Image may be NSFW.
Clik here to view.

Using the Uniqsis FlowSyn flow chemistry system researchers from the UCB Biopharma. Belgium have developed a flow synthesis of 2-substituted 1,2,3-triazoles that demonstrates improvements over the conventional batch route.

The route involves the diazotisation of anilines and condensation with malononitrile followed by the nucleophilic addition of ammonia or an alkylamine and finally a novel copper catalysed cyclisation. The intermediate azide was generated and consumed in situ which enabled safe scale up under the flow-through conditions employed.

J. Jacq, P. Pasau, Chem Eur. J., 2014, 20, (38), 12223.

DOI: 10.1002/chem.201402074

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

Authors, Dr. Jérôme Jacq, Dr. Patrick Pasau

Corresponding author

E-mail address: patrick.pasau@ucb.com

UCB Biopharma, Avenue de l’Industrie, 1420 Braine l’Alleud (Belgium)

UCB Biopharma, Avenue de l’Industrie, 1420 Braine l’Alleud (Belgium)===

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.http://onlinelibrary.wiley.com/wol1/doi/10.1002/chem.201402074/full

http://onlinelibrary.wiley.com/store/10.1002/chem.201402074/asset/supinfo/chem_201402074_sm_miscellaneous_information.pdf?v=1&s=77c885224607254b0d594d6cd190e655dd4ac7ee

Image may be NSFW.
Clik here to view.

1H/13c NMR OF 1a

Image may be NSFW.
Clik here to view.