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