新型吡唑啉酮-六氢山酮素-氧化吲哚衍生物的合成

2020-02-24姜维艳刘雄利邓国栋

合成化学 2020年1期

姜维艳, 岳静, 刘雄利, 邓国栋*

(1. 贵州装备制造职业学院，贵州贵阳 550025;2. 贵州大学贵州省药食同源植物资源开发工程技术研究中心，贵州贵阳 550025)

把两个或多个有生物活性的骨架拼接成具有潜在生物活性的多骨架分子，是重要的新化合物构造策略[1-2]。六氢山酮素骨架在广泛存在于药物和天然产物分子中。如天然产物分子Diversonol， Desoxydiversonol， Ergochrome DD和Isocochlioquinone A共有一个六氢山酮素骨架单元，这类化合物具有良好的镇痛作用[3-5]。螺六元碳环氧化吲哚主要存在于天然产物和合成药物分子中[6-8]，如天然产物分子Satavaptan表现出明显的生物活性。螺环吡唑啉酮是重要的天然产物和药物分子[9-11]，在生物制药领域有重要应用价值。因此，将螺环吡唑啉酮和六氢山酮素骨架拼接到螺环氧化吲哚骨架上，有望合成一系列具有多样性特征的新化合物，为生物活性筛选提供化合物源。目前合成六氢山酮素骨架的方法主要为：以3-吸电子基团的色酮为起始原料[12-14]，经4+2环加成反应合成，反应存在底物局限性。

Scheme 1

本文以色酮-吡唑啉酮合成子(1)与3-烯键氧化吲哚(2)[15]为原料，DABCO为催化剂，氯仿为溶剂，于室温发生分子间Michael加成反应后再发生分子内环化反应，合成了14个新型的吡唑啉酮六氢山酮素骨架拼接氧化吲哚3a～3n，产率75%～89%，dr值7/1～11/1,其结构经1H NMR,13C NMR和HR-MS(ESI-TOF)表征。

1 实验部分

1.1 仪器与试剂

WRS-1B型数字熔点仪；Bruker-500 MHz型核磁共振仪(CDCl3为溶剂，TMS为内标);MicroTMQ-TOF型高分辨质谱仪。

所用试剂均为分析纯。

1.2 3a～3n的合成(以3a为例)

在反应管中依次加入吡唑啉酮-色酮合成子(1a)66.4 mg(0.20 mmol)， 3-烯键氧化吲哚(2a)8.03 mg(0.25 mmol)， 10 mol%DABCO 2.24 mg(0.02 mmol)和氯仿2.0 mL，搅拌下于室温反应约3 d(TLC检测)。经硅胶柱层析[洗脱剂：V(石油醚)/V(乙酸乙酯)=5/1]纯化得化合物3a113.7 mg。

用类似的方法合成3b～3n。

3a: 白色固体,产率87%, m.p.160.4～161.3 ℃, 7/1dr;1H NMRδ: 0.93(s, 9H), 2.19(s, 3H), 2.42～2.47(m, 1H), 2.49～2.53(m, 1H), 2.77(s, 3H), 3.79～3.84(m, 2H), 5.93(d,J=9.6 Hz, 1H), 6.93(d,J=5.6 Hz, 1H), 7.02～7.04(m, 1H), 7.23～7.25(m, 1H), 7.38～7.42(m, 2H), 7.44～7.47(m, 2H), 7.85～7.86(m, 1H), 7.97(d,J=5.2 Hz, 2H), 8.07(s, 1H), 8.30(d,J=5.6 Hz, 1H);13C NMRδ: 13.1, 25.9, 26.7, 27.0, 38.3, 52.1, 52.9, 53.6, 80.2, 83.6, 116.9, 117.8, 119.2, 120.2, 122.3, 125.4, 127.1, 127.3, 128.9, 129.4, 129.8, 131.2, 136.3, 138.0, 140.1, 159.9, 160.3, 165.8, 170.4, 175.2, 178.7, 192.0; HR-MS(ESI-TOF)m/z: Calcd for C36H32N3O7ClNa{[M+Na]+}676.1821, found 676.1827。

3b: 白色固体,产率80%, m.p.123.2～124.7 ℃, 8/1dr;1H NMRδ: 0.88(s, 9H), 2.19(s, 3H), 2.34(s, 3H), 2.41～2.45(m, 1H), 2.52～2.56(m, 1H), 2.76(s, 3H), 3.80～3.86(m, 2H), 5.95(d,J=9.6 Hz, 1H), 6.72(d,J=5.6 Hz, 1H), 6.99～7.02(m, 1H), 7.18～7.20(m, 1H), 7.22～7.25(m, 1H), 7.38～7.41(m, 1H), 7.44～7.47(m, 2H), 7.78(s, 1H), 7.84～7.86(m, 1H), 7.96～7.98(m, 2H), 8.20(d,J=5.6 Hz, 1H);13C NMRδ: 13.2, 21.4, 25.8, 26.8, 26.9, 38.4, 52.3, 53.0, 53.5, 80.3, 83.0, 115.5, 117.9, 119.3, 120.3, 122.0, 125.2, 127.2, 127.3, 127.9, 128.8, 129.7, 135.5, 136.1, 138.2, 139.2, 160.2, 160.4, 166.0, 170.5, 175.2, 179.5, 192.4; HR-MS(ESI-TOF)m/z: Calcd for C37H35N3O7Na{[M+Na]+}656.236, found 656.2361。

3c: 白色固体,产率80%, m.p.126.3～127.4 ℃, 11/1dr;1H NMRδ: 0.88(s, 9H), 1.19(s, 3H), 1.20(s, 3H), 2.18(s, 3H), 2.34(s, 3H), 2.41～2.45(m, 1H), 2.50～2.54(m, 1H), 2.75(s, 3H), 2.83～2.88(m, 1H), 3.78～3.83(m, 2H), 5.91(d,J=9.6 Hz, 1H), 6.66(d,J=5.6 Hz, 1H), 7.19(d,J=5.6 Hz, 1H), 7.22～7.24(m, 1H), 7.26～7.29(m, 1H), 7.44～7.46(m, 2H), 7.69(s, 1H), 7.77(s, 1H), 7.97(d,J=5.2 Hz, 2H), 8.19(d,J=5.6 Hz, 1H);13C NMRδ: 13.2, 21.4, 23.9, 25.9, 26.8, 26.9, 33.3, 38.5, 52.2, 53.0, 53.5, 80.4, 83.0, 115.5, 117.8, 119.3, 119.9, 124.4, 125.2, 127.2, 128.0, 128.8, 129.6, 134.8, 135.5, 138.2, 139.2, 142.7, 158.5, 160.4, 166.1, 170.5, 175.2, 179.5, 192.7; HR-MS(ESI-TOF)m/z: Calcd for C40H41N3O7Na{[M+Na]+}698.2837, found 698.2839。

3d: 白色固体,产率89%, m.p.131.4～132.7 ℃, 9/1dr;1H NMRδ: 0.92(s, 9H), 1.20(s, 3H), 1.21(s, 3H), 2.18(s, 3H), 2.45～2.49(m, 2H), 2.76(s, 3H), 2.84～2.89(m, 1H), 3.77～3.82(m, 2H), 5.84(d,J=9.6 Hz, 1H), 6.67(d,J=5.6 Hz, 1H), 7.22～7.25(m, 2H), 7.29～7.31(m, 1H), 7.43～7.46(m, 2H), 7.70(s, 1H), 7.93(d,J=5.2 Hz, 2H), 7.97(d,J=5.6 Hz, 1H), 8.40(s, 1H);13C NMRδ: 13.1, 23.9, 26.0, 26.7, 27.0, 33.3, 38.3, 52.0, 52.8, 53.4, 80.3, 83.4, 116.3, 117.7, 119.5, 119.9, 124.2, 125.4, 125.8, 126.5, 127.8, 128.9, 135.0, 135.1, 138.0, 142.4, 143.0, 158.3, 160.4, 165.9, 170.4, 175.4, 179.0, 192.4; HR-MS(ESI-TOF)m/z: Calcd for C39H38N3O7ClNa{[M+Na]+}718.2290, found 718.2294。

3e: 白色固体,产率83%, m.p.128.3～129.6 ℃, 8/1dr;1H NMRδ: 0.92(s, 9H), 1.20(s, 3H), 1.21(s, 3H), 2.18(s, 3H), 2.45～2.49(m, 2H), 2.76(s, 3H), 2.84～2.89(m, 1H), 3.77～3.82(m, 2H), 5.84(d,J=5.2 Hz, 1H), 6.68(d,J=5.6 Hz, 1H), 7.23～7.25(m, 1H), 7.29～7.31(m, 1H), 7.38～7.40(m, 1H), 7.43～7.46(m, 2H), 7.70(s, 1H), 7.92～7.94(m, 3H), 8.56(s, 1H);13C NMRδ: 13.1, 23.9, 26.0, 26.7, 27.0, 33.3, 38.3, 52.0, 52.8, 53.5, 80.2, 83.4, 117.7, 119.0, 119.5, 119.9, 123.1, 124.2, 125.5, 127.1, 128.2, 128.8, 128.9, 135.0, 138.0, 142.5, 143.0, 158.3, 160.4, 165.9, 170.4, 175.4, 178.9, 192.4; HR-MS(ESI-TOF)m/z: Calcd for C39H38N3O7BrNa{[M+Na]+}762.1785, found 762.1784。

3f: 白色固体,产率75%, m.p.120.6～121.7 ℃, 9/1dr;1H NMRδ: 0.87(s, 9H), 2.18(s, 3H), 2.43～2.52(m, 2H), 2.77(s, 3H), 3.81～3.86(m, 2H), 5.95(d,J=9.6 Hz, 1H), 6.69～6.71(m, 1H), 7.10～7.13(m, 1H), 7.22～7.26(m, 2H), 7.39～7.42(m, 1H), 7.43～7.46(m, 2H), 7.49～7.51(m, 1H), 7.94(d,J=5.2 Hz, 2H), 7.98(d,J=5.2 Hz, 1H), 8.33(d,J=5.2 Hz, 1H);13C NMRδ: 13.1, 25.8, 26.8, 26.9, 38.4, 52.3, 52.9, 53.4, 80.6, 83.2, 112.2 (d,JCF=24.3 Hz), 115.7, 119.5, 119.6, 123.6 (d,JCF=24.0 Hz), 125.4, 125.9, 126.8, 127.8, 128.9, 129.4, 138.0, 141.5, 156.3, 157.6 (d,JCF=241.5 Hz), 160.3, 165.9, 170.5, 175.3, 179.3, 191.6; HR-MS(ESI-TOF)m/z: Calcd for C36H32N3O7FNa{[M+Na]+}660.2116, found 660.2118。

3g: 白色固体,产率84%, m.p.118.0～119.3 ℃, 7/1dr;1H NMRδ: 0.92(s, 9H), 2.18(s, 3H), 2.45～2.50(m, 1H), 2.77(s, 3H), 3.78～3.83(m, 2H), 5.89(d,J=9.6 Hz, 1H), 6.72～6.75(m, 1H), 7.13～7.16(m, 1H), 7.23～7.26(m, 2H), 7.44～7.47(m, 2H), 7.49～7.51(m, 1H), 7.92～7.96(m, 3H), 8.40(s, 1H);13C NMRδ: 13.1, 25.8, 26.7, 27.0, 38.3, 52.1, 52.8, 53.3, 80.5, 83.5, 112.3(d,JCF=22.5 Hz), 116.3, 119.6, 120.8, 123.8(d,JCF=25.5 Hz), 125.6, 125.9, 126.3, 127.9, 128.9, 135.3, 137.9, 142.3, 156.2, 157.8(d,JCF=231.8 Hz), 160.2, 165.8, 170.4, 175.3, 178.9, 191.4; HR-MS(ESI-TOF)m/z: Calcd for C36H31N3O7FClNa{[M+Na]+}694.1727, found 694.1732。

3h: 白色固体,产率82%, m.p.105.3～106.4 ℃, 10/1dr;1H NMRδ: 0.92(s, 9H), 2.18(s, 3H), 2.45～2.49(m, 2H), 2.77(s, 3H), 3.78～3.83(m, 2H), 5.88(d,J=9.6 Hz, 1H), 6.73～6.75(m, 1H), 7.13～7.16(m, 1H), 7.24～7.26(m, 1H), 7.39～7.41(m, 1H), 7.44～7.47(m, 2H), 7.49～7.51(m, 1H), 7.89～7.93(m, 3H), 8.55(s, 1H);13C NMRδ: 13.1, 25.8, 26.7, 27.0, 38.3, 52.1, 52.8, 53.3, 80.4, 83.5, 112.3 (d,JCF=22.5 Hz), 119.1, 119.6, 123.3, 123.8(d,JCF=24.0 Hz), 125.6, 126.8, 128.2, 128.9, 137.9, 142.4, 156.2, 157.3 (d,JCF=246.0 Hz), 160.2, 165.7, 170.4, 175.3, 178.8, 191.4; HR-MS(ESI-TOF)m/z: Calcd for C36H31N3O7FBrNa{[M+Na]+}738.1222, found 738.1222。

3i: 白色固体,产率82%, m.p.139.1～140.4 ℃, 9/1dr;1H NMRδ: 0.87(s, 9H), 2.18(s, 3H), 2.42～2.47(m, 1H), 2.49～2.53(m, 1H), 2.77(s, 3H), 3.82～3.86(m, 2H), 5.96(d,J=9.6 Hz, 1H), 6.69(d,J=6.0 Hz, 1H), 7.23～7.26(m, 2H), 7.33～7.35(m, 1H), 7.39～7.42(m, 1H), 7.44～7.46(m, 2H), 7.80(s, 1H), 7.95(d,J=5.2 Hz, 2H), 7.98(d,J=4.8 Hz, 1H), 8.32(d,J=5.6 Hz, 1H);13C NMRδ: 13.1, 25.8, 26.8, 26.9, 38.3, 52.3, 52.8, 53.4, 80.6, 83.2, 115.7, 119.5, 119.6, 121.0, 125.4, 126.0, 126.6, 126.8, 127.7, 128.9, 129.4, 136.0, 138.0, 141.5, 158.5, 160.2, 165.9, 170.5, 175.2, 179.3, 191.3; HR-MS(ESI-TOF)m/z: Calcd for C36H32N3O7ClNa{[M+Na]+}676.1821, found 676.1827。

3j: 白色固体,产率84%, m.p.128.5～129.4 ℃, 10/1dr;1H NMRδ: 0.93(s, 9H), 2.19(s, 3H), 2.42～2.52(m, 2H), 2.76(s, 3H), 3.78～3.84(m, 2H), 5.95(d,J=9.6 Hz, 1H), 6.70(d,J=6.0 Hz, 1H), 7.23～7.26(m, 1H), 7.35～7.40(m, 2H), 7.45～7.47(m, 2H), 7.81(s, 1H), 7.96(d,J=5.2 Hz, 2H), 8.05(s, 1H), 8.29(d,J=6.0 Hz, 1H);13C NMRδ: 13.1, 25.8, 26.7, 27.0, 38.2, 52.2, 52.9, 53.5, 80.4, 83.7, 117.0, 119.2, 119.6, 121.0, 125.4, 126.6, 127.1, 127.9, 128.9, 129.5, 129.6, 131.3, 136.1, 138.0, 140.0, 158.3, 160.1, 165.6, 170.3, 175.1, 178.5, 191.0; HR-MS(ESI-TOF)m/z: Calcd for C36H31N3O7Cl2Na{[M+Na]+}710.1431, found 710.1436。

3k: 白色固体,产率87%, m.p.127.6～128.7 ℃, 7/1dr;1H NMRδ: 0.92(s, 9H), 2.19(s, 3H), 2.45～2.48(m, 2H), 2.76(s, 3H), 3.80～3.85(m, 2H), 5.92(d,J=9.6 Hz, 1H), 6.70(d,J=6.0 Hz, 1H), 7.10～7.13(m, 1H), 7.24～7.26(m, 1H), 7.35～7.37(m, 1H), 7.44～7.47(m, 2H), 7.81(s, 1H), 7.84～7.86(m, 1H), 7.95(d,J=5.2 Hz, 2H), 8.32～8.34(m, 1H);13C NMRδ: 13.1, 25.8, 26.7, 27.0, 38.2, 52.1, 52.8, 53.6, 80.5, 83.5, 114.6, 114.8, 115.9, 116.0, 117.1, 119.4, 119.5, 121.0, 125.5, 126.6, 127.9, 128.9, 129.7, 136.1, 137.6, 137.9, 158.3, 159.7, 160.2, 161.3, 165.7, 170.3, 175.3, 178.8, 191.0; HR-MS(ESI-TOF)m/z: Calcd for C36H31N3O7FClNa{[M+Na]+}694.1727, found 694.1727。

3l: 白色固体,产率84%, m.p.146.5～147.3 ℃, 7/1dr;1H NMRδ: 0.97(s, 9H), 2.21(s, 3H), 2.46～2.53(m, 2H), 2.78(s, 3H), 3.79～3.86(m, 2H), 5.98(d,J=11.2 Hz, 1H), 6.72(d,J=7.2 Hz, 1H), 7.25～7.28(m, 1H), 7.37～7.40(m, 1H), 7.46～7.50(m, 2H), 7.56～7.58(m, 1H), 7.83(s, 1H), 7.99(d,J=6.4 Hz, 2H), 8.21(s, 1H), 8.25(d,J=7.2 Hz, 1H);13C NMRδ: 13.0, 25.8, 26.5, 27.0, 38.2, 52.3, 52.9, 53.5, 80.4, 83.7, 117.3, 118.9, 119.2, 119.5, 121.1, 125.4, 126.6, 127.9, 128.8, 129.9, 130.0, 132.4, 136.0, 138.0, 140.5, 158.3, 160.0, 165.6, 170.2, 175.1, 178.4, 190.8; HR-MS(ESI-TOF)m/z: Calcd for C36H31N3O7ClBrNa{[M+Na]+}754.0926, found 754.0922。

3m: 白色固体,产率80%, m.p.121.2～122.4 ℃, 10/1dr;1H NMRδ: 0.88(s, 9H), 2.18(s, 3H), 2.34(s, 3H), 2.40～2.44(m, 1H), 2.50～2.54(m, 1H), 2.76(s, 3H), 3.80～3.85(m, 2H), 5.97(d,J=9.6 Hz, 1H), 6.70(d,J=6.0 Hz, 1H), 7.19(d,J=5.6 Hz, 1H), 7.23～7.25(m, 1H), 7.33～7.35(m, 1H), 7.44～7.47(m, 2H), 7.76(s, 1H), 7.80(s, 1H), 7.96(d,J=5.2 Hz, 2H), 8.19(d,J=5.6 Hz, 1H);13C NMRδ: 13.1, 21.4, 25.7, 26.8, 26.9, 38.4, 52.4, 53.0, 53.3, 80.5, 83.1, 115.6, 119.3, 119.6, 121.1, 125.3, 126.5, 127.2, 127.6, 128.9, 129.8, 135.6, 135.9, 138.1, 139.2, 158.6, 160.2, 165.9, 170.4, 175.2, 179.4, 191.3; HR-MS(ESI-TOF)m/z: Calcd for C37H34N3O7ClNa{[M+Na]+}690.1977, found 690.1971。

Scheme 2

3n: 白色固体,产率86%, m.p.112.9～113.4 ℃, 7/1dr;1H NMRδ: 0.83(s, 9H), 2.08(s, 3H), 2.32～2.42(m, 2H), 2.67(s, 3H), 3.69～3.74(m, 2H), 5.81(d,J=9.6 Hz, 1H), 6.63(d,J=6.0 Hz, 1H), 7.14～7.17(m, 1H), 7.26～7.28(m, 1H), 7.30～7.32(m, 1H), 7.35～7.37(m, 2H), 7.72(s, 1H), 7.79～7.83(m, 3H), 8.46(s, 1H);13C NMRδ: 12.1, 24.7, 25.7, 26.0, 37.2, 51.1, 51.7, 52.3, 79.4, 82.5, 118.0, 118.5, 120.0, 122.3, 124.5, 125.6, 125.7, 126.9, 127.2, 127.9, 135.1, 136.9, 141.4, 157.3, 159.1, 164.7, 169.3, 174.2, 177.7, 190.0; HR-MS(ESI-TOF)m/z: Calcd for C36H31N3O7ClBrNa{[M+Na]+}754.0926, found 754.0928。