J IRAN CHEM SOC DOI 10.

1007/s13738-013-0325-2

ORIGINAL PAPER

Microwave-assisted synthesis of ve-membered S-heterocycles

Navjeet Kaur

Received: 3 April 2013 / Accepted: 27 July 2013 Iranian Chemical Society 2013

Abstract The development of new strategies for synthesis of ve-membered S-heterocycles has remained a highly attractive but challenging proposition. An overview of the application of microwave irradiation in sulfur-containing ve-membered heterocyclic compounds synthesis is presented, focusing on the developments in the last 510 years. This contribution covers the literature concerning the total synthesis of ve-membered S-heterocycles under microwave and combined effect of microwave and solid-phase. Keywords Microwave-assisted synthesis Heterocycles Sulfur

Introduction For more than a century, heterocycles have constituted one of the largest areas of research in organic chemistry. Heterocyclic compounds have always been on the forefront of attention due to their numerous uses in pharmaceutical applications [1]. Among them, sulfur-containing heterocyclic compounds have maintained the interest of researchers and their unique structures have led to several applications in different areas. Due to the widespread interest in heterocycles, the synthesis of these compounds has always been among the most important research areas in synthetic chemistry [2]. In many cases, the classic syntheses provide reliable access to heterocyclic compounds, however, they are simply no longer acceptable by current
N. Kaur (&) Department of Chemistry, Banasthali University, Banasthali, Rajasthan 304022, India e-mail: nvjithaans@gmail.com

environmental and safety standards. For all these reasons, the various possibilities offered by the microwave technology are particularly attractive where fast, high-yielding protocols and the avoidance or facilitation of purication are highly desirable [3]. S-containing heteroaromatics are important substructures found in numerous natural or synthetic alkaloids. The diversity of the structures encountered, as well as their biological and pharmaceutical relevance, has motivated research aimed at the development of new economical, efcient and selective synthetic strategies to access these compounds. A diverse array of S-containing ve-membered heterocycles has been constructed in higher yields and shorter reaction times as compared to conventional conditions [4]. The importance of sulfur-containing heterocyclic compounds for biomedical [5] and material science applications [6] has led to an increase in the number of synthetic methods available for the preparation of this type of heterocyclic compounds [7, 8]. Since organic sulfur compounds have become increasingly useful, development of convenient and practical synthetic methods for these compounds is highly desirable. Five-membered [9] S-heterocycles constitute an important structural component of a diverse range of biologically active natural compounds and pharmaceuticals [10, 11]. Consequently, the synthesis of ve-membered rings has posed a signicantly greater challenge in comparison to the construction of their large ring counterparts [12]. According to the concept of green chemistry, energy requirements of chemical processes should be minimized. Microwave-assisted synthesis has provided signicant energy saving for the chemical transformations in comparison with conventional oil-bath heating. Reusability, stability and ease of handling are the signicant points of

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solid-supported reagents, which make them an interesting eld for an organic chemist. The combination of microwave (MW) irradiation with solid-supported reagent becomes an interesting and popular theme in synthetic organic chemistry [1315]. In recent decades, a large number of reports related to synthesis of S-containing heterocycles have appeared owing to a wide variety of their biological activity. In recent years, numerous reports concerning the synthesis of heterocycles under solvent-free, reactants immobilized on solid support, microwave irradiation conditions have appeared. In this review, we report the important role of solvent-free condition coupled with microwave activation and their advantages in the synthesis of sulfur-containing ve-membered heterocyclic compounds. Microwave-assisted synthesis of sulfur-containing ve-membered heterocyclic compounds: synthesis of S-heterocycles Synthesis of benzothiophenes Pyridobenzimidazoles were synthesized in very good to excellent yields by the condensation of substituted N-phenyl-o-phenylenediamines with indole/benzo[b]thiophene3-aldehydes in methoxyethanol under reux conditions. The diamines were prepared by rst treating 2-chloro-3nitropyridine with suitably substituted anilines then reducing the resulting 3-nitro-N-phenylpyridin-2-amines with tin(II)chloride using microwave heating in each case. Pyridobenzimidazoles were prepared as shown in Scheme 1. In the rst step, 3-nitro-2-chloropyridine and appropriate anilines were converted to the corresponding 3-nitro-2-(N-phenylamino)pyridines by a nucleophilic substitution reaction in nearly quantitative yields using microwave (MW) heating for 10 min at 110 C under solvent-free conditions. Using conventional heating and dimethyl sulfoxide as a solvent, the nitro amines were obtained in lower yields (6070 %) and signicantly longer reaction times were required. In the third step, the amines were condensed with substituted indole/benzo[b]thiophene-3-aldehydes at elevated temperature (125 C) in the presence of methoxyethanol as a solvent to give the pyridobenzimidazoles in good to excellent yields (8196 %) [16]. Kini et al. [17] synthesised benzimidazolo benzothiophenes by liquid-phase combinatorial synthesis using soluble polymer support PEG 5000 and 4-uoro-3-nitrobenzoic acid as starting materials with substituted primary amines (Scheme 2). They rst reacted the polymer-bound diamino compound, dissolved in dichloromethane, with 1.2 mol of 4-mercaptobenzoic acid (MBA), 1.2 mol of

DCC and a pinch of DMAP in the microwave for 20 min to afford PEG-bound compound. The solution was ltered to remove the excess of DCC and DMAP salts. PEG-bound 3-amino-4-mercapto benzene was then treated with triuoroacetic acid and ethylene dichloride in the ratio of 1:10 and was subjected to microwave irradiation for 20 min to precipitate the PEG-bound 2-substituted benzimidazole. The solution of PEG-bound mercaptobenzimidazole was treated with chloroacetone, triethylamine in dichloromethane and heated under microwave irradiation for about 10 min. After completion of the reaction, the reaction mixture was directly treated with cold diethyl ether to precipitate the product. The polyethylene glycol was cleaved from the PEG-bound compound using methanol and sodium methoxide to give compound. 1-Substituted-2(4-aceto-methyl-thio-phenyl)-1 H -benzoimidazole-5carboxylic acid methyl ester is treated with polyphosphoric acid (PPA) and heated on a water bath for 4 h to form 1-substituted-2-(3-methyl-benzo[b]thiophen-6-yl)-3Hbenzoimidazole-5-carboxylic acid methyl ester. Efcient formation of heterocyclic rings via cycloaddition continues to be of great interest for organic chemists. This method includes a three-component reaction to form 2-amino-benzothiophenes via microwave reactions. The use of the microwave greatly increased yields and shortened reaction times. A limiting requirement for activation of this reaction is the need for the presence of the nitro group para to the chloride substituent, as it was observed that no reaction took place when the nitro group was absent. In addition, if the sulfur was not added, a simple SNAr reaction takes place whereby the amine displaces the chloride (Scheme 3) [18]. Interestingly, when NH4Cl was used as the amine source the expected 2-aminobenzothiophene product was not observed, but instead a 3-methylbenzoisothiazole product was obtained in 90 % yield (Scheme 4) [19]. Synthesis of thiolanes The synthesis of dithiolanes and oxathiolanes was performed by Hamelin et al. [20]. Employing the Synthewave S1000 apparatus from Prolabo, the authors investigated the synthesis of the protected carbonyls on a 2-mol scale under open vessel conditions employing highboiling glycols and K-10, an acidic clay, as a catalyst (Scheme 5). Proving that the reaction conditions (regarding time and temperature) were exactly the same going from 10-mmol to a 2-mol scale, they observed an easier workup for the large-scale experiments owing to the possibility of removing the formed alcohol by continuous distillation under microwave irradiation in the Synthewave S1000.

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J IRAN CHEM SOC Scheme 1 .

Scheme 2 .

Scheme 3 .

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J IRAN CHEM SOC Scheme 4 .

Scheme 5 .

Synthesis of thiophenes The microwave-enhanced synthesis of 2-chloro-3-formylbenzo [1,8]naphthyridines has been achieved rapidly in good yield via the VilsmeierHaack cyclisation of N-(4methylquinoline-2-yl)acetamide by adding POCl3 to the substrate in DMF with good yield of 9095 % in a short reaction time. The required key intermediate N-(4-methylquinolin-2-yl)acetamide has been synthesized by the reaction of 2-amino-4-methylquinoline and acetic anhydride in the presence of Amberlite-120A catalyst in microwave irradiation. Condensation of 2-chloro-3-formylbenzo [1,8]naphthyridines with thioglycolic acid under microwave irradiation using anhydrous potassium carbonate as catalyst afforded thieno[2,3-b]benzo [1,8]naphthyridine-2-carboxylic acids (Scheme 6) [21]. Biehls group has made further explorations on these results and extended the method to include preparations of

pyridino-thiophenes and pyridino-isothiazoles, starting with 1-(2-chloropyridin-3-yl)-1-ethanone. In the case of the pyridine-containing scaffolds, the nitro group is not a necessity. Future work will likely involve preparation of other pyridino-thiophenes where the pyridyl nitrogen is located at other positions (Scheme 7) [22]. Treatment of starting compound with benzenediazonium chloride gave thiazepine reaction product. As a possible sequence for the formation of 6-hydroxy-4-methyl-2(phenylazo)thieno[2,3-b]pyridin-3(2H)-one from starting compound, the latter compounds rstly underwent coupling at position 2 to give the corresponding 2-arylazo derivative. Compound 2-arylazo underwent hydrolysis and formed compound underwent cyclization followed by deacylation to give 6-hydroxy-4-methyl-2-(phenylazo)thieno[2,3-b]pyridin-3(2H)-one as shown in Scheme 8 [23]. The most convergent and well-established classical approach for the preparation of 2-aminothiophenes is the

Scheme 6 .

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J IRAN CHEM SOC Scheme 7 .

Scheme 8 .

Gewalds method, which involves a multicomponent condensation of a ketone with an activated nitrile and elemental sulfur in the presence of morpholine as a catalyst [24]. Sridhar et al. [25] applied KF-alumina as a solid base catalyst for the preparation of 2-aminothiophenes by a microwave-accelerated multi-component condensation (Scheme 9). The method is an efcient and convenient modication of the Gewald reaction as it could be carried out in short reaction times under microwave irradiation. Similarly, Huang et al. [26] reported a microwave-assisted synthesis of 2-amino-thiophene-3-carboxylic acid derivatives under solvent-free conditions using the same reagents with silica or alumina as the solid catalyst. Vaghasia and Shah [27] described that the synthesis of thiazolo 5,4-dpyrimidines can be achieved from different 5-thiazolidinones, 2-butyl-1H-imidazole-5-carbaldehyde and thiourea using microwave irradiation within 5 min. The in vitro antimicrobial activity of the synthesized thiazolo 5,4-dpyrimidines, having substituents at the 1- and 3-positions, was determined by the cup-plate method against several standard strains chosen to dene the spectrum and potency of the new compounds. The antimicrobial activities of the thiazolo 5,4-dpyrimidines are compared with those of known chosen standard drugs, viz. ampicillin, chloramphenicol, ciprooxacin, noroxacin and griseofulvin (Scheme 10) [28]. Due to their relevant electronic and optical features, oligothiophenes are among the most important and widely

studied organic materials. Barbarella et al. [29] developed a synthesis of thiophene oligomers under microwave irradiation in the liquid phase and under solvent-free conditions [30]. As an extension, a heterogeneous procedure was reported for the preparation of highly pure thiophene oligomers via microwave-assisted Pd catalysis using silica- and chitosan-supported Pd complexes [31]. Their approach was more efcient and greener than the existing homogeneous methodology as it combined a high-yield reaction with improved catalyst separation. The microwave-assisted approach afforded the selective preparation of the coupled products in high yields (up to 87 % isolated yield, 30100 min.) (Scheme 11). The Suzuki coupling reaction has been transferred to microwave conditions by Barbarella et al. [30] for the preparation of thiophene oligomers. The synthesis of quinquethiophenes, for example, was achieved from bulk conditions of 2-thiophene boronic acid and dibromo precursors with three thiophene units, catalyzed and promoted by [PdCl2(dppf)], KF, and KOH. With a maximum temperature of 70 C, yields of 74 % were obtained after reaction times of 10 min (Scheme 12) [32]. An efcient and highly versatile microwave-assisted PaalKnorr condensation of various 1,4-diketones gave furans, pyrroles and thiophenes in good yields. In addition, transformations of the methoxycarbonyl moiety, such as Curtius rearrangement, hydrolysis to carboxylic acid, or the conversion into amine by reaction with a primary amine in the presence of Me3Al, are described (Scheme 13) [33].

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Scheme 9 .

Scheme 10 .

Scheme 11 .

Scheme 12 .

Huang et al. [26] have reported a simple and convenient synthesis of thiophene derivatives via a solvent-free microwave-assisted reaction. The microwave irradiation of cyanoacetamides with cyclohexanone, sulfur, and aluminum oxide as a solid support in the presence of morpholine as a basic catalyst under solvent-free conditions for several minutes gave thiophene derivatives in high yields (Scheme 14) [34]. The rise of microwave-mediated chemistry recently renewed interest in the development of rapid and efcient variations of the classical Gewald synthesis [25, 3538]. An one-pot procedure for the rapid generation of benzo[b]thiophene from activated nitriles employing

elemental sulfur has been reported. Following a simplied Gewald protocol, a mixture of an appropriate ketone, an activated nitrile and elemental sulfur, was heated to 120 C for 10 min in ethanol as the solvent in the presence of morpholine, acting as organic base (Scheme 15). The use of the nitriles gives immediate access to the desired 2-amino derivatives without any further transformation steps thus avoiding the need to introduce an amino group into an existing thiophene scaffold [39]. The synthesis of new compounds containing thiophene nucleus with furan in one framework has been reported by Iqbal et al. [40]. They have synthesized 2-substituted amino-3-(N-furfuryl amido)-4,5-dimethyl thiophene as the

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Scheme 13 .

Scheme 14 . Scheme 15 .

Scheme 16 .

starting compound, and derivatized the starting compound to various 2-substituted amino-3-(N-furfuryl amido)-4,5dimethyl thiophenes. The parent compound 2-amino-3-(N-

furfuryl amido)-4,5-dimethyl thiophene was synthesized by condensing butan-2-one with furfurylcyano acetamide in the presence of sulphur and diethylamine. It was then

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J IRAN CHEM SOC Scheme 17 .

Scheme 18 . Scheme 19 .

derivatized to various Schiff bases by reacting with various substituted aromatic aldehydes (Scheme 16). Lindsley et al. [41, 42] developed a general procedure towards the collection of diverse heterocyclic scaffolds from common 1,2-diketone intermediates. Substituted thieno[3,4-b]pyrazines have been prepared in excellent yields (Scheme 17). The use of microwave irradiation resulted in reduced reaction times, improved yields as well as the suppressed formation of polymeric species; a characteristic of traditional thermal conditions. Thus, in contrast to heating in an oil bath (at 5070 C) and even to the room temperature reactions, microwave irradiation at 160 C for 5 min afforded thieno[3,4-b]pyrazine in 72 % yield with no detectable polymerization side-product. The reaction between aldehyde and thioglycolic acid in reuxing ethanol containing sodium hydroxide and potassium iodide, afforded a mixture of [(3-formylquinolin-2yl)thio]acetic acids and thieno[2,3-b]quinoline-2-carboxylic acids. The uncyclized compounds, on reuxing with POCl3 in various alcoholic media, gave [(3-formylquinolin-2-yl)thio]acetates. Further cyclization was achieved by reuxing them with DMF to produce thieno[2,3-b]quinoline derivatives. On the other hand, thieno[2,3-b]quinoline2-carboxylic acids and its alkyl esters were synthesized by condensation of aldehyde with thioglycolic acid/alkyl esters under microwave irradiation using anhydrous potassium carbonate (Scheme 18) [43, 44].

Synthesis of S, N-heterocycles Synthesis of benzothiazoles A mild and efcient method was developed for the preparation of 2-arylbenzothiazoles in the presence of a catalytic amount of Cu1.5PMo12O40/SiO2 under microwaveassisted and solvent-free conditions. The catalyst could be reused several times but loss of activity was observed (Scheme 19) [45, 46]. Benzothiazoles were obtained by a direct cyclocondensation of 2-aminothiophenol with a variety of carboxylic acids in the absence of any catalyst or dehydrating agent. The heterocycles were readily formed within 20 min in a microwave oven [47]. Although direct comparison with the conventional thermal conditions was not made, reported literature precedents employed oil-bath heating of aminothiophenol with carboxylic acid at 220 C for 4 h in the presence of polyphosphoric acid [48] or P2O5MeSO3H (70 C, 10 h) [49]. Consequently, the microwave methodology rendered clear advantages both in terms of reaction speed and milder conditions. A variety of carboxylic acids (aromatic, heteroaromatic, a, b-unsaturated, arylalkyl and cycloalkylcarboxylic acids) could be used and the reaction conditions were compatible with different functional groups such as chlorine, methoxy, phenoxy and thiophenoxy moieties. Bis-benzothiazoles could be obtained in the

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J IRAN CHEM SOC Scheme 20 .

Scheme 21 .

Scheme 22 . Scheme 23 .

reaction with succinic and phthalic acids. Reduction of the reaction time was achieved using microwave dielectric heating in the synthesis of 2-cyanobenzothiazoles from anilines and 4,5-dichloro-1,2,3-dithiazolium chloride [50, 51]. Mn(OAc)3 promoted the radical-mediated cyclization of aryl- and benzoyl-thioformanilides. The reaction required microwave heating in acetic acid at 110 C for 6 min to furnish a number of 2-substituted benzothiazoles. The reactions in an oil bath needed 610 h to obtain comparable yields (Scheme 20). An efcient and extremely fast procedure for the synthesis of 4-thiazolidinones by the reaction of arylidene-[(2-benzothiazolylthio)-acetamidyl] with thioglycolic acid in DMF in the presence of a catalytic amount of anhydrous ZnCl2 under microwave irradiation is described. A considerable increase in the reaction rate has been observed with better yield in microwave technique. Condensation of 2-mercaptobenzothiazole with ethyl chloroacetate in dry acetone gave ethyl-2-(benzothiazolylthio)-acetate. The compound ethyl-

2-(benzothiazolylthio)-acetate on aminolysis with hydrazine hydrate in ethanol yielded [2-(benzothiazolylthio)-acetyl]hydrazine. Compound [2-(benzothiazolylthio)-acetyl]hydrazine underwent condensation with different carbonyls to afford the arylidene-[2-(benzothiazolylthio)-acetamidyl]. These intermediates on reaction with thioglycollic acid and anhydrous ZnCl2 in DMF yielded ve-membered sulfurcontaining heterocyclic derivatives 2-(aryl)-3-[2-(benzothiazolylthio)-acetamidyl]-4-oxo-thiazolidines. All the reactions under microwave irradiation (MWI) were completed within 25 min., whereas similar reactions under conventional heating at similar temperature (80100 C) gave poor yields with comparatively longer reaction time periods (Scheme 21) [52]. Baltork et al. [53] developed a very simple and convenient protocol for the synthesis of 2-substituted benzoxazoles, benzothiazoles, benzimidazoles, and oxazolo[4,5b]pyridines using catalytic amounts of Bi(III) salts under solvent-free conditions (Scheme 22).

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Scheme 24 .

Scheme 25 .

Scheme 26 .

Scheme 27 .

Seijas et al. [54] have developed Lawessons reagent (LW) and microwaves for the efcient access to benzothiazoles from carboxylic acids under solvent-free conditions (Scheme 23). Ring closure reactions of appropriate o-substituted anilines to give benzothiazoles takes place much faster and in

signicantly high yield under microwave conditions than conventionally. Triuoroacetyl ketene diethyl acetal was successively condensed with 2-aminothiophenol in the presence of toluene in a multimode microwave oven to give the 2-(1,1,1-triuoroacetonyl) benzothiazole ring in an excellent yield (Scheme 24) [55, 56].

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J IRAN CHEM SOC Scheme 28 .

Scheme 29 .

A series of various substituted benzothiazole derivatives containing 7-chloro-6-uoro-2-chloroacetamidobenzothiazole derivatives was synthesized. The compound 2-aminobenzothiazole is a versatile material for a number of synthesis. 7-chloro-6-uorobenzothiazole-2-yl amine was synthesized from 3-chloro-4-uoro phenylamine by reacting with potassium thiocyanate and bromine solution in glacial acetic acid. The obtained 7-chloro-6-uorobenzothiazole-2-yl-amine was made to react with chloroacetyl chloride in the presence of ethanol to give 7-chloro-6-uoro-2-chloroacetamidobenzothiazole (Scheme 25). 7-Chloro-6-uorobenzothiaozol-2-ylamine was synthesized from 7-chloro-6-uoro-2-chloroacetamidobenzothiazole by reuxing for 2 h in the presence of DMF by microwave method [57]. Synthesis of benzothiazoles under microwave irradiation has been reported from dithiazoles in NMP at 150 C in only 0.53 min (Scheme 26) [50]. 2-Bromo-7-formyl-9,9-diethyluorene and 2-aminothiophenol were condensed to form 2-(7-bromo-9,9-diethyl-2uorenyl)benzothiazole. 2-(7-Bromo-9,9-diethyl-2-uorenyl)benzothiazole reacted with 3-hydroxydiphenylamine, in the presence of Pd(dba)2 and diphenylphosphinoferrocene to form 2-(7-(3-benzyloxydiphenylamino)-9,9-diethyl-2-uorenyl))benzothiazole then the compound was debenzylated to give 2-(7-(3-hydroxydiphenylamino)-9,9-diethyl-2-uorenyl)benzothiazole (Scheme 27) [58]. Benzothiazoles were obtained by a direct cyclocondensation of 2-aminothiophenol with a variety of carboxylic acids in the absence of any catalyst or dehydrating agent. However, some of these methods suffer from one or more of the disadvantages such as high thermal conditions, long reaction time, sometimes require excess of reagents and use of toxic metallic compounds that result in waste streams. Although direct comparison with the conventional thermal conditions was not made, reported literature precedents employed oil-bath heating of aminothiophenol with carboxylic acid at 220 C for 4 h in the presence of polyphosphoric acid [48] or P2O5MeSO3H (70 C, 10 h) [59]. Consequently, the microwave methodology rendered clear advantages both in terms of reaction speed and milder conditions. One of the published microwave-assisted

synthesis of benzothiazoles is the condensation of a dinucleophile such as 2-aminothiophenol, with an ortho-ester in the presence of KSF clay in a monomode microwave reactor operating at 60 W under a nitrogen atmosphere [60] (Scheme 28). Solvent-free microwave-assisted syntheses of benzothiazoles were also described by attack of the dinucleophiles on benzaldehydes and benzaldoximines (Schemes 29, 30) [61]. Condensation of 2-aminothiophenol with the b-chlorocinnamaldehyde in the presence of p-toluene sulphonic acid (p-TSA) gave moderate yield of benzothiazoles (Scheme 31) [62]. Manganese (III)-promoted radical cyclization of arylthioformanilides and a-benzoyl thioformanilides is a recently described microwave-assisted example for the synthesis of 2-arylbenzothiazoles and 2-benzoylbenzothiazoles [63] (Scheme 32). In this study, manganese triacetate is introduced as a new reagent to replace potassium ferricyanide or bromide. The 2-substituted benzothiazoles are generated in 6 min at 110 C under microwave irradiation (300 W) in a domestic oven with no real control of the temperature (reux of acetic acid). Conventional heating (oil bath) of the reaction at 110 C for 6 h gave similar yields. Manganese (III) triacetate [64] was found to be an excellent one-electron oxidant that has been widely employed to produce free radicals for cyclization reactions. Arylthioformanilides were treated [6567] with manganese triacetate dihydrate Mn(OAc)32H2O in acetic acid under microwave irradiation, and the reaction was complete within 6 min to afford 2-arylbenzothiazoles (Scheme 33). Recently, some methods use microwave heating for the synthesis of 2-substituted benzothiazoles such as condensation of aromatic or aliphatic aldehydes with 2-aminothiophenol on SiO2 [68] (Scheme 34), aromatic aldehydes with 2-aminothiophenol in the presence of nitrobenzene/ SiO2 or nitrobenzene/montmorillonite K-10, [69] or carboxylic acids [70] (Scheme 35). Recently 2-substituted benzothiazoles under solventfree microwave-assisted conditions have also synthesized (Scheme 36) [71, 72].

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Scheme 30 .

Scheme 31 .

Scheme 32 .

Scheme 33 .

Scheme 34 .

Scheme 35 .

Scheme 36 .

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The group of Besson [73, 74] has exemplied the preparation of sulfur-containing aromatic heterocycles via an intramolecular aryl sulfur coupling to establish a benzothiazol substructure during a multi-step synthesis. All reactions were duplicated using conventional heating (oil bath) at reux temperature and produced similar yields after 4560 min. Sulfonylation of arenes is normally carried out using sulfonyl chloride and a stoichiometric amount of Lewis or Bronstedt acids as the catalyst. Dubac et al. [75] discovered a practical method using microwave high-temperature conditions that demanded only 510 mol % of FeCl3 (in relation to the sulfonyl chloride) for full conversion. Arenes encompassing alkylbenzenes, anisole and halobenzenes were sulfonylated using different arylsulfonyl chlorides. The sulfonylations generally proceeded with good para-regioselectivity, with the electron-rich bromoanisole substrate being an exception (Scheme 37). Fusion of the thiazole ring onto the heterocyclic skeletons suggested the use of imino-1,2,3-dithiazoles which have proved to be highly versatile intermediates in heterocyclic synthesis, undergoing a variety of reactions initiated by nucleophilic attack at different sites on the dithiazole ring [76, 77]. 5-(N-Arylimino)-4-chloro-5H-1,2,3-dithiazoles are stable crystalline solids, cyclized by vigorous heating to give sulphur, hydrogen chloride, and 2-cyanobenzothiazoles. It was also shown that electron-releasing groups favoured formation of the benzothiazole whilst a strong electronwithdrawing group reduced the yield of benzothiazole dramatically in favour of the cyanoimidoyl chloride, which became the major product. The traditional thermolysis procedures consisted of heating the neat imines under argon at 200250 C with a metal bath for 1 or 2 min. Various methodologies under conventional conditions or microwave irradiation were also developed in our group. Whatever method was used, the microwave procedures were more

rapid than the purely thermal processes but the amount of the desired benzothiazoles was constant and scaling up the quantity of starting material led to lowest yields of products, accompanied by complicated mixtures of carbonaceous compounds and impurities (Scheme 38) [78]. A series of new 4H-pyrimido[2,1-b]benzothiazole-2arylamino-3-cyano-4-ones has been synthesized by the application of microwave-assisted organic synthesis technique (Scheme 39). A literature survey revealed reports on the synthesis of fused pyrimido benzthiazole derivatives [79, 80]. The key intermediate 4H-pyrimido[2,1-b]benzothiazole-2-thiomethyl-3-cyano-4-one was prepared by following a known method [81]. The nucleophilic substitution of its thiomethyl group with different aryl amines resulted in the formation of 4H-pyrimido[2,1-b]benzothiazole-2-arylamino-3-cyano-4-ones [82]. Synthesis of thiazoles Investigations have shown that the MMS product formed between an aromatic aldehyde, aniline and mercaptoacetic acid is controlled by the nature of the solvent and substituents effects of the reaction components [83]. Thus, the reaction shown in Scheme 40 in benzene, dichloromethane, DMF and THF produced thiazolidinones. With aromatic aldehydes containing electron-withdrawing substituents produced thiazolidinones [84]. The green chemoselective synthesis of thiazolo[3,2a]pyridine derivatives was achieved by the Tu group [85] recently. The MCR of malononitrile, aromatic aldehydes and 2-mercaptoacetic acid was preformed to produce two different products by controlling the molar ratios of the starting materials. These products have been screened for their antioxidant activity and cytotoxicity in carcinoma HCT-116 cells and mice lymphocytes. Nearly all of the

Scheme 37 .

Scheme 38 .

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Scheme 39 .

Scheme 40 .

Scheme 41 .

tested compounds possessed potent antioxidant activity (Scheme 41) [86]. A straightforward approach to novel (5-nitropyridin-2yl)alkyl and (5-nitropyridin-3-yl)alkyl carbamate building blocks is presented in this study. Their construction is achieved by condensation of N-carbamate R- and -amino carbonyl derivatives with 1-methyl-3,5-dinitro-2-pyridone under microwave irradiation. The condensation of the pyridone with the methyl ketone was initially chosen to dene an optimal and general protocol. When a mixture of pyridone and methyl ketone was heated under conventional

thermal conditions in the presence of NH3 in methanol at 90 C for 20 min and good to excellent yields were obtained for ve-membered nitrogen-containing rings (Scheme 42) [87]. When equimolar solution of N1-(20 -amino-50 -methylene)0 0 0 1 ,3 ,4 -thiadiazole-2-methyl-benzimidazole and benzaldehyde in methanol with 45 drops of glacial acetic acid was subjected to microwave irradiation in the resonance cavity of the microwave power system for 1.30 min, N1(2-benzylidene-imino-50 -methylene)-10 ,30 ,40 -thiadiazole]2-methyl-benzimidazole resulted. N-[20 -{2-phenyl-1,

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3-thiazolidin-4-one}-5 0 -methylene-1 0 ,30 ,40 -thiadiazole]2-methyl-benzimidazole was formed when the equimolar solution of N1-(2-benzylidene-imino-50 -methylene)-10 , 30 ,40 -thiadiazole]-2-methyl-benzimidazole and mercaptoacetic acid with a pinch of anhydrous ZnCl2 in methanol was subjected to microwave irradiation for about 8 min. The equimolar solution of compound formed and benzaldehyde in methanol in the presence of sodium ethoxide resulted in the product N1-[20 -{2-phenyl-5-benzylidene1,3-thiazolidin-4-one}-50 -methylene-10 ,30 ,40 -thiadiazole]2-methyl-1,3-benzimidazole under microwave irradiation at 300 W for about 5 min (Scheme 43) [28]. Liu et al. [87] have developed a single-step process for the preparation of 2-amino-7-chlorothiazolo[5,4-d]pyrimidines, it was synthesized by the reaction of the commercially available 4,6-dichloro-5-aminopyrimidine with isothiocyanates. Such intermediates reacted with alkyl or arylamine
Scheme 42 .

nucleophiles to afford novel, differentially functionalized 2,7-diaminothiazolo[5,4-d]pyrimidines (Scheme 44). A simple, efcient and practical approach for the synthesis of thiazoline derivatives using Dowex-50W ion exchange resin as ecofriendly catalysts with high catalytic activity under solvent-free conditions has been reported. Dowex-50W ion exchange resin catalyzed the condensation of 2-aminoethanthiol and a wide range of aromatic nitriles under solvent-free conditions at 80 C. In these experiments, the isolation of the catalyst from reaction mixture could be easily performed by its suspension in EtOH. The used catalyst was dried at 50 C for 1 h and then reloaded with fresh reagents for further runs. Apparently, recycling of catalyst is possible for four successive times without signicant loss of activity. Finally, it should be mentioned when reactions were carried out in the absence of catalyst for long period of time (12 h) and in

Scheme 43 .

Scheme 44 .

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solvent-free conditions at 80 C the yields of products were low (\40 %) (Scheme 45) [88]. A novel one-step synthesis of thiazolo-[3,2-b]-1,2,4triazoles was reported from the reaction of chalcones with bis-(1,2,4-triazolyl)-sulfoxide (Scheme 46) [89]. Broadening the scope of thiazole synthesis by the application of microwave technology Zhao et al. [90] developed the rapid synthesis of diverse 2,4-disubstitutedthiazoles in excellent yield and purity. They were prepared from the condensation of thiosemicarbazide with chloroacetic acid under microwave irradiation in a solventless system by Heravi et al. [91] (Scheme 47). Heravi et al. [92] reported the synthesis of [1,3,4]-thiadiazolo[2,3-c][1,2,4]-triazin-4-ones in one-pot condensation and cyclization of 4-amino-[1,2,4]triazine-3-thione-5Scheme 45 .

ones with various aromatic carboxylic acids in the presence of silica-gel/sulfuric acid in solventless condition (Scheme 48). Rao et al. [93] has described the microwave-assisted synthesis of 1H,3H-thiazolo[3,4-a]benzimidazoles, 2-aryl1-benzylbenzimidazoles and 2,3-diaryl-1,3-thiazolidin-4ones, which achieved reductions in reduced reaction times, higher yields, cleaner reactions than for the previously described synthetic processes. In some cases eco-friendly solventless methodology has been used (Scheme 49). Comparative study results obtained by microwaveassisted synthesis versus conventional heating method are that some reactions which required 47 h by conventional method were completed within 25 min by the microwave irradiation technique and yields were improved from

Scheme 46 .

Scheme 47 .

Scheme 48 .

Scheme 49 .

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6174 % to 8393 %. An equimolar mixture of benzotriazole and 1-bromo-3-chloropropane was subjected to microwave irradiation for 2.5 min. The obtained product and hydrazine hydrate were placed in a microwave oven for 3.0 min., furnished product from this reaction was further reacted with benzaldehyde in the presence of a catalytic amount of glacial acetic acid. The resulting crude product was puried by passing it through a chromatographic column packed with silica gel using

chloroform:methanol and on further reaction with SHCH2COOH with a pinch of anhy. ZnCl2 was subjected to microwave irradiation for 3 min to give thiazole derivative (Scheme 50) [94]. A series of new phenothiazinyl-thiazolyl-hydrazine derivatives was synthesized by Hantzsch cyclization of 1-(10-ethyl-10H-phenothiazin-3-yl)-methylidene-thiosemicarbazide with a-halocarbonyl derivatives. Comparison between classical and microwave-assisted synthesis

Scheme 50 .

Scheme 51 .

Scheme 52 .

Scheme 53 .

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emphasizes the great advantages induced by microwaves irradiation which afforded high reaction yields in much shorter reaction time. Acetylhydrazides were obtained in high yields by stirring with acetic anhydride for 15 min at reux, in the presence of catalytic amounts of pyridine (Scheme 51) [95].

A novel and ecofriendly method for the synthesis of thiazolo[3,2-b][1,2,4]-triazoles from 3-mercapto-[1,2,4]triazole and allyl bromide in the presence of acidic silica was also reported (Scheme 52) [96]. A heterogeneous catalytic method for the preparation of 2-substituted-1,3-thiazolines was also recently reported.

Scheme 54 .

Scheme 55 .

Scheme 56 .

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The use of silica-supported 12-tungstophosphoric acid (TPASiO2) as non-toxic, recoverable and reusable heterogeneous catalyst makes this procedure environmentally friendly and economically advantageous (Scheme 53) [97]. Flouro chloro benzimidazolo-substituted thiazolidinone derivatives were synthesized by reacting 3-chloro, 4-ouro ortho phenylenediamine with para amino benzoic acid and followed by different aromatic aldehyde and thioglycolic acid in the presence of aluminium chloride. 2-substituted 3-(4-(4-chloro-5-uoro-1H-benzo[d]imidazol-2yl)phenyl) thiazolidin-4-one are synthesized using three steps: Synthesis of 4-(4-chloro-5-uoro-1H-benzo[d]imidazol-2-yl) benzenamine, synthesis of 2-substituted schiffs base and nally synthesis of 2-substituted 3-(4-(4-chloro-5-uoro1H-benzo[d]imidazol-2-yl)phenyl)thiazolidin-4-one. The intermediate compound was prepared by substituting different aromatic aldehydes with amine of 4-(4-chloro-5uoro-1H-benzo[d]imidazol-2-yl)benzenamine and thioglycolic acid using conventional and microwave method according to the literature (Scheme 54) [98]. An elegant microwave-assisted environmentally benign approach to the synthesis of novel 30 -[40 -N-{4-methyl-2pyrimidinyl}-benzenesuphonamido]-spiro-(3H-indol-3,20 thiazolidin)-1H-2,40 (5H)-dione and their Mannichs bases has been described. Treatment of isatin with sulphamerazine yielded 4-[1,2-dihydro-2-oxo-3H-indol-3-ylidene]amino]-

N(4-methyl-2-pyrimidinyl)benzenesulfonamide. Cyclocondensation of its azomethine function with mercaptoacetic acid over basic alumina afforded 3,-[4-N{4-methyl-2-pyrimidinyl}-benzenesulphonamido]-spiro-(3 H -indol-3,2 0 thiazolidin)-1H-2,40 (5H)dione) which reacted smoothly with secondary amines and formaldehyde to give Mannichs bases in excellent yield (Scheme 55) [99]. The Vilsmeier reaction of acetophenone phenyl hydrazones resulted in the formation of pyrazole-4-carbaldehyde. This inspired the synthesis of 3-(4-nitrophenyl)-1(pyridin-4-ylcarbonyl)-1H-pyrazole-4-carbaldehyde using VilsmeierHaack complex from N0 -[1-(4-nitrophenyl)ethylidene] benzohydrazide. 1,3-Thiazolidin-4-one derivatives are formed, when a carbaldehydes were treated with different amines and thioglycolic acid. Thus, 3-(4-nitrophenyl)-1-(pyridin-4-ylcarbonyl)-1H-pyrazole-4-carbaldehyde when reacted with different substituted amines and thioglycolic acid in the presence of toluene afforded the desired 3-substituted-1, 3-thiazolidin-4-ones (Scheme 56) [100]. A simple and efcient method has been developed for the conversion of arenecarbaldehyde-3-methylquinoxalin2-ylhydrazones to 3-(2-methylquinoxalin-3-yl)-2-(substitutedphenyl)thiazolidin-4-ones in good yields using microwave irradiation technique on silica as solid support under solvent-free conditions. Substituted hydrazones and

Scheme 57 .

Scheme 58 .

Scheme 59 .

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thioglycolic acid were adsorbed onto silica gel and irradiated in a microwave oven under solvent-free conditions for about 35 min at 540 W to afford thiazolidinones. When the reaction mixture was subjected to microwave irradiation at either \540 or [540 W, yields obtained were very poor. Probably at higher power output thioglycolic acid is evaporating (boiling point: 101.5 C) and thereby the reaction progress is hampered giving poor yields (Scheme 57) [101]. The arylidienes of spiro thiazolidines containing unsaturated function have been used as the components of Micheal addition with equimolar amount of 2-aminopyridine to give novel spiro [indole-3,2-pyrido-[1,2-a]thiazolo[5,4-e]pyrimidines] in a single step under microwaves in the presence of montmorillonite KSF as solid support. The new improved synthetic method for spiro [indole-3,2thiazolo-[4,5-d]-pyrimidines] has also been developed involving the reaction of with thiourea under microwaves (Scheme 58). Comparison with conventional synthesis indicated the enhanced yield with faster reactions under microwaves [102, 103]. A mixture of p-chloroacetophenone and thiourea was dissolved in methanol and this mixture was supported on silica gel taken in 100-ml beaker. It was then irradiated under microwaves at pulse of 10 s for 3 min at power level 40 to afford 2-amino-4-chlorophenylthiazole (Scheme 59) [104]. 3-(Bromoacetyl)coumarin, a key precursor of Hantzsch thiazole synthesis for the hydrazinyl thiazolyl coumarin

library, was prepared by a two-step sequence (Scheme 60). Firstly Knoevenagel condensation, with spontaneous apyrone formation, was investigated by heterocyclocondensation of salicylaldehyde and ethyl acetoacetate under microwave irradiation using a range of conditions. It has been reported that the use of microwave heating is benecial for 3-acetylcoumarin synthesis, allowing for lowcatalyst loadings and short reaction times to limit the generation of unwanted side products. With a rapid and highly efcient route to acetylcoumarin established, the rst of the building blocks for Hantzsch thiazole synthesis, bromoacetylcoumarin, was prepared in 68 % yield by the electrophilic bromination of acetylcoumarin, in CHCl3, according to the method of Gursoy and Karali [105]. Microwave irradiation of semicarbazone and bromoketone in ethanol at 60 C for 10 min followed by treatment with ammonium hydroxide gave coumarin derivatives in very good yield [106]. The microwave-assisted Hantzsch condensation reaction of p-toluenesulfonylthiosemicarbazide with some a-halogenocarbonyl derivatives is described. To optimise the reaction conditions, the microwave-assisted organic synthesis experiments conducted at different temperatures (25, 40, 80 C) and reaction times (0.5, 12 h) were applied in the condensation reaction of p-toluenesulfonylthiosemicarbazide with a-halogenocarbonyls such as: chloroacetone; 1,3-dichloroacetone, a-bromoacetophenone, 3-chloroacetylacetone, ethyl a-bromoacetoacetate and ethyl c-bromoacetoacetate, respectively. A comparison between

Scheme 60 .

Scheme 61 .

Scheme 62 .

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Scheme 63 .

Scheme 64 .

Scheme 65 .

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our previous results obtained in the syntheses of compounds performed at room temperature (which required long reaction times of 24 h to achieve good reaction yields and reaction time parameters were modied showing the possibility of obtaining enhanced reaction yields in reduced reaction times (Scheme 61) [107]. 2-Thiazolines are synthesized from carboxylic acids and 1,2-aminoalcohols in the presence of Lawessons reagent under solventless conditions. The developed method is valid for either substituted or unsubstituted aminoalcohols and a wide variety of aromatic, heteroaromatic and aliphatic carboxylic acids; thus it constitutes a general synthetic method for these kinds of compounds. The role of Lawessons reagent is dual: to transform the 1,2-aminoalcohol into 1,2-aminothiol and to activate its reaction with the carboxylic acid leading to the formation of a thiazoline ring, all in one pot. Benzoic acid, aminoalcohol and LR (molar ratio 1:1.5:0.5, respectively) were irradiated with microwaves at 190 C for 4 min. This yielded 2-thiazoline. To improve the yield, different times, temperatures and reagent ratios were studied. The best conditions are: irradiation for 8 min of a mixture 1:1.5:0.75 of the abovementioned reagents, at 150 C/300 W. This yields 80 % of the 2-thiazoline (Scheme 62) [108, 109]. An environmentally benign, efcient and facile route is developed for the synthesis of novel spiro[indoline-3,20 thiazolo[5,4-e]pyrimido[1,2-a]pyrimidine] derivatives. The benzylidene derivatives of spiro[indoline-thiazolidinones] containing an a, b-unsaturated ketonic function [CH = CHCO] have been used as a component of Michael addition with an equimolar amount of 2-aminopyrimidine to give a series of novel spiroindole derivatives in a single step using montmorillonite KSF as inorganic solid support with few drops of DMF. In comparison to conventional synthesis involving tedious multi-step procedures, the present method indicates operational simplicity, shorter reaction time and higher yields which can prove this procedure as a useful alternative for the synthesis of novel spiro heterocycles. The required biologically important

scaffold spiro[indoline-thiazolidinones] were prepared by the improved solvent-free multicomponent condensation between substituted indole-2,3-diones, thioglycolic acid and amines using montmorillonite KSF as solid support. The reaction of spiro[indoline-thiazolidinones] with benzaldehyde yielded 50 -benzylidene-30 -phenylspiro[indoline3,20 -thiazolidine]-2,40 (1H)-dione in situ in 45 min under same reaction conditions in one pot. The spiro[indolinethiazolidinones] system has been synthesized earlier conventionally by a two-step procedure in 4060 % yield using isatin-3-imines as key intermediate, which were synthesized from substituted isatins and aromatic amines. The classical methods involving either the azeotropic removal of water or reaction in the presence of dehydrating agent and use of large amount of volatile and toxic solvents at elevated temperature for several hours of heating were of some utility (Scheme 63) [110]. Different thiosemicarbazone derivatives react with dimethyl acetylene dicarboxylate (DMAD) and diethyl acetylene dicarboxylate (DEAD) by (three-component reaction between thiosemicarbazide, aldehyde/ketone and DMAD or DEAD) microwave-assisted synthesis under solvent-free conditions, to obtain ve-membered S,N-heterocycles thiazolines in good to excellent yields. The effect of the electron-donor group on the progress of the reaction and on the structure of the nal products was also investigated. When such an electron donor group is present on the benzene ring higher yields were obtained without exerting heat or reux the reaction mixture, and in addition the reaction rate is much faster (Schemes 64, 65) [111, 112]. An efcient and extremely fast procedure for the synthesis of 4-thiazolidinones by the reaction of arylidene-[(2-benzothiazolyl-thio)-acetamidyl] with thioglycolic acid in DMF in the presence of a catalytic amount of anhydrous ZnCl2 under microwave irradiation (MWI) was reported. A considerable increase in the reaction rate has been observed with better yield in MW technique (Scheme 66). Alkylation of 2-mercaptobenzothiazole with ethyl chloroacetate in dry

Scheme 66 .

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acetone gave ethyl-2-(benzothiazolylthio)-acetate. The ethyl-2-(benzothiazolylthio)-acetate on aminolysis with hydrazine hydrate in EtOH yielded [2-(benzothiazolylthio)acetyl]-hydrazine, which underwent condensation with different aldehydes to afford the arylidene-[2-(benzothiazolylthio)]acetamides. These intermediates on reaction with
Scheme 67 .

thioglycollic acid yielded ve-membered sulfur-containing heterocyclic derivatives 2-(aryl)-3-[2-(benzothiazolylthio)acetamidyl]-4-oxo-thiazolidines [113]. The procedure developed for the synthesis of oxazolines was successfully applied to the preparation of thiazolines. Thus, condensation of N-acylbenzotriazoles with 2-aminoethanethiol

Scheme 68 .

Scheme 69 .

Scheme 70 .

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hydrochloride in the presence of Et3N under microwave irradiation at 80 C and 80 W irradiation power for 10 min., followed by the addition of SOCl2 and subsequent irradiation for 2 min., furnished the desired 2-substituted 2-thiazolines in excellent yields. This method also avoids multi-step preparation of starting materials or the requirement of special reagents (Scheme 67) [114118]. Sriram et al. [119] prepared several 1,3-thaizolidin-4ones bearing variously unsubstituted diaryl ring at C-2 and N-3 positions and evaluated them for their anti-YFV activity. The synthesis of the 2,3-diaryl-1,3-thiazolidin-4ones (DS1-15) was done by reacting substituted benzaldehyde with equimolar amount of an appropriate substituted aromatic amine in the presence of an excess of mercaptoacetic acid in toluene-utilizing microwave irradiation (Scheme 68) [120]. Mistry and Desai [121] synthesized new series of compounds namely 3-chloro-4-(200 ,400 -dichlorophenyl)-4methyl-1-(substituted-10 ,30 -benzothiazol-20 yl)-azetidin-2ones and 2-(20 ,40 -dichlorophenyl)-2,5-dimethyl-3-(substituted-10 ,30 -benzothiazol-20 -yl)-1,3-thiazolidin-4-ones by the reaction of schiff base derivatives with chloroacetyl chloride in the presence of triethylamine thiolactic acid, respectively (Scheme 69). Tiwari et al. [122] used Zeolite 5A for the synthesis of 2-(2-chloroquinoline-3-yl)-3-substituted phenyl thiazolidin-4-ones starting from N-aryl-2-chloroquinolin-3-ylazomethine and thioglycolic acid under microwave irradiation (Scheme 70). Different thiosemicarbazone derivatives react with dimethyl acetylene dicarboxylate (DMAD) under microwave irradiation and solvent-free conditions to obtain vemembered S,N-heterocycles thiazolines in good to excellent yields. The thiosemicarbazone, DMAD and DEAD reacted in ethyl acetate to give only thiazole, and when they were reacted in dry methanol thiazine was formed. This rearrangement was probably catalyzed by a base.

Since, it did not take place if the methanol contained a few drops of acetic acid. A possible mechanism involves ringopening by attack of methoxide on the strained cyclic amide, followed by ring-closure on the other ester group (Scheme 71) [123]. Two 2-thioxopyrimidines derivatives [Ar = Ph, 2-Cl C6H4] were prepared by the Biginelli reaction protocol (Scheme 72). Thus, the 5-min MW irradiation of a mixture of 1,3-diphenyl-1,3-propanedione, aryl aldehyde and thiourea in glacial acetic acid plus a few drops of concentrated hydrochloric acid gave the products in 7580 % yields [124]. The 2-thione DHPMs were transformed into thiazolopyrimidines and pyrimido thiazine derivatives with bromo acids and MW irradiation. When compared to conventional heating, the MW technology completed the two-step synthesis much faster [10 min. vs. 10 h]. The starting material, 2-amino-4,5,6,7-tetrahydrobenzo[d]thiazole was prepared from cyclohexanone and thiourea in the presence of iodine. Reuxing of compound 2-amino-4,5,6,7-tetrahydrobenzo[d]thiazole with various aromatic aldehydes in ethanol afforded 2-arylideneamino4,5,6,7-tetrahydrobenzo[d]thiazoles (Scheme 73). The present work demonstrated the synthesis of 2-arylideneamino-4,5,6,7-tetrahydrobenzo[d]thiazole deriveatives in excellent yields. These derivatives can be used as precursors for the preparation of thiazolidin-4-ones, azetidin-2ones for biological interest [125]. The precursor pyrimidine derivatives were prepared by the acid-catalyzed condensation of ternary mixtures of aromatic aldehydes, ethyl acetoacetate and thiourea in ethanol containing a catalytic amount of hydrochloric acid, commonly known as Biginelli reaction (Scheme 74). Treating these with bromomalononitrile in an ethanol solution containing potassium hydroxide yielded the 5Hthiazolo[3,2-a]pyrimidine. Compounds 5H-thiazolo[3,2a]pyrimidine, as typical enaminonitriles, could be used as precursors for the preparation of thiazolodipyrimidines.

Scheme 71 .

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Scheme 72 . Scheme 73 .

Scheme 74 .

Scheme 75 .

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Thus, heating under reux with an excess of carbon disulphide yielded the corresponding 9-aryl-2,4-dithioxo-7methylthiazolo[3,2-a:4,5-d]dipyrimidine-8-carboxylate. Finally, the obtained compound was reacted with a-halocarbonyl compounds, namely chloroacetone, phenacyl bromide and 3-chloropentane-2,4-dione, respectively, by heating in ethanolic potassium hydroxide solution to produce the respective thiazolo[300 ,200 :10 ,20 ]pyrimido [40 ,50 :4,5]thiazolo-[3,2-a]pyrimidine-9-carboxylate derivatives. Comparison between conventional and microwave irradiation methods showed that the microwave-assisted method is preferable because of the time reduction and yield improvements achieved [126]. Phenylhydrazine-4-oxothiazolidines and their 5-arylidenes are structural subunits of several biologically active compounds. By observing the importance of the abovetitled compounds, the synthesis of these compounds in which phenyl hydrazine rearranges to schiffs base in the presence of appropriate carbonyl compounds and ultimately reacts with mercapto acetic acid to give 4-oxothiozolidine ring and it further undergoes substitution with appropriate carbonyl compounds in the presence of sodium ethoxide to give 5-arylidenes, has been reported. All these reactions were performed under microwave irradiation using domestic radiator and observed that the reaction underwent faster with better yield than conventional method (Scheme 75) [127].
Scheme 76 .

Conventional preparations of thiazoles require the use of a-haloketones and thioureas (or thioamides). The bridgehead heterocyclic compounds, 3-aryl-5,6-dihydroimidazo[2,1-b][1,3]thiazoles, are known to possess a broad spectrum of anthelmintic and fungicidal activity. In general, synthesis of these heterocyclic compounds involves utilization of lachrymatory starting materials, phenacyl halides, and hazardous reagents, which requires a longer reaction time under drastic conditions and often generates aqueous or organic solvent waste. Thiazole and its derivatives are simply obtained by the reaction of a-tosyloxyketones, which are generated in situ from arylmethyl ketones and [hydroxy(tosyloxy)iodo]benzene (HTIB) with thioamides in the presence of K-10 clay using microwave irradiation in a process that is solvent free in both steps. (Scheme 76) [128]. Cyclocondensation of mercaptoacetic acid with diimines (prepared from two equivalents of isatin or N-methylisatin with one equivalent 1,4-diaminobenzene, was carried out under MWI to yield 3,30 -(1,4-phenylene)bis(spiro[indoline3,20 -thiazolidinone]) (Scheme 77) [129, 130]. The group of Tu [83] described a highly efcient and chemoselective synthetic route to the thiazolidinones via a microwave-assisted three-component reaction of an aromatic aldehyde with aniline and mercaptoacetic acid. The reaction gave best results in water at 110 C. The inuences of electronic effect on the chemoselectivity were

Scheme 77 .

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investigated in these reactions. The aromatic aldehydes bearing electron-withdrawing groups (EDG) on phenyl ring generated thiazolidinones (Scheme 78). The general protocol can be extended to a concise preparation of bridgehead 3-aryl-5,6-dihydroimidazo[2,1b][1,3] thiazoles, which are normally difcult to obtain, require a longer heating time, and use haloketones or tosyloxyketones under strongly acidic conditions. The case of corresponding bridgehead heterocycles, however, is a special one where microwave effects really become apparent since the reactions of a-tosyloxyketones with ethylenethioureas remain incomplete in an oil bath whereas in a microwave oven they are completed in a short time. The present solventless reaction conditions for these bridgehead heterocycles merely require a mixing of tosyloxyketones with thioamides in the presence of montmorillonite K-10 clay. The mixture is then MW-irradiated in for 3 min to afford substituted bridgehead thiazoles (Scheme 79) [128]. A new procedure was developed for the synthesis of bithiazole derivatives. It was based on the condensation of thioamides or thiourea with a-bromo ketones under microwave conditions in the presence of K-10 montmorillonite as a solid acid catalyst (Schemes 80, 81) [131]. Authors reported the synthesis of isatinyl thiazole derivatives, starting from ethyl acetoacetate, by microwave organic reaction enhancement method. Thiourea, ethylacetoacetate, N-bromo succinamide, alumina and 1.5 ml dry ethanol under MWI for 3.5 min produced ethyl-2-

amino-4-methylthiazol-5-carboxylate. A solution of ethyl2-amino-4-methylthiazol-5-carboxylate with isatin was irradiated for 15 min at the power level of 300 W to give 4-methyl-2-(2-oxo-1,2-dihydro-indol-3-ylideneamino)-thiazole-5-carboxylic acid ethyl ester, which on further reaction with hydrazine hydrate in ethanol produced 4-methyl-2-(2-oxo-1,2-dihydro-indol-3-ylideneamino)-thiazole-5-carboxylic acid hydrazide. 4-Methyl-2-(2-oxo-1, 2-dihydroindol-3-ylideneamino)-thiazole-5-carboxylic acid hydrazide with aryl aldehyde was prepared in 10 ml ethanol and irradiated for 1 min at the power level of 300 W to furnish 4-methyl-2-(2-oxo-1,2-dihydro-indol-3-ylideneamino)-thiazole-5-carboxylic acid benzylidene-substituted hydrazide (Scheme 82) [132]. The preparation of the angular 8H-thiazolo[5,4-f]quinazolin-9-one ring via using Appels salt (4,5-dichloro1,2,3-dithiazoliumchloride) chemistry has reported. The thiazolo-quinazoline ring was performed in six steps from commercially available 2-amino-5-nitrobenzonitrile [83]. Comparison of conventional heating (oil or metal bath) and microwave irradiation demonstrates that the overall time for the synthesis was considerably reduced, the reactions were cleaner, and the products rapidly puried. Unfortunately, the pathway described in this case was not well adapted for easy introduction of various substituents onto the skeleton. Thus, to perform structureactivity studies, we decided to re-investigate the synthetic approach to the planar compound (Scheme 83) [78].

Scheme 78 . Scheme 79 .

Scheme 80 .

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Scheme 81 .

Scheme 82 .

Scheme 83 .

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Scheme 84 .

To improve the Niementowski method, several conditions were investigated [131]. Among the various combinations tested, the best results were obtained by treatment of the anthranilic acid with 5 equiv of formamide with an irradiation programmed at 60 W and a xed temperature (150 C). At the same time the synthesis of its novel regioisomer 8H-thiazolo[5,4-f]quinazolin-9-ones, with the aim of allowing the presence of further substituents was

performed. The pharmaceutical interest of the nude thiazoloquinazolinones may be limited because of the lack of substituents, such as basic amino groups. The interest of the multi-step (7 steps from the nitroanilines) synthesis described here is to allow modulations of the ring in various positions (Scheme 84) [78]. The uorous benzaldehydes were readily prepared by the reactions of peruorooctanesulfonyl uoride with

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Scheme 85 .

Scheme 86 .

Scheme 87 .

4-hydroxybenzaldehydes. The 4-thiazolidinone ring was constructed by a three component reaction of benzaldehyde, amine, and mercaptoacetic acid (Scheme 85). The reactions are usually conducted under reux with a Dean-Stark trap or molecular sieves to remove water and drive the reaction to completion, which may not be a good choice for parallel synthesis. Compound benzaldehyde was rst reacted with amine in methanol at room temperature. After the reaction was completed, the solvent was evaporated under reduced pressure, and the resulting imine was dissolved in THF and then reacted with mercaptoacetic acid and DCC to give 4-thiazolidinone. For a non-uorous synthesis of thiazolidinones, the ratio for amine, aldehyde, and mercapatoacetic acid was

suggested to be 1:2:3. The three-component reaction for preparation of 4-thiazolidinones was optimized by changing the amount of three starting materials. It was found that a ratio of 1:2:3 of aldehyde/amine/mercapto acid gave the best yield. Boronic acid and thiol were selected for the palladium-catalyzed coupling reactions to introduce new functional group to the heterocyclic systems. The microwave-assisted reactions were carried out using Pd(dppf)Cl2 as a catalyst, K2CO3 as a base and 4:4:1 acetone/toluene/water as a co-solvent to provide biaryl-substituted 4-thiazolidinones and thioaryl-substituted 4-thiazolidinones. When starting materials had a methoxyl group at 3-position, such as in 4-thiazolidinone the reaction activity was reduced [133].

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Scheme 88 .

The starting compound 6-hydroxy-4-methyl-2-thioxo2,3-dihydropyridine-3-carboxamide was prepared from 3-amino-3-thioxopropanamide [monothiomalonamide, and ethyl acetoacetate. A ve-membered ring is annulated by oxidation of 6-hydroxy-4-methyl-2-thioxo-2,3-dihydropyridine-3-carboxamide with potassium ferricyanide in ethanolic potassium hydroxide solution, which led to the formation of 4-methyl-2,3,6,7-tetrahydroisothiazolo[5,4b]-pyridine-3,6-dione (Scheme 86) [134]. Stereoselective base-catalyzed reaction of starting material with either ethyl-2-mercaptoacetate or diethyl-2-mercaptosuccinate in either ethanol containing potassium carbonate at reux temperature or under solvent-free conditions and without solid support afforded exclusively (Z)-2(2-oxo-2-phenylethylidene)thiazolidin-4-ones [135]. Synthesis of benzothiazole in excellent yield was achieved via microwave irradiation of a 1:1 mixture of starting compound and o-aminothiophenol (Scheme 87) [136]. Synthesis of S,N,N-heterocycles Synthesis of thiadiazoles The title compounds have been synthesised by the condensation reaction of 4-arylidene-2-phenyloxazol-5(4H)one and 5-amino-1,3,4-thiadiazole-2-thiol. The condensation of thiosemicarbazide with carbon disulphide, anhydrous sodium carbonate in a solvent absolute ethanol and DMF (1:1) afforded 5-amino-1,3,4-thiadiazole-2-thiol. The condensation reaction is carried out under domestic microwave oven. When 5-amino-1,3,4-thiadiazole-2-thiol was condensed with substituted 4-arylidene-2-phenyloxazol-5(4H)-one in the presence of a catalytic amount of

pyridine in absolute ethanol and DMF under microwave irradiation, 4-(substitutedbenzylidene)-1-(5-mercapto-1,3, 4-thiadiazol-2-yl)-2-phenyl-1H-imidazol-5(4H)-one were obtained in good yields (Scheme 88) [19]. Synthesis of spiro-thiadiazoline from the respective isatins via their Schif-bases was carried out under MW and conventional heating methods in a nice manner. For example compound Schif bases of isatin and freshly distilled acetic anhydride was reuxed for 6 h. The progress of the reaction was monitored by TLC (EtOAc:CHCl3, 1:3). The reaction mixture was cooled at room temperature. A yellow solid was obtained, which was ltered off and crude solid was recrystallized from MeOH to give spirothiadiazoline (78 %) (Scheme 89) [137]. A series of N-(5-substituted 1,3,4thiadiazol-2yl)maleimides was prepared by cyclization of corresponding maleamic acids. These acids were prepared by the reaction of 2-amino-5-aryloxymethyl-1,3,4thiadiazoles with maleic anhydride. The starting amines were prepared from different aryloxyacetic acids and thiosemicarbazide. Phosphorous oxychloride was added drop wise to an icecooled mixture of thiosemicarbazide and aryloxyacetic acid with shaking. The reaction mixture was irradiated for 3 min in 210-W domestic microwave oven, and it was then worked up as in method (Scheme 90) [138]. Synthesis of 2,5-disubstituted thiadiazoles was accomplished via a conventional method as well as microwave irradiation method. To reduce the reaction time and for better yields, substituted aminothiadiazole was prepared by conventional method as well as MW irradiation method. We had reduced the reaction time considerably in minutes (MW) from hours in conventional method (Scheme 91) [139].

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Microwave-assisted synthesis of some novel compounds, namely, 3-(2-methyl-1H-indol-3-yl)-6-aryl-[1,2,4] triazolo[3,4-b][1,3,4]thiadiazoles was accomplished via bromination of 2-methyl-3-[4-(arylideneamino)-5-mercapto-4H-[1,2,4]triazol-3-yl]-1H-indoles. 2-Methyl-3-[4amino-5-mercapto-4H-[1,2,4]triazol-3-yl]-1H-indole was condensed under microwave irradiation with different aldehydes such as substituted benzaldehydes,

2-thiophenaldehyde and benzo[d]-[1,3]dioxole-4-carbaldehyde in dimethylformamide, in the presence of catalytic amount of HCl, to give the corresponding 4-arylideneamino-[1,2,4]triazole Schiffs base derivatives, respectively (Scheme 92). Room temperature (25 C) bromination of 4-arylideneamino [1,2,4]triazole derivatives in acetic acid in the presence of anhydrous sodium acetate afforded the respective [1,2,4]triazolo[3,4-b][1,3,4]thiadiazoles via

Scheme 89 . Scheme 90 .

Scheme 91 .

Scheme 92 .

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dehydrobromination from the non-isolable intermediates [140]. [1,3,4]Thiadiazoles with indole moieties were prepared by cyclization of 1-[(2-methyl-1H-indole)-3-carbonyl]thiosemicarbazides under microwave irradiation using different reaction conditions. The synthetic utility of 1-[(2methyl-1H-indole)-3-carbonyl]thiosemicarbazides prepared from acid hydrazide and potassium thiocyanate or phenyl isothiocyanate was investigated. Further, treatment with concentrated sulfuric acid at room temperature (25 C) gave the respective [1,3,4]thiadiazole derivatives (Scheme 93).

Changes of the pH of the reaction mixture led to the formation of different ring systems. Thus, reactions with potassium hydroxide, as basic catalyst, led to the formation of [1,2,4]triazoles [140]. Varma and Polshettiwar [141, 142] reported a novel one-pot, solvent-free synthesis of 1,3,4-thiadiazoles by the condensation of acid hydrazide and triethylorthoalkanates under microwave irradiation. It was noted that the solventfree reaction conditions and the use of P4S10/Al2O3 as the catalyst are particularly ecofriendly attributes of this synthetic protocol (Scheme 94). Using the optimized reaction

Scheme 93 .

Scheme 94 .

Scheme 95 . Scheme 96 .

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Scheme 97 .

Scheme 98 .

Scheme 99 .

conditions, the efciency of this protocol was studied for the synthesis of various thiadiazoles. Various aromatic and heterocyclic hydrazides reacted efciently with P4S10/ Al2O3 to yield thiadiazoles in a single step. The reaction proceeds efciently without any solvent, with moderate to good yields of 1,3,4-thiadiazole. Dua et al. [143] synthesised substituted-4-oxothiazolidine and their 5-arylidene derivatives of 2-methyl-benzimidazole from N1-ethylacetate-2-methyl-benzimidazole. N1-ethylacetate-2-methyl-benzimidazole was formed from the reaction between 2-methylbenzimidazole and ethylchloroacetate with K2CO3 under microwave irradiation for 3 min (Scheme 95). When a mixture of compound and thiosemicarbazide was subjected to microwave irradiation at 160 W for 5 min, N1-acetylthiosemicarbazide-2-methylbenzimidazole was the product. N1-(20 -amino-50 -

methylene)-10 ,30 ,40 -thiadiazole-2-methyl-benzimidazole was formed when compound was dissolved in chloroform and concentrated H2SO4 and subjected to microwave irradiation in the resonance cavity of the microwave power system for 1.30 min and neutralized with concentrated liq. ammonia. Some new fused heterobicyclic nitrogen systems such as 1,3,4-thiadiazolo[2,3-c][1,2,4]triazinone have been synthesized by treatment of 4-amino-3-mercapto-6-[2-(2-thienyl)vinyl]-1,2,4-triazin-5(4H)-one with bifunctional oxygen and halogen compounds and CS2/KOH via heterocyclization reactions, in addition to some uncondensed triazines. The reactions of 4-amino-3-mercapto-6-[2-(2-thienyl)vinyl]1,2,4-triazin-5(4H)-one with acid chloride ethyl chloroformate in DMF yielded [1,3,4]thiadiazolo[2,3-c][1,2,4]triazine-4,7(6H)-dione (Scheme 96). Also, boiling compound

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4-amino-3-mercapto-6-[2-(2-thienyl)vinyl]-1,2,4-triazin5(4H)-one with CS2 in dil. ethanolic KOH afforded 3-[2-(2thienyl)vinyl]-7-thioxo-6,7-dihydro-4H-[1,3,4]thiadiazolo [2,3-c][1,2,4]-triazin-4-one (Scheme 96) [144]. The functionalities in 4-amino-3-mecapto-5-substituted1,2,4-triazoles made them valuable key precursors for the formation of fused heterocyclic compounds containing 1,2,4-triazolo[3,4-b][1,3,4]thiadiazoles [145147]. Reaction of 4-amino-3-mecapto-5-substituted-1,2,4-triazoles with boiling acetic anhydride for 18 h caused a ring closure to form the thiadiazole ring in 80 % yield, whereas it was obtained in 91 % within 3 min under MW, via the

possible formation of intermediate which could be isolated in other analogues [148]. Heating compound 4-amino-3mecapto-5-substituted-1,2,4-triazoles under reux for 8 h with carbon disulde in pyridine furnished 3-(3-chlorobenzo[b]thien-2-yl)-1,2,4-triazolo[3,4-b][1,3,4]thiadiazol6(5H)thione of 70 % yield; 4 min was required under MW to produce 81 % yield. Fusion of 4-amino-3-mecapto-5substituted-1,2,4-triazoles with urea gave 3-(3-chlorobenzo[b]thien-2-yl)-1,2,4-triazolo[3,4-b][1,3,4]thiadiazol-6 (5H)one (Scheme 97) [149]. When the reactions were carried out in the presence of NaH in DMF either by heating or under MW, an

Scheme 100 .

Scheme 101 .

Scheme 102 .

Scheme 103 .

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unexpected product was obtained which was found to be identical to that obtained from boiling in DMF only. The 1H NMR of this unexpected product conrmed the structure to be 3-(3-chlorobenzo[b]thien-2-yl)-6-(N,N-dimethylamino)-1,2,4-triazolo[3,4-b][1,3,4]thiadiazole, a result of possible formation of intermediate and subsequent dehydrogenation (Scheme 98). The 1H NMR spectrum indicated the presence of two methyl groups and the absence of a signal corresponding to the formyl proton [149]. Thiadiazole derivatives also attracted great attention due to their broad biological activity [150152]. Li et al. [153] developed an efcient solvent-free microwave-assisted protocol for preparation of 2-amino-5-substituted-1,3,4thiadiazoles using poly(ethyleneglycol)-supported dichlorophosphate (PEGOP(O)Cl2) as the dehydrating agent (Scheme 99). Comprehensive screening of polymer-supported bases revealed that many bases could catalyze cyclodehydration to afford heterocycles, but only especially strong bases such as PS-BEMP for an earlier report on microwaveassisted cyclodehydration of 1,2-diacylhydrazines using polymer-supported phosphazene base (PS-BEMP) and TsCl [154] catalyzed both cyclodehydration and subsequent sulfonamidation. PS-DMAP was the most efcient base to promote the cyclodehydration route to 2-aminoScheme 104 .

1,3,4-thiadiazoles. To separate the desired heterocycles from unreacted ureas, a difference in solubility and basicity between the starting materials and products was exploited, using catch and release purication with a silica-bonded sulfonic acid sorbent. A substrate-dependent transformation to either thiadiazoles occurred upon cyclodehydration of thiosemicarbazides and the selectivity of the reaction was found to be highly dependent on the electronic characteristics of the substituents. Thus, electron-withdrawing substituents directed the formation of thiadiazoles. Alternatively, thiadiazoles were prepared in a microwaveassisted thionation-cyclization sequence from 1,2-diacylhydrazines and Lawessons reagent under solvent-free conditions (Scheme 100) [155]. A solvent-free, microwave-assisted one-pot synthesis of [1,3,4]thiadiazolo[2,3-c][1,2,4]triazinone starting with aromatic aldehydes and triazine derivatives was reported in moderate yields. It was also noted that the reaction was limited to aromatic aldehydes (Scheme 101) [156]. The syntheses of 1,3,4-thiadiazoles via the intramolecular cyclocondensation of benzofuran-substituted thiosemicarbazides in acidic has been reported (Scheme 102). The reactions were carried out employing microwaves [157]. The scope of these reactions was subsequently expanded by Shelke et al. [158] (Scheme 103).

Scheme 105 .

Scheme 106 .

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The reaction of N-[3-(4-amino-5-mercapto-4H-[1,2,3] triazol-3-yl)-4,5,6,7-tetrahydrobenzo[b]thiphen-2-yl]acetamide with carbon disulphide in the presence of alc. KOH (Scheme 104), aromatic carboxylic acid in the presence of POCl3 (Scheme 105) and aromatic carboxaldehydes in the presence of p-toluenesulphonic acid (Scheme 106) yielded the [1,2,4]triazolo[3,4-b][1,3,4]thiadiazole derivatives [159].

Microwave-assisted synthesis of sulfur-containing vemembered heterocyclic compounds under solid-phase support A number of tetra-substituted N-methoxy-2-acetylaminothiophenes with free carboxylic acid functionality in b position next to protected amino group were achieved via a one-pot microwave-assisted Gewald reaction on solid

Scheme 107 .

Scheme 108 .

Scheme 109 .

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Scheme 110 .

Scheme 111 .

support. The Gewald reaction of the resin-bound cyanoacetic ester with substituted ketones and sulfur was accomplished under the microwave conditions using DBU as a base in toluene. The protection of amino group was

performed with methyl 2-chloro-2-oxoacetate in toluene in the presence of diisopropylethylamine (DIPEA) again under the microwave irradiation. Formed resin-linked methyl oxo(2-thienylamino)acetates were cleaved with

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triuoroacetic acid in waterdichloromethane solution into substituted 2-{[methoxy(oxo)acetyl]amino}thiophene-3carboxylic acids (Scheme 107) [160]. Multi-component condensation of ketones (or aldehydes), a-activemethylene nitriles and elementary sulfur (the Gewald reaction) is an efcient methodology to access diverse 2-aminothiophenes. The Gewald reaction, however, suffers from long reaction times (848 h) and laborious purication of the desired products. To address these disadvantages, the reaction was performed on solid support under microwave dielectric heating conditions, furnishing 2-aminothiophenes within 20 min [161]. Moreover, additional diversity was introduced by a one-pot N-acylation of the initially formed 2-aminothiophene within 10 min. The use of a solid support facilitated the workup substantially and the desired heterocycles were obtained after cleavage from the polymer support with 4699 % HPLC purity (Scheme 108). The overall two-step reaction procedure, including the acylation of the initially formed 2-aminothiophenes, could be performed in \1 h. This process is an efcient route to 2-acylaminothiophenes which requires no ltration between the two reaction steps. Various aldehydes, ketones, and acylating agents have been employed to generate the desired thiophene products in high yields and in generally good purity [162]. The solid-phase synthesis of thiazolo[4,5-d]pyrimidine5,7-diones used isocyanates, alkyl halides, and amines as building blocks. The amino ester resin was treated under MW irradiation conditions with isocyanate to give the corresponding thiazolourea resin. The one-pot cyclization/ N-alkylation of thiazolourea resin, using sodium hydride as a base carried out in DMF provided the intermediate, which underwent in situ N-alkylation with alkyl halide to provide the desired thiazolo[4,5-d]pyrimidine-5,7-dione resin. After the oxidation of resin to form the sulfone group on resin, nucleophilic C-2 substitution with the corresponding amines afforded the target 2,4,6-trisubstituted thiazolo[4,5-d]pyrimide-5,7-dione derivatives (Scheme 109) [163]. Merrield resin was prepared from carbon disulphide, cyanamide, and KOH in aqueous ethanol. When DMF was used as a solvent, solid-supported cyanocarbonimidodithioate was obtained with a good loading capacity. In addition, one-pot three-component reaction of Merrield resin with carbon disulphide and cyanamide for resin displayed a lower loading capacity of about 40 % based on a comparison of the stepwise pathway. The resin was treated with 2-bromoacetophenone or ethyl 2-bromoacetate and triethylamine at 80 C to give the corresponding thiazole resin via ThorpeZiegler cyclization. After that the sulfonyl resin was oxidized to form sulfone resin by treatment with m-chloroperoxybenzoic acid, the desired thiazoles were liberated from resin by nucleophilic addition of

various amines. The acylation with acid chloride and the urea formation with isocyanate of intermediate resin afforded other substituent groups onto 4-aminothiazole. Thiazole resin was obtained under microwave (MW) irradiation on reaction with isocyanate and acylation with acid chloride. Similarly, as above sulfanyl resin was converted to sulfonyl resin with m-chloroperoxybenzoic acid and then treatment of sulfonyl resin with appropriate amines furnished the 2,4,5-trisubstituted thiazoles (Scheme 110) [164, 165]. The solid-phase synthesis of trisubstituted thiazoles is described. The synthetic strategy involves the formation of a polymer-bound thiazole by reacting resin-bound cyanodithioimidocarbonic acid and a-bromoketone. The resinbound thiazole was reacted with acyl chlorides or isocyanates. After oxidation activation of a thioether linker to a sulfone linker, traceless cleavage was achieved with nucleophiles to give trisubstituted thiazoles (Scheme 111) [164].

Conclusion Microwave-assisted green synthesis is a very good technique in the eld of green chemistry which governs a exible platform for heterocycles ring formation. This feature article has highlighted the tremendous impact of the application of microwave irradiation on the development of new and efcient synthetic approaches for the generation of ve-membered sulfur-containing heterocycles over the last decade. In conclusion, microwave-assisted reactions have quickly become a powerful and efcient tool in organic chemistry. Microwave-assisted approaches will nd broad applications and will continue to attract much attention in organic synthesis applications.

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