Base-base bifunctional catalysis: A practical strategy for asymmetric Michael addition of malonates to α,β-unsaturated aldehydes

Article abstract of DOI:10.1002/adsc.200800070

Lewis base-Bronsted base bifunctional catalysis is a novel and practical strategy for the asymmetric Michael addition. The addition of malonates to a series of α,β-unsaturated aldehydes can take place under base-base bifunctional catalytic conditions using 0.5-5 mol% of (S)-2-[diphenyl(trimethylsilyloxy) methyl]pyrrolidine as catalyst and 5-30 mol% of lithium 4-fluorobenzoate as additive base with up to 99% ee.

Full text of DOI:10.1002/adsc.200800070

FULL PAPERS
DOI: 10.1002/adsc.200800070
Base–Base Bifunctional Catalysis: A Practical Strategy for
Asymmetric Michael Addition of Malonates to a,b-Unsaturated
Aldehydes
Yongcan Wang,a Pengfei Li,a Xinmiao Liang,a,b,* and Jinxing Yea,b,*
a
Dalian Institute of Chemical Physics, Chinese Academy of Science, 457 Zhongshan Road, Dalian 116023, Peopleꢀs
Republic of China
Fax : (+86)-411-8437-9539; e-mail: liangxm@dicp.ac.cn
Engineering Research Center of Pharmaceutical Process Chemistry, Ministry of Education, School of Pharmacy, East
b
China University of Science and Technology, 130 Meilong Road, Shanghai 200237, Peopleꢀs Republic of China
Received: January 30, 2008; Revised: March 20, 2008; Published online: May 16, 2008
Supporting information for this article is available on the WWW under http://asc.wiley-vch.de/home/.
Abstract: Lewis base–Brønsted base bifunctional cat- silyloxy)methyl]pyrrolidine as catalyst and 5–30
alysis is a novel and practical strategy for the asym- mol% of lithium 4-fluorobenzoate as additive base
metric Michael addition. The addition of malonates with up to 99% ee.
to a series of a,b-unsaturated aldehydes can take
place under base–base bifunctional catalytic condi- Keywords: aldehydes; asymmetric catalysis; bifunc-
tions using 0.5–5 mol% of (S)-2-[diphenyl(trimethyl- tional catalysis; malonates; Michael addition
Introduction
disadvantages in these catalytic systems such as high
catalyst loading and low turnover number.[11] We won-
The catalytic asymmetric synthesis of chiral com- dered if there was a possibility to improve catalytic
pounds is one of the most important, exciting and reactivity and turnover in these Michael additions,
challenging areas in modern synthetic organic chemis- and envisioned that a new concept, namely Lewis
try. In the last decade, many new concepts have been base–Brønsted base bifunctional catalysis combining
introduced into the field of asymmetric catalysis and both HOMO-raising and LUMO-lowering mecha-
have had a significant impact on chemical synthesis. nisms could be a new tool for asymmetric Michael ad-
One of these concepts, bifunctional or multifunctional ditions (Scheme 1).
asymmetric catalysis,[1] has been a very efficient strat-
In this bifunctional catalysis, a Lewis base such as
egy and tool to access a range of chiral compounds chiral amine catalyst was used to activate the a,b-un-
with atomic economy. Shibasaki et al. have developed saturated carbonyl compound and induce the chirality
Lewis acid–Brønsted base,[2] Lewis acid–Lewis base[3] of the reaction by the iminium mechanism and a
and Lewis acid–Lewis acid[4] bifunctional catalysis for Brønsted base such as basic lithium salt was used to
a wide variety of enantioselective transformations. activate the nucleophilic reagent by deprotonation or
List,[5] Deng[6] and Takemoto et al.[7] have developed hydrogen-bond interaction. Thus, it was expected that
Brønsted acid–Lewis base bifunctional organocataly- this kind of bifunctional catalysis could enhance the
sis for a range of asymmetric 1,2- and 1,4-addition re-
actions. These chiral bifunctional catalysts activate
and arrange electrophilic and nucleophilic substrates
with both LUMO-lowering and HOMO-raising mech-
anisms, and deliver unique enantioselectivities.
In 2000, MacMillan et al. elegantly discovered a
new and very general strategy of organocatalysis with
a LUMO-lowering catalyst,[8] and asymmetric organo-
catalysis with the iminium mechanism[9] has devel-
oped into an important tool for asymmetric Michael
Scheme 1. Base–base bifunctional catalytic Michael addi-
additions in the last few years.[10] But there are still tion.
Adv. Synth. Catal. 2008, 350, 1383 – 1389
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Yongcan Wang et al.
FULL PAPERS
Table 1. Effect of additive base.
efficiency and practicability, especially for the addi-
tion of relatively weak nucleophilic reagents.
Results and Discussion
To verify the feasibility of Lewis base–Brønsted base
bifunctional catalysis, the asymmetric Michael addi-
tion of malonates to a,b-unsaturated aldehydes[12] was
selected to test this concept. In an initial screening, di-
ethyl malonate (2a) was added to cinnamaldehyde
(1a) under base–base bifunctional catalytic conditions
using 10 mol% of 2-[diphenyl(trimethylsilyloxy)me-
thyl]pyrrolidine (C1–1) as an amine catalyst[11] and 30
mol% of lithium acetate as an additive base. The
result showed that the reaction proceeded to full con-
version within 12 h with 95% ee. This encouraging
result indicated that base–base bifunctional catalysis
might be an efficient tool for this Michael addition.
Thus, the effects of various reaction conditions on this
reaction were investigated.
Entry
Additive Base[a]
Conversion [%][b]
ee [%][c]
1
2
3
4CF
5
6
7
8
9
10
11
12
13
LiOAc
NaOAc
KOAc
3CO2Li
LiOH
PhCO2Li
4-FC6H4CO2Li
4-MeOC6H4CO2Li
2-NO2C6H4CO2Li
3-NO2C6H4CO2Li
4-NO2C6H4CO2Li
Et3N
95
85
92
67
92
96
95
88
96
95
96
4
95
89
91
76
13
91
96
95
93
92
93
0
93
Et3N-AcOH
63
93
[a]
In each case, the reaction was run with cinnamaldehyde
(1.0 mmol), diethyl malonate (3.0 mmol), C1–1
(0.1 mmol) and additive base (0.3 mmol) in CH2Cl2
(2.0 mL) at room temperature for 12 h.
The conversion was determined by GC.
The enantiomeric excess was determined by GC after
conversion to the corresponding lactone.
Effect of Additive Base
The effects of the additive base including organic
bases and basic salts were first investigated and repre-
sentative results are shown in Table 1.
The addition of diethyl malonate (2a) to cinnamal-
dehyde (1a) proceeded with different results using dif-
ferent kinds of additive. The primary investigation
[b]
[c]
showed that lithium acetate as additive base could and enantioselectivity of the reaction were then inves-
give better conversion and enantioselectivity than tigated. The results are shown in Table 2.
other alkali metal acetates such as sodium or potassi-
The results in Table 2 indicated that addition of di-
um salts (entries 1–3). More experiments showed that ethyl malonate (2a) to cinnamaldehyde (1a) was influ-
a suitable basicity was necessary to obtain satisfactory enced by both the a-substituted group (R) and the O-
conversion and enantioselectivity. For example, low substituted group (R1) of the amine catalyst C. An ar-
enantioselectivity was observed when using strongly omatic group in the a-position gave better results
basic lithium hydroxide, while slightly weak basic lith- than an aliphatic group both in conversion and enan-
ium trifluoroacetate also induced low conversion and tioselectivity. For example, the reaction proceeded to
enantioselectivity (entries 4and 5). Lithium ben-
>90% conversion and ee within 12 h when using cata-
zoates, such as benzoate, fluorobenzoate, methoxy- lysts C1–1, C2 and C3 [R=Ph, 2-naphthyl and 3,5-
benzoate, nitrobenzoate, were suitable bases and 4- (CF3)2C6H3, respectively]; however, when using cata-
fluorobenzoate gave results equivalent to that of ace- lysts C4 and C5 (R=Me and n-Bu, respectively), only
tate (entries 6–11). The results in Table 1 also indicat- 24–32% conversion and 69–71% ee were achieved
ed that an organic base or its salt such as triethyla- (entries 1–5).
mine or triethylaminium acetate could not efficiently
improve the reaction (entries 12 and 13).
A protecting group in the O-position was essential
for the reaction. Very low conversion was observed
when using unprotected catalyst C1–0 (R1 =H) within
12 h (entry 6). This result is in accordance with the re-
ported results.[13] An appropriate size of the protect-
ing group was also important for the reaction (en-
Effect of Amine Catalyst
It is known that a,a-disubstituted-2-pyrrolidinemetha- tries 1, 7–9). If the size of the R1 group was too large,
nols (C) are efficient organocatalysts for many kinds the reaction would proceed with low conversion. For
of asymmetric reaction with the iminium mechanism. example, 70% conversion was obtained when using
Thus, the effect of these catalysts on the conversion catalyst C1–5 (R1 =t-BuMe2Si) within 12 h (entry 10),
but if the R1 group was larger, such as with catalyst
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Base–Base Bifunctional Catalysis
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Table 2. Effect of catalyst.
Entry
Catalyst[a]
Conversion [%][b]
ee [%][c]
Code
R
R1
1
2
3
4
5
6
7
8
C1–1
C2
C3
C4
C5
C1–0
C1–2
C1–3
C1–4
C1–5
C1–6
Ph
Me3Si
Me3Si
Me3Si
Me3Si
Me3Si
H
95
92
92
32
2471
14nd
92
95
97
95
96
92
69
3,5-(CF3)2C6H3
2-Naphthyl
Me
n-Bu
Ph
Ph
Ph
Ph
Ph
Et3Si
95
94
93
90
PhMe2Si
i-PrMe2Si
t-BuMe2Si
Ph3Si
9
10
11
70
4nd
Ph
[a]
In each case, the reaction was run with cinnamaldehyde (1.0 mmol), diethyl malonate (3.0 mmol), catalyst (0.1 mmol) and
LiOAc (0.3 mmol) in CH2Cl2 (2.0 mL) at room temperature for 12 h.
The conversion was determined by GC.
[b]
[c]
The enantiomeric excess was determined by GC after conversion to the corresponding lactone.
Table 3. Effect of solvent.
C1–6 (R1 =Ph3Si), only 4% conversion was obtained
in the same time (entry 11).
Effect of Solvent
We then investigated the effect of the solvents on the
reaction and some representative results are illustrat-
ed in Table 3.
Entry
Solvent[a]
Conversion [%][b]
ee [%][c]
1
2
3
CH2Cl2
CHCl3
Toluene
95
85
98
91
98
98
98
98
95
97
98
97
97
91
93
95
94
89
It is interesting that the reaction proceeded well in
various solvents including chloroalkanes (entries 1
and 2), arenes (entries 3 and 4), alkanes (entries 5 and
6), ethers (entries 7 and 8), ethyl acetate (entry 9), al-
cohols (entries 10 and 11), acetone (entry 12), aceto-
nitrile (entry 13), dimethylformamide (entry 14) and
dimethyl sulfoxide (entry 15). Full conversion was ob-
tained in most of these solvents within 12 h. The
enantioselectivity of the reaction was dependent on
the properties of the solvent. Generally, reactions in
non-polar solvents gave higher ees than in those in
polar solvents, although there were some exceptions,
such as in ethyl acetate and dimethylformamide.
These encouraging results indicated that base–base
bifunctional catalysis might be a general tool for Mi-
chael addition in various solvents. The results also in-
dicated that the chemistry for the further conversion
of the addition product in a “one-pot” manner was
readily accessible because the solvent effect of the
Michael addition was unrestrained.
4Benzene
5
6
7
8
9
10
11
12
13
14DMF
15
97
Hexane
Cyclohexane
Et2O
93
92
90
92
92
86
70
71
66
THF
EtOAc
MeOH
EtOH
Me2CO
MeCN
97
DMSO
85
[a]
In each case, the reaction was run with cinnamaldehyde
(1.0 mmol), diethyl malonate (3.0 mmol), C1–1
(0.1 mmol) and LiOAc (0.3 mmol) in solvent (2.0 mL) at
room temperature for 12 h.
The conversion was determined by GC.
The enantiomeric excess was determined by GC after
conversion to the corresponding lactone.
[b]
[c]
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Effect of Catalyst Loadingand Effect of Mixed
Solvents on the Reduction of Catalyst Loading
tively, 89% and 92% ee (entries 4and 5). It is clear
that the ratio of dichloromethane to methanol affects
both the conversion and the enantioselectivity. An in-
The loading of the catalyst is an important aspect of a crease in the ratio of methanol could increase the re-
catalytic reaction. Thus, we were very interested in action efficiency and decrease the catalyst loading.
whether it was possible to reduce the catalyst loading However, it could also cause a decrease in the enan-
of this bifunctional catalytic reaction. In this section, tioselectivity. On the other hand, a decrease in the
factors that have an effect on the reduction in the ratio of methanol could increase the enantioselectivity
loading of amine catalyst C1–1 were investigated and but decrease the reaction efficiency (entries 5–9).
some representative results are shown in Table 4.
More experiments indicated that the enantioselectivi-
Unfortunately, preliminary results indicated that ty could be increased even using a mixed solvent of
the reaction was incomplete in dichloromethane if the CH2Cl2/MeOH (90:10 v:v) if lithium 4-fluorobenzoate
loading of C1–1 was lower than 10 mol% and if the was used instead of lithium acetate. Under these con-
loading was reduced to 1 mol%, very low conversion ditions, full conversion was afforded using just 1
(22%) was observed even after 72 h (entries 1–3).
mol% of C1–1 with 96% ee (entry 10). Further reduc-
Since the reaction proceeded well in various sol- tion in catalyst loading even to 0.2 mol% of catalyst
vents, it was expected that some solvents would be C1–1 resulted in 58% conversion after 80 h (entries 11
more “active” than dichloromethane, which could and 12).
allow the reaction to proceed with lower catalyst
loading. It has been reported that a similar reaction
could take place in alcohols solely using amine cata- Effect of the Loadingof Additive Base
lyst,[11e] which indicated that alcohols might be more
active solvents. But in our case, the use of alcohols We then investigated the effect of the loading of the
would cause low enantioselectivities. Thus, we hoped additive base, lithium 4-fluorobenzoate, on the reac-
that introduction of a small amount of alcohol to di- tion. The results are shown in Table 5. The loading
chloromethane could increase the reaction efficiency of lithium 4-fluorobenzoate could be reduced to 5
without any decrease in enantioselectivity.
mol% without any decrease in reaction efficiency
Experiments indicated that this treatment was fea- and enantioselectivity (entries 1–5). Further reduc-
sible. For example, full conversion was afforded after tion in the loading of lithium 4-fluorobenzoate even
16 h in a mixed solvent of CH2Cl2/MeOH or CH2Cl2/ to 1 mol% gave 77% conversion after 84h (entries 6
EtOH (90:10 v:v) using 5 mol% of C1–1 with, respec- and 7).
Table 4. Effect of catalyst loading.
Entry
Solvent (v:v)[a]
Catalyst [%]
Additive
Time [h]
Conversion [%][b]
ee [%][c]
1
2
3
CH2Cl2
CH2Cl2
CH2Cl2
10
5
1
5
5
5
2
1
1
LiOAc
LiOAc
LiOAc
LiOAc
LiOAc
LiOAc
LiOAc
LiOAc
12
72
72
16
16
16
72
72
36
40
80
80
95
87
22
95
95
95
85
82
95
95
85
58
95
94
nd
89
92
95
94
95
92
96
96
96
4CH
5
6
7
8
2Cl2:EtOH (90:10)
CH2Cl2:MeOH (90:10)
CH2Cl2:MeOH (95:5)
CH2Cl2:MeOH (95:5)
CH2Cl2:MeOH (95:5)
CH2Cl2:MeOH (90:10)
CH2Cl2:MeOH (90:10)
CH2Cl2:MeOH (90:10)
CH2Cl2:MeOH (90:10)
9
LiOAc
10
11
12
1
0.5
0.2
4-FC6H4CO2Li
4-FC6H4CO2Li
4-FC6H4CO2Li
[a]
In each case, the reaction was run with cinnamaldehyde (1.0 mmol), diethyl malonate (3.0 mmol), C1–1 and additive base
(0.3 mmol) in solvent (2.0 mL) at room temperature.
The conversion was determined by GC.
[b]
[c]
The enantiomeric excess was determined by GC after conversion to the corresponding lactone.
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Table 5. Effect of the amount of additive base.
taking place at a low level of catalyst loading. The re-
action was almost inactive in the absence of additive
base, for example, only 11% conversion was observed
after 84h with 1 mol% of catalyst C1–1 alone
(entry 8). This result indicated that the Brønsted base
was actually playing a role in activating the nucleo-
philic reagent. Thus, Lewis base–Brønsted base bi-
functional catalysis might provide a practical and effi-
cient dual-activation method for enantioselective Mi-
chael additions.
Entry Additive Base
[%][a]
Time
[h]
Conversion
[%][b]
ee
[%][c]
Thus, after investigating the effects of a series of
factors, the optimized reaction conditions can now be
outlined as follows: reaction using 1.0 mol% of amine
catalyst C1–1, 5.0 mol% of lithium 4-fluorobenzoate
and a mixed solvent of CH2Cl2/MeOH (90:10 v:v) at
room temperature. Under these conditions, the addi-
tion of diethyl malonate to cinnamaldehyde could
proceed to full conversion within 40 h with 96% ee.
1
2
3
410
5
6
7
8
50
30
20
4
4
4
0
0
0
96
95
95
95
96
96
96
96
0
4
96
5
2
1
0
4
0
96
8485
8477
8411
96
96
nd
[a]
In each case, the reaction was run with cinnamaldehyde
(1.0 mmol), diethyl malonate (3.0 mmol), C1–1
(0.01 mmol) and 4-F-C6H4CO2Li in CH2Cl2:MeOH=
90:10 (v:v, 2.0 mL) at room temperature.
The conversion was determined by GC.
The enantiomeric excess was determined by GC after
conversion to the corresponding lactone.
Addition of Malonates to Cinnamaldehyde
[b]
[c]
To demonstrate the generality of the base–base bi-
functional catalytic Michael addition, a series of a,b-
unsaturated aldehydes and malonates were then
tested. The addition of various malonates to cinna-
maldehyde was investigated first and the results are
presented in Table 6.
Although it has been reported that this reaction
The addition reaction proceeded well for various
could take place with ordinary iminium catalysis in malonates such as dimethyl, diethyl, dibenzyl and di-
ethanol using C2 solely as organocatalyst, the reaction isopropyl esters with full conversion and excellent
in the base–base bifunctional condition was quite dif- enantioselectivities using only 1 mol% of catalyst C1–
ferent and had higher efficiency. In fact, the existence 1 and 5 mol% of lithium 4-fluorobenzonate within
of additive base was essential when the reaction was 40 h (entries 1–3, 5). Low conversion was observed
Table 6. Addition of malonates to cinnamaldehyde.
Entry
R[a]
Malonate:Cinnamaldehyde [mol:mol]
Time [h]
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
Me
i-Pr
Bn
t-Bu
Et
Et
Et
Et
3.0:1.0
3.0:1.0
3.0:1.0
3.0:1.0
3.0:1.0
1.5:1.0
1.0:1.5
1.0:3.0
40
40
36
72
40
60
60
40
71
82
86
45 (65)
81 (95)
(85)
(75)
(95)
95
95
95
97
96
96
96
96
[a]
In each case, the reaction was run with cinnamaldehyde (1.0 mmol), malonate (3.0 mmol), C1–1 (0.01 mmol) and 4-F-
C6H4CO2Li (0.05 mmol) in CH2Cl2:MeOH=90:10 (v:v, 2.0 mL) at room temperature.
Isolated yield, the values in parenthesis indicated the conversion that was determined on GC.
The enantiomeric excess was determined by GC after conversion to the corresponding lactone.
[b]
[c]
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Yongcan Wang et al.
FULL PAPERS
for less active di-tert-butyl ester while excellent enan- using only 1 mol% of catalyst C1–1 and 5 mol% of
tioselectivity was still obtained (entry 4). lithium 4-fluorobenzonate (entries 1–9). Aromatic
More experiments indicated that the ratio of malo- heterocyclic a,b-unsaturated aldehydes such as 3-
nate to cinnamaldehyde also affected the conversion (furan-2-yl)acrylaldehyde also resulted in full conver-
of the reaction. An excess of one of the substrates, sion and 84% ee under the same conditions
either malonate or cinnamaldehyde, was necessary for (entry 10).
the reaction. For full conversion, at least 3:1 (mole-
cule ratio) of substrate was needed (entries 5–8).
The addition of diethyl malonate to aliphatic a,b-
unsaturated aldehydes also exhibited promising re-
sults. The addition of crotonaldehyde yielded full con-
version with 80% ee using 1 mol% of catalyst C1–1
and 5 mol% of lithium 4-fluorobenzonate (entry 11).
While other kinds of alkyl a,b-unsaturated aldehydes,
such as pentenal and hexenal, yielded full conversion,
Addition of Diethyl Malonate to a,b-Unsaturated
Aldehydes
The addition of diethyl malonate to various a,b-unsa- although 5 mol% of catalyst C1–1 and 30 mol% of
turated aldehydes was also evaluated and some of the lithium 4-fluorobenzonate were needed with, respec-
representative results are shown in Table 7.
tively, 85% and 88% ee (Entries 12, 13). However, 3-
The addition of diethyl malonate to aromatic a,b- methylpentenal was inactive under these conditions,
unsaturated aldehydes achieved good results. Cinna- and only 5% conversion was obtained after 120 h
maldehyde derivatives with an electron-withdrawing (entry 14). These results implied that base–base bi-
or -donating group in the o-, m-, or p-position of the functional catalysis might be an efficient method for
benzene ring all yielded full conversion and good to the enantioselective Michael addition of aliphatic a,b-
excellent enantioselectivity ranging from 87% to 99% unsaturated aldehydes and malonates.
Table 7. Addition of diethyl malonate and a,b-unsaturated Conclusions
aldehydes.
In summary, we have developed a new Lewis base–
Brønsted base bifunctional catalytic method. The
method reported here provides a dual-activation pro-
cedure for the asymmetric catalytic Michael addition
of malonates to a,b-unsaturated aldehydes with high
efficiency and enantioselectivity even using 0.5–1.0
mol% catalyst. The results indicate that this method-
ology might have practical and general utility for
Entry
R[a]
Time [h]
Yield [%][b]
ee [%][c]
enantioselective catalysis. Further investigations on
the scope of this methodology are currently ongoing
and the results of these studies will be presented in
due course.
1
2
3
Ph
4
36
36
36
60
36
36
4
0
81
96
4-ClC6H4
2-NO2C6H4
2C6H4
2-MeOC6H4
3-MeC6H4
4-MeC6H4
4-FC6H4
3-ClC6H4
2-Furanyl
Me
73
85
81
65
76
75
95
>99
95
94
90
-NO 44
5
6
7
8
91
Experimental Section
94
92
General Information and StartingMaterials
0
8
72
76
9
4
40
40
10
11
12
13
14
76
71
61
67
(5)
84
80
85
88
nd
The 1H NMR and 13C NMR were recorded on a Bruker
DRX 400 (400 MHz) instrument. Chromatography was car-
ried out with silica gel (350–400 mesh) using mixtures of pe-
troleum ether and ethyl acetate as eluents. NMR data of
known compounds are in agreement with literature values.
All solvent and inorganic reagents were of p.a. quality and
used without purification. Malonates and a,b-unsaturated al-
dehydes were obtained from commercial sources. Cinnamal-
dehyde and crotonaldehyde were purified by distillation
before use; other materials were used without purification.
All acetate salts were obtained from commercial sources.
Lithium benzoates and trifluoroacetate were prepared by
the reaction of lithium hydroxide with corresponding acid.
Catalyst C was prepared as described in the literature.[14]
Et
n-Pr
i-Pr
120[d]
60[d]
120[d]
[a]
In each case, the reaction was run with a,b-unsaturated
aldehyde (1.0 mmol), diethyl malonate (3.0 mmol), C1–1
(0.01 mmol) and 4-F-C6H4CO2Li (0.05 mmol) in
CH2Cl2:MeOH=90:10 (v:v, 2.0 mL) at room tempera-
ture.
Isolated yield, the values in parenthesis indicated the
conversion that was detected on GC.
The enantiomeric excess was determined by GC or
HPLC after derivatization.
[b]
[c]
[d]
The reaction was run with 5 mol% of C1–1 and 30 mol%
of 4-F-C6H4CO2Li.
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Base–Base Bifunctional Catalysis
FULL PAPERS
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General Procedure for the Base–Base Bifunctional
Michael Addition of Malonates to a,b-Unsaturated
Aldehydes
To a mixed solvent system of CH2Cl2:MeOH=90:10 (v:v,
2.0 mL) was added a,b-unsaturated aldehyde 1 (1.0 mmol),
malonate 2 (3.0 mmol), C1–1 (3.3 mg, 0.01 mmol) and lithi-
um 4-fluorobenzonate (7.3 mg, 0.05 mmol). The reaction
mixture was stirred at room temperature for the time indi-
cated in Table 6 and Table 7 and then water (5.0 mL) was
added. The organic materials were extracted with CH2Cl2
three times. The combined organic phases were dried over
anhydrous Na2SO4, filtered and evaporated under vacuum.
The residue was purified by column chromatography on
silica gel (350–400 mesh) to yield the desired addition prod-
uct.
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Acknowledgements
We acknowledge the start-up fund from East China Universi-
ty of Science and Technology.
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