Table 4 Reaction in watera
Entry
R1
H2O/Cyclohexanoneb
Product
Yield(%)c
Anti/Synd
Ee(%)e
1
2
3
4
5
6
7
8
4-NO2C6H4
4-NO2C6H4
4-NO2C6H4
4-CNC6H4
4-ClC6H4
4-BrC6H4
4-CO2MeC6H4
2-Naphyl
1/1
2/1
3/1
2/1
2/1
2/1
2/1
2/1
3a
3a
3a
3d
3h
3g
3f
62
65
66
65
57
53
70
45
11/1
10/1
9/1
6/1
7/1
6/1
5/1
8/1
96
95
93
93
92
89
94
90
3j
a
b
c
The reactions were performed with 0.2 mmol of aldehyde. Volume ratio, total volume: 1 mL. Combined yield. Determined by
d
1H NMR. Determined by chiral HPLC.
e
decreases in both activity and stereoselectivity. The decreasing
trend became slightly more severe when more water was
included in the reaction system (entries, 1–3).
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¨
The cooperative nature of this catalytic system was revealed by
the fact that Cu(SbF6)2 or the ligand (1a) alone could
not catalyze the aldol reaction of cyclohexanone with
4-nitrobenzaldehyde. All the aldol reactions of cyclohexanone
predominately generated the anti aldol products with (2S, 10R)
configuration. The mechanism is likely to follow that the metal
coordinates with the chelating ligand to form a rigid chiral
structure and acts as a Lewis acid to activate the aldehyde; the
primary amine reacts with cyclohexanone to form an enamine
attacking the activated aldehyde from the re-face to generate the
products (Fig. 2).
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In summary, we have developed a new class of primary
amine-metal Lewis acid cooperative bifunctional catalysts
using simple bidentate ligands. These bifunctional catalysts
displayed exceptionally high activity in the direct asymmetric
aldol reactions of ketones with both electron-rich and
electron-poor aldehydes. The enantioselectivities obtained
from these reactions are comparable with those catalyzed by
the best organocatalysts, and are much higher than those of
the tridentate ligand system. It is notable that these catalysts
possess both advantages of metal Lewis acid and organo-
catalysts, as requiring low catalyst loading and being water
tolerant. The in depth understanding of the coordination
chemistry of these bifunctional catalysts is currently under
investigation. The application of these enamine-metal Lewis
acid bifunctional catalysts to activate ketone acceptors
through a strong Lewis acid in aldol reactions as well as in
inverse-electron-demand hetero-Diels–Alder reactions are
under way, and will be reported in due course.
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We thank Professor Mike Novak for useful discussions.
Financial support was provided by Miami University.
Notes and references
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(v) B. L. Zheng, Q. Z. Liu, C. S. Guo, X. L. Wang and L. He,
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ꢀc
This journal is The Royal Society of Chemistry 2011
226 | Chem. Commun., 2011, 47, 224–226