Highly enantioselective conjugate addition of nitromethane to chalcones using bifunctional cinchona organocatalysts

Article abstract of DOI:10.1021/ol050431s

(Chemical Equation Presented) Cinchona alkaloid-derived chiral bifunctional thiourea organocatalysts were synthesized and applied in the Michael addition between nitromethane and chalcones with high ee and chemical yields.

Full text of DOI:10.1021/ol050431s

ORGANIC
LETTERS
2005
Vol. 7, No. 10
1967-1969
Highly Enantioselective Conjugate
Addition of Nitromethane to Chalcones
Using Bifunctional Cinchona
Organocatalysts
Benedek Vakulya,† Szila´rd Varga,† Antal Csa´mpai,‡ and Tibor Soo´s*,†
Institute of Biomolecular Chemistry, Chemical Research Center of Hungarian Academy
of Sciences, P.O. Box 17, 1525, Budapest, Hungary, and Department of General and
Inorganic Chemistry, Eo¨tVo¨s Lora´nd UniVersity, P.O. Box 32, 1518,
Budapest, Hungary
tibor.soos@chemres.hu
Received February 26, 2005
ABSTRACT
Cinchona alkaloid-derived chiral bifunctional thiourea organocatalysts were synthesized and applied in the Michael addition between nitromethane
and chalcones with high ee and chemical yields.
The conjugate addition of a stabilized carbanion to R,â-
unsaturated carbonyl compounds is one of the fundamental
C-C bond-forming reactions in organic synthesis.1 In the
case of nitroalkanes, the products of a 1,4-addition to enones2
are also useful intermediates for a variety of further
elaborated structures such as aminoalkanes, aminocarbonyls,
and pyrrolidines. As a result, considerable effort has been
directed toward the development of catalytic asymmetric
versions of this process over the past several years, although
the reactions were mostly narrow in substrate scope and
generally low to moderate enantioselectivities have been
obtained.3-5 The best results to date have been achieved by
Shibashaki et al. using a lanthanum tris-binaphthoxide
catalyst in the addition of nitromethane to chalcones with
(3) Methods using chiral metal complexes: (a) Yamaguchi M.; Shiraishi,
T.; Igarashi, Y.; Hirama, M. Tetrahedron Lett. 1994, 35, 8233. (b)
Yamaguchi M.; Igarashi, Y.; Reddy, R. S.; Shiraishi, T.; Hirama, M.
Tetrahedron 1997, 53, 11223. (c) Keller, E.; Veldman, N.; Spek, A. L.;
Feringa, B. L. Tetrahedron: Asymmetry 1997, 8, 3403. (d) Funabashi, K.;
Saida, Y.; Kanai, M.; Arai, T.; Sasai, H.; Shibasaki, M. Tetrahedron Lett.
1998, 39, 7557.
(4) Methods using phase transfer catalysts: (a) Collona, S.; Hiemstra,
H.; Wynberg, H. J. Chem. Soc., Chem. Commun. 1978, 238. (b) Bako´, P.;
Szo¨ll_osy, A.; Bombicz, P.; T_oke. L. Synlett 1997, 291. (c) Corey, E. J.;
Zhang, F.-Y. Org. Lett. 2000, 2, 4257. (d) Kim, D. Y.; Huh, S. C.
Tetrahedron 2001, 57, 8933. (e) Sundararajan, G.; Prabagaran, N. Org. Lett.
2001, 3, 389.
(5) Methods using secondary amine- or guanidine-based organo-
catalysts: (a) Davis, A. P.; Dempsey, K. J. Tetrahedron: Asymmetry 1995,
6, 2829. (b) Hanessian, S.; Pham, V. Org. Lett. 2000, 2, 2975. (c) Halland,
N.; Hazell, R. G.; Jørgensen, K. A. J. Org. Chem. 2002, 67, 8331. (d)
Allingham, M. T.; Howard-Jones, A.; Murphy, P. J.; Thomas, D. A.;
Caulkett, P. W. R. Tetrahedron Lett. 2003, 44, 8677.
† Chemical Research Center of Hungarian Academy of Sciences.
‡ Eo¨tvo¨s Lora´nd University.
(1) Recent reviews dealing with enantioselective conjugate addition: (a)
Dalko, P. I.; Moisan, L. Angew. Chem., Int. Ed. 2004, 43, 5138. (b) Berner,
O. E.; Tedeschi, L.; Enders, D. Eur. J. Org. Chem. 2002, 1788. (c) Krause,
N.; Hoffmann-Ro¨der, A. Synthesis 2001, 171. (d) Sibi, M. P.; Manyem, S.
Tetrahedron 2000, 56, 8033.
(2) Recent review with extensive literature background: Ballini, R.;
Bosica, G.; Fiorini, D.; Palmieri, A.; Petrini, M. Chem. ReV. 2005, 105,
933.
10.1021/ol050431s CCC: $30.25
© 2005 American Chemical Society
Published on Web 04/14/2005

t
up to 97% ee; however, the presence of BuOH (1.2 or 2
equiv) and 20 mol % catalyst were required in order to
achieve efficient catalysis.3a
Table 1. Asymmetric 1,4-Addition of Nitromethane (1) to
trans-Chalcone (2a)a
entry
catalyst
time (h)
% yieldb
% eec,d
1
2
3
4
5
6
4a
4b
5a
5b
6
99
99
99
99
99
99
4
0
71
93
0
42 (S)
Herein, we report that new thiourea catalysts 5a,b and 7
efficiently promote the Michael reaction between nitro-
methane and chalcones with high levels of enantioselectivity.
Due to the privileged role in asymmetric organic synthesis,
we investigated the employment of cinchona alkaloid-based
catalysts in these Michael reactions.6 Wynberg and co-
workers demonstrated that natural cinchona alkaloids, with
a C-9 alcohol and a quinuclidine, could serve as bifunctional
chiral catalysts in Michael addition reactions by activating
the nucleophile and electrophile, respectively.7 However, the
natural cinchona-catalyzed addition of nitromethane (1) to
trans-chalcone (2a) (eq 1) proceeded smoothly only under
400 MPa pressure and resulted in only modest enantio-
selectivities.8
This result led us to conclude that the exploration of more
active bifunctional cinchona catalysts9 might be the key to
the development of more efficient catalytic processes.
Since the discovery of Etter and co-workers10 that diaryl
ureas readily form cocrystals with a variety of proton
acceptors, remarkable advances have been made in chiral
thiourea-catalyzed asymmetric reactions.11 These findings
prompted us to synthesize bifunctional thiourea derivatives
of cinchona alkaloids 5-7 capable of double-hydrogen
bonding Lewis activation (Figure 1) and apply them in the
95 (R)
96 (R)
7
59
86 (S)
a Reactions were carried out with 2a (5 mmol), 3 equiv of 1 (15 mmol)
in toluene (3 mL), and the catalyst indicated (4-7; 10 mol %) in capped
vials at 25 °C. b Yield of isolated product after chromatography. c Deter-
mined by HPLC using a Chiralpak AD column. d Absolute configuration
was determined by comparing the specific rotation of 3a with that of
literature data.13
These novel catalysts and their less acidic Lewis acid
precursor 4a and 4b were then studied for their ability to
mediate enantioselective 1,4-addition (Table 1). Quinine (4a)
turned out to be a poor catalyst, and epiquinine (4b) failed
to accelerate this transformation. However, the epithiourea
catalysts 5a and its pseudoenantiomer 7 afforded an espe-
cially promising result, which could be further improved by
using hydroquinine catalyst 5b. Surprisingly, the organo-
catalyst 6 with the natural configuration showed no actiVity
in this process. The change in the quinine-epiquinine
catalytic activity trend with the introduction of the stronger
Lewis acid thiourea moiety indicates that the proper con-
formation of the cinchona derivatives is crucial for successful
(6) Recent reviews on cinchona alkaloids: (a) Tian, S.-K.; Chen, Y.;
Hang, J.; Tang, L.; Deng, L. Acc. Chem. Res. 2004, 37, 621. (b) Kacprzak,
K.; Gawronski, J. Synthesis 2001, 961.
(7) Hiemstra, H.; Wynberg, H. J. Am. Chem. Soc. 1981, 103, 417.
(8) Sera, A.; Takagi, K.; Katayama, H.; Yamada, H. J. Org. Chem. 1988,
53, 1157.
(9) Other bifunctional cinchona alkaloid-based catalytic applications: (a)
France, S.; Shah, M. H.; Wheatherwax, A.; Wack, H.; Roth, J. P.; Lectka,
T. J. Am. Chem. Soc. 2005, 127, 1206. (b) Liu, X.; Li, H.; Deng, L. Org.
Lett. 2005, 7, 167. (c) Li, H.; Wang, Y.; Tang, L.; Wu, F.; Liu, X.; Guo,
C.; Foxman, B. M.; Deng, L. Angew. Chem., Int. Ed. 2004, 43, 2. (d) Li,
H.; Wang, Y.; Tang, L.; Wu, F.; Liu, X.; Guo, C.; Foxman, B. M.; Deng,
L. Angew. Chem., Int. Ed. 2004, 43, 105. (e) Li, H.; Wang, Y.; Tang, L.;
Deng L. J. Am. Chem. Soc. 2004, 126, 9906. (f) Saaby, S.; Bella, M.;
Jørgensen, K. A. J. Am. Chem. Soc. 2004, 126, 8120. (g) Kawahara, S.;
Nakano, A.; Esumi, T.; Iwabuchi, Y.; Hatakeyama, S. Org. Lett. 2003, 5,
3103. (h) Balan, D.; Adolfsson, H. Tetrahedron Lett. 2003, 44, 2521. (i)
Shi, M.; Xu, Y.-M. Angew. Chem., Int. Ed. 2002, 41, 4507.
(10) Etter, M. C. Acc. Chem. Res. 1990, 23, 120.
(11) Most recent papers using thiourea catalysts: (a) Berkessel, A.;
Cleemann, F.; Mukherjee, S.; Mu¨ller, T. N.; Lex, J. Angew. Chem., Int.
Ed. 2005, 44, 807. (b) Yoon, T. P.; Jacobsen, E. N. Angew. Chem., Int. Ed.
2005, 44, 466. (c) Okino, T.; Hoashi, Y.; Furukawa, T.; Xu, X.; Takemoto,
Y. J. Am. Chem. Soc. 2005, 127, 119. (d) Taylor, M. S.; Jacobsen, E. N. J.
Am. Chem. Soc. 2004, 126, 10558. (e) Joly, G. D.; Jacobsen, E. N. J. Am.
Chem. Soc. 2004, 126, 4102. (f) Taylor, M. S.; Jacobsen, E. N. J. Am.
Chem. Soc. 2004, 126, 119. (g) Okino, T.; Nakamura, S.; Furukawa, T.;
Takemoto, Y. Org. Lett. 2004, 6, 625. (h) Sohtome, Y.; Tanatani, A.;
Hashimoto, Y.; Nagasawa, K. Tetrahedron Lett. 2004, 45, 5589. (i). Okino,
T.; Hoashi, Y.; Takemoto, Y. J. Am. Chem. Soc. 2003, 125, 12672. (j)
Schreiner, P. R.; Wittkopp, A. Org. Lett. 2002, 4, 217.
Figure 1. Bifunctional cinchona organocatalysts 4-7.
conjugate addition of nitromethane (1) to trans-chalcone (2a)
(Table 1).
Catalysts 5-7 (Figure 1) were prepared from quinine (4a),
epiquinine (4b), and quinidine via experimentally simple two-
step protocols.12
(12) For details see Supporting Information.
(13) Botteghi, C.; Paganelli, S.; Schionato, A.; Boga, C.; Fava, A. J.
Mol. Catal. 1991, 66, 7.
1968
Org. Lett., Vol. 7, No. 10, 2005

catalysis. In conclusion, these experiments showed that the
quinuclidine part of the cinchona alkaloid itself is not able
to facilitate the Michael addition in the model reaction.
Furthermore, introduction of a more acidic thiourea moiety
was necessary to obtain efficient catalytic activity.
Table 3. Enantioselective Michael Reaction of Nitromethane
(1) with Chalcones 2b-e Using 5ba
Next, the influence of the three experimental parameters
(solvent, temperature, and catalyst load) was studied using
the most efficient catalyst 5b (Table 2). While variation of
entry
R1
R2
t (h)
% yieldb
% eec,d
1
2
3
4
2b
2c
2d
2e
p-Cl
p-F
o-Me
H
H
H
H
122
122
122
122
94
94
93
80
95 (R)d
98e
Table 2. Optimization of Reaction Conditions for Conjugate
Addition of 1 with 2a Using Catalyst 5ba
89e
p-MeO
96e
T
(°C)
catalyst load
(mol %)
t
(h)
%
yieldb
%
eec
a Reactions were carried out with 2b-e (5 mmol), 5 equiv of 1 (25
mmol), and catalyst 5b (10 mol %) in toluene (3 mL) in capped vials at 25
°C. b Yield of isolated product after chromatography. c Determined by HPLC
by using Chiralpak AD column. d Absolute configuration of 3b was
determined by comparing the specific rotation with that of literature data
(ref 4c). e Absolute configuration was not determined.
entry
solvent
1
2
3
4
5
6
7
8
9
toluene
CH2Cl2
THF
25
25
25
25
25
50
50
50
50
50
75
100
10
10
10
10
10
5
3
2
1
0.5
5
110
110
110
110
48
19
27
45
91
94
84
38
31
95
97
95
94
94
82
94
68d
96
93
95
67
94
91
91
92
93
94
90
85
MeOH
Experiments that probe the scope of the chalcone substrates
are summarized in Table 3. Chalcones 2b-e bearing
electron-withdrawing or electron-donating substituents un-
derwent clean reactions affording the desired product with
high enantioselectivities and yields. Notably, the adduct 3b
is the key intermediate of the Corey (R)-Baclofen synthesis,
and our protocol allows its synthesis with significantly higher
enantioselectivity.4c Therefore, cinchona-based thiourea bi-
functional catalysts 5a,b and 7 present new opportunities for
highly enantioselective synthesis of (R)-Baclofen and other
pharmaceutically important γ-amino acids.
10
11
12
171
10
5
5
a Reactions were carried out with 2a (5 mmol) and 3 equiv of 1 (15
mmol) in an appropriate solvent (3 mL) in capped vials. b Yield of product
isolated after silica gel chromatography. c Determined by HPLC by using
Chiralpak AD column. d Catalyst decomposed at this temperature.
In summary, the cinchona-based thiourea organocatalysts
were synthesized and found to promote highly enantio-
selective addition of nitromethane to chalcones. This envi-
ronmentally friendly procedure represents an advance with
regard to both enantioselectivity and practical simplicity.
Studies aimed at investigating the mechanism and scope of
these catalysts are underway and will be reported in due
course.
the solvents had a pronounced effect on reaction rate (entries
1 and 2 vs 3 and 4), excellent levels of enantioselectivity
were observed for a wide range of dielectric media. Most
notably, when the model reaction was performed in neat
nitromethane, a nearly complete conversion was achieved
in a much shorter time (entry 5). Using this simplified
reaction condition, variation of the catalyst load and reaction
temperature was evaluated. Remarkably, a catalyst load as
low as 0.5 mol % can be utilized without significant loss in
enantiocontrol (entry 10). As might be expected, a much
shorter reaction time was observed at higher temperature:
however, epicinchona catalyst 5b was able to maintain the
high level of enantioselectivities (entries 11 and 12) even at
100 °C. In addition to the excellent enantioselectivities and
chemical yields, it is noteworthy that this metal-free catalytic
reaction has several advantages of practical importance: it
proceeds at ambient temperature with no additive (such as
cosolvent, base, or molecular sieves) required, and these
experiments can be conducted in technical grade solvents in
capped vials but with otherwise no effort to exclude oxygen
and moisture.
Acknowledgment. We thank Ubichem Research, Ltd.,
for financial support. T.S. thanks Bolyai Foundation for an
award. Grants 1/A/005/2004 NKFP MediChemBats2 and
QLK2-CT-2002-90436 are gratefully acknowledged. We
gratefully thank AÄ gnes Go¨mo¨ry for running HRMS experi-
ments.
Supporting Information Available: Complete experi-
mental procedures and characterization of novel compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL050431S
Org. Lett., Vol. 7, No. 10, 2005
1969