有机合成化学反应之甲基醚的脱甲基反应文档格式.docx
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有机合成化学反应之甲基醚的脱甲基反应文档格式.docx
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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。
Table1.CleavageofEtherswith47%HBrinPresenceofHexadecyltributylphosphoniumBromide
R1orAr
R2orR
MolofHBr
MolofCatalyst
Time(hrs)
Yield(%)aof
R1BrorRBr
ArOH
n-C4H9
10
0.1
8
89
n-C8H17
5
91
n-C16H33
CH3
3
88
C6H5
--
24
85
90
4-t-Bu-C6H4
86
a)Yieldofisolatedproduct
TypicalPocedure.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,BCl3
BBr3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。
Table2.CleavageofEthersbyBoronTribromide
Ether
Alcohol
Yield(%)
Bromide
Et2O
EtOH
61
EtBr
i-Pr2O
i-PrOH
50
i-PrBr
80
n-Bu2O
n-BuOH
62
n-BuBr
77
Ph-O-Pr-i
PhOH
64
Ph-O-Bu-n
75
76
81
87
PhCH2-O-Pr-n
n-PrOH
71
PhCH2Br
GeneralProcedureforCleavageofEtherwithBBr3.10Aweighedquantityoftheether(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。
Table3.CleavageofEtherswithBBr3.S(CH2)2Complex
RatioofReagent/Ether
Timea(hrs)
Product
Ph-O-Me
4.0
12
86b
3.97
67c
50c
3.79
78c
3.87
64c
a)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。
Table4.DealkylationofAlkylMethylEtherswithBBr3-NaI-15-crown-5
MethylEther
100
93
a)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。
Table5.CleavageofEtherswith(CH3)2BBr
Substrate
Reagent(equiv.)
Temp.(°
C)
0-25
18
1.3
1.6
6
49
70
30
72
36
96
a)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。
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/CH2Cl2
AlBr3/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。
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。
Table7.DealkylationofAlkylArylEtherwithsodiumN-MethylanilideinpresenceofHMPT
Yield(%)a
6.5
120
95
0.5
9
17
a)YieldofisoatedProduc
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- 有机合成 化学反应 甲基 反应