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. 2011 Jun 3;13(11):2830-3.
doi: 10.1021/ol200784y. Epub 2011 May 2.

Enantioselective Pd(II)-catalyzed aerobic oxidative amidation of alkenes and insights into the role of electronic asymmetry in pyridine-oxazoline ligands

Richard I McDonald  1 , Paul B White, Adam B Weinstein, Chun Pong Tam, Shannon S Stahl
Affiliations

Enantioselective Pd(II)-catalyzed aerobic oxidative amidation of alkenes and insights into the role of electronic asymmetry in pyridine-oxazoline ligands

Richard I McDonald et al. Org Lett. .

Abstract

Enantioselective intramolecular oxidative amidation of alkenes has been achieved using a (pyrox)Pd(II)(TFA)(2) catalyst (pyrox = pyridine-oxazoline, TFA = trifluoroacetate) and O(2) as the sole stoichiometric oxidant. The reactions proceed at room temperature in good-to-excellent yields (58-98%) and with high enantioselectivity (ee = 92-98%). Catalyst-controlled stereoselective cyclization reactions are demonstrated for a number of chiral substrates. DFT calculations suggest that the electronic asymmetry of the pyrox ligand synergizes with steric asymmetry to control the stereochemical outcome of the key amidopalladation step.

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Figures

Scheme 1
Scheme 1
Pd(OAc)2/Pyridine-Catalyzed Intramolecular Aerobic Oxidative Amidation of an Alkene and Ligand Effects. Reaction conditions: 5 mol % PdX2, 7.5 mol % ligand (10 mol % Py), O2 (1 atm), molecular sieves 3 Å, toluene (0.1 M), 50 °C, 12 h.
Scheme 2
Scheme 2
Enantioselective Oxidative Amidation Employing Pyridine Oxazoline Ligands.
Scheme 3
Scheme 3
Ligand Substituent Effects and Reaction Optimization.a a Conditions: 1 (0.075 mmol), 1 atm O2, MS 3 Å (20 mg), toluene (0.75 mL), 12 h. Yield determined by 1H NMR spectroscopy, internal standard = 1,3,5-trimethoxybenzene. Enantiomeric excess deteremined by chiral HPLC (see Supporting Information for details). b 5.5 mol % ligand. c Without MS 3 Å. d 25 °C, 24 h. Isolated yield (0.5 mmol scale).
Scheme 4
Scheme 4
Calculated Ground- and Transition-State Energies Associated with the cis-Amidopalladation of an Alkene at a Pyridine-Oxazoline-Ligated PdII-Center.a a The cationic charge on all structures is omitted for clarity. Final structures were optimized with the following method (Gaussian 03): B3LYP; Stuttgart RSC 1997 ECP/triple-ζ basis for Pd; 6-311+G (d,p) basis on all other atoms; polarizable contiuum solvation model (toluene); see Supporting Information for computational details.
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