C-H Functionalization of Azines.

Azines, which are six-membered aromatic compounds containing one or more nitrogen atoms, serve as ubiquitous structural cores of aromatic species with important applications in biological and materials sciences. Among a variety of synthetic approaches toward azines, C-H functionalization represents the most rapid and atom-economical transformation, and it is advantageous for the late-stage functionalization of azine-containing functional molecules. Since azines have several C-H bonds with different reactivities, the development of new reactions that allow for the functionalization of azines in a regioselective fashion has comprised a central issue. This review describes recent advances in the C-H functionalization of azines categorized as follows: (1) SNAr reactions, (2) radical reactions, (3) deprotonation/functionalization, and (4) metal-catalyzed reactions.

Dehydrogenative Synthesis of 2,2'-Bipyridyls through Regioselective Pyridine Dimerization.

2,2'-Bipyridyls have been utilized as indispensable ligands in metal-catalyzed reactions. The most streamlined approach for the synthesis of 2,2'-bipyridyls is the dehydrogenative dimerization of unfunctionalized pyridine. Herein, we report on the palladium-catalyzed dehydrogenative synthesis of 2,2'-bipyridyl derivatives. The Pd catalysis effectively works with an AgI salt as the oxidant in the presence of pivalic acid. A variety of pyridines regioselectively react at the C2-positions. This dimerization method is applicable for challenging substrates such as sterically hindered 3-substituted pyridines, where the pyridines regioselectively react at the C2-position. This reaction enables the concise synthesis of twisted 3,3'-disubstituted-2,2'-bipyridyls as an underdeveloped class of ligands.

Rapid Access to Kinase Inhibitor Pharmacophores by Regioselective C-H Arylation of Thieno[2,3-d]pyrimidine.

Regioselective C-H arylations of thieno[2,3-d]pyrimidine are accomplished under palladium catalysis. Thieno[2,3-d]pyrimidines react with aryl iodides at the C6-position and with aryl boronic acids at the C5-position, showing excellent regioselectivity. Mechanistic investigations indicate that the regioselectivity is controlled by the nature of the palladium catalyst: the cationic palladium favorably arylates the C5-position. The utility of this direct arylation has been highlighted in the streamlined synthesis of kinase inhibitors and their derivatives.

Regiodivergent Cross-Dehydrogenative Coupling of Pyridines and Benzoxazoles: Discovery of Organic Halides as Regio-Switching Oxidants.

Cross-dehydrogenative coupling (CDC) of two unfunctionalized heteroarenes has been recognized as an ideal transformation to synthesize privileged heterobiaryl scaffolds. However, regioselective activation and transformation of a specific set of two heterocyclic C-H bonds among other bonds have been extremely challenging. Thus, discovering a new controlling element to achieve regio-controlled and regio-divergent heterocyclic CDCs is considered crucial. In this Letter, the unprecedented use of organic halides as an oxidant to achieve the CDC reaction of pyridines and benzoxazoles with palladium catalyst is described. Moreover, the regioselectivity of the pyridine functionalization site can be controlled by the choice of organic halides.