Benzoxazole, benzimidazole. Chapter-2. Synthesis of 2-substituted benzoxazole, benzimidazole and benzothiazole derivatives [33]

Full text

(1)

Chapter-2

Synthesis of 2-substituted benzoxazole,

benzimidazole and benzothiazole

(2)

2.1 Introduction

Five- membered aromatic heterocyclic rings containing a C=N bond, such as benzoxazole, benzimidazole, and benzothiazole are important structural units in natural products, and in synthetic pharmaceutical and agrochemical compounds1,2. These compounds received a considerable amount of attention for their biological and therapeutic activities3,4. Recently, a survey showed that only

5% of all reactions achieved in the process research groups of three major pharmaceutical companies involve construction of a heteroaromatic rings.5

Therefore, the development of new methods for the synthesis of nitrogen-containing heterocycles is still a focus of intense and nitrogen-containing interest in the organic chemistry, as well as in pharmaceutical and agrochemical chemistry.

Molecules with benzoxazole, benzimidazole and benzothiazole moieties are attractive targets for synthesis since they often exhibit diverse and important biological properties. These heterocycles have shown different pharmacological activities such as antibiotic6, antifungal 7, antiviral 8, anticancer 9, antimicrobial 10,

and antiparkinson11 properties. They have also been used as ligands for asymmetric transformations 12. Benzimidazole derivatives are a unique and broad

spectrum class of antirhino/enteroviral agents such as antiulcerative13 and antiallergic14 are effective against the human cytomegalovirus15 and are also efficient selective neuropeptide Y Y1 receptor antagonists 16.

(3)

Figure 1: Pharmacological activities

Benzoxazole is an aromatic organic compound with a molecular formula C7H5NO, a

benzene fused oxazole ring structure, and an odour similar to pyridine. Benzoxazole is used primarily in industry and research, and has no household use. Being a heterocyclic compound, benzoxazole finds use in research as a starting material for the synthesis of larger, usually bioactive structures. It is found within the chemical structures of pharmaceutical drugs such as Flunoxaprofen. Its aromaticity makes it relatively stable, although as a heterocyclic, it has reactive sites which allow for functionalization. Oxazole and its derivatives are used as building block for biochemicals and pharmaceutical as well as in other industrial applications such as pesticides, dyes, fluorescent brightening agents, textile auxiliaries and plastics.

(4)

O N

Figure 2: General structure of benzoxazole

Benzoxazoles are an important class of heterocyclic compounds that have many applications in medicinal chemistry. For example, benzoxazole derivatives have been characterized as melatonin receptor agonists,17amyloidogenesis inhibitors,18

Rho kinase inhibitors,19 and antitumor agents.20 In addition to their use in medicinal chemistry, benzoxazoles are recognized as an important scaffold in fluorescent probes such as anion and metal cation sensors.21

Benzoxazoles are an important class of heterocycles that are encountered in a number of natural products and are used in drug and agrochemical discovery programs, as well as for a variety of other purposes (Figure 3). For example, the benzoxazole core structure is found in a variety of cytotoxic natural products, such as the UK-1,22 AJI9561,23 and salvianen.24 Recent medicinal chemistry applications of benzoxazoles include the cathepsin S inhibitor,25 selective peroxisome

proliferator-activated receptor γ antagonist JTP-426467.26 Other applications of benzoxazoles include their use as herbicides, such as Fenoxaprop, and as fluorescent whitening agent dyes such as bisbenzoxazolyl ethylenes and arenes .27

(5)

Figure 3: Benzoxazole natural products and medicinal/agrochemical applications of benzoxazoles.

The benzimidazole contains a phenyl ring fused to an imidazole ring, as indicated in the structure for benzimidazole (Figure 4). This important group of substances has found practical applications in a number of fields. Recently the interest in benzimidazole chemistry has been revived by the discovery that the 5,6- dimethyl benzimidazole moiety is part of the chemical structure of vitamin B12.28

(6)

N H N

Figure 4: General structure of benzimidazole

Substituted Benzimidazoles display a broad spectrum of potential pharmacological activities and are present in a number of pharmacologically active molecules such as albendazole/ mebendazole/ thiabendazole (antihelmentic), omeprazole (anti-ulcer), etc. Considerable interest has been focused on the benzimidazole structure. The discovery of this class of drugs provides an outstanding case history of modern drug development and also points out the unpredictability of pharmacological activity from structural modification of a prototype drug molecule. It is having a variety of medicinal applications. Benzimidazole derivatives carrying different substituent’s in the benzimidazole structure were associated with a wide range of biological activities including anticancer, antiviral, antibacterial, antifungal, antihelmentic, anti-inflammatory, antihistaminic, proton pump inhibitor, antioxidant, antihypertensive and anticoagulant activities. Their derivatives were also found to exhibit cytotoxic activity. Substituted benzimidazole derivatives is evaluated by their ability to inhibit gastric H+ /K+ ATPase and by blocking the

gastric acid secretion.29

(7)

pathogen Helicobacter pylori, the probable mechanism being as inhibitor of H.pylori30, 31Various therapeutics strategies have been utilized for the acid induced ulcer, such as acid neutralizing agents, acid inhibitory agents, antigastrin agents, ulcer insulators and promoters of ulcer healing agents .32

Omeprazole O S N O H N N O Lanzoprazole O S N H N N O F F F Rabeprazole O S N NH N O O Pantoprazole O S N F2HCO H N N O O esomeprazole O S N O H N N O

Figure 5: Established antiulcer agents in clinical practice

The Benzothiazole ring system bears phenyl ring fused with thiazole ring. Thiazole is a five membered heterocyclic ring system having sulfur and nitrogen as heteroatom. Benzothiazole is a privileged bicyclic ring system. Due to its potent and significant biological activities it has great pharmaceutical importance; hence,

(8)

synthesis of this compound is of considerable interest. The small and simple benzothiazole nucleus if present in compounds involved in research aimed at evaluating new products that possess interesting biological activities.

Figure 6: General structure of benzothiazole

Benzothiazoles are an important class of privileged organic compounds of medicinal significance due to their recognized biological and therapeutic activities. As such, these heterocycles constitute key structural motifs that exhibit a wide range of biological properties such as antimicrobial33 anticancer34, anthelmintic35, diabetic activities. They have also found application in industry as anti-oxidants, vulcanization accelerators. substituted benzothiazole received much attention due to unique structure and its uses as imaging agents for β-amyloid plaques,36 photosensitizers, inhibitors of stearoyl-coenzyme A δ-9 desaturase,37

antitumor (Compound A), 38 LTD4 receptor antagonist, 39 orexin receptor antagonist (Compound B),40 the Gram-positive selective antibacterials (Compound C)41 and also a derivative of benzothiazole is the light-emitting component of luciferin, found in fireflies (Figure 7).

(9)

(10)

2.2 Literature survey

Mainly there are two general methods for synthesizing 2-substituted benzoxazoles, benzimidazoles, and benzothiazoles. One is the coupling of o -substituted aminoaromatics with carboxylic acid derivatives and acyl chlorides, which is either catalyzed by strong acids or microwave conditions. The other is the oxidative cyclization of Phenolic Schiff bases derived from the condensation of o -substituted aminoaromatics and aldehydes. In latter reactions various oxidants have been used. Different catalysts and different methods were also reported for the synthesis of these heterocycles.

Pang Yi et al.,42 described the synthesis of substituted benzoxazoles by using

palladium mediated oxidative cyclization.

Wang Shen et al.,43described an efficient method for the synthesis of substituted

benzimidazoles from 1,1-dibromoethenes and o-diaminobenzenes. The reaction employs DABCO as the base and NMP as the solvent.

(11)

Mohammadpoor-Baltork et al.,44 developed A new and efficient method for the

preparation of benzoxazoles, benzothiazoles, benzimidazoles and

oxazolo[4,5-b]pyridines from reactions of orthoesters with o-substituted aminoaromatics and 2-amino-3-hydroxypyridine in the presence of catalytic amounts of the moisture stable, inexpensive ZrOCl2·8H2O under solvent-free conditions.

Mohammadpoor-Baltork et al., 45 described an efficient method for the

preparation of benzoxazoles, benzimidazoles and oxazolo[4,5-b]pyridines from reactions of orthoesters with o-substituted aminoaromatics and 2-amino-3-hydroxypyridine in the presence of silica sulfuric acid under heterogeneous and solvent-free conditions.

N. Sekar et al.,46 developed a protocol for the preparation of benzimidazoles,

benzoxazoles, and benzothiazoles from reactions of aldehydes with o-substituted aminoaromatics in the presence of catalytic amount of Indion 190 resin in ethanol solvent at 70oC and obtained high yields of the products.

(12)

John Blacker et al.,47developed ruthenium-catalyzed hydrogen-transfer reactions

for the conversion of alcohols into benzimidazoles and aldehydes into benzoxazoles and benzothiazoles.

K.V.Srinivasan et al., 48 described a regioselective one-pot synthesis of 2-aryl

benzimidazoles, benzoxazoles and benzothiazoles and isolated high yields of products under ambient conditions using the ionic liquids, 1-butylimidazolium tetrafluoroborate ([Hbim]BF4) and 1,3-di-n-butylimidazolium tetrafluoroborate

([bbim]BF4) as reaction media and promoters.

A. K. Chakraborti et al.,49 reported an efficient conversion of carboxylic acids to

benzothiazoles by direct condensation with 2-aminothiophenol under microwave irradiation in the absence of solvent.

(13)

A. K. Chakraborti et al.,50 described a method for direct coupling of carboxylic

acids with 2-aminophenol under microwave conditions to get 2-substituted benzoxazoles under metal and solvent-free conditions.

A. K. Chakraborti et al.,51described that methanesulphonic acid has been found to be a highly effective catalyst for a convenient and one-pot synthesis of 2-substituted benzoxazoles by the reaction of 2-aminophenol with acid chlorides.

T. Punniyamurthy et al.,52developed a method for copper(II)-catalyzed conversion

of bis aryloxime ethers to 2-arylbenzoxazoles. The reaction involves a cascade C−H functionalization and C−N/C−O bond formation under oxygen atmosphere.

(14)

T. Punniyamurthy et al.,53 reported a synthesis of substituted benzimidazoles,

2-aminobenzimidazoles, 2-aminobenzothiazoles, and benzoxazoles via intramolecular cyclization of o-bromoaryl derivatives using copper(II) oxide nanoparticles in DMSO under air.

P. T. Perumal et al.,54 reported that Pyridinium chlorochromate (PCC) supported

on silica gel effects the oxidative cyclization of structurally diverse thiophenolic and Phenolic Schiff's bases, thereby providing an efficient and convenient method for the synthesis of a library of 2-arylbenzothiazoles and 2-arylbenzoxazoles.

(15)

Masahiko Hayashi et al.,56 described that 2-arylbenzoxazoles were directly

synthesized from substituted 2-aminophenols and aldehydes in the presence of activated carbon (Darco KB) in Xylene under an oxygen atmosphere.

Wang, Lei et al.,57 reported for the synthesis of benzoxazole derivatives through

the reaction of substituted 2-aminophenols and acyl chlorides in the presence of catalytic amount of In(OTf)3under solvent-free reaction conditions.

S. C. Shim et al.,58reported that 2-amino phenols react with an array of carboxylic

acids in Dioxane at 180oC in the presence of tin(II)chloride to afford the

corresponding 2-substitued benzoxazole in good yields.

(16)

H. J. Lim et al.,59 described the synthesis of benzimidazoles, benzoxazoles, and

benzothiazoles from resin-bound esters under microwave condition.

P. T. Perumal et al.,60reported that Microwave-assisted synthesis of benzothiazole

and benzoxazole libraries via PIFA [Phenyliodonium bis(trifluoroacetate)] promoted cyclocondensation of 2-aminothiophenols/2-aminophenols with aldehydes under one-pot condition in good to excellent yields.

S. Pan et al.,61 described that the Schiff base derived from the condensation of o

-aminophenol with benzaldehydes was induced to undergo oxidative cyclization in the presence of DDQ. The resulting 2-arylbenzoxazoles were separated from the reduced DDQ by-product by treatment of reaction mixture with a strongly basic ion-exchange resin.

(17)

D. B. Shinde et al.,62 reported that substituted benzimidazoles are synthesized in

very good yields in solvent-free conditions from o-phenylenediamine and aldehydes in the presence of BF3.OEt2as a catalyst.

Jun Lu et al.,63 developed an efficient microwave irradiation synthesis of

2-substituted benzimidazoles using polyphosphoric acid (PPA) as a catalyst from organic acid and o-phenylenediamine under solvent-free conditions.

M. Kidwai et al.,64 reported that ceric ammonium nitrate (CAN) is an efficient catalyst for the synthesis of benzimidazole derivatives from o-phenylenediamine and aldehydes in polyethylene glycol (PEG) solvent.

(18)

P. Sun et al.,65 described that in presence of catalytic amount of iodine, in

THF-H2O, the condensation of aldehydes with 1,2-phenylenediamine gave the

benzimidazole derivatives under mild conditions in good yields. The method can be used for the synthesis of 2- substituted benzimidazoles or 1,2-disubstituted benzimidazoles.

B. Sadeghi et al.,66reported that Silica sulfuric acid (SiO

2-OSO3H) as an eco-friendly

and reusable catalyst for the synthesis of benzimidazole derivatives from o -phenylenediamine and aldehydes or benzonitriles under reflux in ethanol.

(19)

phenylenediamine and aldehydes in the presence of a catalytic amount of In(OTf)3

at room temperature.

R. G. Jacob et al.,68 synthesized the 1,2-disubstituted benzimidazoles from o

-phenylenediamine and aromatic or aliphatic aldehydes by using SiO2/ZnCl2 and

solvent-free conditions at room temperature.

C. Mukhopadhyay et al.,69 described the synthesis of 2-substituted benzimidazoles

and bis-benzimidazoles were in high yields by PEG-mediated catalyst-free synthesis under solvent-less conditions.

(20)

P. Salehi et al.,70developed A highly selective synthesis of 2-aryl-1-arylmethyl-1H

-1,3-benzimidazoles from the reaction of o-phenylenediamine and aromatic aldehydes in the presence of silica sulfuric acid was reported. The reactions were performed in ethanol or water and the catalyst could be reused for several runs.

A. K. Chakraborti et al.,71 described that Carboxylic acids are converted into benzothiazoles in a one-pot reaction with thionyl chloride followed by treatment with 2-aminothiophenol under acid and catalyst free conditions.

A. K. Chakraborti et al.,72 described that phenolic esters are efficiently converted

to substituted benzothiazoles in a one-pot reaction by treatment with 2-aminothiophenol in the presence of a catalytic amount of K2CO3 in N

(21)

D. Subhas Bose et al.,73 developed for the synthesis of 2-substituted

benzothiazoles via the intramolecular cyclization of thioformanilides by using hypervalent iodine reagents in dichloromethane at ambient temperature.

Kiyofumi Inamoto et al.,74 achieved catalytic synthesis of 2-substituted

benzothiazoles from thiobenzanilides in the presence of a palladium catalyst through C-H functionalization/C-S bond formation.

Ramrao A. Mane et al.,75 reported the cyclocondensation of 2- aminothiophenol

and aldehydes in dichloromethane using Baker’s yeast as a catalyst for obtaining 2-aryl/heteroaryl benzothiazoles.

(22)

Mohammad Mehdi Khodaei et al.,76synthesized 2-substituted benzothiazoles and

benzimidazoles from 1,2-phenylenediamines or 2-amino thiophenols and aryl aldehydes under solvent-free conditions by using H2O2, Fe(NO3)3.

XH NH2 + Ar-CHO X N Ar H2O2, Fe(NO3)3 Solvent-free R R X NH, S

Jiu Xi Chen et al.,77described the synthesis of 2-substituted benzothiazoles by the

condensation of 2-aminothiophenol with aldehydes in the presence of a catalytic amount of cetyltrimethyl ammonium bromide (CTAB) "on water" by a one-pot procedure without additional organic solvents and oxidants.

Jiu Xi Chen et al.,78 developed an efficient method for synthesis of 2- substituted

(23)

catalyzed by a catalytic amount of Ceric ammonium nitrate (CAN) in polyethylene glycol (PEG).

F. M. Moghadhan et al.,79 described an efficient procedure for one-pot synthesis

of 2-substituted benzothiazoles in the presence of zirconium(IV) oxide chloride octahydrate (ZrOCl2·8H2O) and anhydrous copper(II) sulfate. The reaction of

2-aminothiophenol with aldehydes and anhydrides was carried out efficiently in solvent-free conditions with or without microwave irradiation.

N. Azizi et al.,80reported that p-toluenesulfonic acid (10 mol%) was found to be an

effective and efficient catalyst for the synthesis of 2-substituted benzothiazoles from aromatic aldehydes and 2-aminothiophenol in moderate to excellent yields in water.

(24)

However, many of these methods suffer from one or more drawbacks such as requirement of strong acidic conditions, long reaction times, low yields, tedious workup procedures, requirement of excess amounts of reagents, and use of toxic reagents, catalysts or solvents. Therefore, there is a strong demand for a highly efficient and environmentally benign method for the synthesis of these heterocycles.

In recent years, heterogeneous catalysts have been gained importance in several organic transformations due to their interesting reactivity as well as for economic and environmental reasons. It was observed that silica supported sodium hydrogen sulphate is a heterogeneous catalyst for synthesis of substituted benzoxazoles, benzimidazoles, and benzothiazole derivatives through the reaction of o-substituted aminoaromatics with different acyl chlorides and aldehydes. The catalysts NaHSO4-SiO2 can be easily prepared81 from the readily available NaHSO4

and silica gel (230-400 mesh) and these are inexpensive and nontoxic. Besides, the reaction is heterogeneous in nature; the catalyst can easily be removed by simple filteration.

(25)

Main objective of the present work

This chapter deals with the synthesis of 2-substituted benzoxazoles, benzimidazoles and benzothiazole derivatives through the reaction of o-amino aromatics coupled with different acid chlorides by using silica supported sodium hydrogen sulphate as a catalyst under solvent free conditions. In another part substituted benzoxazoles and benzimidazoles were also prepared from substituted aldehydes in different solvent system. The reusability of the catalyst was also investigated under optimized conditions.

(26)

2.3 Results and Discussion

2.3.1 NaHSO

4

-SiO

2

promoted solvent-free synthesis of benzoxazoles,

benzimidazoles, and benzothiazole derivatives from acid chlorides

In the present investigation, it is of particular interest to synthesize 2-substituted benzoxazoles, benzimidazoles and benzothiazole derivatives via a method suitable for large scale preparations as well as not requiring toxic starting materials or reagents. Reported here is an efficient one pot synthesis of these heterocycles by using o-aminophenol or o-phenylenediamine or o-aminothiophenol and different acid chlorides in the presence of NaHSO4-SiO2as a catalyst.

In order to find the optimum reaction conditions for the condensation reaction, preliminary efforts were mainly focused on the evaluation of different solvents. The model reaction has been carried out between o-phenylenediamine and benzoyl chloride in the presence of NaHSO4-SiO2 catalyst under different solvents

and at different temperatures and results are shown in Table-1.

The effect of solvent, reaction temperature and time on the reaction was systematically investigated and the results were summarized in Table-1. The optimized reaction conditions for the reaction were found to be NaHSO4-SiO2

under solvent-free condition for 12 hr at the temperature of 100oC. Thus, NaHSO4

(27)

phenylenediamine and benzoyl chloride under solvent-free condition in the absence of catalyst. This resulted in the formation of only 7% of the fused product after 12hr at 100oC. However, reaction with same substrate using 25%/wt of

Table-1 Preparation of 2-phenyl benzimidazole using various solvents and

temperature.a

Entry Solvent Time/Temp (oC) Yield (%)b

1 Ethanol 12hr/80oC 90 2 1,4- Dioxane 12hr/100oC 80 3 Toluene 12hr/100oC 72 4 Solvent-free 12hr/100oC 92 5 Solvent-free 16hr/100oC 91 6 Solvent-free 08hr/100oC 82 7 Solvent-free 12hr/70oC 68

aReaction conditions: o-phenylenediamine (1 mmol), benzoyl chloride (1 mmol), NaHSO 4

-SiO2(25%/wt) were stirred in solvent(3ml) or neat, the temperature and time indicated in

(28)

NaHSO4-SiO2 at 100oC for 12hr afforded the product in quantitative yield. Lower

temperatures required more time for the completion of the reaction and obtained low yields compared to the optimized reaction condition.

Scheme-1

As shown in Table-2, different acyl chlorides reacted with different o-substituted aminoaromatics without any significant difference in the reaction time to give the corresponding 2-substituted benzoxazole, benzimidazole and benzothiazole derivatives in good yield. The method has the ability to tolerate other functional groups such as methoxy, methyl, and halides.

(29)

Table-2 Synthesis of 2-substituted benzoxazoles, benzimidazoles and benzothiazoles a.

Entry Amines Acid chlorides Product Yield (%)

1 92 2 87 3 93 4 86 5 91 6 88 7 Cl O Cl 87 8 90

(30)

9 89 10 88 11 93 12 83 13 Cl O OMe 87 14 89 15 81 16 Cl O Cl 86 17 84

(31)

18 83 19 85 20 94 21 93 22 95 23 71 24 89 25 86

aReaction conditions: o-phenylenediamine (1 mmol), acyl chloride (1 mmol), NaHSO 4

-SiO2(25%/wt) were stirred under solvent-free condition at 100oC for 12h.

The reusability of catalyst is important for the large scale operation and industrial point of view. Therefore, the recovery and reusability of NaHSO4-SiO2 was

(32)

and dryied at 100oC. The reusability of catalyst was investigated in the reaction of

o-phenylenediamine with benzoyl chloride (graph-1). The results illustrated in

graph-1 showed that the catalyst can be used for four times with consistent yield.

Graph-1 Investigation of reusability of NaHSO4-SiO2

General experimental procedure

A mixture of 2-aminophenols or o-phenylenediamine or 2-aminothiophenol (1 mmol) and acyl chloride (1 mmol) were placed in a sealed vessel containing NaHSO4-SiO2 (25%/wt). The reaction mixture was stirred at 100oC for 12 hrs. The

progress of the reaction was monitored by TLC hexane: ethyl acetate (4:1). After completion of the reaction, the reaction mixture was cooled and diluted with EtOAc and the catalyst was removed by filteration. The filterate was evaporated under reduced pressure to get the crude product, purified by column chromatography to give 2- substituted benzoxazoles, benzimidazole and

0 20 40 60 80 100 1 2 3 4 yield no of cycles

(33)

2.3.2 NaHSO

4

-SiO

2

promoted synthesis of 2-substituted benzoxazole

derivatives from aldehydes

An efficient method for the preparation of 2 -substituted benzoxazoles through the reaction of 2-aminophenols and aldehydes in the presence of catalytic amount of silica supported sodium hydrogen sulphate (NaHSO4-SiO2) was described. In a

preliminarily investigation on the model reaction of 2-aminophenol and benzaldehyde, it was found that the reaction could be finished under very simple reaction conditions in the presence of catalytic amount of NaHSO4-SiO2in reflux in

dioxane solvent, which gave the desired benzoxazole product in good yield.

The effect of solvent, catalyst, reaction temperature and time of the reaction was systematically investigated and the results were summarized in Table-3. As can be seen from Table-3, the solvent play an important role in the model reaction. It was found that dioxane is the best one among the solvents tested, and the reaction proceeded smoothly in dioxane and gave the desired product in 90% yield, while DMF afforded the product only in 28%. Use of DMSO, THF, p- xylene, toluene, 1,2-dichloroethane and ethanol as solvents led to slower reactions and 63% yield of model product was isolated in solvent-free reaction condition. The optimized reaction conditions for the reaction were found to be NaHSO4-SiO2under reflux in

(34)

Table 3- optimization of the reaction conditionsa

Entry Solvent Time/Temp (oC) Yield (%)b

1 Dioxane 12hr/reflux 90 2 DMSO 12hr/120oC 59 3 DMF 12hr/120oC 28 4 THF 12hr/reflux 81 5 p-Xylene 12hr/120oC 61 6 Toluene 12hr/reflux 58 7 1,2-Dichloroethane 12hr/reflux 55 8 Ethanol 12hr/reflux 70 9 Solvent-free 12hr/100oC 63

aReaction conditions: 2-Amino phenol (1 mmol) , Benzaldehyde (1.2mmol) , NaHSO

4-SiO2 (25

Wt%) stirred in solvent (3 ml) at the temperature and time indicated in Table-3. bIsolated yield.

Scheme-2

(35)

Table -4 Synthesis of benzoxazoles from 2-Amino phenols and aldehydesa

Entry 2-Amino phenol Aldehyde Product Yield (%)

1 90 2 79 3 86 4 92 5 76 6 79 7 72 8 74 9 79

(36)

10 89

11 92

12 94

13 89

14 52

aReaction conditions: 2-Amino phenol (1 mmol) , aldehyde (1.2 mmol) , NaHSO

4-SiO2(25 Wt%)

was stirred for 12 h under reflux in Dioxane solvent.

Having established the optimized reaction conditions, attention was turned over exploration of the scope of this protocol. The results were listed in Table-4. As shown in Table-4, in the most of cases 2-aminophenol reacted with a wide variety of substituted benzaldehydes completely and afforded the corresponding benzoxazoles in good to excellent yields. Substituted benzaldehydes containing electron-donating (or) electron-withdrawing groups on the benzene rings reacted with 2-aminophenol smoothly under optimal reaction conditions to give the desired products. But in case of substituted 2-aminophenol with a strong electron-with drawing group, such as nitro group on the benzene ring, showed lower reactivity and obtained only 52% yield respectively. (Table-4, entry14).

(37)

General procedure for the synthesis of benzoxazoles

A mixture of 2-aminophenol (1 mmol), benzaldehyde (1.2 mmol) and NaHSO4-SiO2

(25 Wt %) in dioxane (4 ml) was placed in a 50 ml round bottom flask and stirred at reflux for 12h. The progress of the reaction was monitored by TLC hexane: EtOAc (4:1). After completion of the reaction, the reaction mixture was cooled and diluted with EtOAc and the catalyst was removed by filteration. The filterate was washed with diluted solution of 1N NaOH, brine solution and dried over Na2SO4

and evaporated under vacuum. The obtained crude product was purified by column chromatography to give 2- substituted benzoxazoles.

2.3.3 NaHSO

4

-SiO

2

promoted synthesis of 2-substituted benzimidazole

derivatives from aldehydes

A simple and practical method for the preparation of benzimidazole derivatives through the reaction of o-phenylenediamine and aldehydes in the presence of catalytic amount of silica supported sodium hydrogen sulphate (NaHSO4-SiO2) was

developed. In the preliminarily investigation on the model reaction of o -phenylenediamine and benzaldehyde, it was found that the reaction could be finished under very simple reaction conditions in the presence of catalytic amount of NaHSO4-SiO2 in reflux in ethanol solvent, which gave the desired 2-phenyl

(38)

Table-5 Preparation of 2-phenyl benzimidazole using various solvents and

temperauresa

Entry Solvent Time/Temp (oC) Yield (%)

1 Ethanol 8hr/80oC 95

2 Dioxane 12hr/100oC 90

3 Toluene 12hr/100oC 74

4 THF 12hr/70oC 72

5 Solvent-free 12hr/100oC 76

aReaction conditions: o-phenylenediamine (1 mmol), benzaldehyde (1 mmol), NaHSO4-SiO 2

(25%/wt) were stirred in solvent (5ml) , the temperature and time indicated in Table-1,bisolated

yields

The effect of solvent, reaction temperature and time of the reaction was systematically investigated and the results were summarized in Table-5. As can be seen from Table-5, the solvent play an important role in the model reaction. It was found that ethanol was found to be the best solvent for this condensation as the reaction was completed in 8h under reflux condition and gave 95% yield. Also, the reaction carried out in dioxane solvent gave best results with good yield; through the time of the reaction is 12h at 100oC. Use of toluene, THF and solvent-free

(39)

The optimized reaction conditions for the reaction were found to be NaHSO4-SiO2

under reflux in Ethanol solvent for 8h.

Herein, we wish to disclose a novel protocol for the rapid synthesis of a variety of biologically significant benzimidazoles using a catalytic amount of NaHSO4-SiO2

under optimized reaction conditions. As shown in Table-6, different aldehydes and o-phenylenediamine react without any significant difference to give the corresponding benzimidazoles in good yield. When the mole ratio of o -phenylenediamine and aldehyde are taken in 1:1 ratio, the product 2-substituted benzimidazoles were obtained selectively. It indicated that silica supported sodium hydrogen sulphate catalyzed reaction has a favorable selectivity for the synthesis of 2-substituted benzimidazoles. Later the reaction was tried with 2 equivalents of aldehyde. In this case it was observed that 1,2-disubstituted benzimidazole was also formed as a major product along with 2-substituted benzimidazole.

Scheme-3

(40)

Table-6 Synthesis of 2-Substituted Benzimidazole derivativesa

Entry Diamine Aldehyde Product Yield (%)

1 95 2 87 3 93 4 89 5 96 6 87 7 91 8 94

aReaction conditions:o-phenylenediamine (1 mmol), aldehyde (1 mmol), NaHSO4-SiO

2 (25%/wt)

(41)

General experimental procedure

A mixture of o-phenylenediamine (1 mmol), aldehyde (1 mmol) and NaHSO4-SiO2

(25%/wt) in ethanol (5ml) were placed in 50 ml round bottom flask and stirred at reflux for 8h. The progress of the reaction was monitored by TLC hexane: ethyl acetate (4:1). After completion of the reaction, the reaction mixture was cooled and diluted with EtOAc and the catalyst was removed by filteration. The obtained filterate was evaporated under reduced pressure to get the crude product and purified by column chromatography to give 2- substituted benzimidazole derivatives.

2.4 Conclusion

In conclusion, NaHSO4-SiO2 was found to be an efficient catalyst for the formation

of benzoxazole, benzimidazole and benzothiazole derivatives from acid chlorides and aldehydes. The use of this inexpensive, easily available and reusable catalyst makes this protocol practical, environment friendly and economically attractive. The simple work-up procedure, high yields of products and nontoxic nature of the catalyst are other advantages of the present method.

2.5 Experimental Section

All the melting points were determined from the open capillary method and were uncorrected. The 1H and 13C NMR were recorded on 400 MHz Varian FT-NMR

(42)

used for NMR analysis were CDCl3 and DMSO-d6. The infrared (IR) spectra were

obtained using Perkin-Elmer’s FT-IR spectrophotometer. The mass spectra were recorded on Waters ZQ-4000 equipped with ESI and API mass detector. The Carbon, Hydrogen and Nitrogen (CHN) analysis was done on Perkin-Elmer PE 2400 Series II machine.

The thin layer chromatography (TLC) was performed either using the Merck precoated TLC plates or on ACME’s silica gel with 13% calcium sulphate (CaSO4) as

binder and the components were visualized under iodine chamber or by UV exposure or by the potassium permanganate (KMNO4) spray technique. Flash

column chromatography was performed using Merck silica gel (100-200 mesh). The chemicals and solvents were purchased from commercial suppliers either from Aldrich, Spectrochem, and Sisco research laboratories (SRL), and they were used without purification prior to use.

Preparation of silica supported sodium hydrogen sulphate:

To a solution of 4.14 g (0.03 mol) of NaHSO4.H2O in 20 mL of water in a 100 mL

beaker containing a stir bar was added 10 g of SiO2 ( column chromatographic

grade, 230-400 mesh). The mixture was stirred for 15 min and then gently heated on a hot plate, with intermittent swirling, until a free-flowing white solid was obtained. The catalyst was further dried by placing the beaker in an oven maintained at 120oC for at least 48 h prior to use. The synthesized catalyst was characterized by FT-IR and XRD spectrum.

(43)

FT-IR spectrum of NaHSO4-SiO2

The FT-IR spectrum of the catalyst is shown in Fig-8. The catalyst is solid and its solid state IR spectrum was recorded using the KBr disc technique. For silica (SiO2), the major peaks are broad antisymmetric Si-O-Si stretching from

1000-1100 cm-1 and symmetric Si-O-Si stretching near 798 cm-1, and bending modes of Si-O-Si lie around 467 cm-1. The spectrum also shows a broad Si-OH stretching

absorption from 3300-3500 cm-1.

X-ray diffraction (XRD) spectrum of NaHSO4-SiO2

Powder X-ray diffraction measurement was performed using Brucker AXS D8 advance diffractometer. The strongest peaks of XRD pattern correspond to the SiO2plane with the other peaks indexed as the (22), (23), (32) planes of supported

sodium hydrogen sulphate.

General experimental procedure

A mixture of 2-amino phenols or o-phenylenediamine or 2-aminothiophenol (1 mmol) and acyl chloride (1 mmol) were placed in a sealed vessel containing NaHSO4-SiO2 (25%/wt) the reaction mixture was stirred at 100oC for 12 hrs. The

progress of the reaction was monitored by TLC Hexane: EtOAc (4:1). After completion of the reaction, the reaction mixture was cooled and dilution with EtOAc and the catalyst was removed by filteration. The obtained filtrate was evaporated under reduced pressure to get the crude product and was purified by

(44)

column chromatography to give 2- substituted benzoxazoles, benzimidazole and benzothiazole derivatives.

2.6 Physical, Spectral and Analytical Data of compounds

(Entry 1-25, Table-2)

2-Phenyl-1H-benzo[d]imidazole (Table-2, entry 1)

Yield: 92%, Off white solid; m.p: 289-291 oC; 1H NMR (DMSO-d6): δ 13.02 (br s,

1H), 8.20 (d, J=7.6 Hz, 2H), 7.67-7.65 (m, 1H), 7.56-7.49 (m, 4H), 7.22-7.18 (m, 2H); (LC-MS) m/z: 195.08 [M+H]+; IR (KBr, cm-1): 3420, 2920, 2627, 1623, 1410, 1276, 1119, 970, 738. Anal. Calcd. For C13H10N2: C, 80.39; H, 5.19; N, 14.42. Found: C,

80.11; H, 5.01; N, 14.38.

2-o-Tolyl-1H-benzo[d]imidazole (Table-2, entry 2)

(45)

Yield: 87%, Colour less solid; m.p: 220-222 oC; 1H NMR (DMSO-d

6): δ 13.03 (br s,

1H), 7.82-7.79 (m, 3H), 7.60-7.58 (m, 1H), 7.56-7.45 (m, 4H), 2.58 (s, 3H); (LC-MS) m/z: 209.10 [M+H]+

2-p-Tolyl-1H-benzo[d]imidazole (Table-2, entry 3)

Yield: 93%, Colourless solid; m.p: 265-267 oC; 1H NMR (DMSO-d

6): δ 12.81 (br s,

1H), 8.06 (d, J=8 Hz, 2H), 7.56 (m, 2H), 7.36 (d, J=8 Hz, 2H), 7.19 (m, 2H), 2.38 (s, 3H); (LC-MS) m/z: 209.10 [M+H]+

2-(2-Methoxyphenyl)-1H-benzo[d]imidazole (Table-2, entry 4)

Yield: 86%, Colourless solid; m.p: 173-175oC; 1H NMR (DMSO-d6): δ13.5 (br s, 1H),

8.29 (d, J =7.2 Hz, 1H), 7.76-7.74 (m, 2H), 7.63-7.59 (m, 1H), 7.39-7.32 (m, 3H), 7.22-7.18 (m, 1H), 4.06 (s, 3H); (LC-MS) m/z: 225.07 [M+H]+

(46)

2-(4-Methoxyphenyl)-1H-benzo[d]imidazole (Table-2, entry 5)

Yield: 91%, Colourless solid; m.p: 218-221 oC; 1H NMR (DMSO-d

6): δ12.90 (br s,

1H), 8.21 (d, J=8.4 Hz, 2H), 7.70-7.68 (m, 2H), 7.38-7.36 (m, 2H), 7.21 (d, J=8.8 Hz, 2H), 3.88 (s, 3H); (LC-MS) m/z: 225.07 [M+H]+

2-(2-Chlorophenyl)-1H-benzo[d]imidazole (Table-2, entry 6)

Yield: 88%, Light pink red solid; m.p: 231-233oC; 1H NMR (DMSO-d

6): δ12.80 (br s,

1H), 7.91-.89 (m, 1H), 7.67-7.62 (m, 3H), 7.57-7.52 (m, 2H), 7.25-7.23 (m, 2H); (LC-MS) m/z: 229.04 [M+H]+

2-(3-Chlorophenyl)-1H-benzo[d]imidazole (Table-2, entry 7)

(47)

Yield: 87%, Colourless solid; m.p: 234-236 oC; 1H NMR (DMSO-d

6): δ13.06 (br s,

1H), 8.40 (s, 1H), 8.27 (d,J= 6.8 Hz, 1H), 7.81-7.72 (m, 4H), 7.49-7.47 (m, 2H); (LC-MS) m/z: 229.04 [M+H]+

2-Benzyl-1H-benzo[d]imidazole (Table-2, entry 8)

Yield: 90%, Off white solid; m.p: 177-179 oC; 1H NMR (DMSO-d

6): δ13.0 (br s, 1H),

7.52-7.50 (m, 2H), 7.34-7.16 (m, 7H), 4.21 (s, 2H); (LC-MS) m/z: 209.10 [M+H]+

2-Heptyl-1H-benzo[d]imidazole (Table-2, entry 9)

Yield: 89%, Off white solid; m.p: 146-147oC; 1H NMR (DMSO-d

6): δ12.11 (br s, 1H),

7.49 (d, J=8 Hz, 1H), 7.38 (d, J= 6.4 Hz, 1H), 7.09-7.12 (m, 2H), 2.78 (t, J= 7.6 Hz, 2H), 1.77-1.73 (m, 2H), 1.31-1.25 (m, 8H), 0.85 (t, J=6.4 Hz, 3H); 13C NMR

(DMSO-d6): δ13.90, 22.06, 27.57, 28.40, 28.52, 28.64, 31.15, 110.50, 117.78, 120.97,

(48)

1624, 1451, 1272, 1028, 750. Anal. Calcd. For C14H20N2: C, 77.73; H, 9.32; N, 12.95.

Found: C, 77.70; H, 9.28; N, 12.86.

2-Heptyl-5-methyl-1H-benzo[d]imidazole (Table-2, entry 10)

Yield: 88%, Light brown colour solid; m.p: 88-89oC; 1H NMR (DMSO-d6): δ11.98

(br s, 1H), 7.36-7.18 (m, 2H), 6.93-6.89 (m, 1H), 2.74 (t, J=7.6 Hz, 2H), 2.37 (s, 3H), 1.78-1.70 (m, 2H), 1.30-1.21 (m, 8H), 0.85 (t, J=6.4 Hz, 3H); 13C NMR (DMSO-d

6): δ

13.88, 21.19, 22.05, 27.61, 28.40, 28.53, 28.64, 31.15, 113.87, 122.28, 129.92, 154.75; (LC-MS) m/z: 231.18 [M+H]+; IR (KBr, cm-1): 2946, 2763, 1861, 1448, 1281,

1030, 803. Anal. Calcd. For C15H22N2: C, 78.21; H, 9.63; N, 12.16. Found: C, 78.19; H,

9.58; N, 12.15.

2-Phenyl benzo[d]oxazole (Table-2, entry 11)

Yield: 93%, Colourless solid; m.p: 102-104oC; 1H NMR (CDCl3): δ 8.27- 8.24 (m,

(49)

(LC-Calcd. For C13H9NO: C, 79.98; H, 4.65; N, 7.17; O, 8.20. Found: C, 79.86; H, 4.61; N,

7.14.

2-(2-Methoxyphenyl)benzo[d]oxazole (Table-2, entry 12)

Yield: 83%, Colourless solid; m.p: 54-56oC; 1H NMR (CDCl

3): δ 8.13 (d, J = 8.8 Hz,

1H), 7.83-7.80 (m, 1H), 7.60-7.57 (m, 1H), 7.51-7.47 (m, 1H), 7.35-7.32 (m, 2H), 7.13-7.07 (m, 2H), 4.02 (s, 3H) ; (LC-MS) m/z: 226.10 [M+H]+

2-(3-Methoxyphenyl) benzo[d]oxazole (Table-2, entry 13)

Yield: 87%, Colourless solid; m.p: 70-73oC; 1H NMR (CDCl

3): δ 7.86-7.76 (m, 3H),

7.60-7.57 (m, 1H), 7.43 (t, J = 8 Hz, 1H), 7.36-7.34 (m, 2H), 7.10-7.07 (m, 1H), 3.92 (s, 3H); (LC-MS) m/z: 226.23 [M+H]+

(50)

2-(4-Methoxyphenyl) benzo[d]oxazole (Table-2, entry 14)

Yield: 89%, Off white solid; m.p: 97-99 oC; 1H NMR (CDCl3): δ 8.20 (d, J = 9.2 Hz,

2H), 7.74-7.72 (m, 1H), 7.56-7.54 (m, 1H), 7.35-7.31 (m, 2H), 7.03 (d, J = 9.2 Hz, 2H), 3.89 (s, 3H); (LC-MS) m/z: 226.23 [M+H]+

2-(2-Chlorophenyl) benzo[d]oxazole (Table-2, entry 15)

Yield: 81%, Light pink red solid; m.p: 70-73oC; 1H NMR (CDCl3): δ 8.15 (dd, J = 1.6,

5.6 Hz, 1H), 7.87-7.83 (m, 1H), 7.64-7.61 (m, 1H), 7.59-7.56 (m, 1H), 7.48-7.37 (m, 4H); (LC-MS) m/z: 230.12 [M+H]+

(51)

Yield: 86%, Light pink red solid; m.p: 131-133 oC; 1H NMR (CDCl

3): δ 8.26 (s, 1H),

8.16-8.13 (m, 1H), 7.80-7.77 (m, 1H), 7.61-7.58 (m, 1H), 7.52-7.44 (m, 2H), 7.39-7.37 (m, 2H); (LC-MS) m/z: 230.12 [M+H]+

2-(2-Bromophenyl) benzo[d]oxazole (Table-2, entry 17)

Yield: 84%, Colourless solid; m.p: 53-56 oC; 1H NMR (CDCl3): δ 8.06 (d, J = 8 Hz,

1H), 7.86-7.83 (m, 1H), 7.76 (d, J = 8.0 Hz, 1H), 7.63-7.60 (m, 1H), 7.48-7.32 (m, 4H); (LC-MS) m/z: 273.95, 275.90 [M+H]+

2-(2-Fluorophenyl) benzo[d]oxazole (Table-2, entry 18)

Yield: 83%, Colourless solid; m.p: 92-94 oC; 1H NMR (CDCl3): δ 8.24-8.22 (m, 1H),

7.85-7.82 (m, 1H), 7.63-7.61 (m, 1H), 7.54-7.52 (m, 1H), 7.39-7.37 (m, 2H), 7.33-7.26 (m, 2H); (LC-MS) m/z: 214.16 [M+H]+

(52)

2-o-Tolyl benzo[d]oxazole (Table-2, entry 19)

Yield: 85%, Off white solid; m.p: 63-66 oC;1H NMR (CDCl3): δ 8.18-8.16 (m, 1H),

7.81-7.79 (m, 1H), 7.60-7.58 (m, 1H), 7.33-7.41 (m, 5H), 2.81 (s, 3H); (LC-MS) m/z: 210.14 [M+H]+

2-p-Tolyl benzo[d]oxazole (Table-2, entry 20)

Yield: 94%, Colourless solid; m.p: 114-116 oC; 1H NMR (CDCl3): δ 8.15 (d, J = 8 Hz,

2H), 7.77- 7.75 ( m, 1H), 7.58-7.56 (m, 1H), 7.35-7.32 (m, 4H), 2.44 (s, 3H); (LC-MS) m/z: 210.20 [M+H]+

2-(furan-2-yl) benzo[d]oxazole (Table-2, entry 21)

N

(53)

Yield: 93%, Off white solid; m.p: 85-87 oC; 1H NMR (CDCl

3): δ 7.77-7.75 (m, 1H),

7.68-7.67 (m, 1H), 7.58-7.55 (m, 1H), 7.37-7.35 (m, 2H), 7.28 (d, J = 3.6 Hz, 1H), 6.62 (dd, J = 3.2, 2 Hz, 1H); (LC-MS) m/z: 186.02 [M+H]+

2-(Thiophen-2-yl) benzo[d]oxazole (Table-2, entry 22)

Yield: 95%, Off white solid; m.p: 104-107oC; 1H NMR (CDCl3): δ 7.92-7.91 (m, 1H),

7.75-7.72 (m, 1H), 7.57-7.54 (m, 2H), 7.36-7.33 (m, 2H), 7.21-7.19 (m, 1H); (LC-MS) m/z: 202.06 [M+H]+

5-Nitro-2-phenyl benzo[d]oxazole (Table-2, entry 23)

Yield: 71%, Off white solid; m.p: 166-169oC; 1H NMR (CDCl

3): δ 8.66 (d, J= 2.4 Hz,

1H), 8.33 (dd, J= 6.8, 2 Hz, 1H), 8.28(d, J= 6.4 Hz, 2H), 7.69 (d, J = 9.2 Hz, 1H), 7.62-7.57 (m, 3H); (LC-MS) m/z: 241.21 [M+H]+

(54)

2-Phenyl benzo[d]thiazole (Table-2, entry 24)

Yield: 89%, Colourless solid; m.p: 108-110oC; 1H NMR (CDCl3): δ8.11-8.07 (m, 3H),

7.91 (d, J= 8.4 Hz, 1H), 7.51-7.40 (m, 4H), 7.39-7.37 (m, 1H); 13C NMR (CDCl 3):

δ121.79, 123.38, 125.35, 126.48, 127.72, 129.19, 131.14, 133.75, 135.20, 154.28, 168.26; (LC-MS) m/z: 212.12 [M+H]+; IR (KBr, cm-1): 3063, 2924, 1686, 1477, 1311,

1223, 961, 766, 685. Anal. Calcd. For C13H9NS: C, 73.90; H, 4.29; N, 6.63; S, 15.18.

Found: C, 73.87; H, 4.27; N, 6.59.

2-(2-chlorophenyl) benzo[d]thiazole (Table-2, entry 25)

Yield: 86%, Off white solid; m.p: 70-72 oC; 1H NMR (CDCl

3): δ 8.22-8.21 (m, 1H),

8.12 (d, J= 8.4 Hz, 1H), 7.93 (d, J= 7.6 Hz, 1H), 7.51-7.54 (m, 2H), 7.38-7.45(m, 3H); (LC-MS) m/z: 246.01 [M+H]+

(55)
(56)
(57)
(58)
(59)
(60)
(61)
(62)
(63)
(64)
(65)
(66)
(67)
(68)
(69)
(70)
(71)
(72)
(73)
(74)
(75)

2.7 References

1. McKee, M. L.; Kerwin, S. M. Bioorg. Med. Chem. 2008, 16, 1775.

2. Mortimer, C. G.; Wells, G.; Crochard, J. P.; Stone, E. L.; Bradshaw, T. D.; Stevens, M. F. G.; Westwell, A. D. J. Med. Chem. 2006, 49, 179.

3. Grobler, J. A.; Dornadula, G.; Rice, M. R.; Simcoe, A. L.; Hazuda, D. J.; Miller, M. D. J. Biol. Chem. 2007, 282, 8005.

4. Rasmussen, K.; Hsu, M. A.; Yang, Y. Neuropsychopharmacology. 2007, 32, 786. 5. Carey, J. S.; Laffan, D.; Thomson, C.; Williams, M. T. Org. Biomol. Chem. 2006, 4,

2337.

6. Evans, D.A.; Sacks, C.E.; Kleshick, W.A.; Taber, T.R. J.Am.Chem.Soc. 1979, 101, 6789-6791.

7. Yamato, M. J. Pharm. Soc. Jpn. 1992, 112, 81-99.

8. Song, X.; Vig, B.S.; Lorenzi, P.L.; Darch, J.C.; Townsend, L.B.; Amidon, G.L. J. Med. Chem. 2005, 48, 1274-1277.

9. Kumar, D.; Jacob, M.R.; Reynolds, M.B.; Kerwin, S.M. Bioorg. Med. Chem. 2002, 10, 3997-4004.

10. Yildiz-Oren, I.; Yalcin, I.; Aki-Sener, E.; Ucarturk, N. Eur. J. Med. Chem. 2004, 39, 291-298.

(76)

11. Benazzou, A.; Boraund, T.; Dubedat, P.; Boireau, J.M.; Stutzmann, C. Eur. J. Pharmcol. 1995, 284, 299-307.

12. Figge, A.; Altenbach, H.J.; Brauer, D.J.; Tielmann, P. Tetrahedron Asymmetr.

2002, 13, 137-144.

13. Scott, L.J.; Dunn, C.J.; Mallarkey, G.; Sharpe, M. Drugs2002, 62, 1503-1538.

14. Nakano, H.; Inoue, T.; Kawasaki, N.; Miyataka, H.; Matsumoto, H.; Taguchi, T.; Inagaki, N.; Nagai, H.; Satoh, T. Bioorg. Med. Chem. 2000, 8, 373-380.

15. Zhu, Z.; Lippa, B.; Darch, J.C.; Townsend, L.B. J. Med. Chem. 2000, 43, 2430-2437.

16. Zarrinmayeh, H.; Nunes, A.M.; Ornstein, P.L.; Zimmerman, D.M.; Arnold, M.B.; Schober, D.A.; Gackenheimer, S.L.; Bruns, R.F.; Hipskind, P.A.; Britton, T.C.; Cantrell, B.E.; Gehlert, D.R. J. Med. Chem. 1998, 41, 2709-2719.

17. Sun, L. Q.; Chen, J.; Takaki, K.; Johnson, G.; Iben, L.; Mahle, C. D.; Ryan, E.; Xu, C. Bioorg. Med. Chem. Lett. 2004, 14, 1197.

18. Johnson, S. M.; Connelly, S.; Wilson, I. A.; Kelly, J. W. J. Med. Chem. 2008, 51, 260.

19. Sessions, E. H.; Yin, Y.; Bannister, T. D.; Weiser, A.; Griffin, E.; Pocas, J.; Cameron, M. D.; Ruiz, C.; Lin, L.; Schuerer, S. C.; Schroeter, T.; LoGrasso, P.; Feng, Y. Bioorg. Med. Chem. Lett. 2008, 18, 6390.

(77)

20. Rida Samia, M.; Ashour Fawzia, A.; El-Hawash Soad, A. M.; ElSemary Mona, M.; Badr Mona, H.; Shalaby Manal, A. Eur. J. Med. Chem. 2005, 40, 949.

21. Taki, M.; Wolford, J. L.; O Halloran, T. V. J. Am. Chem. Soc. 2004, 126, 712. 22. Ueki, M.; Ueno, K.; Miyadoh, S.; Abe, K.; Shibata, K.; Taniguchi, M.; Oi, S. J. Antibiot. 1993, 46, 1089.

23. Sato, S.; Kajiura, T.; Noguchi, M.; Takehana, K.; Kobayashi, T.; Tsuji, T. J. Antibiot. 2001, 54, 102.

24. Don, M. J.; Shen, C. C.; Lin, Y. L.; Syu Jr, W.; Ding, Y. H.; Sun, C. M. J. Nat. Prod.

2005, 68, 1066.

25. Tully, D. C.; Liu, H.; Alper, P. B.; Chatterjee, A. K.; Epple, R.; Roberts, M. J.; Williams, J. A.; Nguyen, K. T.; Woodmansee, D. H.; Tumanut, C.; Li, J.; Spraggon, G.; Chang, J.; Tuntland, T.; Harris, J. L.; Karanewsky, D. S. Bioorg. Med. Chem. Lett.

2006, 16, 1975.

26. Nishiu, J.; Ito, M.; Ishida, Y.; Kakutani, M.; Shibata, T.; Matsushita, M.; Shindo, M. Diabetes Obes. Metab. 2006, 8, 508.

27. Leaver, I. H.; Milligan, B. Dyes Pigm. 1984, 5, 109.

28. Barker, H. A.; Smyth, R. D.; Weissbach, H.; Toohey, J. I.; Ladd, J. N.; Volcani, B. E. J. Biol. Chem. 1960, 235, 480-488.

29. Sih J.C., Im W.B., Robert A., Graber D.R., Blackmann D.P., J.Med. Chem, 1991, 34, 1049 -1062.

30. Kuhler T.C., Fryklund J., Bergman N., Weilitz J., Lee A., and Larsson H., J.Med. Chem, 1995, 38, 4906-4916.

(78)

31. Carcanagu D, Shue Y.K., Wuonola M.A., Nickelsen M.U., Joubran C., Abedi J.K., Jones J., Kuhler T.C., J. Med. Chem, 2002, 45, 4300-4309.

32. Seth S.D., Text Book of Pharmacology, 2nd ed; Elsevier, New Delhi, 1999,

390-391.

33. Murthi, Y.; Pathak, D. J Pharm Res. 2008, 7(3), 153-155.

34. Hutchinson, I.; Chua, M. S.; Browne, H. L.; Trapani, V.; Bradshaw, T. D.; Westwell, A. D. J Med Chem. 2001, 44,1446-1449.

35. Sreenivasa, M.; jaychand, E.; Shivakumar, B.; Jayrajkumar, K.; Vijaykumar, J. Arch Pharm Sci and Res.2009, 1(2), 150-157.

36. Henriksen, G.; Hauser, A. I.; Westwell, A. D.; Yousefi, B. H.; Schwaiger, M.; Drzezga, A.; Wester, H. J. J. Med. Chem. 2007, 50, 1087.

37. Black, C.; Deschenes, D.; Gagnon, M.; Lachance, N.; Leblanc, Y.; Leger, S.; Li, C. S.; Oballa, R. M. PCT Int. Appl. 2006, WO 2006122200 A1 20061116.

38. Bradshaw, T. D.; Wrigley, S.; Shi, D. F.; Schulz, R. J.; Paull, K. D.; Stevens, M. F. G. Br. J. Cancer 1998, 77, 745.

39. Lau, C. K.; Dufresne, C.; Gareau, Y.; Zamboni, R.; Labelle, M.; Young, R. N.; Metters, K. M.; Rochette, C.; Sawyer, N.; Slipetz, D. M. L.; Jones, C. T.; McAuliffe, M.; McFarlane, C.; Ford-Hutchinson, A. W. Bioorg. Med. Chem. 1995, 5, 1615. 40. Bergman, J. M.; Coleman, P. J.; Cox, C.; HartmanLindsley, G. D. C.; Mercer, S. P.; Roecker, A. J.; Whitman, D. B. PCT Int. Appl. 2006, WO 2006127550.

41. Ali, A.; Taylor, G. E.; Graham, D. W. PCT Int. Appl. 2001, WO 2001028561. 42. Pang Y.; Hua, W. Tetrahedron Lett. 2009, 50, 6680-6683.

(79)

43. Shen, W.; Kohn, T.; Fu, Z.; Jiao, X.; Lai, S.; Sahmitt, M. Tetrahedron Lett. 2008, 49, 7284-7286.

44. Baltork, I.M.; Khosropour, A.R.; Hojati, S.F. Catal. Commun. 2007, 8, 1865-1870.

45. Baltork, I.M.; Moghadam, M.; Tangestaninejad, S.; Mirkhani, V.; Zolfigol, M. A.; Hojati, S. F. J. Iran. Chem. Soc. 2008, 5, 65-70.

46. Padalkar, V. S.; Gupta, V. D.; Phatangare, K. R.; Patil, V. S.; Umape, P. G.; Sekar, N. Green Chemistry Letters and Reviews. 2012, 5 (2), 139-145.

47. Blacker, A. J.; Farah, M. M.; Hall, M. I.; Marsden, S. P.; Saidi, O.; Williams, J. M. J. Org. Lett. 2009, 11, 2039-2042.

48. Nadaf, R. N.; Siddiqui, S. A.; Daniel, T.; Lahoti, R. J.; Srinivasan, K. V. J. Mol. Catal. A Chem. 2004, 214, 155-159.

49. Chakraborti, A. K.; Selvam, C.; Kaur,G.; Srikant, B. Synlett, 2004, 851-855. 50. Kumar, R.; Selvam, C.; Kaur, G.; Chakraborti, A. K. Synlett, 2005, 1401-1404.

51. Kumar, D.; Rudrawar, S.; Chakraborti, A. K. Aust. J. Chem. 2008, 61, 881-887.

52. Guru, M. M.; Ali, M. A.; Punniyamurthy, T. Org. Lett. 2011, 13, 1194-1197. 53. Saha, P.; Ramana, T.; Purkait, N.; Ali, M. A.; Paul, R.; Punniyamurthy, T. J. Org. Chem.2009, 74, 8719-8725.

54. Praveen, C.; Kumar, K. H.; Muralidharan, D.; Perumal, P. T. Tetrahedron. 2008, 64, 2369-2374.

55. Pottorf, R. S.; Chada, N. K.; Katekevics, M.; Ozola, V.; Suna, V.; Ghane, H.; Regberg, T.; Player, M. R. Tetrahedron Lett. 2003, 44, 175-178.

(80)

56. Kawashita, Y.; Nakamichi, N.; Kawabata, H.; Hayashi, M. Org. Lett. 2003, 5, 3713-3715.

57. Wang, Bo.; Zhang, Y.; Li, Pinhua.; Wang, Lei. Chin. J. Chem. 2010, 28, 1697-1703.

58. Cho, C. S.; Kim, D. T.; Zhang, J. Q.; Ho, S. L.; Kim, T. J.; Shim, S. C. J. Heterocyclic Chem. 2002, 39, 421-423.

59. Lim, H.J.; Myung, D.; Lee, C.Y.; Jung, M.H. J. Comb. Chem. 2008, 10, 501-503.

60. Praveen. C.; Kumar, A. N.; Kumar, P. D.; Muralidharan, D.; Perumal, P. T. J. Chem. Sci. 2012, 124, 609-624.

61. Chang, J.; Zhao, K.; Pan, S. Tetrahedron Lett. 2002, 43, 951-954. 62. Nagawade, R. R.; Shinde, D. B. Chin. Chem. Lett. 2006, 17, 453-456. 63. Lu, J.; Yang, B.; Bai, Y. Synth. Commun. 2002, 32, 3703-3709.

64. Kidwai, M.; Jahan, A.; Bhatnagar, D. J. Chem. Sci.2012, 122, 607-612. 65. Sun, P.; Hu, Z. J. Heterocyclic Chem. 2006, 43, 773-775.

66. Sadeghi, B.; Nejad, M. G. Journal of Chemistry. Vol. 2013, Article ID 581465, 5 pages, 2013.

67. Trivedi, R.; De, S.K.; Gibbs, R.A. J. Mol. Catal. A Chem. 2006, 245, 8-11.

68. Jacob, R.G.; Dutra, L.G.; Radatz, C.S.; Mendes, S.R.; Perin, G.; Lenardao, E. Tetrahedron Lett. 2009, 50, 1495-1497.

(81)

70. Salehi, P.; Dabiri, M.; Zolfigol, M.A.; Otokesh, S.; Baghbanzadeh, M. Tetrahedron Lett. 2006, 47, 2557-2560.

71. Rudrawar, S.; Kondaskar, A.; Chakraborti, Asit. K. Synthesis. 2005, 2521-2526.

72. Chakraborti, A.K.; Rudrawar, S.; Kaur, G.; Sharma, L. Synlett. 2004, 1533-1536.

73. Subhas Bose, D.; Idrees. M. J. Org. Chem. 2006, 71, 8261-8263.

74. Inamoto, K.; Hasegawa, C.; Hiroya, K.; Doi, T. Org. Lett. 2008, 10, 5147.

75. Pratap, U. R.; Mali, J. R.; Jawale, D. V.; Mane, R. A. Tetrahedron Letters. 2009, 50, 1352-1354.

76. Bahrami, K.; Khodaei, M. M.; Naali, F. Synlett. 2009, 4, 569-572.

77. Yang, X. L.; Xu, C. M.; Lin, S. M.; Chen, J. X.; Ding, J. C.; Wu, H. Y.; Su, W. K. J. Braz. Chem. Soc. 2010, 21, 37-42.

78. Jin, H. L.; Cheng, T. X.; Chen, J. X. Applied Organometallic Chem. 2011, 25, 238-240.

79. Moghadhan, F.M.; Ismaili, H.; Bardajee, C.R. Heteroatom Chem. 2006, 17, 136–141.

80. Azizi, N.; Amiri, A. K.; Baghi, R.; Bolourtchian, M.; Hashemi, M. M. Montash Chem. 2009, 140, 1471-1473.

Figure

Updating...

References

Updating...