3

Reactions of Glucosides and Nucleosides

Many alcohols which can be chemically glycosylated do not react in the β-glucosidase-mediated enzymatic reaction. A computation approach correlates the reactivity of thealcohol (in the enzymatic case) with its nucleophilicity: the charge on the reactingatom is an excellent predictor.7a Using a simplified model of the enzyme active site,transition-state energies have been calculated in two cases. Cyclohexanol, a typi-cal ‘reacting’ alcohol, was found to have an activation energy of 1.3 kcal mol−1,whereas that of phenol (‘non-reacting’) is calculated to be 15.8 kcal mol−1. In termsof charge, the reacting alcohol with the lowest calculated charge (benzyl alcohol)is ca 0.1 electrons more charged than the non-reacting case with the highest charge(p-methoxyphenol). In substantiation of this predictive method, three alcohols whichwere calculated to be reactive were found to be so, contrary to results of a previousstudy.7b

N -Acetylxylosamidoxime (4) has been synthesized: it is intended to use it andderivatives thereof as transition-state analogues for glycosyltransferases specific toN -acetylglucosamines.8

HN

NHAc

NO

H

OBn

OBn

(4)

A range of glycosyl transfer reactions designed to favour intramolecular (1,x)-shifts (x = 3,4,5,9) proceed via intermolecular pathways only.9 Stereocontrolled gly-cosyl transfer reactions, using unprotected glycosyl donors, have been reviewed (87references).10

The kinetics and mechanism of reaction of bromo- and chloro-malonaldehydeswith adenosine in aqueous solution have been studied.11 Such aldehydes are known toarise intracellularly from mutagenic bifunctional halo compounds. The etheno prod-ucts that they yield with nucleobases are also useful tools in nucleic acid chemistry,owing to their fluorescence and, in some cases, the survival of the formyl functionfor further derivatization. The reactions proceed through the attack of the exo-aminogroup of adenine on the carbonyl carbon, and there are relatively small differencesbetween the chloro and bromo reactants, or between the malonaldehydes and themore-studied acetaldehydes. The most efficient conditions for formation of the ethenoproduct (formed via a deformylation) and of the formyletheno product are described.

In a theoretical study of proton transfer in the mutarotation of sugars, 2-tetrahydro-pyranol was chosen as a model sugar. The rate-limiting step of ring opening has beenstudied for two mechanisms: a high-energy intramolecular proton transfer and a low-energy route using formic acid as catalyst.12 The latter process is a double protontransfer reaction, concerted but asynchronous.


The kinetics and mechanism of spontaneous β-glycoside hydrolysis has been inves-tigated for a series of deoxy- and deoxyfluoro-2,4-dinitrophenyl-β-D-glycopyrano-sides.13 Within this series, field effects on the O(5) substituent (i.e. the site of chargedevelopment in the transition state) dominate: Hammett ρI values vary from −2.2to −8.3 in the glucoside series, for example. Inter-series comparisons also involvevariations in steric and solvation effects.

The kinetics of the acetolysis of methyl 2,3,4,6-tetra-O-acetyl-D-mannopyranosidescatalysed by sulfuric acid have been reported for acetic anhydride/acid solution.14

Other reports describe a regioselective α-phosphorylation of aldoses in aqueoussolution,15 phosphorylation of D-aldo-hexoses and -pentoses with inorganic cyclotri-phosphate,16 and a 1,2-trans stereoselective allylation of 1,2-O-isopropylidene-protec- �deted glycofuranosides.17 Intramolecular O-glycoside bond formation has been reviewed(95 references).18

Reactions of Ketenes

An ab initio study of the gas-phase reaction of hydroxyl radical with ketene indi-cates three distinct mechanisms: (i) direct hydrogen abstraction to give water andketenyl (HCCO), a channel which dominates at high temperatures; (ii) olefinic carbonaddition; and (iii) carbonyl carbon addition.19 The results compare well with suchexperimental data as are available, and the implications for atmospheric combustionprocesses are discussed.

Preparation of ketene (5), by Wolff rearrangement from 4-diazo-3-isochromanone,shows direct kinetic evidence for a non-carbene route.20

O

C

O

(5)

A theoretical study of ketene and its thio and seleno analogues suggests that all arebest represented by neutral cumulene structures, that the latter two are more reactive, andthat the thioketene is closer in behaviour to the seleno compound than the oxo case.21

Carbon suboxide (O=C=C=C=O) is calculated to hydrate at the C=C bond,22in contrast to hydration of ketene, where addition to C=O to give the 1,1-enediolis favoured.

Methyl trimethylsilylketene acetals have been oxidized with urea–hydrogen perox-ide to yield α-siloxy esters, using catalytic methyltrioxorhenium; treatment with KFthen gives the corresponding α-hydroxy esters.23

Mechanisms of 2 + 2-cycloaddition of ketenimine (H2C=C=NH) and imine(H2C=NH) have been studied theoretically,24 and the chemistry of α-oxoketenethioacetals has been reviewed (28 references).25


Formation and Reactions of Nitrogen Derivatives

Imines

A computational study of the addition of HCN to methanimine in the gas phase andin aqueous solution has been employed to assess the feasibility of a prebiotic Streckersynthesis of glycine from formaldehyde, hydrogen cyanide, ammonia, and water in theprimitive atmosphere.26 High reaction barriers appear to rule out the process in the gasphase (and hence in interstellar space?), but these barriers are lowered substantially inwater, through both bulk and specific solvation effects on zwitterionic transition states.

In one of many stereoselective imine reactions reported, Strecker addition of tri-methylsilyl cyanide to chiral imines derived from 1-phenylethylamine usually proceedswith modest de. Higher diastereoselectivity has been achieved with a chiral β-diamine: �deNMR evidence suggests an autocatalytic effect.27

Kinetic resolutions of two important ring systems, 3-substituted indanones and 4-substituted tetralones, have been achieved with ees/des of over 90% via an asymmetric �eehydrosilylation of their N -alkylimines.28

Lithium anions of chiral alkyl p-tolyl sulfoxides add to (S)-N -benzylidene-p-toluenesulfonamides to give enantiomerically pure β-(N -sulfinyl)amino sulfoxides, �deand ultimately optically pure β-amino alcohols, via a stereoselective Pummererreaction.29

Enantiopure imines, derived from reaction of (R)- or (S)-α-methylbenzylamine witha ketone, have been reduced to amines in high de, using zinc borohydride.30 Imineshave been condensed diastereoselectively with ester enolates.31 The stereochemistry �deof addition of dialkyl and diaryl phosphites to 1,4-phenylene Schiff bases has beenstudied.32

Several reactions with organometallic reagents are described. Diethylzinc hasbeen added enantioselectively to diphenylphosphinoylaryl-33 and alkyl-imines,34 �eeR−CH=N−P(=O)Ph2(R = Ar, alkyl), using chiral amino alcohols as auxiliaries.Electron-deficient N -sulfonylimines undergo α-substitution with organometallicbases.35 As part of a study of the BF3-mediated addition of lithium phenylacetylide(Ph−C≡C−Li) to an imine, BF3 · R3N adducts have been found to be usefulsubstitutes for boron trifluoride etherate.36 Alkyllithiums and alkyl Grignards havebeen added asymmetrically to 3-methoxynaphthalen-2-ylimines (6) as part of a route �eetowards chiral 2-substituted tetralones.37 1-Benzyltetrazolylimine undergoes additionof an alkyl Grignard to give an N -alkyl product (i.e. azophilic addition), whereas the2-benzyl analogue predominantly reacts at carbon, a contrast explained in terms offrontier orbitals.38 New unsymmetrical diamines have been prepared39 by addition ofGrignards to a chiral bisimine (S,S-7).

Several reports deal with imines as intermediates. Ethyl (Z)-N -(2-amino-1,2-di-cyanovinyl)formimidate (8) reacts with carbonyl compounds under basic conditions toform a Schiff base. The range of subsequent reactions to give a variety of heterocyclicsystems has been investigated.40 Pictet–Spengler combination of dopamine with D-glyceraldehyde under biomimetic conditions is accelerated by transition metal cations,apparently by activating Schiff base intermediates.41 The reaction of benzaldehydewith phenylhydroxylamine apparently proceeds via a hydrogen-bonded pre-association


NR

OMe

N N

PhPh

H

Me

HMe

(S, S-7)

N

H2N

CN

CN

OEtH

(8)(6)

complex involving the planar portion of each, an effect not seen in the stericallyhindered cases of 2,6-dichlorobenzaldehyde and norcamphor.42

In the reaction of hydroxymethanesulfonate (HOCH2SO3−) with anilines, the anion

is found to dissociate to formaldehyde and sulfite; the formaldehyde then forms acarbinolamine with the aniline, which dehydrates.43 Subsequent reaction with thefree sulfite gives the product, an anilinomethanesulfonate (ArNHCH2SO3

−). Kineticstudies in the pH range 1–8 indicate a change in rate-determining step (from carbino-lamine formation to its dehydration), the analysis requiring consideration of sideequilibria, such as that producing the dianion, −OCH2SO3−.

In another Mannich-type reaction, a face-specific intramolecular ring closure of analdehyde has been reported.44 The origin of diastereoselectivity in vinylogous Mannich �dereactions has been studied theoretically.45

The carcinogenic action of benzidene (9) may proceed via peroxidase oxidationto bisimine (10). The latter has been investigated, together with its equilibria tomono- (10 · H+) and di-cationic (10 · H22+) forms, with pKas found to be 9.0 and5.0, respectively.46 These are in stark contrast to its monophenylene analogue (p-benzoquinone diimine), for which the corresponding values are 5.75 and < 1.5. TheN ,N -dimethyl derivative of (9) has also been studied: its two-electron oxidation prod-uct is confined to mono- and di-cationic forms only, and has coincidentally the samepKa (5.0) for their interconversion. The cations survive for minutes to hours, reactingwith water eventually, with the monocation surprisingly more reactive. The mono-cation can be considered, via resonance, to be an amino-stabilized nitrenium ion, butis ca 109 times longer-lived than simple 4-biphenylylnitrenium ions.

(10)(9)

H2N NH2 HN NH

H2N+ +NH2 H2N

+ NH

[O]

(10 H+)(10 H22+) ••


α,β-Ethylenic imines undergo tautomerization to secondary enamines and Michaeladdition with electrophilic alkenes.47 1,3-Oxazolidines can be prepared by reactingimines with epoxides, catalysed by samarium(II) or -(III) iodide.48

The chemistry of imines, enamines, and oximes, and in particular their syntheticapplications, have been reviewed49a (231 references) for the years 1997 and 1998,continuing the coverage of an earlier review.49b N -Functionally substituted iminesof polychlorinated and polybrominated aldehydes and ketones have been reviewed(198 references): groups attached to the nitrogen include acyl, oxycarbonyl, car-bamoyl, sulfonyl, and phosphoryl.50 Addition of electron-deficient alkenes to 2,4,6-cycloheptatrien-1-imines has been the subject of a short review.51

The cycloaddition of benzylidenebenzylamine (PhCH=NPh) to 5-norbornene-2,3-dicarboxylic acid unexpectedly yielded the tricycle (11), together with its aroma-tized analogue.52 The mechanism of the reaction, which was carried out in THFwith boron trifluoride catalysis, was established by reacting the imine with 2,3-dihydrofuran. Other ring formations described include the mechanism of cycliza-tion of 2-ethynylbenzaldehyde derivatives (imines and O-methyloximes) to yieldisoquinolines,53 the kinetics of cyclocondensation of arylimines with thioglycolic acidto yield 4-thiazolidinones,54 and a carbonylative 5 + 1-cycloaddition of α-cyclopropy-limines to yield α,δ-unsaturated six-membered lactams.55

A range of activated, sterically strained N -arylsulfonyl-p-quinone mono- and di-imines undergo several unusual reactions not observed for their unstrained analogues.56

An investigation of the Biginelli dihydropyrimidine synthesis from a benzaldehydeand a urea suggests that recent claims of a ‘non-thermal microwave effect’ on rates andyields are not substantiated.57 Microwaves have no beneficial effect on this reactionover conventional heating at the same temperature. Higher rates can be producedat high pressure, but this is due to the higher temperatures achievable (and, in thisreaction, high pressure also causes a diversion to other products). Acceleration andgreater yield were found only under ‘open’ conditions, where superheating is notthe critical issue: rather, rapid solvent boil-off produces near-solvent-free conditionsand the removal of condensate water. This conclusion is reinforced by near-replicateresults achieved with conventional, rapid, evaporative heating.

The kinetics of condensation of anilines with 4-methyl-5-phenyl-2,3-dihydrofuran-2,3-dione have been described.58

A pH–rate profile has been constructed for the hydrolysis of H2salen [N ,N ′-bis(salicylidene)ethylenediamine] in aqueous methanol.59 Ce(III), Ce(IV), Cu(II), andZn(II) ions retard the rate of hydrolysis, apparently through the formation of tri-cyclic chelates.

(11) (12)

NH

O

Ph

H

H

N+

R2 R2

R1

R1 O−


Iminium Ions and Related Species

(S)-1-Alkyl-2-hydroxy-1,2,3,4-tetrahydroisoquinolines have been prepared by catalyticasymmetric addition of dialkylzincs to 3,4-dihydroisoquinoline N -oxides (12), using �eean (R,R)-tartrate auxiliary.60

α-Aryl-N -phenylnitrones, R−CH=N+(−O−)−Ph, undergo additions with silylketene acetals.61 The reactions are catalysed by lanthanide triflates, catalysts that arewater-soluble, recoverable, and reusable.

Neighbouring group participation effects, with a carbonyl as neighbour, have beeninvestigated in the dehydrogenation of 2-(1-piperidinyl)-benzaldehydes and -aceto-phenones.62

A protonated Schiff base derived from β-ionone has been studied using moleculardynamics.63

The recent chemistry of N -acyliminium ions has been reviewed, with a particularemphasis on their use in C−C bond formation, both inter- and intra-molecular.64

Oximes, Hydrazones, and Related Species

As a demonstration of C−C bond formation under mild aqueous conditions, ethylradicals have been added to a range of C=N functions. Four types of glyoxylic iminederivatives were studied: oximes, oxime ethers, and hydrazones (R1O2CCH=NR2,R2 = OH, OBn, NPh2 respectively), and nitrones [R1O2CCH=N+(O−)Bn]. All butthe oximes added an ethyl group to the imino-carbon in good to quantitative yield,and often taking only 10 min.65 The authors also report a stereocontrolled version in �dethe case of an oxime ether (R1 = Me, R2 = OBn).66

Formation of oximes from pyruvic acid (MeCOCO2H) involves rate-determining �eedehydration of the carbinolamine intermediate under acidic and neutral conditions.67

Addition of hydroxylamine to 9-formylfluorene (13) yields a carbinolamine adduct,and ultimately the oxime.68 Rate and equilibrium constants are reported for theseand related reactions in aqueous solution (pH 4–12), with reaction via protonatedcarbinolamine implicated at high acidity. Derived values for the pKa for the O-protonation of the aldehyde (−4.5), and for the C-protonation of its enol tautomer(−5.7) are also reported.

2-Acetylpyridinephenylhydrazone (14) has been found to be particularly resistant tohydrolysis in acid, with the onset of an A-SE2 process only occurring in 0.6 mol dm

−3H2SO4, followed by a changeover to A2 above 6.0 mol dm

−3.69 This is not merelybecause the pyridine nitrogen acts as a ‘siren effect’ protonation site for the catalyst,but also because the proton further stabilizes the syn conformer of the −N(1)−C−C−N(2)− group of (15). As (15) is hydrolysis resistant, a further protonation is requiredto disrupt the dominance of the syn structure.

A new synthesis of gem-dichlorostyrenes (17) has been reported: unsubstitutedhydrazones of benzaldehydes (16) react with carbon tetrachloride, with copper(I)catalysis.70 The mechanism, although complex, appears to involve (i) oxidation ofCu+ by CCl4, producing dichlorocarbene, (ii) oxidation of (16) by Cu2+, to givethe corresponding phenyldiazomethane, and (iii) combination of the diazo and car-bene intermediates to give (17) plus N2, with evolution of the latter facilitating the


(13)

H

O

(15)(14)

N2

N3H

Me N1

N2

N3H

Me N1

H+

(18)

(17)

R

N NH2

H

R

H

RN

H

R

N

H

Cl

Cl

(16)

CuCl, CCl4

aq. NH3

(+ N2)

monitoring of the kinetic behaviour. Electron-donating substituents divert the reactionin favour of azine (18), via diazo self-combination.

Fluorinated β-diketones, F3C−CO−CH2−COR, react with aryl (or heteroaryl)hydrazines to give a range of pyrazole and �2-pyrazoline derivatives.71 Semiem-pirical calculations suggest that the product balance is determined by dehydration of3,5-dihydroxypyrazolidine intermediates, under kinetic control.

De-aromatized dienylimines (19, syn- and anti-) have been claimed as intermedi-ates in the Fischer indolization of ortho-substituted N -trifluoroacetyl enehydrazines(20; R = Me, OMe; n = 1, 2).72

Addition of carbon nucleophiles to aldehyde tosylhydrazones of aromatic and het-eroaromatic compounds can lead to alkylative reduction or alkylative fragmentation,both potentially synthetically useful.73

(20)(19)

N NH

NCOCF3

(CH2)nR

(CH2)n

H

H

R


A chiral 3-amino-2-oxazolidinone has been employed in a highly stereoselectivealkylation of hydrazones derived from propanal and from benzaldehyde, in up to 98%de.74 �de

For ketone hydrazones containing acetal functionality, ammonium dihydrogenphos-phate buffers selectively hydrolyse the hydrazone.75

General and specific acid catalysis of hydrazone formation from salicylaldehydeand phenylhydrazine have been observed in aqueous ethanol.76

Solvent effects on the formation of thiosemicarbazides have been studied.77

For an oxime transition-state analogue for glycosyltransferases, see Glucosides above.

C−C Bond Formation and Fission: Aldol and Related ReactionsRegio-, Enantio-, and Diastereo-selective Aldol Reactions

Non-linear effects in asymmetric catalysis have been reviewed.78 While the topic is ofwide general relevance, the over-arching importance of enantio- and diastereo-selectiveC−C bond-forming reactions merits its mention here. When an enantioselectivereaction is carried out with an impure chiral catalyst, the ‘normal’ expectation is thatthe selectivity will be linearly related to the purity, i.e. that eeproduct increases linearly �eewith eecatalyst. However, significant non-linear effects, both positive and negative, areincreasingly being reported: the review includes 26 references, and several other paperscovered in this chapter highlight positive effects in particular. Many cases appear toderive from autocatalytic effects. The authors describe the use of non-linear behaviour,and especially the kinetics of such reactions, for identifying active catalytic species andoverall mechanism. Examples are included of trade-offs between product enantiopurityand the extent of conversion. The area holds considerable promise for the design ofmore efficient and more enantioselective catalytic systems.

Other notable trends in aldolizations and elsewhere in this chapter include con-tinuing growth in the use of lanthanide Lewis catalysts and the expansion of greenchemistry, particularly the use of wholly or substantially aqueous solvent systems.

Several reviews cover aldols specifically. The development of an asymmetric aldoli-zation using enoxytrichlorosilane reagents (i.e. trichlorosilane enolates) and chiralphosphoramide Lewis bases has been reviewed (26 references).79 The strategy of �eeusing Lewis bases as catalysts (as opposed to the more familiar acids) is discussed, asare the mechanistic insights achieved to date. The review follows a similar conferencereport.80 Other accounts review asymmetric aldols of fluorocarbonyl compounds (41references),81 and the asymmetric addition of isocyano carboxylates to aldehydes (31references).82

An enantioselective reaction between 2-trimethylsilyloxyfuran (21) and aldehydesin the presence of a BINOL–titanium(IV) complex (BINOL = 1, 1′-binaphthol) hasbeen claimed as the first autocatalytic, asymmetric, autoinductive aldol reaction.83 �ee

The dianionic species PhCH(Li)CMe2C(OLi)=CH2 [derived from reductivecleavage of a methylene oxetane (22)], undergoes regioselective aldol reactions withaldehydes and ketones.84 The same authors report the preparation of a lactone fromreaction of a radical enolate [derived from 2-methylene-3-phenyloxetane (23)] withthe enolate of acetaldehyde.85


(22)(21) (23)

OMe3SiO O OPh Ph

Diastereo- and enantio-selective aldol reactions have been carried out using tita- �denium(IV) alkoxides undergoing ligand exchange with added α-hydroxy acids suchas mandelic acid.86 The mandelic acid binds through its alcohol oxygen, and theexchange process seems to be critical: simple carboxylic acids will not work, nor will �eepreformed complexes made from titanium tetraalkoxide and an α-hydroxy acid.

Theoretical and experimental investigations of intramolecular aldol condensationsof 1,6-diketones and their bis(acylsilane) analogues, [Me3SiCOCH2CH2−]2, showno evidence for spontaneous cyclization, despite an apparently low barrier for thecyclization step itself.87,88

Proline has been found to catalyse a model aldol reaction, that between acetoneand p-nitrobenzaldehyde, in good yield and up to 76% ee, with 96% ee achievable �eein the case of isobutyraldehyde.89 The synthesis does not require inert conditions orprior deprotonation or silylation, and the non-toxic catalyst can be extracted easily.An enamine route is proposed.

Other selective aldol reactions include one dependent on the enolization of chiralα-silyloxy ketones by dicyclohexylchloroborane,90 a chiral diazaborolidine-mediated �deenantioselective aldol reaction of phenylthioacetate ester,91 and a catalytic, enantio-selective homo-aldol reaction of ethyl pyruvate (MeCOCO2Et).92 A solvent effect on �eethe product outcome of an aldol reaction is described.93

The Mukaiyama Aldol

The Mukaiyama aldol methodology has been reviewed (128 references).94

Amphiphilic calix[6]arenes (24; R = Bu, Hx) are efficient surfactants for a Mukai-yama aldol reaction of silyl enol ethers with aldehydes in water, with scandium(III) �detriflate catalysis.95 The alkyl groups on the lower rim appear to stabilize the silyl

(24)

CH2

OR

SO3Na

6


enol ether in a hydrophobic environment; they also promote the aldol reaction, asevidenced by its complete failure if R = H.

A novel lead(II) catalyst system, employing a BINOL–crown ether and Pb(OTf)2,catalyses aldol reactions of benzaldehyde and silyl enol ethers in aqueous solution,with ca 50% de and ee.96 �de

�ee

Using a chiral zirconium catalyst in a Mukaiyama-type aldol reaction, high anti-selectivity has been achieved (up to 93%), with ees up to 99%, in a convenient reaction �eeat 0 ◦C.97 The zirconium–BINOL catalyst requires an alcohol as a protic additive, for

�deturnover purposes.A rhodium(I)-catalysed asymmetric reductive aldol reaction of benzaldehyde and

various acrylate esters has been reported.98 Employing a BINAP (1, 1′-binaphthalene) �eeauxiliary with methyldiethylsilane at ambient temperature, the method provides analternative to the Mukaiyama aldol reaction.

A highly nucleophilic phosphine, tris(2,4,6-trimethoxyphenyl)phosphine, catalysesthe aldol reaction between ketene silyl acetals and aldehydes, apparently through a �de‘naked enolate’ intermediate.99

Trichlorosilyl enolates derived from methyl ketones are competent aldol reagents, �dereacting with aldehydes at ambient temperature without additives.100 Chiral phospho-ramides accelerate the additions and raise the ee substantially (or the de, where either �eepartner bears a stereogenic centre, in ‘matched’ cases).

Other Aldol-type Reactions

Two reviews cover the nitro-aldol reaction: one deals with catalytic asymmetric aspects(48 references)101 and the other assesses the current state of development of diastereo-selectivity in this reaction, and its potential for onward synthesis of nitro-, amino-, and �eeimino-polyols (51 references).102 Tandem nitroaldol–dehydration reactions have beencarried out between phenylsulfonylnitromethane dianion, LiO2N=C(Li)−SO2Ph, andaldehydes.103 The β,γ -unsaturated α-nitrosulfone products are found to equilibrate �dewith their α,β-unsaturated isomers at neutral pH.

α-Bromoacetonitrile undergoes a samarium(II)-mediated nitrile aldol with aliphaticaldehydes and ketones, to yield β-hydroxynitriles; addition of tetra(n-hexyl)ammoniumbromide enhances the diastereoselectivity.104 �de

The vinologous aldol reaction has been reviewed (229 references),105 with particularemphasis on its silyloxy diene version.

α,β-Unsaturated ketones (25) have been cross-coupled with aldehydes in aproticsolvents using chromium dichloride.106 The product cyclopropanols (27) are proposedto arise from the formation of a ketone α,β-dianion (26) equivalent, which reacts withthe aldehyde at the α-position (i.e. aldol), followed by intermolecular cyclopropan-ation. The stereoselectivity of the reaction and its implication for the mechanism arealso discussed.

The diastereoselectivity of the aldol reaction of aldehydes with the C(3) carbanionof a 1,3-dihydro-2H -benzodiazepin-2-one (28) has been investigated at −78 ◦C.107 �de


(25) (27)(26)

O

R

O

R

OH

R′OH

R

' '

R′CHO2 Cr(II) −

−

(29)(28)

N

N

MeO

Cl

3N

N

N

S

OH

C

NH2

MeH

HO

2a

A diastereoselective intramolecular Michael–aldol reaction has been exploited �deunder kinetic and thermodynamic conditions; the menthyl auxiliary employed allowscomplete control of four stereogenic centres at −78 ◦C.108 γ -Nitro ketones are formedby the reaction of tin enolates with α-nitroalkenes, and tetrabutylammonium halidesstrongly accelerate the reaction.109 Cyanoalkenes can be substituted as Michaelacceptor, to give γ -cyano ketones. �de

Mentions of the Baylis–Hillman reaction include titanium tetrachloride-mediatedexamples without the direct use of a Lewis base,110 a mild asymmetric reaction usingtributylphosphine and a chiral binaphthol as cooperative catalysts,111 and a novel �eecamphor-based auxiliary which gives 94–98% de in the synthesis of β-hydroxy-α-

�demethylene carbonyl derivatives.112The decomposition pathways of 2-(1-hydroxybenzyl)thiamine (29), an adduct of

benzaldehyde with thiamine and a reactive intermediate in the thiamine-catalysedbenzoin condensation, have been investigated via a kinetic study of an N1′-benzylatedmodel compound.113 Buffers catalyse the first step, the removal of the C(2α) proton,i.e. that which is originally derived from benzaldehyde.

The self-condensation of indan-1,3-dione has been reinvestigated, to determinethe structures of the minor products.114 In an asymmetric pinacol coupling of aro- �eematic aldehydes, a non-linear temperature effect on the stereoselectivity has been

�deexploited.115The Claisen–Schmidt condensation of benzaldehyde and acetophenone yields the

enone, PhCH=CHCOPh. Following computational studies of the progress of thereaction for a series of para-substituted benzaldehydes,116 a new mechanism is pro-posed to explain the observed kinetics.


A mild and efficient Reformatsky-type coupling of an α-bromo ester and a rangeof aldehydes and ketones produces β-hydroxy esters in good yields; intramolecularexamples are included.117 Samarium(II) iodide mediates an asymmetric Reformatskyreaction of chiral α-bromoacetyl-2-oxazolidinones with aldehydes, in up to 99% de.118 �de

Allylations

Bis(allyl)silanes (30, 31) with convergent silicons are highly efficient allylating agentsin the presence of fluoride ion.119 19F NMR evidence is presented for chelation offluoride as a central feature of the catalysis, and reactions with a range of aldehydes aredemonstrated. With appropriate bis-functionalized silanes, the strategy can be extendedto allenylation and alkynylation of carbonyls.

(31)(30)

Si

Si

Si

Si

1,3-cis-Disubstituted methylenecyclohexanes have been prepared with high regio-and stereo-selectivity via TiCl4-promoted addition of 1,5-dienylallylsilanes to aliphatic �dealdehydes, followed by cyclization.120

Catalytic, enantioselective allylation of aldehydes with chlorosilanes and chiral �eephosphoramide Lewis bases has been shown to be an example of asymmetric ampli-fication via a positive non-linear effect.121 Kinetic studies show that the origin of thisbehaviour lies in the presence of two phosphoramide ligands in the stereochemicallydetermining transition state and in the rate-determining step.

Maruoka and co-workers’ suggestion that allylstannations of aldehydes catalysedby B(C6F5)3 owe their selectivity to hypercoordination at boron122a –c is challenged byan investigation, supported by X-ray and 19F NMR studies, that suggests tin chelationas the more likely explanation.122d

Chemo-, regio-, and stereo-selectivity have been achieved in the allylation of alde-hydes in aqueous organic solution, by hydrostannylation of allenes using PdCl2 · �de(PPh3)2 –HCl–SnCl2, apparently via in situ formation of allyltrichlorotin inter-mediates.123

A short review considers the enantio- and diastereo-selective addition of allyltin �eereagents to aldehydes and imines.124 Aldehydes have been allylated regio- and dias-tereo-selectively by pre-complexing the allyl reactant with a molybdenum centre.125 �deA steroidal aldehyde has been converted to the corresponding homoallylic alcohol inhigh yield and de, using triflic acid as catalyst for addition of allyltributylsilane in anaqueous medium.126 Ytterbium trichloride has been employed to catalyse allylation ofaromatic and aliphatic aldehydes by allyltrimethylsilane.127


Other Addition Reactions

General and Theoretical

Equilibrium constants for reaction of boron trifluoride etherate with carbonyl com-pounds to form complexes, >C=OBF3, have been reported for CDCl3 solution.128The value for benzaldehyde is 0.208, and ρ+ for substituted benzaldehydes is −2.0.Reactions involving complexation to cyclohexanone and isobutyraldehyde are alsoreported, and the implications of the results for Lewis acid-catalysed addition to alde-hydes are discussed.

Facial selectivity in nucleophilic addition to the dioxa cage ketone (32) is low,whereas its trioxa analogue (33) reacts with a high preference for anti attack.129

The factors involved have been studied by a computational approach, and have beenextended to carbene addition to related alkenes.

(33)(32)

OO

O

OO

O

O

A detailed kinetic study of π -facial selectivity in conformationally rigid ketoneshas been undertaken.130 Using 5-substituted adamantan-2-ones (34) and trans-10- �desubstituted decal-2-ones (35), the balance of axial versus equatorial attack in C-methylation has been monitored kinetically for eight different organometallic pro-tocols. Current theories of π -facial selection do not seem to explain the results: whileaxial reactivities increase monotonically with the electronegativity of X, keq shows amore subtle dependence on the conformation of the X group, and on reaction condi-tions.

(34)

O

X

X

O

(35)

O

O

SMe

SMe

(36)

‘Soft’ nucleophiles such as methanol or aziridine add across the centralolefinic bond of 6,7-bis(methylsulfonyl)-1,4-dihydro-1,4-methanonaphthalene-5,8-dione (36).131 However, ‘hard’ species such as sulfinates or cyanide add across thebenzoquinone system to give hydroquinonoid products. In one case, the ambidentnucleophile benzenesulfinate, a mechanistic switchover occurs on changing from


DMSO to dimethoxyethane solvent, with the latter softening the nucleophile and thuspromoting S-addition at the olefinic site.

Protonation

The mechanisms of enantioselective protonation of silyl enol ethers and ketene disilylacetals by Lewis acid-assisted chiral Brønsted acids, to give α-aryl ketones and α-arylcarboxylic acids, respectively, have been investigated using density functional theorycalculations.132 Examples include tin tetrachloride and optically active binaphthol usedstoichiometrically, as well as stoichiometric 2,6-dimethylphenol with catalytic amountsof BINOL monomethyl ether, two methodologies which lead to high ees. �ee

A series of crowded dialkylphenyl ketones, 2, 6-diR1−C6H3−CO−R2, have beenprotonated in the gas phase and in sulfuric acid.133 The gas-phase basicity changeslittle with such substitution, apparently because the bulkiness and the polarizability ofthe R1 and R2 groups cancel out. In solution, however, a variation of 8 pK units isobserved, with steric inhibition of the solvation of the protonated carbonyl emergingas the major effect, unless strong conjugative interactions are present.

Protonation equilibria of substituted benzaldehydes have been calculated for the gasphase and for a solvation model.134

Hydration

The kinetics of hydration of three o-quinone methides (37a–c) have been studiedin aqueous solution in the pH range 0–8.135 The product o-hydroxybenzyl alco-hol was also used as precursor in each case, with the methide being generated byphotodehydration, and its reaction being monitored by the loss of absorbance at 400nm. An acid-catalysed arm in the rate profile gives way to a pH-independent regionfrom ca pH 4 onwards. From deuterium isotope effects and other considerations, themechanisms are

1. pre-equilibrium O-protonation, followed by reaction of the cation with water (inthe acid case); and

(37a) (37b) (37c)

H

O O O

OMe


2. nucleophilic attack of water at the methylene to give a (probably short-lived)zwitterion, followed by inter-oxygen proton transfer (in the pH-independent case).

While saturation of the acid catalysis was not reached for the simple methide (37a),its benzylidene analogue (37b) and its p-methoxyphenyl derivative (37c) did levelout at around pH 0.

‘No barrier’ theory has been used to calculate rate constants for hydration of awide range of carbonyl functions, from formaldehyde to carboxamides, for whichexperimental data are also available; agreement within 1–2 kcal mol−1 for �G �= wasobtained.136 The method allows rate constants to be calculated from equilibria, andvice versa. Results for hydroxide catalysis were particularly good, while in the caseof uncatalysed hydration, the cyclic versus non-cyclic mechanisms are not as yetresolved, although the cyclic mechanism is supported for difficult additions. Similarcalculations using multi-dimensional Marcus theory are also reported.137

The thermodynamics of the addition of water and alcohols to the carbonyl group of1-vinyl-2-formylimidazole, and to its conjugate acid, have been studied spectroscopi-cally, and compared with the corresponding equilibria in several related representativeheterocyclic compounds.138

Addition of Zinc Reagents

Most reports detailed enantioselective addition of diethylzinc to benzaldehyde, oftenfeaturing non-linear effects (see also the introduction to the Aldol and Related Reac-tions section above). For example, positive non-linear effects allow enantio-impurecatalysts to give higher reaction ees than their own ee. To push ees higher, a strategy �eehas been developed in which a diastereomeric catalyst is bound by a chiral substrateanalogue so as to inactivate one diastereomeric form.139 In suitable cases, the relative �deturnover frequencies of the diastereomers can be manipulated to give enhanced enan-tioselectivity for the catalysed reaction, i.e. a catalytic system which ‘self-inhibits’ the‘wrong’ reaction. The strategy is demonstrated for the ethylation of benzaldehyde.

In two other examples, chiral catalysts such as o-hydroxybenzylamines140 and o-hydroxyaryldiazaphosphonamides141 give positive non-linear effects in the ethylation �eeof aromatic aldehydes. The former uses the hydroxyl to ‘steer’ the zinc and the latterinvolves a monomer–dimer equilibrium in the action of the catalyst. A modest non-linear effect is reported for a C2-symmetric ligand with four chiral centres.142

An integrated ab initio plus molecular mechanics procedure (‘IMOMM’) givesan excellent correlation with experiment in predicting the enantioselectivity of addi-tion promoted by (R)-2-piperidino-1,1,2-triphenylethanol (38). The non-transferredethyl group appears to play a crucial role in transferring stereochemical informa-tion from ligand to reaction centre, suggesting that the computationally convenientdimethylzinc that is often employed in calculations is an inappropriate model for itsdiethyl analogue.143 Three (−)-fenchyl alcohol derivatives, characterized by X-raycrystallography, give fair to good ees when used as pre-catalysts.144 The results are �eerationalized via computations on the ‘transferring’ and passive alkyl groups aroundthe zinc.


N

PhOH

Ph

Ph

(38)

A kinetic and calorimetric study involving a (morpholino)isoborneol auxiliary showssignificant product inhibition occurring.145 The alcoholate of the product binds rever- �eesibly, which may be important in setting the balance between conversion and enan-tioselectivity in diethylzinc reactions.

Among several other enantioselective diethylzinc additions,146 – 149 a δ-amino alco-hol derived from camphor promotes quantitative ethylation in moderate to good ee,even with low auxiliary loading.150 Up to 95% ee has been achieved using chiral �eeferrocenyl alcohols derived from L-alaninol or L-leucinol.151

In other accounts, the reactivity and enantioselectivity of dialkylzinc additions usingfenchone-based catalysts have been enhanced via sterically induced distortions of thecatalysts,152 camphor disulfonamides have been used as ligands,153 and diisopropylzinchas been added enantioselectively,154,155 the last case involving a non-linear effect in �eean addition to a pyridine aldehyde.

Improvements in addition of diphenylzinc to aromatic aldehydes include a selectivefluorination of a chiral 1, 1′-binaphthyl ligand to boost its catalysis,156 and the addi- �eetion of diethylzinc to boost the yield based on diphenylzinc,157 apparently throughthe formation and reaction of the mixed organometallic, PhZnEt. The latter strat-egy counteracts the 50% loss of phenyl groups inherent in the standard reaction ofdiphenylzinc.

Synthetic and kinetic aspects of ethylation of cyclohex-2-enone and of aceto-phenones using the mixed organometallics, Et3ZnM (M = Li, Na, K), have beenreported.158

For more additions of zinc and other organometallics, see under Imines above.

Addition of Other Organometallics

Protected α-branched amines have been prepared diastereoselectively by copper(I)-mediated addition of Grignards to chiral p-toluenesulfinimines.159 The mechanisms �deof stereoselective additions of chiral Grignard reagents, particularly those with suchα-amino substituents, has been reviewed.160 �ee

Molecular recognition of particular conformations of α,β-unsaturated carbonyl com-pounds by aluminium tris(2,6-diphenylphenoxide) allows new regio- and stereo-sele-ctivities in alkylation of these substrates.161

Triethylaluminium has been added enantioselectively to aldehydes.162 �eeDiastereoselective addition of organometallics to (−)-menthone is activated by �de

anhydrous cerium(III) chloride.163

organic reaction mechanisms 2000...organic reaction mechanisms · 2000 an annual survey covering the...

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