Nucleophilic reactivity of phosphoric amides and related systems

Abstract

This thesis is focused on the nucleophilic reactivity of selected classes of phosphoryl compounds, i.e. systems of the general formula XYZP(O). In this study, at least one of the substituents X, Y, or Z, represents an electron-rich amino group, NHR (or NR2), hence all systems studied belong to the family of phosphoric amides, or their derivatives. Two major groups of compounds have been investigated in detail: (i) Phosphoric triamides bearing the N-(2-chloroethyl) substituent (compounds 17, Chapter 2), and (ii) 0, 0-diethyl-N-acylphosphoramidates (21, Chapter 3). Substrates 17 have been synthesized and studied under strongly basic conditions, in order to evaluate their reactivity in the two possible intramolecular cyclization reactions. For N-alkyl derivatives ( 17d, e), base-promoted intramolecular displacement of chloride yielded the N-phosphorylated aziridines (29') as exclusive cyclization products. For N-aryl derivatives ( 17a - c), both the aziridine, and the 1,3,2-diazaphospholidine products (30') could be obtained in comparable yields. These products are mutually interconvertible under conditions of nucleophilic or base catalysis. The mechanisms of these interconversions are proposed and discussed. In the second part, a number of N-acylated phosphonamidite derivatives (21) have been synthesized, and their reactivity towards electrophilic reagents was studied. Haloalkanes and trimethylsilyl derivatives were used as electrophiles; neutral substrates 21, or their conjugate bases were employed as the ambient nucleophiles. The reactions were studied under a variety of experimental conditions, including the application of phase-transfer catalysis. It has been found that the regioselectivity (N-, carbonyl 0-, or phosphoryl 0-substitution) varied greatly depending on the substrate, the electrophile, the base, and other reaction conditions. In some cases, however, the reaction can serve as a convenient synthetic route to a specific class of derivatives of 21. In sialylation reactions we observed an interesting behaviour of the intermediate product, which can either undergo a rearrangement, or substitution of the Me3Si0 group by nucleophilic species. The reactivity studies have been followed by structural determinations, aimed at the evaluation of the intra- and intermolecular interactions operating in the systems containing the OPNCO molecular backbone. Crystal structures of three compounds have been determined by X-ray diffraction, and the molecular parameters determined revealed a strong electron-donating effect of the amidine substituent. The molecular structures have then been compared with those reported previously for related systems. This analysis enabled us to arrive at two general models of the intramolecular effects (hence the conformation of the molecule in the solid state), involving mutual donor-acceptor interactions between the carbonyl and the phosphoryl functions. Some extrapolation of the present results to further work is also presented.