Site-Selective Aerobic C–H Monoacylation of Carbazoles Using Palladium Catalysis 2020 Subhadip Maiti.pdf

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Site-SelectiveAerobicC−HMonoacylationofCarbazolesUsing
PalladiumCatalysis
SubhadipMaiti,TirthaMandal,BaradaPrasannaDash,andJyotirmayeeDash*
CiteThis:,86,1396−1407ReadOnline
ACCESSMetrics&MoreArticleRecommendations*sıSupportingInformation
ABSTRACT:Thismanuscriptdescribesthedevelopmentofaremarkablygeneralpalladium-catalyzedmonoacylationofcarbazoles

,theacylationofmonosubstitutedN-pyridylcarbazolestakesplaceregioselectivelyattheC-8
-selectiveacylationproceedsthrough
aradicalprocess.
■INTRODUCTIONenvisionedtocarryoutacylationofcarbazolesusingnaturaland

C−Hbondfunctionalizationhasemergedasoneofthemost2
Tillnow,fewmethodshavebeenknownforthesynthesisof1-
powerfultoolsforgeneratingnewcarbon−carbonandcarbon−-aroylcarbazolesby
,selectiveC−Hfunctionalization
1a,2photolysisofN-aroylcarbazolesinlowyields(∼15−30%)was

themostubiquitousheteroaromaticmotifsfoundinmyriadofof1-aroylcarbazolesbyortho-lithiationofN-pyrrolidinomethyl-
naturalproducts,photorefractivematerials,organicdyes,3and
4carbazoleandsubsequentadditionofelectrophilessuchas
−
thesynthesisandfunctionalizationofcarbazoles,onlyafewCraftsacylationofcarbazolewithbenzoylchloridewasreported
methodsareknowntoaffordC1/C8-
toaffordamixtureofmono-anddibenzoylcarbazole
Further,-workersreportedoneexample
DownloadedviaUNIVOFCALIFORNIASANTABARBARAonMay15,2021at09:22:29(UTC).See,electrophilicsubstitutionoccursmostlyof1-benzoylcarbazolebyPd-catalyzedcross-couplingof(9H-
,regioselectivecarbazol-1-yl)
-protected1-
thecarbazolewithoutprotectingtheC3andC6positions5,7isacylatedcarbazolederivativesbytandemRh-catalyzedC−H
-protectedindolesandsubsequent
Recently,Pd(II)-catalyzeddirect1-arylationofpyridine-Brønstedacid-catalyzedcyclization(Scheme1).19Acylationof
protectedcarbazoles,81,8-diolefinationofcarbazoles,9Ru-andapyrimidine-protectedcarbazolewith4-methylbenzaldehyde
Cu-cocatalyzeddehydrogenativeC1−Ncarbazolation,10andusingbothPd(II)catalystandRu(II)photocatalystinthe
Ru-catalyzedregioselectiveC1andC8diacetoxylationofN-presenceofvisiblelightandexternaloxidantTBHPwasrecently
11reported(Scheme1).
pyridylcarbazoleshavebeenreportedforthefunctionalization

reportedpalladium(II)-catalyzed1,8-diacylationofcarbazolesReceived:July22,2020
:December31,2020
MostoftheoxidativeC−Hactivationprocessesproceed
throughaPd(II)/Pd(IV)13manifoldinvolvingstoichiometric
oxidant(TBHP,K2S2O8,Cu(OAc)2,DDQ,PIDA,etc.).
Focusingonthegrowingdemandforsustainablesynthesis,we
©2020AmericanChemicalSociety/
,86,1396−1407
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-Acylcarbazoles
N-acyl-protected1-acylcarbazolederivativeusingPd-catalyzed10mol%Pd(OAc)2,thereactiongave76%yieldof3aalong
,with5%yieldof1,8-diacylatedcarbazole4aat80°Cfor24h
site-selectivesynthesisof1-acylatedcarbazolederivativesusing(Table1,entry9).Whenthereactionwascarriedoutusing2
easilyaccessiblestartingmaterialsandametalcatalystwithoutmol%ofPd(OAc)2and10mol%ofNHPIatelevated
,atraceamountofproductcouldbedetected(entry
Pd(II)-catalyzedaerobicoxidativeradicalprocessesinvolving10).Pd(PPh3)2Cl2orPd(PPh3)4failedtogiveanydesired
Pd(III)or-(IV)intermediateshavebeenreportedforC−Hproduct(Table1,entries11,12).Thus,Pd(OAc)2wasusedas
-Hydroxyphthalimide(NHPI)isusedas
,insteadof
cocatalyst,whichisoxidizedbyO2togeneratePINONHPI,differentone-electronoxidantssuchasBQ,TEMPO,or
(phthalimido-N-oxyl)
Cu(OAc)
oxidativereactionwiththeformationofbenzoylradicalfromformed(Table1,entries13−15).Theyieldofthereactionwas
,weemployedNHPIslightlydecreasedwhenmolecularoxygenwasreplacedbyair
andO2forthePd(II)-catalyzed1-acylationofcarbazoleusing(Table1,entry16).
tolueneastheacylsource(Scheme1).22,23VersatileC−H
IntheabsenceofeitherNHPIorPd(OAc)2,thereactiondid
functionalizationoftoluenederivativesusingmetalcatalysishasnotproceed(Table1,entries17,20).Evenatelevated

temperatureorinthepresenceofTBHPnoreactionoccurred
intheabsenceofmetalcatalyst(entries18,19).Furthermore,
■RESULTSANDDISCUSSIONthereactiondidnotoccurunderanargonatmosphere(Table1,
Asamodelreaction,theacylationof9-(pyridin-2-yl)-9H-entry21).Itisworthnotingthatthereactioncouldbescaled
carbazole1wasperformedinthepresenceof10mol%PdCl2()withoutalossofyieldundertheoptimized
and30mol%ofNHPIascocatalystin1mLoftoluene2aunderconditions(entry22).Thus,theoptimizationstudyimpliedthat
1atmO2at80°Cfor12h(seeTableS1;SupportingPd(OAc)2,NHPI,andO2arerespectivelythemostsuitable
Information,SI).Thereactionprovided10%yieldof1-acylatedcatalyst,cocatalyst,andoxidantforthesite-selective1-acylation
carbazolederivative3a(Table1,entry1).Theyieldof3awasof9-(pyridin-2-yl)-9H-carbazole1.
onlymarginallyincreasedevenwithprolongedreactiontimeWiththeoptimizedreactionconditions,wethenexploredthe
(Table1,entries2,3).Theyieldofthereactiondidnotimprove1-acylationof9-(pyridin-2-yl)-9H-carbazole1withavarietyof
onincreasingorloweringthereactiontemperature(Table1,-Chlorotoluene2bshowedslightly
entries4,5).Thereactiondidnotproceedatroomtemperaturehigherreactivitythan3-chlorotoluene2c,producingthedesired
(entry6).OtherPdsourcessuchasPd(TFA)2andPd2(dba)3products3b(78%)and3c(71%)-
providedproduct3ain55%and29%isolatedyields,respectivelyBromotoluene2dand3-bromotoluene2edisplayedcomparable
(Table1,entries7,8).Weweredelightedtoobservethatwithreactivity,generatingthedesiredproducts3dand3ein73%and
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entryPdcatalyst(10mol%)co-cat.(30mol%)oxidanttime(h)temperature(°C)yieldbof3a(%)yieldbof4a(%)
1PdCl2NHPIO2128010-
2PdCl2NHPIO2248027trace
3PdCl2NHPIO2368029trace
4PdCl2NHPIO22410026trace
5PdCl2NHPIO2366010trace
6PdCl2NHPIO236rtNRd-
7Pd(TFA)2NHPIO2248055trace
8Pd2(dba)3NHPIO2248029trace
9Pd(OAc)2NHPIO22480765
10cPd(OAc)NHPIO24120trace-
22f
11Pd(PPh3)2Cl2NHPIO22480NR-
12Pd(PPh3)4NHPIO22480NRf-
13Pd(OAc)2BQO22480NRf-
14Pd(OAc)2TEMPOO22480NRf-
15Pd(OAc)2Cu(OAc)2O22480NRf-
16Pd(OAc)2NHPIAir248067NDg
17-NHPIO22480NRd-
18-NHPIO224120NRf-
19d-NHPITBHP2480NRf
20Pd(OAc)2-O22480NRf-
21Pd(OAc)2NHPIAr2480NRf-
22ePd(OAc)2NHPIO224807010
a9-(Pyridin-2-yl)-9H-carbazole1(),toluene2a(1mL).%Pd(OAc)and10mol
def2g
%(2equiv)
determined.
74%isolatedyields,,4-fluorotoluene2fproduct10bin83%yield(Table3).3,6-Dibromo-N-
and3-fluorotoluene2gaffordedthedesiredproducts3fand3gpyridylcarbazole6reactedwithelectron-rich1-methoxy-4-
,thereactivityof2-fluorotoluene2hmethylbenzene2qandelectron-deficient4-methylbenzoate2k
decreasedconsiderably,furnishingthedesiredproduct3hintogive11qand11kin66%and68%yields,respectively(Table
33%-with-3),whereas3,6-diiodo-N-pyridylcarbazole7reactedwith
drawinggroups,apartfromhalogens,alsoparticipatedwellintoluenestoprovidethedesiredproducts12qand12kin
the1-,4-methylbenzonitrile2i,moderateyields(Table3).Itisintriguingtofindthatwhen
3-methylbenzonitrile2j,andmethyl4-methylbenzoate2kunsymmetricalmonosubstitutedN-pyridylcarbazolewasused,
reactedtoprovidethedesiredproducts3i,3j,and3kin77%,acylationoccurredexclusivelyattheorthopositionofthe
75%,and79%yields,-pyridylcarbazole10
Thetoluenederivative4′-methylacetophenone2lreactedhavinga3-chlorosubstituentproduced1-acylatedproduct
with1tofurnishthedesiredproduct3linexcellentyield(94%).13ain69%-ray
Toluenederivativeshavinganelectron-donatinggroupwere25
,2-methylanisole2mafforded1-crystalanalysis(Table3,CCDC1989702;FigureS3,SI).N-
acylatedcarbazolederivative3min67%,m-Pyridylcarbazole12havinga3-methoxygroupfurnishedthe1-
xylene3n,o-xylene2o,andmesitylene2pparticipatedintheacylatedproduct13bin60%yield.
reactioneffectivelytoprovidethedesiredproductsingoodtoTovalidateourhypothesisabouttheinsitugenerationofthe
moderateyields(Table2,products3n,3o,and3p).Thealdehydefromtolueneinthereactionmedia,weperformedthe
structureofmonoacylatedproducts3f(CCDC1989688)and3ireactionbyusingaldehydes16insteadoftoluenes2in
(CCDC1989676)wereconfirmedbysinglecrystalX-raychlorobenzeneassolvent(Table4).Thedesiredproductswere
analysis(Table2;FiguresS1andS2,SI).25Gram-
experimentsusing1gof1weresuccessfultoobtainwithheptaldehyde16e,providingthedesiredproduct3rin75%
monoacylatedcarbazoles3aand3bingoodyields(Table2;yield(Table4).Inspiredbytheresult,wecarriedoutthe
seeexperimentalsectionforsyntheticprocedure).acylationofcarbazole15withheptaldehyde16etosynthesize
Next,the1-
N-,6-dichloro-N-pyridylcarba-acylationprovidedexclusivelytheregioisomericacylderivative
zole5reactedwith4-chlorotoluene2btoafford1-acylated17ein70%yield(Table4).
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-PyridylcarbazoleswithTolueneDerivativesa,b
aN-Pyridylcarbazole1(),Pd(OAc)(10mol%),NHPI(30mol%),toluene2(1mL),O(1atm),80°
22
obtainedwhenreactionwasperformedwith1gof1.
Togaininsightintothereactionmechanism,wecarriedoutToknowwhetherthereactionproceedsthrougharadicalor
,thereactionwasperformedinthepresenceofa
presenceofargonatmosphere(Table1,entry21),suggestingradicalinhibitorTEMPO(2,2,6,6-tetramethylpiperidin-1-yl)-
).Thestartingmaterial1wasfullyrecoveredandtheacyl
18Olabelingexperimentconfirmsthattheoxygenatomoftheadduct19wasobtainedin70%yield(Scheme4;SchemeS5,
keto-carbonylgroupinthemonoacylatedproduct3a′originatesSI).Thisresultindicatedthatacylradicalistrappedbythe
frommolecularoxygen(Scheme2;SchemeS4,SI).TEMPOfreeradical.
Furth