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

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 <i>O</i>-vinyloxime in situ. The <i>O</i>-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 <i>O</i>-vinyloximes. The intermediacy of <i>N</i>-alkenylhydroxylamine <i>O</i>-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