Updated Appel reaction finally fluorinates alcohols

An ingenious twist on a classic reaction provides easy access to chiral alkyl fluorides using a safe fluorine source derived straight from the mineral fluorspar. The reimagined Appel reaction avoids the need for the harsh conditions and problematic reagents that were previously required to directly fluorinate alcohols. The new strategy is part of a wider effort by a University of Oxford team seeking to overhaul synthetic approaches to fluorine chemistry.

The fluorochemicals pipeline is complex and, in many cases, controversial. From pharmaceuticals to polymers, installation of fluorine functionality relies upon highly specialised reagents, all of which are ultimately derived from hydrogen fluoride (HF). ‘HF is the apex fluorochemical for the synthesis of all fluorochemicals and it’s probably one of the most dangerous chemicals we produce on a manufacturing scale,’ says synthetic chemist Véronique Gouverneur, who led the new work. ‘My vision is to reinvent the fluorochemical manufacturing industry by making it safer – so not based on HF, but instead on an alternative apex fluorochemical such as an alkali metal fluoride.’

Back in 2023, Gouverneur’s group reported a simple mechanochemical method to obtain potassium fluoride (KF) directly from fluorspar, potentially negating the need for HF in reagent synthesis. Since then, the team has been revisiting existing fluorination procedures with the goal of simplifying the chemistry and replacing problematic HF-derived reagents with KF or more benign KF-derived analogues. The latest target of this campaign is the direct fluorination of alcohols.

Standard alcohol halogenations rely on the halophosphonium-mediated Appel reaction, but the fluorine analogue is plagued by a dead-end side reaction that sequesters the crucial fluorinating reagent. ‘You form a difluorophosphorane with two phosphorous–fluorine bonds that are so strong they generate a thermodynamic sink and don’t allow you to do the desired fluorination,’ explains Miriam O’Duill, a synthetic chemist at the University of Nottingham who wasn’t involved in the work. ‘Instead, diethylaminosulphur trifluoride (DAST) is the go-to reagent for these reactions, but it’s not the nicest reagent to work with – there’s a real danger of it exploding if you heat it.’

The challenge for Gouverneur’s team was to reengineer the Appel reaction to suppress the formation of the unwanted difluorophosphorane side product, and the key lay in postdoc Anirban Mondal’s design of the phosphorous reagent. ‘It’s simple, yet very effective,’ says Gouverneur. ‘We incorporated a neopentoxy group, which slows down the rate of difluorophosphorane formation, and that gives an opportunity for the reagent to activate the alcohol substrate for fluorination.’

When mixed with a urea catalyst and KF, the phosphorous reagent forms a monofluoro intermediate that then activates the alcohol substrate via exchange with the neopentoxy group. The urea next abstracts the fluoride from the phosphorous centre, priming it for a nucleophilic substitution on the newly activated alcohol. Careful choice of the urea catalyst even enabled the team to do the reaction asymmetrically, transforming racemic alcohols into chiral fluorides.

‘It’s a very exciting paper,’ says O’Duill. ‘Enantioselective fluorination has been a longstanding unsolved problem in medicinal chemistry and this method now really paves the way for new chiral fluorinated drugs.’ She adds that the method’s broad substrate scope – including ketone and aldehyde functionalities that are incompatible with conventional DAST fluorination, and complex alcohols derived from natural products – is a significant advantage.

For Gouverneur, the most important breakthrough remains the simplicity of the reaction. ‘It’s a challenging and intricate reaction, but I think we solve it in a beautiful and simple way,’ she says.