Pyrrolidine-carbamate based new and efficient chiral organocatalyst for asymmetric Michael addition of ketones to nitroolefins

Article abstract of DOI:10.1016/j.tet.2018.09.002

The novel ((S)-pyrrolidin-2-yl)methyl phenylcarbamate was synthesized and used as an efficient organocatalyst for the asymmetric Michael addition of cyclic/acyclic ketones to nitroolefins. Interestingly, the resulting Michael adducts were obtained in good to high yields (up to 96%) with excellent stereoselectivity (ee up to >99%, dr up to >99:1) without using any additive.

Full text of DOI:10.1016/j.tet.2018.09.002

Accepted Manuscript
Pyrrolidine-carbamate based new and efficient chiral organocatalyst for asymmetric
Michael addition of ketones to nitroolefins
Amarjit Kaur, Kamal Nain Singh, Esha Sharma Shilpy, Poonam Rani, Sandeep
Kumar Sharma
PII:
S0040-4020(18)31055-X
10.1016/j.tet.2018.09.002
TET 29774
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 5 April 2018
Revised Date: 30 August 2018
Accepted Date: 2 September 2018
Please cite this article as: Kaur A, Singh KN, Shilpy ES, Rani P, Sharma SK, Pyrrolidine-carbamate
based new and efficient chiral organocatalyst for asymmetric Michael addition of ketones to nitroolefins,
Tetrahedron (2018), doi: 10.1016/j.tet.2018.09.002.
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ACCEPTED MANUSCRIPT
Graphical Abstract
Pyrrolidine-carbamate based new and
efficient chiral organocatalyst for
asymmetric Michael addition of ketones to
nitroolefins.
a,
a
a
a
a
a
Amarjit Kaur * Kamal Nain Singh , Esha Sharma, Shilpy , Poonam Rani , Sandeep Kumar Sharma
Department of chemistry, Panjab University, Chandigarh. 160014.

1
ACCEPTED MANUSCRIPT
Tetrahedron
journal homepage: www.elsevier.com
Pyrrolidine-carbamate based new and efficient chiral organocatalyst for asymmetric
Michael addition of ketones to nitroolefins
Dedicated to Prof. S. V. Kessar.
a,
a
a
a
a
a
Amarjit Kaur ∗ , Kamal Nain Singh , Esha Sharma , Shilpy , Poonam Rani , Sandeep Kumar Sharma.
a
Department of chemistry, Panjab University, Chandigarh, 160014.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
The novel ((S)-pyrrolidin-2-yl)methyl phenylcarbamate was synthesized and used as
an efficient organocatalyst for the asymmetric Michael addition of cyclic/acyclic
ketones to nitroolefins. Interestingly, the resulting Michael adducts were obtained in
good to high yields (up to 96%) with excellent stereoselectivity (ee up to >99%, dr up
to >99:1) without using any additive.
Available online
2
009 Elsevier Ltd. All rights reserved.
Keywords:
Pyrrolidine
Carbamate
Asymmetric synthesis
Nitroolefins
Michael addition
∗
Corresponding author. Tel.: +91-172-253-4425; fax: +91-172-222-2918; e-mail: amarjitk@pu.ac.in

2
N C O
1
. Introduction
ACCEPTED MANUSCRIPT
O
O
BMS
OH
O
HCOOH
O
The development of small molecules as efficient chiral
organocatalysts have attracted considerable attention from a large
number of research groups working in the area of asymmetric
COOH
N
N
N
N
Boc
THF
Boc
4 (93%)
DMAP
DCM
Boc
HN
(91%)
H
HN
(84%)
3
5
1
1,2
N C S
3 2
BF .Et O
synthesis.
The asymmetric Michael addition reaction of
THF, reflux
carbonyl compounds and nitroolefins to afford γ–nitrocarbonyls
is widely recognized due to its versatile utility in organic
S
S
3,4
O
HCOOH
O
synthesis.
Pyrrolidine based organocatalysts bearing other
N
N
H
5a
Boc
HN
HN
functional5 groups such as chiral sulfonamides,
prolinols, the corresponding amide, triazole,
diaryl
6d-f
tetrazole,
b
5c,d
6a-c
6
(42%)
2 (81%)
7
8
Scheme 1: Synthesis of organocatalysts 1 and 2
amine thiourea, thio-hydantoins etc. also proved that such
bifunctional molecules can catalyze a variety of asymmetric
transformations. Carbamates and thiocarbamates have been
studied in the field of medicinal chemistry on account of their
Our initial study commenced with the reaction of cyclohexanone
7a) and trans β-nitrostyrene (8a) in the presence of chiral
catalyst 1. Use of 20 mol% of catalyst 1 in chloroform at room
temperature, without any additive, gave Michael adduct 9a in
(
9
diverse and useful biological activities. However, despite of
having been well studied for their synthesis and biological
properties, there are only a few reports on their application as
8
4% yield with high syn diastereoselectivity (dr >99:1) and good
10
enantioselectivity (87% ee) (Table 1, entry 1). Lowering of
reaction temperature in chloroform as solvent did not further
increase the enantioselectivity (Table 1, entry 2). To further
optimize the reaction conditions, a variety of solvents were
screened. Catalytic system was found to be effective for non
polar, polar and polar-protic solvent systems (Table 1). Best
results were obtained using toluene as the solvent medium and
the corresponding Michael adduct 9a was obtained in excellent
yield 96% and stereoselectivity (ee >99% and dr >99:1) (Table 1,
entry 6). However trace amount of product was observed when
water or brine was used as solvent. To check the importance of
carbamate and O-thiocarbamate functionality in the side chain of
organocatalyst on the stereochemical outcome of the reaction,
organocatalyst 2 was also screened for asymmetric Michael
addition of cyclohexanone (7a) to β-nitrostyrene (8a) under
optimized reaction conditions, surprisingly trace amount of
product was obtained when organocatalyst 2 was employed
organocatalysts for asymmetric organic transformations.
Stimulated by these findings and in continuation with our search
11
for new and efficient organocatalysts, we have developed novel
bifunctional organocatalyst by combining L-prolinol with
phenylisocyanate to give corresponding carbamate 1. We
explored the use of chiral carbamate 1 in asymmetric Michael
addition. This catalyst was found to be very efficient for
stereoselective conjugate addition of ketones (cyclic/acyclic) to
various aryl substituted nitro olefins and afforded the
corresponding Michael adducts in high yield (up to 96%), with
excellent enantio- and diastereoselectivity (ee up to >99%, dr up
to >99:1). The results are described in this paper.
2
. Results and discussion
The chiral catalysts 1 and 2 employed in this work were easily
synthesized, according to reaction scheme 1. Reduction of Boc-
protected L-proline 3 with borane-methyl sulfide complex (BMS)
12
(
Table 1, entry 13). On changing the solvent system from toluene
afforded the alcohol 4.
On treating alcohol 4 with
to toluene:methanol (1:1) under same catalytic system, afforded
the Michael adduct in 42% yield after stirring for 4 days at rt
with enantioselectivity (23% ee) and high diastereoselectivity
phenylisocyante in the presence of catalytic amount of DMAP
gave corresponding carbamate 5. To synthesize the sulfur
analogue of 5, alcohol
4 was refluxed in THF with
(
Table 1, entry 14). The observed results clearly showed that
phenylisothiocyanate in the presence of BF .Et O to give
3
2
carbamate moiety in combination with pyrrolodine –NH itself
effectively catalyze and control the stereochemical outcome of
the reaction. The phenyl ring of the carbamate 1 need not be
substituted with strongly electron withdrawing groups such as –
CF and -NO or with bulkier substituent to stabilize the favored
corresponding O-thiocarbamate 6. N-Boc deprotection of 5 and 6
with formic acid furnished the organocatalysts 1 and 2
respectively.
13
3
2
transition state, which controls the stereochemistry of the
Michael adduct formed as is the case with most of the
14
bifunctional organocatalysts reported in the literature for such
transformations.
a
Table 1 Optimization of reaction conditions :
O
O
NO2
1
, 20 mol %
NO2
solvent, rt
9a
7a
8a
b
c
d
Entry
1
Solvent
Time (h)
Yield (%)
ee (%)
dr (syn:anti)
CHCl
3
3
28
36
26
84
80
86
87
88
90
>99:1
99:1
e
2
CHCl
3
CH
2
Cl
2
98:2

3
4
5
6
7
8
9
THF
Ether
32
82
91
92
>99
98
97
97
95
-
99:1
>99:1
>99:1
>99:1
99:1
98:2
97:3
-
ACCEPTED MANUSCRIPT
35
24
27
30
32
34
72
72
72
96
81
96
Toluene
DMSO
DMF
75
79
MeOH
88
1
0
1
2
EtOH
85
1
1
Water
traces
traces
traces
42
Brine
-
-
f
1
1
3
4
Toluene
Toluene:MeOH
-
-
f
23
99:1
(1:1)
a
b
c
d
e
f
Reaction conditions: nitrostyrene (1.3 mmol), cyclohexanone (2.6 mmol), catalyst 1 (20 mol %), solvent (10.0 mL), rt.
Isolated yield.
Determined by chiral HPLC using Chiralpak AS-H column.
1
Determined by H NMR analysis of crude sample.
Reaction was performed at 0 °C.
Reaction was carried out in the presence of 2 (20 mol %) as an organocatalyst.
concentration of the catalyst i.e. 10 mol% and 15 mol% (Table 2,
entry 2, 3). Increase in the catalyst loading up to 25 mol% did not
show any remarkable effect on reaction time, yield and
stereoselectivity. Hence, the use of 20 mol% of catalyst at room
temperature provided the best optimized reaction conditions.
Next, using toluene as a solvent, the effect of catalyst loading
was evaluated and results are summarized in Table 2. The
decrease in catalyst loading (5 mol %) resulted in lower yield,
without affecting the stereoselectivity of the reaction. Prolonged
reaction time was required to complete the reaction with lower
a
Table 2: Effect of catalyst loading
b
c
d
Entry
Catalyst 1 (mol%)
Time (h)
Yield (%)
ee (%)
dr (syn:anti)
1
2
3
4
5
5
96
90
71
24
24
70
88
89
96
97
99
99
99:1
99:1
10
15
20
25
>99
>99
>99
99:1
>99:1
>99:1
a
b
c
d
Reaction conditions: nitrostyrene (1.3 mmol), cyclohexanone (2.6 mmol), toluene (10.0 mL), rt.
Isolated yield.
Determined by chiral HPLC using Chiralpak AS-H column.
1
Determined by H NMR analysis of crude sample.
With the optimized reaction conditions in hand, asymmetric
Michael addition of ketones 7 (cyclic/acyclic) to various
substituted nitroolefins 8 was investigated and results are shown
in Table 3. The corresponding Michael adducts 9 were obtained
in good to excellent yields with high enatio- and
diastereoselectivity. The catalyst 1 effectively catalyze the
Michael addition of cyclohexanone to nitrostyrenes bearing
different substituents such as methoxy (Table 3 entries 2-4), nitro
as well as chloro (Table 3 entries 7,8) irrespective of their
position on aromatic ring. The benzyl substituent on the aryl
group of nitroolefin 8f causes the significant decrease in the
enantioselectivity (ee =52%) (Table 3, entry 6). The reason may
be the bulkier benzyl group hinders the effective approach of
nitrostyrene to enamine intermediate formed during the course of
reaction. Interestingly, the given catalytic system was also found
to be effective for acetone and diethyl ketone as Michael donor to
afford the corresponding Michael adduct in excellent yield and
stereoselectivity (Table 3, entries 10-12). It is pertinent to note
here that most of the catalytic systems reported, for such
transformations are not simultaneously effective for both cyclic
15
and acyclic Michael donors. However, the reaction with
cyclopentanone gave the corresponding adduct in good yield with
moderate
stereoselectivity
(Table
3,
entry
13).
a
Table 3: Asymmetric Michael addition catalyzed by 1

4
b
c
d
Entry
7
8
Ar
Time (h)
Product 9
Yield (%)
ee (%)
dr (syn:anti)
ACCEPTED MANUSCRIPT
1
2
3
4
5
6
7
8
9
8a
8b
8c
8d
8e
8f
C
6
H
5
24
26
25
32
28
30
28
30
27
24
9a
9b
9c
9d
9e
9f
96
93
90
89
93
89
90
90
93
93
>99
>99
99
>99:1
>99:1
>99:1
99:1
O
3-OCH
3
3
C
6
6
H
4
4
4-OCH
C
H
7
a
2-Cl,3,4-(OCH
3
)
2
C
6
H
2
>99
95
3-OCH
3-OCH
3
,4-OEt,C
6
H
3
>99:1
>99:1
98:2
3
,4-OCH PhC
2
6
H
3
52
8g
8h
8i
4-NO
4-ClC
benzo[d][1,3]dioxol-5-yl
2
C
6
H
4
9g
9h
9i
98
6
H
4
95
>99:1
>99:1
-
98
1
1
0
1
8a
C
6
H
5
9j
98
O
8j
4-ClC
6
H
4
25
35
9k
9l
92
88
95
90
-
7
b
1
2
8a
C
C
6
H
5
99:1
O
7
c
1
3
8a
6
H
5
30
9m
84
82
86:14
O
7
d
a
b
c
d
Reaction conditions: nitroalkene (1.0 equiv, 0.2 g scale), ketone (2.0 equiv), catalyst 1 (20 mol %) toluene (10.0 mL), rt.
Isolated yield.
Determined by chiral HPLC.
1
Determined by H NMR analysis of crude sample.
1
5a,16
The possible transition state model
was proposed to explain
useful in the asymmetric Michael addition of cyclic/acyclic
ketones to nitroolefins. The chiral catalyst was easily prepared
from commercially available N-Boc-L-proline and is highly
efficient in catalyzing the Michael reaction to afford the
corresponding adducts with excellent enantio- as well as
diastereoselectivities in high yields, without any additive. Further
investigations of such chiral catalysts for related asymmetric
transformations are currently in progress.
the stereochemical outcome of the asymmetric Michael addition
reaction (Figure 1). Ketones are activated by the secondary amine
of the pyrrolidine ring of the catalyst through the formation of an
enamine intermediate. The approach of nitroolefin is controlled
by the carbamate functionality by stabilizing the interaction
through hydrogen bond formation, which directs the nitroolefin
in such a manner, so that E-enamine attacks the olefinic double
bond from the Re-face. Finally it seems to be the combined effect
of steric factors and the intermolecular hydrogen bonding which
leads to higher stereoselectivity in the reaction to furnish S, R-
product. The configuration of chiral centres in the Michael
adduct was assigned as on the basis of comparison of retention
time using chiral HPLC with those reported in literature.
4
. Experimental section
4.1 Material and methods
Melting points were obtained on a Thomas-Hoover apparatus in
1
open capillaries and are uncorrected. H NMR spectra were
recorded in CDCl solution on a Jeol AL 300 MHz or Bruker 400
3
MHz spectrometer; the chemical shifts are reported in parts per
O
million (δ) relative to internal standard TMS (0 ppm) and the
coupling constants (J) are reported in hertz (Hz). C NMR
O
N
H
13
N
O
N
O
spectra were obtained at 75 MHz or 100 MHz and are referenced
to the internal solvent signals. MS and HRMS data were obtained
on a Q-Tof micro™ Mass Spectrometer. Chiral HPLC analysis
were carried out on a Waters 2996 system using Daicel Chiralpak
AS-H and Chiralcel OD columns. Elemental analysis was
performed with a Flash 2000 organic elemental analyzer.
E-enamine
Re -face
Figure 1 Putative transition state.
. Conclusion
1
7
Nitroolefins were prepared according to literature procedures.
Products were isolated and purified by column chromatography
over silica gel using hexane–EtOAc (9:1–8:2) as eluent.
3
We have developed novel ((S)-pyrrolidin-2-yl)methyl
phenylcarbamate 1 as new chiral bifunctional organocatalyst

5
ACCEPTED MANUSCRIPT
1
4
.2.1 (S)-tert-Butyl 2-(hydroxymethyl)pyrrolidine-1-carboxylate
H NMR (400 MHz, CDCl ): δ 9.46 (br s, 1H), 8.78 (br s, 1H),
7.53 (d, J = 7.8 Hz, 2H), 7.27 (t, J = 7.7 Hz, 2H), 7.04 (t, J = 7.3
3
12
(4).
Hz, 1H), 4.44-4.33 (m, 2H), 3.81-3.79 (m, 1H), 3.38-3.31 (m,
To
a
solution of (S)-1-(tert-butoxycarbonyl)pyrrolidine-2-
1
1
1
H), 3.26-3.20 (m, 1H), 2.07-1.99 (m, 2H), 1.96-1.86 (m, 1H),
carboxylic acid 3 (2.0 g, 9.3 mmol) in dry THF (25 mL) was
added borane dimethyl sulphide complex (1.66 g, 18.6 mmol)
dropwise under nitrogen atmosphere at 0°C and the reaction mass
was stirred at the same temperature for 5h and then at rt
overnight. Water (30 mL) was added carefully to quench the
reaction and the contents were extracted with ethyl acetate (3×25
mL). The combined organic extract was washed with saturated
sodium bicarbonate solution, water, brine and dried over
anhydrous Na SO and concentrated in vacuo to afford 4 as an oil
13
.77-1.67 (m, 1H). C NMR (100 MHz, CDCl ): δ 153.0, 138.0,
3
28.9, 123.4, 118.7, 62.4, 59.0, 45.2, 26.3, 23.5.
-
1
IR (Neat): ν 3242, 2885, 2739, 2495, 1725, 1596, 1532 cm .
+
+
HRMS (ES ): m/z [M + H] calcd for C H N O : 221.1290;
12
17
2
2
found: 221.1234.
2
4
which spontaneously solidified at room temperature as a white
solid (1.73 g, 93%). mp 57-59 °C, (Lit. mp 58-59 °C).
4
.2.4 O-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)methyl N-
12
phenylcarbamothioate (6)
1
H NMR (300 MHz, CDCl ): δ 3.87 (br s, 1 H), 3.52-3.49 (m, 2
3
(
3
S)-tert-Butyl 2-(hydroxymethyl)pyrrolidine-1-carboxylate (4;
.0 g, 14.93 mmol) was refluxed in THF (60 ml), with
H), 3.40-3.31 (m, 1 H), 3.28-3.22 (m, 1 H), 1.95-1.90 (m, 1 H),
1
.76-1.69 (m, 2 H), 1.51-1.43 (m, 1 H), 1.40 (s, 9 H).
phenylisothiocyanate (1.78 g, 14.93 mmol) in the presence of
BF .Et O (0.96 g, 7.47 mmol) for 12 h. After the completion of
3
2
4
.2.2 ((S)-1-(tert-Butoxycarbonyl)pyrrolidin-2-yl)methyl
reaction as indicated by TLC, reaction mass was concentrated
under reduced pressure to give crude mass which was purified by
column chromatography using hexane–EtOAc (9:1–8:2) as
eluent, afforded 6 as a colorless oil (2.1 g, 42%).
phenylcarbamate (5)
To
a
stirred
solution
of
(S)-tert-butyl
2-
(
hydroxymethyl)pyrrolidine-1-carboxylate (4; 1.0 g, 4.98 mmol)
1
and phenylisocyanate (0.54 g, 4.98 mmol) in dry chloroform (20
mL) was added catalytic amount of DMAP and the reaction mass
was allowed to stir at rt. Fine white colored solid product started
precipitating out soon after the addition and when TLC showed
the complete consumption of both starting materials after about
H NMR (400 MHz, CDCl ): δ 9.50 (br s, 1H), 7.34-7.30 (m,
3
2H), 7.27-7.23 (m, 2H), 7.09-7.05 (m, 1H), 4.18 (br s, 2H), 3.70-
3.66 (m, 1H), 3.44-3.39 (m, 2H), 2.12-2.04 (m, 1H), 1.95-1.81
13
(m, 2H), 1.72-1.70 (m, 1H), 1.18 (s, 9H). C NMR (100 MHz,
CDCl ): δ 172.7, 158.5, 140.3, 128.5, 125.0, 120.9, 99.9, 75.1,
66.9, 61.3, 52.6, 48.1, 29.7, 27.5, 23.3.
3
6
h stirring, reaction mass was diluted with chloroform (30 mL)
and washed with brine (20 mL). Chloroform layer was dried over
anhydrous Na SO and concentrated under reduced pressure to
give 5 as white solid. Compound 5 could be crystallized from
boiling DCM:Hexane to give 5 as colorless crystalline compound
2
4
IR (Neat): ν 3300, 3108, 2975, 2874, 1632, 1600, 1567, 1497,
-1
1
349 cm .
(1.45 g, 91%); mp 115-118 °C.
4
.2.5 O-((S)-pyrrolidin-2-yl)methyl N-phenylcarbamothioate (2)
1
H NMR (400 MHz, CDCl ): δ 7.39 (d, J = 7.56 Hz, 2H), 7.32 (t,
3
O-((S)-pyrrolidin-2-yl)methyl N-phenylcarbamothioate (2) was
synthesized from O-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-
yl)methyl N-phenylcarbamothioate (6; 1.0 g, 2.97 mmol)
following the same procedure as for compound 1. Purification
by column chromatography using hexane–EtOAc (8:2) as eluent,
afforded 2 as colorless oil (0.57 g, 81%).
J = 7.52 Hz, 2H), 7.07 (t, J = 7.08 Hz, 1H), 6.76-6.92 (m, 1H),
4
1
1
2
.27 (d, J = 7.44 Hz, 1H), 4.12- 4.00 (m, 2H), 3.36 (br s, 2H),
13
.90-1.81 (m, 4H), 1.47 (s, 9H). C NMR (75 MHz, CDCl ): δ
3
54.3, 153.3, 137.8, 129.0, 123.4, 118.6, 79.9, 65.3, 55.8, 46.6,
8.4, 23.0.
-
I1R (Neat): ν 3267, 2973, 2879, 1732, 1652, 1601, 1544, 1410 cm
1
H NMR (400 MHz, CDCl ): δ 7.27-7.23 (m, 2H), 7.03 (t, J = 7.4
3
Hz, 1H), 6.95-6.92 (m, 2H), 4.24-4.18 (m, 1H), 3.70-3.63 (m,
1
1
H), 3.41-3.35 (m, 1H), 2.95 (t, J = 9.8 Hz, 1H), 2.27-2.21 (m,
+
+
+
HRMS (ES ): m/z [M + Na] calcd for C H N O Na :
3
17
24
2
4
H), 2.18-2.11 (m, 1H), 2.07-2.00 (m, 1H), 1.62-1.52 (m, 1H).
43.1628; found: 343.1642.
13
C NMR (100 MHz, CDCl ): δ 157.0, 152.0, 128.7, 122.9,
3
1
22.0, 64.7, 45.5, 33.8, 30.8, 27.7.
4
.2.3 ((S)-pyrrolidin-2-yl)methyl phenylcarbamate (1)
-
1
IR (Neat): ν 2970, 2871, 1614, 1578, 1479, 1385 cm
Formic acid (10.0 mL) was slowly added to ((S)-1-(tert-
butoxycarbonyl)pyrrolidin-2-yl)methyl phenylcarbamate (5, 1.0
g, 3.12 mmol) and the resulting solution was allowed to stir at
room temperature for 10 h. Excess formic acid was removed
under reduced pressure and the residue was carefully neutralized
+
+
HRMS (ES ): m/z [M + H] calcd for C H N OS: 237.1061;
12
17
2
found: 237.1052.
4
.3. Typical procedure for enantioselective Michael addition
catalyzed by organocatalyst 1
by saturated Na CO3 solution. The reaction mixture was
2
extracted with chloroform (3x 20 mL) and washed with brine (20
mL) dried over anhydrous Na SO and concentrated in vacuo to
2
4
afford 1 as pale yellow viscous mass. Purification by column
Cyclic ketone (2 equiv) was added to the stirred solution of
organocatalyst 1 (20 mol%) in toluene (10 mL) and the reaction
mixture was allowed to stir at room temperature for half an hour.
chromatography (CHCl -MeOH 9:1) afforded 1 as a colorless oil
3
(0.58 g, 84%).

6
1
3
trans-β-Nitrostyrene (1 equiv, 0.2 g scale) w
A
as
C
ad
C
d
E
ed
P
a
T
nd
E
t
D
he MA
C
NUNM
S
R
I
CR(10PTMHz, CDCl ): δ 210.5, 149.0, 148.3, 127.0,
0
3
reaction mixture was allowed to stir at rt for appropriate time
After complete consumption of nitrostryene, indicated by TLC,
the solvent was evaporated under reduced pressure and residue
was dissolved in ethyl acetate (20 mL). The organic layer was
washed with 10% HCl (10 mL), water (10 mL), saturated
NaHCO3 solution (10 mL), brine (10 mL) and dried over
anhydrous Na SO . The solvent was evaporated under reduced
125.3, 113.1, 76.5, 56.1, 55.8, 51.5, 42.6, 41.1, 33.1, 28.5, 25.4.
-
1IR (Neat): ν 2937, 2852, 1697, 1604, 1546, 1508, 1445, 1381 cm
Anal. Calcd for C H ClNO : C, 56.23; H, 5.90; N, 4.10. Found:
16
20
5
C, 56.24; H, 5.75; N, 4.02.
HPLC (Chiralpak AS-H, hexane/i-PrOH = 90:10, flow rate 0.5
mL/min, λ = 254.0 nm), t (minor) = 20.88 min, t (major) = 26.81
2
4
pressure to afford the crude product which was purified by
column chromatography over silica gel using hexane-ethyl
acetate (9:1-8:2) as an eluent. The configuration of chiral centres
in the Michael adduct was assigned as on the basis of comparison
of retention times in chiral HPLC with those reported in
literature.
R
R
min, syn/anti = 99:1; ee >99%.
4.3.5(S)-2-((R)-1-(4-Ethoxy-3-methoxyphenyl)-2-
nitroethyl)cyclohexanone (9e)
11b
11b
Yield: 0.27 g (93%); white solid, mp 125-127 °C (Lit. mp 123-
1
1
25 °C).
15b
4
.3.1 (S)-2-((R)-2-nitro-1-phenylethyl)cyclohexanone (9a)
H NMR (400 MHz, CDCl ): δ 6.73 (d, J = 7.8 Hz, 1H), 6.62-
6.59 (m, 2H), 4.85 (dd, J = 12.3, 4.6 Hz, 1H), 4.56 (dd, J = 12.3,
9.9 Hz, 1H), 4.01 (q, J = 7.0 Hz, 2H), 3.78 (s, 1H), 3.65 (dt, J =
.9, 4.6 Hz, 1H), 2.60-2.53 (m, 1H), 2.41-2.37 (m, 1H), 2.34-2.30
m, 1H), 2.02-1.97 (m, 1H), 1.74-1.48 (m, 4H), 1.39 (t, J = 7.0
Hz, 3H), 1.21-1.15 (m, 1H).
3
1
8b
Yield: 0.31 g (96%); white solid, mp 125-127 °C (Lit. mp 124-
1
1
26 °C).
9
(
H NMR (300 MHz, CDCl ): δ 7.25-7.17 (m, 3H), 7.08 (d, J =
3
6
.3 Hz, 2H), 4.84 (dd, J = 12.3, 4.5 Hz, 1H), 4.57-4.49 (m, 1H),
.68 (dt, J = 9.9, 4.5 Hz, 1H), 2.65-2.56 (m, 1H), 2.42-2.24 (m,
H), 2.03-1.98 (m, 1H), 1.69-1.51 (m, 4H), 1.19-1.14 (m, 1H).
3
2
13
C NMR (100 MHz, CDCl ): δ 212.1, 149.3, 147.8, 130.0,
20.1, 112.7, 111.7, 79.0, 64.2, 56.0, 52.7, 43.6, 42.7, 33.1, 28.5,
5.0, 14.8.
3
13
1
2
C NMR (75 MHz, CDCl ): δ 211.0, 137.9, 129.0, 128.2, 127.8,
3
7
8.7, 52.5, 44.0, 42.6, 33.2, 28.5, 25.1.
HPLC (Chiralpak AS-H), hexane/i-PrOH = 90:10, flow rate 0.5
HPLC (Chiralpak AS-H), hexane/i-PrOH = 90:10, flow rate 0.5
mL/min, λ= 223.3 nm), t (minor) = 14.74 min, t (major) = 17.38
min, syn/anti >99:1; ee> 99%.
mL/min, λ = 233.4 nm), t (minor) = 18.45 min, t (major) = 23.0
R
R
R
R
min. syn/anti >99:1; ee = 95%.
4
.3.6
(S)-2-((R)-1-(4-(benzyloxy)-3-methoxyphenyl)-2-
4
.3.2 (S)-2-((R)-1-(3-Methoxyphenyl)-2-nitroethyl)cyclohexanone
18c
nitroethyl)cyclohexanone (9f)
(9b).
6c
Yield: 0.24 g (89%); white solid, mp 141-143 °C
Yield: 0.29 g (93%); white solid, mp 131-133 °C (Lit. mp 133-
1
1
34 °C).
H NMR (300 MHz, CDCl ): δ 7.43-7.26 (m, 5H), 6.83-6.62 (m,
3
1
3
3
2
H), 5.10 (s, 2H), 4.91-4.86 (m, 1H), 4.62-4.57 (m, 1H), 3.87 (s,
H), 3.70–3.67 (m, 1H), 2.63–2.62 (m, 1H), 2.45–2.36 (m, 2H),
.08–2.04 (m,1H), 1.80–1.57 (m, 4H), 1.27–1.21 (m,1H).
H NMR (300 MHz, CDCl ): δ 7.24 (t, J = 7.8 Hz, 1H), 6.78-
3
6
3
.67 (m, 3H), 4.89 (dd, J= 12.3, 4.2 Hz, 1H), 4.63-4.55 (m, 1H),
.78 (s, 3H), 3.69- 3.68 (m, 1H), 2.70-2.61 (m, 1H), 2.45-2.36
13
(m, 2H), 2.11-2.06 (m, 1H), 1.78-1.49 (m, 4H), 1.30-1.19 (m,
C NMR (75 MHz, CDCl ): δ 212.0, 149.7, 147.4, 137.0, 130.6,
3
1
H)
128.5, 127.8, 127.2, 120.0, 114.0, 112.1, 78.9, 71.0, 56.1, 52.7,
3.6, 42.7, 33.1, 28.5, 25.0.
IR (Neat): ν 3035, 2944, 2868, 1697, 1591, 1549, 1516, 1455,
13
4
C NMR (75 MHz, CDCl ): δ 211.0, 159.9, 139.4, 129.9, 120.2,
3
114.4, 112.7, 78.6, 55.0, 52.5, 44.0, 42.6, 33.2 28.5, 25.1.
-
1
1
385, 1258, 1230 cm
HPLC (Chiralpak AS-H), hexane/i-PrOH = 90:10, flow rate 0.5
mL/min, λ = 254.0 nm), t (minor) = 20.16 min, t (major) = 27.11
R
R
Anal. Calcd for C H NO : C, 68.91; H, 6.57; N, 3.65. Found: C,
22 25 5
min, syn/anti >99:1; ee >99%.
68.25; H, 6.41; N, 3.64.
4
.3.3 (S)-2-((R)-1-(4-Methoxyphenyl)-2-nitroethyl)cyclohexanone
HPLC (Chiralpak AS-H), hexane/i-PrOH = 90:10, flow rate 0.5
mL/min, λ = 226.5 nm), t (minor) = 29.93 min, t (major) = 38.63
min, syn/anti >99:1; ee = 52%.
18b
(9c).
R
R
18d
Yield:0.28 g (90%); white solid, mp 151-153 °C (Lit. mp 153-
1
54 °C).
4.3.7
(S)-2-((R)-2-nitro-1-(4-nitrophenyl)ethyl)cyclohexanone
1
8a
1
(9g)
H NMR (300 MHz, CDCl ): δ 6.99 (d, J = 8.4 Hz, 2H), 6.75 (d,
3
J= 8.4 Hz, 2H), 4.80 (dd, J = 4.8, 12.3 Hz, 1H), 4.52 (dd, J = 9.6,
Yield: 0.27 g (90%); white solid, mp 124-127 °C.
1
2
1
2.0 Hz, 1H), 3.70 (s, 3H), 3.63-3.55 (m, 1H), 2.60-2.52 (m, 1H),
.41-2.28 (m, 2H), 2.03-1.97 (m, 1H), 1.70-1.48 (m, 4H), 1.18-
.10 (m, 1H)
1
H NMR (300 MHz, CDCl ): δ 8.13 (d, J = 8.7 Hz, 2H), 7.31 (d,
3
J = 8.7 Hz, 2H), 4.87 (dd, J = 12.9, 4.5 Hz, 1H), 4.63 (dd, J =
1
2.9, 9.9 Hz, 1H), 3.83–3.75 (m, 1H), 2.66–2.57 (m, 1H), 2.43–
13
C NMR (75 MHz, CDCl ): δ 211.3, 159.2, 129.7, 129.3, 114.5,
2.23 (m, 2H), 2.03–1.80 (m, 1H), 1.73–1.37 (m, 4H), 1.25–1.16
(m, 1H).
3
7
9.0, 55.2, 52.8, 43.4, 42.7, 33.2, 28.7, 25.3.
13
HPLC (Chiralpak AS-H, hexane/i-PrOH = 85:15, flow rate 0.5
mL/min, λ = 240.1 nm), t (minor) = 24.46 min, t (major) = 26.69
C NMR (75 MHz, CDCl ): δ 209.6, 147.2, 145.4, 129.2, 124.2,
3
R
R
77.8, 52.3, 43.8, 42.6, 33.2, 28.3, 25.3.
min, syn/anti >99:1; ee = 99%.
HPLC (Chiralpak AS-H), hexane/i-PrOH = 85:15, flow rate 1.0
mL/min, λ = 250.0 nm), t (minor) = 23.23 min, t (major) = 26.73
4
.3.4
(S)-2-((R)-1-(2-chloro-3,4-dimethoxyphenyl)-2-
R
R
nitroethyl)cyclohexanone (9d).
min, syn/anti = 98:2; ee = 98%.
Yield:0.25 g (89%); white solid, mp 99-101 °C
Anal. Calcd for C H N O : C, 57.53; H, 5.52; N, 9.58. Found:
14 16 2 5
C, 57.20; H, 5.43; N, 9.49.
1
H NMR (400 MHz, CDCl ): δ 6.75 (s, 1H), 6.59 (s, 1H), 4.87-
3
4
2
1
.80 (m, 1H), 4.72-4.67 (m, 1H), 4.06-3.98 (m, 1H), 3.79 (s, 6H),
.89-2.82 (m, 1H), 2.43–2.26 (m, 2H), 2.08–2.04 (m, 1H), 1.82–
.55 (m, 4H), 1.33–1.21 (m,1H).

7
4
.3.8 (S)-2-((R)-1-(4-Chlorophenyl)-2-nitroeth
A
yl
C
)cy
C
cl
E
oh
P
ex
T
a
E
no
D
ne MA
H
N
PL
U
C
S
(C
C
h
R
ira
I
lcel OD, hexane/i-PrOH = 90:10, flow rate 0.5
P
T
15b
(9h)
mL/min, λ= 219.7 nm), t (minor) = 19.3 min, t (major) = 23.9
R
R
1
8c
min, syn/anti = 99:1; ee = 90%.
Yield: 0.28 g (90%); white solid, mp 91-93 °C (Lit. mp 93-96
1
5b
°
1
C).
4.3.13 (S)-2-((R)-2-nitro-1-phenylethyl)cyclopentanone (9m)
18b
H NMR (300 MHz, CDCl ): δ 7.23 (d, J = 8.4 Hz, 2H), 7.04 (d,
Yield: 0.26 g (84%); white solid, mp 115-117 °C (Lit. mp 116-
3
J = 8.4 Hz, 2H), 4.83 (dd, J = 4.8, 12.6 Hz, 1H), 4.57-4.47 (m,
119 °C).
1
1
2
H), 3.71–3.61 (m, 1H), 2.64–2.52 (m, 1H), 2.41–2.23 (m, 2H),
.05–2.01 (m,1H), 1.76–1.44 (m, 4H), 1.22–1.10 (m,1H).
H NMR (300 MHz, CDCl ): δ 7.25-7.14 (m, 3H), 7.07-7.05 (m,
3
2
H), 5.23 (dd, J= 5.7, 12.9 Hz, 1H), 4.62 (dd, J= 9.0, 12.9 Hz,
1
3
C NMR (75 MHz, CDCl ): δ 210.6, 136.3, 133.8, 129.5, 129.2,
1H), 3.63 (dt, J= 5.4, 9.0 Hz, 1H), 2.33-2.19 (m, 2H), 2.16-1.90
3
7
8.4, 52.4, 43.4, 42.6, 33.1, 28.4, 25.2.
(m, 1H), 1.88-1.56 (m, 3H), 1.48-1.34 (m, 1H).
13
HPLC (Chiralpak AS-H), hexane/i-PrOH = 90:10, flow rate 0.5
mL/min, λ = 254.0 nm), t (minor) = 17.10 min, t (major) = 19.76
CNMR (75 MHz, CDCl ): δ 218.4, 137.8, 128.9, 128.8, 127.9,
3
78.2, 51.2, 44.2, 38.5, 28.4, 20.3.
R
R
min, syn/anti >99:1; ee = 95%.
HPLC (Chiralpak AS-H, hexane/i-PrOH = 85:15, flow rate 0.5
mL/min, λ = 228.9 nm), t (minor) = 17.2 min, t (major) = 23.6
min, syn/anti = 86:14; ee = 82%.
4
.3.9
nitroethyl)cyclohexanone(9i)
Yield: 0.28 g (93%); white solid, mp 141-143 °C (Lit. mp 144-
(S)-2-((R)-1-(Benzo[d][1,3]dioxol-5-yl)-2-
R
R
15b
18b
Acknowledgments
1
1
45 °C).
H NMR (400 MHz, CDCl ): δ 6.66 (d, J = 7.8 Hz, 1H), 6.55-
3
We acknowledge financial support from the Science and
engineering research board (SERB), New Delhi, through Scheme
number EEQ/2016/000574. The NMR spectroscopy and Mass
spectrometry facility of SAIF, Panjab University, Chandigarh is
gratefully acknowledged.
6
.52 (m, 2H), 5.88 (s, 2H), 4.81 (dd, J = 12.3, 4.4 Hz, 1H), 4.49
(dd, J = 12.3, 9.9 Hz, 1H), 3.60 (dt, J = 9.9, 4.4 Hz, 1H), 2.56-
2
.49 (m, 1H), 2.41-2.37 (m, 1H), 2.33-2.25 (m, 1H), 2.04-1.99
(
m, 1H), 1.76-1.42 (m, 4H), 1.22-1.13 (m, 1H).
1
3
C NMR (100 MHz, CDCl ): δ 211.2, 148.1, 147.1, 131.2,
3
1
2
21.6, 108.5, 108.0, 101.1, 78.8, 52.6, 43.7, 42.6, 33.1, 28.5,
5.1.
5
. References and notes
HPLC (Chiralpak AS-H), hexane/i-PrOH = 90:10, flow rate 0.5
mL/min, λ = 236.5 nm), t (minor) = 47.1 min, t (major) =51.9
1
For books, see: (a) Berkessel, A.; Groger, H. Asymmetric
Organocatalysis-From Biomimetic Concepts to Powerful Methods for
Asymmetric Synthesis, ed. Berkessel, A.; Wiley-VCH: Weinheim,
2005. (b) Dalko, P. I. Enantioselective Organocatalysis Reactions and
Experimental Procedure, ed. Dalko, P. I.; Wiley-VCH: Weinheim,
R
R
min, syn/anti >99:1; ee = 98%.
15b
4
.3.10 (R)-5-nitro-4-phenylpentan-2-one (9j)
3g
Yield: 0.26 g (93%); white solid, mp 88-90 °C, (Lit. mp 90-92
2007
For selected reviews on organocatalysis, see: (a) Dalko, P. I.; Moisan,
L. Angew. Chem. Int. Ed. 2004 43, 5138. (b) Seayad, J.; List, B. Org.
Biomol. Chem. 2005 , 719. (c) Enders, D.; Grondal, C.; Hüttl, M. R.
M. Angew. Chem. Int. Ed. 2007 46, 1570. (d) Gaunt, M. J.;
Johansson, C. C. C.; McNally, A.; Vo, N. T. Drug Discovery Today
.
°
1
C).
2
,
H NMR (300 MHz, CDCl ): δ 7.24-7.18 (m, 3H), 7.13-7.11 (m,
3
,
3
2
H), 4.62-4.43 (m, 2H), 3.94-3.83 (m, 1H), 2.84 (d, J = 6.0 Hz,
,
2
H), 2.04 (s, 3H).
1
3
CNMR (75 MHz, CDCl ): δ 204.5, 138.9, 129.0, 127.9, 127.4,
2007
Dondoni, A.; Massi, A. Angew. Chem. Int. Ed. 2008
Bertelsen, S.; Jorgensen, K. A. Chem. Soc. Rev. 2009
Enders, D.; Wang, C.; Liebich, J. X. Chem. Eur. J. 2009
i) Grondal, C.; Jeanty, M.; Enders, D. Nat. Chem., 2010
MacMillan, D. W. Nature 2008 455, 304. (k) Bisai, V.; Bisai, A.;
Singh, V. K. Tetrahedron 2012 68, 4541. (l) Kang, Y. K.; Kim, S.
M.; Kim, D. Y. J. Am. Chem. Soc. 2010 132, 11847. (m) Liu, W.;
Mei, D.; Wang, W.; Duan, W. Tetrahedron Lett 2013 54, 3791. (n)
Mondal, A.; Bhowmick, S.; Ghosh, A.; Chanda, T.; Bhowmick K. C.
Tetrahedron: Asymmetry 2017 28, 849.
,
12, 8. (e) Pellissier, H. Tetrahedron 2007
,
63, 9267. (f)
47, 4638. (g)
38, 2178. (h)
3
7
9.3, 46.1, 39.0, 30.2.
,
,
HPLC (Chiralpak AS-H), hexane/i-PrOH = 90:10, flow rate 0.5
mL/min, λ = 224.5 nm), t (major) = 22.20 min, t (minor) = 27.79
,
15, 11058.
R
R
(
, 2, 167. (j)
min; ee = 98%.
,
,
19a
4
.3.11 (R)-4-(4-Chlorophenyl)-5-nitropentan-2-one (9k)
,
12
,
Yield: 0.24 g (92%); white solid, mp 75-77 °C, (Lit. mp 75-77
.
,
°
1
C).
H NMR (300 MHz, CDCl ): δ 7.24 (d, J = 8.1 Hz, 2H), 7.08 (d,
,
3
J = 8.1 Hz, 2H), 4.60 (dd, J = 12.3, 6.9 Hz, 1H), 4.50 (dd, J =
3
For examples of asymmetric Michael additions of carbonyl
compounds to nitroalkenes, see: (a) Xu, Y.; Córdova, A. Chem.
Commun. 2006, 460. (b) Pansare, S. V.; Pandya, K. J. Am. Chem.
1
2
2.3, 7.5 Hz, 1H), 3.92 (qn, J = 6.9 Hz, 1H), 2.88-2.72 (m, 2H),
.05 (s, 3H).
Soc. 2006
L. Org. Lett. 2006
Gellman, S. H. J. Am. Chem. Soc. 2008
Wang, C.; Bats, J. W. Angew. Chem. Int. Ed. 2008
Wiesner, M.; Revell, J. D.; Tonazzi, S.; Wennemers, H. J. Am. Chem.
Soc. 2008 130, 5610. (g) Lu, A.; Gao, P.; Wu, Y.; Wang, Y.; Zhou,
Z.; Tang, C. Org. Biomol. Chem. 2009 , 3141. (h) Gauchot, V.;
Gravel, J.; Schmitzer, A. R. Eur. J. Org. Chem. 2012, 6280. (i) Tan,
B.; Zeng, X.; Lu, Y.; Chua, P. J.; Zhong, G. Org. Lett. 2009 11
1927. (j) Laars, M.; Ausmees, K.; Uudsemaa, M.; Tamm, T.; Kanger,
T.; Lopp, M. J. Org. Chem. 2009 74, 3772. (k) Wiesner, M.; Upert,
G.; Angelici, G.; Wennemers, H. J. Am. Chem. Soc. 2010 132, 6. (l)
Zheng, Z.; Perkins, B. L.; Ni, B. J. Am. Chem. Soc. 2010 132, 50.
m) Zhao, H.-W.; Li, H.-L.; Yue, Y.-Y.; Sheng, Z.-H. Eur. J. Org.
Chem. 2013, 1740.
,
128, 9624. (c) Reyes, E.; Vicario, J. L.; Badia, D.; Carrillo,
, 6135. (d) Chi, Y.; Guo, L.; Kopf, N. A.;
130, 5608. (e) Enders, D.;
47, 7539. (f)
1
3
C NMR (75 MHz, CDCl ): δ 204.9, 137.9, 134.5, 129.9, 129.4,
3
,
8
7
9.7, 46.5, 39.0, 30.9.
,
HPLC (Chiralpak AS-H), hexane/i-PrOH = 90:10, flow rate 0.5
mL/min, λ = 229.2 nm), t (minor) = 27.9 min, t (major) = 34.9
,
R
R
,
min; ee = 95%.
,
7
19d
4
.3.12 (4S,5R)-4-methyl-6-nitro-5-phenylhexan-3-one (9l)
Yield: 0.28 g (88%); brownish viscous mass.
,
,
1
H NMR (400 MHz, CDCl ): δ 7.25-7.15 (m, 3H), 7.08-7.05 (m,
3
,
2
H), 4.59-4.54 (m, 1H), 4.51-4.47 (m, 1H), 3.61 (dt, J = 9.2, 4.7
,
Hz, 1H), 2.94-2.86 (m, 1H), 2.56-2.46 (m, 1H), 2.36-2.26 (m,
,
1
H), 1.00 (t, J = 7.2 Hz, 3H), 0.89 (d, J = 7.1 Hz, 3H).
(
1
3
CNMR (100 MHz, CDCl ): δ 213.1, 137.7, 129.0, 128.0, 127.9,
3
7
8.3, 48.3, 46.1, 35.4, 16.4, 7.7.

8
4
For synthetic utility of
Seebach, D. Chem. Ber. 1991
J.; Seebach, D. Liebigs Ann. 1995, 1193. (c) Poupart, M. A.; Fazal,
G.; Goulet, S.; Mar, L. T. J. Org. Chem. 1999 64, 1356. (d) Barrett,
A. G. M.; Spilling, C. D. Tetrahedron Lett. 1988 29, 5733. (e) Lloyd,
D. H.; Nichols, D. E. J. Org. Chem. 1986 51, 4294. (f) Mukaiyama,
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Org. React. 1990 38, 655.
(a) Wang, W.; Wang, J.; Li, H. Angew. Chem., Int. Ed. 2005
γ
–nitrocarbonyls, see: (a) Beck, A. K.;
10 (a) Tay, D. W.; Leung, G. Y. C.; Yeung, Y.-Y. Angew. Chem. Int.
ACCEPTED MANUSCRIPT
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124, 2897. (b) Maeri, R. E.; Heinzer,
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Nadkarni, V.; Tilve, S. Synthetic Communications 2013
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D. A.; Nájera, C. New J. Chem. 2011 35, 2766. (d) Zhao, Y.; Jiang,
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11 (a) Singh, K. N.; Singh, P.; Singh, P.; Lal, N.; Sharma, S. K. Bioorg.
Med. Chem. Lett 2012 22, 4225. (b) Singh, K. N.; Singh, P.; Kaur,
A.; Singh, P.; Sharma, S. K.; Khullar, S.; Mandal, S. K. Synthesis
2013 45, 1406.
12 Morris, D. J.; Partridge, A. S.; Manville, C.V.; Racys, D. T.;
,
53, 5161. (b) Bugde, S.; Majik, M.; Mandrekar, V.;
,
43, 2536. (c)
,
,
,
,
,
,
,
.
,
5
6
,
44
,
,
1
2
369. (b) Xu, L.-W.; Li, L.; Shi, Z.-H. Adv. Synth. Catal. 2010
43. (c) Lin, L. L.; Feng, X. Chem. Commun. 2009, 6145. (d) Tzeng,
,
352
,
Z.-H.; Chen, H.-Y.; Reddy, R. J.; Huang, C.-T.; Chen, K.
Tetrahedron 2009 65, 2879.
(a) Chandrasekhar, S.; Tiwari, B.; Parida, B. B.; Reddy, R. Ch.
Tetrahedron: Asymmetry 2008 19, 495. (b) Zhao, Y.-B.; Zhang, L.-
W.; Wu, L.-Y.; Zhong, X.; Li, R.; Ma, J.-T. Tetrahedron: Asymmetry
008 19, 1352. (c) Karthikeyan, T.; Sankararaman, S. Tetrahedron:
Asymmetry 2008 19, 2741. (d) Cobb, A. J. A.; Shaw, D. M.; Ley, S.
Woodward, G.; Docherty, G.; Wills, M. Tetrahedron Lett. 2010, 51,
,
,
209.
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