LETTER 195 Synthesis of 3,5-Diaryl-4-fluorophthalates by [4+2]-Cycloaddition and Subsequent Site-Selective Suzuki–Miyaura Reactions Synthesis of 3,5-Diaryl-4-fluorophthalates Muhammad Farooq Ibad, a Obaid-Ur-Rahman Abid, a Muhammad Nawaz, a Muhammad Adeel, a,b Alexander Villinger, a Peter Langer* a,c a Institut für Chemie, Universität Rostock, Albert Einstein Str. 3a, 18059 Rostock, Germany b Department of Chemistry, Gomal University, Dera Ismail Khan, N.W.F.P, Pakistan c Leibniz Institut für Katalyse an der Universität Rostock e.V., Albert Einstein Str. 29a, 18059 Rostock, Germany Fax +49(381)4986412; E-mail: peter.langer@uni-rostock.de Received 7 October 2009 SYNLETT 2010, No. 2, pp 0195–0198xx.xx.2010 Advanced online publication: 11.12.2009 DOI: 10.1055/s-0029-1218556; Art ID: G34009ST © Georg Thieme Verlag Stuttgart · New York Abstract: The [4+2] cycloaddition of 1-ethoxy-2-fluoro-1,3- bis(trimethylsilyloxy)-1,3-diene with dimethyl acetylenedicarbox- ylate (DMAD) afforded dimethyl 4-fluoro-3,5-dihydroxyphthalate. Site-selective Suzuki–Miyaura reactions of its bis(triflate) provide a convenient approach to 3,5-diaryl-4-fluorophthalates. Key words: arenes, cyclizations, organofluorine compounds, site- selectivity, Suzuki–Miyaura reaction In the last decade, we have witnessed a dramatic increase of the interest in organofluorine compounds because of their great pharmacological relevance. 1 While the size of the fluorine atom is relatively small, its high electronega- tivity often results in an improvement of drug-receptor in- teractions. Due to the chemical and biological stability of the carbon–fluorine bond, undesired metabolic transfor- mations are rather rare and the transport of the drug in vivo is facilitated by the high lipophilicity of organofluo- rine compounds. Fluorinated arenes and heteroarenes are also versatile building blocks in transition-metal-cata- lyzed cross-coupling reactions. 2 In addition, organofluo- rine compounds, such as fluorinated thioureas, are used as organocatalysts 3 and ligands. 4 Direct fluorination reactions of arenes often suffer from their low chemo- and regioselectivity. Multiple fluorina- tion represents an additional drawback. Cyclization reac- tions of fluorinated building blocks provide a powerful alternative for the synthesis of fluorinated arenes and hetarenes. Schlosser et al. reported the synthesis of fluor- inated arenes by Diels–Alder reactions of alkenes or alkynes with fluorinated 1,3-butadienes. 5 Portella et al. developed a versatile approach to fluorinated phenols from 2,2-difluoro-1,5-diketones. 6 Recently, we studied the synthesis of fluorinated arenes and hetarenes based on formal [3+3] and [3+2] cycliza- tions of 1,3-bis(silyloxy)-1,3-butadienes. 7–9 Herein, we report, for the first time, the synthesis of dimethyl 4-fluo- ro-3,5-dihydroxyphthalate by [4+2] cycloaddition of 1- ethoxy-2-fluoro-1,3-bis(trimethylsilyloxy)-1,3-diene with dimethyl acetylenedicarboxylate (DMAD). Suzuki– Miyaura reactions of the bis(triflate) of this product pro- ceeded with very good site-selectivity 10 and provided a convenient approach to novel 3,5-diaryl-4-fluorophtha- lates which are not readily available by other methods. The [4+2] cycloaddition of 1-ethoxy-2-fluoro-1,3-bis(tri- methylsilyloxy)-1,3-diene (1) with DMAD afforded di- methyl 4-fluoro-3,5-dihydroxyphthalate (2) in 40% yield (Scheme 1). 11 The latter was transformed into bis(triflate) 3 in high yield. 12 The structure of 2 was independently confirmed by X-ray crystal structure analysis (Figure 1). 13 Scheme 1 Synthesis of 2 and 3. Reagents and conditions: (i) (1) 1 (1.0 equiv), DMAD (1.5 equiv), –78 °C → 20 °C, 20 h; (2) HCl (10%); (ii) (1) 2 (1.0 equiv), pyridine (4.0 equiv), CH 2 Cl 2 , –78 °C, 10 min; (2) Tf 2 O (2.4 equiv), –78 °C → 0 °C, 4 h. The Suzuki reaction of 3 with boronic acids 4a–f (2.3 equiv) afforded the novel 3,5-diaryl-4-fluorophthalates 5a–f in good yields (Scheme 2, Table 1). The best yields were obtained when Pd(PPh 3 ) 4 (3 mol%) was used as the catalyst, when 2.3 equivalents of the boronic acid was em- ployed, and when the reaction was carried out in 1,4-diox- ane (110 °C, 8 h) using K 3 PO 4 as the base. 14,15 The Suzuki–Miyaura reaction of 3 with arylboronic acids 4a,g–l (1.1 equiv) afforded the 5-aryl-4-fluorophthalates 6a–g in good yields and with very good site-selectivity (Scheme 3, Table 2). 16 The formation of the opposite regioisomers was not observed. OSiMe 3 OEt + 1 F F CO 2 Me CO 2 Me HO OH 2 (40%) i CO 2 Me MeO 2 C DMAD F CO 2 Me CO 2 Me TfO OTf 3 (87%) ii Me 3 SiO Downloaded by: Universität Rostock. Copyrighted material.