eFluorination of activated alcohols using collidinium tetrafluoroborate Cyrille Kiaku 1 , Dorian Martinage 1 , Yasemin Sicim 1 , Matthew Leech 1 , Jamie Walsh 1 , Darren Poole 2 , Joseph Mason 2 , Iain C. A. Goodall 1 , Perry Devo 1 , Kevin Lam 1 1 School of Science, University of Greenwich, UK, 2 Medicinal Chemistry, GlaxoSmithKline Medicines Research Centre, UK Tertiary C-F bonds are structural designs of great importance; by taking advantage of fluorine’s high electronegativity and small size it is possible to use it as a hydrogen bioisostere and modify drugs’ physicochemical properties and pharmacokinetics. 1 However, assembling hindered C-F centres has long been challenging for synthetic chemists. Although methods have been developed, they often rely on using corrosive amine-HF salts, and expensive or hazardous reagents. 2 Herein, we reexplore fluorination with BF 4 - and introduce collidinium tetrafluoroborate as a cheaper and safer alternative to trigger efficient fluorination for anodic deoxyfluorination reactions. 4 Electrochemistry allows new chemical bonds to be forged using electricity, 3 one of the cheapest and greenest reagents. The described conversion from alcohols to the corresponding alkyl fluorides can be achieved by previous activation of this alcohol in an hemioxalate form. The electrolysis allows the hemioxalate salt to undergo successive decarboxylation leading to the alkyl radical, later suroxidised to form the corresponding carbocation. Finally, ion pairing with BF 4 - will provide the desired alkyl fluoride.
Attempts of fluorination in the presence of NBu 4 BF 4 as both supporting electrolyte and fluorinating agent, an hemioxalic acid and a base didn’t lead to satisfactory yields. Indeed, tertiary hemioxalic acids are unstable over time, hence the need to utilize the corresponding ammonium salt, more stable. Switching to collidinium tetrafluoroborate as our supporting electrolyte and fluorine donor was proven to give more satisfactory yields. The collidine moiety is convenient as the collidinium is being reduced at the cathode into hydrogen and collidine, hampering any undesired cathodic side-reaction.
This methodology is tolerant to a vast range of functional groups. Silyl ethers were compatible with our method while they are usually incompatible with most classical fluorination methodologies. While primary alcohols were inevitably taken out of our scope due to the generation of a less stable carbocation, primary benzylic alcohols seem to be tolerated with our method. We reported a safer and greener practical electrochemical method to access hindered alkyl fluorides under mild oxidative conditions from activated alcohols. Our protocol uses collidinium tetrafluoroborate as both a fluoride donor and a supporting electrolyte. We believe this method can be useful to the synthetic community as another addition to the deoxyfluorination toolkit.
References 1. Reddy, V. P. Chapter 1 - General Aspects of Organofluorine Compounds. In Organofluorine Compounds in Biology and Medicine; Reddy, V. P., Ed.; Elsevier: Amsterdam, 2015; pp 1–27. 2. Xiao, P.; Pannecoucke, X.; Bouillon, J.-P.; Couve-Bonnaire, S. Chem. Soc. Rev. 2021, 50 (10), 6094–6151. 3. Lam, K. Synlett 2022, 33 (20), 1953–1960. 4. Leech, M. C.; Nagornîi, D.; Walsh, J. M.; Kiaku, C.; Poole, D. L.; Mason, J.; Goodall, I. C. A.; Devo, P.; Lam, K. Org. Lett. 2023, 25 (9), 1353–1358.
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