Copper-Catalyzed Vinylogous Aerobic Oxidation of Unsaturated Compounds with Air

Abstract

A mild and operationally simple copper-catalyzed vinylogous aerobic oxidation of β,γ- and α,β-unsaturated esters is described. This method features good yields, broad substrate scope, excellent chemo- and regioselectivity, and good functional group tolerance. This method is additionally capable of oxidizing β,γ- and α,β-unsaturated aldehydes, ketones, amides, nitriles, and sulfones. Furthermore, the present catalytic system is suitable for bisvinylogous and trisvinylogous oxidation. Tetramethylguanidine (TMG) was found to be crucial in its role as a base, but we also speculate that it serves as a ligand to copper(II) triflate to produce the active copper(II) catalyst. Mechanistic experiments conducted suggest a plausible reaction pathway via an allylcopper(II) species. Finally, the breadth of scope and power of this methodology are demonstrated through its application to complex natural product substrates.

Scheme 1

Copper-Catalyzed Vinylogous Aerobic Oxidation of β,γ-Unsaturated Compounds and Undesired Oxidation Pathways

Scheme 2

Vinylogous Aerobic Oxidation of 2a under the Reported Reaction Conditions (¹H NMR Yields Are Given)

Scheme 3

Copper-Catalyzed Bisvinylogous and Trisvinylogous Aerobic Oxidation under an Air Atmosphere

Scheme 4

Catalytic Vinylogous Aerobic Oxidation of (E/Z)-β,γ-Unsaturated Esters and (E/Z)-α,β-Unsaturated Esters (¹H NMR Yields Are Given)

Scheme 5

¹⁸O Labeling Experiment

Scheme 6

Treatment of Product 7a with the Reaction Conditions

Scheme 7

Efforts to Capture a Peroxide Species through an Intramolecular Oxa-Michael Addition

Scheme 8

Proposed Mechanism for the Copper-Catalyzed Aerobic Vinylogous Oxidation

Scheme 9

Copper-Catalyzed 10 g-Scale Vinylogous Aerobic Oxidation

Scheme 10

Application of the Present Catalytic Vinylogous Aerobic Oxidation to Structure Modification and Total Synthesis of Natural Products