Novel synthesis of cis-3,5-disubstituted morpholine derivatives

1-tert-Butyl-2-(allyloxymethyl)aziridine has been transformed for the first time diastereoselectively into cis-3,5-di(bromomethyl)-4-tert-butylmorpholine via an electrophile-induced ring closure using bromine in dichloromethane. The latter morpholine has been used as a substrate for the synthesis of the corresponding 3,5-di(methoxymethyl)morpholine and 3,5-di(cyanomethyl)morpholine upon nucleophilic displacement of both bromo atoms. Further evaluation of this protocol toward the synthesis of 4-arylmethyl- and 4-alkylmethyl-3,5-di(bromomethyl)morpholines showed that the premised cyclization of the corresponding 2-(allyloxymethyl)aziridines into 3,5-di(bromomethyl)morpholines only proceeded well for the N-neopentylmorpholine, which was subsequently transformed into a 3-oxa-7-thia-9-azabicyclo[3.3.1]nonane derivative. Also, in some other cases, the desired 3,5-di(bromomethyl)morpholines were isolated in low yields and transformed into the corresponding 3,5-di(cyanomethyl)morpholines.