Remote functionalization reactions as conformational probes for flexible alkyl chains

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.

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“…Remote functionalizations resulting in the formation of C-C bonds are rare 23. Most of these methods involve radical reactions.…”

Section: Discussionmentioning

confidence: 99%

Palladium- and Copper-Catalyzed Arylation of Carbon−Hydrogen Bonds

2009

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“…For example, enzymatic systems such as desaturases can oxidize a single unactivated carbon-hydrogen bond at a specific region on the alkyl chain of stearic acid and convert it to oleic acid, possessing only a cis geometry. In this context, the team of R. Breslow has produced the first chemical example of the application of this principle of remote iunctionalization by undertaking selective oxidation of alkyl chains (399,400). In this context, the team of R. Breslow has produced the first chemical example of the application of this principle of remote iunctionalization by undertaking selective oxidation of alkyl chains (399,400).…”

Section: Remote Functionalization Reactionsmentioning

confidence: 99%

“…400 For example, zinc ions serve as a stabilizer for insulin, the hormone that facilitates the passage of glucose into the cell; they are vital components of spermatozoa; they are important in speeding up the healing of wounds; they are involved in the breakdown of protein food in the intestinal tract.…”

Section: Ch -Ch-chmentioning

confidence: 99%

Bioorganic Chemistry

Dugas¹

1989

Springer Advanced Texts in Chemistry

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“…In this context, the team of R. Breslow has produced the first chemical example of the application of this principle of remote junctionalization by undertaking selective oxidation of alkyl chains (194,195). As the reagent to attack an unactivated CH 2 group they selected the photochemical activation ofbenzophenone triplet (Yang triplet reaction) and studied the intramolecular insertion of benzophenone carboxylic ester of alkanols (Fig.…”

Section: Ohmentioning

confidence: 99%