Heck反应及金属催化偶联反应课件.ppt

1、Heck 反应反应南京航空航天大学南京航空航天大学 仿生结构与材料防护研究所仿生结构与材料防护研究所汝杰过渡金属催化的交叉偶联反应过渡金属催化的交叉偶联反应Transition Metal Catalyzed Cross CouplingAABBOrganic ChemistThe formation of carboncarbon bonds is a fundamentalreaction in organic synthesis the efficiency of which hasinterested organic chemists for a long time ago.Aryla

2、rylbond formation has been known for more than a century andwas one of the first reactions involving a transition metal.1Modern synthetic chemistry is also sustained by the useof transition-metal catalysts as powerful tools for carboncarbon bond-forming processes.2 Among these,carboncarbon coupling

3、reactions through the activationof carbonhydrogen bonds,3 as well as addition reactions,4have experienced an increasing interest in the preparation ofmolecules,the access to which is not so straightforwardusing other methodologies.On the other hand,thetransition-metal catalysed carboncarbon bond for

4、mationdeveloped in the 1970s represented a milestone in syntheticorganic chemistry that allowed the cross coupling ofsubstrates in ways that would have previously been thoughtimpossible2010 Nobel prize 瑞典皇家科学院说，这三名科学家因在有机合成领域中瑞典皇家科学院说，这三名科学家因在有机合成领域中钯催化交叉偶钯催化交叉偶联反应联反应方面的卓越研究获奖。这一成果广泛应用于制药、电子工业和先方面的卓

5、越研究获奖。这一成果广泛应用于制药、电子工业和先进材料等领域，可以使人类造出复杂的有机分子。进材料等领域，可以使人类造出复杂的有机分子。赫克赫克,79,79岁，美国特拉华大学名誉教授；根岸荣一岁，美国特拉华大学名誉教授；根岸荣一,75,75岁岁,美国普渡大美国普渡大学化学教授；铃木彰学化学教授；铃木彰,80,80岁岁,日本札幌北海道大学教授。日本札幌北海道大学教授。Glaser(Hay)CouplingSuzuki CouplingPd or NiBaseR1X2RB(OH)2+1RR2R1HXR2+R1R2Pd-Complex,CuIAmineSonogashira ReactionAmin

6、ation ReactionStille reactionThe Kumada Coupling was the first Pd or Ni-catalyzed cross coupling reaction,developed in 1972.Kumada reactionNegishi reactionFukuyama Coupling 通常把在碱性条件下钯催化的芳基或乙烯基卤代物和活性烯烃之间的偶联反应称为Heck反应反应。自从20世纪60年代末Heck 和Morizoki独立发现该反应以来,通过对催化剂和反应条件的不断改进使其的应用范围越来越广泛,使该反应已经成为构成C-C键的重要反

7、应之一。另外，Heck反应具有很好的Trans选择性R XPd(0)ZRZX=I,Br,OTf,etcZ=H,R,Ar,CN,CO2R,OR,OAc,NHAc,etc 研究表明，Heck反应的机理有一定的规律，通常认为反应共分四步：（a）氧化加成（Oxidative addition）:RX(R为烯基或芳基，X=I TfO Br Cl)与Pd0L2的加成，形成Pd配合物中间体；（b）配位插入（Cordination-insertion）:烯键插入Pd-R键的过程；（c）-H的消除；（d）催化剂的再生：加碱催化使重新得到Pd0L2。XCO2EtPdLnHbHaHcCO2EtHbHcPdLnXHa

8、HbCO2EtHcPdLnXHbCO2EtHcHaPdLnXCO2EtHbHcEAaPdLnXHcCO2EtHaHbPhPdLnXHcCO2EtHbPhHaHaCO2EtHcHbPdLnXCO2EtHaHcZBb 总的说来，Heck反应可以分为两大类：分子内反应和分子间反应。第一篇该反应的报道是Heck 在1972年发表的。I+Pd(OAc)2(20 mol%)nBu3N(1 eq)NMP,100C,2hNolley,J.P.;Heck,R.F.;Tetrahedron 1972,37,2320Mori 和 Ban于1977年首次报道了分子内的Heck反应：BrNAcCO2MeNAcCO2Me

9、Pd(OAc)2(2 mol%)PPh3,DMFTMEDA(2 equaiv)125C,5h43%Indole product formed asresult of Pd-H isomerizationof product clefinMori,M.;Ban,K.;Tetrahedron 1977,12,10372.分子内的分子内的Heck反应反应2.1 生成烯基取代的反应生成烯基取代的反应该类反应主要用于生成环外双键。环外双键是合成上一大难题，该反应成功的应用具有重大意义。目前已有合成的报道。MeOOOMeINONCO2MeOMeMeOOOMeNONCO2MeOMePd(PPh3)4(cat

10、)NEt3(12 eq)MeCN,80C,10h90%Danishefsky,S.J.J.Am.Chem.Soc.1993,115,6094该反应还被Danishefsky应用到全合成Taxol上。OTfOOTBSOOOHOOTBSOOOHPd(PPh3)4(1.1 eq)K2CO3,MeCN,85C49%Danishefsky,S.J.J.Am.Chem.Soc.1996,118,2843（紫杉醇）分子内分子内Heck反应化生成环外双键反应化生成环外双键IOMeOMeON ONCO2MeOMeOMeNOMeOONCO2MeOMePd(PPh3)4,NEt3(12eq)MeCN,80,10h1

11、2A stirred solution of 1,triethylmine and catalytic tetrakispalladium(0)in 2.4 mL of acetonitrile was heated at 80 in a sealed tube under an argon atmosphere for 10 h.The reaction mixture turned dark orange after ca10 minand the catalyst plated out on the walls of the tube as a shiny layer of pallad

12、ium metal upon completion of the reactionThe reaction mixture was cooled to room temperaturethe reaction was quenched with aqueous NaHCO3andthe mixture was extracted with EtOAc The organic extracts were washed with aqueous NaHSO3 water and brine and dried over MgSO4 Filtrationconcentrationand purifi

13、cation of the orange residue by flash column chromatography gave 66mg of19 as acolorless solidmp 193-194 Rf=0.292.2 形成季碳中心的反应形成季碳中心的反应 从20世纪80年代早期研究以来得到了广泛的应用。1989年，Shibasaki 和Overman 首先报道不对称Heck反应。ICO2MeCO2MeHPd(OAc)2(3 mol%)(R)-BINAP(9 mol%)cyclohexene(6 mol%)74%(46%ee)Ag2CO3(2 eq)NMP,60CJ.Org.Che

14、m.1989,54,4738 同一年，Overman及其工作组首先利用Heck 反应合成了手性季碳原子。OOTfPd(OAc)2(10 mol%)(R,R)-DIOP(10 mol%)Et3N,C6H6,rtO90%(45%ee)J.Org.Chem.19891989,54,5846 像天然产物physostigmine的合成，成功的运用和Heck反应构成手性的季碳中心。MeOINMeOOTIPSPd2(dba)3-CHCl3(10 mol%)(S)-BINAP(23 mol%)PMP,DMA,100CMeONMeOTIPSO3 M HClTHF,rtMeONMeCHOOMeNH3Cl,Et3

15、NLiAlH4,THF,reflux84%(95%ee)(88%)MeONMeNMeH(-)-esermethole1)BBr3,CH2Cl2,rt2)Na,Et2O,MeNCO(31%)(-)-physostigmineMeNHCO2NMeNMeHMatsuura,T.;Overman,L.E.J.Am.Chem.Soc.1998,120,65002.2.1 分子内不对称分子内不对称Heck反应反应M eOINHOO T IP S10%P d2(db a)3,23%(s)-B IN A P,C H C l31,2,2,6,6-pentam eth ylpiperidine,D M A,100

16、 oCM eONHOO TIP S12A mixture of Pd2(dba)3CHCl3(360 mg,0.347 mol),(s)-BINAP(504 mg,0.809 mol),and N,N-dimethylacetamide(DMA,21 mL)was stirred at room temperature for 65 min.To the resulting orange solution was added a solution of compound 1(1.82 g,3.51 mol),1,2,2,6,6-pentamethylpiperidine(3.2 mL,18 m

17、mol),and DMA(18 mL),and the reaction was heated at 100 for 90 min.The result dark solution was poured into half-saturated aqueous NaHCO3(100 mL)and extracted with ether(3 150 mL).The combined organic extracts were washed with brine(100 mL),dried(MgSO4),and concentrated,and the residue was purified b

18、y sgc(9:1 1:1 hexane-EtOAc)to give oxindole enoxysilane compound 2(1.29 g,94%)as a 98:2 mixture of geometric isomers:25D 81o(c 0.61 C6H6).2.3 多烯大环的合成多烯大环的合成 分子内Heck反应形成的多烯大环化合物(大于13)。Zeigler就利用Heck反应成功合成十六元环的大环多烯化合物IOOOPdCl2(MeCN)2(100 mol%)NEt3,MeCN,25COOO55%16 member ring formationZeigler,F.Tetrah

19、edron,1981,37,4035 也有多烯经过多次分子内Heck反应，一步构建多个碳碳键和多元环。Overman 就成功应用Heck反应一步构建了二个环和二个季碳中心。OTBSIRHOHR1,Pd(OAc)2(30%mol)PPh3(60%mol)Ag2CO3,THF,2,TBAF,THFOverman,L.E.J.Am.Chem.Soc.,1999,121,54672.2.1 Heck反应用于合成大环多烯反应用于合成大环多烯OTBSIMei:Pd(OAc)2(30 mol%)PPh3(60 mol%)AgCO3,THF,65ii:TBAF,THFMeOHHOOOO12A solution

20、 of vinyl iodide 1(740 mg,1.35 mmol)and THF(75 mL)was degassed(Ar,evacuate-refill),and Ph3P(107 mg,0.41 mmol),Ag2CO3(410 mg,1.5 mmol),and Pd(OAc)2(46 mg,0.20 mmol)were added.The resulting suspension was stirred at room temperature for 15 min and then heated at 65 in a sealed tube for 12 h.A black su

21、spension resulted after 10-20 min at 65.After GC analysis of a filtered aliquot showed that the reaction had not proceeded to completion,additional Ph3P(107 mg,0.41 mmol),Ag2CO3(410 mg,1.5 mmol),and Pd(OAc)2(46 mg,0.20 mmol)were added,and the black suspension was stirred in a sealed tube at 65 for a

22、n additional 6 h.The suspension was then cooled to room temperature and filtered through a plug of silica gel(1.5 cm12 cm,EtOAc),and the filtrate was concentrated to give the crude Heck product as a yellow oil.This sample was dissolved in THF(4 mL),and TBAF(1.0 M solution in THF,2.0 mL)was added.The

23、 resulting solution was maintained at room temperature for 20 h and quenched with saturated aqueous NH4Cl(20 mL).The resulting mixture was extracted with CH2Cl2(320 mL),the combined organic layers were dried(NaSO4),filtered and concentrated,and the residue was purified by flash chromatography(4:1 he

24、xanes-EtOAc)to provide 370 mg(90%)of tricyclic allylic alcohol 2 as a pale yellow oil:Rf=0.25(5:1 hexanes-EtOAc).3.分子间的分子间的Heck 反应反应3.1 常规分子间常规分子间Heck反应反应 端基烯烃与卤代芳香烃发生分子间Heck反应，是研究最早的一类反应。这类反应已经成为芳烃烷基化重要反应。在大多数情况下，Pd-H的消除符合Curtin-Hammett动力学控制规则，即过渡态的能量反应了顺反异构体的比例。一般情况下，除非R特别小（如 CN）,反式异构体是主要产物，（见下例）。

25、其选择性甚至超过Wittig-Horner反应。但由于存在异构化，热力学控制时常常产生二者的混合物，从而导致例外的情况出现。CH2CHCO2CH3+Et3N,100BrPd(OAc)2,POTNO2NO2CO2CH3CH2CHCO2CH3+Et3N,CH3CN,100Pd(OAc)2,POTNBrNCO2CH3 而烯丙基醇与卤代化合物发生分子间Heck反应，通过一系列消去-加成过渡态，可以得到羰基化合物。CH2C(CH3)CH2OH+NBrNCHOPd(OAc)2,PPh3NaHCO3,DMF,100目前，我们应用该反应最多的是芳基卤代物和,-不饱和羰基化合物之间的偶联反应，通过催化剂、配体的

26、选择及反应条件的优化，一般都能以合适的收率得到Trans偶联产物。3.1.1 Pd(OAc)2-P(o-tol)3体系用于不饱和羧酸酯的体系用于不饱和羧酸酯的Heck反应反应C H2C H C O2C H3+NB rP d(O A c)2,P O TNC O2C H3E t3N,C H3C N,100A mixture of 3-bromoquinoline(2.08 g,10.0 mmol),methyl acrylate(1.08 g,12.5 mmol),palladium acetate(23.6 mg,0.1 mmol),tri(o-tolyl)phosphine(0.122 g,0

27、.4 mmol)and triethylamine(3.62 g,35.8 mmol)was heated under argon in a heavy-walled Pyrex tube at 100.deg.C.for 6 h.The cooled reaction mixture was diluted with DCM(60 ML)and distilled water(30 ML).The organic layer was washed with distilled water(3*25 ML).The aqueous layer was extracted with DCM(25

28、 ML).The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to give a pale yellow solid.Purification by recrystallization with EtOAc and hexanes gave an off-white crystalline solid(1.82 g;85percent):3.1.2 不饱和酮的不饱和酮的Heck反应反应Br+OOPOT,DMF,DIEAPd(OAc)2A mixtur

29、e of 4-bromotoluene(10.0 mmol),Cyclohex-2-enone(10 mmol),palladium acetate(0.1-0.5 mmol),tri(o-tolyl)(0.2-1 mmol,催化剂的2-4倍的量)and DIEA(30 mmol)in DMF(30 mL)was heated under N2 at 100 oC for 6-12 h.The reaction mixture was cooled,diluted with 50 mL of water and extracted with ether(2 x 50 mL).The combi

30、ned organic portion was washed with brine solution,dried over anhydrous magnesium sulfate and finally filtered.Evaporatation of the volatiles under reduced pressure purification with column chromatography to give the product.Note:有时可以分离到双键还原的产物。3.1.5 芳香卤代物和不饱和羧酸的芳香卤代物和不饱和羧酸的Heck反应反应合成反式合成反式3-芳基不饱和酸芳

31、基不饱和酸BrICOOH+Pd(OAc)2,Et3NCH3CNBrCOOH123A solution of compound 1(2.8 g,10 mmol),compound 2(0.9 mL,12.5 mmol),Pd(OAc)2(0.022g,0.01 mmol),Et3N(3.5 mL,25 mmol)and 4 mL acetonitrile was heated in a steam bath for 1 hour.After the reaction mixture had been cooled,it was diluted with 250 mL 10%aq.HCl.The

32、solid formed was collected by filtration and re-crystallized from ethanol to give compound 3(1.86 g,yield 82%),mp 215-216.5.3.1.6 非共轭双键非共轭双键Heck反应反应ArXOEtOEtArCHO+(3 eq.)1.3 mol%Pd(OAc)2 2 eq.Bu4NOAc 1.5 eq.K2CO3 1 eq.K2CO3,DMF,90oC2.2N HCl,rt,10 minTypical procedure for the preparation of cinnamald

33、ehyde:To a stirred solution of p-iodoanisole(0.117 g,0.5 mmol)in 2.0 mL of DMF were added acrolein diethyl acetal(0.229 mL,1.5 mmol),nBu4NOAc(0.302 g,1.0 mmol0,K2CO3(0.104 g,0.75 mmol),KCl(0.037 g,0.5 mmol),and Pd(OAc)2(0.003 g,0.015 mmol).The mixture was stirred for 1.5 h at 90oC.After cooling,2 N

34、HCl was slowly added and the reaction mixture was stirred ar room temperature for 10 min.Then,it was diluted with ether and washed with water.The organic layer was dried over Na2SO4 and concentrated under reduced pressure.The residue was purified by chromatography(silica gel,35 g;n-hexane/ethylaceta

35、te 90/10 v/v)to give 0.071 g(88%)of p-methoxycinnamaldehyde.3.2 不对称分子间不对称分子间Heck反应反应 1992年，Tamio Hayashi等报道了手性钯催化的环状烯烃的不对称Heck芳基化反应。ArOTf+OOOArAr+Pd(OAc)2-2(R)-BINAPbase,benzene,40 1a:Ar=Ph(96%ee)1b:Ar=p-ClC6H4(96%ee)1c:Ar=p-MeOC6H4 (87%ee)1d:Ar=2-naphthyl(96%ee)Tamio Hayashi,Pure&Appl.Chem.,1992,64

36、(3),421-427 碱对芳基花产物的对应选择性有一定的影响。例如,用高位阻的强碱性1，8-双（N,N-二甲氨基）萘时，其1a的对应选择性超过96%ee。若用2，6-二甲基吡啶作碱时，1a的对应选择性为69%ee。ArOTf+OPd(OAc)2-2(R)-BINAP+base,-base-HOTfin benzeneOAr(R)-2(S)-3+OArPPh2PPh21a:Ar=Ph(96%ee)1b:Ar=p-ClC6H4(96%ee)1c:Ar=m-ClC6H4(96%ee)1d:Ar=o-ClC6H4(92%ee)1e:Ar=p-AcC6H4(96%ee)1f:Ar=p-NCC6H4(9

37、6%ee)1g:Ar=p-MeOC6H4(87%ee)1h:Ar=2-naphthyl(96%ee)(R)-BINAP3.3 非常用离去基团的非常用离去基团的Heck反应反应 Beller等人报道了重氮盐参与的Heck反应不需要膦催化剂和胺，条件温和，是很实用的芳基化反应。ArN2BF4+COOMeCOOMeAr5%Pd/CMeOH,40-60 Beller,M.;Kuehlein,K.Synlett.1995,441 碘盐参与的Heck反应条件也比较温和，用水作溶剂反应较快，适用于一些惧怕激烈反应条件的底物。对于二芳基碘盐的Heck反应，一般常温下得到一取代的产物，回流条件下得到二取代产物。

38、OHOHPh+Ph2I+BF4-Pd(OAc)2(2mol%)CH3CN/H2O(5:1),rtKang,S.-K.J.Org.Chem.1996,61,2604 酰氯参与的Heck反应一般在非极性溶剂中使用弱碱即可，无需膦催化剂，而且所需钯催化剂用量极少（0.005 mol%）。COClXXXYPd(OAc)2,BnNMe2,p-xylene,100-130NaOAc,DMF,100-130BrBrYSpencer,A.J.Organomet.Chem.1984,265,323 将酸酐应用于Heck反应时20世纪末才发现的，它的优点在于不需要任何碱的存在。(ArCO2)O+RArRPdCl2

39、,NaBrNMP,100 Guertler,C.Chem.Eur.J.1999,5,31073.3.1 重氮盐参与的重氮盐参与的Heck反应反应OMeN2BF4+OOR0.01 eq Pd-catSolvent40-60COMeCO2R30 mmol of corresponding diazonium salt and 60 mmol of acrylic acid ester are suspended in 40 mL of the solvent.Subsequently,0.6 mmol of palladium on activated charcoal(5%weight)is a

40、dded at 0C.Then the reaction mixture is heated to 60C in the course of 1 hour and stirred for 12 hours at this temperature.After cooling to room temperature,the catalyst is filtered off and washed with the solvent.The solvent is evaporated in vacuo and the crude product is further purified by crysta

41、llized or chromatography on silca.Beller,M.;Kuehlein,K.Synlett.1995,4413.3.2 酰氯参与的酰氯参与的Heck反应示例反应示例BrCOCl+COCO2EtCH2NMe2BrCO2EtCH2NHMe2 Cl+-(I)(II)79%Preparation of(E)-ethyl 4-bromocinnamic acid(II)To p-xylene(200 mL)were added palladium acetate(0.02244 g,0.1 mmol),I(21.95 g,0.1 mol),ethyl acrylate(

42、10.83 mL,0.1 mol)and N-benzyldimethylamine(15.06 mL,0.1 mol).The mixture was stirred for 1 h at 130C.At room temperature it was filtered and the precipitate was washed with toluene(50 mL).This gave nearly pure N-benzyldimethylammonium chloride(15.74 g,92%)from which the base can be readily recovered

43、.The combined filtrates were extracted with 2 N hydrochloric acid(50 mL),2 N aqueous sodium hydroxide(50 mL)and water(50 mL).After drying with MgSO4(10 g)for 15 min,the solvents were removed on the rotary evaporator and the crude product was fractionally distilled in vacuum(130-135C/0.2 mmHg).Yield 20.1 g(79%).Colourless liquid.Anal.Found:C,52.07;H,4.50;Br,31.01.C11H11BrO2 calcd.:C,51.79;H,4.35;Br,31.32%.The End