Markovnikov-Selective, Activator-Free Iron-Catalyzed Vinylarene Hydroboration

Two series of structurally related alkoxy-tethered NHC iron­(II) complexes have been developed as catalysts for the regioselective hydroboration of alkenes. Significantly, Markonikov-selective alkene hydroboration with HBpin has been controllably achieved using an iron catalyst (11 examples, 35–90% isolated yield) with up to 37:1 branched:linear selectivity. <i>anti</i>-Markovnikov-selective alkene hydroboration was also achieved using HBcat and modification of the ligand backbone (6 examples, 44–71% yields). In both cases, ligand design has enabled activator-free low-oxidation-state iron catalysis

A highly diastereoselective chloride-mediated dynamic kinetic resolution at phosphorus on-route to a key intermediate in the synthesis of GSK2248761A

A highly diastereoselective chloride-mediated dynamic kinetic resolution at phosphorus has been developed to access a key intermediate in the synthesis of GSK2248761A. This procedure utilises a soluble chloride source and a cheap readily available chiral auxiliary. The practicality of this transformation is demonstrated on a multi-gram scale

Iron-catalysed, general and operationally simple formal hydrogenation using Fe(OTf)(3) and NaBH4

An operationally simple and environmentally benign formal hydrogenation protocol has been developed using highly abundant iron(iii) salts and an inexpensive, bench stable, stoichiometric reductant, NaBH(4), in ethanol, under ambient conditions. This reaction has been applied to the reduction of terminal alkenes (22 examples, up to 95% yield) and nitro-groups (26 examples, up to 95% yield). Deuterium labelling studies indicate that this reaction proceeds via an ionic rather than radical mechanism

The design, synthesis and evaluation of chemical libraries that probe RNA structure and function

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Direct <i>ortho</i>-Arylation of <i>ortho</i>-Substituted Benzoic Acids: Overriding Pd-Catalyzed Protodecarboxylation

<i>ortho</i>-Arylation of <i>ortho</i>-substituted benzoic acids is a challenging process due to the tendency of the reaction products toward Pd-catalyzed protodecarboxylation. A simple method for preventing decarboxylation in sterically hindered benzoic acids is reported. The method described represents a reliable and broadly applicable entry to 2-aryl-6-substituted benzoic acids

Using PAT To Understand, Control, and Rapidly Scale Up the Production of a Hydrogenation Reaction and Isolation of Pharmaceutical Intermediate

The development of a hydrogenation process and subsequent isolation for an intermediate in the manufacture of an active pharmaceutical ingredient is described. In-line process analytical technology (PAT) approaches were applied to gain process understanding and control. First, a calibration-free, qualitative, scale-independent approach using in situ mid-infrared (MIR) spectrometry to determine the end point of a hydrogenation reaction in real time is described. A curve-fitting algorithm was developed using MATLAB software to allow the reaction rate to be calculated at any given time during the reaction on the basis of the consumption of an intermediate species. The algorithm, coupled with understanding of the process, allowed the end point to be correctly identified in triplicate during scale-up of the process from 0.2 to 20 L scale. Second, a quantitative partial least-squares (PLS) regression model was developed using near-infrared (NIR) spectrometry to determine the solvent composition during the subsequent constant-volume distillation process prior to the crystallization of the hydrogenated product. Here the application of in-line NIR spectroscopy allowed the correct crystallization seed point to be determined, enhancing the control of quality and manufacturability