Tailored quinones support high-turnover Pd catalysts for oxidative C-H arylation with O2

Abstract

Palladium(II)-catalyzed carbon-hydrogen (C-H) oxidation reactions could streamline the synthesis of pharmaceuticals, agrochemicals, and other complex organic molecules. Existing methods, however, commonly exhibit poor catalyst performance with high palladium (Pd) loading (e.g., 10 mole %) and a need for (super)stoichiometric quantities of undesirable oxidants, such as benzoquinone and silver(I) salts. The present study probes the mechanism of a representative Pd-catalyzed oxidative C-H arylation reaction and elucidates mechanistic features that undermine catalyst performance, including substrate-consuming side reactions and sequestration of the catalyst as an inactive species. Systematic tuning of the quinone cocatalyst overcomes these deleterious features. Use of 2,5-di-tert-butyl-p-benzoquinone enables efficient use of molecular oxygen as the oxidant, high reaction yields, and >1900 turnovers by the Pd catalyst.

Fig. 1.

Pd-catalyzed aerobic C–H oxidation reactions, highlighting challenges in catalyst performance. (A) Mechanisms for Pd^II-catalyzed oxidative olefination and arylation reactions using O₂ as the oxidant. (B) Catalytic metrics for representative oxidative arylation reactions (–16). (C) Comparison of catalyst turnovers in Pd-catalyzed olefination and arylation reactions (19, 21). MPAA = Mono-N-protected amino acid.

Fig. 2.

Kinetic and spectroscopic analysis of the Pd-catalyzed C–H arylation reaction. (A) Oxidative arylation conditions (R = 2-(trifluoromethyl)C₆H₄CH₂-). (B) Kinetic data showing a burst and the influence of O₂ pressure on the steady state arylation rate. (C) Simplified mechanism rationalizing the kinetic burst and BQ inhibition of steady state turnover. (D) Enhanced steady state rate observed with 2,5-^tBu₂BQ. (E) Reaction progress obtained from ¹⁹F NMR spectroscopic analysis of the reaction mixture to which different reaction components were added sequentially. Interpolative curve fits are included as a guide. (F) Kinetic data [2,5-^tBu₂BQ] for formation of 3 and Ar^F–H, with correlations reflecting a hyperbolic curve fit [y = ax/(1 + bx)]. (G) Spectroscopic observation of palladacycle resting state under 6.9 atm O₂, with linear and interpolative curve fits as a guide. Conditions: (A) [1] = 200 mM, 24 h (B, D, F) [1] = 100 mM, [Pd]_t = 5 mM, [Boc-Val-OH] = 10 mM, [quinone] = 20 mM, 85 °C, 1 mL, 1 atm O₂. (E, G) [1] = 100 mM, [Pd]_t = 10 mM, [Boc-Val-OH] = 20 mM, [2,5-^tBu₂BQ] = 40 mM, 64 °C, 0.55 mL.

Fig. 3.

Catalytic cycle consistent with the experimental data and computational analysis. (A) The proposed catalytic mechanism for C–H arylation of 1 (R = 2-(trifluoromethyl)C₆H₄CH₂-), and (B) calculated free energy diagram for protodemetalation and reductive elimination pathways in the absence and presence of quinones. See text and Supplementary Materials for details of the computational methods. TOF = Turnover Frequency, TON = Turnover Numbers

Fig. 4.

Catalytic performance with low catalyst loading. (A) Catalyst optimization data showing product ratios and catalyst turnover numbers (TON) for the oxidative coupling of 1 and 2. (B) Observed turnovers of 3 with different quinones/alkenes. (C) Application of mechanistic insights to other substrates and coupling partners. Conditions: (A,B) see conditions shown in above and below the arrow in A and B, 0.5 mL scale, Data based on NMR assay yield. (C) Identical to the conditions used in B except 0.5 mol% Pd was used with 30 mol% 2,5-^tBu₂BQ. [**] Reported catalyst turnovers with 5 mol % Pd(OAc)₂ and 20 mol % BQ (21). [^] A 93% isolated yield was obtained. [†] with 0.05 mol% Pd(O₂CR)₂ and 72 hours reaction time. [‡] A 96% isolated yield was obtained. [∫] Yields shown are isolated product yields. [#] 30 mol% 2,6-^tBu₂BQ was used. [§] 5 equivalents of methylboronic acid was used. [¶] K₂CO₃ was used as the base and no Ac-Ile-OH added.