有机合成课件1.ppt

（三）.烯胺的烃化反应1963年,G.Stork使用醛和叔丁基胺形成烯胺sichiff碱p-TsOH,甲苯带水(DeanandStarkapparatus),或用无水K2CO3除水,优点(1)不需要碱或其他催化剂,减少羰基的自身缩合(2)可以制备单烷基化产物(3)对于不对称的酮,取代发生在取代基较少的位置,烯胺的Michael反应:取代基少的位置酮的Michael反应:取代基较多的位置,6-甲氧基-1-甲基-2-四氢萘酮的制备：1.烯胺的制备N2，17.6g(0.1mol)6-甲氧基-2-四氢萘酮10.6g(0.15mol)四氢吡咯（除水）300mL苯,回流分水（约2mL）减压蒸去溶剂，用正己烷重结晶得无色晶体（空气中存放1-2天）。,6-甲氧基-1-甲基-2-四氢萘酮的制备：2.烯胺的反应N2，18.6g(0.08mol)2-四氢吡咯基-1,3-二氢-6-甲氧基萘30mLCH3I75mL1，4-二噁烷（除水）,回流18h加35mL水和1.5mL乙酸，回流5h.减压蒸去溶剂，加200mL水，乙醚萃取，干燥，蒸去溶剂，减压蒸出6-甲氧基-1-甲基-2-四氢萘酮（113-115oC）。(81%),在有支链的一侧，烯醇负离子稳定。,酰基化:可在碳上酰基化,并用于增长碳链,合成昆虫激素的中间体-乙酰基己酸,三、麦克尔Michael反应(一)概述碱性条件,活泼亚甲基化合物与a,b-不饱和羰基化合物发生1,4-加成反应,SO2Ph，,1.（Michael受体）,a,b-不饱和羰基化合物，a,b-不饱和腈等,A：CHO,COR,COOR,COAr，CONR2，NO2，CN，SO2Ph，SOPh,2.亲核试剂：活泼甲基和亚甲基化合物乙酰乙酸乙酯丙二酸酯乙酰丙酮b-酮酸酯醛酮腈硝基化合物,3.碱:醇钠、氨、胺4溶剂：苯类、醇类、二氧六环通式：,（二）应用,1制备1，5双官能团化合物,2Robinson环化,A.2-Methyl-2-(3-oxobutyl)-1,3-cyclopentanedione.A1.0-L,three-necked,round-bottomedflaskequippedwithacondenser,magneticstirringbar,andthermometerischargedwith112.1g(1.0mol)of2-methyl-1,3-cyclopentanedione230mLofdeionizedwater,3.0mLofglacialaceticacid,and140mL(120.96g,1.72mol)ofmethylvinylketone.Thesystemisshieldedfromlightwithaluminumfoilandplacedunderaslightpositivepressureofnitrogen.Theflaskisplacedinanoilbathandthetemperatureisraisedto70C.Thereactionismonitoredbygaschromatography(GLC)untilcomplete(12hr).,Themixtureiscooled,transferredtoaseparatoryfunnel,andextractedwith500mLandthentwo100-mlportionsofdichloromethane.Thecombinedextractsarewashedwith500and100mLofsaturatedbrine.Thecombinedbrinewashisextractedwithafurthertwo100-mLportionsofdichloromethane.Thetotaldichloromethaneextractisdriedoversodiumsulfateandfiltered.Thesolventisremovedonarotaryevaporatorat45C(70mm).Dryingontherotaryevaporatorat4045C(0.03mm)for16hrgives181.8g(100%)ofthedesiredtriketoneasanorangeoil.,B.(+)-(3aS,7aS)-2,3,3a,4,7,7a-Hexahydro-3a-hydroxy-7a-methyl-1H-indene-1,5(6H)-dione.A500-mL,three-necked,round-bottomedflaskequippedwithamagneticstirringbarandanitrogeninletischargedwith188mLofN,N-dimethyl-formamideand863mg(7.5mmol)ofS-()-proline.Themixtureisdegassedfourtimesbyalternateevacuationandrefillingwithnitrogen.Thesystemisshieldedfromlightwithaluminumfoilandthecontentsoftheflaskarestirredina1516Cbathfor1.0hr.Totheresultantsuspensionisadded45.5g(0.25mol)ofthe2-methyl-2-(3-oxobutyl)-1,3-cyclopentanedionepreparedinStepA.Atotalof62.5mLofN,N-dimethylformamideisusedtoensurecompletetransfer.Thedegassingprocedureisrepeatedfourtimesandstirringat1516Ciscontinuedfor40120hasthemixturebecomesyellowandthenbrown.ThereactionismonitoredforcompletenessbyTLC.ThesolutionofthedesiredketolisuseddirectlyinStepC.,C.(+)-(7aS)-7a-Methyl-2,3,7,7a-tetrahydro-1H-indene-1,5(6H)-dione.A100-mL,three-necked,round-bottomedflaskequippedwithamagneticstirringbar,pressure-equalizingdroppingfunnel,andnitrogeninletischargedwith50mLofN,N-dimethylformamide.Thecontentsoftheflaskarecooledto20Cwithadryiceacetonebathand2.70mL(4.97g,48.6mmol)ofconcentratedsulfuricacidisaddedover510minataratetomaintainatemperatureof15to20C.Theflaskcontainingthesolutionofthe(+)-(3aS,7aS)-2,3,3a,4,7,7a-hexahydro-3a-hydroxy-7a-methyl-1H-indene-1,5(6H)-dioneinN,N-dimethylformamideisplacedinanoilbathandheatedto95C.Whenthetemperaturereaches7075C,an18.8-mLaliquotoftheconcdsulfuricacidinN,N-dimethylformamidesolutionisaddedinoneportion.Thereactionmixtureisheatedto95Cfor3.0hr.After1.0hr,anadditional7.5-mLaliquotoftheconcdsulfuricacidinN,N-dimethylformamidesolutionisaddedinoneportion.ThereactionismonitoredforcompletenessbyGLCandcooled.,Thesolventisremovedonarotaryevaporatorat45C(0.30.5mm)togiveabrownoil.Thematerialistakenupin375mLofdichloromethane.Thesolutioniswashedwithtwo190-mLportionsof2.0Nsulfuricacidsolutionthathavebeensaturatedwithsodiumchloride,two190-mLportionsofsaturatedsodiumbicarbonatesolutionthathavebeensaturatedwithsodiumchloride,and190mLofsaturatedbrine.Eachaqueouswashisextracted,inturn,withthesametwo190-mLportionsofdichloromethane.Thecombineddichloromethanesolutionsaredriedoversodiumsulfateandfiltered,andthesolventisremovedonarotaryevaporatorat40C(70mm)togive38.839.6gofoily,brownsemisolid.,Thismaterialistakenupin78mLofethylacetateandthesolutionisappliedtoadrycolumnof78gofsilicagel.Thecolumniselutedwith600mLofethylacetate,andthetotaleluateisstrippedofsolventonarotaryevaporatorat40C(70mm)togive37.238.8goftancrystallinesolid.Thesolidissubjectedtobulb-to-bulbdistillation3at120135C(0.1mm)togive35.936.9gofaslightlyyellowish(creamwhite)solid,mp5661C,D25+324329(toluene,c1.0).Thismaterialistakenupin74mLofetheratreflux.Thesolutionisbroughtatrefluxtothepointofturbiditywith19mLofhexanes.Themixtureisseeded,allowedtostandatambienttemperaturefor2hr,andthenchilledina17Cwaterbathfor30min.Thesolidiscollectedbyfiltrationonmediumporositysinteredglass,washedwithtwo12-mLportionsofcold(3C)1:1v/vether:hexanesanddriedat20C(70mm)togive28.731.3g(7076%)ofwhitecrystallinesolid,mp6466C,D25+347.5349(toluene,c1.0),puritybyGLC99.499.5%.,Hajos的应用：Hajos获得了具有手性的Hajos酮,并完成了天然睾丸酮的全合成紫杉醇的合成维生素D3的合成,Robinson环化的实例,7-甲氧基-4a-甲基-4,4a,9,10-四氢菲,7-甲氧基-4a-甲基-4,4a,9,10-四氢菲的制备：N211.4g(0.01mol)6-甲氧基-1-甲基-2-四氢萘酮25mL甲醇加到4.70g(0.085mol)KOH,80mL甲醇，8mL水-20oC4.34g(0.02mol)甲基乙烯基酮(30min)rt15h,回流4h冷却，加冰水、2M盐酸溶液中和，乙醚提取，干燥、过滤，蒸去溶剂，残留物进行柱层析，得黄色结晶。（62%）,3烯醇硅醚的Michael加成反应羰基的Michael加成反应，除了直接通过现场生成的烯醇或烯醇负离子进行外，也可通过烯醇硅醚或烯胺进行。TiCl4促进的Michael反应可在很低的温度下进行，副反应少，收率高。,四、羟醛缩合反应1自身缩合,Soxhlet索氏提取器使收率570,2交叉的醛或酮的缩合,苯甲醛与苯乙酮缩合的查尔酮（Chalcone）查尔酮类化合物具有多种药理作用和生物活性,同时它也是一种新型的有机非线性光学材料。以它为母体的化合物存在于甘草、红花等多种天然植物体中，是植物体内合成黄酮的前体，其本身也有重要的药理作用。查尔酮具有抗蛲虫作用，抗过敏作用，表现了多种药理作用，类黄酮化合物中的查尔酮，具有化学预防和抗肿瘤活性.,得到反式烯,在取代基较少的a-C位置OH-条件下在取代基较多的a-C位置H条件下,碱性条件下，a-H的酸性占主导，动力学控制酸性条件下，烯醇的稳定性占主导，热力学控制。,甲醛与含活泼a-H羰基化合物，在强碱作用下缩合：羟甲基化反应,制备季戊四醇：涂料工业重要原料,3胺甲基化反应（Mannich）醛酮与甲醛和胺（仲、伯胺）缩合得到Mannich碱。通常加入少量的酸，保持一定的酸性。,历程：,应用较广，醛酮，羧酸，酯，酚或其他含芳香体系（如杂环等）的活泼氢，制备氨基酮。,托品酮：1903年，19步合成出。总收率0.75%。1917年Robinson用Mannich反应合成出。收率17%。丙酮二羧酸、丁二醛和甲胺仅一步就合成了托品酮(颠茄酮)。莨菪，颠茄,一步反应法：,tropinone托品酮,1氨甲基化总是发生在取代基较多的a-C上，酸性条件，形成取代基较多的位置的