The mechanism of formylation of five-membered cyclic phosphorodiamidates

Cyclic N,N'-diphenylethylenephosphorodiamidates, 1, have been found to yield up to 70% of the N-formyldiphenylethylenediamines when reacted in 1 M formate buffers (50 degrees, 25% v/v dioxane-H2O, mu = 1.0). The mechanism proposed for formylation on the basis of kinetic, product ratio, and 18O-labeling studies apparently involves cyclization of a formyl phosphoramidate-amine adduct derived from formate attack on 1H+, the process probably being catalyzed by intramolecular proton transfer between the phosphoryl moiety and aniline nitrogen. An oxygen is transferred from formate to inorganic phosphate in the net reaction. The initial site of formylation with dissymmetric 1 (p-CH3O, p-Cl) was shown by 18O incorporation studies to be the p-anisidine nitrogen, which also corresponds to the isomer of thermodynamic control. Attack by formate on 1H+, therefore, results in expulsion of the more basic nitrogen. Certain mechanistic aspects of the reaction might occur in the enzyme-catalyzed ATP-dependent formylation of tetrahydrofolic acid.