CN106866496B - 六氢苯并喹啉-6-酮和六氢苯并吲哚-5-酮化合物、合成方法及用途 - Google Patents

六氢苯并喹啉-6-酮和六氢苯并吲哚-5-酮化合物、合成方法及用途 Download PDF

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CN106866496B
CN106866496B CN201710267105.7A CN201710267105A CN106866496B CN 106866496 B CN106866496 B CN 106866496B CN 201710267105 A CN201710267105 A CN 201710267105A CN 106866496 B CN106866496 B CN 106866496B
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游书力
徐人奇
顾庆
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Shanghai Institute of Organic Chemistry of CAS
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Abstract

本发明涉及一种六氢苯并喹啉‑6‑酮和六氢苯并吲哚‑5‑酮化合物、合成方法及用途，具体地，所述的化合物具有如下式I所示的结构(取代基定义如说明书中所示)。该类化合物属于天然产物Mesembrine的衍生物，具有潜在的生物及医药应用前途。

Description

六氢苯并喹啉-6-酮和六氢苯并吲哚-5-酮化合物、合成方法 及用途
技术领域
本发明涉及一种六氢苯并喹啉-6-酮和六氢苯并吲哚-5-酮化合物、合成方法及用途，具体地，本发明提供了一类天然产物Mesembrine的衍生物，所述的衍生物具有潜在的生物及医药应用前途。
背景技术
酚类化合物广泛的存在于自然界中并且是廉价易得的化学合成原料。近年来对于酚类化合物的去芳构化反应迅速发展起来，便捷的构建了环状烯酮结构，这些结构是一些天然产物以及生物活性分子的基本骨架。其中，利用金属钯催化的芳基化去芳构反应具有成键高效，产物结构多样的特点。已有的一些报道通过分子内底物设计，构建复杂的产物骨架。然而金属钯催化的分子间芳基化去芳构化反应更具挑战，已知的报道仅有一例[Xu,R.-Q.；Yang,P.；Tu,H.-F.；Wang,S.-G.；You,S.-L.Angew.Chem.Int.Ed.2016,55,15137.]。主要原因是分子间反应相对于分子内反应具有更加激烈的傅克芳基化以及醚化等副反应。在这一领域中，我们发展了金属钯催化的1-萘酚衍生物与芳基卤化物的分子间芳基化去芳构化串联Michael加成反应。有效的避免了傅克芳基化以及醚化等副反应。并且该反应可以高效的构建含氮杂环化合物，如六氢苯并喹啉-6-酮和六氢苯并吲哚-5-酮化合物。含氮化合物存在于大量的具有生物活性的天然产物和药物分子中[(a)Cordell,G.A.The alkaloid；Academic Press:New York,1998.Vol.51.(b)Pelmutter,P.Conjugate AdditionReactions in Organic Synthesis；Pergamon:Oxford,1992.(c)Kibayashi,C.Chem.Pharm.Bull.2005,53,1375.(d)Naito,T.Chem.Pharm.Bull.2008,56,1367.]。尤为重要的是该类六氢苯并喹啉-6-酮和六氢苯并吲哚-5-酮是天然产物(-)-Mesembrine的衍生物。(-)-Mesembrine。该类化合物是从Sceletium tortuosum分离得到的主要生物碱成分，具有显著的生理活性，如抑制血清素再摄入[Gericke,N.P.；VanWyk,B.-E.PCTInt.Appl.,WO 9746234CAN 128:80030,1997.]。其衍生物也很有可能具有多样的生物活性。因而高效便捷的合成该类生物碱的衍生物，对于药物化学或是有机合成化学都具有重要意义。
综上所述，本领域尚待开发新的Mesembrine的衍生物，以及相应的制备方法。
发明内容
本发明的目的是提供一种新的Mesembrine的衍生物，以及相应的制备方法。
本发明的第一方面，提供了一种如下式I所示的化合物：
其中，Y选自下组：CH2或CH2CH2；
R1为H、C1-C4的烷基、C2-C4的酰基、C2-C4的酯基、C1-C4的磺酰基、被1-5个R2取代的苯酰基
Figure BDA0001276336750000022
或被1-5个R2取代的苯磺酰基
Figure BDA0001276336750000023
R2为H、C1-C4的烷基、卤素、硝基，或C1-C4的烷氧基；
Ar选自下组：R3取代或未取代的C6-C20芳基，R3取代或未取代的5-20元杂芳基；其中，所述的杂芳基含有1-3个选自N、O或S的基团；
其中，所述的R3选自下组：卤素、硝基、氰基、苯基、对甲苯磺酰基、C1-C4的烷基、C1-C4的全氟烷基、C2-C4的烯基、C1-C4的甲酸酯基、或C1-C4的烷氧基。
在另一优选例中，所述的芳基选自下组：苯基、萘基或菲基。
在另一优选例中，所述的杂芳基选自下组：噻吩基、呋喃基、吡咯基、吲哚基、苯并噻吩基，或苯并呋喃基。
在另一优选例中，所述的式I化合物选自下组：
Figure BDA0001276336750000031
本发明的第二方面，提供了一种如本发明第一方面所述的化合物的制备方法，所述方法包括步骤：
Figure BDA0001276336750000032
在惰性溶剂中，用1-萘酚衍生物和ArX反应，得到式I化合物；
其中，X为卤素，其余各基团的定义如本发明第一方面中所述。
在另一优选例中，所述的反应在催化剂存在下进行，且所述的催化剂为金属钯前体/膦配体；和/或
所述的反应在碱存在下进行。
在另一优选例中，所述的反应在25℃至100℃下进行。
在另一优选例中，所述的反应时间为2小时-96小时。
在另一优选例中，所述的1-萘酚衍生物、卤素取代芳(杂)基化合物、金属钯前体、膦配体和碱的摩尔比为1：1-3：0.01-0.5：0.01-0.5：1-3。
在另一优选例中，所述的卤素X选自下组：氯、溴、碘。
在另一优选例中，所述的金属钯前体选自下组：PdCl2、PdCl2(MeCN)2、PdCl2(PhCN)2、PdCl2(COD)、Pd(OAc)2、Pd2(dba)3、Pd(dba)2、Pd2(dba)3·CHCl3、[Pd(C3H5)Cl]2、[Pd(prenyl)Cl]2、[Pd(cinnammyl)Cl]2、Pd(PPh3)4，或其组合；和/或
所述的膦配体为：
Figure BDA0001276336750000041
Figure BDA0001276336750000042
或其组合；和/或
所述的碱选自下组：K2CO3、Cs2CO3、Na2CO3、K3PO4、KOH、NaOH、KOAc、NaOAc、tBuOK、tBuOLi、tBuONa、DBU、Et3N、吡啶，或其组合。
在另一优选例中，所述的惰性溶剂选自下组：苯、四氯化碳、石油醚、四氢呋喃、二甲基甲酰胺、乙醚、二氯甲烷、三氯甲烷、甲苯、二甲苯、环己烷、正庚烷、二氧六环、乙腈，或其组合。
在另一优选例中，所述反应完成后，所得产物经过重结晶，薄层层析，和/或柱层析减压蒸馏加以分离。
本发明的第三方面，提供了一种如本发明第一方面所述的式I化合物的用途，用于制备如下结构式II的化合物：
Figure BDA0001276336750000051
本发明的第四方面，提供了一种如下式II所示的化合物的制备方法，包括步骤：
Figure BDA0001276336750000052
在惰性溶剂中，用式I化合物进行还原反应，得到式II化合物；
其中，各基团的定义如本发明第一方面中所述。
在另一优选例中，所述的还原反应在选自下组的还原剂存在下进行：四氢铝锂，硼氢化钠，氰基硼氢化钠、三乙基硼氢化锂，或其组合。
本发明的第五方面，提供了一种所述的式I化合物的用途，用于制备如下结构式III的化合物：
Figure BDA0001276336750000053
其中Ar、R1、Y如本发明第一方面中所述。
本发明的第六方面，提供了一种如下式III所示的化合物的制备方法，所述方法包括步骤：
Figure BDA0001276336750000054
在惰性溶剂中，用式I化合物进行还原反应，得到式III化合物；
其中，各基团的定义如本发明第一方面中所述。
在另一优选例中，所述的还原剂为四氢铝锂，NH2NH2，锌汞齐或钠汞齐。
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。限于篇幅，在此不再一一累述。
具体实施方式
本发明人经过长期而深入的研究，通过将金属钯催化的分子间芳基化去芳构反应运用到该类生物碱衍生物的合成中，并串联Michael加成反应，简单高效地合成了一系列结构多样的Mesembrine衍生物。基于上述发现，发明人完成了本发明。
六氢苯并喹啉-6-酮化合物和六氢苯并吲哚-5-酮化合物
本发明提供了一种六氢苯并喹啉-6-酮化合物和六氢苯并吲哚-5-酮化合物及其制备方法，所述的化合物具有如下结构式：
Figure BDA0001276336750000061
其中Y任意选自CH2或CH2CH2；R1为C1-C4的烷基、C1-C4的酰基、C1-C4的酯基、C1-C4的磺酰基或R2取代苯磺酰基
Figure BDA0001276336750000062
R2为C1-C4的烷基、卤素、硝基或C1-C4的烷氧基；Ar任意选自R3取代的芳基或R3取代的含N,O或S的杂芳基；所述的芳基是苯基、萘基或菲基；所述的杂芳基是噻吩基、呋喃基、吡咯基、吲哚基、苯并噻吩基或苯并呋喃基；R3为苯基、C1-C4的烷基、C1-C4的全氟烷基、卤素、硝基、氰基、C1-C4的甲酸酯基或C1-C4的烷氧基。
本发明的一种手性六氢苯并喹啉-6-酮化合物和六氢苯并吲哚-5-酮是以1-萘酚衍生物和卤素取代芳(杂)基化合物为原料，在有机溶剂的存在下，以金属钯前体以及膦配体为催化剂在碱的协助下反应制得，所述方法可用如下反应式表示：
Figure BDA0001276336750000063
所述反应在有机溶剂中，在温度为25℃至100℃下，用1-萘酚衍生物和卤素取代芳基化合物或卤素取代杂芳基化合物为原料，金属钯前体以及膦配体为催化剂，在碱的协助下反应2小时-96小时。
优选地，所述的1-萘酚衍生物、卤素取代芳(杂)基化合物、金属钯前体、膦配体和碱的摩尔比为1：1-3：0.01-0.5：0.01-0.5：1-3，推荐反应的摩尔比为：1-萘酚衍生物：卤素取代芳(杂)基化合物：金属钯前体：膦配体：碱＝1：1.5：0.05-0.2：0.05-0.2：1.5。
在另一优选例中，推荐的反应温度为：60℃至80℃。
优选的所述的金属钯前体包括：PdCl2、PdCl2(MeCN)2、PdCl2(PhCN)2、PdCl2(COD)、Pd(OAc)2、Pd2(dba)3、Pd(dba)2、Pd2(dba)3·CHCl3、[Pd(C3H5)Cl]2、[Pd(prenyl)Cl]2、[Pd(cinnammyl)Cl]2、Pd(PPh3)4。
优选的所述的膦配体为：
Figure BDA0001276336750000071
Figure BDA0001276336750000072
优选地，所述的碱选自下组：K2CO3、Cs2CO3、Na2CO3、K3PO4、KOH、NaOH、KOAc、NaOAc、tBuOK、tBuOLi、tBuONa、DBU、Et3N、吡啶，或其组合。
本发明方法中，所述水为蒸馏水。
所述有机溶剂可以是极性或非极性溶剂，如苯、四氯化碳、石油醚、四氢呋喃、二甲基甲酰胺、乙醚、二氯甲烷、三氯甲烷、甲苯、二甲苯、环己烷、正己烷、正庚烷、二氧六环、乙腈等。
采用本发明方法所得产物可以经过重结晶，薄层层析，柱层析减压蒸馏等方法加以分离。
如用重结晶的方法，推荐溶剂为极性溶剂与非极性溶剂的混合溶剂，例如二氯甲烷――正己烷，异丙醇――石油醚，乙酸乙酯――石油醚，乙酸乙酯――正己烷，异丙醇――乙酸乙酯――石油醚等混合溶剂。
如用薄层层析和柱层析方法，所用的展开剂为极性溶剂与非极性溶剂的混合溶剂。推荐溶剂可为异丙醇――石油醚，乙酸乙酯――石油醚，乙酸乙酯――正己烷，异丙醇――乙酸乙酯――石油醚等混合溶剂，其体积比可以分别是：极性溶剂：非极性溶剂＝1：0.1-500。例如：乙酸乙酯：石油醚＝1：0.1-50，异丙醇：石油醚＝1：0.1-500。
六氢苯并喹啉-6-酮化合物和六氢苯并吲哚-5-酮化合物的用途
本发明还提供了一种对六氢苯并喹啉-6-酮化合物和六氢苯并吲哚-5-酮化合物进行转化，从而还原酮羰基到亚甲基或羟基的方法。
在本发明的一个优选实施例中，所述的六氢苯并喹啉-6-酮化合物和六氢苯并吲哚-5-酮可以用于制备如下含有羟基结构的化合物：
Figure BDA0001276336750000081
其中，各基团定义如上文中所述。
具体地，所述的制备方法包括步骤：
Figure BDA0001276336750000082
用六氢苯并喹啉-6-酮化合物和六氢苯并吲哚-5-酮经还原剂还原，即可获得该化合物。在上述反应中，所述的还原剂选自下组：四氢铝锂，硼氢化钠，氰基硼氢化钠，或三乙基硼氢化锂。
在本发明的另一个优选实施例中，所述的六氢苯并喹啉-6-酮化合物和六氢苯并吲哚-5-酮还可以用于制备如下化合物：
Figure BDA0001276336750000083
其中，各基团的定义如上文中所述。
具体地，所述的制备方法包括步骤：
Figure BDA0001276336750000084
将六氢苯并喹啉-6-酮化合物和六氢苯并吲哚-5-酮经还原剂还原，即可获得该化合物。在上述反应中，所述的还原剂选自下组：四氢铝锂，NH2NH2，锌汞齐或钠汞齐。
与现有技术相比，本发明的主要优点包括：
1.本发明提供了一种结构新颖的六氢苯并喹啉-6-酮和六氢苯并吲哚-5-酮化合物，及其制备方法；
2.本发明提供了一类Mesembrine衍生物的制备方法，所述方法可以用于制备具有生物活性的Mesembrine系列化合物。
实施例1：钯催化α-naphthols芳基化去芳构化串联Michael加成反应
Figure BDA0001276336750000091
干燥反应管抽换Ar三次，依次加入[Pd(prenyl)Cl]2(4.2mg,0.01mmol,5mol％),Q-Phos(15.7mg,0.022mmol,11mol％),K2CO3(41.5mg,0.3mmol,1.5equiv.)，1-萘酚底物(0.2mmol,1.0equiv.)。再抽换Ar三次，加入钠丝重蒸甲苯(2.0mL)以及溴苯(47.1mg,0.3mmol,1.5equiv.)。加热70℃。TLC监测至反应结束，冷至室温，加入乙酸乙酯(3mL)稀释，过硅藻土抽滤。减压旋干后硅胶拌样，柱层析分离(石油醚/丙酮＝15/1-8/1)得产物。
以下化合物通过选用相应原料制备得到：
Figure BDA0001276336750000092
9b-phenyl-3-tosyl-1,2,3,3a,4,9b-hexahydro-5H-benzo[e]indol-5-one(P1)
9b-苯基-3-对甲苯磺酰基-1,2,3,3a,4,9b-六氢-5H-苯并[e]吲哚-5-酮(P1)
白色固体,m.p.＝171-173℃,76.9mg,92％yield.1H NMR(400MHz,CDCl3)δ8.07(d,J＝7.6Hz,1H),7.61(d,J＝8.0Hz,2H),7.50(t,J＝7.2Hz,1H),7.38(t,J＝7.6Hz,1H),7.25(d,J＝7.6Hz,2H),7.20-7.19(m,3H),7.06(d,J＝8.0Hz,1H),6.92-6.91(m,2H),4.16(t,J＝4.0Hz,1H),3.65-3.60(m,1H),3.30(dd,J＝16.4,5.2Hz,1H),3.05(td,J＝10.4,6.4Hz,1H),2.90(dd,J＝16.4,3.2Hz,1H),2.53-2.38(m,2H),2.44(s,3H).13C NMR(100MHz,CDCl3)δ195.4,144.7,143.6,142.1,134.4,134.3,132.8,129.7,129.0,128.7,127.5,127.4,127.24,127.20,126.4,67.4,53.9,47.6,39.9,37.7,21.5.IR(thin film):νmax(cm-1)＝1691,1596,1493,1443,1345,1293,1241,1158,1087,1062,1011,945,895,821,758,717,700,659,605,550,522,484；HRMS(ESI)高分辨质谱计算值:C25H27N2O3S[M+NH4]+:435.1737；实测值:435.1737.
Figure BDA0001276336750000101
9b-(p-tolyl)-3-tosyl-1,2,3,3a,4,9b-hexahydro-5H-benzo[e]indol-5-one(P2)
9b-对甲基苯基-3-对甲苯磺酰基-1,2,3,3a,4,9b-六氢-5H-苯并[e]吲哚-5-酮(P2)
白色固体,m.p.＝76-78℃,81.0mg,94％yield.1H NMR(400MHz,CDCl3)δ8.07(d,J＝7.6Hz,1H),7.60(d,J＝8.0Hz,2H),7.49(t,J＝7.6Hz,1H),7.37(t,J＝7.6Hz,1H),7.25(d,J＝8.0Hz,2H),7.05(d,J＝7.6Hz,1H),7.00(d,J＝7.6Hz,2H),6.78(d,J＝8.0Hz,2H),4.14(t,J＝3.2Hz,1H),3.64-3.58(m,1H),3.29(dd,J＝16.4,5.6Hz,1H),3.05(td,J＝10.4,6.4Hz,1H),2.91(dd,J＝16.4,3.2Hz,1H),2.50-2.44(m,1H),2.44(s,3H),2.39-2.35(m,1H),2.29(s,3H).13C NMR(100MHz,CDCl3)δ195.5,145.0,143.5,142.7,139.1,137.0,134.3,134.2,132.7,129.5,129.3,129.0,127.3,127.0,126.3,67.4,53.6,47.6,40.0,37.5,21.5,20.8.IR(thin film):νmax(cm-1)＝2973,2900,1692,1596,1450,1407,1334,1300,1258,1159,1087,1062,1022,898,812,772,709,657,599,539；HRMS(ESI)高分辨质谱计算值:C26H29N2O3S[M+NH4]+:449.1893；实测值:449.1894.
Figure BDA0001276336750000102
9b-(4-(tert-butyl)phenyl)-3-tosyl-1,2,3,3a,4,9b-hexahydro-5H-benzo[e]indol-5-one(P3)
9b-对叔丁基苯基-3-对甲苯磺酰基-1,2,3,3a,4,9b-六氢-5H-苯并[e]吲哚-5-酮(P3)
白色固体,m.p.＝87-89℃,79.8mg,84％yield.1H NMR(400MHz,CDCl3)δ8.10(d,J＝8.0Hz,1H),7.68(d,J＝8.0Hz,2H),7.53(t,J＝7.2Hz,1H),7.40(t,J＝7.2Hz,1H),7.32(d,J＝8.0Hz,2H),7.24(d,J＝8.4Hz,2H),7.15(d,J＝8.0Hz,1H),6.84(d,J＝8.4Hz,2H),4.12-4.07(m,1H),3.65-3.61(m,1H),3.35(dd,J＝16.8,4.0Hz,1H),2.92(td,J＝10.4,5.6Hz,1H),2.84(dd,J＝16.8,2.8Hz,1H),2.46(s,3H),2.42-2.32(m,2H),1.27(s,9H).13CNMR(100MHz,CDCl3)δ195.4,150.3,144.6,143.7,138.5,134.6,134.2,133.1,129.7,128.8,127.6,127.5,126.9,126.4,125.6,67.4,53.8,47.7,39.1,38.2,34.3,31.2,21.6.IR(thin film):νmax(cm-1)＝2959,2900,1692,1598,1511,1451,1402,1344,1293,1242,1160,1091,1017,941,821,765,717,659,606,573,548；HRMS(ESI)高分辨质谱计算值:C29H35N2O3S[M+NH4]+:491.2363；实测值:491.2363.
9b-(4-methoxyphenyl)-3-tosyl-1,2,3,3a,4,9b-hexahydro-5H-benzo[e]indol-5-one(P4)
9b-对甲氧基苯基-3-对甲苯磺酰基-1,2,3,3a,4,9b-六氢-5H-苯并[e]吲哚-5-酮(P4)
白色固体,m.p.＝189-191℃,64.7mg,72％yield.1H NMR(400MHz,CDCl3)δ8.06(d,J＝7.6Hz,1H),7.60(d,J＝8.0Hz,2H),7.49(t,J＝7.6Hz,1H),7.37(t,J＝7.6Hz,1H),7.24(d,J＝8.0Hz,2H),7.05(d,J＝7.6Hz,1H),6.82(d,J＝8.8Hz,2H),6.71(d,J＝8.8Hz,2H),4.13(dd,J＝5.6,4.0Hz,1H),3.76(s,3H),3.63-3.58(m,1H),3.28(dd,J＝16.4,5.6Hz,1H),3.06(td,J＝10.0,6.4Hz,1H),2.91(dd,J＝16.4,3.2Hz,1H),2.50-2.35(m,2H),2.44(s,3H).13C NMR(100MHz,CDCl3)δ195.5,158.6,145.1,143.6,134.5,134.2,134.1,132.6,129.6,129.0,128.3,127.4,126.3,113.9,67.4,55.2,53.3,47.5,40.1,37.6,21.5.IR(thin film):νmax(cm-1)＝2946,2898,2834,1685,1598,1510,1469,1449,1338,1299,1249,1186,1156,1018,901,826,810,774,754,701,667,598,547；HRMS(ESI)高分辨质谱计算值:C26H29N2O4S[M+NH4]+:465.1843；实测值:465.1845.
Figure BDA0001276336750000121
9b-([1,1’-biphenyl]-4-yl)-3-tosyl-1,2,3,3a,4,9b-hexahydro-5H-benzo[e]indol-5-one(P5)
9b-[1,1’-联苯基]-3-对甲苯磺酰基-1,2,3,3a,4,9b-六氢-5H-苯并[e]吲哚-5-酮(P5)
浅黄色固体,m.p.＝91-93℃,85.3mg,86％yield.1H NMR(400MHz,CDCl3)δ8.08(d,J＝7.6Hz,1H),7.59(d,J＝8.0Hz,2H),7.54-7.49(m,3H),7.45-7.32(m,6H),7.20(d,J＝8.0Hz,2H),7.07(d,J＝7.6Hz,1H),6.97(d,J＝8.4Hz,2H),4.25-4.22(m,1H),3.67-3.61(m,1H),3.30(dd,J＝16.4,6.0Hz,1H),3.17-3.11(m,1H),2.99(dd,J＝16.4,3.2Hz,1H),2.60-2.52(m,1H),2.46-2.41(m,1H),2.29(s,3H).13C NMR(100MHz,CDCl3)δ195.4,144.8,143.6,141.3,140.0,139.8,134.34,134.32,132.6,129.6,129.1,128.8,127.6,127.54,127.46,127.3,127.1,126.8,126.4,67.4,53.6,47.6,40.4,37.4,21.4.IR(thin film):νmax(cm-1)＝2977,2898,1685,1597,1486,1451,1337,1298,1259,1156,1090,1062,1021,834,811,767,697,662,610,590,547,512；HRMS(ESI)高分辨质谱计算值:C31H31N2O3S[M+NH4]+:511.2050；实测值:511.2050.
Figure BDA0001276336750000122
9b-(4-fluorophenyl)-3-tosyl-1,2,3,3a,4,9b-hexahydro-5H-benzo[e]indol-5-one(P6)
9b-对氟苯基-3-对甲苯磺酰基-1,2,3,3a,4,9b-六氢-5H-苯并[e]吲哚-5-酮(P6)
白色固体,m.p.＝76-78℃,78.9mg,91％yield.1H NMR(400MHz,CDCl3)δ8.06(d,J＝7.6Hz,1H),7.57(d,J＝8.0Hz,2H),7.50(t,J＝7.2Hz,1H),7.38(t,J＝7.6Hz,1H),7.23(d,J＝8.0Hz,2H),6.99(d,J＝8.0Hz,1H),6.88-6.85(m,4H),4.17(dd,J＝5.6,4.0Hz,1H),3.64-3.58(m,1H),3.26(dd,J＝16.8,6.4Hz,1H),3.18-3.11(m,1H),2.94(dd,J＝16.4,3.6Hz,1H),2.44(s,3H),2.55-2.40(m,2H).13C NMR(100MHz,CDCl3)δ195.2,161.6(d,J＝246.2Hz),144.7,143.7,138.2(d,J＝3.3Hz),134.4,134.2,132.4,129.6,129.0,128.9(d,J＝8.0Hz),127.5,127.2,126.4,115.5(d,J＝21.2Hz),67.3,53.3,47.5,40.5,37.4,21.4.19F NMR(376Hz,CDCl3)δ-114.8(m)；IR(thin film):νmax(cm-1)＝2979,2904,1694,1599,1508,1463,1329,1298,1260,1225,1156,1089,1060,1020,836,807,780,698,666,597,558,536,496,440；HRMS(ESI)高分辨质谱计算值:C25H26FN2O3S[M+NH4]+:453.1643；实测值:453.1645.
Figure BDA0001276336750000131
3-tosyl-9b-(4-(trifluoromethyl)phenyl)-1,2,3,3a,4,9b-hexahydro-5H-benzo[e]indol-5-one(P7)
3-对甲苯磺酰基-9b-(4-三氟甲基苯基)-1,2,3,3a,4,9b-六氢-5H-苯并[e]吲哚-5-酮(P7)
白色固体,m.p.＝209-210℃,62.8mg,65％yield.1H NMR(400MHz,CDCl3)δ8.07(dd,J＝8.0,1.2Hz,1H),7.55(d,J＝8.4Hz,2H),7.50(td,J＝8.0,1.2Hz,1H),7.44-7.38(m,3H),7.20(d,J＝8.0Hz,2H),7.05(d,J＝8.0Hz,2H),6.95(d,J＝7.6Hz,1H),4.25(dd,J＝6.4,4.0Hz,1H),3.66-3.60(m,1H),3.29-3.19(m,2H),2.97(dd,J＝16.4,4.0Hz,1H),2.60(dt,J＝13.2,8.0Hz,1H),2.52-2.45(m,1H),2.41(s,3H).13C NMR(100MHz,CDCl3)δ195.0,146.9,144.2,143.8,134.5,134.3,132.4,129.6,129.5(q,J＝32.4Hz),129.1,127.8,127.7,127.2,126.6,125.6(q,J＝3.7Hz),123.7(q,J＝270.8Hz),67.2,53.8,47.4,40.8,37.2,21.4.19F NMR(376Hz,CDCl3)δ-62.6(s)；IR(thin film):νmax(cm-1)＝2921,2888,1696,1597,1473,1410,1330,1303,1261,1236,1202,1161,1120,1065,1020,851,813,771,738,706,661,629,590,549,497；HRMS(ESI)高分辨质谱计算值:C26H26F3N2O3S[M+NH4]+:503.1611；实测值:503.1610.
Figure BDA0001276336750000132
4-((3aR,9bR)-5-oxo-3-tosyl-1,2,3,3a,4,5-hexahydro-9bH-benzo[e]indol-9b-yl)benzonitrile(P8)
4-(5-氧-3-对甲苯磺酰基-1,2,3,3a,4,5-六氢-9bH-苯并[e]吲哚-9b-yl)苯腈(P8)
白色固体,m.p.＝233-235℃,35.2mg,40％yield.1H NMR(400MHz,CDCl3)δ8.08(dd,J＝7.6,1.2Hz,1H),7.56(d,J＝8.0Hz,2H),7.53-7.46(m,3H),7.43-7.40(m,1H),7.22(d,J＝8.0Hz,2H),7.05(d,J＝8.4Hz,2H),6.92(d,J＝7.6Hz,1H),4.23(dd,J＝6.8,4.0Hz,1H),3.67-3.61(m,1H),3.27-3.19(m,2H),2.94(dd,J＝16.8,4.0Hz,1H),2.64-2.57(m,1H),2.52-2.47(m,4H).13C NMR(100MHz,CDCl3)δ194.7,148.2,144.0,143.7,134.6,134.4,132.42,132.39,129.7,129.0,128.2,128.0,127.2,126.8,118.1,111.3,67.1,54.0,47.4,40.8,37.2,21.6.IR(thin film):νmax(cm-1)＝2919,2851,2227,1687,1599,1455,1326,1303,1264,1157,1092,1063,1021,836,816,778,699,665,596,557,505；HRMS(ESI)高分辨质谱计算值:C26H26N3O3S[M+NH4]+:460.1689；实测值:460.1689.
Figure BDA0001276336750000141
9b-(m-tolyl)-3-tosyl-1,2,3,3a,4,9b-hexahydro-5H-benzo[e]indol-5-one(P9)
9b-间甲基苯基-3-对甲苯磺酰基-1,2,3,3a,4,9b-六氢-5H-苯并[e]吲哚-5-酮(P9)
浅黄色固体,m.p.＝157-159℃,78.5mg,91％yield.1H NMR(400MHz,CDCl3)δ8.06(d,J＝7.6Hz,1H),7.60(d,J＝8.0Hz,2H),7.49(t,J＝7.6Hz,1H),7.37(t,J＝7.6Hz,1H),7.24(d,J＝7.6Hz,2H),7.09-6.98(m,3H),6.67-6.69(m,2H),4.18-4.16(m,1H),3.64-3.59(m,1H),3.27(dd,J＝16.8,5.6Hz,1H),3.07(td,J＝9.6,6.0Hz,1H),2.93(dd,J＝16.8,3.2Hz,1H),2.52-2.35(m,2H),2.44(s,3H),2.21(s,3H).13C NMR(100MHz,CDCl3)δ195.6,145.0,143.5,142.2,138.2,134.3,132.6,129.5,129.1,128.5,127.9,127.7,127.35,127.32,126.3,124.5,67.4,53.8,47.7,40.2,37.6,21.5,21.4.IR(thin film):νmax(cm-1)＝2891,1690,1597,1448,1346,1293,1231,1159,1087,1005,966,941,908,852,822,778,754,719,701,659,608,575,546,456,433；HRMS(ESI)高分辨质谱计算值:C26H29N2O3S[M+NH4]+:449.1893；实测值:449.1894.
9b-(3-fluorophenyl)-3-tosyl-1,2,3,3a,4,9b-hexahydro-5H-benzo[e]indol-5-one(P10)
9b-间氟苯基-3-对甲苯磺酰基-1,2,3,3a,4,9b-六氢-5H-苯并[e]吲哚-5-酮(P10)
黄色固体,m.p.＝63-65℃,76.8mg,88％yield.1H NMR(400MHz,CDCl3)δ8.07(d,J＝7.6Hz,1H),7.60(d,J＝8.0Hz,2H),7.51(t,J＝7.6Hz,1H),7.39(t,J＝7.6Hz,1H),7.25(d,J＝8.0Hz,2H),7.19-7.14(m,1H),7.02(d,J＝8.0Hz,1H),6.91-6.87(m,1H),6.69(d,J＝7.6Hz,1H),6.57(d,J＝10.8Hz,1H),4.18-4.16(m,1H),3.65-3.60(m,1H),3.28(dd,J＝16.8,6.0Hz,1H),3.15-3.09(m,1H),2.93(dd,J＝16.8,3.6Hz,1H),2.50-2.39(m,2H),2.44(s,3H).13C NMR(100MHz,CDCl3)δ195.1,162.7(d,J＝245.6Hz),145.2(d,J＝6.6Hz),144.2,143.8,134.4,134.2,132.5,130.2(d,J＝8.3Hz),129.7,129.0,127.7,127.3,126.5,123.2(d,J＝2.8Hz),114.4(d,J＝22.2Hz),114.2(d,J＝20.4Hz),67.2,53.7,47.6,40.4,37.6,21.5.19F NMR(376Hz,CDCl3)δ-111.8(m)；IR(thin film):νmax(cm-1)＝2918,1687,1593,1475,1442,1339,1295,1254,1220,1158,1090,1065,1019,946,865,811,787,768,706,660,597,578,546,497,445；HRMS(ESI)高分辨质谱计算值:C25H26FN2O3S[M+NH4]+:453.1643；实测值:453.1644.
Figure BDA0001276336750000152
9b-(3,4-dimethoxyphenyl)-3-tosyl-1,2,3,3a,4,9b-hexahydro-5H-benzo[e]indol-5-one(P11)
9b-(3,4-二甲氧基苯基)-3-对甲苯磺酰基-1,2,3,3a,4,9b-六氢-5H-苯并[e]吲哚-5-酮(P11)
黄色固体,m.p.＝83-85℃,85.7mg,90％yield.1H NMR(400MHz,CDCl3)δ8.05(d,J＝8.0Hz,1H),7.59(d,J＝8.0Hz,2H),7.49(t,J＝7.6Hz,1H),7.37(t,J＝7.6Hz,1H),7.23(d,J＝8.0Hz,2H),7.05(d,J＝7.6Hz,1H),6.66(d,J＝8.4Hz,1H),6.44(d,J＝8.4Hz,1H),6.32(s,1H),4.18-4.16(m,1H),3.83(s,3H),3.65(s,3H),3.65-3.61(m,1H),3.26(dd,J＝16.4,6.0Hz,1H),3.17-3.10(m,1H),2.96(dd,J＝16.4,3.6Hz,1H),2.43(s,3H),2.50-2.38(m,2H).13C NMR(100MHz,CDCl3)δ195.5,148.7,148.1,145.0,143.6,134.5,134.24,134.19,132.3,129.4,129.1,127.4,127.3,126.2,119.9,110.6,110.0 67.3,55.7,55.5,53.5,47.6,40.5,37.5,21.4.IR(thin film):νmax(cm-1)＝2957,2932,2901,1688,1594,1519,1453,1409,1336,1293,1271,1154,1088,1023,944,915,854,814,756,717,657,626,597,573,544,467；HRMS(ESI)高分辨质谱计算值:C27H31N2O5S[M+NH4]+:495.1948；实测值:495.1949.
Figure BDA0001276336750000161
9b-(2-fluorophenyl)-3-tosyl-1,2,3,3a,4,9b-hexahydro-5H-benzo[e]indol-5-one(P12)
9b-2-氟苯基-3-对甲苯磺酰基-1,2,3,3a,4,9b-六氢-5H-苯并[e]吲哚-5-酮(P12)
白色固体,m.p.＝216-218℃,74.6mg,86％yield.1H NMR(400MHz,CDCl3)δ7.99(dd,J＝8.0,1.6Hz,1H),7.46(d,J＝8.0Hz,2H),7.40(td,J＝7.6,1.2Hz,1H),7.34-7.30(m,1H),7.19-7.13(m,1H),7.04(d,J＝8.0Hz,2H),6.97(td,J＝8.0,1.6Hz,1H),6.89-6.79(m,3H),4.59(dd,J＝8.8,5.2Hz,1H),3.57-3.45(m,2H),3.22-3.19(dd,J＝16.0,5.6Hz,1H),3.11(dd,J＝16.4,8.8Hz,1H),2.85-2.79(m,1H),2.50(dt,J＝13.6,8.0Hz,1H),2.34(s,3H).13C NMR(100MHz,CDCl3)δ195.6,160.7(d,J＝247.4Hz),144.9,143.1,134.0,133.8,131.4(d,J＝1.7Hz),130.2(d,J＝9.5Hz),129.4,129.2(d,J＝9.0Hz),128.4,127.7(d,J＝3.4Hz),127.2,126.8,126.3,124.0(d,J＝3.4Hz),116.9(d,J＝22.8Hz),64.4(d,J＝4.6Hz),51.1,47.2,43.3,35.4,21.4.19F NMR(376Hz,CDCl3)δ-108.1(s)；IR(thinfilm):νmax(cm-1)＝2914,1680,1596,1490,1451,1333,1296,1203,1157,1092,1017,904,859,810,756,702,660,594,543,499,477；HRMS(ESI)高分辨质谱计算值:C25H26FN2O3S[M+NH4]+:453.1643；实测值:453.1641.
Figure BDA0001276336750000171
9b-(naphthalen-2-yl)-3-tosyl-1,2,3,3a,4,9b-hexahydro-5H-benzo[e]indol-5-one(P13)
9b-2-萘基-3-对甲苯磺酰基-1,2,3,3a,4,9b-六氢-5H-苯并[e]吲哚-5-酮(P13)
浅黄色固体,m.p.＝235-236℃,65.3mg,70％yield.1H NMR(400MHz,CDCl3)δ8.07(d,J＝7.2Hz,1H),7.77-7-75(m,1H),7.63(d,J＝8.8Hz,1H),7.60-7.58(m,1H),7.48-7.34(m,6H),6.95-6.91(m,2H),6.87(d,J＝8.0Hz,2H),4.44(dd,J＝7.2,4.4Hz,1H),3.70-3.64(m,1H),3.43-3.39(m,1H),3.22(dd,J＝16.4,7.6Hz,1H),3.12(dd,J＝16.4,4.4Hz,1H),2.82-2.76(m,1H),2.58-2.52(m,1H),2.12(s,3H).13C NMR(100MHz,CDCl3)δ195.7,145.3,143.4,140.1,134.3,134.0,132.7,132.2,132.1,129.6,129.2,128.7,127.8,127.4,127.3,126.9,126.5,126.44,126.38,125.7,125.5,67.2,53.8,47.5,42.0,36.7,21.3.IR(thin film):νmax(cm-1)＝2893,1684,1598,1474,1452,1338,1300,1260,1156,1091,1059,1018,854,812,774,746,701,666,594,550,477；HRMS(ESI)高分辨质谱计算值:C29H29N2O3S[M+NH4]+:485.1893；实测值:485.1893.
3-tosyl-9b-(1-tosyl-1H-indol-5-yl)-1,2,3,3a,4,9b-hexahydro-5H-benzo[e]indol-5-one(P14)
3-对甲苯磺酰基-9b-(1-对甲苯磺酰基-1H-吲哚-5-yl)-1,2,3,3a,4,9b-六氢-5H-苯并[e]吲哚-5-酮(P14)
白色固体,m.p.＝255-257℃,87.2mg,71％yield.1H NMR(400MHz,CDCl3)δ8.06(d,J＝7.6Hz,1H),7.81-7.77(m,3H),7.54(d,J＝3.6Hz,1H),7.48(d,J＝8.4Hz,2H),7.44(d,J＝6.8Hz,1H),7.36(t,J＝7.6Hz,1H),7.25(d,J＝8.0Hz,2H),7.05-7.03(m,3H),6.96(d,J＝7.6Hz,1H),6.87-6.85(m,1H),6.46(d,J＝3.6Hz,1H),4.28(dd,J＝6.0,4.0Hz,1H),3.64-3.58(m,1H),3.25-3.13(m,2H),2.96(dd,J＝16.8,4.0Hz,1H),2.65-2.58(m,1H),2.48-2.44(m,1H),2.36(s,3H),2.33(s,3H).13C NMR(100MHz,CDCl3)δ195.5,145.2,143.5,137.6,135.2,134.32,134.28,133.4,132.4,130.5,130.0,129.4,129.3,127.4,127.2,126.9,126.8,126.4,124.0,120.0,113.6,108.5,67.7,53.7,47.4,40.8,37.5,21.6,21.5.IR(thin film):νmax(cm-1)＝2973,2905,1691,1596,1458,1364,1339,1297,1267,1234,1156,1128,1090,1021,998,886,841,810,770,711,663,594,540,425；HRMS(ESI)高分辨质谱计算值:C34H34N3O5S2[M+NH4]+:628.1934；实测值:628.1932.
Figure BDA0001276336750000181
9b-(benzo[b]thiophen-5-yl)-3-tosyl-1,2,3,3a,4,9b-hexahydro-5H-benzo[e]indol-5-one(P15)
9b-5-苯并噻吩基-3-对甲苯磺酰基-1,2,3,3a,4,9b-六氢-5H-苯并[e]吲哚-5-酮(P15)
黄色固体,m.p.＝205-207℃,80.8mg,85％yield.1H NMR(400MHz,CDCl3)δ8.06(d,J＝7.6Hz,1H),7.65(d,J＝8.4Hz,1H),7.46-7.42(m,4H),7.37-7.34(m,2H),7.14(d,J＝5.2Hz,1H),7.00(d,J＝7.6Hz,2H),6.95(d,J＝8.0Hz,1H),6.84(d,J＝8.4Hz,1H),4.37(dd,J＝6.8,4.4Hz,1H),3.67-3.61(m,1H),3.35-3.29(m,1H),3.22(dd,J＝16.4,7.2Hz,1H),3.07(dd,J＝16.4,4.4Hz,1H),2.74-2.67(m,1H),2.54-2.48(m,1H),2.27(s,3H).13CNMR(100MHz,CDCl3)δ195.6,145.5,143.4,139.5,139.1,138.5,134.3,134.1,132.1,129.4,129.2,127.4,127.3,127.0,126.3,123.8,123.7,122.7,121.9,67.7,53.6,47.5,41.6,37.0,21.4.IR(thin film):νmax(cm-1)＝2951,2895,1686,1597,1476,1451,1418,1337,1299,1258,1155,1091,1059,1018,891,844,808,779,753,698,667,589,550,487,421；HRMS(ESI)高分辨质谱计算值:C27H27N2O3S2[M+NH4]+:491.1458；实测值:491.1457.
9b-(benzofuran-5-yl)-3-tosyl-1,2,3,3a,4,9b-hexahydro-5H-benzo[e]indol-5-one(P16)
9b-5-苯并呋喃基-3-对甲苯磺酰基-1,2,3,3a,4,9b-六氢-5H-苯并[e]吲哚-5-酮(P16)
白色固体,m.p.＝220-222℃,66.1mg,67％yield.1H NMR(400MHz,CDCl3)δ8.06(d,J＝8.0Hz,1H),7.61(d,J＝1.6Hz,1H),7.49(d,J＝8.0Hz,2H),7.45(d,J＝7.6Hz,1H),7.36(t,J＝7.6Hz,1H),7.27(d,J＝8.0Hz,1H),7.13(s,1H),7.06(d,J＝8.0Hz,2H),6.98(d,J＝8.0Hz,1H),6.81(d,J＝8.8Hz,1H),6.62(s,1H),4.32(dd,J＝6.8,4.0Hz,1H),3.67-3.62(m,1H),3.29-3.20(m,2H),3.04(dd,J＝16.4,4.0Hz,1H),2.70-2.63(m,1H),2.53-2.46(m,1H),2.32(s,3H).13C NMR(100MHz,CDCl3)δ195.6,153.7,145.7,145.6,143.4,137.3,134.3,134.2,132.2,129.4,129.3,127.4,127.3,127.1,126.3,123.7,119.9,111.6,106.5,67.8,53.7,47.5,41.2,37.3,21.4.IR(thin film):νmax(cm-1)＝2895,1687,1599,1461,1340,1300,1260,1157,1134,1093,1063,1020,879,810,775,736,703,667,594,551,427；HRMS(ESI)高分辨质谱计算值:C27H27N2O4S[M+NH4]+:475.1686；实测值:475.1686.
9b-(thiophen-3-yl)-3-tosyl-1,2,3,3a,4,9b-hexahydro-5H-benzo[e]indol-5-one(P17)
9b-3-噻吩基-3-对甲苯磺酰基-1,2,3,3a,4,9b-六氢-5H-苯并[e]吲哚-5-酮(P17)
white solid,m.p.＝175-176℃,27.4mg,32％yield.1H NMR(400MHz,CDCl3)δ8.06(d,J＝8.0Hz,1H),7.64(d,J＝8.0Hz,2H),7.53(t,J＝7.6Hz,1H),7.39(t,J＝7.6Hz,1H),7.29(d,J＝8.0Hz,2H),7.23(dd,J＝4.8,2.8Hz,1H),7.17(d,J＝7.6Hz,1H),6.69(d,J＝1.2Hz,1H),6.63(d,J＝4.8Hz,1H),4.18-4.16(m,1H),3.63-3.58(m,1H),3.33(dd,J＝16.8,5.2Hz,1H),3.03(td,J＝10.4,6.0Hz,1H),2.91(dd,J＝16.8,3.6Hz,1H),2.50-2.40(m,4H),2.37-2.30(m,1H).13C NMR(100MHz,CDCl3)δ195.2,144.2,143.8,143.7,134.4,134.2,132.2,129.7,128.6,127.6,127.4,126.8,126.5,126.2,122.7,66.4,51.6,47.6,40.0,38.8,21.6.IR(thin film):νmax(cm-1)＝2912,1684,1596,1472,1449,1424,1401,1336,1300,1258,1200,1159,1092,1018,844,814,775,703,662,589,547,498,434；HRMS(ESI)高分辨质谱计算值:C23H25N2O3S2[M+NH4]+:441.1301；实测值:441.1298.
Figure BDA0001276336750000201
9b-(1-methyl-3a,8-bis(3-methylbut-2-en-1-yl)-1,2,3,3a,8,8a-hexahydropyrrolo[2,3-b]indol-6-yl)-3-tosyl-1,2,3,3a,4,9b-hexahydro-5H-benzo[e]indol-5-one(P18)
9b-(1-甲基-3a,8-二(3-甲基but-2-en-1-yl)-1,2,3,3a,8,8a-六氢吡咯[2,3-b]吲哚-6-yl)-3-对甲苯磺酰基-1,2,3,3a,4,9b-六氢-5H-苯并[e]吲哚-5-酮(P18)
黄色油状物,110.6mg,85％yield,dr＝1.4:1.1H NMR(400MHz,CDCl3)(the minordiastereoisomer was marked with asterisk)δ8.07-8.04(m,1H),7.70-7.67(m,2H),7.53-7.47(m,1H),7.39-7.28(m,1H),7.19(d,J＝7.6Hz,1H*),7.17-7.13(m,1H),6.80(d,J＝8.0Hz,1H),6.78-6.73(m,1H),6.18(dd,J＝7.6Hz,1.6,1H*),6.13(dd,J＝8.0,1.6Hz,1H),5.86(d,J＝1.6Hz,1H),5.78(d,J＝1.6Hz,1H*),4.99-4.93(m,2H),4.15(s,1H),4.12(s,1H*),4.04-4.02(m,1H),3.73-3.66(m,2H),3.61-3.57(m,1H),3.36-3.31(m,1H),2.89-2.75(m,2H),2.64-2.53(m,2H),2.44-2.41(m,6H),2.33-2.32(m,2H),2.28-2.24(m,2H),2.05-1.99(m,1H),1.88-1.81(m,1H),1.63-1.46(m,12H).13C NMR(100MHz,CDCl3)δ195.7,195.6,156.8,151.6,151.2,145.0,144.8,143.65,143.61,141.0,140.7,135.2,134.52,134.48,134.02,133.95,133.81,133.79,133.10,133.08,129.7,129.6,129.3,128.9,128.8,127.6,127.5,127.23,127.19,126.1,122.6,120.7,120.6,120.14,120.10,119.4,116.5,116.2,115.4,106.8,106.2,92.3,91.9,67.4,67.3,56.52,56.49,54.3,54.2,52.8,52.7,47.8,47.7,46.2,46.1,39.0,38.7,38.5,38.4,38.1,38.0,37.9,25.87,25.85,25.6,25.5,21.5,21.4,18.03,18.01,17.8,17.7.IR(thin film):νmax(cm-1)＝2962,2921,2854,1691,1601,1496,1448,1345,1293,1240,1159,1089,1026,966,913,813,752,720,659,597,545,459；HRMS(ESI)高分辨质谱计算值:C40H48N3O3S[M+NH4]+:650.3411；实测值:650.3403.
Figure BDA0001276336750000211
3-((4-nitrophenyl)sulfonyl)-9b-phenyl-1,2,3,3a,4,9b-hexahydro-5H-benzo[e]indol-5-one(P19)
3-(4-硝基苯磺酰基)-9b-苯基--1,2,3,3a,4,9b-六氢-5H-苯并[e]吲哚-5-酮(P19)
白色固体,m.p.＝171-173℃,52.1mg,58％yield.1H NMR(400MHz,CDCl3)δ8.15(d,J＝8.8Hz,2H),8.00(dd,J＝8.0,1.2Hz,1H),7.77-7.74(m,2H),7.46(td,J＝8.0,1.6Hz,1H),7.38-7.34(m,1H),7.15-7.12(m,3H),6.96-6.90(m,3H),4.40(dd,J＝7.6,4.8Hz,1H),3.68-3.62(m,1H),3.43-3.37(m,1H),3.18(dd,J＝16.4,7.6Hz,1H),3.10(dd,J＝16.4,3.6Hz,1H),2.85-2.78(m,1H),2.61-2.54(m,1H).13C NMR(100MHz,CDCl3)δ195.1,149.8,145.0,143.3,142.5,134.5,131.7,129.4,128.8,127.9,127.5,127.3,127.2,126.3,124.1,67.8,53.6,47.5,41.5,36.2.IR(thin film):νmax(cm-1)＝1690,1599,1528,1446,1348,1297,1240,1168,1089,1061,1010,944,854,769,739,704,684,617,553,528,464；HRMS(ESI)高分辨质谱计算值:C24H24N3O5S[M+NH4]+:466.1431；实测值:466.1431.
Figure BDA0001276336750000212
Methyl-5-oxo-9b-phenyl-1,2,3a,4,5,9b-hexahydro-3H-benzo[e]indole-3-carbo xylate(P20)
甲基-5-氧-9b-苯基--1,2,3a,4,5,9b-六氢-3H-苯并[e]吲哚-3-羧酸酯(P20)
黄色油状物,50.8mg,79％yield.1H NMR(600MHz,DMSO-d6,80℃)δ7.91-7.89(m,1H),7.57(td,J＝7.8,1.2Hz,1H),7.41(td,J＝7.8,1.2Hz,1H),7.35-7.30(m,4H),7.27-7.24(m,1H),7.15(d,J＝7.8Hz,1H),4.35(dd,J＝6.6,4.2Hz,1H),3.70-3.66(m,1H),3.57(s,3H),3.20(dd,J＝15.6,6.0Hz,1H),3.06-3.01(m,1H),3.00-2.95(m,1H),2.85(dd,J＝16.2,4.2Hz,1H),2.56-2.52(m,1H).13C NMR(150MHz,DMSO-d6,80℃)δ195.0,154.4,145.6,143.3,133.8,131.6,129.3,128.1,127.0,126.6,126.5,124.9,64.2,52.7,51.5,45.2,38.1,35.5.IR(thin film):νmax(cm-1)＝2995,2954,2892,1687,1598,1446,1380,1293,1224,1189,1116,1029,954,901,858,748,700,650,573,513；HRMS(ESI)高分辨质谱计算值:C20H23N2O3[M+NH4]+:339.1703；实测值:339.1703.
Figure BDA0001276336750000221
3-(4-methylbenzoyl)-9b-phenyl-1,2,3,3a,4,9b-hexahydro-5H-benzo[e]indol-5-one(P21)
3-(4-甲基苯甲酰基)-9b-苯基--1,2,3,3a,4,9b-六氢-5H-苯并[e]吲哚-5-酮(P21)
黄色固体,m.p.＝66-68℃,61.1mg,80％yield.1H NMR(600MHz,DMSO-d6,100℃)δ7.96(d,J＝7.2Hz,1H),7.61-7.59(m,1H),7.45(t,J＝7.2Hz,1H),7.37-7.27(m,5H),7.21-7.15(m,5H),4.55(dd,J＝6.0,4.2Hz,1H),3.63(br,1H),3.23-3.21(m,2H),3.00-2.95(m,2H),2.89-2.86(m,1H),2.56-2.52(m,1H),2.32(s,3H).13C NMR(150MHz,DMSO-d6,100℃)δ194.7,169.1,145.5,143.1,139.3,133.7,133.2,131.8,129.0,128.2,127.9,126.8,126.6,126.4,124.9,64.3,52.3,47.5,37.4,36.5,20.2.IR(thin film):νmax(cm-1)＝3028,2980,2916,1689,1628,1446,1385,1289,1253,1180,1124,1057,1027,999,832,753,699,650,574,529,487；HRMS(ESI)高分辨质谱计算值:C26H24NO2[M+H]+:382.1802；实测值:382.1803.
Figure BDA0001276336750000222
10b-phenyl-4-tosyl-1,3,4,4a,5,10b-hexahydrobenzo[f]quinolin-6(2H)-one(P23)
10b-苯基-4-对甲苯磺酰基-1,3,4,4a,5,10b-六氢苯并[f]喹啉-6(2H)-酮(P23)
白色固体,m.p.＝63-65℃,58.3mg,68％yield.1H NMR(400MHz,CDCl3)δ8.03(d,J＝7.2Hz,1H),7.38-7.23(m,7H),7.13(d,J＝8.0Hz,2H),7.04(d,J＝8.0Hz,2H),6.67(d,J＝8.0Hz,1H),5.36(dd,J＝13.2,4.4Hz,1H),3.44-3.32(m,2H),3.16-3.10(m,1H),2.88(dd,J＝16.8,4.4Hz,1H),2.53(d,J＝11.2Hz,1H),2.35(s,3H),2.11-2.01(m,2H),1.73-1.70(m,1H).13C NMR(100MHz,CDCl3)δ196.0,151.1,143.4,143.1,136.5,134.2,130.1,129.9,129.4,128.6,128.5,127.1,126.7,126.6,55.9,46.6,38.53,38.47,30.0,21.4,21.1.IR(thin film):νmax(cm-1)＝2944,2871,1686,1597,1472,1446,1377,1334,1280,1247,1208,1156,1091,1046,1014,965,924,886,812,760,700,661,572,542；HRMS(ESI)高分辨质谱计算值:C26H29N2O3S[M+NH4]+:449.1893；实测值:449.1895.
Figure BDA0001276336750000231
9b-(4-nitrophenyl)-3-tosyl-1,2,3,3a,4,9b-hexahydro-5H-benzo[e]indol-5-one(P24)
9b-(4-硝基苯基)-3-对甲苯磺酰-1,2,3,3a,4,9b-六氢-5H-苯并[e]吲哚-5-酮(P24)
HRMS(ESI)高分辨质谱计算值:C25H26N3O5S[M+NH4]+:480.1588；实测值:480.1589.
Figure BDA0001276336750000232
10b-(p-tolyl)-4-tosyl-1,3,4,4a,5,10b-hexahydrobenzo[f]quinolin-6(2H)-one(P25)
10b-(p-甲基苯基)-4-对甲苯磺酰基-1,3,4,4a,5,10b-六氢苯并[f]喹啉-6(2H)-酮(P25)
HRMS(ESI)高分辨质谱计算值:C27H31N2O3S[M+NH4]+:463.2050；实测值:463.2051.
Figure BDA0001276336750000233
10b-(4-methoxyphenyl)-4-tosyl-1,3,4,4a,5,10b-hexahydrobenzo[f]quinolin-6(2H)-one(P26)
10b-(p-甲氧基苯基)-4-对甲苯磺酰基-1,3,4,4a,5,10b-六氢苯并[f]喹啉-6(2H)-酮(P26)
HRMS(ESI)高分辨质谱计算值:C27H31N2O4S[M+NH4]+:479.1999；实测值:479.1998.
Figure BDA0001276336750000241
10b-(4-fluorophenyl)-4-tosyl-1,3,4,4a,5,10b-hexahydrobenzo[f]quinolin-6(2H)-one(P27)
10b-(4-氟苯基)-4-对甲苯磺酰基-1,3,4,4a,5,10b-六氢苯并[f]喹啉-6(2H)-酮(P27)
HRMS(ESI)高分辨质谱计算值:C26H28FN2O3S[M+NH4]+:467.1799；实测值:467.1798.
实施例2：苯并mesembranol衍生物的合成
Figure BDA0001276336750000242
干燥反应管氩气保护，加入P1(83.4mg,0.2mmol,1.0equiv.)，七水合三氯化铈(91.7mg,0.28mmol,1.4equiv.)，二氯甲烷(2.0mL)以及甲醇(2.0mL)。冰水浴冷却下加入硼氢化钠(15.2mg,0.4mmol,2equiv.)。TLC监测至反应结束，加饱和氯化铵水溶液(1.0mL)淬灭，减压下除去甲醇，加入乙酸乙酯萃取(10mL×4)，饱和氯化钠溶液洗，无水硫酸钠干燥，过滤。滤液减压旋干后硅胶拌样，柱层析分离产物(石油醚/丙酮＝20/1-5/1)得到T1(76.8mg,92％yield)。
Figure BDA0001276336750000243
9b-phenyl-3-tosyl-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indol-5-ol(T1)
9b-苯基-3-对甲苯磺酰基-2,3,3a,4,5,9b-六氢-1H-苯并[e]吲哚-5-醇(T1)
T1相对构型由核磁二维谱确定。
浅黄色固体,m.p.＝187-188℃,76.8mg,92％yield.1H NMR(400MHz,CDCl3)δ7.62(d,J＝8.0Hz,1H),7.44(d,J＝8.0Hz,2H),7.22(td,J＝7.6,1.2Hz,1H),7.11-7.07(m,1H),7.05-6.99(m,5H),6.76-6.74(m,2H),6.70(dd,J＝8.0,1.2Hz,1H),5.00(br,1H),4.16(dd,J＝10.0,4.0Hz,1H),3.55-3.49(m,1H),3.47-3.40(m,1H),2.87(br,1H),2.66-2.57(m,2H),2.39-2.32(m,1H),2.36(s,3H),2.27-2.19(m,1H).13C NMR(100MHz,CDCl3)δ145.2,143.1,140.1,138.6,133.4,129.4,129.1,128.3,128.0,127.0,126.9,126.7,126.4,126.1,67.3,67.2,53.7,47.3,37.7,36.4,21.4.IR(thin film):νmax(cm-1)＝3519,1596,1486,1448,1326,1251,1156,1088,1063,1034,1007,807,771,751,699,660,590,546,507；HRMS(ESI)高分辨质谱计算值:C25H26NO3S[M+H]+:420.1628；实测值:420.1629.
实施例3：苯并mesembrane衍生物的合成
Figure BDA0001276336750000251
反应管氩气保护下加入底物P1(83.4mg,0.2mmol,1.0equiv.)，氢氧化钾(39.2mg,0.7mmol,3.5equiv.)，一缩二乙二醇(3.0mL)以及水合肼(0.1mL,2.0mmol,10equiv.)。加热170℃。TLC监测至反应结束，冷至室温，加水(2.0mL)淬灭，乙酸乙酯(10mL×3)萃取，合并有机相，无水硫酸钠干燥，过滤。滤液减压旋干后硅胶拌样，柱层析分离(石油醚/乙酸乙酯＝20/1-15/1)得产物T2(64.2mg,80％yield)。
以下化合物通过选用相应原料制备得到：
Figure BDA0001276336750000252
9b-phenyl-3-tosyl-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole(T2)
9b-苯基-3-对甲苯磺酰基-2,3,3a,4,5,9b-六氢-1H-苯并[e]吲哚(T2)
白色固体,m.p.＝133-134℃,64.2mg,80％yield.1H NMR(400MHz,CDCl3)δ7.47(d,J＝8.4Hz,2H),7.13(d,J＝7.6Hz,1H),7.10-6.98(m,6H),6.82-6.80(m,2H),6.70(dd,J＝8.0,0.8Hz,1H),3.99(dd,J＝8.8,3.6Hz,1H),3.48-3.38(m,2H),3.06-2.99(m,1H),2.95-2.87(m,1H),2.58-2.52(m,1H),2.37(s,3H),2.28-2.21(m,2H),2.13-2.04(m,1H).13C NMR(100MHz,CDCl3)δ145.9,142.9,141.3,136.3,134.1,129.5,129.3,128.4,128.2,127.1,126.9,126.4,126.1,125.9,68.8,53.8,47.3,36.7,28.0,26.9,21.4.IR(thin film):νmax(cm-1)＝2950,2884,1597,1492,1447,1334,1304,1160,1090,1033,1012,944,910,849,808,747,704,661,592,545,502,449；HRMS(ESI)高分辨质谱计算值:C25H26NO2S[M+H]+:404.1679；实测值:404.1680.
实施例4mesembrane衍生物的生物活性测试
松叶菊碱(mesembrine)属于番杏科生物碱，由Bodendorf等于1957年从番杏科日中花属植物Mesembryanthemum Tortuosum中首次分离得到。它是血清素再吸收抑制剂(Ki＝1.4nM)，还具有磷酸二酯酶4(PDE4)弱抑制作用。具有抗焦虑活性、抗成瘾性以及抗抑郁等生理活性。
采用文献报道的方法(Harvey,A.L.；Young,L.C.；Viljoen,A.M.；Gericke,N.P.(October 2011)."Pharmacological actions of the South African medicinal andfunctional food plant Sceletium tortuosum and its principal alkaloids".Journal of Ethnopharmacology.137(3):1124–1129.doi:10.1016/j.jep.2011.07.035.PMID21798331)，通过对本发明各个化合物进行血清素再吸收活性测试和PDE4抑制活性测试，结果显示，本发明各化合物具有与松叶菊碱类似的血清素再吸收活性和PDE4抑制活性。
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。

Claims (10)

1.一种如下式I所示的化合物：
其中，Y选自下组：CH2或CH2CH2；
R1为C1-C4的磺酰基、被1-5个R2取代的苯酰基、或被1-5个R2取代的苯磺酰基，
R2为H、C1-C4的烷基、卤素、硝基，或C1-C4的烷氧基；
Ar选自下组：R3取代或未取代的苯基，R3取代或未取代的5-20元杂芳基；其中，所述的杂芳基选自下组：噻吩基、呋喃基、吡咯基、吲哚基、苯并噻吩基，或苯并呋喃基；
其中，所述的R3选自下组：卤素、硝基、氰基、苯基、对甲苯磺酰基、C1-C4的烷基、C1-C4的全氟烷基、C2-C4的烯基、C1-C4的甲酸酯基、或C1-C4的烷氧基；
或所述的化合物为
2.如权利要求1所述的化合物，其特征在于，所述的式I化合物选自下组：
Figure FDA0002130647950000013
Figure FDA0002130647950000021
3.如权利要求1所述的化合物的制备方法，其特征在于，所述方法包括步骤：
Figure FDA0002130647950000022
在惰性溶剂中，用1-萘酚衍生物和ArX反应，得到式I化合物；
其中，X为卤素，其余各基团的定义如权利要求1中所述。
4.如权利要求3所述的方法，其特征在于，所述的反应在催化剂存在下进行，且所述的催化剂为金属钯前体/膦配体；和/或
所述的反应在碱存在下进行。
5.如权利要求4所述的方法，其特征在于，所述的金属钯前体选自下组：PdCl2、PdCl2(MeCN)2、PdCl2(PhCN)2、PdCl2(COD)、Pd(OAc)2、Pd2(dba)3、Pd(dba)2、Pd2(dba)3·CHCl3、[Pd(C3H5)Cl]2、[Pd(prenyl)Cl]2、[Pd(cinnammyl)Cl]2、Pd(PPh3)4，或其组合；和/或
所述的膦配体为：
Figure FDA0002130647950000031
Figure FDA0002130647950000032
或其组合；和/或
所述的碱选自下组：K2CO3、Cs2CO3、Na2CO3、K3PO4、KOH、NaOH、KOAc、NaOAc、tBuOK、tBuOLi、tBuONa、DBU、Et3N、吡啶，或其组合。
6.如权利要求1所述的式I化合物的用途，其特征在于，用于制备如下结构式II的化合物：
Figure FDA0002130647950000033
其中各基团的定义如权利要求1中所述。
7.一种如下式II所示的化合物的制备方法，其特征在于，包括步骤：
Figure FDA0002130647950000034
在惰性溶剂中，用式I化合物进行还原反应，得到式II化合物；
其中，各基团的定义如权利要求1中所述。
8.如权利要求7所述的方法，其特征在于，所述的还原反应在选自下组的还原剂存在下进行：四氢铝锂，硼氢化钠，氰基硼氢化钠、三乙基硼氢化锂，或其组合。
9.如权利要求1所述的式I化合物的用途，其特征在于，用于制备如下结构式III的化合物：
Figure FDA0002130647950000035
其中Ar、R1、Y如权利要求1所述。
10.一种如下式III所示的化合物的制备方法，其特征在于，包括步骤：
Figure FDA0002130647950000041
在惰性溶剂中，用式I化合物进行还原反应，得到式III化合物；
其中，各基团的定义如权利要求1中所述。
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