Regioselective Mannich reaction of phenolic compounds and its application to the synthesis of new chitosan derivatives

A regioselective aminomethylation of 2,4-dihydroxybenzoyl compounds at the C(3) position was accomplished through a Mannich reaction of phenolic substrates with formaldehyde and secondary amines in methanol, whereas the reaction with primary amines included a subsequent cyclization step to yield the 1,3-benzoxazine derivatives. This sequence was successfully applied to the one-pot introduction of N-benzyl side chains to chitosan, a natural polyaminosaccharide, to afford a new chitosan derivative with improved solubility in an organic solvent.