CN114014846A - 一种区域选择性合成茚-吲哚衍生物的方法 - Google Patents
一种区域选择性合成茚-吲哚衍生物的方法 Download PDFInfo
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- ZCAMWXOBYJAHLU-UHFFFAOYSA-N 1h-indene;1h-indole Chemical class C1=CC=C2CC=CC2=C1.C1=CC=C2NC=CC2=C1 ZCAMWXOBYJAHLU-UHFFFAOYSA-N 0.000 title claims abstract description 25
- 238000000034 method Methods 0.000 title claims abstract description 24
- 230000002194 synthesizing effect Effects 0.000 title abstract description 8
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 claims abstract description 22
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 claims abstract description 13
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 claims abstract description 13
- 239000007800 oxidant agent Substances 0.000 claims abstract description 6
- 230000001590 oxidative effect Effects 0.000 claims abstract description 6
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- 238000006243 chemical reaction Methods 0.000 claims abstract description 5
- 150000007517 lewis acids Chemical class 0.000 claims abstract description 5
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- 125000003118 aryl group Chemical group 0.000 claims abstract description 3
- 239000002904 solvent Substances 0.000 claims description 24
- -1 N-substituted indole compound Chemical class 0.000 claims description 20
- JKNHZOAONLKYQL-UHFFFAOYSA-K tribromoindigane Chemical compound Br[In](Br)Br JKNHZOAONLKYQL-UHFFFAOYSA-K 0.000 claims description 14
- 238000003786 synthesis reaction Methods 0.000 claims description 13
- 230000015572 biosynthetic process Effects 0.000 claims description 12
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 10
- PSCMQHVBLHHWTO-UHFFFAOYSA-K indium(iii) chloride Chemical compound Cl[In](Cl)Cl PSCMQHVBLHHWTO-UHFFFAOYSA-K 0.000 claims description 10
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- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 4
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- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 2
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- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
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- 125000003545 alkoxy group Chemical group 0.000 claims 1
- 125000000217 alkyl group Chemical group 0.000 claims 1
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- 150000002367 halogens Chemical class 0.000 claims 1
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims 1
- 239000003814 drug Substances 0.000 abstract description 5
- QNXSIUBBGPHDDE-UHFFFAOYSA-N indan-1-one Chemical group C1=CC=C2C(=O)CCC2=C1 QNXSIUBBGPHDDE-UHFFFAOYSA-N 0.000 abstract description 5
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- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical group CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 17
- YBYIRNPNPLQARY-UHFFFAOYSA-N 1H-indene Chemical compound C1=CC=C2CC=CC2=C1 YBYIRNPNPLQARY-UHFFFAOYSA-N 0.000 description 5
- ADEBPBSSDYVVLD-UHFFFAOYSA-N donepezil Chemical compound O=C1C=2C=C(OC)C(OC)=CC=2CC1CC(CC1)CCN1CC1=CC=CC=C1 ADEBPBSSDYVVLD-UHFFFAOYSA-N 0.000 description 5
- 101710115990 Lens fiber membrane intrinsic protein Proteins 0.000 description 4
- 102100026038 Lens fiber membrane intrinsic protein Human genes 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- KJTPWUVVLPCPJD-AUWJEWJLSA-N (2z)-7-amino-2-[(4-hydroxy-3,5-dimethylphenyl)methylidene]-5,6-dimethoxy-3h-inden-1-one Chemical compound O=C1C=2C(N)=C(OC)C(OC)=CC=2C\C1=C\C1=CC(C)=C(O)C(C)=C1 KJTPWUVVLPCPJD-AUWJEWJLSA-N 0.000 description 2
- 229940100578 Acetylcholinesterase inhibitor Drugs 0.000 description 2
- 208000024827 Alzheimer disease Diseases 0.000 description 2
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- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- 230000000975 bioactive effect Effects 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
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- LNTHITQWFMADLM-UHFFFAOYSA-N gallic acid Chemical compound OC(=O)C1=CC(O)=C(O)C(O)=C1 LNTHITQWFMADLM-UHFFFAOYSA-N 0.000 description 2
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- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 description 1
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- VMJNTFXCTXAXTC-UHFFFAOYSA-N 2,2-difluoro-1,3-benzodioxole-5-carbonitrile Chemical group C1=C(C#N)C=C2OC(F)(F)OC2=C1 VMJNTFXCTXAXTC-UHFFFAOYSA-N 0.000 description 1
- IQHSSYROJYPFDV-UHFFFAOYSA-N 2-bromo-1,3-dichloro-5-(trifluoromethyl)benzene Chemical group FC(F)(F)C1=CC(Cl)=C(Br)C(Cl)=C1 IQHSSYROJYPFDV-UHFFFAOYSA-N 0.000 description 1
- GCXGZFVNNZNGGO-UHFFFAOYSA-N 3-(butanoylamino)propanoic acid Chemical compound CCCC(=O)NCCC(O)=O GCXGZFVNNZNGGO-UHFFFAOYSA-N 0.000 description 1
- CVICEEPAFUYBJG-UHFFFAOYSA-N 5-chloro-2,2-difluoro-1,3-benzodioxole Chemical group C1=C(Cl)C=C2OC(F)(F)OC2=C1 CVICEEPAFUYBJG-UHFFFAOYSA-N 0.000 description 1
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- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 229940118365 Endothelin receptor antagonist Drugs 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N EtOH Substances CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
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- 102100037224 Noncompact myelin-associated protein Human genes 0.000 description 1
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- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 description 1
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- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Substances CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 1
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- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
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- 150000002431 hydrogen Chemical class 0.000 description 1
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- RJMMFJHMVBOLGY-UHFFFAOYSA-N indium(3+) Chemical compound [In+3] RJMMFJHMVBOLGY-UHFFFAOYSA-N 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000036210 malignancy Effects 0.000 description 1
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
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- 229910052703 rhodium Inorganic materials 0.000 description 1
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- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 description 1
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- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
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- MLKXDPUZXIRXEP-MFOYZWKCSA-N sulindac Chemical compound CC1=C(CC(O)=O)C2=CC(F)=CC=C2\C1=C/C1=CC=C(S(C)=O)C=C1 MLKXDPUZXIRXEP-MFOYZWKCSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
- C07D491/056—Ortho-condensed systems with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明公开了一种区域选择性合成茚‑吲哚衍生物的方法。以吲哚类化合物、富电子芳基烯基‑1，3‑二噻烷为原料，在路易斯酸、氧化剂或质子酸作用下，经过一步反应高区域选择性和高收率合成茚‑吲哚衍生物。本发明方法具有选择性好、反应条件温和、收率高、操作简单安全等优点。本发明合成的茚‑吲哚衍生物及其相关茚酮结构是复杂吲哚类天然产物及活性药物分子的重要结构片段,同时，区域选择性合成茚‑吲哚衍生物的方法可制备相关的医药和化工中间体,在药物化学领域具有广泛应用前景。
Description
技术领域
本发明属于有机合成领域,具体涉及一种吲哚C2和C3区域选择性合成茚-吲哚衍生物的方法。。
背景技术
取代茚及其相关的茚酮衍生物是众多天然产物中的重要结构单元，如乙酰胆碱酶抑制剂donepezil、内皮素受体拮抗剂enrasentan、抗炎sulindac、醛固酮合酶抑制剂和抗结核药物等。茚及茚酮衍生物也是药物合成、天然产品和其他生物活性化合物的关键中间体(Eur J Med Chem 138,182-198(2017).)。茚-吲哚衍生物存在于天然产物和多种生物活性的药物中，发现吲哚C2和C3区域选择性合成茚-吲哚衍生物的方法非常关键。此外，吲哚C3位置是亲电取代反应最活跃的位置，然而C2位置官能团化需要导向基团的协助，且需要相对昂贵的贵金属催化剂如铑、钌和钯等来实现。已报道的合成方法仍然面临着一定的局限性，包括难以控制的区域选择性、氧化剂化学计量的使用等不足(Angew.Chem.,Int.Ed.2015,54,11956.)。因此，开发茚-吲哚类化合物的区域选择性合成新方法具有极高的价值。
茚及其衍生物在药物化学中是重要的生物活性分子，已被研究具有优异的生物活性，包括治疗阿尔茨海默病和抗癌活性等。例如，没食子酸茚酮及其2- 苄叉茚二酮衍生物(1)是芳香化酶的抑制剂，具有抑制乳腺癌的活性(Med.Chem. Res.2011,20,661-669.)；Indanocine(2)具有抗耐药性恶性肿瘤的增殖活性(Natl.Cancer Inst.2000,92,217-224.)；多奈哌齐(3)作为乙酰胆碱酯酶抑制剂被FDA批准用于治疗轻度至中度阿尔茨海默病(Curr.Med.Chem. 2000,3,303-339.)。
发明内容
由于取代茚及其相关的茚酮衍生物结构在药物化学中的重要性，本发明提供一种利用富电子芳基烯基-1，3-二噻烷区域选择性合成茚-吲哚衍生物的方法，该方法克服现有方法的不足，本方法操作简单易行，具用原料廉价易得，产物容易分离纯化和环境绿色友好的特点。
一种区域选择性合成茚-吲哚衍生物的方法，其特征在于：在路易斯酸、氧化剂或质子酸作用下，N-取代吲哚化合物和富电子芳基烯基-1，3-二噻烷，在适当反应溶剂和温度下发生偶联反应，区域选择性的生成茚-吲哚类衍生物，如下式：
R1为吲哚2-7位取代基，选自C1-6烷基、C1-6烷氧基、C1-2卤代烷基、卤素、硝基、氰基、乙酰基、卞氧基、甲砜基、氨基、羧基、羟基、羟甲基、酯基；R2为吲哚1位取代基，选自氢、甲基、对甲苯磺酰基、叔丁氧羰基、苄基；N-取代吲哚化合物包括色胺、褪黑素、色胺酸衍生物、氮杂吲哚吲哚；X为为Cl,Br,I,OTf基团；
富电子芳基烯基-1，3-二噻烷取代基，选自3,4,5-三甲氧基苯基、3,4-二甲氧基苯基、 2,5-二甲氧基苯基、富电子杂环(吲哚、吡咯、呋喃和吡啶)、3,5-二甲氧基苯基、萘基、亚甲二氧基苯基。
一种区域选择性合成茚-吲哚衍生物的方法，其特征在于：路易斯酸选自三氯化铟、三溴化铟、三碘化铟、三氯化铁、六水合三氯化铁、三氟化硼乙醚中的一种或多种；氧化剂为NCS、碘单质、NBS、DTBP中的一种；质子酸为三氟甲磺酸、磷酸、亚磷酸中的一种或多种。
一种区域选择性合成茚-吲哚衍生物的方法，其特征在于：所使用的溶剂为甲苯、1,2-二氯甲烷、1,2-二氯乙烷、三氯甲烷、硝基甲烷的一种或数种。
一种区域选择性合成茚-吲哚衍生物的方法，其特征在于：所述的操作步骤中所使用的反应物的摩尔比为富电子芳基烯基-1，3-二噻烷:吲哚＝1:(0.5-3.0)。
所述的一种区域选择性合成茚-吲哚衍生物的方法，其特征在于：反应温度范围为0-100℃。
具体实施方式：
下面结合具体实施例对本发明做出进一步地详细阐述,所述实施例只用于解释本发明,并非用于限定本发明的范围。下述实施例中所使用的试验方法如无特殊说明,均为常规方法:所使用的材料、试剂等,如无特殊说明,为可从商业途径得到的试剂和材料。
具体实施的例的产物结构如下：
3,4,5-三甲氧基苯基茚-吲哚类化合物的合成过程如下:
具体步骤如下：在10毫升圆底烧瓶中，加入吲哚类化合物(0.25mmol)和3,4,5- 三甲氧基苯基-β-氯-乙烯-1，3-二噻烷(69mg，0.2mmol)，用6毫升溶剂溶解后加入催化剂铟(Ⅲ)(0.03mmol)，在室温下搅拌反应24-48h，TLC检测直至原料消失，将反应到入10ml冰水中，并用乙酸乙酯(15ml)萃取3次，合并有机相，并用15ml饱和碳酸氢钠和食盐水洗涤。有机相经过无水硫酸钠干燥后过滤，所得滤液在减压条件下旋干,剩余的油状物经过快速柱层析分离，得到相应的3,4,5-三甲氧基苯基茚-吲哚类化合物。
所述吲哚类化合物
当R1为氢时，所用催化剂为InBr3，所用溶剂为二氯甲烷，所得化合物为MP1；
当R1为5-氟时，所用催化剂为InBr3，所用溶剂为二氯乙烷，所得化合物为MP2；
当R1为5-氯时，所用催化剂为InBr3，所用溶剂为三氯甲烷，所得化合物为MP3；
当R1为6-氯时，所用催化剂为InBr3，所用溶剂为甲苯，所得化合物为MP4；
当R1为4-溴时，所用催化剂为InCl3，所用溶剂为二氯乙烷，所得化合物为MP5；
当R1为5-溴时，所用催化剂为InI3，所用溶剂为二氯乙烷，所得化合物为MP6；
当R1为7-溴时，所用催化剂为碘单质，所用溶剂为二氯乙烷，所得化合物为MP7；
当R1为5-氰基时，所用催化剂为NCS，所用溶剂为二氯乙烷，所得化合物为MP8；
当R1为5-硝基时所用催化剂为InCl3，所用溶剂为二氯乙烷，，所得化合物为MP9；
当R1为5-卞氧基时，所用催化剂为InBr3，所用溶剂为二氯乙烷，所得化合物为MP10；
当R1为5-甲氧基时，所用催化剂为InBr3，所用溶剂为二氯甲烷，所得化合物为MP11；
当R1为5甲基时，所用催化剂为InBr3，所用溶剂为二氯乙烷，所得化合物为MP12；
当R1为5,6-亚甲二氧基时，所用催化剂为InBr3，所用溶剂为二氯乙烷，所得化合物为MP13；
当R2为1-甲基时，所用催化剂为InCl3，所用溶剂为二氯乙烷，所得化合物为MP14；
当R2为1-对甲苯磺酸基时，所用催化剂为InCl3，所用溶剂为二氯乙烷，所得化合物为MP15；
当R1为3-甲基时，所用催化剂为InCl3，所用溶剂为二氯乙烷，所得化合物为MP16；
当R1为3-乙酸甲酯时，所用催化剂为InCl3，所用溶剂为二氯乙烷，所得化合物为MP17；
当R1为3-乙酸时，所用催化剂为InBr3，所用溶剂为二氯乙烷，所得化合物为MP18；
当R1为3-乙醇时，所用催化剂为InBr3，所用溶剂为二氯乙烷，所得化合物为MP19；
当R1为3-乙酰乙胺基时，所用催化剂为InBr3，所用溶剂为二氯乙烷，所得化合物为MP20；
当R1为3-乙基乙酰氨基丙酸时，所用催化剂为InBr3，所用溶剂为二氯乙烷，所得化合物为MP21；
化合物MP1-MP18的核磁数据如下：
1、化合物MP1
1H NMR(400MHz,Chloroform-d)δ8.77(s,1H),7.55(d,J＝7.5Hz,1H),7.24(d,J＝7.7Hz,1H),7.13–7.00(m,2H),6.92(s,1H),6.45(s,1H),4.85(dd,J＝9.4,3.7Hz,1H),3.91(s, 3H),3.82(s,3H),3.43(s,3H),3.43–3.35(m,1H),3.27–3.13(m,3H),2.97–2.87(m,2H),2.31 –2.20(m,1H),2.11–1.98(m,1H).13C NMR(101MHz,CDCl3)δ154.88,150.21,143.41,141.05, 139.54,136.28,128.63,128.50,121.19,120.12,119.50,110.81,103.61,100.16,60.90,60.72,58.82, 56.39,50.74,40.98,29.78,29.30,24.90.
2、化合物MP2
1H NMR(400MHz,Chloroform-d)δ8.81(s,1H),7.25(s,1H),7.18(dd,J＝9.8,2.5Hz, 1H),7.13(dd,J＝8.8,4.6Hz,1H),6.91(s,1H),6.87–6.77(m,1H),6.43–6.36(m,1H),4.82(dd, J＝9.4,3.7Hz,1H),3.91(s,3H),3.82(s,3H),3.46(s,3H),3.39(dd,J＝13.9,9.4Hz,1H),3.26– 3.14(m,3H),2.92(d,J＝15.0Hz,2H),2.28–2.20(m,1H),2.09–2.00(m,1H).13C NMR(101 MHz,CDCl3)δ159.04,156.72,154.92,150.08,143.33,142.97,139.48,132.72,128.80,128.70, 128.37,111.29,111.20,109.44,109.18,105.01,104.78,103.58,100.34,100.29,60.89,60.69,58.76, 56.36,50.56,40.95,29.79,29.24,24.84.
3、化合物MP3
1H NMR(400MHz,Chloroform-d)δ8.87(s,1H),7.50(d,J＝2.0Hz,1H),7.14(d,J＝8.5Hz,1H),7.02(dd,J＝8.6,2.1Hz,1H),6.91(s,1H),6.39(d,J＝1.8Hz,1H),4.82(dd,J＝9.4, 3.6Hz,1H),3.91(s,3H),3.82(s,3H),3.45(s,3H),3.38(dd,J＝13.9,9.4Hz,1H),3.22(dd,J＝ 13.9,3.6Hz,3H),2.92(d,J＝13.0Hz,2H),2.28–2.18(m,1H),2.09–1.99(m,1H).13C NMR (101MHz,CDCl3)δ154.87,149.99,143.24,142.58,139.45,134.50,129.47,128.22,124.97, 121.30,119.39,111.71,103.53,99.79,60.81,60.61,58.68,56.28,50.46,40.81,29.68,29.16,24.76.
4、化合物MP4
1H NMR(400MHz,Chloroform-d)δ8.85(s,1H),7.43(d,J＝8.4Hz,1H),7.24(s,1H), 7.01(dd,J＝8.4,1.9Hz,1H),6.91(s,1H),6.41(s,1H),4.82(dd,J＝9.4,3.6Hz,1H),3.91(s,3H), 3.82(s,3H),3.46(s,3H),3.38(dd,J＝13.9,9.4Hz,1H),3.26–3.14(m,3H),2.93(d,J＝14.2Hz, 1H),2.29–2.19(m,1H),2.06(t,J＝13.3Hz,1H).13C NMR(101MHz,CDCl3)δ154.91,150.04, 143.30,141.85,139.45,136.54,128.25,126.97,126.88,120.83,120.12,110.76,103.57,100.10, 60.85,60.65,58.71,56.33,50.49,40.83,29.73,29.19,24.79.
5、化合物MP5
1H NMR(400MHz,Chloroform-d)δ9.00(s,1H),7.17(dd,J＝16.4,7.9Hz,2H),6.95– 6.88(m,2H),6.50(d,J＝2.1Hz,1H),4.83(dd,J＝9.2,3.9Hz,1H),3.88(s,3H),3.81(s,3H), 3.46(s,3H),3.37(dd,J＝13.9,9.3Hz,1H),3.21–3.09(m,3H),2.88(d,J＝14.5Hz,2H),2.24– 2.14(m,1H),2.04–1.95(m,1H).13C NMR(101MHz,CDCl3)δ154.83,149.98,143.16,141.76, 139.49,136.25,129.05,128.00,122.26,121.99,113.81,109.92,103.46,100.31,60.79,60.59,58.59, 56.25,50.50,40.76,29.57,29.14,24.71.
6、化合物MP6
1H NMR(400MHz,Chloroform-d)δ8.91(s,1H),7.65(s,1H),7.14(dd,J＝8.6,1.9Hz, 1H),7.08(d,J＝8.6Hz,1H),6.91(s,1H),6.38(s,1H),4.81(dd,J＝9.3,3.7Hz,1H),3.88(s,3H), 3.81(s,3H),3.44(s,3H),3.36(dd,J＝13.9,9.3Hz,1H),3.22–3.10(m,3H),2.89(d,J＝14.6Hz, 2H),2.29–2.07(m,1H),2.07–1.94(m,1H).13C NMR(101MHz,CDCl3)δ154.82,149.94, 143.18,142.40,139.41,134.72,130.10,128.16,123.81,122.42,112.54,112.17,103.47,99.64, 60.80,60.59,58.64,56.25,50.41,40.73,29.65,29.12,24.72.
7、化合物MP7
1H NMR(400MHz,Chloroform-d)δ9.33(s,1H),7.47(d,J＝7.8Hz,1H),7.22(d,J＝7.7Hz,1H),6.96–6.87(m,2H),6.51(d,J＝2.2Hz,1H),4.84(dd,J＝9.2,3.5Hz,1H),3.91(s, 3H),3.82(s,3H),3.54(s,3H),3.40–3.35(m,1H),3.32–3.13(m,3H),2.94(t,J＝15.2Hz,2H), 2.33–2.15(m,1H),2.08–1.98(m,1H).13C NMR(101MHz,CDCl3)δ154.92,150.04,143.24, 141.74,139.30,135.11,129.51,128.24,123.43,120.59,119.20,104.28,103.54,101.13,60.84, 60.73,58.74,56.34,50.13,40.79,29.72,29.14,24.75.
8、化合物MP8
1H NMR(400MHz,Chloroform-d)δ9.26(s,1H),7.88(s,1H),7.37–7.27(m,2H),6.92 (s,1H),6.52(s,1H),4.86(dd,J＝9.4,3.3Hz,1H),3.91(s,3H),3.82(s,3H),3.51(s,3H),3.43– 3.34(m,1H),3.31–3.15(m,3H),3.02–2.89(m,2H),2.33–2.22(m,1H),2.12–1.99(m,1H). 13C NMR(101MHz,CDCl3)δ155.16,149.96,143.60,143.31,139.47,137.95,128.20,127.78, 125.59,124.37,121.07,111.64,103.66,102.56,100.72,60.93,60.74,58.74,56.40,50.27,40.76, 29.91,29.17,24.79.
9、化合物MP9
1H NMR(400MHz,Chloroform-d)δ9.38(s,1H),8.50(d,J＝2.2Hz,1H),8.01(dd,J＝ 8.9,2.2Hz,1H),7.26(d,J＝8.8Hz,1H),6.92(s,1H),6.62(s,1H),4.87(dd,J＝9.4,3.2Hz,1H), 3.92(s,3H),3.82(s,3H),3.53(s,3H),3.41(dd,J＝14.0,9.4Hz,1H),3.33–3.18(m,3H),2.97 (dd,J＝9.2,5.3Hz,2H),2.32–2.23(m,1H),2.13–2.00(m,1H).13C NMR(101MHz,CDCl3)δ 155.19,149.92,144.56,143.28,141.74,139.43,139.34,127.71,127.65,117.30,117.13,110.68, 103.63,102.19,60.93,60.76,58.73,56.40,50.10,40.79,29.95,29.14,24.76.
10、化合物MP10
1H NMR(400MHz,Chloroform-d)δ8.65(s,1H),7.50–7.43(m,2H),7.42–7.33(m,2H),7.31(d,J＝7.3Hz,1H),7.13(d,J＝8.7Hz,1H),7.10(d,J＝2.4Hz,1H),6.91(s,1H),6.83 (dd,J＝8.7,2.4Hz,1H),6.36(s,1H),5.08(s,2H),4.82(dd,J＝9.4,3.7Hz,1H),3.91(s,3H),3.82 (s,3H),3.45(s,3H),3.39(dd,J＝13.9,9.4Hz,1H),3.26–3.14(m,3H),2.96–2.86(m,2H),2.25 (d,J＝14.7Hz,1H),2.08–1.96(m,1H).13C NMR(101MHz,CDCl3)δ154.86,153.30,150.18, 143.39,141.94,139.51,137.98,131.63,128.90,128.65,128.57,127.78,127.63,111.91,111.43, 103.84,103.59,100.10,70.99,60.92,60.75,58.81,56.40,50.73,41.03,29.80,29.31,24.90.
11、化合物MP11
1H NMR(400MHz,Chloroform-d)δ8.65(s,1H),7.12(d,J＝8.8Hz,1H),7.02(d,J＝2.4Hz,1H),6.91(s,1H),6.74(dd,J＝8.7,2.5Hz,1H),6.37(d,J＝2.0Hz,1H),4.81(dd,J＝9.3, 3.8Hz,1H),3.90(s,3H),3.82(d,J＝3.0Hz,6H),3.44(s,3H),3.38(dd,J＝13.9,9.3Hz,1H), 3.23–3.13(m,3H),2.94–2.83(m,2H),2.27–2.17(m,1H),2.07–1.95(m,1H).13CNMR(101 MHz,CDCl3)δ154.80,154.01,150.14,143.34,141.87,139.49,131.38,128.88,128.64,111.40, 111.08,103.55,102.18,100.02,60.87,60.69,58.77,56.35,55.91,50.72,40.99,29.73,29.27,24.86.
12、化合物MP12
1H NMR(400MHz,Chloroform-d)δ8.69–8.57(m,1H),7.33(s,1H),7.13(d,J＝8.2Hz,1H),6.93–6.83(m,2H),6.36(d,J＝1.2Hz,1H),4.83(dd,J＝9.3,3.8Hz,1H),3.91(s,3H), 3.82(s,3H),3.42(s,3H),3.40–3.33(m,1H),3.24–3.14(m,3H),2.95–2.87(m,2H),2.41(s, 3H),2.28–2.19(m,1H),2.06–2.00(m,1H).13C NMR(101MHz,CDCl3)δ154.76,150.16, 143.33,139.49,134.52,128.72,128.68,128.56,122.68,119.78,110.41,103.51,99.65,60.84,60.66, 58.76,56.32,50.73,40.96,29.67,29.24,24.84,21.50.
13、化合物MP13
1H NMR(400MHz,Chloroform-d)δ8.65(s,1H),6.92(d,J＝7.4Hz,2H),6.72(s,1H), 6.30(s,1H),5.87(s,2H),4.78(dd,J＝9.3,3.8Hz,1H),3.91(s,3H),3.82(s,3H),3.45(s,3H), 3.37(dd,J＝13.9,9.3Hz,1H),3.24–3.13(m,3H),2.92(d,J＝14.4Hz,2H),2.29–2.19(m,1H), 2.08–1.98(m,1H).13C NMR(101MHz,CDCl3)δ154.77,150.13,144.16,143.37,142.62,139.42, 130.93,128.75,122.13,103.57,100.39,98.89,92.05,60.88,60.71,58.75,56.35,50.73,40.97, 29.74,29.28,24.88.
14、化合物MP14
1H NMR(400MHz,Chloroform-d)δ7.42(d,J＝7.9Hz,1H),7.28(d,J＝8.3Hz,1H),7.19(t,J＝7.0Hz,1H),7.03(t,J＝7.5Hz,1H),6.94(s,1H),6.89(s,1H),4.87(t,J＝7.7Hz,1H), 3.93(s,3H),3.80(s,3H),3.73(s,3H),3.52(dd,J＝13.3,8.1Hz,1H),3.24(s,3H),3.23–3.16(m, 1H),3.11–3.03(m,1H),2.99(dd,J＝13.3,7.3Hz,1H),2.92–2.77(m,2H),2.23–2.14(m,1H), 2.07–1.95(m,1H).13C NMR(101MHz,CDCl3)δ154.02,150.43,142.89,140.00,137.23,129.74, 126.98,126.56,121.34,119.44,118.61,117.23,109.21,103.17,60.81,60.00,58.61,56.25,56.21, 52.49,38.61,32.68,29.96,28.90,25.07.
15、化合物MP15
1H NMR(400MHz,Chloroform-d)δ8.00(d,J＝8.2Hz,1H),7.75(d,J＝8.4Hz,2H),7.38(s,1H),7.29–7.23(m,2H),7.13(t,J＝7.6Hz,2H),6.93(s,1H),4.74(t,J＝7.7Hz,1H), 3.93(s,3H),3.77(s,3H),3.42(dd,J＝13.3,8.2Hz,1H),3.22–3.11(m,1H),3.01(s,4H),2.92– 2.84(m,2H),2.78(d,J＝14.1Hz,1H),2.32(s,3H),2.22–2.11(m,1H),2.03–1.94(m,1H).13C NMR(101MHz,CDCl3)δ154.45,150.08,144.67,142.79,140.09,135.57,135.37,130.02,129.67, 128.01,126.84,125.18,124.51,123.46,122.96,120.05,113.85,103.21,60.72,59.69,58.44,56.23, 51.06,38.24,29.80,28.80,24.88,21.52.
16、化合物MP16
1H NMR(400MHz,Chloroform-d)δ8.63(s,1H),7.55–7.48(m,1H),7.21–7.14(m,1H),7.10–7.01(m,2H),6.92(s,1H),4.95(dd,J＝9.7,3.3Hz,1H),3.91(s,3H),3.80(s,3H), 3.40(dd,J＝14.0,9.7Hz,1H),3.30(s,3H),3.21–3.12(m,3H),2.92(dd,J＝14.2,3.9Hz,2H), 2.40(s,3H),2.27–2.18(m,1H),2.08–2.00(m,1H).13C NMR(101MHz,CDCl3)δ154.72, 150.04,143.37,139.14,136.15,135.36,129.24,128.95,121.11,118.71,118.31,110.55,106.91, 103.39,60.76,60.23,59.02,56.26,50.56,38.26,29.78,29.15,24.78,8.68.
17、化合物MP17
1H NMR(400MHz,Chloroform-d)δ8.77(s,1H),7.60–7.52(m,1H),7.20–7.18(m,1H),7.11–7.06(m,2H),6.92(s,1H),4.98(dd,J＝9.8,3.1Hz,1H),4.00–3.84(m,5H),3.79(s, 3H),3.71(s,3H),3.44(dd,J＝14.2,9.8Hz,1H),3.32(s,3H),3.24–3.13(m,2H),2.99–2.88(m, 2H),2.29–2.18(m,1H),2.09–2.00(m,1H).13C NMR(101MHz,CDCl3)δ172.68,154.94, 150.04,143.25,139.34,138.29,135.28,128.62,128.07,121.48,119.39,118.43,110.86,104.20, 103.36,60.80,60.31,59.03,56.31,51.97,50.53,38.40,30.10,29.84,29.11,24.78.
18、化合物MP18
1H NMR(400MHz,Chloroform-d)δ8.82(s,1H),7.57–7.54(m,1H),7.21–7.15(m,1H),7.09–7.05(m,2H),6.91(s,1H),4.94(dd,J＝9.7,3.2Hz,1H),4.03–3.85(m,5H),3.77(s, 3H),3.40(dd,J＝14.2,9.7Hz,1H),3.33(s,3H),3.19–3.10(m,3H),2.87(d,J＝14.7Hz,2H), 2.23–2.15(m,1H),2.04–1.92(m,1H).13C NMR(101MHz,CDCl3)δ178.25,154.93,149.90, 143.13,139.32,138.43,135.26,128.40,127.91,121.62,119.48,118.39,110.90,103.51,103.36, 60.77,60.33,58.96,56.28,50.48,38.31,30.16,29.76,29.06,24.71.
19、化合物MP19
1H NMR(400MHz,Chloroform-d)δ8.37(s,1H),7.55(d,J＝6.8Hz,1H),7.21(d,J＝7.1Hz,1H),7.13–7.05(m,2H),6.94(s,1H),5.04(dd,J＝9.5,4.3Hz,1H),3.93(s,5H),3.79(s, 3H),3.43(dd,J＝13.9,9.5Hz,1H),3.31(s,3H),3.21–3.10(m,4H),3.03(dd,J＝13.9,4.3Hz, 1H),2.95–2.83(m,2H),2.43(s,1H),2.23(d,J＝14.2Hz,1H),2.09–1.98(m,1H).13CNMR (101MHz,CDCl3)δ154.96,149.81,143.15,139.87,138.21,135.71,128.19,128.16,121.59, 119.24,118.30,110.82,108.17,103.54,63.15,60.82,60.41,58.86,56.34,51.13,38.36,29.59, 29.35,27.91,24.82.
20、化合物MP20
1H NMR(400MHz,Chloroform-d)δ8.43(d,J＝2.6Hz,1H),7.55(d,J＝7.1Hz,1H),7.20(d,J＝6.4Hz,1H),7.14–7.04(m,2H),6.96(s,1H),6.42(s,1H),4.91(dd,J＝9.0,5.4Hz, 1H),3.92(s,4H),3.79(s,3H),3.48–3.33(m,2H),3.26(s,3H),3.18–3.07(m,3H),3.01–2.92 (m,2H),2.92–2.85(m,2H),2.27–2.15(m,1H),2.06–1.95(m,1H),1.88(s,3H).13C NMR(101 MHz,CDCl3)δ170.30,154.95,149.64,143.23,140.15,137.25,135.63,128.05,127.91,121.65, 119.35,118.22,110.76,109.05,103.78,60.77,60.29,58.66,56.33,51.17,40.21,38.31,29.49, 29.33,24.76,24.27,22.98.
21、化合物MP21
1H NMR(400 MHz,Chloroform-d)δ8.34(s,1H),7.55(d,J＝7.9 Hz,1H),7.21(d,J＝ 9.0 Hz,1H),7.17(d,J＝8.0 Hz,1H),7.06(t,J＝7.5 Hz,1H),7.02–6.95(m,1H),6.95(s,1H), 5.15(dt,J＝8.8,4.6 Hz,1H),4.87(dd,J＝9.0,5.5 Hz,1H),3.93(s,3H),3.79(s,3H),3.62(dd,J＝15.0,3.6 Hz,1H),3.45–3.30(m,2H),3.27(s,3H),3.14(d,J＝12.2Hz,2H),2.94–2.82(m, 3H),2.22(d,J＝14.1 Hz,1H),2.02(t,J＝13.3 Hz,1H),1.87(s,3H).13C NMR(101 MHz,CDCl3) δ175.26,170.86,155.11,149.51,143.38,140.34,138.47,135.47,128.76,127.92,121.92,119.72, 118.60,110.67,105.93,103.88,60.83,60.61,58.74,56.42,52.72,51.21,38.66,29.80,29.57,29.38, 26.65,24.83,22.80。
Claims (5)
1.一种区域选择性合成茚-吲哚衍生物的方法，其特征在于：在路易斯酸、氧化剂或质子酸作用下，N-取代吲哚化合物和富电子芳基烯基-1，3-二噻烷，在适当反应溶剂和温度下发生偶联反应，区域选择性的生成茚-吲哚类衍生物，如下式：
R1为吲哚2-7位取代基，选自C1-6烷基、C1-6烷氧基、C1-2卤代烷基、卤素、硝基、氰基、乙酰基、卞氧基、甲砜基、氨基、羧基、羟基、羟甲基、酯基；R2为吲哚1位取代基，选自氢、甲基、对甲苯磺酰基、叔丁氧羰基、苄基；N-取代吲哚化合物包括色胺，褪黑素、色胺酸衍生物、氮杂吲哚吲哚；X为为Cl,Br,I,OTf基团；
富电子芳基烯基-1，3-二噻烷取代基，选自3,4,5-三甲氧基苯基、3,4-二甲氧基苯基、2,5-二甲氧基苯基、富电子杂环(吲哚、吡咯、呋喃和吡啶)、3,5-二甲氧基苯基、萘基、亚甲二氧基苯基。
2.据权利要求1所述的一种区域选择性合成茚-吲哚衍生物的方法，其特征在于：路易斯酸选自三氯化铟、三溴化铟、三碘化铟、三氯化铁、六水合三氯化铁、三氟化硼乙醚中的一种或多种；氧化剂为NCS、碘单质、NBS、DTBP中的一种；质子酸为三氟甲磺酸、磷酸、亚磷酸中的一种或多种。
3.据权利要求1所述的一种区域选择性合成茚-吲哚衍生物的方法，其特征在于：所使用的溶剂为甲苯、二氯甲烷、1,2-二氯乙烷、氯仿、硝基甲烷的一种或数种。
4.据权利要求1所述的一种区域选择性合成茚-吲哚衍生物的方法，其特征在于：所述的操作步骤中所使用的反应物的摩尔比为富电子芳基烯基-1，3-二噻烷:吲哚＝1:(0.5-3.0)。
5.根据权利要求1所述的一种区域选择性合成茚-吲哚衍生物的方法，其特征在于：反应温度范围为0-100℃。
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