An efficient aerobic oxidative cyanation of tertiary amines with sodium cyanide using vanadium based systems as catalysts

Article abstract of DOI:10.1039/b820402k

The first report on the use of vanadium-based catalysts for oxidative cyanation of tertiary amines with molecular oxygen in the presence of sodium cyanide and acetic acid to afford the corresponding α-aminonitriles in good to excellent yields is described

Full text of DOI:10.1039/b820402k

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An efficient aerobic oxidative cyanation of tertiary amines with sodium
cyanide using vanadium based systems as catalysts
Sweety Singhal, Suman L. Jain and Bir Sain*
Received (in Cambridge, UK) 14th November 2008, Accepted 16th February 2009
First published as an Advance Article on the web 11th March 2009
DOI: 10.1039/b820402k
The first report on the use of vanadium-based catalysts for
oxidative cyanation of tertiary amines with molecular oxygen
in the presence of sodium cyanide and acetic acid to afford the
corresponding a-aminonitriles in good to excellent yields is
described.
Table 1 Comparison of various catalysts for oxidative cyanation
using molecular oxygen as oxidanta
Conv.b
(%)
Select.b
(%)
Entry Substrate
Catalyst
t/h
1
V2O5
1.5 99
97
92
90
91
60
5
Oxidative cyanation of tertiary amines is an important synthetic
transformation as a-aminonitriles are extremely useful synthetic
intermediates, which have widely been used in the construction
of a variety of synthetically, as well as biologically important
compounds such as alkaloids.1 Molecular oxygen is an attrac-
tive oxidant and development of synthetic methodologies using
molecular oxygen, as the sole oxidant is a rewarding goal both
from environmental and economic view points.2 To the best of
our knowledge there is only one report on the oxidative
cyanation of tertiary amines to a-aminonitriles using molecular
oxygen as a sole oxidant and ruthenium trichloride as catalyst.3
However, the expensive nature and moisture sensitivity of the
ruthenium trichloride makes its utility limited.
2
11% V2O5/TiO2
15% V2O5/Al2O3
17% V2O5/ZrO2
VO(acac)2
VOSO4Á2H2O
VOPc
1.5 98
1.5 98
1.5 98
1.5 98
2.0 40
2.0 80
2.0 60
3
4
5
6
7
30
32
93
82
79
87
45
8
VO(salen)
RuCl3
In continuation to our studies on oxidation of organic
substrates using molecular oxygen as oxidant,4 herein, we
report for the first time an efficient and cost-effective methodo-
logy for the oxidative cyanation of various tertiary amines to
the corresponding a-aminonitriles with sodium cyanide using
a catalytic amount of V2O5 and molecular oxygen as oxidant
under mild reaction conditions (Scheme 1).
9
2.0
3.0 87
4.0
2.0 92
24 50
—
10
11
12
V2O5
RuCl3
—
V2O5
At first, we studied the catalytic efficiency of various
vanadium based catalysts for oxidative cyanation of N,N-
dimethylaniline with sodium cyanide using molecular oxygen
as oxidant and methanol–acetic acid (4 : 1) as reaction
medium. Among the various vanadium based catalysts, viz
V2O5, its supported analogues such as V2O5/ZrO2, V2O5/Al2O3
and V2O5/TiO2 and complexes such as VO(acac)2, VO(salen),
VOPc studied, V2O5 was found to be most efficient catalyst
for this transformation. Catalytic efficiency of V2O5 was
also compared with RuCl3 for oxidative cyanation of
N,N-dimethylaniline,5 N-phenyl-1,2,3,4-tetrahydroisoquinoline5
and N-phenylpyrrolidine. Vanadium pentoxide yielded better
conversion and selectivity than RuCl3 for all the three tertiary
amines studied. These results are summarized in Table 1.
13
RuCl3
a
Reaction conditions: N,N-dimethylaniline (1 mmol), NaCN
(1.2 mmol), MeOH (1 mL), AcOH (0.3 mL), O2, at 60 1C for 1.5 h.
Determined by GC-MS.
b
The reaction did not proceed in the absence of catalyst
under similar reaction conditions. We also carried out
recycling experiments using N,N-dimethylaniline as substrate
and 15% V2O5/Al2O3 as catalyst under the described reaction
conditions. At the end of the reaction, the catalyst was
separated by filtration, washed with methanol, dried and
reused for subsequent runs (for three runs). The catalytic
efficiency was found to decrease in subsequent runs and
afforded poor yields of the desired product (90, 75, 60%
GC yields), indicating the leaching of metal during the
reaction. These facts indicated that the reactions might
have occurred in homogeneous phase in case of supported
vanadium pentoxides.
Scheme 1
We then generalized the protocol developed for the
oxidative cyanation of various tertiary amines with sodium
cyanide (1.2 mmol) in the presence of a catalytic amount of
Process Engineering Applied Chemistry and Biotechnology Division
Indian Institute of Petroleum, Dehradun, India.
E-mail: birsain@iip.res.in; Fax: 91-135-2660202; Tel: 91-135-2660071
ꢀc
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Table 2 The aerobic oxidative cyanation of various tertiary amines
catalysed by V2O5
a
Yieldb Conv./select.c
Entry Substrate
t/h Product
(%)
95
89
93
92
93
82
(%)
1
2
3
4
5
6
1.5
1.5
1.5
2
99/97
97/92
99/96
97/94
98/96
92/87
2
Scheme 2
2
iminium ion intermediate 4 via single electron transfer (SET)
from a-carbon centered radical 3. Oxidation of the inter-
mediate 4 with molecular oxygen leads to the formation of
vanadium(V) superoxo intermediate 5, which subsequently
reacts with HCN (generated in situ from NaCN and
acetic acid) to yield a-aminonitrile 6 and regeneration of oxo-
vanadium species 1. A similar type of mechanism has been
demonstrated by Murahashi et al.3 for the aerobic oxidative
cyanation of tertiary amines in the presence of ruthenium
chloride.
7
2
3
84
80
90/86
87/82
8
a
Reaction conditions: amine (1 mmol), V2O5 (5 mol%), NaCN
b
(1.2 mmol), AcOH (0.3 mL), MeOH (1 mL), O2 at 60 1C. Isolated
yield. Determined by GC-MS.
c
vanadium pentoxide (5 mol%) under similar experimental
conditions.w All the substrates were selectively and efficiently
converted to the corresponding a-aminonitriles in high to
excellent yields. These results are summarized in Table 2. All
the products were analyzed by GCMS and their identity was
confirmed by comparing their spectral data (IR and 1H NMR)
with the known compounds reported in the literature.3,5
Substituted N,N-dimethylanilines containing both electron
donating and electron withdrawing groups on the phenyl ring
were efficiently converted to the corresponding a-cyanoamines
in excellent yields. Cyclic amines such as N-phenyl piperidine,
N-phenylpyrrolidine and N-phenyltetrahydroisoquinoline
yielded the corresponding a-cyanated compounds in high
yields. In case of N-ethyl-N-methylaniline (Table 2, entry 2),
the N-methyl group was oxidized chemoselectively to yield
N-ethyl-N-phenylaminoacetonitrile in 92% (GC yield) along
with a trace amount of the 2-(N-methyl-N-phenylamino)-
propionitrile (5%).
In summary, the present work describes the first report for
the oxidative cyanation of tertiary amines with sodium
cyanide in presence of vanadium-based catalysts using mole-
cular oxygen as oxidant under mild reaction conditions. The
inexpensive nature of the catalyst, use of environmentally
benign oxidant, excellent product yields and wide substrate
scope makes this method an improved and superior one than
the existing method.
Notes and references
w Experimental procedure: A 25 mL double necked round-bottom flask
equipped with an oxygen balloon and magnetic stirrer, was charged
with N,N-dimethylaniline (1 mmol), MeOH (1 mL), AcOH (0.3 mL)
and V2O5 (5 mol%). After the addition of NaCN (1.2 mmol), the
resulting mixture was continuously stirred at 60 1C under an oxygen
atmosphere. At the end of the reaction as monitored by TLC (SiO2),
the mixture was added into aqueous NaHCO3 and extracted with ethyl
acetate (3 Â 10 mL). The combined organic layer was washed with
brine, dried over anhydrous sodium sulfate and concentrated under
reduced pressure. The conversion of N-methyl-N-phenylacetonitrile
was determined to be 99% by GC-MS.
Thus the protocol developed represents an efficient,
improved and cost-effective methodology for the oxidative
cyanation of tertiary amines including functionalized
nitrogen-containing heterocycles, which find extensive
applications both as pharmaceutical agents and auxiliaries in
asymmetric synthesis.
1 D. Enders and J. P. Shilvock, Chem. Soc. Rev., 2000, 29, 359,
references cited therein.
2 S.-I. Murahashi and D. Zhangab, Chem. Soc. Rev., 2008, 37, 1490;
T. Punniyamurthy and L. Rout, Coord. Chem. Rev., 2008, 252, 134;
J. Piera and J.-E. Backvall, Angew. Chem., Int. Ed., 2006, 47, 3506;
¨
T. Punniyamurthy, S. Velusamy and J. Iqbal, Chem. Rev., 2005, 105,
2329; T. Mallat and A. Baiker, Chem. Rev., 2004, 104, 3037.
3 S.-I. Murahashi, N. Komiya, H. Terai and T. Nakae, J. Am. Chem.
Soc., 2003, 125, 15312.
4 S. L. Jain and B. Sain, Angew. Chem., Int. Ed., 2003, 42, 1265;
S. L. Jain and B. Sain, Chem. Commun., 2002, 1040; V. B. Sharma,
S. L. Jain and B. Sain, Tetrahedron Lett., 2003, 44, 2655;
V. B. Sharma, S. L. Jain and B. Sain, J. Mol. Catal. A: Chem.,
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The exact mechanism of the reaction is not clear at this
stage, however the reaction probably proceeds through a
radical mechanism which is evident from the fact that the
oxidative cyanation of N,N-dimethylaniline did not occur in
the presence of 2,6-di(tert-butyl)-p-cresol (BHT) (2 eq.) as a
free radical scavenger under similar experimental conditions.
The plausible mechanistic pathway shown in Scheme 2
involves coordination of the tertiary amine with oxo-
vanadium species 1 to give intermediate 2, which yields
5 S.-I. Murahashi, N. Komiya and H. Terai, Angew. Chem., Int. Ed.,
2005, 44, 6931.
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2372 | Chem. Commun., 2009, 2371–2372