2-arylbenzo[b]furan derivatives are found frequently in natural products and synthetic compounds with high biological activity . for example , neolignins containing benzo[b]furan derivatives have been reported to have good anti - inflammatory properties . some representatives of this heterocyclic system are also anti - bacterial or potential anti - cancer agents ( figure 1 ) . consequently , facile synthetic approaches to such compounds are of critical importance to further assess and refine the potential of this structural class as bioactive entities . bi(hetero)aryl motifs , including arylated benzo[b]furans , have been synthesized by de novo synthesis using cyclization strategies . this changed with the development of metal - catalyzed cross - coupling reactions , which were then the method of choice for the synthesis of such systems for many years . in recent times , another method has started to complement and even substitute cross - coupling chemistry , namely direct arylation methods , often referred to as c  h activation reactions . the advantage of this type of transformation is the absence of pre - functionalized coupling partners . therefore , in the c  c bond - forming step , either the organometallic species ( preferably ) or the ( pseudo)halide component can be substituted by a reactive ( i.e. , activated ) c  h bond instead . this streamlines the synthesis and increases the efficiency considerably , because pre - functionalization ( often achieved within multi - step sequences ) of substrate(s ) is no longer required . hence , avoiding such pre - functionalization shortens synthetic pathways significantly , which is more effiecient in terms of time , resources , and energy . as a consequence therefore , many research groups , including ours , have focused attention on the development of new methods for the direct arylation of heterocycles . heterocycles are especially suitable for c  h activation chemistry because c  h bonds differ significantly in reactivity due to the presence of one or more heteroatoms . to date , series of electron - rich benzo - fused heterocycles have been activated successfully , often by using palladium species to catalyze the direct arylation. interestingly , the direct arylation of benzo[b]furan has been largely neglected . over the years , only a handful examples have been reported on this subject either with mediocre yields or under peculiar reaction conditions . deboef and co - workers disclosed a protocol for the oxidative coupling of benzo[b]furan and benzene derivatives.[11a ] however , benzene had to be used as solvent ( > 80 equiv . glorius and co - workers disclosed that n , n - diisopropylbenzamide can be oxidatively coupled with benzofuran under rh catalysis , in this case with a 10-fold excess of benzofuran.[11e ] fagnou and co - workers reported the direct arylation of a series of heterocycles by using a common protocol;[11c ] one example is the arylation of benzo[b]furan with o - bromotoluene and in this case the yield was low at 29 % . also , kappe[11d ] and bhanage[11b ] and their co - workers each contributed one example of the arylation of benzo[b]furan with aryl halides . kappe essentially followed the protocol of fagnou and co - workers and obtained a yield of 50 % when benzo[b]furan was coupled with 3-bromoquinoline under microwave irradiation . bhanage and co - workers treated benzo[b]furan with bromo- or iodobenzene using [ pd(tmhd)2 ] as catalyst ( tmhd = 2,2,6,6-tetramethyl-3,5-heptanedione ) in good yields of 65 and 83 % , respectively . mori et al . used iodobenzene , 4-iodoanisol , and ethyl 4-iodobenzoate as coupling partners in the direct arylation of benzo[b]furan.[10a ] for iodobenzene , no isolated yield was reported , only an nmr yield of 41 % and with no further comments . the other two coupling partners applied gave yields of 41 and 53 % , respectively . a more detailed investigation of the direct arylation of benzo[b]furan was reported by ohta in 1990.[13a ] they used the simple [ pd(pph3)4 ] as catalyst , aryl bromides as coupling partners and koac as base in dmac at reflux . of the 10 aryl bromides tested , only six gave the coupling product , but in low yields ( typically ca . the only exception was o - bromonitrobenzene , which gave 50 % of the arylation product . the same group reported the direct arylation of benzo[b]furan with chloropyrazines.[13b ] the most c2 selective protocol was reported by doucet and co - workers just recently.[11h ] by using benzylsulfonyl chlorides as coupling partner in combination with [ pdcl2(mecn)2 ] and li2co3 , they were able to arylate benzo[b]furan selectively at c2 in generally good yields ( 13 examples , 5091 % ) . even though this is the most selective protocol reported so far , hence , there is still demand for a general , direct arylation protocol of benzo[b]furan using readily available aryl donors . comparing the aromaticity of benzo[b]furan with -thiophene or furan , the c2c3 bond on benzo[b]furan behaves chemically more like an olefinic double bond than an aromatic system , as is the case in benzo[b]thiophene.[2d,14 ] consequently , the arylation at c-2 of benzo[b]furan is not very selective . normally , 2- , 3- , and bis - arylated products will be observed as a mixture causing problems for the isolation of the desired product.[13a ] therefore cyclization strategies are still often used to synthesize 2-arylbenzo[b]furans . naturally , this requires more steps than the direct arylation approach and moreover has the intrinsic possibility of encountering difficulties in the synthesis , namely intermediate stability and/or functional group tolerance . on the other hand , oxidative direct arylation is another option , although many functional groups do not tolerate the required reaction conditions . herein we describe our efforts to directly arylate benzo[b]furan by taking advantage of a protocol that can be used for benzo - fused heterocycles in general and also allows coupling with a wide range of coupling partners bearing different functional groups . we started our investigations by using the reaction conditions that we recently introduced for the successful c-5 arylation of n - protected thiazoleamines . there we used palladium acetate [ pd(oac)2 ] as catalyst without an additional ligand , potassium acetate ( koac ) as base and n , n - dimethylacetamide ( dmac ) as solvent at 140 c for 24 h. in the case of the arylation of thiazole , aryl iodides served as the aryl source , whereas for the arylation of benzo[b]furan we wanted to focus on cheaper and more readily available bromides . as a model reaction we investigated the coupling of 4-bromoanisole with benzo[b]furan . initially we started with a catalyst loading of 2 mol-% in the absence of any ligand , however , this gave only 16 % yield of the desired product ( table 1 , entry 1 ) . screening of various catalyst loadings ( 110 mol-% ; see the supporting information ) revealed that 4 mol-% gave the highest but a still unsatisfactory yield ( entry 2 ) as higher catalyst loadings led to increased byproduct formation ( c-3 arylation , debromination , and homocoupling of 4-bromoanisole ) . optimization of the arylation of benzo[b]furan[a ] reaction conditions : benzo[b]furan ( 1 equiv . ) , 4-bromoanisole ( 1.5 equiv . ) , base ( 1.5 equiv . ) , pd cat . ( 4 mol-% ) , ligand ( 8 mol-% ) , 140 c , 24 h , 0.5 m of substrate in solvent ( degassed dmac ) . because the addition of ligands has a significant influence on metal - catalyzed reactions ( change in catalytic species and eventually oxidation state ) , we embarked on ligand screening with several commercially available ligands . because the addition of phosphine ligands changes the electronic and steric ( vacant coordination sites blocked ) environment of the catalytically active metal center , we chose to screen several commercially available phosphine ligands ( see the supporting information ) . in this investigation only two systems ( c - phos and s - phos , figure 2 ) displayed improved yields compared with conditions without an additional ligand ( 40 and 45 % yields , respectively ; entries 3 and 4 ) . it has to be mentioned that none of the investigated conditions led to full conversion . variation of the palladium catalyst precursor species also did not affect the reaction efficiency significantly ( entries 5 and 6 ) . although there is strong evidence that the reaction proceeds through a concerted metalation / deprotonation ( cmd ) pathway,[20a,20b ] we chose a carboxylate base for our screening efforts . this modification was inspired by the work of fagnou and co - workers , who reported that pivalic acid ( in situ becoming potassium pivalate due to the presence of stoichiometric amounts of k2co3 ) acts as a co - catalyst to promote c  h cleavage and phosphine dissociation , ultimately preventing catalyst inhibition by excess phosphine.[11c,20c ] speculating that the nature of the carboxylate base can also have a significant influence on the performance of a direct arylation process , we tested other carboxylate bases such as csoac , kopiv , and csopiv . the reaction starts with the oxidative addition of the aryl bromide to the palladium catalyst . then a pivalate ion from caesium pivalate coordinates to the catalyst . in the subsequent step a concerted metalation deprotonation takes place , as depicted in the transition state . finally , dissociation of pivalic acid and reductive elimination delivers the desired product and regenerates the catalytically active palladium species . proposed mechanism for the direct arylation of benzo - fused heterocycles using pivalate specie as co - catalyst . in contrast to the protocol by fagnou and co - workers , we chose to use pivalate directly and use of either potassium pivalate ( kopiv ) or caesium pivalate ( csopiv ) as base resulted in a significant increase in yield . only when conducting the reactions in the presence of csopiv was full conversion observed ( 72 % yield , table 1 , entry 9 ) . in addition , a minor counter - ion effect was observed favoring cs over k ( 65 % , entry 8) . in both cases , the 3-arylated isomer was detected as a minor byproduct ( < 5 % ) by gc having identified csopiv as the best - performing base we tested several n - based ligands in combination with this base , however , the conversions were significantly lower than those obtained with s - phos ( see the supporting information ) . as a result , the following reaction conditions were used for to evaluate the substrate scope : benzo[b]furan ( 1.0 equiv . ) with aryl bromide ( 1.5 equiv . ) , csopiv ( 1.5 equiv . ) , pd(oac)2 ( 4 mol-% ) , and sphos ( 8 mol-% ) in degassed dmac ( 0.5 m ) at 140 c for 24 h. our results are summarized in table 2 . benzo[b]furan was treated with a series of aryl bromides bearing various functional groups . in several cases , ms , and is responsible for decreased yields of the desired product due to associated separation problems . scope of the direct arylation of benzo[b]furan at the 2-position[a ] reaction conditions : benzo[b]furan ( 1 equiv . ) , aryl bromide ( 1.5 equiv . ) , csopiv ( 1.5 equiv . ) , pd(oac)2 ( 4 mol-% ) , sphos ( 8 mol-% ) , 140 c , 24 h , 0.5 m of substrate in solvent ( degassed dmac ) . to investigate the electronic effects of substituents on the aryl bromide only para - substituted derivatives were subjected to the established reaction conditions to eliminate steric interactions ( table 2 , entries 110 ) . it was found that electron - rich halides ( entries 1 , 3 , 4 ) upon coupling with benzo[b]furan generally result in better yields than electron - deficient substrates . only in the case of 4-bromophenol was no conversion observed ( entry 2 ) , most likely due to the rather acidic phenolic oh group . for electron - withdrawing substituents a significant trend was observed : the yield decreases with increasing electron - withdrawing nature of the substituent ( see trend for entries 510 ) , which accounts for the low yield in the case of the 4-no2 substituent , for which the conversion was especially low , even though the 2-arylated product was formed exclusively ( entry 10 ) . in this case the homocoupled product of the halide was observed in a significant amount . next , we investigated the influence of the position of the aryl functional group on the halide ( entries 1114 ) . a methyl group at the ortho position was still tolerated , even though the yield dropped to 40 % ( entry 12 ) . in contrast , a methoxy group at the ortho position inhibited conversion completely ( entry 11 ) , presumably due to chelating effects . subsequent to the oxidative addition into the c  br bond , a relatively stable palladium complex may be formed due to the adjacent oxygen of the methoxy group ; this results in coordination to the metal center through a lone pair , consequently interfering with any further reaction at the metal center . in addition , we used three different isomers of chlorobromobenzene in the arylation protocol : variation of reactivity was observed with substitution at the para position giving the highest yield ( 57 % ) and ortho substitution the lowest ( 43 % ) ; however , the effect was not very pronounced ( entries 5 , 13 , 14 ) . notably , we never detected any product originating from a reaction at the chloride position rather than the bromide position . next , we investigated whether the same reaction conditions can be translated to other benzo - fused heterocycles as well ( table 3 ) . scope of the direct arylation of other benzo - fused heterocycles[a ] reaction conditions : benzo - fused heterocycle substrate ( 1 equiv . ) , aryl bromide ( 1.5 equiv . ) , csopiv ( 1.5 equiv . ) , pd(oac)2 ( 4 mol-% ) , sphos ( 8 mol-% ) , 140 c , 24 h , 0.5 m of substrate in solvent ( degassed dmac ) . benzo[b]thiophene was subjected to the established reaction conditions as first benchmarking system . in this case bis - arylated benzo[b]thiophenes were also observed in several cases but in low quantities ( < 10 % ) . in the case of benzo[b]thiophene , the byproduct did not impede isolation of the 2-arylated product as observed for benzo[b]furan.[13a ] the more pronounced difference in the polarity of the byproduct and desired product allowed a more facile purification as compared with the benzo[b]furan series . the results of the reactions are quite similar to the data obtained for benzo[b]furan . again , neither a free oh nor an o - methoxy group was tolerated ( table 3 , entries 2 and 7 ) and electron - withdrawing substituents had a negative effect on the reaction ( entries 6 , 1012 ) . it is noteworthy that o - bromotoluene gave a better yield than the corresponding para - substituted isomer ( entries 8 and 9 vs. 3 and 5 ) . finally , we tested our conditions on indole , as well , even though direct arylation is well established on this heterocyclic system . in this context , it was our aim to establish the scope and limitations of the developed protocol as a general method for direct arylation of benzo fused systems . indole itself did not react , corroborating our above indicated hypothesis of a detrimental effect by acidic protons ( entry 13 ) . blocking this position by employing 1-methylindole , the protocol again turned out as very robust to give a good isolated yield of the arylated product ( 64 % , entry 14 ) , again accompanied by minor amounts of bis - arylated side - product . the formation of bis - arylated products as minor contaminant in a number of examples prompted us to exploit the protocol for the synthesis of 2,3-bis - arylated benzo - fused heterocycles as well , starting from c-2 arylated derivatives ( table 4 ) . scope of the direct arylation on c-3 of 2-arylbenzo[b]furan[a ] reaction condition : 2-arylbenzo[b]furan substrate ( 1 equiv . ) , aryl bromide ( 1.5 equiv . ) , csopiv ( 1.5 equiv . ) , pd(oac)2 ( 4 mol-% ) , sphos ( 8 mol-% ) , 140 c in 24 h , 0.5 m of substrate in solvent ( degassed dmac ) , yields were isolated yields initially , we introduced the same aryl residue in the second step at c-3 which was already attached to c-2 ( table 4 , entries 16 ) . again , yields were in the same range ( but slightly lower ) confirming our previously observed trend regarding the electronic nature of substituents on the aryl bromides . the lower yields for c-3 arylation can be rationalized by steric hindrance imposed by the aryl substituent in position 2 ( compare entries 16/table 4 to entries 1 , 59 , 11/table 3 ) . as a further logical extension of the method , we then introduced different aryls in position 3 than in position 2 ( table 4 , entries 79 ) . arylation with 4-chloro - bromobenzene proceeded with similar efficiency compared to the reaction in position 2 ( entry 8) . 4-bromoanisole on the other hand did not react at c-3 at all ( entry 7 ) . coincidentally , no bis - arylated product was observed in case of c-2 arylation with 4-bromoanisole ( entry 4 in table 2 ) . the reason for the failure is not clear at the moment and will be subject of further investigations . introduction of 4-nitrophenyl in position 3 resulted in a low yield of 20 % , which was expected due to previous results obtained with that particular coupling partner . in summary , we developed a generally applicable method to directly arylate benzo - fused heterocycles such as benzo[b]furan , benzo[b]thiophene , and n - methylindole . even though yields are usually moderate , this protocol is very versatile and generally applicable producing highest yields for direct arylation of benzo[b]furan compared to available literature procedures . both electron - rich and electron - poor aryl bromides can be used as aryl source , however , strong electron - withdrawing substitutents have a limiting effect on the efficiency of the protocol . as already indicated , the method can also be applied to benzo[b]thiophene and n - methylindole with similar results . the c2-arylated products were susceptible to undergo additional arylation at c-3 employing the same protocol , showing similar trends in reactivity as for c2-arylation . investigations to translate this protocol to other heterocycles and application of other aryl sources ( aryl iodides or chlorides ) are currently under investigation in our laboratory . general methods : chemicals were purchased from commercial suppliers and used without further purification unless otherwise noted . dimethylacetamide ( dmac ) was distilled and subsequently degassed by bubbling argon through the solvent in an ultrasonic bath for 2 h. palladium catalysts and ligands were stored under argon in a desiccator and weighed in under air . chemical shifts (  ) are reported in parts per million ( ppm ) with trimethylsilane ( tms ) as the internal standard . the abbreviations used to report the data are s ( singlet ) , d ( doublet ) , t ( triplet ) , q ( quartet ) , m ( multiplet ) , and br . ms spectra were recorded either on a thermo finnigan focus gc / dsq ii using a standard capillary column bgb 5 ( 30 m  0.25 mm i d ) or a thermo trace 1300/isq lt using a standard capillary column bgb 5 ( 30 m  0.25 mm i d ) . hr - ms for literature unknown compounds were analyzed by lc - it - tof - ms in only positive ion detection mode with the recording of ms and ms / ms spectra . melting points were determined using a stanford research systems mpa100 optimelt automatic melting point system . general procedure for direct arylation of benzo - fused heterocycles : a 7 ml vial equipped with a screw cap with septum and a magnetic stirring bar was charged with benzo[b]furan or either benzothiophene , indole or 1-methyl indole ( 1.0 mmol , 1.0 equiv . ) , aryl bromide ( 1.5 mmol , 1.5 equiv . ) , caesium pivalate ( 350 mg , 1.5 mmol , 1.5 equiv . ) , pd(oac)2 ( 9 mg , 0.04 mmol , 0.04 equiv . ) and sphos ( 16.4 mg , 0.08 mmol , 0.08 equiv . ) . the mixture was heated to 140 c for 24 h. the reaction mixture was cooled to room temperature and then diluted with 15 ml diethyl ether or ethyl acetate ( depending on the polarity of the product ) and filtered through a pad of celite . the organic phase was washed 3 times with saturated ammonium chloride solution , once with brine and dried with sodium sulfate . purification was performed on silica gel eluting with pe ( petroleum ether ) or pe / etoac ( ethyl acetate ) mixtures ( depending on the polarity of the product ) , if mixed fractions of c2 & c3 arylated compounds were obtained , these fractions were recrystallized . representative examples 2-phenylbenzo[b]furan : synthesized according to the general procedure starting from benzo[b]furan ( 110 l , 118 mg , 1.0 mmol ) , bromobenzene(105 l , 157 mg , 1.5 mmol ) , caesium pivalate ( 350 mg , 1.5 mmol ) , pd(oac)2 ( 9 mg , 0.04 mmol ) and sphos ( 16.4 mg , 0.08 mmol ) . purification was employed in two steps : first column chromatography was carried out ( silica gel , pure pe as eluent ) which afforded 155 mg of a product mixture containing 2-phenylbenzo[b]furan and 2,3-bisphenylbenzo[b]furan ( respective mol ratio 10:1 ) . the precipitated crystals were separated by filtration , washed 3 times with cold pe ( 5 c ) and dried in vacuo to obtain 116 mg ( 60 % ) of 2-phenylbenzo[b]furan as a colorless solid . h nmr ( 200 mhz , cdcl3 ) :  = 7.957.80 ( m , 2 h ) , 7.697.14 ( m , 8 h ) , 7.03 ( s , 1 h ) ppm . c nmr ( 50 mhz , cdcl3 ) :  = 155.9 , 154.9 , 130.5 , 129.2 , 128.8 ( 2 c ) , 128.6 , 124.9 ( 2 c ) , 124.3 , 122.9 , 120.9 , 111.2 , 101.3 ppm . ms analyst , m / z ( int . ) : 194(100 ) [ m ] , 165(50 ) , 97(9 ) , 82(12 ) . 4,4-(benzo[b]furan-2,3-diyl)dibenzonitrile ( 4f ) : synthesized according to the general procedure starting from 4-(benzo[b]furan-2-yl)benzonitrile ( 2 m ) ( 110 mg , 0.5 mmol ) , 4-bromobenzonitrile ( 136 mg , 0.75 mmol ) , caesium pivalate ( 175 mg , 0.75 mmol ) , pd(oac)2 ( 4.5 mg , 0.02 mmol ) and sphos ( 8.2 mg , 0.04 mmol ) . purification by mplc ( silica gel with gradient elution pe  pe / etoac , 95:5 ) afforded 27 mg ( 34 % ) 4f as pale yellow solid . h nmr ( 200 mhz , cdcl3 ) :  = 7.837.79 ( m , 2 h ) , 7.737.69 ( m , 2 h ) , 7.647.59 ( m , 5 h ) , 7.497.39 ( m , 2 h ) , 7.33 ( dd , j = 7.4 , 1.1 hz , 1 h ) ppm . c nmr ( 50 mhz , cdcl3 ) :  = 154.3 , 148.9 , 137.2 , 134.1 , 133.1 ( 2 c ) , 132.5 ( 2 c ) , 130.4 ( 2 c ) , 128.9 , 127.3 ( 2 c ) , 126.4 , 123.9 , 120.0 , 118.6 , 118.5 , 118.4 , 112.1 , 112.1 , 111.6 ppm . ms analyst , m / z ( int . ) : 321(21 ) , 320(100 ) [ m ] , 291(13 ) , 289(11 ) , 264(12 ) , 206(18 ) , 190(10 ) , 118(12 ) . supporting information ( see footnote on the first page of this article ) : complete tables for reaction optimization , experimental details , nmr spectroscopic data and scanned spectra of all prepared compounds . as a service to our authors and readers , this journal provides supporting information supplied by the authors . such materials are peer reviewed and may be re - organized for online delivery , but are not copy - edited or typeset . technical support issues arising from supporting information ( other than missing files ) should be addressed to the authors
the direct arylation of benzo[b]furan , benzo[b]thiophene , and indole has been studied by using aromatic bromides as the aryl source . 
 the protocol employing common reagents and a pd catalyst has led to the regioselective arylation of these heterocycles at the 2-position . 
 a range of functional groups were tolerated , providing quick access to a variety of arylated benzo - fused heterocycles that would be accessible more elaborately using classical synthetic strategies . 
 this is the first systematic study of the direct arylation of benzo[b]furan .