CN111471047A - 选择性合成吡唑并[1,2-a]吡唑酮或2-酰基吲哚类化合物的方法 - Google Patents

选择性合成吡唑并[1,2-a]吡唑酮或2-酰基吲哚类化合物的方法 Download PDF

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CN111471047A
CN111471047A CN202010433328.8A CN202010433328A CN111471047A CN 111471047 A CN111471047 A CN 111471047A CN 202010433328 A CN202010433328 A CN 202010433328A CN 111471047 A CN111471047 A CN 111471047A
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pyrazolo
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CN111471047B (zh
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张新迎
沈檬洋
徐园双
范学森
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Henan Normal University
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Abstract

本发明公开了选择性合成吡唑并[1,2‑a]吡唑酮或2‑酰基吲哚类化合物的方法，属于有机化学技术领域。该方法通过从1‑芳基吡唑烷酮类化合物1和炔基环丁醇类化合物2出发，在二氯(五甲基环戊二烯基)合铑(III)二聚体催化下，通过改变反应的温度、溶剂和添加剂种类，高选择性地合成了吡唑并[1,2‑a]吡唑酮3或2‑酰基吲哚类化合物4。该方法具有原料简单易得、操作简便、条件温和、选择性好及底物适用范围广等优点。

Description

选择性合成吡唑并[1,2-a]吡唑酮或2-酰基吲哚类化合物的 方法
技术领域
本发明属于有机合成技术领域，具体涉及选择性合成吡唑并[1,2-a]吡唑酮或 2-酰基吲哚类化合物的方法。
背景技术
吡唑并[1,2-a]吡唑酮是一类重要的含氮稠杂环类化合物，通常表现出显著的药物特性，例如抗菌、除草、杀虫和缓解阿尔茨海默症等。
2-酰基吲哚类化合物不仅在自然界中普遍存在，而且往往具有良好的生物活性及物理、化学性能，已被广泛应用于医药、农药、香料、食品饲料添加剂、功能染料等领域。
目前，现有文献中已经报道了吡唑并[1,2-a]吡唑酮和2-酰基吲哚类化合物的合成方法，但这些方法仍然存在原料不易得到、合成路线长、产物结构单一和原子经济性低等问题。
因此，研究并开发从简单易得的原料出发，通过改变反应条件来选择性地合成吡唑并[1,2-a]吡唑酮或2-酰基吲哚类化合物的绿色高效新方法，具有十分重要的理论意义和实用前景。
发明内容
本发明解决的技术问题是提供了选择性合成吡唑并[1,2-a]吡唑酮或2-酰基吲哚类化合物的方法，该方法通过1-芳基吡唑烷酮类化合物和炔基环丁醇类化合物之间发生的串联反应，选择性地合成了吡唑并[1,2-a]吡唑酮或2-酰基吲哚类化合物，具有原料简单易得、操作简便、条件温和、选择性好及底物适用范围广等优点。
本发明为解决上述技术问题采用如下技术方案，选择性合成吡唑并[1,2-a]吡唑酮3或2-酰基吲哚类化合物4的方法，包括如下操作：1-芳基吡唑烷酮类化合物1与炔基环丁醇类化合物2，在二氯(五甲基环戊二烯基)合铑(III)二聚体和添加剂存在下，有机溶剂中升温反应得到吡唑并[1,2-a]吡唑酮类化合物3或2-酰基吲哚类化合物4；反应方程式为：
Figure BDA0002501308430000021
其中：添加剂为醋酸钠、醋酸铯或磷酸钾时，反应得到吡唑并[1,2-a]吡唑酮类化合物3；添加剂为碳酸钠时，反应得到2-酰基吲哚类化合物4。
在上述反应方程式中，R1为氢、卤素、三氟甲基、氰基、硝基、C1-4烷基或C1-4烷氧基，R2为氢或C1-4烷基，R3为氢或C1-4烷基，R4为C1-6链状烷基或链状取代烷基、环丙基、噻吩基、吡啶基、苯基或取代苯基，取代苯基苯环上的取代基为卤素、三氟甲基、C1-4烷基或C1-4烷氧基，R5为氢或C1-4烷氧羰基。
进一步地，在上述技术方案中，所述取代基中，卤素选自氟、氯、溴或碘。
进一步地，在上述技术方案中，所述反应溶剂为起到溶解原料的作用，但同时也发现：合成吡唑并[1,2-a]吡唑酮类化合物3时，优选溶剂为1,2-二氯乙烷 (DCE)、二氯甲烷(DCM)、乙腈(CH3CN)、1,4-二氧六环(1,4-dioxane)或甲醇 (CH3OH)等；合成2-酰基吲哚类化合物4时，优选溶剂为四氢呋喃(THF)或2-甲基四氢呋喃(2-MeTHF)等。
进一步地，在上述技术方案中，反应温度为60-120℃。研究还发现，升高温度有利于2-酰基吲哚类化合物4的生成，当温度范围为100-120℃时，反应主要得到2-酰基吲哚类化合物4。
进一步地，在上述技术方案中，所述添加剂为醋酸钠、醋酸铯或磷酸钾时，反应选择性地得到吡唑并[1,2-a]吡唑酮类化合物3，优选醋酸钠或醋酸铯；添加剂为碳酸钠或碳酸钾时，反应选择性发生改变，且随着反应温度升高，产物2- 酰基吲哚类化合物4的比例增加(吡唑并[1,2-a]吡唑酮类化合物3比例明显降低)，升温到100-120℃，反应主要得到2-酰基吲哚类化合物4。
进一步地，在上述技术方案中，所述1-芳基吡唑烷酮类化合物1、炔基环丁醇类化合物2、添加剂与二氯(五甲基环戊二烯基)合铑(III)二聚体的投料摩尔比为 1-1.5:1-1.5:0.2-0.5:0.02-0.03。
发明有益效果：
本发明与现有技术相比具有以下优点：(1)合成过程简单、高效，从1-芳基吡唑烷酮类化合物和炔基环丁醇类化合物出发，在二氯(五甲基环戊二烯基)合铑(III)二聚体催化下，通过改变反应的温度、溶剂和添加剂种类，高选择性地合成了吡唑并[1,2-a]吡唑酮或2-酰基吲哚类化合物；(2)原料价廉易得，反应条件温和，操作简便，底物的适用范围广，反应的原子经济性高，符合绿色化学的要求。
具体实施方式
以下通过实施例对本发明的上述内容做进一步详细说明，但不应该将此理解为本发明上述主题的范围仅限于以下的实施例，凡基于本发明上述内容实现的技术均属于本发明的范围。
实施例1
Figure BDA0002501308430000031
向15mL耐压管中依次加入1a(57mg,0.3mmol)、2a(52mg,0.3mmol)、溶剂(2mL)、二氯(五甲基环戊二烯基)合铑(III)二聚体([RhCp*Cl2]2,4.7mg, 0.0075mmol)和添加剂(0.06mmol)，盖上塞子密封，将其置于油浴中在一定温度下搅拌反应。待反应结束后，冷却至室温，抽滤，旋干，过硅胶柱分离(石油醚/乙酸乙酯＝10/1至石油醚/乙酸乙酯＝1/1)得白色固体产物3a或4a。
通过改变反应的溶剂、添加剂、催化剂、温度、时间及底物的当量比，反应具体结果，见表1。
表1不同反应条件下3a和4a的合成a
Figure BDA0002501308430000032
Figure BDA0002501308430000041
实施例2
向15mL耐压管中依次加入1a(57mg,0.3mmol)、2a(52mg,0.3mmol)、二氯甲烷(2mL)、二氯(五甲基环戊二烯基)合铑(III)二聚体([RhCp*Cl2]2,4.7mg, 0.0075mmol)和醋酸钠(4.9mg,0.06mmol)，盖上塞子密封，将其置于60℃油浴中搅拌反应8小时。待反应结束后，冷却至室温，抽滤，旋干，过硅胶柱分离 (石油醚/乙酸乙酯＝10/1)得白色固体产物3a(94.6mg,87％)。该化合物的表征数据为：1H NMR(600MHz,CDCl3)δ0.80(t,J＝7.2Hz,3H),1.22(s,3H), 1.43-1.49(m,5H),2.22-2.27(m,1H),2.37-2.43(m,1H),3.36(d,J＝18.0Hz,1H), 3.47(d,J＝7.8Hz,1H),3.79(d,J＝7.8Hz,1H),4.30(d,J＝18.0Hz,1H),6.75(d,J ＝7.8Hz,1H),6.99(t,J＝7.8Hz,1H),7.18(d,J＝7.2Hz,1H),7.23(t,J＝7.8Hz, 2H),7.31(t,J＝7.8Hz,2H),7.47(d,J＝8.4Hz,2H).13C{1H}NMR(150MHz, CDCl3)δ13.6,16.9,22.3,23.8,45.1,45.4,47.8,64.5,68.4,110.1,122.32,122.33, 125.5,127.7,128.8,128.9,132.7,143.2,148.1,172.3,206.1.HRMS calcd for C23H26N2O2Na:385.1886[M+Na]+,found:385.1878.
实施例3
依照实施例2的方法和步骤，通过改变反应物1和2，可以合成出各种吡唑并[1,2-a]吡唑酮类化合物3，具体结果见表2。
表2各种吡唑并[1,2-a]吡唑酮类化合物3的合成a,b
Figure BDA0002501308430000051
Figure BDA0002501308430000061
代表性产物表征数据如下：
7-Isopropyl-2,2-dimethyl-9-(2-oxopentyl)-9-phenyl-2,3-dihydropyrazolo[1,2-a]in dazol-1(9H)-one(3c)
White solid(94.7mg,78％).1H NMR(400MHz,CDCl3)δ0.79(t,J＝7.6Hz,3H),1.22(s,9H),1.42-1.50(m,5H),2.21-2.29(m,1H),2.35-2.42(m,1H),2.84-2.91(m, 1H),3.39(d,J＝17.6Hz,1H),3.43(d,J＝8.0Hz,1H),3.76(d,J＝8.0Hz,1H),4.29 (d,J＝18.0Hz,1H),6.68(d,J＝8.0Hz,1H),7.02(s,1H),7.10(d,J＝8.4Hz,1H), 7.23(t,J＝7.2Hz,1H),7.32(t,J＝7.6Hz,2H),7.47(d,J＝8.0Hz,2H).13C{1H} NMR(100MHz,CDCl3)δ13.6,16.9,22.3,23.7,24.2,24.4,33.8,45.2,45.4,47.7, 64.7,68.5,109.9,120.4,125.6,126.9,127.6,128.8,132.5,143.1,143.3,146.2,172.4, 206.1.HRMS calcd forC26H32N2O2Na:427.2356[M+Na]+,found:427.2342.
7-Methoxy-2,2-dimethyl-9-(2-oxopentyl)-9-phenyl-2,3-dihydropyrazolo[1,2-a]ind azol-1(9H)-one(3d)
White solid(98.9mg,84％).1H NMR(400MHz,CDCl3)δ0.82(t,J＝7.2Hz,3H),1.20(s,3H),1.42-1.50(m,5H),2.23-2.31(m,1H),2.38-2.46(m,1H),3.35(d,J＝ 18.0Hz,1H),3.41(d,J＝8.0Hz,1H),3.74-3.76(m,4H),4.29(d,J＝18.0Hz,1H), 6.69(d,J＝8.4Hz,1H),6.76-6.80(m,2H),7.24(t,J＝7.6Hz,1H),7.31(t,J＝7.6 Hz,2H),7.46(d,J＝7.6Hz,2H).13C{1H}NMR(100MHz,CDCl3)δ13.6,16.9, 22.3,23.6,45.0,45.5,47.6,55.9,65.2,68.5,109.4,110.7,113.4,125.5,127.7,128.8, 134.2,142.0,143.0,155.8,172.5,206.0.HRMS calcd for C24H28N2O3Na:415.1992 [M+Na]+,found:415.1989.
7-Fluoro-2,2-dimethyl-9-(2-oxopentyl)-9-phenyl-2,3-dihydropyrazolo[1,2-a]indaz ol-1(9H)-one(3e)
White solid(89.0mg,78％).1H NMR(400MHz,CDCl3)δ0.83(t,J＝7.2Hz,3H),1.20(s,3H),1.43-1.53(m,5H),2.24-2.32(m,1H),2.40-2.48(m,1H),3.32(d,J＝ 18.0Hz,1H),3.44(d,J＝7.6Hz,1H),3.76(d,J＝8.0Hz,1H),4.31(d,J＝18.4Hz, 1H),6.68(dd,J1＝8.8Hz,J2＝4.4Hz,1H),6.89-6.97(m,2H),7.26(t,J＝7.2Hz, 1H),7.33(t,J＝7.6Hz,2H),7.44(d,J＝7.6Hz,2H).13C{1H}NMR(100MHz, CDCl3)δ13.6,16.9,22.3,23.7,44.9,45.4,47.7,64.9,68.4(d,4JC-F＝1.8Hz),109.9 (d,2JC-F＝24.9Hz),110.8(d,3JC-F＝8.4Hz),115.5(d,2JC-F＝23.5Hz),125.3,127.9, 128.9,134.5(d,3JC-F＝8.3Hz),142.6,144.3(d,4JC-F＝1.3Hz),159.0(d,1JC-F＝ 239.1Hz),172.6,206.0.19F NMR(376MHz,CDCl3)δ-121.17(td,J1＝8.3Hz,J2＝ 4.1Hz).HRMS calcd for C23H25FN2O2Na:403.1792[M+Na]+,found:403.1785.
2,2-Dimethyl-9-(2-oxopentyl)-9-phenyl-7-(trifluoromethyl)-2,3-dihydropyrazolo[ 1,2-a]indazol-1(9H)-one(3h)
White solid(85.2mg,66％).1H NMR(600MHz,CDCl3)δ0.81(t,J＝7.2Hz,3H),1.22(s,3H),1.44-1.50(m,5H),2.26-2.31(m,1H),2.39-2.45(m,1H),3.37(d,J＝ 18.6Hz,1H),3.55(d,J＝7.8Hz,1H),3.84(d,J＝7.8Hz,1H),4.35(d,J＝18.6Hz, 1H),6.79(d,J＝8.4Hz,1H),7.28(t,J＝7.2Hz,1H),7.34-7.36(m,3H),7.44(d,J＝ 8.4Hz,2H),7.51(d,J＝7.8Hz,1H).13C{1H}NMR(150MHz,CDCl3)δ13.5,16.9, 22.3,24.0,44.9,45.4,47.9,63.8,68.3,109.6,119.3(q,3JC-F＝4.4Hz),124.3(q,2JC-F＝32.9Hz),124.4(q,1JC-F＝268.4Hz),125.2,126.7(q,3JC-F＝5.3Hz),128.1,129.0, 133.7,142.4,150.7,172.4,206.3.19F NMR(376MHz,CDCl3)δ-61.18(s).HRMS calcd for C24H25F3N2O2Na:453.1760[M+Na]+,found:453.1756.
2,2-Dimethyl-1-oxo-9-(2-oxopentyl)-9-phenyl-1,2,3,9-tetrahydropyrazolo[1,2-a]in dazole-7-carbonitrile(3i)
White solid(65.1mg,56％).1H NMR(400MHz,CDCl3)δ0.83(t,J＝7.2Hz,3H),1.22(s,3H),1.44-1.53(m,5H),2.25-2.33(m,1H),2.40-2.48(m,1H),3.35(d,J＝ 18.4Hz,1H),3.59(d,J＝8.0Hz,1H),3.85(d,J＝8.0Hz,1H),4.34(d,J＝18.4Hz, 1H),6.75(d,J＝8.0Hz,1H),7.29(t,J＝7.6Hz,1H),7.34-7.43(m,5H),7.53(d,J＝ 8.0Hz,1H).13C{1H}NMR(100MHz,CDCl3)δ13.5,16.9,22.3,24.2,44.8,45.4, 48.0,63.2,68.2,104.7,109.8,119.4,125.1,125.8,128.2,129.1,133.8,134.4,141.9, 151.2,172.3,206.4.HRMS calcdfor C24H25N3O2Na:410.1839[M+Na]+,found: 410.1833.
2,2-Dimethyl-7-nitro-9-(2-oxopentyl)-9-phenyl-2,3-dihydropyrazolo[1,2-a]indazol -1(9H)-one(3j)
Yellow solid(77.0mg,63％).1H NMR(400MHz,CDCl3)δ0.83(t,J＝7.2Hz,3H),1.24(s,3H),1.43-1.52(m,5H),2.26-2.34(m,1H),2.41-2.48(m,1H),3.40(d,J＝18.4Hz,1H),3.66(d,J＝8.4Hz,1H),3.90(d,J＝8.0Hz,1H),4.38(d,J＝18.4Hz, 1H),6.73(d,J＝8.8Hz,1H),7.30(t,J＝7.2Hz,1H),7.37(t,J＝7.6Hz,2H),7.46 (d,J＝8.0Hz,2H),8.03(s,1H),8.19(d,J＝8.8Hz,1H).13C{1H}NMR(100MHz, CDCl3)δ13.5,16.9,22.3,24.4,44.7,45.4,48.2,62.8,68.3,108.3,118.4,125.0, 126.3,128.3,129.2,134.3,141.7,142.6,152.6,172.4,206.6.HRMS calcd for C23H25N3O4Na:430.1737[M+Na]+,found:430.1727.
2,2-Dimethyl-9-(2-oxopentyl)-9-(thiophen-2-yl)-2,3-dihydropyrazolo[1,2-a]indazo l-1(9H)-one(3gg)
White solid(67.4mg,61％).1H NMR(400MHz,CDCl3)δ0.80(t,J＝7.6Hz,3H),1.20(s,3H),1.41-1.50(m,5H),2.22-2.29(m,1H),2.37-2.45(m,1H),3.42(d,J＝ 18.0Hz,1H),3.52(d,J＝8.0Hz,1H),3.77(d,J＝7.6Hz,1H),4.43(d,J＝17.6Hz, 1H),6.77(d,J＝8.0Hz,1H),6.89-6.91(m,1H),6.95-6.99(m,2H),7.13(d,J＝7.6 Hz,1H),7.18(d,J＝4.8Hz,1H),7.24(t,J＝7.6Hz,1H).13C{1H}NMR(100MHz, CDCl3)δ13.6,16.9,22.2,23.6,45.1,45.5,47.9,64.2,65.6,110.1,121.7,122.5, 123.8,125.0,127.0,129.2,133.1,147.4,147.9,171.9,205.8.HRMS calcd for C21H24N2O2SNa:391.1451[M+Na]+,found:391.1433.
9-Butyl-2,2-dimethyl-9-(2-oxopentyl)-2,3-dihydropyrazolo[1,2-a]indazol-1(9H)-o ne(3hh)
White solid(85.3mg,83％).1H NMR(400MHz,CDCl3)δ0.76-0.84(m,6H), 1.02-1.06(m,1H),1.20-1.46(m,11H),1.74(td,J1＝13.2Hz,J2＝4.4Hz,1H),2.09 (td,J1＝13.2Hz,J2＝4.0Hz,1H),2.18-2.26(m,1H),2.30-2.38(m,1H),2.96(d,J＝ 17.2Hz,1H),3.50(d,J＝8.0Hz,1H),3.61(d,J＝7.6Hz,1H),3.88(d,J＝17.2Hz, 1H),6.71(d,J＝8.0Hz,1H),6.91-6.95(m,2H),7.18-7.22(m,1H).13C{1H}NMR (100MHz,CDCl3)δ13.5,14.0,16.9,22.2,22.6,23.5,25.7,40.1,45.4,45.7,47.2, 64.1,66.8,109.6,121.1,122.2,128.6,133.6,147.6,172.0,206.9.HRMS calcd for C21H30N2O2Na:365.2199[M+Na]+,found:365.2199.
9-Cyclopropyl-2,2-dimethyl-9-(2-oxopentyl)-2,3-dihydropyrazolo[1,2-a]indazol-1 (9H)-one(3ii)
White solid(78.3mg,80％).1H NMR(400MHz,CDCl3)δ0.28-0.32(m,1H), 0.43-0.50(m,3H),0.79(t,J＝7.2Hz,3H),1.13(s,3H),1.16-1.21(m,1H),1.37(s, 3H),1.40-1.49(m,2H),2.20-2.28(m,1H),2.34-2.42(m,1H),3.13(d,J＝18.0Hz, 1H),3.37(d,J＝7.6Hz,1H),3.70(d,J＝8.0Hz,1H),4.17(d,J＝18.0Hz,1H),6.71 (d,J＝7.6Hz,1H),6.91-6.97(m,2H),7.18-7.22(m,1H).13C{1H}NMR(100MHz, CDCl3)δ0.67,1.42,13.6,16.9,21.1,22.0,23.9,45.1,45.4,46.6,64.5,66.8,109.9, 120.8,122.2,128.5,133.7,147.8,173.3,206.8.HRMS calcd for C20H26N2O2Na: 349.1886[M+Na]+,found:349.1872.
2,2-Dimethyl-9-(2-oxopentyl)-9-phenethyl-2,3-dihydropyrazolo[1,2-a]indazol-1(9 H)-one(3jj)
Yellowish syrup(96.1mg,82％).1H NMR(400MHz,CDCl3)δ0.79(t,J＝7.2Hz,3H),1.23(s,3H),1.39-1.48(m,5H),2.05(td,J1＝12.0Hz,J2＝3.6Hz,1H), 2.18-2.26(m,1H),2.31-2.49(m,3H),2.69(td,J1＝13.2Hz,J2＝4.4Hz,1H),2.99(d, J＝17.2Hz,1H),3.54(d,J＝8.0Hz,1H),3.62(d,J＝8.0Hz,1H),3.91(d,J＝17.2 Hz,1H),6.73(d,J＝8.0Hz,1H),6.93-7.00(m,2H),7.08-7.15(m,3H),7.20-7.25(m, 3H).13C{1H}NMR(100MHz,CDCl3)δ13.6,16.9,22.2,23.6,30.2,42.0,45.5,45.8, 47.1,64.2,66.7,109.8,121.2,122.5,125.9,128.4,128.8,133.1,141.5,147.7,172.2, 206.8.HRMS calcd forC25H30N2O2Na:413.2199[M+Na]+,found:413.2180.
实施例4
向15mL耐压管中依次加入1a(57mg,0.3mmol)、2a(52mg,0.3mmol)、四氢呋喃(2mL)、二氯(五甲基环戊二烯基)合铑(III)二聚体([RhCp*Cl2]2,4.7mg, 0.0075mmol)和碳酸钠(15.9mg,0.15mmol)，盖上塞子密封，将其置于100℃油浴中搅拌反应2小时。待反应结束后，冷却至室温，抽滤，旋干，过硅胶柱分离(石油醚/乙酸乙酯＝1/1)得白色固体产物4a(78.3mg,72％)。该化合物的表征数据为：1H NMR(400MHz,CDCl3)δ0.69(t,J＝7.6Hz,3H),1.20(s,6H), 1.48-1.58(m,2H),2.37(t,J＝7.2Hz,2H),4.89(s,2H),5.79(br s,2H),7.09(t,J＝ 7.6Hz,1H),7.30-7.34(m,1H),7.38-7.49(m,6H),7.57(d,J＝8.4Hz,1H).13C{1H}NMR(100MHz,CDCl3)δ13.6,18.1,24.0,44.7,45.1,51.3,111.8,120.9,121.4, 125.1,125.8,126.9,127.7,128.6,130.5,133.4,134.9,138.6,179.7,198.4.HRMS calcd forC23H27N2O2:363.2067[M+H]+,found:363.2057.
实施例5
依照实施例4的方法和步骤，通过改变反应物1和2，可以合成出各种2- 酰基吲哚类化合物4，具体结果见表3。
表3各种2-酰基吲哚类化合物4的合成a,b
Figure BDA0002501308430000101
代表性产物表征数据如下：
3-(2-Butyryl-5-methyl-3-phenyl-1H-indol-1-yl)-2,2-dimethylpropanamide(4b)
White solid(76.8mg,68％).1H NMR(400MHz,CDCl3)δ0.68(t,J＝7.2Hz,3H),1.19(s,6H),1.47-1.57(m,2H),2.34-2.37(m,5H),4.87(s,2H),5.85(br s,1H),5.90 (brs,1H),7.13-7.17(m,2H),7.37-7.39(m,2H),7.40-7.49(m,4H).13C{1H}NMR (100 MHz,CDCl3)δ13.7,18.2,21.3,24.0,44.7,45.1,51.3,111.6,120.5,124.7, 127.1,127.7,127.8,128.6,130.4,130.5,133.4,135.1,137.2,179.8,198.2.HRMS calcd forC24H28N2O2Na:399.2043[M+Na]+,found:399.2011.
3-(2-Butyryl-5-methoxy-3-phenyl-1H-indol-1-yl)-2,2-dimethylpropanamide(4d)
White solid(81.2mg,69％).1H NMR(400MHz,CDCl3)δ0.60(t,J＝7.2Hz,3H),1.11(s,6H),1.39-1.48(m,2H),2.25(t,J＝7.6Hz,2H),3.65(s,3H),4.78(s,2H), 5.70(brs,2H),0.69(d,J＝2.4Hz,1H),6.91(dd,J1＝9.2Hz,J2＝2.8Hz,1H), 7.30-7.33(m,2H),7.35-7.42(m,4H).13C{1H}NMR(100MHz,CDCl3)δ13.7,18.2, 24.0,44.7,45.0,51.4,55.7,101.0,113.0,117.3,124.6,127.0,127.7,128.7,130.4, 133.8,134.0,135.1,155.0,179.7,198.1.HRMS calcd for C24H28N2O3Na:415.1992 [M+Na]+,found:415.1987.
3-(2-Butyryl-5-fluoro-3-phenyl-1H-indol-1-yl)-2,2-dimethylpropanamide(4e)
White solid(68.5mg,60％).1H NMR(400MHz,CDCl3)δ0.69(t,J＝7.6Hz,3H),1.20(s,6H),1.48-1.57(m,2H),2.35-2.39(m,2H),4.86(s,2H),5.67(br s,1H),5.73 (brs,1H),7.04-7.09(m,2H),7.35-7.38(m,2H),7.41-7.50(m,3H),7.51-7.55(m, 1H).13C{1H}NMR(100MHz,CDCl3)δ13.6,18.0,23.9,44.5,45.1,51.5,105.4(d, 2JC-F＝22.7Hz),113.1(d,3JC-F＝8.8Hz),114.7(d,2JC-F＝26.6Hz),124.6(d,4JC-F＝ 4.8Hz),127.0(d,3JC-F＝9.4Hz),127.9,128.7,130.3,134.4,134.6,135.1,158.4(d, 1JC-F＝236.0Hz),179.5,198.3.19F NMR(376MHz,CDCl3)δ-122.58(td,J1＝8.3 Hz,J2＝4.1Hz).HRMS calcd forC23H25FN2O2Na:403.1792[M+Na]+,found: 403.1786.
3-(2-Butyryl-3-phenyl-5-(trifluoromethyl)-1H-indol-1-yl)-2,2-dimethylpropanami de(4h)
White solid(80.1mg,62％).1H NMR(400MHz,CDCl3)δ0.62(t,J＝7.6Hz,3H),1.12(s,6H),1.41-1.50(m,2H),2.30(t,J＝7.2Hz,2H),4.83(s,2H),5.67(br s,1H), 5.83(br s,1H),7.30(dd,J1＝8.0Hz,J2＝1.6Hz,2H),7.39-7.45(m,4H),7.59-7.62 (m,2H).13C{1H}NMR(100MHz,CDCl3)δ13.6,17.8,23.9,44.5,45.2,51.4,112.4, 119.2(q,3JC-F＝4.3Hz),122.0(q,3JC-F＝3.0Hz),123.4(q,2JC-F＝31.5Hz),124.9(q, 1JC-F＝269.6Hz),125.3,126.1,128.2,128.8,130.3,133.8,134.9,139.6,179.4,198.4. 19F NMR(376MHz,CDCl3)δ-60.75(s).HRMS calcd for C24H25F3N2O2Na: 453.1760[M+Na]+,found:453.1748.
3-(2-Butyryl-5-cyano-3-phenyl-1H-indol-1-yl)-2,2-dimethylpropanamide(4i)
White solid(58.1mg,50％).1H NMR(400MHz,CDCl3)δ0.71(t,J＝7.6Hz,3H),1.21(s,6H),1.49-1.59(m,2H),2.40(t,J＝7.2Hz,2H),4.90(s,2H),5.61(br s,1H), 5.69(br s,1H),7.36(dd,J1＝8.0Hz,J2＝2.0Hz,2H),7.48-7.54(m,4H),7.68(d,J＝ 8.4Hz,1H),7.79(d,J＝1.2Hz,1H).13C{1H}NMR(100MHz,CDCl3)δ13.6,17.7, 23.9,44.4,45.3,51.4,104.2,113.0,119.9,124.8,126.6,127.4,127.6,128.5,128.9, 130.3,133.2,135.1,139.7,179.1,198.3.HRMS calcd for C24H25N3O2Na:410.1839 [M+Na]+,found:410.1839.
3-(2-Butyryl-3-(thiophen-2-yl)-1H-indol-1-yl)-2,2-dimethylpropanamide(4z)
White solid(58.6mg,53％).1H NMR(400MHz,CDCl3)δ0.77(t,J＝7.2Hz,3H),1.19(s,6H),1.54-1.63(m,2H),2.53(t,J＝7.2Hz,2H),4.86(s,2H),5.78(br s,1H), 5.81(br s,1H),7.05(d,J＝3.2Hz,1H),7.11-7.17(m,2H),7.32(t,J＝7.6Hz,1H), 7.47(d,J＝4.8Hz,1H),7.53-7.57(m,2H).13C{1H}NMR(100MHz,CDCl3)δ13.7, 18.2,24.0,44.6,44.9,51.3,111.8,116.4,121.29,121.31,125.8,126.9,127.46, 127.49,128.7,134.6,134.9,138.4,179.6,198.3.HRMS calcd for C21H24N2O2SNa: 391.1451[M+Na]+,found:391.1443.
3-(2-Butyryl-3-(pyridin-3-yl)-1H-indol-1-yl)-2,2-dimethylpropanamide(4aa)
White solid(65.4mg,60％).1H NMR(400MHz,CDCl3)δ0.72(t,J＝7.2Hz,3H),1.21(s,6H),1.51-1.60(m,2H),2.36(t,J＝7.2Hz,2H),4.91(s,2H),5.86(br s,1H), 5.92(br s,1H),7.12(t,J＝7.2Hz,1H),7.32-7.39(m,2H),7.42-7.45(m,1H),7.61(d, J＝8.4Hz,1H),7.75(dt,J＝7.6Hz,J＝2.0Hz,1H),8.66-8.69(m,2H).13C{1H} NMR(100MHz,CDCl3)δ13.6,17.9,24.0,44.6,45.5,51.3,112.0,120.4,120.7, 121.4,123.4,126.0,126.7,131.1,134.0,137.7,138.7,148.9,150.9,179.5,197.6. HRMS calcd forC22H25N3O2Na:386.1839[M+Na]+,found:386.1826.
3-(2-Butyryl-3-cyclopropyl-1H-indol-1-yl)-2,2-dimethylpropanamide(4bb)
White solid(68.6mg,70％).1H NMR(400MHz,CDCl3)δ0.70-0.74(m,2H),1.04(t,J＝7.2Hz,3H),1.09-1.14(m,8H),1.75-1.84(m,2H),2.03-2.08(m,1H),3.25(t,J＝7.6Hz,2H),4.78(s,2H),5.74(br s,1H),5.90(br s,1H),7.10(td,J＝8.0Hz,J＝0.4 Hz,1H),7.24-7.28(m,1H),7.47(d,J＝8.4Hz,1H),7.85(d,J＝8.0Hz,1H).13C{1H} NMR(100MHz,CDCl3)δ7.8,14.1,17.7,24.0,44.7,45.8,51.0,111.8,120.1,121.4, 124.0,125.2,127.5,135.7,138.6,179.7,198.0.HRMS calcd for C20H26N2O2Na: 349.1886[M+Na]+,found:349.1877.
3-(3-Butyl-2-butyryl-1H-indol-1-yl)-2,2-dimethylpropanamide(4cc)
White solid(72.9mg,71％).1H NMR(400MHz,CDCl3)δ0.97(t,J＝7.2Hz,3H),1.04(t,J＝7.2Hz,3H),1.10(s,6H),1.41-1.50(m,2H),1.61-1.69(m,2H),1.75-1.85 (m,2H),2.94(t,J＝7.2Hz,2H),3.02(t,J＝8.0Hz,2H),4.81(s,2H),5.69(br s,1H), 5.86(brs,1H),7.10(t,J＝7.6Hz,1H),7.26-7.30(m,1H),7.47(d,J＝8.4Hz,1H), 7.63(d,J＝8.0Hz,1H).13C{1H}NMR(100MHz,CDCl3)δ14.0,14.1,18.0,23.1, 24.0,25.7,34.2,44.8,45.0,51.2,111.8,120.0,120.6,124.3,125.5,126.7,133.7, 139.3,179.7,197.0.HRMScalcd for C21H30N2O2Na:365.2199[M+Na]+,found: 365.2189.
3-(2-Butyryl-3-phenethyl-1H-indol-1-yl)-2,2-dimethylpropanamide(4dd)
White solid(84.4mg,72％).1H NMR(400MHz,CDCl3)δ0.98(t,J＝7.6Hz,3H),1.08(s,6H),1.67-1.76(m,2H),2.78(t,J＝7.2Hz,2H),2.98(t,J＝8.4Hz,2H),3.31 (t,J＝8.4Hz,2H),4.79(s,2H),5.65(br s,1H),5.83(br s,1H),7.10-7.15(m,3H), 7.18-7.22(m,1H),7.24-7.32(m,3H),7.49(d,J＝8.4Hz,1H),7.65(d,J＝8.0Hz, 1H).13C{1H}NMR(100MHz,CDCl3)δ14.1,17.9,24.0,28.2,37.8,44.8,45.0,51.3, 111.9,120.3,120.5,122.4,125.6,126.3,126.5,128.5,134.2,139.4,141.4,179.6, 196.8.HRMS calcd forC25H30N2O2Na:413.2199[M+Na]+,found:413.2182.
实施例6
本发明所合成的产物吡唑并[1,2-a]吡唑酮类化合物3或2-酰基吲哚类化合物4可以进行一系列反应，从而合成进一步的衍生物。例如：
Figure BDA0002501308430000131
向10mL耐压管中依次加入4a(72.5mg，0.2mmol)、EtOH(2mL)和KOH (224mg，4mmol)，将此混合物置于80℃油浴中搅拌过夜。反应结束后，冷却至室温，缓慢加入1％盐酸水溶液，至体系呈酸性。然后将反应混合物转移至分液漏斗中，用DCM(10mL×3)萃取。合并有机相，用无水硫酸钠干燥，过滤并减压蒸发，得到残余物。将残余物转移至反应瓶中，加入多聚磷酸(2mL)，盖上塞子密封，并置于135℃油浴中加热4小时。待反应完成后，冷却至室温。在剧烈搅拌下将反应混合物倒入冰水中，接着用乙酸乙酯(10mL×3)萃取，合并有机相，用5％氢氧化钠水溶液洗涤两次。分离的有机相用无水硫酸钠干燥，过滤，旋干，过硅胶柱分离(石油醚/乙酸乙酯＝50/1)得到黄色固体5(31.1mg, 45％)。该化合物的表征数据如下：1H NMR(400MHz,CDCl3)δ:0.73(t,J＝7.6Hz, 3H),1.34(s,6H),1.51-1.60(m,2H),2.41(t,J＝7.2Hz,2H),4.58(s,2H),7.24(t,J＝ 7.6Hz,1H),7.44-7.54(m,5H),7.70-7.72(m,1H),7.89-7.91(m,1H).13C NMR(150 MHz,CDCl3)δ:13.5,18.3,23.4,43.6,44.0,55.6,117.4,121.6,123.6,125.3,126.9, 127.7,128.1,128.7,130.3,133.7,134.1,139.0,197.2,198.1.
Figure BDA0002501308430000141
向10mL耐压管中依次加入4o(66.9mg，0.2mmol)和无水二氯甲烷(2mL)，将得到的悬浮液置于0℃下搅拌，并向其加入吡啶(40mg)和三氟乙酸酐(58.8 mg，0.28mmol)，接着盖上塞子密封，在室温下搅拌过夜。反应结束后，加入1％ HCl水溶液至体系呈中性。分液，并用乙酸乙酯(10mL×3)萃取水相。合并有机相，用无水硫酸镁干燥，过滤，旋干，过硅胶柱分离(石油醚/乙酸乙酯＝10/1) 得到无色浆状物6(50.6mg,80％)。该化合物的表征数据如下：1H NMR(400MHz, CDCl3)δ:0.70(t,J＝7.6Hz,3H),1.48-1.57(m,2H),2.37(t,J＝7.2Hz,2H),3.02(t, J＝6.8Hz,2H),4.72(t,J＝6.8Hz,2H),7.14-7.18(m,1H),7.39-7.41(m,2H),7.44-7.52(m,6H).13C NMR(100MHz,CDCl3)δ:13.6,18.3,19.2,41.3,44.3,109.8, 117.9,121.6,122.2,126.1,126.7,127.5,128.0,128.7,130.4,132.3,134.4,137.6, 197.4.HRMScalcd for C21H21N2O:317.1648[M+H]+,found:317.1647.
以上实施例描述了本发明的基本原理、主要特征及优点。本行业的技术人员应该了解，本发明不受上述实施例的限制，上述实施例和说明书中描述的只是说明本发明的原理，在不脱离本发明原理的范围下，本发明还会有各种变化和改进，这些变化和改进均落入本发明保护的范围内。

Claims (8)

1.选择性合成吡唑并[1,2-a]吡唑酮3或2-酰基吲哚类化合物4的方法，其特征在于，包括如下操作：1-芳基吡唑烷酮类化合物1与炔基环丁醇类化合物2，在二氯(五甲基环戊二烯基)合铑(III)二聚体和添加剂存在下，有机溶剂中升温反应得到吡唑并[1,2-a]吡唑酮类化合物3或2-酰基吲哚类化合物4；反应方程式为：
Figure FDA0002501308420000011
其中：添加剂为醋酸钠、醋酸铯或磷酸钾时，反应得到吡唑并[1,2-a]吡唑酮类化合物3；添加剂为碳酸钠或碳酸钾时，反应得到2-酰基吲哚类化合物4；
在上述反应方程式中，R1为氢、卤素、三氟甲基、氰基、硝基、C1-4烷基或C1-4烷氧基，R2为氢或C1-4烷基，R3为氢或C1-4烷基，R4为C1-6链状烷基或链状取代烷基、环丙基、噻吩基、吡啶基、苯基或取代苯基，取代苯基苯环上的取代基为卤素、三氟甲基、C1-4烷基或C1-4烷氧基，R5为氢或C1-4烷氧羰基。
2.根据权利要求1所述选择性合成吡唑并[1,2-a]吡唑酮3或2-酰基吲哚类化合物4的方法，其特征在于：所述取代基中，卤素选自氟、氯、溴或碘。
3.根据权利要求1所述选择性合成吡唑并[1,2-a]吡唑酮3或2-酰基吲哚类化合物4的方法，其特征在于：所述有机溶剂选自1,2-二氯乙烷、二氯甲烷、乙腈、1,4-二氧六环、甲醇、四氢呋喃或2-甲基四氢呋喃。
4.根据权利要求3所述选择性合成吡唑并[1,2-a]吡唑酮3或2-酰基吲哚类化合物4的方法，其特征在于：合成吡唑并[1,2-a]吡唑酮类化合物3时，溶剂选自1,2-二氯乙烷、二氯甲烷、乙腈、1,4-二氧六环或甲醇；合成2-酰基吲哚类化合物4时，溶剂选自四氢呋喃或2-甲基四氢呋喃。
5.根据权利要求3所述选择性合成吡唑并[1,2-a]吡唑酮3或2-酰基吲哚类化合物4的方法，其特征在于：反应温度为60-120℃。
6.根据权利要求5所述选择性合成吡唑并[1,2-a]吡唑酮3或2-酰基吲哚类化合物4的方法，其特征在于：升高温度有利于2-酰基吲哚类化合物4的生成，当温度范围为100-120℃时，反应主要得到2-酰基吲哚类化合物4。
7.根据权利要求1所述选择性合成吡唑并[1,2-a]吡唑酮3或2-酰基吲哚类化合物4的方法，其特征在于：对于吡唑并[1,2-a]吡唑酮类化合物3，所述添加剂为醋酸钠或醋酸铯；对于2-酰基吲哚类化合物4，所述添加剂为碳酸钠。
8.根据权利要求1-7任意一项所述选择性合成吡唑并[1,2-a]吡唑酮3或2-酰基吲哚类化合物4的方法，其特征在于：所述1-芳基吡唑烷酮类化合物1、炔基环丁醇类化合物2、添加剂与二氯(五甲基环戊二烯基)合铑(III)二聚体的投料摩尔比为1-1.5:1-1.5:0.2-0.5:0.02-0.03。
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