A novel approach for the synthesis of 5-substituted-1H-tetrazoles

Article abstract of DOI:10.1590/S0103-50532013005000005

A series of 5-substituted-1H-tetrazoles (RCN₄H) have been synthesized by cycloaddition reaction of different aryl and alkyl nitriles with sodium azide in DMSO using CuSO₄?5H₂O as catalyst. A wide variety of aryl nitriles underwent [3+2] cycloaddition to afford tetrazoles under mild reaction conditions in good to excellent yields. The catalyst used is readily available and environmentally friendly. Short reaction times, good to excellent yields, safe process and simple workup make this method an attractive and useful contribution to present organic synthesis of 5-substituted-1H- tetrazoles. ?2012 Sociedade Brasileira de Qui?mica.

Full text of DOI:10.1590/S0103-50532013005000005

J. Braz. Chem. Soc., Vol. 23, No. 12, 2197-2203, 2012.
Printed in Brazil - ©2012 Sociedade Brasileira de Química
0103 - 5053 $6.00+0.00
Article
A
A Novel Approach for the Synthesis of 5-Substituted-1H-tetrazoles
Batool Akhlaghinia* and Soodabeh Rezazadeh
Department of Chemistry, Faculty of Sciences, Ferdowsi University of Mashhad,
9177948974 Mashhad, Iran
Uma série de 1H-tetrazóis-5-substituídos (RCN4H) foi sintetizada pela reação de cicloadição
•
de diferentes aril e alquil nitrilas com azida de sódio em DMSO, usando CuSO4 5H2O como
catalisador. Uma grande variedade de aril nitrilas sofreu cicloadição [3+2], obtendo-se os
correspondentes tetrazóis sob condições reacionais brandas. O catalisador utilizado é obtido
facilmente e ambientalmente correto. Tempos de reação curtos, bons a excelentes rendimentos,
processo seguro e simples tornam este método uma contribuição atrativa e útil à presente síntese
orgânica de 1H-tetrazóis-5-substituídos.
A series of 5-substituted-1H-tetrazoles (RCN4H) have been synthesized by cycloaddition
•
reaction of different aryl and alkyl nitriles with sodium azide in DMSO using CuSO4 5H2O as
catalyst. A wide variety of aryl nitriles underwent [3+2] cycloaddition to afford tetrazoles under
mild reaction conditions in good to excellent yields. The catalyst used is readily available and
environmentally friendly. Short reaction times, good to excellent yields, safe process and simple
workup make this method an attractive and useful contribution to present organic synthesis of
5-substituted-1H-tetrazoles.
•
Keywords: 5-substituted-1H-tetrazole, arylnitriles, sodium azide, CuSO4 5H2O, cycloaddition
reaction
Introduction
catalysis in aqueous solution is a magnificent improvement
over latter methods,23,24 but occasionally still requires the
tedious and time-consuming removal of zinc salts from
the acidic products. Stoichiometric amounts of inorganic
salts and metal complexes25 as catalysts, use of TMSN3
and TBAF26 instead of metal salts under solvent-free
conditions in micellar media and ionic liquids, and use of
various catalysts27-31 such as BF3.OEt2,21 Pd(OAc)2/ZnBr2,27
Yb(OTf)3,28 Zn(OTf)3,29 AlCl3,30 and Pd (PPh3)4 31 were also
employed for the same purpose. However, a drawback of
these homogeneous catalytic processes lies in the tedious
separation and recovery of the catalysts. Recently, several
heterogeneous catalytic systems 32-40 using nanocrystalline
ZnO, Zn/Al HT,32 Zn hydroxyapatite,33 Cu2O,34,35 Sb2O3,
FeCl3/SiO2,36 CdCl2,37 BaWO4, γ-Fe2O3,38 ZnS,39 and
natural natrolite zeolite40 were reported. Metal-modified
montmorillonites and zeolite were reported widely, and
The chemistry of heterocyclic compounds has been
an interesting field of study for a long time. Tetrazoles
as a group of heterocyclic compounds are reported to
possess a broad spectrum of biological activities such
as antibacterial,1 antifungal,2 antiviral,3-5 analgesic,6,7
anti-inflammatory,8-10 antiulcer11 and antihypertensive12
activities. Also, 5-substituted-1H-tetrazoles can function
as lipophilic spacers and carboxylic acid surrogates,13
specialty explosives14,15 and information recording systems
in materials16 ligands, and precursors of a variety of nitrogen
containing heterocycles in coordination chemistry.17,18
Since 1901,19 conventional synthesis of 5-substituted-
1H-tetrazoles has been reported to proceed via [3 + 2]
cycloaddition of azide with nitriles. This procedure suffers
from numerous drawbacks including use of expensive
and toxic metal organic azide,20 highly moisture-sensitive
reaction conditions, strong Lewis acid,21 and hydrazoic
acid.22 The “click” chemistry approach utilizing zinc
many metals, such as Cu, Zn, Mn, Fe, Cu, V, Mo, Al and
41-48
Co
were commonly used to improve the catalytic
abilities of montmorillonites. These methods require a
large excess of sodium azide, longer reaction time, and
expensive metals. Moreover, the cycloaddition is too slow
*e-mail: akhlaghinia@um.ac.ir

2198
A Novel Approach for the Synthesis of 5-Substituted-1H-tetrazoles
J. Braz. Chem. Soc.
to be synthetically useful except when strong electron-
withdrawing groups activate the nitrile compounds.
Today’s stringent environmental and legislative
concerns demand for the green methods that reduce the
use of toxic and corrosive reagents and stop the formation
of inorganic wastes.49 However, it has been also observed
that the catalysts employed are not always eco-friendly
and because of this, serious environmental pollution often
results. Therefore, in the area of green synthesis, the
development of environmentally friendly alternatives is
desirable for the synthesis of tetrazoles.50
Recently, we have studied the application of cupric
sulfate pentahydrate in the trimethylsilylation of alcohols
and phenols,51 and perceived that cupric sulfate pentahydrate
as a mild Lewis acid, which is readily available, might be
a useful catalyst for the synthesis of 5-substituted-1H-
tetrazoles. In this paper we report a new process for the
synthesis of 5-substituted 1-H-tetrazoles using cupric
sulfate pentahydrate as a safe, environmentally benign,
and inexpensive catalyst.
was separated, washed with 2×10 mL distilled water,
dried over anhydrous sodium sulfate, and concentrated to
give the crude solid 5-phenyl-1H-tetrazole (1). The crude
product was recrystallized from n-hexane:ethylacetate
(1:1) obtaining 0.1430 g of colourless crystals (98% yield).
The other products( 2-17) were also, recrystallized from
n-hexane:ethyl acetate (1:1) .
Characterization data for representative compounds
5-Phenyl-1H-tetrazole (1)
mp 214-216 ºC (Lit. 214-216 ºC);52 FT-IR (KBr)
ν
max/cm-1: 3125, 3043, 2982, 2913, 2835, 2765, 2692, 2606,
2557, 2488, 1613, 1563, 1485, 1465, 1409, 1163, 1056,
726, 703, 687; 1H NMR (400 MHz, DMSO-d6) d 7.61 (s,
3H, Ph), 8.05 (s, 2H, Ph); 13C NMR (100 MHz, DMSO-d6)
d 124.6, 127.4, 129.9, 131.7, 155.7; CHN (C7H6N4)
calc. (%): C (57.5), H (4.1), N (38.3); found (%): C (56.4),
H (4.1), N (37.6).
5-(4-Bromophenyl)-1H-tetrazole (2)
Experimental
mp 264-265 ºC (Lit. 265 ºC);53 FT-IR (KBr)
max/cm-1: 3089, 3063, 2996, 2900, 2844, 2761, 2729, 2633,
ν
The products were purified by column chromatography.
The purity determinations of the products were
accomplished by TLC on silica gel polygram STL G/UV
254 plates. The melting points of products were determined
with an Electrothermal Type 9100 melting point apparatus.
The FT-IR spectra were recorded on an Avatar 370
FT-IR Thermo Nicolet spectrometer. The NMR spectra
were provided on a Bruker Avance 100 and 400 MHz
instrument.All of the products were known compounds and
characterized by the IR, 1H NMR and 13C NMR spectra and
comparison of their melting points with known compounds.
Elemental analyses were performed using a Elementar,Vario
EL III and Thermofinnigan Flash EA 1112 Series instrument.
Mass spectra were recorded with Agilent Technologies
(HP) 5973 Network Mass Selective Detector and Shimadzu
GC-MS-QP5050 instruments at 70 eV.
1652, 1604, 1560, 1482, 1431, 1405, 1157, 1076, 1054,
1018, 829, 744, 502; H NMR (100 MHz, DMSO-d6) d
1
7.80 (d, 2H, J 9.5 Hz, Ph), 7.95 (d, 2H, J 9.5 Hz, Ph);
CHN (C7H5BrN4) calc. (%): C (37.3), H (2.2), N (24.9);
found (%): C (37.2), H (2.1), N (24.6); MS (EI): m/z (%)
226 [M++2], 224 [M+], 198 [(M++2)-N2], 196 (100) [M+-
N2], 185 [(M++2)-N3], 183 [M+-N3].
5-(4-Chlorophenyl)-1H-tetrazole (3)
mp 261-262 ºC (Lit. 261-263 ºC);48 FT-IR (KBr)
ν
max/cm-1: 3092, 3060, 3007, 2978, 2907, 2851, 2725, 2622,
2537, 2471, 1609, 1564, 1486, 1435, 1160, 1096, 1053,
1020, 990, 833, 745, 508;1H NMR (400 MHz, DMSO-d6)
d 7.68 (d, 2H, J 8.4 Hz, Ph), 8.05 (d, 2H, J 8.8 Hz, Ph).
13C NMR (100 MHz, DMSO-d6) d 123.5, 129.2, 130.0,
136.4, 155.3; CHN (C7H5ClN4) calc. (%): C (46.6), H (2.7),
N (31.0); found (%): C (46.5), H (2.7), N (31.0).
Typical procedure for the preparation of 5-phenyl-1H-
tetrazole (1)
4-(1H-Tetrazol-5-yl)benzonitrile (4)
mp 190-191 ºC (Lit. 192 ºC);54 FT-IR (KBr) νmax/cm-1:
3150, 3092, 3013, 2928, 2861, 2758, 2610, 2231, 1585,
1560, 1494, 1433, 1279, 1153, 1014, 976, 944, 850, 749,
554; 1H NMR (100 MHz, CD3CN) d 7.90 (d, 2H, J 7.5 Hz,
Ph), 8.20 (d, 2H, J 7.5 Hz, Ph).
Sodium azide (0.0650 g, 1 mmol) and cupric sulfate
pentahydrate (0.0050 g, 2 mol%) were added to a solution
of benzonitrile (0.1031 g, 1 mmol) in DMSO (2 mL) with
stirring at room temperature. The reaction temperature was
raised up to 140 °C for 1 h. The progress of the reaction
was monitored by TLC. After completion, the reaction
mixture was cooled and treated with 10 mL HCl (4 mol L-1)
and then with 10 mL EtOAc. The resultant organic layer
5-(4-Nitrophenyl)-1H-tetrazole (5)
mp 218-219 ºC (Lit. 219-220 ºC);55 FT-IR (KBr)
ν
max/cm-1: 3448, 3334, 3235, 3109, 3080, 2974, 2900, 2819,

Vol. 23, No. 12, 2012
Akhlaghinia and Rezazadeh
2199
2659, 1562, 1532, 1488, 1357, 1340, 1315, 1143, 1106,
995, 867, 853, 730, 710; 1H NMR (400 MHz, DMSO-d6)
d 8.31 (d, 2H, J 8.4 Hz, Ph), 8.46 (d, 2H, J 8.8 Hz, Ph);
13C NMR (100 MHz, DMSO-d6) d 125.1, 128.6, 131.0,
149.2, 155.9.
5-(Phenanthren-9-yl)-1H-tetrazole (11)
mp 241-242 ºC (Lit. 243-244 ºC);58 FT-IR (KBr)
max/cm-1: 3105, 3076, 3016, 2978, 2878, 2830, 2724, 2686,
ν
2622, 2590, 2520, 2478, 1612, 1565, 1450, 1399, 1246,
1112, 1053, 1038, 992, 934, 771, 737, 721, 424; 1H NMR
(100 MHz, DMSO-d6) d 7.79-7.82 (m, 4H, Ph), 8.08-8.20
(m, 1H, Ph), 8.40-8.52 (m, 2H, Ph), 8.92-9.10 (m, 2H, Ph);
CHN (C15H10N4) calc. (%): C (73.1), H (4.0), N (22.7);
found (%): C (73.1), H (3.9), N (22.3); MS (EI): m/z (%)
246 [M+], 218 (100) [M+-N2], 190 [M++2N2].
4-Nitro-2-(1H-tetrazol-5-yl)benzenamine (6)
mp 268-270 ºC (Lit. 270-271 ºC);56 FT-IR (KBr)
ν
max/cm-1: 3411, 3321, 3199, 3084, 2937, 1645, 1616, 1572,
1477, 1325, 1278, 1141, 1041, 910, 831, 751, 722; 1H NMR
(400 MHz, DMSO-d6) d 7.00 (d, 1H, J 9.2 Hz, Ph), 7.94
(br s, NH), 8.10 (dd, 1H, J 9.2, J 2.4 Hz, Ph), 8.81 (d, 1H,
5-(Thiophen-2-yl)-1H-tetrazole (12)
13
J 2.4 Hz, Ph). C NMR (100 MHz, DMSO-d6) d 104.4,
mp 205-207 ºC (Lit. 205-207 ºC);59 FT-IR (KBr)
116.3, 126.1, 127.6, 136.3, 153.0, 154.4; CHN (C7H6N6O2)
calc. (%): C (40.7), H (2.9), N (40.7); found (%): C (39.7),
H (3.3), N (38.1).
ν
max/cm-1: 3109, 3074, 2974, 2891, 2780, 2722, 2628, 2569,
2500, 2456, 1830, 1595, 1503, 1411, 1233, 1139, 1046,
962, 853, 740, 719; 1H NMR (100 MHz, CD3CN) d 7.20-
7.30 (m, 1H, tiophen), 7.67-7.80 (m, 2H, tiophen); CHN
(C5H4N4S) calc.(%): C (39.4), H (2.6), N (36.8), S (21.1);
found (%): C (39.1), H (2.6), N (37.0), S (21.4); MS (EI)
m/z (%) 152 [M+], 124 (100) [M+-N2], 97 [M+-2N2].
5-(4-Ethoxyphenyl)-1H-tetrazole (7)
mp 234-235 ºC; FT-IR (KBr) νmax/cm-1: 3145, 3101,
3060, 2986, 2921, 2868, 2737, 2647, 1613, 1505, 1470,
1394, 1293, 1262, 1189, 1056, 1041, 923, 827, 751, 653,
522; 1H NMR (100 MHz, acetone-d6) d 1.40 (t, 3H, J 5 Hz,
–OEt), 4.20 (q, 2H, –OEt), 7.15 (d, 2H, J 9.5 Hz, Ph), 8.07
(d, 2H, J 9.5 Hz, Ph); CHN (C9H10N4O) calc. (%): C (56.8),
H (5.2), N (29.5); found (%): C (57.0), H (4.9), N (30.3).
4-(1H-Tetrazol-5-yl)pyridine (13)
mp 255-258 ºC (Lit. 255-258 ºC);52 FT-IR (KBr)
ν
max/cm-1: 3485, 3264, 3099, 3035, 2966, 1624, 1529, 1435,
1388, 1123, 1096, 1042, 1022, 845, 730, 674, 593, 465.
5-(3,5-Dimethoxyphenyl)-1H-tetrazole (8)
2-(1H-Tetrazol-5-yl)pyridine (14)
mp 204-205 ºC (Lit. 204-206 ºC);57 FT-IR (KBr)
mp 211-213 ºC (Lit. 210-213 ºC);48 FT-IR (KBr)
ν
max/cm-1: 3129, 3064, 3011, 2975, 2941, 2843, 2757, 2712,
ν
max/cm-1: 3088, 3060, 2959, 2929, 2864, 2737, 2692, 2622,
2634, 1605, 1562, 1480, 1430, 1287, 1208, 1162, 1167,
1054, 827, 747; 1H NMR (400 MHz, DMSO-d6) d 3.84 (s,
6H, –OMe), 6.73 (t, 1H, J 2 Hz, Ph), 7.21 (d, 2H, J 2 Hz,
Ph), 16.91(br s, NH); 13C NMR (100 MHz, DMSO-d6) d
56.0, 103.4, 105.3, 125.7, 156.3, 161.5; MS (EI): m/z (%)
207 [M+H], 149 (100) [M+-2N2].
2582, 1728, 1602, 1557, 1483, 1449, 1405, 1284, 1158, 1068,
1024, 955, 795, 743, 726, 703, 637, 496; 1H NMR (400 MHz,
DMSO-d6) d 7.65 (s, 1H, Py), 8.10 (s, 1H, Py), 8.24 (d,
1H, J 6.4 Hz, Py), 8.81 (s, 1H, Py); 13C NMR (100 MHz,
DMSO-d6) d 123.1, 126.7, 138.7, 144.0, 150.6, 155.3.
5-Isobutyl-1H-tetrazole (15)
5-m-Tolyl-1H-tetrazole (9)
mp 52-54 ºC (Lit. 53.5-54 ºC);60 FT-IR (KBr) νmax/cm-1:
3089, 3063, 2971, 2901, 2845, 2765, 2729, 2633, 1605,
1482, 1454, 1430, 1156, 1075, 1053, 1017, 990, 829, 772,
743, 502.
mp 149.5-150 ºC (Lit. 151-152 ºC);27 FT-IR (KBr)
ν
max/cm-1: 3120, 3061, 2979, 2917, 2871, 2746, 2611, 2490,
1728, 1605, 1565, 1486, 1463, 1150, 1060, 1038, 802, 741,
705, 687; 1H NMR (100 MHz, CD3CN) d 2.43 (s, 3H, CH3),
7.40-7.90 (m, 4H, Ph); CHN (C8H8N4): calc. (%) C (59.9),
H (5.0), N (34.9); found (%): C (60.0), H (5.0), N (34.7).
5-Isopentyl-1H-tetrazole (16)
mp 94 ºC (Lit. 95-96 ºC);60 FT-IR (KBr) νmax/cm-1: 2962,
2931, 2874, 2709, 2618, 2482, 1867, 1583, 1553, 1469,
1404, 1110, 1048, 772; 1H NMR (100 MHz, CDCl3) d 1.00
(d, 6H, J 5 Hz, 2 CH3), 1.40-2.05 (m, 3H, -CH-, -CH2-),
3.10 (t, 2H, J 6 Hz, -CH2-).
4-(1H-Tetrazol-5-yl)phenol (10)
mp 233-234 ºC ( Lit. 234-235 ºC);55 FT-IR (KBr)
ν
max/cm-1: 3252, 3101, 3066, 3019, 3000-2200, 1615,
1
1599, 1511, 1466, 1413, 1282, 832, 752, 514; H NMR
(400 MHz, DMSO-d6) d 6.97 (d, 2H, J 8.4 Hz, Ph), 7.87 (d,
2H, J 8.8 Hz, Ph), 10.20 (br s, OH); 13C NMR (100 MHz,
DMSO-d6) d 115.0, 116.6, 129.2, 155.2, 160.5.
5-Benzyl-1H-tetrazole (17)
mp 117-119 ºC (Lit. 118-120 ºC);61 FT-IR (KBr)
ν
max/cm-1: 3109, 3031, 2984, 2945, 2863, 2778, 2704,

2200
A Novel Approach for the Synthesis of 5-Substituted-1H-tetrazoles
J. Braz. Chem. Soc.
2594, 1768, 1707, 1638, 1549, 1533, 1494, 1457, 1241,
1108, 1074, 772, 734, 695; 1H NMR (100 MHz, CD3CN)
d 4.30 (s, 2H, -CH2-), 7.31 (s, 5H, Ph); CHN (C8H8N4)
calc. (%): C (60.0), H (5.0), N (34.9); found (%): C (60.6),
H (4.9), N (34.6).
solvents were tested for the preparation of 5-phenyl-1H-
tetrazole(1) from the reaction of benzonitrile with sodium
•
azide in the presence of 2 mol% of CuSO4 5H2O (Table 1,
entries 5-9). No product was obtained when the reaction
was performed in nitromethane, chlorobenzene and anisol
(Table 1, entries 5-7). Other solvents, such as water gave
the desired product in low yield but NMP gave slightly
higher yield (Table 1, entries 8-9). In solvent free condition,
5-phenyl1H-tetrazole was produced in 50% yield after
long period of time (Table 1, entry 10). As shown in Table
1 among the different solvents tested DMSO was found to
be the solvent of choice because of its high dipole moment.
The excellent yield was obtained in DMSO at 140 °C by
Results and Discussion
In a typical experiment, reaction of benzonitrile with
•
sodium azide in the presence of CuSO4 5H2O was first
studied under various reaction parameters. The general
reaction is outlined in Scheme 1 and the results are
summarized in Table 1.
•
•
Generally, with the catalysis of CuSO4 5H2O in DMF
applying 2 mol% of CuSO4 5H2O and 1:1 molar ratio of
(Table 1, entries 2-4), the reaction gave good to excellent
yields, whereas in the absence of catalyst 5-phenyl-1H-
tetrazole (1) was obtained in 40% yield (Table 1, entry 1). On
benzonitrile:sodium azide (Table 1, entry 13).
To understand the scope and the generality of
•
CuSO4 5H2O promoted (3 + 2) cycloaddition reaction, a
•
the basis of data in Table 1, the best amount of CuSO4 5H2O
variety of structurally divergent benzonitriles possessing a
wide range of functional groups was chosen and the results
are presented in Table 2.
as catalyst is 2 mol% (Table 1, entries 2-4 and entry 12).
In an effort to develop better reaction conditions, different
Scheme 1. Synthesis of 5-phenyl1H-tetrazole (1).
•
Table 1. Synthesis of 5-phenyl-1H-tetrazole (1) in the presence of different mol % of CuSO4 5H2O in various solvents, different molar ratios of
benzonitrile:NaN3 and different temperatures
molar ratio
(benzonitrile: NaN3)
entry
solvent
catalyst
none
time / h
Temp. / ºC
conversion / %
1
DMF
DMF
1/1.5
1/1.5
1/1.5
1/1.5
1/1.5
1/1.5
1/1.5
1/1.5
1/1.5
1/1.5
1/1.5
1/1.5
1/1
17
15
2
120
120
40
100
95
95
0
•
2
CuSO4 5H2O (2 mol%)
•
3
DMF
CuSO4 5H2O (5 mol%)
120
•
4
DMF
CuSO4 5H2O (7 mol%)
2
120
•
5
MeNO2
PhCl
CuSO4 5H2O (2 mol%)
24
24
24
24
6
reflux
120
•
6
CuSO4 5H2O (2 mol%)
0
•
7
PhOMe
H2O
CuSO4 5H2O (2 mol%)
120
0
•
8
CuSO4 5H2O (2 mol%)
reflux
120
45
100
50
100
100
100
•
9
NMP
CuSO4 5H2O (2 mol%)
•
10
11
12
13
none
CuSO4 5H2O (2 mol%)
20
3
120
•
DMSO
DMSO
DMSO
CuSO4 5H2O (2 mol%)
120
•
CuSO4 5H2O (2 mol%)
1
140
•
CuSO4 5H2O (2 mol%)
1
140

Vol. 23, No. 12, 2012
Akhlaghinia and Rezazadeh
2201
Table 2. Synthesis of different structurally tetrazoles (1-17) in the presence of CuSO4.5H2O in DMSO
entry
substrate
product
yield / % time / h
entry
1
substrate
product
yield / % time / h
98
1
9
95
85
5
5
2
3
4
5
100
100
100
100
1
10
11
0.5
0.5
0.5
80
4
12
13
100
100
2
1
6
7
> 90
85
2
2
14
85
2
15a
16a
90
90
4
3
8
> 95
5
17
80
3
aReaction temperature: 120 °C.
Among the various nitriles tested, the aromatic nitriles
with electron withdrawing substituent gave excellent yields
in a very short time (Table 2, entries 2-5). Several nitriles
containing electron-donating groups, were successfully
converted into their corresponding tetrazoles with a
prolonged reaction time (Table 2, entries 6-10). Likewise,
aliphatic nitriles react similarly and provide good yields
of the corresponding tetrazoles (Table 2, entries 15-17).
Heteroaromatic nitriles such as thiophene-2-carbonitrile,
4-pyridinecarbonitrile and 2-pyridinecarbonitrile gave the
corresponding tetrazoles in shorter reaction times with
excellent yields (Table 2, entries 12-14). It is noteworthy
that 1,4-dicyanobenzene only gave mono adduct even by
using 1:2 molar ratio of 1,4-dicyanobenzene:sodium azide
and 4 mol% of catalyst (Table 2, entry 4).
The activity of nitrile compound towards azide ion
plays an important role in this cycloaddition reaction. In
comparison the cycloaddition reaction of aromatic nitriles
with electron withdrawing substituents such as –Cl, −
Br, −CN, −NO2 and heteroaromatic nitriles compound
such as thiophene-2-carbonitrile, 4-pyridinecarbonitrile
and 2-pyridinecarbonitrile is faster than the reaction
of aromatic nitrile compound with electron donating
substituent such as −NH2 ,−OCH3, ,−OCH2CH3 and –OH.
From Table 2, it is clear that, excellent to good results were
obtained with alkyl, aryl and heteroaryl nitriles, despite
the different activities of the nitrile derivatives. It seems
likely that the high polarity of solvent and efficient catalytic
•
activity of CuSO4 5H2O have leveled off the activity of
nitrile group.

2202
A Novel Approach for the Synthesis of 5-Substituted-1H-tetrazoles
J. Braz. Chem. Soc.
Scheme 2. A plausible mechanism for the formation of tetrazoles.
The structures of all synthesized compounds were
confirmed by spectral and analytical data. The IR spectra
of all products show absorption bands at 1293-1233 due
to (N-N=N-), 1041-1106 and 1189-1110 due to (tetrazole
ring). A 13C NMR signal at 161-154 ppm is assigned to the
quaternary carbon of NH-C=N.
A plausible mechanism is shown in Scheme 2. Initially,
coordination of nitrogen atoms of nitrile compounds with
CuII forms complex I which accelerates the cyclization
step. This idea is supported by performing the reaction
Supplementary Information
Supplementary information (spectra of synthesized
compounds)isavailablefreeofchargeathttp://jbcs.sbq.org.br
as PDF file.
Acknowledgments
The authors gratefully acknowledge the partial support
of this study by Ferdowsi University of Mashhad Research
Council.
•
in the absence of CuSO4 5H2O.Without any catalyst,
cycloaddition reaction is not completed even after long
period of time (Table1, entry 1). The [3+2] cycloaddition
between the C≡ N bond of nitrile compound and azide ion
takes place readily to form the intermediate II. Acidic
work-up, affords III and IV. The equilibrium leads to
formation of the more stable tautomer IV (5-substituted
1H-tetrazole).
References
1. Okabayashi, T.; Kano, H.; Makisumi, Y.; Chem. Pharm. Bull.
1960, 8, 157.
2. Sangal, S. K.; Ashok Kumar, A.; J. Indian Chem. Soc. 1986,
63, 351.
3. Witkowski, J. K.; Robins, R. K.; Sidwell, R.W.; Simon, L. N.;
J. Med. Chem. 1972, 15, 1150.
Conclusions
4. Tsov, K. C.; Su, H. C. F.; J. Med. Chem. 1963, 6, 693.
5. Bary, V. C.; Conalty, M. C.; O’Sllivan, J. P.; Twomey, D.;
Chemotherapy 1977, 8, 103.
We have reported an efficient synthetic method
for 5-substituted-1H-tetrazoles by a successive [3+2]
cycloaddition of various nitriles with sodium azide in the
6. Maxwell, J. R.; Wasdahl, D. A.; Wolfson, A. C.; Stenberg,V. I.;
J. Med. Chem. 1984, 27, 1565.
•
presence of catalytic amount of CuSO4 5H2O. This method
is applicable to a range of nitriles including aliphatic,
aromatic, and heterocyclic nitriles. It has also been shown
that, the yields are high and reaction completion time is
within 0.5-5 h. The catalyst used is readily available and
is environmentally friendly. Short reaction time, good to
excellent yields, safe process and simple workup make this
method an attractive and useful contribution to the present
organic synthesis for the preparation of 5-substituted
1H-tetrazoles.
7. Stewart, K. D.; Bioorg. Med. Chem. Lett. 1998, 529.
8. Shukla, J. S.;Ahmed, J.; Saxena, S.; J. Indian Chem. Soc. 1979,
41, 70.
9. Shishoo, C. J.; Devani, M. B.; Karvekar, M. D.; Vilas,G. V.;
Anantham, S.; Bhaati, V. S.; Indian J. Chem., Sect B 1982, 21,
666.
10. Ray, S. M.; Lahiri, S. C.; J. Indian Chem. Soc.1990, 67, 324.
11. Hayao, S.; Havera, H. J.; Strycker, W. G.; Leipzig, T. J.;
Rodriguez, R.; J. Med. Chem. 1965, 10, 400.

Vol. 23, No. 12, 2012
Akhlaghinia and Rezazadeh
2203
12. Fig dor, S. K.; Von Wittenau, M. S.; J. Med. Chem. 1967, 10,
1158.
37. Venkateshwarlu, G.; Premalatha,A.; Rajanna, K. C.; Saiprakash,
P. K.; Synth. Commun. 2009, 39, 4479.
13. Singh, H.; Chala,A. S.; Kapoor,V. K.; Paul, D.; Malhotra, R. K.;
Prog. Med. Chem. 1980, 17, 151.
38. Qi, G.; Dai, Y.; Chin. Chem. Lett. 2010, 21, 1029.
39. Lang, L.; Li, B.; Liu, W.; Jiang, L.; Xu, Z.; Yin, G.; Chem.
Commun. 2010, 46, 448.
14. Ostrovskii, V. A.; Pevzner, M. S.; Kofmna, T. P.; Shcherbinin,
M. B.; Tselinskii, I.V.; Targets Heterocyclic Syst. 1999, 3, 467.
15. Hiskey,M.;Chavez,D.E.;Naud,D.L.;Son,S.F.;Berghout,H.L.;
Bome, C.A.; Proceedings of the International Pyrotechnics
Seminars, 27th seminar, Grand Junction, CO, USA, 2000, p. 3.
16. Koldobskii, G. I.; Ostrovskii, V. A.; Usp. Khim. 1994, 63, 847.
17. Huisgen, R.; Sauer, J.; Sturn, H. J.; Markgraf, J. H.; Chem. Ber.
1960, 93, 2106.
40. Nasrollahzadeh, M.; Habibi, D.; Shahkarami, Z.; Bayat, Y.;
Tetrahedron 2009, 65, 10715.
41 Ben Achma, R.; Ghorbel, A.; Dafinov, A.; Medina, F.; Appl.
Catal., A 2009, 349, 20.
42. Varma, R. S.; Tetrahedron 2002, 58, 1235.
43. Shinde, A. B.; Shrigadi, N. B.; Samant, S. D.; Appl. Catal., A
2004, 276, 5.
18. Moderhack, D.; J. Prakt. Chem. 1988, 340, 687.
19. Hantzsch, A.; Vagt, A.; Justus Liebigs Ann.Chem. 1901, 314,
339.
44. Clark, P. D.; Mesher, S. T. E.; Primak, A.;Yao, H.; Catal. Lett.
1997, 43, 79.
45. Yin, W.; Shi, M.; Tetrahedron 2005, 61, 10861.
46. Gue’lou, E.; Barrault, J.; Fournier, J.; Tatibouet, J. M.; Appl.
Catal., B 2003, 44, 1.
20. Curran, D. P.; Hadida, S.; Kim, S.-Y.; Tetrahedron 1999, 55,
8997.
21. Kumar, A.; Narayanan, R.; Shechter, H.; J. Org. Chem. 1996,
61, 4462.
47. Caudo, S.; Centi, G.; Genovese, C.; Perathoner, S.;Appl. Catal., B
2007, 70, 437.
22. Koguro, K.; Oga, T.; Mitsui, S.; Orita, R.; Synthesis 1998, 910.
23. Demko, P. Z.; Sharpless, K. B.; J. Org. Chem. 2001, 66, 7945.
24. Himo, F.; Demko, P. Z.; Noodleman, L.; Sharpless, K. B.;
J. Am. Chem. Soc 2002, 124, 12210.
48. Rama,V.; Kanagaraj, K.; Pitchumani, K.; J. Org. Chem. 2011,
76, 9090.
49. Sheldon, R. A.; J. Chem. Technol. Biotechnol. 1997, 68, 381.
50. Nandre,K.P.;Salunke,J.K.;Nandre,J.P.;Patil,A.U.;Borse,V.S.;
Bhosale, S. V.; Chin. Chem. Lett. 2012, 23, 161.
51. Akhlaghinia, B.; Tavakoli, S.; Synthesis 2005, 1775.
52. Aureggi, V.; Sedelmeier, G.; Angew. Chem., Int. Ed. 2007, 46,
8440.
25. Bonnamour, J.; Bolm, C.; Chem. Eur. J. 2009, 15, 4543.
26. Amantini, D.; Beleggia, R.; Fringuelli, F.; Pizzo, F.;Vaccoro, L.;
J. Org. Chem. 2004, 69, 2896.
27. Yizhong, Z.;Yiming, R.; Chun, C.; Helv. Chim. Acta 2009, 92,
171.
53. Lossen,S.; Ann. Chem. 1897, 298, 102.
54. Köennecke, A.; Döme, R.; Kleinpeter, E.; Lippmann, E.;
Tetrahedron 1997, 35, 1957.
28. Su, W. K.; Hong, Z.; Shan, W. G.; Zhang, X. X.; Eur. J. Org.
Chem. 2006, 2723.
29. Hajra, S.; Sinha, D.; Bhowmick, M.; J. Org. Chem. 2007, 72,
1852.
55. Tienan, J.; Fukuzou, K.; Shin, K.; Yoshinori, Y.; Tetrahedron
Lett. 2008, 49, 2824.
30. Matthews, D. P.; Green, J. E.; Shuker, A. J.; J. Comb. Chem.
2000, 2, 19.
56. Ek, F.; Wistrand, L.-G.; Frejd, T.; J. Org. Chem. 2003, 68, 1911.
57. Sreedhar, B.; Kumar, A. S.; Yada, D.; Tetrahedron Lett. 2011,
52, 3565.
31. Gyoung, Y. S.; Shim, J.-G.; Yamamoto, Y.; Tetrahedron Lett.
2000, 41, 4193.
58. Satzinger, G.; Justus Liebigs Ann. Chem. 1960, 638, 159.
59. Najafi Chermahini, A.; Teimouri, A.; Moaddeli, A.; Heteroat.
Chem. 2011, 22, 168.
32. Kantam, M. L.; Shiva Kumar, K. B.; Raja, K. P.; J. Mol. Catal. A:
Chem. 2006, 247, 186.
33. Kantam, M. L.; Balasubrahmanyam, V.; Shiva Kumar, K. B.;
Synth. Commun. 2006, 36, 1809.
60. Herbst, M.; J. Org. Chem. 1950, 15, 1082.
61. Katritzky, A. R.; El-Gendy, B. E. M.; Draghici, B.; Hall, C. D.;
Steel, P. J.; J. Org. Chem. 2010, 75, 6468.
34. Jin, T.; Kitahara, F.; Kamijo, S.; Yamamoto, Y.; Tetrahedron
Lett. 2008, 49, 2824.
35. Jin, T.; Kitahara, F.; Kamijo, S.;Yamamoto,Y.; Chem. Asian J.
2008, 3, 1575.
Submitted: August 30, 2012
Published online: January 9, 2013
36. Nasrollahzadeh, M.; Bayat, Y.; Habibi, D.; Moshaee, S.;
Tetrahedron Lett. 2009, 50, 4435.