Michael reaction of ketones and β-nitrostyrenes catalyzed by camphor-10-sulfonamide-based prolinamide

Article abstract of DOI:10.1016/j.tetasy.2010.09.012

Novel camphor sulfonamide based organocatalysts were evaluated for their catalytic activity in the Michael reaction of ketones with nitroolefins. Reaction of ketones with β-nitrostyrenes in the presence of 20 mol % organocatalyst 1a and benzoic acid under

Full text of DOI:10.1016/j.tetasy.2010.09.012

Tetrahedron: Asymmetry 21 (2010) 2487–2492
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journal homepage: www.elsevier.com/locate/tetasy
Michael reaction of ketones and b-nitrostyrenes catalyzed by
camphor-10-sulfonamide-based prolinamide
⇑
Rashmi Rani, Rama Krishna Peddinti
Department of Chemistry, Indian Institute of Technology, Roorkee 247 667, Uttarakhand, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Novel camphor sulfonamide based organocatalysts were evaluated for their catalytic activity in the
Michael reaction of ketones with nitroolefins. Reaction of ketones with b-nitrostyrenes in the presence
of 20 mol % organocatalyst 1a and benzoic acid under solvent-free conditions at 0 °C provided the desired
Michael adducts with high chemical yields (up to 97%) and excellent stereoselectivities (>99:1).
Ó 2010 Elsevier Ltd. All rights reserved.
Received 23 August 2010
Accepted 21 September 2010
Available online 26 October 2010
1. Introduction
1a
R =
Catalytic asymmetric Michael addition plays an important role
among the numerous asymmetric carbon–carbon bond-forming
reactions, since it represents one of the most elegant and attractive
ways to introduce chirality into a Michael acceptor.1,2 Due to the
simplicity of the asymmetric organocatalytic approach, the Michael
addition of various donors and acceptors has been studied in the
presence of organcatalysts.3 The proline-catalyzed Michael addition
between ketones and trans-b-nitrostyrene was first demonstrated
by Barbas,4a List,4b and Enders,4c the adducts were obtained with
good yields but with very low enantioselectivities. Since then,
numerous pyrrolidine-based5–9 and thiourea-based10 organocata-
lysts have been used in asymmetric Michael additions. Michael
additions of carbonyl compounds onto nitroalkenes using chiral
amines as organocatalysts, which promote the reaction via an enam-
ine pathway, have been studied in several laboratories.7,9,11 Among
these, good levels of asymmetric induction could be obtained by
proline derivatives7,9 where the amide moiety is a part of a chiral
cavity in which the reaction takes place.
H
N
1b
1c
N
H
O
O
S
NR2
O
Figure 1. Structures of organocatalysts 1a–c.
ketones to nitroolefins proceeds via an enamine intermediate,
similar to the proline-promoted aldol reaction, we reasonedthat this
class of organocatalysts could also be successfully used in this
reaction. To verify this hypothesis, the camphor sulfonamide-based
prolinamides were initially tested as organocatalysts in the asym-
metric Michael addition of cyclohexanone to aromatic nitroolefins.
Herein, we report our preliminary results on camphorsulfona-
mide-based prolinamide mediated organocatalytic intermolecular
Michael reactions.
In continuation of our work on asymmetric synthesis,12 we re-
cently synthesized camphor-based novel organocatalysts 1a–c
(Fig. 1) with the appended prolinamide group and found that these
catalysts exert good stereochemical control in the aldol reactions
of ketones with aromatic aldehydes.13 The bifunctional organocata-
lyst 1a plays a significant role in determining the stereochemical
outcome of the reaction presumably by stabilizing the transition
state via hydrogen bonding between the aldehyde and amide moiety
of the enamine formed from the catalyst and ketone and effective
shielding of one of the faces of the enamine by the benzyl moiety
of the catalyst. Since the amine catalyzed Michael addition of
2. Results and discussion
We chose the Michael addition of cyclohexanone to b-nitrosty-
rene 2a as the model reaction by using organocatalyst 1a. A survey
of polar and non-polar solvents revealed that all of the reactions
proceeded smoothly and were complete within 16–30 h at room
temperature without using any co-catalyst. However, high chemi-
cal yields with poor selectivity were observed between syn and anti
Michael adducts in all cases. When the reaction was performed in
15 equiv of cyclohexanone without using an additional solvent, the
reaction was complete within 14 h to afford adduct 3a with high
chemical yield and acceptable enantioselectivity (Table 1, entry 6).
⇑
Corresponding author. Tel.: +91 13 3228 5438; fax: +91 13 3227 3560.
E-mail addresses: rkpedfcy@iitr.ernet.in, ramakpeddinti@rediffmail.com (R.K.
Peddinti).
0957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2010.09.012

2488
R. Rani, R. K. Peddinti / Tetrahedron: Asymmetry 21 (2010) 2487–2492
Table 1
acid afforded the best result in terms of reaction time and selectiv-
Screening of reaction conditions and organocatalystsa
ity (Table 2, entry 1, 95:5 dr, 65% ee). Thus the acidic co-catalyst
plays an important role on the reaction. Moreover, the reaction
temperature was found to be an essential factor with regard to
the enantioselectivity of the reaction. The stereoselectivity was
gradually increased by decreasing the reaction temperature from
20 to 0 °C (Table 2, entries 1 and 5). However, further lowering
of the temperature to À30 °C resulted in a slight decrease in the
enantiomeric purity of adduct 3a as well as the reaction rate
(Table 2, entry 6). Under the optimal reaction conditions
(20 mol % catalyst, 15 mol % PhCOOH as the co-catalyst at 0 °C,
entry 5, Table 2) organocatalyst 1a demonstrated the best catalytic
activity. All of the reactions proceeded with a diastereoselectivity
in favor of syn-diastereoisomer.
Encouraged by these initial results, we next investigated the
reactions of other nitroolefins 2b–k to expand upon the scope of
the Michael addition with cyclohexanone under the optimal reac-
tion conditions in the presence of organocatalyst 1a. The results are
summarized in Table 3. In all of the cases studied, the adducts were
obtained in very high to excellent chemical yields regardless of the
electronic nature of the substitutions on the aromatic nucleus. The
diastereomeric discrimination of the products was high to excel-
lent with the exception of adduct 3i derived from 4-methoxynitro-
styrene 2i (Table 3, entry 9) where the syn and anti adducts were
obtained in moderate 84:16 ratio. The reaction of nitrostyrene 2b
(R = o-NO2) provided better asymmetric induction in comparison
to that of nitrostyrene 2c (R = m-NO2) (Table 3, entries 2 and 3).
However, the halogen-substituted nitrostyrenes 2d–g afforded
the corresponding Michael adducts 3d–g in comparable enantio-
meric excess. Among the 4-methyl and 4-methoxy-nitoolefins
2h,i as Michael acceptors, the former furnished the Michael adduct
in better dr and ee values (Table 3, entries 8 and 9). The reaction of
O
O
NO2
Catalyst
NO2
+
rt
3a
2a
c
Entry Catalyst
(mol %)
Solvent
Time
(h)
Yield
(%)
drb
(anti:syn)
ee
(%)
1
2
3
4
5
6
7
8
9
1a (20)
1a (20)
1a (20)
1a (20)
1a (20)
1a (15)
1a (20)
1a (30)
1b (20)
1c (20)
CHCl2
CHCl3
MeOH
H2O
16
20
20
28
77
80
85
60
80
88
92
90
80
93
80:20
85:15
80:20
65:35
70:30
88:12
90:10
90:10
92:8
36
53
30
32
45
53
61
59
44
53
H2O:MeOH 30
Neat
Neat
Neat
Neat
Neat
14
10
10
14
8
10
85:15
a
All reactions were carried out with cyclohexanone (3 mM) and b-nitrostyrene
2a (0.2 mM).
Determined by 1H NMR (500 MHz) analysis of the crude sample.
b
c
Determined by HPLC analysis using Chiralpak AS-H column.
Optimum results were obtained with 20 mol % catalyst. The use of
15 mol % and 30 mol % of the organocatalyst led to a minor loss of
stereocontrol (Table 1, entries 6–8). The prolinamides 1b and 1c
derived from N,N-diisopropyl camphor-10-sulfonamide and N,N-
dicyclohexyl camphor-10-sulfonamide, respectively, were used as
catalysts; the catalytic activity was found to be less in comparison
with the prolinamide 1a derived from N,N-dibenzyl camphor-10-
sulfonamide.
cyclohexanone with a-naphthylnitrostyrene 2j resulted in the for-
mation of adduct 3j almost exclusively with syn stereochemistry
and a very high enantiomeric excess of 89% (Table 3, entry 10).
Moreover, 2-(2-nitrovinyl)furan 2k yielded adduct 3k in very high
diastereoselectivity and very good enantioselectivity.
The asymmetric induction was further improved upon by carry-
ing out the reaction at different temperatures, under solvent-free
conditions using a catalyst and a co-catalyst8,9,14 (Table 2). The
addition of 15 mol % carboxylic acid as co-catalyst significantly
accelerated the reaction rate relative to that carried out in the ab-
sence of a co-catalyst. From the carboxylic acids employed, benzoic
The use of other symmetrical cycloalkanones, such as 4-methyl,
4-ethyl-cyclohexanones, and
c-pyrone as Michael donors was
Table 2
Effect of additives on the Michael reaction of cyclohexanone with b-nitrostyrene 2a in the presence of 1aa
O
O
NO2
20 mol% 1a
NO2
+
2a
3a
Entry
Solvent
Additive
Temp (°C)
Time (h)
Yield (%)
drb (anti:syn)
eec (%)
1
2
3
Neat
CHCl3
Neat
PhCOOH
PhCOOH
4-NO2C6H4
COOH
rt
rt
rt
7
18
18
94
88
85
95:5
80:20
80:20
65
57
53
4
5
6
7
Neat
Neat
Neat
Neat
—
0
0
18
12
24
30
90
95
92
80
92:8
95:5
92:8
85:15
71
79
75
59
PhCOOH
PhCOOH
4-NO2C6H4
COOH
À30
0
8
9
10
Neat
Neat
Neat
Et3N
0
0
0
36
30
32
75
70
89
93:7
77:23
90:10
62
60
61
Isobutyric acid
3-CF3C6H4
COOH
a
b
c
The reactions were carried out with cyclohexanone (3 mM) and b-nitrostyrene (0.2 mM) and 15 mol % of additive.
Determined by 1H NMR (500 MHz) analysis of the crude sample.
Determined by HPLC analysis using Chiralpak AS-H column.

R. Rani, R. K. Peddinti / Tetrahedron: Asymmetry 21 (2010) 2487–2492
2489
Table 3
Michael reaction of ketones with substituted b-nitrostyrenes in presence of 1aa
R
O
O
20 mol% 1a
R
+
NO2
NO2
PhCO2H
0 ºC
X
X
2a-k
3-8
Entry
1
Product
Time (h)
12
Yield (%)
drb (anti:syn)
ee (%)c
O
95
96
95:5
79
3a
3b
NO2
O
NO2
NO2
2
3
14
14
97:3
93:7
77d
NO2
NO2
O
O
O
92
67d
3c
Cl
4
5
18
18
94
92
92:8
97:3
69
68
3d
3e
No2
Br
NO2
Cl
6
7
8
18
18
24
95
92
90
95:5
92:8
95:5
71
O
O
O
3f
NO2
NO2
NO2
Br
70d
3g
3h
CH3
72
(continued on next page)

2490
R. Rani, R. K. Peddinti / Tetrahedron: Asymmetry 21 (2010) 2487–2492
Table 3 (continued)
Entry
Product
Time (h)
Yield (%)
drb (anti:syn)
ee (%)c
OCH3
9
24
89
84:16
60
O
3i
NO2
O
O
10
11
16
18
94
90
>99:1
95:5
89
3j
NO2
NO2
O
78d
3k
O
O
O
12
14
92
—
76e
NO2
4a
4b
NO2
NO2
13
14
96
—
65d
NO2
14
15
94
—
71
5a
6a
O
15
16
16
97
93:7
75d
NO2
O
O
12
18
90
89
85:15
75d
NO2
NO2
7a
8a
17
—
50
O
NO2
a
All the reactions were carried out with cycloalkanone (3 mM) and b-nitrostyrene (0.2 mM) at 0 °C.
Determined by 1H NMR (500 MHz) analysis of the crude sample.
Determined by HPLC analysis using Chiralpak AS-H column unless otherwise mentioned.
Determined with Chiralpak AD-H column.
b
c
d
e
Determined with Chiralcel OD-H column.

R. Rani, R. K. Peddinti / Tetrahedron: Asymmetry 21 (2010) 2487–2492
2491
Table 4
Comparison of results from 1a and proline-catalyzed reactionsa
Entry
Catalyst (mol %)
Product
Yield (%)
dr (anti:syn)
ee (%)
1
2
Proline (15)
1a (20)
94
95
95:5
95:5
À23
79
O
NO2
3a
3
4
Proline (15)
1a (20)
97
89
—
—
À7
50
O
NO2
8a
a
Organocatalyst 1a-catalyzed reactions were performed at 0 °C under neat conditions and proline-catalyzed reactions were performed at room temperature in DMSO.
evaluated as well and products 4a,b, 5a and 6a were obtained in
excellent yields and with good to very good enantioselectivities.
The results are shown in Table 3. The reaction of nitrostyrene 2b
(R = o-NO2) with cyclopentanone as a Michael donor was also per-
formed to afford the adduct 7a with very good enantiomeric ex-
cess. The reaction between acetone and nitrostyrene 2a under
the present catalytic system was then examined. Product 8a was
obtained in very high chemical yield albeit in moderate enantio-
meric purity.
the Michael adduct was performed on a chiral stationary phase
using hexane-isopropanol as the eluting solvent.
Acknowledgments
We are grateful to the Department of Science and Technology
(DST), New Delhi for financial support (Research Grant No. SR/S1/
OC-15/2005).
The asymmetric induction achieved by the catalytic system pre-
sented herein was good to very good. The results obtained from a
couple of Michael reactions mediated by
in Table 4.
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In conclusion, new prolinamide derived organocatalysts that
contain a structural rigid bicyclic camphor scaffold and amide moi-
ety were used for the first time in Michael additions. We have dem-
onstrated a practical application of camphor-10-sulfonamide based
prolinamide for the Michael additions of ketones with b-nitrosty-
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activity and the reaction proceeded in excellent diastereoselectivity
with good to high enantioselectivity, which may be potentially use-
ful for preparing enantiomerically enriched c-nitroketones.
4. Experimental
4.1. General
The structures of Michael adducts were confirmed from their IR,
1H NMR (500 MHz) and 13C NMR (125 MHz) spectral studies. The
absolute configuration of the major syn adducts is as shown in
structures and is based on the retention times reported in the
literature.7a,11b,15
4.2. Typical procedure for the enantioselective Michael reaction
catalyzed by organocatalyst 1a
A mixture of a nitrostyrene (0.2 mmol), organocatalyst 1a
(20 mol %), benzoic acid (15 mol %), and cycloalkanone/acetone
(05–1.0 mL) was stirred for 12–24 h at 0 °C. The reaction was mon-
itored by TLC at regular intervals. Upon completion of reaction, the
crude product was submitted to 1H NMR (500 MHz) to determine
the diastereomeric excess. The residue was subjected to column
chromatography on silica gel to afford pure product. The HPLC of

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