Transition-metal Catalyzed Regioselective Functionalization Of Indoles At The Benzene Core

Indoles and their derivatives are a class of the most important frameworks in natural products and pharmacologically active molecules.The functionalization of indoles has been remaining as an important subject in the field of organic synthesis.Due to the strong electron avaibility,it is easy to be functionalized at C2 and C3 position of the pyrrole ring of indoles.While a large number of protocols have been developed for such transformations,however,the work about the functionalization of inactive benzene core is sparse.Herein,this thesis aims to developing a series of transition-metal catalyst systems for the regioselective functionlization of the benzene core of indoles by introducing some proper direction groups.The contents of this thesis has been divided as following:Part ?:In this part,C-H arylation of indoles at C7 position is presented in the presence of Pd-catalysis with arylboronic acids as the source of aryl group.By using 2-chloro pyridine as the ligand,Cu?OTf?₂ and Ag₂O as the oxidants,C7 arylated indoles were synthesized in high regioselectivities for the first time.The key to this high regioselectivity is the appropriate choice of a phosphinoyl directing group?TBPO?as the direction group and a pyridine-type ligand in the presence of Pd?OAc?₂ catalyst.This reaction is explored to overcome the intrinsic selectivity for C2 and C3 positions perfectly and it also exhibits a wide of substrates scope.This reaction has laid the foundation for the following research.Part ?:The first example of direct and site-selective arylation of indoles at the C6 position has been discussed by using catalytic amounts of CuO.Here also,the key to the high regioselectivity is the appropriate choice of the directing group N-P?O?tBu₂?TBPO?which was appended to the N atom of indole and the utilization of diaryliodonium triflate salts as the coupling partners.This protocol is distinguished by a mild catalytic system without any ligands and additives.The reaction exhibits excellent substrates scope,including various indoles and arene coupling components,without compromising its efficiency and scalability.Part ?:With the aid of a readily accessible,cheap,and removable pivaloyl directing group installed at the C3 position,a series of highly regioselective C4 arylated indoles have been achieved.By using Pd?PPh₃?₂Cl₂ as the catalyst,Ag₂O as the oxidant,and DBU as the base,indoles reacted with aryl iodides in HFIP to provide C4 arylated products.This transformation shows good functional group compatibility and can serve as a powerful synthetic tool for synthesis of medicinally relevant compounds.Part ?:By using the TBPO functionalized indoles as the substrates,other important reactions about C6 functionalization has been achieved.In presence of amounts of catalytic P?p-CF₃C₆H₄?₃AuNTf₂ and HNTf₂,indoles reacted with?-Aryl-?-diazoacetates to generate C6 functionalized products in high regioselectivity.The reaction exhibits good substrate scope with high functional group tolerance.