COMMUNICATION
Table 2. Examination of different malonates 1 with the 3i/TFA combina-
values (Table 1, entry 10). Our further optimizing efforts
were shifted to the examination of the effect of several acid
additives, which are well-documented to be beneficial for
the formation of an iminium intermediate.[9] To our delight,
the addition of acid additives not only improved the yield
and ee values, but also decreased the reaction time signifi-
cantly from 48 to 24 h (Table 1, entries 11–15). Thus, the re-
action was best performed using a 1:1 combination of 3i/
TFA (trifluoro acetic acid) with 99% yield and 97% ee
(Table 1, entry 13). The absolute configuration of the prod-
uct 4aa was determined by comparison of the specific opti-
cal rotation with that of the literature data.
tion.[a]
Entry
1
R1
Product
Yield [%][b]
ee [%][c]
1
2
3
4
1a
1b
1c
1d
1e
1 f
Me
Et
iPr
allyl
Bn
4aa
4ba
4ca
4da
4ea
–
99
97
72
99
99
–
97
98
>99
98
99
–
5
6[d]
tBu
[a] Reaction conditions: 2a (1.0 equiv), 1 (2.0 equiv), 3i/TFA (20 mol%),
CHCl3 (1.0 mL). [b] Yield of the isolated product after column chroma-
tography. [c] The ee value was determined by HPLC on a chiral phase.
[d] No reaction was detected.
Table 1. Screening of catalysts for the asymmetric Michael addition of di-
methyl malonate 1a to benzylideneacetone 2a.[a]
nature or positions of the substituents on the phenyl ring
(Table 3, entries 1–10). Heterocyclic furan enone 2j also per-
formed well to give the desired product in 92% yield and
99% ee (Table 3, entry 11). No decrease in yield and ee
value was observed for the slightly sterically hindered enone
2l (Table 3, entry 12). Interestingly, chalcone 2m, which was
presumed to be a better Michael acceptor for this type of re-
action,[4–7] was found to react rather slowly and a longer re-
action time was required to obtain good yield, however, ex-
cellent enantioselectivity was still achieved (Table 3,
entry 13). Poor reactivity was also observed for the alkyl-
substituted enone 2n and 2-cyclohexenone 2o, in which only
moderate yields were obtained while still in excellent enan-
tioselectivities with prolonged reaction times (Table 3, en-
tries 14 and 15).
Entry
Catalyst 3
Additive
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
3a
3b
3c
3d
3e
3 f
3g
3h
3i
3i
3i
3i
3i
none
none
none
none
none
none
none
none
27
43
51
93
85
trace
77
55
92
90
98
99
99
93
97
36
79
81
90
87
–
82
36
91
91
93
94
97
96
96
9
none
none
10[d]
11[d,e]
12[d,e]
13[d,e]
14[d,e]
15[d,e]
PhCO2H
CH3CO2H
CF3CO2H
CF3SO3H
d-CSA
3i
3i
A bifunctional iminium mechanism similar to those previ-
ously proposed for the primary amine salt catalysts in the
iminium catalysis[9] of enone may be invoked to explain the
observed enantioselectivity. We presume that the reaction
may proceed via the iminium ion I (Figure 2), in which the
primary amine moiety of the catalyst 3i activates the enone
2 via the formation of an iminum ion while the secondary
amine activates the nucleophile malonate 1. The Re face of
the enone in this pretransition state assembly I is shielded
by the bulky indolyl group driving the malonate to attack
the Si face of the enone 2. The strong acid additives may fa-
cilitate the formation of the iminium ion and foster the re-
generation of the catalyst in the hydrolysis of the enamine
intermediate after the addition step. However, the exact ex-
isting or functioning forms of the strong acid additives in
the reaction system are difficult to be determined.
In summary, we have devel-
oped a novel readily available
primary–secondary diamine cat-
alyst system for the Michael ad-
ditions of malonates to enones.
Excellent yields and enantiose-
lectivities were achieved for a
range of both malonates and
enones. Efforts are being fo- Figure 2. Pretransition state I.
[a] Reaction conditions: 2a (1.0 equiv), 1a (10.0 equiv), 3 (20 mol%),
CHCl3 (1.0 mL). [b] Yield of the isolated product after column chroma-
tography. [c] The ee value was determined by HPLC on a chiral phase.
[d] Two equiv of 1a was used. [e] The reaction was run for 24 h. d-CSA:
d-camphor sulfonic acid.
Subsequently, the addition of a series of malonates 1 to
enone 2a was performed under the optimized conditions
(Table 2). It seems that the reaction was quite sensitive to
the steric hindrance on the malonates. While excellent
yields and enantioselectivity were obtained for the less steri-
cally demanding malonates 1a, b, d, and e, a lower yield was
observed for the diisopropyl malonate 1c but still with up to
>99% ee (Table 2, entry 3). The reaction even failed to pro-
ceed when the more sterically demanding di-tert-butyl malo-
nates 1 f was employed (Table 2, entry 6). The use of diben-
zyl malonate 1e furnished the best results with up to 99%
yield and ee value (Table 2, entry 5). Notably, it is favorable
to use dimethyl or dibenzyl malonates for further useful
conversions of the Michael adducts in organic synthesis.[2]
Then the scope of the addition of dibenzyl malonate to a
variety of enones 2 was explored (Table 3). For 4-aryl-3-
buten-2-ones 2a–j, almost optically pure products could be
obtained in excellent yields, irrespective of the electronic
Chem. Eur. J. 2008, 14, 10888 – 10891
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
10889