The transition-metal-catalyzed functionalization of C-H bonds is a powerful method for generating carbon-carbon bonds. Although significant advances to this field have been reported during the last decade, many challenges remain. First, most of the methods are substrate-specific and thus cannot be generalized. Second, conversions of unactivated (i.e. not benzylic or alpha to heteroatom) sp 3 C-H bonds to C-C bonds are rare, with most examples limited to t-butyl groups-a conversion that is inherently simple because there are no β-hydrogens that can be eliminated. Finally, the palladium, rhodium, and ruthenium catalysts routinely used for the conversion of C-H bonds to C-C bonds are expensive. Catalytically active metals that are cheaper and less exotic (e.g. copper, iron, and manganese) are rarely used.This Account describes our attempts to provide solutions to these three problems. We have developed a general method for directing-group-containing arene arylation by aryl iodides. Using palladium acetate as the catalyst, we arylated anilides, benzamides, benzoic acids, benzylamines, and 2-substituted pyridine derivatives under nearly identical conditions. We have also developed a method for the palladium-catalyzed auxiliary-assisted arylation of unactivated sp 3 C-H bonds. This procedure allows for the β-arylation of carboxylic acid derivatives and the γ-arylation of amine derivatives. Furthermore, copper catalysis can be used to mediate the arylation of acidic arene C-H bonds (i.e. those with pKa values <35 in DMSO). Using a copper iodide catalyst in combination with a base and a phenanthroline ligand, we successfully arylated electron-rich and electron-deficient heterocycles and electron-poor arenes possessing at least two electron-withdrawing groups. The reaction exhibits unusual regioselectivity: arylation occurs at the most hindered position. This coppercatalyzed method supplements the well-known C-H activation/borylation methodology, in which functionalization usually occurs at the least hindered position. We also describe preliminary investigations to determine the mechanisms of these transformations. We anticipate that other transition metals, including iron, nickel, cobalt, and silver, will also be able to facilitate deprotonation/arylation reaction sequences.

A general method for copper-catalyzed arylation of sp 2 C-H bonds with pKa's below 35 has been developed. The method employs aryl halide as the coupling partner, lithium alkoxide or K 3 PO 4 base, and DMF, DMPU, or mixed DMF/xylenes solvent. A variety of electron-rich and electron-poor heterocycles such as azoles, caffeine, thiophenes, benzofuran, pyridine oxides, pyridazine, and pyrimidine can be arylated. Furthermore, electron-poor arenes possessing at least two electronwithdrawing groups on benzene ring can also be arylated. Two arylcopper-phenanthroline complex intermediates were independently synthesized.

Because many pharmaceuticals contain heterocycle-aryl linkages, arylation of heterocycles has received significant attention in the recent years. 1 The shortest and most efficient routes to these compounds involve direct functionalization of heterocycle C-H bonds. 2 In general, most efforts in cross-coupling methodologies currently are geared toward the replacement of aryl iodides with cheaper aryl chlorides. 3 However, for realistic catalyst loadings it is more cost-efficient to replace the expensive transition metal catalyst, usually palladium or rhodium, with a cheaper one. 4 Use of copper catalysts for the amination and Stilleor Suzuki-type couplings has been demonstrated. 5 Copper-catalyzed direct heterocycle C-H arylation reactions are unknown. 6,7 We report here a general method for the copper-catalyzed heterocycle arylation by aryl iodides. In addition to electron-rich five membered heterocycles, electron-deficient pyridine oxides can also be arylated. Preliminary mechanistic studies of the arylation are also reported.

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.

The development of a mild and general method for the alkylation of amides with relatively unreactive alkyl halides (i.e., poor substrates for S N 2 reactions) is an ongoing challenge in organic synthesis. We describe herein a versatile transition-metal-catalyzed approach: in particular, a photoinduced, copper-catalyzed monoalkylation of primary amides. A broad array of alkyl and aryl amides (as well as a lactam and a 2-oxazolidinone) couple with unactivated secondary (and hindered primary) alkyl bromides and iodides using a single set of comparatively simple and mild conditions: inexpensive CuI as the catalyst, no separate added ligand, and C−N bond formation at room temperature. The method is compatible with a variety of functional groups, such as an olefin, a carbamate, a thiophene, and a pyridine, and it has been applied to the synthesis of an opioid receptor antagonist. A range of mechanistic observations, including reactivity and stereochemical studies, are consistent with a coupling pathway that includes photoexcitation of a copper−amidate complex, followed by electron transfer to form an alkyl radical.