Robust and General Late-Stage Methylation of Aryl Chlorides: Application to Isotopic Labeling of Drug-like Scaffolds.

The preparation of isotopically labeled compounds for drug discovery and development presents a unique challenge. Both stable and radioactive isotopes must be incorporated into complex bioactive molecules as efficiently as possible, using precious, and often expensive, isotopically enriched reagents. Due to the ubiquity and importance of methyl groups in drug molecules, there is a requirement for a general, late-stage methylation that allows for the incorporation of both carbon and hydrogen isotopes. Herein, we report a highly efficient, robust palladium-catalyzed approach, optimized via high-throughput experimentation, for the methylation of aryl chlorides using potassium methyltrifluoroborate. A practically straightforward route to isotopically labeled methylating agents has also been developed, and the methodology applied to isotopologue synthesis, including the installation of isotopic labels in a range of drug-like scaffolds.

Transition-Metal-Free Allylic Borylation of 1,3-Dienes.

This work explains the reactivity of diboron reagents with 1,3-dienes in a transition-metal-free context. The sole addition of Na2CO3 (30 mol %) to bis(pinacolato)diboron in MeOH allows the 1,4-hydroboration of cyclic and noncyclic 1,3-dienes. The electronic influence on the substrate guarantees the conjugated 1,4-hydroboration versus 1,2-diboration. DFT calculations show that the distribution of charge in the allylic anion intermediate governs the selectivity toward 1,4-hydroboration, while the favored trans configuration in diene reagents determines the preference for the E allyl boronate products.

Transition-metal-free synthesis of vicinal triborated compounds and selective functionalisation of the internal C-B bond.

1,2,3-Triborated compounds can be prepared by simple nucleophilic borylation of 1,3-dienes, without the assistance of metal catalysts. Selective functionalisation of the internal C-B bond of the 1,2,3-triborated compounds, through cross-coupling with aryl iodides, highlights the powerful methodology toward polyfunctionalisation.