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Buchwald Ligands for C–N Coupling

Aldrich ChemFiles 2007, 7.1, 8.

Although many methodologies have been developed for C–N coupling reactions, until recently there were no general methods available for the N-arylation of imidazoles. Traditional methods for arylation included nucleophilic aromatic substitution of an activated aryl halide or by copper-mediated coupling of the imidazole with an aryl iodiole (Ullmann coupling). The former approach was limited in scope because it required an aryl halide bearing strongly electron-withdrawing substituents, while the latter protocol necessitated harsh reaction conditions and stoichiometric copper. The Buchwald group at MIT has developed a mild and high-yielding approach to arylated imidazoles using catalytic Cu(I) and a 1,10-phenanthroline ligand scaffold.1 Both aryl bromides and iodides are effective electrophiles, and the reaction conditions tolerate bulky substituents on either coupling partner. Additionally, the reaction is functional group tolerant, with cyano, nitro, ester, amino, hydroxyl, and halogen groups remaining intact during the course of the reaction (Scheme 1).


Scheme 1

The Buchwald group has also made significant advances in the area of mild Ullmann-type couplings of aryl halides with primary and secondary amines in the presence of CuI and a b-diketone ligand (Scheme 2).2 Heterocyclic structures may be present in either coupling partner, and a variety of functional groups are tolerated in the reaction conditions (e.g. carboxylic acids, Boc protecting groups, ketones, and olefins). Moreover, reactions of aryl iodides can typically be performed at ambient temperatures


Scheme 2

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Materials

     

References

  1. (a) Altman, R. A.; Buchwald, S. L. Org. Lett. 2006, 8, 2779. (b) Kiyomori, A. et al. Tetrahedron Lett. 1999, 40, 2657.
  2. Shafir, A.; Buchwald, S. L. J. Am. Chem. Soc. 2006, 128, 8742.

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