Chemoselective aminomethylation of bifunctional substrates: carbonyl versus phenolic hydroxyl, carbonyl versus pyrazole and pyrrole versus phenolic hydroxyl as competing activating groups

Chemoselectivity in the Mannich reaction for three different types of bifunctional substrates has been investigated. 1-Hydroxy-2-naphthalenylethanone affords either phenolic Mannich bases at high pH (free amines), or ketonic Mannich bases at low pH (amine hydrochlorides), whereas the use of N,N-dimethylmethyleneiminium chloride as a preformed dimethylaminomethylation reagent gave the phenolic Mannich base. 1-Aryl-3-(1H-pyrazol-1-yl)-1-propanones undergo aminomethylation at position 4 of the pyrazole ring, and not at the methylene group α to the carbonyl function, regardless of the reaction conditions. 4-(2,5-Dimethyl-1H-pyrrol-1-yl)phenol is aminomethylated chemoselectively on the pyrrole ring under mild reaction conditions.