Enantioselective Michael addition of ketones to maleimides catalyzed by bifunctional monosulfonyl DPEN salt

Article abstract of DOI:10.1039/c0cc00774a

An unprecedented enantioselective Michael addition of various ketones to maleimides catalyzed by a simple bifunctional primary amine, monosulfonyl DPEN salt, is reported and provides the desired adducts in good to excellent yields (up to 99%) with excellent enantioselectivities (up to 99%).

Full text of DOI:10.1039/c0cc00774a

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Enantioselective Michael addition of ketones to maleimides catalyzed
by bifunctional monosulfonyl DPEN saltw
Feng Yu, Xiaomin Sun, Zhichao Jin, Shigang Wen, Xinmiao Liang* and Jinxing Ye*
Received 5th April 2010, Accepted 22nd April 2010
First published as an Advance Article on the web 18th May 2010
DOI: 10.1039/c0cc00774a
An unprecedented enantioselective Michael addition of various
ketones to maleimides catalyzed by a simple bifunctional primary
amine, monosulfonyl DPEN salt, is reported and provides the
desired adducts in good to excellent yields (up to 99%) with
excellent enantioselectivities (up to 99%).
It is well known that substituted maleimides are an important
class of compounds that are found in many biologically
interesting substances, such as substituted succinimides and
functionalized pyrrolidines.1 The catalytic asymmetric Michael
addition to electron-deficient alkenes is a useful strategy for
the construction of carbon–carbon bonds.2 In sharp contrast,
Fig. 1 Organocatalysts for the conjugate addition of ketones to
maleimides.
the asymmetric addition to maleimides remains elusive. To
date, only several elegant protocols have been reported. Chiral
metal complexes were kind of powerful catalysts in asym-
metric addition of aryl boronic acids,3 hydrazoic acid,4 and
hydroxyketones5 to maleimides. Natural cinchona alkaloids6
and chiral bicyclic guanidines7 were also successfully used
as catalysts for the Michael addition of 1,3-dicarbonyl com-
pounds to maleimides. Wang demonstrated an ingenious domino
Michael-Aldol reaction between 2-mercaptobenzaldehydes and
malemindes catalyzed by chiral amine thiourea.8 An efficient
method for the addition of unmodified aldehydes to maleimides
was reported by Cordova, employing chiral diphenylprolinol silyl
ether as the enamine activation organocatalyst.9
presence of benzoic acid at room temperature in dichloro-
methane. Several kinds of simple chiral primary amine
catalysts were screened because they can activate acetone by
formation of an enamine intermediate (Fig. 1). The results are
summarized in Table 1. Bifunctional catalysts 1 and 2 readily
Table 1 Screening of reaction conditions for the organic catalytic
Michael Reaction of 5a to 6aa
In the past few years, chiral primary amines have been
increasingly considered as powerful organocatalysts in many
asymmetric reactions.10 Many reports revealed that primary
amines were suitable for the generation of nucleophilic enamines,
which could lead to an efficient addition to electron-deficient
alkenes.11–13 To the best of our knowledge, only Barbas and
co-workers reported the Michael addition of acetone to
maleimide without asymmetric induction.14 Therefore, catalytic
asymmetric Michael addition of ketones to maleimides remains a
challenge, and both stereoselectivity and substrate scope are
highly desirable to explore. In this communication, we disclosed
an enantioselective Michael addition of ketones to maleimides
catalyzed by a chiral monosulfonyl DPEN salt in good yields
(up to 99%) with excellent enantioselectivities (up to 99%).
Our investigation initially performed a model reaction
between acetone (5a) and N-phenylmaleimide (6a) in the
Entry
Catalyst
Solvent
Conv.%b
ee%c
1
2
3
4
5
6
7
8
1
2
3
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
Methanol
Acetonitrile
THF
79
29
87
72
70
78
52
56
39
36
80
79
o5
19
34
36
47
34
full
full
83
33
13
49
93
94
93
94
90
95
94
96
96
nd
96
93
94
98
97
95
95
98
4a
4b
4c
4d
4e
4f
4g
4h
4i
9
10
11
12
13
14d
15
16
17
18
19
20
21
4j
4h
4h
4h
4h
4h
4h
4h
4h
1,4-dioxane
Et2O
n-Hexane
Toluene
Engineering Research Centre of Pharmaceutical Process Chemistry,
Ministry of Education, School of Pharmacy, East China University of
Science and Technology, 130 Meilong Road, Shanghai 200237, China.
E-mail: yejx@ecust.edu.cn, liangxm@ecust.edu.cn
w Electronic supplementary information (ESI) available: Experimental
procedures and characterization of the Michael addition products.
CCDC 772273. For ESI and crystallographic data in CIF or other
electronic format see DOI: 10.1039/c0cc00774a
a
Experimental conditions: The reaction was carried out in a 0.2 mmol
scale in undistilled solvent with a 5 : 1 ratio of 5a to 6a for 48 h.
b
Conversion was determined by GC analysis of the crude product
c
mixture. Enantiomeric excess was determined by chiral HPLC analysis.
d
Without acidic additive.
ꢀc
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prepared from (R, R)-1,2-cyclohexanediamine showed moderate
conversions with low enantioselectivities (entries 1–2). When the
primary amine framework was switched to (R, R)-1,2-diphenyl-
ethylenediamine, to our delight, the sulfonamide catalyst 4a15
showed a promising result with an excellent ee value (93%) and
good conversion (72%) (entry 4).
Table 2 Scope of organocatalytic conjugate addition of ketones to
maleimides forming one stereogenic centera
Encouraged by this result, we surveyed 4a’s analogues 4b–j
bearing various sulfonyl groups for the model reaction.
Excellent enantioselectivities and good conversions were
obtained when catalysts 4b–c were employed (entries 5–6). When
4e–f with a CF3 and NO2 group in the ortho position of the
phenylsulfonyl substituents were used, the catalytic activity
decreased to moderate levels (entries 8–9). In the case of 4g,
replacing the aryl group with a less bulky methyl group, a
moderate conversion was also observed (entry 10). 4h and 4i
gave the best results both in catalytic activities and ee values
(96% ee) (entries 11–12). Almost no reaction occurred when the
more hindered catalyst 4j was employed (entry 13). This
indicates that suitable sterically hindered sulfonyl groups in 4
may play a role in enhancing both enantioselectivity and
reactivity. Notably, in the absence of benzoic acid additive, the
conversion significantly depreciated to 19% (entry 14). This
result clearly evinces that acidic additives can promote the
formation of enamine effectively and favor the catalytic reaction.
The reaction conditions were further optimized for 4h. The
solvent was found to have remarkable effects on the catalytic
activity. In solvents of MeOH, CH3CN, THF and 1,4-dioxane,
the reaction became sluggish likely due to the great effect of the
hydrogen-bonding between catalyst and solvent (entries 15–18).
In contrast, high catalytic activities toward the reaction were
generally obtained in non-polar solvents. Toluene was the best
solvent giving the highest ee of 98% with good conversion
(83%) (entry 21).
Entry R1
R2 R3
Yieldb (%,7) ee%c
1
2
Me
Me
H
H
H
H
H
H
H
H
H
H
H
H
H
Ph(6a) 87(7a)
p-CH3Ph(6b) 91(7b)
98
98
96
97
94
98
98
96
96
99
99
92
99
93
96
99
98
94
98
95
97
91
nd
3
4
Me
Me
p-CF3Ph(6c)
p-BrPh(6d)
p-ClPh(6e)
p-OCH3(6f)
m-ClPh(6g)
99(7c)
93(7d)
94(7e)
96(7f)
94(7g)
5
6
Me
Me
7
8
Me
Me
m-CF3Ph(6h) 98(7h)
9
Me
Me
Me
Me
Me
Me
Me
Me
m-CH3Ph(6i)
Bn(6j)
Pr(6k)
i-Pr(6l)
t-Bu(6m)
97(7i)
86(7j)
94(7k)
92(7l)
69(7m)
93(7n)
73(7o)
99(7p)
98(7q)
72(7r)
62(7s)
10
11d
12e
13e
14f
15f
16f
17f
18g
19g
20g
21g
22g
23
Me Ph(6a)
Me p-CF3Ph(6c)
Me p-BrPh(6d)
Me p-ClPh(6e)
Me
Trans-PhC2H2
Trans-PhC2H2
Trans-PhC2H2
Trans-o-FPhC2H2
Trans-p-BrPhC2H2
Ph
H
H
H
H
H
H
Ph(6a)
p-ClPh(6e)
p-CH3Ph(6b) 76(7t)
Ph(6a)
p-ClPh(6e)
Ph(6a)
63(7u)
72(7v)
o10
a
Experimental conditions: The reaction was carried out using
0.05 mmol of catalyst 4h (10 mol%) and benzoic acid (10 mol%),
0.5 mmol of 6, and 2.5 mmol of ketones 5 (5.0 equiv.) in 0.50 mL
b
c
toluene. Isolated yield. Determined by chiral HPLC analysis
d
e
f
g
(see ESI for details). Reaction time: 72 h. 120 h. 140 h. Experi-
mental conditions: The reaction was carried out using 0.1 mmol of
catalyst 4a (20 mol%) and benzoic acid (20 mol%), 0.5 mmol of 6, and
1.0 mmol of enones 5 (2.0 equiv.) in 0.50 mL toluene at 50 1C.
Under the optimized conditions, the scope of the catalytic
asymmetric Michael addition was explored. Experiments of
different ketones to N-substituted maleimides forming one
stereogenic center are summarized in Table 2. It appears that
for the aromatic maleimides, the patterns of the substituents
have little effect on the reaction in terms of enantioselectivity
(94–98%) and yield (87–98%) (entries 1–9). In addition,
similar enantioselectivities were obtained in the reaction of
acetone and N-alkyl substituted maleimides (entries 10–13).
Interestingly, methyl isopropyl ketone 5b as an a-branched
ketone gave exclusive products at the sterically more hindered
side with high yields and excellent enantioselectivities, but
their reaction time was prolonged probably due to the steric
reasons (entries 15–17). Moreover, the protocol also proved to
be effective with respect to aromatic enones affording the
Table 3 Scope of organocatalytic conjugate addition of ketones to
maleimides forming two stereogenic centersa
Entry
6
R2
R3
Et
Time/h Yieldb(%, 9) drc
ee%d
1
2
3
4
5
6
6i Et
48
48
96(9a)
96(9b)
80(9c)
96(9d)
93(9e)
93(9f)
1 : 1 97 : 99
>4 : 1 99 : 95
>4 : 1 99 : 94
3 : 1 93 : 94
2 : 1 96 : 99
2 : 1 92 : 96
6a n-Pr n-Pr
6a n-Bu n-Bu
6j –(CH2)5–
6a –(CH2)6–
6c –(CH2)6–
72
48
72
120
expected Michael adducts (entries 18–22).
A dramati-
cally decreased reactivity was observed for aromatic ketones
(entry 23).
a
Experimental condition: The reaction was carried out using
0.05 mmol of catalyst 4 h (10 mol%) and benzoic acid (10 mol%),
0.5 mmol of 6, and 2.5 mmol of 8 (5.0 equiv.) in 0.50 mL toluene.
The reaction appears quite general with respect to other
acyclic ketones and cyclic ketones without compromising the
yields as shown in Table 3. The addition of 3-pentanone to
maleimide afforded the 1,4-adduct and approximately a 1 : 1
diastereomeric mixture was observed (entry 1), but both
diastereomers were formed in excellent ee (96–99%). The
reaction of long chain ketones gave considerably higher
diastereoselectivities (>4 : 1) (entries 2–3). Addition of the
b
c
Isolated yield. The diastereoisomer ratios were determined by
d
1H NMR of crude products. Determined by chiral HPLC analysis
(see Supporting Information for details).
cyclic ketones also proceeded in high yields (>93%)
with good enantioselectivities (>92%) in approximately 2 : 1
diastereomeric ratios (entries 6–8).
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Fig. 2 Proposed transition state of the asymmetric Michael reaction
catalyzed by monosulfonyl DPEN and absolute configuration of the
adduct 7d.
The S absolute configuration of the asymmetric Michael
adduct 7d was determined by X-ray crystallographic analysis
(see ESI).w A transition state model was invoked to account for
the observed stereochemical outcome of the reaction (Fig. 2).
Acetone is activated through an enamine intermediate. The
hydrogen bonding activation of the acceptor maleimide by the
acidic proton of sulfonamide triggers the reaction to proceed via
the enamine mechanism. This transition state model avoids the
steric repulsion between the maleimide and the phenyl of the 1,2-
diphenylethylenediamine and substituted sulfonyl group, as well
as the maleimide and enamine. Therefore, the bulky substituent
in the sulfonamide (2,4,6-i-Pr3C6H2 in 3j) induced strong steric
repulsion between the maleimide and the substituted sulfonyl
group, which diminished the hydrogen bonding interaction, and
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In summary, we have demonstrated an unprecedented
example in the asymmetric Michael addition of ketones to
maleimides catalyzed by a simple bifunctional monosulfonyl
DPEN salt, providing Michael adducts in good to excellent
yields with excellent enantioselectivities. Further efforts to
evaluate the scope of the catalytic chemistry are currently
under the way.
12 For selected examples of asymmetric conjugate addition of
a,b-unsaturated ketones in enamine activations, see:
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We are grateful for the financial support from the Shanghai
Pujiang Program (08PJ1403300), the National Natural Science
Foundation of China (20902018) and the Fundamental Research
Funds for the Central Universities.
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ꢀc
This journal is The Royal Society of Chemistry 2010
Chem. Commun., 2010, 46, 4589–4591 | 4591