Cyclization Reactions of Nitrogen-centered Radicals

McCombie, S. W.; Quiclet-Sire, B.; Zard, S. Z.


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.