β-Keto esters from ketones and ethyl chloroformate: a rapid, general

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Transcript of β-Keto esters from ketones and ethyl chloroformate: a rapid, general

  • Ragavan et al. Organic and Medicinal Chemistry Letters 2013, 3:6http://www.orgmedchemlett.com/content/3/1/6ORIGINAL ARTICLE Open Access-Keto esters from ketones and ethylchloroformate: a rapid, general, efficient synthesisof pyrazolones and their antimicrobial, in silicoand in vitro cytotoxicity studiesRamasamy Venkat Ragavan1, Kalavathi Murugan Kumar2, Vijayaparthasarathi Vijayakumar1*,Sundaramoorthy Sarveswari1, Sudha Ramaiah2, Anand Anbarasu1,2, Sivashanmugam Karthikeyan1,3,Periyasamy Giridharan4 and Nalilu Suchetha Kumari5Abstract

    Background: Pyrazolones are traditionally synthesized by the reaction of -keto esters with hydrazine and itsderivatives. There are methods to synthesize -keto esters from esters and aldehydes, but these methods havemain limitation in varying the substituents. Often, there are a number of methods such as acylation of enolates inwhich 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 tosynthesize -keto esters from ketones like caboxylation of ketone enolates using carbon dioxide and carbonmonoxide sources in the presence of palladium or transition metal catalysts. Currently, the most general and simplemethod to synthesize -keto ester is the reaction of dimethyl or ethyl carbonate with ketone in the presence ofstrong 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 -keto esters by changing the base and reagent.Results: A series of -keto esters were synthesized from ketones and ethyl chloroformate in the presence of basewhich in turn are converted to pyrazolones and then subjected to cytotoxicity studies towards various cancer celllines and antimicrobial activity studies towards various bacterial and fungal strains.

    Conclusion: The -keto esters from ethyl chloroformate was successfully attempted, and the developed method issimple, fast and applicable to the ketones having the alkyl halogens, protecting groups like Boc and Cbz that weretolerated and proved to be useful in the synthesis of fused bicyclic and tricyclic pyrazolones efficiently using cyclicketones. Since this method is successful for different ketones, it can be useful for the synthesis of pharmaceuticallyimportant pyrazolones also. The synthesized pyrazolones were subjected to antimicrobial, docking and cytotoxicityassay 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 tohave promising activity against different bacterial and fungal strains tested.

    Keywords: -keto esters; Ethyl chloroformate; Pyrazolones; Efficient synthesis; Anti-bacterial activity;Fungicidal activity; Cytotoxicity studies* Correspondence: kvpsvijayakumar@gmail.com1Centre for Organic and Medicinal Chemistry, VIT University, Vellore 632 014,IndiaFull list of author information is available at the end of the article

    2013 Ragavan et al.; licensee Springer. This is an Open Access article distributed under the terms of the Creative CommonsAttribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproductionin any medium, provided the original work is properly cited.

    mailto:kvpsvijayakumar@gmail.comhttp://creativecommons.org/licenses/by/2.0

  • Ragavan et al. Organic and Medicinal Chemistry Letters 2013, 3:6 Page 2 of 15http://www.orgmedchemlett.com/content/3/1/6BackgroundPyrazolones are important class of heterocyclic ring sys-tems that have been used extensively in pharmaceuticalindustry [1,2] due to their numerous applications as anal-gesic, antipyretic, antiarthritic, uricosuric, anti-inflamma-tory and antiphlogistic properties. Especially, a pyrazolonederivative (edaravone) [3] acts as a radical scavenger tointerrupt the peroxidative chain reactions and membranedisintegrations associated with ischemia [4-6]. Some ofthe aryloxypyrazolone derivatives are useful in the treat-ment of a variety of disorders caused by human immu-nodeficiency virus and other genetic ailments caused byretroviruses such as acquired immune deficiency syndro-me [7]. In addition, these compounds are appropriate pre-cursors for industrial preparation of herbicides [8], liquidcrystals [9,10], dyes [11], thermally stable polymers [12]and colour photographical compounds [13]. Azadienophi-les from the chemical oxidation of pyrazolones are actingas suitable substrates for hetero Diels-Alder reactions [14].Pyrazolones are traditionally synthesized by the reac-

    tion of -keto esters with hydrazine and its derivatives[15-21]. There are a number of alternative methods tosynthesize pyrazolones which are documented in the lit-erature [22-33] but tend to have serious drawbacks suchas step-intensive, carbon monoxide usage and sensitivepalladium catalysts. These factors revealed that using -keto esters as an intermediate is the broadest and mostefficient way to synthesize pyrazolones. There are methodsto synthesize -keto esters from esters [34-37] (Claisencondensation) and aldehydes [38,39], but these methodshave main limitation in varying the substituents. Often,a number of methods such as acylation of enolates ofmalonates [40,41], acylation of Meldrum's acid [42-45],mixed malonate esters [46,47] and bistrimethylsilylmalo-nate [48,49] have a chelating effect employed to lock theenolate anion of malonate using lithium and magnesiumsalts [50,51]; however, these methods suffer from incon-sistent yields in the case of aliphatic acylation. There aremethods to synthesize -keto esters from ketones likecaboxylation of ketone enolates [52-54] using carbon di-oxide and carbon monoxide sources in the presence ofpalladium or transition metal catalysts. Currently, themost general and simple method to synthesize -ketoester is the reaction of dimethyl or ethyl carbonate withketone in the presence of strong bases [55,56]. Thismethod requires long reaction time, use of excessiveamount of reagent and inconsistent yield. These factorslead us to develop a simple method to synthesize -ketoesters by changing the base and reagent.

    MethodsAntibacterial studyThe newly synthesized pyrazoles for their antibac-terial activity against Escherichia coli (ATTC-25922),Staphylococcus aureus (ATTC-25923), Pseudomonasaeruginosa (ATTC-27853) and Klebsiella pneumonia(recultured) bacterial strains by the disc diffusion method[57,58]. The discs measuring 6.25 mm in diameter werepunched from Whatman No. 1 filter paper (GE Health-care, Little Chalfont, UK). Batches of 100 discs were dis-pensed to each screw-capped bottle and sterilized by dryheat at 140C for an hour. The test compounds were pre-pared with different concentrations using DMF. One mil-liliter containing 100 times the amount of chemical ineach disc was added to each bottle, which contains 100discs. The discs of each concentration were placed in trip-licate in a nutrient agar medium separately seeded withfresh bacteria. The incubation was carried out at 37C for24 h. Solvent and growth controls were kept, and thezones of inhibition and minimum inhibitory concen-trations (MIC) were noted. Results of these studieswere given in Table 1 and compared with the stan-dard ciprofloxacin.

    Antifungal activityNewly synthesized pyrazoles were screened for their an-tifungal activity against Aspergillus flavus (NCIM no.524), Aspergillus fumigates (NCIM no. 902), Penicilliummarneffei (recultured) and Trichophyton mentagrophytes(recultured) in dimethylsulfoxide (DMSO) by the serialplate dilution method [34-36]. Sabouraud agar mediawas prepared by dissolving peptone (1 g), D-glucose(4 g) and agar (2 g) in distilled water (100 mL), and thepH was adjusted to 5.7. Normal saline was used to makea suspension of spores of fungal strain for lawning. Aloopful of particular fungal strain was transferred to3 mL of saline to get a suspension of corresponding spe-cies. Agar media of 20 mL was poured into each Petridish. An excess of suspension was decanted, and theplates were dried by placing them in an incubator at37C for 1 h. Using an agar, punch wells were made onthese seeded agar plates, and 10 to 50 g/mL of the testcompounds in DMSO were added into each labelledwell. A control was also prepared for plates in thesame way using solvent DMSO. The Petri dishes wereprepared in triplicate and maintained at 37C for 3 to4 days. Antifungal activity was determined by measur-ing the inhibition zone. The results of these studieswere given in Table 2 and compared with the stan-dard ciclopiroxolamine.

    Docking studiesAll the synthesized compounds 1 to 26 have beensubjected to the docking studies against ACHN (humanrenal cell carcinoma), Panc-1 (human pancreatic adeno-carcinoma) and HCT-116 (human colon cancer) andthen subjected to WST-1 cytotoxicity assay. Based onthe crystal structures of the target proteins and high-

  • Table 2 Antifungal activities of the newly synthesizedcompounds

    Trichophyton Penicillium A. flavus A. fumigates

    Compoundnumber

    1 25 (6.25) 23 (6.25) 26 (6.25) 27 (6.25)

    2 24 (6.25) 25 (6.25) 24 (6.25) 26 (6.25)

    3 29 (6.25) 26 (6.25) 27 (6.25) 28 (6.25)

    4 21 (6.25) 22 (6.25) 26 (6.25) 22 (6.25)

    5 16 (12.5) 17 (12.5) 12 (12.5) 14 (12.5)

    6 17 (12.5) 17 (12.5) 11 (12.5) 15 (12.5)

    7 24 (12.5) 21 (12.5) 21 (12.5) 20 (12.5)

    8 26 (12.5) 24 (12.5) 27 (12.5) 23 (12.5)

    9 27 (12.5) 25 (12.5) 28 (12.5) 22 (12.5)

    10 20 (6.25) 22 (6.25) 17 (6.25) 22 (6.25)

    11 21 (6.25) 21 (6.25) 23 (6.25) 21 (6.25)

    13 22 (12.5) 25 (12.5) 27 (12.5) 23 (12.5)

    14 30 (12.5) 22 (12.5) 26 (12.5) 24 (12.5)

    15 26 (12.5) 23 (12.5) 27 (12.5) 23 (12.5)

    17 31 (12.5) 25 (12.5) 28