A Three‐Component Palladium‐Catalyzed Oxidative CC Coupling Reaction: A Domino Process in Two Dimensions

Abstract

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...

Copper-catalyzed dehydrogenative γ-C(sp3)-H amination of saturated ketones for synthesis of polysubstituted anilines

“…Metal-catalyzed dehydrogenative β -C(sp 3 )–H functionalization reactions via dehydrogenative desaturation 28,29 were also amenable to esters 30–34 , lactams 35 , and other substrates 36–48 , demonstrating the ability of this type of reaction to rapidly construct complex molecule from simple substrates. Such reactions will continue to flourish in the future in view of the recent advance in the development of catalytic methods for generation of unsaturated compounds via dehydrogenation 39–49 as well as the versatility of unsaturated compounds as synthetic intermediates.…”

Recent advances in the application of indoles in multicomponent reactions

“…The three-component coupling reaction of indoles 1, β-ketoesters 34 and arylboronicacids 111 via the regioselective palladium-catalyzed oxidative reaction was studied for the preparation of indole-based heterocycles 112 ( Scheme 49 ). 113 Indole coupled more rapidly than β-ketoester with the arylboronic acid, and this rate variation was important under the three-component reaction conditions, possibly because the coupling with β-ketoester involves an unstable enone intermediate.…”

Palladium‐Catalyzed Domino Dehydrogenation/Heck‐Type Reactions of Carbonyl Compounds

“…(36)] close to those used in the absence of the third component [see Eqs (34) and (35)]. [73] Studies of two-component coupling experiments led to favor a domino reaction involving firstly the coupling between the indole and the arylboronate [74] and subsequent reaction of the resulting OHR product with the dehydrogenated -ketoester, as depicted in Scheme 9. Control experiments have nevertheless shown that the KTR-PHR product independently obtained from -ketoester/indole coupling (see Subchapter 6.2) reacts with the aryboronate to also afford the three-component product, but that would be, at the best, a minor reaction pathway under the three-component domino reactions conditions.…”