Ni-Catalyzed C-H Functionalization in the Formation of a Complex Heterocycle: Synthesis of the Potent JAK2 Inhibitor BMS-911543

Article abstract of DOI:10.1021/acs.joc.5b00572

BMS-911543 is a complex pyrrolopyridine investigated as a potential treatment for myeloproliferative disorders. The development of a short and efficient synthesis of this molecule is described. During the course of our studies, a Ni-mediated C-N bond formation was invented, which enabled the rapid construction of the highly substituted 2-aminopyridine core. The synthesis of this complex, nitrogen-rich heterocycle was accomplished in only eight steps starting from readily available materials.

Full text of DOI:10.1021/acs.joc.5b00572

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Featured Article
Ni-Catalyzed C-H Functionalization in the Formation of a Complex
Heterocycle, the Synthesis of the Potent JAK2 Inhibitor, BMS-911543
Monica A. Fitzgerald, Omid Soltani, Carolyn Wei, Dimitri Skliar, Bin Zheng, Jun Li, Jacob Albrecht,
Michael Schmidt, Michelle Mahoney, Richard J. Fox, Kristy Tran, Keming Zhu, and Martin D. Eastgate
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.5b00572 • Publication Date (Web): 07 Apr 2015
Downloaded from http://pubs.acs.org on April 9, 2015
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Ni-CatalyzedꢀC-HꢀFunctionalizationꢀinꢀtheꢀFormationꢀofꢀaꢀComplexꢀHeterocycle,ꢀtheꢀ
SynthesisꢀofꢀtheꢀPotentꢀJAK2ꢀInhibitor,ꢀBMS-911543ꢀ
ꢀ
MonicaꢀAꢀFitzgerald,ꢀOmidꢀSoltani,ꢀCarolynꢀWei,ꢀDimitriꢀSkliar,ꢀBinꢀZheng,ꢀJunꢀLi,ꢀJacobꢀAlbrecht,ꢀ
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MichaelꢀSchmidt,ꢀMichelleꢀMahoney,ꢀRichardꢀJ.ꢀFox,ꢀKristyꢀTran,ꢀKemingꢀZhuꢀandꢀMartinꢀD.ꢀEastgate*ꢀꢀ
ChemicalꢀDevelopment,ꢀBristol-MyersꢀSquibb,ꢀOneꢀSquibbꢀDrive,ꢀNewꢀBrunswick,ꢀNJꢀ08903,ꢀUnitedꢀ
Statesꢀ
martin.eastgate@bms.comꢀꢀ
Abstract:ꢀ
BMS-911543ꢀisꢀaꢀcomplexꢀpyrrolopyridineꢀinvestigatedꢀasꢀaꢀpotentialꢀtreatmentꢀforꢀmyeloproliferativeꢀdisorders.ꢀ
Theꢀ developmentꢀ ofꢀ aꢀ shortꢀ andꢀ efficientꢀ synthesisꢀ ofꢀ thisꢀ moleculeꢀ isꢀ described.ꢀ Duringꢀ theꢀ courseꢀ ofꢀ ourꢀ
studies,ꢀaꢀNi-mediatedꢀC-Nꢀbondꢀformationꢀwasꢀinvented,ꢀwhichꢀenabledꢀtheꢀrapidꢀconstructionꢀofꢀtheꢀhighlyꢀ
substitutedꢀ2-aminopyridineꢀcore.ꢀTheꢀsynthesisꢀofꢀthisꢀcomplex,ꢀnitrogenꢀrichꢀheterocycleꢀwasꢀaccomplishedꢀinꢀ
onlyꢀ8ꢀstepsꢀstartingꢀfromꢀreadilyꢀavailableꢀmaterials.ꢀ
Introduction:ꢀ
Myeloproliferativeꢀdisordersꢀ(MPDs)ꢀ[orꢀmyeloproliferativeꢀneoplasmsꢀ(MPNs)]ꢀareꢀaꢀgroupꢀofꢀdiseasesꢀofꢀtheꢀ
boneꢀmarrowꢀinꢀwhichꢀmyleosites,ꢀorꢀyoungꢀbloodꢀcells,ꢀgrowꢀabnormallyꢀproducingꢀexcessiveꢀconcentrationsꢀofꢀ
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matureꢀcellsꢀ(i.e.,ꢀredꢀbloodꢀcells,ꢀwhiteꢀbloodꢀcellsꢀorꢀplatelets). ꢀTheseꢀhematologicalꢀneoplasmsꢀareꢀclassifiedꢀ
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intoꢀ fourꢀ mainꢀ diseases,ꢀ chronicꢀ myelogenousꢀ leukemia, ꢀ essentialꢀ thrombocytopenia, ꢀ polythemiaꢀ vera ꢀ andꢀ
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myelofibrosis. ꢀInꢀ2005,ꢀaꢀstrongꢀcorrelationꢀbetweenꢀtheseꢀdiseasesꢀandꢀaꢀmutationꢀofꢀtheꢀ617ꢀcodonꢀofꢀtheꢀ
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JAK2ꢀkinaseꢀwasꢀdescribed,ꢀprovidingꢀevidenceꢀofꢀaꢀcommonalityꢀacrossꢀaꢀsubsetꢀofꢀpatients. ꢀApproachesꢀtoꢀtheꢀ
treatmentꢀofꢀMPDsꢀhaveꢀfocusedꢀonꢀtheꢀdevelopmentꢀofꢀsmallꢀmoleculesꢀthatꢀselectivelyꢀinhibitꢀthisꢀmutatedꢀ
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pathway, ꢀ withꢀ theꢀ firstꢀ compoundꢀ inꢀ thisꢀ class,ꢀ ruxolitinib ꢀ (Jakafi™),ꢀ gainingꢀ FDAꢀ approvalꢀ inꢀ 2011. ꢀ BMS-
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11543 ꢀ1ꢀ(Figureꢀ1)ꢀwasꢀrecentlyꢀidentifiedꢀasꢀaꢀpotentꢀandꢀselectiveꢀinhibitor,ꢀshowingꢀexcellentꢀspecificityꢀ
withꢀrespectꢀtoꢀotherꢀmembersꢀofꢀtheꢀJAK-familyꢀofꢀkinases,ꢀtheꢀpotentialꢀforꢀimprovedꢀefficacyꢀandꢀreducedꢀoff-
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targetꢀliabilitiesꢀversusꢀotherꢀMPDꢀtreatmentꢀoptions. ꢀꢀꢀꢀꢀ
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Figureꢀ1:ꢀBMS-911543ꢀ
ꢀ
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TheꢀinitialꢀsynthesisꢀofꢀBMS-911543ꢀ(1)ꢀreliedꢀonꢀaꢀretrosyntheticꢀstrategyꢀdisconnectingꢀtheꢀmoleculeꢀtoꢀ2,6-
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dichloropyridineꢀ (Figureꢀ 2). ꢀ Whileꢀ thisꢀ synthesisꢀ wasꢀ optimalꢀ forꢀ supportingꢀ initialꢀ targetꢀ identification,ꢀ 19ꢀ
linearꢀ stepsꢀ wereꢀ requiredꢀ toꢀ prepareꢀ theꢀ selectedꢀ compound.ꢀ Theꢀ highꢀ stepꢀ countꢀ wasꢀ dueꢀ toꢀ stepwiseꢀ
functionalizationꢀ ofꢀ theꢀ pyridineꢀ ringꢀ system.ꢀ Multipleꢀ functionalꢀ groupꢀ manipulationsꢀ wereꢀ utilizedꢀ toꢀ
regioselectivelyꢀ functionalizeꢀ theꢀ 2,6-dichloropyridineꢀ andꢀ installꢀ theꢀ requiredꢀ functionalityꢀ onꢀ theꢀ pyridineꢀ
nucleus,ꢀ especiallyꢀ withꢀ respectꢀ toꢀ theꢀ requiredꢀ nitrogenꢀ substitutionꢀ pattern.ꢀ Indeed,ꢀ functionalizingꢀ theꢀ
peripheryꢀ ofꢀ pyridineꢀ isꢀ aꢀ long-standingꢀ problem,ꢀ andꢀ theꢀ synthesisꢀ ofꢀ penta-substitutedꢀ pyridinesꢀ areꢀ
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particularlyꢀchallenging. ꢀꢀꢀ
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Figureꢀ2:ꢀOriginalꢀdisconnectionꢀstrategyꢀtoꢀprepareꢀBMS-911543. ꢀ
ꢀ
Whenꢀ devisingꢀ aꢀ newꢀ syntheticꢀ strategyꢀ forꢀ theꢀ synthesisꢀ forꢀ BMS-911543ꢀ (1),ꢀ andꢀ inꢀ contrastꢀ toꢀ theꢀ priorꢀ
approach,ꢀweꢀsurmisedꢀthatꢀaꢀdisconnectionꢀthroughꢀtheꢀcentralꢀringꢀofꢀtheꢀmolecule,ꢀviaꢀoneꢀofꢀthreeꢀpotentialꢀ
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bonds,ꢀ wouldꢀ allowꢀ usꢀ toꢀ startꢀ fromꢀ simplerꢀ heterocyclesꢀ andꢀ deliverꢀ aꢀ moreꢀ convergentꢀ synthesisꢀ ofꢀ thisꢀ
complexꢀstructureꢀ(Figureꢀ3).ꢀRetrosynthetically,ꢀweꢀenvisionedꢀthatꢀtheꢀdicyclopropylamineꢀ(DCPA)ꢀandꢀpyrazoleꢀ
moietiesꢀcouldꢀbeꢀinstalledꢀatꢀtheꢀendꢀofꢀtheꢀsynthesis,ꢀthroughꢀstandardꢀamidationꢀandꢀC−Nꢀbondꢀcouplingꢀ
reactionsꢀ(Figureꢀ3).ꢀNext,ꢀweꢀsoughtꢀtoꢀseparateꢀtheꢀtwoꢀexternalꢀheterocyclesꢀ(i.e.,ꢀaꢀpyrroleꢀandꢀanꢀimidazole),ꢀ
buildingꢀtheꢀcentralꢀpyridineꢀthroughꢀtheꢀunionꢀofꢀtheꢀsmallerꢀsystems.ꢀItꢀwasꢀhopedꢀthatꢀtheꢀconstructionꢀofꢀtheꢀ
pyridineꢀ inꢀ thisꢀ mannerꢀ wouldꢀ obviateꢀ manyꢀ ofꢀ theꢀ challengesꢀ presentꢀ inꢀ theꢀ originalꢀ synthesis,ꢀ minimizeꢀ
functionalꢀ groupꢀ interconversions,ꢀ andꢀ resultꢀ inꢀ aꢀ simplerꢀ andꢀ moreꢀ efficientꢀ approachꢀ toꢀ ourꢀ desiredꢀ
heterocycleꢀ1.ꢀOutꢀofꢀtheꢀthreeꢀpotentialꢀ‘ring-forming’ꢀbondsꢀformationsꢀwithinꢀthisꢀstrategy,ꢀweꢀfocusedꢀonꢀ
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disconnectingꢀ theꢀ 1,2-C-Nꢀ bondꢀ viaꢀ aꢀ proposedꢀ 6π-cyclization ꢀ ofꢀ amidineꢀ 2.ꢀ Theꢀ synthesisꢀ ofꢀ thisꢀ keyꢀ
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intermediateꢀ wouldꢀ comeꢀ fromꢀ couplingꢀ aꢀ C5-activatedꢀ cyanoimidazoleꢀ 3ꢀ withꢀ theꢀ knownꢀ bromopyrroleꢀ 4. ꢀ
Despiteꢀtheꢀlackꢀofꢀsolidꢀprecedentꢀforꢀamidineꢀelectrocyclizationsꢀofꢀthisꢀtype,ꢀweꢀfeltꢀthatꢀtheꢀeaseꢀofꢀmanyꢀ
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electrocyclizations, ꢀ coupledꢀ withꢀ theꢀ potentialꢀ forꢀ multipleꢀ conditionsꢀ toꢀ mediateꢀ thisꢀ keyꢀ cyclization,ꢀ
supportedꢀ theꢀ explorationꢀ ofꢀ thisꢀ strategy.ꢀ Hereinꢀ weꢀ describeꢀ theꢀ realizationꢀ ofꢀ thisꢀ approachꢀ andꢀ theꢀ
developmentꢀofꢀaꢀNi-mediatedꢀcyclization,ꢀwhichꢀenabledꢀtheꢀefficientꢀconstructionꢀofꢀthisꢀhighlyꢀfunctionalizedꢀ
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pyrrolopyridineꢀinꢀjustꢀ8ꢀstepsꢀandꢀ29%ꢀoverallꢀyield. ꢀꢀꢀꢀ
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Figureꢀ3.ꢀDisconnectionꢀstrategyꢀandꢀkeyꢀtransformationsꢀforꢀtheꢀproposedꢀsynthesisꢀofꢀBMS-911543,ꢀ1ꢀ
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ꢀ
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ResultsꢀandꢀDiscussionꢀ
Inꢀorderꢀtoꢀevaluateꢀtheꢀproposedꢀ6π-electrocyclization,ꢀitꢀwasꢀnecessaryꢀtoꢀsynthesizeꢀtheꢀpyrrole-imidazoleꢀ7ꢀ
Schemeꢀ1).ꢀWeꢀproposedꢀtoꢀaccomplishꢀthisꢀviaꢀaꢀSuzukiꢀcoupling,ꢀstartingꢀfromꢀtheꢀC4-borylatedꢀpyrroleꢀ4.ꢀ
(
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Preparationꢀofꢀtheꢀknownꢀ4-bromopyrroleꢀ4ꢀwasꢀaccomplishedꢀinꢀ2ꢀstepsꢀfromꢀtrichloroacetylpyrrole, ꢀwhichꢀ
wasꢀ followedꢀ byꢀ N-ethylationꢀ toꢀ giveꢀ theꢀ N-ethylpyrroleꢀ 5ꢀ (Schemeꢀ 1).ꢀ Theꢀ borylationꢀ ofꢀ electron-richꢀ
heteroaromaticꢀcompoundsꢀcanꢀbeꢀdifficult,ꢀdueꢀtoꢀtheꢀgeneralꢀlackꢀofꢀstabilityꢀofꢀtheꢀresultingꢀelectron-richꢀ
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boronates; ꢀ indeed,ꢀ theꢀ formationꢀ ofꢀ pyrroleꢀ 6ꢀ provedꢀ challenging.ꢀ Initialꢀ screeningꢀ resultsꢀ indicatedꢀ thatꢀ aꢀ
combinationꢀ ofꢀ KOAc/Pd(OAc)
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Pꢀ inꢀ tolueneꢀ wasꢀ capableꢀ ofꢀ givingꢀ highꢀ yieldsꢀ ofꢀ theꢀ desiredꢀ boronateꢀ 6ꢀ
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(>95%ꢀ conversionꢀ withꢀ ~99:1ꢀ selectivityꢀ forꢀ Miyauraꢀ borylationꢀ overꢀ proto-dehalogenation).ꢀ However,ꢀ theseꢀ
conditionsꢀ provedꢀ toꢀ beꢀ extremelyꢀ capriciousꢀ inꢀ aꢀ laboratoryꢀ setting,ꢀ withꢀ significantꢀ amountsꢀ ofꢀ theꢀ proto-
dehalogenatedꢀpyrroleꢀ8ꢀbeingꢀproducedꢀasꢀtheꢀscaleꢀofꢀtheꢀreactionꢀincreasedꢀ(upꢀtoꢀ50%ꢀproto-dehalogenationꢀ
couldꢀbeꢀobservedꢀonꢀgramꢀscale).ꢀDuringꢀourꢀdevelopmentꢀofꢀthisꢀpalladium-mediatedꢀborylation,ꢀseveralꢀkeyꢀ
observationsꢀwereꢀmadeꢀthatꢀprovedꢀtoꢀbeꢀimportantꢀforꢀachievingꢀhighꢀyieldsꢀandꢀreproducibility;ꢀa)ꢀaꢀsolubleꢀ
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base,ꢀsuchꢀasꢀNMe OAc,ꢀwasꢀcritical.ꢀTheꢀuseꢀofꢀinsolubleꢀbasesꢀ(suchꢀasꢀKOAcꢀinꢀtoluene)ꢀcanꢀresultꢀinꢀbaseꢀ
starvationꢀandꢀsignificantlyꢀimpactꢀbothꢀcatalystꢀturnoverꢀandꢀstability;ꢀb)ꢀtheꢀformationꢀofꢀunligatedꢀpalladiumꢀ
duringꢀcatalystꢀactivationꢀ(andꢀassociatedꢀformationꢀofꢀPd-black)ꢀwasꢀtheꢀmainꢀsourceꢀofꢀproto-debromination;ꢀ
ensuringꢀcontrolledꢀreductionꢀofꢀtheꢀmetalꢀcenterꢀtoꢀaꢀligatedꢀspeciesꢀwasꢀcriticalꢀtoꢀmaintainꢀhighꢀselectivityꢀforꢀ
borylationꢀoverꢀreductiveꢀdehalogenation;ꢀc)ꢀtheꢀreductionꢀofꢀPd(OAc)
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ꢀwasꢀsmoothlyꢀmediatedꢀ(eitherꢀpre-ꢀorꢀ
post-phosphineꢀligation)ꢀbyꢀB Pin .ꢀThisꢀfindingꢀrepresentsꢀanꢀalternateꢀmodeꢀofꢀpalladiumꢀreductionꢀwhich,ꢀinꢀ
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contrastꢀtoꢀtheꢀbase/waterꢀmediatedꢀpathway, ꢀdoesꢀnotꢀresultꢀinꢀphosphineꢀoxidation.ꢀBasedꢀonꢀthisꢀfinding,ꢀ
weꢀdiscoveredꢀthatꢀtheꢀorderꢀofꢀreagentꢀadditionꢀcouldꢀimpactꢀtheꢀidentityꢀ(andꢀthereforeꢀactivityꢀandꢀstability)ꢀ
ofꢀtheꢀcatalystꢀcomplex.ꢀInꢀtheꢀabsenceꢀofꢀaꢀreducingꢀagent,ꢀsuchꢀasꢀB
fromꢀ Pd(OAc) /PCy ꢀ couldꢀ beꢀ reducedꢀ byꢀ theꢀ ligatedꢀ PCy ꢀ toꢀ formꢀ anꢀ unstable,ꢀ mono-ligatedꢀ [(PCy
complexꢀ andꢀ theꢀ correspondingꢀ phosphineꢀ oxide.ꢀ Inꢀ contrast,ꢀ additionꢀ ofꢀ theꢀ ligatedꢀ palladiumꢀ complexꢀ
(PCy Pd(OAc) ]ꢀ ꢀ toꢀ aꢀ solutionꢀ containingꢀ B Pin ꢀ resultedꢀ inꢀ formationꢀ ofꢀ aꢀ stable,ꢀ thoughꢀ lessꢀ activeꢀ Pd(0)ꢀ
complex,ꢀPd(PCy .ꢀThus,ꢀwithoutꢀanyꢀchangeꢀinꢀstoichiometry,ꢀtwoꢀdistinctꢀcatalystsꢀcouldꢀbeꢀformed;ꢀd)ꢀitꢀwasꢀ
alsoꢀ demonstratedꢀ thatꢀ theꢀ mono-ligatedꢀ palladiumꢀ tricyclohexylphosphineꢀ wasꢀ unstableꢀ inꢀ solutionꢀ inꢀ theꢀ
absenceꢀofꢀAr-Br,ꢀdisproportionatingꢀtoꢀL PdꢀandꢀPd-black,ꢀtheꢀroute-causeꢀofꢀproto-dehalogenationꢀ(Schemeꢀ2).ꢀ
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Thus,ꢀensuringꢀfullꢀPd-ligationꢀpriorꢀtoꢀreduction,ꢀwithꢀreductionꢀoccurringꢀinꢀtheꢀpresenceꢀofꢀtheꢀarylꢀbromide,ꢀ
wereꢀ bothꢀ criticalꢀ factorsꢀ forꢀ reproduciblyꢀ conductingꢀ thisꢀ borylation.ꢀ Ourꢀ workꢀ elucidatingꢀ theseꢀ factors,ꢀ
establishingꢀtheꢀsourceꢀofꢀpalladiumꢀreduction,ꢀandꢀitsꢀcorrespondingꢀimpactꢀonꢀcatalystꢀstructureꢀwasꢀrecentlyꢀ
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Withꢀtheꢀborylatedꢀpyrroleꢀ6ꢀinꢀhand,ꢀaꢀSuzukiꢀcouplingꢀwasꢀenvisionedꢀtoꢀjoinꢀtheꢀkeyꢀheterocycles.ꢀHowever,ꢀ
theꢀcyanoimidazoleꢀcouplingꢀpartnerꢀ3ꢀprovedꢀdifficultꢀtoꢀobtain.ꢀTheꢀreportedꢀregioselectiveꢀsynthesisꢀofꢀthisꢀ
smallꢀ moleculeꢀ requiredꢀ anꢀ extraordinaryꢀ numberꢀ ofꢀ steps,ꢀ proceedingꢀ viaꢀ 2ꢀ stepsꢀ fromꢀ theꢀ correspondingꢀ
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carboxylicꢀ acid, ꢀ itselfꢀ preparedꢀ inꢀ 4ꢀ stepsꢀ fromꢀ maleonitrile. ꢀ Thus,ꢀ weꢀ choseꢀ toꢀ developꢀ anꢀ alternateꢀ
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approach,ꢀexploringꢀaꢀconjugateꢀbisaminomethylenation/cyclizationꢀbasedꢀstrategy,ꢀoriginallyꢀreportedꢀbyꢀBiereꢀ
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etꢀalꢀ(Schemeꢀ3). ꢀAfterꢀsignificantꢀoptimization,ꢀanꢀefficientꢀtwoꢀstepꢀprotocolꢀinvolvingꢀcondensationꢀofꢀaminoꢀ
acetonitrileꢀ 9ꢀ withꢀ DMF·DMAꢀ toꢀ giveꢀ azadieneꢀ 10,ꢀ followedꢀ byꢀ anꢀ N-methylꢀ anilineꢀ catalyzedꢀ additionꢀ ofꢀ
methylamine,ꢀpreparedꢀimidazoleꢀ11ꢀinꢀgoodꢀoverallꢀyieldꢀandꢀexcellentꢀpurity.ꢀThisꢀapproachꢀwasꢀfoundꢀtoꢀbeꢀ
generalꢀforꢀpreparingꢀ1,4-N-substitutedꢀimidazoles,ꢀprovidingꢀcompleteꢀregiochemicalꢀcontrolꢀinꢀtheꢀformationꢀ
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ofꢀaꢀwideꢀrangeꢀofꢀ1N-substituted-4-carboxyꢀimidazoles. ꢀFinally,ꢀregioselectiveꢀbrominationꢀwasꢀaccomplishedꢀ
usingꢀN-bromosuccinimideꢀ(NBS)ꢀinꢀDMF,ꢀproducingꢀtheꢀC5ꢀregioisomerꢀ3ꢀwithꢀ>90:10ꢀ(C5:C2)ꢀselectivity.ꢀC5-
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Bromoimidazoleꢀ3ꢀcouldꢀbeꢀisolatedꢀasꢀaꢀsingleꢀisomerꢀbyꢀdirectꢀcrystallization. ꢀWithꢀbothꢀcouplingꢀpartnersꢀinꢀ
hand,ꢀtheꢀSuzukiꢀcouplingꢀofꢀboronicꢀesterꢀ6ꢀwithꢀC5-bromoimidazoleꢀ3ꢀproceededꢀunderꢀstandardꢀconditionsꢀ
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2 3
usingꢀPd(OAc) /PPh ,ꢀdeliveringꢀtheꢀbiarylꢀcompoundꢀ7ꢀwithoutꢀissueꢀ(Schemeꢀ1). ꢀ
Schemeꢀ1:ꢀSynthesisꢀofꢀNitrileꢀ7.ꢀ
ꢀ
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Schemeꢀ2:ꢀControlledꢀPalladiumꢀReduction. ꢀ
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Schemeꢀ3:ꢀImidazoleꢀSynthesis. ꢀ
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ꢀ
Inꢀorderꢀtoꢀtestꢀourꢀproposedꢀ6π-electrocyclization,ꢀweꢀrequiredꢀtheꢀconversionꢀofꢀtheꢀnitrileꢀinꢀpyrroleꢀ7ꢀtoꢀtheꢀ
correspondingꢀ amidineꢀ 13ꢀ (Schemeꢀ 4).ꢀ However,ꢀ theꢀ desiredꢀ amidineꢀ 13ꢀ provedꢀ surprisinglyꢀ challengingꢀ toꢀ
prepare,ꢀwithꢀdirectꢀaminolysisꢀofꢀnitrileꢀ7ꢀreturningꢀonlyꢀunreactedꢀstartingꢀmaterial.ꢀThisꢀlackꢀofꢀreactivityꢀwasꢀ
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circumventedꢀ byꢀ convertingꢀ nitrileꢀ 7ꢀ toꢀ hydroxyamidineꢀ 12ꢀ (byꢀ treatmentꢀ withꢀ ethanolicꢀ NH OH,ꢀ Schemeꢀ 4),ꢀ
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followedꢀbyꢀreductionꢀunderꢀstandardꢀconditionsꢀ(Pd/C), ꢀprovidingꢀtheꢀdesiredꢀamidineꢀ13ꢀinꢀexcellentꢀoverallꢀ
yield.ꢀ Asꢀ describedꢀ (videꢀ supra),ꢀ itꢀ wasꢀ hopedꢀ thatꢀ amidineꢀ 13ꢀ wouldꢀ undergoꢀ aꢀ 6πꢀ electrocyclizationꢀ eitherꢀ
spontaneously,ꢀorꢀunderꢀbasic,ꢀacidic,ꢀorꢀthermalꢀconditions.ꢀUnfortunately,ꢀinitialꢀeffortsꢀtoꢀaffectꢀcyclizationꢀ
failed.ꢀꢀAtꢀtheꢀtimeꢀofꢀthisꢀwork,ꢀlimitedꢀexamplesꢀofꢀsuchꢀcyclizationsꢀhadꢀbeenꢀreported,ꢀtheꢀmostꢀrelevantꢀ
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beingꢀaꢀhighlyꢀconjugatedꢀπ-systemꢀcyclizingꢀwithꢀaerobicꢀoxidation. ꢀRe-evaluatingꢀourꢀconceptualizationꢀofꢀthisꢀ
approachꢀ ledꢀ usꢀ toꢀ considerꢀ theꢀ pyrroleꢀ actingꢀ asꢀ aꢀ nucleophilicꢀ component.ꢀ Weꢀ thereforeꢀ beganꢀ studyingꢀ
activatedꢀformsꢀofꢀtheꢀhydroxylamineꢀ12.ꢀUnfortunately,ꢀactivationꢀofꢀtheꢀhydroxyamidineꢀthroughꢀtosylation,ꢀ
acylationꢀorꢀphosphorylation,ꢀfailedꢀtoꢀyieldꢀtheꢀdesiredꢀproduct,ꢀresultingꢀonlyꢀinꢀnon-productiveꢀreactivity.ꢀWeꢀ
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thereforeꢀconsideredꢀaꢀradicalꢀbasedꢀapproachꢀandꢀsurveyedꢀtheꢀhydroxyamidineꢀ12ꢀandꢀseveralꢀanaloguesꢀ(O-
acetylation,ꢀ tosylationꢀ etc)ꢀ inꢀ theꢀ presenceꢀ ofꢀ variousꢀ mediatorsꢀ (CAN,ꢀ NaNO ,ꢀ Cuꢀ salts,ꢀ Fe,ꢀ Smꢀ etc).ꢀ Afterꢀ
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screeningꢀaꢀwideꢀvarietyꢀofꢀconditions,ꢀRaney-Niꢀwasꢀshownꢀtoꢀbeꢀsingularlyꢀeffective,ꢀmediatingꢀtheꢀdesiredꢀ
cyclizationꢀunderꢀreductiveꢀconditionsꢀ(Schemeꢀ 5).ꢀInꢀourꢀinitialꢀexperimentsꢀonlyꢀaꢀmodestꢀ~2:1ꢀratioꢀofꢀtheꢀ
desiredꢀ cyclizedꢀ pyridineꢀ 14ꢀ andꢀ theꢀ reducedꢀ amidineꢀ 13ꢀ wasꢀ obtained,ꢀ cyclizationꢀ toꢀ theꢀ C3-positionꢀ ofꢀ theꢀ
pyrroleꢀwasꢀnotꢀobserved.ꢀEncouragedꢀbyꢀtheseꢀresultsꢀweꢀsoughtꢀtoꢀfurtherꢀoptimizeꢀthisꢀtransformation.ꢀꢀꢀꢀ
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Schemeꢀ4:ꢀFormationꢀofꢀAmidineꢀ13.ꢀ
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Schemeꢀ5:ꢀDiscoveryꢀofꢀaꢀNi-CatalyzedꢀCyclization.ꢀ
ꢀ
ꢀ
Theꢀdesiredꢀproductꢀ14ꢀandꢀamidineꢀ13ꢀwereꢀformedꢀalongꢀwithꢀaꢀsignificantꢀamountꢀofꢀoxadiazoleꢀ15ꢀ(formedꢀ
throughꢀcondensativeꢀself-cyclizationꢀofꢀtheꢀO-acylatedꢀamidine,ꢀSchemeꢀ6,ꢀpathwayꢀb).ꢀInꢀseekingꢀtoꢀoptimizeꢀ
thisꢀtransformation,ꢀweꢀquicklyꢀdeterminedꢀthatꢀhydrogenꢀandꢀO-acylationꢀwereꢀcritical;ꢀcontrolꢀexperimentsꢀ
showedꢀthatꢀexposureꢀofꢀtheꢀhydroxyamidineꢀ12ꢀtoꢀtheꢀreactionꢀconditionsꢀresultedꢀinꢀquantitativeꢀconversionꢀ
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toꢀtheꢀamidineꢀ13.ꢀWhileꢀnoꢀmechanisticꢀstudiesꢀwereꢀperformed,ꢀweꢀrationalizedꢀtheꢀreactionꢀcoordinateꢀasꢀ
shownꢀ (Schemeꢀ 6);ꢀ thisꢀ proposalꢀ helpedꢀ guideꢀ ourꢀ optimization,ꢀ thoughꢀ otherꢀ mechanismsꢀ couldꢀ easilyꢀ beꢀ
proposed.ꢀWeꢀpresumedꢀthatꢀtheꢀamidineꢀwasꢀformedꢀbyꢀtwoꢀpathways,ꢀmethanolysisꢀofꢀtheꢀacetateꢀ(returningꢀ
theꢀhydroxyamidine,ꢀpathwayꢀc,ꢀwhichꢀwouldꢀthenꢀreduce)ꢀalongꢀwithꢀaꢀcompetitiveꢀreductionꢀofꢀtheꢀacetylatedꢀ
intermediateꢀ(pathwayꢀd),ꢀthusꢀtheꢀstabilityꢀandꢀactivityꢀofꢀtheꢀO-acylatedꢀamidineꢀofꢀ12ꢀwasꢀcritical.ꢀInꢀorderꢀtoꢀ
optimizeꢀ thisꢀ reactionꢀ weꢀ neededꢀ toꢀ limitꢀ self-condensationꢀ ofꢀ theꢀ O-acylatedꢀ amidineꢀ (pathwayꢀ b),ꢀ ensureꢀ
stabilityꢀofꢀtheꢀO-acylatedꢀspeciesꢀ(i.e.,ꢀlimitꢀmethanolysis,ꢀpathwayꢀc)ꢀandꢀenhanceꢀtheꢀproductiveꢀcyclizationꢀ
(pathwayꢀ a)ꢀ overꢀ competitiveꢀ reductionꢀ (pathwayꢀ d).ꢀ Givenꢀ theꢀ requirementꢀ forꢀ reducingꢀ conditions,ꢀ weꢀ
hypothesizedꢀthatꢀtheꢀdesiredꢀtransformationꢀoccursꢀthroughꢀaꢀradicalꢀprocessꢀmediatedꢀbyꢀaꢀlow-valentꢀformꢀofꢀ
nickel;ꢀsingleꢀelectronꢀtransferꢀfromꢀaꢀnickelꢀspeciesꢀintoꢀtheꢀacetateꢀcarbonylꢀwouldꢀyieldꢀaꢀradicalꢀanion.ꢀN-Oꢀ
bondꢀcleavageꢀwithꢀadditionꢀofꢀtheꢀsingleꢀelectronꢀintoꢀtheꢀpyrroleꢀwouldꢀformꢀtheꢀdesiredꢀC-Nꢀbond,ꢀwithꢀlossꢀ
ofꢀacetateꢀanion.ꢀTheꢀresultingꢀradicalꢀwouldꢀthenꢀaromatizeꢀtoꢀyieldꢀtheꢀobservedꢀproductꢀ(Schemeꢀ6).ꢀꢀ
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Schemeꢀ6.ꢀReactionꢀConceptꢀLeveragedꢀforꢀOptimization.ꢀ
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Toꢀoptimizeꢀtheꢀtransformationꢀweꢀsystematicallyꢀvariedꢀparametersꢀwhichꢀcouldꢀcontributeꢀtoꢀtheꢀrateꢀofꢀeachꢀ
side-reactionꢀ notedꢀ above.ꢀ Toꢀ reduceꢀ theꢀ rateꢀ ofꢀ directꢀ reductionꢀ (pathwayꢀ d),ꢀ theꢀ hydrogenꢀ pressureꢀ wasꢀ
reducedꢀfromꢀ80ꢀtoꢀ3ꢀpsigꢀ(Tableꢀ1,ꢀentryꢀ1),ꢀwhichꢀincreasedꢀtheꢀratioꢀtoꢀ8:1ꢀinꢀfavorꢀofꢀtheꢀring-closedꢀproduct.ꢀ
Theꢀ propensityꢀ forꢀ self-cyclizationꢀ (pathwayꢀ b)ꢀ wasꢀ reducedꢀ byꢀ usingꢀ aꢀ moreꢀ stericallyꢀ demandingꢀ acylatingꢀ
agent,ꢀ pivalicꢀ anhydride.ꢀ Thisꢀ alsoꢀ resultedꢀ inꢀ aꢀ smallꢀ improvementꢀ inꢀ theꢀ product:amidineꢀ ratio,ꢀ potentiallyꢀ
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throughꢀlimitingꢀtheꢀamountꢀofꢀO-acetateꢀmethanolysis,ꢀpathwayꢀcꢀ(Tableꢀ1,ꢀentryꢀ3).ꢀSubstitutingꢀMeOHꢀforꢀ
tolueneꢀremovedꢀtheꢀpossibilityꢀofꢀmethanolysisꢀallꢀtogether,ꢀfurtherꢀimprovingꢀtheꢀobservedꢀselectivityꢀtoꢀ13:1ꢀ
(
cyclization:reduction,ꢀ 14:13).ꢀ Finally,ꢀ weꢀ focusedꢀ onꢀ theꢀ sourceꢀ ofꢀ low-valentꢀ nickel,ꢀ bothꢀ toꢀ continueꢀ
optimizationꢀandꢀinꢀanꢀattemptꢀtoꢀremoveꢀRaney-Niꢀfromꢀtheꢀreaction.ꢀSeveralꢀalternateꢀnickel-complexesꢀwereꢀ
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surveyedꢀ[suchꢀasꢀNi(acac)
activeꢀinꢀtheꢀdesiredꢀtransformation.ꢀThisꢀnewꢀsystemꢀresultedꢀinꢀaꢀfurtherꢀimprovementꢀinꢀselectivityꢀtoꢀ~16:1ꢀ
ratioꢀ(Tableꢀ1,ꢀentryꢀ5).ꢀInterestingly,ꢀunsupportedꢀNiꢀsourcesꢀ(suchꢀasꢀNi(acac) (H O) )ꢀprovedꢀunreactiveꢀevenꢀ
underꢀtheꢀreductiveꢀconditionsꢀ(H2(g)).ꢀTheꢀpyridineꢀ14ꢀwasꢀeasilyꢀisolatedꢀfromꢀtheseꢀreactionsꢀinꢀgoodꢀyieldꢀ(caꢀ
4-77%)ꢀandꢀexcellentꢀpurityꢀ(>99:1ꢀ14:13),ꢀthroughꢀazeotropicꢀremovalꢀofꢀaceticꢀacidꢀandꢀdirectꢀprecipitationꢀ
2 2 2
(H O) ]ꢀwithꢀnickelꢀoxideꢀsupportedꢀonꢀsilicaꢀ(PRICAT) ꢀꢀbeingꢀfoundꢀtoꢀbeꢀhighlyꢀ
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fromꢀtoluene.ꢀItꢀisꢀworthꢀnotingꢀthatꢀsinceꢀthisꢀworkꢀwasꢀcompleted,ꢀsomeꢀexamplesꢀofꢀthisꢀstyleꢀofꢀcyclizationꢀ
haveꢀ beenꢀ reported,ꢀ thoughꢀ theyꢀ appearꢀ toꢀ operateꢀ throughꢀ thermalꢀ dehydrationꢀ underꢀ harshꢀ reactionꢀ
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conditionsꢀ(caꢀ>200°C). ꢀAnꢀinterestingꢀcopperꢀmediatedꢀamino-brominationꢀofꢀindoles,ꢀleveragingꢀN-Oꢀcleavageꢀ
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ofꢀoximeꢀesters,ꢀwasꢀalsoꢀrecentlyꢀreported. ꢀ
Tableꢀ1.ꢀOptimizationꢀofꢀtheꢀNi-catalyzedꢀCyclizationꢀ
ꢀ
ꢀ
Weꢀ nextꢀ focusedꢀ ourꢀ attentionꢀ onꢀ attachingꢀ theꢀ finalꢀ pyrazoleꢀ heterocycle.ꢀ Theꢀ priorꢀ synthesisꢀ leveragedꢀ aꢀ
condensation-basedꢀstrategy,ꢀwhichꢀrequiredꢀseveralꢀstepsꢀandꢀtheꢀuseꢀofꢀBoc-protectedꢀmethylꢀhydrazine,ꢀtoꢀ
obtainꢀ regiochemicalꢀ controlꢀ (withꢀ respectꢀ toꢀ theꢀ N-methylꢀ substituent).ꢀ Weꢀ envisionedꢀ aꢀ moreꢀ convergentꢀ
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approachꢀutilizingꢀaꢀC−Nꢀcoupling,ꢀwhichꢀwouldꢀallowꢀusꢀtoꢀcoupleꢀaꢀregiochemicallyꢀpureꢀ3-halopyrazoleꢀandꢀ
obviateꢀanyꢀconcernsꢀofꢀisomerꢀformation.ꢀꢀꢀ
Schemeꢀ7.ꢀFormationꢀofꢀPyrazoleꢀ16.ꢀ
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Unfortunately,ꢀourꢀabilityꢀtoꢀdevelopꢀthisꢀC-Nꢀcouplingꢀwasꢀlimitedꢀbyꢀtheꢀsynthesisꢀofꢀtheꢀpyrazoleꢀcomponent.ꢀ
Whileꢀtheꢀpyrazoloneꢀ16ꢀwasꢀeasyꢀtoꢀprepareꢀinꢀgoodꢀyieldꢀandꢀselectivityꢀfromꢀbutynoicꢀacid,ꢀtheꢀsubsequentꢀ
dehydrativeꢀhalogenationꢀprovedꢀdifficultꢀtoꢀaccomplishꢀ(Schemeꢀ7).ꢀForꢀexample,ꢀclassicꢀconditionsꢀ(POCl
POBr ꢀ eitherꢀ neatꢀ orꢀ inꢀ toluene,ꢀ withꢀ orꢀ withoutꢀ variousꢀ additives)ꢀ failedꢀ toꢀ yieldꢀ theꢀ desiredꢀ chlorideꢀ (orꢀ
bromide). ꢀSubsequentꢀNMRꢀstudiesꢀindicatedꢀthatꢀwhileꢀactivationꢀofꢀtheꢀamideꢀcarbonylꢀwasꢀoccurring,ꢀtheꢀ
Arꢀ withꢀ chlorideꢀ wasꢀ not,ꢀ evenꢀ underꢀ theꢀ mostꢀ forcingꢀ conditionsꢀ (neatꢀ POCl ꢀ atꢀ 120°C).ꢀ However,ꢀ sinceꢀ
3
ꢀorꢀ
3
3
2
S
N
3
pyrazoloneꢀ 16ꢀ wasꢀ easilyꢀ prepared,ꢀ weꢀ examinedꢀ itsꢀ reactivityꢀ toꢀ electrophilicꢀ reagents,ꢀ toꢀ formꢀ potentialꢀ
couplingꢀ partners;ꢀ thusꢀ theꢀ pyrazoleꢀ O-mesylate,ꢀ O-triflate,ꢀ O-phosphateꢀ andꢀ O-tosylateꢀ wereꢀ prepared.ꢀ
However,ꢀ palladiumꢀ mediatedꢀ couplingsꢀ ofꢀ theseꢀ compoundsꢀ provedꢀ difficultꢀ toꢀ develop,ꢀ withꢀ littleꢀ toꢀ noꢀ
productꢀbeingꢀobservedꢀunderꢀmostꢀconditions.ꢀThus,ꢀweꢀturnedꢀtoꢀaꢀSandmeyerꢀhalogenationꢀtoꢀprepareꢀtheꢀ
3
3
iodopyrazoleꢀ19, ꢀhopingꢀthatꢀalternateꢀmetalsꢀ(suchꢀasꢀcopper)ꢀwouldꢀeffectivelyꢀmediateꢀtheꢀdesiredꢀcoupling.ꢀ
34
Theꢀsynthesisꢀofꢀaminopyrazoleꢀ18ꢀwasꢀknown,ꢀstartingꢀfromꢀcrotononitrileꢀ(Schemeꢀ8). ꢀWeꢀfoundꢀthatꢀwhileꢀ
theꢀinitialꢀadditionꢀofꢀbromineꢀtoꢀcrotononitrileꢀwasꢀextremelyꢀslow,ꢀcatalyticꢀamountsꢀofꢀHBrꢀcouldꢀbeꢀemployedꢀ
toꢀ improveꢀ theꢀ reactionꢀ rate;ꢀ thusꢀ HBrꢀ wasꢀ addedꢀ toꢀ theꢀ brominationꢀ reactionꢀ providingꢀ goodꢀ yieldsꢀ ofꢀ
dibromideꢀ 17.ꢀ Significantꢀ optimizationꢀ wasꢀ thenꢀ requiredꢀ toꢀ obtainꢀ highꢀ regioselectivityꢀ inꢀ theꢀ hydrazineꢀ
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addition/cyclization.ꢀ Highlyꢀ basicꢀ reactionꢀ conditionsꢀ wereꢀ necessaryꢀ toꢀ obtainꢀ theꢀ desiredꢀ regioisomerꢀ withꢀ
goodꢀ selectivityꢀ (>95:5);ꢀ underꢀ acidicꢀ conditionsꢀ theꢀ oppositeꢀ regiochemicalꢀ outcomeꢀ wasꢀ obtained.ꢀ Theꢀ
Sandmeyerꢀ reaction,ꢀ convertingꢀ aminopyrazoleꢀ 18ꢀ toꢀ iodopyrazoleꢀ 19,ꢀ occurredꢀ smoothlyꢀ albeitꢀ inꢀ modestꢀ
3
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yield. ꢀ
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Schemeꢀ8.ꢀFormationꢀofꢀPyrazoleꢀ19.ꢀ
ꢀ
Withꢀ iodopyrazoleꢀ 19ꢀ inꢀ handꢀ weꢀ focusedꢀ onꢀ developingꢀ aꢀ copperꢀ mediatedꢀ Ullmann-Goldberg-Buchwaldꢀ
3
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couplingꢀ (Tableꢀ 2). ꢀ Anꢀ initialꢀ screenꢀ ofꢀ ligandꢀ typesꢀ focusedꢀ onꢀ theꢀ useꢀ ofꢀ diamine, ꢀ diketone, ꢀ andꢀ
3
9
phenanthrolineꢀ ligands. ꢀ Itꢀ wasꢀ quicklyꢀ foundꢀ thatꢀ diamineꢀ ligandsꢀ offeredꢀ uniqueꢀ reactivityꢀ inꢀ thisꢀ
transformation,ꢀwithꢀdimethylꢀethyleneꢀdiamineꢀ(DMEDA)ꢀappearingꢀoptimal.ꢀAdditionally,ꢀitꢀwasꢀdeterminedꢀ
thatꢀstoichiometricꢀamountsꢀofꢀcopperꢀwereꢀneededꢀtoꢀdriveꢀtheꢀreactionꢀtoꢀcompletion,ꢀwithꢀCuIꢀbeingꢀtheꢀbestꢀ
metalꢀsource.ꢀWeꢀfeltꢀthatꢀtheꢀneedꢀforꢀtheꢀhighꢀCuꢀloadingsꢀmayꢀhaveꢀbeenꢀdueꢀtoꢀcompetitiveꢀcoordinationꢀofꢀ
theꢀproductꢀpyridine-pyrazoleꢀsystem,ꢀcompetingꢀwithꢀtheꢀactiveꢀligand.ꢀIndeed,ꢀtheꢀcoupledꢀproductꢀ20,ꢀwhichꢀ
precipitatedꢀfromꢀtheꢀreactionꢀmixture,ꢀcontainedꢀanꢀalmostꢀ1:1ꢀmoleꢀratioꢀofꢀcopper.ꢀ
WithꢀDMEDAꢀandꢀCuIꢀselectedꢀasꢀourꢀbestꢀconditions,ꢀweꢀfocusedꢀonꢀoptimizingꢀtheꢀotherꢀparametersꢀofꢀtheꢀ
reaction,ꢀ specificallyꢀ theꢀ baseꢀ andꢀ ligandꢀ loadingsꢀ (Tableꢀ 2).ꢀ Weꢀ surveyedꢀ aꢀ wideꢀ varietyꢀ ofꢀ inorganicꢀ bases,ꢀ
varyingꢀbothꢀtheꢀcationicꢀandꢀanionicꢀcomponents,ꢀandꢀfoundꢀthatꢀbothꢀcarbonateꢀandꢀphosphateꢀbasesꢀshowedꢀ
2 3
promise,ꢀ withꢀ Cs CO ꢀ providingꢀ aꢀ goodꢀ levelꢀ ofꢀ reactivityꢀ (Tableꢀ 2,ꢀ entriesꢀ 1ꢀ andꢀ 4).ꢀ Interestingly,ꢀ halideꢀ
extractingꢀcounterꢀionsꢀsuchꢀasꢀAgꢀ(entriesꢀ2ꢀandꢀ3)ꢀresultedꢀinꢀdiminishedꢀyields.ꢀIncreasingꢀtheꢀequivalentsꢀofꢀ
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baseꢀ gaveꢀ higherꢀ conversionꢀ (entryꢀ 5)ꢀ whileꢀ increasingꢀ theꢀ ratioꢀ ofꢀ diamineꢀ toꢀ Cuꢀ hadꢀ onlyꢀ aꢀ minimalꢀ effectꢀ
entryꢀ6).ꢀAfterꢀadditionalꢀexperimentation,ꢀweꢀinitiallyꢀsettledꢀonꢀconditionsꢀofꢀ1.2ꢀequivalentsꢀDMEDAꢀwithꢀ3.0ꢀ
equivalentsꢀofꢀK PO ,ꢀwhichꢀreliablyꢀgaveꢀfullꢀconversionꢀonꢀscreeningꢀ(mg)ꢀscale.ꢀHowever,ꢀinꢀperformingꢀtheseꢀ
(
3
4
conditionsꢀonꢀlaboratoryꢀ(gram)ꢀscale,ꢀgreatꢀvariabilityꢀwasꢀobservedꢀ–ꢀwithꢀveryꢀlowꢀconversionꢀoftenꢀbeingꢀ
observedꢀ (forꢀ example,ꢀ entryꢀ 7).ꢀ Afterꢀ exploringꢀ aꢀ varietyꢀ ofꢀ parameters,ꢀ weꢀ tracedꢀ thisꢀ variabilityꢀ toꢀ
contaminationꢀofꢀiodopyrazoleꢀ19.ꢀi-Amylꢀalcohol,ꢀleftꢀoverꢀfromꢀtheꢀSandmeyerꢀreactionꢀ(Schemeꢀ8),ꢀwasꢀfoundꢀ
toꢀbeꢀcriticalꢀinꢀachievingꢀgoodꢀratesꢀandꢀreactivityꢀinꢀtheꢀUllmannꢀprocess.ꢀWeꢀproposedꢀthatꢀtheꢀalcoholꢀwasꢀ
0
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3 4
actingꢀasꢀaꢀproton-shuttle,ꢀnegatingꢀtheꢀlowꢀsolubilityꢀofꢀK PO ꢀinꢀtoluene.ꢀIndeed,ꢀtheꢀadditionꢀofꢀalcoholꢀ(i-amylꢀ
orꢀt-butyl,ꢀentriesꢀ8ꢀandꢀ9)ꢀrestoredꢀtheꢀreactivityꢀseenꢀduringꢀscreening.ꢀWithꢀthisꢀdata,ꢀweꢀrefocusedꢀourꢀeffortsꢀ
onꢀ moreꢀ solubleꢀ organicꢀ bases,ꢀ quicklyꢀ findingꢀ thatꢀ sodiumꢀ t-butoxideꢀ providedꢀ excellentꢀ conversionꢀ andꢀ
reactionꢀrates,ꢀbeingꢀslightlyꢀmoreꢀeffectiveꢀthanꢀtheꢀcorrespondingꢀt-amylateꢀ(entriesꢀ11ꢀandꢀ12).ꢀWithꢀtheseꢀ
optimizedꢀconditionsꢀinꢀhand,ꢀtheꢀcouplingꢀofꢀtheꢀanilineꢀ14ꢀwithꢀiodo-pyrazoleꢀ19ꢀproceededꢀsmoothly;ꢀtheꢀCu-
containingꢀproductꢀprecipitatedꢀfromꢀtheꢀreactionꢀmixtureꢀandꢀwasꢀisolatedꢀbyꢀfiltration.ꢀTreatmentꢀofꢀthisꢀcrudeꢀ
productꢀwithꢀammoniumꢀhydroxideꢀremovedꢀtheꢀcopperꢀandꢀenabledꢀtheꢀisolationꢀofꢀtheꢀesterꢀinꢀgoodꢀyieldꢀandꢀ
purityꢀ(caꢀ80%,ꢀSchemeꢀ9).ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
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Tableꢀ2.ꢀOptimizationꢀofꢀtheꢀꢀUllmann-Goldberg-BuchwaldꢀCouplingꢀ
0
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ꢀ
Entryꢀ
Scaleꢀ
Baseꢀ
Cs CO
Baseꢀ
equiv.)ꢀ
3.0ꢀ
3.0ꢀ
3.0ꢀ
2.5ꢀ
5.0ꢀ
5.0ꢀ
3.0ꢀ
3.0ꢀ
3.0ꢀ
3.0ꢀ
3.0ꢀ
DMEDAꢀ
(equiv.)ꢀ
1.5ꢀ
1.5ꢀ
1.5ꢀ
1.5ꢀ
1.5ꢀ
3.0ꢀ
1.2 ꢀ
1.5ꢀ
1.5ꢀ
1.5ꢀ
1.5ꢀ
1.5ꢀ
Alcoholꢀ
Convꢀ
(%) ꢀ
64ꢀ
a
(
1
ꢀ
mgꢀ
mgꢀ
mgꢀ
mgꢀ
mgꢀ
mgꢀ
gꢀ
gꢀ
gꢀ
gꢀ
gꢀ
2
3
ꢀ
ꢀ
ꢀ
-ꢀ
-ꢀ
-ꢀ
-ꢀ
-ꢀ
-ꢀ
-ꢀ
2ꢀ
3ꢀ
4ꢀ
5ꢀ
6ꢀ
7ꢀ
Ag
Ag
2
CO
PO
3
31.1ꢀ
5.8ꢀ
60ꢀ
3
4
K
K
K
K
K
K
3
3
3
3
3
3
PO
PO
PO
PO
PO
PO
4
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
4
4
4
4
4
85ꢀ
84.3ꢀ
c
b
58 ꢀ
8
9
ꢀ
ꢀ
i-BuOHꢀ0.1ꢀeqꢀ
t-BuOHꢀ1.0ꢀeqꢀ
72ꢀ
71ꢀ
79ꢀ
1
1
1
0ꢀ
1ꢀ
2ꢀ
KOt-Buꢀ
NaOt-Buꢀ
NaOt-Amylꢀ
-ꢀ
-ꢀ
-ꢀ
97.6ꢀ
88.9ꢀ
gꢀ
3.0ꢀ
(
a)ꢀConversionꢀafterꢀ20ꢀh;ꢀ(b)ꢀadditionalꢀ0.6ꢀequiv.ꢀCuI/DMEDAꢀandꢀ20ꢀhꢀresultedꢀinꢀanꢀimprovementꢀtoꢀ75%ꢀconversionꢀ–ꢀthoughꢀreactionꢀwasꢀmuchꢀslowerꢀ
thanꢀscreeningꢀscale,ꢀwithꢀsignificantlyꢀmoreꢀdeiodinationꢀobserved;ꢀ(c)ꢀfurtherꢀoptimizationꢀonꢀscreeningꢀscaleꢀ(mg)ꢀsuggestedꢀ1.2ꢀequiv.ꢀofꢀDMEDAꢀwasꢀ
sufficient.ꢀ
Withꢀesterꢀ20ꢀinꢀhand,ꢀcompletionꢀofꢀtheꢀsynthesisꢀappearedꢀtrivialꢀ -ꢀesterꢀsaponificationꢀfollowedꢀbyꢀamideꢀ
bondꢀ formation.ꢀ Inꢀ actuality,ꢀ bothꢀ stepsꢀ provedꢀ challenging.ꢀ Theꢀ saponificationꢀ ofꢀ esterꢀ 20ꢀ inꢀ EtOHꢀ wasꢀ
extremelyꢀsensitiveꢀtoꢀtraceꢀcopperꢀandꢀoxygenꢀwithꢀrapidꢀformationꢀofꢀanꢀimpurity,ꢀwhichꢀcouldꢀoccurꢀinꢀnearꢀ
quantitativeꢀ levelsꢀ ifꢀ neitherꢀ parameterꢀ wasꢀ controlledꢀ (Figureꢀ 4).ꢀ Givenꢀ theꢀ challengesꢀ observedꢀ withꢀ theꢀ
pyrazoleꢀ couplingꢀ (videꢀ supra),ꢀ itꢀ wasꢀ surprisingꢀ whenꢀ thisꢀ impurityꢀ wasꢀ identifiedꢀ asꢀ theꢀ productꢀ ofꢀ aꢀ
decarboxylativeꢀcoupling,ꢀformingꢀheterocycleꢀ21ꢀ(Figureꢀ4);ꢀpresumablyꢀ21ꢀisꢀformedꢀthroughꢀcopperꢀmediatedꢀ
C2-indoleꢀdecarboxylationꢀandꢀC-NꢀcouplingꢀofꢀtheꢀresultingꢀC2-cuprate.ꢀToꢀcontrolꢀthisꢀimpurity,ꢀtheꢀCuꢀlevelsꢀinꢀ
esterꢀ20ꢀneededꢀtoꢀbeꢀcontrolledꢀbelowꢀ50ꢀppmꢀandꢀoxygenꢀrigorouslyꢀexcludedꢀfromꢀtheꢀsystem.ꢀWithꢀcontrolꢀ
overꢀbothꢀofꢀtheseꢀparameters,ꢀsmoothꢀsaponificationꢀwasꢀobserved,ꢀgivingꢀtheꢀNa-saltꢀ23ꢀinꢀhighꢀyieldꢀ(Schemeꢀ
9).ꢀ
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Figureꢀ4.ꢀTheꢀMainꢀImpuritiesꢀFormedꢀinꢀtheꢀLastꢀ2ꢀSteps.ꢀ
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ꢀ
Theꢀamideꢀbondꢀformationꢀalsoꢀprovedꢀcomplex,ꢀdueꢀinꢀnoꢀsmallꢀpartꢀtoꢀtheꢀlackꢀofꢀavailabilityꢀofꢀhighꢀqualityꢀ
dicyclopropylamineꢀ (DCPA,ꢀ 24);ꢀ indeed,ꢀ duringꢀ theꢀ courseꢀ ofꢀ ourꢀ studiesꢀ weꢀ developedꢀ threeꢀ proceduresꢀ toꢀ
4
0
prepareꢀ thisꢀ challengingꢀ smallꢀ molecule. ꢀ Surprisingly,ꢀ standardꢀ methodsꢀ ofꢀ amideꢀ bondꢀ formationꢀ
41
42
43
(
EDAc/HOBt, ꢀHATU, ꢀCDI, ꢀetc)ꢀfailedꢀtoꢀcleanlyꢀconvertꢀacidꢀ23ꢀtoꢀamideꢀ1.ꢀSignificantꢀlevelsꢀofꢀtheꢀmono-
cyclopropylꢀ compoundꢀ 22ꢀ wereꢀ oftenꢀ observedꢀ (Figureꢀ 4).ꢀ Thisꢀ wasꢀ attributedꢀ toꢀ theꢀ inherentꢀ instabilityꢀ ofꢀ
3
9a
DCPA,ꢀwhichꢀisꢀknownꢀtoꢀconvertꢀtoꢀcyclopropylamineꢀunderꢀbasicꢀconditions. ꢀAfterꢀscreeningꢀaꢀvarietyꢀofꢀ
4
4
moreꢀ unusualꢀ conditions,ꢀ weꢀ foundꢀ thatꢀ DMCꢀ (2-chloro-1,3-dimethylimidazolidiniumꢀ chloride) ꢀ wasꢀ ableꢀ toꢀ
cleanlyꢀandꢀquantitativelyꢀformꢀtheꢀacidꢀchlorideꢀofꢀcarboxylateꢀ23.ꢀWithꢀthisꢀreagent,ꢀtheꢀacidꢀchlorideꢀformedꢀ
directlyꢀ fromꢀ theꢀ Na-saltꢀ (thereforeꢀ underꢀ basicꢀ toꢀ neutralꢀ conditions)ꢀ whichꢀ wasꢀ criticalꢀ toꢀ avoidingꢀ
precipitationꢀ ofꢀ anꢀ insolubleꢀ formꢀ ofꢀ carboxylateꢀ 23.ꢀ Withꢀ theꢀ higherꢀ reactivityꢀ ofꢀ theꢀ acidꢀ chloride,ꢀ smoothꢀ
couplingꢀwithꢀDCPAꢀ(inꢀtheꢀpresenceꢀofꢀDIPEA)ꢀwasꢀobservedꢀ–ꢀcompletingꢀtheꢀsynthesisꢀofꢀBMS-911543ꢀ(1)ꢀinꢀ
onlyꢀ8ꢀstepsꢀandꢀhighꢀoverallꢀyield.ꢀ
ꢀ
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ꢀ
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ꢀ
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Schemeꢀ9:ꢀEnd-gameꢀtoꢀBMS-911543ꢀ
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ꢀ
ꢀ
Conclusionꢀ
Inꢀsummary,ꢀweꢀhaveꢀdevelopedꢀaꢀshortꢀandꢀhighlyꢀconvergentꢀrouteꢀtoꢀtheꢀcomplexꢀpyrrole-pyridine,ꢀBMS-
11543ꢀ(1),ꢀthatꢀproceedsꢀinꢀ8ꢀstepsꢀfromꢀtheꢀknownꢀbromopyrroleꢀ4ꢀinꢀanꢀoverallꢀyieldꢀofꢀ27-32%.ꢀꢀInventionꢀofꢀ
ꢀ
9
aꢀNi-mediatedꢀC-Hꢀaminationꢀenabledꢀtheꢀkeyꢀcyclization,ꢀprovidingꢀtheꢀdesiredꢀhighlyꢀsubstitutedꢀpyridineꢀinꢀ
excellentꢀ yieldꢀ andꢀ selectivity.ꢀ Optimizationꢀ ofꢀ thisꢀ reactionꢀ leveragedꢀ rational,ꢀ stepwiseꢀ improvementsꢀ inꢀ
conditions,ꢀ basedꢀ onꢀ aꢀ coreꢀ mechanisticꢀ hypothesis.ꢀ ꢀ Additionally,ꢀ aꢀ newꢀ andꢀ broadlyꢀ impactfulꢀ palladiumꢀ
reduction/activationꢀpathwayꢀwasꢀelucidated,ꢀalongꢀwithꢀitsꢀimpactꢀtoꢀcatalystꢀidentity,ꢀreactivityꢀandꢀstabilityꢀinꢀ
theꢀMiyauraꢀborylationꢀofꢀpyrroleꢀ4.ꢀꢀNewꢀsyntheticꢀroutesꢀtoꢀthreeꢀofꢀtheꢀfourꢀkeyꢀbuildingꢀblocksꢀwereꢀalsoꢀ
developed,ꢀsignificantlyꢀimprovingꢀuponꢀtheꢀknownꢀsynthesesꢀofꢀtheseꢀimportantꢀfragments.ꢀꢀꢀꢀ
ExperimentalꢀSectionꢀ
2
General:ꢀ Allꢀ proceduresꢀ wereꢀ conductedꢀ underꢀ anꢀ inertꢀ (N )ꢀ atmosphere,ꢀ inꢀ standardꢀ laboratoryꢀ equipmentꢀ
usingꢀ standardꢀ techniquesꢀ (unlessꢀ otherwiseꢀ noted).ꢀ Commercialꢀ solventsꢀ (reagentꢀ grade),ꢀ reagentsꢀ andꢀ
catalystsꢀwereꢀusedꢀdirectlyꢀasꢀsuppliedꢀfromꢀcommercialꢀsourcesꢀandꢀwithoutꢀfurtherꢀpurification.ꢀReactionsꢀ
wereꢀmonitoredꢀbyꢀstandardꢀanalyticalꢀtechniquesꢀandꢀtheꢀproductsꢀcharacterizedꢀbyꢀ1HꢀNMRꢀ(atꢀeitherꢀ500ꢀorꢀ
4
00MHzꢀasꢀnoted)ꢀandꢀ13CꢀNMRꢀ(100MHz)ꢀinꢀtheꢀappropriateꢀdeuteratedꢀsolventꢀ(listed).ꢀChemicalꢀshiftsꢀareꢀ
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quotedꢀ inꢀ partsꢀ perꢀ million.ꢀ Allꢀ compoundsꢀ wereꢀ isolatedꢀ byꢀ crystallization,ꢀ unlessꢀ otherwiseꢀ noted,ꢀ withꢀ
reportedꢀyieldsꢀcorrectedꢀforꢀbothꢀstartingꢀmaterialꢀandꢀproductꢀpotenciesꢀ(asꢀdeterminedꢀeitherꢀbyꢀquantitativeꢀ
NMRꢀorꢀHPLCꢀanalysis).ꢀNMRꢀdataꢀareꢀreportedꢀasꢀfollows:ꢀchemicalꢀshift,ꢀmultiplicityꢀ(sꢀ=ꢀsinglet,ꢀdꢀ=ꢀdoublet,ꢀtꢀ=ꢀ
triplet,ꢀqꢀ=ꢀquartet,ꢀmꢀ=ꢀmultiplet,ꢀbrꢀ=ꢀbroad),ꢀcouplingꢀconstant,ꢀintegration.ꢀHighꢀresolutionꢀmass-spectraꢀwereꢀ
obtainedꢀusingꢀelectro-sprayꢀionizationꢀ(ESI+)ꢀwithꢀanꢀLTQ-Oribtrapꢀmassꢀanalyzer.ꢀ
ꢀ
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1
-(4-bromo-1H-pyrrol-2-yl)-2,2,2-trichloroethanoneꢀ
3
Toꢀaꢀcooledꢀsolutionꢀ(0ꢀ°C)ꢀofꢀtrichloroacetylpyrroleꢀ(200ꢀg,ꢀ0.94ꢀmol,ꢀ1.00ꢀequiv.)ꢀinꢀCH CNꢀ(1.0ꢀL,ꢀ5.0ꢀmL/g)ꢀwasꢀ
addedꢀNBSꢀ(168ꢀg,ꢀ0.94ꢀmol,ꢀ1.00ꢀequiv.)ꢀslowlyꢀportionwise.ꢀTheꢀreactionꢀwasꢀstirredꢀatꢀ23ꢀ°Cꢀforꢀ1.5ꢀh.ꢀTheꢀ
reactionꢀmixtureꢀwasꢀquenchedꢀbyꢀtheꢀslowꢀadditionꢀofꢀwaterꢀ(3.0ꢀL,ꢀ15.0ꢀmL/g),ꢀcooledꢀtoꢀ0ꢀ°Cꢀandꢀtheꢀsolidsꢀ
wereꢀallowedꢀtoꢀdesaturateꢀforꢀanꢀadditionalꢀ1ꢀh.ꢀTheꢀsolidsꢀwereꢀfiltered,ꢀwashedꢀwithꢀwaterꢀ(1.0ꢀL,ꢀ5.0ꢀmL/g)ꢀ
andꢀdriedꢀinꢀvacuoꢀtoꢀyieldꢀbromopyrroleꢀ(264ꢀg,ꢀ96%ꢀyield)ꢀasꢀtanꢀplatesꢀ(mpꢀ140-143ꢀ°C).ꢀ
1
6
HꢀNMRꢀ(400MHz,ꢀDMSO-d )ꢀδꢀ12.84ꢀ(brꢀs,ꢀ1H),ꢀ7.53ꢀ(brꢀs,ꢀ1H),ꢀ7.31ꢀ(s,ꢀ1H)ꢀ
13
CꢀNMRꢀ(100MHz,ꢀDMSO-d
6
)ꢀδꢀ171.6,ꢀ129.0,ꢀ122.0,ꢀ121.5,ꢀ97.5,ꢀ94.5ꢀ
-
HRMS-ESIꢀ(m/z)ꢀcalc’dꢀforꢀC
ꢀ
6
H
2
BrCl
3
NOꢀ[M-H] ꢀ287.8380ꢀandꢀ289.8365,ꢀfoundꢀ287.8374ꢀandꢀ289.8346ꢀ
Ethylꢀ4-bromo-1H-pyrrole-2-carboxylate,ꢀ4ꢀ
Toꢀ aꢀ cooledꢀ solutionꢀ (0ꢀ °C)ꢀ ofꢀ 1-(4-bromo-1H-pyrrol-2-yl)-2,2,2-trichloroethanoneꢀ (261.3ꢀ g,ꢀ 896.8ꢀ mmol,ꢀ 1.0ꢀ
equiv.)ꢀinꢀEtOHꢀ(914.6ꢀmL,ꢀ3.5ꢀmL/g)ꢀwasꢀslowlyꢀaddedꢀaꢀ25ꢀwt%ꢀsolutionꢀofꢀNaOEtꢀinꢀEtOHꢀ(0.1ꢀequiv.)ꢀoverꢀ45ꢀ
minꢀwhileꢀmaintainingꢀanꢀinternalꢀtemperatureꢀbelowꢀ5ꢀ°C.ꢀTheꢀreactionꢀwasꢀstirredꢀatꢀ25-30ꢀ°Cꢀforꢀanꢀadditionalꢀ
1
ꢀ hꢀ beforeꢀ beingꢀ concentratedꢀ toꢀ approximatelyꢀ 340ꢀ mLꢀ orꢀ 1.3ꢀ mL/gꢀ withꢀ respectꢀ toꢀ startingꢀ material.ꢀ Toꢀ aꢀ
separateꢀ flaskꢀ containingꢀ waterꢀ atꢀ 0ꢀ °Cꢀ wasꢀ slowlyꢀ addedꢀ theꢀ concentratedꢀ reactionꢀ mixtureꢀ overꢀ 1ꢀ hꢀ toꢀ
precipitateꢀtheꢀproduct.ꢀTheꢀslurryꢀwasꢀheldꢀatꢀ0ꢀ°Cꢀforꢀanꢀadditionalꢀ1ꢀhꢀtoꢀcompleteꢀtheꢀdesaturation,ꢀthenꢀtheꢀ
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solidsꢀwereꢀfiltered,ꢀwashedꢀwithꢀwaterꢀ(1.3ꢀL,ꢀ5.0ꢀmL/g)ꢀandꢀdriedꢀinꢀvacuoꢀtoꢀyieldꢀethylꢀesterꢀ4ꢀ(181.9ꢀg,ꢀ92%ꢀ
15
yield)ꢀasꢀanꢀsemi-crystallineꢀtoꢀamorphousꢀsolidꢀ(mpꢀ60-63ꢀ°C). ꢀ
1
HꢀNMRꢀ(400MHz,ꢀDMSO-d
H)ꢀ
6
)ꢀδꢀ12.25ꢀ(brꢀs,ꢀ1H),ꢀ7.15ꢀ(s,ꢀ1H),ꢀ6.79ꢀ(s,ꢀ1H),ꢀ4.23ꢀ(q,ꢀJ=7.1ꢀHz,ꢀ2H),ꢀ1.26ꢀ(t,ꢀJ=7.1ꢀHz,ꢀ
3
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CꢀNMRꢀ(100MHz,ꢀDMSO-d
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)ꢀδꢀ159.5,ꢀ123.7,ꢀ122.8,ꢀ115.9,ꢀ95.8,ꢀ59.9,ꢀ14.2ꢀ
-
HRMS-ESIꢀ(m/z)ꢀcalc’dꢀforꢀC
ꢀ
7
H
7
BrNO
2
ꢀ[M-H] ꢀ215.9660ꢀandꢀ217.9640,ꢀfoundꢀ215.9647ꢀandꢀ217.9621ꢀ
Ethylꢀ1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrole-2-carboxylate,ꢀ6ꢀ
Toꢀaꢀsolutionꢀofꢀpyrroleꢀ4ꢀ(207ꢀg,ꢀ0.951ꢀmol,ꢀ1.00ꢀequiv.)ꢀinꢀDMFꢀ(2.07ꢀL,ꢀ10.0ꢀmL/g)ꢀwasꢀaddedꢀK
2
3
CO ꢀ(325ꢀmesh,ꢀ
197ꢀ g,ꢀ 1.43ꢀ mol,ꢀ 1.50ꢀ equiv.)ꢀ portionwise,ꢀ whileꢀ maintainingꢀ anꢀ internalꢀ temperatureꢀ belowꢀ 25ꢀ °C.ꢀ Toꢀ thisꢀ
mixtureꢀwasꢀaddedꢀdropwiseꢀethylꢀiodideꢀ(178ꢀg,ꢀ1.14ꢀmol,ꢀ1.20ꢀequiv.).ꢀTheꢀreactionꢀmixtureꢀwasꢀallowedꢀtoꢀstirꢀ
forꢀ16ꢀhꢀbeforeꢀbeingꢀquenchedꢀbyꢀtheꢀslowꢀadditionꢀofꢀwaterꢀ(2.07ꢀL,ꢀ10ꢀmL/g).ꢀꢀMTBEꢀ(1.24ꢀL,ꢀ6.00ꢀmL/g)ꢀwasꢀ
addedꢀandꢀtheꢀbiphasicꢀmixtureꢀwasꢀstirredꢀforꢀ10ꢀmin.ꢀTheꢀphasesꢀwereꢀseparatedꢀandꢀtheꢀaqueousꢀlayerꢀwasꢀ
extractedꢀwithꢀMTBEꢀ(3ꢀxꢀ1.2ꢀL,ꢀ6.0ꢀmL/g).ꢀTheꢀcombinedꢀorganicꢀlayersꢀwereꢀwashedꢀwithꢀwaterꢀ(3ꢀxꢀ1.04ꢀL,ꢀ5.00ꢀ
mL/g)ꢀ andꢀ thenꢀ concentratedꢀ underꢀ reducedꢀ pressureꢀ toꢀ provideꢀ ethylatedꢀ pyrroleꢀ 5ꢀ (203.9ꢀ g)ꢀ asꢀ aꢀ reddishꢀ
brownꢀoil.ꢀTheꢀoilꢀwasꢀthriceꢀdilutedꢀwithꢀPhMeꢀ(1.7ꢀL,ꢀ8.0ꢀmL/g)ꢀandꢀconcentrated.ꢀꢀTheꢀresidueꢀwasꢀredissolvedꢀ
inꢀPhMeꢀ(725ꢀmL,ꢀ3.5ꢀmL/g)ꢀandꢀaddedꢀactivatedꢀcarbonꢀ(10.4ꢀg,ꢀ5.0ꢀwt%).ꢀTheꢀsolutionꢀwasꢀstirredꢀ30ꢀmin.,ꢀ
filteredꢀthroughꢀcelite,ꢀandꢀusedꢀdirectlyꢀwithoutꢀfurtherꢀpurification.ꢀꢀ
Toꢀ aꢀ flaskꢀ wasꢀ chargedꢀ Pd(OAc)
2
ꢀ (0.912ꢀ g,ꢀ 4.06ꢀ mmol,ꢀ 0.01ꢀ equiv.),ꢀ tricyclohexylphosphineꢀ tetrafluoroborateꢀ
(
3.74ꢀ g,ꢀ 10.2ꢀ mmol,ꢀ 0.025ꢀ equiv.),ꢀ tetramethylammoniumꢀ acetateꢀ (5.41ꢀ g,ꢀ 40.6ꢀ mmol,ꢀ 0.10ꢀ equiv.)ꢀ andꢀ dry,ꢀ
degassedꢀ PhMeꢀ (50ꢀ mL,ꢀ 0.5ꢀ mL/g).ꢀ Theꢀ solutionꢀ wasꢀ stirredꢀ atꢀ 23ꢀ °Cꢀ forꢀ 2ꢀ hꢀ andꢀ filteredꢀ underꢀ nitrogen.ꢀ ꢀ Aꢀ
separateꢀflaskꢀchargedꢀwithꢀtetramethylammoniumꢀacetateꢀ(157ꢀg,ꢀ1.18ꢀmol,ꢀ2.9ꢀequiv)ꢀandꢀwaterꢀ(22.0ꢀmL,ꢀ1.22ꢀ
mol,ꢀ3.00ꢀequiv.)ꢀandꢀdegassedꢀPhMeꢀ(0.750ꢀL,ꢀ7.5ꢀmL/g)ꢀwasꢀwarmedꢀtoꢀ80ꢀ°Cꢀforꢀ30ꢀmin.ꢀTheꢀsolutionꢀwasꢀ
cooledꢀtoꢀ23ꢀ°Cꢀandꢀtheꢀsolutionꢀofꢀpyrroleꢀ5ꢀ(100ꢀg,ꢀ0.406ꢀmol,ꢀ1.0ꢀequiv.,ꢀLimitingꢀreagent)ꢀinꢀPhMeꢀ(20-25ꢀ
wt%)ꢀfromꢀtheꢀpreviousꢀstepꢀandꢀbis(pinacolato)boraneꢀ(124ꢀg,ꢀ0.487ꢀmol,ꢀ1.2ꢀequiv.)ꢀwereꢀaddedꢀfollowedꢀbyꢀ
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theꢀsolutionꢀofꢀcatalyst.ꢀTheꢀreactionꢀmixtureꢀwasꢀwarmedꢀtoꢀ80ꢀ°Cꢀandꢀstirredꢀforꢀ4ꢀh.ꢀTheꢀreactionꢀwasꢀcooledꢀ
toꢀ23ꢀ°C,ꢀquenchedꢀbyꢀtheꢀadditionꢀofꢀaqueousꢀsodiumꢀthiosulfateꢀ(5ꢀwt%,ꢀ1.00ꢀL,ꢀ10ꢀmL/g),ꢀandꢀwasꢀstirredꢀforꢀ3ꢀ
h.ꢀ Theꢀ heterogeneousꢀ blackꢀ solutionꢀ wasꢀ filteredꢀ throughꢀ aꢀ padꢀ ofꢀ celiteꢀ andꢀ washedꢀ withꢀ PhMeꢀ (0.3ꢀ L,ꢀ 3.0ꢀ
mL/g).ꢀTheꢀlayersꢀwereꢀseparatedꢀandꢀtheꢀorganicsꢀwereꢀwashedꢀwithꢀaqueousꢀsodiumꢀthiosulfateꢀ(5ꢀwt%,ꢀ1.00ꢀ
L,ꢀ10ꢀmL/g).ꢀTheꢀheterogeneousꢀsolutionꢀwasꢀstirredꢀforꢀ1ꢀhꢀatꢀ25ꢀ°Cꢀandꢀfilteredꢀagainꢀthroughꢀaꢀpadꢀofꢀcelite.ꢀ
Theꢀlayersꢀwereꢀseparatedꢀandꢀtheꢀorganicꢀlayerꢀwasꢀconcentratedꢀunderꢀreducedꢀpressure.ꢀTheꢀresidueꢀwasꢀ
thriceꢀdissolvedꢀinꢀEtOHꢀ(0.7ꢀL,ꢀ7.0ꢀmL/g)ꢀandꢀconcentratedꢀinꢀvacuo.ꢀTheꢀresidueꢀwasꢀredissolvedꢀinꢀEtOHꢀ(0.7ꢀL,ꢀ
7.0ꢀmL/g),cooledꢀtoꢀ0ꢀ°Cꢀandꢀwaterꢀ(1.4ꢀL,ꢀ14ꢀmL/g)ꢀwasꢀslowlyꢀaddedꢀdropwiseꢀoverꢀ2ꢀh.ꢀTheꢀslurryꢀwasꢀstirredꢀatꢀ
0
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ꢀ°Cꢀforꢀanꢀadditionalꢀ2ꢀhꢀandꢀfiltered.ꢀTheꢀsolidsꢀwereꢀwashedꢀwithꢀwaterꢀ(0.4ꢀL,ꢀ4.0ꢀmL/g)ꢀandꢀdriedꢀinꢀvacuoꢀtoꢀ
affordꢀboronateꢀ6ꢀ(112ꢀg,ꢀ95.3ꢀwt%,ꢀ90%ꢀyield)ꢀasꢀlightꢀtanꢀplatesꢀ(mpꢀ44-49ꢀ°C).ꢀ
1
HꢀNMRꢀ(400MHz,ꢀDMSO-d
6
)ꢀδꢀ7.42ꢀ(d,ꢀJ=1.8ꢀHz,ꢀ1H),ꢀ7.02ꢀ(d,ꢀJ=1.8ꢀHz,ꢀ1H),ꢀ4.29ꢀ(q,ꢀJ=7.1ꢀHz,ꢀ2H),ꢀ4.19ꢀ(q,ꢀJ=7.2ꢀ
ꢀ
Hz,ꢀ2H),ꢀ1.26ꢀ(t,ꢀJ=7.2ꢀHz,ꢀ3H),ꢀ1.27ꢀ(t,ꢀJ=7.1ꢀHz,ꢀ3H),ꢀ1.23ꢀ(s,ꢀ12H)
13
CꢀNMRꢀ(100MHz,ꢀDMSO-d
6
)ꢀδꢀ160.0,ꢀ136.4,ꢀ123.8,ꢀ122.3,ꢀ117.6,ꢀ82.8,ꢀ59.4,ꢀ43.4,ꢀ24.6,ꢀ16.8,ꢀ14.1ꢀ
+
HRMS-ESIꢀ(m/z)ꢀcalc’dꢀforꢀC15
ꢀ
H
25BNO
4
ꢀ[M+H] ꢀꢀ294.1871,ꢀfoundꢀ294.1863ꢀ
4
5
1
-Me-4-CN-Imidazole,ꢀ11 ꢀ
Toꢀ aꢀ flaskꢀ wasꢀ addedꢀ methylammoniumꢀ chlorideꢀ (86.93ꢀ g,ꢀ 2.25ꢀ equiv),ꢀ AcOHꢀ (396ꢀ mL,ꢀ 3ꢀ mL/g)ꢀ andꢀ N-
methylanilineꢀ(6.12ꢀmL,ꢀ0.10ꢀequiv.).ꢀTheꢀmixtureꢀwasꢀheatedꢀtoꢀanꢀinternalꢀtemperatureꢀofꢀ105ꢀ°C.ꢀꢀSeparately,ꢀ
2
2
theꢀazadieneꢀ10ꢀ(preparedꢀusingꢀtheꢀreportedꢀprocedure,ꢀ123.05ꢀg) ꢀwasꢀdissolvedꢀinꢀAcOHꢀ(246ꢀmL,ꢀ2ꢀmL/g,ꢀ
minorꢀexotherm),ꢀandꢀwasꢀaddedꢀoverꢀ30ꢀminꢀmaintainingꢀanꢀinternalꢀtemperatureꢀofꢀ99-105ꢀ°C.ꢀTheꢀmixtureꢀ
wasꢀheldꢀatꢀ100-105ꢀ°Cꢀuntilꢀtheꢀazadieneꢀwasꢀconsumed.ꢀꢀTheꢀreactionꢀmixtureꢀwasꢀcooledꢀtoꢀ50ꢀ°C,ꢀandꢀthriceꢀ
dilutedꢀwithꢀtolueneꢀ(615ꢀmL)ꢀandꢀconcentratedꢀtoꢀapproximatelyꢀ200ꢀmL.ꢀꢀTheꢀmixtureꢀwasꢀdilutedꢀwithꢀwaterꢀ
(
615ꢀmL)ꢀandꢀbroughtꢀtoꢀpHꢀ6.5ꢀbyꢀtheꢀadditionꢀofꢀ50ꢀwtꢀ%ꢀNaOH,ꢀkeepingꢀtheꢀinternalꢀtemperatureꢀbelowꢀ30ꢀ°C.ꢀꢀ
Activatedꢀcarbonꢀ(DarcoꢀG-60,ꢀ40.6ꢀg,ꢀ33%ꢀwtꢀwithꢀrespectꢀtoꢀazadieneꢀstartingꢀmaterial)ꢀwasꢀadded,ꢀtheꢀmixtureꢀ
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stirredꢀforꢀ30ꢀmin,ꢀfiltered,ꢀandꢀrinsedꢀwithꢀwaterꢀ(40ꢀmL),ꢀthenꢀdichloromethaneꢀ(615ꢀmL,ꢀ5ꢀmL/g).ꢀꢀTheꢀlayersꢀ
wereꢀ separatedꢀ andꢀ theꢀ aqueousꢀ layerꢀ wasꢀ extractedꢀ withꢀ dichloromethaneꢀ (2ꢀ xꢀ 615ꢀ mL,ꢀ 2ꢀ xꢀ 5ꢀ mL/g).ꢀ ꢀ Theꢀ
combinedꢀorganicꢀlayersꢀwereꢀconcentratedꢀtoꢀapproximatelyꢀ2ꢀmL/g,ꢀthenꢀpetroleumꢀetherꢀ(bpꢀ30-60ꢀ°C,ꢀ1.23ꢀL,ꢀ
1
7
0ꢀ mL/g)ꢀ wasꢀ slowlyꢀ addedꢀ overꢀ 1ꢀ hꢀ toꢀ precipitateꢀ theꢀ desiredꢀ imidazoleꢀ 11ꢀ asꢀ lightꢀ orangeꢀ needlesꢀ (73-
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
5°C)whichꢀwereꢀusedꢀwithoutꢀfurtherꢀpurification.ꢀꢀTypicalꢀisolatedꢀyieldꢀ~50%.ꢀꢀAllꢀspectroscopicꢀdataꢀmatchedꢀ
43
priorꢀliterature. ꢀ
5
-Bromo-1-methyl-1H-imidazole-4-carbonitrile,ꢀ3ꢀ
Toꢀaꢀsolutionꢀofꢀcyanoimidazoleꢀ11ꢀ(200ꢀg,ꢀ1.87ꢀmol,ꢀ1.0ꢀequiv.)ꢀinꢀDMFꢀ(1.0ꢀL,ꢀ5.0ꢀmL/g)ꢀatꢀ30-35ꢀ°Cꢀwasꢀaddedꢀ
NBSꢀ(365ꢀg,ꢀ2.05ꢀmol,ꢀ1.1ꢀequiv.)ꢀslowlyꢀportionwise.ꢀTheꢀreactionꢀmixtureꢀwasꢀstirredꢀatꢀ30-35ꢀ°Cꢀforꢀ5ꢀh.ꢀTheꢀ
reactionꢀmixtureꢀwasꢀcooledꢀtoꢀ10ꢀ°Cꢀandꢀquenchedꢀbyꢀtheꢀslowꢀadditionꢀofꢀwaterꢀ(4.0ꢀL,ꢀ20ꢀmL/g)ꢀandꢀstirredꢀforꢀ
anꢀ additionalꢀ 5ꢀ h.ꢀ Theꢀ solidsꢀ wereꢀ filtered,ꢀ washedꢀ withꢀ waterꢀ (0.8ꢀ L,ꢀ 4.0ꢀ mL/g)ꢀ andꢀ driedꢀ inꢀ vacuoꢀ toꢀ yieldꢀ
bromocyanoimidazoleꢀ3ꢀ(250.2ꢀg,ꢀ70%ꢀyield)ꢀasꢀaꢀwhiteꢀplatesꢀ(mpꢀ140-147ꢀ°C).ꢀ
1
6
HꢀNMRꢀ(400MHz,ꢀDMSO-d )ꢀδꢀ8.05ꢀ(s,ꢀ1H),ꢀ3.66ꢀ(s,ꢀ3H)ꢀ
13
CꢀNMRꢀ(100MHz,ꢀDMSO-d
6
)ꢀδꢀ141.4,ꢀ115.0,ꢀ114.3,ꢀ113.4,ꢀ33.4ꢀ
+
HRMS-ESIꢀ(m/z)ꢀcalc’dꢀforꢀC
ꢀ
5
H
5
N
3
Brꢀ[M+H] ꢀꢀ185.9664,ꢀfoundꢀ185.9660ꢀ
Ethylꢀ4-(4-cyano-1-methyl-1H-imidazol-5-yl)-1-ethyl-1H-pyrrole-2-carboxylate,ꢀ7ꢀ
2 3
ToꢀaꢀflaskꢀchargedꢀwithꢀPd(OAc) ꢀ(0.574ꢀg,ꢀ2.56ꢀmmol,ꢀ0.01ꢀequiv.)ꢀandꢀPPh ꢀ(1.34ꢀg,ꢀ5.12ꢀmmol,ꢀ0.025ꢀequiv.)ꢀ
wasꢀaddedꢀDMAcꢀ(12.8ꢀmL,ꢀ0.17ꢀmL/g).ꢀTheꢀsolutionꢀwasꢀdegassedꢀandꢀstirredꢀatꢀambientꢀtemperatureꢀforꢀ10ꢀ
min.ꢀToꢀaꢀseparateꢀflaskꢀchargedꢀwithꢀboronateꢀ6ꢀ(75.0ꢀg,ꢀ0.256ꢀmol,ꢀ1.00ꢀequiv.)ꢀasꢀaꢀsolutionꢀinꢀDMAcꢀ(375ꢀmL,ꢀ
5
0
ꢀmL/g)ꢀwasꢀaddedꢀbromocyanoimidazoleꢀ3ꢀ(42.8ꢀg,ꢀ0.230ꢀmol,ꢀ0.9ꢀequiv.)ꢀandꢀpotassiumꢀcarbonateꢀ(53.0ꢀg,ꢀ
.384ꢀmmol,ꢀ1.5ꢀequiv.)ꢀfollowedꢀbyꢀDMAcꢀ(750ꢀmL,ꢀ10ꢀmL/g)ꢀandꢀwaterꢀ(375ꢀmL,ꢀ5.0ꢀmL/g).ꢀTheꢀslurryꢀwasꢀ
degassed,ꢀandꢀtheꢀpalladiumꢀcatalystꢀsolutionꢀwasꢀadded,ꢀheldꢀforꢀ10ꢀminꢀatꢀambientꢀtemperature,ꢀandꢀthenꢀ
ACS Paragon Plus Environment

Page 21 of 32
The Journal of Organic Chemistry
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6
warmedꢀtoꢀ80ꢀ°Cꢀforꢀanꢀadditionalꢀ2ꢀh.ꢀTheꢀreactionꢀmixtureꢀwasꢀquenchedꢀbyꢀtheꢀslowꢀadditionꢀofꢀwaterꢀ(2.18ꢀL,ꢀ
o
2
9ꢀmL/g)ꢀwhileꢀmaintainingꢀanꢀinternalꢀtemperatureꢀbelowꢀ35ꢀ Cꢀandꢀstirredꢀforꢀanꢀadditionalꢀ2ꢀh.ꢀTheꢀsolidsꢀ
wereꢀfiltered,ꢀwashedꢀwithꢀwaterꢀ(975ꢀmL,ꢀ13ꢀmL/g)ꢀandꢀdriedꢀinꢀvacuoꢀtoꢀprovideꢀimidazolpyrroleꢀ7ꢀ(58.6ꢀg,ꢀ84%ꢀ
yield)ꢀasꢀwhiteꢀplatesꢀ(mpꢀ208-216ꢀ°C).ꢀ
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
HꢀNMRꢀ(400MHz,ꢀDMSO-d
6
)ꢀδꢀ7.85ꢀ(s,ꢀ1H),ꢀ7.68ꢀ(d,ꢀJ=1.8ꢀHz,ꢀ1H),ꢀ7.21ꢀ(d,ꢀJ=1.8ꢀHz,ꢀ1H),ꢀ4.39ꢀ(q,ꢀJ=7.1ꢀHz,ꢀ2H),ꢀ
4
.27ꢀ(q,ꢀJ=6.9ꢀHz,ꢀ2H),ꢀ3.72ꢀ(s,ꢀ3H),ꢀ1.35ꢀ(t,ꢀJ=7.1ꢀHz,ꢀ3H),ꢀ1.29ꢀ(t,ꢀJ=7.1ꢀHz,ꢀ3H)ꢀ
1
3
CꢀNMRꢀ(100MHz,ꢀDMSO-d
6
)ꢀδꢀ159.7,ꢀ140.4,ꢀ136.2,ꢀ127.9,ꢀ122.2,ꢀ116.5,ꢀ116.1,ꢀ108.9,ꢀ108.2,ꢀ59.9,ꢀ43.9,ꢀ33.0,ꢀ
16.8,ꢀ14.2ꢀ
+
HRMS-ESIꢀ(m/z)ꢀcalc’dꢀforꢀC14
ꢀ
H
17
N
4
O
2
ꢀ[M+H] ꢀꢀ273.1346,ꢀfoundꢀ273.1342.ꢀ
Ethylꢀ1-ethyl-4-(4-(N-hydroxycarbamimidoyl)-1-methyl-1H-imidazol-5-yl)-1H-pyrrole-2-carboxylate,ꢀ12ꢀ
Toꢀ aꢀ solutionꢀ ofꢀ pyrroleꢀ 7ꢀ (58.6ꢀ g,ꢀ 0.215ꢀ mol,ꢀ 1.00ꢀ equiv.)ꢀ inꢀ EtOHꢀ (762ꢀ mL,ꢀ 13.0ꢀ mL/g)ꢀ atꢀ 40ꢀ °Cꢀ wasꢀ addedꢀ
NH
2
OH•HClꢀ(59.8ꢀg,ꢀ0.861ꢀmol,ꢀ4.00ꢀequiv.)ꢀfollowedꢀbyꢀEtOHꢀ(117ꢀmL,ꢀ2.0ꢀmL/g).ꢀTheꢀreactionꢀmixtureꢀwasꢀ
Nꢀ(123ꢀmL,ꢀ0.882ꢀmol,ꢀ4.1ꢀequiv.)ꢀoverꢀ1ꢀhꢀwhileꢀ
stirredꢀatꢀ40ꢀ°Cꢀforꢀ10ꢀminꢀfollowedꢀbyꢀtheꢀslowꢀadditionꢀofꢀEt
3
maintainingꢀanꢀinternalꢀtemperatureꢀbelowꢀ40ꢀ°C,ꢀthenꢀwasꢀstirredꢀatꢀ40ꢀ°Cꢀforꢀanꢀadditionalꢀ16ꢀh.ꢀTheꢀreactionꢀ
mixtureꢀwasꢀcooledꢀtoꢀambientꢀtemperatureꢀandꢀstirredꢀforꢀanꢀadditionalꢀ1ꢀh.ꢀTheꢀsolidsꢀwereꢀfiltered,ꢀwashedꢀ
withꢀwaterꢀ(234ꢀmL,ꢀ4.0ꢀmL/g)ꢀandꢀdriedꢀinꢀvacuoꢀtoꢀprovideꢀhydroxyamidineꢀ12ꢀ(58.2ꢀg,ꢀ0.191ꢀmol,ꢀ89%ꢀyield)ꢀasꢀ
off-whiteꢀplatesꢀ(mpꢀ226-229ꢀ°C).ꢀ
1
HꢀNMRꢀ(400MHz,ꢀDMSO-d
6
)ꢀδꢀ9.15ꢀ(s,ꢀ1H),ꢀ7.67ꢀ(s,ꢀ1H),ꢀ7.50ꢀ(d,ꢀJ=1.8ꢀHz,ꢀ1H),ꢀ7.04ꢀ(d,ꢀJ=1.8ꢀHz,ꢀ1H),ꢀ5.33ꢀ(s,ꢀ2H),ꢀ
4
.32ꢀ(q,ꢀJ=7.1ꢀHz,ꢀ2H),ꢀ4.23ꢀ(q,ꢀJ=7.1ꢀHz,ꢀ2H),ꢀ1.34ꢀ(t,ꢀJ=7.1ꢀHz,ꢀ3H),ꢀ1.28ꢀ(t,ꢀJ=7.1ꢀHz,ꢀ3H)ꢀ
13
CꢀNMRꢀ(100MHz,ꢀDMSO-d
6
)ꢀδꢀ160.1,ꢀ148.0,ꢀ137.2,ꢀ130.9,ꢀ129.8,ꢀ123.8,ꢀ120.5,ꢀ118.8,ꢀ110.5,ꢀ59.5,ꢀ43.5,ꢀ32.2,ꢀ
1
6.8,ꢀ14.3ꢀ
+
HRMS-ESIꢀ(m/z)ꢀcalc’dꢀforꢀC14
H
20
N
5
O
3
ꢀ[M+H] ꢀꢀ306.1561,ꢀfoundꢀ306.1551ꢀ
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 22 of 32
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ꢀ
Ethylꢀ4-amino-6-ethyl-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxylateꢀaceticꢀacidꢀsaltꢀ14ꢀ
Toꢀaꢀpressureꢀvesselꢀchargedꢀwithꢀhydroxyamidineꢀ12ꢀ(50.0ꢀg,ꢀ0.164ꢀmol,ꢀ1.0ꢀequiv.)ꢀinꢀAcOHꢀ(0.650ꢀL,ꢀ13.0ꢀmL/g)ꢀ
andꢀPhMeꢀ(0.500ꢀL,ꢀ10.0ꢀmL/g)ꢀwasꢀaddedꢀPiv
2
Oꢀ(30.5ꢀg,ꢀ0.164ꢀmol,ꢀ1.0ꢀequiv.)ꢀfollowedꢀbyꢀPhMeꢀ(0.150ꢀL,ꢀ3.0ꢀ
ꢀandꢀtheꢀreactionꢀmixtureꢀwasꢀstirredꢀatꢀ20-30ꢀ°Cꢀforꢀ0.5ꢀh.ꢀ
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
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4
5
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7
8
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1
2
3
4
5
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7
8
9
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1
2
3
4
5
6
7
8
9
0
mL/g).ꢀTheꢀpressureꢀvesselꢀwasꢀdegassedꢀwithꢀN
2
PRICATꢀ(9.00ꢀg,ꢀ18-20ꢀwt%)ꢀasꢀaꢀslurryꢀinꢀAcOHꢀ(0.100ꢀL,ꢀ2.0ꢀmL/g)ꢀandꢀPhMeꢀ(0.1ꢀL,ꢀ2.0ꢀmL/g)ꢀwasꢀaddedꢀandꢀtheꢀ
pressureꢀvesselꢀdegassedꢀwithꢀnitrogenꢀandꢀthenꢀpressurizedꢀwithꢀhydrogenꢀ(3ꢀpsig).ꢀTheꢀreactionꢀmixtureꢀwasꢀ
stirredꢀatꢀ20-30ꢀ°Cꢀforꢀ20ꢀh.ꢀUponꢀcompletion,ꢀtheꢀhydrogenꢀwasꢀpurgedꢀfromꢀtheꢀpressureꢀvesselꢀwithꢀnitrogen.ꢀꢀ
TheꢀreactionꢀmixtureꢀwasꢀfilteredꢀthroughꢀaꢀplugꢀofꢀceliteꢀandꢀtheꢀcakeꢀwasꢀwashedꢀwithꢀPhMeꢀ(2ꢀxꢀ0150ꢀL,ꢀ2ꢀxꢀ
3
.0ꢀ mL/g).ꢀ Theꢀ reactionꢀ mixtureꢀ wasꢀ concentratedꢀ andꢀ thriceꢀ dissolvedꢀ inꢀ PhMeꢀ (0.250ꢀ L,ꢀ 5.0ꢀ mL/g)ꢀ andꢀ
concentratedꢀtoꢀremoveꢀexcessꢀAcOH.ꢀToꢀtheꢀresidueꢀwasꢀaddedꢀPhMeꢀ(0.200ꢀL,ꢀ4.0ꢀmL/g)ꢀandꢀtheꢀmixtureꢀwasꢀ
warmedꢀtoꢀ50ꢀ°Cꢀforꢀ2-5ꢀhꢀtoꢀeffectꢀcrystallization.ꢀTheꢀmixtureꢀwasꢀcooledꢀtoꢀ0ꢀ°Cꢀandꢀstirredꢀforꢀanꢀadditionalꢀ2-
5
ꢀh.ꢀTheꢀsolidsꢀwereꢀfilteredꢀandꢀwashedꢀwithꢀPhMeꢀ(2ꢀxꢀ0.100ꢀL,ꢀ2ꢀxꢀ2.0ꢀmL/g)ꢀandꢀdriedꢀinꢀvacuoꢀtoꢀprovideꢀtheꢀ
AcOHꢀsaltꢀofꢀaminopyridineꢀ14ꢀ(36.4ꢀg,ꢀ64%ꢀyield)ꢀasꢀwhiteꢀrodsꢀ(mpꢀ208-210ꢀ°C).ꢀ
1
HꢀNMRꢀ(400MHz,ꢀDMSO-d
6
)ꢀδꢀ12.00ꢀ(brꢀs,ꢀ1H),ꢀ7.96ꢀ(brꢀs,ꢀ1H),ꢀ7.38ꢀ(s,ꢀ1H),ꢀ6.57ꢀ(brꢀs,ꢀ2H),ꢀ4.59ꢀ(q,ꢀJ=6.8ꢀHz,ꢀ2H),ꢀ
4
.28ꢀ(q,ꢀJ=7.1ꢀHz,ꢀ2H),ꢀ3.99ꢀ(s,ꢀ3H),ꢀ1.91ꢀ(brꢀs,ꢀ3H),ꢀ1.32ꢀ(t,ꢀJ=7.1ꢀHz,ꢀ3H),ꢀ1.25ꢀ(t,ꢀJ=6.9ꢀHz,ꢀ3H)ꢀ
13
CꢀNMRꢀ(100MHz,ꢀDMSO-d
6
)ꢀδꢀ160.8,ꢀ151.4,ꢀ145.5,ꢀ140.2,ꢀ133.2,ꢀ119.3,ꢀ106.1,ꢀ98.0,ꢀ59.5,ꢀ37.7,ꢀ32.2,ꢀ21.0,ꢀ15.8,ꢀ
1
4.3ꢀ
+
HRMS-ESIꢀ(m/z)ꢀcalc’dꢀforꢀC14
ꢀ
H
18
N
5
O
2
ꢀ[M+H] ꢀꢀ288.1455,ꢀfoundꢀ288.1448ꢀ
1
,5-dimethyl-1H-pyrazol-3-olꢀhydrochloride,ꢀ16ꢀꢀꢀ
Toꢀaꢀsolutionꢀofꢀ2-butynoicꢀacidꢀ(10.0ꢀg,ꢀ118ꢀmmol,ꢀ1.00ꢀequiv.)ꢀandꢀDMAPꢀ(1.45ꢀg,ꢀ11.9ꢀmmol,ꢀ0.1ꢀequiv.)ꢀinꢀ
dichloromethaneꢀ(100ꢀmL,ꢀ10ꢀmL/g)ꢀwasꢀchargedꢀN-Bocꢀmethylꢀhydrazineꢀ(18.5ꢀg,ꢀ126ꢀmmol,ꢀ1.06ꢀequiv.)ꢀoverꢀ1ꢀ
min.ꢀꢀTheꢀreactionꢀmixtureꢀwasꢀcooledꢀtoꢀ0ꢀ°CꢀandꢀEDACꢀ(25.1ꢀg,ꢀ131ꢀmmol,ꢀ1.10ꢀequiv.)ꢀwasꢀchargedꢀinꢀ5ꢀequalꢀ
ACS Paragon Plus Environment

Page 23 of 32
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6
portionsꢀoverꢀ50ꢀmin.ꢀꢀTheꢀresultingꢀpaleꢀyellowꢀsolutionꢀwasꢀthenꢀallowedꢀtoꢀwarmꢀtoꢀambientꢀtemperature,ꢀ
stirredꢀanꢀadditionalꢀ1.5ꢀh,ꢀthenꢀwasꢀdilutedꢀwithꢀ1ꢀNꢀaqueousꢀHClꢀ(100ꢀmL,ꢀ10ꢀmL/g)ꢀandꢀagitatedꢀforꢀ5ꢀmin.ꢀꢀTheꢀ
organicꢀlayerꢀwasꢀseparated,ꢀandꢀwashedꢀwithꢀ1ꢀNꢀaqueousꢀHClꢀ(100ꢀmL,ꢀ10ꢀmL/g)ꢀandꢀthenꢀwaterꢀ(100ꢀmL,ꢀ10ꢀ
4
mL/g).ꢀꢀTheꢀsolutionꢀwasꢀdriedꢀoverꢀMgSO ,ꢀfilteredꢀandꢀconcentratedꢀinꢀvacuo.ꢀꢀTheꢀresidueꢀwasꢀthenꢀchargedꢀ
0
1
2
3
4
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8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
withꢀ2-propanolꢀ(125ꢀmL,ꢀ12.5ꢀmL/g),ꢀfollowedꢀbyꢀconcentratedꢀHClꢀ(25.9ꢀg,ꢀ261ꢀmmol,ꢀ2.20ꢀeq)ꢀoverꢀ1ꢀmin.ꢀꢀTheꢀ
reactionꢀmixtureꢀwasꢀthenꢀwarmedꢀtoꢀ63ꢀ°C,ꢀatꢀwhichꢀpointꢀgasꢀevolutionꢀwasꢀobserved.ꢀꢀAfterꢀ30ꢀh,ꢀtheꢀreactionꢀ
mixtureꢀ wasꢀ cooledꢀ toꢀ ambientꢀ temperatureꢀ andꢀ concentratedꢀ inꢀ vacuo.ꢀ ꢀ ꢀ Theꢀ resultingꢀ residueꢀ wasꢀ thenꢀ
chargedꢀwithꢀCH
3
CNꢀ(100ꢀmL,ꢀ10ꢀmL/g)ꢀandꢀconcentratedꢀinꢀvacuo.ꢀꢀThisꢀprocessꢀwithꢀrepeatedꢀthriceꢀmore.ꢀꢀTheꢀ
°
finalꢀresidueꢀwasꢀthenꢀchargedꢀwithꢀCH
3
CNꢀ(40ꢀmL,ꢀ4ꢀmL/g)ꢀandꢀwarmedꢀtoꢀ75ꢀ C.ꢀꢀTheꢀresultingꢀslurryꢀwasꢀthenꢀ
cooledꢀtoꢀambientꢀtemperatureꢀoverꢀ1ꢀh,ꢀandꢀallowedꢀtoꢀcontinueꢀtoꢀdesaturateꢀovernight.ꢀꢀTheꢀsolidsꢀwereꢀ
filteredꢀandꢀwashedꢀwithꢀCH CNꢀ(2ꢀxꢀ40ꢀmL,ꢀ2ꢀxꢀ4ꢀmL/g),ꢀthenꢀdriedꢀunderꢀvacuumꢀatꢀambientꢀtemperatureꢀtoꢀ
3
affordꢀsaltꢀ16ꢀ(13.7ꢀg,ꢀ78%ꢀyield)ꢀasꢀaꢀwhiteꢀcrystallineꢀsolidꢀ(mpꢀ178-182ꢀ°C).ꢀ
1
3
H-NMRꢀ(400MHz,ꢀCDCl )ꢀδꢀ5.72ꢀ(s,ꢀ1ꢀH);ꢀ3.65ꢀ(s,ꢀ3ꢀH);ꢀ2.24ꢀ(s,ꢀ3ꢀH)ꢀ
1
3
C-NMRꢀ(100MHz,ꢀCDCl
3
)ꢀδꢀ156.6,ꢀ146.0,ꢀ90.6,ꢀ34.1,ꢀ10.8ꢀ
+
HRMS-ESIꢀ(m/z)ꢀcalc’dꢀforꢀC
ꢀ
5
H
9
N
2
Oꢀ[M+H] ꢀꢀ113.0709,ꢀfoundꢀ113.0712ꢀ
1
,5-dimethyl-1H-pyrazol-3-ylꢀmethanesulfonateꢀ
Toꢀaꢀmixtureꢀofꢀ1,5-dimethyl-1H-pyrazol-3-olꢀhydrochlorideꢀ16ꢀ(0.400ꢀg,ꢀ2.69ꢀmmoles,ꢀlimitingꢀreagent),ꢀ
potassiumꢀcarbonateꢀ(0.930ꢀg,ꢀ6.73ꢀmmoles,ꢀ2.5ꢀequiv.)ꢀandꢀtetraethylammoniumꢀbromideꢀ(0.170ꢀg,ꢀ0.809ꢀ
mmoles,ꢀ0.3ꢀequiv.)ꢀinꢀCH
3
CNꢀ(8ꢀmL,ꢀ20ꢀmL/g)ꢀatꢀambientꢀtemperatureꢀwasꢀchargedꢀmethanesulfonylꢀchlorideꢀ
o
(
0.460ꢀg,ꢀ4.02ꢀmmoles,ꢀ1.5ꢀequiv.).ꢀꢀTheꢀresultingꢀwhiteꢀslurryꢀwasꢀwarmedꢀtoꢀ45ꢀ C,ꢀandꢀafterꢀ2.5ꢀh,ꢀwasꢀcooledꢀ
2
toꢀambientꢀtemperatureꢀandꢀconcentratedꢀꢀinꢀvacuo.ꢀꢀPurificationꢀbyꢀSiO ꢀ[40ꢀgꢀISCOꢀcolumn,ꢀflowꢀrateꢀ30ꢀ
mL/min,ꢀgradientꢀ10%ꢀtoꢀ65%ꢀEtOAcꢀinꢀhex;ꢀRfꢀ=ꢀ0.31ꢀ(1:1ꢀhex:EtOAc)]ꢀaffordedꢀ0.410ꢀgꢀ(80%ꢀyield)ꢀasꢀaꢀwhiteꢀ
crystallineꢀsolidꢀ(mpꢀ88-89ꢀ°C)ꢀafterꢀdryingꢀinꢀvacuumꢀoven.ꢀ
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2
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7
8
9
1
1
1
1
1
1
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2
2
2
2
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4
4
4
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5
5
5
5
5
5
5
5
5
6
1
1
H-NMRꢀ(400ꢀMHz,ꢀCDCl
3
)ꢀδꢀ5.85ꢀ(s,ꢀ1ꢀH);ꢀ3.68ꢀ(s,ꢀ3ꢀH);ꢀ3.25ꢀ(s,ꢀ3ꢀH),ꢀ2.23ꢀ(s,ꢀ3ꢀH)ꢀ
3
C-NMRꢀ(100ꢀMHz,ꢀCDCl
3
)ꢀδꢀ152.1,ꢀ140.7,ꢀ96.3,ꢀ37.9,ꢀ36.1,ꢀ11.3ꢀ
+
HRMS-ESIꢀ(m/z)ꢀcalc’dꢀforꢀC
ꢀ
6
H
11
N
2
O
3
Sꢀ[M+H] ꢀꢀ191.0485,ꢀfoundꢀ191.0483ꢀ
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1,5-dimethyl-1H-pyrazol-3-ylꢀ4-methylbenzenesulfonateꢀꢀꢀꢀ
Toꢀaꢀmixtureꢀofꢀ1,5-dimethyl-1H-pyrazol-3-olꢀhydrochlorideꢀ16ꢀ(0.400ꢀg,ꢀ2.69ꢀmmoles,ꢀlimitingꢀreagent),ꢀ
potassiumꢀcarbonateꢀ(0.930ꢀg,ꢀ6.73ꢀmmoles,ꢀ2.5ꢀequiv.)ꢀandꢀtetraethylammoniumꢀbromideꢀ(0.170ꢀg,ꢀ0.809ꢀ
mmoles,ꢀ0.3ꢀequiv.)ꢀinꢀCH
(0.770ꢀg,ꢀ4.04ꢀmmoles,ꢀ1.5ꢀequiv.).ꢀꢀTheꢀresultingꢀwhiteꢀslurryꢀwasꢀwarmedꢀtoꢀ45ꢀ C,ꢀandꢀafterꢀ2.5ꢀh,ꢀwasꢀcooledꢀ
toꢀambientꢀtemperatureꢀandꢀconcentratedꢀinꢀvacuo.ꢀꢀPurificationꢀbyꢀSiO ꢀ[40ꢀgꢀISCOꢀcolumn,ꢀflowꢀrateꢀ30ꢀ
3
CNꢀ(8ꢀmL,ꢀ20ꢀmL/g)ꢀatꢀambientꢀtemperatureꢀwasꢀchargedꢀp-toluenesulfonylꢀchlorideꢀ
o
2
mL/min,ꢀgradientꢀ10%ꢀtoꢀ50%ꢀEtOAcꢀinꢀhex;ꢀRfꢀ=ꢀ0.24ꢀ(2:1ꢀhex:EtOAc)]ꢀaffordedꢀ0.612ꢀgꢀ(85%ꢀyield)ꢀasꢀaꢀwhiteꢀ
crystallineꢀsolidꢀ(mpꢀ93-94ꢀ°C)ꢀafterꢀdryingꢀinꢀvacuumꢀoven.ꢀ
1
H-NMRꢀ(400ꢀMHz,ꢀCDCl
.18ꢀ(s,ꢀ3ꢀH)ꢀ
3
)ꢀδꢀ7.79ꢀ(d,ꢀJ=ꢀ8ꢀHz,ꢀ2ꢀH);ꢀ7.31ꢀ(d,ꢀJꢀ=ꢀ8ꢀHz,ꢀ2ꢀH);ꢀ5.70ꢀ(s,ꢀ1ꢀH),ꢀ3.59ꢀ(s,ꢀ3ꢀH),ꢀ2.43ꢀ(s,ꢀ3ꢀH),ꢀ
2
1
3
C-NMRꢀ(100ꢀMHz,ꢀCDCl
3
)ꢀδꢀ151.8,ꢀ145.2,ꢀ140.2,ꢀ132.5,ꢀ129.6,ꢀ128.4,ꢀ95.9,ꢀ36.0,ꢀ21.6,ꢀ11.3ꢀ
+
HRMS-ESIꢀ(m/z)ꢀcalc’dꢀforꢀC12
H
15
N
2
O
3
Sꢀ[M+H] ꢀꢀ267.0797,ꢀfoundꢀ267.0795ꢀ
1,5-dimethyl-1H-pyrazol-3-ylꢀtrifluoromethanesulfonateꢀꢀ
Toꢀaꢀmixtureꢀofꢀ1,5-dimethyl-1H-pyrazol-3-olꢀhydrochlorideꢀ16ꢀ(5.00ꢀg,ꢀ33.65ꢀmmoles,ꢀlimitingꢀreagent)ꢀandꢀDCMꢀ
(
100ꢀmL,ꢀ20ꢀmL/g)ꢀwasꢀchargedꢀDIPEAꢀ(10.5ꢀg,ꢀ81.24ꢀmmoles,ꢀ2.4ꢀequiv.).ꢀꢀTheꢀresultingꢀclear,ꢀcolorlessꢀsolutionꢀ
o
wasꢀcooledꢀtoꢀ-7ꢀ Cꢀandꢀtreatedꢀwithꢀtrifluromethanesulfonicꢀanhydrideꢀ(10.7ꢀg,ꢀ37.92ꢀmmoles,ꢀ1.13ꢀequiv.)ꢀ
o
dropwiseꢀoverꢀ~30ꢀminꢀmaintainingꢀtheꢀinternalꢀtemperatureꢀbelowꢀ0ꢀ C.ꢀꢀTheꢀresultingꢀyellowꢀsolutionꢀwasꢀthenꢀ
o
o
3
agedꢀbetweenꢀ-5ꢀ Cꢀandꢀ0ꢀ Cꢀforꢀ1ꢀh.ꢀꢀReactionꢀmixtureꢀwasꢀthenꢀchargedꢀwithꢀ50%ꢀsaturatedꢀaqueousꢀNaHCO ꢀ
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1
o
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
(100ꢀmL,ꢀ20ꢀvol)ꢀoverꢀ~5ꢀmin,ꢀmaintainingꢀtheꢀinternalꢀtemperatureꢀ<10ꢀ C.ꢀꢀBiphasicꢀmixtureꢀwasꢀthenꢀwarmedꢀ
toꢀambientꢀtemperatureꢀandꢀtheꢀresultingꢀlowerꢀDCMꢀlayerꢀwasꢀdriedꢀoverꢀMgSO
vacuo.ꢀꢀPurificationꢀbyꢀSiO ꢀ(160ꢀgꢀISCOꢀcolumn,ꢀflowꢀrateꢀ40ꢀmL/min,ꢀgradientꢀ0%ꢀtoꢀ35%ꢀEtOAcꢀinꢀhex)ꢀaffordedꢀ
.17ꢀgꢀ(63%ꢀyield)ꢀofꢀtheꢀtriflateꢀasꢀaꢀpaleꢀyellowꢀoil.ꢀꢀ
4
,ꢀfilteredꢀandꢀconcentratedꢀinꢀ
2
5
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
3
H-NMRꢀ(400ꢀMHz,ꢀCDCl )ꢀδꢀ5.90ꢀ(s,ꢀ1ꢀH),ꢀ3.70ꢀ(s,ꢀ3ꢀH),ꢀ2.23ꢀ(s,ꢀ3ꢀH)ꢀ
1
3
C-NMRꢀ(100ꢀMHz,ꢀCDCl
3
)ꢀδꢀ150.8,ꢀ141.2,ꢀ118.6ꢀ(q,ꢀJ=ꢀ1020ꢀHz),ꢀ95.5,ꢀ36.2,ꢀ11.3ꢀ
+
HRMS-ESIꢀ(m/z)ꢀcalc’dꢀforꢀC
6
H
8
F
3
N
2
O
3
Sꢀ[M+H] ꢀꢀ245.0208,ꢀfoundꢀ245.0200ꢀ
1
,5-dimethyl-1H-pyrazol-3-ylꢀdiphenylꢀphosphateꢀ
Toꢀaꢀmixtureꢀofꢀ1,5-dimethyl-1H-pyrazol-3-olꢀhydrochlorideꢀ16ꢀ(0.400ꢀg,ꢀ2.69ꢀmmoles,ꢀlimitingꢀreagent),ꢀ
potassiumꢀcarbonateꢀ(0.930ꢀg,ꢀ6.73ꢀmmoles,ꢀ2.5ꢀequiv.)ꢀandꢀtetraethylammoniumꢀbromideꢀ(0.170ꢀg,ꢀ0.809ꢀ
mmoles,ꢀ0.3ꢀequiv.)ꢀinꢀCH
3
CNꢀ(8ꢀmL,ꢀ20ꢀmL/g)ꢀatꢀambientꢀtemperatureꢀwasꢀchargedꢀdiphenylꢀchlorophosphateꢀ
o
(
0.800ꢀg,ꢀ2.98ꢀmmoles,ꢀ1.1ꢀequiv.).ꢀꢀTheꢀresultingꢀslurryꢀwasꢀwarmedꢀtoꢀ45ꢀ C,ꢀandꢀafterꢀ4ꢀh,ꢀwasꢀfiltered,ꢀrinsingꢀ
2
withꢀDCMꢀ(3ꢀxꢀ8ꢀmL),ꢀandꢀconcentratedꢀinꢀvacuo.ꢀꢀPurificationꢀbyꢀSiO ꢀ[12ꢀgꢀISCOꢀcolumn,ꢀflowꢀrateꢀ15ꢀmL/min,ꢀ
gradientꢀ0%ꢀtoꢀ66%ꢀEtOAcꢀinꢀhex;ꢀRfꢀ=ꢀ0.29ꢀ(1:1ꢀhex:EtOAc)]ꢀaffordedꢀ728ꢀgꢀ(79%ꢀyield)ꢀasꢀanꢀoilꢀwhichꢀsolidifiedꢀ
uponꢀstanding.ꢀ
1
3
H-NMRꢀ(400ꢀMHz,ꢀCDCl )ꢀδꢀ7.33ꢀ(m,ꢀ4ꢀH),ꢀ7.28ꢀ(m,ꢀ4ꢀH),ꢀ7.19ꢀ(m,ꢀ2ꢀH),ꢀ5.81ꢀ(s,ꢀ1ꢀH),ꢀ3.65ꢀ(s,ꢀ3ꢀH),ꢀ2.19ꢀ(s,ꢀ3ꢀH)ꢀ
1
3
C-NMRꢀ(100ꢀMHz,ꢀCDCl
3
)ꢀδꢀ152.5,ꢀ150.4,ꢀ140.2,ꢀ129.ꢀ7,ꢀ125.ꢀ5,ꢀ120.1,ꢀ93.7,ꢀ35.8,ꢀ11.3ꢀ
+
HRMS-ESIꢀ(m/z)ꢀcalc’dꢀforꢀC17
H
18
N
2
O
4
Pꢀ[M+H] ꢀꢀ345.0998,ꢀfoundꢀ345.0987ꢀ
2
ꢀ
,3-Dibromobutanenitrileꢀ17ꢀꢀ
Toꢀaꢀsolutionꢀofꢀcrotononitrileꢀ(500ꢀg,ꢀ7.45ꢀmol,ꢀ1.0ꢀequiv.)ꢀinꢀdichloromethaneꢀ(6.5ꢀL,ꢀ13ꢀmL/g)ꢀatꢀ5ꢀtoꢀ7ꢀ°Cꢀwasꢀ
addedꢀbromineꢀ(1.19ꢀKg,ꢀ7.45ꢀmol,ꢀ1.0ꢀequiv.)ꢀasꢀaꢀsolutionꢀinꢀdichloromethaneꢀ(1.0ꢀL,ꢀ2.0ꢀmL/gꢀbasedꢀonꢀnitrile)ꢀ
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2
2
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5
5
5
6
viaꢀanꢀadditionꢀfunnelꢀoverꢀaꢀperiodꢀofꢀ60ꢀmin,ꢀwhileꢀmaintainingꢀtheꢀinternalꢀtemperatureꢀatꢀ5ꢀtoꢀ10ꢀ°C.ꢀꢀ33%ꢀ
HBrꢀinꢀaceticꢀacidꢀ(9.0ꢀg,ꢀ0.0373ꢀmol,ꢀ0.005ꢀequiv.)ꢀwasꢀthenꢀaddedꢀatꢀ10ꢀtoꢀ12ꢀ°C,ꢀthenꢀtheꢀreactionꢀwasꢀstirredꢀ
forꢀ30ꢀminꢀatꢀ10ꢀtoꢀ12ꢀ°C,ꢀthenꢀraisedꢀtoꢀ18ꢀtoꢀ20ꢀ°Cꢀandꢀheldꢀforꢀ2ꢀtoꢀ4ꢀh.ꢀ(Note:ꢀanꢀexothermꢀwasꢀobservedꢀthatꢀ
increasedꢀtheꢀinternalꢀtemperatureꢀtoꢀ28ꢀ°C).ꢀTheꢀreactionꢀmixtureꢀwasꢀthenꢀconcentratedꢀinꢀvacuo,ꢀandꢀtheꢀ
crudeꢀmaterialꢀwasꢀusedꢀdirectlyꢀwithoutꢀpurificationꢀ(1.510ꢀkg,ꢀ89%ꢀyield).ꢀꢀ
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
ꢀ
4
6
1
,5-dimethyl-1H-pyrazol-3-amine,ꢀ18 ꢀꢀ
ꢀ
Dibromideꢀ17ꢀ(250ꢀg,ꢀ1.10ꢀmol,ꢀ1.00ꢀequiv.)ꢀwasꢀaddedꢀdropwiseꢀtoꢀaꢀsolutionꢀofꢀNaOHꢀ(132.2ꢀg,ꢀ3.30ꢀmol,ꢀ3.00ꢀ
equiv.)ꢀandꢀmethylꢀhydrazineꢀhydrogenꢀsulfateꢀ(50.7ꢀg,ꢀ1.10ꢀmol,ꢀ1.0ꢀequiv.)ꢀinꢀwaterꢀ(1.25ꢀL,ꢀ5ꢀmL/g).ꢀꢀOnceꢀtheꢀ
additionꢀwasꢀcomplete,ꢀtheꢀaqueousꢀmixtureꢀwasꢀextractedꢀwithꢀtolueneꢀ(250ꢀmL,ꢀ1.0ꢀmL/g)ꢀtoꢀremoveꢀorganicꢀ
impuritiesꢀ(theꢀproductꢀremainedꢀinꢀtheꢀaqueousꢀphase)ꢀandꢀthenꢀtheꢀaqueousꢀlayerꢀwasꢀwashedꢀwithꢀDCMꢀ(3ꢀxꢀ
2
-2.5mL/g)toꢀ extractꢀ theꢀ product.ꢀ Theꢀ dichloromethaneꢀ phasesꢀ wereꢀ combined,ꢀ driedꢀ overꢀ Na
2 4
SO ꢀ andꢀ
concentratedꢀinꢀvacuoꢀtoꢀgiveꢀpyrazoleꢀ18ꢀ(196ꢀg,ꢀ82%,ꢀ69:1ꢀN-Meꢀisomerꢀratio)ꢀasꢀaꢀlightꢀyellowꢀsolid.ꢀꢀTheꢀ
4
4
spectralꢀdataꢀwasꢀconsistentꢀwithꢀpreviousꢀreports. ꢀ
ꢀ
ꢀ
Ethylꢀ 4-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-6-ethyl-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-
7
-carboxylate,ꢀ20.ꢀ
Preparationꢀ ofꢀ 3-Iodo-1,5-dimethyl-1H-pyrazole,ꢀ 19:ꢀ Toꢀ aꢀ solutionꢀ ofꢀ pyrazoleꢀ 18ꢀ (41.6ꢀ g,ꢀ 374.28ꢀ mmol,ꢀ 1.00ꢀ
equiv.)ꢀinꢀisopropylꢀalcoholꢀ(0.21ꢀL,ꢀ5ꢀmL/g)ꢀwasꢀaddedꢀisobutylꢀnitriteꢀ(74.19ꢀmL,ꢀ561.42ꢀmmol,ꢀ1.50ꢀequiv.)ꢀandꢀ
diiodomethaneꢀ(52.79ꢀmL,ꢀ654.99ꢀmmol,ꢀ1.75ꢀequiv.)ꢀatꢀambientꢀtemperature.ꢀAfterꢀcompletionꢀofꢀtheꢀaddition,ꢀ
theꢀmixtureꢀwasꢀslowlyꢀheatedꢀtoꢀ55ꢀ°Cꢀoverꢀ1ꢀh,ꢀandꢀstirredꢀ5-6ꢀh.ꢀꢀTheꢀmixtureꢀwasꢀthenꢀcooledꢀtoꢀambientꢀ
temperature,ꢀandꢀaꢀ6ꢀNꢀaqueousꢀsolutionꢀofꢀHClꢀ(420ꢀmL,ꢀ10ꢀmL/g)ꢀwasꢀaddedꢀandꢀtheꢀresultingꢀsolutionꢀwasꢀ
washedꢀwithꢀheptaneꢀ(420ꢀmL,ꢀ10ꢀmL/g).ꢀTheꢀaqueousꢀphaseꢀwasꢀthenꢀneutralizedꢀwithꢀaꢀ10ꢀNꢀaqueousꢀsolutionꢀ
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Page 27 of 32
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1
2
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5
5
5
5
5
5
5
6
ofꢀNaOHꢀ(260ꢀmL,ꢀ6.25ꢀmL/g)ꢀtoꢀpHꢀ8-10,ꢀandꢀtheꢀproductꢀwasꢀextractedꢀwithꢀtolueneꢀ(420ꢀmL,ꢀ10.0ꢀmL/g).ꢀTheꢀ
resultingꢀ tolueneꢀ layerꢀ wasꢀ washedꢀ withꢀ aꢀ 0.5ꢀ Nꢀ aqueousꢀ solutionꢀ ofꢀ HClꢀ (210ꢀ mL,ꢀ 5.0ꢀ mL/g)ꢀ andꢀ aꢀ 5ꢀ wtꢀ %ꢀ
3 4
aqueousꢀ solutionꢀ ofꢀ K PO ꢀ (210ꢀ mL,ꢀ 5.0ꢀ mL/g).ꢀ ꢀ Theꢀ solutionꢀ wasꢀ thenꢀ concentratedꢀ inꢀ vacuoꢀ toꢀ affordꢀ
iodopyrazoleꢀ 19ꢀ (43.8ꢀ g,ꢀ 84.1ꢀ wt%;ꢀ 45%ꢀ correctedꢀ yield)ꢀ asꢀ aꢀ brownꢀ solid,ꢀ whichꢀ wasꢀ usedꢀ directlyꢀ withoutꢀ
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furtherꢀpurification.ꢀꢀ
ꢀ
Toꢀaꢀflaskꢀunderꢀaꢀnitrogenꢀblanket,ꢀwasꢀchargedꢀamineꢀ14ꢀ(62.0ꢀg,ꢀ179ꢀmmol,ꢀ1.00ꢀequiv.),ꢀiodopyrazoleꢀ19ꢀ(75.5ꢀ
g,ꢀ253.2ꢀmmol,ꢀ1.40ꢀequiv.),ꢀcopper(I)ꢀiodideꢀ(51.7ꢀg,ꢀ271.3ꢀmmol,ꢀ1.50ꢀequiv.),ꢀsodiumꢀt-butoxideꢀ(52.6ꢀg,ꢀ539.2ꢀ
mmol,ꢀ3.00ꢀequiv.)ꢀandꢀtolueneꢀ(1.24ꢀL,ꢀ20ꢀmL/g).ꢀSym-Dimethylethyleneꢀdiamineꢀ(24ꢀg,ꢀ271ꢀmmol,ꢀ1.50ꢀequiv.)ꢀ
wasꢀchargedꢀandꢀtheꢀbatchꢀwasꢀheatedꢀtoꢀ95-100ꢀ°Cꢀandꢀheldꢀforꢀ20ꢀh.ꢀTheꢀreactionꢀmixtureꢀwasꢀthenꢀcooledꢀtoꢀ
3
0ꢀ°Cꢀandꢀfiltered.ꢀTheꢀcakeꢀwasꢀrinsedꢀwithꢀTHF,ꢀfollowedꢀbyꢀdichloromethane.ꢀꢀTheꢀcakeꢀwasꢀchargedꢀbackꢀtoꢀ
theꢀflaskꢀandꢀwaterꢀ(620ꢀmL,ꢀ10.0ꢀmL/g)ꢀandꢀammoniumꢀhydroxideꢀ28ꢀwt%ꢀsolutionꢀ(620ꢀmL,ꢀ10.0ꢀmL/g)ꢀwereꢀ
added.ꢀTheꢀslurryꢀwasꢀstirredꢀforꢀ2ꢀh,ꢀthenꢀfilteredꢀandꢀtheꢀcakeꢀwasꢀwashedꢀwithꢀwater.ꢀꢀꢀTheꢀcakeꢀwasꢀthenꢀ
transferredꢀtoꢀaꢀflaskꢀcontainingꢀaceticꢀacidꢀ(309ꢀmL,ꢀ5.00ꢀmL/g)ꢀandꢀdichloromethaneꢀ(180ꢀmL,ꢀ2.90ꢀmL/g)ꢀandꢀ
stirredꢀtoꢀdissolve.ꢀꢀTheꢀsolutionꢀwasꢀthenꢀtransferredꢀslowlyꢀ(gasꢀevolution,ꢀexothermic)ꢀtoꢀaꢀflaskꢀcontainingꢀaꢀ
biphasicꢀsolutionꢀofꢀdichloromethaneꢀ(1.86ꢀL,ꢀ30.0ꢀmL/g)ꢀandꢀ28ꢀwt%ꢀaqueousꢀammoniumꢀhydroxideꢀ(1.61ꢀL,ꢀ
2
6.0ꢀ mL/g).ꢀ Theꢀ layersꢀ wereꢀ separated,ꢀ andꢀ theꢀ organicꢀ phaseꢀ wasꢀ washedꢀ withꢀ brineꢀ andꢀ concentratedꢀ inꢀ
vacuo.ꢀTheꢀresidueꢀwasꢀstirredꢀinꢀaꢀsolutionꢀofꢀTHFꢀ(868ꢀmL,ꢀ14.0ꢀmL/g)ꢀandꢀwaterꢀ(434ꢀmL,ꢀ7.0ꢀmL/g)ꢀatꢀ58ꢀ°Cꢀforꢀ
howꢀlong?.ꢀTheꢀsolidsꢀwereꢀfiltered,ꢀwashedꢀwithꢀTHF/waterꢀ1:3,ꢀthenꢀdriedꢀinꢀvacuoꢀatꢀ55ꢀ°Cꢀtoꢀaffordꢀesterꢀ20ꢀ
(
58.2ꢀg,ꢀ81%ꢀyield)ꢀasꢀoff-whiteꢀplatesꢀ(mpꢀ262-266ꢀ°C).ꢀꢀꢀꢀ
1
H-NMRꢀ(400ꢀMHz,ꢀCD
2 2
Cl )ꢀδꢀꢀ8.04ꢀ(s,ꢀ1ꢀH),ꢀ7.66ꢀ(s,ꢀ1ꢀH),ꢀ7.39ꢀ(s,ꢀ1ꢀH),ꢀ6.90ꢀ(s,ꢀ1ꢀH),ꢀ4.80ꢀ(q,ꢀJꢀ=ꢀ7.1ꢀHz,ꢀ2ꢀH),ꢀ4.35ꢀ
(q,ꢀJꢀ=ꢀ7.2ꢀHz,ꢀ2ꢀH),ꢀ4.02ꢀ(s,ꢀ3ꢀH),ꢀ3.69ꢀ(s,ꢀ3ꢀH),ꢀ2.32ꢀ(s,ꢀ3ꢀH),ꢀ1.44ꢀ(t,ꢀJꢀ=ꢀ6.9ꢀHz,ꢀ3ꢀH);ꢀ1.41ꢀ(t,ꢀJꢀ=ꢀ7.1ꢀHz,ꢀ3ꢀH);ꢀꢀ
1
3
C-NMRꢀ(100ꢀMHz,ꢀCDCl
3
)ꢀδꢀ162.0,ꢀ147.6,ꢀ146.1,ꢀ140.2,ꢀ139.5,ꢀ134.1,ꢀ125.6,ꢀ122.0,ꢀ105.7,ꢀ99.5,ꢀ96.6,ꢀ60.6,ꢀ51.0,ꢀ
3
9.6,ꢀ36.0,ꢀ33.2,ꢀ16.0,ꢀ14.9,ꢀ11.9;ꢀꢀ
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The Journal of Organic Chemistry
Page 28 of 32
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+
HRMS-ESIꢀ(m/z)ꢀcalc’dꢀforꢀC19
H
24
N
7
O
2
ꢀ[M+H] ꢀꢀ382.1986,ꢀfoundꢀ382.1977ꢀ
Sodiumꢀ
4-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-6-ethyl-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-
b]pyridine-7-carboxylate,ꢀ23ꢀ
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Toꢀ aꢀ flaskꢀ underꢀ aꢀ nitrogenꢀ blanketꢀ wasꢀ chargedꢀ esterꢀ 20ꢀ (8.0ꢀ g,ꢀ 21.0ꢀ mmol,ꢀ 1.0ꢀ eq),ꢀ followedꢀ byꢀ absoluteꢀ
ethanolꢀ(132ꢀmL,ꢀ16.5ꢀmL/g)ꢀandꢀ2ꢀMꢀaqueousꢀsodiumꢀhydroxideꢀ(18.4ꢀmL,ꢀ36.76ꢀmmoles,ꢀ1.75ꢀeq).ꢀTheꢀresultingꢀ
mixtureꢀwasꢀthenꢀdegassedꢀbyꢀreducingꢀpressureꢀdownꢀtoꢀ200ꢀtorrꢀandꢀbackfillingꢀwithꢀnitrogen.ꢀꢀThisꢀdegassingꢀ
processꢀwasꢀperformedꢀaꢀtotalꢀofꢀ5ꢀtimes.ꢀꢀTheꢀreactionꢀwasꢀthenꢀwarmedꢀtoꢀ70ꢀ°Cꢀandꢀheldꢀforꢀanꢀadditionalꢀ4ꢀh.ꢀ
Theꢀresultingꢀslurryꢀwasꢀthenꢀchargedꢀwithꢀabsoluteꢀethanolꢀ(120ꢀmL,ꢀ15ꢀmL/g)ꢀviaꢀadditionꢀfunnelꢀoverꢀ0.5ꢀh,ꢀ
°
maintainingꢀanꢀinternalꢀtemperatureꢀbetweenꢀ65-70ꢀ°C.ꢀTheꢀreactionꢀmixtureꢀwasꢀthenꢀcooledꢀtoꢀ55ꢀ Cꢀoverꢀ0.5ꢀ
°
°
h,ꢀheldꢀatꢀ55ꢀ Cꢀforꢀ1ꢀhꢀandꢀthenꢀcooledꢀtoꢀ20ꢀ Cꢀoverꢀ2ꢀh.ꢀꢀAfterꢀanꢀadditionalꢀ1.5ꢀh,ꢀtheꢀslurryꢀwasꢀfilteredꢀandꢀ
theꢀsolidsꢀwereꢀwashedꢀwithꢀaꢀsolutionꢀofꢀabsoluteꢀethanolꢀ(43.2ꢀmL,ꢀ5.4ꢀmL/g)ꢀandꢀwaterꢀ(4.8ꢀmL,ꢀ0.6ꢀmL/g),ꢀ
thenꢀwithꢀTHFꢀ(64.3ꢀmL,ꢀ8ꢀmL/g)ꢀandꢀdriedꢀinꢀvacuoꢀatꢀ80ꢀ°Cꢀtoꢀaffordꢀsodiumꢀsaltꢀ23ꢀ(7.24ꢀg,ꢀꢀ92%ꢀꢀyield)ꢀasꢀwhiteꢀ
toꢀpale-pinkꢀrodsꢀ(mpꢀ290-300ꢀ°C).ꢀꢀ
1
H-NMRꢀ(400ꢀMHz,ꢀD
2
O)ꢀδꢀ7.28ꢀ(s,ꢀ1H);ꢀ6.71ꢀ(s,ꢀ1H);ꢀ6.17ꢀ(s,ꢀ1H);ꢀ4.18ꢀ(m,ꢀ2H);ꢀ3.46ꢀ(s,ꢀ3H);ꢀ3.42ꢀ(s,ꢀ3H),ꢀ2.01ꢀ(s,ꢀ
3
H);ꢀ1.09ꢀ(t,ꢀJ=4ꢀHz,ꢀ3H)ꢀ
1
3
C-NMRꢀ(100ꢀMHz,ꢀD
2
O)ꢀδꢀ169.2,ꢀ146.9,ꢀ142.9,ꢀ142.2,ꢀ140.4,ꢀ139.7,ꢀ132.8,ꢀ128.0,ꢀ121.7,ꢀ102.3,ꢀ97.7,ꢀ95.0,ꢀ38.2,ꢀ
3
4.3,ꢀ31.9,ꢀ15.2,ꢀ10.3.ꢀ
+
HRMS-ESIꢀ(m/z)ꢀcalc’dꢀforꢀC17
H
19
N
7
O
2
ꢀ[M+H] ꢀꢀ354.1673,ꢀfoundꢀ354.1667ꢀ
N,N-dicyclopropyl-4-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-6-ethyl-1-methyl-1,6-dihydroimidazo[4,5-
d]pyrrolo[2,3-b]pyridine-7-carboxamide,ꢀ1ꢀ
Aꢀsolutionꢀofꢀ2-chloro-1,3-dimethylimidazoliniumꢀchlorideꢀ(104.9ꢀg,ꢀ620.6ꢀmmol,ꢀ1.15ꢀequiv.)ꢀinꢀdichloromethaneꢀ
(
1.00ꢀL,ꢀ5.0ꢀmL/g)ꢀwasꢀquicklyꢀaddedꢀtoꢀaꢀstirredꢀslurryꢀofꢀsodiumꢀsaltꢀ23ꢀ(200ꢀg,ꢀ517.1ꢀmmol,ꢀ1.00ꢀequiv.)ꢀinꢀ
dichloromethaneꢀ(5.00ꢀL,ꢀ25.0ꢀmL/g)ꢀoverꢀapproximatelyꢀ2ꢀminꢀunderꢀnitrogen.ꢀTheꢀreactionꢀwasꢀheldꢀatꢀ20ꢀ°Cꢀ
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The Journal of Organic Chemistry
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forꢀ 1ꢀ h,ꢀ andꢀ thenꢀ dicyclopropylamineꢀ hydrochlorideꢀ (24,ꢀ ꢀ 87.26ꢀ g,ꢀ 646.4ꢀ mmol,ꢀ 1.2ꢀ equiv.)ꢀ andꢀ
diisopropylethylamineꢀ(200.5ꢀg,ꢀ1.55ꢀmol,ꢀ3.00ꢀequiv.)ꢀwereꢀaddedꢀfollowedꢀbyꢀaꢀrinseꢀofꢀdichloromethaneꢀ(1.00ꢀ
L,ꢀ5.00ꢀmL/g).ꢀTheꢀreactionꢀwasꢀheldꢀatꢀ20-25ꢀ°Cꢀforꢀ3ꢀh,ꢀandꢀthenꢀwashedꢀwithꢀwaterꢀ(3ꢀxꢀ2.40ꢀL,ꢀ3ꢀxꢀ12.0ꢀmL/g)ꢀ
andꢀconcentratedꢀinꢀvacuoꢀtoꢀ1.00ꢀL.ꢀꢀTheꢀsolutionꢀwasꢀbroughtꢀtoꢀ35ꢀ°C,ꢀandꢀthenꢀseededꢀwithꢀaꢀslurryꢀofꢀamideꢀ
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1
ꢀ (2.0ꢀ g,ꢀ 1%ꢀ wt/wt)ꢀ inꢀ tetrahydrofuranꢀ (400ꢀ mL,ꢀ 2.0ꢀ mL/g).ꢀ ꢀ Afterꢀ 30ꢀ min,ꢀ theꢀ solventꢀ wasꢀ exchangedꢀ toꢀ
tetrahydrofuranꢀbyꢀconstantꢀvolumeꢀdistillationꢀuntilꢀdichloromethaneꢀwasꢀ<ꢀ3%ꢀv/v.ꢀTheꢀslurryꢀwasꢀthenꢀcooledꢀ
toꢀ0ꢀ°C,ꢀagedꢀforꢀ1ꢀh,ꢀfilteredꢀandꢀwashedꢀwithꢀcoldꢀtetrahydrofuranꢀ(400ꢀmL,ꢀ2.0ꢀmL/g).ꢀꢀTheꢀsolidsꢀwereꢀdriedꢀinꢀ
vacuoꢀatꢀ50ꢀ°Cꢀtoꢀobtainꢀamideꢀ1ꢀ(198.3ꢀg,ꢀ89%ꢀyield)ꢀasꢀoff-whiteꢀplatesꢀ(mpꢀ271-274ꢀ°C),ꢀwhichꢀcontainedꢀ
0
.13%wtꢀwaterꢀbyꢀKarlꢀFisherꢀanalysis.ꢀ
ꢀ
1
H-NMRꢀ(600ꢀMHz,ꢀDMF-d
7
)ꢀδꢀꢀ8.15ꢀ(brꢀs,ꢀ1H),ꢀ8.07ꢀ(s,ꢀ1H),ꢀ7.30ꢀ(s,ꢀ1H),ꢀ6.96ꢀ(s,ꢀ1H),ꢀ4.66ꢀ(q,ꢀJ=7.1ꢀHz,ꢀ2H),ꢀ4.11ꢀ
(
s,ꢀ3H),ꢀ3.72ꢀ(s,ꢀ3H),ꢀ2.35ꢀ(s,ꢀ3H),ꢀ3.01ꢀ(m,ꢀ2H),ꢀ1.43ꢀ(t,ꢀJ=7.1ꢀHz,ꢀ3H),ꢀ0.81-0.73ꢀ(m,ꢀ8H)ꢀ
1
3
C-NMRꢀ(125ꢀMHz,ꢀDMF-d
7
)ꢀδꢀꢀꢀ167.6,ꢀ148.5,ꢀ145.4,ꢀ144.7,ꢀ141.7,ꢀ139.7,ꢀ134.9,ꢀ128.0,ꢀ125.4,ꢀ102.9,ꢀ99.5,ꢀ96.9,ꢀ
39.4,ꢀ36.0,ꢀ33.1,ꢀ32.0,ꢀ16.5,ꢀ11.6,ꢀ9.6ꢀ
+
29 8
HRMS-ESIꢀ(m/z)ꢀcalc’dꢀforꢀC23H N Oꢀ[M+H] ꢀꢀ433.2464,ꢀfoundꢀ433.2457ꢀ
ꢀ
ASSOCIATED CONTENT
Supportingꢀ Information.ꢀ NMRꢀ Spectra.ꢀ Thisꢀ materialꢀ isꢀ availableꢀ freeꢀ ofꢀ chargeꢀ viaꢀ theꢀ Internetꢀ atꢀ
http://pubs.acs.org.ꢀ
ꢀ
AuthorꢀInformationꢀꢀ
CorrespondingꢀAuthorꢀ
*
Email:ꢀmartin.eastgate@bms.comꢀ
Acknowledgementsꢀ
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