甲基醚的脱甲基反应

1、经典化学合成反应标准操作1 .前言12 .酸性试剂12.1. 浓HI,HBr,HCl12.2. 48%HBr加入相转移催化剂22.3. BBr3,BI3,BC1332.4. BX3和Me2s的络合物42.5. BBr3/NaI/15-crown-552.6. Me2BBr52.7. AIX3/CH3CN,AIX3/CH2CI2,62.8. A旧r3/EtSH,AlCl3/EtSH,AlCl3/HSCH2CH2SH,AlCEEtS印CH2CI273 .碱性试剂83.1. .氨基钠83.2. N-甲基苯基氨基钠/HMPT83.3. EtSNa94 .其它试剂104.1. Me3SiI104.2.

2、LiCl/DMF114.3. 叱噬盐酸盐12经典合成反应标准操作 一酚醍去甲基化反应1 .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，形成甲基芳基醴，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，在JOHNILEY&SON

3、S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，很多甲基芳基醴的去甲基化方法也适用于甲基姓基醴，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姓基醴。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醴水解去甲基的方法。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

4、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：48% HBrrefluxOOHOHTypicalPocedure.8Theether(300mg)wasdissolvedin48%HBr(50mL)andheatedfor1hrunderreflux.Thereactionmixturewasevaporatedtodrynessandextractedwithether.Theetherealextractwaswashedwithsodiumcarbonatesolutionandwater,d

5、riedandevaporated.Theresiduewasrecrystallizedfromchloroformtogivetheproduct(120mg,40%).2248%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澳化俊，十六碳烷基三丁基澳化磷,四辛基澳化俊，三辛基甲基澳化俊等。对于甲基芳基醴，一般使用5mol量的HBr,对于甲基姓基醴，一般使用10mol量的HBr；值得注意的是，反应的收率和时间不是

6、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.

7、18-904-t-Bu-C6H4n-C4H950.1248691a)YieldofisolatedproductTypicalPocedure9CleavageofDi-n-octylEther.Di-n-octylether(12.1g,0.05mol),47%aqueoushydrobromicacid(56mL,0.5mol),andhexadecyltributylphosphoniumbromide(2.5g,0.005mol)aremixedinaflaskequippedwithamagneticstirrerandrefluxcondenser,andheatedat115C(

8、innertemperature)withstirringfor5hrs.AfterthistimeGLCanalysis(SE30,3%overchromosorbsulfate,anddistilledtogivepure1-bromooctane.Theorganiclayerisseparated,driedwithsodiumsulfate,anddistilledtogivepure1-bromooctane;yield:17.5g(91%),bp88/torr.Bytreatingthedistillationresiduewithhexane,2.3g(92%)ofpureph

9、osphoniumbromidearerecovered,mp54-56C.Inthecaseofarylalkylethers,aqueousalkalineextractionoftheorganicphaseaffordsthecorrespondingphenol.1.3. BBr3,BI3,BC13BBr3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，在许多大然产物的全合成中常使用它。一般使用CH2c12,benzene,pentane乍为溶剂，在-78C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

10、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,BC13的使用如同BBrs范例：Table2.CleavageofEthersbyBoronTribromideEtherAlcoholYield(%)BromideYield(%)Et2OEtOH61EtBr86i-Pr2Oi-PrOH50i-PrBr80n-Bu2。1n-BuOH62n-BuBr77Ph-O-Pr-i1PhOH64i-PrBr62Ph-O-Bu-nPhOH75n-BuBr76BrBrOJOMe4T。'81-一:O%-OMe87-PhCH2-

11、O-Pr-nn-PrOH71PhCH2Br75GeneralProcedureforCleavageofEtherwithBBr3.10Aweighedquantityoftheether(usually15to20g)isintroducedintothereactionflaskandcooledinanice-bath.Thecalculatedquantityofborontribromideisslowlyintroducedthroughadroppingfunnel.Inallcasesborontribromideandetherareallowedtoreactinthera

12、tioof1molofborontribromideto3molofether.Afteradditionofborontribromide,thereactionmixtureisheatedonawaterbathfor40min.Thealkylbromideisdistilleddirectlyfromthereactionmixture.Afterremovalofthealkylbromidebydistillation,theresidureremainingintheflaskishydrolyzedwithaminimumamountof10%sodiumhydroxides

13、olution.Theresultingsolutionisacidifiedwithhydrochloricacidandextractedwithether.1.4. BX3和Me2s的络合物其为BBr3的改良方法。BBr3或BC13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-Me14.012PhOH86b3.971267c、OMe1OHA3.

14、9712A50c'''OMe1OHJ/人"OMeII3.7912XX78cOMeOHIrS3.8724xS64cOMe人八OHa)Reactionrunat83C.b)GLCyield.C)Isoatedyield.GeneralProcedurefortheCleavageofEtherswithBoronTrihalide-MethylsulfideComplex.11Toaflame-dried100mLflaskunderanatmosphereofnitrogenisadded1,2-dichloroethane(30mL)andanamountof

15、borontrihalide-methylsulfidecomplexasindicatedinTable3.Tothissolutionisaddedthedesirednumberofequivalentsofthearylether.ThereactionmixtureisstirredatrefluxandmonitoredbyeitherTLCorGLCwhereconvenient.Whenthestartingmaterialdisappears,thereactionmixtureishydrolyzedbyaddingwater(30mL),stirringfor20mina

16、nddilutingwithether.Theorganicphaseisseparatedandwashedwith1MNaHCO3andthephenolissubsequentlytakenupwith1NNaOH(3x20mL).ThecombinedNaOHwashingsareacidifiedandtheproductissubsequentlyextractedintoether,dried(MgSO)andthesolventisremovedinvacuum.1.5. 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醴范例：

17、TypicalProcedure.Cleavageof3-PhenylpropanolMethylEther11Toastirredsolutionof3-phenylpropanolmethylether(103mg,0.687mmol)indrymethylenechloride(0.5mL)isadded0.3Msolutionof15-crown-5(13.7mL,6equiv.)withNaIinmethylenechloridefollowedbyadditionof1MsolutionofBBr3(2.1mL,3equiv.)inmethylenechlorideat-30Cun

18、derargon.Thereactionmixtureisstirredatthesametemperaturefor3hrs,quenchedbytheadditionofsaturatedaqueousNaHCO3solution(2mL)andworkedupintheusualmanner.Chromatographicpurificationofthecrudeproductgivesthepurealcohol(93mg,100%),identicalinallrespectswithanauthenticsample.1.6. Me2BBr文献报道，这个试剂去甲基化经由SN2机理

19、，因此，非常有效的只是断裂C-O键,从而形成酚或醇，不易产生澳代副产物。范例：Table5.CleavageofEtherswith(CH3)2BBrSubstrateReagent(equiv.)Temp.(C)Time(hrs)ProductYield(%)30-2518XjdHO*VXXJ93MeO-V-XI1di1.30-253a75YOMeXOHOMe1.60-25649XOMe0Ha4.07030a72OX4.07036caOH96a)YieldofisoatedProduct.TypicalProcedure.Cleavageof1-Methoxydecane.12Toacold

20、(0C),stirredsolutionof1-methoxydodecane(1.03mmol)andtriethylamine(0.21mmol,toneutralizetracesoffreeacid)indrymethylenechloride(4.1mL)underargon,isaddedasolutionofdimethylboronbromide(1.34M,0.99mL)inmethylenechloride.Thecoolingbathisthenremovedandtheresultantsolutionisthenstirredatroomtemperaturefor3

21、hrs.Thereactionmixtureisthencooledto0C,°quenchedwithsaturatedaqueoussodiumbicarbonate(2mL)anddilutedwithether(30mL).Theorganiclayerisseparated,washedwithsaturatedsodiumbicarbonate(2mL),water(2mL)andbrine(2mL).Theaqueouswashingsareextractedwithetherandtheorganiclayersarecombined.Afterdryingthere

22、sultantsolutionisconcentratedandsubjectedtoflashchromatographytoprovidepure1-dodecanol(89%).1.7. AIX3/CH3CN,AIX3/CH2CI2,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0C-室温。范例：OOMeOOH!.OMeAlCl3,75%'-OMe0°C,3hTypicalProcedure.13Todichloromethane(1mL)orCH3CN(1mL)wasaddedalumi

23、numchloride(3.0mmol)at0OC.Theresultingsolutionwaswarmedtoroomtemperature,andtheether(1.0mmol)wasaddedwithstirring.Afterbeingstirredfor3-12h,thereactionmixturewaspouredintowater,acidifiedwithdiluteHC1,andextractedwithdichloromethane.Theorganiclayerwastreatedasusualtogiveacrudeproduct.Chromatographyov

24、erasilicagelcolumngavethedesiredproduct.1.8. AlBTEtSH,AlCl3/EtSH,AlCl3/HSCH2CH2SH,AlCl3/EtS川CH2CI2AlBr3/EtSH,AlClJEtSH,AlCWHSCHzCWSH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:a:R"=Brb:R"=HGeneralProcedureforDemethylation.15Toastirredsolutionofaluminumhalideinethanethiolcooledinani

25、ce-waterbathwasaddedthesubstrate.ThereactionwasmonitoredbyTLC(aluminumhalidewasquenchedbymethanolinthecapillary).Thereactionmixturewaspouredintowater,acidifiedwithdiluteHC1,andextractedwithdichloromethane.Theorganiclayerwasshakenwithbrine,dried(Na2SO4),filtered,andthenevaporatedtoleaveacrudematerial

26、,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,there

27、actionmixturewaspouredintowater,acidifiedwithdiluteHC1,andextractedwithdichloromethane.Theorganiclayerwastreatedasusualtogiveacrudeproduct.Chromatographyoverasilicagelcolumngavethedesiredproduct(0.157g,95.5%)identicalwithanauthenticsample.AlCl3/EtSH体系：15Toasolutionofaluminumchloride(47mg,0.35mmol)in

28、dryethanethiol(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

29、物易发生取代反应。范例:Table7.DealkylationofAlkylArylEtherwithsodiumN-MethylanilideinpresenceofHMPTSubstrateTime(hrs)Temp.(C)ProductaYield(%)入OMe9r6.512095OcH2Ph101209r0H80cc0.595Cf95X''4：(OMeOMeOMeOMe24120aOHOH90OMeOHAMeOi-、OMe995MeO-'e"。Me85OMeOMeOMe685夕90TOMeOMeOMeOMe6But17120701OMeTOHa)Yie

30、ldofisoatedProduct.TypicalProcedure.Cleavageof1,2,4-Trimethoxybenzene17N-Methylaniline(2.68g,25mmol)isaddeddropwiseat65Ctoa°stirredsuspensionofsodiumhydride(0.6g,25mmol)insodium-driedxylene(5mL)andHMPT(4.26g,25mmol,distilledovercalciumhydrideandstoredindarkovermolecularsieves,8A°).After15m

31、in,theether(12.5mmolintheminimumamountofxylene)isaddedandthemixtureisheatedat85C.ThereactionismonitoredbyGLC(3mSE30column)andbyTLC.Whenthestartingmaterialdisappears(6hrs)themixtureispouredintowater,acidifiedwithdilutehydrochloricacid,andtheproductisextractedwithether.Theetherphaseiswashedwithdiluteh

32、ydrochloricacid(290mL)toremoveHMPTandtheaminesandthentheproductisextractedwith10%sodiumhydroxidesolution(2X90mL).Theaqueousphaseisacidifiedwithdilutehydrochloricacidandextractedwithether(3X90mL).Theorganicphaseisdriedovercalciumchlorideandconcentratedonarotaryevaporatortogivepure2,5-dimethoxyphenol;

33、yield:1.9g(90%).Theproductmaybefurtherpurifiedbycolumnchromatographyonsilicagel.3.3. EtSNa在EtSNa/DMF体系中，双键和澳代物不受影响；有时具有选择性去甲基化，如下表。范例:Table8.DealkylationofEthersbySodiumEthanethiolateEtherEquiv.ofReagentTime(hrs)ProductYield(%)OMe9r1OMeQBut、OMevOMe1OMeMeO.OMeOMeOMe111BrOMe1HHHCH3(CH2)7XaMeOOMe2.5I2.

34、5515i52.5i-3333320-.OHqOHQButhOMe_OHMeO"OHXOHIIyBrO._HHCH3(CH2)7-j心MeOhOH969684988993-TypicalProcedure.Dealkylationofm-Methoxytoluene.18Ethanethiol(1.25g,11.8mmol)dissolvedindryDMF(20mL)isaddedtoasuspensionofsodiumhydride(1.0gofa50%oildispersion)indryDMF(10mL)underanatmosphereofnitrogen.Themixt

35、ureisstirredfor5minbeforesolutionofm-methoxytoluene(1.09g)indryDMFisadded.Thesolutionisthenrefluxedfor3hrs.Thecooledmixtureisacidifiedwith10%aqueoushydrochloricacidandextractedwithether.Theetherlayeriswashedwithwaterandextractedwith5%sodiumhydroxide.Thealkalineextractsarethenacidifiedandreextractedw

36、ithether.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、酮染基、氨基和卤代物稳定,但甲醴、三苯甲基醴、叔丁基醴不稳定。三甲基碘硅烷能裂解酯但比醴慢。范例：Table10.DealkylationofEthersbyTrimethylsilylIodideR1-O-R2+(CH3)3SiIR1-O-Si(CH3)3+R2I1R2Rr,八.aReac

37、tionConditionsTime/TemperatureYieldofproducts(%)R1-°Si(CH3)3R2Ic-C6HiiCH36hrs/25°955c-C6HiiC2H5112hrs/25°4951c-C6Hiit-C4H910.1hrs/25b°1000c-C6HiiC6H5CH210.1hrs/25°1000°OCH32.5hrs/25°1000C6H5CH348hrs/25°100-3-CH3c6H4C2H5140hrs/25b°100-a)SolventCDCl3,unless

38、otherwisementioned.b)InCCl4.GeneralProcedureforDealkylationofEther.19Toa2Msolutionofether(1equiv.)inasuitablesolvent(Table10)isaddedneattrimethylsilyliodide(1.3equiv.)throughadrysyringe.ThereactionismaintainedattemperatureindicatedinTable10andmonitoredbyNMRforcompletion.YieldsarecalculatedbyNMRinteg

39、rationofpertinentpeaks.Forisolationofthealcohols,atthecompletionofthereaction,theexcesstrimethylsilyliodideisdestroyedandtheintermediatetrimethylsilyletherformedduringthereactionishydrolyzedtoalcoholbypouringthereactionmixtureintomethanol(4equiv.).Thevolatilecomponentsareremovedatreducedpressureandt

40、heresidueistakenupinether,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.CleavageofAlkylA

41、rylEtherswithLiClinDMFRX1X2ReactionTime(hrs)aYield(%)Me2-NO2H698Me3-NO2H650Me4-NO2H2498Et2-NO2H2290i-Pr2-NO2H2435PhCH22-NO2H2298Et4-NO2H2410Me2-NO24-Br495Me2-ClH7255Me2-BrH7267Me2-CHOH2270Et2-CHOH2225i-Pr2-CHOH225Me2-CO2MeH2290CH2CO2Me2-MeH225TypicalProcedure.Cleavageof2,3-Dimethoxybenzaldehyde.2,3-

42、Dimethoxybenzaldehyde(1.0g,6mmol)andLiCl(0.76g,18mmol)areheatedinboilingDMF(10mL),thereactionbeingmonitoredbyGLC.Whenthestartingmaterialdisappears,10%aqueousNaOH(30mL)isadded;thesolutioniswashedwithether(2X25mL),thenacidifiedwith10%aqueousHCl(50mL),andextractedwithether(2x25mL).Theorganicphaseiswash

43、edwithbrine(30mL),dried(sodiumsulfate)andconcentratedinarotaryevaporatortoafford2-hydroxy-3-methoxybenzaldehyde(0.88g,98%).4.3. 叱噬盐酸盐将底物和大大过量的叱噬盐酸盐混合均匀，加热到200c左右进行，反应完后，常规后处理即可21。范例:H3COOHOCH3Py.HCl»H3CONOHOHDemethylationofp-DihydrothebainolMethylEtherwithPyridineHydrochloride.21Amixtureof204mg

44、.of0-dihydrothebainolmethyletherand247mg.offreshlyfusedpyridinehydrochloridewasheatedforfourhoursat195-00'(bath).Thecooledbrownishresiduewasdissolvedinwater,niadebasicwithpotassiumhydroxidecontaininghydrosulfite,andextractedseveraltimeswithchloroform.Thechloroform,afterprocessing,wasfoundtocontainonlyatraceofnon-volatileresidue.Theaqueousalkalinelayerwasthencarbonatedtoexcessandextractedseveraltimeswithbutanol.Thebutanolextractswerewashed,filteredthroughanhydroussodiumsulfate,andconcentratedundernitrogen.Crystallizationoccurredduringtheconcentration,andtheresiduemeltedat239-