Pd/C-catalyzed ligand-free and aerobic Suzuki reaction in water

Article abstract of DOI:10.1016/S1872-2067(12)60754-2

A general and efficient catalytic system for Pd/C-catalyzed ligand-free aerobic Suzuki cross-coupling reactions was developed. The reaction tolerated a wide range of aryl bromides with a hydrophilic group or a hydrophobic group without any additives in water. Moreover, the catalytic system was successfully extended to the cross-couplings of heteroaryl halides with various arylboronic acids. The Pd/C catalyst could be reuse three times without significant loss of catalytic activity.

Full text of DOI:10.1016/S1872-2067(12)60754-2

ChineseꢀJournalꢀofꢀCatalysisꢀ35ꢀ(2014)ꢀ357–361
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ꢀ ꢀ ꢀ
ꢀ ꢀ ꢀ ꢀ
ava i l a b l e a t w w w. s c i e n c ed i r e c t . c o m
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j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e /c h n j c
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ꢀ
Article
Pd/C‐catalyzedꢀligand‐freeꢀandꢀaerobicꢀSuzukiꢀreactionꢀinꢀwaterꢀ
ꢀ
XiaofengꢀRao,ꢀChunꢀLiu*,ꢀYixiaꢀZhang,ꢀZhanmingꢀGao,ꢀZilinꢀJin
ꢀ
StateꢀKeyꢀLaboratoryꢀofꢀFineꢀChemicals,ꢀDalianꢀUniversityꢀofꢀTechnology,ꢀDalianꢀ116024,ꢀLiaoning,ꢀChinaꢀ
A R T I C L E ꢀ I N F O ꢀ
A B S T R A C T ꢀ
Articleꢀhistory:ꢀ
AꢀgeneralꢀandꢀefficientꢀcatalyticꢀsystemꢀforꢀPd/C‐catalyzedꢀligand‐freeꢀaerobicꢀSuzukiꢀcross‐couplingꢀ
reactionsꢀwasꢀdeveloped.ꢀTheꢀreactionꢀtoleratedꢀaꢀwideꢀrangeꢀofꢀarylꢀbromidesꢀwithꢀaꢀhydrophilicꢀ
groupꢀorꢀaꢀhydrophobicꢀgroupꢀwithoutꢀanyꢀadditivesꢀinꢀwater.ꢀMoreover,ꢀtheꢀcatalyticꢀsystemꢀwasꢀ
successfullyꢀextendedꢀtoꢀtheꢀcross‐couplingsꢀofꢀheteroarylꢀhalidesꢀwithꢀvariousꢀarylboronicꢀacids.ꢀ
TheꢀPd/Cꢀcatalystꢀcouldꢀbeꢀreusedꢀthreeꢀtimesꢀwithoutꢀsignificantꢀlossꢀofꢀcatalyticꢀactivity.ꢀ
Receivedꢀ20ꢀOctoberꢀ2013ꢀ
Acceptedꢀ22ꢀNovemberꢀ2013ꢀ
Publishedꢀ20ꢀMarchꢀ2014ꢀ
©
ꢀ2014,ꢀDalianꢀInstituteꢀofꢀChemicalꢀPhysics,ꢀChineseꢀAcademyꢀofꢀSciences.
Keywords:ꢀ
PublishedꢀbyꢀElsevierꢀB.V.ꢀAllꢀrightsꢀreserved.
Suzukiꢀreactionꢀ
Palladiumꢀ ꢀ
Carbonꢀ
Ligand‐freeꢀ
Diisopropylamineꢀ
Biaryl
1
.ꢀ ꢀ Introductionꢀ
powerfulꢀtoolsꢀforꢀC–Cꢀbondꢀformationꢀinꢀtheꢀsynthesisꢀofꢀbiarylꢀ
compounds,ꢀtheꢀskeletonsꢀofꢀwhichꢀareꢀfoundꢀinꢀaꢀwideꢀrangeꢀofꢀ
importantꢀ compounds,ꢀ includingꢀ pharmaceuticals,ꢀ naturalꢀ
products,ꢀandꢀadvancedꢀfunctionalꢀmaterialsꢀ[8–10].ꢀ
Theꢀneedꢀforꢀsustainableꢀdevelopmentꢀinꢀtheꢀ21stꢀcenturyꢀisꢀ
employingꢀnewꢀtechnologiesꢀandꢀefficientꢀprocessesꢀforꢀsolvingꢀ
manyꢀ environmentalꢀ problems,ꢀ andꢀ isꢀ gainingꢀ increasingꢀ im‐
portanceꢀinꢀtheꢀchemicalꢀindustryꢀ[1–4].ꢀSoꢀfar,ꢀmuchꢀeffortꢀhasꢀ
beenꢀmadeꢀtoꢀimproveꢀtheꢀefficienciesꢀofꢀorganicꢀreactionsꢀus‐
ingꢀstandardꢀsyntheticꢀoperations.ꢀMostꢀresearchꢀhasꢀfocusedꢀ
onꢀ homogeneousꢀ catalysis,ꢀ whichꢀ providesꢀ excellentꢀ activityꢀ
andꢀselectivity,ꢀhowever,ꢀitꢀhasꢀaꢀnumberꢀofꢀdrawbacks,ꢀmainlyꢀ
associatedꢀwithꢀtheꢀrecoveryꢀandꢀreuseꢀofꢀtheꢀcatalyst.ꢀHetero‐
geneousꢀ catalysisꢀ providesꢀ aꢀ possibleꢀ solutionꢀ toꢀ theseꢀ prob‐
lemsꢀ[5,6].ꢀPdꢀonꢀactivatedꢀcharcoalꢀ(Pd/C),ꢀaꢀwidelyꢀusedꢀhet‐
erogeneousꢀcatalystꢀforꢀhydrogenation,ꢀhasꢀbeenꢀusedꢀforꢀvari‐
ousꢀ transformations,ꢀ includingꢀ C–C,ꢀ C–N,ꢀ andꢀ C–Oꢀ bondꢀ for‐
mations,ꢀ becauseꢀ ofꢀ itsꢀ easyꢀ accessꢀ andꢀ lowꢀ costꢀ [7].ꢀ Theꢀ
Pd‐catalyzedꢀ Suzukiꢀ reactionꢀ isꢀ oneꢀ ofꢀ theꢀ mostꢀ versatileꢀ andꢀ
TheꢀsolventꢀisꢀaꢀkeyꢀparameterꢀinꢀtheꢀSuzukiꢀreaction.ꢀWaterꢀ
hasꢀ manyꢀ advantagesꢀ overꢀ commonꢀ organicꢀ solvents:ꢀ abun‐
dant,ꢀcheap,ꢀnon‐toxic,ꢀandꢀnon‐flammable.ꢀTheꢀneedꢀtoꢀdevel‐
opꢀsustainableꢀchemistryꢀhasꢀincreasinglyꢀledꢀchemistsꢀtoꢀcon‐
siderꢀusingꢀwaterꢀasꢀaꢀbenignꢀsolventꢀ[11,12].ꢀAsꢀreportedꢀbyꢀ
Blackmondꢀ andꢀ coworkers,ꢀ theꢀ useꢀ ofꢀ waterꢀ isꢀ onlyꢀ environ‐
mentallyꢀfriendlyꢀifꢀorganicsꢀandꢀmetalsꢀcanꢀbeꢀfullyꢀextractedꢀ
fromꢀtheꢀaqueousꢀphaseꢀ[13].ꢀHeterogeneousꢀcatalysisꢀusingꢀaꢀ
metalꢀ sequesteredꢀ onꢀ aꢀ water‐insolubleꢀ supportꢀ couldꢀ meetꢀ
theseꢀrequirementsꢀbecauseꢀtheꢀsupportedꢀcatalystꢀcanꢀbeꢀeas‐
ilyꢀremovedꢀbyꢀfiltrationꢀ[14,15].ꢀInꢀ1997,ꢀBumaginꢀetꢀal.ꢀ[16]ꢀ
reportedꢀtheꢀfirstꢀexampleꢀofꢀPd/C‐catalyzedꢀcross‐couplingꢀinꢀ
water,ꢀ byꢀ reactingꢀ water‐solubleꢀ 3‐bromobenzoicꢀ acidꢀ withꢀ
*ꢀCorrespondingꢀauthor.ꢀTel:ꢀ+86‐411‐84986182;ꢀE‐mail:ꢀcliu@dlut.edu.cnꢀ ꢀ ꢀ
ThisꢀworkꢀwasꢀsupportedꢀbyꢀtheꢀNationalꢀNaturalꢀScienceꢀFoundationꢀofꢀChinaꢀ(21276043)ꢀandꢀtheꢀMinistryꢀofꢀEducationꢀProgramꢀforꢀNewꢀCenturyꢀ
ExcellentꢀTalentsꢀinꢀUniversityꢀ(NCET‐10‐0283).ꢀ ꢀ
DOI:ꢀ10.1016/S1872‐2067(12)60754‐2ꢀ|ꢀhttp://www.sciencedirect.com/science/journal/18722067ꢀ|ꢀChin.ꢀJ.ꢀCatal.,ꢀVol.ꢀ35,ꢀNo.ꢀ3,ꢀMarchꢀ2014ꢀ ꢀ ꢀ

ꢀ
XiaofengꢀRaoꢀetꢀal.ꢀ/ꢀChineseꢀJournalꢀofꢀCatalysisꢀ35ꢀ(2014)ꢀ357–361ꢀ
tetraphenylborateꢀinꢀneatꢀwater.ꢀLater,ꢀXuꢀandꢀcoworkersꢀ[17]ꢀ
confirmedꢀ thatꢀ water‐solubleꢀ arylꢀ bromidesꢀ couldꢀ reactꢀ effi‐
addedꢀtoꢀbrineꢀ(10ꢀmL)ꢀandꢀextractedꢀwithꢀethylꢀacetateꢀ(3ꢀ×ꢀ10ꢀ
mL).ꢀTheꢀresidueꢀwasꢀpurifiedꢀbyꢀflashꢀcolumnꢀchromatographyꢀ
onꢀsilicaꢀgelꢀ(200–300ꢀmesh)ꢀtoꢀgiveꢀtheꢀcorrespondingꢀbiarylꢀ
compound.ꢀ
cientlyꢀwithꢀNaBPh
4
ꢀandꢀNaBtol ꢀinꢀrefluxingꢀwaterꢀwithꢀaꢀlowꢀ
4
catalystꢀ loading.ꢀ However,ꢀ theseꢀ methodsꢀ areꢀ limitedꢀ toꢀ wa‐
ter‐solubleꢀarylꢀbromidesꢀorꢀarylꢀiodides.ꢀThisꢀproblemꢀcanꢀbeꢀ
solvedꢀ byꢀ addingꢀ surfactantsꢀ [18,19]ꢀ orꢀ organicꢀ cosolventsꢀ
3.ꢀ ꢀ Resultsꢀandꢀdiscussionꢀ
[20,21]ꢀ toꢀ increaseꢀ theꢀ solubilitiesꢀ ofꢀ non‐water‐solubleꢀ arylꢀ
halides.ꢀ Toꢀ theꢀ bestꢀ ofꢀ ourꢀ knowledge,ꢀ aꢀ generalꢀ approachꢀ toꢀ
Pd/C‐catalyzedꢀ Suzukiꢀ reactionsꢀ ofꢀ arylꢀ halidesꢀ withꢀ aꢀ broadꢀ
rangeꢀofꢀwaterꢀsolubilitiesꢀinꢀneatꢀwaterꢀinꢀtheꢀabsenceꢀofꢀaddi‐
tivesꢀhasꢀnotꢀbeenꢀreported.ꢀ
Ourꢀ groupꢀ hasꢀ aꢀ long‐standingꢀ interestꢀ inꢀ developingꢀ effi‐
cientꢀ aerobicꢀ andꢀ aqueousꢀ catalyticꢀ systemsꢀ forꢀ Pd‐catalyzedꢀ
ligand‐freeꢀ cross‐couplingꢀ reactions,ꢀ andꢀ aꢀ seriesꢀ ofꢀ efficientꢀ
andꢀuniversalꢀcatalyticꢀsystemsꢀhasꢀbeenꢀdevelopedꢀ[22–25].ꢀInꢀ
thisꢀ paper,ꢀ weꢀ describeꢀ aꢀ recyclableꢀ catalyticꢀ systemꢀ forꢀ theꢀ
Pd/C‐catalyzedꢀcross‐couplingꢀofꢀaꢀwideꢀrangeꢀofꢀarylꢀbromidesꢀ
withꢀarylboronicꢀacids,ꢀwithoutꢀanyꢀadditives,ꢀinꢀwater.ꢀ
3.1.ꢀ ꢀ Optimizationꢀofꢀreactionꢀconditionsꢀ
Theꢀ cross‐couplingꢀ ofꢀ 4‐bromoanisoleꢀ andꢀ phenylboronicꢀ
acidꢀinꢀtheꢀpresenceꢀofꢀ1.5ꢀmol%ꢀPd/Cꢀatꢀ100ꢀ°Cꢀinꢀwaterꢀwasꢀ
chosenꢀasꢀtheꢀmodelꢀreaction.ꢀTheꢀinfluenceꢀofꢀvariousꢀbasesꢀonꢀ
theꢀ cross‐couplingꢀ reactionꢀ wasꢀ investigated;ꢀ theꢀ resultsꢀ areꢀ
summarizedꢀinꢀTableꢀ1.ꢀInitially,ꢀaꢀseriesꢀofꢀtypicalꢀorganicꢀba‐
sesꢀ wasꢀ examinedꢀ (Tableꢀ 1,ꢀ entriesꢀ 1–8).ꢀ Triethylamineꢀ orꢀ
diisopropylethylamine,ꢀ whichꢀ areꢀ oftenꢀ usedꢀ asꢀ basesꢀ inꢀ
Pd‐catalyzedꢀcross‐couplingꢀreactionsꢀ[26,27],ꢀshowedꢀsimilarꢀ
activityꢀ inꢀ theꢀ presentꢀ protocolꢀ (Tableꢀ 1,ꢀ entriesꢀ 1ꢀ andꢀ 2).ꢀ
Diisopropylamineꢀ andꢀ isopropylamineꢀ gaveꢀ veryꢀ differentꢀ re‐
sultsꢀ(Tableꢀ1,ꢀentriesꢀ3ꢀandꢀ4).ꢀItꢀisꢀclearꢀthatꢀdiisopropylamineꢀ
isꢀ theꢀ mostꢀ efficientꢀ baseꢀ inꢀ thisꢀ catalyticꢀ system,ꢀ providingꢀ
93%ꢀ isolatedꢀ yieldꢀ ofꢀ theꢀ cross‐coupledꢀ productꢀ inꢀ 20ꢀ min.ꢀ
Tripropylamineꢀ andꢀ dipropylamineꢀ wereꢀ inefficientꢀ (Tableꢀ 1,ꢀ
entriesꢀ 5ꢀ andꢀ 6),ꢀ evenꢀ thoughꢀ theirꢀ structuresꢀ areꢀ similarꢀ toꢀ
thatꢀ ofꢀ diisopropylamine.ꢀ Theꢀ cyclicꢀ amineꢀ piperazineꢀ andꢀ
1,4‐diazabicyclo[2.2.2]octaneꢀ(DABCO)ꢀwereꢀalsoꢀtestedꢀinꢀthisꢀ
catalyticꢀsystemꢀ(Tableꢀ1,ꢀentriesꢀ7ꢀandꢀ8).ꢀLowerꢀyieldsꢀwereꢀ
obtainedꢀ withꢀ theꢀ organicꢀ alkaliꢀ sodiumꢀ methoxideꢀ (Tableꢀ 1,ꢀ
entryꢀ9).ꢀCommonꢀinorganicꢀbasesꢀgaveꢀdisappointingꢀresultsꢀinꢀ
theꢀpresentꢀprotocolꢀ(Tableꢀ1,ꢀentriesꢀ10–12),ꢀevenꢀthoughꢀtheyꢀ
areꢀsolubleꢀinꢀwaterꢀandꢀhaveꢀbeenꢀsuccessfullyꢀusedꢀinꢀefficientꢀ
ligand‐freeꢀ catalyticꢀ systemsꢀ [28].ꢀ Inꢀ thisꢀ Pd/C‐catalyzedꢀ sys‐
tem,ꢀtheꢀreasonꢀforꢀtheꢀhighꢀefficiencyꢀisꢀprobablyꢀthatꢀdiiso‐
propylamineꢀactsꢀnotꢀonlyꢀasꢀaꢀbaseꢀbutꢀalsoꢀasꢀaꢀligand,ꢀandꢀhasꢀ
aꢀhighꢀtendencyꢀtoꢀcoordinateꢀtoꢀPdꢀtoꢀformꢀactiveꢀspecies,ꢀasꢀ
reportedꢀbyꢀBoykinꢀetꢀal.ꢀ[26]ꢀandꢀasꢀsuggestedꢀinꢀourꢀpreviousꢀ
workꢀ[27].ꢀ
2.ꢀ ꢀ Experimentalꢀ
2.1.ꢀ ꢀ Generalꢀremarksꢀ
Theꢀ waterꢀ usedꢀ inꢀ theꢀ experimentsꢀ wasꢀ deionized.ꢀ Arylꢀ
bromidesꢀandꢀarylboronicꢀacidsꢀwereꢀpurchasedꢀfromꢀAlfaꢀAe‐
sar.ꢀ Otherꢀ chemicalsꢀ wereꢀ obtainedꢀ commerciallyꢀ andꢀ usedꢀ
1
1
withoutꢀpurification.ꢀ Hꢀnuclearꢀmagneticꢀresonanceꢀ( HꢀNMR)ꢀ
spectraꢀwereꢀrecordedꢀwithꢀaꢀBrukerꢀAvanceꢀIIꢀ400ꢀMHzꢀspec‐
trometer,ꢀusingꢀtetramethylsilaneꢀ(TMS)ꢀasꢀanꢀinternalꢀstand‐
ard.ꢀAllꢀtheꢀproductsꢀwereꢀisolatedꢀbyꢀshortꢀchromatographyꢀonꢀ
aꢀ silica‐gelꢀ (200–300ꢀ mesh)ꢀ column,ꢀ usingꢀ petroleumꢀ etherꢀ
(60–90ꢀC)ꢀasꢀtheꢀeluent,ꢀunlessꢀotherwiseꢀstated.ꢀCompoundsꢀ
thatꢀhadꢀpreviouslyꢀbeenꢀdescribedꢀinꢀtheꢀliteratureꢀwereꢀchar‐
1
acterizedꢀbyꢀcomparisonꢀofꢀtheirꢀ HꢀNMRꢀspectraꢀwithꢀtheꢀre‐
portedꢀdata.ꢀ ꢀ
2.2.ꢀ ꢀ GeneralꢀprocedureꢀforꢀSuzukiꢀreactionꢀ
Anꢀ arylꢀ halideꢀ (0.5ꢀ mmol),ꢀ arylboronicꢀ acidꢀ (0.75ꢀ mmol),ꢀ
Tableꢀ1ꢀ ꢀ
(
i‐Pr)
2
NHꢀ(1.0ꢀmmol),ꢀPd/Cꢀ(1.5ꢀmol%,ꢀ16ꢀmg),ꢀandꢀwaterꢀ(1.0ꢀ
Effectꢀofꢀbaseꢀonꢀcross‐couplingꢀofꢀ4‐bromoanisoleꢀwithꢀphenylboronicꢀ
acid.ꢀ
mL)ꢀwereꢀallowedꢀtoꢀreactꢀatꢀ100ꢀC.ꢀAfterꢀaꢀcertainꢀperiod,ꢀtheꢀ
reactionꢀ mixtureꢀ wasꢀ addedꢀ toꢀ brineꢀ (10ꢀ mL)ꢀ andꢀ extractedꢀ
withꢀethylꢀacetateꢀ(3ꢀ×ꢀ10ꢀmL).ꢀTheꢀsolventꢀwasꢀconcentratedꢀ
underꢀvacuum,ꢀandꢀtheꢀproductꢀwasꢀisolatedꢀbyꢀshortꢀchroma‐
tographyꢀonꢀaꢀsilica‐gelꢀ(200–300ꢀmesh)ꢀcolumn.ꢀ
Entryꢀ
Baseꢀ
Et Nꢀ
(i‐Pr) NEtꢀ
(i‐Pr) NHꢀ
i‐PrNH
(n‐Pr) Nꢀ
(n‐Pr) NHꢀ
Piperazineꢀ
DABCOꢀ
NaOMeꢀ
Isolatedꢀyieldꢀ(%)ꢀ
1
ꢀ
3
69ꢀ
59ꢀ
93ꢀ
35ꢀ
ꢀ 8ꢀ
ꢀ 7ꢀ
ꢀ 7ꢀ
85ꢀ
47ꢀ
40ꢀ
30ꢀ
31ꢀ
2
ꢀ
2
2
.3.ꢀ ꢀ Recyclabilityꢀtestsꢀ
3ꢀ
2
4
ꢀ
2
ꢀ
5
ꢀ
3
Forꢀ theꢀ firstꢀ run,ꢀ aꢀ mixtureꢀ ofꢀ 4‐bromobenzonitrileꢀ (0.5ꢀ
6
ꢀ
2
mmol),ꢀ 4‐methylphenylboronicꢀ acidꢀ (0.75ꢀ mmol),ꢀ (i‐Pr)
2
NHꢀ
7
ꢀ
(1.0ꢀmmol),ꢀPd/Cꢀ(1.5ꢀmol%,ꢀ16ꢀmg),ꢀandꢀwaterꢀ(1.0ꢀmL)ꢀwasꢀ
8
ꢀ
allowedꢀtoꢀreactꢀatꢀ100ꢀCꢀforꢀtheꢀindicatedꢀtime.ꢀTheꢀsystemꢀ
wasꢀcooledꢀtoꢀroomꢀtemperatureꢀandꢀtheꢀreactionꢀmixtureꢀwasꢀ
passedꢀthroughꢀaꢀmembraneꢀfilterꢀ(0.45ꢀµm),ꢀandꢀwashedꢀse‐
quentiallyꢀ withꢀ ethanolꢀ (15ꢀ mL)ꢀ andꢀ waterꢀ (5ꢀ mL).ꢀ Theꢀ filterꢀ
residueꢀwasꢀnaturallyꢀairꢀdriedꢀforꢀ24ꢀhꢀforꢀtheꢀnextꢀreactionꢀ
cycle.ꢀ Theꢀ filtrateꢀ wasꢀ concentratedꢀ underꢀ vacuum,ꢀ andꢀ thenꢀ
9ꢀ
1
1
1
0ꢀ
1ꢀ
2ꢀ
K
PO
2
CO
3H
NaOHꢀ
3
ꢀ
K
3
4
2
Oꢀ
Reactionꢀ conditions:ꢀ 4‐bromoanisoleꢀ 0.5ꢀ mmol,ꢀ phenylboronicꢀ acidꢀ
.75ꢀmmol,ꢀPd/Cꢀ1.5ꢀmol%,ꢀbaseꢀ1.0ꢀmmol,ꢀH Oꢀ1.0ꢀmL,ꢀ100ꢀ°C,ꢀinꢀair,ꢀ
20ꢀmin.ꢀ
0
2

ꢀ
XiaofengꢀRaoꢀetꢀal.ꢀ/ꢀChineseꢀJournalꢀofꢀCatalysisꢀ35ꢀ(2014)ꢀ357–361ꢀ
.2.ꢀ ꢀ Substrateꢀscopeꢀandꢀlimitationsꢀ ꢀ
Tableꢀ2ꢀ ꢀ
ꢀ
3
Pd/C‐catalyzedꢀcross‐couplingꢀofꢀarylꢀbromidesꢀwithꢀarylboronicꢀacids.
Withꢀtheꢀoptimizedꢀconditionsꢀinꢀhand,ꢀweꢀfurtherꢀexploredꢀ
theꢀ scopeꢀ andꢀ limitationsꢀ ofꢀ thisꢀ catalyticꢀ system;ꢀ theꢀ resultsꢀ
areꢀ listedꢀ inꢀ Tableꢀ 2.ꢀ Variousꢀ arylꢀ bromidesꢀ bearingꢀ elec‐
tron‐withdrawingꢀgroups,ꢀsuchꢀasꢀnitro,ꢀnitrile,ꢀandꢀacetylꢀmoi‐
eties,ꢀandꢀelectron‐donatingꢀgroups,ꢀsuchꢀasꢀhydroxyl,ꢀmethyl,ꢀ
andꢀmethoxyꢀmoieties,ꢀcoupledꢀwithꢀarylboronicꢀacidꢀwithꢀal‐
mostꢀcompleteꢀconversionꢀwithinꢀ45ꢀminꢀ(Tableꢀ2,ꢀentriesꢀ1–7).ꢀ
Arylboronicꢀ acidsꢀ withꢀ electron‐withdrawingꢀ groupsꢀ suchꢀ asꢀ
fluoroꢀandꢀnitrileꢀcoupledꢀwithꢀ4‐bromoanisoleꢀtoꢀgiveꢀgoodꢀtoꢀ
excellentꢀyieldsꢀonꢀextensionꢀofꢀtheꢀreactionꢀtimeꢀ(Tableꢀ2,ꢀen‐
triesꢀ8ꢀandꢀ9).ꢀThisꢀcatalyticꢀsystemꢀfollowedꢀtheꢀbasicꢀruleꢀofꢀ
theꢀ Suzukiꢀ reaction,ꢀ i.e.,ꢀ thatꢀ electron‐withdrawingꢀ groupsꢀ onꢀ
theꢀ arylꢀ bromidesꢀ andꢀ electron‐donatingꢀ groupsꢀ onꢀ theꢀ aryl‐
boronicꢀ acidsꢀ accelerateꢀ theꢀ ratesꢀ ofꢀ theꢀ cross‐couplingꢀ reac‐
tionsꢀ(Tableꢀ2,ꢀentriesꢀ3ꢀandꢀ9).ꢀWhenꢀtheꢀstericꢀeffectꢀofꢀtheꢀ
arylꢀbromideꢀorꢀarylboronicꢀacidꢀincreased,ꢀtheꢀcross‐couplingꢀ
reactionꢀ proceededꢀ smoothlyꢀ withinꢀ 2ꢀ hꢀ (Tableꢀ 2,ꢀ entriesꢀ
ꢀ
Timeꢀaꢀ Isolatedꢀ
Entry
1ꢀ
Ar‐Brꢀ
Productꢀ
(min) yieldꢀ(%)
2
0ꢀ
0ꢀ
96ꢀ
97ꢀ
98ꢀ
ꢀ
ꢀ
2ꢀ
2
3ꢀ
45ꢀ
ꢀ
4ꢀ
2
2
3
2
0ꢀ
0ꢀ
0ꢀ
0ꢀ
97ꢀ
96ꢀ
85ꢀ
93ꢀ
99ꢀ
86ꢀ
ꢀ
5ꢀ
ꢀ
6ꢀ
ꢀ
7ꢀ
ꢀ
8ꢀ
10–14).ꢀ Increasingꢀ theꢀ stericꢀ effectꢀ ofꢀ bothꢀ theꢀ arylꢀ bromideꢀ
120ꢀ
120ꢀ
ꢀ
andꢀ arylboronicꢀ acidꢀ decreasedꢀ theꢀ reactivityꢀ ofꢀ theꢀ
cross‐coupling,ꢀbutꢀ98%ꢀofꢀisolatedꢀyieldꢀwasꢀobtainedꢀinꢀ3ꢀhꢀ
9ꢀ
ꢀ
forꢀ theꢀ reactionꢀ betweenꢀ 2‐bromobenzonitrileꢀ andꢀ o‐
tol‐
ꢀ
10ꢀ
ylboronicꢀacidꢀ(Tableꢀ2,ꢀentryꢀ15).ꢀOverall,ꢀthisꢀcatalyticꢀsystemꢀ
toleratedꢀaꢀbroadꢀrangeꢀofꢀarylꢀbromidesꢀandꢀarylboronicꢀacidsꢀ
1
20ꢀ
20ꢀ
90ꢀ
99ꢀ
99ꢀ
80ꢀ
ꢀ
–
ꢀnotꢀonlyꢀarylꢀbromidesꢀwithꢀhydrophilicꢀgroupsꢀbutꢀalsoꢀwithꢀ
hydrophobicꢀgroups.ꢀ
Aryl‐substitutedꢀ pyridinesꢀ areꢀ theꢀ mostꢀ commonꢀ N‐
11ꢀ
1
ꢀ
ꢀ
het‐
12ꢀ
eroarylꢀ unitsꢀ presentꢀ inꢀ pharmaceuticallyꢀ activeꢀ compounds.ꢀ
Toꢀ extendꢀ theꢀ scopeꢀ ofꢀ thisꢀ methodology,ꢀ weꢀ furtherꢀ investi‐
gatedꢀ theꢀ Suzukiꢀ reactionsꢀ ofꢀ pyridylꢀ bromidesꢀ withꢀ aryl‐
boronicꢀ acids.ꢀ 3‐Pyridylꢀ bromidesꢀ wereꢀ successfullyꢀ coupledꢀ
withꢀphenylboronicꢀacidꢀinꢀexcellentꢀyieldsꢀ(Tableꢀ2,ꢀentriesꢀ16ꢀ
andꢀ 17).ꢀ 2‐Pyridylꢀ bromideꢀ wasꢀ lessꢀ activeꢀ inꢀ couplingꢀ withꢀ
arylboronicꢀ acidsꢀ usingꢀ thisꢀ catalyticꢀ system,ꢀ providingꢀ
60ꢀ
ꢀ
1
3ꢀ
4ꢀ
6
0ꢀ
0ꢀ
ꢀ
1
6
98ꢀ
98ꢀ
ꢀ
50%–86%ꢀisolatedꢀyieldsꢀwithinꢀ24ꢀhꢀ(Tableꢀ2,ꢀentriesꢀ18–20).ꢀ
15ꢀ
However,ꢀtheꢀpresentꢀmethodꢀisꢀmoreꢀefficientꢀthanꢀourꢀprevi‐
ouslyꢀ resultꢀ [27]ꢀ forꢀ theꢀ cross‐couplingꢀ ofꢀ 2‐pyridylꢀ bromideꢀ
withꢀphenylboronicꢀacid,ꢀwhichꢀdidꢀnotꢀactivateꢀ2‐pyridylꢀbro‐
mideꢀ atꢀ all.ꢀ Itꢀ shouldꢀ beꢀ notedꢀ thatꢀ thisꢀ catalyticꢀ systemꢀ wasꢀ
alsoꢀ suitableꢀ forꢀ sulfur‐containingꢀ heteroarylꢀ bromide.ꢀ Theꢀ
reactionꢀ betweenꢀ 2‐bromothiopheneꢀ andꢀ phenylboronicꢀ acidꢀ
gaveꢀ83%ꢀyieldꢀafterꢀ4ꢀhꢀ(Tableꢀ2,ꢀentryꢀ21).ꢀ
Theꢀ reusabilityꢀ ofꢀ Pd/Cꢀ isꢀ aꢀ greatꢀ advantageꢀ inꢀ processꢀ
chemistry,ꢀbothꢀeconomicallyꢀandꢀenvironmentallyꢀ[29–34].ꢀWeꢀ
examinedꢀtheꢀrecyclabilityꢀofꢀPd/Cꢀinꢀtheꢀcross‐couplingꢀreac‐
1
80ꢀ
40ꢀ
ꢀ
ꢀ
16ꢀ
2
95ꢀ
98ꢀ
57ꢀ
86ꢀ
53ꢀ
ꢀ
17ꢀ
18ꢀ
19ꢀ
30ꢀ
ꢀ
1440
ꢀ
1
020
440
ꢀ
tion,ꢀ usingꢀ 4‐bromobenzonitrileꢀ (0.5ꢀ mmol)ꢀ andꢀ 4‐
ꢀ
20ꢀ
21ꢀ
1
methylphenylboronicꢀ acidꢀ (0.75ꢀ mmol)ꢀ asꢀ substrates,ꢀ inꢀ theꢀ
presenceꢀ ofꢀ Pd/Cꢀ (1.5ꢀ mol%)ꢀ andꢀ diisopropylamineꢀ (twoꢀ
equiv.)ꢀatꢀ100ꢀ°Cꢀinꢀwaterꢀ(1ꢀmL).ꢀAsꢀshownꢀinꢀTableꢀ3,ꢀtheꢀre‐
coveredꢀPd/Cꢀgaveꢀcompleteꢀconversionꢀwithinꢀaꢀslightlyꢀpro‐
longedꢀ periodꢀ (60ꢀ min)ꢀ forꢀ theꢀ secondꢀ run.ꢀ Theꢀ catalystꢀ wasꢀ
reusedꢀthreeꢀtimesꢀwithoutꢀsignificantꢀlossꢀofꢀcatalyticꢀefficien‐
cy.ꢀFromꢀtheꢀfourthꢀtoꢀtheꢀsixthꢀruns,ꢀtheꢀcatalystꢀstillꢀprovidedꢀ
ꢀ
240ꢀ
83ꢀ
ꢀ
Reactionꢀ conditions:ꢀ arylꢀ bromideꢀ 0.5ꢀ mmol,ꢀ arylboronicꢀ acidꢀ 0.75ꢀ
mmol,ꢀPd/Cꢀ1.5ꢀmol%,(i‐Pr) NHꢀ1.0ꢀmmol,ꢀH Oꢀ1.0ꢀmL,ꢀ100ꢀ°C,ꢀinꢀair.ꢀ ꢀ
Theꢀtimeꢀwasꢀnotꢀoptimized.ꢀ
ꢀ
2
2
a
ꢀ
85%,ꢀ81%,ꢀandꢀ79%ꢀisolatedꢀyields,ꢀrespectively,ꢀbutꢀtheꢀeffi‐
(i‐Pr) NHꢀ inꢀ neatꢀ waterꢀ forꢀ 20ꢀ minꢀ underꢀ theꢀ conditionsꢀ de‐
2
ciencyꢀdecreasedꢀinꢀtheꢀseventhꢀrun.ꢀToꢀidentifyꢀtheꢀactualꢀac‐
tiveꢀcatalystꢀinꢀtheꢀSuzukiꢀreaction,ꢀPd/Cꢀwasꢀpretreatedꢀwithꢀ
scribedꢀinꢀTableꢀ3,ꢀandꢀpassedꢀthroughꢀaꢀ0.45ꢀμmꢀmembraneꢀ
filter.ꢀ Theꢀ filtrateꢀ wasꢀ thenꢀ usedꢀ forꢀ theꢀ Suzukiꢀ reactionꢀ ofꢀ

ꢀ
XiaofengꢀRaoꢀetꢀal.ꢀ/ꢀChineseꢀJournalꢀofꢀCatalysisꢀ35ꢀ(2014)ꢀ357–361ꢀ
NdjokoꢀIosetꢀK,ꢀBringmannꢀG.ꢀAngewꢀChemꢀIntꢀEd,ꢀ2011,ꢀ50:ꢀ8482ꢀ
5] LamblinꢀM,ꢀNassar‐HardyꢀL,ꢀHiersoꢀJꢀC,ꢀFouquetꢀE,ꢀFelpinꢀFꢀX.ꢀAdvꢀ
SynthꢀCatal,ꢀ2010,ꢀ352:ꢀ33ꢀ
6] MolnarꢀA.ꢀChemꢀRev,ꢀ2011,ꢀ111:ꢀ2251ꢀ
[7] SekiꢀM.ꢀSynthesis,ꢀ2006:ꢀ2975ꢀ
Tableꢀ3ꢀ ꢀ
ReusabilityꢀofꢀPd/Cꢀcatalyticꢀsystem.ꢀ
[
CN
B(OH)2
Pd/C, (i-Pr)2NH
[
+
CN
o
H O, 100 C
Br
2
[
8] MiyauraꢀN,ꢀYanagiꢀT,ꢀSuzukiꢀA.ꢀSynthꢀCommun,ꢀ1981,ꢀ11:ꢀ513ꢀ
9] LiuꢀC,ꢀHanꢀN,ꢀYuanꢀH,ꢀHeꢀXꢀY,ꢀJinꢀZꢀL.ꢀChinꢀJꢀCatal,ꢀ2011,ꢀ32:ꢀ1204ꢀ
Runꢀ
Isolatedꢀyieldꢀ(%)ꢀ
[
1
ꢀ
98ꢀ
98ꢀ
96ꢀ
85ꢀ
81ꢀ
79ꢀ
59ꢀ
[
10] JohanssonꢀSeechurnꢀCꢀCꢀC,ꢀKitchingꢀMꢀO,ꢀColacotꢀTꢀJ,ꢀSnieckusꢀV.ꢀ
2
ꢀ
AngewꢀChemꢀIntꢀEd,ꢀ2012,ꢀ51:ꢀ5062ꢀ
3
ꢀ
[
11] LiꢀCꢀJ.ꢀChemꢀRev,ꢀ2005,ꢀ105:ꢀ3095ꢀ
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[13] BlackmondꢀDꢀG,ꢀArmstrongꢀA,ꢀCoombeꢀV,ꢀWellsꢀA.ꢀAngewꢀChemꢀIntꢀ
Ed,ꢀ2007,ꢀ46:ꢀ3798ꢀ
4
ꢀ
[
5
ꢀ
6
ꢀ
7ꢀ
Reactionꢀ conditions:ꢀ 4‐bromobenzonitrileꢀ 0.5ꢀ mmol,ꢀ 4‐
ꢀ
methylphenyl‐
[14] FelpinꢀFꢀX,ꢀAyadꢀT,ꢀMitraꢀS.ꢀEurꢀJꢀOrgꢀChem,ꢀ2006:ꢀ2679ꢀ
boronicꢀacidꢀ0.75ꢀmmol,ꢀPd/Cꢀ1.5ꢀmmol%,ꢀ(i‐Pr)
mL,ꢀ100ꢀ°C,ꢀinꢀair.ꢀ
2
NHꢀ1.0ꢀmmol,ꢀH Oꢀ1.0
2
[
15] KimꢀSꢀW,ꢀKimꢀM,ꢀLeeꢀWꢀY,ꢀHyeonꢀT.ꢀJꢀAmꢀChemꢀSoc,ꢀ2002,ꢀ124:ꢀ
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16] BykovꢀVꢀV,ꢀBumaginꢀNꢀA.ꢀRussꢀChemꢀBull,ꢀ1997,ꢀ46:ꢀ1344ꢀ
7
[
4
‐bromoanisoleꢀ withꢀ phenylboronicꢀ acid.ꢀ However,ꢀ theꢀ reac‐
[17] LuꢀG,ꢀFranzénꢀR,ꢀZhangꢀQ,ꢀXuꢀYꢀJ.ꢀTetrahedronꢀLett,ꢀ2005,ꢀ46:ꢀ4255ꢀ
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tionꢀ wasꢀ sluggish,ꢀ andꢀ onlyꢀ aꢀ traceꢀ amountꢀ ofꢀ cross‐coupledꢀ
productꢀwasꢀobservedꢀafterꢀ20ꢀmin.ꢀTheseꢀresultsꢀsuggestꢀthatꢀ
theꢀPd/C‐catalyzedꢀSuzukiꢀreactionꢀproceedsꢀheterogeneously,ꢀ
andꢀtheꢀactiveꢀcomponentꢀisꢀPdꢀlocatedꢀonꢀtheꢀcarbon;ꢀthisꢀisꢀ
consistentꢀwithꢀSajiki’sꢀreportꢀ[29].ꢀTheꢀcauseꢀofꢀtheꢀdecreaseꢀinꢀ
catalyticꢀactivityꢀisꢀunderꢀinvestigation.ꢀ
[19] ArcadiꢀA,ꢀCerichelliꢀG,ꢀChiariniꢀM,ꢀCorreaꢀM,ꢀZorzanꢀD.ꢀEurꢀJꢀOrgꢀ
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1555ꢀ
[
[
[
22] LiuꢀC,ꢀYangꢀWꢀB.ꢀChemꢀCommun,ꢀ2009:ꢀ6267ꢀ
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4.ꢀ ꢀ Conclusionsꢀ
Aꢀ highlyꢀ efficient,ꢀ recyclable,ꢀ andꢀ universalꢀ protocolꢀ hasꢀ
[25] LiuꢀC,ꢀRaoꢀXꢀF,ꢀSongꢀXꢀL,ꢀQiuꢀJꢀS,ꢀJinꢀZꢀL.ꢀRSCꢀAdv,ꢀ2013,ꢀ3:ꢀ526ꢀ
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zukiꢀ reactionꢀ withoutꢀ anyꢀ additivesꢀ usingꢀ waterꢀ asꢀ theꢀ soleꢀ
medium.ꢀTheꢀcatalystꢀwasꢀrecycledꢀthreeꢀtimesꢀwithoutꢀsignifi‐
cantꢀlossꢀofꢀcatalyticꢀactivity.ꢀThisꢀaerobicꢀandꢀaqueousꢀprotocolꢀ
isꢀinꢀaccordanceꢀwithꢀtheꢀconceptꢀofꢀgreenꢀchemistry,ꢀandꢀsyn‐
theticꢀapplicationsꢀofꢀthisꢀapproachꢀareꢀcurrentlyꢀunderꢀinves‐
tigationꢀinꢀourꢀlaboratory.ꢀ
[
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[
[
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GraphicalꢀAbstractꢀ
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Pd/C‐catalyzedꢀligand‐freeꢀandꢀaerobicꢀSuzukiꢀreactionꢀinꢀwaterꢀ
ꢀ
ꢀ
ꢀ
XiaofengRao,ꢀChunꢀLiu*,ꢀYixiaZhang,ꢀZhanmingꢀGao,ꢀZilinꢀJinꢀ
DalianꢀUniversityꢀofꢀTechnologyꢀ ꢀ
ꢀ
ꢀ
AꢀhighlyꢀefficientꢀandꢀrecyclableꢀcatalyticꢀsystemꢀforꢀtheꢀPd/C‐catalyzed,ꢀ
ligand‐freeꢀSuzukiꢀreactionꢀwasꢀdeveloped;ꢀaꢀwideꢀrangeꢀofꢀarylꢀbromidesꢀ
wereꢀ tolerated,ꢀ andꢀ theꢀ reactionꢀ proceededꢀ withoutꢀ anyꢀ additivesꢀ inꢀ
water.ꢀ