A General Strategy for Organocatalytic Activation of C–H Bonds via Photoredox Catalysis: Direct Arylation of Benzylic Ethers

Direct C–H functionalization and arylation of benzyl ethers has been accomplished via photoredox organocatalysis. The productive merger of a thiol catalyst and a commercially available iridium photoredox catalyst in the presence of household light directly affords benzylic arylation products in good to excellent yield. The utility of this methodology is further demonstrated in direct arylation of 2,5-dihydrofuran to form a single regioisomer

Protocol for the Direct Conversion of Lactones to Lactams Mediated by 1,5,7-Triazabicyclo[4.4.0]dec-5-ene: Synthesis of Pyridopyrazine-1,6-diones

We present an operationally simple lactone-to-lactam transformation utilizing diverse amine nucleophiles. The key steps of amidation, alcohol activation, and cyclization are all mediated by one reagent (TBD) in a single vessel at room temperature. We illustrate the convenience of this protocol by synthesizing a wide range of <i>N</i>-alkyl, <i>N</i>-aryl, and <i>N</i>-hetereoaryl pyridopyrazine-1,6-diones, an important class of medicinally significant lactams. Furthermore, the reported methodology can be applied to the synthesis of milligram to hundred gram quantities of pyridopyrazine-1,6-diones without the use of specialized equipment

Ru/Ni Dual Catalytic Desulfinative Photoredox C_sp²–C_sp³ Cross‑Coupling of Alkyl Sulfinate Salts and Aryl Halides

A mild Ru/Ni dual catalytic desulfinative photoredox C_sp²–C_sp³ cross-coupling reaction of alkyl sulfinate salts with aryl halides has been developed. The optimized catalyst system, consisting of Ru­(bpy)₃Cl₂, Ni­(COD)₂, and DBU, smoothly mediates the coupling of a diverse set of secondary and primary nonactivated alkyl sulfinate salts with a broad range of electron-deficient aryl bromides, electron-rich aryl iodides, and heteroaryl bromides under irradiation with blue light. The procedure is ideal for late-stage introduction of alkyl groups on pharmaceutical intermediates, and the C_sp²–C_sp³ cross-coupling reaction allowed the rapid synthesis of caseine kinase 1δ inhibitor analogues via a parallel medicinal chemistry effort

Discovery of cyclopropyl chromane-derived pyridopyrazine-1,6-dione γ-secretase modulators with robust central efficacy† †Electronic supplementary information (ESI) available. CCDC 1452774. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c6md00406g

γ-Secretase modulators for the treatment of Alzheimer's disease. Herein we describe the discovery of a novel series of cyclopropyl chromane-derived pyridopyrazine-1,6-dione γ-secretase modulators for the treatment of Alzheimer's disease (AD). Using ligand-based design tactics such as conformational analysis and molecular modeling, a cyclopropyl chromane unit was identified as a suitable heterocyclic replacement for a naphthyl moiety that was present in the preliminary lead 4 . The optimized lead molecule 44 achieved good central exposure resulting in robust and sustained reduction of brain amyloid-β42 (Aβ42) when dosed orally at 10 mg kg –1 in a rat time-course study. Application of the unpaced isolated heart Langendorff model enabled efficient differentiation of compounds with respect to cardiovascular safety, highlighting how minor structural changes can greatly impact the safety profile within a series of compounds