Use of a Curtius Rearrangement as Part of the Multikilogram Manufacture of a Pyrazine Building Block

Commercial route definition for a glucokinase activator called for a reevaluation of the synthesis and processes used to access multikilogram quantities of 2-amino-5-methylpyrazine. After consideration of different options, a variation of the Curtius rearrangement used by the medicinal chemistry route was selected for further development. The formation of an acyl azide for the Curtius rearrangement required a process safety control strategy to be put in place. The process developed was used to successfully deliver multikilogram quantities of 2-amino-5-methylpyrazine in an overall yield of 68%, starting from 5-methylpyrazine-2-carboxylic acid

Decoration of an α‑Resorcylate Nucleus as Part of the Manufacture of a Glucokinase Activator

The need to define a set of processes for the manufacture of a glucokinase activator called for an evaluation of different strategies to differentiate the hydroxyls of an α-resorcylic acid derivative. While direct functionalization proved possible, it did not allow access to crystalline intermediates that offered control over the rejection of process impurities. The strategy taken forward involved the installation of a benzoyl protecting group using careful control of pH in order to achieve useful levels of selectivity. This allowed the remaining α-resorcylate hydroxyl to be functionalized using a Mitsunobu reaction, with liquid–liquid partitioning being used to separate downstream intermediates of interest away from the redox byproducts of this reaction. Downstream challenges that were overcome in order to deliver a commercially viable means of manufacturing the API included developing an amidation reaction with a poorly reactive aminopyrazine coupling partner

Broad Scope Hydrofunctionalization of Styrene Derivatives Using Iron-Catalyzed Hydromagnesiation

The highly regioselective iron-catalyzed formal hydrofunctionalization of styrene derivatives with a diverse range of electrophiles has been developed using a single, operationally simple hydromagnesiation procedure and only commercially available, bench-stable reagents. Using just 0.5 mol % FeCl₂·4H₂O and <i>N,N,N′,N′</i>-tetra­methyl­ethylene­diamine, hydromagnesiation and electrophilic trapping have been used to form new carbon–carbon bonds (13 examples) and carbon–heteroatom bonds (5 examples) including the products of formal cross-coupling reactions, hydroboration, hydroamination, hydrosilylation, and hydrofluorination

Mechanistic Insight into Palladium-Catalyzed Cyclo­isomer­ization: A Combined Experimental and Theoretical Study

The cyclo­isomer­ization of enynes catalyzed by Pd­(OAc)₂ and bis-benzylidene ethylene­diamine (bbeda) is a landmark methodology in transition-metal-catalyzed cyclo­isomerization. However, the mechanistic pathway by which this reaction proceeds has remained unclear for several decades. Here we describe mechanistic investigations into this reaction using enyn­amides, which deliver aza­cycles with high regio- and stereo­control. Extensive ¹H NMR spectroscopic studies and isotope effects support a palladium­(II) hydride-mediated pathway and reveal crucial roles of bbeda, water, and the precise nature of the Pd­(OAc)₂ pre-catalyst. Computational studies support these mechanistic findings and lead to a clear picture of the origins of the high stereo­control that can be achieved in this transformation, as well as suggesting a novel mechanism by which hydro­metalation proceeds