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.

Chemical Biology: What is Its Role in Drug Discovery?

“…Incorporation of the CF 3 group in a bioactive compound can have a dramatic effect on its properties. For this reason the synthesis of CF 3 -substituted heterocyclic boronic acids and esters has been reported and their utility in the synthesis of novel pharmacophores has been demonstrated (Clapham et al, 2009). Using an intramolecular [3+2] azide-alkyne cycloaddition, a number of new heterocyclic core structures were obtained which may possess novel biological activities (R. .…”

Recent progress in the synthesis of pyridinylboronic acids and esters

“…14 The selectivity depends upon the halogens and their positions in the pyridine ring. Systematic studies by Rault et al 5,[23][24][25][26][27][28] and Bryce et al [29][30][31][32] resulted in the preparation of shelf-stable halopyridinylboronic acids and esters. 3-and 4-Halopyridines bearing other functional groups such as 6´-methoxy, 22,31 6´-ethoxy 29 and 6´-trifluoromethyl 32 also undergo such transformations with yields typically between 60 and 90%.…”

2-(5-Chloro-3-methyl-1-phenyl-1H-pyrazol-4-yl)-6-(4-nitrophen­yl)-4-phenyl-1,3-diazabicyclo[3.1.0]hex-3-ene

“…Pyrazoles and their derivatives have been known to exhibit a wide range of physiological and pharmacological activities, such as anti-inflammatory [38], antibacterial [39,40], anti-convulsant [41], anticancer [42,43], anti-depressant [44], anti-hyperglycemic [45], antiviral [46], antipyretic [47], antioxidant [48], antitubercular [49], fungicides [50], and analgesic activities [51]. These heterocycles have also found applications in transition-metal chemistry as an analytical reagent [52], ligand used for complexation with metals and as antioxidant additives to fuels [53,54].…”