Bismuth (III) Triflate: A Mild, Efficient Promoter for the Synthesis of Trisubstituted Alkenes through Knoevenagel Condensation

In this work, smooth efficient and eco-friendly two component coupling method is reported for the synthesis of Knoevenagel Condensation product in presence of Bi(OTf)3 catalyst under solvent free condition. Catalyst has participated in condensation between substituted aldehydes (aromatic and hetero-aromatic) and active methylene compounds (ethyl cyanoacetate, malononitrile and cyanoacetamide) effectively to generate an excellent yield of the product. Bi(OTf)3 catalyst is stable, inexpensive and easily available was used for four times in this reaction without loss of catalytic activity.


INTRODUCTION
The Knoevenagel reaction first reported in 1890 by Emil Knoevenagel which is an Aldol type condensation is extensively applied to the formation of the carbon-carbon double bond in synthetic organic chemistry. This important methodology has been used to produce different α,β-unsaturated acids like cinnamic acid. 1 This reaction is assisted for the production of such compounds which have immense biological significance 2 that is therapeutic activity and drug discovery. 3,4 In addition these compounds are used for production of polymers, 5,6 cosmetics, 7 perfumes 8 and natural products. 9 Malononitrile, ethyl cyanoacetate, cyanoacetamide are active methylene compounds and usually used in the string of carbon-carbon double bond formation in organic transformation. 6 A large no of methods for the synthesis of Knoevenagel Condensation products has been reported because of their immense biological activity and synthetic viewpoint. Bases such as amines (piperidine and N methyl piperidine), metal alkoxides, metal hydroxide and pyridine catalyzed Knoevenagel condensation reaction in either solvent free or organic solvents were reported. 10 Ammonium salts 10 and amino acids 10 were also used to construct this condensation product. These catalysts are homogeneous and very effective to increase the reaction rate but some disadvantages of these catalysts were (a) toxic to human 11 (b) difficult to separate from the reaction mixture because of homogeneity and can't be recycled and (c) neutralization was required at the end of the process. In many published papers green methodology was used to develop the Knoevenagel condensation product. 12,13 Analysis of the literature reveals that many Lewis acid catalysts for Knoevenagel condensation were used compared to bases as catalysts in huge numbers to overcome the above difficulties. Some Lewis acid catalysts such as TiCl4, 14 26 This catalyst was successfully used to synthesize the Substituted 2-Alkenylfurans in nitro methane solvent 27 and 2-aryl-1-arylmethyl benzimidazole derivatives in water. 28 So my aim was to search an environmentally benign catalyst to build up a scheme for the synthesis of Knoevenagel Condensation products and for this purpose herein, I explore a scheme in presence of Bismuth (III) triflate catalyst under solvent free condition.

ExPERIMENTAL
Chemicals were purchased from SRL India and Spectrochem Pvt. Ltd. 1 H and 13 C NMR spectra were recorded on a Bruker 300 MHz instrument. From Aldrich chemical company NMR solvents CDCl 3 , DMSO-d 6 and TMS as the internal standard were purchased. Electrical melting point apparatus were used to determine the melting point. Perkin Elmer Spectrophotometer was used to study FT-IR spectra. Thin layer chromatography was used to monitor the reaction. For recrystallisation, distilled ethyl acetatepetroleum ether was used as solvents.

General procedure
An active methylene compound 2 (2.2 mmol), aldehyde 1 (2 mmol) and Bi(OTf) 3 (0.10 mmol) were taken and mixed in a 50 mL Erlenmeyer flask with a condenser containing ice water circulation and it was heated in an oil bath at 80 0 C with a specific time period. The reaction was monitored by TLC time to time. After the complete conversion of the reaction indicated by brown spot in TLC then the crude product was cooled and diluted with 10 mL water stirred and filtered. After the separation of organic portion the crude product was crystallized from minimum volume of distilled ethylacetate-petroleum ether to get pure product. All 1 H-NMR and 13 C-NMR spectral data of all known compounds (3a-u) were checked with the data of authentic known compounds.

RESULT AND DISCUSSIONS
In order to investigate the effect of catalyst, solvent, time and yield; a model reaction had been chosen for this purpose. Initially 4-methoxybenzaldehyde (2 mmol) and ethyl cyanoacetate (2.2 mmol) were taken as model substrate and reagent under different conditions to focus the feasibility of the catalyst in solvent free medium at suitable temperature. The reaction was performed systematically and results were shown in Table 1. Mixture of the reaction was warmed with different amount of Bi(OTf) 3 (BT) catalyst in solvent free condition at changeable temperature and it was noticeable that the product yield depends on the amount of BT catalyst and as well as temperature. The reaction sluggish without catalyst in solvent less condition at 80 0 C and no yield was isolated when 10 mol% of BT catalyst was used at room temperature although reaction was continually monitored for 6 h (Entry 1, Table 1). When the mol% of the catalyst was varied from 1 to 10, the yield of the product gradually increased. 5 mol% of the catalyst at 80 0 C gave only 60% yield of the product (Entry 4, Table 1). Increasing the amount of the catalyst from 5 to 10 mol% resulted in a drastic increase of the yield to 90% (Entry 6, Table  1). More over in presence of 10 mol% of catalyst at 90 0 C no improved yield was observed (Entry 7, Table  1). More than 10 mol% of the catalyst that means 15 and 20 mol% of the catalyst at 80 0 C did not improve the yield of the product (Entries 8 and 10, Table 1) and at comparatively high temperature (90 0 C) no better result was observed (Entries 9 and 11, Table 1). So I came to the point that only 10 mol% of catalyst was adequate to complete the reaction at 80 0 C (Entry 6, Table 1) with excellent yield of the product.
Then I have studied the influence of the solvent effect on Knoevenagel condensation product catalyzed by 10 mol% of BT using the model substrate 4-methoxy benzaldehyde and reagent ethylcyanoacetate at 80 0 C temperature and the results were shown in Table 2. In presence of less polar solvent (Entries 1 and 2, Table 2) the yield was very low even after 6 h of the continuous heating of the reaction mixture. Polar aprotic solvent increases the yield slightly (Entries 3 and 4, Table 2) but the reaction gave moderate yield in polar protic solvent (Entries 5, 6 and 7, Table 2). Under solvent free condition 90% yield of the product was determined, so I can conclude that BT catalyst worked well under solvent less condition (Entry 8, Table 2) than protic solvent to generate high yield of the condensation product. In solvent free condition the substrates and reagents are very close to each other and that's why high yield was observed under this conditions.  From the analysis of the reported data in Table 3, I can say that electron pulling group like NO 2 , Cl, Br present in the aromatic aldehyde increases the electrophilicity of the aldehyde group and then enol form of the active methylene compound reacted with the aldehyde group smoothly and it was reflected in the yield of the products. Temperature was required to complete the dehydration step of the reaction. Electron donating group like OMe, NMe 2 gave slightly lower yield because of lower electrophilicity of aldehyde group (Entries 2 and 10, Table 3). However, all the substrates reacted very fine and produce excellent yields of the products. Beside this, it was also observed that when 4-bromobenzaldehyde was reacted separately with three different active methylene compound then different time was required to complete the reaction so the reactivity order is malanonitrile>ethyl cyanoacetate>cyanoacetamide of three active methylene compounds. Lewis acid catalysed mechanism was reported in many previously published papers. Here Bi (III) acts as a Lewis acid catalyst which polarizes the aldehyde group by the formation of Lewis acid-Lewis base complex and beside this, catalyst helps to generate the nucleophilic activity of the active methylene compound by enolisation and then nucleophilic addition to aldehyde take place rapidly. In recent published paper where they shown the mechanism of the reaction. 39 I have represented here the details mechanism in Scheme 3 like that paper. In the previous published paper the products configuration was Trans. 31 According to this information all the products obtained through this methodology were Trans in nature. Recycling experiment of the catalyst always gets importance in industrial method and for this purpose an experiment was carried out to check the reusability of the catalyst in the present work. After complete conversion of the reaction the isolated crude product was incubated in 10 mL of  water then stirred and filtered. Then aqueous layer was dried and regenerated catalyst was reused for next reaction under the same reaction condition. It was observed that no loss of efficiency of the catalyst even after using four times in the reaction and it is clearly represented graphically in Figure 1.

CONCLUSION
In outline, it is clear that catalyst proves it efficiency and effectiveness towards the synthesis of trisubstituted alkene and provides a new synthetic methodology. Catalyst is inexpensive, easily obtainable and shows its eco friendly behavior. Moreover, the protocol offers some advantages with operational simplicity, clean reaction conditions, high yields with three different active methylene compounds under solvent less condition and causes less environmental pollution which makes the method more useful and interesting.

ACKNOwLEDGEMENT
Author is very much grateful to his PhD supervisor Professor Chhanda Mukhopadhyay, Department of Chemistry, University of Calcutta for providing him laboratory facility and financial support.