Organobismuth Redox Manifolds: Versatile Tools for Synthesis

Bismuth’s ability to manoeuvre between oxidation states supports several distinct reaction manifolds. Recent advances in the design, synthesis and application of organobismuth reagents and catalysts illustrate the potential of these redox manifolds as complementary tools to conventional transition metal-based synthesis strategies

Umpolung Synthesis of Pyridyl Ethers by Bi(V)‐Mediated O‑Arylation of Pyridones

We report that O-selective arylation of 2- and 4-pyridones with arylboronic acids is affected by a modular, bismacycle-based system. The utility of this umpolung approach to pyridyl ethers, which is complementary to conventional methods based on S N Ar or cross-coupling, is demonstrated through the concise synthesis of Ki6783 and picolinafen, and the formal synthesis of cabozantib and golvatinib. Computational investigations reveal that arylation proceeds in a concerted fashion via a 5-membered transition state. The kinetically-controlled regioselectivity for O-arylation – which is reversed relative to previous Bi(V)-mediated pyridone arylations – is attributed primarily to the geometric constraints imposed by the bismacyclic scaffold

Bismuth-Mediated Arylation of Weak Nucleophiles

Building upon recent advances in bismuth-mediated arylations which have seen the development of mild transmetallation procedures and utilisation of bismacycle scaffolds, several methodologies for the bismuth-mediated arylation of weak nucleophiles have been established. The development and scope of a procedure for the bismuth-mediated ⍺-arylation of cyclic 1,3-diones with sterically demanding boronic acids is described in Chapter 2. The one-pot process utilises a bismacycle precursor and, through a two-step process involving transmetallation and oxidative arylation, provides direct access to ⍺-arylated cyclic 1,3-diones. Identification and interrogation of reactive Bi(V) intermediates was instrumental to the optimisation process, with Bi(V) intermediates found to influence both the steric tolerance and the selectivity of the reaction. The mild nature of the developed system is demonstrated through a broad substrate scope and, in combination with a robustness screen, highlights the compatibility of the procedure with a diverse array of functionality including halides, alkenes, carboxylic acids, esters and aldehydes. Extension of the protocol towards the arylation of fluoroalkyl 1,3-diones is presented in Section 2.5. The system incorporates the oxidative arylation step within a one-pot procedure, which efficiently converts the ⍺-arylated diones into fluoroalkyl pyrazoles via condensation with hydrazine reagents. Chapter 3 builds on the success of the bismacycle methodology, with the development and scope of a protocol for the bismuth-mediated O-arylation of 2- and 4-pyridones described. The procedure demonstrates complete O-selectivity, providing access to phenoxypyridines with a range of sterically demanding and synthetically useful functionality tolerated in the mild two step, transmetallation and oxidative arylation process. A series of substituted bismacycles were synthesised and assessed in the arylation reaction, allowing the effect of modifying the electronic and steric properties of the bismacycle to be studied. The origin of the O-selectivity observed in the procedure, which stands in contrast to previous reports, was investigated experimentally and computationally. DFT calculations highlight the influential role of the geometry and hydrogen bonding interactions of the bismacycle scaffold in the regioselectivity of the reaction

Bismuth-Mediated Arylation of Weak Nucleophiles

Building upon recent advances in bismuth-mediated arylations which have seen the development of mild transmetallation procedures and utilisation of bismacycle scaffolds, several methodologies for the bismuth-mediated arylation of weak nucleophiles have been established. The development and scope of a procedure for the bismuth-mediated ⍺-arylation of cyclic 1,3-diones with sterically demanding boronic acids is described in Chapter 2. The one-pot process utilises a bismacycle precursor and, through a two-step process involving transmetallation and oxidative arylation, provides direct access to ⍺-arylated cyclic 1,3-diones. Identification and interrogation of reactive Bi(V) intermediates was instrumental to the optimisation process, with Bi(V) intermediates found to influence both the steric tolerance and the selectivity of the reaction. The mild nature of the developed system is demonstrated through a broad substrate scope and, in combination with a robustness screen, highlights the compatibility of the procedure with a diverse array of functionality including halides, alkenes, carboxylic acids, esters and aldehydes. Extension of the protocol towards the arylation of fluoroalkyl 1,3-diones is presented in Section 2.5. The system incorporates the oxidative arylation step within a one-pot procedure, which efficiently converts the ⍺-arylated diones into fluoroalkyl pyrazoles via condensation with hydrazine reagents. Chapter 3 builds on the success of the bismacycle methodology, with the development and scope of a protocol for the bismuth-mediated O-arylation of 2- and 4-pyridones described. The procedure demonstrates complete O-selectivity, providing access to phenoxypyridines with a range of sterically demanding and synthetically useful functionality tolerated in the mild two step, transmetallation and oxidative arylation process. A series of substituted bismacycles were synthesised and assessed in the arylation reaction, allowing the effect of modifying the electronic and steric properties of the bismacycle to be studied. The origin of the O-selectivity observed in the procedure, which stands in contrast to previous reports, was investigated experimentally and computationally. DFT calculations highlight the influential role of the geometry and hydrogen bonding interactions of the bismacycle scaffold in the regioselectivity of the reaction

meta-Selective C–H arylation of phenols via regiodiversion of electrophilic aromatic substitution

Electrophilic aromatic substitution is among the most widely used mechanistic manifolds in organic chemistry. Access to certain substitution patterns is, however, precluded by intrinsic and immutable substituent effects that ultimately restrict the diversity of the benzenoid chemical space. Here we demonstrate that the established regioselectivity of electrophilic aromatic substitution can be overcome simply by diverting the key σ-complex intermediate towards otherwise inaccessible substitution products. This ‘regiodiversion’ strategy is realized through the development of a general and concise method for the meta-selective C–H arylation of sterically congested phenols. Consisting of a Bi(V)-mediated electrophilic arylation and a subsequent aryl migration/rearomatization, our process is orthogonal to conventional C–H activation and cross-coupling approaches, and does not require prefunctionalization of the substrate. Mechanistically informed applications in synthesis showcase its utility as a versatile and enabling route to highly functionalized, contiguously substituted aromatic building blocks that defy synthesis via existing methods

Bismuth-Mediated α-Arylation of Acidic Diketones with ortho-Substituted Boronic Acids

The α-arylation of cyclic and fluoroalkyl 1,3-diketones is made challenging by the highly stabilized nature of the corresponding enolates, and is especially difficult for sterically demanding aryl partners. As a general solution to this problem, we report the Bi-mediated oxidative coupling of acidic diones and ortho-substituted arylboronic acids. Starting from a bench-stable bismacycle precursor, a sequence of B-to-Bi transmetallation, oxidation and C−C bond formation furnishes the arylated diones. Development of methodology that tolerates both sensitive functionality and steric demand is supported by interrogation of key reactive intermediates. Application of our strategy to cyclic diones enables the concise synthesis of important agrochemical intermediates which were previously prepared using toxic Pb reagents. This methodology also enables the first ever arylation of fluoroalkyl diones which, upon condensation with hydrazine, provides direct access to valuable fluoroalkyl pyrazoles

Diazophosphonates: Effective Surrogates for Diazoalkanes in Pyrazole Synthesis

Diazophosphonates, readily prepared from -ketophosphonates by oxidation of the corresponding hydrazones in batch or in flow, are useful partners in 1,3-dipolar cycloaddition reactions to alkynes to give N-H pyrazoles, including the first intramolecular examples of such a process. The phosphoryl group imbues a number of desirable properties in the diazo 1,3-dipole. The electron-withdrawing nature of the phosphoryl stabilizes the diazo compound making it easier to handle, whilst the ability of the phosphoryl group to migrate readily in a [1,5]-sigmatropic rearrangement enables its transfer from C to N to aromatize the initial cycloadduct, and hence its facile removal from the final pyrazole product. Overall, the diazophosphonate acts as a surrogate for the much less stable diazoalkane in cycloadditions, with the phosphoryl group playing a vital, but traceless, role. The cycloaddition proceeds more readily with alkynes bearing electron-withdrawing groups, and is regiospecific with unsymmetrical alkynes. The potential for use of diazophosphonates in bioorthogonal cycloadditions is demonstrated by their facile addition to strained alkynes