M.C. White Chem 153 Cross Coupling -84- Week of october, 2002 C-C Bond Formation Csp-Csp2 Csp -csp Bonds Csp.-Csp" Bonds R R AlkyI-Ar R Alkyl R Csp-Csp"Bonds General mechanism a paradigm shift nucleophi lic substitution at an sp hybridized Alkyl-Alkyl carbon is made routine R-M R by using transition metal R2 X=I Br, OTe, CI Classifications based on the main group metal RIR2 L. Pd(o) RIx used to transfer r2 in the transmetalation event reductive oxidative Kumada coupling Negishi Coupli elimination addition Ni(0)or pd(0) Ni(O)or Pd(o) M=MgX, Li M=Al(i-Buh d-updo Zr(cl)cp2 Stille reaction Hiyama Coupling M=SiR Suzuki reaction X-M R-MR-=aryl, vinyl, alkyl PQ(0) Pd(0) transmetalation M=BX M= Cu(in situ)
M.C. White, Chem 153 Cross Coupling -84- Week of October1, 2002 C-C Bond Formation A paradigm shift: nucleophilic substitution at an sp2 hybridized carbon is made routine by using transition metal mediated catalysis. R R R R Ar R Alkyl R Alkyl Ar Csp2-Csp2 Bonds Csp3-Csp2 Bonds R R R Csp-Csp2 Alkyl Alkyl Csp3-Csp3 Bonds Kumada Coupling Ni(0) or Pd(0) M = MgX, Li Stille Reaction Pd(0) M = SnR3 Negishi Coupling Ni(0) or Pd(0) M = Al(i-Bu)2 Zr(Cl)Cp2 ZnX Suzuki Reaction Pd(0) M = BX2 Classifications based on the main group metal used to transfer R2 in the transmetalation event. Hiyama Coupling Pd(0) M = SiR3 Sonogashira Pd(0) M = Cu (in situ) R = aryl, vinyl X = I, Br, OTf, Cl Pd(II) LnPd(0) R1-X LnPd(II) R1 X R2-M LnPd(II) R1 R2 oxidative addition transmetalation X-M R1 R2 General Mechanism reductive elimination R2= aryl, vinyl, alkyl R2-M R2 R2 Cl Cl (or Ni(II) Cl Cl )
M.C. White. Chem 153 Cross-Coupling-85 Week of october 1, 2002 Kumada pushes the frontier All the pieces of the catalytic cycle were in the literature. Transmetallation: Chatt and Shaw J. Chem. Soc. 1960 1718 Report the synthesis of alkyl and aryl nickel(lI)complexes from the corresponding nickel(ln) halides n-BuMgBr (2 eq) PPh] 2 RMgBr a PPh Br h2 0.7 mol% Meb Reductive elimination/Oxidative addition: Yamamoto JOMC amada JACS1972(94)4374 1970(24)C63. " Preparation of a phenyl-nickel complex, phenyl ( dipyridyl)nickel chloride, an olefin dimerization catalyst L_Ni RI arvi. v R-xX=CI>BpI elimination
M.C. White, Chem 153 Cross-Coupling -85- Week of October 1, 2002 Kumada pushes the frontier P Ph2 Ni(II) Ph2 P Cl Cl Cl Cl n-BuMgBr (2 eq) P Ph2 Ni(II) Ph2 P Cl Cl Cl MgBr Kumada JACS 1972 (94) 4374. 0.7 mol% 94% 0.7 mol% 80% Reductive elimination/Oxidative addition: Yamamoto JOMC 1970 (24) C63. "Preparation of a phenyl-nickel complex, phenyl (dipyridyl)nickel chloride, an olefin dimerization catalyst. N N Ni(II) Cl N N Ni(II) Cl + butane N N Ni(II) Cl N N Ni(0) Cl Transmetallation: Chatt and Shaw J. Chem. Soc. 1960 1718. Report the synthesis of alkyl and aryl nickel(II) complexes from the corresponding nickel(II) halides. Ph3P Ni(II) Br PPh3 Br 2 RMgBr Ph3P Ni(II) R PPh3 R R = R' All the pieces of the catalytic cycle were in the literature... LnNi(II) LnNi(II) R1 X LnNi(II) R1 R2 MgX2 R1 R2 R2 R2 Cl Cl R1 = aryl, vinyl L X = Cl > Br> I nNi(0) R1-X R2-MgX oxidative addition transmetalation reductive elimination R2 R = aryl, vinyl, alkyl 2-MgX
M.C. White Chem 153 Cross-Coupling -86- Week of october 1, 2002 Kumada Coupling Common Bidentate Phosphine Effect of the ligand BuMgBr (2 eq) Ligand yield dppp 100 dentate phosphine liga dppm, n=0, bis( diphenylphosphino)methane exhibit higher catalytic activity dppe, n=l, bis( diphenylphosphino)ethane than monodentate phosphines dppp, n=2, bis(diphenylphosphino propane PhaP(2eq) 84 with dppp being optimal for a dppb, 3, bis(diphenylphosphino)butane ppe halides e dmpe, bis( dimethylphosphinoJethane Reactivity of ary/ halide: 2 Unlike othe 6-coupling methods, aryl and vinyl chlorides 3l(2h) exhibit higher reactivities than dmpf, bis( dimethylphosphino)ferrocene 95(31 their br or I analogs. It Br 54(4.5h)noteworthy that even ary 80(3h) Kumada Bull. Chem. Soc. Jpn. 1976(49)1958
M.C. White, Chem 153 Cross-Coupling -86- Week of October 1, 2002 Kumada Coupling P P ( )n dppm, n=0, bis(diphenylphosphino)methane dppe, n=1, bis(diphenylphosphino)ethane dppp, n=2, bis(diphenylphosphino)propane dppb, n=3, bis(diphenylphosphino)butane P P dmpe, bis(dimethylphosphino)ethane P P Fe dmpf, bis(dimethylphosphino)ferrocene Common Bidentate Phosphines Kumada Bull. Chem. Soc. Jpn. 1976 (49) 1958. P Ni(II) P Cl Cl Cl n-BuMgBr (2 eq) 0.7 mol% R2 R2 Ligand dppp dmpf Ph3P (2eq) dppe dmpe dppb % yield 100 94 84 79 47 28 Effect of the ligand: · Bidentate phosphine ligands exhibit higher catalytic activity than monodentate phosphines with dppp being optimal for a wide range of aryl and vinyl halides. Reactivity of aryl halide: P Ni(II) P Cl Cl X n-BuMgBr (2 eq) 0.7 mol% Ph2 Ph2 X % yield F Cl Br I 31 (2h) 95 (3h) 54 (4.5h) 80 (3h) · Unlike other cross-coupling methods, aryl and vinyl chlorides exhibit higher reactivities than their Br or I analogs. It is noteworthy that even aryl fluorides undergo the nickel catalyzed cross-coupling
M.C. White Chem 153 Cross-Coupling-87- Week of octo berl. 2002 Kumada Coupling: Applications Industrial production of p-substituted styrene derivatives(Hokka Chemical Industry, Japan) . CI Mecl 0. 1 mol% Strem 2001-2003 catalog bUy t-Buo S7.6/g(very cheap) Banno JOMC 2002(653)288 Functionalization of heterocyclic halides Me3 SiCH2Mga Formation of sterically hindered biaryls Nucleophilic N-heterocyclic carbenes an used as a phosphine mimics that (unlik monodentate phosphines) donot BFA- dissociate from the metal 3 mol% imidazolium salt RMgX R=CF3 H, CH3, OCH3 H,>99% steric hinderance tolerated CH3,95% only on the Grignard OCH3,98% Herrmann ACIEE 2000(39)1602
M.C. White, Chem 153 Cross-Coupling -87- Week of October1 , 2002 Kumada Coupling: Applications P Ni(II) P Cl MgCl Cl Ph2 Ph2 t-BuO Cl t-BuO P Ni(II) P Cl Cl Ph2 Ph2 N Br P Ni(II) P Cl Cl Ph2 Ph2 S MgBr Me3SiCH2MgCl BuMgBr N S N N SiMe3 0.1 mol% · Industrial production of p-substituted styrene derivatives (Hokka Chemical Industry, Japan) Strem 2001-2003 catalog $7.6/g (very cheap) Banno JOMC 2002 (653) 288. · Functionalization of heterocyclic halides 0.5-1 mol% 78% 72% 71% · Formation of sterically hindered biaryls Kumada Tetrahedron 1982 (38) 3347. Cl R R = CF3, H, CH3, OCH3 O NiII O O O 3 mol% + 3 mol% N N BF4- N N BF4- imidazolium salt RMgX Nucleophilic N-heterocyclic carbenes are used as a phosphine mimics that (unlike monodentate phosphines) do not dissociate from the metal BrMg steric hinderance tolerated only on the Grignard + R N N BF4- R= CF3, 91% H, >99% CH3, 95% OCH3, 98% Herrmann ACIEE 2000 (39) 1602
M.C. White. Chem 153 Cross-coupling -88- Week of october 1, 2002 Pd Kumada Coupling: stereospecific transmetallation Oxidative addition to Pd(o) had been reported: Fitton Chem Comm.1968.6 The nickel catalyzed Kumada coupling is stereospecific for vinyl mono-halides(complete retention of geometric configuration) but non-stereospecific for alkenyl Grignards Phap 阝2 Ph PPh3 Memebr 96%(Z)阝 bromostyrene 96%(STilbene Palladium(0)shown to be an effective, stereospecific catalyst for cross-coupling of alkenyl halides with Grignard reagents Murahashi JOMC 1975(91)C39 Ph3 C Phap 3 mol% Me Mebr MeMel 99%E阝 bromostyrene >99%(El-stilbene 99 cis-P-bromostyrene 99% cis-stilbene Palladium(0)shown to be stereospecific for alkenyl Grignards reagents. Linstrumelle TL 1978.191 Br Mg I-C6HB Ph Phap 5 mol% Note: Nickel catalysis may involve radical pathways Kumada TL 19751719 (E)-l-iodo- Me I-octene Kumada Pure& App/. Chem. 1980(52)669 >97%,(2Z, 4E)-2, 4-undecadiene (Z)-1-propenyl-l 87% yield Note: Pd cataly sts can also transmetal late with organolithium Pd(O): Br>>CI reagents: Murahashi JOMC 2002(653)27
M.C. White, Chem 153 Cross-coupling -88- Week of October 1, 2002 Pd Kumada Coupling: stereospecific transmetallation The nickel catalyzed Kumada coupling is stereospecific for vinyl mono-halides (complete retention of geometric configuration) but non-stereospecific for alkenyl Grignards: Ph Br MeMgBr P Ni(II) P Cl Cl R2 R2 Ph Me 96% (Z)-stilbene Ph MeMgBr Ph >99% (E)-stilbene Br Me 96% (Z)-β-bromostyrene >99% (E)-β-bromostyrene P Ni(II) P Cl Cl R2 R2 BrMg Me 96% Z P Ni(II) P Cl Cl R2 R2 Br Ph Me 27% Z: 73% E Kumada TL 1975 1719. Kumada Pure & Appl. Chem. 1980 (52) 669. Oxidative addition to Pd(0) had been reported: Fitton Chem. Comm. 1968, 6. PPh3 PPh3 Pd Ph3P Ph3P I Ph3P Pd(II) Ph3P I Palladium (0) shown to be an effective, stereospecific catalyst for cross-coupling of alkenyl halides with Grignard reagents. Murahashi JOMC 1975 (91) C39. Ph Br MeMgI Ph Me 99% cis-stilbene >99% yield 99% cis-β-bromostyrene PPh3 PPh3 Pd Ph3P Ph3P Palladium (0) shown to be stereospecific for alkenyl Grignards reagents. Linstrumelle TL 1978, 191. I n-C6H13 BrMg Me 3 mol% PPh3 PPh3 Pd Ph3P Ph3P 5 mol% (E)-1-iodo- 1-octene (Z)-1-propenyl-1 magnesium bromide n-C6H13 >97%, (2Z,4E)-2,4-undecadiene 87% yield Note: Pd catalysts can also transmetallate with organolithium reagents: Murahashi JOMC 2002 (653) 27. Pd(0): I>Br>>Cl Note: Nickel catalysis may involve radical pathways
M.C. White. Chem 153 Cross-Coupling-89 Week of octo ber 1. 2002 Negishi Coupling: towards FG tolerance Negishi demonstrates for the first time that metals less electropositive than Mg or Li can act as effective transmetalation reagents in the Kumada ni and pd catalyzed cross-coupling reaction. The stereospecificity observed in the Pd catalyzed reaction confirms that it is the preferred metal for alkenyl-alkenyl couplings to form 1, 3-dienes n1-CsHml n1-C+H9 (PPh3))Pd(0) (PPh3h2Ni(O C Al(i-Bu 5 mol Pd:749,>999(EE) PdCl2(PPh3h+2 eq DIBAL Ni: 70%,95%(E, E), 5%(E, Z) Ni(acach2+2 eq. DIBAL Negishi JACS 1976(98)6729 The lack of functional group compatibility in both the alkyne hydroalumination and of the resulting alkenylalane prompted a shift to alkeny Zirconium transmetalating reager generated via hydrozirconation of terminal alkynes)which can tolerate such functionalities as ethers, ketones and esters, etc... Problems still exist with highly electrophilic (e.g. aldehydes)and protic functionality (e.g. alcohols). In addition, these intermediates are moisture sensitive 0 (PPh3)2Pd(0)0 50%C,4h 70% Rccl Meo L1978(12)1027 The addition of Zn] increased the reactivity of the transmetalating reagent making the cross coupling of sterically hindered substrates possible. It is thought that the alkenylzirconium, alkenylalane undergo in situ transmetalation with ZnCl to form alkenylzinc, a more reactive transmetalating reagent i-Bu,AI 5 mol% (or ZrCp2 CI No rxn after I wk w/out ZnCl2 ZnCh2,Ih,25℃,88% Negishi Acc. Chem. Res 1982(15)340
M.C. White, Chem 153 Cross-Coupling -89- Week of October 1, 2002 Negishi Coupling: towards FG tolerance Negishi Acc. Chem. Res. 1982 (15) 340. n-C5H11 Al(i-Bu)2 n-C4H9 I 5 mol% n-C5H11 n-C4H9 or (PPh3)2Pd(0)* (PPh3)2Ni(0) Pd: 74%, >99% (E,E) Ni: 70%, 95% (E,E), 5% (E,Z) + * PdCl2(PPh3)2 + 2 eq. DIBAL Ni(acac)2 + 2 eq. DIBAL Negishi JACS 1976 (98) 6729. ZrCp2Cl O O Br O MeO + (PPh3)2Pd(0)* 50oC, 4h O O O MeO 70% Negishi TL 1978 (12) 1027. I Et Et i-Bu2Al (or ZrCp2Cl) PPh3 PPh3 Pd Ph3P Ph3P 5 mol% ZnCl2, 1h, 25oC, 88% Et Et No rxn after 1 wk w/out ZnCl2 Negishi demonstrates for the first time that metals less electropositive than Mg or Li can act as effective transmetalation reagents in the Kumada Ni and Pd catalyzed cross-coupling reaction. The stereospecificity observed in the Pd catalyzed reaction confirms that it is the preferred metal for alkenyl-alkenyl couplings to form 1,3-dienes. The lack of functional group compatibility in both the alkyne hydroalumination and of the resulting alkenylalane prompted a shift to alkenylzirconium transmetalating reagents (generated via hydrozirconation of terminal alkynes) which can tolerate such functionalities as ethers, ketones and esters, etc... Problems still exist with highly electrophilic (e.g. aldehydes) and protic functionality (e.g. alcohols). In addition, these intermediates are moisture sensitive. The addition of ZnCl2 increased the reactivity of the transmetalating reagent making the cross coupling of sterically hindered substrates possible. It is thought that the alkenylzirconium, alkenylalane undergo in situ transmetalations with ZnCl2 to form alkenylzinc, a more reactive transmetalating reagent
M.C. White. Chem 153 Cross Coupling-90- Week of octo ber 1. 2002 Negishi Coupling: Csp'-Csp' and Csp-Csp' Formation of csp-Csp' bonds using alkylic reagents n-BuMgCl n-BuZnCl β hydride elimination 51% 2% Pd(PPh3)4 n1-CHHo elimination n-CAHe nI-CqHo 25% 76% n1-CAHo Negishi JACS 1980(102)3298 Q: B-hydride elimination and reductive elimination presumably go through a similar Pd organometallic intermediate formed after the transmetalation event. Develop a hypothesis for why less B-hydride elimination product is observed when a zinc versus magnesium transmetalating reagent is used Recall formation of Csp'-Csp' bonds using alkyinc reagents Pent F3C 50mo9% 70% yield, Ih Knochel ACIEE 1998(37)2387
M.C. White, Chem 153 Cross Coupling -90- Week of October 1, 2002 n-C4H9 I PdII PPh3 PPh3 n-C4H9 β-hydride elimination reductive elimination n-C4H9 n-C4H9 H n-BuZnCl or n-BuMgCl n-BuMgCl 51% 25% n-BuZnCl 2% 76% Pd(PPh3)4 Formation of Csp2-Csp3 bonds using alkylzinc reagents. O Bu I O NiII O Bu O F3C Pent2Zn possible intermediate F3C 50 mol% O NiII O O O 10 mol% O Bu Pent 70% yield, 1h w/out π-acid: 20%, 15h Recall: formation of Csp3-Csp3 bonds using alkylzinc reagents. Negishi JACS 1980 (102) 3298. Knochel ACIEE 1998 (37) 2387. Negishi Coupling: Csp3-Csp2 and Csp3-Csp3 Q: β-hydride elimination and reductive elimination presumably go through a similar Pd organometallic intermediate formed after the transmetalation event. Develop a hypothesis for why less β-hydride elimination product is observed when a zinc versus magnesium transmetalating reagent is used
M.C. White/Q. Chen, Chem 153 Cross-Coupling- 91 Week of octo ber 1. 2002 Negishi Coupling: Csp-Csp? Note: p-hydride present in alkyl zinc I ZnCh, -BuLi(3 eq) OO OTBS otbs OO OTBS Et,0,-78C to rt 0O OTBS PMP PMP PMP PPh3 OPMB transmetalation l Ph 5%Pd(Ph3)4 OTBS Et O, rt O OTBS OPMB OMB PMP OPMB Ligand dissociation to the 人人 trigonal planar intermediate is thought to favor reductive elimine elimination from square Yamamoto OM 1989(8)180 0、 O OTBS OTBS 13 steps (+i-Discodermolide Smith JACS 2000 (8654)
M.C. White/Q. Chen, Chem 153 Cross-Coupling -91- Week of October 1, 2002 Negishi Coupling: Csp3-Csp2 O O PMP I OTBS O O PMP Zn OTBS O O PMP OTBS OPMB OTBS OPMB OTBS I O NH2 OH OH O O HO O Ph3P O O PMP OTBS PdII PPh3 OPMB ZnCl2, t-BuLi (3 eq) OTBS Et2O, -78 °C to rt 5% Pd(PPh3)4 Et2O, rt 66% (+)-Discodermolide Note: β-hydride present in alkyl zinc. 13 steps transmetalation I Ph3P PdII PPh3 OPMB OTBS I oxidative addition + transmetalation II -PPh3 O O PMP OTBS PdII OPMB OTBS PPh3 reductive elimination Ligand dissociation to the trigonal planar intermediate is thought to favor reductive elimination from square planar complexes. Yamamoto OM 1989 (8) 180. Smith JACS 2000 (8654)
MC White. Chem 153 Cross-Coupling-92 Week of october 1. 2002 Stille coupling The original report Catalyst Palladium(0) Br Me Sn HMPA62℃ Me snCl Phal PPh3 Stille JACS1979(101)4992 Stren2001-2003 Strem2001-2003 alkynypalkenyparyPbenzypallyp>alkyL. Allows for simple alkyl groups(Me, Bu)to R substituents thereby avoiding using four identical expensive and/or Palladium(D difficult to synthesize r- groups. Alkyl transfers are only practical for methyl or buty HICCN CI Strem2001-2003 Strem2001-2003 RSnR2R=dl时0L-l RLR2 RLX X=>BrOTD>>CI Monodentate MiNation revent catalyst decomposition(plating out")to metallic Pd(0). B hosphines result in low reaction rates and poor yields LaPd tR The rate-determining step in Stille-couplings wi electrophiles(i unsaturated iodides, triflates) tri-2-furylphosphine
M.C White, Chem 153 Cross-Coupling-92- Week of October 1, 2002 P O O O Catalyst PPh3 PPh3 Pd Ph3P Ph3P Palladium(0) Palladium(II) Pd2(dba)3 O dibenzylideneacetone (dba) Strem 2001-2003 $53/g Strem 2001-2003 $28/g Cl PdII H3CCN Cl NCCH3 Strem 2001-2003 $39/g O PdII O O O Strem 2001-2003 $52/g Monodentate phosphines are added to palladium sources with poorly coordinating ligands to prevent catalyst decomposition ("plating out")to metallic Pd(0). Bidentate phosphines result in low reaction rates and poor yields. PPh3 As tri-2-furylphosphine triphenylarsine Ligands Stille Coupling Stille JACS 1979 (101) 4992. LnPd(II) LnPd(II) R1 X LnPd(II) R1 R2 XSn(R3)3 R1 R2 R2 R2 Cl Cl R1 = aryl, vinyl, alkynyl L X = I>Br>OTf>>Cl nPd(0) R1-X R2-Sn(R3)3 oxidative addition transmetalation reductive elimination R2 R = alkynyl, aryl, vinyl, alkyl 2-Sn(R3)3 Transfer from tin: alkynyl>alkenyl>aryl>benzyl>allyl>alkyl. Allows for simple alkyl groups (Me, Bu) to serve as"dummy" R3 substituents thereby avoiding using four identical expensive and/or difficult to synthesize R2 groups. Alkyl transfers are only practical for methyl or butyl. Br Me4Sn Ph3P PdII Ph3P Cl Ph HMPA, 62oC Me Me3SnCl The original report: + 1 mol% + The rate-determining step in Stille-couplings with reactive electrophiles (i.e. R1-X= unsaturated iodides, triflates)
M C. White/M. w. Kanan Chem 153 Cross-Coupling-93 Week of octo ber 1. 2002 Unmatched stability and low crosS-reactivity of organotins Organotin reagents are Highly functional group Readily synthesized via a variety of methods* Air and moisture stable(often distillable) Stable to the vast majority of organic reagents oxidation (u-BuzSnyBuCuLILICN 3 eq SO3 Py, 3eq. Et3N, HWE condensation CO,E PO(EtOh 人CHO Bus COrEt )nBuL,DMPU,THF,0°C i) aldehyde,-78°C>-20°C oTf CO,Et 2.5 mol% Pd, (dba)3 20 mol% AsPh,. NMP retinoic acid precursor Dominguez Tetrahedron 1999(55)15071 s For comprehensive review of synthesis of aryl and vinyl stannanes see AG Myers/A. Haidle Chem 115: "The Stille Reaction
M.C. White/M.W. Kanan Chem 153 Cross-Coupling -93- Week of October 1, 2002 Unmatched stability and low cross-reactivity of organotins Organotin reagents are: · Highly functional group tolerant · Readily synthesized via a variety of methods* · Air and moisture stable (often distillable) · Stable to the vast majority of organic reagents. OH OH Bu3Sn CHO Bu3Sn Bu3Sn CO2Et OTf CO2Et PO(EtO)2 CO2Et i) n-BuLi, DMPU, THF, 0°C ii) aldehyde, -78°C-> -20°C 2.5 mol% Pd2(dba)3 20 mol% AsPh3, NMP Dominguez Tetrahedron 1999 (55) 15071 3 eq. SO3 Py, 3eq. Et3N, CH2Cl2/DMSO 96% 73% 62% oxidation HWE condensation retinoic acid precursor Stille Coupling (n-Bu3Sn)(Bu)CuLi.LiCN * For comprehensive review of synthesis of aryl and vinyl stannanes see A.G Myers/A. Haidle Chem 115: "The Stille Reaction