catalyzed N-Arylation of Nitrogen

    Heterocycles

    ChineseChemicalLettersVo1.17,No.3,PP313—316,20O6

    http://www.imm.ac.cn/journal/cc1.html

    CuI/Proline—catalyzedN-ArylationofNitrogenHeterocycles

    WeiDENG,YeFengWANG,ChenZHANG,LeiLIU,QingXiangGUO*

    DepartmentofChemistry,UniversityofScienceandTechnologyofChina,Hefei230026 313

    Abstract:Ma'sCuI/prolineprocedureforthecatalyticcrosscouplingbetweennitrogen heterocyclesandarylhalideswasmarkedlyimproved.ThekeyfindingwasthatKPO4wasa muchbetterbasethanK2CO3forthereaction.Withthisnewreactionconditionthecross couplingwitharyliodidescouldbeaccomplishedin1.4-dioxaneinsteadofDMSO.Thisreactin

    alsocouldbecarriedoutinDMF.Furthermore,thecouplingyieldsunderthenewconditionsare

    usuallyhigherthaninMa'soriginalmethods.

    Keywords:Crosscouplingreaction,CuI,N—arylation,nitrogenheterocycle,proline

    N—Arylaedheterocyclessuchaspyrroles.indoles.andimidazolesareimportant buildingblocksforthesynthesisofnaturalproducts,pharmaceuticals,andfunction materials.UsuallythesecompoundsweresynthesizedbvCu.catalyzedUllmann couplingreactionofarylhalideswithN—heterocycles.Thistraditionalmethodhas

    somedrawbacks:withhighlypolaraproticsolvents.strongbasesandlargeamountsof arylhalides,Cureagent,hightemperature(210.C)isalsorequired. In2004Maela1.reposedthatusingL—prolineasadditive.theUllmanncoupling

    reactionsofaryliodidesandN—heterocyclescouldoccurat80—90.C.givingN—aryl—

    pyrroles,N—arylindoles,andN—arylimidazolesingoodtoexcellentyields.InthesalTle yearBuchwaideta1.reposedthatthecouplingofary1halideswithvariousN.hetero—

    cyclescouldbesuccessfullyperformedingoodyieldat1l0.Cwithcatalystsderived fromCuIandsomediamineligands.Furthermore,veryrecentlyWaneta1.reporteda mildandefficientcopper—catalyzedsystemforN—arylationofN—

    Hheterocycleswithary1

    iodidesusingalloxime—functionalizedphosphineoxideligand4.

    Sincetheaminoacidligandisinexpensive,readilyavailable.andenvironmentally benign,weenvisagedthatMa'sprocedurewouldbemoreapplicabletorealistic synthesis.However,inMa'sprocedure,f.e.thereactionwascarriedoutinDMSO. whichwasoftendifficulttoremovecompletelyfromtheproduct.Thuswedecidedto findabetterreactionconditionforMa'sN—arylationmethod.Avarietyofcatalyst

    loadings,solvents,bases,reactiontemperatures,andreactiondurationshavebeen systematicallyexamined.Tooursatisfaction,wefoundthatbyusingK3P04as base,thedesiredcouplingreactioncouldoccursmoothlyin1.4一dioxaneforaryl

    iodides(SeeTablel17.Itisworthnotingthatdioxaneisconsiderablyeasiertoremove E—mail"qxguo@ustc.edu.ca

314WeiDENG"f

    thanDMSO.InMa'soriginalstudy1,4一dioxanewasalsoutilizedasthesolvent,but

    onlyfew.

    Table1CuI/proline—catalyzedcouplingreactionbetweenN—heterocyclesandaryl

    iodidesindioxane

    (a)Generalcondition:5mo1%CuI,20mo1%L-proline,10mLdioxane,5mmolaryliodide,6 mmolN-heterocycle,12.5mmolK3PO4,reactiontime24hours,at100.C.

    CuI/Proline?-catalyzedN?-ArylationofNitrogenHeterocycles315 Anumberofaryliodidesweretestedwiththenewprocedure.FromTable1itcan beseenthatthenewprocedureworksverywellformostofthearyliodides,expectfor2一

    nitroiodobenzene.Theyieldsofthecouplingreationarein山erangeof80—99%,higher

    thanthatreposedinMa'Soriginalpaperz.

Bothelectron-deficientandelectron—rich

    arylbromidesCansuccessfullyproceedthecrosscouplingreaction,Interestingly, couplingwith4一BrC6I-~I,wecouldobtainthemonosubstitutedcompoundasthemajor product.

    TheyieldofthecouplingofarylbromideiSlowindioxane,butitincreasedto57—

    92%inDMFat140.C(SeeTable2).Bothelectron—deficientandelectron—richaryl

    bromidesCansuccessfullyproceedthecrosscoupling.ItiSworthnotingthatthe boilingpointofDMFisstillmuchlowerthanthatofDMS0.ThUSournewprocedure hasbeensignificantlyimprovedthanMa'Soriginalprocedure.

    Table2CuI/proline-catalyzedcouplingreactionbetweenN-heterocyclesandaryl bromidesinDMP

3l6WeiDENGetal

    Inconclusion.Ma'sprocedurefortheCul—catalyzedcrosscouplingbetween兀一

    excessivenitrogenheterocyclesandarylhalideshasbeenimproved.Thekeyfinding wasthatKPO4wasamuchbetterbasethanK2CO3inthereaction.Usingthenew reactionconditionwecouldaccomplishthecrosscouplingwitharyliodidesin1.4一

    dioxaneinsteadofDMSO.ByusingDMFassolventwealsoaccomplishedthecross couplingswitharylbromides.Furthermore,thecouplingyieldsunderthenew conditionsareusuallyhigherthanthatofMa'soriginalmethods.Duetothegreat importanceofN—arylheterocyclesinpharmaceuticalandmaterialscience.weenvisage thattheimprovedMa'sprocedureWOUldfindmanyapplicationsinorganicsynthesis. Acknowledgment

    ThisresearchwassupposedbytheNNSFC(No.20332020,20472079)

    ReferencesandNotes

    1.(a)D.Z.Wang,L.H.Cao.ChP.R.Chin,C.,2005,2,,172.

    (b)G.Liu,B.A.Song,W.J.Sang,Y.Song,L.1I.Jin,X.Ding,Chin.Org.Chem.,2004,24, l296.

    (c)D.S.Guo,Chin.0rg.Chem.,2004,24,lll8.

    (d)S.X.Li,Y.G.Wang,(n.D,.(em.,2003,23,1311.

(e)Z.S.Lu,Z.P.Ni,D.Z.Niu,S.J.Tu,C.Org.Chem..2OO3,23,89.

    2.D.Ma,O.Cai,Synlett,2004,l28.

    3.CAntilla..MBaskinT.E.BarderS.LBuchwald,J.0rg.Chem.2帕4695578.

    4.L.Xu,D.Zhu,F.Wu,RWang,B.Wan,Tetrahedron,2005,61,6553.

    5.ForMa'sotherCu/aminoacidcatalysts,see:(a)D.Ma,Y.Zhang,J.Yao,S.Wu,F.Tao, Am.Chem.Soc.,1998,120,l2459.(b)D.Ma,C.Xia,0rg.Lett.,2001,3,2583.(c)D.Ma,Q. Cai,H.Zhang,Org.Lett.,2003,5,2453.(d)D.Ma,Q.Cai,Org.Lett.,2003,5,3799.(e)W. Zhu,D.Ma,Chem.Commun.,2004,888,(f)X.Pan,Q.Cai,D,Ma,Org.Lett.,2004,6,1809. (譬)D,Ma,F.Liu,Chem,Commun.,20o4,l934.(h)W.Zhu,D.Ma,Org,Chel'n.,20o5,7D, 2696.(i)Q.Cai,W.Zhu,H.Zhang,Y.Zhang,D.Ma,Synthesis,2005,496. 6.ForourownCu/aminoacidcatalysts,see:

    (a)W.Deng,Y.Zou,Y,F.Wang,L.Liu,Q.X.GUO,Synlett,20O4,l254.

    (b)W.Deng,Y.F,Wang,Y.Zou,L.Liu,Q.X.Guo,TetrahedronLel1.,2004,,23l1. (c)W,Deng,L.Liu,Q,X.Guo,(fn.D,em.,2004,24,l50.

    7,Typicalexperimentalprocedureforaryliodidecoupling:Amixtureofaryliodide(5.0 mmo1),indole(6.0mmo1),K3PO4(12.5mmo1),CuI(O.25mmo1),andL—

    proline(I.0mmo1)in

    l0mLofdioxanewasheatedatl00.Cundernitrogenatmospherefor24h.Theresulting suspensionwascooledtoroomtemperatureandfilteredthrougha2-3cmpadofsilicagel with1o0mLofEt0Ac.Thefiltratewasconcentratedandtheresiduewaspurifiedby chromatographytoaffordthepureproduct.

    8.Typicalexperimentalprocedureforarylbromidecoupling:Amixtureofarylbromide(5.0 mmo1),indole(6.0retoo1),K3PO4(12,5mmo1),Cul(1.0retoo1),andL—

    proline(1.0mmo1)in

    lOmLofDMFwasheatedatl40.CunderniWogenatmospherefor48h.Theresulting suspensionwascooledtoroomtemperatureandfilmredthrougha2—3cmpadofsilicagel

    withlo0mLofEtOAc.Thefiltratewasconcentratedandtheresiduewaspurifiedby chromatographytoaffordthepureproduct.

    Received27June,2005