Erik V. Van der Eycken

Microwave-assisted C–C bond forming cross-coupling reactions: an overview

Among the fundamental transformations in the field of synthetic organic chemistry, transition-metal-catalyzed reactions provide some of the most attractive methodologies for the formation of C-C and C-heteroatom bonds. As a result, the application of these reactions has increased tremendously during the past decades and cross-coupling reactions became a standard tool for synthetic organic chemists. Furthermore, a tremendous upsurge in the development of new catalysts and ligands, as well as an increased understanding of the mechanisms, has contributed substantially to recent advances in the field. Traditionally, organic reactions are carried out by conductive heating with an external heat source (for example, an oil bath). However, the application of microwave irradiation is a steadily gaining field as an alternative heating mode since its dawn at the end of the last century. This tutorial review focuses on some of the recent developments in the field of cross-coupling reactions assisted by microwave irradiation.

A Diversity‐Oriented Approach to Spiroindolines: Post‐Ugi Gold‐Catalyzed Diastereoselective Domino Cyclization

Gold-catalyzed carbocyclization and heteroannulation strategies have recently attracted much attention owing to the selective and efficient activation of the C C bond towards a wide range of nucleophiles that these methods provide. Domino approaches involving gold-catalysis lead to complex heterocyclic compounds under exceedingly mild reaction conditions. Although gold-catalyzed approaches are rising to prominence, they suffer in terms of diversity and procedural length. Multistep sequences are usually required for assembling the starting material for cyclization. We have recently reported a concise route to indoloazocines by a sequential Ugi/gold-catalyzed intramolecular hydroarylation approach. Inspired by these findings and as a result of our continued synthetic interest in the indole core, multicomponent reactions and transition metal-catalysis, we have developed a post-Ugi gold-catalyzed domino cyclization method to generate spiroindolines. The Ugi four-component reaction (4-CR) of indole-3carboxaldehyde (1a) with p-methoxybenzyl amine (2a), 2-butynoic acid (3a) and tert-butyl isonitrile (4a) in methanol at 50 8C gave Ugi-adduct 5a in 71% yield. When this was treated with 5 mol% of Au[PPh3]OTf (OTf= trifluoromethanesulfonate) in CDCl3 at RT, the expected outcome of the reaction was indoloazepinone 6a’ through an endo-dig cyclization followed by rearrangement (Scheme 1). Surprisingly, an exo-dig cyclization followed by intramolecular trapping of the spiro intermediate occurred instead, resulting in the diastereoselective formation of tetracyclic spiroindoline 6a in 61% yield (Scheme 1). This observation was remarkable, as the attack on the a-position of an alkyne conjugated with an amide is rare, and trapping of the spiro intermediate by a sterically hindered tert-butyl amide is rather unexpected, as was the diastereoselectivity observed. Spiroindolines are prominent molecular motifs that are frequently encountered among the large family of alkaloids; for example, it is present in communesines and perophoramidines (Figure 1), which display distinct pharmacological properties. These fused polycyclic systems, which feature quaternary stereocenters, present a nontrivial challenge for organic chemists to develop synthetic approaches.

Efficient Microwave-Assisted Synthesis of Secondary Alkylpropargylamines by Using A3-Coupling with Primary Aliphatic Amines

Multicomponent reactions (MCRs) have attracted much attention in the framework of combinatorial chemistry owing to their synthetic efficiency, intrinsic atom economy, high selectivity and procedural simplicity. These reactions constitute a valuable approach for the creation of large libraries of structurally related, drug-like compounds, thereby enabling rapid lead identification and optimisation in drug discovery. They represent environmentally friendly processes by reducing the number of steps, energy consumption and waste production. The three-component coupling of an aldehyde, an alkyne and an amine, commonly called an A-coupling, is an MCR that has received much attention in recent years. The resulting propargylamines are synthetically versatile key intermediates for the preparation of biologically active compounds and drugs. Classical methods for the synthesis of propargylamines use strong bases, such as butyllithium, organomagnesium reagents or lithium diisopropylamide (LDA), exploiting the relatively high acidity of the terminal acetylene to form alkynyl metal compounds. The stoichiometric quantities of the reagents required, as well as their high sensitivity to moisture, render these processes fairly unattractive. During recent years, substantial progress has been made in A-coupling reactions. Several transition-metal catalysts have been exploited that activate the C H bond of the terminal alkyne. Ag salts, Au/Au salts, Au–salen (salen =N,N’-bis(salicylidene)ethylenediamine) complexes, Cu salts, Ir complexes, Hg2Cl2, [10] Cu/Ru bimetallic systems, InCl3, [12] ZnCl2, [13] FeCl3 [14] and nano CuO compounds have all been used to run this reaction under homogeneous conditions. Moreover, Au, Ag and Cu in ionic liquids and supported Au, Ag, Cu and CuCl were successfully used to catalyse A-coupling reactions under heterogeneous conditions with preservation of the transition-metal catalyst. Additionally, the enantioselective addition of terminal alkynes to imines provides access to optically active propargylamines. A variety of chiral ligands have been used for this reaction. High asymmetric induction has been reported by applying 1-(2-di ACHTUNGTRENNUNGphenyl ACHTUNGTRENNUNGphosphino-1-naphthyl)isoquinoline (QUINAP) ligands. In addition to these ligands, metal complexes of chiral amino acids, chiral alcohols, chiral binaphthylamines and 2,6-bis(2-oxazolinyl)pyridine (PyBOX) ligand have been used successfully. Despite huge advancements, A-coupling reactions have mainly been optimised for reactions involving anilines and secondary amines, which result in the formation of N-arylpropargylamines or tertiary propargylamines. Primary amines are considered to be difficult substrates for A-coupling reactions; this limits access to secondary propargylamines. Nevertheless, secondary alkylpropargylamines are potent synthetic intermediates that have mainly been explored for the synthesis of pyrrolidin, 5-alkylideneselenazolin-2-ones, pyrroles, quinolines and oxazolidinones. The synthesis of secondary alkylpropargylamines by using A-coupling reactions is scarcely reported in the literature and, to the best of our knowledge, no systematic study has ever been described. Herein, we present an optimised protocol for the synthesis of secondary alkylpropargylamines by using a microwave-assisted A-coupling reaction. In an optimisation study, benzylamine (1{1}) was used as a primary amine in combination with phenylacetylene (2{1}) and isobutyraldehyde (3{1}) (Table 1). As stated in the literature, the initial reagent ratio was selected as 1.3 equivalents of amine, 1.0 equivalent of aldehyde and 1.6 equivalents of alkyne with toluene as the solvent. Reactions were carried out in the presence of different copper salts under microwave irradiation at various ceiling temperatures (Table 1). Relatively low concentrations of the CuI catalyst [a] Dr. J. B. Bariwal, Dr. D. S. Ermolat ev, Prof. E. V. Van der Eycken Laboratory for Organic and Microwave-Assisted Chemistry (LOMAC) Department of Chemistry, Katholieke Universiteit Leuven Celestijnenlaan 200F, 3001 Leuven (Belgium) Fax: (+32) 16-32-79-90 E-mail : erik.vandereycken@chem.kuleuven.be Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.200903143.

Microwave-assisted synthesis of heterocycles

N. Pemberton, E. Chorell, F. Almqvist: Microwave-Assisted Synthesis and Functionalization of 2-Pyridones, 2-Quinolones and other Ring-Fused 2-Pyridones.- M.C. Bagley, M.C. Lubinu: Microwave-Assisted Multicomponent Reactions for the Synthesis of Heterocycles.- T. Besson, V. Thiery: Microwave-Assisted Synthesis of Sulfur and Nitrogen-Containing Heterocycles M. Erdelyi: Solid-Phase Methods for the Microwave-Assisted Synthesis of Heterocycles.- S. Crosignani, B. Linclau: Synthesis of Heterocycles Using Polymer-Supported Reagents under Microwave Irradiation.- B.U.W. Maes: Transition Metal-Based Carbon-Carbon and Carbon-Heteroatom Bond Formation for the Synthesis and Decoration of Heterocycles.- M. Rodriquez and M. Taddei: Synthesis of Heterocycles via Microwave-Assisted Cycloadditions and Cyclocondensations.- N. Kaval, P. Appukkuttan, E. Van der Eycken: The Chemistry of 2-(1H)-Pyrazinones in Solution and on Solid Support

Unprecedented Cu(I)-Catalyzed Microwave-Assisted Three-Component Coupling of a Ketone, an Alkyne, and a Primary Amine

An efficient, microwave-assisted Cu(I)-catalyzed one-pot coupling of a ketone, an alkyne, and a primary amine (KA(2) coupling) is described, giving access to secondary propargylamines.

Gold(I) and platinum(II) switch: a post-Ugi intramolecular hydroarylation to pyrrolopyridinones and pyrroloazepinones.

A regioselective approach for the synthesis of pyrrolopyridinones and pyrroloazepinones is reported employing an Ugi reaction followed by a gold(I) or platinum(II) catalyzed intramolecular hydroarylation.

Developments in Direct CH Arylation of (Hetero)Arenes under Microwave Irradiation

This minireview describes the progress made in the development of direct C-H arylation approaches through the application of focused microwave irradiation. The synergistic combination of microwave-assisted techniques with the rapidly evolving domain of C-H arylation has opened new vistas in the efficient synthesis of a diverse array of biologically important (hetero)arenes.

Efficient synthesis of the indoloazocine framework via intramolecular alkyne carbocyclization

A microwave-assisted protocol based on an Hg(OTf)(2) catalyzed intramolecular alkyne carbocyclization reaction was developed for selective construction of the indoloazocine core.

The First Palladium-Catalyzed Desulfitative Sonogashira-Type Cross-Coupling of (Hetero)aryl Thioethers with Terminal Alkynes

An unprecedented desulfitative Sonogashira-type cross-coupling protocol is exemplified by the synthesis of substituted 5-chloro-3-alkynylpyrazinones from the corresponding 5-chloro-3-(phenylsulfanyl) pyrazin-2(1H)-ones. The applicability of the method is extended to solid-phase linked pyrazin-2(1H)-ones as well as to some oxazinones, pyrazines, and phenyl thioesters.

An expedient route to imidazo[1,4]diazepin-7-ones via a post-Ugi gold-catalyzed heteroannulation.

A novel diversity-oriented post-Ugi/gold(I)-catalyzed heteroannulation process for the synthesis of imidazo[1,4]diazepin-7-ones is elaborated. The scope and limitations of the protocol are discussed.