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.

ABSTRACT:Cross-dehydrogenative coupling reactions between -ketoesters and electron-rich arenes, such as indoles, proceed with high regiochemical fidelity with a range of -ketoesters and indoles. The mechanism of the reaction between a prototypical -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 (B97X-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 -keto ester ligand from an O,O'-chelate to an C-bound Pd enolate. This ligand tautomerization event is assisted by the -bound indole ligand. Subsequent scission of the '-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.

The Brønsted aids: The first dehydrogenative arylation of β-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.

In multicomponent reactions (MCRs), three or more reactants combine in a single chemical step to give a product that contains nearly all the atoms of the individual reactants. Compared with multistep reaction routes, MCRs are highly attractive in terms of step economy. [1,2] Typical MCRs proceed in a linear domino mode: in the first stage, the components A and B (Scheme 1 a) give rise to a reactive intermediate (AB) which then reacts with a third component (C), and so on, until the sequence is terminated. Very often, the first steps are reversible, and only the terminating steps are irreversible (type I or type II MCRs). [3,4] In contrast, if three components A, B, and C could react with each other in any order, such three-component domino reactions (3CR) could proceed through an alternative twodimensional split domino process (Scheme 1 b). In such a process, there are two kinetic alternatives to give the final ABC product, via the AB or the BC intermediates. If the steps are irreversible, the efficiency of the process could be compromised if one of the pathways leads to a dead end (see the box in Scheme 1 b). Alternatively, unwanted homocoupling or heterocoupling reactions between the components could also jeopardize the projected 3CR process. Given these constraints, it is not surprising that nearly all known MCRs and domino reactions proceed in a strict linear fashion, with the functionalities of the individual components determining the order of events. [5] Herein, we describe a successful two-dimensional 3CR that proceeds through a mild Pd-catalyzed oxidative coupling between b-ketoesters (component A), indoles (component B), and aryl boronates (component C; Scheme 1 c). This 3CR could theoretically proceed via both AB and BC intermediates, and we demonstrate herein that both pathways are viable. To the best of our knowledge, catalytic oxidative 3CRs have not been reported in the literature. [6] The 3CR generates densely functionalized 2,3-disubstituted indoles directly from the three components. [7] We hypothesized that the reaction conditions of our previously reported [8] cross-dehydrogenative coupling reaction between b-ketoesters and indoles could also enable other oxidative coupling reactions at the free 2-position of the indole. Two-component oxidative couplings between indoles at the 2-position and arylboronates have previously been reported, by the groups of Shi, [9a] Zhang, [9b] and Studer. [10] However, direct oxidative 2,3-difunctionalization reactions of indoles have not been developed, and we were concerned that owing to the increased steric requirements of such a process a Cu II co-catalyst might be required, [9a,b] and this could compromise the regioselectivity for the b-ketoester. [8a] However, we anticipated that the use of the more-electrophilic Pd II precursor Pd(TFA) 2 , might overcome these problems, as this catalyst was shown to be superior to other Pd II sources in the cross-dehydrogenative coupling reactions. [8a] Scheme 1. The difference between a) linear and b) two-dimensio...

Palladium-Catalyzed Dehydrogenative β'-Functionalization of β-Keto Esters with Indoles at Room Temperature. -The title reaction proceeds with high C-3-selectivity for the indole and β'-selectivity for the β-keto ester. All products obtained from cyclic keto esters have trans stereochemistry. -(LESKINEN, M. V.; YIP, K.-T.; VALKONEN, A.; PIHKO*, P. M.; J. Am. Chem. Soc. 134 (2012) 13, 5750-5753, http://dx.doi.org/10.1021/ja300684r ; Dep. Chem., NanoSci. Cent., Univ. Jyvaeskylae, SF-40014 Jyvaeskylae, Finland; Eng.) -Klein 37-104