Abstract
A new four-membered P–N–P–N heterocyclic compound, 1,3-bis(4-phenylthiazol-2-yl)-2,4-bis(N,N-diethylamino)-1,3-diazo-2,4-diphosphetidine (Compound 3, C₂₆H₃₂N₆P₂S₂, M = 554.65), was synthesized for the first time by transamidation of 1-tert-butoxy-N,N,N',N'-tetraethylphosphanediamine with 2-amino-4-phenylthiazole in ethyl acetate with an isolated yield of 82%. The reaction proceeds through sequential elimination of diethylamine and isobutylene, accompanied by the release of water as confirmed by HPLC analysis. This pathway is mechanistically distinct from the classical Arbuzov rearrangement: instead of forming the expected phosphonate or amidophosphate products, concentration of the reaction mixture promotes intramolecular cyclisation, in which the aminothiazole N–H proton attacks the tert-butyl oxygen, driving formation of the strained diphosphetidine ring. The structure of Compound 3 was unambiguously established by ¹H, ¹³C, and ³¹P NMR spectroscopy, IR spectroscopy, high-resolution mass spectrometry, elemental analysis, and single-crystal X-ray diffraction analysis. The ³¹P NMR chemical shift of δ 176.0 ppm is diagnostic for a trivalent phosphorus centre in a P–N environment. Biological screening demonstrated that Compound 3 exhibits significant antimicrobial and cytotoxic activity. Against Staphylococcus aureus ATCC 6538, the MIC was 6.3 µg/mL, equal to that of ceftriaxone and more potent than benzylpenicillin sodium salt (MIC = 12.5 µg/mL). Moderate activity was observed against Escherichia coli ATCC 25922 (MIC = 25 µg/mL), while no inhibitory activity was detected against Bacillus subtilis, Pseudomonas aeruginosa, or Candida albicans. Cytotoxic activity against Artemia salina nauplii was confirmed with an LC₅₀ of 82.8 µg/mL, classifying Compound 3 as cytotoxically active according to Meyer et al. (1982) and indicating its potential for further evaluation against mammalian cancer cell lines.