Bert U. W. Maes

Palladium-catalyzed migratory insertion of isocyanides: an emerging platform in cross-coupling chemistry.

Isocyanides have been important building blocks in organic synthesis since the discovery of the Ugi reaction and related isocyanide-based multicomponent reactions. In the past decade isocyanides have found a new application as versatile C1 building blocks in palladium catalysis. Palladium-catalyzed reactions involving isocyanide insertion offer a vast potential for the synthesis of nitrogen-containing fine chemicals. This Minireview discusses all the achievements in this emerging field.

Direct α‐Functionalization of Saturated Cyclic Amines

Recent advances in synthetic methods for the direct α-functionalization of saturated cyclic amines are described. Methods are categorized according to the in situ formed reactive intermediate (α-amino cation, α-amino anion, and α-amino radical). Transition-metal-catalyzed reactions involving other intermediates have been treated as a separate and fourth class.

Sustainable Synthesis of Diverse Privileged Heterocycles by Palladium‐Catalyzed Aerobic Oxidative Isocyanide Insertion

O(2) in, H(2)O out: Various diamines and related bisnucleophiles readily undergo oxidative isocyanide insertion with Pd(OAc)(2) (1 mol %) as the catalyst and O(2) as the terminal oxidant to give a diverse array of medicinally relevant N heterocycles. The utility of this highly sustainable method is demonstrated by a formal synthesis of the antihistamines astemizole and norastemizole.

Palladium-catalyzed synthesis of 4-aminophthalazin-1(2H)-ones by isocyanide insertion.

Palladium-catalyzed cross-coupling of a wide range of substituted o-(pseudo)halobenzoates and hydrazines with isocyanide insertion followed by lactamization efficiently affords 4-aminophthalazin-1(2H)-ones that are difficult to obtain regioselectively by classical methods.

On the importance of an acid additive in the synthesis of pyrido[1,2-a]benzimidazoles by direct copper-catalyzed amination.

Pyrido[1,2-a]benzimidazoles1, 2a are interesting compounds both from the viewpoint of medicinal chemistry2–7 (solubility,7 DNA intercalation3) and materials chemistry8 (fluorescence). Of note among the former is the antibiotic drug Rifaximin,5 which contains this heteroaromatic core. The classical synthetic approach for the assembly of pyrido[1,2-a]benzimidazoles is by [3+3] cyclocondensation of benzimidazoles containing a methylene group at C2 with appropriate bielectrophiles.2a However, these procedures are often low-yielding, involve indirect/lengthy sequences, and/or provide access to a limited range of products, primarily providing derivatives with substituents located on the pyridine ring (A ring, Scheme 1).2–4 Theoretically, a good alternative synthetic method for the synthesis of pyrido[1,2-a]benzimidazoles with substituents in the benzene ring (C ring) should be accessible by intramolecular transition-metal-catalyzed CN bond formation in N-(2-chloroaryl)pyridin-2-amines, based on chemistry recently developed in our research group.9 These substrates themselves are easily available through SNAr or selective Pd-catalyzed amination10 of 2-chloropyridine with 2-chloroanilines.11 If a synthetic procedure that eliminated the need for preactivation of the 2-position of the 2-chloroarylamino entity could be developed, this would be even more powerful, as anilines are more readily commercially available than 2-chloroanilines. Therefore the synthesis of pyrido[1,2-a]benzimidazoles (4) by a transition-metal-catalyzed intramolecular CH amination approach from N-arylpyridin-2-amines (3) was explored (Scheme 1).

Synthesis of 4-Aminoquinazolines by Palladium-Catalyzed Intramolecular Imidoylation of N-(2-Bromoaryl)amidines

Compared with the widespread use of carbonylative Pd-catalyzed cross-coupling reactions, similar reactions involving isocyanide insertion are almost virgin territory. We investigated the intramolecular imidoylative cross-coupling of N-(2-bromoaryl)amidines, leading to 4-aminoquinazolines. After thorough optimization of the reaction with respect to palladium source and loading, ligand, base, temperature, and solvent, a small library of 4-aminoquinazolines was prepared to determine the scope of this method. Various substituents are tolerated on the amidine and the isocyanide, providing efficient access to a broad range of diversely substituted 4-aminoquinazolines of significant pharmaceutical interest.

Synthesis of Aryl(di)azinyl Ketones through Copper- and Iron-catalyzed Oxidation of the Methylene Group of Aryl(di)azinylmethanes†

Sustainable Oxidations: an oxidation method to transform aryl(di)azinylmethanes into aryl(di)azinyl ketones is described. Base metals (copper and iron) as catalysts in combination with O(2) as the oxidant are used, which makes this method sustainable. The utility of this method is illustrated by the synthesis of 6-(4-methylbenzoyl)pyridine-2-carbaldehyde, which is an intermediate in the preparation of the drug Acrivastine.

C-2 arylation of piperidines through directed transition-metal-catalyzed sp3 C-H activation.

The development of transition-metal-catalyzed methods for the direct functionalization of C H bonds has attracted much attention during the past decade. While the direct functionalization of sp C H bonds is an active field of research, the corresponding knowledge on sp C H bonds is still limited and remains one of the current challenges in organic chemistry. Within the area of sp C H activation, the transformation of a C H bond in the a-position to the nitrogen atom of saturated cyclic amines is of particular importance, since such heterocyclic motifs can be found in an impressive number of natural products and marketed drugs. The intermolecular, direct transition-metal-catalyzed functionalization of saturated cyclic amines adjacent to nitrogen offers a simple and efficient synthetic approach towards valuable building blocks. To the best of our knowledge, only six articles are hitherto published on this topic, wherein the main focus is on five-membered cyclic subACHTUNGTRENNUNGstrates.[6,7a] In 2006, Sames and co-workers reported the first direct arylation of saturated cyclic amines through transition-metal-catalyzed sp C H activation, involving arylboronate esters as a coupling partner. Pyrrolidines were successfully arylated adjacent to nitrogen by using a Ru-catalyzed C-H activation process, directed by a pyrroline group and mediated by ketone (used also as a solvent). The authors suggested that the key role of the ketone (pinacolone) is to allow a transmetalation by transforming the initially formed metal hydride species into a metal alkoxide intermediate. The pyrroline directing group could be removed by treatment of the a-arylated pyrrolidines with NH2NH2/ AcOH. One example of a piperidine substrate also appeared in this work, which was C-2 p-methoxyphenylated in moderate yield (38 %). The six-membered piperidine ring is inherently less reactive than its five-membered analogue (pyrrolidine) due to its chair conformation. Consequently, there are very few examples in the literature of direct functionalization of piperidines by means of a transition-metalcatalyzed, sp C H activation process. We report here a novel method for the direct C-2 arylation of piperidines with arylboronate esters, resulting from a mechanistic study of the transmetalation step of the catalytic cycle. As part of our interest in C-2 functionalized 4-substituted piperidines, we first applied the conditions described by Sames and co-workers to 1-(pyrrolin-2-yl)-4-piperidinone ethylene ketal (Scheme 1, 1). Unfortunately, the reaction of 1 with phenylboronic acid pinacol ester resulted in a low conversion to the arylated product, and directing group in[a] Dr. H. Prokopcov , Dr. S. D. Bergman, Dr. K. Aelvoet, V. Smout, Prof. Dr. B. U. W. Maes Organic Synthesis, University of Antwerp Groenenborgerlaan 171, 2020 Antwerp (Belgium) Fax: (+32) 32653233 E-mail : bert.maes@ua.ac.be [b] Prof. Dr. W. Herrebout, Prof. Dr. B. Van der Veken Cryospectroscopy, University of Antwerp Groenenborgerlaan 171, 2020 Antwerp (Belgium) [c] Dr. L. Meerpoel Johnson & Johnson Pharmaceutical Research & Development A Division of Janssen Pharmaceutica N.V. Turnhoutseweg 30, 2340 Beerse (Belgium) Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201001887. Scheme 1. 4-Piperidinone ethylene ketal bearing a pyrroline or pyridine directing group: substrates designed to explore the C-2 arylation process.

Selective palladium-catalyzed aminations on dichloropyridines

Abstract Palladium-catalyzed amination proved to be a valuable strategy for the selective introduction of aromatic and heteroaromatic amines, including aminopyridines and aminodiazines, on dichloropyridines. The use of mild amination conditions resulted in maximum selectivity and excellent base sensitive functional group tolerance.

Synthesis and antiplasmodial activity of aminoalkylamino-substituted neocryptolepine derivatives.

A series of chloro- and aminoalkylamino-substituted neocryptolepine (5-methyl-5H-indolo[2,3-b]quinoline) derivatives were synthesized and evaluated as antiplasmodial agents. The evaluation also included cytotoxicity (MRC5 cells), inhibition of beta-hematin formation, and DNA interactions (DNA-methyl green assay). Introduction of aminoalkylamino chains increased the antiplasmodial activity of the neocryptolepine core substantially. The most efficient compounds showed antiplasmodial activities in the nanomolar range. N(1),N(1)-Diethyl-N(4)-(5-methyl-5H-indolo[2,3-b]quinolin-8-yl)pentane-1,4-diamine 11c showed an IC(50) of 0.01 microM and a selectivity index of 1800.