Hydrodecarboxylation of Carboxylic and Malonic Acid Derivatives via Organic Photoredox Catalysis: Substrate Scope and Mechanistic Insight

Abstract

A direct, catalytic hydrodecarboxylation of primary, secondary, and tertiary carboxylic acids is reported. The catalytic system consists of a Fukuzumi acridinium photooxidant with phenyldisulfide acting as a redox-active cocatalyst. Substoichiometric quantities of Hünig's base are used to reveal the carboxylate. Use of trifluoroethanol as a solvent allowed for significant improvements in substrate compatibilities, as the method reported is not limited to carboxylic acids bearing α heteroatoms or phenyl substitution. This method has been applied to the direct double decarboxylation of malonic acid derivatives, which allows for the convenient use of dimethyl malonate as a methylene synthon. Kinetic analysis of the reaction is presented showing a lack of a kinetic isotope effect when generating deuterothiophenol in situ as a hydrogen atom donor. Further kinetic analysis demonstrated first-order kinetics with respect to the carboxylate, while the reaction is zero-order in acridinium catalyst, consistent with another finding suggesting the reaction is light limiting and carboxylate oxidation is likely turnover limiting. Stern-Volmer analysis was carried out in order to determine the efficiency for the carboxylates to quench the acridinium excited state.

Figure 1

Comparison between efficiency of decarboxylation of (a) malonic acids and (b) malonate monoesters. Control experiments were done without catalyst to ensure a thermal decomposition pathway was not active.

Figure 2

Deuterium labeling experiments (a) decarboxylation of 2,2-dimethyl 3-phenyl propanoic acid run in d₂-TFE to determine if TFE was a catalytically active hydrogen atom donor. (b) Decarboxylation in d₁-TFE showing that the proton from the carboxylic acid starting material is incorporated in the product.

Figure 3

Initial rates of decarboxylation for (a) 2,2-dimethyl 3-phenyl propanoic acid and (b) the deuterated analogue. The rate of decarboxylation of the deuterated analogue was determined using d₁-TFE as a solvent; ¹H NMR analysis shows the complete deuterium incorporation in the product. Each initial rate was calculated based on 3 trials, giving an average KIE of 1.01.

Figure 4

Comparison of initial rate of reaction for the decarboxylation of 2,2-dimethyl 3-phenyl propanoic acid under irradiation with 2 blue LED lamps and 1 blue LED lamp.

Figure 5

Oxidation potentials of the tetrabutylammonium salts of three representative carboxylic acids were measured in a 0.1 M solution of tetrabutylammonium hexafluorophosphate in acetonitrile, vs SCE.

Figure 6

Bimolecular quenching constants measured for the potassium salts of each carboxylic acid in TFE.

Figure 7

Competition experiments in (a) TFE and (b) 9:1 MeOH/H₂O in which equimolar amounts (0.25 mmol) of each substrate were in the same reaction vessel. Other reagents were added in their respective quantities relative to the total amount of carboxylate in the reaction. The reactions were stopped at about 30% conversion. Yields were measured by analysis of crude ¹H NMR spectra.

Figure 8

UV/vis absorption spectra of the catalyst before and after adding carboxylate salt. The red line shows Mes-Acr-Ph before the addition of carboxylate. The yellow line shows the absorption spectrum of the catalyst after adding the carboxylate. The blue line is the absorption spectrum of the carboxylate and the dashed black line is the subtraction of the carboxylate from the absorption spectrum of the catalyst with added quencher (yellow-blue).

Figure 9

(a) ¹H NMR spectra of Mes-Acr-Ph BF₄ [25 mM] in CD₃OD. Residual methanol solvent peak was set to 3.31 ppm in each ¹H NMR. (b) ¹⁹F NMR spectra of Mes-Acr-Ph BF₄ [25 mM] in CD₃OD. Samples were spiked with 20 μL of TFE before taking ¹⁹F NMRs and the corresponding peak was set to −78.82 ppm in each spectrum. TBA⁺ RCOO⁻ = tetrabutylammonium hydrocinnamate.

Scheme 1

Progression of Hydrodecarboxylation Strategies

Scheme 2

Proposed Mechanism for Decarboxylation

Chart 1. Hydrodecarboxylation Reaction Scope^a

^aReactions carried out in N₂-sparged TFE [0.5 M]. ^bYields for volatile compounds were determined by GC. ^cAverage of two isolated yields on >100 mg scale. ^d[0.3 M] in TFE/EtOAc (4:1). ^eTwenty mole percent Ph₂S₂.

Chart 2. Malonic Acid Derivative Decarboxylation^a

^aReactions carried out in N₂-sparged TFE [0.5 M]. ^bYields for volatile compounds were determined by GC. ^c1.1 equiv of KOH used in place of KOt-Bu. ^dAverage of two isolated yields on >100 mg scale.