An Efficient and Facile Synthesis of 1,2,4-Aryl Triazoles and 4-Thiazolidinones Bearing 6-Fluorochroman Nucleus

A new generation of chroman bearing heterocyclic five membered ring such as 1,2,4-triazoles and thiazolidinones was designed and synthesized. New chroman based nucleus 5-(6-fluorochroman-2-yl)-4-aryl-4H-1,2,4-triazole-3-thiol and 6-fluorochroman-N-(4-oxo-2-arylthiazolidinin-3-yl) chroman-2-carboxamides were synthesized. Aryl triazole compounds 4a–4j were synthesized from 6-fluorochroman-2-carbohydrazide 2 on reaction with base in methanol and CS2 followed by reaction with substituted aniline. Thiazolidinone compounds 5a–5j were synthesized from 6-fluorochroman-2-carbohydrazide 2 on reaction with substituted aryl aldehyde and thioglycolic acid.


Introduction
The design and synthesis of hybrid molecules encompassing two pharmacophores in one molecular scaffold is a wellestablished approach to the synthesis of more potent drugs with dual activity. With this aspect, 6-fluorochroman-2carboxylic acid derivatives in connection with thiazolidinone and 1, 2, 4-triazoles were found as a promising target for the current research project. 1, 2, 4-Triazoles and 4thiazolidinones are the broadly investigated molecules. They have proved to be the most useful framework for biological activities among nitrogen containing five membered heterocycles. Amongst the diverse classes of heterocyclic compounds chroman, a class of oxygen containing heterocycle forms an important part of many pharmacologically active compounds. For example, the chroman ring is a constituent of various bioactive compounds that are sodium channel blocker [1], 5HT 1A inhibitor [2], and so forth. Commercially available antihypertensive drugs of chroman repinotan [3], robalzotan [4], and specifically 6-fluorochroman nebivolol [5] are well known. Hence, the synthesis of 6-fluorochroman derivatives is currently of significant interest in organic synthesis.

Result and Discussion
The syntheses of triazole and thiazolidinone derivatives have been previously reported by many researchers, and they normally required additional additives and long reaction time. So in this paper, we described an efficient and safe procedure for the synthesis of 4-aryl triazole containing chroman nucleus, using 6-fluorochroman-2-carboxylic acid. methanol in the presence of concentrated H 2 SO 4 at room temperature gave compound 1 (Scheme 1) with good yield which on reaction with hydrazine hydrate (99%) gave compound 2. Compound 2 on reaction with carbon disulphide in the presence of KOH in methanol at RT afforded compound 3. This on further reaction with substituted aniline without use of any solvent in fused condition yielded compounds 4a-4j (Scheme 1). 1 H and 13 C NMR spectra of the products clearly indicated the formation of triazoles 4a-4j in 75-95% yields ( Table 1). The formation of thiol group -SH was identified by a sharp singlet at around = 11.43 ppm. By the 13 C NMR spectrum also supported the presence of -SH group from the deshielding value of carbon attached to -SH group at 168.71 ppm.
Here we introduce the one-pot synthesis of thiazolidinone from hydrazide (Scheme 2) with thioglycolic acid, substituted aryl aldehydes in toluene using a Dean-Stark assembly to synthesized compounds 5a-5j (Scheme 2). 1 H and 13 C NMR spectra of the products clearly indicated the formation of 4-thiazolidinone 5a-5j in 71-95% yields ( Table 2). The formation of -NH group was identified by a sharp singlet at around 10.46-10.43 ppm, which is further supported by D 2 O exchange. 13 C NMR spectrum also supported the presence of amide group from the deshielding value of carbon attached to -CONH group at 169.3 ppm and carbonyl group (part of a five member ring) at 169.47 ppm.

Conclusion
In summary, an efficient protocol for the synthesis of new 1, 2, 4-aryl triazoles and 4-thiazolidinones has been described. Herein, we are reporting the solvent free protocol for the synthesis of N-substituted 1, 2, 4-aryl triazoles (4a-4j) from potassium salt (3). In literature, the synthesis of 4thiazolidinones was carried out via 2 steps, but, to avoid multisteps and to make it more viable, we have developed a single-step reaction for the synthesis of 4-thiazolidinones (5a-5j) from hydrazide (2).

Experimental
Melting points were determined in open capillary tubes and are uncorrected. Formation of the compounds was checked by TLC on silica gel-G plates of 0.5 mm thickness. IR spectra were recorded on Shimadzu FT-IR-8400 instrument using DRS (diffusive reflectance system) method. Mass spectra were recorded on Shimadzu GC-MS system (model QP-2010) using direct inlet probe technique. 1 (4a-4j). To a stirred solution of 6fluorochroman-2-carboxylic acid (0.01 mol) in methanol at room temperature, concentrated H 2 SO 4 (0.01 mol) was added and reaction mixture was allowed to stir at RT for 10 hours. After completion of the reaction, solvent was evaporated and the resulting mass was poured on to ice, neutralized with saturated sodium bicarbonate solution. Separated solid precipitate was filtered, washed with water, and dried to afford methyl 6-fluorochroman-2-carboxylate 1.
Compound 1 (0.01 mol) in absolute ethanol was taken into the RBF and cooled at (−5) ∘ C. To the previously cooled solution hydrazine hydrate (99%, 0.08 mol) was added and reaction mixture was allowed to stir at 0-(−5) ∘ C for 10 hours. After the completion of reaction separated solid residues were filtered, washed with cold ethanol, and dried to afford 6fluorochroman-2-carbohydrazide 2, yield: 2.0 g (98%).
To a mixture of compound 2 (0.1 mol) and potassium hydroxide (0.15 mol) in methanol carbon disulphide (0.15 mol) was added dropwise. Reaction mass was allowed to stir at RT for 22-24 hours. After completion of reaction the obtained solid was filtered, washed with diethyl ether, and dried to afford compound 3. There is no need to purify the salt for further reaction.
An equimolar mixture of potassium 2-[(6-fluorochroman-2-yl) carbonyl] hydrazine carbodithioate 3 (0.01 mol) and substituted aniline (0.01 mol) was taken in RBF and heated at 140-150 ∘ C for 12-15 hours until the evolution of H 2 S gas ceased. After completion of reaction solid residue was dissolved in DMF, treated with dilute HCl, and poured on crushed ice. The product was isolated and crystallized from ethanol to give compounds 4a-4j as analytical pure product.

General Procedure for the Synthesis of Functionalized 4-Thiazolidinones 5a-5j.
An equimolar mixture of 6fluorochroman-2-carbohydrazide 2 (0.01 mol) and different aryl aldehydes (0.01 mol) was taken in RBF and to this, thioglycolic acid (mercaptoacetic acid) (0.29 mol) in toluene was added. Then reaction mixture was allowed to reflux in a Dean-Stark assembly with continuous stirring. After completion of the reaction (48 hrs monitoring by TLC), the content was cooled to room temperature and then neutralized with saturated sodium bicarbonate solution. The organic extracts were washed with water and dried over Na 2 SO 4. The solvent was evaporated in vacuo and the resulting crude product was purified by column chromatography to give the analytical pure compounds 5a-5j. Column chromatography was carried out in hexane: ethyl acetate solvent system. Pure compound was eluted in 23% ethyl acetate in hexane.