Biing-Jiun Uang and Yu-Chao Huang
group of 1a, catalysts 1b and 1c were prepared and tested
for the reaction. Catalyst 1b, with a CF3 group at the para-
position of the benzene ring, catalyzed the reaction and
gave a similar enantioselectivity and yield (Table 1, entry 2).
However, catalyst 1c, with a OMe group at the para-posi-
tion of the benzene ring, gave a similar enantioselectivity
but lower yield. This result might be due to the electron-do-
nating behavior of the OMe group, which could have de-
(Table 2, entry 1). When the reaction was conducted in sol-
vents such as CH2Cl2, THF, or toluene at 308C for 24 h, it
gave higher enantioselectivities (92~96% ee), but the yields
remained low (Table 2, entries 2–4). The reaction was faster
in polar protic solvents such as MeOH, EtOH, or iPrOH
and gave higher yields and enantioselectivities (Table 2, en-
tries 5–7). However, despite achieving >99% enantioselec-
tivity when the reaction was conducted in tBuOH, the yield
was low. This could be due to the low solubility of the cata-
lyst and substrate in tBuOH. The reaction in iPrOH was se-
lected for further studies as judged from the yield and enan-
tioselectivity (Table 2, entry 7).
To improve the reaction yield, we turned our attention to
study the effect of the acid additive, and the results are sum-
marized in Table 3. When benzoic acid was replaced with
acetic acid, the reaction gave a similar yield with the same
enantioselectivity. When acid additives such as 4-fluoroben-
zoic acid, 4-nitrobenzoic acid, and 2,4-dinitrophenol were
employed, this resulted in similar enantioselectivity, but
lower yields (Table 3, entries 3–5). Interestingly, when the
reaction was run in the absence of the acid additive it gave
almost the same yield and enantioselectivity (Table 3,
entry 6 vs entry 1). Therefore, the reaction without an acid
additive was further investigated.
À
creased the assistance of the sulfonamido N H moiety
(Table 1, entry 3). To further examine the influence of the
À
sulfonamido N H group, catalysts 1d–f were synthesized.
When the reaction was catalyzed with N,N-disubstituted sul-
fonamide catalyst 1d, it gave poor enantioselectivity
(Table 1, entry 4). When the reaction was catalyzed with cat-
alyst 1e, in which the hydroxy group at the C4 position of
the pyrrolidine ring was removed, it resulted in slightly
lower enantioselectivity (62% ee; Table 1, entry 5) as com-
pared with catalyst 1a. The hydroxy group on the catalyst
played a minor role in the enantioselective Michael addi-
tion. When the reaction was catalyzed by 1 f, in which the
sulfonamido group was removed, it resulted in the racemic
Michael adduct and a significantly lower yield after 24 h
(Table 1, entry 6). This result suggested that the enhance-
ment in the reactivity and enantioselectivity might be due to
the hydrogen-bond interactions between the nitroalkane
À
and the sulfonamido N H moiety of catalyst 1a. To improve
Table 3. The effect of acid additive on the asymmetric conjugate addition
reaction.
the reaction yield of the Michael reaction, the reaction time
was prolonged from 24 h to 48 h in the presence of catalyst
1a, however, the yield decreased unexpectedly (Table 1,
entry 7). This is presumably due to the formation of side
products from the Henry reaction of 2a, 3a and/or iminium
intermediates with nitromethane over the prolonged reac-
tion period.
Entry
Additive
Yield [%][a]
ee [%][b]
Next, we studied the effect of the solvents and the results
are summarized in Table 2. When the reaction was conduct-
ed in N,N-dimethylformamide (DMF) at 308C for 24 h, it af-
forded 3a in a poor yield with lower enantioselectivity
1
2
3
4
5
6
PhCO2H
AcOH
4-F-C6H4CO2H
4-NO2-C6H4CO2H
2,4-dinitrophenol
–
62
61
42
50
54
57
97
97
96
96
97
97
Table 2. The effect of solvent on the asymmetric conjugate addition reac-
tion.[a]
[a] Yield of isolated product. [b] Determined by HPLC using a Chiracel
AD-H column.
Based on some previous reports[8] and our experience, the
addition of an appropriate amount of water could accelerate
the reaction, and furnish the product in promising yield and
stereoselectivity. To explore this effect, five equivalents of
water were added to the reaction mixture. It was found that
the reaction gave a better yield in a shorter reaction time
with excellent enantioselectivity (Table 4, entry 2). Next, we
examined the effect of catalyst loading and when the reac-
tion was conducted in the presence of 10 mol%, 5 mol%,
2.5 mol%, or 1 mol% catalyst, it resulted in almost the
same enantioselectivity (Table 4, entries 2, and 4–6), and the
yield was improved slightly at the expense of the reaction
time. When 1 mol% of 1a was used, the Michael adduct
was afforded in 74% yield and 96% ee (Table 4, entry 6).
Entry
Solvent
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
DMF
CH2Cl2
THF
Toluene
MeOH
EtOH
iPrOH
tBuOH
33
24
31
41
69
59
62
39
68
92
94
96
76
95
97
>99
[a] Reaction conditions: cinnamaldehyde (0.2 mmol), nitromethane
(0.6 mmol), 1a (10 mol%), and PhCO2H (10 mol%) in solvent (0.4 mL)
at 308C. [b] Yield of isolated product. [c] Determined by HPLC using
a Chiracel AD-H column.
Chem. Asian J. 2014, 9, 2444 – 2448
2445
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