Within the pharmaceutical industry, one of the main carbon-carbon bond-forming transformations employed are cross-coupling reactions, in particular the Suzuki-Miyaura cross-coupling reaction, which combines aryl boronates or boronic acids with aryl halides under the action of a palladium catalyst. Unfortunately, this approach often becomes unreliable, or fails completely, when substituted pyridine rings are employed as nucleophilic substrates, which is most pronounced for 2-substituted pyridines. We have recently established that pyridine sulfinates are excellent coupling partners in palladium-catalyzed coupling reactions with aryl and heteroaryl halides, and have reported a coupling process of exceptional scope. The use of these heterocycle sufinates addresses many of the limitations of the corresponding boronic acids; they are straightforward to prepare via a number of methods, they are stable to storage and use, and they deliver highly efficient reactions.
While sulfinates have proven to be a useful and efficient solution, they do have two main limitations of their own. The first is the high temperatures (120-150 °C) required for these couplings to occur, in stark contrast to more classic Suzuki-Miyaura couplings that can be achieved with far milder conditions (henceforth named issue A). The second is the fact that sulfinates are salts, which leads to issues in solubility, purification, and further chemical transformations (henceforth known as issue B). Solving both these issues was the main aim of this project.
Concerning issue A :
By combining traditional coupling reactions with photoredox catalysis, thermal activation is replaced by light activation, solving the high temperature issue by modifying the mechanistic pathway. Numerous similar alternatives for other cross-coupling reactions have previously used sulfinates as radical precursors in photoredox reactions, however they were alkyl radicals, while our aim focuses on heteroaryl radicals. The project around issue A is further divided into two parts : first, making sure the heteroaryl radicals can be properly and efficiently formed from heteroaryl sulfinates, and then building on those results, using these radicals in cross-coupling type reactions.
Regarding issue B :
The solution chosen by our group was to use specific sulfones that act as protected sulfinates that undergo deprotection during the reaction to enable the sulfinate to be released and react. The first generation of protected sulfinates were allyl sulfones, with the allyl moiety being removed by the same palladium catalyst as used for the cross-coupling. This lead to excellent results but had new problems of its own : the allyl tether prevented the protected sulfinate from undergoing orthogonal redox and cross-coupling reactions, as the tether would react in those conditions as well. This project aimed at solving those issues by modifying the protecting group, from an allyl tether to a beta Electron Withdrawing Group (EWG) tether that is deprotected in basic conditions, making these protected sulfinate species stable to redox and organometallic reaction conditions.
The main objectives of this project were therefore developing reactions that solve one or both of the two main issues, A and B, of the current sulfinate coupling reaction to allow for efficient, straightfoward heterocyclic cross-couplings, essential in the synthesis of numerous pharmaceutical compounds.
