Regioselective Palladium-Catalyzed Arylation of 3-Carboalkoxy Furan and Thiophene

Abstract

[reaction: see text] The regioselective palladium(0)-catalyzed arylation of 3-furoate and 3-thiophenecarboxylate esters with aryl bromides is described. Conditions were developed that allow for the selective synthesis of either 2-aryl or 5-aryl products.

Direct transition metal-catalyzed functionalization of heteroaromatic compounds

“…16 Additionally, it was demonstrated that arylation of furans and thiophenes bearing an EWG at C-3 can be achieved selectively at C-2 or C-5 by switching reaction conditions to favor either electrophilic or Heck-type mechanisms, leading to different products. 5 Arylation of azoles, in most cases, is not selective and leads to the mixtures of C-2 and C-5 arylated products or results in bis-arylation. Nevertheless, excellent C-2 selectivity can be achieved in the presence of stoichiometric amounts of Cu salts.…”

Direct Transition Metal Catalyzed Functionalization of Heteroaromatic Compounds

“…This mechanism has often been considered as the most probable mechanism for arylation of heterocycles. 3,5,13,14 Naturally, the absence of an isotope effect in the arylation of 11 (Scheme 6) does not contradict pathway A, as the deprotonation event in the electrophilic mechanisms is not a rate-limiting step. 15 Additionally, it is well known that the pyrrole ring of an indolizine is electron-rich and easily undergoes electrophilic substitution reactions.…”

“…four distinct mechanisms have been proposed to date: electrophilic aromatic substitution (A), 3 C-H activation (B), 4 cross-coupling (C), 3 and Heck-type arylation (D) 5 (Scheme 2).…”

“…However, numerous efforts to perform this transformation under a variety of reduction conditions failed. It was rationalized that if this reaction does operate via a Hecktype mechanism, 5 the arylation of 6-carboethoxyindolizine 8 should lead to 7-arylindolizine 10 (Scheme 5). However, 8 was selectively arylated at C-3 instead, producing 9 as a sole regioisomer.…”

“…5,17,18 In this case, the process would involve a carbopalladation step, followed by anti-dehydropalladation or by isomerization and syn-elimination. 19 However, the isomerization step requires a reversible α-hydride elimination to form a carbene intermediate, a process unknown for palladium (unlike for Pt or Ru).…”