Final Report Summary - PHOCATSORS (Photoredox Catalysis for Sustainable Organic Synthesis)
Developing synthetic methodologies that streamline approaches to valuable structural motifs or that enable access to previously challenging bond disconnections are useful tools for industrial and academic chemists. The emergence of visible light-mediated photoredox catalysis within the field of synthetic organic chemistry has facilitated the discovery and invention of numerous unique and valuable transformations. The sustainable nature of these protocols is due to the use of visible light as a driving force, which is non-harmful, obtainable from renewable sources, and does not produce chemical waste. Therefore, we sought to exploit this activation mode in concert with transition-metal catalysis to accomplish new and powerful bond forming reactions.
Over the last half-century, transition metal-mediated cross-coupling reactions have changed the way in which complex organic molecules are synthesized. The predictable and chemoselective nature of these transformations has led to their widespread adoption across a vast array of chemical research areas. However, the construction of sp3−sp3 bonds, a fundamental unit of organic chemistry, in this way has proved challenging but would provide a powerful methodology for constructing carbon-carbon bonds. Moreover, the application of bench-stable and readily available coupling partners would offer further advantages over traditional organometallic nucleophiles.
During the first year of the Fellowship, a new sp3-sp3 coupling methodology utilizing carboxylic acids as coupling partners was developed that merged photoredox catalysis with nickel catalysis. Initial findings demonstrated that a range of electrophiles were suitable reaction partners including allylic carbonates, benzylic chlorides, and unactivated alkyl bromides. These transformations required distinct sets of reaction conditions and the allylation protocol, which gave more promising initial results, was chosen for further optimization. Pleasingly, a wide range of cyclic and acyclic amino acids were suitable coupling partners for this protocol and generated a range of functionalized homoallylic amines. Homoallylic ethers could also be synthesized from commercially available -oxy acids. The presence of radical stabilizing groups was not vital for reactivity and simple substrates such as cyclohexylcarboxylic acid were also viable in this coupling reaction. Interestingly, the introduction of substituents onto the allyl carbonate resulted in reduced reactivity and only 2-substitution was well tolerated.
During the second year of the Fellowship, Tonge et al. published a closely related photoredox-mediated decarboxylative allylation reaction and that encouraged us to focus more towards a general platform for the cross-coupling of carboxylic acids to introduce a wide array of different substituents. This would greatly broaden the scope of products that can be formed using this dual catalytic photoredox-nickel sp3-sp3 coupling procedure. This would ultimately be of greater synthetic value, especially within the field of drug discovery, as there is a demonstrated statistical correlation between clinical success and the molecular complexity of medicinal candidates with respect to the inherent ratio of sp2−sp3 to sp3−sp3 bond content. Following optimization, the reaction was found to be amenable to a wide array of primary and secondary carboxylic acids and does not require the presence of radical stabilizing groups. By selecting the appropriate electrophile the carboxylic acid moiety can be converted, for example, into a benzyl, cyclopropyl, or methyl group in a single step. The breadth of tolerated functional groups, including epoxides and aldehydes, exemplified the benign nature of the reaction conditions. Furthermore, the synthetic utility of this decarboxylative coupling protocol was illustrated by the expedient synthesis of a known pharmaceutical from commercially available starting materials. It is expected that the generality of this methodology and the ready availability of the starting materials used will aid the uptake of sp3−sp3 cross-coupling across several fields of synthetic organic chemistry. Finally, a screen of chiral ligands demonstrated the feasibility for developing an asymmetric sp3-sp3 coupling protocol. An initial hit provided the cross-coupled product in 88% ee albeit in modest yield. Further studies to optimize this reaction as well as explore the substrate scope are ongoing and will be disclosed in due course.
During the incoming phase of the Fellowship, efforts were made to develop a new sp2-sp3 coupling methodology that would synergistically unite gold and photoredox catalysis. In tandem with the development of this reaction, studies were also planned to probe the mechanism of the transformation to inform its optimization. The introduction of a photocatalyst was seen as a green alternative to stoichiometric oxidants that have been traditionally used in gold-catalysed processes. A variety of radical precursors amenable to single-electron reduction were screened but no evidence of the desired product was observed. A range of photocatalysts, solvents, ligands, additives, and reaction conditions were screened but no productive reactivity was observed.
In a separate project the nucleophilic trifluoromethylation of carbonyl compounds with the Ruppert-Prakash reagent (TMSCF3), first published in 1989 by Prakash and Olah, was investigated. Currently, no detailed mechanistic or kinetic studies have been disclosed for this transformation despite its widespread use. Initially, 19F NMR kinetic studies were conducted using an acetophenone as a model system. These experiments illustrated that the rate of this reaction is significantly higher than previously thought. This allowed for a dramatic decrease in catalyst loading with no decline in efficiency. Most commonly, fluoride sources such as TBAF or CsF are used but a range of alternative salts can be utilised. The nature of the promotor can have an impact on the overall rate of the reaction as well as the distribution of products and by-products formed. Variation of the starting materials enabled the reaction order with respect to each component to be established. Kinetic modelling with DynoChem has facilitated the construction of a mechanistic scheme that fits well with the experimental data. The nature of the active nucleophile in trifluoromethylation reactions with TMSCF3 is currently unknown. A combination of NMR kinetics, low temperature studies, DFT calculations, and labelling studies are being pursued to elucidate this important intermediate. Overall, this project has revealed many dormant mechanistic details about nucleophilic trifluoromethylations with TMSCF3. This information will enable future reactions to be run under well informed conditions that minimize by-products and maximize efficiency, which is of great importance in chemical industries. Furthermore, the new knowledge gleaned from this study can be applied to the design of new transformations that have eluded discovery.
Over the last half-century, transition metal-mediated cross-coupling reactions have changed the way in which complex organic molecules are synthesized. The predictable and chemoselective nature of these transformations has led to their widespread adoption across a vast array of chemical research areas. However, the construction of sp3−sp3 bonds, a fundamental unit of organic chemistry, in this way has proved challenging but would provide a powerful methodology for constructing carbon-carbon bonds. Moreover, the application of bench-stable and readily available coupling partners would offer further advantages over traditional organometallic nucleophiles.
During the first year of the Fellowship, a new sp3-sp3 coupling methodology utilizing carboxylic acids as coupling partners was developed that merged photoredox catalysis with nickel catalysis. Initial findings demonstrated that a range of electrophiles were suitable reaction partners including allylic carbonates, benzylic chlorides, and unactivated alkyl bromides. These transformations required distinct sets of reaction conditions and the allylation protocol, which gave more promising initial results, was chosen for further optimization. Pleasingly, a wide range of cyclic and acyclic amino acids were suitable coupling partners for this protocol and generated a range of functionalized homoallylic amines. Homoallylic ethers could also be synthesized from commercially available -oxy acids. The presence of radical stabilizing groups was not vital for reactivity and simple substrates such as cyclohexylcarboxylic acid were also viable in this coupling reaction. Interestingly, the introduction of substituents onto the allyl carbonate resulted in reduced reactivity and only 2-substitution was well tolerated.
During the second year of the Fellowship, Tonge et al. published a closely related photoredox-mediated decarboxylative allylation reaction and that encouraged us to focus more towards a general platform for the cross-coupling of carboxylic acids to introduce a wide array of different substituents. This would greatly broaden the scope of products that can be formed using this dual catalytic photoredox-nickel sp3-sp3 coupling procedure. This would ultimately be of greater synthetic value, especially within the field of drug discovery, as there is a demonstrated statistical correlation between clinical success and the molecular complexity of medicinal candidates with respect to the inherent ratio of sp2−sp3 to sp3−sp3 bond content. Following optimization, the reaction was found to be amenable to a wide array of primary and secondary carboxylic acids and does not require the presence of radical stabilizing groups. By selecting the appropriate electrophile the carboxylic acid moiety can be converted, for example, into a benzyl, cyclopropyl, or methyl group in a single step. The breadth of tolerated functional groups, including epoxides and aldehydes, exemplified the benign nature of the reaction conditions. Furthermore, the synthetic utility of this decarboxylative coupling protocol was illustrated by the expedient synthesis of a known pharmaceutical from commercially available starting materials. It is expected that the generality of this methodology and the ready availability of the starting materials used will aid the uptake of sp3−sp3 cross-coupling across several fields of synthetic organic chemistry. Finally, a screen of chiral ligands demonstrated the feasibility for developing an asymmetric sp3-sp3 coupling protocol. An initial hit provided the cross-coupled product in 88% ee albeit in modest yield. Further studies to optimize this reaction as well as explore the substrate scope are ongoing and will be disclosed in due course.
During the incoming phase of the Fellowship, efforts were made to develop a new sp2-sp3 coupling methodology that would synergistically unite gold and photoredox catalysis. In tandem with the development of this reaction, studies were also planned to probe the mechanism of the transformation to inform its optimization. The introduction of a photocatalyst was seen as a green alternative to stoichiometric oxidants that have been traditionally used in gold-catalysed processes. A variety of radical precursors amenable to single-electron reduction were screened but no evidence of the desired product was observed. A range of photocatalysts, solvents, ligands, additives, and reaction conditions were screened but no productive reactivity was observed.
In a separate project the nucleophilic trifluoromethylation of carbonyl compounds with the Ruppert-Prakash reagent (TMSCF3), first published in 1989 by Prakash and Olah, was investigated. Currently, no detailed mechanistic or kinetic studies have been disclosed for this transformation despite its widespread use. Initially, 19F NMR kinetic studies were conducted using an acetophenone as a model system. These experiments illustrated that the rate of this reaction is significantly higher than previously thought. This allowed for a dramatic decrease in catalyst loading with no decline in efficiency. Most commonly, fluoride sources such as TBAF or CsF are used but a range of alternative salts can be utilised. The nature of the promotor can have an impact on the overall rate of the reaction as well as the distribution of products and by-products formed. Variation of the starting materials enabled the reaction order with respect to each component to be established. Kinetic modelling with DynoChem has facilitated the construction of a mechanistic scheme that fits well with the experimental data. The nature of the active nucleophile in trifluoromethylation reactions with TMSCF3 is currently unknown. A combination of NMR kinetics, low temperature studies, DFT calculations, and labelling studies are being pursued to elucidate this important intermediate. Overall, this project has revealed many dormant mechanistic details about nucleophilic trifluoromethylations with TMSCF3. This information will enable future reactions to be run under well informed conditions that minimize by-products and maximize efficiency, which is of great importance in chemical industries. Furthermore, the new knowledge gleaned from this study can be applied to the design of new transformations that have eluded discovery.