over the past decade , 
 c  h arylation has emerged as a powerful 
 methodology for the synthesis of biaryls , important motifs in pharmaceuticals , agrochemicals , organic materials , 
 and natural products . arenes containing 
 a wide variety directing groups can now be readily ortho - arylated . some progress has also been made in recent years 
 toward achieving selective meta- and para - arylation . however , c  h arylation of so - called simple arenes , that is arenes without a directing group , remains 
 a challenge : ( 1 ) their low reactivity results in large amounts of 
 the arene being generally required and ( 2 ) useful regioselectivity 
 is rarely obtained , thus limiting these reactions to symmetrical substrates . the only exceptions are highly electron - deficient substrates , such 
 as polyfluorobenzenes , where the more acidic c  h bonds can 
 be readily activated . in this context , 
 the efficient arylation of anisole , a ubiquitous motif in biologically 
 active compounds ( scheme 1a ) , still represents a remarkable reactivity and selectivity 
 challenge ( scheme 1b ) . fagnou s initial report on the pd - catalyzed direct 
 arylation 
 of anisole with para - bromotoluene highlighted its low reactivity and poor site selectivity 
 ( o : m : p 25:50:25 ) . subsequent reports on pd - catalyzed oxidative couplings 
 with anisole described the formation of mixtures of regioisomers with 
 a preference for the para isomer . conversely , fe- , rh- , and ir - catalyzed and metal - free 
 couplings show a slight preference for the ortho isomer 
 ( 59:41 to 71:29 of o : m+p ) . besides the overall lack of regioselectivity , 
 all of these reported methodologies also require a large excess of 
 anisole ( 10100 equiv ) and high reaction temperatures ( 100180 
 c ) . groundbreaking developments were reported in 2011 by the 
 groups of yu and gaunt , with two elegant examples of highly regioselective pd- 
 and cu - catalyzed para - arylation reactions of anisoles ( scheme 1b ) . in both methods , the regioselectivity of arylation 
 was associated with a sterics - biased electrophilic - type pathway . here we report the first example of an ortho - selective direct arylation 
 of anisoles ( scheme 1c ) , using a -complexation strategy for the enhancement 
 of reactivity and regioselectivity . recently , our group reported 
 that -complexation of a strongly 
 electron - withdrawing cr(co)3 unit to fluorobenzene greatly 
 enhances its reactivity toward c  h arylation via a proposed 
 concerted metalation  deprotonation ( cmd ) pathway . we initially hypothesized that the increased 
 reactivity was due to the formation of a highly electron - poor arene , 
 resulting in weaker c  h bonds . however , computational studies 
 indicated that a more facile out - of - plane bending of the c h 
 bond to adopt the cmd transition state geometry was the dominating 
 factor . thus , we reasoned that this effect may also operate on electron - rich 
 arenes , allowing a previously inaccessible cmd pathway . interestingly , 
 computational studies by fagnou and gorelsky showed that , despite the general low reactivity of anisole , a cmd 
 process would selectively proceed at the ortho position . therefore , 
 we hypothesized that -complexation could have a triple effect 
 on the reactivity of anisole : ( 1 ) enhance reactivity toward a cmd 
 process , avoiding the need for using a large excess of the arene ; 
 ( 2 ) eliminate sear - type reactivity ( and therefore para - reactivity ) , 
 and ( 3 ) afford the cmd - preferred ortho - regioisomer . to test our hypothesis , we chose ( ethoxymethoxy)benzene 
 as a benchmark substrate ( table 1 ) . chromium 
 complexes of anisoles are easily prepared , and 1a was 
 obtained in high yield ( 81% ) from reaction of 1.0 equiv of the arene 
 with 1.3 equiv of cr(co)6 . initially , we tested the catalytic 
 system previously developed in our group , followed by in situ demetalation 
 ( table 1 , entry 1 ) . gratifyingly , biaryl 3aa was obtained in good yield ( 58% ) and excellent ortho - selectivity , 
 confirming that -complexation for enhancement of reactivity 
 is not exclusive to electron - poor arenes . screening of different carboxylic 
 acid cocatalysts ( table 1 , entries 14 ) 
 showed that acids with low a pka , such 
 as p - no2c6h4co2h ( pka 3.4 ) , provide 
 no reactivity , while p - nme2c6h4co2h ( pka 4.9 ) can impart similar reactivity to that of 1-adco2h ( pka 5.0 ) . we hypothesized that 
 a more reactive catalytic system may be achieved by addition of an 
 organic base soluble in toluene , which could assist in the deprotonation 
 of 1-adco2h . screening of basic additives ( entries 57 ) 
 showed that the highly hindered amine tmp ( 2,2,6,6-tetramethylpiperidine ) provided 3aa in high yield and 
 with excellent ortho - selectivity ( o : m : p 95:0:5 ) . the reaction proceeded in lower yields in the absence of 
 k2co3 or 1-adco2h , and not at all 
 in the absence of ag2co3 ( entries 911 ) . 
 finally , a control experiment with 20 equiv of ( ethoxymethoxy)benzene 
 ( entry 12 ) gave no yield of the c  h arylation product , highlighting 
 the outstanding reactivity - enhancing effect imparted by cr(co)3 . 20 equiv of ( ethoxymethoxy)benzene 
 were used instead of complex 1a . with the optimal reaction conditions in hand , we set 
 out to explore 
 the generality of the method with respect to different substituted 
 anisoles ( scheme 2 ) . varied alkyl substitution at the oxygen was possible , with the corresponding 
 biaryls 3aa3da obtained in high 
 yields and with high ortho - selectivities , even when using a sterically 
 hindered isopropyl substituent ( 3da ) . para- and meta - substituted 
 anisole complexes led to the corresponding biaryl products in excellent 
 yields ( 3ea3la ) and complete regioselectivity . it is noteworthy that a strongly electron - withdrawing co2me para - substituent is compatible with the reaction , with the regioselectivity 
 still being governed by the meo group ( 3la ) . furthermore , 
 more electron - rich arenes , containing two meo groups ( 3ma3oa ) , were still highly reactive under the reaction 
 conditions , strongly supporting our hypothesis that reactivity in 
 this case does not correlate with electron density at the arene . interestingly , 
 ortho - substituted anisole , 1r , provided only a low yield 
 of product 3ra . this may result from a c  ome conformation 
 with increased steric hindrance at the ortho - c  h bond . indeed , 
 while the meo group in 1r would be projected toward the 
 ortho - c  h bond , when this conformation is prevented via ring 
 closure , as in dihydrobenzofuran ( 1s ) , high reactivity 
 is restored . this effect was used to impart complete regioselectivity 
 in the direct arylation of the unsymmetrical 1,4-hydroquinone derivative 1 t . reactions carried out on a 0.5 
 mmol scale with respect to the limiting reagent . o , p - bisarylated product 3ca ( 4% ) 
 was also obtained . o , p - bisarylated product 3ra ( 3% ) 
 was also obtained . we then explored the compatibility of 
 our reaction conditions with 
 a variety of functional groups in the aryl iodide coupling partner . our optimized conditions were applicable to a wide range of electron - donating 
 and -withdrawing substituents in the ortho , meta , and para positions , 
 affording the corresponding biaryl products 3ka3ko in excellent yields ( scheme 3 ) . 
 in particular , the reaction is compatible with cl and br substituents 
 ( 3ke , 3kf ) , which would allow for further 
 pd - catalyzed cross - couplings , as well as esters , ketones , and thioethers 
 among other functionalities . reactions carried out on a 0.5 
 mmol scale with respect to the limiting reagent . .   performed with 2.0 equiv of 2 for 40 h. c  h functionalization 
 is an attractive tool for late - stage 
 functionalization of bioactive compounds . steroidal derivatives possess broad spectrum utility in modern medicine 
 and currently find wide application as adjuvants in cancer chemotherapy . we explored the applicability of our novel approach to the selective 
 ortho - arylation of estradiol ( scheme 4 ) . cr - complexation 
 of dimethylestrone ( 4 ) yielded complex 1u in 93% yield and a 1:1 diastereomeric mixture . application of our 
 methodology to this mixture with different iodoarenes provided the 
 desired arylated adducts ( 3ub , 3uf , and 3uh ) with complete regioselectivity and excellent yields . treatment with alcl3 allowed simultaneous demethylation 
 of both hydroxyl groups , producing aryl - estradiol derivative 5 in excellent yield . furthermore , the air - stable cr - complexed 
 biaryls could also be easily isolated in high yields , and the cr(co)3 unit was then utilized to control other functionalizations 
 on the steroid core . application of walsh s benzylic arylation 
 conditions to 6 allowed selective arylation at the less 
 hindered benzylic position , forming 8 with good yield 
 and diastereoselectivity . anisole is approximately 10 times less reactive 
 than 
 1,3,5-trifluorobenzene under standard cmd - type reaction conditions . interestingly , competition experiments indicate that anisole complex 1b is 4.7 times more reactive than 1,3,5-trifluorobenzene , 
 showcasing a 4 orders of magnitude enhancement of reactivity toward 
 c  h arylation of anisole after complexation . a competition experiment between deuterated complex 1p-5,7-d2 and 1q highlighted 
 the latter as 2.0 times more reactive , consistent with the kie previously 
 measured for complexed fluorobenzene , suggesting a similar reaction pathway is in operation . in conclusion , we have demonstrated that -complexation of 
 a cr(co)3 unit to anisole - type arenes can  switch 
 on  a highly ortho - selective pd - catalyzed direct arylation 
 process . our method allows for the easy ortho - arylation of a range 
 of ( di)alkoxybenzenes . the high reactivity achieved with just 1 equiv 
 of the arene under mild conditions ( no strong acids / bases , 60 c ) 
 makes this approach suitable for the late - stage functionalization 
 of anisole - containing bioactive compounds . in addition , the cr - unit 
 can be used as a handle for further transformations on and around 
 the arene , allowing for quick access to a variety of structures from 
 a common precursor . this process is likely occurring via a concerted 
 metalation  deprotonation type pathway , which is normally not 
 accessible to electron - rich arenes . a flame - dried round - bottom flask 
 equipped with a magnetic stirrer and a reflux condenser was charged 
 with cr(co)6 ( 6.50 mmol , 1.3 equiv ) , evacuated , and backfilled 
 with ar . the required o - substituted phenol ( 5.00 mmol , 1.0 equiv ) was added to the flask , followed by the addition of anh . nbu2o and thf ( 9:1 v / v , 0.15 m ) . the resulting suspension 
 was subjected to freeze  pump  thaw cycles ( 3  30 
 min ) and then refluxed ( external temperature 150 c ) for 48 h. 
 the solution was then cooled down to room temperature and filtered 
 through a short pad of silica . the silica pad was washed with et2o ( 3  20 ml ) , and the organic layer was then concentrated in vacuo . recrystallization from a cold mixture of hexane / et2o 9:1 provided the arene tricarbonyl chromium complex 1 . general procedure a was 
 applied by using cr(co)6 ( 1.43 g , 6.5 mmol , 1.3 equiv ) 
 and ( ethoxymethoxy)benzene ( 0.760 g , 5 mmol , 1.0 equiv ) . recrystallization from cold hexane gave the title product 1a as a yellow solid in 81% yield ( 1.17 g , 4.06 mmol ) . h nmr ( 400 mhz , ( cd3)2co ) :  ( ppm ) = 
 5.84 ( app . t , j = 6.6 hz , 2h ) , 5.54 ( d , j = 6.4 hz , 2h ) , 5.225.16 ( m , 3h ) , 3.75 ( q , j = 7.2 hz , 2h ) , 1.21 ( t , j = 7.2 hz , 3h ) . c nmr ( 101 mhz , ( cd3)2co ) :  ( ppm ) = 
 235.6 , 143.2 , 97.7 , 95.4 , 89.0 , 83.2 , 66.5 , 16.0 . ir :  = 3096 , 
 1949 , 1843 , 1531 , 1226 , 1082 , 959 cm . hrms ei+ m / z calcd c12h13cro5 : [ m + h ] 289.0163 ; 
 found : [ m + h ] 289.0162 . to an oven - dried microwave 10 ml glass vial equipped with a round 
 stirrer bar , the following reagents were added in this order : k2co3 ( 172.5 mg , 1.25 mmol , 2.5 equiv ) , 1-adco2h ( 45.0 mg , 0.25 mmol , 0.5 equiv ) , ag2co3 ( 70 mg , 0.25 mmol , 0.5 equiv ) , pd(pph3)4 ( 5 
 mol % , 28.9 mg , 0.01 mmol ) , the required arene cr(co)3 complex 1 ( 0.65 mmol , 1.3 equiv ) , and iodoarene 2 ( 0.50 
 mmol , 1.0 equiv ) . phch3 ( 0.3 ml , 1.7 m ) and 2,2,6,6-tetramethylpiperidine 
 ( 170 l , 1.00 mmol , 2.0 equiv ) were added , and the glass vial 
 was sealed with a disposable microwave cap . the reaction was then cooled down , 
 and acoh ( 2 ml ) was slowly added with moderate stirring . after 5 min , 
 mno2 ( 130 mg , 1.50 mmol , 3 equiv ) was added in small portions 
 and the black suspension was vigorously stirred for 30 min . the suspension 
 was then loaded on a short silica plug ( 2 cm  4 cm ) and eluted 
 with et2o ( 30 ml ) before concentrating in vacuo . purification 
 via flash chromatography column on silica gel provided the required 
 biaryl product . general 
 procedure 
 b was applied with arene chromium complex 1a and 4-iodotoluene 2a . flash chromatography ( gradient 15% et2o in hexane ) that was performed prior to demetalation afforded the 
 corresponding biaryl cr(co)3 complex . acoh ( 2 ml ) and mno2 ( 130 mg , 1.5 mmol , 3 equiv ) were then added , and the black 
 suspension was vigorously stirred for 30 min . the suspension was then 
 loaded on a short silica plug ( 2 cm  4 cm ) and eluted with et2o ( 30 ml ) . removal of solvent in vacuo afforded the title 3aa as a colorless oil in 73% yield ( 88.6 mg , 0.366 mmol ) . crude h nmr of the reaction shows an isomer ratio o : o , o : o , p 
 = 26:1:1.7 which corresponds to an o : m : p = 95:0:5 ratio . h nmr ( 400 mhz , cdcl3 ) :  ( ppm ) = 7.43 ( d , j = 7.6 hz , 2h ) , 7.357.20 ( m , 5h ) , 7.07 ( app t , j = 6.8 hz , 1h ) , 5.16 ( s , 2h ) , 3.66 ( q , j = 7.2 hz , 2h ) , 2.40 ( s , 3h ) , 1.19 ( t , j = 6.8 hz , 
 6h ) . c nmr ( 101 mhz , cdcl3 ) :  ( ppm ) 
 = 154.6 , 136.7 , 135.9 , 131.9 , 131.0 , 129.6 , 128.9 , 128.5 , 122.2 , 115.8 , 
 93.9 , 64.4 , 21.3 , 15.2 . ir :  = 2976 , 1600 , 1485 , 1218 , 1103 , 
 993 cm . hrms ei+ m / z calcd c16h21o2n : [ m+nh4 ] 260.1645 ; found : [ m+nh4 ] 260.1647 . to an oven - dried microwave 10 ml glass vial equipped 
 with a round stirrer bar , the following reagents were added in this 
 order : k2co3 ( 172.5 mg , 1.25 mmol , 2.5 equiv ) , 
 1-adco2h ( 45.0 mg , 0.250 mmol , 0.5 equiv ) , ag2co3 ( 105 mg , 0.375 mmol , 0.75 equiv ) , pd(pph3)4 ( 5 mol % , 28.9 mg , 0.010 mmol ) , the required arene 
 cr(co)3 complex 1 ( 0.5 mmol , 1.0 equiv ) , and 
 iodoarene 2 ( 0.75 mmol , 1.5 equiv ) . phch3 ( 0.3 
 ml , 1.7 m ) and 2,2,6,6-tetramethylpiperidine ( 170 l , 
 1 mmol , 2.0 equiv ) were added , and the glass vial was sealed with 
 a disposable microwave cap . the reaction was then cooled down , and acoh ( 2 
 ml ) was slowly added with moderate stirring . after 5 min , mno2 ( 130 mg , 1.5 mmol , 3 equiv ) was added in small portions and 
 the black suspension was vigorously stirred for 30 min . the suspension 
 was then loaded on a short silica plug ( 2 cm  4 cm ) and eluted 
 with et2o ( 30 ml ) before concentrating in vacuo . purification 
 via flash chromatography column on silica gel provided the required 
 biaryl product . general 
 procedure 
 c was applied with arene chromium complex 1f and 4-iodotoluene 2a . flash chromatography ( gradient 0.015% dcm in hexane ) 
 afforded the title product 3fa as colorless oil in 64% 
 yield ( 77.1 mg , 0.321 mmol ) . h nmr ( 400 mhz , cdcl3 ) :  ( ppm ) = 7.49 ( d , j = 8.0 hz , 2h ) , 
 7.23 ( d , j = 7.6 hz , 2h ) , 7.18 ( d , j = 2.0 hz , 1h ) , 7.09 ( dd , j = 8.4 , 2.0 hz , 1h ) , 
 6.92 ( d , j = 8.4 hz , 1h ) , 4.35 ( septet , j = 6.0 hz , 1h ) , 2.42 ( s , 3h ) , 2.36 ( s , 3h ) , 1.25 ( d , j = 6.0 hz , 6h ) . c nmr ( 101 mhz , cdcl3 ) : 
  ( ppm ) = 152.9 , 136.3 , 136.2 , 132.2 , 131.8 , 130.6 , 129.5 , 128.9 , 
 128.7 , 116.2 , 71.4 , 22.2 , 21.3 , 20.7 . ir :  = 3021 , 2975 , 1492 , 
 1230 , 1110 , 953 cm . hrms ei+ m / z calcd c17h21o : [ m + h ] 241.1587 ; found : [ m + h ] 241.1587 .
current approaches 
 to achieve site selectivity in the c  h 
 activation of arenes involve the use of directing groups or highly 
 electron - poor arenes . 
 in contrast , simple arenes , such as anisole , 
 are characterized by poor reactivity and selectivity . 
 we report that 
 -complexation to a cr(co)3 unit enhances the reactivity 
 of anisoles providing an unprecedented ortho - selective 
 arylation . 
 this mild methodology can be used for the late stage functionalization 
 of bioactive compounds containing the anisole motif , allowing the 
 construction of novel organic scaffolds with few synthetic steps .