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.

Palladium(II)-catalyzed oxidative cascade cyclization reactions of anilides and anilines: scope and mechanistic investigations.

With Pd(OAc)(2)/pyridine as the catalyst system and molecular oxygen as a green oxidant, acrylanilides and N-allylanilines undergo oxidative cascade cyclization to form heterocyclic rings in high yields. This methodology is applicable to acrylanilides of different substitution patterns on olefinic units. Mechanistic studies revealed that cyclization of acrylanilides proceeded through an intramolecular syn-amidopalladation pathway. The reversible nature of amidopalladation serves as a "scavenging process" to prevent ß-hydride elimination from occurring halfway through the catalytic cycle, thus favoring the formation of cascade cyclization products. In addition, internal coordination between an σ-alkylpalladium species and a tethered olefinic C=C double bond also appears to disfavor ß-hydride elimination.

Pd(II)-catalyzed intramolecular amidoarylation of alkenes with molecular oxygen as sole oxidant.

Stereoselective palladium-catalyzed synthesis of structurally versatile indoline derivatives, using molecular oxygen as the sole oxidant, is described. New C-N and C-C bonds form across an alkene in an intramolecular manner. The C-N bond-forming step proceeds via a syn-amidopalladation pathway. The moderate kinetic isotope effects (intramolecular KIE = 3.56) suggest that electrophilic aromatic substitution occurs in the arylation step.

Pd(II)/(t)Bu-quinolineoxazoline: an air-stable and modular chiral catalyst system for enantioselective oxidative cascade cyclization.

An air-stable and structurally tunable chiral (t)Bu-quinolineoxazoline/Pd(II) catalyst system has been developed for the enantioselective oxidative cascade cyclization of a variety of disubstituted olefinic substrates, with the apparent advantages of good yields and excellent enantioselectivities (up to 98% ee) and diastereoselectivities (dr >24:1). A transition-state model has also been proposed to account for the excellent stereocontrol.

Palladium-catalyzed highly diastereoselective oxidative cascade cyclization reactions.

Isoquinoline and quinoline have been discovered as novel ligands for palladium-catalyzed oxidative cascade cyclization reactions. With our new catalyst systems (Pd(OAc)(2)/isoquinoline or quinoline), unsaturated anilides cyclize under an oxygen atmosphere (1 atm) to furnish structurally versatile indoline derivatives in good yields. One C-N bond and two C-C bonds are formed in a single step with excellent diastereoselectivities (dr > 24:1).

Pd(II)-catalyzed enantioselective oxidative tandem cyclization reactions. Synthesis of indolines through C-N and C-C bond formation.

We have developed an efficient Pd(II)-catalyzed enantioselective oxidative tandem cyclization strategy using molecular oxygen as a green oxidant for the double 5-exo-trig cyclizations of N-(2-allylaryl) amides to afford a variety of indolines in good yields without the formation of undesired monocyclization products. By employing Pd(TFA)2/(-)-sparteine as the chiral catalyst, we obtained tandem cyclization products with high enantioselectivity (up to 91% ee).

Aerobic oxidative cyclization under Pd(II) catalysis: a regioselective approach to heterocycles.

[chemical reaction: see text]. An efficient Yb(OTf)3-promoted palladium-catalyzed oxidative cyclization of gamma-heteroalkenyl beta-keto amides has been developed. Under simple aerobic condition, a variety of six-, seven-, and eight-membered-ring N- and O-heterocycles were obtained regioselectively in excellent yield.