Synthesis of 3-Substituted Bicyclic Imidazo[1,2-d][1,2,4]thiadiazoles and Tricyclic Benzo[4,5]imidazo[1,2-d][1,2,4]thiadiazoles

Abstract

A versatile synthetic route to potentially useful fused-ring [1,2,4]thiadiazole scaffolds (e.g., 7a and 10b) via exchange reactions of the precursor [1,2,4]thiadiazol-3-(2H)one derivatives (e.g., 6 and 9) with appropriately substituted nitriles (e.g., cyanogen bromide or p-toluenesulfonyl cyanide) under mild conditions is described. For example, the tricyclic 3-bromo [1,2,4]THD derivative (7a) underwent S(N)Ar substitution with a variety of nucleophiles, which included amines, malonate esters and alcohols. Likewise, the bicyclic 3-p-tosyl [1,2,4]THD (10b) was employed as a template in reaction with diamines, and the resulting substituted diamines (e.g., 12a or 12e) were further selectively derivatized at the N1 and/or N2 positions in a linear fashion. The X-ray crystal structure of the 3-methyl bicyclic [1,2,4]THD (21) was obtained, and selective methylation at the N1 position via a protection-alkylation-deprotection protocol, as illustrated in Scheme 6, was confirmed. Alternatively, a short convergent synthesis of N1-functionalized derivatives from the reaction of 10b with appropriately substituted secondary amines was also developed. Hence, these synthetic strategies were advantageously exploited to provide access to a variety of diversely derivatized 3-substituted fused-ring [1,2,4]thiadiazole derivatives.

Building 1,2,4‐Thiadiazole: Ten Years of Progress

“…In the same year, Leung‐Toung and colleagues defined a new approach for the synthesis of the bicyclic 3‐substituted 1,2,4‐thiadiazole derivatives 7a and 7b (Scheme ) . The authors stated that product 5 , obtained from 2‐mercaptoimidazole and n ‐butyl isocyanate, was subjected to oxidative ring closure with bromine and triethylamine at ice‐bath temperature to afford 2‐butylimidazo[1,2‐ d ][1,2,4]thiadiazol‐3(2 H )‐one ( 6 ) in >70 % combined yield.…”

“…(A) Preparation of tricyclic 1,2,4‐thiadiazoles 49a – f . (B) Nucleophilic displacement reactions of tricyclic 1,2,4‐thiadiazole scaffold 49a …”

“…Some of the thiadiazoles possess remarkable thiol‐trapping properties and demonstrate pronounced muscarinic and cardiprotective activities . Furthermore, monocyclic 1,2,4‐thiadiazoles have been claimed as useful insecticidal, herbicidal, and fungicidal agents …”

Tribromo Phloroglucinol as a Novel and Highly Efficient Reagent for the Conversion of Benzothioamides to the Corresponding 1,2,4-Thiadiazoles

“…[9] Meanwhile, the reaction of 1-monosubstituted thioureas with bis(acyloxyiodo)arene derivatives has been utilized as a synthetic procedure to obtain 3,5-bis-(phenylamino)-1,2,4-thiadiazoles. [10] Thiadiazoles are interesting building blocks in medicinal chemistry [11][12][13] and industrial chemical [14] that are easy to access.…”

Green protocol for synthesis of the 3,5-disubstituted 1,2,4-thiadiazoles using N-benzyl-DABCO-tribromide in aqueous media

“…Some of these show intense muscarinic [7] and cardiprotective activities [8]. Monocyclic 1,2,4-thiadiazoles have been widely claimed to be useful insecticidal, herbicidal and fungicidal agents [9]. Recently the thioltraping properties of 1,2,4-thiadiazole systems have been surveyed [10].…”