Uses of Naphthyridines

A large number of 4-oxo derivatives of the 1,8-naphthyridine ring system have been synthesized and screened for their antibacterial activity. In general, the active compounds are similar to the 1,5-naphthyridine derivative nalidixic acid.114-117 

The following 7-substituted compounds have shown some antibacterial activity1l8 122  

Other 1,8-napht hyridines have demonstrated antithrombic activity (162)123 and tranquilizer, muscle relaxant, and hypnotic properties (163),124 as well as anticonvulsant behavior (163124 and 164125 ). Some other derivatives (165) 

Nishigaki, M. Ichiba, S. Fukazawa, M. Kanahori, K. Shinomura, F. Yoneda, and K. Senga, Cliem. Pharm. Bull. 23, 3170 (1975). 

124 Chinese Academy of Medical Sciences. Shanghai, Yao Hsueli Hsueh Pao 15, 630 (1980). 

Chinese Academy of Medical Sciences, Shanghai, Yao Hsueh Hsueh Pao 15, 630 (1980). S. Carboni, A. Da Settimo, D. Bertini, P. L. Ferrarini, O. Livi, and 1. Tonetti, Farmaco. Ed.Sci. 30, 237(1975). 

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The 2,7-naphthyridine system 53 (Scheme 8.4.18) was combined with 2,4-dinitrochlorobenzene and 2-amino glycerol for in situ reaction of the resulting Zincke salt. The resulting naphthyridinium 54 was trapped by Bradsher cycloaddition with (Z)-vinyl ether 55, providing tetracycle 56 (X-ray) upon internal addition of one of the diastereotopic hydroxymethyl groups to the resulting iminium. This approach was also extended to the use of chiral 2,7-naphthyridinium salts, prepared via the analogous Zincke process. ... 

Tliis methodology has also been extended to the use of liquid methylamine/ potassium permanganate (LMA/PP system). When this system is applied to a number of 3-nitro-l,8-naphthyridines (92a-92g), the C-4 position could be successfully substituted by methylamino group yielding 93a-93f. Tire intermediary 4-methylamino-[Pg.305]

I n the above procedure, the use of 4-hydroxy-1,5-naphthyridine-3-carbonyl chloride in place of 4-hydroxy-1,5-naphthyridine-3-carboxyllc acid N-succinimide ester can also afford the same objective compound as above. The use of sodium thio-n-propoxide in place of sodium thiophenoxide can also give the objective compound in the form of the sodium salt. 

A different type of synthesis, which leads to a benzannulated indolo[2,3-3][l,6]naphthyridine 15, is illustrated in Scheme 3 <1999TL3797>, and the use of an azaindolone as starting material may introduce an additional heteroatom into the indole moiety of the product, as in 16 (Equation 2) <1994TL1995>. The dipyrrolo[2,3-3 2, 3 -g][l,8]naphthyridine 18 is produced by reaction of the naphthyridine 17 with ethyl glycinate in the presence of a phase-transfer catalyst (Scheme 4) <2000PS(163)29>. 

Amides of aminopyridines have also been widely used to direct lithiation, and are most effective when lithiated with BuLi in the absence of TMEDA (Scheme 38) . The lithiation of 80 can be used as a key step in the synthesis of naphthyridines and other condensed polycyclic heterocycles" . 

MI21104, 75JSP(54)167>. Correlation between molecular orbital energies calculated using the MIEH method and photoelectron spectra of naphthyridines showed more recognizable lone pair orbitals than did the extended Hiickel method (74MI21100). 

Substituted-3-aryl[l,6]naphthyridin-2-amines and 7-substituted-3-aryl[l,6]naphthyridin-2(l//)-ones have been prepared by diazotization of 3-aryl[l,6]naphthyridine-2,7-diamines, themselves obtained by the condensation cycli-zation of 4,6-diaminonicotinaldehyde and phenylacetonitrile <2000J(P1)1843>. Derivatives of cyanoacetic acid have rarely been used in the synthesis of naphthyridines, although a recent study has shown that they may be reacted with 4-piperidone derivatives to give [l,6]naphthyridines <2000CHE496>. 

The first derivative of the naphthyridine ring system was prepared by Reissert5 in 1893, who suggested the use of the name. No unsubstituted naphthyridine was known until 1926, when 1,5-naphthyridine ... 

The use of PMR spectroscopy in the structure determination of a large number of naphthyridines has greatly facilitated investigations involving cyclizations and substitution reactions. 

As in the case of the 1,5-naphthyridines, the Skraup reaction can be modified to prepare various methyl derivatives. The use of crotonalde-hyde, methacrolein, and methyl vinyl ketone affords the 2-methyl-,40 3-methyl-,41 and 4-methyl-l,6-naphthyridines,40 respectively. 

The dehalogenation of naphthyridines with hydrogen over palladium on calcium carbonate in a weakly basic alcoholic solution gives excellent yields (90-95%) of reduced compounds.38,45,134,137,138 This method for removal of halogens has been extensively used and generally surpasses the classic hydrazine-copper sulfate reduction method. 

The use of other metal catalysts in attempted reductions of halo-naphthyridines has resulted in reduction of the ring or, at best, in the formation of mixtures. 

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. 

The first paper on the addition of water to the C=N bond in naphthyridines (covalent hydration) appeared in 1963,9 but it was not until 1976 that the first report concerning covalent amination of naphthyridines using potassium amide in liquid ammonia was published.10... 

The use of infrared and Raman spectra of 1,6- and 1,8-naphthyridine has allowed the assignment of all 42 fundamental vibrations of these two ring systems.137 A transferable valence force field has been developed and applied to the calculation of the out-of-plane vibrations of 1,5-, 1,6- 1,7-. 1,8-, and... 

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. 

Note The chlorolysis of naphthyridinones or naphthyridinoles is usually done with neat phosphoryl chloride to which may be added phosphorus pentachlor-ide or dimethylformamide in difficult cases corresponding bromolysis is achieved by the use of phosphoryl bromide and the chlorolysis of (extra-nuclear) hydroxyalkyl-1,8-naphthyridines may be done with thionyl chloride with or without added zinc chloride. Typical examples of these procedures are given here. 

Although a substantial number of papers are devoted, at least in part, to 2, 7-naphthyridines, the spread of information is quite unbalanced in favor of primary syntheses. Accordingly, the 2,7-naphthyridine system will be covered in a single chapter. Several reviews of naphthyridine chemistry include material on the 2,7-system.49 50 53 61 265 407 456 1357 1430 1432 The original system name, copyrin/ copyrine,13 cf 39,40 is still used occasionally. 

The six possible pyridopyridine systems have been known almost universally since circa 1930 as 1,5- (1), 1,6- (2), 1,7- (3), 1,8- (4), 2,6- (5), and 2,7-naphthyridine (6), However, the occasional use of an appropriate pyridopyridine or diazanaphthalene may still be found in some publications, Historically, the word naphthyridin(e) was coined by Arnold Reissert in 1893 specifically for the 1,8-naphthyridine system (4) and was so used for some years, especially in the German literature. Other terms, such as isonaphthyridine [for 1,5-naphthyridine (1)], benzodiazines (very misleading), pyridinopyridines , 2,5-naphthyridine [for 1,6-naphthyridine (2)], and copyrin(e) 13,40 or copurine39 [for 2,7-naphthyridine (6)] have appeared in the literature. 

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