Nontautomeric 1,5-Naphthyridinones

Ethyl 4,8-dimethoxy-l,5-naphthyridine-3-carboxylate (28, R = C02Et) underwent thermal rearrangement to ethyl 1,5-dimethyl-4,8-dioxo-1,4,5,8-tetrahy-dro-l,5-naphthyridine-3-carboxylate (29, R = C02Et) (Ph20, reflux, 6.5 h 5% after a difficult separation from other products) 301 somewhat similarly, 4,8-dimethoxy-l,5-naphthyridine (28, R = H) gave 1,5-naphthyridine-4,8(lff,5fl)-dione (29, R = H) (neat substrate, 225°C, 10 h 62%).301 

Reports on the chemistry of these naphthyridinones are scarce. Available information is summarized here. 

Note Most of these naphthyridinones have been made by either primary synthesis (see Chapter 1) or alkylation of tautomeric 1,5-naphthyridinones (see Section 4.1.2). A third route, involving direct oxylation, is illustrated here. 

5-Naphthyridine methiodide (30) gave 1 -methyl-1,5-naphthyridin-2(l //)-one (31) [substrate, H20, 0°C NaOH/H2OJ, during 5 min then K3Fe(CN)6 during 30 min then 0°C, 90 min then 20°C, 5 h 56%] this was converted into its 5-methiodide (32) (Mel, PhH, reflux, 2 days %) which underwent oxidation (as above) to afford 1,5-di methyl-1,5-naphthyridine-2,6( 1 II,5H)-dione (33) ( 70%) analogs likewise.155 

Note The rearrangement of such a fixed naphthyridinone to a tautomeric C-alkylnaphthyridinone has been described in Section 2.2.1. The halogenolysis of a fixed naphthyridinone with concomitant /V-dealkylation has been exemplified in Section 3.1.4. 

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The term oxy-1,5-naphthyridine includes the tautomeric and nontautomeric 1,5-naphthyridinones, extranuclear hydroxy-l,5-naphthyridines, alkoxy-and aryloxy-... 

Many tautomeric and nontautomeric naphthyridinones have been made by primary synthesis (see Chapter 8) and a few by ozonolysis of alkylidene-l,6-naphthyridines (see Section 9.2.2) or by hydrolysis of halogeno-l,6-naphthyridines (see Section 10.4.2). Other preparative routes are illustrated by the following examples. 

Note This example affords only a nontautomeric naphthyridinone. 

Note The oxidation of nalidixic acid (1) to its 6-hydroxy derivative by microorganisms has been reported.219 Oxidative routes to nontautomeric naphthyridinones have been described using chemical oxidants64,1214 or aerial oxidation with or without irradiation.344,949... 

The conversion of a tautomeric 1,5-naphthyridinone into the corresponding chloro- or bromo-l,5-naphthyridine is usually done by heating for several hours with neat phosphoryl chloride or phosphoryl bromide, respectively. A mixture of phosphoryl chloride and phosphorus pentachloride has been used for a few difficult cases. In addition, exceptional reactions have been reported in which a nontautomeric /V-alkyl-1,5-naphthyridinone or a hydroxymethyl-1,5-naphthyridine was used successfully as substrate. The following examples illustrate the foregoing possibilities. 

The conversion of a 1,6-naphthyridinone into the corresponding halogeno-1, 6-naphthyridine is usually done by refluxing with phosphoryl chloride or bromide, with or without the addition of a tertiary base alternatively, a phosphorus pentahalide can be used but additional C-halogenation may result. Nontautomeric... 

TAUTOMERIC/NONTAUTOMERIC 1,6-NAPHTHYRIDINONES AND EXTRANUCLEAR HYDROXY-1,6-NAPHTHYRIDINES... 

Most known tautomeric and nontautomeric 1,7-naphthyridinones have been made by primary synthesis (see Chapter 15). Of the many potential indirect preparative routes, only two appear to have been used, as indicated in the following examples. 

Note This reaction amounts to the conversion of a nontautomeric to a tautomeric 1,7-naphthyridinone. 

Naphthyridinones are usually tautomeric with corresponding naphthyridi-nols, but they may be fixed (become nontautomeric) by /V-alkylation. As in related series, 1,8-naphthyridinones prefer to exist as oxo rather than hydroxy... 

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