Tandem reductive alkylation of quinolines to functionalized tetrahydroquinolines enabled by HFIP

Abstract

Hexafluoroisopropanol (HFIP)-mediated one-pot tandem reduction of quinolines to tetrahydroquinolines followed by reductive alkylation by the aldehyde has been demonstrated through H-bonding network-enabled substrate activation. This step-economical synthetic approach is well suited for late-stage functionalization of complex bioactive molecules. The reaction is highly chemoselective and tolerates a wide range of reducible-sensitive functional groups. The current reductive N-alkylation approach was also successfully utilized to synthesize novel tricyclic oxazino-fused-tetrahydroquinoline/benzoxazine compounds via tandem reductive cyclization of 1-aryl-2-(8-quinolinyloxy) ethanones and synthesis of lilolidine derivatives through the reductive N-alkylation of quinoline followed by a dehydration cyclization sequence. The scope of the reaction has been further extended to C-functionalized N-alkylated THQ derivatives in a one-pot by using para-quinone methides (p-QMs) or nitroolefins as alkylating precursors. The elucidation of an underlying mechanism was achieved through a combination of several control experiments, kinetic studies, and isotopic labeling experiments.