1 SYNTHESIS: PAPER Template for SYNLETT and SYNTHESIS © Thieme Stuttgart · New York 2015-04-27 page 1 of 12 Abstract: The coupling reaction between aryl bromides and boron reagents has been efficiently catalyzed by an in situ generated palladium complex obtained from palladium acetate (0.1 mol%) and 1,3-bis(carboxymethyl)imidazole 1 (0.2 mol%). The catalytic system is very active in protic solvents, especially in MeOH. Biaryl derivatives have been prepared in good isolated yields (up to >99%), and additionally styrene and stilbene derivatives have also been prepared by means of this protocol. Key words: palladium, organometallic reagents, heterocycles, solvent effects, cross-coupling The chemistry of N-heterocyclic carbenes (NHCs) is a field of great current interest, and has witnessed remarkable development in the last two decades. 1 NHCs have been firmly established as one of the most versatile ligands in the toolkit of the synthetic chemist. The NHC complexes show a variety of interesting applications, including homogeneous catalysis, 2 antimicrobial, antitumor and cytoxic agents, 3 and chemistry of materials. 4 More recently, NHCs have emerged as powerful organic catalysts in molecular chemistry, and in metal-free polymer synthesis. 5 Imidazolium cations are the most investigated compounds as precursors for NHCs, and the introduction of functionalities into the nitrogen substituents has gradually increased the attention of research. Thus, a variety of functional groups have been attached to modify their physical and chemical properties, including, among others, phosphines, 6 amines, 7 alcohols, 8 esters, 9 amides, 10 and sulfonic 11 and carboxylic acids. 9,12 1,3-Bis(carboxymethyl)imidazole 1, which was first observed as a product in the glucose-glycine Maillard reaction, 13 has been prepared by reaction of glycine, glyoxal, and formaldehyde (Scheme 1). 14 Also, it can be prepared by the condensation of glyoxal and glycine. 15 Moreover, the reaction of 1- trimethylsilylimidazole with two equivalents of methyl chloroacetate and subsequent ester hydrolysis followed by basic treatment has also allowed the preparation of compound 1. 9 Imidazole dicarboxylate derivatives have been employed in the preparation of a series of coordination dimers and polymers containing different metal centres, such as lanthanides, 16 cesium, calcium, strontium, barium, 17 manganese, 18 and zinc. 19 Consequently, in addition to the σ-donor ability of the NHC ligands, the presence of carboxyl moieties in the imidazolium salt can interact with the corresponding metal centre in the complexation. In fact, the effect of this functional group on the rhodium-catalyzed hydrosilylation of alkenes has been studied by the research group of Li and Peng. 20 H 2 N CO 2 H gly oxal ( 0.5 e q uiv. ) formaldehyde ( 0.5 e q uiv. ) H 2 O, 90 ºC N N CO 2 - 1 CO 2 H Scheme 1 Synthesis of zwiterionic imidazole 1 from glycine. The synthesis of biaryl compounds in aqueous media from aryl and heteroaryl bromides and chlorides, by means of Suzuki-Miyaura reaction, can be performed at room temperature using the non-ionic vitamin E based amphiphile polyoxyethanyl α-tocopheryl sebacate (PTS) as surfactant, in the presence of different palladium catalysts. 21 Among them, the NHC-palladium complex [1,3-bis(2,6- diisopropylphenyl)imidazol-2-ylidene]chloro[3- phenylallyl] palladium(II) have been employed (2 mol%) in the presence of Et 3 N as base, with good to excellent results. 22 Furthermore, palladium catalysts with sulfonate-functionalized-NHC ligands have been prepared and employed for the Suzuki-Miyaura reaction in aqueous phase (i.e. water and i- PrOH/water mixtures). 23 Çetinkaya and co-workers have described the preparation of water-soluble NHC complexes of PEPPSI type, 24 having a carboxyl- functionalized pyridine. 25 More recently, poly(ethylene glycol)-functionalized imidazolium salts have been also employed in the Suzuki reaction in water. 26 Consequently, it would be interesting to study the suitability of carboxy-functionalized imidazole derivatives in combination with palladium to perform a cross-coupling reaction, such as Suzuki- Miyaura reaction. During the last five years, we have been studying different transformations mediated by catalytic systems prepared by hydroxy-functionalized imidazolium derivatives and palladium 27 or rhodium. 28 We wish to present herein a study on the catalytic system formed by palladium and bis(carboxymethyl)imidazole 1 for the cross-coupling between aryl bromides and boron reagents (i.e. aryl boronic acids and potassium aryltrifluoroborates) in protic solvents, such as water and methanol. Biscarboxy-Functionalized Imidazole and Palladium as Highly Active Catalytic System in Protic Solvents: Methanol and Water Regina Martínez, Isidro M. Pastor,* Miguel Yus* Departamento de Química Orgánica, Facultad de Ciencias and Instituto de Síntesis Orgánica (ISO), Universidad de Alicante, Apdo. 99, 03080 Alicante, Spain Fax: (+34)965903549 E-mail: ipastor@ua.es, yus@ua.es Received: The date will be inserted once the manuscript is accepted.