J. He et al. / Tetrahedron Letters 55 (2014) 3030–3032
3031
Table 1
Table 2
Optimization of Michael reaction conditions of isobutyraldehyde to b-nitrostyrene
Asymmetric Michael addition of isobutyraldehyde to nitroolefinsa
catalyzed by 1a
1c 10 mol%
PhCO2H 10 mol%
O
O
R
catalyst 10 mol%
additive 10 mol%
O
Ph
NO2
O
NO2
R
H
NO2
H
NO2
4°C, neat
H
4
Ph
H
H2O, 24 h, rt
4a
Entry
R
Time (h)
Product
Yieldb (%)
eec (%)
N
N
N
1
2
3
4
5
6
7
8
9
Ph
4-BrC6H4
24
19
19
12
19
12
12
24
12
48
4a
4b
4c
4d
4e
4f
4g
4h
4i
90
93
82
98
94
92
76
92
82
90
88
88
87
87
88
89
88
84
89
97
N
H
N
N
H
H
H
1c
1a
1b
CO2H
4-OMeC6H4
3-OMeC6H4
4-MeC6H4
4-NO2C6H4
4-ClC6H4
2-FC6H4
2-furyl
PhCH2CH2
SO3H
N
N
N
N
n-Bu
X-
3a: X = CF3SO3
3b
X-
n-Bu
2a: X = PF6
2b
: X = NTf2
: X = NTf2
Entry
Catalyst
Additive
T
Yieldb (%)
eec (%)
10
4j
1
2
3
4
5
6
7
8
9
1a
1b
1c
1c
1c
1c
1c
1c
1c
1c
1c
1c
2a
2a
2a
TFA
PhCO2H
TsOH
2b
3a
3b
rt
56
17
93
75
81
85
76
93
94
76
40
90
80
12
82
82
84
82
82
82
80
87
86
88
a
Reactions performed on 0.5 mmol scale using catalyst 1c, benzoic acid, isobu-
rt
rt
rt
rt
rt
rt
rt
rt
tyraldehyde (4 equiv).
b
Yields of isolated product.
Determined by chiral HPLC.
c
Table 3
Asymmetric Michael addition of cyclopentanecarboxaldehyde to nitroolefinsa
10
11
12d
PhCO2H
3a
PhCO2H
4 °C
4 °C
4 °C
1c 10 mol%
PhCO2H 10 mol%
O
R
O
NO2
NO2
H
H
R
4°C, neat
5
a
Reactions performed on 0.5 mmol scale using catalyst 1, additive, isobutyral-
dehyde (5 equiv), and water (1.0 mL).
Entry
R
Time (h)
Product
Yieldb (%)
eec (%)
b
Yields of isolated product.
Determined by chiral HPLC.
The reaction was carried out with 4 equiv of isobutyraldehyde at neat
c
1
2
3
4
5
Ph
4-MeC6H4
4-OMeC6H4
4-NO2C6H4
PhCH2CH2
19
24
19
12
96
5a
5b
5c
5d
5e
93
78
82
98
76
95
93
92
96
94
d
condition.
a
Reactions performed on 0.5 mmol scale using catalyst 1c, benzoic acid,
enantioselectivity of Michael adduct 4a were low (entry 2),
whereas in the presence of 1c, 93% yield was attained along with
82% ee (entry 3). These results indicated that the catalyst 1c exhib-
ited higher efficacy in water than 1a and 1b in terms of reactivity
and selectivity. In light of the above results, we further optimized
the reaction conditions using catalyst 1c by screening acid addi-
tives. The influence of reaction temperature was also investigated
(entries 4–12). When other ILS acidic additives 2b, 3a–b, and
unimmobilized Brønsted acids TFA, TsOH, and PhCOOH were also
examined, all the reactions underwent smoothly to give Michael
adduct 4a with comparable enantioselectivity. The enantioselec-
tivity increased when the reaction was carried out at 4 °C by the
use of PhCOOH and 3a as additives, respectively (entries 10 and
11). Although good results were achieved in aqueous media at
4 °C, the reaction still suffered from the low chemical yields
(40–76%) (entries 10 and 11). However, this problem was solved
when the reaction was carried out under neat conditions with even
less amount of Michael donor (4 equiv) and the yield dramatically
increased to 90% with slightly increasing enantioselectivity (88%
ee) (entry 12).
cyclopentanecarboxaldehyde (4 equiv.).
b
Yields of isolated product.
Determined by chiral HPLC.
c
providing product 4j in high yield (90%) and excellent enantiose-
lectivity (97% ee) (entry 10).
Next, the cyclopentanecarboxaldehyde was also selected as
Michael donor to react with a wide range of nitroolefins under
optimized reaction conditions and the results are summarized in
Table 3. These results showed that all the reactions proceeded
smoothly to give the corresponding Michael adducts 5a–e in high
yields (up to 98%) with high level of enantioselectivity (up to
96% ee) (entries 1–5). Both electron-rich and electron-deficient
nitroolefins were excellent Michael acceptors for cyclopentanecar-
boxaldehyde (entries 1–4). Again, the aliphatic nitroolefin was also
a suitable Michael acceptor for the reaction and the corresponding
Michael adduct 5e was obtained in 76% yield with high enantiose-
lectivity (94% ee) in 96h (entry 5).
In conclusion, a highly efficient asymmetric Michael addition of
a,a-disubstituted aldehydes to nitroolefins catalyzed by a diamine
On the basis of the results summarized in Table 1, the reaction
conditions of entry 12 (Table 1) were chosen to study the scope of
the asymmetric Michael addition of isobutyraldehyde to a variety
of nitroolefins with catalyst 1c in combination with benzoic acid,
and the results are summarized in Table 2.11 The results showed
that the reactions proceeded efficiently with isobutyraldehyde
and nitroolefins bearing both electron-deficient and electron-rich
substituents on the phenyl ring affording the corresponding prod-
ucts 4b–h in high yields (76–98%) with high enantioselectivities
(ee: up to 89%) (entries 2–8). 2-(2-Nitrovinyl)furan was also a suit-
able Michael acceptor to give Michael adduct 4i in 82% yield with
89% ee (entry 9). Furthermore, catalyst 1c is also highly effective
for Michael addition of isobutyraldehyde to aliphatic nitroolefin
1c organocatalyst in combination with benzoic acid has been devel-
oped. The present reactions accommodated a range of Michael
acceptors providing quaternary carbon-containing products in high
to excellent yields and high levels of enantioselectivities under sol-
vent-free reaction conditions. In addition, the diamine catalyst used
herein is simple and easily accessible. These remarkable advantages
make this approach very suitable for practical use.
Acknowledgements
This research was supported by start-up funds from the College
of Science, Engineering & Agriculture, Texas A&M University-
Commerce, National Science Foundation (CHE-1213287), and