Superbase‐Mediated Indirect Friedländer Reaction: A Transition Metal‐Free Oxidative Annulation toward Functionalized Quinolines

Abstract

A superbase mediated indirect Friedländer reaction towards functionalized quinolines has been realized. The reaction was performed with o-aminobenzyl alcohol and ketones having an active methylene moiety in the presence of KOH and in DMSO. The reaction proceeds predominantly via initial formation of an imine intermediate and subsequent oxidation of the benzyl alcohol functionality and condensation to afford substituted quinolines. We could also demonstrate that a minor [a] fraction of the reaction proceeds via a chalcone intermediate. The transition metal-free oxidative annulation was found to be general affording 2-substituted, 2,3-disubstituted/fused or multi-substituted quinolines. The reaction was extended towards the functionalization of natural products and the applicability of the reaction for gram-scale synthesis of quinolines was also demonstrated. group containing carbonyl derivative followed by dehydration. Recently, modified or indirect Friedländer quinoline synthesis protocols with dehydrogenative cyclization of 2-aminobenzyl alcohol with carbonyl compounds (or alcohols) were developed in the presence of metal catalysts (Scheme 1). [6] Different complexes of metals such as Ru, [6b] Rh, [6c] Ir, [6d-6f ] Cu, [6g] Ni [6h-6i] and Re [6j] were utilized as catalysts in indirect Friedländer quinoline synthesis. In addition, several heterogeneous catalysts including Ru-HT (ruthenium on hydrotalcite support), Pd/C, Pd(OAc) 2 / PEG-2000, Ag-Pd alloy on carbon and a Cu based MOF were also developed and used for synthesizing substituted quinolines (Scheme 1). [7] Scheme 1. Indirect Friedländer synthesis of quinolines from 2-aminobenzyl alcohol.