Synthesis, reactivity, and structural studies of N-phosphorylated nitrogen mustards

Abstract

Preliminary research conducted in our laboratory indicated that the degradation behavior of phosphoramidates such as, eg. dimethyl N, N-bis(2-chloroethyl)phosphoramidate is complex. In principle, the substrates can react in three independent directions : 1. 1, 5-cyclization. 2. 1, 3- cyclization. 3. Fragmentation (P-N bond cleavage). In Chapter l, methyl N, N-diethyl-N', N'bis( 2-chloroethyl)phosphoramidate ( diamidate) was prepared. Its reactivity in different media (Lil/ 2-butanone, pyridine-d/ D2O, PhSH/ Et3N/ acetonitrile-d3) was studied. Its O-demethylated product led to a highly unstable ion, which underwent spontaneous fragmentation. It is concluded that the electron-rich ionic phosphoramidate substituent, -o(R2N)P(O), highly activates the N-(2- chloroethyl) functional group in the alkylation reactions. In Chapter 2, a series of N-bis(2-chloroethyl)phosphoric triamides (and diamidoesters) was prepared. The suitable bases for the mono- and dicyclization of those compounds were found. Among the prepared compounds, several single crystals of the crystalline products were grown. In Chapter 1, the molecular parameters of those compounds were discussed. The value of the torsion angle of the O=P-N-H function which determines the packing of the molecules was found to determine also the ability of a substrate to form diastereomeric hydrogen-bonded complexes with optically active acids. Based on the crystal parameters of N-P-N bond angles of those non-, mono-, di-, tricyclic compounds and their specific-range of the 31P NMR chemical shift values, the correlation of 31P NMR chemical shift and N-P-N bond angle was discussed in Chapter _1. The result is consistent with the analogous studies for similar oxygen and sulfur series (O-P-O, S-P-S). In Chapter 5, the inter and intra molecular nucleophilic competitive reactions of phosphoramidates were studied. The corresponding product of intermolecular reaction showed interesting 1H NMR spectrum which was correlated with the x-ray structure of that compound.