Denis S. Ermolat'ev

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.

A divergent synthesis of substituted 2-aminoimidazoles from 2-aminopyrimidines

A new divergent and efficient synthesis of substituted 2-aminoimidazoles 5 and 6 has been developed starting from the readily available 2-aminopyrimidines 1 and alpha-bromocarbonyl compounds 2, using conventional heating or microwave irradiation. Thus, the cleavage of 1,2,3-substituted imidazo[1,2-a]pyrimidin-1-ium salts 4 with hydrazine or secondary amines led to 1,4,5-trisubstituted 2-aminoimidazoles 5, when the hydrazinolysis of 2-hydroxy-2,3-dihydro-1H-imidazo[1,2-a]pyrimidin-4-ium salts 3, followed by a novel Dimroth-type rearrangement, resulted in formation of 2-amino-1H-imidazoles 6. The relevant pathway of transformations was identified by characterization of the intermediates.

Tetrasubstituted 2-Imidazolones via Ag(I)-Catalyzed Cycloisomerization of Propargylic Ureas

A one-pot protocol based on a Ag(I)-catalyzed cycloisomerization of propargylic ureas, derived from secondary propargylamines and isocyanates, was developed for the generation of the 2-imidazolone core.

Facile and diverse microwave-assisted synthesis of secondary propargylamines in water using CuCl/CuCl2

A highly efficient microwave-assisted three-component reaction between an aldehyde, a primary amine and an alkyne was developed using an inexpensive Cu(I)/Cu(II) catalytic system and water as solvent. A wide range of diversely substituted secondary propargylamines was prepared in good and high yields within a short period of time.

Diversity-Oriented Synthesis of Substituted Furo[2,3-b]pyrazines

A highly efficient method for the synthesis of diversely substituted furo[2,3-b]pyrazines has been elaborated. The Ag+- or iodine-mediated electrophilic cyclization of readily generated 5-chloro-3-substituted ethynyl-1-(4-methoxybenzyl)-pyrazin-2(1H)-ones affords substituted furo[2,3-b]pyrazines, which undergo various palladium catalyzed reactions to generate a library of difficult to attain diversely substituted furo[2,3-b]pyrazines.

Iodine-mediated regioselective guanylation-amination of propargylamines towards the synthesis of diversely substituted 2-aminoimidazoles

A diversity-oriented approach for the synthesis of 2-aminoimidazoles is presented. The method involves the cyclization of secondary propargylamines using iodine allowing the generation of diversely-substituted 2-aminoimidazoles. The iodo group generated during cyclization can be used for further modification, which is an additional asset of this method.