Multistep Flow Synthesis of 5‐Amino‐2‐aryl‐2H‐[1,2,3]‐triazole‐4‐carbonitriles

Abstract

1,2,3-Triazole has become one of the most important heterocycles in contemporary medicinal chemistry. The development of the copper-catalyzed Huisgen cycloaddition has allowed the efficient synthesis of 1-substituted 1,2,3-triazoles. However, only a few methods are available for the selective preparation of 2-substituted 1,2,3-triazole isomers. In this context, we decided to develop an efficient flow synthesis for the preparation of various 2-aryl-1,2,3-triazoles. Our strategy involves a three-step synthesis under continuous-flow conditions that starts from the diazotization of anilines and subsequent reaction with malononitrile, followed by nucleophilic addition of amines, and finally employs a catalytic copper(II) cyclization. Potential safety hazards associated with the formation of reactive diazonium species have been addressed by inline quenching. The use of flow equipment allows reliable scale up processes with precise control of the reaction conditions. Synthesis of 2-substituted 1,2,3-triazoles has been achieved in good yields with excellent selectivities, thus providing a wide range of 1,2,3-triazoles.

Analogs of biologically active compounds IX. Synthesis of several new uracil and pteridine 6-aza-analogs based on cyclization of arylhydrazones derived from mesoxalic acid

“…20 These compounds can exist in two tautomeric forms 6A-6B. Although some literature articles have described similar derivatives as hydrazones, 21,22 our results, supported by NMR spectra, are in accordance with the published literature where the azo form was reported. 20 We also observed no NH proton signal in 1 H NMR spectra of compounds 6 which would correspond to the hydrazono group.…”

Taming Hazardous Chemistry in Flow: The Continuous Processing of Diazo and Diazonium Compounds

“…Researchers at UCB Biopharma have reported the continuous diazotisation of 42 a in a telescoped synthesis of 2-substituted [1,2,3]-triazoles (Scheme 11). [90] Their synthesis begins with a tert-butylnitrite (47)-mediated oxidation of 42 a to a reactive diazonium species (43 b). This reaction notably proceed-ed in the absence of an acid which would typically stabilise 43 b as its salt.…”

“… Continuous generation of a phenyldiazonium species ( 43 b ) and immediate reaction with malononitrile ( 48 ) in a tubular reactor ( R1 ). The formed 2‐arylhydrazonomalononitrile ( 49 ) was reacted with ammonia ( 50 ) in a telescoped flow process 90 . P =pump, R =reactor coil.…”

Flow chemistry as a versatile tool for the synthesis of triazoles

“…Although many synthetic challenges in triazole chemistry have already been addressed or at least simplified by the toolbox of continuous-flow chemistry and catalysis, and alternative continuous-flow cyclization strategies have also emerged for the synthesis of various biologically relevant triazoles, 129,130 numerous gaps still remain. For example, there is a compelling need for ruthenium-and iridium-based heterogeneous catalytic systems in association with complementary flow chemistry-based synthetic techniques to facilitate the selective production of novel 1,5-disubstituted and 1,4,5-trisubstituted triazoles.…”