erate the DABCO-promoted MBH reaction of arylaldehydes
with methyl acrylate as recoverable H-bonding organocata-
lysts.5 In 2005, Wang’s group reported a novel type of
bifunctional organocatalyst, the chiral amine-thiourea com-
pound derived from 1,1′-binaphthyl-2,2′-diamine (BINAM),
for catalyzing highly enantioselective MBH reactions of
2-cyclohexen-1-one with various aldehydes to give the
corresponding adducts in high yields and enantiomeric
excesses.6 Recently, Lattanzi described a simple chiral amino
alcohol derived thiourea for the same MBH reaction to
produce the corresponding adducts in up to 88% ee.7 On
the other hand, bis(thio)ureas derived from chiral trans-1,2-
diaminocyclohexane and isophorone-diamine [3-(amino-
methyl)-3,5,5-trimethylcyclohexylamine, IPDA] were also
proven to be suitable organocatalysts for the asymmetric
MBH reactions of various aldehydes with 2-cyclohexen-1-
one as described by Nagasawa and Berkessel.8
Although the MBH reactions of aliphatic aldehydes with
2-cyclohexen-1-one have achieved very high yields and ee’s
by these organocatalysts mentioned above, using aromatic
aldehydes usually afforded the corresponding products in
moder-ate yields and moderate ee’s. To the best of our know-
ledge, the highest ee of this kind of MBH reaction regarding
aromatic aldehyde is 77%. Herein, we report that the
improved bis(thio)urea organocatalysts, derived from axially
chiral (R)-5,5′,6,6′,7,7′,8,8′-octahydro-1,1′-binaphthyl-2,2′-
diamine (H8-BINAM), were fairly effective chiral organo-
catalysts for the enantioselective MBH reaction of aryl-
aldehydes with 2-cyclohexen-1-one to give the corresponding
adducts in up to 88% ee and good to excellent yields.
The organocatalysts 1a-c and 2a-h are easily accessible
by condensation of chiral BINAM and H8-BINAM with 2
equiv of the corresponding iso(thio)cyanate under mild con-
ditions (see Supporting Information) (Figure 1). Organo-
with 2-cyclohexen-1-one (4a) in toluene at room temperature
in combination with 1,4-diazabicyclo[2.2.2]octane (DABCO)
to find out the best catalyst and the results of these
experiments are summarized in Table 1. As can be seen from
Table 1, the structure of these organocatalysts significantly
affects the enantioselectivities and chemical yields of 5a
(Table 1, entries 1-11). Three structural features of these
catalysts were found to be important for achieving high
enantioselectivity: (1) Bisthioureas are better catalysts
because bisthioureas 1c, 2b, and 2d are slightly more
effective than those of bisureas 1b, 2a, and 2c under identical
conditions, presumably due to the stronger H-bonding ability
of thiourea than that of urea, which makes them more
effectively interact with the substrates (Table 1, entries
2-7).11 (2) H8-BINAM derived organocatalysts are more
effective than those BINAM derived ones since bisthiourea
2b derived from (R)-H8-BINAM was found to be the
optimum catalyst for this reaction, providing the correspond-
ing product 5a in 66% yield and 29% ee after 72 h, whereas
the bis(thio)ureas 1a and 1c derived from BINAM gave very
low enantioselectivities (Table 1, entries 1, 3, and 5), and
(3) Substitution at the 3,3′-positions gave higher ee than
others (Table 1, entries 6-11). When the substituents at the
3,3′-positions are phenyl group, 4-methylphenyl group, or
(2) Selected papers on asymmetric MBH and aza-Morita-Baylis-Hillman
reaction (aza-MBH) reaction: (a) Barrett, A. G. M.; Cook, A. S.; Kamimura,
A. Chem. Commun. 1998, 2533-2534. (b) Shi, M.; Xu, Y.-M. Angew.
Chem., Int. Ed. 2002, 41, 4507-4509. (c) Yang, K.-S.; Lee, W.-D.; Pan,
J.-F.; Chen, K.-M. J. Org. Chem. 2003, 68, 915. (d) Shi, M.; Chen, L. H.
Chem. Commun. 2003, 1310-1311. (e) Kawahara, S.; Nakano, A.; Esumi,
T.; Iwabuchi, Y.; Hatakeyama, S. Org. Lett. 2003, 5, 3103-3105. (f)
Imbriglio, J. E.; Vasbinder, M. M.; Miller, S. J. Org. Lett. 2003, 5, 3741-
3743. (g) Shi, M.; Xu, Y.-M.; Shi, Y.-L. Chem.-Eur. J. 2005, 11, 1794-
1802. (h) Matsui, K.; Takizawa, S.; Sasai, H. J. Am. Chem. Soc. 2005,
127, 3680-3681. (i) Shi, M.; Chen, L.-H.; Li, C.-Q. J. Am. Chem. Soc.
2005, 127, 3790-3800. (j) Shi, M.; Li, C.-Q. Tetrahedron: Asymmetry 2005,
16, 1385-1391. (k) Raheem, I. T.; Jacobsen, E. N. AdV. Synth. Catal. 2005,
347, 1701-1708. (l) Shi, M.; Chen, L.-H.; Teng, W.-D. AdV. Synth. Catal.
2005, 347, 1781-1789. (m) Matsui, K.; Tanaka, K.; Horii, A.; Takizawa,
S.; Sasai, H. Tetrahedron: Asymmetry 2006, 17, 578-583. (n) Matsui, K.;
Takizawa, S.; Sasai, H. Synlett 2006, 761-765. (o) Liu, Y.-H.; Chen,
L.-H.; Shi, M. AdV. Synth. Catal. 2006, 348, 973-979. (p) Gausepohl, R.;
Buskens, P.; Kleinen, J.; Bruckmann, A.; Lehmann, C. W.; Klankermayer,
J.; Leitner, W. Angew. Chem., Int. Ed. 2006, 45, 3689-3692. (q) Nakano,
A.; Takahashi, K.; Ishihara, J.; Hatakeyama, S. Org. Lett. 2006, 8, 5357-
5360. (r) Utsumi, N.; Zhang, H.; Tanaka, F.; Barbas, C. F., III. Angew.
Chem., Int. Ed. 2007, 46, 1878-1880. (s) Vesely, J.; Dziedzic, P.; Cu¨rdova,
A. Tetrahedron Lett. 2007, 48, 6900-6904. (t) Krafft, M. E.; Haxell, T. F.
N. J. Am. Chem. Soc. 2005, 127, 10168-10169.
(3) Iwabuchi, Y.; Nakatani, M.; Yodoyama, N.; Hatakeyama, S. J. Am.
Chem. Soc. 1999, 121, 10219-10220.
(4) (a) McDougal, N. T.; Schaus, S. E. J. Am. Chem. Soc. 2003, 125,
12094-12095. (b) McDougl, N. T.; Trevellini, W. L.; Rodgen, S. A.;
Kliman, L. T.; Schaus, S. E. AdV. Synth. Catal. 2004, 346, 1231-1240.
(5) Maher, D. J.; Connon, S. J. Tetrahedron Lett. 2004, 45, 1301-1305.
(6) Wang, J.; Yu, X.; Zu, L.; Wang, W. Org. Lett. 2005, 7, 4293-4296.
(7) Lattanzi, A. Synlett. 2007, 2106-2110.
(8) (a) Sohtome, Y.; Tanatani, A.; Hashimoto, Y.; Nagasawa, K.
Tetrahedron Lett. 2004, 45, 5589-5592. (b) Berkessel, A.; Roland, K.;
Neudo¨rfl, J. M. Org. Lett. 2006, 8, 4195-4198. (c) Roussel, C.; Roman,
M.; Andreoli, F.; Delrio, A.; Faure, R.; Vanthuyne, N. Chirality 2006, 18,
762-771.
Figure 1. Screened organocatalysts.
(9) Fleming, E. M.; McCabe, T.; Connon, S. J. Tetrahedron Lett. 2006,
47, 7037-7042.
catalysts 1a-c and 2b were first prepared by Connon’s
group, which have been used for a Friedel-Crafts type
reaction.9 Organocatalysts 2a and 2c-h were first prepared
by our group, and 2a-f have been already used in asym-
metric Henry reaction.10
(10) Liu, X. G.; Jiang, J. J.; Shi, M. Tetrahedron: Asymmetry 2007, 18,
2773-2781.
(11) For recent reviews on organocatalysis by hydrogen-bonding donors
with thioureas, see: (a) Takemoto, Y. Org. Biomol. Chem. 2005, 3, 4299-
4306. (b) Taylor, M. S.; Jacobsen, E. N. Angew. Chem., Int. Ed. 2006, 45,
1520-1543. (c) Connon, S. J. Chem.-Eur. J. 2006, 12, 5418-5427. (d)
Akiyama, T.; Itoh, J.; Fuchibe, K. AdV. Synth. Catal. 2006, 348, 999-
1010.
The chiral organocatalysts 1a-c and 2a-h were first
examined in the MBH reaction of 4-nitrobenzaldehyde (3a)
1044
Org. Lett., Vol. 10, No. 6, 2008