Organic Letters
Letter
a
p-CN-substituted maleimides were isolated in 61%, 6%, and
7% yield, respectively. β-Elimination possibly occurred at the
chiral center. When β-nitrostyrenes with o-, m-, and p-bromo-
substituted phenyl moieties were used, the corresponding
Michael adducts were obtained in appropriate yields with
high enantioselectivities (3eb−gb). However, when β-nitro-
styrene with a p-bromo-substituted phenyl group was
employed, the catalyst loading had to be increased from 1
to 5 mol % to execute the reaction (3eb). Furthermore, the
reactivity of the para electron-donating group of β-nitro-
styrene was lower than those of the other groups, and thus, a
higher catalyst loading was required. The Michael adduct was
obtained in 94% yield with 90% ee when the catalyst loading
was increased from 1 to 5 mol % (3ib). Naphthyl and thienyl
groups were appropriately tolerated, and the desired products
3jb and 3kb were obtained in moderate yields with high ee’s.
However, β-nitrostyrene with a pyridyl moiety did not react
at all (3ib)
Finally, we examined the tolerance of α-aminomaleimides.
α-Aminomaleimides with a halogen-substituted phenyl ring
provided the corresponding Michael adducts in suitable yields
with high enantioselectivities (3ad and 3ae). When α-
aminomaleimides with a phenyl group containing an
electron-donating group were employed, the desired products
were obtained in appropriate yields with high enantioselec-
tivities (3af and 3ag). Our attempt to synthesize α-
aminomaleimides with electron-withdrawing groups, such as
a p-nitro group, was unsuccessful. When α-aminomaleimides
with an aliphatic moiety at the α-amino position were used,
the desired Michael adducts were rarely obtained (3ah−ak).
In conclusion, we have performed the asymmetric Michael
addition of α-aminomaleimides to β-nitrostyrenes using an
organocatalyst derived from Cinchona alkaloid for the first
time to afford chiral maleimides with up to 92% ee. This
reaction provides a new route to various useful chiral
maleimide derivatives. Furthermore, DFT results guided the
improvement of the ee of the adduct and revealed the
reaction mechanism, including the stereochemistry of the
adduct.
Table 3. Optimization of the Reaction Conditions
b
c
entry
X (mol %)
Y (mL)
temp. (°C)
yield (%)
ee (%)
1
2
3
4
5
6
7
8
9
20
20
20
10
5
2.5
1
1
1
0.5
0.3
0.3
0.3
0.3
0.3
0.3
0.3
0.3
0.3
rt
rt
rt
rt
rt
rt
rt
10
0
−10
−20
86
85
85
85
84
85
86
86
66
79
56
88
88
88
88
88
89
88
90
90
91
92
1
5
20
10
11
a
b
Reaction conditions: 1a (0.1 mmol), 2b (0.1 mmol), 48 h, open air.
Isolated yields. Determined by HPLC with a chiral IA column.
c
a b c
, ,
Scheme 4. Substrate Scope
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
General information, catalyst screening using N-iBu
maleimide, experimental procedure, characterization
data, fluorescence data, details and references of
computational study, IRC analysis, EDA analysis, NCI
analysis, ECD spectra, and copies of NMR and HPLC
FAIR data, including the primary NMR FID files, for
compounds 2b, 2d−k, 3aa−ag, 3bb, and 3eb−kb
AUTHOR INFORMATION
Corresponding Authors
■
a
Takeshi Oriyama − Department of Chemistry, Faculty of
Science, Ibaraki University, Mito, Ibaraki 310-8512, Japan;
Seiji Mori − Department of Chemistry, Faculty of Science
and Institute of Quantum Beam Science, Ibaraki University,
Mito, Ibaraki 310-8512, Japan; Frontier Research Center
Reaction conditions: 1 (0.1 mmol), 2 (0.1 mmol), catalyst J (1 mol
b
%), CH2Cl2 (0.3 mL), 10 °C, 48 h, open air. Isolated yields are
shown. The enantiomeric excess was determined by HPLC with a
chiral IA column. Decomposition of the Michael adduct. The
catalyst loading was 5 mol %.
c
d
e
5717
Org. Lett. 2021, 23, 5714−5718