[PDF] A radical approach to the copper oxidative addition problem

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ORGANICC HEMISTRY

A radicalapproacht othe copper

oxidativeadditionproblem:

Trifluoromethylationofbromoarenes

Chip Le,*TiffanyQ. Chen,*Tao Liang,*Patricia Zhang,David W.C. MacMillan† Transitionmetal-catalyzedar enefunctionalizationhas beenwidelyusedfor molecular synthesiso verthepastcentury. Inthis arena, coppercatalysishas longbeen considered a privilegedplatf ormduetothe propensity ofhigh-v alentcopper toundergo reductiv e elimination witha widev arietyof couplingfragments.How ever ,the sluggishnature of oxidativeadditionhas limitedcopper 's capacityto broadly facilitatehaloarene coupling protocols.Her e,wedemonstratethat thiscopper oxidativeadditio npr oblemcan be overcomewithanaryl radical -capturemechanism ,whereinthe arylradicalis gener ated througha silylr adicalhalog enabstraction.This strategywasapplied toagener al trifluoromethylationofaryl bromides through dualcopper-photoredo xcatalysis. Mechanisticstudies supportthe formation ofan open-shellarylspecies. T he developmentof fragmentcoupling trans- formationsby tran sitionmetalcatalysishas substantiallyexpandedacce sstovaluable, complexorganic molecules (1). Majore fforts in thisfieldh aveb eendevotedtoward the buildingblocks,asc ouplingp artners forthe constructionoffunctio naliz edarenes(2). The success ofthese transformationsgene rallyre- lies onthe transitionmetal catalystto activate haloarenes throughan oxidativeaddition step and,th ereafter,forgethedesire dbondbyare - ductivee liminationstep. Thisp aradigmisexem- plifiedin modernpalladium andnickelc atalysis, wherein catalystdesign overfour decadeshas renderedthese elementaryst epsgenericallyef- ficient,thereb yenablingthede velopmentofa vast arrayofc ouplingmanifoldsthat convert (hetero)arylC-XbondstoC sp2 -carbon, -nitrogen, -sulfur,and -oxygenbonds (3,4).Incontrast, copper catalysishas beenless successfulthan

Pd orNi with respect todiverseapplic atio nsin

cross-coupling chemistry,despiteits potential foreco nomicalandoperat ionalbe nefits.Indeed, the mostrob ustcoppercro ss-cou plingreactions are limitedto transmetallingreagents suchas organoboronic acids,specifically tobypass the challenge ofoxidative addition( 5).

Theli mitedcapacity ofcoppertoparticip ate

in haloarenefunctionalizationsh asbeenat trib- uted toi tsrelatively lowrateofoxidativead- dition incomparison tonickel andpalladium.

Formationoft hekeyCu( III)-areneinter mediate

has beencalculated topos sessah ighkineticbar- rier andi styp icallytherate-determinings tepin such catalyticcycle s(

6-8). Althoughelegant

studies inligand designhav eallowed forim- provements inthe ratesof oxidativeaddition for certainsub strateclasses,functionalization of arylhal idesbycoppe rcatal ysisremainsla rgely restrictedtoary lio didesandactiva tedaryl bro- mides (9-11). Then eedtoovercome thisoxida- tiveadditionproblemi sf urt herunder scored by thekn owledgethatthesubsequentr educ- tiveel iminationstepfromhigh- valentCu (III) complexesisextre mely facileforawide range of couplingpartners (12). Inma nycases, the reductiveelimina tionofhighlyelectronegat ive groupssuch asC sp2 -CF 3 ,C sp2 -F, andC sp2 -N bonds is morefavorable and morefacilewith Cu than

Pd andN i(Fig. 1)(5,13,14). Assuc h,thein- vention ofamec hanistic paradigmthatbypas sesthe Cu-haloareneoxidativea dditionproblemshould enablearange ofcatalytic cross-couplingreactions ofscope andu tilitythathasnotbeen

broadlyreal izedusingotherforms ofmetalca- talysis( includingPd,Ni,or Cu).Here,we describe a silylradica l/halogenabstraction/coppercap- ture mechanismthat effectivelyfunctions asa surrogatef orthiselemen tary oxidativeaddition step and,in doingso, allowscopper-mediated bromoarene functionalizationi nageneralf ormat and undermildconditions (visibleligh ta ndroom temperature).Moreover ,thiscatalyticstrategy has beenex ploitedtodelivera gene ralapproachto thetr ifluoromethylationofheteroarylandaryl bromidesthroug hthecombinatio nofcopp er andph otoredoxcatalysis.

Trifluoromethylarenesare valuablestructural

motifs inthe area ofdrug discover yduetot he enhancementof desiredphysicochemicalprop- erties uponthe introductio n ofthe trifluoromet hyl group( 15,16).A mongsynthet icstrategies,tran- sition metal-catalyzed conversionofarylhali des to thecorresponding trifluoromethylarenesis considered oneo fthemos tattractiveapproaches (9,17). Despiteextensiveeffort,nickelc atalysisof thistransformati onhasnotbeenachieved, and onlya sing lereportof palladium-catal yzed tri- fluoromethylationo fary lchlorideshasbeendis- closed(18). Suchdimi nishedcatalyticreac tivity incomparison toother well-known coupling re- actionsisascribedtotheC sp2 -CF 3 reductiveelim- inationstep,a well-docu mentedchal lengeforboth palladium andn ickelcatalysts(

17,19,20). In

contrast, coppercomp lexeshavebeenshownto generallyundergofacil eC sp2 -CF 3 reductiveelim- ination (21,22). Thisrealizati onhaspropelled

RESEARCH

Leet al.,Science360, 1010-1014 (2018)1 June2018 1of5 Merck Centerfor Catalysisat Princeton University ,Princeton,

NJ 08544,USA.

*These authorscontributed equallyto thiswork. †Correspondingauthor.Emai l:dmacmill@p rinceton.edu(D .W.C.M.) Z X sluggishfacile oxidative additionreductive elimination E a

Generally slower than Pd or Ni

Often requires weak C-X bonds (C-I)

and/or high temperatures

Scope complementary to Pd or Ni

Often superior for challenging bonds

E a Cu III L ArL R oxidativereductive additionelimination Z R Cu aryl halidescoupled arenes Typically rate determining step Rapid for C-N, C-O, C-F and C-CF 3 aryl bromide Z Br Si Can a photoredox-mediated mechanism circumvent Cu sluggish oxidative add ition? Z facile radical capture L n Cu(CF 3 x surrogate oxidative addition Cu III L CF 3 L Z Fig. 1.Trifluoromethylationwithdualcopper /photor edox catalysis.Aryl radicalcaptur eby coppercatalysts canb ypasso xidativeaddition.Ar, (hetero)aryl. on June 9, 2018 http://science.sciencemag.org/Downloaded from extensive researchefforts todevelop copper- catalyzed trifluoromethylationprotocols with haloarenes. Althoughrecentexample sofc opper- mediated( 23-25) andcopper- catalyzed(26-28) methodologieshave provide dpromisingresults fort hecons tructionofaryl-CF 3 motifs, theli m- itedcap acityofCu(I)topa rticipa teinoxidative additionhasr estricte dtheapplicationofthes e elegantsystems tomostlyaryl iodi desoracti- vatedaryl bromides ,oftenemployingel evated temperatures.A ssuch,a mechanistic pathway that can bypassthecopper oxidativeadditionprob- lem, whilebenefi tingfromthe facilityofCu(I II) to engageindifficult reductive elimination,might enableamilda ndb roadlygen erals trategytoward thetr ifluoromethylationofarylbromides.

We recentlydeveloped ametallaphotore dox-

catalyzed (29) cross-electrophilecoupling protocol in whichalkylradi calsweregenerated byasil yl radical-mediated halogena bstraction(30). This manifoldwass hownto providefaci le accesstoa widerange ofalkylrad icalsfr omthecor re- sponding alkylbromides,a featurethat has beenfo undtoberema rkab lyge neral.Litera- turepr ecedentsindicatethat thisfacilesila ne- mediatedhalogena bstractionme chanismshould alsofu nctionbroadlywit harylbromides (k5× 10 6 M Š1 s Š1 to1. 1×10 8 M Š1 s Š1 forb romobenzene with ar angeofsilylradica ls) togenera tethe correspondingaryl radicalsundermil dcondi-tions (31,32).Giventhat ary lradicals areknown to bec apturedbyCu(II)speci es atarateap- proaching diffusion(33,34),wequest ioned whetherthisli ght-driv enhalogenabstraction mechanismmightbe exploitedto forg eCu(III)- areneinterme diatesfromadiverse rangeo fa ryl halidesatroom temp erature (Fig.1),effectively overcomingthecop peroxid ativeadditionp rob- lem. Thes uccessfulexecutionoft hismechanistic concept wouldsolvea long-st and ingchallengein copper catalysis,the reafterprovidingageneral platform tocatalyticall yaccess trifluoromethylarenes.

Our proposedmechanismf orthelight-

enabledtriflu oromethylationprotocolisout- linedinFi g.2A .Uponex posure tovisibl elight, photocatalystIr(dFFpp y) 2 (4,4´-dCF 3 bpy)PF 6 [dFFppy =2 -(2,4-difluorophenyl)-5-fluoropyridine;

4,4´-dCF

3 bpy= 4,4 ´-di(trifluoromethyl)-2,2´- bipyridyl)] (1) shouldpr oduceexcitedtriplet statespec ies2. Thishig hlyoxidizingIr com- plex [E

1/2red

(*Ir III /Ir II ) =+1.55 Vversus sat urated calomelelec trode(SCE)inCH 3

CN]can undergo

single-electrontransfer(SET) withtris-(trimethylsilyl) silanol (4)[supersilanol,E p (4 /4)=+1.54 V versus SCEin CH 3

CN] togive Ir(II)complex 3

(35). Wehy pothesizethatsupersilan ol4,upon oxidationanddepr otonati on,wouldthenun- dergo rapidsilylm igration(Fig .2B) toyield species5as thec atalyticallyrelevantsilylradical (36). Subsequentbro mineatomabstraction fromarylbromide6would thenyield thecorrespond- ing arylradical7.Concurrently,Ir(II) complex 3[E

1/2red

(Ir III /Ir II )=-0.83 Vversus SCEin CH 3

CN] couldfacilitate theformation ofthe

CF 3 radical (9)througha SETevent withelec- trophilic CF 3 reagent8[E p (8/8 )=-0.52 V versusSCE inCH 3

CN].At this time,we believe

theCu (II)-CF 3 adduct(11)shouldbegenerated throughi nteractionbetweentheCF 3 radical(9) andthe activeCu(I)com plex( 10), formedinsitu by SETreduction ofa Cu(II)catalyst precursor by thepho tocatalyst.Arylradical7shouldquickl y undergo radicaltrapping byCu(II)complex 11to yieldt hekeyar yl-Cu(III)-CF 3 adduct12(37,38).

Reductiveeliminationfr omthishigh-valentCu(II I)

intermediatewould yield thede siredproduct13 and simultaneouslyregenerate Cu(I)catalyst10(39).

A surveyofvarious combinationsof differ-

ent electrophilicCF 3 reagents, coppersources, and solventsrevealed thatblue light-emitting diode( LED)irradiatio nofamixtureo f4- bromobenzonitrile,supersilanol(4), dMesSCF 3 (8), CuBr 2 photocatalyst1(0.25 mol%)in acetonea tr oo m temperature affordedthedesiredt rifl uoro methyl- arene in89%yield (Fig .2C). Theuseofsuper- silanolinplac eof hydrosilane swa sfoundtobe crucial, becausei tminimizes unproductiveproto- dehalogenationofthebro moarene,which presum- ably proceedst hroughhydrogen atomabstraction Leet al.,Science360, 1010-1014 (2018)1 June2018 2of5 metallaphotoredox catalytic platform photoredox-enabled Cu II -CF 3 formation SiMe 3 SiMe 3 OH Me 3 Si Si silyl radical SiMe 3 SiMe 3 O Me 3 Si Si silyloxide radical Cu II X Cu III ArL n X Cu I XL n CF 3 arene-CF 3 product L n CF 3 CF 3

Catalytic

Photoredox

Cycle Ir III 1 )Ir II 3 oxidant visible light

CatalyticCopper

Cyclefacile radical

capturing mechanism silyl radical precursor Br aryl radicalaryl bromide e e dMesSCF 3

1-step synthesis

or commercially availableunique silyl radical precursor *Ir III 2 reductant SET NCNC NC SMes CF 3 Mes OTf - H - e eliminate

H-atom source- H

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