Reaction of Benzocyclobutenoxides with Aldehydes: Synthesis of Peshawarine and Other 3,4-Dihydroisocoumarins

Article abstract of DOI:10.1021/jo00094a022

Deprotonation of benzocyclobutenols 6 in presence of aromatic aldehydes affords benzopyranols 7 in high yield.In the key step of this process, an o-tolualdehyde anion generated by the known ring-opening of benzocyclobutenoxides adds to the aldehyde to give 7 which is easily oxidized to 3-substituted 3,4-dihydroisocoumarins 8 including intermediates in some natural product syntheses.For example, reaction of 6-methoxybenzocyclobutenol (1) with LTMP and p-anisaldehyde gave in 96percent yield to benzopyranol 16, which subsequently was converted to (+/-)-hydrangenol (17).Similar treatment of 1 with LDA and isovanillin benzyl ether afforded the benzopyranol 19 (87percent yield) which already has been converted to (+/-)-phyllodulcin (21).Finally, reaction of 5,6-(methylenedioxy)benzocyclobutenol (10) with LTMP and the aldehyde 26 (from treatment of hydrastinine with ClCO2Me) followed by methanolysis produced the acetal 28 in 96percent yield.The overall yield was 65percent for the five-step synthesis of the alkaloid (+/-)-peshawawine (24) from 10 and 26.Extension of the process to aliphatic aldehydes was illustrated by the preparation of 32 from benzocyclobutenol and isobutyraldehyde in 69percent overall yield after oxidation with PCC.