Synthesis of 6-Formyl Derivatives of 5,8-Dimethoxycarbostyryl

Abstract

W -An efficient method is described for the preparation of 5,8-dimethoxy-2- oxo-IH-quinoline-6-carbaldehyde. Alternative strategies aimed at the synthesis of 4- methyl analogues are also studied.Heterocyclic quinones are increasingly important compounds due to their interesting and challenging chemisuy and their relevant biological properties, including antitumour activity.' Some natural products, such as streptonigrin, lavendamycit? and diazaquinomycin3 are particularly interesting in this respect, and intensive efforts are being devoted to their total synthesis and the preparation of analogues. Within the scope of our research on antitumour heterocyclic quinones bearing the 2,5,8-quinolinetrione m~i e t y .~ we required 6-formyl derivatives (1) as key synthetic intermediates.The PI-eparation of compounds (1) was planned according to several strategies, which are summarized in Scheme 1. Route a involves oxidation of 6-methyl-5.8-dimethoxycarbostyryl, prepared by cyclization of precursors obtained from 4-methyl-2.5-dimethoxyaniline (2). available in three quantitative steps from 2-methylhydroquinone.5 Similar results might be achieved starting with 4-amino-2.5-dimethoxybenzaldehyde (route b).Finally, direct formylation6 of 5,8-dimethoxycarbostyryls7 (route c) must also be considered.According to strategy a , 4-methyl-2.5-dimethoxyaniline (2) was acylated with 3,3-dimethoxypropionic acids togive the diacetal (3). One-pot deprotection and Knorr cyclization of 3 afforded the precursor (4), which was oxidized to the desired aldehyde (la) by benzylic bromination with N-bromosuccinimide followed by oxidation with N-methylmotpholine-N-oxide9 without isolation of the intermediate bromide (5). The overall yield for the