Synthesis of o,m-cymene-cored biaryls through a carbanion-induced ring transformation strategy I Fateh Veer Singh, Amit Kumar and Atul Goel * Division of Medicinal and Process Chemistry, Central Drug Research Institute, Lucknow 226 001, India Received 20 July 2006; revised 23 August 2006; accepted 23 August 2006 Available online 15 September 2006 Abstract—Aromatic compounds derived from two or more ‘isoprene units’ are the core structures found in several natural products of biological importance. Among them, cymene derivatives are of particular interest due to the unique structural and biological properties associated with them. In this letter, we describe an expeditious synthesis of cymene-cored unsymmetrical biaryls function- alized with donor and acceptor substituents prepared in excellent yields by the carbanion-induced ring transformation of 2H-pyran- 2-ones with ketones. Ó 2006 Elsevier Ltd. All rights reserved. Benzene scaffolds functionalized with methyl and iso- propyl functionalities in flexible or rigid conformations are encountered in many natural products 1 (terpenoids such as o,m,p-cymene) as well as in synthetic pharma- ceuticals. 2 Several of the biaryls, in which one of the aryl rings is substituted with one or more isopropyl units, have recently been reported as potent glucagon receptor antagonists for the treatment of diabetes. 3 The biaryl, Bay-27-9955 functionalized with two isopropyl units has been reported to inhibit glucagon from the human glucagon receptor with an IC 50 value of 110 nM. 4 The compound was found to be orally active with a bioavail- ability of 40% and a half-life of 11–17 h in male rats and was selected for advanced clinical trials. 5 In addition, several 1,3-diisopropylbenzene-based imidazolium salts are used as chiral auxiliaries for a variety of asymmetric catalysis processes. 6 Recently, Buchwald’s chiral biaryl phosphine ligands with triisopropyl moieties (XPhos and tert-butyl Xphos) have emerged as versatile chiral ligands for palladium-catalyzed asymmetric syntheses. 7 Therefore, the necessity for an efficient and concise synthesis of biaryls having desired functionalities is important in natural product chemistry as well as in the discovery of new reagents for asymmetric synthesis. The aryl–aryl bond formation for the preparation of symmetrical and unsymmetrical biaryls is one of the most useful and important tools in modern organic chemistry. The construction of biaryls can be achieved either by intermolecular or by intramolecular cross-cou- pling of two similar or dissimilar aromatic rings in the presence of organo-metal complexes. Palladium-cata- lyzed cross-coupling reactions between electrophilic compounds, Ar-X (X being mainly Cl, Br, I and OTf) and organometallic species Ar-M (M being Mg, Zn, Sn and B) are versatile procedures for the construction of biaryl systems. The asymmetric version can be accomplished by the use of chiral reagents or auxiliaries and a plethora of examples are available in the litera- ture. 8 Generally, the preparation of these compounds is based on the Pd-mediated Suzuki–Miyaura coupling procedure, which has been frequently used to prepare a wide array of biaryl scaffolds. Despite the wide syn- thetic potential of these metal-assisted cross-coupling reactions, they suffer from the requirements for expen- sive organometallic reagents/catalysts, harsh reaction conditions and undesired by-products. Thus, there exists a need to develop an expedient route for the synthesis of biaryls that does not require specialized reagents or catalysts and which could offer an economical general route with flexibility for introducing electron donor or acceptor groups. Herein, we report a new route for the synthesis of functionalized biaryls through a ring transformation reaction of 2H-pyran-2-ones with either 2-methyl-pen- tan-3-one or substituted phenyl acetones in high yields. 0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved. doi:10.1016/j.tetlet.2006.08.105 Keywords: Biaryl; Cymene; Isopropyl ketone; Lactone; Pyran-2-one. q CDRI Communication No. 7028. * Corresponding author. Fax: +91 522 2623405; e-mail: agoel13@ yahoo.com Tetrahedron Letters 47 (2006) 7767–7770