高等有機合成

AdvancedOrganicSynthesis緒論一、有機合成的歷史回顧二、有機合成化學的發展趨勢三、學習內容和方法四、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.顛茄酮的合成

1)1902年，德國化學家Willstatter(1915年獲Noble化學獎）21steps,overallyield0.7%2）1917年，英國化學家Robinson(1947年獲Noble化學獎）3steps,overallyield90%Robinson為什么能是發現這條合成路線？MannichReaction(1912)3.維生素B12的合成（Woodward,1977年）在Woodward及Eschenmoser

領導下,經過兩個實驗室，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展現在世人面前。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展現在世人面前，那么Corey則是將有機合成從藝術轉變成為科學的一個關鍵人物。他的逆合成分析是現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域的蓬勃發展。逆合成分析(Retrosyntheticanalysis)

Woodward(1981)紅霉素的全合成

Y.Kishi(1987)海葵毒素的全合成

S.L.Schreiberetal(1993)FK-1012的全合成

K.C.Nicolaou&S.L.Schreiber（1994）

紫杉醇（Taxol)的全合成5.K.C.Nicolaou&S.L.Schreiber

K.C.Nicolaou,etal.

Theartandscienceoftotalsynthesisatthedawnoftwenty-firstcentury,Angew.Chem.Int.Ed.Engl.,2002,39,44

S.L.Schreiber,etal.

Target-orientedanddiversity-orientedorganicsynthesisindrugdiscovery,Science,2000,287,1964高立體選擇性（HighStereoselectivity)原子經濟性反應（AtomEconomicalReaction)綠色化學（GreenChemistry)二、有機合成化學的發展趨勢1.新試劑、新反應、新方法的發現永無止境

Epibatidine

的研究

Y(OTf)3-catalyzednovelMannichreactionofN-alkoxy-carbonylpyrroles,formaldehydeandprimaryaminehydrochlorides

C.X.Zhuan,J.C.Dong,T.M.Cheng,R.T.Li*,TetrahedronLetters,2001,43(3),461-463

Aldol

縮合反應的研究2.與生命科學和材料科學的聯系越來越緊密三、學習內容和方法內容1.對重要的基礎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，創造性地借鑒和運用方法四、重要參考書及期刊參考書F.A.Carey著，王積濤譯，高等有機化學，B.反應與合成，高等教育出版社，1986。岳保珍，李潤濤，有機合成基礎，北京醫科大學出版社，2000。吳毓林，姚祝軍，現代有機合成化學，科學出版社，2001。W.Carruthers

著，李潤濤等譯，有機合成的一些新方法，河南大學出版社，1991。黃憲，王彥廣，陳振初，新編有機合成化學，化學工業出版社，2003。王詠梅等，高等有機化學習題解答，南開大學出版社，2002。DaleL.Boger,ModernOrganicSynthesis,TheScrippsResearchInstitute,TsriPress,1999.ComprehensiveOrganicSynthesis,Vol.1-9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，強調學思路。考試

1）寫綜述一篇（近5年的進展）（40%）

2）筆試（60%）Chapter2FormationofCarbon-CarbonSingleBonds一、GeneralPrinciples烷化反應：E=烷化劑縮合反應：E=醛、酮、酯等Michael加成：E=Mannich

反應二、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EWG

A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。c.溶劑（Solvent)SolventO-alkylationC-alkylation反應速度常用的非質子極性溶劑（polaraproticsolvent):DMFDMSOHMPAd.親電試劑（Electrophilicreagent)所有能與負碳離子發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.區域選擇性（Regioselectivity)區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繼承與發展5.芳基鹵化物與烯醇鹽的反應(Reactionsofaromatichalidewithenolates)ExampleMechanism關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

縮合反應發生的方法：烷化劑要待酮完全轉化為烯醇式后再加入。常用的堿：NaNH2,KNH2,NaH,Ph3CNa等；有副產物。

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制成結構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，可以高產率生成C-烷基化產物；但對于一般的鹵代烴，C-烷基化產物收率較底。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-烷基化產物。

對于不對稱酮，主要在取代基較少的-位發生烷基化。Example1Example27.對映選擇性烷基化反應（Enantioselective

alkylations)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體。羧酸的-不對稱烷基化Example8.極性翻轉（Umpolung)俞凌翀，劉志昌，極性轉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)經典Aldol

反應的兩大缺點

不同醛、酮之間的反應常得到混合產物；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.ExamplesofmorerecentmethodstocontrolboronenolategeometryAldolCondensationwithChiral

Enolates

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（SmallOrganicMoleculesCatalysted

AldolReactions)NovelSmallOrganicMoleculesforaHighlyEnantioselectiveDirectAldolReactionJ.AM.CHEM.SOC.2003,125,5262-5263ZhuoTang,?,?FanJiang,§Luo-TingYu,?XinCui,?Liu-ZhuGong,*,?Ai-Qiao

Mi,?Yao-Zhong

Jiang,?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’sWorkSmallOrganicMoleculecatalyzedasymmetricMichaelreactionsTheFirstEnantioselective

Organocatalytic

Mukaiyama-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、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.TheSyntheticMethodsofAlklenes

2.Pyrolytic

syneliminations（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

及有關反應）

WittigReaction

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

Mildreactionconditions;

Thepositionofthedoublebondisunambiguous.

FeaturesRepresentativeExamplesExample1Example2Example3Example4Mechanism[2+2]cycloaddition.Influenceofsolventontheselectivity

ActivityandstereoselectivityofYild

Schl?ssermodification:allowsthepreparationoftransvs.cisolefins.Schl?sser

Angew.Chem.,Int.Ed.Eng.1966,5,126.Anextensionofthismethod

Anextensionofthismethodcanbeusedtoprepareallylicalcohols.Insteadofbeing

protonated,the-oxido

ylideisallowedtoreactwithformaldehyde.The-oxidoylideandformaldehydereacttogive,onwarming,anallylicalcohol.Entry12isanexampleofthisreaction.ThereactionisvaluableforthestereoselectivesynthesisofZ-allylicalcoholsfromaldehydes

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.-Arbuzov

Rearragement-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反應及與有關穩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-sulphenate

rearragement: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-alkylationofallylic

alcohlosExample1Example26.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反應結合，是制備環狀烯烴的好方法。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(烯烴構型轉換反應）

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.RobinsonAnnulationAlkylation

DiastereoselectivityDirectedEpoxidationReactionFragmentationReactionSelectiveReduction-saturatedvs.a,b-unsaturatedcarbonyl-ringstrainassociatedwith5-memberedringcarbonylreleasedonreduction-attackfromleasthinderedfaceTHPProtectingGroup-ifRgroupcontainschiralcenters,diastereomersresult-removedbymildacidThermodynamicEnolate-severe1,3-diaxialinteractioninchair-likeT.S.axialalkylation-nosteric

incumberancetoaxialalkylationonleasthinderedfaceoftwistboatT.S.LiAlH(OtBu)3Reduction-largereagent,usuallyequatorialH–delivery-1,2-interaction(torsionalstrain)relativelyinvarianttoNu–size-1,3-stericinteractionhighlydependenton

Nu–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.Olefinic

Ketal

ClaisenReaction-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與氮烯有關的重排反應SynthesisprimaryamineGabrielSynthesisHarshhydrolysisconditionsImprovementSynthesis,1990,8,735;1995,7,756Synlett,1996,2,179;Synth.Commun.,1999,29,2685SynthesisofArylaminesfrom

aminationofArylHalides

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,Hartig

et.al.發現Pd可循環使用從1985到1994近10年沒有關于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-freeAminationofArX

HartwigandBuchwald,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.AminationInvolvingArylBromidesandIdodideswithVariousAmines

Mostinterestinginthesestudiesinvolvinganarylbearingbothchloroandiodo(orbromo)substituentsistheobservationthatbromoandiodofunctionalitiescanbeconvertedatroomtemperature(entries3and4)andtheremainingchlorofunctionalitycansubsequentlybeconvertedatmoreelevatedtemperatures.Thiscouldprovetobeasignificantadvantageinprocesschemistry.Table4.InfluenceofPalladium(0)/ImidazoliumSaltRatioonAminationReactionsTable5.AminationofChlopyridinesandBromopyridineswithVariousAminesGeneralcatalyticcycleforaminationreaction.Table6.AminationofArylChlorideswithBenzophenone

ImineTable7.AminationofArylBromideswithBenzophenone

ImineTable9.EffectoftheImidazoliumChloridesandBasesonN-ArylSubstitutionofIndolewithBromobenzeneTable10.AminationofArylBromideswithVariousIndoles

Thestandardaminationconditionsdidnotaffectthearylationofindoles.Table10ContinuedSynthesisofLinezolidIntermediate

Linezolidismemberofanewclassofantibiotics.AnImprovedMethodforthePalladium-CatalyzedAminationofArylIodidesMayssamH.AliandStephenL.Buchwal