om8b00468_si_001.pdf (7.36 MB)
Scalable and Chemoselective Synthesis of γ‑Keto Esters and Acids via Pd-Catalyzed Carbonylation of Cyclic β‑Chloro Enones
journal contribution
posted on 2018-09-14, 13:18 authored by Justin M. Kaplan, Damian P. Hruszkewycz, Iulia I. Strambeanu, Christopher J. Nunn, Kelsey F. VanGelder, Anna L. Dunn, Derek I. Wozniak, Graham E. Dobereiner, David C. LeitchThe
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.