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Synthesis of 5,6,7,8‐tetrahydro‐5‐oxopyrido[2,3‐ d ]pyrimidine‐6‐carbonitriles and ‐6‐carboxylic acid esters
Author(s) -
Santilli Arthur A.,
Wanser Stephen V.,
Kim Dong H.,
Scotese Anthony C.
Publication year - 1975
Publication title -
journal of heterocyclic chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.321
H-Index - 59
eISSN - 1943-5193
pISSN - 0022-152X
DOI - 10.1002/jhet.5570120220
Subject(s) - chemistry , thionyl chloride , alkylation , methyl iodide , pyrimidine , dehydrogenation , medicinal chemistry , pyridine , ring (chemistry) , ethyl iodide , stereochemistry , organic chemistry , chloride , catalysis
Dieckmann ring closure reactions of 4‐[(2‐cyanoethyl)substituted amino]‐2‐phenyl‐5‐pyrimidinecarboxylates (Ha‐f) afforded several 5,6,7,8‐tetrahydro‐5‐oxo‐2‐phenylpyrido[2,3 ‐d] pyrimidine‐6‐ carbonitriles (IIIa‐f). The open‐chain intermediates (IIa‐f) were prepared by dechloroamination of 5‐carbethoxy‐4‐chloro‐2‐phenylpyrimidine (1a) with several 3‐substituted amino‐ propionitriles. Alkylation of the sodium salt of 5,6,7,8‐tetrahydro‐8‐methyl‐5‐oxo‐2‐phenyl‐pyrido[2,3 ‐d] pyrimidine‐6‐ carbonitrile (IIIa) with methyl iodide in DMF resulted in methylation at C‐6 to afford IV. Tosylation of IIIa in pyridine gave the corresponding tosyl ester (V) of the enolic form. Oxidative dehydrogenation at the 6,7‐position resulted when IIIa reacted with thionyl chloride, affording 5,8‐dihydro‐8‐methyl‐5‐oxo‐2‐phenylpyrido[2,3 ‐d] pyrimidine‐6‐ carbonitrile (VII). Dechloroamination of la or 5‐carbethoxy‐4‐chloro‐2‐methylthiopyrimidine (Ib) with ethyl 3‐ethylaminopropionate followed by Dieckmann cyclization of the resulting open‐chain intermediates gave the corresponding ethyl 5,6,7,8‐tetrahydro‐5‐oxopyrido[2,3 ‐d] pyrimidine‐6‐carboxylates IX'a and IX'b, respectively. These exist predominately in the enol form and undergo alkylation and oxidation reactions similar to IIIa.