Vol. 29, No. 4 (2017)
Syntheses of 5-Substituted 1H-tetrazoles Catalyzed by Reusable Cu(II)-NaY Zeolite from Nitriles 865
5-Phenyl-1H-1,2,3,4-tetrazole (Table-2, entry 1): 1H
NMR (200 MHz, DMSO-d6) δ (ppm): 8.04 (m, 2H), 7.61 (m,
3H). 13C NMR (125 MHz, DMSO-d6) δ (ppm): 124.17, 127.02,
129.45, 131.28, 155.2 (br). MS (ESI): M = 146, found 146
[M-H].
TABLE-1
SCREENING OF REACTION PARAMETERS FOR THE
FORMATION OF 5-PHENYL TETRAZOLEa
H
N
R
R
Azide
N
N
CN
Catalyst, Solvent
N
5-Benzyl-1H-1,2,3,4-tetrazole (Table-2, entry 5): 1H
NMR (200 MHz, DMSO-d6) δ (ppm): 3.8 (s, 2H), 7.3- 7.5 (m,
5H). 13C NMR (125 MHz, DMSO-d6) δ (ppm): 155.2, 135.9,
128.7, 128.6, 127.0, 28.9. MS (ESI): M = 160, found 159
[M-H]–.
5-(2-Methoxybenzyl)-1H-1,2,3,4-tetrazole (Table-2,
entry 6):1H NMR (200 MHz, DMSO-d6) δ (ppm): 3.6 (s, 2H),
3.85 (s, 3H), 6.8-7.0 (m, 2H), 7.2-7.4 (m, 2H). 13C NMR (125
MHz, DMSO-d6) δ (ppm): 23.9, 55.4, 111.0, 120.4, 123.6,
128.7, 130.1, 156.9. MS (ESI): M = 190, found 191 [M+H]+.
4-(1H-1,2,3,4-Tetrazol-5-yl)benzaldehyde (Table-2,
entry 10): 1H NMR (200 MHz, DMSO-d6) δ (ppm): 8.0 (d,
2H), 8.15 (d, 2H), 10.1 (s, 1H). 13C NMR (125 MHz, DMSO-
d6) δ (ppm): 128.07, 130.00, 130.82, 138.07, 155.77, 193.13.
MS (ESI): M = 173, found 173 [M-H].
Entry
Catalyst
H-Y
Na-Y
Azide
Solvent
Yieldb (%)
1
2
3
4
5
6
7
8
9
NaN3
NaN3
NaN3
NaN3
NaN3
TMSN3
NaN3
NaN3
NaN3
NaN3
NaN3
DMF
DMF
DMF
DMF
DMF
19.0
15.7
15.0
18.0
99, 99c
42.0
63.0d
47.0
9.0
Zn Na-Y
Fe Na-Y
Cu Na-Y
Cu Na-Y
Cu(OAc)2
Cu Na-Y
Cu Na-Y
Cu Na-Y
Cu Na-Y
DMF
DMF
DMSO
H2O
CH3OH
C6H5CH3
10
11
17.0
Trace
aReaction condition: Nitrile (2.5 mmol), NaN3 (2.75 mmol) catalyst 0.1
g, solvent (5 mL); Reaction time (4 h); Temperature (120 °C);
bIsolated yield; cYield after third cycle; dCu(OAc)2, 2.5 mol %
within 4 h (Table-2, entries 1-4), which shows that there is no
effect of substitution on benzonitrile. Phenylacetonitrile and
4-methoxyphenyl acetonitrile are also provided quantitative
yields in shorter reaction times (Table-2, entries 5 and 6), whereas
the previous reported longer reaction times. This catalytic
system provided good compatibility to other functional groups
(Table-2, entries 7 and 8) and mono addition product was obtained
when 1,3-dicyanobenzene and 1,4-dicyanobenzene are used
(Table-2, entries 9 and 10,). Heteroaromatic nitriles such as 2-
pyridinecarbonitrile and cyanopyrazine gave corresponding
tetrazoles in quantitative yields in shorter reaction times (Table-2,
entries 11 and 12,). Interestingly simple acetonitrile is also
converted to 5-methyltetrazole in quantitative yields in 3 h
(Table-2, entry 13). Irbesartan nitrile intermediate (Table-2,
entries 14) gave corresponding finalAPI in good yield. Irbesartan
marketed under the trade name Avapro, a tetrazole derivative,
is an antihypertensive drug which is a potent, long acting non
pepetide Ang II receptor antagonist with high selectivity for
the AT1 sub type [24].
2-Butyl-3-({4-[2-(2H-1,2,3,4-tetrazol-5-yl)phenyl]-
phenyl}methyl)-1,3-diazaspiro[4.4]non-1-en-4-one (Table-
2, entry 14): White solid; m.p.: 180-181 °C: H NMR (400
1
MHz, CDCl3) δ (ppm): 0.83 (t, J = 7.4 Hz, 3H, CH3), 1.41-
1.20 (m, 2H, CH2), 1.60-1.45 (m, 2H, CH2), 2.0-1.59 (m, 8H,
CH2), 2.30 (t, J = 7.5 Hz 2H, CH2), 4.57 (s, 2H, CH2), 7.12(d,
2H, J = 8 Hz, ArH), 7.28-7.33 (m, 3H, ArH), 7.40-7.49 (m,
3H, ArH); 13C NMR (300 MHz, CDCl3); δ 14.0, 19.0, 26.1,
29.8, 37.6, 44.2, 72.7, 124.4, 127.7, 128.8, 130.2, 131.4, 131.5,
131.9, 134.9, 139.9, 141.8, 155.9, 172.5, 180.4; MS (ESI): M
= 428, found 429 [M+H]+.
RESULTS AND DISCUSSION
Initially, various reaction parameters were studied for the
preparation of 5-phenyltetrazole by the reaction of benzonitrile
with sodium azide and the results are summarized in Table-1.
First we conducted this reaction using H-Y zeolite in DMF
solvent at 120 °C afforded 19 % yield after 4 h and 15 % with
NaY zeolite (Table-1, entries 1 and 2). Later the use of Zn(II)-
NaY and Fe(II)-NaY catalysts resulted in 15 and 18 % yields,
respectively (Table-1, entries 3 and 4). But with Cu(II)-NaY
catalyst, the reaction was complete within 3.5 h and quantitative
yields were obtained (Table-1, entry 5). When TMSN3 was
used as the azide source, the reaction gave 42 % yield (Table-1,
entry 6). The homogeneous copper(II) acetate catalyst afforded
63 % yield (Table-1, entry 7). The solvent has pronounced effect
in this reaction (Table-1, entries 8-11) in which DMSO provided
better yields when compared to methanol and water while
traces amount of the product was obtained in toluene. The used
catalyst was recovered by centrifugation and reused for three
cycles with consistent activity (Table-1, entry 5).
TABLE-2
Cu(II) Na-Y MEDIATED PREPARATION OF
5-SUBSTITUTED 1H-TETRAZOLESa
N
N
R
Cu(II)-NaY
R
N
C
NaN
3
NH
+
DMF, 120oC, 3-4 h
N
Entry
1
Substrate
CN
Time (h)
3.5
Yieldb (%)
99
Cl
CN
CN
2
3
4.0
4.0
99
98
Table-2 summarizes the scope and the generality of the
Cu(II)-NaY promoted formation of 5-substituted 1H-tetrazoles.
A variety of structurally divergent benzonitriles possessing a
wide range of functional groups are studied in this regard. All
the nitriles gave the corresponding tetrazoles in quantitative
yields. 2-Chloro-, 4-chloro- and 4-methoxybenzonitriles are
converted to the corresponding tetrazoles in quantitative yields
Cl
H3CO
CN
4
5
3.0
3.0
99
99
CN