PREPARATION OF SOME ORGANOZINC COMPOUNDS

AND THEIR ENANTIOSELECTIVE ADDITION TO

ALDEHYDES

THESIS

SUBMITTED TO THE

UNIVERSITY OF PUNE FOR THE DEGREE OF

DOCTOR OF PHILOSOPHY

IN

CHEMISTRY

BY

Mr. RAVINDRA SUBHASH JAGTAP

DR. N. N. JOSHI

(RESEARCH SUPERVISOR)

DIVISION OF ORGANIC CHEMISTRY

NATIONAL CHEMICAL LABORATORY

PUNE 411 008, INDIA

Dedicated to my beloved parents

CERTIFICATE

The research work presented in thesis entitled “Preparation of some

organozinc compounds and their enantioselective addition to aldehydes” has

been carried out under my supervision and is a bonafide work of Mr. Ravindra

Subhash Jagtap. This work is original and has not been submitted for any other

degree or diploma of this or any other university.

March, 2012 Dr. N. N. Joshi

(Research Supervisor)

National Chemical Laboratory, Pune (India)

 

 

DECLARATION

I hereby declare that the thesis entitled “Preparation of some organozinc

compounds and their enantioselective addition to aldehydes” submitted for Ph.

D. degree to the University of Pune has been carried out at National Chemical

Laboratory, under the supervision of Dr. N. N. Joshi. This work is original and has

not been submitted in part or full by me for any degree or diploma to this or any

other university.

March, 2012 Ravindra S. Jagtap

Acknowledgements First of all I wish to express my deep sense of gratitude and profound thanks to my

teacher and research supervisor Dr. N. N. Joshi for introducing me in the fascinating field of asymmetric synthesis. I am indebted to him for his personal care and his enthusiastic encouragement in the progress of my research work. His wide knowledge and logical way of thinking have been of great value for me. My interaction with him have improved my quality of research and developing me a critical research attitude. I will be always obliged to him for teaching me the finest skill and giving excellent training required for the research as well as for his constant effort to instill us with several essential habits, like group meeting, monthly report and daily planning of work. His systematic working style, discipline and humanitarianism is an attribute that I wish to take forward with me along with the chemistry that I learnt from him. My sincere regards and respect are for him forever.

I would like to thank Dr. S. P. Chavan and prof. D. D. Dhawale for their valuable suggestions and scientific discussion during assessment of my Ph.D. work.

I would like to thank the Council of Scientific and Industrial Research (CSIR), New Delhi for the award of fellowship. I am thankful to Dr. G. P. Pandey, Head of organic chemistry division and Dr. Sivram (ex. Director, NCL), Dr. Sourav Pal, Director, NCL who gave me an opportunity to work in this prestigious research institute and providing all necessary infrastructure and facilities.

My sincere thanks to Dr. M. S. Shasidhar, Dr. C. V. Ramana, Dr. U. R. Kalkote, Dr. N. P. Argade, Dr. H. B. Borate, Dr. P. K. Tripathi, Dr. B. G. Hazara, Dr. H. V. Thulasiram, Dr. D. Dethe, Dr. G. Sanjayan, Dr. Gumaste, Dr. (Mrs) A. P. Likhithe, Dr. (Mrs) S. P. Maybhate, Dr. Gajbhiye, Dr. Muthukrishnan, Dr. M. K. Dongare, Dr. P. P. Wadgaonkar, Dr. B. Idage Dr. (Mrs). Idage, Dr. (Mrs) Umbharkar and to other scientist of NCL.

I take this opportunity to express my great sense of gratitude to thank my teachers; Prof. R. A. Mane, Prof. M. S. Shingare, Prof. B. R. Arbad, Prof. T. K. Chondekar, Dr. Lande (M. Sc., Dr. B. A. M. university, Aurangabad), Dr. Nalawade, Mrs. Nalawade madam, Dr. Mahadik, Dr. Dhumure, Dr. Ghodke, Mungare sir, Fulsagar sir, Thorat sir (B. Sc., R. P. College Osmanabad), Bhosale Sir and Mahadik Sir (I. T. I. Osmanabad), late Sarang Sir, Bangar Sir, Naikawadi Sir, Padwal Sir, Raut Sir, Shinde Sir, Salunke Guruji, Sheikh Guruji, Nimbalkar Sir (School teachers) for their support and constant encouragement.

Help from spectroscopy, microanalysis and X-ray crystallographic groups is greatfully acknowledged. I sincerely thanks to Dr. Rajmohan, Dr. (Mrs) Phalgune, Mr. Sathe for NMR, Mrs. S. P. Kunte for recording chiral HPLC, Mr. Kalal, Dr. Borikar for GC analysis, Dr. P. L. Joshi for microanalysis. Help from IR and mass facility is also acknowledged. I express my thanks to the office staff, Library members and administrative staff for their timely help.

It gives me immense pleasure to express my sincere thanks to my senior colleagues; Dr. Kartick Bhoumick, Dr. Anamitra Chatterjee, Dr. M. Sasikumar for their friendly nature, giving excellent training, valuable discussion and support. I am very thankful my senior colleague Dr. Mannamth Patil for helpful scientific discussion, moral support and being a good fried.

I also would like to mention special thanks to Dr. (Mrs) B. N. Joshi and Rohit Joshi for rendering pleasant association during my research period.

I feel very fortunate to have friends like Kishor, Rahul, Ramchandra and seema. I have no word to express my emotions for their love, care and support in a tough time of my stay. I thank them and their family for everything that they gave.

Special thanks to dear friends; Amol, Goroba (samya), Sunil, Tirupati, Dr. Sanjay, Kiran, Jayant, Nana, Praveen, Ajit, Madhav, Kalyan, Appa, Ravi, Sanjay Chavan, Rajkanya, Shubhangi, Deepali, Meera, Dr. Sachin Navle, Prashant Mangshetti, Sunil sontakke, Tanaji gapat, Gurunath, Laxman, Sanjay, and Sakharam, Sambhaji, Sachin, Sandeep, Amar.

Help from my seniors, Dr. Bapu Shingate, Dr. Bhaskar Sathe, Dr. Rajiv Sawant and Dr. Sandeep Udawant is greatfully and sincerely appreciated.

It is a pleasure to thank all my friend at NCL, Scientist apartment and GJ hostel for their cheerfull company, which made my stay at NCL memorable one, especially Nilesh, Lalit, Dhanlaxmi, Namrata, Satish biradar, Ganesh Gogdand, Dr. Sudhir bavikar, Dr. Kondekar, Dr. Giri, Dr. Sharad, Amrut, Deepak, Ganesh, Ankush, Prakash, Bhausaheb, Dr. Bhange, Dhanu, Kiran, Pankaj, Abhijeet, Dayanand, dattatraya, Dr. Aabasaheb, Dr. Suleman, Sumantho, Prakash, Pradeep, kailash, Harshali, Balaji selukar, Pitambar, Dr. Sunil Pandey, Sachin, Dr. Vikhe, Dr. Pushpesh, Dr. Abhishek, Krishanu, Sangmash, Gopi, Dhiraj, Dr. Pandurang, Dr. Amol, Dr. Shriram, Dr. Deepak, Dr. Murli, Dr. Ajay kale, Dr. Shafi, Dr. Manish Shimpi, Dr. Kalpesh Rana, Dr. Haval, Dr. Umesh, Dr. Ramesh, Dr. Prasad, Mandeep, Tukaram, Sangram, Vijaykumar, Prasana, Swaroop, Priyanka, Ravindra, Debashish, Sridhar, Mahesh, Rohan, Ganesh, Nitin, Prakash sultane, Sachin mali, Jaman, Eknath, Anand (bapu), Kedar, Vinay, Dr. Omprakash bande, Dr. Viswas, Amit, Mahendra, Balaji Bhosale.

My special thanks to Madhuri patil, Dr. Rajendra, Bharat, Shobhana, Alson, Richa, and Majid for their support, help and cheerful atmosphere during my thesis writing.

There are no words to acknowledge my parents (Baba and Aai) for their blessing, love, care and continuous encouragement throughout all my life. Whatever I am and whatever I will be in future is because of their commitment to my ambitions, their patience and selfless sacrifices. I also express my heartfelt gratitude to my elder brother (Aaba) and my sister-in-law (Archana), younger brother Manojkumar, Sharad and sister in law (Laxmi), late Grandfather and grandmother for their moral support, love and blessing. Thanks to little members of my family Amar (dada) and Amruta (didi), for giving happiness to all of us.

I also express my heartfelt gratitude to my dear wife Bhakti for her constant support and love and my dear son Atharva for giving happiness and love.

I also express my heartfelt gratitude to late dada, Aai, Bhau, Nani, Bapu, Appa, Tatya, Babasaheb, Vahini, Mama, Mami, Kaka, Mavsi for their support and love.

Finally I thank God for giving me strength to carry out this work. Ravi

CONTENTS Page No. Abbreviations i

General remarks iv

Abstract v Chapter 1: Preparation and applications of organozinc compounds:

A literature survey

Introduction 1

Organozinc halides 2

Organozincates 42

Summary and Outlook 54

References 55

Chapter 2: Present work on organozinc compounds

Introduction 62

Section 2A: Preparation of alkylzinc halides and alkylzinc acetates 63

Section 2B: Enantioselective addition of RZnX to benzaldehyde 72

Section 2C: Organozincates and their enantioselective addition to

benzaldehyde 84

Conclusions 91

Experimental section 92

References 102

Spectra 109

Chapter 3: Potential chiral ligands

Introduction 117

Section 3A: Synthesis and resolution of cis- and trans-2,3-diphenyl

Morpholines 118

Section 3B: Attempted resolution of 2,3-diphenylbuatane-2,3-diol 146

Conclusions 159

Experimental section 160

References 172

Spectra 179

i

ABBREVIATIONS

Ac Acetyl

AcOH Acetic acid

Ar Aryl

aq Aqueous

acac acetylacetone

BINOL 2,2’-Dihydroxy-1,1’-binaphthol

BINAP 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl

Bn Benzyl

i-Bu Iso-butyl

n-Bu n-butyl

n-BuLi n-butyllithium

t-Bu tertiary butyl

Cat. Catalytic oC Temperature in degrees Centigrade

Config. Configuration

DCM Dichloromethane

DEPT Distortionless Enhancement by Polarization

Transfer

DIBAL-H Diisobutylaluminium hydride

DIEA Diisopropylethyl amine

DMA N,N-dimethylacetamide

DMAP 4-Dimethylaminopyridine

DME Dimethoxy ethane

DMF N,N-Dimethylformamide

DMI 1,3-dimethyl-2-imidazolidinone

DMPU N,N-dimethylpropyleneurea

DMSO Dimethyl sulfoxide

Dpp Diphenylphosphino

Dppf (diphenylphosphino)ferrocene

de Diastereomeric excess

ee Enantiomeric excess

ii

eq Equation

equiv. Equivalent

Et Ethyl

ET electron transfer

Et3N Triethyl amine

EtOAc Ethyl acetate

EtOH Ethyl alcohol

EWG Electron withdrawing group

FG Functional group

g Gram(s)

GC Gas Chromatography

h Hour(s)

HMPA Hexamethylphosphoramide

HPLC High Performance Liquid Chromatography

Hz Hertz

IR Infrared

M Molar

Me Methyl

MeOH Methanol

min. Minute(s)

mL Milliliter(s)

mmol Millimole

mp Melting point

Ms Mesyl

MS Mass spectroscopy

MsCl Methanesulfonyl chloride

MTBE Methyl tert-butyl ether

NaH Sodium hydride

NMP N-methyl-2-pyrrolidone

NMR Nuclear magnetic resonance

ORTEP Oak Ridge Thermal Ellipsoid Plot

Oct Octyl

PE Pet ether

Ph Phenyl

iii

Piv Pivaloyl

i-Pr Isopropyl

PTSA para-Toluene sulfonic acid

Py Pyridyl

Red-Al bis(2-methoxyethoxy)aluminumhydride

RT Room temperature

TADDOL α,α,α´,α´-Tetraaryl-1,3-dioxolan-4,5-

dimethanol

TBAB Tetrabutylammonium bromide

TBAF Tetrabutylammonium fluoride

TBAI Tetrabutylammonium Iodide

TEEDA N,N,N,N-Tetraethylethylenediamine

TFA Trifluoroacetic acid

THF Tetrahydrofuran

TLC Thin Layer Chromatography

TMEDA N,N,N,N-tetramethylethylenediamine

TMSCl Trimethylsilyl chloride

TMU 1,1,3,3-tetramethyl urea

Tr Triphenylmethyl

Ts Tosyl

iv

GENERAL REMARKS

• Independent compound numbering, scheme numbers and reference numbers

have been employed for abstract, as well as each chapter (Chapter 1-3).

• All the solvents and reagents were purified and dried according to procedures

given in D. D. Perin’s “Purification of Laboratory Reagents.” All reactions were

carried out under argon atmosphere using freshly distilled solvents, unless

otherwise specified. Yields refer to isolated product unless otherwise mentioned.

Column chromatographic separations were carried out by gradient elution using

silica gel (100-200 mesh / 230-400 mesh) using light petroleum ether-ethyl

acetate as the eluent, unless otherwise mentioned. Petroleum ether used in the

experiments was of 60-80 °C boiling range.

• TLC was performed on E-Merck pre-coated silica gel 60 F254 plates and the spots

were rendered visible by exposing to UV light, iodine, charring or staining with

ninhydrin, p-anisaldehyde or phosphomolybdic acid solutions in ethanol.

• All the melting points reported are uncorrected and were recorded using Buchi

melting point B-540 apparatus.

• IR spectra were recorded on Shimadzu FTIR instrument, for solid in chloroform

and neat in case of liquid compounds and are measured in cm-1.

• 1H NMR spectra were recorded on Bruker ACF 200 MHz, AV200 MHz, AV 400

MHz, DRX 500 MHz spectrometers using tetramethylsilane (TMS) as an internal

standard in CDCl3. Chemical shifts have been expressed in parts per million

(ppm) on δ scale downfield from TMS. The abbreviations s, bs, d, t, dd, dt, td

and m refer to the singlet, broad singlet, doublet, triplet, doublet of doublet,

doublet of triplet, triplet of doublet and multiplet respectively. Coupling

constants whenever mentioned have been given in MHz.

• 13C NMR spectra were recorded at 50 MHz and 75 MHz with CDCl3 (δ = 77

ppm) as the reference.

• Microanalytical data were obtained using a Carlo-Erba CHNS-O EA 1108

Elemental Analyzer.

• Optical rotations were obtained on Bellingham & Stanley ADP-220 Polarimeter.

Specific rotations, [α]D are reported in deg, and the concentration (c) is given in

g/100 mL in the specific solvent.

v

ABSTRACT

Introduction

Enantioselective addition of organometallic reagents to aldehydes is one of the most

important contemporary reactions. Such asymmetric reaction allows the preparation

of enantioriched secondary alcohols, which are building blocks for the synthesis of

natural products and pharmaceuticals. Enantioselctive addition of alkyllithium and

Grignard reagents is a straightforward approach to synthesize optically active

alcohols. However the method is of limited use due to the need of stoichiometric

amount of valuable chiral ligand to achieve high enantioselectivity. Use of less

reactive organozinc reagents has emerged as the solution to overcome above

difficulties. Organozinc reagents are very attractive owing to their mild reactivity

and excellent chemoselectivity. Amongst different approaches, catalytic

enantioselective addition of dialkylzincs to aldehydes is the most studied reaction.

However lack of wide commercial availability of dialkylzincs, high cost and their

pyrophoric nature demands an easy in situ preparation of these reagents. The

reagents of type RZnX (X = Cl, Br, I) which are easily accessible, represent the best

choice in this context. However, these reagents are not much explored in asymmetric

catalysis. The present work deals with the preparation of RZnX (X = Cl, Br, I, OAc)

and the corresponding organozincates and their applications in enantioselective

alkylation of aldehydes. The thesis entitled “Preparation of some organozinc

compounds and their enantioselective addition to aldehydes” is divided into three

chapters.

Chapter 1: Preparation and applications of organozinc compounds: A literature

survey

This chapter is a review of the literature on preparation of RZnX (X = Cl, Br, I,

OAc) and organozincates and their applications in various asymmetric reactions.

Chapter 2: Present work on organozinc compounds

This chapter is divided into three sections. Section 2A describes the preparation of

RZnX (X=Cl, Br, I) by oxidative insertion and preparation of RZnX (X = Cl, OAc)

by transmetallation or ligand exchange method. Section 2B deals with a detailed

vi

study on reactivity and enantioselective addition of RZnX to benzaldehyde. Section

2C describes the preparation, reactivity and enantioselective addition of

organozincates to benzaldehyde.

Section 2A: Preparation of alkylzinc halides and alkylzinc acetates

1. Preparation of RZnX (R= alkyl, allyl, benzyl, X= Cl, Br, I) by oxidative

insertion

Apart from the preparation of organozinc halides using highly reactive Rieke Zinc,

which is tedious, there are very few methods for the preparation of alkylzinc

bromides from commercial zinc and unactivated alkyl bromides. The two reliable

methods known in the literature require use of polar solvents like N,N-dimethyl

acetamide (DMA) or use of 1,2-dibromoethane as activator. However DMA is not

suitable for large scale preparation, whereas dibromoethane has limitations due to its

carcinogenic toxicity. Our aim was to develop easier preparative method for

alkylzinc halides in solvent like tetrahydrofuran which is more convenient and easy

to handle.

In our initial effort, the reaction of zinc dust and BuBr was carried out to

explore the reactivity pattern (Table 1).

Table 1. Oxidative insertion of zinc dust into butyl halides

Zn + RX THF, additives

50-55 oC(1 equiv.) (1.1 equiv.)RZnX

Entry RX Additives (equiv.)

Time (h) RZnX, yield a

(%) Zn consumed

(%) 1 BuI none 24 60 >95 2 BuI LiCl (1.1) 2 70 quantitative 3 BuBr LiCl (1.1) 48 - 20 4 BuBr 5 mol% I2 48 - 28 5 BuBr LiCl (1.1) + 5 mol% I2 18 65 quantitative 6 BuBr LiCl (1.1) + 2 mol% I2 + 5

mol% TMSCl 48 52 >95

7 BuBr LiCl (1.1) + 10 mol% LiI 24 62 quantitative 8 BuBr LiCl (1.1) + 10 mol%

TBAI 26 62 quantitative

9 BuCl LiCl (1.1) + 5 mol% I2 + 5 mol% TMSCl

48 - 25

a Determined by iodometric titration.

vii

It was found that butyl iodide reacts with zinc without any additive (entry 1).

However the use of LiCl dramatically increase the rate of the reaction (entry 2). As

expected, BuBr was much less reactive and required 1.1 equivalent LiCl along with

5 mol % I2 for complete dissolution of zinc (entry 5). Use of other activators like LiI

or TBAI also gave complete conversion (entry 7 and 8). Butyl chloride was found to

be unreactive under these reaction conditions (entry 9). Reaction does not proceed

even in polar solvents like EtOAc and DMA. In the course of our study, we have

observed the formation of small amount of butyl iodide when I2 / LiI / TBAI was

used. This could explain the increased reactivity for BuBr.

Several other alkylzinc bromides were prepared using excess zinc under the

optimized reaction conditions in good yields (Scheme 1). Due to steric bulk around

bromide, reaction of isobutyl and isopropyl bromide was slow and incomplete even

after 48 h. Reaction of tert-butyl bromide lead to complete dissolution of zinc in 24

h, although with only 40% yield of the zinc reagent. Allylzinc chloride and

benzylzinc chloride were also prepared in good yield from the corresponding

chlorides. To confirm the reagent formation, some of these reagents were further

reacted with electrophiles like benzoyl chloride and benzaldhyde.

Zn+RX5 mol% I2LiCl (1.1 equiv.)

(1.5 equiv.)(1 equiv.)RZnX.LiCl

THF, 50-55 oC

RX= EtBr (75%), BuBr (74%), HexBr (74%), OctBr (72%), Ethyl-4-bromobutyrate (73%) iBuBr (42%), iPrBr (25%), tBuBr (40%), allyl chloride (68%), benzyl chloride (75%).

Scheme 1. Preparation of RZnX using Zn, LiCl and catalytic iodine

2. Preparation of RZnX by transmetallation or ligand exchange

Organozinc halides also can be prepared by transmetallation that is, reaction

of RLi or RMgX with zinc halide. We have prepared RZnCl by stoichiometric

reaction of RMgBr (R = alkyl) with ZnCl2 (eqn.1). We extended this method for the

preparation of RZnOAc. Thus reaction of RMgBr (R = alkyl) with Zn(OAc)2 gives

RZnOAc with more than 95% yield (eqn.2). Using this method, there is always

formation of magnesium salts in stoichiometric amount along with the zinc reagent.

viii

Salt-free RZnX (X = Cl, Br, I, OAc) can be prepared by reaction of R2Zn and ZnX2,

so called ligand exchange. Thus ethylzinc chloride and ethylzinc acetate were

RMgBr + ZnCl2THF

0 to 25 oC, 1h(1)

RMgBr + Zn(OAc)2THF

0 to 25 oC, 1h(2)

Et2Zn + ZnCl2THF:Hexane

25 oC, 1h2 EtZnCl (3)

Et2Zn + Zn(OAc)2THF:Hexane

25 oC, 1h2 EtZnOAc (4)

RZnCl.Mg(Br)Cl

RZnOAc.Mg(OAc)Br

obtained by the reaction of diethylzinc with ZnCl2 and Zn(OAc)2 respectively (eqn. 3

& 4). All these reagents can be stored for several days as THF solution under inert

atmosphere.

Section 2B: Enantioselective addition of RZnX to benzaldehyde

Alkylzinc halides (RZnX) are known to be weakly active nucleophiles. It should be

possible to enhance the reactivity of these reagents by (i) reagent activation with

Lewis base catalyst, and (ii) substrate activation with Lewis acid. Initially we

examined the reactivity of salt free RZnX (prepared by ligand exchange method, R =

Et, X = Cl, OAc) with benzaldehyde in the presence of various chelating

agent/catalysts. It was thought that a bidentate chelating agent can coordinate with

zinc centre and forms reactive tetrahedral complex (fig.1).

ZnR X

YX

Figure 1

( reactive tetrahedral complex)

However the strategy did not prove fruitful. We also examined reactivity of

RZnX.LiX (prepared by insertion method) in the presence of various catalysts

(Scheme 2).

ix

RZnX.LiCl + PhCHOcatalyst (10 mol%)

THF, 0 to 25oC, 24 h Ph R

OH

R = Me, Et(X= Br, I) tracecatalysts:

N

O

Me

O

O

OMgBrPh Ph

OMgBrPh Ph

(-)

Ph O

NMeTi

(-)Ts

OiPr

OiPr

Ph O

NMeMgBr

(-)

Scheme 2. Addition of RZnX.LiCl to benzaldehyde

Only trace amount of expected product was observed in all the cases. As we found

MgX2 has role on the reactivity of RZnX, we prepared EtZnX (X= Cl, OAc) by

transmetallation method in which stoichiometric amount of MgX2 is present. Initially

EtZnCl.Mg(Br)Cl was reacted with PhCHO in the presence of various chelating

agents/catalysts (Scheme 3). Metal dialkoxides were prepared by the reaction of

corresponding diol with 2 equivalent of BuLi/EtMgBr. In our initial experiment, the

reaction of EtZnCl.Mg(Br)Cl with PhCHO without any additive gave only 11%

alkylated product in 4 h at 25 oC. To obtain enantioselectivity we tried chiral

chelating agent like (2R,3S)-(−)-4-methyl-2,3-diphenyl morpholine (1) and

lithium/magnesium dialkoxides (2), (3) and (5) derived from corresponding chiral

diols. One equivalent of 1, 4-dioxane was added to reduce the Lewis acidic effect of

Mg(Br)Cl. Although good yields were obtained, negligible enantioselectivity was

realized in all the cases.

EtZnCl.Mg(Br)Cl + PhCHO Ph

OHcatalyst (10 mol%)

THF, 0 oC

catalysts:

N

OPh

PhMe

(-)-(1)

Ph

OM

OM

Ph

M = Li (2) = MgBr (3)

(-)

O

O

OMOM

Ph Ph

Ph Ph

M = Li (4) = MgBr (5)

(-)

OMgBrOMgBr

(+)-(6)

(62-66%), <1% ee

Scheme 3. Addition of EtZnCl.Mg(Br)Cl to benzaldehyde

x

We then examined the reactivity of EtZnOAc.Mg(OAc)Br (prepared by

transmetallation method) with benzaldehyde in the presence of various additives

(Table 2). Without any additive, the reaction was slow at 0 oC, alkylated product was

obtained with 29% yield in 4h at 25 oC. Use of chiral morpholine (−)-(1) gave

racemic product with 18% yield in 8h at 0 oC. Interestingly the reaction with

benzaldehyde in the presence of 10 mol% lithium-dialkoxide (−)-(4) derived from

(−)-TADDOL gave 31% yield of the product with 13% ee (entry 3). The

corresponding Mg-dialkoxide (−)-(5) provided 28% ee (entry 4). Efforts to reduce

the Lewis acidic effect of Mg(OAc)Br by addition of one equivalent of 1,4-dioxane

or TMEDA did not help (entry 5&6). We observed increase in yield as well as

enantioselectivity by changing solvent from THF to MTBE. Under similar reaction

conditions product was obtained in 44% yield with 50% ee (entry 7). When the

reaction was carried out at room temperature, yield increased up to 60% with

decrease in ee (entry 8). Similar results were obtained when diethyl ether was used

as solvent (entry 9). Other Mg-dialkoxide (−)-(3) and (+)-(6) proved inferior to

TADDOL (entry 10 and 11).

Table 2. Enantioselective addition of EtZnOAc.Mg(OAc)Br(a) to benzaldehyde

EtZnOAc.Mg(OAc)Br + PhCHO Ph

OHcatalyst (10 mol%)

(S

)

Entry Catalyst

Solvent Temp (oC), Time (h)

Product, Yield (%)

ee

1 none THF 0 to 25, 4 29 - 2 (−)-(1) THF 0, 8 18 - 3 (−)-(4) THF 0, 8 31 13 4 (−)-(5) THF 0, 8 34 28 5 (−)-(5) THF 0, 8 37 18 6 (−)-(5) THF 0, 8 22 21 7 (−)-(5) MTBE 0, 8 44 50 8 (−)-(5) MTBE 25, 24 60 39 9 (−)-(5) Et2O 25, 24 54 38 10 (−)-(3) MTBE 25, 24 45 <5 11 (+)-(6) MTBE 25, 24 49 <1

xi

To avoid heterogeneous reaction conditions in solvent like MTBE and diethyl ether,

we decided to use THF. After extensive optimization it was found that by adding

Grignard reagent to a suspension of Zn(OAc)2 and (−)-TADDOL in THF, gave a

homogenous solution at 0 oC (Scheme 4). Under these conditions, up to 50%

enantiselectivity was obtained with moderate yields. We also found that rate of the

reaction as well as enantioselectivity vary with the stoichiometry of RMgBr with

respect to Zn(OAc)2. Best results were obtained with 1:1 ratio. In the study of halide

effect in RMgX, bromide and iodide were found better as compared to chloride.

Other Grignard reagents like butyl and isobutyl magnesium bromide gave 13% and

16% ee with lower yields. In the case of tBuMgCl, no reaction took place.

RMgX + Zn(OAc)2 + (-)-TADDOLi) THF, 0 oC, 1h

ii) PhCHO (1.0), 0 oC,Ph

OH

R(-)

R = Et, Bu, Bui, But

X = Cl, Br, Iup to 50% ee

(0.1)(1.7) (1.5)

Scheme 4. Enantioselective addition of various RZnOAc.Mg(OAc)X to

benzaldehyde

Section 2C: Organozincates and their enantioselective addition to

benzaldehyde

Addition of organozinc reagents to various organic electrophiles has become

one of the most common method to construct carbon-carbon bond. Pure dialkylzinc

reagents react sluggishly with aldehydes and ketones. However, their reactivity can

be enhanced by Lewis acid like MgX2 and chelating agent or metal alkoxide derived

from aminoalcohols. The preparation of dialkylzincs and organozincates is well

documented in the literature. In the present work, ethylzinc reagents were prepared

by the reaction of ZnX2 (X = Cl, OAc) with n equivalent of EtMgBr (n = 2, 3), eqn.5

and 6. In our initial experiment, the reaction of Et2Zn.2Mg(X)Br (X = Cl, OAc) with

0.9 equivalent benzaldehyde proceeds quantitatively in 1h at 0 oC. Next, the reagent

prepared from two equivalent of EtMgBr with ZnCl2/Zn(OAc)2 was then reacted

with 1.9 equivalent benzaldehyde. After 1h GC analysis showed formation of 73%

product in both the cases. These results indicate that more than one equivalent of

alkyl group transfer takes place. When the mixture of ZnX2 (X= Cl, OAc) and

xii

2EtMgBr was equilibrated for longer time (16 h) at room temperature, approximately

50% yield of the product was obtained in both cases. This difference in the

2 EtMgBr + ZnX2THF Et2Zn.2Mg(X)Br

X= Cl, OAc

(5)

3 EtMgBr + ZnX2THF (6)[Et3Zn]MgBr

reactivity can be attributed to the formation of the ate complexes I and II depicted in

eqn.7 and 8 respectively. After longer stirring the ate complex decomposes to give

Et2Zn, which can transfer only one alkyl group.

2 EtMgBr + ZnCl2THF

0 oCMg

ClZn

Br

Et

Et

ate complex-I

25 oC

overnightEt2Zn + 2Mg(Br)Cl (7)

2 EtMgBr+Zn(OAc)2THF0 oC

BrMg

O

OZnEt

Et

ate complex-II

25 oC

overnightEt2Zn + 2Mg(OAc)Br (8)

MgEt

ZnEt

ZnX2 + 3 EtMgBr

X= Cl, OAc

THFEt Br

ate complex-III

+ 2Mg(X)Br (9)0 oC

Next we studied the reactivity of trialkylzincates with benzaldehyde. In the present

study, the zincate III was prepared by reacting ZnX2 (X = Cl, OAc) with three

equivalents of EtMgBr at 0 oC (eqn. 9). The reaction of III with 2.9 equivalent

PhCHO gave 78% and 86% yield of the product in case of ZnCl2 and Zn(OAc)2

respectively. These results indicate that more than two equivalents of alkyl group

transfer in both cases. From the above results it can be concluded that zincate species

generated from ZnX2 and RMgBr can transfer all the three alkyl groups to

benzaldehyde. Based upon these findings we planned to use optically active diols as

chirality source for the preparation of chiral zincates.

xiii

Enantioselective addition of organozincates to benzaldehyde

The reaction of chiral diol is known to form zinc alkoxide (Scheme 5), which on

treatment with stoichiometric Grignard reagent would give chiral zincate complex-

IV. This chiral zincate complex can react with aldehyde to give enantioselective

product.

OH

OH* + Et2Zn

Toluene

80oC, 30 min.-2 Ethane

O

OZn

RMgXO

OZn R* *

Chiral zincate complex- IV

MgX

Chiral diol

Scheme 5: Preparation of chiral zincates

Various chiral diols were examined for enantioselective addition to benzaldehyde

under different reaction conditions. Up to 50% enantioselectivity was obtained using

(−)-TADDOL. The use of EtMgBr.LiCl (a structurally different Grignard reagent)

did not help. Poor ee was realized in case of hydrobenzoin and BINOL as diols.

Moderate ee may be due to background reaction of free Grignard reagent with

PhCHO.

Chapter 3: Potential chiral ligands

Section 3A: Synthesis and resolution of cis and trans-2,3-diphenyl morpholines

Synthesis of the title compounds 7 and 8 was reported by Stefanovsky and co-

workers in low overall yields starting from optically active aminoalcohol 10 and 15

respectively. We have synthesized cis and trans-2,3-diphenyl morpholines with

excellent overall yields after optimizing the reported procedure.

N

OPh

PhH

N

OPh

PhH

7 8 1. Synthesis of cis-(±)-2,3-diphenyl morpholine (7)

Synthesis of reacmic 7 starts from commercially available α-benzoin oxime

9. The benzoin oxime 9 was hydrogenated to cis-amino alcohol 10 in 80% yield

(Scheme 6). Reaction of 10 with chloroacetyl chloride in the presence of NaHCO3

gave hydroxy amide 11 as single product. Without further purification, compound 11

xiv

was cyclized to the lactam 12 using potassium hydroxide in EtOH. Relative

stereochemistry of phenyl rings in 12 was confirmed by single X-ray crystal

structure. The crude compound 12 was reduced with LiAlH4 to obtain 7 in overall

59% yield from 10.

Ph OH

NPh

9

Ph OH

NH2PhOH

a Ph OH

NPhH

O

Cl

b

10 11

c

N

OPh

PhH

O

12

d(±)-7

Scheme 6. (a) H2-Pd/C, MeOH, rt, 6 h, 80% (b) Chloroacetyl chloride, NaHCO3, MeOH, -10 oC to rt, 24 h; (c) KOH, EtOH, Reflux, 1.5 h; (d) LiAlH4, THF, reflux, 16 h, 59% (over three steps).

2. Synthesis of trans-(±)-2,3-diphenyl morpholine (8)

Similar reaction sequence was used for the preparation of trans-(±)-8 (Scheme 7).

The trans-amino alcohol 15 was obtained following the literature procedure. Further,

trans-amide 16 was prepared by N-Acylation of 15 using chloroacetyl chloride. Then

16 was further cyclized to trans-lactam 17 followed by LiAlH4 reduction give trans-

(±)-8 in 56% overall yield starting from 15.

Ph OH

NH2Ph

Ph OH

NPhH

O

N

OPh

PhH

OCl

Ph OH

NH2Ph

Ph OH

NH3ClPh

Ph OH

NPhH

H

O

10 13 14

16 17

a b c

d fe

15

(±)-8

Scheme 7. (a) conc. HCl, MeOH, 50 oC, 1.5 h 98%; (b) HCONH2, 150 oC, 15 min.; (c) (i) SOCl2, 0 oC to rt; (ii) H2O, reflux, 77% (over two steps); (d) Chloroacetyl chloride, NaHCO3, MeOH:THF, -10 oC to rt, 24 h; (e) KOH, EtOH, Reflux, 1.5 h; (f) LiAlH4, THF, reflux, 16 h, 56% (over three steps).

xv

3. Resolution of cis and trans-2,3-diphenyl morpholines

The most practical method for the resolution of racemic amines is the

preparation of diastereomeric salt with optically active acid, and then separation

through crystallization. In the present work, resolution of 7 was accomplished

through sequential use of L and D-tartaric acid (Scheme 8). Both the enantiomers

were obtained in good yield and high enantiomeric purity. Optical purity of both the

enantiomer was found to be ≥ 99% by chiral HPLC.

Solid salt

Filtrate

i) Recrystallization

ii) aq. NaOH, DCM(2R, 3S)-(-)-7

36%, 99% ee

(±)-7

i) L-(+)-Tartaric acid (0.25 equiv.)

ii) Et2O

i) D-(-)-Tartaric acidii) Recrystallization

iii) aq. NaOH, DCM(2S, 3R)-(+)-7

43%, > 99% ee

N

OPh

PhH

Scheme 8. Resolution of cis-2,3-diphenyl morpholine 7.

However L-tartaric acid failed to resolve the racemic trans-2,3-diphenyl morpholine

8. Success was achieved by using (−)-mandelic acid as resolving agent (Scheme 9).

+ R-(-)-mandelic acid Diastereomeric salt (DS)

(±)-8

Filtrate

aq. NaHCO3, DCM (2S, 3S)-(-)-8

39%, 92% eePreferentialprecipitation

i) Recrystallization

ii) aq. NaHCO3, DCM(2R, 3R)-(+)-8

44%, > 99% ee

MeOH

(DS)2-propanol

PPT

N

OPh

PhH

Scheme 9. Resolution of trans-2,3-diphenyl morpholine 8.

xvi

4. Application of 2,3-diphenyl morpholines in enantioselective diethylzinc

addition

Previously our research group had reported conceptually different and

efficient catalytic system viz zinc-amide, derived from oxazolidines in which both

zinc centres are tri-coordinate. We anticipated that morpholine based catalytic

system would be more efficient due to formation of tetra coordinate zinc centre. The

reaction of PhCHO with Et2Zn was carried out using 10 mol% of the ligand (Table

3). In case of 7 although good yields were obtained, only moderate enantioselectivity

was realized. Use of the corresponding lithium amide did not help (Table 3, entry 3).

Trans isomer (−)-8 proved inferior to cis. At this stage we are unable to provide

reason for low ee. Further optimization of reaction conditions and modification of

ligand structure is underway.

Table 3. Enantioselective addition of Et2Zn to benzaldehyde

Ph H

O Et2Zn (1.5 equiv.)

Ph

OH

(s) Ligand (10 mol%)

Entry Ligand Temp. (oC) Time (h) Yielda (%) eeb (%) 1 (−)-7 0 8 68 40 2 (−)-7 25 4 86 36 3 (−)-7/BuLi 25 2 85 29 4 (−)-8 25 24 73 12

a Isolated yield. b Determined by chiral GC analysis

Section 3B: Attempted resolution of 2,3-diphenylbuatane-2,3-diol

C2-Symmetric chiral diols have found numerous applications in asymmetric

synthesis as chiral auxiliaries, chiral ligands as well as chiral building blocks. We

wanted to explore sterically demanding chiral tertiary diol like 2,3-diphenyl-butane-

2,3-diol 18 in asymmetric synthesis. Although synthesis of enantiopure 18 was

reported by Cram et. al. resolution of this diol is not known in the literature. The

resolution of diols could be accomplished through diasereomeric esters or ketals, and

also through borate esters.

We have prepared dl-18 by pinacol coupling of acetophenone according to

the literature procedure, with excellent diastereoselectivity, equation 10.

xvii

+ Mn*25 oC, 2h

THF

Mn* = highly reactive manganese dl-1849%, >99% de

(10)Ph Me

O MePh

PhMe

OH

OH

1. Attempted resolution of dl-18 through addition complex

This method is based on formation of diastereomeric addition complex

between diol and resolving agent through hydrogen bonding. We examined various

resolving agent like trans-(−)-1,2-diamino cyclohexane, trans-(−)-1,2-

diphenylethane-1,2-diamine, (+)-cinchonine, and (−)-cinchonidine using various

solvents. However no addition compound could be isolated.

2. Resolution of dl-18 through chiral borate complex

This method involves formation of well defined covalent borate complex

between boric acid, diol and a resolving agent. We examined (−)-α-methyl benzyl

amine and (−)-phenyl glycinol as resolving agents. Only partial resolution of 18

could be realized using (S)-Proline as resolving agent (Scheme 10).

(S)-Proline

+ B(OH)3(i) Toluene, Reflux, 12 h

(ii) dl-18, Toluene reflux, 12 h

PPT-1+ Filtrate

PPT-1

PPT-2

Filtrate

THF, RT, 24h

Aq. 3N HCl:THF(-)-18

29%, 30% eeRT, 4h

N COOH

H

Scheme 10. Resolution of 18 by (S)-Proline and boric acid

CHAPTER-1

Preparation and applications of organozinc compounds: A

literature survey

1

Introduction

Enantioselective addition of organometallic reagents to aldehydes is one of

the fundamental asymmetric reactions and it is a powerful tool for the construction of

chiral carbon-carbon bond. This method provides enantiorich secondary alcohols,

which are building blocks for the synthesis of natural products and pharmaceuticals.1

Asymmetric addition of alkyllithium and Grignard reagents is a straightforward

approach for the synthesis of optically active alcohols. Although several examples

involving organolithium and Grignard reagents have been reported, these usually

require stoichiometric amounts of valuable chiral ligands.2 Due to the high

background reactivity of these reagents, catalytic version remained unexplored until

the recent report of Harada and co-workers.3 Furthermore, these reagents preclude

the presence of many functional groups due to their high reactivity which reduces

their attractiveness in organic synthesis. In contrast, organozinc reagents show very

mild reactivity and excellent chemoselectivity.4 In addition to the Reformatsky

reaction5 and the Simmons−Smith6 reaction, a number of carbon-carbon bond

forming reactions using organozinc reagents have been reported.4 Organozinc

reagents can be classified as four types,

(I) Organozinc halides (R-Zn-X, X = Cl, Br, I)

(II) Diorganozincs (R-Zn-R)

(III) Organozincates R3ZnM (M= MgX, Li) or R4ZnLi2

(IV) Reformatsky reagentOR

OZnX

Despite their discovery in 1849 by Frankland,7 organozinc reagents were

unexplored in asymmetric synthesis for a long period of time due to their poor

reactivity. After the report of Oguni and Omi in 1984,8a the enantioselective addition

of diorganozinc reagents to carbonyl compounds emerged as one of the attractive

tools for the preparation of optically active alcohols.1c,8 However lack of wide

commercial availability, high cost and pyrophoric nature limits their use to only

lower homologues.9 Therefore a search for the other alternatives is desirable. The

reagents of type RZnX (X = Cl, Br, I) which are easily accessible, are good

2

alternatives to diorganozincs. Organozinc halides have very less reactivity towards

most class of organic electrophiles due to high covalent character of carbon-zinc

bond and less Lewis acidity of Zn(II) metal centre. However, transmetallation with

transition metals such as Pd, Ni, Cu etc. generates reactive complex which shows

excellent reactivity.4b Their use has been mainly in Ni and Pd-catalyzed cross-

coupling reactions.10

Organozincates11 is another class of organozinc compounds which are more

reactive as compared to organozinc halides and diorganozincs. These reagents were

found to be attractive by synthetic organic chemists due to their unique reactivity and

excellent chemoselectivity.4a Organozincates have shown their usefulness in many

chemoselective organic transformations.4a,11c,d,g As compared to diorganozinc

reagents, reagent of type I and III are not much explored in asymmetric synthesis.

The present chapter will focus on reviewing the literature on preparation and

applications of organozinc halides and triorganozincates in asymmetric synthesis.

1. Preparation of organozinc halides

There are three general methods for the preparation of organozinc halides;

(i) Oxidative insertion (direct insertion of metallic zinc into carbon-halogen bond)

(ii) Transmetallation (the reaction of RM (M = Li or MgX) with zinc salt) and

(iii) Ligand exchange (the exchange of ligands between R2Zn and zinc salt)

1.1. Preparation of organozinc halides by oxidative insertion

The oxidative insertion is the most general and attractive protocol for the

preparation of organozinc halides. This method shows very broad scope and it is

applicable to the preparation of a number of simple as well as functionalized

organozinc reagents. In 1942 Hunsdiecker12a reported the preparation of number of

functionalized alkylzinc iodides 1 by the reaction of zinc with corresponding alkyl

iodide in ethyl acetate (Scheme 1).

RO2C(CH2)nI + ZnEtOAc

refluxn > 5

RO2C(CH2)nZnI

1

Scheme 1. Oxidative insertion of zinc into alkyl iodide in EtOAc

3

After this report, various other procedures have been reported. Some of the

important ones are described below.

In 1962, Gaudemar et al.12b reported that the primary alkyl iodide reacts with

zinc foil in THF at 50 oC in few hours to give corresponding alkylzinc iodide

whereas secondary iodide reacts at ambient temperature (Scheme 2).

RI + Zn RZnITHF, 25−50 oC

RI = primary or secondary alkyl iodide

Scheme 2. Preparation of alkylzinc iodides in THF

In 1964 Paleeva et al.12c reported the preparation of ethylzinc iodide by the

reaction of zinc-copper couple13 (8% copper) with ethyl iodide under reflux

condition (Scheme 3).

EtI + Zn-Cureflux

EtZnI

68%

Scheme 3. Preparation of ethylzinc iodide using Zn-Cu couple

In 1988 Knochel et al.14a observed fast reaction rates when zinc was

activated successively with a catalytic amount of 1,2-dibromoethane and TMSCl.

Thus, in the case of primary alkyl iodides insertion is complete in 2−3 h in THF at 40 oC, whereas secondary iodides react at room temperature. Under the optimized

conditions, various simple as well as functionalized alkylzinc iodides (RZnI) were

prepared in good yield (Scheme 4).

RI + Zn RZnITHF, 25−40 oC

Up to 90% yield

(CH2Br)2 (4 mol%)TMSCl (3 mol%)

R = alkyl, FG-alkyl; FG = CN, CO2R'

Scheme 4. Preparation of alkylzinc iodides using in situ activated zinc

4

In the same year Knochel′s group observed that the presence of cyano group

at β-carbon greatly accelerates the rate of the insertion reaction.14b The reaction of 2-

cyano iodides 2 with in situ activated zinc14c (cut foil or dust) in THF provided

corresponding zinc reagents 3 in good yield14d (Scheme 5).

R

CNI

R

CNIZn

80-90% yieldR = H, Pr

+ Zn

2 3

THF

5−30 oC, 3−5 h

Scheme 5. Preparation of 2-cyanozinc iodides

Knochel et al. also observed the presence of oxygen at α-carbon accelerates

the rate of the insertion reaction.15a,b For example, treatment of iodomethyl pivalate 4

with activated zinc foil14c in THF at 12 oC furnished PivOCH2ZnI 5 in excellent

yield15a (Scheme 6).

O

O

I

4

THF, 12 oC, 1 h+ Zn PivOCH2ZnI

5>85% yield

Scheme 6. Preparation of iodomethylzinc pivalate 5

Later in 2004 Kimura and Seki15c reported the preparation of alkylzinc iodide

7 by the treatment of zinc dust (activated with bromine) with corresponding alkyl

iodide 6 in excellent yield (Scheme 7). In comparison with other activators such as

TMSCl or 1,2-dibromoethane, use of bromine proved better for the large scale

preparation.

EtO2CI + Zn

Br2 (0.5 equiv)

THF:toluene50-60 oC, 1 h

EtO2CZnI

6 794% yield

Scheme 7. Preparation of ethyl iodovalerate

5

Simple alkyl bromides and chlorides usually cannot be converted to the

corresponding organozinc compounds in THF under the normal reaction conditions.

In 1990 Knochel et al.15d reported that the presence of phosphate group

considerably accelerates the rate of formation of organozinc bromides. Thus, the

treatment of primary bromophosphonates 8a with activated zinc dust14c in THF at 30 oC for 12 h gave the corresponding alkylzinc bromide 9a in excellent yield.

Secondary bromophosphonates 8b-d requires only 0.5 h for completion of the

reaction (Scheme 8).

PO Br

R1R2OR2O

THF, 25−30 oCPO ZnBr

R1R2OR2O

8a = R1 = H, R2 = Et8b = R1 = Me, R2 = Me8c = R1 = Pr, R2 = Me8d = R1 = Pr, R2 = Et

+ Zn

9a-d

0.5−12 h

upto 90% yield

Scheme 8. Oxidative insertion of zinc into bromophosphonates 8a-d

In the same year, Knochel et al. reported that the presence of sulfur allows

smooth insertion of zinc into carbon-chlorine bond.15e,f Thus, the reaction of α-

chloroalkyl phenyl sulfides 10a-e with activated zinc dust14c in THF at room

temperature for 2 h provided corresponding organozinc chlorides 11a-e in good

yield15e (Scheme 9).

PhS Cl

R+ Zn

THF, 25 oC, 2 h

PhS ZnCl

R

10a R = H10b R = CH310c R = Pr10d R = CH2CN10e R = (CH2)2CO2Et

11a-e

>85% yield

Scheme 9. Oxidative insertion of zinc into α-chloroalkyl phenyl sulfide 10a-e

6

In 1992 Knochel et al.16a reported that the use of polar solvents such as N,N-

dimethylacetamide (DMA) or N,N-dimethylpropyleneurea (DMPU) allows the

preparation of functionalized alkylzinc bromides 13 by the reaction of activated zinc

dust14c with corresponding primary alkyl bromides 12 using catalytic amount of

alkali iodide (Scheme 10). The insertion is reported to be complete in few hours at

70−80 oC.

FG Brn

FG ZnBr+ ZnMI (0.2 equiv)

DMA or DMPU70−80 oC, 2.5 h

n = 3, 4M = Li or CsFG = Cl, CO2Et

12 13

n

Scheme 10. Preparation of alkylzinc bromides in polar solvent

This reaction was extended for the preparation of functionalized alkylzinc

chlorides, tosylates, mesylates and diphenylphosphates using additional equivalent of

LiBr (or NaBr) (Scheme 11).

+ Zn

MI (0.2 equiv)MBr (1.0 equiv)

DMA or DMPU40−80 oC, 6−12 h

n = 3 to 8FG = Cl, CO2RX = Cl, OMs, OTs, OP(O)(OPh)2M = Li, Na, Cs

FG Xn

FG ZnXn

Scheme 11. Preparation of RZnX (X = Cl, OMs, OTs, OP(O)(OPh)2)

Later in 2003 Huo et al.16b reported a very efficient method for the

preparation of alkylzinc bromides in DMA. The treatment of zinc metal (activated by

5 mol % iodine) with primary alkyl bromide 14a in polar solvent such as DMA at 80 oC afforded the corresponding alkylzinc bromide 15a in excellent yield (Scheme 12).

Number of simple as well as functionalized alkyl bromides 14b-i (Figure 1) were

reacted with zinc under the optimized conditions to obtain corresponding zinc

reagent in >90% yield. However, the reaction of secondary alkyl bromides was

sluggish whereas, tertiary alkyl bromide did not even require iodine for activation.

7

On the other hand, no zinc reagent was formed when less polar solvents such as

diethyl ether, THF, dioxane, DME and acetonitrile were used.

n-OctBr + ZnDMA, 80 oC, 3 h

n-OctZnBrI2 (5 mol%)

14a 15a

Scheme 12. Preparation of n-Octylzinc bromide in DMA

Cl Br6

O Br5

O

NC Br4

Br3

EtO

O

Br Br Br Br

14b 14c 14d 14e

14f 14g 14h 14i

Figure 1

Use of other polar solvents such as DMF, DMSO, DMPU or NMP, and also

the various forms of zinc metal provided comparable results (Table 1).

8

Table 1. Direct insertion of zinc into n-Octyl bromide under various conditions

n-Oct-Br + Zncat. I2

80 oCn-OctZnBr

14a 15a

Entry Zn I2 (mol %) Solvent Time (h) Conversion (%)

1 dust 5 DMA 3 >99

2 dust 1 DMA 9 >98

3 dust 5 DMF 4.5 >99

4 dust 5 DMSO 3 >99

5 dust 5 DMPU 3 >99

6 dust 5 NMP 6 >98

7 powder 5 DMA 3 >99

8 granule 5 DMA 3 >98

9 shot 5 DMA 12 >98

Using this methodology alkylzinc chlorides 17a,b were also prepared from

the corresponding alkyl chlorides 16a,b in very good yield. The presence of

stoichiometric amount of salts like LiBr or R4NBr is required to achieve efficient

conversion (Scheme 13).

RCl + Zn

I2 (5 mol%) LiBr or Bu4NBr (1 equiv)

DMA, 80 oC, 12 hRZnCl

RCl = Cl7

Cl3EtO

O

16a,b 17a,b

16a 16b

Scheme 13. Preparation of alkylzinc chlorides in DMA

Later in 2006 Knochel et al.16c described LiCl-accelerated preparation of

alkylzinc bromides in THF. This method allows the preparation of alkylzinc

bromides from simple as well as functionalized alkyl bromides. Thus, the treatment

of zinc powder in situ activated by catalytic 1,2-dibromoethane and TMSCl, with

9

primary or secondary alkyl bromides (14a-c and 14j-o) in the presence of

stoichiometric amount of LiCl furnished the corresponding alkylzinc bromides in

excellent yield (Scheme 14). Author proposed that LiCl rapidly removes the formed

organozinc reagent from the metal surface by generating highly soluble RZnX⋅LiCl

complex, and freshly activated metal surface gets exposed to further insertion

process.

RBr + Zn 50 oC, 1−50 h

LiCl, THFRZnBr LiCl

Cl Br5

O Br4

O

Br

5

Br Br

Br

14k

14m 14n 14o

14j 14l

14a-c, 14j-o >92% yield

Scheme 14. LiCl-accelerated preparation of alkylzinc bromides

Unlike alkyl iodides, vinyl or aryl iodides do not undergo insertion in THF

under normal conditions and requires higher temperature or polar solvents such as

DMF, DMA.

In 1990 Knochel et al.17a reported the preparation of arylzinc iodides by the

reaction of commercial zinc with aryl iodides. The treatment of aryl iodides 18 with

zinc dust (in situ activated using 1,2-dibrmoethane) in DMF or DMA at 25 to 55 oC

afforded the corresponding arylzinc iodides 19 in good yield (Scheme 15). It was

observed that the substituent on the aromatic ring strongly influence the rate of the

zinc insertion. For example, iodobenzene requires 22 h at 55 oC for 80% conversion

whereas 2-iodobenzonitrile undergoes complete insertion within 2 h at 35 oC. A

comparison between the zinc insertion rates of o-, m- and p-iodobenzonitrile

indicated that o-iodobenzonitrile reacts significantly faster.

10

I

FG

+ Zn25−55 oC, 2−22 h

DMF or DMA ZnI

FG

FG = CN, Cl, COR, CO2Et

18 19

65-85% yield

Scheme 15. Preparation of arylzinc iodides in polar solvent

Author has also reported the preparation of alkenylzinc iodide 20 under these

conditions. The (E)-1-iodo-1-octene reacts with zinc in 14 h at 70 oC (Scheme 16).

H

Hex

I + Zn70 oC, 14 h H

Hex

E :Z(1:1 to 1 :1.5)

DMF

ZnI20

Scheme 16. Preparation of alkenylzinc iodide

In 1993 Takagi et al.17b reported the ultrasound-promoted insertion of zinc

into functionalized aryl iodides. Various functionalized aryl iodides were reacted

under different reaction conditions to obtain the corresponding arylzinc iodides in

good yield. One representative example is described below. Under ultrasound-

irradiation, the reaction of methyl 2-iodobenzoate with zinc powder in TMU (1,1,3,3-

tetramethyl urea) at 30 oC for 5 h gave arylzinc iodide 21 in good yield (Scheme 17).

Same reaction without irradiation of ultrasound requires 15 h for the completion.

CO2Me

I+ Zn

TMU, 30 oC

CO2Me

ZnI

ultrasound-irradiation 5 hwithout ultrasound-irradiation 15 h 87% yield

21

Scheme 17. Ultrasound-promoted preparation of arylzinc iodide

11

Later in 2003 the same author17c reported the preparation of functionalized

arylzinc iodides in ethereal solvents such as THF, diglyme or triglyme. The reaction

of zinc powder with functionalized aryl iodides 18 provided corresponding arylzinc

iodides 19 in good yield (Scheme 18).

I

FG

+ ZnZnI

FG

FG = H, CN, Cl, Br, CO2R', CH3, OCH3

18 19

TMSCl (3 mol%)

THF or diglymeor triglyme70−180 oC

Up to 95% yield

Scheme 18. Preparation of arylzinc iodides in ethereal solvents

It was observed that the aryl iodides containing EWG at the ortho-position

smoothly reacts in THF at 70 oC (Table 2), whereas those containing EWG at the

meta- and para-position or electron-rich aryl iodides were less reactive and requires

elevated temperature as well as solvents such as diglyme or triglyme.

Table 2. Preparation of various arylzinc iodides in etheral solvents

I

FG

+ ZnZnI

FG18 19

TMSCl (3 mol%)

24 h

Entry R Solvent Temp (oC) Yield (%)

1 o-CO2Me THF 70 87

2 m-CO2Me THF 70 20

3 m-CO2Me diglyme 100 84

4 p-CO2Me diglyme 100 89

5 p-CH3 diglyme 130 87

6a p-CH3 triglyme 180 83 a The reaction time was 1.5 h.

12

In the same year Gosmini et al.18a reported a new method for the preparation

of arylzinc bromides and iodides. In this method the treatment of aryl halide 22a-c

with zinc dust in the presence of catalytic amounts of PhBr, CoBr2, ZnBr2 and TFA

in acetonitrile furnished corresponding arylzinc halide 23 in moderate to excellent

yield (Scheme 19). In their initial study, they observed the formation of byproducts

such as reduction product (ArH) and the homocoupling product Ar-Ar. The addition

of catalytic amount of phenyl bromide prior to the addition of aryl halide (the

substrate) allows this side reaction to proceed on PhBr rather than on aryl halide

which results in increased yield of the desired product. Number of simple as well as

functionalized aryl and hetero arylzinc halides were prepared under mild reaction

conditions in good yield. The role of TFA was to activate the zinc metal. Author

proposed that the activated zinc reduces the Co(II) to Co(I) species which initiates

the insertion process.

ArX + Zn

TFA (cat.)PhBr (0.1 equiv.)CoBr2 (0.1 equiv.)

ZnBr2 (0.1 equiv.)Acetonitrile, RT, 30 min.

ArZnX

ArX =X

FG

X = Br, IFG = H, Cl, CN, OCH3, NR2, OCOR, COR, SO2Me

SBr

Up to 100% yield

S

Br

22a-c 23

22a 22b 22c

Scheme 19. CoBr2 catalyzed preparation of arylzinc halides

Aromatic chlorides are generally inexpensive and readily available substrates

as compared to the corresponding bromides and iodides. Later in 2005 the same

group18b extended the above reaction for the preparation of functionalized aryl and

hetero arylzinc chlorides using optimized reaction conditions.18c In this protocol the

reaction of aryl chlorides 24a-c with zinc dust in the presence of catalytic amount of

TFA, CoBr2, allyl chloride and use of pyridine as co-solvent furnished the

corresponding arylzinc chlorides 25 in moderate to excellent yield (Scheme 20).

13

ArCl + Zn

24a-c

TFA (cat.)allyl chloride (0.33 equiv.)CoBr2 (0.33 equiv.)

25Acetonitrile:PyridineRT, 2−31 h

ArZnCl

ArCl =Cl

FG

FG = H, CN, CF3, COMe, SO2Me

SCl

S

Cl

24a 24b 24c

45-95% yield

Scheme 20. CoBr2 catalyzed insertion of zinc into aryl chlorides

In 2006 Knochel et al.16c reported LiCl-accelerated preparation of arylzinc

iodides from activated zinc powder and corresponding aryl iodides in THF. Various

simple as well as functionalized aryl iodides 18 were converted to the corresponding

zinc reagent in excellent yield (Scheme 21).

I

FG

+ Zn50 oC, 1−90 h

LiCl, THF ZnI LiCl

FG

FG = H, CF3, CN, OMe, CHO, COR, CO2Et, CONR2

Up to 98% yield18

Scheme 21. LiCl-accelerated insertion of zinc into aryl iodides

This method was successfully extended for the preparation of vinyl and

arylzinc bromides. The treatment of aryl bromide 26a,c or vinyl bromide 26b

(containing electron withdrawing substituent) with activated zinc powder furnished

corresponding organozinc bromides 27 in very good yield (Scheme 22).

14

ArBr + Zn

26a-c

LiCl, THF

2725 oC, 24 h

ArZnBr LiCl

ArBr = BrCO2Et

EtO2C

Br

O BrEtO2C

26a 26b 26c

>90% yield

Scheme 22. LiCl-accelerated insertion of zinc into activated aryl bromides

In contrast to alkyl and aryl halides, allyl and benzyl halides are highly

reactive towards oxidative insertion of zinc. In 1962 Gaudemar et al.12b reported the

preparation of allylic and benzyliczinc bromides. The reaction of cinnamyl bromide

with zinc in THF at −15 to −5 oC gave corresponding zinc reagent in good yield

(Scheme 23). Benzyl bromide was also reacted under the similar reaction conditions

to obtain benzylzinc bromide.

Ph + ZnTHF, −15 to −5 oC

Br Ph ZnBr

Scheme 23. Preparation of cinnamylzinc bromide

Later in 1978 Bellassoued and Frangin19a reported the preparation of allylzinc

bromide by the reaction of allyl bromide and zinc in THF at ambient temperature

(Scheme 24).

Br + ZnTHF, 20 oC, 1 h

ZnBr

Scheme 24. Preparation of allylzinc bromide

15

The zinc insertion to substituted allylic halides is less satisfactory due to the

formation of substantial amount of homocoupling product. Knochel et al.19b in 2007

described the preparation of substituted allyliczinc chlorides 29 by the reaction of

allylic chloride 28a-d with zinc dust in the presence of LiCl in THF with moderate to

good yield (Scheme 25).

+ ZnLiCl, THF

0 oC to RTClR ZnClR

28a-d 29

ClR =

Cl

Me

Cl Cl

Ph Cl

55-84% yield

28a 28b 28c 28d

Scheme 25. Preparation of substituted allyliczinc chlorides

In 1988 Knochel et al.20a reported the preparation of various benzyliczinc

bromides. The reaction of benzylic halides 30 with zinc foil activated with 1,2-

dibromoethane in THF at 5 oC for 2−3 h gave corresponding benzylzinc bromides 31

in >90% yield along with the formation of homocoupling product in <5% yield

(Scheme 26). In the case of secondary benzyl bromides addition was done at −15 oC

to obtain good yield while corresponding chloride requires higher temperature (30 oC) for smooth conversion.

R

Br

+ Zn(CH2Br)2 (cat.)

THF, 5 oC, 2−3 hFG

R = H, CH3 FG = Cl, I, CN, OMe, COR', OAc

R

ZnBr

FG3031

> 90% yield

Scheme 26. Preparation of benzyliczinc bromides

16

Recently, Knochel et al.20b reported excellent method for the preparation of

benzyliczinc chlorides. Various functionalized benzylic chlorides 32 were converted

to the corresponding zinc organometallics 33 at room temperature in excellent yields

using activated zinc dust14c and stoichiometric amount of LiCl (Scheme 27). In the

absence of LiCl the reaction was incomplete and proceeds at slow rate.

R

Cl

+ ZnTHF, 25 oC, 3 h

FG

32a R = H32b R = Me

FG = Cl, Br, I, F, CN, COR', CO2R'.

R

ZnCl LiCl

FG

LiCl

32 33

Up to 99% yield

Scheme 27. Preparation of various benzyliczinc chlorides

1.1.1. Preparation of organozinc halide using highly reactive zinc (Zn*)

In 1973 Rieke et al.21a reported that the metallic zinc can be generated in situ

by the reduction of zinc halide with alkali metals. The zinc prepared by the reduction

of ZnCl2 with alkali metals such as Li, Na or K using electron carriers like

naphthalene shows higher reactivity than the commercial zinc powder and reacts

with unreactive alkyl as well as aryl bromides in less polar solvents like THF to give

corresponding organozinc bromides in excellent yield21b-f (Scheme 28).

ZnCl2 + 2 Li +THF or DME

(cat.)

Zn* + 2 LiClRT

RX + Zn*THF or DME

RZnXRT to reflux

Zn* = Highly reactive zincRX = 1o, 2o or 3o alkyl bromides, simple or functionalized aryl bromides and iodides

Scheme 28. Preparation of RZnX (R = alkyl, aryl, X= Br, I) using Rieke zinc (Zn*)

17

However alkyl chlorides are unreactive under these conditions and requires

Zn* prepared by the reduction of Zn(CN)2 with lithium using catalytic amount of

naphthalene.21g The zinc obtained by this method smoothly reacts with alkyl

chlorides 16a,c-f in THF at room temperature to provide corresponding alkylzinc

chlorides in good yield (Scheme 29).

Zn(CN)2 + 2 Li +

(cat.)

Zn* + 2 Li(CN)2RT, 5 h

RCl + Zn* RZnClRT, 12 h

RCl = Cl5

NC Cl4

Cl7

NC Cl6

OClN

N

THF

THF

16a 16c 16d 16e 16f

16a, c-f

Scheme 29. Preparation of alkylzinc chlorides using Rieke zinc

Later in 1999 Rieke's group21h has done a detailed study on oxidative addition

of highly reactive zinc to organic bromides. On the basis of kinetic and linear free

energy relationship studies (LFERs) they have suggested a mechanism in which the

insertion reaction proceeds through electron transfer (ET) and it is the rate

determining step. It was observed that the rate of insertion of zinc into organic

bromides follows the order allyl > benzyl > 3o alkyl > 2o alkyl > 1o alkyl > aryl >

vinyl. Authors proposed that zinc transfers the electron to alkyl halide and reaction

proceeds through intermediate I which upon transfer of second electron gives

alkylzinc halide (Scheme 30).

Zn + Br-R Zn Br R Zn-Br R RZnBrET ETδ

I

Scheme 30. Proposed mechanism for the oxidative insertion of zinc into R-Br

18

1.2. Preparation of organozinc halides by transmetallation

The second method for the preparation of organozinc halides is

transmetallation that is the reaction of highly reactive organometallics like RLi or

RMgX with zinc halide (Scheme 31). In this method, there is always formation of

lithium / magnesium salts in stoichiometric amount along with the zinc reagent. Due

to the high reactivity of alkyl lithium and Grignard reagent, this method cannot be

applied for the preparation of functionalized organozinc halides. There are several

reports on preparation of organozinc halides by transmetallation method.22,23 Few

important reports where the preparation and characterization of organozinc halides

have been done are described below.

RMX + ZnX2Transmetallation

R = Alkyl, Aryl, benzyl etcM = Li, MgX X = Cl, Br, I

RZnX MX2

Scheme 31. Preparation of organozinc halides by transmetallation

In 2009, Marder and Aiwen23e reported the preparation of PhZnCl⋅MgCl2 34

by the stoichiometric reaction of PhMgCl with ZnCl2 in THF (Scheme 32). The

complex was shown by single crystal X-ray analysis to be the novel dichloro-bridged

Zn/Mg complex (Figure 2).

PhMgCl + ZnCl2THF

0 oC to RT, 2 hPhZnCl MgCl2

34 Scheme 32. Preparation of phenylzinc chloride

Cl

Zn

Cl

Mg

Ph

Cl

THF

THF

THF

THF

Figure 2

19

Recently, Hevia et al.23f reported the preparation of complex t-BuZnCl⋅MgCl2

35 by the stoichiometric reaction of t-BuMgCl with ZnCl2 in THF (Scheme 33).

tBuMgCl + ZnCl2THF

tBuZnCl MgCl2 4THF35

Scheme 33. Preparation of tbutylzinc chloride complex

The complex 35 was characterized by X-ray crystallography. The structure of

the complex is depicted in figure 3, where zinc and magnesium are connected

through two chlorine bridges. Zinc forms distorted tetrahedral geometry whereas

magnesium achieves distorted octahedral geometry through bonding with four THF

molecules.

Cl

Zn

Cl

Mg

But

Cl

THF

THF

THF

THF

Figure 3

1.3. Preparation of organozinc halides by ligand exchange

The third method is ligand exchange,24 that is the exchange of ligands

between diorganozinc reagent and zinc halide. The reaction of R2Zn with ZnX2 gives

corresponding RZnX (Scheme 34). This method provides organozinc halides which

are free of magnesium or lithium salts.

R2Zn + ZnX2 2 RZnX

R = alkyl, aryl etc.X = Cl, Br, I

Scheme 34. Preparation of organozinc halides by ligand exchange

Important contributions made by different research groups for the preparation

of organozinc halides by ligand exchange method are described below.

20

In 1966, Boersma and Noltes24a prepared EtZnX (X = Cl, Br, I) by heating

the ZnX2 with diethylzinc at 70 oC (Scheme 35). These compounds were found to be

colorless, crystalline solids.

Et2Zn + ZnX270 oC, 10-20 min.

2 EtZnX

X = Cl, Br, I

Scheme 35. Preparation of salt-free ethylzinc halide

On the basis of cryoscopic molecular weight determination it was suggested

that ethylzinc chloride and bromide forms tetramer in benzene and have cubic

arrangement of Zn and halogen (Figure 4).

X

Zn X

Zn

Zn

X Zn

X

Et

Et

Et

Et

X = Cl, Br

Figure 4

Later in 1973, Shearer et al.24b crystallized EtZnI from ethyl iodide solution.

The X-ray crystallographic studies showed that ethylzinc iodide forms polymeric

structure which is consistent with the results obtained by Boersma and Noltes.24a

In 2006 Bochmann et al.24d prepared EtZnCl by heating the mixture of

diethylzinc and ZnCl2 in toluene for 72 h (Scheme 36). The X-ray crystallographic

studies showed that ethylzinc chloride forms infinite sheets [EtZnCl]∞ in which each

zinc atom is tetrahedrally coordinated to one ethyl and three chloride ligands.

Et2Zn + ZnCl270 oC, 72 h

2 EtZnCltoluene

Scheme 36. Preparation of salt-free ethylzinc chloride

21

In 2007 Woodward et al.24e reported the preparation of ethylzinc chloride in

THF by the treatment of diethylzinc with ZnCl2 at ambient temperature (Scheme 37).

Et2Zn + ZnCl225 oC, 1 h

2 EtZnClTHF

Scheme 37. Preparation of salt-free ethylzinc chloride

1.4. Miscellaneous methods

1.4.1. From diethylzinc and alkyl iodide

Higher homologues of alkylzinc halides can be prepared from Et2Zn and

alkyl halide in the presence of transition metal catalyst such as palladium or nickel.

In 1993 Knochel et al.25a reported the preparation of higher alkylzinc halides

for e.g. n-octylzinc iodide by the treatment of 1-iodooctane with Et2Zn in the

presence of catalytic PdCl2(dppf)2 in THF with good yield (Scheme 38).

n-OctI + 2 Et2ZnPdCl2(dppf)2 (1.5 mol%)

THF, 25 oC, 1.5 hn-OctZnI

78% yield

Scheme 38. Preparation of salt-free octylzinc iodide

A tentative mechanism25b was proposed for the above transformation. The in

situ generated L2Pd (L2 = dppf) inserts into OctI to give Pd(II) intermediate, which

undergoes transmetallation with Et2Zn to give OctZnI and L2Pd(Et)2 complex. This

complex rapidly decomposes to ethylene and ethane regenerating Pd(0) catalyst.

In 1994 Knochel and Cahiez25c reported Mn/Cu catalyzed preparation of

alkylzinc bromides using alkyl bromide and Et2Zn. The treatment of n-octyl bromide

14a with Et2Zn in the presence of MnBr2 (5 mol %) and CuCl (3 mol %) in DMPU

under mild reaction conditions provided n-octylzinc bromide 15a in good yield

(Scheme 39). Other functionalized alkylzinc halides were also prepared in good

yield.

22

n-OctBr + Et2Zn

MnBr2 (5 mol%)CuCl (3 mol%)

DMPU, 25 oC, 4−10 hn-OctZnBr

80-90% yield-(CH2=CH2, H3C-CH3)14a 15a

Scheme 39. Preparation of alkylzinc bromide from RBr and Et2Zn

Later in 1996, the same author25d reported Ni-catalyzed preparation of

alkylzinc halides from diethylzinc and alkyl halide without use of solvent. The

reaction of primary alkyl bromide or chloride (14a or 16a) with Et2Zn in the

presence of catalytic Ni(acac)2 afforded the corresponding alkylzinc halide in 70-

80% yield along with protonated product RH (~10%) and elimination product

(~10%) (Scheme 40).

RX + Et2Zn

70-80% yield14a or 16a

X = Cl, Br

Ni(acac)2 (5 mol%)

neat, 50−60 oCRZnX

Scheme 40. Ni-catalyzed preparation of alkylzinc halides from Et2Zn and RX

Author proposed the mechanism in which the in situ formed Ni(0) from

Ni(acac)2 and Et2Zn undergoes insertion reaction with alkyl halide to form RNiXLn

complex. This complex on transmetallation with Et2Zn gives RZnX and diethyl

nickel complex, which decomposes to give Ni(0), ethylene and ethane.

In 2008 Knochel et al.26a reported one pot procedure for the preparation of

benzyliczinc chlorides by using magnesium, ZnCl2 and LiCl. In this method

magnesium metal was reacted with benzylic chlorides 32a,b in the presence of ZnCl2

and LiCl in THF at room temperature to provide corresponding benzyliczinc

chlorides in excellent yield (Scheme 41). The formation of homocoupling product

was observed in <5% amount.

23

R

Cl

FG

32a R = H32b R = Me

FG = Cl, F, CN, CF3, CO2Et, OMe, SMe

32

+ Mg + ZnCl2 + LiCl R

FG25 oC, 2 h

THF

ZnCl

Scheme 41. One pot preparation of benzyliczinc chlorides using Mg, ZnCl2 and LiCl

Later, using this methodology various alkylzinc bromides, arylzinc chlorides,

bromides and iodides were prepared from corresponding halides in excellent yield

under the mild reaction conditions.26b-d Various functional groups like cyano, esters,

amides etc. were tolerated.

24

2. Applications of organozinc halides

2.1. Enantioselective 1,2-addition

In 2007 Woodward et al.27a reported the Me3Al promoted addition of arylzinc

bromides and iodides to aromatic aldehydes. In this protocol PhZnBr was first

converted to PhZnMe by stoichiometric amount of Me3Al. 13C NMR studies of the

mixture indicated rapid ligand exchange takes place between zinc and aluminum. In

situ formed PhZnMe was then treated with the 4-chlorobenzaldehyde in the presence

of catalytic amount of chiral β-aminoalcohols 36a-d, 37 and 38 (Scheme 42).

H

O

+

THF:Toluene RT, 16 h

OHPh

Me NBu2

PhZnX + AlMe3 PhZnMe + Me2AlX

AlMe336- 38 (10 mol%)

36b

OHPh

Me NMe2

OHPh

Me N

OHPh

Me N

OHPh

Ph NBu2

OHPh

Ph N

Ph

Ph

Ph

36a 36c 36d

37 38

Cl

PhZnX

Cl

Ph

OH

S

63% yieldup to 83 % ee

Scheme 42. Me3Al promoted addition of PhZnBr to 4-chloro benzaldehyde

The ligand 36b was found to be the most efficient ligand and therefore used

for the addition of ArZnX to various aldehydes (Table 3). Authors proposed that the

addition of Ph group takes place from Si face as shown in Figure 5.

25

Table 3. Enantioselective addition of ArZnMe to aromatic aldehydes using 36b

Entry Aldehyde ArZnX Yield (%) ee (%) Config.

1 4-ClC6H4CHO PhZnBr 67 83 S

2 4-ClC6H4CHO PhZnI 50 89 S

3 4-FC6H4CHO PhZnBr 76 90 S

4 4-MeC6H4CHO PhZnBr 61 89 S

5 4-MeOC6H4CHO PhZnBr 70 86 S

6 3-MeC6H4CHO PhZnBr 58 91 S

7 2-MeC6H4CHO PhZnBr 51 86 S

8 C6H5CHO 4-MeOC6H4ZnI 73 84 R

MePh

Bu2NO

ZnPh

Al

XO

HArSi

Me

Me

Figure 5. Proposed transition state

Later in 2010, the same research group27b studied the scope of the above

reaction in detail. They have examined number of other promoters such as ZnR2 (R =

Me, Et, Bu), AlR3 (R = Et, i-Bu), methylaluminooxane (MAO) and BR3 (R = Et,

OMe, F). However Me3Al proved to be the best. Under optimized conditions, the

addition of ArZnBr to various aromatic as well as aliphatic aldehydes afforded good

to excellent enantioselectivities. Few important examples of aliphatic aldehydes are

given in (Table 4).

26

Table 4. Enantioselective addition of ArZnMe to aliphatic aldehydes

R H

O+

CH3CN:Toluene RT, 16 h

AlMe3 36b (10 mol%)

ArZnBrAr

OH

R

Entry Aldehyde Ar Yield (%) ee (%)

1 n-BuCHO 4-MeOC6H4 87 82

2 t-BuCHO 4-MeOC6H4 96 93

3 t-BuCHO 4-EtO2CC6H4 76 96

4 i-PrCHO 4-EtO2CC6H4 48 93

5 c-C6H11CHO 4-EtO2CC6H4 53 97

In 2009 Walsh et al.27c used EtZnCl for the preparation of mixed

phenylethylzinc (PhZnEt) by treatment with PhLi in methyl tert-butyl ether (MTBE).

This reagent was then reacted with 2-benzofurancarbaldehyde 39 in the presence of

isoborneol based ligand (−)-MIB 40 (5 mol %) to obtain arylated product 41 in 92%

yield with 90% ee (Scheme 43). The role of N,N,N,N-tertaethylethylenediamine

(TEEDA) was to reduce the Lewis acidic effect of lithium halide generated during

the preparation of PhZnEt. In the absence of TEEDA poor enantioselectivity was

realized. The alcohol 41 was further converted to (S)-1-(benzofuran-3-

yl(phenyl)methyl)-1H-imidazole, a potential anticancer compound.

2 PhBr

i) n-BuLi (2 equiv) MTBE

ii) EtZnCl (2 equiv) −78 oC

PhZnEt

iii) TEEDA (0.8 equiv) toluene, 0 oC

iv) 40 (5 mol%)v) 39, 0 oC, 12 h

O

PhHO

92% yield90% ee

OHN

O

40

41

O

HO

39

Scheme 43. Enantioselective addition of PhZnEt to aldehyde

27

2.2. Diastereoselective 1,2-addition

2.2.1. Diastereoselective addition to keto esters

In 1991 Basavaiah et al.28a described cyclohexyl based chiral auxiliary

mediated preparation of various optically active α-hydroxy acids by the

diastereoselective addition of RZnCl to (1R,2S)-2-phenylcyclohex-1-yl

phenylglyoxalate 42. The treatment of 42 with alkylzinc chlorides, prepared from

RMgBr and ZnCl2, afforded corresponding α-hydroxy ester 43 which on hydrolysis

gave the desired α-hydroxy acid 44 in moderate to good yield with high optical

purity (Scheme 44).

Ph

O

OPh

O+ RZnCl

ether

−78 to 0 oC

Ph

O

OPh

HO R43

KOH

MeOH PhHOOC

HO R

50- 80% yield84- 99% ee

44R = Et, n-Bu, n-Hex i-Pr, i-Bu

42(R)

Scheme 44. Diastereoselective addition of RZnCl to α-keto esters

Encouraged by these result, the same group28b,c later examined various

cyclohexyl based chiral auxiliaries 45a-d (Figure 6) to study the steric effect. The

result showed that introduction of more bulky group on cyclohexyl ring does not

have significant variation on the diastereoselectivity.

OH

ONO2

OH

O

tBu

OH

O

OH

O

Ph

45a 45b 45c 45d

Figure 6

28

Later in 2002, Monteux et al.28d used the protected isomannide and isosorbide

as chiral auxiliaries in diastereoselective addition of various alkylzinc halides to

corresponding glyoxalate. The outcome of study was described below with one

representative example. Treatment of phenyl glyoxylate 46a (Figure 7) with i-PrZnX

(prepared from i-PrMgX and ZnCl2) in the presence of stoichiometric amount of

ZnCl2 gave corresponding α-hydroxy ester 47a in 78% yield with 88% de (Table 5,

entry 1). On the basis of outcome of the stereoselectivity, it was suggested that the

addition takes place in accordance with Whitesell′s model.28e However dramatic

decrease in selectivity was observed by interchanging the positions of α-ketoester

and protecting group. Thus, addition of i-PrZnX to 46b furnished the desired α-

hydroxy ester 47b with only 12% de whereas 46c afforded the ester 47c with >99%

de (Table 5, entry 2 and 3). In the case of 46c conformational arrangement allows the

л-stacking between the dicarbonyl moiety and phenyl ring of protecting group, which

is responsible for high stereoselectivity. Lack of such interactions in the case of 46b

explains the low selectivity. Saponification of 47a provided the corresponding α-

hydroxy acid with good enantioselectivity.

O

O

H

H

BnO

O

46b

O

O

H

H

O

OBn

O

O

Ph

46a

O

Ph

OO

O

H

H

BnO

O

O

Ph

O

46c

Figure 7

29

Table 5. Diastereoselective addition of RZnX to 46a-c

46a-ci) ZnCl2

ii) RZnX

O

O

H

H

BnO

O

O

Ph

OH

47a-cR

*MeOH/H2O

KOHO

OHR OH

Ph *

82% ee

Entry Substrate R 47, Yield (%) de (%)

1 46a i-Pr 78 88

2 46b i-Pr 51 12

3 46c i-Pr 53 >99

In 2006 Gaertner et al.28f reported the diastereoselective addition of RZnX to

α-ketoesters containing chiral m-hydrobenzoin auxiliaries. This reaction was studied

in solution as well as on solid support. Addition of alkylzinc chlorides to α-

ketoesters 48 afforded corresponding α-hydroxy esters 50a-c with moderate to

excellent diastereoselectivity (Table 6, entries 1−3). The larger nucleophiles like n-

BuZnCl and i-PrZnCl gave excellent diastereoselectivity, whereas the reaction with

small nucleophile like MeZnCl resulted in only moderate diastereoselectivity. Under

similar reaction conditions the keto ester 49 containing polymer supported chiral

auxiliary showed similar results affording the hydroxyl esters 51a-c (Table 6, entries

4−6). Author proposed that chelation of Zn2+ cation forces the two carbonyls of the

keto carboxylic ester into syn-conformation29 which effectively shields one face of

the elcetrophile (Figure 8). This methodology was employed for the preparation of

frontalin which is an aggregation pheromone of a pine beetle population in the

Dendroctonus family.

30

Table 6. Diastereoselective addition of RZnCl to 48 and 49

O

O

O

Ph

Ph

OR'

48 R' = O

O = Wang resin49 R' =

RZnCl

O

O

Ph

Ph

OR'R OH

50a-c51a-c

Up to 98% yield30-98% de

THF, -78 to -20 oC

Entry Substrate R Product de (%)

1 48 n-Bu 50a >98

2 48 i-Pr 50b 94

3 48 Me 50c 45

4 49 n-Bu 51a 90

5 49 i-Pr 51b 84

6 49 Me 51c 30

HO

Ph

O

PhH

O

Ph

O

OR'

Zn

X

Nure-attack

Figure 8. Proposed model for the diastereoselective addition

2.2.2. Diastereoselective addition to imino esters

The reaction of α-imino esters with organometallic reagents is an interesting

and potentially useful reaction for the synthesis of optically active amino acids and

amino alcohols.

In 1988 Yamamoto et al.30a reported the diastereoselective addition of

benzylzinc bromide to imino esters. The reaction of iminoester 52 with PhCH2ZnBr

in THF gave the desired product 53 (C-alkylation at imino carbon) in moderate yield

31

with 48% de (Scheme 45). Other organometallic reagents such as RMgX, R3Al,

RTi(O-i-Pr)3 provide the N-alkylated product.

NPh

Me

H CO2Bu

+ PhCH2ZnBrTHF

RT, overnight NPh

Me

CO2Bu

H

Ph

NPh

Me

CO2Bu

H

Ph

+

52 53a (major) 53b (minor)

S

R

S

S

50% yield48% de

Scheme 45. Diastereoselective addition of PhCH2ZnBr to 52

Later in 2002, Roland et al.30b studied this reaction in detail. In their

preliminary investigation they found that the presence of a chelating atom such as

oxygen in amine part or chiral alcohol in ester moiety and use of ZnBr2 is necessary

to achieve excellent diastereoselectivity in the addition of t-BuZnBr to α-imino ester.

Under the optimized conditions various organozinc bromides were reacted with α-

imino ester 54 to obtain desired product 55 in moderate to good yield with good

diastereoselectivity (Scheme 46).

NPh

OMe

OEt

O

i) ZnBr2, Et2Oii) RZnBr, 0 oC to RT

iii) NH4ClNH

Ph

OMe

OEt

O

R

54 55

Up to 68% yieldUp to 92% deR = t-Bu, sec-Bu, c-Hex, Bn

Scheme 46. Diastereoselective addition of RZnBr to 54

The stereochemical outcome of the reaction was explained by the proposed

chelate models A and B (Figure 9). Both the models lead to (R)-product. In chelate

A, ZnBr2 coordinates to imine nitrogen and two oxygen atoms (from the ester and

OMe) to form rigid five-membered rings and the zinc reagent attacks from less

hindered re face. In chelate B, zinc reagent may coordinate with oxygen atom of

methoxy group leading to preferential attack from re face.

32

N

O

O

OEtPh

H

ZnBr2

re face

N

O

O

OEtPh

H

Zn

Br

Br

Zn

R

X

chelate A chelate B

re face

Figure 9

Very recently Ellman et al.30c reported highly diastereoselective addition of

benzylzinc reagents to N-tert-butanesulfinyl aldimines. The treatment of benzylzinc

chloride with imine 56a gave the corresponding addition product 57a in good yield

and diastereoselectivity (Scheme 47). Under the optimized conditions, various

benzyliczinc chlorides were reacted with number of substituted imines. Few

representative examples are given in table 7.

H

N

MeO

SO

tBu

+ Ph ZnCl

THF, RTHN

MeO

SO

tBu

Ph

57a56a70% yield86% de

Scheme 47. Diastereoselective addition of PhCH2ZnCl to imine 56a

33

Table 7. Diastereoselective addition of benzyliczinc chlorides to various imines

R H

NS

O

tBu

THF, RTR

HNS

O

tBu

ZnCl

X

+

X56 57

Entry R X Yield (%) de (%)

1 4-CO2MeC6H4 H 86 84

2 4-ClC6H4 H 87 84

3 3-ClC6H4 H 86 84

4 2-ClC6H4 H 79 >98

5 3-Py H 98 92

6 4-CO2MeC6H4 4-OMe 69 88

7 4-CO2MeC6H4 4-F 86 88

8 t-Bu 4-F 77 52

2.3. Enantioselective 1,4-addition

In 2004 Hayashi et al.31a reported Rh-catalyzed enantioselective 1,4-

addition31b,c of arylzinc chlorides to protected 2,3-dihydro-4-pyridone to prepare

synthetically useful 2-aryl-4-piperidones 60a-f. In their initial study, they found that

PhZnCl was superior to other organometallics such as PhB(OH)2 or PhTi(O-i-Pr)3.

The addition of Phenylzinc chloride to 2,3-dihydro-4-pyridone 58 in the presence of

catalytic amount of [RhCl((R)-BINAP)]2 in THF afforded the desired product 60a in

excellent yield with high enantioselectivity (Scheme 48). This reaction showed broad

scope and the addition of various functionalized arylzinc reagents afforded excellent

enantioselectivities (Table 8). The methodology was successfully applied in the

preparation of a key intermediate for tachykinin antagonists B.

34

N

O

CO2Bn

+ ArZnCl

3 mol%[RhCl ((R)-BINAP)]2

THF, 20 oC, 2 h N

O

CO2BnAr

95% yield> 99.5% ee

58 60a Ar = Ph

PPh2

PPh2

(R)-BINAP =

59

Scheme 48. Enantioselective 1,4-addition of PhZnCl to 58

Table 8. Enantioselective 1,4-addition of various ArZnCl to 58

Entry Ar Product Yield (%) ee (%)

1 4-PhC6H4 60b 97 >99.5

2 4-MeOC6H4 60c 90 99

3 4-FC6H4 60d 91 >99.5

4 3,5-Me2C6H3 60e 87 99

5 2-MeC6H4 60f 100 99

The same author in 200531d described the preparation of 2-aryl-2,3-dihydro-4-

quinolones which are antimitotic antitumor agents. Initially the treatment of PhZnCl

with 4-quinolone 61 under the above reported conditions31a resulted in very low

yield. However, the addition of TMSCl (as a Lewis acid) gave smooth conversion

under mild conditions and expected product 62 was obtained with excellent

enantioselectivity (Scheme 49). The outcome of the stereoselectivity in Rh/(R)-

BINAP catalyzed 1,4-addition was rationalized by the re face approach of the

substrate to avoid the steric repulsion between the phenyl ring on the phosphorus

atom of (R)-BINAP and fused benzene ring of the substrate.

35

N

O

CO2Bn

+ PhZnClTMSClTHF, 20 oC, 20 hthen 10% aq. HCl

88% yield98% ee

61 62

[RhCl (C2H4)2]2 (7.5 mol% Rh)59 (8.2 mol%)

N

O

CO2BnPh

Scheme 49. Enantioselective 1,4-addition of PhZnCl to 61

In the same year Hayashi′s group31e reported the use of above methodology35d

in enantioselective 1,4-addition of phenylzinc chloride to α,β-unsaturated ketones

catalyzed by [Rh((1R,5R)-Ph-cod)((R)-1,1′-binaphthyl-2,2′-diamine)] 64. Treatment

of α,β-unsaturated ketones or esters 63a-d with phenylzinc chloride in the presence

of catalytic amount of 64 provided the expected product 65a-d in excellent yield with

high enantioselectivity (Scheme 50). The reaction was very fast and completes in 20

minutes at 0 oC.

X

O

63a-d

+ PhZnClTMSCl (1.5 equiv)

64 (3 mol%)THF, 0 oC, 20 min.

X

O

(R)-65a-dPh

O O

O

O

O

O

63a 63b 63c 63d

RhN

N

Ph

BF4

H

H

H

HPh

64

86-99% yield90-98% ee

X = CH2, O

Scheme 50. Enantioselective 1,4-addition of PhZnCl to 63

Later in 2006, Hayashi et al.31f described the enantioselective 1,4-addition of

arylzinc halides to α,β-unsaturated aldehydes. The reaction of various (E)-3-

arylpropenal 66 with ArZnCl in the presence of TMSCl and catalytic amount of

36

Rhodium catalyst (coordinated with (R)-BINAP 59) in THF at 20 oC furnished

corresponding 3,3-diarylpropanal 67 with excellent enantioselectivity (Scheme 51).

Ar1 H

O

+ ArZnCl

[RhCl((R)-BINAP)]2 (3 mol% of Rh)

TMSCl, THF20 oC 1 h

K2CO3

MeOH/H2ORT, 1 h

Ar1 H

OAr

55-80% yield98-99% ee

66 67

Ar1 = 4-MeOC6H4, 2-MeOC6H4, 2-FC6H4, C6H5

Ar = C6H5, 4-MeOC6H4, 3-MeOC6H4, 3,5-Me2C6H3 2-naphthyl, 4-ClC6H4, 3-ClC6H4

Scheme 51. Rh-catalyzed enantioselective 1,4-addition to enal 66

In 2008 Frost et al.31g reported the enantioselective 1,4-addition of substituted

thienylzinc and 2-furanylzinc bromides to α,β-unsaturated ketones and esters using

catalyst prepared from [Rh(C2H4)2Cl]2 and chiral phosphorous ligand. Initial

investigations showed (R,R)-Me-DUPHOS 69 gave excellent results as compared to

other phosphorus ligands. Excellent enantioselectivities were obtained in 1,4-

addition of 68a and 68b to α,β-unsaturated ketones (63a and 63b) and ester 63c

using catalytic amount of 69 (Scheme 52).

X

O

63a-c

+

TMSCl, THF, 20 oC

X

O

38-91% yieldUp to 98% ee

O ZnBr

R1

S ZnBr

[Rh(C2H4)2Cl]2 (cat.) 69 (cat.)

(R)

(R,R)-Me-DUPHOS

P P

69

X = CH2, O

68a 68bR1 = Br, Me,

68a,bY

R1Y = O, S

Scheme 52. Enantioselective 1,4-addition to 63 using ligand 69

In 2009 Martin et al.31h reported Rhodium-catalyzed enantioselective 1,4-

addition of 2-heteroarylzinc chlorides to cyclic enones, unsaturated lactones, and

unsaturated lactams using (R)-MeO-BIPHEP ligand 71. The addition of benzofuran-

37

2-ylzinc chloride 70a or benzothiophene-2-ylzinc chloride 70b to Michael acceptors

63a-e in the presence of TMSCl and catalytic amount of 71 afforded the

corresponding 1,4-addition product in moderate to good yield with high

enantioselectivity (Scheme 53).

63a-e

N

OMe

63e

TMSCl, THF−78 to 0 oC

[Rh(cod)acac] (cat.) 71 (cat.)

Ar1ZnCl X

O

Ar1

47-93% yield91- 98% ee

OS

70a 70b

P(Ph)2P(Ph)2

MeOMeO

(R)-MeO-BIPHEP

71

+

70a,b

Ar1 =

Scheme 53. Enantioselective 1,4-addition of 70 using ligand 71

2.4. Asymmetric cross-coupling reactions

In 1983 Kumada et al.32a reported Pd-catalyzed cross-coupling of organozinc

halides with vinyl bromide. The reaction of secondary alkylzinc halides 72 with vinyl

bromide in the presence of Palladium catalyst 73 afforded olefin 74a-c in good yield

with up to 86% enantioselectivity (Scheme 54).

Ar

RZnX + CH2=CHBr

THF, -78 to 0 oC

73 (cat.)

73 PdCl2[(R)-(S)-PPFA]

Ar

HR

7274a-c

X = Cl, Br, I72a Ar = Ph, R = Me72b Ar = p-Tol, R = Me72c Ar = Ph, R = Et

(s) FePPh2

NMe2

PdCl

Cl

H

Scheme 54. Pd-catalyzed enantioselective cross-coupling

Later in 1989, Hayashi and Ito32b reported Pd-catalyzed enantioselective

cross-coupling of l-phenylethylzinc chloride 72a with vinyl bromide using catalytic

amount of ferrocenylphosphine ligand 75. The expected product was obtained in

quantitative yield with excellent enantioselectivity (Scheme 55).

38

93% ee

Ph

MeZnCl + CH2=CHBr

THF, 0 oC

75 (0.5 mol%) Ph

MeH

74a(R)

72a

NMe2H

Me

NMe2Me

H

Ph2P

PPh2

PdCl2Fe

75

Scheme 55. Pd-catalyzed enantioselective cross-coupling catalyzed by 75

In 2005 Fu et al.33a reported first example of Ni-catalyzed asymmetric

Negishi cross-coupling33b of alkylzinc bromides with secondary α-bromo amides.

The treatment of various secondary α-bromo amides 76 with simple as well as

functionalized alkylzinc bromides in DMI/THF (DMI = 1,3-dimethyl-2-

imidazolidinone) using catalytic amount of NiCl2⋅glyme and (R)-i-Pr-Pybox ligand

77 provided desired product 78 in moderate to good yield with excellent

enantioselectivity (Scheme 56).

NN

OO

NPri iPr

+

NiCl2.glyme (10 mol%) ligand 77(13 mol%)

DMI/THF, 0 oC

51-90% yield87 to >98% ee

R1ZnBrN

ORBn

Ph BrN

ORBn

Ph R1

77

76

R = Me, Et, n-Bu, i-BuR1 = alkyl, functionalized alkyl

(R)-i-Pr-Pybox

(Recemic)

78

Scheme 56. Nickel-catalyzed asymmetric Negishi coupling of R1ZnBr with 76

The same year Fu′s group33c described Ni-catalyzed cross-coupling of

alkylzinc bromides with secondary benzylic halides. Thus, the reaction of 1-bromo or

1-chloro indanes 79 with various alkylzinc bromides in the presence of NiBr2⋅glyme

and (R)-i-Pr-Pybox ligand 77 in DMA gave desired product 80 in moderate to good

yield with moderate to excellent enantioselectivity (Scheme 57). Author

39

demonstrated that this methodology can be used in the synthesis of bioactive

molecules such as LG 121071.

+

NiBr2.glyme (10 mol%) ligand 77 (13 mol%)

DMA, 0 oC, 24 h

41-89% yield75-99% ee

X

R2

R1

R2

X = Cl, BrR1 = alkyl, functionalized alkylR2 = Cl, CN, Me, OMe

R1ZnBr

79(Racemic)

80

ferentially occurs at less hindered carbon with the regioselectivity

>20:1. The addition of NaCl accelerates the rate of cross-coupling, but has little

effect on ee. Author applied this methodology for the formal synthesis of

fluvirucinine A1.

Scheme 57. Nickel-catalyzed asymmetric Negishi coupling of R1ZnBr with 79

Later in 2008, the same author33d reported the Ni-catalyzed asymmetric cross-

coupling of allylic chlorides with various alkylzinc bromides. The reaction of various

symmetrical as well as unsymmetrical allylic chlorides 81 with alkylzinc bromides in

the presence of excess NaCl and catalytic amount of (S)-BnCH2-Pybox ligand 82

gave the corresponding coupling product 83 in good yield with excellent

enantioselectivity (Scheme 58). In the case of unsymmetrical allylic chlorides the

cross-coupling pre

R2 R3

Cl

+

NiCl2.glyme (5 mol%)ligand 82 (5.5 mol%)NaCl (4 equiv)

DMA/DMF, −10 oC, 24 hR2 R3

R1

Up to 95% yieldUp to 98% ee

R1 = alkyl, functionalized alkylR2 = n-Bu, i-Pr, t-Bu, COOEt, CONEt2, CON(OMe)Me, PO(OEt)2R3 = Me, n-Pr, i-Pr

R1ZnBr8381

NO

N N

O

82Bn Bn(S)-BnCH2-Pybox

Scheme 58. Nickel-catalyzed asymmetric Negishi coupling of R1ZnBr with 81

40

In 2009 Fu et al.33e reported the asymmetric cross-coupling of arylzinc

iodides with α-bromoketones. After extensive optimization of the reaction

conditions, they found that this reaction proceeds smoothly in the presence of

NiCl2⋅glyme (5 mol%), Pybox ligand 85 (6.5 mol%) in glyme/THF. Under optimized

conditions, treatment of α-bromoketones 84 with various arylzinc iodides provided

corresponding cross coupled product in good yield and good enantioselectivity

(Scheme 59). Decreased yield as well as ee was observed when Ar1 and R were the

bulky substituent.

NN

OO

N

+

NiCl2.glyme (5 mol%) ligand 85(6.5 mol%)

glyme/THF, −30 oCArZnI

OR

Br

8584

O

A

r = Ph, 2-MeOC6H4, 3-MeOC6H4, 4-MeOC6H4, 4-FC6H4, 4-Me2NC6H4, 4-MeSC6H4.

H , 4-F CC H , 2-thienyl

Ar1

Ar1 = Ph, 2-FC H , 3-EtC H , 4-Me6 4 6 4 OC6 4 3 6 4

(Recemic)

R

Ar

Ar1

Ph Ph

MeOOMe

Up to 93 % yield

In 1997 Knochel et al.34a reported the preparation of various chiral ferrocenes

by the reaction of ferrocenyl acetate with various organozinc reagents. The treatment

of chiral ferrocenyl acetate 86 with RZnX in the presence of BF3⋅OEt2 provided the

expected product 87 in good yield with >95% retention of stereochemistry (Scheme

60).

Up to 96 % ee

Scheme 59. Nickel-catalyzed asymmetric Negishi coupling of ArZnI with 84

2.5. Miscellaneous reactions

FeR1

OAc

+ RZnX

R

64-98% yield95-98% ee

THF

-78 oC to RT, 1.5 h FeR1

86 87X = Br, IR = i-Pr, (E)-PhCH=CH, allyl, 3-MeC6H4CH2R1 = Me, Ph

Scheme 60. Substitution of ferrocenyl acetate 86 with RZnX

41

Later in 2003, Xue et al.34b reported the preparation of C-Glycosides by

. Treatment of 88 (prepared by

Danishefsky′s protocol35) with organozinc halides, prepared from RLi and ZnCl2,

provided α-glycoside 89a as major product (Table 9). However, low

diastereoselectivity was observed when RZnX was prepared from RMgX and ZnCl2.

Table 9. Addition of various RZnX to epoxide 88

addition of organozinc halides to glycal epoxide 88

RR OOO

BnOOBn

BnO+ RZnX

Et2O

0 oC to RT

OBnO

BnOOBn

BnO

BnO+

OBnOHOH

88 89a 89b Entry RZnXa Yie ) 8 ld (% 9a:89b

1 n-BuZnCl 69 >95:5

2 PhZnCl 78 >95:5

3 O 72 >95:5 ZnCl

4 Ph-C C-ZnCl 86 100:0

5 C-ZnClC3H7 - 80 100:0

6 n-BuZnClb 41 66:34 a prepared from RLi and ZnCl2. b Prepared from RMgX and ZnCl2.

In 2004 Ready et al.36 found that alkylzinc chlorides prepared from Grignard

reagent and ZnCl2 undergo efficient cross-coupling with α-halo ketones in the

presence of copper catalyst. Using this methodology optically pure α-chloroketone

90 was reacted with iso-propylzinc chloride to obtain desired product 91 in good

enantioselectivity with 100% inversion of stereochemistry (Scheme 61).

OOCH3

Cl

i-PrZnCl MgCl2

Cu(acac)2 (5 mol%)Et2O/THF, 25 oC, 14 h

CH3

MeMe

90 9195% ee 77% yield

95% ee Scheme 61. Cu-catalyzed coupling of α-haloketones

42

3. Preparation of organozincates

The organometallic reagent having Lewis acidic metal centre possess ability

to react with anionic fragment. Due to the presence of vacant orbitals on the metal

centre these reagents when reacted with Lewis base, form a new organometallic

species which is termed as an ‘ate’ complex.11c,37 The outer shell of zinc atom in

dialkylzinc (e. g. Me2Zn) is filled with 14 electrons and there are two empty orbitals

which can occupy two pairs of electrons. Therefore it can react with one or two

Lewis basic reagent (e.g. MeLi) which results in the formation of organozincate

mple

incates. The

following literature survey therefore is mainly focused on preparation and

applications of triorganozincates in asymmetric reactions.

Triorganozincates are generally prepared by the reaction of zinc halide with

three equivalents of alkyllithium or Grignard reagent or from stoichiometric reaction

of organolithium or Grignard reagent with diorganozinc4a (Scheme 62).

co x Me3ZnLi or Me3ZnLi2 respectively. Organozincates are further classified

into two classes: i) Triorganozincates [R3Zn]M and ii) Tetraorganozincates

[R4Zn]M2. We were particularly interested in the chemistry of triorganoz

ZnX2 + 3 RM [R3Zn]M

ZnR2 + RM [R3Zn]M

M = Li, MgX

Schemer 62. Methods for the preparation of triorganozincates

These reagents have very old history and are known since the report of

Wanklyn in 1858.38 Author prepared [Et3Zn]M (M = Na, K) from the reaction of

Et2Zn and alkali metals (Na or K). However very little information was known about

such complexes at that time. There are several reports on the preparation of

iorganozincates. Some of the important methods are discussed below.

On the basis of spectroscopic evidence, Waack and Doran39a reported in 1963

that the 1:1 mixture of Et2Zn and 1,1-diphenyl-n-hexyllithium forms triorganozincate

species (Scheme 63).

tr

43

Et2Zn + RLi [Et2ZnR]Li

R = 1,1-diphenyl-n-hexyllithium

Scheme 63. Preparation of lithium triorganozincate

In 1986 Kjonaas et al.39b reported the preparation of magnesium

trialkylzincate [R3Zn]MgBr by the reaction of ZnCl2⋅TMEDA complex with 3

equivalent of Grignard reagent in THF (Scheme 64). Authors have observed that this

complex reacts chemoselectively with α,β-unsaturated ketones to give 1,4-addition

as the major product.

ZnCl2 TMEDA + 3 RMgX [R3Zn]MgXTHF

R = alkyl, aryl X = Cl, Br, I

Scheme 64. Preparation of magnesium triorganozincates

In 1991 Richey Jr. et al.40 reported the preparation of heteroleptic

triorganozincate 92. The reaction of stoichiometric amount of diethylzinc with

potassium tert-butoxide in toluene provided the zincate 92 (Scheme 65). NMR

plex exists in spectroscopy and X-ray crystallographic studies showed that the com

dimeric form.

Et2Zn + t-BuOKtoluene

[Et2ZnO-t-Bu]K

92

Scheme 65. Preparation of potassium triorganozincates

In 1992 Purdy et al.41 prepared the trialkylzincates 93a-c using the method of

Wanklyn (Scheme 66). These complexes were characterized using NMR

spectroscopy and X-ray crystallography. The alkyl groups on zinc adopt trigonal-

planar geometry.

44

3 R2Zn + 2 M 2 [ZnR3]M benzene, RT, 24 h

93a M = Na, R = CH2CMe393b M = K, R = CH2CMe393c M = K, R = CH2SiMe3

93a-c

Scheme 66. Preparation of trialkylzincates 93 from R2Zn and alkali metals

In 1993 Weiss et al.11b e crystal structure of potassium

imethylzincate 94 in which methyl groups exhibit trigonal-planar coordination

reported th

tr

(Figure 10). No details of preparation method were reported.

Zn K

Me

Me

Me

94

Figure 10

In 1994 Purdy et al.42 reported the preparation of tri-tert-butoxyzincates 95a

f t-BuOM (M = Na, K) in THF

or ether (Scheme 67). These complexes were purified by sublimation under reduced

roscopic and X-ray crystallographic studies showed that both the

comple

and 95b by the reaction of ZnCl2 with 3 equivalent o

pressure. Spect

x exists in dimeric form.

ZnCl2 + 3 t-BuOMTHF or Et2O

4 days[(t-BuO)3Zn]M

95a M = Na95b M = K

Scheme 67. Preparation of tri-tert-butoxyzincates 95

Later in 1996, Uchiyama et al.43a prepared Lithium trimethylzincate

(Me3ZnLi) and dilithium tetramethylzincate (Me4ZnLi2) by the reaction of ZnCl2

tively (Scheme 68). The 1H NMR

studies clearly indicated the upfield shift of methyl protons in Me3ZnLi and

with 3 and 4 equivalent of MeLi in THF respec

45

Me4ZnLi2 c to that Table 10), which indicates more anionic

ch cter of th tes.

ompared of Me2Zn (

ara e zinca

ZnCl2 + 3 MeLiTHF

[Me3Zn]Li

+ 4 MeLiZnCl2THF

[Me4Zn]Li2

Scheme 68. Lithium tri- and tetraorganozincates

Table 10. 1H NMR of zincates in THF

Entry Reagent δMe (ppm)a

1 MeLi −1.96

2 Me2Zn 0.84 −

3 Me3ZnLi 1.08 −

4 Me4ZnLi2 1.44 −a The δ values are relative to β methylene proton (1.85 ppm) of THF.

In 1998 Krieger et al.43b isolated the magnesium triphenylzincate

[Mg2Br3(THF)6][ZnPh3] 96 from the reaction of phosphoraneiminato complex

[ZnBr(NPMe3)]4 with excess PhMgBr (Scheme 69). The structure of the complex

was established by X-ray crystallographic studies.

[ZnBr(NPMe3)]4 + PhMgBrexcess

THF[MgBr(NPMe3)]4 + 96

Mg

Br

Mg

Br

Zn

Ph

Ph THFTHFTHF THFPh Br

THFTHF

96

cheme 69. Preparation of magnesium triphenylzincate 96

S

46

Recently in 2010, Hevia et al.23f reported the preparation of magnesium tri-

tert-butylzincate [t-Bu3Zn][Mg2Cl3⋅(THF)6] 97 by the reaction of ZnCl2 with 3

equivalent of t-BuMgCl in THF (Scheme 70).

ZnCl2 + 3 t-BuMgClTHF

[t-Bu3Zn][Mg2Cl3(THF)6]

97

Scheme 70. Preparation of tri-(tert-butyl)zincate complex

X-ray crystallographic studies of 97 showed that in the anionic moiety, the

inc centre is bonded to three tert-butyl groups with trigonal planar geometry

hereas cationic moiety consists of two distorted octahedral magnesium atoms

haring three chlorines and with three molecules of THF completing the coordination

phere of magnesium (Figure 11).

z

w

s

s

Mg

Cl

Mg

Cl THFTHF

THF

THFTHF

THFClZn

tBu

tBu

But

Figure 11

47

4. Applications of organozincates

Triorganozincates have been used in many organic reactions such as 1,2-

addition to carbonyl compounds,44 1,4-conjugated addition to α,β-unsaturated

carbonyl compounds,39b,45 addition to imines,44d,46 metalation of aromatic

halides,11c,43a,47 epoxide opening43a and Pd-catalyzed cross coupling23f,47b, (Fig. 12).

[R3Zn]M

R1

R2

OO

R1 R2

NR3

O

R1 ArI

ArI

Pd(II)

R1 R2

OH

R O

R

R

Ar-R

R3RHN1 R2R

[R2ZnAr]M

OHR1

and α,β-unsaturated ketones.

4.1. Asymmetric 1,2-addition

In 1979 Seebach et al.48a reported the enantioselective addition of lithium

tributylzincate (prepared from ZnCl2 and 3 equivalent of BuLi) to benzaldehyde

using (+)-DBB 98 as a chiral cosolvent (Scheme 71). Although good yield was

obtained, the enantioselectivities was very low.

Figure 12

However, these reagents have been used in a only few asymmetric reactions

such as addition to carbonyl compounds, imines

48

Me2NNMe2

OMe

OMe

[Bu3Zn]Li + PhCHOEt2O:(+)-DBB

Ph Bu

OH

(R)

85% yield15% ee

(+)-DBB 98

Scheme 71. Asymmetric addition of lithium tributylzincate to benzaldehyde

48b ition of

chiral organozincate 99 to Ethyl 2,2,2-trifluoropyruvate 100. Initial investigation

showed that (R)-BINOL was superior to other chiral modifiers. The chiral zincate 99

was prepared in situ by first treatment of the (R)-BINOL with stoichiometric amount

of Et2Zn followed by addition of Grignard reagent. The reaction of resulting chiral-

zincate complex with keto ester 100 in 1,2-dichloroethane:THF followed by

hydrolysis provided enantiomerically enriched α-hydroxy acids 101 with moderate to

good enantioselectivities (Table 11). Later in 2010, the same author48c used this

methodology in the preparation o iologic ta oxygenase inhibitor

MK-0633.

Table 11. Enantioselec e addit hiral-org zincates to 100

Later in 2007, Gosselin et al. reported the enantioselective add

f b ally impor nt 5-lip

tiv ion of c ano

Oi) Et2Zn i) CF3 OEt

(R)-BINOL

DCE:THF−40 oC to RT

[(R1O)2Zn(R)]MgClii) RMgCl −40 oC to RT

O O

-40 C, 18 ho

ROH

CF3HO

Up to 74% yieldUp to 83% ee

ii) KOH, H2OR1 = (R)-BINOL-ate

99101

Entry R Yield (%) ee (%)

100

1 Me 29 50 2 Et 74 74 3 Bu 35 83 4 vinyl 29 13 5 phenyl 38 69 6 allyl 37 4 7 benzyl 36 <5

49

4.2. Asymmetric 1,4-addition

In 1979 Seebach et al.49a reported the enantioselective addition of lithium

tributylzincate to 2-cyclohexenone using (+)-DBB 98 as chiral cosolvent. Moderate

yield of expected product was realized with poor enantioselectivity (Scheme 72).

Other Michael acceptors such as 2-cyclpentenone, crotonaldehyde and 1-nitro-1-

propene gave similar results.

O

+ [Bu

O

3Zn]LiEt2O:(+)-DBB

Bu*

62% yield16% ee

−78 oC

Scheme 72. Asymmetric 1,4-addition of lithium tributylzincate

In 1988 Feringa et al.49b found that the use of alkoxide as non-transferable

ligand in 1,4-addition of triorganozincates to 2-cyclohexenone. Encouraged by these

results, they examined chiral menthoxide as non-transferable ligand. Thus, chiral

zincate complex 102 was prepared in situ by the treatment of ZnCl2⋅TMEDA

complex with one equivalent of 1-menthyloxymagnesium bromide followed by the

addition of 2 equivalent of i-PrMgBr in THF. The reaction of resulting zincate

complex with 2-cyclohexenone provided the desired product with only 9% ee

(Scheme 73). Examination of triorganozincates obtained from chiral TMEDA⋅ZnCl2

analogue 103 provided similar results.

O

THF, 0 oC

O

iPr*

OR* = menthyloxy

TMEDA [(iPr)2Zn(OR*)]MgBr

80%9%

yield ee

102

N N

H H

Zn

ClCl

103

Scheme 73. Enantioselective 1,4-addition of chiral-zincate 102

50

In further study, Feringa′s group found that catalytic amount of ClZnOR can

be used in 1,4-addition.49c Later in 1990, they examined chiral-zinc alkoxides 104a

and 104b in enantioselective addition of Grignard reagent to 2-cyclohexenone.49d

The chiral zinc-alkoxide (prepared by the reaction of ZnCl2 with lithium alkoxides

derived from corresponding aminoalcohols) was first reacted with Grignard reagent

to form chiral organozincate species which on further treatment with to 2-

cyclohexenone afforded desired product in excellent yield with moderate

enantioselectivity (Scheme 74). Authors examined a library of various type of

ligands for this reaction but couldn’t achieve better results.

O

+ R*OZnCl

O

5 mol%

i-PrMgBr

THF, −90 oC, 15 min iPr

Up to 92% yieldUp to 33% eeR*OZnCl

N N

ZnOCl

NNMe

MeMe

OZn

Me Me

PhCl

104a 104b

Scheme 74. Catalytic enantioselective 1,4-addition of triorganozincates

4.3. Diastereoselective addition to imines

In 1997 Savoia et al.50a reported diastereoselective addition of

triorganozincates to imines. Initial study showed that valine-derived imine 105 was

better as compared to other imines. The reaction of imine 105 with various lithium

and magnesium triorganozincates provided corresponding amines 106a-h in

oderate to excellent diastereoselectivity (Table 12). It was also found that the

zincates derived from Grignard reagents were more effective than the corresponding

′ = Me),

selective transfer of R group was observed rather than R′. The diastereoselectivity

was slightly affected by the nature of R group and decreased in the order vinyl > i-Pr,

n-Bu > Me > Bn > allyl > t-Bu.

m

lithium zincates. In the case of mixed organozincates [R′2ZnR]M (R

51

Table 12. Diastereoselective addition of triorganozincates to imine 105

NN COOEt THF, −78 oC

NN COOEt

R

H

Up to 90% yieldUp to 98% de

+ [R'2ZnR]M

105M = Li, MgXR' = Me, t-BuR = alkyl, vinyl, allyl, benzyl

(S) (S)

106a-h

E y Yield (%) Product de (%) ntr [R'2ZnR]M

1 [Me3Zn]MgCl 50 106a 84

2 [Me3Zn]Li 50 106b 54

3 [Me2Zn-n-Bu]MgCl 86 106c 88

4 [Me2Zn-i-Pr]MgCl 90 106d 90

5 [Me2Zn-t-Bu]MgCl 80 106e 14

6 [Me2ZnBn]MgCl 88 106f 76

7 [Me2Zn(allyl)]MgBr 91 106g 46

8 [Me2Zn(vinyl)]MgBr 95 106h 98

On the basis of these results, the outcome of stereoselectivity was explained

through the formation of six-membered cyclic transition state (Figure 13).

Mg

N R

ZnMe

N

X Me

HEtO2C

iPr

f these zincates with (R)-N-

(tert-butanesulfinyl)benzaldimine 107 furnished corresponding chiral amines 108

with moderate to good diastereoselectivity (Scheme 75).

Figure 13

In 2008 Guijarro and Yus50b prepared various mixed trialkylzincates by the

treatment of Me2Zn with Grignard reagent. The reaction o

52

+ [Me2ZnR]MgBrPh H

NS

O

tBu THF, −78 oC

Ph R

HNS

O

tBu

107(Rs,R)-108

R = Et, i-Pr, n-C5H11, vinyl 85-93% yield88-96% de

1−3 h

Scheme 75. Diastereoselective addition of triorganozincates to 107

Later in 2009, the same author50c reported the catalytic version of the above

method. After extensive study they found that the use of 0.15 equivalent of Me2Zn

gave optimum results. Under the optimized conditions various Grignard reagents

were reacted with imine 107 to obtain corresponding chiral amine 108 with excellent

diastereoselectivity (Scheme 76). Author proposed that the reaction of RMgX with

Me2Zn generates triorganozincate [Me2ZnR]MgX, which transfers the R group

selectively to the imine and Me2Zn gets recycled to continue the reaction. This

methodology was later used for the preparation of various optically active α- and β-

amino acids.50d,e

+ Me2Zn + RMgBrPh H

NS

O

tBu THF, −78 oC

Ph R

HNS

O

tBu

107 (Rs,R)-108

R = Et, i-Pr, n-C5H11, vinyl83-99% yield86-96% de

(cat.)

Scheme 76. Catalytic diastereoselective addition of triorganozincates to 107

53

4.4. Miscellaneous reactions

4.4.1. Diastereoselective addition to vinylic sulfoxides

In 1997 Houpis and Molina51a reported the addition of triphenylzincates

[Ph3Zn]M (M = Li, MgBr) to optically active vinyl sulfoxide 109. Treatment of

[Ph3Zn]M (M = Li or MgBr) with 109 in the presence of catalytic amount of

Ni(acac)2 gave the sulfoxide 110 in good yield. Compound 110 upon desulfurization

provided the phosphodiesterase IV inhibitor 111 with good enantioselectivity

(Scheme 77).

NS

tolyl

O

MeO

CpO

[Ph3Zn]M

Ni(acac)2 (cat.)THF, −25 oC

NS

tolyl

O

MeO

CpO Ph

ZnTHF:AcOH 23 oC

N

MeO

CpO Ph

109 110 111M = Li, MgBrCp = cyclopentyl >90% yield 70-75% yield

82-92% ee

Scheme 77. Diastereoselective addition of triphenylzincates to sulfoxide 109

4.4.2. Enantiospecific cross-coupling

In 2008 Briet et al.51b reported ZnCl2-catalyzed enantiospecific cross

coupling of α-hydroxy ester triflates 112 with Grignard reagents. Under optimized

conditions, various RMgX (X = Cl, Br) provided the coupling product 113 in good

yield with 100% transfer of chirality (Scheme 78). In the absence of ZnCl2, low yield

of expected product was observed.

ButO

OR1

OTf

ZnCl2 (5 mol%)RMgX

THF, 0 oCButO

OR1

R112113

R1 = Me, n-Bu, i-Bu, i-Pr, Bn, CH2OR, CH2CORR = Me, Et, n-Bu, i-Bu, i-Pr, Oct, Bn, lauryl

(97 to >99% ee) 72 to >99% yield97 to >99% ee

Scheme 78. Zn-catalyzed cross-coupling of Grignard reagents with 112

This methodology was later used for the synthesis of

(Oligo)deoxypropionates which are common motifs in a large number of biologically

54

relevant natural products of polyketide origin. In this report, the author proposed a

catalytic cycle (originally postulated by Ishihara et al.44d) as shown in figure 14. The

addition of RMgX to zinc chloride generates diorganozinc species (R2Zn) which then

reacts with a third molecule of Grignard reagent to give a triorganozincate species

(R3ZnMgX). Lewis acid activation of the triflate with magnesium ion followed by

SN2 attack of triorganozincate gives the expected product with very high

stereoselectivity.51c cat. ZnCl2 + 2 RMgX

RMgX

[R3Zn]MgXZn(II)-ate complex

OButO

O

R1

SO2CF3

MgX

ZnR3

Product (R2Zn)

112

Figure 14. Proposed catalytic cycle

Summary and Outlook

It is evident from the above account that efficient methodologies now exist

for the preparation of organozinc halides.12-26 However, there is still need to develop

simple methods for their preparation, for example using zinc dust in THF as solvent.

Moreover, less reactive alkyl chlorides and aryl bromides are still useless substrates

for the reaction with zinc. These reagents have found applications mainly in Pd- or

Ni-catalyzed enantioselective cross coupling and Rh-catalyzed 1,4-additions. Unlike

diorganozincs, organozinc halides could not gain popularity for the enantioselective

addition to carbonyl group.

Organozincates are reactive species and have proved their utility in

asymmetric synthesis. However there are no catalytic protocols for their use in

enantioselective transformations.

To sum up, the oldest organometallic reagent still remains significantly

unexplored, and promises rich dividend for researchers.

55

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Angew. Chem. Int. Ed. 2008, 47, 5451. (c) Brand, G. J.; Studte, C.; Breit, B.

Org. Lett. 2009, 11, 4668.

61

CHAPTER-2

Present work on organozinc compounds

62

Introduction As discussed in the Ist chapter, organozinc reagents are important

organometallics in asymmetric synthesis. Amongst these, dialkylzincs have proved to

be excellent nucleophiles in asymmetric addition to carbonyl compounds mainly

because of well established methods and use of simple ligands.1 However, lack of

wide commercial availability, high cost and their pyrophoric nature demands an easy

in situ preparation of these reagents. Significant efforts have been made by various

research groups to circumvent these difficulties,2 which includes preparation of

diorganozincs by boron-zinc3 or iodine-zinc4 exchange and transmetallation of

alkyllithium or Grignard reagents with zinc salts.5 One of the major drawbacks in the

case of in situ preparation of diorganozinc reagents from alkyllithium or Grignard

reagent and ZnX2, is the formation of lithium and magnesium salts which affect

enantioselectivity.5c,e To overcome this difficulty, additional tasks like centrifugation

/ filtration5a-c or the use of complexing agent like TMEDA have been explored.5d,e

Therefore search for other alternatives is desirable. We have been interested in the

reagents of type RZnX6 (X = Cl, Br, I) which are easily accessible and represent the

best choice in this context. Organozinc halides have been used as nucleophiles in few

asymmetric reactions like catalytic enantioselective 1,4-addition7 and asymmetric

Negishi coupling.8 Only few examples of the use of organozinc halides in catalytic

enantioselective addition to aldehyde are known.9 Similar to organozinc halides,

triorganozincate reagents are also less explored in asymmetric synthesis.10-13

Development of new methods for their application in asymmetric synthesis would

lead these reagents as a valuable organometallics.

The present chapter describes the preparation of RZnX (X = Cl, Br, I, OAc)

and the corresponding organozincates and their applications in enantioselective

alkylation of aldehyde. It has been divided into three sections.

Section 2A: Preparation of alkylzinc halides and alkylzinc acetates

Section 2B: Enantioselective addition of RZnX to benzaldehyde

Section 2C: Organozincates and their enantioselective addition

to benzaldehyde

63

Section 2A

Preparation of alkylzinc halides and alkylzinc acetates

1. Preparation of RZnX by oxidative insertion

It is evident from the literature that the oxidative insertion of zinc into organic

halides is the most studied reaction. The oxidative insertion is most general and

attractive protocol for the preparation of organozinc halides. After the discovery of

first oxidative addition of zinc into a carbon-halogen bond in 1849 by Frankland,14

numerous procedures have been developed for the activation of zinc15 to achieve

efficient conversion. The heterogeneous reaction conditions and the nature of zinc

often pose a problem of reproducibility in the oxidative insertion. After longer

expose to air, the surface of metallic zinc gets coated with a layer of zinc oxide that

creates the difficulty in initiating the insertion reaction. Therefore the oxide layer

must be removed before the zinc metal gets engaged in insertion process with

organic halide. The most common initial step for the activation of zinc metal

involves washing of the commercial zinc with aqueous HCl.16 Further activation can

be done by making alloys with Cu,17 Ag,18 Hg.19 Another methods for in situ

activation of zinc metal includes treatment of the zinc metal with activators such as

1,2-dibromoethane,20 TMSCl,21 Bromine,22 Iodine,23 DIBALH24 and ultrasound

irriadiation.25

The rate of oxidative insertion of zinc depends on various factors such as,

nature of organic moiety in the substrate, the halide, method for activation of zinc

and reaction parameters such as temperature, concentration and the solvent. Apart

from the preparation of organozinc halides using highly reactive Rieke Zinc,26 which

is tedious, there are very few methods for the preparation of alkylzinc bromides from

commercial zinc and unactivated alkyl bromides. The two reliable methods known in

the literature require use of polar solvents like N,N-dimethyl acetamide23c or use of

1,2-dibromoethane27 as activator. However DMA is not suitable for large scale

preparation, whereas 1,2-dibromoethane has limitations due to its carcinogenic

toxicity.28 Our aim was to develop a easier preparative method for alkylzinc halides

in solvent like tetrahydrofuran which is more convenient and easy to handle.

We examined various additives / activators for the preparation of alkylzinc

bromides by oxidative insertion and the results obtained are discussed below.

64

Results and discussion

The efficiency of oxidative insertion into carbon-halogen bond can be

increased in number of ways like activation of zinc and use of additives which can

form soluble complex with zinc reagent to give freshly active metallic surface for

further reaction.

We examined various additives / activators for the reaction of primary alkyl

bromides with zinc dust in THF at 50 to 55 oC (Table 1). Initially we have reacted

zinc dust with RBr (R = Et, n-Bu) using catalytic amount of zinc activators like MeI,

Br2, and HCl (in Et2O). Most of the zinc was unreacted in all the cases (Table 1,

entries 1−3). Similar kind of results were obtained in the case of radical initiator such

as CuI, CeCl3 and InCl3 (entries 4−6). The examination of iodide salts such as LiI

and TBAI, which can convert alkyl bromide into more reactive iodide, also failed to

give the zinc reagent (entries 7 and 8). We also examined the complexing agents like

TBAB and ethane-1,2-dimethyl thioether in stoichiometric amount. But in both the

cases most of the zinc was unreacted (entries 9 and 10).

65

Table 1. Reaction of alkyl bromides with zinc

RBr + ZnTHF

50-55 oCRZnBr

R = Et, n-Bu

Entry RBr Additives (equiv) Time (h) Result

1 EtBr MeI (0.1) 24

Most of

the zinc

was

unreacted

2 BuBr Br2 (0.2) 24

3 BuBr HCl in Et2O (0.2) 24

4 EtBr CuI (0.05) 40

5 EtBr CeCl3 (0.1) 48

6 EtBr InCl3 (0.1) 48

7 EtBr LiI (0.1) 48

8 EtBr TBAI (0.1) 48

9 BuBr Bu4NBr (1.0) 24

10 BuBr MeSCH2CH2SMe (1.0) 24

We therefore decided to investigate the reaction systematically using n-BuX

(X = Cl, Br, I). Without the use of any additive, more than 95% zinc was consumed

in the reaction of butyl iodide (1.1 equiv) with zinc dust (1 equiv) in THF at 50−55 oC in 24 h (Table 2, entry 1). However iodometric titration29 revealed yield of 60%.

When 1.1 equivalent of LiCl was used, the rate of the reaction was dramatically

increased and the reaction was completed in only 2 h under similar reaction

conditions (entry 2). However, butyl bromide was found to be unreactive under these

reaction conditions (entry 3). We then employed activators like TMSCl, 1,2-

dibromoethane and iodine in catalytic amount. Most of the zinc was unreacted in all

the cases (entries 4−6). Use of catalytic amount of TMSCl in combination with

stoichiometric LiCl gave only 8% yield of the butylzinc bromide after 48 h (entry 7),

whereas 1,2-dibromoethane did not initiate the reaction (entry 8). Interestingly, in the

presence of 5 mol% I2 and 1.1 equivalents of LiCl, butylzinc bromide was obtained

in 65% yield (entry 9). The reaction was completed in 18 h with high reproducibility.

The presence of both LiCl and iodine is necessary for the complete conversion

66

(comparison between entries 3, 6 and 9). Encouraged by these results, we examined

other activators such as LiI and TBAI. Comparable results were obtained in both the

Table 2. Reaction of butyl halides with zinc

BuX + Zn50-55 oC

RZnX

Entry BuX Solvent Additives Time (h)

Yield a (%)

Zn consumed

(%) 1 BuI THF none 24 60 >95 2 BuI THF 1.1 equiv. LiCl 2 70 quantitative 3 BuBr THF 1.1 equiv. LiCl 48 − 16 4 BuBr THF 10 mol% TMSCl 48 − 20 5 BuBr THF 10 mol% (CH2Br)2 48 − 20 6 BuBr THF 5 mol% I2 48 − 28 7 BuBr THF 1.1 equiv. LiCl

5 mol% TMSCl 48 8 24

8 BuBr THF 1.1 equiv. LiCl 10 mol% (CH2Br)2

48 − 26

9 BuBr THF 1.1 equiv. LiCl 5 mol% I2

18 65 quantitative

10 BuBr THF 1.1 equiv. LiCl 10 mol% LiI

24 62 quantitative

11 BuBr THF 1.1 equiv. LiCl 10 mol% TBAI

26 62 quantitative

12 BuBr THF 1.1 equiv. LiCl 2 mol% I2

5 mol% TMSCl

48 52 >95

13 BuBr THF 1.1 equiv. LiCl 5 mol% LiI

5 mol% TMSCl

48 48 >95

14 BuCl THF 1.1 equiv. LiCl 5 mol% I2

5 mol% TMSCl

48 − 25

15 BuCl EtOAc 1.1 equiv. LiCl 5 mol% I2

5 mol% TMSCl

48 − 24

16 BuCl DMA 5 mol% I2 5 mol% TMSCl

48 − 31

a Yields were determined by iodometric titration.

67

cases with slight longer reaction time (entries 10 and 11). We also studied the effect

of iodine loading on the reaction rate. When iodine loading was reduced to 2 mol %,

the reaction proceeds much slowly (entry 12). Similar results were observed in the

case of LiI (entry 13). Next, less reactive butyl chloride was subjected to the

oxidative insertion in the presence of LiCl and catalytic amount of iodine and

TMSCl. However most of the zinc was unreacted even after 48 h (entry 14). Use of

polar solvents such as EtOAc and DMA also did not help (entries 15 and 16).

The mechanism of zinc insertion is well studied by Rieke et al.26h In the

course of our study, GC-MS analysis of the hydrolyzed reaction mixture (entries 9,

10 and 11, Table 2) showed the formation of a small amount of butyl iodide. On the

basis of these results, we proposed the possible mechanism as shown in scheme 1.

The formation of butyl iodide could be explained by the nucleophilic displacement of

bromide of BuBr by I¯ generated from the reaction of zinc and I2. This more reactive

butyl iodide reacts with zinc in the presence of LiCl to form the complex A. The

complex A exchanges30 the iodide with butyl bromide to give complex B and BuI is

recycled back in the insertion process.

BuBr + I BuI + Br

BuI + ZnLiCl

BuZnI LiCl

(A)

BuZnI LiCl

(A)

BuBrBuZnBr LiCl + BuI

(B) (recycled)

Scheme 1. Proposed mechanism for the oxidative insertion

Since iodides provided good results, we further examined these reaction

conditions for the preparation of various alkylzinc bromides. Under optimized

reaction conditions, various alkyl bromides were reacted with zinc dust (Table 3).

Thus, the reaction of ethyl bromide with zinc dust (1.5 equiv) in the presence of LiCl

(1.1 equiv) and 5 mol% iodine provided EtZnBr·LiCl in 75% yield (entry 1). Other

68

Table 3. Preparation of RZnX (X = Br, Cl) using LiCl and catalytic I2

RX + Zn + LiClTHF, 50-55 oC

RZnX LiCl

(1.0) (1.5) (1.1)

5 mol% I2

Entry RX Time (h) Yielda (%)

1 Ethyl bromide 14 75

2 n-Butyl bromide 18 74

3 n-Hexyl bromide 20 74

4 n-Octyl bromide 24 72

5 Ethyl-4-bromo-butyrate 10 73

6 iso-Butyl bromide 48 42

7 iso-Propyl bromide 48 25

8 tert-Butyl bromide 24 40

9 Allyl chloride 10 68

10 Benzyl chloride 5 75 a Yields were determined by iodometric titration.

bromides like n-butyl, n-hexyl and n-octyl bromide were also converted to the

corresponding zinc reagent in good yield (entries 2–4). Functionalized alkyl bromide

like ethyl 4-bromo-butyrate provided corresponding zinc reagent in 73% yield (entry

5). Due to the steric bulk around bromide, the reaction of iso-butyl and iso-propyl

bromide was slow and incomplete after 48 h (entries 6 and 7). In the case of tert-

butyl bromide only 40% yield of the product was obtained although zinc was used

quantitatively. To find out the reason for this abnormal result, we performed the

above reaction without LiCl under similar reaction conditions (eq 1). In this case,

t-BuBr + Zn5 mol% I2, THF

50-55 oC, 24 ht-BuZnBr

Zinc consumed 84%Yield 0%

(1)

69

iodometric titration of the reaction mixture did not show the presence of zinc reagent

although 84% zinc was reacted. The GC-MS analysis of reaction mixture showed

two major peaks at (m/z 168) and (m/z 226) which corresponds to the probable

structures of 1 and 2 respectively (Figure 1). The above results clearly indicates that

LiCl stabilizes the zinc reagent by forming the complex t-BuZnBr⋅LiCl and also

explain the reason for low yield.

21

Figure 1

At this stage, the mechanism for the formation of 1 and 2 is not clear.

However, it can be explained by assuming the formation of tert-butyl radical (I)

(Scheme 2), which can decompose to give 2-methyl-1-propene (II). The intermediate

II can generate radical at allylic positions (path-a) and consequent coupling with I

gives hydrocarbon 1. The formation of 2 can be explained by generation of radical

III by coupling of I with II at vinylic position (path-b), which on homocoupling

gives hydrocarbon 2.

ZnBr

(I)

1

homocoupling(II)

(III)

2path-a

path-b

2

Scheme 2. Proposed mechanism for the formation of hydrocarbon 1 and 2

Allyl chloride and benzyl chloride were also reacted under the above

optimized conditions. Corresponding zinc reagents were obtained in good yield

(Table 3, entries 9 and 10).

70

To confirm the formation of the above described reagents, some of these were

reacted with carbonyl electrophiles. Thus, the reaction of BuZnBr⋅LiCl with benzoyl

chloride in the presence of CuCN⋅2LiCl20d provided 1-phenyl-1-pentanone (3) in

86% isolated yield (eq 2). Also the treatment of benzylzinc chloride with

benzaldehyde gave expected product 4 in good yield (eq 3).

BuZnBr LiCl

O

Cl +CuCN 2LiCl

THF−10 to 0 oC, 6 h

O

Bu

86% yield

3

O

H + 0 oC to RT, 6 h

OH

85% yield

4

PhCH2ZnCl LiCl PhTHF

(2)

(3)

2. Preparation of RZnX by transmetallation or ligand exchange

Organozinc halides also can be prepared by transmetallation31,32 that is,

reaction of RLi or RMgX with zinc halide. We have prepared EtZnCl⋅Mg(Br)Cl (5)

by stoichiometric reaction of RMgBr (R = alkyl) with ZnCl2 (eq 4). To study the

ligand effect in RZnX, we extended this method for the preparation of RZnOAc.

Thus, the reaction of EtMgBr with Zn(OAc)2 gave EtZnOAc⋅Mg(OAc)Br (6) with

more than 95% yield (eq 5). The yield was determined by iodometric titration. Using

this method, there is always formation of magnesium salts in stoichiometric amount

EtMgBr + ZnCl2THF

0 to 25 oC, 1 h(4)

EtMgBr + Zn(OAc)2THF

0 to 25 oC, 1 h(5)

Et2Zn + ZnCl2THF:hexane

25 oC, 1 h2 EtZnCl (6)

Et2Zn + Zn(OAc)2THF:hexane

25 oC, 1 h2 EtZnOAc (7)

EtZnCl Mg(Br)Cl

EtZnOAc Mg(OAc)Br

5

6

7

8

71

along with zinc reagent. To study the magnesium / lithium salt effect on the

reactivity of RZnX, we also prepared salt-free alkylzinc halides. The salt-free RZnX

(X = Cl, Br, I, OAc) can be prepared by reaction of R2Zn and ZnX2, the so called

“ligand exchange.”33 Thus ethylzinc chloride (7) and ethylzinc acetate (8) were

obtained by the reaction of diethylzinc with ZnCl233c and Zn(OAc)2

33d respectively

(eq 6 and 7) according to the literature procedures. All these reagents can be stored

for several days as a THF solution under inert atmosphere.

72

Section 2B

Enantioselective addition of RZnX to benzaldehyde

Enantioselective addition of diorganozinc reagents to carbonyl compounds

emerged as one of the powerful tools for the preparation of optically active alcohols.

Introduction of chiral heteroatom containing ligands to the zinc complex allows

facial differentiation in the addition of the alkyl group to carbonyl substrate. After

the first report of Oguni and Omi34 and pioneering work of Noyori and Soai,

numbers of ligand accelerated methods have been developed for the catalytic

enantioselective addition of dialkylzinc reagents to aldehyde. A majority of the

catalyst for this reaction were based on chiral β-amino alcohols.1 Our interest in this

field led us to study the reagent of type RZnX (X = Cl, Br, I, OCOR′) which have

been rarely studied. High covalent character and less Lewis acidity of zinc centre are

responsible for the poor reactivity of these reagents. The reactivity of these reagents

towards carbonyl substrates can be enhanced by, (i) substrate activation with Lewis

acid (Figure 2a), (ii) Reagent activation with Lewis base catalyst (Figure 2b). Lewis

acid coordinates with carbonyl oxygen resulting in increased electrophilicity of

carbonyl carbon. Organozinc halides (RZnX) have bent structure and differ

fundamentally from diorganozinc compounds (RZnR) which occur as monomers

with sp-hybridized linear geometry.35a Due to the presence of electronegative atom,

accepter character of zinc in RZnX is enhanced. This leads to association of

molecules and hence such compounds are always exists as dimers or higher

associates.35b Addition of nitrogen/oxygen containing ligand can break this

unreactive oligomeric association and provide reactive organozinc halides

monomeric species.

R' R''

O

Lewis Base

R' R''

O

Lewis acid

(a) (b)

ZnR X

YX

(c)

(tetrahedral complex)R-Zn-X

R-Zn-X

Figure 2

73

We presumed that a bidentate chelating agent can coordinate with zinc centre

and forms tetrahedral complex33a,36 (Figure 2c), resulting in enhanced metal-alkyl

bond polarity and hence increased nucleophilicity of the alkyl group. We have done a

systematic study on the reactivity of alkylzinc halides towards aldehyde by

examining various catalysts / chelating agent derived from N-Me ephedrine and

simple diols. These results are discussed below.

Results and discussion

For our present study, we chose simple chiral ligands (9−14) as shown in

figure 3.

Ph OH

NMe2Me

Ph OH

NHTsMe

OHPh

OHPh

O

O

OHOH

Ph Ph

Ph Ph

OHOH

N

OPh

PhMe

(1R,2S)-(−)-9 (1R,2S)-(−)-10

(R)-(+)-14

(2R,3S)-(−)-11

(1S,2S)-(−)-12 (4R,5R)-(−)-13

Figure 3

Preparation of catalysts

Several catalysts 15−24 (Figure 4) were prepared by the treatment of chiral

ligand with organometallic reagent. The change in the metal center (aluminum,

titanium, zinc, magnesium, lithium) provides change in Lewis acidities and also the

coordinating ability of nitrogen/oxygen atoms.

74

Ph O

NMeM

Ph O

NMeZn

Ts

O

O

OO

Ph Ph

Ph Ph

Al Cl

Ph O

NMeTi

Ts

OiPr

OiPr

Ph

OM

OM

Ph

M = Li 20 = MgBr 21

O

O

OMOM

Ph Ph

Ph Ph

M = Li 22 = MgBr 23

OMgBrOMgBr

24

15M = Li = 16M = MgBr = 17 18 19

Figure 4

Aluminum alkoxide 15 was prepared by the reaction of (−)-13 with Et2AlCl

(Scheme 3).

O

O

OHOH

Ph Ph

Ph Ph

(−)-13

Et2AlCl

toluene, RT, 1 h − 2 EtH

O

O

OO

Ph Ph

Ph Ph

Al Cl

15

Scheme 3. Preparation of catalyst 15

N-Me ephedrine derived alkoxides 16 and 17 were prepared by treatment of

(−)-9 with BuLi/EtMgBr (Scheme 4).

Ph OH

NMe2Me

n-BuLi, THF

0 oC to RT, 15 min.

EtMgBr, THF

0 oC to RT, 15 min.

(-)-9

Ph O

NMeLi

Ph O

NMeMgBr

16 17

Scheme 4. Preparation of catalyst 16 and 17

75

Catalysts 18 and 19 were prepared by the treatment of (−)-10 with diethylzinc

and Ti(OiPr)4 respectively (Scheme 5).

Ph OH

NHTsMe

(-)-10

8 0 oC, 30 min.

Et2Zn, toluene Ti(OiPr)4, toluene

0 oC to RT, 1 h

Ph O

NMeZn

Ts

19

Ph O

NMeTi

Ts

OiPr

OiPr

18

Scheme 5. Preparation of catalyst 18 and 19

Magnesium-dialkoxides 21, 23 and 24 were prepared by the treatment of

corresponding diols (12, 13 and 14) with 2 equivalent of EtMgBr (Scheme 6).

0 oC to RT, 15 min.

2 EtMgBr, THF OMgBr

OMgBr

*

OH

OH

*

12−14 21, 23, 24

Scheme 6. Preparation of magnesium-dialkoxides

Lithium-dialkoxides 20 and 22 were prepared by the treatment of n-BuLi

with corresponding diols (−)-12 and (−)-13 respectively (Scheme 7).

OHPh

OHPh

O

O

OHOH

Ph Ph

Ph Ph

(−)-13

orn-BuLi, THF

0 oC to RT, 15 min.20 or 22

(−)-12

Scheme 7. Preparation of lithium-dialkoxides

We then evaluated these catalysts for the addition of RZnX to benzaldehyde.

Alkylzinc halides (RZnX) are known to be weakly active nucleophiles.6b,37 Initially

we examined the reactivity of salt free RZnX 7 and 8 (prepared by ligand exchange

method, R = Et, X = Cl, OAc) with benzaldehyde in the presence of various

76

catalysts/chelating agent (Table 4). Without any additive, both the reagents 7 and 8

do not react with benzaldehyde (Table 4, entry 1). Similar kind of reactivity was

observed in the case of catalytic amount of Lewis acid catalyst 15 (entry 2). We then

examined N-Me ephedrine derived bifunctional catalysts 16 and 18. These catalysts

can play a dual role by acting as Lewis acids to activate the carbonyl substrate and

also as Lewis base to activate the zinc reagent38 (Figure 5). However the strategy did

not prove fruitful (entries 3 and 4).

N

O

R2

R1M

O

ZnXEt

PhH

Figure 5

We decided to examine next bidentate chelating agents. First we used

chelating agent like N-Me morpholine. But these reagents did not reacted with

benzaldehyde in the presence of catalytic or stoichiometric amount of N-Me

morpholine (entries 5 and 6). We then employed metal dialkoxides39 20 and 23

which are stronger chelating agent. Only starting material was recovered in both the

cases (entries 7 and 8). When the reaction of EtZnCl 7 was carried out in the

presence of one equivalent of MgCl2, alkylated product (25) was obtained in 31%

yield along with the formation of propiophenone (26) and benzyl alcohol (27) (entry

9). Origin of byproducts can be explained by Oppenauer oxidation40 of intermediate

zinc-alkoxide I (Scheme 8). The zinc reagent 8 also gave similar kind of results in

the presence of Mg(OAc)Br (entry 10). However other Lewis acids such as ZnCl2

and LiCl failed to provide the alkylated product (entries 11 and 12).

77

Table 4. Addition of EtZnX (X = Cl, OAc) to benzaldehyde

EtZnX + PhCHOTHF:Hexane

0 oC to RT, 24 hPh Et

OH

Ph Et

O

Ph OH+ +

25 26 27Salt free

(X= Cl, OAc)

Entry Catalyst (equiv) RZnXa Productb (%)

25 26 27

1 none EtZnCl or EtZnOAc <1 - -

2 15 (0.1) EtZnOAc <1 - -

3 16 (0.1) EtZnOAc <1 - -

4 18 (0.1) EtZnCl <1 - -

5 N-Me morpholine (0.1) EtZnCl or EtZnOAc <1 - -

6 N-Me morpholine (1.0) EtZnCl or EtZnOAc <1

7 20 (0.2) EtZnOAc <1 - -

8 23 (0.1) EtZnOAc <1 - -

9 MgCl2 (1.0) EtZnCl 31 19 20

10 Mg(OAc)Br (1.0) EtZnOAc 28 15 28

11 ZnCl2 (1.0) EtZnCl or EtZnOAc 1 - -

12 LiCl (1.0) EtZnCl or EtZnOAc <1 - - a Prepared from Et2Zn and ZnX2, (X= Cl , OAc). b Yields by GC analysis; remaining unreacted benzaldehyde.

PhCHO + EtZnX Ph

OZnX

O

ZnO

H

Ph

H

PhX

Ph

O

Ph OH+

PhCHO

(I)

26 27

Scheme 8. Proposed mechanism for the formation of byproducts 26 and 27

78

Above results suggest that the reaction is not a Lewis catalyzed one. Instead,

MgX2 in stoichiometric amount forms addition complex32f (Figure 6), which is

responsible for the reaction.

Zn

Cl

X

MgS

S

X

R Zn

OMg

O

O

X

Ac

R

S = solvent molecule

S

S

Figure 6

We also examined reactivity of RZnX⋅LiX (prepared by insertion method) in

the presence of various catalysts (Scheme 9). Only trace amount of expected product

was observed in all the cases.

RZnX LiCl + PhCHOcatalyst (10 mol%)

THF, 0 oC to RT, 24 h Ph R

OH

R = Me, Et (X= Br, I) trace

N

O

Me

O

O

OMgBrPh Ph

OMgBrPh Ph

Ph O

NMeTi

Ts

OiPr

OiPr

Ph O

NMeMgBr

Catalysts

17 19 23

Scheme 9. Reaction of RZnX⋅LiCl with benzaldehyde

Since MgX2 has role on the reactivity of RZnX, we next examined the

reactivity of the zinc reagents 5 and 6 in which stoichiometric amount of MgX2 is

present. In our initial experiment, the reaction of reagent 5 with PhCHO without any

additive gave only 11% 1-phenyl-1-propanol (25) in 4 h at 25 oC (Table 5, entry 1).

This suggested that the effect of MgX2 is not very pronounced.

79

Table 5. Addition of EtZnCl⋅Mg(Br)Cl to benzaldehyde

EtZnCl Mg(Br)Cl + PhCHOPh

OHcatalyst (10 mol%)

THF

Entry Catalyst

Temp (oC)

Time (h) Yield a (%) ee

1 none 0 to 25 4 11 -

2 11 0 to 25 16 63 <1

3 20 0 8 66 <1

4 21 0 8 62 <1

5 23 0 8 64 <1 a Isolated yields; remaining was PhCOCH2CH3, PhCH2OH and unreacted PhCHO.

We therefore proceeded to evaluate various dicordinating ligands for the

reaction. These were, chiral chelating agent like (2R,3S)-(−)-4-methyl-2,3-diphenyl

morpholine (11) and lithium/magnesium dialkoxides 20, 21 and 23. One equivalent

of 1,4-dioxane was added to reduce the Lewis acidic effect of Mg(Br)Cl. Although

good yields were obtained, negligible enantioselectivity was realized in all the cases.

One of the difficulties in handling the zinc halides is their hygroscopic nature.

We decided to use zinc acetate which is non-hygroscopic and can be a good

alternative to zinc halides. The zinc reagent EtZnOAc⋅Mg(OAc)Br (6), prepared by

the transmetallation of EtMgBr with zinc acetate, was reacted with benzaldehyde

without any additive. It revealed reactivity pattern similar to that of reagent 5. In the

presence of chiral chelating agent 11, expected product 25 was obtained in 18% yield

as a racemate (Table 6, entry 2). Interestingly, the reaction of 6 in the presence of

lithium-dialkoxide 22 provided 31% yield with 13% ee (entry 3). The corresponding

magnesium-dialkoxide 23 furnished 34% yield with 28% ee (entry 4). Our attempts

to isolate the reagent 6 were unsuccessful. To verify the formation of EtZnOAc from

EtMgBr and Zn(OAc)2, salt free zinc reagent 8 was reacted with benzaldehyde in the

presence of stoichiometric amount of Mg(OAc)Br (prepared by stoichiometric

reaction of EtMgBr with AcOH) (eq 8).

80

i) Mg(OAc)Br (1 equiv)

ii) 23 (10 mol%)iii) PhCHO, THF

8Ph

OH

(S)

33% yield, 25% ee

(8)

These results obtained were comparable to the results with the reagent 6. Also

the comparison of reactivity difference between the reagent 8 (Table 4, entry 8) and

reagent 6 (Table 6, entry 4) revealed that the presence of MgX2 was crucial. One of

the reasons for moderate selectivity was attributed to MgX2-promoted background

reaction.41 To overcome this problem, we added complexing agents like 1,4-dioxane

or TMEDA. However, this modification proved inconsequential (entries 5 and 6). By

changing the solvent from THF to methyl tert-butyl ether (MTBE), enantioselectivity

increased to 50% (entry 7). Enantiomeric excess was determined by chiral HPLC.

When the reaction was carried out at room temperature, the product was isolated in

60% yield but the enantioselectivity was dropped to 39% (entry 8). Similar results

were obtained when diethyl ether was used as the solvent (entry 9). Other

magnesium-dialkoxides 21 and 24 proved inferior to 23 (entries 10 and 11).

81

Table 6. Enantioselective addition of EtZnOAc⋅Mg(OAc)Br to benzaldehyde

EtZnOAc Mg(OAc)Br + PhCHO Ph

OHcatalyst (10 mol%)

(S)

Entry Catalyst Solventa Temp (oC) Time (h) Yield b (%) eec

1 none THF 0 4 29 -

2 11 THF 0 8 18 -

3 22 THF 0 8 31 13

4 23 THF 0 8 34 28

5 d 23 THF 0 8 37 18

6 e 23 THF 0 8 22 21

7 23 MTBE 0 8 44 50

8 23 MTBE 25 24 60 39

9 23 Et2O 25 24 54 38

10 21 MTBE 25 24 45 <5

11 24 MTBE 25 24 49 <1

a The reactions were carried out at 0.4-0.5 molar concentrations. b Isolated yields of the desired product. c Determined by comparison of optical rotation with known literature value or chiral GC / HPLC analysis. d One equivalent of 1,4-dioxane was added. e One equivalent of TMEDA was added.

Heterogeneous reaction mixtures result during the use of solvents other than

THF. After extensive optimization, it was found that by adding the Grignard reagent

to a suspension of zinc acetate and (−)-13 in THF, homogenous solution was

obtained at 0 oC. This reagent was then reacted with benzaldehyde to obtain 30%

yield of the product with 40% ee (Table 7, entry 1). We also studied the effect of

stoichiometry of Grignard reagent with respect to zinc acetate. It was found that the

rate of the reaction as well as enantioselectivity varied with the change in

stoichiometry. Best results were obtained when the ratio was 1:1 (entries 1, 2 and 3).

In the case of 1.2 equivalent EtMgBr (Table 7, entry 3), the excess Grignard reagent

can generate diethylzinc by reacting with preformed EtZnOAc. This hypothesis was

supported by addition of commercial diethylzinc to benzaldehyde, which gave

82

comparable results (eq 9). In terms of halide effect in RMgX, bromide and iodide

were found to be better than chloride (entries 4, 5 and 6). We also examined other

Grignard reagents under these conditions. n-Butyl and iso-butyl magnesium bromide

provided 13% and 16% enantioselectivity respectively (entries 5 and 7). In the case

of t-BuMgCl, no reaction took place at all.

Table 7. Enantioselective addition of various RZnOAc⋅Mg(OAc)X to benzaldehyde

PhCHO, THF

Ph

OH

R(S)

25, R = Et 28, R = Bu29, R = i-Bu

RMgX + Zn(OAc)2 +

(−)-13

O

O

OHOH

Ph Ph

Ph Ph

Entry RMgXa Temp. (oC) Time (h) Product Yieldb (%) eec (%)

1 EtMgBr 0 8 25 30 40

2d EtMgBr 0 24 25 18 36

3e EtMgBr 0 4 25 60 8

4 BuMgCl 0 8 28 5 0

5 BuMgBr 0 4 28 17 13

6f BuMgI 0 4 28 41 50

7 i-BuMgBr 0 8 29 5 16

8 t-BuMgCl 0−25 24 - g -

a The stoichiometric ratio of RMgX:Zn(OAc)2:(−)-13:PhCHO was 1.7:1.5:0.1:1.0 respectively unless otherwise noted. b Isolated yields of the desired product. c ee Was determined by chiral GC or HPLC analysis. d 0.8 equiv. EtMgBr was added with respect to Zn(OAc)2.

e 1.2 equiv. EtMgBr was added with respect to Zn(OAc)2. f The reaction was carried out in THF:Et2O. g The starting material was recovered.

H

O

+ Et2Zn23 (10 mol%)

THF:Hexane 0 oC, 2 h

Ph

OH

(S)76% yield14% ee

(9)

83

Mechanism:

The difference in the selectivity showed by ligand (−)-13 compared to other

diols was attributed to the rigid backbone and the steric bulk due to phenyl rings

present in the molecule. At this stage a precise model which explains the outcome of

stereoselectivity using reagent 6 is not clear. However we presume that the oxygen

atoms of the metal alkoxide 23, EtZnOAc, BrMg(OAc), and PhCHO bind as

depicted in figure 7a. The resulting cyclic transition state could be responsible for

stereoselection. This would also explain the lack of enantioselectivity with the

reagent 5, which proceeds through MgX2-catalyzed acyclic pathway (Figure 7b).

O

O

Ph

Ph

O

O

M

Zn

Cl

R HPh

O

M = MgX

Ph

Ph

M

Mg(Br)Cl

(acyclic-TS)(cyclic-TS)

O

O

Ph

Ph

O

O

M

Zn

O

Et

O

Mg

Br

OAc

HPh

O

Ph

Ph

M

(a) (b)

Figure 7. Proposed mechanism for enantioselective alkylation

84

Section 2C

Organozincates and their enantioselective addition to

benzaldehyde

Addition of organozinc reagents to various organic electrophiles has become

one of the common methods to construct carbon-carbon bond. The preparation of

dialkylzincs2,31 and organozincates6a,32f,42 is well documented in the literature.

Diorganozinc reagents have sp-hybridized linear geometry (Figure 8a). Pure

dialkylzinc reagents react sluggishly with aldehydes and ketones. However, their

reactivity can be enhanced by incorporation by a third substituent like alkyl or

heteroatom containing ligand on zinc centre (Figure 8b). Richey et al.42f reported that

the treatment of alkali metal alkoxide with diethylzinc produces triorganozincates

species (R2ZnOR)M, which reacts rapidly with aldehyde and ketones. We envisaged

that introduction of two chiral alkoxides would form chiral-zincate species (Figure

8c) which can react enantioselectively with aldehyde. In this context, optically active

diols would be ideal ligands.

R-Zn-RR

ZnR

R'

R' = alkyl, OR''

(less reactive) (reactive)

RZn

OR**RO

R* = chiral alkyl group

(a) (b) (c)

Figure 8

We have prepared various chiral-zincates using optically active diols. The present

section deals with the results obtained in this study.

Results and discussion

In our initial study, we examined the reactivity pattern of alkylzincates

prepared from ZnX2 and RMgX. In the present work, alkylzinc reagents were

prepared by the reaction of ZnX2 (X = Cl, OAc) with n equivalent of EtMgBr (n = 2

and 3) (eq 10, 11 and 12).

85

2 EtMgBr + ZnCl2THF Et2Zn 2Mg(Br)Cl

X= Cl, OAc

(10)

3 EtMgBr + ZnX2THF

(12)[Et3Zn]MgBr

2 EtMgBr + Zn(OAc)2THF

Et2Zn 2Mg(OAc)Br (11)

The reaction of Et2Zn⋅2Mg(X)Br (X = Cl, OAc) with 0.9 equivalent

benzaldehyde proceeds quantitatively in 1 h at 0 oC (Table 8, entries 1 and 2). This

indicates the presence of magnesium salt (Mg(X)Br (X = Cl, OAc)) increases the

reactivity of diethylzinc reagent. In addition to this, we observed that there is

dramatic decrease in reactivity when Mg(X)Br is replaced by less Lewis acidic

Mg(OAc)2. It was done by the reaction of Zn(OAc)2 with two equivalent of EtMgBr

in the presence of excess NaOAc (Scheme 10). The treatment of in situ formed

reagent with benzaldehyde provided only 49% yield of the product.

2 EtMgBr + Zn(OAc)2 + 2.5 NaOAc

ii) PhCHO (0.9 equiv) 0 oC to RT, 24 h

i) THF 0 oC to RT, 4 h

Ph

OH

49% yield

Scheme 10

Next, the reagent prepared from two equivalent of EtMgBr with ZnCl2/Zn(OAc)2

was reacted with 1.9 equivalent benzaldehyde. After 1 h GC analysis revealed

formation of 73% product in both the cases (entries 3 and 4). These results indicate

that more than one equivalent32c,41 of alkyl group gets transferred, which can be

explained by scheme 11. When the mixture of ZnX2 (X = Cl, OAc) and 2EtMgBr

was equilibrated for longer time (16 h) at room temperature, approximately 50%

yield of the product was obtained in both the cases (entries 5 and 6). This difference

in the reactivity can be attributed to the formation of ate complexes I and II depicted

in eq 13 and 14 respectively. After longer stirring ate complex decomposes to give

Et2Zn, which can transfer only one alkyl group.

86

2 EtMgBr + ZnCl2THF

0 oC MgCl

ZnBr

Et

Et

ate complex-I

25 oC

overnightEt2Zn + 2Mg(Br)Cl (13)

2 EtMgBr+Zn(OAc)2THF0 oC

BrMg

O

OZnEt

Et

ate complex-II

25 oC

overnightEt2Zn + 2Mg(OAc)Br (14)

MgEt

ZnEt

3 EtMgBr + ZnX2

X = Cl, OAc

THFEt Br

ate complex-III

+ 2Mg(X)Br (15)0 oC

Table 8. Addition of ethylzincates to benzaldehyde

n EtMgBr + ZnX2 + PhCHOTHF

0 oC, 1 h Ph

OH

X = Cl, OAc

Entry n EtMgBr + ZnX2 [Temp (oC), Time (h)]a PhCHO

(equiv.)

Productb (%)

1 2 EtMgBr + ZnCl2 0−25, 1 h 0.9 94

2 2 EtMgBr + Zn(OAc)2 0−25, 1 h 0.9 quantitative

3 2 EtMgBr + ZnCl2 0, 0.5 1.9 73

4 2 EtMgBr + Zn(OAc)2 0, 0.5 1.9 73

5 2 EtMgBr + ZnCl2 0−25, 16 h 1.9 58

6 2 EtMgBr + Zn(OAc)2 0−25, 16 h 1.9 48

7 3 EtMgBr + ZnCl2 0, 0.5 2.9 78

8 3 EtMgBr + Zn(OAc)2 0, 0.5 2.9 86

a The mixture of EtMgBr and ZnX2 was stirred at mentioned temperature and time before the addition of aldehyde. bYields by GC analysis; remaining propiophenone benzyl alcohol and unreacted benzaldehyde.

We also studied the reactivity of trialkylzincates with benzaldehyde. In the

present study, the triethylzincate III was prepared by reacting ZnX2 (X = Cl, OAc)

87

with three equivalents of EtMgBr at 0 oC (eq 15). The reaction of III with 2.9

equivalent PhCHO gave 78% and 86% yield of the product in case of ZnCl2 and

Zn(OAc)2 respectively. These results indicate that more than two equivalents of alkyl

group can transfer in both cases. The possible explanation for the above results can

be that the ate complex III first reacts with one equivalent of PhCHO via a six-

membered42g TS-1 (Scheme 11) to give the expected product and Et2Zn. The

resulting ate complex I / II further react with 2nd equivalent of PhCHO via TS-2 and

gives product and EtZnX, (X = Cl or OAc). Finally EtZnX then reacts with 3rd

equivalent of PhCHO in the presence of Mg(X)Br via TS-3. From the above results it

can be concluded that the zincate species generated from ZnX2 and RMgBr can

transfer all the three alkyl groups to benzaldehyde. Based upon these findings we

planned to prepare optically active triorganozincates10b to achieve enantioselective

version.

MgEt

ZnEt

Et Br

ate complex-III

1st PhCHO Mg

Zn

BrO

PhH

EtEt

Et

TS-1

Ph

OMgBr+ Et2Zn

Mg(X)Br I (or II)

ate complex

2nd PhCHO Mg

Zn

BrO

PhH

EtX

Et

TS-2

Ph

OMgBr+ EtZnX

3rd PhCHO

Mg(X)Br

Zn

Et

MgXX Br

OH

PhTS-3

Ph

OH

Scheme 11. Possible mechanism for the transfer of all three alkyl group.

88

Enantioselective addition of organozincates to benzaldehyde

We anticipated that simple C2-symmetric chiral diols43 would serve as non

transferrable ligand and effective chiral inducer for this transformation. We chose

simple chiral diols such as (−)-12, (−)-13 and (+)-14 as chiral source. Diols are

known39f to form alkoxide 30 when reacted with diethylzinc at 80 oC (Scheme 12,

path-a). Alkoxide 30 also can be prepared from sodium/magnesium dialkoxide and

ZnCl2 (path-b and path-c respectively). The alkoxide 30 on treatment with

stoichiometric Grignard reagent would give chiral zincate complex-IV, which can

react with aldehyde enantioselectively.

OH

OH* + Et2Zn

Toluene

80 oC, 30 min.−2 EtH

O

OZn*

Chiral diol 30

OH

OH*

Chiral diol

ONa

ONa*

ZnCl2

THF

OH

OH*

Chiral diol

2 RMgXOMgX

OMgX*

ZnCl2

THF

Path-a

Path-b

Path-c

RMgX O

OZn R*

Chiral zincate complex- IV

MgXTHF

2 NaH

Scheme 12

In our initial study, zincate complex prepared from diol (−)-13 via path-b (or

path-c) on reaction with benzaldehyde gave desired product in low enantioselectivity

(Scheme 13). Increased enantioselectivity was realized when the chiral zincate-

complex was prepared using path-a. Therefore we prepared chiral zinc-alkoxides

30a, 30b and 30c (Figure 9) by heating the equimolar quantity of diethylzinc and

corresponding diols at 80 oC according to path-a in scheme 12.

89

i) 2 EtMgBr, THF

ii) EtMgBr, 0 oCiii) PhCHO, 0 oC, 2 h

Ph

OH

(S)

71% yield16% ee

(-)-13i) 2 NaH, THF

ii) EtMgBr, 0 oCiii) PhCHO, 0 oC, 2 h

Ph

OH

(S)

44% yield6% ee

Scheme 13

O

OZn

O

O

Ph PhO

OPh Ph

ZnPh O

OPh

Zn

30a 30b 30c

Figure 9

We then examined these in situ generated zinc-alkoxides (30a-c) in

enantioselective addition to benzaldehyde under different reaction conditions (Table

9). First we examined the zinc-alkoxide 30a. One equivalent of EtMgBr was added

to a suspension of 30a in toluene at oC. The resulting zincate complex was then

treated with benzaldehyde at 0 oC (Condition A). The product was isolated in 66%

yield with 24% ee (Table 9, entry 1). Low enantioselectivity was observed when

addition sequence of Grignard reagent and aldehyde was reversed (Condition B)

(entry 2). The enantioselectivity was increased substantially (to 50%) when the

addition was done simultaneously (Condition C) (entry 3). Lowering the temperature

from 0 to −78 oC diminished the enantioselectivity (entry 4). Less solubility of 30a at

low temperature promotes the direct addition of Grignard regent to aldehyde, which

could be the reason for lower enantioselectivity. The use of EtMgBr⋅LiCl (a

structurally different Grignard reagent44) did not help (entry 5). Poor

enantioselectivity was realized in the case of zinc-alkoxides 30b and 30c (entries 6

and 7).

90

Table 9. Enantioselective addition of chiral-zincates to benzaldehyde

O

OZn*

30a-c

PhCHO Ph

OH

(S)

EtMgBr THF:Toluene

Entry Alkoxidea Conditionb Temp (oC), Time (h) Yieldc (%) eed

1 30a A 0 2 66 24

2 30a B 0 2 72 9

3 30a C 0 2 59 50

4 30a C −78 to 0 2 64 2

5e 30a C 0 2 67 5

6 30b C 0 2 74 <1

7 30c C 0 2 69 6

a The ratio of zinc-alkoxide:RMgX:PhCHO was 1:1:1 respectively. b Condition A:

Grignard reagent was added to zinc-alkoxide and after 15 minutes benzaldehyde was added; Condition B: Benzaldehyde was added before the addition of Grignard reagent; Condition C: Grignard reagent and aldehyde were added simultaneously. cIsolated yields of the desired product. d Determined by comparison of optical rotation with known literature value. eEtMgBr⋅LiCl complex was added instead of EtMgBr.

91

Conclusions

We have found a simple procedure for the preparation of alkylzinc bromides

in THF by the use of LiCl as additive and I2 as activator. Using optimized

conditions, various alkylzinc bromides were prepared in good yields. We

have also prepared successfully alkylzinc acetates by transmetallation

method.

Salt-free RZnX exhibit poor reactivity towards benzaldehyde. Moderate

enantioselectivity was achieved in the case of TADDOL-magnesium

dialkoxide using RZnOAc as alkylating agent.

We have also observed that ate complex formed by the reaction of ZnX2 and

RMgX can transfer all alkyl groups to benzaldehyde. Moderate

enantioselectivity was realized in the case of TADDOL-zincate.

92

Experimental Section

General

All the solvents and reagents were purified and dried according to procedures

given in D. D. Perrin’s purification of Laboratory chemicals.45 Zinc dust (325 mesh)

was purchased from Sisco Research Laboratories, India. Diethylzinc was purchased

from Sigma-Aldrich chemical company. Benzaldehyde was freshly distilled before

use. THF was freshly distilled over sodium benzophenone ketyl. Anhydrous zinc

acetate was obtained by heating Zn(OAc)2.2H2O at 90 oC for 4 h under the reduced

pressure. All the reactions were performed in oven dried (120 oC) glasswares under

an argon atmosphere. Ligand 10 was prepared by reacting (1R,2S)-(-)-norephedrine

and p-toluenesulfonyl chloride following literature procedure.46a Diol 13 was

prepared according to the literature procedure.46b GC analysis was carried out using

HP-5 (30m x 0.25 m x 0.25 μ) column.

Preparation of organozinc halides by oxidative insertion using LiCl as additive

and I2 as catalyst.

The following procedure for preparation of n-BuZnBr⋅LiCl is representative (entry 2

in table-3)

To a 25 mL two-necked round bottom flask equipped with a stir bar and a

reflux condenser was added zinc dust (0.490 g, 7.5 mmol) and LiCl (0.233 g, 5.5

mmol). The mixture was heated at 150 oC for 1 h under high vacuum and cooled to

room temperature under argon. Anhydrous THF (5 mL) and I2 (0.063 g, 0.25 mmol)

were introduced in the flask and the mixture was stirred at room temperature for 15

minutes (red color of I2 disappears completely). n-Butyl bromide (0.53 mL, 5 mmol)

was then added and the reaction mixture was stirred at 50−55 oC for 18 h. The flask

was cooled to room temperature and mixture was allowed to settle for 1 h. The yield

of the zinc reagent was determined by iodometric titration.

Iodometric titration:

One mL of supernatant aliquot from the reaction mixture was transferred to

10 mL round bottom flask under argon atmosphere. To this, I2 (0.5 M solution in

benzene or THF) was added dropwise at 0 oC until solution becomes brown. The

93

amount of I2 consumed corresponds to one equivalent of alkylzinc halide.29

Calculation for total volume indicated 74% yield of the n-butylzinc bromide.

Reaction of butylzinc bromide with benzoyl chloride

A 50 ml two neck round bottom flask was charged n-BuZnBr⋅LiCl (6 mmol,

8.1 mL of 0.74 M solution in THF) and cooled to −10 oC. CuCN⋅2LiCl (6 mmol, 6

mL of 1 M solution in THF) was added to the solution. The resulting faint green

colored solution was stirred for 15 minutes. Then benzoyl chloride (0.58 mL, 5

mmol) was added dropwise over 5 minutes and the reaction mixture was allowed to

warm to 0 oC and stirred for 6 h. The reaction mixture was quenched cautiously by 2

mL saturated aqueous NH4Cl, acidified with 1N HCl and extracted with diethyl ether

(3 x 20 mL). The combined extract was washed with brine, dried over Na2SO4 and

concentrated under reduced pressure. The residue was purified by “flash

chromatography” on silica gel (230-400 mesh) using ethyl acetate: petroleum ether

as the eluent to obtain 3 as oily liquid.

O

3

Yield : 0.70 g (86%)

IR (neat) : 3063, 2958, 1681, 1450 cm-1 1H NMR (CDCl3) : δ 0.96 (t, J = 7.20 Hz, 3H), 1.31−1.52 (m, 2H),

1.64−1.83 (m, 2H), 2.97 (t, J = 7.58 Hz, 2H),

7.38−7.62 (m, 3H, ArH), 7.90−8.04 (m, 2H, ArH)

Reaction of benzylzinc chloride with benzaldehyde

The same procedure (described for n-BuZnBr⋅LiCl) was followed for the preparation

of PhCH2ZnCl⋅LiCl.

A 25 ml two neck round bottom flask was charged with PhCH2ZnCl⋅LiCl (6

mmol, 8 mL of 0.75 M solution in THF) and the solution was cooled to 0 oC.

Benzaldehyde (0.5 mL, 5 mmol) was added dropwise over 5 minutes and the reaction

mixture was allowed to warm to room temperature and stirred for 6 h. The mixture

94

was then quenched cautiously by 1 mL MeOH at 0 oC. Saturated aqueous NH4Cl (20

mL) was added and the mixture was extracted with ethyl acetate (3 x 20 mL). The

combined extract was washed with brine, dried over Na2SO4 and concentrated under

reduced pressure. The crude compound was purified by “flash chromatography” on

silica gel using ethyl acetate: petroleum ether as the eluent to obtain 4 as a white

solid.

PhOH

4

Yield : 0.84 g (85%)

Melting point : 64–66 oC (Lit.47 67−67.5 oC )

IR (CHCl3) : 3599, 3016, 2920, 1454 cm-1 1H NMR (CDCl3) : δ 1.95 (d, J = 2.9 Hz, 1H, OH), 2.95−3.06 (m,

2H), 4.84−4.96 (m, 1H), 7.15−7.43 (m, 10H, ArH)

Preparation of (2R,3S)-(–)-4-methyl-2,3-diphenylmorpholine (11)

A 10 mL round bottom flask was charged with (2R,3S)-(–)-2,3-

diphenylmorpholine48 (0.239 g, 1 mmol), formic acid (2 mL) and formaldehyde (2

mL). The reaction mixture was then refluxed for 1.5 h and cooled to room

temperature. Unreacted formic acid and formaldehyde were removed on rotary

evaporator. The residue was treated with 10 mL water followed by 5 mL of 2N

aqueous NaOH and extracted with DCM (3 x 10 mL). The combined extract was

washed with water (10 mL) followed by brine, dried over Na2SO4 and concentrated

under reduced pressure. The crude compound was treated with HCl in MeOH. The

resulting hydrochloride was washed with ether, and basified using aqueous NaOH to

obtain 11 as a white solid.

N

OPh

PhMe

11

95

Yield : 0.232 g (92%)

TLC data : Rf (EtOAc): 0.46

Melting point : 54−56 oC

[α]25 D : −126.4 (c 1.06, CHCl3)

IR (CHCl3) : 3018, 2860, 1492, 1450 cm-1 1H NMR (CDCl3) : δ 2.16 (s, 3H,), 2.47 (brd, J = 11.28 Hz, 1H),

2.95 (td, J = 12.11 Hz and 3.85 Hz, 1H), 3.9 (d, J =

3.02 Hz, 1H), 4.05 (td, J = 11.55 Hz and 3.30 Hz,1H),

4.31 (brdd, J = 11.28 Hz and 3.3 Hz, 1H), 5.10 (d, J =

3.02 Hz, 1H), 7.0−7.37 (m, 10H, ArH) 13C NMR (CDCl3) : δ 139.4, 134.2, 131.2, 127.6, 127.2, 126.9, 126.5,

125.8, 81.2, 68.1, 67.6, 47.6, 43.1

Analysis for : C17H19NO

Calculated (%) : C, 80.60; H, 7.56; N, 5.53

Found (%) : C, 80.20; H, 7.62; N, 5.12

Preparation of EtZnCl·Mg(Br)Cl (5)

In a 25 mL two neck round bottom flask, anhydrous zinc chloride (0.654 g,

4.8 mmol) was dissolved in anhydrous THF (3.4 mL). The solution was cooled to 0 oC, treated with EtMgBr (4.8 mmol, 6.15 mL of 0.78 M solution in THF) dropwise

over 10 minutes. The resulting solution was stirred at 0 oC for 1 h. Ice bath was then

removed and reaction mixture was stirred for 1 h at room temperature to provide 0.5

M solution (by iodometric titration) of 5.

Preparation of EtZnOAc·Mg(OAc)Br (6)

To the suspension of anhydrous Zn(OAc)2 (2.75 g, 15 mmol) in anhydrous

THF (13.3 mL) was added EtMgBr (15 mmol, 16.66 mL of 0.9 M solution in THF)

dropwise at 0 oC over 10 minutes. Zinc acetate was dissolved within 10–15 min. and

solution became clear. Resulting solution was stirred at 0 oC for 1 h and then at room

temperature for 1 h to obtain 0.5 M solution (by iodometric titration) of 6.

96

Preparation of reagent (7) and (8)

To a solution of ZnCl2 (or Zn(OAc)2) (5 mmol) in 16.5 mL THF was added

diethylzinc (5 mmol, 3.44 mL of 1.45 M solution in hexane) dropwise at room

temperature over 5 minutes. The resulting clear solution was then stirred for 1 h to

obtain 0.5 M solution (by iodometric titration) of 7 or 8.

General procedure for the preparation of magnesium-dialkoxides (21, 23 and

24)

In a 10 mL round bottom flask containing magnetic stir bar and rubber

septum, the diol ((−)-12 or (−)-13 or (+)-14) (0.4 mmol) was dissolved in 2 mL

anhydrous THF. The solution was cooled to 0 oC and treated with EtMgBr (0.8

mmol, 0.84 mL of 0.95 M solution in THF). After 15 minutes ice bath was removed

and the mixture was stirred at room temperature for 15 minutes. The resulting

solution of magnesium-dialkoxides (21, 23 and 24 respectively) was used as it is for

alkylation step.

General procedure for the preparation of lithium-dialkoxides (20 and 22)

In a 10 mL round bottom flask containing magnetic stir bar and rubber

septum, the diol ((−)-12 or (−)-13) (0.22 mmol) was dissolved in 1.5 mL anhydrous

THF. The solution was cooled to 0 oC and treated with n-BuLi (0.44 mmol, 0.27 mL

of 1.6 M solution in cyclohexane). After 15 minutes ice bath was removed and

stirring was continued at room temperature for 15 minutes to obtain lithium-

dialkoxides 20 and 22 respectively.

Magnesium-dialkoxide catalyzed addition of EtZnCl·Mg(Br)Cl (5) to

benzaldehyde

The following procedure for the addition of EtZnCl·Mg(Br)Cl to benzaldehyde

catalyzed by 23 is representative (entry 5 in table-5).

To a 50 mL two necked round bottom flask was added EtZnCl·Mg(Br)Cl (5)

(4.8 mmol, 9.6 mL of 0.5 M solution in THF) followed by 1,4-dioxane (0.41 mL, 4.8

mmol) at 0 oC. After 15 minutes, the catalyst 23 (0.4 mmol, solution in THF) was

added. The resulting heterogeneous reaction mixture was stirred for next 10 minutes

and was treated with benzaldehyde (0.4 mL, 4 mmol). After 8 h at 0 oC, the mixture

was cautiously quenched with MeOH (1 mL), diluted with EtOAc (20 mL), washed

97

with saturated NH4Cl solution and dried over anhydrous Na2SO4. Evaporation of the

solvent followed by Kugelrohr distillation (150 oC, 0 torr) provided the product

contaminated with benzyl alcohol and unreacted benzaldehyde. The crude compound

was then purified by flash chromatography on silica gel (230-400 mesh) using ethyl

acetate: petroleum ether as the eluent to obtain 25 as an oil.

OH

25

Yield : 0.348 g (64%)

[α]25 D : 0

ee : 0 1H NMR (CDCl3) : δ 0.91 (t, J = 7.45 Hz, 3H), 1.68−1.90 (m, 3H, CH2

and OH), 4.59 (t, J = 6.57 Hz, 1H), 7.22−7.37 (m, 5 H,

ArH).

Addition of EtZnOAc·Mg(OAc)Br (6) to benzaldehyde catalyzed by

magnesium-dialkoxide (23)

The following procedure for the addition of EtZnOAc·Mg(OAc)Br to benzaldehyde

catalyzed by 23 is representative (entry 7 in table-6). The catalyst 23 was prepared in

MTBE by following the same procedure as described for THF.

To the catalyst 23 (0.2 mmol) in MTBE was added EtZnOAc·Mg(OAc)Br

(2.4 mmol, 0.5 M solution in MTBE) at 0 oC under argon atmosphere. The

heterogeneous reaction mixture was stirred vigorously for next 5 minutes and treated

with benzaldehyde (0.2 mL, 2 mmol). After 8 h at 0 oC the reaction was cautiously

quenched with MeOH (1 mL). Usual work-up and purification provided desired

product (S)-25.

Yield : 0.12 g (44%)

[α]25 D : –25.5 (c 5.0, CHCl3) [lit.49a ─ 46.7 (c 5.1, CHCl3)]

ee : 50% (by HPLC)

98

HPLC : Chiralcel OD-H column, i-PrOH:n-Hexane (2:98),

flow rate 0.5 mL/min., detection at 254 nm., tR =

24.375 min, tR = 31.333 min.

One pot procedure for enantioselective addition of RZnOAc⋅Mg(OAc)Br to

benzaldehyde

The following procedure for the addition of RZnOAc·Mg(OAc)Br to benzaldehyde is

representative (Table-7).

In a 50 mL two neck round bottom flask anhydrous Zn(OAc)2 (1.1 g, 6

mmol) and (−)-13 (0.186 g, 0.4 mmol) were suspended in anhydrous THF (5 mL).

The mixture was cooled to 0 oC and treated dropwise with RMgBr (6.8 mmol, 6.8

mL of 1 M solution in THF) under argon atmosphere. The reaction mixture was

stirred for next 1 h resulting in a clear solution. Benzaldehyde (0.4 mL, 4 mmol) was

then added and the mixture was stirred for the time indicated in table-7. The reaction

was cautiously quenched with MeOH (1 mL). Usual work-up and purification

provided pure alcohol.

(S)-1-phenylpropan-1-ol (25)

Yield : 0.163 g (30%)

[α]25 D : −19.3 (c 5.18, CHCl3) [lit.49a ─ 46.7 (c 5.1, CHCl3)]

ee : 40% (by chiral GC)

Chiral GC : CP-Cyclodextrin-B-2,3,6-M-19 capillary column, at

100 oC (1 min.), 20 deg./min., 110 oC (40 min.), 20

deg/min, 230 deg (5 min.) tR = 33.261 min., tR =

34.370 min.

(S)-1-phenylpentan-1-ol (28)

OH

28

99

Yield : 0.11 g (17%)

[α]26 D : −5.0 (c 3.2, C6H6) [lit.49b −39.9 (c 3.08, C6H6)]

ee : 13% (by HPLC)

HPLC : Chiralcel OD-H column, i-PrOH:n-Hexane (10:90),

flow rate 0.5 mL/min., detection at 254 nm., tR =

12.350 min, tR = 13.200 min. 1H NMR (CDCl3) : 0.88 (t, J = 6.69 Hz, 3H), 1.16−1.45 (m, 4H), 1.65−

1.85 (m, 3H, CH2 and OH), 4.61−4.71 (m, 1H),

7.22−7.40 (m, 5 H, ArH).

(S)-3-methyl-1-phenylbutan-1-ol (29)

OH

29

Yield : 0.032 g (5%)

[α]28 D : −8.33 (c 3.2, n-heptane) [lit.49c −32.3 (c 16.7, n-

heptane)]

ee : 16% (by chiral GC)

Chiral GC : CP-Cyclodextrin-B-2,3,6-M-19 capillary column, at

122 oC (50 min.), 20 deg./min., 230 oC (1 min.), tR =

36.519 min., tR = 37.742 min. 1H NMR (CDCl3) : δ 0.95 (d, J = 6.06 Hz, 6H), 1.44−1.56 (m, 1H),

1.65−1.85 (m, 3H, CH2 and OH), 4.68−4.81 (m, 1H),

7.27−7.38 (m, 5 H, ArH).

Addition of diethylzinc to benzaldehyde catalyzed by 23 (as described in eq 9)

To a solution of diethylzinc (3.6 mmol, 2.48 mL of 1.45 M solution in

hexane) was added 0.3 mmol of catalyst 23 (solution in THF) followed by

benzaldehyde (0.3 mL, 3 mmol) at 0 oC. After 2 h at 0 oC TLC indicated

100

benzaldehyde was consumed completely. Thereafter the reaction mixture was

quenched with 1 mL MeOH. Usual work-up and purification provided desired

product (S)-25.

Yield : 0.31 g (76%)

[α]25 D : –6.66 (c 5.4, CHCl3) [lit.49a ─ 46.7 (c 5.1, CHCl3)]

ee : 14%

Addition of ethylzinc reagents prepared from ZnX2 and n EtMgBr (entries 3−6

in table-8)

The following procedure for the addition of ethylzinc reagent (prepared from two

equivalent of EtMgBr and ZnX2) to benzaldehyde is representative.

A solution of ZnCl2 (or Zn(OAc)2) (1 mmol) in 1 mL THF was cooled to 0 oC. EtMgBr (2 mmol, 2.44 mL of 0.82 M solution in THF) was then added dropwise

over 5 minutes. The reaction mixture was then stirred at mentioned temperature and

time indicated in table-8 (entries 3−6). The mixture was then treated with PhCHO

(0.19 mL, 1.9 mmol) at 0 oC. After 1 h the reaction mixture was analyzed by GC.

Addition of triethylzincates to benzaldehyde (entries 7 and 8 in table-8)

A solution of ZnCl2 (or Zn(OAc)2) (2 mmol) in 2 mL THF was cooled to 0 oC

and treated with EtMgBr (6 mmol, 6 mL of 1 M solution in THF) dropwise over 10

minutes. The reaction mixture was stirred at 0 oC for 30 minutes. PhCHO (0.58 mL,

5.8 mmol) was then added and after 1 h the reaction mixture was analyzed by GC.

General procedure for the preparation of zinc-alkoxides (30a-c)

To a 50 mL two neck round bottom flask with a stir bar and a reflux

condenser was added the diol ((−)-13 or (−)-12 or (+)-14) (3 mmol) in 5 mL

anhydrous toluene. The mixture was heated at 80 oC to dissolve the diol completely

and diethylzinc (3 mmol, 2.06 mL of 1.45 M solution in hexane) was added dropwise

at the same temperature. Immediate evolution of ethane was observed. The reaction

mixture was stirred at 80 oC for 0.5 h. A viscous solution of zinc alkoxide (30a or

30b or 30c respectively) was obtained, which was utilized as such for alkylation step.

101

Addition of chiral-zincate catalyzed by zinc-alkoxide (30a-c)

The following procedure for the addition of chiral-zincate to benzaldehyde using zinc

alkoxide 30a is representative (Condition C, entry 3 in table-9).

The suspension of zinc-alkoxide 30a (3 mmol) was cooled to 0 oC and treated

with EtMgBr (3 mmol, 3 mL of 1 M solution in THF) and benzaldehyde (3 mmol,

0.3 mL in 2 mL toluene) simultaneously over 10 minutes. As addition proceeds,

zinc-alkoxide dissolves completely and solution becomes clear. Reaction mixture

was stirred for 2 h at 0 oC and cautiously quenched by 1 mL MeOH. Usual work-up

and purification provided the desired product (S)-25.

Yield : 0.24 g (59%)

[α]25 D : –23.15 (c 4.96, CHCl3) [lit.49a ─ 46.7 (c 5.1,

CHCl3)]

ee : 50%

102

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108

NMR Spectra and Chiral HPLC / GC Chromatogram

109 1H-NMR of compound 3 (CDCl3, 200MHz)

9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 -0.5 -1.0

2.992.94 2.092.001.93

TMS

0.00

0.92

0.96

0.99

1.36

1.39

1.43

1.47

1.65

1.69

1.73

1.77

1.80

2.93

2.97

3.01

7.42

7.46

7.49

7.52

7.55

7.56

7.60

7.95

7.98

Ph

O

3

1H-NMR of compound 4 (CDCl3, 200MHz)

10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0

10.29 1.911.00 0.96

TMS

0.00

1.95

1.96

2.99

3.01

3.03

3.04

4.86

4.87

4.89

4.90

4.91

4.93

4.94

7.21

7.22

7.23

7.28

7.30

7.31

7.35

7.37

OH

4

110 1H-NMR of compound 11 (CDCl3, 200MHz)

9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 -0.5

10.22 3.191.07 1.071.00

TMS

0.00

2.16

2.45

2.48

2.92

2.93

2.95

2.95

2.97

2.98

3.90

3.91

4.03

4.05

4.06

4.07

4.08

4.29

4.32

5.10

5.11

7.04

7.11

7.12

7.14

7.16

7.21

7.22

7.34

7.36

4.0 3.5 3.0 2.5

1.07 1.07 1.051.05 1.04

2.45

2.48

2.92

2.93

2.95

2.95

2.97

2.98

3.90

3.91

4.03

4.05

4.06

4.07

4.29

4.30

4.32

4.32N

OPh

PhMe

11

13C-NMR of compound 11 (CDCl3, 50.32MHz)

200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0

Chloroform-d

43.1

947

.65

67.6

168

.19

77.0

081

.22

125.

8612

6.58

126.

9612

7.23

127.

6213

1.21

134.

2713

9.43

128.0 127.5 127.0 126.5 126.0 125.5

125.

86

126.

58

126.

9612

7.23

127.

62

N

OPh

PhMe

11

111

DEPT NMR of compound 11

200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0

43.1

947

.63

67.6

168

.18

81.2

1

125.

8412

6.57

126.

9612

7.23

127.

6113

1.20

N

OPh

PhMe

11

1H-NMR of compound 25 (CDCl3, 200MHz)

9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 -0.5 -1.0

4.98 3.27 3.000.95

TMS

0.00

0.88

0.91

0.95

1.70

1.74

1.77

1.80

1.84

1.87

4.56

4.59

4.63

7.26

7.26

7.29

7.29

7.31

7.33

7.36

OH

25

112 1H-NMR of compound 28 (CDCl3, 200MHz)

10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 -0.5

4.87 4.053.17 3.000.91

TMS

0.00

0.85

0.88

0.92

1.27

1.29

1.32

1.33

1.35

1.37

1.73

1.76

1.78

1.84

4.63

4.66

4.69

7.24

7.26

7.28

7.29

7.31

7.32

7.34

7.36

OH

28

1H-NMR of compound 29 (CDCl3, 200MHz)

9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0

6.005.02 2.980.96

TMS

0.00

0.94

0.97

1.50

1.60

1.67

1.70

1.73

1.73

1.74

1.78

1.81

4.71

4.74

4.75

4.78

7.26

7.26

7.29

7.31

7.32

7.34

7.36

7.36

1.8 1.7 1.6 1.5 1.4

2.98 1.00

1.48

1.50

1.53

1.55

1.67

1.70

1.73

1.73

1.74

1.75

1.78

1.81OH

29

113

Determination of enantiomeric excess for RZnOAc⋅Mg(OAc)Br addition

product OH

(±)-25

OH

(−)-25

50% ee, Chiralcel OD-H column; i-PrOH:n-Hexane (2:98); 0.5 mL/min.; 254 nm.

Retention time: tR = 24.375 min, tR = 31.333 min.

114

OH

(±)-28

OH

(−)-28

13% ee, Chiralcel OD-H column; i-PrOH:n-Hexane (10:90); 0.5 mL/min.; 254 nm.

Retention time: tR = 12.35 min, tR = 13.20 min.

115

OH

(±)-29

OH

(−)-29

16% ee; GC analysis (CP-Cyclodextrin-B-2,3,6-M-19 capillary column), at 122 oC

(50 min.), 20 deg./min., 230 oC (1 min.), Retention time: tR = 36.519 min., tR =

37.742 min.

116

CHAPTER-3

Potential chiral ligands

117

Introduction Asymmetric catalysis is a topic of increasing interest and is one of the most

important focal areas in organic synthesis.1 Asymmetric catalysis with enzymes,

chiral metal complexes and chiral organic molecules has emerged as powerful tools

for the synthesis of optically active compounds. Most asymmetric catalysts that have

been developed so far are metal complexes with chiral organic ligands.2 The chiral

ligand plays a crucial role and modifies the reactivity and selectivity of the metal

center in such a way that one of two possible enantiomeric products is formed

preferentially. Therefore, the design of new chiral ligands aimed at asymmetric

catalysis is of increasing importance in organic synthesis.3 The main requirement of a

chiral ligands is the presence of at least two hetero atoms capable of the formation of

a structurally well defined metal complex which can differentiate between

enantiotopic faces of the electrophile. The two hetero atoms allow flexibility as one

or both can be bound to Lewis acidic metal centre. Significant work has been done

for the development of chiral catalysts using various chiral ligands such as

phosphorus containing ligands,2c-e,j,4 oxygen containing ligands5 and nitrogen

containing ligands.6 As compared to phosphorous ligands, the nitrogen containing

ligands offer many advantages, such as the ease of preparation, high stability and

easy separation. C2-symmetric chiral diols are also excellent chirality inducers and

have been used in different types of asymmetric transformations.7

Amongst different approaches, ligand-accelerated enantioselective addition of

organozinc reagents to carbonyl compounds has emerged as one of the powerful

tools for the construction of chiral carbon stereocentre.8 Our interest in this area led

us to explore morpholine based ligands and sterically also demanding C2-symmetric

diols.

The chapter is divided into two sections.

Section 3A: Synthesis and resolution of cis- and trans-2,3-diphenyl morpholines

Section 3B: Attempted resolution of 2,3-diphenylbuatane-2,3-diol

118

Section 3A

Synthesis and resolution of cis- and trans-2,3-diphenyl

morpholines Introduction

Substituted morpholines constitute an important class of heterocyclic

compounds found in many naturally occurring as well as synthetically important

organic molecules that exhibit interesting biological and pharmacological properties.9

This class of compounds has found important applications as antitumors,10

antimicrobials,11 antidepressants,12 antioxidants,13 other biological activity14 and in

agricultural use.15 Morpholine derivative such as reboxetine is a potent

antidepressant drug, which selectively inhibits the norepinephrine reuptake and is

widely studied for its pharmacological properties.16 These compounds have gained

much interest in recent years as a result of the pronounced biological activities and

their applications in asymmetric synthesis.17,18

Various methods are known in the literature for the synthesis of morpholine

derivatives.9,19-21 In most cases morpholine ring has been constructed by the reaction

of 1,2-amino alcohols with various electrophiles, such as chloroacetyl chloride,22

epoxides,14a,23 activated alkenes24 and others.18a,25 Some of the important literature

methods for the preparation of chiral morpholine derivatives are described below.

1. Synthesis of chiral morpholine derivatives: A literature review

1.1 From β-amino alcohol and chloroacetyl chloride

In 1985 Brown et al.22a described the preparation of morpholine derivative 4

(Scheme 1). Commercially available (R) or (S)-serine 1 was converted to N-benzyl

serine 2 by reductive amination. Compound 2 was reacted with chloroacetyl chloride

in the presence of sodium hydroxide to obtain morpholinone 3. Reduction of 3 using

borane-dimethyl sulphide complex provided optically pure morpholine 4 with good

optical purity.

119

OH

NH2HO2C*

(R) or (S)

1

OH

NHHO2C *

CH2Ph

2

N

O

HO2CCH2Ph

*O N

O

HOH2CCH2Ph

*

(R) or (S)

ab c

3 4

>90% ee

Scheme 1. Reagents and conditions: (a) PhCHO, NaBH4, 6−10 oC; (b) (i) ClCH2COCl, NaOH, 0 oC; (ii) 30% aq. NaOH, 30−33 oC; (c) BH3⋅SMe2, THF, 0 oC.

The same author in 1987 prepared racemic morpholines 5a and 5b starting

from the corresponding racemic amino alcohols using above methodology.22b The

morpholine derivatives (5a and 5b) were resolved into corresponding enantiomers

using dibenzoyl tartaric acid in good yield with high enantiomeric purity (Scheme 2).

N

O

HO

p-R-C6H4

(±)-5a,b

5a = R = H5b = R = F

i) (+)-dibenzoyl tartaric acid(+)-5a or (+)-5b + (−)-5a or (−)-5b

ii) (−)-dibenzoyl tartaric acid> 98% ee

(+)-5a, 39% (−)-5a, 28% (+)-5b, 32% (−)-5b, 35%

Scheme 2. Resolution of 5a and 5b.

In 2005 Tamagnan et al.22f reported the preparation of morpholine 9 from

commercially available (S)-3-amino-1,2-propanediol 6 (Scheme 3). Treatment of 6

with chloroacetyl chloride in the presence of Et3N provided amide 7, which was

cyclized to lactam 8 using potassium tert-butoxide. Compound 8 was reduced with

Red-Al to furnish morpholine (S)-9 in good yield. The morpholine 9 was further

converted to (S,S)-Reboxetine which is known to be a potent selective

norepinephrine reuptake inhibitor.

120

OH

NH2

6

a

OHOH

N

OH

H

OCl

7

N

O

HO

b

OH

N

O

H

OHc

8 (S)-9

Scheme 3. Reagents and conditions: (a) ClCH2COCl, Et3N, CH3CN/MeOH −10 to 0 oC, 94%; (b) t-BuOK, t-AmOH, RT, 92%; (c) Red-Al, THF, 0 oC to RT, 85%. 1.2 From β-amino alcohol and epoxide

In 1998 Servi et al.14a reported the preparation of morpholine 13 starting from

chiral epoxide 10 (Scheme 4). The epoxide 10 was reacted with ethanolamine

sulphate 11 at 40 oC in the presence of sodium hydroxide to give intermediate 12,

which was converted in situ to morpholine 13 by heating the reaction mixture at 65 oC.

O

Ph

+

H2NOSO3Na

NH

OSO3NaOHPha

N

O

H

13

b Ph10

11 12

Scheme 4. Reagents and conditions: (a) NaOH, MeOH, 40 oC; (b) NaOH, 65 oC, 66%.

In 1999 Quirion et al.23a reported the preparation of 2,5-disubstituted

morpholine 20 starting from chiral epoxide 15 (Scheme 5). The O-protected amino

alcohol 14 was reacted with epoxide 15 in methanol at 40 °C to furnish amino

alcohol 16. Subsequent condensation of 16 with chloroacetyl chloride gave amide 17

which on cyclization using sodium hydride followed by deprotection of silyl group

provided lactam 18. Next, the amide enolate of compound 18 was generated by

treatment with sec-BuLi in the presence of HMPA which on treatment with MeI

provided alkylated product 19 with >95% diastereoselectivity. Compound 19 was

converted to morpholine 20 by reduction with LiAlH4 followed by removal of chiral

121

auxiliary under hydrogenation. This methodology was also applied for the

preparation of other chiral morpholines derivative by using various enantiopure

epoxides.

14

OTBDMS

NH2Ph

a NH

Ph

OTBDMS

OHR

N

OHR

bOTBDMS

O

Cl

Ph

O

N

R

OHPh

O

O

N

R

OHPh

O

MeO

N

R

H

Me

O

R

+

16 17

181920

15

c, d

ef

R = Ph, PhCH2OCH2

Scheme 5. Reagents and conditions: (a) MeOH, 40 oC, 78%; (b) ClCH2COCl, 50% aq. NaOH, THF, 76%; (c) NaH, THF, 90%; (d) TBAF, THF, 0 oC to RT, 96%; (e) sec-BuLi, HMPA, THF, −78 oC then MeI, 74%; (f) (i) LiAlH4, THF; (ii) H2, Pd/C, MeOH, 50%. In 2004 Myers et al.23b described the preparation of trans 2,5-disubstituted

morpholine. Treatment of epoxide (S)-21 with excess of D-alaninol 22 in n-propanol

provided exclusively monoalkylated product 23 (Scheme 6). Compound 23 on

treatment with p-toluenesulfonyl chloride gave N-tosyl diol 24, which was cyclized

to 25 using sodium hydride and p-toluenesulfonyl imidazole. Deprotection of N-tosyl

group using sodium in ethanolic ammonia provided desired morpholine derivative 26

in excellent yield.

122

O

TBSO

H

CH3HO

NH2

+

aTBSO

OHN

H

CH3

OH

33 b

TBSO

OHN

Ts

CH3

OH

3

O

NTs

TBSO3

CH3

O

NH

TBSO3

CH3

c

d

21

22

2324

2526

Scheme 6. Reagents and conditions: (a) n-PrOH, 97 oC, 99%; (b) p-TsCl, Et3N, DCM, 77%; (c) NaH, TsIm, THF, 99%; (d) Na, NH3, EtOH, 100%. In 2007 Bruening et al.23c reported one pot procedure for the preparation of

various optically active morpholine derivatives by the reaction of chiral β-amino

alcohols with optically pure epichlorohydrin. Initial investigation showed that

LiClO4 as Lewis acid and NaOMe as Lewis base proved better as compared to other

reagents. Thus, the reaction of chiral β-amino alcohol 27 with (S)-epichlorohydrin 28

furnished desired morpholine derivative 29 in moderate to good yield with excellent

stereoselectivity (Table 1).

123

Table 1. LiClO4 mediated one-pot preparation of morpholine derivatives

NHR1

OH

R

R2 +

O

ClLiClO4, toluene 20−50 oC

thenNaOMe, MeOH 20−50 oC

O

NR1

R2

R

OH

27a-f 28 29a-f

Entry 27 R R1 R2 Yield of 29 ee/de

1 a Bn H H 59 94

2 b Bn i-Pr H 63 >97

3 c Bn t-Bu H 60 >97

4 d Bn H Ph 77 >97

5 e Bn Me H 57 97

6 f Me H H 61 >97

1.3 From β-amino alcohol and alkenes

In 1993 Hayashi et al.24b reported Pd-BINAP catalyzed preparation of vinyl

morpholines. Initial screening of the phosphorous ligand showed that BINAP 32 was

proved the best ligand. Under the optimized conditions, treatment of protected

ethanol amine 30 with activated alkene 31 in the presence of chiral Pd-BINAP

catalyst provided optically active vinyl morpholine 33 with moderate

enantioselectivity (Scheme 7).

124

X

X

31

31a = X = OCOCH331b = X = OCO2CH331c = X = OCO2

tBu

OH

NHR

30

30a = R = CH2Ph30b = R = SO2C6H4-p-CH3

+Pd(0)/L*, THF

40 oC, 24 h

O

NR

32-64% yield50-61% ee

33a-b

PPh2

PPh2

(R)-BINAP (32)

*

L* =

Scheme 7. Pd-catalyzed enantioselective synthesis of 33

In 2000 Nishi et al.24c prepared morpholine derivative (R)-38, which is key

intermediate for tachykinin receptor antagonist, starting from alkene 35. In this

protocol, excess N-Boc-aminoethanol 34 was reacted with styrene derivative 35 in

the presence of N-iodosuccinimide in acetonitrile to obtain iodide 36 (Scheme 8).

Treatment of 36 with sodium hydride furnished N-Boc morpholine 37, which on

deprotection of both the triphenylmethyl (Tr) and Boc group by treatment with 4N

HCl provided racemic 38 in good yield. Morpholine 38 was resolved using D-(−)-

tartaric acid to obtain (R)-38 with high optical purity.

OTrCl

Cl

OTrCl

Cl

IO

NHBoc

OTrCl

Cl

ON

Boc

OHCl

Cl

ON

H

OHCl

Cl

ON

H

a b

c

d

35

36 37

(R)-38, >99% ee (±)-38

NHBocHO

+34

Scheme 8. Reagents and conditions: (a) NIS, CH3CN, 70 oC, 72%; (b) NaH, DMF, 70 oC, 77%; (c) 4N HCl, dioxane/EtOH, 79%; (d) D-(−)-tartaric acid.

125

In 2008 Aggarwal et al.24e described one pot procedure for the construction of

morpholine unit starting from vinyl sulfonium salt 40. The salt 40 was prepared from

2-bromoethyl trifluoromethanesulfonate 39 (Scheme 9). Treatment of 40 with N-

tosyl amino alcohol 41a-c in the presence of Et3N provided desired morpholine

derivative 42 in excellent yield (Scheme 10). The possible explanation for the

formation of 42 involves the base assisted conjugate addition of nitrogen atom of 41

to 40 followed by cyclization at oxygen gives desired morpholine derivative.

BrOTf

BrSPh2

SPh2

OTfa b

39 40

OTf

Scheme 9. Reagents and conditions: (a) Ph2S, toluene, reflux, 81%; (b) KHCO3, THF/H2O, RT, 96%.

R1 OH

NHR2

Ts

40, Et3N, CH2Cl2

0 oC−RT N

O

Ts

R1

R2

41a-c 42a-c

OH

NHTs

OH

NHTs

PhOH

NHMeO2CTs

41a 41b 41c

96-98% yield

Scheme 10. One-pot preparation of morpholines 42a-c using vinyl sulfonium salt 40

Recently Bagnoli et al.24g reported the use of vinyl selenones as Michael

acceptors for the synthesis of morpholine derivatives. Enantiopure N-protected

amino alcohols 27d and 41b,d were treated with selenones 43a-c in the presence of

sodium hydride in THF to obtain corresponding morpholine derivatives in good yield

(Scheme 11). In the case of substituted selenones 43b and 43c, the reaction was not

126

selective and the formation of a diastereomeric mixture of morpholine derivative was

observed.

OH

NHR1

R

27d = R1 = Ph, R = Bn41b = R1 = CO2Me, R = Ts41d = R1 = Ph, R = Ts

+SeO2Ph

R2

43a = R2 = H43b = R2 = Ph43c = R2 = C6H13

NaH, THF

0 oC to reflux

O

NR1

R2

R

71-88% yield

Scheme 11. One-pot preparation of morpholine derivatives using selenones 43a-c

It was suggested that the reaction of aminoalcohol with 43 in the presence of

sodium hydride initially gives the carbanion 44 by the attack of oxygen atom of the

aminoalcohol at the β-carbon of the selenones (Scheme 12). Subsequent proton

transfer gives the nitrogen anion 45, which upon intramolecular displacement of

PhSeO2 group gives morpholine derivative.

OH

NHR1

R

+NaH

SeO2Ph

R2 O

NHR1

R

SeO2Ph

R2O

NR1

R

SeO2Ph

R2

O

NR1

R2

R

44 45

Scheme 12. Proposed mechanism

127

1.4. From β-amino alcohol and other electrophiles

Otto et al.25a in 1956 reported the preparation of morpholine 48 using

chloroethanol as electrophile. L-Ephedrine 46 was reacted with chloroethanol to give

diol 47, which upon treatment with concentrated sulfuric acid provided trans-3,4-

dimethyl-2-phenyl morpholine 48 (Scheme 13).

OHPh

NHMeMe

+

ClOH

N

OH OH

MeMe

Ph

N

OPh

MeMe

toluene

130 oC

conc. H2SO4

46

47 48

Scheme 13. Synthesis of morpholine 48

In 2004 Sasaki et al.25c reported preparation of chiral trans-3,5-disubstituted

morpholines. The reaction of N-Boc protected amino alcohol 49, derived from L-

serine, with (R)-2,3-O-isopropylideneglycerol triflate 50 in the presence of sodium

hydride gave compound 51 (Scheme 14). Acid hydrolysis of compound 51 provided

diol 52, which upon regioselective protection of the primary hydroxyl with

TBDPSCl provided alcohol 53. Compound 53 on O-mesylation gave 54, which upon

deprotection of Boc-group followed by base mediated cyclization furnished desired

enantiopure morpholine 55.

128

NH

OH

Boc

TBDPSO

O

OTfO

+49

50

NH

O

Boc

TBDPSO

51

OO

NH

O

Boc

TBDPSO

OTBDPSOH

NH

O

Boc

TBDPSO

OTBDPSOSO2CH3

N

O

H

OTBDPSTBDPSO

NH

O

Boc

TBDPSO

OHOH

52

5354

55

a b

c

d

e

Scheme 14. Reagents and conditions: (a) NaH, THF, 83%; (b) 80% aq. AcOH, RT, 86%; (c) TBDPSCl, Imidazole, DMF, 87%; (d) MsCl, Et3N, DMAP, DCM, 93%; (e) (i) CF3COOH, DCM; (ii) Et3N, DIEA, MeOH, reflux, 89%.

The same author in 2006 reported the preparation of morpholine 60 by using

tert-butyl bromoacetate as electrophile.18a Treatment 49 with tert-butyl bromoacetate

in the presence of 30% aq. NaOH and catalytic TBAI in toluene gave ester 56

(Scheme 15). The ester 56 was first reduced with DIBAL-H and the resulting crude

aldehyde was further reduced to 57 with LiBH4. O-mesylation of 57 provided

compound 58, which was converted to morpholine derivative 59 by removal of the

Boc-group followed by base-mediated cyclization. Compound 59 was converted to

desired morpholine 60 by removal of silyl group using TBAF.

129

OtBuBr

O+

a

NH

O

Boc

TBDPSO

OtBu

O

NH

O

Boc

TBDPSO

OH

NH

O

Boc

TBDPSO

OMs

N

O

H

TBDPSON

O

H

HO

b

c

de

49

56 57

585960

Scheme 15. Reagents and conditions: (a) 30% aq. NaOH, TBAI, toluene, 87%; (b) (i) DIBAL-H, DCM; (ii) LiBH4, Et2O, 85%; (c) MsCl, Et3N, DCM, 93%; (d) (i) TFA, DCM; (ii) DIEA, DCM, reflux, 83%; (e) TBAF, THF, 87%.

In 2009 Wolfe et al.25e described the preparation of morpholine derivatives 64

using allyl bromide as electrophile. In this protocol, the treatment of enantiopure N-

Boc protected amino alcohol 61 with allyl bromide in the presence of sodium hydride

gave allyl ether 62 (Scheme 16). Deprotection of Boc-group followed by Pd-

catalyzed N-arylation of the resulting amine trifluoroacetate salt furnished N-aryl

derivative 63. Compound 63 was cyclized to desired cis-3,5-disubstituted morpholine

64 using catalytic amount of Pd(OAc)2 under the optimized conditions in moderate

yield with >90% de. This methodology was also applied for the preparation of

various bicyclic morpholine derivatives.

130

OH

NHRBoc

O

NHRBoc

O

NHRAr

N

O

RAr

R1a b c

R = Me, Bn, (CH2)2SMe, CH2OBn, CH2[(N-Bn)-3-indolyl]Ar = Ph, p-MeO-Ph, p-Cl-Ph, m-CN-PhR1 = Ph, p-MeO-Ph, o-MeO-Ph, p-Me-Ph, p-tBu-Ph, PhCH2=CH

61 62 63 64> 90% de

Scheme 16. Reagents and conditions: (a) (i) NaH, DMF; (ii) allyl bromide; (b) (i) TFA, DCM; (ii) ArBr, t-BuONa, 1 mol% Pd2(dba)3, 2 mol % (±)–BINAP or 8 mol % P(tBu)3⋅HBF4, toluene, 40−80 oC ; (c) R1Br, 2 mol% Pd(OAc)2, 8 mol% P(2-furyl)3, t-BuONa, toluene, 105 oC, 21-58%.

1.5. Preparation of morpholine derivatives from aziridine

In 2009 Ghorai et al.19b described highly regio- and stereoselective one pot

procedure for the preparation of chiral morpholines. This protocol involves Cu(OTf)2

catalyzed ring opening of chiral N-tosyl aziridine 65a in the presence of

chloroethanol followed by potassium hydroxide mediated intramolecular cyclization

to give corresponding morpholine 66a in excellent yield with good enantioselectivity

(Scheme 17). When R was alkyl (65b-d) the reaction was not regioselective and the

formation of mixture of regioisomeric product was observed. The above strategy was

successfully demonstrated for the preparation of 2,3-disubstituted morpholines from

enantiopure 2,3-disubstituted aziridines with excellent diastereoselectivity.

N

R

+ Cu(OTf)2 OCl

OH

R

Cl

NHTsKOH

N

O

TsR

Ts

65

65a = R = Ph65b = R = Bn65c = R = i-Pr65d = R = i-Bu

66a

R = Ph

Scheme 17. One-pot preparation of chiral morpholines from aziridine 65

131

1.6. Preparation of morpholine derivatives from aldehydes

In 2010 Waghmode et al.20a reported the proline catalyzed asymmetric α-

aminoxylation and reductive amination as key steps for the preparation of chiral

morpholine (R)-9 (Scheme 18). In this protocol, aldehyde 67 was treated with

nitrosobenzene in the presence of D-proline in acetonitrile followed by in situ

reduction with NaBH4 to give aminoxy alcohol, which upon treatment with catalytic

amount of CuSO4 provided diol 68. Selective tosylation of primary hydroxyl group

followed by treatment with sodium azide in DMF provided azido alcohol 69.

Treatment of 69 with allyl bromide using sodium hydride gave azido allyl ether 70,

which on potassium osmate mediated dihydroxylation and subsequent oxidative

cleavage of the resulting diol using NaIO4 furnished azido aldehyde 71.

Simultaneous Pd-catalyzed intramolecular reductive amination and benzyl

deprotection of 71 provided desired morpholine (R)-9 in good yield.

N

O

H

HO

BnO H

OBnO

OH

OHBnO

N3

OH

O

N3

BnOO

ON3

BnO

a b

c

de

67 6869

7071(R)-9

Scheme 18. Reagents and conditions: (a) (i) PhNO, 25 mol% D-proline, CH3CN, −20 oC, then NaBH4, MeOH; (ii) 30 mol% CuSO4, MeOH, 0 oC, 66%; (b) (i) 2 mol% Bu2SnO, p-TsCl, Et3N, DCM, 0 oC to RT; (ii) NaN3, DMF, 70 oC, 89%; (c) NaH, allyl bromide, DMF, 0 oC, 97%; (d) (i) 2 mol% K2OsO4⋅H2O, NMO, acetone/H2O, RT; (ii) NaIO4, acetone/H2O, RT; (e) H2, Pd/C, MeOH, RT.

In the same year Rutjes et al.20b described chemoenzymatic synthesis of cis-

and trans-2,5-disubstituted morpholine derivatives starting from benzaldehyde.

Treatment of benzaldehyde with HCN in the presence of Hydroxynitrile lyases

(HNL) using citrate buffer furnished cyanohydrin 72 (Scheme 19). Subsequent MIP

protection of 72 provided compound 73 in excellent yield with high enantiomeric

excess. MIP protection was mandatory to prevent racemization of 72. Compound 73

132

was converted to ester 74 using three step-one-pot protocol. Treatment of 73 with

excess DIBAL-H followed by subsequent transimination with glycine methyl ester in

the presence of Et3N gave intermediate secondary imine, which on reduction with

NaBH4 furnished ester 74. LiAlH4 reduction of 74 gave amino alcohol 75, which was

treated with p-toluenesulfonyl chloride to give N-tosyl derivative 76. Deprotection of

MIP group using aqueous hydrochloric acid followed by cyclization of resulting diol

using p-toluenesulfonyl imidazole and sodium hydride provided N-Ts morpholine

derivative 77. Finally, samarium iodide mediated deprotection of tosyl group

furnished desired morpholine derivative 78 in good yield. This methodology was

also used for the preparation of enantiopure cis- and trans-2,5-disubstituted

morpholines using (R) and (S)-selective HNL and various chiral amino acid methyl

esters.

Ph H

O

Ph CN

OH

Ph CN

OMIP

Ph

OMIP

NH

CO2Me

Ph

OMIP

NH

Ph

OMIP

NTs

N

OPh

TsN

OPh

H

a b c

d

efg

7273

74

75767778

OHOH

>99% ee

Scheme 19. Reagents and conditions: (a) (R)-HNL, MTBE/H2O, PH = 5; (b) 2-methoxy propene, cat. POCl3, then Et3N, RT; (c) (i) DIBAL-H, Et2O; (ii) H2NCH2COOMe, Et3N; (iii) NaBH4, MeOH, −78 oC; (d) LiAlH4, THF, 0 oC; (e) p-TsCl, Et3N, DCM, 0 oC to RT, 82%; (f) (i) aq. HCl, THF; (ii) TsIm, NaH, THF 0 oC to RT, 83%; (g) SmI2, pyrrolidine, H2O/THF.

As evident from foregoing account, the chiral morpholine derivatives are

easily accessible from simple and easily available starting material.

Over the course of our work on enantioselective addition of organozinc

reagents to aldehydes,26 we wanted to use morpholine ligands 79 and 80 (Figure 1).

We anticipated that a six-membered heterocyclic ring containing heteroatom such as

oxygen allow extra coordination site in the catalyst which may influence its ligand

133

catalytic properties. The present section describes the optimized synthesis and

resolution of morpholine ligands 79 and 80.

N

OPh

PhH

N

OPh

PhH

79 80

Figure 1

In 1969 Stefanovsky et al.27a reported the synthesis of morpholines 79 and 80

starting from corresponding amino alcohols 81 and 82 respectively. The reaction of

racemic 81 (or 82) with chloroacetyl chloride in the presence of Et3N gave N-

chloroacetyl derivative 83 (or 84) (Scheme 20). Intramolecular cyclization of

compound 83 (or 84) using sodium hydroxide furnished lactam 85 (or 86). Lithium

aluminum hydride reduction of 85 (or 86) provided corresponding racemic cis- and

trans-2,3-diphenyl derivatives 79 and 80 respectively. Similar strategy was used for

the synthesis of morpholines (−)-79 and (+)-80 starting from corresponding chiral

amino alcohols.

Ph OH

NH2Ph

Ph OH

NPhH

O

N

OPh

PhH

O N

OPh

PhHCl

erythro-(±)-(81)erythro-(−)-(81)threo-(±)-(82)threo-(+)-(82)

81, 82

erythro-(±)-(83)erythro-(−)-(83)threo-(±)-(84)threo-(+)-(84)

cis-(±)-(85)cis-(−)-(85)trans-(±)-(86)trans-(+)-(86)

cis-(±)-(79) (11%)cis-(−)-(79) (14%)trans-(±)-(80) (22%)trans-(+)-(80) (23%)

79, 80

a b c

Scheme 20. Reagents and conditions: (a) ClCH2COCl, Et3N, 0 oC to RT; (b) NaOH, EtOH, 40 oC; (c) LiAlH4, THF or Et2O, RT.

Although the preparation of the two stereoisomers of these molecules is

known (viz. (−)-79 and (+)-80), we found the procedure unsatisfactory in terms of

yield. Also, the reported rotations were incorrect. We describe here an optimized

preparation of (±)-79 and (±)-80 which were then efficiently resolved into

134

corresponding enantiomers in good yield with high enantiomeric purity. The results

are discussed below.

Present work

Results and discussion

1. Preparation of (±)-cis-2,3-diphenyl morpholine (79)

Both the cis- and trans-2,3-diphenyl morpholines can be accessed from a

common intermediate that is, erythro-2-amino-1,2-diphenylethanol 81. The amino

alcohol 8128 was prepared by hydrogenation of α-benzoin oxime 87 (Scheme 21).

The racemic amino alcohol 81 was converted to its threo-isomer 82 according to the

literature procedure.28a In this procedure, the amino alcohol 81 was treated with conc.

hydrochloric acid to obtain hydrochloride salt, which was reacted with excess

formamide to obtain N-formyl derivative 88. Subsequent treatment with thionyl

chloride followed by hydrolysis provided racemic threo-2-amino-1,2-

diphenylethanol 82 in good yield.

Ph OH

NPh

87

Ph OH

NH2PhOH

81

Ph OH

NH2Ph

82

Ph OH

NHPhCHO

88

a b c

Scheme 21. Reagents and conditions: (a) H2, Pd/C, MeOH, RT, 80%; (b) (i) conc. HCl, MeOH, 50 oC, 98%; (ii) HCONH2, 150 oC, 88%; (c) (i) SOCl2, 0 oC to RT; (ii) H2O, reflux, 88%.

With both the starting material in hand, our next job was to construct

morpholine ring. Initially we tried one step protocol29 for the preparation of cis-

morpholine 79. In the case of reaction of erythro amino alcohol 81 with 1,2-dibromo

ethane using potassium hydroxide in DMSO, starting material was recovered

(Scheme 22). We then examined ethylene-di-p-toluenesulfonate as electrophile.

Treatment of racemic 81 with ethylene-di-p-toluenesulfonate in THF using Et3N

gave complex reaction mixture. Similar kind of results were realized when the

reaction was carried out in N,N-dimethyl formamide as solvent.

135

81

BrBr

KOH, DMSO, RT

TsOOTs

TsOOTs

THF, Et3N, reflux

DMF, Et3N, 100 oC

complex reaction mixture

complex reaction mixture

N

OPh

PhH

X

Scheme 22

We then changed strategy to two step protocol. It was thought that cis-5,6-

diphenylmorpholin-3-one 85 could be directly obtained in single step using method

of Clarke et al.30 Therefore the amino alcohol 81 was reacted with ethyl

chloroacetate using sodium hydride in THF under reflux to obtain 85 (Scheme 23).

However, we did not observe expected product, instead racemic erythro-2-

(chloroacetylamino)-1,2-diphenylethanol 83 was isolated in low yield. The structure

of the compound was confirmed by IR, 1H NMR and microanalysis.

81

OEt

OCl

NaH, THF, reflux

N

OPh

PhH

X

83, (5%) yield

Ph OH

NPh

O

ClH

unexpected

O

Scheme 23

As mentioned previously, Stefanovsky et al. reported the synthesis of (–)-79 and (+)-

80 in 14% and 23% overall yields starting from homochiral aminoalcohols (–)-81

and (+)-82 respectively.27a In asymmetric synthesis, it is always desirable to

introduce the chirality at last possible step. We therefore decided to redesign the

136

reported procedure for 79 and 80. To improve the yield, erythro amino alcohol 81

was reacted with chloroacetyl chloride in the presence of NaHCO3 using methanol as

the solvent at −10 oC. Amide 83 was obtained as sole product in 98% yield (Scheme

24). Due to competitive O-acylation, low yield was observed when the reaction was

carried out in THF solvent using pyridine as base. The crude compound 83 was

cyclized to lactam 85 in 97% yield using potassium hydroxide in ethanol under

reflux. 1H NMR of the unpurified 85 was clean and showed no isomerization at

stereocenters under the reflux conditions.

Ph OH

NH2Ph

a

81

b

N

OPh

PhH

O

85

c(±)-79

Ph OH

NPh

O

ClH83

SR

cheme 24. Reagents and conditions: (a) ClCH2COCl, NaHCO3, MeOH, −10 oC to T, 98%; (b) KOH, EtOH, reflux, 97%; (c) LiAlH4, THF, reflux, 62%.

stal X-ray analysis. The ORTEP diagram for compound 85 is shown in

figure 2.

The structure of compound cis-(±)-85 was confirmed by IR, NMR,

microanalysis. The cis- stereochemistry of two phenyl group in 85 was confirmed by

single cry

Figure 2. ORTEP diagram for (±)-85

137

Cyclization of 83 to 85 also can be carried out using other bases. First we tried to

cyclize amide 83 using weak base like pyridine or potassium carbonate. However,

complex TLC pattern was observed in both the cases (Table 2, entries 1 and 2). Use

of sodium hydride gave complete conversion in THF as well as DMF solvent (entries

Table 2. Intramolecular cyclization of 83 to 85

83

N

OPh

PhH

O

85

Ph OH

NPh

O

ClH

Reagent

Entry Reagent Solvent Temp, (oC) Time, (h) Crude yield, (%)

1 Pyridine DMF 100 10 a

2 K2CO3 DMF 100 12 a

3 NaH THF 25 7 99

4 NaH DMF 25 1.5 99

5 t-BuOK THF 25 24 a

6 t-BuOK t-BuOH 25 4.5 100 a Complex reaction mixture was observed.

3 and 4). We observed complex reaction mixture, when potassium tert-butoxide was

used in THF solvent (entry 5). However, clean conversion was observed when the

reaction was carried out in tert-butanol (entry 6). Due to easy handling and cheap

reagents, we carried forward the synthesis with potassium hydroxide in ethanol.

Next, the reduction of 85 to 79 using Red-Al resulted in low yield (42%). We were

able to obtain good yield when 85 was reduced with LiAlH4 in THF under reflux for

16 h (Scheme 24). Racemic cis-2,3-diphenyl morpholine 79 was obtained in overall

59% yield from 81 without the need for chromatographic purification. We preferred

purification of 79 through preparation of its salt with acid rather than tedious column

chromatography. We observed that the oxalate salt of 79 has very low solubility in

ethanol. Therefore the purification of 79 was better achieved through oxalate salt

rather than reported hydrochloride method. After usual work up, the crude compound

was treated with oxalic acid (0.5 equiv) to obtain oxalate salt, which was

138

subsequently recrystallized from ethanol and basified with aqueous NaOH to give

(±)-79 in 62% yield. The structure of 79 was confirmed by IR, NMR, microanalysis.

Our attempts to obtain X-ray quality crystal of compound 79 failed. We therefore

converted racemic morpholine 79 to its N-acetate derivative 89 by treatment with

acetic anhydride using sodium bicarbonate (eq 1). In the IR spectrum of 89,

disappearance of peak due to N-H stretching and appearance of peak at 1635 cm-1

N

OPh

PhH

(±)-79

Ac2O, NaHCO3

THF:H2O, 0 oC, 45 min. N

OPh

Ph

CH3O

(±)-89, 68% yield

(1)

shows the formation of N-acetate derivative. However, due to the restricted rotation

of C-N amide bond,31 the 1H NMR spectrum of compound 89 in CDCl3 showed

complex pattern. We tried to obtain clean NMR by changing the solvent to DMSO-d6

or increase the temperature. But similar kind of NMR spectrum pattern was observed

in both the cases. Crystallization of compound 89 from ethanol provided X-ray

quality crystal. The single crystal X-ray analysis of 89 revealed that two phenyl rings

in the molecule are cis- to each other. The ORTEP diagram for compound 89 is

shown in figure 3.

Figure 3. ORTEP diagram for (±)-89

139

2. Preparation of (±)-trans-2,3-diphenyl morpholine (80)

After successful optimization of the reaction conditions, we used this protocol

for the preparation of racemic trans-2,3-diphenylmorpholine 80 (Scheme 25). The

reaction of racemic threo-2-amino-1,2-diphenylethanol 82 with chloroacetyl chloride

furnished threo-amide 84 in 95% yield. Treatment of 84 with potassium hydroxide

gave trans-lactam 86, which upon reduction with LiAlH4 provided (±)-80 in 56%

overall yield.

Ph OH

NH2Ph

Ph OH

NH

Ph N

OPh

PhH

O

84

a cb(±)-80

Cl

O

82 86

Scheme 25. Reagents and conditions: (a) ClCH2COCl, NaHCO3, MeOH:THF, −10 oC to RT, 95%; (b) KOH, EtOH, reflux, 93%; (c) LiAlH4, THF, reflux, 64%. 3. Resolution of 79 and 80

Introduction

Optical resolution is a process of separation of a racemate into its enantiomer

constituents.32 In resolution method, the point of departure is a racemate, therefore

the maximum yield of each enantiomer is 50%. Several techniques for the resolution

of racemate are available which includes,

a) Resolution by direct crystallization

b) Resolution through formation and separation of diastereomers

c) Resolution through equilibrium asymmetric transformation

Among these methods, resolution through the formation of diastereomers is

most popular technique and is applicable to wide range of compounds. In this

method, the essence of resolution is the differential interaction of the components of

a racemic mixture with the single enantiomer of a chiral compound (the resolving

agent) to form a pair of diastereomeric complex. The nature of diastereomeric

complex could be covalent, ionic, or inclusion type, which have then to be separated

by achiral methods such as preferential crystallization, column chromatographic

separation etc.32b Finally the pure diastereomers have to be decomposed to obtain the

pure enantiomers.

The most practical method for the resolution of racemic amines is the

preparation of diastereomeric salt with optically active acid, and then separation

140

through crystallization.33 To the best of our knowledge, the optical resolution of 79

and 80 is not known in the literature. We have resolved both the molecules through

corresponding diastereomeric salt as described below.

Results and discussion

3.1. Resolution of (±)-79

Initially we examined various resolving agents like (−)-menthoxyacetic acid,

(−)-mandelic acid, (−)-glutamic acid, (1R)-(−)-camphorsulphonic acid, (−)-

Pyroglutamic acid and (+)-O-acetyl mandelic acid for the resolution of cis-2,3-

diphenyl morpholine. The salt obtained from (−)-menthoxyacetic acid, (−)-mandelic

acid and (−)-glutamic acid failed to crystallize due to gummy nature. (−)-

Pyroglutamic acid or (+)-O-acetyl mandelic acid provided resolution, but needed

multiple crystallizations which resulted in low yield (Table 3, entries 1 and 2).

Finally the resolution of (±)-79 was accomplished through sequential use of L- and

D-tartaric acid. It was observed that stoichiometry of the resolving agent affects the

yield as well as enantiomeric excess. A ratio of 1:1 did not provide any resolution at

all (Table 3, entry 3). When (±)-79 and L-(+)-tartaric acid were used in 1:0.5 ratio,

(−)-79 and (+)-79 were isolated in 39% and 42% yields with 94% and 72% ee

respectively (entry 4). Best results were obtained with the ratio 1:0.25 (entry 5). This

proportion separates (−)-79 as salt leaving (+)-79 in solution. Optically enriched and

free amine (+)-79 was then purified through the salt of D-(−)-tartaric acid.

141

Table 3. Resolution of 79 by using various chiral acids.

N

OPh

PhH

(±)-79

Resolving agent(−)-79 + (+)-79

Entry Resolving agent equiv. (−)-79 (+)-79

Yield

(%)

ee

(%)

Yield

(%)

ee

(%)

1 (−)-pyroglutamic acid 1 19 >99 - -

2 (+)-O-Acetyl mandelic acid 1 33 >99 - -

3 L-(+)-tartaric acid 1 - a - a

4 L-(+)-tartaric acid 0.5 39 94 42 72

5 L-(+)-tartaric acid 0.25 36 99 - -

6 D-(−)-tartaric acid 0.25 - - 43 >99 a Racemic 79 was obtained.

In an optimized protocol, (±)-79 and L-(+)-tartaric acid (0.25 equiv) were

mixed in ethanol and stirred overnight (Scheme 26). Evaporation of the solvent

followed by addition of diethyl ether and filtration gave tartarate salt.

Recrystallization of crude salt from ethanol provided pure L-tartarate salt in 36%

yield [mp 181-184 oC, [α]25 D ─19.0 (c 0.42, MeOH)]. Basification of the salt using

aqueous NaOH gave (−)-79 ([α]25 D −77.2 (c 2.59, CHCl3)). The (+)- enantiomer was

obtained from mother liquor by similar treatment with D-(−)-tartaric acid. The

obtained crude salt after recrystallization from ethanol provided D-tartarate salt in

43% yield [mp 182-185 oC, [α]25 D +19.7 (c 0.44, MeOH)], which on basification

provided (+)-79 ([α]25 D +76.4 (c 2.59, CHCl3)). Both the enantiomers were obtained

in good yields and high enantiomeric purity after single crystallization of the

corresponding tartarate salts. Optical purity of both the enantiomers was found to be

≥99% by chiral HPLC. Solvent played crucial role in the resolution process as

revealed by the fact that racemic 79 was obtained when the salt was prepared in

methanol.

142

solid salt

filtrate

1. recrystallization

2. aq. NaOH, DCM(2R, 3S)-(−)-79

36%, 99% ee

(±)-79

1. L-(+)-Tartaric acid (0.25 equiv.) EtOH

2. Et2O

1. D-(-)-Tartaric acid2. recrystallization

3. aq. NaOH, DCM(2S, 3R)-(+)-79

43%, >99% ee

N

OPh

PhH

Scheme 26. Resolution of cis-2,3-diphenyl morpholine 79

3.2. Resolution of (±)-80

To resolve the corresponding racemic trans-2,3-diphenyl morpholine 80, first

we examined L-(+)-tartaric acid. However, we could isolate only one enantiomer in

very low yield with 95% enantiomeric excess. Success was achieved using (−)-

mandelic acid as the resolving agent (Scheme 27). The diastereomeric salt was

prepared by mixing the acid and racemic 80 in methanol. However we could not

(R)-(−)-mandelic acid diastereomeric salt (DS)

(±)-80

filtrate

aq. NaHCO3, DCM (2S, 3S)-(−)-80

39%, 92% eepreferentialprecipitation

1.recrystallization

2. aq. NaHCO3, DCM(2R, 3R)-(+)-80

44%, >99% ee

MeOH

(DS)iso-propanol

precipitate

N

OPh

PhH

+

Scheme 27. Resolution of trans-2,3-diphenyl morpholine 80

separate the diastereomeric salts by crystallization. Gratifyingly, the preferential

precipitation26c method resulted in clean separation. The resulting solid was dissolved

in boiling isopropanol and then stirred at room temperature for 2 h followed by

filtration gave solid salt in 39% yield [mp 175-177 oC, [α]25 D −116 (c 1, MeOH)]. The

purified salt after basification gave (−)-80 (39% yield, [α]25 D −100 (c 2, CHCl3)). The

143

mother liquor from the aforementioned resolution process was evaporated to dryness

and the solid was crystallized from ethyl acetate [44% yield, mp 150-151 oC, [α]25 D

+32 (c 1, MeOH)]. The basification of the salt provided (+)-80 (44% yield, [α]25 D

+102 (c 2, CHCl3)). Enantiomeric purity was determined by chiral HPLC. We

observed higher specific rotation for cis- as well as trans-isomers as compared to the

known values reported in literature27a (see experimental section for details).

4. Application of 2,3-diphenyl morpholines in enantioselective diethylzinc

addition

The enantioselective addition of Et2Zn to aldehydes is one of the most

intensely investigated carbon-carbon bond forming reactions and serves as a test for

new ligands. A variety of ligands such as chiral amino alcohols, amino thiols, amino

disulfides, amino diselenides, diamines and diols, for the asymmetric diethylzinc

addition reactions have been reported.8 Among these chiral β-amino alcohols are

most used ligands. Previously our research group26a had reported conceptually

different and efficient catalytic system viz zinc-amide, derived from oxazolidines

(Scheme 28). In this method, catalyst 91, prepared from oxazolidine ligand 90,

efficiently catalyzed the addition of diethylzinc to benzaldehyde to give (S)-1-

phenyl-1-propanol 92 with high enantioselectivity.

NH

OPh

Ph Et2Zn, Toluene

80 oC, 30 min.

Et2Zn, PhCHOPh

OH

85% yield> 99% ee

(S)-92N

OPh

Ph

ZnEttoluene, 0 oC

(10 mol%) 91

90

Scheme 28. Enantioselective diethylzinc addition catalyzed by chiral zinc-amide

In the proposed mechanism, zinc atom in 91 activates the aldehyde. Due to

steric bulk around oxygen atom, the diethylzinc molecule coordinates to the nitrogen

atom of the catalyst 91 and both the zinc centre becomes tri-coordinate as shown in

figure 4. Transfer of ethyl group from diethylzinc molecule gives enantiopure

alcohol.

144

We anticipated that morpholine based catalytic system would be more

efficient due chelation of both heteroatoms to zinc centre. Both the heteroatoms

(oxygen and nitrogen) in morpholine ligand can co-ordinate with diethylzinc and

forms a tetra-coordinate zinc centre, which could have enhanced nucleophilicity as

compared to tri-coordinate zinc (Figure 5).

NEtZn Zn Et

O

Ph

EtH

O

PhPh

(tri-coordinate zinc centre)

N O

Ph

Zn

EtO

PhH

EtZn Et

Ph

Figure 5Figure 4

(tetra-coordinate zinc centre)

We examined both the ligands 79 and 80 for the addition of diethylzinc to

benzaldehyde. The results obtained are described below.

Present work

Results and discussion

Chiral zinc-amide was prepared in situ by heating the mixture of diethylzinc

and chiral morpholine ligand [(−)-79 or (−)-80] at 80 oC for 30 minutes according to

the literature procedure.26a Treatment of diethylzinc with benzaldehyde in the

presence of above prepared catalyst (10 mol%) provided alcohol (S)-92. In the case

of (−)-(79), although good yields were obtained only moderate enantioselectivity was

realized (Table 4, entries 1 and 2).

145

Table 4. Enantioselective addition of Et2Zn to benzaldehyde

N

OPh

PhH

i) Et2Zn, Toluene 80 oC, 30 min.

Ph

OH

N

OPh

PhZnEt

PHCHO

toluene:Hexane

(S)-92

(−)-79 or (−)-80

Entry Ligand

(10 mol%)

Temp. (oC) Time (h) Yielda (%) eeb (%)

1 (−)-79 0 8 68 40

2 (−)-79 25 4 86 36

3 93 25 2 85 29

4 (−)-80 25 24 73 12 a Isolated yield. b Determined by chiral GC analysis.

We have also examined lithium amide 93. Catalyst 93 was prepared by the reaction

of (−)-(79) with BuLi (eq 2). However this modification did not help (entry 3) either.

Trans isomer (−)-80 proved inferior to corresponding cis-isomer.

N

OPh

PhH

toluene-hexane0 oC to RT, 15 min.

N

OPh

PhLi

n-BuLi

(−)-79 93

(2)

At this stage we are unable to provide reason for low enantioselectivity.

However, one of the reasons for moderate results can be explained by intramolecular

coordination of zinc centre to the oxygen atom (Figure 6), which results in the

reduced reactivity of the catalyst.

N O

Ph

Zn

Ph

Et

Figure 6

146

Section 3B

Attempted resolution of 2,3-diphenylbuatane-2,3-diol

Introduction

Chiral diols are an important class of organic compounds in asymmetric

synthesis because of their applications in various asymmetric transformations. A

variety of chiral 1,2-, 1,3-, and 1,4-diols have been used as chiral auxiliaries, chiral

ligands as well as chiral building blocks in asymmetric synthesis.7 Presence of C2

symmetry axis within the chiral auxiliary / ligand is advantageous, serving the very

important function of reducing the number of possible diastereomeric transition

states to achieve high level of asymmetric induction.7a Consequently synthesis of C2

symmetric chiral diols has been of deep interest. In continuation of our work on

asymmetric catalysis,26 we wanted to explore sterically more demanding C2

symmetric chiral diol such as 2,3-diphenylbuatane-2,3-diol 94 (Figure 7) in

asymmetric synthesis. As described in section-2 of the chapter-2, moderate

enantioselectivity was realized for the enantioselective addition of RZnOAc to

benzaldehyde. We anticipated that use of bulky diol such as 94 will be more effective

for the above transformation.

MePh

PhMe

OH

OH

94

Figure 7

Various methods are available in the literature for the synthesis of C2-

symmetric chiral diols. These methods include resolution, asymmetric

dihydroxylation, asymmetric reduction, enantioselective Pinacol coupling and other

synthetic transformations.7a

In 1959 Cram et. al.34 reported the synthesis of enantiopure (−)-94 (eq 3). In

this method, the treatment of chiral ketone (−)-95 with methylmagnesium iodide at 0 oC gives mixture of (−)-94 and corresponding meso-isomer, which upon repeated

crystallization provided enantiopure (−)-94 in 20% yield.

147

MePh

OHO

Ph

MeMgI, Et2O

0 oC, 5 h

(−)-95

20% yield

(3)

PhMe

MePh

OH

OH

(−)-94

To the best of our knowledge, the resolution of 94 is not known in the

literature. The chiral resolution method is advantageous because it provides both the

enantiomers in a single step. The resolution of diols could be accomplished through

diastereomeric esters, or ketals, borate esters and inclusion complexes.7a,35 Tertiary

diols are sensitive to strong acidic as well as basic conditions. Therefore, last two

methods would be more suitable for the resolution of 94 because of the mild reaction

conditions. We examined various resolving agents for the resolution 94. The results

obtained are described below.

1. Attempted resolution of dl-94 through addition complex

The resolution of diol through formation of diastereomeric addition complex

(also called inclusion complex) is a very simple and preferred method. In this

method, the formation of diastereomeric addition complex between diol and the

resolving agent through hydrogen bonding favors the resolution. During 1980’s Toda

et al. have done pioneering work in this area and variety of inclusion complexes of

diols (host compounds) with various organic guest compounds such as alcohols,

ketone, amine, amides, xylene, benzene, CCl4, CHCl3 etc. were reported.36 The X-ray

crystal analysis of these complexes showed that the host and guest molecules are

associated with each other through hydrogen bond formation and van der Wall’s

interactions.37

Some important literature reports for the resolution of diol through addition

complex are described below.

In 1975 Cripps et al.38 reported the resolution of prefluoro(2,3-

diphenylbuatane-2,3-diol 96 using (−)-cinchonidine 97 as the resolving agent.

Treatment of diol 96 with 97 in CHCl3:hexane gave 1:1 adduct (Scheme 29).

Repeated crystallization of residue followed by treatment with aqueous hydrochloric

acid provided (+)-96. While (−)-96 was obtained from mother liquor. No details for

the yield and optical purity are mentioned.

148

N

HO NH

cinchonidine

C6F5

F3C

F3CC6F5

OH

OH

(±)-96 (−)-97

+ (+)-96 + (−)-96

CHCl3:hexane RT, 3 days

Scheme 29. Resolution of diol 96 using cinchonidine

In 1988 Toda et al.39a reported the resolution of BINOL 98 using (+)-2,3-

dimethoxy-N,N,N',N'-tetramethylsuccinamide 99 as the resolving agent (Scheme 30).

In this procedure, racemic 98 was treated with (+)-99 in benzene:hexane solvent to

give mixture of diastereomeric addition complex. Precipitated complex on

recrystallization furnished pure complex of (−)-98 with (+)-99. X-ray

crystallographic analysis39b of this complex showed presence of hydrogen bonds

between carbonyl oxygen of 99 and OH-hydrogen of 98. The silica gel column

chromatography of this complex provided (−)-98 with high optical purity. While (+)-

98 was obtained from filtrate. Using similar strategy, diols 100 and 101 (Figure 8)

were resolved using resolving agents 102 and 103 respectively. Later in 2004 Zhou

et al.39c reported the X-ray crystal structure obtained from (+)-101 and 103.

OMeMe2N

O OMeNMe2

O

OH

OH(±)-98

(+)-99

benzene:hexane

RT, 12 h

precipitate

i) crystallizationii) silica gel chromatography

(−)-98

36% yield100% ee

filtrate

i) silica gel chromatographyii) (−)-99

iii) crystallizationiv) silica gel chromatography

(+)-98

29.5% yield100% ee

+

Scheme 30. Resolution of 98 using (+)-99

149

OMe(C6H11)2N

O OMeN(C6H11)2

O

OH

OH

(±)-100

(+)-102

OH

OH

(±)-101

O

O

O

CONMe2

O

CONMe2

(+)-103

Figure 8

In 1990 Kawashima et al.40a reported the resolution of 98 using (1R,2S)-(−)-

1,2-diamino cyclohexane 104. In this method, heating the mixture of racemic 98 and

(–)-104 in benzene forms diastereomeric addition complex (Scheme 31). Separation

of these complexes by filtration and recrystallization from benzene followed by

treatment with aqueous hydrochloric acid provided both the enantiomers of 98 in

good yield with high enantiomeric excess.

(±)-98

NH2

NH2

(1R,2R)-(−)-104

+benzene:hexane

heat

i) crystallizationii) aq. HCl

(+)-98

43% yield 94% ee

filtrate

i) crystallizationii) aq. HCl

(−)-98

42% yield 96% ee

precipitate

Scheme 31. Resolution of 98 using (−)-104

In 1991 the same author40b extended the above methodology for the

resolution of various aliphatic 1,2-diols. Racemic trans-cyclohexane-1,2-diol 105

was resolved in moderate ee by using (−)-104 as the resolving agent (Scheme 32).

150

OH

OH

trans-(±)-105

+ (−)-104

i) benzene, heatii) filtration followed by silica gel chromatography

OH

OH

36.4% yield67% ee

(-)-105

Scheme 32. Resolution of aliphatic diol using (−)-104

Using this method, diols 106, 107, 108 (Figure 9) were also resolved with

good enantiomeric excess.

OH

OH

trans-(±)-106

OH

OH

threo-(±)-107

Ph OH

OHPh

threo-(±)-108

Figure 9

In 1993 Toda et al.41a reported the use of cihchonidium halide salt 109

(Figure 10) as the resolving agent for the resolution of diols. In this protocol, the

N

HO NH

R X

109

109a = R = PhCH2, X = Cl109b = R = n-Bu, X = Br

Figure 10

mixture of racemic 98 and N-benzyl cinchonidium chloride 109a at room

temperature gave diastereomeric complex (Scheme 33). The X-ray analysis study of

resulting diastereomeric complex showed hydrogen bonding between chloride anion

of 109a and OH-hydrogen of 98 (O-H---Cl, bond distance 3.1−3.2 Ao).41b

151

(±)-98 + 109aMeOH, RT

Diastereomeric complexes

i) aq. HClii) crystallization

(+)-98

30% yield100% ee

filtrate aq. HCl

(−)-98

62% yield42% ee

precipitate

Scheme 33. Resolution of 98 using 109a

(+)-Enantiomer of 98 was obtained in good yield with very high enantiomeric purity

by usual separation method. However, corresponding (−)-isomer was obtained from

mother liquor with moderate ee. Author also resolved diol 100 with high optical

purity using 109b as the resolving agent.

One of the disadvantage of the above method was only one enantiomer was

obtained with high enantiomeric purity. Later in 1995 Cai et al.41c described

improved procedure for the resolution of 98. The key success in this method was

selection of suitable solvent. In the modified procedure, heating the mixture of

racemic 98 and 109a (0.55−0.6 equiv) in acetonitrile under reflux gives complex-I

and (−)-98 (Scheme 34). Treatment of complex-I with aqueous hydrochloric acid

provided (+)-98 with >99% ee, whereas (−)-98 was obtained from mother liquor in

good yield with high enantiomeric purity.

(±)-98109a (0.55−0.6 equiv)

CH3CN, reflux(+)-98 109a + (−)-98

complex-I

aq. HCl

(+)-98

>99% ee

>99% ee

Scheme 34. Modified procedure for the resolution of 98 using 109a

152

Present work

Results and discussion

Various methods are available in the literature for the preparation of diol 94.

42-44 We have prepared dl-94 by manganese mediated pinacol coupling of

acetophenone (Scheme 35), according to the method of Rieke et al.44a Treatment of

anhydrous MnCl2 with lithium metal in the presence of catalytic amount of

naphthalene gave black slurry of highly reactive manganese (Mn*). The reaction of

in situ prepared Mn* with acetophenone gave mixture of dl- and meso isomers in the

ratio of (70:30) in 95% yield. The ratio was determined by 1H NMR by comparison

of the δ value of methyl protons with the literature.44g Recrystallization of the

mixture from ethyl acetate / petroleum ether provided pure dl-94 in 49% yield with

>99% diastereomeric excess.

MnCl2 + Li + Naphthalene

(cat.)RT, 3 h

THFMn*

Highly reactive manganese

Ph Me

O

dl-94

49% yield>99% de

MePh

PhMe

OH

OH

MePh

PhMe

OH

OH

MePh

MePh

OH

OH+

dl meso70:30

recrystallization

(95% yield)

Scheme 35. Preparation of dl-94

Next, we examined various resolving agents for the resolution of 94 (Table

5). Initially we tried (−)-104 as resolving agent. The 1:1 complex of racemic 94 and

(−)-104 was prepared by boiling the mixture in benzene (or toluene). We tried

various solvent for the separation of the addition complex (Table 5, entry 1). For

example, in the case of benzene and cyclohexane, the complex did not crystallize /

precipitate. In petroleum ether formation of gummy mass was observed. We then

tried mixture of pet ether:diethyl ether as the solvent. In this case the complex

became soluble and did not crystallize / precipitate at all. We could not isolate the

addition compound in any of the case. Changing the ratio of diol and (−)-104 from

153

1:1 to 2:1 did not help, racemic diol was recovered (entry 2). Similar kind of results

were obtained in the case of other resolving agents such as (1S,2S)-(−)-1,2-

diphenylethane-1,2-diamine 110 (Figure 11), (−)-cinchonidine 97 and (+)-cinchonine

111.

Table 5. Attempted resolution of 94 using various resolving agents

dl-94

MePh

PhMe

OH

OH(+)-94 + (−)-94

Resolving agent x

Entry Resolving agent

Ratio Solvent Result

1 (−)-104 1:1 Benzene or cyclohexane Pet ether Per ether:Et2O

Complex was highly soluble. Gummy mass formation which does not crystallizes. Complex was soluble at RT, no crystallization at −10 oC.

2 (−)-104 2:1 Toluene Pet ether

Complex was highly soluble. Racemic diol was obtained.

3 (−)-110 1:1 Toluene Pet ether or Et2O or PE:Et2O

Complex was highly soluble. Racemic diol crystallize out.

4 (−)-110 2:1 Toluene Toluene:PE

Complex was highly soluble. Racemic diol precipitates out.

5 (−)-97 1:1 Toluene or THF or CHCl3:PE or CHCl3:CH3CN

Cinchonidine precipitates out.

6 (+)-111 1:1 Toluene or THF or CHCl3 EtOH

Mixture was not soluble even at boiling condition Cinchonine precipitates out.

a Ratio of (±)-94 with resolving agent.

154

N

HO NH

cinchonine

(+)-111

Ph NH2

NH2Ph

(−)-110

Figure 11

The reason for the unexpected results was attributed to the formation of weak

hydrogen bonding between diol and the resolving agents. We thought that formation

well defined covalent complex between diol and the resolving agent would provide

the resolution. For this purpose we planned the resolution through formation of

borate complex.

2. Resolution of dl-94 through chiral borate complex

The resolution through borate ester is an attractive method for the preparation

of enantiomerically pure diols due to easy formation or cleavage of boron-oxygen

bond.

In 1996 Shan et al.45a reported the resolution of 98 using quinine 113 as the

resolving agent. In this method, the reaction of racemic 98 with borane-dimethyl

sulfide complex in diethyl ether gave binaphthol borane 112 which upon treatment

with 113 gave diastereomeric borate esters. Hydrolysis of these esters furnished (−)-

98 and (+)-98 in good yield with high enantiomeric purity (Scheme 36).

155

(±)-98H3B.SMe2

aq. HCl(−)-98

41% yield100% ee

filtrate aq. HCl

(+)-98

39% yield100% ee

precipitate

Et2O

O

OB H

N

HO N

MeO

Quinine 113

113

THF

112

Scheme 36. Resolution of 98 through borate ester using 113

The same author45b in 1998 described resolution of 98 using boric acid and

(S)-proline (Scheme 37). In this protocol, the mixture of racemic 98 and boric acid

was refluxed for several hours with simultaneous azeotropic removal of water to

obtain binaphthol boric anhydride 114. It was then treated with excess (S)-proline in

THF under reflux to give binaphtholboric acid-(S)-proline complex 115a and 115b,

which upon treatment with sodium hydroxide followed by aqueous hydrochloric acid

provided (+)-98 and (−)-98 respectively in good yield with high enantiomeric purity.

O

OB O2 (±)-98 + 2 B(OH)3

O

OB

Toluene

azeotropic distillation

(S)-prolineTHF, reflux

O

OB

O

N

O

HO

OB

O

N

O

H

+

i) aq. NaOHii) aq. HCl

(−)-98

39.5% yield100% ee

(+)-98

37% yield100% ee

i) aq. NaOHii) aq. HCl

115a 115b

114

Scheme 37. Resolution of 98 using boric acid and (S)-proline

156

In 1999 Periasamy et al.46a described the resolution of 98 using boric acid and

(+)-1-phenylethyl amine 116 (Scheme 38). In this method, the mixture of diol 98,

boric acid and amine (+)-116 was refluxed in acetonitrile to give diastereomeric

borate complex. Author observed that the precipitated and mother liquor borate

complex have different solubilities in acetonitrile and THF, which helped in the

separation of both the enantiomers of 98 with high optical purity.

(±)-98 + B(OH)3 Ph NH2

Me

(R)-(+)-116

+

i) CH3CN, reflux

(−)-98

35% yield>99% ee

filtrate

i) THF, reflux

(+)-9826% yield>99% ee

precipitate

Reflux

CH3CNii) aq. HCl

ii) aq. HCl

(1 equiv) (0.5 equiv) (1.5 equiv)

Scheme 38. Resolution of 98 using boric acid and (+)-116

X-ray crystallographic analysis of the borate complex obtained from mother liquor

revealed that it was a Bronsted acid-amine complex 117 (Figure 12).

O

OB

O

O

Ph NH3

Me

117

Figure 12

Later in 2001 the same author46b described the resolution of aliphatic diol

using boric acid and (S)-proline (Scheme 39). In this protocol, first mixture of (S)-

proline and boric acid was refluxed in benzene (or toluene) for 12 h to give complex,

which on treatment with racemic 2,3-diphenylbutane-1,4-diol 118 under reflux for 12

h furnished diastereomeric borate esters. Precipitated borate complex gave (+)-118 in

157

moderate yield with excellent enantiomeric purity. While borate ester obtained from

filtrate gave (−)-118 with moderate ee.

N COOH

H

i) toluene or benzene reflux, 12 h

Ph OH

OHPh

reflux, 12 h

ii) then,

B(OH)3

+

i) THF, aq. HCl

(−)-118

12-18% yieldUp to 98% ee

filtrate

(+)-118

26-30% yieldUp to 57% ee

precipitate

i) THF, aq. HCl

(±)-118

ii) crystallization

ii) column chromatography

Scheme 39. Resolution of 118 using boric acid and (S)-proline

Present work

Results and discussion

Initially we tried the resolution of dl-94 by using chiral amine (+)-116 and

boric acid. In this experiment, the mixture of dl-94 (2 equiv), boric acid (1 equiv) and

(+)-116 (3 equiv) in acetonitrile was refluxed for 12 h with simultaneous removal of

water by azeotropic distillation (Table 6, entry 1). But the complex formed was

highly soluble

Table 6. Resolution of dl-94 through borate complex

Entry Resolving agent Solvent Result

1 (+)-116 Acetonitrile no resolution

2 (−)-phenyl glycinol Toluene no resolution

3 (S)-proline Toluene (−)-94, 29% yield

30% ee

in acetonitrile and did not precipitated / crystallized at all. We then examined (−)-

phenyl glycinol as the resolving agent. In this case first mixture of diol and boric acid

in toluene was refluxed for 3 h with simultaneous azeotropic removal of water.

Complete dissolution of boric acid indicated the formation of borate complex. The

158

resulting complex was then treated with phenyl glycinol under reflux for 3 h to give

diastereomeric borate complex. We tried various solvent for the separation of this

mixture. For example, in toluene and THF or mixture of solvents like THF:hexane or

hexane:ethyl acetate, the diastereomeric mixture was highly soluble. In the case of

hexane, formation of gummy mass was observed, which does not crystallized.

Finally, we could achieve partial resolution of dl-94 by using (S)-proline as the

resolving agent (Scheme 40).

(S)-Proline

+ B(OH)3(i) Toluene, Reflux, 12 h

(ii) dl-94, toluene reflux, 12 h

precipitate-1+ filtrate

precipitate-1

precipitate-2

filtrate

THF, RT, 24h

3N aq. HCl:THF(−)-94

29%, 30% eeRT, 4 h

N COOH

H

Scheme 40. Resolution of 94 using (S)-Proline and boric acid

First, the mixture of boric acid and (S)-proline was refluxed in anhydrous toluene for

12 h with simultaneous azeotropic removal of water. TLC of the reaction mixture

showed that proline has reacted completely. The resulting complex was then treated

with dl-94 under reflux for 12 h. Filtration of the reaction mixture gave precipitate-1,

which was washed with THF to obtain borate ester (precipitate-2) in 37% yield [mp

263−268 oC (dec.), [α]26 D −8 (c 0.5, EtOH)]. Treatment of precipitate-2 with 3N

hydrochloric acid followed by column chromatographic purification provided (−)-94

in 29% yield with 30% ee.

159

Summary:

We have synthesized and resolved all the four stereoisomers of 2,3-diphenyl

morpholine in good yields and high optical purity using tartaric acid and

mandelic acid.

These ligands were examined for enantioselective addition of diethylzinc to

aldehyde and moderate enantioselectivity was realized.

Partial resolution of 2,3-diphenylbutane-2,3-diol could be accomplished

through a chiral borate complex.

160

Experimental Section General

All the solvents and reagents were purified and dried according to procedures

given in D. D. Perrin’s purification of Laboratory chemicals.47 Diethylzinc was

purchased from Sigma-Aldrich chemical company. Benzaldehyde was freshly

distilled before use. All the reactions were performed in oven dried (120 oC)

glasswares. The reactions were monitored by TLC using silica gel 60 F254 pre-coated

plates. The products were purified by column chromatography on silica gel (100−200

or 230−400 mesh). All melting points were recorded on a Büchi B-540 electro

thermal melting point apparatus and are uncorrected. Optical rotations were

measured on Bellimheam+Standley ADP220 digital polarimeter. IR spectra were

recorded on a Shimadzu FTIR-8400 spectrophotometer. 1H spectra were recorded at

200 MHz with TMS as internal standard. 13C NMR spectra were recorded at 50 MHz

with CDCl3 (δ = 77) as the reference. Micro analytical data were obtained using a

Carlo-Erba CHNS-0 EA 1108 elemental analyzer. Ligand (−)-10448a and (−)-phenyl

glycinol48b were prepared according to the literature procedures. GC analysis was

carried using HP-5 (30m x 0.25 m x 0.25 μ) column. Chiral HPLC was performed

using Kromasil-5-Amycoat column (250 x 4.6 mm).

(±)-Erythro-2-amino-1,2-diphenylethanol (81)

Ph OH

NH2Ph

(±)-81

A solution of racemic α-benzoin oxime 87 (11.36 g, 50 mmol) in methanol

(130 mL) was hydrogenated at room temperature and at 50 psi pressure using 10%

Pd/C (0.5 g) for 6 h. Usual work-up28b provided crude solid 10.13 g (95%).

Recrystallization of the solid from methanol gave racemic erythro-2-amino-1,2-

diphenylethanol 81 as white crystals.

Yield : 8.53 g (80%)

TLC data : Rf (20% MeOH/EtOAc): 0.3

Melting point : 163−165 oC (lit.28a 163 oC).

161

(±)-Erythro-2-(chloroacetylamino)-1,2-diphenylethanol (83)

Ph OH

NPh

O

ClH

(±)-83

A two liter round bottom flask equipped with a magnetic stir bar and addition

funnel was charged with 81 (10.67 g, 50 mmol), NaHCO3 (12.6 g, 150 mmol) and

methanol (700 mL). The assembly was cooled to −10 oC. Freshly distilled

chloroacetyl chloride (4.4 mL, 55 mmol) was added dropwise through addition

funnel over 1 h and the mixture was gradually allowed to warm to room temperature

and stirred for further 2 h. The procedure was repeated by the addition of additional

chloroacetyl chloride (5.6 mL, 70 mmol) in three portions. The reaction mixture was

stirred at room temperature for 24 h. Methanol was then removed on a rotary

evaporator. The residue was suspended in water (300 mL) and stirred for 15 min.

The reaction mixture was then filtered and dried to obtain 83 as a white solid, which

was used for the next step without any purification.

Yield : 14.18 g (98%)

TLC data : Rf (30% EtOAc/PE): 0.26

Melting point : 193-194 oC (lit.27a 187−188 oC)

IR (CHCl3) : 3321, 3020, 2939, 1647 cm-1

1H NMR (CDCl3) : δ 2.43 (d, J = 4.29 Hz, 1 H, OH), 4.06 (ABq, J =

15.28 Hz, 2 H), 5.12 (t, J = 4.29 Hz, 1H), 5.28 (dd, J =

8.46, 4.17 Hz, 1 H), 6.97−7.35 (m, 10 H, ArH), 7.42

(bs, 1H, NH) ppm

Analysis for : C16H16ClNO2

Calculated (%) : C, 66.32; H, 5.57; N, 4.83

Found (%) : 66.61; H, 5.55; N, 4.86

162

(±)-cis-5,6-diphenylmorpholin-3-one (85)

N

OPh

PhH

O

(±)-85

A two liter round bottom flask equipped with a magnetic stir bar and a reflux

condenser was charged with crude 83 (28.97 g, 100 mmol), KOH (8.41 g, 150 mmol)

and ethanol (700 mL). The reaction mixture was stirred under reflux. After 1.5 h the

mixture was allowed to cool to room temperature. Ethanol was then removed on a

rotary evaporator. To the residue 0.5N aqueous HCl (200 mL) was added and the

mixture was extracted with dichloromethane (1 x 300 mL, 2 x 150 mL). The

combined extracts were washed with brine, dried over Na2SO4 and concentration

under reduced pressure gave 85 as a white solid, which was used for the next step

without any purification.

Yield : 24.54 g (97%)

TLC data : Rf (50% EtOAc/PE): 0.29

Melting point : 181-182 oC (lit.27a 177−179 oC)

IR (CHCl3) : 3394, 3020, 2885, 1678 cm-1

1H NMR (CDCl3) : δ 4.40−4.73 (m, 3 H), 5.15 (d, J = 3.28 Hz, 1 H), 6.70

(bs, 1H, NH), 6.80−7.21 (m, 10 H, ArH) ppm 13C NMR (CDCl3) : δ 60.7, 68.4, 78.3, 125.9, 127.6, 127.7, 127.8, 128.2,

136.3, 136.6, 168.8 ppm

Analysis for : C16H15NO2

Calculated (%) : C, 75.87; H, 5.97; N, 5.53

Found (%) : C, 75.71; H, 6.01; N, 5.29

163

(±)-cis-2,3-diphenylmorpholine (79)

N

OPh

PhH

(±)-79

An oven dried one liter round bottom flask with side arm equipped with a stir

bar, addition funnel and a reflux condenser, was charged with LiAlH4 (8.47 g, 223

mmol). The flask was cooled to 0 oC in an ice bath and 50 mL freshly distilled

anhydrous THF was added under argon atmosphere. To the resulting suspension a

solution of 85 (20.42 g, 80.61 mmol) in 600 mL THF was added dropwise over a

period of 2.5 h. After the addition ice bath was removed and the mixture was heated

at reflux for 16 h. The reaction mixture was cooled to 0 oC, diluted with diethyl ether

(200 mL) and quenched cautiously by dropwise addition of 1 N NaOH (50 mL). The

white solid was removed by filtration. The filtrate was dried over Na2SO4 and

concentrated under reduced pressure to obtain crude sticky mass (14.06 g), which

was then dissolved in ethanol (400 mL) and treated with oxalic acid.2H2O (3.7 g, 0.5

equiv.) and filtered. The resulting oxalate salt after recrystallization from ethanol

followed by basification with aqueous NaOH gave (±)-79 as a white solid.

Yield : 12 g (62%)

TLC data : Rf (EtOAc): 0.22

Melting point : 82-84 oC (lit.27b 82−84 oC)

IR (CHCl3) : 3325, 3014, 2858, 1490, 1450 cm-1 1H NMR (CDCl3) : δ 1.89 (bs, 1 H, NH), 2.72 (dt, J = 12.13, 2.78 Hz, 1

H), 3.16−3.38 (m, 1 H), 3.97 (td, J = 10.73, 2.9 Hz,

1H), 4.16−4.34 (m, 2 H), 5.13 (d, J = 3.29 Hz, 1 H),

7.0−7.50 (m, 10 H, ArH) ppm 13C NMR (CDCl3) : δ 40.2, 60.6, 67.7, 79.9, 126.0, 126.6, 126.7, 127.7,

127.8, 129.3, 139.5, 139.8 ppm

Analysis for : C16H17NO

Calculated (%) : C, 80.30; H, 7.16; N, 5.85

Found (%) : C, 80.41; H, 7.38; N, 5.95

164

(±)-cis-1-(2,3-diphenylmorpholino)ethanone (89)

(±)-89

N

OPh

Ph

CH3O

To a mixture of (±)-79 (0.478 g, 2 mmol) and NaHCO3 (0.336 g, 4 mmol) in

10 mL THF:water (1:1) was added freshly distilled acetic anhydride (0.23 ml, 2.5

mmol) dropwise at 0 oC and stirring was continued for 45 minutes. The reaction

mixture was diluted with ethyl acetate (10 mL). The organic layer was separated and

the aqueous layer was extracted with ethyl acetate (2 x 10 mL). The combined

extracts were washed with water, brine, dried over Na2SO4 and concentrated under

reduced pressure. Recrystallization of the residue from ethyl acetate provided the

white crystals of (±)-89 suitable for single crystal X-ray analysis.

Yield : 0.38 g (68%)

TLC data : Rf (50% EtOAc/PE): 0.3

Melting point : 153−155 oC

IR (CHCl3) : 3014, 2860, 1635, 1419 cm-1

1H NMR (CDCl3) : δ 2.07−2.23 (m, 3 H), 3.35−3.75 (m, 2 H), 3.81−3.98

(m, 1 H), 4.26−4.51 (m, 1 H), 4.83−5.0 (m, 1 H), 6.05

(d, J = 3.53 Hz, 1 H) 7.05−7.56 (m, 10 H, ArH) ppm

Analysis for : C18H19NO2

Calculated (%) : C, 76.84; H, 6.81; N, 4.98

Found (%) : C, 76.62; H, 6.77; N, 4.66

Resolution of (±)-cis-2,3-diphenylmorpholine (79)

To a solution of L-(+)-tartaric acid (1.5 g, 10 mmol) in ethanol (30 mL) was

added a solution of (±)-79 (9.57 g, 40 mmol) in ethanol (160 mL) and the resulting

mixture was stirred overnight at room temperature. Ethanol was then removed on a

rotary evaporator at 40 oC. To the residue diethyl ether (150 mL) was added and the

mixture was stirred for 1 h. Filtration of the reaction mixture provided the tartarate

165

salt (6.52 g), which was recrystallized from ethanol (90 mL) to obtain white crystals

4.53 g (36%), mp 181-184 oC; [α]25 D ─19.0 (c 0.42, MeOH).

The second isomer of morpholine was isolated from mother liquor. After

evaporation of the solvent, the residue was basified with aqueous NaOH and

resulting morpholine was mixed with etherial filtrate of the first step. Combined free

morpholine (6.18 g, 25.82 mmol) was then treated with D-(−)-tartaric acid (1.91 g,

12.72 mmol) in ethanol as described above. The resulting tartarate salt after

recrystallization from ethanol provided white crystals 5.4 g (43%), mp 182-185 oC,

[α]25 D +19.7 (c 0.44, MeOH). Basification of the salt was carried out using aqueous

NaOH to provide the corresponding optically pure morpholines in quantitative yield.

(−)-79 Isomer of morpholine was obtained from (−)-tartarate salt while (+)-79 isomer

was obtained from (+)-tartarate salt.

Yield of (−)-79 isomer : 3.44 g (36%)

Nature : White solid

Melting point : 73−75 oC

[α]25 D : −77.2 (c 2.59, CHCl3) [lit.27a ─28.3 (c 2.6, CHCl3)]

Ee : 99% (Kromasil-5-Amycoat column; i-

PrOH:PE:TFA)

Absolute configuration : 2R, 3S

Yield of (+)-79 isomer : 4.11 g (43%)

Nature : White solid

Melting point : 73−75 oC

[α]25 D : +76.4 (c 2.59, CHCl3)

Ee : >99% ee (Kromasil-5-Amycoat column; i-

PrOH:PE:TFA)

Absolute configuration : 2S, 3R

166

(±)-Threo-2-(chloroacetylamino)-1,2-diphenylethanol (84)

Ph OH

NPh

O

ClH

(±)-84

The procedure described above for compound 83 was followed for 82 (14.78

g, 69.30 mmol), NaHCO3 (17.44 g, 207.6 mmol), chloroacetyl chloride (12.5 mL,

156 mmol) and THF:MeOH (250 mL).

Yield : 19.04 g (95%)

Nature : White solid

TLC data : Rf (30% EtOAc/PE): 0.28

Melting point : 149−150 oC (lit.27a 147−148 oC)

IR (CHCl3) : 3325, 3020, 2950, 1645 cm-1

1H NMR (CDCl3) : δ 2.39 (d, J = 3.53 Hz, 1 H, OH), 3.96 (ABq, J =

15.28 Hz, 2 H), 5.06 (t, J = 3.41 Hz, 1H), 5.20 (dd, J =

8.21, 3.54 Hz, 1 H), 7.20−7.42 (m, 10 H, ArH), 7.51

(bs, 1H, NH) ppm

Analysis for : C16H16ClNO2

Calculated (%) : C, 66.32; H, 5.57; N, 4.83

Found (%) : C, 66.33; H, 5.57; N, 4.62

(±)-Trans-5,6-diphenylmorpholin-3-one (86)

N

OPh

PhH

O

(±)-86

The procedure described above for compound 85 was followed for 84 (21.34

g, 73.64 mmol), KOH (6.2 g, 110.5 mmol), EtOH (443 mL).

167

Yield : 17.37 g (93%)

Nature : White solid

TLC data : Rf (50% EtOAc/PE): 0.44

Melting point : 185−187 oC (lit.27a 185−186 oC)

IR (CHCl3) : 3390, 3020, 2897, 1674 cm-1

1H NMR (CDCl3) : δ 4.36−4.74 (m, 4 H), 6.30 (bs, 1H, NH), 6.95−7.33

(m, 10 H, ArH) ppm

13C NMR (CDCl3) : δ 63.2, 67.9, 82.5, 127.1, 127.4, 128.0, 128.5, 128.6,

136.2, 136.6, 168.7 ppm

Analysis for : C16H15NO2

Calculated (%) : C, 75.87; H, 5.97; N, 5.53

Found (%) : C, 75.65; H, 5.69; N, 5.11

(±)-Trans-2,3-diphenylmorpholine (80)

N

OPh

PhH

(±)-80

The same procedure described above for compound 79 was followed for 86

(3.6 g, 14.2 mmol), LiAlH4 (1.34 g, 35.3 mmol) and THF (160 mL).

Yield : 2.17 g (64%)

Nature : White solid

TLC data : Rf (EtOAc): 0.38

Melting point : 85−87 oC

IR (CHCl3) : 3328, 3018, 2862, 1492, 1450 cm-1

1H NMR (CDCl3) : δ 1.83 (bs, 1 H, NH), 3.0−3.13 (m, 1 H), 3.27 (td, J =

11.5, 3.41 Hz, 1 H), 3.77 (d, J = 8.84 Hz, 1H), 3.93 (td,

J = 11.24, 2.65 Hz, 1 H), 4.05−4.16 (m, 1 H), 4.36 (d, J

= 8.84 Hz, 1H) 6.95−7.20 (m, 10 H, ArH) ppm 13C NMR (CDCl3) : δ 46.5, 67.4, 67.9, 85.2, 127.3, 127.4, 127.5, 127.6,

127.8, 128.0, 139.0, 140.1 ppm

Analysis for : C16H17NO

168

Calculated (%) : C, 80.30; H, 7.16; N, 5.85

Found (%) : C, 80.29; H, 7.46; N, 5.90

Resolution of (±)-trans-2,3-diphenylmorpholine (80)

To a solution of (±)-80 (7.42 g, 31.03 mmol) in MeOH (120 mL) was added

(R)-(−)-mandelic acid (4.73 g, 31.03 mmol) and the reaction mixture was stirred at

room temperature for 1 h. Methanol was then evaporated on a rotary evaporator. The

resulting salt was dissolved in boiling isopropanol (160 mL). The mixture was then

allowed to cool to room temperature, stirred for 2 h and filtered. The residue was

washed with hot ethyl acetate to obtain one of the diastereomeric salt as a white

precipitate 4.74 g (39%), mp 175-177 oC, [α]25 D −116 (c 1, MeOH). The second

isomer of the salt was obtained from mother liquor by evaporation followed by

recrystallization from ethyl acetate 5.36 g (44%), mp 150-151 oC, [α]25 D +32 (c 1,

MeOH). Basification of the salt was carried out using aqueous NaHCO3 to provide

the corresponding optically pure morpholines in quantitative yield. (−)-80 Isomer of

the morpholine was obtained from the precipitated salt while (+)-80 was obtained

from the salt left in the filtrate.

Yield of (−)-80 isomer : 2.89 g (39%)

Nature : White solid

Melting point : 74−76 oC

[α]25 D : −100 (c 2, CHCl3)

Ee : 92% (Kromasil-5-Amycoat column; i-PrOH:PE:TFA)

Absolute configuration : 2S, 3S

Yield of (+)-80 isomer : 3.26 g (44%)

Nature : White solid

Melting point : 74−76 oC

[α]25 D : +102 (c 2, CHCl3) [lit.27a +92.7 (c 2.2, CHCl3)]

Ee : >99% ee (Kromasil-5-Amycoat column; i-

PrOH:PE:TFA)

Absolute configuration : 2R, 3R

169

General procedure for the enantioselective addition of Et2Zn to benzaldehyde

To a solution of ligand (−)-79 (0.071 g, 0.3 mmol) in toluene (2 mL) was

added diethylzinc (4.5 mmol, 3.1 mL of 1.45 M solution in hexane) and the reaction

mixture was stirred at 80 oC for 30 min. The resulting solution was cooled to 0 °C,

and was treated with benzaldehyde (0.3 mL, 3 mmol). The reaction mixture was

stirred at room temperature for 4 h, TLC indicated complete absence of

benzaldehyde. The reaction mixture was then cautiously quenched with MeOH (1

mL) followed by 1 N HCl (15 mL) and the mixture was extracted with EtOAc (3 x

10 mL). The combined organic extracts were washed with water followed by brine

and dried over anhydrous Na2SO4. The residue obtained after evaporation of the

solvent was purified by flash column chromatography followed by Kugelrohr

distillation to obtain pure (S)-(−)-1-phenyl-1-propanol.

OH

(−)-92

Yield : 0.35 g, (86%)

[α]25 D : − 19.2 (c 5 CHCl3) [lit.26a −46.7 (c 5.1, CHCl3)]

Ee : 36% (by Chiral GC)

Chiral GC : CP-Cyclodextrin-B-2,3,6-M-19 capillary column, at

100 oC (1 min.), 20 deg./min., 110 oC (40 min.), 20

deg/min, 230 deg (5 min.) tR = 33.261 min., tR =

34.370 min.

Preparation of (dl)-2,3-diphenylbutane-2,3-diol (94)

MePh

PhMe

OH

OH

dl-94

An oven dried three necked one liter round bottom flask was charged with

MnCl2 (25.16 g, 200 mmol), naphthalene (8.09 g, 62.8 mmol) and lithium wire (2.84

g, 410 mmol). The flask was kept in water bath and was added anhydrous THF (500

170

mL), the reaction mixture was then stirred vigorously at room temperature. After 3 h,

black slurry of manganese was obtained. To this mixture acetophenone (11.66 mL,

100 mmol) was added dropwise over 10 minutes and stirred at room temperature for

2 h. The reaction mixture was then cooled to 0 oC and quenched cautiously with 2N

HCl (400 mL). After 30 minutes at room temperature the reaction mixture was

extracted with ethyl acetate (1 x 250 mL, 2 x 150 mL). The combined organic layers

were washed with brine, dried over Na2SO4 and concentrated under reduced pressure.

Naphthalene was separated by filtration column chromatography using pet

ether/ethyl acetate as eluent to give 11.5 g (95%) mixture of dl- and meso- isomers in

the ratio of 70:30 respectively (by 1H NMR). Crystallization of the mixture from

EtOAc/PE (1:9) provided pure dl-94 as a white solid.

Yield : 5.9 g (49%)

TLC data : Rf (20% EtOAc/PE): 0.48

Melting point : 121−123 oC (lit.34 122−124 oC)

IR (CHCl3) : 3452, 3016, 2935, 1492, 1446 cm-1

1H NMR (CDCl3) : δ 1.51 (s, 6 H), 2.59 (s, 2 H, OH), 7.15−7.30 (m,

10H, ArH) ppm

Resolution of dl-94 using (S)-proline

To a 250 mL three neck round bottom flak was added (S)-proline (0.63 g, 5.5

mmol), boric acid (0.34 g, 5.5 mmol) and anhydrous toluene (40 mL). The reaction

mixture was refluxed for 12 h. The liberated water was removed by simultaneous

azeotropic distillation using 4 Ao molecular sieves. During reflux the solid

disappeared completely and the formation of gummy mass was observed. To this

reaction mixture was added dl-94 (1.21 g, 5 mmol, solution in 20 mL toluene). The

reaction mixture was then refluxed for 12 h and filtered to give white solid. The solid

was suspended in anhydrous THF (10 mL) and stirring at room temperature for 24 h

followed by filtration gave borate ester as a white solid in 37% yield (0.67 g, mp

263−268 dec., [α]26 D −8 (c 0.5, EtOH)). Borate ester was suspended in 1:1 mixture

THF:3N aq. HCl and stirred at room temperature for 3 h. The reaction mixture was

then extracted with ethyl acetate. The combined organic organic layer was washed

with brine, dried over Na2SO4 and concentrated on rotary evaporator to give crude

171

diol (0.42 g). Column chromatographic purification of the crude compound using pet

ether/ethyl acetate as eluent provided (−)-94 as a white solid.

Yield : 0.356 g (29%)

Melting point : 110−115 oC (for (−)-isomer lit.34 104−105 oC)

[α]25 D : − 10.3 (c 2.7 EtOH) [lit.34 −34.4 (c 2.7, EtOH)]

Ee : 30%

Absolute configuration : 2S,3S

172

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Mukaiyama, T. Can. J. Chem. 2000, 78, 657. (f) Shi, L.; Fan, C.-A.; Tu, Y.-Q.;

Wang, M.; Zhang, F.-M. Tetrahedron 2004, 60, 2851. (g) Matiushenkov, E. A.;

Sokolov, N. A.; Kulinkovich, O. G. Synlett 2004, 77. (h) Banik, B. K.; Banik, I.;

Aounallah, N.; Castillo, M. Tetrahedron Lett. 2005, 46, 7065.

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177

46. (a) Periasamy, M.; Venkatraman, L.; Sivakumar, S.; Sampathkumar, N.;

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Seenivasaperumal, M. Tetrahedron: Asymmetry 2001, 12, 1887.

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Pergamon: Oxford, NewYork, NY, 1988.

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Schwarm, M. J. Org. Chem. 1993, 58, 3568.

178

NMR Spectra and Chiral HPLC / GC Chromatogram

179

1H-NMR of compound 83 (CDCl3, 200MHz)

9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 -0.5

10.01 2.081.00 0.96

TMS

0.00

2.42

2.44

3.98

4.06

4.07

4.15

5.10

5.12

5.14

5.25

5.27

5.29

5.31

7.04

7.05

7.06

7.24

7.26

7.27

7.42

7.45

5.30 5.25 5.20 5.15 5.10

1.00 0.99

Ph OH

NPh

O

ClH

83

1H-NMR of compound 85 (CDCl3, 200MHz)

10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 -0.5 -1.0

10.03 3.091.000.90

TMS

0.00

4.43

4.52

4.62

4.63

4.65

4.71

5.15

5.16

6.84

6.85

6.88

6.89

6.91

6.92

7.08

7.13

7.19

7.20

N

OPh

PhH

O

85

180

13C-NMR of compound 85 (CDCl3, 50.32MHz)

210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0

Chloroform-d

60.7

1

68.4

8

77.0

078

.38

125.

9712

7.60

127.

8212

8.21

136.

3213

6.64

168.

84N

OPh

PhH

O

85

DEPT NMR of compound 85

190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10

60.7

1

68.4

8

78.3

9

125.

9712

7.61

127.

8312

8.22

129 128 127 126 125

125.

97

127.

6112

7.75

127.

8312

8.22

N

OPh

PhH

O

85

181

1H-NMR of compound 79 (CDCl3, 200MHz)

TMS

9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 -0.5

10.19 2.12 1.391.04 1.031.00

0.00

1.89

2.69

2.74

2.75

2.76

3.27

3.29

3.29

3.96

3.98

4.02

4.19

4.20

4.22

4.26

4.29

4.30

5.13

5.14

7.04

7.13

7.14

7.15

7.16

7.17

7.18

7.29

7.4243

7.

4.0 3.5 3.0

2.12 1.09 1.04 1.03

2.69

2.74

2.75

2.76

3.22

3.23

3.27

3.28

3.29

3.29

3.33

3.35

3.92

3.96

3.98

4.02

4.20

4.22

4.26

4.29

4.30

13 pound 79 (CDCl , 50.32MHz) C-NMR of com 3

200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10

Chloroform-d

40.2

1

60.6

1

67.7

3

77.0

079

.97

126.

0512

6.63

127.

7312

7.80

129.

3013

9.55

139.

86

140 135 130 125

126.

0512

6.63

126.

7312

7.73

127.

8012

9.30

139.

5513

9.86

N

OPh

PhH

79

N

OPh

PhH

79

182

DEPT NMR of compound 79

200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0

40.2

1

60.6

1

67.7

5

79.9

7

126.

0612

6.75

127.

7512

7.82

129.

31

N

OPh

PhH

1H-NMR of compound 89 (CDCl3, 200MHz)

10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 -0.5 -1.0

10.04 3.001.711.27 1.26 0.990.68

TMS

0.00

2.11

2.17

2.21

3.38

3.53

3.55

3.65

3.67

3.85

3.89

3.91

3.95

3.97

4.29

4.30

4.35

4.93

4.95

4.96

6.05

6.06

7.10

7.11

7.12

7.14

7.15

7.20

7.26

7.30

7.50

7.50

79

89

N

OPh

Ph

CH3O

183

1H-NMR of compound 84 (CDCl3, 200MHz)

TMS

10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 -0.5 -1.0

9.80 2.05 1.021.00

0.00

2.39

2.40

3.88

3.96

3.97

4.05

5.04

5.06

5.07

5.17

5.19

5.21

5.23

7.33

7.36

7.51

7.55

5.2 5.1 5.0

1.001.00

5.04

5.06

5.07

5.17

5.19

5.21

5.23

OHPh

1H-NMR of compound 86 (CDCl , 200MHz) 3

9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 -0.5 -1.0

10.06 4.000.83

TMS

0.00

1.72

4.38

4.43

4.47

4.48

4.51

4.59

4.64

4.68

6.30

6.98

7.02

7.02

7.03

7.21

7.24

7.25

7.26

7.27

O

NPh ClH

84

N

OPh

Ph OH

(±)-86

184

13C-NMR of compound 86 (CDCl3, 50.32MHz)

200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0

Chloroform-d

63.2

867

.97

77.0

0

82.5

7

127.

1412

7.49

128.

0912

8.54

128.

6413

6.26

136.

61

168.

78

136.5 136.0

136.

26

136.

61

129.0 128.5 128.0 127.5 127.0

127.

14

127.

49

128.

09

128.

5412

8.64

N

OPh

PhH

O

(±)-86

DEPT NMR of compound 86

190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10

63.2

867

.97

82.5

8

127.

1512

7.50

128.

1012

8.55

129.0 128.5 128.0 127.5 127.0 126.5

127.

15

127.

50

128.

10

128.

5512

8.65

N

OPh

PhH

O

(±)-86

185

1H-NMR of compound 80 (CDCl3, 200MHz) TMS

9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 -0.5 -1.0

10.05 1.061.04 1.031.00

0.00

1.83

3.04

3.10

3.10

3.27

3.28

3.75

3.80

3.93

3.94

3.99

4.06

4.07

4.08

4.34

4.39

7.02

7.03

7.07

7.09

7.12

7.13

4.0 3.5 3.0

1.04 1.03 1.021.02 1.021.00

3.09

3.10

3.10

3.11

3.21

3.23

3.27

3.28

3.32

3.34

3.75

3.80

3.87

3.89

3.93

3.94

3.99

4.00

4.06

4.07

4.08

4.09

4.12

4.12

4.34

4.39N

OPh

PhH

(±)-80

13C-NMR of compound 80 (CDCl3, 50.32MHz)

200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0

Chloroform-d

46.5

7

67.4

767

.91

77.0

0

85.2

5

127.

3312

7.64

127.

8912

8.08

139.

0914

0.12

128.5 128.0 127.5 127.0

127.

3312

7.47

127.

5212

7.64

127.

89

128.

08

N

OPh

PhH

(±)-80

186

DEPT NMR of compound 80

200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0

46.5

7

67.4

767

.91

85.2

4

127.

3412

7.53

127.

6512

7.89

128.

08

N

OPh

PhH

(±)-80

1H-NMR of compound 92 (CDCl3, 200MHz)

9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 -0.5 -1.0

4.98 3.27 3.000.95

TMS

0.00

0.88

0.91

0.95

1.70

1.74

1.77

1.80

1.84

1.87

4.56

4.59

4.63

7.26

7.26

7.29

7.29

7.31

7.33

7.36

OH

(-)-92

187

1H-NMR of compound 94 (CDCl , 200MHz) 3

9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.

TMS

5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 -0.5

9.96 6.001.91

0.00

1.51

1.60

2.59

7.16

7.22

7.23

7.25

7.27

MePh

PhMe

OH

OH

dl-94

188

Determination of enantiomeric excess for chiral 2,3-diphenyl

morpholines

(±)-79

N

OPh

PhH

(−)-79

N

OPh

PhH

>99% ee Kromasil-5-Amycoat column; i-PrOH:PE:TFA (20:80:0.1); 0.5 mL/min.;

220 nm; major isomer: tR = 7.76 min; minor isomer tR = 9.34 min.

189

(+)-79

N

OPh

PhH

>99% ee Kromasil-5-Amycoat column; i-PrOH:PE:TFA (20:80:0.1); 0.5 mL/min.;

220 nm; minor isomer: tR = 8.10 min; major isomer tR = 9.04 min.

(±)-80

N

OPh

PhH

190

(−)-80

N

OPh

PhH

92% ee Kromasil-5-Amycoat column; i-PrOH:PE:TFA (20:80:0.1); 0.5 mL/min.;

220 nm; minor isomer: tR = 9.06 min.; major isomer tR = 10.32 min.

(+)-80

N

OPh

PhH

>99% ee Kromasil-5-Amycoat column; i-PrOH:PE:TFA (20:80:0.1); 0.5 mL/min.;

220 nm; major isomer: tR = 8.68 min; minor isomer tR = 10.77 min.

191

X-ray Data (Collection, Structure Solution and Refinement)

Single crystal X-ray studies were carried out on a Bruker SMART APEX

single crystal X-ray CCD diffractometer with graphite-monochromatized (Mo

Kα?= 0.71073Å) radiation. The X-ray generator was operated at 50 kV and 30

mA. Diffraction data were collected with ω scan width of 0.3° at different

settings of ϕ (0°, 90°, 180° and 270°) keeping the sample-to-detector distance

fixed at 6.145 cm and the detector position (2θ) fixed at -28°. The X-ray data

acquisition was monitored by SMART program (Bruker, 2003). All the data

were corrected for Lorentzian and polarization effects using SAINT programs

(Bruker, 2003). A semi-empirical absorption correction based on symmetry

equivalent reflections was applied by using the SADABS program (Bruker,

2003). Lattice parameters were determined from least squares analysis of all

reflections. The structure was solved by direct method and refined by full

matrix least-squares, based on F2, using SHELX-97 software package.

(Sheldrick, G. M. Acta Cryst. 2008, A64, 112). Molecular diagrams were

generated using ORTEP-32 (Farrugia, L. J. J. Appl. Cryst. 1997, 30, 565).

192

cis-5,6-diphenylmorpholin-3-one (85)

ORTEP diagram for 85

Crystal data table for compound 85

Empirical formula C16 H15 NO2 Formula weight 253.29 Temperature (K) 293(2) Wavelength (Å) 0.71073 Crystal system, Space group monoclinic, P21/c Unit cell dimensions a = 9.346(12) Å, α = 90°.

b = 5.483(7) Å, β = 104.64(4)°. c = 26.74(3) Å, γ = 90°.

Volume 1326(3) Å3 Z, Calculated density 4, 1.269 Mg/m3 Absorption coefficient 0.084 mm-1 F(000) 536 Crystal size 0.94 x 0.05 x 0.04 mm Theta range for data collection 2.25 to 25.00°. Limiting indices -10<=h<=11, -6<=k<=6, -31<=l<=31 Reflections collected / unique 11825 / 2330 [R(int) = 0.1109] Completeness to theta = 25.00° 99.7 % Absorption correction Semi-empirical from equivalents Max. and min. transmission 0.9967 and 0.9253

Refinement method Full-matrix least-squares on F2 Data / restraints / parameters 2330 / 0 / 176 Goodness-of-fit on F2 0.982 Final R indices[I>2sigma(I)] R1 = 0.0556, wR2 = 0.0990 R indices (all data) R1 = 0.1338, wR2 = 0.1179 Largest diff. peak and hole 0.141 and -0.161 e.Å-3

193

cis-1-(2,3-diphenylmorpholino)ethanone (89)

ORTEP diagram for 89

Crystal data table for compound 89

Empirical formula C18 H19 NO2 Formula weight 281.34 Temperature (K) 297(2) Wavelength (Å) 0.71073 Crystal system, Space group Triclinic, P-1 Unit cell dimensions a = 8.950(4) Å, α = 84.580(7)°.

b = 12.098(5) Å, β = 82.993(7)°. c = 14.211(6) Å , γ= 81.209(7)°.

Volume 1504.9(10) Å3 Z, Calculated density 4, 1.242 Mg/m3 Absorption coefficient 0.081 mm-1 F(000) 600 Crystal size 0.66 x 0.37 x 0.06 mm Theta range for data collection 2.85 to 25.00°. Limiting indices -10<=h<=10, -14<=k<=14, -16<=l<=16 Reflections collected / unique 14533 / 5282 [R(int) = 0.0290] Completeness to theta = 25.00° 99.5 % Absorption correction Semi-empirical from equivalents Max. and min. transmission 0.9952 and 0.9487 Refinement method Full-matrix least-squares on F2 Data / restraints / parameters 5282 / 0 / 381 Goodness-of-fit on F2 1.046 Final R indices[I>2sigma(I)] R1 = 0.0437, wR2 = 0.0973 R indices (all data) R1 = 0.0580, wR2 = 0.1058 Largest diff. peak and hole 0.148 and -0.131 e.Å-3