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J. Yu et al. / Tetrahedron Letters 55 (2014) 5751–5755
catalyst, additive, TEMPO, bases, solvent, gas, temperature, and
time. As shown in Table 1, when the reaction was conducted the
aerobic oxidation of benzylamine was catalyzed by TEMPO/acet-
aldoxime/InCl3 in toluene and the reaction was performed at
100 °C for 4 h. To our delight, the desired benzaldoxime was
obtained in 89% yield (Table 1, entry 1). A lower yield was obtained
in the absence of one of the TEMPO/acetaldoxime/InCl3 (entries 2–
4). Other four metal catalysts also had considerable catalytic activ-
ity, among them InCl3 exhibited the highest (entries 5–8). Various
acetaldoxime analogues were compared, and we found that acet-
aldoxime gave the highest yield (entries 1, 9–11). After screening
the loadings of TEMPO, acetaldoxime, and InCl3, we found that
10 mol % TEMPO, 5 mol % InCl3 and 3.1 equiv acetaldoxime were
the most appropriate proportion (entries 1, 12–18). Solvent screen-
ing, demonstrated that Toluene is the best one compared with all
the others (entries 1, 19–22). Besides, we also tested the influence
of the gas, and we found that the O2 is significant for the reaction,
and O2 is better than air (entries 1, 23–24). Further optimization by
screening the reaction temperature and time showed that 100 °C
and 4 h were optimal for this reaction, higher temperatures and
longer reaction time do not increase the yields (entries 25–30).
Encouraged by the good catalytic activity, we expanded the
scope of the present catalytic system to a series of primary amines
under our optimized conditions. As shown in Table 2, a variety of
primary amines were examined to the corresponding oximes.
The reaction could be successfully applied to a range of different
substituted benzylamines and gave the corresponding products
in moderate to excellent yields. Benzylamine with either elec-
tron-donating or electron-withdrawing groups on the benzene ring
smoothly generated the corresponding products in moderate to
good yields. Clearly, the reaction conditions were compatible with
fluoro, chloro, and bromo substituent groups (entries 2–4). When
the benzylamines bear electron-donating substituents, the yield
of the aromatic oxime with substituent at ortho or meta position
was slightly lower than those with substituent at the para position
(entries 4–9). That may be, in part, due to steric hindrance. Addi-
tionally, electronic effects play an important role, as electron-with-
drawing substituents (entry 9) on the benzene ring favor the
transformation, whereas electron-donating substituents (entries
7, 10–12) objected the transformation. Fortunately, 1-naphthale-
nemethylamine and 3-phenyl-2-propylene amine could also be
successfully converted to the corresponding oximes in good yields
in this reaction system (entries 15–16). Moreover, we also con-
ducted heterocyclic primary amines under the employed reaction
conditions (entries 17–21). To our surprise, heterocyclic amines
show high reactivity to give the corresponding oximes in good
yields. To demonstrate the scope and efficiency of the present
method, this catalytic system was then extended for the synthesis
of aliphatic oximes (entry 22). We found that octylamine could oxi-
date to octanal oxime in an yield of 38%.
Preliminary mechanistic studies of the reaction were also con-
ducted. First, we turn our attention to the reaction of benzylamine
to N-benzylidenebenzylamine as shown in Table 3. After optimiz-
ing the reaction condition, we found that, almost no N-benzylide-
nebenzylamine occurred in the absence of TEMPO (entries 1 and
4). When TEMPO was added in the reaction, the yield increased
up to 56% (entry 2), and reached the highest when 10 mol %
acetaldoxime and 10 mol % TEMPO were added (entry 5). Besides,
we found that the yield of N-benzylidenebenzylamine would
decrease in the presence of InCl3 (entries 2, 3, 5, and 6), that may
Table 1
Screen of reaction conditionsa
Entry
Catalyst (mol %)
Additive (equiv)
TEMPO (mol %)
Solvent
Gas
T. (°C)
Time (h)
Yieldb (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
InCl3 (5)
—
Acetaldoxime (3.1)
Acetaldoxime (3.1)
—
Acetaldoxime (3.1)
Acetaldoxime (3.1)
Acetaldoxime (3.1)
Acetaldoxime (3.1)
Acetaldoxime (3.1)
Acetoxime (3.1)
Dimethylglyoxime (3)
cyclohexanone oxime (5)
Acetaldoxime (3.1)
Acetaldoxime (3.1)
Acetaldoxime (3)
Acetaldoxime (2)
Acetaldoxime (5)
Acetaldoxime (3.1)
Acetaldoxime (3.1)
Acetaldoxime (3.1)
Acetaldoxime (3.1)
Acetaldoxime (3.1)
Acetaldoxime (3.1)
Acetaldoxime (3.1)
Acetaldoxime (3.1)
Acetaldoxime (3.1)
Acetaldoxime (3.1)
Acetaldoxime (3.1)
Acetaldoxime (3.1)
Acetaldoxime (3.1)
Acetaldoxime (3.1)
10
10
10
0
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
DMSO
O2
O2
O2
O2
O2
O2
O2
O2
O2
O2
O2
O2
O2
O2
O2
O2
O2
O2
O2
O2
O2
O2
Air
N2
O2
O2
O2
O2
O2
O2
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
80
100
100
100
100
110
80
60
rt
100
100
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
6
10
89
56
Trace
Trace
65
52
13
39
77
61
75
65
89
85
73
89
88
89
Trace
21
Trace
Trace
77
Trace
89
84
69
Trace
89
89
InCl3 (5)
InCl3 (5)
AlCl3 (5)
ZnCl2 (5)
CuCl2 (5)
FeCl3 (5)
InCl3 (5)
InCl3 (5)
InCl3 (5)
InCl3 (1)
InCl3 (10)
InCl3 (5)
InCl3 (5)
InCl3 (5)
InCl3 (5)
InCl3 (5)
InCl3 (5)
InCl3 (5)
InCl3 (5)
InCl3 (5)
InCl3 (5)
InCl3 (5)
InCl3 (5)
InCl3 (5)
InCl3 (5)
InCl3 (5)
InCl3 (5)
InCl3 (5)
10
10
10
10
10
10
10
10
10
10
10
10
5
20
10
10
10
10
10
10
10
10
10
10
10
10
EtOH
DMF
MeCN
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
a
1 mmol benzylamine, InCl3, oxime, TEMPO, O2, 5 ml solvent.
Isolated yields.
b