Application Of Transition-metal Catalysis In 1H-indazole Directed Synthesis And Indole Derivatization

In recent decade,transition metal-catalyzed C–H functionalization develops rapidly.Indazole and Indole are important heterocyclic building blocks in small-molecule drugs,which have attracted great attention of the synthesis and application of indazole and indole derivatives due to their wide bioactivities.Based on their unique electronic distribution properties,the indazole moiety has been frequently used as directing group or ligand in transition metal-catalyzed regioselective functionalization,while the transition metal-catalyzed indole derivatization has also been often reported..This dissertation focuses on 1H-indazole directed C-H bond activation and regioselective functionalization of indoles via transition-metal catalysis,including:1)1H-Indazole directed C（sp³）-H oxygenation,2)2-（1H-Indazol-1-yl）quinoline directed Wacker-type oxidation and oxo-acyloxylation of olefins,3)Indole alkenylation–annulation and alkenylation–elimination.These studies mainly include the following three parts.Part I.Pd-mediated 1H-indazole directedγ-C（sp³）-H oxygenation.We developed herein Pd-catalyzedγ-C（sp³）-H acyloxylation and alkoxylation using1H-indazole as the directing group（DG）and TBHP as the oxidant.Unexpectedly,the alkoxypalladium（II）intermediate was captured,which goes through a SN₂process that is redox-neutral at the Pd（II）center to afford the oxygenation products.Notably,this is the first time that C（sp³）-H oxygenation is realized through a C（sp³）-O-[Pd（II）（Ln）]species in contrast to the classical proposed catalytic pathway with alkylpalladium（IV）species.Experimental and computational experiments were performed to study the reaction mechanism.A variety of acids,N-protected amino acids,acid-containing drugs,and alcohols are all compatible with this reaction.The preliminary simple DG removal and one-step efficient product conversion reaction demonstrate this protocol’s potential for structural manipulation to amine-containing diverse functional molecules.Part II.Pd-catalyzed selective Wacker-type oxidation and oxo-acyloxylation of olefins using 2-（1H-Indazol-1-yl）quinoline ligand.We have developed a general method for selective Wacker-type oxidation and oxo-acyloxylation of olefins to ketones andα-acetoxyacetone products using TBHP as the oxidant and 2-（1H-indazol-1-yl）quinoline as the ligand.Experimental studies showed that the ketone products are generated through 1,2-hydride migration as previously reported,whereas theα-acetoxyacetone products are obtained by reductive elimination of Pd enolate intermediates.A variety of olefins were well tolerated for this reaction system.The resulting diverse ketones and the potential hydroxyl group from theα-acetoxyacetone products demonstrate this protocol’s potential for further structural manipulation of functional molecules.Part III.Rh-catalyzed selective alkenylation–annulation and alkenylation–elimination of indole.We present here a Rh（III）-catalyzed regioselective indole C–H functionalization using N-acetyl amide as the DG in the presence of Ag Sb F₆.The assistance of KHSO₄ renders the chelating amide group of DG much more reactive to give annulation products with N-acetyl amide acting as the annulation partner.Notably,the addition of Cs OAc resulted in the DG-free alkenylation product formation,which shows the first example of in situ elimination of N-acetyl amide.Notably,in situ hydrolysis and benzoyl protection of the annulated product successfully afford easily separableβ-（1H-indol-2-yl）-β-amino acid derivatives.Experimental studies,including the isolation of Rh intermediates and further kinetic studies,were performed to further elucidate the underlying selective reaction mechanism.In summary,these strategies expand the application of transition-metal catalysis in1H-indazole-directed functionalization and regioselective functionalization of indole,which provide potential for the discovery of novel synthetic strategies.