Synthetic Process Improvement Of 3,4,5-Trisubstituted Pyrazoles And Antibacterial Activity Determination

Pyrazoles,an important class of N-heterocycles,are widely found in natural products,bioactive molecules,pharmaceuticals,and agrochemicals.Many compounds containing pyrazole skeletons have excellent herbicidal,insecticidal,and bactericidal activities with the advantages of high efficiency and low toxicity.In addition,Pyrazole derivatives exhibit anti-inflammatory,anti-Parkinson’s disease,anti-Alzheimer’s disease,anti-tuberculosis,and anti-cancer activities,and thus such medicines have been developed and marketed.Therefore,the development of highly efficient,operationally simple,cost-effective,highly selective method and synthetic process for the preparation of pyrazoles has been of significant value.There are rare examples of the synthesis of 3,4,5-trisubstituted pyrazoles.Previously reported synthetic methods generally exist some disadvatages,such as low regioselectivity,uneasily available starting materials,multi-step synthesis,complicated operation,and the difficulty of scale-up synthesis.Among reported synthetic protocols,the domino cycloaddition/rearrangement reaction between hydrazones and alkynes has been documented to be simple and highly efficient.However,there still exist some shortcomings including relatively narrow substrate scope,incapability of gram-scale synthesis,the use of the time-consuming,laborious and uneconomical column chromatography purification,and etc.In this dissertation,the domino cycloaddition/rearrangement reactions between hydrazones and alkynes were used as the synthetic strategy to construct 3,4,5-trisubstituted pyrazoles.The optimal reaction conditions were established by the screening of reaction parameters including bases and solvents.The substrate scope of hydrazones and alkynes was next investigated under the optimized reaction conditions.24 products were obtained in good yields,of which 19 were new compounds that have not been reported previously.All products were well characterized by NMR(¹H NMR and ¹³C NMR),high-resolution mass spectrometry（HRMS）,and melting points.Furthermore,antifungal activity test has been conducted for all the synthetic target compounds..More importantly,systematical investigations on the synthetic process demonstrated that the current synthetic approach was amenable to gram-scale preparation without the use of the time-consuming and laborious column chromatography purification.The pure 3,4,5-trisubstituted pyrazoles（gram scale）could be easily obtained by washing the crude products with petroleum and ethyl acetate（10:1）mixture.In addition,3,4,5-trisubstituted pyrazole products could also be effectively prepared from inexpensive aryl methyl ketones,Ts NHNH₂ and alkynes with toluene as a solvent in one-pot fashion.In summary,the improved synthetic method and process were characterized by broad substrate scope,high regioselectivities,low cost,simple operation,high efficiency,and the easiness of scale up.Antifungal activity studies have shown that some compounds have good antifungal activity against the tested fungi.It is anticipated that the related results have potential applications for the discovery of lead compounds as well as new fungicides.