M.C. White Chem 153 Cross Coupling-126- Week of october 8. 2002 Sn free c-n bond formation: Pd-mediated soft deprotonation Initial results limited to coupling of 2 amines and /amines with electron-deficient aryl bromides 1 amine: only w/para electron Buchwald ACIEE 1995(34)1348. P山dba)2 Po-tol)32mol9 Me,n Br HN(Ph)Me NabU(1.4 eq Me 65-100C toler 72% Hartwig TL 1995(36)3609 1° amIne PdCl(P(o-tol)3h, 5 mol% Meo LiNTMSh2(1.2 eq) 100°C. toluene 94% 2%(1: 50, amine: arene) Buchwald OM 1996(15)2745 and 2755 Buchwald OM 1996(15)3534 RIRA bridging amido complex ArNER esists reductive elimination olap RIR oxidati 阝 hydride elimination (o-tol)3 PPd(K (o-toI3PPd (o-toll3 PPd(Aryl N(CHRR HOr-B NaBr Reduced side-product is observed in large R HN(CHR R HN(CHR R quantities when using 1 aliphatic amines deprotonation (o-tol3P NaOt-Bu Making use of a bidentate ligand may be a way to inhibit pathways that errode product P(o-toI)3HN(CH2RR formation(i.e B-hydride elimination, bis(amine)aryl halide and bridging amido complex formation). However, kinetic studies by Hartwig showing that both oxidative ddition and reductive elimination go through 3 coordinate intermediates indicated that bidentate ligands may shut the reaction down PaqIr HN(CHR)R2 catalytically inactive is( amine)aryl halide R(RHC)NHM.C. White, Chem 153 Cross Coupling -126- Week of October 8, 2002 Sn Free C-N bond formation: Pd-mediated soft deprotonation Making use of a bidentate ligand may be a way to inhibit pathways that errode product formation (i.e. β-hydride elimination, bis(amine) aryl halide and bridging amido complex formation). However, kinetic studies by Hartwig showing that both oxidative addition and reductive elimination go through 3 coordinate intermediates indicated that bidentate ligands may shut the reaction down. (o-tol)3PPd(II) Aryl Br (o-tol)3PPd(II) Aryl N(CH2R1)R2 Aryl NR1R2 P(o-tol)3Pd(0) Aryl-Br oxidative addition reductive elimination P(o-tol)3 Pd(II) HN(CH2R1)R2 Br Aryl (o-tol)3P HN(CH2R1)R2 + NaBr (o-tol)3PPd(II) Aryl H β-hydride elimination reductive elimination Ar-H P(o-tol)3Pd(0) Reduced side-product is observed in large quantities when using 1o aliphatic amines soft deprotonation N R1 H R2 HN(CH2R1)R2 Pd(II) HN(CH2R1)R2 Br Aryl R2(R1H2C)NH catalytically inactive bis(amine) aryl halide complexes HOt-Bu NaOt-Bu Pd(II) R1R2 N N R1R2 Aryl (o-tol)3P Pd(II) P(o-tol)3 Aryl bridging amido complex resists reductive elimination Buchwald OM 1996 (15) 2745 and 2755. Buchwald OM 1996 (15) 3534. Me2N Br HN(Ph)Me Me2N N Ph Me N Ph O n-hexyl H MeO HN N Br MeO Bu N n-Bu H Initial results limited to coupling of 2o amines and 1o amines with electron-deficient aryl bromides Buchwald ACIEE 1995 (34) 1348. + [Pd(dba)2]/2 P(o-tol)3, 2 mol% or PdCl2(P(o-Tol)3)2 NaOtBu (1.4 eq) 65-100oC, toluene 89% 72% 1o amine: only w/ para electron withdrawing groups: Why? Hartwig TL 1995 (36) 3609. PdCl2(P(o-Tol)3)2 , 5 mol% LiN(TMS)2 (1.2 eq) 100oC, toluene + 94% <2% (1:50; amine:arene) 1o amine