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

Synthesis Pub Date : 2024-08-01 DOI:10.1055/s-0043-1775377
Cameron H. M. Zheng, Laurel L. Schafer
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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

Abstract Image

饱和 N-杂环 C-H 键官能化用于烷基化 N-杂环合成的最新进展
饱和 N-杂环基团在制药领域的突出地位毋庸置疑。与饱和 N-terocycle 支架的烷基化相关的挑战是如何有效地获得新的药物类似物,这受到合成路线费力的阻碍。饱和 N-杂环上的立体控制烷基取代尤其难以通过传统合成方法获得高产率。另外,C-H 键官能化通过直接和选择性地官能化/烷基化/芳基化饱和 N-terocycles 中大量可用的 C-H 键,提供了一种新的、强大的合成途径。本综述重点介绍了通过化学、区域和或立体选择性地直接激活饱和 N-杂环的 C-H 键并使其官能化,从而获得烷基化产物的互补方法。这一合成挑战需要催化剂的开发,以获得有用的 N-杂环构件或进行后期官能化。本文讨论了早期过渡金属、晚期过渡金属、光氧化和电化学方法。介绍了选择性官能化 α、β 和 γ C-H 键以形成新的 C-C、C-N、C-O 和 C-B 键的方法。1 引言 2 早期过渡金属催化的 α 烷基化 3 晚期过渡金属催化的 α 功能化 4 光氧催化的 α 功能化 5 电化学 α 功能化 6 β 和 γ C-H 键的 C-H 功能化 7 结论/展望
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