One-Pot Synthesis of Functionalized Benzo[b]thiophenes and Their Hetero-Fused Analogues via Intramolecular Copper-Catalyzed S-Arylation of In Situ Generated Enethiolates

Abstract

An efficient one-pot synthesis of highly functionalized multisubstituted benzo[b]thiophenes and their hetero-fused analogues, such as thieno[2,3-b]thiophenes, indolo[2,3-b]thiophenes, and pyrazolo[3,2-c]thiophenes, has been reported. The overall strategy involves sequential base-mediated condensation of 2-bromohet(aryl)acetonitrile precursors with (het)aryl/alkyl dithioesters or other thiocarbonyl species such as dimethyl trithiocarbonate, S-methyl xanthates, methyl N-imidazolyl dithioate, N-alkyl dithiocarbamate, and phenyl isothiocyanate, followed by intramolecular copper-catalyzed arylthiolation of in situ generated enethiolates, furnishing a broad range of 2-functionalized 3-cyanobenzo[b]- and/hetero-fused thiophenes in high yields.

Synthesis of Benzothiophene‐Containing 10‐ and 11‐Membered Cyclic Phostones

“…The formation of the thiophene ring from benzenethiol 12 is presumed to proceed through intermediate acetylide 13a . Various acetylides have been independently synthesized and cyclized in the presence of various catalysts, including elemental iodine; intermediates 13b (Scheme , b) and 13c (Scheme , c) represent a few key examples leading to structurally diverse 2,3‐disubtituted benzo[ b ]thiophene cores …”

Diversity‐Oriented Synthesis of Substituted Benzo[b]thiophenes and Their Hetero‐Fused Analogues through Palladium‐Catalyzed Oxidative CH Functionalization/Intramolecular Arylthiolation

“…We have developed an effective Pd‐catalyzed oxidative intramolecular CH functionalization–arylthiolation approach for substituted benzothiophenes, which is an important structural motif that is prevalent in natural and designed compounds displaying interesting biological and physical properties. Unlike, our previous benzothiophene synthesis1a via 2‐bromo(het)arylacetonitriles, this protocol requires simple precursors without any 2‐halo substitution. Furthermore, the method also allows for the synthesis of benzothiophenes carrying an acyl or carboalkoxy functionality, from readily accessible deoxybenzoins and (het)aryl acetates.…”

“…Substituted benzo[ b ]thiophenes represent an important class of heterocyclic compounds because they exhibit a broad range of biological activities and provide useful properties in material science 1a. b, 2 The benzo[ b ]thiophene ring system and its derivatives are the core structures of numerous drug molecules,1a, b such as clinically used raloxifene,3a–c arzoxifene,3d and zileuton 3e–f. Consequently, the synthesis of this privileged structure has attracted much attention in recent years and many efficient methods have been developed 1.…”

“…Consequently, the synthesis of this privileged structure has attracted much attention in recent years and many efficient methods have been developed 1. 2, 4 Most of these approaches rely upon electrophilic cyclization reactions of o ‐alkynylbenzenethiol derivatives 1a. 5, 6 Recently, transition‐metal‐catalyzed Cheteroatom bond‐forming cross‐coupling reactions have also been developed, which provide more efficient, practical, and straightforward approaches for the construction of benzo‐fused heterocycles 1a.…”

“…2, 4 Most of these approaches rely upon electrophilic cyclization reactions of o ‐alkynylbenzenethiol derivatives 1a. 5, 6 Recently, transition‐metal‐catalyzed Cheteroatom bond‐forming cross‐coupling reactions have also been developed, which provide more efficient, practical, and straightforward approaches for the construction of benzo‐fused heterocycles 1a. 7 In this context, we have also recently described an efficient one‐pot synthesis of substituted benzo[ b ]thiophenes 4 and their hetero analogues involving sequential base‐mediated condensation of substituted 2‐bromohet(aryl)acetonitriles 1 with a range of dithioesters 2 and other thiocarbonyl variants, followed by Cu I ‐catalyzed intramolecular CS arylation of the resulting thioenolate intermediates 3 in situ (Scheme a) 1a…”