β-Keto esters from ketones and ethyl chloroformate: a rapid, general, efficient synthesis of pyrazolones and their antimicrobial, in silico and in vitro cytotoxicity studies

Abstract

BackgroundPyrazolones are traditionally synthesized by the reaction of β-keto esters with hydrazine and its derivatives. There are methods to synthesize β-keto esters from esters and aldehydes, but these methods have main limitation in varying the substituents. Often, there are a number of methods such as acylation of enolates in which a chelating effect has been employed to lock the enolate anion using lithium and magnesium salts; however, these methods suffer from inconsistent yields in the case of aliphatic acylation. There are methods to synthesize β-keto esters from ketones like caboxylation of ketone enolates using carbon dioxide and carbon monoxide sources in the presence of palladium or transition metal catalysts. Currently, the most general and simple method to synthesize β-keto ester is the reaction of dimethyl or ethyl carbonate with ketone in the presence of strong bases which also requires long reaction time, use of excessive amount of reagent and inconsistent yield. These factors lead us to develop a simple method to synthesize β-keto esters by changing the base and reagent.ResultsA series of β-keto esters were synthesized from ketones and ethyl chloroformate in the presence of base which in turn are converted to pyrazolones and then subjected to cytotoxicity studies towards various cancer cell lines and antimicrobial activity studies towards various bacterial and fungal strains.ConclusionThe β-keto esters from ethyl chloroformate was successfully attempted, and the developed method is simple, fast and applicable to the ketones having the alkyl halogens, protecting groups like Boc and Cbz that were tolerated and proved to be useful in the synthesis of fused bicyclic and tricyclic pyrazolones efficiently using cyclic ketones. Since this method is successful for different ketones, it can be useful for the synthesis of pharmaceutically important pyrazolones also. The synthesized pyrazolones were subjected to antimicrobial, docking and cytotoxicity assay against ACHN (human renal cell carcinoma), Panc-1 (human pancreatic adenocarcinoma) and HCT-116 (human colon cancer) cell line, and lead molecules have been identified. Some of the compounds are found to have promising activity against different bacterial and fungal strains tested.

Inversion of cpADH5 Enantiopreference and Altered Chain Length Specificity for Methyl 3‐Hydroxyalkanoates

“…β‐Keto esters, such as methyl 3‐ketoalkanoates, are important synthons in organic synthesis for the production of a number of natural products . Methyl 3‐oxobutyrate has been used for the synthesis of pharmaceuticals, dye compounds and agricultural chemicals .…”

Synthesis and Pharmacological Investigations of Novel Pyrazolyl and Hydrazonoyl Cyanide Benzimidazole Entities

“…Secondly, the aryl/heteryl hydrazonyl derivatives (5a-e to 7a-e) were allowed to react with 2-(hydrazineylmethyl)-1H-benzimidazole (2) in the presence of sodium ethoxide (Schemes 3-5). In traditional way, the Knorr pyrazole synthesis was reported widely using an acid catalyst [31], as the β-keto esters acted as Michael donors and hence underwent cycloaddition reaction with hydrazineyl derivative to obtain pyrazolone derivatives [32][33][34]. As a new route, using basic catalyst, the mechanism of the reaction was assumed to go on the pathway in order to afford the hydrazono intermediate before cyclization to obtain the target pyrazolone derivatives (8a-e) as basic heterocyclic nucleus as illustrated in Scheme 3 and Figure 1.…”

Convenient synthesis and anticancer evaluation of novel pyrazolyl‐thiophene, thieno[3,2‐b]pyridine, pyrazolo[3,4‐d]thieno[3,2‐b]pyridine and pyrano[2,3‐d]thieno[3,2‐b]pyridine derivatives

“…The second strategy involves the intramolecular cyclization between amino group (at C-3 of thiophene) and ester function to construct annulated thienopyridine-based compounds. Thus, the reaction of functionalized thiophene 2 with hydrazine hydrate [37] was performed by reflux in ethanol at the β-ketoester part to produce the corresponding pyrazolyl-thiophene derivative 3 (Scheme 2). The 1 H The reactivity of methylene group of the pyrazolone moiety in compound 3 proved to be active toward the…”