F lu o rin a tio n o f O rg a n ic C o m p o u n d s

1 FluorinationofOrganicCompoundsShunSuBara nGroupMeeting05/24/2008 Introduction F2: Isolated in 1886 by Moissan; 13th most abound element; only 13 naturallyoccurring organic compound are known. The usefulness of fluorinated material was first realized during the ManhattanProject (manipulation of UF6) Fluorine Effects: Enhanced thermal stability (C-F 107 kcal/mol) Increased lipophilicity to enhance bioavailability Mimicking of enzyme substrate (comparable in size to H, vs ) Isoelectronic effects to O- and -OH The high electronegativity of fluorine frequently alerts chemical reactivity Blocking effect in metabolic transformations Utility of some highly fluorinated compound: Coolants and aerosol propellants: CCl2F2, CF2Cl-CFCl2, cyclo-C4F8 Fire extinguisher: CF3Br, CF2 ClBr Inhalation anaesthesis: THF-F8, Dioxane-F8 Surfactants: C7F15 to C10F21-SO3H Polymers: high melting point; high thermal and chemical stability Blood substitutes: perfluorinated cycloalkanes, amines, and O-heterocycles Perfluorinated solvents and reagentsReaction Types Electrophilic Fluorination Nucleophilic Fluorination Fluorinated Synthons Electrochemical FluorinationFluorination ReagentsReviewsGeneral Reviews: Chemistry of Organic Fluorine Compound II: A Critical Review ACS, 1995.

2 ACIEE 1981, 20, 647. Organic Process Research & Development 2008, 12, Fluorination: Tetrahedron 2004, 60, Compounds: Aldrichimica Acta 1988, 21, : Synthesis 2002, : ACIEE 2005, 44, : Acc. Chem. Res. 2005, 38, :Tetrahedron 1995, 51, Fluorination: Tetrahedron 1999, 55, Compounds: Tetrahedron 1996, 52, : Tetrahedron 1992, 48, !+!-CCF3 CFFF!*InorganicReagents:AgF2,CoF3,CsSO4F ,HgF2,RbSO4F,PbF2(OAc)2,Tl(O2 CCF3)3 (TREAT-HF),(HF) (Olah'sReagent)Hypofluorites:CH3 COOF,CF3 COOF,CF3OF,FOClO3N-FluoroReagents:NFOTf- NFClBF4-selectfluorNSFSPhPhOOOONSFISNMeM eFOOF luoroaminosulfuranes:Et2 NSF3(DAST),(Me2N)3S(Me)3 SiF2(TASF)OtherReagents:PhIF2,BF3,XeF2 MeMeNSFOOPPHFR-O-R'R-FR'=H:DAST,SF4/Et3 NorPyr,CHClFCF2 NEt2,(HF) (benzylicprimaryOH)OHMeMeOHOOCDAST,DCM0o C,30minFMeMeFOOC77%Perkin11981,427 FluorinationofOrganicCompoundsShunSuBara nGroupMeeting05/24/2008sp3-C-Fsp3-C-FR-O -R'R-FR'=-OTsandanalogues:KF,CsF,TREAT-H F,TBAFCOOMeOTsCOOMeFROROKF,18-C-6 DMF,70oC73% ,20,2023 EpoxideOpening:CsF,KF,TREAT-HF,PPHF,DSAT ,SF4 OOCO2 MeO49% ,30,3711R-NR-FR-NH2:NaNO2/PPHF(!)

3 -aminoacids);2,4,6-triphenylpyrliumflour ide(1oalkyl,benzylic)OPhPhPhFRNH2 NPhPhPhRF80-120oCRFR-CHN2:Diazoalkanes-- acylfluoride/HF/KF; , :NO+BF4-PhCOCHN2 NXS,PPHFPhCOCHFX-15-25oCCl49%;Br63%;I62% ,44, ,44, +BF4-CHCl3,25oC[NCCH2CH2N4O+BF4-]50% ,47, ,HF/F2,HF/NCSCO2 HNH2 MeMeHSHF,CF3OF-78oCCO2 HNH2 MeMeFR-Cl/Br/IR-Fspray-driedKF,CsF,AgF,A gBF4,TBAF,HgF2R-FR-MgXFormationof!-fluor ocarbonylcompounds:R-CO2 HXeF2R-FSelectfluorR1OR3R2R1OR2 FElectrophilicFluorinationReagentsOMe3 SiOOTHPOTBSNCH2 OMeMeOH2 CFTfO-OOOTHPOTBSFA lkenefluorinationR1R2R4R3R1R2R4R3 FAA=H:HF, ,polyvinylpyridiumpoly(hydrogenfluoride) A=F:TREAT-HForPPHF/Selectfluoror(CF3SO2) NF,XeF2,CsSO4FA=Cl,Br,I:NXS/TREAT-HForPP HFA=RO,RCOO,OH:Selectfluoror(CF3SO2)NF/R OH,RCOOH,H2 ONBS, ,0-20oCFBr78% ,112, , generated via fluorinated synthonsAr-Fsp2-C-FR-HR-FHFHFF2,XeF2,CsS O4F,CF3OF,NO2BF4 ,CsSO4F,AgF/TiO2/hvORROMeMeR=CF3 COORROMeMeFCF3OF35% ,98, ,58, :F2A=Cl,Br,I:NXS,PPHFA=Se:A=H: +,F-R2R1 FEeliminationR2R1 FSnMe3R3R1R2 XeF2,AgOTfFR3R1R2 OFMeMeOHC5H11 OSnMe3 MeMeOHC5H11 XeF2,AgOTfDCM,rt,52%Tetrahedron1993,49, [O] ,31, :NaNO2/HCl/HBF4,tBuONO/NaBF4/hvHOMeONH2 CHOtBuONONaBF4 HOMeON2+ ,22,1493Ar-NR3 ArFKF/CsFinDMSOPhClFClLDA,THF62% ,41, ,238, :KF,CsF,TBAFanhR=NO2,CN,CHO,SO3Me,COCl,S O2Cl, ,48, :KF,KF/(Ph)4 PBr,(n-Bu4N)HF2,TBAFanhCHOClClTBAFanhDMS O,rt>90%CHOFFACIEE2006,45.

4 (PhSO2)2NF,(CF3SO2)2NF,SNSFOOOOM=MgX:sel ectfluor,NFOTf-MeMeMeONFSNSFOOOOM=B(OH)2 :CsSO4F,(HOCH2CH2)2 NMe/CsSO4FM=SiR3:F2,CsSO4F,XeF2M=SnR3:F2 ,CsSO4F,CF3OF,CH3CO2FM=HgX:CF3 OFAr-F+ArIIFBF4-Ar-I+-ArBF4-KF,DMF120oC, 54% ,21, ,THF, ,THF,-78oCMeOMeONOMeMeF65% ,35, :CsSO4F,Cf3OF,CH3 COOF, ,XeF2 OHtButBuXeF2,DCM-60to0oC49%OHtButBuFAlCl 3 PhMe40-50oC85% ,58,594 ForunactivedAr:AgF2,XeF2/HF,CF3OF,CsSO4F ,Hg(O2 CCF3)2,Tl(O2 CCF3)3,Pb(OAc)4 FluorinationofOrganicCompoundsShunSuBara nGroupMeeting05/24/2008gem-CF2gem-CF2Cl/ Br/IRFFD ifluoromethyleneSynthons:FR2OR1 FFFBr/Sn/SiR(EtO)2 PCF2 HOPhMe2 SiCF2 RCF2Br2CF2 BrClFFFFF2C:CF2Br2/PPh3 FFLi/BR'2 RAr-CF3Ar-CX3toAr-CF3X=Cl:SbF3,HFanh,AlC l3/FCCl3,HF/CCl4CX3=CS2H:XeF2;CX3=CO2H:D SAT,SF4/HFTheuseofCuCF3withAr-Cl/Br/IPre paration:Cu(I)/CF3 SiR3,Cu(I)/(CF3)ZnX,Cu/ICF3,Cu/BrCF3,Cu/ (CF3)2 HgCu(I)/CF3CO2M,Cu/CF3N(NO)SO2CF3,Cu/CF3 SO2Cl,Cu/CF2Br2 OPh3 COOBnNHNOOICF3Br/Cu60oC,78% ,113,152982mTheuseofF3 CPreparation:ICF3,BrCF3,Hg(CF3)2/hv,F3 CSO2Na/tBuOOH,F3 CCO2H/XeF2F3CN(NO)SO2Ph/hv,F3CN=NCF3/hvO MetBuF3CN(NO)SO2 PhhvOMetBuCF350%Tetrahedron1982,23, +/F-FFConditions:BrF,IF,NXS/PPHF,NOBF4/P PHFNNH2orNOHFFC onditions:IF,NISorNBS/PPHFC8H17H2 NNIF70% ,109, ,HFDCM,68%FFSynlett1994, +Ph3 CHNMeOMeOBn2 XKHMDS,TBSC lthenXeF2Ph3 CHNMeOMeOBnFFConditions:PPHFC onditions:DAST,BF3 ,56, ,48, :PPHF/NXSF luorinationofOrganicCompoundsShunSuBaran GroupMeeting05/24/2008Ar-CF3 Alkane, alkene, and alkyne CF3 Alkane, alkene, and alkyne CF3RO-CF3 SCF3 TfO-NH2NH2CF383%o:p=.

5 1 OOEt3 SiCF3 KFOF3 COSiEt372% ,65, ,115, ,vinylBr/I/OH,benzylOHC10H21 ICuCF3 HMPA48%C10H21CF3 OTsCuCF3 CCH2HF3C68%TheuseofF3C Additiontoalkenesandalkynesn-C5H11CH=CH- n-C5H11+F3 CIEt3Bn-C5H11C(CF3)CHI-n-C5H1167%F3 CNOF3 CNOhvNH2NH2 NNNCF3 NCF3CF3CF335%OtherMethodsPhCCLi+Se+TfO-C F346%PhCCCF3F3 CMXH2C=CHCH2 COCH3Zn,CF3 IultrasoundH2C=CHCH2C(CF3)(CH3) ,47, ,31, , ,16, ,31, ,107, ,56, ,105,827;Tetrahedron1992,48, (=S)ClPhOCCl3 SbF353%Cl271%PhOCF3 OHRCCl4,HF,100-150oCOCF3 ROMeClCl2,hvOCCl3 ClHF80-140oCOCF3 ClArOH+COF2 ArOCOFArOCF3SF4CF3OF+R1R2hvR1R2FF3C(Me2N )3S+CF3O-(TAS+CF3O-)OBrOMeMeOMeOOMeTAS+C F3O-OOCF3 OMeMeOMeOOMe65% ,4, ,29, ,6, ,44, ,28, MonofluorinationForreviews:ACIEE2008,47, 1179;2006,45, )Base2)NFSINOOROPhMe86-99%deReagentContr olMeMeNFSOOMeONAcOHN+HFBF4-CatalystContr olMetal-MediatedCatalystControlNOBocOrga nocatalysisFOOOONpNpNpNpNpNpTiClClMeMeON NOPhPhCu,Zn, ,Acetone,0oCNOBocF3 CClMeOF93ee%NHArOSiMe3 ArNHNOPhMeMeMeNOHN+ ,127,10164.