Selective Functionalization of Normal Alkyl C-H Bonds Using Amides as Directing Groups

Abstract

Normal alkyl C—H bonds refer to those sp 3 C—H bonds not linking with any carbon functional groups or hetero- atoms at their adjacent positions. They are fundamental chemical bonds, which are widespread both in raw materials such as petroleum oil, natural gas etc. for chemical industries and in various kinds of intermediates for chemical syntheses. Selective transformation of these ubiquitous alkyl C—H bonds into new carbon-carbon, carbon-nitrogen, or carbon-oxygen bonds is an ideal method in construction of molecular skeletons, extension of carbon-chains and introduction of functional groups, which is urgently desired in either large-scale production or laboratory synthesis. However, these normal sp 3 C—H bonds are ex- tremely chemical inert, due to their high bond dissociation energy and low acid dissociation constant. Thus, they are not used directly and conveniently as other available functional groups in synthetic chemistry. Since the beginning of this century, the functionalization of normal alkyl C—H bonds has been developed rapidly through C—H activation which is to cleave these inert C—H bonds with the assistance of some special directing groups by use of catalytic transition-metal complexes under mild conditions. Amides as one of the effective directing groups, which are prevalent in natural products and pharmaceuti- cals, has also received particular attention. A series of novel reactions using various amides as directing groups to produce carbon-carbon and carbon-heteroatom bonds, including alkyl-aryl, alkyl-alkenyl, alkyl-carbonyl, alkyl-alkynyl, alkyl-alkyl linkages and carbon-nitrogen, carbon-oxygen, carbon-chlorine, carbon-bromine, carbon-boron, carbon-sulfur, carbon- selenium bonds, etc. have been established, and some of them have been applied to the practical synthesis already. This re- view describes the development on the functionalization of normal alkyl C—H bonds according to the formed bonds, reaction substrates, and chronological order. It is emphasized that the structures of amide groups, properties of transition metals, re- gional and stereo-selectivities in C—H activations, reaction mechanisms, subsequent transformations and their synthetic ap- plications, etc.