Synthesis and Characterization of New Triheterocyclic Compounds Consisting of 1,2,4-Triazol-3-one, 1,3,4-Thiadiazole and 1,3,4-Oxadiazole Rings

Turk J Chem 29 (2005) , 125 – 133. c TÜBİTAK Synthesis and Characterization of New Triheterocyclic Compounds Consisting of 1,2,4-Triazol-3-one, 1,3,4-Thiadiazole and 1,3,4-Oxadiazole Rings Neslihan DEMİRBAŞ Karadeniz Technical University, Department of Chemistry, 61080 Trabzon-TURKEY e-mail: Received 16.07.2004 A series of acetic acid derivatives (2a-c) was synthesized by the condensation of compounds 1a-c with chloroacetic acid. The treatment of carboxylic acid derivatives with thiosemicarbazide in phosphorus oxychloride and subsequent diazotation of the products (3a-c) afforded 5-alkyl-2-[(5-chloro-1,3,4thiadiazol-2-yl)methyl]-2,4-dihydro-3H-1,2,4-triazol-3-one derivatives (4a-c). The treatment of compounds 4a-c with thiourea produced 5-alkyl-2-[(5-mercapto-1,3,4-thiadiazol-2-yl)methyl]-2,4-dihydro3H-1,2,4-triazol-3-one derivatives (5a-c). Subsequently, compounds 5a-c were converted to acid hydrazides by treatment with hydrazine hydrate after esterification (7a-e). Moreover, the reaction of compounds 7a-c with carbon disulfite in the presence of KOH afforded 5-alkyl-2-[(5-{[(5-mercapto-1,3,4oxadiazol-2-yl)methyl]thio}-1,3,4-thiadiazol-2-yl)methyl]-2,4-dihydro-3H-1,2,4-triazol-3-ones (8a-c). Key Words: 1,2,4-triazol-3-one 1,3,4-thiadiazole, 1,3,4-oxadiazole, thiosemicarbazide, diazotation, deamination. Introduction The synthesis of compounds incorporating both 1,2,4-triazole and 1,3,4-thiadiazole rings has been attracting widespread attention due to their diverse pharmacological properties such as antimicrobial, antiinflammatory, analgesic and antitumoral activities1−7 . In addition, several 1,3,4-oxadiazole derivatives have been reported to possess diverse biological activities8−13. Although there are a number of antibiotics which are commercially used in medicine, the synthesis of new compounds is of vital importance due to increasing drug resistance. Moreover, it is important to obtain therapeutical compounds having less toxic effects. 4-Amino-1,3,4-thiadiazoles, which can be prepared via the cyclization of the compounds involving a thiosemicarbazone structure in the presence of ammonium ferric sulfate or from the reaction of carboxylic acids with thiosemicarbazide in the presence of phosphorus oxychloride, are useful intermediates for further reactions, and some piperazinyl quinolone derivatives have been obtained as antimicrobial agents by using some 4-amino-1,3,4-thiadiazoles14−16. Moreover, 4-amino-5-alkyl-2,4-dihydro-3H-1,2,4-triazol-3-ones 125 Synthesis and Characterization of New Triheterocyclic Compounds..., N. DEMİRBAŞ (1) behave as good nucleophiles in most reactions, and some N -substituted derivatives have been prepared in our laboratories as biologically active compounds17−19 . It has been reported that compounds containing an –SH group can be easily converted to their Ssubstituted derivatives 5,20−24. Prompted by these observations, we aimed to obtain 1,2,4-triazol-3-one derivatives also incorporating 1,3,4-thiadiazole and 1,3,4-oxadiazole rings as possible biological active compounds. The alkyl groups at position 5 of the 1,2,4-triazol-3-one ring were selected as an aliphatic (methyl), an aromatic-aliphatic (benzyl) and an aromatic (phenyl) group (Figure). Results and Discussion Compounds 2a-c were obtained from the reaction of compounds 1a-c with chloroacetic acid in basic media and their structures were confirmed using IR, 1 H NMR and 13 C NMR spectral data and elemental analysis (for compound 2a only). The IR spectrum of compounds 2a-c displayed no absorption derived from NH stretching; instead, a new signal representing the carboxyl group was observed. In the NMR spectra of compounds 2a-c 2 new signals originating from the CH2 COOH group were recorded. Compounds 3a-c were prepared by the reaction of carboxylic acid derivatives (2a-c) with thiosemicarbazide in phosphorus oxychloride. The 1 H NMR spectra of compounds 3a-c showed 2 different –NH2 signals (exch. with D2 O). It has been reported that the diazotation of amino thiadiazoles in hydrochloric acid in the presence of copper powder results in the substitution of the amino group with chlorine14 . On the other hand, deamination can be achieved when 4-amino-5-alkyl-2,4-dihydro-3H-1,2,4-triazol-3-ones are treated with nitrous acid25 . In the 1 H NMR spectrum, the –NH2 signals disappeared when compounds 3a-c were converted to compounds 4a-c; instead a new signal originating from triazole-NH was observed. The reaction of compounds 4a-c with thiourea in ethanol produced 5-alkyl-[(5-mercapto-1,3,4-thiadiazol-2-yl)methyl]-2,4-dihydro-3H-1,2,4-triazol-3-ones (5a-c). The signal appeared at 12.04-12.53 ppm in the 1 H NMR spectra of compounds 5a-c was attributed to the –SH group. Ethyl ({5-[(3-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl]-1,3,4-thiadiazol-2-yl}thio)aceta- tes (6a-c) were obtained from the reaction of compounds 5a-c with ethyl bromoacetate in the presence of sodium ethoxide. The NMR spectra of compounds 6a-c displayed additional 3 signals due to the esteric group. The treatment of acetic acid ethyl ester derivatives (6a-c) with hydrazine hydrate afforded 2-({[(3alkyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl]-1,3,4-thiaidazol-2-yl}thio)aceto-hydrazide derivatives (7a-c). In the 1 H NMR spectra of compounds 7a-c new signals belonging to the –NHNH2 group were observed, while the signals originating from the ester group disappeared. The reaction of compounds 7a-c with carbon disulfite in the presence of KOH caused the conversion of the hydrazide group to the 1,3,4-oxadiazole ring, and hence 5-alkyl-2-[(5-{[(5-mercapto-1,3,4-oxadiazol-2yl)methyl]thio}-1,3,4-thiadiazol-2-yl)methyl]- 2,4-dihydro-3H-1,2,4-triazol-3-ones (8a-c) were obtained after acidic treatment. In the 1 H NMR spectra of 1,3,4-oxadiazole derivatives (8a-c) no signal belonging to the –NHNH2 group was observed, which appeared at 4.71-4.75 ppm (-NHNH2 ) and 9.19-9.25 ppm (-NHNH2 ) (exch. with D2 O) in the 1 H NMR spectra of the parent compounds (7a-c). 126 Synthesis and Characterization of New Triheterocyclic Compounds..., N. DEMİRBAŞ 2 1 2+ 1 1+ 1 6 1 1 2 &O&+ &2 2 +  1 + 1 1 +&1 +  1 D2 (W 5 5 1 1 + DF 1  32 & O  2 5 1 1 + 6 1 2 1 + 1+ DF DF  1 D1 2  +&O &X  1 1 5 1 + 1 &1+   5 2 1 1 6 6+ 6 1 1 1 &O 6 1 2 1 + + DF DF 1 D2 (W %U&+ &2 2 (W  1 1 5 1 2 & + 6 6 1 2 2 1 + DF + 11+   1  5 D E F &+  &+ & + & +      2 1 & 1 5 6 6 1 1 +1 +  2 1 + DF &6  . 2 +  1 1 5 6 1 1 1 1 6 1 2 6+ 2 + DF Figure 127 Synthesis and Characterization of New Triheterocyclic Compounds..., N. DEMİRBAŞ Experimental Melting points were determined on a Gallenkamp melting point apparatus and are uncorrected. 1 H NMR and 13 C NMR spectra were recorded on a Varian-Mercury 200 MHz spectrometer. The IR spectra were measured as potassium bromide pellets using a Perk (...truncated)