Exploiting Carbonyl Groups to Control Intermolecular Rhodium-Catalyzed Alkene and Alkyne Hydroacylation

Readily available β-carbonyl-substituted aldehydes are shown to be exceptional substrates for Rh-catalyzed intermolecular alkene and alkyne hydroacylation reactions. By using cationic rhodium catalysts incorporating bisphosphine ligands, efficient and selective reactions are achieved for β-amido, β-ester, and β-keto aldehyde substrates, providing a range of synthetically useful 1,3-dicarbonyl products in excellent yields. A correspondingly broad selection of alkenes and alkynes can be employed. For alkyne substrates, the use of a catalyst incorporating the Ampaphos ligand triggers a regioselectivity switch, allowing both linear and branched isomers to be prepared with high selectivity in an efficient manner. Structural data, confirming aldehyde chelation, and a proposed mechanism are provided

Mechanistic studies of rhodium-catalysed intermolecular hydroacylation

Chapter 1 â Introduction: The concept of rhodium-catalysed intermolecular hydroacylation is introduced. The research that has led to significant improvements in substrate scope and catalytic activity are described, with the reactions being classified into three sub-groups: aldehyde-tethered hydroacylation, alkene-tethered hydroacylation and non-tethered hydroacylation. The mechanistic studies that have facilitated these developments are then detailed. Chapter 2 â Mechanistic Studies of β-Amido Aldehyde Hydroacylation: One of the recent developments in aldehyde-tethered hydroacylation has been the use of β-amido aldehyde substrates. This chapter describes the mechanistic studies of the reaction of a β-amido aldehyde substrate with 1-octyne, catalysed by the Rh(I)-complex [Rh(cis-κ2-P,P-DPEPhos)(acetone)2][BArF4]. Chapter 3 â Cyclotrimerisation and Optimisation of Hydroacylation: In chapter 2, cyclotrimerisation of 1-ocytne was discovered to be a competitive side-reaction with hydroacylation under certain conditions. The mechanism of the cyclotrimerisation reaction is explored with the pre-catalyst [Rh(cis-κ2-P,P-DPEPhos)(acetone)2][BArF4], and the point at which the reactions become competitive is discovered. This understanding is then used to optimize the catalyst loading, reagent stoichiometry, reaction concentration and reaction temperature, leading to the realisation of an exceptionally efficient, and selective, gram-scale hydroacylation process. Chapter 4 â Non-tethered Aldehyde Hydroacylation of Acrylates: The discovery of a non-tethered aldehyde Tishchenko reaction catalysed by [Rh(Cy2PCH2PCy2)(η6-fluoroarene)][AlOF4] complexes, in weakly coordinating fluoroarene solvents is described. The subsequent discovery and optimization of a hydroacylation reaction of non-tethered aldehydes with acrylates, catalysed by a {Rh(DPEPhos)}+ catalyst system in 1,2-difluorobenzene is detailed.</p

Mechanistic studies of rhodium-catalysed intermolecular hydroacylation

Chapter 1 – Introduction: The concept of rhodium-catalysed intermolecular hydroacylation is introduced. The research that has led to significant improvements in substrate scope and catalytic activity are described, with the reactions being classified into three sub-groups: aldehyde-tethered hydroacylation, alkene-tethered hydroacylation and non-tethered hydroacylation. The mechanistic studies that have facilitated these developments are then detailed. Chapter 2 – Mechanistic Studies of β-Amido Aldehyde Hydroacylation: One of the recent developments in aldehyde-tethered hydroacylation has been the use of β-amido aldehyde substrates. This chapter describes the mechanistic studies of the reaction of a β-amido aldehyde substrate with 1-octyne, catalysed by the Rh(I)-complex [Rh(cis-κ2-P,P-DPEPhos)(acetone)2][BArF4]. Chapter 3 – Cyclotrimerisation and Optimisation of Hydroacylation: In chapter 2, cyclotrimerisation of 1-ocytne was discovered to be a competitive side-reaction with hydroacylation under certain conditions. The mechanism of the cyclotrimerisation reaction is explored with the pre-catalyst [Rh(cis-κ2-P,P-DPEPhos)(acetone)2][BArF4], and the point at which the reactions become competitive is discovered. This understanding is then used to optimize the catalyst loading, reagent stoichiometry, reaction concentration and reaction temperature, leading to the realisation of an exceptionally efficient, and selective, gram-scale hydroacylation process. Chapter 4 – Non-tethered Aldehyde Hydroacylation of Acrylates: The discovery of a non-tethered aldehyde Tishchenko reaction catalysed by [Rh(Cy2PCH2PCy2)(η6-fluoroarene)][AlOF4] complexes, in weakly coordinating fluoroarene solvents is described. The subsequent discovery and optimization of a hydroacylation reaction of non-tethered aldehydes with acrylates, catalysed by a {Rh(DPEPhos)}+ catalyst system in 1,2-difluorobenzene is detailed.</p

Rh(DPEPhos)-Catalyzed Alkyne Hydroacylation Using β‑Carbonyl-Substituted Aldehydes: Mechanistic Insight Leads to Low Catalyst Loadings that Enables Selective Catalysis on Gram-Scale

The detailed mechanism of the hydroacylation of β-amido-aldehyde, 2,2-dimethyl-3-morpholino-3-oxopropanal, with 1-octyne using [Rh­(<i>cis</i>-κ²-_P,P-DPEPhos)­(acetone)₂]­[BAr^F₄]-based catalysts, is described [Ar^F = (CF₃)₂C₆H₃]. A rich mechanistic landscape of competing and interconnected hydroacylation and cyclotrimerization processes is revealed. An acyl-hydride complex, arising from oxidative addition of aldehyde, is the persistent resting state during hydroacylation, and quaternary substitution at the β-amido-aldehyde strongly disfavors decarbonylation. Initial rate, KIE, and labeling studies suggest that the migratory insertion is turnover-limiting as well as selectivity determining for linear/branched products. When the concentration of free aldehyde approaches zero at the later stages of catalysis alkyne cyclotrimerization becomes competitive, to form trisubstituted hexylarenes. At this point, the remaining acyl-hydride turns over in hydroacylation and the free alkyne is now effectively in excess, and the resting state moves to a metallacyclopentadiene and eventually to a dormant α-pyran-bound catalyst complex. Cyclotrimerization thus only becomes competitive when there is no aldehyde present in solution, and as aldehyde binds so strongly to form acyl-hydride when this happens will directly correlate to catalyst loading: with low loadings allowing for free aldehyde to be present for longer, and thus higher selectivites to be obtained. Reducing the catalyst loading from 20 mol % to 0.5 mol % thus leads to a selectivity increase from 96% to ∼100%. An optimized hydroacylation reaction is described that delivers gram scale of product, at essentially quantitative levels, using no excess of either reagent, at very low catalyst loadings, using minimal solvent, with virtually no workup