NiH-Catalyzed Remote Hydroamination of Alkenes with Nitroarenes and Related Studies Towards the Asymmetric Transformation

Author:Xiao Ji Chao

Supervisor:zhu shao lin


Degree Year:2019





Arylamines are prevalent in pharmaceuticals,natural products,agrochemicals,and novel materials.Many of top-selling drugs(such as Lidoderm,Crestor,Abilify and Gleevec)contain arylamine skeletons.Classical methods for their construction include nucleophilic substitution,amine-carbonyl reductive amination,and Buchwald-Hartwig&Ullman-type amination.Recently,direct amination of the ubiquitous sp3 C-H bond has received great attention.However,most of the conventional C-H aminations require a pre-installed polar directing group nearby to ensure good reactivities and selectivities which limits their application in organic synthesis.In contrast,the direct installation of a distal amino group at a remote sp3 C-H position is a valuable yet unexplored process.My doctoral dissertation is focused on the nickel-catalyzed remote hydroamination of alkenes with nitroarenes,two common feedstock chemicals,to achieve highly regioselective remote hydroamination.The research in this thesis includes nickel-catalyzed remote amination of alkenes with nitroarenes and the related studies towards the asymmetric transformation.In the first part,we developed a nickel-catalyzed remote hydroamination of alkenes with nitroarenes,using NiI2 as catalyst,6,6’-dimethyl-2,2-bipyridine(2-L1)as ligand,Me(MeO)2SiH as hydride source,DMPU/DMA as solvent.Remote benzyl arylamination products were obtained with high yields and high regioselectivelies.The one step conversion of two simple feedstock building blocks,olefins and nitroarenes,to value-added remote arylamination products is an attractive strategy for both aryla1ine synthesis and remote sp3 C-H amination.The reaction has lots of advantages such as mild conditions,broad substrate scope,and good compatibility of functional groups.The practical value of this process is further highlighted by large-scale synthesis and regioconvergent amination of unrefined isomeric mixture of olefins.We also explored the mechanism through a series of control experiments,deuteration experiments and intermediate experiments.Based on these results,we proposed the possible mechanism for this transformation.In the second part,we focused on the nickel-catalyzed asymmetric remote hydroamination of alkenes with nitroarenes.We designed and synthesized over 100 chiral nitrogen ligands.Ligand screening indicates that chiral Box and Pyrox ligands could obtain moderate enantioselectivies,with better enantioselectivity in case of Pyrox ligands.We also summarized the structure-activity relationship of the Pyrox ligands,which would be helpful for ligand design in future.