Novel Strategies for the Assembly of Carbon-Boron Bonds via the Photoinduced Generation of Boryl-Radicals
Lead Research Organisation:
University of Manchester
Department Name: Chemistry
Abstract
Boron-containing small organic molecules are one of the most important class of compounds in modern synthetic chemistry due to their use in the Nobel Prize-winning hydroboration-oxidation and Suzuki cross-coupling. Borylated building-blocks are routinely used in the preparation of high-value materials both in academia and industry. Therefore, the invention of novel chemical reactions that form C-B bonds in unprecedented ways is of strategic importance to facilitate the discovery, evolution and manufacture of molecules that impact our society.
In general, boron-based functionalities are introduced into organic molecules using two-electron processes like the reaction of Grignards with B-electrophiles or the aromatic C-H borylation using transition metal catalysis.
The overarching aim of this project is to explore a complementary approach where C-B bonds are assembled through the reactivity of B-centred radicals (boryl radicals). The use and application of these reactive intermediates is considerably underdeveloped but can provide many orthogonal and complementary solutions to current ionic and metal-mediated borylation strategies.
The project is divided in three Aims that will target specific challenges relevant to the preparation of borylated materials.
Aim 1. We develop a photochemical approach for the generation of boryl radicals from amine-boranes, a class of stable and abundant materials. These open-shell intermediates will be used to achieve direct and selective C-H borylation of N-heterocycles, one of the most important motifs in pharmaceutical and agrochemical materials. This reactivity will provide a novel approach to functionalise these high-value molecules with a selectivity orthogonal to the one displayed by current metal-catalysed methodologies. We will also benchmark the applicability of the chemistry by applying it to a series of "real-world" substrates of industrial interest that will be provided through a collaboration with Janssen Pharmaceutical. Furthermore, we will evaluate the use of these novel borylated materials in main-stream cross-coupling reactions.
Aim 2. Here we will develop divergent multicomponent reactions based on the intramolecular cyclization of boryl radicals. We will use our knowledge in radical cascades to provide unprecedented borylation-functionalization processes. This chemistry involves the generation of homo-allylic amine-boryl radicals that will undergo an intramolecular cyclization followed by a diversification through a final reaction with a broad range of trapping agents. We will evaluate the full scope and limitation of this reactivity and also apply it to the preparation of blockbuster drug analogues.
Aim 3. This strategy for olefin borylation-functionalization will be expanded by merging it with nickel catalysis. This will enable the development of an innovative dual photoredox-nickel platform for tandem radical borylation and cross-coupling that will generate in a divergent manner complex and densely functionalised materials.
A relevant aspect will be investigating the scalability of the various processes that we will develop. This part of the project will be executed through a collaboration with Janssen Pharmaceutical that will allow to use their state-of-the-art flow-chemistry facilities.
Overall, this project will provide novel reactivity modes for the formation of C-B bonds exploring the reactivity of boryl radicals in photoredox catalysis. Given the importance of borylated building blocks in a synthetic, bio-organic, medicinal and material chemistry, this project will facilitate the discovery, development and manufacture of high-value materials with overall impact to the well-being of UK society.
In general, boron-based functionalities are introduced into organic molecules using two-electron processes like the reaction of Grignards with B-electrophiles or the aromatic C-H borylation using transition metal catalysis.
The overarching aim of this project is to explore a complementary approach where C-B bonds are assembled through the reactivity of B-centred radicals (boryl radicals). The use and application of these reactive intermediates is considerably underdeveloped but can provide many orthogonal and complementary solutions to current ionic and metal-mediated borylation strategies.
The project is divided in three Aims that will target specific challenges relevant to the preparation of borylated materials.
Aim 1. We develop a photochemical approach for the generation of boryl radicals from amine-boranes, a class of stable and abundant materials. These open-shell intermediates will be used to achieve direct and selective C-H borylation of N-heterocycles, one of the most important motifs in pharmaceutical and agrochemical materials. This reactivity will provide a novel approach to functionalise these high-value molecules with a selectivity orthogonal to the one displayed by current metal-catalysed methodologies. We will also benchmark the applicability of the chemistry by applying it to a series of "real-world" substrates of industrial interest that will be provided through a collaboration with Janssen Pharmaceutical. Furthermore, we will evaluate the use of these novel borylated materials in main-stream cross-coupling reactions.
Aim 2. Here we will develop divergent multicomponent reactions based on the intramolecular cyclization of boryl radicals. We will use our knowledge in radical cascades to provide unprecedented borylation-functionalization processes. This chemistry involves the generation of homo-allylic amine-boryl radicals that will undergo an intramolecular cyclization followed by a diversification through a final reaction with a broad range of trapping agents. We will evaluate the full scope and limitation of this reactivity and also apply it to the preparation of blockbuster drug analogues.
Aim 3. This strategy for olefin borylation-functionalization will be expanded by merging it with nickel catalysis. This will enable the development of an innovative dual photoredox-nickel platform for tandem radical borylation and cross-coupling that will generate in a divergent manner complex and densely functionalised materials.
A relevant aspect will be investigating the scalability of the various processes that we will develop. This part of the project will be executed through a collaboration with Janssen Pharmaceutical that will allow to use their state-of-the-art flow-chemistry facilities.
Overall, this project will provide novel reactivity modes for the formation of C-B bonds exploring the reactivity of boryl radicals in photoredox catalysis. Given the importance of borylated building blocks in a synthetic, bio-organic, medicinal and material chemistry, this project will facilitate the discovery, development and manufacture of high-value materials with overall impact to the well-being of UK society.
Related Projects
| Project Reference | Relationship | Related To | Start | End | Award Value |
|---|---|---|---|---|---|
| EP/V015982/1 | 18/07/2021 | 31/12/2023 | £375,981 | ||
| EP/V015982/2 | Transfer | EP/V015982/1 | 01/01/2024 | 17/04/2025 | £79,824 |
| Description | The introduction of boron-containing functionalities into organic molecules is integral since boron allows further derivatization by forming chemical bonds with oxygen, nitrogen, carbon and fluoro. So far, the most commonly used ways to introduce boron into organic molecules require the use of either transition metal catalysis (C-H activation) or highly reactive reagents that require tailored reaction conditions. In this work we aimed to use boron as a radical species. This is a very underdeveloped research area that however can provide strong complementarity to the way we prepare borylated reagents. |
| Exploitation Route | It is too early for us to say but some aspects of the project have been recently discussed with scientists from the pharmaceutical sector (Janssen and AstraZeneca) to evaluate potential collaboration. This means that in the future this project might impact the way industrialists approach the discovery and the development of molecules with high relevance to our society. We are currently exploiting the possibility to activate small organic molecules to introduce isotopes of H like deuterium and tritium as well as isotopes of carbon that can enable biological studies. |
| Sectors | Chemicals Pharmaceuticals and Medical Biotechnology |