The preparation of 2,3,5-tri- and 2,3-disubstituted furans by regioselective palladium(0)-catalyzed coupling reactions: Application to the syntheses of rosefuran and the F₅ furan fatty acid

The 5-acceptor-substituted 2,3-dibromofurans 1 and 2 underwent a regioselective Pd⁰-catalyzed coupling reaction at the C-2 carbon atom. With alkynes the corresponding 2-alkynylfurans 4 and 5 were accessible (49-97% yield) Alkyl-, aryl-, and alkenylzinc reagents gave the 2-substituted furans 8 starting from compound 2 (66-84% yield). The 2-allylfurans 8e and 8f were obtained by a regioselective Stille coupling in 79% and 73% yield. The latter reaction was also applied to the parent 2,3-dibromofuran (27) and yielded the substitution product 28 (60% yield). Subsequent Pd⁰-catalyzed reactions to introduce a methyl group in 3-position by a methyldebromination were successfully conducted for 2-alkynyl-3-bromofurans with MeZnCl and PdCl₂(PPh₃)₂ as the catalyst in THF (reflux) to yield compounds 13-16 and 24 (67-76%) and with SnMe₄ and PdCl₂[P(o-Tol)₃]₂ as the catalyst in DMA (90 °C) for the 2-allyl-3-bromofuran 8e to yield 18 (70%). The more facile reaction of the 2-alkynylfurans relative to those of furans bearing an sp³- carbon atom at C-2 appears to be due to steric reasons. Studies on the 2- alkyl-3-bromofuran 20 supported this notion. With the regioselective coupling methodology the terpene rosefuran (22) was prepared in four steps starting from furan 2 (35% yield overall). The F₅ furan fatty acid (26) was synthesized from furan 1 in five steps (29% yield overall).