Enantioselective conjugate addition of nitroalkanes to vinyl sulfone: An organocatalytic access to chiral amines

Article abstract of DOI:10.1021/ol9003349

Organocatalytic asymmetric conjugate addition of nitroalkanes to vinyl sulfone mediated by cinchona alkaloid-derived thiourea catalyst afforded the desired Michael product with good enantioselectivity. The described method, in combination with ready desul

Full text of DOI:10.1021/ol9003349

ORGANIC
LETTERS
2009
Vol. 11, No. 8
1721-1724
Enantioselective Conjugate Addition of
Nitroalkanes to Vinyl Sulfone: An
Organocatalytic Access to Chiral
Amines
Qiang Zhu and Yixin Lu*
Department of Chemistry & Medicinal Chemistry Program, Life Sciences Institute,
National UniVersity of Singapore, 3 Science DriVe 3, Republic of Singapore, 117543
chmlyx@nus.edu.sg
Received February 15, 2009
ABSTRACT
Organocatalytic asymmetric conjugate addition of nitroalkanes to vinyl sulfone mediated by cinchona alkaloid-derived thiourea catalyst afforded
the desired Michael product with good enantioselectivity. The described method, in combination with ready desulfonation, represents a novel
approach to access r-alkylated chiral amines.
The catalytic asymmetric Michael addition is one of the
most powerful carbon-carbon bond-forming reactions,
and remarkable progress has been made in organocatalytic
Michael additions in recent years.1 Nitroalkanes are
versatile donors, and their Michael adducts have been
demonstrated to be valuable intermediates in organic
synthesis. The conjugate additions of nitroalkanes to
imines,2 nitrostyrenes,3 and R,ꢀ-unsaturated carbonyl
compounds4 are well documented in the literature and
shown to be extremly useful in accessing a wide range of
chiral structural scaffolds. Vinyl sulfones, on the other
hand, are less-explored acceptors in the asymmetric
Michael reactions.5 D’Angelo et al. reported stereoselec-
tive addition of imines derived from cyclic ketones and
(3) (a) Lu, S.-F.; Du, D.-M.; Xu, J.; Zhang, S.-W. J. Am. Chem. Soc.
2006, 128, 7418. (b) Wang, J.; Li, H.; Zu, L.; Jiang, W.; Wang, W. AdV.
Synth. Catal. 2006, 348, 2047.
(4) For the enantioselective addition of nitroalkanes to R,ꢀ-unsaturated
ketones, see: (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) Hanessian,
S.; Pham, V. Org. Lett. 2000, 2, 2975. (d) Halland, N.; Hazell, R. G.;
Jorgensen, K. A. J. Org. Chem. 2002, 67, 8331. (e) Prieto, A.; Halland, N.;
Jorgenson, K. A. Org. Lett. 2005, 7, 3897. For the enantioselective addition
of nitroalkanes to R,ꢀ-unsaturated aldehydes, see: (f) Hojabri, L.; Hartikka,
A.; Moghaddam, F. M.; Arvidsson, P. I. AdV. Synth. Catal. 2007, 349, 740.
(g) Wang, Y.; Li, P.; Liang, X.; Zhang, T. Y.; Ye, J. Chem. Commun. 2008,
1232.
(1) For recent reviews on organocatalytic conjugate additions, see: (a)
Almasi, D.; Alonso, D. A.; Najera, C. Tetrahedron: Asymmetry 2007, 18,
299. (b) Tsogoeva, S. B. Eur. J. Org. Chem. 2007, 1701. (c) Sulzer-Mosse,
S.; Alexakis, A. Chem. Commun. 2007, 3123.
(2) (a) Robak, M. T.; Trincado, M.; Ellman, J. A. J. Am. Chem. Soc.
2007, 129, 15110. (b) Yoon, T. P.; Jacobsen, E. N. Angew. Chem., Int. Ed.
2005, 44, 466. (c) Palomo, C.; Oiarbide, M.; Halder, R.; Laso, A.; Lopez,
R. Angew. Chem., Int. Ed. 2006, 45, 117. (d) Wang, C.; Zhou, Z.; Tang, C.
Org. Lett. 2008, 10, 1707. (e) Okino, T.; Nakamura, S.; Furukawa, T.;
Takemoto, Y. Org. Lett. 2004, 6, 625. (f) Xu, X.; Furukawa, T.; Okino, T.;
Miyabe, H.; Takemoto, Y. Chem.sEur. J. 2006, 12, 466.
(5) For the early reports on nonstereoselective Michael addition of
ketones to vinyl sulfone, see: (a) Risaliti, A.; Fatutta, S.; Forchiassin, M.
Tetrahedron 1967, 23, 1451. (b) Benedetti, F.; Fabrissin, S.; Risaliti, A.
Tetrahedron 1984, 40, 977. (c) Lucchi, O. D.; Pasquato, L.; Modena,
G. Tetrahedron Lett. 1984, 25, 3643.
10.1021/ol9003349 CCC: $40.75
Published on Web 03/24/2009
2009 American Chemical Society

chiral 1-phenyethylamine to vinyl sulfones.6 Recently,
Deng and co-workers described the construction of all-
carbon quaternary stereocenters based on a cinchona
alkaloid-catalyzed addition of substituted cyanoacetates
to vinyl sulfones.7 The group of Alexakis was the first to
disclose an organocatalytic Michael addition of aldehydes
to vinyl sulfones mediated by their N-iPr-2,2′-bipyrrolidine
catalyst.8 Very recently, our group reported highly enan-
tioselective organocatalytic Michael addition of aldehydes
to various vinyl sulfones by employing prolinol silyl ether
catalyst.9 Subsequently, we applied a cinchona alkaloid-
derived primary amine to achieve the first organocatalytic
enantioselective conjugate addition of cyclic ketones to
vinyl sulfone.10 The utilization of hydrogen bonding
interactions has become a popular approach in asymmetric
catalysis in recent years. In particular, thiourea-based
organocatalysts have found wide applications in a huge
number of organic reactions.11 To the best of our
knowledge, the asymmetric Michael addition of nitroal-
kanes to vinyl sulfone is unknown in the literature. We
hypothesized that bifunctional catalysts containing a
suitable hydrogen bond donor and tertiary amine moiety
should be able to activate nitroalkane and facilitate their
conjugate addition to vinyl sulfone, and enantioselective
addition may be feasible with the careful selection of chiral
structural scaffolds (Figure 1). Herein, we wish to
on the conjugate addition of nitrohexane 1 to vinyl sulfone
2 (Table 1).12 Quinidine 4 catalyzed the reaction with low
Table 1. Screening of Organocatalysts for the Conjugate
Addition of Nitrohexane to Vinyl Sulfonea
entry catalyst
solvent
temp (°C) yieldb (%) eec (%)
1
2
3
4
5
6
7
8
4
5
6
7
8
9
6
6
6
6
6
6
6
6
6
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
CHCl3
CH2Cl2
CH3CN
THF
MeOH
Dioxane
Et2O
Acetone
Toluene
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
-10
91
<10
92
85
87
85
81
83
86
61
73
<30
82
75
87
40
-
76
70
54
47
70
61
40
43
44
-
9
10
11
12
13
14
15
63
45
86
Figure 1. Working hypothesis.
a The reactions were performed with nitrohexane (0.3 mmol), vinyl
sulfone (0.05 mmol), and catalyst (0.01 mmol) in anhydrous solvent (0.5
mL) at indicated temperature, unless otherwise specified. For the determi-
nation of absolute configuration, see Supporting Information. b Isolated yield.
c The ee value was determined by chiral HPLC analysis.
communicate our investigation on the first example of
asymmetric organocatalytic addition of nitroalkanes to
vinyl sulfone.
For the initial exploration, we examined the catalyic effects
of a number of cinchona alkaloid-based bifunctional catalysts
enantioselectivity (entry 1). Quinidine-derived sulfonamide,
which promoted enantioselective Michael addition of bicyclic
R-substituted ꢀ-ketoesters to nitroolefins,13 was found to be
completely ineffective (entry 2). Various quinidine-derived
thiourea-containing bifunctional catalysts were shown to be
good catalysts (entries 3-6). Among the thioureas tested, 6
was most efficient, yielding the desired product with 76%
ee at room temperature. Solvent screening revealed that
toluene was the best solvent (entries 7-14). By lowering
the reaction temperature to -10 °C, we were able to obtain
the desired adduct in excellent yield and with 86% ee (entry
15).
(6) (a) Pinheiro, S.; Guingant, A.; Desmae¨le, D.; d’Angelo, J. Tetrahe-
dron: Asymmetry 1992, 3, 1003. (b) Desmae¨le, D.; Delarue-Cochin, S.; Cave,
C.; d’Angelo, J.; Morgant, G. Org. Lett. 2004, 6, 2421.
(7) Li, H.; Song, J.; Liu, X.; Deng, L. J. Am. Chem. Soc. 2005, 127,
8948.
(8) Mosse, S.; Alexakis, A. Org. Lett. 2005, 7, 4361.
(9) Zhu, Q.; Lu, Y. Org. Lett. 2008, 10, 4803.
(10) Zhu, Q.; Cheng, L.; Lu, Y. Chem. Commun. 2008, 6315.
(11) For recent reviews on thiourea catalysts, see: (a) Doyle, A. G.;
Jacobsen, E. N. Chem. ReV. 2007, 107, 5713. (b) Connon, S. J. Chem.
Commun. 2008, 2499. For selected examples of thiourea-containing
bifunctional catalysts, see: (c) Huang, H.; Jacobsen, E. N. J. Am. Chem.
Soc. 2006, 128, 7170. (d) Lalonde, M. P.; Chen, Y.; Jacobsen, E. N. Angew.
Chem., Int. Ed. 2006, 45, 6366. (e) Okino, T.; Hoashi, Y.; Takemoto, Y.
J. Am. Chem. Soc. 2003, 125, 12672. (f) Wang, J.; Li, H.; Yu, X.; Zu, L.;
Wang, W. Org. Lett. 2005, 7, 4293. (g) Li, B.-J.; Jiang, L.; Liu, M.; Chen,
Y.-C.; Ding, L.-S.; Wu, Y. Synlett 2005, 603. (h) Vakulya, B.; Varga, S.;
Csampai, A.; Soos, T. Org. Lett. 2005, 7, 1967. (i) McCooey, S. H.; Connon,
S. J. Angew. Chem., Int. Ed. 2005, 44, 6367. (j) Ye, J.; Dixon, D. J.; Hynes,
P. S. Chem. Commun. 2005, 4481.
(12) The conjugate addition using vinylsulfonylbenzene as the acceptor
did not yield any desired product under the same reaction conditions.
(13) Luo, J.; Xu, L.-W.; Hay, A. S. Robyn; Lu, Y. Org. Lett. 2009, 11,
437.
1722
Org. Lett., Vol. 11, No. 8, 2009

The optimized conditions were applied to various nitroal-
kanes to establish the scope of the reactions (Table 2). The
The adducts of conjugate addition of nitroalkanes to vinyl
sulfone are very useful intermediates in organic synthesis.
In particular, the reduction of a nitro group to an amino
function, in combination with ready desulfonation, provides
an easy access to chiral amines.15 To demonstrate the
synthetic application of our methodology, we prepared
1,2,3,4-tetrahydroisoquinoline, which is a potent inhibitor of
phenylethanolamine N-methyltransferase.16 As shown in
Scheme 1, the Michael addition of 1-(2-nitroethyl)benzene
Table 2. Conjugate Addition of Various Nitroalkanes to Vinyl
Sulfone 2 Catalyzed by Thiourea 6
Scheme 1. Conversion of the Michael Adduct to
(R)-1,2,3,4-Tetrahydroisoquinoline
10g to vinyl sulfone 2 yielded chiral sulfone 11g with 74%
ee. The reduction of the nitro group with zinc in acetic acid
afforded chiral amine 12, which was protected with Cbz.
The subsequent desulfonation17 proceeded smoothly to give
intermediate 13, which was then converted into known
intermediate 14, the transformation of which to 1,2,3,4-
tetrahydroisoquinoline was well-established in the literature.16
To account for the observed stereochemical outcome of
the reaction, we propose a transition state model as depicted
in Figure 2. The N-H groups of the thiourea moiety in the
a The reactions were performed with nitroalkane (0.3 mmol), vinyl
sulfone (0.05 mmol), and catalyst (0.01 mmol) in anhydrous toluene (0.5
mL) at -10 °C. b Isolated yield. c The ee value was determined by chiral
HPLC analysis.
Figure 2. Proposed transition state model.
catalyst are belived to form hydrogen bonding interacions
with the nitro group in the substrate to increase the acidity
of the R-hydrogen, and the approach of nitroalkanes from
its Si face to vinyl sulfone leads to the formation of the major
stereoisomers.
conjugate addition of unbranched nitroalkanes proceeded
smoothly, affording the desired products in high yield and
with high enantioselectivity. However, R-substituted nitroal-
kanes and 2-aryl-substituted vinyl sulfones were found to
be unsuitable for the conjugate additions.14
In conclusion, we have disclosed the first organocatalytic
enantioselective conjugate addition of nitroalkanes to vinyl
(14) When 2-nitropropyl benzene was treated with vinyl sulfone 2 in
the presence of 6 at room temperature for 48 h, no product was formed.
2-Phenyl vinyl sulfone decomposed under the reaction conditions.
(15) For a recent review on enantioselective synthesis of R-branched
amines, see: Brase, S.; Baumann, T.; Dahmen, S.; Vogt, H. Chem. Commun.
2007, 1881.
Org. Lett., Vol. 11, No. 8, 2009
1723

sulfone promoted by a quinidine-derived thiourea catalyst.
The described asymmetric conjugate addition, together with
facile reduction and desulfonation, represents a novel ap-
proach to access R-branched chiral amines. Further extension
to include a broader scope of nitroalkanes and to improve
the enantioselectivity of such reactions is in progress in our
laboratory and will be reported in due course.
Supporting Information Available: Representative ex-
perimental procedure for Michael addition to vinyl sulfone,
procedures to convert the Michael adduct into tetrahydroiso-
quinoline, determination of absolute configurations, HPLC
chromatogram, analytical data, and NMR spectra of the
conjugate addition products. This material is available free
of charge via the Internet at http://pubs.acs.org.
OL9003349
Acknowledgment. We wish to thank the National Uni-
versity of Singapore and the Ministry of Education (MOE)
of Singapore (R-143-000-362-112) for generous financial
support.
(16) Grunewald, G. L.; Sall, D. J.; Monn, J. A. J. Med. Chem. 1988,
31, 824.
(17) (a) Najera, C.; Yus, M. Tetrahedron 1999, 55, 10547. (b) Kundig,
E. P.; Cunningham, A. F., Jr. Tetrahedron 1988, 44, 6855.
1724
Org. Lett., Vol. 11, No. 8, 2009