Synthesis of Novel 2- and 8-Substituted 4-Amino-7-chloroquinolines and their N-Alkylated Coupling Products

The synthesis of a series of 2- and 8-substituted 4-amino-7-chloroquinolines is presented. The chloro in the 7-position can be effectively substituted using amino alcohols to yield novel analogues of the antimalarial (hydroxy)chloroquine. Both short chain (2-aminoethanol) and long chain (5-[N-ethyl-N-(2-hydroxyethyl)amino]-2-aminopentane) coupling partners can be used. While ketone and nitro functionalities were found to be incompatible with the coupling conditions, electron-donating amino and dimethylamino substituents were tolerated. In addition to characterization in solution using multinuclear NMR spectroscopy and high-resolution mass spectrometry, single-crystal X-ray structures are presented of two 4,7-dichloroquinolines as well as three of the N-alkylated products including a unique species in which a pyrrole heterocycle formed at the 2-position of the quinoline sub-unit and a rare example of a 4-aza-1,10-phenanthroline.