Padghan SV, Ade S, Chopade M. Ferric Chloride and DABCO as a Versatile and Effective Catalytic System for Synthesis Thiazolidinedione Phamacophore

Research Article

Austin J Anal Pharm Chem. 2024; 11(2): 1173.

Ferric Chloride and DABCO as a Versatile and Effective Catalytic System for Synthesis Thiazolidinedione Phamacophore

Santosh V Padghan¹; Suraj Ade²; Manojkumar Chopade¹*

¹Department of Chemistry, Sant Dnyaneshwar Mahavidyalaya, Soegaon, Chhatrapati Sambhaji Nagar 431120, India

²Department of Chemistry, Maulana Azad College, Chhatrapati Sambhaji Nagar, India

*Corresponding author: Manojkumar Chopade, Department of Chemistry, Sant Dnyaneshwar Mahavidyalaya, Soegaon, Chhatrapati Sambhaji Nagar 431120, India. Email: chopademanojkumar@gmail.com

Received: November 23, 2024; Accepted: December 13, 2024;Published: December 20, 2024

Abstract

A mild and efficient procedure for the synthesis of synthetic approach for creating 2, 4-thiazolidinedione derivatives through the Knoevenagel condensation reaction, substituted benzaldehyde with 2,4-thiazolidinedione in ethanol catalysed by Ferric chloride and DABCO as a versatile and effective catalyst. These 2, 4-thiazolidinedione derivatives are significant due to their diverse biological activities’ significant advantages, such as cost-effectiveness, non-toxicity, and operational simplicity and high yield.

Keywords: Knoevenagel condensation; Benzaldehyde; 2, 4-thiazolidinedione; Ferric chloride; DABCO

Introduction

Heterocyclic compounds have been used extensively in the field of medicinal chemistry, where they occupy a central position in the development of new and novel therapeutic agents. Thiazolidinediones are five membered heterocyclic compounds which have attracted considerable attention from chemist over the last 20 years because of their wide range of biological properties including antidiabetic, antibacterial, antifungal, antiproliferative effect on vascular smooth muscle, anti-HIV, antitubercular and anti-inflammatory [1-7]. Additionally some of the rhodamine based compounds shows aldose reductase inhibitory activity [8] and 15-hydroxy prostaglandin dehydrogenase inhibitors [9] (Figure 1). Instead of these biological activities, thiazolidinedione acts as inhibitors of MurD ligase [10].

Figure 1: Drug of 2, 4-thiazolidinedione.

    
    
    Figure 1: Drug of 2, 4-thiazolidinedione.

Encouraged by all these facts and as part of our continuing research programme dealing with the synthesis of heterocyclic system containing 2, 4-thiazolidinediione moiety we have undertaken the synthesis of 5-arylidine-2, 4-thiazolidinedione. Due to the important pharmacological potential of thiazolidinedione, consequently, a number of synthetic strategies have been reported for the construction thiazolidinedione phamacophore moiety. However, most existing methodology synthesis of thiazolidinedione phamacophore moiety includes KAl(SO4)2.2H2O at 900C [11], baker’s yeast [12], KF-Al2O3 under microwave irradiation [13], glycine under microwave irradiation [14], polyethylene glycol-300 at 100-120°C [15], L-Tyrosine [16], Aqueous media under Ultrasound-Irradiation [17], Mg-doped Ce-Zr solid catalysts [18], Cu(acac)2 [19]. Recentlyionic liquids [bnmim]Cl, C3[min]2.2[Br-] catalyzed synthesis of 5-arylidene-2,4-thiazolidinediones have also been reported [20-21].

However, the above-reported methods suffer from several drawbacks, including prolonged reaction times and the use of environmentally unfavourable solvents. To address these issues, the development of new methodologies in current organic synthesis, mainly focused on the principles of green chemistry, is critical for a sustainable future. Therefore, we decided to explore the potential of our clean and inexpensive catalyst for performing these types of condensation reactions efficiently, aiming to provide a more ecofriendly and cost-effective approach.

The development of FeCl3 and DABCO as a new catalytic system for the Knoevenagel condensation reaction presents a novel approach, utilizing substrates that can serve as valuable intermediates for further transformations. A literature search has revealed some existing reports on the Knoevenagel condensation; however, no previous work has employed ferric chloride FeCl3 and DABCO as a combined catalytic system for this reaction. This innovative methodology has the potential to offer improved efficiency and sustainability in the synthesis of important organic intermediates.

Therefore, we are the first to demonstrate the use of ferric chloride (FeCl3) and DABCO as a catalytic system for the Knoevenagel condensation reaction. To evaluate the applicability of this catalytic methodology, we explored a variety of substituted benzaldehyde, as indicated in Scheme 1. Our final goal was to expand the group of substrates to obtain versatile adducts that can serve as easily transformable intermediates, possessing significant pharmacological activity. This approach aims to develop a more sustainable and efficient method for synthesizing compounds with potential medicinal applications.

Material and Methods

All reactions were carried out in dry solvents, unless otherwise stated. Reactions were monitored by Thin Layer Chromatography (TLC) on silica gel plates (Kieselgel 60 F254, Merck). Visualization of the spots on TLC plates was achieved either by UV light or by staining the plates in 2, 4-dinitrophenylhydrazine/ anisaldehyde and charring on hot plate. All products were characterized by 1H NMR and 13C NMR, IR, Mass and Elemental analysis. 1H NMR and 13C NMR were recorded on Varian Mercury 500 MHz spectrometer. IR spectra were obtained on a Shimadzu FTIR-8400 with samples loaded as thin films on KBr plate, neat or with CH2Cl2 as indicated. Mass spectra were recorded at an ionization potential of 70 eV; Melting points recorded are uncorrected. Column chromatography on silica gel (100-200 mesh) was performed with reagent grade ethyl acetate and hexane as an eluent.

Experimental Section

Typical experimental procedure: In two neck round bottom flask was charged with a mixture of FeCl3 (25 mg, 10 mol%), Benzaldehyde was taken and DABCO (0.010 mg) was added in MeOH 10 mL This mixture was stirred under atmosphere for 10 min then add to it 2, 4-thiazolidinedione and resulting solution was stirred 5h at room temperature till the completion of reaction. The reaction monitored by TLC. The reaction was quenched with a saturated aqueous solution of HCl (2 mL), extracted with ethyl acetate (3 x 20 mL). The combined organic layers were collected and add to it activated charcoal to remove color impurities and filter. The combined organic layer dried using anhydrous Na2SO4, filtered, and the solvent was removed by evaporation. The crude product was purified by crystallization method to afford desired product as colorless solid 5-(4-Chloro-benzylidine)- thiazolidine-2,4-dione (3b) Yield : 89% State : Pale Yellow Solid ,IR (KBr) : 3155, 3049, 879, 2868, 1739, 1691 cm-1, 1HNMR : (500MHz, DMSO)d 13.86 (s, 1H, NH), 8.12 (s, 1H), 7.69-7.57 (m, 4H) 13CNMR : (125MHz, DMSO) d 127.1, 131.8, 132.8, 133.7, 134.8, 134.7, 135.9, ) 171.0, GCMS m/z 237

Result and Discussion

Herein, we performed the Knoevenagel condensation of Benzaldehyde with 2,4-thiazolidinedione in methanol catalysed by Ferric chloride and DABCO as a versatile and effective catalyst the reaction to get 5-arylidene-2, 4-thiazolidinedione with 88 % yield as indicated in Scheme 1.

Optimization of Reaction Conditions

To examine the catalytic efficiency of different transition metal complexes, reaction of benzaldehyde and 2, 4-thiazolidinedione was performed. It is clear that; copper acetyl acetonate promotes reaction more effectively than other transition metal complexes.

The numbers of metal catalysts like CuCl2: DABCO to get desirable product with 82% yield, FeCl3: DABCO, to provided desirable product with 86 % yield, CoCl2: DABCO require longer reaction times with 69% yield, NiCl2: DABCO this catalytic system formation of little amount of side product with less yield (Table 1). The results showed that FeCl3: DABCO is the most efficient catalyst under these conditions and effective for good yield (Table 1 entry 3).

Table 1: Study of Several Transition Metal Based Catalysts for Knoevenagel Condensation.




  
    Entry
    Catalyst
    Time
    Yield (%)b
  
  
    1
    CuCl2 
    12.0 h
    45
  
  
    2
    CuCl2: DABCO
    8.5 h
    60
  
  
    3
    FeCl3 : DABCO
    6.0 h
    89
  
  
    4
    CoCl2: DABCO
    8.0h
    69
  
  
    5
    NiCl2: DABCO
    9.0 h
    65
  
  
    6
    ZnCl2: DABCO
    7.0 h
    58



Table 1: Study of Several Transition Metal Based Catalysts for Knoevenagel
Condensation.

Next, we focused on finding the optimal solvent for synthesizing the target molecule. Initially the model reaction was performed under solvent free condition; low yield of desired product was obtained. The same reaction was performed using different solvents, we performed the model reaction in the presence of various solvents, and the results are summarized in Table 2. We observed that the highest yields were achieved with methanol and ethanol as polar aprotic solvents (Table 2, entries 4 & 5). Among all these solvents, in MeOH maximum yield was obtained hence MeOH was selected as optimal solvent.

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Citation: Padghan SV, Ade S, Chopade M. Ferric Chloride and DABCO as a Versatile and Effective Catalytic System for Synthesis Thiazolidinedione Phamacophore. Austin J Anal Pharm Chem. 2024; 11(2): 1173.

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Entry	R	Product	Time	Yield %b
Entry	R	Product	Time	Yield %b
1	Benzaldehyde	3a	5.0	84
2	4-Chloro Benzaldehyde 1b	3b	4.5	89
3	4-Bromo Benzaldehyde 1c	3c	4.5	89
4	4-Nitrobenzaldehyde 1d	3d	3.0	85
5	3-Nitrobenzaldehyde 1e	3e	3.5	82
6	2-Chlorobenzaldehyde 1f	3f	6.5	80
7	2,4-Chlorobenzaldehyde 1g	3g	8.0	86
8	4-Methoxy benzaldehyde 1h	3h	8.0	86
9	4-Methyl benzaldehyde 1i	3i	7.0	87
aReaction conditions: substituted Benzaldehyde(1mmol), 2,4thiazolidinedione(1mmol), ferric chloride, DABCO, in MeOH, were stirred at room temp, bIsolated Yield.

Ferric Chloride and DABCO as a Versatile and Effective Catalytic System for Synthesis Thiazolidinedione Phamacophore

Abstract

Introduction

Material and Methods

Experimental Section

Result and Discussion

Optimization of Reaction Conditions

Conclusion

Author Statements

Acknowledgement

References