高等有機(jī)合成

AdvancedOrganicSynthesis緒論一、有機(jī)合成的歷史回顧二、有機(jī)合成化學(xué)的發(fā)展趨勢三、學(xué)習(xí)內(nèi)容和方法四、重要參考書及期刊五、課程安排一、有機(jī)合成的歷史回顧1.尿素的合成（1828年，德國化學(xué)家Wohler）有機(jī)化學(xué)的開始2.顛茄酮的合成

1)1902年，德國化學(xué)家Willstatter(1915年獲Noble化學(xué)獎）21steps,overallyield0.7%2）1917年，英國化學(xué)家Robinson(1947年獲Noble化學(xué)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(dǎo)下,經(jīng)過兩個實(shí)驗(yàn)室，100多位科學(xué)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(jī)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(fù)雜天然產(chǎn)物而1965年獲Noble化學(xué)獎E.J.Corey,(1990年獲Noble化學(xué)獎)

如果說Woodward一生奮斗的成就是將有機(jī)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(jī)合成從藝術(shù)轉(zhuǎn)變成為科學(xué)的一個關(guān)鍵人物。他的逆合成分析是現(xiàn)代有機(jī)合成化學(xué)的重要基石，推動了20世紀(jì)70年代以來整個有機(jī)合成領(lǐng)域的蓬勃發(fā)展。逆合成分析(Retrosyntheticanalysis)

Woodward(1981)紅霉素的全合成

Y.Kishi(1987)?？舅氐娜铣?/p>

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(jīng)濟(jì)性反應(yīng)（AtomEconomicalReaction)綠色化學(xué)（GreenChemistry)二、有機(jī)合成化學(xué)的發(fā)展趨勢1.新試劑、新反應(yīng)、新方法的發(fā)現(xiàn)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(yīng)的研究2.與生命科學(xué)和材料科學(xué)的聯(lián)系越來越緊密三、學(xué)習(xí)內(nèi)容和方法內(nèi)容1.對重要的基礎(chǔ)有機(jī)反應(yīng)要能夠熟練運(yùn)用新化合物的合成比葫蘆畫瓢逆合成分析跟蹤文獻(xiàn)，盡可能將最新的試劑、反應(yīng)和方法應(yīng)用于自己的研究工作中。3.學(xué)習(xí)別人的思路，創(chuàng)造性地借鑒和運(yùn)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(jī)化學(xué)，B.反應(yīng)與合成，高等教育出版社，1986。岳保珍，李潤濤，有機(jī)合成基礎(chǔ)，北京醫(yī)科大學(xué)出版社，2000。吳毓林，姚祝軍，現(xiàn)代有機(jī)合成化學(xué)，科學(xué)出版社，2001。W.Carruthers

著，李潤濤等譯，有機(jī)合成的一些新方法，河南大學(xué)出版社，1991。黃憲，王彥廣，陳振初，新編有機(jī)合成化學(xué)，化學(xué)工業(yè)出版社，2003。王詠梅等，高等有機(jī)化學(xué)習(xí)題解答，南開大學(xué)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(jìn)度安排

2.講授原則復(fù)習(xí)老反應(yīng)，補(bǔ)充新反應(yīng)，重點(diǎn)講進(jìn)展，強(qiáng)調(diào)學(xué)思路。考試

1）寫綜述一篇（近5年的進(jìn)展）（40%）

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

反應(yīng)二、影響反應(yīng)的主要因素

a.

反應(yīng)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(yīng)該能使其-碳上的H活化的基團(tuán)，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(yīng)活性理想的堿：堿性強(qiáng)，親核性弱，并不進(jìn)攻那些較敏感的基團(tuán)，另外能溶于非極性溶劑中。c.溶劑（Solvent)SolventO-alkylationC-alkylation反應(yīng)速度常用的非質(zhì)子極性溶劑（polaraproticsolvent):DMFDMSOHMPAd.親電試劑（Electrophilicreagent)所有能與負(fù)碳離子發(fā)生反應(yīng)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(yīng)時(shí)，應(yīng)該綜合分析考慮這四種影響因素。

三、烷基化反應(yīng)(Alkylation)1.O-alkylation&C-alkylationExample1Example2Degreeofsubstitutionofalkylatingagent:Example32.區(qū)域選擇性（Regioselectivity)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.熱力學(xué)控制條件下主要生成取代基較多的烯醇;動力學(xué)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(yīng)(-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(yīng)(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(yīng)(Alkylationsofketonesandesters)避免Aldol

縮合反應(yīng)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(yīng)(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(fù)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(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。Example1Example27.對映選擇性烷基化反應(yīng)（Enantioselective

alkylations)利用手性胺利用二甲基肼

擴(kuò)展：二甲基腙鋰化合物的另一應(yīng)用二甲基腙鋰化合物容易轉(zhuǎn)化成有機(jī)銅化合物，而有機(jī)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(jī)合成中的應(yīng)用，科學(xué)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(yīng)。Example4乙基乙硫甲基亞砜法1,4–二酮四、縮合反應(yīng)(Condensation)AldolReactionMichaelAdditionMannichReactionClaisenCondensationDieckmann

CondrnsationDarzen’sReactionReformatslyreactionAldolReaction(condensation)1)經(jīng)典Aldol

反應(yīng)的兩大缺點(diǎn)

不同醛、酮之間的反應(yīng)常得到混合產(chǎn)物；立體選擇性差2)定向醇醛縮合反應(yīng)（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(yīng)；但立體選擇性較差。3)有機(jī)小分子催化醇醛縮合反應(yīng)（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(fā)生三、雙、單Mannich

反應(yīng)

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(yīng)）I.TheSyntheticMethodsofAlklenes

2.Pyrolytic

syneliminations（順式熱消去反應(yīng)）Applications:SynthesisofterminalalkenesfromprimaryacetatesDisadvantages:HighreactiontemperatureCopereactionChugavereaction反應(yīng)條件比對應(yīng)的酯熱消去溫和。3.Wittigandrelatedreactions（Wittig

及有關(guān)反應(yīng)）

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(yīng)及與有關(guān)穩(wěn)定化鈦試劑的亞甲基化反應(yīng)）-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(nèi)酯的脫羧反應(yīng)）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(yīng)）Sheldon,R.A.,etal.,OrganicReactions,1972,19,279.Jahngen,B.G.E.,J.Org.Chem.,1974,39,1650.與Dieal-Alder反應(yīng)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(yīng)）X=leavinggroup,e.g.:-OSO2C6H4CH3-p,-OSO2CH3100%stereospecificExample12.OlefinInversionReactions(烯烴構(gòu)型轉(zhuǎn)換反應(yīng)）

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(yīng)迅速，收率高。J.Org.Chem.1995,60,26383.FormationofAminesGeneralMethods與氮烯有關(guān)的重排反應(yīng)SynthesisprimaryamineGabrielSynthesisHarshhydrolysisconditionsImprovementSynthesis,1990,8,735;1995,7,756Synlett,1996,2,179;Synth.Commun.,1999,29,2685SynthesisofArylaminesfrom

aminationofArylHalides

Development

EarlyPalladium-CatalyzedAmination該反應(yīng)僅限于仲胺與電中性的鹵代苯。要求等當(dāng)量的有機(jī)鈀催化劑。J.Am.Chem.Soc.,1994,116,5969-5970P.Patt,Hartig

et.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(yīng)的報(bào)道。存在的問題：1）要將胺變成錫胺化物；

2）不適應(yīng)于伯胺；

3）反應(yīng)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