Abstract
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 α, β, and γ 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 α-Alkylation
3 Late Transition Metal Catalyzed α-Functionalization
4 Photoredox-Catalyzed α-Functionalization
5 Electrochemical α-Functionalization
6 C–H Functionalization of β and γ C–H Bonds
7 Conclusions/Outlook
Key words
amines - catalysis - electrocatalysis - photoredox catalysis - transition-metal catalysis
- N-heterocycles - late-stage functionalization
