A practical route to 1-(6-chloropyridazin-3-yl)-3(5)-aryl-5(3)-trifluoromethylpyrazoles using Aliquat 336

The objective of the study is to simplify the synthetic strategy for the synthesis of 1-(6-chloropyridazin-3-yl)-3(5)-aryl-5(3)-trifluoromethylpyrazoles. An elaborated literature survey has been reported by us which documents several routes for the synthesis of 3(5)-trifluoromethylpyrazoles, but none of the methods involves the synthesis of 3(5)-trifluoromethylpyrazoles utilising the Aliquat 336 catalyst21. So, the present study has been undertaken to explore the new synthetic routes. Route A: One-pot synthesis of 1-(6-chloropyridazin-3-yl)-3-aryl-5-trifluoromethylpyrazoles 5(b-e) was undertaken via refluxing 3-chloro-6-hydrazinopyridazine 2 with 4,4,4-trifluoro-1-phenylbutane-1,3-dione 1(b-e) under anhydrous methanol for 2h. Later, in situ addition of 4-5 drops of sulphuric acid (concentrated) to the reaction mixture was carried out, and it was boiled for 1h till the completion of the reaction. Meticulously, condensation of 3-chloro-6-hydrazinopyridazine 2 along with trifluoromethylacetylacetone 1a was carried out under anhydrous methanol refluxing conditions for 2 h and resulted in the exclusive formation of 5-trifluoromethylpyrazoles 5a. Route B: Further, Aliquat 336-catalyzed regioselective synthesis of 1-(6-chloropyridazin-3-yl)-5-aryl-3-trifluoromethylpyrazoles 6(b-e) was carried out, without the major side products formation, via stirring 3,6-dichloropyridazine 9 with 3(5)-trifluoromethyl-5(3)-substituted-1H-pyrazoles 10 using the Aliquat 336 catalyst along with NaOH like a base under toluene reflux for 1h. Interestingly, the condensation of 2 with 2-thienyltrifluoromethyl-β-diketone 1f resulted in the exclusive formation of 3-trifluoromethylpyrazoles 6a. Tetra-alkylammonium ions (R4N+) obtained from Aliquat 336 i.e., Tetra-alkylammonium salts (R4N+X¯) have an unique property. They are soluble in aqueous medium due to their ionic nature but, at the same time, they are also soluble in non-polar organic solvents such as toluene, DCM due to the presence of four alkyl groups. Hence, tetra-alkylammonium ions (R4N+) are able to move back and forth between two phases. So, Aliquat 336 act as a phase transfer catalyst as it carries the inorganic anion such as ¯OH which is insoluble in toluene. Hence, ¯OH ion helps in generating the anion of 3(5)-trifluoromethyl-5(3)-substituted-1H-pyrazoles in organic phase and the anion attacks the target compound 3,6-dichloropyridazine to replace the Cl¯ group. The structure of all the synthesized candidates were reasonably characterized with the analysis of ^1H, ^13C, and ^19F-NMR spectroscopy. Route A: provides easy handling and improved yield. Route B provides easily accessible way without the formation of side products.