Site-Selective C(sp³)–H Functionalizations Mediated by Hydrogen Atom Transfer Reactions via α-Amino/α-Amido Radicals

Abstract

Amines and amides, as N-containing compounds, are ubiquitous in pharmaceutically-active scaffolds, natural products, agrochemicals, and peptides. Amides in nature bear a key responsibility for imparting three-dimensional structure, such as in proteins. Structural modifications to amines and amides, especially at their positions α to N, bring about profound changes in biological activity oftentimes leading to more desirable pharmacological profiles of small drug molecules. A number of recent developments in synthetic methodology for the functionalizations of amines and amides omit the need of their directing groups or pre-functionalizations, achieving direct activation of the otherwise relatively benign C(sp³)–H bonds α to N. Among these, hydrogen atom transfer (HAT) has proven a very powerful platform for the selective activation of amines and amides to their α-amino and α-amido radicals, which can then be employed to furnish C–C and C–X (X = heteroatom) bonds. The abilities to both form these radicals and control their reactivity in a site-selective manner is of utmost importance for such chemistries to witness applications in late-stage functionalization. Therefore, this review captures contemporary HAT strategies to realize chemo- and regioselective amine and amide α-C(sp³)–H functionalization, based on bond strengths, bond polarities, reversible HAT equilibria, traceless electrostatic-directing auxiliaries, and steric effects of in situ-generated HAT agents.

1 Introduction

2 Functionalizations of Amines

3 Functionalizations of Carbamates

4 Functionalizations of Amides

5 Conclusion

Key words

C–H functionalization - hydrogen atom transfer - N-radical cation - α-amino radical - α-amido radical - photocatalysis - regioselectivity - late-stage functionalization

Publication History

Received: 20 September 2021

Accepted after revision: 25 October 2021

Accepted Manuscript online:
25 October 2021

Article published online:
02 February 2022

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Promising future directions include: 1. The direct HAT activation of unprotected 2° amines which was recently achieved, see:
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