Dimethyl sulfate as methylation agent in highly regioselective synthesis of methyl salicylate using sodium bicarbonate as a base in solvent-free medium

Abstract

Methyl salicylate (MS), the principal constituent of Wintergreen oil (WO), was obtained from salicylic acid (SA) by regioselective methylation of the carboxyl group. A new procedure involved exclusive capture of carboxylic hydrogen (-COOH) through the use of the selective base, NaHCO3. and methylation via an SN2 mechanism employing the previously formed carboxylate as a nucleophile and the dimethyl sulfate [(CH3)2SO4 or DMS] as the electrophilic reagent or substrate in a solvent-free reaction process. The reagents were added separately. SA and NaHCO3 was added, followed by DMS after 30 min. The reaction involved the esterification by nucleophilic substitution in Csp3 with heating by a heating mantle. The reaction was accompanied by thin layer chromatography and gas chromatography. The conversion rate via GC was 100%, and the MS yield was 96%. The DMS used in excess was transformed into MeOH and H2SO4 during the washing with water. The MeOH was stored, and H2SO4 was transformed in Na2SO4 by neutralization with NaOH. Na2SO4 can be used as a desiccant. The simplicity of the procedure, readily available MS, short reaction times, excellent yield and mild reaction condition are other advantages of this protocol. Cytotoxicities of 50% and 64% for cultured S. aureus and metastatic melanoma cells, respectively, were observed for a concentration of 0.6 mg/mL of the MS produced, whereas no cytotoxicity against non-tumor cells was observed at this concentration, and this is considered to be the optimum concentration.