Synthesis of Hydroxyaromatic Carboxylic Acids via Homogeneous Kolbe-Schmitt Carboxylation of Phenoxides

TL;DR

This paper presents a mild and efficient method for synthesizing hydroxyaromatic carboxylic acids using phenoxide carboxylation under homogeneous conditions.

Contribution

The study identifies optimal cations, solvents, and additives for high-yield and regioselective carboxylation of phenoxides.

Findings

DMSO directs CO2 attack to the para-position of phenoxide, while DMF provides higher overall yields.

Mesitolate salt addition can drive the reaction to completion with up to 98% yields.

Gasometry and NMR experiments reveal insights into carbonate complex stability and reactivity.

Abstract

Homogeneous Kolbe-Schmitt carboxylation of phenoxides offers a mild and effective alternative to the classical high-temperature solid-phase Kolbe-Schmitt reaction. To develop this into a practical synthetic approach, we investigated several fundamental dependencies, particularly the impact of cations (Na, K, Li, Cs, and Rb), phenoxide concentration, and solvents (DMSO or DMF) on the yield and regioisomeric ratio of hydroxyaromatic carboxylic acids (HACAs). We identified optimal conditions for the effective carboxylation of different phenoxides, including a chiral Ellman’s sulfinamide derived from ortho-vanillin. Both solvents and cations were found to be crucial in the carboxylation of phenoxides. Due to solvation effects, DMSO directs CO2 attack to the para-position of phenoxide, while DMF, although less selective, generally affords higher HACA yields. The addition of equiv. amounts of mesitolate salt to phenoxide in either DMSO or DMF solution often drives the reaction to completion, resulting in yields of up to 98%. Phenoxides containing several EWG groups, such as halogens or alkyl groups, adjacent to the reaction center show considerably lower reactivity in carboxylation; however, by carefully adjusting parameters, acceptable conversions (>70%) can be achieved. Using the gasometry, we assessed the stability of phenoxide and mesitolate carbonate complexes in DMSO. These experiments revealed distinct stages for the onset of decomposition and carboxylation at atmospheric pressure, indicating a lower energy barrier in the homogeneous process. Further insight into carbonate complex behavior was obtained through DOSY and 13C NMR experiments, which support increased molecular association in solution and correlate with enhanced reactivity.

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