Synthesis of Functionalized Thiophenes by Four‐component Reactions of 1,3‐Thiazolidinedione, Aromatic Aldehydes, Cyanoacetamide and Cyclic Secondary Amines

Abstract

The polysubstituted thiophene derivatives were conveniently prepared by the four-component reactions of 1,3-thiazolidinedione, aromatic aldehydes, cyanoacetamide and cyclic secondary amines such as pyrrolidine, morpholine and piperidine. The reaction mechanism is believed to involve domino reactions of Knoevenagel condensation, Michael addition, ring-opening and recyclization of 1,3-thiazolidinedione.

Chemistry and Applications of Functionalized 2,4‐Thiazolidinediones

“…Pivaloylacetonitrile, [353] cyanoacetamide [354] and ethyl 2‐cyanoacetate also work as alternatives to malononitrile. Despite of functionalization for many synthetic routes, this reaction has not been exploited in production of new biological agents according to literature survey.…”

“…For instance, equimolar amounts of unsubstituted 2,4-thiazolidinedione, aldehyde, malononitrile and primary or secondary amine are refluxed together in a onepot reaction with a catalytic base to afford multisubstituted dihydrothiophenes ). [351] Pivaloylacetonitrile, [353] cyanoacetamide [354] and ethyl 2-cyanoacetate also work as alternatives to malononitrile. Despite of functionalization for many synthetic routes, this reaction has not been exploited in production of new biological agents according to literature survey.…”

New One Pot and Efficient Four‐Components Reaction for Synthesis of 2,3‐Dihydrothiophene Carbamate Derivatives

“…All of these methods consist of a fourcomponent reaction between aromatic aldehydes, malononitrile, 2,3-thiazolinedione and amino derivatives such as αaminoesters, primary and secondary aliphatic or cyclic amines, in the presence of a variety of catalysts and under different conditions. [14,[36][37][38][39][40][41][42][43][44][45] It has been described that a mixture of arylidenemalononitrile and 1,3-thiazolidinedione brought to reflux in ethanol in the presence of piperidine leads to pyrano [2,3-d][1,3]thiazole derivatives with good yields. [46][47] Given that arylidenemalonitrile can be easily formed in situ, via the condensation of Knovenogel between an aromatic aldehyde with malononitrile, and in the continuation of our research of new methods of synthesis in heterocyclic series, we set out to study the threecomponent reaction between an aromatic aldehyde, malonotrile and 1,3-thiazolidinedione, refluxed in ethanol, in the presence of N,N-dimethylaminopyridine, as a catalyst.…”

“…This unexpected result is important to us not only because we believe to establish a new one-pot four-component domino reaction, but also because of the biological interest of 2,3dihydrothiophene derivatives while all the described preparation procedures of dihydrothiophenes and the like have suffered from synthetic restriction to only a limited range of dihydrothiophene ureidoformamides. [14,[36][37][38][39][40][41][42][43][44][45]…”

“…Only a few multicomponent methods have been disclosed for the construction of dihydrothiophene derivatives. All of these methods consist of a four‐component reaction between aromatic aldehydes, malononitrile, 2,3‐thiazolinedione and amino derivatives such as α‐aminoesters, primary and secondary aliphatic or cyclic amines, in the presence of a variety of catalysts and under different conditions [14,36–45] …”