Scalable and Chemoselective Synthesis of γ‑Keto Esters and Acids via Pd-Catalyzed Carbonylation of Cyclic β‑Chloro Enones

The Pd-catalyzed carbonylation of cyclic β-chloro enones using simple phosphine ligands is described. Screening identified P­(Me)­(t-Bu)₂ as the most general ligand for an array of chloro enone electrophiles. The reaction scope has been evaluated on a milligram scale across 80 examples, with excellent reactivity observed in nearly every case. Carbonylation can be achieved even in the presence of potentially sensitive or inhibitory functional groups, including basic nitrogens as well as aryl chlorides or bromides. Twenty examples have been run on a gram scale, demonstrating scalability and practical utility. Using P­(Me)­(t-Bu)₂, the reaction rate depends on both nucleophile and electrophile identity, with completion times varying between 3 and >18 h under a standard set of conditions. Switching to P­(t-Bu)₃ for the carbonylation of 3-chlorocyclohex-2-enone with methanol results in a dramatic rate increase, enabling effective catalysis with kinetics consistent with rate-limiting mass transfer. Stoichiometric oxidative addition of 3-chlorocyclohex-2-enone and 3-oxocyclohex-1-enecarbonyl chloride to both Pd­[P­(t-Bu)₃]₂ and Pd­(PCy₃)₂ has enabled characterization and isolation of several potential catalytic intermediates, including Pd–vinyl and Pd–acyl species supported by P­(t-Bu)₃ and PCy₃ ligands. Monitoring the oxidative addition of 3-chlorocyclohex-2-enone to Pd­(PCy₃)₂ by NMR spectroscopy indicates that coordination of the alkene precedes oxidative addition. As a result of these studies, methyl 3-oxocyclohex-1-enecarboxylate has been synthesized via Pd-catalyzed carbonylation of 3-chlorocyclohex-2-enone in 90% yield on a 60 g scale with only 0.5 mol % catalyst loading.