Metal-free couplings for molecules, materials and bioactive targets
Lead Research Organisation:
University of Manchester
Department Name: Chemistry
Abstract
Synthetic chemistry powers scientific advances on many fronts as molecules and materials are vital to the work of millions of scientists around the world: if we can't make the molecular systems we need, we can't advance science and benefits for society will be lost. In particular, the selective formation of carbon-carbon bonds in aromatic and heteroaromatic systems is one of the most important goals in synthesis as aromatic scaffolds form the structural basis of many pharmaceuticals, agrochemicals and materials.
A range of metal-catalyzed cross-coupling processes - now familiar to every practising chemist worldwide - have been developed to address the formation of these particular carbon-carbon bonds and the resultant benefits for society have been remarkable. In recognition, the 2010 Nobel Prize in Chemistry was awarded jointly to Heck, Negishi and Suzuki "for palladium-catalyzed cross couplings in organic synthesis". More recently, methods for the formation of carbon-carbon bonds to sites on an aromatic ring with substitution of a C-H bond, rather than a halide (so called "C-H activation") have been developed. Such processes are highly desirable as the starting materials are often more available, inexpensive and processes usually generate less waste.
The majority of these 'classical' and 'cutting-edge' cross-coupling processes have one thing in common: they are mediated by expensive late transition metals (e.g. ruthenium, rhodium, palladium and platinum). Unfortunately, the supply of these metals is at risk and their use will become unsustainable in the future. An important course, therefore, involves the development of coupling reactions that do not involve the use of a metal. Such an approach has additional benefits, as trace metal contamination in products arising from metal-catalyzed processes is a major problem in industry - particularly the pharmaceutical and organic electronic industries.
During my Fellowship project I will develop metal-free processes that complement existing metal-catalyzed cross-coupling technologies and could eventually lead to their replacement. Readily-accessible aromatic and heteroaromatic systems will be used in metal-free cross-couplings with electron-rich carbon-based partners. Our strategy will use a sulfoxide directing group on the aromatic ring to orchestrate carbon-carbon bond formation at the position next door: sulfur will catch the incoming carbon coupling partner before passing it to the aromatic ring. Thus, an easy carbon-sulfur bond forming event will be used to trigger the formation of a more-challenging carbon-carbon bond, with substitution of a hydrogen on the aromatic ring (so called "C-H substitution"). The aromatic and heteroaromatic sulfoxide starting materials are very easy to make by oxidation of a wide-range of commercially available sulfides. Importantly, the sulfur directing group in our approach can be viewed as a 'safety-catch' directing group: the sulfur in the starting material lies dormant and only upon oxidation to the sulfoxide is the substrate 'switched on' and becomes receptive to metal-free cross-coupling. During the coupling, the sulfur directing group is reduced and the directing effect is 'switched-off'. This 'safety-catch' feature leads to many advantages: for example, premature reaction or over reduction of the substrate is impossible.
The products of the metal-free couplings are of high value in their own right and are also ripe for manipulation. For example, metal-free conversion to industrially-important benzothiophene motifs is possible. To illustrate the great potential of our metal-free approach to cross-coupling we will apply the technology in the synthesis and modification of functional molecules, organic materials and bioactive targets: syntheses that would usually be carried out using supply-risk late transition metals.
A range of metal-catalyzed cross-coupling processes - now familiar to every practising chemist worldwide - have been developed to address the formation of these particular carbon-carbon bonds and the resultant benefits for society have been remarkable. In recognition, the 2010 Nobel Prize in Chemistry was awarded jointly to Heck, Negishi and Suzuki "for palladium-catalyzed cross couplings in organic synthesis". More recently, methods for the formation of carbon-carbon bonds to sites on an aromatic ring with substitution of a C-H bond, rather than a halide (so called "C-H activation") have been developed. Such processes are highly desirable as the starting materials are often more available, inexpensive and processes usually generate less waste.
The majority of these 'classical' and 'cutting-edge' cross-coupling processes have one thing in common: they are mediated by expensive late transition metals (e.g. ruthenium, rhodium, palladium and platinum). Unfortunately, the supply of these metals is at risk and their use will become unsustainable in the future. An important course, therefore, involves the development of coupling reactions that do not involve the use of a metal. Such an approach has additional benefits, as trace metal contamination in products arising from metal-catalyzed processes is a major problem in industry - particularly the pharmaceutical and organic electronic industries.
During my Fellowship project I will develop metal-free processes that complement existing metal-catalyzed cross-coupling technologies and could eventually lead to their replacement. Readily-accessible aromatic and heteroaromatic systems will be used in metal-free cross-couplings with electron-rich carbon-based partners. Our strategy will use a sulfoxide directing group on the aromatic ring to orchestrate carbon-carbon bond formation at the position next door: sulfur will catch the incoming carbon coupling partner before passing it to the aromatic ring. Thus, an easy carbon-sulfur bond forming event will be used to trigger the formation of a more-challenging carbon-carbon bond, with substitution of a hydrogen on the aromatic ring (so called "C-H substitution"). The aromatic and heteroaromatic sulfoxide starting materials are very easy to make by oxidation of a wide-range of commercially available sulfides. Importantly, the sulfur directing group in our approach can be viewed as a 'safety-catch' directing group: the sulfur in the starting material lies dormant and only upon oxidation to the sulfoxide is the substrate 'switched on' and becomes receptive to metal-free cross-coupling. During the coupling, the sulfur directing group is reduced and the directing effect is 'switched-off'. This 'safety-catch' feature leads to many advantages: for example, premature reaction or over reduction of the substrate is impossible.
The products of the metal-free couplings are of high value in their own right and are also ripe for manipulation. For example, metal-free conversion to industrially-important benzothiophene motifs is possible. To illustrate the great potential of our metal-free approach to cross-coupling we will apply the technology in the synthesis and modification of functional molecules, organic materials and bioactive targets: syntheses that would usually be carried out using supply-risk late transition metals.
Planned Impact
The selective formation of C-C bonds in aromatic and heteroaromatic systems is one of the most important goals in organic chemistry as aromatic scaffolds form the structural basis of many pharmaceuticals, agrochemicals and industrial materials. As a result, a range of metal-catalyzed cross-coupling processes - now familiar to every practising chemist worldwide - have been developed and the resultant benefits for society have been remarkable. More recently, methods for the formation of C-C bonds to sites on an aromatic ring with substitution of a C-H bond, rather than a halide/pseudohalide (so called "C-H activation") have been developed. Such processes are highly desirable as the starting materials are often more available, inexpensive and processes may be highly atom-economical, generating less waste.
The majority of 'classical' and 'cutting-edge' cross-couplings have one thing in common: they are mediated by expensive late transition metals (e.g. ruthenium, rhodium, palladium and platinum). Unfortunately, the supply of these metals is at risk and their use will become unsustainable. An important future course, therefore, involves the development of coupling reactions that do not involve the use of a metal. Such an approach has additional benefits, as trace metal contamination in products arising from metal-catalyzed processes is a major problem in industry - particularly the pharmaceutical and organic electronic industries.
The project will deliver innovative, new metal-free carbon-carbon bond-forming processes involving important aromatic and heteroaromatic substrates that exploit an intriguing strategy and proceed by new mechanisms. Some of these couplings are C-H/C-H-type couplings - arguably the most desirable class of cross-coupling process.
In the short term, this project will provide valuable tools for synthetic chemists in their day-to-day work in industrial laboratories and plants. More specific beneficiaries include the pharmaceutical, biotech, biopharmaceutical, agrochemical, organic electronic industries, and custom research organizations. The selective synthetic technology developed during our studies will allow chemists to improve future processes, streamline routes and avoid the metal contamination of products. Our work will therefore improve economic competitiveness and aid wealth creation in the UK. The timescale for impact will be short, with benefits arising 1-2 years after the completion of the project. Our track record in method development leaves us uniquely placed to meet the objectives of the project and to achieve the predicted impact. In the long term, the development of metal-free coupling processes is crucial for the advancement of science long after the supply of late-transition metals is compromised.
As carbon-carbon bond forming methods are indispensible tools for scientists in established (pharmaceutical, agrochemical) and emerging (organic electronics, biotech/biopharmaceutical) industries in the UK (and beyond), our fundamental studies on metal-free couplings are aligned with the needs of UK industry (and academia) and the EPSRC portfolio (Physical Sciences: "Dial-a-molecule" Physical Science Grand Challenge; Chemical Biology and Biological Chemistry; Materials for Energy Applications. Healthcare Technologies: Diagnostics). In particular, my Fellowship will focus on two of the three themes identified in the "Dial-a-molecule" Roadmap: "A Step Change in Molecular Synthesis" and "Catalytic Paradigms for Efficient Synthesis". In doing so, my work will attempt to break down a key barrier to progress identified in the roadmap - "Sustainable synthesis for a sustainable future". The roadmap also highlights that "the long-term security of precious metal supplies creates a further challenge" and that "much catalysis for fine chemical synthesis relies upon precious metals which are nearing depletion". Our plans will directly address this urgent challenge.
The majority of 'classical' and 'cutting-edge' cross-couplings have one thing in common: they are mediated by expensive late transition metals (e.g. ruthenium, rhodium, palladium and platinum). Unfortunately, the supply of these metals is at risk and their use will become unsustainable. An important future course, therefore, involves the development of coupling reactions that do not involve the use of a metal. Such an approach has additional benefits, as trace metal contamination in products arising from metal-catalyzed processes is a major problem in industry - particularly the pharmaceutical and organic electronic industries.
The project will deliver innovative, new metal-free carbon-carbon bond-forming processes involving important aromatic and heteroaromatic substrates that exploit an intriguing strategy and proceed by new mechanisms. Some of these couplings are C-H/C-H-type couplings - arguably the most desirable class of cross-coupling process.
In the short term, this project will provide valuable tools for synthetic chemists in their day-to-day work in industrial laboratories and plants. More specific beneficiaries include the pharmaceutical, biotech, biopharmaceutical, agrochemical, organic electronic industries, and custom research organizations. The selective synthetic technology developed during our studies will allow chemists to improve future processes, streamline routes and avoid the metal contamination of products. Our work will therefore improve economic competitiveness and aid wealth creation in the UK. The timescale for impact will be short, with benefits arising 1-2 years after the completion of the project. Our track record in method development leaves us uniquely placed to meet the objectives of the project and to achieve the predicted impact. In the long term, the development of metal-free coupling processes is crucial for the advancement of science long after the supply of late-transition metals is compromised.
As carbon-carbon bond forming methods are indispensible tools for scientists in established (pharmaceutical, agrochemical) and emerging (organic electronics, biotech/biopharmaceutical) industries in the UK (and beyond), our fundamental studies on metal-free couplings are aligned with the needs of UK industry (and academia) and the EPSRC portfolio (Physical Sciences: "Dial-a-molecule" Physical Science Grand Challenge; Chemical Biology and Biological Chemistry; Materials for Energy Applications. Healthcare Technologies: Diagnostics). In particular, my Fellowship will focus on two of the three themes identified in the "Dial-a-molecule" Roadmap: "A Step Change in Molecular Synthesis" and "Catalytic Paradigms for Efficient Synthesis". In doing so, my work will attempt to break down a key barrier to progress identified in the roadmap - "Sustainable synthesis for a sustainable future". The roadmap also highlights that "the long-term security of precious metal supplies creates a further challenge" and that "much catalysis for fine chemical synthesis relies upon precious metals which are nearing depletion". Our plans will directly address this urgent challenge.
People |
ORCID iD |
David Procter (Principal Investigator / Fellow) |
Publications
Perry G
(2019)
Copper-Catalyzed Functionalization of 1,3-Dienes: Hydrofunctionalization, Borofunctionalization, and Difunctionalization
in ACS Catalysis
Jia T
(2019)
Enantioselective and Regioselective Copper-Catalyzed Borocyanation of 1-Aryl-1,3-Butadienes
in ACS Catalysis
Péter Á
(2020)
Radical C-C Bond Formation using Sulfonium Salts and Light
in Advanced Synthesis & Catalysis
Bisht R
(2023)
Metal-Free Arylation of Benzothiophenes at C4 by Activation as their Benzothiophene S -Oxides
in Angewandte Chemie
He Z
(2019)
The Interrupted Pummerer Reaction in a Sulfoxide-Catalyzed Oxidative Coupling of 2-Naphthols.
in Angewandte Chemie (International ed. in English)
Talbot FJT
(2020)
Copper-Catalyzed Borylative Couplings with C-N Electrophiles.
in Angewandte Chemie (International ed. in English)
He Z
(2018)
Synthesis of C2 Substituted Benzothiophenes via an Interrupted Pummerer/[3,3]-Sigmatropic/1,2-Migration Cascade of Benzothiophene S-Oxides.
in Angewandte Chemie (International ed. in English)
Yan J
(2019)
Metal-Free Synthesis of Benzothiophenes by Twofold C-H Functionalization: Direct Access to Materials-Oriented Heteroaromatics.
in Angewandte Chemie (International ed. in English)
Bisht R
(2023)
Metal-Free Arylation of Benzothiophenes at C4 by Activation as their Benzothiophene S-Oxides.
in Angewandte Chemie (International ed. in English)
Aukland MH
(2018)
An Interrupted Pummerer/Nickel-Catalysed Cross-Coupling Sequence.
in Angewandte Chemie (International ed. in English)
Wang D
(2020)
Trifluoromethyl Sulfoxides: Reagents for Metal-Free C-H Trifluoromethylthiolation.
in Angewandte Chemie (International ed. in English)
Šiauciulis M
(2019)
Transition-Metal-Free Cross-Coupling of Benzothiophenes and Styrenes in a Stereoselective Synthesis of Substituted (E,Z)-1,3-Dienes.
in Angewandte Chemie (International ed. in English)
Manna S
(2020)
Enantio- and Diastereoselective Synthesis of Homopropargyl Amines by Copper-Catalyzed Coupling of Imines, 1,3-Enynes, and Diborons.
in Angewandte Chemie (International ed. in English)
Pulis AP
(2016)
C-H Coupling Reactions Directed by Sulfoxides: Teaching an Old Functional Group New Tricks.
in Angewandte Chemie (International ed. in English)
Huang HM
(2018)
Reductive cyclisations of amidines involving aminal radicals.
in Chemical communications (Cambridge, England)
Fernández-Salas JA
(2016)
Metal-free C-H thioarylation of arenes using sulfoxides: a direct, general diaryl sulfide synthesis.
in Chemical communications (Cambridge, England)
Eberhart AJ
(2016)
Sulfoxide-directed metal-free cross-couplings in the expedient synthesis of benzothiophene-based components of materials.
in Chemical science
Šiauciulis M
(2018)
Dual vicinal functionalisation of heterocycles via an interrupted Pummerer coupling/[3,3]-sigmatropic rearrangement cascade.
in Chemical science
Dherbassy Q
(2020)
Copper-catalyzed functionalization of enynes
in Chemical Science
He Z
(2020)
Sulfoxide-mediated oxidative cross-coupling of phenols.
in Chemical science
Eberhart AJ
(2015)
Sulfoxide-Directed Metal-Free ortho-Propargylation of Aromatics and Heteroaromatics.
in Chemistry (Weinheim an der Bergstrasse, Germany)
Eberhart AJ
(2015)
Sulfoxide-Directed Metal-Free ortho-Propargylation of Aromatics and Heteroaromatics.
in Chemistry (Weinheim an der Bergstrasse, Germany)
Fernández-Salas JA
(2016)
Metal-Free CH-CH-Type Cross-Coupling of Arenes and Alkynes Directed by a Multifunctional Sulfoxide Group.
in Journal of the American Chemical Society
Aukland M
(2020)
Metal-free photoredox-catalysed formal C-H/C-H coupling of arenes enabled by interrupted Pummerer activation
in Nature Catalysis
Dewanji, A
(2023)
A general arene C-H functionalization strategy via electron donor-acceptor complex photoactivation
in Nature Chemistry
Plesniak M
(2018)
Samarium(II) folding cascades involving hydrogen atom transfer for the synthesis of complex polycycles
in Nature Communications
Shrives HJ
(2017)
Regioselective synthesis of C3 alkylated and arylated benzothiophenes.
in Nature communications
Plesniak M
(2017)
Radical cascade reactions triggered by single electron transfer
in Nature Reviews Chemistry
Yang K
(2018)
Transition-Metal-Free Synthesis of C3-Arylated Benzofurans from Benzothiophenes and Phenols
in Organic Letters
He Z
(2019)
Pummerer chemistry of benzothiophene S -oxides: Metal-free alkylation and arylation of benzothiophenes
in Phosphorus, Sulfur, and Silicon and the Related Elements
He Z
(2020)
Para-coupling of phenols with C2/C3-substituted benzothiophene S-oxides
in Tetrahedron
Description | We have developed novel metal-free cross-coupling technology and have applied the technology for the synthesis and late-stage modification of bioactive small molecules and materials. |
Exploitation Route | We hope that our technology will be adopted by industry and by other academic teams. |
Sectors | Agriculture, Food and Drink,Chemicals,Electronics,Healthcare |
Description | - New reagents were developed that have now been commercialised |
First Year Of Impact | 2021 |
Sector | Chemicals,Pharmaceuticals and Medical Biotechnology |
Impact Types | Economic |
Description | AZ Case award |
Amount | £28,000 (GBP) |
Organisation | AstraZeneca |
Sector | Private |
Country | United Kingdom |
Start | 10/2015 |
End | 03/2018 |
Description | Lilly UK - CASE award |
Amount | £34,000 (GBP) |
Organisation | Eli Lilly & Company Ltd |
Sector | Private |
Country | United Kingdom |
Start | 10/2016 |
End | 10/2020 |
Description | Sulfoxides as substrate activators: New cross-couplings for making materials and medicines |
Amount | £730,401 (GBP) |
Funding ID | EP/T013419/1 |
Organisation | Engineering and Physical Sciences Research Council (EPSRC) |
Sector | Public |
Country | United Kingdom |
Start | 08/2020 |
End | 02/2024 |