Mono- naphthyridines

The relation of activation by para vs. ortho ring-nitrogen in bicy-clics is altered by these special cases. For example, 4-chloroquinazoline (4-Cl-l,3-diaza) is much more reactive than the 2-chloro isomer (2-Cl-l,3-diaza) for two reasons, one being the poor activation in 2-Le-3-aza compounds. 4-Chloro-l,8-naphthyridine will be decreased in reactivity relative to its 2-chloro isomer due to the very poor activation in 4-Le-8-aza compounds and it may be only slightly more reactive than the mono-aza analog 4-chloroquinoline. The greater reactivity at the 2-position of 2,4-dichloro-l,8-naphthyri-dine 3 can be ascribed to this 4-Le-8-aza effect. ... 

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... 

Deactivation (weak) from the adjoining ring does not prevent facile disubstitution of 4-methyl- and 4-phenyl-2,7-dichloro-1,8-naphthyridines wdth alkoxides (65°, 30 min), p-phenetidine (ca. 200°, 2 hr), hydrazine hydrate (100°, 8 hr), or diethylaminoethylmer-captide (in xylene, 145°, 24 hr) mono-substitution has not been reported. Nor does stronger deactivation prevent easy 2-oxonation of 5,7-dimethoxy-l-methylnaphthyridinium iodide wdth alkaline ferricyanide via hydroxide ion attack adjacent to the positive charge and loss of hydride ion by oxidation. 

Amino-dehydrogenation (SnH) using the LA/PP system was also studied with the 3,6-dinitro-l,8-naphthyridines (87a-87d) (86JHC473 93LA471). Besides mono amino products, diamino products are also obtained the yields are, however, moderate. 

It is interesting that only mono- and not di-pseudo bases are obtained, and that with 1,6-naphthyridine, pseudo base formation occurs at the quinolinoid site, the diquatemary salt (79) yielding (80) and not (81). However naphthyridinediones are formed on reaction with alkaline K3Fe(CN)6 (72CJC917, 74CJC962). 

Dinitro[l,8]naphthyridine and its 2-substituted derivatives are dehydro-methylaminated with a solution of potassium permanganate in liquid methylamine to afford the corresponding mono- or bis-methylamino-3,6-dinitro[l,8]naphthyridines (Scheme 7) <2000CJC950>. When the 2-substituent is either chlorine or OMe, then some substitution by NHCH3 also occurs. Quantum-chemical calculations have shown that the reaction is controlled by the interaction of the frontier MOs. 

The condensation reactions of mono- and bicyclic 4-piperidones has proven a popular method for the preparation of substituted 5,6,7,8-tetrahydro[l,6]naphthyridines, with several different examples being reported <2001SC787, 2003BML1627, 2004JME5167>. 

As mentioned in Part I, all the naphthyridines and their mono- and diquaternary salts should be reducible, and this has now been shown. The stability of the radicals formed in acidic solution depends on pH and their structure the symmetric naphthyridines form more stable radicals than the unsymmetric. The structures of the dimerized products have not been established.323-326... 

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... 

The polarography of mono- and dimethiodides of 1,5-naphthyridine has been examined,997,1303 the influence of /V-methylation on the 13NNMR spectra of... 

Note A few such oxides have been made by primary synthesis (see Chapter 15), and the oxidation of unsubstituted 1,7-naphthyridine to its mono- and di-A-oxides has been covered in Section 16.1.3. 

In recent years, nucleophilic addition reaction has been widely used for the synthesis of various derivatives of isomeric naphthyridines. For example, nucleophilic addition of indole to 1,5-, 1,6- and 1,8-naphthyridine derivatives in the presence of benzoyl chloride in toluene or DMF yields, depending on the temperature and reactant ratio, hydrogenated mono- (256-265) or fc-(3-indolyl)naphthyridines 259-264 (1985MI2, 1986KGS1218, 1986MI3). Hetarylation includes the in situ formation of /V-acyl heteroaromatic cations and the addition of nucleophiles to them. Aromatization of the N-acylated hydrogenated naphthyridine derivatives 259 and 264 on treatment with tetrachloroquinone affords the same compound, naphthyridine 265. 

Thieno[3,2-c][l,5]naphthyridine 5A-oxide (54) and 9A-oxide (53) underwent non-selective bromination with DBI and the corresponding mono- and dibrominated compounds were formed in... 

A route in which a synthon for such a dialdehyde is central depends on ortho lithiation of an aryl bromide for conversion to ortho bromoaryl aldehyde, then palladium-catalysed replacement of the halide with an alkyne, subsequent reaction with ammonia producing the isoquinoline. The sequence below shows how this type of approach can be used to produce naphthyridine mono-A-oxides by reaction of the alkynyl-aldehyde with hydroxylamine instead of ammonia. 

It has been found that replacing benzoyl chloride by a mild oxidising agent, normally potassium ferricyanide, results in the N-oxide function being retained and in improved yields of the nitrile products [112, 113]. Thus, quinoline-N-oxide gave 2-cyanoquinoline-N-oxide in 85% yield and l,6-naphthyridine-l,6-di-N-oxide gave a mixture of mono- and disubsiituted products [113]. 

A new heterocyclic ring system, pyrrolo(3,2-3,4]-l,8-naphthyridine (IX-121) is obtained from the cyclization of mono- and diW-acyl derivatives of 2-aminonicotyrine (IX-120) with phosphoms oxychloride. Thus, 2-dibenzoyl-aminonicotyrine is dissolved in toluene and phosphorus oxychloride and heated... 

---