Scalable and Chemoselective Synthesis of γ‑Keto Esters and Acids via Pd-Catalyzed Carbonylation of Cyclic β‑Chloro Enones
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. Leitch
10.1021/acs.organomet.8b00468.s001
https://acs.figshare.com/articles/journal_contribution/Scalable_and_Chemoselective_Synthesis_of_Keto_Esters_and_Acids_via_Pd-Catalyzed_Carbonylation_of_Cyclic_Chloro_Enones/7088600
The
Pd-catalyzed carbonylation of cyclic β-chloro enones using simple
phosphine ligands is described. Screening identified P(Me)(<i>t</i>-Bu)<sub>2</sub> 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)(<i>t</i>-Bu)<sub>2</sub>, 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(<i>t</i>-Bu)<sub>3</sub> for <i>t</i>he 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(<i>t</i>-Bu)<sub>3</sub>]<sub>2</sub> and Pd(PCy<sub>3</sub>)<sub>2</sub> has enabled characterization and isolation of several potential
catalytic intermediates, including Pd–vinyl and Pd–acyl
species supported by P(<i>t</i>-Bu)<sub>3</sub> and PCy<sub>3</sub> ligands. Monitoring the oxidative addition of 3-chlorocyclohex-2-enone
to Pd(PCy<sub>3</sub>)<sub>2</sub> 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.
2018-09-14 13:18:28
rate-limiting mass transfer
Bu
60 g scale
NMR
chloro enone electrophiles
3- oxocyclohex -1-enecarbonyl chloride
3- chlorocyclohex -2-enone
Stoichiometric oxidative addition
Pd-catalyzed carbonylation
cyclic β- chloro enones
oxidative addition
PCy 3 ligands
methyl 3- oxocyclohex -1-enecarboxylate