Direct α-Arylation of Ketones 958 Seminars_pdf/FS03_SS04...Direct α-Arylation of Ketones Zhensheng Ding January 29, 2003 Department of Chemistry Michigan State University

Directα-ArylationofKetones

ZhenshengDing

January29,2003

DepartmentofChemistry

MichiganStateUniversity

Directα-ArylationofKetone

Outline

■Introduction

■MechanisticStudy

■FactorsInfluencingtheArylationofKetone◆Bases

◆Ligands

◆ArylationReagents

■ArylationReactionsofOtherStabilizedCarbanions

■Applications◆IntramolecularArylationReaction◆AsymmetricArylationReaction

■Prospects

■Conclusion

Directα-ArylationofKetone

Outline

■Introduction◆CouplingReactions◆Whatisdirectα-arylationofketones

◆Previousmethodsofketonearylation

◆Discoveryofcatalyticketonearylationreaction

■MechanismStudy

■FactorsInfluencingthearylationofketone


■Applications

■Prospects

■Conclusion

Introduction

Littke,AdamF.;Fu,GregoryC.Angew.Chem.Int.Ed.,2002,41,4183

CrossCouplingReactions

X=Br,I,OTf,Cl

M=

MgKumada

SnStilleBSuzuki

SiHiyamaZnNegishi

etc.

Introduction

Hamann,BlakeC.;Hartwig,J.F.,J.Am.Chem.Soc.,1997,119,12382

WhatisDirectα-ArylationofKetone?

‘DirectCrossCouplingofarylhalideswithketonescatalyzedbytransitionmetals’.

Introduction

■Catalyticmethodstoformα–arylketonesarelesscommon

Abramovitch,RudolphA.;Barton,DerekH.;Finet,Jean-PierreTetrahedron,1988,44,3039

DrawbacksofPreviousMethodsofDirectα-ArylationofKetones

■Multiple-steppreparationofstoichiometricarylationreagents

■Useoftoxicmain-groupreagents

■Onlyonearylgroupwastransferred

■Lowproductyields

Introduction

Palucki,Michael;Buchwald,StephenL.J.Am.Chem.Soc.,1997,119,11108Hamann,BlakeC.;Hartwig,J.F.,J.Am.Chem.Soc.,1997,119,12382

DiscoveryofPd-Catalyzedα-ArylationofKetone

■FrombyproductofC-OcouplingreactionsbyProf.BuchwaldinMIT:

■FromextensionofC-NcouplingreactionsbyProfHartwiginYale:

Introduction

SelectedExamplesofKetoneα-Arylation

Palucki,Michael;Buchwald,StephenL.J.Am.Chem.Soc.,1997,119,11108

■Generalmethodforalargenumberofα-arylketonesundermildconditions■Compatiblewithseveralfunctionalgroups■Goodyieldwithhighregioselectivity■Inmostcasesmono/diarylationratiosarehigh

Mechanism

Fox,JosephM.;Huang,X.;Chieffi,Andre;Buchwald,StephenL.J.Am.Soc.Chem.,2000,122,1360

MechanismofKetoneArylationReaction

Proposedcatalyticcycleofketonearylationreactionwithbidentateligand

FactorsInfluencingtheArylationofKetones

MainFactorsInfluencingtheArylationofKetone

ArylationofKetones-Base

■Strongenough

■Nointroductionofside-reactions

◆AldolReaction

Pivsa-Art,Sommai;Satoh,Tetsuya;Kawamura,Yoshiki;Miura,MasahiroBull.Chem.Soc.Jpn,1998,71,476

◆C-OCouplingReaction

■Solubilityinthesolvent

Na2CO3<K2CO3<Cs2CO3

RequirementforBase


SomeBasesUsedinArylationofKetones


NaOtBu:

NaHMDS:

■Strong,bulkybases

■Notcompatiblewithseveralbase-sensitivegroups


UseK3PO4asBase



UseK3PO4asBase



■When1eqbaseisusedforarylationofacetophenone


■Equilibriumbetween2and4willfavorenolateofarylketone4

■Moredi-arylatedproductswouldform

ExcessiveBaseisFavoredforMono-arylatedProduct



■When2eqbaseisusedforarylationofacetophenone

ExcessiveBaseisFavoredforMono-arylatedProduct

■Alltheketonesareintheirenolateform

■Highratioofmono/di-arylatedproductisexpected

■Aldolreactioncanbesuppressed



Ligand-freeArylationofKetones

■Simple&Cheap

■Onlysuitableforlimitedsubstrates

Arylationofketones-Ligands

.

■Phosphinesarealsoelectronacceptor

◆Theπ-acceptor abilityfrommetals:

PtBu3<PR3<PAr3<P(OMe)3<P(OAr)3<PCl3<PF3

Crabtree,RobertH.TheOrganometallicChemistryoftheTransitionMetals,2001,91McAuliffeC.A.andLevasonW.Phosphine,ArsineandStibineComplexesoftheTransitionElements,1979,68

■Introductionofchiralcenteriseasy

CharacteristicsofPhosphinesLigands

■Metalcentercanbestabilizedbyphosphineligands

■Stericpropertiescanbetunedsystematically

◆Thestericeffect:

PtBu3>PPh3>P(OPh)3>PMe3>P(OR)3>PF3

■Increasetheelectrondensityonmetalcenter

◆Theσ-donationabilitytothemetal:

PtBu3>P(OR)3>PR3⋍PPh3>PF3>P(OPh)3

ArylationofKetones-Ligands

■Stericallyhinderedligandscanmakereactionfaster,affordhigheryields


StericEffectofChelatingPhosphineLigands


■Reactionsaffordhigheryieldsbyusingelectron-richligands

Kawatsura,Motoi;Hartwig,J.F.,J.Am.Chem.Soc.,1999,121,1473

ElectronicEffectsofPhosphineLigands

Arylationofketones-Ligands

.

■Stericallyhinderedligandsfacilitatereductiveelimination

■Electron-richerphosphinesaccelerateoxidativeaddition


ActivitiesofPhosphineLigandsinKetoneArylationReactions


.Kawatsura,Motoi;Hartwig,J.F.,J.Am.Chem.Soc.,1999,121,1473

Experimentallyobserved:One31Psingletat57.2ppm,anothersingletat24.6ppm

FurtherDiscussionofChelatingModel—lowtemperature31PNMR

ProposedChelationoftwophosphorousatomsTwo31Psingletsaround57ppm

Onephosphorousatomisboundtopalladiumcenter

■StericallyhinderedmonophosphinesPR3mayworkforketonearylation


.Kawatsura,Motoi;Hartwig,J.F.,J.Am.Chem.Soc.,1999,121,1473

KetoneArylationCatalyzedbyAlkyl-monophosphines

■Alkyl-monophosphinescanpromoteketonearylationinhighyield■Reactionconditionismild■Usuallyonlyworkwellforaromaticketones


.

KetoneArylationCatalyzedbyBuchwald’sLigand4



.

■Readilyavailableandcheap

■Stable,easytohandleandstore

■Lessreactivethanbromo-&iodoarenes

BonddissociationenergiesforC-XbondinPh-X:C-Cl:96kcal/mol,C-Br:81kcal/mol,C-I:65kcal/mol

α-ArylationofKetonewithChloroarenes

■C-ClbondisdifficulttobeactivatedthanotherC-Xbond

Grushin,V.V;Alper,HChem.Rev,1994,94,1047


.

■Oxidativeadditionofarylhalides:

MethodstoActivateArylChlorides

■Activatechloroarenesbyelectron-withdrawinggroupsonaromaticrings

■Increaseelectrondensityonmetalsbyuseofelectron-richligands



.

■Theycanfacilitateoxidativeaddition◆Increaseelectron-densityonmetalbecauseoftheirelectronrichness◆FormationofhighlyactivePd(PR3)2-3speciesduetosterichindrance■Theycanpromotereductiveelimination◆Theyarehighlystericallyhinderedligands

Ehrentraut,Andreas;Zapf,Alex;Beller,MatthiasAdv.Synth.Catal.2002,344,209

ActiveLigandsForArylChlorides


Ehrentraut,Andreas;Zapf,Alex;Beller,MatthiasAdv.Synth.Catal.2002,344,209

ArylationofKetonesbyArylChlorides


.

■Efficientlyincreaseelectron-densityonmetalcenter

■Stericeffectcanbetunedbyarylgroupsonnitrogen

Bourissou,D.;Guerret,O.;Gabbai,F.P.;Bertrand,G.Chem.Rev,2000,100,39

KetoneArylationCatalyzedbyPd-N-HeterocyclicCarbeneComplex

σ-Donationfromcarbenetometal

π-Backbondingfrommetaltocarbene

Strongdonationfromnitrogentocarbenecenter

Weakπ-acceptor


.

■Airstable,well-definedpalladiumN-heterocycliccarbenecomplex■Efficientlycatalyzeketonearylationreactionwitharylchlorides

Viciu,MihaiS;Germaneau,RomainF.;Nolan,StevenP.OrgLett.,2002,4,4053

ArylationofKetonesCatalyzedbyPd-NHCComplex

ArylationofOtherStabilizedAnions

.

StabilizedAnionsasPotentialSubstratesofArylationReaction


.Fox,JosephM.;Huang,X.;Chieffi,Andre;Buchwald,StephenL.J.Am.Soc.Chem.,2000,122,1360.

ArylationofCyclo-DiketonesandNitroalkanes

■Reactioncanundergobyusingmildbase

■Excellentfunctionalgrouptoleranceforarylationofnitroalkanes

.

ArylationofNitroalkanes

.Vogl,Erasmus.M.;Buchwald,S.L.,J.Org.Chem.,2002,67,106.

GroupToleranceinNitroalkaneArylationReaction

■Reactionconditionismild

■Nodi-arylatedproductsobserved

■Excellentchemoselectivity

.


..Wolkowski,JoannaP.;Hartwig,J.F.,Angew.Chem.Int.Ed.,2002,41,4289

ArylationofMalonates

■Approach:Useofmorestericallyhinderedligands

■Challenge:Lowreactivitytowardarylationreactiondueto:

◆Stabilizingeffectoftwocarbonylretardsthereductiveelimination

◆η2-O,O-coordinationmodeofofmalonateanion

.


..Beare,NeilA.;Hartwig,J.F.,J.Org.Chem.,2002,67,541

■Limitation:Fewarylgroupssuchaspyridylgroupcannotbetransferred


.

■Challenge:LowerreactivityofestersUnstableunderbasiccondition—Claisenreaction

■Noregioselectivityissuestobeconsidered

ArylationofOtherStabilizedAnions–Esters

..Rathke,M.W.;Sullivan,D.F.J.Am.Chem.Soc.1973,95,3050.

ArylationofEsters

■Approach:Useofstericallyhinderedtert-butylesters

.

ArylationofEsters

..

■Challenge:Doublearylationofesterenolates■ChangebasefromNaHMDStoLiHMDSExcessiveenolates(2.3eqoftert-Butylesters,2.5eqofLiHMDS)

Moradi,W.A.;Buchwald,S.L.,J.Am.Chem.Soc.,2001,123,7996

PromotionofMono-ArylationProductsofEsters

.

ArylationofEsters

..Jogensen,Morten;Hartwig,J.F.,et.al,J.Am.Chem.Soc.,2002,124,12557

■Useofstrongerbase

PromotionofMono-ArylationProductsofEsters

■Twofoldofbase

ApplicationofArylationReaction

.

Outline

■Introduction

■MechanismStudy

■FactorsInfluencingtheArylationofKetone


■Applications◆IntramolecularArylationReaction

◆AsymmetricArylationReaction

■Prospects

■Conclusion

Applications–ConstructionofHeterocyclic

Beare,NeilA.;Hartwig,J.F.,J.Org.Chem.,2001,66,3402Gaertzen,OliverandBuchwald,StephenL.J.Org.Chem.,2002,67,465

IntramolecularArylationReactionofStabilizedAnions

■Provideasimplewaytoconstructmanyringsystems■Representavaluablesyntheticbuildingblocksforfurtherreaction

Applications–Totalsynthesis

.

SynthesisofAnalogsofDuocarmycinSA

Muratake,H.,Natsume,M.Tetrahedronletters1997,38,7577

■Resource:isolatedfromstreptomycesspeciesinJapan.

■Bio-activities:extremelypotentantitumorantibiotic

Applications–Totalsynthesis

.Muratake,H.,Natsume,M.Tetrahedronletters1997,38,7577

SynthesisofAnalogsofDuocarmycinSA

Applications–AsymmetricQuaternaryCenterConstruction

.

■Newcatalyticmethodsofformationofquaternarystereocenters

■Preparationofsomeimportantintermediatesfornaturalproductsynthesis

Ahman,Jens;Wolfe,John,P.;Troutman,MalisaV.;Palucki,Michael;Buchwald,StephenL.

J.Am.Soc.Chem.,1998,120,1980

EnantioselectiveConstructionofQuaternaryCenters

Applications–AsymmetricQuaternaryCenterConstruction

.

■Highenantioselectivityandyield

■Lowcatalystsloadings

■Mildconditions

■Notefficientforortho-substitutedarylbromides

Hamada,Takayuki;Cheffi,Andre;Ahman,Jens;Buchwald,StephenL..J.Am.Soc.Chem.,2002,124,1261

EnantioselectiveConstructionofQuaternaryCenters

Prospects–UseofOtherMetalCatalysts

■Arylationofmalonatescatalyzedbycopper

.

■Cheapcatalystandligand,excellentfunctionalgrouptolerance■Onlyaryliodideisreactive

■Enantioselectivearylationofγ-butyrolactonescatalyzedbynickel

Hennessy,Edward;Buchwald,StephenL..Org.Lett.,2002,4,269Spielvogel,DirkJ.;Buchwald,StephenL..J.Am.Soc.Chem.,2002,124,3500

ProspectsofArylationReactionsofStabilizedCarbanions

■Higheeandgoodyield■Notefficientforortho-substitutedarylbromides

Prospects–Tandem&One-potSynthesis

.Mutter,Roger;Campbell,IanB.,Wills,Martin;et.al.J.Org.Chem.,2001,66,3284Beare,NeilA.;Hartwig,J.F.,J.Org.Chem.,2002,67,541

TandemandOne-potSynthesis

■Tandemsynthesisof1-Vinyl-1H-isochromenederivatives

■One-potpreparationofdiethyl2-Aryl-2-methylmalonates

.

Conclusions

Conclusions

■Directketonearylationreactionisageneralmethodtoselectivelyinstallarylgroupatα-positionofketones.

■Ketonearylationreactionhasbeengreatlyextendedtootherstablecarbanions

■Theintramoleculararylationreactioncanfurnishanumberofheterocyclics.

■Asymmetricarylationreactionshavebeenestablished

■Mostrecentworkwasbrieflydiscussed.Theirpotentialdevelopmentisexpected

.

Acknowledgement

Prof.Wulff

Prof.Borhan

Yana,Yu,Yiqian,Zhenjie,Gang,Zhiyiandallthosewhohelpedme

Direct α-Arylation of Ketones 958 Seminars_pdf/FS03_SS04...Direct α-Arylation of Ketones Zhensheng Ding January 29, 2003 Department of Chemistry Michigan State University

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