A SIMPLE , EXPEDITIOUS AND GREEN PROCESS FOR KNOEVENAGEL CONDENSATION OF PYRAZOLE ALDEHYDES

[a] Department of Chemistry, Vinayakrao Patil Mahavidyalaya, Vaijapur, Aurangabad-423701, Maharashtra, India [b] Polymer Science and Engineering Division, National Chemical Laboratory, Dr. Homi Bhabha Road, Pashan, Pune 411008, Maharashtra, India. [c] Department of Chemistry, Majalgaon Arts, Science and Commerce College, Majalgaon, Dist. Beed431131, Maharashtra, India. [d] Department of Chemistry, Deogiri College, Station Road, Aurangabad431 005, India


Introduction
Emil Knoevenagel (in 1890) developed a method for the synthesis of substituted alkenes, by the condensation of an aldehyde with active methylene compounds in the presence of base and water.Knoevenagel condensation is typical C-C bond forming reaction in organic synthesis.This reaction is useful to generate a variety of intermediates which are used in the synthesis of pharmaceutical precursors; because of this, Knoevenagel condensation has been extensively studied by researchers.Scientist and academicians are still inventing novel methods and catalysts for Knoevenagel condensation.Several methods have been developed by using the microwave, 1 or ultrasonication, 2 photochemical condensations with fruit extract as a catalyst, 3 solvent free conditions. 4ecently Franca Bigi et al., 5 reviewed Knoevenagel reactions in an aqueous medium with and without a catalyst.According to Franca although reaction involves a dehydration step, the reaction can be carried out in water.Following this interpretation, we have carried out the Knoevenagel reaction of pyrazole aldehyde in water but resulted in lower yield due to less solubility of pyrazole aldehyde.Then we have carried out the reaction in the water-ethanol mixture and obtained a high yield of products; these results prompted us to investigate this reaction further.
4] To eliminate or reduce some harsh reaction conditions, harmful and expensive reagents and solvents, we have developed a green method, for Knoevenagel condensation of substituted pyrazole aldehydes with malononitrile in an aqueous medium, using ammonium carbonate as cheap, environmentally friend catalyst.The striking features of reaction are shorter reaction time, ambient reaction temperature, cost effective, simple workup procedure, an aqueous medium (Scheme 1).

Experimental
All chemicals used were of the synthetic grade.The solvents were distilled before use.The progress of the reaction was monitored by TLC using ethyl acetate: nhexane system.Melting points were recorded by using the open capillary method and are uncorrected.The Ultrasonicator used was made by Cyberlab Ultrasonic Stericleaner model number CB2080 with operation voltage 220 V AC and electric cycle 50/60 Hz.IR spectra were recorded on Shimadzu IR Affinity 1 instrument using KBr discs.H 1 NMR was recorded on BRUKER Avance II 400 NMR Spectrometer using DMSO d6 as a solvent.The mass was recorded on WATERS, Q-TOF Micro mass (ESI-MS) using methanol as a solvent.

General procedure for the Knoevenagel condensation
In 50 mL round bottom flask pyrazole aldehyde (1 mmol), malononitrile (1 mmol), were taken in 10 ml water-ethanol (1:1) mixture and stirred for 3-5 minutes to mix the reaction mixture; after that ammonium carbonate (20 mol %) was added.The resulting reaction mixture was stirred for 3-20 minutes at reflux temperature, and the reaction was monitored by TLC.After the completion of the reaction, the reaction mixture was allowed to cool down to room temperature and then filtered off, washed with water and dried.Similarly, other derivatives were also prepared (Table-2).Similar results were obtained when the reactions were carried out using sonication method (Table 2).

Result and Discussions
Owing to the importance of Knoevenagel condensation reaction to synthesise pharmaceutical intermediates, we have developed a green and efficient method, for the synthesis of heterocyclic, substituted alkenes, by reacting pyrazole aldehyde, malononitrile in the presence of ammonium carbonate (20 mol%) in water: ethanol (1:1) mixture at reflux temperature.
To optimize reaction conditions we have performed the reaction of 1,3-diphenyl-1H-pyrazole-4-carbaldehyde with malononitrile and ammonium carbonate which was considered as a standard model reaction.In search of a suitable solvent, we have achieved reaction by using different solvent mixtures and results were summarized in (Table1 ).
Table 1.The reaction of 1,3-diphenyl-1H-pyrazole-4-carbaldehyde and malononitrile in the presence of 20 % and ammonium carbonate in 10 ml of the solvent system at reflux temperature.
Water: ethanol (1:1) mixture is proved to be the best solvent system for this reaction.If the reaction was carried out either in water or ethanol; yield of product was decreased due to the higher solubility of either pyrazole aldehyde or ammonium carbonate.The amount of ammonium carbonate has a large influence on the reaction time and yield, the reaction in the absence or presence of 10 % ammonium carbonate only 30 or 60 % yield could be achieved, respectively, and unreacted aldehyde remained back even after 1 h reaction time.Isolated yield obtained after using 20 mol % ammonium carbonate in 10 ml of water-ethanol (1:1) solvent system.

Solvent
We have also carried out the same reaction by using sonication to increase yield and reduce the period of reaction.But much difference was not found (Table 2).

Conclusion
The reported method described a simple and fast way for the condensation of pyrazole aldehydes with malononitriles, in 1:1 EtOH: an H2O solvent mixture in the presence of 20 mol % (NH4)2CO3 and under 10 min reflux or sonication.