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

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.

Functionalized heteroarylpyridazines and pyridazin-3(2H)-one derivatives via palladium-catalyzed cross-coupling methodology.

A general method for the synthesis of functionalized pyridazinylboronic acids/esters is described involving a directed ortho metalation (DoM)--boronation protocol (Schemes 1 and 2). A comprehensive study of the reactivity of the C-B bond in palladium-catalyzed cross-couplings with aryl/heteroaryl halides is presented. Aryl-/heteroarylpyridazines are thereby obtained in synthetically viable yields (typically 40-75%) although in some cases competing protodeboronation has been observed. A series of pyridazin-3(2H)-one derivatives, including 4,6-diaryl/heteroaryl derivatives, have been obtained from the corresponding 3-methoxypyridazines in straightforward procedures (Schemes 3 and 4). Several X-ray crystal structures of aryl-/heteroarylpyridazines and derived pyridazin-3(2H)-one derivatives are reported. These multi-ring systems are of considerable interest in contemporary N-heterocyclic chemistry.

Palladium-catalyzed cross-coupling reactions of pyridylboronic acids with heteroaryl halides bearing a primary amine group: synthesis of highly substituted bipyridines and pyrazinopyridines.

A range of halogenated aromatics and heteroaromatics bearing a primary amine group are shown to be suitable substrates for Suzuki cross-coupling reactions with arylboronic acids and pyridylboronic acids under standard conditions, without the need for protection/deprotection steps. New amino-substituted arylpyridines, bipyridines, and pyrazinopyridines have thereby been obtained. Conditions for the efficient syntheses of 2-methoxy-5-pyridylboronic acid 1 and 2-methoxy-3-pyridylboronic acid 2 in ca. 75 g batches have been defined. A 2-fold reaction of 2-amino-5-bromopyrazine with 2,5-dimethoxy-1,4-benzenediboronic acid affords 1,4-dimethoxy-2,5-bis[2-(5-aminopyrazyl)]benzene 31. The X-ray crystal structures of 1 and 31.DMF are reported.

5-Formyl-2-furylboronic acid as a versatile bifunctional reagent for the synthesis of pi-extended heteroarylfuran systems.

5-Formyl-2-furylboronic acid reacts cleanly with a range of heteroaryl bromides under Suzuki-Miyaura cross-coupling conditions to produce 2-formyl-5-heteroarylfuran derivatives. Subsequent Wittig olefination reactions afford pi-conjugated alkene-pyridyl-furan derivatives.

Functionalized pyridylboronic acids and their Suzuki cross-coupling reactions to yield novel heteroarylpyridines.

2-Bromo-5-pyridylboronic acid 2a, 2-chloro-5-pyridylboronic acid 2b, 2-methoxy-5-pyridylboronic acid 2c, and 5-chloro-2-methoxy-4-pyridylboronic acid 4 have been synthesized and shown to undergo palladium-catalyzed cross-coupling reactions with heteroaryl bromides to yield novel heteroarylpyridine derivatives. The X-ray crystal structures of 2a and 2b have been obtained.