烷化反應(yīng)化劑縮合醛酮酯等michael加成案例

ChapterChapterFormationofCarbon-CarbonSingleBonds1一、GeneralAAA-EHBBB烷化反應(yīng)E烷化縮合反一、GeneralAAA-EHBBB烷化反應(yīng)E烷化縮合反應(yīng)E=醛、酮、酯Michael加成：EMannich反2~二、影響反應(yīng)的主要因二、影響反應(yīng)的主要因AB不活潑C-A和B應(yīng)該能使其-碳上的H活化的基團，通常為吸電子基（Electronwithdrawgroup，EWG）。-NO2>-COR>SO2R>-CN>-CO2R>-Ph,A和B至少要有一個3理想理想的堿：堿性強，親核性弱，并不進攻那些較敏感的基團，另能溶于非極性溶劑中>常用的堿：Ph3C-Me2CH)2N-EtO-堿的選擇取決于底物的反應(yīng)活455反應(yīng)速（polaraprotic反應(yīng)速（polaraprotic6Chem.Soc.Rev.,2012,41,Solvent-freeO 親電試（Electrophilic親電試（Electrophilic所有能與負碳離子發(fā)生反應(yīng)的碳正離子或分子RX,R-SO3H,RCO2Et,R-OTs>R-I>R-Br>R-Cl>>R-這四種影響因素之間是相互聯(lián)系，相互影響的。在分一個具體反應(yīng)時，應(yīng)該綜合分析考慮這四種影響因素7三、烷基化反O-alkylation&C-OOHardalkylatingR三、烷基化反O-alkylation&C-OOHardalkylatingRRISolftalkylating8ExampleExample9ExampleDegreeExampleDegreeofsubstitutionofalkylatingExample OOOO+ r.r. OAcO O OExample OOOO+ r.r. OAcO O O O++R.T.LietSynth.Commun.1997,27(8),1351-區(qū)域選擇區(qū)域選擇區(qū)域選擇性受熱力學(xué)控制和動力學(xué)控制的反應(yīng)條件影響很大Example動力學(xué)控制條件下主要生成取代基較少的烯醇ExampleExample立體選擇立體選擇烯醇化合物的立體選擇性形成稱合成提供平臺將為不ExampleExampleExampleExampleExampleExampleExampleExample4.二羰基化合物-烷基化反-Alkylationof1,3-dicarbonylcompounds)OOOOOO2equiv.1)RR R2)H2J.Am.Chem.Soc.,1974,4.二羰基化合物-烷基化反-Alkylationof1,3-dicarbonylcompounds)OOOOOO2equiv.1)RR R2)H2J.Am.Chem.Soc.,1974,90,1082;1963,85,3237;1965,87,ExampleOOOO1)2/liq.2)n-ExampleOOOO1)1equivNaOH/THF/1equiv.n-OOOOO2equiv.OOO1)H2OExampleOOOO1)1equivNaOH/THF/1equiv.n-OOOOO2equiv.OOO1)H2O2,CH2Cl2,O2)-OOdiplodialideExampleOSOOSO2NaH/THF/OC4H9-OSOn-C4H9-OExampleOSOOSO2NaH/THF/OC4H9-OSOn-C4H9-OH3C4H9-繼承與發(fā)芳基鹵化物與烯醇鹽的反應(yīng)halidewithCCH+ liq.芳基鹵化物與烯醇鹽的反應(yīng)halidewithCCH+ liq.liq.KNH2/NNN關(guān)鍵是KNH2/NNN關(guān)鍵是要有形成苯炔的條件酮和酯的烷基化反應(yīng)(AlkylationsofketonesandbaRYRXOROOOO常用的堿：NaNH2,KNH2,NaH,Ph3CNa等；有副產(chǎn)物L(fēng)DA,酮和酯的烷基化反應(yīng)(AlkylationsofketonesandbaRYRXOROOOO常用的堿：NaNH2,KNH2,NaH,Ph3CNa等；有副產(chǎn)物L(fēng)DA,LTMPLHMDS等效果很好~~~~~~~~AldolExampleOONaNH2/C6H6,88Example1)LDA/THF,-78ExampleOONaNH2/C6H6,88Example1)LDA/THF,-781)LDA/THF,-7890CO2不對稱酮的選擇性烷基化反不對稱酮的選擇性烷基化反(Selectivealkylationofasymmetricketones)baRO在一個-位引入一個活化基(略如：DieckmannReaction;Claisen制成結(jié)構(gòu)專屬性的烯醇負離在取代基較多-位烷基(烯醇硅醚法ONaH+2)Me3SiCl/堿性條MeLi在取代基較多-位烷基(烯醇硅醚法ONaH+2)Me3SiCl/堿性條MeLi/+25OO+酸性條OMeMe33LewisRRLewisTiCl4,酸性條OMeMe33LewisRRLewisTiCl4,SnCl4,O1)t-BuX/CH2Cl2/-2)在取代基較少-位烷基(烯胺法,Stork在取代基較少-位烷基(烯胺法,StorkEnamineONNN-C-E 通常，用活潑的鹵代烷，可以高產(chǎn)率生成C-烷基化產(chǎn)物；但對于一般的鹵代烴，C-烷基化產(chǎn)物收率較底。若用LDA在低溫下反應(yīng)，則對各種鹵代烴均可得到高收率的C-烷基化產(chǎn)物。對于不對稱酮，主要在取代基較少的-位發(fā)生烷基化ExampleOH3ON+Example1)DME/-ONOExampleOH3ON+Example1)DME/-ONO對映選擇性烷基化反應(yīng)利用手性HLDA/THF,-Oyield94%NHHHNN對映選擇性烷基化反應(yīng)利用手性HLDA/THF,-Oyield94%NHHHNN HONC2HH利用SAMPNNON+NNON1)1)N2)2)HH3H利用SAMPNNON+NNON1)1)N2)2)HH3Hyield99.5%羧酸的-不對稱烷基OO羧酸的-不對稱烷基OOOOOOOOLDA/NONO-78OOO2NO2H2/OOOOLDA/NONO-78OOO2NO2H2/75%,>O極性翻轉(zhuǎn)俞凌翀，劉志昌，極性轉(zhuǎn)換及其在有機合成中的用，科學(xué)版社Example1安息香縮-極性翻轉(zhuǎn)俞凌翀，劉志昌，極性轉(zhuǎn)換及其在有機合成中的用，科學(xué)版社Example1安息香縮-HOOCHCH- CExample醛氰醇Me-1)3CCH3 3OCCC33Example醛氰醇Me-1)3CCH3 3OCCC33StetterOO+HEWG=COR，CO2R,CN,.NN+-SNS- NStetterOO+HEWG=COR，CO2R,CN,.NN+-SNS- NOONaCN,35oC,OH+ONNStetter,H;Schreckenberg,M.Chem.OONaCN,35oC,OH+ONNStetter,H;Schreckenberg,M.Chem.Ber.1974,107,Example1,3二噻烷SHCl/HR+SSRSRHO+/Example1,3二噻烷SHCl/HR+SSRSRHO+/Hg3OSRS不易發(fā)生加成反應(yīng)Example乙基乙硫甲基亞砜R1)OSSROSSOExample乙基乙硫甲基亞砜R1)OSSROSSOOOROMicheal1,4二四、縮合反四、縮合反AldolReactionMichaelAdditionMannichReactionDarzen’sReactionAldolReaction1)AldolReaction1)經(jīng)典Aldol反應(yīng)的兩大缺不同醛、酮之間的反應(yīng)常得到混合產(chǎn)物立體選擇性2)定向醇醛縮2)定向醇醛縮合反（DirectedAldolMetoodPreformedLithiumZ-enolatesgivepredominantlysyn(orthreo)aldolproducts(thermodynamicenolates).E-enolatesgivepredominantlyanti(orerythro)aldolproducts(kineticenolates).OriginofOriginofa.Z-b.E-b.E-EffectofEffectofEffectofEffectofEffectofEffectofMethodPreformedMethodPreformedBorona.Z-enolatea.Z-enolatePreparationandb.E-enolatePreparationb.E-enolatePreparationand烯醇化構(gòu)型不易控-Originally-Originallydifficulttocontrolc.Examplesc.ExamplesofmorerecentmethodstocontrolboronenolateAldolCondensationAldolCondensationwithChiralTienolateTienolatepromotedEvansChelatedandChelatedandnon-chelatedTiMetoodOOR2 4R-在酸性條MetoodOOR2 4R-在酸性條立體選擇較差OOO有機小分子催化醇醛縮合反O有機小分子催化醇醛縮合反OAldolaseAntibody Barbas,C.F.,IIIetal.J.Am.Chem.Soc.1997,119,8131OOOHajos-Eder-Sauer-WiechertHajos,Z.G.etal.J.Org.Chem.1974,39,Eder,U.;Sauer;G.,Wiechert,R.Angew.Chem.Int.Ed.Engl.1971,10,496OOHowever,proline-catalyzedintermolecularasymmetricaldolhasnotbeendescribed.Further,therearenoasymmetricsmall-moleculealdolcatalyststhatuseanenaminemechanism.BasedonourownresultsandShibasaki'sworkonlanthanum-basedsmall-moleculealdolcatalysts,werealizedthegreatpotentialofcatalystsforthedirectasymmetricaldolreaction.OOOH+68%(76%aminoacidOOOH+L-prolineisOOOOOH+68%(76%aminoacidOOOH+L-prolineisOOOH+RRyield:54-97%;%ee:60-HH H +H-NNN+abOcOO-OH HOH+NRRN fROOHOHOedH RH+gHH H +H-NNN+abOcOO-OH HOH+NRRN fROOHOHOedH RH+gOProposedEnamineMechanismoftheProline-catalyzedAsymmetricAldolReactionCarlosF.BarbasIIIet.al.J.Am.Chem.Soc.2000,122(10),2395-CatalyticAsymmetricSynthesisofanti-1,2-OOO+CatalyticAsymmetricSynthesisofanti-1,2-OOO+r.t.HRsyn:anti:15:1-20:1;yield:38-95%;%ee:67-CarlosF.BarbasIIIet.al.J.Am.Chem.Soc.2000,122(30),7386-Proline-CatalyzedAsymmetricAldolReactionsbetweenKetonesanda-UnsubstitutedAldehydesOOOOR +RR+H3-7BA20yield:A22-35%,B35-50%;%ee:36-OO+Proline-CatalyzedAsymmetricAldolReactionsbetweenKetonesanda-UnsubstitutedAldehydesOOOOR +RR+H3-7BA20yield:A22-35%,B35-50%;%ee:36-OO+N-R2HRHOORAO-NORRBCompoundBwasformedviaMannichBenjaminlistetal.Org.Lett.2001,3(4),573-MacMillanD.W.C.etal.J.Am.Chem.MacMillanD.W.C.etal.J.Am.Chem.Soc.2002,124(24),6798- L-R1 DMF, %ee:N 10mol DMF, 80%yield,4:1anti:syn,99% + R'+ArCHOamino Barbas,C.F.etal.J.Am.Chem.Soc.2001,123(22),5260-TheFirstDirectandEnantioselectiveCross-AldolReactionofNovelSmallNovelSmallOrganicMoleculesforaHighlyEnantioselectiveDirectAldolReactionZhuoTang,?,?FanJiang,§Luo-TingYu,?XinCui,?Liu-ZhuGong,*,?Ai-QiaoMi,?Yao-ZhongJiang,?andYun-DongKeyLaboratoryforAsymmetricSynthesisandChirotechnologyofSichuanProvince,ChengduInstituteofOrganicChemistry,ChineseAcademyofSciences,Chengdu,610041,China,CollegeofChemicalEngineering,SichuanUniVersity,Chengdu,610065,China,andStateKeyLaboratoryofMolecularDynamicsandStableStructures,CollegeofChemistryandMolecularEngineering,PekingUniVersity,Beijing,100871,ChinaJ.AM.CHEM.SOC.2003,125,5262-Two-StepSynthesisTwo-StepSynthesisofCarbohydratesbySelectiveAldolReactionsAlanB.NorthrupandDavidW.C.SCIENCEVOL305,TableTableHighlyDiastereo-andEnantioselectiveHighlyDiastereo-andEnantioselectiveDirectAldolReactionsinWater*YujiroHayashi,*TatsunobuSumiya,JunichiTakahashi,HiroakiGotoh,TatsuyaUrushima,andMitsuruShojiAngew.Chem.Int.Ed.2006,45,9581:5OrganocatalyticDirectAsymmetricAldolReactionsinWaterOrganocatalyticDirectAsymmetricAldolReactionsinWaterC.F.BarbasIII*J.AM.CHEM.SOC.2006,128,734-存在的問存在的問OOO(L)-Pro-(L)-Phe-OHO+HDMSO,PGME5000,OOO(L)-Pro-(L)-Phe-OHO+HDMSO,PGME5000,yield:uptoee:uptoL.Shi;R.Li;etal.Synlett,2004,12,OO**Cat.(20mol+RRCO2upOO**Cat.(20mol+RRCO2upto78%yieldupto94%eeY.Liuetal./TetrahedronLetters52(2011)MichaelAdditionGeneral CRREWG,EWG'-CHO,-CO-,-COR,MichaelAdditionGeneral CRREWG,EWG'-CHO,-CO-,-COR,-CN,-NO2,-etSynthesisof1,5-dicarbonylAsymmetryMichaelAddition手性金屬配位化合物催OOAsymmetryMichaelAddition手性金屬配位化合物催OO10mol%Li-Al-(R)-THF,r.t.,72H+CH(CO2288%,99%AraiT.etAngew.Chem.Int.Ed.,1996,35,ONONA + 20mol N N HClO4 R1 %ee:90- yield:66-J.Am.Chem.Soc.2000,122(40),9874- R N %ee:89-123(18),4370-R20mol%A- X+ X%ee:83-J.Am.Chem.Soc.2000,122(17),4243-X 20mol%A-91-99%X+J.Am.Chem.Soc.2001,123(18),4370-4371ZOZO20mol%A-X 20mol%A-91-99%X+J.Am.Chem.Soc.2001,123(18),4370-4371ZOZO20mol%A-+OCH2Cl2,-40oC56%NNNOONNNHHBAO20mol%B- +ONNHX=TFASolvent:CH2Cl2-i-OptimalRO20mol%B-+ROO20mol%B- +ONNHX=TFASolvent:CH2Cl2-i-OptimalRO20mol%B-+RO>90%NNZZ20mol%B-O+O>89%YYNRNRJoelF.AustinandDavidW.C.)OOLewisH+OOONOrganocatalysis:1,4-)OOLewisH+OOONOrganocatalysis:1,4-OOH+OOOO+ROORR=Me,Pr,i-Pr,Ph,CH2OBz,Yield:77-87%,%84-OORROO+ROORR=Me,Pr,i-Pr,Ph,CH2OBz,Yield:77-87%,%84-OORROOR=H,Me,Et,Yield:73-87%,%ee:90-S.P.Brown,C.Goodwin,andD.W.Chem.Soc.2003,125(5),1192-環(huán)己二胺催環(huán)己二胺催化的不對稱Michael加一些代表性的不對稱Michael加成反應(yīng)的催化J.F.Wang,R.T.Li,etal.Chem.Commun.2010,46,OOOOOO*Cat.(20J.F.Wang,R.T.Li,etal.Chem.Commun.2010,46,OOOOOO*Cat.(20RMeOH/CH2Cl136-78%80-96%J.F.Wang,R.T.Li,etal.Chem.Commun.2010,46,NH2 CO22Proposeddi-iminiumProposeddi-iminiummechanismintheMichaelreactionsof-butenolidesandchalcones.MannichGeneralOOORR+HR3CH++2胺組MannichGeneralOOORR+HR3CH++2胺組氨、伯胺、仲可分別發(fā)生三、雙、單反醛組H組醛、酮、活潑亞甲基化合物、酚類化合物、雜環(huán)、炔等ExampleNHOOHExampleOO.++OOOAldolOMichael-O+/-O2)ExampleNHOOHExampleOO.++OOOAldolOMichael-O+/-O2)AsymmetryMannichAsymmetryMannichLewisacid-catalyzedasymmetricMannichFujii,A.;Hagiwara,E.;Sodeoka,M.J.Am.Chem.Soc.1999,121,Ishitani,H.;Ueno,M.;Kobayashi,S.J.Am.Chem.Soc.2000,122,Ishihara,K.;Miyata,M.;Hattori,K.;Yamamoto,H.J.Am.Chem.Soc.1994,116,10520;Ishitani,H.;Ueno,M.;Kobayashi,S.J.Am.Chem.Soc.1997,119,Ferraris,D.;Yong,B.;Dudding,T.;Leckta,T.J.Am.Chem.Soc.1998,120,4548;Ferraris,D.;Young,B.;Cox,C.;Dudding,T.;Drury,W.J.,III;Ryzhkov,L.;Taggi,A.E.;Lectka,T.J.Am.Chem.Soc.2002,124,Kobayashi,S.;Hamada,T.;Manabe,K.J.Am.Chem.Soc.2002,124,5640.SmallOrganicMoleculeSmallOrganicMoleculecatalyzedasymmetricMannichNotz,W.;Sakthivel,K.;Bui,T.;Zhong,G.;Barbas,C.F.,IIITetrahedronLett.2001,42,199;Juhl,K.;Gathergood,N.;Jorgensen,K.A.Angew.Chem.,Int.Ed.2001,40,2995;Yamasaki,S.;Iida,T.;Shibasaki,M.Tetrahedron1999,55,8857;List,B.J.Am.Chem.Soc.2000,122,Co′rdova,A.;Notz,W.;Zhong,G.;Betancort,J.M.;Barbas,C.F.,IIIJ.Chem.Soc.2002,124,Co′rdova,A.;Watanabe,S.-i.;Tanaka,F.;Notz,W.;Barbas,C.F.,IIIJ.Chem.Soc.2002,124,TheDirectCatalyticAsymmetricNH-OO r.++94%NH-OOO+HRRRyield:35-ee:73-TheDirectCatalyticAsymmetricNH-OO r.++94%NH-OOO+HRRRyield:35-ee:73-i-NH-OO r.++a.R1=NH-OO r.++a.R1=H,R2=Me,99%R1=Me,R2=H,94%totalyieldb.R1=H,R2=OMe,98%ee,yieldBenjaminList.J.Am.Chem.Soc.2000,122(38),9336-TheDirectandEnantioselective,One-Pot,Three-Component,Cross-MannichTheDirectandEnantioselective,One-Pot,Three-Component,Cross-MannichReactionofAldehydesDepartmentofIndustrialChemistry,FacultyofEngineeringTokyoUniversityofScience,KagurazakaAngew.Chem.Int.Ed.2003,42,3677Three-componentMannichreactionThree-componentMannichreactionwithvariousacceptorThree-componentMannichThree-componentMannichreactionwithvariousdonorTheDirectCatalyticTheDirectCatalyticAsymmetricCross-MannichReaction:AHighlyEnantioselectiveRouteto3-AminoAlcoholsanda-AminoAcidDepartmentofOrgan