Palladium-Catalyzed Enantioselective Oxidations of Alcohols Using Molecular Oxygen

Abstract

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...

An Efficient Approach to Chiral Ferrocene‐Based Secondary Alcohols via Asymmetric Hydrogenation of Ferrocenyl Ketones

“…[11] A similar approach was introduced by Hayashi et al using chiral cyclopentadienyllithium generated from 6-(dimethylamino)fulvene in the presence (À)-sparteine. [12] Given that nucleophilic substitution at the chiral acarbon attached directly to the ferrocene proceeds with stereoretention, [10] some catalytic methods under non-reducing conditions such as asymmetric arylation of ferrocenecarboxaldehyde, [13] (À)-sparteine/Pd-mediated aerobic oxidative kinetic resolution [14,15] and stereoselective enzymatic acylation of racemic 2 [16] have been explored in attempts to synthesize optically pure 2, a precursor to Ugis amine. However, acquisition of both enantiomers of 2 is often difficult using these methods due to the unavailability of the antipodic catalyst.…”

Anaerobic Palladium‐Catalyzed Chemoselective Oxidation of Allylic and Benzylic Alcohols with α‐Bromo Sulfoxide as a Co‐oxidant

“…The mixture was degassed by alternative vacuum and argon purge cycles. a-Bromo sulfoxide (86.8 mg, 0.4 mmol) and THF (4 mL) were added and the mixture was heated at 65 8C for 12 h. The reaction mixture was taken up in ether (20 mL) and washed with a saturated NH 4 Cl aqueous solution and brine. The organic phase was dried over MgSO 4 , filtered, and concentrated under vacuum.…”

“…[2] In this context, the development of procedures that use molecular oxygen as the sole re-oxidant has been extensively pursued for economic and ecological reasons. [3,4] However, there are some persistent problems: a) the stability of metal ligands under aerobic oxidation conditions and b) metal aggregation and precipitation, which cause catalyst decomposition with a considerable loss of catalytic activity that occurs mainly under ligand-free conditions. This problem is particularly important in the case of Pd.…”

Asymmetric Catalysis Using Air: Clean Kinetic Resolution of Secondary Alcohols

“…One of the most significant discoveries in this area was the finding in 2001 that a palladium(II) complex of sparteine (2) was capable of catalyzing the aerobic oxidative kinetic resolution of alcohols, and particularly aryl alcohols, to give products of remarkably high ee under optimized conditions. [13][14][15] Some examples are given in Scheme 4, which serve to highlight the versatility of this method.…”