Highly enantioselective Michael addition of α,α-disubstituted aldehydes to maleimides catalyzed by new primary amine-squaramide bifunctional organocatalysts

Article abstract of DOI:10.1016/j.tetlet.2017.10.026

New bifunctional primary amine-squaramides catalyzed asymmetric Michael addition reaction of α,α-disubstituted aldehydes to maleimides has been developed. This organocatalytic asymmetric reaction provides easy access to functionalized succinimides with a

Full text of DOI:10.1016/j.tetlet.2017.10.026

Accepted Manuscript
Highly enantioselective Michael addition of α,α-disubstituted aldehydes to mal-
eimides catalyzed by new primary amine-squaramide bifunctional organocata-
lysts
Zhi-wei Ma, Xiao-feng Liu, Jun-tao Liu, Zhi-jing Liu, Jing-chao Tao
PII:
S0040-4039(17)31304-7
https://doi.org/10.1016/j.tetlet.2017.10.026
TETL 49388
DOI:
Reference:
Tetrahedron Letters
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Received Date:
Revised Date:
Accepted Date:
5 July 2017
3 October 2017
9 October 2017
Please cite this article as: Ma, Z-w., Liu, X-f., Liu, J-t., Liu, Z-j., Tao, J-c., Highly enantioselective Michael addition
of α,α-disubstituted aldehydes to maleimides catalyzed by new primary amine-squaramide bifunctional
organocatalysts, Tetrahedron Letters (2017), doi: https://doi.org/10.1016/j.tetlet.2017.10.026
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Tetrahedron Letters
journal homepage: www.els evier.com
Highly enantioselective Michael addition of α,α-disubstituted aldehydes to
maleimides catalyzed by new primary amine-squaramide bifunctional organocatalysts
Zhi-wei Maa, ∗, Xiao-feng Liub, Jun-tao Liua, Zhi-jing Liua and Jing-chao Taob,*
aDepartment of Fundamental Courses, Henan University of Animal Husbandry and Economy, No. 2 Yingcai Street, Huiji District, Zhengzhou 450044, Henan,
People’s Republic of China
bCollege of Chemistry and Molecular Engineering, Zhengzhou University, No.100 Science Avenue, High-Tech Zone, Zhengzhou 450001, Henan, People’s
Republic of China
ARTICLE INFO
ABSTRACT
Article history:
Received
New bifunctional primary amine-squaramides catalyzed asymmetric Michael addition reaction
of α,α-disubstituted aldehydes to maleimides has been developed. This organocatalytic
asymmetric reaction provides easy access to functionalized succinimides with a broad substrate
scope. Both enantiomers of desired succinimide derivatives were obtained in good to excellent
yields (up to 98%) with excellent enantioselectivities (up to >99% ee).
Received in revised form
Accepted
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
Primary Amine-Squaramide
Organocatalysis
Michael addition
Aldehyde
Maleimide
Succinimide Derivative
Introduction
Chiral squaramide is a novel type of H-bonding promoted
asymmetric organocatalyst 11. Since the pioneering work by
Rawal in 2008 12, who reported a chiral squaramide in the
conjugated addition reactions of 1,3-dicarbonyl compounds to β-
nitrostyrenes, squaramide-based organocatalysts have been
The Michael reaction promoted by organocatalysts has been
widely utilized for the efficient formation of C-C bond due to the
1
value of the Michael adducts as synthetic building blocks
.
widely utilized in various asymmetric reactions 13
.
Among the various unsaturated Michael acceptors, maleimides
are an important class of substrates. The asymmetric
organocatalytic functionalization of maleimides could produce
chiral substituted succinimide derivatives which are widely
distributed in natural products and pharmaceuticals 2. As a result,
much attention has been paid to the development of catalytic
asymmetric Michael addition using maleimides as the substrates
and impressive progress have been achieved 3.
In 2007, Córdova first described the asymmetric Michael
reaction of aldehydes to maleimides catalyzed by
diphenylprolinolsilyl ether with moderate yields and
Figure 1. Chiral primary amine–squaramide
As part of our ongoing interest in the asymmetric
organocatalysis 5h,14, we have demonstrated for the first time that
the novel chiral primary amine–squaramide organocatalysts
derived from commercially available natural product stevioside
could promote the asymmetric conjugated addition of
isobutyraldehyde to various nitroolefins at room temperature in
high yields (up to 98%) with high to excellent enantioselectivities
(up to 99% ee). This catalytic protocol provided both
enantiomers of the corresponding products with almost the same
ee value. Based on our previous work, and in order to broaden
the application scope of the novel organocatalysts, we herein
enantioselectivities obtained when sterically hindered α,α-
4
disubstituted aldehydes were employed as the nucleophiles
Since then, many types of chiral organocatalysts such as primary
.
5
6
amine thioureas , 1,2-diamines , monoprotected 1,2-diamines 7,
8
primary amine guanidines
,
primary amine 2-amino
9
10
benzimidazole , and primary amine 2-amino pyrimidine have
been developed for this important carbon–carbon bond forming
reaction. However, no report was described on this asymmetric
reaction using chiral squaramide as catalyst to date.
———
∗ Corresponding author. e-mail: zwma@hnuahe.edu.cn, jctao@zzu.edu.cn

2
Tetrahedron Letters
report the asymmetric Michael addition of α,α-disubstituted
aldehydes to maleimides catalyzed by chiral primary amine-
squaramide catalysts.
stereoselectivity of the catalytic system. For example, it has been
shown that PhCOOH was often applied as an efficient promoter
for the chiral thiourea catalyzed asymmetric Michael
reaction.6a,6b,8g-i,8k To our delight, when PhCOOH was utilized as
an additive, not only the reaction rate was dramatically
accelerated, but the yield and enantioselectivity were promoted
significantly(Table 2, entry 5). Encouraged by this result, we
attempted to further decrease the catalyst loading to 0.5 mol%,
the product was still obtained in high yield with excellent
enantioselectivity (Table 2, entry 6). However, when the amount
of catalyst was reduced to 0.2 mol%, the reaction was rather
sluggish so that the yield was only 56% after 36 hours. (Table 2,
entry 7). Taking into account the beneficial effects of benzoic
acid on accelerating the reaction, 1.0 mol% PCOOH with 0.2
mol% 1a were introduced as catalysts. The reaction was still
proceeding slowly (Table 2, entry 8). 0.2 mol% catalyst was not
applicable. Based on the above results, the optimal reaction
conditions employed 0.40 mmol 2a (2.0 equiv.) and 0.20 mmol
3a(1.0 equiv.) as the substrates, 0.5 mol% PhCOOH as the
additive, and 0.5 mol% 1a or 1b as the catalyst in 1.0 mL toluene
at ambient temperature for 12 h (Table 2, entry 9).
Results and Discussion
Table 1. Solvent screening a
Entry
Catalyst
1a
Solvent
CHCl3
CHCl3
Ether
Yield (%)b
ee (%)c
98 (S)
97 (R)
87 (S)
97 (S)
99 (S)
98 (S)
11 (S)
28 (S)
82 (S)
1
2
87
71
10
27
94
86
22
24
86
1b
3
1a
4
THF
1a
5
Toluene
CH2Cl2
CH3OH
H2O
1a
6
1a
7
1a
Table 2. Optimization of conditions a
8
9d
1a
Neat
1a
a Unless otherwise specified, all reactions were carried out using
isobutyraldehyde (2a, 0.40 mmol), N-phenylmaleimide (3a, 0.20 mmol) and
10 mol% 1a or 1b in 1.0 mL solvent at room temperature for 5-20 h.
bIsolated yield.
c Determined by chiral HPLC analysis.
d 0.80 mmol isobutyraldehyde was used.
Entry
X
10
5
Y
-
Time (h)
Yield (%)b
ee (%)c
99 (S)
99 (S)
99 (S)
ndd
The efficacy of bifunctional amine-squaramides 1a and 1b as
chiral organocatalysts was initially evaluated using the reaction
of isobutylaldehyde and N-phenylmaleimide in CHCl3 at room
temperature (Table 1, entries 1-2). Under the same conditions,
both the catalyst 1a and 1b gave the desired product 4a in good
yields with high enantioselectivities, as well as a reversal of the
absolute configuration of product 4a. These results indicate that
both the (S,S) and the (R,R) configuration of 1,2-
diaminocyclohexane moiety can well match the isosteviol
scaffold of 1a and 1b. Furthermore, the configuration of 1,2-
diaminocyclohexane moiety predominates the absolute
configuration of product 4a.
1
2
3
4
5
6
7
8
9e
5
94
93
-
12
48
48
5
2
-
51
1
-
trace
95
1
1
99 (S)
>99 (S)
98 (S)
99 (S)
>99 (R)
0.5
0.2
0.2
0.5
0.5
0.2
1.0
0.5
12
48
36
12
95
56
92
98
a
Unless otherwise specified, all reactions were carried out using
isobutyraldehyde (2a, 0.40 mmol) and N-phenylmaleimide (3a, 0.20 mmol)
in 1.0 mL toluene at room temperature.
bIsolated yield.
c Determined by chiral HPLC analysis.
d Not determined.
Next, various solvents were examined at room temperature
using 1a as the catalyst. When the reaction was carried out in
ether and THF, poor yields were observed (Table 1, entries 3-4).
In the case of toluene, the Michael adduct could be obtained in
higher yield and excellent enantioselectivity (Table 1, entry 5). In
dichloromethane, catalyst 1a also efficiently promoted the
reaction but the yield and ee value were almost the same as those
in chloroform (Table 1, entry 6). Solvents such as MeOH and
H2O, which could disturb the H-bonding of 1a with 3a, reduced
the yield and enantioselectivity dramatically (Table 1, entries 7-
8). With respect to the neat condition, the reaction carried out
smoothly to furnish the product in high yield with good
enantioselectivity (Table 1, entry 9). A screen of solvents
revealed that toluene was the most suitable solvent.
e Catalyst 1b was used.
With the optimized conditions in hand, the reaction of various
isobutylaldehydes and N-phenylmaleimides were examined to
explore the generality of this novel catalytic system, which are
summarized in Tables 3. A broad range of N-aryl maleimide
derivatives reacted smoothly with isobutylaldehyde in high yields
with excellent enantioselectivities (Table 3, entries 1-22).
Generally, substituents on the aromatic rings slightly influenced
the yields and enantioselectivities. Electron-neutral (Table 3,
entries 1-2), -withdrawing (Table 3, entries 3-16), and-donating
(Table 3, entries 17-22) substituted N-phenylmaleimides were all
well tolerated to provide highly enantioselective adducts. In the
change to alkyl-substituted maleimides, benzyl maleimide 3l and
cyclohexyl maleimide 3m were observed to perform similarly to
aryl maleimides (Table 3, entries 23-26). We found that
maleimide 3n bearing no substituent group on the nitrogen atom
was also effective reaction partner in the Michael reaction with
isobutylaldehyde (Table 3, entries 27-28). It is clear that the
product's enantioselectivity actually decreased more than a little
compared to other substrates. The hydrogen of maleimide may
Subsequently, the effects of the catalyst loadings, additives,
and reaction time were investigated. Surprisingly, lowing the
catalyst loading from 10 mol% to 5 mol% did not affect the yield
and enantioselectivity (Table 2, entries 1-2). Further decrease of
the catalyst loading to
2
mol% did not affect the
enantioselectivity, but the yield was diminished significantly
(Table 2, entry 3). When the 1 mol% catalyst loading was
employed, the reaction was very sluggish and only trace amount
of the product was obtained (Table 2, entry 4). To make the
organocatalyst more effective, the role of suitable additive, or co-
catalyst, could be crucial in enhancing the reactivity and

affect the H-bonding interaction between the catalyst and the
substrate.
yields with excellent enantioselectivities (Table 2, Entries 29-38).
Next, two nonsymmetrical aldehydes were utilized, since in this
manner the formation of two contiguous (quaternary-tertiary)
stereogenic centers will be possible (Table 2, Entries 39-42). In
all cases, high yields and excellent enantioselectivities were
obtained. Unfortunately, the dr was not very good, from 58/42 to
66/34.
We next investigated the Michael reaction of other aldehydes
to maleimide. For symmetrical α,α-disubstituted aldehyde,
cyclohexyl formaldehyde 2b reacted with maleimides smoothly,
and the corresponding Michael adducts were obtained in good
Table 3. Substrate Scope of the Michael Addition a
Entry
1
R1,R2
R3
Adduct
(S)-4a
(R)-4a
(S)-4b
(R)-4b
(S)-4c
(R)-4c
(S)-4d
(R)-4d
(S)-4e
(R)-4e
(S)-4f
Yield (%)b
97
98
91
95
91
90
92
95
96
92
90
87
89
92
93
91
97
97
98
95
90
93
95
97
99
99
96
98
97
98
91
88
88
85
90
86
92
90
95
93
92
98
drc
ee (%)c
99
Cat.
1a
1b
1a
1b
1a
1b
1a
1b
1a
1b
1a
1b
1a
1b
1a
1b
1a
1b
1a
1b
1a
1b
1a
1b
1a
1b
1a
1b
1a
1b
1a
1b
1a
1b
1a
1b
1a
1b
1a
1b
1a
1b
-
Me, Me (2a)
C6H5 (3a)
2
-
>99
99
3
-
Me, Me (2a)
Me, Me (2a)
Me, Me (2a)
Me, Me (2a)
Me, Me (2a)
Me, Me (2a)
Me, Me (2a)
Me, Me (2a)
Me, Me (2a)
Me, Me (2a)
Me, Me (2a)
Me, Me (2a)
Me, Me (2a)
-(CH2)5- (2b)
-(CH2)5- (2b)
-(CH2)5- (2b)
-(CH2)5- (2b)
-(CH2)5- (2b)
Me, Et (2c)
4-FC6H4 (3b)
3-ClC6H4 (3c)
4-ClC6H4 (3d)
3-BrC6H4 (3e)
4-BrC6H4 (3f)
3-NO2C6H4 (3g)
4-NO2C6H4 (3h)
4-OCH3C6H4 (3i)
4-CH3C6H4 (3j)
2,6-(CH3)2C6H3 (3k)
C6H5CH2 (3l)
c-hexyl (3m)
H (3n)
4
-
>99
98
5
-
6
-
>99
98
7
-
8
-
>99
98
9
-
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
-
99
-
99
(R)-4f
(S)-4g
(R)-4g
(S)-4h
(R)-4h
(S)-4i
-
>99
98
-
-
>99
98
-
-
>99
>99
>99
99
-
(R)-4i
-
(S)-4j
-
(R)-4j
(S)-4k
(R)-4k
(S)-4l
-
>99
>99
>99
>99
>99
>99
>99
86
-
-
-
(R)-4l
-
(S)-4m
(R)-4m
(S)-4n
(R)-4n
(S)-4o
(R)-4o
(S)-4p
(R)-4p
(S)-4q
(R)-4q
(S)-4r
(R)-4r
(S)-4s
-
-
-
-
86
-
98
C6H5 (3a)
-
>99
99
-
4-FC6H4 (3b)
4-CH3C6H4 (3i)
2,6-(CH3)2C6H3 (3j)
C6H5CH2 (3l)
C6H5 (3a)
-
>99
98
-
-
99
-
97
-
97
-
97
(R)-4s
(S,S)-4t
(R,R)-4t
(S,S)-4u
(R,R)-4u
-
97
58/42
59/41
66/34
65/35
>99(>99)d
>99(>99)
>99(>99)
>99(>99)
Me, n-Pr (2d)
C6H5 (3a)
a
Unless otherwise specified, all reactions were carried out using aldehyde (2, 0.40 mmol), maleimide (3, 0.20 mmol), 0.5 mol% 1a or 1b and 0.5 mol%
PhCOOH in 1.0 mL toluene at room temperature.
b Isolated yield.
c Determined by chiral HPLC analysis.
d Ee of the minor diastereomer in parentheses.

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activated maleimide via H-bonding interaction. The enamine
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In conclusion, we have shown that the novel isoteviol-based
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the addition of α,α-disubstituted aldehydes with maleimides to
generate versatile chiral substituted succinimide derivatives. Both
enantiomers of the adducts were obtained in high yields and
excellent enantioselectivities, which makes the current strategy
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Acknowledgments
The authors gratefully acknowledge the Key Project of
Colleges and Universities of Henan Province of China (15
A150049), Program for Second batch of Science and Technology
Innovation Team of Henan University of Animal Husbandry and
Economy (HUAHE2015008) for generous financial support.
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5
Michael addition of α,α-disubstituted aldehydes to
maleimides.
Bifunctional primary amine-squaramides were used
as catalyst for this transformation.
Enantioselective synthesis of succinimide
derivatives.

Graphical Abstract
Highly enantioselective Michael addition of
α,α-disubstituted aldehydes to maleimides
catalyzed by new primary amine-squaramide
bifunctional organocatalysts
Leave this area blank for abstract info.
Zhi-wei Maa, ∗, Xiao-feng Liub, Jun-tao Liua, Zhi-jing Liua and Jing-chao Taob,*