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-triazin-6(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.
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) [
Zrin et al. [
4-(4’-Chloro-3-phenyl)-oxazol-5-one (1) used as starting material obtained according to the repeated method [
Formation of compound 2 from the oxazolidinone 1 may be tacks place via a double nucleophilic attack of NH2 and NH to the cyclic ketone followed by carbon-enolic center (
Similarly, acylation of compound 2 by reflux with diethyl carbonate in a non polar solvent as THF, produced the 2-thioxo-1,2,4-triazolo-1,2,4-triazin-7,9-dione (6). Full hydrocyclization of compound 6 by reflux with 4-toluenesulfonic acid hydrazide in ethanol with drops of piperidine, afforded the fused hetero-polycyclic system 7 via its warming with trifluoroethyl acetate, yielded the
Scheme 1. Formation of 5 from 2.
corresponding N-trifluoroacetyl derivative 8 (Scheme 2). Formation of compound 8 from 2 may be as shown in (
Due to the biological activity of fluorine-substituted 3-thioxo-1,2,4-triazin-5- ones [
Scheme 2. Formation of 8 from 2.
Scheme 3. Formation 11 from 2.
The higher stability of polyheterocyclic systems 3, 4, 6, 7, 9 and 10 may be due to the presence of thion thiol and keto enol forms as tautomeric structures (
The former structure of new compounds 2-11 established from their correct
elemental analysis and spectral measurements. Compound 1 prepared according to the literature reported method [
The 1H NMR spectrum of 2 showed resonated signals at δ 6.52, 5.5 and 6.63 ppm attributed to NH, styryl and NH2 protons, while that of 3 recorded a lack’s of NH2 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. 13C 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 (
The IR spectrum of compound 4 recorded γ at 1337 and 1120, 1488 cm−1 for
SO2 and CH3 groups. Also, γ at 3200, 1180 and 720 cm−1 for NH, C=S, and C-Cl functional groups structure of 4 confirmed from 1H NMR spectrum, were showed δ at 6.7, 6.52 and 2.55 ppm for P-H, NH and CH3 protons.
On the other hand, 13C NMR spectrum of compound 5 exhibited different types of carbon atoms at δ 162, 158 (2 C=O), 145 (C-F), 138 (C-SO2), 170 (C=S), 22 (Me) and at 131 - 127 (aromatic carbon). Mass fragmentation pattern of compound 5 recorded a molecular on the peak with M+2 due to isomeric, F and Cl atoms with a base peak at m/e 139 attribute to 4-chlorobenzylidene followed by 4-methylphenylsylfonyl radical at 155 (90%) (
One aim of the present work is to synthesize of fluorine-substituted pyrazolo-1,2,4-triazino-1,2,4-triazine as wholly fused hetero-polycyclic nitrogen conjugated systems. Thus, the synthetic of these groups deduced to give new compounds 6-11 (Scheme 3). Thus, IR spectra of both the compounds 6, 9 & 11 showed the new additional C=O groups than the compound 2, which confirmed their structures. 13C NMR spectra of compounds 9, 10 & 11 recorded the presence of C=S and C-F carbons at 180 and 145 ppm.
On the other hand, IR absorption spectra of all the compounds 8 & 11 recorded a lack’s of NH group, with the presence of two C=O and C-F groups at γ 1710, 1690, and 1250 cm−1. Moreover, all the compounds 5-11 showed the γ at 1200 - 1170 cm−1 for functional groups. Also, IR spectra of compound 9 & 11 showed a three of true carbonyl groups 1740, 1710 & 1690 cm−1.
Also, 1H 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 COCF3 fragment, followed by small ions and finally a base peak at 4-chlorobenzylidene radical at m/e 139 (
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
1H and 13C NMR spectra of the compounds on deuterated DMSO-d6 (ppm). AGC-MS-GP 1000 Ex model used for recording the mass spectra of the compounds (m/z).
A mixture of 4-chlorobenaldehyde (0.01 mol), hippuric acid (0.01 mol), fused NaOAc (0.02 mol), acetic anhydride (0.02 mol) and glacial acetic acid (100 ml) refluxed for 2 h, cooled then poured onto ice. The solid thus obtained filtered off and crystallized from EtOH to give 1; yield 80%, m.p 140˚C. IR (γ) cm−1: 1700 (C=O), 1610 (C=N), 1596 (C=C), 1070 (C-O-C), 850, 830, 810 (phenyl CH), 710 (C-Cl) [
A mixture of 1 (0.01 mol) and thiosemicarbazide (0.01 mol) in acetic acid (50 ml) heated under reflux for 3 h. Then cold and poured onto ice. The solid produced filtered off and crystallized from acetic acid to give 2; yield 75%, m.p 198˚C - 200˚C. IR (γ) cm−1: 3250 (NH), 3159 (NH2), 1710 (C=O), 1620 (C=N), 1600 (C=C), 1180 (C=S), 900, 850 (aromatic CH), 708 (C-Cl). 1H NMR (DMSO-d6) δ: 6.63 (s, 2H, NH2), 6.88 - 7.77 (m, 9H, Ar-H, H-olefinic), 10.8 (s,1H, NH).13C NMR DMSO - d6) δ: 175.8 (C=S), 167 (C=O), 152 (C=C), 140 (C-Cl),130 - 120 (aromatic carbon). Anal. Calcd. For C17H13N4ClSO (357), C, 57.14; H, 3.64; N, 15.68; Cl, 10.08%. Found: C, 57.0; H, 3.45; N, 15.49; Cl, 9.89%.
A mixture of 2 (0.01 mol) and diethylphosphite (0.01 mol) in THF (50 ml) refluxed for 2 h, cooled. The obtained solid filtered off and crystallized from dioxan to give 3. Yield 70%; m.p. 184˚C - 185˚C. IR (γ) cm−1: 3300 (NH), 1710 (C=O), 1600 (C=C), 1580 (C=N), 1380 (cyclic NCSN), 1190 (C=S), 880, 850 (aromatic CH), 700 (C-Cl). 1H NMR (DMSO-d6) δ: 6.7 (d, P-H), 10.35 (s, H, NH), 6.95 - 7.91(m, 8H, Ar-H & H-olefinic). Anal. Calcd. For C17H11N4ClSOP (386), C, 62.17; H, 2.84; N, 14.50; Cl, 9.32; S, 8.29; P, 8.03%. Found: C, 61.98; H, 2.75; N, 14.30; Cl, 9.55%.
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 ice- drops acetic. The solid produced filtered off and crystalized from dioxan to give 4, yield 65%, m.p. 238˚C - 240˚C. IR (γ) cm−1: 3200 (NH), 1600 (C=N), 1488 (deformation CH3), 1337 & 1120 (C-SO2), 1188 (C=S), 900, 860, 810 (aromatic CH), 720 (C-Cl). 1H NMR (DMSO-d6) δ: 6.7 (s, 1H, P-H) 10.55 (s, 1H, NH), 7 - 6 (m, 13H, aromatic protons), 7.4, 7.2 (d, d, 2H of C-Cl), 1.05 (s, 3H, CH3). Anal. Calcd. For C24H18N6ClS2O2P (525): C, 54.85; H, 3.42; N, 10.66; Cl, 6.85; S, 12.19; P, 5.90%. Found: C, 54.66; H, 3.25; N, 10.49; Cl, 6.55%.
Equimolar mixture of 4 and trifluoro ethyl acetate in THF (50 ml) refluxed for 2 h, cooled. The yielded solid filtered off and crystalized from dioxan to give 5. Yield 60%, m.p. 218˚C - 220˚C, IR (γ) cm−1: 1700 (C=O), 1600 (C=N), 1480 (deformation CH3), 1335, 1130 (C-SO2), 1180 (C=S), 1250 (C-F), 900, 880, 860, (aromatic CH), 705 (C-Cl), 650 (C-F). 1H NMR (DMSO-d6) δ: 6.75 (s, P-H), 7.6, 7.4 (d, d, 2H, 7.2 - 6.11 (m, 13H aromatic protons), 0.95 (s, 1H, CH3). 13C NMR (DMSO-d6) δ: 170 (C=S), 162 (C=O), 145 (C-F), 138 (C-SO2), 131 - 127 (aromatic carbons), 125(NCN), 22 (CH3).M/S (Int.%) = 650 (M+1, 1.15%), 155(90.01), 139 (100%). Anal. Calcd. For C26H17N6F3ClS2O3P (649): C, 48.07; H, 2.61; N, 12.94; F, 8.78; Cl, 5.54; S, 9.86; P, 4.77%. Found: C, 47.88; H, 2.55; N, 12.90; F, 8.66; Cl, 5.40%.
A mixture of 2 (0.01 mol) and diethyl carbonate (0.01 mol) in THF (50 ml) refluxed 3 h, cooled. The solid obtained filtered off and crystallized from dioxan to give 6.Yield 70%, m.p.190˚C - 192˚C, IR (γ) cm−1: 3150 (NH), 1710, 1690 (2C=O), 1600 (C=C), 1580 (C=N), 1180 (C=S), 880, 850, 810 (aromatic CH), 706 (C-Cl), 1H NMR (DMSO-d6) δ: 10.35 (s, 1H, NH), 8.9 (s, 1H, olefinic proton), 7.8 - 6.2 (m, 8H, aromatic H). Anal. Calcd. For C18H11N4ClSO2 (383): C, 56.39; H, 2.87; N, 14.62; Cl, 9.35; S, 8.35%. Found: C, 56.21; H, 2.57; N, 14.49; Cl, 9.15; S, 8.11%.
Equimolar mixture of 6 and 4-tolune sulfonyl acid hydrazide in ethanol (100 ml) with a few drops of piperidine, refluxed for 8 h. Cooled then poured onto ice. The yielded solid filtered off and crytallized from EtOH to give 7. Yield 60%, m.p. 258˚C - 260˚C, IR (γ) cm−1: 3150 (NH), 1680 (CONH), 1590 (C=N), 1480 (deformation CH3), 1330 (C-SO2), 1188 (C=S), 880, 850, 810 (aromatic CH), 700 (C-Cl). 1H NMR(DMSO-d6) δ: 10 - 11 (s, 1H, NH), 7.8, 7.6 (d, d, 2H, C-Cl), 7.4 - 6.2 (m, 3H, aromatic H). Anal. Calcd. For C25H17N6ClS2O3 (549): C, 54.64; H, 3.09; N, 15.30; Cl, 6.55; S, 11.65%. Found: C, 54.51; H, 2.89; N, 15.11; Cl, 6.39; S, 11.51%.
A mixture of 7 (0.01 mol) and trifluoroethyl acetate (0.01 mol) in THF (100 ml) refluxed for 2 h, cooled. The solid obtained filtered off and crystallized from dioxan to give 8. Yield 66%, m.p. 240˚C - 241˚C, IR (γ) cm−1: 1710, 1690 (2C=O), 1480 (deformation CH3), 1330 (C-SO2), 1250 (C-F), 1189 (C=S), 900, 860, 810, (aromatic CH), 710 (C-Cl), 650 (C-F). 1H NMR (DMSO-d6) δ: 7.8 - 7.7 (d, d, 2H, C-Cl), 7.4 - 7.2 (d, d, 2H, C-SO2), 7.0 - 6.0 (m, 13H, aromatic H). 13C NMR (DMSO-d6) δ: 178 (C=S), 168, 162 (2C=O), 152 (C=N), 145 (C-F), 149(NCN), 131 - 121 (aromatic carbons). Anal. Calcd. For C27H16N6F3ClS2O4 (645): C, 50.23; H, 2.48; N, 13.02; F, 8.83; Cl, 5.58; S, 9.92%. Found: C, 50.11; H, 2.38; N, 12.59; F, 8.71; Cl, 5.38; S, 9.78%.
A mixture of 2 (0.01 mol) and diethyl oxalate (0.01 mol) in THF (50 ml) refluxed for 3 h, coold. The yieled solid filtered off and crystallized from dioxan to give 9. Yield 72%, m.p. 270˚C - 271˚C, IR (γ) cm−1: 3200 (NH), 1740, 1710, 1690 (3C=O), 1600 (C=C), 1580 (C=N), 1710 (C=S), 880, 810 (aromatic CH), 700 (C-Cl). 1H NMR (DMSO-d6) δ: 11.10 (s, 1H, NH), 7.4, 7.2 (d, d, 2H, C-Cl), 7.0 - 6.2 (m, 9H, aromatic protons). Anal. Calcd. for: C19H11N4ClSO3 (411): C, 55.47; H, 2.67; N, 13.62; Cl, 8.75; S, 7.7%. Found: C, 55.47; H, 2.42; N, 13.51; Cl, 8.66; S, 7.55%.
Equimolar mixture of 9 and 4-toluenesulfonic acid hydrazide in ethanol (50 ml) with few drops of piperidine refluxed for 8h, cooled then poured onto ice. The produced solid filtered off and crystallized from ethanol to give 10. Yield 68%, m.p. 184˚C - 185˚C, IR (γ) cm−1: 3150 (NH), 1700, 1680 (2C=O), 1590 (C=N), 1488 (deformation CH3), 1335 (C-SO2), 1188 (C=S), 890, 860, 810 (aromatic CH), 710(C-Cl). 1H NMR (DMSO-d6) δ: 10.55 (s, 1H, NH), 7.6, 7.4, 7.2, 7.0 (each d, d, aromatic proton), 6.9 - 6.1 (m, 13H, aromatic protons). Anal. Calcd. for C26H17N6ClS2O4(577): C, 54.07; H, 2.94; N, 14.55; Cl, 6.23 S, 11.09% Found: C, 53.88; H, 2.81; N, 14.35; Cl, 6.01; S, 10.90%.
A mixture of 10 (0.01 mol) and trifluoroethyl acetate (0.01 mol) in THF (50 ml) refluxed 2 h, cooled. The solid produced filtered off and crystallized from dioxan to give 11. Yield 55%, m.p. 208˚C - 210˚C, IR (γ) cm−1: 1720, 1700, 1690 (3C=O), 1600, 1580 (C=N), 1488 (deformation CH3), 1370 (C-SO2), 1250 (C-F), 1185 (C=S), 860, 840, 810 (aromatic CH), 710 (C-Cl), 660 (C-F). 1H NMR (DMSO-d6) δ: 7.4, 7.2, 7.1 - 7.0 (each d, d, C-Cl, C-SO2, aromatic protons), 6.85 - 6.1 (m, 13H, aromatic protons), 1.55 (3H Me). 13C NMR (DMSO-d6) δ: 180 (C=S), 172 (C=C), 167 (C=O), 164 (C=O), 152 (C=N), 145 (C-F), 130 - 120 (aromatic carbons). M/S (Int.%): 678 M+2, 77.8%), 192(5.11), 138(100), 103(18.9), 97(23.1), 56.13(15.11). Anal. Calcd. For C28H16N6F3 ClS2O5 (673): C, 49.92; H, 2.37; N, 12.48; F, 8.46; Cl, 5.34; S, 9.50% Found: C, 49.81; H, 2.11; N, 12.35; F, 8.31; Cl, 5.11; S, 9.35%.
Abdel-Rahman et al. [
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 [
Sample No. | Bacterial | Fungi | |
---|---|---|---|
S. aurens | S. tyhi | A. niger | |
2 | 10.5 | 8.5 | 6.5 |
3 | 12.5 | 10.5 | 11.5 |
4 | 8.5 | 8.0 | 7.0 |
5 | 12.5 | 11.5 | 12.0 |
6 | 9.5 | 9.0 | 9.5 |
7 | 8.5 | 8.0 | 10.0 |
8 | 10.5 | 10.5 | 12.0 |
9 | 8.0 | 7.0 | 8.0 |
10 | 8.5 | 7.5 | 10.0 |
11 | 10.5 | 11.5 | 17.5 |
DMF (Control) | 5 | 7 | 14 |
Stander | 5 | 5 |
*Ciproflaxacin & Miconazole (for bacteria) (for fungi) *DMF: used as control.
From the results obtained we can be concluded that:
The presence of both the COCF3 and P-atom led to the enhanced activity of compounds 3, 5, 8, 11. The compounds containing 1,2,4-triazole-3-thione (4,6) and 1,2,4-triazino-1,2,4-triazin-3-thione showed moderate activity.
The presence of aryl sulfonyl group with synthetic systems (4-8 & 10, 11) also improves the antibacterial activity.
The synthetic compounds containing a phosphorus atom characterized as antifungal agents. It is clear that the biocidal effect’s of the new synthesized systems towards S. aurens (bacteria) is more than the other tested bacteria and fungi, which it maybe the biodynamic formed between S. aurens and synthetic systems are considered a strong state. Also, the effects of DMF as control is highly on S. aurens than other bacteria and moderate effect’s on the tested fungi.
Finally, the compounds 3, 5, 8, & 11 exhibited a high antimicrobial activity which may be due to the presence a type of bio-dynamic systems, via the interaction between the microbial and the fluorinated compound synthesized.
New fluorinated fused hetero-polycyclic nitrogen systems containing pyrazolo- 1,2,4-triazine moiety and sulfonyl groups have been synthesized and evaluated as antimicrobial agents. The results obtained showed that presence of trifluoro acetyl, a phosphorus atom, and sulfonyl groups enhanced the activities. The higher activity of compound 5 can be attributed to the presence of phosphorus atom as donation and back-donation of the electron, with additive properties of CF3 groups also of sulfonyl group at the terminal of fused heteroconjugation systems formed.
Taib, L.A. and Adibani, S.A. (2018) Synthesis of New Fluorinated Fused Heteropolycyclic Nitrogen Systems Containing a Pyrazolotriazine Moiety as Antimicrobial Agents Part I. International Journal of Organic Chemistry, 8, 176-189. https://doi.org/10.4236/ijoc.2018.81013