Recent advances of 5-endo-trig radical cyclization: promoting strategies and applications

Abstract

5-endo-trig radical cyclization has long been recognized as one of the most straightforward ways for the construction of densely functionalized five-membered rings. Nevertheless, according to Baldwin's rules, the 5-endo-trig radical cyclization is kinetically disfavored due to stereoelectronic effects and thus usually proceeds via a slow rate, which renders its application a challenging task. In recent years, with the emergence of efficient radical generation methods and effective cyclization strategies, 5-endo-trig radical cyclization has been successfully accelerated to a synthetically useful rate and has been utilized in the access of diverse five-membered carbo- and heterocyclic compounds. This review comprehensively summarizes the methodologies involving the 5-endo-trig radical cyclization process, with particular emphasis on the elucidation of the promoting strategies, which include the polar effect, geometrical constraints, spin delocalization effect, and persistent radical effect. Each of these strategies is discussed in detail, with illustrative examples from recent literature studies to highlight their practical applications and effectiveness. It is anticipated that the in-depth understanding of the 5-endo-trig radical cyclization provided by this review would inspire further innovation of this privileged reaction mode and expand its applications. Moreover, the potent ring-closure-promoting strategies revealed herein would also contribute to achieving other challenges of cyclizations with particular significance for organic synthesis.