M.C. White. Chem 153 Cross-Coupling- 120- Week of octo ber 8. 2002 Sonogashira: in situ, metal assisted deprotonation Cul(10 mol%), Et] NH solvent 3h nogashira TL 1975 (50) 100% stereospecificity catalytic cycle Order of reactivity of Csp-X component NHX Mild aryl bromide sonogashi P(t-Bu Pa(CHCN)Cl2(3%) R' Cu(39%) note: can also start with a pd(o) NEt3 (1.2 eq) source(e.g. Pd(Ph3 P) R=COMe, H, Me R'=Ph, hexyl, dioxane,rt OMe. NMe, C(OH(CH3)70-90% d RXR=aryl, alkeny =L. Br. otf Cl reductive P(t-Bu)3 is uniquely effective under these conditions. All other phosphines screened(PPh3, P(o-tol)3, dppf, PCy3)gave less Buchwald Fu OL 2000(2)1729 Php (PhaP),Pd Compare pKa's EtnA The acidity of the acetylene hydrogen is enhanced via T-complexation CuX R2NH'X nogashira JOMC 2002 (653)46
M.C. White, Chem 153 Cross-Coupling -120- Week of October 8, 2002 Sonogashira: in situ, metal assisted deprotonation Cl PdII Ph3P Cl PPh3 Ph H Br + (5 mol%) CuI (10 mol%), Et2NH solvent rt, 3h The first report: Ph 90% yield Sonogashira TL 1975 (50) 4467. 100% stereospecificity p Ka = 23 Cl PdII Ph3P Cl PPh3 catalytic cycle: ICu R CuX H R R3NH+ XPdII PPh3 PPh3 R R transmetalation (PPh3)2Pd0 note: can also start with a Pd(0) source (e.g. Pd(Ph3P)4). R' PdII Ph3P X PPh3 R R R' X R' = aryl, alkenyl X = I, Br, OTf, Cl CuX ICu R H R R3NH+ X- (Ph3P)nPdII R' R transmetalation oxidative addition reductive elimination R R' Ph H Et3NH+ p Ka = 10.75 Compare pKa's: The acidity of the acetylene hydrogen is enhanced via π-complexation : R H CuI Order of reactivity of Csp2-X component: I , Br > I > Cl >> Br Mild aryl bromide Sonogashira couplings with P(t-Bu)3 Br R R= COMe, H, Me OMe, NMe2 R' R' = Ph, hexyl, C(OH)(CH3)2 R' R CuI (3%) NEt3 (1.2 eq) dioxane, rt Pd(CH3CN)2Cl2 (3%) P(t-Bu)3 (6%) 70-90% P(t-Bu)3 is uniquely effective under these conditions. All other phosphines screened (PPh3, P(o-tol)3, dppf, PCy3) gave less than 2% yield. Buchwald & Fu OL 2000 (2) 1729. Sonogashira JOMC 2002 (653) 46
M.C. White. Chem 153 Cross-coupling -121- Week of october 8. 2002 Sonogashira: Csp-Csp2 coupling method of choice OH o OMe o o OMe o Meo n Meo Me Leucascandrolide a Pd(PPh3)4(10 mo%) yOMe Cul (5 mol%) TBDPSO OMe TBDPSQ dioxane. rt 84% oxidative addition Pd(PPh3)4 CuL. 2. 6-lutidine off deprotonation PPh2+ TBDPSO、 OMe reductive elimination PPh PhaR OMe TBDPSO Panek joc2002676812-6815
M.C. White, Chem 153 Cross-coupling -121- Week of October 8, 2002 O Me Me Me OMe O O O O MeO N H O N O O O Me Me Me OMe O OH O O HO MeO N H O N O O + Leucascandrolide A Sonogashira: Csp-Csp2 coupling method of choice Panek JOC 2002 67 6812-6815 O N OTf TBDPSO N H OMe O H N H OMe O ICu Pd(PPh3)4 O N Pd TBDPSO PPh3 Ph3P O N Pd TBDPSO PPh3 Ph3P HN OMe O O N TBDPSO NH OMe O + Pd(PPh3)4 (10 mo%) CuI (5 mol%) 2,6-lutidine dioxane, rt 84% CuI, 2,6-lutidine soft deprotonation oxidative addition transmetalation reductive elimination TfO- +
MC White/Q Chen Chem 153 Cross-Coupling- 122 Week of october 8, 2002 Sonogashira: FG Tolerance pd(CHaCN)cl(4 mol%) PMBO OH CO,Me Cul(14%), Et3N(5 eq) CO,Me CH3CN,-20° C to rt reduc oxidative addition Mec Meo Cul OrMe Meo,c OMe OMe n azole c Hillier, M.C. Meyers, A L JOC 2001, 66, 6037-6045
M.C White/Q. Chen Chem 153 Cross-Coupling-122- Week of October 8, 2002 Sonogashira: FG Tolerance PMBO OH H O N CO2Me MeO I O N MeO2C MeO Pd I L L PMBO OH CuI L Pd L PMBO OH O N CO2Me MeO PMBO OH O N CO2Me MeO + Pd(CH3CN)2Cl2 (4 mol%), CuI (14%), Et3N (5 eq) CH3CN, -20 °C to rt 87% L = CH3CN in situ deprotonation oxidative addition transmetalation reductive elimination O OMe N O O N OMe O O O Disorazole C1 Functional groups well tolerated: ester, free hydroxyl, allylic ether, and benzylic ethers, etc. Hillier, M.C.; Meyers, A.I. JOC 2001, 66, 6037-6045
MC White. Chem 153 Cross-Coupling- 123 Week of october 8. 2002 Sonogashira/Suzuki 3-Component Coupling Pd(PPh3hCh(2.5 mol%) O2M Et,N (2 eq. NH2 THF, rt, OM (OiPrh OMe CsF (3 eq. Pd-dba3 (l mol%) reductive oxidative addition I CO2MeH2O, acetone50℃ 59% Yield elimination 2 MeOc ome B(OiPrh PhaP PdL C NH2 (PriO)28 Pri0-B-OiPr B(OiPrh transmetalation 2 elimination Nh E小N| in situ depro HN Yu1998(39)9347
M.C White, Chem 153 Cross-Coupling-123- Week of October 8, 2002 Sonogashira/Suzuki 3-Component Coupling Br B(OiPr)2 NH2 Cl Cl Br CO2Me OMe H2N Cl Cl Pd Br Ph3P Ph3P B(OiPr)2 CuI Et3N H2N Cl Cl ICu Pd Ph3P Ph3P B(OiPr)2 Cl Cl NH2 NH2 Cl Cl CO2Me OMe Br CO2Me OMe Pd Br L L MeO CO2Me NH2 Cl Cl (PriO)2B CuI (5 mol%), Pd(PPh3)2Cl2 (2.5 mol%) Et3N (2 eq.) THF, rt; CsF (3 eq.) Pd2dba3 (1 mol%) H2O, acetone 50 oC 59% Yield Pd2dba3 NH2 Cl Cl Pd MeO2C OMe L oxidative addition 1 transmetalation 1 reductive elimination 1 in situ deprotonation transmetalation 2 oxidative addition 2 reductive elimination 2 CsFPr B OiPr iO F _ Yu TL 1998 (39) 9347
M.C. White Chem 153 Cross Coupling-124- Week of october 8. 2002 Stille: C-N bond formation Migita's original report Plan P(o-tol)] 10 mol% Br +(Bu3Sn + n-Bu SnBr toluene,100°C,3h reactions limited to electron neutral aryl bromides Migita chem lett 1983. 927 Elegant mechanistic studies (o-tolB3(L-P(o-tol) Paqur-CI Bu]SnNEt!(o-tolBgR Pd (EthAN P(o-tol)3 3 was independently synthesized to 2 was isolated /characterized by x-ray confirm that the reaction procedes via Pd(o) intermediates. Reaction with 3 AryF-NEtz P(o-tol)3Pd() Arvk-Br crystallography and shown to be a viable catalyst for the aryl amination was faster than those with 2, making it reductive (ields identical to those obtained for 1) kinetically competent as an intermediate in the reaction. Th eaction was retarded by excess dissociation occurs before oxidative (o-tol)3 PPd/t-Ary Aryl a-tol3 (o-tol3h amsmmetalat was isolated/characterized by X-ra crystallography and shown to react with Et,N-Sn Bu BuaSnNEt2 to give the arylamine product in 90% yield. The inability of 4 to undergo xchange with other aryl bromides(i.e Hartwig JACS 1994(116)5969 p-BuAr-Br) indicates that it is a legitimate ntermediate in the catalytic cycle
M.C. White, Chem 153 Cross Coupling -124- Week of October 8, 2002 Migita's original report: Br + (Bu)3Sn N (o-tol)3P Pd(II) Cl P(o-tol)3 Cl 10 mol% toluene, 100oC, 3h 87% N + n-Bu3SnBr Migita Chem Lett 1983, 927. reactions limited to electron neutral aryl bromides Stille: C-N bond formation Hartwig JACS 1994 (116) 5969. Pd(II) (o-tol)3PPd(II) Aryl Br (o-tol)3PPd(II) Aryl NEt2 Aryl NEt2 Cl P(o-tol)3 P(o-tol)3Pd(0) Aryl-Br oxidative addition transmetalation reductive elimination Elegant mechanistic studies: (o-tol)3P Cl Pd(II) Cl Cl (o-tol)3P (Et)2HN 2 1 2 was isolated /characterized by x-ray crystallography and shown to be a viable catalyst for the aryl amination (yields identical to those obtained for 1). Bu3SnNEt2 Pd(0) 3 (o-tol)3P P(o-tol)3 3 was independently synthesized to confirm that the reaction procedes via Pd(0) intermediates. Reaction with 3 was faster than those with 2, making it kinetically competent as an intermediate in the reaction. The reaction was retarded by excess phosphine, indicating phosphine dissociation occurs before oxidative addition. P(o-tol)3 Pd(II) Cl Cl Aryl (o-tol)3P 4 Pd(II) P(o-tol)3 Aryl 4 was isolated/characterized by x-ray crystallography and shown to react with Bu3SnNEt2 to give the arylamine product in 90% yield. The inability of 4 to undergo exchange with other aryl bromides (i.e. p-BuAr-Br) indicates that it is a legitimate intermediate in the catalytic cycle. Et BrSnBu3 2N-SnBu3