Rapid photoassisted access to N,O,S-polyheterocycles with benzoazocine and hydroquinoline cores: intramolecular cycloadditions of photogenerated azaxylylenes.

Abstract

o-Azaxylylenes have been known for half a century, but remained in relative synthetic obscurity until a decade ago, when Corey and Steinhagen reported their first preparation under simple mild conditions by base-induced elimination of hydrogen chloride from derivatives of o-chloromethylaniline. It was noted that “Surprisingly, simplest method possible for o-azaxylylene production ... has never been reported.” Synthetically useful reactions of o-xylylenes (i.e. allcarbon o-quinodimethanes) are plentiful, and their generation from aromatic o-alkyl ketones by an intramolecular photoinduced hydrogen abstraction is well documented. Given this fact, it was surprising to us that the equally simple photogeneration of o-azaxylylenes from o-aminoketones by an excited-state intramolecular proton transfer (ESIPT) has never been utilized in synthetic chemistry. It is conceivable that such implementation was attempted but failed due to the fast back proton transfer successfully competing with bimolecular cycloadditions. Intramolecular proton transfers from one heteroatom to another (and back) are fast; a typical example is the much studied photophysics of salicylaldehyde or o-hydroxyacetophenone, although the elusive tautomeric form is not impossible to characterize. We, however, found that the intramolecular cycloaddition reactions of o-azaxylylenes photogenerated by excited-state proton transfer can successfully compete with the back proton transfer. Herein, we report the first example of [4+ 2] and [4+ 4] cycloaddition reactions of photogenerated azaxylylenes with unsaturated pendant groups; this reaction offers expeditious access to a diverse array of N,S,O-polyheterocycles with mostly unprecedented topologies (Scheme 1). As the azaxylylenes are expected to act as acceptors in the inverse-electron-demand cycloaddition reactions, we synthesized photoactive azaxylylene precursors 1 and 4 by coupling o-aminoketones with furanor thiophenepropionic acid chlorides. These o-acylamido precursors have broad UV Scheme 1. Photogeneration of azaxylylenes and their intramolecular photocyclizations.