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

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.

Dimethyl Acetylenedicarboxylate: A Versatile Tool in Organic Synthesis

“…Furthermore, a gold-catalyzed approach for the regioselective synthesis of highly substituted pyrroles 155 directly from oximes 153 and DMAD was recently developed (Scheme 41). 45…”

Superbase‐catalyzed domino 3H‐pyrroles synthesis from ketoximes and acetylene: DFT study vs experiment

“…The synthesis of pyrroles from ketoximes and acetylene (Trofimov reaction) is considered as a domino reaction starting from the formation of O ‐vinylketoximes B , which undergo 3,3‐sigmatropic shift to iminoaldehydes D further cyclizing to 5‐hydroxypyrrolines E and giving final products G after a water molecule elimination (Scheme ). This mechanism has been repeatedly confirmed by observation and isolation of main intermediates ( O ‐vinylketoximes B , N , O ‐dialkenylhydroxylamines C and iminoaldehydes D ,), but rarely studied computationally …”

Gold(I)-catalyzed formation of furans from γ-acyloxyalkynyl ketones

“…the ability of gold cations to act as π or σ Lewis acids (Scheme 3) [21,55–56]. Intramolecular [1,4]-addition of the acyloxy function by oxophilic activation of γ-acyloxyalkynyl ketones could lead to the formation of gold allenolate A , which is in equilibrium with both Z or E vinylgold B and C [57].…”