Synthesis of chiral salalen ligands and their in-situ generated Cu-complexes for asymmetric Henry reaction

Article abstract of DOI:10.1002/chir.23019

Chiral salalen ligands derived from (S)-proline and derivatives of salicyaldehydes were synthesized, and their in-situ generated Cu (II) complexes were evaluated in the asymmetric Henry reaction. Salalen ligand of different substituents on the phenyl moiety showed remarkable effect on the enantioselectivity of nitro-aldol product of 4-nitrobenzaldehyde and nitromethane. Cu (II) complex generated in situ with (S)-2-(tert-butyl)-6-((2-(((2-hydroxy-3-methylbenzylidene)amino)methyl)pyrrolidin-1-yl)methyl) phenol (10?mol%) and Cu (OAc)₂.H₂O (10?mol%), found to be better catalyst for nitro-aldol reaction between 4-nitrobenzaldehyde and nitromethane, gave corresponding product in 85% yield and 88% enantiomeric excess (ee) in isopropanol at 35°C after 40?hours. The catalyst also used for the Henry reaction with different substituted benzaldehydes and corresponding products were obtained in 22% to 99% yields with 66% to 92% ee. Henry reaction of 4-nitrobenzaldehyde and prochiral nitroethane gave anti-selective product (dr?=?79/21; anti/syn) in a 91% yield with 80% ee.

Full text of DOI:10.1002/chir.23019

Received: 26 July 2018
DOI: 10.1002/chir.23019
Revised: 23 August 2018
Accepted: 23 August 2018
R E G U L A R A R T I C L E
Synthesis of chiral salalen ligands and their in‐situ
generated Cu‐complexes for asymmetric Henry reaction
Ashish Dixit | Pramod Kumar | Surendra Singh
Department of Chemistry, University of
Abstract
Delhi, North Campus, Delhi, India
Chiral salalen ligands derived from (S)‐proline and derivatives of
Correspondence
Surendra Singh, Department of
salicyaldehydes were synthesized, and their in‐situ generated Cu (II) complexes
were evaluated in the asymmetric Henry reaction. Salalen ligand of different
Chemistry, University of Delhi, North
Campus, Delhi 110007, India.
substituents on the phenyl moiety showed remarkable effect on the
enantioselectivity of nitro‐aldol product of 4‐nitrobenzaldehyde and nitrometh-
ane. Cu (II) complex generated in situ with (S)‐2‐(tert‐butyl)‐6‐((2‐(((2‐hydroxy‐
3‐methylbenzylidene)amino)methyl)pyrrolidin‐1‐yl)methyl) phenol (10 mol%)
and Cu (OAc)2.H2O (10 mol%), found to be better catalyst for nitro‐aldol reaction
between 4‐nitrobenzaldehyde and nitromethane, gave corresponding product in
85% yield and 88% enantiomeric excess (ee) in isopropanol at 35°C after 40 hours.
The catalyst also used for the Henry reaction with different substituted benzalde-
hydes and corresponding products were obtained in 22% to 99% yields with 66%
to 92% ee. Henry reaction of 4‐nitrobenzaldehyde and prochiral nitroethane gave
anti‐selective product (dr = 79/21; anti/syn) in a 91% yield with 80% ee.
Email: ssingh1@chemistry.du.ac.in
Funding information
CSIR, Grant/Award Number: 02(0152)/
13/EMR‐II
KEYWORDS
asymmetric Henry reaction, C1‐symmetric salalen ligand, Cu‐salalen complex, nitro‐aldol reaction,
proline
1 | INTRODUCTION
asymmetric nitro‐aldol raection.38-46 Diastereo‐ and
enantioselective nitro aldol reaction using prochiral
The Henry reaction (nitro‐aldol reaction) is a very effi-
cient and atom economic method for the formation of
C―C bond which afford β‐nitro alcohols containing two
functional groups (ie, nitro and hydroxyl groups) and
can easily be transformed to the β‐amino alcohols,
α‐hydroxy acids, α‐hydroxy ketones, and other various
biological active compounds.1-5 Asymmetric version of
this reaction attracted more attention of the chemists
since 1992, when Shibasaki and co‐workers reported
the reaction.6 In the last two decades, various chiral
transition metal complexes and rare earth metal com-
plexes have been developed for asymmetric nitro‐aldol
reaction.7-32,33-37 Besides chiral metal complexes,
organocatalysts and biocatalysts were also used in
nitroethane and other nitroalkanes are limited in the liter-
ature, and syn‐selective asymmetric nitro aldol reactions
have been established by Shibasaki and others.47-52 Anti‐
selective reaction in basic conditions is reported by Ooi
and co‐workers and later reported by other
researchers.53-61 Salen ligands are one of the most
privileged ligands for the asymmetric catalysis, and Cu
(II) complexes of salen and salan ligands were largely
used for nitro‐aldol reaction and efficiently active at mild
reaction conditions.62-72 (S)‐Proline‐based single chiral
center salalen and salan ligands were first reported by
Katsuki and co‐workers for the asymmetric epoxidation
of non‐functionalised alkenes.73 These ligands were also
used by Kol and co‐workers for polymerisation of
Chirality. 2018;1–12.
wileyonlinelibrary.com/journal/chir
© 2018 Wiley Periodicals, Inc.
1

2
DIXIT ET AL.
α‐olefins and stereoselective polymerization of lactide.74-76
We have already reported Mn (III) and Cu (II) salalen
and salan complexes of ligands derived from (S)‐proline
and derivatives of salicyaldehyde for asymmetric Strecker
and Henry reactions.77-79 Herein, we wish to report the
synthesis of salalen ligands and their in situ generated
Cu (II) salalen complexes for diastereo‐ and
enantioselective nitro‐aldol reaction.
phase to yield ligand 4b as yellow oil. Spectroscopic data
of ligands 4a‐f are given below.
• (4a): Yield (0.615 g, 70%, yellow oil). 1H NMR
(400 MHz, CDCl3): δ = 13.80 (brs, 1H), 8.41 (s, 1H),
7.6 (d, J = 7.2 Hz, 2H), 7.43 to 7.37 (m, 3H), 7.33 to
7.30 (m, 1H), 7.25 to 7.24 (m, 1H), 7.13 (d, J = 8 Hz,
1H), 6.93 (t, J = 7.6 Hz, 1H), 6.82 (d, J = 7.6 Hz, 1H),
6.68 (t, J = 7.6 Hz, 1H), 4.17 (d, J = 12.8 Hz, 1H), 3.82
(dd, J = 4 Hz, 12.4 Hz, 1H), 3.63 (dd, J = 6.8 Hz,
12.4 Hz, 1H), 3.54 (d, J = 13.6 Hz, 1H),3.05 to 2.90
(m, 2H), 2.34 (q, J = 8.4 Hz, 1H), 2.11 to 2.02 (m, 1H),
1.86 to 1.75 (m, 3H), 1.36 (s, 9H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 166.73, 158.33, 156.70,
137.72, 136.34, 133.27, 130.96, 129.59, 129.29,
128.05, 127.00, 126.06, 125.75, 122.62, 118.84,
118.52, 118.15, 64.68, 62.87, 58.66, 54.27, 34.56,
2 | MATERIALS AND METHODS
2.1 | Instruments and materials
All reagents were purchased commercially and used as
received. HPLC grade isopropyl alcohol was used as sol-
vent for the reactions. The synthesis of compound 1 and
ligand 4g was reported in literature.77,78 Proton and car-
bon nuclear magnetic resonance spectra (1H and 13C
NMR, respectively) were recorded on 400 MHz (operating
25
29.39, 22.99 ppm. [α]D = −42.5 (c 0.5 in CH2Cl2).
FT‐IR (CHCl3, Film) ῡ = 2953, 1630 cm−1. HRMS
(ESI): m/z [M + H]+ calcd. For C29H35N2O2:
443.2698; found 443.2699.
1
frequencies: H, 400.13 MHz; 13C, 100.61 MHz) Jeol‐FT‐
NMR spectrometers at ambient temperature. In the case
• (4b): Yield (0.308 g, 81%, yellow oil). 1H NMR
(400 MHz, CDCl3): δ = 13.54(brs, 1H), 8.41 (s, 1H),
7.23 (d, J = 7.6 Hz, 2H), 7.16 (d, J = 7.6 Hz, 1H),
6.91 (d, J = 6.8 Hz, 1H), 6.84 (t, J = 7.6 Hz,1H), 6.75
(t, J = 7.6 Hz, 1H), 4.25 (d, J = 13.6 Hz, 1H), 3.88
(dd, J = 4.4 Hz, 12.4 Hz, 1H), 3.7 to 3.61 (m, 2H),
3.13 to 2.98 (m, 2H), 2.46 to 2.39 (m, 1H), 2.32 (s,
3H), 2.19 to 2.09 (m, 1H), 1.93 to 1.83 (m, 3H), 1.43
(s, 9H) ppm. 13C NMR (100 MHz, CDCl3): δ
=166.66, 159.23, 156.73, 136.36, 133.28, 129.16,
126.07, 125.79, 125.76, 122.67, 118.14, 118.09, 117.92,
64.76, 63.09, 58.75, 54.32, 34.56, 29.45, 29.38, 23.05,
1
of H and 13C NMR spectra, the chemical shifts (δ) for
all compounds are listed in parts per million downfield
from tetramethylsilane as an internal reference in the
NMR solvent. 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 car-
ried out using Merck Kieselgel 60 F254 silica gel plates.
Column chromatographic separations were performed
using silica gel (200‐400 mesh). All the new compounds
25
15.47 ppm. [α]D = −17.2 (c 0.378 in CH2Cl2). FT‐
1
were characterized by H and 13C NMR and mass spec-
IR (CHCl3, Film) ῡ = 2953, 1628, 1042 cm−1. HRMS
(ESI): m/z [M + H]+ calcd. C24H33N2O2: 381.2542;
found 381.2542.
trometry (HRMS), and known compounds were charac-
terized by 1H‐NMR and 13C‐NMR. The enantiomeric
excess was determined using Schimadzu 2010 HPLC
using Chiralpak AD‐H, Chiralcel OD‐H, and Chiralpak
IC as chiral columns.
• (4c): Yield (0.331 g, 61%). M.p. = 91°C to 93°C.1H
NMR (400 MHz, CDCl3): δ = 13.15 (brs, 1H), 8.30 (s,
1H), 7.49 (s, 1H), 7.24 to 7.13 (m, 7H), 6.80 (d,
J = 7.6 Hz, 1H), 6.66 (t, J = 7.6 Hz, 1H), 4.12 (d,
J = 13.6 Hz, 1H), 3.75 to 3.70 (m, 1H), 3.50 to 3.43
(m, 3H), 2.99 to 2.86 (m, 2H), 2.29 (q, J = 8.4 Hz,
1H), 2.00 to 1.88 (m, 1H), 1.74 to 1.70 (m, 8H), 1.34
(d, J = 15.2 Hz, 18H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 167.08, 157.36, 156.74, 150.76, 139.87,
136.27, 135.90, 127.71, 127.45, 126.37, 126.07, 125.67,
125.62, 124.95, 122.73, 118.08, 117.95, 64.65, 63.29,
58.71, 54.27, 42.21, 34.58, 34.11, 31.50, 29.61, 29.44,
2.2 | General procedure for synthesis of
ligand 4b
(S)‐2‐((2‐(Aminomethyl)pyrrolidin‐1‐yl)methyl)‐6‐(tert‐
butyl) phenol (2) (0.262 g, 1 mmol) was dissolved in eth-
anol (2 mL); then, 2‐methylsalicylaldehyde (3b) (0.136 g,
1 mmol) dissolved in ethanol (3 mL) was added to it
dropwise, and reaction mixture was stirred for 16 hours
at room temperature. Solvent was removed on rotavapor
under reduced pressure, and product was purified from
column chromatography by passing on short column on
silica gel using ethyl acetate:hexane (10:90) as a mobile
25
29.26, 22.95 ppm. [α]D = −26.45 (c 0.24 in CH2Cl2).
FT‐IR (CHCl3, Film) ῡ = 2958, 1631 cm−1. HRMS
(ESI): m/z [M + H]+ calcd. For C36H49N2O2:
541.3794; found 541.3777.

DIXIT ET AL.
3
1
• (4d): (0.340 g, 86%, yellow oil). H NMR (400 MHz,
CDCl3): δ = 13.72 (brs, 1H), 8.34 (s, 1H), 7.14
(d, J = 7.6 Hz, 1H), 6.91 to 6.76 (m, 4H), 6.67 (t, J = 8 Hz,
1H), 4.15 d, J = 13.6 Hz, 1H), 3.88 (s, 3H), 3.81 (dd,
J = 4.8 Hz, 13.2 Hz, 1H), 3.63 to 3.55 (m, 2H), 3.08 to
2.91 (m, 2H), 2.35 (q, J = 8.4 Hz, 1H), 2.16 to 2.03 (m,
1H), 1.88 to 1.76 (m, 3H), 1.33 (s, 9H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 166.59, 156.66, 151.56, 148.26,
136.29, 126.05, 125.71, 123.05, 122.63, 118.46, 118.12,
117.88, 113.86, 64.65, 62.63, 58.73, 55.97, 54.38, 34.51,
triethylamine (11.87 g, 117.6 mmol) were added to the
reaction mixture and stirred at room temperature for
1 hour, then paraformaldehyde (8.82 g, 294 mmol) was
added to it. The resulting mixture was refluxed for
24 hours. Solvent was removed on reduced pressure by
rotavapor, and it was then acidified with 11.16 N HCl,
and resulting mixture was extracted with ethyl acetate,
dried over Na2SO4. Solvent was recovered at the reduced
pressure by rotavapor to yield yellowish oil which was
then purified by column chromatography on silica gel
using hexane as an eluent to give light greenish solid
product (3a) (8.0 g, 69%). M.p. = 44°C.1H NMR
(400 MHz, CDCl3): δ = 11.46 (s, 1H), 9.87 (s, 1H), 7.55
to 7.47 (m, 4H), 7.37 (t, J = 7.6 Hz, 2H), 7.29 (t, J = 7.6 Hz,
1H), 7.03 (t, J = 7.6 Hz, 1H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 196.84, 158.83, 137.79, 136.23, 133.16,
130.42, 129.22, 128.25, 127.64, 120.80, 119.89 ppm.
25
29.35, 29.18, 23.14 ppm. [α]D = −29.0 (c 0.62 in
CH2Cl2). FT‐IR (CHCl3, Film) ῡ = 2953, 1631,
1083 cm−1. HRMS (ESI): m/z [M + H]+ calcd. For
C24H33N2O3: 397.2491; found 397.2489.
• (4e): Yield (0.333 g, 91%, yellow oil). 1H NMR
(400 MHz, CDCl3): δ = 8.35 (s, 1H), 7.29 to 7.23 (m,
2H), 7.23 (d, J = 6.8 Hz, 1H), 6.92 (d, J = 8.4 Hz,
1H), 6.87 to 6.82 (m, 2H), 6.68 (t, J = 7.6 Hz, 1H),
4.18 (d, J = 14 Hz, 1H), 3.82 (dd, J = 4 Hz, 12.4 Hz,
1H), 3.72 to 3.55 (m, 2H), 3.05 to 2.97 (m, 2H), 2.40
to 2.34 (m, 1H), 2.15 to 2.02 (m, 1H), 1.87 to 1.76
(m, 3H), 1.37 to 1.34 (m, 9H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 166.49, 160.89, 156.65,
136.26, 132.19, 131.43, 126.02, 125.69, 122.58, 118.66,
118.50, 118.12, 116.79, 64.63, 63.02, 58.65, 54.25,
2.3.2 | 2‐Methylsalicylaldehyde (3b)
2‐Methylphenol (4 g, 36.9 mmol) was taken in dry THF
(50 mL); then, MgCl2 (5.25 g, 55.3 mmol) and
triethylamine (7.47 g, 73.9 mmol) were added to it and
stirred for 30 minutes at room temperature. Then, parafor-
maldehyde (5.54 g, 184.9 mmol) was added, and resulting
reaction mixture was refluxed for 24 hours. Solvent was
removed under reduced pressure by rotavapor, and it
was acidified with 11.16 N HCl. The resulting mixture
was extracted with ethyl acetate, dried over Na2SO4. Sol-
vent was recovered at the reduced pressure on rotavapour
to yield yellowish oil which was purified by column chro-
matography on silica gel using hexane as an eluent to give
product (3b) as greenish oil (1.9 g, 38%). 1H NMR
(400 MHz, CDCl3): δ = 11.25 (s, 1H), 9.84 (s, 1H), 7.36
(d, J = 7.6 Hz, 2H), 6.90 (t, J = 7.6 Hz, 1H), 2.25 (s, 3H)
ppm. 13C NMR (100 MHz, CDCl3): δ = 196.65, 159.85,
137.72, 131.27, 126.69, 119.90, 119.26, 14.92 ppm.
25
34.49, 29.36, 29.28, 23.02 ppm. [α]D = −22.7 (c
0.892, CH2Cl2). FT‐IR (CHCl3, Film) ῡ = 2953,
1631 cm−1. HRMS (ESI): m/z [M + H]+ calcd. For
C24H33N2O3: 367.2385; found 367.2380.
• (4f): Yield (0.377 g, 85%, yellow oil). 1H NMR
(400 MHz, CDCl3): δ = 14.42 (brs, 1H), 10.98 (brs,
1H), 8.33 (s, 1H), 7.58 (d, J = 8.4 Hz, 1H), 7.20 (dd,
J = 7.6 Hz, 20.8 Hz, 2H), 6.86 (d, J = 7.6 Hz, 1H),
6.79 to 6.69 (m, 2H), 4.16 (d, J = 13.2 Hz, 1H), 3.85
(dd, J = 4.4 Hz, 12 Hz, 1H), 3.68 to 3.59 (m, 2H),
3.08 to 2.96 (m, 2H), 2.40 (q, J = 8.4 Hz, 1H), 2.20 to
2.08 (m, 1H), 1.93 to 1.80 (m, 3H), 1.37 (s, 9H) ppm.
13C NMR (100 MHz, CDCl3): δ = 165.96, 158.54,
156.58, 136.32, 135.61, 130.73, 126.05, 125.78, 122.49,
2.3.3 | 5‐(tert‐Butyl)‐2‐hydroxy‐3‐(2‐
phenylpropan‐2‐yl) benzaldehyde (3c)
119.19, 119.00, 118.21, 111.01, 64.57, 62.16, 58.71,
54.32, 34.51, 29.35, 23.11 ppm. [α]D
25
= −75.3
(c = 0.2, CH2Cl2). FT‐IR (CHCl3, Film) ῡ = 2954,
1632 cm−1. HRMS (ESI): m/z [M + H]+ calcd. For
C23H30BrN2O2: 445.1490; found 445.1488.
4‐(tert‐Butyl)‐2‐(2‐phenylpropan‐2‐yl) phenol (2.06 g,
7.66 mmol) was dissolved in dry THF (50 mL); then,
MgCl2 (1.09 g, 11.4 mmol) and triethylamine (1.54 g,
15.3 mmol) were added to it and stirred for 30 minutes
at room temperature, and later paraformaldeyde (1.14 g,
38.3 mmol) was added and refluxed for 24 hours. Solvent
was removed under reduced pressure by rotavapor, and it
was acidified with 11.16 N HCl. The resulting mixture
was extracted with ethyl acetate, dried over Na2SO4. Sol-
vent was recovered at the reduced pressure on rotavapour
to yield yellowish oil which was purified by column chro-
matography on silica gel using hexane as an eluent to
2.3 | Synthesis of derivatives of
salicyaldehyde 3a‐c
2.3.1 | 2‐Phenylsalicylaldehyde (3a)
2‐Phenylphenol (10 g, 58.8 mmol) was dissolved in dry
THF (100 mL), and then MgCl2 (8.38 g, 88.2 mmol) and

4
DIXIT ET AL.
1
give product (3c) as light greenish oil (1.2 g, 54%). H
NMR (400 MHz, CDCl3): δ = 11.13 (s, 1H), 9.75 (s, 1H),
7.66 (d, J = 2 Hz, 1H), 7.32 (d, J = 2.4 Hz, 1H), 7.20 to
7.07 (m, 5H), 1.67 (s, 6H), 1.29 (s, 9H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 196.94, 158.30, 149.78, 141.55,
137.04, 132.07, 128.13, 127.87, 125.56, 125.37, 120.09,
42.08, 34.27, 31.33, 29.21 ppm.
J = 8.4, 4.4 Hz, 1H), 4.58 to 4.53 (m, 2H), 3.20 (brs, 1H)
ppm. 13C NMR (100 MHz, CDCl3): δ = 148.0, 144.9,
126.9 (2C), 124.2 (2C), 80.6, 69.9 ppm.
3 | RESULTS AND DISCUSSION
Chiral salalen ligands (4a‐g) were synthesized in 61% to
91% yields from reaction of (S)‐2‐((2‐(aminomethyl)
pyrrolidin‐1‐yl)methyl)‐6‐(tert‐butyl) phenol (2) and deriv-
atives of salicyaldehyde 3a‐g in ethanol (Scheme 1). (S)‐2‐
((2‐(Aminomethyl)pyrrolidin‐1‐yl)methyl)‐6‐(tert‐butyl)
phenol (2) was synthesized by the reduction of (S)‐1‐(3‐
(tert‐butyl)‐2‐hydroxybenzyl)pyrrolidine‐2‐carboxamide
(1) with LiAlH4.73 (S)‐1‐(3‐(tert‐Butyl)‐2‐hydroxybenzyl)
pyrrolidine‐2‐carboxamide (1) was synthesized from (S)‐
proline as a starting material according to literature
reports.73,77 The synthesis of derivatives of salicyaldehyde
(3a‐g) was carried out according to scheme 2.80
Substituted phenols were reacted with paraformaldehyde
in the presence of anhydrous MgCl2 and triethylamine
in THF under reflux condition for 24 hours to afford cor-
responding salicyaldehyde derivatives 3a‐c in 38% to 69%
2.4 | General procedure for asymmetric
Henry (nitro‐aldol) reaction
The mixture of salalen ligand 4b (19 mg, 10 mol%) and Cu
(OAc)2.H2O (9.9 mg, 10 mol%) in isopropanol (2.0 mL)
was stirred for 30 minutes; then, CH3NO2 (267 μL,
5 mmol, 10 equiv.) was added, and resulting reaction
mixture was stirred for 30 minutes at 35°C, at the end
benzaldehyde/substituted benzaldehydes (0.5 mmol) was
added. Reaction mixture was stirred for specified time
and monitored by TLC. Solvent was evaporated on
rotavapor and nitro‐aldol product was purified by column
chromatography on silica gel using hexane/ethyl acetate
as a mobile phase. Enantiomeric excess was determined
by HPLC using Chiracel OD‐H, AD‐H and IC columns.
HPLC chromatogram and 1H‐NMR and 13C‐NMR spectra
of the nitro‐aldol products are given in SI.
1
yields. All salalen ligands were characterized by H, 13C
NMR, IR, and HRMS.
In our initial investigation, we have evaluated in situ
generated Cu (II) complexes of the ligands 4a‐g
(5 mol%) and Cu (OAc)2.H2O (5 mol%) for Henry (nitro‐
aldol) reaction between 4‐nitrobenzaldehyde and nitro-
methane in isopropanol at 25°C. The results shown in
Table 1 indicate that the R1 group on the phenol influ-
ences the yield and ee of product 7. Yield of the product
7 was found to be better in case of ligand 4e (R1 = H
and R2 = H), but when bulky and electron donating
group was attached to imine contained phenyl ring, yield
of product 7 was decreased (Table 1, entries 2, 3, 4, 6, and 7).
2.4.1 | 2‐Nitro‐1‐(4‐nitrophenyl) ethanol
(7)19
Yellow oil, yield: 90.1 mg (85%), ee: 88%. HPLC condi-
tions: Chiralcel OD‐H (hexane/iPrOH, 80:20 v/v,
1.00 mL/min, 25°C, UV 230 nm), tr (minor) = 10.5 minutes
25
and tr (major) = 12.7 minutes. ½αꢀD = +19.7 (c 0.63
CH2Cl2). 1H NMR (400 MHz, CDCl3): δ = 8.25 (d,
J = 8.4 Hz, 2H), 7.60 (d, J = 8.4 Hz, 2H), 5.58 (dd,
SCHEME 1 Synthesis of chiral salalen ligands 4a‐g

DIXIT ET AL.
5
SCHEME 2 Synthesis of salicyaldehyde
derivatives 3a‐g
TABLE 1 Screening of different ligands for Henry reactiona
Entry
Ligand
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
4a
4b
4c
4d
4e
4f
74
26
31
44
83
38
30
71
91
66
79
24
53
66
4g
aLigand 4a‐g (5 mol%) and Cu (OAc)2.H2O (5 mol%) was stirred in isopropanol (2 mL) at 25°C for 30 min, and then nitromethane (5 mmol) was added to it and
again stirred for 30 min; finally, 4‐nitrobenzaldehyde (0.5 mmol) was added, and the reaction was carried out for 18 h at same temperature.
bYield after purification by column chromatography.
cEnantiomeric excess was determined by HPLC on Chiralpak OD‐H column.
In our recent report we have used ligand 4g (R1 = ‐C
(CH3)3) and product was obtained in a 66% ee (Table 1,
entry 7).79 Bulkiness of substituents R1 = ―C (CH3)2Ph
and R2 = ―C (CH3)3 in the ligands 4c also gave the product
in 66% ee (Table 1, entry 3 and 7). Enantiomeric excess of
nitroaldol product was better in case of ligand 4b
(R1 = CH3, Table 1, entry 2) compared with other ligand
(4a, 4c, 4d, 4f, and 4g) bearing bulky groups (Table 1,
entries 1, 3, 4, 6, and 7). Product was obtained with (S)‐
absolute configuration which was determined by
comparing the optical rotation of literature reports.79
After screening of the ligands, we found that ligand
4b is a better ligand among all the ligands. Then, we
varied Cu sources with ligand 4b for catalysis in Henry
reaction of 4‐nitrobenzaldehyde (6) and nitromethane,
and Cu (OAc)2.H2O gave best yield and ee compared
to CuCl, CuSO4.5H2O, and CuCN (Table 2, entries
1‐4,) whereas in case of Cu (NO3)2.3H2O, CuCl2.2H2O,
and Cu (OTf)2 did not form desired product 7 at 25°C
(Table 2, entries 5‐7).
Reaction conditions of Henry reaction between 4‐
nitrobenzaldehyde (6) and nitromethane were optimized
by varying catalyst loading, temperature, and additive.
We have increased the in situ generated catalyst loading
(ligand 4b (10 mol%) with Cu (OAc)2.H2O (10 mol%)) at
25°C and increased the yield of the product 7 up to 41%.
Low loading of in‐situ generated Cu (II) catalyst
(2 mol%) gave 15% yield and poor ee of the product 7
(Table 3, entries 1 and 2). We also increased the reaction
temperature from 25°C to 35°C using in‐situ generated
Cu (II) catalyst (10 mol%) which improved yield and ee
of the product 7 (Table 3, entry 3), but further increase of
temperature up to 45°C enhanced the yield of the product
up to 91% but ee was decreased (Table 3, entry 5). The yield
of product 7 was increased with longer reaction time, but
slight drop in ee was observed (Table 3, entries 4). At this
stage again, we have increased the in‐situ generated cata-
lyst loading up to 20 mol%, and results show that yield of
product 7 was improved but ee decreased (Table 3, entries
6 and 7). We examined the efficacy of nitrogen containing

6
DIXIT ET AL.
TABLE 2 Screening of various cu source with ligands 4b for Henry reactiona
Entry
Cu Source
Yieldb, %
eec, %
1
2
3
4
5
6
7
Cu (OAc)2.H2O
CuCl
26
8
91
79
77
40
‐
Cu (SO4).5H2O
CuCN
11
5
Cu (NO3)2.3H2O
CuCl2.2H2O
Cu (OTf)2
‐
‐
‐
‐
‐
aLigand 4b (5 mol%) and Cu source (5 mol%) were stirred in isopropanol (2 mL) at 25°C for 30 min, and then nitromethane (5 mmol) was added to it and again
stirred for 30 min; finally, 4‐nitrobenzaldehyde (0.5 mmol) was added, and reaction was carried out for 18 h at same temperature.
bYield after purification by column chromatography.
cEnantiomeric excess was determined by HPLC on Chiralpak OD‐H column.
TABLE 3 Optimization of reaction conditionsa
Entry
Additive, mol%
Mol% of 4b and Cu (OAc)2.H2O
Time, h
Temp., °C
Yieldb, %
eec, %
1
‐
10
2
18
25
25
35
45
35
35
35
35
35
35
35
41
91
43
94 (88)
68
74
77
0
2
‐
18
18 (40)d
15
3(4)
5
‐
10
10
15
20
10
10
10
10
10
58 (85)
91
‐
18
18
18
2
6
‐
80
7
‐
89
8
NEt3
95
9
DIEPA
2
98
0
10
11
12
NMO
21
21
40
90
50
70
90
4‐methylphenol
4‐methoxyphenol
76
77
aLigand 4b and Cu (OAc)2.H2O were stirred in isopropanol (2 mL) for 30 min; additive (10 mol%) and nitromethane (5 mmol) were added to it and stirred for
30 min. Then, 4‐nitrobenzaldehyde (0.5 mmol) was added to it, and reaction mixture was stirred for respective time at specified temperature.
bYield after purification by column chromatography.
cEnantiomeric excess was determined by HPLC on chiralpak OD‐H column.
dResult in parenthesis is given for reaction time 40 h.
bases as additive, and it worked well in very short span of
time to get the desired nitro‐aldol product 7 in good yield,
but poor enantiomeric excess was observed (Table 3, entry
8, 9, and 10). We also study the effect of O‐donor additives
like 4‐methylphenol and 4‐methoxyphenol. In the pres-
ence of additive 4‐methoxyphenol, the nitroaldol product
7 was obtained in slight low yield and comparable ee
which indicate that additive is not playing a significant
role in catalysis (Table 3, entries 11 and 12). These
experiments provided optimized reaction conditions for
nitro‐aldol reaction that is ligand 4b (10 mol%) and Cu
(OAc)2.H2O (10 mol%) in isopropanol (2 mL) at 35°C.

DIXIT ET AL.
7
We also checked the dependency of enantiomeric
excess (ee) with time during the course of reaction
(Figure 1). For this, we have carried out asymmetric
Henry reaction between 4‐nitrobenzaldehyde (6) and
nitromethane using ligand 4b (10 mol%) and Cu (OAc)2.
H2O (10 mol%) in isopropanol at 35°C, and ee of the reac-
tion was monitored for different interval of time. When
reaction was started, ee of product 7 was found to be high
90%, but the ee of product 7 slightly decreased with
respect to reaction time. After 24 hours, the reaction pro-
ceeds with constant enantioselectivity till 44 hours. The
results show that decrease in enantioselectivity may be
due to formation of thermodynamically more stable prod-
uct over kinetically stable product because of retro‐Henry
reaction.81
FIGURE 2 Plausible mechanism for Henry reaction catalyzed by
Cu (II) complex
We are proposing the plausible reaction mechanism
for the Henry reaction between 4‐nitrobenzaldehyde
and nitromethane catalyzed by in situ generated Cu (II)
complex of ligand 4b (Figure 2). Ligand 4b was reacted
with Cu (CH3COO)2.H2O in isopropanol which generate
a complex Cu (II)L* and acetate anions. Acetate anion
acts as a base and abstracts a proton of the nitromethane
and forming a nitro enolate. The Cu metal center of this
complex is interacting with nitro enolate and oxygen of
4‐nitrobenzaldehyde. The transition state (a) of Figure 3
found to be disfavored because the Si‐face arrangement
of 4‐nitrobenzaldehyde is hindered by the imine part of
the in situ generated complex (Cu (II)L*) from ligand 4b
and Cu (CH3COO)2.H2O. Another transition state (b) in
the Figure 3 is favorable since 4‐nitrobenzaldehyde is
far away from the imine part of in situ generated Cu
(II)L* complex of ligand 4b and nucleophile nitro enolate
is attacking on the Re‐face of 4‐nitrobenzaldehyde which
is giving the (S)‐enantiomer of the nitro‐aldol product 7.
FIGURE 3 Transition state of Henry reaction catalyzed by in situ
generated Cu (II) complex of salalen ligand 4b and Cu (OAc)2.H2O
Scope and limitations of asymmetric Henry reaction
catalyzed by in situ generated Cu(II) complex was studied
for a variety of substituted benzaldehydes with nitro-
methane (Table 4). Electron withdrawing group on benz-
aldehyde such as nitro reacted fastest to afford the
corresponding nitro‐aldol products in excellent yields
and good enantiomeric excesses (Table 4, entries 1 and
2). Electron withdrawing group makes the carbonyl
group of benzaldehyde more electrophilic and found to
be more reactive for nitro‐aldol reaction, while electron
donating group reduces the electrophilicity of the car-
bonyl group and therefore found to be less reactive. The
nitro‐aldol reaction of halo‐benzaldehydes gave corre-
sponding products in good yields and ee. The reactivity
of 4‐halobenzaldehyde was found to be in order Br > Cl > F
but poor than 4‐nitrobenzaldehydes (Table 4, entries 1, 3,
FIGURE 1 Graph represents the enantiomeric excess (ee) of
product 7 v/s reaction time

8
DIXIT ET AL.
TABLE 4 Scope and limitations of in situ generated Cu (II) salalen complex as a catalyst for nitro‐aldol reactiona
Entry
R
Time, h
Yieldb, %
eec, %
1
4‐NO2‐Ph
2‐NO2‐Ph
4‐Br‐Ph
2‐Br‐Ph
4‐Cl‐Ph
2‐Cl‐Ph
4‐F‐Ph
40
40
72
72
72
72
72
72
72
72
72
72
72
72
72
85
91
81
95
68
99
53
90
22
69
50
61
69
32
80
88
85
72
91
77
92
66
85
72
87
69
69
69
74
73
2
3
4
5
6
7
8
2‐F‐Ph
9
4‐MeO‐Ph
2‐MeO‐Ph
4‐Me‐Ph
2‐Me‐Ph
Ph
10
11
12
13
14
15
Cinnamyl
Ethyl
aLigand 4b (10 mol%) and Cu (OAc)2.H2O (10 mol%) were stirred in isopropanol (2 mL) for 30 min, and nitromethane (5 mmol) was added to it and stirred for
30 min; then, substituted benzaldehyde (0.5 mmol) was added to it, and reaction mixture was stirred at 35°C for respective time.
bYield after purification by column chromatography.
cEnantiomeric excess was determined by HPLC on chiralpak OD‐H and AD‐H column.
5, and 7). 2‐Halobenzaldehydes after 72 hours afforded
corresponding products in better yields and ee compared
with corresponding products of 4‐halobenzaldehydes
(Table 4, entries 3‐8). Electron donating group on benzal-
dehyde such as methoxy and methyl was found to be less
reactive than benzaldehyde and 4‐nitrobenzaldehyde and
afforded corresponding products in 22% to 69% yields with
69% to 87% ee (Table 4, entries 9‐13). We also used
conjugated aldehydes cinnamaldehyde for nitro‐aldol
reaction, and poor yield of product was obtained with
moderate ee (Table 4, entry 14). Aliphatic aldehyde like
propanal was also efficiently catalyzed to give the corre-
sponding product in an 80% yield with 73% ee (Table 4,
entry 15). The results show that the better ee was obtained
with most of the 2‐substituted benzaldehydes, which may
be due to steric effect of substrate and the ligand 4b.
TABLE 5 Asymmetric Henry reaction between substituted benzaldehydes and prochiral nitroethanea
Entry
R
Time, h
Yield, %b
dr (anti/syn)d
ee, %c (anti/syn)
1
2
3
NO2
Br
48
72
96
91
76
38
79/21
65/35
47/53
80/66
52/58
3/45
OMe
aLigand 4b and Cu (OAc)2.4H2O (10 mol%) were stirred in isopropanol (2 mL) for 30 min; nitroethane was added to it and further stirred for 30 min. Then,
substituted benzaldehyde (0.5 mmol) was added to it, and reaction mixture was stirred respective time at 35°C.
bYield after purification by column chromatography.
cEnantiomeric excess (ee) was determined by HPLC on chiralpak IC and AD‐H column.
dDiasteiomeric ratio (dr) was determined from 1H NMR.

DIXIT ET AL.
9
We also carried out the Henry reaction between 4‐
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SUPPORTING INFORMATION
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How to cite this article: Dixit A, Kumar P, Singh
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