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1、AFISFVIFRTetrahedronLeiters47(2006)6425-6427TetrahedronLettersDeprotectionofN-tosylatedindolesandrelatedstructuresusingcesiumcarbonateJoginderS.Bajwa/Guang-PeiChen,KapaPrasad,OljanRcpicandThomasJ.BlacklockProcessR&D.ChemicalandAnalyticalDevelopment,NovartisPharmaceuticalsCorporation,OneHealthPlaza,E
2、astHanover,NJ07936,USAReceived12June2006：revised22June2006:accepted23June2(X)6AbstractAverymild,efficient,andconvenientmethodfordeprotectionofN-losylaledindolesandrelatedstructuresbycesiumcarbonateinTHF-MeOHisdescribed.4384:e-mail:2006ElsevierLtd.Allrightsreserved.Manycompoundsinmedicinalchemistryco
3、ntainheteroaromaticsaspartofthestructureandtheNH-functionality,thatis,presentinsomeofthesemoleculesneedstobeprotectedduringthesynthesisbyasuitablegroup,thatis,easilyremovable.Tosylgroupisonesuchblockinggroup,anditsdeprotectionisusuallyaccomplishedbyoneoffollowingmethods:dissolvingmetalreductions(Lio
4、rNa)inammonia,alcoholorHMPA;singleelectrontransferreagentssuchassodiumnapthalenide,Na-Hg,n-BusSnH;reducingagentsL-Selectride,Red-AI;photolysis.1,2OtherreagentsusedforthisdeprotectionarehighlynucleophilicGiimansreagentPhMeiSiLi,1highlybasicNaOH(orKOH)inalcoholsolventsathightemperature,3-4KF5onalumina
5、undermicrowaves,n-BmNFinrefluxingTHE6Mg-MeOH,7polymer-supportedpotassiumthiophenolate,sandHSCHjCOOH/LiOH.9Mostofthesemethods,whileeffectiveinanumberofcases,haveseriousincompatibilitieswithotherfunctionalgroups.Whilemakinganindolederiveddrugsubstance,weneededtoeffectN-detosylation.Severalliteratureme
6、thodsweretriedwhichinvariablygavelowyieldsduetotheformationofmanyby-products.ThisledtothedevelopmentofanewandaverymildmethodforN-dctosylationofindolesandrelatedstructuresusingcesiumcarbonate(Scheme1).Todeterminetheoptimumstoichiometryofcesiumcarbonate,asetofKeywords:N-detosylation;Azaindoles;Indoles
7、;Imidazoles;Cesiumcarbonate.Correspondingauthor.Tel.:+18627783474;fax:+1973781p-MePhSO3H+CH3OCH30040-4039/S-seefrontmatter2006ElsevierLid.Allrightsreserved.doi:l0.1016/j.tetlet.2006.06.l32SchemeI.experimentswasperformedwithN-tosyl-5-bromoindole9,andtheresultsareshowninTable1.Thereactionswerecarriedo
8、utinamixedsolventTHFMeOH(2:1).Ideally,thesolventofchoiceismethanolbutsimpleN-tosylindoles(suchas9)arehighlyliphophilicandarenotsolubleinmethanol.Whenthereactionswerecarriedoutinasinglesolventmethanolorethanol,thereactionstimeswerelonger.Thereactiondidnotworkwhencarriedoutiniso-propanol.Itisapparentf
9、romtheresultsinTable1that3cquivofcesiumcarbonatearerequiredtoachieveareasonablereactionrateforN-detosylalionofindole9.ItisalsoTableI.ReaciionJofN-tosyl-5-bromoindolc9withvaryingamountsofcesiumcarbonateinTHF-MeOHEntryAmountofCs；CO(equiv)Reactiontime(h)Conversion1110/911.01569/3122.01595/533.01599/1*A
10、mixtureof9(0.25mmol)andCs2CO?(I-3equiv)inTHF-MeOH(3mL.2:1)wasstirredat22CandfollowedbyHPLC.bDeterminedbyHPLC.6426J.S.Bajwactal./leirahcdronLeiters47(2(X)6)6425-6427Table2.RcaclionJofN-tosyl-5-broinoindolc9withvariousalkaliTable3.DcproicclionofN-losylindolesandrclalcdhctcrucyclesametalcarbonatesinTHF
11、-MeOHinthepresence/absenceofwaterl?SubstrateFemperaiure(C*ProductEntryAlkalimetalcarbonate(3.0cquiv)Additive(cquiv)Conversion1*10/91Ligh0.l/i99.92NazCChh0.l/i99.93K2CO324/764CS2CO399.8/0.25LiiCOxH0(1.0)h0.1/i99.9HQ(40.0)h0.1/i99.96NagHQ(1.0)hO.1099.9HQ(40.0)h0.1/i99.97K2CO3H2O(1.0)23/77HQ(40.0)0.4/9
12、9.68CS2CO3HQ(1.0)99.7/0.3H，0(40.0)7/93EntryAlkalimetalcarbonate(3.0cquiv)Additive(cquiv)Conversion1*10/91Ligh0.l/i99.92NazCChh0.l/i99.93K2CO324/764CS2CO399.8/0.25LiiCOxH0(1.0)h0.1/i99.9HQ(40.0)h0.1/i99.96NagHQ(1.0)hO.1099.9HQ(40.0)h0.1/i99.97K2CO3H2O(1.0)23/77HQ(40.0)0.4/99.68CS2CO3HQ(1.0)99.7/0.3H，
13、0(40.0)7/93Awater(0,1or40equiv)inTHF-MeOH(3ml,2:1)wasstirredat22Cfor15h.reaciiontime(h);conversionTs522/90:95/5(2/1)64/0.5;99/1(2/1)22/70;2/98(4/3)64/48:97/3(4/3)22/70;12/88(6/5)mixtureof9(0.25inmol),alkaliH64/8;98/2(6/5)DeterminedbyHPLC.metalcarbonate(3cquiv)andinterestingtonotethat(heinitialby-pro
14、ductobservedinthisreactionismethylp-toluenesulfonate(Scheme1).Ifthereaciionrateisslowenoughasitisinthepresentcase,thep-McPhSOMeformedreactsfurtherwith3BrBrmethanoltogivep-MePhSO.?HandMeOMe.Ontheotherhand,anddimethylether22/15;99/1(10/9)NextwcexaminedN-dctosylationofNtosyl-5-brorno-aretheonlyby-produ
15、ctsobsenedwhenthereactionwascarriedoutatrefluxtemperature.10ofwateronthisreactionwasalsostudied.TheresultsarcshowninTable2.differentalkalimetalcarbonates.Theeffecttotallyineffectiveindeprotectionoftosylgroupin9.Potassiumcarbonatedoeseffectdetosylationof9(entry3)butitismuchlesseffectivethanCS2CO3(entry4).ItisclearfromtheresultsinTable2(entries1,2,5,andO2NO2N6)tha
