Oxidative Biaryl Coupling of Thiophenes and Thiazoles with Arylboronic Acids through Palladium Catalysis: Otherwise Difficult C4‐Selective CH Arylation Enabled by Boronic Acids

Abstract

It adds up to 4! Thiophenes and thiazoles can be arylated in the 4‐ rather than the expected 5‐position in a new CH functionalization reaction (see scheme; TEMPO: 2,2,6,6‐tetramethylpiperidine‐N‐oxyl). The boronic acid proved to be the key to achieving the otherwise difficult C4 selectivity. The method was applied to a concise synthesis of a key pharmacological structure with potential for treatment of Alzheimer's disease.

New Arylating Agents in Pd-Catalyzed C–H Bond Functionalization of 5-Membered Ring Heteroarenes

“…In contrast to other coupling partners, which allowed direct C2 arylation [28,29,31,32,37,48,[68][69][70], the reaction exclusively occurred at the C-3 position (Scheme 12, top). The best reaction conditions were found using 5 mol% Sensitive functional groups such as cyano, bromo, nitro, and ester on both coupling partners were tolerated, offering a broad substrate scope.…”

“…They recently extended this procedure to a broad range of substrates [29,30]. Studer and Itami also described a procedure for the β-arylations of thiophenes with arylboronic acids under Pd/TEMPO catalysis (Scheme 2, bottom) [31]. Even sterically very hindered arylboronic acids were successfully coupled [32].…”

Biaryl Synthesis through Metal‐Catalyzed C–H Arylation

“…In 2011, Itami and Studer [183] developed a palladium-catalyzed C4-selective arylation of thiophenes and thiazoles with arylboronic acids. Although they had already reported the C4(β)-selective arylation of thiophenes with aryl iodides [88] (Scheme 17.18), this C-H/C-B coupling method [using a Pd II /bipy or phen/TEMPO ((2,2,6,6-tetramethylpiperidin-1-yl)oxyl) catalyst system] enabled the use of thiazoles as aryl nucleophiles.…”

Funktionalisierung von C‐H‐Bindungen: neue Synthesemethoden für Naturstoffe und Pharmazeutika

“…Wir entwickelten ein durch Pd/ bipy/TEMPO katalysiertes Verfahren zur b-selektiven C-HArylierung von Thiophenen mit Arylboronsäuren und wendeten es auf eine kurze enantioselektive Synthese der Kernstruktur von SCH-785532 (123; R = H) an (Schema 26). [76] Hierzu wurde der Ester 119, der aus 2-Acetylthiophen nach der von Ellman beschriebenen Iminmethode [77] Ellman und Bergman beschrieben die erste effiziente C-H-Arylierung von elektronenarmen Heteroarenen wie Pyridinen; sie erfolgte unter Rhodiumkatalyse an der C2-Position von Pyridin. [78] Yu und Sames berichteten kürzlich über eine durch dirigierende Gruppen gestützte C3-oder C4-Arylierung von Pyridin.…”