https://ebookmass.com/product/organofluorine-chemistrysynthesis-and-applications-1st-edition-reddy-v-prakash/
Instant digital products (PDF, ePub, MOBI) ready for you
Download now and discover formats that fit your needs...
N-Sulfonated-N-Heterocycles: Synthesis, Chemistry, and Biological Applications Galal H. Elgemeie
https://ebookmass.com/product/n-sulfonated-n-heterocycles-synthesischemistry-and-biological-applications-galal-h-elgemeie/
ebookmass.com
Recent Trends in Carbohydrate Chemistry: Synthesis and Biomedical Applications of Glycans and Glycoconjugates 1st Edition Amelia Pilar Rauter (Editor)
https://ebookmass.com/product/recent-trends-in-carbohydrate-chemistrysynthesis-and-biomedical-applications-of-glycans-andglycoconjugates-1st-edition-amelia-pilar-rauter-editor/
ebookmass.com
Nanomaterials in Clinical Therapeutics. Synthesis and Applications 1st Edition Mainak Mukhopadhyay
https://ebookmass.com/product/nanomaterials-in-clinical-therapeuticssynthesis-and-applications-1st-edition-mainak-mukhopadhyay/
ebookmass.com
Craniomandibuläre Dysfunktion (German Edition) Paul Ridder
https://ebookmass.com/product/craniomandibulare-dysfunktion-germanedition-paul-ridder/
ebookmass.com
Czechoslovak Armies 1939–45 1st Edition Nigel Thomas https://ebookmass.com/product/czechoslovak-armies-1939-45-1st-editionnigel-thomas/
ebookmass.com
The Island Home: The book making life brighter in 2021
Libby Page
https://ebookmass.com/product/the-island-home-the-book-making-lifebrighter-in-2021-libby-page/
ebookmass.com
Strategy in the Age of Disruption: A Handbook to Anticipate Change and Make Smart Decisions 1st Edition
Henrik Von Scheel
https://ebookmass.com/product/strategy-in-the-age-of-disruption-ahandbook-to-anticipate-change-and-make-smart-decisions-1st-editionhenrik-von-scheel/
ebookmass.com
Stay Present (Kincaid Brothers Book 6) Kaylee Ryan
https://ebookmass.com/product/stay-present-kincaid-brothersbook-6-kaylee-ryan/
ebookmass.com
Development in Wastewater Treatment Research and Processes : Innovative Microbe-Based Applications for Removal Maulin
P. Shah
https://ebookmass.com/product/development-in-wastewater-treatmentresearch-and-processes-innovative-microbe-based-applications-forremoval-maulin-p-shah/
ebookmass.com
The Neo-Assyrian Empire in the Southwest: Imperial Domination and its Consequences 1st Edition Avraham Faust
https://ebookmass.com/product/the-neo-assyrian-empire-in-thesouthwest-imperial-domination-and-its-consequences-1st-editionavraham-faust/ ebookmass.com
OrganofluorineChemistry OrganofluorineChemistry SynthesisandApplications V.PrakashReddy
DepartmentofChemistry,MissouriUniversityofScience andTechnology,Rolla,MO,UnitedStates
Elsevier
Radarweg29,POBox211,1000AEAmsterdam,Netherlands
TheBoulevard,LangfordLane,Kidlington,OxfordOX51GB,UnitedKingdom 50HampshireStreet,5thFloor,Cambridge,MA02139,UnitedStates
Copyright©2020ElsevierInc.Allrightsreserved.
Nopartofthispublicationmaybereproducedortransmittedinanyformorbyanymeans,electronicor mechanical,includingphotocopying,recording,oranyinformationstorageandretrievalsystem,without permissioninwritingfromthepublisher.Detailsonhowtoseekpermission,furtherinformationaboutthe Publisher’spermissionspoliciesandourarrangementswithorganizationssuchastheCopyrightClearance CenterandtheCopyrightLicensingAgency,canbefoundatourwebsite: www.elsevier.com/permissions.
ThisbookandtheindividualcontributionscontainedinitareprotectedundercopyrightbythePublisher (otherthanasmaybenotedherein).
Notices
Knowledgeandbestpracticeinthisfieldareconstantlychanging.Asnewresearchandexperiencebroaden ourunderstanding,changesinresearchmethods,professionalpractices,ormedicaltreatmentmaybecome necessary.
Practitionersandresearchersmustalwaysrelyontheirownexperienceandknowledgeinevaluatingand usinganyinformation,methods,compounds,orexperimentsdescribedherein.Inusingsuchinformationor methodstheyshouldbemindfuloftheirownsafetyandthesafetyofothers,includingpartiesforwhom theyhaveaprofessionalresponsibility.
Tothefullestextentofthelaw,neitherthePublishernortheauthors,contributors,oreditors,assumeany liabilityforanyinjuryand/ordamagetopersonsorpropertyasamatterofproductsliability,negligenceor otherwise,orfromanyuseoroperationofanymethods,products,instructions,orideascontainedinthe materialherein.
BritishLibraryCataloguing-in-PublicationData
AcataloguerecordforthisbookisavailablefromtheBritishLibrary LibraryofCongressCataloging-in-PublicationData
AcatalogrecordforthisbookisavailablefromtheLibraryofCongress
ISBN:978-0-12-813286-9
ForInformationonallElsevierpublications visitourwebsiteat https://www.elsevier.com/books-and-journals
Publisher: JoeHayton
AcquisitionsEditor: KostasMarinakis
EditorialProjectManager: MichelleW.Fisher
ProductionProjectManager: MariaBernard
CoverDesigner: MatthewLimbert
TypesetbyMPSLimited,Chennai,India
ToMyParentsandTeachers Contents Prefacexi
1.Nucleophilicreactionsinthesynthesisof organofluorinecompounds1
1.1Introduction2
1.2Reagentsfornucleophilicfluorinations2
1.3Nucleophilicdeoxyfluorination3
1.4Nucleophilicfluorinationofpyridinesanddiazines8
1.5Nucleophilic gem-difluorinationofcarbonylcompounds10
1.6Nucleophilicfluoroalkylations12
1.7Nucleophilictrifluoromethylthiolation31
1.8Trifluoromethoxylations31 References35
2.Electrophilicreactionsinthesynthesisof organofluorinecompounds43
2.1Introduction43
2.2Reagentsforelectrophilicfluorination44
2.3Enantioselectiveelectrophilicfluorination48
2.4Electrophilicfluorinationinthesynthesisof α-fluorinated aminoacids53
2.5Electrophilicfluoroalkylation54
2.6Electrophilictrifluoromethylthiolationand trifluoromethoxylation61
2.7Syntheticmethodsfortrifluoromethylthiolation63
2.8Difluoromethylthiolation68 References70
3.Free-radicalreactionsinthesynthesisof organofluorinecompounds75
3.1Introduction75
3.2Reagentsforthefree-radicaltrifluoromethylation77
3.3Decarboxylativefluoroalkylation78
3.4 β-Amino-fluoroalkylationofalkenes80
3.5Fluoroalkylationusingsodiumtriflinate(Langloisreagent)82
3.6Photoredox-catalyzed S-fluoroalkylationandarylation94
3.7Radicalfluoroalkylationofenolates96 References98
4.Organotransitionmetalcatalysisinthe synthesisoforganofluorinecompounds103
4.1Introduction104
4.2Pd-catalyzedfluorinationofarylhalidesandtriflates105
4.3Transitionmetal catalyzedC Hfluorination106
4.4Au(I)-catalyzedhydrofluorinationofalkenesandalkynes114
4.5Ni-catalyzedfluoroalkylationofaromatics116
4.6Ag(II)-catalyzedoxidativering-openingfluorinationofcyclic amines121
4.7Ag(I)-catalyzeddecarboxylativefluorination123
4.8Cu(I)-mediateddediazoniativedifluoromethylation124
4.9Fluoroalkylationofarylboronicacidsandesters125
4.10Cu(I)-catalyzedfluoroalkylationofarylhalides126
4.11Ni-catalyzedtrifluoromethylthiolation127
4.12Pd(II)-catalyzed(amino)trifluoromethoxylation129 References131
5.Pharmaceuticalapplicationsof organofluorinecompounds133
5.1Introduction134
5.2Antibacterialpharmaceuticals141
5.3Antidiabeticpharmaceuticals146
5.4Anti-Alzheimerpharmaceuticals152
5.5Anti-HIVpharmaceuticals163
5.6Antimalarialpharmaceuticals165
5.7Anticancerpharmaceuticals167
5.8Antiviralpharmaceuticals185
5.9Fluorinatedpharmaceuticalsforcardiovasculardiseases195
5.10Antiinflammatorypharmaceuticals199
5.11Antidepressants202 References204
6.Synthesisandapplicationsof 18F-labeledcompounds215
6.1Introduction216
6.2Syntheticmethodsforradiofluorination220
6.3Sharplessclickreactionsforpositronemissiontomography tracers225
6.4Staudingerligationreactionsforpositronemissiontomography tracers232
6.5Radiofluorinationviaaromaticnucleophilicsubstitution235
6.6Transitionmetal mediatedradiofluorination243
6.7Radiofluorinationviadiaryliodoniumsalts250
6.8Enzymaticfluorinationreactionsfor[18F]-labeledpositron emissiontomographytracers256
6.9PositronemissiontomographytracersinAlzheimer’ s disease258
6.10 18F-positronemissiontomographytracersincancer diagnosis264 References271
7.Materialsapplicationsoforganofluorinecompounds279
7.1Introduction280
7.2Fluorinatedsurfactants280
7.3Fluoropolymers286
7.4Fluorinated π-conjugatedpolymericmaterialsinphotovoltaic devices289
7.5Fluorinatedpoly(arylthioethers)inorganicelectronic materials298
7.6Polymerelectrolytes300
7.7Fluorinatedionomersasproton-exchangemembranes infuelcells304
7.8Fluorinatedcarbonnanoparticlesandnonaqueous electrolytesinlithium-andlithium-ionbatteries307
7.9Fluorinatedhyperbrancheddendrimers:synthesisand applications308
7.10Fluorinatedcompoundsindrugdeliveryandmagnetic resonanceimaging310
7.11Organofluorineliquidcrystalmaterials313
7.12Organofluorinecompoundsinhigh-energymaterials313 References321
Index329
Preface Thisbookisfocusedonmodernsyntheticmethodsfortheincorporationoffluorineand fluoroalkylmoietiesintoorganiccompounds,andonthepharmaceuticalandmaterials applicationsoforganofluorinecompounds.Itishopedthatthisbookwouldserveasatext bookforthespecializedgraduate-levelcoursesinorganofluorinechemistryaswellasareferencebookforindustrialandacademicscientistsinvolvedinthedrugdesign,materials chemistry,andorganofluorinechemistry.Rapidadvancesintheefficientsyntheticmethods oforganofluorinecompoundscontributetotheirever-increasingapplicationindiverseareas, includingthedesignofmaterials,pharmaceuticals,agrochemicals,andawiderangeofconsumergoods.Notably,fluoropolymers,whichincludepoly(tetrafluoroethylene),poly(vinylidenefluoride),poly(vinylfluoride),andNafion,aperfluorinatedion-exchangemembrane, areintegralpartsofchemicalindustry.
Chapters1 4arefocusedonthesyntheticmethodsforthefluorinations,fluoroalkylations,fluoroalkoxylations,andfluoroalkylthiolations.Thesyntheticmethodsarebroadlyclassifiedtoincludenucleophilic,electrophilic,free-radical,andorganotransition metal catalyzed/mediatedreactions.Emphasisisplacedonthosereactionsthatareof broadsignificanceinthesynthesisoffluorinatedpharmaceuticals,positronemissiontomography(PET)imagingagents,andmaterials.
Chapter1,Nucleophilicreactionsinthesynthesisoforganofluorinecompounds,outlines avarietyofcommerciallyavailablenucleophilicfluorinationreagents,includingDAST, DeoxoFluor,XtalFluor,PhenoFluor,andFluoLead.Nucleophilictrifluoromethylations, difluoromethylations,trifluoromethoxylations,andtrifluoromethylthiolationshavebeen widelyusedinthedesignofpharmaceuticalsandmaterials.Deoxyfluorinationofalcohols, phenols,andcarboxylicacidscanbeachievedwithavarietyofcommerciallyavailable reagents,includingPhenoFluor,PyFluor,XtalFluor,DAST,andrelatedreagents. Nucleophilicfluorinatingreagentsofbroaderscopearebeingcontinuallydevelopedastaskspecificreagentsinthesynthesisofpharmaceuticallyinterestingcompounds.Thereis emerginginterestintheenantioselectivenucleophilicfluorinationsandtrifluoromethylations.Enantioselectivetrifluoromethylation,insomecases,canbeachievedwithupto93% enantioselectivityusingcinchonidine-basedchitalcatalysts.
Chapter2,Electrophilicreactionsinthesynthesisoforganofluorinecompounds,outlines variouselectrophilicreagents,suchasSelectfluorandNFSI,andelectrophilicfluoroalkylations, fluoroalkylthiolations,andfluoroalkoxylations,focusingonelectrophilictrifluoromethylation, trifluoromethylthiolations,anddifluoromethylthiolationreactions.Electrophilictrifluoromethylationofawidevarietyofalkynes,aromatics,amines,andalcoholshasfoundapplicationsin thesynthesisofpharmaceuticals.Electrophilicdifluoromethylationofalcoholsprovidesaccess tothecorrespondingdifluoromethoxycompounds,andthesereactionscanbeusedinthe
late-stagemodificationofpharmaceuticals.Recentprogressintheenantioselectiveelectrophilic fluorinationofaldehydes,amides,allylsilanes,andenolsilylethersisalsooutlined,focusingon thereactionsthatareofbroadscopeinthedesignofpharmaceuticals.
Chapter3,Free-radicalreactionsinthesynthesisoforganofluorinecompounds,covers free-radicalreactionsinthefluorinationsandfluoroalkylations.Commerciallyavailable Togni’sorUmemoto’sreagents,originallydevelopedfortheelectrophilictrifluoromethylations,canbeusedinthefree-radicaltrifluoromethylation,underphotoredoxororganometalliccatalysis.Free-radicalreactions,suchasdecarboxy-trifluoromethylationand difluoromethylations,mediatedbyorganometalliccatalysts,areusefulinthelate-stagemodificationofpharmaceuticals.Thereisemerginginterestinthefree-radicaltrifluoromethylationsusingthecost-effectiveLangloisreagent,usingorganometalliccatalystsandunder photoredoxconditions.Organotransitionmetal catalyzedfluorinationandfluoroalkylations areanemergingareathathasbroadapplicabilityinthesynthesisofpharmaceuticals,agrochemicals,materials,andPETtracers.
Chapter4,Organotransitionmetalcatalysisinthesynthesisoforganofluorinecompounds,outlinesavarietyoftransitionmetal catalyzedreactions,suchasPd(0)-catalyzed fluorinationandtrifluoromethoxylationofaromatics,Mn(III)-catalyzedmono-fluorinations, Ni(I)-catalyzedfluoroalkylationandtrifluoromethylthiolationofaromatics,andAg(I)-catalyzeddecarboxylativefluorinationofcarboxylicacids.Thetransitionmetal catalyzedreactionsprovideanattractiverouteforthelate-stagemodificationofpharmaceuticalsandin thesynthesisofthe 18F-labeledPETtracers.
Chapter5,Pharmaceuticalapplicationsoforganofluorinecompounds,andChapter6, Synthesisandapplicationsof 18F-labeledcompounds,focusonthemedicalandpharmaceuticalapplications.Incorporationoffluorineorfluoroalkylgroupsasbioisosteresinthelead compoundshasemergedasthemajorfocusofdrugdesignefforts.Fluorine-containingpharmaceuticalcandidates,ingeneral,exhibitenhancedpotency,bioavailability,andmetabolic stability,ascomparedtotheirnonfluorinatedanalogs.Numerousblockbusterdrugs,includingthecholesterol-loweringdrugatorvastatin(Lipitor)anddrugsforthetreatmentofhepatitisC,suchassofosbuvir(Sovaldi),arefluorine-containingcompounds.Furthermore,PET using 18F-labeledcompoundsaffordaccesstononinvasivemonitoringofthediseaseprogressionandtofollowtheeffectivenessofthedrugcandidates.
Chapter5,Pharmaceuticalapplicationsoforganofluorinecompounds,outlinesthedrug designusingorganofluorinechemistry,focusingontherecentlyFDA-approveddrugs,and widelyprescribedpharmaceuticals,fortreatingvariousdiseases,includingdiabetes,cardiovasculardiseases,Alzheimer’sdisease(AD),variouscancers,andbacterial(malaria)and viralinfections(HIV).Fluorine-containingcompoundsplayakeyroleinthedesignofpharmaceuticals.Structuralmodificationofpharmaceuticallyinterestingcompoundsthrough introductionoffluorine,fluoroalkyl,fluoroalkoxy,orfluoroalkylthiomoietiesenhancestheir metabolicstability,bioavailability,andpotency.In2018alonenearlyone-thirdoftheFDAapproveddrugsareorganofluorinecompounds.Fluorine-containingpharmaceuticalsare usedinthetreatmentofawidevarietyofdiseases,includingdiabetes(sitagliptin),malaria (e.g.,mefloquine),HIVinfections(e.g.,bictegravir),antiviralagents(e.g.,sofosbuvir,a
nucleotideanaloginhibitoroftheHCVNS5BRNA-polymerase3inhibitor,forthetreatment ofhepatitisC),antibacterialagents(e.g.,fluoroquinolonesandtetracyclines),cancer(e.g., afatinib,dacomitinib,andlorlatinib),cardiovasculardiseases(e.g.,ezetimibeandatorvastatin),andasinti-inflammatoryagents(e.g.,celecoxib,aselectiveCOX-2inhibitor,totreat rheumatoidarthritis).Fluorine-containingcompoundshaveemerginginterestaspharmaceuticalcandidatestotreatAD.Althoughseveralclinicaltrialsusingorganofluorinedrug candidates(andotherdrugcandidates),asBACE-1inhibitors, γ-secretaseinhibitors,and γ-secretasemodulatorshavenotbeensuccessfultodate,afluorinatedselectiveBACE-1 inhibitor,CNP540,iscurrentlyundergoingclinicaltrialsforitsefficacyinpreventingADin individualssusceptibletothedevelopmentofAD.
Chapter6,Synthesisandapplicationsof 18F-labeledcompounds,outlinestherecent progressinthesynthesisandapplicationsofthe 18F-PETtracersinthediagnosisofvarious diseases,includingtheADandcancers.Syntheticmethodsusingthelate-stageradiofluorinationshavesignificantlycontributedtotheadvancementofthisarea. 18F-labeledPETtracers, incombinationwithmagneticresonanceimaging(MRI),PET/MRI,areemergingasalternativetothewidelyusedPET/computedtomography(PET/CT),atechniquethatrequires patientstobeexposedtohazardousX-rayradiation,inthediagnosisandmonitoringofthe diseaseprogressioninvariouscancers,Alzheimer ’sdisease,andcardiovasculardiseases. Furthermore,insomecases,thePET/MRIprovidessuperiorimagingofthesitesoflesions overthatofthePET/CTscans.PET/MRIcanbeusedinprobingtheblood brainbarrierof pharmaceuticals,akeyfeatureforadrugtobeactiveintheneurologicaldisorders. 18F-PET/ MRIimagingofthelungcancers,includingadenocarcinoma,squamouscellcarcinoma,and small-celllungcarcinoma,isindispensableinmonitoringtheeffectivenessofthevarious chemotherapeuticagents.Untilrecently,2-[18F]-fluoro-2-deoxy-D-glucoseistheonlyFDAapproved 18F-PETimagingagent,fortheclinicaldiagnosisofAD,cancers,andotherglucose metabolism linkedlesions.Emerging,efficientsyntheticmethodsforthelate-stageradiofluorinationarenowbeingadaptedforthesynthesisofvariousdisease-specific 18F-PET agents.Forexample,FDA-approved 18F-PETimagingagents,florbetapir(Amyvid),florbetaben(Neuraceq),andflutemetamol(Vizamyl),showhighspecificityforbindingtotheAβ plaquesandarenowwidelyusedintheclinicaldiagnosisoftheADpatients.Ontheother hand,flortaucipir(AV-1451)showssubstantialselectivityinitsbindingtotheneurofibrillary tanglesandisusefultodistinguishADfromotherneurodegenerativediseases,suchas behavioralvariantfrontotemporaldementia,Parkinson’sdiseasewithorwithoutcognitive impairment,andvasculardementia.ThelatterPETimagingagentisalsousefulinthediagnosisofthechronictraumaticencephalopathy,alsocalledtraumaticbraininjury,asdemonstratedinthePETscansofthefootballplayerswithconcussionsymptoms.Fluciclovineisan 18F-PETtracerthatisusedthediagnosisofprostatecancer.
Chapter7,Materialsapplicationsoforganofluorinecompounds,outlinessynthesisand applicationsofawiderangeoforganofluorine-basedmaterials.Numerousmaterials,biomaterials,smartmaterials,liquidcrystaldisplays,solarcells,fuelcells,andnumerousconsumer goodsarefluorine-containingcompounds.Forexample,fluorinatedionomers,suchas Nafion-Handfluorinatedversionsofpoly(ethersulfone)andpoly(imide)materials,are
extensivelyusedasproton-exchangemembranesinfuelcells.Fluorinated π-conjugated polymericmaterialshavefoundapplicationsinthedesignofphotovoltaicdevices.Forexample,theall-organicsolarcells,consistingoffluorinatedmaterials,affordpowerconversion efficiencies,ashighas13.1%.Furthermore,fluoropolymershavebeenusedasphotoresist materialsinthe157nmlithography,astheyaretransparentatthiswavelength. Perfluorinatednanomaterialsalsohavemedicinalapplications.Forexample,theoxygenenrichedfluorinatedhydrocarbonandpolymericnanomaterialsarebeingdevelopedforuse inthephotodynamictherapyofcancer.Fluorinateddendrimeramphiphilesarefinding applicationsasprobesfor 19FMRIprobesandindrugdelivery.
Iamgratefulforthecontinuedencouragementandsupportoftheeditorsandeditorial staff,inparticular,Dr.KostasMarinakisandMs.MichelleFisher,duringthepreparationof themanuscript.IappreciateMs.SwapnaPraveen,Sr.CopyrightsCoordinator,forheradvice andhelpingettingcopyrightpermissions,andMs.MariaBernadetteVidhyaBernardJ, ProjectManager,forpatientlyreviewingthemanuscriptandforincorporatingmanycorrections.IthankProfessorG.K.SuryaPrakash(UniversityofSouthernCalifornia)forcareful readingofmanychaptersandforhisvaluablesuggestionsandcorrections.Ialsothank ProfessorJinboHu(ShanghaiInstituteofOrganicChemistry)forhishelpfulcommentson oneofthechapters.Ithankallmyfriends,facultycolleagues,andmygraduatestudentsfor theirencouragement.Someofthecutting-edgeadvancesinthesynthesisoforganofluorine compoundsmayhavebeeninadvertentlyomittedduetothesheernumberoftheeverincreasingpublicationsinthisareaintherecentyears,althougheveryeffortismadeto includethesyntheticmethodsthatareofbroadapplicabilityforthedesignofpharmaceuticalsandmaterials.Ihopethereaderswillfindthisbookusefulandappreciatetheirsuggestionsandcorrectionsforfutureeditions.
Nucleophilicreactionsinthe synthesisoforganofluorine compounds ChapterOutline
1.1Introduction.....................................................................................................................................2
1.2Reagentsfornucleophilicfluorinations........................................................................................ 2
1.3Nucleophilicdeoxyfluorination......................................................................................................3
1.4Nucleophilicfluorinationofpyridinesanddiazines....................................................................8
1.5Nucleophilic gem-difluorinationofcarbonylcompounds.........................................................10
1.6Nucleophilicfluoroalkylations.....................................................................................................12
1.6.1Nucleophilicdifluoromethylationofaldehydes...............................................................12
1.6.2Ruppert Prakashreagent(CF3SiMe3)fortrifluoromethylation.....................................13
1.6.2.1Enantioselectivetrifluoromethylation.........................................................................14
1.6.2.2Synthesisoftrifluoromethylketones..........................................................................16
1.6.2.3Trifluoromethylationofimines...................................................................................18
1.6.3Fluoroacetonehydratesforthenucleophilicfluoroalkylations......................................18
1.6.4Trifuoromethylationsusingfluoroform(CHF3).................................................................19
1.6.5Borazine-mediatedtrifluoromethylationanddifluoroalkylation...................................23
1.6.6 N-Trifluoromethylationofamines.....................................................................................26
1.6.7Tetrakis(dimethylamino)ethylene-mediatedfluoroalkylations.......................................28
1.6.7.1Trifluoromethylationofacylchlorides........................................................................29
1.6.7.2Synthesisof gem-(difluoromethyl)thioethers.............................................................30
1.7Nucleophilictrifluoromethylthiolation....................................................................................... 31
1.8Trifluoromethoxylations...............................................................................................................31
1.8.1Trifluoromethylbenzenesulfonate mediatedvicinal (bromo)trifluoromethoxylation..........................................................................................33
1.8.2Trifluoromethylbenzoate mediatedtrifluoromethoxylation.......................................34 References.............................................................................................................................................35
1.1Introduction Nearlyone-thirdofthepharmaceuticalsarefluorinatedcompounds.Oftenasinglefluorine atthestrategicsitemodulatesthepharmacokineticpropertiesofthepharmaceuticals. 18F-labeledcompoundsareusedasthestate-of-the-artpositronemissiontomography(PET) tracersinthediagnosisofcancers,cardiovasculardiseases,andneurodegenerativediseases. Furthermore,fluorinatedcompoundsareincreasinglyusedinthedesignofnovelmaterials forabroadrangeofapplications,includingphotovoltaicsolarcellsandenergystorage devices.Polyfluorinatedcompounds(fluorouscompounds)areusedinthe 19Fnuclearmagneticresonance(19F-NMR)imaging(alsocalledas 19F-magneticresonanceimaging, 19F-MRI),andasrecyclablefluorouscatalysts,fluoroussolvents,andfluorousstationary phases,inorganicsynthesis.Earlysyntheticmethodsfornucleophilicfluorinationsreliedon hydrogenfluoride(HF)anditsaminecomplexes[e.g.,Olah’sreagent,pyridiniumpoly (HF;PPHF),andsulfurtetrafluoride(SF4)].Therearecurrentlymanysaferandmoreeffectivefluorinatingreagentsthathavewidefunctionalgrouptoleranceandthatwouldafford highregio-andstereoselectivity.Theseselectivefluorinatingagentsareinvaluableinthe synthesisofcomplexfluorine-containingorganiccompounds.Nucleophilicfluoroalkylations, especially gem-difluoromethylationandtrifluoromethylation,arewidelyusedinthedesign offunctionalmaterialsandpharmaceuticalsbecauseoftheuniqueandfavorablephysicochemicalandpharmacokineticpropertiesofthesefluoroalkylcompounds.
gem-Difluoromethylene( CF2 )moietyisisopolarand,tosomeextent,isostericwith respecttooxygen,andthusthe gem-difluoromethyl( CHF2)anddifluoromethylene ( CF2 )moietiesserveasbioisosteresofalcoholsandethers,respectively,inthedrug designapplications.ItisalsoalipophilicbioisostereofSHandCH3 whenattachedtothe aryloralkylmoieties.TheCF2Hisahydrogen-bonddonoraswellasacceptor,andthe lipophilicityofthecompoundsisdramaticallyenhancedwhenthismoietyisintroduced adjacenttotheether,sulfoxide,andsulfonemoieties.1,2 Thetrifluoromethylmoietyis bioisostericwithrespecttothe tert-butylandisopropylgroupsandisused,forexample,in thedesignof γ-secretaseinhibitors.3 Manyofthenucleophilicreagentsforfluorinationand fluoroalkylationarenowcommerciallyavailable.Thischapteraimstogiveacomprehensive coverageofthenucleophilicfluorinationsandfluoroalkylationsthathavebroadscopeinthe designofpharmaceuticals,agrochemicals,andmaterials.
1.2Reagentsfornucleophilicfluorinations Avarietyofreagentsfornucleophilicfluorinationarenowcommerciallyavailable. Deoxyfluorinationofalcoholsand gem-difluoromethylationofcarbonylcompoundscanbe achievedbyreagents,suchasDAST((diethylamino)sulfurtrifluoride),4 Morpho-DAST (morpholinosulfurtrifluoride),4 Deoxo-Fluor[bis(2-methoxyethyl)aminosulfurtrifluoride],5 7 XtalFluor-E[(diethylamino)difluorosulfiniumtetrafluorobrate],8 XtalFluor-M(morpholinodifluorosulfiniumtetrafluoroborate), 8 FluoLead((4- tert -butyl-2,6-dimethylphenyl)sulfur
Cyanuric fluoride Ishikawa's reagent
FIGURE1–1 Selectedcommerciallyavailablereagentsforthetransformationofthecarbonylcompoundstothe gem-difluoromethyland-methylenecompounds.
trifluoride).9 PhenoFluor[1,3-bis(2,6-diisoproylphenyl)-2,2-difluoro-4-imidazoline]10 and PyFluor(2-pyridinesulfonylfluoride)11 reagentsareusefulforselectivedeoxyfluorinationof alcoholsinthepresenceofcarbonylfunctionalgroups.Otherreagentsthatareusefulinthe deoxyfluorinationsincludePetrov’sreagent(1,1,2,2-tetrafluoroethyl-N,N-dimethylamine), cyanuricfluoride,Ishikawa’sreagent(N,N-diethyl-1,1,2,3,3,3-hexafluoropropylamine),and 3,3-difluoro-1,2-diarylcyclopropenes(Fig.1 1).12,13
DASTandDeoxo-Fluorreagentsarewidelyusedforthedeoxyfluorinationofalcoholsin thesynthesisofnumerousbiologicallyandpharmaceuticallyinterestingfluorine-containing compounds.14 DeoxyfluorinationreactionsusingDASTareusuallycarriedoutatalow temperaturetoavoidthedecompositionofthereagent.Similarly,carbonylgroupsare effectively gem-difluorinatedatarelativelylowtemperature.15 (Trifluoromethyl)trimethylsilane (CF3SiMe3;Ruppert Prakashreagent)iswidelyusedforthenucleophilictrifluoromethylation ofcarbonylcompounds,includingaldehydes,ketones,imines,andesters(videinfra).16,17
1.3Nucleophilicdeoxyfluorination NucleophilicdeoxyfluorinationofalcoholscanbeachievedusingvariouscommerciallyavailablereagentssuchasDAST,Deoxo-Fluor,Morpho-DAST,XtalFluor-E,XtalFluor-M,PyFluor, andPhenoFluor.Deoxo-FluorisrelativelymorethermallystableascomparedtoDASTand isthepreferredreagentoverDASTwhenhightemperaturesarerequiredforthereactions.
Selectedexamples:
Selectivefluorinatingreagents,especiallythosethatcanbeusedinthestereoselectivedeoxyfluorinationofalcohols,areofgreatimportanceforthesynthesisofpharmaceuticalcompounds.Amongseveralsuchreagentsrecentlydeveloped,PhenoFluorandPyFluorareof broadscopeinthedeoxyfluorinationofalcohols,althoughDASTisstillwidelyusedfordeoxyfluorinationreactions.18 XtalFluorreagents(XtalFluor-EandXtalFluor-M)showimproved selectivityindeoxyfluorinationreactions,comparedtoDAST,astheeliminationbyproducts areminimized.SimilartothatofDASTandDeoxo-Fluor-mediateddeoxyfluorinationreactions,theXtalFluorreagent mediateddeoxyfluorinationofalcoholsproceedthroughaSN2 mechanism,withpredominantinversionofconfiguration.14
PhenoFluorwasoriginallydiscoveredbyRitterandcoworkersforthedeoxyfluorination ofphenols.19,20 Phenolsaswellasheteroarylphenoliccompoundsweredeoxyfluorinatedto theircorrespondingfluorinatedcompoundsusingthisreagent.Toovercomethemoisture instabilityofthisreagent,toluenesolutionsofthisreagentcanbeusedforthedeoxyfluorinations(Fig.1 2).
PhenoFluorcanalsobeusedforthedeoxyfluorinationofprimaryandsecondaryalcohols,usingslightlydifferentconditionsasforthephenols.21 AdditionofHunig’sbase,in thesereactions,shortensthereactiontime,andpotassiumfluoride(KF)minimizestheeliminationproductsfromthealiphaticalcohols.Deoxyfluorinationsofsecondaryalcoholsusing PhenoFluorproceedinhighyieldswithinversionofconfiguration. 21 Althoughthesedeoxyfluorinationsproceedat0 Ctoroomtemperature,eliminationproductsareformedas minorbyproducts.However,at80 Cintoluene,theeliminationreactionissuppressed,and thereactionproceedsinhighyieldstogivethecorrespondingdeoxyfluorinationproducts. Avarietyofpharmaceuticallyinterestingcompounds,suchasmorphine,galantamine,testosterone,andepi-androsterone,couldbestereoselectivelytransformedintotheircorrespondingfluorinatedproductswiththeinversionofconfigurationinhighyieldsandwithhigh stereoselectivity(Fig.1 3).PhenoFluorprovidesaccesstothelate-stagefluorinationofpharmaceuticalsandissuitableforthepreparationof 18F-labeledcompoundsforthePET.
FIGURE1–2 PhenoFluor-mediateddeoxyfluorinationofphenols.
FIGURE1–3 PhenoFluor-mediateddeoxyfluorinationofalcohols. Chapter1 • Nucleophilicreactionsinthesynthesisoforganofluorinecompounds5
Doyleandcoworkershavedeveloped2-pyridinesulfonylfluoride(PyFluor)asalow-cost nucleophilicfluorinatingreagentforthefluorinationofprimaryandsecondaryalcohols. PyFluorisconvenientlypreparedonamultigramscaleviatheoxidationof2-mercaptopyridinewithsodiumhypochlorite(NaOCl),followedbythehalideanionexchangeoftheresulting2-pyridylsulfonylchloride,usingpotassiumbifluoride(KHF2).Deoxyfluorinationof alcoholsusingPyFluorreagent,inthepresenceofastericallycrowdedbase,suchas1,8diazabicyclo-[5.4.0]undec-7-ene(DBU),givesthealkylfluoridesinhighyieldsandwithhigh diastereoselectivity.11 Eliminationreactionsareminimizedusingthestericallycrowded amines,suchasDBUor7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene(MTBD).Variousbiologicallyinterestingfluorinatedcompounds,including2-deoxy-2-fluoro-D-glucoseandits 18F-labeledanalog,couldbesynthesizedinaone-potprocedure.The 18F-labeledPyFluor reagent,[18F]PyFluor,usedintheradiofluorinationswassynthesizedthroughthereactionof the 18F-labeledKFwiththe2-pyridylsulfonylchloride,insitu(Fig.1 4A).11 Thereaction proceedsthroughtheintermediateformationofthe2-pyridylsulfonateester(1),throughSN2 reactionpathway,withtheinsitugeneratedDBU HFprovidingthenucleophilicfluoride anion.EliminationreactionsareminimizedusingtheDBUorMTBDreagents,ascompared totheotheramine-basedreagents.
Amongotherrelatednucleophilicreagentsforthedeoxyfluorination, N-tosyl-p-chlorobenzene-sulfonimidoylfluoride(SulfoxFluor)hasdramaticallyhighreactivity(10 30minat RT)andsimilarmechanismasthatofthePyFluor,andisalsoreadilysynthesizedinlarge scalefromtheN-Tosyl-p-chlorobenzenesulfonimidoylchloride(Fig.1 4B).22
Sanfordandcoworkershavedevelopedanoperationallysimplemethodforthedeoxyfluorinationofphenolsusingtherelativelyinexpensivereagentcombinationofsulfurylfluoride(SO2F2)andtetramethylammoniumfluoride(Me4NF).Thisreagentachievesthe deoxyfluorinationsundermildconditions,oftenatroomtemperature,andinhighyields (Fig.1 5).23 Thesedeoxyfluorinationreactionsproceedthroughtheformationofthearyl fluorosulfonateintermediates.Thissyntheticmethodwasdemonstratedtobeapplicablefor thesynthesisofpharmaceuticallyinterestingcompounds,suchasMPPF[20 -methoxyphenyl(N-20 -pyridinyl)- p-fluorobenzamide-ethylpiperazine],aserotonin1Areceptorligand.
DASTandrelatedreagents,suchasDeoxo-FluorandXtalFluorreagents,canbeusedfor theconversionofcarboxylicacidstothecorrespondingacidfluorides.24 26 DASTand Deoxo-FluorarethermallynotasstableasXtalFluorandcandecomposeviolentlyunder somecircumstances.Thesereagents,however,areusedwidelyforthedeoxyfluorinationof alcohols,carboxylicacids,and gem-difluorinationofcarbonylcompounds.Ontheother hand,theaminodifluorosulfiniumtetrafluoroboratesalts XtalFluor-EandXtalFluor-M arecrystallinesaltsthatshowenhancedthermalstabilityoverDASTandDeoxo-Fluorand donotreactviolentlywithwater,unlikeDAST.XtalFluor-Eisconvenientlysynthesized throughthereactionoftheDASTwithBF3 Et2O.XtalFluor,inthepresenceofEt3N 3HF, transformscarboxylicacidsintothecorrespondingacidfluoridesinhighyields(Fig.1 6).26
FIGURE1–4 DeoxyfluorinationreactionsmediatedbyPyFluor(A),andSulfoxFluor(B).
FIGURE1–5 DeoxyfluorinationofphenolsusingSO2F2 andMe4NF.
(B)
–6 DeoxyfluorinationofcarboxylicacidsusingXtalFluorreagents.
Prakashandcoworkershaveachievedthedeoxyfluorinationofcarboxylicacidstothe correspondingacylfluorides,usingareagentcombinationoftriphenylphosphine(Ph3P), Nbromosuccinimide(NBS),andEt3N 3HF,undermildreactionconditions,inhighyields. Throughthisefficientandcost-effectivesyntheticprocedure,pharmaceuticalswithacarboxylicacidfunctionalgroup,suchasibuprofen,naproxen,andketoprofen,weretransformed tothecorrespondingacidfluoridesinhighyields.Theacidfluoridescouldbetransformed, insitu,totheircorrespondingamidederivativesinaone-potprocedure.27 Theacylfluorides havenumeroussyntheticapplications,includingtheirconversionstotrifluoromethylarenes, ketones,aldehydes,amides,esters,andhydrocarbons(Fig.1 7).27 33
Theabovedeoxyfluorinationreactionsmayproceedthroughthetransientlyformedacyloxyphosphoniumsalt(2),theidentityofwhichwasconfirmedbyNMRspectroscopy.The latteracyloxyphosphoniumsalt, 2,ispresumablyprotonatedbyEt3N 3HFtogivethedicationicintermediate 3,whichuponnucleophilicsubstitutionbythefluorideanionwouldgive theacylfluoride(Fig.1 7).27
1.4Nucleophilicfluorinationofpyridinesanddiazines Fluorinatedheterocyclesareubiquitousinagrochemicals,pharmaceuticals,andmaterials. Hartwighasdevelopedabroadlyapplicablesyntheticmethodforthe ortho-fluorinationof pyridinesanddiazinesusingAg(II)F2.34 Thesefluorinationreactionshaveabroadscopeand arangeofpyridinesanddiazines,includingquinolines,pyrazines,pyrimidines,andpyridazines,havebeenregioselectivelyfluorinatedinmoderatetohighyields.Pharmaceutically interestingcompounds,suchas 4, 5,and 6,couldbesynthesizedinmoderatetohighyields throughthisaryl-fluorination(Fig.1 8).Thisreactiontoleratesbothelectron-donatingand electron-withdrawingsubstituents,suchasketone,ester,amide,amine,andnitrilemoieties, inpyridinesanddiazines.34
FIGURE1
Chapter1 • Nucleophilicreactionsinthesynthesisoforganofluorinecompounds9
for example for example
FIGURE1–7 Deoxyfluorinationofcarboxylicacidstotheacidfluorides.
AproposedmechanisminvolvescomplexationofAgF2 topyridinenitrogen,followedby intramoleculartransferoffluoridetothe ortho-positionandthenAgF2-mediatedrearomatization.ThereactionmechanismresemblesthatofChichibabinreaction,areactioninvolving ortho-aminationofpyridinesbyNaNH2 (Fig.1 8).34
FIGURE1–8 ortho-FluorinationofpyridinesanddiazinesusingAgF2.
1.5Nucleophilic gem-difluorinationofcarbonylcompounds
gem-Difluorinationofcarbonylcompoundscanbeachievedusingnucleophilicfluorinating reagents,suchasDAST,Deoxo-Fluor,andXtalFluor.XtalFluor-EandXtalFluor-Mreagents, synthesizedfromthecorrespondingdialkylaminosulfurtrifluorides,arecrystallinecompoundsandarerelativelymorestableandmoisture-sensitivethantheconventionalfluorinatingagents,DASTandDeoxo-Fluor.WhenusedinthepresenceofEt3N.3HF,these reagentstransformaldehydesandketonesintothecorresponding gem-difluorocompounds.8
Estermoietiesandthe N-benzyloxycarbonyl(Cbz)protectinggroupsareunaffectedunder thereactionconditions(Fig.1 9).XtalFluorreagentscanalsobeusedforthetransformation ofalcoholstothealkylfluorides,andcarboxylicacidstotheacidfluorides,undersimilar reactionconditions(videsupra).8
Chapter1 • Nucleophilicreactionsinthesynthesisoforganofluorinecompounds11
HBF4 .OEt2
Et 3 N.3HF, Et3 N, DCM RT, 24 h
Et 3 N.3HF, Et3 N, DCM RT, 24 h
°C to RT
6 N HCl/60 °C/5 h
NaHCO3 /THF RT, 24 h
PPHF (1.7 equiv) DCM, RT, 24 h
H FluoLead, 100 °C, 3 h
FIGURE1–9 gem-Difluorinationofcarbonylcompoundsandtrifluoromethylationofcarboxylicacids;Cbz 5 carbobenzyloxy.
Peptidesconsistingoffluorinatedprolinemoieties,suchasthe3,3-gem-difluoroproline 9, canactasselectiveenzymeinhibitors,withfavorablepharmacokinetics.35 Towardthisgoal,the N-carbobenzyloxy-3,3-gem-difluoroproline 9 wassynthesizedthroughtheDAST-mediated deoxy-gem-difluorinationofthe3-prolinonederivative 7,followedbyhydrolysisoftheester moietyanddeprotectionofthe N-benzyloxycarbonyl(Cbz)protectinggroup(Fig.1 9).
25 °C, 4 h
25 °C, 4 h
–10 gem-Difluorinationofcarbonylcompoundsusingsulfurylfluoride.
FluoLead(Fig.1 1)hasrelativelyhigherthermalstabilityandisstableupto100 C. FluoLeadachievestransformationofcarbonylcompoundstothe gem-difluorocompoundsat 0 Ctoroomtemperature,inhighyields.9 ReactionofcarboxylicacidswithFluoLeadathigh temperatures(50 C 100 C)givesthecorrespondingtrifluoromethylcompounds(Fig.1 9).
Thetransformationofthecarbonylcompoundstothe gem-difluorocompoundscanalso beachievedusingtheabundantlyavailablesulfurylfluoride(SO2F2)asthefluorinatingagent. Thusreactionofbenzaldehydesand α-ketoesterswithsulfonylfluoride,inthepresenceof tetrabutylammoniumfluoride(TBAF),atroomtemperature,givesthecorresponding gemdifluorocompounds(Fig.1 10).36
The1,3-dithiolanes,hydrazones,oroximederivativesofthecarbonylcompoundscould betransformedintotheircorresponding gem-difluorocompounds,usingPPHF,inthepresenceofanelectrophilicreagentsuchasNBSornitrosoniumtetrafluoroborate(NOBF4).37 Thusreactionofthe1,3-dithiolaneswith1,3-dibromo-5,5-dimethylhydantoin(DBDMH)(or NBS),38 sulfurylchloridefluoride(SO2ClF),39 nitrosoniumtetrafluoroborate(NOBF4),40 or Selectfluor,41 inPPHF,givesthecorresponding gem-difluorocompounds.Thedithioketals weretransformedintothecorresponding gem-difluorocompoundsbyreactionwith p-iodotoluenedifluoride. 42 The gem-difluorocompoundscanalsobesynthesizedthroughthereactionofthehydrazonederivativesofcarbonylcompoundswithNBSinPPHF,43 orthrough thereactionoftheoximeswithNOBF4 inPPHF(Fig.1 11).44
1.6Nucleophilicfluoroalkylations 1.6.1Nucleophilicdifluoromethylationofaldehydes
ThedifluoromethylationofcarbonylcompoundscouldbeachievedusingCHF2TMSandCsF inapolarsolventsuchasdimethylformamide(DMF).45,46 ActivationofCHF2TMSfordifluoromethylationofcarbonylcompoundsrequiressomewhatharsherconditionsthanforthe CF3TMS.Difluoromethylmoiety,similartothetrifluoromethylgroup,altersthepharmacokineticpropertiesofthedrugcandidates.Inanattempttosynthesizeawiderangeofderivativesoftheinsecticidetebufenpyradforscreeningtheantiangiogenicpotential,thepyrazole
FIGURE1
Chapter1 • Nucleophilicreactionsinthesynthesisoforganofluorinecompounds13
FIGURE1–11 gem-Difluorinationofcarbonylcompounds.
FIGURE1–12 Difluoromethylationofpyrazolealdehydeinthesynthesisoftebufenpyradanalogs,aspotential antiangiogenicagents.
aldehydemoietywasdifluoromethylatedusingthisreagent(Fig.1 12).Variousdifluoromethylatedaswellaspoly-fluoroalkylatedderivatives,thussynthesized,exhibitedthedesired antiangiogeniceffect,althoughtheirundesiredmitochondrialinhibitionactivityprecluded theiruseasmedicinalagents.47
1.6.2Ruppert Prakashreagent(CF3SiMe3)fortrifluoromethylation
Trifluoromethylationofaldehydesandketonesusingthetrifluoromethyltrimethylsilane (CF3TMS;Ruppert Prakashreagent)iswidelyusedinthesynthesisofthe α-trifluoromethyl alcohols.16,48 50 TheC SibondinCF3TMSislabileandthereforeinsitugenerationofthe
