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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
INDIAN J. CHEM., SEC B, JANUARY 2013
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
ANANTHI et al.: ASYMMETRIC HENRY REACTION
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
INDIAN J. CHEM., SEC B, JANUARY 2013
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
ANANTHI et al.: ASYMMETRIC HENRY REACTION
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
INDIAN J. CHEM., SEC B, JANUARY 2013
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
ANANTHI et al.: ASYMMETRIC HENRY REACTION
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
INDIAN J. CHEM., SEC B, JANUARY 2013
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
ANANTHI et al.: ASYMMETRIC HENRY REACTION
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
INDIAN J. CHEM., SEC B, JANUARY 2013
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.
ANANTHI et al.: ASYMMETRIC HENRY REACTION
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
INDIAN J. CHEM., SEC B, JANUARY 2013
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
ANANTHI et al.: ASYMMETRIC HENRY REACTION
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
INDIAN J. CHEM., SEC B, JANUARY 2013
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
ANANTHI et al.: ASYMMETRIC HENRY REACTION
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
INDIAN J. CHEM., SEC B, JANUARY 2013
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
ANANTHI et al.: ASYMMETRIC HENRY REACTION
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
INDIAN J. CHEM., SEC B, JANUARY 2013
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
ANANTHI et al.: ASYMMETRIC HENRY REACTION
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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