Copper-Catalyzed Arylation and Alkenylation of Polyfluoroarene C−H Bonds

Abstract

An efficient, copper-catalyzed method for the arylation, alkenylation, and benzylation of polyfluoroarenes has been developed. Arenes containing two or more fluorine substituents on the aromatic ring can be efficiently functionalized. The best results are obtained by using a combination of copper iodide catalyst, phenanthroline ligand, aryl bromide or aryl iodide coupling partner and DMF or DMF/xylene mixed solvent.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 aryl-aryl 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 transmetallation and reaction of the organocopper species with aryl iodide. It is reasonable to assume that relatively acidic polyfluorobenzenes 8 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 olafs@uh.edu.

Ligand-free Palladium/Copper Co-catalyzed Direct Arylation of Polyfluoroarenes with Aryl Iodides

“…In 2008, Daugulis developed a general method for the copper-catalyzed arylation of polyfluoroarenes with aryl halides in the presence of phenanthroline [11]. Fagnou in 2010 made further modifications to the arylation of polyfluoroarenes with aryl iodides, in which excellent yields were obtained under mild biphasic conditions at room temperature [17].…”

Iron‐Catalyzed Direct Arylation of Unactivated Arenes with Aryl Halides

“…[2,3] This strategy efficiently avoids the disposal of stoichiometric amounts of metal waste generated from the organometallic reagent, ArM, in the traditional coupling manner. [2,3] Various transition metals have been reported as efficient catalysts for this transformation, for example, Pd, [4][5][6][7][8][9][10][11] Rh, [12][13][14][15] Ru, [16][17][18] Ir, [19,20] Cu, [21][22][23][24][25][26][27] and other transition metals. [28][29][30] The application of inexpensive, non-toxic, commercially available, and environmentally benign iron complexes as catalysts in chemical syntheses has attracted much attention.…”

Copper‐Catalyzed Direct C Arylation of Heterocycles with Aryl Bromides: Discovery of Fluorescent Core Frameworks

“…[1,2] Sogar aktivierte Arylchloride waren in der kupferkatalysierten Arylierung reaktiv. Somit war es unzutreffend, das zuvor beschriebene System als nur für Aryliodide effizient einzustufen.…”

“…2) Es wurde behauptet, die Regioselektivität und Verträglichkeit mit funktionellen Gruppen wäre bei der zuvor beschriebenen Methode [1,2] dadurch beeinträchtigt, dass dort starke Basen notwendig wären, während die im Beitrag beschriebene Methode als kompatibel mit Ester-, Cyan-, Aldehyd-und anderen Funktionen herausgestellt wurde. Aber auch die zuvor beschriebene Methode ist nachweislich mit den meisten dieser funktionellen Gruppen kompatibel.…”

“…Aber auch die zuvor beschriebene Methode ist nachweislich mit den meisten dieser funktionellen Gruppen kompatibel. [1,2] Daher war es nicht richtig, eine verbesserte Verträglichkeit mit funktionellen Gruppen zu postulieren. 3) Die vorherige Verwendung von K 3 PO 4 als Base in kupferkatalysierten Arylierungen wurde übersehen; die im Beitrag beschriebenen Bedingungen waren somit beinahe identisch mit zuvor beschriebenen Bedingungen.…”