Palladium(II) chloride/EDTA-catalyzed biaryl homo-coupling of aryl halides in aqueous medium in the presence of ascorbic acid Ram N. Ram * and Virinder Singh Department of Chemistry, Indian Institute of Technology, Delhi, Hauz Khas, New Delhi 110 016, India Received 6 June 2006; revised 9 August 2006; accepted 17 August 2006 Available online 7 September 2006 Abstract—Both electron-deficient and electron-rich aryl bromides undergo biaryl homo-coupling in a basic aqueous-ethanolic med- ium in the presence of PdCl 2 –EDTA (1:1 molar ratio, 3 mol %) as catalyst and ascorbic acid as reductant (1 mol equiv) in acceptable to good yields. Ó 2006 Elsevier Ltd. All rights reserved. 1. Introduction The potential applications of compounds containing a biaryl sub-unit in the areas of organometallic catalysis, 1 materials science 2,3 and supramolecular chemistry, 4 and its occurrence in several bioactive natural products, 5,6 pharmaceuticals and agrochemicals 7,8 have generated tremendous activity in aryl–aryl bond forming reactions. Several modern methods for the preparation of biaryls are available, such as Suzuki, Stille, Negishi, Kumada and Hiyama cross-coupling reactions, which involve the palladium (or nickel) catalyzed coupling of aryl halides (or less frequently pseudo-halides) with an aryl organometallic, Ar–M (M = B, Sn, Zn, Mg or Si). 9–11 The palladium-catalyzed intermolecular direct arylation of electron-rich arenes and heteroarenes with aryl halides 12 and one-pot two-step borylation-Suzuki cross-coupling 8 (BSC) of two electronically complemen- tary aryl halide molecules are two noteworthy recent advances amongst many in this area. There are several reports on metal-catalyzed/promoted self-coupling of various organometallics, such as aryl Grignards, zinc, boronic acids, stannanes, and silanes, as well as oxida- tive coupling of electron-rich arenes for the preparation of symmetrical biaryls. 9,13 However, for a general synthesis of symmetrical biaryls, the direct reductive homo-coupling of aryl halides is more convenient and straightforward as it bypasses the synthesis of the aryl organometallic and does not suffer as much with structural constraint. Although the classical Ullmann coupling for the preparation of symmetrical biaryls has this advantage, it requires stoichiometric amounts or more of copper and harsh reaction conditions (neat, >200 °C). 14 Several milder methods have since been developed by replacing copper with an Ni(0) 9,15–17 or Pd(0) 9,18 catalyst and a reducing agent. The latter is required to regenerate the active me- tal catalyst in the zero oxidation state to allow a second oxidative addition of the aryl halide to the metal catalyst to occur. The reductive elimination then yields the biaryl. However, it appears that the reactivity and selec- tivity of these reactions significantly depend on the nature of the transition metal catalyst, the reducing reagent and the solvent. While Pd catalysts have gener- ally been found to be more efficient than Ni catalysts and require milder reducing agents, several methods still use reducing agents such as zinc dust 9,19,20 and mole- cular hydrogen 21 which are too strong to be successful with electron-deficient haloarenes or those having easily reducible groups, such as nitro, aldehyde and keto where a competing reductive dehalogenation or, generally reduction of the functional group occurs without biaryl coupling, as with Ni catalysts. Of the reported Pd-catalyzed reactions using relatively milder organic co-reductants, 9,22–29 such as isopropanol, tertiary amines, formates and DMF (probably due to impurities such as dimethylamine and formate present or generated in situ), 22 tetrakis(dimethylamino)ethyl- ene 23,24 and hydroquinone 25,26 appear to be the most 0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved. doi:10.1016/j.tetlet.2006.08.056 Keywords: Aryl halides; Biaryls; Reductive homo-coupling; Palladium chloride; EDTA; Ascorbic acid; Aqueous medium. * Corresponding author. Tel.: +91 11 26581508; fax: +91 11 26582037; e-mail: rnram@chemistry.iitd.ernet.in Tetrahedron Letters 47 (2006) 7625–7628