&Ketoesters and pdiesters react with @-enaminonitriles in the presence of stoichiometric amounts of tin (IV) chloride to give 4-aminopyridines and pyridones while they react with aromatic ortho-amitwnimIes to give I-aminoquinolines and quinolones. ,
The metal-promoted formation of a carbon-carbon bond between the cyan0 group of nitriles and the intercarbonylic methylene group of p-dicarbonyls affords P-enaminodione derivativesl. which, in particular cases, dimerise to pyrimidines2 or cyclise to pyrrolines3.
In order to explore further the role of metals in promoting the formation of heterocycles, we undertook the synthesis of 4-aminopyridines and of 4-aminoquinolines, mainly because of the importance of these rings in medicinal chemist@.
The synthesis of pyridines was carried out according to scheme 1. Two different approaches were investigated. In the first, we allowed cyclic p-enaminonitriles to react with p-ketoesters and P&esters in the presence of stoichiometric amounts of tin (lV) chloride. ln a typical reaction, p-enaminonitrile, P-dicsrbonyl and tin (Iv) chloride, in 1: 1:2 molar ratio, were heated under reflux in toluene for 3-12 h. After the removal of the solvent, the residue was stirred with an aqueous solution of sodium carbonate. The resulting suspension was extracted with ethyl acetate and the extracts were dried and concentrated to give the desired heterocycles.
The 4-aminopyridine derivatives (2sb)sa were obtained in cu. 60% yield in the reaction of l-amino-Zcyano-cyclopentene (la) and of 1-amino-2-cyano-cyclohexene (lb) with methyl acetoacetate. Lower yields (32%) of the 4-amino2-pyridone (958were obtained in the reaction of niuile (lb) with diethyl malonate.
In an alternative approach, the N-acetoacetylation of enaminonitrile (lb) with diketene afforded the N-acetoacetamide (4, yield 92%). Attempts to cyclise compound (4), heating it under reflux in toluene in the presence of tin (IV) chloride, failed to yield the desired pyridone ring, the only isolated compound being the amid0 N-acetoacetamide (5) (yield 62%).