Dearomatization Strategy To Achieve Isoquinoline Trifunctionalization Reaction

Tetrahydro(iso)quinolines and hydrogenated pyridines are a very important class of nitrogen-containing organic compounds that are widely distributed in natural products and pharmaceutical molecules.These compounds have a variety of pharmaceutical activities and are a hot topic for researchers.Currently,the direct dearomatization of isoquinolines and pyridines to synthesize hydrogenated(iso)quinolines and pyridines is favored by many researchers.Although researchers have undertaken great efforts in this field,it is highly challenging to realize the polyfunctionalization of aza-aromatics during dearomatization.Therefore,the search for an efficient and green dearomatization strategy toward the polyfunctionalization of aza-aromatics is still of great importance and practical value.The present thesis focuses on the development of novel dearomatization strategies for the trifunctionalization of isoquinolines,with the following three parts of research.In the first part,it is demonstrated that copper catalysts promote the three-component reactions of 3-haloisoquinolines,alkyl halides,and 2-methylquinolines under mild conditions.New C–N,C=O,and C–C bonds were constructed by sequential trifunctionalization of the N1,C3,and C1 positions of 3-haloisoquinolines in a one-pot multicomponent tandem reaction to efficiently synthesize structurally novel 1,2-disubstituted isoquinolinone derivatives.The second part investigates the construction of disubstituted isoquinolinone derivatives via a one-pot three-component reaction of 3-haloisoquinolines,alkyl halides,and indoles under transition-metal-free conditions.The reaction achieves the trifunctionalisation of3-haloisoquinolines by a dearomatization strategy with high chemoselectivity,a wide range of substrates and is environmentally friendly.The three-component coupling reaction constructs new C–N,C=O,and C–C bonds in a single-step with high atom economy.In the third part,a series of structurally novel 1,2-disubstituted-3-isoquinolinones were developed by the three-component cascade coupling of 3-haloisoquinolines,haloalkanes,and reactive methyl compounds(acetophenones and nitromethanes)to construct C(sp~2)–C(sp~3),C–N,and C=O bonds.The reaction is promoted by Na OAc,which is easy to handle,environmentally friendly,and highly selective.