Periodic Reporting for period 4 - FarCatCH (Innovative Strategies for Unprecedented Remote C-H bond Functionalization by Catalysis)
Reporting period: 2022-07-01 to 2023-12-31
Over the last years, the landscape of the organic chemistry has been reshaped with impressive advances made in the transition metal-catalyzed carbon-hydrogen (C-H) bond functionalization field. Indeed, the functionalization of building blocks that do not display a reactive functional group but only a simple C-H bond is attractive as it avoids time-consuming and expensive prefunctionalization steps and limits the generation of waste. However, as energies required to break C-H bonds are similar, the differentiation between two C-H bonds and the selective functionalization of only one of them remain a key challenge. Therefore, the available approaches are still unsatisfactory due to important limitations: low reactivity, limited scopes and selectivity issues.
In this proposal, a general approach to functionalize a CH bond located at a Far position (from a functional group) by Catalysis (FarCatCH) will be implemented with a special focus on underexplored transformations, affording important sulfur-and fluorine-containing compounds. Herein, I will develop new synthetic approaches for the remote functionalization of molecules based on i) a substrate-selectivity control and ii) the design of new catalysts using supramolecular tools. I will then iii) address a longstanding reactivity issue in organic synthesis: the trifluoromethylation of aliphatic compounds and apply the supramolecular catalysts for a remote enantioselective transformation.
Designing a full set of tools as Swiss army knife for the selective functionalization at unconventional positions inaccessible so far, can considerably change the way organic molecules are made. These original technologies will offer new synthetic routes to access original sulfur- and fluorine-containing molecules, compounds of interest in drugs discovery, material sciences, pharmaceutical and agrochemical industry.
In this proposal, a general approach to functionalize a CH bond located at a Far position (from a functional group) by Catalysis (FarCatCH) will be implemented with a special focus on underexplored transformations, affording important sulfur-and fluorine-containing compounds. Herein, I will develop new synthetic approaches for the remote functionalization of molecules based on i) a substrate-selectivity control and ii) the design of new catalysts using supramolecular tools. I will then iii) address a longstanding reactivity issue in organic synthesis: the trifluoromethylation of aliphatic compounds and apply the supramolecular catalysts for a remote enantioselective transformation.
Designing a full set of tools as Swiss army knife for the selective functionalization at unconventional positions inaccessible so far, can considerably change the way organic molecules are made. These original technologies will offer new synthetic routes to access original sulfur- and fluorine-containing molecules, compounds of interest in drugs discovery, material sciences, pharmaceutical and agrochemical industry.
The FarCatCH project is organized in three work packages. Significant advances were made regarding the substrate-selectivity control (WP1), the design of new catalysts using supramolecular tools (WP2) and access to original fluorinated molecules (WP3). In general, the project followed the main lines of what was initially planned in the proposal. As part of the progress we made, the design of efficient synthetic routes towards various classes of ligands was set up. Thus, a small library of ligands has been synthesized. Besides, innovative strategies for the remote functionalization of aromatic and aliphatic derivatives were successfully developed.
As a recognition of the PI’s expertise in the C-H bond activation research field, the PI was involved in the writing of a review providing an overview on directing groups in transition metal catalyzed C-H functionalization reactions (Chem. Soc. Rev. 2018, 47, 6603) and three book chapters. Moreover, the development of an original method to synthesize sulfur-containing compounds of interest by C-H bond activation as a modern tool was achieved (J. Org. Chem. 2019, 84, 13194). Pleasingly, the first remote trifluoromethylthiolation reaction of non-activated aliphatic alcohol derivatives under visible light was developed and these preliminary results paved the way for further developments in the quest of synthetic tools approaches for the remote functionalization of molecules (Adv. Synth. Catal. 2022, 364, 1498 & Tetrahedron 2020, 76, 131153, Invited contribution for the special issue for Nuno Maulide). Besides, the design of new reagents to achieve original sulfur-and fluorine-containing compounds was investigated. For a selection of key publications, see: Chem. Commun. 2019, 55, 8784, Adv. Synth. Catal. 2020, 362, 760, Chem. Commun. 2021, 57, 12337. In line with my interests in organofluorine chemistry and especially the design of original reagents to promote unprecedented transformations, closely related to the ERC project, the PI wrote two reviews. These latter highlighted the recent advances made towards a promising fluorinated moiety and summarized the newly- designed reagents and their applications for the synthesis of fluorinated molecules (Chem. Soc. Rev. 2021, 50, 8178., Angew. Chem. Int. Ed. 2021,60, 12170, Front. Chem. 2019, 7, 111) as well as more specifically copper-based fluorinated reagents for the construction of CF2R-containing molecules (Beilstein J.Org. Chem. 2020, 16, 1051-1065). In addition, the PI was invited to write a book chapter dedicated to “Extension to the SCF2H, SCH2F, and SCF2R motifs” in a book entitled “Emerging Fluorinated Motifs: Synthesis, Properties and Applications, 2 Volumes” in agreement with the PI's expertise.
Several conferences in research institutes in France and in the world (Europe, China, India) were given to disseminate the science the PI’s group is developing and as an ERC laureate. Plenary lectures and keynotes were given as an invited speaker in national (eg. RCOM10, Progress in Organofluorine Chemistry, SECO55…) and international conferences (ICOC2018, 22th International Symposium on Fluorine Chemistry, 21st European Symposium on Organic Chemistry, OMCOS21, EFMC, EuCOMC25, 26th Winter Fluorine Conference, ESFC 2022, ISHC2022, and to virtual lectures (OCF virtual symposium 2022, virtual ISCHA 2020 and 3rd EurJOc Virtual symposium), amongst others (For more details, please see: http://www.bessetgroup.cnrs.fr/).
As a recognition of the PI’s expertise in the C-H bond activation research field, the PI was involved in the writing of a review providing an overview on directing groups in transition metal catalyzed C-H functionalization reactions (Chem. Soc. Rev. 2018, 47, 6603) and three book chapters. Moreover, the development of an original method to synthesize sulfur-containing compounds of interest by C-H bond activation as a modern tool was achieved (J. Org. Chem. 2019, 84, 13194). Pleasingly, the first remote trifluoromethylthiolation reaction of non-activated aliphatic alcohol derivatives under visible light was developed and these preliminary results paved the way for further developments in the quest of synthetic tools approaches for the remote functionalization of molecules (Adv. Synth. Catal. 2022, 364, 1498 & Tetrahedron 2020, 76, 131153, Invited contribution for the special issue for Nuno Maulide). Besides, the design of new reagents to achieve original sulfur-and fluorine-containing compounds was investigated. For a selection of key publications, see: Chem. Commun. 2019, 55, 8784, Adv. Synth. Catal. 2020, 362, 760, Chem. Commun. 2021, 57, 12337. In line with my interests in organofluorine chemistry and especially the design of original reagents to promote unprecedented transformations, closely related to the ERC project, the PI wrote two reviews. These latter highlighted the recent advances made towards a promising fluorinated moiety and summarized the newly- designed reagents and their applications for the synthesis of fluorinated molecules (Chem. Soc. Rev. 2021, 50, 8178., Angew. Chem. Int. Ed. 2021,60, 12170, Front. Chem. 2019, 7, 111) as well as more specifically copper-based fluorinated reagents for the construction of CF2R-containing molecules (Beilstein J.Org. Chem. 2020, 16, 1051-1065). In addition, the PI was invited to write a book chapter dedicated to “Extension to the SCF2H, SCH2F, and SCF2R motifs” in a book entitled “Emerging Fluorinated Motifs: Synthesis, Properties and Applications, 2 Volumes” in agreement with the PI's expertise.
Several conferences in research institutes in France and in the world (Europe, China, India) were given to disseminate the science the PI’s group is developing and as an ERC laureate. Plenary lectures and keynotes were given as an invited speaker in national (eg. RCOM10, Progress in Organofluorine Chemistry, SECO55…) and international conferences (ICOC2018, 22th International Symposium on Fluorine Chemistry, 21st European Symposium on Organic Chemistry, OMCOS21, EFMC, EuCOMC25, 26th Winter Fluorine Conference, ESFC 2022, ISHC2022, and to virtual lectures (OCF virtual symposium 2022, virtual ISCHA 2020 and 3rd EurJOc Virtual symposium), amongst others (For more details, please see: http://www.bessetgroup.cnrs.fr/).
The work achieved during this project provides the chance to fulfill most of the original goals of the FarCatCH project. Beyond the initial expected results, we have also developed innovative and sustainable synthetic tools for the remote functionalization of derivatives. We believe that the FarCatCH project will provide a general manifold to access a wide range of original sulfur- and fluorine-containing molecules, particularly interesting for pharmaceutical and agrochemical industry and material sciences. These tools are of interest for the late-stage diversification of complex molecules in the quest for new leads for drugs discovery.