Cyclization Reactions of Nitrogen‐Centered Radicals

Abstract

The cyclization of nitrogen‐centered radicals constitutes a powerful approach for the synthesis of a broad variety of nitrogen heterocycles. As with carbon‐centered radicals, the most common ring‐closure mode is the 5‐ exo cyclization onto an internal unsaturation, and the stereoselectivity is similar. Numerous methods for the generation of almost every type of nitrogen‐centered radical have been described. They involve the direct or indirect rupture of N–Y bonds, with Y = halogen (except fluorine), oxygen, nitrogen, sulfur, and hydrogen. Indirect methods, such as the addition of carbon radicals to imines, azides, and nitriles, have also been devised. The extended choice of methods and precursors, and the general mildness of the experimental conditions and tolerance for numerous functional groups, represent valuable synthetic advantages. Furthermore, the cyclization step can be part of a radical cascade leading to multiple bond formations and the rapid construction of complex molecular frameworks. This chapter describes the types, structures, and reactivity of nitrogen‐centered radicals, and details the mechanistic basis of the methods used to generate them. The methods include stannane‐based processes, oxidations and reductions by single‐electron transfer, thermolysis, electrolysis, photolysis, and photoredox catalysis. The factors that influence the stereoselectivity of the ring‐closures are discussed briefly. Applications to the total synthesis of natural products, as well as functional‐group compatibilities, reaction variants, and comparison to other methods for the synthesis of nitrogen heterocycles by ionic, organometallic, and uncatalyzed ring‐closures onto alkenes are also presented. The tabular surveys are organized according to the type of nitrogen‐centered radical involved in the cyclization step: aminyls, amidyls, carbamyls, iminyls, amidinyls, and other types of nitrogen‐centered radicals.

Microwave- and Thermally Promoted Iminyl Radical Cyclizations: A Versatile Method for the Synthesis of Functionalized Pyrrolines

“…Iminyl radical cyclizations occupy a central role in the growing field of nitrogen-centered radical chemistry . Seminal observations by Forrester were followed by Zard’s pioneering work and Weinreb’s contributions that rendered these transformations practical.…”

δ-C–H Halogenation Reactions Enabled by a Nitrogen-Centered Radical Precursor

“…The transformations use readily available electrophilic halogenation reagents and proceed in up to 82% and 64% yield, respectively. Preparation of the new precursor was scalable up to 15 mmol, and our remote C–H fluorination protocol proved to be scalable to over 1 g. Given that methods for the generation of nitrogen radicals are relatively scarce, − we expect that this newly disclosed hydrazonyl carboxylic acid precursor will facilitate the development of a diverse range of new transformations, both by the development of other remote C–H functionalization reactions and through other patterns of reactivity available to nitrogen-centered radicals, such as β-scission processes or addition across unsaturated systems for N–C bond formation.…”

“…to over 1 g. Given that methods for the generation of nitrogen radicals are relatively scarce,56−58 we expect that this newly disclosed hydrazonyl carboxylic acid precursor will facilitate the development of a diverse range of new transformations, both by the development of other remote C−H functionalization reactions and through other patterns of reactivity available to nitrogen-centered radicals,59 such as βscission processes or addition across unsaturated systems60 for N−C bond formation. sı Supporting InformationThe Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.orglett.2c01261.…”