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

Research output: Contribution to journalArticle

40 Citations (Scopus)

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

Original languageEnglish
Pages (from-to)920-934
Number of pages15
JournalJournal of Organic Chemistry
Volume78
Issue number3
Early online date27 Dec 2012
DOIs
Publication statusPublished - 1 Feb 2013
Externally publishedYes

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Pyrroles
Cycloaddition
Gold
Catalysis
Oximes
Alkynes
Ketones
Aldehydes
Functional groups
Esters
Nuclear magnetic resonance
Oxygen
X rays
Catalysts
Experiments
Temperature

Cite this

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

In: Journal of Organic Chemistry, Vol. 78, No. 3, 01.02.2013, p. 920-934.

Research output: Contribution to journalArticle

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