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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
■ArylationReactionsofOtherStabilizedCarbanions
■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
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
ArylationofKetones-Base
SomeBasesUsedinArylationofKetones
Fox,JosephM.;Huang,X.;Chieffi,Andre;Buchwald,StephenL.J.Am.Soc.Chem.,2000,122,1360
NaOtBu:
NaHMDS:
■Strong,bulkybases
■Notcompatiblewithseveralbase-sensitivegroups
ArylationofKetones-Base
UseK3PO4asBase
Fox,JosephM.;Huang,X.;Chieffi,Andre;Buchwald,StephenL.J.Am.Soc.Chem.,2000,122,1360
ArylationofKetones-Base
UseK3PO4asBase
Fox,JosephM.;Huang,X.;Chieffi,Andre;Buchwald,StephenL.J.Am.Soc.Chem.,2000,122,1360
ArylationofKetones-Base
■When1eqbaseisusedforarylationofacetophenone
Hamann,BlakeC.;Hartwig,J.F.,J.Am.Chem.Soc.,1997,119,12382
■Equilibriumbetween2and4willfavorenolateofarylketone4
■Moredi-arylatedproductswouldform
ExcessiveBaseisFavoredforMono-arylatedProduct
ArylationofKetones-Base
Hamann,BlakeC.;Hartwig,J.F.,J.Am.Chem.Soc.,1997,119,12382
■When2eqbaseisusedforarylationofacetophenone
ExcessiveBaseisFavoredforMono-arylatedProduct
■Alltheketonesareintheirenolateform
■Highratioofmono/di-arylatedproductisexpected
■Aldolreactioncanbesuppressed
FactorsInfluencingtheArylationofKetones
Fox,JosephM.;Huang,X.;Chieffi,Andre;Buchwald,StephenL.J.Am.Soc.Chem.,2000,122,1360
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
Hamann,BlakeC.;Hartwig,J.F.,J.Am.Chem.Soc.,1997,119,12382
StericEffectofChelatingPhosphineLigands
ArylationofKetones-Ligands
■Reactionsaffordhigheryieldsbyusingelectron-richligands
Kawatsura,Motoi;Hartwig,J.F.,J.Am.Chem.Soc.,1999,121,1473
ElectronicEffectsofPhosphineLigands
Arylationofketones-Ligands
.
■Stericallyhinderedligandsfacilitatereductiveelimination
■Electron-richerphosphinesaccelerateoxidativeaddition
Littke,AdamF.;Fu,GregoryC.Angew.Chem.Int.Ed.,2002,41,4183
ActivitiesofPhosphineLigandsinKetoneArylationReactions
ArylationofKetones-Ligands
.Kawatsura,Motoi;Hartwig,J.F.,J.Am.Chem.Soc.,1999,121,1473
Experimentallyobserved:One31Psingletat57.2ppm,anothersingletat24.6ppm
FurtherDiscussionofChelatingModel—lowtemperature31PNMR
ProposedChelationoftwophosphorousatomsTwo31Psingletsaround57ppm
Onephosphorousatomisboundtopalladiumcenter
■StericallyhinderedmonophosphinesPR3mayworkforketonearylation
ArylationofKetones-Ligands
.Kawatsura,Motoi;Hartwig,J.F.,J.Am.Chem.Soc.,1999,121,1473
KetoneArylationCatalyzedbyAlkyl-monophosphines
■Alkyl-monophosphinescanpromoteketonearylationinhighyield■Reactionconditionismild■Usuallyonlyworkwellforaromaticketones
ArylationofKetones-Ligands
.
KetoneArylationCatalyzedbyBuchwald’sLigand4
Fox,JosephM.;Huang,X.;Chieffi,Andre;Buchwald,StephenL.J.Am.Soc.Chem.,2000,122,1360
FactorsInfluencingtheArylationofKetones
.
■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
FactorsInfluencingtheArylationofKetones
.
■Oxidativeadditionofarylhalides:
MethodstoActivateArylChlorides
■Activatechloroarenesbyelectron-withdrawinggroupsonaromaticrings
■Increaseelectrondensityonmetalsbyuseofelectron-richligands
Littke,AdamF.;Fu,GregoryC.Angew.Chem.Int.Ed.,2002,41,4183
FactorsInfluencingtheArylationofKetones
.
■Theycanfacilitateoxidativeaddition◆Increaseelectron-densityonmetalbecauseoftheirelectronrichness◆FormationofhighlyactivePd(PR3)2-3speciesduetosterichindrance■Theycanpromotereductiveelimination◆Theyarehighlystericallyhinderedligands
Ehrentraut,Andreas;Zapf,Alex;Beller,MatthiasAdv.Synth.Catal.2002,344,209
ActiveLigandsForArylChlorides
FactorsInfluencingtheArylationofKetones
Ehrentraut,Andreas;Zapf,Alex;Beller,MatthiasAdv.Synth.Catal.2002,344,209
ArylationofKetonesbyArylChlorides
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
ArylationofKetonesbyArylChlorides
.
■Airstable,well-definedpalladiumN-heterocycliccarbenecomplex■Efficientlycatalyzeketonearylationreactionwitharylchlorides
Viciu,MihaiS;Germaneau,RomainF.;Nolan,StevenP.OrgLett.,2002,4,4053
ArylationofKetonesCatalyzedbyPd-NHCComplex
ArylationofOtherStabilizedAnions
.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
.
ArylationofOtherStabilizedAnions
..Wolkowski,JoannaP.;Hartwig,J.F.,Angew.Chem.Int.Ed.,2002,41,4289
ArylationofMalonates
■Approach:Useofmorestericallyhinderedligands
■Challenge:Lowreactivitytowardarylationreactiondueto:
◆Stabilizingeffectoftwocarbonylretardsthereductiveelimination
◆η2-O,O-coordinationmodeofofmalonateanion
.
ArylationofMalonates
..Beare,NeilA.;Hartwig,J.F.,J.Org.Chem.,2002,67,541
■Limitation:Fewarylgroupssuchaspyridylgroupcannotbetransferred
ArylationofMalonates
.
■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
■ArylationReactionsofOtherStabilizedCarbanions
■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