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Indian Journal of Chemistry Vol. 52B, January 2013, pp 87-108

Advances in Contemporary Research

Asymmetric Henry reaction catalysed by transition metal complexes:

A short review

Nallamuthu Ananthi & Sivan Velmathi*

Organic and Polymer Synthesis Laboratory, Department of Chemistry, National Institute of Technology, Tiruchirappalli 620 015, India

E-mail: [email protected]

Received 22 June 2011; accepted (revised) 27 September 2012

An asymmetric Henry reaction, the coupling of a nitro alkane and a carbonyl group is an important C-C bond forming reaction in organic chemistry giving chiral nitro alkanols which are useful versatile intermediates in synthetic organic chemistry. It is well known that the chiral nitroaldol products find increasing applications in the pharmaceutical industry. These converted products are important precursors of biologically active compounds. Chiral nitroalcohols can be further transformed into synthetically useful derivatives such as carboxylic acids, polyamino alcohols, polyhydroxylated amides and amino alcohols. For the catalytic asymmetric Henry reaction, among the catalysts reported so far, the transition metal complexes catalyse asymmetric Henry reaction plays an important role. Transition metal complexes catalyse the asymmetric Henry reaction efficiently and in most of the cases give the product chiral nitro alkanols in good yield and enantiomeric

excess. This review summarizes the reported remarkable transition metal complex catalysts for asymmetric Henry reaction, their advantages, limitations, mechanism for their catalytic activity and the challenges that need to be addressed in this research area.

Keywords: Asymmetric C-C bond forming reaction, asymmetric Henry reaction, chiral transition metal

complexes, chiral nitroaldols

The first asymmetric version of the Henry reaction was reported by Sasai et al. in 1991(Ref 1). Since

then, interest in this area has been expanded upon

considerably and various reports have been

continuously appearing in the literature on development of various metal and nonmetal based

catalysts for the asymmetric Henry reaction. An

example for the asymmetric Henry reaction is shown in Scheme I. Benzaldehyde reacts with nitromethane

in the presence of chiral ligand giving the product

chiral β-nitroaldols. It is well known that the chiral nitroaldol products

find increasing applications in pharmaceutical

industries. The synthetic utility of the chiral nitro-

aldol reaction is based on the versatility of the 1,2-nitro alcohols, which can be converted into 1,2-amino

alcohols, amino sugars, nitroketones, nitroalkenes,

α,β-unsaturated nitrocompounds, ketones (Nef reaction), carboxylic acids

2,3, in the synthesis of

natural products, poly amino alcohols and

polyhydroxylated amides4. These converted products

are important precursors of biologically active compounds

5,6. Many of these uses have been

exemplified in the syntheses of various pharmaceuticals including the β-blocker (S)-

propranolol6,7

, the HIV protease inhibitor Amprenavir

(Vertex 478), and construction of the carbohydrate

subunit of the anthracycline class of antibiotics, L-Acosamine

6.

Not only are aromatic chiral nitro aldols important,

aliphatic nitro aldols also play an essential role in synthetic organic chemistry. An early review of the

data on the synthesis, chemical transformations and

practical use of aliphatic nitro alcohols have been described systematically and analysed by

Shvekhgeimer in 1998 (Ref 8). The review outlines

the preparation of nitro alcohols by nitroaldol

condensation (Henry reaction), the studies high-lighting novelty either in the procedure of

condensation of nitro-compounds with carbonyl

derivatives or in the use of the target compounds are discussed in greater detail. The data about other

known methods for the synthesis of nitro alcohols and

new information on their chemical transformations

are presented. The review also mentioned potential practical applications of these compounds.

INDIAN J. CHEM., SEC B, JANUARY 2013

88

One of the many features of the Henry Reaction that makes it synthetically attractive is that it utilizes

only a catalytic amount of base to drive the reaction.

Additionally, a wide variety of bases can be used including ionic bases such as alkali metal hydroxides,

alkoxides, carbonates, and sources of fluoride anion

[e.g. TBAF (tetra-n-butylammonium fluoride)] or nonionic organic amine bases including TMG (1,1,3,3-

tetramethylguanidine), DBU (1,8-diazabicyclo[5.4.0]-

undec-7-ene), DBN (1,5-diazabicyclo[4.3.0]non-5-

ene), and PAP (2,8,9-trialkyL-2,5,8,9-tetraaza-1-phospha-bicyclo[3.3.3]undecane). It is important to

note that the base and solvent used do not have a large

influence on the overall outcome of the reaction9.

Like all other catalytic asymmetric reactions,

asymmetric Henry reaction has also been classified by

the major three types of catalysts which include

biocatalysts, organocatalysts, and metal complex catalysts. Among the three types of catalytic

asymmetric Henry reaction, the metal complex

catalyzed enantioselective Henry reaction is an attractive and quite powerful method in asymmetric

synthesis of chiraly pure nitroalcohols. Well designed

compact molecular catalysts that consist of a metallic species and chiral organic ligands can precisely

control the stereochemical outcome of any

asymmetric transformation. The use of chiral metal

catalysts is one of the most frequently employed ways to induce enantio- or diastereoselectivity in the Henry

reaction in which the nitro group and carbonyl oxygen

coordinate to a metal that is bound to a chiral organic molecule. Suitably designed chiral metal complexes

control the steric course in the sense that free energy

difference between enantiomers of 10 KJ/mol corresponds to 99:1 stereoselectivity.

The key features of any asymmetric metal complex

catalyst include the ability to catalyze the desired

reaction, as well as induction of chirality into the products. The first criterion is fulfilled by allowing

coordination sites on the metal center to be accessible

to the substrates during the catalytic transformation. The second criterion is satisfied by transferring

stereochemical information to the products from the

chiral environment surrounding the metal.

A detailed review on asymmetric Henry reaction was done by Barua et al. in 2001 (Ref 10). This

review consists of two parts. The first part includes

the metal based catalyst so far reported in asymmetric Henry reaction. The metal complexes reported are

lathanum, zinc, copper, cobalt and the supported

metal complexes. The second part includes the organocatalysts reported in asymmetric Henry

reaction. Organocatalysts include Guanidine derived

organocatalysts, cinchona alkaloid derived catalysts

and silyl nitronates as activated nitroalkanes. The metal-complex catalysts reported for

enantioselective asymmetric Henry reaction include

alkali metal complexes, alkaline metal complexes, transition metal complexes and rare earth metal

complexes. Among the metal complexes reported to

catalyse the enantioselective Henry reaction, the

transition metal complexes occupy an important place. Transition metal complexes often have the

advantage of providing high selectivity under mild

reaction conditions. They are cost effective compared to the rare earth metal complexes. Their activity and

selectivity may be tailored by varying the ligand

attached to the metal. Asymmetric Henry reaction was successfully

catalyzed by many transition metal complexes and the

product chiral nitroaldols were formed in excellent

yield and selectivity. This review summarizes transition metal complex catalysts reported so far for

enantioselective Henry reaction, their advantages,

limitations and mechanism for their catalytic activity and selectivity.

Types of transition metal complex catalyzed asym-

metric Henry reaction The asymmetric Henry reaction using transition

metal complex as catalyst can be carried out in two

ways. The first method involves the participation of

isolable transition metal complex as catalyst; the second method involves the participation of in situ

formed transition metal complex as catalyst from an

organic chiral ligand and a transition metal salt. The metal complex catalysed asymmetric Henry

reaction was developed by Sasai et al. in 1992 who

O

H+ CH3-NO2

Chiral ligand

OH

NO2*

Scheme I — Asymmetric Henry reaction between benzaldehyde and nitromethane

ANANTHI et al.: ASYMMETRIC HENRY REACTION

89

utilized (S)-(2,2′)-binaphthol in conjunction with a

lanthanum alkoxide 1 which is able to promote the direct reaction between unmodified nitroalkanes and

aldehydes enantioselectively11-14

by making use of the

general principle of two-center catalysis15-17

.

Enantiomeric excesses (ee) between 79-91% were

obtained.

A metal/chiral ligand complex was designed possessing two sites of opposite character, a basic site

and an acidic site, each capable of independently

activating in close proximity the nitro compound and

the aldehyde substrate, respectively.

Copper complexes

Among the chiral transition metal complexes used

as catalysts for asymmetric Henry reaction, chiral copper complexes play an important role. Most of the

asymmetric Henry reactions reported are catalysed by

chiral copper complexes. Due to the relative non toxicity of the metal copper, its ready availability and

low cost makes it attractive to researchers for the

synthesis of chiral copper complexes. The first chiral

copper complex catalysed enantioselective addition reaction of α-keto esters with nitromethane was

developed by Christensen et al. in 2001 (Ref 18). For

the first time, it was shown that ketones undergo catalytic highly enantioselective Henry reactions

producing novel optically active β-nitro α-hydroxy

esters having a chiral quaternary carbon center. Of the three chiral bisoxazoline–copper(II) catalysts

presented for the reaction, the combination of (S)-t-

Bu-BOX 2 as ligand and Cu(OTf)2 as the Lewis acid gave the most promising result with greater than 95%

conversion and 92% ee of the Henry adduct at room

temperature, compared to 95% conversion and 14%

ee for (R)-Ph-BOX (3)–Cu(OTf)2 and 11% conversion and 18% ee for (4R,5S)-DiPh-BOX (4)–Cu(OTf)2.

The catalytic enantioselective Henry reaction of α-

keto esters with nitromethane was also developed using copper(II)−tert-butyl bisoxazoline complex in

combination with triethylamine in 2002 (Ref 19)

(Scheme II). The product optically active β-nitro-α-hydroxy esters were formed in high yield with

excellent ee. The scope of the reaction is

demonstrated by the reaction of a wide variety of α-

keto esters. The catalytic enantioselective Henry reaction of β,γ-unsaturated-α-keto esters proceeds

exclusively as a 1,2-addition reaction, in contrast to

+ La3(O-t -Bu)9

OH

OH

1

N

O

N

O

H3C CH3

t-Bu t-Bu

N

O

N

O

H3C CH3

Ph Ph

N

O

N

O

Ph Ph

Ph Ph

(S)-t-Bu-BOX (R)-Ph-BOX (4R,5S)-DiPh-BOX

2 3 4

R

O

COOEt+ CH3NO2

Et3N

BOX-Cu(II)-catalystR

OH

COOEt

NO2

Scheme II — Catalytic enantioselective Henry reaction of α-keto esters with nitromethane reported by Christensen et al.

18


90

the uncatalysed reaction where both 1,2- and 1,4-

addition products are formed. In the proposed

mechanism for the reaction it was suggested that both the α-keto ester and nitromethane/nitronate ion are

coordinated to the metal center during the reaction

course. Catalytic enantioselective Henry reaction of silyl

nitronates with aldehydes was developed by Risgaard

et al. in the same year20

(Scheme III). Different chiral Lewis acids have been tested for

the reaction and it has been found that a variety of

chiral copper–ligand complexes can catalyse the

enantioselective Henry reaction. The best yield, diastereo- and enantioselectivity of the nitroalcohols

formed are obtained by the application of a

copper(II)-diphenyl–bisoxazoline complex 4 as

catalyst in the presence of tetrabutylammonium

triphenylsilyldifluorosilicate (TBAT). In order to

minimize the epimerization of the nitroaldol products, they were converted into the corresponding Mosher

esters. The reaction proceeds well for different

aromatic aldehydes reacting with alkyl nitronates.

In 2003, Evans et al. reported copper complexes of bis(oxazoline) (BOX) 5a-e derived from

Cu(OAc)2.H2O for enantioselective Henry reaction

candidates21

. The substrate scope of the catalyst has been extended to various prochiral aldehydes

including aliphatic and substituted aromatic alde-

hydes. The corresponding product chiral nitro aldols

were formed in good yield and ee. Benzaldehyde gave the product in 76% yield and 94% ee as maximum

among the aromatic aldehydes. Among aliphatic

aldehydes, isobutyraldehyde gave the chiral product in 86% yield and 94% ee as maximum.

Ligands 5a-e catalysed the asymmetric Henry

reaction between p-nitrobenzaldehyde and nitro-methane in combination with Cu(OAc)2.H2O. The

results are given in Table I.

The chiral ligands 5a-d catalysed the asymmetric

Henry reaction and gave the product chiral nitro aldol with ‘S’ configuration (Table I, entries 1-4). The

enantiomeric excess of the chiral product is in the

range of 43-67%. The chiral ligand 5e catalysed the asymmetric Henry reaction and gave the product

chiral nitro aldol with ‘R’ configuration (Entries 5 and

6). They showed that the solvent played a remarkable effect on the enantiomeric excess of the chiral

product. Catalyst 5e gave the chiral product with 74%

ee when the asymmetric Henry reaction was carried

out in methanol as solvent (Entry 5). The same catalyst gave the chiral product with 81% ee when the

reaction was carried out in ethanol as solvent (Entry

6). Among the catalysts 5a-e, catalyst 5e catalysed the asymmetric Henry reaction efficiently and gave the

product chiral nitro aldol in better ee (81%) as

compared to the other catalysts.

The X-ray structure of the chiral copper-ligand complex 5f reveals the expected square planar

geometry with the acetate carbonyl moieties oriented

toward the vacant apical positions.

O O

H3C CH3

R R

O

N N

O

H3C CH3

5a-d 5e

5a: R = Ph5b: R = i-Pr5c: R = Bn5d: R = t-Bu

O

N N

O

H3C CH3

CuAcO OAc

5f

Table I — Asymmetric Henry reaction catalysed by copper

bisoxazoline complexes

Entry Ligand Solvent Configura-

tion

ee (%)

1 5a Methanol S 43 2 5b Methanol S 67 3 5c Methanol S 45 4 5d Methanol S 37 5 5e Methanol R 74 6 5e Ethanol R 81

TMSON

C2H5

O+

O

Ph

2- Cu(OTf)2, TBAT

Py, CH2Cl2, RT

HO NO2

Ph C2H5

Scheme III — Catalytic enantioselective Henry reaction of silyl nitronates with aldehydes developed by Risgaard et al.

20


91

The asymmetric induction imparted from complex

5f could be rationalized with a statement of the impact of the Jahn-Teller (JT) effect on Cu(II) coordination.

As illustrated in Figure 1, JT distortion of an

octahedral Cu(II) complex creates four strongly coordinating and two weakly coordinating sites

labeled red and blue, respectively. Addition of a

bidentate ligand 5e affords a complex positioning the two cis-oriented strongly coordinating sites in the

ligand plane and two trans-oriented weakly

coordinating sites perpendicular to the ligand plane.

For those complexes that simultaneously bind to both electrophiles and nucleophiles, the most reactive

transition states should position the nucleophile

perpendicular to the ligand plane, while the electro-

phile, for maximal activation, should be positioned in one of the more Lewis acidic equatorial sites in the

ligand plane as illustrated for complex A. By the same

argument, complex C should exhibit the lowest reactivity (greatest stability). While transition states

A-1 (boat), A-2 (chair), and B-1 (chair) all follow the

observed sense of asymmetric induction, the pre-disposition is to favor A-1 on the basis of both steric

and electronic considerations.

A new chiral Cu(II) complex of N,N′-bis(2-

pyridylmethylidene)-(R,R)-1,2-cyclohexanediamine 6, a tetradentate chiral Schiff base ligand, was evaluated

for its catalytic capacity for asymmetric Henry

reaction between benzaldehyde and nitromethane22

. The yield of asymmetric Henry reaction between

benzaldehyde and nitromethane in the presence of

triethylamine or diiospropylethylamine by using the

complex 6 as catalyst was high (94%), however, the enantiomeric excesses were not greater than 30%.

In 2006, Gan et al.23

reported the mild and efficient

enantioselective nitroaldol reactions of nitromethane with various prochiral aldehydes catalyzed by chiral

copper Schiff-base complexes 7a,b which can be

readily prepared from amino acid, yielding the corresponding adducts with high yields (87%) and

good enantiometric excess (80%). The two

Cu

5eCu

L

L5f

Cu

NuL

L EI

A (highest reactivity)

CuNuL

L EI

B (intermediate reactivity)

Cu

EIL

L Nu

C (lowest reactivity)

Cu

OOAcL

L O

R

R

N

O

H

H

H

R

Cu

O

OAcL

L O

R

R

NO

H

H

H

R

Cu

OAc

L

L O

R

R

O

N

H RO

H

HB-1A-1 A-2

Figure 1 — Plausible transition structures for the asymmetric Henry reaction

N N

N NCu

CNCH36

7a,b

OPh

Ph

Cu

N

O

R

R

a; R = Hb; R = t-Bu


92

enantiomers of phenylalanine (D and L) were used, and catalysts of different configurations were

prepared and utilized in the reaction. It was found that

absolute configuration of the product can be controlled by the configuration of the catalyst. The

catalyst without substitution in the salicylaldehyde

part catalysed the asymmetric Henry reaction better

than the catalyst with substitution. Sedlak et al. introduced Cu(II) complexes of chiral

N,N′-bidentate ligands 8a-f (Scheme IV) derived

from substituted 2-(4-isopropyl-4-methyl-5-oxo-4,5-dihydro-1H-imidazol-2-yl)pyridines to catalyse

asymmetric Henry reaction24

. The overall yield of 41–

97% and maximum enantiomeric excess of 19% was

obtained. Among the chiral ligands 8a-f screened for

the copper catalysed asymmetric Henry reaction, chiral ligand 8b gave the chiral nitro aldol product in

high enantiomeric excess (18.6%).

Chiral iminopyridines prepared by Blay et al. in 2007 from monoterpenic (camphor-derived) ketones

and pyridinylalkylamines 9a-e (Scheme V) were found to catalyse the enantioselective Henry reaction

between nitromethane and o-methoxy benzaldehyde

(Scheme VI) in the presence of Cu(OAc)2.H2O. High

yield and good ee (upto 86%) could be obtained under straightforward experimental conditions without the

need for air or moisture exclusion25

.

A new series of chiral hydrogenated salen catalysts 10a-h was developed by Xiong et al. in 2007 for the

asymmetric Henry reaction which produces the product chiral nitro aldol in moderate to high yield (upto 98%)

with excellent enantiomeric excess (upto 96% ee)26

.

A variety of aromatic, heteroaromatic, enal, and aliphatic aldehydes were found to be suitable

substrates in the presence of hydrogenated salen 10f

N

N

N

O

R

CuCl

Cl

2

N

N

N

O

R

CuCl

ClClCu

ClN

N

N

O

R

Scheme IV — Copper complexes of chiral N,N′-bidentate ligands

O

+ N

NH2

BF3. Et2O

Toluene

N N

N N

N N

N N

N N

Ph PhOH

9a

9b 9c 9d 9e

Scheme V — Synthesis of iminopyridine ligands derived from monoterpenic ketones and pyridinylalkylamines and their application in asymmetric Henry reaction

OCH3

CHO

+ CH3NO2

9a-e, M(OAc)n

Base

H3COOH

NO2

Scheme VI — Asymmetric Henry reaction of o-methoxy benzaldehyde with nitromethane catalysed by 9a-e

N

N

NO

R 8a:R = CH38b :R = CH2Ph8c:R = CH2-2-Py8d :R = CH2CN8e:R = CH2COOC2H58f:R = CH2CONH2

8a-f


93

(10 mol%), (CuOTf)2·C7H8 (5 mol%), and molecular sieves. This process is air-tolerant and easily

manipulated with readily available reagents, and has

been successfully extended to the synthesis of (S)-norphenylephrine in 67% overall yield, starting from

commercially available m-hydroxybenzaldehyde.

Based on experimental investigations and MM+ calculations, a possible catalytic cycle (Figure 2) was

proposed to explain the origin of reactivity and

asymmetric inductivity.

The chiral diamine ligand 11 was designed and synthesized from (R,R)-1,2-diphenylethylenediamine,

(S)-2,2′-bis(bromomethyl)-1,1′-binaphthalene, and o-

xylene dibromide. The resulting 11-Cu(OAc)2.H2O

complex was a highly efficient catalyst for the Henry reaction. The reaction was performed in n-propyl

alcohol at room temperature, and the Henry adducts

were produced in high yield (99%) with excellent enantiomeric excess (95%) (Ref 27).

In the same year Jiang et al. reported the

asymmetric Henry reaction catalysed by chiral

phosphine salen type ligands 12a-j. The chiral nitroaldols were formed with 80% ee as maximum

with the chiral ligand 12d and (CuOTf)2.C6H6

(Ref 28). The chiral ligands 12g-j did not impart any

asymmetry in the catalytic reaction. Gao et al.

synthesized copper–Schiff base complexes 13a-e

from Cu(OAc)2.H2O, salicylaldehydes, and amino alcohols. The complexes were shown to be effective

as catalysts in the asymmetric Henry reaction

affording nitro alkanols in 98% yield with moderate to good enantiomeric excess (38.6% ee)

29. Catalyst

13a gave the best ee and yield.

A copper complex of N,N′-bis(pyridin-2-ylmethyl)-(S,S)-1,2-cyclohexanediamine 14 was

synthesized by Zhang et al. in 2008. The complex was

employed as catalyst in asymmetric Henry reaction

between benzaldehyde and nitromethane with triethylamine as promoter. The product chiral β-

nitroaldol was formed in 78% yield with 29% ee30

.

NH HN

R1

R2

HOOH

R2

R1

10a: R1 = H, R2 = H10b: R1 = H, R2 = Ph10c: R1 = Ph, R2 = H10d: R1 = t- Bu, R2 = adamantyl10e: R1 = Cl, R2 = H10f: R1 = t- Bu, R2 = t-Bu

NH HN

OH HO t-Bu

t-But-Bu

t-Bu

N N

OH HO t -Bu

t-But-Bu

t-Bu

10g 10h

(CuOTf)2. C7H8

L*Cu*L*OTf

CH3NO2 TfOHL*Cu

O N+

O

Cu*L

O

O

N

H

R

HH

TfOH

RNO2

OH

RCHO

O Figure 2 — Possible catalytic cycle proposed by Xiong et al.

26

N N

11


94

In the same year Kowalczyk et al. reported that

chiral C2-symmetric, secondary bisamines 15a-n based on the 1,2-diaminocyclohexane framework and

Cu(OAc)2.H2O could promote the asymmetric Henry

reaction. Aromatic and aliphatic aldehydes were reacted with nitromethane to provide the

corresponding β-nitroalcohols in very good yield and

enantioselectivity31

.

Among the chiral ligands screened 15a-n for the

copper catalysed asymmetric Henry reaction, ligand 15k catalysed the reaction efficiently and gave the

product chiral nitroaldol in excellent ee (91%) and

yield (95%). A series of new binaphthyl-containing sulfonyl-

diamine ligands-CuCl complex were used as catalysts

in asymmetric Henry reaction by Arai et al. in 2008.

N

PPh2

R3

R2

R1HO

12a: R1 = H, R2 = H, R3 = H12b: R1 = t-Bu, R2 = H, R3 = t-Bu12c: R1 = Cl, R2 = H, R3 = Cl12d: R1 = H, R2 = H, R3 = CH312e: R1 = H, R2 = OCH3, R3 = H

N

PPh2

HO

12f

N

PPh2

R2R1

12g: R1 = H, R2 = H12h: R1 = Cl, R2 = H12i: R1 = Cl, R2 = Cl

N

PPh2

N

12j

N

OCu/2 O

CH3

t-Bu

OBu-t

t-Bu

OBu-tN

OCu/2 O

CH3

t-Bu

OC8H17OC8H17

t-Bu 13a 13b

N

OCu/2 O

Ph

N

OCu/2 O

Ph

O NN

CH3

Cu

O

Cu

O

CH3Ph

H

OPh

H

13c 13d 13e


95

The (R,R)-diamine-(R)-binaphthyl ligand 16-CuCl

complex smoothly catalysed the enantioselective Henry reaction with the assistance of pyridine to give

the corresponding adduct with high enantiomeric

excess (93%). Moreover, they showed that the 16−CuCl−pyridine system promotes the

diastereoselective Henry reaction in syn-selective

manner to give the adduct in 99% yield with 92:8

syn/anti selectivity. The reported enantiomeric excess of the syn-adduct was 84% (Ref 32).

A novel catalytic enantioselective Henry reaction

was developed by Gan in 2008 using tetradentate copper complexes 17a,b derived from D-tartaric acid

to give β-nitroalkanols in moderate to high

enantioselectivity33

. They found that the tetradentate complex 17b (65%

yield, 72% ee), with a bulky tert-butyl substituent

catalysed the asymmetric Henry reaction much better

than the complex 17a (38% yield, 12% ee). Sanjeevakumar et al. in 2009 reported a new chiral

C2-symmetric N,N′-bis(isobornyl)ethylenediamine–

copper complex derived in situ from bis(isobornyl)-

ethylenediamine 18 and Cu(OAc)2.H2O which catalysed the enantioselective Henry reaction between

nitromethane and various aldehydes to provide β-

hydroxy nitroalkanes with high chemical yield (95%) and high enantiomeric excess (90%)

34.

Zielinska-Blajet et al. reported copper (II)

catalysed asymmetric Henry reaction using cinchona alkaloids derived thiols and disulfides synthesised

from cinchona alkaloids35

.

Commercially available

cinchona alkaloids, namely cinchonidine (CD),

quinine (QN), and quinidine (QD), the respective dihydro derivatives, and their synthetic C-9-epi-

configured analogues (epi-QN/epi-QD) were used as

starting materials. A new series of Schiff bases derived from

Cinchona alkaloids were developed and used as chiral

ligands for the copper(II)-catalyzed asymmetric

Henry reaction by Zhang et al.36

The optimized catalyst was found to promote the asymmetric Henry

reaction of both aromatic and aliphatic aldehydes with

nitromethane and nitroethane. These reactions could afford the chiral β-nitro alcohol adducts with high

enantioselectivities (99%).

Quinine derived thiols 19 and disulfides 20 are shown in Scheme VII. It was found that thiols gave

better enantioselectivity than disulfides in the

N

N

N

N

Cu OH2

H

HCl2

14

15a: R = furyl 15h: R = 2-(OH)C6H515b: R = 1-naphthyl 15i: R = 2-ClC6H515c: R = 2-naphthyl 15j: R = 3-ClC6H515d: R = 9-anthryl 15k: R = 4-ClC6H515e: R = mesityl 15l: R = 2,6-ClC6H515f: R = 2-(OCH3)C6H5 15m: R = 2-BrC6H415g: R = 2-(C8H17O)C6H5 15n: R = 4-BrC6H5

NH HN

R R15a-n

NH

NS

O

O

H3C

16

O

O N

N

R

O

R

OR

R

Cu

17a,b

17a: R = H17b: R = t-Bu

N N

H H 18


96

asymmetric Henry reaction in all of the alkaloids

tested. Among the alkaloids used, the thiol derived from quinine alkaloid catalysed the asymmetric Henry

reaction effectively and gave the chiral β-nitro aldols

in good yield and enantiomeric excess (83%). In 2009, Kowalczyk et al. reported the asymmetric

Henry reaction catalysed by copper- diamine

complexes. The secondary bisamines 21 were derived from 1,2-diaminocyclohexane

37.

The reactions were carried out in the presence of

10 mol% of the Cu(II) complex with i-Pr2NEt as

promoter. Good to excellent yield, 99% enantio-selectivity and moderate to excellent diastereoselecti-

vity were obtained for both aromatic and aliphatic

aldehydes. Various prochiral nitro compounds forming the corresponding β-nitroalcohols with two

contiguous stereocenters were also reported.

New tridentate enantiomerically pure heteroatom

copper catalysts 22a-f, Table II, containing hydroxyl, sulfinyl and amino groups, proved to be highly

efficient catalysts in the enantioselective Henry

reaction to give the desired adducts in high yield (90%) and enantiomeric excess (98%) by Rachwalski

et al. in 2009. The influence of the stereogenic centres

located on the sulfinyl sulfur atom and in the amine

moiety with the enantioselectivity of the product38

were also discussed.

Among the chiral ligands 22a-f screened for the catalytic activity in the copper catalysed asymmetric

Henry reaction, ligands 22b and 22c catalysed the

reaction efficiently and gave the chiral products (S)-β-nitro aldol (90% yield, 98% ee) and (R)-β-nitro aldol

(87% yield, 98% ee) respectively.

N OCH3

N

SH

C2H3

N OCH3

N

S

C2H3

2

19 20 Scheme VII — Quinine alkaloid derived chiral thiol and disulfide

HO

S

NR1-R2O

22a-f

CH3

H3C H

NH2

H3C NH2H

N

CH3

CH3

H

N

i-Pr

H

H

N

H

Pr

H

a b, c d e f

N N

ClCl

H H

CuAcO OAc

21

Table II — Chiral amines used in the synthesis of chiral ligands 22a-f

22a (‒)-cis-myrtanylamine

22b (‒)-(S)-1-(1′-naphthyl)ethylamine

22c (+)-(R)-1-(1′-naphthyl)ethylamine

22d 2,2-dimethylaziridine

22e (‒)-(S)-2-isopropylaziridine

22f (+)-(R)-2-isopropylaziridine


97

Chiral copper (II) complexes generated in situ from C2-symmetric chiral secondary bisamines 23-26 based

on 1,2-diaminocyclohexane structure having H, t-Bu

and Cl substituents with Cu(OAc)2. H2O were reported by Khan et al. in 2010.

They were used as

catalysts for an environmentally benign protocol for

highly enantioselective Henry reaction of various aldehydes with nitromethane in the presence of

different ionic liquids as a greener reaction medium at

0°C. Excellent yield (90%) of β-nitroalcohols with

high enantioselectivity (94% ee) were achieved when [emim]BF4 was used as ionic liquid. This reported

ionic liquid mediated nitroaldol protocol is recyclable

(upto five cycles) with no significant loss in its performance

39.

In the same year Xin et al. reported the synthesis of

new planar chiral [2.2] para-cyclophane Schiff base

ligands of the type 27 and their application in asymmetric Henry reaction. A series of new planar

and central chiral ligands were synthesized based on

[2.2] para-cyclophane backbones from enantiomeri-

cally pure 4-amino-13-bromo [2.2] para-cyclophane and commercially available chiral amino alcohols.

Their application in copper catalysed asymmetric

Henry reaction resulted in secondary alcohols with

high yield and excellent selectivity for active aldehydes (upto 94% ee)

40.

In 2010 Noole et al. found that a complex derived

from the enantiopure bipiperidine 28 and

Cu(OAc)2.H2O was acting as an efficient catalyst for enantioselective Henry reaction. Nitromethane and

nitroethane were chosen to react with benzaldehyde.

The product chiral nitroaldols were obtained with a maximum of 96% ee (Scheme VIII). The easy

availability of the catalyst components, mild reaction

conditions, high yield and good to excellent enantioselectivity make this catalyst useful for most

applications41

.

An efficient in situ three component formation of

chiral oxazoline-Schiff base copper(II) complexes (Scheme IX) were introduced by Du et al. in 2010

(Ref 42). The product chiral nitro aldols were formed

in 97% yield and upto 92% ee. In 2010 the catalytic activity of the chiral ligands

synthesized from the amino acid L-valine in the

asymmetric Henry reaction were reported. Two chiral salen ligands 29a and 29b have been synthesized

from L-valinol and L-diphenyl valinol with

salicylaldehyde respectively43

.

NH HN

Cl Cl

NH HN

ClCl

NH HN

OEt EtO

OH HO

NH HN

23 24

25 26

Br

HO

H3C

N

OH

Ph

27

O

H

OHNH N

RCH2NO2

R

NO2

OH

R

NO2

+ R = H upto 96% eeR = CH3 ant i:syn = 4:1

upto 96% ee

28

Cu(OAc)2.H2O Scheme VIII — Asymmetric Henry reaction


98

The chiral ligands were employed as catalysts with

Cu(OAc)2.H2O in the asymmetric Henry reaction

between nitromethane and substituted banzaldehydes.

The relationship of the enantiomeric excess of the product with the steric bulkinesss of the chiral ligands

was discussed. As the steric bulkiness of the ligand

increases, the enantioselectivity of the asymmetric reaction increases. Chiral ligand 29a catalysed the

asymmetric Henry reaction and gave the product

chiral nitro aldol in 99% yield and 54% ee. Whereas, the chiral ligand 29b catalysed the reaction and gave

the product nitro aldol in 99% yield with 70% ee. The

substrate scope of the chiral ligand was explored by

performing the reaction with variation of functional groups on substituted benzaldehydes. The product

chiral nitroaldols were formed with 77-95% ee and in

good yield. The mechanism for the formation of particular enantiomer is also discussed.

First, the coordination of nitronate anion with

copper takes place through the oxygen of the nitronate anion near salicylaldimine part (a). Benzaldehyde

occupies the fourth equatorial position forming the

distorted square planar intermediate (b). The attack of

the nitronate anion on the carbonyl group of benzaldehyde takes place at the si face, via a stable

six membered transition state. The product (R)-(‒)-2-

nitro-1-phenylethanol (c) is formed after work up (Figure 3).

This salen ligand 29b derived from L-diphenyl-

valinol and Cu(OAc)2.H2O system has been proven to

be a good catalytic system for the asymmetric Henry reaction, by providing the corresponding nitroalkanols

with good yield and high enantiomeric excess. This

reaction can be carried out without the need of air and

moisture exclusion which makes the catalyst more

attractive.

Catalytic asymmetric Henry reaction has been developed using a novel chiral Cu(II) complex

derived from L-proline and pyridine 30 with

copper(II) acetate in ethanol under mild conditions by Basi et al.

44 The corresponding chiral 2-nitro-1-

arylethanol derivatives could be obtained in high

yields with moderate to good enantiomeric excess (upto 86% ee). It was found that the coordination of a

metal atom to the nitrogen of the pyridine ring is

essential in determining the stereochemistry of the

reaction. Out of the two copper sources, Cu(OTf)2 and Cu(OAc)2.H2O used, copper(II) acetate provides

better enantioselectivity.

The catalytic asymmetric Henry reaction of nitro-methane with various aldehydes was developed using

chiral binaphthylazepine derived amino alcohol 31

and Cu(OAc)2.H2O as catalyst by Guo et al. in 2011. High yield and good enantioselectivity (97%) were

obtained for both aromatic and aliphatic aldehydes.

Moreover, this catalytic system also works well for

the diastereoselective Henry reaction to afford the corresponding adducts in upto 95:5 syn/anti

selectivity and 95% enantioselectivity45

.

Zhou et al. synthesised a small library of C1-symmetric chiral diamines 32-41 via condensing exo-

(‒)-bornylamine or (+)-(1S,2S,5R)-menthylamine with

various cbz-protected amino acids46

. Among these,

ligand 32-CuCl2.2H2O complex (2.5 mol%) shows outstanding catalytic efficiency in Henry reaction

between a variety of aldehydes and nitroalkanes to

Scheme IX — Three component formation of chiral oxazoline-Schiff base copper (II) complexes by Du et al.42

29a: R = H 29b: R = C6H5

N

OH

R

R

HO

H3C CH3

N

Ph Ph

OH

N OH

Ph Ph

30 31

A combinatorial library of catalyst generated

in situ by Yang et al.


99

afford the expected products in high yields (upto 98%)

with excellent enantioselectivities (upto 99%) and

moderate to good diastereoselectivities (upto 90:10). This process is air- and moisture tolerant and has been

applied to the synthesis of (S)-2-amino-1-(3,4-

dimethoxyphenyl)ethanol, a key intermediate for (S)-

epinephrine and (S)-norepinephrine. The low catalyst

loading, excellent yields and enantioselectivities, inexpensive copper salt and mild reaction conditions

has made this catalytic system practically useful.

O

N

H3CCH3

O

Cu

N

O CH2

O

O

N

H3CCH3

OCu

N

O

OR

OH

R

O

H

N

O

O CH2

O

N

H3C CH3

OCu

N

O

O CH2

O

R

H

O

N

H3C CH3

OCu

N

O

O CH2

OH

R

H

a b

c

Figure 3 — Possible mechanism for ligand 29b-Cu(OAc)2.H2O catalysed asymmetric Henry reaction between nitromethane and benzaldehyde

NH

O

NH NH

NH

NH

O

HN NHHN

H2N

O

HN H2N HN

Ph

H2N

O

HN

Ph

H2N HN

O

HNN

Bn

HNN

Bn

32 33 34 35

36 37 3839

40 41


100

Gong et al. reported a successful synthetic route to

chiral 1H-isochromenes and 1,3-dihydridobenzo-furans by combining the copper(II)-catalyzed asym-

metric Henry reaction of o-alkynylbenzaldehydes 42

with subsequent gold(I)-catalyzed cycloisomeriza-

tion47

. The product optically active 1H-isochromenes and 1,3-dihydroisobenzofurans were successfully

synthesized in good overall yields with good to

excellent enantioselectivities (upto 98%, Scheme X). They were investigated with various substrates, and a

correlation between the regioselectivity and electronic

nature of the substrates was studied. It was found that the substrates with electron donating groups at the

alkynyl moiety preferred a 6-endo-dig manner to

generate 1H-isochromenes 44 as the main products

(upto >30:1) while the ones with electron withdrawing groups were inclined to undergo 5-exo-

dig cyclization to form 1,3-dihydroisobenzofurans 45

(upto 1:5). Among the copper salts, Cu(OAc)2.H2O, CuCl2.2H2O, CuBr2, CuSO4.5H2O, Cu(OTf)2 used for

complex formation with ligand 31, the CuCl2.2H2O-

31 combination gave the highest enantiomeric excess. A series of bis(sulfonamide)-diamine (BSDA)

ligands were synthesised from commercially available

chiral α-amino alcohols and diamines by Jin et al. in

2011 (Ref 48). The chiral BSDA ligand 46, coordi-nated with Cu(I), catalyses the enantioselective Henry

reaction with excellent enantioselectivity (upto 99%,

Scheme XI). Moreover, with the assistance of pyridine, CuBr-46 system promotes the diastereo-

selective Henry reaction with various aldehyde

substrates and gives the corresponding syn-selective adduct upto 99% yield and 32.3:1 syn/anti selectivity.

The enantiomeric excess of the syn adduct was 97%.

In the same year an enantioselective Henry reaction

was efficiently carried out under mild reaction conditions in the presence of catalytic 9-epi and

natural cinchona alkaloids and copper (II) acetate by

Zielinska-Blajet et al.49

Aromatic and aliphatic aldehydes with nitromethane and its α-substituted

CHO

R

32/CuCl2.2H2O

R

OH

NO2* Ph3PAu(OTf)

TfOH, CH2Cl2

O

NO2

R

*

+ O

NO2

R

*

42a-o 43a-o 44a-o 45a-i

a (R = Ph)b (R = 4-Me-Ph)c (R = 3-Me-Ph)d (R = 2-Me-Ph)

e (R = Ph)f (R = 4-Me-Ph)g (R = 3-Me-Ph)h (R = 2-Me-Ph)

i (R = Ph)j (R = 4-Me-Ph)k (R = 3-Me-Ph)l (R = 2-Me-Ph)

m (R = Ph)n (R = 4-Me-Ph)o (R = 3-Me-Ph)

CH2NO2

Scheme X — Synthetic route to chiral 1H-isochromenes and 1,3-dihydridobenzofurans by combining the copper(II)-catalyzed

asymmetric Henry reaction of o-alkynylbenzaldehydes 42 with subsequent gold(I)-catalyzed cycloisomerization47.

R

O

H+ R'CH2NO2

CuBr, Pyridine

R

OH

R'

NO2

R' = H ee upto 99%R' = Et syn/anti upto 32.3:1

(ee of syn 97%)

R' = H, Me, Et, Ph

NH HN

HNNH

S S

PhPh

46

46,

OO O O

CH3CH3

Scheme XI — Asymmetric Henry reaction between aldehyde and substituted nitro compounds using copper complex of bis(sulfonamide)diamine 46 as catalyst


101

derivatives provided the corresponding β-nitroalco-

hols in good to reasonable yields, high syn-diastereo-

selectivity, and (S)-enantioselectivity upto 94%.

Recently in 2009, Oh et al. reported a new approach to synthesise both enantiomers of Henry

products chiral nitroaldols by the use of different

molecularities of metal-ligand complexes synthesised from copper (I) and zinc (II) with readily available

Brucine derived amino alcohol 47 (Ref 50).

Out of the two complexes (copper and zinc

complexes) copper complex gave the highest enantio-meric excess (95%). The two metal salts used for the

complex formation were Cu(OAc)2 and Zn(OTf)2.

Camphor derived annulated imidazole ligands 48 have also been tested for the catalytic activity and

selectivity in the copper (II) catalyzed asymmetric

Henry reaction by Bures et al.51

Good enantio-selectivity upto 67% was achieved. Starting from (R)-

camphordiamine, 13 new camphor-annulated imida-

zoline ligands were synthesized in good yields as two

regioisomeric series. The product stereoselectivity varied according to the regioisomer used.

A practical synthesis of (R)-salmeterol 49 has been

accomplished from 3-bromo salicylaldehyde, which involved a Cu(II)–sparteine complex catalyzed

asymmetric Henry reaction as the key step by Lu

et al. this year52

(Scheme XII). (R)-Salmeterol 49 was obtained in 39% overall yield and 95% ee.

Zinc and molybednum complexes

In 2005, Uwe Kohn, et al. reported the synthesis of three bidentate zinc (II) complexes and molybednum

(0) complexes of tridentate neutral chiral guanidine

ligands 50a-c and their application in asymmetric

Henry reaction of aliphatic aldehydes with nitro-

methane (Scheme XIII). Although the chiral

nitroaldols were formed in excellent yield (90%), the enantiomeric excess is very poor (2%) (Ref 53).

Chiral dinuclear zinc catalysts for the asymmetric

aldol and nitroaldol (Henry) reactions which led to

efficient syntheses of the β-receptor agonists (−)-denopamine 58 and (−)-arbutamine 59 was reported

by Trost et al. in 2002 (Ref 54). (‒)-Denopamine is a

cardiotonic drug which acts as a Beta-1 adrenergic receptor agonist. It is used in the treatment of angina

and may also have potential uses in the treatment of

congestive heart failure and for clearing pulmonary

edema. (‒)-Arbutamine is a cardiac stimulant. It is used to stimulate adrenergic receptors. Various

modified chiral ligands 52a-d, 53a-b, 54, 55, 56

(Figure 4) were synthesised for this purpose from L-diphenylprolinol as chiral source (Scheme XIV).

(R)-(‒)-denopamine was synthesised by enantio-

selective Henry reaction of substituted benzaldehyde

and nitromethane catalysed by zinc complex 57

synthesised from the chiral ligand 55 as initial step

(Scheme XV). Starting from the chiral product

nitroaldol, upon various transformations, the final product (R)-(‒)-denopamine 58 was obtained.

(R)-(‒)-Arbutamine was synthesised by enantio-

selective Henry reaction catalysed by the zinc

complex formed in situ from the chiral ligand 54 and Et2Zn as initial step (Scheme XVI). Starting from the

chiral product nitroaldol upon various transforma-

tions, the final product (R)-(‒)-arbutamine 59 was

obtained as yellow coloured solid in 90% yield.

C2-Symmetric tridentate bis(oxazoline) 60 and bis-

(thiazoline) ligands with a diphenylamine backbone

have been investigated in the catalytic asymmetric

Henry reaction of α-keto esters with different Lewis acids by Du et al. in the year 2005 (Ref 55). It was

found that the metal controlled reversal of

enantioselectivity. The Cu(OTf)2 complexes of the chiral ligand furnished ‘S’ enantiomers, while Et2Zn

R1

O

+

R2

NO2

Cu(I)/47

Zn(II)/47

R1

NO2

OH

R2

R1

NO2

OH

R2

OCH3

OCH3

N

OH

N

O

O

H

HO

H

H

H

47

N

NHN

H H

48


102

complexes of the chiral ligand afforded ‘R’

enantiomers, both of them gave the product with

higher enantioselectivities (upto 85% ee,

Scheme XVII). Reversal of enantioselectivity in asymmetric Henry reaction was achieved with the

same chiral ligand by changing the Lewis acid

center from Cu(II) to Zn(II). It was reported that the NH group in C2-symmetric tridentate chiral ligands

play a very important role in controlling both the

yield and enantiofacial selectivity of the Henry

products.

Ferrocenyl-substituted aziridinylmethanol (Fam)

61 was used as catalyst with zinc for the asymmetric

nitroaldol (Henry) reaction by Bulut et al. in 2008

(Ref 56). This catalyst worked with a variety of aldehydes (aromatic, aliphatic, α,β-unsaturated, and

heteroaromatic) and α-ketoesters to give the nitroaldol

product in 97% yield and 91% ee. It was found that the recyclability of the chiral ligand was retained

without losing its activity.

Zinc-based catalysts are especially interesting

because they might be compatible with aqueous

O

O

O

HCuCl2.2H2O, (-)-sparteine

CH3NO2, Et3N, MeOH

O

O

NO2

OH

79% yield, 96% ee

HO

HN

O

H

HO 49

Scheme XII — Synthesis of (R)-salmeterol 49 via catalytic asymmetric Henry reaction

N

NH

N

N

O

Mo CO

COCO

N

NH

N

NR1R2

Zn Cl

Cl

50a R1R2 = (CH2)450b R1R2 = (CH2)2O(CH2)250c R1R2 = (CH2)5

51

O

H + CH3NO2

OH

NO2*

CH3CN

50a-c, 51

Scheme XIII — Asymmetric Henry reaction of aliphatic aldehydes with nitromethane catalysed by

Zn (II) and Mo (0) complexes 50a-c and 51 of chiral guanidine ligands

OH

CH3

BrBrNH

Ph

PhHO

OH NN

Ph

Ph

OH HOPh

Ph

52a

Scheme XIV — Synthesis of chiral ligand from L-diphenylprolinol by Trost et al.54


103

systems in the light of the fact that zinc enolates have

been identified as intervening species in aldol

reactions catalyzed by type II aldolases57

.

The enantioselective Henry reaction between nitromethane and various aldehydes catalyzed by in

situ prepared chiral amino alcohol ligand 62–Zn

(Me2Zn) complex was described by Guo et al.58

The resulting product β-nitroalcohols were obtained in

high yields and with moderate to good enantiomeric

excesses. Symmetric bisoxazolidine 63-Me2Zn combination

was found to effectively catalyze the asymmetric

Henry reaction of aliphatic and aromatic aldehydes by

Wolf et al.59

β-Hydroxy nitroalkanes were produced in upto 99% yield and 95% ee. It was found that the

bisoxazolidine-Me2Zn complex catalyzed nitroaldol formation requires relatively short reaction times,

proceeds under mild conditions and the method can

be applied to a wide range of substrates including

sterically hindered aldehydes. To date, a few other zinc complexes bearing amino

alcohol ligands60

and macrocyclic thioaza ligands61

have been described for the Henry reaction. Because the results are still poor, future developments in the

area can be expected.

Chromium complexes Kowalczyk et al. in 2007 prepared chiral

chromium(III)–salen-type complexes 64a-c derived

from 1,2-diaminocyclohexane and 1,2-diphenyl-

ethylenediamine and employed the chromium (III) complexes (2 mol%) as catalyst in the enantio-

selective Henry reaction62

. Various arylaldehydes,

trans-cinnamaldehyde, and cyclohexanecarbaldehyde reacted with nitromethane in the presence of (i-

Pr)2NEt to give the corresponding adducts in 40-76%

ee and in moderate to good yield.

Zulauf et al. in 2009 reported a new chiral thiophene-salen chromium complex 65 for the

asymmetric Henry reaction of several aldehydes

(Scheme XVIII) (Ref 63). The anodic polymerization of this complex led to an insoluble powder that was

successfully used as a heterogeneous catalyst for the

transformation of 2-methoxybenzaldehyde with enantiomeric excess upto 85%.

OH

R

NN

Ph

Ph

OH HOPh

Ph

52a R = CH3, 52b R = Cl, 52c R = F, 52d R = OCH3

OH NN

Ph

Ph

OH HOPh

Ph

53a R = H, 53b R = Cl

R

OH NN

OH HO

OH NN

OH HO

OH NN

OH HOF

F

F

F

54 55 56

Figure 4 — Chiral ligands reported by Trost et al.

54

O NN

O O

57

Zn Zn

Et


104

The product chiral nitroaldols were formed in good yield and enantiomeric excess (85%). It was reported

that the polymerized catalyst can be recovered by an

original multi substrate procedure.

Cobalt complexes

In 2004 Kogami et al. synthesised a few chiral

ketiminato cobalt complexes 66-69 and employed them in the asymmetric Henry reaction

64.

Investigation of the catalytic activity of these complexes revealed that in the presence of i-Pr2EtN, 2

mol % of cobalt complexes, optically active 1,2-

diarylethylene diamines 66 and 67 can mediate the reaction between nitromethane and aldehyde in ee

upto 84%. They also employed commercially

available cobalt salen complexes 68 and 69 for the

enantioselective Henry reaction65

. In the presence of i-Pr2EtN, as little as 2 mol % of the cobalt salen

CHO

TBSO

57

TBSOCH3NO2

OH

NO2

HO

OHHN OCH3

OCH3

(R)-(-)-denopamine 58

Scheme XV — Synthesis of (R)-(‒)-denopamine 58 by Henry reaction (Trost et al.

54)

CHO

TBSO

(R)-(-)-arbutamine

54, Et2Zn

TBSOCH3NO2

OH

NO2

HO

OHHHClN

OTBDMS OTBDMSOH

OH

59RR

Scheme XVI — Synthesis of (R)-(‒)-arbutamine 59 by Henry reaction by Trost et al.54

R COOEt

OH

NO2

R

O

COOEt+ CH3NO2

60

Cu(Otf)2

60

Et2ZnR COOEt

OH

NO2

(S)Upto 82% ee

(R)Upto 85% ee

NH

O N N O

Bn Bn

60

Scheme XVII — Metal controlled reversal of enantioselectivity reported by Du et al.

55

Fe

H OH

N

H CH3

Ph

H

O

N OH

Ph

Ph

NH

O

HN

O(S)

(S) (S)

(S)

(R)

(R)

61 62 63


105

complexes promotes condensation of nitromethane

with aromatic aldehydes with enantioselectivity ranging from 62% to 98%.

A chiral bimetallic Co(II)-salen catalyst (70,

Figure 5) self-assembled through hydrogen bonding,

was developed by Park et al. in 2008 which results in significant rate acceleration as well as excellent

enantioselectivity in Henry reaction66

. The self-

assembly through hydrogen bonding was confirmed by the X-ray structure and

1H NMR experiments. A

bimetallic mechanism is suggested by the kinetic

experiment. This result proves the validity of novel self

assembly based approaches toward the efficient

construction of chiral bimetallic catalyst systems. The

product chiral nitroaldol was formed in 87% yield with 96% ee.

Supported chiral catalysts for asymmetric Henry

reaction

A new catalytic system of chirally modified MCM-

41-Cu(salen) complex 71 has been prepared and

examined in the asymmetric Henry reaction between various aldehydes and nitromethane at room

temperature by Rajagopal et al. recently67

. It was

found that aromatic, aliphatic, and heterocyclic

aldehydes can be converted into the corresponding

nitro alcohols in 60-92% yields with 60-90% ee. This

catalyst was separated by filtration and reused several times without any significant loss of reactivity or

enantioselectivity.

Chiral bis(oxazoline) ligand 72 was immobilized

onto a magnetically separable hierarchically ordered mesocellular mesoporous silica (M-HMMS) and this

new catalytic system was examined in the asymmetric

Henry reaction between various aldehydes and nitromethane atambient temperature by Kim et al.

68

Good enantioselectivity (upto 86.0% ee) could be

observed when the free silanol groups of the mesoporous silica were capped by trimethylsilyl

group. The interesting aspect of this research is the

separation of the reused catalyst magnetically and it

has been used several times without significant loss of reactivity or enantioselectivity. This magnetic

separation of catalysts could lead to further

development towards practical industrial scale application due to the simplicity of procedure without

cumbersome filtration.

Conclusion

In this short review, an attempt has been made to

cover the different transition metal complex catalyst

systems used for carrying out asymmetric Henry

N N

O O

R1 R1

R2R2

Cr

64a R1, R2 = t-Bu64b R1 = t-Bu, R2 = Me

N N

O O

t-Bu t-Bu

t -But-Bu

Cr

Cl

64c

Scheme XVIII — Asymmetric Henry reaction catalysed by chiral thiophene-salen chromium complex


106

O O

NCo

O

N

O

Ph Ph

O O

N

Co

O

N

O

O

N

Co

O

N

Ph Ph

i-Pr

i-Pri-Pr

i-Pr O

N

Co

O

N

i-Pr

i-Pri-Pr

i-Pr

66 67

68 69

N N

N

N

H

O

t-Bu

N

ON

O

HN

N

t-Bu

O

H

O O

O

t-Bu

N N

Co

Co

t-Bu t-Bu

t-BuO

H

70

Figure 5 — Structure of self-complementary dinuclear Co(salen) complex

N N

O O

N

O O O

MCM-41

Cu

OTMS

O

O

OTMS

O

O

OTMS

OTMS

Si

Si

OEtHN O

O

N

NNO

O

O

ONN

N

OEtNH

O

O

N

O

O

N

Cu2+

2OAc-

5

5

71 72


107

reaction. Most of the catalytic asymmetric reactions

involve the participation of in situ formed catalysts.

From the current degree of development, it is understandable that most of the catalysts developed

for asymmetric Henry reaction are chiral copper

complexes. Some chiral zinc, cobalt and chromium

complexes are also reported. Studies on other chiral transition metal complexes for the asymmetric Henry

reaction are in progress. Similarly, the substrates

participating in the asymmetric Henry reaction should also be challenging in order to synthesize novel chiral

compounds useful for synthetic organic chemistry.

Acknowledgement

Authors thank Dr. M. Chidhambaram, former director, NITT for his encouragement and support.

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