Unprecedented Aromatic Homolytic Substitutions and Cyclization of AmideIminyl Radicals: Experimental and Theoretical Study

Abstract

Amide-iminyl radicals are versatile and efficient intermediates in cascade radical cyclizations of N-acylcyanamides. They are easily trapped by alkenes or (hetero-)aromatic rings and cyclize into a series of new heterocyclic compounds which bear a pyrroloquinazoline moiety. As an illustration of the synthetic importance of these compounds, the total synthesis of the natural antitumor compound luotonin A was achieved through a tin-free radical cascade cyclization process. Not only do amide-iminyl radicals lead to new tetracyclic heterocycles but these nitrogen-centered radical species also react in aromatic homolytic substitutions. Indeed, the amide-iminyl radical moiety unprecedentedly displaces methyl, methoxy, and fluorine radicals from an aromatic carbon atom. This seminal reaction in the field of radical chemistry has been developed experimentally and its mechanism has additionally been investigated by a theoretical study.

A new era for homolytic aromatic substitution: replacing Bu3SnH with efficient light-induced chain reactions

“…There are examples of iminyl radicals undergoing HAS, 20 including cascades from N-acyl cyanamides with aromatic substitution facilitated by virtue of displacement of a substituent (hydrogen or alkyl) on the aromatic ring. [21][22][23] Although HAS is part of the cascade due to the migration of the hydrogen atom an overall reduction occurs (Scheme 5). A HAS chain reaction is possible using Bu 3 SnH with azo-initiator if cyclization is accompanied by ipso-substitution.…”

Interplay of ortho- with spiro-cyclisation during iminyl radical closures onto arenes and heteroarenes

“…This research initiated spiralling interest by synthetic chemists in iminyl radical-mediated preparations. Recently iminyls have been generated from quite a variety of precursors [10–15], and their cyclisations onto arenes [16–21] and heteroarenes [22–24] have attracted attention. Iminyl cyclisations have also been utilised in natural-product syntheses [10,16,25–26].…”

Recent Advances in the Studies on Luotonins

“…Courillon and coworkers reported a cascade radical cyclization of N -acylcyanamides as an alternative procedure for the 4(3 H )-quinazolinone nucleus, which led to the total synthesis of luotonin A [46,47] (Scheme 15). Cyanation of N -[(2-iodoquinol-3-yl)methyl]benzamide with cyanogen bromide afforded the corresponding N -CN compound which was subjected to radical cyclization to yield luotonin A.…”