Organocatalytic and enantioselective direct vinylogous Michael addition to maleimides

Article abstract of DOI:10.1002/adsc.200800259

An organocatalytic enantioselective direct vinylogous Michael addition of α,α-dicyanoolefins to maleimide has been developed; the products could be obtained in good yields and high enantioselectivities.

Full text of DOI:10.1002/adsc.200800259

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DOI: 10.1002/adsc.200800259
Organocatalytic and Enantioselective Direct Vinylogous Michael
Addition to Maleimides
Jun Lu,a Wei-Juan Zhou,a Feng Liu,a and Teck-Peng Loha,*
a
Division of Chemistry and Biool gicalChemistry, Schoolof Physicaland MathematicalSciences, Nanyang Technool gical
University, 1 Nanyang Link, Singapore 637371
Fax : (+65)-6791-1961; phone: (+65)-6316-8899; e-mail: teckpeng@ntu.edu.sg
Received: April 30, 2008; Published online: July 24, 2008
Supporting information for this article is available on the WWW under http://asc.wiley-vch.de/home/.
Abstract: An organocatalytic enantioselective
direct vinylogous Michael addition of a,a-dicyanoo-
lefins to maleimide has been developed; the prod-
ucts could be obtained in good yields and high
enantioselectivities.
Keywords: Cinchona alkaloids; dicyanoolefins;
enantioselective Michael addition; maleimides; or-
ganocatalysis
highly functionalized products with two adjacent ste-
reogenic carbon atoms in high levels of enantio- and
diastereoselectivities.
The feasibility of our organocatalytic asymmetric
approach was first tested by mixing a,a-dicyanoolefin
(1a) and maleimide (2a) in dichloromethane (0.1M)
In recent years, organocatalysis has become a power- in the presence of a catalytic amount of a Cinchona
[1]
fultoolin the fiedl of organic chemistry.
Organoca- alkaloid derivative (10 mol%). Representative results
talysts that possess both an acidic and a basic/nucleo- of the extensive screening of reaction conditions using
philic structural moiety constitute an increasingly the alkaloids shown in Figure 1 are listed in Table 1.
powerful platform for the development of asymmetric The results of the investigation revealed that the reac-
catalysis.[2] Among them, the catalytic enantioselective tion could proceed smoothly to yield the desired
conjugate addition of compounds using organocata- products. However, the enantioselectivities varied
lysts with a prochiral nucleophilic carbon atom to a,b- greatly depending on the Cinchona alkaloid deriva-
substituted Michaelacceptors provides one of the
tive used. Organocatalyst 4i exhibited the most prom-
most versatile and attractive approaches for the gen- ising results in terms of ee (74%), dr (9/1), and con-
eration of optically active compounds. To date, the ac- version (90%). The studies showed that the free hy-
ceptors employed in the enantioselective Michael re- droxy group R2 in catalyst 4i plays a key role in sub-
actions have been nitroalkenes,[3] enones,[4] and unsa- strate activation, since the corresponding catalyst 4j
turated imides.[5] Our interest in the use of conjugate showed significantly lower efficiency (ee 17%,
addition for the synthesis of complex molecules has Table 1, entry 10). As shown from the results (Table 1,
encouraged us to investigate the asymmetric conju- entry 7 vs. 8), it was also necessary that the C-9 alco-
gate addition of carbon-centered nucleophiles to mal- holgroup be protected in the form of ether.
eimides. Succinimides are such moieties, found in nu-
Therefore, catalyst 4i was selected for the subse-
merous biologically interesting molecules and phar- quent studies. We next investigated the effect of the
maceuticals; therefore, they are often used as phar- reaction medium, reaction temperature and catalyst
macophores in drug discovery.[6] However, the enan- loading in the presence of a catalytic amount of 4i. It
tioselective Michael reaction using maleimides as the was found that the reaction proceeded smoothly in
acceptors has been relatively unexplored.[7] In this non-polar solvents (Table 2, entries 1–7), but poor
paper, we report the development of the first enantio- result was obtained with polar protic solvent (Table 2,
selective direct conjugate addition of a,a-dicyanoole- entry 8). This is expected since non-polar solvents can
fins to maleimides promoted by Cinchona alkaloids as minimize the disruption of the hydrogen-bonding in-
[8]
chiralcataylsts [Eq. (1)].
The reactions afforded teractions between catalyst and substrates; and thus
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Adv. Synth. Catal. 2008, 350, 1796 – 1800

Organocatalytic and Enantioselective Direct Vinylogous Michael Addition
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Figure 1. Structures of the Cinchona alkaloid catalysts.
Table 1. Organocatalytic asymmetric conjugate addition of
1a to 2a.[a]
Entry
Catalyst
Conv. [%][b]
dr[b]
ee [%][c]
1
2
3
4
5
6
7
8
9
4a
4b
4c
4d
4e
4f
4g
4h
4i
93
97
93
89
86
85
92
10
90
88
90/10
80/20
70/30
70/30
78/22
85/15
88/12
70/30
90/10
90/10
5
11
5
11
44
36
66
30
74
17
Figure 2. Structures of the a,a-dicyanoolefins and male-
10
4j
imides used in this study.
[a]
The reactions were performed on a 0.1 mmolscael
(0.1M).
[b]
[c]
1
Conversion and dr were determined by H NMR spectro- results, it was found that catalyst 4n also showed good
scopic analysis of the crude product mixture.
ee of the major diastereoisomer.
reactivity and selectivity for the asymmetric Michael
addition of a,a-dicyanoolefins to maleimides.
Having optimized the reaction conditions for the
asymmetric Michaeladdition of a,a-dicyanoolefins to
high catalytic activity and stereoselectivity toward the maleimides in toluene, it was extended to other sub-
reaction are generally observed. The most encourag- strates using both the catalysts, 4i and 4n. A variety of
ing result was obtained when the reaction was carried a,a-vinylmalononitriles and -maleimides (Figure 2)
out in toluene (Table 2, entry 9). By lowering the tem- were evaluated under the optimized reaction condi-
perature to À208C, the desired product could be fur- tions, and the results are summarized in Table 3. In
nished in good yield and high enantioselectivity. Fur- most of the cases, the reactions proceeded smoothly
thermore, only the anti-Michaeladdition product was
to furnish the desired products in good yields and
obtained (Table 2, entry 9, Figure 3). No further im- high enantioselectivities, and only the anti-products
provement could be found when the process was car- were observed in the reactions. However, when the
ried out under other reaction conditions (Table 2, en- cyclic aliphatic substrate 1e was tested, the major
tries 10–13). Prompted by these results, more catalysts product could be obtained in excellent enantioselec-
were synthesized, and their catalytic activities were tivity and moderate yield while the minor diastereo-
also investigated (Table 2, entries 14–18). From the mer could also be isolated with moderate enantiose-
Adv. Synth. Catal. 2008, 350, 1796 – 1800
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Jun Lu et al.
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Table 2. Optimization of reaction conditions of asymmetric conjugate addition of 1a to 2a.[a]
Entry
Catalyst (mol%)
Solvent
Temp. [8C]
Time [h]
Conv. [%][b]
dr[b]
ee [%][c]
1
2
3
4
5
6
7
8
4i (10)
4i (10)
4i (10)
4i (10)
4i (10)
4i (10)
4i (10)
4i (10)
4i (10)
4i (20)
4i (15)
4i (10)
4i (5)
DCM
THF
toluene
t-BuOMe
ClCH2CH2Clr.t.
xylene
4-CF3C6H5
i-PrOH
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
r.t.
r.t.
r.t.
r.t.
8
8
8
8
90
44
94
93
90/10
82/18
89/11
95/5
74
81
85
45
8
88
50/50
75
r.t.
r.t.
r.t.
À20
r.t.
0
À40
À20
r.t.
r.t.
r.t.
r.t.
À20
8
8
8
48
8
24
80
48
8
8
8
90
65
85
80
96
94
62
48
90
92
86
92
82
91/9
78
70
83/17
50/50
100
90/10
89/11
100
100
91/9
86/14
89/11
90/10
>98/2
5
9
88 (95)[d]
10
11
12
13
14
15
16
17
18
84
80
83
88
40
12
50
86
89
4k (10)
4l (10)
4m (10)
4n (10)
4n (10)
8
48
[a]
The reactions were performed on a 0.1 mmolscael (0.1M).
Conversion and dr were determined by H NMR spectroscopic analysis of the crude product mixture.
ee of the major diastereoisomer.
[b]
[c]
[d]
1
After a single crystallization.
To determine the absolute configuration of the vi-
nylogous Michael addition products, enantiopure 3ca
(>99% ee), which contains a sulfur atom, was crystal-
lized slowly from 2-propanol. The crystals obtained
were suitable for X-ray structural analysis. The rela-
tive and absolute configurations of the two contiguous
stereogenic carbons in 3ca could easily be determined
by X-ray crystallographic analysis. As shown in
Figure 4, the two newly created stereocenters of 3ca
Figure 3. X-ray crystallographic structure of rac-3aa.
lectivity (Table 3, entries 13 and 16). Surprisingly,
when the reaction of 1a and 2b was carried out under
the present reaction conditions, the enantioselectivity
was improved to >99% ee (Table 3, entries 11 and
14). In addition, an electron-donating substituent on
the arylring of the a,a-dicyanoolefin substrate tended
to decrease their reactivity without affecting the good
enantioselectivity (Table 3, entries 4 and 9).
Figure 4. X-ray crystallographic structure of 3ca.
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Organocatalytic and Enantioselective Direct Vinylogous Michael Addition
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Table 3. Asymmetric conjugate addition of a,a-dicyanoolefins to maleimides.[a]
Entry
Catalyst
1
2
Product
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
4i
4i
4i
4i
1a
1b
1c
1d
1e
1a
1b
1c
1d
1e
1a
1c
1e
1a
1c
1e
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2b
2b
2b
2b
2b
2b
3aa
3ba
3ca[e]
3da
3ea
3aa
3ba
3ca
3da
3ea
3ab
3cb
3eb
3ab
3cb
3eb
80
81
90
35
78
86
82
88
36
74
81
89
41 (16)
85
88
88 (95)[d]
85
85 (99)[d]
81
4i
80
92
96
82
82
82
4n
4n
4n
4n
4n
4i
4i
4i
4n
4n
4n
9
10
11
12
13
14
15
16
>99
92
94 (70)[f]
>99
95
42 (14)
95 (74)[f]
[a]
The reaction was carried out on a 0.1 mmolscael (0.1M).
Isolated yield.
Determined by HPLC analysis on a chiral phase.
After a single recrystallization.
The absolute configuration was determined to be C-8: S, C-13: R by X-ray crystallographic analysis.
Data in brackets are for the separable minor diastereomer.
[b]
[c]
[d]
[e]
[f]
AS, 30% 2-propanol/hexane, 1.5 mLminÀ1): tminor
26.126 min, tmajor =43.415 min.
=
were revealed to possess (8S,13R)-configuration with
an anti-structure.
In summary, to the best of our knowledge, this
paper represents the first organocatalytic and asym-
metric direct vinylogous Michael addition of a,a-di-
cyanoolefins to maleimides, generating the products
in good yields with excellent diastereo- and enantiose-
lectivities. Further studies are well under way to
Acknowledgements
We gratefully acknowledge A*STAR (Grant No. 072101
0024) for the funding of this research and we thank Dr. Y.-X.
expand the synthetic utility of this new reaction, as Li for X-ray support.
well as the application of this catalytic system in other
asymmetric transformations.
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