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New aryl/heteroaryl C-N bond cross-coupling reactions via arylboronic acid/cupric acetate arylation

Patrick Y. S. Lam*, Charles G. Clark, Simon Saubern, Jessica Adams, Michael P. Winters, Dominic M. T. Chan and Andrew Combs

*Bristol-Myers Squibb, P.O. Box 5400, Princeton, New Jersey 08543-5400, Email: patrick.lambms.com

P. Y. S. Lam, C. G. Clark, S. Saubern, J. Adams, M. P. Winters, D. M. T. Chan, A. Combs, Tetrahedron Lett., 1998, 39, 2941-2944.

DOI: 10.1016/S0040-4039(98)00504-8


Abstract

A mild, new aryl/heteroaryl C-N bond cross-coupling reaction via the arylboronic acid/cupric acetate arylation of N-H containing heteroarenes proceeds at room temperature exposed to air, and works for many heteroarenes and arylboronic acids providing good yields of N-arylated heteroarenes.


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Details

The document discusses a new aryl/heteroaryl C-N bond cross-coupling reaction using arylboronic acid and cupric acetate for the arylation of N-H containing heteroarenes. ​ This methodology is mild, operates at room temperature, and is exposed to air, providing good yields for various heteroarenes and arylboronic acids. ​ Traditional methods like the Ullmann reaction require high temperatures and give variable yields, while newer methods using aryl halides with palladium or nickel catalysts have limitations. ​ The new reaction involves adding arylboronic acid, base (pyridine), heteroarene, anhydrous cupric acetate, and molecular sieves in methylene chloride, stirred at room temperature for 2 days. ​ The reaction tolerates different electronic natures of arylboronic acids and works well for nucleophilic heterocycles like pyrazole, imidazole, indazole, and benzimidazole, but yields are lower for less nucleophilic heterocycles. ​ The reaction mechanism likely involves cupric acetate forming a complex with the heterocycle, transmetallating with arylboronic acid, and undergoing reductive elimination. ​ This methodology is ideal for generating heterocycle-containing libraries and is being optimized further. ​ The document also includes a representative procedure and references for further reading.


New N- and O-arylations with phenylboronic acids and cupric acetate

D. M. T. Chan, K. L. Monaco, R.-P. Wang, M. P. Winteres, Tetrahedron Lett., 1998, 39, 2933-2936.


Key Words

Chan-Lam Coupling, N-Arylation


ID: J72-Y1998-440