Synthesis of new 2,5-bis(3,5-disubstitutedpyrazolyl-1-carbonyl)thiophene compounds

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)

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)

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.

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新型2,5-双（3，5-二取代吡唑-1-羰基）噻吩化合物的合成
丁树红²，朱万仁^1,2, 童张法²
(¹玉林师范学院化学与生物系, 广西 537000; ²广西大学化学化工学院, 南宁 530004)
摘要 四种新型吡唑的杂环酰胺衍生物分别被合成, 四种吡唑包括: 3,5-二甲基吡唑, 3-甲基-5-苯基吡唑, 3,5-二苯基吡唑, 3-乙氧甲酰基-5-苯基吡唑; 四种杂环酰胺衍生物包括: 2,5-双(3,5-二甲基吡唑基-1-羰基)噻吩(L1), 2,5-双(3-甲基-5-苯基吡唑基-1-羰基)噻吩(L2), 2,5-双(3,5-二苯基吡唑基-1-羰基)噻吩(L3), 和2,5-双(3-乙氧甲酰基吡唑基-1-羰基)噻吩(L4)。产物分别进行元素分析和IR、¹HNMR、¹³CNMR和MS进行表征验证。
关键词 吡唑衍生物；合成；杂环酰胺；表征