Halogeno-1,8-naphthyridines reactions

Ring transformations were found in numerous reactions of halogeno-naphthyridines with potassium amide in liquid ammonia, in addition to the formation of amino compounds, which involve a Chichibabin adduct (Section I1,B,1), the intermediacy of a naphthyridyne (Section a tele... 

Extensive investigations have been carried out in order to establish the intermediary occurrence of didehydro-1,5-, -1,6-, -1,7-, and -1,8-naphthyri-dines in aminations of halogenonaphthyridines with potassium amide in liquid ammonia. These studies have definitively proved that 3,4-didehydro-1, X-naphthyridines (X = 5, 6, 7, 8) are intermediates in aminations of the 3-and 4-bromo (chloro) derivatives of the I. X-naphthyridines.22,24-48-50 No evidence has been found for the occurrence of 2,3-didehydro-1,X-naphthyridines in these reactions. Also, in the reaction of the 2-halogeno-l,X-naphthyridines no evidence for these 2,3-didehydro intermediates was obtained. 

One example has been reported of the occurrence of an even tele substitution within one ring of the 1,7-naphthyridine system. Amination of 5-halogeno-l,7-naphthyridines (27) with potassium amide gave 8-amino-1,7-naphthyridine (54).28 This reaction bears a close analogy to the formation... 

The conversions of 1,5-naphthyridine A-oxides into C-halogeno-l,5-naphthyr-idines by the Meissenheimer reaction (POCl3 or POBr3) or a related reaction (Br2 in Ac20) both suffer from the fact that two or more products are usually formed in each case. This introduces a sometimes difficult separation procedure, so that such... 

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. 

Each of the other reported reactions of halogeno-l,5-naphthyridines is illustrated by the following classified examples. 

Note The conversion of 1,5-naphthyridine N-oxides to C-halogeno-1,5-naphthyridines (Meissenheimer reaction) has been discussed in Section 3.1.3. Other reported reactions are illustrated here. 

The main use of nitro-1,5-naphthyridines has been as precursors for 1,5-naphthyridinamines. However, the presence of a powerfully electron-withdrawing nitro group is often of use to activate adjacent leaving groups such as halogeno toward nucleophilic replacement reactions. 

Halogeno-l,6-naphthyridines have also been made by the Meissenheimer reaction from 1,6-naphthyridine N-oxides and by a (copperless) Sandmeyer-type reaction from 1,6-naphthyridinamines. However, neither route has been developed into a practical preparative procedure, as indicated in the following examples. 

Halogeno-1,6-naphthyridines undergo a variety of useful reactions, as illustrated in the following subsections. 

A few rarely used reactions of halogeno-l,6-naphthyridines are exemplified... 

The aminolysis of halogeno-l,7-naphthyridines is fairly well represented in the literature, but other potential reactions have seldom been used. Reported reactions are illustrated in the following examples. 

Note The conversion of such oxides to halogeno-l,7-naphthyridines by the Meissenheimer reaction has been exemplified in Section 17.1. 

Halogeno substituents at the 2-, 4-, 5-, and 7-positions of 1,8-naphthyridine will be activated toward aminolysis and similar reactions those at the 3- and 6-positions will be only mildly so activated and extranuclear halogeno substituents will resemble at best that in benzyl chloride. 

Note At least in simple cases, the Meissenheimer reaction appears to be unsatisfactory for the production of halogeno-l,8-haphthyridines. Thus 1,8-naphthyridine 1-oxide with phosphoryl chloride gave a difficult-to-separate mixture of 2-, 3-, and 4-chloro-l,8-naphthyridine (in ratio 36 7 57) 225 phosphoryl bromide and bromine/acetic acid both gave even worse mixtures... 

The interchange of halogeno substituents has been covered at the end of Section 2.4.1. The many other important reactions of halogeno-1,8-naphthyridines are illustrated in the following classified examples. 

The conversion of amino- into halogeno-1,8-naphthyridines has been covered in Section 24.1. Other reported reactions of amino-, hydrazino-, hydroxyamino-, and azido-1,8-naphthyridines are illustrated in the following groups of examples. 

The relatively few reported reactions of halogeno-2,6-naphthyridines are illustrated by the following examples. 

The literature contains some basic information on the preparation and reactions of halogeno-2,7-naphthyridines. In this system, halogeno substituents are active at the 1-, 3-, 6-, and 8-positions but inactive at the 4- and 5-positions. The effect of fluoro substituents on the ultraviolet spectra of 2,7-naphthyridines has been investigated.1313 Reviews have appeared.1266,1363... 

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