Trifluoromethyl-substituted pyridyl- and pyrazolylboronic acids and esters: synthesis and Suzuki–Miyaura cross-coupling reactions?

Organic & Biomolecular Chemistry Pub Date: 2009-03-26 DOI: 10.1039/B901024F

Abstract

The synthesis of trifluoromethyl-substituted pyridylboronic acids and pyrazolylboronic esters is described via lithiation–boronation protocols (Schemes 1, 3 and 4). A study of their palladium-catalysed cross-couplings with heteroaryl halides is presented. CF3-substituted aryl/heteroaryl-pyridines are thereby obtained (51–98% yields). Analogous cross-couplings have yielded heteroaryl-3-(trifluoromethyl)pyrazoles (60–85% yields); homocoupling of the pyrazolylboronic esters is suppressed by the addition of potassium formate, although competing protodeboronation is observed. Halogenation of the 4-position of selected pyrazole coupling products allows for further cross-couplings to yield tetra-substituted pyrazolyl derivatives (Scheme 5). X-Ray crystal structures are reported for selected pyridylboronic acids, pyrazolylboronic esters and derived trifluoromethyl-substituted heterobiaryl systems. These multi-ring CF3-substituted systems are of interest as building blocks for drug discovery and materials chemistry.

Graphical abstract: Trifluoromethyl-substituted pyridyl- and pyrazolylboronic acids and esters: synthesis and Suzuki–Miyaura cross-coupling reactions
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