Exploring the reaction of formaldehyde with α-N-protected amino acid hydrazides

The reaction of formaldehyde with enantiomerically pure α-N-protected amino acid hydrazides is described. The system has been investigated in different solvents, including both aqueous formaldehyde and paraformaldehyde, with the aim of simplifying the final reaction mixture. Aqueous formaldehyde in refluxing THF proved to be the best combination, affording mainly the corresponding monomelic N-methylene and 1,3,5-trisubstituted-1,3,5- hexahydrotriazine derivatives. The monomelic form was the only one present at high temperature, as evidenced by 1H and 13C NMR spectroscopy.