Exploitation of differential reactivity of the carbon–chlorine bonds in 1,3-dichloroisoquinoline. Routes to new N,N-chelate ligands and 1,3-disubstituted isoquinolines

Abstract
Under Pd(PPh3)4 catalysis, coupling of arylboronic acids to the 1-position of 1,3-dichloroisoquinoline takes place, leading exclusively to 1-aryl-3-chloroisoquinolines. This regiochemistry is demonstrated by the crystal structure of 3-chloro-1-(8-methoxy-1-naphthyl)isoquinoline. The 3-chloro group may be modified by nickel-catalysed reaction with Grignard reagents or direct nucleophilic displacement with LiSCH2Ph. Attempted lithiation of the 3-position is not successful (either deprotonation or complex reactivity results). Under zinc reduction in the presence of NiCl2–PPh3 and NaI, the 1-aryl-3-chloroisoquinolines furnish 3,3′-biisoquinolines in good yield.

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