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其他方法合成胺
经典化学合成反应标准操作
1.Curtius重排合成胺及相应的衍生物
Curtius重排是一种常用的将羧酸转化为少一个碳的胺及相应衍生物的方法。
其机理如下
首先酰氯被转化为酰基叠氮,其加热重排脱去一分子氮气后得到相应的异氰酸酯,异氰酸酯水解或和其他亲核试剂反应得到胺及相应的衍生物。
早期的合成方法都是将酸转变为相应的酰氯,再生成酰基叠氮。
后来Shiori(JACS,1972,94,6203)等人报道了DPPA和羧酸在室温下很温和的生成酰基叠氮,可一锅法合成胺。
若直接用过量的醇或直接用醇做溶剂可得到相应的胺的衍生物。
如用苄醇可一步得到Cbz保护的胺;用叔丁醇可一步得到Boc保护的胺。
一般情况下,用此方法直接做胺并不是一个好的方法,特别是制备烷基胺,其主要有两个原因:
一是得到的胺特别是烷基胺不易纯化;二是加水分解异氰酸酯时得到的胺会和未反应完全的异氰酸酯反应成脲,因此分解时要剧烈搅拌,另外也有人使用稀酸水解异氰酸酯得到相应的胺的盐酸盐。
1.1酰基叠氮重排合成胺示例
2,6-difluoro-4-methoxyphenylcarboxylicacid(2.00g,10.6mmol)wasdissolvedinthionylchloride(16mL).OnedropofDMFwasaddedandthemixturewasheatedtorefluxfor2h.Thecrudemixturewasevaporatedtodrynessandtheresiduewasdissolvedin5mLacetone.Asolutionofsodiumazide(970mg,14.9mmol)inwater(2mL)wasaddeddropwiseatroomtemperature.After30min,water(10mL)wasaddedandthesolutionwasextractedwithtoluene(50mL).Theorganiclayersweredriedoversodiumsulfateandheatedtorefluxfor30min.Then10mLofa45%sodiumhydroxidesolutionwasaddedandthemixturewasheatedforafurther30min.Theorganiclayerwasseparated,driedoversodiumsulfateandevaporated.Theresiduewaspurifiedbycolumnchromatography(dichloromethane)toyield660mg(39%)ofthetitlecompound.
Reference:
TetrahedronLett.,2004,45,95-98.
1.2使用DPPA合成胺示例
2-benzyloxy-3-methoxy-4-nitroanilinacid(27.9g,91.8mmol)wasdissolvedinTHF(400mL)andtreatedwithEt3N(30mL).Diphenylphosphorylazide(26.5g,96.4mmol)wasaddeddropwiseandthereactionmixturewasstirredfor3hat25oC.H2O(150mL)wasaddedandthereactionmixturewasrefluxedfor2h.ThesolventwasremovedinvacuoandtheresiduewastreatedwithsaturatedaqueousK2CO3(100mL),dilutedwithH2O(500mL),andextractedwithEtOAc(2×500mL).ThecombinedorganicextractswerewashedwithsaturatedaqueousNaCl(500mL),dried(Na2SO4),andconcentratedinvacuo.Thecruderesiduewaspurifiedbyflashchromatography(SiO2,25%EtOAc−hexanes)toaffordthetitlecompound(19.5g,78%)asayellowsolid.
Reference:
J.Am.Chem.Soc.,2004,126,8396-8398.
叠氮酰胺在H2O里加热重排成胺还是有一些报道的。
如下:
1.3使用DPPA和苄醇合成Cbz保护的胺示例
Underanargonatmosphere,amixtureofacid(200mg,0.59mmol),diisopropylethylamine(0.36mL,2.0mmol),diphenylphosphorylazide(0.32mL,1.5mmol)intoluene(25mL)washeatedatrefluxfor3h.Afterbeingcooledtoroomtemperature,benzylalcohol(0.2mL,2mmol)wasadded,andthemixturewasstirredforanother1h.Afterremovingthesolventinvacuo,silicagelcolumnchromatographygavethetitlecompound(230mg,0.50mmol,85%).
Reference:
J.Org.Chem.,2001,6,557-563.
1.4使用DPPA和叔丁醇合成Boc保护的胺示例
由于叔丁醇的活性不高,一般都使用叔丁醇作溶剂,在研究过程中我们发现若在反应液中加入3-5当量的Boc2O可抑制副反应,提高反应产率。
Drytert-butylalcohol(123mL),triethylamine(16.7g,0.65mol),andDPPA(45.5g,0.165mol)wereaddedtoasolutionof5-fluoro-1,3-benzodioxole-4-carboxylicacid(29g,0.157mol)indioxane(430mL)undernitrogen.Themixturewasheatedat100°Cfor4.5h.Uponcooling,thecloudymixturewasfiltered.Thefiltratewasevaporatedundervacuum,dilutedinethylacetate,washedwitha5%aqueouscitricacid,a5%aqueoussodiumbicarbonate,water,andbrine,driedovermagnesiumsulfate,andconcentratedundervacuumtoprovidedesiredcompound(37.6g,93%).
Reference:
J.Med.Chem.2004,47,871-887
2.Hofmann降解
Hofmann降解是将伯酰胺通过氧化降解成少一个碳原子的伯胺,其机理如下:
最早期的Hofmann降解是使用NaOH水溶液和Br2来实施的。
这个条件比较剧烈,后续有许多改进的方法陆续被报道,主要是通过改进氧化剂和碱。
如Keillor等人1997年报道了用NBS做氧化剂,DBU做碱,甲醇中回流25分钟就得到了甲氧羰基保护的胺(JOC,1997,62,7495-7496).
2.1经典的Br2-NaOH体系Hofmann降解示例
Sodiumhydroxide(3.48kg,87.0mol)wasdissolvedinwater(22L),andthesolutionwascooledto0°C.Bromine(0.63L,11.8mol)wasaddedover30minwhilethetemperaturewasmaintainedat0-10°C.Inasecondvessel,(R)-tosylasparagine(2.86kg,9.48mol)wasaddedinportionstoasolutionofNaOH(0.8kg,20.0mol)inwater(7.2L)keptcoldat0-10°C.Thesolutionwascooledto0°C,andthesodiumhypobromitesolutionwasaddedover10minwhilemaintainingatemperature<10°C.Aftertheaddition,theresultingyellowsolutionwasagedfor15minat10-15°C,andthenheatedto40°Cwithin30min.Heatingwassuspendedandthereactiontemperaturewasallowedtoincreaseto50°Cover20minduetotheexothermicreaction.Whentheinternaltemperaturedroppedto45°C,thereactionsolutionwasheatedto70°Cover20minandkeptat70°Cfor10min.HPLCanalysismeasureda90%solutionyieldofcompound2.Thereactionwascooledto10-15°C,andwithvigorousstirringthepHofthemixturewasadjustedto7bytheadditionofconcentratedhydrochloricacid(4L),whereupontheproductprecipitated.Themixturewasstirredfor20minat15°C,andtheproductwasfiltered.Thecakewasslurrywashedwithwater(2-8L)andthendisplacementwashedwithwater(8L).Theproductwasdriedwithanitrogenstreamat20°Caffording(2R)-3-aminotosylaminoalanine(1.67kg,70%).
Reference:
JOC,1998,63,9533-9534.
2.2NBS作氧化剂用于Hofmann降解示例
p-Methoxybenzamide(76mg,0.5mmol),NBS(90mg,0.5mmol),andDBU(230uL)inmethanol(5mL)wereheatedatrefluxfor15min,atwhichpointmoreNBS(90mg,0.5mmol)wasadded.Thereactionwasallowedtocontinueforanother10min.Methanolwasthenremovedbyrotaryevaporation,andtheresiduewasdissolvedin50mLofEtOAc.TheEtOAcsolutionwaswashedwith5%HClandsaturatedNaHCO3andwasthendriedoverMgSO4.Theproduct,methyl(p-methoxyphenyl)carbamate,waspurifiedbyflashcolumnchromatography(silicagel,eluant5%EtOAcinCH2Cl2)togiveawhitesolid(86mg,95%),
Reference:
JOC,1997,62,7495-7496.
2.3PhI(OCOCH3)作氧化剂用于Hofmann降解示例
AslurryofN-benzyloxycarbonyl-L-asparagine(140g,0.53mol),ethylacetate(680mL),acetonitrile(680mL),water(340mL),andIodobenzeneI,I-diacetate(200g,0.62mol)wascooledandstirredat16°Cfor30min.thetemperaturewasallowedtoreachto20°C,andthereactionwasstirreduntilcompletion(4h).Themixturewascooledto5°C,andtheproductwasfiltered,washedwithethylacetate(100mL),anddriedinvacuoat50°Ctoaffordthetargetcompound(100g,79%)1HNMR:
zsf030373,TLC:
(Chloroform/Methanol/aceticacid5:
3:
1)
PreparationofIodobenzeneI,I-diacetate
Toaflaskwaschargedwithiodobenzene(20.4g,0.10mol)andimmersedinawaterbathmaintainedat30°C.Commercial40%peraceticacid(31mL.,0.24mole)wasaddeddropwisetothewell-stirrediodobenzeneoveraperiodof30–40minutes.Afterfurther20minutesatabathtemperatureof30°C,ahomogeneousyellowsolutionwasformed.Crystallizationofiodosobenzenediacetatemaybeginduringthisperiod.Thebeakerischilledinanicebathfor1hour.ThecrystallinediacetatewascollectedonaBüchnerfunnelandwashedwithcoldwater(3*20mL).Afterdryingfor30minutesonthefunnelwithsuction,thediacetatewasdriedovernightinavacuumdesiccatorcontaininganhydrouscalciumchloridetoprovidethediacetate(26.7–29.3g.83–91%).
2.4NaClO作氧化剂用于Hofmann降解示例(JACS,1958,965)
Amixtureofindazole(4g,0.02mole)andsodiumhydroxide(4g,0.1mole)in30mloficewatercontaining1.5g.(0.02mole)ofchlorinewasstirredatroomtemperaturefor2hours.Thenthereactionwaswarmedonasteam-bathfor1hourduringwhichtimethesolutionwaseffected.Thesolutionwasextractedfourtimeswith50ml.ofethylacetate,andtheextractsweredriedwithanhydrousmagnesiumsulfate.Ethercontaininghydrogenchloridewasadded,andthemixturewasallowedtostandforseveraldays.Thesolidwascollectedrecrystallizedfromethylalcoholtogivethetargetcompound(3g,64%yield)
Reference:
JACS,1958,965
2.5PhI(OCF3)2(BTI)作氧化剂用于Hofmann降解示例
A500-mL,round-bottomedflaskisequippedwithamagneticstirringbarandcoveredwithaluminumfoil.TotheflaskwasaddedasolutionofBTI(16.13g,37.5mmol)in37.5mLofacetonitrile,andtheresultingsolutionwasdilutedwith37.5mLofdistilleddeionizedwater.Cyclobutanecarboxamide(2.48g,25mmol)wasadded;theamidequicklydissolves.Stirringwascontinuedfor4hr,andtheacetonitrilewasremovedwitharotaryevaporator.Theaqueouslayerwasstirredwith250mLofdiethylether;tothestirringmixturewasadded50mLofconcdhydrochloricacid.Themixturewastransferredtoaseparatoryfunnelandthelayerswereseparated.Theaqueouslayerwasextractedwithether(2*150mL).Theorganicfractionswerecombinedandextractedwith75mLof2Nhydrochloricacid.Theaqueousfractionsarecombinedandconcentratedwitharotaryevaporatorusingavacuumpump.Benzene(50mL)wasaddedtotheresidueandthesolutionwasconcentratedwiththerotaryevaporator,againusingavacuumpump.Additionofbenzeneandconcentrationwasrepeatedfivemoretimes.Thecrudesolidwasdriedunderreducedpressureoversulfuricacidovernight.Totheproductwasadded5mLofabsoluteethanoland35mLofanhydrousether,andthesolutionwasheatedatrefluxonasteambath.Ethanolwasaddedslowlytothemixture,withswirling,untilallthematerialwasdissolved;thesolutionwascooledtoroomtemperature.Anhydrousetherwasaddedslowlyuntilcrystallizationjustbegins.Theflaskwasplacedinthefreezerandtheproductwasallowedtocrystallize.Filtrationoftheproductanddryingovernightunderreducedpressureoverphosphoruspentoxidetoprovidecyclobutylaminehydrochloride(1.86–2.06g,69–77%).
Reference:
OrganicSyntheses,Coll.Vol.8,p.132;Vol.66,p.132
3.通过Burgess试剂直接将伯醇转化为烷氧羰基酰胺
最近Wood等人报道了使用Burgess试剂可以一步将伯醇转化为相应的烷氧羰基酰胺,其机理如下:
3.1通过Burgess试剂直接将伯醇转化为烷氧羰基酰胺示例
Toastirredsolutionofchlorosulfonylisocyanate(1.30mL,14.9mmol)indrybenzene(35mL)undernitrogeninacoolwate