A Selective and Mild Oxidation of Primary Amines to Nitriles with Trichloroisocyanuric Acid

Article abstract of DOI:10.1055/s-2003-42431

An efficient and highly selective method for the oxidative conversion of primary amines to the corresponding nitriles using trichloroisocyanuric acid in the presence of catalytic TEMPO under mild reaction conditions is described. Other functional groups such as C,C-double bonds, benzyloxy etc. were found to be unaffected under the reaction conditions. This procedure provides a new entry to the synthesis of various aliphatic, aromatic and heterocyclic nitriles in excellent yield.

Full text of DOI:10.1055/s-2003-42431

SHORT PAPER
2629
A Selective and Mild Oxidation of Primary Amines to Nitriles with
Trichloroisocyanuric Acid
O
F
xidation of
P
e
rimary Am
n
ines to Nitri
-
T
E
richloroisocya
r
nuric
A
cid Chen,* Yun-Yan Kuang, Hui-Fang Dai, Liang Lu, Ming Huo
Department of Chemistry, Fudan University, Shanghai, 200433, P. R. China
Fax +86(21)65642021; E-mail: rfchen@fudan.edu.cn
Received 4 August 2003; revised 8 September 2003
ramethyl-1-piperidinyloxy, free radical (TEMPO) under
mild reaction conditions as outlined in Scheme 1.
Abstract: An efficient and highly selective method for the oxida-
tive conversion of primary amines to the corresponding nitriles us-
ing trichloroisocyanuric acid in the presence of catalytic TEMPO
under mild reaction conditions is described. Other functional groups
such as C,C-double bonds, benzyloxy etc. were found to be unaf-
fected under the reaction conditions. This procedure provides a new
entry to the synthesis of various aliphatic, aromatic and heterocyclic
nitriles in excellent yield.
Scheme 1
Key words: trichloroisocyanuric acid, primary amines, nitriles, ox-
idation
Our preliminary studies were carried out with benzyl-
amine (1d) as a model substrate in order to establish the
best reaction conditions. At the outset, the influence of
The oxidation of primary amines into the corresponding
nitriles constitutes a very useful functional group transfor-
mation in organic synthesis, and the plethora of oxidizing
agents for such a transformation documented in literature
directly demonstrates the importance with which the func-
solvent on this oxidation was investigated. In Et O, diox-
2
ane, and THF, only low yield of benzonitrile (2d) was ob-
tained (Table 1, entries 1–3); a dramatic increase in the
yield, however, was obtained in CH Cl (Table 1, entry
2
2
1
4), which was therefore used as the solvent in all further
experiments. Next, the effect of temperature was exam-
ined. Enhancing the temperature from 0 to 10 °C resulted
in a considerable increase in the yield (49 to 88%, Table 1,
entries 5,6). A somewhat higher temperature (10 °C in-
stead of 5 °C) led to shorter reaction time, but also resulted
in a significant decrease in the yield (Table 1, entry 7).
tional group transformation has been addressed. Howev-
er, a lot of drawbacks may be encountered in using some
of these reagents such as low yields, harsh reaction condi-
tions, tedious work-up procedures, and some limitations.
In addition, some of them are corrosive, toxic, expensive,
or commercially unavailable. Consequently, there is a
need for the development of protocols using readily avail-
able and safe reagents, which lead to high yield of nitriles
from primary amines.
Table 1 Optimization of the Reaction Conditions for the TCCA-
Mediated Oxidation of Benzylamine (1d) to the Benzonitrile (2d)a
Trichloroisocyanuric acid (TCCA) is a stable and inex-
pensive reagent frequently used for swimming-pool disin-
fection. Some recent application of the utilization of
TCCA in organic synthesis include thioacetalization of
carbonyl compound, conversion of alcohols to halides,
carboxylic acids to acid chlorides, alkenes to
chloroethers , N-nitrosation of N,N-dialkylamines, selec-
tive mononitration of phenols , and oxidation of alcohols
to carbonyl compounds, aldehydes to methyl esters, al-
doximes to nitrile oxides, thiols to disulfides, selenols
to diselenides and sulfides to sulfoxides, etc. To the
best of our knowledge, however, there is no indication in
the literature on the utilization of TCCA as an oxidant for
the conversion of primary amines into nitriles. Herein, we
wish to report a new, simple and extremely efficient pro-
cedure for the preparation of nitriles from primary amines
utilizing TCCA in the presence of catalytic 2,2,6,6-tet-
Yieldb
(%)
Entry Solvent
Temp
(°C)
1d/TCCA
(mole ratio) (h)
Time
2
3
1
2
3
4
5
6
7
8
9
0
1
Et
2
O
5
5
1:1.2
1:1.2
1:1.2
1:1.2
1:1.2
1:1.2
1:1.2
1:0.5
1:0.8
1:1.3
1:1.5
4
5
5
3
6
3
1
5
3
2
2
70
71
62
85
49
88
69
45
72
90
90
3
-
dioxane
THF
4
5
6
5
7
8
CH Cl
5
2
2
2
2
2
2
2
2
2
9
10
1
1
12
13
CH Cl
0
2
CH Cl
10
10
5
2
CH Cl
2
CH Cl
2
CH
Cl
5
2
1
1
CH Cl
5
2
CH Cl
5
SYNTHESIS 2003, No. 17, pp 2629–2631
x
x.
x
x
.
2
0
0
3
2
Advanced online publication: 14.10.2003
DOI: 10.1055/s-2003-42431; Art ID: F06403SS
Georg Thieme Verlag Stuttgart · New York
a
All reactions were carried out according to the typical procedure.
Yield of isolated pure product.
b
©

2
630
F.-E. Chen et al.
SHORT PAPER
The following experiments were therefore carried out at 5 phatic counterparts, just as reported in the dehydrogena-
C. Finally, the oxidation was carried out by varying the tion procedure of amines to nitriles using NiSO /K S O
°
4
2
2
8
1
e
molar ratio of 1d to TCCA from 1:0.5 to 1:1.5. It was ob- system. At the same time, it is noteworthy that the pres-
served that an increase in the 1d/TCCA molar ratio in- ence of catalytic TEMPO was essential for the dehydroge-
creased the yield of 2d, while further increase in the nation of amines to nitriles. No desirable nitriles were
amount of TCCA was not effective and gave only compa- formed in its absence and the reaction did not go to com-
rable yields. When 1 equivalent of 1d was used with 1.3 pletion when lesser catalytic amounts of TEMPO was
equivalents of TCCA, 90% yield of 2d was achieved (en- used.
try 10). Thus, a ratio of 1:1.3 was found to be the most
suitable for this reaction.
In conclusion, we have developed an efficient method for
oxidative conversion of the primary amines to nitriles em-
Guided by the above experiments with benzylamine (1d), ploying trichloroisocyanuric acid. Prominent advantages
a standard procedure was employed for the oxidation of of this new method are its mild reaction conditions, oper-
other aliphatic, aromatic and heterocyclic primary amines ational simplicity, and high yields.
with TCCA, and the results are summarized in Table 2.
The results illustrated in the Table 2 indicate that this ox-
idation is very successful for a variety of primary amines.
Moreover, benzyloxy (entry 11), C,C-double bonds (entry Procedure
Oxidation of Benzylamine (1d) to Benzonitrile (2d); Typical
9
), hydroxy (entry 12), N,N-dimethlylamino (entry 8) Trichloroisocyanuric acid (30.23 g, 130 mmol) was slowly added to
a solution of benzylamine (1d; 10.7 g, 100 mmol) in CH Cl (200
groups present in the molecule were found to be resistant
under the reaction conditions employed, which were also
described in the oxidation of alcohol to carbonyl com-
pounds. It is interesting to note that benzylic amines were
oxidized more readily with a higher yield than their ali-
2
2
mL), followed by addition of TEMPO (0.195 g, 1.3 mmol). The re-
action mixture was then stirred for 2 h at 10 °C and then quenched
with H O (150 mL). The organic layer was separated and the aque-
7
2
ous layer was extracted with CH Cl (3 × 10 mL). The combined or-
2
2
ganic layers were washed successively with 0.5 N aq NaHSO3
Table 2 Oxidation of Primary Amines 1a–q into Nitriles 2a–q with TCCA
Prod-ucta
Yield (%)
b
Mp (°C) or Bp (°C)/Torr
Entry
R
Time (h)
Found
Reported
1
2
3
4
5
6
7
8
9
C H
4
2a
2b
2c
2d
2e
2f
80
81
80
90
91
90
90
91
90
90
89
91
90
90
89
89
89
115–116/760
160–162/760
162–164
189–190/760
216–218/760
61–63
115/7601d
162–1701d
1621d
3
7
C H
4
5
11
HO C(CH )
4.5
2
2
2 5
Ph
189–191/76014
217–218/76014
61–6314
4-MeC H4
2
6
4-MeOC H
2
6
4
4-NO C H
4
2.5
2
2g
2h
2i
148–150
75–77
148–15014
74–7614
2
6
4-Me NC H
4
2
6
(E)-PhCH=CH
2
253–254/760
145–147/12
94–95
254–255/76014
106–107/115
94–9616
1
1
1
1
1
1
1
0
1
2
3
4
5
6
7
1-naphthyl
1.5
2
2j
3-(4-methoxybenzyloxy)C H
2k
2l
6
4
3,4-(HO) C H
3
2
154–156
228–229/760
93–95
153–15417
228–230/76017
92–9417
2
6
2-ClC H4
2
2m
2n
2o
2p
6
3,4-(CH O )C H
3
2
2
2
6
2-furyl
2
148–149
52–54
146–1481d
50–521f
3-pyridyl
piperonyl
2
1
2.5
2q
70–72
68–701f
a
1
All products were identified by comparison with their spectral data (IR, H NMR and GC/MS) and physical properties with those of the au-
thentic samples.
b
Yields of isolated pure product.
Synthesis 2003, No. 17, 2629–2631 © Thieme Stuttgart · New York

SHORT PAPER
Oxidation of Primary Amines to Nitriles with Trichloroisocyanuric Acid
2631
(
(
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2
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Synthesis 2003, No. 17, 2629–2631 © Thieme Stuttgart · New York