New substrates and catalysts for reactivity and sustainability in catalytic sulfination
Lead Research Organisation:
University of Oxford
Abstract
This project falls within the EPSRC Synthetic Organic Chemistry research area.
Molecules containing the sulfonyl (-SO2-) group, including sulfones, sulfonamides, sulfonate esters and sulfonyl fluorides, have become increasingly important within medicinal and agrochemistry due to the unique physicochemical properties they impart on the molecule. Many methods for their preparation are available, such as oxidation of disulfides or reactions of sulfonyl chlorides. These methods suffer from poor functional group compatibility of oxidation conditions, odorous thiols and disulfides being unfavourable starting materials and instability of sulfonyl chlorides.
Modern methods for the synthesis of sulfonyl-containing functional groups focus upon the fixation of sulphur dioxide; an inexpensive feedstock chemical, to generate a sulfinate, a stable and versatile intermediate that can be used to generate a broad variety of sulfonyl-containing functional groups. Issues related to handling the toxic, odorous gas led to the Willis group developing the charge transfer complex DABCO-(SO2)2 (DABSO), which can be used as a sulfur dioxide surrogate. A number of novel methods have been developed utilising DABSO to generate sulfinates, including methods using organometallic reagents, or catalytic methods using aryl halides, however, these too are limited in the diversity of substrates available for use, as both require halides as starting materials, and catalytic methods have only been developed for sulfination of aryl substrates. The focus of this research will be to develop new methods allowing sulfination of a broader variety of substrates, with a particular focus on generating alkyl sulfinates.
In our preliminary work, we explored alkyl amines and substrates for sulfination chemistry. Katritzky pyridinium salts can be readily prepared from amines, and have been of interest in recent research due to their ability to generate unstabilised alkyl radicals under mild conditions. In the literature, it had been shown that alkyl radicals can attack SO2 to generate a sulfonyl radical, which could then be trapped by electron-poor alkenes to generate sulfones. We envisaged that using Katritzky salts, we could generate the sulfonyl radical, which would subsequently be reduced under the reaction conditions, thus generating an alkyl sulfinate. We successfully developed conditions for the generation of alkyl sulfinates from secondary alkyl amines via a Katritzky pyridinium salt intermediate, achieving a good yield of 80% for the model substrate. We will optimise conditions to enable the use of primary alkyl amines, and subsequently assess the scope of the reaction. We will also explore the applicability of the reaction conditions for use with sulfinylamine reagents (aza-analogues of SO2) to generate alkyl sulfonimidoyl (-SNO-) derived functional groups.
Other substrate classes will also be explored within this project, including carbonyl derivatives such as acyl fluorides, redox-active esters and carboxylic acids in decarbonylative/decarboxylative catalytic regimes, to further diversify the variety of substrates amenable to sulfination, and thus improve the sustainability of and versatility of sulfination processes.
In summary, this project will improve the scope of substrates amenable to sulfination, improving access to medicinally and agrochemicially relevant sulfonyl and sulfonimidoyl functional groups.
Molecules containing the sulfonyl (-SO2-) group, including sulfones, sulfonamides, sulfonate esters and sulfonyl fluorides, have become increasingly important within medicinal and agrochemistry due to the unique physicochemical properties they impart on the molecule. Many methods for their preparation are available, such as oxidation of disulfides or reactions of sulfonyl chlorides. These methods suffer from poor functional group compatibility of oxidation conditions, odorous thiols and disulfides being unfavourable starting materials and instability of sulfonyl chlorides.
Modern methods for the synthesis of sulfonyl-containing functional groups focus upon the fixation of sulphur dioxide; an inexpensive feedstock chemical, to generate a sulfinate, a stable and versatile intermediate that can be used to generate a broad variety of sulfonyl-containing functional groups. Issues related to handling the toxic, odorous gas led to the Willis group developing the charge transfer complex DABCO-(SO2)2 (DABSO), which can be used as a sulfur dioxide surrogate. A number of novel methods have been developed utilising DABSO to generate sulfinates, including methods using organometallic reagents, or catalytic methods using aryl halides, however, these too are limited in the diversity of substrates available for use, as both require halides as starting materials, and catalytic methods have only been developed for sulfination of aryl substrates. The focus of this research will be to develop new methods allowing sulfination of a broader variety of substrates, with a particular focus on generating alkyl sulfinates.
In our preliminary work, we explored alkyl amines and substrates for sulfination chemistry. Katritzky pyridinium salts can be readily prepared from amines, and have been of interest in recent research due to their ability to generate unstabilised alkyl radicals under mild conditions. In the literature, it had been shown that alkyl radicals can attack SO2 to generate a sulfonyl radical, which could then be trapped by electron-poor alkenes to generate sulfones. We envisaged that using Katritzky salts, we could generate the sulfonyl radical, which would subsequently be reduced under the reaction conditions, thus generating an alkyl sulfinate. We successfully developed conditions for the generation of alkyl sulfinates from secondary alkyl amines via a Katritzky pyridinium salt intermediate, achieving a good yield of 80% for the model substrate. We will optimise conditions to enable the use of primary alkyl amines, and subsequently assess the scope of the reaction. We will also explore the applicability of the reaction conditions for use with sulfinylamine reagents (aza-analogues of SO2) to generate alkyl sulfonimidoyl (-SNO-) derived functional groups.
Other substrate classes will also be explored within this project, including carbonyl derivatives such as acyl fluorides, redox-active esters and carboxylic acids in decarbonylative/decarboxylative catalytic regimes, to further diversify the variety of substrates amenable to sulfination, and thus improve the sustainability of and versatility of sulfination processes.
In summary, this project will improve the scope of substrates amenable to sulfination, improving access to medicinally and agrochemicially relevant sulfonyl and sulfonimidoyl functional groups.
Planned Impact
This programme is focused on a new cohort-driven approach to the training of next-generation doctoral scientists in the practice of novel and efficient chemical synthesis coupled with an in-depth appreciation of its application to biology and medicine.
This collaborative academic-industrial SBM CDT will have long-term benefit to the chemical industry, including the pharmaceutical, agrochemical and fine chemical sectors. These industries will benefit through: (i) the potential to employ individuals trained with broad and relevant scientific and transferable skills; (ii) new approaches to the investigation of complex biological and medical problems through novel chemistry; and (iii) better and more efficient synthetic methods.
We will link the work of DSTL, and our pharmaceutical and agrochemical partners (GSK, UCB, Vertex, Evotec, Eisai, AstraZeneca, Syngenta, Novartis, Takeda, Sumitomo and Pfizer) through a common theme of synthesis training. The design and synthesis of new compounds is essential for disease treatment and prevention, and for maintaining food security. Synthesis contributes significantly to UK tax revenue and results in sustained employment across a number of sectors. Employers in the finance, law, health, academic, analytical, government, and teaching professions, for example, also recognise the value of the translational skill-sets possessed by synthesis postgraduates, which this programme will provide.
The SBM CDT training programme will adopt an IP-free model to enable completely free exchange of information, know-how and specific expertise between students and supervisors on different projects and across different industrial companies. This will lead to better knowledge creation through unfettered access to information from all academics, partners and students involved in the project. By focussing on basic science, we will engender genuine collaboration leading to enabling technology that will be of use across a wide range of industries.
We will train the next generation of multidisciplinary synthetic chemists with an appreciation of the impact of synthesis in biology and medicine. Their unconstrained view of synthesis will aid in new scientific discoveries leading to new products, which (with appropriate inward investment), can lead to the formation of new companies and new UK employment.
We will, in part through an alliance with the Defence, Science and Technology Laboratory, engage with policy-makers to influence future policy issues involving chemistry such as food security and the rise of antibiotic resistance (both of which are relevant to our programme and are important for society as a whole).
Outreach and public engagement will be a key aspect of our programme; and all students in the proposed SBM CDT will take part in at least one outreach activity. Typical activities include: open days in the Chemistry Department through the 'Outreach Alchemists', engaging with the Oxfordshire Science Festival and participation in the various other activities already in place through the public engagement programme of the Department of Chemistry.
The research output of the students will be disseminated via high impact international publications and lectures; these will be of value to other academics in relevant fields and will be of value in the development of further research funding applications. Outreach activities and research output will also be advertised on a website dedicated to the proposed SBM programme.
This collaborative academic-industrial SBM CDT will have long-term benefit to the chemical industry, including the pharmaceutical, agrochemical and fine chemical sectors. These industries will benefit through: (i) the potential to employ individuals trained with broad and relevant scientific and transferable skills; (ii) new approaches to the investigation of complex biological and medical problems through novel chemistry; and (iii) better and more efficient synthetic methods.
We will link the work of DSTL, and our pharmaceutical and agrochemical partners (GSK, UCB, Vertex, Evotec, Eisai, AstraZeneca, Syngenta, Novartis, Takeda, Sumitomo and Pfizer) through a common theme of synthesis training. The design and synthesis of new compounds is essential for disease treatment and prevention, and for maintaining food security. Synthesis contributes significantly to UK tax revenue and results in sustained employment across a number of sectors. Employers in the finance, law, health, academic, analytical, government, and teaching professions, for example, also recognise the value of the translational skill-sets possessed by synthesis postgraduates, which this programme will provide.
The SBM CDT training programme will adopt an IP-free model to enable completely free exchange of information, know-how and specific expertise between students and supervisors on different projects and across different industrial companies. This will lead to better knowledge creation through unfettered access to information from all academics, partners and students involved in the project. By focussing on basic science, we will engender genuine collaboration leading to enabling technology that will be of use across a wide range of industries.
We will train the next generation of multidisciplinary synthetic chemists with an appreciation of the impact of synthesis in biology and medicine. Their unconstrained view of synthesis will aid in new scientific discoveries leading to new products, which (with appropriate inward investment), can lead to the formation of new companies and new UK employment.
We will, in part through an alliance with the Defence, Science and Technology Laboratory, engage with policy-makers to influence future policy issues involving chemistry such as food security and the rise of antibiotic resistance (both of which are relevant to our programme and are important for society as a whole).
Outreach and public engagement will be a key aspect of our programme; and all students in the proposed SBM CDT will take part in at least one outreach activity. Typical activities include: open days in the Chemistry Department through the 'Outreach Alchemists', engaging with the Oxfordshire Science Festival and participation in the various other activities already in place through the public engagement programme of the Department of Chemistry.
The research output of the students will be disseminated via high impact international publications and lectures; these will be of value to other academics in relevant fields and will be of value in the development of further research funding applications. Outreach activities and research output will also be advertised on a website dedicated to the proposed SBM programme.
Organisations
People |
ORCID iD |
| Michael Willis (Primary Supervisor) | |
| Jonathan Andrews (Student) |
| Description | New methods have been developed using solid surrogates of the readily available gas, SO2. These methods are useful as SO2 gas has many hazards associated with its use, which can be alleviated through the use of solid surrogates. This work utilises the addition of radicals (reactive molecules with unpaired electrons) to SO2, ultimately to give various useful compounds containing the -SO2- motif. These have various applications in medicinal chemistry, so methods to make these are valuable. Subsequently, these findings were used and applied to the "mono-aza" analog of SO2, where one of the oxygen atoms is replaced with a nitrogen atom. These are known as sulfinylamines. These are less easy to access and use than SO2, but have useful applications in preparing challenging compounds analogous to those prepared in my first project, but again where one oxygen atom is replaced with a nitrogen atom. We developed this work further by developing a method to prepare sulfinylamines in the reaction, which helped address the problem with some of these reagents where they react quickly with water to form SO2. Further preliminary work was also carried out on the di-aza analogues of SO2, where both oxygen atoms are replaced with nitrogen atoms, known as sulfurdiimide. These are very challenging to prepare, but we have developed some new reliable methods of making them, and shown their reactions with radicals for the first time. |
| Exploitation Route | The preliminary work on sulfurdiimides has resulted in several new projects from new students, which will further explore the chemistry of these exciting molecules. |
| Sectors | Chemicals,Pharmaceuticals and Medical Biotechnology |
| URL | https://doi.org/10.1021/acs.orglett.1c03194 |