Copper-catalyzed arylation and alkenylation of polyfluoroarene C-H bonds.

Many directing group containing arenes can now be arylated or alkylated under palladium, rhodium, or ruthenium catalysis.1 Even arenes lacking traditional directing groups can be functionalized representing the most atom-efficient method for creation of arylaryl bonds.2 However, in this case, regioselectivity issues often are unsolved. An exception can be found in recent elegant work by Fagnou who showed that polyfluorobenzene C-H bonds can be arylated under palladium catalysis.3 The regioselectivity is imparted by the acidification of ortho-C-H bonds by fluorine substituents. While palladium catalysts can be replaced by copper in many coupling processes,4 use of this cheaper and more convenient alternative in C-H activation reactions is not common.5 Fluorinated polyaryls are important in medicinal chemistry, and direct methods for synthesis of these compounds may allow the development of more efficient pathways to pharmaceuticals.6 We report here a general method for the copper-catalyzed arylation and alkenylation of polyfluorobenzene C-H bonds. We have recently shown that palladium catalyst can be replaced by copper in the arylation of electron-rich and electron-poor heterocycles.7 The reaction mechanism presumably includes a deprotonation of an acidic heterocycle followed by lithium/copper transmetalation and reaction of the organocopper species with aryl iodide. It is reasonable to assume that relatively acidic polyfluorobenzenes8 can be arylated if a proper combination of base, solvent, and copper catalyst is used. A brief optimization of reaction conditions was carried out. For pentafluorobenzene arylation by aryl bromides, the best results were obtained in mixed DMF/xylene solvent (1:1) and by employing phenanthroline ligand. Lower conversions were observed in DMF. Pentafluorobenzene can be arylated by both aryl bromides and aryl iodides. For other, less reactive substrates, the reaction with aryl iodide in DMF solvent results in higher yields. In most cases, potassium phosphate base affords the best results. Less acidic fluorobenzenes that contain fewer than three fluorines in the molecule can be arylated by employing lithium tert-butoxide base. The reaction scope with respect to aryl halide is presented in Table 1. Both electron-rich (entries 1-5) and electron-poor (entries 6-9) aryl halides are reactive. Functional groups, including ester (entry 8) and cyano (entry 9) are tolerated. Pyridyl (entries 10 and 11) and electronrich thienyl (entry 12) bromides can be employed for the arylation. If a 5.7/1 E/Z mixture of â-bromostyrene was used in alkenylation of pentafluorobenzene, a 5.7/1 E/Z ratio of pentafluorostilbene was obtained (analysis of crude reaction mixture; 77% E and 12% Z isolated, entry 13). Substantial steric hindrance is tolerated on the aryl halide (entries 2 and 3). Mesitylation requires the use of aryl iodide to obtain high yield. Mesityl bromide afforded only 20% isolated yield of the coupling product. Pentafluorobenzene is benzylated in fair yield (entry 14). A side reaction between benzyl bromide and DMF solvent is responsible for the reduced yield. On a 10 mmol scale, yield is almost the same as on 1 mmol scale (88% vs 91%, entry 1). The scope with respect to fluoroarene is presented in Table 2. Two of the three tetrafluorobenzenes can be arylated in good yields (entries 1 and 2). The arylation of 1,2,3,4-tetrafluorobenzene affords only a low yield of the cross-coupling product (entry 3). 1,3,5Trifluoroand 1,3-difluorobenzenes are reactive; however, for the arylation of less acidic difluorobenzene, a stronger base, LiOtBu, is necessary. Fluorinated pyridines can also be arylated (entries 6 Table 1. Arylation Scope with Respect to Halidesa