高等有机合成-全套课件

高等有机合成

AdvancedOrganicSynthesis绪论一、有机合成的历史回顾二、有机合成化学的发展趋势三、学习内容和方法四、重要参考书及期刊五、课程安排一、有机合成的历史回顾1.尿素的合成（1828年，德国化学家Wohler）有机化学的开始2.颠茄酮的合成

1)1902年，德国化学家Willstatter(1915年获Noble化学奖）21steps,overallyield0.7%2）1917年，英国化学家Robinson(1947年获Noble化学奖）3steps,overallyield90%Robinson为什么能是发现这条合成路线？MannichReaction(1912)3.维生素B12的合成（Woodward,1977年）在Woodward及Eschenmoser

领导下,经过两个实验室，100多位科学家的共同努力，于1977年完成了维生素B12的全合成工作。将有机合成作为一种艺术展现在世人面前。因在1945-1954年人工合成了奎宁、类固醇、马钱子碱、羊毛甾醇、麦角碱等近20种复杂天然产物而1965年获Noble化学奖E.J.Corey,(1990年获Noble化学奖)

如果说Woodward一生奋斗的成就是将有机合成作为一种艺术展现在世人面前，那么Corey则是将有机合成从艺术转变成为科学的一个关键人物。他的逆合成分析是现代有机合成化学的重要基石，推动了20世纪70年代以来整个有机合成领域的蓬勃发展。逆合成分析(Retrosyntheticanalysis)

Woodward(1981)红霉素的全合成

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高立体选择性（HighStereoselectivity)原子经济性反应（AtomEconomicalReaction)绿色化学（GreenChemistry)二、有机合成化学的发展趋势1.新试剂、新反应、新方法的发现永无止境

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

缩合反应的研究2.与生命科学和材料科学的联系越来越紧密三、学习内容和方法内容1.对重要的基础有机反应要能够熟练运用新化合物的合成比葫芦画瓢逆合成分析跟踪文献，尽可能将最新的试剂、反应和方法应用于自己的研究工作中。3.学习别人的思路，创造性地借鉴和运用方法四、重要参考书及期刊参考书F.A.Carey著，王积涛译，高等有机化学，B.反应与合成，高等教育出版社，1986。岳保珍，李润涛，有机合成基础，北京医科大学出版社，2000。吴毓林，姚祝军，现代有机合成化学，科学出版社，2001。W.Carruthers

著，李润涛等译，有机合成的一些新方法，河南大学出版社，1991。黄宪，王彦广，陈振初，新编有机合成化学，化学工业出版社，2003。王咏梅等，高等有机化学习题解答，南开大学出版社，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、课程安排进度安排

2.讲授原则复习老反应，补充新反应，重点讲进展，强调学思路。考试

1）写综述一篇（近5年的进展）（40%）

2）笔试（60%）Chapter2FormationofCarbon-CarbonSingleBonds一、GeneralPrinciples烷化反应：E=烷化剂缩合反应：E=醛、酮、酯等Michael加成：E=Mannich

反应二、影响反应的主要因素

a.

反应底物（Substrate)-NO2>-COR>SO2R>-CN>-CO2R>-Ph,SOR

A和B至少要有一个是EWG

A和B应该能使其-碳上的H活化的基团，通常为吸电子基（ElectronwithdrawgroupEWG）。b.碱（Base）常用的碱：Ph3C->(Me2CH)2N->EtO->OH->R3N

碱的选择取决于底物的反应活性理想的碱：碱性强，亲核性弱，并不进攻那些较敏感的基团，另外能溶于非极性溶剂中。c.溶剂（Solvent)SolventO-alkylationC-alkylation反应速度常用的非质子极性溶剂（polaraproticsolvent):DMFDMSOHMPAd.亲电试剂（Electrophilicreagent)所有能与负碳离子发生反应的碳正离子或分子。例：RX,R-SO3H,RCO2Et,RCOR’

这四种影响因素之间是相互联系，相互影响的。在分析一个具体反应时，应该综合分析考虑这四种影响因素。

三、烷基化反应(Alkylation)1.O-alkylation&C-alkylationExample1Example2Degreeofsubstitutionofalkylatingagent:Example32.区域选择性（Regioselectivity)区域选择性受热力学控制和动力学控制的反应条件影响很大.热力学控制条件下主要生成取代基较多的烯醇;动力学控制条件下主要生成取代基较少的烯醇;Example1Example23.立体选择性（Steroselectivity)烯醇化合物的立体选择性形成,将为不对称合成提供平台.Example1Example2Example3Example44.二羰基化合物的-烷基化反应(-Alkylationof1,3-dicarbonylcompounds)J.Am.Chem.Soc.,1974,90,1082;1963,85,3237;1965,87,82.Example1Example2Example3继承与发展5.芳基卤化物与烯醇盐的反应(Reactionsofaromatichalidewithenolates)ExampleMechanism关键是要有形成苯炔的条件。6.酮和酯的烷基化反应(Alkylationsofketonesandesters)避免Aldol

缩合反应发生的方法：烷化剂要待酮完全转化为烯醇式后再加入。常用的碱：NaNH2,KNH2,NaH,Ph3CNa等；有副产物。

LDA,LTMP,LHMDS等效果很好。Example1Example2不对称酮的选择性烷基化反应(Selectivealkylationofasymmetricketones)在一个-位引入一个活化基(略）如：DieckmannReaction;Claisencondensation制成结构专属性的烯醇负离子在取代基较多的-位烷基化(烯醇硅醚法)碱性条件酸性条件在取代基较少的-位烷基化(烯胺法,StorkEnamineSynthesis)

通常，用活泼的卤代烷，可以高产率生成C-烷基化产物；但对于一般的卤代烃，C-烷基化产物收率较底。若用

LDA在低温下反应，则对各种卤代烃均可得到高收率的

C-烷基化产物。

对于不对称酮，主要在取代基较少的-位发生烷基化。Example1Example27.对映选择性烷基化反应（Enantioselective

alkylations)利用手性胺利用二甲基肼

扩展：二甲基腙锂化合物的另一应用二甲基腙锂化合物容易转化成有机铜化合物，而有机铜化合物在C-C键的形成中很有用。利用SAMP和RAMP若用RAMP，则得到另一种对映异构体。羧酸的-不对称烷基化Example8.极性翻转（Umpolung)俞凌翀，刘志昌，极性转换及其在有机合成中的应用，科学出版社，1991Example1安息香缩合Example2醛氰醇法Example31,3–二噻烷法不易发生Michael加成反应。Example4乙基乙硫甲基亚砜法1,4–二酮四、缩合反应(Condensation)AldolReactionMichaelAdditionMannichReactionClaisenCondensationDieckmann

CondrnsationDarzen’sReactionReformatslyreactionAldolReaction(condensation)1)经典Aldol

反应的两大缺点

不同醛、酮之间的反应常得到混合产物；立体选择性差2)定向醇醛缩合反应（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该方法是在酸性条件下反应；但立体选择性较差。3)有机小分子催化醇醛缩合反应（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手性金属配位化合物催化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

胺组份氨、伯胺、仲胺

醛组份

HCHO,PhCHO,RCHO可分别发生三、双、单Mannich

反应

活泼H

组份醛、酮、活泼亚甲基化合物、酚类化合物、杂环、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

一种酯的自身缩合Scopeofapplication

一种含-H的酯与一种不含-H的酯之间的缩合Examples

DirectedClaisencondensation5.DickmannCondensationChapter3FormationofCarbon-CarbonDouleBonds1.-Eleminationreactions（-消去反应）I.TheSyntheticMethodsofAlklenes

2.Pyrolytic

syneliminations（顺式热消去反应）Applications:SynthesisofterminalalkenesfromprimaryacetatesDisadvantages:HighreactiontemperatureCopereactionChugavereaction反应条件比对应的酯热消去温和。3.Wittigandrelatedreactions（Wittig

及有关反应）

WittigReaction

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

Mildreactionconditions;

Thepositionofthedoublebondisunambiguous.

FeaturesRepresentativeExamplesExample1Example2Example3Example4Mechanism[2+2]cycloaddition.Influenceofsolventontheselectivity

ActivityandstereoselectivityofYild

Schlössermodification:allowsthepreparationoftransvs.cisolefins.Schlösser

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反应及与有关稳定化钛试剂的亚甲基化反应）-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(亚砜-次磺酸酯重排：烯丙醇类化合物的合成)

Combinedwithalkylationofsulphoxidesthereactionprovidesaversatilesynthesisofdi-andtri-substitutedallylicalcoholsEvansandAndrews,Acc.Chem.Res.,1974,7,147-alkylationofallylic

alcohlosExample1Example26.Alkenesfromsulphones(由砜制备烯烃）-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(-内酯的脱羧反应）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、四取代烯烃的立体选择性合成）

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(

羧酸的氧化脱羧反应）Sheldon,R.A.,etal.,OrganicReactions,1972,19,279.Jahngen,B.G.E.,J.Org.Chem.,1974,39,1650.与Dieal-Alder反应结合，是制备环状烯烃的好方法。Example1TanzawaT.etal.TetrahedronLett.,1992,33,6783Example2Example310.Alkenesfromarylsulphonylhydrazones(由芳基磺酰腙制备烯烃）KolonkoK.,etal.J.Org.Chem.,1978,43,1404;AdlingtonR.M.,etal.Acc.Chem.Res.,1983,16,55MechanismLesssubstitutedalkeneExample1Example211.FragmentationReactions(裂解反应）X=leavinggroup,e.g.:-OSO2C6H4CH3-p,-OSO2CH3100%stereospecificExample12.OlefinInversionReactions(烯烃构型转换反应）

Deoxygenationofepoxides(withretentionofgeometry)Otherexamples13.Srereospecificsynthesisofalkenesfrom1,2-diols(由1,2-二醇立体选择性地合成烯烃）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

该方法对苄醇、伯醇、烯丙醇、叔醇，室温下反应迅速，收率高。J.Org.Chem.1995,60,26383.FormationofAminesGeneralMethods与氮烯有关的重排反应SynthesisprimaryamineGabrielSynthesisHarshhydrolysisconditionsImprovementSynthesis,1990,8,735;1995,7,756Synlett,1996,2,179;Synth.Commun.,1999,29,2685SynthesisofArylaminesfrom

aminationofArylHalides

Development

EarlyPalladium-CatalyzedAmination该反应仅限于仲胺与电中性的卤代苯。要求等当量的有机钯催化剂。J.Am.Chem.Soc.,1994,116,5969-5970P.Patt,Hartig

et.al.发现Pd可循环使用从1985到1994近10年没有关于Pd催化胺化反应的报道。存在的问题：1）要将胺变成锡胺化物；

2）不适应于伯胺；

3）反应速度较慢；

4）催化剂用量较大。

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