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

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.