Asymmetric Henry reaction catalyzed by chiral Cu(II) salalen and salan complexes derived from (S)-proline

Article abstract of DOI:10.1016/j.ica.2018.04.048

Single chiral center C₁ symmetric salalen and salan ligands were synthesized from (S)-proline and their Cu(II) complexes were used as catalysts for the asymmetric Henry reaction between aromatic aldehydes and nitromethane/nitroethane. The react

Full text of DOI:10.1016/j.ica.2018.04.048

Accepted Manuscript
Research paper
Asymmetric Henry reaction catalyzed by chiral Cu(II) salalen and salan com-
plexes derived from (S)-proline
Ashish Dixit, Pramod Kumar, Geeta Devi Yadav, Surendra Singh
PII:
S0020-1693(18)30063-X
https://doi.org/10.1016/j.ica.2018.04.048
ICA 18239
DOI:
Reference:
Inorganica Chimica Acta
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12 January 2018
20 April 2018
24 April 2018
Please cite this article as: A. Dixit, P. Kumar, G.D. Yadav, S. Singh, Asymmetric Henry reaction catalyzed by chiral
Cu(II) salalen and salan complexes derived from (S)-proline, Inorganica Chimica Acta (2018), doi: https://doi.org/
10.1016/j.ica.2018.04.048
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Asymmetric Henry reaction catalyzed by chiral Cu(II) salalen and salan
complexes derived from (S)-proline
Ashish Dixit, Pramod Kumar, Geeta Devi Yadav and Surendra Singh*
Department of Chemistry
University of Delhi, Delhi 110007
Email: ssingh1@chemistry.du.ac.in
Abstract: Single chiral center C1 symmetric salalen and salan ligands were synthesized from (S)-proline and their
Cu(II) complexes were used as catalysts for the asymmetric Henry reaction between aromatic aldehydes and
nitromethane/nitroethane. The reaction of 4-nitrobenzaldehyde and nitromethane using salalen ligand (10 mol%) and
Cu(OAc)2.H2O (10 mol%) in isopropanol with 4-methoxyphenol (10 mol%) as an additive at room temperature,
afforded the (S)-2-nitro-1-(4-nitrophenyl)ethanol in 82% yield and 81% ee. We have also generalized the catalysis
of nitro-aldol reaction for a variety of substrates using nitromethane, gave 67–94% yields with 46–98% ee after 96–
120h. The absolute configuration of nitro-aldol product was governed by the use of the metal, Mn(III) complex of
the ligand 2 gives (R)-enantiomer while Cu(II) complex of same ligand gives the (S)-enantiomer.
Key words: Cu(II) Salalen complex, Henry reaction, (S)-Proline, Asymmetric Nitro-aldol reaction and C1-
Symmetric ligand
1. Introduction
The Henry reaction (nitro-aldol reaction) is very efficient and atom economic method for the
formation of C-C bond.1-2 The asymmetric version of this reaction attracts more attention of the
chemists since 1992, when Shibasaki and co-workers reported the reaction.3 The products of
nitro-aldol reactions are β-nitro alcohols, which contains two functional groups (i.e. nitro and
hydroxyl groups), can easily be transformed to the β-amino alcohols, α-hydroxy acids, α-
hydroxy ketones, and other various biological active compounds.4-8
Asymmetric nitro-aldol reaction catalyzed by various transition metal complexes9-30 as well as
rare earth metal complexes30-33 been developed in last two decades. Beside chiral metal
complexes, organocatalysts35-40 and biocatalysts41-42 were also used in asymmetric nitro-aldol
raection. Salen ligands are one of the most privileged ligands in asymmetric catalysis and Cu(II)
complexes of salen and salan were largely used for this reaction because these can be generated
in situ and efficiently working at mild reaction conditions.43-52 (S)-Proline based single chiral
center salalen and salan ligands are useful for the asymmetric epoxidation of non-functionalised
alkenes,53 polymerisation of -olefins54 and stereoselective polymerization of lactide.55,56
Recently we have reported the Mn(III) salalen and salan complexes derived from (S)-proline for
asymmetric Strecker and Henry reactions.57,58 Herein, we wish to report Cu(II) salalen and salan
complexes for asymmetric nitro-aldol reaction at room temperature.
2. Experimental
1

2.1. Materials and Methods
All reagents were purchased commercially and used as received. HPLC grade isopropyl alcohol
was used as solvent for the reactions. Proton and carbon nuclear magnetic resonance spectra (1H
and 13C NMR, respectively) were recorded on 400 MHz (operating frequencies: 1H, 400.13
MHz; 13C, 100.61 MHz) Jeol-FT-NMR spectrometers at ambient temperature. In the case of 1H
and 13C NMR spectra, the chemical shifts () for all compounds are listed in parts per million
downfield from tetramethylsilane using the NMR solvent as an internal reference. The reference
values used for deuterated chloroform (CDCl3) were 7.26 and 77.00 ppm for 1H and 13C NMR
spectra, respectively. High resolution mass spectra were measured on an Agilent instrument.
Optical rotation values were measured on a Rudolph digital polarimeter. Thin layer
chromatography (TLC) was carried out using Merck Kieselgel 60 F254 silica gel plates. Column
chromatographic separations were performed using silica gel (200–400 mesh). All the new
compounds were characterized by 1H and 13C NMR and mass spectroscopy and the known
compounds was characterized by 1H-NMR. The enantiomeric excess was determined using
Schimadzu 2010 HPLC using Chiralpak AD-H, Chiralcel OD-H and Chiralpak IC as chiral
columns. The details on the crystal structure data can be obtained from the Cambridge
Crystallographic Data Centre via www.ccdc.chem.ac.uk/data_request/cif, on quoting the
depository numbers CCDC 1411751.
2.2. Synthesis of Ligands 1-6
Synthesis of ligands 1-6 were carried out using our earlier reported procedures.57 Here we are
giving procedure of the synthesis ligand 2 and its spectroscopic data. Synthesis of precursors of
the ligands was also reported in our earlier report.57
2.2.1. (S)-2-tert-butyl-6-(((1-(3-tert-butyl-2-hydroxybenzyl)pyrrolidin-2-
yl)methylimino)methyl)phenol (2)
(S)-2-((2-(Aminomethyl)pyrrolidin-1-yl)methyl)-6-tert-butylphenol (498 mg, 1.9 mmol) was
taken in methanol (10 mL) and 3-tert-butyl-2-hydroxy-benzaldehyde (338 mg, 1.9 mmol, in
methanol (5 mL)) was added drop wise over a period of 30 min. Reaction mixture was stirred for
30 min at room temperature to give a yellow precipitate of ligand 2 (627 mg, 78%). M.p. =
102.4 C. [α]D27 = - 29.69 (c 1 in CH2Cl2). 1H NMR (CDCl3, 400 MHz): δ = 13.73 (s, 1H), 7.31
(d, J = 8.05 Hz, 1H), 7.17 (d, J = 7.32 Hz, 1H), 7.10 (d, J = 7.32 Hz, 1H), 6.85 (d, J = 7.32 Hz,
1H), 6.80 (t , J = 7.32 Hz, 1H), 6.70 (t, J = 7.32 Hz, 1H), 4.21 (d, J = 13.91 Hz, 1H), 3.85–3.78
(m, 1H), 3.68–3.62 (m, 1H), 3.58 (d, J = 13.91 Hz, 1H), 3.10–2.92 (m, 2H), 2.43–2.30 (m, 1H),
2.17–2.03 (m, 1H), 1.90–1.74 (m, 3H), 1.43 (s, 9H), 1.38 (s, 9H) ppm. 13C NMR (CDCl3, 100
MHz): δ = 167.11, 160.28, 156.76, 137.26, 129.81, 129.41, 126.08, 125.76, 122.70, 118.58,
118.14, 117.78, 64.70, 62.97, 58.63, 54.31, 34.79, 34.59, 29.40, 29.28, 22.96 ppm. FTIR (KBr) υ
+
= 3051, 2959, 1635, 1046 cm-1. ESI MS calcd. for C27H39N2O2 [M+H]+ 423.3006; found
423.3030.
2

2.3. General procedure for the catalytic asymmetric nitro-aldol reaction
The mixture of salalen ligand 2 (21.1 mg, 10 mol%), Cu(OAc)2.H2O (9.9 mg, 10 mol%) and
CH3NO2 (265 µL, 10 eq.) was stirred for 1 h at room temperature in iso-propanol (2.0 mL), then
4-methoxyphenol (6.2 mg, 10 mol%) was added and reaction mixture further stirred for 0.5 h, at
the end benzaldehydes/substituted benzaldehydes (0.5 mmol) was added. Reaction mixture was
stirred for specified time and monitored by TLC. Solvent was evaporated by rotary evaporator
and nitro-aldol product was purified by column chromatography on silica gel (hexane/ethyl
acetate 80:20). The ee’s were determined by HPLC using Chiralcel OD-H, AD-H and IC
column. HPLC chromatogram and copy of 1H-NMR and 13C-NMR spectra of the nitro-aldol
products are given in SI.
2.3.1. 2-Nitro-1-phenylethanol (Table 3, entry 1)30
Yellow oil, Yield: 122 mg (73%), ee: 95%. HPLC Conditions: Chiralcel OD-H, hexane/iPrOH,
90:10 v/v, 0.8mL/min, 25 oC, UV λmax 230 nm): tr (minor) = 15.46 min, tr(major) = 17.36 min.
= +21.26 (C 0.40 CH2Cl2). 1H NMR (400 MHz, CDCl3):  = 7.60-7.30 (m, 5H), 4.44 (dd, J
= 9.2, 2.8 Hz, 1H), 4.59 (dd, J = 13.2, 9.2 Hz, 1H), 4.49 (dd, J = 13.2, 3.2 Hz, 1H), 2.90 (brs,
1H) ppm. 13C NMR (100 MHz, CDCl3):  = 138.1, 129.0 (2C), 128.9, 125.9 (2C), 80.2, 70.9
ppm.
3. Results and Discussion
The C1-symmetric chiral salalen (1–3) and salan (4–6) ligands shown in figure 1 were
synthesized from (S)-proline and detailed procedure for synthesis is reported in our earlier
report.57 The Cu(II) complexes of these ligands (1–6) were generated in situ with Cu(OAc)2.H2O
in iso-propanol (IPA) and used as catalysts for asymmetric Henry (nitro-aldol) reaction.
Figure 1. Structures of ligands 1-6.
3.1. Crystal structure of the Cu(II) complex of ligand 2
Copper complex of ligand 2 was prepared in iso-propanol by using Cu(OAc)2.H2O : ligand 2
(1:1) at room temperature and after removal of iso-propanol, single crystal of complex was
obtained by crystalizing in dichloromethane. The structure of Cu(II) complex of ligand 2 was
confirmed by single crystal X-ray study. Complex of ligand 2 crystallizes in the chiral space
3

group P21 and consists of one Cu(II) ion and one dianoinic L (Fig 2). The distorted square
planar Cu(II) is coordinated by two oxygen atoms and two nitrogen atoms from ligand 2 (L2-).
The Cu(II) atom deviates by 0.036 Å from the mean plane constituted by four ligating atoms.
Thus L2- acts as a tetratopic chelating unit. The bond lengths of Cu-O [Cu-O1 = 1.896(2) Å, Cu-
O2 = 1.888(2) Å ] and for Cu-N [ Cu-N1 = 2.026(2), Cu-N2 = 1.916(2) Å], are similar to the
many of Cu(II) salen complexes.57-59 From the X-ray structure of complex of ligand 2, it is
confirmed that pyrrolidine ring adopted the envelop-shaped conformation with nitrogen atom out
of the plane from the remaining four carbon atoms. In the crystal structure each molecule
interacts with a neighboring molecule through C-H…..π interaction [d(C21···C26π) = 3.755 Å;
C-H···π = 162.96°] resulting in the formation of zig-zag chain. Ligand 2 showed absorption band
at 272 nm and 338 nm, the 338 nm absorption may be assigned to n-π* transition in ligand. The
crystal of the isolated Cu(II) complex of ligand 2 the band at 338 nm was shifted to 388 nm (red
shift), which may be due to ligand to metal charge transfer of non-bonding lone pair of the
phenoxide oxygen to the d-orbital of the Cu(II) i.e., LMCT. It affirms the complex formation of
the ligand 2 with the Cu(OAc)2.H2O.
Figure 2. Crystal structure of Cu(II) complex of ligand 2.
3.2. Optimization of the reaction conditions for Henry reaction
3.2.1. Screening of different ligands
Initially, we have screened the ligands 1–6 (5 mol%) with Cu(OAc)2.H2O (5 mol%) in iso-
propanol (IPA) for the reaction of 4-nitrobenzaldehyde (7) and nitromethane at 25 °C. Yields of
the (S)-2-nitro-1-(4-nitrophenyl)ethanol (8) were better with salen ligands (4–6) compared to
salalen ligands (1–3) but the enantiomeric excesses (ee’s) were better in case of salalen ligands
(1–3) (Table 1, entries 1–6). The ee of product (S)-2-nitro-1-(4-nitrophenyl)ethanol (8) was
better with salalen ligand 2 compared to other salalen ligands 1 and 3. These preliminary results
show that bulky group like tert-butyl group(s) at different position on phenol in a ligand made a
significant influence on yield and ee of the product 8. 2-tert-Butyl group on phenol in salalen
ligand (2) induced better ee compared to 2,4-di-tert-butyl group on phenol in salalen ligand (1)
and 4-tert-butyl group on phenol in a salalen ligand (3). Similar trends were observed with salan
ligands 4–6 (Table 1, entries 4–6). We have also screened Cu(II) salts with salalen ligand 2 for
the asymmetric nitro-aldol reaction at room temperature in IPA. The Cu(OAc)2.H2O was only
4

found to be good source of Cu(II) for the nitro-aldol reaction compared to other salts,
Cu(NO3)2.3H2O and CuCl2.2H2O did not catalyze the reaction (entries 2, 7 and 8).
Table 1. Screening of different ligands for asymmetric nitro-aldol reaction.a
Entry
Ligand
Cu source
Yieldb
19
30
53
62
86
90
No
ee (%)c
50
67
33
17
22
15
-
1
2
3
4
5
6
7
Cu(OAc)2.H2O
Cu(OAc)2.H2O
Cu(OAc)2.H2O
Cu(OAc)2.H2O
Cu(OAc)2.H2O
Cu(OAc)2.H2O
CuCl2.2H2O
1
2
3
4
5
6
2
reaction
8
9
Cu(NO3)2.3H2O
No
reaction
-
2
-
Mn(III) complex of 81
-17
ligand 2
a Ligand 1-6 (5 mol %) was dissolved in iso-propanol (2 mL), Cu(OAc)2.H2O (5 mol %), CH3NO2 (10 eq., 5 mmol)
and nitrobenzaldehyde (0.5 mmol) were added and stirred at 25 °C for 20 h. b Yield of isolated product after
purification by column chromatography. c Enantiomeric excess was determined by HPLC using a Chiralpak OD-H
column and absolute configuration of product was determined by comparison of optical rotation with literature
value.
The interesting observation is that the nitro-aldol reaction using Mn(III) salalen complex of
ligand 2 giving opposite enantiomer of product 8 in 81% yield with 17% ee (Table 1, entry 9).58
The absolute configuration of the nitro-aldol product is governed by the metal (Mn and Cu) with
same configuration of (S)-ligand (2). It is worthy that different metal complex of same ligand 2
can give two different enantiomers. Reversible enantioselectivity in Henry reaction also observed
by Wu et al using complex of C2-symmetric ligand by changing Co(II) to Yb(III).62
3.2.2. Effect of solvent, temperature and additive on catalysis of Henry Reaction
Effect of temperature, solvent, catalyst loading and additive on asymmetric Henry reaction using
4-nitrobenzaldehyde and nitromethane as substrate catalyzed by Cu(II) complex of ligand 2 were
evaluated. Initially, we have varied reaction temperature in a range of 20–35 C for the
asymmetric nitro-aldol reaction of 4-nitrobenzaldehyde (7) with nitromethane using ligand 2 (5
mol%) and Cu(OAc)2.H2O (5 mol%) in IPA at 20 C, gave product (S)-2-nitro-1-(4-
nitrophenyl)ethanol (8) in lower yield 19%, than room temperature 25 C (Table 2, entries 1 and
5

2). When temperature was increased from 25 C to 35 C, yield of the product 8 was slightly
improved but ee was decreased (entry 3). In order to improve the catalytic activity, the loading of
catalyst increased to 10 mol% at 25 C and yield of nitro-aldol product (8) improved up to 43%
with 65% ee (entry 4). Solvent makes a significant influence on the yield as well as on ee. We
have screened different solvent or solvent systems for the reaction and IPA was found to be best
choice of solvent for the reaction (entries 5–8). These investigation, led us to use ligand 2 and
Cu(OAc)2.H2O (10 mol%) in IPA at room temperature (25 C) for this reaction. The literature
reports show that additives like bases and phenols were known to influence the yield and ee.48
Initially, we used various bases as additives (10 mol%) like CsCO3, lutidine, triethylamine
(TEA) and diisopropylethylenediamine (DIPEA), afforded racemic products in 60–91% yields
after 3–20 h. Racemic product formation is due to background reaction of nitromethane and 4-
nitrobenzaldehyde catalyzed by base at room temperature (entries 9–12).61 We also tested
benzoic acid as an additive and product 8 obtained in 64% yield after 50 h but again ee was
lower (entry 13). Later we used some phenolic additives such as 4-methoxyphenol and 4-tert-
butylphenol, afforded product in 47–70% yields but in case of 4-methoxyphenol the ee was 74%
(entries 14 and 15). Additive phenol may form the hydrogen bonding with oxygen of enolate of
nitromethane which shown in figure 3 and results of these two additive show that strong
hydrogen bonding is stabilizes the nitroenolate therefore increases the reactivity.
N
N
H
O
OMe
H
O
O
O
O
O
(I)
(II)
Figure 3. Hydrogen bonding between nitro enolate and 4-methoxyphenol and 4-tert-butylphenol.
Table 2. Optimization of reaction conditions.a
6

Entry
Additive
Solvent
Time Yieldb eec
(h)
1
2
3
4
5
6
7
8
-
-
-
-
-
-
-
-
IPA
IPA
IPA
IPA
20
20
20
20
19
30
43
53
43
23
55
-
91
60
84
91
47
64
70
47
67d
67e
55f
65
66
50
33
-
0
0
0
0
IPA/DCM (1/0.5) 20
MeOH
IPA/THF (1/0.5)
Toluene
IPA
IPA
IPA
20
20
40
7
13
20
3
21
50
50
50
9
CsCO3
DIPEA
Lutidine
TEA
Triphenylphosphine IPA
Benzoic acid
10
11
12
13
13
14
15
IPA
0
IPA
IPA
IPA
51
44
74
4-tert-butylphenol
4-methoxyphenol
a Ligand 2 (10 mol %) was dissolved in solvent (2.0 mL), Cu(OAc)2.H2O (10 mol %), CH3NO2 (10 eq., 5 mmol),
additive (10 mol%) and nitrobenzaldehyde (0.5 mmol) were added and stirred at 25 °C for 20 h. b Yield of isolated
c
product after purification by column chromatography. Enantiomeric excess was determined by HPLC using a
Chiralpak OD-H column and absolute configuration of product was determined by comparison of optical rotation
with literature value. d Ligand (5 mol%) and Cu(OAc)2.H2O (5 mol%) was used at 20 °C. e Ligand (5 mol%) and
Cu(OAc)2.2H2O (5 mol%) was used at 25 °C. f Ligand (5 mol%) and Cu(OAc)2.2H2O (5 mol%) was used at 35 °C.
3.2.3. Plausible mechanism for Henry reaction
We have proposed the plausible mechanism for the Henry reaction between 4-nitrobenzaldehyde
and nitromethane catalyzed by in situ generated Cu complex of ligand 2 (Figure 4). Ligand 2
treated with Cu(CH3COO)2.H2O to generate a complex CuL* and acetate anions. Acetate anion
acts as base to abstract a proton of the nitromethane to form nitro enolate. The oxygen of nitro
enolate and oxygen of 4-nitrobenzaldehyde interact with CuL*. The transition state (a) of figure 5
indicate that the Si-face arrangement of 4-nitrobenzaldehyde is hindered by the imine part of
ligand and found to be disfavored. Another transition sate (b) in figure 5 is favorable since 4-
nitrobenzaldehyde is far away from the imine part of ligand and attacks of nucleophile nitro
enolate on the Re-face of 4-nitrobenzaldehyde giving the (S)-enantiomer of the nitro-aldol
product 8.
7

Figure 4. Plausible mechanism for Henry reaction catalyzed by Cu(II) complex.
Figure 5. Transition state for in situ generated complex of Cu(OAc)2.2H2O and salalen ligand 2 catalysed
Henry reaction
Nitro-aldol reaction between 4-nitrobenzaldehyde catalyzed by salalen Mn(III)-Cl complex is
giving an opposite enantiomer of nitroaldol product compared to its salalen Cu(II) complex.
Mn(III) in salalen complex is penta-coordinated and the chloride is in apical position this
restricts interaction of 4-nitrobenzaldehyde and nitro enolate from the plane where Cl is located.
8

As a result, the substrates approaches Mn(III) in a plane opposite to Cl which enables the
formation of opposite enantiomer (Figure 6).
Figure 6. Crystal structures of Mn(III)Cl salalen complex57
The interaction of 4-nitrobenzaldehyde and nitro enolate approaches Mn(III) in a plane opposite
to Cl and nitro enolate is attacking on the Re-face of the 4-nitrobenzaldehyde which give (R)-
enantiomer of product 8 (Figure 7).
Figure 7. Transition state for Mn(III)salan complex catalyzed Henry reaction
3.2.4. Scope and limitation of the catalytic system
After optimizing the reaction conditions, the scope and limitations of methodology was
examined with a variety substrates (aldehydes) for the asymmetric nitro-aldol reaction by using
ligand 2 (10 mol%), Cu(OAc)2.H2O (10 mol%) and 4-methoxyphenol (10 mol%) as an additive
in IPA at 25 °C, in all the cases we have obtained (S)-β-nitro alcohols as nitro-aldol products
(Table 3). The simplest aromatic aldehyde such as benzaldehyde gave β-nitro alcohol in a 73%
yield with 95% ee after 120 h (Table 3, entry 1). Benzaldehyde substituted with electron
withdrawing group like 4-nitro and 2-nitro took less reaction time (96 h) and yielded
corresponding products in 82-84% with 61-81% ee’s (entries 2 and 3). Benzaldehyde substituted
with electron donating group like 4-methoxy and 2- methoxy took longer reaction time, gave
corresponding nitro-aldol products in 67–68% yields with 49–88% ee’s after 120 h (entries 4 and
5). Nitro-aldol products of 2-methyl and 4-methylbenzaldehyde were obtained in 67–71% yields
with excellent ee up to 98% after 120 h. The halogenated benzaldehyde like 2-bromo and 4-
bromobenzaldehyde gave 72–78% yields with 64–76% ee (entries 8 and 9). In case of chloro and
fluoro substituted benzaldehyde gave corresponding nitro-aldol products in better ee’s compared
9

to nitro-aldol products obtained from bromo substituted benzaldehyde (entries 8–13). We have
also used 1-napthaldehyde as substrate and gave 82% yield of the product but ee was poor
compared to nitro-aldol product of benzaldehyde (entry 14).
Table 3. Nitro-aldol reaction of variety of aldehydes with nitromethane.a
eec (%)
Entry
R
Time (h) Yieldb
(%)
1
2
3
4
5
6
7
8
C6H5
120
96
96
120
120
120
120
96
96
96
96
96
73
82
84
68
67
67
71
78
72
80
94
70
76
82
95
81
61
49
88
97
98
64
76
91
90
90
90
49
4-NO2C6H4
2-NO2C6H4
4-OMeC6H4
2-OMeC6H4
4-MeC6H4
2-MeC6H4
4-BrC6H4
2-BrC6H4
4-FC6H4
9
10
11
12
13
14
2-FC6H4
4-ClC6H4
2-ClC6H4
1-Napthyl
96
96
aLigand 2 (10 mol %) was dissolved in iso-propanol (2.0 mL), Cu(OAc)2.H2O (10 mol %), CH3NO2 (10 eq., 5
mmol), 4-methoxyphenol (10 mol%) and benzaldehyde derivatives (0.5 mmol) were added and stirred at 25 °C for
c
specified time. bYield of isolated product after purification by column chromatography. Enantiomeric excess was
determined by HPLC using a Chiralpak OD-H and AD-H columns and absolute configuration of products were
determined by comparison of optical rotation with literature value.
The effect of catalyst on the diastereoselectivity and enantioselectivity of the nitro-aldol reaction
between benzaldehyde or substituted benzaldehydes with nitroethane was also studided at 25°C
using ligand 2 (10 mol%), Cu(CH3COO)2.H2O (10 mol%) and 4-methoxyphenol (10 mol%) as
additive. We obtained the anti-diastereomer of β-nitro alcohols as major products. Anti-selective
asymmetric Henry reaction catalyzed by Cu(I)-amine-imine complex and heterobimetallic Cu-
Sm-aminophenol sulfonamide complexes are reported in literature.64,65 The anti and syn ratio of
nitro-aldol products were determined by 1H-NMR of the crude products by comparing literature
value of chemical shift and coupling constant of proton (–CHOH-).30,41 The best diastereomeric
ratio (dr) anti/syn (98/2) and 71% ee of anti-product (1S, 2R) was obtained with benzaldehyde
(Table 4, entry 1). Electron withdrawing group on benzaldehyde like -NO2 gave product in 90%
yield anti/syn (81/19) with poor ee of both diastereomer (entries 2 and 3). Benzaldehyde having
electron donating group like methoxy at 4-positions gave only 16% yield after 120 h and anti/syn
10

(90/10) (entry 3). Halogenated benzaldehydes afforded corresponding products in 54-81% yields
and best dr and ee was obtained in case of 4-fluorobenzaldehyde compared to the other
halogenated benzaldehydes (entries 4-6).
Table 4. Scope of substrates with nitroethane.a
eed (%)
Entry R
Yieldb drc (anti/syn)
(%)
(anti/syn)
71/57
36/22
77/58
51/33
1
2
3
4
5
6
C6H5
83
90
16
60
54
81
98/2
4-NO2C6H4
4-OMeC6H4
4-BrC6H4
4-ClC6H4
4-FC6H4
81/19
90/10
80/20
78/22
95/5
36/34
60/67
a Ligand 2 (10 mol %) was dissolved in iso-propanol (2.0 mL), Cu(OAc)2.H2O (10 mol %), CH3CH2NO2 (10 eq., 5
mmol), 4-methoxyphenol (10 mol%) and substituted benzaldehyde (0.5 mmol) were added and stirred at 25 °C for
c
120 h. b Yield of isolated product after purification by column chromatography. Diastereomeric ratio was
determined by 1H-NMR. d Enantiomeric excess was determined by HPLC using a Chiralpak OD-H and AD-H
columns and absolute configuration of products were determined by comparison of optical rotation with literature
value.
4. Conclusions
In summary, C1-symmetric salalen and salan ligands derived from (S)-proline and their in situ
generated Cu (II) complexes by Cu(OAc)2.H2O, act as catalysts for asymmetric Henry reaction.
The Cu(II) complex generated in situ from ligand 2 (10 mol%) and Cu(OAc)2.H2O (10 mol%) in
iso-propanol demonstrated as an efficient catalyst for the asymmetric nitro-aldol reaction
between 4-nitrobenzaldehyde and nitromethane using 4-methoxyphenol (10 mol%) as an
additive at 25°C, gave corresponding nitro-aldol product in 82% yield and 81% ee. Additives
like base giving the racemic product at room temperature but 4-methoxyphenol is choice of
additive which improved the ee of the product. The catalytic system was found to be an efficient
for various aromatic aldehydes and gave 67–94% yields with 49–98% ee’s of the corresponding
products. The nitro-aldol reaction of a variety of 4-substituted benzaldehydes with nitroethane
were also carried out and anti-nitro-aldol products were obtained as major products with best
anti:syn 98:2 with 71% ee. Development of new C1 symmetric ligands derived from proline for
asymmetric Henry reaction will be reported in due course.
Acknowledgement
11

SS thanks to CSIR for research grant 02(0152)/13/EMR-II. We are also thankful to University
Science Instrumentation Centre (USIC), University of Delhi, for providing instrumental
facilities. PK is thankful to UGC for awarding JRF and SRF.
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Graphical Abstract
Leave this area blank for abstract info.
Asymmetric Henry reaction catalyzed by chiral Cu(II)
salalen and salan complexes derived from (S)-proline
Ashish Dixit, Pramod Kumar, Geeta Devi Yadav and Surendra Singh*
15

Highlights
 Chiral Salalen ligands were derived from readily available (L)-proline
 The in situ generated Cu(II) complex of Ligand and Cu(OAC)2.H2O was used as a
catalyst and 4-methoxyphenol as an additive for asymmetric Henry reaction.
 The in situ generated Cu(II) complex of ligand 2 are found to be efficient catalyst for
Henry reaction of a variety of aromatic aldehydes with nitromethane and nitroethane
 The absolute configuration of nitro-aldol product was governed by the use of the metal,
Mn(III) complex of the ligand 2 gives (R)-enantiomer while Cu(II) complex of same
ligand gives the (S)-enantiomer

16