Copper(II)-Catalyzed Alkoxyhalogenation of Alkynyl Ureas and Amides as a Route to Haloalkylidene-Substituted Heterocycles Silvia Gazzola, † Egle M. Beccalli, ‡ Tea Borelli, † Carlo Castellano, § Maria Assunta Chiacchio, ∥ Daria Diamante, † and Gianluigi Broggini* ,† † Dipartimento di Scienza e Alta Tecnologia, Universita ̀ dell’Insubria, via Valleggio 11, 22100 Como, Italy ‡ DISFARM, Sezione di Chimica Generale e Organica “A. Marchesini”, Universita ̀ degli Studi di Milano, via Venezian 21, 20133 Milano, Italy § Dipartimento di Chimica, Universita ̀ degli Studi di Milano, via Golgi 19, 20133 Milano, Italy ∥ Dipartimento di Scienze del Farmaco, Universita ̀ di Catania, Viale Andrea Doria 6, 95125 Catania, Italy * S Supporting Information ABSTRACT: A highly effective synthesis of haloalkylidene-substituted heterocycles by copper(II)-catalyzed cyclization of alkynyl ureas and secondary amides has been developed. The reaction, which involves a catalytic amount of CuCl 2 and a stoichiometric amount of N- halosuccinimide, occurs selectively through an alkoxyhalogenation process. Alternatively, alkoxychlorination and alkoxybromination reac- tions can be performed working solely with stoichiometric CuCl 2 and CuBr 2 , respectively. ■ INTRODUCTION Intramolecular transition-metal-catalyzed alkoxylation of car- bon−carbon multiple bonds represents one of the most effective approaches to prepare oxygenated heterocycles, which are important motifs in many biologically active compounds. 1 Processes leading to the generation of new bonds in addition to the first-formed C−O bond have been reported in the literature. 2 While this approach is substantially devoted to the functionalization of alkenes and allenes, related reactions involving alkynes are somewhat limited. 3 Among the procedures of alkoxylation, transition-metal-catalyzed reactions based on the use of secondary amides 4 or ureas 5 as nucleophiles represent a useful tool to perform directly functionalized oxygenated heterocycles. The attractiveness of the copper catalysts stems from their low cost and their tolerance toward many reactive functional groups, and the reactions do not require rigorously anaerobic and anhydrous conditions. These features strongly increased the development of procedures for C−O 6 and C−N 7 bond forming reactions. However, despite various kinds of reactivities, the examples of copper-promoted exo-selective intramolecular alkyne hydralkoxylation are rather restricted. 8 Among these methods, a chlorocyclization of N-alkoxy-2- alkynylbenzamides by CuCl 2 and NCS, both in large excess amounts, was reported as a synthetic protocol for isobenzofur- an-1-one derivatives. 9 Recently, the iodocyclization of terminal propargyl amides in the presence of stoichiometric CuI and Selectfluor was described by Xu and co-workers. 10 On the basis of the picture emerging from the literature, as part of our ongoing project on intramolecular transition-metal- catalyzed amination and alkoxylation reactions involving C−H and heteroatom−H functionalization, 11 we tried to perform a copper-catalyzed alkoxylation/halogenation of alkynyl ureas and secondary amides to afford a range of haloalkylidene- substituted heterocycles (Scheme 1). In principle, the formation of an intramolecular bond with these substrates Received: June 1, 2015 Scheme 1. General Copper-Promoted Procedure for Haloalkylidene-Substituted Heterocycles Article pubs.acs.org/joc © XXXX American Chemical Society A DOI: 10.1021/acs.joc.5b01227 J. Org. Chem. XXXX, XXX, XXX−XXX