A straightforward anionic coupling for the synthesis of ortho-bromobiaryls Jean-Michel Becht, Silve `re Ngouela, Alain Wagner * and Charles Mioskowski * Laboratoire de Synthe `se Bioorganique, UMR 7514 associe ´e au CNRS, Faculte ´ de Pharmacie, Universite ´ Louis Pasteur de Strasbourg, 74 Route du Rhin, 67400 Illkirch, France Received 22 April 2004; revised 26 May 2004; accepted 3 June 2004 Available online 4 July 2004 Abstract—Non-catalyzed anionic coupling of aryllithiums with 1,2-dibromobenzene gives straightforward access to valuable ortho- bromobiaryls. q 2004 Elsevier Ltd. All rights reserved. 1. Introduction In recent years, ortho-functionalized biaryls have been found as central motifs of active molecules in various therapeutic areas 1,2 and molecular recognition devices. 3 Such biaryl structures are usually prepared through Pd- catalyzed Stille or Suzuki cross-coupling reactions 4 of ortho-functionalized precursors. 5 However, these methods have some drawbacks. For instance, the Stille coupling requires the use of toxic tin reagents and both cross- couplings precursors are often tedious to prepare and require expensive reactants. The alternative route, by functionaliza- tion of an ortho-bromobiaryl through metal – halogen exchange and subsequent reaction with various electro- philes, offers another synthetic strategy. However, here again, the synthesis of the ortho-halobiaryl intermediate is not often straightforward since it is achieved through a Pd-catalyzed cross-coupling reaction. 5 In a previous paper 6 we have shown that, contrary to the common belief, 7 aryllithiums react with 2-chloroanisole to afford regio- specifically 2-methoxybiaryls. These results, together with previous reports of Gilman 8 and Schlosser, 9 prompted us to investigate whether other classes of substrates, and particularly 1,2-dihalobenzenes, could undergo a similar regiospecific reaction and thus provide easy access to synthetically valuable ortho-halobiaryls. In 1957, Gilman and Gaj observed that 2 equiv. of 1,2-di- bromobenzene react with 1 equiv. of n-BuLi in THF at 278 8C to give 2,2 0 -dibromo-biphenyl in 74% yield. 8 More recently, taking advantage of this homocoupling reaction, Schlosser reported the synthesis of halogenated biaryls featuring uncommon substitution patterns. 9 Building on these reports and on our previous work, we show herein that non-catalyzed anionic coupling of aryllithiums with 1,2-dibromobenzene provides efficient access to valuable ortho-bromobiaryls. 2. Results and discussion Addition of 1 equiv. of 1,2-dibromobenzene to a solution containing 1.2 equiv. of 2-lithio-1,3-dimethoxybenzene (2-lithio-1,3-DMB) 1 in THF at rt for 3 h gives regio- specifically the expected ortho-bromobiaryl structure in 95% yield (Table 1, entry 1). While the condensation is rapid at rt, it proceeds at 278 8C in 6 h. The aryllithium 1 reacts with various 1-bromo-2-halobenzenes. 1-Bromo-2- chlorobenzene (entry 2) and 1-bromo-2-fluorobenzene (entry 3) afford regiospecifically the expected ortho- bromobiaryl 2a in 70 and 63% yields, respectively. Interestingly, this ortho isomer is regiospecifically obtained 0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.tet.2004.06.010 Tetrahedron 60 (2004) 6853–6857 Table 1. Reaction of 2-lithio-1,3-DMB and 1,2-dihalobenzenes Entry X X 0 Product Yield (%) a 1 Br Br 2a 95 2 Cl Br 2a 70 3 F Br 2a 63 4 I I 2b 77 a Isolated yields. * Corresponding authors. Tel.: þ33-3-90-24-42-95; fax: þ33-3-90-24-43- 06; e-mail address: alwag@aspirine.u-strasbg.fr Keywords: C –C Coupling; Biaryls; Metallation; Synthetic methods.