Utilizing an Encapsulated Solution of Reagents to Achieve the Four‐Component Synthesis of (Benzo)Thiophene Derivatives

Abstract

Reagent capsules can help to resolve the compatibility problem of reagents in multicomponent processes. Herein we demonstrate a facile method for encapsulating smelly liquid chemicals and its application in a modular palladium‐catalyzed carbonylative synthesis of multi‐substituted thiophenes from terminal alkynes and aryl iodides as well as a palladium‐catalyzed carbonylative synthesis of benzothiophene derivatives from aryl iodides and arylboronic acids. Here, the capsule plays a pivotal role in solving the issues on reaction condition incompatibilities and selectivity of multicomponent reactions as well as avoiding deactivation of the catalyst by releasing the reagents when the reaction temperature is raised. It greatly facilitates the development of highly‐efficient multicomponent reactions and demonstrates a modular pathway to obtain functionalized molecules.magnified image

Heterocycle Synthesis through Pd‐Catalyzed Carbonylative Coupling

“…Particularly, they reported an efficient palladium‐catalyzed carbonylative synthesis of multi‐substituted thiophenes 56 , employing an encapsulated solution of reagents. These four‐component reactions were carried out with aryl iodides, phenyl acetylene derivatives and a reagent capsule containing ethyl thioglycolate under CO atmosphere (Scheme a) . Although the whole process is based on three synthetic steps, Pd‐catalyzed carbonylative Sonogashira reaction, 1,4‐addition of thiol to alkynone and intramolecular condensation, the reactions afforded the desired thiophene derivative in moderate to good yields.…”

“…Moreover, the capsule of ethyl thioglycolate was further applied in the synthesis of a benzothiophene derivative 57 from an aryl iodide and arylboronic acid as the substrates (Scheme b). Since the release of the reagents takes place at a specific temperature, the capsule plays an important role in solving the issues on reaction conditions incompatibilities and selectivity of MCR as well as avoiding deactivation of the catalyst …”

“…In 2017, Wu and co-workers described the use and the advantage of reagent capsules, generally with applications in pharmaceutical field, [69] in organic synthesis such as in multicomponent reactions (MCRs). [70] Particularly, they reported an efficient palladium-catalyzed carbonylative synthesis of multisubstituted thiophenes 56, employing an encapsulated solution of reagents. These four-component reactions were carried out with aryl iodides, phenyl acetylene derivatives and a reagent capsule containing ethyl thioglycolate under CO atmosphere (Scheme 32a).…”

“…These four-component reactions were carried out with aryl iodides, phenyl acetylene derivatives and a reagent capsule containing ethyl thioglycolate under CO atmosphere (Scheme 32a). [70] Although the whole process is based on three synthetic steps, Pd-catalyzed carbonylative Sonogashira reaction, 1,4-addition of thiol to alkynone and intramolecular condensation, the reactions afforded the desired thiophene derivative in moderate to good yields. Moreover, the capsule of ethyl thioglycolate was further applied in the synthesis of a benzothiophene derivative 57 from an aryl iodide and arylboronic acid as the substrates (Scheme 32b).…”

“…Since the release of the reagents takes place at a specific temperature, the capsule plays an important role in solving the issues on reaction conditions incompatibilities and selectivity of MCR as well as avoiding deactivation of the catalyst. [70] Scheme 32. a) Synthesis of multi-substituted thiophenes 56 via Pd-catalyzed four-component reaction of aryl iodides with substituted phenylacetylene derivatives; the content of reagent capsule A is an EtOH solution of ethyl thioglycolate and DBU. b) Palladium-catalyzed carbonylative synthesis of the benzothiophene derivative 57; reagent capsule B is a DMSO solution of thioglycolate.…”