Enantioselective Henry and aza-Henry reaction in the synthesis of (R)-tembamide using efficient, recyclable polymeric CuII complexes as catalyst

Article abstract of DOI:10.1002/cplu.201402078

Chiral copper(II) polymeric [H₄]salen (salen=bis[(salicylidene) ethylenediaminato]) complexes Cu^II-1-3 were generated in situ and used as efficient catalysts in the asymmetric Henry and aza-Henry reaction of various aromatic and alip

Full text of DOI:10.1002/cplu.201402078

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DOI: 10.1002/cplu.201402078
Enantioselective Henry and Aza-Henry Reaction in the
Synthesis of (R)-Tembamide Using Efficient, Recyclable
Polymeric CuII Complexes as Catalyst
Anjan Das,[a, b] Manoj K. Choudhary,[a, b] Rukhsana I. Kureshy,*[a, b] Tamal Roy,[a] Noor-
ul H. Khan,[a, b] Sayed H. R. Abdi,[a, b] and Hari C. Bajaj[a, b]
Chiral copper(II) polymeric [H4]salen (salen=bis[(salicylidene)e-
thylenediaminato]) complexes CuII-1–3 were generated in situ
and used as efficient catalysts in the asymmetric Henry and
aza-Henry reaction of various aromatic and aliphatic aldehydes
and N-tosylimines in the presence of various nitroalkanes at
room temperature (27Æ28C) for 20 hours. This group of poly-
meric [H4]salen complexes demonstrated excellent per-
formance (product yield and enantiomeric excess ee up to
98%) in the formation of b-nitroalcohol by using nitromethane
with low catalyst loading of 1 mol% (with respect to the mon-
omeric salen unit) and high enantioinduction (ee 94%) in the
aza-Henry product; b-nitroamines were obtained with moder-
ate yield (78%). This catalytic system also worked well with ni-
troethane and 1-nitropropane in the case of Henry reaction, to
furnish the corresponding products in high yields and enantio-
selectivities for syn diastereomers. The CuII-2 complex retained
its performance at the gram level and was expediently recy-
cled eight times with no significant loss in its performance.
The kinetic study with CuII-2 complex for the enantioselective
aza-Henry reaction of N-Ts-benzylimine (Ts=tosyl) revealed
a first-order dependence on catalyst and nitromethane concen-
tration and was zero order with respect to the substrate. The
product obtained was transformed straightforwardly to the
pharmaceutically important enantiomerically pure (R)-temba-
mide (b-adrenergic agonist) drug in good yield by the asym-
metric nitroaldol reaction of 4-methoxybenzaldehyde in three
successive steps.
Introduction
The high demand for enantiomerically pure drugs[1] has gained
a surge of interest owing to the inherent therapeutic behavior
of the individual enantiomers of the drug in the biological
system. Chiral b-amino alcohols containing enantiopure drugs
have received much attention and several routes have been re-
ported for their synthesis. Among them, catalytic enantioselec-
tive addition of nitroalkanes to carbonyl compounds provides
optically active b-nitroalkanols,[2] useful intermediates in the
asymmetric synthesis of the b-receptor agonists (À)-denopa-
mine[3] and (À)-arbutamine,[3] b-blockers (S)-metoprolol,[4] (S)-
propanolol,[5] and (S)-pindolol,[6] and pharmacologically impor-
tant b-amino alcohol derivatives, such as chloramphenicol,[7]
ephedrine,[7] sphingosine,[8] and so forth. On the other hand,
the addition of nitroalkanes to imines (aza-Henry reaction) is
a powerful and efficient carbon–carbon bond forming reac-
tion[9] in which the resulting products of the aza-Henry reac-
tion can easily be converted to 1,2-diamines[10] under reductive
conditions or oxidatively cleaved to afford a-amino acids.[11]
Shibasaki and co-workers demonstrated a series of heterobi-
metallic catalysts that proved to be effective for asymmetric
Henry reactions.[12] Starting from these promising results, in
recent years lots of different organocatalytic[13] and chiral
metal-based catalytic systems[14] have been reported to accom-
plish the enantioselective Henry and aza-Henry reactions.
Among them, copper-catalyzed Henry/aza-Henry reactions
with bis[(salicylidene)ethylenediaminato] (salen)-type C2-sym-
metric ligands[14d–f,15] have shown better performance over or-
ganocatalytic systems in terms of low temperature, high cata-
lyst loading, long reaction time, and use of organic and inor-
ganic bases as additives, but with no recyclability data. As
chiral catalysts are quite expensive, their recyclability is an im-
portant aspect in offsetting the catalyst cost.
[a] A. Das, M. K. Choudhary, Dr. R. I. Kureshy, T. Roy, Dr. N.-u. H. Khan,
Dr. S. H. R. Abdi, Dr. H. C. Bajaj
Discipline of Inorganic Materials and Catalysis
Central Salt and Marine Chemicals Research Institute (CSIR-CSMCRI)
Bhavnagar 364021, Gujarat (India)
Fax: (+91)0278-2566970
E-mail: rukhsana93@yahoo.co.in
Herein, we report a couple of modifications in the catalyst
design. First, to improve the efficiency of the catalyst, a poly-
meric ligand with about eight repeating catalytic sites was in-
corporated, thereby increasing the molecular weight of the
catalyst to facilitate its recyclability. Second, incorporation of
basic sites in the catalyst might assist abstraction of the proton
from nitromethane to generate a nitronate ion, which func-
tions as a nucleophile and provides excellent results with alde-
hydes/imines. With this knowledge, and in the quest for the
[b] A. Das, M. K. Choudhary, Dr. R. I. Kureshy, Dr. N.-u. H. Khan, Dr. S. H. R. Abdi,
Dr. H. C. Bajaj
Academy of Scientific and Innovative Research (AcSIR)
CSIR-CSMCRI
Bhavnagar 364021, Gujarat (India)
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/cplu.201402078.
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development of recyclable chiral catalysts, we have previously
reported Cu-catalyzed Henry/aza-Henry reactions of aldehydes/
imines with various nitroalkanes as active nucleophiles in the
presence of monomeric and dimeric macrocyclic salen and
[H4]salen ligands with the trigol, piperazine, 1,1’-bi-2-naphthol
(BINOL), and homopiperazine motif.[14d–f] Herein, we report the
synthesis of a polymeric [H4]salen ligand having inbuilt base
functionality (melamine–piperazine) as linker that can facilitate
the abstraction of protons from nitroalkane to form the nitro-
nate ion, which works as a nucleophile in the Henry and aza-
Henry reactions. The complex of [H4]salen ligand with Cu
metal ion was generated in situ and used for asymmetric
Henry and aza-Henry reactions with very low catalyst loading
(1 mol% with respect to the monomeric salen unit, the lowest
so far reported in the literature) and effective recyclability
(eight times reuse) of the active catalyst with preservation of
its catalytic activity and selectivity.
cyclable character of the catalyst as well as reducing the cata-
lyst loading. Accordingly, the polymeric salen ligands 1–3 were
synthesized by the interaction of (melamine–piperazine) tri-
meric aldehyde A with diamines of different bulkiness at the
chiral collar, namely (1R,2R)-(À)-1,2-diaminocyclohexane,
(1R,2R)-(+)-1,2-diphenyl-1,2-diaminoethane, and (R)-(+)-1,1’-bi-
naphthyl-2,2’-diamine, respectively, followed by reduction with
NaBH4 (Scheme 1).
Initial screening was conducted with all these ligands, which
possess different bulkiness in the diamine collar, in combina-
tion with Cu(OAc)2·H2O as metal source for the asymmetric
Henry reaction of 3,4-dimethoxybenzaldehyde and nitrome-
thane as model substrate by using ethanol and dichlorome-
thane solvent mixture at room temperature for 20 hours.
Among them, CuII-2 featuring the diphenyldiamine collar was
proved to be the best with respect to both yield and selectivi-
ty of the corresponding nitroalcohol (Table 1, entry 2).
Encouraged by the preliminary result with the optimized
catalyst and to ascertain an effective metal complex for the
catalytic reaction, we performed systematic screening of vari-
ous copper salts (both monovalent and divalent) with the
chiral ligand 2 (the most active and enantioselective). The ra-
tionale behind this is based on the concept that copper sour-
ces with different counterions are well known to form structur-
ally different complexes with a given ligand, and hence strong-
ly influence the catalytic activity. Among all the copper salts
screened it was found that Cu(OAc)2·H2O with the chiral
[H4]salen ligand 2 could generate an active catalyst to promote
the enantioselective addition of nitromethane to the 3,4-dime-
thoxybenzaldehyde giving an effective yield and selectivity in
20 hours (Figure 1). These results are in agreement with our
previous reports.[14d,f]
Results and Discussion
According to the mechanism of the Henry and aza-Henry reac-
tions, it is known that designing an efficient catalyst requires
the presence of cooperative activation of two reactive sites
(acidic and basic sites) for achieving the corresponding prod-
ucts in higher yield and enantioselectivity. The acidic site helps
to amplify the electrophilic nature of the carbonyl compounds
by binding with the lone pair of electrons of the carbonyl
group in the case of the Henry reaction, and with nitrogen
atoms in the case of the aza-Henry reaction. On the other
hand, basic sites are required for abstracting the proton from
the nitroalkane to generate the active nucleophile. The poly-
meric ligands, because of their high molecular weight, have
lower solubility in nonpolar solvent, and hence provide the re-
Table 1. Screening of the ligands 1–3.[a]
1
Entry
1
2
3
Yield[b] [%]
82
ee[c] [%]
81
Entry
2
Yield[b] [%]
90
ee[c][%]
92
Entry
3
Yield[b] [%]
84
ee[c] [%]
88
[a] All the reactions were performed with 0.5 mmol aldehyde and 5 mmol nitromethane for 20 h. [b] Yield of isolated product after flash column chroma-
tography.[c] Determined by Chiracel OD column.
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Scheme 1. Synthesis of polymeric [H4]salen ligands 1–3. Boc=tert-butoxylcarbonyl, THF=tetrahydrofuran.
The solvent is known to influence the activity and enantiose-
lectivity of a catalytic protocol. Therefore, a group of solvents
was screened for the asymmetric Henry reaction of 3,4-dime-
thoxybenzaldehyde and nitromethane as model substrate
(Table 2, entries 1–7). Aprotic solvents, such as THF, nitrome-
thane, diethyl ether, dimethylformamide (DMF), and acetoni-
trile (Table 2, entries 1, 2, 4–6), halogenated solvents such as di-
chloromethane (Table 2, entry 3), and mixed solvent (ethanol/
dichloromethane, 1:1; Table 2, entry 7) were used. Gratifyingly,
THF proved to be the most suitable solvent for this reaction in
view of the enantioselectivity and yield of the corresponding
b-nitroalcohol in 20 hours (Table 2, entry 1). Temperature had
a significant effect on the enantioselectivity of the product.
Lowering the temperature from room temperature (RT) to 0
and À108C showed a decreased yield of the product b-nitroal-
cohol without any increase in enantioselectivity (Table 2, en-
Figure 1. Variation of metal sources. Tf=trifluoromethanesulfonyl.
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Table 2. Optimization of solvent and reaction temperature.[a]
Entry
Solvent
T [8C]
Yield[b] [%]
ee[c] [%]
1
2
3
4
5
6
7
8
9
10
tetrahydrofuran
nitromethane
dichloromethane
diethyl ether
dimethylformamide
acetonitrile
ethanol/dichloromethane (1:1)
tetrahydrofuran
tetrahydrofuran
tetrahydrofuran
RT
RT
RT
RT
RT
RT
RT
À10
0
91
76
92
80
94
88
90
65
70
92
95
70
80
75
45
55
86
95
95
68
Figure 2. Variation of catalyst loading.
erature, and our own system containing inbuilt base functiona-
lity.[14d]
40
[a] All the reactions were performed with 0.5 mmol aldehyde and 5 mmol
nitromethane for 20 h. [b] Yield of isolated product after flash column
chromatography.[c] Determined by chiral cell OD column.
Inspired by the above observations under optimized reac-
tion conditions, next we evaluated the nitroaldol reaction pro-
tocol for various aldehydes having aromatic, aliphatic, or a,b-
unsaturated substituents with nitromethane and the results
are summarized in Figure 3. All the aldehydes used in the pres-
tries 8 and 9). On the other
hand, upon increasing the tem-
perature from room temperature
to 408C the yield of the corre-
sponding b-nitroalcohol was
little enhanced but there was
a detrimental effect on its enan-
tioselectivity (Table 2, entry 10).
Hence, room temperature was
the optimized temperature for
giving an excellent yield (91%)
of the corresponding b-nitroal-
cohol with 95% enantioinduc-
tion (Table 2, entry 1).
For its consequences in poten-
tial industrial processes, the cata-
lyst loading was further assessed
for a wide range of values from
0.5 to 2 mol% with respect to
the representative substrate 3,4-
dimethoxybenzaldehyde. It was
found that 1 mol% of the cata-
lyst was sufficient to provide ex-
cellent yield (85%) and enantio-
selectivity (95%) in 20 hours
(Figure 2), whereas 2 mol% of
the catalyst was able to produce
the desired product in high yield
(89%) in less reaction time but
with a decrease in enantiomeric
excess ee (81%). Hence, 1 mol%
catalyst loading is considered as
optimum. These results are su-
perior in terms of the lowest cat-
alyst loading reported so far for
Figure 3. Variation of substrates under the optimized reaction conditions with nitromethane. TOF=turnover fre-
the systems described in the lit- quency.
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ent study underwent nitroaldol reaction to give the corre-
sponding b-nitroalcohol in good to excellent yields of isolated
products (68–90%) and with moderate to excellent enantiose-
lectivity (ee, 64–98%) depending on the substituents on the
substrate. The highest ee value of up to 98% accompanied by
an 88% yield was furnished for 4-methoxybenzaldehyde.
To further investigate this reaction protocol, several less ex-
plored nitroalkanes (nitroethane and 1-nitropropane) other
than nitromethane were then evaluated with various alde-
hydes (Table 3). High yields (95%) with excellent enantioselec-
Table 4. Screening of the solvent for the asymmetric aza-Henry reaction
of N-Ts-benzylimine with nitromethane.[a]
Entry Solvent
Catalyst loading [mol%] T [8C] Yield[b] [%] ee[c] [%]
1
2
3
4
5
6
7
8
9
acetonitrile
EtOH+CH2Cl2
MeOH+CH2Cl2
THF
THF
THF
THF
THF
THF
THF
1
1
1
0.5
1
1.5
2
1.5
1.5
1.5
RT
RT
RT
RT
RT
RT
RT
56
58
50
56
62
68
69
64
54
50
75
82
85
80
78
76
65
Table 3. Variation of substrates at the optimized reaction conditions with
nitroethane and 1-nitropropane.[a]
À10 52
0
57
69
10
40
[a] All the reactions were performed with 0.5 mmol substrate and 5 mmol
nitromethane at RT for 25 h. [b] Yield of isolated product after flash
column chromatography. [c] Determined by chiral cell OD, AD, IC, IA col-
umns.
Entry
R
R’
Yield[b] [%]
syn:anti[c]
ee[d] [%]
syn
anti
1
2
3
4
5
6
7
8
C6H5
Me
Me
Me
Me
Et
Et
Et
Et
88
90
84
95
87
92
86
94
91:9
98
85
88
85
85
98
82
98
64
58
52
62
35
62
61
61
model substrate with nitromethane in the presence of CuII-2
as active complex in different solvents, namely acetonitrile,
THF, and mixtures of solvents (EtOH+CH2Cl2 and MeOH+
CH2Cl2), for which THF was the solvent of choice (Table 4,
entry 6). Next, the loading of the catalyst was varied from 0.5
to 2 mol% (Table 4, entries 4–7) and the reaction temperature
from À10 to 408C (Table 4, entries 8–10) in the presence of
THF. It is evident from the results that 1.5 mol% catalyst load-
ing at room temperature is optimum in THF as solvent
(Table 4, entry 6).
3-MeO-C6H5
4-F-C6H5
4-NO2-C6H5
C6H5
2-F-C6H5
2-Br-C6H5
4-NO2-C6H5
87:13
74:26
92:08
86:14
72:28
64:36
78:22
[a] All the reactions were performed with 0.5 mmol aldehyde and 5 mmol
nitroalkane at RT for 20 h. [b] Yield of isolated product after flash column
chromatography. [c] Determined from 1H NMR spectra. [d] Determined by
chiral cell OD, AD, IC, IA columns.
With these optimized reaction conditions, a series of N-tosy-
limines having different substituents at the aromatic ring were
tested with nitromethane to find the generality of substrate
scope in the aza-Henry reaction (Scheme 2). A moderate yield
(78%) of b-nitroamines with high enantioinduction (up to
ee 94%) was achieved at room temperature in THF. However,
no clear trend was observed for the electronic effect of the
substituents on the yield as well as on selectivity. These results
of the aza-Henry reaction using the active complex CuII-2 are
quite comparable to those of the reaction with aromatic alde-
hydes.
tivities (98%) and moderate to good diastereoselectivities (up
to 90:10, favoring the syn product) were achieved. It was ob-
served that the electronic properties and the steric hindrance
of the aromatic aldehydes have a limited effect on the diaste-
reoselectivity and enantioselectivity of the corresponding prod-
uct. A probable working model of the catalytic system for fa-
voring the syn diastereomer was proposed by the Newman
projection in Figure 4.
Kinetics of the reaction
To understand the dependence
of the reaction on catalyst load-
ing, substrate concentration, and
nitromethane concentration and
Figure 4. Newman projections of transition states (TSs) for the diastereoselective nitroaldol reaction.
to find out a probable reaction
mechanism of the asymmetric
aza-Henry reaction, we studied
To further explore the catalytic application of the present
system, this protocol was extended for the asymmetric aza-
Henry reaction of various N-tosylimines with nitromethane. To
begin with the optimized reaction conditions, we conducted
the aza-Henry reaction using N-Ts-benzylimine (Ts=tosyl) as
the kinetics of the CuII-2 complex generated in situ from
ligand 2 and Cu(OAc)2·H2O as catalysts for the aza-Henry reac-
tion of the N-Ts-benzylimine as substrate with nitromethane at
room temperature.
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Scheme 2. Variation of substrates for the asymmetric aza-Henry reaction with nitromethane.
Effect of concentration of catalyst on reaction rate
with fixed concentrations of N-Ts-benzylimine and catalyst with
variable concentration of nitromethane (0.5–2.5m). The kobs
values were found at the different concentrations of nitrome-
thane in a similar way to the catalyst concentration variation.
In this case also, the plot of logkobs against log[nitromethane]
(Figure 6) gave a straight line with a slope of almost unity, thus
indicating the first-order dependency of the reaction on nitro-
methane concentration.
To screen the effect of catalyst concentration on the rate of re-
action (kobs), we performed the aza-Henry reaction of N-Ts-ben-
zylimine with nitromethane at different concentrations of the
catalyst CuII-2 (0.69–3.75 mm) keeping all other parameters
identical. The kobs at each concentration of the catalyst was ob-
tained by plotting the log[product] against the time at three
different time intervals (60, 180, and 300 min) at that particular
concentration of the catalyst, and from the slope of the plot
the kobs values were obtained. The plot of logkobs versus log[
catalyst] (Figure 5) gives a straight line with slope of approxi-
mately 1, which indicates the first order with respect to the
catalyst concentration.
Effect of concentration of nitromethane on reaction rate
To find out the effect of nitromethane (nucleophile) concentra-
tion on reaction rate, we performed the aza-Henry reaction
Figure 6. Plot of logkobs versus log[nitromethane] at RT, [catalyst]=2.5 mm,
[imine]=0.25m.
Variation of imine concentration
For further evaluating order with respect to N-Ts-benzylimine,
the aza-Henry reaction of N-Ts-benzylimine was performed
with substrate concentrations ranging from 0.1 to 0.35 mm.
The plot of logkobs for different concentrations of the imine
versus log[imine] gave zero-order dependence of the rate on
the substrate concentration (Figure 7).
Figure 5. Plot of logkobs versus log[catalyst] at RT, [imine]=0.25 mm, [nitro-
methane]=1.0 mm.
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Figure 7. Plot of logkobs versus log[imine] at RT, [catalyst]=2.5 mm, [nitro-
methane]=1m.
To support the mechanism (Scheme 3) of the catalytic aza-
Henry reaction, a stepwise UV–visible spectral study was per-
formed with N-Ts-benzylimine and nitromethane in THF as sol-
vent at room temperature (Figure 8). After addition of sub-
strate to the solution of the complex, both the d–d and
ligand-to-metal charge transfer (LMCT) bands showed a blue-
shift with isosbestic points at approximately 420 and 595 nm.
These observations confirm the direct coordination of the sub-
strate to the copper complex through the lone pair of the ni-
trogen atom of the N-Ts-benzylimine. The generation of the
isosbestic points may result from the changes in the geometry
of the copper complex on complexation of substrate to the
copper. On further addition of nitromethane to the reaction
Figure 8. Stepwise UV/Vis spectra recorded in THF: A) ligand, B) complex,
C) complex and substrate, D) complex, substrate, and nitromethane (after
1 h), E) complex, substrate, and nitromethane (after 10 h).
mixture, we did not observe a considerable blueshift without
an isosbestic point (ꢀ437 nm) confirming further changing of
the geometry of the copper complex.
To perform a recycling study of the catalytic protocol using
CuII-2 as catalyst, benzaldehyde with nitroethane were chosen
as the model substrates with 1 mmol aldehyde in THF at room
temperature. After eight successive cycles of the catalytic
system, there was no significant change in the activity, enan-
Scheme 3. Probable mechanism for the asymmetric aza-Henry reaction. R.D.S. =rate-determining step.
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Figure 9. Recycling study of CuII-2 with benzaldehyde and nitroethane as model substrates.
tioselectivity of the syn and anti products, or diastereomeric
excess (de) of the b-nitroalcohol (Figure 9). To confirm the sta-
bility of the recovered catalyst during the course of the asym-
metric nitroaldol reaction, the IR spectra (Figure 10) were re-
corded for both virgin catalyst and recovered catalyst. The
spectra matched well, which suggests that no major structural
changes had taken place during the course of the post-catalyt-
ic workup procedure.
As a synthetic relevance of this asymmetric catalytic proce-
dure, (R)-tembamide, a naturally occurring hydroxyamide (hy-
poglycemic agent)[16] isolated from various members of the Ru-
taceae family,[17] was synthesized from 4-methoxybenzaldehyde
with nitromethane to give the corresponding nitroalcohol (A)
in 88% yield and 98% ee on the 50 mmol scale (Scheme 4).
Catalytic hydrogenation of A in the presence of 10% Pd/C in
methanol gave the corresponding amino alcohol (B) in 92%
yield followed by condensation with benzoyl chloride; the final
product was obtained in good yield and enantioselectivity.
Conclusion
We have developed a new, recyclable, polymeric chiral CuII-
[H4]salen catalyst for both the asymmetric Henry and aza-
Henry reactions with good substrate generality. The catalytic
system works well with very low catalyst loading (1 mol%) to
produce the corresponding products in moderate to high
yields with excellent enantioselectivities as well as diastereose-
lectivities in the case of nitroethane and 1-nitropropane, using
THF as solvent at room temperature. The catalytic system was
recycled and reused for eight consecutive catalytic runs with
Figure 10. IR spectra of ligand 2, CuII-2, and CuII-2 after eight cycles.
Scheme 4. Synthesis of (R)-tembamide.
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1946, 68, 12–14; d) D. Lucet, T. Le Gall, C. Mioskowski, Angew. Chem.
1998, 110, 2724–2772; Angew. Chem. Int. Ed. 1998, 37, 2580–2627.
[11] R. Ballini, M. Petrini, Tetrahedron 2004, 60, 1017–1047.
[12] H. Sasai, T. Suzuki, M. Shibasaki, J. Am. Chem. Soc. 1992, 114, 4418–
4420.
virtually the same activity and selectivity. The valuable drug
(R)-tembamide (hypoglycemic agent) was synthesized starting
from 4-methoxybenzaldehyde with good yield and enantiose-
lectivity. Based on our knowledge this catalytic protocol
worked well at a very low catalyst loading, the lowest so far re-
ported for both Henry and aza-Henry reactions.
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Experimental Section
Preparation of chiral polymeric [H4]salen ligands 1–3
A solution of trialdehyde A (2 mmol) in THF (10 mL) was added to
a solution of (1R,2R)-(À)-1,2-diaminocyclohexane/(1R, 2R)-(+)-1,2-di-
phenyl-1,2-diaminoethane and (R)-(+)-1,1’-binaphthyl-2,2’-diamine
(3.2 mmol) in THF (10 mL). The resulting mass was heated at reflux
for 3 h (checked by TLC). The resulting dark yellow solution was
cooled to room temperature followed by reduction with NaBH4 to
obtain the polymeric ligands 1--3.[18] (Data are given in the Sup-
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Acknowledgements
CSMCRI Communication No. 035/2014. A.D. and R.I.K. are grateful
to DST and CSIR-Indus Magic Project CSC0123 for financial assis-
tance. A.D. is grateful to UGC for awarding SRF and to AcSIR for
Ph.D. registration. We are also grateful to the Analytical Disci-
pline and Centralized Instrument Facility of CSMCRI for providing
instrumental facilities.
Keywords: asymmetric catalysis · enantioselectivity · Henry
reaction · kinetics · polymeric ligands
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Received: March 24, 2014
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Published online on && &&, 0000
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ChemPlusChem 0000, 00, 1 – 10
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9
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These are not the final page numbers!

FULL PAPERS
A. Das, M. K. Choudhary, R. I. Kureshy,*
T. Roy, N.-u. H. Khan, S. H. R. Abdi,
H. C. Bajaj
&& – &&
Enantioselective Henry and Aza-Henry
Reaction in the Synthesis of (R)-
Tembamide Using Efficient, Recyclable
Polymeric CuII Complexes as Catalyst
Henry the eighth: Chiral polymeric CuII-
[H4]salen (salen=bis[(salicylidene)ethyl-
enediaminato]) complexes are efficient
catalysts in the asymmetric Henry and
aza-Henry reaction of various aromatic
and aliphatic aldehydes and N-tosyli-
mines in the presence of nitroalkanes,
with very low catalyst loading (see
figure). Upon recycling the catalyst, the
yield, enantiomeric excess (ee), and dia-
stereomeric excess (de) were unchanged
for up to eight cycles.
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ChemPlusChem 0000, 00, 1 – 10
&10
&
ÞÞ
These are not the final page numbers!