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

Abstract

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...

C–H heteroarylation of aromatics via catalyst free SN2′ coupling cycloaromatization

“…4 Typically, these conventional strategies require metal catalysts or prefunctionalized aromatic precursors. 4 On the other hand, as a promising and representative approach to manipulate the underlying carbon skeleton of complex molecules, S E Ar reactions have received constant attention (Fig. 1a).…”

Brønsted Acid-Catalyzed Synthesis of 1,2,5-Trisubstituted Imidazoles via a Multicomponent Reaction of Vinyl Azides with Aromatic Aldehydes and Aromatic Amines

“…Imidazoles are ubiquitous in numerous natural products and act as the core fragments in many biologically active compounds and medicines as well as in materials sciences . Polysubstituted imidazole derivatives are known to display a broad range of biological activities, such as metronidazole and tinidazole (Figure ), which were recognized as antibiotic drugs against anaerobic bacteria.…”

Regiodivergent C–N Coupling of Quinazolinones Controlled by the Dipole Moments of Tautomers

“…8,9 Similarly, Pdand Cu-catalyzed annulative π-extension and N-arylation of unmasked 2-phenylquinazolin-4(3H)-ones were achieved in the presence of iodonium salts. 10 In this context, Du and coworkers reported the PhI(OCOOCF 3 ) 2 -or PIFA-mediated divergent synthesis of spiro [4,5]trienones and iodinated quinilin-2-ones from N-arylpropynamides, where PIFA acted as an iodination reagent and an oxidant. 11 Finding efficient methodologies for synthesizing complex molecular architecture is one of the popular research topics in chemistry.…”

“…Recently, regiodivergent strategies have attracted significant attention in synthetic organic chemistry due to its product selectivity, efficiency, and atom economy. , However, divergent synthesis was well documented for the construction of structurally diverse molecular skeletons, which play an essential role in synthesis . In particular, regiodivergent C–H functionalization is one of the popular techniques. − Various metal-catalyzed divergent reactions for the synthesis of heterocyclic scaffolds were well explored. , Similarly, Pd- and Cu-catalyzed annulative π-extension and N-arylation of unmasked 2-phenylquinazolin-4­(3 H )-ones were achieved in the presence of iodonium salts . In this context, Du and co-workers reported the PhI­(OCOOCF 3 ) 2 - or PIFA-mediated divergent synthesis of spiro­[4,5]­trienones and iodinated quinilin-2-ones from N -arylpropynamides, where PIFA acted as an iodination reagent and an oxidant …”