Ligand-free nano copper oxide catalyzed cyanation of aryl halides and sequential one-pot synthesis of 5-substituted-1H-tetrazoles

Article abstract of DOI:10.1016/j.tetlet.2013.06.107

An expedient and sequential one-pot synthesis of 5-substituted-1H- tetrazoles via [2+3] cycloaddition of aryl nitriles with sodium azide is reported. The required aryl nitriles were synthesized via the nano-copper oxide promoted cyanation of aryl iodides generated in situ.

Full text of DOI:10.1016/j.tetlet.2013.06.107

Tetrahedron Letters 54 (2013) 4732–4734
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Ligand-free nano copper oxide catalyzed cyanation of aryl halides
and sequential one-pot synthesis of 5-substituted-1H-tetrazoles
Umanadh Yapuri a,b, Sadanandam Palle b, Omprakash Gudaparthi a, Srinivasa Reddy Narahari a,b
,
Dhwajbahadur K. Rawat c, Khagga Mukkanti b, , Jyothi Vantikommu b,
⇑
⇑
a Pharmazell (R&D) India Pvt. Ltd, Vizianagaram 531162, Andhra Pradesh, India
b Department of Chemistry, I.S.T., J.N.T. University, Hyderabad 500085, Andhra Pradesh, India
c Department of Biochemistry and Molecular Biology, University of South Alabama, Mobile, AL, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
An expedient and sequential one-pot synthesis of 5-substituted-1H-tetrazoles via [2+3] cycloaddition of
aryl nitriles with sodium azide is reported. The required aryl nitriles were synthesized via the nano-copper
oxide promoted cyanation of aryl iodides generated in situ.
Received 18 March 2013
Revised 19 June 2013
Accepted 22 June 2013
Available online 1 July 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
5-Substituted-1H-tetrazoles
[2+3] Cycloaddition
Cyanation
Nano copper oxide
The nitrile functional group is widely recognized as a useful
intermediate in organic synthesis.1 Their utility also stems from
the possible nitrile transformations, including the synthesis of ben-
zoic acids/esters, amidines, amides, imidoesters, benzamidines,
amines, heterocycles such as thiazoles, oxazolidones, triazoles,
and tetrazoles aldehydes, etc.2 Aromatic nitriles constitute a key
component of numerous commercially and pharmaceutically
important compounds such as agrochemicals (herbicides, pesti-
cides), and pigments and dyes.3
Among the different heterocycles generated from benzonitriles,
tetrazoles are an increasingly popular functionality with a wide
range of applications in the field of medicinal chemistry as a met-
abolically stable surrogate for carboxylic acid group and also have
found use in materials science, including photography, information
recording systems, and explosives.4 As the tetrazoles generally
offer a more favorable pharmacokinetic profile, they have been
widely incorporated into angiotensin II antagonist class of com-
pounds like ‘Sartans’ which includes Losartan and Valsartan.5
Many methods have been developed to introduce cyano groups
into molecules. The traditional approaches for the preparation of
aryl nitriles involve the Rosenmund–von Braun reaction from the
corresponding halides or the Sandmeyer reaction from aniline. In
an industrial setting, the ammoxidation reaction is typically used.
Recently, a useful alternative for the preparation of aryl nitriles
was developed using transition metal-catalyzed cyanation of
aryl-halides (chlorides, bromides, and iodides). The cyanating
agents used in this approach include MCN (M = Cu, K, Na, Zn),
TMSCN, and K4Fe(CN)6.
On the other hand, the most direct and versatile method for the
synthesis of 5-substituted 1H-tetrazoles is via [2+3] cycloaddition
between corresponding nitriles and azides. A plethora of synthetic
protocols and variations on this general theme have been reported
in the literature.6 In majority of the cases, sodium azide has been
used as an inorganic azide source in combination with an ammo-
nium halide as the additive employing dipolar aprotic solvents.6,7
In some instances, the use of Brønsted8 or Lewis acids,9 or stoichiom-
etric amounts of Zn(II) salts10 have also been reported as suitable
additives to afford the desired azide–nitrile addition process. As an
alternative to inorganic azide salts, trimethylsilyl,11 trialkyl, tin,12
and organoaluminum azides13 have been introduced as
comparatively safe azide sources (sometimes prepared in situ), that
have the added advantage of being soluble in organic solvents under
homogeneous conditions. Unfortunately, with a very few excep-
tions, all of these methods require long reaction times (several hours
to days) in combination with high reaction temperatures.
Herein, we report the cyanation of aryl iodides to the corre-
sponding aryl nitriles using copper(II) oxide nanoparticles as a
catalyst by the use of sodium cyanide as a cyanide source. The
formed aryl nitriles were subsequently converted to 5-substituted
1H-tetrazoles through copper catalyzed [2+3] cycloaddition using
⇑
Corresponding authors. Tel.: +91 40 32405057; fax: +91 40 23058729.
E-mail addresses: kmukkanti@jntuh.ac.in (K. Mukkanti), jyothi.vantikommu@
gmail.com (J. Vantikommu).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.06.107

U. Yapuri et al. / Tetrahedron Letters 54 (2013) 4732–4734
4733
Table 2
sodium azide as an azide source under a sequential one-pot oper-
ation (Scheme 1).
Sequential one-pot synthesis of 5-substituted-1H-tetrazoles from aryl iodides via
cyanation followed by [2+3] cycloaddition with sodium azide using nano copper
oxide as a catalysta
In our initial studies, various copper catalysts in combination
with different solvents were investigated using iodobenzene 1 as
a model substrate for the synthesis of benzonitriles 2 (see Table
1). The conditions were optimized and the best condition was
found to be 10 mol % of nano copper oxide, 1.2 equiv of sodium
cyanide with N,N-dimethylformamide as the choice of solvent
and the results are summarized in Table 1, entry 1. By virtue of
these optimized conditions, the reaction afforded the desired aryl
nitrile in 87% yield. Whereas, when the reaction carried out with
the copper oxide generates only moderate yield of benzonitriles
under the optimized reaction conditions. Reactions with other cop-
per catalysts such as copper acetate, copper(II) chloride did not
generate the desired products (Table 1, entries 3 and 4). However,
the reaction with the copper(I) iodide gave the product in a mod-
erate yield (Table 1, entry 5). Subsequently, the reaction conditions
were optimized by employing different solvents. Thus, various po-
lar and non-polar solvents were examined and it was found that
the product was obtained in a moderate yield with toluene and
all other solvents had a negative influence on the reaction and no
product was formed (Table 1, entries 6 and 7). When trimethylsilyl
cyanide was used instead of sodium cyanide as a cyanide source,
no reaction was observed.
The mild conditions of the cyanation reaction permitted us to
examine various processes that fetch the conversion of the product
to other useful compounds without the need of isolation and puri-
fication of aryl nitriles themselves. The formed aryl nitriles from
the aryl iodides were treated with sodium azide to furnish 5-
substituted 1H-tetrazoles in a one-pot operation.
As exemplified in Table 2, the reaction proceeds smoothly to
completion and the products were obtained in good yields with
excellent purity without isolating the intermediate aryl nitriles.
Various aryl iodides were subjected to reaction with sodium cya-
nide followed by sodium azide in the presence of nano copper
oxide and it was found that the reaction was fairly general and
tolerated a variety of substituted aryl iodides. Unsubstituted aryl
iodides are more reactive when compared to methoxy, methyl,
Entry Substrate
Product
HN
Time (h) Yield (%)
I
N
N
1
8
8
80
77
N
I
N
HN
N
2
N
I
N
HN
N
N
3
12
12
70
72
H3CO
H3CO
I
N
HN
N
N
4
OCH3
OCH3
I
N
HN
N
5
12
12
70
65
N
I
N
O
HN
N
O
O
6
N
O
I
N
HN
N
N
7
8
8
7
8
72
80
90
82
F
F
I
N
HN
N
N
8
Cl
Cl
I
N
HN
N
N
N
CuO (10 mol %)
NaCN
DMF, 100 oC
12 h
N
N
9
I
CN
1.5 equiv NaN3
F3C
N
H
F3C
DMF, 120 o
4 - 8 h
C
3
1
2
I
N
HN
N
one-pot operation
N
10
Scheme 1.
a
Reaction conditions: aryl iodide (1 mmol), sodium cyanide (1.2 equiv), sodium
azide (2 mmol), nano-copper(II)oxide(10 mol %), N,N-dimethylformamide, 100 °C.14
Table 1
Screening of various solvents for the reaction of iodobenzene with sodium cyanidea
CN
I
catalyst
methylenedioxy substituted aryl iodides and gave the products in
good yields (Table 2, entries 1–6). p-Fluoro, m-chloro, p-trifluoro-
methyl substituted aryl iodides underwent the reaction smoothly
to furnish tetrazoles in good to excellent yields (Table 2, entries
7–9). Furthermore, p-phenylsubstituted iodobenzene also reacted
smoothly and gave the product in good yield (Table 2, entry 10).
To check the reusability of the catalyst, as can be seen from
Figure 1, the reaction was performed with iodobenzene, sodium
cyanide and sodium azide under the optimized reaction conditions.
Recovery of the catalyst is easy and efficient. The catalyst was
separated from the reaction mixture by centrifugation after
completion of the reaction, washed with ethyl acetate, dried on
air to reuse. The catalyst turn over number (TON) was found to
NaCN
solvent, 100 oC
2
1
Entry
Solvent
Catalyst
Time (h)
Yield (%)
1
2
3
4
5
6
7
DMF
DMF
DMF
DMF
DMF
Toulene
Nano CuO
CuO
CuCl2
Cu(OAc)2
CuI
Nano CuO
Nano CuO
3
12
12
12
12
12
12
86
52
0
0
60
45
0
THF, H2O, 1,4-dioxane, CH3NO2
a
Reaction conditions: iodobenzene (1 mmol), sodium cyanide (1.2 mmol),
copper(II) oxide (10 mol %) in DMF, 100 °C.

4734
U. Yapuri et al. / Tetrahedron Letters 54 (2013) 4732–4734
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14. Synthesis of 5-substituted-1H-tetrazoles (general procedure): To a solution of aryl
iodide (1 mmol) in DMF (5 ml) was added sodium cyanide (1.2 mmol), catalyst
(10 mol %) and the reaction mixture was stirred under heating at 100 °C for
appropriate time to obtain nitrile compound (see Table 1). To the nitrile
compound generated in situ was added sodium azide (1.5 mmol) and the
reaction was continued till the complete conversion of nitrile to tetrazole. After
the completion of the reaction, the catalyst from the reaction mixture was
easily separated out by centrifuging the reaction mixture. After the separation
of the catalyst the crude material was then taken into ethyl acetate and washed
with 5 N HCl and the layers separated. The organic layer was then washed with
water, dried over anhyd sodium sulfate and concentrated to obtain the crude
product. The crude product was purified by silica gel column chromatography
using appropriate solvent mixtures to obtain the pure products (see Tables 1
and 2). Detailed experimental conditions and spectroscopic data were given in
supplementary data.
Figure 1. Recovery and reuse of copper(II) oxide nanoparticles for the synthesis of
5-phenyl-1H-tetrazole from iodobenzene via benzonitrile. (a) Reaction conditions:
iodobenzene (1 mmol), sodium cyanide (1.2 equiv), nano copper(II)oxide
(10 mol %), N,N-dimethylformamide and reaction stirred at 100 °C.
be five times without any significant loss of catalytic activity as
shown in Figure 1.
In conclusion, we have developed an efficient route for the
synthesis of benzonitriles from aryl iodides through copper oxide
nanoparticle catalyzed cyanation. In addition, the reaction can be
coupled with copper-catalyzed [2+3] cycloaddition to generate
5-phenyl-1H-tetrazole in a sequential one-pot without isolating
the cyanide intermediate. This should prove to be useful for gener-
ating multivalent structures of biological significance. This new
coupling reaction underlines the potential of using nanocrystalline
CuO as a very user-friendly, inexpensive, and efficient catalyst for
the coupling of carbon-heteroatom. The catalyst can be easily
recovered and reused.
Acknowledgment
J.V. thanks the UGC for the Dr. D.S. Kothari postdoctoral
fellowship.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.06.
107.
References and notes
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