Non-Directed β- or γ-C(sp³)–H Functionalization of Saturated Nitrogen-Containing Heterocycles

Abstract

Reactions that take place via C–H functionalization are valuable tools in organic synthesis because they can be used for the synthesis of target compounds and for the late-stage functionalization of bioactive compounds. Among these, non-directed C(sp³)–H functionalization reactions of saturated nitrogen-containing heterocycles have been developed in recent years. However, most of these lead to functionalization at the α-position relative to the heteroatom, and reactions at the β- or γ-positions are limited since these bonds are stronger and less electron-rich. Hence, in this review, we will discuss non-directed β- or γ-C(sp³)–H functionalization reactions of saturated nitrogen-containing heterocycles, which are of recent interest to medicinal chemists. These methods are attractive in order to avoid the pre-functionalization of substrates, and to reduce the number of synthetic steps and the formation of byproducts. Such non-directed β- and γ-C(sp³)–H functionalization reactions can be divided into enamine-intermediate-mediated processes and other reaction types described in this review.

1 Introduction

2 Non-Directed β-C(sp³)–H Functionalization of Saturated Nitrogen­-Containing Heterocycles via an Enamine Intermediate

2.1 Non-Directed β-C(sp³)–H Functionalization of Saturated Nitrogen­-Containing Heterocycles under Acidic, Basic or Thermal Conditions

2.2 Non-Directed β-C(sp³)–H Functionalization of Saturated Nitrogen­-Containing Heterocycles under Oxidative Conditions

2.3 Non-Directed β-C(sp³)–H Functionalization of Saturated Nitrogen­-Containing Heterocycles under Redox-Neutral Conditions

3 Strategies for Non-Directed β- or γ-C(sp³)–H Functionalization of Saturated Heterocycles Excluding Examples Proceeding via an Enamine Intermediate

4 Summary

Key words

directing-group-free - C(sp³)–H functionalization - nitrogen-containing heterocycles - enamine intermediate - borrowing hydrogen - late-stage functionalization

Publikationsverlauf

Eingereicht: 05. März 2021

Angenommen nach Revision: 15. April 2021

Accepted Manuscript online:
15. April 2021

Artikel online veröffentlicht:
19. Mai 2021

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