Synthesis of tris-hydroxymethyl-based nitrone derivatives with highly reactive nitronyl carbon

Abstract

A novel series of α-phenyl-N-tert-butyl nitrone derivatives, bearing a hydrophobic chain on the aromatic ring and three hydroxyl functions on the tert-butyl group, was synthesized through a short and convenient synthetic route based on a one-pot reduction/condensation of tris(hydroxymethyl)nitromethane with a benzaldehyde derivative. Because of the presence of hydroxyl functions on the tert-butyl group, an intramolecular Forrester-Hepburn reaction leading to the formation of an oxazolidine-N-oxyl compound was observed by electron paramagnetic resonance (EPR). The mechanism of cyclization was further studied by computational methods showing that intramolecular hydrogen bonding and high positive charge on the nitronyl carbon could facilitate the nucleophilic addition of a hydroxyl group onto the nitronyl carbon. At high nitrone concentrations, a second paramagnetic species, very likely formed by intermolecular nucleophilic addition of two nitrone molecules, was also observed but to a lesser extent. In addition, theoretical data confirmed that the intramolecular reaction is much more favored than the intermolecular one. These nitrones were also found to efficiently trap carbon-centered radicals, but complex spectra were observed due to the presence of oxazolidine-N-oxyl derivatives. © 2011 American Chemical Society.