Synthesis of 1-alkyl-2,3-dihydro-2-(4-pyridinyl)-1H-isoindoles as potential selective serotonin reuptake inhibitors

✍ Scribed by Kevin J. Kapples; Gregory M. Shutske

• Publisher: Journal of Heterocyclic Chemistry
• Year: 1997
• Tongue: English
• Weight: 305 KB
• Volume: 34
• Category: Article
• ISSN: 0022-152X
• DOI: 10.1002/jhet.5570340440

✦ Synopsis

Abstract

Two 2,3‐dihydro‐2‐(4‐pyridinyl)‐1__H__‐isoindoles 2a,b have been synthesized by the reaction of isoindoline with 4‐chloropyridines. In addition, a number of 1‐alkyl‐2,3‐dihydro‐2‐(4‐pyridinyl)‐1__H__‐isoindoles 2c‐h were obtained from 2‐(4‐pyridinyl)phthalimide (5). The addition of alkyl Grignard reagents to 5 gave 1‐alkylhydroxyisoindolones 6a‐f which, in two cases 6a,b, were dehydrated and subjected to three separate reductions to give targets 2c,d. In three cases, the intermediate hydroxyisoindolones 6c‐e were reduced in one step to the target compounds 2c‐g with lithium aluminum hydride‐aluminum chloride. When 6f, the product of the addition of phenyl Grignard to 5, was subjected to these conditions, a hydroxyisoindoline 7 was obtained which was further reduced to 2h with triethylsilane‐trifluoroacetic acid. The lithium aluminum hydride‐aluminum chloride conditions were successfully applied to the synthesis of a 1‐benzyl‐4‐piperidine derivative 21.