The α-arylation of cyclic and fluoroalkyl 1,3diketones 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 Bimediated oxidative coupling of acidic diones and orthosubstituted arylboronic acids. Starting from a benchstable bismacycle precursor, a sequence of B-to-Bi transmetallation, oxidation and CÀ 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.

Electrophilic aromatic substitution (EAS) 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 benzenoid chemical space. Here we demonstrate that the established regioselectivity of EAS can be overcome simply by diverting the key σ-complex intermediate towards otherwise

An improved process to an aldehyde en route to an LSD1 inhibitor was developed using an aerobic oxidation with a CuI and TEMPO (2,2,6,6-tetramethylpiperdine 1-oxyl) catalyst system. In this report, kinetic information is utilized to understand the generation a of number of key byproducts that affect catalyst performance and aldehyde yield. Insight into factors affecting the formation of these byproducts is presented. This Cu I /TEMPO catalyst facilitates rapid conversion of the starting aliphatic alcohol in 1−2 h with apparent zero-order kinetics unprecedented for this substrate class with this catalyst system. Process optimization of catalyst components and reaction solvent led to the successful 400 g scale-up of this oxidation with bubbling air in a batch reactor.

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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 SNAr or crosscoupling, 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 kineticallycontrolled regioselectivity for O-arylationwhich is reversed relative to previous Bi(V)-mediated pyridone arylationsis attributed primarily to the geometric constraints imposed by the bismacyclic scaffold.