Functionalized proline with double hydrogen bonding potential: Highly enantioselective Michael addition of carbonyl compounds to β-nitrostyrenes in brine

Article abstract of DOI:10.1016/j.tetlet.2010.07.164

Simple synthetic manipulation of S-proline allows access to prolinamides 5-7 as organocatalysts capable of double hydrogen bonding for enantioselective Michael addition reactions of carbonyl compounds to β-nitrostyrenes. It is shown that prolinamide catalyst 7 leads to addition products with a high diastereo- as well as enantioselectivity. The transition state structure involving the binding of electrophilic nitrostyrene via two H-bonds is believed to be further stabilized by π,π stacking interactions mediated by the tosyl ring.

Full text of DOI:10.1016/j.tetlet.2010.07.164

Tetrahedron Letters 51 (2010) 5281–5286
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Functionalized proline with double hydrogen bonding potential: highly
enantioselective Michael addition of carbonyl compounds to b-nitrostyrenes
in brine
*
Satyajit Saha, Saona Seth, Jarugu Narasimha Moorthy
Department of Chemistry, Indian Institute of Technology, Kanpur 208 016, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Simple synthetic manipulation of S-proline allows access to prolinamides 5–7 as organocatalysts capable
of double hydrogen bonding for enantioselective Michael addition reactions of carbonyl compounds to b-
nitrostyrenes. It is shown that prolinamide catalyst 7 leads to addition products with a high diastereo- as
well as enantioselectivity. The transition state structure involving the binding of electrophilic nitrosty-
Received 29 April 2010
Revised 27 July 2010
Accepted 29 July 2010
Available online 4 August 2010
rene via two H-bonds is believed to be further stabilized by
tosyl ring.
p
,
p
stacking interactions mediated by the
Ó 2010 Elsevier Ltd. All rights reserved.
The growing interest in environmental-friendly and metal-free
reactions has led to great progress in organocatalysis.1 In particu-
lar, Michael reaction represents one of the most important reac-
tions for C–C bond formation in organic synthesis, and offers
atom-efficient access to 1,4-bifunctional products.2 Since the pio-
neering work by Barbas and List, independently on the asymmetric
Michael reaction,3 significant strides have been made in the design
and development of organocatalysts that lead to high catalytic effi-
ciency.4,5 Some of the organocatalysts that promote Michael reac-
tions with a high enantioselectivity are shown in Figure 1.6 Despite
a wide variety of catalysts, the quest for new and simpler catalytic
systems that surpass the existing ones in terms of catalytic behav-
ior continues unabated.
We have recently shown that the organocatalysts 1–4 (Fig. 2)
with enhanced acidity and double hydrogen bonding potential effi-
ciently catalyze direct Aldol reaction with excellent enantio- and
diastereoselectivity.7a As a logical extension of our studies on
organocatalysts with enhanced acidity and hydrogen bonding,7
the catalyst 4 was particularly screened for catalyzing the Michael
addition reaction of cyclohexanone to b-nitrostyrenes. The frus-
tratingly poor enantioselectivities observed with 4 led us to mod-
ified catalysts 5–7 (Fig. 2), which were designed based on the
following rationale: first, a quick perusal of the reported organo-
catalysts for Michael reaction in Figure 1 reveals that the catalysts
ought to enjoy conformational flexibility, which is introduced in
5–7 via reduction of the carbonyl group; second, the bis-amide
functionality created from o-aminobenzoic acid permits enhanced
acidity and double hydrogen bonding for binding the electrophilic
nitrostyrene reactant. Herein, we report that the readily accessible
catalyst 7, which is devoid of additional chiral center other than
that of proline, catalyzes the Michael reactions of diverse carbonyl
compounds with nitrolefins in high enantioselectivity; the reac-
tions are found to occur in brine at rt in the presence of benzoic
acid as an additive.
The synthetic routes for the preparation of catalysts 5–7 are
shown in Scheme 1. The catalysts were readily prepared by cou-
pling o-nitrobenzoic acid with Boc-protected prolinamine followed
by the reduction of the nitro functionality to amine; the latter was
subsequently derivatized with tosyl, mesyl, and pentafluorosul-
phonyl groups. The Boc group was deprotected at the end to get
hold of catalysts 5–7.
In our initial experiments, the catalyst 7 containing tosyl group
was employed to establish experimental conditions at which the
Michael addition between b-nitrostyrene and cyclohexanone, rep-
resentative reactants, leads to high enantioselectivity. A variety of
solvents were screened in the presence of 10 mol % of 7 with/with-
out an additive by conducting the reactions on a 0.3–0.4 mmol
scale at room temperature. The results of screening shown in Table
1 reveal that the reaction in solvents such as DCM, water, and brine
works better as compared to that in other solvents such as DMSO,
MeOH, dioxane, and THF Further, the reaction in brine (saturated
NaCl solution, ca. 5.0 M) gave relatively better yields and enantio-
discrimination as compared to that in water (entries 7 and 8). Thus,
the influence of additive was examined carefully in an organic sol-
vent such as DCM and brine carefully. Clearly, best results are ob-
served with benzoic acid as an additive in brine as the reaction
medium and with only 5 equiv of cyclohexanone (entry 19). The
change of additive from benzoic acid to 2,4-dinitrobenzoic acid/
tartaric acid/pentafluorobenzoic acid/p-toluenesulphonic acid/o-
nitrobenzoic acid/TFA led to either longer reaction times or no
reaction at all and poor enantiodiscrimination.
* Corresponding author. Tel.: +91 512 2597438; fax: +91 512 2597436.
E-mail address: moorthy@iitk.ac.in (J.N. Moorthy).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.07.164

5282
S. Saha et al. / Tetrahedron Letters 51 (2010) 5281–5286
CF3
S
S
H
N
CH3
N
H
N
H
CF3
N
H
N
H
N
H
NH
NH
C
H3
CF3
OAc
O
S
O
S
O
HN
N
H
N
H
HN SO2CF3
AcO
AcO
NH
N
H
NH2
OAc
CF3
HO
O
O
N
Si
Ph
N
H
N
Ph
N
N
H
H
H
X
CH3
N
Ph
Ph
OTMS
N
N
S
H
N
S
N
N
H
N
H
H
NH
N
H
CH3
Figure 1. Structures of organocatalysts typically employed for enanatioselective Michael addition reactions.
O
O
O
O
N
H
HN
N
H
HN
N
H
HN
N
H
HN
HN
Ac
HN
Ms
HN
Tf
HN
Ts
1
2
3
4
O
O
O
N
N
H
HN
HN
N
H
HN
HN
H
HN
S
HN
S
S
O
O
O
O
O
O
CH3
F
F
F
F
CH3
F
5
6
7
Figure 2. The structures of catalysts explored for enantioselective Michael reaction.
Under the optimized conditions, the other two catalysts, that
is, 5 and 6, were found to be inferior to 7 in terms of reactivity
as well as enantioselectivity. Thus, with catalyst 7 in 10 mol %,
enantioselective Michael addition reactions of a variety of alde-
hydes and ketones with differently substituted nitrostyrene
derivatives were conducted on 0.3–0.4 mmol of nitrostyrene
with 10 mol % of benzoic acid additive in brine at 25 °C. The re-
sults of enantioselective Michael additions are compiled in the
Table 2. It is noteworthy that a critical dependence of the reac-
tions was observed on the temperatures; while the reactions
were found to be too sluggish at lower temperatures (3–5 °C),
only moderate reactivity was observed even at 15 °C. At 25 °C,
all the reactions were found to proceed smoothly to completion
in 10–18 h.
As can be seen, the reactions work well with cyclohexanone lead-
ing to excellent enantio- as well as diastereoselectivity. However,
the catalyst 7 leads to rather lower selectivity with cyclopentanone
and acyclic ketones as substrates. For cyclohexanone as the reac-
tant, the diastereoselectivity for syn product is found to vary from
94–97% with no discernible effect of the nature of nitrostyrene (en-
tries 1–13). The ee values are found to range from 92–95%. For cyclo-
pentanones, the diastereo- as well as enantioselectivities are
markedly low (entries 14–16). This, indeed, is generally the case
with a variety of organocatalysts. With propanaldehyde, the diaste-
reoselectivity in favor of the syn product is 92%, while the enantiose-
lectivity is only 83% (entry 19). For simple acetone and anthrone, the
enantioselectivity for the conjugate addition product is 80–84% (en-
tries 17, 18 and 20).8

S. Saha et al. / Tetrahedron Letters 51 (2010) 5281–5286
5283
NH2
N
NH2
COOH
NO2
NO2
Boc
H2-Pd/C
HN
O
ClCO2Et, Et3N
THF, 0 o C to rt
reflux, 12 h
HN
O
MeOH, rt, 6h
N
N
Boc
Boc
O
N
H
S
O
CH3
HN
O
6
NH
1) CH3 SO2Cl, pyridine
DCM, 0 oC to rt
6 h
2) TFA/DCM (20 %)
2 h
SO2Cl
F
F
F
1)
F
F
F
F
O
S
O
O
S
O
F
N
H
CH3
NH2
N
H
F
,pyridine
1) p-TsCl, pyridine
F
HN
O
HN
O
HN
O
DCM, 0 oC to rt
6 h
2) TFA/DCM (20 %)
2 h
DCM, 0 oC to rt
6 h
2) TFA/DCM (20 %)
2 h
7
NH
N
5
NH
Boc
Scheme 1. Synthetic routes for the preparation of catalysts 5–7.
Table 1
Results of screening of the direct catalytic enantioselective Michael addition reaction of cyclohexanone to b-nitrostyrene in various solvents using catalyst 7 with/without an
additivea
O
O
NO2
NO2
catalyst
additive
solvent
Entry
Solvent
Additive
Time (h)
Yieldb (%)
95
drc (syn:anti)
eed (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
DCM
—
—
—
—
—
—
—
—
28
48
48
48
48
48
48
48
24
48
48
50
32
48
48
16
12
18
14
30
48
97:3
—
80
—
e
DMSO
MeOH
THF
Dioxane
DMF
Water
Brine
DCM
—
—
e
—
—
15
18
ndi
ndi
—
ndi
ndi
—
e
—
54
60
94:6
95:5
—
80
86
—
e
TFA
—
DCM
DCM
DCM
DNBA
(+)-CSA
PhCOOH
PhCOOH
PhCOOH
PhCOOH
PhCOOH
PhCOOH
PhCOOH
PhCOOH
PhCOOH
20
ndi
—
ndi
—
e
—
85
94
98:2
98:2
—
83
88
—
CHCl3
DMSO
MeOH
Water
Brine
Brine
Brine
Brine
Brine
e
—
30
88
95:5
98:2
98:2
98:2
98:2
—
78
90
90
90
94
—
90
92f
94g
e,h
—
o-Nitrobenzoic acid
24
ndi
ndi
(continued on next page)

5284
S. Saha et al. / Tetrahedron Letters 51 (2010) 5281–5286
Table 1 (continued)
Entry
Solvent
Additive
Time (h)
Yieldb (%)
drc (syn:anti)
eed (%)
e
e
e
22
23
24
Brine
Brine
Brine
TFA
C6F5COOH
Tartaric acid
48
30
30
—
—
—
—
—
—
—
—
—
a
The reactions were run on 0.3–0.4 mmol of b-nitrostyrene, 10 equiv of cyclohexanone and 10 mol % additive at 25 °C under identical conditions by employing 10 mol % of 7.
b
c
d
e
f
Based on b-nitrostyrene.
From 400 MHz 1H NMR spectroscopy.
Based on chiral HPLC analysis of the major syn diastereomer.
Sluggish reaction.
With 20 mol % of PhCOOH as an additive.
5 equiv cyclohexanone was used.
Reaction performed at 3 °C.
g
h
i
Not determined.
Table 2
Table 2 (continued)
Results of enantioselective Michael reactions with catalyst 7a
c
Entry Product
Time (h) Yieldb (%) dr (syn:anti) eed (%)
c
Entry Product
Time (h) Yieldb (%) dr (syn:anti) eed (%)
OMe
OMe
O
1
14
12
94
92
94:6
94:6
94
94
8
14
14
12
97
96
94
94:6
96:4
97:3
95
94
92
O
NO2
NO2
Me
OMe
O
OMe
NO2
2
O
9
NO2
NO2
OMe
10
11
3
4
5
14
12
12
95
96
96
97:3
95:5
96:4
95
93
93
O
O
O
NO2
NO2
CF3
OMe
NO2
12
18
96
84
94:6
95:5
93
94
O
NO2
Br
Me
Me
N
O
O
O
NO2
12
O
NO2
F
6
7
14
12
97
90
96:4
94:6
92
94
NO2
13
14
16
13
90
85
97:3
92
84
O
NO2
OBn
O
75:25
NO2
NO2

S. Saha et al. / Tetrahedron Letters 51 (2010) 5281–5286
5285
O
N
Table 2 (continued)
c
Entry Product
Time (h) Yieldb (%) dr (syn:anti) eed (%)
N
H
O
H
N
OCH3
S O
O
O
N
15
16
14
74
72
77:23
75:25
81
83
O
CH3
NO2
NO2
Figure 3. The proposed transition state structure for the Michael reaction between
ketone and b-nitrostyrene.
16
O
Accordingly, the electrophilic b-nitrostyrene is proposed to be
bound by two hydrogen bonds formed with the amide part of
the catalyst. The fact that the catalyst 5 with enhanced acidity of
the NH hydrogen due to pentafluorophenyl ring does not function
as good is intriguing. We believe that charge transfer interaction or
NO2
17
12
12
94
86
—
—
81
80
O
p,p stacking between the bound electrophilic b-nitrostyrene and
the tosyl group possibly contributes to the stabilization of the tran-
NO2
OCH3
sition state to some degree.
In conclusion, we have designed organocatalysts based on pro-
line that are capable of double hydrogen bonding for asymmetric
Michael reactions between carbonyl compounds and nitroolefins.
It is shown that the catalyst 7, which can be readily accessed by
a simple synthetic protocol, works remarkably well in brine to af-
ford addition products in a high diastereo- as well as enant-
ioselectivty. Thus, superior performance of 7 as compared to
analogous catalysts 5 and 6 presumably arises from the possible
18
19
O
NO2
O
12
10
95
94
92:8
83
84
NO2
H
Me
O
p,p stacking interactions between the tosyl ring of the catalyst 7
and aromatic ring of the nitroolefin. Given that the incorporation
of additional stereogenic center for reinforced chirality is pre-
cluded and that the Michael reactions occur with a very high
enantioselectivity with catalyst 7, the advantage of double hydro-
gen bonding to bind the electrophilic reactant and regulate the ste-
reochemical outcome of the reactions is compellingly evident from
the results described herein.
20
—
NO2
Ar
a
The reactions were run on 0.3–0.4 mmol of b-nitrostyrene derivatives at 20 °C
under identical conditions by employing 10 mol % of 7 and 10 mol % PhCOOH as an
additive.
b
Acknowledgments
Based on nitroolefins.
c
Ratios of diastereomers were calculated based on integrations in the 1H NMR
spectrum of the crude reaction mixture in each case.
The ee values were calculated from HPLC profiles of the silica-gel column
purified enantiomeric mixture of the syn diastereomers. The values reported are for
J.N.M. is thankful to the Department of Science and Technology
(DST), India for funding through Ramanna fellowship. S.S. is grate-
ful to the CSIR, India for a senior research fellowship.
d
Why is it that the reactions work best in brine in which the
reactants as well as the catalyst are not soluble? Indeed, the reac-
tion mixture appeared truly biphasic. The fact that added NaCl in
water brings about perceptible reduction in the reaction times
together with enhancement of enantiodiscrimination as compared
to the result in plain water (entries 7 and 8, Table 1) clearly empha-
sizes the role of the medium, and excludes the possibility of the
reaction occurring in neat conditions without any role of the med-
ium. There are two possible ways that the reactions in brine are
supposedly promoted: (i) hydrophobic aggregation9 and (ii) reac-
tions under biphasic conditions.4f,10 While we are not sure which
of the two considerations is applicable to our reaction conditions,
we believe that brine and the additive, namely benzoic acid, should
somehow stabilize the polar transition state via local medium
effects to account for the observed differences in results going from
organic media to highly polar medium.11 Further, why the reac-
tions work better with benzoic acid only as an additive is intrigu-
ing. Presumably, TFA, dinitrobenzoic acid, camphor sulfonic acid,
etc. with lower pKa values lead to catalyst poisoning; the reactions
did not progress at all with these acids. We, therefore, believe that
there appears to be an optimum pKa for the acid to be effective,
which in the present case is benzoic acid.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2010.07.164.
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