Journal of Organic Chemistry 2013-02-01

Development of a gold-multifaceted catalysis approach to the synthesis of highly substituted pyrroles: mechanistic insights via Huisgen cycloaddition studies.

Simbarashe Ngwerume, William Lewis, Jason E Camp

Index: J. Org. Chem. 78(3) , 920-34, (2013)

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Abstract

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 (1)H, (2)H{(1)H}, and (13)C{(1)H} NMR experiments. X-ray crystallographic evidence was used to further support the mechanistic hypothesis.