A new, mild one-pot synthesis of iodinated heterocycles as suitable precursors for N-heterocyclic carbene complexes

N-heterocyclic carbenes (NHCs) have been shown to be versatile ligands for transition metal complexes. Most importantly, these ligands have an outstanding impact on many homogeneous catalysts, often outperforming more common phosphine ligands. Metal coordination to NHCs has been achieved by a variety of methods. Among these, oxidative addition is particularly attractive because of the typically mild reaction conditions and the high product selectivity. Moreover, oxidative addition avoids the synthesis of the corresponding free carbene or the silver carbene intermediates, which may not be easily accessible or even unfeasible due to their low stability. For the generation of N-heterocyclic carbene complexes via C–X bond oxidative addition, iodo-functionalized heterocycles serve particularly as convenient precursors. In addition, the iodination of aromatic heterocycles is a matter of continuing interest in medicinal chemistry and in modern organic chemistry, which is making extensive use of iodinated derivatives as building blocks for carbon–carbon bond-forming reactions. The synthesis of iodinated aromatic heterocycles can be achieved by direct iodination of CHet–H bonds or by nucleophilic substitution of CHet–X, where X is a good leaving group. The former method relies on the presence of Lewis acids or strong oxidizing agents to overcome the low electrophilicity of iodine. On the other hand, the latter method requires the pre-installation of a good leaving group. Even though the literature offers a variety of synthetic protocols for the preparation of iodinated (hetero)aromatic compounds, harsh conditions and expensive or toxic chemicals are often required. In addition, one single methodology typically does not perform well for different substrates, thus illustrating the need for the further development of efficient and reliable methodologies for the synthesis of iodinated heterocycles. Herein we report convenient and inexpensive methods for the synthesis of a range of iodinated N-heterocycles that are suitable precursors for non-classical NHC transition metal complexes (Scheme 1). We successfully applied the iodine–iodide (I2 and KI) methodology for the preparation of compound 2a and its N-methylated derivative 2b from the corresponding halide-free imidazoles 1a and 1b, respectively (Table 1, entries 1 and 2). However, this method failed to iodinate 3,5-dimethylisoxazole (1c) for which mainly the starting material was recovered (entry 3). In contrast, the use of silver acetate and iodine afforded the desired 3,5-dimethyl-4-iodoisoxazole (2c) in almost quantitative yield (98%). In addition, better yields were obtained for the iodination