Regime Switch in the Dual-Catalyzed Coupling of Alkyl Silicates with Aryl Bromides.

Metallaphotoredox catalyzed cross-coupling of an arylbromide (Ar-Br) with an alkyl bis(catecholato)silicate (R-Si⊖ ) has been analyzed in depth using a continuum of analytical techniques (EPR, fluorine NMR, electrochemistry, photophysics) and modeling (micro-kinetics and DFT calculations). These studies converged on the impact of four control parameters consisting in the initial concentrations of the iridium photocatalyst ([Ir]0 ), nickel precatalyst ([Ni]0 ) and silicate ([R-Si⊖ ]0 ) as well as light intensity I0 for an efficient reaction between Ar-Br and R-Si⊖ . More precisely, two regimes were found to be possibly at play. The first one relies on an equimolar consumption of Ar-Br with R-Si⊖ smoothly leading to Ar-R, with no side-product from R-Si⊖ and a second one in which R-Si⊖ is simultaneously coupled to Ar-Br and degraded to R-H. This integrative approach could serve as a case study for the investigation of other metallaphotoredox catalysis manifolds of synthetic significance.

Phenyl Silicates with Substituted Catecholate Ligands: Synthesis, Structural Studies and Reactivity.

While the generation of aryl radicals by photoredox catalysis under reductive conditions is well documented, it has remained challenging under an oxidative pathway. Because of the easy photo-oxidation of alkyl bis-catecholato silicates, a general study of phenyl silicates bearing substituted catecholate ligands has been achieved. The newly synthesized phenyl silicates have been fully characterized, and their reactivity has been explored. It was found that, thanks to the substitution of the catecholate moiety, notably with the 4-cyanocatecholato ligand, the phenyl radical could be generated and trapped. Computational studies provided a rationale for these findings.

Carbonylation of Alkyl Radicals Derived from Organosilicates through Visible-Light Photoredox Catalysis.

Primary, secondary, and tertiary alkyl radicals formed by the photocatalyzed oxidation of organosilicates underwent efficient carbonylation with carbon monoxide (CO) to give a variety of unsymmetrical ketones. This study introduces the possibility of radical carbonylation under a photooxidative regime.

Easy-to-Implement Hydrogen Isotope Exchange for the Labeling of N-Heterocycles, Alkylkamines, Benzylic Scaffolds, and Pharmaceuticals.

Facilitating access to deuterated and tritiated complex molecules is of paramount importance due to the fundamental role of isotopically labeled compounds in drug discovery and development. Deuterated analogues of drugs are extensively used as internal standards for quantification purposes or as active pharmaceutical ingredients, whereas tritiated drugs are essential for preclinical ADME studies. In this report, we describe the labeling of prevalent substructures in FDA-approved drugs such as azines, indoles, alkylamine moieties, or benzylic carbons by the in situ generation of Rh nanoparticles able to catalyze both C(sp2)-H and C(sp3)-H activation processes. In this easy-to-implement labeling process, Rh nanocatalysts are formed by decomposition of a commercially available rhodium dimer under a deuterium or tritium gas atmosphere (1 bar or less), using the substrate itself as a surface ligand to control the aggregation state of the resulting metallic clusters. It is noteworthy that the size of the nanoparticles observed is surprisingly independent of the substrate used and is homogeneous, as evidenced by transmission electron microscopy experiments. This method has been successfully applied to the one-step synthesis of (1) deuterated pharmaceuticals usable as internal standards for MS quantification and (2) tritiated drug analogues with very high molar activities (up to 113 Ci/mmol).

Identification of a Series of N-Methylpyridine-2-carboxamides as Potent and Selective Inhibitors of the Second Bromodomain (BD2) of the Bromo and Extra Terminal Domain (BET) Proteins.

Domain-specific BET bromodomain ligands represent an attractive target for drug discovery with the potential to unlock the therapeutic benefits of antagonizing these proteins without eliciting the toxicological aspects seen with pan-BET inhibitors. While we have reported several distinct classes of BD2 selective compounds, namely, GSK620, GSK549, and GSK046, only GSK046 shows high aqueous solubility. Herein, we describe the lead optimization of a further class of highly soluble compounds based upon a picolinamide chemotype. Focusing on achieving >1000-fold selectivity for BD2 over BD1 ,while retaining favorable physical chemical properties, compound 36 was identified as being 2000-fold selective for BD2 over BD1 (Brd4 data) with >1 mg/mL solubility in FaSSIF media. 36 represents a valuable new in vivo ready molecule for the exploration of the BD2 phenotype.