Copper-Catalyzed Oxidation of Amines with Molecular Oxygen

Article abstract of DOI:10.1246/bcsj.76.2399

An improved system for selective aerobic oxidation of amines to imines or nitriles is presented. It involves commercially available and inexpensive copper(I) or (II) chloride as catalyst, toluene as solvent, and MS3A as dehydrating agent under an atmospheric pressure of oxygen. A variety of amines can be used as substrates for this oxidation system to give the corresponding nitriles from primary amines (up to 97% yield; TON, up to 60) and the imines from secondary amines (up to 90% yield; TON, up to 45).

Full text of DOI:10.1246/bcsj.76.2399

Ó 2003 The Chemical Society of Japan
Bull. Chem. Soc. Jpn., 76, 2399–2403 (2003) 2399
Copper-Catalyzed Oxidation of Amines with Molecular Oxygen
ꢀ
Yasunari Maeda, Takahiro Nishimura, and Sakae Uemura
Department of Energy and Hydrocarbon Chemistry, Graduate School of Engineering, Kyoto University,
Sakyo-ku, Kyoto 606-8501
Received June 9, 2003; E-mail: uemura@scl.kyoto-u.ac.jp
An improved system for selective aerobic oxidation of amines to imines or nitriles is presented. It involves com-
mercially available and inexpensive copper(a) or (b) chloride as catalyst, toluene as solvent, and MS3A as dehydrating
agent under an atmospheric pressure of oxygen. A variety of amines can be used as substrates for this oxidation system
to give the corresponding nitriles from primary amines (up to 97% yield; TON, up to 60) and the imines from secondary
amines (up to 90% yield; TON, up to 45).
Oxidation of organic compounds with molecular oxygen as a
sole oxidant is valuable, because the use of such an inexpensive
Cu cat.
ð1Þ
RCH2NH2
RCN
and clean oxidant, instead of other organic oxidants, has advan-
tages from economical point of view as well as from the view-
point of green chemistry.1 For these reasons, efforts have been
devoted in recent years to developing the transition metal-cat-
alyzed aerobic oxidation of organic substrates. The direct syn-
thesis of nitriles by the oxidation of primary amines2,3 is impor-
tant because nitriles are useful intermediates of medicines or
biologically active compounds including heterocycles.4 Some
ruthenium catalysts have been known to work effectively for
aerobic oxidation of primary amines to the corresponding ni-
triles: RuCl3,5a [RuCl2(RCH2NH2)2(PPh3)2],5b,5c Ru–porphy-
rin,5d Ru–hydroxyapatite,5e [Ru2Cl(OAc)4],5f and Ru/Al2O3.5g
Catalytic oxidation using more economical copper salts has al-
so been reported, but the examples are still quite limited. Thus,
Capdevielle and co-workers reported that the combination of
copper(a) chloride/O2/pyridine/MS4A worked as a good oxi-
dant system for some primary amines.6a–6c Unfortunately, how-
ever, this system showed only low catalytic activity (TON =
5.5 when applied to piperonylamine (3,4-methylidenedioxy-
benzylamine)). Komatsu and co-workers used binuclear
copper(b) complex of 7-azaindole as a catalyst, which worked
efficiently for dehydrogenation of several amines, although the
selectivity for the products was sometimes low.6d To overcome
such drawbacks in direct synthesis of nitriles from primary
amines, we have searched for a more effective aerobic oxida-
tion system of primary amines. First, we attempted to use pal-
ladium7a–7f or vanadium complexes7g,7h as catalysts for the
aerobic oxidation of primary amines, which were efficient cat-
alysts for the aerobic oxidation of alcohols, but these systems
could not be applied to the aerobic oxidation of amines. Next,
we carefully examined Capdevielle’s system using copper(a) or
(b) chloride, and eventually we found that the use of toluene in
place of pyridine much improved the yields of the correspond-
ing nitriles (TON: up to 60). Herein, we report the efficient
copper-catalyzed oxidation of amines with molecular oxygen
(Eq. 1).
O2
Results and Discussion
First, the oxidation of benzylamine was examined under var-
ious reaction conditions (Table 1). Treatment of benzylamine
(1 mmol) with an atmospheric pressure of oxygen in toluene (2
mL) in the presence of a catalytic amount of copper(a) chloride
ꢀ
(0.01 mmol) and 3 A molecular sieves (MS3A: 500 mg) at 80
ꢁC for 3 h gave benzonitrile in 34% yield together with a small
amount of N-benzylidenebenzylamine (entry 1). Other solvents
were examined, such as 1,2-dichloroethane, chlorobenzene,
1,2-dimethoxyethane, acetonitrile, N,N-dimethylformamide,
and pyridine, but toluene was revealed to be the solvent of
choice (entries 1–7).8 Next, some copper salts were examined
as catalyst for this oxidation system in toluene. Copper(b) ace-
tate, copper(a) oxide, and copper(b) acetylacetonate did not
work at all (entries 10–12). When copper(b) nitrate was used
as catalyst, benzonitrile was obtained in moderate yield (entry
13). Some copper halides such as copper(a) and (b) chlorides
and copper(a) and (b) bromides worked as catalysts to give ben-
zonitrile (entries 1, 8, 14, and 15) in moderate to good yields,
among which copper(b) chloride was most effective (entry
14). Some other transition metal chlorides such as FeCl2,
CoCl2, NiCl2, RuCl3 3H2O, AgCl, and IrCl3 were not effective
ꢂ
under this reaction condition. Then, we investigated the effects
of the amounts of the catalyst and MS3A on the selectivity for
benzonitrile (Table 2). When the amount of copper(b) chloride
doubled, the selectivity for benzonitrile increased (entry 2).
Higher concentration of the substrate decreased the yield of
benzonitrile (entry 4), while the reaction in lower concentration
of the substrate did not improve its yield even after a longer re-
action time (entries 5 and 6). Interestingly, MS4A, which was
used as a drying agent by Capdevielle et al., was less effective
than MS3A (entry 7). Further, the smaller amount of MS3A
gave the smaller amount of the corresponding nitrile (entries
Published on the web December 15, 2003; DOI 10.1246/bcsj.76.2399

2400 Bull. Chem. Soc. Jpn., 76, No. 12 (2003)
Table 1. Copper-Catalyzed Oxidation of Benzylamine
Copper-Catalyzed Oxidation of Amines
Cu catalyst (0.01 mmol)
PhCN +
Ph
NH2
Ph
N
Ph
solvent (2 mL)
1 mmol
MS3A (500 mg)
80 °C, 3 h, O2 (1 atm)
Yield/%a)
Entry
Solvent
Cu catalyst
Nitrile
Imineb)
1
2
3
4
5
Toluene
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
34
16
30
0
13
35
1
8
4
4
10
70
65
9
1,2-Dichloroethane
Chlorobenzene
1,2-Dimethoxyethane
Acetonitrile
N,N-Dimethylformamide
Pyridine
6
7
8
9
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
CuBr SMe2
ꢂ
32
19
4
0
0
44
60c)
50
10
44
6
1
0
24
18
24
CuI
10
11
12
13
14
15
Cu(OAc)2
Cu2O
[Cu(acac)2]
CuNO3 3H2O
ꢂ
CuCl2
CuBr2
a) Based on benzylamine employed (%). b) 0.5 mmol N-benzylidenebenzylamine corresponds to
100%. c) TON is 60.
Table 2. Optimization of the Reaction
CuCl2 (0.01-0.05 mmol)
PhCN
+
Ph
NH2
Ph
N
Ph
toluene (1-5 mL)
MS3A, 80 °C, O2 (1 atm)
1 mmol
Yield/%a)
Entry
Toluene/mL
Time/h
CuCl2/mmol
MS3A/mg
Nitrile
Imineb)
1
2
3
4
5
2.0
2.0
2.0
1.0
5.0
5.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
3
3
3
3
3
6
3
3
3
3
3
3
1
2
6
12
24
0.01
0.02
0.05
0.02
0.02
0.02
0.02
0.02
0.02
0.02
0.02
0.02
0.02
0.02
0.02
0.02
0.02
500
500
500
500
500
500
500
100
250
750
0
500
500
500
500
500
500
60
67
60
47
38
65
37
28
40
61
2
18
14
37
46
16
28
7
17
14
33
2
4
6
10
24
25
25
6
7c)
8
9
10
11
12d)
13
14
15
16
17
2
27
55
71
75
75
a) Based on benzylamine employed (%). b) 0.5 mmol N-benzylidenebenzylamine corresponds to
100%. c) MS4A was used instead of MS3A. d) Under N2.
2, 8, and 9). The presence of MS3A was essential for this ox-
most cases of benzylamine oxidation, N-benzylidenebenzyl-
amine was obtained as a by-product. Benzylamine was con-
sumed almost completely after 6 h to give both benzonitrile
and N-benzylidenebenzylamine (entry 15) and the product ratio
did not change much by prolonging the reaction time (entries
idation and the oxidation scarcely proceeded at all without
MS3A (entry 11). The reaction under nitrogen atmosphere
gave very little of the corresponding nitrile (entry 12), indicat-
ing that the presence of oxygen is essential for this reaction. In

Y. Maeda et al.
Bull. Chem. Soc. Jpn., 76, No. 12 (2003) 2401
Table 3. Copper-Catalyzed Aerobic Oxidation of Primary
Amines
Table 4. Copper-Catalyzed Aerobic Oxidation of Secondary
Amines
Cu catalyst (0.02 mmol)
R'
CuCl (0.02 mmol)
R'
R''
N
RCN
R
NH2
R''
toluene (2 mL)
MS3A (500 mg)
80 °C, 12 h, O2 (1 atm)
toluene (2 mL)
MS3A (500 mg)
80 °C, 12 h, O2 (1 atm)
R
N
1 mmol
R
H
1 mmol
a)
Cu catalyst Isolated yield/%a)
Entry
Substrate
Product Isolated yield/%
Entry
Substrate
R = H
2-Cl
1
2
3
4
5
6
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl
75b)
78b)
73
90b)
N
N
1
H
NH2
3-Cl
4-Cl
4-Me
R
88
72
66
92b)
2
3
NH
N
73
NH2
N
N
H
H
7
CuCl
96
NH2
8
9
CuCl
97
17
24
4
5
N
N
NH2
CuCl2
H
CuCl
CuCl2
84
28
10
11
34
NH2
N
N
H
a) Based on amine employed (%): In all reactions except for en-
tries 9 and 11, complete consumption of amines was confirmed.
b) GLC yield.
a) Based on amine employed (%). b) GLC yield. TON is 45.
16 and 17). Other efforts to improve the selectivity of benzo-
nitrile, such as the change of addition rate of benzylamine,
the change of reaction temperature, and so on, were unfortu-
nately in vain.
mmol
1.0
O2 uptake
The oxidation of some other primary amines was examined
under the condition of entry 16 of Table 2; typical results are
listed in Table 3. Some primary benzylic amines having chloro
or methyl substituent on aromatic nuclei were converted to the
corresponding nitriles in good yields (entries 1–5). Aliphatic
amines including the allylic one were oxidized to give the cor-
responding nitriles in high yields using copper(a) chloride as
catalyst (entries 6–8, and 10); unlike the case of benzylic
amines the use of copper(b) chloride was not effective and un-
reacted amines were recovered under this condition (entries 9
and 11). In the cases of the oxidation of benzylic amines, the
corresponding N-benzylidenebenzylamines were obtained as
by-products in at most 20% yield (entries 1–5).
Ph C N
0.5
Ph
N
Ph
0
0
5
10 15
20 24 h
Fig. 1. Correlation between O2 uptake and the product
yield. Reaction conditions: benzylamine (1 mmol), CuCl2
(0.02 mmol), toluene (2 mL), MS3A (500 mg), 80 ꢁC, un-
der O2 (1 atm).
When this catalytic system was applied to the secondary
amines,9 the corresponding imines were obtained, as summariz-
ed in Table 4. Some secondary benzylic amines such as diben-
zylamine and 1,2,3,4-tetrahydroisoquinoline were converted to
the corresponding imines in high yields (entries 1 and 2).
Treatment of indoline as a substrate gave an indole in good
yield (entry 3). When N-phenylbenzylamine was used as a sub-
strate, the corresponding imine was obtained in low yield (entry
4). 1,2,3,4-Tetrahydroquinoline afforded quinoline with aro-
matization in moderate yield (entry 5). In the cases of entries
4 and 5, the corresponding unreacted amines were recovered.
The measurement of O2 uptake during the reaction was per-
formed with benzylamine as a substrate to obtain some infor-
mation about the reaction pathway. The molar amount of ob-
served O2 consumption was found to be equal to the sum of that
of benzonitrile and N-benzylidenebenzylamine produced in this
reaction (Fig. 1). Next, the oxidation of benzylamine and iso-
amylamine was carried out in the presence of a radical scaveng-
er (Scheme 1). When benzylamine was used as a substrate in
the presence of garvinoxyl (0.1 mmol) under the reaction con-
dition of Table 3, N-benzylidenebenzylamine was obtained se-
lectively (0.42 mmol: 84% yield) instead of benzonitrile (0.01
mmol: 1% yield; compare with the result of Table 3, entry 1 ob-
tained in the absence of the scavenger). Similarly, the treat-
ment of isoamylamine as a substrate in the presence of garvi-
noxyl did not produce the corresponding nitrile, while the ni-
trile was formed in 92% yield in the absence of the scavenger
(Table 3, entry 6).10 These results suggest that this copper-cat-
alyzed aerobic oxidation of amines to nitriles in toluene pro-
ceeds through a reaction pathway including an ammoniumyl
radical (A) and an alkylideneaminyl radical (B) (Fig. 2)11 sim-
ilar to suggested by Capdevielle et al.,6b,c in contrast to the
ruthenium catalysis where an ionic pathway has been recogni-
zed.5d,e,g

2402 Bull. Chem. Soc. Jpn., 76, No. 12 (2003)
Copper-Catalyzed Oxidation of Amines
CuCl2 (0.02 mmol)
garvinoxyl (0.1 mmol)
+
PhCN
1%
(0.01 mmol)
Ph NH2
1 mmol
Ph
N
84%
Ph
toluene (2 mL)
MS3A (500 mg)
80 °C, 12 h, O2
(0.42 mmol)
in the absence of garvinoxyl
75%
25%
(0.75 mmol)
(0.13 mmol)
CuCl (0.02 mmol)
garvinoxyl (0.1 mmol)
CN
NH2
toluene (2 mL)
MS3A (500 mg)
80 °C, 12 h, O2
0%
1 mmol
(0 mmol)
in the absence of garvinoxyl
92%
(0.92 mmol)
Scheme 1. Copper-catalyzed aerobic oxidation of primary amines in the presence or absence of a radical scavenger.
tomed flask was added MS3A (500 mg, powder). A solution of pri-
mary amine (1 mmol) in toluene (0.5 mL) was then added and the
resulting mixture was stirred. Oxygen gas was then introduced into
H
RCH2
N
H
RCH N
the flask from an O2 balloon under atmospheric pressure and then
the mixture was stirred vigorously for 3–12 h at 80 ꢁC under
oxygen. After the reaction, the mixture was cooled to room tem-
perature and MS3A was separated by filtration through a glass
filter. The amount of the product was determined by GLC analysis
using bibenzyl as an internal standard. For isolation of the product
the solvent was evaporated and the residue was purified by column
chromatography (hexane–ethyl acetate as an eluent) and identified
B
A
Fig. 2. Ammoniumyl radical (A) and alkylideneaminyl
radical (B).
In summary, we found that copper(a) or (b) chloride, which
was a commercially available and inexpensive compound,
worked efficiently as a catalyst in toluene for the aerobic oxida-
tion of primary amines to the corresponding nitriles in good
yields and selectivity. Especially, the oxidation of aliphatic pri-
mary amines gave the corresponding nitriles in excellent yield
(up to 97% yield; TON, up to 60). This catalytic system could
also be applied to secondary amines to give the corresponding
imines (up to 90% yield; TON, up to 45).
1
by H NMR and 13C NMR.
References
1
a) R. A. Sheldon and J. K. Kochi, ‘‘Metal-Catalyzed Oxida-
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Experimental
General Procedures. NMR spectra were recorded on JEOL
EX-400 (1H NMR, 400 MHz; 13C NMR, 100 MHz) and JNM-
AL-300 (1H NMR, 300 MHz; 13C NMR, 75.5 MHz) instruments
for solutions with Me4Si as an internal standard. GLC analyses
were performed on a Shimadzu GC-14A instrument (25 m ꢃ
0.33 mm, 5.0 mm film thickness, Shimadzu fused silica capillary
column HiCap CBP10-S25-050) with a flame-ionization detector
and helium as carrier gas. Analytical thin-layer chromatography
(TLC) was performed with Merck silica gel 60 F-254 plates. Col-
umn chromatography was performed with Merck silica gel 60 or
ICN alumina N. Commercially available organic and inorganic
compounds were used without further purification except for the
solvent. Commercial MS3A (powder) (Nacalai Tesque) was acti-
vated by calcination just before use. All amines and the corre-
sponding nitriles or imines were commercial products and were pu-
rified by normal methods just before use.
2
Stoichiometric oxidation of primary amines to the corre-
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¨
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¨
3
Metal-catalyzed oxidation of amines to the corresponding
Typical Procedure for the Oxidation of Primary Amines
with Molecular Oxygen. To a suspension of CuCl or CuCl2
(0.02 mmol) in toluene (1.5 mL) in a 10 mL two-necked round-bot-
nitriles using some organic or inorganic compounds as oxidants,
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4
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5
Ruthenium-catalyzed aerobic oxidation of primary amines
8
Although Capdevielle and co-workers used pyridine as sol-
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vent in the presence of a stoichiometric amount of Cu(a) chloride
[Refs. 6a–c], almost no reaction proceeded using a catalytic
amount of it in our hand.
9
Metal-catalyzed aerobic oxidation of secondary amines to
the corresponding imines, see Refs. 3e (Ru), 3f (Ru), and 4d
(Cu), and also: a) (Co); A. Nishinaga, S. Yamazaki, and T.
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41, 773 (1995).
6
Copper-catalyzed aerobic oxidation of primary amines to
10 Isoamylamine was completely consumed under this reac-
tion condition. The use of n-octylamine as a substrate in the pres-
ence of garvinoxyl gave a mixture of unidentified compounds
among which the presence of the corresponding imine (around
20% yield) was confirmed by 1H NMR and 13C NMR.
11 a) W. Brackman and P. J. Smit, Recl. Trav. Chim. Pays-Bas,
82, 757 (1963). b) A. Misono, T. Osa, and S. Koda, Bull. Chem.
Soc. Jpn., 40, 912 (1967).
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thesis, 1989, 453. b) P. Capdevielle, A. Lavigne, and M. Maumy,
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7
a) T. Nishimura, T. Onoue, K. Ohe, and S. Uemura, Tetra-