Cross-dehydrogenative couplings between indoles and ß-keto esters: ligand-assisted ligand tautomerization and dehydrogenation via a proton-assisted electron transfer to Pd(II).

Cross-dehydrogenative coupling reactions between ß-ketoesters and electron-rich arenes, such as indoles, proceed with high regiochemical fidelity with a range of ß-ketoesters and indoles. The mechanism of the reaction between a prototypical ß-ketoester, ethyl 2-oxocyclopentanonecarboxylate, and N-methylindole has been studied experimentally by monitoring the temporal course of the reaction by (1)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 N-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 ß-keto ester ligand from an O,O'-chelate to an α-C-bound Pd enolate. This ligand tautomerization event is assisted by the π-bound indole ligand. Subsequent scission of the ß'-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)2 and TFA-catalyzed pathways were examined experimentally and computationally for this cycle, and both were found to be viable routes for the coupling step.

Palladium-catalyzed dehydrogenative ß'-arylation of ß-keto esters under aerobic conditions: interplay of metal and Brønsted acids.

The Brønsted aids: The first dehydrogenative arylation of ß-keto esters with arenes under ambient aerobic conditions is described. Under a Pd(II)/Brønsted acid co-catalytic system, regioselective arylations with alkoxylated arenes and phenols were achieved in good yields, even in gram-scale conditions.

Palladium-catalyzed dehydrogenative ß'-functionalization of ß-keto esters with indoles at room temperature.

The dehydrogenative ß'-functionalization of α-substituted ß-keto esters with indoles proceeds with high regioselectivities (C3-selective for the indole partner and ß'-selective for the ß-keto ester) and good yields under mild palladium catalysis at room temperature with a variety of oxidants. Two possible mechanisms involving either late or early involvement of indole are presented.