Multicomponent Synthesis of Benzothiophen‐2‐acetic Esters by a Palladium Iodide Catalyzed S‐cyclization – Alkoxycarbonylation Sequence

Abstract

A catalytic carbonylative approach to the multicomponent synthesis of benzothiophene derivatives from simple building blocks [1‐(2‐(methylthio)phenyl)prop‐2‐yn‐1‐ols, carbon monoxide, and an alcohol)] is presented. It is based on an S‐cyclization‐demethylation‐alkoxycarbonylation‐reduction sequence promoted by the PdI2/KI catalytic system, occurring under relatively mild conditions (40 atm, 80 °C, 15 h). Benzothiophene‐2‐acetic esters are obtained in moderate to good yields (35–70%) starting from variously substituted substrates in combination with different alcohols as external nucleophiles (17 examples).

Metal‐Catalysed Synthesis of Benzofused Five‐Membered N/O/S‐Heterocycles, a Progressive Area in Synthetic Organic Chemistry

“…Gabriele and co‐workers reported in 2021 a PdI 2 /KI catalysed multicomponent reaction of 1‐(2‐(methylthio)phenyl)prop‐2‐1‐ols 87 , carbon monoxide and alcohol as external nucleophiles towards the synthesis of functionalized benzothiophene‐2‐acetic ester derivatives 88 at good yields (Scheme 30). [126] The reaction was initiated by the coordination of the triple bond to the Pd(II) centre followed by S‐cyclization via intramolecular nucleophilic attack of the thiomethyl group by the co‐ordinated triple bond. Subsequent iodide‐promoted de‐methylation and alkoxycarbonylation led to the 2‐(3‐hydroxybenzo[ b ]thiophen‐2(3 H )‐ylidene)acetate intermediate and π‐allylpalladium complex which on protonolysis furnished the desired product.…”

Transition-Metal-Catalyzed Carbonylative Multifunctionalization of Alkynes

“…In this case, DMSO acts as a neutral ligand and plays a crucial role in the generation of esters by stabilizing the palladium complex intermediate and suppressing the formation of dimeric ketones. Recently, Gabriele and co-workers also achieved an S-cyclization–demethylation–alkoxycarbonylation–reduction sequence promoted by the PdI 2 /KI catalytic system. , Different (benzo)­thiophene-2-acetic esters were synthesized in moderate to good yields (35–70%) from simple substrates. In order to prevent the possible oxidation of a free thiol group, a methylthio group was used as the sulfur nucleophile since it could be deprotected by the iodide anion to give methyl iodide (Scheme ).…”

Discovery of Pyrido[1,2-a]pyrimidine Mesoionic Compounds Containing Benzo[b]thiophene Moiety as Potential Pesticide Candidates

“…Benzo­[ b ]­thiophenes commonly exist in natural heterocycles , and also serve as important building blocks for the construction of sulfur-containing heterocyclic compounds. , Furthermore, benzo­[ b ]­thiophene has a wide range of biological activities such as antifungal, anticancer, antidepressant, etc. , Significantly, the benzothiophene ring has unique lipophilicity, which can improve its penetration ability and make it easier to enter cells through the lipid bilayer to play its role . This essential character is worth noting as insecticides must be diffused through the plant cell wall and transported through the cuticle of the pest to achieve a balance between mobility and stability .…”

“…28,29 Benzo[b]thiophenes commonly exist in natural heterocycles 30,31 and also serve as important building blocks for the construction of sulfur-containing heterocyclic compounds. 32,33 Furthermore, benzo[b]thiophene has a wide range of biological activities such as antifungal, 34 anticancer, 35 antidepressant, 36 etc. 37,38 Significantly, the benzothiophene ring has unique lipophilicity, which can improve its penetration ability and make it easier to enter cells through the lipid bilayer to play its role.…”