Highly Regioselective Friedländer Annulations with Unmodified Ketones Employing Novel Amine Catalysts:  Syntheses of 2-Substituted Quinolines, 1,8-Naphthyridines, and Related Heterocycles

Peter G. Dormer, Kan K. Eng, Roger N. Farr, Guy R. Humphrey, J. Christopher McWilliams,* P. J. Reider, Jess W. Sager, and R. P. Volante
Department of Process Research, Merck & Co., Inc., P.O. Box 2000, Rahway, New Jersey 07065
J. Org. Chem., 2003, 68 (2), pp 467–477
DOI: 10.1021/jo026203i
Publication Date (Web): December 6, 2002
Copyright © 2003 American Chemical Society
*

In papers with more than one author, the asterisk indicates the name of the author to whom inquiries about the paper should be addressed.

, chris_mcwilliams@merck.com

Abstract

Abstract Image

Catalysts were evaluated on the preparation of 2-substituted quinolines, 1,8-naphthyridines, and chromone derivatives from unmodified methyl ketones and o-aminoaromatic aldehydes. While oxide catalysts yielded the 2,3-dialkyl substituted products, cyclic secondary amines provided the 2-alkylsubstutited products regioselectively. In particular, pyrrolidine derivatives provided the highest regioselectivity favoring the 2-substituted products. The most reactive and regioselective catalyst was the bicyclic pyrrolidine derivative, TABO (1,3,3-trimethyl-6-azabicyclo[3.2.1]octane), yielding 1,8-naphthyridines with as high as 96:4 regioselectivity. Regioselectivity increased with slow addition of the methyl ketone substrate to the reaction mixture, and was positively related to temperature. Isolated yields of single regioisomers were typically 65−84%, while observed regioselectivities were ≥90:10 for 1,8-naphthyridines and ≥84:16 for quinolines.

View: Full Text HTML | Hi-Res PDF

Tools

History

  • Published In Issue January 24, 2003
  • Received July 16, 2002

Recommend & Share

Related Content

Other ACS content by these authors: