The Influence of the Quinoline Moiety on Direct Pd‐Catalyzed Arylation of Five‐Membered Heterocycles

Abstract

Herein we report a study on the reactivity of C2‐quinoline‐substituted furan, thiophene and pyrrole derivatives in palladium‐catalyzed direct C–H arylation. The regioselectivity of the reaction was strongly influenced by site position of the attached five‐membered heterocycle thus giving rise to C3‐ and/or C5‐arylated products. Furthermore, the Hammett correlation performed on 5‐substituted‐8‐(furan‐2‐yl)quinolines indicates that a marginally positive charge is building up in the rate determining transition state and thus pointing towards the electrophilic metalation‐deprotonation reaction mechanism.

Regioselective Ru(II)/Pd(0) Dual Catalysis: One-Pot C–H Diarylation of Five-Membered Heterocyclic Derivatives

“…On the basis of our previous study, we chose 2-(thiophene-2-yl)­quinoline ( 1a ) as the model substrate for the optimization of the Ru-catalyzed C–H functionalization step. We anticipated that the reaction would proceed exclusively on the C3 position of the thiophene ring through the formation of a more stable five-membered ruthenacycle, whereas using palladium already in the first C–H functionalization step would afford C3 as well as C5 arylated products, as reported by us and Doucet and co-workers. , We initiated our investigation with the reaction of 1a with 4-bromoacetophenone ( 4a ) in the presence of [Ru­( p -cymene)­Cl 2 ] 2 as the selected (pre)­catalyst.…”

“…On the basis of our previous study, we chose 2-(thiophene-2-yl)­quinoline ( 1a ) as the model substrate for the optimization of the Ru-catalyzed C–H functionalization step. We anticipated that the reaction would proceed exclusively on the C3 position of the thiophene ring through the formation of a more stable five-membered ruthenacycle, whereas using palladium already in the first C–H functionalization step would afford C3 as well as C5 arylated products, as reported by us and Doucet and co-workers. , We initiated our investigation with the reaction of 1a with 4-bromoacetophenone ( 4a ) in the presence of [Ru­( p -cymene)­Cl 2 ] 2 as the selected (pre)­catalyst. The reactions were run at 140 °C for 24 h. The use of solely [Ru­( p -cymene)­Cl 2 ] 2 (10 mol %) gave only a 10% conversion to the desired product 5aa (Table , entry 1), whereas the combination of PPh 3 and KOPiv allowed the exclusive formation of the monoarylated product 5aa in quantitative yield (Table , entry 4).…”

“…Recently, we have reported a paper that focuses on the reactivity of C2-quinoline-substituted five-membered heterocycles in a Pd-catalyzed direct C–H functionalization reaction (Scheme a) . Unfortunately, the presence of only one TM catalyst rendered the protocol to be nonregioselective, as direct arylation proceeded on both the C3 (nitrogen-directed reaction) and the C5 (reaction at more reactive position) position of the five-membered heterocycle; however, the synthesized compounds were exemplified as promising inhibitors toward human cysteine protease Cathepsin B in tumor progression .…”

“…23 Recently, we have reported a paper that focuses on the reactivity of C2-quinoline-substituted five-membered heterocycles in a Pd-catalyzed direct C−H functionalization reaction (Scheme 1a). 24 Unfortunately, the presence of only one TM catalyst rendered the protocol to be nonregioselective, as direct arylation proceeded on both the C3 (nitrogen-directed reaction) and the C5 (reaction at more reactive position) position of the five-membered heterocycle; however, the synthesized compounds 25 were exemplified as promising inhibitors toward human cysteine protease Cathepsin B in tumor progression. 26 Driven to develop a methodology that would allow highly regioselective C−H arylation of fivemembered heterocyclic derivatives, we turned our attention to the combination of palladium and ruthenium catalysis, as the latter functions solely through the directing group coordination.…”

Catalytic C−H Functionalization of Unreactive Furan Cores in Bio‐Derived Platform Chemicals

“…[17] In contrast, the functionalization of the furanic core at the C3 and C4 positions is a much more difficult task [18] . Even in the presence of DG at C2 or C3 position, the significantly higher reactivity of the α‐hydrogen atom complicates implementation of regioselective reactions in the furanic core [17d] …”