Beyond game changing

Sometimes a new piece of chemistry fills a gap perfectly. While a study might not feature a novel reaction, it can still be very important if it optimises conditions for a new set of substrates – such as those used in the life sciences. These substrates are often missing from the brilliant ‘game changing’ reports that describe new reactivity, so it is often later publications that consolidate a reaction’s usefulness.

Over the last 10 years, photoredox catalysis has arguably been the most innovative field of synthetic chemistry. One of the most important of these reactions is decarboxylative cross-coupling of carboxylic acids and aryl halides. Typically, an iridium catalyst and visible light drive decarboxylation to generate an alkyl radical that is trapped and coupled with the (hetero)aryl halide by a nickel catalyst.

Somewhat disappointingly from the perspective of medicinal chemists, cross-coupling reactions of α-fluorocarboxylates have been elusive. The prospective benzyl fluorides are desirable as the fluorine can stabilise the oxidatively vulnerable position to the activity of metabolic enzymes, as well as giving a molecule conformational rigidity through the gauche effect or by tweaking its physicochemical properties. Given that the starting materials are also easy to prepare, it is great to see that a team led by Ming Joo Koh of the National University of Singapore has found a way to make this reaction work.¹

The team began by considering the challenges of using α-fluorinated acids in the reaction, with α-fluorophenylacetic acid giving only 15% yield under ‘standard’ conditions. It isn’t clear if any of the acid remains after the reaction, although the comparable oxidation potentials of the analogues suggest radical generation isn’t critical.

Presuming the alkyl radical readily forms, the team then used density functional theory (DFT) to propose a mechanistic pathway. Direct oxidative addition of the aryl halide by Ni(0) is discounted as it would involve a high energy transition state, leaving two more energetically reasonable pathways: radical addition to Ni(0), followed by oxidative addition of the aryl bromide and subsequent radical dissociation to give a square planar Ni(ii) species; or a near barrierless nucleophilic aromatic substitution (S_N Ar) addition of the aryl group and subsequent addition of the bromide to generate the same complex. Isomerisation to a tetrahedral Ni(ii) species and addition of the F-alkyl radical then allows for inner-sphere bond formation.

The DFT calculations show an approximately two-fold energetic penalty for reductive elimination of fluorinated substrates compared to their unsubstituted counterparts, potentially accounting for their poor reactivity. For reasons that are unclear, the team plumps for the S_N Ar type mechanism over the radical addition-dissociation pathway, although this is a moot point given they do not appear to use the mechanistic hypothesis for rational reaction optimisation.

The optimised reaction conditions are fairly typical for photoredox reactions, which is somewhat surprising given the limited success with these substrates to date. The most interesting aspect is the addition of stoichiometric potassium triflate, suggesting a critical role for the counterion in the reaction mechanism. The reaction is reasonably tolerant of various solvents and bases, which is very useful when it comes to applying it on more complex substrates.

The reaction scope is decent with relatively simple aryl and alkyl acids all giving acceptable yields, and a couple of great reactions give easily modified N-Boc-piperidine products with a fluorinated tertiary carbon atom that are worth exploring further. The diversity of the aryl halides is significant, and often includes sensitive functionality and N-containing heterocycles. The work rounds off nicely with a couple of examples for how this reaction could be used to access drug-like compounds.

However, the publication overall leaves me with a feeling of incompleteness. While the reaction could provide simple access to some great molecules, the authors missed a chance to demonstrate its utility. Examples of modifiable products with diverse functionality would have been a simple and valuable addition. Aspects of the paper also undermine its value – such as reporting isolated yields on a 0.1mmol scale for the reaction optimisation and scope, and no apparent attempt to understand the reaction; although the mechanistic study is interesting, given the authors state the new reaction proceeds through a mechanism ‘likely very different’ to the one discussed, a study on the reported reaction seems more appropriate.