STEREOSPECIFIC SYNTHESIS OF TRANS- AND CIS-2-ISOPROPYL-3-HYDROXY-5-ACETYL-2,3-DIHYDROBENZOFURAN (DIHYDROTOXOL) . DIHYDROBENZOFURAN DERIVATIVES IN WHICH JTRANS-2,3]JCIS-2,3

2′-Hydroxy-2,5′-dibromo-3-methylbutyrophenone (II) has been converted into trans-2-isopropy1-2-hydroxy-5-acetyl-2,3-dihydrobenzofuran (VIII) by successive treatment with sodium borohydride in aqueous ethanolic potassium hydroxide, butyllithium, then carbon dioxide and finally methyllithium. When II was reduced with sodium borohydride and the product then treated with potassium hydroxide, cis-2-isopropyl-3-hydroxy-5-bromo-2,3-dihydrobenzofuran (X) was obtained, which was converted by an identical sequence of reactions into cis-2-isopropyl-3-hydroxy-5-acetyl-2,3-dihydrobenzofuran (racemic dihydrotoxol, IX). The sodium borohydride reduction of II in alkaline medium is believed to lead first to cyclization to 2-isopropyl-5-bromocoumaran-3-one (XIV) followed by reduction to give the thermodynamically more stable trans isomer (III), while in the absence of alkali II is first reduced to give the erythro isomer (steric approach control) which then leads to the cis isomer (X) by backside displacement of the α-bromo atom by the phenolic OH group. The unexpected observation that Jtrans-2,3 > Jcis-2,3 in the two families of 2,3-dihydrobenzofurans is believed to arise from a stereochemical dependence of the electronegativity effect of the hydroxyl groups in the cis series as observed by Booth10 for six-membered rings. © 1969, American Chemical Society. All rights reserved.