Regiodivergent Arylation of Pyridines via Zincke Intermediates

Abstract

An arylation protocol for pyridines is described, via the ring‐opened Zincke intermediate. Treatment of pyridines with triflic anhydride and a secondary amine produces an azahexatriene species, which undergoes regioselective Pd‐catalyzed arylation at the putative C4 position. Recyclization then provides the pyridine products. Alternatively, metal‐free arylation with a diaryliodonium salt is selective for the pyridine meta‐position, affording a regiodivergent approach to pyridine biaryls from a common intermediate.

Meta‐Selective Copper‐Catalyzed C−H Arylation of Pyridines and Isoquinolines through Dearomatized Intermediates

“…Temporary dearomatization approaches can transfer electron‐deficient pyridines into electron‐rich enamine type intermediates that show high reactivity at the meta ‐position, and accordingly allow after C−H functionalization and rearomatization to access meta ‐substituted heteroarenes [4a,6] . Along these lines, Greaney and co‐workers disclosed the meta ‐arylation of pyridines through the corresponding ring‐opened Zincke intermediates [6e] with moderate yields ranging from 32 % to 41 % (six examples) [16] . We have successfully developed a general method for meta ‐C−H functionalization of pyridines through a redox‐neutral dearomatization‐rearomatization strategy (Scheme 1C) [17] .…”

“…[4a,6] Along these lines, Greaney and co-workers disclosed the meta-arylation of pyridines through the corresponding ringopened Zincke intermediates [6e] with moderate yields ranging from 32 % to 41 % (six examples). [16] We have successfully developed a general method for meta-CÀ H functionalization of pyridines through a redox-neutral dearomatization-rearomatization strategy (Scheme 1C). [17] The bench-stable oxazino pyridine intermediates were shown to react as efficient carbon-radical acceptors or as nucleophiles with various electrophilic trapping reagents through radical or ionic processes with excellent metaselectivity (Scheme 1).…”

Synthesis of Benzenes from Pyridines via N to C switch

“…Recent work from McNally, Paton and co-workers has exploited the facility of triflic anhydride for in situ Zincke imine generation from pyridines under mild conditions, 14 and we have employed this method for the Pd-catalyzed arylation of pyridines. 15 Accordingly, we envisaged that direct triflation of pyridine and addition of a compatible carbon nucleophile could access the carbo-Zincke analog 12, with subsequent recyclization and aromatization. We began by examining diethylmalonate as the nucleophile with 2-phenylpyridine and 4-phenylpyridine substrates.…”