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

Under Pd(PPh(3))(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 LiSCH(2)Ph. Attempted lithiation of the 3-position is not successful (either deprotonation or complex reactivity results). Under zinc reduction in the presence of NiCl2-PPh(3) and NaI, the 1-aryl-3-chloroisoquinolines furnish 3,3'-biisoquinolines in good yield.