Mechanistic Studies On Cu-catalyzed/Mediated C（sp~3）-H Amidation And Acetoxylation

With notable applications to material sciences,crop protection,drug discovery,and pharmaceutical industries,among others C-H functionalization has become an essential driving force largely accelerating the development of synthetic organic chemistry since it promotes the immediate transformation of omnipresent C-H bonds into C-X（X=C,N,O,S,Cl,Br,etc.）bonds in a single pass,avoiding troublesome functional group manipulations and greatly improving the reaction step economy.Despite major advances,the vast majority of these C-H functionalizations required precious 4d or 5d transition metal catalysts.Given the cost-effective and sustainable nature of earth-abundant first row transition metals,the development of less toxic,inexpensive 3d metal catalysts for C-H activation has gained considerable recent momentum as a significantly more environmentally-benign and economically-attractive alternative.Copper are omnipresent inexpensive 3d metal in organic synthesis because of their easily accessible oxidation states,predominantly ranging from 0 to+3 that enable new bondforming processes through both radical pathways and proposed two-electron transfer manifolds via organometallic intermediates.Thus,based on the pioneering studies by Ullmann and Goldberg,an impressive number of organic transformations have been reported for both C-C and C-heteroatom bond formations via cross-coupling,oxidation,addition,and radical reactions.Although the earlier copper-catalyzed C-H activation reactions,such as oxidative dimerization of electron rich arenes,proceeded through proposed SET mechanisms,many of the recent C-H activation studies were shown to proceeded through organometallic C-Cu intermediates.Those mechanistic findings have set the stage for the utilization of copper complexes in C-H activation reactions.Mechanistic studies on Cu-catalyzed/mediated C（sp~3）-H amidation and acetoxylation are investigated from experimental and computational aspects.The concerted metalation-deprotonation（CMD）mechanism rather than a radical-involved pathway is proved to occur in amidation and acetoxylation reactions,and this is the rare example of CMD mechanism involved in the more challenging C（sp~3）-H activations.Theoretical calculations demonstrated that CMD is the rate deter-mining step either for methylic or benzylic positions in amidation and acetoxylation reactions,and intermolecular nucle-ophilic addition of acetate anions is more favorable than ring-opening ofβ-lactam and intramolecular acetoxylation.These mechanistic researches on the divergent and condition-dependent product formation are critical for developing Cu-promoted C-H functionalization via CMD mechanism.