Synthesis of Indoles by Reductive Cyclization of Nitro Compounds Using Formate Esters as CO Surrogates

• Published in: European journal of organic chemistry 2021-09, Vol.2021 (34), p.4876-4894
• Main Authors: Ahmed Fouad, Manar, Ferretti, Francesco, Formenti, Dario, Milani, Fabio, Ragaini, Fabio
• Format: Article
• Language: English
• Subjects: Carbon monoxide; Catalysts; CO Source; C−H Amination; Formate esters; Functional groups; Indoles; Nitro compounds; Nitrogen heterocycles; Palladium; Phenyl Formate; Ruthenium
• ISSN: 1434-193X; 1099-0690
• DOI: 10.1002/ejoc.202100789

Alkyl and aryl formate esters were evaluated as CO sources in the Pd‐ and Pd/Ru‐catalyzed reductive cyclization of 2‐nitrostyrenes to give indoles. Whereas the use of alkyl formates requires the presence of a ruthenium catalyst such as Ru3(CO)12, the reaction with phenyl formate can be performed by using a Pd/phenanthroline complex alone. Phenyl formate was found to be the most effective CO source and the desired products were obtained in excellent yields, often higher than those previously reported using pressurized CO. The reaction tolerates many functional groups, including sensitive ones like a free aldehydic group or a pendant pyrrole. Detailed experiments and kinetic studies allow to conclude that the activation of phenyl formate is base‐catalyzed and that the metal doesn't play a role in the decarbonylation step. The reactions can be performed in a single thick‐walled glass tube with as little as 0.2 mol‐% palladium catalyst and even on a 2 g scale. The same protocol can be extended to other nitro compounds, affording different heterocycles. A very efficient, general and scalable protocol for the preparation of indoles and other N‐heterocycles from suitably substituted nitroarenes using alkyl and phenyl formates as CO surrogates was described. Using phenyl formate, the products were isolated in yields often higher than those previously achieved by using gaseous CO. The mechanism of both the decarbonylation reaction of phenyl formate and the cyclization reaction were clarified by kinetic and mechanistic studies.