Chemistry of N-phosphorylated nitrogen mustards: The effect of a second nitrogen substituent at phosphorus on the stability of the system

Article abstract of DOI:10.1080/10426509608029648

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 product 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 metaphosphoramidate and N-substituted ethyleneimine as primary intermediates. In the presence of pyridine, bis-alkylation of two pyridines took place 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 nucleophilic displacements: (i) the O-demethylation followed by bisalkylation of two molecules of thiophenol, together with some 1,5-cyclization; (ii) initial direct displacement of the chlorine at the β-carbon of the precursor, followed by the fragmentation of the system. It is concluded that the electron-rich ionic phosphoramidate substituent, ^-O(R₂N)P(O), highly activates the N-(2-chloroethyl) functional group in alkylation reactions.

Full text of DOI:10.1080/10426509608029648

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Phosphorus, Sulfur, and Silicon and
the Related Elements
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CHEMISTRY OF N-PHOSPHORYLATED
NITROGEN MUSTARDS: THE
EFFECT OF A SECOND NITROGEN
SUBSTITUENT AT PHOSPHORUS ON
THE STABILITY OF THE SYSTEM
Huijie Wan a & Tomasz A. Modro a
a Centre for Heteroatom Chemistry, Department of
Chemistry, University of Pretoria, Pretoria 0002, South Africa
Published online: 24 Sep 2006.
To cite this article: Huijie Wan & Tomasz A. Modro (1996) CHEMISTRY OF N-PHOSPHORYLATED
NITROGEN MUSTARDS: THE EFFECT OF A SECOND NITROGEN SUBSTITUENT AT PHOSPHORUS
ON THE STABILITY OF THE SYSTEM, Phosphorus, Sulfur, and Silicon and the Related Elements,
108:1-4, 155-168
To link to this article: http://dx.doi.org/10.1080/10426509608029648
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