Overcoming the "oxidant problem": strategies to use O2 as the oxidant in organometallic C-H oxidation reactions catalyzed by Pd (and Cu)

Abstract

Oxidation reactions are key transformations in organic chemistry because they can increase chemical complexity and incorporate heteroatom substituents into carbon-based molecules. This principle is manifested in the conversion of petrochemical feedstocks into commodity chemicals and in the synthesis of fine chemicals, pharmaceuticals, and other complex organic molecules. The utility and function of these molecules correlate directly with the presence and specific placement of oxygen and nitrogen heteroatoms and other functional groups within the molecules. Methods for selective oxidation of C-H bonds have expanded significantly over the past decade, and their role in the synthesis of organic chemicals will continue to increase. Our group's contributions to this field are linked to our broader interest in the development and mechanistic understanding of aerobic oxidation reactions. Molecular oxygen (O(2)) is the ideal oxidant. Its low cost and lack of toxic byproducts make it a highly appealing reagent that can address key "green chemistry" priorities in industry. With strong economic and environmental incentives to use O(2), the commmodity chemicals industry often uses aerobic oxidation reactions. In contrast, O(2) is seldom used to prepare more-complex smaller-volume chemicals, a limitation that reflects, in part, the limited synthetic scope and utility of existing aerobic reactions. Pd-catalyzed reactions represent some of the most versatile methods for selective C-H oxidation, but they often require stoichiometric transition-metal or organic oxidants, such as Cu(II), Ag(I), or benzoquinone. This Account describes recent strategies that we have identified to use O(2) as the oxidant in these reactions. In Pd-catalyzed C-H oxidation reactions that form carbon-heteroatom bonds, the stoichiometric oxidant is often needed to promote difficult reductive elimination steps in the catalytic mechanism. To address this challenge, we have identified new ancillary ligands for Pd that promote reductive elimination, or replaced Pd with a Cu catalyst that undergoes facile reductive elimination from a Cu(III) intermediate. Both strategies have enabled O(2) to be used as the sole stoichiometric oxidant in the catalytic reactions. C-H oxidation reactions that form the product via β-hydride or C-C reductive elimination steps tend to be more amenable to the use of O(2). The use of new ancillary ligands has also overcome some of the limitations in these methods. Mechanistic studies are providing insights into some (but not yet all) of these advances in catalytic reactivity.

Figure 1

Ligand effects on stoichiometric acetoxylation of π–allyl–Pd complexes.

Figure 2

Evidence for reversible C–O reductive elimination from (DAF)Pd(η³–allyl) complexes (A), and mechanistic rationale for (L)Pd(η³–allyl)-catalyzed acetate exchange in cinnamyl acetate and the influence of an oxidant on the extent of exchange (B).

Figure 2

Evidence for reversible C–O reductive elimination from (DAF)Pd(η³–allyl) complexes (A), and mechanistic rationale for (L)Pd(η³–allyl)-catalyzed acetate exchange in cinnamyl acetate and the influence of an oxidant on the extent of exchange (B).

Figure 3

Dependence of the rate of o-xylene homocoupling on the identity of the ancillary pyridine ligands. The pK_a values correspond to those for the pyridinium ions in DMSO.

Scheme 1

Proposed Catalytic Mechanism of the Shilov Reaction.

Scheme 2

Simplified Catalytic Cycle for Pd^II/Pd⁰-catalyzed Aerobic Oxidation Reactions.

Scheme 3

Proposed Mechanism for Pd-Catalyzed Allylic Acetoxylation Using BQ as the Oxidant

Scheme 4

Net Anti-Markovnikov Hydration of Terminal Alkenes Involving Aerobic Allylic Acetoxylation, Acetate Cleavage, Alkene Hydrogenation Sequence.

Scheme 5

Oxidative Cross-Coupling of Indoles and Benzene with Stoichiometric Transition-Metal Oxidants.

Scheme 6

Proposed Mechanism for Pd^II-Catalyzed Dehydrogenation of Saturated C–C Bonds.

Scheme 7

Stepwise Sequence of Pd^II-Mediated Dehydrogenation of Cyclohexanones.

Scheme 8

Aerobic Dehydrogenation Provides access to Phenols or Cyclohexenones.

Scheme 8

Possible Mechanisms for Cu^II-Mediated C–H Activation and Formation of Aryl-Cu^III Species.

Scheme 9

Stepwise Mechanism for Cu-Catalyzed Aerobic C–H Oxidation.

Scheme 10

Oxidative Functionalization of 6 Catalyzed by Cu^II

Scheme 11

Aerobic Copper-Catalyzed Synthesis of Ynamides from Terminal Alkynes

Chart 1

Ligand Effects in Pd-Catalyzed Aerobic Allylic Acetoxylation.

Chart 2

Aerobic Allylic Acetoxylation of Terminal Alkenes

Chart 3

Identification of a Ligand for Aerobic Pd-Catalyzed Indole-Arene Cross-Coupling

Chart 4

Ligand Effects for Aerobic Dehydrogenation of 3-Methyl Cyclohexanone.

Chart 5

Phenols Prepared via Dehydrogenation of Cyclohexanone or Cyclohexenone Derivatives. ^a3% Pd(TFA)₂/6% ^NMe2py/12% TsOH ^b 5% Pd(TFA)₂/10% ^NMe2py/20% TsOH

Chart 6

Enones Prepared via Dehydrogenation of Cycloketone Derivatives.