Synthesis of Novel Multifluorinated Pyrazolone-5-one Derivatives via Conventional and Non-conventional Methods

An efficient synthesis of 3-trifluoromethyl-1-(3,4-difluorophenyl)-1H-pyrazol-5(4H)-one (3) and their Knoevenagel condensation reaction with 1,4-diphenyl -1H-pyrazole-3-carbaldehydes 4, 4-oxo-4H-chromene-3-carbaldehydes 6 and 2-chloroquinoline-3-carbaldehydes 8 have been described by using conventional and non-conventional techniques. Comparison of conventional and non-conventional techniques like Microwave , Ultrasonic assisted reactions showed that, the later procedure require shorter reaction time, good yield and was applicable for larger set of substrates emphasizing the importance of eco-friendly conditions.


Introduction
Pyrazolone are very important class of heterocycles due to their wide applications in pharmacological and biological activities (Arnost et al. 2010;Gursoy et al. 2000;Venkat Ragavan et al. 2009).Large numbers of 2-pyrazolin-5-ones have been used as therapeutics agents such as analgesics and antipyretics, (Himly et al. 2003).It is also well known that they exhibit varied biological activities like antiinflammatory, antibacterial, antifungal, etc. (Karale et al. 2000;Rena et al. 2005).
The chemistry of chromones and its derivatives received considerable attention as it was found readily in natural products, which exhibit antimicrobial activities (Deng et al. 2000;Khan et al 2000).Also, quinoline moiety is of great importance to the chemists as well as biologists as it is found in a large variety of naturally occurring compounds and also chemically useful molecules having diverse biological activities (Nasveld et al. 2005; Denny et al. 2006; Mohamoud et al. 2006;Muruganantham et al. 2004).In the view of various therapeutic aspects of introduction of fluorine in various drugs and biologically active heterocycles, we have decided to incorporate the CF 3 and fluorine group in various positions of pyrazolinones to enhance their reactivity.
In recent years due to increasing environmental awareness in chemical and industrial research, the challenge for a clean environment calls for best procedures like reducing pollution, hazardous byproduct formations.
Keeping a perception on above problems, Microwave and Ultrasound assisted techniques are found to be more effective from environmental as well as from shorter reaction time, high yields, ease of work-up and isolation of products (Maruthikumar et al. 2005; Dalvi et al. 2004; Chornous et al. 2004; Breeuwer et al. 2003; Mojtahedi et  al. 2008).Compared with traditional methods, the organic reaction can be easily controlled, more convenient, with higher yield, shorter reaction time or milder conditions under ultrasound irradiation.

Result and Discussion
In one 9 with a yield of 68-79% using conventional and 82-92% of yields using nonconventional methods (Scheme-2).The exact regioisomerism we could not interpreted for all the obtained products due to multiple fluorine couplings and the complexicity pattern in the 1 H-NMR.
The characterization data of the newly synthesized compounds were given in (Table -1).The reaction reported here by using ultrasonication and microwave techniques are superior in terms of higher yields and rapid, environmental friendly, compared to conventional techniques.

General
All the recorded melting points were determined on electro thermal melting point apparatus and are uncorrected.IR spectra were recorded on Shimadzu-470 infrared spectrophotometer.The 1 H-NMR spectra were recorded on Bruker-AMX 300 MHz instrument in (CD 3 ) 2 SO and TMS as an internal standard. 13C NMR spectra were recorded on 75MHz with TMS as an internal standard. 19F NMR were recorded on 282 MHz.Microwave Initiator-02 Biotage (700Watt) was used to carry out the reactions.The ultrasonic cleaner from Madhu Lab Tech (Tensil India) 230V, 50 Hz 10006H used to carry out sonication reactions.The purity of compounds was confirmed by thin layer chromatography using Merck silica gel 60 F 254 coated aluminium plates.

Conventional method (A)
Pyrazolone 3 (1 mmol) and respective carbaldehydes 4, 6, and 8 (1 mmol) were taken in ethanol (20-25ml) along with catalytic amount of acetic acid (0.1 mmol) and heated the reaction mass to reflux for about 14-26min as mentioned in (Table 1) to obtain respective products.After completion of reaction (monitored by TLC), the reaction mass was allowed to cool to room temperature.The precipitated solid was filtered and dried.Most of the compounds obtained in pure form without recrystallization.

Microwave method (B)
Starting material 3 and respective carbaldehyde analogues 4, 6, and 8 were taken in equimolar quantities along with catalytic amount of acetic acid in ethanol (1-2ml) in sealed tube and irradiated for 5 min at temperature 100-125 o C in Biotage microwave.The progress of reaction was monitored by TLC.After completion of reaction, the reaction mass was allowed to cool to room temperature.The sealed tube was opened and the precipitated solid was filtered out and suck dried.Most of the compounds obtained in pure form without further recrystallization.

Ultrasounds method (C)
Both 3 and the respective starting carbaldehyde analogues 4, 6 and 8 were taken in equimolar quantities along with catalytic amount of acetic acid in ethanol (5ml) in R.B. flask and reaction mass was subjected to ultrasonication for 10 min.The reaction temperature was monitored.After completion of reaction, precipitated solid was filtered and dried.Most of the compounds obtained in pure form without recrystallization.Some of the product which was not pure recrystallized from acetic acid as a solvent.
In conclusion, we have designed and synthesized a new series of novel multifluorinated pyrazolone-5-one derivatives using ultrasonicated and microwave assisted techniques and are more convenient, environmentally safe as they require less volume of solvent, short reaction span and better yields as compared to conventional techniques.