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 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.

本研究开发了一种新颖的基于金催化的区域选择性合成高度取代吡咯的方法，该方法通过独立优化工艺的两个关键步骤而实现。尤为重要的是，阳离子金(I)物种被证实可以激活反应途径中的多个步骤，从而发挥多面性催化剂的作用。金催化的初步加成反应使亚砜氧直接与活化后的炔烃反应，生成了原位生成的O-乙烯氧亚胺。随后，O-乙烯氧亚胺通过金催化的互变异构化、[3,3]-σ键迁移重排和环脱水过程转变为吡咯。值得注意的是，该方法在3/4位提供了一个酯官能团作为进一步利用的基团。所提出的机理途径得到了Huisgen环加成点击反应的全新应用的支持，该反应用于探究取代O-乙烯氧亚胺的相对稳定性。通过高温1H、2H{1H}和13C{1H} NMR实验确定了反应途径中的中间体N-烯丙基羟胺O-乙烯醚和亚胺酮或亚胺醛。X射线晶体学证据进一步支持了机理假设。