Ligandless Palladium-Catalyzed Direct C-5 Arylation of Azoles Promoted by Benzoic Acid in Anisole

Molecules. 2022 Dec 2;27(23):8454. doi: 10.3390/molecules27238454.

Abstract

The palladium-catalyzed direct arylation of azoles with (hetero)aryl halides is nowadays one of the most versatile and efficient procedures for the selective synthesis of heterobiaryls. Although this procedure is, due to its characteristics, also of great interest in the industrial field, the wide use of a reaction medium such as DMF or DMA, two polar aprotic solvents coded as dangerous according to environmental, health, safety (EHS) parameters, strongly limits its actual use. In contrast, the use of aromatic solvents as the reaction medium for direct arylations, although some of them show good EHS values, is poorly reported, probably due to their low solvent power against reagents and their potential involvement in undesired side reactions. In this paper we report an unprecedented selective C-5 arylation procedure involving anisole as an EHS green reaction solvent. In addition, the beneficial role of benzoic acid as an additive was also highlighted, a role that had never been previously described.

Keywords: C–C coupling; aromatic solvents; azoles; direct arylation; palladium; regioselectivity.

MeSH terms

  • Azoles*
  • Benzoic Acid
  • Catalysis
  • Palladium*
  • Solvents

Substances

  • Palladium
  • Azoles
  • Benzoic Acid
  • Solvents

Grants and funding

This research was funded by Università di Pisa (Project PRA_2020_219).