Catalytic , Transition Metal-Free Semireduction of Propiolamide Derivatives Scope and Mechanistic Investigation - Grams et al. - Unknow

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Catalytic,TransitionMetal-FreeSemireductionofPropiolamideDerivatives:ScopeandMechanisticInvestigationR.JustinGrams,ChristopherJ.Garcia,ConnorSzwetkowski,andWebsterL.Santos*DepartmentofChemistry,VirginiaTech,900WestCampusDrive,Blacksburg,VA24061(USA)*E-mail:santosw@vt.eduTableofContents1.MaterialsandMethods…………………………………………………………………………∙∙S22.Instrumentation…………………………………………………………………………………∙∙S23.GeneralProceduresforPreparingPropiolamides………………………………………………∙S2-S34.CharacterizationofPropiolamides………………………………………………………………S5-S75.GeneralProceduresforSemireductionofPropiolamides………………………………………∙S86.CharacterizationofE-Cinnamamides…………………………………………………………∙∙S8-S157.SynthesisandCharacterizationofFK866Analog:IntermediatesandFinalE-Cinnamamide…S16-S188.DeuteriumLabelingStudy………………………………………………………………………S199.CharacterizationofE-β-Borylacrylamide12……………………………………………………S1910.ProceduresforControlReactionswithBH3(Scheme7Cinthemanuscript)…………………S2011.NMRSpectraofPropiolamides………………………………………………………………∙∙S21-S3112.NMRSpectraofE-Cinnamamides……………………………………………………………∙∙S32-S6413.NMRSpectraofFK866Analog:IntermediatesandFinalE-Cinnamamide…………………∙S65-S6814.NMRSpectraof11……………………………………………………………………………∙S69-7015.NMRSpectraof12……………………………………………………………………………∙S7116.References……………………………………………………………………………………∙∙∙S72S1

11.MaterialsandMethodsReactionswereperformedusingSchlenktechniqueunderArgonorNitrogenatmosphere.Allglasswareusedwasflame-driedoroven-driedovernight.Chemicalswereobtainedfromcommercialsourcesunlessotherwisenoted.THFandDCMweredriedusingtheInnovativeTechnologyPureSolvMDsolventpurificationsystem.ColumnchromatographywasperformedusingSiliaFlashP6040-63μm,60Å.TLCanalyseswereperformedusingSilicyclealuminumbackedsilicagelF-254plates.2.InstrumentationNMRspectroscopicexperimentswereperformedusinganAgilent400-MR400MHz,anAgilentU4-DD2400Hz,oraBrukerAvanceII500MHzspectrometer.Chemicalshiftsarereportedinδppmand1Hand13CNMRarereferencedtoaninternalstandard(CDCl3,CD3OD,DMSO-d6,TMS,orAcetone-d6).Dataarereportedasfollows:chemicalshift,multiplicity(s=singlet,d=doublet,t=triplet,q=quartet,dd=doubletofdoublets,dt=doubletoftriplets,ddd=doubletofdoubletofdoublets,m=multiplet),couplingconstants(Hz),andintegration.Allpropiolamidesexistedasa9:1mixtureofrotamersandrotamerpeaksareassignedanasterisk.Inthecasewhereacinnamamidewasisolatedandcontainedrotamers,therotamerpeaksareassignedanasterisk.E-orZ-isomersofcinnamamidesarereportedasmajor(E/trans-isomer)andminor(Z/cis-isomer).ESImassspectrawereacquiredusinganAgilent6220TOFLC-MS.3.GeneralProceduresforPreparingPropiolamidesPropiolamides1a-c,1e-k,1m-o,3a-b,3d-e,5a-c,and5fwerepreparedinaccordancewithpreviousliteratureandreferencesforthespectraofpreviouslyknownpropargylamidesareprovidedinTableS1.Propiolamides1d,1l,1p,3c,3f,5d-eand5g-iwerepreparedaccordingtothefollowinggeneralproceduresunlessnotedotherwise.Allpropiolamidesexistedasa9:1mixtureofrotamersandrotamerpeaksareassignedanasterisk.Procedure3.1.Toaflame-oroven-driedroundbottomflaskfixedwithastirbarwasaddeddryTHF(20mL)andtheterminalacetylene(5.0mmol)underinertatmosphereandcooledto–78°C(dryice/acetonebath).n-Butyllithium(5.0mmol,2.5Minhexanes),wasthenaddeddropwisetothemixtureat–78°Cfor15minutes.Methylchloroformate(5.0mmol)wasthenaddeddropwisetothemixtureat–78°Candthereactionwasstirredfor2hours.Uponcompletion,thereactionwasdilutedwithwaterandextractedwithethylacetate.Theorganiclayerwaswashedwithbrineanddriedoveranhydroussodiumsulfate.Concentrationinvacuoyieldedayellowoilwhichuponpurificationbysilicagelcolumnchromatography(1:10,EtOAc:hexanes)yieldedthemethylpropiolateesterasacolorlessoil.Themethylpropiolateester(2.0mmol)wasaddedtoaround-bottomflaskfixedwithastirbaranddilutedwithTHF(2mL)whichwasthenaddeddropwisetoasolutionofmethylamine(8MinEtOH,4.0mmol)orammonia(7NinMeOH,4.0mmol)at0°C(brine/icebath).After2hours,thereactionwasdilutedwithwaterandextractedwithethylacetate.Theorganiclayerwaswashedwithbrineanddriedoveranhydroussodiumsulfate.Concentrationinvacuoyieldedthecrudeproductasayellowoil,whichwasthenpurifiedbysilicagelcolumnchromatography(elutedwitha2:3ethylacetate:hexanessolventsystem)toaffordthepurepropiolamideasawhitesolid,whichwasdriedbydissolvingintoluene(3mL,3x)andconcentratingtheproductinvacuo.S2

2Procedure3.2.Toanoven-dried25mL2-neckroundbottomflaskwithstirbarwasfixeda15mLliquidadditionfunnel.Totheroundbottomflaskwasaddedpotassiumcarbonate(14mmol),PdCl2(PPh3)3(5mol%),andcopperiodide(5mol%),whichwasthenpurgedwithN2viaSchlenktechnique.1,2-dimethoxyethane(DME)andaryliodide(7.1mmol)werethenadded,followedbyanadditional20minutesofpurgingthesolutionwithN2.Totheadditionfunnelwasaddedpropiolateester(14mmol)andDME(tomakea0.6Msolution).Thesolutionintheroundbottomflaskwasheatedto70⁰C.Onceheated,thepropiolateestersolutionwasslowlyaddeddropwiseoverthecourseof1hour.Theproductwaspurifiedbysilicagelcolumnchromatography(elutedwitha2:3ethylacetateinhexanessolventsystem)yieldingthepropiolateasaclearoil.ThepropiolatewasthensubjectedtoamideformingconditionsasdescribedinProcedure3.1.Procedure3.3.Toa15mLroundbottomflaskfixedwithastirbarwasaddedDCC(0.99mmol)andDMAP(0.090mmol)anddichloromethane(0.90mL).Theroundbottomflaskwassubmergedinanice/brinebathandthesolutionwasallowedtocoolto0⁰Cover15minutes.Propiolicacid(0.90mmol)wasdilutedwithdichloromethane(1.6mL)andwasaddedtotheDCC/DMAPsolution.Thereactionwasstirredat0⁰Cforca.10minutes.Propargylamine(0.99mmol)wasdilutedwithdichloromethane(0.99mL)andaddeddropwisetothereactionmixture.Thereactionwasallowedtoslowlywarmtoroomtemperatureandwasstirredovernight.Thereactionmixturewasdilutedwithethylacetateandfilteredthroughashortbedofsilica.Theorganiclayerwaswashedwithwaterandbrine,thendriedoversodiumsulfate.Theorganiclayerwasconcentratedinvacuoandpurifiedbysilicagelcolumnchromatography(elutedwitha2:3ethylacetateinhexanessolventsystem)toaffordthepurepropiolamideasawhitesolid,whichwasdriedbydissolvingintoluene(3mL,3x)andconcentratingtheproductinvacuo.S3

3TableS1.ReferencesforPropargylamideSubstratesSubstrateR1R2Reference1aHCH3J.Org.Chem.1985,50,39791bHCH(CH3)2Angew.Chem.Int.Ed.2017,56,51111cHPhAngew.Chem.Int.Ed.2017,56,51111eHCH2CCHTetrahedron,2019,75,35861fp-OCH2CH3CH3Angew.Chem.Int.Ed.2017,56,51111go-OCH3CH3Angew.Chem.Int.Ed.2017,56,51111hp-OBnCH3Angew.Chem.Int.Ed.2017,56,51111im-CH3CH3Angew.Chem.Int.Ed.2017,56,51111jp-C(CH3)3CH3Angew.Chem.Int.Ed.2017,56,51111ko-ClCH3Angew.Chem.Int.Ed.2017,56,51111m3,5-difluoroCH3Angew.Chem.Int.Ed.2017,56,51111np-CNCH3Chem.Eur.J.2017,23,155341othiophen-3-ylCH3Angew.Chem.Int.Ed.2017,56,51113acyclohex-1-en-1-ylCH3Org.Lett.2019,21,67953bcyclohexan-1-ylCH3Org.Lett.2019,21,67953dcycloprop-1-ylCH3Org.Lett.2019,21,67953eHCH3J.Org.Chem.1985,50,39795aHHCommerciallyAvailable5bp-C(CH3)3HOrg.Lett.2019,21,67955cp-CF3HOrg.Lett.2019,21,67955f5-methylthiophen-HOrg.Lett.2019,21,67952-ylS4

44.CharacterizationofPropiolamides:tert-butyl(3-(2-chlorophenyl)propioloyl)glycinate(1d)PreparedaccordingtoProcedure3.3.Whitesolid(36mg,0.123mmol,14%).R1f(3:2hexanes:ethylacetate)=0.41.HNMR(CDCl3,400MHz)δ7.54–7.49(dd,J=7.6,1.7Hz,1H),7.39–7.34(m,1H),7.33–7.27(dt,J=7.4,1.8Hz,1H),7.23–7.18(dt,J=7.5,1.5Hz,1H),6.66–6.61(t,J=5.3Hz,1H),*6.42–6.36(t,J=6.0Hz,1H),*4.21–4.18(d,J=6.2Hz,2H),4.04–3.98(d,J=5.0Hz,2H),1.48–1.44(s,9H),*1.44–1.41(s,9H).13CNMR(CDCl3,100MHz)δ168.3,*168.1,*155.7,152.9,*137.0,136.9,*134.7,134.4,*131.6,131.2,129.5,*126.9,126.7,120.3,*87.2,87.0,82.8,81.8,*45.5,42.3,28.1.HRMS(ESI-TOF)m/z:[M+H]+CalcdforC+15H17ClNO3294.0891;Found294.0894.N-methyl-3-(4-(trifluoromethoxy)phenyl)propiolamide(1l)PreparedaccordingtoProcedure3.2.Off-whitesolid(64.2mg,0.264mmol,32%).R1f(3:2dichloromethane:ethylacetate)=0.76.HNMR(Acetone-d6,500MHz)δ7.79(s,1H),*7.79–7.76(m,2H),7.72–7.64(m,2H),*7.45–7.42(d,J=9.0Hz,2H),7.43–7.37(d,J=8.0Hz,2H),*3.08–3.07(d,J=4.8Hz,3H),2.82–2.80(d,J=4.9Hz,3H);19FNMR(Acetone-d136,376MHz)δ-58.59;CNMR(Acetone-d6,126MHz)δ153.7,150.7(q,J=1.9Hz),*135.3,135.2,122.2,121.3(q,J=257Hz),120.7,85.2,*82.9,81.8,26.3.HRMS(ESI-TOF)m/z:[M+H]+CalcdforC+11H9F3NO2244.0579;Found244.0571.N-methyl-3-(pyridin-3-yl)propiolamide(1p)Substrate5hwassynthesizedusinganadaptedprotocol.1N-methylpropiolamide(223mg,2.69mmol)wasaddedtoa6dramvial,purgedwithN2viaSchlenktechnique,andthendilutedwithTHF(3.4mL).Toa10mLroundbottomflaskwasaddedPd(PPh3)4(141mg,0.122mmol)and3-iodopyridine(500mg,2.44mmol)whichwassubsequentlypurgedwithN2viaSchlenktechnique.TothismixturewasaddedTHF(1.6mL)andDBU(4.88mmol,0.729mL).ThemixturewaspurgedwithN2foranadditional30minutes.TheN-methylpropiolamidesolutionwasthenaddedtothe10mLroundbottomflaskandtheresultingmixturewasstirredat35°Cfor18hours.Thereactionmixturewasdilutedwithethylacetate(10mL).Theorganiclayerwaswashedwithwaterandbrinethendriedoveranhydroussodiumsulfate.Theorganiclayerwasfilteredandconcentratedinvacuo.Theresultingcrudeproductwaspurifiedbysilicagelcolumnchromatography(elutedwitha30–60%gradientethylacetateindichloromethane).Lightorangesolid(221mg,1.38mmol,56%).Rf(3:2dichloromethane:ethylacetate)=0.15.1HNMR(CD3OD,400MHz)δ*8.79–8.78(dd,J=2.1,1.0Hz,1H),8.76–8.69(dd,J=2.4,0.9Hz,1H),*8.64–8.62(dd,J=8.6,1.7Hz,1H),8.62–8.57(dd,J=5.0,1.7Hz,1H),*8.08–8.05(ddd,J=8.0,2.2,1.9Hz,1H),8.03–7.98(ddd,J=8.0,2.1,2.0Hz,1H),*7.53–7.49(ddd,J=7.8,5.0,1.0Hz,1H),7.51–7.46(ddd,J=8.1,5.0,1.0Hz,1H),*3.08(s,3H),2.8(s,3H).13CNMR(Acetone-d6,100MHz)δ*153.5,153.3,*151.3,151.1,*140.2,140.0,124.4,118.6,87.2,*87.2,*80.3,80.3,26.4,26.2.HRMS(ESI-TOF)m/z:[M+H]+CalcdforC+9H9N2O161.0709;Found161.0709.S5

57-(benzyloxy)-N-methylhept-2-ynamide(3c)PreparedaccordingtoProcedure3.1.Clearoil,(291mg,1.19mmol,71%).R1f(3:2hexanes:ethylacetate)=0.08.HNMR(CDCl3,400MHz)δ7.36–7.24(m,5H),5.95–5.81(s,1H),*5.78–5.69(s,1H),4.48(s,2H),3.50–3.46(t,J=6.0Hz,2H),*2.98–2.96(d,J=5.2Hz,3H),2.82–2.79(d,J=5.1Hz,3H),*2.42–2.38(t,J=7.0Hz,2H),2.33–2.28(t,J=7.0Hz,2H),1.75–1.60(m,4H).13CNMR(CDCl3,100MHz)δ154.2,138.4,128.4,127.6,127.6,86.9,75.8,73.0,69.7,*69.6,*29.0,28.9,26.5,*24.8,24.7,18.8,18.5.HRMS(ESI-TOF)m/z:[M+H]+CalcdforC+15H20NO2246.1489;Found246.1477.3-(dimethyl(phenyl)silyl)-N-methylpropiolamide(3f)Substrate3fwassynthesizedusinganadaptedprotocol.2Toaflame-dried15mLroundbottomflaskwasaddedN-methylpropiolamide(415mg,5.00mmol)thatwassubsequentlypurgedwithN2viaSchlenktechnique.THF(9.0mL)wasaddedandthemixturecooledto–78°Cwithadryice/acetonebath.Aftercoolingfor15minutes,LiHMDS(5.00mmol,1.0MinTHF)wasaddeddropwise.Themixturewasstirredfor30minat–78°C,afterwhichchlorodimethyl(phenyl)silane(5.00mmol,0.839mL)wasaddedandthemixtureallowedtowarmtoroomtemperatureovernight.Themixturewaspouredintosat.NH4Cl(5mL)andwasextractedwithdiethylether(2x5mL).Theorganiclayerwaswashedwithbrine(5mL),driedoveranhydroussodiumsulfate,filtered,andconcentratedinvacuo.Theresiduewaspurifiedbysilicagelcolumnchromatography(elutedwitha10-30%gradientethylacetateindichloromethane).Off-whitesolid,(627mg,5.00mmol,58%).Rf(3:2dichloromethane:ethylacetate)=0.32.1HNMR(CDCl3,400MHz)δ7.63–7.58(m,2H),7.44–7.35(m,3H),5.95–5.73(s,1H),*5.61–5.53(s,1H),*3.05–3.03(d,J=5.4Hz,3H),2.87–2.84(d,J=5.0Hz,3H),0.48–0.46(s,6H).13CNMR(CDCl3,100MHz)δ153.2,135.0,133.7,129.9,128.1,99.0,89.4,26.6,-1.4.HRMS(ESI-TOF)m/z:[M+H]+CalcdforC+12H16NOSi218.0996;Found218.0987.3-(4-(trifluoromethoxy)phenyl)propiolamide(5d)PreparedaccordingtoProcedure3.2.Off-whitesolid,(58.3mg,0.254mmol,66%).R1f(3:2dichloromethane:ethylacetate)=0.68.HNMR(Acetone-d6,500MHz)δ7.72–7.68(m,2H),7.54(s,1H),7.41(d,J=7.9Hz,2H),7.03(s,1H);19FNMR(Acetone-d6,376MHz)δ-58.20–-58.31(m);13CNMR(Acetone-d6,126MHz)δ154.7,150.7(q,J=2.2Hz),135.2,122.2,121.3(q,J=257Hz),120.6,85.1,82.3;HRMS(ESI-TOF)m/z:[M+H]+CalcdforC+10H7F3NO2230.0423;Found230.0417.S6

6N-methyl-3-(4-nitrophenyl)propiolamide(5e)PreparedaccordingtoProcedure3.2.Lightyellowsolid,(20.4mg,0.100mmol,24%).R1f(3:2dichloromethane:ethylacetate)=0.59.HNMR(Acetone-d6,400MHz)δ8.34–8.29(m,2H),7.87–7.82(m,2H),7.60(s,1H),7.08(s,1H);13CNMR(Acetone-d6,126MHz)δ154.0,149.2,134.21,128.0,124.7,87.9,81.5;HRMS(ESI-TOF)m/z:[M+H]+CalcdforC+9H7N2O3191.0451;Found191.0450.3-(pyridin-2-yl)propiolamide(5g)PreparedaccordingtoProcedure3.1.Purifiedusinga1–4%gradientmethanolindichloromethane.Off-whitesolid,(49.0mg,0.335mmol,36%).Rf(95:5dichloromethane:methanol)=0.59.1HNMR(CD3OD,400MHz)δ8.62–8.57(ddd,J=4.9,1.8,0.9Hz,1H),7.93–7.87(dt,J=7.8,1.8Hz,1H),7.72–7.68(dt,J=7.8,1.1Hz,1H),7.52–7.47(ddd,J=7.7,4.9,1.1Hz,1H).13CNMR(CD3OD,100MHz)δ156.6,151.2,141.7,138.7,129.8,126.2,83.6,83.0.HRMS(ESI-TOF)m/z:[M+H]+CalcdforC+8H7N2O147.0553;Found147.0552.3-(pyridin-3-yl)propiolamide(5h)PreparedaccordingtoProcedure3.2.Purifiedusinga3–5%gradientmethanolindichloromethane.Off-whitesolid(254mg,1.74mmol,78%).Rf(3:2dichloromethane:ethylacetate)=0.21.1HNMR(CD3OD,400MHz)δ8.76–8.72(dd,J=2.2,0.9Hz,1H),8.63–8.59(dd,J=5.0,1.7Hz,1H),8.04–8.00(ddd,J=8.0,2.1,1.6Hz,1H),7.52–7.47(ddd,J=7.9,5.0,0.9Hz,1H).13CNMR(CD3OD,100MHz)δ156.9,153.4,151.0,141.5,125.1,119.5,86.8,82.1.HRMS(ESI-TOF)m/z:[M+H]+CalcdforC8H7N2O,147.0553;Found147.0554.3-(pyridin-3-yl)propiolamide(5i)PreparedaccordingtoProcedure3.1.Whitesolid(239mg,1.58mmol,58%).Purifiedusinga0-10%gradientethylacetateindichloromethane.Rf(9:1dichloromethane:ethylacetate)=0.31.1HNMR(CDCl3,400MHz)δ5.71–5.52(s,2H),2.52–2.44(m,1H),1.87–1.79(m,2H),1.76–1.66(m,2H),1.57–1.43(m,4H),1.38–1.26(m,4H).13CNMR(CDCl3,100MHz)δ155.6,92.6,74.9,31.7,28.9,25.7,24.8.HRMS(ESI-TOF)m/z:[M+H]+CalcdforC+9H14NO152.1070;Found152.1069.S7

75.GeneralProceduresforSemi-reductionofPropiolamides:Procedure5.1Anoven-orflame-dried5mLroundbottomflaskwaschargedwithdrypropiolamide(32mg,0.2mmol)andplacedunderN2viaSchlenktechnique.ThereactionwasdilutedwithTHF(0.4mL,0.5Malkynamide)andstirredatroomtemperature.KOtBu(0.02mmol)wasaddedasasolidtotheroundbottomflask.Pinacolborane(0.032mL,0.22mmol)wasthenslowlyaddeddropwise(1dropevery3-4seconds).Thisorderofadditionisimportanttoobtainhighyield,regio-andstereoselectivity.Thereactionwasstirredatroomtemperaturefor10minutes.Thereactionmixturewasconcentratedinvacuoandtheresultingcruderesiduewaspurifiedbysilicagelcolumnchromatography(elutedwitha30-40%gradientethylacetateindichloromethane)toaffordtheproductasawhitesolid.Whereapplicable,theE-isomerislabeledasmajorwhentheZ-isomerispresent,whichislabeledasminor.Procedure5.2Anoven-orflame-dried5mLroundbottomflaskwaschargedwithdrypropiolamide(30mg,0.21mmol)andplacedunderN2viaSchlenktechnique.ThereactionwasdilutedwithTHF(1.0mL,0.2Mpropiolamide)andstirredatroomtemperature.KOtBu(0.21mmol)wasaddedasasolidtotheroundbottomflask.Pinacolborane(0.033mL,0.23mmol)wasthenslowlyaddeddropwise(1dropevery3-4seconds).Thisorderofadditionisimportanttoobtainhighyield,regio-andstereoselectivity.Thereactionwasstirredatroomtemperaturefor10minutes.Thereactionmixturewasconcentratedinvacuoandtheresultingcruderesiduewaspurifiedbysilicagelcolumnchromatography(elutedwitha30-40%gradientethylacetateindichloromethane)toaffordtheproductasawhitesolid.Whereapplicable,theE-isomerislabeledasmajorwhentheZ-isomerispresent,whichislabeledasminor.6.CharacterizationofE-cinnamamides:(E)-N-methyl-3-phenylacrylamide(2a)PreparedaccordingtoProcedure5.1.Whitesolid(33.7mg,0.209mmol,96%,>99:1E:Z).R1f(3:2dichloromethane:ethylacetate)=0.38.HNMR(CDCl3,400MHz)δ7.65–7.60(d,J=15.9Hz,1H),7.51–7.45(m,2H),7.37–7.30(m,3H),6.46–6.40(d,J=15.7Hz,1H),6.05–5.96(s,1H),2.96–2.92(d,J=5.0Hz,3H).13CNMR(CDCl3,100MHz)δ166.8,140.8,135.0,129.7,128.9,127.9,120.8,26.6.HRMS(ESI-TOF)m/z:[M+H]+CalcdforC+10H12NO162.0913;Found162.0897.3.2mmolscale:Whitesolid(497mg,3.2mmol,97%,>99:1E:Z)Procedurefor3.2mmolscale:Aflame-dried15mLroundbottomflaskwaschargedwithdrypropiolamide(509mg,3.2mmol)andplacedunderN2viaSchlenktechnique.ThereactionwasdilutedwithTHF(5.0mL)andstirredatroomtemperature.KOtBu(36mg,0.32mmol)wasaddedasasolid.Pinacolborane(0.51mL,3.5mmol)wasthenslowlyaddeddropwise(1dropevery3-4seconds).Thereactionwasstirredatroomtemperaturefor10minutes.Thereactionmixturewasconcentratedinvacuoandtheresultingcruderesiduewaspurifiedbysilicagelcolumnchromatography(elutedwitha30-40%gradientethylacetateindichloromethane)toaffordtheproductasawhitesolid.(E)-N-isopropylcinnamamide(2b)PreparedaccordingtoProcedure5.1.Whitesolid(24.5mg,0.129mmol,69%,>99:1E:Z).Rf(9:1dichloromethane:ethylacetate)=0.40.Purifiedusinga0-10%gradientethylacetateindichloromethane.1HNMR(CDCl3,400MHz)δ7.64–7.58(major,d,J=15.7Hz,1H),7.50–7.44(m,2H),7.36–7.29(m,3H),6.76S8

8–6.72(minor,d,J=12.6Hz,1H),6.45–6.36(major,d,J=15.2Hz,1H),6.00–5.96(minor,d,J=13.0Hz,1H),5.83–5.68(d,J=6.8Hz,1H),4.29–4.16(m,1H),1.24–1.19(d,J=7.0Hz,6H).13CNMR(CDCl3,100MHz)δ165.2,140.8,135.1,129.6,128.9,127.8,121.3,41.7,22.9.HRMS(ESI-TOF)m/z:[M+H]+CalcdforC+12H16NO190.1226;Found190.1220.(E)-N-phenylcinnamamide(2c)PreparedaccordingtoProcedure5.1.Off-whitesolid(48.2mg,0.216mmol,81%,>99:1E:Z).Rf(3:2dichloromethane:ethylacetate)=0.91.Purifiedusinga100%isocraticdichloromethanesolventsystem.1HNMR(CDCl3,400MHz)δ7.78–7.71(major,d,J=15.6Hz,1H),7.75–7.71(s,1H),7.67–7.61(m,2H),7.51–7.46(m,2H),7.38–7.31(m,5H),7.17–7.08(t,J=7.4Hz,1H),6.94–6.90(minor,d,J=12.5Hz,1H),6.65–6.54(major,d,J=15.3Hz,1H),6.14–6.10(minor,d,J=12.2Hz,1H).13CNMR(CDCl3,100MHz)δ164.3,142.5,138.2,134.7,130.1,129.2,129.0,128.1,124.6,121.0,120.2.HRMS(ESI-TOF)m/z:[M+H]+CalcdforC+15H14NO224.1070;Found224.1068.tert-butyl(E)-(3-(2-chlorophenyl)acryloyl)glycinate(2d)PreparedaccordingtoProcedure5.1.Off-whitesolid(37.0mg,0.130mmol,73%,>99:1E:Z).Rf(3:2dichloromethane:ethylacetate)=0.59.Purifiedusinga10-20%gradientethylacetateindichloromethane.1HNMR(CDCl3,400MHz)δ8.03–7.95(d,J=16.0Hz,1H),7.58–7.53(m,1H),7.41–7.34(m,1H),7.30–7.21(m,2H),6.52–6.40(d,J=15.7Hz,1H),6.32–6.26(s,1H),4.10–4.06(d,J=4.9Hz,2H),1.51–1.46(s,9H).13CNMR(CDCl3,100MHz)δ169.3,165.4,137.6,134.9,133.2,130.7,130.3,127.7,127.1,123.1,82.7,42.4,28.2.HRMS(ESI-TOF)m/z:[M+H]+CalcdforC+15H19ClNO3296.1048;Found296.1057.(E)-N-(prop-2-yn-1-yl)cinnamamide(2e)PreparedaccordingtoProcedure5.1.Off-whitesolid(40.0mg,0.220mmol,79%,>99:1E:Z).Rf(3:2dichloromethane:ethylacetate)=0.83.Purifiedusinga40-60%gradientethylacetateinhexanes.1HNMR(CDCl3,400MHz)δ7.79–7.63(major,d,J=15.9Hz,1H),7.52–7.45(m,2H),7.39–7.32(m,3H),6.83–6.79(minor,d,J=13.5Hz,1H),6.46–6.40(major,d,J=15.8Hz,1H),6.14–6.01(s,1H),4.22–4.18(dd,J=5.0,2.6Hz,2H),2.27–2.25(t,J=2.8Hz,1H).13CNMR(CDCl3,100MHz)δ165.7,142.0,134.7,130.0,129.0,128.0,119.9,79.6,71.9,29.6.HRMS(ESI-TOF)m/z:[M+H]+CalcdforC+24H23N2O2371.1754;Found371.1730.(E)-3-(4-ethoxyphenyl)-N-methylacrylamide(2f)PreparedaccordingtoProcedure5.1.Whitesolid(35.5mg,0.173mmol,89%,>99:1E:Z).R1f(3:2dichloromethane:ethylacetate)=0.32.HNMR(CDCl3,400MHz)δ7.57–7.52(d,J=15.3Hz,1H),7.41–7.36(d,J=8.3Hz,2H),6.84–6.78(d,J=8.8Hz),6.32–6.26(d,J=15.6Hz,1H),4.05–3.97(q,J=6.9Hz,2H),2.92–2.87(s,3H),1.42–1.36(t,J=6.6Hz,3H).13CNMR(CDCl3,100MHz)δ167.1,160.2,140.3,129.3,127.4,118.1,114.7,63.5,26.3,14.7.HRMS(ESI-TOF)m/z:[M+H]+CalcdforC+12H16NO2206.1176;Found206.1155.S9

9(E)-3-(2-methoxyphenyl)-N-methylacrylamide(2g)PreparedaccordingtoProcedure5.1.Whitesolid(32.2mg,0.121mmol,73%,>99:1E:Z).R1f(3:2dichloromethane:ethylacetate)=0.32.HNMR(CDCl3,400MHz)δ7.89–7.84(d,J=16.1Hz,1H),7.46–7.43(dd,J=7.7,1.5Hz,1H),7.31–7.26(m,1H),6.93–6.86(m,2H),6.56–6.51(d,J=16.4Hz,1H),6.08–5.94(s,1H),3.85–3.82(s,3H),2.94–2.91(d,J=4.9Hz,3H).13CNMR(CDCl3,100MHz)δ166.2,158.2,136.7,130.6,128.2,124.6,121.6,112.8,57.7,27.0.HRMS(ESI-TOF)m/z:[M+H]+CalcdforC+11H14NO2192.1019;Found192.1012.(E)-3-(4-(benzyloxy)phenyl)-N-methylacrylamide(2h)PreparedaccordingtoProcedure5.1.Whitesolid(37.0mg,0.140mmol,92%,>99:1E:Z).R1f(3:2dichloromethane:ethylacetate)=0.44.HNMR(CDCl3,400MHz)δ7.61–7.54(major,d,J=15.6Hz,1H),7.45–7.30(m,7H),6.95–6.89(d,J=8.7Hz,2H),6.67–6.63(minor,d,J=12.6Hz,1H),6.36–6.24(major,d,J=15.6Hz,1H),6.08–5.95(d,J=5.5Hz,1H),5.88–5.84,(minor,d,J=12.6Hz,1H),5.07–5.04(s,2H),2.96–2.87(d,J=4.9Hz,3H).13CNMR(CDCl3,100MHz)δ167.0,160.0,140.2,136.5,129.3,128.6,128.1,127.8,127.5,118.5,115.1,70.0,26.5.HRMS(ESI-TOF)m/z:[M+H]+CalcdforC+17H18NO2268.1332;Found268.1310.(E)-N-methyl-3-(m-tolyl)acrylamide(2i)PreparedaccordingtoProcedure5.1.Whitesolid(24.0mg,0.140mmol,79%,>99:1E:Z).R1f(3:2dichloromethane:ethylacetate)=0.46.HNMR(CDCl3,400MHz)δ7.61–7.55(d,J=15.6Hz,1H),7.31–7.26(m,2H),7.25–7.19(t,J=7.8Hz,1H),7.16–7.12(d,J=8.0Hz,1H),6.46–6.39(d,J=15.7Hz,1H),6.13–6.01(s,1H),2.96–2.91(d,J=2.9Hz,3H),2.34–2.31(s,3H).13CNMR(CDCl3,100MHz)δ168.4,140.3,139.1,135.7,131.6,129.2,128.6,126.2,120.6,27.2,22.3.HRMS(ESI-TOF)m/z:[M+H]+CalcdforC+11H14NO176.1070;Found176.1055.(E)-3-(4-(tert-butyl)phenyl)-N-methylacrylamide(2j)PreparedaccordingtoProcedure5.1.Whitesolid(26.70mg,0.123mmol,88%,>99:1E:Z).R1f(3:2dichloromethane:ethylacetate)=0.52.HNMR(CDCl3,400MHz)δ7.63–7.57(d,J=15.6Hz,1H),7.45–7.40(d,J=8.3Hz,2H),7.38–7.32(d,J=8.5Hz,2H),6.44–6.38(d,J=15.7Hz,1H),6.09–6.03(d,J=6.9,1H),2.95–2.91(d,J=4.9Hz,3H),1.32–1.29(s,9H).13CNMR(CDCl3,126MHz)δ167.1,153.1,140.7,132.2,127.7,125.9,119.9,34.9,32.3,26.6.HRMS(ESI-TOF)m/z:[M+H]+CalcdforC+14H20NO218.1539;Found218.1534.(E)-3-(2-chlorophenyl)-N-methylacrylamide(2k)PreparedaccordingtoProcedure5.1.Whitesolid(49.9mg,0.255mmol,88%,>99:1E:Z).R1f(3:2dichloromethane:ethylacetate)=0.26.HNMR(CDCl3,400MHz)δ7.98–7.93,(major,d,J=15.7Hz,1H),7.54–7.50(dd,J=7.7,1.8Hz,1H),7.36–7.32(dd,J=8.0,1.3Hz,1H),7.23=7.18(td,J=7.7,1.8Hz,1H),7.18S10

10–7.12(m,1H),6.71–6.64(s,1H),6.53–6.47(major,d,J=15.7Hz,1H),6.13–6.08(minor,d,J=12.2Hz,1H),2.94–2.91(d,J=4.9Hz,3H).13CNMR(CDCl3,100MHz)δ166.6,136.4,134.7,133.3,130.4,130.1,127.5,127.0,123.8,26.6.HRMS(ESI-TOF)m/z:[M+H]+CalcdforC+10H11ClNO196.0524;Found196.0518.(E)-N-methyl-3-(4-(trifluoromethoxy)phenyl)acrylamide(2l)PreparedaccordingtoProcedure5.1.Whitesolid(19.2mg,0.0783mmol,68%,>99:1E:Z).R1f(3:2dichloromethane:ethylacetate)=0.52.HNMR(Acetone-d6,400MHz)δ7.72–7,68(m,2H),7.57–7.50(major,d,J=15.7Hz,1H),7.37–7.29(d,J=7.9Hz,2H),6.72–6.65(major,d,J=15.7Hz,1H),6.10–6.06(minor,d,J=12.7Hz,1H),2.84–2.82(d,J=4.70Hz,3H).19FNMR(Acetone-d136,376MHz)δ-58.4.CNMR(Acetone-d6,100MHz)δ166.2,150.3(q,J=1.8Hz),138.2,135.6,130.2,124.2,122.7,121.15(q,J=254Hz),26.3.HRMS(ESI-TOF)m/z:[M+H]+CalcdforC+11H11F3NO2246.0736;Found246.0722.(E)-3-(3,5-difluorophenyl)-N-methylacrylamide(2m)PreparedaccordingtoProcedure5.1.Whitesolid(23.6mg,0.120mmol,71%,>99:1E:Z).R1f(3:2dichloromethane:ethylacetate)=0.46.HNMR(CDCl3,400MHz)δ7.53–7.47(d,J=15.6Hz,1H),7.00–6.93(m,2H),6.79–6.73(m,1H),6.45–6.39(d,J=15.6Hz,1H),6.15–6.08(s,1H),2.96–2.92(d,J=4.9Hz,3H).19FNMR(CDCl133,376MHz)δ-109.4(t,J=7.9Hz).CNMR(CDCl3,100MHz)δ165.8,164.4(d,J=12.9Hz),161.9(d,J=12.9Hz),138.4(t,J=2.6Hz),138.1(5,J=9.5Hz),123.2,110.8(m),104.7(t,J=25.5Hz),26.6.HRMS(ESI-TOF)m/z:[M+H]+CalcdforC+10H10F2NO198.0725;Found198.0723.(E)-3-(4-cyanophenyl)-N-methylacrylamide(2n)PreparedaccordingtoProcedure5.1.Whitesolid(21.0mg,0.110mmol,86%,94:6E:Z).R1f(3:2dichloromethane:ethylacetate)=0.08.HNMR(CD3OD,400MHz)δ7.73–7.64(major,m,4H),7.64–7.57(minor,m,4H),7.55–7.50(major,d,J=15.8Hz,1H),6.79–6.75(minor,d,J=12.4Hz,1H),6.69–6.63(major,d,J=16.2Hz,1H),6.16–6.12(minor,d,J=12.6Hz,1H),2.87–2.84(s,3H).13CNMR(CD3OD,100MHz)δ167.9,140.6,139.0,133.4,129.1,125.1,119.2,113.3,26.6.HRMS(ESI-TOF)m/z:[M+H]+CalcdforC+11H11N2O187.0866;Found187.0851.(E)-N-methyl-3-(thiophen-3-yl)acrylamide(2o)PreparedaccordingtoProcedure5.1.Whitesolid(35.3mg,0.211mmol,90%,>99:1E:Z).R1f(3:2dichloromethane:ethylacetate)=0.43.HNMR(CDCl3,400MHz)δ7.64–7.57(major,d,J=16.2Hz,1H),7.41–7.37(dd,J=2.9,1.3Hz,2H),7.29–7.25(ddd,J=5.7,2.6,0.7,1H),7.24–7.21(m,1H),6.69–6.65(minor,d,J=12.7Hz,1H),6.34–6.26(major,d,J=15.6Hz,1HJ),6.34–6.26(s,1H),5.87–5.83(minor,d,J=12.5Hz,1H),2.94–2.91(d,J=4.9Hz,3H).13CNMR(CDCl3,100MHz)δ167.2,137.9,134.3,127.0,126.8,125.1,120.6,26.6.HRMS(ESI-TOF)m/z:[M+H]+CalcdforC+8H10NOS168.0478;Found168.0473.S11

11(E)-N-methyl-3-(pyridin-3-yl)acrylamide(2p)PreparedaccordingtoProcedure5.1.Whitesolid(43.3mg,0.267mmol,88%,>99:1E:Z).R1f(3:2dichloromethane:ethylacetate)=0.22.HNMR(CD3OD,400MHz)δ8.72–8.67(d,J=2.3Hz,1H),8.53–8.48(dd,J=4.9,1.6Hz,1H),8.05–8.00(dt,J=7.4,2.0Hz,1H),7.57–7.50(d,J=15.9Hz,1H),7.48–7.43(ddd,J=8.0,4.9,0.9Hz,1H),6.73–6.67(d,J=15.9Hz,1H),6.70–6.68(d,J=2.1Hz,1H),2.87–2.84(s,3H).13CNMR(CD3OD,100MHz)δ168.3,150.7,149.7,137.3,136.2,132.8,115.5,124.6,124.5,26.5.HRMS(ESI-TOF)m/z:[M+H]+CalcdforC+9H11N2O163.0866;Found163.0858.(E)-3-(cyclohex-1-en-1-yl)-N-methylacrylamide(4a)PreparedaccordingtoProcedure5.1.Whitesolid(55.9mg,0.338mmol,91%,>99:1E:Z).R1f(3:2dichloromethane:ethylacetate)=0.31.HNMR(CDCl3,400MHz)δ7.22–7.16(d,J=15.4Hz,1H),6.12–6.08(t,J=4.1Hz,1H),5.74–5.67(d,J=15.5Hz,1H),5.65–5.57(s,1H),2.91–2.86(d,J=4.90Hz,1H),2.22–2.14(m,2H),2.14–2.07(m,2H),1.72–1.64(m,2H),1.64–1.55(m,2H).13CNMR(CDCl3,100MHz)δ167.6,144.3,137.3,134.7,117.0,26.5,26.4,24.4,22.3,22.3.HRMS(ESI-TOF)m/z:[M+H]+CalcdforC+10H16NO166.1226;Found166.1223.(E)-3-cyclohexyl-N-methylacrylamide(4b)PreparedaccordingtoProcedure5.2.Whitesolid(51.3mg,0.307mmol,62%,81:19E:Z).R1f(3:2dichloromethane:ethylacetate)=0.41.HNMR(CDCl3,400MHz)δ6.77–6.70(major,dd,J=15.5,6.8Hz,1H),5.97–5.89(s,1H),*5.85–5.75(s,1H),5.78–5.72(minor,dd,J=11.7,9.9Hz,1H),5.74–5.68(major,dd,J=15.5,1.4Hz,1H),5.57–5.54(minor,dd,J=11.5,0.9Hz,1H),2.85–2.82(d,J=4.9Hz,3H),2.82–2.80(minor,d,J=4.9Hz,3H),*2.78–2.75(d,J=4.8Hz,3H),2.19–2.12(m,2H),2.11–2.01(m,1H),1.76–1.57(m,13H),1.53–1.44(m,2H),1.38–0.97(m,12H),0.91–0.79(m,2H).13CNMR(CDCl3,100MHz)δ174.3,*167.3,151.0(minor),149.5,121.2,120.1(minor),40.3,27.5,27.0,34.2,33.3,33.2,32.8,32.1,26.6,26.4,26.3,26.1,25.9,25.6.HRMS(ESI-TOF)m/z:[M+H]+CalcdforC+10H18NO168.1383;Found168.1381.(E)-7-(benzyloxy)-N-methylhept-2-enamide(4c)PreparedaccordingtoProcedure5.2.Whitesolid(42.5mg,0.172mmol,70%,83:17E:Z).Rf(3:2dichloromethane:ethylacetate)=0.29.1HNMR(CDCl3,400MHz)δ7.37–7.29(m,7H),7.30–7.24(m,2H),6.84–6.75(major,dt,J=16.0,6.7Hz,1H),5.99–5.91(minor,dt,J=11.5,7.5Hz,1H),5.78–5.71(major,dt,J=15.2,1.4Hz,1H),5.69–5.65(minor,dt,J=11.6,1.7Hz,1H),5.67–5.51(s,1H),4.49–4.47(s,2H),*4.49–4.47(s,2H),3.48–3.43(t,J=7.0Hz,2H),*3.48–3.43(t,J=7.1Hz,2H),2.86–2.83(major,d,J=4.9Hz,3H),2.82–2.80(minor,d,J=4.9Hz,3H),*2.79–2.76(major,d,J=4.8Hz,3H),2.21–2.11(m,2H),*2.21–2.11(m,2H),1.70–1.58(m,2H),*1.70–1.58(m,2H),1.58–1.48(m,2H),*1.58–1.48(m,2H),1.42–1.27(m,2H),*1.42–1.27(m,2H).13CNMR(CDCl3,100MHz)δ*173.8,166.8,145.2(minor),144.2,138.7,128.5,*128.5,127.7,*127.6,127.6(minor),123.8,73.0,*73.0,*70.4,70.1,36.7,31.8,29.8(minor),*29.7,29.4(minor),29.3,29.2,28.5(minor),26.4,*26.0,*25.9,25.0.HRMS(ESI-TOF)m/z:[M+H]+CalcdforC+15H22NO2248.1645;Found248.1637.S12

12(E)-3-cyclopropyl-N-methylacrylamide(4d)PreparedaccordingtoProcedure5.1.Clearoil(28.9mg,0.231mmol,71%,>99:1E:Z).R1f(3:2dichloromethane:ethylacetate)=0.29.HNMR(CDCl3,400MHz)δ6.33–6.25(major,dd,J=15.0,10.0Hz,1H),5.86–5.81(major,d,J=14.9Hz,1H),5.62–5.51(s,1H),5.25–5.19(minor,t,J=10.8Hz,1H),2.86–2.83(d,J=4.9Hz,3H),1.55–1.45(m,1H),0.90–0.83(m,2H),0.60–0.55(m,2H).13CNMR(CDCl3,100MHz)δ166.9,148.6,120.5,26.4,15.8,8.3.HRMS(ESI-TOF)m/z:[M+H]+CalcdforC+7H12NO126.0913;Found126.0912.N-methylacrylamide(4e)PreparedaccordingtoProcedure5.1withtheexceptionthatpinacolboranewasaddedfirstfollowedbyadditionofbase.Clearoil(50.1mg,0.862mmol,68%,).Rf(3:2dichloromethane:ethylacetate)=0.24.1HNMR(CDCl3,400MHz)δ6.30–6.23(dd,J=17.0,1.5Hz,1H),6.13–6.05(dd,J=17.0,10.3Hz,1H),5.83–5.66(s,1H),5.65–5.59(dd,J=10.2,1.5Hz,1H),2.90–2.87(d,J=4.9Hz,3H).13CNMR(CDCl3,100MHz)δ164.3,130.0,126.3,26.5,25.0.HRMS(ESI-TOF)m/z:[M+H]+CalcdforC+4H8NO86.0600;Found86.0600.(E)-3-(dimethyl(phenyl)silyl)-N-methylacrylamide(4f)PreparedaccordingtoProcedure5.1withtheexceptionthatpinacolboranewasaddedfirstfollowedbyadditionofbase.Paleyellowoil(43.7mg,0.250mmol,80%,>99:1E:Z).R1f(3:2dichloromethane:ethylacetate)=0.55.HNMR(CDCl3,400MHz)δ7.55–7.47(m,2H),7.40–7.31(m,3H),7.19–7.11(d,J=18.5Hz,1H),6.23–6.16(d,J=18.5Hz,1H),5.76–5.66(s,1H),2.88–2.85(d,J=4.9Hz,3H),0.40–0.38(s,6H).13CNMR(CDCl3,100MHz)δ166.1,141.7,138.1,136.9,134.0,129.5,128.1,26.5,-2.9.HRMS(ESI-TOF)m/z:[M+H]+CalcdforC+12H18NOSi220.1152;Found220.1142.(E)-cinnamamide(6a)PreparedaccordingtoProcedure5.2.Whitesolid(21.5mg,0.146mmol,70%,>99:1E:Z).R1f(3:2dichloromethane:ethylacetate)=0.27.HNMR(CDCl3,400MHz)δ7.68–7.62(major,d,J=15.7Hz,1H),7.54–7.49(m,2H),7.40–7.35(m,3H),6.88–6.83(minor,d,J=12.5Hz,1H),6.51–6.43(major,d,J=15.7Hz,1H),6.01–5.97(minor,d,J=12.5Hz,1H).13CNMR(CDCl3,100MHz)δ168.5,142.0,135.8,130.1,129.0,128.5,120.8.HRMS(ESI-TOF)m/z:[M+H]+CalcdforC+9H10NO148.0757;Found148.0738.2.8mmolscale:Whitesolid(372mg,2.53mmol,92%,>99:1E:Z)Procedurefor2.8mmolscale:Aflame-dried25mLroundbottomflaskwaschargedwithdrypropiolamide(402mg,2.8mmol)andplacedunderN2viaSchlenktechnique.ThereactionwasdilutedwithTHF(13.0mL)andstirredatroomtemperature.KOtBu(310mg,2.8mmol)wasaddedasasolid.Pinacolborane(0.44mL,3.0mmol)wasthenslowlyaddeddropwise(1dropevery3-4seconds).Thereactionwasstirredatroomtemperaturefor10minutes.Thereactionmixturewasconcentratedinvacuoandtheresultingcruderesiduewaspurifiedbysilicagelcolumnchromatography(elutedwitha30-40%gradientethylacetateindichloromethane)toaffordtheproductasawhitesolid.S13

13(E)-3-(4-(tert-butyl)phenyl)acrylamide(6b)PreparedaccordingtoProcedure5.2.Whitesolid(23.1mg,0.190mmol,60%,97:3E:Z).R1f(3:2dichloromethane:ethylacetate)=0.38.HNMR(CD3OD,400MHz)δ7.56–7.50(major,d,J=15.8Hz,1H),7.50–7.46(m,2H),7.44–7.39(m,2H),6.73–6.69(minor,d,J=12.7Hz,1H),6.63–6.57(major,d,J=15.8Hz,1H),5.99–5.95(minor,d,J=12.7Hz,1H),1.33–1.29(s,9H).13CNMR(CD3OD,100MHz)δ171.2,154.5,142.6,133.4,128.8,126.9,120.5,35.7,31.6.HRMS(ESI-TOF)m/z:[M+H]+CalcdforC+13H18NO204.1383;Found204.1383.(E)-3-(4-(trifluoromethyl)phenyl)acrylamide(6c)PreparedaccordingtoProcedure5.2.Whitesolid(30.3mg,0.141mmol,62%,>99:1E:Z).R1f(3:2dichloromethane:ethylacetate)=0.33.HNMR(CD3OD,400MHz)δ7.76–7.71(d,J=8.2Hz,2H),7.71–7.64(d,J=8.3Hz,2H),7.62–7.55(major,d,J=15.9Hz,1H),6.78–6.72(major,d,J=15.9Hz,1H),6.20–6.16(minor,d,J=12.6Hz,1H).19FNMR(CD3OD,376MHz)δ-64.3.13CNMR(CD3OD,100MHz)δ170.2,140.7,140.0,132.1(q,J=32.6Hz),129.3,126.8(q,J=3.9Hz),125.6(q,J=269Hz),124.4,124.1.HRMS(ESI-TOF)m/z:[M+H]+CalcdforC+10H9F3NO216.0631;Found216.0631.(E)-3-(4-(trifluoromethoxy)phenyl)acrylamide(6d)PreparedaccordingtoProcedure5.2.Whitesolid(20.5mg,0.0887mmol,78%,>99:1E:Z).R1f(3:2dichloromethane:ethylacetate)=0.34.HNMR(Acetone-d6,400MHz)δ7.74–7.69(m,2H),7.59–7.53(major,d,J=15.8Hz,1H),7.39–7.33(m,2H),7.10–7.00(s,1H),6.78–6.72(major,d,J=15.9Hz,1H),6.62–6.50(s,1H),6.16–6.11(minor,d,J=12.8Hz,1H).19FNMR(Acetone-d136,376MHz)δ-58.6.CNMR(Acetone-d6,100MHz)δ167.4,150.4(q,J=1.8Hz),138.2,135.4,130.3,123.9,122.2,121.36(q,J=255Hz).HRMS(ESI-TOF)m/z:[M+H]+CalcdforC+10H9F3NO2232.0580;Found232.0573.(E)-3-(4-nitrophenyl)acrylamide(6e)PreparedaccordingtoProcedure5.2.Lightyellowsolid(10.6mg,0.0552mmol,52%,95:5E:Z).Rf(95:5dichloromethane:methanol)=0.28.Purifiedusinga1-2%gradientofmethanolindichloromethane.1HNMR(CD3OD,400MHz)δ8.29–8.24(major,m,2H),8.20–8.17(minor,m,2H),7.82–7.78(major,m,2H),7.75–7.71(minor,m,2H),7.65–7.59(major,d,J=15.9Hz,1H),6.90–6.86(minor,d,J=12.6Hz,1H),6.84–6.78(major,d,J=15.9Hz,1H),6.27–6.23(minor,d,J=12.6Hz,1H).13CNMR(CD3OD,126MHz)δ169.8,149.7,142.6,139.9,136.4(minor),131.2(minor),129.8,125.9,125.1,124.2(minor).HRMS(ESI-TOF)m/z:[M+H]+CalcdforC+9H9N2O3193.0608;Found193.0596.S14

14(E)-3-(5-methylthiophen-2-yl)acrylamide(6f)PreparedaccordingtoProcedure5.2.Whitesolid(14.2mg,0.0849mmol,74%,98:2E:Z).R1f(3:2dichloromethane:ethylacetate)=0.35.HNMR(CD3OD,400MHz)δ7.61–7.54(major,d,J=15.5Hz,1H),7.08–7.06(d,J=3.6Hz,1H),6.89–6.85(minor,d,J=13.1Hz,1H),6.76–6.73(m,1H),6.31–6.22(major,d,J=15.5Hz,1H),5.73–5.69(minor,d,J=12.4Hz,1H),2.49–2.47(s,3H).13CNMR(CD3OD,100MHz)δ170.9,144.5,139.2,135.8,132.4,127.6,118.7,15.5.HRMS(ESI-TOF)m/z:[M+H]+CalcdforC+8H10NOS168.0478;Found168.0477.(E)-3-(pyridin-2-yl)acrylamide(6g)PreparedaccordingtoProcedure5.2.Whitesolid(28.7mg,0.194mmol,80%,>99:1E:Z).Rf(95:5dichloromethane:methanol)=0.13.Purifiedusinga4-6%gradientmethanolindichloromethane.1HNMR(CD3OD,400MHz)δ8.58–8.56(ddd,J=4.9,1.8,0.9Hz,1H),7.87–7.81(td,J=7.7,1.8Hz,1H),7.62–7.58(dt,J=7.9,1.0Hz,1H),7.58–7.54(d,J=15.7Hz,7.39–7.35(ddd,J=7.6,4.9,1.1Hz,1H),7.03–6.98(d,J=15.6Hz,1H),7.01–6.99(t,J=2.1Hz,2H).13CNMR(CD3OD,100MHz)δ170.2,154.6,150.8,141.0,138.8,126.1,126.0,125.5,125.2.HRMS(ESI-TOF)m/z:[M+H]+CalcdforC+8H9N2O149.0709;Found149.0705.(E)-3-(pyridin-3-yl)acrylamide(6h)PreparedaccordingtoProcedure5.2.Whitesolid(29.2mg,0.197mmol,99%,>99:1E:Z).Rf(95:5dichloromethane:methanol)=0.11.Purifiedusinga4-6%gradientmethanolindichloromethane.1HNMR(CD3OD,400MHz)δ8.74–8.69(s,1H),8.55–8.49(d,J=4.9Hz,1H),8.07–8.03(dddd,J=8.0,2.2,1.6,0.5Hz,1H),7.60–7.54(major,d,J=16.0Hz,1H),7.49–7.44(m,1H),6.81–6.74(major,d,J=15.9Hz,1H),6.25–6.21(minor,d,J=12.5Hz,1H).13CNMR(CD3OD,100MHz)δ169.9,150.8,149.8,138.4,136.3,132.8,125.5,124.4.HRMS(ESI-TOF)m/z:[M+H]+CalcdforC+8H9N2O149.0709;Found149.0714.(E)-3-cyclohexylacrylamide(6i)PreparedaccordingtoProcedure5.2.Whitesolid(30.8mg,0.201mmol,35%,84:16E:Z).Rf(3:2dichloromethane:ethylacetate)=0.29.Purifiedusinga20-40%gradientofethylacetateindichloromethane.1HNMR(CD3OD,400MHz)δ6.78–6.71(major,dd,J=15.6,6.9Hz,1H),5.93–5.87(major,dd,J=15.6,1.4Hz,1H),5.86–5.80(minor,dd,J=11.6,9.6Hz,1H),5.75–5.71(minor,dd,J=11.6,0.8Hz,1H),2.20–2.08(m,1H),1.82–1.64(m,8H),1.41–1.10(m,8H).13CNMR(CD3OD,100MHz)δ171.4,155.4(minor),151.8,121.9,120.3(minor),41.0,38.2(minor),33.7,33.1,27.1,27.1(minor),26.9,26.7(minor).HRMS(ESI-TOF)m/z:[M+H]+CalcdforC+9H16NO154.1226;Found154.1219.S15

157.SynthesisandCharacterizationofFK866Analog:IntermediatesandFinalE-CinnamamideEsterification:Thefollowingprocedurewasadaptedfromasimilarprotocol.3Thionylchloride(3.79g,31.8mmol)wasaddeddropwiseover1minuteto10mLofMeOHat−10°C(brine/icebath).Tothissolutionwasadded4-piperidinebutyricacidhydrochloride(1.99g,9.58mmol)at−10°C.Themixturestirredatroomtemperaturefor20hours.Theobtainedclearsolutionwasconcentratedinvacuo.Theremainingwhitesolidwassuspendedinetherandfiltered.Thecruderesiduewascarriedforwardtobenzoylation(Rf(95:5dichloromethane:methanol)=0.21)withoutfurtherpurification.Benzoylation:ToasuspensionofcruderesiduefromEsterificationin10mLofdichloromethanewasaddedbenzoylchloride(1.48g,10.5mmol)whichwaspreviouslycooledto0⁰Cwithabrine/icebath.Tothismixturewasaddedtriethylamine(2.7mL,19.2mmol)inadropwisefashion.Themixturestirredatroomtemperatureovernight.Theorganiclayerwaswashedwithwaterandsat.NaHCO3solutionanddriedoveranhydroussodiumsulfate.Thesolutionwasconcentratedinvacuoyieldingaredoilasacrudeproduct(Rf(3:2dichloromethane:ethylacetate)=0.68),whichwascarriedforwardwithoutfurtherpurification.EsterReduction:AsuspensionofcrudeesterfromBenzoylationandNaBH4(1.81g,47.9mmol)in1,2-dimethoxyethane(32mL)washeatedto50⁰C.Methanol(7.0mL)wasaddeddropwise.Thereactionwasthenheatedto80⁰Candstirredfor4hours.Uponcompletion,waterwascarefullyaddedtothereactionmixture.Thereactionwasextractedwithethylacetate(30mL,3x).Thecombinedorganiclayerswerewashedwithbrineanddriedoveranhydroussodiumsulfate.Theorganiclayerwasconcentratedinvacuo(Rf(3:2dichloromethane:ethylacetate)=0.21)andcarriedforwardwithoutfurtherpurification.AlcoholtoAzide:Thefollowingprocedurewasadaptedfromasimilarprotocol.4ThecrudereactionmixturefromEsterReductionwasaddedtoa6dramvialandpurgedwithN2viaSchlenktechnique.ThereactionwasdilutedwithdryDMF(32mL),followedbyadditionofDPPA(4.32mL,20.1mmol)andsodiumazide(1.31g,20.1mmol).TotheresultingsolutionwasaddedDBU(3.0mL,20.1mmol)inadropwisefashion.Thereactionwasheatedto90⁰Cfor30minutes.Thereactionwasdilutedwithwater(20mL)anddiethylether(30mL).Theorganiclayerwasextractedandwashedwithwater(20mL,2x).Thecombinedorganicextractswerewashedwithbrine,driedoveranhydroussodiumsulfate,andconcentratedinvacuo.Theresiduewaspurifiedbysilicagelcolumnchromatography(elutedwitha10-30%gradientofethylacetateinhexanessolventsystem)yieldingthe8Iasayellowoil.(4-(4-azidobutyl)piperidin-1-yl)(phenyl)methanone(8I)Yellowoil(1.34g,4.68mmol,49%).Rf(3:2dichloromethane:ethylacetate)=0.76.1HNMR(CDCl3,400MHz)δ7.41–7.36(m,5H),4.77–4.64(m,1H),3.81–3.66(m,1H),3.30–3.24(t,J=7.2Hz,2H),3.04–2.66(m,2H),1.88–1.72(m,1H),1.72–1.46(m,5H),1.46–1.34(m,2H),1.34–1.04(m,5H).13CNMR(CDCl3,100MHz)δ170.3,136.5,129.4,128.4,126.8,51.3,48.0,42.4,36.1,35.9,32.8,31.9,29.0,23.8.HRMS(ESI-TOF)S16

16m/z:[M+H]+CalcdforC+16H23N4O287.1866;Found287.1851.Thedataareinaccordancewiththosereportedintheliterature.[4]AzidetoAmine:Thefollowingprocedurewasadaptedfromasimilarprotocol.4A100mLroundbottomflaskwaschargedwithazide8I(1.34g,4.68mmol)followedbydilutionwithTHF(47mL).Tothestirredsolutionwasaddedtriphenylphosphine(1.23g,4.68mmol)andwater(0.51mL,28.1mmol).Thereactionwasheatedtorefluxfor3hours.Thereactionmixturewasconcentratedinvacuoandpurifiedbysilicagelcolumnchromatography(elutedusinga10%(98:2methanol:NH4OH)inethylacetateisocraticsolventsystem).(4-(4-aminobutyl)piperidin-1-yl)(phenyl)methanone(8II)Lightorangeoil(994mg,3.82mmol,81.6%).Rf(9:1ethylacetate:(98:2methanol:NH14OH))=0.05.HNMR(CD3OD,400MHz)δ7.49–7.42(m,3H),7.41–7.35(m,2H),4.66–4.55(m,1H),3.75–3.64(m,1H),3.28–3.22(t,J=6.7Hz,1H),3.13–3.02(t,J=12.4Hz,1H),2.90–2.77(t,J=12.2Hz,1H),2.72–2.67(t,J=6.8Hz,1H),1.90–1.77(m,2H),1.74–1.46(m,5H),1.45–1.27(m,5H),1.27–1.01(m,3H).13CNMR(CD3OD,100MHz)δ170.9,135.9,129.5,128.3,126.3,54.6,51.9,43.7,42.2,37.3,37.3,37.2,37.2,33.9,33.1,31.6,25.6,24.4.HRMS(ESI-TOF)m/z:[M+H]+CalcdforC+16H25N2O261.1961;Found261.1958.Thedataareinaccordancewiththosereportedintheliterature.[4]Propiolamidesynthesis:N-(4-(1-benzoylpiperidin-4-yl)butyl)-3-phenylpropiolamide(8)PreparedaccordingtoProcedure3.3.Lightorangeoil(209mg,0.539mmol,67%).Rf(3:2dichloromethane:ethylacetate)=0.45.1HNMR(CD3OD,400MHz)δ7.61–7.54(m,2H),7.50–7.33(m,8H),4.66–4.56(m,1H),3.74–3.65(m,1H),3.29–3.24(t,J=6.6Hz,2H),3.14–3.01(t,J=12.7Hz,1H),2.90–2.77(t,J=12.5Hz,1H),1.92–1.79(m,1H),1.75–1.65(m,1H),1.65–1.51(m,3H),1.48–1.28(m,5H),1.28–1.04(m,3H).13CNMR(CD3OD,126MHz)δ172.4,155.7,137.4,*133.5,133.5,*131.7,131.3,130.9,130.0,129.8,129.7,127.7,121.6,85.7,83.8,57.5,43.7,40.7,37.1,37.0,33.9,33.1,30.3,25.0.HRMS(ESI-TOF)m/z:[M+H]+CalcdforC+25H29N2O2389.2224;Found389.2221.S17

17(E)-N-(4-(1-benzoylpiperidin-4-yl)butyl)cinnamamide(9)PreparedaccordingtoProcedure5.1.Lightorangeoil(159mg,0.409mmol,76%,>99:1E:Z).Rf(3:2dichloromethane:ethylacetate)=0.42.1HNMR(CDCl3,400MHz)δ7.64–7.59(d,J=15.8Hz,1H),7.51–7.46(m,2H),7.41–7.31(m,8H),6.40–6.35(d,J=15.3Hz,1H),5.73–5.66(t,J=5.3Hz,1H),4.76–4.63(m,1H),3.79–3.65(m,1H),3.42–3.34(q,J=7.1Hz,2H),3.03–2.65(m,2H),1.87–1.70(m,1H),1.70–1.44(m,6H),1.44–1.25(m,5H),1.25–1.01(m,3H).13CNMR(CDCl3,126MHz)δ.170.4,166.0,141.1,136.6,135.0,129.8,129.6,129.0,128.6,127.9,127.0,120.8,48.2,42.6,39.8,36.2,36.2,33.0,32.1,30.1,25.0,24.1.HRMS(ESI-TOF)m/z:[M+H]+CalcdforC+25H31N2O2391.2380;Found391.2370.S18

188.Deuteriumlabelingstudy:Aflame-dried5mLroundbottomflaskwaschargedwithdrypropiolamide(93mg,0.58mmol)andpurgedwithN2viaSchlenktechnique.Thesolidalkynamidewasthenheatedto100⁰Cwhilepurgingtheroundbottomflaskwithargonfor1hour.ThereactionwasdilutedwithTHF(2.7mL,0.2M)andthencooledto0⁰Cwithaice/brinebath.Aftercoolingthereactionfor15minutes,NaH(17mg,0.64mmol,90wt%)wasaddeddropwise.Thereactionwasstirredfor30minutesat0⁰C.dOCd3(1.0mL,26.9mmol)wasaddeddropwise.Thereactionwasstirredat0⁰Cfor30minutesbeforewarmingtoroomtemperaturebyremovingtheice/brinebath.ThereactionwasconcentratedinvacuoanddriedonhighvacuumovernighttoremoveresidualdOCd13.TheHNMRofthedeuteratedamiderevealed>99%d-incorporationoftheamide.TheresultingwhitesolidwasdilutedwithTHF(1.2mL,0.5M).FreshlydriedKOtBu(6.6mg,0.058mmol)wasaddedtothereactionmixture.Pinacolborane(93µL,0.64mmol)wasslowlyaddedtothereactiondropwise(1dropever3-4seconds).Thereactionwasstirredfor10minutesatroomtemperature.Thereactionmixturewasconcentratedinvacuoandthecrudereactionsubjectedto1HNMRanalysis.Aprotonsignalwasvisibleat6.4ppm,whichrepresentstheprotonsignalontheα-carbonof2a,buttheprotonsignalat7.6ppm,whichrepresentstheprotonontheβ-carbonof2a,wasnotpresent.Thereactionwaspurifiedbysilicagelcolumnchromatography(elutedwitha20-30%gradientofethylacetateindichloromethane)yieldingawhitesolid.Thepurifiedreactionmixturecontainedca.1:12a:11.(E)-N-methylcinnamamide-3-d(11)Preparedasdescribedabove.Whitesolid(25mg,0.192mmol,~40%,>99:1E:Z).R1f(3:2CH2Cl2/EtOAc)=0.39.HNMR(CDCl3,400MHz)δ7.50–7.45(m,2H),7.36–7.30(m,3H),6.42(t,J=2.2Hz,1H),6.03(brs,1H),2.94(d,J=5.0Hz,3H).13CNMR(CDCl3,100MHz)δ166.9,140.8,134.9,129.7,129.9,127.8,120.8,120.7,26.6.HRMS(ESI-TOF)m/z:[M+H]+CalcdforC+10H11DNO163.0976;Found163.0975.9.CharacterizationofE-β-borylacrylamide(12)1HNMR(CDCl3,400MHz)δ10.34-10.29(m,1H),7.50-7.45(m,2H),7.31-7.23(m,3H),6.32(s,1H),2.62(d,J=4.8Hz,3H),1.28(s,12H).13CNMR(CDCl3,100MHz)δ174.3,137.8,129.0,128.3,127.9,120.5,80.8,27.1,26.4.11BNMR(CDCl3,128MHz)δ13.1.HRMS(ESI-TOF)m/z:[M+H]+CalcdforC+16H23BNO3288.1766;Found288.1779.Thedataareinaccordancewithpreviousliterature.5S19

1910.ProceduresforControlreactionswithBH3(Scheme7Cinthemanuscript)ReactionA:Anoven-orflame-dried5mLroundbottomflaskwaschargedwithdrypropiolamide(39mg,0.24mmol)andplacedunderN2viaSchlenktechnique.ThereactionwasdilutedwithTHF(0.2mL,1Malkynamide)andstirredatroomtemperature.KOtBu(0.024mmol)wasaddedasasolidtotheroundbottomflask.Borane(0.27mL,0.27mmol,1MinTHF)wasthenslowlyaddeddropwise(1dropevery3-4seconds).Thereactionwasstirredatroomtemperaturefor10minutes.Thereactionmixturewasconcentratedinvacuoandtheresultingcruderesiduewaspurifiedbysilicagelcolumnchromatography(elutedwitha30-40%gradientethylacetateindichloromethane)toaffordtheproductasawhitesolid(4.2mg,0.26mmol,77:23E:Z).Whereapplicable,theE-isomerislabeledasmajorwhentheZ-isomerispresent,whichislabeledasminor.ReactionB:Anoven-orflame-dried5mLroundbottomflaskwaschargedwithdrypropiolamide(33mg,0.21mmol)andplacedunderN2viaSchlenktechnique.ThereactionwasdilutedwithTHF(0.42mL,0.5Malkynamide)andstirredatroomtemperature.KOtBu(0.021mmol)wasaddedasasolidtotheroundbottomflask.Inaseparateflame-dried2dramvial,borane(0.021mL,0.021mmol,1MinTHF)wasmixedwithpinacolborane(0.033mL,0.23mmol)andthenslowlyaddeddropwise(1dropevery3-4seconds).Thereactionwasstirredatroomtemperaturefor10minutes.Thereactionmixturewasconcentratedinvacuoandtheresultingcruderesiduewaspurifiedbysilicagelcolumnchromatography(elutedwitha30-40%gradientethylacetateindichloromethane)toaffordtheproductasawhitesolid(29mg,0.18mmol,>99:1E:Z).Whereapplicable,theE-isomerislabeledasmajorwhentheZ-isomerispresent,whichislabeledasminor.S20

2011.NMRSpectraofPropiolamides1HNMR(CDCl3400MHz)of1d13CNMR(CDCl3100MHz)of1dS21

211HNMR(Acetone-d6500MHz)of1l19FNMR(Acetone-d6376MHz)of1lS22

2213CNMR(Acetone-d6100MHz)of1l1HNMR(CD3OD400MHz)of1pS23

2313CNMR(Acetone-d6100MHz)of1p1HNMR(CDCl3400MHz)of3cS24

2413CNMR(CDCl3100MHz)of3c1HNMR(CDCl3400MHz)of3fS25

2513CNMR(CDCl3100MHz)of3f1HNMR(Acetone-d6400MHz)of5dS26

2619FNMR(Acetone-d6376MHz)of5d13CNMR(Acetone-d6100MHz)of5dS27

271HNMR(Acetone-d6400MHz)of5e13CNMR(Acetone-d6126MHz)of5eS28

281HNMR(CD3OD400MHz)of5g13CNMR(CD3OD100MHz)of5gS29

291HNMR(CD3OD400MHz)of5h13CNMR(CD3OD100MHz)of5hS30

301HNMR(CDCl3400MHz)of5i13CNMR(CDCl3100MHz)of5iS31

3112.NMRSpectraof(E)-Cinnamamides1HNMR(CDCl3400MHz)of2a13CNMR(CDCl3100MHz)of2aS32

321HNMR(CDCl3400MHz)of2b13CNMR(CDCl3100MHz)of2bS33

331HNMR(CDCl3400MHz)of2c13CNMR(CDCl3100MHz)of2cS34

341HNMR(CDCl3400MHz)of2d13CNMR(CDCl3100MHz)of2dS35

351HNMR(CDCl3400MHz)of2e13CNMR(CDCl3,100MHz)of2eS36

361HNMR(CDCl3400MHz)of2f13CNMR(CDCl3100MHz)of2fS37

371HNMR(CDCl3400MHz)of2g13CNMR(CDCl3100MHz)of2gS38

381HNMR(CDCl3400MHz)of2h13CNMR(CDCl3,100MHz)of2hS39

391HNMR(CDCl3400MHz)of2i13CNMR(CDCl3100MHz)of2iS40

401HNMR(CDCl3400MHz)of2j13CNMR(CDCl3126MHz)of2jS41

411HNMR(CDCl3400MHz)of2k13CNMR(CDCl3,100MHz)of2kS42

421HNMR(Acetone-d6400MHz)of2l19FNMR(Acetone-d6376MHz)of2lS43

4313CNMR(Acetone-d6100MHz)of2l1HNMR(CDCl3,400MHz)of2mS44

4419FNMR(CDCl3376MHz)of2m13CNMR(CDCl3100MHz)of2mS45

451HNMR(CD3OD400MHz)of2n13CNMR(CD3OD100MHz)of2nS46

461HNMR(CDCl3400MHz)of2o13CNMR(CDCl3100MHz)of2oS47

471HNMR(CD3OD400MHz)of2p13CNMR(CD3OD100MHz)of2pS48

481HNMR(CDCl3400MHz)of4a13CNMR(CDCl3100MHz)of4aS49

491HNMR(CDCl3400MHz)of4b13CNMR(CDCl3100MHz)of4bS50

501HNMR(CDCl3400MHz)of4c13CNMR(CDCl3100MHz)of4cS51

511HNMR(CDCl3400MHz)of4d13CNMR(CDCl3100MHz)of4dS52

521HNMR(CDCl3400MHz)of4e13CNMR(CDCl3100MHz)of4eS53

531HNMR(CDCl3,400MHz)of4f13CNMR(CDCl3,100MHz)of4fS54

541HNMR(CDCl3400MHz)of6a13CNMR(CDCl3100MHz)of6aS55

551HNMR(CD3OD400MHz)of6b13CNMR(CD3OD100MHz)of6bS56

561HNMR(CD3OD400MHz)of6c19FNMR(CD3OD376MHz)of6cS57

5713CNMR(CD3OD100MHz)of6c1HNMR(Acetone-d6400MHz)of6dS58

5819FNMR(Acetone-d6376MHz)of6d13CNMR(Acetone-d6100MHz)of6dS59

591HNMR(CD3OD400MHz)of6e13CNMR(CD3OD126MHz)of6eS60

601HNMR(CD3OD400MHz)of6f13CNMR(CD3OD100MHz)of6fS61

611HNMR(CD3OD400MHz)of6g13CNMR(CD3OD100MHz)of6gS62

621HNMR(CD3OD400MHz)of6h13CNMR(CD3OD100MHz)of6hS63

631HNMR(CD3OD400MHz)of6i13CNMR(CD3OD100MHz)of6iS64

6413.NMRSpectraofFK866Analog:IntermediatesandFinalE-Cinnamamide1HNMR(CDCl3400MHz)of8I13CNMR(CDCl3100MHz)of8IS65

651HNMR(CD3OD400MHz)of8II13CNMR(CD3OD100MHz)of8IIS66

661HNMR(CD3OD400MHz)of813CNMR(CD3OD100MHz)of8S67

671HNMR(CDCl3400MHz)of913CNMR(CDCl3126MHz)of9S68

6814.NMRSpectraof111HNMR(CDCl3400MHz)ofN-deuterated1a1HNMR(CDCl3400MHz)ofcrudereactionmixtureS69

691HNMR(CDCl3400MHz)of1113CNMR(CDCl3100MHz)of11S70

7015.NMRSpectraof121HNMR(CDCl3400MHz)of1213CNMR(CDCl3100MHz)of12S71

7116.References:1.K.Park,J.-M.You,S.Jeon,S.Lee,Eur.J.Org.Chem.2013,1973-1978.2.T.Rankin,R.R.Tykwinski,Org.Lett.2003,5,213-216.3.J.Alfaro-Lopez,T.Okayama,K.Hosohata,P.Davis,F.Porreca,H.I.Yamamura,V.J.HrubyJ.Med.Chem.1999,42,5359-5368.4.U.Galli,E.Ercolano,L.Carraro,C.R.B.Roman,G.Sorba,P.L.Canonico,A.A.Genazzani,G.C.Tron,R.A.BillingtonChemMedChem2008,3,771-779.5.R.JustinGrams,RussellG.Fritzemeier,CarlaD.Slebodnick,WebsterL.SantosOrg.Lett.2019,21,6795-6799.S72