Benzazetidine synthesis via palladium-catalysed intramolecular C-H amination

Gang He, Gang Lu, Zhengwei Guo, Peng Liu, Gong Chen

Research output: Contribution to journalArticlepeer-review

61 Scopus citations

Abstract

Small-sized N-heterocycles are important structures in organic synthesis and medicinal chemistry. Palladium-catalysed intramolecular aminations of the C-H bonds of unfunctionalized amine precursors have recently emerged as an attractive new method for N-heterocycle synthesis. However, the way to control the reactivity of high-valent Pd intermediates to form the desired C-N cyclized products selectively remains poorly addressed. Herein we report a strategy to control the reductive elimination (RE) pathways in high-valent Pd catalysis and apply this strategy to achieve the synthesis of highly strained four-membered benzazetidines via the Pd-catalysed intramolecular Câ 'H amination of N-benzyl picolinamides. These reactions represent the first practical synthetic method for benzazetidines and enable access to a range of complex benzazetidines from easily obtainable starting materials. The use of a newly designed phenyliodonium dimethylmalonate reagent is critical, as oxidation of Pd(II) palladacycles with this reagent favours a kinetically controlled C-N RE pathway to give strained ring-closed products.

Original languageEnglish (US)
Pages (from-to)1131-1136
Number of pages6
JournalNature Chemistry
Volume8
Issue number12
DOIs
StatePublished - Dec 1 2016

All Science Journal Classification (ASJC) codes

  • Chemistry(all)
  • Chemical Engineering(all)

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