DOI: 10.1002/adsc.201000708 Ligand-Free Copper-Catalyzed Amination of Heteroaryl Halides with Alkyl- and Arylamines Zhen-Jiang Liu, a Jean-Pierre Vors, b Ernst R. F. Gesing, c, * and Carsten Bolm a, * a Institute of Organic Chemistry, RWTH Aachen University, Landoltweg 1, 52056 Aachen, Germany Fax: (+ 49)-241-809-2391; phone: (+ 49)-241-809-4675; e-mail: Carsten.Bolm@oc.rwth-aachen.de b Bayer CropScience SAS, Centre de Recherche de La Dagoire, 14 Impasse Pierre Baizet, BP99163, 69009 Lyon, France c Bayer CropScience AG, BCS-R-I-CI, Building 6550, Alfred-Nobel-Strasse 50, 40789 Monheim am Rhein, Germany Fax: (+ 49)-2173-38-3671; phone: (+ 49)-2173-38-3987; e-mail: ernst-rudolf.gesing@bayer.com Received: September 15, 2010; Published online: December 1, 2010 Supporting information for this article is available on the WWW under http ://dx.doi.org/10.1002/adsc.201000708. Abstract: N-Heteroarylations of alkyl- and aryl- ACHTUNGTRENNUNGamines with various heteroaryl halides have been achieved by ligand-free copper-catalyzed cross-cou- plings affording aminopyridines and aminopyrimi- dines in moderate to high yields (up to 99% yield). Keywords: aminopyridines; aminopyrimidines; copper; N-heteroarylation; ligand-free conditions Heteroaromatic compounds are ubiquitous in natural products and biologically active molecules. [1] Among them, aminopyridines and aminopyrimidines are of great interest in the fine chemical industry owing to their importance as intermediates for pharmaceuti- ACHTUNGTRENNUNGcals, [2a–e] agrochemicals [2f,g] and materials. [2h–j] Tradi- tional preparations of such compounds involve nucle- ophilic aromatic substitutions of pyridine or pyrimi- dine halides, but those methods suffer from a limited substrate scope due to the requirement of activated substrates or harsh reaction conditions. [3] C À N cross- coupling reactions catalyzed by palladium and copper complexes offer an alternative approach to such com- pounds. Significant progress has been achieved in pal- ladium-catalyzed N-heteroarylations of alkyl- and arylamines, [4] but their industrial applications are often problematic due to the high costs of the palladi- um catalysts and the requirement of air- and mois- ture-sensitive phosphine ligands. In recent years, copper-catalyzed Ullmann-type reactions have emerged as alternatives. [5] Many efficient copper/ ligand combinations have been developed that allow one to perform these reactions under comparatively mild conditions. However, cross-couplings between heteroaryl halides and alkyl- or arylamines have re- mained challenging, [6] and the development of simple and general copper catalyst systems for efficiently promoting N-heteroarylations of alkyl- and aryl- ACHTUNGTRENNUNGamines is highly desirable. Recently, we described mi- crowave-accelerated copper-catalyzed aminations of halopyridines with various nitrogen nucleophiles under solvent- and ligand-free conditions. [7] To our disappointment, however, alkyl- and arylamines did not react. In continuation of those studies and in the context of our general search for simple and environ- mentally friendly catalysts for C À X couplings, [8] we have now discovered a reaction variant that overcame this problem. Hence, the previously unreactive alkyl- and arylamines can now be applied, [9] and the use of ligand-free copper catalysts allows N-heteroarylations providing coupling products in moderate to high yields. While searching for an efficient ligand for the pro- motion of the copper-catalyzed coupling between 3- iodopyridine (1a) with benzylamine (2a), we were sur- prised to find that the reaction proceeded well in the absence of a ligand affording the corresponding cou- pling product 3a in 74% yield (Scheme 1). [10] Hence, we turned our attention to the coupling of less reactive and economically more attractive hetero- aryl bromides. Unfortunately, the coupling of 3-bro- mopyridine (1b) with benzylamine (2a) gave only trace amounts of 3a when the reaction was carried out under the same reaction conditions as before (10 mol% of CuI and 2 equiv. of Cs 2 CO 3 , 100 8C, Scheme 1. Ligand-free copper-catalyzed amination of 3-io- dopyridine (1a) with benzylamine (2a). 3158  2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Adv. Synth. Catal. 2010, 352, 3158 – 3162 COMMUNICATIONS