F. Nikbakht, A. Heydari / Tetrahedron Letters 55 (2014) 2513–2516
2515
Table 2 (continued)
Entry
Substrate
Product
Timeb (h)
8
Yieldc (%)
90
Refs.
N
H
1k
N
O
25
11
12
2k
2l
N
H
N
O
26
8
95
1l
N
O
N
H
26
27
13
8
8
88
65
1m
2m
N
N
O
14
H
2n
1n
a
Reaction conditions for the oxidation of amines 1a–j: amine (1 mmol), trichloroacetonitrile (2 mmol), THF (2 mL), NaHCO3 (0.5 mmol), hydrogen peroxide (2 mmol),
rt, 4–12 h; reaction conditions for the oxidation of amines 1k–n: amine (1 mmol), trichloroacetonitrile (2 mmol), MeOH (2 mL) hydrogen peroxide (2 mmol), rt, 8 h.
b
10 min at 0 °C, then warmed to rt.
The yield refers to those of isolated products.
c
isolated yield of pyridine N-oxide was as much as 85% (Table 1,
entry 3).
aliphatic and aromatic tertiary amines converted (Table 2, entries
1–10). A mechanism is proposed for this reaction according to the
experimental evidence (Scheme 2). The trichloromethylperoxycar-
boximidic acid intermediate was formed from the reaction of tri-
chloroacetonitrile with hydrogen peroxide in the presence of a
base.10 The reaction of this intermediate with a tertiary amine led
to formation of the tertiary amine N-oxide and trichloroacetamide.
The process was also extended to other amines. When primary
aliphatic amines such as benzylamine were subjected to this reac-
tion system (CCl3CN/H2O2/NaHCO3 in THF at 0 °C), it was found
that the major product was that produced by addition of the amine
to trichloroacetonitrile (N-alkyltrichloroacetamidines).28 Primary
aromatic amines such as anilines gave a mixture of products. Con-
trary to what was expected, secondary amines were converted effi-
ciently into their corresponding nitrones under these conditions
(Table 3, entry 1). Optimization of the reaction conditions using
dibenzylamine (1k) as a model substrate showed that, in contrast
to the oxidation of tertiary amines, there was no need for a base for
oxidation of secondary amines to nitrones, and methanol proved to
be a good solvent for this oxidation. The results are summarized in
Table 3. The yield of N-benzylidenebenzylamine N-oxide (2k) was
reduced when the oxidation of dibenzylamine was carried out in
the presence of sodium bicarbonate as the base (Table 3, entries
1 and 2).
The reaction was found to be dependent upon the pH of the
system (entries 3–6). Reaction conditions were varied by changing
the reagent stoichiometry, using NaHCO3 as the base and THF as
the solvent. The results are summarized in Table 1. The highest
yield and the highest selectivity were obtained using 2 equiv of
trichloroacetonitrile, 2 equiv of H2O2, and 0.5 equiv of sodium
bicarbonate (entry 5). Increasing the reaction time from 8 to 12 h
produced no real difference in the isolated yield of pyridine
N-oxide (entry 7). Oxidation of pyridine using acetonitrile or ben-
zonitrile rather than trichloroacetonitrile as the nitrile source was
also successful, but complete conversion of pyridine required more
time. Other bases such as Na2CO3 and K2CO3 were also tested and
the isolated yield of pyridine N-oxide was lower than when using
NaHCO3 (Table 1, entries 10 and 11).
With the initial reaction conditions identified, the scope of the
reagent combination was next determined for trichloroacetoni-
trile/H2O2/NaHCO3 using a variety of tertiary amines.21 The results
are summarized in Table 2, the reaction proceeded well with a
number of pyridines to provide the corresponding pyridine N-oxi-
des in modest to good yields. It was noted that the initial reactivity
of this system for electron-deficient pyridines such as 2-chloropyr-
idine and nicotinamide was low, although both were converted into
their corresponding N-oxides, 2f and 2g, completely after 12 h. The
generality of the method was demonstrated by the range of
Under the optimized conditions,29 dibenzylamine (1k) was con-
verted into N-benzylidenebenzylamine N-oxide in a yield of 90%
using 2 equiv of trichloroacetonitrile and 2 equiv of H2O2 in meth-
anol as the solvent (Table 3, entry 3).
NH
N
cat. NaHCO3
H2O2
Cl3C
O
Cl3C
Table 3
Optimization of the reaction conditions for the oxidation of dibenzylamine to
HO
N-benzylidenebenzylamine N-oxidea
Entry
TCAb/H2O2/NaHCO3
Timec (h)
Solvent
Yieldd (%)
N
NH2
1
2
3
4
5
6
2:2:0.5
2:2:0.5
2:2:0
2:2:0
2:2:0
12
12
8
12
12
24
THF
65
75
90
70
70
n.r.
MeOH
MeOH
EtOH
No solvent
MeOH
O
N
O
CCl3
O
H
NH
O
0:2:0
a
b
c
All reactions were run with dibenzylamine as the substrate.
Trichloroacetonitrile.
10 min at 0 °C, then warmed to rt.
CCl3
Scheme 2. Proposed mechanism for the N-oxidation of pyridine using trichloro-
d
Isolated yield of N-benzylidenebenzylamine N-oxide.
acetonitrile–hydrogen peroxide.