A Strategy for Generalization of the Regiospecific Synthesis of Substituted Quinones from Cyclobutenediones

Article abstract of DOI:10.1021/jo00042a009

Documented within is a straightforward protocol for the synthesis of generally substituted benzoquinones and ring-fused quinones.Previously, the crucial issue of quinone substituent regiochemistry was resolved at the stage of addition of an unsaturated carbon nucleophile to a cyclobutenedione by using either symmetrically substituted cyclobutenediones or 3-alkoxy (or amino)-4-substituted-3-cyclobutenediones.In the former case there are no regioisomeric quinones formed, while in the latter, through resonance delocalization, the alkoxy (or amino) substituent renders one of the two carbonyl groups less reactive and directs the incoming nucleophile to the other.The placement of a wide variety of substituents about the quinone ring periphery has now been solved by the less restrictive strategy of sequential introduction of substituents onto a cyclobutenedione core.The chemistry commences with 3-isopropoxy-4-substituted-3-cyclobutene-1,2-diones.Addition of an aromatic, heteroaromatic, or alkenyl nucleophile to the more reactive carbonyl group provides 4-hydroxy-4-R_unsat-2-cyclobutenones, which are protected as the methyl ethers by treatment with MeI/Ag2O/K2CO3 in MeCN.A second nucleophile is added, again in a 1,2-sense, providing highly substituted 3-isopropoxy-2-cyclobutenols that are arranged to cyclobutenones under acidic conditions.The resulting cyclobutenones are converted into substituted quinones by thermolysis at 140 deg C in o-xylene followed by oxidative workup with ceric ammonium nitrate.The substitution pattern about the quinone core is rigorously controlled by the sequence of introduction of the substituents.