Enantioselective Decarboxylation of β‐Keto Esters with Pd/Amino Alcohol Systems: Successive Metal Catalysis and Organocatalysis

Abstract

The kinetics and mechanisms of one-pot cascade reactions of racemic beta-keto esters to give chiral ketones in the presence of Pd/C-chiral amino alcohol catalyst systems were studied. Transformation of 2-methyl-1-tetralone-2-carboxylic acid benzyl ester (1) into 2-methyl-1-tetralone (4) in the presence of Pd/C and cinchona alkaloids or ephedrine was chosen as a model reaction. After the first reaction step, the Pd-catalysed debenzylation of 1 to afford the corresponding beta-keto acid (2), there are two possible reaction routes that may be catalysed by the chiral amino alcohol in solution or by Pd(0) sites on the metal surface in cooperation with the adsorbed amino alcohol. The reaction intermediate 2 was synthesized, and the kinetics of decarboxylation were followed by NMR, UV and IR spectroscopy. The studies revealed that the role of Pd is to trigger the reaction series by deprotection of 1. The subsequent dominant reaction route from the racemic beta-keto acid 2 to the chiral ketone 4 is catalysed by the chiral amino alcohol in the liquid phase. It is shown that kinetic resolution of the diastereomeric salt of rac-2 and the chiral amino alcohol plays a key role in the enantioselection. High enantioselectivity necessitates an amino alcohol/rac-2 ratio of at least 2. A high ratio favours the formation of 1:1 amino alcohol/acid diastereomeric complexes, and the second amino alcohol molecule may be responsible for the enantioselective protonation of 2 in the diastereomeric complex.

On the mechanism of the domino reaction of 2-methyl-2-benzyloxycarbonyl-1-indanone mediated by palladium, hydrogen and aminoalcohols

“…11,12 Interestingly, Baiker and co-workers showed that the reaction of such a β-ketoacid with AH* leads to the corresponding diastereomeric ammonium β-ketocarboxylates, and that their subsequent evolution towards the ketone proceeds at different rates. 13 According to these authors, this evolution would implicate the protonation of the ammonium salts by a second molecule of AH*, which would occur from the side opposed to their carboxylate unit and simultaneously with the breaking of the C-CO 2 bond. 13 They also assumed that the Pd/AH*-mediated domino reaction of a benzyl β-ketoester involves the corresponding β-ketoacid as the only intermediate responsible of the enantioselection, and its transformation via their concerted mechanism proposal.…”

“…13 According to these authors, this evolution would implicate the protonation of the ammonium salts by a second molecule of AH*, which would occur from the side opposed to their carboxylate unit and simultaneously with the breaking of the C-CO 2 bond. 13 They also assumed that the Pd/AH*-mediated domino reaction of a benzyl β-ketoester involves the corresponding β-ketoacid as the only intermediate responsible of the enantioselection, and its transformation via their concerted mechanism proposal. 13 We were not confident in this mechanism of the enantioselective reaction of benzyl β-ketoesters, which was based on computational studies from Strassner et al on the enantioselective decarboxylation of a Naproxen intermediate.…”

“…13 They also assumed that the Pd/AH*-mediated domino reaction of a benzyl β-ketoester involves the corresponding β-ketoacid as the only intermediate responsible of the enantioselection, and its transformation via their concerted mechanism proposal. 13 We were not confident in this mechanism of the enantioselective reaction of benzyl β-ketoesters, which was based on computational studies from Strassner et al on the enantioselective decarboxylation of a Naproxen intermediate. 14 Moreover, Brunner and Baur have denied the Strassner proposal.…”

Cinchona‐Mediated Enantioselective Protonations

“…Overall, the same level of selectivity was achieved compared to Muzart/H enins work. However, Baiker concluded from a thorough mechanistic study to an organocatalytic process by the cinchona alkaloid alone, the Pd being only necessary for the initial debenzylation of the ester [32].…”

Asymmetric one-pot reactions using heterogeneous chemical catalysis: recent steps towards sustainable processes

“…95 Kinetic studies of decarboxylation by NMR, IR and UV spectroscopy using cinchona alkaloids confirmed that following hydrogenolysis the dominant reaction route was catalysed by the chiral compound in the liquid phase as a homogeneous asymmetric organocatalytic reaction (Scheme 2). 96 Recently, asymmetric cascade reactions using combinations of a soluble chiral organocatalyst and supported Pd catalysts were developed for the preparation of chiral five membered unsaturated cyclic compounds. 97 Good yields and high stereoselectivities were obtained in reactions of cinnamaldehyde derivatives (6) with propargylic C-, O-or N-nucleophiles (7,9,11), leading to the formation of cyclopentene, dihydrofuran or pyrroline derivatives (Scheme 3).…”