Cross-Dehydrogenative
Couplings between Indoles and
β‑Keto Esters: Ligand-Assisted Ligand Tautomerization
and Dehydrogenation via a Proton-Assisted Electron Transfer to Pd(II)
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Abstract
Cross-dehydrogenative
coupling reactions between β-ketoesters
and electron-rich arenes, such as indoles, proceed with high regiochemical
fidelity with a range of β-ketoesters and indoles. The mechanism
of the reaction between a prototypical β-ketoester, ethyl 2-oxocyclopentanonecarboxylate,
and <i>N</i>-methylindole has been studied experimentally
by monitoring the temporal course of the reaction by <sup>1</sup>H
NMR, kinetic isotope effect studies, and control experiments. DFT
calculations have been carried out using a dispersion-corrected range-separated
hybrid functional (ωB97X-D) to explore the basic elementary
steps of the catalytic cycle. The experimental results indicate that
the reaction proceeds via two catalytic cycles. Cycle A, the dehydrogenation
cycle, produces an enone intermediate. The dehydrogenation is assisted
by <i>N</i>-methylindole, which acts as a ligand for Pd(II).
The computational studies agree with this conclusion, and identify
the turnover-limiting step of the dehydrogenation step, which involves
a change in the coordination mode of the β-keto ester ligand
from an <i>O</i>,<i>O</i>′-chelate to an
α-C-bound Pd enolate. This ligand tautomerization event is assisted
by the π-bound indole ligand. Subsequent scission of the β′-C–H
bond takes place via a proton-assisted electron transfer mechanism,
where Pd(II) acts as an electron sink and the trifluoroacetate ligand
acts as a proton acceptor, to produce the Pd(0) complex of the enone
intermediate. The coupling is completed in cycle B, where the enone
is coupled with indole. Pd(TFA)<sub>2</sub> and TFA-catalyzed pathways
were examined experimentally and computationally for this cycle, and
both were found to be viable routes for the coupling step