Abstract
The site selectivities of intermolecular, aliphatic C-H bond functionalizations are central to the value of these transformations. While the scope of these reactions continues to expand, the site selectivities remain largely dictated by the inherent reactivity of the substrate C-H bonds. Herein, we introduce reagent-dictated site selectivity to intermolecular aliphatic C-H functionalizations using nitrogen-centered amidyl radicals. Simple modifications of the amide lead to high levels of site selectivity in intermolecular C-H functionalizations across a range of simple and complex substrates. DFT calculations demonstrate that the steric demand of the reacting nitrogen-centered radical is heavily affected by the substitution pattern of the starting amide. Optimization of transition state structures consistently indicated higher reagent-dictated steric selectivities using more hindered amides, consistent with experimental results.
Highlights
Recent advances in intermolecular aliphatic C–H functionalization have provided unique tools for the synthesis and latestage derivatization of complex molecules.[1]
We commenced our studies with the functionalization of trans decalin, a benchmark substrate used in studies of intermolecular, aliphatic C–H functionalizations.[6]
Iron-catalyzed oxidations of trans decalin with bulky tetradentate ligands poorly discriminated between these sites.6b Manganese-catalyzed C–H chlorination using a hindered tetramesitylporphyrin (TMP) system achieved good selectivity (4.0 : 1), tertiary functionalization was observed.6c The C–H chlorination using our reported N-chloroamide 3 proceeded with no selectivity between the methylene sites.5b
Summary
Recent advances in intermolecular aliphatic C–H functionalization have provided unique tools for the synthesis and latestage derivatization of complex molecules.[1]. We report our studies towards this goal using an prepared, modi ed amide to provide high levels of site selectivity in C–H functionalizations of diverse substrates. Computational studies of both the amidyl radical structures and representative C–H abstraction transition states were performed to shed light on the unique, reagent-dictated site selectivities observed.
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