Metrics & MoreArticle Recommendations CONSPECTUS: 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 threecomponent reactions with other azoles through the Pd−norbornene adducts or Catell...

Pd-catalyzed C–H alkenylations targeting the least hindered position of N-alkyl pyrroles and 3-substituted thiophenes, as opposed to electronically controlled approaches, are developed. The steric demand and stable bidentate binding mode...

Pd-catalyzed multicomponent coupling reactions of five-membered heteroaryl halides and norbornadiene (NBD) were developed. Either direct addition of (benzo)­azoles or 2:1 annulation was achieved depending on the propensity of the intermediate complex to undergo palladacycle formation, determined by the nature and substitution pattern of the heteroarene. The obtained exo- and cis-diheteroaryl norbornenes underwent epimerization and retro-Diels–Alder reactions to afford the corresponding trans-isomers and π-extended heteroaromatic systems, respectively, demonstrating the versatility of NBD as an acetylene synthon.

In this study, Au(III)-catalyzed cyclization reactions of alkynyl norbornene derivatives were developed to provide benzofused (hetero)arenes with substitutions at the benzocyclic ring. The combination of Au(OAc)3 and AgNTf2 allowed for the annulation of (hetero)arenes by intramolecular hydro(hetero)arylation followed by retro-Diels–Alder reactions to afford fully conjugated benzofused (hetero)arenes in higher yields as compared to the yield obtained using our previously developed Pd(OAc)2-catalyzed protocol. Furthermore, when Au(OAc)3 was replaced with AuCl3, (hetero)arenes with the norbornene bridge installed at the more electron-rich and sterically demanding position underwent a rearrangement to afford the corresponding regioisomeric products in a divergent manner. The result indicates that the rigid norbornene ring creates a steric effect, in addition to placing two reactive sites in proximity and serving as an acetylene synthon. This illustrates the importance of the steric effect in addition to the electronic effects of the catalyst and substrate on the rearrangement.