Green synthetic approach to 5-substituted-1h-tetrazoles via recycle and reuse of tributyltin chloride

Article abstract of DOI:10.14233/ajchem.2013.13106

A simple, safe and efficient process for the recycle of tributyltin chloride from tributyltin hydroxide is developed and its reuse in the synthesis of 5-substituted-1H-tetrazoles is successfully demonstrated, which paved a way to reduce the toxic tin waste significantly. Recycling of tributyltin chloride is possible over six cycles without loss of its activity.

Full text of DOI:10.14233/ajchem.2013.13106

Asian Journal of Chemistry; Vol. 25, No. 1 (2013), 393-396
http://dx.doi.org/10.14233/ajchem.2013.13106
Green Synthetic Approach to 5-Substituted-1H-Tetrazoles
via Recycle and Reuse of Tributyltin Chloride
1,*
2
1
3
A. SAMPATH , V. PRABHAKAR REDDY , A. KALYAN CHAKRAVARTHY and P. PRATAP REDDY
1Research and Development, Integrated Product Development, Innovation Plaza, Dr Reddy's Laboratories Ltd., Survey Nos. 42, 45, 46 and
54, Bachupally, Qutubullapur, Ranga Reddy District-500 123, India
2Department of Chemistry, P.G. College of Science, Osmania University, Saifabad, Hyderabad-500 004, India
3Research and Development, Macleods Pharmaceuticals Limited, G-2, Mahakali Caves Road, Andheri (E), Mumbai-400 093, India
*Corresponding author: E-mail: sampathreddyaalla@yahoo.com
(Received: 25 November 2011;
Accepted: 28 July 2012)
AJC-11886
A simple, safe and efficient process for the recycle of tributyltin chloride from tributyltin hydroxide is developed and its reuse in the
synthesis of 5-substituted-1H-tetrazoles is successfully demonstrated, which paved a way to reduce the toxic tin waste significantly.
Recycling of tributyltin chloride is possible over six cycles without loss of its activity.
Key Words: 5-Substituted-1H-tetrazole, [3+2] Cycloaddition, Nitrile, Recycle, Tributyltin chloride, Tributyltin hydroxide.
fluorous tin bromide, used in the preparation of tetrazoles as
fluorous tin chloride by acidic hydrolysis of stannyl tetrazole.
But the usage of fluorous tin bromide is commercially not
viable, as it is more expensive than tributyltin chloride. More-
over, treatment with acid poses safety issues as it generates
hydrazoic acid if any unreacted azide is present in the reaction
mixture. Hydrazoic acid is toxic and extremely explosive in
organic solutions4. Recently Wang and co-workers11 recycled
the tributyltin chloride via tributyltin fluoride by treating with
sodium fluoride, which requires polytetrafluoroeth-ylene
(PTFE) reactor and extreme care to deal with the highly
corrosive and contact poisonous by-product, hydrofluoric acid.
In addition, this process involves the fractional distillation of
tributyltin chloride, increases the handling risk12. All together
this process is less attractive in view of scalability and safety.
Hence there arises a need to develop the safe and scalable
process for recycle and reuse the tributyltin chloride in the
synthesis of tetrazoles to minimize the toxic tin waste to the
possible extent. Herein we describe a simple, safe and green
synthetic approach to 5-substituted-1H-tetrazoles via recycle
and reuse of tributyltin chloride.
INTRODUCTION
The nitrogen-rich tetrazole moiety is an integral part of
several molecules, which find application as propellants1,
explosives2 and pharmaceuticals3. Although many syntheses
have been reported for tetrazoles4,5, the [3+2] cycloaddition
between nitrile component and alkyltin azide is the most
known, preferable and efficiently practicable route4. Among
the various alkyltin azides, the preferred is tributyltin azide
keeping in view the availability, safety and solubility in the
organic solvents6. Generation of tributyltin azide in situ from
tributyltin chloride and sodium azide is a superior method, as
it limits the risks that arise from handling the corresponding
azide7. Synthesis of tetrazole containing active pharmaceutical
ingredients like valsartan, candesartan and irbesartan involves
utilization of tributyltin chloride in the tetrazole ring construc-
tion8. Usage of tributyltin chloride generates lot of toxic tin
waste and leads to the environmentally unfriendly processes.
However, the usage of tributyltin chloride becomes obligatory
despite its toxicity and environmentally hazardous nature9, due
to the superiority of [3+2] cycloaddition of nitrile and
tributyltin azide amongst all other processes in terms of higher
yields and scalability in producing tetrazoles.
EXPERIMENTAL
It is widely recognized that there is a growing need for
more environmentally friendly processes in the chemical
industry. Even from an economic perspective it is very impor-
tant that chemical processes are designed to minimize or
recycle the waste produced. Curran et al.10 have recycled the
Melting points are measured in open capillary tubes and
1
are uncorrected. The H NMR spectra were recorded on a
Mercury plus Varian 400 MHz NMR instrument using TMS
as internal standard (δ = 0.00 ppm). Chemical shifts are given
in parts per million (δ-scale) and coupling constants are given

394 Sampath et al.
Asian J. Chem.
in Hertz. IR spectra were recorded on a Perkin-Elmer FT IR
instrument (KBr pellet method). Mass spectra were recorded
using a 4000-Q-trap LC-MS mass spectrometer.
5-(4-Nitro-phenyl)-1H-tetrazole (4h):Yield: 81 %; m.p.
218-221 ºC (lit.5d 218-220 ºC); IR (KBr, νmax, cm-1): 3447, 3113,
2914, 2854, 1606, 1532, 1489, 1341, 867, 854; 1H NMR (400
MHz, DMSO-d6): δ = 8.31 (d, J = 8.8 Hz, 2H, aromatic), 8.46
(d, J = 8.8 Hz, 2H, aromatic); MS (m/z): 190 (M-H)–.
5-(2,4-Difluoro-phenyl)-1H-tetrazole (4i):Yield: 72 %;
m.p. 142-144 ºC; IR (KBr, νmax, cm-1): 3452, 3096, 1625, 1489,
1360, 855, 822; 1H NMR (400 MHz, DMSO-d6): δ = 7.37 (t,
J = 8.0 Hz, 1H, aromatic), 7.59 (t, J = 9.2 Hz, 1H, aromatic),
8.13 (t, J = 8.8 Hz, 1H, aromatic); MS (m/z): 181 (M + H)+.
5-(2-Bromo-phenyl)-1H-tetrazole (4j): Yield: 73 %;
m.p. 179-182 ºC (lit.14 181-183 ºC); IR (KBr, νmax, cm-1): 3429,
3033, 1604, 1574, 1475, 1395, 773, 749; 1H NMR (400 MHz,
CD3OD): δ = 7.48-7.57 (m, 2H, aromatic), 7.68 (d, J = 7.6 Hz,
1H, aromatic), 7.82 (δ, J = 8.4 Hz, 1H, aromatic); MS (m/z): 126
(M + H)+.
General procedure for the synthesis of 5-substituted
1H-tetrazoles (4a-j): Tributyltin chloride (2.5 equiv) and
sodium azide (2.5 equiv) were charged to a solution of appro-
priate nitrile (1.0 equiv) in o-xylene (20 mL). The reaction
mixture was stirred at reflux for stipulated time (Table-1). Then
the reaction mixture was cooled to room temperature and a
solution of sodium hydroxide (2.5 equiv) in water (15 mL)
was added.After stirring for 1 h at room temperature, aqueous
layer and organic layers were separated. The aqueous layer
was diluted with water (10 mL), cooled to 5-10 ºC and acidified
to pH - 2 with 6 N hydrochloric acid to precipitate the corres-
ponding tetrazole, which was filtered after 1 h and dried. In
case of tetrazoles 4c and 4d, after acidified to pH-2, product
was extracted into ethyl acetate (2 × 10 mL) and distilled comp-
letely. Dichloromethane (10 mL) was charged and distilled
again to isolate the solid.
Procedure for recycle of tributyltin chloride: To a
suspension of tributyltin hydroxide (1.0 equiv) in o-xylene
(obtained after alkaline hydrolysis reaction) was added conc
hydrochloric acid (35 % assay, 1.0 equiv) at room temperature.
After stirring for 0.5 h, the reaction mixture was allowed to
settle and the o-xylene layer containing tributyltin chloride
was separated and reused in the synthesis of tetrazoles. To
confirm the structure, o-xylene was removed under reduced
5-Benzyl-1H-tetrazole (4a): Yield: 78 %; m.p. 121-123
ºC (lit.13 123.1-123.8 ºC); IR (KBr, νmax cm-1): 3444, 1549, 1533,
1
1494, 1457, 1074, 1056, 892, 734, 711, 695, 673; H NMR
(400 MHz, DMSO-d6): δ = 4.28 (s, 2H, CH2), 7.20-7.40 (m,
5H, aromatic); MS (m/z): 161 (M+H)+, 183 (M+Na)+.
5-(4'-Methyl-biphenyl-2-yl)-1H-tetrazole (4b): Yield:
82 %; m.p. 143-145 ºC (lit.14 144 ºC); IR (KBr, νmax, cm-1):
3428, 3121, 1601, 1567, 1483, 1396, 824, 756, 740; 1H NMR
(400 MHz, CD3OD): δ = 2.31 (s, 3H, CH3), 6.98 (d, J = 8.4
Hz, 2H, aromatic), 7.11 (d, J = 8.0 Hz, 2H, aromatic), 7.54 (d,
J = 8.0 Hz, 2H, aromatic), 7.63 (d, J = 7.6 Hz, 2H, aromatic);
MS (m/z): 237 (M + H)+.
1
pressure and analyzed for IR and H NMR spectral data. IR
(KBr, νmax, cm-1): 2957, 2925, 2872, 2855, 1463, 1377, 1075,
876; 1H NMR (400 MHz, CDCl3): δ = 0.87-0.97 (m, 9H, CH3),
1.27-1.39 (m, 12H, CH3CH2CH2), 1.61-1.68 (m, 6H, CH2Sn).
RESULTS AND DISCUSSION
[3+2] Cycloaddition of nitrile compound and tributyltin
azide, generated in situ provides tributyltin protected tetrazole.
Removal of the tributyltin moiety from the tetrazole ring can
be achieved by treatment with sodium hydroxide, wherein
tributyltin hydroxide would be obtained as a by-product
(Scheme-I). Basic hydrolysis would generate sodium azide
instead of hydrazoic acid, if unreacted tin azide is present in
the reaction mixture. Sodium azide is not explosive, but
decomposes in a more controlled way upon heating, releasing
spectroscopically pure N2 gas16. It was envisioned that the thus
obtained tributyltin hydroxide can be recycled as tributyltin
chloride, which can be used in the tetrazole ring construction.
To the best of our knowledge such approach is hitherto not
reported earlier.
5-Cyclopropyl-1H-tetrazole (4c):Yield: 73 %; m.p. 147-
149 ºC (lit.15 149-150 ºC); IR (KBr, νmax, cm-1): 3428, 3027,
2905, 1590, 1444, 1128, 1042; 1H NMR (400 MHz, CD3OD):
δ = 1.05 (m, 2H, CH2), 1.22 (m, 2H, CH2), 2.21 (m, 1H, CH);
MS (m/z): 109 (M-H)–.
5-Butyl-1H-tetrazole (4d): Yield: 89 %; m.p. 45-47 ºC
(lit.13 46-47 ºC); IR (KBr, νmax, cm-1): 2960, 1583, 1550, 1467,
1260, 1108; 1H NMR (400 MHz, CDCl3): δ = 0.94 (t, J = 7.2
Hz, 3H, CH3), 1.43 (sextet, J = 7.2 Hz, 2H, CH3CH2CH2),
1.88 (p, J = 7.2 Hz, 2H, CH2CH2CH2), 3.14 (t, J = 7.6 Hz, 2H,
CH2CH2C); MS (m/z): 127 (M + H)+.
5-o-Tolyl-1H-tetrazole (4e): Yield: 80 %; m.p. 151-154
ºC (lit.13, 153.2-153.8 ºC); IR (KBr, νmax, cm-1): 3430, 3128,
1
1607, 1563, 1485, 1386, 782, 746; H NMR (400 MHz,
SnBu3
N
DMSO-d6): δ = 2.49 (s, 3H, CH3), 7.38-7.71 (m, 4H, aromatic);
MS (m/z): 161 (M + H)+.
NaN3, Bu3SnCl
Aq. NaOH
CN
N
o-xylene, reflux
N
N
5-(2-Nitro-phenyl)-1H-tetrazole (4f):Yield: 81 %; m.p.
157-159 ºC (lit.13 157.2-157.6 ºC); IR (KBr, νmax, cm-1): 3400,
3085, 1624, 1583, 1519, 1486, 1359, 786, 740; 1H NMR (400
MHz, DMSO-d6): δ = 7.85-7.96 (m, 3H, aromatic), 8.19 (d, J
= 7.6 Hz, 1H, aromatic); MS (m/z): 190 (M-H)–.
1a
2a
Bu3SnOH
Na
N
H
N
Aq. HCl
N
N
N
N
N
N
5-(3-Nitro-phenyl)-1H-tetrazole (4g):Yield: 77 %; m.p.
145-147 ºC (lit.13 144.7-145.6 ºC); IR (KBr, νmax, cm-1): 3400,
3078, 1627, 1569, 1529, 1461, 1349, 872, 823; 1H NMR (400
MHz, DMSO-d6): δ = 7.92 (t, J = 8.4 Hz, 1H, aromatic), 8.45
(d, J = 8.4 Hz, 1H, aromatic), 8.49 (d, J = 8.0 Hz, 1H,
aromatic), 8.85 (s, 1H, aromatic); MS (m/z): 190 (M-H)–.
4a
3a
Scheme-I: Synthesis of tetrazole, 4a
As a representative example, benzylcyanide (1a) was
treated with the sodium azide and tributyltin chloride in

Vol. 25, No. 1 (2013)
Green Synthetic Approach to 5-Substituted-1H-Tetrazoles via Recycle 395
o-xylene at reflux temperature to result in the tributyltin
substituted tetrazole derivative 2a. At this point, quenching of
the reaction with aqueous sodium hydroxide resulted in
tributyltin hydroxide which forms a suspension with the
organic layer while the sodium salt of tetrazole 3a is retained
in the aqueous layer.Acidification of the aqueous layer resulted
in the free tetrazole, 5-benzyltetrazole (4a), which precipitated
as a solid in 78 % yield (Scheme-I).
On treatment with hydrochloric acid, tributyltin hydroxide gets
converted into tributyltin chloride. By this manner, tributyltin
chloride will be regenerated continuously without loss of its
activity and it can be reused in the tetrazole ring construction.
Our next task was to convert the tributyltin hydroxide to
tributyltin chloride. Tributyltin hydroxide suspended in o-
xylene was treated with conc HCl at room temperature to
furnish the tributyltin chloride (Scheme-II). The dissolution
of the suspension indicated the formation of tributyltin chloride
as it is highly soluble in o-xylene and further confirmed by
spectral data.
Conc HCl
Fig. 2. Cyclic pathway of recycle and reuse of tributyltin chloride
Sn Cl
Sn OH
RT
Recovery and reuse of tributyltin chloride concept was
extended to nine other aromatic and aliphatic nitrile compounds
to check the versatility of greener approach and resulted in
the tetrazoles in good yields (Table-1). It can be further
extended for the synthesis of tetrazole containing active
pharmaceutical ingredients, such as valsartan, candesartan and
irbesartan.
Scheme-II: Synthesis of tributyltin chloride
Having achieved the regeneration of tributyltin chloride,
the crucial reuse of the recycled tributyltin chloride was
studied. To the o-xylene layer containing the regenerated
tributyltin chloride was added sodium azide and nitrile
compound 1a and refluxed to result in the tetrazole in a yield
of 78 % following the work up procedure mentioned above.
The tributyltin hydroxide generated was once again recycled
to tributyltin chloride and reused. Such sequence of reactions
was performed six times and in all the cases the yield of the
product was consistent (Fig. 1). These consistent results are
indicating that, the recovery of tributyltin chloride can be
extended to more than six cycles.
For nitriles 1b and 1j, the reported reaction times using
1 equivalent each of tributyltin chloride and sodium azide are
43 h and 48 h, respectively17,18. During the studies, it was
observed that the quantity of tributyltin chloride and sodium
azide played a pivotal role in the rate of reaction. It was
observed that, with 2.5 equivalents each of tributyltin chloride
and sodium azide for nitriles 1b and 1j, the reaction was comp-
leted within 6 h and 4 h, respectively, in good yields. Hence a
combination of 2.5 equivalents of tributyltin chloride and 2.5
equivalents of sodium azide was found to be effective, the
reaction being completed in shorter period (Table-1). Further
increase in the molar ratio had no significant impact on the
rate of reaction.
Conclusion
In conclusion, it was demonstrated that tributyltin
hydroxide, the by-product in tetrazole ring construction can
be recycled to tributyltin chloride without loss in activity and
reused over several cycles in the synthesis of 5-substituted
1H-tetrazoles. A safe and easily scalable process having
advantages over the reported processes was developed for the
recycle of tributyltin chloride. Furthermore, this methodology
paved a way to develop a greener synthetic approach to
5-substituted 1H-tetrazoles, reducing the toxic tin waste
produced in the tetrazole ring construction.
Runs
Fig. 1. Reusability testing of recycled tributyltin chloride
The cycle pathway of recycle and reuse of tributyltin
chloride in the synthesis of 5-substituted-1H-tetrazole can be
represented as in Fig. 2. Tributyltin chloride reacts with sodium
azide to furnish tributyltin azide, which undergoes [3+2]
cycloaddition with nitrile compound to produce tributyltin
protected tetrazole. Upon treatment with sodium hydroxide,
tributyltin moiety will be released as tributyltin hydroxide.
ACKNOWLEDGEMENTS
One of the authors (AS) thank the Management of DRL
for providing facility to carry out this work. AS also gratefully
acknowledged the Analytical and Research and Development
Departments for their support.

396 Sampath et al.
Asian J. Chem.
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TABLE-1
SYNTHESIS OF TETRAZOLES FROM NITRILES
Time
Yield
(%)b
Entry
a
1
4a
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(h)
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CN
N
78
HN
N
N N
N NH
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6
82
N
N
CN
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c
6
5
73
89
N
H
N
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CN
N
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N
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e
f
4
80
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N
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CH3
CN
CH3
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N
N
N
12
N
H
NO2
NO2
N
N
CN
N
N
H
g
12
77
NO2
NO2
N
N
N
CN
N
h
i
12
4
81
72
73
N
H
O2N
O2N
N
CN
N
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F
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N
N
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Br
N
j
4
N
H
Br
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