Metallation of<i>N</i>-(Pivaloyl)- and<i>N</i>-(<i>tert</i>-Butoxycarbonyl)difluoroanilines : Regiocontrol by Fluorine in the Synthesis of 4-Methoxycarbonyl Derivatives

Abstract

Methyl 2,6-difluoro-4-(pivaloylamino)benzoate (3) and the corresponding 4-(tert-butoxycarbonylamino)-analogue 6 have been synthesised by reacting the appropriate 3,5-difluoroaniline derivatives with butyllithium followed by methyl chloroformate. N-(tert-Butoxycarbonyl)-2,3-difluoroaniline (9) required the "super-basic" butyllithium/potassium tert-butoxide mixture to convert it into methyl 4-(tert-butoxycarbonylamino)-2,3-difluorobenzoate (14): the 2,5-difluoro-analogue was formed in a similar manner. In all cases the regiocontrol of metallation was directed by fluorine rather than by the amide substituent.