primary amine, thiourea bifunctional catalyst system12 to
facilitate this key transformation.
this reaction proceeded in low yield. Interestingly, addition
of Brønsted acid additives such as p-TsOH completely
suppressed the reaction (entry 2). We next screened a series
of bifunctional thiourea/primary amine catalysts 12ꢀ15.13
While cyclohexyl-based catalyst 12 performed poorly in
this transformation (entry 3), use of an acyclic diamine
backbone (e.g., catalyst 13) provided dramatic increases in
both chemical yield (49%) and enantioselectivity (98%)
(entry 4). Further increases in chemical yield were achieved
using the benzyl thiourea derivative 15, now providing the
optimum level of chemical yield (95%) with continued high
enantioselectivity (98% ee) (entry 6). The absolute config-
uration was established by comparison with the optical
rotation with literature values.2a Use of alternate solvents
(xylenes, 1,4-dioxane, MeCN, DMF) or lower tempera-
tures (e.g., 60 °C) provided inferior chemical yields. The
thiourea motif appeared important to catalytic turnover, as
use of a sulfonamide derivative 16 or the parent diamine 17
led to a significant reduction in chemical yield.
Scheme 1. Precedent for Enamine-Mediated Michael Additions
of R-Substituted Cycloalkanones
Table 1. Optimization of Organocatalyzed Michael Addition to
2-Methylcyclohexanone
The development of an organocatalyzed method for the
synthesis of R,R-disubstituted cyclohexanone 11 is shown
in Table 1. In order to facilitate a catalytic version of
enamine-mediated, R,R-disubstituted cycloalkanone synth-
esis, we first attempted to simply use substoichiometric
amounts of primary amine 2 (entry 1). Not surprisingly,
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entry
conditions
% yield
% eea
1
2
2 (20 mol %)
10
0
90
2 (20 mol %),
p-TsOH (1 mol %)
12 (20 mol %)
13 (20 mol %)
14 (20 mol %)
15 (20 mol %)
15 (10 mol %)
16 (20 mol %)
17 (20 mol %)
n/a
3
4
5
6
7
8
9
18
49
80
95
76
17
5
67
98
98
98
98
98
n/d
a Determined by chiral HPLC analysis.
With these catalytic reaction conditions established,
we studied the scope of the reaction of nucleophiles with
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Asymmetry 1997, 8, 3319–3326. (c) He, T.; Qian, J.-Y.; Song, H.-L.;
Wu, X.-Y. Synlett 2009, 3195–3197. (d) Han, B.; Liu, Q.-P.; Li, R.; Tian,
X.; Xiong, X.-F.; Deng, J.-G.; Chen, Y.-C. Chem.;Eur. J. 2008, 14,
8094–8097. (e) Yu, F.; Jin, Z.; Huang, H.; Ye, T.; Liang, X.; Ye, J. Org.
Biomol. Chem. 2010, 8, 4767–4774. (f) Isobe, T.; Fukuda, K.; Tokunaga,
T.; Seki, H.; Yamaguchi, K.; Ishikawa, T. J. Org. Chem. 2000, 65, 7774–
7778.
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