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
