Synthesis of Novel 6-( Substituted benzyl ) imidazo [ 2 , 1-b ] [ 1 , 3 ] thiazole Catalyzed by Polystyrene-Supported Palladium ( II ) Ethylenediamine Complex

O complexo etilenodiamina paládio(II) suportado em polímero, [PS-en-Pd(II)], é um catalisador altamente ativo, usado para a reação de acoplamento de Sonogashira entre um iodeto de arila e brometo de 2-amino-3-(2-propinila)1,3-tiazólio, 3. Esse catalisador heterogêneo de paládio é eficiente, estável e reciclável. A reação do composto 3 com vários iodetos de arila, 4a-f, na presença do complexo [PS-en-Pd(II)] leva à produção dos 6-(benzil)imidazo[2,1-b][1,3]tiazóis, 5a-f.


Introduction
The Sonogashira cross-coupling of aryl halides and terminal alkynes or arylenes is a useful tool for the synthesis of alkyl-aryl and diaryl-substituted acetylenes. 1 Functionalized alkynes are important building blocks for the synthesis of biologically active molecules and, surprisingly, are common structural features of natural products that have been isolated from plants and marine organisms or synthetic drugs. 2 Therefore, the Sonogashira reaction is frequently used as a key step in the synthesis of the pharmaceuticals such as the enediyne antibiotics or the contraceptive pill. 3he reaction is generally carried out in organic solvents such as benzene, toluene, THF, DMF, and dioxane.It requires a base, which is usually an amine such as triethylamine, diethylamine, and diisopropylethylamine.The most widely used catalysts are Pd(PPh 3 ) 2 Cl 2 and Pd(PPh 3 ) 4 in conjunction with copper(I) iodide. 4o extend the Sonogashira reaction for fine chemical applications, numerous studies have been reported in the literature over the last 15 years including the use of a phase transfer agent, 5 reaction in aqueous media or without solvent, 6 reaction in ionic liquids, 7 copper-free versions, 8 and the use of promoters such as Zn, Mg, Sn, and R 4 NI. 9 While these examples contributed to the improvement of the Sonogashira coupling reaction, they remained based on a homogeneous palladium complex catalyst, which makes the separation and recovery of the catalysts tedious, if not impossible, and might result in unacceptable palladium contamination of the products.A way to overcome these difficulties would be the use of a heterogeneous palladium catalyst.Although a great deal of effort has been made to carry out the coupling reaction using immobilized palladium catalysts, 10 what seems to be lacking is the efficiency of the catalytic systems.It is obvious that the heterogeneous catalytic systems generally exhibit lower activities than the homogeneous ones, and the activity of the catalysts decreases gradually in the recycled systems.To overcome this limitation, a novel methodology for creating insoluble and highly active catalysts is needed.Our approach was guided by three imperatives: (i) the support should be easily accessible; (ii) starting with readily available and cheap reagents; and (iii) the ligand anchored on the support should be air stable at room temperature, which should allow its storage in normal bottles with unlimited shelf life.
To date, a few palladium complexes on functionalized polystyrene support have been prepared and successfully used in organic reactions. 11However, to the best of our knowledge, there has been no examples involving arylation of imidazo [1,3]thiazole by [PS-en-Pd(II)] catalyzed (Sonogashira coupling) reactions described to date.
In this paper we wish to report the synthesis of the polystyrene-supported palladium(II) ethylenediamine complex, abbreviated as [PS-en-Pd(II)], 13 and its catalytic properties in the Sonogashira coupling reaction for the synthesis of 6-(substituted benzyl)imidazo [2,1-b][1,3]thiazoles.The supported catalyst could be reused for several times without a significant degradation in its catalytic activity.

Results and Discussion
We used the well known chloromethylated polystyrene cross-linked with 2% divinylbenzene as support because it is flexible enough and allows metallic atoms to graft on it via the ligands that are attached to the polymer beads.Reaction of the polystyrene resin with ethylenediamine in acetonitrile under reflux and the subsequent reaction of the aminated polystyrene with a solution of [PdCl 2 (C 6 H 5 CN) 2 ] in ethanol gave the polymer-supported palladium(II) complex catalyst 1 (Scheme 1).
Successful functionalization of the polymer was confirmed by elemental analysis.The N content of the resin was found to be 2.42% (0.82 mmol g -1 ), which indicates that only 58% of the total chlorines were substituted by amine.The metal loading of the polymer-supported palladium complex, which was determined by neutron activation analysis (NAA), was found to be 4.35% (0.41 mmol g -1 ).In the IR spectrum of the polymer-bound ethylenediamine, the sharp C-Cl peak (due to the −CH 2 Cl groups) at 1264 cm -1 in the starting polymer was practically omitted or was seen as a weak band after introduction of ethylenediamine and palladium onto the polymer.The various IR frequencies for the catalyst were assigned as (Pd−N) ca.506 cm -1 , (C−N) ca.1100 cm -1 , and (N-H) ca.3400 cm -1 .
The presence of electron-withdrawing groups such as -NO 2 , or -Cl on the aryl iodide was essential for successful reaction.When p-iodoanisole or iodobenzene was used as the aryl iodide, Sonogashira coupling did not occur.
For optimization of the reaction conditions, we chose the reaction of 2-amino-3-(2-propynyl)-1,3-thiazolium bromide 3 with 4-chloro-2-nitroiodobenzene 4e as the model reaction, and the effects of the base, solvent, amount of copper(I) iodide, and the catalyst on the catalytic property of the [PS-en-Pd(II)] complex were examined.The results were tabulated in Table 1.
Among the bases tested, triethylamine proved to be the most efficient, and among the solvents used, dimethylformamide was the best choice (entry 3).Increasing the amount of the palladium catalyst could shorten the reaction time but does not increase the yield (entry 10).Low palladium concentration often prolonged the reaction time and decreased the yield (entries 11 and  12).We also found that with increase in the amount of copper(I) iodide, the reaction yield did not increase (entry 13).No product was obtained under copper-free conditions (entry 14).Copper(I) iodide was found to be an essential co-catalyst.
Subsequently, the reaction of a variety of aryl iodides, 4a-f, with 2-amino-3-(2-propynyl)-1,3-thiazolium bromide 3 was studied under the optimal conditions.The reactions had to be carried out under an argon atmosphere, and we had to degas the DMF and triethylamine mixture prior to use.The experimental results were summarized in Table 2.As it could be seen in this table, reaction of the aryl iodides with compound 3 proceeded smoothly under very mild conditions, giving the corresponding products in excellent yields.
The stability of [PS-en-Pd(II)] was studied in the repeated Sonogashira coupling reactions.The coupling reaction of 4-chloro-2-nitroiodobenzene 4e with compound 3 was chosen as a model substrate to study the catalyst reuse and stability.The catalyst was separated from the reaction mixture after each experiment by filtration, washed with acetonitrile, and dried carefully before using it in the subsequent run.The reaction promoted by the 5 th recycled catalyst gave 5e in 80% yield (Table 3, entry 5).
This reusability demonstrates the stability of the heterogeneous catalyst.Although no significant change in the activity of the catalyst was observed, we performed analysis of the catalyst after the 5 th run in order to determine any change in the catalyst structure.The nature of the recovered catalyst was traced by IR spectroscopy.The results indicated that the catalyst showed no change in its IR spectrum after reuse for several times.All reactions were performed using 1.5 mmol of 3, 1.0 mmol of 4-Chloro-2-nitroiodonitrobenzene, 0.08 mmol of PPh 3 , 3.0 mmol of base, and 5 mL of solvent at room temperature.
To determine the absolute amount of the palladium species leached into the solution, the crude reaction mixtures were evaporated to dryness and analyzed by NAA.It was shown that less than 0.5% of the total amount of the original palladium species was lost into the solution during the course of the reaction.

Conclusions
We developed the reusable heterogeneous catalyst [PS-en-Pd(II)] by reacting the commercially available crosslinked chloromethylated polystyrene with ethylenediamine, and the subsequent reaction of the product thus formed with dibenzonitrile palladium chloride.The catalyst is efficient for syntheses of various 6-(substituted benzyl) imidazo [2,1-b][1,3]thiazoles via Sonogashira coupling reaction of aryl iodides with 2-amino-3-(2-propynyl)-1,3thiazolium bromide 3. The advantages of our heterogeneous catalytic system over others are as follow: (i) the catalyst could be conveniently prepared from commercially available reagents; (ii) excellent performance and reusability of the catalyst.

Experimental
All the reagents used were of commercial reagent grade.Chloromethylated polystyrene (4-5% Cl and 2% cross-linked with divinylbenzene) was a Merck product.The scanning electron micrographs of the catalyst and polymer were taken on an SEM Philips XL 30 instrument.IR spectra were obtained as potassium bromide pellets in the range 400-4000 cm -1 on a Shimadzu Model 460 spectrometer. 1H NMR spectra were recorded on a Bruker BRX 500 AVANCE spectrometer.Elemental analysis was performed on a Thermo Finnigan Flash EA microanalyzer.

Table 1 .
Heterocyclization during the Sonogashira coupling of 4-Chloro-2-nitroiodonitrobenzene with compound 3 in the presence of several bases, solvents, and amounts of catalyst a