ECO-FRIENDLY SYNTHESIS OF 1,2,4-TRIAZINE DERIVATIVES

1,2,4-Triazines are well known compounds. A large number of 1,2,4-triazine derivatives including 1,2,4-triazin6-ones were reported in the literature discussing their special aspects in chemistry and medicine.1-7 Interest in the biochemical properties of 1,2,4-triazines is high because some 3,5–disubstituted 1,2,4-triazines represent analogues of pyridine nucleobases and a number of antibiotics belong to pyrimido[5,4-e]1,2,4-triazine family. 1,2,4-Triazines are reported as both uncondensed and condensed systems. As reported in the literature, there are a large number of 1,2,4triazines of uncondensed systems having substituent to the carbon atom or nitrogen atom exhibiting profound biological activities. 1,2,4-Triazin-6-ones have exhibited anticancer, antitumor, antibacterial and antifungal, antimicrobial, biological activities of cell lines cytotoxicity, antimalarials, antivirals and herbicides. 1,2,4-Triazine ring system is very significant for its applications as corrosion inhibitors, additives to photographic development baths, UV absorbers for textiles, plastic resins and papers and indicators for volumetric analysis of NH-acids in acetonitriles. The foregoing survey reveals that 1,2,4-triazin-6-ones are characterized by multifarious physiological activities and a scant information regarding synthetic methods is observed. In view of the importance associated with the structural motif, an attempt was made to develop a simple and facile synthesis of substituted 1,2,4-triazin-6-oxo derivatives with high yields, purities and simple processing methods from easily available ecofriendly chemicals. This investigation deals with simple and facile synthesis of (Z)-3-alkyl/aryl-5(benzylidene/substituted benzylidene)-2-N-(carbothioamido)-6-oxo-1,2,5,6-tetrahyd-ro-1(NH)-1,2,4-triazine derivatives possessing different functional groups attached to triazine ring with a sole view to arrive a new heterocyclic system of high antibacterial activity. RESULTS AND DISCUSSION

All isolated 1,2,4-triazin-6-one derivatives (3a-3f) are stable crystalline solids with high melting points whose structure has been established on the basis of spectral and analytical data. The appearance of NH absorptions at 3471 cm -1 , absence of stretching absorption peak for NH2 at 3248 cm -1 , appearance of C=O absorption at 1714 cm -1 and C=S absorption at 1270 cm -1 in the IR spectrum of the compounds 3a confirmed cyclocondensation of 2a to produce 1,2,4-triazine-6-one derivative 3a. The all 1,2,4triazin-6-oxo derivatives were synthesized in moderate to good yields. The 1 H NMR spectra showed the appearance of signal at δ 2.1 and 2.6 indicate methyl protons of (C-CH3) and (N-CH3) groups, two trans olefinic protons were observed at 10.4 along with the signals for aromatic hydrogens at 7.8 and 8.4, signal at 6.8 and 7.4 indicate two -NH group which are D2O exchangeable. 13 C NMR confirms the presence C=S group at δ = 177 and C-N linkage at 164 ppm for the title compound 3a. The fragmentation of all the compounds follows the pattern as given in Scheme 2. It shows that the fragmentation starts with the loss of nitrogen. The IR, NMR and Mass spectral data of the compounds confirm the proposed structure of all the compounds as per the Scheme 2.

Scheme 3.
A plausible mechanism for the synthesis of 3a.
The conversation of 4-(benzylidene-2-methyloxazolin-5ones to the corresponding acetamides 2 is confirmed by spectral data. The IR spectra of 2a showed the presence of NH-stretching absorptions for NH2 and NH at 3574 and 3249 cm -1 and absence of stretching absorptions of lactone ring at 3444 cm - The cyclocondensation of 2 to 3 is confirmed by IR spectra showing the absence of N-H stretching absorptions of the amino group of hydrazine and presence of N-H stretching of amide group. The 1 H NMR spectra showed the disappearance of signals for NH2 protons and appearance of D2O exchangeable signals for NH-CH3 and NH-N at δ 6.8 and 7.2 ppm, respectively. The 13 C NMR spectra of the compound 3a showed signals for the presence of Ar, C=O, C=C, C-N, C=S and O-C at δ 24, 42, 149, 164 and 177 ppm, respectively. Finally, the mass spectrum of the compound 3a confirms the molecular weight of the compound and the mass fragmentation pattern supports the structure of the title compound. All the 1,2,4-triazin-6-ones were synthesized with good yields and the structure was confirmed by elemental analysis, IR, 1 H NMR, 13 C NMR and MS data.

EXPERIMENTAL
Melting points are uncorrected and taken in open capillary tubes in sulphuric acid bath. TLC was run on silica gel-G and visualization was done using UV light. IR spectra were recorded using Perkin -Elmer 1000 instrument in KBr pellets. 1 H NMR and 13 C NMR spectra were recorded in CDCl3 solvent using TMS as an internal standard with Bruker AM-400 spectrometer at 400 and 100 MHz respectively. Mass spectra were recorded on Agilent-LCMS instrument under CI conditions and given by Q+1 values only.

Preparation of 2a-2f
Starting compound (1a-1l, 10 mM) was added to hydrazine hydrate (15 mM) in EOH and stirred at room temperature for 30 min. The deep yellow colour of the solution changed to light yellow. Solid was separated, washed with H2O (10 mL), dried and recrystallised from EtOH to afford 2a-2f.

Preparation of 3a-3f
Equimolar quantities of 2a-2f (10mM) and MITC (10mM) were mixed together in DBU (20 mL). The mixture was heated at 60-65 o C for 20-30 min. The completion of the reaction was checked by TLC. Om completion the reaction mixture was cooled to 20-30 o C and poured into ice-cold water (50 mL). A solid separated out, which was collected, washed with water (10 mL) and dried. The product was recrystallised from ethanol to obtain 3a-3f.