Efficient Synthesis of 1,5-Disubstituted Tetrazoles - University of ...

Efficient Synthesis of 1,5-Disubstituted Tetrazoles
Alan 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
Abstract: A general method for the synthesis of 1,5 disubstituted
tetrazoles from imidoylbenzotriazoles involves mild reaction
conditions and short reaction time.
Key words: amides, imidoylbenzotriazoles, tetrazoles, phasetransfer
catalysis, sodium azide
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
antagonists and antimigraine agents. 1d 1,5-Disubstituted
tetrazoles are also useful synthetic intermediates 2a for
synthesis of energetic salts, 2b 3,4-dihydro-pyrimidin-
2(1H)-ones, 2c
piericidins, 2d (+)-trans-5allylhexahydroindolizidin-3-ones,
2e
acacetin, 2f (+)strictifolione,
2g vinylsilianes 2h and leucascandrolide A. 2i
The many published preparative methods for 1,5disubstituted
tetrazoles 3 include reactions of (i) amides
with PCl5 or triflic anhydride and HN3 or NaN3, 4,5 (ii)
thioamides with trimethylsilyl azide, 6 (iii) imidoyl chlorides
with NaN3, 7 (iv) ketones with NaN3 8 or trimethylsilyl
azide, 9 (v) oximes with HN3, 10 (vi) nitriles with
alkyl chloride and trimethylstannyl azide 11 or with alkyl
azide, 12 (vii) nitrilium triflate with NaN3 13 and (viii)
amidrazones with N2O4 or HNO2 (Scheme 1). 14
Cl
R N R'
R R'
O
R CN
R NHR'
S
R'-N3 R N
R NHR' TMS-N3 R'
+
Lawesson's
(i)
(vi)
reagent
PCl5 or Tf2O R'-Cl/TMS-N3 HN3 or NaN3 or
- OTf
(ii)
R'
(vii) NaN3 (iii)
NaN 3
NaN 3
(iv)
or TMS-N3 O
HN 3
(v)
N-OH
R R'
R
N
N N
N
R'ZnCl
or
R'-B(OH) 2
N N
R
N
H
N
(viii) N 2 O 4
or HNO2 (ix)
R'-X
R
R NHR'
Scheme 1 Literature methods of preparation of 1,5-disubstituted
tetrazoles
(x)
N
N
H
N-NH 2
Further preparations involving conversion of substituted
tetrazoles into 1,5-disubstituted tetrazoles include (ix)
alkylation of 5-substituted tetrazoles 15 and (x) coupling
of substituted 5-halotetrazoles with organozinc 16 or vinylboronic
acid (Scheme 1). 17
N
N
PAPER
However, many of these reported methods suffer from
one or more of (i) long reaction time, (ii) use of toxic
and/or explosive reagents, (iii) tedious work up and low
yields, (iv) high temperatures (v) formation of inseparable
regio-isomers and (vi) use of uncommon starting
materials. Thus, a mild and efficient method is required
for the preparation of 1,5-disubstituted tetrazoles.
Imidoylbenzotriazoles which are stable to water and
easily prepared 18 are useful substitutes for imidoyl chlorides
and we now report they can be used to synthesize
1,5-disubstituted tetrazoles in high yield under mild
conditions.
Preparation of Imidoylbenzotriazoles
Imidoylbenzotriazoles 1a–p (Table 1) were prepared
from corresponding secondary carboxamides 2a–p and
benzotriazoles using method A: oxalyl chloride and
pyridine or method B: thionyl chloride under microwave
(80 W/80 o C) following a literature procedure. 18 Thus,
1a–d were prepared following method A and 1e–o were
prepared following method B. The compound 1p was
prepared using method B, but at 60 W/60 o C (Scheme 2).
Imidoylbenzotriazoles 1h and 1p were novel and were
completely characterized.
R 1
O
N
H
2a-p
R 2
+
BtH
(COCl) 2 /Pyridine
or
SOCl 2
R 1
Bt
MW: 80 W/80 oC 1a-p
Scheme 2 Preparation of imidoylbenzotriazoles 1a–p
Preparation of 1,5-Disubstituted Tetrazoles
Imidoylbenzotriazoles are stable in water and do not
react with sodium azide at room temperature. Although
the reaction of 1-[1-[(4-methylphenyl)imino]ethyl]-1Hbenzotriazole
(1b) with sodium azide in the presence of
trifluoroacetic acid (1 equiv) to give 5-methyl-1-(4methylphenyl)-1H-tetrazole
(3b) was slow and incomplete,
a catalytic amount (20 mol%) of tetrabutylammonium
bromide (TBAB) as phase-transfer catalyst in a
two-phase (methylene chloride and water) system at 20
o C gave complete reaction in 30 min. Column chromatography
on basic alumina using ethyl acetate/hexanes
(1/2) gave 5-methyl-1-(4-methylphenyl)-1H-tetrazole
(3b) in 93% yield.
This method generalized the preparation of 1,5disubstituted
tetrazoles with diverse substituents (aliphatic,
aromatic or heteroaromatic) in the starting imidoylbenzotriazole.
The progress of reaction was monitored
by thin layer chromatography. The 1,5-
N
R 2
1204

disubstituted tetrazoles prepared in high yields (90–94%,
Scheme 3, Table 2) were fully characterized by 1 H and
13 C NMR spectroscopy. Novel compounds gave satisfactory
elemental analysis; melting points of all known
compounds were compared with the literature and found
satisfactory except 3k, which may be due to the difference
in crystallizing solvents. The molecular formula for
3k was supported by satisfactory elemental analysis.
Table 1 Preparation of Imidoylbenzotriazoles 1a–p
a Isolated yield.
R 1
Bt
1a-p
N
R 2
NaN 3 /TFA
TBAB (20 mol%)
CH 2 Cl 2 /H 2 O, r.t.
R 1
R 2
N
N N
3a-p
Scheme 3 Preparation of 1,5-disubstituted tetrazoles 3a–p
Imidoylbenzotriazoles Lit. 18
Entry R 1
R 2
Yield (%) a Mp ( o C) Mp ( o C) Yield (%)
a Me Ph 1a (68) 107–108 106–108 75
b Me p-Tolyl 1b (65) 112–113 113–115 65
c Bn p-Tolyl 1c (63) 125–126 124–126 62
d PhCH2CH2 p-Tolyl 1d (62) Oil Oil 65
e Ph Ph 1e (85) 129–130 129–131 88
f Ph Bn 1f (90) 109–110 108–110 93
g p-Tolyl p-Tolyl 1g (85) 138–140 138–140 82
h p-Tolyl Me 1h (85) 95–98 New -
i p-Methoxyphenyl Bn 1i (82) 114–116 115–118 78
j p-Chlorophenyl p-Tolyl 1j (90) 119–120 118–120 90
k p-Nitrophenyl Ph 1k (86) 182–184 183–185 88
l p-Nitrophenyl Bn 1l (85) 118–120 117–119 86
m 2-Furyl p-Tolyl 1m (80) 121–124 120–123 84
n 2-Furyl Cyclohexyl 1n (90) Oil Oil 95
o 2-Thienyl p-Tolyl 1o (87) 134–135 133–135 91
p p-Tolyl CH2CO2Et 1p (86) 119–121 New -
Table 2 Preparation of 1,5-disubstituted tetrazoles 3a–p
PAPER
Entry R 1,5-Disubstituted tetrazoles Lit.
1
R 2
Yield (%) a Mp ( o C) Mp ( o C) Yield (%)
a Me Ph 3a (90) 95–97 98–99 63 8b
b Me p-Tolyl 3b (93) 101–103 106 96 19
c Bn p-Tolyl 3c (94) 92–94 New -
d
e
PhCH2CH2
Ph
p-Tolyl
Ph
3d (92)
3e (90)
Oil
141–143
New
144–145
-
85 17b
f Ph Bn 3f (95) 88–90 90–91 79 20
g p-Tolyl p-Tolyl 3g (92) 142–144 148 b 21
h p-Tolyl Me 3h (92) 113–115 117–118 30 22
i p-Methoxyphenyl Bn 3i (94) 106–108 c 97 17a
j p-Chlorophenyl p-Tolyl 3j (90) 132–134 New -
k p-Nitrophenyl Ph 3k (90) 144–146 177–178 95 8b
l p-Nitrophenyl Bn 3l (93) 131–133 New -
m 2-Furyl p-Tolyl 3m (92) 118–120 c -
n 2-Furyl Cyclohexyl 3n (94) 58–60 New -
o 2-Thienyl p-Tolyl 3o (92) 115–117 c -
p p-Tolyl
a
Isolated yield.
b
Yield not available in the literature
c
Found in literature with no characterization
CH2CO2Et 3p (90) Oil New -
pounds. This method can be performed in aqueous solution
without decomposition and requires a shorter reaction
time, thus offers advantages over other methods.
This transformation has also been studied in different
solvents. Thus, the reaction of 1e was carried out in acetonitrile/water
and THF/water under the standardized
conditions to obtain tetrazole 3e in 90% yield.
Herein we presented a general, mild and convenient
method of preparation of 1,5-disubstituted tetrazoles
with variable substituents on the nitrogen atom. The
starting imidoylbenzotriazoles easily be prepared from
readily available amides, are stable and crystalline com-
Melting points are uncorrected. Reactions under microwave
irradiation were conducted in heavy-walled pyrex
tubes sealed with aluminum 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 Synthesizer
(CEM Corporation, NC, USA), producing continuous
irradiation at 2450 MHz. Purification by column
N
1205

chromatography was carried out using basic alumina. 1 H
NMR (300 MHz) and 13 C NMR (75 MHz) spectra were
recorded in CDCl3 (with TMS for 1 H and chloroform-d
for 13 C as the internal reference).
Characterization of Imidoyl benzotriazoles
N-[1H-1,2,3-Benzotriazol-1-yl(4methylphenyl)methylene]-N-methylamine
(1h)
Yellow microcrystals (from chloroform); mp 95–98 o C;
yield: 1.06 g (85%).
1 H NMR: δ = 2.44 (s, 3H), 3.39 (s, 3H), 7.29 (d, J = 8.1
Hz, 2H), 7.34 (d, J = 8.0 Hz, 2H), 7.42 (t, J = 7.6 Hz,
1H), 7.56 (t, J = 7.7 Hz, 1H), 8.09 (d, J = 8.2 Hz, 1H),
8.37 (d, J = 8.3 Hz, 1H).
13 C NMR: δ = 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.
Ethyl 2-{[(E)-1H-1,2,3-benzotriazol-1-yl(4methylphenyl)methylidene]amino}acetate
(1p)
Colorless needles (from chloroform/hexanes); mp 119–
121 o C; yield: 2.72 g (86%).
1 H NMR: δ = 1.32 (t, J = 7.2 Hz, 3H), 2.46 (s, 3H), 4.27
(q, J = 7.2 Hz, 2H), 4.40 (s, 2H), 7.31–7.38 (m, 4H),
7.45–7.51 (m, 1H), 7.61–7.67 (m, 1H), 8.11 (d, J = 8.1
Hz, 1H), 8.66 (d, J = 8.4 Hz, 1H).
13 C NMR: δ = 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.
General Procedure for the Preparation of 1,5-
Disubstituted Tetrazoles
To a mixture of methylene chloride and water (10
mL/10mL) was added imidoylbenzotriazole (1a–p) (0.50
mmol), sodium azide (0.065 g, 1.0 mmol), tetrabutylammonium
bromide (0.032 g, 0.10 mmol) and
trifluoroacetic acid (0.06 g, 0.50 mmol). The reaction
mixture was stirred for half an hour (for entry k, table 2,
the reaction time was 12 h) under room temperature. The
organic layer was separated and the water layer was
washed methylene chloride (10 mL). Purification of the
combined organic layer by column chromatography on
basic alumina with ethyl acetate/hexanes (1/2) as eluent
gave pure 1,5-disubstituted tetrazoles (3a–p).
5-Methyl-1-phenyl-1H-tetrazole (3a)
Colorless needles (from chloroform/hexanes); mp 95–97
o C (lit. 8b mp 98–99 o C); yield: 0.072 g (90%).
1
H NMR: δ = 2.63 (s, 3H), 7.46–7.49 (m, 2H), 7.59–7.63
(m, 3H).
13
C NMR: δ = 9.8, 124.6, 130.0, 130.4, 133.9, 151.5.
5-Methyl-1-(4-methylphenyl)-1H-tetrazole (3b)
Colorless needles (from chloroform/hexanes); mp 101–
103 o C (Lit. 19 mp 106 o C); yield: 0.081 g (93%).
PAPER
1
H NMR: δ = 2.47 (s, 3H), 2.60 (s, 3H), 7.32–7.42 (m,
4H).
13
C NMR: δ = 9.7, 21.2, 124.3, 130.4, 131.2, 140.6,
151.5.
5-Benzyl-1-(4-methylphenyl)-1H-tetrazole (3c)
White microcrystals (from chloroform); mp 92–94 o C;
yield: 0.118 g (94%).
1 H NMR: δ = 2.44 (s, 3H), 4.25 (s, 2H), 7.06–7.11 (m,
2H), 7.12–7.18 (m, 2H), 7.22–7.26 (m, 3H), 7.27–7.33
(m, 2H).
13 C NMR: δ = 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 C15H14N4: C, 71.98; H, 5.64; N, 22.38.
Found: C, 72.26; H, 5.76; N, 22.42.
1-(4-Methylphenyl)-5-(2-phenylethyl)-1H-tetrazole
(3d)
Colorless oil; yield: 0.126 g (95%).
1 H NMR: δ = 2.43 (s, 3H), 3.14 (s, 4H), 7.02–7.07 (m,
4H), 7.20–7.30 (m, 5H).
13 C NMR: δ = 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 C16H16N4: C, 72.70; H, 6.10; N, 21.20.
Found: C, 73.04; H, 6.26; N, 21.11.
1,5-Diphenyl-1H-tetrazole (3e)
Colorless needles (from chloroform/hexanes); mp 141–
143 o C (lit. 17b mp: 144–145 o C); yield: 0.100 g (90 %).
1 H NMR: δ = 7.39–7.43 (m, 4H), 7.48–7.58 (m, 6H).
13 C NMR: δ = 123.6, 125.3, 128.4, 128.9, 129.0, 129.9,
130.4, 131.3, 153.6.
1-Benzyl-5-phenyl-1H-tetrazole (3f)
White microcrystals (from chloroform/hexanes); mp 88–
90 o C (lit. 20 mp 90-91 o C); yield: 0.112 g (95%).
1 H NMR: δ = 5.62 (s, 2H), 7.14–7.17 (m, 2H), 7.32–7.36
(m, 3H), 7.47–7.59 (m, 5H).
13 C NMR: δ = 51.3, 123.6, 127.1, 128.7, 128.8, 129.1,
131.3, 133.8, 154.6.
1,5-Bis(4-methylphenyl)-1H-tetrazole (3g)
Colorless needles (from chloroform/hexanes); mp 142–
144 o C (lit. 21 mp 148 o C); yield: 0.115 g (92%).
1 H NMR: δ = 2.38 (s, 3H), 2.45 (s, 3H), 7.20 (d, J = 8.0
Hz, 2H), 7.27 (d, J = 8.5 Hz, 2H), 7.31 (d, J = 8.5 Hz,
2H), 7.45 (d, J = 8.1 Hz, 2H).
13 C NMR: δ = 21.3, 21.5, 120.7, 125.1, 128.7, 129.6,
130.4, 132.1, 140.6, 141.6, 153.6.
1-Methyl-5-(4-methylphenyl)-1H-tetrazole (3h)
Colorless needles (from chloroform/hexanes); mp 113–
115 o C (lit. 22 mp 117–118 o C); yield: 0.080 g (92%).
1 H NMR: δ = 2.46 (s, 3H), 4.17 (s, 3H), 7.37 (d, J = 8.0
Hz, 2H), 7.64 (d, J = 8.1 Hz, 2H).
13 C NMR: δ = 21.4, 35.0, 120.7, 128.4, 129.9, 141.7,
154.4.
1206

1-Benzyl-5-(4-methoxyphenyl)-1H-tetrazole (3i)
Colorless needles (from chloroform/hexanes); mp 106–
108 o C (Lit. 17a no NMR data and melting point were
reported in this paper); yield: 0.125 g (94%).
1 H NMR: δ = 3.86 (s, 3H), 5.61 (s, 2H), 6.96–7.04 (m,
2H), 7.15–7.18 (m, 2H), 7.34–7.38 (m, 3H), 7.51–7.58
(m, 2H).
13 C NMR: δ = 51.2, 55.4, 114.6, 115.6, 127.0, 128.6,
129.1, 130.3, 134.0, 154.5, 161.8.
Anal. Calcd for C15H14N4O: C, 67.65; H, 5.32; N, 21.04.
Found: C, 67.86; H, 5.32; N, 21.40.
5-(4-Chlorophenyl)-1-(4-methylphenyl)-1H-tetrazole
(3j)
Colorless needles (from chloroform); mp: 132–134 o C;
yield: 0.122 g (90 %).
1 H NMR: δ = 2.47 (s, 3H), 7.26 (d, J = 8.5 Hz, 2H), 7.34
(d, J = 8.3 Hz, 2H), 7.39 (d, J = 8.7 Hz, 2H), 7.52 (d, J
= 8.7 Hz, 2H).
13 C NMR: δ = 21.3, 122.1, 125.1, 129.3, 130.1, 130.6,
131.8, 137.6, 141.1, 152.7.
Anal. Calcd for C14H11 N4: C, 62.11; H, 4.10; N, 20.70.
Found: C, 62.50; H, 4.04; N, 21.07.
5-(4-Nitrophenyl)-1-phenyl-1H-tetrazole (3k)
Colorless needles (from ethyl acetate/hexanes); mp 145–
147 o C (Lit. 8b mp 179–181 o C); yield: 0.120 g (90%).
1 H NMR: δ = 7.46–7.51 (m, 2H), 7.53–7.61 (m, 3H),
7.62–7.67 (m, 2H), 8.36–8.42 (m, 2H).
13 C NMR: δ = 122.9, 125.3, 125.8, 129.0, 129.4, 131.9,
139.1, 148.3, 153.8.
Anal. Calcd for C13H9N5O2: C, 58.43; H, 3.40; N, 26.22.
Found: C, 58.77; H, 3.15; N, 26.38.
1-Benzyl-5-(4-nitrophenyl)-1H-tetrazole (3l)
Colorless needles (from chloroform/hexanes); mp 131–
133 o C; yield: 0.131 g (93%).
1 H NMR: δ = 5.68 (s, 2H), 7.14–7.16 (m, 2H), 7.37–7.39
(m, 3H), 7.79 (d, J = 8.9 Hz, 2H), 8.36 (d, J = 8.9 Hz,
2H).
13 C NMR: δ = 51.8, 124.2, 127.0, 129.1, 129.4, 129.8,
130.0, 133.2, 149.4, 152.9.
Anal. Calcd for C14H11N5O2: C, 59.78; H, 3.94; N, 24.90.
Found: C, 60.11; H, 3.80; N, 25.27.
5-(2-Furyl)-1-(4-methylphenyl)-1H-tetrazole (3m)
Colorless needles (from chloroform/hexanes); novel
(appeared in catalog, but no characterization data could
be found in literature); mp 118–120 o C; yield: 0.104 g
(92%).
1 H NMR: δ = 2.48 (s, 3H), 6.49–6.51 (m, 1H), 6.75–6.83
(m, 1H), 7.32–7.39 (m, 4H), 7.54 (s, 1H).
13 C NMR: δ = 21.3, 112.0, 115.0, 125.5, 130.2, 131.6,
138.9, 141.2, 145.7, 146.6.
Anal. Calcd for C12H14N4O: C, 63.71; H, 4.46; N, 24.76.
Found: C, 63.96; H, 4.35; N, 25.11.
5-(2-Furyl)-1-cyclohexyl-1H-tetrazole (3n)
PAPER
White microcrystals (from chloroform); mp 58–60 o C;
yield: 0.103 g (94%).
1 H NMR: δ = 1.20–1.48 (m, 3H), 1.65–1.77 (m, 1H),
1.80–2.15 (m, 6H), 4.70–4.80 (m, 1H), 6.58 (dd, J = 3.5,
1.9 Hz, 1H), 7.12–7.18 (m, 1H), 7.58–7.77 (m, 1H).
13 C NMR: δ = 24.8, 25.2, 32.7, 59.0, 112.1, 114.5, 139.7,
145.2, 145.6.
Anal. Calcd for C11H14N4O: C, 60.53; H, 6.47; N, 25.67.
Found: C, 60.88; H, 6.74; N, 25.71.
1-(4-Methylphenyl)-5-thien-2-yl-1H-tetrazole (3o)
Colorless needles (from chloroform); mp 115–117 o C;
yield: 0.111 g (92%); novel (appears in catalog, but no
characterization data could be found in literature).
1 H NMR: δ = 2.51 (s, 3H), 7.02–7.07 (m, 1H), 7.24–7.29
(m, 1H), 7.32–7.44 (m, 4H), 7.49–7.53 (m, 1H).
13 C NMR: δ = 21.4, 124.3, 128.0, 130.4, 130.5, 130.6,
131.4, 141.7, 149.8.
Anal. Calcd for C12H10N4S: C, 59.48; H, 4.16; N, 23.12.
Found: C, 59.82; H, 4.07; N, 23.20.
Ethyl 2-[5-(4-methylphenyl)-1H-1,2,3,4-tetrazol-1yl]acetate
(3p)
Pale yellow oil; yield: 0.111 g (90%).
1 H NMR: δ = 1.24 (t, J = 7.2 Hz, 3H), 2.43 (s, 3H), 4.24
(q, J = 7.2 Hz, 2H), 5.22 (s, 2H), 7.34 (d, J = 8.1 Hz,
2H), 7.54 (d, J = 8.4 Hz, 2H).
13 C NMR: δ = 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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