Microwave-assisted synthesis of tetrazolyl pyrazole amides

Article abstract of DOI:10.3184/174751911X13149561530439

A rapid and efficient microwave-assisted synthesis N-(1H-tetrazol-5-yl) derivatives of 3-methyl-1-phenyl-1H-pyrazole- 5-carboxamide is described. These tetrazole pyrazole amides have interesting bacteriocidal, pesticidal, herbicidal and antimicrobial activities. They were identified by IR and ¹H NMR elemental analyses. The target compounds were obtained in a shorter reaction time compared to conventional heating methods.

Full text of DOI:10.3184/174751911X13149561530439

JOURNAL OF CHEMICAL RESEARCH 2011
RESEARCH PAPER 525
SEPTEMBER, 525–527
Microwave-assisted synthesis of tetrazolyl pyrazole amides
Jun Hua, Jikui Wangb, Taoyu Zhoua and Yanhua Xua*
aCollege of Environment, Nanjing University ofTechnology/ Jiangsu Key Laboratory of Industrial water-Conservation & Emission Reduction,
Nanjing 210009, P. R. China
bCollege of Sciences, Nanjing University ofTechnology, Nanjing 210009, P. R. China
A rapid and efficient microwave-assisted synthesis N-(1H-tetrazol-5-yl) derivatives of 3-methyl-1-phenyl-1H-pyrazole-
5-carboxamide is described. These tetrazole pyrazole amides have interesting bacteriocidal, pesticidal, herbicidal
and antimicrobial activities. They were identified by IR and 1H NMR elemental analyses. The target compounds were
obtained in a shorter reaction time compared to conventional heating methods.
Keywords: tetrazole, pyrazole, microwave-assisted synthesis
Recently, there has been considerable study of N-heterocyclic
compounds in the context of their bacteriocidal and other bio-
logical activities.1–3 Among various N-heterocyclic scaffolds,
tetrazole and pyrazole rings have attracted attention for their
promising bioactive potency. The tetrazole ring is of impor-
tance as a pharmacophore due to its well known biological
activities including bacteriocidal, pesticidal, herbicidal and
other activities.4–7 Studies of the synthesis and activity of
tetrazole derivatives have attracted interest in recent years.
Compounds containing the pyrazole nucleus have pronounced
biological properties such as antipyretic, analgesic, insecti-
cidal, herbicidal and antimicrobial activities.8–12
Compared with the traditional heating reactions, the micro-
wave (MW) reaction technique has rapid, convenient, environ-
mental and economic advantages.13–15 MW irradiation is
currently used to carry out a wide range of reactions.16–18
According to the principles of hybridisation, a series of
novel derivatives with tetrazole and pyrazole rings were
designed and synthesised under microwave irradiation.
short reaction time and a high yield made this procedure a
useful and attractive alternative to the currently available
methods.
Experimental
Melting points were recorded on an X-4 binocular microscope
melting point apparatus. 1H NMR spectra were recorded on an Avance
Bruker-500 instrument and chemical shifts in ppm are reported with
TMS as the internal standard. IR spectra in KBr were recorded by a
Perkin-Elmer PE-683 infrared spectrometer. Elemental analyses were
performed on an Elementer Vario EL III elementary analysis instru-
ment. MW experiments were carried out on a WF-4000M microwave
fast reaction system (Shanghai Qiyao Analysis Instrument Co.,
Shanghai, China).
Preparation of 2a–f; general procedure
A mixture of 10 mmol of ethyl acetopyruvate (1) and 5 mL of ethanol
was added dropwise with stirring, at 0 °C, to a suspension consisting
of 10 mmol of the substituted phenylhydrazine and 15 mL of ethanol,
over a period of one hour, and then the catalytic amount of acetic acid
was added. After stirring had been continued for a further 4 hours at
room temperature, the reaction mixture was evaporated under reduced
pressure, then the compounds 2a–f were obtained which were used
immediately.
Ethyl 1-(4-methoxyphenyl)-3-methyl-1H-pyrazole-5-carboxylate
(2c):Yield 83%; m.p. 211–212 °C; 1H NMR(DMSO-d6, 300 MHz) δ:
1.15(t, 3H, CH2CH3), 2.25(s, 3H, CH3), 3.37(s, 3H, OCH3), 4.15(m,
2H, –CH2–), 6.84(s, 1H, pyrazole C–H), 6.98–7.32(m, 4H, ArH); IR
(KBr) υ: 3135, 2840, 1731, 1518, 1370, 1251cm−1. Anal. Calcd for
C14H16N2O3: C, 64.60; H, 6.20; N, 10.76. Found: C, 64.36; H, 6.46; N,
10.33%.
Results and discussion
Substituted 3-methyl-1-phenyl-N-(1H-tetrazol-5-yl)-1H-pyr-
azole-5- carboxamide (6a–f) were prepared by the reaction of
various 3-methyl-1-phenyl-1H-pyrazole-5-carbonyl chlorides
(4a–f) and 1H-tetrazol-5-amine (5) under microwave irradia-
tion as shown in Scheme 1. The compound 5 was prepared by
the reaction of dicyandiamide with sodium azide. The reactive
acid chlorides 4a–f were synthesised from the corresponding
pyrazole-5-carboxylic acids (3a–f) with oxalyl chloride. The
acids 3a–f were obtained by hydrolysing 3-methyl-1-substi-
tuted phenyl-1H-pyrazole-5-carboxylic ester (2a–f) which
were synthesised by the condensation of ethyl acetopyruvate
(1) with substituted phenyl hydrazines. Compound 1 was
prepared by the reaction of diethyl oxalate with acetone in
presence of sodium ethylate.
Preparation of 3a–f; general procedure
A mixture of 2a–f (10 mmol), and NaOH (5 g) in water was stirred
and the temperature raised to reflux. After stirring had been continued
for a further 2 hours, the pH of the reaction solution was adjusted
to the range of 2–3 with concentrated hydrochloric acid. The crude
product was precipitated, filtered, washed with water, dried and
recrystallised from ethanol to afford compounds 3a–f.
Preliminary experiments to define the reaction time and
irradiation power were performed using 4a (10 mmol) and 5
(10 mmol) as a model system to synthesise compound 6a
(Table 1). Various reaction times and irradiation power were
tested (Table 1, entries 1–7). The optimum yield of 6a (85%)
was obtained by carrying out the reaction under MW irradia-
tion (400 W) for 20 min at 110 °C. The reaction was also car-
ried out with conventional heating (Table 1, entry 8), which
required more heating time (5 h) but gave a lesser yield (62%).
The preparative reactions were carried out under these optimal
microwave conditions to give 6a–f in yields of 78–90%.
In conclusion, we have developed a fast, convenient, and
efficient preparation of 3-methyl-1-substituted phenyl-N-(1H-
tetrazol-5-yl)-1H-pyrazole-5- carboxamides under MW irra-
diation. The simplification of the reaction procedure with very
1-(4-methoxyphenyl)-3-methyl-1H-pyrazole-5-carboxylic acid (3c):
Yield 89%; m.p. 234–235 °C; H NMR(DMSO-d6, 300 MHz) δ:
2.22(s, 3H, CH3), 3.79(s, 3H, OCH3), 6.84(s, 1H, pyrazole C–H),
6.98–7.32(m, 4H, ArH), 13.03(s, 1H, COOH); IR (KBr) υ: 3141,
2837, 1701, 1517, 1338cm−1. Anal. Calcd for C12H12N2O3: C, 62.06;
H, 5.21; N, 12.06. Found: C, 62.23; H, 5.12; N, 12.33%.
1
Preparation of 4a–f; general procedure
Oxalyl chloride (20 mmol) was added dropwise with stirring, at
room temperature, to a suspension consisting of 10 mmol of 3a–f and
20 mL of dry toluene. After the reaction was completed, the reaction
mixture was distilled under reduced pressure to remove the solvent
and residual oxalyl chloride to afford compound 4a–f which were
used immediately.
Preparation of 5; general procedure
A suspension of dicyandiamide(10 mmol) and sodium azide (15
mmol) in 15 mL water was stirred and allowed to rise in temperature
at 65 °C on the water-bath. After stirring had been continued for a
* Correspondent. E-mail: yhxu2008@163.com

526 JOURNAL OF CHEMICAL RESEARCH 2011
Scheme 1 The synthetic route of compounds 6a–f.
Table 1 Synthesis of compound 6a
MHz) δ: 2.27(s, 3H, CH3), 6.83(s, 1H, pyrazole C–H), 7.38–7.41(m,
5H, ArH), 9.39–9.41(t, 1H, –NH–CO–), 14.26(s, 1H, tetrazole N–H);
IR(KBr) υ: 3131, 2976, 1701, 1658, 1314cm−1. Anal. Calcd for
C12H11N7O: C, 53.53; H, 4.12; N, 36.41. Found: C, 54.06; H, 4.06; N,
37.03%.
Entry Mode of activation Time
Power/temp. Yield %
1
2
3
4
5
6
7
8
MW
MW
MW
MW
MW
MW
MW
CH
5 min
400 W
400 W
30
48
69
85
87
65
88
62
10min
3-Methyl-N-(1H-tetrazol-5-yl)-1-p-tolyl-1H-pyrazole-5-carbox-
15 min 400 W
20 min 400 W
30 min 400 W
20 min 300 W
20 min 500 W
1
amide 6b: Yield 83%; m.p. 246–247 °C; H NMR(DMSO-d6, 300
MHz) δ: 2.24(s, 3H, CH3), 2.27(s, 3H, CH3), 6.83(s, 1H, pyrazole C–
H), 7.19–7.36(m, 4H, ArH), 9.41(d, 1H, –NH–CO–), 14.19(s, 1H,
tetrazole N–H); IR(KBr)υ: 3140, 2972, 1699, 1606, 1377cm−1. Anal.
Calcd for C13H13N7O: C, 55.12; H, 4.63; N, 34.61. Found: C, 55.62; H,
4.71; N, 34.41%.
5h
110 °C
MW, microware irradiation; CH, conventional heating.
1-(4-Methoxyphenyl)-3-methyl-N-(1H-tetrazol-5-yl)-1H-pyrazole-
5-carboxamide (6c): Yield 82%; m.p. 229–231 °C; 1H NMR(DMSO-
d6, 300 MHz) δ: 2.24(s, 3H, CH3), 3.80(s, 3H, OCH3), 6.83(s, 1H,
pyrazole C–H), 7.10–7.35(m, 4H, ArH), 9.41(d, 1H, –NH–CO–),
14.26(s, 1H, tetrazole N–H); IR(KBr) υ: 3134, 2964, 1691, 1602,
1312cm−1. Anal. Calcd for C13H13N7O2: C, 52.17; H, 4.38; N, 32.76.
Found: C, 52.30; H, 4.13; N, 32.20%.
further 1 hour, concentrated hydrochloric acid (20 mmol) was added.
After complete addition of the acid the mixture was kept at 65–70 °C
on the water-bath for 6 hours during which the product began to crys-
tallise. The semi-solid mass was allowed to stand overnight and was
chilled thoroughly before the product was filtered off and washed with
ice water. The compound 5 was recrystallised from boiling water. The
yield was 73%, M.p. 206–207 °C.19
1-(4-Chlorophenyl)-3-methyl-N-(1H-tetrazol-5-yl)-1H-pyrazole-5-
1
carboxamide (6d): Yield 78%; m.p. 264–265 °C; H NMR (DMSO-
d6, 300 MHz) δ: 2.26(s, 3H, CH3), 6.86(s, 1H, pyrazole C–H), 7.32–
7.62(m, 4H, ArH), 9.42(d, 1H, –NH–CO–), 14.29(s, 1H, tetrazole
N–H); IR(KBr) υ: 3135, 2965, 1691, 1520, 1312cm−1. Anal. Calcd for
C12H10ClN7O: C, 47.46; H, 3.32; N, 32.28. Found: C, 46.67; H, 3.72;
N, 32.69%.
1-(4-Fluorophenyl)-3-methyl-N-(1H-tetrazol-5-yl)-1H-pyrazole-5-
carboxamide (6e):Yield 90%; m.p. 249–250 °C; 1H NMR(DMSO-d6,
300 MHz) δ: 2.20(s, 3H, CH3), 6.83(s, 1H, pyrazole C–H), 7.28–
7.98(m, 4H, ArH), 9.50(d, 1H, –NH–CO–), 14.29(s, 1H, tetrazole
N–H); IR(KBr) υ: 3184, 2972, 1699, 1607, 1378cm−1. Anal. Calcd for
Preparation of 6a–f; general procedure
A mixture of compounds 4a–f (10 mmol) and 5 (10 mmol) in absolute
toluene was stirred and irradiated in WF-4000M microwave fast
reaction system under 300W for minutes at 110 °C. After cooling and
filtering, crude compounds were recrystallised from EtOH to obtain
6a–f.
3-Methyl-1-phenyl-N-(1H-tetrazol-5-yl)-1H-pyrazole-5-carbox-
1
amide (6a): Yield 85%; m.p. 223–225 °C; H NMR(DMSO-d6, 300

JOURNAL OF CHEMICAL RESEARCH 2011 527
References
C12H10FN7O: C, 50.17; H, 3.51; N, 34.13. Found: C, 50.08; H, 3.28; N,
34.30.
1
2
3
4
5
6
7
8
9
M. León Paumen, P. de Voogt, C.A.M. Van Gestel and M.H.S. Kraak, Sci.
Total Environ., 2010, 407, 4605.
K. Okuda, N. Watanabe, T. Hirota and K. Sasaki, Tetrahedron Lett., 2010,
51, 903.
E.I. Rabea, M.E.I. Badawy, W. Steurbaut and C.V. Stevens, Eur. Polym. J.,
2009, 45, 237.
M.R. Couri, I. Luduvico, L. Santos, R. Alves, M.A. Prado and R.F. Gil,
Carbohydr. Res., 2007, 342, 1096.
M. Nikpour, H. Eshtiagh-Hosseini, M. Mirzaei, A.A. Kaju, Y.G. Chen and
S. Zarinabadi, Chin. Chem. Lett., 2010, 21, 501.
T. Kikuchi, N. Ito, M. Suzuki, A. Kusai, K. Iseki and H. Sasaki, Int. J.
Pharm., 2005, 299, 100.
J. Pirnat, J. Luznik, V. Jazbinsek, V. Zagar, J. Seliger, T.M. Klapötke and
Z. Trontelj, Chem. Phys., 2009, 364, 98.
R. Sridhar, P.T. Perumal, S. Etti, G. Shanmugam, M.N. Ponnuswamy, V.R.
Prabavathy and N. Mathivanan, Bioorg. Med. Chem. Lett., 2004, 14, 6035.
E.V. Pimerova and E.V.Voronina, Pharm. Chem. J., 2001, 35, 18.
3-Methyl-1-(4-nitrophenyl)-N-(1H-tetrazol-5-yl)-1H-pyrazole-5-
carboxamide (6f):Yield 85%; m.p. 296–297 °C; 1H NMR(DMSO-d6,
300 MHz) δ: 2.27(s, 3H, CH3), 6.86(s, 1H, pyrazole C–H), 8.14–
8.62(m, 4H, ArH), 9.42(d, 1H, –NH–CO–), 14.31(s, 1H, tetrazole
N–H); IR(KBr) υ: 3178, 2972, 1699, 1697, 1378cm−1. Anal. Calcd for
C12H10N8O3: C, 45.86; H, 3.21; N, 35.66. Found: C, 45.17; H, 3.42;
N, 35.63.
We acknowledge generous financial support of this work from
2011 Key projects of Natural Science of Jiangsu province-
owned colleges (NO.11KJA610001), the National High Tech-
nology Research and Development (863 Program) of China
(No. 2007AA06A402), Key Projects in the National Science
and Technology Pillar Program (No. 2006BAC02A15), Key
Projects in the National Water pollution control and manage-
ment Pillar Program (No. 2008ZX07101-003) and PhD
thesis innovation fund of Nanjing University of technology
(No. BSCX201003).
10 V.A. Chornous, M.K. Bratenko and M.V. Vovk, Pharm. Chem. J., 2001, 35,
203.
11 T. Wang, S. Liu, C.H. Zheng, H.W. He, J. Chem. Res., 2008, 32, 619.
12 Y. Zhou, N. Xue, G. Wang, J. Qu, J. Chem. Res., 2010, 34, 684.
13 A. Patra and T. Mahapatra, J. Chem. Res., 2010, 21, 689.
14 J. Hu, J. Sun, T. Zhou and Y Xu, J. Chem. Res. (in press).
15 D. Dallinger and C.O. Kappe, Nat. Protoc., 2007, 2, 1713.
16 Z.G. Zhao, X.L. Liu, Y. Chen and Z.C. Shi, J. Chem. Res., 2010, 34, 481.
17 A. Pawelczyk and L. Zaprutko, Eur. J. Med. Chem., 2009, 44, 3032.
18 D. Prajapati, M. Gohain and A.J. Thakur, Bioorg. Med. Chem. Lett., 2006,
16, 3537.
Received 20 July 2011; accepted 23 August 2011
Paper 1100805 doi: 10.3184/174751911X13149561530439
Published online: 30 September 2011
19 J.S. Mihina and R.M. Herbst, J. Org. Chem., 1950, 15, 1082.