Enantioselective Michael Reaction of Malonates to Nitroolefins Catalyzed by Bifunctional Organocatalysts

Article abstract of DOI:10.1021/ja036972z

Michael reaction of malonates to nitroolefins with chiral bifunctional organocatalysts, bearing both a thiourea and tertiary amino group, afforded Michael adducts with high yields and enantioselectivities (up to 95%, up to 93% ee). Copyright

Full text of DOI:10.1021/ja036972z

Published on Web 09/30/2003
Enantioselective Michael Reaction of Malonates to Nitroolefins Catalyzed by
Bifunctional Organocatalysts
Tomotaka Okino, Yasutaka Hoashi, and Yoshiji Takemoto*
Graduate School of Pharmaceutical Sciences, Kyoto UniVersity, Yoshida, Sakyo-ku, Kyoto 606-8501, Japan
Received June 30, 2003; E-mail: takemoto@pharm.kyoto-u.ac.jp
One of the important Michael additions in organic chemistry is
the addition of nucleophiles to nitroolefins due to their multiple
reactivity and the valuable synthetic building blocks that are
Table 1. Results for Optimal Reaction Conditions
1
created. Various enantioselective reactions have been reported by
2
employing stoichiometric amounts of enantiopure additives. Al-
though the catalytic asymmetric versions of this reaction were
achieved, most required metal catalysts or strict reaction conditions.3
L-Proline derivatives have catalyzed the stereoselective addition of
carbonyl compounds to nitroolefins, but only with moderate
-7
8
enantioselectivites.
Urea derivatives act as acid catalysts9,10 in only a few reactions
% yieldb
%eec,d
entry
solvent
3a (equiv)
11
compared to the enantioselective reactions catalyzed by L-proline,
1
2
3
4
5
6
MeOH
MeCN
THF
CH2Cl2
toluene
toluene
1
1
1
1
1
2
33
47
29
53
60
86
29
75
88
90
92
93
1
2
13
chiral Lewis bases, and phase-transfer catalysts. Furthermore,
chiral urea and thiourea derivatives have only catalyzed enantiose-
lective, nucleophilic additions of HCN and ketene silyl acetals to
imines.1
0f-h
Herein a highly enantioselective Michael reaction of
malonates to nitroolefins is reported using novel metal-free chiral
bifunctional organocatalysts.
a The reaction was conducted with 1a (0.1 equiv), 3a (1-2 equiv), and
several solvents at room temperature. b Isolated yield. c Enantiomeric excess
We previously reported that thiourea catalyzed the nucleophilic
addition of TMSCN and ketene silyl acetals to nitrones and
aldehydes.1 Unlike imines, aldehydes, and nitrones, nitroolefins
d
was determined by HPLC analysis of 4a using a chiral column. Absolute
configuration was determined by comparing the specific rotation of 4a with
0a
that of literature data.6
have two oxygen atoms, which potentially can be activated by the
acidic hydrogens of thiourea.1
4,15
Table 2. Optimization of Thioureas
We anticipated that introduction
of an additional basic, nucleophile-activating group in the thiourea
catalyst might facilitate a synergistic interaction between the
functional groups and thereby lead to an efficient catalyst for the
Michael reaction. In other words, the nitroolefin and the nucleophile
are simultaneously activated. Moreover, chiral thiourea catalysts
with these functional groups on a chiral scaffold should yield the
addition products with excellent enantioselectivity. This type of
bifunctional catalyst has yet to be reported.16
The reaction conditions were optimized with thiourea 1a, which
has (R,R)-1,2-cyclohexyldiamine as a chiral scaffold. The reaction
of trans-â-nitrostylene 2a with diethyl malonate 3a in the presence
of 10 mol % of 1a in methanol afforded the desired Michael adduct
% yieldb
%eec,d
entry
additive
TEA
1b
TEA+1c
1d
1e
1f
time (h)
1
2
3
4
5
6
7
24
24
24
48
48
48
48
17
14
57
29
76
58
40
-
35
-
91
87
80
52
4a in 33% yield and 29% ee (Table 1, entry 1). Since methanol
and 1a competitively activate 2a, the enantioselectivity of 4a might
be poor. Therefore, other solvents were examined. As expected,
polar solvents (THF, MeCN), which reduced the activity of 1a,
resulted in poor yields of 4a (entries 2, 3). In contrast, 1a in nonpolar
1g
solvents (CH
a in moderate yields of 4a with excellent enantioselectivities
entries 4, 5). In addition, using 2 equiv of 3a improved the yield
2 2
Cl , toluene) efficiently promoted the reaction with
a
2
(
The reaction was conducted with 3a (2 equiv) and toluene in the
b
presence of various additives (0.1 equiv) at room temperature. Isolated
yield. c Enantiomeric excess was determined by HPLC analysis of 4a using
of 4a (86%, 93% ee, entry 6).
Next, the effects of the thiourea catalysts were investigated (Table
d
a chiral column. Absolute configuration was determined by comparing
the specific rotation of 4a with that of literature data.6
2). 2a and 3a reacted very slowly in the presence of TEA and chiral
amine 1b without a thiourea moiety to give a poor yield and
enantioselectivity of 4a (entries 1, 2). Although combining thiourea
thiourea and tertiary amino group within the molecule. In addition,
1
2
these results reveal that substituents (R and R ) in the amino groups
of 1d and 1e have a significant effect on the reaction rate, but only
marginally affect the enantioselectivity of 4a (entries 4, 5). In
contrast, replacing 3,5-bis(trifluoromethyl)phenyl group of 1a with
1c and TEA enhanced the reaction rate, only a moderate chemical
yield of 4a was achieved (entry 3). These results indicate that for
a high yield and selectiVity the catalyst should possess both a
12672
9
J. AM. CHEM. SOC. 2003, 125, 12672-12673
10.1021/ja036972z CCC: $25.00 © 2003 American Chemical Society

C O MMU N I C A T I O N S
Table 3. Michael Addition of Malonates to Nitroolefins Catalyzed
by Thiourea
Supporting Information Available: Experimental procedures and
spectroscopic data for the products (PDF). This material is available
free of charge via the Internet at http://pubs.acs.org.
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2a:3a:1a ) 1:2:0.05) afforded 4a with a good enantioselectivity
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8
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Acknowledgment. This work was supported by grants from
the NOVARTIS Foundation (Japan) for the promotion of Science
and Grant-in-Aid for Scientific Research from the Ministry of
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