TMSN3-Bu2Sn(OAc)2: A modified and mild reagent system for Wittenberger tetrazole-synthesis

Article abstract of DOI:10.1016/j.tetlet.2019.151517

Treatments of various nitriles with TMSN₃ and Bu₂Sn(OAc)₂ at 30 °C in benzene for 60 h yielded the corresponding 5-substituted 1H-tetrazoles in good to excellent yields. This method is a mild and efficient alternative reagent system for Wittenberger tetrazole-synthesis that uses TMSN₃ and Bu₂SnO in toluene at high temperature (93–110 °C) for 24–72 h.

Full text of DOI:10.1016/j.tetlet.2019.151517

Journal Pre-proofs
TMSN -Bu Sn(OAc) : A modified and mild reagent system for Wittenberger
3
2
2
tetrazole-synthesis
Hiroki Yoneyama, Naoki Oka, Yoshihide Usami, Shinya Harusawa
PII:
S0040-4039(19)31316-4
DOI:
https://doi.org/10.1016/j.tetlet.2019.151517
TETL 151517
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
5 November 2019
9 December 2019
12 December 2019
Please cite this article as: Yoneyama, H., Oka, N., Usami, Y., Harusawa, S., TMSN -Bu Sn(OAc) : A modified and
3
2
2
mild reagent system for Wittenberger tetrazole-synthesis, Tetrahedron Letters (2019), doi: https://doi.org/10.1016/
j.tetlet.2019.151517
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TMSN -Bu Sn(OAc) : A modified and mild
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3
2
2
reagent system for Wittenberger tetrazole-
synthesis
Hiroki Yoneyama, Naoki Oka, Yoshihide Usami, Shinya Harusawa*
TMSN (2 eq)
3
The present method
Bu Sn(OAc) (1 eq)
2 2
o
benzene, 30 C, 60 h
H
N
N
N
R C N
R
TMSN (2 eq)
R SnO (0.1 eq)
2
3
N

1
Tetrahedron Letters
journal homepage: www.elsevier.com
TMSN -Bu Sn(OAc) : A modified and mild reagent system for Wittenberger
3
2
2
tetrazole-synthesis
Hiroki Yoneyama, Naoki Oka, Yoshihide Usami, and Shinya Harusawa*
Osaka University of Pharmaceutical Sciences, 4-20-1 Nasahara, Takatsuki, Osaka 569-1094, Japan
ARTICLE INFO
ABSTRACT
o
Article history:
Received
Received in revised form
Accepted
3 2 2
Treatments of various nitriles with TMSN and Bu Sn(OAc) at 30 C in benzene for 60 h yielded
the corresponding 5-substituted 1H-tetrazoles in good to excellent yields. This method is a mild
and efficient alternative reagent system for Wittenberger tetrazole-synthesis that uses TMSN and
Bu SnO in toluene at high temperature (93–110 °C) for 24–72 h.
3
2
Available online
2
009 Elsevier Ltd. All rights reserved.
Keywords:
5
-substituted 1H-tetrazole
Wittenberger tetrazol-synthesis
TMSN
Bu Sn(OAc)
3
2
2
corresponding aromatic or alkyltetrazoles.3 In this paper, we
describe a modified and mild reagent system for the Wittenberger
1
. Introduction
Tetrazoles are useful in various applications owing to their
3
tetrazole-synthesis that uses TMSN (2 eq) and dibutyltin diacetate
1
wide-ranging potentials in a variety of different fields. 1H-
Tetrazoles have long been recognized as metabolically stable
bioisosteres of carboxylate groups. In medicinal chemistry, this
property has been notably popularized in anti-hypertensive drugs
that include losartan, candesartan, and valsartan which contain the
(
Bu Sn(OAc) , 1 eq). This methodology provides both 5-aromatic
2
2
and aliphatic 1H-tetrazoles in good-to-excellent yields under safer
reaction conditions (30 °C , 60 h, benzene).
1
5
-(4’-methyl-1,1’-biphenyl-2-yl)-1H-biphenyl tetrazole subunit.1
The present method
Furthermore, due to the chemical instabilities of these nitrogen-
rich heterocycles, they have been exploited as components of
explosives.
TMSN (2 eq)
3
1
Bu Sn(OAc) (1 eq)
2
2
5
-Substituted 1H-tetrazoles are basically synthesized by the
2
[2+3] cycloaddition of nitriles and azides, which only takes place
o
3
0 C, 60 h
at a sufficient rate if electron-withdrawing groups are present on
the nitrile. Many of the established approaches for [2+3]
cycloadditions are still severely limited in their use due to a lack
of generality, including high temperatures >100 °C, longer
reaction times, the use of microwave (MW) irradiations, and lower
H
N
benzene
N
N
R
R C N
TMSN (2 eq)
N
3
2
yields.
R SnO (0.1 eq)
2
Among the above-mentioned methods, in 1993 Wittenberger
reported an efficient method for the preparation of 5-substituted
o
93 -110 C, 24 - 72 h
1
2
H-tetrazoles from nitriles that uses trimethylsilyl azide (TMSN
eq.) as a comparatively safe azide source in the presence of
SnO or
SnO, 0.1 eq) (Scheme 1, bottom). The mechanism of the
SnO-catalyzed TMSN -nitrile cycloaddition has been also
3
,
toluene
Wittenberger method
catalytic dibutyltin oxide or dimethyltin oxide (Bu
Me
Bu
studied in detail. Unfortunately, the Wittenberger conditions for
aromatic or less-reactive alkyl nitriles requires long reaction times
2
3
2
2
3
4
Scheme 1. The Wittenberg tetrazole-synthesis and our
method.
(24–72 h) and high temperatures (93–110 °C) to form the

2
suggests that this method is applicable to less active alkyl
8
nitriles. Thus, the optimized procedure (Table 1, entry 6) was
obtained from Table 1 and 2.
2
. Results and discussion
5
Although Bu SnO (DBTO) is usually used as the organotin
2
Meanwhile, the formation of 2a from 1a using the Wittenberger
catalyst in the Wittenberger method, the low solubility of solid
DBTO (mp: 105 °C) in most solvents appears to be partially
responsible for the need for refluxing toluene. The use of an
method [TMSN
in toluene for 72 h to give 2a in 60% yield. Furthermore, in
contrast, the reaction of 1a with TMSN (2 eq)/DBTO (1 eq) in
3
(2 eq), BDTO (0.1 eq)] required heating at 93 °C
3
6
3
alternative organotin compound that more-easily dissolves in a
variety of solvents may lead to tetrazole formation under milder
reaction conditions. From this viewpoint, we directed our attention
benzene at 30 °C for 60 h resulted in only the unreacted starting
material 1a (see S. D.).
2 2
to dibutyltin diacetate [Bu Sn(OAc) ; b.p.: 130 °C (5 mmHg) ],
which is a liquid at room temperature (rt) and is used as a stabilizer
for chlorinated organics, and as a catalyst for condensation
reactions.
Table 2. Formation of 5-phenyltetrazole 2a from benzonitrile 1a
in various solvents.
7
N
HN
TMSN (2 eq)
N
3
We first investigated the reaction of benzonitrile (1a) with
N
C
TMSN
Bu Sn(OAc)
phenyltetrazole (2a) in 28% yield after 24 h, as shown in entry 1
of Table 1. This result suggests that Bu Sn(OAc) can be used as
an alternate reagent to DBTO. Increasing the amount of
Bu Sn(OAc) (1 eq) as well as extention of the reaction time (60
h) were effective in provided improved yields (71%) of 2a (entry
). In particular, when 1a was reacted with TMSN (2 eq) in the
presence of Bu Sn(OAc) (1 eq) in benzene at 30 °C for 60 h,
3
(1 eq) in the presence of a catalytic amount of
Bu2Sn(OAc)2 (1 eq)
N
2
2
(0.1 eq) at 30 °C in benzene, which produced 5-
o
30 C, 24 h
1a
2a
2
2
2
2
solvent
2a
entry
1
(%)
3
3
benzene
73
2
2
tetrazole 2a was produced in 99% yield (entry 6), while the
reaction at 15 °C for 60 h gave 2a in only 50% yield (entry 7). This
result suggests that a reaction temperature of about 30 °C is
necessary for the conversions of nitriles 1 into tetrazoles 2. Since
tetrazole 2a settles as a while precipitate in the flask as the reaction
progresses in these cases, it was easily separated by filtration [see
Supplementary Data (S. D.)].
2
3
toluene
CH Cl
64
58
2
2
MeOH
THF
4
31
5
6
58
3
40 a)
CH CN
Table 1. Formation of 5-phenyltetrazole from benzonitrile using
TMSN
3
/ Bu
2
2
Sn(OAc) .
a) The formation of 5-methyltetrazole (40%) was accompanied
N
HN
by 2a (40%).
N
TMSN3
Bu Sn(OAc)
N
C
2
2
o
N
3 2 2
Using the optimized procedure [TMSN (2 eq)/Bu Sn(OAc) (1
benzene, 30 C
eq), benzene, 30 °C, 60 h], many nitriles 1 were transformed into
various 5-substituted tetrazoles 2, as summarized in Table 3 (see
1a
A white precipitate: 2a
S. D.). 4’-Functionalized phenyltetrazoles 2b–e [X = MeO, Me
2
N,
entry TMSN3 (eq)
Bu2Sn(OAc)2 (eq)
0.1
time (h)
24
2a (%)
NO , and CH C(O)] were readily obtained from the corresponding
2
3
nitriles 1b–e in yields of 82–99%. 2-Bromobenzonitrile 1f was
transformed into 5-(2-bromophenyl)tetrazole 2f in 40% yield
under these conditions (30 °C for 60 h), while 50 °C for 60 h gave
a better yield (78%) of 2f. 3-Bromobenzonitrile 1g was converted
into the corresponding tetrazole 2g at 30 °C in 78% yield.
1
1
28
2
3
1
1
2
2
2
2
1
1
1
1
1
1
24
60
24
48
60
60
43
71
73
86
99
50
4
Meanwhile, application of the Wittenberger method [TMSN
3
(2
eq), Me SnO (0.1 eq)] to 1f and 1g gave 2f and 2g in 74% and 80%
2
5
3
yields, respectively, at 93 °C for 72 h. Using the present method,
phenyltetrazoles 2b-e and 2g produced white precipitates that were
easily worked up (see S. D.).
6
7a
Alkylnitriles 1h and 1i, which are deactivated by electron-
donating alkyl groups, gave better yields of 5-substituted
alkyltetrazoles 2h (89%) and 2i (89%), respectively, under the
standard conditions, compared to those (85% and 50%) produced
by the Wittenberger method in refluxing toluene for 25 h.
Cyclohexanecarbonitrile 1j as well as functionalized acetonitriles
a) Reaction temperature: 15 °C
3
The effect of solvent on the reaction was also investigated for a
reaction time of 24 h (Table 2). Toluene can be used as an
alternative solvent to give 2a in 64% yield (entry 2), while
dichloromethane, methanol, and THF led to lower yields of 2a
1k (X = OMe), 1l (X = F), and 1m (X = CF ) afforded high yields
3
of the corresponding tetrazoles 2j (93%), 2k (99%), 2l (99%), and
8
(
entries 3–5), compared to the reactions performed in benzene or
toluene. When acetonitrile was used as solvent, 2a was obtained in
0% yield, along with 5-methyltetrazole (40%) (entry 6), which
2m (99%). 1,2-Di(1H-tetrazol-5-yl)ethane 2n was also prepared
4

3
in moderate yield (67%) from 1,2-dicyanoethane 1n by the present
method.
Conclusion
In this study, we demonstrated that the TMSN
3
2 2
/Bu Sn(OAc)
Transformation of nitrile 1o bearing terminal alkyne and ester
moieties into the corresponding tetrazole 2o proceeded smoothly
in 98% yield. The results demonstrate that the present method is
relatively tolerant toward nitriles bearing a range of functional
groups.
method furnishes 5-substituted 1H-tetrazoles from a variety of
nitriles at 30 °C for 60 h in good to excellent yields, when
compared to the Wittenberger conditions that require higher
temperatures. Although many current methods use reaction
2
temperatures above 100 °C, the developed method avoids these
The potential of this reaction was further explored by applying
it to the synthesis of tetrazole-containing biofunctional molecules.
We previously attempted to prepare tetrazoles 2p and 2q as ligands
for Pt(II) complexes that exhibit antitumor activities,8,9 in which
reactions of ethyl cyanoformate (1p: n = 1, m = 0) or propyl
harsh conditions, which is important for the preparation of
explosive tetrazoles. Therefore, the present method is flexible and
broadly applicable to the synthesis of tetrazole.
Acknowledgments
cyanoacetate (1q: n = 2, m = 1) with NaN
3
in the presence of
.
Et
3
N HCl in DMF with MW irradiation (130 °C, 2 h) resulted only
We would like to thank Professor Emeritus Takayuki Shioiri at
Nagoya City University for providing encouragement. We thank
Miss Megumi Yoshii for technical support.
8
in decomposition of the products. In contrast, the present method
easily provided the desired tetrazoles 2p (99%) and 2q (99%) from
1
p and 1q. Furthermore, four aliphatic tetrazoles (2r-u) containing
adamantane as Pt(II)-ligands were prepared from the
Supplementary Data
corresponding nitriles (1r–u) in yields of 71–99%.9
Supplementary data for this article can be found online at --------.
References and notes
The present method was also applied to the synthesis of 3-
(
tetrazol-5-yl)-3,5-pregnadien-20-one (2v) which is a potent 5-
1
0
reductase inhibitor (IC50: 15.6 nM). When 3-cyano-3,5-
pregnadien-20-one (1v) was subjected to the present method, diene
1
.
For recent reviews on tetrazoles, see: (a) U. Bhatt, Five-membered
Heterocycles with Four Heteroatoms: Tetrazoles, In Modern
Heterocyclic Chemistry; Vol. 3; J. Alvarez-Builla; J. J. Vaquero;
J. Barluenga, Eds.; Wiley-VCH: Weinheim, 2011, 1401-1430.
tetrazole 2v was produced in 58% yield, while the transformation
.
of 1v into 2v using NaN
3
-Et
3
N HCl or TMSN
3
(2 eq)-DBTO (0.1
eq) required refluxing toluene for 24 h to give 2v in 67% or 98%
yield, respectively.10 In our study for probing RNA catalysis,11, 12
(
b) V. A. Ostrovski; E. A. Popova; R. E. Trifonov, Developments
_
tetrazole C5-linked C
n = 2) were synthesized, in which 2x was obtained from the
normally inactive alkylcyanide 1x under MW irradiation
0
- and C
2
-ribonucleosides 2w (n = 0) and 2x
in Tetrazole Chemistry (2009 16), In Advances in Heterocyclic
Chemistry; Vol. 123, E. Scriven; C. A. Ramsden, Eds.; Academic
Press: New York, 2017, 1-62.
(
2
.
For recent reviews on the synthesis of 5-substituted 1H-tetrazoles,
see: (a) R. Mittal, S. K. Awasthi, Synthesis 51 (2019) 3765-3783.
.
8,12
3 3
conditions (NaN -Et N HCl, 130 °C, 2 h, DMF) in 95% yield.
Tetrazole 2w (n = 0) was easily prepared in 92% yield by the
present method from the active sugar nitrile 1w, while the
transformation of inactive alkylnitrile 1x (n = 2) gave a moderate
yield (52%) of tetrazole 2x. Furthermore, the synthesis of 5-(4’-
methyl-1,1’-biphenyl-2-yl)-1H-tetrazol (2y) is of particular
interest because it represents the basic structure of most
angiotensin II antagonists.1,2 However, the reaction produced only
(
b) J. Roh, K. Vávrová, A. Hrabálek, Eur. J. Org. Chem. (2012)
6101-6118.
3.
S. J. Wittenberger, B. G. Donner, J. Org. Chem. 58 (1993) 4139-
4
141.
D. Cantillo, B. Gutmann, and C. O. Kappe, J. Am. Chem. Soc.,
33 (2011) 4465-4475.
4
5
.
.
1
T. V. RajanBabu, Di-n-butyltin Oxide, In Handbook of Reagents
for Organic Synthesis, Activating Agents and Protecting Groups,
A. J. Pearson; W. R. Roush, Eds.; John Wiley & Sons: New York,
2000, 130-133.
5
% yield of 2y at 30 °C for 60 h, while an improved yield (58%)
1
,2
was obtained at 50 °C. The methylester precursor 2z of valsartan
6
7
.
.
3
For a recent review on the use of TMSN /DBTO, see: H.
was similarly produced from nitrile 1z in 41% yield at 50 °C, with
the starting 1z (58%). In addition, l-pyrrolidine-2-yl-1H-tetrazole
Yoneyama, S. Harusawa, Heterocycles 96 (2018) 2037-2078.
S. Kobayashi, T. Kawasuji, Tetrahedron Lett. 35 (1994) 3329-
3332.
(
2aa), which is a proline-derived organocatalyst for a variety of
1
3
reactions,
is usually prepared in four steps from
8.
9
H. Yoneyama, Y. Usami, S. Komeda, S. Harusawa, Synthesis 45
(2013) 1051-1059.
benzyloxycarbonyl(Cbz)-L-proline via N-Cbz-L-prolinamide (3),
as illustrated in Scheme 2.13a Interestingly, the present method
directly afforded 2aa from commercially available (S)-
pyrrolidine-2-carbonitrile (1aa) in 85% yield.
.
(a) S. Komeda, H. Yoneyama, M. Uemura, T. Tsuchiya, M.
Hoshiyama, T. Sakazaki, K. Hiramoto, S. Harusawa, J. Inorg.
Biochem. 192 (2019) 82-86;
(b) S. Komeda, M. Uemura, H. Yoneyama, S. Harusawa,T.
Tsuchiya, K. Hiramoto, Inorganics 7 (2019) 5-10;
(
c) S. Komeda, H. Yoneyama, M. Uemura, A. Muramatsu, N.
TMSN3 (2 eq)
N
Okamoto, H. Konishi, H. Takahashi, A. Takagi, W. Fukuda, T.
Imanaka, T. Kanbe, S. Harusawa, Y. Yoshikawa, K.Yoshikawa,
Inorg. Chem. 56 (2017) 802-811.
HN
Bu Sn(OAc)2 (1 eq)
2
N
CN
benzene, 30 oC, 60 h
N
1
0. (a) S. Aggarwal, M. K. Mahapatra, R. Kumar, T. R. Bhardwaj, R.
W. Hartmann, J. Haupenthal, M. Kumar, Bioorg. Med. Chem. 24
NH
aa
NH
(85%)
(2016) 779-788;
1
2aa
(b) H. Yoneyama, Y. Usami, S. Harusawa, Synthesis 51 (2019)
1
) NaN , NH Cl
toluene, 95 oC, 24 h
1791-1794.
CN
3
4
(
78-89%,
2
steps
11. For a review on for the probing RNA catalysis, see: S. Harusawa,
Chem. Pharm. Bull. 68 (2020) 1-34.
over 2 steps)
Cbz-1-proline
N
(87-92%)
2) Pd / H2 , EtOH, rt, 15 h
12. S. Harusawa, H. Yoneyama, D. Fujisue, M. Nishiura, M. Fujitake,
Y. Usami, Z. Zhao, S. A. McPhee, T. J. Wilson, D. M. Lilley,
Tetrahedron Lett. 53 (2012) 5891-5894.
Cbz
3
1
3. (a) V. Aureggi, V. Franckevicius, M. O. Kitching, S. V. Ley, D.
A. Longbottom, A. J. Oelke, G. Sedelmeier, Org. Synth. 85 (2008)
Scheme 2. Comparing the present and previous methods for the
synthesis of l-pyrrolidine-2-yl-1H-tetrazole (2aa).
7
2-87;

4
(b) N. Momiyama, H. Torii, S. Saito, H. Yamamoto PNAS 101
2004) 5374-5378.
(

5
Table 3. Transformation of nitriles 1 into 5-substituted tetrazoles 2 by the present method
TMSN (2 eq)
3
N
HN
Bu Sn(OAc) (1 eq)
2
2
N
R C
N
1
2
o
R
N
benzene, 30 C, 60 h
N
N
HN
Br
HN
Br
N
N
N
N
H
N
N
H
N
N
X
X
N
N
N
N
2
b, X = MeO : 82%
2d, X = NO : 93%
2
a
b
2g, 78% (80%)b
2
c, X = Me N: 90%
2e, X = MeC(O): 99%
2f, 78% (74%)
2
N
HN
N
HN
N
N
2
k, X = OMe: 99%
N
HN
N
CH (CH )
N
3
2 n
N
2l, X = F: 99%
X
N
2
2
h, n = 3: 89% (85%)c
2m, X = CF : 99%
3
i, n = 4: 89% (50%)c
2j, 93%
O
O
N
H
N
N
N
O
(CH2)m
N
H C(H C)
N
3
2
n
N
N
N
N
H
N
HN
N
O
HN
N
N
2
p, n = 1, m = 0: 99%
q, n = 2: m = 1: 99%
2
2n, 67%
2o, 98%
O
2
s, n = 0, m = 1: 99%
N
(CH )
2 m
N
(CH2)2
N
(
CH2)
O
n
N
2t
, n = 0: m = 2: 95%
u, n = 1: m = 1: 86%
HN N
HN
N
2
2r, 71%
O
N
N
N
NH
BnO
(
CH )
O
2 n
N
2
w, n = 0 : 92%
N
d
c
2x, n= 2; 52% (95%e)
NH
2v, 58% (67% ; 98% )
N
BnO OBn
O
N
O
O
N
N
HN
N
2y, 58%a
2z (valsartan-methyl ester), 41%a
N
HN
N
N
a) TMSN
3
3
(2 eq), Bu
2
Sn(OAc)
2
(1 eq), toluene, 50 °C, 60 h.
b) TMSN
(2 eq), Me
2
SnO (0.1 eq), toluene, 93 °C, 72 h.

6
3 2
c) TMSN (2 eq), Bu SnO (0.1 eq), toluene, 110 °C, 25 h.
.
d) NaN
3
3
(3 eq), Et
3
3
N HCl (3 eq), toluene, 110 °C, 24 h.
.
e) NaN
(3 eq), Et
N HCl (3 eq), DMF, MW, 130 °C, 2 h.
Highlights
o
1
2
. The present tetrazole synthesis uses TMSN and Bu Sn(OAc) at 30 C.
3 2 2
. This method is an alternative reagent system for Wittenberger tetrazole-synthesis.
. This method may avoid harsh conditions for the preparation of explosive tetrazoles.
3