Synthesis of aza and carbocyclic β-carbolines for the treatment of alcohol abuse. Regiospecific solution to the problem of 3,6-disubstituted β- and aza-β-carboline specificity

A novel two step protocol was developed to gain regiospecific access to 3-substituted beta- and aza-beta-carbolines, 3-PBC (1), 3-ISOPBC (2), beta CCt (3), 6-aza-3-PBC (4) and 6-aza-3-ISOPBC (5). These beta-carbolines (1-3) are potential clinical agents to reduce alcohol self-administration, especially 3-ISOPBC center dot HCl (2 center dot HCl) which appears to be a potent anti-alcohol agent active against binge drinking in a rat model of maternally deprived (MD) rats. The method consists of two consecutive palladium-catalyzed reactions: a Buchwald-Hartwig amination followed by an intramolecular Heck-type cyclization in high yield.