不对称催化氢化.docx
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不对称催化氢化.docx
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不对称催化氢化
第二章碳碳双键的不对称催化氢化及羰基还原反应
2.1碳碳双键的不对称催化氢化
2.1.1发展概况
60年代以前,以非均相催化为主。
非均相的不对称催化只能得到10-15%e.e.的产物。
1965年Wilkson发现了均相催化剂,Rh(Ph3P)3Cl,溶解度好,活性高。
1968年Honer和Knowles分别报道了双键的不对称均相催化氢化反应。
1971年Kagan取得了突破性的进展,用DIOP催化得到了72%e.e.的产物。
1972年Knowles用DIPAMP手性催化剂获得了大于95%e.e.的对映选择性。
随后催化剂种类越来越多,体系越来越完善,适用的底物越来越广。
2.1.2手性催化剂
手性配体
不对称反应,催化剂是重点,配体是关键。
催化氢化都是膦配体。
有如下三种途径合成手性膦配体。
手性中心在膦上,P-手性配体;手性中心在碳上,C-手性配体;既有膦又有碳手性中心的配体。
常见的手性膦配体
单齿配体
PAMPCAMPMonoPhos
双齿配体
DEGPHOSDuPHOSPNNP
RROPHOSNORPHOSBPPFA
CYCPHOS(R,R)-DIPAMP(S,S)-CHIRAPHOS
(R)-BINAP(S,S)-BPPMDIOP
(R,R)-DPCP(+)-DIPMC(2R,3R)-NORPHOS
(-)-MENO
BIPHEMPSpirOPBICP
中心金属
主要限于铑(Rh)和钌(Ru)两种贵金属,另外铱(Ir)有少量的应用。
手性铑(Rh)膦催化剂只对α-酰氨基丙烯酸衍生物的催化氢化有很好的结果,对其它底物对映体选择性很低。
手性钌(Ru)膦催化剂底物适用范围广,尤其是Noyori等发展的[Ru(BINAP)(OCOR)2]催化剂能用于C=C,C=O,C=N等的不对称氢化,得到特别优异的对映体选择性。
2.1.3不对称催化机理
手性铑(Rh)膦催化剂对α-酰氨基丙烯酸衍生物的氢化催化结果如下:
PhosphineLigand
%e.e.oftheproduct
R=C6H5
R=H
(R,R)-DIPAMP
96(S)
94(S)
(S,S)-CHIRAPHOS
99(R)
91(R)
(S,S)-NORPHOS
95(S)
90(R)
(R,R)-DIOP
85(R)
73(R)
(S)-BINAP
91(R)
98.5(R)a
(S,S)-BPPM
100(R)a
98(R)
(S)-BPPFA
93(S)
(S,S)-SKEWPHOS
92(R)
(S,S)-CYCPHOS
88(R)
(S,S)-Et-DuPHOS
99(S)
a.hydrogenateonofN-benzoylderivative
Halpern等人以及Brown等人对手性铑(Rh)膦催化剂的机理进行了详尽的研究。
烯烃能用Re面或者Si面与手性催化剂配位生成两个非对映体,氧化加成(K2)是速率控制步骤。
手性钌(Ru)膦催化剂催化机理
Ru(II)的配位数比Rh(I)大,可形成六配位数的八面体结构,后者只形成四面体结构。
机理更加复杂,形成单氢形式的活性中间体。
Halpern提出了机理如下
OrganicSyntheses,CV9,169
ASYMMETRICHYDROGENATIONOFALLYLICALCOHOLSUSINGBINAP-RUTHENIUMCOMPLEXES:
(S)-(−)-CITRONELLOL
[6-Octen-1-ol,3,7-dimethyl,(S)-]
SubmittedbyHidemasaTakaya1,TetsuoOhta1,Shin-ichiInoue2,MakotoTokunaga2,MasatoKitamura2,andRyojiNoyori2.
CheckedbyAndrewMadinandLarryE.Overman.
1.Procedure
Caution!
BINAP-Rucomplexesarerapidlyoxidizedinsolutioninthepresenceofair,andallproceduresshouldbecarriedoutunderanaerobicconditionsusingdegassedsolvents.
A.[(R)-2,2'-Bis(diphenylphosphino)-1,1'-binaphthyl]rutheniumdiacetate,Ru(OCOCH3)2[(R)-BINAP].Adry,150-mLSchlenktube(Note1)connectedtoasupplyofargon(Note2)isequippedwithaTeflon-coatedmagneticstirringbarandaglassstopper.Thevesselischargedwithbenzeneruthenium(II)chloridedimer,[RuCl2(benzene)]2,(800mg,1.60mmol)(Note3)and(R)-BINAP(1.89g,3.04mmol)(Note4),evacuated,andthenfilledwithargon.N,N-Dimethylformamide(DMF)(30mL)(Note5)isintroducedwithahypodermicsyringeunderthestreamofargon.Thereddishbrownsuspensionisstirredat100°Cfor10min(Note6)andtheresultingclearreddishbrownsolution(Note7)iscooled.Anotherdry,60-mLSchlenktubeischargedwithsodiumacetate(5.20g,63.4mmol)andmethanol(50mL)(Note8)andthesolutionisdegassedbythreefreeze-thawcycles.ItistransferredintotheDMFsolutionofBINAP-Ru(II)complexpreparedaboveviacannulaandthesolutionisstirredat25°Cfor5min.Tothesolutionareaddedwater(50mL)andtoluene(25mL)underargonandtheresultingtwolayersaremixedbyvigorousstirring.Theupperorganiclayeristransferredintoanother200-mLSchlenktube(Note9)usingacannula.Theaqueouslayerisvigorouslymixedwithtoluene(25mL)andtheupperorganiclayerisagaintransferredintotheSchlenktube.Thisprocedureisrepeatedoncemore.Thecombinedorganiclayersarewashedwithfour10-mLportionsofwater(Note10).Removalofthesolventat1mmand40°Cfor30minwithvigorousstirring(Note11)andevacuationat0.1mmand25°Cfor12hrgives2.54–2.67gofsolidRu(OCOCH3)2[(R)-BINAP](99–104%crudeyieldbasedonBINAP)(Note12).Itisdissolvedintoluene(20–25mL)withheating.Hexane(80–100mL)isaddedverycarefullytothesolutiondownthesideoftheflasktoformtwolayers.Thesolutionisleftat25°Cfor12hrandthenat4°Cfor3daystogivesolidmaterial.Removalofthemotherliquorisfollowedbywashingwithhexane(20mL)anddryingunderreducedpressuretoafford1.8–2.2g(71–85%yield)ofpureRu(OCOCH3)2[(R)-BINAP]asfineyellowneedlesorpowderycrystals;mp188–190°Cdec(Note13).
B.(S)-(−)-Citronellol.Geraniol(12.9mL,74mmol)(Note14)and95%methanol(15mL)(Note15)areplacedinadry,80-mLSchlenktubeandthemixtureisdegassedbyfivefreeze-thawcycles.Anotherdry,80-mLSchlenktube,equippedwitharubberseptumandamagneticstirringbarandfilledwithargon,ischargedwithRu(OCOCH3)2[(R)-BINAP](45mg,53μmol)(Note16).Thesystemisevacuatedandrefilledwithargonthreetimes.Byuseofacannula,thesolutionofgeraniolinmethanolisintroducedintotheSchlenktubecontainingtherutheniumcomplexunderargon.Theresultinglightyellowsolution(Note17)isthentransferredwithacannulaintoa100-mL,stainlesssteelautoclaveequippedwithaglassvessel(Note18)andamagneticstirringbarbyuseofaslightpositivepressureofargon.Theautoclaveisconnectedtoahydrogensource(Note19)usingthearrangementshowninFigure1,andtheairoriginallypresentinthegas-inlettubeisreplacedbyhydrogen(Note20).ValveAisopenedandhydrogenisintroduceduntilpressuregaugeBindicates100atm.Thesolutionisstirredat20°Cfor8–16hr(Note21).Duringhydrogenation,thehydrogenpressureiskeptabove90atmbytheoccasionalintroductionofhydrogenfromthecylinder(Note22).Whenconsumptionofhydrogenceases,thegas-inlettubeisdisconnected.ExcesshydrogeniscarefullyreleasedbyopeningvalveAandthentheapparatusisdisassembled.Theyellowishbrowncontents(Note23)aretransferredtoa50-mLflaskandthesolventisremovedbyarotaryevaporator.Theresidue(Note24)isdistilledunderreducedpressuretogive10.7–11.2g(93–97%yield)of(S)-(−)-citronellolin98%ee(Note25)and(Note26);bp58–62°C/0.01mm.
Figure1
2.Notes
1.Beforeuse,allapparatusisdriedovernightina120°Coven.
2.Argon(99.998%)ispurifiedbypassingthroughaBASFcatalystRC-11columnat80°Candthenthrough4Åmolecularsieves.
3.[RuCl2(benzene)]2,availablefromAldrichChemicalCompany,Inc.,isusedwithoutpurification.
4.BINAP[2,2'-bis(diphenylphosphino)-1,1'-binaphthyl]iscommerciallyavailableorcanbepreparedaccordingtoaliteratureprocedure.3Thediphosphineisslowlyoxidizedinairtogivethecorrespondingmono-anddiphosphineoxidesthatcanberemovedbycolumnchromatography(silicagel,benzene)underaninertatmosphere.
5.GuaranteedgradeDMF,availablefromNACALAITESQUE,Inc.,isdistilledover4Åmolecularsievesunderargonbeforeuseandstoredina100-mLSchlenktube.Itisdegassedbythreefreeze-thawcycles.
6.Reactionatahighertemperatureforalongerperiodleadstoformationoftherutheniumcarbonylcomplex[IR(KBr)1964cm−1].
7.ThesolutionmaybeacrudemixtureofcationicBINAP-Ru(II)complexessuchas[RuCl(BINAP)(DMF)3]Cland[Ru(BINAP)(DMF)4]Cl2.Physicalpropertiesincludeconductivity,27Scm2/mol(DMF);31PNMR(4:
1DMF-CDCl3)δ:
60.6(d,J=46),61.4(d,J=46),61.8(s).The(R)-BINAP-Ru(II)complexobtainedbyremovalofthesolventcancatalyzehydrogenationofgeraniol(98.7%purecommercialgeraniolcontaining1.3%ofnerol,distilledfrom4Åmolecularsieves).However,inadditionto(S)-citronellolin95–96%ee,dihydrocitronellol,anoverreductionproduct,isobtainedin3–7%yield(1.1Msubstratein95%aqueousmethanol,1.7mMcatalyst,100atmofH2,20°C,8hr).
8.Guaranteedgrademethanolisdistilledunderargon.
9.Thediameterisabout4cm.
10.Theextractionproceduremustbecarriedoutunderanargonatmosphere.
11.Underreducedpressure,thesolutionsometimesfoams.ThiscanbeavoidedbyheatingthetoppartoftheSchlenktubewithahotairgun.
12.CrudeBINAP-Rucomplexwithconsistentspectralcharacteristicscanbeusedforhydrogenationofgeraniol(98.7%purecommercialgeraniolcontaining1.3%ofnerol,distilledfrom4Åmolecularsieves,4.7Msubstratein95%aqueousmethanol,2.8mMRu(OCOCH3)2[(R)-BINAP],100atmofH2,20°C,8hr),togive(S)-citronellolin96%ee,97%isolatedyield.
13.Theproducthasthefollowingspectralproperties:
1HNMR(CDCl3)δ:
1.80(s,2OCOCH3),6.47–7.84(m,aromaticprotons);31PNMR(CDCl3)δ:
65.13(s);13CNMR(CDCl3)δ:
23.50,125.2–138.3,188.1;IR(CH2Cl2)cm−1:
1452,1518.Ananalyticalsampleispreparedbydryingat110°Cand0.01mmfor12hr:
CalcdforC48H38O4P2Ru:
C,68.5;H,4.6.Found:
C,68.4;H,4.5.
14.Puregeraniolisobtainedbyfractionaldistillationusinga1000theoreticalplatecolumn.Thecheckersobtainedgeraniol,>99.5%puritybyGCanalysis,fromFlukaChemicalCompanyanduseditdirectly.
15.The95%methanolispreparedbymixingdistilled,guaranteedmethanol(95mL)andwater(5mL).Ifabsolutemethanolor90%aqueousmethanolisusedassolvent,somewhatlongerreactiontimesareneeded.
16.Thecomplexcanbestoredunderargonwithoutnoticeablelossofcatalyticactivity.Itisweighedunderanargonatmosphere.
17.Therutheniumcomplexismoderatelysolubleinmethanol.Ultrasonicstirringisemployedforcompletesolution.
18.Aglassvesselisusedforkeepingthereactionmixtureawayfromthestainlesssteelwall.Thereactionsystemisevacuatedandfilledwithargonthreetimesbeforeuse.
19.Thepurityofhydrogen(NipponSansoCo.)usedbythesubmittersis99.99999%.Thecheckersusedhydrogenof99.99%purity.
20.Thegas-inlettubeisattachedtotheautoclaveandthenthemainvalveofthecylinderisopened.Afterclosingthemainvalveofthecylinder,theconnectorofthegas-inlettubeisloosenedtoreleasehydrogenpressureandtightenedimmediately.Thisprocedureisrepeatedfivetimes.
21.To
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