sioned that an appropriate combination of urea (thiourea)
and pyrrolidine in a chiral scaffold could result in a potential
bifunctional organocatalyst. Therefore, we designed two
pyrrolidine-urea based catalysts 2a and 2b as shown in
Scheme 1 and found that both of them were excellent for
We were pleased to find that the newly designed pyr-
rolidine-ureas 2a and 2b, which were easily prepared from
L-proline as shown in Scheme 1,12 catalyzed the reaction of
cyclohexanone with both alkyl- and arylnitroolefins smoothly
in good to high yields with high diastereoselectivities and
excellent enantioselectivities.
Initially, various solvents and additives were examined at
room temperature using 2a as a catalyst and trans-nitroolefin
4a as a substrate. As shown in Table 1, in polar solvents
Scheme 1. Synthesis of 2a and 2b
Table 1. Effects of Solvents and Additives on the Reaction of
Cyclohexanone to trans-Nitrostyrenea
catalyzing the asymmetric Michael addition of cyclohex-
anone to nitroolefins.6-11 In this paper, we report the
preliminary results.
The organocatalytic asymmetric Michael addition of
ketone with nitroolefins was pioneered by List and Barbas,
independently.7h,8 Since then, Barbas,7h,i,9 Alexakis,10 and
Kotsuki11 have shown that aminomethylpyrrolidine, 2,2′-
bipyrrolidine, and pyrrolidine-pyridine derivatives could
serve as powerful asymmetric catalysts for such a Michael
addition. In these cases, high diastereoselectivities and
enantioselectivities were achieved. Very recently, Wang
reported the reactions of aldehydes with nitroolefins catalyzed
by pyrrolidine sulfonamide with high diastereo- and
enantioselectivities.6b These protocols provide unique meth-
odology in asymmetric Michael addition. However, to the
best of our knowledge, no example was described on the
reaction of cyclohexanone with alkyl nitroolefins to date,
probably due to the fact that they are less reactive than aryl
nitroolefins.10b
entry
solvent
T/°C t (d) convb (%) syn/antib eec (%)
1
2
3
4
5
6
7
8
9
MeOH
i-PrOH
THF
hexane
benzene
benzened
benzenee
neate,f
neate,f
neate,f
25
25
25
25
25
25
25
25
0
6
4
6
4
2
1
0.5
0.5
1.5
1.5
trace
trace
trace
73
90/10
92/8
90/10
94/6
94/6
97/3
96/4
80
67
77
80
87
89
90
68
100
100
100
100
100
10g
0
a Unless otherwise noted, all reactions were carried out in solvent (1
mL) using 3 (0.25 mL, 10 equiv) and 4 (0.25 mmol, 1 equiv) in the presence
of 20 mol % of 2a. b Determined by 1H NMR. c Determined by chiral HPLC
analysis (chiralpak AD-H, hexane/2-propanol ) 90/10). d Acetic acid (10
mol %) was added. e n-Butyric acid (10 mol %) was added. f 20 equiv of
cyclohexanone was used. g 2b as a catalyst, 0 °C.
(5) (a) Maher, D. J.; Connon, S. J. Tetrahedron Lett. 2004, 45, 1301-
1305. (b) Okino, T.; Hoashi, Y.; Takemoto, Y. Tetrahedron Lett. 2003, 44,
2817-2821. (c) Schreiner, P. R. Chem. Soc. ReV. 2003, 32, 289-296. (d)
Wittkopp, A.; Schreiner, P. R. Chem. Eur. J. 2003, 9, 407-414. (e)
Schreiner, P. R.; Wittkopp, A. Org. Lett. 2002, 4, 217-220. (f) Curran, D.
P.; Kou, L. H. Tetrahedron Lett. 1995, 36, 6647-6650. (g) Curran, D. P.;
Kou, L. H. J. Org. Chem. 1994, 59, 3259-3261.
(6) (a) Xu, Y.-M.; Co´rdova, A. Chem. Commun. 2006, 460-462. (b)
Wang, W.; Wang, J.; Li, H. Angew. Chem., Int. Ed. 2005, 44, 1369-1371.
(c) Kotrusz, P.; Toma, S.; Schmalz, H.-G.; Adler, A. Eur. J. Org. Chem.
2004, 1577-1583.
such as MeOH, i-PrOH, and THF, only a trace amount of
the desired adduct was observed (entries 1-3), whereas in
nonpolar solvents, such as hexane and benzene, the Michael
addition reaction proceeded smoothly to give product 5a in
moderate to excellent conversions with good to high enan-
tioselectivities (entries 4 and 5). Interestingly, the addition
of a catalytic amount of organic acids could increase
dramatically the reaction rate (entries 6 and 7) without a loss
of enantiomeric excess. For example, when n-butyric acid
was used as an additive, trans-nitroolefin was converted into
the desired product rapidly with high diastereoselectivity (94/
6) and good enantioselectivity (80%) (entry 7). In solvent-
free condition, the ee was improved to 87%, which further
increased to 89% ee when the reaction temperature was
lowered to 0 °C without a significant reduction of the reaction
rate (entry 9). The use of catalyst 2b instead of 2a under the
same conditions gave 90% ee (entry 10).
(7) Selected enamine-based organocatalytic Michael reactions: (a) Chi,
Y.; Gellman, S. H. Org. Lett. 2005, 7, 4253-4256. (b) Mosse´, S.; Alexakis,
A. Org. Lett. 2005, 7, 4361-4364. (c) Cobb, A. J. A.; Shaw, D. M.;
Longbottom, D. A.; Gold, J. B.; Ley, S. V. Org. Biomol. Chem. 2005, 3,
84-96. (d) Mitchell, C. E. T.; Cobb, A. J. A.; Ley, S. V. Synlett. 2005,
611-614. (e) Mase, N.; Thayumanavan, R.; Tanaka, F.; Barbas, C. F., III.
Org. Lett. 2004, 6, 2527-2530. (f) Planas, L.; Perand-Viret, J.; Royer, J.
Tetrahedron: Asymmetry 2004, 15, 2399-2403. (g) Cobb, A. J. A.;
Longbottom, D. A.; Shaw, D. M.; Ley, S. V. Chem. Commun. 2004, 1808-
1809. (h) Betancort, J. M.; Sakthivel, K.; Thayumanavan, R.; Barbas, C.
F., III. Tetrahedron Lett. 2001, 42, 4441-4444. (i) Betancort, J. M.; Barbas,
C. F., III. Org. Lett. 2001, 3, 3737-3740.
(8) List, B.; Pojarlier, P.; Martin, H. J. Org. Lett. 2001, 3, 2423-2425.
(9) Betancort, J. M.; Sakthivel, K.; Thayumanavan, R.; Tanaka, F.;
Barbas, C. F., III. Synthesis 2004, 1509-1521.
Under the optimized conditions, a variety of nitroolefins
with different structures were investigated, and the results
are summarized in Table 2. Various styrene-type nitroolefins
(10) (a) Andrey, O.; Alexakis, A.; Tomassini, A.; Bernardinelli, G. AdV.
Synth. Catal. 2004, 346, 1147-1168. (b) Andrey, O.; Alexakis, A.;
Bernardinelli, G. Org. Lett. 2003, 5, 2559-2561. (c) Andrey, O.; Vidonne,
A.; Alexakis, A. Tetrahedron Lett. 2003, 44, 7901-7904. (d) Alexakis,
A.; Andrey, O. Org. Lett. 2002, 4, 3611-3614.
(11) Ishii, T.; Fujioka, S.; Sekiguchi, Y.; Kotsuki, H. J. Am. Chem. Soc.
2004, 126, 9558-9559.
(12) For the synthesis of compound 1: Dahlin, N.; Boegevig, A.;
Adolfsson, H. AdV. Synth. Catal. 2004, 346, 1101-1105.
2902
Org. Lett., Vol. 8, No. 14, 2006