CHEMISTRY OF N-PHOSPHORYLATED NITROGEN MUSTARDS - THE EFFECT OF A 2NDNITROGEN SUBSTITUENT AT PHOSPHORUS ON THE STABILITY OF THE SYSTEM

Methyl N,N-diethyl-N'N'-bis(2-chloroethyl)phosphoramidate was prepared as a precursor for the corresponding phosphordiamidate anion, a model for the phosphoramidate mustard, biologically active degradation prod uct of cyclophosphamide drug. Demethylation of the precursor led to a highly unstable ion which underwent spontaneous fragmentation. In the absence of an external nucleophile, the ion decomposed yielding metaph osphoramidate and N-substituted ethyleneimine as primary intermediates . In the presence of pyridine, bis-alkylation of two pyridines took pl ace yielding bis [2-(N-pyridinio)ethyl]amine dication, in addition to some 1,3,2-oxazaphospholidine derivative, formed via the competitive 1 ,5-cyclization of the demethylated anion. Incubation of the precursor in the presence of thiophenol/triethylamine resulted in two parallel n ucleophilic displacements: (i) the O-demethylation followed by bisalky lation of two molecules of thiophenol, together with some 1,5-cyclizat ion; (ii) initial direct displacement of the chlorine at the beta-carb on of the precursor, followed by the fragmentation of the system. It i s concluded that the electron-rich ionic phosphoramidate substituent, O--(R(2)N)P(O), highly activates the N-(2-chloroethyl) functional grou p in alkylation reactions.