Synthesis of sterically hindered stilbenes of biological importance

Abstract

A series of (2-, 6-, α-)alkyl-substituted 4,4′-dimethoxystilbenes, of biological interest, have been synthesised by employing appropriate deoxybenzoins and benzylic phosphonium ylides as key intermediates.

3,5-Dimethylphenol was converted in six steps into the benzylphosphonium salt (11e) and the benzylphosphonate (11f). Condensations between (11e) and appropriate aryl carbonyl compounds led to mixtures of Z- and E-isomers of the stilbenes (21), (25), (33), (34), and (38). Forcing conditions were required to obtain the stilbenes (34) and (38)(yields [graphic omitted]5%), which probably reflects steric limitations to the Wittig synthesis of these molecules. The secondary phosphonium salts (29), (35), and (37) were also synthesised, but whereas (29) reacted with the benzaldehyde (20) giving (25), no stilbene products were formed from similar condensations with (35) and (37). Attempts to prepare stilbenes from the phosphonate (11f) and aryl ketones instead led to chalcones [e.g.(31)]. The phenylacetic acid (11h) was prepared and used in the synthesis of deoxybenzoins (13) and (14) by appropriate Friedel–Crafts reactions. Grignard reactions with the deoxybenzoins led to intermediate tertiary alcohols, which were dehydrated to the corresponding stilbenes [e.g.(25), (34), and (38)]. The geometrical isomers of the stilbenes (21), (25), (34), and (38) were separated by chromatography and characterised.

The hexamethylstilbene (48), which represents the most sterically hindered (2-, 6-, α-)methyl-substituted stilbene, was synthesised from acetophenone (41) by intermolecular deoxygenation with the reagent from titanium trichloride and lithium aluminium hydride.