Reactions of Halogeno-2,7-Naphthyridines

The utility of halogeno-l,5-naphthyridines as intermediates is indicated by the variety of their reactions. In terms of nucleophilic displacement, the positional order of reactivity is 2(6)-halogeno 4(8)-halogeno 3(7)-halogeno-l,5-naphthyridines, but individual reactivities may be affected significantly by the presence of electronreleasing or electron-withdrawing substituents. This situation is especially evident in Sections 3.2.1 and 3.2.2. 

Although alkoxy ion is a more powerful nucleophile than aryloxy ion, both types react vigorously with activated halogeno-l,5-naphthyridines and even (albeit sluggishly) with 3(7)-halogeno-l,5-naphthyridines. In the absence of kinetic data, the following preparative examples illustrate the practicalities of such displacement reactions. 

2-Chloro-l,5-naphthyridine (39, R H) gave 2-methoxy-l,5-naphthyridine (40, R = H) (MeONa, MeOH, reflux, 4h 38%) 234 2-chloro-6-methyl- (39, R = Me) gave 2-methoxy-6-methyl- (40, R = Me) (likewise, 7h 75%), 2-butoxy-6-methyl- (BuONa, BuOH no further details), or 6-methyl-2-phenoxy-l,5-naphthyridine (substrate, PhOH, 180°C, NH [, 7h %).1051 

2-Chloro-3-nitro-l,5-naphthyridine (41, R = C1) gave 2-ethoxy-3-nitro-l,5-naphthyridine (41, R = OEt) (KOH, EtOH, 20°C, 12 h 90% note mild conditions due to the activating effect of the nitro group).827 

2-Iodo-l,5-naphthyridine with sodium nitrite in dimethylformamide gave bis(l,5-naphthyridin-2-yl) ether (140°C, 3h 44% mechanism unclear).692 Also other examples.271 

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