A scalable Nenitzescu synthesis of 2-methyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile

✍ Scribed by Eric E. Boros; Istvan Kaldor; Philip S. Turnbull

• Publisher: Journal of Heterocyclic Chemistry
• Year: 2011
• Tongue: English
• Weight: 133 KB
• Volume: 48
• Category: Article
• ISSN: 0022-152X
• DOI: 10.1002/jhet.571

✦ Synopsis

Abstract

2‐Methyl‐4‐(trifluoromethyl)‐1__H__‐indole‐5‐carbonitrile is a key intermediate in the synthesis of selective androgen receptor modulators discovered in these laboratories. A practical and convergent synthesis of the title compound starting from 4‐nitro‐3‐(trifluoromethyl)phenol and __tert‐__butyl acetoacetate was developed, including a telescoped procedure for synthesis (without isolation) and Nenitzescu reaction of 2‐trifluoromethyl‐1,4‐benzoquinone. Conversion of the known Nenitzescu indole product to a novel triflate intermediate followed by palladium‐catalyzed cyanation afforded a penultimate carbonitrile. Removal of the C‐3 tert‐butyl ester group on the indole through a decarboxylative pathway completed the synthesis of the title compound in six steps (27% overall yield) from 4‐nitro‐3‐(trifluoromethyl)phenol (five steps, 37% overall yield from tert‐butyl acetoacetate). J. Heterocyclic Chem., (2011).