Palladium-Catalyzed Dehydrogenative β′-Functionalization of β-Keto Esters with Indoles at Room Temperature

Abstract

The dehydrogenative β'-functionalization of α-substituted β-keto esters with indoles proceeds with high regioselectivities (C3-selective for the indole partner and β'-selective for the β-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.

Cross-Dehydrogenative Couplings between Indoles and β-Keto Esters: Ligand-Assisted Ligand Tautomerization and Dehydrogenation via a Proton-Assisted Electron Transfer to Pd(II)

“…Although the above experiments established that enone 4a is indeed a viable intermediate for the reaction, control experiments without indole 2a clearly demonstrated that enone formation is very slow in the absence of indole. 5 The reaction progress method allowed us to obtain kinetic isotope effect (KIE) data for all key reaction components, using deuteriumlabeled starting materials. 12 The first KIE experiment involved a comparison of C2-H vs C2-D-labeled indole (Figure 2 a).…”

Photoredox Activation for the Direct β-Arylation of Ketones and Aldehydes

“…Although the study of such reactivity has delivered many useful transformations, this chemistry requires substrates that are not as widely available or require an additional preoxidation step from a saturated precursor (5–9). Previous studies in transition metal catalysis have shown that direct β-functionalization of esters or amides is possible through the use of palladium catalysis, albeit with only a few examples known to date (10–13). A direct aldehyde or ketone β-coupling mechanism would obviate the need for preactivated substrates.…”

Direct β-Functionalization of Cyclic Ketones with Aryl Ketones via the Merger of Photoredox and Organocatalysis

“…Drawing from the mechanistic insights gained in the course of our β-arylation program, 1a we envisioned a direct β-coupling of saturated ketones with aryl–alkyl and diaryl ketone precursors. Specifically, we postulated that a transiently formed nucleophilic β-enaminyl 5πe − species ( 1 ) would be intercepted by a ketyl radical ( 2 ) to directly form a γ-hydroxyketone adduct (Eq 2).…”

“…Formation of the desired enaminyl radical cation 5 would then induce an increase in the acidity of the allylic C–H bond, facilitating deprotonation at the β-position. 1a The transiently formed 5pe − species 1 (an intermediate which represents the desired activation mode) should then readily couple with ketyl radical 2 to form the γ-hydroxyketone enamine 6 . Finally, enamine hydrolysis would serve to release the β-union product 7 and regenerate the amine catalyst 3 , thereby completing the organocatalytic cycle.…”

“…In this context, our lab has recently introduced an unprecedented 5πe − carbonyl activation mode that capitalizes on the synergistic merger of photoredox catalysis and amine organocatalysis to accomplish the direct β-arylation of saturated aldehydes and ketones (Eq 1). 1a This strategy relies on the coupling of two catalytically generated radical species: a β-enaminyl radical formed via oxidation and deprotonation of a ketone-derived enamine and a radical anion generated by photocatalytic reduction of an aryl nitrile. 6 In this communication, we further advance this activation concept to describe the first β-functionalization of saturated cyclic ketones with aryl ketones to deliver γ-hydroxyketone motifs, a protocol that formally represents a homo-enolate aldol reaction using simple carbonyl substrates, a household light source, and two commercial catalysts (Eq 2).…”