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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,HCI
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%HBr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:
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%HBrinPreseneeofHexadecyltributylphosphoniumBromide
R1orAr
r2rRorR
Molof
HBr
Catalyst
Time
(hrs)
a
Yield(%)of
1
RBrorRBr
ArOH
n-C4Hg
n-C4Hg
10
0.1
8
89
n-C8H仃
n-C8H17
5
91
n-C16H33
CH3
3
88
C6H5
--
C6H5
n-C4H9
24
85
90
4-t-Bu-C6H4
4-t-Bu-C6H4
86
a)Yieldofisolatedproduct
9
TypicalPocedure.CleavageofDi-n-octylEther.Di-n-oetylether(12.1g,0.05mol),47%aqueoushydrobromieacid(56mL,0.5mol),andhexadeeyltributylphosphoniumbromide(2.5g,0.005mol)aremixedinaflaskequippedwithamagneticstirrerandrefluxcondenser,andheatedat115C°
nnertemperature)withstirringfor5hrs.AfterthistimeGLCanalysis(SE30,3%overchromosorbsulfate,anddistilledtogivepure1-bromooctane.Theorganiclayerisseparated,driedwithsodiumsulfate,anddistilledtogivepure1-bromooctane;
yield:
17.5g(91%),bp887torr.Bytreatingthedistillationresiduewithhexane,2.3g(92%)ofpurephosphoniumbromidearerecovered,mp54-56C.Inth7caseofarylalkylethers,aqueousalkalineextractionoftheorganicphaseaffordsthecorrespondingphenol.
2.3.BBr®
Bl3,BCb
BBz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CH2CI2,benzene,pentand乍为溶剂,在-78°
C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,
BCI3的使用如同BBb
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
Br
fOMe
C^oh
81
一:
'
V~OMe
87
PhCH2-O-Pr-n
n-PrOH
71
PhCH2Br
GeneralProcedureforCleavageofEtherwithBBr3.Aweighedquantityoftheether
(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BCI3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
Ratioof
Reagent/Ether
Time(hrs)
Product
Ph-O-Me
4.0
12
86b
QC
3.97
Of
67c
、fOMe
A
50c
xx
Jh^OMe
3.79
XX
78c
OMe
OH
I
rS
3.87
xS
64c
人”'
a)Reactionrunat83C.b)GLCyield.C)Isoatedyield.
GeneralProcedurefortheCleavageofEtherswithBoronTrihalide-Methylsulfideii
Complex.Toaflame-dried100mLflaskunderanatmosphereofnitrogenisadded1,2-dichloroethane(30mL)andanamountofborontrihalide-methylsulfidecomplexasindicatedinTable3.Tothissolutionisaddedthedesirednumberofequivalentsofthearylether.ThereactionmixtureisstirredatrefluxandmonitoredbyeitherTLCorGLCwhereconvenient.Whenthestartingmaterialdisappears,thereactionmixtureishydrolyzedbyaddingwater(30mL),stirringfor20minanddilutingwithether.Theorganicphaseisseparatedandwashedwith1MNaHCO3andthephenolissubsequentlytakenupwith1NNaOH(3x20mL).ThecombinedNaOHwashingsareacidifiedandtheproductissubsequentlyextractedintoether,dried(MgSOandthesolventisremovedinvacuum.
2.5.BBr3/Nal/15-crown-5
这种体系为比BBX更强的去甲基化方法。
也可用于脱除烷基甲基醚
Table4.DealkylationofAlkylMethylEtherswithBBr3-Nal-15-crown-5
MethylEther
O---^OH
100
MeO
HO■■■■-■'
■-■'
d
人
But
6
93
Oh
b
FOMe
*^OH
a)Yieldofisoatedalcohol.
11
TypicalProcedure.Cleavageof3-PhenylpropanolMethylEther.Toastirredsolutionof
3-phenylpropanolmethylether(103mg,0.687mmol)indrymethylenechloride(0.5mL)isadded0.3Msolutionof15-crown-5(13.7mL,6equiv.)withNaIinmethylenechloridefollowedbyadditionof1MsolutionofBBr3(2.1mL,3equiv.)inmethylenechlorideat-30°
underargon.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
Xjd
di
1.3
^Y^"
「OMe
1.6
C^Br
49
70
30
72
OX
36
caOH
96
a)YieldofisoatedProduct.
TypicalProcedure.Cleavageof1-Methoxydecane.Toacold(0°
),stirredsolutionof1-methoxydodecane(1.03mmol)andtriethylamine(0.21mmol,toneutralizetracesoffreeacid)indrymethylenechloride(4.1mL)underargon,isaddedasolutionofdimethylboronbromide(1.34M,0.99mL)inmethylenechloride.Thecoolingbathisthenremovedandtheresultantsolutionisthenstirredatroomtemperaturefor3hrs.Thereactionmixtureisthencooledto0C,°
uenchedwithsaturatedaqueoussodiumbicarbonate(2mL)anddilutedwithether(30mL).Theorganiclayerisseparated,washedwithsaturatedsodiumbicarbonate(2mL),water(2mL)andbrine(2mL).Theaqueouswashingsareextractedwithetherandtheorganiclayersarecombined.Afterdryingtheresultantsolutionisconcentratedandsubjectedtoflashchromatographytoprovidepure1-dodecanol(89%).
2.7.AIX3/CH3CN,AIX3/CH2CI2,
AICI3/CH3CN13和AIBr3/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。
OOMe
0°
C,3h
13
TypicalProcedure.Todichloromethane(1mL)orCH3CN(1mL)wasaddedaluminumchloride(3.0mmol)at0°
C.Theresultingsolutionwaswarmedtoroomtemperature,andtheether(1.0mmol)wasaddedwithstirring.Afterbeingstirredfor3-12h,thereactionmixturewaspouredintowater,acidifiedwithdiluteHC1,andextractedwithdichloromethane.Theorganiclayerwastreatedasusualtogiveacrudeproduct.Chromatographyoverasilicagelcolumngavethedesiredproduct.
2.8.AIBr3/EtSH,AICX/EtSH,AICI3/HSCH2CH2SH,AICX/EtSH/CH2CI2
酮、双
AIBr3/EtSH,AICI/EtSH,AICI3/HSCH2CH2SH体系的活性很高,分子中酯、醛、键不稳定,但酯在AICI3/EtSH/CH2Cl2体系相对稳定。
a:
R"
=Brb:
=H
halidein
15
GeneralProcedureforDemethylation.Toastirredsolutionofaluminumethanethiolcooledinanice-waterbathwasaddedthesubstrate.ThereactionwasmonitoredbyTLC(aluminumhalidewasquenchedbymethanolinthecapillary).Thereactionmixturewaspouredintowater,acidifiedwithdiluteHC1,andextractedwithdichloromethane.Theorganiclayerwasshakenwithbrine,dried(Na2S°
4),filtered,andthenevaporatedtoleaveacrudematerial,whichwaspurifiedbychromatographyoverasilicagelcolumn.
AICI3/EtSH/CH2CI2体系:
15Toamixtureofdryethanethiol(1mL)anddichloromethane(1
O
mL)wasaddedaluminumchloride(0.40g,3.0mmol)at0C.Theresultingsolutionwaswarmedtoroomtemperature,andtheether(0.194g,1.0mmol)wasaddedwithstirring.Afterbeingstirredfor9.5h,thereactionmixturewaspouredintowater,acidifiedwithdiluteHC1,andextractedwithdichloromethane.Theorganiclayerwastreatedasusualtogiveacrudeproduct.Chromatographyoverasilicagelcolumngavethedesiredproduct(0.157g,95.5%)identicalwithanauthenticsample.
AICX/EtSH体系:
Toasolutionofaluminumchloride(47mg,0.35mmol)indryethanethiol(1mL)wasaddedtheether(11mg,0.03mmol)at0"
C.Afterbeingstirredfor2.5hat0"
C,thereactionmixturewaspouredintowaterandextracted