Bifunctional chiral urea catalyzed highly enantioselective Michael addition of cyclic 1,3-dicarbonyl compounds to 2-enoylpyridines

Article abstract of DOI:10.1016/j.tetlet.2013.04.003

A highly efficient cinchona alkaloid based bifunctional urea catalyzed enantioselective conjugate addition of cyclic 1,3-dicarbonyl compounds to a range of β-substituted 2-enoylpyridines has been developed. Chiral 2,4-diaryl substituted 1,4-dihydropyridines could easily be accessible from these Michael adducts. Significantly, this asymmetric methodology could afford both enantiomers of the products with the same level of enantioselectivities by using pseudoenantiomeric catalysts with up to 98% ee and in excellent yields.

Full text of DOI:10.1016/j.tetlet.2013.04.003

Tetrahedron Letters 54 (2013) 3241–3244
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Bifunctional chiral urea catalyzed highly enantioselective Michael addition
of cyclic 1,3-dicarbonyl compounds to 2-enoylpyridines
Nagaraju Molleti a, Suresh Allu a, Sumit K. Ray b, Vinod K. Singh a,b,
⇑
a Department of Chemistry, Indian Institute of Science Education and Research, Bhopal, Bhopal 460 023, India
b Department of Chemistry, Indian Institute of Technology, Kanpur, 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:
A highly efficient cinchona alkaloid based bifunctional urea catalyzed enantioselective conjugate addition
of cyclic 1,3-dicarbonyl compounds to a range of b-substituted 2-enoylpyridines has been developed. Chi-
ral 2,4-diaryl substituted 1,4-dihydropyridines could easily be accessible from these Michael adducts.
Significantly, this asymmetric methodology could afford both enantiomers of the products with the same
level of enantioselectivities by using pseudoenantiomeric catalysts with up to 98% ee and in excellent
yields.
Received 20 February 2013
Revised 29 March 2013
Accepted 1 April 2013
Available online 13 April 2013
Keywords:
Organocatalyst
Ó 2013 Elsevier Ltd. All rights reserved.
Thiourea(urea)
Chiral 2,4-diaryl substituted 1,4-
dihydropyridine
1,3-Dicarbonyl compounds
b-Substituted 2-enoylpyridines
1,4-Dihydropyridine constitutes a key structural feature present
in a vast majority of polyhydroquinolines. These polyhydroquino-
lines are important Ca2+ channel modulators, which are widely
used for treatment of hypertension, Parkinson’s disease, restless
leg syndrome, diabetic, and Alzheimer’s diseases. These have
now been recognized as vital drugs such as nifedipine, niguldipine,
nicardipine, amlodipine and are now available in the market.1
Hence, the synthesis of enantiomerically pure 1,4-dihydropyri-
dines via catalytic enantioselective process has emerged as an area
of active research.2 Among several polyhydroquinolines, 2,4-diaryl
polyhydroquinolines have been found to show important antidia-
betic activity via inhibition of PTP-1B, as well as antidyslipidemic
activities via significant lipid lowering activity.3 Although there
are a few reports on enantioselective synthesis of 2,4-disubstituted
polyhydroquinoline available in the literature, to the best of our
knowledge there has been no report on the enantioselective syn-
thesis of 2,4-diaryl polyhydroquinoline published till date. There-
fore, the development of highly enantioselective version of this
reaction still remains a worthwhile goal to achieve.
for thesynthesis of enantioenriched 2,4-diaryl polyhydroquinolines.
However, when we carried out the reaction between dimedone and
simple chalcone using thiourea catalyst (1a) derived from quinine,
longer reaction time (in days) and moderate enantioselectivity were
found to be the main limitations in this reaction (Scheme 1). Inspired
from our recent success with 2-enoylpyridines as powerful electro-
philes in highly enantioselective conjugate addition of malononitri-
le,6 we predicted that since the presence of pyridine moiety in
2-enoylpyridines makes them relatively stronger and directional
H-bond acceptors in comparison to simple chalcones, it might help
to increase the reaction rate as well as enantioselectivity. The prod-
ucts so obtained are very useful in the synthesis of heteroaryl-
substituted 1,4-dihydropyridines. Moreover, the importance of
nitrogen containing hetero aryl substituted products in organic syn-
thesis makes the reaction highly desirable.
Of late, our group has been involved in cinchona derived thio-
urea(urea) bifunctional catalyzed several Michael and aldol reac-
tions.7 These bifunctional catalysts have proven to be highly
efficient in synergetic catalysis wherein the catalyst simulta-
neously activates both the nucleophile as well as the electrophile.
On the basis of our previous report using 2-enoylpyridine as the
electrophile in the highly efficient organocatalyzed Michael addi-
tion of malononitrile, we hypothesized that chiral urea derived
from cinchona alkaloid8 would catalyze this reaction by forming
hydrogen bonds with 2-enoylpyridine effectively to give the enan-
tioenriched Michael adduct.
In continuation of our ongoing research program in the area of
the organocatalytic enantioselective Michael addition4 reaction of
active methylene compounds to various a,b-unsaturated carbonyl
compounds, we thought of exploring the enantioselective organo-
catalytic Michael addition of 1,3-dicarbonyl compounds5 to various
chalcones. The corresponding adducts resulting from this Michael
addition reaction could potentially provide chiral intermediates
Our studies commenced with performing a Michael addition
reaction of dimedone (3a) to chalcone (2) in toluene using thiourea
⇑
Corresponding author. Fax: +91 512 2597436.
E-mail address: vinodks@iitk.ac.in (V.K. Singh).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.04.003

3242
N. Molleti et al. / Tetrahedron Letters 54 (2013) 3241–3244
1. 1a (10 mol %),
Toluene, rt, 120 h
2. Et3N (3.0 eq),
CH3COCl (2.0 eq)
O
O
O
OAc
Ph
Ph
O
O
2
3a
4
55% yield,
72% ee
Scheme 1. Enantioselective Michael addition–acetylation.
Table 1
shown in Table 1. All of them promoted the reaction with higher
level of enantioselectivities (Table 1, entries 1–9). We were pleased
to find the pseudo enantiomer10 catalysts such as 1d and 1h gave R
and S enantiomers, respectively, with the same level of enantiose-
lectivity (Table 1, entries 4 and 8). Among these catalysts, we chose
urea catalyst (1h) derived from cinchonine to optimize the reaction
conditions and the results are summarized in Table 2.
Optimization studies with respect to catalyst loading revealed
that we could successfully decrease the loading of the catalyst
without compromising on the enantiopurity (entries 1–3). Subse-
quently, we investigated the effect of temperature on this reaction.
Lowering the temperature had no significant effect on the enanti-
oselectivity of the reaction but affected the rate of the reaction (en-
tries 4 and 5). As shown in Table 3, screening of the various
solvents revealed, except acetonitrile, the reaction has shown same
level of compatibility in all general solvents and afforded the Mi-
chael adduct with higher level of yields and enantioselectivities
(Table 3).
Screening of different chiral catalystsa
1. 1 (10 mol %),
toluene, rt
O
O
O
OAc
N
2. Et3N (3.0 eq),
CH3COCl (2.0 eq)
N
Ph
Ph
O
O
5a
3a
7a
Entry
Catalyst
Yield (%)
eeb (%)
1c
2c
3c
4c
5
1a
1b
1c
1d
1e
1f
1g
1h
1i
95
95
93
94
92
95
94
96
93
96
96
96
96
94
97
94
97
97
6
7
8
9c
With the identification of the optimized conditions, we further
proceeded to evaluate the substrate scope of the reaction (Table 4).
We were gratified to notice the generality of this highly enantiose-
lective Michael reaction with a wide range of 2-enoylpyridines
bearing electron releasing and withdrawing substituents at various
positions on the phenyl ring (entries 2–12). We then tested ali-
phatic substituted 2-enoylpyridines. The reaction of 7p (b-cin-
namyl substituted 2-enoylpyridine) with dimedone also yielded
the desired product with good enantioselectivity (86% ee) (entry
16) whereas the Michael acceptor having the cyclohexyl group at
b-position gave the corresponding Michael adduct with good yield
but moderate ee (entry 17). In addition, we have changed the
nucleophile part dimedone to cyclohexane-1,3-dione (3b) and
the reaction proceeded smoothly to give the Michael adduct with
high yield and excellent enantioselectivity (Scheme 2).
a
Reactions were carried out on 0.12 mmol of 5a and 0.1 mmol of 3a in 1 mL of
toluene at rt; after complete conversion of 3a (ca. 12 h) the acetylation was per-
formed (1 h).
b
Determined by HPLC using Diacel chiralpak IA-3 column.
Opposite enantiomer as major was obtained.
c
catalyst derived from quinine (1a). Reaction took prolonged time
(5 days) and resulted in the Michael adduct with moderate yield
(70%). Tautomeric forms of the dimedone make the NMR of Michael
adduct complex. Moreover Xia and co-workers,9 found the unstabil-
ity of these Michael adducts due to aerobic oxidation. These practical
problems prompted us to make the acetyl derivative of the Michael
adduct which resulted in stable product with clean NMR. Owing to
its high reactivity, 2-enoylpyridine (5a) was taken as the electro-
phile in place of chalcone and conducted the thiourea catalyzed Mi-
chael addition. To our delight, the reaction completed in 12 h,
affording 7a with high enantioselectivity (96% ee) and yield (95%)
(Table 1, entry 1).
Furthermore, we have shown our interest to explore other het-
eroaromatic Michael acceptors such as 8a–b, in which thiophene
and furan were attached to the carbonyl carbon. Albeit, these reac-
tions took prolonged time for completion, the corresponding Mi-
chael adducts 9a–b were obtained with good yield and
enantioselectivities (Scheme 2).
Encouraged by this promising result, several thiourea and urea
catalysts (1a–i, Fig. 1) were examined in the selected reaction, as
F3C
CF3
HN
HN
X
HN
HN
O
N
F3C
N
H
N
H
H
H
N
N
N
H
X
R
R
MeO
F3C
N
N
1e: R = OMe, X = S
1a: R = OMe, X = S
1i
1f
1b
: R = OMe, X = O
1g
: R = OMe, X = O
1c: R = H, X = S
1d: R = H, X = O
: R = H, X = S
1h: R = H, X = O
Figure 1. Cinchona alkaloid derived (thio)urea catalysts.

N. Molleti et al. / Tetrahedron Letters 54 (2013) 3241–3244
3243
Table 2
Table 4
Optimization of reaction conditionsa
Substrate scope of the enantioselective conjugate addition of dimedone to b-
substituted 2-enoylpyridinesa
1h
1. catalyst
toluene
1. 1h (10 mol %),
O
O
O
OAc
N
2. Et3N (3.0 eq),
CH3COCl (2.0 eq)
CH2Cl2, rt
O
O
O
OAc
N
N
2. Et3N (3.0 eq),
CH3COCl (2.0 eq)
Ph
Ph
N
R1
R1
O
O
5a
O
3a
O
5
3a
7a
7
Entry
1h (mol %)
Temp (°C)
Time (h)
Yield (%)
eeb (%)
Entry
R1
7
Time (h)
Yield (%)
eeb (%)
1
2
3
4
5
10
15
5
10
10
rt
rt
rt
0
12
7
25
38
76
96
96
95
94
90
97
96
96
95
96
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
Ph
7a
7b
7c
7d
7e
7f
7g
7h
7i
7j
7k
7l
7m
7n
7o
7p
7q
8
10
6
12
6
97
95
96
88
96
95
94
90
87
94
97
86
95
96
87
84
93
98
90
97
97
97
97
97
98
98
98
91
92
93
97
96
86
70
4-MeO–C6H4
4-Me–C6H4
4-Cl–C6H4
3-Cl–C6H4
4-F–C6H4
3-NO2–C6H4
4-NO2–C6H4
4-CN–C6H4
4-CF3–C6H4
2-Cl-6-F–C6H3
3,4-CH2O2–C6H3
1-Naphthyl
2-Naphthyl
2-Furyl
À20
a
Reactions were carried out on 0.12 mmol of 5a and 0.1 mmol of 3a in 1 mL of
toluene at rt using catalyst 1h; after complete conversion of 3a the acetylation was
performed (1 h).
6
10
10
10
6
12
10
17
10
13
72
72
b
Determined by HPLC using Diacel chiralpak IA-3 column.
Table 3
Effect of solvents on enantioselectivitya
(E) PhCH@CH
Cyclohexyl
1h
1.
(10 mol %),
a
solvent, rt
O
Reactions were carried out on 0.1 mmol of 5 and 0.12 mmol of 3a in the pres-
ence of 10 mol % of 1h in 1 mL of CH2Cl2 at rt; after complete conversion of 3a the
O
O
OAc
N
2. Et3N (3.0 eq),
CH3COCl (2.0 eq)
N
acetylation was performed (1 h).
Ph
Ph
b
Determined by HPLC using Diacel chiralpak IA-3 column.
O
O
5a
3a
7a
1h
1.
(10 mol %),
Entry
Solvent
Time (h)
Yield (%)
eeb (%)
CH2Cl2, rt, 9 h
O
O
O
OAc
N
2. Et3N (3.0 eq),
CH3COCl (2.0 eq)
1
2
3
4
5
Toluene
m-Xylene
CH2Cl2
DCE
CHCl3
THF
12
12
8
9
9
24
12
8
96
95
97
97
97
92
94
97
97
97
98
97
96
88
28
98
N
Ph
Ph
O
O
5a
3b
7r
96% yield, 95% ee
6
7
CH3CN
CH2Cl2
8c
a
Reactions were carried out on 0.12 mmol of 5a and 0.1 mmol of 3a in 1 mL of
1h
1.
(10 mol %),
solvent at rt using 10 mol % of catalyst 1h; after complete conversion of 3a the
CH2Cl2, rt, 96 h
2. Et3N (3.0 eq),
CH3COCl (2.0 eq)
O
acetylation was performed (1 h) unless noted otherwise.
O
O
OAc
b
Determined by HPLC using Diacel chiralpak IA-3 column.
Catalyst 1d was used and (R) enantiomer was obtained as major.
X
c
Ph
Ph
O
X
O
The adducts obtained from the Michael addition of dimedone
and 2-enoylpyridines are very useful intermediates in organic syn-
thesis. We have demonstrated their synthetic utility by making
chiral 1,4-dihydropyridines, which are very easily accessible from
these Michael adducts. Treatment of 6 with ammonium acetate
in ethanol at 32 °C smoothly furnished the corresponding chiral
1,4-dihydropyridines in good yield with only a slight loss in enan-
tiopurity (Scheme 3). With the help of single crystal X-ray diffrac-
tion analysis, we have assigned the absolute configuration of 7k to
be R (see Supplementary data).
9a: X = S, 70% yield,
8a: X = S
8b:
3a
83% ee
X = O
9b:
X = O, 69% yield,
82% ee
Scheme 2. Extended substrate scope of the catalytic system.
was established by transforming the product to
dihydropyridine.
a
1,4-
In summary, we have described a highly efficient methodology
for the conjugate addition of cyclic 1,3-dicarbonyl compounds to a
range of b-substituted 2-enoylpyridines by using cinchona based
urea catalysts. The Michael products were obtained in excellent
enantioselectivities (up to 98% ee) and in high yields. We have also
accomplished both the enantiomers of Michael adduct with the
same level of enantioselectivity by using naturally available cin-
chona derived urea catalysts. Substantially, the synthetic viability
of the present catalytic asymmetric Michael addition reaction
Acknowledgments
V.K.S. thanks the Department of Science and Technology (DST),
India for a research Grant through J. C. Bose fellowship. N.M. and
S.K.R. thank the Council of Scientific and Industrial Research (CSIR),
New Delhi for research fellowships. We thank Sourav Das and
Venkatesh Viruthakasi (IIT Kanpur) for their help. Facilities from
IIT Kanpur and IISER Bhopal are gratefully acknowledged.

3244
N. Molleti et al. / Tetrahedron Letters 54 (2013) 3241–3244
O
R1
O
NH4OAc, EtOH,
4 h, 32°c
1h (10 mol%),
CH2Cl2, rt
O
O
OH
N
R1
N
R1
N
H
O
N
5
O
3a
10
5a : R1 = Ph
6
10a : R1 = Ph : 9 0% yield, 95 % ee
5c : R1 = 4-Me-C6H4
5f : R1 = 4-F-C6H4
10c : R1 = 4-Me-C6H4 : 85 % yield, 92 % ee
10f : R1 = 4-F-C6H4 : 87 % yield, 96 % ee
10g : R1 = 3-NO2-C6H4 : 75 % yield, 95 % ee
5g : R1 = 3-NO2-C6H4
5n :
R
1 = 2-naphthyl
R
1 = 2-naphthyl : 81 % yield, 94 % ee
10n :
Scheme 3. Synthesis of 2,4-diaryl substituted 1,4-dihydropyridine derivatives.
5. (a) Halland, N.; Hansen, T.; Jørgensen, K. A. Angew. Chem. Int. Ed. 2003, 42, 4955;
Supplementary data
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the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.
04.003.
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