Preparation of 2,7-Naphthyridine

5- Naphthyridine is usually made from 2-pyridinamine by a Skraup-like reaction (see Section 1.3.3), but it has also been prepared by removal of unwanted substituents as illustrated in the following examples. 

5- Naphthyridine 1-oxide (1) underwent deoxygenation by phosphorus trichloride to give 1,5-naphthyridine (2) (substrate, CHCI3, PCI3I, CPC— reflux, 1 h 60%).1033 

2-Chloro-l,5-naphthyridine (3) gave 1,5-naphthyridine (2) (H2, Pd/CaC03, KOH, MeOH %).87 

The Naphthyridines The Chemistry of Heterocyclic Compounds, Volume 63, by D.J. Brown Copyright 2008 John Wiley Sons, Inc. 

Two parent hydro-1,5-naphthyridines have been made by reductive methods as exemplified here. 

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The condensing agents used in the Skraup and related reactions are not limited to glycerol. Table VII lists some of the carbonyl compounds and aminopyridines which have been successfully used to prepare various 1,5-naphthyridines. The majority of the dimethyl-and trimethyl-1,5-naphthyridines still remain unknown simply because of the difficulties involved in the preparation of the various 3-aminopicolines and 3-aminolutidines,... 

Another general procedure 72, 78 for the preparation of 1,5-naph-thyridines requires the heating of the condensation product of 3-aminopyridine or a substituted 3-aminopyridine and diethyl ethoxymethylenemalonate (EMME) in refluxing Dowtherm A to afford 3-carbethoxy-4-hydroxy-1,5-naphthyridine (22). This reaction allows the introduction of various groups into the 3- and the 4-positions, as illustrated. 

A diquatemary salt of 1,5-naphthyridine was prepared by refluxing the parent compound in dimethyl sulfate.150... 

An essentially similar type of reaction has been used to prepare fused 1,5-naphthyridines such as 2,8-dimethyl-6,12-bis(p-tolylimino)-5,6,ll,12-tetrahydrodi-benzo[ >, g][l,5]-naphthyridine (3).688... 

Complexes. The iodine complexes of 1,5-naphthyridine and other heterocycles have been used under anhydrous conditions to estimate the pK.t values for such heterocycles.885 The structures of 1 1 complexes of 1,5-naphthyridine with oxalic acid,1024 fumaric acid,1024 or meso- 1,2-diphenyl- 1,2-ethane-diol1021 have been studied. Complexes of 1,5-naphthyridine with Co(II), Ni(II), Cu(II), Zn(II), and Ag(I) salts have been prepared 705 the mono- and... 

Note The preparative nuclear reduction of 1,5-naphthyridine has been covered in Section 2.1.1. 

Azolo[1,5]naphthyridines. Imidazonaphthyridines can be prepared by the reaction of ammonium acetate with appropriately substituted naphthyridinium salts. For example, reaction of the ketone 236 in acetic acid with iron(m) chloride produces the tetracycle 237 <2001AJC105> (Equation 64). 

Attempts to prepare tricyclic homologues of the naphthyridines have been partially successful. 4-Amino-1,5-naphthyridine (109) reacts under Skraup conditions to give 4,5,9-triazaphenanthrene (110), and 1,8,9-triazaanthracene derivatives (111) can be isolated from the mixtures of products obtained by treatment of 2-amino-l,8-naphthyridin-7-one and its derivatives with ethyl ethoxymethylenemalonate, acetylacetone and alkyl /3-oxoglutarates (72JHC801) (see also earlier papers in that series). However, 2-amino-1,8-naphthyridine (112 R = H) reacts under Skraup conditions to give the 2-oxo derivative (113 R = H) instead of a 1,8,9-triazaanthracene, and 2-amino-1,6-naphthyridine behaves similarly (75MI21103). Under non-hydrolytic conditions, naphthyridines (112 R = Aik, Ar, H) cyclize... 

Naphthyridine will form complexes of the type ML2 with Cu(II), Co(II) and Ni(II) but not with Cd(II), Pd(II), Ba(II) or Zn(II) (66MI21101). 1,5-Naphthyridine 1,5-dioxide forms coordination compounds with Cu(II) salts (76IC2916), and metal complexes of l,7-naphthyridin-8-ones with Cu(II), Ni(II), Fe(II) and Fe(III) have also been prepared (54JCS505). A more detailed account of metal ion-naphthyridine complex formation is given in a recent review (83AHC(33)147). 

The majority of the methods for obtaining the naphthyridines (l)-(4) are similar to the methods employed for the preparation of quinolines, and aminopyridines are therefore the required starting compounds. Thus, 1,5-naphthyridines (1) may be obtained, sometimes together with the isomeric 1,7-naphthyridines (3), starting from 3-aminopyridine, 1,6-naphthyridines (2) are synthesized from 4-aminopyridines, and the 1,8-naphthyridines (4) are best obtained from 2-aminopyridine or its derivatives. 

Naphthyridines (see Sections II and V,D). Diquaternary salts of 1,5-25,165 ( 57), 1,6-,25 1,7-,25 1,8-25 ( 8), and 2,7-25 naphthyridines have been prepared by the action of methyl sulfate165 or methyl fluorosulfonate.25l,8-Naphthyridine does not react with methyl sulfate to give a diquaternary salt but does so with 1,2-dibromoethane to give 58,166 an interesting observation. 

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 unsubstituted compound, 1,5-naphthyridine, can easily be prepared by application of the Skraup reaction to 3-aminopyridine. This reaction has been modified several times,17,59,60 and a yield of 60-70% may now be realized. Rapoport and Batcho16 have shown that cyclization takes place exclusively at the 2-position of the 3-aminopyridine in the Skraup reaction since none of the isomeric 1,7-naphthyridine is formed in the absence of a blocking group at that site. 

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. 

Czuba07 prepared 2-, 3-, and 4-bromo-1,5-naphthyridine and treated them with potassium amide in liquid ammonia. The results of this study were explained by the intermediacy of 1,5-naphthyridyne-3,4 (133)149 in the reaction of the 3- and 4-bromo derivatives. A competing addition-elimination mechanism was also suggested since the ratios of the amino products from the 3- and 4-bromo compounds were not the same.147... 

Metal complexes, analogous to 8-hydroxyquinoline,54,151 of 4-hydroxy-1,5-naphthyridine,54 8-hydroxy-1,6-naphthyridine,54 151 and 8-hydroxy-1,7-naphthyridine54 with Cu(II), Ni(II), Fe(II), and Fe(III) have been prepared. The hydroxynaphthyridines chelate less readily than 8-hydroxyquinoline since they are weaker bases.151... 

This chapter covers information on the preparation, physical properties, and reactions of 1,5-naphyhyridine and its C-alkyl, C-aryl, /V-alkyl, and /V-aryl derivatives as well as their respective ring-reduced analogs. In addition, it includes methods for introducing alkyl or aryl groups (substituted or otherwise) into 1,5-naphthyridines already bearing substituents and the reactions specific to the alkyl or aryl groups in such compounds. For simplicity, the term alkyl-l,5-naphthyridine in this chapter is intended to include alkyl-, alkenyl-, alkynyl-, aralkyl-, and cycloalkyl-1,5-naphthyridines likewise, aryl-l,5-naphthyridine includes both aryl-and heteroaryl-1,5-naphthyridines. 

Most such naphthyridinones have been made by primary synthesis (see Chapter 1) and some by hydrolysis of halogeno-1,5-naphthyridines (see Section 3.2.3). Other preparative routes are illustrated by the following examples. 

Not many such 1,5-naphthyridines have been reported, but the X-ray structure of 4,8-dimethoxy-l,5-naphthyridine has been determined.777 Their preparation and reactions are illustrated by examples in the following lists. 

Note One such sulfone has been prepared by primary synthesis (see Section 1.3.3) another by oxidation of an alkylthio-1,5-naphthyridine (see a preceding subsection). 

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