Chiral amine catalyzed enantio- and diastereoselective Michael reaction in brine

Article abstract of DOI:10.1016/j.tetasy.2012.06.026

Simple pyrrolidine-based chiral amines were synthesized and used for the Michael addition of different ketones to a variety of nitro-olefins in brine. The effect of different surfactants and acids on the yields and stereochemical outcome of the Michael ad

Full text of DOI:10.1016/j.tetasy.2012.06.026

Tetrahedron: Asymmetry 23 (2012) 1068–1079
Contents lists available at SciVerse ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Chiral amine catalyzed enantio- and diastereoselective Michael reaction in brine
⇑
Sarbjit Singh, Swapandeep Singh Chimni
Department of Chemistry, U.G.C. Centre of Advance Studies in Chemistry, Guru Nanak Dev University, Amritsar 143005, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 28 May 2012
Accepted 29 June 2012
Simple pyrrolidine-based chiral amines were synthesized and used for the Michael addition of different
ketones to a variety of nitro-olefins in brine. The effect of different surfactants and acids on the yields and
stereochemical outcome of the Michael adducts was studied in detail. Chiral amine 1g was found to cat-
alyze the formation of Michael adducts with high enantioselectivity (up to >99%), diastereoselectivity [up
to 98:2 (syn:anti)] and yield (up to 94%).
Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction
thetic transformations in aqueous media,16 so we planned to de-
sign simple organocatalysts for enantioselective Michael
The development of organic molecules as catalysts for asym-
metric organic transformations in aqueous media is a major chal-
lenge for organic chemists. Such aqua-organocatalyzed reactions
have also found a great deal of application in green chemistry be-
cause of their environmentally benign and inexpensive nature. In
recent years, a large number of carbon–carbon and carbon–hetero-
atom bond forming reactions have been reported to be catalyzed
by organic molecules in aqueous media.1
Among the different methods of carbon–carbon bond forma-
tion, the Michael addition is of special importance and has been
widely used to generate valuable building blocks in organic syn-
thesis.2 Among the different types of Michael donors and acceptors
used for the Michael reaction, the conjugate addition of aldehydes
reactions in aqueous media. Herein we report the synthesis of
new -proline based chiral amines and their application as organo-
catalysts for the Michael addition of ketones to different nitrosty-
rene derivatives in brine.
L
2. Results and discussion
A series of simple pyrrolidine-based chiral amines (Fig. 1) were
synthesized based on the assumption that the pyrrolidine ring
should act as the catalytic site by forming an enamine with the do-
nor ketones, while the side chain should function as the chiral
induction group by appropriately orienting the nitro-olefins using
suitable steric and hydrophobic interactions.
Initially, a model reaction of cyclohexanone 2 and b-nitrosty-
rene 3a was performed in brine using 10 mol % of diamine catalyst
1a containing an aromatic moiety as side chain. The aromatic moi-
ety was supposed to enhance the hydrophobic interactions in the
aqueous medium12f,i (Scheme 1). Brine was chosen as the solvent
instead of water because it is known in the literature that in the
presence of amines, nitrostyrenes can polymerize and this poly-
merization could be inhibited by using an electrolyte solution as
the solvent.17
The reaction was allowed to run for 30 h and its progress was
observed at regular intervals. The crude reaction mixture obtained
upon extraction and concentration was purified by column chro-
matography to obtain pure Michael adduct 4a in 12% yield (Table 1,
entry 1). The 1H NMR of the product showed the presence of two
diastereomers in a ratio of 94:6 (syn:anti), which was calculated
from the integration of the 1H signal at d 3.75–3.80 (syn) and d
3.96–4.05 (anti). The chiral HPLC analysis of product 4a gave the
enantiomeric excess of the syn diastereomer was 80%. By compar-
ing the HPLC data and specific rotation of the Michael adduct with
that reported in literature,13 the absolute configuration of syn dia-
or ketones to nitroalkenes to afford
c-nitrocarbonyl compounds
containing contiguous stereocenters is of special interest mainly
due to the ready availability of the starting materials, inherent sim-
plicity of the process and the ease of transformation of the nitro
group into other groups such as amines, nitrile oxides, ketones,
and carboxylic acids.3 The
c-nitrocarbonyl compounds are also
key precursors of various important compounds such as alkaloids,4
aminoacids,5,25a antitumorals,6 antibiotics,7 peptidomimetics,8 and
marine metabolites9 among others.10 In recent years, tremendous
effort has been made in developing efficient organocatalysts for
enantioselective Michael reactions.11 Among the different organo-
catalysts used for Michael reactions, the cinchona alkaloid and L-
proline based chiral amines,12a–e,g–k chiral thioureas,13
L-proli-
nols,14 and chiral sulfonamides15 have been widely used and pro-
ven to be most efficient. However, only a few of these catalysts
have been found to be effective in an aqueous medium.1d,e,12h–
j,15f
Since we are interested in developing organocatalyzed syn-
⇑
Corresponding author. Fax: +91 183 2258820.
E-mail address: sschimni@yahoo.com (S.S. Chimni).
0957-4166/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2012.06.026

S. Singh, S. S. Chimni / Tetrahedron: Asymmetry 23 (2012) 1068–1079
1069
NO2
H
N
H
N
N
H
N
H
N
H
N
H
1a
1c
1b
CH3
N
N
H
N
N
N
N
H
N
H
H
1d
1e
1f
N
N
N
H
1g
Figure 1. Structures of di-and triamine catalysts.
the surfactant had any effect on the yield of the reaction in brine,
a reaction was performed with the addition of SDS. Under these
conditions the Michael product 4a was obtained in a slightly high-
er yield (18%), but there was no effect on its enantiomeric excess
(Table 1, entry). Since the use of surfactants had a positive impact
on the yields of reaction, we decided to perform further screening
of the catalysts as well as optimization using a brine-SDS system.
The screening of the other proline based di- and triamine catalysts
1a–1h was performed using the model reaction in the brine-SDS
reaction medium.
R
(S)
O
O
(E)
Ph
N
NO2
H
(10 mol%)
brine
+
O2N
4a
3a
2
Scheme 1.
Catalyst 1b with a nitro group on the phenyl moiety catalyzed
the reaction providing 4a in 25% yield in 2 days with a diastereo-
meric ratio of 96:4 (syn:anti) and enantiomeric excess of 79%
(syn) (Table 1, entry 5). Catalyst 1c with a naphthyl group did
not catalyze the reaction, even when the reaction was run for
2 days (Table 1, entry 6). Catalysts 1d and 1e containing a cyclo-
hexylamine or piperidine moiety gave 4a in 48% and 47% yields,
respectively (Table 1, entries 7–8). The Michael product 4a, ob-
tained as a result of catalysis by 1e, showed a higher level of stere-
oselectivity; dr of 97:3 (syn:anti) and ee of 86% (syn). Michael
reactions with catalysts 1f and 1g were performed which gave 4a
with similar levels of stereoselectivity; a comparatively high yield
of product 4a was obtained using catalyst 1g (Table 1, entries 9–
10). The probable reason for higher yield observed in case of cata-
lyst 1g seems to be hydrophobic effects provided by phenyl group.
Little to no yield was observed in the cases of secondary-sec-
ondary diamine catalysts 1a–1c containing aromatic rings adjacent
to the –NH group due to the formation of aminal A (Scheme 2). Due
to the formation of A, the catalyst may become engaged in the cyc-
lic form and so only a small amount of the catalyst is available to
form an enamine with cyclohexanone.
Table 1
Screening of different catalystsa
Entry
Catalyst
Additive
Time (h)
Yield (%)c
drd
eee (syn)
1
2
1a
1a
1a
1a
1b
1c
1d
1e
1f
—
SDS
—
30
30
24
12
18
—
—
25
—
48
47
41
82
36
58
94:6
95:5
—
—
96:4
—
94:6
97:3
98:2
96:4
93:7
94:8
80
80
—
—
79
—
78
86
81
85
82
80
3b
4b
5
SDS
SDS
SDS
SDS
SDS
SDS
SDS
SDS
—
30
2 days
2 days
20
6
7
8
9
10
11b
12
22
24
24
24
1g
1g
1g
24
a
Reaction conditions: 10 mol % of catalyst, 10 mol % of SDS, 1.25 mmol of
cyclohexanone, 0.25 mmol of nitrostyrene, 0.5 mL of brine at 25 °C.
b
Reaction was performed in water.
c
Isolated yield.
d
Diastereoselectivity determined from 1H NMR.
e
Determined by HPLC using chiral column.
From the screening of different di- and triamine catalysts, cata-
lyst 1g was found to be the best, affording Michael product 4a with
a yield of 82%, a dr of 96:4 (syn:anti) and an enantioselectivity of
85% in brine using SDS as the additive (Table 1, entry 1). Further
optimization of the reaction conditions was performed by varying
the amount of brine. The results are summarized in Table 2.
The Michael reaction without brine was very slow and gave
product 4a with a yield of 65%, dr of 92:8 (syn:anti) and ee of
83% after 3 days (Table 2, entry 1). The addition of 0.1 mL of brine
to the reaction mixture reduced the reaction time to 34 h along
with a slight increase in the yield and stereoselectivity of product
4a (Table 2, entry 2). Increasing the amount of brine to 0.5 mL in-
stereomer was designated as (2S,10R). When the same reaction was
carried out in water, only trace amounts of 4a were obtained prob-
ably due to polymerization of the nitrostyrene (Table 1, entry 3).
Surfactants are known to facilitate organic reactions in water, so
a reaction of cyclohexanone and b-nitrostyrene catalyzed by 1a
was performed in water containing sodium dodecyl sulfate (SDS)
as the surfactant. The addition of the surfactant (SDS) did not help
in increasing the yield of product 4a (Table 1, entry 4). Therefore,
brine was found to be the best solvent system, while water and
the water-surfactant solvent system were not a suitable medium
for the organocatalytic Michael reaction. In order to determine if

1070
S. Singh, S. S. Chimni / Tetrahedron: Asymmetry 23 (2012) 1068–1079
N
N
R
A
R
N
R
N
O
Ph
R
N
+
H
H
N
N
NO2
H
N
H
NO2
catalysts containing
secondary amines
(low yield)
Ph
(small amount
available)
O
R
N
R
R
R
N
H
N
O
Ph
N
+
R
R
catalysts containing
tertiary amines
N
N
NO2
NO2
(high yield)
Ph
Scheme 2. The plausible reason of low yields observed in case of secondary–secondary diamine catalysts.
Table 2
Table 3
Variation of amount of brinea
Variation of the amount of cyclohexanonea
Entry
2 (equiv)
Brine (mL)
Time (h)
Yieldb
drc (syn:anti)
eed
Entry 2 (equiv) Brine (mL) Time (h) Yieldb drc
(syn:anti)
eed (syn)
1
2
3
4
5
5
5
5
5
5
—
3 days
34
65
71
76
82
81
92:8
94:6
94:6
96:4
94:6
83
85
84
85
82
0.1
0.25
0.5
0.75
1
3
5
0.5
0.5
0.5
0.5
2 days
24
74 94:6
86
85
84
85
24
24
24
2
82 96:4
81 93:7
82 94:6
3e
4
5
10
24
20
a
a
Reaction conditions: 10 mol % of catalyst, 10 mol % of SDS, 0.25 mmol of
Reaction conditions: 10 mol % of catalyst, 10 mol % of SDS, 0.25 mmol of
nitrostyrene at 25 °C.
nitrostyrene, 0.5 mL of brine at 25 °C.
b
b
Isolated yield.
Isolated yield.
c
c
Determined from 1H NMR.
Determined from 1H NMR.
d
d
Determined by HPLC using a chiral column.
Determined by HPLC using a chiral column.
e
20 mol % of SDS were used.
creased the yield of 4a to 82% and also reduced the reaction time to
24 h (Table 2, entries 3–4). Using an excess amount of brine
(0.75 mL) resulted in a lower yield and enantioselectivity of prod-
uct 4a (Table 2, entry 5).
Next, the amount of cyclohexanone and catalyst was varied by
fixing the amount of brine to 0.5 mL. The results are summarized in
Tables 3 and 4, respectively.
Decreasing the amount of cyclohexanone decreased the yield of
4a as well as increasing the reaction time (Table 3, entry 1).
Increasing the amount of cyclohexanone slightly lowered the reac-
tion rate (Table 3, entry 4). Any variation of the catalyst loading
from 10 mol % did not give better results (Table 4).
Table 4
Variation in the catalyst loadinga
Entry Catalyst loading (mol %) Time (h) Yieldb (%) drc (syn:anti) eed
1
2
3
5
10
20
36
24
16
62
81
85
93:7
93:7
96:4
79
84
80
a
Reaction conditions: 1.25 mmol of cyclohexanone, 0.25 mmol of nitrostyrene,
10 mol % of SDS, 0.5 mL of brine at 25 °C.
b
Isolated yield.
c
Determined from 1H NMR.
d
Determined by HPLC using a chiral column.
Thus our standard conditions consisted of using 10 mol % of cat-
alyst 1g, 10 mol % of SDS, 5 equiv of cyclohexanone, 0.5 mL of
brine, and 0.25 mmol of nitrostyrene at 25 °C. We next planned
to screen different surfactants in order to study their effects on
the yield and stereoselectivity of the Michael reaction. A variety
of cationic, anionic, and non-ionic surfactants were screened. The
results are summarized in Table 5.
The use of both cationic and anionic surfactants (except SDS) as
additives yielded the Michael product 4a in low yield (Table 5, en-

S. Singh, S. S. Chimni / Tetrahedron: Asymmetry 23 (2012) 1068–1079
1071
Table 5
Table 6
Screening of different surfactantsa
Screening of different acid additivesa
O
O
Ph
O
O
Ph
Ph
Ph
surfactant (10 mol%)
1g (10 mol%)
Acid (10 mol%)
NO2
1g (10 mol%)
NO2
+
+
O2N
O2N
brine
brine
4a
3a
2a
2a
4a
3a
Entry
Acid
Time (h)
Yieldb (%)
drc (syn:anti)
eed
Entry
Surfactant
Time (h)
Yieldb (%)
drc (syn:anti)
eed (syn)
1
2
3
4
5
6
7
8
TFA
DNP
TCA
24
28
12
24
24
16
24
30
72
53
90
77
67
90
61
—
94:6
96:4
96:4
95:5
92:8
92:8
93:7
—
84
85
89
84
83
87
83
—
1
2
3
4
5
6
7
8
HTPB
TTPB
DTPB
HTAB
TTAB
DTAB
Triton X-100
CHAPS
Tween-20
Tween-80
SDS
SDBS
AOT
HPyBr
28
21
22
36
36
36
24
28
19
24
24
24
28
30
34.41
26.46
18.18
31
93:7
92:8
93:7
93:7
93:7
93:7
90:10
90:10
95:5
93:7
95:5
95:5
91:8
91:9
80
80
77
78
82
79
80
82
87
82
85
84
84
80
2-Chlorobenzoic acid
Acetic acid
Benzoic acid
TsOH
35
33.70
41.07
22.56
86
73
82
31.0
41.72
46.91
TfOH
a
9
Reaction conditions: 10 mol % of catalyst, 10 mol % of acid, 1.25 mmol of
cyclohexanone, 0.25 mmol of nitrostyrene, 0.5 mL of brine at 25 °C.
10
11
12
13
14
b
Isolated Yield.
Diastereoselectivity determined from 1H NMR.
c
d
Determined by HPLC using a chiral column.
a
Reaction conditions: 10 mol % of catalyst, 10 mol % of surfactant, 1.25 mmol of
cyclohexanone, 0.25 mmol of nitrostyrene, 0.5 mL of brine at 25 °C.
decided to study the effect of other salt solutions on the yield and
stereoselectivity of Michael product 4a. The results are summa-
rized in Table 7.
b
Isolated Yield.
c
Diastereoselectivity determined from 1H NMR.
d
Determined by HPLC using a chiral column.
In all of the salt solutions, the Michael addition proceeded with
excellent level of enantioselectivity but with slight differences in
the yield of the Michael adduct (Table 7). A lower yield and stere-
oselectivity of Michael product were observed when the Michael
reaction was performed in KCl and KBr solutions in comparison
to NaCl and NaBr solutions (Table 7, entries 1–2 and 3–4). A mod-
erate yield was obtained in saturated LiCl solution (Table 7, entry
6). Similar levels of stereoselectivity and yield were observed in
both NaCl and NaBr solutions (Table 7, entries 1 and 2) but from
an economical point of view, NaCl is more inexpensive and largely
available. As a result, a saturated solution of NaCl (brine) was used
as solvent for further screening of different substrates to explore
the scope and limitation of the organocatalytic transformation.
Thus, the optimization of the reaction conditions gave the two
best conditions, one using a Tween-20 surfactant (A) (Table 5, en-
try 9) and the other using TCA as the co-catalyst (B) (Table 6, entry
3). Since the results obtained using both conditions were compara-
ble, we decided to screen the substrates using both sets of
conditions.
tries 1–6). High stereoselectivity was observed with anionic surfac-
tant SDBS (Table 5, entry 12). However, the non-ionic surfactant
Tween-20 yielded the Michael product 4a with the highest yield
and stereoselectivity (Table 5, entry 9). The yield and enantioselec-
tivity of 4a were found to be better when using the non-ionic sur-
factant Tween-20 than SDS (Table 5, entries 9 and 11).
The organocatalytic reactions in aqueous media were found to
proceed with high stereoselectivity and yield when performed in
the presence of an acid as the co-catalyst. This observation was
made in the aldol reaction catalyzed by (S)-prolinamide, where
the aldol products were obtained with high enantioselectivity
and diastereoselectivity when reaction was performed in the pres-
ence of acids as co-catalysts.16 We also observed that the pH of the
reaction mixture could control the overall stereoselectivity of aldol
product. In general, high stereoselectivity of the aldol product was
observed when the pH of the reaction mixture was 4.5 0.2.16 As a
result we planned to investigate the role of acids as co-catalysts in
the Michael reaction of cyclohexanone and trans-b-nitrostyrene in
brine. A number of acid co-catalysts were screened for the reaction.
The results showed that the product was obtained with excellent
enantioselectivity and diastereoselectivity with all acid additives
(Table 6).
The highest yield of 90% and enantioselectivity of 89% of 4a
were observed with trichloroacetic acid (TCA) (Table 6, entry 3).
A similar yield was also observed with benzoic acid but with
slightly lower enantioselectivity (Table 6, entry 6). A good range
of enantioselectivity and diastereoselectivity of 4a were observed
with TFA and 2-chlorobenzoic acid but with moderate yields (Ta-
ble 6, entries 1 and 4). The product was obtained in low yield
but high stereoselectivity with 2,4-dinitrophenol (DNP), acetic
acid, and p-toluenesulfonic acid (TsOH) additives (Table 6, entries
2, 5 and 7).
Table 7
Screening of different salt solutionsa
O
O
Ph
1g (10 mol%)
Ph
NO2
TCA (10 mol%)
+
O2N
salt solution (0.5 mL)
Entry
Salt solution (satd)
Time (h)
Yieldb (%)
drc (syn:anti)
eed
1
2
3
4
5
6
NaCl
NaBr
KCl
KBr
NH4Cl
LiCl
12
12
12
12
12
12
90
88
82
80
82
74
94:6
95:5
84:16
86:14
88:12
92:8
89
89
87
86
85
84
No Michael product was formed with trifluoromethanesulfonic
acid (TfOH), even after 30 h (Table 6, entry 8). This may be due to
the strong ion-pair formation which results in inactivation of the
catalyst. Since the use of brine had a clear advantage over water
as evident from Table 1 (Table 1, entries 2, 4 and 10–11), we next
a
Reaction conditions: 10 mol % of catalyst, 10 mol % of TCA, 1.25 mmol of
cyclohexanone, 0.25 mmol of nitrostyrene, 0.5 mL of salt solution at 25 °C.
b
Isolated Yield.
c
Diastereoselectivity determined from 1H NMR.
d
Determined by HPLC using a chiral column.

1072
S. Singh, S. S. Chimni / Tetrahedron: Asymmetry 23 (2012) 1068–1079
Conditions A: 10 mol % of catalyst 1g, 10 mol % of TCA (trichol-
roacetic acid), 5 equiv of cyclohexanone, 0.25 mmol of nitrostyrene
and 0.5 mL of brine at 25 °C (Table 6, entry 3).
ate enantioselectivity and diastereoselectivity were observed with
cyclopentanone under both conditions (Table 9, entries 5–6). To
further explore the scope of catalyst 1g, 4-substituted cyclohexa-
nones were next selected as the Michael donors. The Michael reac-
tion of 4-substituted cyclohexanones led principally to chiral
adducts with the formation of three carbon stereocenters. Despite
the numerous numbers of organocatalytic processes for the Mi-
chael additions of carbonyl compounds to nitroolefins, catalytically
stereoselective versions involving such types of ketones are rare.18
We thus decided to perform the Michael reactions of 4-substituted
cyclohexanones with different nitrostyrenes under both conditions
A and B. The results are summarized in Table 9.
In general, moderate to good level of enantioselectivity was
observed with all substrates under both conditions A and B.
The highest enantioselectivity (of major isomer) was observed
with Michael product 4r, formed by the addition of 2-chloro
nitrostyrene to 4-methyl substituted cyclohexanone (under both
conditions A and B) (Table 9, entries 9–10). Good enantioselec-
tivity was observed with other Michael products 4q, 4s, 4t, 4u
under both conditions (Table 9, entries 7–8 and 11–16,). Good
enantioselectivity was also observed with product 4v formed
by the addition of 4-tert-butylcyclohexanone to nitrostyrene (Ta-
ble 9, entries 17–18).
Conditions B: 10 mol % of catalyst 1g, 10 mol % of Tween-20
surfactant, 5 equiv of cyclohexanone, 0.25 mmol of nitrostyrene
and 0.5 mL of brine at 25 °C (Table 5, entry 9).
Conditions A gave slightly better results than conditions B, but
since the differences in stereoselectivity and yield were very small,
we decided to select both conditions to explore the scope of cata-
lyst 1g. The results are summarized in Table 8.
In general, reaction rates were faster under condition A (TCA as
an additive) compared to conditions B (Tween-20 as an additive)
albeit with similar yields but with slightly different stereoselectiv-
ities. The highest enantioselectivity of >99% was observed with 4-
chloro substituted nitrostyrene under both reaction conditions A
and B (Table 8, entries 11–12). Excellent enantioselectivity and dia-
stereoselectivity were also observed with 2-naphthyl (under con-
ditions A) (Table 8, entry 7) and 4-methoxy substituted
nitrostyrenes (under conditions A and B) (Table 8, entries 19–20).
Moderate levels of enantioselectivity were observed with 4-methyl
(condition A), 3,4-dimethoxy, (conditions A and B) and 1-naphthyl
(conditions B) substituted nitrostyrenes (Table 8, entries 3, 5, 6,
and 10).
Different cyclic and acyclic ketones were screened by employ-
ing catalyst 1g under conditions A and B to afford Michael products
with moderate to excellent enantioselectivity (Table 9). Low
enantioselectivity was observed with acetone as the donor in both
conditions A and B (Table 9, entries 1–2). Excellent enantioselectiv-
ity was observed with 3-pentanone (Table 9, entries 3–4). Moder-
Nitro-diene14b,25 was also used as the Michael acceptor using
catalyst 1g under both reaction conditions (Scheme 3). Interest-
ingly, the 1,6-addition adduct was not observed, and only the
1,4-addition product 4w was formed with very good enantioselec-
tivity and diastereoselectivity, thus highlighting the broad utility of
the catalyst with structurally different substrates.
Table 8
Screening of different nitrostyrene derivativesa
O
R
O
1g (10 mol%)
conditions A or B
R
NO2
+
brine
O2N
4a-4l
Entry
Product R =
A or B
Time (h)
Yieldb (%)
drc (syn:anti)
eed (syn)
1
2
3
4
5
6
7
8
Ph 4a
A
B
A
B
A
B
A
B
A
B
A
B
A
B
A
B
A
B
A
B
A
B
A
B
12
19
10
14
8
12
10
13
12
14
9
10
10
13
14
17
12
16
10
14
8
90
86
86
84
89
82
87
90
89
92
93
88
90
92
80
78
88
84
89
89
91
86
88
84
96:4
95:5
95:5
95:5
93:7
92:8
97:3
98:2
86:14
87:13
91:9
90:10
91:9
89
87
88
77
87
79
97
89
78
83
>99
>99
76
78
76
75
78
78
94
93
75
74
84
84
4-MePh 4b
3,4-(MeO)2Ph 4c
2-Naphthyl 4d
1-Naphthyl 4e
4-ClPh 4f
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
4-FPh 4g
92:8
Cyclohexyl 4h
2-Thienyl 4i
4-MeOPh 4j
4-NO2-Ph 4k
2-ClPh 4l
57:43
58:42
86:14
85:15
93:7
92:8
75:25
74:26
95:5
12
14
17
94:6
a
Conditions A: 10 mol % of catalyst, 10 mol % of TCA, 1.25 mmol of cyclohexanone, 0.25 mmol of nitroalkene, 0.5 mL of salt solution at 25 °C. Conditions B: 10 mol % of
catalyst, 10 mol % of Tween-20, 1.25 mmol of cyclohexanone, 0.25 mmol of nitroalkene, 0.5 mL of salt solution at 25 °C.
b
Isolated yield.
c
Diastereoselectivity determined from 1H NMR.
d
Determined by HPLC using a chiral column.

S. Singh, S. S. Chimni / Tetrahedron: Asymmetry 23 (2012) 1068–1079
1073
Table 9
Screening of different ketone derivativesa
Entry
1
Product
A or B
A
Time (h)
28
Yieldb (%)
74
drc
—
eed (%)
25
O
2
B
30
79
—
27
NO2
(R)
(S)
4n
3
A
3 days
64
97:3
87
O
NO2
4
5
B
A
4 days
2 days
58
69
96:4
87
52
(R)
4o
70:30
O
(S)
NO2
6
7
B
A
2.5 days
16
75
89
72:28
—
51
79
(R)
4p
OMe
O
8
B
18
90
—
79
(S)
NO2
(R)
(S)
4q
+
isomers
9
A
B
14
16
82
84
—
—
89
88
O
Cl
(S)
NO2
10
(R)
(S)
4r
+
isomers
Cl
11
12
A
B
14
19
77
81
—
—
81
81
O
(S)
NO2
(R)
(S)
4s
+
isomers
CH3
13
14
A
B
17
20
82
85
—
—
77
77
O
(S)
NO2
(R)
(S)
4t
+
isomers
NO2
15
16
A
B
18
18
71
76
—
—
82
86
O
NO2
(S)
(R)
(S)
4u
+
isomers
(continued on next page)

1074
S. Singh, S. S. Chimni / Tetrahedron: Asymmetry 23 (2012) 1068–1079
Table 9 (continued)
Entry
17
Product
A or B
A
Time (h)
14
Yieldb (%)
94
drc
—
eed (%)
78
O
(S)
NO2
(R)
(S)
18
B
17
88
—
79
4v
+
isomers
a
Conditions A: 10 mol % catalyst 1 g, 10 mol % TCA (trichloroacetic acid), 1.25 mmol of cyclohexanone, 0.25 mmol nitrostyrene and 0.5 mL of brine at 25 °C. Conditions B:
10 mol % catalyst 1g, 10 mol % Tween-20, 1.25 mmol of cyclohexanone, 0.25 mmol nitrostyrene and 0.5 mL of brine at 25 °C.
b
Isolated yield.
c
Determined from 1H NMR.
d
Determined from HPLC using chiral columns.
Ph
O
O
NO2
catalyst 1g (10 mol%)
NO2
+
Ph
brine
4w
conditions A
conditions B
Time = 12 hrs
Yield = 92%
ee = 85%
Time = 10 hrs
Yield = 94%
ee = 84%
dr = 96:4 (syn:anti)
dr = 96:4 (syn:anti)
Scheme 3. Michael reaction of cyclohexanone and a nitrodiene.
gel 60F254 (Merck, India) or (ii) glass plates (7.5 ꢁ 2.5 cm) coated
3. Conclusions
with silica gel GF-254 (Spectrochem India) containing 13% calcium
sulfate as binder and various combinations of dichloromethane
and methanol were used as eluents. Visualization of the spots
was accomplished by exposing to UV light or iodine vapors. Col-
umn chromatography was performed on Spectrochem silica gel
(60–120 mesh) using an increasing concentration of methanol in
dichloromethane as the eluent.
In conclusion, we have successfully demonstrated that very
simple chiral amines can efficiently catalyze an enantioselective
and diastereoselective Michael reaction in brine. The catalyst
developed is capable of promoting efficient conjugate additions
of cyclic and acyclic ketones to a wide range of nitro-olefins. More-
over, the methodology developed is very simple, environmentally
benign, and highly enantioselective.
4.2. General procedure for the synthesis of catalysts 1a–g
4. Experimental
4.1. General
First, the protonated
ing to the literature.16a The deprotonation of these protonated
prolinamides was carried with Na2CO3. The deprotonated -proli-
L-prolinamides were synthesized accord-
L-
L
namides were further reduced into the corresponding di- and tri-
amines by using BH3 as the reducing agent.
NMR spectra were obtained at 300 MHz (JEOL AL-300) and
500 MHz (Bruker Avanced 500 MHz) for 1H NMR and at 75 MHz
(JEOL AL-300) and 100 MHz (Bruker Avanced 400 MHz) for 13C
NMR with Me4Si (in CDCl3) as the internal standard. Chemical
shifts are reported in d values relative to TMS and coupling con-
stants (J) are expressed in Hz. Spectroscopic patterns are desig-
nated as s = singlet; d = doublet; dd = doublet of doublets;
q = quartet; t =triplet; br = broad; m = multiplet. When necessary,
assignments were aided by DEPT-135 experiments. IR spectra were
obtained with FT-IR Bruker (270–30) spectrophotometer and Var-
ian 660-IR FT-IR spectrometer and reported in wave numbers
(cmꢀ1). Mass spectra were recorded on JEOL-MSD-300, Bruker Es-
quire 300 LC Mass spectrometer and JEOL AccuTOF DART mass
spectrometer. Optical rotations were noted on JASCO DIP-360 dig-
ital polarimeter. Analytical thin-layer chromatography (TLC) was
performed on either (i) aluminum sheets pre-coated with silica
4.3. Synthesis of (S)-2-(N-alkyl/arylaminometh-1-yl)pyrrolidine
To a stirred solution of (S)-2-(alkyl/arylcarbamoyl)pyrrolidini-
um bromide (0.184 mmol) in water (1.5 mL), was slowly added a
saturated solution of sodium carbonate in water until the efferves-
cence ceased and a clear solution was obtained. The mixture was
extracted with chloroform (3 ꢁ 10 mL) and the combined organic
layer was dried over anhydrous sodium sulfate, filtered, and dis-
tilled to give the product (S)-2-(alkyl/arylcarbamoyl)pyrrolidine
with 72–89% yield.
To a completely dry 10 mL round bottomed flask, NaBH4 (80 mg
or 2.1 mmol) and dry THF (5 mL) were added and stirred for 5–
10 min at 0 °C followed by the addition of (S)-2-(alkyl/arylcarba-

S. Singh, S. S. Chimni / Tetrahedron: Asymmetry 23 (2012) 1068–1079
1075
moyl)pyrrolidine (0.525 mmol). The reaction mixture was again
stirred for 10–15 min and then a boron trifluoride:etherate (1:1)
solution (4.68 equiv) was added slowly to the reaction mixture
using a dropping funnel. The mixture was again stirred for 3 h at
0 °C and then refluxed for 10–12 h followed by quenching with
methanol at room temperature until the effervescence ceased.
The solvent was distilled on a water bath under reduced pressure.
The residue was cooled to 0 °C and 6 M HCl (10 mL) was added to
it. The resulting mixture was refluxed for 1 h in an oil bath and
cooled to room temperature. The mixture was washed with ethyl
acetate (2 ꢁ 8 mL) and ether (2 ꢁ 8 mL) to remove any organic
impurities. The mixture was again cooled to 0 °C and a chilled solu-
tion of 4 M NaOH was added slowly to it with stirring until it at-
tained a pH in the range of 9–10. The aqueous solution was
extracted with dichloromethane (3 ꢁ 30 mL) and the organic ex-
tract was dried over anhydrous sodium sulfate and distilled to ob-
tain (S)-2-(N-alkyl/arylaminometh-1-yl)pyrrolidine in 62–79%
yield.
4.3.5. (S)-1-(Pyrrolidin-2-ylmethyl)piperidine20 1e
Yield, 63%; dark yellow liquid; Rf 0.22 (methanol/chloroform,
6:94), MS (DART) (m/z): 169.24 (M+); IR (KBr): 1456, 3296 cmꢀ1
;
½
a 2D0
ꢂ
¼ þ18:3 (c 0.84, CHCl3); 1H NMR (CDCl3, 300 MHz): d 1.28–
2.12 (m, 10H, CH2), 2.27–2.59 (m, 6H, CH2), 2.88–4.0 (m, 3H, CH2
and CH), 3.49 (br s, 1H, NH); 13C NMR (CDCl3, 75 MHz,): d 24.1,
25.6, 26.7, 27.8, 47.4, 54.2, 56.3, 59.8.
4.3.6. (S)-1-Methyl-4-(pyrrolidin-2-ylmethyl)piperazine 1f
Yield, 62%; dark yellow liquid; Rf 0.15 (methanol/chloroform,
6:94), MS (DART) (m/z): 184.20 (M+); HRMS (ESI) calcd for
C
10H22N3 (M++H): 184.1814, found 184.1807; IR (KBr): 1415,
3494 cmꢀ1
;
½
a 2D0
ꢂ
¼ þ17:1 (c 0.83, CHCl3); 1H NMR (CDCl3,
300 MHz): d 1.22–1.41 (m, 1H, CH2), 1.65–1.99 (m, 3H, CH2),
2.25–2.30 (s, 3H, NCH3), 2.32–2.72 (m, 10H, CH2), 2.85–2.96 (m,
1H, CH2), 2.98–3.10 (m, 1H, CH2), 3.29–3.39 (m, 1H, CH), 3.51 (br
s, 1H, NH); 13C NMR (CDCl3, 75 MHz): d 24.6, 29.6, 45.7, 45.9,
53.3, 55.0, 55.4, 62.8, 77.4.
4.3.1. (S)-2-(N-Phenylaminometh-1-yl)pyrrolidine27 1a
4.3.7. (S)-1-Phenyl-4-(pyrrolidin-2-ylmethyl)piperazine 1g
Yield, 72%; dark brown thick liquid; Rf 0.19 (methanol/chloro-
form, 6:94), MS (DART) (m/z): 246.21 (M+); HMRS (ESI) calcd for
Yield, 77%; dark yellow liquid; Rf 0.22 (methanol/chloroform,
6:94); IR (KBr); 1506, 1603, 3332 cmꢀ1; ½a D20
¼ þ18:6 (c 0.72,
ꢂ
CHCl3); 1H NMR (CDCl3, 300 MHz): d 1.40–1.53 (m, 1H, CH2),
1.66–1.98 (m, 3H, CH2), 2.55–2.65 (br s, 1H, NH), 2.81–3.0 (m,
3H, CH2), 3.13–3.22 (m, 1H, CH2), 3.34–3.44 (m, 1H, CH), 3.95–
4.20 (br, 1H, NH), 6.60–6.70 (m, 3H, ArH), 7.12–7.24 (m, 2H,
ArH); 13C NMR (CDCl3, 75 MHz): d 25.5 (ꢀve), 29.4 (ꢀve), 46.3
(ꢀve), 48.3 (ꢀve), 57.7 (+ve), 112.9 (+ve), 117.2 (+ve), 129.1
(+ve), 148.4.
C
15H24N3 (M++H) 246.1970, found 246.1965; IR (KBr): 1497,
1599, 3421 cmꢀ1; ½a D20
ꢂ
¼ þ17:0 (c 0.77, CHCl3); 1H NMR (CDCl3,
300 MHz,): d 1.37–1.51 (m, 1H, CH2), 1.72–1.85 (m, 2H, CH2),
1.91–2.10 (m, 1H, CH2), 2.30–2.45 (m, 2H, CH2), 2.49–2.65 (m,
2H, CH2), 2.69–2.80 (m, 2H, CH2), 2.93–3.11 (m, 2H, CH2), 3.13–
3.29 (m, 4H, CH2), 3.28–3.53 (m, 2H, CH and NH), 6.80–6.95 (m,
3H, ArH), 7.20–7.31 (m, 2H, ArH); 13C NMR (CDCl3, 75 MHz): d
24.5, 29.5, 45.0, 45.6, 49.0, 53.4, 55.6, 62.3, 115.9, 119.6, 129.0,
151.2.
4.3.2. (S)-2-(N-3-Nitrophenylaminometh-1-yl)pyrrolidine 1b
Yield, 62%; brown liquid; Rf 0.20 (methanol/chloroform, 6:94),
MS (Q-TOF) (m/z): 222.1257 (M+); IR (KBr); 1527, 1622,
3420 cmꢀ1
;
½
a 2D0
ꢂ
¼ þ16:7 (c 0.61, CHCl3); 1H NMR (CDCl3,
4.4. General procedure for the organocatalyzed asymmetric
Michael reaction of cyclohexanone with trans-b-nitrostyrene in
brine21
300 MHz): d 1.44–1.58 (m, 1H, CH2), 1.67–2.09 (m, 3H, CH2), 2.24
(br s, 1H, NH), 2.90–3.08 (m, 3H, CH2), 3.13–3.27 (m, 1H, CH2),
3.38–3.54 (m, 1H, CH), 4.71 (br s, 1H, NH), 6.87–6.90 (m, 1H,
ArH), 7.21–7.28 (m, 1H, ArH), 7.38 (s, 1H, ArH), 7.48–7.50 (d, 1H,
J = 8.1 Hz, ArH); 13C NMR (CDCl3, 75 MHz) ; 25.3, 29.1, 46.0, 47.1,
57.7, 106.1, 111.7, 118.9, 129.6, 149.1, 149.3.
To a brine solution (0.5 mL), diamine 1g (6.12 mg, 0.025 mmol)
and trichloroacetic acid (2.5
lL, 0.025 mmol) were added at 25 °C
and the mixture stirred for 2 min. Cyclohexanone (129
lL,
1.25 mmol) and trans-b-nitrostyrene (37.2 mg, 0.25 mmol) were
then added to the brine and the reaction mixture was stirred for
24 h. The brine phase was extracted with ethyl acetate
(3 ꢁ 8 mL) and organic extracts were dried over anhydrous Na2SO4,
filtered, and concentrated to obtain a crude reaction mixture. The
diastereoselectivity was determined by 1H NMR analysis of the
crude Michael product after short column chromatography purifi-
cation. The enantiomeric excess (ee) of the Michael product was
determined by chiral HPLC analyses. The relative and absolute con-
figurations of the products were determined by comparison with
the known 1H NMR, chiral HPLC analysis, and specific rotation
values.
4.3.3. (S)-2-(N-Naphth-1-ylaminometh-1-yl)pyrrolidine 1c
Yield, 78%; dark brown sticky liquid; Rf 0.54 (methanol/chloro-
form, 6:94), MS (Q-TOF) (m/z): 227.1406 (M+); HRMS calcd for
C
15H19N2 (M++H): 227.1548, found 227.1548; IR (KBr): 1474,
1581, 3047, 3366 cmꢀ1; ½a D20
ꢂ
¼ þ17:9 (c 0.65, CHCl3); 1H NMR
(CDCl3, 300 MHz): d 1.40–1.50 (m, 1H, CH2), 1.60–1.69 (m, 1H,
CH2), 1.72–1.80 (m, 1H, CH2), 1.82–1.90 (m, 1H, CH2), 2.80–2.94
(m, 2H, CH2), 3.09–3.16 (m, 1H, CHCH2NH), 3.25–3.32 (m, 1H,
CHCH2NH), 3.45–3.53 (m, 1H, CH), 3.60 (br s, 1H, NH), 5.19 (br s,
1H, NH), 6.50–6.59 (d, 1H, J = 7.4 Hz, ArH,), 7.16–7.23 (m, 1H,
ArH), 7.28–7.31 (m, 1H, ArH), 7.39–7.41 (m, 2H, ArH), 7.73–7.75
(d, 1H, J = 6.78 Hz), 7.95–7.98 (m, 1H, ArH); 13C NMR (CDCl3,
75 MHz): d 25.4, 29.3, 46.1, 48.0, 57.4, 104.0, 117.0, 120.5, 123.5,
124.50, 125.5, 125.6, 126.5, 128.3, 134.2, 143.6.
4.4.1. (S)-2-((R)-20-Nitro-10-phenylethyl)cyclohexanone 4a12i
Yield: 90%; white solid; mp 121–123 °C; Rf 0.33 (ethyl acetate/
hexane, 20:80); IR (KBr): 1349, 1551, 1699 cmꢀ1; syn/anti = 96:4;
a 2D0
ꢂ
¼ ꢀ27:8 (c 0.87, CHCl3); enantiomeric excess of syn diastereo-
4.3.4. (S)-2-(N-Cyclohexylaminometh-1-yl)pyrrolidine19 1d
Yield, 75%; dark yellow liquid; Rf 0.41 (methanol/chloroform,
6:94), MS (Q-TOF) (m/z): 183.1758 (M+); IR (KBr): 2929,
½
mer: 89%, determined by HPLC (Diacel chiralpak AS-H, hexane/i-
PrOH 85:15, flow rate 0.5 mL/min, k = 208 nm); tR (syn, minor)
= 25.01 min, tR (syn, major) = 36.47 min; 1H NMR (CDCl3,
300 MHz): d 1.19–1.29 (m, 1H, CH2), 1.53–1.80 (m, 4H, CH2),
2.05–2.19 (m, 1H, CH2), 2.36–2.55 (m, 2H, CH2), 2.63–2.76 (m,
1H, CH), 3.75–3.80 (dd, 0.96H (syn), J1 = 9.9 Hz, J2 = 4.5 Hz,
CHCH2NO2), 3.96–4.05 (dd, 0.04H (anti), J1 = 9.9 Hz, J2 = 4.5 Hz,
CHCH2NO2), 4.59–4.67 (m, 1H, CHCH2NO2), 4.91–4.96 (m, 1H,
CHCH2NO2), 7.14–7.17 (m, 2H, ArH), 7.23–7.35 (m, 3H, ArH); 13C
3434 cmꢀ1
;
½
a 2D0
ꢂ
¼ þ14:45 (c 0.78, CHCl3); 1H NMR (CDCl3,
300 MHz): d 0.97–1.25 (m, 5H, CH2),1.30–1.46 (m, 1H, CH2),
1.52–2.06 (m, 9H, CH2 and NH), 2.44–2.50 (m, 1H, CH), 2.55–2.65
(m, 1H, CHCH2NH), 2.75–2.83 (m, 1H, CHCH2NH), 2.96–3.10 (m,
2H, CH2), 3.28–3.40 (m, 1H, CH), 3.69 (br s, 1H, NH); 13C NMR
(CDCl3, 75 MHz): d 25.0, 25.6, 26.1, 29.6, 31.0, 33.3, 46.1, 47.2,
51.2, 57.0, 58.6.

1076
S. Singh, S. S. Chimni / Tetrahedron: Asymmetry 23 (2012) 1068–1079
NMR (CDCl3, 75 MHz): d 25.0, 28.5, 29.7, 33.2, 42.7, 43.9, 52.5, 78.9,
127.7, 128.1, 128.9, 137.7, 211.9.
1.40–1.78 (m, 4H, CH2), 2.01–2.17 (m, 1H, CH2), 2.37–2.57 (m,
2H, CH2), 2.75–3.03 (brs, 1H, CH), 4.61–4.82 (brs, 0.86H (syn),
CHCH2NO2), 4.83–4.99 (m, 1H, CHCH2NO2), 5.01–5.09 (dd, 1H,
J1 = 12.45 Hz, J2 = 4.5 Hz, CHCH2NO2), 5.19–5.29 (brs, 0.14H (anti),
CHCH2NO2), 7.30–7.60 (m, 4H, ArH), 7.60–7.79 (d, 1H, J = 8.1 Hz,
ArH), 7.84–7.87 (m, 1H, ArH), 8.08–8.25 (brs, 1H, ArH); 13C NMR
(CDCl3, 75 MHz): d (syn + anti isomers) 25.0, 25.2, 27.2, 28.6, 33.2,
36.8, 42.0, 42.8, 52.9, 53.7, 74.8, 78.7, 122.34, 122.7, 123.5, 124.9,
125.3, 125.8, 126.5, 126.7, 128.2, 129.0, 132.3, 134.0, 134.6,
210.3, 212.2.
4.4.2. (S)-2-((R)-20-Nitro-10-p-tolylethyl)cyclohexanone 4b22a
Yield: 86%; white sticky solid; Rf 0.36 (ethyl acetate/hexane,
20:80); MS (m/z): 283.8 (M++Na); IR (CHCl3): 1379, 1551,
1707 cmꢀ1; syn/anti = 95:5; ½a 2D0
¼ ꢀ29:4 (c 0.91, CHCl3); enantio-
ꢂ
meric excess of syn diastereomer: 88%, determined by HPLC (Diacel
chiralpak AS-H, hexane/i-PrOH 90:10, flow rate 0.8 mL/min,
k = 254 nm); tR (syn, minor) = 11.47 min, tR (syn, major) = 16.40 -
min; 1H NMR (CDCl3, 300 MHz): d 1.15–1.35 (m, 1H, CH2), 1.48–
1.85 (m, 4H, CH2), 2.02–2.16 (m, 1H, CH2), 2.31 (s, 3H, CH3),
2.35–2.53 (m, 2H, CH2), 2.61–2.73 (m, 1H, CH), 3.62–3.78 (m,
0.95H (syn), CHCH2NO2), 3.89–4.01 (m, 0.05H (anti), CHCH2NO2,
4.57–4.64 (dd, 1H, J1 = 12.15 Hz, J2 = 9.9 Hz, CHCH2NO2), 4.88–
4.94 (dd, 1H, J1 = 12.3 Hz, J2 = 4.5 Hz, CHCH2NO2), 7.03–7.06 (d,
2H, J = 8.1 Hz, ArH), 7.11–7.14 (d, 2H, J = 8.4 Hz, ArH). 13C NMR
(CDCl3, 75 MHz): d 21.0, 24.9, 28.4, 33.1, 42.6, 43.5, 52.5, 79.0,
128.0, 129.5, 134.6, 137.4, 212.0.
4.4.6. (S)-2-((R)-10-(400-Chlorophenyl)-20-nitroethyl)cyclohex-
anone 4f12i
Yield: 93%; white solid; mp 125–126 °C; Rf 0.38 (ethyl acetate/
hexane, 20:80); MS (m/z): 303.8 (M++Na); IR (CHCl3): 1379, 1551,
1707 cmꢀ1; syn/anti = 91:9; ½a 2D0
¼ ꢀ40:2 (c 0.91, CHCl3); enantio-
ꢂ
meric excess of syn diastereomer: >99%, determined by HPLC (Dia-
cel chiralpak AS-H, hexane/i-PrOH 90:10, flow rate 1.0 mL/min,
k = 254 nm); tR (syn, minor) = 13.23 min, tR (syn, major) = 19.79 -
min; 1H NMR (CDCl3, 300 MHz,): d 1.13–1.35 (m, 1H, CH2), 1.50–
1.81 (m, 4H, CH2), 2.0–2.19 (m, 1H, CH2), 2.31–2.55 (m, 2H, CH2),
2.60–2.72 (m, 1H, CH), 3.70–3.83 (m, 0.91H (syn), CHCH2NO2),
3.85–3.99 (m, 0.09H (anti), CHCH2NO2), 4.56–4.64 (dd, 1H,
J1 = 12.6 Hz, J2 = 9.9 Hz, CHCH2NO2), 4.90–4.96 (dd, 1H,
J1 = 12.6 Hz, J2 = 4.5 Hz, CHCH2NO2), 7.10–7.14 (m, 2H, ArH),
7.26–7.31 (m, 2H, ArH); 13C NMR (CDCl3, 75 MHz): d 25.0, 28.4,
33.1, 42.7, 43.3, 52.3, 78.5, 129.1, 129.5, 129.8, 133.5, 136.2, 211.5.
4.4.3. (S)-2-((R)-10-(300,400-Dimethoxyphenyl)-20-nitroethyl)
cyclohexanone 4c22b
Yield: 89%; white solid; mp 125–126 °C; Rf 0.34 (ethyl acetate/
hexane, 20:80); MS (m/z): 330.0 (M++Na); IR (CHCl3): 1310, 1550,
1706 cmꢀ1; syn/anti = 93:7; ½a 2D0
¼ ꢀ33:8 (c 0.78, CHCl3); enantio-
ꢂ
meric excess of syn diastereomer: 87%, determined by HPLC (Diacel
chiralpak AS-H, hexane/i-PrOH 90:10, flow rate 1.0 mL/min,
k = 254 nm); tR (syn, minor) = 24.79 min, tR (syn, major)
= 43.87 min; 1H NMR (CDCl3, 300 MHz): d 1.19–1.35 (m, 1H,
CH2), 1.50–1.92 (m, 4H, CH2), 2.06–2.17 (m, 1H, CH2), 2.32–2.56
(m, 2H, CH2), 2.60–2.77 (m, 1H, CH), 3.64–3.77 (m, 1H, CHCH2NO2),
3.79–3.94 (2s, 6H, 2ꢁ OCH3), 4.56–4.68 (dd, 1H, J1 = 12.45 Hz,
J2 = 9.9 Hz, CHCH2NO2), 4.83–4.97 (dd, 1H, J1 = 12.15 Hz,
J2 = 4.8 Hz, CHCH2NO2), 6.66–6.72 (m, 2H, ArH), 6.78–6.82 (m,
1H, ArH); 13C NMR (CDCl3, 300 MHz): d (syn + anti isomers) 24.9,
27.2, 28.4, 30.2, 33.0, 42.6, 43.5, 52.7, 53.7, 55.7, 55.90, 55.9,
78.9, 111.4, 111.5, 120.1, 120.3, 130.1, 148.4, 149.1, 211.9.
4.4.7. (S)-2-((R)-10-(400-Fluorophenyl)-20-nitroethyl)cyclohex-
anone 4g12i
Yield: 90%; brown solid; mp 69–70 °C; Rf 0.34 (ethyl acetate/
hexane, 20:80); MS (m/z): 287.8 (M++Na); IR (CHCl3): 1379, 1551,
1708 cmꢀ1; syn/anti = 91:9; ½a 2D0
¼ ꢀ30:4 (c 0.82, CHCl3); enantio-
ꢂ
meric excess of syn diastereomer: 76%, determined by HPLC (Diacel
chiralpak AS-H, hexane/i-PrOH 90:10, flow rate 1.0 mL/min,
k = 254 nm); tR (syn, minor) = 14.82 min, tR (syn, major) = 20.88 -
min; 1H NMR (CDCl3, 300 MHz): d 1.17–1.30 (m, 1H, CH2), 1.47–
1.85 (m, 4H, CH2), 2.03–2.16 (m, 1H, CH2), 2.31–2.54 (m, 2H,
CH2), 2.60–2.73 (m, 1H, CH), 3.74–3.79 (m, 0.91H (syn),
CHCH2NO2), 3.88–3.99 (m, 0.09H (anti), CHCH2NO2), 4.55–4.63
(dd, 1H, J1 =12.45 Hz, J2 = 9.9 Hz, CHCH2NO2), 4.90–4.95 (dd, 1H,
J1 = 12.6 Hz, J2 = 4.5 Hz, CHCH2NO2), 6.97–7.04 (m, 2H, ArH),
7.12–7.17 (m, 2H, ArH); 13C NMR (CDCl3, 75 MHz): d (syn + anti iso-
mers): 25.0, 26.9, 28.4, 33.1, 42.6, 43.2, 52.5, 78.8, 115.7, 115.9,
129.7, 129.8, 133.4, 133.5, 160.4, 163.7, 211.6.
4.4.4. (S)-2-((R)-10-Naphthalen-200-yl-20-nitro-ethyl)-cyclohexa-
none 4d12i
Yield: 87%; light brown solid; mp 115–117 °C; Rf 0.40 (ethyl
acetate/hexane, 20:80); MS (m/z): 319.9 (M++Na); IR (CHCl3):
1379, 1550, 1707 cmꢀ1; syn/anti = 97:3; ½a 2D0
¼ ꢀ37:3 (c 0.91,
ꢂ
CHCl3); enantiomeric excess of syn diastereomer: 97%, determined
by HPLC (Diacel chiralpak AS-H, hexane/i-PrOH 70:30, flow rate
0.8 mL/min, k = 254 nm); tR (syn, minor) = 9.59 min, tR (syn, ma-
jor) = 16.27 min; 1H NMR (CDCl3, 300 MHz): d 1.18–1.35 (m, 1H,
CH2), 1.49–1.78 (m, 4H, CH2), 2.01–2.18 (m, 1H, CH2), 2.31–2.57
(m, 2H, CH2), 2.74–2.85 (m, 1H, CH), 3.92–3.98 (m, 0.97H (syn),
CHCH2NO2), 4.12–4.24 (m, 0.03H (anti), CHCH2NO2), 4.68–4.76
(dd, 1H, J1 = 12.4 Hz, J2 = 9.9 Hz, CHCH2NO2), 4.98–5.04 (dd, 1H,
J1 = 12.4 Hz, J2 = 4.5 Hz, CHCH2NO2), 7.25–7.29 (m, 1H, ArH),
7.44–7.51 (m, 2H, ArH), 7.63 (s, 1H, ArH), 7.75–7.83 (m, 3H,
ArH); 13C NMR (CDCl3, 75 MHz): d 24.9, 28.4, 33.3, 42.7, 44.1,
52.5, 78.8, 125.2, 126.1, 126.4, 127.6, 127.8, 128.8, 132.8, 133.3,
135.1, 211.8.
4.4.8. (S)-2-((R)-10-Cyclohexyl-20-nitroethyl)cyclohexanone 4h12i
Yield: 80%; white liquid; Rf 0.28 (ethyl acetate/hexane, 20:80);
MS (m/z): 275.8 (M++Na); IR (CHCl3): 1379, 1550, 1707 cmꢀ1
;
syn/anti = 57:43; ½a D20
¼ ꢀ16:8 (c 0.68, CHCl3); enantiomeric excess
ꢂ
of syn diastereomer: 76%, determined by HPLC (Diacel chiralpak
AD-H, hexane/i-PrOH 95:5, flow rate 1.0 mL/min, k = 214 nm); tR
(syn, major) = 7.55 min, tR (syn, minor) = 8.35 min; 1H NMR (CDCl3,
300 MHz): d 0.83–1.44 (m, 6H, CyH), 1.48–1.84 (m, 8H, CyH), 1.90–
2.0 (m, 1H, CyH), 2.02–2.20 (m, 2H, CyH), 2.22–2.90 (m, 4H, CyH
and CHCH2NO2), 4.29–4.40 (m, 1.43H (syn + anti), CHCH2NO2),
4.61–4.68 (dd, 0.57H (syn), J1 = 13.9 Hz, J2 = 6 Hz, CHCH2NO2); 13C
NMR (CDCl3, 75 MHz): d (syn + anti isomers) 25.1, 25.3, 26.2,
26.3, 26.4, 27.4, 27.8, 29.6, 29.8, 30.0, 31.0, 31.4, 32.3, 38.9, 39.0,
39.9, 42.1, 42.6, 43.6, 50.6, 50.8, 75.9.
4.4.5. (S)-2-((R)-10-(Naphthalen-100-yl)-20-nitroethyl)cyclohexa-
none 4e23
Yield: 89%; brown solid; mp 110–112 °C; Rf 0.41 (ethyl acetate/
hexane, 20:80); MS (m/z): 319.8 (M++Na); IR (CHCl3): 1341, 1550,
1706.5 cmꢀ1; syn/anti = 86:14; ½a 2D0
ꢂ
¼ ꢀ72:2 (c 0.79, CHCl3); enan-
4.4.9. (S)-2-((S)-10-Thien-200-yl-20-nitro-ethyl)-cyclohexanone
4i12i
tiomeric excess of syn diastereomer: 78%, determined by HPLC
(Diacel chiralpak AS-H, hexane/i-PrOH 70:30, flow rate 0.8 mL/
min, k = 254 nm); tR (syn, minor) = 10.88 min, tR (syn, major)
=14.53 min; 1H NMR (CDCl3, 300 MHz): d 1.17–1.37 (m, 1H, CH2),
Yield: 88%; dark brown solid; mp 69–71 °C; Rf 0.34 (ethyl ace-
tate/hexane, 20:80); MS (m/z): 275.7 (M++Na); IR (CHCl3): 1378,
1552, 1706 cmꢀ1; syn/anti = 86:14; ½a 2D0
¼ ꢀ32:2 (c 0.88, CHCl3);
ꢂ

S. Singh, S. S. Chimni / Tetrahedron: Asymmetry 23 (2012) 1068–1079
1077
enantiomeric excess of syn diastereomer: 78%, determined by HPLC
(Diacel chiralpak AS-H, hexane/i-PrOH 95:5, flow rate 0.5 mL/min,
k = 254 nm); tR (syn, minor) = 38.17 min, tR (syn, major) = 48.03 -
min; 1H NMR (CDCl3, 300 MHz): d 1.22–1.40 (m, 1H, CH2), 1.53–
1.77 (m, 2H, CH2), 1.79–1.98 (m, 2H, CH2), 2.07–2.23 (m, 1H,
CH2), 2.28–2.55 (m, 2H, CH2), 2.61–2.78 (m, 1H, CH), 4.08–4.25
(m, 1H, CHCH2NO2), 4.61–4.68 (dd, 1H, CHCH2NO2, J1 = 12.6 Hz,
J2 = 9.3 Hz), 4.86–4.92 (m, 1H, CHCH2NO2), 6.86–6.94 (m, 2H,
ArH), 7.20–7.26 (m, 1H, ArH); 13C NMR (CDCl3, 75 MHz): d (sy-
n + anti isomers) 25.0, 28.2, 32.7, 39.3, 42.2, 42.5, 53.3, 53.5, 79.1,
124.9, 125.17, 126.6, 126.7, 126.9, 140.5, 211.1.
cel chiralpak AS-H, hexane/i-PrOH 80:20, flow rate 0.5 mL/min,
k = 225 nm); tR (minor) = 39.32 min, tR (major) = 48.69 min; 1H
NMR (CDCl3, 300 MHz): d 2.11 (s, 3H, CH3), 2.90–2.92 (d, 2H,
J = 6 Hz, CH2CO), 3.90–4.05 (m, 1H, CHCH2NO2), 4.55–4.72 (m,
2H, CHCH2NO2), 7.15–7.37 (m, 5H, ArH); 13C NMR (CDCl3,
75 MHz): d 30.4, 39.0, 46.1, 79.4, 127.4, 127.9, 129.1, 138.8, 205.4.
4.4.14. (4S,5R)-4-Methyl-6-nitro-5-phenylhexan-3-one 4o26
Yield: 64%; light yellow liquid; Rf 0.28 (ethyl acetate/hexane,
20:80), syn/anti = 97:3; IR (KBr): 1384, 1551, 1699 cmꢀ1
;
½
a 2D0
ꢂ
¼ ꢀ35:4 (c 0.81, CHCl3); enantiomeric excess of syn diastereo-
mer: 87%, determined by HPLC (Diacel chiralpak IB, hexane/i-PrOH
99:1, flow rate 1.0 mL/min, k = 220 nm); tR (syn, major)
= 20.21 min, tR (syn, minor) = 25.71 min; 1H NMR (CDCl3,
300 MHz): d 0.95–0.98 (d, 2.7H, J = 7.2 Hz, CHCH3), 1.04–1.09 (t,
2.7H, J = 7.2 Hz, CH2CH3), 1.17–1.20 (d, 0.3H, J = 7.2 Hz, CHCH3),
1.23–1.28 (t, 0.3H, J = 7.2 Hz, CH2CH3), 2.26–250 (m, 1H, CH2CH3),
2.53–2.70 (m, 1H, CH2CH3), 2.92–3.05 (m, 1H, CHCH3), 3.63–3.82
(m, 0.97H (syn), CHAr, 4.08–4.17 (m, 0.03H (anti), CHAr), 4.52–
4.84 (m, 2H, CH2NO2), 7.12–7.21 (m, 2H, ArH), 7.22–7.40 (m, 3H,
ArH); 13C NMR (CDCl3, 75 MHz): d 7.6, 16.3, 35.4, 46.0, 48.3, 78.3,
127.8, 127.9, 128.9, 129.0, 137.6, 213.6.
4.4.10. (S)-2-((R)-10-(400-Methoxyphenyl)-20-nitroethyl)cyclohexa-
none 4j12i
Yield: 89%; brown solid; mp 107–109 °C; Rf 0.31 (ethyl acetate/
hexane, 20:80); MS (m/z): 299.9 (M++Na); IR (CHCl3): 1380, 1551,
1706 cmꢀ1; syn/anti = 93:7; ½a 2D0
¼ ꢀ22:3 (c 0.94, CHCl3); enantio-
ꢂ
meric excess of syn diastereomer: 94%, determined by HPLC (Diacel
chiralpak AD-H, hexane/i-PrOH 80:20, flow rate 0.5 mL/min,
k = 254 nm); tR (syn, minor) = 17.92 min, tR (syn, major) = 21.71 -
min; 1H NMR (CDCl3, 300 MHz): d 1.14–1.32 (m, 1H, CH2), 1.47–
1.85 (m, 4H, CH2), 2.01–2.18 (m, 1H, CH2), 2.30–2.54 (m, 2H,
CH2), 2.60–2.71 (m, 1H, CH), 3.66–3.78 (m, 1H, CHCH2NO2), 3.79
(s, 3H, OCH3), 4.54–4.61 (dd, 1H, J1 = 12.3 Hz, J2 = 9.9 Hz,
CHCH2NO2), 4.88–4.93 (dd, 1H, J1 = 12.3 Hz, J2= 4.5 Hz, CHCH2NO2),
6.82–6.86 (m, 2H, ArH), 7.06–7.09 (m, 2H, ArH); 13C NMR (CDCl3,
75 MHz): d (syn + anti isomers) 24.9, 28.4, 30.1, 33.1, 42.3, 42.6,
43.1, 52.6, 53.7, 55.2, 79.1, 114.1, 114.3, 129.1, 129.4, 159.0, 212.0.
4.4.15. (S)-2-((R)-20-Nitro-10-phenyl-ethyl)-cyclopentanone 4p12i
Yield: 69%; dark brown liquid; Rf 0.35 (ethyl acetate/hexane,
20:80), syn/anti = 70:30; IR (KBr): 1382, 1552, 1733 cmꢀ1
;
½
a 2D0
ꢂ
¼ ꢀ29:9 (c 0.78, CHCl3); enantiomeric excess of syn diastereo-
mer: 52%, determined by HPLC (Diacel chiralpak AS-H, hexane/i-
PrOH 90:10, flow rate 0.5 mL/min, k = 211 nm); tR (syn, minor)
= 26.29 min, tR (syn, major) = 35.50 min; 1H NMR (CDCl3,
300 MHz): d 1.39–1.53 (m, 1H, CH2), 1.55–1.98 (m, 4H, CH2),
2.05–2.22 (m, 1H, CH2), 2.28–2.55 (m, 1H, CH), 3.62–3.76 (m,
0.7H (syn), CHAr), 3.76–3.88 (m, 0.3H (anti), CHAr), 4.62–4.78 (m,
0.7H, CH2NO2), 4.95–5.07 (m, 0.7H, CH2NO2), 5.20–5.40 (m, 0.6H,
CH2NO2), 7.02–7.49 (m, 5H, ArH); 13C NMR (CDCl3, 75 MHz): d (sy-
n + anti isomers) 20.2, 20.5, 26.9, 28.2, 38.6, 39.2, 43.9, 44.1, 50.4,
51.4, 77.4, 77.9, 78.2, 127.8, 127.9, 128.3, 128.4, 128.8, 128.9,
129.0, 137.7, 218.51.
4.4.11. (S)-2-((R)-10-(400-Nitrophenyl)-20-nitroethyl)cyclohexa-
none 4k24
Yield: 91%; brown solid; mp 107–109 °C; Rf 0.28 (ethyl acetate/
hexane, 20:80); MS (m/z): 314.9 (M++Na); IR (CHCl3): 1348, 1379,
1521, 1552, 1707 cmꢀ1; syn/anti = 75:25; ½a 2D0
¼ ꢀ22:4 (c 0.94,
ꢂ
CHCl3); enantiomeric excess of syn diastereomer: 75%, determined
by HPLC (Diacel chiralpak IB, hexane/i-PrOH 90:10, flow rate
0.5 mL/min, k = 254 nm); tR (syn, minor) = 63.25 min, tR (syn, ma-
jor) = 68.75 min; 1H NMR (CDCl3, 300 MHz): d 1.16–1.46 (m, 1H,
CH2), 1.50–1.98 (m, 4H, CH2), 2.0–2.21 (m, 1H, CH2), 2.24–2.58
(m, 2H, CH2), 2.64–2.88 (m, 1H, CH), 3.85–4.01 (m, 0.75H (syn),
CHCH2NO2), 4.02- 4.13 (m, 0.25H (anti), CHCH2NO2), 4.88–5.02
(m, 2H, CHCH2NO2), 7.38–7.49 (m, 2H, ArH), 8.16–8.22 (m, 2H,
ArH); 13C NMR (CDCl3, 75 MHz): d (syn + anti isomers) 25.1, 27.3,
28.3, 30.6, 33.2, 42.3, 42.7, 43.3, 43.7, 52.2, 53.4, 76.4, 77.9,
123.9, 124.1, 129.3, 129.5, 145.5, 146.0, 147.5, 210.8.
4.4.16. (2S,4S)-2-((R)-10-(400-Methoxyphenyl)-20-nitroethyl)-4-
methylcyclohexanone 4q18
Yield: 89%; white liquid; Rf 0.32 (ethyl acetate/hexane, 20:80);
MS (m/z): 313.8 (M++Na); IR (CHCl3): 1380, 1551, 1708 cmꢀ1
;
½
a 2D0
ꢂ
¼ ꢀ32:3 (c 0.78, CHCl3); enantiomeric excess of major diaste-
reomer: 80%, determined by HPLC (Diacel chiralpak AS-H, hexane/
i-PrOH 90:10, flow rate 0.5 mL/min, k = 254 nm); tR (min-
or) = 32.95 min, tR (major) = 73.31 min; 1H NMR (CDCl3,
300 MHz): d 0.87–0.89 (d, 0.88H, J = 6.6 Hz, CH3), 0.96–0.98 (d,
2.12H, J = 6.6 Hz, CH3), 1.28–1.70 (m, 3H, CH2), 1.84–2.11 (m, 2H,
CH2), 2.38–2.51 (m, 2H, CH2 and CH), 2.54–2.70 (m, 1H, CH),
3.55–3.76 (m, 1H, CHAr), 3.77 (s, 3H, OCH3), 4.40–4.65 (m, 1.56H,
CH2NO2), 4.78–4.90 (m, 0.44H, CH2NO2), 6.77–6.83 (m, 2H, ArH),
7.0–7.06 (m, 2H, ArH); 13C NMR (CDCl3, 75 MHz): d (all isomers)
19.5, 21.0, 26.5, 32.3, 34.4, 36.4, 37.8, 38.6, 41.2, 42.2, 43.2, 43.4,
50.3, 55.2, 79.3, 114.3, 114.5, 128.9, 129.01, 129.2, 159.2, 213.2.
4.4.12. (S)-2-((R)-10-(200-Chlorophenyl)-20-nitroethyl)cyclohexa-
none 4l12i
Yield: 88%; yellow liquid; Rf 0.36 (ethyl acetate/hexane, 20:80);
MS (m/z): 303.8 (M++Na); IR (CHCl3): 1379, 1551, 1707 cmꢀ1; syn/
anti = 95:5; ½a 2D0
¼ ꢀ23:2 (c 0.84, CHCl3); enantiomeric excess of
ꢂ
syn diastereomer: 84%, determined by HPLC (Diacel chiralpak AS-
H, hexane/i-PrOH 99:1, flow rate 1 mL/min, k = 211 nm); tR (syn,
minor) = 26.69 min, tR (syn, major) = 34.03 min; 1H NMR (CDCl3,
300 MHz): d 1.22–1.45 (m, 1H, CH2), 1.53–1.87 (m, 4H, CH2),
2.05–2.18 (m, 1H, CH2), 2.33–2.56 (m, 2H, CH2), 2.83–2.99 (m,
1H, CH), 4.02–4.37 (m, 0.95H (syn), CHCH2NO2), 4.60–4.72 (m,
0.05H (anti), CHCH2NO2), 4.88–4.92 (m, 2H, CHCH2NO2), 7.16–
7.28 (m, 3H, ArH), 7.35–7.41 (m, 1H, ArH); 13C NMR (CDCl3,
75 MHz): d (syn + anti isomers) 25.2, 28.5, 33.0, 40.9, 42.7, 51.7,
77.4, 127.3, 128.8, 129.4, 130.3, 134.5, 135.4, 211.5.
4.4.17. (2S,4S)-2-((R)-10-(200-Chlorophenyl)-20-nitroethyl)-4-
methylcyclohexanone 4r18
Yield: 82%; light yellow liquid; Rf 0.37 (ethyl acetate/hexane,
20:80); MS (m/z): 317.8 (M++Na); IR (CHCl3): 1379, 1553,
1709 cmꢀ1; ½a 2D0
¼ ꢀ55:4 (c 0.96, CHCl3); enantiomeric excess of
ꢂ
major diastereomer: 89%, determined by HPLC (Diacel chiralpak
AD-H, hexane/i-PrOH 98:2, flow rate 0.5 mL/min, k = 254 nm); tR
(minor) = 34.32 min, tR (major) = 43.24 min; 1H NMR (CDCl3,
300 MHz): d 0.99–1.01 (d, 0.81H, J = 6.3 Hz, CH3), 1.07–1.10 (d,
0.39H, J = 6.6 Hz, CH3), 1.14–1.16 (d, 1.74H, J = 6.9 Hz, CH3), 1.45–
4.4.13. (R)-5-Nitro-4-phenyl-pentan-2-one 4n12i
Yield: 74%; white solid; mp 81–83 °C; Rf 0.18 (ethyl acetate/
hexane, 20:80); IR (KBr): 1383, 1546, 1715 cmꢀ1; ½a D20
¼ ꢀ4:6 (c
ꢂ
0.91, CHCl3); enantiomeric excess: 25% determined by HPLC (Dia-

1078
S. Singh, S. S. Chimni / Tetrahedron: Asymmetry 23 (2012) 1068–1079
1.70 (m, 2H, CH2), 1.72–1.90 (m, 1H, CH2), 2.0–2.35 (m, 2H, CH2),
2.41–2.75 (m, 2H, CH2 and CH), 2.94–3.30 (m, 1H, CH), 4.25–4.55
(m, 1H, CHAr), 4.82–5.04 (m, 2H, CH2NO2), 7.35–7.38 (m, 3H,
ArH), 7.49–7.52 (m, 1H, ArH); 13C NMR (CDCl3, 75 MHz): d (all iso-
mers) 18.7, 20.8, 26.8, 32.2, 34.0, 36.2, 37.9, 38.5, 40.8, 42.0, 48.6,
50.3, 127.3, 127.4, 128.8, 128.9, 130.3, 134.5, 135.2, 211.8, 212.4.
(minor) = 24.02 min, tR (major) = 36.40 min; 1H NMR CDCl3,
300 MHz): d 0.77 (s, 4H, (CH3)3), 0.81 (s, 2H, (CH3)3), 0.92 (s, 2H,
(CH3)3), 0.97 (s, 1H, (CH3)3), 1.35–1.90 (m, 4H, CH2), 2.05–2.20
(m, 1H, CH2), 2.30–2.88 (m, 3H, CH2 and CH), 3.74–3.95 (m, 0.7H,
CHAr), 3.97–4.07 (m, 0.3H, CHAr), 4.52–4.77 (m, 1.2H, CH2NO2),
4.90–5.07 (m, 0.8H, CH2NO2), 7.18–7.46 (m, 5H, ArH); 13C NMR
(CDCl3, 75 MHz): d (all isomers) 26.9, 27.1, 27.3, 27.4, 27.5, 27.9,
29.1, 29.5, 30.8, 32.2, 32.3, 32.4, 34.2, 38.9, 40.8, 41.2, 41.5, 42.0,
43.3, 44.0, 44.1, 46.6, 46.9, 47.2, 51.5, 51.9, 52.7, 76.5, 78.7, 79.0,
127.4, 127.6, 128.0, 128.1, 128.3, 128.6, 128.8, 129.0, 136.6,
137.8, 213.7.
4.4.18. (2S,4S)-2-((R)-10-(400-Chlorophenyl)-20-nitroethyl)-4-me-
thylcyclohexanone 4s18
Yield: 82%; light yellow solid; mp 70–72 °C; Rf 0.37 (ethyl ace-
tate/hexane, 20:80), IR (KBr): 1378, 1553, 1710 cmꢀ1
;
½
a 2D0
ꢂ
¼ ꢀ37:4 (c 0.91, CHCl3); enantiomeric excess of major diaste-
reomer: 81%, determined by HPLC (Diacel chiralpak OD-H, hexane/
i-PrOH 90:10, flow rate 0.5 mL/min, k = 208 nm); tR (min-
or) = 33.32 min, tR (major) = 41.65 min; 1H NMR (CDCl3,
300 MHz): d 0.81–0.89 (d, 0.78H, J = 6.6 Hz, CH3), 0.95–1.02 (d,
2.26H, J = 6.9 Hz, CH3), 1.35–1.45 (m, 1H, CH2), 1.55–1.72 (m, 2H,
CH2), 1.80–2.10 (m, 2H, CH2), 2.25–2.55 (m, 2H, CH2 and CH),
2.60–2.77 (m, 1H, CH), 3.65–3.80 (m, 1H, CHAr), 4.50–4.98 (m,
2H, CH2NO2), 7.07–7.11 (m, 2H, ArH), 7.24–7.32 (m, 2H, ArH);
13C NMR (CDCl3, 75 MHz): d 19.1, 26.5, 32.2, 34.2, 37.8, 38.4,
43.3, 43.4, 49.5, 51.15, 78.8, 129.1, 129.3, 129.3, 129.6, 135.8.
4.4.22. (E)-(S)-2-((S)-10-Nitro-40-phenylbut-30-en-20-yl)cyclohe-
xanone 4w25
Yield: 94%; brown solid; mp 96–98 °C; Rf 0.44 (ethyl acetate/
hexane, 20:80); MS (m/z): 295.8 (M++Na); IR (CHCl3): 1380, 1550,
1707 cmꢀ1; syn/anti = 87:13; ½a 2D0
¼ ꢀ45:4 (c 0.91, CHCl3); enan-
ꢂ
tiomeric excess of syn diastereomer: 84%, determined by HPLC
(Diacel chiralpak AS-H, hexane/i-PrOH 90:10, flow rate 1.0 mL/
min, k = 254 nm); tR (syn, minor) = 10.82 min, tR (syn, ma-
jor) = 15.44 min; 1H NMR (CDCl3, 300 MHz): d 1.37–1.51 (m, 1H,
CH2), 1.60–1.80 (m, 2H, CH2), 1.82–1.99 (m, 1H, CH2), 2.01–2.26
(m, 2H, CH2), 2.31–2.65 (m, 3H, CH2 and CH), 3.15–3.24 (m,
0.13H (anti), CHCH2NO2), 3.27–3.45 (m, 0.87H (syn), CHCH2NO2),
4.50–4.79 (m, 2H, CHCH2NO2), 5.93–6.14 (dd, 1H, J1 = 15.75 Hz,
J2 = 9.2 Hz, Ar–CH@C–H, 6.45–6.52 (m, 1H, Ar–CH@C–H), 7.23–
7.35 (m, 5H, ArH); 13C NMR (CDCl3, 75 MHz): d (syn + anti isomers)
25.0, 28.0, 29.6, 32.5, 41.8, 42.6, 51.6, 78.0, 125.6, 126.4, 126.4,
127.9, 128.5, 134.4, 136.2, 211.2.
4.4.19. (2S,4S)-2-((R)-10-(p-Tolylethyl)-20-nitroethyl)-4-meth-
ylcyclohexanone 4t18
Yield: 82%; light yellow liquid; Rf 0.37 (ethyl acetate/hexane,
20:80); MS (m/z): 297.8 (M++Na); IR (CHCl3): 1379, 1552,
1709 cmꢀ1; ½a 2D0
¼ ꢀ40:1 (c 0.72, CHCl3); enantiomeric excess of
ꢂ
major diastereomer: 77%, determined by HPLC (Diacel chiralpak
IB, hexane/i-PrOH 95:5, flow rate 0.5 mL/min; k = 254 nm); tR
(minor) = 23.90 min, tR (major) = 26.55 min; 1H NMR (CDCl3,
300 MHz): d 0.83–0.89 (d, 0.75H, J = 6.3 Hz, CH3), 0.94–1.01 (d,
2.25H, J = 6.6 Hz, CH3), 1.30–1.54 (m, 2H, CH2), 1.57–1.72 (m, 1H,
CH2), 1.85–2.14 (m, 2H, CH2), 2.32 (s, 3H, Ar–CH3), 2.39–2.55 (m,
2H, CH2 and CH), 2.65–2.82 (m, 1H, CH), 3.62–3.83 (m, 1H, CHAr),
4.52–4.70 (m, 1.69H, CH2NO2), 4.72–5.01 (m, 0.31H, CH2NO2),
7.02–7.06 (m, 2H, ArH), 7.09–7.15 (m, 2H, ArH); 13C NMR: (CDCl3,
75 MHz): d (all isomers) 19.4, 20.9, 21.0, 26.4, 32.2, 34.4, 36.4, 37.8,
38.5, 41.2, 42.1, 43.5, 43.7, 50.1, 51.3, 79.0, 79.2, 127.8, 128.0,
129.5, 129.7, 134.1, 137.6, 213.1.
Acknowledgments
We are grateful for financial support from CSIR, India to S.S.C.
(research Grant No. 02(0009)/11/EMR-II) and SRF (NET) fellowship
to S.S.
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