偶联反应小结

1、偶联反应偶联反应Cross-Coupling Reaction经典反应式经典反应式R-X+R-MXCatalystR-R+MXXSubstrateCoupling PartnerCoupling ProductMetal HalideR = Alkyl, aryl, vinyl, allyl, alkynyl, benzylR = Alkyl, aryl, vinyl, allyl, alkynyl, benzyl, acylX = I, Br, Cl, OTf, OTsM = Mg, Zn, Cu, Sn, Si, B,.(OrganometallicNucleophile)(Organic

2、Electrophile)(Ni or Pd.?)Cat. = Pd, Ni, others Cu Fe.R-X+CatalystR-R+R-MXMXXCross-Coupling ReactionsCatalystMRRXKumada-Corriu (1972)Ni or PdMgAryl, alkyl, vinylAryl, alkyl, vinylCl, Br, I, OTsSonogashira (1975)Pd/CuICuAryl, alkylAryl, alkyl, vinylBr, INegishi (1977)Ni or PdZnAryl, allyl, benzyl, pro

3、pargylAryl, alkyl, vinyl, alkynyl, benzyl, allylCl, Br, I, OTsStille (1978)PdSnAryl, vinyl,benzyl, alkynylAryl, alkyl, vinyl, benzyl, allyl, acylCl, Br, I, OTsSuzuki (1979)PdBAryl, alkylAryl, alkyl, alkynylCl, Br, I, OTsHiyama (1988)Ni or PdSiArylAryl, alkyl, vinylBr, I, OTs 1. Kumada, Suzuki, Still

4、e, Negishi, Hiyama coupling (C-C Formation：C-X + C-M)2. Buchwald-Hartwig coupling (C-N, C-O, C-S Formation: C-X + Nu (N, O, S)-H)3. a-Arylation of Ketone (C-C Formation: C-X + C-H)4. Heck, Sonogashira coupling (Alkene and alkyne Formation: C-X + C-H)General MechanismKumada, Kumada-Corriu Coupling196

5、0年年Chatt和和Shaw: L2NiRX+RMgXL2NiRR+12L2NiXXMgX2(bipy)Ni+34RRR-X(bipy)NiRXR-R1970年年Uchino等等: RMgXRXNiX2L2R - R +MgXX+催化剂: NiX2L2 ( L2 = 双 膦 )溶剂: Et2O or THF反应条件: 0 oC R.T., reflux, 1 20 h, Ni / RX = 10 -2 10 -RX: sp2 碳 的 卤 化 物Sp3 C-X substrate?RXR - RMgXXRMgXL2NiX22 RMgX2 MgX2L2NiR2R - RRL2 NiRXL2 NiR

6、RL2 NiRRXRX56723NiCl2L2 ( 1 % )Et2O, reflux20h+PhClBuMgBrPhBu dppp dmpf dppe dmpe dppc cis - dpen Ph2P(CH2)nPPh2 Me2P(CH2)2PMe2 cis-Ph2PCH=CHPPh2 n = 2 dppe dmpe cis-dpen n = 3 dppp n = 4 dppb 配体的影响配体的影响 FePR2PR2R = Me dmpfR = Ph dppfH10B10PhPhPhPhdppcMgClH3CCH3L2NiClPh+NiCH3H3CL2PhCH2 = CHCH3H - Ni

7、 - PhL2CH2CH2CH3 Ni - PhL2PhH3CCH3CH2 = CHCH3+PhHPhCH2CH2CH3格氏试剂上烷基部分的异构化格氏试剂上烷基部分的异构化 PhMgBr+ Ni-P* H2C CHCH2CH2BrH2CHCCMePhH*( (3 3) ) 反反应应中中涉涉及及的的双双键键的的立立体体化化学学MeMgBr+NiCl2L2MeMgBr+NiCl2L2PhBrPhCH3PhBrPhCH3+NiCl2 ( dmpe )PhMgBrPhArPhArArX(4) 碳碳碳碳键键的的不不对对称称形形成成(Asymmetric formation of carbon-carbo

8、n single bonds)PhMeCHMgCl+Br Ni * PhMeCHCH = CH2*PPFA Y: 83 99% ee: 52 63% (R)-(S)-PPFA 63% ee (S) (S)-(R)-PPFA 59% ee (R)(S) - (R) - PPFANMe2HMePPh2PPh2Me2NHRR3R2R1R3R2R1R4 X ML*R3R2R1(S)-Valphos (R = i-Pr)81% ee (S)(R)-t-Leuphos (R = t-Bu) 94% ee (R)R4 X ML*R3R2R1R4CCH2CMgXCXMgCR4CDynamic kinetic

9、ResolutionFe-catalystLow initial temperature (-20 C) is beneficialMolander, G. A. et. al. Tetrahedron Lett. 1983, 24, 5449. HBrHPh+PhMgXReaction condition: Fe(dbm)3 cat., 1-2 hDME, -20 oC to rtHPhHPh(1 equiv)(1 equiv)HBrHPh+PhMgXHPhHPh(1 equiv)(3 equiv)THF, 25 oC(32%)(90%)New development of the cata

10、lystPhOO-Phdbm Aryl chlorides, triflates and tosylates are better substrates than aryl bromides and iodidesEntryXYield (GC, %)ab1I27462Br38503Cl95-4OTf95-5OTs95-Frstner, A. et. al. Angew. Chem. Int. Ed. Engl. 2002, 41, 609.XOMeOn-HexMgBrFe(acac)3 (5 mol%)THF-NMP 0oC to rt, 5 minHexOMeOOMeO+a, coupli

11、ng productb, reduction product-Hydride elimination and homocoupling are the major setback with the cross-coupling of 1o and 2o alkyl substrates with aryl Grignard reagentsEntrySolventProduct Yield (%)CDEF*1THF/NMP252524262THF272720253Et2O601912124Et2O (reflux)691899Hayashi, T. et. al. Org. Lett. 200

12、4, 6, 1297. *Amount after 0.05 mmol (equivalent to catalyst) subtracted. MgBr+BrFe(acac)3 (5 mol%)Solvent, 20 oC, 30 min(CH2)5PhC+EFDBA(Desired product)Alkyl Derivatives as SubstrateAlkyl Derivatives as SubstrateTMEDA plays a crucial role to reduce -hydride eliminationEntryaAdditiveProduct Yield (GC

13、, %)CDEAF1None5790462Et3N37801153N-Methyl morpholine8720454DABCO20207535NMP153Trace7946TMEDA71193Trace10Nakamura, E. et. al. J. Am. Chem. Soc. 2004, 126, 3686. aPhMgBr (1.2 equiv), additive (1.2 equiv), 30 min. Br+PhMgBrFeCl3 Cat.THF, AdditivePhPh-Ph+ABCDEFMe2NNMe2TMEDA(Desired product)-78 oC to 0 o

14、C 30 minFrstner, A. et. al. Angew. Chem. Int. Ed. 2003, 42, 308.Frstner, A. et. al. J. Org.Chem. 2004, 69, 3950.Synthesis of R-(+)-Muscopyridine and immuno suppressive agent FTY720NFe-catalyzed cross-coupling(R)-(+)-MuscopyridineNNClOTfMgBrMgBr1.Fe(salen)Cl 1 (5 mol%)THF-NMP 0 oC2.(60%)Fe(salen)Cl 1

15、NFeNOOHHClH2NOHOHImmunosuppressive agent FTY720OOFe(acac)3 cat.OOTfOTHF-NMP, rt, 2 h(84%)Fe-catalyzed cross-couplingOctMgBr1. RCM2. H2/cat.Frstner, A. et. al. Angew. Chem. Int. Ed. 2003, 42, 5358.Synthesis of Latrunculin BOOOHNSOOHFe-catalyzedcross-couplingFe-catalyzedcross-couplingLatrunculin BOORT

16、fOOORMgBrFe(acac)3 (10 mol%)THF, -30 oCRNSOORNSOClOFe(acac)3 (1.5 mol%)(97%)(85%)THF, -78 oC to 0 oCMeMgBrIndustrial examplesHokko Chemical Industry, JapanScale: 20t/ySolvent: From Ether to THF, with Toluene as co-solvent.Suzuki Coupling R - X Pd R - R+R-B(1) 催化量的钯(2) 反应是区域及立体专一性的 (Regio- and Stereo

17、-specific)(3) 碱的存在Pd(PPh3)4TON 74,000 910,000环钯催化剂PtBu328,000,000ArCl substrateWater soluble反应底物反应底物 有机硼酸（酯）有机硼酸（酯） ArBr 经格氏反应，或者经格氏反应，或者nBuLi，与，与B(OR)3反应得到反应得到 硼氢化反应硼氢化反应+X2 = ( Sia )2OOHRHBX2RHHBX2RPhB(Sia)2+Pd (0)Base87 42 %RB(Sia)2+Pd (0)BaseBrRPhCH2BrR9 - BBNPdCl2 (dppf)222324OOBrOOBrBOONaOHPh+

18、K3PO4-3H2Otoluene, 100oCPhB(OH)2RBrR83-98%Pd(PPh3)4 Ph+RBrHCOORK3PO4-3H2Otoluene, 100oCRHCOORPhB(OH)2Pd(PPh3)4 BuC4H9+Ph86 %X2 = (Sia)21 % PdCl2 / 2 % PPh3NaOEt - EtOHBenzene+88 % ( purity: 98 % )+BrPhn-BuBX2OOn-C4H9OBOC4H9C6H13Brn-C6H13n-C4H9BX2BrC6H13-n49 % ( purity: 98 % )C6H13-nHexBX2HexCl1210+Y

19、 = OAc, OMe ClClClYes11ClClClPdY (PPh3)2NoLosartan, Merck (1994), 抗高血压药物JOC, 1994, 59, 6391Pharmacia Co. and Dow抗真菌剂fungizide Boscalid, BASF, 1000t/yCancer cell growth inhibitor, NovartisTreatment for HIVStille偶联偶联, Stille Coupling Stille反反应应虽虽使使用用了了高高毒毒性性的的锡锡试试剂剂，但但有有以以下下三三个个特特点点： (1) 广广谱谱的的官官能能团团兼

20、兼容容性性 (2) 立立体体专专一一性性(Stereospecificity) (3) 区区域域选选择择性性(Regioselectivity) SubstratesRRRXR - CC - SnR3SnR3RRRRXRRRRRSnR3( X = Cl, Br )H - SnR3Aryl-CH2 - X ( X = Cl, Br )( X = I, OTf )Aryl- SnR3( X = Br, I )Aryl - CH2 - SnR3CnH2n+1SnR3RXCOORHR3R1R2OTfRCOClArXStille偶联反应中两组份的组合偶联反应中两组份的组合 对于锡试剂上不同的取代基在St

21、ille偶联反应中发生金属交换反应的迁移速率是不同的，甲基、正丁基等1o烷基基本上不发生迁移，基团的迁移相对速率如下： R3SnR R = CH3, n-Bu 慢 RCH = CH Aryl RCH = CH - CH2 ArCH2 CH3OCH2 CnH2n+1R OMeRH-78 oC -20 oCOMeRLiOMeRSnMe3t-BuLiMe3SnCl 锡试剂的制备锡试剂的制备 E - C6H4Br+E - C6H4SnMe30 oCE = p-CN, o- / m- / p- CH3CO, OAc60-80%Me3SnNaCOORClCOORn-Bu3Sn+n-Bu3SnCuXYSnR

22、3Y( R3Sn )2+ PdLn NSnMe3NPd ( PPh3 )2Cl2+CORRCOClIPhRn-Bu3SnPhR+ Pd THF, 40 oCC6H13CH2BrOC5H11-n+n-Bu3SnCH2COCH3PdCl2 (PhCN)2C6H6, 80 oC66 %DihydrojasmoneC6H13OO63%OOOTfMe3SnSiMe3SiMe3OTfMe3SnSiMe3SiMe31. LDA2. Tf2NPh91 %1. i-Pr2NMgBr2. Tf2NPh63 %PdL4, LiCl100 %PdL4, LiCl90 %98 : 2293095:597:395:5构

23、型 保 持重 排 为 主构 型 翻 转RS nR3P h - C H - S n R3RS nR3ROONHOSiNHBocSnMe3CH3H3CNNORRClONH2ROSiMeMeFONHFmocROSiMeMeNHONH2RRNNORSiMeMe1.2. TFA / CH2Cl21.2. Pip. DMF1. 5% HOAc, 65 oC3. RI, DMF2.HF / DMSRRONPhOLiRR.n-Prn-PrEEPdLnXn-Prn-PrEEPhn-Prn-PrIEE64%E = COOEt2728PhSn(n-Bu)3PdR - MR - ZnXZnX2R - CC - ZnX

24、XR - CC - A rR - CCArXPdLnPdLnRZnX+RCOClPdLnRCOROI(OTf)OCH = CHRCat. PdLnTHF and / or DMFRCH = CHZnXTBDMSOIOTMSTBDMSOZnXLnOTMSTBDMSOOTMSOTBDMSHOOOH1. n - BuLi, -110 oC2. ZnBr2 / THF3. evaporation4. DMF5 % PdCl2 P(furyl)32+ 10 % n - BuLi- 78 oC 23 oC2 h, 95 % by NMRNakienone AIOTBDMSN+HMe2Cl-O Ni (ac

25、ac)2(Z) - Tamoxifen1.2.cat. PdPhIPhEtPhEtPh2ZnI2O (CH2)2NMe2ZnBrPhPhEtHiyama偶联反应偶联反应 F- (TBAF) activator neededAr1IAr2Si(R)F2KF, DMFAr1-Ar2+(3-C3H5PdCl)245-94%R2R3SiMen(OR)3-nR1+P(OEt)3, TBAFTHF, 50oCR2R3R1R431-96%R4-X(3-C3H5PdCl)2X = Br, IR4 = 1-alkenyl, arylR2OTfR1SiRnF3-nR1-R2n = 0,1,2R1 = aryl, alkenyl, alkynyl, alkylR2 = alkenyl, arylR = Me, Et(50)n-Bu4NFTHFR1SiRnF4-n_Pd(PPh3)462-99%Me3SiSiMeF2+Pd(PPh3)4TBAF, 50oC(CH2)5CH3TfO4 hMe3Si(CH2)5CH33231SiF333+TfOCHO35CHO3460oC 46% 32% ee (S)100oC 28% ee (R)34% eePd(PPh3)4TBAFSiF3+dppb, TASFOTf85%SiF3+IOO100oC, 12 h