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The discovery and investigation of ligand-modulated Pd-catalyzed aerobic alcohol oxidations is documented. The project has evolved from a simple empirical discovery that (-)-sparteine, in combination with Pd(II) salts, facilitates the aerobic oxidative kinetic resolution of secondary alcohols to an in-depth physical organic investigation that has provided key insights into how new, more effective catalysts can be designed. Mechanistic investigations, the substrate scope for the catalysts developed, and implications to oxidation catalysis are discussed.

The use of molecular oxygen as a stoichiometric reoxidant in combination with a catalytic metal has exceptional practical advantages for applications in organic synthesis. 1 This is in part due to the favorable economics associated with molecular oxygen and the formation of environmentally benign byproducts in the oxidation manifold (water and hydrogen peroxide). An excellent example of the use of molecular oxygen in organic synthesis is the metal-catalyzed aerobic oxidation of alcohols to aldehydes and ketones. 2,3 We became interested in extending the scope of these oxidations to asymmetric catalysis. 4 To this end, we envisioned two potentially useful reactions: (1) the oxidative kinetic resolution of racemic secondary alcohols, 5 kinetic resolutions that have previously been accomplished using acylation 6 and oxidation, 7,8 and (2) the oxidative desymmetrization of mesodiols. 9 Herein we report a convenient, enantioselective aerobic oxidation of alcohols mediated by Pd(II) and a chiral diamine.Aerobic oxidations of alcohols using catalytic Pd(II) salts have been reported. 3a-d Of particular interest is the observation that amine additives 3a-c both effect ligand-accelerated catalysis 10 and extend the substrate scope. Therefore, we initiated our investigation for an oxidative kinetic resolution catalyst by screening various chiral amine ligands in addition to common ligands for Pd-mediated asymmetric reactions (Table 1, eq 1). Bi-and tridentate ligands were generally poor templates for oxidation giving low conversions (entries b, f, g, and h). In contrast, Pd(II) complexes derived from pyridine ligands with 3-substitution gave high conversions, albeit with low k rel values 11 (entries c and e). The most promising result from this initial screen was that (-)-sparteine, a chiral tertiary diamine, gave the best k rel (2.6).To improve both the reaction rate and k rel , the reaction parameters of the (-)-sparteine/Pd(II) catalyst system were optimized. Ten reaction parameters in a single apparatus were simultaneously examined under identical temperature and oxygen pressure (balloon pressure). 12,13 During each screen, aliquots were periodically analyzed using an autosampling GC equipped with a chiral column. The optimization procedure allowed us to efficiently examine the effect of solvent, component concentration, Pd(II) source, and molecular sieves 14 on k rel and reaction rate. After screening these parameters, two sets of conditions were identified. Conditions A: 0.5 M 1a in 1,2-dichloroethane, 15 20 mol % (-)-sparteine, and 5 mol % of Pd(OAc) 2 and conditions B: 0.25 M 1a in 1,2-dichloroethane, 20 mol % (-)-sparteine, and 5 mol % of a soluble PdCl 2 source (Pd(MeCN) 2 Cl 2 and Pd-(COD)Cl 2 gave similar results). Using both conditions the effect of temperature was evaluated. For Pd(OAc) 2 , the temperature was found to have a significant influence on enantioselectivity wherein a temperature of 60°C gave the highest k rel value, while no significant temperature effect was observed for PdCl 2 sources. Overall fo...

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A breath of fresh air: A variety of alcohols are oxidized using 0.5–0.1 mol % of the catalyst, and in some cases the oxidation can simply be carried out open to the air (see scheme). Mechanistic insight into the mechanism is provided by a crystal structure that shows remarkable hydrogen bonds between the coordinated water and acetate ligands and an unprecedented large kinetic isotope effect.