Tetrahydroisoxazolo[2,3-d][1,4]benzodiazepinone ring system: synthesis, stereochemistry, and conformation

Abstract

Reaction of 7-chloro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one 4-oxide (diazepam 4-oxide) with acrylic esters produces annelated substituted isoxazolidines : 1,3-dipolar cycloaddition is regiospecific, the adducts with methyl crotonate showing a ‘reverse’ direction of addition, in comparison with the ‘normal’ products of the reaction between diazepam 4-oxide and acrylic or methacrylic esters. Structures and conformations of cycloadducts have been assigned by means of ¹H n.m.r. spectroscopy, largely by the computer simulation of the lanthanide-induced shifts and broadenings of the n.m.r. spectral lines: a small increase in the conformational rigidity of the seven-membered ring is observed, on going from diazepam to the previously unknown isoxazolobenzodiazepinones. Their structural assignments are supported by the results of catalytic hydrogenation (Raney nickel).