Asymmetric Michael addition catalysed by sugar-based prolinamides in solvent-free conditions

Article abstract of DOI:10.1016/j.tetlet.2010.10.148

Sugar-based prolinamides derived from glucosamine have been developed as organocatalysts for the asymmetric Michael addition between cyclohexanones and nitroolefins. Numerous polar and nonpolar solvents and additives have been screened in the current stud

Full text of DOI:10.1016/j.tetlet.2010.10.148

Tetrahedron Letters 52 (2011) 117–121
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Asymmetric Michael addition catalysed by sugar-based prolinamides
in solvent-free conditions
⇑
Jyoti Agarwal, 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:
Sugar-based prolinamides derived from glucosamine have been developed as organocatalysts for the
asymmetric Michael addition between cyclohexanones and nitroolefins. Numerous polar and nonpolar
solvents and additives have been screened in the current study. The organocatalyst 1c in the presence
of benzoic acid as additive catalysed the reaction under neat conditions to afford Michael adducts in high
yields (up to 98%) with excellent diastereoselectivities (up to >99:1) and moderate enantiomeric ratios
(up to 84:16).
Received 20 September 2010
Revised 27 October 2010
Accepted 29 October 2010
Available online 2 November 2010
Ó 2010 Elsevier Ltd. All rights reserved.
The development of organocatalytic asymmetric reactions has
drawn much attention in recent years since environmentally
friendly and metal-free transformations are desired.1 Within this
field, the conjugate Michael addition of carbon nucleophiles to
the electron deficient nitroalkenes is particularly interesting and
challenging as it involves the generation of two chiral centres in
a single step.2 Furthermore, these nitro compounds can be con-
verted into a wide range of synthetically useful compounds such
as amines, ketones, carboxylic acids and nitrile oxides, which are
valuable building blocks for the preparation of several agricultural
and pharmaceutical compounds.3
from commercially available L-proline and D-glucosamine as effi-
cient organocatalysts for asymmetric aldol reactions (Fig. 1). With
the delighting results for aldol reaction, we extended our investiga-
tions on the catalytic activity of these prolinamides for asymmetric
Michael reaction between cyclohexanones and various nitroole-
fins. Model experiments were conducted with trans-b-nitrostyrene
and cyclohexanone. Initially, conjugate addition was examined by
using 20 mol % of prolinamide 1a as an organocatalyst in various
polar and nonpolar solvents (Table 1, entries 1–4). The reactions
those performed in dichloromethane, methanol and water were
completed in 79–96 h at room temperature with high chemical
yield (Table 1, entries 1, 2 and 4). However, the syn and anti selec-
tivity of the Michael product in these cases was very low. The reac-
tion carried out in DMSO afforded poor results. However, when the
reaction was performed with 15 equiv of cyclohexanone in neat
condition, it reached completion in 6 h with 94% isolated chemical
yield (Table 1, entry 5). To our delight, the diastereoselectivity of
this reaction also improved drastically to 95:5 for syn and anti
products, respectively. For the further improvement, organocata-
lysts 1b and 1c were also screened and the effect of various sol-
vents on the reaction was studied. It has been observed that in
each nonpolar and polar solvent the reaction proceeded for com-
pletion albeit at different rates. With catalyst 1c in dichlorometh-
ane, the reaction reached completion in 48 h; however, the
reaction proceeded slowly in methanol and acetonitrile (Table 1,
entries 7–9). In most of the solvents, the reaction afforded the
product in high to excellent chemical induction despite very low
enantioselectivity. When we performed the reaction in neat
The first organocatalytic asymmetric reaction of ketones to
trans-b-nitrostyrene using L-proline as a catalyst was reported by
Barbas4, List5 and Enders6 independently resulting in the formation
of the corresponding Michael adducts in good to high yield with
low enantioselectivity. Since then, extraordinary progress has been
made with respect to both stereoselectivity and substrate scope
using various primary and secondary amine organocatalysts. In
this context, many pyrrolidine-based catalysts7 as well as chiral
acyclic primary amines such as alanine,8 thiourea–amine bifunc-
tional catalysts9 and small dipeptides10 have been employed suc-
cessfully to achieve high chemical as well as optical yields in
asymmetric Michael addition of ketones to the nitroalkenes. How-
ever, only sporadic reports are available that produce (1R,2S)-syn
products as the major enantiomers.8b,11 Herein we report sugar-
based prolinamide organocatalyst mediated Michael addition of
cyclohexanones to the nitroalkenes leading to (1R,2S)-syn adducts
as major antipodes.
In continuation of our work on asymmetric organocatalysis,12
recently, we reported sugar-based prolinamides 1a–c13 derived
OR2
R1
R2
O
R2O
R2O
1a
1b
1c
Me
Me
Bn
Bn
⇑
Corresponding author. Tel.: +91 13 3228 5438; fax: +91 13 3227 3560.
E-mail addresses: rkpedfcy@iitr.ernet.in, ramakpeddinti@rediffmail.com (R.K.
HN
OR1
O
4-tert-butylbenzyl
Bn
N
H
Peddinti).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.10.148
Figure 1. Structures of sugar-based organocatalysts 1a–c.

118
J. Agarwal, R. K. Peddinti / Tetrahedron Letters 52 (2011) 117–121
Table 1
Screening of solvents and organocatalysts
O
NO2
O
solvent
NO2
+
20 mol% catalyst
3a
2a
Entry
Catalyst
Solvent
Temp
Time
Yielda (%)
drb (syn/anti)
ee (syn)c (%)
1
2
3
4
5
6
7
8
9
1a
1a
1a
1a
1a
1b
1c
1c
1c
1c
1c
1c
CH2Cl2
MeOH
DMSO
H2O
—
—
CH2Cl2
MeOH
CH3CN
—
MeOH
—
rt
rt
rt
rt
rt
rt
rt
rt
79 h
80 h
96 h
96 h
6 h
97
96
58
90
94
91
97
90
86
94
90
96
83:17
37:63
60:30
67:33
95:5
95:5
95:5
95:5
98:2
4
8
4
9
8
9 h
9
48 h
72 h
75 h
12 h
7 days
24 h
12
14
À10
15
19
33
rt
rt
10
11
12
90:10
98:2
96:4
À20 °C
À20 °C
a
b
c
Of pure and isolated product.
Determined by 1H NMR (500 MHz) analysis of the crude sample.
Determined by HPLC analysis using Chiralpak AD-H column.
Table 2
Screening of additives
O
O
20 mol% catalyst 1c
NO2
+
NO2
20 mol% additive
3a
2a
Entry
Additive
Temp
Time
Yielda (%)
drb (syn/anti)
eec (syn)
1
2
3
4
5
6
7
8
9
10
11
12
13
(S)-CSA
(R)-CSA
Acetic acid
2,4-Dinitrobenzoic acid
3-Trifluoromethylbenzoic acid
4-Nitrobenzoic acid
Benzoic acid
3-Trifluoromethylbenzoic acid
4-Nitrobenzoic acid
Benzoic acid
3-Trifluoromethylbenzoic acid
4-Nitrobenzoic acid
Benzoic acid
rt
rt
rt
rt
rt
rt
rt
144 h
144 h
144 h
144 h
10 h
12 h
12 h
24 h
24 h
24 h
30 h
30 h
24 h
—
—
—
—
—
—
—
—
—
—
—
—
98
93
94
96
94
92
92
92
98
91:9
90:10
91:9
96:4
91:9
96:4
92:8
94:6
95:5
15
16
16
17
23
23
28
39
41
0 °C
0 °C
0 °C
À20 °C
À20 °C
À20 °C
a
Of pure and isolated product.
b
c
Determined by 1H NMR (500 MHz) analysis of the crude sample.
Determined by HPLC analysis using Chiralpak AD-H column.
condition with 15 equiv of cyclohexanone without any solvent in
the presence of 20 mol % organocatalyst 1c, the reaction was com-
pleted within 12 h with 94% chemical yield and high diastereose-
lectivity (90:10). Again, the ee of reaction was only 15% at room
temperature (Table 1, entry 10). The Michael reaction at À20 °C
in methanol was very slow; however, the diastereoselectivity of
the reaction slightly improved (Table 1, entry 11). On the contrary,
the reaction under neat conditions at low temperature was com-
pleted in one day and the product was obtained in moderate
enantioselectivity (Table 1, entry 12). When the temperature of
the reaction was further reduced to À40 °C, formation of the
product was not observed even after 7 days presumably due to
the insolubility of the reaction contents at that temperature.
At this juncture, we used various organic acids as additives to
study the stereochemical outcome of the reaction. These acids
are believed to accelerate the rate of reaction and improve the ste-
reochemical outcome of the reaction by increasing the polarization
of carbonyl group of cyclohexanone during the formation of enam-
ine, as well as by activating the Michael acceptors through hydro-
gen bonding. It has been observed that the presence of additive has
a significant influence on the reaction in terms of stereochemical
induction.14 Initially, when we studied camphor-10-sulfonic acids
and acetic acid as additives, no reaction was observed. This may
be due to the poisoning of catalyst through salt formation. Then
we utilized mild and bulky aromatic carboxylic acids such as ben-
zoic acid, 4-nitro-, 3,5-dinitro- and 2,4-dinitro-benzoic acids to

J. Agarwal, R. K. Peddinti / Tetrahedron Letters 52 (2011) 117–121
119
Table 3
Michael reaction of ketones with substituted b-nitrostyrenes in the presence of 1c
R1
O
O
20 mol% 1c
20 mol% benzoic acid
NO2
NO2
S
R
+
-20oC
R1
R2
R2
3-5
2a-k
R2 = H, Me, Et
Entry
1
Product
Time (h)
Yielda (%)
drb (syn/anti)
erc (syn)
O
3a
3b
36
24
96
94
95:5
71:29
76:24
NO2
O
NO2
NO2
2
3
4
90:10
93:7
NO2
NO2
O
O
3c
24
37
96
98
84:16
77:23
Br
3d
86:14
NO2
Br
5
6
7
3e
3f
36
48
36
92
94
91
98:2
89:11
95:5
78:22
76:24
70:30
O
O
NO2
Cl
NO2
Cl
3g
O
NO2
Me
8
9
3h
3i
48
25
88
94
97:3
76:24
O
O
NO2
NO2
>99:1
79:21
(continued on next page)

120
J. Agarwal, R. K. Peddinti / Tetrahedron Letters 52 (2011) 117–121
Table 3 (continued)
Entry
Product
Time (h)
30
Yielda (%)
drb (syn/anti)
erc (syn)
O
O
10d
3j
95
95:5
32:68
NO2
O
O
O
e
11
4a
34
34
89
94
—
76:24
80:20
NO2
NO2
NO2
e
12
4b
5a
—
e
NO2
13
33
91
—
78:22
a
Of pure and isolated product.
b
c
Determined by 1H NMR (500 MHz) analysis of the crude sample.
Determined by HPLC analysis on chiral stationary phase.
The structure of minor enantiomer is shown.
d
e
85–95% of major diastereomer was found for entries 11–13 from 1H NMR and/or HPLC analyses.
promote the reaction. Among the employed acids, benzoic acid
afforded the best results.
methyl and 4-ethyl-cyclohexanones were also examined (Table 3,
entries 11–13). The Michael adducts 4a,b and 5a were obtained
in excellent chemical yield with high diastereomeric excesses
and moderate enantioselectivities. The absolute configuration of
Michael adducts 3a–j, 4a,b and 5a were determined by comparing
the retention times on HPLC of the products with the literature
data.8b,9d,11,16
In conclusion, we have employed the sugar-based prolinamide
1c as organocatalyst to the asymmetric Michael reaction in neat
condition. Though all adducts were furnished in high to excellent
chemical yield with very high diastereomeric ratio, moderate to
good asymmetric induction was observed. The present catalytic
system provided (1R,2S)-syn adducts as major antipodes in the Mi-
chael addition of cyclohexanones to the nitroalkenes.
Furthermore, the influence of the temperature on the reaction
was also investigated and the results are summarized in Table 2.
It has been observed that as the temperature of the reaction was
decreased, the rate of the reaction was decreased; however, the
stereochemical outcome of the reaction was improved. For exam-
ple, when the reaction was performed by using 20 mol % organo-
catalyst 1c in the presence of benzoic acid as additive at room
temperature, the reaction was completed in 12 h with 16% ee (Ta-
ble 2, entry 7). However, the benzoic acid promoted reactions at
0 °C and À20 °C provided the adduct 3a in excellent chemical yield
and diastereoselectivity with moderate asymmetric induction of
23% ee and 41% ee, respectively (Table 2, entries 10 and 13).
Thus, the screening of the catalysts in various solvents and neat
condition and the screening of various additives at different tem-
peratures identified the optimal catalyst as well as optimal condi-
tions to carry out further asymmetric Michael reactions.15 We then
turned our attention to broadening the substrate scope for the su-
gar-based prolinamide catalyst 1c. The results are summarized in
Table 3. As shown in Table 3, regardless of the electronic nature
of the aromatic substitution, high to excellent isolated yields as
well as diastereoselectivities were realized in the reactions of each
nitroolefin. The enantioselectivity from the reaction of cyclohexa-
none with m-nitro derivative 2c is better than that of o-nitro deriv-
ative 2b (Table 3, entries 2 and 3). The bromo-styrenes 2d and 2e
provided comparable optical yields for the corresponding syn
adducts (Table 3, entries 4 and 5). Among the reactions of o- and
p-chloro derivatives 2f and 2g with cyclohexanone, the former
furnished better asymmetric induction (Table 3, entries 6 and 7).
The Michael adducts 3h and 3i were obtained in very high yields
with excellent preference to syn diastereomer and with good enan-
tiocontrol (Table 3, entries 8 and 9). Other cyclic ketones such as 4-
Acknowledgements
We are grateful to DST, New Delhi, for the financial support (re-
search Grant No. SR/S1/OC-15/2005). J.A. thanks UGC for the award
of research fellowship.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2010.10.148.
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