A regioselective palladium-free protocol for accessing unsymmetrical biaryls through ring transformation of 6-aryl-a-pyrones I Amit Kumar, Fateh V. Singh and Atul Goel * Division of Medicinal and Process Chemistry, Central Drug Research Institute, Lucknow 226 001, India Received 6 July 2007; revised 8 August 2007; accepted 13 August 2007 Available online 16 August 2007 Abstract—A regioselective synthesis of unsymmetrical biaryls with electron withdrawing or donating substituents is described and illustrated by carbanion-induced ring transformation of 6-aryl-a-pyrones with methoxyacetone in excellent yield. Our methodology is an alternative to classical organometal-catalyzed aryl–aryl coupling reactions and can be applied to the synthesis of functionally demanding naphthyl biaryls for the development of new ligands for asymmetric synthesis. Ó 2007 Elsevier Ltd. All rights reserved. Aryl–aryl bond formation for the preparation of sym- metrical and unsymmetrical biaryl compounds is a very useful and important tool in organic chemistry. Biaryl ring systems functionalized with electron donor or acceptor moieties are constituents of a large number of natural products 1 and synthetic pharmaceuticals and are useful as versatile auxiliaries for asymmetric synthe- ses, 2 as chiral phases for chromatography 3 and as important substrates for chiral liquid crystalline materi- als. 4 Several biaryl derivatives have been designed as po- tent glucagon receptor antagonists for the treatment of diabetes. 5 Biaryls can be prepared by transition metal-catalyzed intermolecular or intramolecular aryl–aryl cross-cou- pling reactions. Reductive dimerization of aryl halides is one of the oldest methods 6 for the construction of biaryls using copper bronze as a reducing agent. Oxida- tive coupling of electron-rich aromatic phenols has also led to the formation of biaryls in moderate yields. 7 Pal- ladium-catalyzed cross coupling between electrophilic aromatic halides or triflates and the organometallic spe- cies Ar–M (M being Mg, Zn, Sn, and B) has become a general approach for the construction of symmetrical and unsymmetrical biaryls. 8 For example, the palla- dium-catalyzed aryl-boronic acid coupling (Suzuki reac- tion) has become a general and versatile route to access functionalized biaryls. 8f Despite the wide synthetic po- tential of these metal-assisted cross-coupling reactions, they are associated with expensive organometallic re- agents/catalysts, in some cases harsh reaction conditions and undesired byproducts. Thus, there exists a need to develop an expedient route for the synthesis of biaryls that does not require specialized reagents or expensive catalysts, which could offer flexibility with respect to variation in the substitution pattern. Although numer- ous regio- and stereoselective Diels–Alder reactions 9 of a-pyrones with electron-deficient and electron-rich dienophiles provide benzene derivatives, they require forcing thermal reaction conditions to eliminate carbon dioxide from the adduct and/or are associated with the formation of a mixture of positional isomers. Herein, we report a new palladium-free protocol for the synthesis of functionalized biaryls through a ring trans- formation reaction of 6-aryl-a-pyrones with methoxy- acetone in high yields. The procedure utilizes a simple transformation strategy without using an expensive organometallic reagent or a catalyst. During our studies on the chemistry of a-pyrones, we observed 10 that a-pyrones prepared from a-oxo-ke- tene-S,S-acetal 11 were useful substrates for ring trans- formation reactions, possessing flexible substitution patterns and a good alkylsulfanyl leaving group for gen- erating molecular diversity. Our recent efforts 12 have indicated that the a-pyranone ring can be converted to 0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.tetlet.2007.08.051 q C.D.R.I. Communication No. 7255. * Corresponding author. Tel.: +91 522 2612411; fax: +91 522 2623405; e-mail: agoel13@yahoo.com Tetrahedron Letters 48 (2007) 7283–7286