Highly enantioselective conjugate addition of malononitrile to 2-enoylpyridines with bifunctional organocatalyst

Article abstract of DOI:10.1021/ol3015607

An efficient enantioselective conjugate addition of malononitrile to a range of β-substituted 2-enoylpyridines catalyzed by cinchona alkaloid-based bifunctional urea catalysts has been developed. Both enantiomers of the products could be achieved with the same level of enantioselectivity by using pseudoenantiomeric catalysts in up to 97% ee and in excellent yields. One of the enantioenriched products has been transformed to a highly functionalized piperidone derivative.

Full text of DOI:10.1021/ol3015607

ORGANIC
LETTERS
2012
Vol. 14, No. 17
4322–4325
Highly Enantioselective Conjugate
Addition of Malononitrile to
2‑Enoylpyridines with Bifunctional
Organocatalyst
Nagaraju Molleti,† Nirmal K. Rana,‡ and Vinod K. Singh*,†,‡
Department of Chemistry, Indian Institute of Science Education and Research Bhopal,
ITI (Gas Rahat) Building, Govindpura, India 460 023, and Department of Chemistry,
Indian Institute of Technology Kanpur, India 208 016
vinodks@iitk.ac.in
Received June 6, 2012
ABSTRACT
An efficient enantioselective conjugate addition of malononitrile to a range of β-substituted 2-enoylpyridines catalyzed by cinchona alkaloid-
based bifunctional urea catalysts has been developed. Both enantiomers of the products could be achieved with the same level of enantio-
selectivity by using pseudoenantiomeric catalysts in up to 97% ee and in excellent yields. One of the enantioenriched products has been
transformed to a highly functionalized piperidone derivative.
Asymmetric conjugate addition of nucleophiles to
activated olefins is one of the most exploited reactions
for the construction of CÀC and CÀX bonds in organic
synthesis.1 In particular, the enantioselective Michael ad-
dition of carbon-based nucleophiles to R,β-unsaturated
carbonyls is a convenient route to optically active carbon-
yls, which are of great synthetic importance.2 Over the
past decade, considerable efforts have been made to devel-
op efficient synthetic methods for such Michael reactions,
especially those employing 1,3-dicarbonylcompounds such
as malonate ester,3 keto ester,4 diketones,5 and R-nitro and
R-cyano esters6 as nucleophiles. However, there are limited
reports on the enantioselective conjugate addition of
nitrile derivatives, specifically malononitrile.7 Moreover,
the addition of malononitrile is limited to very few electro-
philes like nitroolefins, chalcones, and R,β-unsaturated
(3) For recent examples of asymmetric Michael addition of malonate
ester, see: (a) Bartoli, G.; Bosco, M.; Carlone, A.; Cavalli, A.; Locatelli,
M.; Mazzanti, A.; Ricci, P.; Sambri, L.; Melchiorre, P. Angew. Chem.,
Int. Ed. 2006, 45, 4966. (b) Lattanzi, A. Tetrahedron: Asymmetry 2006,
17, 837. (c) Ye, J.; Dixon, D. J.; Hynes, P. S. Chem. Commun. 2005, 4481.
(d) Li, H.; Wang, Y.; Tang, L.; Deng, L. J. Am. Chem. Soc. 2004, 126,
9906. (e) Okino, T.; Hoashi, Y.; Furukawa, T.; Xu, X.; Takemoto, Y.
J. Am. Chem. Soc. 2005, 127, 119. (f) McCooey, S. H.; Connon, S. J.
Angew. Chem., Int. Ed. 2005, 44, 6367. (g) Brandau, S.; Landa, A.;
ꢀ
Franzen, J.; Marigo, M.; Jørgensen, K. A. Angew. Chem., Int. Ed. 2006,
45, 4305. (h) Evans, D. A.; Seidel, D. J. Am. Chem. Soc. 2005, 127, 9958.
(i) Ma, A.; Zhu, S.; Ma, D. Tetrahedron Lett. 2008, 49, 3075. (j) Zhou, L.;
Lin, L.; Wang, W.; Ji, J.; Liu, X.; Feng, X. Chem. Commun. 2010, 46,
3601. (k) Wang, Z.; Chen, D.; Yang, Z.; Bai, S.; Liu, X.; Lin, L.; Feng, X.
Chem.;Eur. J. 2010, 16, 10130. (l) Ray, S. K.; Singh, P. K.; Singh, V. K.
Org. Lett. 2011, 13, 5812.
(4) (a) Hoashi, Y.; Yabuta, T.; Takemoto, Y. Tetrahedron Lett. 2004,
45, 9185. (b) Majima, K.; Takita, R.; Okada, A.; Ohshima, T.; Shibasaki,
M. J. Am. Chem. Soc. 2003, 125, 15837. (c) Wu, F.; Li, H.; Hong, R.; Deng,
L. Angew. Chem., Int. Ed. 2006, 45, 947. (d) Watanabe, M.; Ikagawa, A.;
Wang, H.; Murata, K.; Ikariya, T. J. Am. Chem. Soc. 2004, 126, 11148.
(e) Cui, H.-P.; Li, P.; Wang, X.-W.; Chai, Z.; Yang, Y.-Q.; Cai, Y.-P.; Zhu,
S.-Z.; Zhao, G. Tetrahedron 2011, 67, 312. (f) Yu, Z.; Liu, X.; Zhou, L.;
Lin, L.; Feng, X. Angew. Chem., Int. Ed. 2009, 48, 5195.
† Indian Institute of Science Education and Research Bhopal.
‡ Indian Institute of Technology Kanpur.
(1) For review, see: (a) Enders, D.; Wang, C.; Liebich, J. X. Chem.;
Eur. J. 2009, 15, 11058. (b) Zhang, Y.; Wang, W. Catal. Sci. Technol.
2012, 2, 42.
(2) (a) Miyazaki, T.; Maekawa, H.; Yonemura, K.; Yamamoto, Y.;
Yamanaka, Y.; Nishiguchi, I. Tetrahedron 2011, 67, 1598. (b) Somaiah,
S.; Sashikanth, S.; Raju, V.; Reddy, K. V. Tetrahedron: Asymmetry
2011, 22, 1. (c) Fang, H.; Wu, X.; Nie, L.; Dai, X.; Chen, J.; Cao, W.;
Zhao, G. Org. Lett. 2010, 12, 5366. (d) Sun, Y.; Fan, R. Chem. Commun.
2010, 46, 6834. (e) Figueiredo, R. M.; Christmann, M. Eur. J. Org.
Chem. 2007, 2575.
r
10.1021/ol3015607
Published on Web 08/24/2012
2012 American Chemical Society

acidderivatives. Since the nitrilegroupin the malononitrile
can easily undergo further transformations to 1,3-dicarbo-
nyls or amines, it serves as an extremely useful substrate in
organic synthesis.8 Therefore, further development of en-
antioselective catalytic processes involving new electrophi-
lic partners, such as R,β-unsaturated carbonyls attached to
a heteroaryl group is highly desirable. The products so
obtained could easily be transformed into highly functi-
onalized lactams, which are useful intermediates for the
synthesis of heteroaryl-substituted chiral piperidines,
natural products, and several pharmaceutically active
compounds.6a,9
of highly enantioselective version of this reaction still re-
mains a worthwhile goal to achieve. Herein, we report a
highly enantioselective catalytic conjugate addition of
malononitrile to 2-enoylpyridines12 with cinchona-derived
bifunctional urea as organocatalyst.
At the outset, the conjugate addition of malononitrile
to 2-enoylpyridine was carried out in the presence of
10 mol % of quinine-derived thiourea 1a in toluene
at room temperature. Interestingly, the corresponding
Michael adduct was formed in excellent yield and enantio-
selectivity (Table 1, entry 1). Encouraged by this initial re-
sult, welookedforward tothecatalystscreening(Figure1).
In the past decade, cinchona alkaloid and its derivatives
have been increasingly used as efficient organocatalysts for
catalyzing several asymmetric organic transformations.10
Enantioenriched thiourea (urea) catalysts derived from
cinchona alkaloid have gained particular importance be-
causeoftheir high levelof efficiencyintermsofasymmetric
induction.11 Along this path, we envisioned that if the
asymmetric Michael addition of malononitrile to R,β-
unsaturated carbonyls in the catalytic influence of cincho-
na alkaloid derived (thio)urea is feasible, it would be easy
to access functionalized lactam and pyran derivatives.
There are only a few literature reports for the preparation
of such valuable scaffolds with high enantiopurity in an
organocatalytic fashion.6a,7d Therefore, the development
Figure 1. Cinchona alkaloid derived (thio)urea catalysts.
(5) (a) Pulkkinen, J.; Aburel, P. S.; Halland, N.; Jørgensen, K. A.
Adv. Synth. Catal. 2004, 346, 1077. (b) Wang, J.; Li, H.; Duan, W.; Zu,
L.; Wang, W. Org. Lett. 2005, 7, 4713. (c) Terada, M.; Ube, H.; Yaguchi,
Y. J. Am. Chem. Soc. 2006, 128, 1454. (d) Dong, Z.; Feng, J.; Cao, W.;
Liu, X.; Lin, L.; Feng, X. Tetrahedron Lett. 2011, 52, 3433.
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11204. (b) Raheem, I. T.; Goodman, S. N.; Jacobsen, E. N. J. Am. Chem.
Soc. 2004, 126, 706. (c) Ikariya, T.; Wang, H.; Watanabe, M.; Murata,
K. J. Organomet. Chem. 2004, 689, 1377. (d) Prieto, A.; Halland, N.;
Jørgensen, K. A. Org. Lett. 2005, 7, 3897. (e) Liu, C.; Lu, Y. Org. Lett.
2010, 12, 2278.
(7) (a) Hoashi, Y.; Okino, T.; Takemoto, Y. Angew. Chem., Int. Ed.
2005, 44, 4032. (b) Wang, J.; Li, H.; Zu, L.; Jiang, W.; Xie, H.; Duan, W.;
Wang, W. J. Am. Chem. Soc. 2006, 128, 12652. (c) Inokuma, T.; Hoashi,
Y.; Takemoto, Y. J. Am. Chem. Soc. 2006, 128, 9413. (d) Li, X.; Cun, L.;
Lian, C.; Zhong, L.; Chen, Y.; Liao, J.; Zhu, J.; Deng, J. Org. Biomol.
Chem. 2008, 6, 349. (e) Shi, J.; Wang, M.; He, L.; Zheng, K.; Liu, X.; Lin,
L.; Feng, X. Chem. Commun. 2009, 4711. (f) Russo, A.; Perfetto, A.;
Lattanzi, A. Adv. Synth. Catal. 2009, 351, 3067. (g) Oliva, C. G.; Silva,
A. M. S.; Resende, D. I. S.P.; Paz, F. A. A. F.; Cavaleriro, J. A. S. Eur. J.
Org. Chem. 2010, 3449. (h) Russo, A.; Capobianco, A.; Perfetto, A.;
Lattanzi, A.; Peluso, A. Eur. J. Org. Chem. 2011, 1922. (i) Fusco, C. D.;
Lattanzi, A. Eur. J. Org. Chem. 2011, 3728. (j) Li, X.-M.; Wang, B.;
Zhang, J.-M.; Yan, M. Org. Lett. 2011, 13, 374. (k) Yang, W.; Jia, Y.;
Du, D.-M. Org. Biomol. Chem. 2012, 10, 332.
(8) (a) McElvain, S. M.; Nelson, J. W. J. Am. Chem. Soc. 1942, 64,
1825. (b) Meyers, A. I.; Smith, E. M.; Ao, M. S. J. Org. Chem. 1973, 38,
2129. (c) Savoia, D.; Tagliavini, E.; Trombini, C.; Umani-Ronchi, A.
J. Org. Chem. 1980, 45, 3227. (d) Weiberth, F. J.; Hall, S. S. J. Org. Chem.
1987, 52, 3901. (e) Peterson, M. A.; Polt, R. J. Org. Chem. 1993, 58, 4309.
(f) Erdelmeier, I.; Tailhan-Lomont, C.; Yadan, J.-C. J. Org. Chem. 2000,
65, 8152. (g) Yasuda, K.; Shindo, M.; Koga, K. Tetrahedron Lett. 1996,
37, 6343. (h) Taylor, M. S.; Zalatan, D. N.; Lerchner, A. M.; Jacobsen,
E. N. J. Am. Chem. Soc. 2005, 127, 1313. (i) Chen, Y.-C.; Xue, D.; Deng,
J.-G.; Cui, X.; Zhu, J.; Jiang, Y.-Z. Tetrahedron Lett. 2004, 45, 1555.
(9) (a) Al-Haiza, M. A.; Mostafa, M. S.; El-Kady, M. Y. Molecules
2003, 8, 275. (b) Greiner-Bechert, L.; Sprang, T.; Otto, H.-H. Monatsh.
Chem. 2005, 136, 635.
After intensive catalytic screening with catalysts 1aÀi
(Figure 1), we found that there were two major structural
features that were essential for high enantioselection.
First, the urea catalysts were superior over corresponding
thiourea catalysts, and second, the N-3,5-bis(trifluoromethyl)-
phenyl group in the aromatic part was essential for achiev-
ing high asymmetric induction (Table 1). It is noteworthy
that both the enantiomers of the Michael products could
be obtained with the same level of enantioselectivity by
employing pseudoenantiomeric catalysts. Although, all
urea catalysts employed for the reaction gave enantio-
selectivities in the range of 90%, cinchonine derived urea
catalyst 1h afforded products in 94% ee with 95% yield
(Table 1, entry 8). Thus, further optimization of reaction
conditions were conducted with urea catalyst 1h.
Optimization studies with respect to catalyst loading
does not make any observable difference on the enantio-
selectivity (Table 2). It is interesting to note that catalyst
loading could be decreased to 2 mol % without any com-
promise in the optical yield of the reaction (entry 5). Similarly,
when the reaction was conducted at lower temperatures,
enantioselectivities did not change, but in this case pro-
longed reaction time was required to achieve appreciable
yield (entry 7). Next, the influence of the solvent on the
(12) (a) Gu, C.-L.; Liu, L.; Sui, Y.; Zhao, J.-L.; Wang, D.; Chen,
Y. ÀJ. Tetrahedron: Asymmetry 2007, 18, 455. (b) Albada, H. B.; Rosati, F.;
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Coquiere, D.; Roelfes, G.; Liskamp, R. M. J. Eur. J. Org. Chem. 2011,
(10) (a) Song, C. E., Ed. Cinchona Alkaloids in Synthesis and Cata-
lysis; Wiley-VCH Verlag: Weinheim, 2009. For a recent review, see:
(b) Marcelli, T.; Hiemstra, H. Synthesis 2010, 1229. (c) Yeboah,
E. M. O.; Yeboah, S. O.; Singh, G. S. Tetrahedron 2011, 67, 1725.
(11) For review, see: (a) Connon, S. J. Chem.;Eur. J. 2006, 12, 5418.
(b) Connon, S. J. Chem. Commun. 2008, 2499.
1714. (c) Evans, D. A.; Fandrick, K. R.; Song, H.-J.; Scheidt, K. A.; Xu,
R. J. Am. Chem. Soc. 2007, 129, 10029. (d) Hua, M.-Q.; Wang, L.; Cui,
H.-F.; Nie, J.; Zhang, X.-L.; Ma, J.-A. Chem. Commun. 2011, 47, 1631.
(e) Boersma, A. J.; Bruin, B. D.; Feringa, B. L.; Roelfes, G. Chem.
Commun. 2012, 48, 2394. (f) Singh, P. K.; Singh, V. K. Org. Lett. 2008,
10, 4121. (g) Singh, P. K.; Singh, V. K. Org. Lett. 2010, 12, 80.
Org. Lett., Vol. 14, No. 17, 2012
4323

Table 1. Screening of Different Chiral Catalystsa
Table 3. Effect of Solvents on Enantioselectivitya
entry
catalyst
yield (%)
eeb (%)
entry
solvent
toluene
time (h)
yield (%)
eeb (%)
1c
2c
3c
4c
5
1a
1b
1c
1d
1e
1f
94
94
94
93
94
92
94
95
90
92
93
82
94
84
88
93
94
89
1
11
11
12
12
12
12
20
12
12
11
24
20
24
12
95
96
95
95
95
94
95
93
95
94
72
70
84
94
94
90
94
96
93
96
93
92
87
92
80
35
40
95
2
benzene
o-xylene
m-xylene
p-xylene
mesitylene
CH2Cl2
DCE
3
4
5
6
6
7
1g
1h
1i
7
8
9c
8
9
CHCl3
10
11
12
13
14c
Et2O
a Reactions were carried out on 0.1 mmol of 2a and 0.12 mmol of
malononitrile in 1 mL of toluene at rt, unless noted otherwise. b Deter-
mined by HPLC using chiral column. c Opposite enantiomer as major
was obtained.
THF
1,4-dioxane
CH3CN
m-xylene
a Reactions were carried out on 0.1 mmol of 2a and 0.12 mmol of
malononitrile in 1 mL of solvent at rt using 10 mol % of catalyst 1h,
unless noted otherwise. b Determined by HPLC using chiral column.
c Catalyst 1d was used and (R) enantiomer was obtained as major.
Table 2. Optimization of Reaction Conditionsa
Table 4. Enantioselective Conjugate Addition of Malononitrile
to a Serise of β-Substituted 2-Enoylpyridinesa
entry
mol %
temp (°C)
time (h)
yield (%)
eeb (%)
1
2
3
4
5
6
7
10
15
20
5
rt
rt
11
9
95
95
96
90
80
90
88
94
94
93
93
92
94
93
rt
6
rt
24
60
30
60
entry
R1
3
time (h) yield (%)
eeb (%)
2
rt
10
10
0
1c
2
Ph
3a
3b
3c
3d
3e
3f
11
24
12
22
9
95
85
90
92
91
90
80
94
93
79
82
81
86
89
80
78
80
96 (>99.9)
94
À20
4-MeO-C6H4
4-Me-C6H4
a Reactions were carried out on 0.1 mmol of 2a and 0.12 mmol of
malononitrile in 1 mL of toluene using 10 mol % of catalyst 1h, unless
noted otherwise. b Determined by HPLC using chiral column.
3
94
4
4ÀCl-C6H4
3ÀCl-C6H4
4ÀF-C6H4
95
5
95
6
11
24
10
10
9
95
7
3-NO2ÀC6H4
4-NO2ÀC6H4
4-CN-C6H4
4-CF3ÀC6H4
2-Cl-6ÀF-C6H3
3g
3h
3i
93
enantioselectivity of the reaction was investigated. A series
of conventional solvents were screened, and the results are
summarized in Table 3. Except for 1,4-dioxane (entry 12)
and acetonitrile (entry 13), almost all organic solvents
yielded the product 3a in high enantioselectivity (entries
1À11). A less polar solvent like m-xylene was chosen as
optimum, and the product was obtained in 96% ee (entries
4 and 14).
With the optimized conditions (Table 3, entry 4), we
looked forward to substrate scopes of enantioselective
Michael reaction of malononitrile to 2-enoylpyridines,
and results are summarized in Table 4. Both aryl- and
alkyl-substituted 2-enoylpyridines proved to be good
eletrophiles with malononitrile as nucleophilic partner. A
maximum of 96% enantioselectivity was obtained for
compound 3a. It is worth noting that the product could
be recrystallized to enhance the enantioselctivities up
8
96
9
95
10
11
12
13
14
15
16
17
3j
95
3k
22
29
18
18
18
29
28
94
3,4-CH2O2ÀC6H3 3l
92
1-naphthyl
2-naphthyl
2-furyl
3m
95
3n
3o
3p
3q
94
94
(E) PhCHdCH
cyclohexyl
94
97
a Reactions were carried out on 0.1 mmol of 2 and 0.12 mmol of
malononitrile in the presence of 10 mol % of 1h in 1 mL of m-xylene at rt,
unless noted otherwise. b Determined by HPLC using chiral column.
c Data in parentheses were obtained after recrystallization, and absolute
configuration was determined as (S) by X-ray crystallography.
to >99.9% ee (Table 4, entry 1). It was also observed that
neither the steric hindrance of the substituents at the
4324
Org. Lett., Vol. 14, No. 17, 2012

Scheme 1. Substrate Scope and Large-Scale Reaction
Figure 2. Possible transition-state model.
(figure 2). The bifunctional catalyst simultaneously acti-
vates malononitrile and Michael aceptor 2 via double
H-bonding as shown in Figure 2. Tertiary amine of 1h
deprotonates malononitrile and the resulting pronucleo-
phile is hydrogen bonded to the protonated quinuclidine
nitrogen, while the electrophile 2 is activated through
double hydrogen bonding of the urea moiety of the
catalyst. Subsequent addition of pronucleophile to the
bottom (Re face) face of the 2 leads to the formation of
required product as major stereoisomer.
Scheme 2. Synthesis of Functionalized Lactam 6
In conclusion, we have developed an efficient methodol-
ogy for the conjugate addition of malononitrile to a range
of β-substituted 2-enoylpyridines by using cinchona-based
urea catalysts. The Michael products were obtained in
excellent enantioselectivities (up to 97% ee) and in higher
yields. It has been shown that both enantiomers of pro-
ducts could be achieved with the same level of enantio-
selectivity. The synthetic utility of the present catalytic
asymmetric Michael addition reaction was established by
transforming the product to a highly functionalized piper-
idone derivative 6. Further studies focusing on enantiose-
lective reactions with cinchona derived (thio)ureas are
currently underway in our laboratory.
aromatic rings nor the electronic nature had any effect on
the enantioselectivity of the product. Excellent enantio-
selectivities were obtained in almost all the cases. Michael
acceptors having a cyclohexyl group at the β-position also
reacted smoothly with malononitrile to yield the corre-
sponding product in high ee (Table 4, entry 17).
The scope of the reaction was further extended to
heteroaromatic Michael acceptors such as 4aÀb, in which
thiophene and furan were attached to the carbonyl carbon.
In this case also, the Michael adducts were formed in high
enantiopurity with excellent yields under optimized con-
ditions (Scheme 1). In order to check the synthetic viability
of our catalytic system, we prepared compound 3a on a
5.0 mmol scale (Scheme 1) and found that the catalytic
system was equally efficient on a gram scale to afford the
product 3a in excellent yield and enantiomeric excess (96% ee).
Finally, we were inclined to check the synthetic utility of
the catalytic protocol developed by us. Toward this end,
the Michael adduct 3a was charged with NaBH4 to con-
vert it into highly functionalized piperidone derivative 6
(Scheme 2) in 90% yield with 45:55 of diastereoselectivity.
Lactam 6 could serve as an advanced intermediate for
further synthetic transformations.
Acknowledgment. V.K.S. thanks the Department of
Science and Technology (DST), India, for a research grant
through a J. C. Bose fellowship. N.M. and N.K.R. thank
the Council of Scientific and Industrial Research (CSIR),
New Delhi, for research fellowships. We thank Dr. Sanjit
Konar and Dr. Vishnumaya Bisai from IISER Bhopal and
Atanu Dey from IIT Kanpur for their help.
Supporting Information Available. Experimental pro-
cedures and spectral data for all products. This material is
available free of charge via the Internet at http://pubs.acs.org
To explain the high stereochemical outcome of the re-
action, a plausible transition-state model has been proposed
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 17, 2012
4325