Palladium and Lewis-Acid-Catalyzed Intramolecular Aminocyanation of Alkenes: Scope, Mechanism, and Stereoselective Alkene Difunctionalizations

Zhongda Pan, Shengyang Wang, Jason T. Brethorst, Christopher J. Douglas

Research output: Contribution to journalArticlepeer-review

21 Scopus citations

Abstract

An expansion of methodologies aimed at the formation of versatile organonitriles, via the intramolecular aminocyanation of unactivated alkenes, is herein reported. Importantly, the need for a rigid tether in these reactions has been obviated. The ease-of-synthesis and viability of substrates bearing flexible backbones has permitted for diastereoselective variants as well. We demonstrated the utility of this methodology with the formation of pyrrolidones, piperidinones, isoindolinones, and sultams. Furthermore, subsequent transformation of these motifs into medicinally relevant molecules is also demonstrated. A double crossover 13C-labeling experiment is consistent with a fully intramolecular cyclization mechanism. Deuterium labeling experiments support a mechanism involving syn-addition across the alkene.

Original languageEnglish (US)
Pages (from-to)3331-3338
Number of pages8
JournalJournal of the American Chemical Society
Volume140
Issue number9
DOIs
StatePublished - Mar 7 2018

Bibliographical note

Funding Information:
We thank National Institutes of Health for funding this work (R01 GM095559). We thank Dr. Letitia Yao (UMN) for assistance with nOe experiments. We thank Mr. Xiao Xiao (UMN) for discussions regarding NMR chemical shift prediction.

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