Periodic Reporting for period 4 - ReverseAndCat (Reversible Creation of Non-Inherent Reactivity Patterns in Catalytic Organic Synthesis)
Berichtszeitraum: 2023-05-01 bis 2024-12-31
Summary of the Context and Objectives of the Project
Chemical catalysis is essential for accelerating reactions, playing a key role in organic synthesis and industrial production of pharmaceuticals, agrochemicals, and materials. However, selectively functionalizing unactivated bonds, such as C-H, C-C, C=C bonds remote from other functional groups, remains a major challenge in catalysis. Achieving this would simplify synthetic routes, reduce costs, and minimize environmental impact by eliminating preactivation steps.
Current catalytic methods are largely limited to inherently reactive bonds or those influenced by directing groups. To address this, the "Reverse&Cat" project explores catalytic reversible reactions to enable new multicatalytic transformations. This strategy integrates a dynamic equilibrium process, mediated by one catalyst, with a functionalization reaction catalyzed by a second.
By leveraging such dynamic processes, the project introduces a novel way to induce non-inherent reactivity, unlocking transformations beyond current methodologies. The findings could enhance synthetic efficiency and sustainability, with broad applications in fine chemical and material production.
Chemical catalysis is essential for accelerating reactions, playing a key role in organic synthesis and industrial production of pharmaceuticals, agrochemicals, and materials. However, selectively functionalizing unactivated bonds, such as C-H, C-C, C=C bonds remote from other functional groups, remains a major challenge in catalysis. Achieving this would simplify synthetic routes, reduce costs, and minimize environmental impact by eliminating preactivation steps.
Current catalytic methods are largely limited to inherently reactive bonds or those influenced by directing groups. To address this, the "Reverse&Cat" project explores catalytic reversible reactions to enable new multicatalytic transformations. This strategy integrates a dynamic equilibrium process, mediated by one catalyst, with a functionalization reaction catalyzed by a second.
By leveraging such dynamic processes, the project introduces a novel way to induce non-inherent reactivity, unlocking transformations beyond current methodologies. The findings could enhance synthetic efficiency and sustainability, with broad applications in fine chemical and material production.
The Reverse&Cat project explores how reversible processes can facilitate challenging or inaccessible transformations, crucial for advancing fine chemical and material production. These processes modify starting materials to enhance reactivity, stabilize products to prevent decomposition, or optimize catalyst performance for sustained activity under milder conditions. Key studies include:
• Relay Catalysis & Dynamic Kinetic Resolution (Angew. Chem. Int. Ed. 2024, 63, e202408418): Developed a strategy enabling regio- and enantioselective β-C(sp3)-H arylation of alcohols. This mild protocol, using readily available reagents, provides high selectivity (>90:10 er) and offers catalyst-controlled diastereoselectivity.
• Dual Rh/Pd Relay Catalysis for β-C(sp3)–H Arylation of Amines (Chem. Sci. 2025, 16, 4167-4174): Introduces a relay catalytic approach using reversible Rh dehydrogenation and Pd C–H functionalization. Unlike existing methods, this strategy enables regioselective β-arylation across diverse amines, opening new possibilities for dual relay catalysis in amine functionalization.
• Multicatalytic One-Pot Synthesis of Secondary Benzylic Alcohols (Org. Lett. 2021, 23, 3502): A one-pot method integrating alkene cross-metathesis, isomerization, and nucleophilic addition yields stereoselective secondary benzylic alcohols (>95:5 er).
• Enantioselective α-Arylation of Primary Alcohols (J. Org. Chem. 2021, 86, 9253): Developed a sequential Ru-catalyzed oxidation and nucleophilic addition, enabling broad functional group tolerance for primary alcohols.
• Multi-Stimuli-Responsive Multicatalytic Network (Angew. Chem. Int. Ed. 2024, 63, e202404687): Inspired by metabolic adaptability, this system employs a multifunctional Pd/Pt catalyst to selectively synthesize distinct products through controlled activation and suppression mechanisms.
• Photoinduced Cu(II)-Mediated Decarboxylative Thianthrenation (Angew. Chem. Int. Ed. 2024, 63, e202410616): Converts (hetero)aryl carboxylic acids into high-value thianthrenium salts, enabling versatile downstream functionalization. The strategy facilitates late-stage modification of pharmaceuticals and isotopic labeling applications.
• Rh(I)-Catalyzed Transfer C–H Borylation of Alkenes (Chem Catal. 2022, 2, 762-778): Provides a practical synthetic tool for alkene borylation, featuring excellent functional group compatibility and bioactive molecule derivatization. Mechanistic studies reveal an unprecedented β-boryl elimination pathway for Rh catalysis.
• DFT Study of Rh(I)-Catalyzed Transfer C–H Borylation (Organometallics 2022, 41, 1649–1658): Computational insights into ligand effects on selectivity and activity, offering design principles for enhanced catalysis.
• Ir-Catalyzed Transfer C–H Borylation of Alkenes (To be reported): A novel boryl-transfer method enabling direct borylation of diverse alkenes, including late-stage functionalization of bioactive compounds. Uniquely, some cases involve double-bond transposition, expanding alkene functionalization strategies.
• Dehomologative C–C Borylation via Rh-Catalyzed Relay Catalysis (To be reported): Introduces a dehomologation strategy converting aldehydes and alcohols into shortened vinyl boronates. This auto-relay catalysis approach establishes the first triple relay catalytic process, offering a valuable framework-editing tool.
• Binuclear Pd(I)−Pd(I) Catalysis for Selective Hydroformylation (J. Am. Chem. Soc. 2020, 142, 18251): Overcomes hydroformylation limitations through a Pd(I)−Pd(I) mechanism with iodide-assisted product release, achieving β-selective carbonylation of alkenes and alkynes.
• Isoselective Hydroformylation of Propylene via Pd/Iodide Catalysis (Angew. Chem. Int. Ed. 2022, 61, e2021164): A patent-pending strategy producing iso-butanal with unprecedented selectivity, demonstrating industrial viability.
• Mechanistic Insights into Halide Effects in Pd Hydrocarbonylations (To be reported): A detailed mechanistic study elucidating halide-mediated control over Pd-catalyzed hydroformylation and alkoxycarbonylation, revealing neutral phosphine-halide-ligated Pd intermediates as key players.
• Regio- & Enantioselective Alkoxycarbonylation of Alkenes (To be reported): Developed a palladium-bromide system using a novel ValleyPhos ligand, achieving highly selective hydrocarbonylation of unactivated olefins to chiral esters (>95:5 er).
Through these studies, Reverse&Cat has expanded the synthetic toolkit, addressing key challenges in catalysis. The project's innovative approaches contribute to fine chemical synthesis and energy-efficient bulk material production, with potential industrial applications pending maturation.
• Relay Catalysis & Dynamic Kinetic Resolution (Angew. Chem. Int. Ed. 2024, 63, e202408418): Developed a strategy enabling regio- and enantioselective β-C(sp3)-H arylation of alcohols. This mild protocol, using readily available reagents, provides high selectivity (>90:10 er) and offers catalyst-controlled diastereoselectivity.
• Dual Rh/Pd Relay Catalysis for β-C(sp3)–H Arylation of Amines (Chem. Sci. 2025, 16, 4167-4174): Introduces a relay catalytic approach using reversible Rh dehydrogenation and Pd C–H functionalization. Unlike existing methods, this strategy enables regioselective β-arylation across diverse amines, opening new possibilities for dual relay catalysis in amine functionalization.
• Multicatalytic One-Pot Synthesis of Secondary Benzylic Alcohols (Org. Lett. 2021, 23, 3502): A one-pot method integrating alkene cross-metathesis, isomerization, and nucleophilic addition yields stereoselective secondary benzylic alcohols (>95:5 er).
• Enantioselective α-Arylation of Primary Alcohols (J. Org. Chem. 2021, 86, 9253): Developed a sequential Ru-catalyzed oxidation and nucleophilic addition, enabling broad functional group tolerance for primary alcohols.
• Multi-Stimuli-Responsive Multicatalytic Network (Angew. Chem. Int. Ed. 2024, 63, e202404687): Inspired by metabolic adaptability, this system employs a multifunctional Pd/Pt catalyst to selectively synthesize distinct products through controlled activation and suppression mechanisms.
• Photoinduced Cu(II)-Mediated Decarboxylative Thianthrenation (Angew. Chem. Int. Ed. 2024, 63, e202410616): Converts (hetero)aryl carboxylic acids into high-value thianthrenium salts, enabling versatile downstream functionalization. The strategy facilitates late-stage modification of pharmaceuticals and isotopic labeling applications.
• Rh(I)-Catalyzed Transfer C–H Borylation of Alkenes (Chem Catal. 2022, 2, 762-778): Provides a practical synthetic tool for alkene borylation, featuring excellent functional group compatibility and bioactive molecule derivatization. Mechanistic studies reveal an unprecedented β-boryl elimination pathway for Rh catalysis.
• DFT Study of Rh(I)-Catalyzed Transfer C–H Borylation (Organometallics 2022, 41, 1649–1658): Computational insights into ligand effects on selectivity and activity, offering design principles for enhanced catalysis.
• Ir-Catalyzed Transfer C–H Borylation of Alkenes (To be reported): A novel boryl-transfer method enabling direct borylation of diverse alkenes, including late-stage functionalization of bioactive compounds. Uniquely, some cases involve double-bond transposition, expanding alkene functionalization strategies.
• Dehomologative C–C Borylation via Rh-Catalyzed Relay Catalysis (To be reported): Introduces a dehomologation strategy converting aldehydes and alcohols into shortened vinyl boronates. This auto-relay catalysis approach establishes the first triple relay catalytic process, offering a valuable framework-editing tool.
• Binuclear Pd(I)−Pd(I) Catalysis for Selective Hydroformylation (J. Am. Chem. Soc. 2020, 142, 18251): Overcomes hydroformylation limitations through a Pd(I)−Pd(I) mechanism with iodide-assisted product release, achieving β-selective carbonylation of alkenes and alkynes.
• Isoselective Hydroformylation of Propylene via Pd/Iodide Catalysis (Angew. Chem. Int. Ed. 2022, 61, e2021164): A patent-pending strategy producing iso-butanal with unprecedented selectivity, demonstrating industrial viability.
• Mechanistic Insights into Halide Effects in Pd Hydrocarbonylations (To be reported): A detailed mechanistic study elucidating halide-mediated control over Pd-catalyzed hydroformylation and alkoxycarbonylation, revealing neutral phosphine-halide-ligated Pd intermediates as key players.
• Regio- & Enantioselective Alkoxycarbonylation of Alkenes (To be reported): Developed a palladium-bromide system using a novel ValleyPhos ligand, achieving highly selective hydrocarbonylation of unactivated olefins to chiral esters (>95:5 er).
Through these studies, Reverse&Cat has expanded the synthetic toolkit, addressing key challenges in catalysis. The project's innovative approaches contribute to fine chemical synthesis and energy-efficient bulk material production, with potential industrial applications pending maturation.
The Reverse&Cat project has advanced beyond the state of the art by developing novel reversible and relay catalytic strategies that unlock previously inaccessible transformations in fine chemical and material production. Key breakthroughs include enantioselective C–H functionalization through dual relay catalysis, metabolism-inspired multi-stimuli-responsive reaction networks, and dehomologative editing of molecular scaffolds. The project has also expanded the scope of transfer C–H borylation and hydrocarbonylation reactions by revealing unprecedented mechanistic insights into ligand and counterion effects. These innovations not only enhance reaction efficiency, selectivity, and sustainability but also open new synthetic pathways for pharmaceuticals, bioactive molecules, and industrially relevant compounds.