An efficient one-pot protocol for the conversion of benzaldehydes into tetrazole analogs

Article abstract of DOI:10.1016/j.tetlet.2015.12.067

An efficient protocol has been developed for the one-pot synthesis of tetrazole derivatives in moderate to good yields starting from substituted benzaldehydes and proceeding via non-isolated oxime and nitrile intermediates. The structures of the desired products were confirmed by IR, and NMR spectroscopy as well as mass spectrometry. A plausible reaction mechanism is also discussed.

Full text of DOI:10.1016/j.tetlet.2015.12.067

Accepted Manuscript
An efficient one-pot protocol for the conversion of benzaldehydes into tetrazole
analogs
Khalid Mohammed Khan, Itrat Fatima, Syed Muhammad Saad, Muhammad
Taha, Wolfgang Voelter
PII:
S0040-4039(15)30482-2
DOI:
http://dx.doi.org/10.1016/j.tetlet.2015.12.067
TETL 47114
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
30 January 2015
1 December 2015
17 December 2015
Please cite this article as: Khan, K.M., Fatima, I., Saad, S.M., Taha, M., Voelter, W., An efficient one-pot protocol
for the conversion of benzaldehydes into tetrazole analogs, Tetrahedron Letters (2015), doi: http://dx.doi.org/
1
0.1016/j.tetlet.2015.12.067
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An efficient one-pot protocol for the
conversion of benzaldehydes into tetrazole
analogs
Leave this area blank for abstract info.

,a
a
a
b,c
d
Khalid Mohammed Khan, Itrat Fatima, Syed Muhammad Saad, Muhammad Taha, and Wolfgang Voelter

1
Tetrahedron Letters
An efficient one-pot protocol for the conversion of benzaldehydes into tetrazole
analogs

,a
a
a
b,c
Khalid Mohammed Khan, Itrat Fatima, Syed Muhammad Saad, Muhammad Taha, and Wolfgang
Voelter
d
a
H. E. J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi-75270, Pakistan
b
Atta-ur-Rahman Institute for Natural Product Discovery, Universiti Teknologi MARA (UiTM), Puncak Alam Campus, 42300 Bandar Puncak Alam, Selangor D.
E. Malaysia
c
Faculty of Applied Science Universiti Teknologi MARA, 40450 Shah Alam, Malaysia
d
Interfakultäres Institut für Biochemie, Universität Tübingen, Hoppe-Seyler-Str. 4, D-72076 Tübingen, Germany
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
An efficient protocol has been developed for the one-pot synthesis of tetrazole derivatives in
moderate to good yields starting from substituted benzaldehydes and proceeding via non-
isolated oxime and nitrile intermediates. The structures of the desired products were confirmed
by IR, and NMR spectroscopy as well as mass spectrometry. A plausible reaction mechanism is
also discussed.
Available online
2
009 Elsevier Ltd. All rights reserved.
Keywords:
One-pot Synthesis
Oximes
Nitriles
Tetrazoles
1
. Introduction
One-pot protocols for tetrazole formation have been previously
14-16
reported using ammonia and iodine.
However, the use of
Tetrazoles are pentacyclic heteroaromatic moieties composed of
four nitrogen atoms in a ring. Besides applications in material
sciences, mainly in the field of explosives, tetrazole containing
compounds are valuable catalysts in asymmetric reactions. For
example, the chiral tetrazole catalyst (S)-pyrrolidinyltetrazole,
has been utilized for the enantioselective synthesis of flavanone
derivatives, while an imidazolidine-tetrazole catalyst has been
successfully utilized in the Michael addition of nitroalkanes to
α,β-unsaturated ketones, proceeding with high enantiomeric
excess and short reaction times. Tetrazole containing δ-selective
opioid peptide analogues have been found to chelate copper
salts. The most important property is their metabolic stability as
an isosteric replacement for carboxylic acids and therefore are
frequently used as substitutes for the synthesis of metabolism-
resistant isosters. Synthetic tetrazole derivatives have been
demonstrated to possess antifungal, antidiabetic, and anti-HIV
activities. They have also been developed for the treatment of
asthma. Finally tetrazole-functionalized silica gel is a stable
weak cation-exchange support for bio-separations. Due to the
ammonia should be avoided in order to prevent the formation of
hydrazoic acid which is generated from the reaction with sodium
1
17
azide and may be explosive under certain conditions.
Additionally when iodine and ammonia are mixed together, they
18
may generate triiodide monoamine, which is also explosive.
2
In order to avoid the generation of these unwanted and hazardous
by-products, herein, we report the replacement of ammonia and
iodine with hydroxylamine and phosphorus pentoxide for nitrile
formation resulting in the synthesis of a number of known
3
1
9-23
tetrazole derivatives 1-10
complex reaction conditions for the synthesis of tetrazoles using
[bmim]N as an azide source has been reported by Heravi and co-
in moderate yields (Table 1). More
4
5
3
2
4
workers. However, our newly developed route is quite simple,
generating meta-phosphoric acid as by-product which can be
removed easily at the end of the reaction by washing.
6
7
8
9
10
2. Results and discussion
11
The synthesis of tetrazoles 1-10 was accomplished by the
addition of hydroxylamine hydrochloride in DMF to various
benzaldehydes and heating at reflux to afford the corresponding
oximes. Phosphorus pentoxide was then added resulting in in situ
nitrile formation. This direct conversion of aldehydes into nitriles
broad applications of tetrazole-based structures, efficient, and
economical synthetic routes are still worth exploring. One-pot
procedures are particularly desirable as they avoid the isolation of
intermediate products.
—
12
13
——
Corresponding author: Tel.: +92-21-34824910; fax: +92-21-34819018; e-mail: hassaan2@super.net.pk; khalid.khan@iccs.edu

2
Tetrahedron Letters
is well reported in the literature with varied reaction
The mechanism begins with nucleophilic attack of
25-28
conditions.
Finally, the addition of sodium azide and further
hydroxylamine onto the aromatic aldehyde which after proton
transfer and loss of water produces the oxime intermediate.
Reaction of the oxime with phosphorus pentoxide, followed by
proton transfer and subsequent loss of meta-phosphoric acid
generates the intermediate nitrile. Finally the nitrile reacts with
the azide ion in a [3+2] cycloaddition to afford the corresponding
tetrazole after acidic workup.
heating at reflux followed by acidic work-up, furnished the
desired products (Scheme 1). Spectroscopic data confirmed the
formation of the desired products and were in full accord with the
reported literature for these tetrazoles. Proposed intermediates are
shown in Scheme 2.
To validate our proposed reaction mechanism, the intermediate
nitrile was quenched with water (Scheme 3).
Scheme 1. One-pot synthesis of tetrazoles 1-10 from their
respective aldehydes
Scheme 3. One-pot synthesis of benzonitrile 11 from
benzaldehyde
2
-Methylbenzaldehyde
was
smoothly
reacted
with
hydroxylamine hydrochloride to form the corresponding
benzonitrile 11, after treatment with phosphorous pentoxide. This
experiment proved the proposed sequence of formation of
intermediates as described in Scheme 2.
Scheme 2. Proposed intermediates for tetrazole formation
Table 1. List of tetrazole derivatives 1-10
a
a
Entry
Compound
Yield (%)
Entry
6
Compound
Yield (%)
1
67
71
2
3
4
5
69
80
85
66
7
8
67
71
88
90
9
10
a
Reaction Conditions: (i) Benzaldehyde (2 mmol), hydroxylamine hydrochloride (4 mmol), DMF (10 mL), reflux, 3 h; (ii)
oxime, P (4 mmol), reflux, 2 h; (iii) NaN (5 mmol), reflux, 4 h.
O
2 5
3
DAAD (Deutscher Akademischer Austauschdienst), Bonn
Germany) for granting a fellowship to Prof. Dr. Khalid M.
3. Conclusion
(
Khan.
A powerful one-pot protocol has been developed for tetrazole
formation from the corresponding aldehydes without isolation of
the intermediate oximes and nitriles. This newly developed
method avoids the usage of toxic chemicals or formation of
potentially explosive by-products as previously reported.
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