Nucleophiles, reaction with naphthyridines

It is not surprising that the behavior of naphthyridines toward nucleophiles has been a subject of numerous studies1 8 and that nucleophilic substitution in naphthyridines has become a very valuable and efficient method to synthesize substituted naphthyridines. In the last decade many important and new features of nucleophilic substitution in naphthyridines using nitrogen nucleophiles (especially liquid ammonia and potassium amide/liquid ammonia) have been found. In view of these recent results it seems worthwhile to review this area of research. The present chapter is concerned with the reactions of naphthyridine with nitrogen nucleophiles for a full review of naphthyridine chemistry, see the chapter by Paudler and Sheets, p. 147 of this volume. 

For a detailed account of naphthyridine reactions with nitrogen nucleophiles, see chapter by van der Plas et al., p. 95 of this volume. 

Perturbation Molecular Orbital (PMO) theory has been used to account for the regioselectivity of the reaction of naphthyridines (l)-(6) with amide and dimsyl anions. The reaction with the amide ion (a hard nucleophile) is under charge control, whereas the reaction with the dimsyl ion (a soft nucleophile) is determined by the distribution of the LUMO <91PJC1449>. 

In a so-called vicarious nucleophilic substitution of hydrogen,75 2,3-diphenylpyrido[2,3-6]-pyrazine is alkylated in the 8-position by [(chloromethyl)sulfonyl]benzene. This reaction proceeds by addition of the carbanion to the electron-deficient ring position of a nitroarene or electrophilic heteroaromatic system, followed by base-induced -elimination of the corresponding hydrogen halide.76,77 As with quinoxalines and naphthyridines, the reaction with pyrido[2,3-6]pyrazines also affords products bisannulated at the pyrazine or the pyridine moiety, depending on the kind of 2/3-substitution (cf. Section 7.2.3.1.2.2.2.). 

Nucleophilic chlorination of 1,5-naphthyridine mono- and di-N-oxides yields 2-chloro- and 2,6-dichloro-naphthyridines via electrophilic catalysis of the reaction of intermediates such as 430 with chloride ion. An interesting example of electrophilic catalysis is the... 

The reaction of 8-chloro-I,7-naphthyridine with KNH2 in liquid NH3 brings about the formation of adduct 57 by addition of the nucleophile to position 2.111,112 The pair of doublets due to H-2 centered at S 9.16 in the substrate are replaced by a new doublet at 5 5.16. The higher shielding of H-2 and the new multiplicity pattern substantiate the structure of the adduct. 

Amination of 5-bromo-l,6-naphthyridine (113) gives as tele product 2-amino-l,6-naphthyridine (51 ),24 but in addition to the intermediacy of anionic cr-adduct (114) (as proved by H-NMR spectroscopy), its formation involves anionic cr-adduct 115, which is formed by a proton shift from 114. The number of atoms between positions 2 and 5 is five, thus this reaction is referred to as an odd tele substitution. Both types of tele substitution involve Addition of the nucleophile as the initial step and Elimination of the leaving group as the last step. However, in the even tele substitution the elimination can be described to take place from a neutral dihydro species, while in the odd tele substitution the elimination must occur from an anionic intermediate. In the naphthyridines several examples of even and odd tele substitutions are found, and in the following sections the results of studies concerned with tele amination are presented. 

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. 

In the reaction of perfluoro-2-methylpent-2-ene with 2-methoxy-5-aminopyridine it is converted to a derivative of [l,5]naphthyridine (94JCS(CC)134). It is interesting to note that the carbon atom next to the amino group in the l,3(N,C)-binucleophilic reagents acts as the second nucleophilic center to form a heterocycle. Two equivalents of a- and / -aminonaphthalene react with one equivalent of perfluoro-2-methylpent-2-ene to yield the final product (02BKCS1017). 

The chemistry and physical properties of 1,7-naphthyridines (3) <82H(19)363> and of heterocycles (l)-(6) <83AHC(33)147) have been reviewed. The reactions of heterocycles (l)-(6) with nitrogen nucleophiles have also been reviewed <83AHC(33)95>. Reviews covering pyranopyridines (87AKZ104) and pyranopyrans <75MI 715-01) have been published. 

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