Trifluoromethoxy substituted anilines: metalation as the key step for structural elaboration

Trifluoromethoxy-substituted anilines undergo hydrogen/lithium permutation ("metalation") with optional site selectivity depending on the N-protective group employed. N-tert-Butoxycarbonyl-2- and -4-(trifluoromethoxy)aniline react with tert-butyllithium at the nitrogen-adjacent 6- and 2-position affording, after electrophilic trapping, products 1-6. In contrast, deprotonation of the para isomer occurs at the oxygen-neighboring 3-position, giving rise to the acid 12, when the amino group is carrying two trimethylsilyl groups. sec-Butyllithium attacks 3-trifluoromethoxy-N-mono(trimethylsilyl)aniline at the 2-position, but 3-trifluoromethoxy-N,N-bis(trimethylsilyl)aniline at the 4-position to provide respectively the acids 10 and 11 after carboxylation. The synthesis of two new benzodiazepines illustrates (19 and 22) the preparative potential of the aniline functionalization mediated by organometallic reagents.