多取代吡喃[2,3-c]吡唑类化合物的在离子液体[Bmim]BF₄催化下的四组分一锅法合成

One-Pot Four-Component Synthesis of Multi-Substituted Pyrano[2,3-c] Pyrazole under Ionic Liquid [Bmim]BF₄ Catalysis

摘要: 本文报道了在离子液体[Bmim]BF₄催化下以丙酰乙酸甲酯或丙酰乙酸乙酯，苯肼，芳醛和丙二腈等四组分为原料经过一锅法合成了一系列多取代吡喃[2,3-c]吡唑类化合物的方法。该方法具有方便，产率较高等特点，为合成此类化合物提供了一个参考依据。产物的结构通过IR，1H NMR和MS进行表征。

Abstract: A series of multi-substituted pyrano[2,3-c]pyrazole derivatives were synthesized by one-pot reac-tion of ethyl propionyl acetate, phenylhydrazine, aromatic aldehyde and malononitrile. We developed an efficient and convenient method for the synthesis of multi-substituted pyrano[2,3-c]pyrazoles in high yields using ionic liquid [Bmim]BF₄ as a catalyst. And structures of the products were characterized by IR, 1H NMR and MS.

1. 引言

多组分反应(MCRs)是从三个或四个相对简单易得的原料出发，不经中间体的分离，直接获得结构复杂的分子的合成方法 [1] 。多组分反应具有操作简单、分离和纯化步骤少、原子经济性高和环境友好等诸多特点 [2] [3] 。多组分一锅法作为一类重要的有机化学反应，在新药设计与合成、组合化学、农药研究领域和天然产物合成中有着广泛的应用 [4] [5] 。

多取代吡喃[2,3-c]吡唑衍生物的研究一直得到广泛的关注，它具有广泛的药理活性，例如抗炎 [6] ，抗癌 [7] ，抗菌 [8] 和镇痛 [9] 等。

本文以丙酰乙酸甲酯或丙酰乙酸乙酯，苯肼，芳香醛和丙二腈等四组分为反应物，在离子液体[Bmim]BF₄的催化下，在乙醇中用一锅反应生成了6-氨基-4-芳基-3-乙基-1-苯基-4H-吡喃[2,3-c]吡唑-5-腈(5a~5j)。该反应具有反应时间短和产率较高等特点。本文利用IR，¹H NMR和质谱方法对所得到的产物进行了结构表征。

2. 实验部分

2.1. 仪器与试剂

产物的熔点用瑞士BUCHIB2540型熔点仪测定(温度计未校正)；质谱用API 2000质谱仪测定；核磁共振用VARIANINOVA400型核磁共振仪测定(DMSO-d₆为溶剂，TMS为内标)；红外光谱用BRUKER- EQUINOX55红外光谱仪测定(KBr压片)；元素分析用EA-1110元素分析仪测定。实验所用选的剂试均为分析纯试剂，除殊特说明外均没经处理直接使用。

2.2. 6-氨基-4-芳基-3-乙基-1-苯基-4-氢吡喃[2,3-c]吡唑-5-腈的合成(5a~5j)

将2.0 mmol丙酰乙酸甲酯或丙酰乙酸乙酯和2.0 mmol苯肼溶于2.0 mmol离子液体[Bmim]BF₄中加热反应2分钟，向反应物中依次加入2.0 mmol芳香醛，2.0 mmol丙二腈，继续加热15~25分钟。反应完成后，冷却至室温，加入10 mL蒸馏水，抽滤，用EtOH/H₂O洗涤，然后用DMF/H₂O重结晶粗产物得到目标化合物5a~5j。光谱数据如下：

6-Amino-4-phenyl-1,4-dihydro-3-ethyl-1-phenyl pyrano[2,3-c]pyrazole-5-carbonitrile ( 5 a ).白色晶体；m.p. 223℃~224℃. IR (KBr, ν/cm⁻¹): 3472, 3319 (NH₂), 2195 (C≡N), 1660, 1592, 1515 (C=N, C=C). ¹H NMR (400 MHz, DMSO-d₆) δ: 0.85 (t, 3H, J = 7.2 Hz, CH₃), 2.12 (q, 2H, J = 7.6 Hz, CH₂), 4.70 (s, 1H, CH), 7.20 (s, 2H, NH₂), 7.25~7.81 (m, 10H, 2Ph-H). MS, m/z (%): 365 ([M+Na]⁺, 45), 343 ([M+H]⁺, 100). Anal. Calcd for C₂₁H₁₈N₄O (342.40): C 73.67, H 5.30, N 16.36; found C 73.48, H 5.26, N 16.19.

6-Amino-4-(4-methylphenyl)-1,4-dihydro-3-ethyl-1-phenyl pyrano[2,3-c]-pyrazole-5-carbonitrile (5b). m.p. 225℃~226℃. IR (KBr, ν/cm⁻¹): 3468, 3318 (NH₂), 2199(C≡N), 1660, 1592, 1515 (C=N, C=C). ¹H NMR (400 MHz, DMSO-d₆) δ: 0.88 (t, 3H, J = 7.6 Hz, CH₃), 2.14 (q, 2H, J = 7.2 Hz, CH₂), 2.29 (s, 3H, CH₃), 4.65 (s, 1H, CH), 7.14 (s, 2H, NH₂), 7.10~7.16 (dd, 4H, J = 8.0 Hz, p-H ₃C -C₆H₄), 7.30 (t, 1H, J = 7.2 Hz, J = 7.6 Hz, Ph-H), 7.48 (t, 2H, J = 7.6 Hz, J = 8.8 Hz, Ph-H), 7.80 (d, 2H, J = 8.8 Hz, Ph-H). MS, m/z (%): 379 ([M+Na]⁺, 35), 357 ([M+H]⁺, 100). Anal. Calcd for C₂₂H₂₀N₄O (356.43): C 74.14, H 5.66, N 15.72; found C 74.02, H 5.55, N 15.67.

6-Amino-4-(4-methoxyphenyl)-1,4-dihydro-3-ethyl-1-phenyl pyrano[2,3-c]-pyrazole-5-carbonitrile ( 5 c ). 白色晶体； m.p. 247℃~248℃. IR (KBr, ν/cm⁻¹): 3399, 3204(NH₂), 2191(C≡N), 1660, 1595, 1513(C=N, C=C). ¹H NMR (400 MHz, DMSO-d₆) δ: 0.88 (t, 3H, J = 7.6 Hz, CH₃), 2.15 (q, 2H, J = 7.6 Hz, CH₂), 3.74 (s, 3H, OCH₃), 4.65 (s, 1H, CH), 6.88 (d, 2H, J = 8.8 Hz, p-H₃CO-C₆H₄), 7.15 (s, 2H, NH₂), 7.16 (d, 2H, J = 8.8 Hz, p-H₃CO-C₆H₄), 7.32 (t, 1H, J = 7.2 Hz, J = 7.6 Hz, Ph-H), 7.48 (t, 2H, J = 7.6 Hz, Ph-H), 7.80 (d, 2H, J = 7.6 Hz, Ph-H). MS, m/z (%): 395 ([M+Na]⁺, 100), 373 ([M+H]⁺, 90). Anal. Calcd for C₂₂H₂₀N₄O₂ (372.43): C, 70.95; H, 5.41; N, 15.04; found C 70.82, H 5.38, N 14.94.

6-Amino-4-(4-chlorophenyl)-1,4-dihydro-3-ethyl-1-phenyl pyrano[2,3-c]-pyrazole-5-carbonitrile (5d). 白色晶体；m.p. 232℃~235℃. IR (KBr, ν/cm⁻¹): 3452, 3323 (NH₂), 2198 (C≡N), 1660, 1594, 1517 (C=N, C=C). ¹H NMR (400 MHz, DMSO-d₆) δ: 0.89 (t, 3H, J = 8Hz, CH₃), 2.15 (q, 2H, J = 7.2 Hz, CH₂), 4.75 (s, 1H, CH), 7.25 (s, 2H, NH₂), 7.30 (d, 2H, J = 8.4Hz, p-Cl-C₆H₄), 7.32 (t, J = 8.4 Hz, J = 7.6 Hz, 1H, Ph-H), 7.40 (d, 2H, J = 8.4 Hz, p-Cl-C₆H₄), 7.50 (t, J = 8.4 Hz, 2H, Ph-H), 7.80 (d, J = 7.6 Hz, 2H, Ph-H). MS, m/z (%): 400 ([M+1+Na]⁺, 8), 399 ([M+Na]⁺, 20), 378 ([M+1+H]⁺, 30), 377 ([M+H]⁺, 100). Anal. Calcd for C₂₁H₁₇ClN₄O (376.85): C 66.93, H 4.55, N 14.87; found C 66.82, H 4.52, N 14.74.

6-Amino-4-(4-bromophenyl)-1,4-dihydro-3-ethyl-1-phenyl pyrano[2,3-c]-pyrazole-5-carbonitrile (5e). 白色晶体； m.p. 243℃~245℃; IR (KBr, ν/cm⁻¹): 3448, 3324 (NH₂), 2195 (C≡N), 1659, 1596, 1518 (C=N, C=C). ¹H NMR (400 MHz, DMSO-d₆) δ: 0.89 (t, 3H, J = 7.2 Hz, CH₃), 2.15 (q, 2H, J = 7.6 Hz, CH₂), 4.74 (s, 1H, CH), 7.24 (d, 2H, J = 8.4 Hz, p-Br-C₆H₄), 7.25 (s, 2H, NH₂), 7.33 (t, 1H, J = 7.2 Hz, J = 7.6 Hz, Ph-H), 7.49 (t, 2H, J = 7.6 Hz, J = 8.4 Hz, Ph-H), 7.53 (d, 2H, J = 8.4 Hz, p-Br-C₆H₄), 7.80 (d, 2H, J = 8.4 Hz, Ph-H). MS, m/z (%): 445 ([M+2+Na]⁺, 35), 443 ([M+Na]⁺, 30), 423 ([M+2+H]⁺, 98), 421 ([M+H]⁺, 100). Anal. Calcd for C₂₂H₁₉BrN₄O (421.30): C 59.87, H 4.07, N 13.30; found C 59.68, H 4.04, N 13.14.

6-Amino-4-(4-floroyphenyl)-1,4-dihydro-3-ethyl-1-phenyl pyrano[2,3-c]-pyrazole-5-carbonitrile (5f). 白色晶体；m.p. 233℃~234℃. IR (KBr, ν/cm⁻¹): 3456, 3325 (NH₂), 2200 (C≡N), 1665, 1596, 1515 (C=N, C=C). ¹H NMR (400 MHz, DMSO-d₆) δ: 0.87 (t, 3H, J = 7.6 Hz, CH₃), 2.13 (q, 2H, J = 7.6 Hz, CH₂), 4.74 (s, 1H, CH), 7.15 (d, 2 H, J = 8.8 Hz, p-F-C₆H₄), 7.21 (s, 2H, NH₂), 7.30 (t, 1H, J = 7.6 Hz, Ph-H), 7.50 (t, 2H, J = 7.6 Hz, J = 8.4 Hz, Ph-H), 7.32 (d, 2H, J = 8.8 Hz, p-F-C₆H₄), 7.80 (d, 2H, J = 8.8 Hz, J = 8.0 Hz, Ph-H). MS, m/z (%): 384 ([M+Na]⁺, 10), 383 ([M+Na]⁺, 25), 362 ([M+1+H]⁺, 58), 361 ([M+H]⁺, 100). Anal. Calcd for C₂₁H₁₇FN₄O (360.39): C 69.99, H 4.75, N 15.55; found: C 69.72, H 4.72, N 15.44.

6-Amino-4-(4-nitrophenyl)-1,4-dihydro-3-ethyl-1-phenyl pyrano[2,3-c]-pyrazole-5-carbonitrile ( 5 g ). 土黄色晶体； m.p. 221℃~222℃. IR (KBr, ν/cm⁻¹): 3435, 3328 (NH₂), 2205 (C≡N), 1666, 1591, 1517 (C=N, C=C). ¹H NMR (400 MHz, DMSO-d₆) δ: 0.89 (t, 3H, J = 7.6 Hz, CH₃), 2.14 (q, 2H, J = 7.2 Hz, CH₂), 4.95 (s, 1H, CH), 7.32 (t, 1H, J = 7.2 Hz, Ph-H), 7.37 (s, 2H, NH₂), 7.49 (t, 2H, J = 7.6 Hz, J = 8.4 Hz, Ph-H), 7.58 (d, 2H, J = 8.8 Hz, p-O₂N-C₆H₄), 7.81 (d, 2H, J = 8.8 Hz, Ph-H ), 8.22 (d, 2H, J = 8.8 Hz, p-O₂N-C₆H₄). MS, m/z (%):410 ([M+Na]⁺, 40), 388 ([M+H]⁺, 100). Anal. Calcd for C₂₁H₁₇N₅O₃ (387.40): C 65.11, H 4.42, N 18.08; found C 65.02, H 4.32, N 17.94.

6-Amino-4-(4-hydroxyphenyl)-1,4-dihydro-3-ethyl-1-phenyl pyrano[2,3-c]-pyrazole-5-carbonitrile (5h). 白色晶体； m.p. 227℃~229℃. IR (KBr, ν/cm⁻¹): 3396 (OH), 3320, 3202 (NH₂), 2177 (C≡N), 1657, 1579, 1516 (C=N, C=C). ¹H NMR (400 MHz, DMSO-d₆) δ: 0.88 (t, 3H, J = 7.6 Hz, CH₃), 2.14 (q, 2H, J = 7.6 Hz, CH₂), 4.58 (s, 1H, CH), 6.70 (d, 2H, J = 8.4 Hz, p-HO-C₆H₄), 7.03 (d, 2H, J = 8.4 Hz, p-HO-C₆H₄), 7.11 (s, 2H, NH₂), 7.32 (t, 1H, J = 7.2 Hz, J = 7.6 Hz, Ph-H), 7.49 (t, 2H, J = 8.4 Hz, J = 7.6 Hz, Ph-H), 7.78 (d, 2H, J = 7.6 Hz, Ph-H), 9.33 (s, 1H, OH). MS, m/z (%): 381 ([M+Na]⁺, 40), 359 ([M+H]⁺, 100). Anal. Calcd for C₂₁H₁₈N₄O₂ (358.40): C 70.38, H 5.06, N 15.63; found C 70.22, H 4.99, N 15.54.

6-Amino-4-(3-pyridyl)-1,4-dihydro-3-ethyl-1-phenyl pyrano[2,3-c]pyrazole-5-carbonitrile (5i). 白色晶体； m.p. 249℃~251℃. IR (KBr, ν/cm⁻¹): 3362, 3090 (NH₂), 2189 (C≡N), 1661, 1585, 1517 (C=N, C=C). ¹HNMR (400 MHz, DMSO-d₆) δ: 0.87 (t, 3H, J = 7.6 Hz, CH₃), 2.14 (q, 2H, J = 7.6 Hz, CH₂), 4.81 (s, 1H, CH), 7.30 (s, 2H, NH₂), 7.31(t, 1H, J = 7.6 Hz, J = 8.4 Hz, Ph-H), 7.38 (m. 2 H, J = 4.8 Hz, J = 7.6 Hz, pyridyl-H), 7.50 (t, 2H, J = 8.4 Hz, Ph-H), 7.66 (d. 1H, J = 2.4 Hz, J = 1.6 Hz, J = 8.4 Hz, pyridyl-H), 7.80 (d, 2H, J = 8.0 Hz, Ph-H), 8.50 (d, 1H, J = 1.6 Hz, J = 2.4 Hz, J = 5.2 Hz, pyridyl-H), 8.55 (d, 1H, J = 2.4 Hz, pyridyl-H). MS, m/z (%): 366 ([M+Na]⁺, 55), 344 ([M+H]⁺, 100). Anal.Calcd for C₂₀H₁₇N₅O (343.39): C 69.96, H 4.99, N 20.39; found C 69.82, H 4.90, N 20.22.

6-Amino-4-(1-naphtyl)-1,4-dihydro-3-ethyl-1-phenyl pyrano[2,3-c]pyrazole-5-carbonitrile (5j).白色晶体； m.p. 189℃~190℃. IR (KBr, ν/cm⁻¹): 3375, 3176 (NH₂), 2185 (C≡N), 1658, 1591, 1515 (C=N, C=C). ¹H NMR (400 MHz, DMSO-d₆) δ: 0.65 (t, 3H, J = 7.6Hz, CH₃), 1.91 (q, 2H, J = 7.6 Hz, CH₂), 4.35 (s, 1H, CH), 7.22 (s, 2H, NH₂), 7.32−7.99 (m, 12H, Ar-H). MS, m/z (%): 415 ([M+H]⁺, 100), 393 ([M+Na]⁺, 50). Anal. Calcd for C₂₅H₂₀N₄O (392.46): C 76.51, H 5.14, N 14.28; found C 76.40, H 5.10, N 14.17.

目标化合物5a~5j用¹H NMR进行结构表征，在δ 4.35~4.95呈现的单峰为吡喃环4位上的CH质子信号，在δ7.11~7.37范围内呈现的单峰为NH₂中的质子信号。

3. 结果与讨论

该反应在离子液体[Bmim]BF₄催化下，以丙酰乙酸甲酯或丙酰乙酸乙酯，苯肼，芳香醛和丙二腈原料，经过一锅法以较高的产率合成了以下10种目标化合物(5a~5j)。该反应具有时间短(7~15 min)，产率较高，操作简便等特点(图1)。

从实验结果可以总结出(表1)，芳环上取代基的对该反应速度有一定的影响，当苯环对位有吸电子基团时，反应速度比有供电子基团的化合物要快，这可能是因为吸电子基团有利于亲核加成反应的进行有关。

Scheme 1. Synthesis of 6-amino-4-aryl-1,4-dihydro-3-ethyl-1-phenyl pyrano[2,3-c]-pyrazole-5-carbonitrile (5a~5j)

图1. 6-氨基-4-芳基-3-乙基-1-苯基-4-氢吡喃[2,3-c]吡唑-5-腈的合成(5a~5j)

Table 1. The reaction times and yields of compounds 5a~5j

表1. 化合物5a~5j的反应时间和产率

^aIsolated yields.

4. 结论

在离子液体[Bmim]BF₄催化下以丙酰乙酸甲酯或丙酰乙酸乙酯，苯肼，芳醛和丙二腈等四组分为原料经过一锅法合成了一系列多取代吡喃[2,3-c]吡唑类化合物。该方法具有时间短，产率较高，操作简便等特点。

致谢

新疆教育部研究生科研创新项目基金(No. XJGRI2014019)。

^*通讯作者。