Synthesis of Heterocycle-Annelated Naphthyridones with a Bridgehead Nitrogen Atom

Synthesis of [b]-fused [2,7]naphthyridones

A variety of hetarylacetonitriles featuring a ring nitrogen atom in ortho position to the CH2CN side chain (2-pyridylacetonitrile (1a), 2-quinolinylacetonitrile (1b) [2], 2-benzimidazolylacetonitrile (1c) [3], (1-methyl-2-benzimidazolyl)acetonitrile (1d) [4], and 2-benzothiazolylacetonitrile (1e) [5]) were treated with ethyl 2,6-dimethyl-4-chloronicotinoate (4) [6] in dimethylformamide solution in the presence of a base. After 1.5 to 3 hours of refluxing, followed by aqueous work-up, the target naphthyridones 6-10 were isolated as almost insoluble solids in good to high yields. In most cases, employment of potassium tert-butoxide gave the best results, but also weaker bases like potassium carbonate, cesium carbonate, and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) were found to be suitable to effect this reaction.

The formation of the naphthyridine ring can be rationalized by nucleophilic attack of the carbanion which is generated from the hetarylacetonitrile methylene group at the pyridine carbon atom bearing the chloro substituent and - after loss of chloride - spontaneous cyclization as a result of intramolecular N-acylation of the heterocycle by the ester function as shown below.

In a similar fashion, ethyl 4-chloronicotinoate (5) [7] was transformed into the [b]-annelated [2,7]-naphthyridones 11 and 12 in yields of 78% and 86%, respectively.

Scheme 2


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nh, 9 May 1996