A continuous flow synthesis and derivatization of 1,2,4-thiadiazoles

• Published in: Bioorganic & medicinal chemistry Vol. 25; no. 23; pp. 6218 - 6223
• Main Authors: Baumann, Marcus, Baxendale, Ian R.
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 01.12.2017; Elsevier
• Subjects: Biochemistry & Molecular Biology; Chemistry; Chemistry, Medicinal; Chemistry, Organic; Crystallography, X-Ray; Flow synthesis; Hazardous Substances - chemistry; Heterocycles; Life Sciences & Biomedicine; Medicinal chemistry; Microreactors; Molecular Conformation; Nitrogen - chemistry; Oxygen - chemistry; Pharmacology & Pharmacy; Physical Sciences; Science & Technology; Sulfur - chemistry; Thiadiazoles; Thiadiazoles - chemical synthesis; Thiadiazoles - chemistry; Thiadiazoles; Heterocycles; Medicinal chemistry; Flow synthesis; Microreactors; DRUG DESIGN; CHEMISTRY; 1,3,4-THIADIAZOLE
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2017.01.022

[Display omitted] A continuous flow process is presented that enables the efficient synthesis and derivatization of 1,2,4-thiadiazole heterocycles. Special attention was given to the safe handling of the versatile yet hazardous trichloromethane sulfenylchloride reagent including its in-line quenching in order to eliminate malodourous and corrosive by-products. Based on this flow method gram quantities of 5-chloro-3-phenyl-1,2,4-thiadiazole were safely prepared allowing for further elaboration of this valuable building block by reaction with different nitrogen-, sulfur- and oxygen-based nucleophiles. This synthetic approach was subsequently applied to generate a series of bromophenyl-5-chloro-1,2,4-thiadiazoles providing a valuable entry towards further structural diversification on this important heterocyclic scaffold.