1.7- Naphthyridine-3-carboxylate 3-oxides

The cyclization of the condensation product of 3-aminopyridine-l-oxide with diethyl ethoxymethylenemalonate (EMME) yields ethyl 4-hydroxy-1,7-naphthyridine-7-oxide-3-carboxylate (IX-108) the -oxide function need not be present if the o-positions of 3-aminopyridines are blocked. The Skraup reaction with 3-amino-2-pyridone yields l,7-naphthyridin-8-one. Several... 

Tile same methodology as mentioned for the preparation of (9) was applied for the synthesis of 8-nitro-l,6-naphthyridines. Heating diethyl N- 3-nitropyridin-4-yl)aminomethylenemalonate (12) in diphenyl ether yields ethyl 8-nitro-l,6-naphthyridin-4(lH)-one 3-carboxylate (13) (63JCS4237, 30%) and acid treatment of 4-( y, y-diethoxypropylamino)-5-nitro-2-(/3,/3 -trifluoroethoxy)-pyridine (14) gives in a similar way 8-nitro-5-(/3, /3-triflu-oroethoxy)-l,2-dihydro-l,6-naphthyridine (15, 76%). Subsequent oxidation with chloranil, acid hydrolysis, and methylation with methyl iodide gives 8-nitro-6-methyl-l,6-naphthyridin-5(6H)-one (16,63%) (81JHC941). 

Treatment of 2-methyl-l,5-naphthyridine (103 R = Me) with selenium dioxide gave the carboxylic acid (103 R = C02H) whereas the analogous oxidation of the N,N - dioxide of... 

Naphthyridine-2-carbaldehyde 1,5-dioxide (1) underwent oxidation to 1, 5-naphthyridine-2-carboxylic acid 1,5-dioxide (2) (30% H202, AcOH, 25°C,... 

These carboxylic acids have been made by primary synthesis (see Chapter 8), oxidation of alkyl-1,6-naphthyridines (see Section 9.2.2), or the routes illustrated in the following classified examples. 

Ethyl 4-oxo-1,4-dihydro-l,7-naphthyridine-3-carboxylate 6-oxide underwent N-deoxygenation to give the 4-oxo-l,4-dihydro-l,7-naphthyridine-3-... 

Dimethylpyrido 2,3-/ ]11,8 naphthyridine-2,6(l//,9//)-dione (62) underwent oxidation to give 2-amino-5-methyl-7-oxo-7,8-dihydro-l,8-naphthyr-idine-3-carboxylic acid IV-oxide, probably the 1-oxide (63) (MeCC H ... 

Amino-8-hydroxy-5-methyl-7-oxo-7,8-dihydro-l,8-naphthyridine-3-carboxylic acid (28, R = OH) (a tautomer of the 8-oxide) underwent reduction to 2-amino-5-methyl-7-oxo-7,8-dihydro-l,8-naphthyridine-3-carboxylic acid (28, R=H) (TiCl3, HC1, H20, 20°C -75%).748... 

Note The oxidative degradation of a partly specified extranuclear carboxylated tetrahydro-l,8-naphthyridine has been studied by MS/NMR means.1261... 

Unsubstituted 2,7-naphthyridine (50) is probably best made by oxidation of 2,7-naphthyridine-4-carbaldehyde to 2,7-naphthyridine-4-carboxylic acid (49) (KMn04, AcMe, 20°C 88%) and subsequent thermal decarboxylation (Cu powder, gentle heat 78%) 630 earlier syntheses involved direct hydrogenolysis of 1,3,6,8-tetrachloro-2,7 naphthyridine (51 R = Cl) (Pd/C, H2, MeOH, AcOK 71 %)1374 cf 22 or indirect dechlorination of l-chloro-2,7-haphthyridine (51, R = H) by hydrazi-nolysis and subsequent oxidation (ILNNIL-ILO, EtOH, 100°C then CuS04, fUO 76% overall) 1279 also homologs.188... 

Selective reduction of the C(2)=C(3) bond in naphthyridone 379 followed by treatment with BuLi in THF and methylation affords compound 380. Subsequent regeneration of the double bond occurs as a result of successive selenation, oxidation and yyn-elimination to form naphthyridone 381 (1991JHC541). Earlier, an analogous scheme has been used for the synthesis of ethyl 7-chloro-l-ethyl-6-fluoro-2-mrthyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylate (1989JHC1675). 

The additional signals in the H NMR spectrum indicated that the esteri-fying unit was l,2-dihydro-l-methyl-2,7-naphthyridine-4-carboxylic acid (69), and this was confirmed by methanolysis to afford the methyl ester of 69 and tetrahydrocantleyine (16). The absolute configuration of the methyl group at 1 on the 1,2-dihydronaphthyridine unit could not be determined due to rapid aerial oxidation to 70. Hence the structure of scaevodimerine A was deduced to be 71 (69). 

A mixture of 0.12 g. 2-amino-7-hydroxy-5-methyl-l,8-naphthyridine-3-carboxylic acid 8-oxide, aq. 18%-HCl, and TiClg allowed to stand 30-40 hrs. at room temp, under CO2 0.07 g. 2-amino-7-hydroxy-5-methyl-l,8-naphthyridine-3-carboxylic acid. - Other methods were not successful. S. Carboni et al., G. 96, 1443 (1966). 

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