Cadmium chloride as an efficient catalyst for neat synthesis of 5-substituted 1H-tetrazoles

Article abstract of DOI:10.1080/00397910902917682

Cadmium chloride (CdCl₂) has been found to be an efficient catalyst for a neat [2+3]-cycloaddition of NaN₃ with nitriles to afford 5-substituted 1H-tetrazoles in good yields. The shorter reaction times, greater yields of the product, and easy workup are the advantages of this methodology.

Full text of DOI:10.1080/00397910902917682

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Cadmium Chloride as an
Efficient Catalyst for Neat
Synthesis of 5-Substituted 1H-
Tetrazoles
G. Venkateshwarlu a , A. Premalatha a , K. C.
Rajanna a & P. K. Saiprakash a
a Department of Chemistry, Osmania University,
Hyderabad, India
Published online: 12 Nov 2009.
To cite this article: G. Venkateshwarlu , A. Premalatha , K. C. Rajanna & P. K.
Saiprakash (2009): Cadmium Chloride as an Efficient Catalyst for Neat Synthesis of 5-
Substituted 1H-Tetrazoles, Synthetic Communications: An International Journal for
Rapid Communication of Synthetic Organic Chemistry, 39:24, 4479-4485
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Synthetic Communications1, 39: 4479–4485, 2009
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910902917682
Cadmium Chloride as an Efficient Catalyst for
Neat Synthesis of 5-Substituted 1H-Tetrazoles
G. Venkateshwarlu, A. Premalatha, K. C. Rajanna,
and P. K. Saiprakash
Department of Chemistry, Osmania University, Hyderabad, India
Abstract: Cadmium chloride (CdCl2) has been found to be an efficient catalyst
for a neat [2 þ 3]-cycloaddition of NaN3 with nitriles to afford 5-substituted
1H-tetrazoles in good yields. The shorter reaction times, greater yields of the
product, and easy workup are the advantages of this methodology.
Keywords: Cadmium chloride as efficient catalyst, good product yields, NaN3,
neat [2 þ 3]-cycloaddition, shorter reaction times, 5-substituted 1H-tetrazoles
INTRODUCTION
Tetrazole chemistry has been largely associated with a broad spectrum of
applications in pharmaceuticals, medicine, biochemistry, agriculture, and
photography. Tetrazoles serve as effective ligands for a number of useful
biochemical transformations and also as precursors for a wide variety
of N-containing heterocycles.[1] Several tetrazoles are pharmaceutical
agents, which act as a pharmacophores for the carboxylate group by
increasing their utility. Although tetrazoles were discovered more than
100 years ago, a systematic examination of these compounds was
initiated only in the latter half of the 20th century. Tetrazole was first pre-
pared by the reaction of anhydrous hydrazoic acid and hydrogen cyanide
under pressure. The reagents used in the basic method are highly toxic,
Received December 27, 2008.
Address correspondence to P. K. Saiprakash or K. C. Rajanna, Department of
Chemistry, Osmania University, Hyderabad 500 007, India. E-mail: kcrajannaou@
rediffmail.com
4479

4480
G. Venkateshwarlu et al.
expensive, and water-sensitive. In particular, hydrazoic acid is not only
highly toxic but also explosive and volatile. In view of these drawbacks,
there has been an upsurge to modify the method of preparation of
tetrazoles.[2–12] Su et al.[7] reported a series of 1-substituted 1H-1,2,3,4-
tetrazoles synthesized in good yields from amines, triethyl orthoformate,
and NaN3 through a catalyzed reaction with Yb(OTf)3. A series of
primary alcohols and aldehydes were treated with I2 in NH3=H2O under
microwave irradiation to give the intermediate nitriles, which, without
isolation, underwent [2 þ 3]-cycloaddition with dicyandiamide and NaN3
to afford the corresponding triazines and tetrazoles in high yields.[8]
Katritzky and coworkers[9] suggested a general method for the synthesis
of 1,5-disubstituted tetrazoles from imidoylbenzotriazoles under mild
reaction conditions and shorter reaction times. A versatile and highly
efficient Zn(OTf)2-mediated one-pot synthesis of 1,5-disubstituted tetra-
zoles derivatives has been achieved by Hajra et al.[10] from alkenes,
N-bromosuccinimide (NBS), nitriles, and trimethyl silyl azide (TMSN3).
Demko and Sharpless reported an innovative and safe procedure for the
synthesis of tetrazoles by the addition of sodium azide to nitriles using
stoichiometric amounts of Zn(II) salts in H2O.[5] Amantini et al. effi-
ciently synthesized tetrazoles by the addition of TMSN3 to organic
nitriles using 10 mol% Bu4NF as catalyst.[6] Recently, Lakshmi Kantham
et al.[11] have developed a simple and efficient method for the preparation
of 5-substituted 1H-tetrazoles via [2 þ 3]-cycloaddition using nano-ZnO
as a heterogeneous catalyst. Various nitriles reacted with NaN3 at
120–130ꢀC to yield the corresponding 5-substituted 1H-tetrazoles with
moderate to good yields. The catalyst could also be readily recovered
and reused. Keith[12] has developed a single-step protocol, in which pyr-
idine N-oxides were converted to tetrazolo[1,5-a]pyridines in good yield
in the presence of sulfonyl or phosphoryl azides and pyridine by heating
in the absence of solvent. Diphenyl phosphorazidate (DPPA) was the
most convenient reagent. Smoleski et al.[13] developed an easy metal-
mediated synthesis and isolation of 5-substituted tetrazoles using water-
soluble azido- and derived tetrazolato-platinum(II) complexes with
purified terephthalic acid (PTA) as catalyst. The reactions afforded
good yields of end products.
Catalysis plays an ever-increasing role in pharmaceutical and indus-
trial manufacturing because of process efficiency. CdCl2 is an economic-
ally cheap Lewis acid used in a variety of reactions as an efficient
catalyst.[14–16] Electron-deficient olefins undergo rapid aza-Michael
reaction with a wide range of amines catalyzed by CdCl2 at room tem-
perature.[14] CdCl2 is described as an efficient catalyst for a one-pot
synthesis of 3,4-dihydropyrimidin-2-ones from a three-component
Biginelli reaction of acetoacetate, aldehydes, and urea.[13] An improved

Catalytic Synthesis of 5-Substituted 1H-Tetrazoles
4481
Scheme 1. Synthesis of 5-substituted 1H-tetrazoles catalyzed by CdCl2.
safe method that does not contaminate the environment with cadmium
chloride, a toxic heavy-metal salt, was developed for the synthesis of
phosphatidylcholine.[14] However, to the best of our knowledge, CdCl2
has not been employed as a catalyst for the synthesis of tetrazoles. In this
communication, we report the synthesis of 5-substituted 1H-tetrazoles
from a wide variety of organic nitriles with NaN3 using CdCl2 as a Lewis
acid catalyst for the first time (Scheme 1).
RESULTS AND DISCUSSION
In an effort to develop a better catalytic system, various reaction
parameters were screened for [2 þ 3]-cycloaddition of benzonitrile with
NaN3 to yield 5-phenyltetrazole and are presented in Table 1. The solvent
has a pronounced effect in these reactions (Table 1, entries 1–4), in which
dimethylformamide (DMF) proved to be the best solvent to give good
yields of the corresponding tetrazole, whereas dimethylsulfoxide
(DMSO) and N-methylpyridine (NMP) provided moderate yields and
H2O gave poor yields of 5-phenyltetrazole. TMSN3 is also used in the
reaction with benzonitrile in DMF at about 80ꢀC (Table 1, entry 5).
Table 1. Screening of reaction parameters for the formation phenyltetrazolea
Entry
Solvent
Azide
Yield (%)b
1
2
3
4
5
Water
DMSO
NMP
DMF
DMF
NaN3
NaN3
NaN3
NaN3
TMSN3
10
26
29
91
62
aReaction conditions: Benzonitrile (1 mmol), NaN3 (2 mmol), CdCl2 (0.1mmol),
and DMF (5 mL); reaction time (6 h); 80ꢀC.
bYields of isolated products.

4482
G. Venkateshwarlu et al.
Table 2. CdCl2-mediated preparation of 5-substituted 1H-tetrazolesa
Entry
1
Substrate
Time (h)
6
Yield (%)b
91
2
5
82
3
4
5
6
7
5
4
6
6
8
80
95
75
90
76
8
5
72
9
3
4
85
72
10
11
12
12
12
65
62
aReaction conditions: Benzonitrile (1 mmol), NaN3 (2 mmol), CdCl2 (0.1 mmol),
and DMF (5 mL) at 80–90ꢀC.
bIsolated yields.

Catalytic Synthesis of 5-Substituted 1H-Tetrazoles
4483
To clarify the scope and limitations of the CdCl2-mediated
[2 þ 3]-cycloaddition reaction, various structurally divergent benzonitriles
possessing a wide range of functional groups were reacted with NaN3 to
give the corresponding tetrazoles, and the results are summarized in
Table 2. The various nitriles tested are aromatic, heteroaromatic, and
benzylic; the aromatic benzonitrile gave moderate to good yields
(Table 2, entries 1–11). 4-Chlorobenzonitriles provided the corresponding
tetrazole with good yield, whereas 2-chlorobenzonitriles (not included in
the table) gave slightly less yield compared to their paracounterpart. This
might be due to a more pronounced steric effect of the chloro group at
orthoposition. Compared with electron-withdrawing groups such as
hydroxy, chloro, cyano, and formyl groups present on the aromatic ring
(Table 2, entries 2–7), 4-formylbenzonitrile gave only 1H-tetrazole with
carbonyl (aldehyde) functionality untouched (Table 2, entry 3). 1,2-
Dicyanobenzene and 1,4-dicyanobenzene afforded mono addition pro-
duct (Table 2, entries 2 and 5). Aliphatic nitriles such as 4-chlorophenyl
acetonitrile, phenyl acetonitrile, and (phenylsulfonyl) acetonitrile provided
moderate yields of corresponding tetrazoles with long duration of time
(Table 2, entries 11 and 12). Heteroaromatic nitriles such as 2-pyridine-
carbonitrile and cyanopyrazine gave the corresponding tetrazoles in
shorter reaction times with excellent yields (Table 2, entries 9 and 10).
In conclusion, an efficient and clean method has been developed for
the synthesis of 5-substituted 1H-tetrazoles via [2 þ 3]-cycloaddition using
an economically cheap CdCl2 catalyst. A number of structurally divergent
nitriles were used with NaN3 in the reactions at 80ꢀC to yield the corre-
sponding 5-substituted 1H-tetrazoles with moderate to good yields. The
methodology developed in this work may find widespread use for the pre-
paration of 5-substituted 1H-tetrazoles in the field of organic synthesis.
EXPERIMENTAL
CdCl2 was added (0.1 mmol) to a mixture of benzonitrile (1 mmol) and
sodium azide (2 mmol) in DMF (5 mL) and stirred at 80ꢀC for 6 h. After
completion of reaction (as monitored by thin-layer chromatography,
TLC), the reaction mixture was treated with ethyl acetate (30 mL) and
washed with distilled water, and then the organic layer was treated with
5 N HCl (20 mL) and stirred vigorously. The resultant organic layer was
separated, and the aqueous layer was again extracted with ethyl acetate
(20 mL). The combined organic layers were washed with water and
concentrated to give the crude solid crystalline 5-phenyltetrazole.
Column chromatography was performed using silica gel (100–200 mesh)
to afford pure 5-phenyltetrazole.

4484
G. Venkateshwarlu et al.
1H NMR (200 MHz, CDCl3 þ DMSO) d 8.04 (m, 2H), 7.61 (m, 3H);
MS (70 eV) m=z (%) 146 (Mþ, 12.65%), 118 (100%), 103 (13.94%), 91
(36.70%), 77 (30.37%), 63 (26.58%), 39 (17.72%).
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