SOMMELET-HAUSER REARRANGEMENT OF AN AMMONIUM YLIDE DERIVED FROM THE HIV-1 REVERSE-TRANSCRIPTASE INHIBITOR NEVIRAPINE

Functionalization at the 3-position of the dipyridodiazepinone nevirap ine (1) has been accomplished by Sommelet-Hauser rearrangement of an y lide derived from 1. Treatment of N-cyanomethylpyrrolidinium salt 4 wi th potassium tert-butoxide in a mixture of dimethylsulfoxide and tetra hydrofuran at -10 degrees, followed by acid hydrolysis, afforded a mix ture of compounds 5 and 6 in a ratio of 1:1.8. Upon treatment of 4 wit h sodium amide in liquid ammonia, 5 and 6 were obtained in a ratio of 1.5:1 and a combined yield of 83%. Compound 5 is the desired product r esulting from Sommelet-Hauser rearrangement of 4, whereas 6 derives fr om competing Stevens rearrangement and intramolecular cyclization of t he aldehyde produced upon hydrolysis. Baeyer-Villiger oxidation of 5 a fforded the 3-hydroxy derivative 2, a recently identified metabolite o f nevirapine.