Telescoped continuous flow generation of a library of highly substituted 3-thio-1,2,4-triazoles

Author(s)

Damiao, Mariana C. F. C. B. ^[1] ; Galaverna, Renan ^[1] ; Kozikowski, Alan P. ^[2] ; Eubanks, James ^[3] ; Pastre, Julio C. ^[1]

Affiliation

^[1] Univ Campinas UNICAMP, Inst Chem, POB 6154, BR-13083970 Campinas, SP - Brazil

^[2] StarWise Therapeut LLC, Univ Res Pk, Madison, WI 53719 - USA

^[3] Krembil Res Inst, Div Genet & Dev, Toronto, ON M5T 2S8 - Canada

• Document type: Journal article
• Source: REACTION CHEMISTRY & ENGINEERING; v. 2, n. 6, p. 896-907, DEC 2017.
• Web of Science Citations: 4

Abstract

We report herein the successful application of continuous flow micro reactors to prepare important building blocks based on the 3-thio-1,2,4-triazole core. A telescoped continuous flow process was developed based on the condensation of hydrazides and isothiocyanates to deliver an in situ stream of a thiosemicarbazide, which subsequently was cyclized under basic conditions. The obtained 1,2,4-triazole-3-thiol was further alkylated with benzyl/alkyl halides. In addition, we evaluated the scope of heterocycle formation and alkylation using different hydrazides, isothiocyanates, and aryl/alkyl chlorides, bromides and iodides. We were able to synthesize a small library of 18 compounds in 48 minutes of residence time for each synthesis, and in moderate to excellent yields, in a telescoped fashion. The fully integrated synthesis flow platform enables the fast generation of compound libraries, reducing the time consumed in preliminary stages of a drug discovery process. (AU)

• FAPESP's process: 15/18572-6 - Continuous flow synthesis of 3-thio-1,2,4-triazoles and biological evaluation
• Grantee: Mariana Celestina Frojuello Costa Bernstorff Damião
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 14/25770-6 - New frontiers in cross-coupling reactions promoted by palladium: combining enantioselective catalysis, C-H activations, new materials and in flux reactions aiming at high efficiency and sustainability in synthetic processes
• Grantee: Carlos Roque Duarte Correia
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 14/26378-2 - Development of methodologies and synthetic processes employing a new technological platform: micro and meso reactor assisted synthesis of natural products and derivatives with potential pharmacological activity
• Grantee: Júlio Cezar Pastre
• Support Opportunities: Research Grants - Young Investigators Grants
• FAPESP's process: 13/07607-8 - OCRC - Obesity and Comorbidities Research Center
• Grantee: Licio Augusto Velloso
• Support Opportunities: Research Grants - Research, Innovation and Dissemination Centers - RIDC