Toward the synthesis of thiadiazole-based therapeutic agents: synthesis, spectroscopic study, X-ray analysis, and cross-coupling reactions of the key intermediate 3,5-diiodo-1,2,4-thiadiazole

Abstract

The 1,2,4-thiadiazole moiety is an important component of several biologically active compounds, and varying substituents on this aromatic ring is one of the possible methods to develop novel thiadiazole-based drugs for medicine. A key building block to this end, namely 3,5-diiodo-1,2,4-thiadiazole (1), has been synthesized and characterized in this work for the first time. 1 has exhibited high selectivity for the replacement of iodine atom at position C5 (carbon next to sulfur) in Sonogashira-type cross-coupling reactions with phenylacetylene. Therefore, 3-iodo-5-(phenylethynyl)-1,2,4-thiadiazole (4) or 3,5-bis(phenylethynyl)-1,2,4-thiadiazole (5) could be synthesized selectively depending on reaction conditions. All three novel molecules have been characterized by NMR, IR, Raman, mass, and UV spectroscopies, and their solid phase structures have been determined by single-crystal X-ray diffraction. 1 is expected to be a key starting material for producing thiadiazole-based therapeutic agents using cross-coupling reactions.

Synthesis, structure and in vitro antiproliferative effects of alkyne-linked 1,2,4-thiadiazole hybrids including erlotinib- and ferrocene-containing derivatives

“…The structure of 7 was published in our previous paper. 25 The crystal structures of 4, 5, 6, 8, 10, and 11 are shown in Fig. 3 and 4 with geometric parameters listed in Tables S4–S9, ESI.…”

“…Compounds 3, 7 and 9 were synthesized as described recently. 25 Synthetic reactions were monitored by thin-layer chromatography (TLC) using Merck Silica gel 60 F254 TLC plates, and plates were visualised under a Camag model UV lamp 4 dual wavelength 254/366 nm. Column chromatography was performed using Merck silica gel 60 (0.063–0.200 mm) using a column (diameter 2.5 cm) with sintered glass disc.…”

Applications of Oxone® in Organic Synthesis: An Emerging Green Reagent of Modern Era

“…The applicability of the hypervalent iodine reagents in the synthesis of 1,2,4-thiadiazoles have some issues like toxic reagents, harsh reaction conditions and usually produce isothiocyanates and nitriles as by-products. [448][449][450][451][452] Therefore, in order to address these critical problems, Yoshimura et al developed an efficient synthesis of 1,2,4-thiadiazoles 623 a-i by the oxidative dimerization of thioamides and carbothioamides 622 in the presence of oxone under mild reaction conditions (Scheme 192). [453] This procedure was successful to collect a variety of dimerization products in impressive yields as can be seen from the Scheme 192. Pyrroles and the structures made from this unique fivemembered heterocyclic aromatic skeleton are not only of significant interest from the medical, biological, and pharmaceutical perspective but also have a wide range of applications in natural products synthesis, polymer sciences, material sciences, supramolecular architectures, and coordinating ligands of special consideration as well.…”

“…The most common approach for the construction of 1,2,4‐thiadiazoles is the oxidative dimerization of thioamides using organohypervalent iodine reagents as oxidants. The applicability of the hypervalent iodine reagents in the synthesis of 1,2,4‐thiadiazoles have some issues like toxic reagents, harsh reaction conditions and usually produce isothiocyanates and nitriles as by‐products [448–452] . Therefore, in order to address these critical problems, Yoshimura et al .…”