Ding Shuhong ², Zhu Wanren ^1,2, Tong Zhangfa ²
(¹ Department of Chemistry and Biology, Yulin Teacher’s College, Yulin 537000, China; ² School of Chemistry & Chemical Engineering, Guangxi University, Nanning 530004, China)

Abstract Four pyrazoles and their new heterocyclic acylamide derivatives, which are 3,5- di- methylpyrazole, 5-methyl-3-phenylpyrazole, 3,5-diphenylpyrazole, 3-ethoxycarbonyl-5-phenyl- pyrazole, 2,5-bis(3,5-dimethylpyrazolyl-1-carbonyl)thiophene(L1), 2,5-bis(5-methyl-3-phenyl- pyrazolyl-1-carbonyl)thiophene(L2), 2,5-bis(3,5-diphenylpyrazolyl-1-carbonyl)thiophene(L3) and 2,5-bis(3-ethoxycarbonyl-5-phenyl-1-carbonyl)thiophene(L4) were synthesized, and their relevant structures were characterized by elemental analysis, MS, IR, ¹ HNMR and ¹³CNMR spectra.

1. INTRODUCTION
   Thiophene derivative are widely used in medicine and agriculture,for example,used as anticancer drugs ^[1-3], antiaids virus drugs ^[4], antihepatitis B virus drugs^[4], antifungal reagent^[5] , pesticide and hebicide^[4] , plant growth reagents ^[6]. Meanwhile , pyrazole derivatives have also attracted much attention due to diverse biological activities, such as antibacterial ^[7-9] , antitumor ^[10], antipyretic ^[11], antagonist ^[12], analgesic ^[13], anti-inflammatory agents^[14] . A wide range of procedures for the synthesis of pyrazoles ^[7-14] has been reported. However, the derivatives containing pyridine and pyrazole groups have been received much less attention , probably owing to the lack of general methods for their synthesis. In view of above, we report here in the preparation of new series of compounds bearing both thiophene and pyrazole with amide bridge , based on the objective of obtaining new biologically active compounds. The synthesis route is shown in Scheme .

R₁=R₂=Me(L1); R₁=Ph,R₂=Me(L2)
R₁=R₂=Ph(L3); R₁=Ph,R₂=CO₂Et(L4)

Scheme

2 EXPERIMENT SECTION
2.1 Reagents
2,5- thiophenediformyl chlroride was prepared as the literature ^[15] with stoichiometric yield 100%. 3,5-dimethylpyrazole, 5-methyl-3-phenylpyrazole, 3,5-diphenylpyrazole were synthesized according to the literature ^[16]. 3-ethoxycarbonyl-5-phenylpyrazole was synthesized according to the literature ^[17].
2.2 Synthesis of compounds L1-L4
2.2.1. Synthesis of 2,5-bis(3,5- dimethylpyrazolyl -1-carbonyl) thiophene (L1)
To a solution of 2,5-pyridinedicarbonyl dichloride (1.045 g, 5 mmol) in toluene (30 mL) was added 3,5-ditert-butylpyrazole (0.96 g, 10 mmol), followed by Et₃N (3 mL). The reaction mixture was refluxed for 24 h. The salt, Et₃N·HCl, gradually formed and was removed by filtration and the filtrate evaporated to give a colorless solid. 1.10 g of pure product was obtained after recrystallization from CH₂Cl₂: EtOH (1:1) at room temperature with yield of 67%. m. p. 165.1°C～165.7°C, IR(KBr) v: 3129, 3013（=C-H）, 1686(C=O), 1581, 1542, 1512, 1488, 1350 (Thio, Pyraz., C=C, C=N)cm^-1, ¹H-NMR(500MHz, CDCl₃): d: 8.26 (s, 2H, Thio), 6.07 (s, 2H, 4- Pyraz), 2.65 (s, 6H, 5-CH₃), 2.35 (s, 6H, 3-CH₃), ¹³C-NMR(500MHz, CDCl₃): d: 161 (C=O), 152 (Thio, C-2, C-5), 135 (Thio, C-3, C-4), 145 (Pyraz., C-3), 142 (Pyraz., C-5), 111 (Pyraz., C-4), 14 (Pyraz., C-5-CH₃), 13 (Pyraz.,C-3-CH₃), MS m/z(%): 329(M+1, 100), Ana1.calcd for C₁₆H₁₆N₄O₂S: C 58.52, H 4.91, S 9.76, found C 58.93, H 5.11, S 9.45.
Compounds L2, L3, and L4 were synthesised using the same procedureas described for L1.
2.2.2. Synthesis of 2,5-bis(5-methyl-3-phenylpyrazolyl -1-carbonyl) thiophene (L2)
Compound L2 was prepared from the reaction of 5-methyl-3-phenylpyrazole (1.58 g, 10 mmol) and 2,5-pyridinedicarbonyl dichloride (1.045 g, 5 mmol). Yield =1.45 g, 64%, m.p. 170°C～171°C, IR(KBr) v: 3156, 3071（=C-H）, 1677(C=O), 1569, 1506, 1467, 1374, 1341(Thio, Pyraz. ,C=C, C=N)cm^-1, ¹H-NMR(500MHz, CDCl₃): d: 8.32 (s, 2H, Thio), 7.20-7.93 (m,J=6Hz, 10H, ph), 6.63 (s, 2H, 4- Pyraz), 2.76 (s, 6H, 5-CH₃), ¹³C-NMR (500MHz, CDCl₃): d: 161 (C=O), 154 (Thio, C-2, C-5), 137 (Thio, C-3, C-4)，147 (Pyraz., C-3), 142 (Pyraz., C-5), 108 (Pyraz., C-4), 132 (Ph, C-1), 129 (Ph, C-3, C-5), 128 (Ph, C-4), 126 (Ph, C-2, C-6) ,14 (CH₃), MS m/z(%): 453(M+1, 100), Ana1.calcd for C₂₆H₂₀N₄O₂S: C 69.01, H 4.45, S 7.09, found C 69.54, H 5.05, S 6.41.
2.2.3. Synthesis of 2,5-bis(3,5-diphenylpyrazolyl -1-carbonyl) thiophene (L3)
Compound L3 was prepared from the reaction of 3,5-diphenylpyrazole (2.20 g, 10 mmol) and 2,5-pyridinedicarbonyl dichloride (1.045 g, 5 mmol). Yield =1.86 g, 64.5%, m. p.194.1°C～195.1°C, IR(KBr) v: 3142, 3047（=C-H）, 1686(C=O), 1557, 1491, 1461, 1401, 1362 (Thio, Pyraz., C=C, C=N)cm^-1, ¹H-NMR(500MHz, CDCl₃): d: 8.30(s, 2H, Thio), 7.27-8.04(m, J=6Hz, 20H, 3,5-Ph), 6.93(s, 2H, 4- Pyraz.) , ¹³C-NMR(500MHz, CDCl₃): d: 160 (C=O), 154 (Thio, C-2, C-5), 138 (Thio ,C-3, C-4), 148 (Pyraz.,C-3), 143 (Pyraz., C-5), 110 (Pyraz., C-4), 131 (Ph, C-1), 129 (Ph, C-3, C-5), 128 (Ph, C-4), 126 (Ph, C-2, C-6), MS m/z(%): 577(M+1, 100), Ana1.calcd for C₃₆H₂₄N₄O₂S: C 74.98, H 4.19, S 5.56, found C 75.66, H 4.61, S 5.06.
2.2.4. Synthesis of 2,5-bis(3-ethoxycarbonyl-5-phenyl -1-carbonyl) thiophene (L4)
Compound L4 was prepared from the reaction of 3-ethoxycarbonyl-5-phenylpyrazole (2.16 g, 10 mmol) and 2,5-pyridinedicarbonyl dichloride (1.045 g, 5 mmol).Yield =1.48 g, 52%, m. p.188.4°C～189.7°C, IR(KBr) v: 3174, 3064（=C-H）, 1725, 1701(C=O), 1560, 1500, 1461, 1422, 1359 (Thio, Pyraz. ,C=C, C=N)cm^-1, ¹H-NMR(500MHz, CDCl₃): d: 8.31(s, 2H, Thio), 7.51-7.53 (m, J=6Hz, 10H, 5-Ph), 7.03(s, 2H, 4-Pyraz), 4.49-4.54(q, 4H), 1.45-1.48(t, 6H), ¹³C-NMR (500MHz, CDCl₃): d: 161, 160(C=O), 148(Thio, C-2, C-5), 137(Thio, C-3, C-4), 146(Pyraz., C-3), 143 (Pyraz., C-5), 113(Pyraz., C-4), 133(Ph, C-1), 129(Ph, C-3, C-5), 128(Ph, C-4), 126(Ph, C-2, C-6), 61(CH₂), 14(CH₃), MS m/z(%): 567(M⁺, 100), Ana1.calcd for C₃₀H₂₄N₄O₆S: C 63.37, H 4.25, S 5.64, found C 62.56, H 4.47, S 5.29.

3 RESULTS AND DISCUSSION
Compounds L1 to L4 are very stable in air and can be stored at room temperature for a long period of time. These compounds were characterized by multinuclear NMR and IR spectroscopy, as well as by microanalysis and MS. ¹ H-NMR spectra show a singlet for the proton in position 4 of the pyrazolyl ring (L1 – L4), and a singlet for the proton in position 3 and 5 of the pyrazolyl ring for L1 and a singlet for the proton in position 5 of the pyrazolyl ring for L2, the compounds (L2 – L4) show multiplets (7.20 – 8.04 ppm) for phenyl protons (L2 – L4) and a doublet and a triplet for the 3-ethoxycarbonyl protons in L4. In addition, all the compounds (L1 – L4) show a singlet for thienyl protons (L1 – L4). Infrared spectra of L1 – L4 have the characteristic carbonyl stretching frequencies in the 1677 – 725 cm^-1 range.

Acknowledgement
This work was funded by a grant from the department of Science and Technology in Guangxi Research Foundation(0640207)