Aryl fluorides synthesis via a Balz-Schiemann type reaction: organotrifluoroborates as promising fluoride sources

The prominence of fluorinated aromatic compounds[1] in pharmaceuticals, agrochemicals, material sciences and 18F radiotracers for positron emission tomography (PET) have urged significant advances in the methods for aryl C-F... [ view full abstract ]

The prominence of fluorinated aromatic compounds[1] in pharmaceuticals, agrochemicals, material sciences and ¹⁸F radiotracers for positron emission tomography (PET) have urged significant advances in the methods for aryl C-F bond formation.[2] Nevertheless, interest in Balz-Schiemann reaction[3] and variants thereof persists as fluorination on aryls continues to be a challenge, even if the Balz-Schiemann reaction suffers from several drawbacks such as harsh conditions, variable yields and safety concerns related to the stability of some aryl diazonium intermediates.[4] Thus, there is an urgent need to develop an improved environmentally friendly fluorination protocol that would provide a rapid and safe access to aryl fluorides.

A single report demonstrated the efficiency of potassium perfluoroorganyltrifluoroborates as fluoride sources in Balz-Schiemann transformation.[5] To the best of our knowledge, this is the only protocol that makes use of organotrifluoroborates, however with several limitations as the narrow scope (one diazonium substrate tested), high temperatures (>138 °C) and the necessity of isolating and drying the aryldiazonium organylfluoroborates.

In this context, we developed an efficient protocol promoting mild and practical one-pot synthesis of aryl fluorides from aryl amines using cheap and easy accessible organotrifluoroborates (Scheme 1).[6]

A range of substrates was synthesized in a similar fashion to the classical Blaz-Schiemann, but without the need of any intermediate or salt isolation.

Further optimization allowed the extension of this method to solid-supported fluorination using recyclable solid-supported RBF₃^-. This procedure will be applied to flow reactors where continuous in situ diazotization/fluorodediazoniation would enable the elution of the desired fluoroarenes while retaining the boronic acid that can be regenerated as the organotrifluoroborate.

[1] T. Okazoe, Proc. Jpn. Acad., Ser. B, 2009, 85, 276 – 289.

[2] M. G. Campbell, T. Ritter, Chem. Rev. 2015, 115, 612 – 633.

[3] G. Balz, G. Schiemann, Ber. Dtsch. Chem. Ges. 1927, 60, 1186 – 1190.

[4] A. J. Cresswell, S. G. Davies, P. M. Roberts, J. E. Thomson, Chem. Rev. 2015, 115, 566 – 611. 

[5] O. Sadek, T. Mohy El Dine, E. Gras, D. Perrin, manuscript under preparation.

[6] V. V. Bardin, H.-J. Frohn, J. Fluor. Chem. 2013, 156, 333 – 338.