Click chemistry for the synthesis of 5-substituted 1H-tetrazoles from boron-azides and nitriles

Article abstract of DOI:10.1016/j.tetlet.2013.10.019

A novel and metal free catalysis of synthesizing 5-substituted 1H-tetrazoles through 1,3-dipolar cycloaddition of boron-azides and nitriles is reported with broad substrate scope and excellent yields.

Full text of DOI:10.1016/j.tetlet.2013.10.019

Tetrahedron Letters 54 (2013) 6779–6781
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Click chemistry for the synthesis of 5-substituted 1H-tetrazoles
from boron-azides and nitriles
b,
Yue-Wei Yao a, Yi Zhou b, Bao-Ping Lin a, , Cheng Yao
⇑
⇑
a School of Chemistry and Chemical Engineering, Southeast University, Nanjing 211189, China
b Department of Applied Chemistry, College of Science, Nanjing University of Technology, Nanjing 211816, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel and metal free catalysis of synthesizing 5-substituted 1H-tetrazoles through 1,3-dipolar cycload-
dition of boron-azides and nitriles is reported with broad substrate scope and excellent yields.
Ó 2013 Elsevier Ltd. All rights reserved.
Received 24 June 2013
Revised 30 September 2013
Accepted 4 October 2013
Available online 9 October 2013
Keywords:
Click chemistry
Tetrazole
Boron-azide
Nitrile
1,3-Dipolar cycloaddition
Introduction
are due to high energy surface areas combined with unusually
reactive morphologies.11 Considering the rich activation of boron
Tetrazoles are important heterocycles with a wide range of
applications in specialty explosives, information recording sys-
tems, photography, and coordination chemistry and pharmaceuti-
cals.1 In the latter application, they are carboxylic acid
bioisosteres.2 The synthesis of tetrazoles from cyanides has re-
ceived much attention.3 Currently, most common methods involve
the use of sodium azide in the presence of silicon, zinc,4 tin azide,5
aluminum azide,1b solid acidic resin,6 and ammonium azide (NH4Cl
catalyst),7 which are highly dangerous. In addition, another major
drawback of these methods is the difficulty in removing toxic me-
tal residual. Sharpless and co-workers recently described a safe,
convenient, and environmentally friendly procedure for the prepa-
ration of 5-substituted 1H-tetrazoles in aqueous solution with zinc
salts as catalyst.8 However, sterically hindered aromatic or deacti-
vated alkyl nitriles required high temperature (140–170 °C) and it
was difficult to completely separate products from tetrazole coor-
dination polymers.
azides, we hypothesized that they could also be useful in the 1,3-
dipolar cycloaddition. The realization of this idea is demonstrated
here.
Results and discussion
We started our investigation by using commercially available
benzonitrile (1a) and azides12 as model substrates and tested the
reaction under a variety of different reaction conditions (Table 1).
Conducting the reaction in DMF/MeOH (9/1) at 100 °C generated
the product 1b in low yield (Table 1, entry 1). In contrast, changing
sodium azide to boron azides, such as LiB(N3)4 (A), C5H5NÁB(N3)3
(B), (N3)3BÁNC4H4NÁB(N3)3 (C), and C9H7NÁB(N3)3 (D) gave the ex-
pected adduct in moderate yields (Table 1, entries 2–5). Addition
of catalytic amount of amine salts or heteropolyacids further im-
proved the yields (entries 6, 7, and 9), except for H3PW12O40 (entry
8). We screened solvent effect on the reaction outcome (Table 1,
entry 10–14). Toluene, water, and THF (Table 1, entries 11–13)
failed to provide any product and DMF generated the product 1b
in low yield. Conducting the reaction with LiB(N3)4 in the presence
of 10 mol % NH4OAc in DMF/MeOH (9/1) was proven to be the best
conditions. Pure tetrazoles were isolated in good to excellent
yields, without the need for chromatographic separations.
Boron azides, first reported by Wiberg et al. in 1954,9 were fur-
ther investigated by Paetzold.10 Although the boron azides have
been known for more than 40 years and are used as an important
energy material, no click-type cycloadditions of boron azides with
nitriles have been reported yet. The high reactivity of boron azides
With the optimized conditions in hand, we then examined the
scope of this cycloaddition with different nitriles as shown in Ta-
ble 2. All the examined aryl substrates provide good to excellent
⇑
Corresponding authors. Tel.: +86 25 52090619; fax: +86 25 52090616 (B.-P.
Lin); tel./fax: +86 25 58139482 (C. Yao).
E-mail addresses: lbp@seu.edu.cn (B.-P. Lin), yaocheng@njut.edu.cn (C. Yao).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.10.019

6780
Y.-W. Yao et al. / Tetrahedron Letters 54 (2013) 6779–6781
Table 1
Table 2
Optimization of reaction parameters for the formation of 5-phenyltetrazole
Synthesis of 5-substituted 1H-tetrazolesa
H
N
Entry
1
T (c)/Time (h)
Product
Yieldb (%)
86
Boron- Azides
N
CN
N
N
N
N
solvent, cat
N
100/8
1b
1a
N
H
N3
N3
N3
N3
N3
N
LiB(N3)4
A
N3
N
N
N
B
B
N
N B
N3
N3
N3
N3
H C
3
N
B
2
3
4
5
6
100/8
100/8
120/8
100/8
120/8
79
90
76
86
73
N3
N
H
N3
B
C
D
N
N
Cl
N
N
H
Entry
Catalyst
Azide
Solvent
Yieldb(%)
1
2
3
4
5
6
7
8
9
10
11
12
13
—
—
—
—
NaN3
A
B
C
D
A
A
A
A
A
DMF/MeOH (9/1)
DMF/MeOH (9/1)
DMF/MeOH (9/1)
DMF/MeOH (9/1)
DMF/MeOH (9/1)
DMF/MeOH (9/1)
DMF/MeOH (9/1)
DMF/MeOH (9/1)
DMF/MeOH (9/1)
DMF
21
69
62
74
42
86
75
41
76
63
0
N
N
N
N
H
Cl
—
N
NH4OAcc
N
HO
NH4Clc
N
N
H
d
H3PW12O40
e
H3PMo12O40
NH4OAcc
NH4OAcc
NH4OAcc
NH4OAcc
N
N
N
A
A
A
H2O
N
H
Toluene
Trace
0
OH
THF
N
N
N
aReaction conditions: Benzonitrile (1 mmol), N3- (2 mmol), catalyst (10 mol %),
7
8
120/8
80/6
76
94
92
93
81
90
N
H
solvent (5 ml), 100 °C, reaction time (8 h).
Br
Yield of isolated products. Structures confirmed by comparison of IR and 1H
b
N
N
NMR with those of authentic materials.
O N
2
c
NH4OAc, 10 mol %.
N
N
H
N
d
H3PW12O40, 10 mol %.
H3PMo12O40, 10 mol %.
e
N
N
MeO
N
9
120/8
100/8
110/12
100/8
N
H
yields. Substrates with substitutions at the para-, ortho-positions
are well-tolerated (entries 2–9). Generally, substitutions at the
para-position generate products in slightly higher yields than the
products with ortho-substitutions. Both the electron-donating
groups (entry 2 and 9) and electron-withdrawing groups (entries
3–4 and 7–8) afford tetrazole products in good yields. Electron-rich
groups require relatively long reaction times and high tempera-
tures, while electron-withdrawing groups (entry 3, 5, and 10) pos-
sessed faster and lower temperature to give excellent yields.
Presumably, this is because electron-withdrawing groups can facil-
itate the attack of azide anion to the cyano group and make the tet-
razole anion stable. It is worth to mention that heteroatom-
substituted aromatic nitrile compounds such as 2, 3, 4-cyanopyri-
dine, and 2-furancarbonitrile reacted smoothly with LiB(N3)4 and
gave products in excellent yields (entries 10–13). Aryl dicyano
derivatives also reacted smoothly with LiB(N3)4 to give the corre-
sponding tetrazoles (entry 14–16). An electron-poor arylnitrile,
4-Nitrophthalonitrile, provided the product in 96% yield (entry
16), and 1,2-dicyanobenzene, an hindered arylnitrile, gave the
product in 72% yield (entry 15). In contrast to the excellent reactiv-
ity with aryl nitriles, the reaction with alkyl nitrile, such as ben-
zylic nitrile failed to provide any product (entry 17). Alkyl
nitriles are particularly difficult to be converted into the corre-
sponding tetrazoles because aromatic groups can facilitate the at-
tack of azide anion to the cyano group and stabilize the
intermediates.
N
N
10
11
12
N
N
H
N
N
N
N
N
H
N
N
N
N
N
H
O
N
N
N
13
14
100/8
100/8
87
82
N
H
N
N
N
N
N
N
N
H
N
H
N
HN
HN
N
N
15
100/16
72
N
N
N
N
HN
N
N
N
16
17
80/6
96
0
O2N
N
HN
N
N
By analogy with previous reports,13 a plausible two-step mech-
anism (Scheme 1) for the addition of boron azides to nitriles is pro-
posed. Initially, NH4OAc reacts with LiB(N3)4 to produce
N
N
120/24
N
H
Å
a
NH4 ÁB(N3)4, which then undergoes the [2+3] cycloaddition with
Reaction conditions: aromatic nitrile (1 mmol), LiB(N3)4 (0.5 mmol), NH4OAc
(15 mg), DMF/MeOH (9/1) (5 ml).
the triple bond of nitrile to form the boron-tetrazole intermediates.
b
Yield of isolated products.
Due to the low pKa (3–5) value of tetrazoles and their highly

Y.-W. Yao et al. / Tetrahedron Letters 54 (2013) 6779–6781
6781
extracted with ethyl acetate three times, and the combined organic
layers were washed with 1 M HCl. The organic layer was dried over
anhydrous Na2SO4 and concentrated to furnish pure 5-phenyl-1-H-
tetrazole 1b as a white solid (125 mg) in 86% yield. (mp 216–
218 °C).
LiB(N3)4
NH4OAc
LiOAc
N
N
N
R
NH4· B(N3)4
N
H
R-CN
HCl
Acknowledgments
N
N
N
N
[2 + 3
] cycloadd
ition
R
This research was supported by Jiangsu Provincial Natural Sci-
ence Foundation of China (Grant No. BY2011153).
N
Na
a
O
H
N
N
Supplementary data
B· NH4
R
N
N
4
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.
10.019.
Scheme 1. Proposed mechanism for NH4OAc catalyzed [2+3] cycloaddition.
crystalline nature,14 after a sequential basic and acidic work-up
provides the pure products without any further purification. The
References and notes
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In conclusion, we have developed a simple and efficient method
for the preparation of 5-substituted 1H-tetrazoles via [2+3] cyclo-
addition of boron azides and nitriles. The reaction proceeded
smoothly under mild reaction conditions. This method shows sim-
ple, economical, and practical advantages over the previous meth-
ods, providing diverse molecules for organic chemistry and
medicinal chemistry.
Experiments
General procedure for the 5-substituted 1H-tetrazoles (Table 2,
entry 1): NH4OAc (15 mg) was added to a mixture of benzonitrile
(103 mg, 1 mmol) and LiB(N3)4 (93 mg, 0.5 mmol) in DMF/MeOH
(9/1) solution (5 mL) and the mixture was stirred at 100 °C for
8 h. After completion of the reaction (monitored by TLC), the mix-
ture was cooled to room temperature and diluted with ethyl ace-
tate. The resulting solution was washed with 1 M HCl, dried over
anhydrous Na2SO4, and concentrated. An aqueous solution of
NaOH (1 M) was added to the residue, and the mixture was stirred
for 30 min at room temperature. The resulting solution was
washed with ethyl acetate, and then 2 M HCl was added until the
pH value of the water layer became 1–2. The aqueous layer was
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