Enantioselective Michael addition to α,β-unsaturated imides catalyzed by a bifunctional organocatalyst

Article abstract of DOI:10.1002/anie.200500459

(Chemical Equation Presented) High enantioselectivities (up to 94 % ee) were attained in the Michael addition of a variety of α,β-unsaturated imides 1 and malononitrile (2) catalyzed by bifunctional thiourea 4. The pyrrolidinone moiety of 1 plays a key ro

Full text of DOI:10.1002/anie.200500459

Communications
Organocatalysis
Enantioselective Michael Addition to a,b-
Unsaturated Imides Catalyzed by a Bifunctional
Organocatalyst**
Yasutaka Hoashi, Tomotaka Okino, and
Yoshiji Takemoto*
The catalytic asymmetric formation of a carbon–carbon bond
represents one of the most challenging fields in organic
chemistry. A number of asymmetric Michael additions to a,b-
unsaturated carbonyl acceptors catalyzed by chiral catalysts
have been reported.[1] However, the acceptors employed in
the asymmetric Michael additions of 1,3-dicarbonyl com-
pounds generally have been restricted to enones[2–4] and
nitroalkenes.[5] Similarly, although organocatalysts that bear
chiral secondary amine groups have been shown to be
efficient catalysts for the Michael reaction with such accept-
ors,[6] their applications to a,b-unsaturated acid derivatives
seems to be difficult. Therefore, the development of general
and highly enantioselective versions of the reactions of a,b-
unsaturated acid derivatives still remains a challenging goal.
Quite recently, two groups achieved the initial breakthroughs
on these problems. The Jacobsen and Kanemasa groups
independently reported the highly enantioselective metal-
catalyzed Michael additions of malononitrile, which is equiv-
alent to a 1,3-dicarbonyl compound, to a,b-unsaturated
imides.[7,8] However, there have been no reports of such
asymmetric Michael addition without any metal catalysts.
Herein, we report the first enantioselective Michael reactions
of malononitrile to acyclic a,b-unsaturated imides in the
presence of a chiral organocatalyst.
Although we recently reported that the bifunctional-
thiourea-catalyzed Michael reaction of 1,3-dicarbonyl com-
pounds to nitroalkenes proceeded with high enantioselectiv-
ity (up to 93% ee),[9] the same reaction of other nucleophiles
such as malononitrile to nitroalkenes gave the corresponding
product with low enantioselectivity. To extend the synthetic
utility of the bifunctional thiourea 1a in the asymmetric
reaction, we undertook the screening of proper Michael
acceptors other than nitroalkenes to react with malononitrile.
For the purpose, a,b-unsaturated imides seem to have an ideal
structure to form hydrogen bonds with the thiourea catalyst
1a as shown in Scheme 1.[10,11]
[*] Y. Hoashi, T. Okino, Prof. Dr. Y. Takemoto
Graduate School of Pharmaceutical Sciences
Kyoto University
Yoshida, Sakyo-ku, Kyoto 606-8501 (Japan)
Fax: (+81)75-753-4569
E-mail: takemoto@pharm.kyoto-u.ac.jp
[**] This work was supported by grants from the 21st Century COE
Program “Knowledge Information Infrastructure for Genome
Science” and KAKENHI (16390006).
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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DOI: 10.1002/anie.200500459
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Angewandte
Chemie
ature in the presence of 1a (10 mol%). Although the
conjugate addition of 2 with amide 3a gave no desired
product, the same reaction with N-acyl-1,3-oxazolidinone
3b[10e] was completed after 96 h to give the Michael adduct 4b
in 89% yield (Table 1, entries 1 and 2). The enantiopurity of
4b was revealed to be 83% ee by means of HPLC analysis. In
the hope of enhancing the hydrogen-bonding interaction with
thiourea 1a, we employed N-acyl-1,3-imidazolidinone 3c,
which bears a cyclic urea moiety, as a Michael acceptor, but
both the yield of 4c and enantioselectivity were poorer (59%,
81% ee; Table 1, entry 3). In contrast with 3c, N-acylpyrro-
lidinone 3d was revealed to be a good acceptor of 2, providing
the corresponding product 4d in 93% yield with the best
enantioselectivity (87% ee) (Table 1, entry 4). Use of N-
acylpiperidinone 3e and acyclic imide 3 f for the Michael
addition reaction resulted in a significant decrease in both
chemical yield and enantioselectivity (Table 1, entries 5 and
6). On the other hand, the conjugate addition of 2 with imide
3g proceeded smoothly, but the enantioselectivity (84% ee)
was somewhat lower than that with 3d (Table 1, entry 7).
Notably, the same reaction with 3d under dilute conditions
(0.1m solution in toluene) improved the stereoselectivity up to
93% ee.
Scheme 1. Hydrogen-bond interaction with thiourea 1a.
Encouraged by the excellent results obtained with N-
acylpyrrolidinone 3d and thiourea 1a, we explored the
effectiveness of a bifunctional urea 1b and other bifunctional
thioureas 1c–f for the Michael addition (Table 2). The
We first investigated the Michael addition of malononi-
trile (2) to several types of a,b-unsaturated acid derivatives
3a–g (Table 1). The reaction of 2 (2 equiv) with a solution of
imides 3 in toluene (0.5m) was carried out at room temper-
Table 2: Enantioselective Michael addition of 2 and imide 3d in the
presence of several bifunctional thioureas 1a–f.
Entry
1
t [h]
Yield [%][a]
ee [%][b]
Table 1: Enantioselective Michael addition of malononitrile 2 with a,b-
unsaturated acid derivatives 3a–g.[a]
1
2
3
4
5
b
c
d
e
f
48
120
120
120
120
78
66
78
61
13
87 (R)
60 (R)
69 (R)
48 (R)
3 (S)
Yield [%][b]
0
ee [%][c]
[a] Yield of isolated product. [b] Determined by HPLC analysis of 4d with
a chiral column.
Entry
1
Substrate (R)
3a
Product
t [h]
4a
48
–
reaction of 2 with 3d in the presence of urea 1b gave a
similar result, affording the desired product 4d in somewhat
lower yield (78%, 87% ee; Table 2, entry 1). However, the
introduction of phenyl and 3,5-bis(trifluoromethyl)phenyl
groups on the aromatic ring of 1a as well as modification of its
dimethylamino group led to significant decrease in reaction
rate and enantioselectivity (Table 2, entries 2–4). Further-
more, the (N-methylpyrrolidin-2-yl)methyl derivative 1 f was
not catalytically active in the Michael reaction and resulted in
a low yield of 4d. These results demonstrated that the original
thiourea 1a was the best choice as a chiral organocatalyst.
Having established the optimal reaction conditions for the
enantioselective Michael reaction of malononitrile (2), we
next screened a series of analogues 5a–h, which bear various
b substituents. As illustrated in Table 3, imides 5a–h under-
went conjugate addition of 2 in the presence of catalyst 1a in
high yields and enantioselecivities, which were almost inde-
pendent of the b substituents in terms of steric hindrance and
electronic properties. The reaction with aryl-substituted
2
3
4
3b
3c
3d
4b
4c
4d
96
120
60
89
59
93
83
81
87
5
3e
4e
140
42
59
6
7
3 f
4 f
216
8
27
94
56
84
3g
4g
[a] The reaction was conducted with 1a (10 mol%), 2 (2 equiv), and 3a–
g in toluene (0.5m). [b] Yield of isolated product. [c] The ee values were
determined by HPLC analysis of 4a–g with a chiral column.
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Table 3: Asymmetric Michael addition of 2 and various a,b-unsaturated
imides 5a–h with 1a.
Entry
5 (R)
t [h][a]
6
Yield [%][a,b]
ee [%][a,c]
1
2
3
4
5
6
7
8
a (p-ClC6H4)
b (p-FC6H4)
c (p-MeOC6H4)
d (1-naphthyl)
e (2-furyl)
f (PhCH2CH2)
g (Me)
h (tBu)
72 (192)
48 (168)
216
48 (168)
192
24 (144)
24 (120)
168
a
b
c
d
e
f
85 (88)
99 (84)
77
93 (87)
79
96 (98)
82 (86)
78
89 (93)
88 (93)
85
88 (93)
85
88 (94)
84 (93)
92
Scheme 3. 1H NMR spectroscopic experiments of a substrate–catalyst
complex A and proposed transition state B for the Michael reaction
with 1a.
g
h
[a] The values in parentheses were obtained from reactions carried out in
a 0.1m solution. [b] Yield of isolated products, after chromatography, of
reactions carried out in a 0.5m solution. [c] Determined by chiral HPLC
analysis.
B of catalyst 1a, malononitrile (2), and imide 5 as a plausible
transition state in which 5 and the anion of 2 coordinate to the
thiourea moiety and the tertiary amine group of 1a,
respectively, through hydrogen-bonding interactions. The
predominant production of R adducts is reasonably explained
by this transition-state model.
In summary, we have developed the first highly enantio-
selective organocatalytic Michael reaction of malononitrile
(2) with a,b-unsaturated imides 5a–h in the presence of a
bifunctional thiourea 1a. The pyrrolidinone moiety of a,b-
unsaturated imides is demonstrated to play a key role in the
thiourea-catalyzed Michael reaction. The reaction is appli-
cable to a variety of a,b-unsaturated imides that bear aryl and
alkyl groups as a b substituent, and high enantioselectivities
are attained. Unfortunately, the Michael addition of other
carbon nucleophiles such as malonates and b-ketoesters with
4d gave no desired products owing to their low reactivities.
Further investigations into the mechanism and synthetic
application are underway and will be reported in due course.
imides 5a–c proceeded with high enantioselectivity to furnish
the addition adducts 6a–c, while the rate of the reaction was
somewhat lower for 5c (R = p-methoxyphenyl) owing to the
electron-rich substrate (Table 2, entries 1–3). Similarly,
imides 5d–e bearing 1-naphthyl and furyl groups as the
b substituent underwent clean reaction as well, and gave the
corresponding adducts 6d–e with 85–88% ee (Table 2,
entries 4–5). In contrast to the previously reported Michael
addition with nitroalkenes,[9] the present reaction of 2 with
imides 5 f–h, which bear alkyl groups as the b substituent,
occurred smoothly to afford the desired products 6 f–h in
good yields with high enantioselectivities similar to those of
5a–e. The highest enantioselectivity (92% ee) was obtained
under the standard conditions in the case of tert-butyl
derivative 5h. Furthermore, it is noteworthy that when the
reactions were carried out in a 0.1m solution, the all the
corresponding products were obtained with higher enantio-
selectivities (> 93% ee).
Received: February 7, 2005
Published online: May 20, 2005
The absolute configuration of the Michael adduct 6b was
determined by the transformation of 6b into a known
compound 7[7b] (Scheme 2). Treatment of 6b with a catalytic
Keywords: imides · Michael addition · nitriles · organocatalysis ·
thiourea
.
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