Study On Synthesis Of 4-Alkyl-Isoquinoline Derivatives Via Palladium-Catalyzed Domino Heck/Cross-Coupling Reactions

Isoquinoline alkaloids are a class of biologically active alkaloids that are widely found in nature.Isoquinoline is not only the core structure unit of many natural products and drugs,but also important intermediates in organic synthesis.Therefore,developing new synthetic methods for isoquinoline has become one of the hot spots in organic chemistry.In this thesis,a palladium-catalyzed domino Heck/intermolecular cross-coupling reaction for the synthesis of 4-alkylated isoquinolines has been developed.In Chapter 1:synthesis of isoquinolines by the transition-metals-catalyzed C-H bond activation/cyclization of alkyne,annulation of o-halobenzaldehyde imines and electrophilic cyclization of o-alkynylbenzaldehyde imines were reviewed.Formation of C(sp~3)-C(sp),C(sp~3)-C(sp~2),C(sp~3)-C(sp~3)and C(sp~3)-heteroatoms bonds involving ?-alkyl-palladium intermediate were also reviewed.In Chapter 2,synthesis of starting materials including o-alkynylbenzaldehydi-mines and ortho-iodobenzene with distal double bonds have been described.In Chapter 3,(E)-N-tert-butyl-1-(2-(phenylethynyl)phenyl)formaldehydeimi-ne and 1-iodo-2-((2-methylallyl)oxy)benzene were used as model to optimize the reaction.The scope of this method was examined by changing the substitution on iodobenzene with distal double bond,substitution on the end of o-alkynylbenzaldehydimine and benzaldehyde imines.The linkers between ortho-iodobenzene and distal double bond have also been varied to prepare different five-membered ring and six-membered ring products.A three-component cross-coupling reaction of 2-phenylethynyl benzaldehyde,tert-butylamine and 1-iodo-2-((2-methylallyl)oxy)benzene has been conducted.30 new 4-alkylated isoquinolines were prepared and characterized by IR,NMR,HRMS.The structure of product 3aa was verified by X-ray.This thesis reported the first example of a ?-alkylpalladium intermediates promoting electrophilic cyclization of alkynes,which creates a quaternary carbon center,two heterocycles and three ? bonds in one step.It has good functional group compatibility and provides a new method for the efficient synthesis of 4-alkyl-substituted isoquinolines.