DOI: 10.1002/adsc.201400189 Zeo-Click Synthesis: Copper-Zeolite-Catalyzed Synthesis of Ynamides Hassina Harkat, a Sophie Borghse, b Matteo De Nigris, b Serguei Kiselev, b ValØrie BØnØteau, b and Patrick Pale b, * a Faculty of Sciences, University of Batna, Batna, Algeria b Laboratoire de Synthse, RØactivitØ Organiques & Catalyse, Institut de Chimie de Strasbourg, associØ au CNRS, University of Strasbourg, 4 rue Blaise Pascal, 67070 Strasbourg, France Fax: (+ 33)-(0)3-6885-1517; phone: (+ 33)-(0)3-6885-1517; e-mail: ppale@unistra.fr Received: February 20, 2014; Revised: June 21, 2014; Published online: && &&, 0000 Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201400189. Abstract: Copper(I)-zeolites, especially copper(I)- ultra stable Y zeolite (USY), are very efficient heter- ogeneous catalysts for the coupling of functionalized 1-bromoalkynes and various nitrogen derivatives. Under these conditions, sulfonylated alkyl- or aryl- ACHTUNGTRENNUNGamines and various N-heterocycles, such as oxazoli- dinones or indoles, could be efficiently transformed into the corresponding N-alkynyl derivatives. How- ever, imidazoles gave addition products rather than coupling products. The reaction conditions proved compatible with a variety of functional and protect- ing groups. Such zeolitic catalysts can be recycled and reused at least five times without significant de- activation. Low catalyst loading could be used (4 mol%) and as low as 0.8 mol% of this heterogene- ous copper catalyst still gave good conversion and yields. Keywords: copper; coupling; ynamides; zeolites Introduction The last decade has witnessed the emergence of yn- ACHTUNGTRENNUNGamides [1] as a powerful and versatile tool in organic synthesis. [2] Ynamides exhibit high reactivity due to the strong polarization of the triple bond induced by ynamine conjugation, while the electron-withdrawing group carried by the nitrogen atom modulates this re- activity (Scheme 1). Ynamides thus exhibit enhanced stability compared to ynamines, [3] and their reactivity can be tuned depending on the nature of the nitrogen substituent. Although ynamines were not easily obtained, [3] yn- ACHTUNGTRENNUNGamides can be readily produced either by elimination of b-bromo-, b-dichloro- or a-chloroenamides or by coupling reactions. [2] Among the latter, Ullman-type coupling reactions have been successfully extended to such compounds, providing a rapid and convenient access to ynamides from bromoalkynes and deactivat- ed amines (Scheme 2). Hsung and co-workers were the first to develop such copper-catalyzed couplings, but the use of N,N’- dimethyl-1,2-ethanediamine (DMEDA) as ligand and high temperatures led to limitations in terms of sub- strate scope, especially with sulfonamides and some heterocycles (Scheme 2a). [4] Danheiser and co-work- ers in part solved this problem by using stoichiometric amounts of copper iodide and potassium hexamethyl- disilazane. [5] These reagents allowed the reaction to proceed at room temperature, but the strong base also led to limitations (Scheme 2b). After an exten- sive conditions screening, Hsung and co-workers later reported more general and milder conditions based on copper sulfate pentahydrate with 1,10-phenanthro- line (Phen) as catalyst and potassium phosphate as base (Scheme 2c). [6] More recently, direct coupling Scheme 1. Ynamides: stability and reactivity. Adv. Synth. Catal. 0000, 000,0–0  2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 1 These are not the final page numbers! ÞÞ FULL PAPERS