10.1007_s13738-013-0325-2

ORIGINAL PAPER

Microwave-assisted synthesis of five-membered S-heterocycles

Navjeet Kaur

Received: 3 April 2013 / Accepted: 27 July 2013

� Iranian Chemical Society 2013

Abstract The development of new strategies for syn-

thesis of five-membered S-heterocycles has remained a

highly attractive but challenging proposition. An overview

of the application of microwave irradiation in sulfur-con-

taining five-membered heterocyclic compounds synthesis

is presented, focusing on the developments in the last

5–10 years. This contribution covers the literature con-

cerning the total synthesis of five-membered S-heterocy-

cles 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. Het-

erocyclic compounds have always been on the forefront of

attention due to their numerous uses in pharmaceutical

applications [1]. Among them, sulfur-containing hetero-

cyclic 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 syn-

theses provide reliable access to heterocyclic compounds,

however, they are simply no longer acceptable by current

environmental and safety standards. For all these reasons,

the various possibilities offered by the microwave tech-

nology are particularly attractive where fast, high-yielding

protocols and the avoidance or facilitation of purification

are highly desirable [3].

S-containing heteroaromatics are important substruc-

tures 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,

efficient and selective synthetic strategies to access these

compounds. A diverse array of S-containing five-mem-

bered heterocycles has been constructed in higher yields

and shorter reaction times as compared to conventional

conditions [4].

The importance of sulfur-containing heterocyclic com-

pounds for biomedical [5] and material science applica-

tions [6] has led to an increase in the number of synthetic

methods available for the preparation of this type of het-

erocyclic compounds [7, 8]. Since organic sulfur com-

pounds have become increasingly useful, development of

convenient and practical synthetic methods for these

compounds is highly desirable.

Five-membered [9] S-heterocycles constitute an impor-

tant structural component of a diverse range of biologically

active natural compounds and pharmaceuticals [10, 11].

Consequently, the synthesis of five-membered rings has

posed a significantly 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 significant

energy saving for the chemical transformations in com-

parison with conventional oil-bath heating. Reusability,

stability and ease of handling are the significant points of

N. Kaur (&)

Department of Chemistry, Banasthali University, Banasthali,

Rajasthan 304022, India

e-mail: [email protected]

123

J IRAN CHEM SOC

DOI 10.1007/s13738-013-0325-2

solid-supported reagents, which make them an interesting

field for an organic chemist. The combination of micro-

wave (MW) irradiation with solid-supported reagent

becomes an interesting and popular theme in synthetic

organic chemistry [13–15].

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

five-membered heterocyclic compounds.

Microwave-assisted synthesis of sulfur-containing

five-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-phe-

nyl-o-phenylenediamines with indole/benzo[b]thiophene-

3-aldehydes in methoxyethanol under reflux conditions.

The diamines were prepared by first treating 2-chloro-3-

nitropyridine 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 first 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 (60–70 %) and significantly longer

reaction times were required. In the third step, the amines

were condensed with substituted indole/benzo[b]thio-

phene-3-aldehydes at elevated temperature (125 �C) in the

presence of methoxyethanol as a solvent to give the pyri-

dobenzimidazoles in good to excellent yields (81–96 %)

[16].

Kini et al. [17] synthesised benzimidazolo benzothi-

ophenes by liquid-phase combinatorial synthesis using

soluble polymer support PEG 5000 and 4-fluoro-3-nitro-

benzoic acid as starting materials with substituted primary

amines (Scheme 2). They first 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 filtered to

remove the excess of DCC and DMAP salts. PEG-bound

3-amino-4-mercapto benzene was then treated with triflu-

oroacetic 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 dichloro-

methane 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)-1H-benzoimidazole-5-

carboxylic 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)-3Hben-

zoimidazole-5-carboxylic acid methyl ester.

Efficient formation of heterocyclic rings via cycloaddi-

tion 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 short-

ened 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 per-

formed by Hamelin et al. [20]. Employing the Synthe-

wave S1000 apparatus from Prolabo, the authors

investigated the synthesis of the protected carbonyls on a

2-mol scale under open vessel conditions employing high-

boiling 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 con-

tinuous distillation under microwave irradiation in the

Synthewave S1000.

J IRAN CHEM SOC

123

Scheme 1 .

Scheme 2 .

Scheme 3 .

J IRAN CHEM SOC

123

Synthesis of thiophenes

The microwave-enhanced synthesis of 2-chloro-3-form-

ylbenzo [1,8]naphthyridines has been achieved rapidly in

good yield via the Vilsmeier–Haack cyclisation of N-(4-

methylquinoline-2-yl)acetamide by adding POCl3 to the

substrate in DMF with good yield of 90–95 % in a short

reaction time. The required key intermediate N-(4-meth-

ylquinolin-2-yl)acetamide has been synthesized by the

reaction of 2-amino-4-methylquinoline and acetic anhy-

dride in the presence of Amberlite-120A catalyst in

microwave irradiation. Condensation of 2-chloro-3-form-

ylbenzo [1,8]naphthyridines with thioglycolic acid under

microwave irradiation using anhydrous potassium carbon-

ate as catalyst afforded thieno[2,3-b]benzo [1,8]naphthyr-

idine-2-carboxylic acids (Scheme 6) [21].

Biehl’s 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 firstly underwent cou-

pling 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)thi-

eno[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 .

Scheme 5 .

Scheme 4 .

J IRAN CHEM SOC

123

Gewald’s method, which involves a multicomponent con-

densation of a ketone with an activated nitrile and ele-

mental 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 efficient and convenient

modification 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 deriva-

tives 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 define the spec-

trum and potency of the new compounds. The antimicro-

bial activities of the thiazolo 5,4-dpyrimidines are

compared with those of known chosen standard drugs, viz.

ampicillin, chloramphenicol, ciprofloxacin, norfloxacin and

griseofulvin (Scheme 10) [28].

Due to their relevant electronic and optical features, oli-

gothiophenes 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 micro-

wave-assisted Pd catalysis using silica- and chitosan-sup-

ported Pd complexes [31]. Their approach was more efficient

and greener than the existing homogeneous methodology as it

combined a high-yield reaction with improved catalyst sepa-

ration. The microwave-assisted approach afforded the selec-

tive preparation of the coupled products in high yields (up to

87 % isolated yield, 30–100 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 pre-

cursors with three thiophene units, catalyzed and promoted

by [PdCl2(dppf)], KF, and KOH. With a maximum tem-

perature of 70 �C, yields of 74 % were obtained after

reaction times of 10 min (Scheme 12) [32].

An efficient and highly versatile microwave-assisted

Paal–Knorr 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].

Scheme 7 .

Scheme 8 .

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123

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 alumi-

num 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 efficient

variations of the classical Gewald synthesis [25, 35–38].

An one-pot procedure for the rapid generation of

benzo[b]thiophene from activated nitriles employing

elemental sulfur has been reported. Following a simplified

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

Scheme 12 .

Scheme 9 .

Scheme 10 .

Scheme 11 .

J IRAN CHEM SOC

123

starting compound, and derivatized the starting compound

to various 2-substituted amino-3-(N-furfuryl amido)-4,5-

dimethyl 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

Scheme 13 .

Scheme 14 .

Scheme 15 .

Scheme 16 .

J IRAN CHEM SOC

123

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 thi-

eno[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 50–70 �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

refluxing ethanol containing sodium hydroxide and potas-

sium iodide, afforded a mixture of [(3-formylquinolin-2-

yl)thio]acetic acids and thieno[2,3-b]quinoline-2-carbox-

ylic acids. The uncyclized compounds, on refluxing with

POCl3 in various alcoholic media, gave [(3-formylquino-

lin-2-yl)thio]acetates. Further cyclization was achieved by

refluxing them with DMF to produce thieno[2,3-b]quino-

line derivatives. On the other hand, thieno[2,3-b]quinoline-

2-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 efficient method was developed for the prep-

aration of 2-arylbenzothiazoles in the presence of a cata-

lytic amount of Cu1.5PMo12O40/SiO2 under microwave-

assisted 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 cycloconden-

sation 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 amino-

thiophenol with carboxylic acid at 220 �C for 4 h in the

presence of polyphosphoric acid [48] or P2O5–MeSO3H

(70 �C, 10 h) [49]. Consequently, the microwave method-

ology 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 thiophen-

oxy moieties. Bis-benzothiazoles could be obtained in the

Scheme 17 .

Scheme 18 .

Scheme 19 .

J IRAN CHEM SOC

123

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 6–10 h to obtain

comparable yields (Scheme 20).

An efficient and extremely fast procedure for the synthesis

of 4-thiazolidinones by the reaction of arylidene-[(2-ben-

zothiazolylthio)-acetamidyl] with thioglycolic acid in DMF

in the presence of a catalytic amount of anhydrous ZnCl2under microwave irradiation is described. A considerable

increase in the reaction rate has been observed with better

yield in microwave technique. Condensation of 2-mercap-

tobenzothiazole 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 five-membered sulfur-

containing heterocyclic derivatives 2-(aryl)-3-[2-(benzo-

thiazolylthio)-acetamidyl]-4-oxo-thiazolidines. All the

reactions under microwave irradiation (MWI) were com-

pleted within 2–5 min., whereas similar reactions under

conventional heating at similar temperature (80–100 �C)

gave poor yields with comparatively longer reaction time

periods (Scheme 21) [52].

Baltork et al. [53] developed a very simple and conve-

nient protocol for the synthesis of 2-substituted benzox-

azoles, benzothiazoles, benzimidazoles, and oxazolo[4,5-

b]pyridines using catalytic amounts of Bi(III) salts under

solvent-free conditions (Scheme 22).

Scheme 20 .

Scheme 21 .

Scheme 22 .

Scheme 23 .

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123

Seijas et al. [54] have developed Lawesson’s reagent

(LW) and microwaves for the efficient access to benzo-

thiazoles from carboxylic acids under solvent-free condi-

tions (Scheme 23).

Ring closure reactions of appropriate o-substituted ani-

lines to give benzothiazoles takes place much faster and in

significantly high yield under microwave conditions than

conventionally. Trifluoroacetyl 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-trifluoroacetonyl) benzothiazole ring in an

excellent yield (Scheme 24) [55, 56].

Scheme 24 .

Scheme 25 .

Scheme 26 .

Scheme 27 .

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123

A series of various substituted benzothiazole derivatives

containing 7-chloro-6-fluoro-2-chloroacetamidobenzothiazole

derivatives was synthesized. The compound 2-aminobenzo-

thiazole is a versatile material for a number of synthesis.

7-chloro-6-fluorobenzothiazole-2-yl amine was synthesized

from 3-chloro-4-fluoro phenylamine by reacting with potas-

sium thiocyanate and bromine solution in glacial acetic acid.

The obtained 7-chloro-6-fluorobenzothiazole-2-yl-amine was

made to react with chloroacetyl chloride in the presence of

ethanol to give 7-chloro-6-fluoro-2-chloroacetamidobenzo-

thiazole (Scheme 25). 7-Chloro-6-fluorobenzothiaozol-2-yl-

amine was synthesized from 7-chloro-6-fluoro-2-chlor-

oacetamidobenzothiazole by refluxing for 2 h in the presence of

DMF by microwave method [57].

Synthesis of benzothiazoles under microwave irradia-

tion has been reported from dithiazoles in NMP at 150 �C

in only 0.5–3 min (Scheme 26) [50].

2-Bromo-7-formyl-9,9-diethylfluorene and 2-aminothio-

phenol were condensed to form 2-(7-bromo-9,9-diethyl-2-

fluorenyl)benzothiazole. 2-(7-Bromo-9,9-diethyl-2-fluore-

nyl)benzothiazole reacted with 3-hydroxydiphenylamine, in

the presence of Pd(dba)2 and diphenylphosphinoferrocene to

form 2-(7-(3-benzyloxydiphenylamino)-9,9-diethyl-2-flu-

orenyl))benzothiazole then the compound was debenzylated

to give 2-(7-(3-hydroxydiphenylamino)-9,9-diethyl-2-flu-

orenyl)benzothiazole (Scheme 27) [58].

Benzothiazoles were obtained by a direct cycloconden-

sation 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 car-

boxylic acid at 220 �C for 4 h in the presence of poly-

phosphoric acid [48] or P2O5–MeSO3H (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 dinu-

cleophile 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 benzothiaz-

oles were also described by attack of the dinucleophiles on

benzaldehydes and benzaldoximines (Schemes 29, 30) [61].

Condensation of 2-aminothiophenol with the b-chloro-

cinnamaldehyde in the presence of p-toluene sulphonic

acid (p-TSA) gave moderate yield of benzothiazoles

(Scheme 31) [62].

Manganese (III)-promoted radical cyclization of aryl-

thioformanilides and a-benzoyl thioformanilides is a

recently described microwave-assisted example for the

synthesis of 2-arylbenzothiazoles and 2-benzoylbenzo-

thiazoles [63] (Scheme 32). In this study, manganese tri-

acetate 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 irradi-

ation (300 W) in a domestic oven with no real control of

the temperature (reflux 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 [65–67] with manganese

triacetate dihydrate Mn(OAc)3�2H2O 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 conden-

sation of aromatic or aliphatic aldehydes with 2-amino-

thiophenol on SiO2 [68] (Scheme 34), aromatic aldehydes

with 2-aminothiophenol in the presence of nitrobenzene/

SiO2 or nitrobenzene/montmorillonite K-10, [69] or car-

boxylic acids [70] (Scheme 35).

Recently 2-substituted benzothiazoles under solvent-

free microwave-assisted conditions have also synthesized

(Scheme 36) [71, 72].

Scheme 28 .

Scheme 29 .

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123

Scheme 30 .

Scheme 31 .

Scheme 32 .

Scheme 33 .

Scheme 34 .

Scheme 35 .

Scheme 36 .

J IRAN CHEM SOC

123

The group of Besson [73, 74] has exemplified the prep-

aration of sulfur-containing aromatic heterocycles via an

intramolecular aryl sulfur coupling to establish a ben-

zothiazol substructure during a multi-step synthesis. All

reactions were duplicated using conventional heating (oil

bath) at reflux temperature and produced similar yields after

45–60 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-tem-

perature conditions that demanded only 5–10 mol % of

FeCl3 (in relation to the sulfonyl chloride) for full conver-

sion. Arenes encompassing alkylbenzenes, anisole and

halobenzenes were sulfonylated using different arylsulfonyl

chlorides. The sulfonylations generally proceeded with

good para-regioselectivity, with the electron-rich bromo-

anisole 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 electron-

withdrawing group reduced the yield of benzothiazole dra-

matically in favour of the cyanoimidoyl chloride, which

became the major product. The traditional thermolysis pro-

cedures consisted of heating the neat imines under argon at

200–250 �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-2-

arylamino-3-cyano-4-ones has been synthesized by the

application of microwave-assisted organic synthesis tech-

nique (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]ben-

zothiazole-2-thiomethyl-3-cyano-4-one was prepared by

following a known method [81]. The nucleophilic substi-

tution of its thiomethyl group with different aryl amines

resulted in the formation of 4H-pyrimido[2,1-b]ben-

zothiazole-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 substit-

uents 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[3,2-

a]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 38 .

Scheme 37 .

J IRAN CHEM SOC

123

tested compounds possessed potent antioxidant activity

(Scheme 41) [86].

A straightforward approach to novel (5-nitropyridin-2-

yl)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

define 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 five-membered nitrogen-containing rings

(Scheme 42) [87].

When equimolar solution of N1-(20-amino-50-methylene)-

10,30,40-thiadiazole-2-methyl-benzimidazole and benzalde-

hyde in methanol with 4–5 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,

Scheme 40 .

Scheme 41 .

Scheme 39 .

J IRAN CHEM SOC

123

3-thiazolidin-4-one}-50-methylene-10,30,40-thiadiazole]-

2-methyl-benzimidazole was formed when the equi-

molar solution of N1-(2-benzylidene-imino-50-methylene)-10,30,40-thiadiazole]-2-methyl-benzimidazole and mercaptoa-

cetic 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 benzal-

dehyde in methanol in the presence of sodium ethoxide

resulted in the product N1-[20-{2-phenyl-5-benzylidene-

1,3-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 isothiocya-

nates. Such intermediates reacted with alkyl or arylamine

nucleophiles to afford novel, differentially functionalized

2,7-diaminothiazolo[5,4-d]pyrimidines (Scheme 44).

A simple, efficient and practical approach for the syn-

thesis 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 condensa-

tion 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. Appar-

ently, recycling of catalyst is possible for four successive

times without significant 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 44 .

Scheme 42 .

Scheme 43 .

J IRAN CHEM SOC

123

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]-1,2,4-

triazoles 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-disubstituted-

thiazoles in excellent yield and purity. They were prepared

from the condensation of thiosemicarbazide with chloro-

acetic 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]-thi-

adiazolo[2,3-c][1,2,4]-triazin-4-ones in one-pot condensa-

tion and cyclization of 4-amino-[1,2,4]triazine-3-thione-5-

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-aryl-

1-benzylbenzimidazoles and 2,3-diaryl-1,3-thiazolidin-4-

ones, 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 microwave-

assisted synthesis versus conventional heating method are

that some reactions which required 4–7 h by conventional

method were completed within 2–5 min by the microwave

irradiation technique and yields were improved from

Scheme 45 .

Scheme 46 .

Scheme 47 .

Scheme 48 .

Scheme 49 .

J IRAN CHEM SOC

123

61–74 % to 83–93 %. An equimolar mixture of benzotri-

azole 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 purified by passing it through a chromato-

graphic 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 deriv-

ative (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-thiosemi-

carbazide with a-halocarbonyl derivatives. Comparison

between classical and microwave-assisted synthesis

Scheme 51 .

Scheme 52 .

Scheme 53 .

Scheme 50 .

J IRAN CHEM SOC

123

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

reflux, 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 55 .

Scheme 56 .

Scheme 54 .

J IRAN CHEM SOC

123

The use of silica-supported 12-tungstophosphoric acid

(TPA–SiO2) as non-toxic, recoverable and reusable heter-

ogeneous 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-flouro

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-fluoro-1H-benzo[d]imidazol-2yl)phenyl)

thiazolidin-4-one are synthesized using three steps: Syn-

thesis of 4-(4-chloro-5-fluoro-1H-benzo[d]imidazol-2-yl)

benzenamine, synthesis of 2-substituted schiffs base and

finally synthesis of 2-substituted 3-(4-(4-chloro-5-fluoro-

1H-benzo[d]imidazol-2-yl)phenyl)thiazolidin-4-one. The

intermediate compound was prepared by substituting dif-

ferent aromatic aldehydes with amine of 4-(4-chloro-5-

fluoro-1H-benzo[d]imidazol-2-yl)benzenamine and thio-

glycolic 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-2-

pyrimidinyl}-benzenesuphonamido]-spiro-(3H-indol-3,20-thiazolidin)-1H-2,40(5H)-dione and their Mannich’s 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. Cyclocon-

densation of its azomethine function with mercaptoacetic

acid over basic alumina afforded 3,-[4-N{4-methyl-2-pyri-

midinyl}-benzenesulphonamido]-spiro-(3H-indol-3,20-thiazolidin)-1H-2,40(5H’)dione) which reacted smoothly

with secondary amines and formaldehyde to give Mannich’s

bases in excellent yield (Scheme 55) [99].

The Vilsmeier reaction of acetophenone phenyl hydra-

zones resulted in the formation of pyrazole-4-carbalde-

hyde. This inspired the synthesis of 3-(4-nitrophenyl)-1-

(pyridin-4-ylcarbonyl)-1H-pyrazole-4-carbaldehyde using

Vilsmeier–Haack complex from N0-[1-(4-nitrophenyl)eth-

ylidene] benzohydrazide. 1,3-Thiazolidin-4-one derivatives

are formed, when a carbaldehydes were treated with dif-

ferent amines and thioglycolic acid. Thus, 3-(4-nitro-

phenyl)-1-(pyridin-4-ylcarbonyl)-1H-pyrazole-4-carbalde-

hyde 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 efficient method has been developed for

the conversion of arenecarbaldehyde-3-methylquinoxalin-

2-ylhydrazones to 3-(2-methylquinoxalin-3-yl)-2-(substi-

tutedphenyl)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 .

J IRAN CHEM SOC

123

thioglycolic acid were adsorbed onto silica gel and irradi-

ated in a microwave oven under solvent-free conditions for

about 3–5 min at 540 W to afford thiazolidinones. When

the reaction mixture was subjected to microwave irradia-

tion 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 unsat-

urated function have been used as the components of

Micheal addition with equimolar amount of 2-aminopyri-

dine to give novel spiro [indole-3,2-pyrido-[1,2-a]thiazol-

o[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-3,2-

thiazolo-[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 a-

pyrone formation, was investigated by heterocyclocon-

densation of salicylaldehyde and ethyl acetoacetate under

microwave irradiation using a range of conditions. It has

been reported that the use of microwave heating is bene-

ficial for 3-acetylcoumarin synthesis, allowing for low-

catalyst loadings and short reaction times to limit the

generation of unwanted side products. With a rapid and

highly efficient route to acetylcoumarin established, the

first 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-halo-

genocarbonyl derivatives is described. To optimise the

reaction conditions, the microwave-assisted organic syn-

thesis experiments conducted at different temperatures (25,

40, 80 �C) and reaction times (0.5, 1–2 h) were applied in

the condensation reaction of p-toluenesulfonylthiosemi-

carbazide with a-halogenocarbonyls such as: chloroace-

tone; 1,3-dichloroacetone, a-bromoacetophenone, 3-chlo-

roacetylacetone, ethyl a-bromoacetoacetate and ethyl

c-bromoacetoacetate, respectively. A comparison between

Scheme 60 .

Scheme 61 .

Scheme 62 .

J IRAN CHEM SOC

123

Scheme 63 .

Scheme 64 .

Scheme 65 .

J IRAN CHEM SOC

123

our previous results obtained in the syntheses of compounds

performed at room temperature (which required long reac-

tion times of 24 h to achieve good reaction yields and

reaction time parameters were modified showing the pos-

sibility 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 Lawesson’s reagent

under solventless conditions. The developed method is

valid for either substituted or unsubstituted aminoalcohols

and a wide variety of aromatic, heteroaromatic and ali-

phatic carboxylic acids; thus it constitutes a general syn-

thetic method for these kinds of compounds. The role of

Lawesson’s reagent is dual: to transform the 1,2-aminoal-

cohol 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: irra-

diation for 8 min of a mixture 1:1.5:0.75 of the above-

mentioned reagents, at 150 �C/300 W. This yields 80 % of

the 2-thiazoline (Scheme 62) [108, 109].

An environmentally benign, efficient 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 =

CH–CO–] 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 pro-

cedure 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 benz-

aldehyde yielded 50-benzylidene-30-phenylspiro[indoline-

3,20-thiazolidine]-2,40(1H)-dione in situ in 4–5 min under

same reaction conditions in one pot. The spiro[indoline-

thiazolidinones] system has been synthesized earlier con-

ventionally by a two-step procedure in 40–60 % 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 five-membered S,N-het-

erocycles 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 final products was also inves-

tigated. When such an electron donor group is present on

the benzene ring higher yields were obtained without

exerting heat or reflux the reaction mixture, and in addition

the reaction rate is much faster (Schemes 64, 65) [111,

112].

An efficient and extremely fast procedure for the synthesis

of 4-thiazolidinones by the reaction of arylidene-[(2-ben-

zothiazolyl-thio)-acetamidyl] with thioglycolic acid in DMF

in the presence of a catalytic amount of anhydrous ZnCl2under microwave irradiation (MWI) was reported. A con-

siderable 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 .

J IRAN CHEM SOC

123

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 dif-

ferent aldehydes to afford the arylidene-[2-(benzothiazol-

ylthio)]acetamides. These intermediates on reaction with

thioglycollic acid yielded five-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 67 .

Scheme 68 .

Scheme 69 .

Scheme 70 .

J IRAN CHEM SOC

123

hydrochloride in the presence of Et3N under microwave irra-

diation at 80 �C and 80 W irradiation power for 10 min., fol-

lowed 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 prepara-

tion of starting materials or the requirement of special reagents

(Scheme 67) [114–118].

Sriram et al. [119] prepared several 1,3-thaizolidin-4-

ones 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-4-

ones (DS1-15) was done by reacting substituted benzal-

dehyde with equimolar amount of an appropriate substi-

tuted aromatic amine in the presence of an excess of

mercaptoacetic acid in toluene-utilizing microwave irradi-

ation (Scheme 68) [120].

Mistry and Desai [121] synthesized new series of

compounds namely 3-chloro-4-(200,400-dichlorophenyl)-4-

methyl-1-(substituted-10,30-benzothiazol-20yl)-azetidin-2-

ones and 2-(20,40-dichlorophenyl)-2,5-dimethyl-3-(sub-

stituted-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 thiazoli-

din-4-ones starting from N-aryl-2-chloroquinolin-3-yl-

azomethine and thioglycolic acid under microwave irradi-

ation (Scheme 70).

Different thiosemicarbazone derivatives react with

dimethyl acetylene dicarboxylate (DMAD) under micro-

wave irradiation and solvent-free conditions to obtain five-

membered S,N-heterocycles thiazolines in good to excel-

lent 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 ring-

opening 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 thio-

urea in glacial acetic acid plus a few drops of concentrated

hydrochloric acid gave the products in 75–80 % yields

[124]. The 2-thione DHPMs were transformed into thiaz-

olopyrimidines 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-tetrahydro-

benzo[d]thiazole was prepared from cyclohexanone and

thiourea in the presence of iodine. Refluxing of compound

2-amino-4,5,6,7-tetrahydrobenzo[d]thiazole with various

aromatic aldehydes in ethanol afforded 2-arylideneamino-

4,5,6,7-tetrahydrobenzo[d]thiazoles (Scheme 73). The

present work demonstrated the synthesis of 2-arylidenea-

mino-4,5,6,7-tetrahydrobenzo[d]thiazole deriveatives in

excellent yields. These derivatives can be used as precur-

sors for the preparation of thiazolidin-4-ones, azetidin-2-

ones 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 5H-

thiazolo[3,2-a]pyrimidine. Compounds 5H-thiazolo[3,2-

a]pyrimidine, as typical enaminonitriles, could be used as

precursors for the preparation of thiazolodipyrimidines.

Scheme 71 .

J IRAN CHEM SOC

123

Scheme 74 .

Scheme 75 .

Scheme 72 .

Scheme 73 .

J IRAN CHEM SOC

123

Thus, heating under reflux with an excess of carbon

disulphide yielded the corresponding 9-aryl-2,4-dithioxo-7-

methylthiazolo[3,2-a:4,5-d]dipyrimidine-8-carboxylate.

Finally, the obtained compound was reacted with a-halo-

carbonyl 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 deriva-

tives. 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-arylid-

enes are structural subunits of several biologically active

compounds. By observing the importance of the above-

titled compounds, the synthesis of these compounds in

which phenyl hydrazine rearranges to schiff’s base in the

presence of appropriate carbonyl compounds and ulti-

mately reacts with mercapto acetic acid to give 4-ox-

othiozolidine 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 conven-

tional method (Scheme 75) [127].

Conventional preparations of thiazoles require the use of

a-haloketones and thioureas (or thioamides). The bridge-

head heterocyclic compounds, 3-aryl-5,6-dihydroimi-

dazo[2,1-b][1,3]thiazoles, are known to possess a broad

spectrum of anthelmintic and fungicidal activity. In gen-

eral, 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 deriv-

atives are simply obtained by the reaction of a-tosyl-

oxyketones, 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[indoline-

3,20-thiazolidinone]) (Scheme 77) [129, 130].

The group of Tu [83] described a highly efficient and

chemoselective synthetic route to the thiazolidinones via a

microwave-assisted three-component reaction of an aro-

matic aldehyde with aniline and mercaptoacetic acid. The

reaction gave best results in water at 110 �C. The influ-

ences of electronic effect on the chemoselectivity were

Scheme 77 .

Scheme 76 .

J IRAN CHEM SOC

123

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[2,1-

b][1,3] thiazoles, which are normally difficult to obtain,

require a longer heating time, and use haloketones or to-

syloxyketones under strongly acidic conditions. The case of

corresponding bridgehead heterocycles, however, is a spe-

cial one where microwave effects really become apparent

since the reactions of a-tosyloxyketones with ethylenethi-

oureas 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 montmo-

rillonite 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, ethy-

lacetoacetate, 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 ethyl-

2-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)-thi-

azole-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)-thi-

azole-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 etha-

nol and irradiated for 1 min at the power level of 300 W to

furnish 4-methyl-2-(2-oxo-1,2-dihydro-indol-3-ylidenea-

mino)-thiazole-5-carboxylic acid benzylidene-substituted

hydrazide (Scheme 82) [132].

The preparation of the angular 8H-thiazolo[5,4-f]qui-

nazolin-9-one ring via using Appel’s salt (4,5-dichloro-

1,2,3-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 purified. Unfortu-

nately, the pathway described in this case was not well

adapted for easy introduction of various substituents onto

the skeleton. Thus, to perform structure–activity studies,

we decided to re-investigate the synthetic approach to the

planar compound (Scheme 83) [78].

Scheme 79 .

Scheme 80 .

Scheme 78 .

J IRAN CHEM SOC

123

Scheme 81 .

Scheme 82 .

Scheme 83 .

J IRAN CHEM SOC

123

To improve the Niementowski method, several condi-

tions were investigated [131]. Among the various combi-

nations 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 fixed temperature

(150 �C). At the same time the synthesis of its novel reg-

ioisomer 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 thia-

zoloquinazolinones 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 var-

ious positions (Scheme 84) [78].

The fluorous benzaldehydes were readily prepared by

the reactions of perfluorooctanesulfonyl fluoride with

Scheme 84 .

J IRAN CHEM SOC

123

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 reflux 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 first reacted with

amine in methanol at room temperature. After the reaction was

completed, the solvent was evaporated under reduced pres-

sure, and the resulting imine was dissolved in THF and then

reacted with mercaptoacetic acid and DCC to give 4-thiazo-

lidinone. For a non-fluorous 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-cata-

lyzed 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 pro-

vide biaryl-substituted 4-thiazolidinones and thioaryl-substi-

tuted 4-thiazolidinones. When starting materials had a

methoxyl group at 3-position, such as in 4-thiazolidinone the

reaction activity was reduced [133].

Scheme 85 .

Scheme 86 .

Scheme 87 .

J IRAN CHEM SOC

123

The starting compound 6-hydroxy-4-methyl-2-thioxo-

2,3-dihydropyridine-3-carboxamide was prepared from

3-amino-3-thioxopropanamide [monothiomalonamide, and

ethyl acetoacetate. A five-membered ring is annulated by

oxidation of 6-hydroxy-4-methyl-2-thioxo-2,3-dihydropyr-

idine-3-carboxamide with potassium ferricyanide in etha-

nolic potassium hydroxide solution, which led to the

formation of 4-methyl-2,3,6,7-tetrahydroisothiazolo[5,4-

b]-pyridine-3,6-dione (Scheme 86) [134].

Stereoselective base-catalyzed reaction of starting mate-

rial with either ethyl-2-mercaptoacetate or diethyl-2-mer-

captosuccinate in either ethanol containing potassium

carbonate at reflux temperature or under solvent-free con-

ditions and without solid support afforded exclusively (Z)-2-

(2-oxo-2-phenylethylidene)thiazolidin-4-ones [135]. Syn-

thesis 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 con-

densation reaction of 4-arylidene-2-phenyloxazol-5(4H)-

one and 5-amino-1,3,4-thiadiazole-2-thiol. The condensa-

tion of thiosemicarbazide with carbon disulphide, anhy-

drous 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-phenylox-

azol-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 is-

atins 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 dis-

tilled acetic anhydride was refluxed 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 filtered off and

crude solid was recrystallized from MeOH to give spiro-

thiadiazoline (78 %) (Scheme 89) [137].

A series of N-(5-substituted 1,3,4–thiadiazol-2-

yl)maleimides was prepared by cyclization of correspond-

ing maleamic acids. These acids were prepared by the

reaction of 2-amino-5-aryloxymethyl-1,3,4–thiadiazoles

with maleic anhydride. The starting amines were prepared

from different aryloxyacetic acids and thiosemicarbazide.

Phosphorous oxychloride was added drop wise to an ice-

cooled 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 accom-

plished 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].

Scheme 88 .

J IRAN CHEM SOC

123

Microwave-assisted synthesis of some novel com-

pounds, 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-mer-

capto-4H-[1,2,4]triazol-3-yl]-1H-indoles. 2-Methyl-3-[4-

amino-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-carbalde-

hyde in dimethylformamide, in the presence of catalytic

amount of HCl, to give the corresponding 4-arylidenea-

mino-[1,2,4]triazole Schiff’s 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 92 .

Scheme 89 .

Scheme 90 .

Scheme 91 .

J IRAN CHEM SOC

123

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]thi-

osemicarbazides under microwave irradiation using dif-

ferent reaction conditions. The synthetic utility of 1-[(2-

methyl-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 for-

mation 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 solvent-

free reaction conditions and the use of P4S10/Al2O3 as the

catalyst are particularly ecofriendly attributes of this syn-

thetic protocol (Scheme 94). Using the optimized reaction

Scheme 94 .

Scheme 95 .

Scheme 96 .

Scheme 93 .

J IRAN CHEM SOC

123

conditions, the efficiency of this protocol was studied for

the synthesis of various thiadiazoles. Various aromatic and

heterocyclic hydrazides reacted efficiently with P4S10/

Al2O3 to yield thiadiazoles in a single step. The reaction

proceeds efficiently without any solvent, with moderate to

good yields of 1,3,4-thiadiazole.

Dua et al. [143] synthesised substituted-4-oxothiazoli-

dine and their 5-arylidene derivatives of 2-methyl-benz-

imidazole from N1-ethylacetate-2-methyl-benzimidazole.

N1-ethylacetate-2-methyl-benzimidazole was formed from

the reaction between 2-methylbenzimidazole and ethyl-

chloroacetate 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-methyl-

benzimidazole 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 irradia-

tion in the resonance cavity of the microwave power sys-

tem 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 synthe-

sized by treatment of 4-amino-3-mercapto-6-[2-(2-thie-

nyl)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 chlorofor-

mate in DMF yielded [1,3,4]thiadiazolo[2,3-c][1,2,4]tri-

azine-4,7(6H)-dione (Scheme 96). Also, boiling compound

Scheme 97 .

Scheme 98 .

Scheme 99 .

J IRAN CHEM SOC

123

4-amino-3-mercapto-6-[2-(2-thienyl)vinyl]-1,2,4-triazin-

5(4H)-one with CS2 in dil. ethanolic KOH afforded 3-[2-(2-

thienyl)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-substituted-

1,2,4-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 [145–147]. Reac-

tion of 4-amino-3-mecapto-5-substituted-1,2,4-triazoles

with boiling acetic anhydride for 18 h caused a ring clo-

sure 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-3-

mecapto-5-substituted-1,2,4-triazoles under reflux for 8 h

with carbon disulfide in pyridine furnished 3-(3-chloro-

benzo[b]thien-2-yl)-1,2,4-triazolo[3,4-b][1,3,4]thiadiazol-

6(5H)thione of 70 % yield; 4 min was required under MW

to produce 81 % yield. Fusion of 4-amino-3-mecapto-5-

substituted-1,2,4-triazoles with urea gave 3-(3-chloro-

benzo[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 .

J IRAN CHEM SOC

123

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 confirmed the struc-

ture to be 3-(3-chlorobenzo[b]thien-2-yl)-6-(N,N-dimeth-

ylamino)-1,2,4-triazolo[3,4-b][1,3,4]thiadiazole, a result of

possible formation of intermediate and subsequent dehy-

drogenation (Scheme 98). The 1H NMR spectrum indi-

cated 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 [150–152]. Li et al. [153]

developed an efficient solvent-free microwave-assisted

protocol for preparation of 2-amino-5-substituted-1,3,4-

thiadiazoles using poly(ethyleneglycol)-supported dichlo-

rophosphate (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 microwave-

assisted cyclodehydration of 1,2-diacylhydrazines using

polymer-supported phosphazene base (PS-BEMP) and

TsCl [154] catalyzed both cyclodehydration and sub-

sequent sulfonamidation. PS-DMAP was the most efficient

base to promote the cyclodehydration route to 2-amino-

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 purification with a silica-bonded

sulfonic acid sorbent. A substrate-dependent transforma-

tion to either thiadiazoles occurred upon cyclodehydration

of thiosemicarbazides and the selectivity of the reaction

was found to be highly dependent on the electronic char-

acteristics of the substituents. Thus, electron-withdrawing

substituents directed the formation of thiadiazoles. Alter-

natively, thiadiazoles were prepared in a microwave-

assisted thionation-cyclization sequence from 1,2-diacy-

lhydrazines and Lawesson’s 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 intramolec-

ular cyclocondensation of benzofuran-substituted thiose-

micarbazides 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 .

Scheme 104 .

J IRAN CHEM SOC

123

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]acet-

amide 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 deriva-

tives [159].

Microwave-assisted synthesis of sulfur-containing five-

membered heterocyclic compounds under solid-phase

support

A number of tetra-substituted N-methoxy-2-acet-

ylaminothiophenes 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 108 .

Scheme 109 .

Scheme 107 .

J IRAN CHEM SOC

123

support. The Gewald reaction of the resin-bound cyano-

acetic 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

Scheme 110 .

Scheme 111 .

J IRAN CHEM SOC

123

trifluoroacetic acid in water–dichloromethane solution into

substituted 2-{[methoxy(oxo)acetyl]amino}thiophene-3-

carboxylic acids (Scheme 107) [160].

Multi-component condensation of ketones (or alde-

hydes), a-activemethylene nitriles and elementary sulfur

(the Gewald reaction) is an efficient methodology to access

diverse 2-aminothiophenes. The Gewald reaction, how-

ever, suffers from long reaction times (8–48 h) and labo-

rious purification 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, addi-

tional 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 46–99 % HPLC purity

(Scheme 108). The overall two-step reaction procedure,

including the acylation of the initially formed 2-amino-

thiophenes, could be performed in\1 h. This process is an

efficient route to 2-acylaminothiophenes which requires no

filtration between the two reaction steps. Various alde-

hydes, 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]pyrimidine-

5,7-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 corre-

sponding amines afforded the target 2,4,6-trisubstituted

thiazolo[4,5-d]pyrimide-5,7-dione derivatives (Scheme

109) [163].

Merrifield resin was prepared from carbon disulphide,

cyanamide, and KOH in aqueous ethanol. When DMF was

used as a solvent, solid-supported cyanocarbonimido-

dithioate was obtained with a good loading capacity. In

addition, one-pot three-component reaction of Merrifield

resin with carbon disulphide and cyanamide for resin dis-

played 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 Thorpe–Ziegler cyclization. After that the sulfo-

nyl 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) irra-

diation 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 fur-

nished 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 cya-

nodithioimidocarbonic acid and a-bromoketone. The resin-

bound thiazole was reacted with acyl chlorides or isocya-

nates. 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 tech-

nique in the field of green chemistry which governs a

flexible 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 efficient synthetic approaches for the generation

of five-membered sulfur-containing heterocycles over the

last decade. In conclusion, microwave-assisted reactions

have quickly become a powerful and efficient tool in

organic chemistry. Microwave-assisted approaches will

find broad applications and will continue to attract much

attention in organic synthesis applications.

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