Ring walking is an important mechanistic phenomenon leveraged in many catalytic C-C bond forming reactions. However, ring walking has been scarcely studied under Buchwald-Hartwig amination conditions despite the importance of such transformations. An in-depth mechanistic study of the Buchwald-Hartwig amination is presented focussing on ligand effects on ring walking behavior. The ability of palladium catalysts to promote or inhibit ring walking is strongly influenced by the chelating nature of the ligand. In stark contrast, the resting state of the catalyst had no impact on ring walking behavior. Furthermore, the complexity of the targeted system enabled the differentiation between catalysts which undergo ring walking versus diffusion-controlled coupling. The insights gained in this study were leveraged to achieve desymmetrization of a tetrabrominated precursor. A small library of asymmetric 2,2′,7,7′-tetrakis[N,N-di(4-methoxyphenyl)amino]-9,9’spirobifluorene (SpiroOMeTAD) derivatives were successfully synthesized using this strategy highlighting the ease with which libraries of these compounds can be accessed for screening.
Kinetic investigations can provide critical mechanistic information for the optimization of the reaction parameters and reaction development. Modern kinetic analyses such as RPKA and VTNA provide many advantages over traditional initial rate methods and are especially powerful when coupled with reaction monitoring technologies. While these are robust analytical methods, the lack of careful observation and optimization can lead to misinterpretation of the data. In this Perspective, we highlight some commonly overlooked considerations in kinetic studies based on our experiences and present a general guide to proper optimization of reactions and analytics prior to acquiring kinetic data.
A new general de novo synthesis of pharmaceutically
important N-(hetero)aryl piperidines is reported. This protocol uses
a robustly diastereoselective reductive amination/aza-Michael reaction
sequence to achieve rapid construction of complex polysubstituted
ring systems starting from widely available heterocyclic amine nucleophiles
and carbonyl electrophiles. Notably, the diastereoselectivity of this
process is enhanced by the presence of water, and DFT calculations
support a stereochemical model involving a facially selective protonation
of a water-coordinated enol intermediate.
Online HPLC reaction
progress monitoring provides detailed data-rich
profiles; however, extracting kinetic information requires ultraviolet–visible
response factors to determine concentrations from peak areas. If the
reaction’s overall mass balance is known and some analytical
trend for all relevant species can be recorded, it is possible to
estimate the absolute response factors of all species using a system
of linear equations. We delineate a method using the Microsoft Solver
plug-in to convert time course profiles to reagent concentrations
without analytical standards.
Background: In 1948, the synthesis and Plasmodium lophurae activity of 2-hydroxy-1,4-naphthoquinones containing 3-alkyldiarylether side chains was reported. Method/results: The synthesis of five related compounds, designed to be more metabolically stable, was pursued. The compounds were synthesized using a radical alkylation reaction with naphthoquinones. One compound had a lower IC50 value against various strains of Plasmodium falciparum and assay data indicate that it binds to the Qo site of cytochrome bc1. With a low yield for the radical alkylation of the most active compound, a reductive alkylation method with used to improve reaction yields. Conclusion: Further synthetic knowledge was obtained, and the assay data indicate that there are sensitivity differences between avian and human malarial parasites for these molecules.
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