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The ability of chemists to harness and control reversible reactions provides a potent tool to synthesis, as illustrated by the impact that the transfer of molecular hydrogen and alkene metathesis have already had. However, the extension of this strategy to other types of either molecule or chemical bonds remains elusive, despite its significant potential to streamline synthesis and chemical processes. Recently, transition-metal catalyzed isofunctional reactions, such as functional group transfer reaction by shuttle catalysis and metathesis, are reinvigorating this approach as a tool for providing more flexible and safer target-oriented synthesis. This thesis describes the development of a number of unique and valuable catalytic transformations involving halogenation and carbonylation, enabled by palladium-catalyzed reversible processes.
First, the development of a catalytic reversible functional group metathesis reaction is demonstrated, which relies on swapping the substituents on two distinct chemical bonds in a rare example of single-bond metathesis (Scheme I, top). A phosphine ligand, Xantphos, acts as a temporary storage unit for the aryl groups, facilitating a rapid equilibration of a mixture of different electrophiles (Scheme I, bottom). This novel strategy using an unusual type of ligand non-innocence enables the use of a single catalytic system to perform two highly challenging processes, namely the conversion of an aroyl chloride into an aryl iodide, and vice versa, without the use of toxic CO gas or pressurized systems, providing a safer and more general tool for the manipulation of two synthetically important classes of electrophiles.
Given the synthetic importance of creating new C–C bonds to rapidly increase molecular complexity, our attempts to manipulate the reversibility of the two promising independent processes, the formation of C(sp2)–I and C(sp2)–COCl bonds, led to the development of diverse carbofunctionalization reactions, merging with a tandem carbometallation process of unsaturated hydrocarbons.
The intermolecular Pd-catalyzed carboiodination reaction of alkynes was realized, which involves the formation of C(sp2)–I via reductive elimination to generate a synthetically versatile class of building blocks (Scheme II). The use of an electron-poor bidentate phosphine ligand was crucial to promoting the addition reaction with high yield and stereoselectivity, featuring unusually broad functional group tolerance, including protic functionalities.
Subsequently, an intermolecular carboformylation reaction of internal alkynes using aroyl chlorides as a source of a carbon electrophile and CO, and a hydrosilane as a hydride source, has been developed, offering a facile route to tetrasubstituted α,β-unsaturated aldehydes (Scheme IIIA). Notably, this is the first example of an intermolecular carboformylation reaction that parallels the industrially relevant hydroformylation reaction. The Pd-catalyzed process is postulated to involve an aromatic acid chloride being formally deconstructed to its aryl, CO, and Cl subcomponents by a Pd catalyst. Thereafter the individual subcomponents are then shuffled and merged with an alkyne and a trapping hydrosilane reagent in a programmed order. Using the molecular shuffling strategy, a series of chemodivergent carbonylation reactions was developed. The replacement of either an acid chloride electrophile or a hydride nucleophile with other types of electrophiles or nucleophiles allowed for CO-free carboacylation (Scheme IIIB), hydroformylation (Scheme IIIC), and hydroacylation (Scheme IIID) processes of alkynes, highlighting the modularity of this chemodivergent process.
Finally, the intermolecular construction of polysubstituted cyclopentenones using palladium catalysis is described. This reaction is achieved via a molecular shuffling process involving an α,β-unsaturated acid chloride, an alkyne and s hydrosilane to create three new C-C bonds (Scheme IV, top). This process also could be extended to several divergent processes (Scheme IV, bottom), reemphasizing the synthetic potential of the shuffling strategy.
