Enantioselective Michael addition of aldehydes to nitroolefins catalyzed by pyrrolidine-HOBt

Article abstract of DOI:10.1016/j.tetasy.2017.02.005

The oxytriazole catalyst “pyrrolidine-HOBt” developed for asymmetric Michael addition of cyclohexanone to nitroolefins is now evaluated for the asymmetric Michael addition of aldehydes to nitroolefins under similar reaction conditions. The results of this

Full text of DOI:10.1016/j.tetasy.2017.02.005

Tetrahedron: Asymmetry xxx (2017) xxx–xxx
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Enantioselective Michael addition of aldehydes to nitroolefins
catalyzed by pyrrolidine-HOBt
a
Togapur Pavan Kumar a,b, , Mohammad Abdul Sattar , Sthanikam Siva Prasad a,c, Kothapalli Haribabu a,
⇑
Cirandur Suresh Reddy c
a Division of Natural Products Chemistry, CSIR-Indian Institute of Chemical Technology, Hyderabad 500007, India
b Academy of Scientific and Innovative Research (AcSIR), CSIR-Indian Institute of Chemical Technology, Hyderabad 500007, India
c Department of Chemistry, Sri Venkataswara University, Tirupati 517502, India
a r t i c l e i n f o
a b s t r a c t
Article history:
The oxytriazole catalyst ‘‘pyrrolidine-HOBt” developed for asymmetric Michael addition of cyclohex-
anone to nitroolefins is now evaluated for the asymmetric Michael addition of aldehydes to nitroolefins
under similar reaction conditions. The results of this study indicate that, the oxytriazole catalyst ‘‘pyrro-
lidine-HOBt” is equally effective in promoting the Michael addition of aldehydes to nitroolefins on
Received 22 October 2016
Revised 30 January 2017
Accepted 7 February 2017
Available online xxxx
employing benzoic acid as an additive. The desired products,
in good yields and high enantioselectivities.
c
-nitrocarbonyl compounds were obtained
Ó 2017 Published by Elsevier Ltd.
1. Introduction
all-carbon quaternary stereogenic centers is considered to be a
challenging task in asymmetric synthesis.7 Although, a large num-
ber of organocatalysts were known to be highly efficient for
Michael addition of unmodified carbonyls to nitroolefins, only a
few of them were found to be effective for the Michael reaction
aldehydes and nitroolefins.8 Therefore, an investigation into new
catalytic methods for this transformation is desirable.
Organocatalytic asymmetric synthesis is regarded as a standard
for effective organic synthesis these days. Over the past few years,
remarkable efforts and impartial advancements have been wit-
nessed in the development of catalytic asymmetric synthesis. As
a result, asymmetric organocatalysis1 has gained significant atten-
tion from the scientific community and has become a powerful
alternate and/or complementary protocol to enzymatic and
organometallic catalysis. In particular, asymmetric aminocatalysis
has emerged as a handy tool for the construction of chiral building
blocks by means of enamine or iminium mechanisms.2 Undoubt-
edly, the Michael addition reaction is one of the favorite choices
to explore effectiveness of new catalyst designs. As the Michael
addition reaction results in the formation of functionalized prod-
ucts with multiple stereogenic centers in a single step, it has been
the focus of many research groups. In this endeavour, a large num-
ber of designed organocatalysts bearing pyrrolidine moiety were
developed and investigated on a wide variety of donor and accep-
tor substrates and found to be efficient with varied levels of suc-
In continuation of our research on organocatalysis,9 we recently
developed a proline-oxytriazole compound, ‘‘pyrrolidine-HOBt” 1
(Fig. 1) as an efficient catalyst for the asymmetric Michael addition
reaction of ketones to nitroolefins in water under additive-free
conditions. Having been encouraged by this study and considering
the consistency of the catalytic mechanism via an enamine path-
way,10 we therefore started our investigations to evaluate catalyst
1 for the asymmetric Michael reaction of aldehydes to nitroolefins.
Herein we report on the use of pyrrolidine-HOBt 1 as an effective
organocatalyst for the asymmetric Michael reaction of aldehydes
to nitroolefins providing Michael adducts with high yields and
selectivities.
cess.3–5 Among the Michael products,
c-nitrocarbonyls were
more prominent as they serve as versatile templates for the con-
struction of various bioactive compounds.5,6 The generation of
O
N
⇑
Corresponding author at present address: Division of Natural Products Chem-
istry, CSIR-Indian Institute of Chemical Technology, Hyderabad 500007, India. Tel.:
+91 40 27191727; fax: +91 40 27160512.
N
N
N
H
E-mail address: pavantogapur@gmail.com (T.P. Kumar).
Figure 1. Pyrrolidine-HOBt.
http://dx.doi.org/10.1016/j.tetasy.2017.02.005
0957-4166/Ó 2017 Published by Elsevier Ltd.
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T. P. Kumar et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
combination with catalyst 1 (Table 2, entries 7–10) and the subse-
2. Results and discussion
quent experiments were carried out with 20:10 mol% catalyst-
additive combination (Table 2, entry 8).
Herein we have studied two types of aldehydes (a,a-disubsti-
tuted and
a-substituted) to establish the scope of this catalyst
for this transformation. In this effort, we started our investigations
using two different model reactions and then extended our studies
with screening experiments. The two sets of experimental results
are presented. The first set was conducted on a model reaction
using isobutyraldehyde 2a as the donor and nitrostyrene 3a as
the acceptor (Scheme 1) to evaluate the efficacy of ‘‘pyrrolidine-
Table 2
Screening of additivesa
Entry
additive
Time (h)
36
Yieldb (%)
61
eec(%)
64
(mol%)
5
1
TFA
2
3
4
5
TFA
10
5
10
5
36
48
48
36
70
63
65
62
66
61
69
73
PhOH
PhOH
HCOOH
HOBt” catalyst 1 for asymmetric Michael additions of a,a-disubsti-
tuted aldehydes to nitroolefins. The reaction optimization involved
experimental screening involving variation of solvent, additive,
temperature and substrates. Initially, the reactions were simulta-
neously carried out in various solvents using 10–20 mol% of the
catalyst at room temperature and the results are summarized in
Table 1. As evident from the survey, the Michael reaction worked
well in all solvents irrespective of the polar/non-polar nature to
HCOOH
PhCOOH
PhCOOH
6
7
8
10
5
36
36
36
76
73
81
74
71
76
10
a Reaction conditions: isobutyraldehyde (4 mmol), nitrostyrene (1 mmol)
catalyst 1 (20 mol%), water, rt.
b Isolated yields.
c Determined by chiral stationary phase HPLC.
afford the product
c-nitrocarbonyl compound 4a in good yield
and enantioselectivity (Table 1, entries 1–20). However, the reac-
tion performed in water was found to be more effective in terms
of yield (64–78%) and enantioselectivity (67–76% ee) among the
conditions tested and formed a basis for further screening (Table 1,
entries 7–9).
After establishing the optimal solvent and additive factors, we
then conducted temperature screening experiments to find out
the optimal temperature conditions required to catalyze maximum
output for the reaction. As shown in Table 3, the highest catalytic
performance was observed at 0 °C (Table 3, entry 2), while the
reactions conducted at other temperatures suffered either from
long reaction times or loss of yield with no substantial improve-
ment in enantioselectivities (Table 3, entries 1, 3 and 4).
O
O
NO2
catalyst 1
NO2
H
H
solvent (0.5 mL)
rt
3a
2a
4a
Table 3
Effect of temperaturea
Scheme 1. Michael addition of isobutyraldehyde to nitrostyrene.
Entry
Temp.(oC)
25
Time (h)
Yieldb (%)
eec(%)
1
2
3
4
36
36
60
72
83
87
75
68
84
89
87
89
Table 1
Screening of solvents and catalyst loadinga
0
-10
-20
Entry
1
Solvent
Neat
Time (d) Yieldb (%)
eec(%)
1 (mol%)
10
3
51
46
53
a Reaction conditions: isobutyraldehyde (4 mmol), nitrostyrene (1 mmol)
catalyst 1 (20 mol%), PhCOOH (10 mol%), water, rt.
b Isolated yields.
2
3
4
5
Neat
20
10
20
10
2
3
2
3
56
62
64
55
THF
5
5
c Determined by chiral stationary phase HPLC.
THF
63
49
Toluene
Toluene
CHCl3
CHCl3
MeOH
MeOH
6
7
8
9
20
10
20
10
20
10
20
10
20
10
20
10
20
2
3
2
3
2
3
2
3
2
2
2
2
2
59
61
65
57
60
65
71
58
63
65
69
67
73
51
54
62
52
61
65
69
61
64
43
52
51
58
Having set the optimal reaction conditions for the Michael addi-
tion of isobutyraldehyde 2a to nitrostyrene 3a, we then conducted
substrate screening experiments to determine the generality of the
catalyst for this transformation. As shown in Tables 4 and 5, all
substrate combinations involving variations in nitroolefins 3b–k
reacted smoothly with isobutyraldehyde 2a (Table 4, entries 1–9)
and cyclopentanecarboxaldehyde 2b (Table 5, entries 1–8) under
the optimized reaction conditions and the corresponding Michael
products 4b–j and 5a–h were obtained in good yields with high
levels of enantioselectivities regardless of the nature of substitu-
tion pattern on the nitroolefins. However, reactions of nitroolefins
with electron donating substitutions were found to be slightly infe-
rior in overall productivity over that of electron withdrawing sub-
stituents (Tables 4 and 5, entries 4 and 5, respectively). However,
this complete study indicates a good scope for ‘‘pyrrolidine-HOBt”
10
11
H2O
12
13
14
15
16
17
18
H2O
Dioxane
Dioxane
DMSO
DMSO
DMF
DMF
a Reaction conditions: isobutyraldehyde (4 mmol), nitrostyrene (1 mmol).
b Isolated yields.
c Determined by chiral stationary phase HPLC.
Encouraged by these results, we then tested the effect of acid
additives in the above transformation. The role of an acid additive
in promoting the proline organocatalysis is well studied and
widely accepted. In anticipation, we examined the effect of various
acid additives using 20 mol% of catalyst at room temperature and
benzoic acid played effective role in promoting the reaction in
in promoting the conjugate addition of
des to nitroolefins using and providing access to a variety of
nitrocarbonyl compounds with an all-carbon quaternary center
in high enantioselectivities.
The second set of experimental studies were conducted on a
model reaction designed with propaldehyde 6a as the donor sub-
a,a-disubstituted aldehy-
c-
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T. P. Kumar et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
3
Table 4
In order to improve the reaction outcome, we then conducted
additive screening experiments to ascertain the effect of acid addi-
tives on the catalytic performance of 1. It has been well docu-
mented that the presence of an acid additive accelerates enamine
formation and thereby enhances the catalytic efficiency as the
reaction progress. As shown in Table 5, screening experiments
were conducted using 5 mol% or 10 mol% of various acid additives
and 20 mol% of catalyst 1 in water at room temperature. Again the
use of 10 mol% of benzoic acid turned out to be the most efficient
additive in combination with catalyst 1 (Table 5, entry 8).
Having improved the reaction outcome with additive screening,
we then turned our attention to evaluate the effect of catalyst load-
ing and temperature on the overall reaction performance. As
shown in Table 6, screening experiments were designed in a man-
ner to define both the parameters at each attempt. The results indi-
cate the supremacy of the pre-established conditions (Table 5,
entry 8), over these modifications (Table 6, entries 1–5). In compar-
ison, this study suffered either with long reaction times or loss of
yield with no considerable improvement in stereoselectivities
(Table 6 Vs Table 5, entry 8).
Screening of solvents using 1a
c
Entry
1
Solvent
Neat
Time (h)
36
(syn/anti)
eed(%)
63
Yieldb (%)
55
7:3
DMF
THF
24
24
79
64
8:2
9:1
53
71
2
3
4
5
CH3CN
CH2Cl2
24
36
24
61
59
85:15
6:4
58
66
70
6
68
7:3
CHCl3
Dioxane
Toluene
24
24
65
69
85:15
8:2
59
69
7
8
9
Hexane
MeOH
63
66
36
24
7:3
8:2
62
71
10
DMSO
H2O
24
24
81
73
85:15
9:1
55
77
11
12
a Reaction conditions: propaldehyde (4 mmol), nitrostyrene (1 mmol), solvent
(0.5 mL), catalyst (20 mol%); b Isolated yields of syn-product; c Determined by
1H NMR of crude produt; d Ee of syn-product determined by chiral stationary
phase HPLC.
Table 6
Effect of temperature and catalyst loadinga
Table 5
eed
(%)
c
Catalyst
(mol%)
Time
(h)
Yieldb
(%)
(syn/anti)
Screening of additivesa
Temp.
Entry
1
(oC)
(syn/anti)c
Entry additive
Time (h) Yieldb(%)
eed(%)
65
(mol%)
5
84
96:6
20
0
48
88
1
TFA
24
73
9:1
81
72
75
65
94:6
92:8
92:8
92:8
RT
15
15
10
5
36
48
36
60
83
86
81
63
2
3
4
5
2
3
4
5
TFA
10
5
10
5
24
36
24
24
78
65
69
71
93:7
8:2
8:2
73
57
59
67
0
pTSA
pTSA
HCOOH
RT
RT
91:9
HCOOH
PhCOOH
PhCOOH
CSA
6
10
5
24
24
24
36
24
36
36
79
81
93
68
74
63
77
94:6
93:7
95:5
8:2
75
74
87
60
69
61
75
a Reaction conditions: propaldehyde (4 mmol), nitrostyrene (1 mmol),
7
PhCOOH (10 mol%), neat; b Isolated yields of syn-product; c Determined by
1H NMR of crude produt; d Ee of syn-product determined by chiral stationary
phase HPLC.
8
10
5
9
CSA
10
11
12
10
5
8:2
PhOH
9:1
PhOH
10
9:1
a Reaction conditions: propaldehyde (4 mmol), nitrostyrene (1 mmol)
With the optimal assessment on model substrate, we then
extended the study to evaluate the substrate generality of this
transformation. In order to achieve this, experiments are designed
using a series of aldehydes and nitroolefins in different combina-
tions as shown in Tables 9 and 10. All substrate designs involving
variations in nitroolefins 7b–j reacted smoothly with propionalde-
hyde 6a (Table 9, entries 1–9) and other aldehydes 6b–f (Table 10,
entries 1–9) under the optimized reaction conditions and the cor-
responding Michael products 8b–j and 8k–s were obtained in good
yields and high stereoselectivities irrespective of the nature of sub-
stitution pattern in nitroolefins. However, reactions involving
branched aldehydes (Table 10, entries 5 and 9) were found to be
slightly inferior in overall productivity over that of others. Signifi-
cantly, the catalytic effect of ‘‘pyrrolidine-HOBt” could be extended
to Michael reaction of aldehydes and nitroolefins meeting to the
objectives and in good agreement to those reported in the
literature.3
The absolute stereochemical outcome of the above two set of
experimental results for asymmetric Michael reaction of aldehydes
and nitroolefins could be rationized by considering the possible
transition state10,11 model as shown in Figure 2. The pyrrolidine
ring of the catalyst activates aldehyde towards enamine formation
and the bulky oxytriazole template serves as an efficient stereo-
control element, providing effective steric coverage and also par-
ticipates in H-bonding interactions in the pool of nitroolefin,
benzoic acid with the aid of water molecule as depicted in Figure 2.
The complete arrangement results in a compact transition state,
wherein the nucleophilic enamine attacks the nitroolefin from Si
catalyst 1 (20 mol%), water, rt; b Isolated yields of syn-product; c Determined by
1HNMR of crude product; d Ee of syn-product determined by chiral stationary
phase HPLC.
strate and nitrostyrene 7a as the acceptor (Scheme 2) and then
extended to other substrates. This study includes screening of sol-
vents, additives, concentrations and temperature to establish opti-
mal parameters required for the productive outcome of the
catalytic cycle. To start with, solvent screening experiments were
conducted using 20 mol% of the catalyst 1 at room temperature
and the results are summarized in Table 4. The Michael reaction
progressed well in all solvents irrespective of the polar/non-polar
nature to afford the product
c-nitroaldehyde 8a with moderate
to good yields and stereoselectivities (Table 4, entries 1–12). How-
ever, water mediated reaction was found to be more effective
(Table 4, entry 12) among the conditions screened and was
adopted for further screening studies.
O
O
NO2
catalyst 1
NO2
H
H
solvent (0.5 mL)
rt
7a
6a
8a
Scheme 2. Michael addition of propaldehyde to nitrostyrene.
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T. P. Kumar et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
Table 7
Enantioselective Michael addition of isobutyraldehyde to nitroolefinsa
O
O
Ar
1 (20 mol%)
PhCOOH (10 mol%)
NO2
NO2
H
H
Ar
water, 0 oC
3b-j
2a
4b-j
Time (h)
36
eec (%)
93
Yieldb (%)
Entry
1
Product
NO2
4b
91
O
O
O
O
NO2
NO2
NO2
NO2
H
H
H
H
Br
2
4c
36
89
91
Cl
3
4
4d
4e
36
48
86
78
88
84
OMe
Me
5
48
73
81
4f
O
O
NO2
H
H
NO2
NO2
6
7
4g
4h
36
48
85
82
84
77
OMe
NO2
O
O
O
H
H
H
S
8
9
48
48
81
84
83
79
4i
4j
NO2
NO2
O
a Reaction conditions: isobutyraldehyde (4 mmol), nitroolefin (1 mmol).
b Isolated yields.
c Determined by chiral stationary phase HPLC.
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T. P. Kumar et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
5
Table 8
Enantioselective Michael addition of cyclopentanecarboxyaldehyde to nitroolefinsa
O
O
Ar
1 (20 mol%)
PhCOOH (10 mol%)
NO2
NO2
H
H
Ar
water, 0 oC
2b
3a,b,d,e,f,i,j,k
5a-h
Time (h)
36
eec (%)
Yieldb (%)
85
Entry
1
Product
O
O
O
O
5a
79
NO2
NO2
NO2
NO2
H
H
H
H
NO2
2
5b
36
91
92
Br
3
4
5c
36
48
89
69
90
74
OMe
5d
Me
5
48
71
76
5e
O
O
O
O
NO2
H
H
H
H
Br
NO2
6
7
5f
36
48
87
82
83
81
S
5g
NO2
NO2
O
8
5h
48
84
80
a Reaction conditions: cyclopentanecarboxaldehyde (4 mmol), nitroolefin (1 mmol).
b Isolated yields.
c Determined by chiral stationary phase HPLC.
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T. P. Kumar et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
Table 9
Enantioselective Michael addition of propaldehyde to nitroolefinsa
O
O
Ar
1 (20 mol%)
PhCOOH (10 mol%)
NO2
NO2
H
H
Ar
water, rt
7b-j
6a
8b-j
(syn/anti)c
Time (h)
24
eed(%)
89
Yieldb (%)
Entry
1
Product
Cl
8b
91
92:8
O
NO2
H
H
Br
2
3
8c
24
24
93
91
91
87
95:5
93:7
O
O
NO2
F
8d
NO2
H
OMe
4
5
8e
8f
36
36
79
82
82
85
91:9
O
O
O
NO2
H
H
OMe
90:10
NO2
6
7
8g
8h
36
36
89
85
84
79
91:9
92:8
NO2
H
H
H
H
N
O
O
O
NO2
NO2
NO2
S
8
9
8i
8j
36
36
84
86
86
83
92:8
93:7
O
a Reaction conditions: propaldehyde (4 mmol), nitroolefin (1 mmol); b Isolated yields.
c Determined by 1H NMR of crude product; d Ee of syn-product determined by chiral stationary phase HPLC.
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T. P. Kumar et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
7
Table 10
Enantioselective Michael addition of different aldehyde to nitroolefinsa
O
O
Ar
1 (20 mol%)
PhCOOH (10 mol%)
NO2
NO2
H
H
Ar
water, rt
R
R
6b-f
7a,d,e,j
8k-s
(syn/anti)c
Time (h)
eed(%)
Yieldb (%)
91
Entry
1
Product
8k
24
94:6
86
O
O
NO2
NO2
H
H
Et
2
8l
24
95
91
96:4
n-Pr
3
4
8m
8n
24
24
92
91
88
85
92:8
93:7
O
O
O
NO2
NO2
NO2
H
H
H
n-Bu
n-Pent
5
36
77
73
8o
85:15
i-Pr
Br
O
6
7
8p
8q
24
24
95
86
92
78
95:5
NO2
H
n-Pr
OMe
O
O
90:10
NO2
NO2
H
H
n-Pr
S
8
9
24
36
89
79
83
71
8r
8s
92:8
n-Pr
S
80:20
O
NO2
H
i-Pr
a Reaction conditions: aldehyde (4 mmol), nitroolefin (1 mmol); b Isolated yields.
c Determined by 1HNMR of crude product; d Determined by chiral stationary phase HPLC.
Please cite this article in press as: Kumar, T. P.; et al. Tetrahedron: Asymmetry (2017), http://dx.doi.org/10.1016/j.tetasy.2017.02.005

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T. P. Kumar et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
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N
O
N
N
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H
O
O
O
H
N
O
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Ar
Figure 2. Proposed transition state.
face and leads to the formation of desired products with high
stereooselectivities.
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In conclusion, we have demonstrated the application of ‘‘pyrro-
lidine-HOBt” 1 as an effective organocatalyst for the enantioselec-
tive Michael addition of aldehydes to nitroolefins. This catalytic
method was found to be effective in terms of yield and enantioselec-
tivities, when performed in water using 20 mol% of catalyst and
10 mol% of benzoic acid as an additive at 0 °C/rt for 24–48 h. Further
investigations to extend the scope of this catalyst for other transfor-
mations are underway in our laboratory.
4. Experimental
4.1. General
All solvents and reagents were purified by standard techniques.
Crude products were purified by column chromatography on silica
gel of 100–200 mesh. IR spectra were recorded on Perkin–Elmer
683 spectrometer. Optical rotations were obtained on Jasco Dip
360 digital polarimeter. 1H and 13C NMR spectra were recorded
in CDCl3 solution on Brucker Avance 300. Chemical shifts were
reported in parts per million with respect to internal TMS. Cou-
pling constants (J) are quoted in Hz. Mass spectra were obtained
on an Agilent Technologies LC/MSD Trap SL. Chiral HPLC analysis
was carried out on chiral pak OD-H, IA or columns using a mixture
of isopropanol and hexanes as the eluent.
4.1.1. General procedure for the Michael addition of
disubstituted aldehydes to nitroolefins
a,a-
To a mixture of catalyst 1 (20 mol%), and aldehyde (4 mmol) in
water (0.5 mL)was added PhCOOH (10 mol%) and stirred for
20 min. at 0 °C or at rt. Then, nitroolefin (1 mmol) was added to the
resulting mixture and stirred for appropriate time (Tables 7–10) at
0 °C or at rt. After completion of the reaction (monitored by TLC),
the mixture was purified by silica-gel column chromatography to
afford the desired product. Relative and absolute configurations of
the products were determined by comparison of 1H NMR, 13C NMR
and specific rotation values with those reported in the literature.8
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Acknowledgements
T.P.K thank DST New Delhi for INSPIRE Faculty Award (IFA12-
CH-30). Authors thank Director, CSIR-IICT for valuable support.
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