The ability of pyridine to undergo formal C-H insertion by nucleophilic radicals has been expanded into a novel method for the annulation of a fused saturated ring onto pyridine. The method exploits the known reaction of Fe(III) with a double bond and an organosilane to produce a carbon centered radical which undergoes a Minisci-like addition to a pendant pyridine. Tertiary radicals derived from 1,1-disubstituted double bonds performed best resulting in products with a quaternary carbon adjacent to the aromatic ring, however, a variety of double bond types is competent in the transformation. The optimal conditions were found to be 0.5 equiv. Fe(acac)3, 2.5 equiv. PhSiH3, 3 equiv. (tBuO)2 and 2 equiv. TFA in EtOH solvent at 60 C. The reaction was not sensitive to oxygen or moisture and could be run under ambient air. Under these conditions the desired radical addition product predominated, however, in some cases reduction of the double bond without cyclization occurred as a minor side reaction. When multiple regioisomeric products were possible, a statistical mixture of products was observed, consistent with a Minisci-like radical addition mechanism. Bromopyridines were found to be stable to the reaction conditions allowing use of bromine as a removable blocking group to control the regiochemical outcome of the reaction. Optimization and scope of this new reaction will be presented.

Synthesis of bicyclic pyridines by iron mediated intramolecular radical cyclization

254th National Meeting (2017)

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