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.

Graphical abstract: Tandem reductive alkylation of quinolines to functionalized tetrahydroquinolines enabled by HFIP

Supplementary files

Article information

Article type
Research Article
Submitted
17 Mar 2025
Accepted
27 May 2025
First published
11 Jun 2025

Org. Chem. Front., 2025, Advance Article

Tandem reductive alkylation of quinolines to functionalized tetrahydroquinolines enabled by HFIP

S. K. Senapati, T. Das and A. Das, Org. Chem. Front., 2025, Advance Article , DOI: 10.1039/D5QO00519A

To request permission to reproduce material from this article, please go to the Copyright Clearance Center request page.

If you are an author contributing to an RSC publication, you do not need to request permission provided correct acknowledgement is given.

If you are the author of this article, you do not need to request permission to reproduce figures and diagrams provided correct acknowledgement is given. If you want to reproduce the whole article in a third-party publication (excluding your thesis/dissertation for which permission is not required) please go to the Copyright Clearance Center request page.

Read more about how to correctly acknowledge RSC content.

Social activity

Spotlight

Advertisements