Amine salt-catalyzed synthesis of 5-substituted 1H-tetrazoles from nitriles

Article abstract of DOI:10.1080/00397910903318583

The [3+2] cycloaddition reaction between sodium azide and various organic nitriles proceeds smoothly in the presence of amine salts as catalyst in dimethylformamide. The corresponding 5-substituted 1-H tetrazoles were obtained under mild condition in good to excellent yields. Supplemental materials are available for this article. Go to the publisher's online edition of Synthetic Communications to view the free supplemental file. Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910903318583

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Amine Salt–Catalyzed Synthesis of 5-
Substituted 1H-Tetrazoles from Nitriles
Yi Zhou a b , Cheng Yao a , Renjie Ni a & Gaowen Yang b
a Department of Applied Chemistry, College of Science, Nanjing
University of Technology, Nanjing, China
b Jiangsu Laboratory of Advanced Functional Materials, Changshu
Institute of Technology, Changshu, China
Version of record first published: 05 Aug 2010.
To cite this article: Yi Zhou , Cheng Yao , Renjie Ni & Gaowen Yang (2010): Amine Salt–Catalyzed
Synthesis of 5-Substituted 1H-Tetrazoles from Nitriles, Synthetic Communications: An International
Journal for Rapid Communication of Synthetic Organic Chemistry, 40:17, 2624-2632
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Synthetic Communications1, 40: 2624–2632, 2010
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910903318583
AMINE SALT–CATALYZED SYNTHESIS OF
5-SUBSTITUTED 1H-TETRAZOLES FROM NITRILES
Yi Zhou,1,2 Cheng Yao,1 Renjie Ni,1 and Gaowen Yang2
1Department of Applied Chemistry, College of Science, Nanjing University of
Technology, Nanjing, China
2Jiangsu Laboratory of Advanced Functional Materials, Changshu Institute
of Technology, Changshu, China
The [3 þ 2] cycloaddition reaction between sodium azide and various organic nitriles
proceeds smoothly in the presence of amine salts as catalyst in dimethylformamide. The
corresponding 5-substituted 1-H tetrazoles were obtained under mild condition in good to
excellent yields. Supplemental materials are available for this article. Go to the publisher’s
online edition of Synthetic Communications1 to view the free supplemental file.
Keywords: Amine salt catalyst; azide; [3 þ 2] cycloaddition; heterocycles; tetrazole
INTRODUCTION
Tetrazoles are a class of heterocycles with a wide range of applications, and
they are receiving considerable attention.[1] This functional group is regarded as
biologically equivalent to the carboxylic acid in medicinal chemistry,[2] such as poly-
dentate aromatic N-donor ligands in coordination chemistry, and in various
material sciences, including specialty explosives, information recording systems,
and photography.[3,4]
The most widely used method of preparation for 5-substituted 1-H tetrazoles is
[2 þ 3] cycloaddition of azide anion to organic nitriles, and many methods are
reported in the literature.[5] The addition of hydrazoic acid to the cyanide group,
resulting in the formation of 5-substituted tetrazole derivatives, was first reported
in 1932.[6] Currently, the most common methods involves the use of sodium azide
in the presence of silicon, tin azide,[7] and ammonium azide (NH4Cl catalyst).[8]
However, each of those protocols has disadvantages, including the use of expensive
reagents, toxic metals, drastic reaction conditions, water sensitivity, the presence of
dangerous hydrazoic acid, and sublimation of explosive NH4N3, which is highly
dangerous. In addition, the major drawback of these methods is the difficulty of
removing the highly toxic residue at the end of the reaction. Sharpless and coworkers
recently described a safe, convenient, and environmentally friendly procedure for the
Received March 28, 2009.
Address correspondence to Cheng Yao, Department of Applied Chemistry, College of Science,
Nanjing University of Technology, Nanjing 210009, China. E-mail: yaocheng@njut.edu.cn
2624

AMINE SALT–CATALYZED SYNTHESIS
2625
preparation of 5-substituted 1H-tetrazoles, which can be accomplished with water as
a solvent and zinc salts as catalyst.[9] However, sterically hindered aromatic or
deactivated alkyl nitriles usually require high temperatures (140–170 ꢀC), and it is
difficult to completely separate tetrazole coordination polymers.
We develop a novel synthetic method that is free from these problems, and can
safely proceed for the preparation of tetrazoles on an industrial scale without met-
allic catalysts. In continuation of our work on tetrazole chemistry, we herein report
the synthesis of 5-substituted 1-H-tetrazoles from a wide variety of organic nitriles
with sodium azide using amine salt catalysts.
RESULTS AND DISCUSSION
In an effort to develop a better catalytic system, various experimental para-
meters were carried out in the reaction of benzonitrile 1a with sodium azide as a
model substrate, and the results are summarized in Table 1. First, we examined
the effect of amine salt on the reaction. A mixture of 1a, NaN3, and amine salts
in dimethylformamide (DMF) was heated at 110 ꢀC for 8 h with stirring. It was
Table 1. Optimization of reaction conditions in amine salt–catalyzed [2 þ 3] cycloaddition
on the formation of tetrazole 1b from 1aa
Entry
Solvent
Catalyst
Yield (%)b
01
02
03
04
05
06
07
08
09
10
11
12
13
14
15
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
Water
DMSO
THF
Py ꢁ HCl
C6H5NH2 ꢁ HCl
NH4Cl
84
78
86
76
Et3N ꢁ HCl
None
26
63
(CH3)4NBr
Ac
26
32
Bc
Cc
61
42
58,93e
19
68
CTABd
Py ꢁ HCl
Py ꢁ HCl
Py ꢁ HCl
Py ꢁ HCl
Py ꢁ HCl
0
29
Toluene
aReaction conditions: benzonitrile (10 mmol), NaN3 (12 mmol, 0.78 g), catalyst (10 mmol),
solvent (20 ml), 110 ꢀC, reaction time (8 h).
bYield of isolated products. Structures confirmed by comparison of IR and 1H NMR with
those of authentic materials.
cCatalyst structure A, B, and C (Scheme 1).
dHexadecyl trimethyl ammonium bromide (CTAB).
eReaction carried out with NaN3 (7 mmol): Py ꢁ HCl (10 mmol), yield 58%; NaN3
(12 mmol): Py ꢁ HCl (10 mmol), yield 84%; NaN3 (15 mmol): Py ꢁ HCl (10 mmol), yield 93%.

2626
Y. ZHOU ET AL.
Scheme 1. Catalyst structure (A, B, and C).
found that the reactivity of the amine salts differs depending on the structure of the
amine. Quaternary amine salts (entries 6 and 10), which had no protons, could cat-
alyze the reaction in poor yields (63% and 42%). Tertiary, secondary, and primary
amine salts were better reagents than quaternary amine salts to catalyze the [2 þ 3]
cycloaddition reaction. When pyridine hydrochloride (Py ꢁ HCl; entry 1) and ali-
phatic amine (entry 4) were compared, the yield for the Py ꢁ HCl (yield 84%) was rela-
tively greater for product 1b. By using NH4Cl catalyst (yield 86%) in DMF at 110 ꢀC,
hydrazoic acid was clearly present in the headspace above the refluxing solvent. In
contrast, when the reactions were run with Py ꢁ HCl catalyst, no hydrazoic acid could
be detected.[10] Furthermore, we synthesized diethyl ether-bis(dimethyl alkyl
ammonium bromide) as catalyst (Scheme 1), and the catalytic efficiency decreased
with the length of carbochain. Second, the effect of solvent was examined. As shown
in Table 1, the reaction proceeded with DMF, H2O, tetrahydrofuran (THF), tolu-
ene, and dimethylsulfoxide (DMSO) as the solvent, and it was found that polar
organic solvents are more favored. With H2O, THF, and toluene, yields are com-
paratively poor. Consequently, DMF was chosen as the medium of choice for this
cycloaddition. Moreover, production of 1b was not affected by little water (1–5%
volume) in DMF; therefore, recycled DMF and Py, which can be separated from
the product without any treatment, can be used for the next reaction only by adding
HCl and 0.45 equiv of Py.
For this reaction, the addition of a little excess of NaN3 was essential (entries 1
and 11): by using only 1.2 equiv of NaN3, the yield was a little less (84%) compared
to a 93% yield of 1b when 1.5 equiv of NaN3 was used. After optimized reaction con-
ditions were obtained, we decided to investigate the reaction scope by using the best
conditions outlined in Table 1 on a variety of organic nitriles a (Table 2) and c
(Table 3).
The results indicate clearly that this protocol is generally applicable for wide
variety of electron-rich and electron-poor aromatic nitriles (Table 2) with NaN3
and that the yields are good. Substrates possessing electron-rich groups on the ben-
zene ring (such as p-CH3, p-OH, and p-OCH3) afford tetrazole products in good
yields but require relatively high temperatures and long reaction times. In contrast,
arylnitriles having electron-withdrawing groups on the benzene ring (such as p-Cl,
p-NO2, o-Cl, and Py groups) react faster and need lower temperatures to give excel-
lent yields. It is noteworthy that electron-poor groups can facility the azide anion
attack on the N atom of the cyano group. The present protocol also tolerates many
other functional groups as by-products are not observed. It is reported ortho-
hydroxy, -chloro, and -bromo benzonitriles are particularly difficult to convert into
the corresponding tetrazoles.[11] However, the sterically hindered ortho-substituted
aromatic nitriles predictably take longer (18 h) to undergo complete conversion
using our protocol. Heteroatom-substituted aromatic nitrile compounds such as

AMINE SALT–CATALYZED SYNTHESIS
2627
Table 2. Synthesis of aromatic 1H-tetrazolesa
Entry
Temp (ꢀC)=Time (h)
Product
Yield (%)b
84
1a
110=8
120=12
90=8
2a
80
93
79
90
78
89
81
86
79
96
91
3a
4a
110=12
90=8
5a
6a
120=18
110=15
120=18
120=18
120=18
90=6
7a
8a
9a
10a
11a
12a
120=24
13a
100=16
89
aReaction conditions: aromatic nitrile (10 mmol), NaN3 (12 mmol, 0.78 g), pyridine hydrochloride
(0.01 mol, 1.15 g), and DMF (20 ml).
bYield of isolated products.

2628
Y. ZHOU ET AL.
Table 3. Synthesis of other 1H-tetrazolesa
Entry
Temp (ꢀC)=Time (h)
Product
Yield (%)b
16,71c
1c
90=12
90=12
2c
3c
4c
5c
67,89d
90=12
86
100=24
120=18
81d
92
6c
120=18
76
7c
8c
90=12
96
32
120=24
aReaction conditions: nitrile (10 mmol), pyridine hydrochloride (0.01 mol, 1.15 g), and NaN3 (12 mmol,
0.78 g) in DMF (20 ml) for 1c–3c, NaN3 (30 mmol, 1.95 g) in DMF (30 ml) for 5c–8c.
bIsolated yield.
cGlacial acetic acid (30 ml) as solvent.
dWater (30 ml) as solvent.
2,4-cyanopyridine and 2-furancarbonitrile react smoothly with NaN3 to give pro-
ducts in excellent yields. Control experiments suggest that among 2,3,4-cyanopyri-
dines, the cycloaddition proceeds readily with 2,4-cyanopyridine but is inert with
3-cyanopyridine.
Our method is complementary to that which uses zinc salts as catalyst.[9b] We
have been able to achieve good yields with dicyano derivative compounds (Table 3).
This reaction provided good to excellent yields for 4d–7d. An electron-poor arylni-
trile, 4-nitrophthalonitrile, provided a yield of 96% (7d) for this reaction, and
1,2-dicyanobenzene, an hindered arylnitrile, gave a yield of 76% (6d). Regrettably,

AMINE SALT–CATALYZED SYNTHESIS
2629
Scheme 2. Synthesis of 1H-tetrazole and 5-amino-1H-tetrazole.
in this way, the cycloaddition product of more hindered tetrachloro-
terephthalonitrile 8c could not be obtained with good yields under our standard con-
ditions and was not pure. The most widely used method to synthesize 1H-tetrazole 1c
is cycloaddition of azide to toxic HCN. We changed the solvent from DMF to acetic
acid in our catalytic system, and the product was obtained in 71% yield (Scheme 2).
A plausible two-step mechanism (Fig. 1) for the addition of hydrazoic acid=
azide anion to a nitrile is proposed in accordance with previous reports.[9e,12] First,
Py ꢁ HCl reacts with NaN3 to produce Py ꢁ HN3 and is polarized as PyHþ and N3ꢂ.
Subsequent [2 þ 3] cycloaddition between the triple bond of nitrile and Nꢂ3 takes
place readily to form the Py ꢁ tetrazole intermediate. After the addition of water,
the intermediate can be resolved into amine salt and the product. Because of the
low pKa (3–5) value of tetrazoles and their highly crystalline nature,[1b,9d] we can
use an acid=base system to purify the product. The high-performance liquid chroma-
tography (HPLC) trace (see supporting information available online) showed that
the reactant PyHþ was quite stable, and no decrease was observed after reacting
for 8 h. It should be noted that Py ꢁ HCl only reacts with 1 equivalent of the substrate
because PyHþ can make the tetrazole anion stable, and it cannot be recycled in the
system. DMF and Py could be recovered in alkaline condition and recycled without
Figure 1. Proposed mechanism for Py ꢁ HCl-catalyzed synthesis of 5-substituted 1H-tetrazoles.

2630
Y. ZHOU ET AL.
any further treatment on an industrial scale or recovered by only simple distillation,
and the NaCl waste could be easily disposed.
CONCLUSIONS
In conclusion, we have described a useful and convenient method for the syn-
thesis of 1H-tetrazole products, which provides good yields under mild conditions.
This catalytic system is not only capable of processing a wide range of aryl and other
nitriles in cycloaddition but also tolerates a broad range of a series of functional
groups. This method may provide an excellent opportunity for parallel synthesis
and industrial production of 5-substituted 1H-tetrazoles, despite the limiting use
of DMF as solvent. It can also provide a method for the synthesis of 5-substituted
1H-tetrazole products from aldehydes without preparation of nitrile compounds
from halides and toxic cyanides.
EXPERIMENTAL
Typical Procedure for Transformation of Nitriles into 5-Substituted
1H-Tetrazoles
Nitrile (10 mmol), NaN3 (12 mmol, 0.78 g), and Py ꢁ HCl (10 mmol, 1.15 g) in
20 mL of DMF were added to a 50-mL round-bottomed flask. The reaction mixture
was heated at 110 ꢀC for 8 h with vigorous stirring. Conversion was monitored by
HPLC and thin-layer chromatography (TLC). After that, the reaction mixture
was cooled to room temperature and dissolved in 4 mL of NaOH aqueous solution
(5 M) with 30 min of stirring. The solution was concentrated under reduced pressure
by the removal of DMF and Py; the reaction residue was dissolved in 10 mL water.
The pH value was adjusted to 1 with HCl (3 M, 10 mL) to form a precipitate. The
precipitate was then filtered, washed with 2 ꢃ 10 mL of 3 M HCl, and dried at
80 ꢀC overnight to furnish pure 5-phenyl-1-H-tetrazole 1b as a white solid (1.23 g)
in 84% yield (mp 216–218 ꢀC).
5-Phenyl-1H-tetrazole (1b)
1H NMR (500 MHz, DMSO-d6) d: 8.04 (m, 2H), 7.63 (m, 3H); 13C NMR
(125 MHz, DMSO-d6) d: 131.3, 129.5, 127.0, 124.2; IR (neat): 3207, 3000–2400,
1611, 1562, 1493, 1466, 688 cmꢂ1; FAB-MS: m=z 146.0 (Mþ). Crystal data for
˚
1b (C7H6N4): Mr ¼ 146.16, orthorhombic, space group Ama2, a ¼ 9.810(4) A,
3
˚
˚
˚
b ¼ 15.257(7) A, c ¼ 4.546(2) A, V ¼ 680.4(5) A , Z ¼ 4, R1 ¼ 0.0302, wR2 ¼ 0.0658
[I > 2r(I)], qcal. ¼ 1.427 g=cm3, T ¼ 291(2) K, crystal dimensions 0.16 ꢃ 0.12 ꢃ
0.10 mm3.
ACKNOWLEDGMENTS
We thank the State Key Laboratory of Materials-Oriented Chemical
Engineering Foundation support of this work. We also thank Xiaoming Ren for
his important contribution in the sample analysis of this work.

AMINE SALT–CATALYZED SYNTHESIS
2631
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