Transition-Metal-Catalyzed Divergent C-H Functionalization of Five-Membered Heteroarenes

Conversion of common reactants to diverse products is a key objective of organic syntheses. Recent developments in transition-metal-catalyzed C-H functionalization have increased the interest in such conversions. Both the position of functionalization and the type of the substituent can be varied, allowing systematic diversification of common structural cores. Because five-membered heteroarenes (pyrazole, imidazole, thiazole, pyrrole, and thiophene) are ubiquitous in pharmaceuticals and organic functional materials, the selective C-H functionalization of these heterocyclic cores facilitates both the optimization of their physicochemical properties and streamlining of their preparation. In addition, the parent forms of these heterocycles are more readily available and inexpensive than any other derivatives of their families. Hence, their nondirected C-H functionalization is highly desirable. Although various regioselective reactions have been developed, many of them target the most reactive site; hence, except for some extensively studied arylation reactions, regiodivergent functionalization of two or more sites has been limited.This Account summarizes our work on the regiodivergent, nondirected C-H functionalization of five-membered heteroarenes with alkenes and alkynes. These unsaturated hydrocarbons are readily available, and all the composing atoms can be incorporated into products with high atom efficiency. Furthermore, the installed alkenyl groups can be transformed to other useful functional groups. To achieve comparable selectivity to that observed in the traditional reactions of these heteroarenes with highly electrophilic reagents and strong bases, a transition metal catalytic system was carefully devised with a more streamlined synthesis. A judicious choice of metals, ligands, acid and base additives, and solvents orchestrates divergent transformations using electronic and steric effects of the heteroarenes. Although C-H cleavage is a rate- and site-selectivity-determining step in most cases, the subsequent steps involving the formation of C-C bonds are often more critical than the other steps. For the C-H cleavage step, modulating the electronic properties of catalysts to make them electrophilic allows preferential alkenylation at the nucleophilic position. In addition, the presence of an internal base that can be exploited for concerted metalation-deprotonation of the acidic C-H bond offers alternative regioselectivity. Furthermore, we developed our own ligand system based on a conformationally rigid pyrazolonaphthyridine scaffold that enables aerobic C-H alkenylation reactions with steric control. We showed that the electronic and steric effects of heteroarenes can be further extended to chemodivergent reactions with norbornene derivatives. Depending on whether the palladacycle is formed, heteroarenes selectively undergo 1:2 annulation with norbornene derivatives and three-component reactions with other azoles through the Pd-norbornene adducts or Catellani and 2:1 annulation reactions through the palladacycle intermediates.Other research groups have also contributed to the development of divergent reactions, in investigations ranging from the pioneering studies in the early days of research on C-H functionalization to recent studies with new ligands. We have also discussed these studies in context. These approaches provide access to many heteroarenes with systematically varied substituents. We believe that new ligand systems and mechanistic insights gained through these studies will enrich fields beyond C-H functionalization of five-membered heteroarenes.