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Diversity‐Oriented Synthesis of Substituted Benzo[ b ]thiophenes and Their Hetero‐Fused Analogues through Palladium‐Catalyzed Oxidative CH Functionalization/Intramolecular Arylthiolation
Author(s) -
Acharya Anand,
Kumar S. Vijay,
Ila Hiriyakkanavar
Publication year - 2015
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.201501828
Subject(s) - chemistry , benzothiophene , aryl , intramolecular force , palladium , catalysis , medicinal chemistry , combinatorial chemistry , organic chemistry , thiophene , alkyl
Abstract An efficient, high yielding route to multisubstituted benzo[ b ]thiophenes has been developed through palladium‐catalyzed intramolecular oxidative CH functionalization–arylthiolation of enethiolate salts of α ‐aryl‐ β ‐(het)aryl/alkyl‐ β ‐mercaptoacrylonitriles/acrylates or acrylophenones. The overall strategy involves a one‐pot, two‐step process in which enethiolate salts [generated in situ through base‐mediated condensation of substituted arylacetonitriles, deoxybenzoins, or arylacetates with (het)aryl (or alkyl) dithioates] are subjected to intramolecular CH functionalization–arylthiolation under the influence of a palladium acetate (or palladium chloride)/cupric acetate catalytic system and tetrabutylammonium bromide as additive in N , N ‐dimethylformamide (DMF) as solvent. In a few cases, the yields of benzo[ b ]thiophenes were better in a two‐step process by employing the corresponding enethiols as substrates. In a few examples, Pd(OAc) 2 (or PdCl 2 ) catalyst in the presence of oxygen was found to be more efficient than cupric acetate as reoxidant, furnishing benzothiophenes in improved yields by avoiding formation of side products. The method is compatible with a diverse range of substituents on the aryl ring as well as on the 2‐ and 3‐positions of the benzothiophene scaffold. The protocol could also be extended to the synthesis of a raloxifene precursor and a tubulin polymerization inhibitor in good yields. The versatility of this newly developed method was further demonstrated by elaborating it for the synthesis of substituted thieno‐fused heterocycles such as thieno[2,3‐ b ]thiophenes, thieno[2,3‐ b ]indoles, thieno[3,2‐ c ]pyrazole, and thieno[2,3‐ b ]pyridines in high yields. A probable mechanism involving intramolecular electrophilic arylthiolation via either a Pd‐S adduct or palladacycle intermediate has been proposed on the basis of experimental studies.