Synthesis and dynamic study of new ortho-(alkylchalcogen)acetanilide atropisomers. A second look at the hydrolysis of quaternary 2-methylbenzazol-3-ium salts

The base-catalysed hydrolysis of N-ethyl-2-methylbenzazol-3-ium iodides was re-examined performing the reaction in boiling 96% ethanol, in the presence of triethylamine. The resulting unstable intermediates were isolated as the corresponding ether, thioether or selenoether derivatives, depending on the starting benzazole salt, by trapping via alkylation with ethyl and hexyl iodides, in moderate to good yields. Reduction of the o-(alkylchalcogen)acetanilides so obtained afforded the corresponding o-(alkylchalcogen)anilines. This methodology provides potential access to o-(alkylchalcogen)anilines bearing up to three different N-alkyl groups introduced in an unambiguous and regioselective way. (alkylchalcogen)acetanilides are axially chiral molecules due to restricted rotation around the N-aryl bond. The resulting atropisomerism has been studied using dynamic variable temperature NMR spectroscopy and the corresponding rotational barriers were determined for the first time in acetanilides bearing a single ortho-substituent other than the tert-butyl and iodine groups. The estimated free energy of activation of the interconversion of the rotamers ranged from 17.1 to 20.5 kcal/mol.