6236
Y. Nakayama et al. / Tetrahedron Letters 52 (2011) 6234–6237
Table 2
around 80% ee, were obtained, irrespective of the electronic nature
of the aryl substituent, except for 4-nitrobenzaldehyde (entries 1–
6). As we expected, the reactions of aliphatic aldehydes also
showed high enantioselectivities (entries 7–10). In particular,
excellent enantioselectivity (96% ee) was obtained in the reaction
of cyclohexanecarboxaldehyde (entry 10).10 It is noteworthy that
the amount of the catalyst could be reduced to 10 mol % without
diminishing enantioselectivity (entry 11).
Enantioselective MBH reaction of aldehydes and 2-cyclohexen-1-one with 1d as a
catalysta
OH
O
O
1d (20 mol%)
DABCO (20 mol%)
R
+
RCHO
neat, r.t.
Absolute configuration of all the products was determined to be
S.3d–f,4a The observed stereochemistry can be explained by the
transition state model, in which the re-face of aldehyde was pref-
erentially attacked by the enolate (Fig. 2). However, further study is
required to fully understand the mechanism of asymmetric
induction.
In conclusion, we have demonstrated that the newly developed
bis(thiourea) 1d is an efficient chiral organocatalyst for asymmet-
ric MBH reaction. To the best of our knowledge, this is the first
example of high enantioselectivities in the reactions of 2-cyclohex-
en-1-one with both aromatic and aliphatic aldehydes using the
same organocatalyst. Further studies on the scope of the reaction
and clarification of the reaction mechanism are under way in our
laboratory.
Entry
R in RCHO
Time (h)
Yield (%)
% eeb
1
2
3
4
5
6
7
8
9
Phenyl
96
96
86
48
78
51
54
80
70
54
61
71
69
81
80
83
62
78
84
84
86
96
96
96
4-Methoxyphenyl
4-Fluorophenyl
4-Nitrophenyl
3-Chlorophenyl
3-Fluorophenyl
2-Phenylethyl
n-Hexyl
i-Propyl
c-Hexyl
c-Hexyl
43c
10c
96
96
96
10c
10c
10c
18c
10
11d
a
All reactions were carried out at room temperature with molar ratios of alde-
hyde/enone/1d/DABCO = 1:3:0.2:0.2 unless otherwise indicated.
b
Determined by HPLC analysis using chiral stationary phase column according to
Acknowledgments
the literature (Refs. 3d–f and 4a).
c
All the substrate was consumed.
10 mol % of 1d was used.
We would like to thank Dr. Hiroshi Furuno, Institute for Mate-
rials Chemistry and Engineering (IMCE), Kyushu University, for
the measurement of HR-MS spectra and X-ray analysis. We would
also like to thank Ms. Keiko Ideta, Ms. Yasuko Tanaka, and Mr. Tai-
suke Matsumoto (Evaluation Center of Materials Properties and
Function, IMCE, Kyushu University) for the measurement of NMR
and HR-MS spectra and X-ray analysis. K.I. also acknowledges the
Kaneka Award in Synthetic Organic Chemistry, Japan. A part of this
work was performed under the Cooperative Research Program of
the ‘‘Network Joint Research Center for Materials and Devices
(IMCE, Kyushu university)’’.
d
F3C
S
CF3
N
N+R3
R
H
OH
O
N
O
re-face attack
H
H
R
O-
S
N
H
H
S
N
References and notes
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811; (b) Masson, G.; Housseman, C.; Zhu, J. Angew. Chem., Int. Ed. 2007, 46,
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F3C
CF3
Figure 2. Possible transition state model for MBH reaction with 1d.
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McDougal, N. T.; Trevellini, W. L.; Rodgen, S. A.; Kliman, L. T.; Schaus, S. E. Adv.
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Nagasawa, K. Tetrahedron Lett. 2004, 45, 5589; (d) Sohtome, Y.; Takemura, N.;
Takagi, R.; Hashimoto, Y.; Nagasawa, K. Tetrahedron 2008, 64, 9423; (e) Wang,
J.; Li, H.; Yu, X.; Zu, L.; Wang, W. Org. Lett. 2005, 7, 4293; (f) Berkessel, A.;
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2106.
bis(urea) 1a,b and bis(thiourea) 1c,d by treatment with isocyanate
or isothiocyanate.
With chiral catalysts 1a–d in hand, we first examined the reac-
tion of 4-chlorobenzaldehyde with 2-cyclohexen-1-one without
solvent at room temperature in the presence of 1,4-diazabicy-
clo[2.2.2]octane (DABCO) and 1a–d (Table 1). Reaction with bis(ur-
ea) 1a showed a low chemical yield and enantioselectivity, while
that with bis(urea) 1b bearing trifluoromethyl groups on phenyl
groups showed moderate enantioselectivity, although the chemical
yield was still low (entries 1 and 2). Alternatively, bis(thiourea) 1c
was a less efficient catalyst in terms of chemical yield and enanti-
oselectivity (entry 3). High enantioselectivity and chemical yield
(83% ee, 87%) were obtained in the reaction with bis(thiourea) 1d
(entry 4).9 With 1d, we also examined the effect of temperature,
but neither lowering nor raising the reaction temperature im-
proved enantioselectivity (entries 5 and 6). Reactivity and/or
enantioselectivity was also largely dependent on the structure of
enone. The use of other enones instead of 2-cyclohexen-1-one re-
sulted in a significant drop in chemical yield and enantioselectivity
(entries 7 and 8).
4. (a) Shi, M.; Liu, X.-G. Org. Lett. 2008, 10, 1043; (b) Bugarin, A.; Connell, B. T.
Chem. Commun. 2010, 46, 2644.
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Vasbinder, M. M.; Imbriglio, J. E.; Miller, S. J. Tetrahedron 2006, 62, 11450; (c)
Tang, H.; Gao, P.; Zhao, T.; Zhou, Z.; He, L.; Tang, C. Catal. Commun. 2007, 8,
1811; (d) Tang, H.; Zhao, G.; Zhou, Z.; Gao, P.; He, L.; Tang, C. Eur. J. Org. Chem.
2008, 126; (e) Yuan, K.; Zhang, L.; Song, H.-L.; Hu, Y.; Wu, X.-Y. Tetrahedron Lett.
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Yacob, Z.; Bunge, A.; Liebscher, J. Synlett 2010, 2079.
6. Fujii, A.; Hashiguchi, S.; Uematsu, N.; Ikariya, T.; Noyori, R. J. Am. Chem. Soc.
1996, 118, 2521.
7. Absolute configuration of alcohol 4 was determined by comparison of elution
order of HPLC with the reported value (Ref. 6) after its conversion to known 1-
indanol by hydrogenation.
8. (a) Mizuno, M.; Shioiri, T. Chem. Commun. 1997, 22, 2165; (b) Thompson, A. S.;
Humphrey, G. R.; DeMarco, A. M.; Mathre, D. J.; Grabowski, E. J. J. J. Org. Chem.
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9. Reactions using other bases for this reaction gave less satisfactory results
(DMAP: 96 h, 47% yield, 39% ee, imidazole: 96 h, 2% yield, 58% ee).
10. Typical experimental procedure is exemplified by MBH reaction of
To explore the scope of the present MBH reaction, we next
examined the reactions of several other aldehydes with bis(thio-
urea) 1d as a catalyst (Table 2). Equally high enantioselectivities,
cyclohexanecarboxaldehyde with 2-cyclohexen-1-one: To
a mixture of 1d