M.C. White. Chem 153 Cross-Coupling-129- Week of october 8. 2002 C-C coupling: a-arylation of ketones Proposed mechanism Pd-dba)3, 1.5 mol% Tol-BINAP 3.6 mol% NaOl-Bu. THF 70c 76% AryI-Br B-hydride elimination when unhindered are substrates. Moreover, the steric bulk of biNaP is thought to (士}BIAP account for the high levels of steric selectivity for ketones with 2 enolizable positions. Buchwald JACS 1997(119)11108 Asymmetric generation of all carbon quaternary centers Pd: dba)3, 10-20 mol% ( -BINAP,12-24 mol% Buchwald JACS 1998(120)1918 Milder base extends substrate scope: Buchwald JACS 2000(122)1360 Soft deprotonation when a weak base is used COMe 00款區 pKa of K2HPO4 +12 binding to electrophilic metal CO, Me base sensitive Pd(oAch, 1.0 mol% 2 mol% COMe CO,Me XantphosM.C. White, Chem 153 Cross-Coupling -129- Week of October 8, 2002 C-C coupling: α-arylation of ketones PdII Aryl Br P P Pd0 Ph Ph Ph Ph P P PdII Aryl P P Aryl-Br oxidative addition reductive elimination (±)-BINAP R ONa NaBr R O O R Ar Br O O O Pd2(dba)3, 1.5 mol% Tol-BINAP, 3.6 mol% NaOt-Bu, THF, 70oC O O O 76% Buchwald JACS 1997 (119) 11108 Br O Asymmetric generation of all carbon quaternary centers Pd2(dba)3, 10-20 mol% (-)-BINAP, 12-24 mol% NaOt-Bu, tol, 100oC 66%, 73% ee O Ph Bidentate ligands are required to prevent β-hydride elimination when unhindered aliphatic ketones are substrates. Moreover, the steric bulk of BINAP is thought to account for the high levels of steric selectivity for ketones with 2 enolizable positions. Proposed mechanism Buchwald JACS 1998 (120) 1918. Milder base extends substrate scope: Soft deprotonation when a weak base is used: PdII Aryl Br P P O R H B: O PPh2 PPh2 (t-Bu)2P Xantphos Buchwald 1 Br CO2Me O K3PO4, THF, 80oC O CO2Me Pd2(dba)3, 1.5 mol% Xantphos, 3.6 mol% 74% base sensitive functionality pKa = 16.7 note: pKa of K2HPO4 ~ 12 deprotonation must be assisted by ketone binding to electrophilic metal Br CO2Me O O K3PO4, dioxane, 100oC Pd(OAc)2, 1.0 mol% 1, 2 mol% 96% O O CO2Me Buchwald JACS 2000 (122) 1360