À
Dual Activation Catalysis for C C Bond-Forming Reactions
FULL PAPER
tries 5 and 6). In addition, the reaction scarcely proceeded
in the presence of the mixture of triethylamine and SA
(Table 5, entry 4). Notably, the SA–NEt2-catalyzed reaction
of ethyl phenylcyanoacetate (4b) with methyl acrylate (5b)
successfully proceeded to give 2-cyano-2-phenyl glutaric
acid 1-ethyl-5-methyl ester, which is a highly useful inter-
mediate for glutarimide synthesis (Table 5, entry 7).[18] The
SA–NEt2 catalyst was reusable at least four times with re-
tention of its high catalytic activity and selectivity in the Mi-
chael reaction (Table 5, entries 8 and 9). In addition, SA–
NEt2 showed higher catalytic activity for the reaction of 4a
with acrylonitrile (5c; Table 5, entries 10 and 11) than the
homogeneous amine (Table 5, entry 12).
rated nitro compounds, which are important building blocks
in the synthesis of pharmaceutical products.[20] The a-hydro-
gen atom of a nitroalkane can be abstracted by strong bases
owing to its acidity, but the selective production of a nitroal-
kene using conventional strong bases is generally difficult
because the side reaction of a conjugate addition of the ni-
troalkane to the carbon–carbon double bond of the nitroal-
kene occurs to give a bis
(nitro) compound.[21] Because of
A
the highly useful nature of nitroalkenes, the nitro-aldol reac-
tion of nitroalkanes with aldehydes was also investigated
(Table 7).[22] The SA–NH2 catalyst gave a quantitative yield
Table 7. Nitro-aldol reaction of aldehydes with nitroalkanes using various
catalysts.[a]
It is noteworthy that the SA–NEt2 catalyst also showed
excellent performance for the bis-substitution reaction of
ethyl cyanoacetate (4c) with methyl vinyl ketone (5d), thus
producing 5-carboethoxy-5-cyano-2,8-nonanedione (6 cd) in
90% yield within 30 minutes (Table 6, entry 1). A SiO2-sup-
Entry Catalyst
R1
R4
Time Yield
[h]
[%][b]
1
2
SA–NH2
SA–NEt2
Ph (1a)
Ph
H (7a)
6
6
6
6
99 (97)[c]
<1
12
Table 6. Michael reaction of 4c with 5d using various catalysts.[a]
H
H
H
3[d,e] n-hexylamine+SA Ph
4[d,f]
n-hexylamine+
p-TsOH·H2O
n-hexylamine
SA
Ph
<1
5[d]
6[e]
Ph
Ph
Ph
H
H
H
H
6
6
6
2
2
4
13
<1
<1
88
88
90
Entry
Catalyst
Conversion [%][b]
Yield [%][b]
7[e,f]
8[g]
none
1
2
3
SA–NEt2
SiO2–NEt2
SA–NH2
Et3N+SA
Et3N
SA
SiO2
MgO
None
>99
83
<1
90
<1
<1
<1
82
90
43
<1
66
<1
<1
<1
52
SA–NH2
SA–NH2
SA–NH2
c-hexyl (1j)
n-octyl (1h)
Ph
9[g]
H
10[g]
Me (7b)
4[c,d]
5[c]
6[d]
7[d]
8[d]
9
[a] Reagents and conditions: catalyst (0.015 mmol of amine),
(5.0 mmol), (2 mL), 1008C. [b] Determined by GC, based on 1.
[c] Fourth reuse experiment. [d] n-Hexylamine (0.015 mmol). [e]Catalyst
(0.0145 g). [f] p-TsOH acid (0.015 mmol). [g] Aldehyde (1 mmol); SA–
NH2 (0.056 mmol).
1
7
<1
<1
[a] Catalyst (0.091 mmol of amine), 5d (1.5 mmol), 4c (0.5 mmol), tolu-
ene (1 mL), 608C, 30 min. [b]Determined by GC, based on 4c. [c]Trie-
thylamine (0.091 mmol). [d]Catalyst (0.1 g).
of b-nitrostyrene from 1a and nitromethane (7a; Table 7,
entry 1). The homogeneous primary amine was much less
active (Table 7, entry 5) and the low catalytic activity was
not improved by the addition of SA (Table 7, entry 3). Nota-
bly, the reaction hardly proceeded using SA–NEt2 instead of
SA–NH2 (Table 7, entry 2). In the case of the SA–NH2-cata-
lyzed reaction of 7a with 1a, the turnover number (TON)
based on the amine reached up to 330. This value is signifi-
cantly higher than that of the previously reported amine cat-
alysts: MCM-41-supported amine (TON=37),[22c] aminopro-
pylsilica (TON=17),[22d] and a silica-supported urea–amine
bifunctional catalyst (TON=125).[6] The SA–NH2 catalyst
was found to be applicable to the nitro-aldol reaction of
other aldehydes with nitroalkanes. The reaction of aliphatic
aldehydes, such as cyclohexanecarboxyaldehyde (1j) and n-
octylaldehyde (1h), produced the corresponding nitroal-
kenes in excellent yields (Table 7, entries 8 and 9). Nitro-
ethane (7b) also acted as a good donor substrate (Table 7,
entry 10). After the nitro-aldol reaction of 7a with 1a, the
recovered SA–NH2 catalyst was washed with toluene and re-
usable under the same reaction conditions: the first and
ported tertiary amine catalyst also gave 6 cd in a moderate
yield of 43% (Table 6, entry 2). Neither triethylamine nor
SA produced 6 cd (Table 6, entries 5 and 6), whereas the
mixture of triethylamine and SA gave a 66% yield of 6 cd
(Table 6, entry 4). A typical heterogeneous base of MgO
also gave the corresponding product (Table 6, entry 8), but
the catalytic activity was lower than for the same weight of
SA–NEt2. Generally, strong bases or transition-metal cata-
lysts are needed for the 1,4-addition of nitrile compounds to
electron-deficient alkenes.[19] However, these reaction sys-
tems present difficulty in their handling as a result of mois-
ture sensitivity and deactivation by air containing carbon di-
oxide. The present SA–NEt2 catalyst can solve these prob-
lems because of the use of the simple and stable alkylamines
immobilized on the stable SA as a heterogeneous catalyst,
which contributes to environmentally friendly organic syn-
theses.
The condensation reaction of nitroalkanes with carbonyl
compounds, namely, the nitro-aldol reaction, is one of the
most powerful procedures for the production of a,b-unsatu-
Chem. Eur. J. 2008, 14, 4017 – 4027
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4023