Remote C-H Functionalization of Aliphatic Amines

[摘要] This thesis summarizes our efforts in the development of methodologies aimed at remote C(sp3)–H functionalization of aliphatic amines. Amines are an important functional group present in a variety of biologically relevant molecules; however, examples of remote C–H functionalization of unprotected amines remain scarce. Many of the challenges associated with the remote functionalization of amines are related to the susceptibility of C–H functionalization proximal to the nitrogen center.Chapter 1 provides a perspective and summary of the field and Chapters 2-5 cover strategies we have developed to perform selective, remote C(sp3)–H functionalization of aliphatic amines. We have employed protonation as a strategy in combination with platinum-catalysis to achieve terminal-selective functionalization of aliphatic amines (Chapter 2). This strategy is based on the in situ formation of an ammonium salt to deactivate the C–H bonds proximal to nitrogen. Similarly, Chapter 3 describes the remote oxidation of 2º and 3º C–H bonds of protonated aliphatic amines mediated by potassium persulfate. In contrast to Chapters 2 and 3, Chapters 4 and 5 describe our efforts on the palladium-catalyzed, directed method that takes advantage of the basic nitrogen atom to enable transannular C–H functionalization of biologically relevant cyclic amine scaffolds. In Chapter 4, we optimized conditions to accelerate functionalization and directing group removal steps to enable the rapid generation of fragments. Chapter 5 describes the ligand-effects that led to our second-generation conditions for transannular C‒H arylation that allowed for the functionalization of pharmaceutically relevant bicyclic amines. Mechanistic studies are presented along with preliminary studies on the incorporation of additional functional groups.

[发布机构] University of Michigan

[效力级别] catalysis

[关键词] C-H functionalization;catalysis;amines;Chemistry;Science;Chemistry