Synthesis of New Fluorinated Fused Heteropolycyclic Nitrogen Systems Containing a Pyrazolotriazine Moiety as Antimicrobial Agents Part I

A simple route to synthesize novel fluorinated fused hetero-polycyclic nitrogen systems containing a pyrazolotriazine moiety (5,8,11) have been deduced from cyclization of 2-aminothiocarbonyl-5-arylidene-3-phenyl-1,2,4-triazin6(1H)one (2) with diethoxy-phosphine, diethyl carbonate and/or diethyl oxalate in boil THF followed by cyclo condensation with aryl sulfonic acid hydrazide in EtOH/piperidine and finally fluorination with trifluoroethyl acetate. Structures of the products have been established from their elemental analysis and spectral measurements. The antimicrobial activity of the targets has also been evaluated.


Introduction
The introduction of phosphorus atom to heterocyclic nitrogen system improves their biocidal properties, which may be the unique behavior of donation and back donation of a phosphorus atom (P~N) [1] [2].Most of the organic phosphorus systems exhibited high biocidal properties as herbicides, insecticide, and pesticide [3] [4] [5].1,2,4-Triazine derivatives are a prominent structural core system present in numerous biologically active compounds, exhibit a wide range of biological activities, as anticancer [6], antitumor [7] [8] [9], anti-inflammatory, anti-fungal, antibacterial [10] [11] [12] [13] [14] as well as potential inhibitors [15].Zrin et al. [6] [7] [8] [9] [10], reported that 2-aminothiocarbonyl-1,2,4-triazin-6-ones have a significantly greater cytotoxic effect compared to that other compounds.Functionalized 1,2,4-triazines are used to remove metal ions by formation an stable metal complexes [16].On the other hand, substituted pyrazoles bearing or containing a 1,2,4-triazine nucleus, showed a wide spectrum of biological activities [17].A survey of the literature revealed that fluorine atoms bonded with 1,2,4-triazines often enhance their properties [18] [19] [20].Upon these observations, the present work tends to synthesize of novel fluorine substituted pyrazolotriazine derivatives, and evaluation of their antimicrobial activity.Formation of compound 2 from the oxazolidinone 1 may be tacks place via a double nucleophilic attack of NH 2 and NH to the cyclic ketone followed by carbon-enolic center (Figure 1), while formation of 3 from compound 2 may be a nucleophilic of NH 2 and NH of compound 2 to the P-OR center followed by cyclocondensation with acid hydrazide and finally fluoroacylation (Figure 2).

Result and Discussion
The former structure of new compounds 2-11 established from their correct  The 1 H NMR spectrum of 2 showed resonated signals at δ 6.52, 5.5 and 6.63 ppm attributed to NH, styryl and NH 2 protons, while that of 3 recorded a lack's of NH 2 protons with the presence of P-H proton at γ 6.7 ppm as a doublet resonating with a double constant of 6.35 Hz. 13 C NMR of compound 2 showed δ at 165.8, 167, 152 and 140 ppm attributed to C=S, C=O, C=C and C-Cl carbons (Figure 5).
The IR spectrum of compound 4 recorded γ at 1337 and 1120, 1488 cm −1 for International Journal of Organic Chemistry Also, 1 H NMR spectra of compounds 8 & 11 showed a lack's of NH protons, which confirm their reactions.Mass spectrum of compound 11 recorded a splitting of the COCF 3 fragment, followed by small ions and finally a base peak at 4-chlorobenzylidene radical at m/e 139 (Figure 7).

Experimental
Melting point determined with an Electrothermal Bibby Stuart Scientific melting point sample (U K).A Perkin Elmer Model RXI-FT IR system 55529 was used for recording IR spectra of the prepared compounds (cm −1 ).A Bruker advance DPX 400 MHZ model uses TMS as internal standard was used for recording the
The synthesized compounds were evaluated for their antibacterial activity against the gram-positive bacterial strain.S. aureus and gram-negative bacterial strain.S. typhi, in addition, some fungi as A. niger according to the reported method [30] via DMF as a blank and Ciprofloxacin and Miconazole used as standard drugs.All the compounds exhibit antibacterial activity ranging from 50 to 150 mg m/ml.Also, the minimum inhibitory concentration (MIC) for the active compounds determined (Table 1).
Equimolar amounts of 3 and 4-tolulene sulfonic acid hydrazide in ethanol (100 ml), with a few drops of piperidine, refluxed for 8h, cooled then poured onto icedrops acetic.The solid produced filtered off and crystalized from dioxan to give

Table 1 .
The antimicrobial activity of the synthesized compounds 2-11 by inhibition zones (m m)*.