Recent Developments in C−H Functionalisation of Benzofurans and Benzothiophenes

Abstract

Benzofurans and benzothiophenes are important pharmaceutical motifs, appearing in a broad range of small molecule therapeutic classes. Often overlooked by synthetic methodologists in favour reactions of the analogous indole bicyclic system, there is nevertheless a plurality of approaches to effecting benzofuran and benzothiophene C−H functionalisations. In this review, we summarise progress in this area over the past five years, including 1) alkylations, 2) arylations and heteroarylations, 3) carboxylations, carbamoylations, and C‐heteroatom bond formations and 4) cyclisations.

Heterogenization of a Molecular Ni Catalyst within a Porous Macroligand for the Direct C–H Arylation of Heteroarenes

“…[3][4][5][6][7][8] The direct C-H arylation of heteroarenes is a key reaction for the synthesis of advanced heterobiaryls compounds. [9][10][11] In particular, the arylation of benzothiophene 12 is highly desirable because the (aryl)benzothiophene motif is widely present in active pharmaceutical ingredients (API) of marketed drugs [13][14][15] and in optoelectronic performance materials found in organic lightemitting diodes, organic field effect transistors and organic photovoltaic solar cells. [16][17][18][19] Moreover, the regioselective derivatization is of a paramount importance for structure-related activity.…”

Rh(III)-Catalyzed Oxidative C–2 Coupling of N-Pyridinylindoles with Benzo[b]thiophene 1,1-Dioxides via C–H Bond Activation

“…Based on the reported metal-catalyzed directing-group-assisted C–H bond activation, − oxidative cross-coupling reactions, and our exposure in C–H activation, a suitable mechanism is proposed to account for the present rhodium-catalyzed heteroaryl coupling (Scheme ). First, an active Rh­(III) species is generated with AgOAc, and then, coordination of Rh­(III)­Cp*­(OAc) 2 with 1a , followed by the subsequent indole C–H bond cleavage, led to five-membered rhodacycle I with the release of AcOH.…”

“…Recently, the transition-metal-catalyzed conversion of an inert C–H bond into functionalized organic molecules has been an exploited powerful tool in organic synthesis . This transformation has found valuable synthetic applications in pharmaceutical and material industries, owing to atom and step economical, less toxic byproducts, and environmentally friendly, compared with conventional synthesis . On the other hand, the combination of the metal-catalyzed directing-group-assisted oxidative C–H/C–H cross-dehydrogenative coupling (OCDC) between two different heteroarenes is a synthetically straightforward route for accessing biheteroaryl compounds .…”

Chiral Benzothiophene Synthesis via Enantiospecific Coupling of Benzothiophene S‐Oxides with Boronic Esters

“…Direct C−H functionalization of benzothiophenes can provide more efficient and direct approaches that greatly facilitate the preparation of analogues by avoiding the need for de novo synthesis [5] . Whilst direct C2 C−H arylation of functionalized benzothiophenes is well established, [5a] related alkylations remain synthetically challenging and relatively few examples have been reported [5e] . One of the most explored strategies for direct C2 C−H alkylations of benzothiophenes is transition‐metal‐catalyzed Minisci‐type homolytic substitutions with alkyl radicals, including under thermal and photochemical conditions [6, 7] .…”