Efficient synthesis of 1,5-disubstituted tetrazoles

Article abstract of DOI:10.1055/s-2007-966001

A general method for the synthesis of 1,5-disubstituted tetrazoles from imidoylbenzotriazoles that involves mild reaction conditions and short reaction times. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-966001

1204
PAPER
Efficient Synthesis of 1,5-Disubstituted Tetrazoles
S
ynthesis of 1,5-D
l
isubstit
a
uted Tetraz
n
ole
s
R. Katritzky,* Chunming Cai, Nabin K. Meher
Center for Heterocyclic Compounds, Department of Chemistry, University of Florida, Gainesville, FL 32611-7200, USA
Fax +1(352)3929199; E-mail: katritzky@chem.ufl.edu
Received 22 December 2006; revised 22 January 2007
O
Abstract: A general method for the synthesis of 1,5-disubstituted
R1 CN
R1
NHR2
tetrazoles from imidoylbenzotriazoles that involves mild reaction
conditions and short reaction times.
(i)
Lawesson's
reagent
(vi)
PCl5 or Tf2O
HN3 or NaN3
R2-Cl/TMS-N3
–OTf
N+ R2
or
Key words: amides, imidoylbenzotriazoles, tetrazoles, phase-
transfer catalysis, sodium azide
S
R2-N3
R1
(ii)
R1
Cl
NHR2
TMS-N3
NaN3
(vii)
R2
N
R1
(iii)
N-NH2
NaN3
NaN3
(viii) N2O4
N
1,5-Disubstituted tetrazoles are important in biology and
medicine as NAD(P)H oxidase inhibitors,1a glucokinase
activators,1b hepatitis C virus (HCV) serine protease NS3
inhibitors,1c calcitonin gene-related peptide receptor an-
tagonists, and antimigraine agents.1d 1,5-Disubstituted tet-
razoles are also useful synthetic intermediates2a for the
synthesis of energetic salts,2b 3,4-dihydropyrimidin-
2(1H)-ones,2c piericidins,2d (+)-trans-5-allylhexahydroin-
dolizidin-3-ones,2e acacetin,2f (+)-strictifolione,2g vinyl-
silianes,2h and leucascandrolide A.2i
R2
(iv)
R1
N
NHR2
N
N
or HNO2
(ix)
R1
N
R2-X
or TMS-N3
(x)
(v)
HN3
O
R1ZnCl
N
N
R1
R1
R2
or
N
H
R1-B(OH)2
N-OH
R2
X
R1
N
R2
N
N
N
Scheme 1 Literature methods for the preparation of 1,5-disubstitut-
ed tetrazoles
The many published preparative methods for 1,5-disubsti-
tuted tetrazoles3 include reactions of (i) amides with phos-
phorus(V) chloride or triflic anhydride and hydrogen
azide or sodium azide,4,5 (ii) thioamides with trimethylsi-
lyl azide,6 (iii) imidoyl chlorides with sodium azide,7 (iv)
ketones with sodium azide8 or trimethylsilyl azide,9 (v)
oximes with hydrogen azide,10 (vi) nitriles with alkyl
chlorides and trimethylstannyl azide11 or with alkyl
azides,12 (vii) nitrilium triflates with sodium azide,13 and
(viii) amidrazones with dinitrogen tetroxide or nitrous
acid (Scheme 1).14
disubstituted tetrazoles in high yield under mild condi-
tions.
Imidoylbenzotriazoles 2a–p (Table 1) were prepared
from the corresponding secondary carboxamides 1a–p
and benzotriazoles using Method A: oxalyl chloride and
pyridine or Method B: thionyl chloride under microwave
(80 W/80 °C) following a literature procedure.18 Thus,
2a–d were prepared following Method A and 2e–o were
prepared following Method B. The compound 2p was pre-
pared using Method B, but at 60 W/60 °C (Scheme 2).
Imidoylbenzotriazoles 2h and 2p were novel and were
completely characterized.
Further preparations involving conversion of substituted
tetrazoles into 1,5-disubstituted tetrazoles include (ix)
alkylation of 5-substituted tetrazoles15 and (x) coupling of
substituted 5-chlorotetrazoles with organozinc16 or vinyl-
boronic acid (Scheme 1).17
Method A:
O
(COCl)2, pyridine
or
R1
Bt
R2
However, many of these reported methods suffer from
one or more of the following drawbacks: (i) long reaction
times, (ii) the use of toxic and/or explosive reagents, (iii)
tedious workup and low yields, (iv) high temperatures, (v)
the formation of inseparable regioisomers, and (vi) the use
of uncommon starting materials. Thus, a mild and effi-
cient method is required for the preparation of 1,5-disub-
stituted tetrazoles.
R2
+
BtH
N
R1
N
H
Method B:
SOCl2
2a–p
1a–p
MW (80 W/80 °C)
Scheme 2 Preparation of imidoylbenzotriazoles 2a–p
Imidoylbenzotriazoles are stable in water and do not react
with sodium azide at room temperature. Although the re-
action of N-[1-(1H-benzotriazol-1-yl)ethylidene]-4-meth-
ylaniline (2b) with sodium azide in the presence of
trifluoroacetic acid (1 equiv) to give 5-methyl-1-(4-meth-
ylphenyl)-1H-tetrazole (3b) was slow and incomplete, a
catalytic amount (20 mol%) of tetrabutylammonium bro-
mide (TBAB) as phase-transfer catalyst in a two-phase
Imidoylbenzotriazoles, which are stable to water and eas-
ily prepared,18 are useful substitutes for imidoyl chlorides
and we now report that they can be used to synthesize 1,5-
SYNTHESIS 2007, No. 8, pp 1204–1208
x
x
.
x
x
.2
0
0
7
Advanced online publication: 23.03.2007
DOI: 10.1055/s-2007-966001; Art ID: M07806SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
Synthesis of 1,5-Disubstituted Tetrazoles
1205
Table 1 Preparation of Imidoylbenzotriazoles 2a–p
Entry
Imidoylbenzotriazole
R1
Lit.18
R2
Yielda (%)
68
Mp (°C)
107–108
112–113
125–126
oil
Yield (%)
Mp (°C)
1
2
2a
2b
2c
2d
2e
2f
Me
Ph
75
65
62
65
88
93
82
106–108
113–115
124–126
oil
Me
4-Tol
4-Tol
4-Tol
Ph
65
3
Bn
63
4
CH2CH2Ph
Ph
62
5
85
129–130
109–110
138–140
95–98
129–131
108–110
138–140
6
Ph
Bn
90
7
2g
2h
2i
4-Tol
4-Tol
Me
85
b
b
8
4-Tol
85
–
–
9
4-MeOC6H4
4-ClC6H4
4-O2NC6H4
4-O2NC6H4
2-furyl
2-furyl
2-thienyl
4-Tol
Bn
82
114–116
119–120
182–184
118–120
121–124
oil
78
90
88
86
84
95
91
115–118
118–120
183–185
117–119
120–123
oil
10
11
12
13
14
15
16
2j
4-Tol
Ph
90
2k
2l
86
Bn
85
2m
2n
2o
2p
4-Tol
Cy
80
90
4-Tol
CH2CO2Et
87
134–135
119–121
133–135
b
b
86
–
–
a Isolated yield.
b Novel compound.
(CH2Cl2–H2O) system at 20 °C gave complete reaction in This transformation has also been studied in different sol-
30 minutes. Column chromatography on basic alumina vents. Thus, the reaction of 2e was carried out in aceto-
using ethyl acetate–hexanes (1:2) gave 5-methyl-1-(4- nitrile–water and tetrahydrofuran–water under the
methylphenyl)-1H-tetrazole (3b) in 93% yield.
standardized conditions to obtain tetrazole 3e in 90%
yield.
This method generalized the preparation of 1,5-disubsti-
tuted tetrazoles with diverse substituents (aliphatic, aro- Herein we presented a general, mild and convenient meth-
matic, or heteroaromatic) in the starting imidoyl- od of preparation of 1,5-disubstituted tetrazoles with vari-
benzotriazole. The progress of reaction was monitored by able substituents on the nitrogen atom. The starting
thin-layer chromatography. The 1,5-disubstituted tetra- imidoylbenzotriazoles, easily prepared from readily avail-
zoles, prepared in high yields (90–94%, Scheme 3, able amides, are stable and crystalline compounds. This
1
Table 2), were fully characterized by H and 13C NMR method offers advantages over other methods as it can be
spectroscopy. Novel compounds gave satisfactory ele- performed in aqueous solution without decomposition
mental analysis; melting points of all known compounds and requires a shorter reaction time.
were compared with the literature values and were found
to be satisfactory with the exception of 3k, which may be
due to the difference in crystallizing solvents. The molec-
ation were conducted in heavy-walled Pyrex tubes sealed with alu-
Melting points are uncorrected. Reactions under microwave irradi-
ular formula for 3k was supported by satisfactory elemen-
tal analysis.
minum crimp caps fitted with a silicon septum or in round-bottomed
flasks equipped with a reflux condenser. Microwave heating was
carried out with a single mode cavity Discover Microwave Synthe-
sizer (CEM Corporation, NC, USA), producing continuous irradia-
tion at 2450 MHz. Purification by column chromatography was
carried out using basic alumina. 1H NMR (300 MHz) and 13C NMR
(75 MHz) spectra were recorded in CDCl3 (with TMS for H and
CDCl3 for 13C as the internal reference). Characterization of imi-
doylbenzotriazoles as novel compounds is given.
R2
R1
R2
NaN3, TFA
N
R1
N
N
1
TBAB (20 mol%)
CH2Cl2/H2O, r.t.
N
N
Bt
3a–p
2a–p
Scheme 3 Preparation of 1,5-disubstituted tetrazoles 3a–p
Synthesis 2007, No. 8, 1204–1208 © Thieme Stuttgart · New York

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A. R. Katritzky et al.
PAPER
Table 2 Preparation of 1,5-Disubstituted Tetrazoles 3a–p
Entry
1,5-Disubstituted tetrazoles
R1
Lit.
R2
Yielda (%)
Mp (°C)
95–97
Yield (%)
Mp (°C)
98–99
106
1
2
3a
3b
3c
3d
3e
3f
Me
Ph
90
93
94
92
90
95
92
92
94
90
90
93
92
94
92
90
638b
9619
Me
4-Tol
4-Tol
4-Tol
Ph
101–103
92–94
b
b
3
Bn
–
–
b
b
4
CH2CH2Ph
Ph
oil
–
–
5
141–143
88–90
8517b
7920
144–145
90–91
6
Ph
Bn
c,21
7
3g
3h
3i
4-Tol
4-Tol
Me
142–144
113–115
106–108
132–134
144–146
131–133
118–120
58–60
–
148
8
4-Tol
3022
117–118
d
9
4-MeOC6H4
4-ClC6H4
4-O2NC6H4
4-O2NC6H4
2-furyl
2-furyl
2-thienyl
4-Tol
Bn
9717a
–
b
b
10
11
12
13
14
15
16
3j
4-Tol
Ph
–
–
3k
3l
958b
177–178
b
b
Bn
–
–
d
3m
3n
3o
3p
4-Tol
Cy
–
–
b
b
–
–
d
4-Tol
CH2CO2Et
115–117
oil
–
–
b
b
–
–
a Isolated yield.
b Novel compound.
c Yield not available in the literature.
d Found in literature with no characterization.
N-[1H-Benzotriazol-1-yl(4-methylphenyl)methylene]methyl-
amine (2h)
Yellow microcrystals (CHCl3); yield: 1.06 g (85%); mp 95–98 °C.
1,5-Disubstituted Tetrazoles 3a–p; General Procedure
To a mixture of CH2Cl2–H2O (1:1, 20 mL) was added imidoylben-
zotriazole 2a–p (0.50 mmol), NaN3 (0.065 g, 1.0 mmol), TBAB
(0.032 g, 0.10 mmol), and TFA (0.06 g, 0.50 mmol). The mixture
was stirred at r.t. for 30 min (for 3k, the reaction time was 12 h). The
organic layer was separated and the aqueous layer was washed
CH2Cl2 (10 mL). Purification of the combined organic layers by
column chromatography (basic alumina, EtOAc–hexanes, 1:2) gave
pure 1,5-disubstituted tetrazoles 3a–p.
1H NMR: d = 2.44 (s, 3 H), 3.39 (s, 3 H), 7.29 (d, J = 8.1 Hz, 2 H),
7.34 (d, J = 8.0 Hz, 2 H), 7.42 (t, J = 7.6 Hz, 1 H), 7.56 (t, J = 7.7
Hz, 1 H), 8.09 (d, J = 8.2 Hz, 1 H), 8.37 (d, J = 8.3 Hz, 1 H).
13C NMR: d = 21.4, 38.8, 114.9, 119.6, 124.9, 127.2, 128.0, 128.5,
129.2, 131.7, 140.3, 146.2, 156.0.
Anal. Calcd for C15H14N4: C, 71.98; H, 5.64; N, 22.38. Found: C,
72.30; H, 5.61; N, 22.68.
5-Methyl-1-phenyl-1H-tetrazole (3a)
Colorless needles (CHCl3–hexanes); yield: 0.072 g (90%); mp 95–
97 °C (Lit.8b 98–99 °C).
Ethyl {[(E)-(1H-Benzotriazol-1-yl)(4-methylphenyl)methyl-
ene]amino}acetate (2p)
Colorless needles (CHCl3–hexanes); yield: 2.72 g (86%); mp 119–
121 °C.
1H NMR: d = 2.63 (s, 3 H), 7.46–7.49 (m, 2 H), 7.59–7.63 (m, 3 H).
13C NMR: d = 9.8, 124.6, 130.0, 130.4, 133.9, 151.5.
1H NMR: d = 1.32 (t, J = 7.2 Hz, 3 H), 2.46 (s, 3 H), 4.27 (q, J = 7.2
Hz, 2 H), 4.40 (s, 2 H), 7.31–7.38 (m, 4 H), 7.45–7.51 (m, 1 H),
7.61–7.67 (m, 1 H), 8.11 (d, J = 8.1 Hz, 1 H), 8.66 (d, J = 8.4 Hz, 1
H).
5-Methyl-1-(4-methylphenyl)-1H-tetrazole (3b)
Colorless needles (CHCl3–hexanes); yield: 0.081 g (93%); mp 101–
103 °C (Lit.19 mp 106 °C).
1H NMR: d = 2.47 (s, 3 H), 2.60 (s, 3 H), 7.32–7.42 (m, 4 H).
13C NMR: d = 9.7, 21.2, 124.3, 130.4, 131.2, 140.6, 151.5.
13C NMR: d = 14.2, 21.6, 53.2, 61.2, 115.6, 119.7, 125.4, 126.8,
128.7, 129.2, 129.5, 132.1, 141.1, 146.4, 157.7, 170.1.
Anal. Calcd for C18H18N4O2: C, 67.07; H, 5.63; N, 17.38. Found: C,
67.24; H, 5.70; N, 17.41.
5-Benzyl-1-(4-methylphenyl)-1H-tetrazole (3c)
White microcrystals (CHCl3); yield: 0.118 g (94%); mp 92–94 °C.
1H NMR: d = 2.44 (s, 3 H), 4.25 (s, 2 H), 7.06–7.11 (m, 2 H), 7.12–
7.18 (m, 2 H), 7.22–7.26 (m, 3 H), 7.27–7.33 (m, 2 H).
Synthesis 2007, No. 8, 1204–1208 © Thieme Stuttgart · New York

PAPER
Synthesis of 1,5-Disubstituted Tetrazoles
1207
13C NMR: d = 21.2, 29.4, 124.9, 127.4, 128.4, 128.8, 130.2, 131.0,
134.2, 140.9, 153.8.
Anal. Calcd for C14H11ClN4: C, 62.11; H, 4.10; N, 20.70. Found: C,
62.50; H, 4.04; N, 21.07.
Anal. Calcd for C15H14N4: C, 71.98; H, 5.64; N, 22.38. Found: C,
72.26; H, 5.76; N, 22.42.
5-(4-Nitrophenyl)-1-phenyl-1H-tetrazole (3k)
Colorless needles (EtOAc–hexanes); yield: 0.120 g (90%); mp 145–
147 °C (Lit.8b 179–181 °C).
1-(4-Methylphenyl)-5-(2-phenylethyl)-1H-tetrazole (3d)
Colorless oil; yield: 0.126 g (95%).
1H NMR: d = 7.46–7.51 (m, 2 H), 7.53–7.61 (m, 3 H), 7.62–7.67
(m, 2 H), 8.36–8.42 (m, 2 H).
1H NMR: d = 2.43 (s, 3 H), 3.14 (s, 4 H), 7.02–7.07 (m, 4 H), 7.20–
7.30 (m, 5 H).
13C NMR: d = 122.9, 125.3, 125.8, 129.0, 129.4, 131.9, 139.1,
148.3, 153.8.
13C NMR: d = 21.2, 25.6, 33.4, 124.8, 126.6, 128.3, 128.6, 130.2,
130.9, 139.3, 140.7, 154.5.
Anal. Calcd for C13H9N5O2: C, 58.43; H, 3.40; N, 26.22. Found: C,
58.77; H, 3.15; N, 26.38.
Anal. Calcd for C16H16N4: C, 72.70; H, 6.10; N, 21.20. Found: C,
73.04; H, 6.26; N, 21.11.
1-Benzyl-5-(4-nitrophenyl)-1H-tetrazole (3l)
Colorless needles (CHCl3–hexanes); yield: 0.131 g (93%); mp 131–
133 °C.
1,5-Diphenyl-1H-tetrazole (3e)
Colorless needles (CHCl3–hexanes); yield: 0.100 g (90%); mp 141–
143 °C (Lit.17b 144–145 °C).
1H NMR: d = 5.68 (s, 2 H), 7.14–7.16 (m, 2 H), 7.37–7.39 (m, 3 H),
7.79 (d, J = 8.9 Hz, 2 H), 8.36 (d, J = 8.9 Hz, 2 H).
1H NMR: d = 7.39–7.43 (m, 4 H), 7.48–7.58 (m, 6 H).
13C NMR: d = 51.8, 124.2, 127.0, 129.1, 129.4, 129.8, 130.0, 133.2,
149.4, 152.9.
13C NMR: d = 123.6, 125.3, 128.4, 128.9, 129.0, 129.9, 130.4,
131.3, 153.6.
Anal. Calcd for C14H11N5O2: C, 59.78; H, 3.94; N, 24.90. Found: C,
60.11; H, 3.80; N, 25.27.
1-Benzyl-5-phenyl-1H-tetrazole (3f)
White microcrystals (CHCl3–hexanes); yield: 0.112 g (95%); mp
88–90 °C (Lit.20 90-91 °C).
5-(2-Furyl)-1-(4-methylphenyl)-1H-tetrazole (3m)
Colorless needles (CHCl3–hexanes); yield: 0.104 g (92%); mp 118–
120 °C; novel (appeared in catalogue, but no characterization data
could be found in literature).
1H NMR: d = 5.62 (s, 2 H), 7.14–7.17 (m, 2 H), 7.32–7.36 (m, 3 H),
7.47–7.59 (m, 5 H).
13C NMR: d = 51.3, 123.6, 127.1, 128.7, 128.8, 129.1, 131.3, 133.8,
154.6.
1H NMR: d = 2.48 (s, 3 H), 6.49–6.51 (m, 1 H), 6.75–6.83 (m, 1 H),
7.32–7.39 (m, 4 H), 7.54 (s, 1 H).
1,5-Bis(4-methylphenyl)-1H-tetrazole (3g)
Colorless needles (CHCl3–hexanes); yield: 0.115 g (92%); mp 142–
144 °C (Lit.21 148 °C).
13C NMR: d = 21.3, 112.0, 115.0, 125.5, 130.2, 131.6, 138.9, 141.2,
145.7, 146.6.
Anal. Calcd for C12H10N4O: C, 63.71; H, 4.46; N, 24.76. Found: C,
63.96; H, 4.35; N, 25.11.
1H NMR: d = 2.38 (s, 3 H), 2.45 (s, 3 H), 7.20 (d, J = 8.0 Hz, 2 H),
7.27 (d, J = 8.5 Hz, 2 H), 7.31 (d, J = 8.5 Hz, 2 H), 7.45 (d, J = 8.1
Hz, 2 H).
1-Cyclohexyl-5-(2-furyl)-1H-tetrazole (3n)
White microcrystals (CHCl3); yield: 0.103 g (94%); mp 58–60 °C.
13C NMR: d = 21.3, 21.5, 120.7, 125.1, 128.7, 129.6, 130.4, 132.1,
140.6, 141.6, 153.6.
1H NMR: d = 1.20–1.48 (m, 3 H), 1.65–1.77 (m, 1 H), 1.80–2.15
(m, 6 H), 4.70–4.80 (m, 1 H), 6.58 (dd, J = 3.5, 1.9 Hz, 1 H), 7.12–
7.18 (m, 1 H), 7.58–7.77 (m, 1 H).
1-Methyl-5-(4-methylphenyl)-1H-tetrazole (3h)
Colorless needles (CHCl3–hexanes); yield: 0.080 g (92%); mp 113–
115 °C (Lit.22 117–118 °C).
13C NMR: d = 24.8, 25.2, 32.7, 59.0, 112.1, 114.5, 139.7, 145.2,
145.6.
1H NMR: d = 2.46 (s, 3 H), 4.17 (s, 3 H), 7.37 (d, J = 8.0 Hz, 2 H),
7.64 (d, J = 8.1 Hz, 2 H).
Anal. Calcd for C11H14N4O: C, 60.53; H, 6.47; N, 25.67. Found: C,
60.88; H, 6.74; N, 25.71.
13C NMR: d = 21.4, 35.0, 120.7, 128.4, 129.9, 141.7, 154.4.
1-(4-Methylphenyl)-5-(2-thienyl)-1H-tetrazole (3o)
Colorless needles (CHCl3); yield: 0.111 g (92%); mp 115–117 °C;
novel (appears in catalogue, but no characterization data could be
found in literature).
1-Benzyl-5-(4-methoxyphenyl)-1H-tetrazole (3i)
Colorless needles (CHCl3–hexanes); yield: 0.125 g (94%); mp 106–
108 °C (Lit.17a no NMR data or mp were reported).
1H NMR: d = 3.86 (s, 3 H), 5.61 (s, 2 H), 6.96–7.04 (m, 2 H), 7.15–
7.18 (m, 2 H), 7.34–7.38 (m, 3 H), 7.51–7.58 (m, 2 H).
1H NMR: d = 2.51 (s, 3 H), 7.02–7.07 (m, 1 H), 7.24–7.29 (m, 1 H),
7.32–7.44 (m, 4 H), 7.49–7.53 (m, 1 H).
13C NMR: d = 51.2, 55.4, 114.6, 115.6, 127.0, 128.6, 129.1, 130.3,
134.0, 154.5, 161.8.
13C NMR: d = 21.4, 124.3, 128.0, 130.4, 130.5, 130.6, 131.4, 141.7,
149.8.
Anal. Calcd for C15H14N4O: C, 67.65; H, 5.32; N, 21.04. Found: C,
67.86; H, 5.32; N, 21.40.
Anal. Calcd for C12H10N4S: C, 59.48; H, 4.16; N, 23.12. Found: C,
59.82; H, 4.07; N, 23.20.
5-(4-Chlorophenyl)-1-(4-methylphenyl)-1H-tetrazole (3j)
Colorless needles (CHCl3); yield: 0.122 g (90%); mp 132–134 °C.
Ethyl [5-(4-Methylphenyl)-1H-tetrazol-1-yl]acetate (3p)
Pale yellow oil; yield: 0.111 g (90%).
1H NMR: d = 2.47 (s, 3 H), 7.26 (d, J = 8.5 Hz, 2 H), 7.34 (d,
J = 8.3 Hz, 2 H), 7.39 (d, J = 8.7 Hz, 2 H), 7.52 (d, J = 8.7 Hz, 2 H).
1H NMR: d = 1.24 (t, J = 7.2 Hz, 3 H), 2.43 (s, 3 H), 4.24 (q, J = 7.2
Hz, 2 H), 5.22 (s, 2 H), 7.34 (d, J = 8.1 Hz, 2 H), 7.54 (d, J = 8.4 Hz,
2 H).
13C NMR: d = 21.3, 122.1, 125.1, 129.3, 130.1, 130.6, 131.8, 137.6,
141.1, 152.7.
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A. R. Katritzky et al.
PAPER
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13C NMR: d = 13.7, 21.2, 48.5, 62.5, 120.1, 128.2, 129.8, 141.8,
155.0, 165.4.
Anal. Calcd for C12H14N4O2: C, 58.53; H, 5.73; N, 22.75. Found: C,
58.85; H, 5.92; N, 21.92.
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Synthesis 2007, No. 8, 1204–1208 © Thieme Stuttgart · New York