Visible Light-mediated Chemodivergent Cyclization Of Alkyl Halides Toward 1-pyrrolines And 1-tetralones

Objective:1-pyrroline compounds are ubiquitous in many biologically active molecules and natural products.They can also be used as synthetic intermediates for important compounds such as pyrrolidine alkaloids,ligands,and pharmaceuticals.In recent years,photocatalytic iminyl radical-mediated cyclization reaction has developed rapidly due to its predictability,high selectivity and mild conditions,which provides a simple and efficient strategy for the construction of 1-pyrroline skeleton.At present,these synthetic methods are mainly based on the intramolecular cyclization of single-component ketooxime derivatives.However,the simple and easy-to-obtain two-component intermolecular cyclization method mediated by iminyl radicals has not been developed.Therefore,the purpose of this paper is to develop a convenient and efficient photocatalytic iminyl radical-mediated[3+2]cyclization method to construct a series of structure-rich and diverse 1-pyrroline compounds,providing a potential compound library for new drug development.Methods:With alkyl bromides as the precursor of 1,2-diradical precursors and iminyl radical source vinyl azides as the radical acceptor,through optimizing the reaction conditions and exploring the substrate scope,1-pyrroline compounds with diverse structures were obtained through the processes of photocatalytic intermolecular radical addition,intramolecular1,5-hydrogen atom transfer（1,5-HAT）mediated by iminyl radical and radical cyclization cascade.Further derivative the product to explore its practicability.The possible reaction mechanism was investigated through a series of control experiments and ESI-HRMS analysis.Results:By optimizing the reaction conditions,the optimal reaction system for the photocatalytic iminyl radical-mediated intermolecular[3+2]cyclization product 1-pyrroline compounds was obtained:under anhydrous and anaerobic conditions,Ru（bpy）₃（PF₆）₂（2 mol%）was used as photocatalyst,K₂CO₃（1.5 eq）was used as additive,dry CH₂Cl₂（0.1 M）was used as solvent,30 W blue light was used as light source,and the reaction was carried out at room temperature for 9 h.Thirty-three novel 1-pyrroline compounds were obtained with the highest yield of 81%.In addition,a new method for the preparation of 1-tetralone compounds by photocatalytic iminyl radical-mediated intermolecular[4+2]cyclization was established by changing the reaction conditions.The optimum reaction system for the synthesis of 1-tetralone compounds is as follows:under anhydrous and anaerobic conditions,fac-Ir（ppy）₃（2 mol%）as photocatalyst,Ac OH（1.0 eq）as additive,dry CH₂Cl₂（0.05 M）as solvent,30 W blue light as light source,room temperature reaction for 9 h.A total of 27 structurally diverse1-tetralone compounds were obtained with a yield of up to 75%.Conclusion:In this study,a controllable visible light-mediated[3+2]and[4+2]cyclization reaction system involving alkyl halides was developed through the precise regulation of photocatalysts and additives.A series of1-pyrroline and 1-tetralone compounds with diverse structures were obtained with high selectivity and high yield.In addition,the mild reaction conditions,easy-to-handle feedstocks,good tolerance of functional groups,easy scalability,facile derivatization of products provide great potential for the application of this method in pharmaceutical chemistry and organic synthetic chemistry.