Iron-Catalyzed C(sp2)−C(sp3) Cross-Coupling of Chlorobenzamides with Alkyl Grignard Reagents: Development of Catalyst System, Synthetic Scope, and Application

Elwira Bisz, Michal Szostak

Research output: Contribution to journalArticle

6 Scopus citations

Abstract

Direct preparation of alkylated amide-derivatives by cross-coupling chemistry using sustainable protocols is challenging due to sensitivity of the amide functional group to reaction conditions. Herein, we report the synthesis of alkyl-substituted amides by iron-catalyzed C(sp2)−C(sp3) cross-coupling of Grignard reagents with aryl chlorides. The products of these reactions are broadly used in the synthesis of pharmaceuticals, agrochemicals and other biologically-active molecules. Furthermore, amides are used as versatile intermediates that can participate in the synthesis of valuable ketones and amines, providing access to motifs of broad synthetic interest. The reaction is characterized by its good substrate scope, tolerating a range of amide substitution, including sterically-bulky, sensitive and readily modifiable amides. The reaction is compatible with challenging organometallics possessing β-hydrogens, and proceeds under very mild, operationally-simple conditions. Optimization of the catalyst system demonstrated the beneficial effect of O-coordinating ligands on the cross-coupling. The reaction was found to be fully chemoselective for the mono-substitution at the less sterically-hindered position. Mechanistic studies establish the order of reactivity and provide insight into the role of amide to control mono-selectivity of the alkylation. The protocol provides the possibility for convenient access to alkyl-amide structural building blocks using sustainable cross-coupling conditions with high efficiency. (Figure presented.).

Original languageEnglish (US)
Pages (from-to)85-95
Number of pages11
JournalAdvanced Synthesis and Catalysis
Volume361
Issue number1
DOIs
Publication statusPublished - Jan 11 2019

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All Science Journal Classification (ASJC) codes

  • Catalysis
  • Organic Chemistry

Keywords

  • C(sp)−C(sp) Kumada coupling
  • alkylation
  • amides
  • cross-coupling
  • iron catalysis
  • sustainability

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