24th International Conference on Phosphorus Chemistry (ICPC24)

Amino-functionalized phosphoryl compounds are among the most useful molecular scaffolds in medicinal chemistry, while the potential of their thiophosphorylated analogs, especially those having an alkylamino moiety, is still largely unexplored. This is mainly due to the lack of convenient synthetic routes to these organophosphorus derivatives. To address this issue, we have suggested the facile approaches to α-(aminomethyl)- and substituted/unsubstituted α-(aminobenzyl)diphenylphosphine sulfides based on either the sequential transformations of (hydroxymethyl)diphenylphosphine sulfide, with the Staudinger reaction of an azide derivative as the key stage, or the addition of Ph₂P(S)H to hydrobenzamides followed by the acid hydrolysis. The possibility of producing the related compounds in an enantiomerically pure form has been exemplified by the isopropyl-substituted derivative. The resulting thiophosphorylated amines were used as convenient building blocks for the synthesis of a whole library of functionalized carboxamides, with particular emphasis on N-heterocyclic carboxylic acid derivatives which readily underwent direct cyclopalladation, affording nonclassical N-metalated Pd(II) pincer complexes (Fig. 1). The latter exhibit promising cytotoxic activity against several human cancer cell lines and apoptosis inducing ability along with the remarkable cytotoxic effects on doxorubicin-resistant cell sublines. The reactivity and cytotoxicity of the related phosphoryl-functionalized derivatives were studied for comparison.Amino-functionalized phosphoryl compounds are among the most useful molecular scaffolds in medicinal chemistry, while the potential of their thiophosphorylated analogs, especially those having an alkylamino moiety, is still largely unexplored. This is mainly due to the lack of convenient synthetic routes to these organophosphorus derivatives. To address this issue, we have suggested the facile approaches to α-(aminomethyl)- and substituted/unsubstituted α-(aminobenzyl)diphenylphosphine sulfides based on either the sequential transformations of (hydroxymethyl)diphenylphosphine sulfide, with the Staudinger reaction of an azide derivative as the key stage, or the addition of Ph₂P(S)H to hydrobenzamides followed by the acid hydrolysis. The possibility of producing the related compounds in an enantiomerically pure form has been exemplified by the isopropyl-substituted derivative. The resulting thiophosphorylated amines were used as convenient building blocks for the synthesis of a whole library of functionalized carboxamides, with particular emphasis on N-heterocyclic carboxylic acid derivatives which readily underwent direct cyclopalladation, affording nonclassical N-metalated Pd(II) pincer complexes (Fig. 1). The latter exhibit promising cytotoxic activity against several human cancer cell lines and apoptosis inducing ability along with the remarkable cytotoxic effects on doxorubicin-resistant cell sublines. The reactivity and cytotoxicity of the related phosphoryl-functionalized derivatives were studied for comparison.

This work was supported by the Russian Science Foundation, project no. 22-73-10044.