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

Deprotonation of benzocyclobutenols 6 in the 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 96% yield the benzopyranol 16, which subsequently was converted to (±)-hydrangenol (17). Similar treatment of 1 with LDA and isovanillin benzyl ether afforded the benzopyranol 19 (87% 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 ClCO 2 -Me) followed by methanolysis produced the acetal 28 in 96% yield. The overall yield was 65% for the five-step synthesis of the alkaloid (±)-peshawarine (24) from 10 and 26. Extension of the process to aliphatic aldehydes was illustrated by the preparation of 32 from benzocyclobutenol and isobutyraldehyde in 69% overall yield after oxidation with PCC