4.7 Article

Synthesis of Imidazo[1,2-a]pyridines: Triflic Anhydride-Mediated Annulation of 2H-Azirines with 2-Chloropyridines

Journal

JOURNAL OF ORGANIC CHEMISTRY
Volume 86, Issue 1, Pages 388-402

Publisher

AMER CHEMICAL SOC
DOI: 10.1021/acs.joc.0c02148

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Funding

  1. NSERC (USRA)
  2. BioTalent

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The study describes a new method for the synthesis of imidazo[1,2-a]pyridines through the reaction between 2-chloropyridines and 2H-azirines, which involves the formation of electrophilic trifloyl-aziridin-2-yl triflate species and transient pyridinium salts. Thorough optimization of the activation/cyclization process resulted in selective formation of C3-substituted imidazo[1,2-a]pyridines with yields ranging from 15% to 85% for a variety of substituted heterocycles.
The discovery and optimization of a reaction between 2-chloropyridines and 2H-azirines producing imidazo[1,2-a]pyridines is described. The treatment of 2H-azirines with triflic anhydride (Tf2O) forms an electrophilic 1-trifloyl-aziridin-2-yl triflate species which, when reacted in situ with 2-halopyridines, generates transient pyridinium salts. These salts were treated in the same pot with triethylamine (Et3N), leading to the selective formation of C3-substituted imidazo[1,2-a]pyridines, an heterocyclic moiety commonly found in medicinal chemistry leads and drugs. Thorough optimization of the activation/cyclization resulted in yields ranging from 15 to 85% for a variety of substituted heterocycles.

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