M.C. White. Chem 153 Cross Coup pling-I Week of octo ber 8. 2002 Migita's original report Stille: C-N bond formation Br +(BusIn toluene,100°C,3h Bu SnBr 87% reactions limited to electron neutral aryl bromides Migita Chem Lett 1983. 927 Demonstration of Synthetic Utility Buchwald JACS 1994(116)7901 one-pot amine is removed transamination a Potol) via the Ar purge (Bu)Sm. HNRR R 1-2.5mol% toluene 105C Et, 55-88% Buchwald hypothesizes that the lack of generality of Migata's system is due to the high reactivity/instability of aminostannes which hinders their isolation and further use. To address this problem he develops a one-pot procedure that involves in situ generation of the aminostannes coupled with Migata's Pd catalyzed aryl amination. The substrate scope is significantly expanded to include a wide variety of 2 aryl /alkyl amines(only example of a 1 amine is aniline)and aryl bromides substituted with both electron withdrawing and electron donating groups Representative examples Ph EtO,c Me,n 81% 79
M.C. White, Chem 153 Cross Coupling -125- Week of October 8, 2002 Migita's original report: Stille: C-N bond formation 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 Demonstration of Synthetic Utility: (Bu)3Sn N + HNRR' 80oC Ar purge HNEt2 (Bu)3Sn N R R' Br R' Buchwald hypothesizes that the lack of generality of Migata's system is due to the high reactivity/instability of aminostannes which hinders their isolation and further use. To address this problem he develops a one-pot procedure that involves in situ generation of the aminostannes coupled with Migata's Pd catalyzed aryl amination. The substrate scope is significantly expanded to include a wide variety of 2o aryl /alkyl amines (only example of a 1o amine is aniline) and aryl bromides substituted with both electron withdrawing and electron donating groups. transamination the more volatile amine is removed via the Ar purge (o-tol)3P Pd(II) Cl P(o-tol)3 Cl 1-2.5 mol% toluene, 105oC 55-88% N R R' R' Representative examples: EtO2C N Ph 88% Me2N N Ph 81% N (CH2)17CH3 79% N 66% Buchwald JACS 1994 (116) 7901. one-pot
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)NH
M.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