Synthesis of 2 ,5 -disubstituted indoles by metal mediated reactions

Abstract

Indole derivatives are one of the most privileged structure motifs frequently found in natural products, pharmaceuticals, functional materials, and agrochemicals. Synthesis and biological evaluation of indole derivatives have been a topic of special interest to organic and medicinal chemist. Here a convenient method for the synthesis of 2, 5-disubstituted indole derivatives through palladium catalyzed cross-coupling reaction followed by base catalyzed and palladium catalyzed intramolecular cyclization reaction is reported. In this purpose, 2-iodo-4-substituted-N-ethanoyl anilines 4, 7 were synthesized by the iodination of their parent 4-sustituted anilines using I2, (CH3COO)2Cu in CH3COOH. The cross-coupling reaction of 2-iodo-4-substituted-N-ethanoyl anilines 4, 7 with terminal alkynes 11-13 were carried out in the presence of (Ph3P)2PdCl2, CuI, and Et3N in DMF at 60-80°C for 24-48 h under nitrogen atmosphere to yield 2-alkynyl-4-substituted-N-ethanoyl anilines 14-18. The condensed products 14, 15, 17 were subjected to base catalyzed cyclization by EtONa in EtOH at 80°C for 4-6 h to yield 2, 5-disubstituted-1H indoles 20, 22 along with acyclic by products 2-alkynyl-4-substituted anilines 21, 23, 24. The condensed products 15-17 were also subjected to intramolecular cyclizaton by PdCl2 in CH3 CN at 80°C for 0.5-2 h to yield 2, 5-disubstituted –N-ethanoyl indoles 25-27 only. In vitro antimicrobial activities of the synthesized compounds 4, 7, 14-18, 25-27 were evaluated. None of the compound showed inhabitant activity against the gram positive and gram negative bacteria as well as human fungal pathogens.