Substituted 2,7-naphthyridine-3,6-diones

Various approaches to the synthesis of 2,7-naphthyridines are available. Thus, the dianilide of 3-oxoglutaric acid 133 reacted with malononitrile in the presence of sodium acetate to give pyridone derivative 134, whereas the reaction of 133 with ethyl cyano-acetate in pyridine afforded tetrahydropyridinedione derivative 135. The compounds 134 and 135 underwent cyclization upon heating with triethylamine in DMF to form substituted 2,7-naphthyridine-3,6-diones 136 and 137, respectively (1989JPR745). 

Pharmaceutically important 3-substituted-[l,8]naphthyridine-2,4-diones have been prepared by the reaction of 2-methyl-477-pyrido[2,3-r/][3,l]oxazin-4-one with active methylene compounds (Scheme 66) <1997J(P1)1487, 2003JOC4567> and by the same group via an intramolecular azadiene-ketene electrocyclization reaction of amino-nicotinic acid derivatives in a related process <2001JOC4413>. 

Naphthyridin-2(1 //)-ones 66 were prepared from pyrano[4,3-/ ]pyridine-2,7-diones 67 by successive treatment with NH3, HBr and Zn in acetic acid (1993H1). It was believed that the attack of the ammonia molecule on the C(5) atom led to pyran ring opening. Subsequent decarboxylation afforded a tautomeric mixture of substituted tetrahydropyridines 68a,b. Dinitrile 69 generated by elimination of ammonia underwent cyclization under the action of HBr to form 1,6-naphthyridine derivative 70. Dehydrobromination with Zn in acetic acid gave the final products 66. 

Of the other procedures for the synthesis of 1,6-naphthyridines, noteworthy is the three-component cyclization of 2,3-dioxobutanal phenylhydrazone 88 with diethyl 3-amino-2-cyanopent-2-enedioate 89 and ammonium acetate to form substituted 1,6-naphthyridine-5,7-(3/f, 6//)-dione 90. Polyfunctionalized pyridine derivative 91 was obtained as the intermediate (1996JCR(S)434). 

Naphthyridines have been obtained in poor yields by the reaction of pyrido[2,3-i7]pyrimidine 3-oxide with ketones without a base at temperatures between 140 and 180°C (see also Section 7.2.2.1.1.5.5.). According to the presumed mechanism, the first step occurs across the 3,4-bond. Similar reactions with ethyl cyanoacetate, malononitrilc, ethyl acctoacctatc, and l-phenylbutane-l,3-dione also give 1,8-naphthyridines, whereas treatment with symmetric / -diketones yields 2-substituted pyrido[2,3-rf]pyrimidines.304 342... 

The treatment of 2,5-dichloro-3,6-dihydroxycyclohexa-2,5-diene-l,4-dione 269 with 2-substituted-l,8-naphthyr-idine-3-carboxylic acid hydrazides 270 in ethanol under reflux resulted in the formation of 3,8-di(2-substituted-l,8-naphthyridin-3-yl)benzo(l,2-r 4,5- )bis[l,3,4]oxadiazine-5,10[l//,6//]diones 271 <2000IJH311> (Equation 42). 

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