the 
 biaryl structure is a central building block in a large number 
 of natural products , organic materials , and biologically active compounds . direct arylation through c  h bond cleavage 
 represents an efficient alternative to classical methods for polyaryl 
 preparation . second - row transition metals 
 such as palladium , ruthenium , rhodium , and iridium have emerged as 
 catalysts in direct arylation reactions . h bonds has been achieved for arylation 
 of heterocycles as well as directing - group - containing and electron - poor 
 arenes . more recently , the use of inexpensive 
 first - row metal catalysts has attracted substantial interest . copper , 
 nickel , and iron have been shown to catalyze direct arylation of sp c several reports 
 describe processes for the assembly of biaryl structures using aryl 
 iodonium salts or photochemical methods . recently specifically , alkali 
 metal alkoxide bases combined with amine bases were reported to promote 
 formation of biaryls in the coupling of arenes with aryl halides . however , arylation of simple compounds such 
 as anisole or pyridine affords isomer mixtures , and the arene coupling 
 component is often used in up to 100 equiv excess . we have recently 
 described direct base - promoted intermolecular 
 arylation of heterocycle and arene c  h bonds . in these reactions , less than 2.5 equiv of c  h bond 
 coupling partner is used , and functionalization occurs at the most 
 acidic carbon  hydrogen bond . in the presence of hindered amide 
 bases , addition of aryl anion to the aryne affords the o - anionic biaryl intermediate 1 , which is subsequently 
 protonated to form product 2 ( scheme 1 ) . trapping of 2 with electrophiles other than 
 h should be possible , leading to o - substituted 
 biaryls of type 3 . overall , the reaction product 3 can be thought of as a result of 2-fold c  h bond 
 functionalization : c  h / c - cl coupling followed by a c  h / electrophile 
 reaction . in order for this sequence of reactions to be successful , 
 arylmetal intermediate 1 has to be compatible with protonated 
 base formed during formation of benzyne and 1 . several 
 examples of aryne reactions with nucleophiles followed by trapping 
 of aryl metal intermediates with electrophiles have been reported . a general procedure employing an accessible aryl 
 halide or triflate aryne precursor , c  h bond nucleophiles , 
 and diverse trapping reagents has not been demonstrated . we report here ( 1 ) an expansion 
 of scope of our previous methodology 
 that allows a general , highly regioselective arylation of a wide range 
 of arenes and heterocycles by aryl halides and triflates , and ( 2 ) 
 trapping of intermediate aryl anions with a variety of electrophiles , 
 resulting in ortho - functionalized biaryls and polyaryls . we have previously 
 used commercially available aryl halides as benzyne sources in direct 
 arylation reactions . formation of arynes 
 from halobenzenes was achieved by deprotonation affording 2-haloaryl 
 anion followed by elimination of halide ion . a better leaving group 
 than chloride would accelerate formation of benzyne , allowing generation 
 of benzyne at low temperatures , avoiding competitive protonation by 
 tmph , and allowing electrophilic trapping of intermediate aryl metals . comparison of aryl triflates and chlorides in benzyne generation 
 is shown in table 1 . at 78 c , chlorobenzene is unreactive in thf and diethyl ether ( entries 1 and 
 3 ) . in thf , which facilitates the deprotonation / halide elimination 
 sequence , chlorobenzene forms benzyne at 62 c , albeit 
 relatively slowly ( entry 2 ) thus , at least some chloroarenes should 
 be usable for arylation / electrophilic quench sequences if solvent / temperature 
 optimization is performed . phenyl triflate does not form appreciable 
 amounts of benzyne when treated with lda in diethyl ether at 78 
 c ( entry 4 ) . however , under the same conditions , tmpli base 
 was efficient ( entry 5 ) . addition of a small amount of thf to diethyl 
 ether solvent increases the yield of coupling product and decreases 
 the reaction time ( entry 6 ) . consequently , use of aryl triflates to 
 generate benzyne at low temperatures should allow arylation of sensitive 
 substrates . total volume of solvent 1.5 ml , 
 0.25 mmol scale , phx / base 1/2 ; 10 h ; 6 h for entry 6 . temperature : 62 c , 
 time : 12 h. we 
 have reported a method for base - mediated arylation of ( hetero)arenes 
 by aryl halides . the best results in 
 arene arylation were obtained by employing litmp base in a pentane / thf 
 solvent mixture . arynes had to be generated at an appreciable rate 
 to avoid prohibitively slow reactions . the rate of generation is highly 
 dependent on the structure of the aryl halide . simultaneously , aryl 
 anions from the c  h bond coupling component had to be generated 
 in appreciable concentrations . if aryl anions were present in low 
 concentrations , aryne was consumed in side reactions . consequently , 
 the temperature for each reaction had to be optimized . compounds possessing 
 sensitive functional groups were either incompatible with the arylation 
 conditions or relatively complex temperature regimes were required . in contrast , aryl triflates can be used to generate arynes at 78 
 c , allowing greater functional group tolerance and simplified 
 temperature regimes ( table 1 ) . the results 
 of heterocycle and arene arylation by aryl triflates are presented 
 in table 2 . all reactions were carried out 
 at 78 c in diethyl ether / thf mixed solvent . dihalobenzenes 
 such as 1,3-dichloro- , 1,3-difluoro- , 1,2-difluoro- , and 2-chloro-1-fluorobenzene 
 afford products in good yields ( entries 14 ) . 2-chloro-1,4-bis(trifluoromethyl)benzene 
 is reactive , and the arylation product was obtained in 62% yield ( entry 
 5 ) . these examples show that formation of arynes from 2-lithiohalobenzenes 
 ( halogen = cl , f ) is slow on the time scale of benzyne formation from 
 phenyl triflate . interestingly , benzothiophene arylation by 2-trimethylsilylphenyl 
 triflate , a common benzyne precursor , affords the ortho - substituted product in good yield 
 with the silyl group intact ( entry 9 ) . 2-chlorophenyl triflate can be used to arylate 
 benzothiophene in 53% yield ( entry 10 ) . the product contains a halogen 
 functionality which can be used for further cross - coupling reactions . it can be concluded that aryl triflates can be used for arylation 
 of substrates possessing dmso pka s 
 at or below 35 . conditions : arotf ( 24 equiv ) , 
 ar  h ( 1 equiv ) , tmpli ( 46 equiv ) , et2o / thf 
 solvent ( 3040/1 ) , 78 c , 18 h , 0.25 mmol scale . aryl triflates allow 
 for uniform c  h bond arylation conditions 
 at low temperature . in contrast , use of aryl chloride reagents requires 
 substantial optimization of reaction temperature , solvents , and stoichiometry . 
 in many cases , however , there are advantages in using aryl chlorides second , aryl triflates can not be used for the arylation of nonacidic 
 arenes ( pka > 35 , dmso solvent ) due to fast aryne formation relative to deprotonation 
 of arh , resulting in low product yields . additional examples are presented in table 3 showing several other arene and heterocycle classes that 
 are reactive . diphenyl ether can be arylated by chlorobenzene in 53% 
 yield ( entry 1 ) . dibenzofuran arylation by 2-bromocumene and 
 2-chloronaphthalene affords the m - substituted products 
 in good yields ( entries 2 and 3 ) . 2,4-dimethoxybenzonitrile can be 
 arylated in 42% yield , showing that nitrile functionality is compatible 
 with the reaction conditions ( entry 4 ) . the c - arylation 
 of nh - containing heterocycles such as 2-methyl- and 2,3-dimethylindoles 
 is possible under the conditions developed for aniline arylation ( entries 
 5 and 6 ) . interestingly , 4- and 5-hydroxybenzofurans 
 are arylated at the 2-position ( entries 7 and 8) . the o - arylation product was not observed in the crude reaction mixture 
 for entry 8 . this experiment shows that heterocycle c - arylation is compatible with a phenolic hydroxyl group , in contrast 
 to related copper - catalyzed reactions where o - arylation 
 of phenols is observed . methoxypyridines 
 can also be arylated in good yields ( entries 9 and 10 ) . for these 
 substances , reactions are typically run at 15 
 to 65 c , with the exception of indole arylation ( entries 
 5 and 6 ) , which occurs at room temperature . most reactions give the 
 best yields in thf / diethyl ether mixtures ( entries 13 , 7 , 
 8) , however , more sensitive substrates such as nitriles ( entry 4 ) 
 require low temperatures . thus , thf solvent , where benzyne generation 
 occurs even at 65 c , is optimal . conditions : arene ( 0.25 mmol ) , arx 
 ( 0.3750.75 mmol ) , tmpli ( 11.25 mmol ) , et2o / thf , pentane / thf , thf , or et2o solvent , 65 to 
 15 c . heterocycle ( 1 mmol ) , phcl ( 0.5 
 mmol ) , tmpli ( 1.8 mmol ) , cyclohexane / et2o solvent , 23 c . the synthesis of highly functionalized polyaryls 
 has been extensively 
 investigated due to their widespread applications . additional complexity could be introduced in hetero(arene ) 
 arylation products if the intermediate aryllithium reagent , formed 
 in the reaction of arylmetal with benzyne , was trapped by an electrophile 
 ( scheme 1 , structure 3 ) . in this 
 way , structures inaccessible by other direct arylation methods could 
 be accessed . in essence , a three - component coupling between arx , arh , 
 and electrophile would be realized . three major products were 
 formed  the desired 
 iodophenylbenzothiophene 4 , 2-phenylbenzothiophene 5 , and biphenylated compound 6 formed in the 
 reaction of 2-lithiobenzothiophene with 2 equiv of benzyne . slow generation 
 of benzyne from chlorobenzene was observed in thf at 65 c 
 when tmpli was used . attempts to trap o - anionic biaryl 
 intermediates with i2 at this temperature failed to give 
 a good yield of 4 ( entry 1 ) . instead , 5 and 6 were formed predominately , showing that arli protonation 
 by tmph is relatively fast under those conditions . changing solvent 
 from thf to diethyl ether gave an improved 15/1 ratio of 4/(5 + 6 ) . however , only 5% conversion was 
 observed , showing inefficient formation of benzyne under these conditions 
 ( entry 2 ) . at 20 c in diethyl ether , 75% conversion was observed , but the iodinated 4 was formed as a minor 
 product due to aryllithium protonation by tmph ( entry 3 ) . reaction 
 at 45 c resulted in slow benzyne formation , but good 
 selectivity for 2-iodobenzothiophene 4 was observed ( entry 
 4 ) . as expected , addition of thf facilitated benzyne formation and 4 was obtained in 80% yield when reaction was performed at 
 -45 c in a 9/1 et2o / thf mixture . use of photf under 
 the conditions employed in table 2 afforded 
 an excellent yield of 4 in short reaction times ( entry 
 6 ) . thus , two sets of conditions can be applied for arylation with 
 subsequent electrophilic trapping of aryl lithium intermediates . the 
 first set of conditions involves the use of aryl chlorides in a et2o / thf mixture at about 45 c . the second set 
 involves the use of aryl triflates in a et2o / thf mixture 
 at 78 c . trapping by i2 , cbr4 , ccl4 , and n - fluorobenzenesulfonimide afforded the corresponding 2-(2-halophenyl)benzothiophenes 
 in good to excellent yields ( entries 14 ) . these products can 
 be further functionalized by cross - coupling reactions . when dmf was used as electrophile , reaction with pivaldehyde yielded 
 a secondary alcohol ( entry 6 ) . trapping of reaction mixture with methyl 
 chloroformate or co2 followed by mei / nah afforded carboxylate 
 ester in good yield ( entry 7 ) . both tmscl and 4-chlorobenzoyl chloride 
 are reactive , and functionalized products were obtained in reasonable 
 yields ( entries 8 and 9 ) . treating the reaction mixture with chlorodiphenylphosphine 
 generates corresponding triarylphosphine in good yield ( entry 10 ) . benzothiophene ( 0.25 mmol ) , photf 
 ( 0.5 mmol ) , tmpli ( 1.0 mmol ) , et2o / thf , 78 c , 
 12 h ; then electrophile . arylation of various ( hetero)arenes 
 by aryl halides and triflates 
 with subsequent trapping of aryl lithium intermediates is presented 
 in table 6 . arylation of benzothiophene by 
 2-bromocumene followed by quenching with i2 reagent afforded o - iodinated product in good yield ( entry 1 ) . when 9-bromophenanthrene 
 was used and reaction mixture was quenched with pivaldehyde , 1-aryl-2,2-dimethylpropanol 
 was obtained in 77% yield ( entry 2 ) . arylation of benzothiophene by o - tmsc6h4otf followed by addition 
 of ccl4 afforded chlorobiaryl product ( entry 3 ) . interestingly , 
 increasing the amount of o - tmsc6h4otf from 1.25 to 2.4 equiv relative to benzothiophene allows 
 trapping the first aryne addition product with a molecule of another 
 aryne , affording triaryl in a good yield ( entry 4 ) . this reaction 
 was repeated on 2.5 mmol scale , and product was isolated in 69% yield . trapping of double - addition product with ccl4 is also possible , 
 affording a highly functionalized triaryl in 74% yield ( entry 5 ) . similarly , double addition of benzyne to benzothiophene followed by 
 trapping with tmscl is successful if a 1/3 ratio of benzothiophene / photf 
 is employed ( entry 6 ) . these examples allow efficient syntheses of 
 highly functionalized polyaryls which can not be easily made by any 
 other means . thus , arylation of benzofuran followed by trapping 
 with dmf gives 2-(benzofuran-2-yl)benzaldehyde in a yield comparable 
 to the one obtained for benzothiophene ( entry 7 ) . 3-methoxypyridine was treated with chlorobenzene 
 followed by trapping with iodine , and 4-(2-iodophenyl)-3-methoxypyridine 
 was obtained in acceptable yield ( entry 8) . intermediate 
 aryllithium was trapped by a cyano group , forming 4-methoxy-9-fluorenone 
 after hydrolysis ( entry 9 ) . 1,3-dimethoxybenzene is reactive , and 2,6-dimethoxybiphenyl-2-carbaldehyde 
 was prepared in 64% yield by reaction with benzyne followed by trapping 
 with dmf ( entry 11 ) . a polysubstituted biaryl was produced in the 
 reaction between dimethoxybenzene and aryne derived from 2-bromocumene 
 followed by quench with iodine ( entry 12 ) . hetero(arene ) ( 0.25 mmol ) , arx ( 0.31.0 
 mmol ) , tmpli ( 1.01.75 mmol ) , thf / et2o or thf solvent , 
 35 to 78 c , 1239 h ; then quench with 
 an electrophile . the methodology allows for an efficient 
 synthesis of buchwald s 
 sphos ligand in a one - pot reaction from simple and readily accessible 
 starting materials ( scheme 2 ) . while the current 
 synthesis of sphos is highly efficient and uses cheap starting materials , 
 it requires 1,2-dihalobenzene reactants that might be less available 
 if sphos analogues are prepared . an important use of organolithium reagents is in the preparation 
 of other organometallic complexes through transmetalation . among those , thus , transmetalation of biaryl lithium intermediates to aryl copper 
 reagents and their further reactivity was investigated ( table 7 ) . biaryl lithium was generated by reaction of benzothiophene , 
 phenyl triflate , and tmpli . transmetalation of the reaction mixture 
 with cucn2licl followed by addition of electrophiles results 
 in functionalized arylation products . thus , reaction with mei electrophile 
 afforded 2-o - tolylbenzothiophene in excellent yield 
 ( entry 1 ) . bromomethyl acrylate 
 ester can be used , and product was obtained in good yield ( entry 3 ) 
 showing compatibility of the reaction conditions with ester functionality . epoxide opening is possible , and substitution takes place at the less 
 hindered position ( entry 4 ) . when oxygen is used as oxidant , a variety of 
 arene and heterocycles can be efficiently dimerized . by employing 
 this methodology , dimerization of aryl copper reagents dichlorobenzene was reacted with phenyl triflate in 
 the presence of tmpli to afford 2-arylphenyllithium reagent . following 
 lithium - to - copper transmetalation , oxygen was introduced into the 
 reaction mixture and tetraaryl product was isolated in 44% yield ( entry 
 5 ) . interestingly , when c  h bond coupling component is used 
 in excess , cross - dimerization between biaryl copper and starting aryl 
 copper species can be achieved . for example , if excess of 1,3-dichlorobenzene 
 is used under the conditions of entry 5 , cross - dimerization product 
 was obtained in moderate yield ( entry 6 ) . similarly , n - butylthiophene 
 can be reacted with phcl in the presence of tmpli followed by cross - dimerization 
 affording a 1,2-difunctionalized arene ( entry 7 ) . in this case , a 
 4.3/1 ratio of cross- vs homocoupling was observed . hetero(arene ) 
 ( 0.25 mmol ) , photf 
 ( 0.5 mmol ) , tmpli ( 1.0 mmol ) , 78 c , 12 h ; then cucn2licl 
 followed by electrophile or o2 . phcl as benzyne source ; n - butylthiophene / phcl = 1/1 ; 4.3/1 ratio of product / butylthiophene 
 dimer . benzyne and its 
 derivatives have been well - explored . in 
 contrast , relatively few heterocyclic arynes have been investigated . 
 pyridynes and indolynes have been employed in the synthesis of complex 
 natural products . several attempts were 
 made to investigate the formation and reactivity of heterocyclic arynes . the reaction of benzothiophene with 2-bromopyridine in the presence 
 of tmpli afforded 42% of coupling product ( scheme 3 ) . the regioselectivity of the reaction is consistent with 
 the one reported previously for 2,3-pyridynes . formation of arynes from five - membered ring heterocycles 
 is difficult , and use of five - membered ring arynes for synthetic purposes 
 is exceedingly rare . the challenging 
 thiophyne generation requires use of a triflate leaving group , as 
 2,5-dilithiodichlorothiophene has been described as a free - flowing , 
 white powder that decomposes slowly at 115120 c . reaction of 2-butylthiophenyl triflate with 
 benzothiophene afforded a single product in 21% yield ( scheme 3 ) . we describe 
 here a method for base - promoted arylation of arenes 
 and heterocycles by aryl halides and aryl triflates . despite the use 
 of lithium amide bases , the reaction is highly functional - group tolerant , 
 with alkene , ether , dimethylamino , trifluoromethyl , ester , cyano , 
 halide , hydroxyl , and silyl functionalities compatible with reaction 
 conditions . moreover , nh - containing indole arylation 
 at the 3-position by aryl chlorides was achieved . additionally , we 
 describe a general method for electrophilic trapping of arli intermediates 
 that are generated in the reaction of benzyne with deprotonated arenes 
 or heterocycles . the trapping provides rapid and easy access to a 
 wide range of highly functionalized polyaryls from readily available 
 starting materials . the base - promoted arylation methodology complements conventional 
 direct arylation processes , possesses high functional group tolerance , 
 and allows access to structures that are not easily accessible via 
 other direct arylation methods .
a method for base - promoted arylation 
 of arenes and heterocycles 
 by aryl halides and aryl triflates is described . additionally , in 
 situ electrophilic trapping of arli intermediates generated in the 
 reaction of benzyne with deprotonated arenes or heterocycles has been 
 developed , providing rapid and easy access to a wide range of highly 
 functionalized polyaryls . 
 base - promoted arylation methodology complements 
 transition - metal - catalyzed direct arylation and allows access to structures 
 that are not easily accessible via other direct arylation methods . 
 the reactions are highly functional - group tolerant , with alkene , ether , 
 dimethylamino , trifluoromethyl , ester , cyano , halide , hydroxyl , and 
 silyl functionalities compatible with reaction conditions .