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书籍名称 Practical Synthetic Organic Chemistry: Reactions, Principles, and Techniques 书籍作者 Stéphane Caron (Editor) 出版社 W1Ley 出版日期 August 2011

PRACTICALSYNTHETICORGANICCHEMISTRYPRACTICALSYNTHETICORGANICCHEMISTRYReactions,Principles,andTechniquesEditedbySTEPHANECARONCopyright2011byJohnWiley&Sons,Inc.AllrightsreservedPublishedbyJohnWiley&Sons,Inc.,Hoboken,NewJerseyPublishedsimultaneouslyinCanadaNopartofthispublicationmaybereproduced,storedinaretrievalsystem,ortransmittedinanyformorbyanymeans,electronic,mechanical,photocopying,recording,scanning,orotherwise,exceptaspermittedunderSections107or108ofthe1976UnitedStatesCopyrightAct,withouteitherthepriorwrittenpermissionofthePublisher,orauthorizationthroughpaymentoftheappropriateper-copyfeetotheCopyrightClearanceCenter,Inc.,222RosewoodDrive,Danvers,MA01923,(978)750-8400,fax(978)750-4470,oronthewebatwww.copyright.com.RequeststothePublisherforpermissionshouldbeaddressedtothePermissionsDepartment,JohnWiley&Sons,Inc.,111RiverStreet,Hoboken,NJ07030,(201)748-6011,fax(201)748-6008,oronlineathttp://www.wiley.com/go/permission.LimitofLiability/DisclaimerofWarranty:Whilethepublisherandauthorhaveusedtheirbesteffortsinpreparingthisbook,theymakenorepresentationsorwarrantieswithrespecttotheaccuracyorcompletenessofthecontentsofthisbookandspecificallydisclaimanyimpliedwarrantiesofmerchantabilityorfitnessforaparticularpurpose.Nowarrantymaybecreatedorextendedbysalesrepresentativesorwrittensalesmaterials.Theadviceandstrategiescontainedhereinmaynotbesuitableforyoursituation.Youshouldconsultwithaprofessionalwhereappropriate.Neitherthepublishernorauthorshallbeliableforanylossofprofitoranyothercommercialdamages,includingbutnotlimitedtospecial,incidental,consequential,orotherdamages.Forgeneralinformationonourotherproductsandservicesorfortechnicalsupport,pleasecontactourCustomerCareDepartmentwithintheUnitedStatesat(800)762-2974,outsidetheUnitedStatesat(317)572-3993orfax(317)572-4002.Wileyalsopublishesitsbooksinavarietyofelectronicformats.Somecontentthatappearsinprintmaynotbeavailableinelectronicformats.FormoreinformationaboutWileyproducts,visitourwebsiteatwww.wiley.com.LibraryofCongressCataloging-in-PublicationData:Practicalsyntheticorganicchemistry:reactions,principles,andtechniques/editedbyStephaneCaron.p.cm.Includesindex.ISBN978-0-470-03733-1(pbk.)1.Organiccompounds–Synthesis.I.Caron,Stephane.QD262.P6882011547’.2–dc222011008293PrintedintheUnitedStatesofAmericaoBooKISBN:978-1-118-09355-9ePDFISBN:978-1-118-09357-3ePubISBN:978-1-118-09356-610987654321CONTENTSForewordviiPrefaceixContributorsxi1AliphaticNucleophilicSubstitution1JadeD.Nelson2AdditiontoCarbon–HeteroatomMultipleBonds73RajappaVaidyanathanandCarrieBrockwayWager3AdditiontoCarbon–CarbonMultipleBonds167JohnA.Ragan4NucleophilicAromaticSubstitution237StephaneCaronandArunGhosh5ElectrophilicAromaticSubstitution255StephaneCaron6SelectedMetal-MediatedCross-CouplingReactions279StephaneCaron,ArunGhosh,SallyGutRuggeri,NathanD.Ide,JadeD.Nelson,andJohnA.Ragan7Rearrangements341DavidH.B.Ripin8Eliminations383SallyGutRuggeriv9Reductions419SallyGutRuggeri,StephaneCaron,PascalDube,NathanD.Ide,KristinE.Price,JohnA.Ragan,andShuYu10Oxidations493DavidH.BrownRipin11SelectedFreeRadicalReactions557NathanD.Ide12Synthesisof“Nucleophilic”OrganometallicReagents575DavidH.BrownRipin13SynthesisofCommonAromaticHeterocycles609StephaneCaron14AccesstoChirality649RobertW.Dugger15SyntheticRouteDevelopmentofSelectedContemporaryPharmaceuticalDrugs661StephaneCaron16GreenChemistry683JuanC.Colberg17NamingCarbocyclesandHeterocycles703HeatherN.FrostandDavidH.BrownRipin18pKa771DavidH.BrownRipin19GeneralSolventProperties805StephaneCaron20PracticalChemistryConcepts:TipsforthePracticingChemistorThingsTheyDon’tTeachYouinSchool819SallyGutRuggeriFunctionalGroupInterconversionIndex837Index845viCONTENTSFOREWORDWhileallpractitionersintheartrecognizethatsyntheticorganicchemistryservessociety,itisnotalwaysappreciatedtheotherwayaround;namelythatsocietydoesnotassociatethephenomenalrewardsthatarederivedfromourabilitytoassemblecomplexfunctionalmolecules.Indeed,theachievementsofthepharmaceuticalindustryareunderpinnedbymoleculardesignandsynthesisofvirtuallyallthehealingdrugsubstancesthatarecurrentlyonthemarket,whichbenefitmankindandcurehumandiseases.Thereis,inmyview,nothingnoblerthanthisworthwhiletask.However,synthesisofthecomplexfunctionalarchitecturesisnotatrivialorroutineprocess.Thisisalwaysmademoredifficultonscalingupofthechemistriestocomplywithcurrentstandardsofsafety,robustness,costs,quality,andenvironmentalimpact.I,therefore,verymuchwelcomethisnewtextbook,PracticalSyntheticOrganicChemistry:Reactions,Principles,andTechniques,whichgivesusaninspiringandpragmaticglimpseatthemostcommonlyusedandeffectivesynthesisproceduresonscale.Thisuniquetextbookhasbeenwrittenbyexpertsinthefieldandprovidesaninsightandcritiqueofthekeyeffectivemethodsformolecularassembly.Itwillbeagreatstartingpointforanyonedevelopingtheircareerinthisworthyindustry.Theorganizationandchaptertitlesreflectarefreshingapproachtoexplainingacomplicatedsciencecoveringallthemajorbondconstructionmethodsandfunctionalcontrolelementsnecessaryformodernsyntheticplanningandexecution.Theauthorshaveincorporatedchaptersonimportanttopicssuchastheeffectivenessofrearrangementprocesses,radicalreactions,accesstochirality,andgreenchemistry,whicharenotcapturedasagroupinmoretraditionaltexts.Furthermore,theeducationalcomponentofthisbookhighlightingnomenclature,pKaknowledge,solventproperties,andtipsofthetradefromthepracticingchemistagainaddsvalueinprovidingafeastofinformationthatotherwiseisdispersedovermanysourcesorissimplylockedupinthepersonaldatabaseofknowledgeofthoseexperiencedintheart.viiThecreativespiritofthisareaofscienceinbringingnewfunctionalmoleculesinourworldforthefirsttimeforthebettermentofusallisenduringandwillcontinuetoseednewdiscoveriesformanyyearstocome.STEVENV.LEYCambridge,UK2011viiiFOREWORDPREFACEDespitetherelativematurityofthefieldoforganicchemistry,moleculescontinuetopresentsyntheticchemistswithsignificantchallenges,especiallyastheexpectationsforsynthetic,material,andenergyefficiencycontinuetointensify.Inresponsetothesechallenges,organicchemistshavecontinuedtodevelopinnovativenewsyntheticmethods.Manyoftheserecentlydevelopedsyntheticmethodsallowforachievementofevermoreimpressivechemo-,enantio-,diastereo-,andregioselectivity.Additionally,newsyntheticmethodsareprovidingchemistswithnovelreactionsandenablingsyntheticstrategiesthatwouldhavepreviouslybeenimpracticalorimpossible.Whilewearefascinatedbythemultitudeofpowerfulsyntheticmethodsthathavebeendevelopedinrecentyears,thesemethodswerenotthedirectinspirationforthisbook.Instead,theimpetusforthisbookwasactuallyanarticlerequestforaspecialissueofChemicalReviewsonprocesschemistry(Vol.106,No.7,July2006).AgroupofPfizerprocesschemists,attheGroton(CT)site,electedtowriteareviewofoxidationsperformedonlargescale.ThisreviewwasdividedamongseveralauthorsandservedasthebasisforChapter10inthisbook.1MypersonalcontributiontothereviewarticlewasthesectioncoveringC–Ooxidations,andIwassurprisedbywhatIlearneduponfurtherinvestigationofthisseeminglymundanetopic.Whileanumberofeffectivemethodsexistfortheconversionofprimaryalcoholstoaldehydes,onlytwogeneralmethodshavebeenusedconsistentlyandsuccessfullyonmanufacturingscale:Moffatt-typeandTEMPO-mediatedoxidations.Uponcompletionofthisreview,Iaskedmyselfifthiswouldbetrueforotherchemicaltransformations.Beyondsimplecuriosity,thisquestionisrelevantbecausesearchengineslikeSciFinderandReaxyscanrapidlysearchthroughthechemicalliteratureandidentifylargenumbersofpotentiallyrelevantreactions/references.Forexample,asimplesearchforthenitrationofanareneresultsinthousandsofexamplesofthistransformation.Howdoesonesortthroughthisincrediblewealthofinformation?1Caron,S.;Dugger,R.W.;Ruggeri,S.G.;Ragan,J.A.;Ripin,D.H.B.Chem.Rev.2006,106,2943.ixInthisageofinformationoverload,wethoughtthatasimplecollectionofprovenmethodologiesmightbeofvaluetopracticingsyntheticchemists.Whilemanytextbooksofferacompendiumofthemanysyntheticmethodsthatareavailable,wesetouttocreateaguidethatwouldhelpselectthefirstfewconditionstoattemptforagiventransformation.Thismightbeofparticularvaluewhenthesubstrateofinterestisdifficulttoaccessinsufficientquantitiesforalargescreenofreactionconditions.Theauthorsagreedthattheobjectivewouldnotnecessarilybetofindtheoriginalreportortheverybestprocedureforagivenreaction,butrathertoidentifyreactionconditionsthatworkreliablywelloverthebroadestpossiblerangeofsubstrates.Itwasaprerequisiteforthereferencescitedinthistextbookthatexperimentaldatawasprovided,preferablyonamulti-gramscale,andpreferablyusingreactionconditionsthatwouldbeamenabletoscale-up.Intherarecaseswheresuchexperimentaldatawasnotidentified,theauthorsusedtheirdiscretiontoselectreactionconditionsthatwewouldexpecttoscaleupreasonablywell.Notsurprisingly,manyoftheexamplescitedinthistextbookcomefromOrganicSynthesesorfromjournalslikeOrganicProcessResearchandDevelopmentandTheJournalofOrganicChemistry.Wealsoagreedthatpatentliteraturewouldbeavoided,ifpossible,sinceitisnotalwayseasilyaccessedand/orinterpreted.Finally,wemadeanefforttofocusonreferencespublishedafter1980.Inadditiontothecompilationofreliablemethodsforaccomplishingvariouschemicaltransformations,wehavetriedtoprovidethereaderwithsomeinformationthatmaynotbecommonknowledgeoutsideofprocesschemistrygroups.Thesecondportionofthisbookfocusesonthistypeofinformation.Howcanchiralbuildingblocksbeaccessedmostefficiently?Whatarethemostreliablemethodsforpreparingandnamingcommonheterocycles?Whyaresomesolventsfavoredoverothers?Howdoesthesynthesisofadrugevolvethroughoutdevelopment?Whatdoesitmeantohaveagreensynthesis?Wehopethatreaderswillfindsomeusefulandpracticalinformationinthissectionofthebook.ThecompletionofthisendeavorwouldhaveneverbeenpossiblewithoutthecommitmentofseveralofmycolleaguesatPfizerwhoagreedtothepreparationandcollectivereviewofthechapters.Wearealsoextremelygratefultoourmanagementforsupportingtheproject.IwouldspecificallyliketothankJodiGaynor,LisaLentini,andKimWhitefortheiradministrativesupport.IwouldalsoliketothankKrisN.Jonesforherassistanceineditingthebook.ThecommitmentandsupportofourcollaboratorsatWiley-Interscienceareverymuchappreciated.Weespeciallyappreciatedtheirpatienceasourdeadlinecameandpassed.Buildingeachchapterofthismanuscriptservedasanexcellentchemistryrefreshercoursefortheauthors,andwelearnedalotofnewchemistryintheprocess.Wesincerelyhopeyouenjoythesameexperienceasyoureadthisbook.xPREFACECONTRIBUTORSStephaneCaron,SeniorDirector,ChemicalR&D,PfizerWorldwideR&D,EasternPointRoad,MS8118D-4002,GrotonCT,06340,stephane.caron@pfizer.com.JuanColberg,APIandAnalyticsTechnologyLeader,Technology&StrategicSourcing,PfizerWorldwideR&D,EasternPointRoad,MS8118D-4025,GrotonCT,06340,Juan.colberg@pfizer.com.PascalDube,PrincipalScientist,ChemicalR&D,PfizerWorldwideR&D,EasternPointRoad,MS8118D-4060,GrotonCT,06340,pascal.dube@pfizer.com.RobertW.Dugger,ResearchFellow,ChemicalR&D,PfizerWorldwideR&D,EasternPointRoad,MS8118D-4031,GrotonCT,06340,robert.w.dugger@pfizer.com.HeatherN.Frost,ChemistrySourcingLead,ExternalResearchSolutionsCenterofEmphasis,PfizerWorldwideR&D,EasternPointRd,MS8200-4001,Groton,CT06340,heather.n.frost@pfizer.com.ArunGhosh,ArchChemicals,ProcessTechnologiesGroup,350KnotterDrive,CheshireCT,06410,arun.ghosh@sbcglobal.net.NathanD.Ide,PrincipalScientist,ChemicalR&D,PfizerWorldwideR&D,EasternPointRoad,MS8118D-4058,GrotonCT,06340,nathan.d.ide@pfizer.com.JadeD.Nelson,AssociateResearchFellow,ChemicalR&D,PfizerWorldwideR&D,EasternPointRoad,MS8118D-4047,Groton,CT06340,jade.nelson@pfizer.com.KristinE.Price,SeniorScientist,ChemicalR&D,PfizerWorldwideR&D,EasternPointRoad,MS8156-066,Groton,CT06340,kristin.e.price@pfizer.com.JohnA.Ragan,AssociateResearchFellow,ChemicalR&D,PfizerWorldwideR&D,EasternPointRoad,MS8118D-4010,Groton,CT06340,john.a.ragan@pfizer.com.xiDavidH.BrownRipin,ScientificDirector,DrugAccessTeam,ClintonHealthAccessInitiative,Boston,MA02127,dripin@clintonHealthAccess.org.SallyGutRuggeri,AssociateResearchFellow,ResearchAPI,PfizerWorldwideR&D,EasternPointRoad,MS8156-078,Groton,CT06340,sally.gut@pfizer.com.RajappaVaidyanathan,AssociateResearchFellow,ChemicalR&D,PfizerWorldwideR&D,EasternPointRoad,MS8118D-4067,Groton,CT06340,rajappa.vaidyanathan@pfizer.com.CarrieB.Wager,SeniorPrincipalScientist,ChemicalR&D,PfizerWorldwideR&D,EasternPointRoad,MS8118D-4017,Groton,CT06340,carrie.b.wager@pfizer.com.ShuYu,AssociateResearchFellow,ChemicalR&D,PfizerWorldwideR&D,EasternPointRoad,MS8118D-4028,Groton,CT06340,shu.yu@pfizer.com.xiiCONTRIBUTORS1ALIPHATICNUCLEOPHILICSUBSTITUTIONJadeD.Nelson1.1INTRODUCTIONNucleophilicsubstitutionreactionsatanaliphaticcenterareamongthemostfundamentaltransformationsinclassicalsyntheticorganicchemistry,andprovidethepracticingchemistwithproventoolsforsimplefunctionalgroupinterconversionaswellascomplextarget-orientedsynthesis.ConventionalSN2displacementreactionsinvolvingsimplenucleophilesandelectrophilesarewell-studiedtransformations,areamongthefirstconceptslearnedbychemistrystudentsandprovidealaunchingpadformorecomplexsubjectmattersuchasstereochemistryandphysicalorganicchemistry.Ahighlevelsurveyofthechemicalliteratureprovidesanoverwhelmingmassofinformationregardingaliphaticnucleophilicsubstitutionreactions.Thischapterattemptstohighlightthosemethodsthatstandoutfromtheothersintermsofscope,practicality,andscalability.1.2OXYGENNUCLEOPHILES1.2.1ReactionswithWater1.2.1.1HydrolysisofAlkylHalidesThereactionofwaterwithanalkylhalidetoformthecorrespondingalcoholisrarelyutilizedintarget-orientedorganicsynthesis.Instead,conversionofalcoholstotheircorrespondinghalidesismorecommonsincemethodsforthesynthesisofhalidesarelessabundant.Nonetheless,alkylhalidehydrolysiscanprovidesimple,efficientaccesstoprimaryalcoholsundercertaincircumstances.Namely,thehydrolysisofactivatedbenzylicorallylichalidesisafacilereaction,andfollowingbenzylicorallylichalogenation,providesasimpleapproachtothesynthesisofthisPracticalSyntheticOrganicChemistry:Reactions,Principles,andTechniques,FirstEdition.EditedbyStephaneCaron.2011JohnWiley&Sons,Inc.Published2011byJohnWiley&Sons,Inc.1subsetofalcohols.Typicalconditionsinvolvetreatmentofthealkylhalidewithamildbaseinanacetone-wateroracetonitrile-watermixedsolventsystem.Moderateheatingwillacceleratethereaction,andiscommonlyemployed.1O2NCO2HBrO2NCO2HHONa2CO31:1acetone/H2O93%60C,2h1.2.1.2Hydrolysisofgem-DihalidesGeminaldihalidescanbeconvertedtoaldehydesorketonesviadirecthydrolysis.Thedesiredconversioncanbemarkedlyacceleratedbyheatinginthepresenceofanacidorabase,orbyincludinganucleophilicaminepromotersuchasdimethylamine.2OMeMeOBrBrOMeMeOOH40%aq.HNMe260C,2–3h86%IntheexamplebelowfromSnapperandcoworkers,atrichloro-intermediatewaspreparedfromp-methoxystyreneviatheKharaschadditionof1,1,1-trichloroethane.Contactwithsilicageleffectedeliminationofthebenzylicchlorideaswellashydrolysisofthegeminaldichloridemoietytoyieldthea,b-unsaturatedmethylketoneingoodoverallyield.3MeOMeOMeClClClMeOMeOSiO269%RuPhPCy3PCy3ClClCl3CCH375C,2h1.2.1.3Hydrolysisof1,1,1-Trihalides1,1,1-Trihalidesareattheappropriateoxidationstatetoserveascarboxylicacidprecursors.ThesecompoundsreactreadilywithwateratacidicpH,providingthecorrespondingacidsinhighyield,andoftenatambienttemperature.4Trichloromethylgroups,ratherthantribromo-ortriiodo-analogs,aremoreoftenutilizedduetosuperioraccessvianucleophilicdisplacementreactionsbytrichloromethylanions.1Lee,H.B.;Zaccaro,M.C.;Pattarawarapan,M.;Roy,S.;Saragovi,H.U.;Burgess,K.J.Org.Chem.2004,69,701–713.2Bankston,D.Synthesis2004,283–289.3Lee,B.T.;Schrader,T.O.;Martin-Matute,B.;Kauffman,C.R.;Zhang,P.;Snapper,M.L.Tetrahedron2004,60,7391–7396.4Martins,M.A.P.;Pereira,C.M.P.;Zimmermann,N.E.K.;Moura,S.;Sinhorin,A.P.;Cunico,W.;Zanatta,N.;Bonacorso,H.G.;Flores,A.C.F.Synthesis2003,2353–2357.2ALIPHATICNUCLEOPHILICSUBSTITUTIONNNEtOCCl3NNEtOCO2H20%HCl,12h95%HHThetrifluoromethylgrouphasseenincreasedapplicationinthepharmaceuticalindustryinrecentyearsduetoitsrelativemetabolicstability.Althoughtrifluoromethylgroupsaresusceptibletovigoroushydrolyticconditions,5theyarenotfrequentlyutilizedascarboxylicacidprecursorsduetotherelativeexpenseofincorporatingfluorineintobuildingblocks.However,anincreasinglycommonsyntheticapplicationoftheCF3functionishighlightedbytheexamplebelow.Alkalinehydrolysisofatrifluoromethylketoneprovidesthecorrespondingcarboxylicacidingoodyield.Here,theCF3groupisnotthepointofnucleophilicattackbywater.Instead,thestronginductiveeffectofthethreehighlyelectronegativefluorineatomsmakesthetrifluoromethylanionanexcellentleavinggroup,andattackoccursatthecarbonylcarbon.6OOCF3OOOHKOH,H2O,EtOHrt,3hOEt60%1.2.1.4HydrolysisofAlkylEstersofInorganicAcidsAlkalinehydrolysisofinorganicestersmayproceedthroughcompetingmechanisms,asillustratedbythemesylateandboricacidmonoesterinthefollowingscheme.Sulfonatehydrolysisfavorstheproductofstereochemicalinversion,viadirectSN2attackatthecarbonbearingthesulfonate.Incontrast,thecorrespondingboronderivativeishydrolyzedunderid

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