Synthesis of Imidazo[2,1-b]thiazoles via Copper-Catalyzed A³-Coupling in Batch and Continuous Flow

Abstract

A straightforward method for the synthesis of functionalized imidazo[2,1-b]thiazoles starting from benzaldehydes, 2-aminothiazoles, and alkynes under copper(I,II) catalysis was developed. The protocol allows the construction of a variety of aryl-substituted imidazo[2,1-b]benzothiazoles, -[2,1-b]thiazoles, and -[2,1-b][1,3,4]thiadiazoles. The reactions were easy to perform affording most of the desired products in 33-93% yields. The intensification of the process in a continuous-flow reactor increases the products' yields up to quantitative.

Recent Advances in the A3 Coupling Reactions and their Applications

“…Volkova and co‐workers applied A 3 coupling protocol to synthesize a series of functionalized imidazo[2,1‐ b ]thiazoles 87 (Scheme ). The reaction consisted the three‐component couplings of benzaldehydes 1 , 2‐aminothiazoles 86 , and alkynes 4 in the presence of Cu(I)/Cu(II) catalyst, followed by a 5‐ exo ‐dig cyclization.…”

Synthesis and Applications of Imidazothiazoles: An Overview

“…Visible light triggered, catalyst-free approach for the synthesis of imidazo[2,1-b]thiazole (9) in ethanol:water (EtOH:H 2 O) green medium was developed by Mishra and co-workers. [28] The condensation reaction is carried out by the use of substituted phenacyl bromide (7) and 2-aminothiazole (8) as Kerala, India, in 1993 reactants, and afforded 55 % yield of the product within 5 h. They also tried to increase the product yield with different ratios of the mixed solvent system of EtOH:H 2 O, the solubility of reactants increased by the benefit of EtOH and H 2 O, and it also increased the yield of the product. The combination of EtOH:H 2 O (4 : 1) gave the best results (Scheme 3).…”

“…Imidazothiazoles and its derivatives are synthesized by a plethora of reactions involving multicomponent reactions (MCRs), [24][25] biosynthesis of staphyloxanthin produced by staphylococcus aurease in the presence of dehydrosqualene synthase enzyme, [27] transition metal catalysed reactions, [28] visible light synthesis, [29] regioselective reaction, [30] Groebke-Blackburn-Bienayme-Reaction (GBBR) mechanism, [24,31] oxidative cyclisation, [32] Claisen-Schmidt condensation, [33] microwave assisted green synthesis [34] and ring-opening and ring-closing reconstruction reactions. [35] Multi-component reactions are reactions involving a combination of three or more substrates, which are carried out in a one-pot system to obtain the desired product.…”

Metal‐Free Synthesis of Imidazo[2,1‐b]thiazoles from Thioimidazoles and Ketones Mediated by Selectfluor

“…[4] In view of the importance of imidazo[2,1-b]thiazole derivatives, a number of procedures have been developed to prepare them. [5] According to literature reports, 2-aminobenzothiazoles could yield imidazo [2,1-b]thiazole molecules via the heterocyclization reaction with traditional α-bromoketone, [6] aryl methyl ketones, chalcones, [7] cyclic ketones, [8] 2-phenoxyacetophenones, [9] aryl aldehydes coupled with alkynes, [10] aryl aldehydes coupled with isocyanides, [11] and so on. [12] On the other hand, 2-mercaptobenzoimidazoles were also able to afford this class of heterocyclic compounds through the annulation reactions with terminal alkynes, [13] Nitroalkenes, [14] dihaloalkenes.…”