Synthesis and antimicrobial activity of some oxazaphosphinine oxides

A new family of phosphorus heterocycle, namely 2-substituted 3-[4-(2-oxo-3,4-dihydro-2λbenzo[e][1,3,2]oxazaphosphinin-3-yl)phenyl]-3,4-dihydrobenzo[e][1,3,2]oxazaphosphinin-2oxides (5a–j) has been synthesized by the condensation of 2-[[4-(2-hydroxy-benzylamino)phenylamino]methyl]phenol (1) with phosphorus oxychloride in presence of triethylamine in dry tetrahydrofuran, followed by the reaction with various phenols 3a–j. Alternatively, some of these compounds 5a-e were prepared by the cyclocondensation of 1 with aryl phosphorodichloridates 4a–e. All title compounds were characterized by elemental and spectral analyses. Their antimicrobial activity was also evaluated.


Introduction
Organophosphorus heterocycles containing O and N in a six-membered ring have gained much attention ever since cyclophosphamide was discovered as anti-cancer drug. 1 Compounds of this class also have high anti-tumor activity, [2][3][4][5] significant bioactivity, 6 and outstanding medicinal properties. 7The significant activity of all these compounds was accredited to the presence of sixmembered heterocyclic rings.In our present research, synthesis of compounds containing two such rings was accomplished successfully.All compounds were characterized by elemental, IR, 1 H, 13 C and 31 P NMR and mass spectral analysis.Their antimicrobial activity was also evaluated.

Antimicrobial activity
Compounds 5a-j were screened for their antibacterial activity 16,17 against gram-positive Staphylococcus aureus and gram-negative Klebsiella pneumoniae by the disc-fusion method in nutrient agar medium at two concentrations (200, 400 ppm) in DMF.These solutions were added to each filter disc, and the plates were incubated at 35 °C and examined for zone of inhibition around each disc after 24 h.Results were compared with the activity of the standard antibiotic Penicillin.Antifungal activities were evaluated against Pellicularia solmanicolor and Macrophomina phaseolina at two concentrations 18 (200, 400 ppm) using Griseofulvin as reference compound.Fungal cultures were grown on potato dextrose broth at 25 °C and spore suspension was adjusted to 10 5 spore/mL.All compounds exhibited antimicrobial activity comparable with that of reference compounds.Some of the compounds showed high acivity againist both the bacteria and fungi.) in dry THF (25 mL) was added dropwise phosphorus oxychloride (0.932 g, 10 mmol) in dry THF (10 mL) in the presence of triethylamine (2.02 g, 20 mmol) at 0 °C.After addition, the temperature was slowly raised to 50-60 °C; the progress of the reaction was monitored by TLC.
Triethylamine hydrochloride was sucked off.To the filtrate was added freshly distilled phenol (3a, 0.47 g, 5 mmol) in dry THF (15 mL) and triethylamine (1.01 g, 10 mmol), and the progress of the reaction was monitored by TLC.Triethylamine hydrochloride was filtered off, the solvent was removed under reduced pressure.The crude product was recrystallized from 2-propanol to get colorless crystals 5a (1.93 g, 65%).(b) To a stirred solution of 1 (1.65 g, 5 mmol) in dry THF (25 mL) was added dropwise phenyl phosphorodichloridate (4a, 2.1 g, 10 mmol) in dry THF (15 mL) in the presence of triethylamine (2.02 g, 20 mmol) at 0 °C.After addition, the temperature was maintained between 50-55 °C, and the progress of the reaction was monitored by TLC.The crude product was recrystallized from 2-propanol to yield 5a (2.02 g, 68%).5b-e were prepared by the above two procedures, 5f-j were prepared following route (a).

H
In the13  C NMR spectra of compounds 5a-j, the oxygen-bearing C-8a exhibits signals in the range of δ 149.5-153.

Table 1 .
Antibacterial and antifungal activities of 5a-j All compounds were dissolved in DMSO-d 6 , chemical shifts are referenced to TMS ( 1 H,13C) and 85% H 3 PO 4 ( 31 P).Microanalytical data were obtained from Central Drug Research Institute, Lucknow, India.
a In DMF, concentration in ppm.bStandard reference.Experimental SectionGeneral Procedures.Melting points were determined in open capillary tubes on a Mel-Temp apparatus.IR spectra were recorded on a Perkin Elmer 1000 unit.The 1 H,13C and 31 P NMR spectra were recorded on Varian Gemini 300 and Varian AMX 400 NMR spectrometers operating at 300 or 400 MHz ( 1 H), 75.46 or 100.57MHz ( 13 C) and 121.7 MHz ( 31 P).Mass spectra were recorded by Fast Atom Bombardment mass spectrometer.