DOI: 10.1002/chem.201302645 Heterogeneous Cu II -Catalysed Solvent-Controlled Selective N-Arylation of Cyclic Amides and Amines with Bromo-iodoarenes Debasish Kundu, [a] Sukalyan Bhadra, [a] Nirmalya Mukherjee, [a] Bojja Sreedhar, [b] and Brindaban C. Ranu* [a] Introduction The formation of C À N bonds is one of the most important reactions in chemical and pharmaceutical industries, [1] as a majority of the pharmaceutically active molecules are de- rived from heterocyclic units. In particular, N-arylation of nitrogen heterocycles such as cyclic amides and amines by aryl halides has received current attention as a series of compounds containing both cyclic amides and amines at- tached with an aromatic ring through a nitrogen centre are found as structural motifs of biologically active molecules and drugs as outlined in Figure 1. [2] Interestingly, no straight- forward and efficient methodology was available for the syn- thesis of these molecules. This prompted us to initiate an in- vestigation to find a suitable protocol for an access to these molecules. The transition-metal-catalysed cross-coupling reaction is one of the efficient tools for the N-arylation of heterocy- cles. [3] These reactions are usually mediated by palladium, [4] nickel, [5] copper [6] , more recently, iron [7] catalysts in pres- ence of a ligand. However, copper and iron being less ex- pensive and toxic, have received more attention. Although N-arylation of a variety of cyclic amines such as imidazoles, pyrazoles and indoles were studied extensively by these pro- cedures, less active cyclic amides have not been addressed adequately. In addition, we did not find a single report on the selective N-arylation of a cyclic amide over an amine and vice versa, which would be of much significance towards Figure 1. Potent molecules containing both cyclic amide and amine moieties. Abstract: A selective N-arylation of cyclic amides and amines in DMF and water, respectively, catalysed by Cu II / Al 2 O 3 has been achieved. This protocol has been employed for the synthesis of a library of arenes bearing a cyclic amide and an amine moiety at two ends, including a few scaffolds of thera- peutic importance. The mechanism has been established based on detailed electron paramagnetic resonance (EPR) spectroscopy, X-ray photoelec- tron spectroscopy (XPS), UV diffuse reflectance spectroscopy (DRS) and in- ductively coupled plasma-mass spec- trometry (ICP-MS) studies of the cata- lyst at different stages of the reaction. The Cu II /Al 2 O 3 catalyst was recovered and recycled for subsequent reactions. Keywords: amides · amines · bioac- tive scaffolds · heterogeneous catal- ysis · solvent-controlled selectivity [a] D. Kundu, Dr. S. Bhadra, N. Mukherjee, Prof. Dr. B. C. Ranu Department of Organic Chemistry Indian Association for the Cultivation of Science Jadavpur, Kolkata-700032 (India) Fax: (+ 91) 33-24732805 E-mail: ocbcr@iacs.res.in [b] Dr. B. Sreedhar Inorganic Chemistry Divison Indian Institute of Chemical Technology Hyderabad-500007 (India) Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201302645. Chem. Eur. J. 2013, 19, 15759 – 15768  2013 Wiley-VCH Verlag GmbH&Co. KGaA, Weinheim 15759 FULL PAPER