Base-controlled regioselective functionalization of chloro-substituted quinolines.

We prepared a number of di- and trifunctionalized quinolines by selective metalation of chloro-substituted quinolines with metal amides followed by reaction with different electrophiles. Metalation of the C-3 position of the quinolinic ring with lithium diisopropylamide at -70 degrees C is easy to achieve, whereas reaction with lithium magnesium and lithium zinc amides affords C-2 or C-8 functionalized derivatives in a regioselective fashion. These complementary methods could be rationalized by DFT calculations and are convenient strategies toward the synthesis of bioactive quinoline derivatives such as chloroquine analogues.