制备2-苯基吲哚

TetrahedronLettersjournalhomepage:www.elsevier.com/locate/tetletPalladium-freezinc-mediatedhydroaminationofalkynes:efficientsynthesisofindolesfrom2-akynylanilinederivatives

KentaroOkuma*,Jun-ichiSeto,Ken-ichiSakaguchi,SaoriOzaki,NoriyoshiNagahora,KoseiShioji

DepartmentofChemistry,FukuokaUniversity,Jonan-ku,Fukuoka814-0180,Japanarticleinfoabstract

Reactionof2-phenylethynylN-tosylanilidepreparedbyPd-freeprocedurewithZnBr2(3equiv)inreflux-ingtoluenegaveN-tosyl-2-phenylindolein93%yield.Treatmentof2-phenylethynylanilinewithZnBr2(1equiv)inrefluxingtolueneresultedintheformationof2-phenylindolein91%yield.CatalyticZnBr2(0.05equiv)effectivelyreactedwith2-alkynylanilinestoafford2-substitutedindolesinhighyields.Thus,completePd-freezinccatalyzedhydroaminationof2-alkynylanilineswasachieved.Ó2009ElsevierLtd.Allrightsreserved.Articlehistory:Received17March2009Accepted30March2009Availableonline5April2009Nitrogen-containingheterocycles,especiallyindolederivatives,haveattractedmuchattentionbecausetheywidelyoccurinnatureaspartialstructuresofalkaloidsandhavinguniquebiologicalactivities.1Untilnow,manykindsofcatalystshavebeenreportedforthesynthesisofindolederivativesfrom2-ethynylanilinederiv-atives(1).2Asthesyntheticprocedureforthefunctionalized2-eth-ynylanilines1byusingPd(II)orCu(II)catalystshasbeenestablished,3themethodsforindolessyntheseswiththesecom-poundsasthestartingmaterialsaresomeofthemostefficientprocedures.4However,notonlythepalladium-mediatedreactions,butalsootherreagents(Et2Zn,ZnCl2–PdCl2,Zn–Cu,etc.)areknowntohavesomedisadvantagesdependingonthenatureofthereagents,namely,metalalkoxidemediatedreactionscannotbeappliedtothealkaline-sensitivesubstratesandthecarbonylorsulfonylgroupshavetobeonthenitrogenatomformostprocedures(e.g.,sulfonamides,amides,andcarbamatesareusuallyused).2,4,5Fromthebackgrounddescribedabove,wedecidedtodevelopanefficientandcost-effectiveprocedureforthepalladium-freezinccatalyzedsynthesisofindolesfrom1.Herein,wenowreportamild,applicable,andversatilemethodforindolecyclizationcat-alyzedbyzinchalidesanditsapplicationtothesequentialcycliza-tionreaction.Asastartingpointforthedevelopmentofourtransitionmetal-freemethodology,wechosetostudythereactionof2-phenyleth-ynylN-tosylanilide(2a)withLewisacid.Toshowthatthereactionisindeedpalladium-free,wehaveusednewglassware,apparatus,andreagents.Startinganilide2awassynthesizedbythefollowingthreesteps:palladium-freeSonogashiracouplingreaction(micro-wave,CuIasacatalyst)of2-nitroiodobenzenewithphenylacety-lene,6reductionof2-phenylethynylnitrobenzenewithSn/HClandNaBH4,2andprotectionwithtosylchloride.Optimizationdataare*Correspondingauthor.Tel.:+81928716631;fax:+81928656030.E-mailaddress:kokuma@fukuoka-u.ac.jp(K.Okuma).0040-4039/$-seefrontmatterÓ2009ElsevierLtd.Allrightsreserved.doi:10.1016/j.tetlet.2009.03.210showninTable1.Reactionofanilide2awithSnCl2,AlCl3,orTiCl4resultedinrecoveryofstartingmaterial(entries1–3).Reactionofanilide2awithZnBr2inrefluxingEtOHfor12hresultedinthefor-mationof2-phenyl-N-tosylindole(3a)in36%yield(entry4).When3equivofZnBr2wastreatedwithanilide2ainrefluxingtoluene,thereactionwascompletedwithin16h(entry5).Similarly,thereactionof3equivofZnI2with2agave3ain92%yield(entry9).CatalyticamountofZnBr2gaveindole3ainlowyields(10–21%)(entries7and8).WhenthereactionwascarriedoutintheabsenceofLewisacid,starting2awasrecoveredunchanged(entry10).Undertheseoptimumconditions(3equivZnBr2,refluxingtolu-ene),weturnedourattentiontocompareavarietyof2-alkynyl-N-tosylanilidesbearingdifferentsubstitutedgroupsatmetapositiononthearomaticring.AsshowninTable2,N-tosylindoles(3a–d)wereobtainedinhighyields.Table1

Reactionof2awithLewisacids

PhLewis AcidNHTssolventrefluxNPhTs3a:yield(%)00036935221109202aEntry12345678910LewisacidSnCl2AlCl3TiCl4ZnBr2ZnBr2ZnBr2ZnBr2ZnBr2ZnI2NoneEquiv3333310.10.053—SolventTolueneTolueneTolueneEtOHTolueneTolueneTolueneTolueneTolueneToluene242424241616161616243aTime(h)2944K.Okumaetal./TetrahedronLetters50(2009)2943–2945Table2

Reactionof2withZnBr2R2 ZnBr2 (3 eq)RR1NHtoluene2refluxR1NTs2Ts32R1R2Time(h)3Yield(%)2aHPh163a932bOMePh483b882cHn-Pr333c902dHPentyl323d91ItiswellknownthatAg(I)orZn(II)saltshavemildLewisacidityandhavebeenusedascatalystsinorganicsynthesis.72-Alkynyla-rylmethylphosphatereactedwithAgOTfleadingtoisoquinolinesingoodyields.8Recently,Yinetal.havereportedtheEt2Zncatalyzedhydroaminationofalkynylsulfonamides,whichproducedN-tosylindoles3,whereassynthesisofunprotectedindolesfailedundertheseconditions.5Nakamuraetal.alsoreportedthetandemcycli-zationofN-benzylprotectedalkynylanilinesbyusingBuLi/ZnCl2/[Pd2(dba)3]orBuLi/ZnCl2/CuCNleadingtoN-benzylindoles,whereasthereactionproceededunderbasicconditions.9Gold,In-dium,orRuthenium-catalyzedhydroaminationof2-alkynylani-linestogiveunprotectedindoleswasrecentlyreported.10However,toourknowledge,thereisnoreportonthesynthesisofunprotectedindolesfrom2-alkynylanilinesandcatalyticamountofZnX2underneutralconditions.Wetheninvestigatedthereactionofunprotected2-alkynylan-ilineswithzinchalideswhetherunprotectedindoleswouldbeformedinthepresenceofcatalyticamountofzinchalides.Whenasolutionof2-phenylethynylaniline(1a)intoluenewastreatedwithZnBr2(1equiv)inrefluxingtoluenefor2h,2-phenylindole(4a)wasobtainedin91%yield(Table3,entry1).WhenZnI2wasusedasaLewisacid,asimilarresultwasobtained(entry5).Interestingly,byusingcatalyticamountofZnBr2(0.05equiv),4awasformedin90%yield(entry3).When0.01equivofZnBr2wasused,theyielddecreasedto21%(entry4),whereas0.01equivofZnI2gave4ain90%yield(entry8).Thus,Zncatalyzedintramo-lecularhydroaminationof2-alkynylanilineswasachieved.Undertheseoptimumconditions(ZnBr20.05equivorZnI20.01equiv,toluenereflux,24h),andothersubstitutedindoleswereobtainedinhighyields(Table4).Howdoweaccountforthereactionmechanism?Wehaveper-formedtheoreticalcalculationsonthereactionmechanismfortheintramolecularhydroaminationreactionof2-(1-propynyl)anilineTable3

Reactionof2-Phenylethynylaniline1awithZnX214PhZnX2PhNHtoluene2refluxNH1a4aEntryZnX2EquivTime(h)Yield(%)1ZnBr213912ZnBr20.53913ZnBr20.056904ZnBr20.0124215ZnI210.5916ZnI20.0524907ZnI20.0124908ZnCl2324729None—240Table4

Reactionof1withcat.ZnBr2andZnI2R2ZnX2R2R1NHreflux, 24 htoluene2R1NH141R1R2ZnX2Equiv4Yield(%)1bOMePhZnBr20.054b921cHPrZnBr20.054c901cHPrZnI20.014c901dHPentylZnBr20.054d911dHPentylZnI20.014d911eBrPhZnBr20.054e921fClPhZnBr20.054f92withZnCl2giving2-methylindoleasamodelsystem.11Thestruc-turaloptimizationforthereactiongavefourstableintermediates,thatis,N-coordinatedcomplexA,p-coordinatedcomplexB,N-andp-coordinatedcomplexC,andr-complexD.ThecalculationsuggestedthatthemoststablestructurewascomplexC.12SincethedifferenceinpotentialenergybetweenBandCiswithin16.8kcal/mol,thereactionmightproceedasfollows:catalyticZnX2reactedwith2-alkynylaniline1togivethemoststablecom-plexC,whichequilibratestoaffordcomplexB.StructureBfinallycyclizedtogivesigmacomplexD,protodemetallationofwhichaffordedindole4andZnX2(Scheme1).Thereactionmechanismwasalsosupportedbythefollowingresults.Thereactivityof2abearingatosylgroup(Table1,entries6–8)islowerthanthatofunprotectedalkynylanilines(Table3),thenucleophilicityofN-Tsgroupislowerthanthatofunprotectedaminogroup.Whenethanolwasusedasasolvent,catalyticreac-tiondidnotproceed,suggestingthatzinchalidewassolvatedwithpolarsolvent.Sincezincdustreductionofnitrobenzenestoanilinesiswellknown,13wethentriedtheone-potsynthesisofindolesfrom2-phenylethynylnitrobenzene(5a)preparedbypalladium-freeSono-gashiracouplingreactionof2-iodonitrobenzenewithphenylacety-RRNH2ZnX1NRXHNAH4HZnX2XXZnRXZnXNBHHNRRDHHZnXNXCHHScheme1.K.Okumaetal./TetrahedronLetters50(2009)2943–29452945RZn/ BrCH2CH2BrRNO2EtOHrefluxNH5a: R = Ph8 h4a: R = Ph 84%5b: R = butyl4g: R = butyl 76%Scheme2.lene.6When5awastreatedwithzinc(8equiv)anddibromoethaneinrefluxingethanolfor12h,2-phenylindole4awasobtainedin86%yield.Similarly,2-heptynylnitrobenzene(5b)reactedwithzinc/dibromoethanetogive2-butylindole4gin76%yield(Scheme2).Inconclusion,wehavedemonstratedthatzinchalidesserveaseffectivecatalystsfortheintramolecularhydroaminationof2-alk-ynylanilines.Thusapracticalandcosteffectivemethodforthepreparationofunprotectedindoleshasbeendemonstratedbyusingthesecatalysts.SupplementarydataSupplementarydataassociatedwiththisarticlecanbefound,intheonlineversion,atdoi:10.1016/j.tetlet.2009.03.210.Referencesandnotes1.Humphrey,G.R.;Kuethe,J.T.Chem.Rev.2006,106,2875;Cacchi,S.;Fabrizi,G.Chem.Rev.2005,105,2873;Hibino,S.;Choshi,T.Nat.Prod.Rep.2002,19,148;Gupta,R..InHeterocyclicChemistry;SpringerPublishing:NewYork,1999;Vol.2;Rahman,A.;Basha,A.IndoleAlkaloids;HarwoodAcademic:Amsterdam,TheNetherlands,1998;Dewick,P.M.MedicinalNaturalProducts;Wiley&Sons:Chichister,UK,1997.2.Sakai,N.;Annnaka,K.;Konakahara,T.TetrahedronLett.2006,47,631;Hiroya,K.;Itoh,S.;Skamaot,T.J.Org.Chem.2004,69,1126;Hiroya,K.;Matsumoto,S.;Sakamoto,T.Org.Lett.2004,6,2953;Kamijo,S.;Sasaki,Y.;Yamamoto,Y.TetrahedronLett.2004,45,35;Koradin,C.;Dhohle,W.;Rodriguez,A.L.;Schmid,B.;Knochel,P.Tetrahedron2003,59,1571.3.Sonogashira,K.;Tohda,Y.;Hagihara,N.TetrahedronLett.1975,17,4467–4470;Sonogashira,K.J.Organomet.Chem.2002,653,46.4.Kondo,Y.;Kojima,S.;Sakamoto,T.J.Org.Chem.1997,62,6507;Ezquerra,J.;Pedregal,C.;Lamas,C.;Barluenga,J.;Perez,M.;Garcia-Martin,M.A.;Gonzarez,J.M.J.Org.Chem.1996,61,5804;Kondo,Y.;Kojima,S.;Sakamoto,T.Heterocycles1996,43,2741;Rudisill,D.E.;Stille,J.K.J.Org.Chem.1989,54,5856.5.Hong,K.B.;Lee,C.W.;Yum,E.K.TetrahedronLett.2004,45,693;Yin,Y.;Ma,W.;Chai,Z.C.;Zhao,G.J.Org.Chem.2007,72,5731.6.Chen,G.;Zhu,X.;Cai,J.;Wan,Y.Synth.Commun.2007,37,1355.7.Black,T.H..InEncyclopediaofReagentsforOrganicSynthesis;Paquette,L.A.,Ed.;JohnWiley&Sons:Chichister,UK,1995;Vol.6,p4476.8.Ding,Q.;Ye,Y.;Fan,R.;Wu,J.J.Org.Chem.2007,72,5439.9.Nakamura,M.;Ilies,L.;Otsubo,S.;Nakamura,E.Org.Lett.2006,8,2803;Nakamura,M.;Ilies,L.;Otsubo,S.;Nakamura,E.Angew.Chem.,Int.Ed.2006,45,944.10.Ambrogio,I.;Arcadi,A.;Cacchi,S.;Fabrizi,G.;Marinelli,F.Synlett2007,1775;Miyazaki,Y.;Kobayashi,S.J.Comb.Chem.2008,10,355;Sakai,N.;Annaka,K.;Fujita,A.;Sato,A.;Konakahara,T.J.Org.Chem.2008,73,4160;Kondo,T.;Okada,T.;Suzuki,T.;Mitsudo,T.J.Organomet.Chem.2001,622,149.11.Thetheoreticalcalculationsforreactionof2-(1-propynyl)anilinewithZnCl2giving2-methylindoleareshownintheSupplementarydata.12.Relativestabilizationenergies[kcal/mol]ofintermediatesA–Dbasedonthesumofallelectronenergyof2-(1-propynyl)anilineandZnCl2wereestimatedtobeÀ24.9forA,À18.9forB,À29.3forC,andÀ12.5forDattheB3LYP/6-31G(d)level.ThemolecularstructuresandtheoreticallyoptimizedcoordinatesofA–DareshowninFigureS8andTablesS1–S4,respectively,intheSupplementarydata.13.Naffziger,M.R.;Ashburn,B.O.;Perkins,J.R.;Carter,R.G.J.Org.Chem.2007,72,9857;Maya,A.B.S.;Melero,C.P.;Mateo,C.;Alonso,D.;Fernandez,J.L.;Gajate,C.;Mollinedo,F.;Pelaez,R.;Caballero,E.;Madarde,M.J.Med.Chem.2005,556;Aerssens,M.H.P.J.;Brandsma,L.J.Chem.Soc.,Chem.Commun.1984,735.14.Typicalreactionisasfollows:Toarefluxingsolutionof2-phenylethynylaniline1a(1.0mmol)intoluenewasaddedzincbromide(0.05mmol)inoneportion.Afterrefluxingfor6h,thereactionmixturewaswashedwithwaterandextractedwithdichloromethane.Thecombinedextractsweredriedoversodiumsulfate,filtered,andevaporatedtogiveapalebrownsolid,whichwaschromatographedoversilicagelbyelutionwithhexane/ethylacetate(5:1)toafford2-phenylindole4a(0.90mmol).