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Development of a Gold-Multifaceted Catalysis Approach to the Synthesis of Highly Substituted Pyrroles: Mechanistic Insights via Huisgen Cycloaddition Studies

Ngwerume, Simbarashe, Lewis, William, Camp, Jason E.
Journal of organic chemistry 2013 v.78 no.3 pp. 920-934
X-ray diffraction, aldehydes, alkynes, catalysts, catalytic activity, deuterium, ethers, gold, ketones, moieties, nuclear magnetic resonance spectroscopy, organic chemistry, oximes, oxygen, pyrroles, regioselectivity, stable isotopes, tautomerization
A novel gold-catalyzed method for the regioselective synthesis of highly substituted pyrroles directly from oximes and alkynes was developed via independent optimization of two key steps of the process. Importantly, a cationic gold(I) species was shown to activate multiple steps along the reaction pathway and therefore act as a multifaceted catalyst. Initial gold-promoted addition of the oxime oxygen to the activated alkyne afforded the O-vinyloxime in situ. The O-vinyloxime was subsequently transformed into the pyrrole via a gold-catalyzed tautomerization, [3,3]-sigmatropic rearrangement, and cyclodehydration process. Notably, this method provides a functional group handle in the form of an ester at the 3/4-position for further exploitation. The proposed mechanistic pathway is supported by a novel application of the Huisgen cycloaddition click reaction, which was used to probe the relative stability of substituted O-vinyloximes. The intermediacy of N-alkenylhydroxylamine O-vinyl ethers and imino ketones or imino aldehydes along the reaction pathway were determined by high-temperature ¹H, ²H{¹H}, and ¹³C{¹H} NMR experiments. X-ray crystallographic evidence was used to further support the mechanistic hypothesis.