The Mechanism of Pd-Catalyzed Amination Controversy….. And Conclusion? Br R1 Pd(dba)2 R1 R HN N R2 BINAP, PhMe R R2 Steve Tymonko SED Group Meeting 5/9/06 Pd-Catalyzed Amination- Tin Initial Report- Kosugi, 1983 Br PdCl2(o-tolyl3P)2 NEt2 n-Bu SnNEt 3 2 PhMe, 1000C 87 % Hartwig, 1994 Me P(o-tolyl) 3 Br PhMe, rt Pd n-Bu3SnNEt2 NEt2 Pd(o-tolyl P) Br Br 3 2 Me 87 % Pd or LiNEt Me 2 (o-tolyl) P 3 60- 90 % Me Tin mediated cross-couplings were rarely used due to poor substrate scope and toxicity Kosugi, M. et al. Chem. Lett. 1983, 927 Hartwig, J. et al. J. Am. Chem. Soc. 1994, 116, 5969 Moving Beyond Tin Pd(dba) / P(o-tolyl) 2 3 Pd(o-tolyl P) 3 2 or PdCl (o-tolyl P) 2 3 2 or PdCl (o-tolyl P) ArylBr HNRR' ArylNRR' ArylBr HNRR' 2 3 2 ArylNRR' NaOt-Bu LiN(SiMe ) or NaOt-Bu 3 2 PhMe, 65 - 1000C PhMe, 1000C, 2h Me Ph O N N Ph N N N N Me Ph MeO Ph Me2N C4H9 C4H9 86 % 86 % 71 % 84 % 72 % 94 % NHBn N Bn Br 92 % Preparatively simple reactions with no need for Sn Limited to secondary amines Buchwald, S. et al. Angew. Chem. Int. Ed. 1995, 34, 1348 Hartwig, J. et al. Tetrahedron Lett. 1995, 36, 3609 New Ligands, Better Generality Pd (dba) / BINAP 2 3 (DPPF)PdCl ArylBr HNRR' ArylNRR' ArylBr HNRR' 2 ArylNRR' NaOt-Bu NaOt-Bu PhMe, 800C THF, 1000C Ph Me Me Me H N Ph Me N C6H13 Me NH HN C H OMe HN N Ph 4 9 Ph NC Me Me O Me 94 % 88 % 79 % 93 % 96 % 87 % Bidentate ligands prevent !-hydride elimination Buchwald, S. et al. J. Am. Chem. Soc. 1996, 118, 7215 Hartwig, J. et al. J. Am. Chem. Soc. 1996, 118, 7217 Other Early Observations and Advances t-Bu t-Bu t-Bu Ph Ph Ph Ph PhNH H P NaOt-Bu P 2 Ph Ph N Fe Pd Fe Pd P P Br THF, rt P Ot-Bu THF, rt Fe Pd Ph Ph Ph Ph P NHPh t-Bu Ph Ph 92 % (DPPF)PdCl 2 ArylOTf HNRR' ArylNRR' NaOt-Bu THF, 1000C Pd(dba) / Pt-Bu 2 3 ArylCl HNRR' ArylNRR' NaOt-Bu PhMe, rt Pd(dba) / BINAP 2 ArylBr HNRR' compatible with esters, ketones, nitriles, etc Cs CO 2 3 PhMe, 1000C Greatly expanded substrate scope for both amine and halide coupling partners Hartwig, J. et al. J. Am. Chem. Soc. 1996, 118, 13109 Hartwig, J. et al. Angew. Chem. Int. Ed. 1198, 37, 2407 Hartwig, J. et al. J. Org. Chem. 1999, 64, 5575 Buchwald, S. el al. J. Org. Chem. 2000, 65, 1144 Hartwig- Pd(0) Catalyst Preparation PhH Pd[P(o-tolyl )] BINAP (BINAP) Pd 3 2 2 (racemic or resolved) 87 % PhH Pd[P(o-tolyl )] DPPF (DPPF) Pd Pd (DPPF) 3 2 2 2 3 P-Pd-P angles: in BINAP complexes 90-91o in DPPF complexes 98-101o Ligated Pd(0) complexes will simplify kinetic analysis Hartwig, J. et al. J. Am. Chem. Soc. 2000, 122, 4618 Oxidative Addition Ph Ph Br P Br PPh (BINAP) Pd 2 2 Pd faster in THF PhMe, 400C P PhMe, 400C Pd Br 2h Ph Ph 12h PPh3 Ph Ph Br Ph Ph P (DPPF) Pd 2 Fe Pd P PhMe, 400C P Br xylenes, 1300C Fe 2h Ph Ph 18h Pd PPh3 Br 89 % Oxidative addition products can decompose under the reaction conditions Hartwig, J. et al. J. Am. Chem. Soc. 2000, 122, 4618 Oxidative Addition Ph Ph Br P Br (BINAP) Pd BINAP Pd 2 solvent P 2.26 x 10-5 M Ph Ph solvent rate (x10-5 s-1) PhH 9.9 THF 7.3 PhMe 8.1 bromide rate (x10-4 s-1) 2-OMe 3.9 2-Me 4.4 1st order in bromide under 1.78 x 10-3 M -1st order in ligand H 4.3 0th order at high bromide concentration taken in saturation range With DPPF all data matches except always 1st order in bromide Hartwig, J. et al. J. Am. Chem. Soc. 2000, 122, 4618 Oxidative Addition Mechanism Given the previous data, which of the following mechanisms is operative? Hartwig, J. et al. J. Am. Chem. Soc. 2000, 122, 4618 Reductive Elimination Ph P 3 Pd PPh Me N Me N PPh 3 3 PhMe, 1100C 22 to 68mM 0.23 mM Me Me Rate between 0 and -1st order in ligand 1st order in Pd Paths C and E both operate Hartwig, J. et al. J. Am. Chem. Soc. 1997, 119, 8232