htu2 An efficient method is proposed for the preparation of 3-substituted carbos@rilquinone derivatives, based on Friedlander synthesis of the 5,8- dialkoxyquinolines followed by cerium ammonium nitrate oxidative demethylation.Derivatives of 2.5.8-(1H)-quinolinemone("carbostyrilquinone") have been used as dienophiles in an hetero Diels-Alder approach to analogues of the antibiotic Diazaquinomycin A,' an inhibitor of thymidilate synthase that shows great promise as a new lead compound in the field of antitumor agents.'b.2.3The main limitation in this strategy lies in the scarcity of literature references to the preparation of carbostyrilquinones~ in spite of recent eff~rts.~Indeed,some derivatives of this system, such as 3-substituted carbostyrilquinones, are unknown.In this paper we report an efficient synthesis of carbostyrilquinones bearing electron-withdrawing groups at C3, based on the use of the Friedlander quinoline ~~n t h e s i s , ~. ~, a reaction that continues to attract the attention of synthetic chemist^.^,^Its main drawback, namely the tendency to self-condensation and hence the low stability of o-aminobenzaldehydes required as starting materials, was not an unsurmountable difficulty in our case.Thus, 2-amino-3,6-dimethoxy-benzaldehyde (1).a suitable starting compound for our proposed synthesis, could be obtained from the corresponding nitro 1388 HETEROCYCLES.Vol.36, No. 6,1993 by catalytic hydrogenation over Pd-C (78 % yield), or, alternatively, by means of Heck's uiethylammonium formate/Pd-C reagent (58 % yield).'1Treatment of 1 with several acetates bearing electron-withdrawing substituents in the a position in a refluxing mixture of ethanol and piperidine for 15min to 10 h afforded the desired 3-substituted 5.8-dimethoxy-2-(1H)-quinolinones (2a-Zd) in good yields, generally as colored (yellow to orange) crystalline solids that precipitated from the reaction medium (Scheme 1).In contrast, an attempted reaction with ethyl 2-phenylacetate gave a poor yield ( 17%, after 24 h) of an impure product that could not be properly characterized.C2H5 86 b CN C2H5 80 c NO2 C2H5 78 d C02H H 73 Reagents and conditions: i. Hz, 10% Pd-C, 35 psi, room temperature, 6 h u.HCQ-( C ~H ~) ~N H + , 10 % Pd-C.DMF, 140 "C, 6 h iii.Piperidine, CzH50H.LOO to 180 T, 15 min to 10 h Scheme 1Compound (Ze, R = COCH3), however, was obtained in only moderate yields, as a consequence of the low cbemoselectivity of the reaction between 1 and ethyl acetoacetate, even under conditions that have been described to promote formation of 2-quinolimones,L2 leading to formation of the quinoline derivative(3) in 29 % yield, together with the expected Ze (42 %).In order to improve this result, the P-0x0 ester was replaced by 2,2,6-~imeth~l-4~-1,3-dioxin-4-one,'~ an alternative acetoacetylating reagent, affording 2e in 72 % yield (Scheme 2).It is worth mentioning that reaction between 1 and malonic acid gave, together with the expected quinolinone (2d), varying amounts (6 % in the optimized reaction) of compound (4), depending on
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Avendaño et al. (1993) studied this question.