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Current Organic Chemistry, 2010, 14, 48-64

2-Acetylbenzofurans: Synthesis, Reactions and Applications

Mohamed A. Metwallya, Bakr F. Abdel-Wahabb and Gamal A. El-Hiti*c

a b c

Department of Chemistry, Faculty of Science, University of Mansoura, P.O. Box 23, Mansoura, Egypt Applied Organic Chemistry Department, National Research Center, Dokki, Giza, Egypt School of Chemistry, Cardiff University, Main Building, Park Place, Cardiff CF10 3AT, UK

Abstract: This review deals with synthesis and reactions of 2-acetylbenzofurans. Some of these reactions have been applied successfully to the synthesis of biologically important compounds. The main purpose of this review is to present a survey of the literature on 2-acetylbenzofurans chemistry and provides useful and up-to-date data for their applications since such compounds have not been previously reviewed.

1. INTRODUCTION 2-Acetylbenzofuran, known as 2-benzofuryl methyl ketone, was named as 1-(benzofuran-2-yl)ethanone using the IUPAC system. 2-Acetylbenzofurans have been employed successfully as starting materials for the production of biologically active compounds. Due to the wide spectrum of activities shown by benzofuran moiety, various substituted benzofurans with various substituents at different positions have been synthesized. Also, reactions of benzofuran derivatives were studied and have been applied to the synthesis of more complex valuable materials. 2. METHODS OF SYNTHESIS 2.1. Friedel-Craft Acetylation Friedel­Crafts acetylation of benzofuran (1) provides a fundamental method for the preparation of 2-acetylbenzofuran (2a), which is a useful intermediate for the synthesis of many valuable compounds. Benzofuran itself is known to be sensitive to the ordinary Friedel-Crafts acetylation in the presence of AlCl3 as a catalyst [1,2]. However, benzofuran (1) can be acetylated at high temperature using acetic anhydride in the presence of phosphoric acid. However, such method suffers from low product yield and the reaction succeeds only when the anhydride was employed as the solvent [3]. For example, treatment of benzofuran (1) with acetic anhydride in acetic acid in the presence of phosphoric acid as a catalyst, at 130 °C for 4 h, gave 2-acetylbenzofuran (2a; Scheme 1) in moderate yields (33-55%) [3].

Ac2O Ac O 1

Scheme 1.

Generally, Friedel-Crafts acetylation of 1 suffer serious disadvantages, including some or all of the following: the requirement for large quantities of mineral or Lewis acids as activators, which on work-up may be hydrolysed with generation of large quantities of corrosive and toxic waste by-products; poor yields or production of mixtures of regioisomers. Major efforts are therefore being made to develop clean and environmentally friendly processes for the production of 2a via Friedel-Crafts acetylation of benzofuran (1). It is well recognized that zeolite catalysts can play an important role in the development of greener synthesis of 2a through their abilities to act as recyclable heterogeneous catalysts, support reagents, entrain by-products and avoid aqueous work-ups. Indeed, zeolites have been used as catalysts for the acetylation of 1 under mild conditions [5-8]. It was found that acetylation of 1 with acetic anhydride at 60 °C for 10 h in the presence of zeolite Y produced 2a in 43% yield [5]. However, the sustainability of the process that improved the yield of 2a was still low. 2.2. From 1-(benzofuran-2-yl)ethanol Oxidation of 1-(benzofuran-2-yl)ethanol (3) with dimethyldioxirane (three mole equivalents) at 0 °C for 12 h gave 2-acetylbenzofuran (2a) in 38% yield (Scheme 2) [9]. Since 2a was produced in only low yield, expoxidation of the enol ether bond could take place. It is believed that dimethyldioxirane oxidation of 3 initially afforded the corresponding epoxide, which subsequently could arrange 2a via 1,2-migration.

O Me Me O Me O 2a (38%) Me O

Catalyst

O 2a

Scheme 2.

O 3

OH

0 °C, 12 h

Also, catalytic Friedel­Crafts acetylation of 1 has been achieved with acetic anhydride in the presence of metal triflates as catalysts in acetonitrile as a solvent [4]. 2-Acetylbenzofurane (2a) was produced in the yield of 30-72% along with a small proportion of 3-acetylbenzofuran as a side product [4].

2.3. From 2-(trimethylsilyl)benzofuran 2-Acetylbenzofuran (2a) was synthesized in 88% yield from the reaction of 2-(trimethylsilyl)benzofuran (4), available quantitatively from 1 itself via lithiation followed by reaction with chlorotrimethylsilane at low temperature, with acetyl chloride in the presence of titanium chloride at -78 °C (Scheme 3) [10,11]. 2.4. From 2-hydroxybenzaldehydes

*Address correspondence to this author at the School of Chemistry, Cardiff University, Main Building, Park Place, Cardiff CF10 3AT, UK; Tel: +442920870601; Fax: +442920874030; E-mail: [email protected]

The yield of 2a obtained from direct acetylation of benzofuran is always low. This problem could be overcome by incorporation of

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2-Acetylbenzofurans: Synthesis, Reactions and Applications

Current Organic Chemistry, 2010, Vol. 14, No. 1 49

n-BuLi, -78 °C O 1 Me3ClSi, -78 °C SiMe3 O 4 (100%)

AcCl, TiCl4 Ac -78 °C O 2a (88%)

Scheme 3.

the 2-acetyl group in the starting materials, in which benzofuran ring was constructed during reaction. Indeed, reactions of 2-hydroxybenzaldehydes 5 with chloroacetone in the presence of alcoholic potassium hydroxide gave the corresponding 2-acetylbenzofuran derivatives 2 (Scheme 4) [12-16]. For example, treatment of salicylaldehyde with chloroacetone in the presence of alcoholic KOH produced 2a in 67% yield after purification [12].

R1 CHO AcCH2Cl alc. KOH R1 Ac R2 OH R2 2 O

Fig. (1).

OMe

OMe

MeO 9

OH

MeO 10

O

Ac

5 R1 = R2 = H, OMe

Scheme 4.

Also, compound 2b could be produced but in only low yield (19%) from direct reaction of 9 (Fig. 1) with DMF-DMA in acetonitrile at 90 °C for 48 h [18]. The yield was improved to 35% when the reaction was carried out under microwave conditions in the presence of zinc chloride as a catalyst [18]. 2.7. From 2-acetylbenzofuranhydrazone Hydrolytic cleavage of 2-acetylbenzofuranhydrazone (11) under acidic conditions in the presence of 4-chlorobenzaldehyde is a convenient method for the regeneration of 2a (Scheme 7) along with formation of bis(4-chlorobenzylidene)hydrazine as a sideproduct [19].

2.5. From -oxoacyloxybenzylphosphonium Salt Intramolecular Witting reaction of (2-(2-oxopropanoyloxy) benzyl)triphenyl-phosphonium salt (6) afforded 2-acetylbenzofurans 2 but as a mixture with 3-methylcoumarin (7; Scheme 5) [17].

R1

CH2PPh3X

R1 Ac + O R2

R1

Me

OCOAc R2 6 R1 = R2 = H, Br; R2 = NO2

O R2 7

O

2

Scheme 5.

2.6. From (Z)-3-(3,5-dimethoxyphenoxy)-4-(dimethylamino)but3-en-2-one Intramolecular cyclization of (Z)-3-(3,5-dimethoxyphenoxy)-4(dimethylamino)but-3-en-2-one (8) catalyzed by ZnCl2, at room temperature for 48 h, afforded 2-acetyl-4,6-dimethoxybenzofuran (2b), the naturally occurring compound known as calebertin, in 60% yield (Scheme 6) [18].

OMe Ac MeO 8 O Me N Me ZnCl2 Ac DCM, 48 h MeO O 2b (60%) OMe

3. REACTIONS 3.1. Reduction Catalytic hydrogenation of 2a was found to be dependent on the type of reducing agent. For example, hydrogenation of 2a using platinum/hydrogen or sodium borohydride afforded 2-(1hydroxyethyl)benzofuran (3; Scheme 8) in high yield [20,21]. However, use of Raney nickel catalyst produced 1-(2,3dihydrobenzofuran-2-yl)ethanol (12) in 81-90% yields [20]. Also, it was found that hydrogenation of 2a in the presence of colloidal platinum resulted in a mixture of 3, 12, 13 and 2-ethyl-2,3dihydrobenzofuran [20]. On the other hand, Wolf-Kishner reduction of 2a gave 2-ethylbenzofuran (13; Scheme 8) [15,22]. 2-Acetylbenzofuran (2a) was reduced selectively with borane/oxazaborolidine, generated in situ from triisopropoxyborane and (1S,3S,4R,6R)-4-amino-3,7,7-trimethylbicyclo[4.1.0]heptan-3ol, to afford (S)-1-(benzofuran-2-yl)ethanol (14, Scheme 9) in 98% ee [23]. Also, reduction of 2a with borane/oxazaborolidines, generated in situ from (1S,2R)-norephedrine or (S)-diphenylvalinol, resulted in the production of 14 but in a lower enantiomeric excess.

Scheme 6.

Reaction of 3,5-dimethoxyphenol (9; Fig. 1) with chloroacetone in the presence of K2CO3, under reflux conditions for 12 h in acetone, gave the corresponding ether 10 (Fig. 1) in 72% yield which on reaction with N,N-dimethylformamide-dimethyl acetal (DMFDMA) at 80 °C for 6 h gave 8 in 82% yield [18].

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O

N Me

NH2 + Cl CHO

HCl/H2O/EtOH reflux, 30 min O 2a

O Me

11

Scheme 7.

Me O 3 OH

Pd/H2 or NaBH4 O 2a

Me O

Wolf-Kishner Et O 13

Raney-Ni Me O 12

Scheme 8.

O BOPri NH

OH

Br Me O O Br2 AcOH or CS2 O 18 O

, BH3/THF Me O 2a O 0 °C, 4 h 14 O Me OH

2a

Scheme 12.

Scheme 9.

3.2. Oxidation Oxidation of 2a with selenium dioxide in aqueous dioxane, under reflux conditions for 3 h, gave 2-( , -dihydroxyacetyl)benzofuran (15) which could be dehydrated to give 2-(benzofuran-2-yl)2-oxoacetaldehyde (16; Scheme 10) [24]. Benzofuran acetic acids 17 can be conveniently synthesized from reactions of 2 with sulfur in the presence of morpholine followed by hydrolysis of the resulting thiomorpholides (Scheme 11) [25]. 3.3. Halogenation Bromination of 2a with bromine in acetic acid, dioxane/ether or carbon disulfide as a solvent gave 1-(benzofuran-2-yl)-2bromoethanone (18; Scheme 12) [26-29].

Bromination of 5-chloro-3-methyl-2-acetylbenzofuran (2c) with bromine in acetic acid as a solvent gave 5-chloro-3-methyl-2bromoacetylbenzofuran (19; Scheme 13) [30].

Me Cl O 2c

Scheme 13.

Me Br Me O Br2 AcOH Cl O 19 O

1-(1-Benzofuran-2-yl)-2-chloroethanone (20; Scheme 14) was synthesized from 2a by chlorination with thionyl chloride. From the X-ray study, it was found that the benzofuran ring and the carbonyl group are coplanar. Also, the carbonyl group was found to be in a syn position relative to both the O atom of the benzofuran ring and the C-l atom [31].

HO

Me O 2a

Scheme 10.

SeO2 O 15 O

OH

- H2O O 16

CHO O

O

Me R O Me O 1, S/morphline 2, Hydrolsis 17 R

Me COOH O

2 R = H, Cl, F, Me, Me3C, OMe, Ph, PhCH2, cyclohexyl

Scheme 11.

2-Acetylbenzofurans: Synthesis, Reactions and Applications

Current Organic Chemistry, 2010, Vol. 14, No. 1 51

Cl Me O 2a

Scheme 14.

Me O O

HBr LiAlH4 O 24

Me Br

SOCl2 O 20

Scheme 17.

O

O

2a

Treatment of 2a with TIPSOTf in the presence of Pr2NEt in dichloromethane gave the corresponding ether 21 (Scheme 15) in 98% yield. Chlorination of 21 with N-chlorosuccinimide (NCS; 1.1 equivalents) in THF under reflux conditions gave the corresponding chloro derivative 22 (Scheme 15) in 99% yield but as a mixture of two geometric isomers. 1-(1-Benzofuran-2-yl)-2-chloroethanone

Me O 2a O TIPSOTF

iPr NEt, 2

i

Reaction of N-(2-acetylbenzofuran-3-yl)acetamide (25) with bromine in THF or phenyltrimethylammonium tribromide (Me3NPhBr3) gave N-(2-(2-bromoacetyl)benzofuran-3-yl)acetamide (26; Scheme 18) in 51 or 59% yield, respectively. While, reaction of 25 with two equivalents of sulfuryl chloride (SO2Cl2) in acetic acid gave N-(2-chlorobenzofuran-3-yl)acetamide (27; Scheme 18) in 78% yield after purification [35]. Compound 27 was

CH2Cl2

O 21 (98%)

OTIPS

Cl NCS, THF O 22 (99%)

Scheme 15.

Cl OTIPS

48% aq. HF MeCN O 20 (67%) O

(20; Scheme 15) was isolated in 67% yield after desilylation of 22 with aqueous HF (48%) in acetonitrile as a solvent [32]. Direct -iodination of 2a with elemental iodine in the presence of 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis (tetrafluoroborate) afforded 1-(benzofuran-2-yl)-2-iodoethanone (23; Scheme 16) [33].

I Me O 2a

Scheme 16.

obtained in 51% yield when excess chlorine in chloroform was used as the chlorinating reagent [36]. On the other hand, 1-(3-methylbenzofuran-2-yl)ethanone (2d) was easily halogenated with SO2Cl2 in chloroform or Me3NPhBr3 in THF to give the corresponding haloacetyl derivatives 28 (Scheme 19) in high yields after crystallization [35].

Me Me O O SO2Cl2 or Me3N+Ph Br3O 28 X = Cl, Br Me O X

I2 O 23 O

2d

Scheme 19.

O

Reaction of 2a with hydrobromic acid in the presence of lithium aluminum hydride gave 2-(1-bromoethyl)benzofuran (24; Scheme 17) [34].

NHAc O O 26 (51-59%)

Scheme 18.

Reaction of 2a with ethylene glycol in benzene and in the presence of 4-tolylsulfonic acid afforded 2-(2-methyl-1,3-dioxolan-2yl)benzofuran (29) which on bromination with bromine in chloroform gave 2-(2-(dibromomethyl)-1,3-dioxolan-2-yl)benzofuran (30; Scheme 20) [36].

NHAc NHAc Me O 25 O SO2Cl2 AcOH O 27 (78%) Cl

Me3N+Ph Br3Br or Br2

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HO Me O 2a

Scheme 20.

HO benzene O 29

Me O O

B Br2 CHCl3 O 30 O

Br O

O

NO2 O2N Ac O 31

Fig. (2).

Ac O2N 32 O 33 O

Ac O NO2 34

Ac O 35

NO2

OMe HNO3 Ac2O O2N

OMe

OMe

Ac O 2e

Scheme 21.

Ac O 36

+ O NO2 37

Ac

3.4. Nitration

Me

NR2 i, HCHO, R2NH ii, NaBH4 O 39 OH

Nitration of 2a with a mixture of nitric acid and acetic anhydride was mostly successful at the 5 and 6-positions and in some instances at the 4-position and possibly at the 7-position to give the corresponding nitro derivatives 31-34 (Fig. 2), respectively. In some cases, the acetyl group at the 2-position was replaced by the nitro group to produce 2-nitrobenzofuran (35; Fig. 2) [37]. Bachelet et al. [38] reported the synthesis of 1-(4-methoxy-5nitrobenzofuran-2-yl)ethanone (36) but as a mixture with 1-(4methoxy-7-nitrobenzofuran-2-yl)ethanone (37) from nitration reaction of 2-acetyl-4-methoxybenzofuran (2e) with a mixture of nitric acid and acetic anhydride (Scheme 21). 3.5. Acetylation 2-Acetylbenzofurans 2 (R = 4-OMe, 5-OMe, 6-OMe, 7-OMe) could be acetylated, but not regioselectively, at the 4-, 5- and 7postions or at the 4- and 7-positions [39]. However, regioselective acetylation of 2a with acetic anhydride at 60 °C in the presence of zeolite HY (Si/Al = 16) as a catalyst gave 3-(benzofuran-2carbonyl)pentane-2,4-dione (38) as the main product (Scheme 22) as a result of two consecutive acetylation steps on the side chain [40]. Other minor products were also obtained but the purity of 38 was high (ca. 96%) and the conversion of 2a was ca. 50%.

Ac Me O 2a

Scheme 22.

O 2a

O

NR2 = 4-phenylpiperazino, piperidino, morpholino, 4-(2-methylphenyl)piperazino

Scheme 23.

3.7. Schmidt Rearrangement Schmidt rearrangement of 2-acetylbenzofuran (2a) gave N-methylbenzofuran-2-carboxamide (40; Fig. 3) [34,42].

O O 40

Fig. (3).

NHMe

3.8. Claisen Condensation Claisen condensation of 2a with diethyl oxalate in the presence of sodium methoxide gave ethyl 4-(benzofuran-2-yl)-2,4dioxobutanoate (41, Scheme 24) [43]. Recently, compound 41 was used as intermediate for the synthesis of biologically active heterocycles such as 5-(benzofuran-2yl)-pyrazole-3-carboxamides 42 (Fig. 4) and 3-(5-(benzofuran-2yl)-1-phenyl-1H-pyrazol-3-yl)-4-(2-chloro-4nitrobenzylideneamino)-1H-1,2,4-triazole-5(4H)-thione (43; Fig. 4) [44,45]. 3.9. Reaction with Grignard Reagents The reaction of 2a with a Grignard reagent followed by dehydration gave 2-(1-propenyl)benzofuran (44; Fig. 4) [46].

Ac2O, 60 °C HY O 38 O

Ac

O

3.6. Mannich Reaction Mannich reaction of 2a with various amines followed by reduction with NaBH4 gave the corresponding benzofuranoaminopropan1-ols 39 (Scheme 23) [41].

2-Acetylbenzofurans: Synthesis, Reactions and Applications

Current Organic Chemistry, 2010, Vol. 14, No. 1 53

EtO Me O 2a O O

O CO2Et OEt O MeONa O 41 O

Scheme 24.

O O N H O R 42 R = H, Ph

Fig. (4).

N N O O N Ph N

H N S N N Cl O Me

N

N

43

NO2

44

3.10. Aldol Condensations Reaction of 2-acetylbenzofuran (2a) with aldehydes took place smoothly and easily to produce the corresponding condensation product that could be easily cyclised to produce various heterocyclic compounds [47-50]. For example, treatment of 2a with various aldehydes in solvent-free reactions under microwave irradiation conditions [48] or in the presence of a strong base [49] gave the corresponding chalcones 45 (Scheme 25). Also, (E)-1-(benzofuran2-yl)-3-phenylprop-2-en-1-one (45, R = Ph; Scheme 25) was obtained from reaction of 2a with benzaldehyde in DMF and in the presence of chlorotrimethylsilane (three molar equivalents), as a promoter and water-acceptor agent, at 100 °C in a sealed tube [47].

R Me O 2a

Scheme 25.

RCHO O 45 O

Condensation of 45 with guanidine hydrochloride, thiourea and urea, in the presence of a strong base or under microwave conditions, afforded the corresponding 4-substituted 6-(benzofuran-2yl)pyrimidines 46 (Scheme 26) [48,49]. Also, it was found that condensation of 45 with hydrazines gave the corresponding pyrazolines 47 (Scheme 27) [51-57]. 3-Aryl-1-(benzofuran-2-yl)prop-2-en-1-ones 45 also undergo condensation with heterocyclic hydrazines to give the corresponding hydrazones 48 (Scheme 28) [58-60]. On the other hand, condensation of 45 with mefenamic acid hydrazide gave the corresponding pyrazolines 49 (Scheme 29) [5860]. Cyclocondensation of 45 with different hydrazides resulted in the formation of benzofuran-2-pyrazolines 50 (Scheme 30) [61,62]. Similarly, condensation of 45 with o-phenylenediamine or 2-aminothiophenol gave the corresponding benzodiazepines 51 (Scheme 31) [51-57].

O R = alkyl, aryl

R H2N O 45 O

X NH2

R N

MW or base

O 46

N XH

R = alkyl, aryl; X = NH.HCl, S, O

Scheme 26.

Ar RNHNH2 O 45

Scheme 27.

Ar O N 47 N R

O R = H, Me, Ph, 4-NO2C6H4

Ar Het-NHNH2

Ar Het

O 45

Scheme 28.

O

O 48

N

NH

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Ar mefenamic acid O 45 O hydrazide O 49 N O N

Ar O

N

Et

F N

N H

Scheme 29.

O Ar Ar1 N H NH2 Ar O 50 O N NH

O 45

Scheme 30.

O

Ar1

R1 R2 O 45

Scheme 31.

NH2 Ar XH O R1, R2 = H, Me, Cl, X = NH, S R2

R1 N O 51 X Ar

O Me + O 2a

Scheme 32.

Me KOH N 52 N EtOH CPh3 O 53 O N N

Me

O

CPh3

O Me O 2a

Scheme 33.

O OH AcOH O 54 O HO O

O

North and Oxford [63] have synthesized 1-(benzofuran-2-yl)-3(5-methyl-1-trityl-1H-imidazol-4-yl)prop-2-en-1-one (53) by stirring 2a with 5-methyl-1-trityl-1H-imidazole-4-carbaldehyde (52) in ethanolic potassium hydroxide for overnight (Scheme 32). Bianchi and Barzaghi [64] reported the successful synthesis of 4-(benzofuran-2-yl)-4-oxobut-2-enoic acid (54) from reaction of 2a with glyoxalic acid in acetic acid (Scheme 33).

Condensation of 2a with 2-(2,2-dimethylhydrazono)propanal (55) gave 1-(benzofuran-2-yl)-4-(2,2-dimethylhydrazono)pent-2en-1-one (56; Scheme 34) [65]. 3.11. Synthesis of Quinolines Substituted quinoline 57 was prepared using Friedländer synthesis from reaction of 2a with 2-aminobenzophenone in DMF and

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Current Organic Chemistry, 2010, Vol. 14, No. 1 55

Me O Me + O 2a

Scheme 34.

N N N Me 55 Me O 56 O Me N Me Me

O

O Me + O 2a

Scheme 35.

Ph NH2

Me3SiCl DMF O 57

N

O

Ph

O O Me + O 2a

Scheme 36.

OH O base O 58 N

O

N H

MeO

OMe

CHO Me + O 2a

Scheme 37.

NH4OAc + OMe OMe NC CO2Et O HN 59 (30%) O CN

O

Ar Me + O 2a

Scheme 38.

ArCHO

NH4OAc + NC CN O N NH2 CN

O Ar = Ph, 4-ClC6H4, 4-MeOC6H4

60 25-30%)

in the presence of chlorotrimethylsilane as a promoter and wateracceptor agent (Scheme 35) [66]. Also, reaction of 2a with isatin in alkaline medium, by the Pfitzinger reaction, gave quinoline-4-carboxylic acid (58, Scheme 36) [67]. 3.12. Reactions with Arylidene Nitriles Reactions of 2a with a mixture of 3,4-dimethoxybenzaldehyde and ethyl cyanoacetate in the presence of ammonium acetate, in dry ethanol under reflux conditions for 3 h, afforded 3-cyano-4-(3,4dimethoxyphenyl)-6-(1-benzofuran-2-yl)-lH-pyrid-2-one (59; Scheme 37) in 30% yield after purification [68].

Similarly, reaction of 2a with a mixture of aromatic aldehydes and malononitrile in the presence of ammonium acetate, in dry ethanol under reflux conditions for 3-4 h, gave the corresponding 2-amino-4-aryl-6-(benzofuran-2-yl)nicotinonitrile 60 (Scheme 38) in 25-30% yields after crystallization [68]. Treatment of 2a with 2-(3,4,5-trimethoxybenzylidene)malononitrile, in the presence of sodium alkoxide, gave the corresponding 6-(benzofuran-2-yl)-2-alkoxy-4-(3,4,5-trimethoxyphenyl)nicotinonitriles 61 (Scheme 39) [69]. 3.13. Reactions with Schiff's Bases Reactions of 2a with Schiff bases 62 gave the corresponding 3-aryl-1-(benzofuran-2-yl)benzo[f]quinolines 63 (Scheme 40) [70].

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MeO OMe MeO Me + O 2a

Scheme 39.

OMe OMe

OMe RONa NC NC ROH R = Me, Et, Pr O 61 N OR CN

O

Ar Me + O 2a O 62 63 O N Ar N

Ar = 3-pyridinyl, 2-quinolinyl, (un)substituted phenyl

Scheme 40.

Me N Me Me O 2a

Scheme 41.

O CONH2 NaOMe O 65 HN CN

DMF-DMA DMF O 64 O

NC

O

Ar Me N Me Cl O 64

Scheme 42.

O

R H N

N Ar O 66 O

N O R

N

O

Me Me + O 2a

Scheme 43.

O

NH H2N NH2 NH O 67 N NH2

O

3.14. Reactions with DMF-DMA Condensation of 2a with dimethylformamide-dimethylacetal (DMF-DMA) afforded 1-(benzofuran-2-yl)-3-(dimethylamino)prop-2-en-1-one (64; Scheme 41). Addition of cyanoacetamide to 64 in the presence of sodium methoxide gave 3-cyano-6-(benzofuran-2yl)pyridin-2(1H)-one (65; Scheme 41) [71]. Recently, Abdelhamid et al., reported the synthesis of 3-acyl-4(1-benzofuran-2-ylcarbonyl)pyrazoles 66 via reaction of 64 with the appropriate hydrazonoyl chlorides (Scheme 42) [72].

3.15. Reaction with Guanidine 4,6-Di(benzofuran-2-yl)-6-methyl-1,6-dihydropyrimidin-2amine (67) can be synthesized from the reaction of equimolar amounts of 2a and guanidine (Scheme 43) [73]. 3.16. Reactions with Amines, Hydroxylamine, Hydrazines and Hydrazides Schiff's bases 68 were produced from reaction of 2 (R = H, Me) with aromatic amines, which on treatment with chloroacetyl chloride in dioxane produced azetidinones 69 (Scheme 44) [74].

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Current Organic Chemistry, 2010, Vol. 14, No. 1 57

R O + ArNH2 O 2a

Scheme 44.

R EtOH/AcOH O 68 N Me Ar ClCH COCl 2

R

Ar N

O

Me

O 69

Me

Me O 2a Me HN Ph O

H2NOH.HCl AcONa reflux, 3 h O 70 (95%)

Me N OH

1, NaH, DMF, 0 °C 2, BnCl, RT O 71 (90%)

Me N OBn

B H

O , THF, 0 °C, 6 h RT, 24 h

Me O HN OBn

1, ClSO2NCO, THF, -78 °C, 2 h 2, H2O, RT, 18 h

aq. HCl, RT, 18 h

72 (64%); 75% ee Me NH2 O BnO 73 (95%)

Scheme 45.

H2, Pd(OH)2/C, MeOH, RT, 2 h C O O HO

Me NH2 N C O

N

74 (83%); 99% ee

HO O O 2a

Scheme 46.

HO

NH2.HCl O 75

N Me

Me

R O O 2 R = H, Me;

Scheme 47.

R1NHNH2 AcOH/EtOH O 76

N Me

NHR1

Me

R1

= Ph, CO2Et, CSNHNHAr

Reaction of 2a with hydroxylamine hydrochloride in the presence of sodium acetate, in ethanol under reflux conditions for 3 h, gave the corresponding oxime 70 in 95% yield (Scheme 45) after crystallization [23]. Oxime 70 could be converted to its benzyl ether 71, in 90% yield, on treatment with sodium hydride followed by reaction with benzyl chloride at room temperature for 18 h (Scheme 45). Reduction of 71 with borane/oxazaborolidine, generated in-situ from (1S,2R)-norephedrine, gave (R)-(+)-N-(1-(benzofuran-2yl)ethyl)-O-benzylhydroxylamine (72) in 64% yield with 75% ee (Scheme 45). In contrast, borane/oxazaborolidine, generated in-situ from (1R,2S,3R,4S)-3-amino-1,7,7-trimethylbicyclo[2.2.1]heptan-2ol, reduced 71 to 72 in 92% ee [23]. Compound 72 was converted into its N-benzyloxyurea derivative 73 in 95% yield, which was

readily debenzylated by palladium catalyzed hydrogenolysis to produce (R)-1-(1-(benzofuran-2-yl)ethyl)-1-hydroxyurea (74) in 83% yield with 92% ee, which was raised up to 99% ee by crystallization [23]. Compound 74 was the first 5-lipoxygenase inhibitor. Treatment of 2a with 2-aminoethanol hydrochloride gave the corresponding oxime 75 (Scheme 46) [75]. 2-Acetylbenzofurans 2 on treatment with phenyl hydrazine [74], ethyl hydrazinecarboxylate [76] and thiosemicarbazides [77], in ethanol containing acetic acid under reflux conditions, gave the corresponding condensation products 76 in good to excellent yields (Scheme 47). Treatment of 76 (R1 = Ph) with Vilsmeier reagent underwent cyclization to produce the corresponding substituted pyrazoles [47].

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Me S N O 76 Cl COOH Me NH Ar NH MeCOCH2Cl dioxane O N Me 77 (54-67%) N S N Ar

S O Me 78 (55-58%)

Scheme 48.

N

O N N Ar Ar = n-Bu, Ph, Bn, 4-MeC6H4

O O Me + O 2a O NH Na2S2O4 O O 80 (78%)

Scheme 49.

H N EtOH/HCl HO

O N H

Et2NH EtOH O O 79 (86%) O NH

O

heat (-H2O)

H2O/EtOH

O

O 81 (63%)

N

N N n-BuLi SMe

N

MeS N N Li 2a SMe O Me 84 (72%) OH N N N

82

Scheme 50.

83

Compound 76 (R1 = CSNHNHAr) was used as a precursor for the synthesis of many valuable compounds. For example, treatment of 76 with chloroacetone in dry dioxane under reflux conditions for 2-3 h gave the corresponding N-(1-benzofuran-2-yl-ethylidene)-N'(4-methyl-3-aryl-3H-thiazol-3-ylidene)hydrazines 77 (Scheme 48) in 54-67% yield [77]. Similarly, treatment of 76 (R1 = CSNHNHAr) with chloroacetic acid in glacial acetic acid and sodium acetate under reflux conditions for 4-5 h afforded the corresponding 2-((1-benzofuran-2-yl-ethylidene)hydrazono)-3-substituted-thiazolidin-4-ones 78 (Scheme 48) in 55-85% yield after crystallization from acetone [77]. 3.17. Synthesis of (benzofuran-2-yl)indolin-2-one Reaction of 2a with isatin in ethanol and in the presence of diethylamine as a catalyst at room temperature gave 3-(2-

(benzofuran-2-yl)-2-oxoethyl)-3-hydroxyindolin-2-one (79; Scheme 49) in 86% yield. Dehydration of 79, on heating in ethanolic hydrochloric acid solution for 30 min, gave 3-(2-(benzofuran-2yl)-2-oxoethylidene)indolin-2-one (80; Scheme 49) in 78% yield [25,78]. Treatment of 80 with Na2S2O4 in aqueous ethanol gave 3-(2-(benzofuran-2-yl)-2-oxoethyl)indolin-2-one (81; Scheme 49) in 63% yield [78]. 3.18. Reaction with 1-[(methylthio)methyl]-1H-benzotriazole Lithiation of 1-[(methylthio)methyl]-1H-benzotriazole (82) with n-BuLi under anhydrous conditions in THF at -78 °C for 1 h followed by reaction of the lithium reagent 83 thus obtained in-situ with 2a at -78 °C for 1 h gave 2-benzotriazolyl alcohol 84 (Scheme 50) in 72% yield [79].

2-Acetylbenzofurans: Synthesis, Reactions and Applications

Current Organic Chemistry, 2010, Vol. 14, No. 1 59

Me O 2a

Scheme 51.

Br

CO2Et O 85

HO

CO2Et - H2O

CO2Et O 86 Me

O

Me

Me Me Me O 2a

Scheme 52.

CO2Et Br O 87

Me Me CO2Et 1, dehydration 2, hydrolysis O Me 88 Me CO2H

O

OH Me

O O O Me O 2a

Scheme 53.

Me3SiCl Et3N O 89

(PhIO)n-BF3.Et2O OSiMe3 90 (63%)

O

O

O Br H2N Cl O 17

Scheme 54.

O Cl NH O 91 O

Cl Cl

O

Me R O 2 O

1, Chlorination 2, [H] 3, - HCl R O 92 O

R1NH2 R O 93 OH

NHR1

R = 5,6-di-Me, 6,7-(CH2)3, 7-Et; R1 = Pr, iPr, tBu

Scheme 55.

3.19. Reformatsky Reaction Reformatsky reaction of 2a with methyl bromoacetate in dry benzene containing Zn under reflux conditions gave the corresponding -hydroxyester 85 which was dehydrated to produce , unsaturated ester 86 (Scheme 51) in high yield [80,81]. Ethyl 2-bromo-2-methylpropanoate was reacted with 2a to give ethyl 3-(benzofuran-2-yl)-3-hydroxy-2,2-dimethylbutanoate (87; Scheme 52). Dehydration of 87 followed by hydrolysis gave 3-(benzofuran-2-yl)-2,2-dimethylbut-3-enoic acid (88; Scheme 52) [81]. 3.20. Reaction with Trimethylsilyl Chloride Reaction of 2-acetylbenzofuran (2a) with chlorotrimethylsilane in DMF and in the presence of triethylamine gave (1-(benzofuran2-yl)vinyloxy)trimethylsilane (89; Scheme 53) [82]. Reaction of 89

with a mixture of iodosobenzene and boron trifluoride in DCM, at -40 °C for 1 h and at room temperature for another 1 h, gave 1,4-di(benzofuran-2-yl)propane-1,3-dione (90; Scheme 53) in 63% yield after crystallization from chloroform [82]. 3.21. Reaction with Dichloroacetamide Reaction of 1-(benzofuran-2-yl)-2-bromoethanone (17) with 2,2-dichloroacetamide gave N-(2-(benzofuran-2-yl)-2-oxoethyl)2,2-dichloroacetamide (91; Scheme 54) [83]. 3.22. Formation of Benzofuran-2-ethanolamines Chlorination of the acetyl group in compounds 2 followed by reduction of the carbonyl group, to produce the corresponding alcohols, and then elimination of HCl from the produced chlorohydrins gave the corresponding oxiranes 92 (Scheme 55) [64,65]. Reactions of 92 with aliphatic amines gave the corresponding benzofuran-2ethanolamines 93 (Scheme 55) [84,85].

60 Current Organic Chemistry, 2010, Vol. 14, No. 1

Metwally et al.

F3C Me O 2a

Scheme 56.

O CF3 OMe O 94 O OH CO2Me N O 95 CF3 NH O

O

N2H4.H2O AcOH

O

O Me O 2a O Cu2O, I2 DMSO Ar Ar SMe O SnCl2 H+ Ar O

SMe Raney-Ni Ar 97 (69%) Ar O 98 (90%) Ar

96 (65%) KI, HCl

SMe HCO2NH4 Ar N H 100 (80%)

Scheme 57.

Me O 70 N HC CH

O Ar SMe 99 (80%) O Ar = 2-benzofuryl Ar Lawesson's reagent Ar S

SMe

Ar

Ar

101 (88%)

Me O 102 N O

- H2O O 103 N H

OH KOH/DMSO 75 °C, 5min

Scheme 58.

3.23. Synthesis of Pyridazines Reaction of 2a with methyl 3,3,3-trifluoropyruvate (MeTFP) gave the aldol product 94 which was reacted readily with hydrazine hydrate in acetic acid to give 4-trifluoromethyl-(2H)-pyridazin-3one (95, Scheme 56) [86]. 3.24. Miscellaneous Reactions Reaction of 2a with dimethyl sulfoxide, in the presence of copper(II) oxide and iodine, gave 1,4-di(benzofuran-2-yl)-2(methylthio)but-2-ene-1,4-dione (96) in 65% yield (Scheme 57) [87]. Compound 96 could be used as precursor for the synthesis of various heterocycles. For example, 96 was converted to (Z)-2,2'-(3(methylthio)furan-2,5-diyl)dibenzofuran (97) in 69% yield on reduction with SnCl2 in acid medium (Scheme 57) which on reductive desulfuration using Raney nickel gave 2,5-di(benzofuran-2yl)furan (98) in 90% yield (Scheme 57). Treatment of 96 with KI in an acid medium gave 99 in 80% yield. Reactions of 99 with ammonium formate and Lawesson's reagent gave 100 and 101 in 80 and 88% yield, respectively (Scheme 57) [87]. Zaitsev, et al. reported the synthesis of 2-(benzofuran-2-yl)-1Hpyrrole (103) from reaction of 2-acetylbenzofuranoxime (70) with acetylene under pressure in KOH/DMSO system via intermediate 102 (Scheme 58) [88]. 4. APPLICATIONS The chemistry of 2-acetylbenzofurans has attracted many researchers due to their biological activities and their potential appli-

cations as pharmacological agents. Also, such compounds are widely distributed in nature, e.g., ailanthoidol and have been reported to have antiviral, antioxidant and antifungal activities [89]. Many compounds that synthesised from 2-acetylbenzofurans have shown antitumor, antiflammatory and fungicidal activities [52,53,86,90]. Furthermore, compounds containing benzofuran moiety also have in-vitro antibacterial activities. Examples include bacterial enzymes involved in the methionine cycle (e.g. methionine aminopeptidase and deformylase), enzymes involved in peptidoglycan synthesis (e.g. UDP-N-acetylmuramyl-L-alanine ligase) and chorismate synthase [45,50]. 2-Acetylbenzofurans are flavor agents and flavor modifiers that added to coffee and food. They are used for treatment of hyperuricemia [91,92], while, 5,6-dimethoxy-2-acetylbenzofuran are used as herbicide [93]. 4-(Benzofuran-2-yl)-2-(3,5-dimethyl-1H-pyrazol1-yl)thiazole (104; Fig. 5) have been reported to show antimicrobial activities [70]. While, 4-aryl-6-(benzofuran-2-yl)pyrimidines 46 (X = NH, S, O; Scheme 26) have shown antitumor and antibacterial activities [55]. 1,2,4-Oxadiazoles 105 (Fig. 5) was found to inhibit the rotamase activity of FKBP12 binding protein on a substrate L-1605 peptide in the presence of -chymotrypsin with IC50 of 0.035 M [94]. Pyridoquinoxalines 106 (Fig. 6) used as antiviral agents for treatment of herpes, varicella zoster, cytomegalovirus and EpsteinBarr virus infections [95]. Chiral benzofuran derivatives 107 (Fig. 7) are used for treatment of cardiac arrhythmias [96].

2-Acetylbenzofurans: Synthesis, Reactions and Applications

Current Organic Chemistry, 2010, Vol. 14, No. 1 61

Me N O 104 S N Me N O

O O O N O R3 F R2 105 R1 = R2 = C3-8 cycloalkyl; R2 = H; R1 R3 F N

N

= H, OH

Fig. (5).

O O OH N Me N R2 N O

O N H R1

106 R1 = F, Cl; R2 = alkyl, hydroxyalkyl, alkoxyalkyl

Fig. (6).

NEt2 X1 O 107 X1, X2 = I, F, Br, Cl R1 = H, alkyl, alkenyl, aryl, alkylaryl, alkenylaryl, heteroaryl, alkylheteroaryl, alkenylheteroaryl, cycloalkyl, heterocycloalkyl, alkylheteroycloalkyl, alkylcycloalkyl O

X2

O O O R1

Me

Fig. (7).

OMe O I Me Me N O I 108

Fig. (8).

X

O O O N N 109 X = H, F

Methyl 2-{3-[4-(2-(dimethylamino)ethoxy)-3,5-diiodobenzoyl) benzofuran-2-yl]}acetate (108; Fig. 8) is useful in regulating cardiac arrhythmia, including atrial fibrillation, in animals and humans [97]. While, 1-[benzofuran-2-yl(phenyl)methyl]-1H-imidazole and its 4-fluoro derivative (109; Fig. 8) were used as inhibitors of aromatase (P 450 AROM) [98]. N-{[2-(Benzofuran-2-yl(phenyl)methylene)hydrazinyl](imino) methyl}-4-nitrobenzamide (110; Fig. 9) is useful as class-III antiarrhythmic agents [99].

Ph N O

H N HN

NH

NO2

O 110

Fig. (9).

62 Current Organic Chemistry, 2010, Vol. 14, No. 1

Metwally et al.

Ac O O 111

Fig. (10).

Ac O O 112

1-(7-(Dodecyloxy)benzofuran-2-yl)ethanone (111; Fig. 10) and 1-(7-(tridecyloxy)benzofuran-2-yl)ethanone (112; Fig. 10) exhibited a specific activity against respiratory syncytial virus in HeLa [100]. 1-(Benzofuran-2-yl)-3-(5-methyl-1-trityl-1H-imidazol-4yl)prop-2-en-1-one (53; Scheme 32) is useful as serotonin antagonists [60]. Also, benzofuran acetic acids 17 (Scheme 11; R = H, Cl, F, Me, Me3C, MeO, Ph, PhCH2, cyclohexyl) are useful as analgesics and inflammation inhibitors [101]. Substituted 3-(benzofuran2-yl)-4,5-dihydro-1H-pyrazoles 113 (Fig. 11) are used as potential antiinflammatory agents [65]. While, substituted 2-benzofuranyl derivatives 114 (Fig. 11) are used as antitubercular agents [58].

R2 O R1

Fig. (11).

[5]

[6]

[7]

[8]

[9]

[10] [11]

N 113

N

R1 R3 O 114 O

R

[12] [13] [14] [15]

2-(1-(Benzofuran-2-yl)ethyl)-7-chloro-2,3-dihydropyridazino[4, 5-b]quinoline-1,4,10(5H)-trione (115; Fig. 12) was found to have potent activity at the glycine site of the NMDA receptor [102].

O O N Cl N H O 115 NH O Me

[16]

[17]

[18]

[19]

[20]

Fig. (12).

CONCLUSIONS The chemistry of 2-acetylbenzofuran has exhibited promise on a number of fronts; the full evaluation of its utility in heterocycles synthesis was not sufficiently investigated. The aim of this review was to demonstrate the wide synthetic application of 2-acetylbenzofuran in organic synthesis and especially the production of biologically useful compounds. REFERENCES

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Received: 09 July, 2009

Revised: 08 Seprember, 2009

Accepted: 11 September, 2009

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