Highly enantioselective direct Michael addition of nitroalkanes to nitroalkenes catalyzed by amine thiourea bearing multiple hydrogen-bonding donors

Article abstract of DOI:10.1021/ol900025b

A highly diastereoselective and enantioselective Michael addition of nitroalkanes to nitroalkenes has been achieved by chiral bifunctional amine-thiourea catalyst bearing multiple hydrogen-bonding donors. This catalytic system performs well over a broad s

Full text of DOI:10.1021/ol900025b

ORGANIC
LETTERS
2009
Vol. 11, No. 6
1265-1268
Highly Enantioselective Direct Michael
Addition of Nitroalkanes to Nitroalkenes
Catalyzed by Amine-Thiourea Bearing
Multiple Hydrogen-Bonding Donors
Xiu-Qin Dong, Huai-Long Teng, and Chun-Jiang Wang*,†,‡
College of Chemistry and Molecular Sciences, Wuhan UniVersity, Hubei 430072,
China, and State Key Laboratory of Elemento-organic Chemistry, Nankai UniVersity,
Tianjin 300071, China
cjwang@whu.edu.cn
Received January 7, 2009
ABSTRACT
A highly diastereoselective and enantioselective Michael addition of nitroalkanes to nitroalkenes has been achieved by chiral bifunctional
amine-thiourea catalyst bearing multiple hydrogen-bonding donors. This catalytic system performs well over a broad scope of substrates,
furnishing various 1,3-dinitro compounds in high diastereoselectivity (up to 98:2) and excellent enantioselectivity (up to 99% ee) under mild
conditions. Multiple hydrogen bonding donors play a significant role in accelerating reactions, improving diastereoselectivities and
enantioselectivities.
The conjugate addition of stabilized carbanions to electron-
deficient R,ꢀ-unsaturated compounds is one of the funda-
mental carbon-carbon bond-forming reactions in organic
synthesis and offers an extremely powerful tool for the
synthesis of highly functionalized organic molecules.1-3 The
asymmetric addition using various nitroalkanes as excellent
Michael donors4 or nitroalkenes as prominent Michael
acceptors5 has been extensively investigated due to the strong
electron-withdrawing property of the nitro group and its facile
transformations to highly valuable nitro-containing building
blocks.6 However, only three studies7 existed on the catalytic
asymmetric direct Michael addition of nitroalkanes to ni-
troalkenes for a limited substrate scope despite the fact that
the generated 1,3-dinitro compounds bearing two contiguous
stereogeneric centers can be readily converted to chiral 1,3-
diamines, which are of great importance and synthetic
potential.8 This problem is partially due to extreme difficulty
of suppressing the unfavored subsequent oligomerization to
achieve high chemoselectivity and enantio-/diastereo-
(2) For recent reviews of asymmetric Michael addition reactions, see:
(a) Tomioka, K.; Nagaoka, Y.; Yamaguchi, M. In ComprehensiVe Asym-
metric Catalysis; Jacobsen, E. N., Pfaltz, A., YamamotoH., Eds.; Springer:
New York, 1999. (b) Krause, N.; Hoffmann-Ro¨der, A. Synthesis 2001, 171.
(c) Berner, O. M.; Tedeschi, L.; Enders, D. Eur. J. Org. Chem. 2002, 1877.
(d) Christoffers, J.; Baro, A. Angew. Chem., Int. Ed. 2003, 42, 1688. (e)
Sibi, M.; Manyem, S. Tetrahedron 2001, 5, 6–8033.
(3) For recent reviews of organocatalytic asymmetric Michael addition,
see: (a) Almasi AlmaC¸ si, D.; Alonso, D. A.; Na´jera, C. Tetrahedron:
Asymmetry 2007, 18, 299. (b) Tsogoeva, S. B. Eur. J. Org. Chem. 2007,
1701. (c) Dalko, P. I.; Moisan, L. Angew. Chem., Int. Ed. 2001, 40, 3726.
(d) Berner, O. M.; Tedeschi, L.; Enders, D. Eur. J. Org. Chem. 2002, 1877.
(e) Christoffers, J.; Baro, A. Angew. Chem., Int. Ed. 2003, 42, 1688.
† Wuhan University.
‡ Nankai University.
(1) Perlmutter, P. Conjugate Addition Reactions in Organic Synthesis;
Pergamon: Oxford, 1992
.
10.1021/ol900025b CCC: $40.75
Published on Web 02/16/2009
2009 American Chemical Society

selectivity.7b Two chiral metal complex catalyzed asymmetric
Michael additions of nitroalkanes to nitroalkenes have been
reported by Du using Zn(II)/bis(oxazoline) or bis(thiozoline)9
and Feng using La(III)/N,N′-dioxide complexes,10 respec-
tively. Wang’s seminal work showed that organocatalysis
also provides a possible approach to this challenging reaction
despite the lower reactivity of the cinchona alkaloid catalysts
employed.11 Despite these important contributions, the direct
asymmetric Michael addition of nitroalkanes to nitroalkenes
is still in its infancy and the development of a new and
efficient catalytic system showing high reactivity and enan-
tio-/diastereoselectivity for a broad scope of substrates is still
in great demand. Herein, we report a highly syn-selective
(up to 98:2) and excellent enantioselective (up to 99% ee)
Michael addition of nitroalkanes to nitroalkenes catalyzed
by bifunctional amine-thiourea bearing multiple hydrogen-
bonding donors (Figure 1).12,13
results are summarized in Table 1. It is noteworthy that only
2.3:1 syn-selectivity and 74% enantioselectivity were achieved
for 3a by using the modified cinchona alkaloid organocatalyst
in 6 days.7a,11 To our delight, the reaction was finished in
8-12 h at room temperature with those fine-tunable orga-
nocatalysts 1a-d, and 1d was revealed as the best catalyst
in terms of diastereoselectivity and enantioselectivity (Table
1, entries 1-4). This finding is in agreement with our recently
developed amine-thiourea-catalyzed nitro-Mannich reaction
and Michael addition reaction.12 No addition product was
observed when using methylated 1e as the catalyst, which
further indicates that the multiple hydrogen bonding donors
play a significant role in this efficient system (Table 1, entry
5). A study of reaction with 1d in various solvents identified
PhMe and ether as suitable alternatives to DCM (Table 1,
entries 6-12). Interestingly, this Michael addition reaction
could also be carried out under neat conditions affording 78:
22 dr and 89% ee (Table 1, entry 13). Reducing the
temperature to -30 °C in DCM led to full conversion with
98:2 diastereoselectivity and 97% ee for the major syn-
diastereomer within 16 h (Table 1, entry 14). A comparable
result (96:4 dr and 97% ee) was still achieved even when
catalyst loading was reduced to 5 mol % (Table 1, entry
15). The current catalysis demonstrated significant improve-
ments over the previous reported catalytic systems that gave
lower diastereo-/enantioselectivity or required longer reaction
time (2-6 d).7a,9-11
The asymmetric Michael addition of nitroethane 3a to
various nitroolefins 2 in the presence of organocatalyst 1d
was investigated under the optimized experimental condi-
tions. As shown in Table 2, a wide array of aromatic
nitroolefins 2a-j, which bear electron-rich, electron-neutral,
or electron-withdrawing groups, reacted smoothly with
nitroethane 3a to afford the corresponding product 4aa-ja
in good yields and with high levels of diastereoselectivity
(84:16-98:2) and enantioselectivity (94-99% ee) (Table 2,
entries 1-10). It appears that the position and the electronic
Figure 1. Amine-thioureas bearing multiple hydrogen-bonding
donors.
Our initial investigation began with the reaction of
nitroethane 3a with nitroolefin 2a, and the representative
(7) During the preparation of this paper, Wulff et al. presented the direct
asymmetric Michael addition of nitropropane or nitrobutane to aromatic
nitroalkenes with bifunctional DMAP-thiourea catalyst; however, only 57:
43 diastereoselectivity and 62% ee was achieved for nitroethane. See: (a)
Rabalakos, C.; Wulff, W. D. J. Am. Chem. Soc. 2008, 130, 5452. Maruoka
et al. reported that N-spiro chiral ammonium bifluorides catalyzed indirect
Michael addition with performed silyl nitronates; see: (b) Ooi, T.; Takada,
S.; Doda, K.; Maruoka, K Angew. Chem., Int. Ed. 2006, 45, 7606.
(8) (a) Escribano, F. C.; Alca´ntara, M. D.; Gomez-Sa´nchez, A. Tetra-
hedron Lett. 1988, 29, 6001. (b) Axenrod, T.; Watnick, C.; Yazdekhasti,
H.; Dave, P. R. J. Org. Chem. 1995, 60, 1959. (c) Marchand, A. P.;
Rajagopal, D.; Bott, S. G.; Archibold, T. G. J. Org. Chem. 1995, 60, 4943.
(d) Wade, P. A.; Dailey, W. P.; Carroll, P. J. J. Am. Chem. Soc. 1987, 109,
5452.
(9) Lu, S. F.; Du, D. M.; Xu, J.; Zhang, S. W. J. Am. Chem. Soc. 2006,
128, 7418.
(10) Yang, X.; Zhou, X.; Lin, L.; Chang, L.; Liu, X.; Feng, X. Angew.
Chem., Int. Ed. 2008, 47, 7079.
(11) Wang, J.; Li, H.; Zu, L.; Jiang, W.; Wang, W. AdV. Synth. Catal.
2006, 348, 2047.
(12) (a) Wang, C.-J.; Zhang, Z.-H.; Dong, X.-Q.; Wu, X.-J. Chem.
Commun. 2008, 1431. (b) Wang, C.-J.; Dong, X.-Q.; Zhang, Z.-H.; Xue,
Z.-Y.; Teng, H.-L. J. Am. Chem. Soc. 2008, 130, 8606. (c) Zhang, Z.-H.;
Dong, X.-Q.; Chen, D.; Wang, C.-J. Chem.sEur. J. 2008, 14, 8780.
(13) For other kind of organocatalysts having multiple hydrogen-bonding
donors, see:(a) Herrera, R. P.; Sgarzani, V.; Bernardi, L.; Ricci, A. Angew.
Chem., Int. Ed. 2005, 44, 6576. (b) Sohtome, Y.; Tanatani, A.; Hashimoto,
Y.; Nagasawa, K. Tetrahedron Lett. 2004, 45, 5589. (c) Berkessel, A.;
Roland, K.; Neudorfl, J. M. Org. Lett. 2006, 8, 4195.
(4) (a) Ballini, R.; Bosica, G.; Fiorini, D.; Palmieri, A.; Petrini, M. Chem.
ReV. 2005, 105, 933. (b) Dalko, P. I.; Moisan, L. Angew. Chem., Int. Ed.
2004, 4, 3–5138.
(5) (a) Li, H.; Wang, Y.; Tang, L.; Wu, F.; Liu, X.; Guo, C.; Foxman,
B. M.; Deng, L. Angew. Chem., Int. Ed. 2005, 44, 105. (b) Li, H.; Wang,
Y.; Tang, L.; Deng, L. J. Am. Chem. Soc. 2004, 126, 9906. (c) Tsogoeva,
S.; Wei, B.; S. Chem. Commun. 2006, 1451. (d) Huang, H.; Jacobsen, E. N.
J. Am. Chem. Soc. 2006, 128, 7170. (e) Yalalov, D. A.; Tsogoeva, S. B.;
Schmatz, S. AdV. Synth. Catal. 2006, 348, 826. (f) Lalonde, M. P.; Chen,
Y.; Jacobsen, E. N. Angew. Chem., Int. Ed. 2006, 45, 6366. (g) Wei, S.;
Yalalov, D. A.; Tsogoeva, S. B.; Schmatz, S. Catal. Today 2007, 121, 151.
(h) McCooey, S. H.; Connon, S. J. Angew. Chem., Int. Ed. 2005, 44, 6367.
(i) Ye, J.; Dixon, D. J.; Hynes, P. S. Chem. Commun. 2005, 4481. (j) Okino,
T.; Hoashi, Y.; Takemoto, Y. J. Am. Chem. Soc. 2003, 125, 12672. (k)
Okino, T.; Hoashi, Y.; Furukawa, T.; Xu, X.; Takemoto, Y. J. Am. Chem.
Soc. 2005, 127, 119. (l) Lubkoll, J.; Wennemers, H. Angew. Chem., Int.
Ed. 2007, 46, 6841. (m) Dixon, D. J.; R. Richardson, D Synlett 2006, 81.
(n) Liu, Y.-K.; Liu, H.; Du, W.; Yue, L.; Chen, Y.-C. Chem.sEur. J. 2008,
14, 9873. (o) Xue, D.; Chen, Y.-C.; Wang, Q.-W.; Cun, L.-F.; Zhu, J.;
Deng, J.-G. Org. Lett. 2005, 7, 5293. (p) Cao, Y.-J.; Lu, H.-H.; Lai, Y.-Y.;
Lu, L.-Q.; Xiao, W.-J. Synthesis 2006, 3795. (q) Cao, Y.-J.; Lai, Y.-Y.;
Wang, X.; Li, Y.-J.; Xiao, W.-J. Tetrahedron Lett. 2007, 48, 21.
(6) (a) Ono, N. The Nitro Group in Organic Synthesis; Wiley-VCH:
New York, 2001. For a recent example of facile transformations of optically
active organonitro compounds, see: (b) Czekelius, C.; Carreira, E. M. Angew.
Chem., Int. Ed. 2005, 44, 612.
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Org. Lett., Vol. 11, No. 6, 2009

Table 1. Screening Studies of Organocatalytic Asymmetric Michael Addition Reaction of Nitroalkane 3a to Nitroalkene 2aa
entry
catalyst
x (mol %)
solvent
T (°C)
t (h)
yieldb (%)
syn/antic
eed,e (%)
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1d
1d
1d
1d
1d
1d
1d
1d
1d
1d
10
10
10
10
10
10
10
10
10
10
10
10
10
10
5
DCM
DCM
DCM
DCM
DCM
DCM
Et2O
acetone
PhMe
CH3Cl
EtOAc
MeCN
EtNO2
DCM
DCM
rt
rt
rt
rt
rt
0
0
0
0
0
0
0
0
-30
-30
12
12
11
8
89
84
85
87
66:24
73:27
78:22
73:27
26
73
79
83
12
24
14
15
10
12
15
13
16
24
91
89
88
85
89
85
92
88
87
81
83:17
86:14
88:12
84:16
80:20
73:27
80:20
78:22
98:2
93
89
83
91
80
81
77
89
97
97
9
10
11
12
13
14
15
96:4
a Unless otherwise noted, the reactions was carried out with 0.15 mmol of 2a, 0.6 mmol of 3a in 0.6 mL of solvent. b Isolated yield. c Syn/anti ratio was
determined by HPLC analysis except entries 1-4 which were calculated from the isolated two diastereomers. d Determined by chiral HPLC analysis. e The
configuration of 4aa was determined to be (2R,3R) by comparing the optical rotation with that of the reported data.
Table 2. Asymmetric Direct Michael Addition Reaction of Nitroalkanes 3 to Nitroalkenes 2 Using Oganocatalyst 1da
3
entry
R
R1
R2
Prod
yieldb (%)
drc syn/anti
eed (%)
1
2
3
4
5
6
7
8
Ph (2a)
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
H (3a)
H (3a)
H (3a)
H (3a)
H (3a
4aa
4ba
4ca
4da
4ea
4fa
4ga
4ha
4ia
4ja
4ka
4la
4ma
4ab
4bb
4cb
4fb
4ac
4ad
87
89
92
91
89
87
83
92
90
91
85
88
60
92
89
90
88
89
88
98:2
92:8
91:9
91:9
93:7
93:7
88:12
84:16
85:15
91:9
80:20
82:18
55:45
95:5
97:3
95:5
96:4
96:4
-
97
97
98
94
96
95
96
99
95
97
92
89
80e
96
99
94
93
95
64f
p-Me-Ph (2b)
o-Me-Ph (2c)
p-MeO-Ph (2d)
m-MeO-Ph (2e)
o-Cl-Ph (2f)
m-Cl-Ph (2g)
2,4-Cl2C8H3 (2h)
p-F-Ph (2i)
1-Naphthyl (2j)
2-Furyl (2k)
Cinnamyl (2l)
iPr (2m)
H (3a)
H (3a
H (3a)
H (3a)
H (3a)
H (3a)
H (3a)
H (3a)
H (3b)
H (3b)
H (3b)
H (3b)
H (3c)
Me (3d)
9
10
11
12
13
14
15
16
17
18
19
Ph(2a)
p-Me-Ph (2b)
o-MeO-Ph (2c)
o-Cl-Ph(2f)
Ph (2a)
Ph (2a)
Et
Et
Et
Bn
Me
a Unless otherwise noted, the reactions was carried out with 0.15 mmol of 2 and 0.6 mmol of 3 in 0.6 mL of solvent. b Isolated yield. c Syn/anti ratio
was determined by HPLC analysis. d Determined by chiral HPLC analysis. e In 48 h. f The reaction was carried out at rt in 20 h without solvent.
property of the substituents on the aromatic rings have a very
limited effect on the enantioselectivities. Heteroaromatic
system 2k was also a viable substrate as R,ꢀ-unsaturated
nitroolefin 2l (Table 2, entries 11 and 12). The relatively
challenging aliphatic nitroolefin 2m also worked in this
catalytic system and gave rise to the product in good
enantioselectivity albeit lower diastereoselectivity (Table 2,
entry 13). The potential of this catalytic approach is further
Org. Lett., Vol. 11, No. 6, 2009
1267

demonstrated by the reaction of other nitroalkanes (3b and
3c) with nitroolefins to afford the corresponding products in
high diastereoselectivities (95:5-97:3) and excellent enan-
tioselectivities (93-99% ee) for the major syn diastereomer
(Table 2, entries 14-18). Noticeably, the sterically hindered
2-nitropropane 3d was also able to undergo the Michael
addition affording the product in 88% yield with 64% ee in
20 h (Table 2, entry 19).14 To the best of our knowledge,
this is the best result for asymmetric direct Michael addition
of nitroalkanes to nitroalkenes reported so far in terms of
reaction rate, enantio-/diastereoselectivity, and substrate
scope.
bearing multiple hydrogen-bonding donors. This catalytic
system performs well over a broad scope of substrates,
furnishing various 1,3-dinitro compounds in high diastereo-
selectivity (up to 98:2) and excellent enantioselectivity (up
to 99% ee) under mild conditions. The mechanistic origin
of the high enantiocontrol and future application of this
methodology are ongoing in our laboratory.
Acknowledgment. We are grateful for the financial
support from National Natural Science Foundation of China
and the startup fund from Wuhan University.
In conclusion, we have described a highly efficient
organocatalyzed direct Michael addition of nitroalkanes to
nitroalkenes by chiral bifunctional amine-thiourea catalyst
Supporting Information Available: Experimental pro-
cedures and compound characterization data. This material
is available free of charge via the Internet at http://pubs.acs.org.
(14) Only one protocol has been reported to achieve moderate yield and
enantioselectivity for this branched substrate in 6 days; see ref 11.
OL900025B
1268
Org. Lett., Vol. 11, No. 6, 2009