Synthesis of 1-substituted tetrazoles via the acid-catalyzed [3+2] cycloaddition between isocyanides and trimethylsilyl azide

Article abstract of DOI:10.1016/j.tetlet.2004.10.103

1-Substituted tetrazoles were synthesized via the [3+2] cycloaddition between isocyanides and trimethylsilyl azide in the presence of an acid catalyst and MeOH. Various 1-substituted tetrazoles were obtained in good to high yields. The reaction probably p

Full text of DOI:10.1016/j.tetlet.2004.10.103

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 9435–9437
Synthesis of 1-substituted tetrazoles via the acid-catalyzed [3+2]
cycloaddition between isocyanides and trimethylsilyl azide
Tienan Jin, Shin Kamijo and Yoshinori Yamamoto*
Department of Chemistry, Graduate School of Science, Tohoku University, Sendai 980-8578, Japan
Received 19 August 2004; revised 11 October 2004; accepted 19 October 2004
Available online 6 November 2004
Abstract—1-Substituted tetrazoles were synthesized via the [3+2] cycloaddition between isocyanides and trimethylsilyl azide in the
presence of an acid catalyst and MeOH. Various 1-substituted tetrazoles were obtained in good to high yields. The reaction prob-
ably proceeds through the in situ formation of hydrazoic acid, followed by a successive [3+2] cycloaddition with the isocyanide acti-
vated by an acid.
Ó 2004 Published by Elsevier Ltd.
Tetrazoles are regarded as biologically equivalent to the
carboxylic acid group, and extensive work on tetrazoles
has been carried out in the field of medicinal chemistry.1
Among them, 1-substituted tetrazoles have received
much attention because of their wide utility.2 The
acid-catalyzed cycloaddition between hydrazoic acid
and isocyanides has long been one of the main routes
to 1-substituted tetrazoles. However, this standard pro-
cedure needs the direct addition of large excess amounts
of dangerous and harmful hydrazoic acid (Eq. 1).3
Therefore, it is desirable to develop a more efficient
and convenient method for the synthesis of 1-substituted
tetrazoles. We now report that the acid-catalyzed [3+2]
cycloaddition between isocyanides 1 and trimethylsilyl
azide in the presence of MeOH gives the desired 1-substi-
tuted tetrazoles 2 in good to high yields (Eq. 2).
would be produced by a proper choice of the catalyst
system. We examined the cycloaddition between p-meth-
oxyisocyanobenzene 1a and trimethylsilyl azide using
several different catalysts and solvents (Table 1). When
YbCl3 was used as catalyst, the protic solvent (H2O)
gave a better result than the organic solvent (THF) (en-
tries 1 vs 2) whilst MeOH gave the best result (entry 3).
R
cat. H2SO4
H
C
N
R
NC
+
HN3
ð1Þ
ð2Þ
N
N
Et2O, reflux, 24 h
N
R
cat.HCl
N
CH
N
R
NC
TMSN3
+
MeOH, 60 o
C
N
N
1
NC
1a
2
cat.Pd (
0
)
R
H
N
CN
R
+
TMSN3
THF, 60 o
C
ð3Þ
We previously reported that palladium-catalyzed cyan-
amide synthesis from the isocyanide 1a and trimethylsilyl
azide via cleavage of a Si–N bond gave the cyanamide 3a
in a high yield (Eq. 3).4 During the course of this study,
we found that the 1-substituted tetrazole 2a was pro-
duced in a low yield when the reaction of 1a with tri-
methylsilyl azide was carried out in the presence of a
Lewis acid catalyst, instead of the Pd(0) catalyst.
Accordingly it was expected that 1-substituted tetrazoles
3a
Among the acid catalysts we tested, HCl gave the high-
est yield of 2a (entry 6). Other Lewis acid catalysts such
as CeCl3 and ZnCl2 were also effective (entries 4 and 5).
The reaction without an acid catalyst gave a low yield of
2a (entry 7).
The results of the [3+2] cycloaddition of various isocya-
nides 1 with trimethylsilyl azide are summarized in
Table 2. When a mixture of p-methoxyisocyanobenzene
1a and trimethylsilyl azide in MeOH was stirred at 60°C
for 6h in the presence of 2mol% of HCl (1.0M in Et2O
solution), 1-(p-methoxyphenyl)tetrazole 2a was formed
Keywords: Tetrazole; 1-Substituted tetrazole; [3+2] Cycloaddition;
Isocyanide; Trimethylsilyl azide; Acid-catalyzed reaction; Hydrazoic
acid.
*
Corresponding author. Tel.: +81 22 217 6581; fax: +81 22 217
6784; e-mail: yoshi@yamamoto1.tohoku.ac.jp
0040-4039/$ - see front matter Ó 2004 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2004.10.103

9436
T. Jin et al. / Tetrahedron Letters 45 (2004) 9435–9437
Table 1. Effect of catalysts and solvents on the formation of tetrazole
2aa
group also produced the corresponding tetrazole 2j in
81% yield (entry 10). The 1-substituted tetrazole-form-
ing reaction was applicable to a substrate having two
reactive sites, such as 1,4-diisocyanobutane 1k, and the
corresponding product 2k was obtained in high yield
(entry 11).
Entry
Catalyst
Solvent
Yield of 2a,b
%
1
YbCl3
YbCl3
YbCl3
CeCl3
ZnCl2
HCl
THF
24c
2
H2O76
MeOH
MeOH
MeOH
MeOH
MeOH
3
82 (77)
86
82
4
5
A proposed mechanism for the 1-substituted tetrazole-
forming reaction in the presence of an acid catalyst
and MeOH is shown in Scheme 1. At the initial stage
of the catalytic cycle, the reaction of isocyanides 1 with
H+ would produce the intermediate A; HN3 B would be
formed in situ via the reaction of TMSN3 and MeOH.6
The [3+2] cycloaddition between the N–C bond of the
intermediate A and HN3 B takes place readily to form
the intermediate C. Deprotonation of the intermediate
C finally affords the 1-substituted tetrazoles 2.
6d
7
87
22
None
a The reaction of the isocyanide 1a and TMSN3 (2.0equiv) was con-
ducted in the presence of a catalytic amount of catalyst (5mol%) at
60°C for 24h.
b 1HNMR yield using p-xylene as an internal standard. Isolated yield is
shown in parentheses.
c 1a was recovered in 61% 1HNMR yield.
d 1.0M HCl in Et2Osolution was used.
in 92% yield (entry 1).5 We investigated the reaction of
the other arylisocyanides 1b–f. The isocyanobenzenes
1b and 1c, bearing electron-donating groups at the ortho
positions of the aromatic rings, gave the corresponding
tetrazoles 2b and 2c in high yields, respectively, although
a prolonged reaction time was required in the case of
sterically hindered ortho disubstituted isocyanobenzene
1c (entries 2 and 3). The reaction of isocyanobenzene
1d was complete in 5h to afford 1-phenyltetrazole 2d
in good yield (entry 4). The reactions of the isocyanides
1e and 1f, having electron-withdrawing groups at the
para position of the aromatic ring, also produced the
corresponding tetrazoles 2e and 2f in 58% and 77%
yields, respectively (entries 5 and 6). The above results
indicate that the tetrazole-forming reaction tolerates a
wide range of functional groups and the [3+2] cycload-
dition proceeds well, irrespective of the position and
electronic nature of the substituents on the aromatic
ring. We next investigated the reactivity of the alkyl iso-
cyanides 1g–k. The reaction of n-butyl isocyanide 1g,
sterically bulky cyclohexyl isocyanide 1h and t-butyl iso-
cyanide 1i furnished the desired tetrazoles 2g–i in good
to high yields, although longer reaction times were
needed (entries 7–9). The reaction of (trimethylsil-
yl)methyl isocyanide 1j containing the TMS functional
We are now in a position to synthesize 1-substituted
tetrazoles 2 with a wide range of substituents in very
good to high yields through the efficient and convenient
acid-catalyzed cycloaddition reaction between isocyan-
ides 1 and trimethylsilyl azide in MeOH. Further studies
on the application of the present methodology to the
synthesis of biologically active compounds and the
extension of the present finding to 5-substituted tetraz-
ole synthesis are under investigation.
H+
R
NC
R
1
N
CH
N
N
N
+
N
2
R
C H
A
HN3
TMSN3
+
MeOH
B
R
+
N
CH
N
TMSOMe
N
H
N
C
Scheme 1. Proposed mechanism for the formation of tetrazoles 2.
Table 2. Synthesis of tetrazoles 2 under acid catalysisa
Entry
R
1
Time, h
2
Yield,b
%
1
p-MeO–C6H4
o-MeO–C6H4
2,6-Dimethyl-C6H3
C6H5
1a
1b
1c
1d
1e
1f
6
6
2a
2b
2c
2d
2e
2f
92
85
87
67
58
77
57
78
92
81
2
3
24
5
4
5
p-CO2Me–C6H4
p-NO2–C6H4
CH3(CH2)3
Cyclohexyl
t-Bu
10
4
6
7
1g
1h
1i
24
24
24
24
2g
2h
2I
2j
8
9
10
Me3SiCH2
1j
H
C
H
C
N
N
N
N
11
1k
24
2k
90
2
N
2
N
N
N
a The reaction of isocyanides 1 and TMSN3 (1.5equiv) was conducted in MeOH (0.5M) in the presence of a catalytic amount of HCl (2mol%, 1.0M
in Et2Osolution) at 60 °C for the time shown in Table 2.
b Isolated yield.

T. Jin et al. / Tetrahedron Letters 45 (2004) 9435–9437
9437
Watson, S. P.; Bountra, C.; Evans, D. C. J. Med. Chem.
1995, 38, 4985.
Acknowledgements
3. (a) Zimmerman, D. M.; Olofson, R. A. Tetrahedron Lett.
1969, 58, 5081; (b) Fallon, F. G.; Herbst, R. M. J. Org.
Chem. 1957, 22, 933; (c) Oliver-Mandela, E.; Alagna, B.
Gazz. Chim. Ital. 1910, 40(II), 442.
4. Kamijo, S.; Jin, T.; Yamamoto, Y. Angew. Chem., Int. Ed.
2002, 41, 1780.
We thank the faculty members in the Instrumental
Analysis Center at Tohoku University for the measure-
ments of NMR spectra, mass spectra, and elemental
analyses.
5. The procedure for the synthesis of tetrazole 2a: to a mixture
of MeOH (1mL), a solution of HCl (0.01mL, 1.0M in Et2O
solution) and p-methoxyisocyanobenzene 1a (66.5mg,
0.5mmol) was added trimethylsilyl azide (0.1mL,
0.75mmol) in a pressure vial. The reaction mixture was
stirred at 60°C for 6h. After consumption of 1a, the
mixture was cooled to room temperature and concentrated.
The residue was purified by silica gel chromatography (n-
hexane/AcOEt = 5:1 to 1:1) to afford 1-(p-methoxyphenyl)-
tetrazole 2a in 92% yield (81.2mg). 1H NMR (400MHz,
CDCl3): d 3.89 (3H, s), 7.09–7.05 (2H, m), 7.62–7.57 (2H,
m), 8.90 (1H, s); 13C NMR (100.40MHz, CDCl3): 55.67,
115.06, 122.80, 126.77, 140.40, 160.51; IR (KBr) 3130, 1614,
1517, 1253, 1020, 827cmꢀ1. Anal. Calcd for C8H8N4O : C,
54.54; H, 4.57; N, 31.80. Found: C, 54.50; H, 4.76; N, 31.53;
HRMS (EI) Calcd for C8H9N4O(M ++H) 177.0771. Found
177.0770.
References and notes
1. For reviews on the chemistry of tetrazoles, see: (a) Meier,
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Chemie (Houben-Weyl); Schumann, E., Ed.; Georg
Thieme: Stuttgart, 1994; Vol. E8d, p 664; (b) Bulter, R.
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791.
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Malhotra, R. K. Medicinal Chemistry of Tetrazoles. Prog.
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