Green solvents for the hydroaminomethylation of estragole

Abstract

Hydroaminomethylation (HAM) is a simple route to synthesize amines through a highly atom-economic reaction of alkene with syngas (carbon monoxide/hydrogen mixture) and a primary or secondary amine. HAM consists of three successive steps occurring in the same reactor: hydroformylation, condensation of the aldehyde with the amine, and hydrogenation. Both hydroformylation and hydrogenation are catalyzed by transition metal complexes. In this work, a series of novel amines withpotential bioactivity was obtained in excellent yields. Some eco-friendly solvents were employed for the first time in this reaction. p-Cymene, anisole and ethanol proved to be excellent greener alternatives for toluene, the solvent conventionally used for hydroaminomethylation. The performance of p-Cymene and anisole was similar to that of toluene; whereas the reactions in ethanol solutions showed better yields and selectivity for the products. Propyl anisole was also tested, but the resultswere not as good as the others solvents, as significant amounts of enamines were not hydrogenated. The regioselectivity varied with the amine counterpart: the / ratio was 40/60 in the reactions with di-n-butylamine vs. 50/50 in those with 4-methylpiperidine. Thus, thenature of the amine counterpart seems to affect the reactivity of rhodium species operating in the hydroformylation step of the HAM process. The reactions with morpholine gave excellent yields of main products, with their isomeric composition being dependent on the solvent nature. In toluene, p-Cymene, anisole and propyl anisole, the substrate isomerization and the hydroformylation of the resulting anethole were significant. In ethanol, the isomerization of estragole was much lesssignificant. HAM of estragole with 2,6-dimethylmorpholine, gave excellent yields in all solvents, except propyl anisole where the last step (hydrogenation) was not favourable, and enamine intermediate remained in significant amounts.