The Exploration Of C2-Substituent Promoted Oxidative Coupling Of Indole And Enolate

2,3-disubstituted indoles are the core scaffolds of many indole alkaloids,lead compounds and drug molecules with important physiological activities.Thus,it is of significance to explore novel methods for their preparation.The traditional methods of indole preparation,represented by Fischer indole synthesis,mainly focused on the construction of indole ring.Albeit being widely used even in industry,it is not efficient enough for the rapid establishment of multi-substituted complex indole library and the SAR（structure-activity relationship）studies of corresponding drug molecules.Multiple steps are normally required to introduce corresponding functional groups on the substrate from the commercial starting materials.The direct selective functionalization of indoles,by contrast,is an ideal strategy,especially in the construction of a small molecular library of 2,3-disubstituted indoles bearing multiple functional groups.Among many approaches of selective functionalization of indoles,the direct oxidative cross coupling of indoles and enolates mediated by cheap metals is attractive,from the perspective of atom-and step-economy.Herein,we presented a Fe Cl₃-mediated C2-substituent promoted oxidative cross coupling of indoles and enolates.The yields are significantly improved（up to 96%）in preparation of 2,3-disubstituted indoles by utilizing Fe Cl₃ as oxidant in our approach.Mechanism study indicates the reaction go through a well-defined“Fe-chelated radical-anion coupling”procedure.The Fe^II or Fe^III cation chelated the enolate and indole anion first to form a stable transition state,followed by single electron transfer（SET）process to generate enolate radical captured by adjacent indole ring.The cross coupling product was obtained after another SET oxidation and aromatization.The substituent on C2position of indole can stabilize the indoline radical intermediate,thus promotes the reaction.Further application of this method to prepare bioactive molecules was conducted.Indomethacin and its analogues were quickly constructed in a simple three step sequence.The C3-aryl indoles can be successfully accessed,after oxidative aromatization of the cyclohexenone fragments in products assisted by I₂/DMSO.The installation of C3-axial chirality on indole was explored as well via point to axial chirality transfer strategy.Morevoere,some of 2,3-disubstituted indole products exhibited inhibitory activity of tumor cell proliferation in A549,H1299,HCT116,HT29,K562,MV-4-11,Hep G2 and drug-resistant KB cell lines.