甲基醚的脱甲基反应-060120

经典合成反应标准操作—酚醚去甲基化反应药明康德新药开发有限公司PAGEPagePAGE14ofNUMPAGES15药明康德内部保密资料药明康德内部保密资料经典化学合成反应标准操作甲基芳基醚去甲基化反应编者：彭作中药明康德新药开发有限公司化学合成部目录TOC\o"1-3"\u1．前言PAGEREF_Toc125431071\h22．酸性试剂PAGEREF_Toc125431072\h32.1．浓HI，HBr，HClPAGEREF_Toc125431073\h32.2．48%HBr加入相转移催化剂PAGEREF_Toc125431074\h32.3．BBr3,BI3,BCl3PAGEREF_Toc125431075\h42.4．BX3和Me2S的络合物PAGEREF_Toc125431076\h52.5．BBr3/NaI/15-crown-5PAGEREF_Toc125431077\h62.6．Me2BBrPAGEREF_Toc125431078\h72.7．AlX3/CH3CN,AlX3/CH2Cl2,PAGEREF_Toc125431079\h82.8．AlBr3/EtSH，AlCl3/EtSH,AlCl3/HSCH2CH2SH，AlCl3/EtSH/CH2Cl2PAGEREF_Toc125431080\h83．碱性试剂PAGEREF_Toc125431081\h93.1．氨基钠PAGEREF_Toc125431082\h93.2．N-甲基苯基氨基钠/HMPTPAGEREF_Toc125431083\h93.3．EtSNaPAGEREF_Toc125431084\h104．其它试剂PAGEREF_Toc125431085\h114.1．Me3SiIPAGEREF_Toc125431086\h114.2．LiCl/DMFPAGEREF_Toc125431087\h124.3．吡啶盐酸盐PAGEREF_Toc125431088\h141．前言酚羟基广泛存在天然产物中，酚羟基易被氧化、亲电试剂取代或形成氧负离子进行亲核反应，因此天然产物的合成中常先将其保护起来，然后在合成的最后通过去保护策略游离出酚羟基。使用甲基作为酚羟基的保护基，形成甲基芳基醚，从而通过去甲基化还原出酚羟基一直是非常实用、也广泛采用的策略之一。去甲基化的 方法 快递客服问题件处理详细方法山木方法pdf计算方法pdf华与华方法下载八字理论方法下载 已经发展了相当的多，并不断在开发新的方法。在1954年1，1965年2，1967年3，1983年4，1987年5，1988年6和1996年7，都有一篇综述对去甲基化方法进行归纳和 总结 初级经济法重点总结下载党员个人总结TXt高中句型全总结.doc高中句型全总结.doc理论力学知识点总结pdf ，在JOHNILEY&SONS公司出版的PROTECTIVEGROUPSINORGANICSYNTHESIS一书中也有专门的章节阐述去甲基化方法。在这，编者着重列举一些适用范围广，仅使用常规试剂的去甲基化方法，并从三个方面加以归纳总结：1，酸性试剂；2，碱性试剂；3，其它类型试剂。事实上，很多甲基芳基醚的去甲基化方法也适用于甲基烃基醚，反之亦然。因此，在本文的典型操作列举的范例中可以看到一些底物是甲基烃基醚。2．酸性试剂2.1．浓HI，HBr，HCl这是最为经典和简单的甲基芳基醚水解去甲基的方法。一般使用过量的浓HI酸回流下、或者大大过量的48%HBr8或37%HCl在HOAc或Ac2O中回流，反应完后，浓缩去除过量的酸，加入水，用有机溶剂萃取，然后进一步纯化即可。特点是操作和后处理简单、方便。但要求底物对强酸稳定，对于有些底物，易形成卤代苯副产物。范例：TypicalPocedure.8Theether(300mg)wasdissolvedin48%HBr(50mL)andheatedfor1hrunderreflux.Thereactionmixturewasevaporatedtodrynessandextractedwithether.Theetherealextractwaswashedwithsodiumcarbonatesolutionandwater,driedandevaporated.Theresiduewasrecrystallizedfromchloroformtogivetheproduct(120mg,40%).2.2．48%HBr加入相转移催化剂在48%HBr中加入相转移催化剂是对仅使用强质子酸如48%HBr的改进。加入相转移催化剂后，能提高去甲基化的效率，大大缩短反应的时间。此反应是在一个多相体系（水和有机）中进行，可使用的相转移催化剂有四丁基溴化铵，十六碳烷基三丁基溴化磷,四辛基溴化铵，三辛基甲基溴化铵等。对于甲基芳基醚，一般使用5mol量的HBr，对于甲基烃基醚，一般使用10mol量的HBr；值得注意的是，反应的收率和时间不是依赖于使用那一种相转移催化剂，而是依赖于相转移催化剂的浓度和其在有机相的溶解度。范例：Table1.CleavageofEtherswith47%HBrinPresenceofHexadecyltributylphosphoniumBromideR1orArR2orRMolofHBrMolofCatalystTime(hrs)Yield(%)aofR1BrorRBrArOHn-C4H9n-C4H9100.1889n-C8H17n-C8H17100.1591n-C16H33CH350.1388C6H5CH350.15--91C6H5n-C4H950.12485904-t-Bu-C6H4CH350.18--904-t-Bu-C6H4n-C4H950.1248691a)YieldofisolatedproductTypicalPocedure.9CleavageofDi-n-octylEther.Di-n-octylether(12.1g,0.05mol),47%aqueoushydrobromicacid(56mL,0.5mol),andhexadecyltributylphosphoniumbromide(2.5g,0.005mol)aremixedinaflaskequippedwithamagneticstirrerandrefluxcondenser,andheatedat115°C(innertemperature)withstirringfor5hrs.AfterthistimeGLCanalysis(SE30,3%overchromosorbsulfate,anddistilledtogivepure1-bromooctane.Theorganiclayerisseparated,driedwithsodiumsulfate,anddistilledtogivepure1-bromooctane;yield:17.5g(91%),bp88°/torr.Bytreatingthedistillationresiduewithhexane,2.3g(92%)ofpurephosphoniumbromidearerecovered,mp54-56°C.Inthecaseofarylalkylethers,aqueousalkalineextractionoftheorganicphaseaffordsthecorrespondingphenol.2.3．BBr3,BI3,BCl3BBr3是一种温和、优良的去甲基化试剂，并且不影响分子中的酯基和双键，在许多天然产物的全合成中常使用它。一般使用CH2Cl2,benzene,pentane作为溶剂，在-78℃到室温下进行。有一点需注意，当底物分子中杂原子数多时，应增加BBr3量。使用BBr3有一个最大的缺点是BBr3对空气敏感，使用时会冒出大量气雾；并在加水后处理时常出现大量的络合物，此时最好使用其它的方法，否则后处理艰难并导致收率下降。BI3,BCl3的使用如同BBr3。范例：Table2.CleavageofEthersbyBoronTribromideEtherAlcoholYield(%)BromideYield(%)Et2OEtOH61EtBr86i-Pr2Oi-PrOH50i-PrBr80n-Bu2On-BuOH62n-BuBr77Ph-O-Pr-iPhOH64i-PrBr62Ph-O-Bu-nPhOH75n-BuBr7681----87----PhCH2-O-Pr-nn-PrOH71PhCH2Br75GeneralProcedureforCleavageofEtherwithBBr3.10Aweighedquantityoftheether(usually15to20g)isintroducedintothereactionflaskandcooledinanice-bath.Thecalculatedquantityofborontribromideisslowlyintroducedthroughadroppingfunnel.Inallcasesborontribromideandetherareallowedtoreactintheratioof1molofborontribromideto3molofether.Afteradditionofborontribromide,thereactionmixtureisheatedonawaterbathfor40min.Thealkylbromideisdistilleddirectlyfromthereactionmixture.Afterremovalofthealkylbromidebydistillation,theresidureremainingintheflaskishydrolyzedwithaminimumamountof10%sodiumhydroxidesolution.Theresultingsolutionisacidifiedwithhydrochloricacidandextractedwithether.2.4．BX3和Me2S的络合物其为BBr3的改良方法。BBr3或BCl3和Me2S的络合物是固体物，容易制备并在惰性气体中能长期保存。一般使用2到4倍量即可。范例：Table3.CleavageofEtherswithBBr3.S(CH2)2ComplexEtherRatioofReagent/EtherTimea(hrs)ProductYield(%)Ph-O-Me4.012PhOH86b3.971267c3.971250c3.791278c3.872464ca)Reactionrunat83°C.b)GLCyield.C)Isoatedyield.GeneralProcedurefortheCleavageofEtherswithBoronTrihalide-MethylsulfideComplex.11Toaflame-dried100mLflaskunderanatmosphereofnitrogenisadded1,2-dichloroethane(30mL)andanamountofborontrihalide-methylsulfidecomplexasindicatedinTable3.Tothissolutionisaddedthedesirednumberofequivalentsofthearylether.ThereactionmixtureisstirredatrefluxandmonitoredbyeitherTLCorGLCwhereconvenient.Whenthestartingmaterialdisappears,thereactionmixtureishydrolyzedbyaddingwater(30mL),stirringfor20minanddilutingwithether.Theorganicphaseisseparatedandwashedwith1MNaHCO3andthephenolissubsequentlytakenupwith1NNaOH(3×20mL).ThecombinedNaOHwashingsareacidifiedandtheproductissubsequentlyextractedintoether,dried(MgSO4)andthesolventisremovedinvacuum.2.5．BBr3/NaI/15-crown-5这种体系为比BBr3更强的去甲基化方法。也可用于脱除烷基甲基醚。范例：Table4.DealkylationofAlkylMethylEtherswithBBr3-NaI-15-crown-5MethylEtherAlcoholYield(%)100100759310a)Yieldofisoatedalcohol.TypicalProcedure.Cleavageof3-PhenylpropanolMethylEther.11Toastirredsolutionof3-phenylpropanolmethylether(103mg,0.687mmol)indrymethylenechloride(0.5mL)isadded0.3Msolutionof15-crown-5(13.7mL,6equiv.)withNaIinmethylenechloridefollowedbyadditionof1MsolutionofBBr3(2.1mL,3equiv.)inmethylenechlorideat-30°Cunderargon.Thereactionmixtureisstirredatthesametemperaturefor3hrs,quenchedbytheadditionofsaturatedaqueousNaHCO3solution(2mL)andworkedupintheusualmanner.Chromatographicpurificationofthecrudeproductgivesthepurealcohol(93mg,100%),identicalinallrespectswithanauthenticsample.2.6．Me2BBr文献报道，这个试剂去甲基化经由SN2机理，因此，非常有效的只是断裂C-O键，从而形成酚或醇，不易产生溴代副产物。范例：Table5.CleavageofEtherswith(CH3)2BBrSubstrateReagent(equiv.)Temp.(°C)Time(hrs)ProductYield(%)30-2518931.30-253751.60-256494.07030724.0703696a)YieldofisoatedProduct.TypicalProcedure.Cleavageof1-Methoxydecane.12Toacold(0°C),stirredsolutionof1-methoxydodecane(1.03mmol)andtriethylamine(0.21mmol,toneutralizetracesoffreeacid)indrymethylenechloride(4.1mL)underargon,isaddedasolutionofdimethylboronbromide(1.34M,0.99mL)inmethylenechloride.Thecoolingbathisthenremovedandtheresultantsolutionisthenstirredatroomtemperaturefor3hrs.Thereactionmixtureisthencooledto0°C,quenchedwithsaturatedaqueoussodiumbicarbonate(2mL)anddilutedwithether(30mL).Theorganiclayerisseparated,washedwithsaturatedsodiumbicarbonate(2mL),water(2mL)andbrine(2mL).Theaqueouswashingsareextractedwithetherandtheorganiclayersarecombined.Afterdryingtheresultantsolutionisconcentratedandsubjectedtoflashchromatographytoprovidepure1-dodecanol(89%).2.7．AlX3/CH3CN,AlX3/CH2Cl2,AlCl3/CH3CN13和AlBr3/CH3CN14是另外一类常用的去甲基化方法，其操作类似BBr3的使用，只是一般反应温度在0℃-室温。范例：TypicalProcedure.13Todichloromethane(1mL)orCH3CN(1mL)wasaddedaluminumchloride(3.0mmol)at0OC.Theresultingsolutionwaswarmedtoroomtemperature,andtheether(1.0mmol)wasaddedwithstirring.Afterbeingstirredfor3-12h,thereactionmixturewaspouredintowater,acidifiedwithdiluteHC1,andextractedwithdichloromethane.Theorganiclayerwastreatedasusualtogiveacrudeproduct.Chromatographyoverasilicagelcolumngavethedesiredproduct.2.8．AlBr3/EtSH，AlCl3/EtSH,AlCl3/HSCH2CH2SH，AlCl3/EtSH/CH2Cl2AlBr3/EtSH,AlCl3/EtSH,AlCl3/HSCH2CH2SH体系的活性很高，分子中酯、醛、酮、双键不稳定，但酯在AlCl3/EtSH/CH2Cl2体系相对稳定。范例：GeneralProcedureforDemethylation.15Toastirredsolutionofaluminumhalideinethanethiolcooledinanice-waterbathwasaddedthesubstrate.ThereactionwasmonitoredbyTLC(aluminumhalidewasquenchedbymethanolinthecapillary).Thereactionmixturewaspouredintowater,acidifiedwithdiluteHC1,andextractedwithdichloromethane.Theorganiclayerwasshakenwithbrine,dried(Na2SO4),filtered,andthenevaporatedtoleaveacrudematerial,whichwaspurifiedbychromatographyoverasilicagelcolumn.AlCl3/EtSH/CH2Cl2体系：15Toamixtureofdryethanethiol(1mL)anddichloromethane(1mL)wasaddedaluminumchloride(0.40g,3.0mmol)at0OC.Theresultingsolutionwaswarmedtoroomtemperature,andtheether(0.194g,1.0mmol)wasaddedwithstirring.Afterbeingstirredfor9.5h,thereactionmixturewaspouredintowater,acidifiedwithdiluteHC1,andextractedwithdichloromethane.Theorganiclayerwastreatedasusualtogiveacrudeproduct.Chromatographyoverasilicagelcolumngavethedesiredproduct(0.157g,95.5%)identicalwithanauthenticsample.AlCl3/EtSH体系：15Toasolutionofaluminumchloride(47mg,0.35mmol)indryethanethiol(1mL)wasaddedtheether(11mg,0.03mmol)at0"C.Afterbeingstirredfor2.5hat0"C,thereactionmixturewaspouredintowaterandextractedwithdichloromethane.Theusualworkupoftheorganiclayergavetheproduct:7.5mg(81.5%).3．碱性试剂3.1．氨基钠适合于苯环上没有电负性取代基，否则易发生birch还原反应16。3.2．N-甲基苯基氨基钠/HMPT对于苯环上有电负性取代基的底物易发生取代反应。范例：Table7.DealkylationofAlkylArylEtherwithsodiumN-MethylanilideinpresenceofHMPTSubstrateTime(hrs)Temp.(°C)ProductYield(%)a6.51209510120800.59595241209099585685901712070a)YieldofisoatedProduct.TypicalProcedure.Cleavageof1,2,4-Trimethoxybenzene.17N-Methylaniline(2.68g,25mmol)isaddeddropwiseat65°Ctoastirredsuspensionofsodiumhydride(0.6g,25mmol)insodium-driedxylene(5mL)andHMPT(4.26g,25mmol,distilledovercalciumhydrideandstoredindarkovermolecularsieves,8A°).After15min,theether(12.5mmolintheminimumamountofxylene)isaddedandthemixtureisheatedat85°C.ThereactionismonitoredbyGLC(3mSE30column)andbyTLC.Whenthestartingmaterialdisappears(6hrs)themixtureispouredintowater,acidifiedwithdilutehydrochloricacid,andtheproductisextractedwithether.Theetherphaseiswashedwithdilutehydrochloricacid(2×90mL)toremoveHMPTandtheaminesandthentheproductisextractedwith10%sodiumhydroxidesolution(2×90mL).Theaqueousphaseisacidifiedwithdilutehydrochloricacidandextractedwithether(3×90mL).Theorganicphaseisdriedovercalciumchlorideandconcentratedonarotaryevaporatortogivepure2,5-dimethoxyphenol;yield:1.9g(90%).Theproductmaybefurtherpurifiedbycolumnchromatographyonsilicagel.3.3．EtSNa在EtSNa/DMF体系中，双键和溴代物不受影响；有时具有选择性去甲基化，如下 表 关于同志近三年现实表现材料材料类招标技术评分表图表与交易pdf视力表打印pdf用图表说话 pdf 。范例：Table8.DealkylationofEthersbySodiumEthanethiolateEtherEquiv.ofReagentTime(hrs)ProductYield(%)2.53962.53965384539853892.52093------TypicalProcedure.Dealkylationofm-Methoxytoluene.18Ethanethiol(1.25g,11.8mmol)dissolvedindryDMF(20mL)isaddedtoasuspensionofsodiumhydride(1.0gofa50%oildispersion)indryDMF(10mL)underanatmosphereofnitrogen.Themixtureisstirredfor5minbeforesolutionofm-methoxytoluene(1.09g)indryDMFisadded.Thesolutionisthenrefluxedfor3hrs.Thecooledmixtureisacidifiedwith10%aqueoushydrochloricacidandextractedwithether.Theetherlayeriswashedwithwaterandextractedwith5%sodiumhydroxide.Thealkalineextractsarethenacidifiedandreextractedwithether.Theetherealsolutioniswashedwithwater,driedandevaporatedtogivem-cresolasalightbrownoil;yield:0.85g(78%).4．其它试剂4.1．Me3SiI另一种常用的去甲基试剂，在此体系中，双键、三键、酮羰基、氨基和卤代物稳定，但苄醚、三苯甲基醚、叔丁基醚不稳定。三甲基碘硅烷能裂解酯但比醚慢。范例：Table10.DealkylationofEthersbyTrimethylsilylIodideR1R2ReactionConditionsaTime/TemperatureYieldofproducts(%)R1-OSi(CH3)3R2Ic-C6H11CH36hrs/25°955c-C6H11C2H512hrs/25°4951c-C6H11t-C4H90.1hrs/25°b1000c-C6H11C6H5CH20.1hrs/25°1000CH32.5hrs/25°1000C6H5CH348hrs/25°100--3-CH3C6H4C2H5140hrs/25°b100--a)SolventCDCl3,unlessotherwisementioned.b)InCCl4.GeneralProcedureforDealkylationofEther.19Toa2Msolutionofether(1equiv.)inasuitablesolvent(Table10)isaddedneattrimethylsilyliodide(1.3equiv.)throughadrysyringe.ThereactionismaintainedattemperatureindicatedinTable10andmonitoredbyNMRforcompletion.YieldsarecalculatedbyNMRintegrationofpertinentpeaks.Forisolationofthealcohols,atthecompletionofthereaction,theexcesstrimethylsilyliodideisdestroyedandtheintermediatetrimethylsilyletherformedduringthereactionishydrolyzedtoalcoholbypouringthereactionmixtureintomethanol(4equiv.).Thevolatilecomponentsareremovedatreducedpressureandtheresidueistakenupinether,washedwithaqueoussodiumbisulfite,aqueoussodiumbicarbonateandbrineanddried.Theresidueleftafterevaporationofsolventisfurtherpurified(ifnecessary)bycolumnchromatographyonsilicagel.4.2．LiCl/DMF当邻位和对位有吸电子基团存在时，此体系去甲基化容易进行。底物中有醛和酯时，去甲基需更长的时间，甲酯会去甲基形成酸。范例：Table12.CleavageofAlkylArylEtherswithLiClinDMFRX1X2ReactionTime(hrs)Yield(%)aMe2-NO2H698Me3-NO2H650Me4-NO2H2498Et2-NO2H2290i-Pr2-NO2H2435PhCH22-NO2H2298Et4-NO2H2410Me2-NO24-Br495Me2-ClH7255Me2-BrH7267Me2-CHOH2270Et2-CHOH2225i-Pr2-CHOH225Me2-CO2MeH2290CH2CO2Me2-MeH225TypicalProcedure.Cleavageof2,3-Dimethoxybenzaldehyde.202,3-Dimethoxybenzaldehyde(1.0g,6mmol)andLiCl(0.76g,18mmol)areheatedinboilingDMF(10mL),thereactionbeingmonitoredbyGLC.Whenthestartingmaterialdisappears,10%aqueousNaOH(30mL)isadded;thesolutioniswashedwithether(2×25mL),thenacidifiedwith10%aqueousHCl(50mL),andextractedwithether(2×25mL).Theorganicphaseiswashedwithbrine(30mL),dried(sodiumsulfate)andconcentratedinarotaryevaporatortoafford2-hydroxy-3-methoxybenzaldehyde(0.88g,98%).4.3．吡啶盐酸盐将底物和大大过量的吡啶盐酸盐混合均匀，加热到200℃左右进行，反应完后，常规后处理即可21。范例：Demethylationofp-DihydrothebainolMethylEtherwithPyridineHydrochloride.21Amixtureof204mg.ofβ-dihydrothebainolmethyletherand247mg.offreshlyfusedpyridinehydrochloridewasheatedforfourhoursat195-00'(bath).Thecooledbrownishresiduewasdissolvedinwater,niadebasicwithpotassiumhydroxidecontaininghydrosulfite,andextractedseveraltimeswithchloroform.Thechloroform,afterprocessing,wasfoundtocontainonlyatraceofnon-volatileresidue.Theaqueousalkalinelayerwasthencarbonatedtoexcessandextractedseveraltimeswithbutanol.Thebutanolextractswerewashed,filteredthroughanhydroussodiumsulfate,andconcentratedundernitrogen.Crystallizationoccurredduringtheconcentration,andtheresiduemeltedat239-242'dec.(162ing.).Severalcrystallizationsfrombutanolgave72mg.ofsmallprisms,m.p.258-262"dec.,[a]%D1-46'(c1.32,diox.).参考文献：R.L.Rurwell,Jr.,Chem.Rev.,1954,54,615.H.Meerwin,“Houben-Weyl-Muller:MethodenderorganischemChemie”,Vol.6/3,p.143,GeorgThiemeVerlag,Stuttgart,1965,4thEdn.E.staudeandF.Patat,“ThechemistryoftheEtherLinkage”,p.21,S.Patai,Ed.,WileyInterscience,NewYork,1967.M.V.BhattandS.U.Kulkarni,Synthesis,1983,249.A.Maercher,Angew.Chem.Int.Ed.Engl.,1987,26,972.M.Tiecco,Synthesis,1988,749.BrindabanC.RanuandSanjayBhar.OrganicPreparationsandProceduresINT.,1996,28(4),371-409.I.Kawasaki,K.Matsuda,andT.Kaneko,Bull.Chem.Soc.Jpn.,1971,44,1986.D.Landini,F.MontanariandF.Rolla,Synthesis,1978,771.F.L.BentonandT.E.Dillon,J.Am.Chem.Soc.1942,64,1128H.Niwa,T.HidaandK.Yamada,TetrahedronLett.,1981,22,4239Y.Guindon,C.YoakimandH.E.Morton,TetrahedronLett.,1983,24,2969Y.Kawamura,H.Takatsuki,F.Torii,andT.Horie,Bull.Chem.Soc.Jpn.,1994,67,511.T.Horie,T.Kobayashi,Y.Kawamura,I.Yoshida,H.Tominaga,andK.Yamashita,Bull.Chem.Soc.Jpn.,1995,68,2033.M.node,K.Nishide,K.FujiandE.Fujita,J.Org.Chem.1980,45,4275.A.J.Birch,Quart.Rev.,1950,4,69.B.Loubinoux,G.CoufertandG.Guillaumet,Synthesis,1980,638.G.I.FeutrillandR.N.Mirrington,TetrahedronLett.,1970,11,1327.M.E.JungandM.A.Lyster,J.Org.Chem.,1977,42,3761.A.M.Bernard,M.R.Ghiani,P.P.PirasandA.Rivoldini,Synthesis,1989,287M.GatesandG.Tschudi,J.Am.Chem.Soc.,1956,78,1380.TheEnd