The functionalization of C(sp3 )-H bonds streamlines chemical synthesis by allowing the use of simple molecules and providing novel synthetic disconnections. Intensive recent efforts in the development of new reactions based on C-H functionalization have led to its wider adoption across a range of research areas. This Review discusses the strengths and weaknesses of three main approaches: transition-metal-catalyzed C-H activation, 1,n-hydrogen atom transfer, and transition-metal-catalyzed carbene/nitrene transfer, for the directed functionalization of unactivated C(sp3 )-H bonds. For each strategy, the scope, the reactivity of different C-H bonds, the position of the reacting C-H bonds relative to the directing group, and stereochemical outcomes are illustrated with examples in the literature. The aim of this Review is to provide guidance for the use of C-H functionalization reactions and inspire future research in this area.

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Complementary Strategies for Directed C(sp3 )-H Functionalization: A Comparison of Transition-Metal-Catalyzed Activation, Hydrogen Atom Transfer, and Carbene/Nitrene Transfer.

The selective functionalization of remote C–H bonds via intramolecular hydrogen atom transfer (HAT) is transformative for organic synthesis This radical-mediated strategy provides access to novel reactivity that is complementary to closed-shell pathways As modern methods for mild generation of radicals are continually developed, inherent selectivity paradigms of HAT mechanisms offer unparalleled opportunities for developing new strategies for C–H functionalization This review outlines the history, recent advances, and mechanistic underpinnings of intramolecular HAT as a guide to addressing ongoing challenges in this arena 1 	Introduction 2 	Nitrogen-Centered Radicals 21 	sp 3 N-Radical Initiation 22 	sp 2 N-Radical Initiation 3 	Oxygen-Centered Radicals 31 	Carbonyl Diradical Initiation 32 	Alkoxy Radical Initiation 33 	Non-alkoxy Radical Initiation 4 	Carbon-Centered Radicals 41 	sp 2 C-Radical Initiation 42 	sp 3 C-Radical Initiation 5 	Conclusion

Remote C-H Functionalization via Selective Hydrogen Atom Transfer.

Increasing interest in C(sp3)–H bond functionalization has led to a multitude of recent advances in intramolecular C(sp3)–H amination. Direct, intramolecular C(sp3)–N bond-forming processes provide expedient access to a range of azacycles without the need for prefunctionalized amine precursors such as aminoaldehydes, aminoalkyl halides or aminoalkenes. Some of these methods have been successfully applied to the synthesis of complex natural products. This Perspective provides a historical context for these methods and describes recent contributions, as well as the remaining challenges to intramolecular C(sp3)–H amination.

Intramolecular C(sp3)–H amination

Iodine reagents have been identified as economically and ecologically benign alternatives to transition metals, although their application as molecular catalysts in challenging C-H oxidation reactions has remained elusive. An attractive iodine oxidation catalysis is now shown to promote the convenient conversion of carbon-hydrogen bonds into carbon-nitrogen bonds with unprecedented complete selectivity. The reaction proceeds by two interlocked catalytic cycles comprising a radical chain reaction, which is initiated by visible light as energy source. This unorthodox synthetic strategy for the direct oxidative amination of alkyl groups has no biosynthetic precedence and provides an efficient and straightforward access to a general class of saturated nitrogenated heterocycles.

An Iodine-Catalyzed Hofmann–Löffler Reaction†

Remote intramolecular free radical functionalizations: An update

Synthesis of 1,4-epimine compounds. Iodosobenzene diacetate, an efficient reagent for neutral nitrogen radical generation

Photolysis of 3β-methoxymethoxy-5α-cholestan-6β-ylcyanamide (6), 29-methoxyfriedelan-3β-yl-cyanamide (15), (22R,25R)-5α-furostan-26-ylcyanamide (23), 8α,12-(12R/12S)-epoxylabdan-15-ylcyanamides, (32) and (33), in the presence of iodine and lead tetra-acetate leads to neutral cyanimyl radicals which undergo intramolecular hydrogen abstraction to produce N-cyanoepimino compounds. Better results are obtained with the system iodine and diacetoxyiodobenzene. The starting cyanamides have been prepared by reduction of the oximes (3) and (13) and of the amides (20), (28), and (29), respectively, with lithium aluminium hydride followed by cyanation with cyanogen bromide or with sodium cyanate and subsequent dehydration of the urea derivative with methanesulphonyl chloride.

R. Carrau

Papers

Synthesis of 1,4-epimine compounds. Iodosobenzene diacetate, an efficient reagent for neutral nitrogen radical generation

Intramolecular functionalization of N-cyanamide radicals: synthesis of 1,4-and 1,5-N-cyanoepimino compounds

Dehydrogenation of cyanamides. An approach to cyanimides and carbonyl compounds

Thermal rearrangement of allylic cyanamides

Intramolecular Functionalization of N-Cyanamide Radicals: Synthesis of 1,4- and 1,5-N-Cyanoepimino Compounds.