Sustainable Oxidative Coupling of Natural Bioactive Hydroxylated Phenols

Hydroxylated phenols like vanillin (4-hydroxy-3-methoxybenzaldehyde), apocynin (1-(4-hydroxy-3-methoxyphenyl)-ethanone, iso-apocynin 1-(2-hydroxy-3-methoxyphenyl)ethanone), creosol (2-methoxy-4-methylphenol), zingerone (4-(4-hydroxy-3-methoxyphenyl)-2-butanone) and eugenol (2-methoxy-4-(propen-2-yl)-phenol), are natural occurring compounds, present, as main components, in various plants like, Vanilla planifolia, Picrorhiza kurroa, Guaiacum officinale, Zingiber officinalis and Eugenia carofillata. These compounds show a broad spectrum of biological properties such as antiinflammatory, antiseptic, antioxidant and fungicide.a,b The corresponding C2-symmetric dimmers, named hydroxylated biphenyls, generally show a higher bioactivity in comparison to the monomers.c Our interest in the field of hydroxylated biphenyls pushed us towards the optimization of oxidative coupling reactions of natural phenols with particular attention to aspects of environmental sustainability of the synthesis. The reactions reported in the literature for symmetric dimerization of phenols, contemplate reactions mediated by chemical inorganic oxidants,d,e typically iron sulphate and potassium persulfate, or enzymatic reactionsf (e.g. horseradish peroxidase). Surprisingly, to the best of our knowledge, there are not reported oxidative coupling reactions carried out with the aid of microwaves. Dimers of hydroxylated natural phenols are important precursors of most of bioactive hydroxylated biphenyls recently prepared by our group.g-i Our work is therefore aimed at optimizing, with the aid of microwaves, the synthetic process in terms of reduction of the amount of solvent, exclusive use of water as reaction medium and simplification of work-up operations.