Tetrabutylammonium bromide and K2CO3: an eco-benign catalyst for the synthesis of 5-arylidene-1,3-thiazolidine- 2,4-diones via Knoevenagel condensation

Phase-transfer catalyzed, energy-efficient and facile synthesis of 5-arylidene-1,3-thiazolidine-2,4-diones was developed. Three independent variables (temperature, bases and phase-transfer catalyst (PTC)) were screened through one-factor-at-a time (OFAT) study. The optimum reaction conditions suggested by the OFAT analysis were the use of tetrabutylammonium bromide (8 mol%) and potassium carbonate (1 mmol) for the reaction at 100°C. The nitrogen of PTC stabilizes carbonyl groups of thiazolidine-2,4-dione (TZD). The active methylene hydrogen of TZD forms potassium salt with potassium carbonate and generates 5-arylidene-1,3-thiazolidine-2,4-diones (1–16) through nucleophilic attack on the carbonyl carbon of arylaldehydes. The prominent advantages of this new process are economic viability, shorter reaction time (15 min), simple product isolation (non-chromatographic method), good to excellent yields (78–96%) and solvent-free conditions. GRAPHICAL ABSTRACT


Introduction
Design of benign organic transformations to reduce, eliminate and replace hazardous resources (energy and solvents) is a major concern of green chemistry. [1] Knoevenagel condensation generates carbon-carbon (C-C) bonds and plays a pivotal role in synthetic transformations of medicinal chemistry research. [2] Knoevenagel condensation is useful in the construction of clinical candidates [3] such as pioglitazone, rosiglitazone and englitazone (PPARγ agonists), epalrestat (aldose reductase inhibitor), nifedipine (calcium channel blocker), atorvastatin (HMG-CoA reductase inhibitor), entacapone (COMT inhibitor), sulindac (anti-inflammatory agent) and lumefantrin (antimalarial agent).

Results and discussion
In continuation of our research interest on PTCs, [32,33] herein we report that the PTC promoted efficient synthesis of 5-arylidene-1,3-thiazolidine-2,4-diones (Scheme 1) through Knoevenagel condensation. The condensation of anisaldehyde and 2,4-thiazolidinedione generated 5-(4methoxybenzylidene)-1,3-thiazolidine-2,4-dione (compound 1) and was selected as our model reaction. The effects of temperature, bases and catalysts (PTCs) in the model reaction were examined. The reaction at room temperature with tetrabutylammonium bromide (TBAB) and piperidine gave trace yields (detected in TLC) and the reaction at 60°C produced 38% yield (requires purification). However, the reaction at 100°C gave higher yield (52%) of compound 1.  At higher temperatures, collision of molecules is appreciable due to their substantial kinetic energy and enhances the reaction yield. The effect of seven different bases, namely piperidine, potassium carbonate, tyrosine, ammonium acetate, potassium hydroxide, potassium phosphate and triethyl amine at 2 mmol concentration was studied. In the presence of potassium carbonate, the reaction gave a good yield (69%, Table 1, entry 2) of compound 1. The reaction with potassium hydroxide, piperidine and ammonium acetate produced fairly good yields (58%, 52% and 47%, respectively), while triethyl amine produced a very poor yield (26%). However, tyrosine and potassium phosphate gave only trace yields. Potassium carbonate was chosen as the suitable base from this analysis for further investigation and it was examined at four different concentrations (0.5, 1, 1.5 and 2 mmol). The reaction with 1 mmol concentration of potassium carbonate gave excellent yield (91%, Table 1, entry 4).
The available literature describes only small-scale synthesis. Hence, the condensation of multifold concentrations (1, 2, 5 and 10 folds) of 4-hydroxybenzaldehyde and thiazolidine-2,4-dione under the optimized conditions was carried out to test the utility of the reaction for process development programs. The trends indicated linearity between 2-fold and 10-fold concentration increases ( Table 4). The yields are appreciable and high ( > 69%). The R 2 values of curvelinear trend (0.9177) and log scale (0.9991) are indicative of the significance of prediction. Therefore, the present work demonstrates that the optimized conditions can be applied to multifold reaction.

Entry
Catalysts (8 mol%   and zirconium are expensive. [38,39] In the present method, purification of the compounds is done through simple washing (non-chromatographic method) with cold toluene-ethanol mixture (1:1, 1 mL), and this is a major advantage of our method.

Conclusion
The utility of PTC in the straight forward synthesis of 5-arylidene-1,3-thiazolidine-2,4-diones by Knoevenagel condensation was established for the first time. This solvent-free (benign) methodology is applicable to a wide range of substrates (aryl aldehydes and heteroaryl aldehydes). This energy-efficient procedure is consistent with high atom economy (economic viability) of a green chemistry strategy. The multifold reactions substantiated the utility of this protocol in pharmaceutical process chemistry. The attractive features of this new protocol are shorter reaction time, simple product isolation (non-chromatographic method) and good to excellent yields.

Experimental section
Melting points were determined in the DBK program melting point apparatus and expressed in°C and were uncorrected. Aluminum-backed plates coated with silica 60 F 254 (Merck) were used for reactions monitoring by thin layer chromatography. The chromatograms were visualized under UV light (254 and 366 nm) and by staining with iodine. The structures of the synthesized compounds were established using IR, NMR ( 1 H and 13 C) and mass spectra. The IR spectra were recorded on an IR affinity-1 spectrophotometer (Schimadzu, Japan) using DRS 8000 and are expressed in cm −1 . 1 H NMR and 13 C NMR spectra were recorded on an Avance 300 NMR spectrophotometer (Bruker, Switzerland). The chemical shifts were reported as parts per million (δ ppm), using tetramethylsilane as an internal standard. Mass spectrum was recorded on GC-AccuTOF (Jeol, USA, Inc).

General method for one-factor-at-a-time investigations
A mixture of anisaldehyde (5 mmol), thiazolidine-2,4-dione (5 mmol), base and PTC loaded in the 25 ml flat bottom flask was heated with stirring. The reaction mixture was cooled to room temperature, poured into a beaker containing crushed ice (5 g). The isolated precipitate was washed with cold toluene-ethanol mixture (1:1, 1 mL) and air dried.