Periodic Reporting for period 1 - DECOCHEM (Developing heterocylic sulfinates as general coupling partners in transition metal catalysedprocesses)
Berichtszeitraum: 2019-04-29 bis 2021-04-28
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.
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.
The first task performed by the researcher, and the easiest and most recurring throughout the 2 years, was the synthesis of desired starting material through various known methods.
One of the main projects developed by the researcher was a desulfinative photoredox reaction. While sulfinates have been previously used as radical precursors, the initial hit observed was the first time a heteroaryl radical was produced from the sulfonyl radical, with a 26% yield of the final product after radical addition on an electron poor alkene. This reaction underwent an extensive optimisation, during which the following were looked into: light source, substrates and photocatalysts, additives, loading and stoichiometry, solvents and concentration, reaction time and temperature. It was discovered that the main contributing factor was the solvent and concentration, with substantial dilute conditions in ethanol leading to yields around 70%. Unfortunately the reaction was substantially substrate dependant, highly limiting its use and value. This reaction would require to be re-optimised for more general use.
The second main project the researcher was involved in was the use of protected sulfinate derivatives in cross-coupling desulfinative reactions. Previously in the group, heteroaryl sulfinates had been used extensively in a newly developed desulfinative cross-coupling reaction, serving as a useful solution to the limitations of the widely used Suzuki reaction. However sulfinates being salts, they present difficulties in solubility and further transformations and purification steps. The group had already solved this by turning the sulfinates into allyl sulfones. However, an allyl tether came with its own limitations, being incompatible with other cross-coupling and redox reactions, as well as having some reproducibility issues.
We developed a new protective tether which carries a β-Electron Withdrawing Group (βEWG) and can be deprotected in basic conditions. Starting from reaction conditions similar to ones using the allyl tether, significant optimisation of the reaction conditions was undertaken. In particular, the solvent, temperature, and additives that controlled the pH (and therefore the rate of release of the sulfinate) were the main contributors to the reaction’s success. This has lead to the development of a large and diverse scope with excellent yields.
A review concerning this issue with the suzuki coupling, as well as the solutions employed (including the group's research described above), was also written and published by the researcher and coworkers.
One of the main projects developed by the researcher was a desulfinative photoredox reaction. While sulfinates have been previously used as radical precursors, the initial hit observed was the first time a heteroaryl radical was produced from the sulfonyl radical, with a 26% yield of the final product after radical addition on an electron poor alkene. This reaction underwent an extensive optimisation, during which the following were looked into: light source, substrates and photocatalysts, additives, loading and stoichiometry, solvents and concentration, reaction time and temperature. It was discovered that the main contributing factor was the solvent and concentration, with substantial dilute conditions in ethanol leading to yields around 70%. Unfortunately the reaction was substantially substrate dependant, highly limiting its use and value. This reaction would require to be re-optimised for more general use.
The second main project the researcher was involved in was the use of protected sulfinate derivatives in cross-coupling desulfinative reactions. Previously in the group, heteroaryl sulfinates had been used extensively in a newly developed desulfinative cross-coupling reaction, serving as a useful solution to the limitations of the widely used Suzuki reaction. However sulfinates being salts, they present difficulties in solubility and further transformations and purification steps. The group had already solved this by turning the sulfinates into allyl sulfones. However, an allyl tether came with its own limitations, being incompatible with other cross-coupling and redox reactions, as well as having some reproducibility issues.
We developed a new protective tether which carries a β-Electron Withdrawing Group (βEWG) and can be deprotected in basic conditions. Starting from reaction conditions similar to ones using the allyl tether, significant optimisation of the reaction conditions was undertaken. In particular, the solvent, temperature, and additives that controlled the pH (and therefore the rate of release of the sulfinate) were the main contributors to the reaction’s success. This has lead to the development of a large and diverse scope with excellent yields.
A review concerning this issue with the suzuki coupling, as well as the solutions employed (including the group's research described above), was also written and published by the researcher and coworkers.
Concerning starting material synthesis, While these reactions were mostly known, there were nonetheless optimised to increase their efficiency and were applied to a wider scope range than any previously developed, leading to their increased potential use in the future.
Concerning the desulfinative photoredox reaction, heteroaryl sulfinates have shown great potential as radical precursors towards hard-to-achieve aryl radicals, as easier-to-handle alternatives to more unstable compounds such as diazonium salts. This new reaction therefore should be used as proof of concept that such radicals can be formed from heteroaryl sulfinates, paving the way towards further breakthroughs. However, for now, it is still in its early days and has many limitations to overcome.
Concerning the latent desulfinative cross-coupling reaction, this reaction now solves the issues of both the Suzuki reaction, as well as the previous issues with sulfinates and allyl sulfones. It is simple to set up, from commercial or easily accessible starting material, and has unlocked the potential for a practical pathway towards hetero-hetero biaryl synthesis, with significant industrial potential uses. This work’s manuscript has been recently submitted. The main issue still remaining, namely reducing the high temperature required so far, is being currently investigated by the group.
Concerning the desulfinative photoredox reaction, heteroaryl sulfinates have shown great potential as radical precursors towards hard-to-achieve aryl radicals, as easier-to-handle alternatives to more unstable compounds such as diazonium salts. This new reaction therefore should be used as proof of concept that such radicals can be formed from heteroaryl sulfinates, paving the way towards further breakthroughs. However, for now, it is still in its early days and has many limitations to overcome.
Concerning the latent desulfinative cross-coupling reaction, this reaction now solves the issues of both the Suzuki reaction, as well as the previous issues with sulfinates and allyl sulfones. It is simple to set up, from commercial or easily accessible starting material, and has unlocked the potential for a practical pathway towards hetero-hetero biaryl synthesis, with significant industrial potential uses. This work’s manuscript has been recently submitted. The main issue still remaining, namely reducing the high temperature required so far, is being currently investigated by the group.