Kiloscale Buchwald–Hartwig Amination: Optimized Coupling of Base-Sensitive 6‑Bromoisoquinoline-1-carbonitrile with (<i>S</i>)‑3-Amino-2-methylpropan-1-ol

This work describes the optimization and scale-up of a Buchwald–Hartwig amination reaction for the preparation of a pharmaceutical intermediate. This C–N bond formation is challenged by the use of a chiral primary amine, which both adds cost and favors formation of biaryl byproducts. In order to develop a scalable process, a number of factors had to be investigated including catalyst selection and stoichiometry of the chiral amine. These all needed to be optimized while maintaining low palladium levels in the isolated product. The reaction was found to be most effective using Pd­(dba)₂ with BINAP and Cs₂CO₃ in THF. When executed on 2.5 kg scale, these conditions provided 2.06 kg of the desired product in 80% yield with only 73 ppm residual palladium. To date, this process has been successfully executed to produce more than 12 kg of compound <b>(</b><i><b>S</b></i><b>)-3</b>

Introduction of a Crystalline, Shelf-Stable Reagent for the Synthesis of Sulfur(VI) Fluorides

The design, synthesis, and application of [4-(acetylamino)­phenyl]­imidodisulfuryl difluoride (AISF), a shelf-stable, crystalline reagent for the synthesis of sulfur­(VI) fluorides, is described. The utility of AISF is demonstrated in the synthesis of a diverse array of aryl fluorosulfates and sulfamoyl fluorides under mild conditions. Additionally, a single-step preparation of AISF was developed that installed the bis­(fluorosulfonyl)­imide group on acetanilide utilizing an oxidative C–H functionalization protocol