New fluoroalkylazides commercialized

Czech academic-industrial tandem expands the medicinal chemist´s tool box – fluoroalkyl azides

Press release at IOCB website

The company CF Plus Chemicals has a history of long and fruitful cooperation with the group of Dr. Petr Beier at IOCB Prague.

Their cooperation started as early as in 2010 when Václav Matoušek, the founder of CF Plus Chemicals, did his PhD studies in the group of Prof. Dr. Antonio Togni at ETH Zurich, who is linked to the discovery and development cyclic hypervalent iodine-fluoroalkyl reagents, now commonly termed as Togni reagents. The result of this Swiss-Czech cooperation was a discovery and IP protection of the second generation of Togni reagents that can transfer various substituted fluoroalkyl groups to a wide range of substrates¹.

The mutual collaboration between CF Plus Chemicals and IOCB has been continuing further, resulting in several joint publications covering the area of fluoroalkylation chemistry.

In 2017, they published a new, elegant and scalable synthesis of trifluoromethylazide (CF₃N₃) and pentafluoroethylazide (C₂F₅N₃) by electrophilic azidation of nucleophilic fluoroalkyl sources².

These otherwise difficult-to-access perfluoroalkylazides proved to be highly reactive in copper catalyzed alkyne-azide cycloaddition reaction (“click reaction”) affording stable N-CF₃ and N-C₂F₅ triazoles in a highly regioselective manner.

Recently, the fluoroalkyl azide portfolio has been recently enriched by access to difluoromethyl azide. Difluoromethyl azide shares practically the same reactivity as trifluoromethyl azide in copper catalysed alkyne-azide cycloadditions, providing an expedient route to regioisomerically pure N-CF₂H triazoles which are highly attractive for medicinal chemistry discovery programmes³.

Besides the established copper catalyzed alkyne-azide cycloadditon, trifluoromethyl⁴ and difluoromethylazide³ were shown to undergo an enamine mediated azide-ketone [3+2] cycloadditions, affording the corresponding disubstituted N-fluoroalkyl triazoles.

The chemistry of these N-fluoroalkyl heterocycles was recently expanded when Beier et al. showcased that N-(per)fluoroalkyl triazoles can be transformed to a plethora of hitherto unreported five-membered N-(per)fluoroalkyl heterocycles using Rh-carbene chemistry⁵.

To sum up, the newly developed and potentially highly attractive chemistry of fluoroalkyl azides is a result of a Czech academic-industrial cooperation and opens new possibilities in design of structures used in drug candidates.

Thanks to that, medicinal chemists can now benefit from these reagents as CF Plus Chemicals commercializes all of these fluoroalkyl azides as safe and easily handled solutions in etheral solvents.

References:

1)     a) V. Matoušek, J. Václavík, P. Hájek, J. Charpentier, Z. E. Blastik, E. Pietrasiak, A. Budinská, A. Togni, P. Beier, Chemistry – A European Journal 2016, 22, 417-424.

b) J. Václavík, R. Zschoche, I. Klimánková, V. Matoušek, P. Beier, D. Hilvert, A. Togni, Chem. Eur. J. 2017, 23, 6490.

c) EP2982672A1

2)     Z.E. Blastik, S. Voltrová, V. Matoušek, B. Jurásek, D.W. Manley, B. Klepetářová, P. Beier, Angew. Chem. Int. Ed. 2017, 56, 346

3)     Voltrová, S. , Putovný, I. , Matoušek, V. , Klepetářová, B. and Beier, P., Eur. J. Org. Chem. 2018, doi:10.1002/ejoc.201800650

4)     Z.E. Blastik, B. Klepetářová, P. Beier, Chemistry Select, 2018, 3, 7045-7048

5)     V. Motornov, A. Markos, P. Beier, Chem. Commun. 2018, 54, 3258-3261