Highly regioselective Friedländer annulations with unmodified ketones employing novel amine catalysts: syntheses of 2-substituted quinolines, 1,8-naphthyridines, and related heterocycles.
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 > or =90:10 for 1,8-naphthyridines and > or =84:16 for quinolines.
Dormer
Peter G
PG
Department of Process Research, Merck & Co., Inc., P.O. Box 2000, Rahway, New Jersey 07065, USA.
Eng
Kan K
KK
Farr
Roger N
RN
Humphrey
Guy R
GR
McWilliams
J Christopher
JC
Reider
P J
PJ
Sager
Jess W
JW
Volante
R P
RP