高等有機合成課件

AdvancedOrganicSynthesis緒論一、有機合成的歷史回顧二、有機合成化學的發(fā)展趨勢三、學習內(nèi)容和方法四、重要參考書及期刊五、課程安排一、有機合成的歷史回顧1.尿素的合成（1828年，德國化學家Wohler）有機化學的開始2）1917年，英國化學家Robinson(1947年獲Noble化學獎）3steps,overallyield90%Robinson為什么能是發(fā)現(xiàn)這條合成路線？MannichReaction(1912)3.維生素B12的合成（Woodward,1977年）在Woodward及Eschenmoser領(lǐng)導下,經(jīng)過兩個實驗室，100多位科學家的共同努力，于1977年完成了維生素B12的全合成工作。將有機合成作為一種藝術(shù)展現(xiàn)在世人面前。因在1945-1954年人工合成了奎寧、類固醇、馬錢子堿、羊毛甾醇、麥角堿等近20種復雜天然產(chǎn)物而1965年獲Noble化學獎E.J.Corey,(1990年獲Noble化學獎)

如果說Woodward一生奮斗的成就是將有機合成作為一種藝術(shù)展現(xiàn)在世人面前，那么Corey則是將有機合成從藝術(shù)轉(zhuǎn)變成為科學的一個關(guān)鍵人物。他的逆合成分析是現(xiàn)代有機合成化學的重要基石，推動了20世紀70年代以來整個有機合成領(lǐng)域的蓬勃發(fā)展。逆合成分析(Retrosyntheticanalysis)二、有機合成化學的發(fā)展趨勢1.新試劑、新反應、新方法的發(fā)現(xiàn)永無止境

Epibatidine

的研究

Y(OTf)3-catalyzednovelMannichreactionofN-alkoxy-carbonylpyrroles,formaldehydeandprimaryaminehydrochloridesC.X.Zhuan,J.C.Dong,T.M.Cheng,R.T.Li*,TetrahedronLetters,2001,43(3),461-4632.與生命科學和材料科學的聯(lián)系越來越緊密三、學習內(nèi)容和方法內(nèi)容1.對重要的基礎(chǔ)有機反應要能夠熟練運用新化合物的合成比葫蘆畫瓢逆合成分析跟蹤文獻，盡可能將最新的試劑、反應和方法應用于自己的研究工作中。3.學習別人的思路，創(chuàng)造性地借鑒和運用方法期刊Angew.Chem.Int.Ed.J.Am.Chem.Soc.J.Org.Chem.Org.LettersChem.Commun.TetrahedronTetrahedronLetters.TetrahedronAsymm.SynthesisSynlett11.Synth.Commun.12.Eur.J.Chem.13.Eur.J.Org.Chem.14.Heterocyclics15.J.HeterocyclicChem.16.J.Med.Chem.Bioorg.Med.Chem.Bioorg.Med.Chem.Lett.Eur.J.Med.Chem.20.J.Comb.Chem.五、課程安排進度安排

2.講授原則復習老反應，補充新反應，重點講進展，強調(diào)學思路?？荚?/p>

1）寫綜述一篇（近5年的進展）（40%）

2）筆試（60%）Chapter2FormationofCarbon-CarbonSingleBonds二、影響反應的主要因素

a.

反應底物（Substrate)-NO2>-COR>SO2R>-CN>-CO2R>-Ph,SOR

A和B至少要有一個是EWGA和B應該能使其-碳上的H活化的基團，通常為吸電子基（ElectronwithdrawgroupEWG）。b.堿（Base）常用的堿：Ph3C->(Me2CH)2N->EtO->OH->R3N堿的選擇取決于底物的反應活性理想的堿：堿性強，親核性弱，并不進攻那些較敏感的基團，另外能溶于非極性溶劑中。d.親電試劑（Electrophilicreagent)所有能與負碳離子發(fā)生反應的碳正離子或分子。例：RX,R-SO3H,RCO2Et,RCOR’

這四種影響因素之間是相互聯(lián)系，相互影響的。在分析一個具體反應時，應該綜合分析考慮這四種影響因素。

三、烷基化反應(Alkylation)1.O-alkylation&C-alkylationExample1Example2Degreeofsubstitutionofalkylatingagent:Example32.區(qū)域選擇性（Regioselectivity)區(qū)域選擇性受熱力學控制和動力學控制的反應條件影響很大.熱力學控制條件下主要生成取代基較多的烯醇;動力學控制條件下主要生成取代基較少的烯醇;Example1Example23.立體選擇性（Steroselectivity)烯醇化合物的立體選擇性形成,將為不對稱合成提供平臺.Example1Example2Example3Example44.二羰基化合物的-烷基化反應(-Alkylationof1,3-dicarbonylcompounds)J.Am.Chem.Soc.,1974,90,1082;1963,85,3237;1965,87,82.Example1Example2Example3繼承與發(fā)展5.芳基鹵化物與烯醇鹽的反應(Reactionsofaromatichalidewithenolates)ExampleMechanism關(guān)鍵是要有形成苯炔的條件。6.酮和酯的烷基化反應(Alkylationsofketonesandesters)避免Aldol縮合反應發(fā)生的方法：烷化劑要待酮完全轉(zhuǎn)化為烯醇式后再加入。常用的堿：NaNH2,KNH2,NaH,Ph3CNa等；有副產(chǎn)物。LDA,LTMP,LHMDS等效果很好。Example1Example2不對稱酮的選擇性烷基化反應(Selectivealkylationofasymmetricketones)在一個-位引入一個活化基(略）如：DieckmannReaction;Claisencondensation制成結(jié)構(gòu)專屬性的烯醇負離子在取代基較多的-位烷基化(烯醇硅醚法)堿性條件酸性條件在取代基較少的-位烷基化(烯胺法,StorkEnamineSynthesis)

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，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。Example1Example27.對映選擇性烷基化反應（Enantioselectivealkylations)利用手性胺利用二甲基肼擴展：二甲基腙鋰化合物的另一應用二甲基腙鋰化合物容易轉(zhuǎn)化成有機銅化合物，而有機銅化合物在C-C鍵的形成中很有用。利用SAMP和RAMP若用RAMP，則得到另一種對映異構(gòu)體。羧酸的-不對稱烷基化Example8.極性翻轉(zhuǎn)（Umpolung)俞凌翀，劉志昌，極性轉(zhuǎn)換及其在有機合成中的應用，科學出版社，1991Example1安息香縮合Example2醛氰醇法Example31,3–二噻烷法不易發(fā)生Michael加成反應。Example4乙基乙硫甲基亞砜法1,4–二酮四、縮合反應(Condensation)AldolReactionMichaelAdditionMannichReactionClaisenCondensationDieckmann

CondrnsationDarzen’sReactionReformatslyreactionAldolReaction(condensation)1)經(jīng)典Aldol反應的兩大缺點

不同醛、酮之間的反應常得到混合產(chǎn)物；立體選擇性差2)定向醇醛縮合反應（DirectedAldolcondensation)Metood1PreformedLithiumEnolates

Z-enolatesgivepredominantly

syn

(orthreo)aldolproducts(thermodynamicenolates).

E-enolatesgivepredominantlyanti(orerythro)aldolproducts(kineticenolates).Example1-StericsizeofR1affectsdiastereoselectivity

OriginofDiastereoselectivitya.Z-enolates

DiastereoselectivityforZ-enolate(givingsyn

aldolproduct)ismaximizedwhenR1andR3arestericallydemanding(R1/R3interactionismaximized).

Diastereoselectivityalsoincreasesasmetalischangedtoboron.ThisisattritubtedtoatighterT.S.(B–Obondshorter,soR1/R3

stericinteractionsaremagnifiedinT.S.forantiproduct).

WhenR2isverylargetheR3/R2gaucheinteraction>R1/R31,3-diaxialinteraction(Why?).b.E-enolates

DiastereoselectivityincreasesasR1andR3becomestericallylarge,andaswitchtotheboronenolatewillincreaseselectivity.

DiastereoselectivitymayswitchwhenR2isverylarge(Why?).EffectofR1EffectofR3EffectofR2Metood2PreformedBoronEnolatesa.Z-enolatePreparationandReactionsb.E-enolatePreparationandReactions-Originallydifficulttocontrolbut:c.ExamplesofmorerecentmethodstocontrolboronenolategeometryAldolCondensationwithChiralEnolates

TienolatepromotedEvansaldol(non-Evanssyn

aldol)

Chelatedandnon-chelatedTienolatesMetood3Acid-CatalysedDirectedAldolReactions該方法是在酸性條件下反應；但立體選擇性較差。3)有機小分子催化醇醛縮合反應（SmallOrganicMoleculesCatalystedAldolReactions)NovelSmallOrganicMoleculesforaHighlyEnantioselectiveDirectAldolReactionJ.AM.CHEM.SOC.2003,125,5262-5263ZhuoTang,?,?FanJiang,§Luo-TingYu,?XinCui,?Liu-ZhuGong,*,?Ai-QiaoMi,?Yao-ZhongJiang,?andYun-DongWu*KeyLaboratoryforAsymmetricSynthesisandChirotechnologyofSichuanProvince,ChengduInstituteofOrganicChemistry,ChineseAcademyofSciences,Chengdu,610041,China,CollegeofChemicalEngineering,SichuanUniVersity,Chengdu,610065,China,andStateKeyLaboratoryofMolecularDynamicsandStableStructures,CollegeofChemistryandMolecularEngineering,PekingUniVersity,Beijing,100871,China2.MichaelAdditionReactionApplications:Synthesisof1,5-dicarbonylcompoundsGeneralSchemeDevelopment:AsymmetryMichaelAdditionReaction手性金屬配位化合物催化MacmillanGroup’sWorkSmallOrganicMoleculecatalyzedasymmetricMichaelreactionsTheFirstEnantioselectiveOrganocatalyticMukaiyama-MichaelReaction:S.P.Brown,N.C.Goodwin,andD.W.C.MacMillan*,

J.Am.Chem.Soc.2003,125(5),1192-11943.MannichReactionGeneralScheme

胺組份氨、伯胺、仲胺

醛組份HCHO,PhCHO,RCHO可分別發(fā)生三、雙、單Mannich反應

活潑H組份醛、酮、活潑亞甲基化合物、酚類化合物、雜環(huán)、炔等。Example2Example1

Development:AsymmetryMannichReaction

Lewisacid-catalyzedasymmetricMannichreactions(a)Fujii,A.;Hagiwara,E.;Sodeoka,M.J.Am.Chem.Soc.1999,121,5450;(b)Ishitani,H.;Ueno,M.;Kobayashi,S.J.Am.Chem.Soc.2000,122,8180;(c)Ishihara,K.;Miyata,M.;Hattori,K.;Yamamoto,H.J.Am.Chem.Soc.1994,116,10520;(d)Ishitani,H.;Ueno,M.;Kobayashi,S.J.Am.Chem.Soc.1997,119,2060;(e)Ferraris,D.;Yong,B.;Dudding,T.;Leckta,T.J.Am.Chem.Soc.1998,120,4548;(f)Ferraris,D.;Young,B.;Cox,C.;Dudding,T.;Drury,W.J.,III;Ryzhkov,L.;Taggi,A.E.;Lectka,T.J.Am.Chem.Soc.2002,124,67.(g)Kobayashi,S.;Hamada,T.;Manabe,K.J.Am.Chem.Soc.2002,124,5640.

(a)Notz,W.;Sakthivel,K.;Bui,T.;Zhong,G.;Barbas,C.F.,IIITetrahedronLett.2001,42,199;(b)Juhl,K.;Gathergood,N.;Jorgensen,K.A.Angew.Chem.,Int.Ed.2001,40,2995;(c)Yamasaki,S.;Iida,T.;Shibasaki,M.Tetrahedron1999,55,8857;(d)List,B.J.Am.Chem.Soc.2000,122,9336;(e)Co′rdova,A.;Notz,W.;Zhong,G.;Betancort,J.M.;Barbas,C.F.,IIIJ.Am.Chem.Soc.2002,124,1842;(f)Co′rdova,A.;Watanabe,S.-i.;Tanaka,F.;Notz,W.;Barbas,C.F.,IIIJ.Am.Chem.Soc.2002,124,1866.

SmallOrganicMoleculecatalyzedasymmetricMannichreactionsTheDirectandEnantioselective,One-Pot,Three-Component,Cross-MannichReactionofAldehydesAngew.Chem.Int.Ed.2003,42,3677–3680Y.Hayashi,W.Tsuboi,I.Ashimine,T.Urushima,Dr.M.ShojiDepartmentofIndustrialChemistry,FacultyofEngineeringTokyoUniversityofScience,KagurazakaThree-componentMannichreactionwithvariousacceptoraldehydesN-methyl-2-pyrrolidinone(NMP)Three-componentMannichreactionwithvariousdonoraldehydes.4.ClaisenCondensationGeneralSchemeMechanism

一種酯的自身縮合Scopeofapplication

一種含-H的酯與一種不含-H的酯之間的縮合Examples

DirectedClaisencondensation5.DickmannCondensationChapter3FormationofCarbon-CarbonDouleBonds1.-Eleminationreactions（-消去反應）I.TheSyntheticMethodsofAlklenes2.Pyrolyticsyneliminations（順式熱消去反應）Applications:SynthesisofterminalalkenesfromprimaryacetatesDisadvantages:HighreactiontemperatureCopereactionChugavereaction反應條件比對應的酯熱消去溫和。3.Wittigandrelatedreactions（Wittig及有關(guān)反應）

WittigReactionG.Wittigreceivedthe1979NobelPrizeinChemistryfor"manysignificantcontributionstoOrganicChemistry"whichincludednotonlytheWittigreaction,butalsoPhLipreparedbymetal-halogenexchange,benzyne,andtheWittigrearrangement.GeneralScheme

Mildreactionconditions;

Thepositionofthedoublebondisunambiguous.

FeaturesRepresentativeExamplesExample1Example2Example3Example4Mechanism[2+2]cycloaddition.Influenceofsolventontheselectivity

ActivityandstereoselectivityofYild

Schl?ssermodification:allowsthepreparationoftransvs.cisolefins.Schl?sserAngew.Chem.,Int.Ed.Eng.1966,5,126.

StabilizedYlides-Stabilizedylidesaresolid;stabletostorage,notparticularlysensitivetomoisture,andcanevenbepurifiedbychromatography.-Becausetheyarestabilized,theyaremuchlessreactivethanalkylylides.Theyreactwellwithaldehydes,butonlyslowlywithketones.-Thefirststep,involvingtheadditiontothealdehyde,isslowandreversiblewithstabilizedylides.Influenceofsolventontheselectivity

Wadsworth–Horner–EmmonsReactionHornerChem.Ber.1958,91,61;1959,92,2499.Wadsworth,EmmonsJ.Am.Chem.Soc.1961,83,1733.Reviews:Org.React.1977,25,73–253.ComprehensiveOrg.Syn.,Vol.1,761.

PreparationofPhosphonateEstersArbuzovJ.Russ.Phys.Chem.Soc.1906,38,687.-ArbuzovRearragement-Thesameapproachtothepreparationof-ketophosphonatesisnotsuccessful:-ButcanusevariationonClaisenconditions:ModificationsandScope-LiCl/tertiaryamines(DBU,iPr2NEt,Et3N)Masamune,RoushTetrahedronLett.1984,25,2183.Cansubstituteforconventionalconditionsandisespeciallygoodforbasesensitivesubstrates.-HinderedphosphonatesandhinderedaldehydesincreaseE-selectivity(trans).-Still–GennarimodificationselectiveforZ-alkenes(cis):-AdditionalZ-selectivestabilizedphosphonates.

SelecteddiarylphosphonatesprovideHighZ-selectivityaswell.PetersonReactionReviews:Org.React.1990,38,1.PetersonreactionoffersanalternativetoWittigprocedure.TheyaremorereactiveandstericallylessdemandingthanaWittigreagentandthevolatilebyproduct(Me3SiOH/Me3SiOSiMe3)issimplertoremovethanPh3PO.Itdoes,however,requireasecondsteptopromoteeliminationofthe-hydroxysilane.-Theeliminationisstereospecific:acid-promotedbeingantiandbase-promotedbeingsyn.Hudrlik,PetersonJ.Am.Chem.Soc.1975,97,1464.StabilizedPetersonReagents-ThestabilizedPetersonreagentsgivepredominantlythemoststabletransolefins(E)-Additionalexamples:4.TheTebbeReactionandRelatedTitanium-stabilizedMethylenations(Tebbe反應及與有關(guān)穩(wěn)定化鈦試劑的亞甲基化反應）-Toleratesketalandalkenederivatives.

ScopedefinedbyEvansandGrubbsJ.Am.Chem.Soc.1980,102,3270.ExtendedtotertiaryamidesbyPineJ.Org.Chem.1985,50,1212.ForananalogoususeofCp2TiMe2:PetasisJ.Am.Chem.Soc.1990,112,6392.5.Sulphoxide-sulphenaterearragement:Synthesisofallylalcohols(亞砜-次磺酸酯重排：烯丙醇類化合物的合成)Combinedwithalkylationofsulphoxidesthereactionprovidesaversatilesynthesisofdi-andtri-substitutedallylicalcoholsEvansandAndrews,Acc.Chem.Res.,1974,7,147-alkylationofallylicalcohlosExample1Example26.Alkenesfromsulphones(由砜制備烯烴）-JuliaOlefinationReview:ComprehensiveOrg.Syn.,Vol.1,792.-Example:JuliaTetrahedronLett.1973,4833.Juliadevelopedamorerecent,single-stepvariantthatavoidsthereductiveeliminationJuliaBull.Soc.Chim.,Fr.1993,130,336.Julia,M.etal.,TetrahedronLett.,1973,4833Kocienski,P.J.etal.,J.Chem.Soc.PerkinI,1978,829.-Example:-Ramberg–BacklundreactionOrg.React.1977,25,1.Base-SO2NicolaouK.C.etal.,J.AmChem.Soc.,1992,114,7360.BoockmanR.K.etal.,J.AmChem.Soc.,1991,113,9682.AlvarzeE.etal.,J.AmChem.Soc.,1995,117,1437.7.Decarboxylationof-lactones(-內(nèi)酯的脫羧反應）ReformatskyReactionNote:NostilbenewasformedSynthesisoftri-ortetrasubsitutedalkenesExample1FehrC.etal.TetrahedronLett.,1992,33,2465MolbierW.R.etal.J.Org.Chem.,1995,60,5378Example2Example3MulzerJ.,etal.,J.Chem.Soc.Chem.Commun.,1979,528.Stereoselectivesynthesisoftri-andtetra-substitutedalkenes(三、四取代烯烴的立體選擇性合成）

Thefirststepishighlystereoselective.TheR4andthelargerofthegroupsR1andR2areantitoeachother.EarlyMethodCornforth,J.W.etal.,J.Chem.Soc.,1959,112DevelopmentMethod1Corey,E.J.etal.,J.Am.Chem.Soc.,1967,89,4246.Example(54%;97%E)Method2Example:R=Et,Yield72%Zweifel,G.etal.,J.Am.Chem.Soc.,1967,89,2754.Zweifel,G.etal.,J.Am.Chem.Soc.,1967,89,5085.9.Oxidativedecarboxylationofcarboxylicacids(羧酸的氧化脫羧反應）Sheldon,R.A.,etal.,OrganicReactions,1972,19,279.Jahngen,B.G.E.,J.Org.Chem.,1974,39,1650.與Dieal-Alder反應結(jié)合，是制備環(huán)狀烯烴的好方法。Example1TanzawaT.etal.TetrahedronLett.,1992,33,6783Example2Example310.Alkenesfromarylsulphonylhydrazones(由芳基磺酰腙制備烯烴）KolonkoK.,etal.J.Org.Chem.,1978,43,1404;AdlingtonR.M.,etal.Acc.Chem.Res.,1983,16,55MechanismLesssubstitutedalkeneExample1Example211.FragmentationReactions(裂解反應）X=leavinggroup,e.g.:-OSO2C6H4CH3-p,-OSO2CH3100%stereospecificExample12.OlefinInversionReactions(烯烴構(gòu)型轉(zhuǎn)換反應）

Deoxygenationofepoxides(withretentionofgeometry)Otherexamples13.Srereospecificsynthesisofalkenesfrom1,2-diols(由1,2-二醇立體選擇性地合成烯烴）Corey–WinterOlefinSynthesisCoreyJ.Am.Chem.Soc.1963,85,2677.CoreyJ.Am.Chem.Soc.1965,87,934.EastwoodAust.J.Chem.1964,17,1392.EastwoodTetrahedronLett.1970,5223.Burgstahler,BogerTetrahedron1976,32,309.14.[3,3]-SigmatropicRearrangements

ClaisenandCopeRearrangementExamplesEvansJ.Am.Chem.Soc.1975,97,4765.BurgstahlerJ.Am.Chem.Soc.1961,83,198.CarnduffJ.Chem.Soc.,Chem.Commun.1967,606.

Thio-ClaisenRearrangement

Anadvantageofthethio-Claisenrearrangementisthattheprecursorcanbedeprotonatedandalkylated.CoreyJ.Am.Chem.Soc.1970,92,5522.YamamotoJ.Am.Chem.Soc.1973,95,2693and4446.BlockJ.Am.Chem.Soc.1985,107,6731.TheCarrollReactionCarrollJ.Chem.Soc.1940,704,1266.HartungJ.Chem.Soc.1941,507.CopeJ.Am.Chem.Soc.1943,65,1992.TanabeJ.Am.Chem.Soc.1980,102,862.15.[2,3]-SigmatropicRearrangementsReview:ComprehensiveOrg.Syn.,Vol.6,pp834,873–908.Org.React.1994,46,105–209.-Analogousto[3,3]-sigmatropicrearrangementexceptitenlistsalocalizedcharge(anion)inplaceofadoublebond.ExamplesJuliaTetrahedronLett.1974,2077.LythgoeJ.Chem.Soc.,Chem.Commun.1972,757.EvansTetrahedronLett.1973,4691.

Amino-ClaisenRearrangement-Thisreactionoccursbestwhennitrogenisconvertedtotheammoniumsalt.GilbertTetrahedronLett.1984,25,2303.StilleJ.Org.Chem.1991,56,5578.NakaiChem.Lett.1990,2069.SatoJ.Am.Chem.Soc.1990,112,1999.II.OlefinSynthesisExemplifiedwithJuvenileHormone(保幼激素的合成）JuvenileHormone（HJ)1.TrostSynthesis:J.Am.Chem.Soc.1967,89,5292.2.SyntexSynthesis:J.Am.Chem.Soc.1968,90,6224.3.CoreySynthesis:J.Am.Chem.Soc.1968,90,5618.4.JohnsonSynthesis:J.Am.Chem.Soc.1968,90,6225.5.CoreySynthesis:J.Am.Chem.Soc.1970,92,6635,6636,6637.6.JohnsonSynthesis:J.Am.Chem.Soc.1970,92,4463.7.Stotter–KondoSynthesis:J.Am.Chem.Soc.1973,95,4444.J.Chem.Soc.,Chem.Commun.1972,1311.8.StillSynthesis:TetrahedronLett.1979,593.9.OtherSyntheses:(1).TrostSynthesisWadsworth–Horner–EmmonsReactionStereoselectivity-notmuchdifferencebetweenMeandH(secondatomstericeffect)-bothisomersobtainedfromtheWadsworth–Horner–Emmonsreaction(Modernimprovementsnowavailable)RetrosyntheticAnalysis-repeatingsubunitsrecognized-repeatingreactionsutilizedJ.Am.Chem.Soc.1967,89,5292.(2).SyntexSynthesisJ.Am.Chem.Soc.1968,90,6224.RobinsonAnnulationAlkylationDiastereoselectivityDirectedEpoxidationReactionFragmentationReactionSelectiveReduction-saturatedvs.a,b-unsaturatedcarbonyl-ringstrainassociatedwith5-memberedringcarbonylreleasedonreduction-attackfromleasthinderedfaceTHPProtectingGroup-ifRgroupcontainschiralcenters,diastereomersresult-removedbymildacidThermodynamicEnolate-severe1,3-diaxialinteractioninchair-likeT.S.axialalkylation-nostericincumberancetoaxialalkylationonleasthinderedfaceoftwistboatT.S.LiAlH(OtBu)3Reduction-largereagent,usuallyequatorialH–delivery-1,2-interaction(torsionalstrain)relativelyinvarianttoNu–size-1,3-stericinteractionhighlydependentonNu–size-duetoabsenceofaxialC(3)–H,largereagentnowgivesaxialdeliveryEpoxidation-inEt2O,coordinationofperacidtosolventgivesdeliveryfromtheleasthindereda-face-inCH2Cl2,H-bondingofOHtoperacidprovidesdeliverytothelessaccessibleb-face-TeranishiJ.Am.Chem.Soc.1979,101,159.FragmentationReaction-utilizedtocontrolC=Cbondstereochemistry-transperiplanarorientationofbreakingbonds-dictatesZolefingeometryinproduct3.CoreySynthesisDissolvingMetalReductionsCyclicPrecursorstoTrisubstitutedOlefinsOxidativeCleavageofEnolEthersLiAlH4ReductionofPropargylAlcoholsCuprateCouplingReactionsAllylicAlcoholOxidationJ.Am.Chem.Soc.1968,90,5618.StereospecificSynthesisofTrisubstitutedOlefinsMnO2Oxidation-mildoxidationofallylicalcohols-direct,mildmethodforoxidationtoamethylesterEpoxidation-selective-inpolarsolventthemoleculefoldsupsuchthattheterminalC=Cismoreaccessible4.JohnsonSynthesis:TrimethylpyridineJ.Am.Chem.Soc.1968,90,6225.5.CoreySynthesis:J.Am.Chem.Soc.1970,92,6635,6636.1,5-HShiftDiimideReduction-lesssubstitutedC=Creducedmorerapidly-generatedin-situ6.JohnsonSynthesis:J.Am.Chem.Soc.1970,92,4463.OlefinicKetalClaisenReaction-selectivitydependenton1,3-interactioninchair-likeT.S.-secondClaisenmoreselectiveduetolargerRgroupvs.CO2Me7.Stotter–KondoSynthesis:J.Am.Chem.Soc.1973,95,4444.J.Chem.Soc.,Chem.Commun.1972,1311.8.StillSynthesis:TetrahedronLett.1979,593.[2,3]-SigmatropicRearrangementChapter4ConversionofFunctionalGroups1.AdditionofCarbon-CarbonDoubleBonds2.HalogenationofAlcoholsGeneralMethodsOrg.Lett.,2002,4(4),553-555TCT/DMFMethodDevelopment2,4,6-trichloro[1,3,5]triazineTCTTable1.ConversionofAliphaticAlcoholsintotheCorrespondingAlkylHalidesa

Forcompleteconversionofthealcohol.b

Thecorrespondingchlorideisformedalso.Table2.ConversionofDiolsandUnsaturatedand-aminoAlcoholsintotheCorrespondingAlkylHalidesa

Forcompleteconversionofthealcohol.b

Thecorrespondingchlorideisformedalso.MechanismMe3SiCl

該方法對芐醇、伯醇、烯丙醇、叔醇，室溫下反應迅速，收率高。J.Org.Chem.1995,60,26383.FormationofAminesGeneralMethods與氮烯有關(guān)的重排反應SynthesisprimaryamineGabrielSynthesisHarshhydrolysisconditionsImprovementSynthesis,1990,8,735;1995,7,756Synlett,1996,2,179;Synth.Commun.,1999,29,2685SynthesisofArylaminesfromaminationofArylHalides

Development

EarlyPalladium-CatalyzedAmination該反應僅限于仲胺與電中性的鹵代苯。要求等當量的有機鈀催化劑。J.Am.Chem.Soc.,1994,116,5969-5970P.Patt,Hartiget.al.發(fā)現(xiàn)Pd可循環(huán)使用從1985到1994近10年沒有關(guān)于Pd催化胺化反應的報道。存在的問題：1）要將胺變成錫胺化物；2）不適應于伯胺；3）反應速度較慢；4）催化劑用量較大。

InitialTin-freeAminationofArXHartwigandBuchwald,Angew.Chem.Int.Edu.,1995,34,1348-1350;TetrahedronLett.1995,36,3609RoomTemperatureCatalyticAminationofArylIodidesJ.Org.Chem.1997,62,6066-6068JohnP.WolfeandStephenL.Buchwald*DepartmentofChemistry,MassachusettsInstituteofTechnology,Cambridge,Massachusetts02139Table2.RoomTemperatureCatalyticAminationofArylIodidesTable2.ContinuedAHighlyActiveCatalystforPalladium-CatalyzedCross-CouplingReactions:Room-TemperatureSuzukiCouplingsandAminationofUnactivatedArylChloridesDavidW.Old,JohnP.Wolfe,andStephenL.Buchwald*J.Am.Chem.Soc.1998,120,9722-9723AminationReactionsofArylHalideswithNitrogen-ContainingReagentsMediatedbyPalladium/ImidazoliumSaltSystemsGabrielaA.Grasa,MihaiS.Viciu,JinkunHuang,andStevenP.Nolan*DepartmentofChemistry,UniversityofNewOrleans,NewOrleans,Louisiana70148J.Org.Chem.2001,66,7729-7737Imes·HClImes:1,3-bis(2,4,6-trimethylphenyl)imidazol-2-ylideneIpr:1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene)ImidazoliumChlorideLigandsTable2.AminationofArylChlorideswithVariousAminesTable2ContinuedTable3.AminationInvolvingArylBromidesandIdodideswithVariousAminesMostinterestinginthesestudiesinvolvinganarylbearingbothchloroandiodo(orbromo)substituentsistheobservationthatbromoandiodofunctionalitiescanbeconvertedatroomtemperature(entries3and4)andtheremainingchlorofunctionalitycansubsequentlybeconvertedatmoreelevatedtemperatures.Thiscouldprovetobeasignificantadvantageinprocesschemistry.Table4.InfluenceofPalladium(0)/ImidazoliumSaltRatioonAminationReactionsTable5.AminationofChlopyridinesandBromopyridineswithVariousAminesGeneralcatalyticcycleforaminationreaction.Table6.AminationofArylChlorideswithBenzophenoneImineTable7.AminationofArylBromideswithBenzophenoneImineTable9.EffectoftheImidazoliumChloridesandBasesonN-ArylSubstitutionofIndolewithBromobenzeneTable10.AminationofArylBromideswithVariousIndoles

Thestandardaminationconditionsdidnotaffectthearylationofindoles.Table10ContinuedSynthesisofLinezolidIntermediateLinezolidismemberofanewclassofantibiotics.AnImprovedMethodforthePalladium-CatalyzedAminationofArylIodidesMayssamH.AliandStephenL.Buchwald*DepartmentofChemistry,MassachusettsInstituteofTechnology,Cambridge,Massachusetts02139J.Org.Chem.2001,66,2560-2565Table2.AminationofArylIodideswithNaOt-BuasBaseTable2.ContinuedTable3.AminationofArylIodideswithCs2CO3asBaseCs2CO3Pd-CatalyzedIntermolecularAmidationofArylHalides:TheDiscoverythatXantphosCanBeTrans-ChelatinginaPalladiumComplexJingjunYinandStephen

L.Buchwald*ContributionfromtheDepartmentofChemistry,MassachusettsInstituteofTechnology,Cambridge,Massachusetts02139J.AM.CHEM.SOC.2002,124,6043-6048

CuI,K3PO4Table1.Cu-CatalyzedAminationofArylBromidesTable1.ContinuedTable2.Copper-CatalyzedAminationofortho-SubstitutedAndHeteroarylBromidesTable3.IntramolecularCopper-CatalyzedAminationofArylHalidesTable4.Solvent-FreeCu-CatalyzedAminationofArylBromidesSolvent-freeAminoacid-mediatedGoldbergreactionsbetweenamidesandaryliodidesWeiDeng,Ye-FengWang,YanZou,LeiLiu*,

andQing-XiangGuo*DepartmentofChemistry,UniversityofScienceandTechnologyofChina,Hefei230026,ChinaTetrahedronLetters45(2004)2311–2315Table1.YieldsofthecouplingreactionbetweencaprolactamandiodobenzeneunderdifferentconditionsaIsolatedyield.b5mol%.c20mol%.Table3.YieldsoftheCuI-catalyzedcouplingreactionsbetweeniodobenzeneandvariousamides(baseK3PO4,solventdioxane,temperature100oC,reactiontime24h)Table4.YieldsoftheCuI-catalyzedcouplingreactionsbetweenvariousarylhalidesandamides(ligandglycine,baseK3PO4,solventdioxane,temperature100oC,reactiontime24h)MechanismPalladium-CatalyzedAminationofArylBromidesUsingTemperature-ControlledMicrowaveHeatingYiqiangWan,MathiasAlterman,AndersHallbergSynthesis,2002,11,1597-1600MatsLarhedandAndersHallbergDDT,6(8),406-416,2001Microwave-assistedHigh-speedchemistry:ANewTechniqueinDrugDiscoveryFigure2.Examplesofpalladium(Pd)-catalyzedHeckarylationsdemonstratingretainedregioselectivitiesunderMicrowaveinducedflash-heatingconditions.Microwave-assistedintramolecularandtwo-componentreactionsFigure4.Examplesoffastmicrowave-assistedorganicreactionsonpolymericsupports.Microwave-assistedmulti-componentreactionsThedrugdiscoveryprocessandtheforeseenimpactofmicrowavechemistryonautomatedmedicinal/combinatorialchemistryChapter5Application