Recent Advances in Saturated N -Heterocycle C-H Bond Functionalization for Alkylated N -Heterocycle Synthesis

The prominence of saturated N -heterocycle motifs in pharmaceuticals is undeniable. Challenges associated with the alkylation of saturated N -heterocycle scaffolds to efficiently access new drug analogues are hampered by synthetically laborious routes. Stereocontrolled alkyl-substitutions onto saturated N -heterocycles are particularly difficult to access in high yields by traditional synthetic methods. Alternatively, C-H bond functionalization provides a new and powerful synthetic avenue by directly and selectively functionalizing/alkylating/ arylating the abundantly available C-H bonds of saturated N -heterocycles. This review highlights complementary methods for directly activating and functionalizing C-H bonds of saturated N -heterocycles chemo-, regio-, and or stereoselectively to access alkylated products. This synthetic challenge has required catalyst development to access useful N -heterocyclic building blocks or for late-stage functionalization. Early transition metal, late transition metal, photoredox, and electrochemical methods are discussed. The selective functionalization of alpha, beta, and gamma C-H bonds to form new C-C, C-N, C-O, and C-B bonds is presented. 1 Introduction 2 Early Transition Metal Catalyzed alpha-Alkylation 3 Late Transition Metal Catalyzed alpha-Functionalization 4 Photoredox-Catalyzed alpha-Functionalization 5 Electrochemical alpha-Functionalization 6 C-H Functionalization of beta and gamma C-H Bonds 7 Conclusions/Outlook