2.7- Naphthyridine aromaticity

The discovery of new broad spectmm antibiotics has been accompanied by the development of processes for fluorinated feedstocks ring-fluorinated aromatics for those quinolones containing a fluorobenzopyridone group, and fluorinated pyridine precursors for those antibiotics containing a naphthyridine nucleus (enoxacin, tosufloxacin) (see Table 14). 

Hexahydro pyrrolo-benzdiazepinetrione 394 in boiling phosphorous oxychloride produces 3,5-dichlorobenzo[/z][l,6]naphthyridine 396 as rearrangement product of trichloride 395 (Scheme 81 (2003JHC255)). The suggested mechanism includes thermal aromatization in the final step. 

Comparison of the bond lengths with those of benzene, naphthalene and pyridine suggests that whilst there is certainly aromatic character some bond fixation occurs in the naphthyridines. It is probable that canonical structure (1) (of, for example, 1,5-naphthyridine) and to a lesser extent structures (7) and (8) are the major contributors to the ground state, but the charged structures (9) and (10) must also be included in order to account for the chemical properties of the naphthyridines. 

The air oxidation and aromatization of substituted 6,7-dihydro-5/7-[l,6]naphthyridin-8-ones to substituted 8-hydroxy-[ 1,6]naphthyridines has been reported <2003JME453>. 

The formation of a series of thioethers from 2-thioxo-l,2,5,6,7,8-hexahydro- or from 3-thioxo-2,3,5,6,7,8-hexahydro-[2,7]naphthyridine, with the establishment of aromaticity, has been reported <1997PCJ34, 2003IZK2069>. 

Aryl-l,2-dihydro-3-nitro[l,8]naphthyridines have been obtained by the 6jt-thermal electrocyclization of l-(2-arylide-neamino-3-pyridyl)-2-nitroethylenes, obtained in situ from aromatic aldehydes and l-(2-amino-3-pyridyl)-2-nitroethylene in xylene <2002SC747>. 2-Chlorotetrahydro[l,8]naphthyridines have also been obtained from 2,6-dichloropyridines using a free radical xanthate-mediated cyclization <20040L3671>. 

Bismuth(lll) chloride catalyzes the intramolecular hetero-Diels-Alder reaction of aldimines, generated in situ from aromatic amines and the A -allyl derivative of o-aminobenzaldehyde, in acetonitrile at reflux to generate [l,6]naphthyridine derivatives <2002TL1573>. The hetero-Diels-Alder reaction of 3-aryl-2-benzoyl-2-propeneni-triles and enol ethers yields 2-alkoxy, 6-diaryl-3,4-dihydro-2//-pyran-5-carbonitriles (Scheme 29) <1997M1157>. 

Another structurally related series is the 2-ary 1-1,8-naphthyridin-4-ones (37 to 48, see Table 6.7), which contain a second nitrogen in the aromatic A ring. Compounds with meta-substituted phenyls (methoxy-, chloro-, or fluoro-) or a-naphthyl groups at the C-2 position showed potent cytotoxicity in the NCI 60 human tumor cell line panel with GI50 values in the low micromolar to nanomolar range (Tables 6.7 and 6.8).51 The tumor cell line selectivity varies with the various substituents. 2-(3 -Methoxyphenyl)-naphthyridinone (37) was significantly more cytotoxic in several cancer cell lines than the corresponding 2-(3 -meth-oxyphenyl)-quinolone (36). Both compound classes were potent inhibitors of tubulin polymerization the 2-ary 1-1,8-naphthyridin-4-ones had activity nearly comparable with those... 

The amino carbinol pyridines 264, prepared from 263 by DoM reaction and aliphatic or aromatic carboxaldehyde quench, are useful intermediates for condensed naphthyridines 266-268. The thermolytic reaction proceeds via intramolecular Diels-Alder reactions of the aza-orf/io-quinodimethane species 265 (Scheme 79) (84CC1304). 

Numerous other aromatic nitrogen compounds are known, and a significant number have been used to prepare complexes of platinum(II). Phthalazine (101) is one such compound, and the complex ds-PtCl(phthalazine)(PEt3)2 has been prepared in order to compare its fluxional properties with the phenanthroline and naphthyridine analogues. The monodentate complex is fluxional, but in this phthalazine case the orientation of the lone pairs is unsuitable for the five-coordinate intermediate required by an intramolecular process and the mechanism of exchange becomes dissociative.11 6... 

Of the bicyclic aza-aromatic molecules, only two, pteridine (36) (Hamor and Robertson, 1956) and 1,5-naphthyridine (37) (Brufani... 

Ethoxalylmethyl-6-methoxy-3-nitropyridine (9) underwent reductive cycliza-tion to 3-hydroxy-6-methoxy-3,4-di hydro-1,5-naphthyridin-2(l//)-one (10) (Pt02, H2, 3 atm, EtOH, 20°C, 2 h 69%) that was easily aromatized to give 6-methoxy-1,5-naphthyridine-2,3( 1 //, 5//)-dione (11) [TsCl, pyridine, 150°C ( ), 4h 83%] 234... 

Diphenyl-3-[3-(2-phenylimidazol-l-yl)propyl]-l,2,4-triazine (70) underwent thermal intramolecular addition (with loss of nitrogen) to give the tricyclic intermediate (71) and thence (by loss of benzonitrile) 2,3-diphenyl-5,6,7,8-tetrahydro-l,5-naphthyridine (72) [substrate, antioxidant (2,6-di-terf-butyl-4-methylphenol), l,3,5-Pr 3C6H3, reflux, 3 h 92%] that could be aromatized to 2,3-diphenyl-1,5-naphthyridine (73) (l,3,5-Pr 3C6H3, reflux, air, 24h 91%) the latter product (73) was also made directly from the triazine (70) (neat substrate, Se, 330°C, 10 h 85%) analogs likewise.137,522... 

Dimethoxypropylamino)-3-nitro-6-(2,2,2-trifluoroethoxy)pyridine (30) gave 8-nitro-5-(trifluoromethoxy)-l,2-dihydro-l,6-naphthyridine (31) (85% H3PO4, 100°C, 2 h 776%), which was aromatized in unstated yield (tetrachloro-l,4-benzoquinone, CHC13, reflux, 2.5 h).1116... 

Electron Density/Resonance Energy. Such phenomena have been calculated for 1,7-naphthyridine, mainly for comparison with those of related systems, to reveal the effect of ring nitrogen atoms on aromaticity, and for correlation with observed electronic spectra.676 840 1126 1173... 

Such syntheses are more suited to the preparation of hydro rather than aromatic 1,8-naphthyridines and may require auxiliary synthons. A few typical examples follow. 

Aromatization of the nitro compound (102) giving 3-nitro-l,6-naphthyridine (103) (24% yield) has been achieved by treatment with iodine <89T2693>. 

Imidazole and 2-phenylimidazole undergo intramolecular Diels-Alder reaction with 1,2,4-triazines tethered between an imidazole nitrogen and the triazinyl C-3 position to produce tetrahydro-l,5-naphthyridines. The reaction proceeds by a cycloaddition with subsequent loss of N2, followed by a presumed stepwise loss of a nitrile. Addition of antioxidant BHT inhibits aromatization to greatly improve the yield of tetrahydronaphthyridine 504 (Scheme 115) <2004JOC7171, 1997TL7499>. 

In the laboratory of N. Suzuki, the synthesis of several heterocyclic condensed 1,8-naphthyridine derivatives with potential antimicrobial activity was executed. The preparation of pyrazolo[3,4-b][1,8]naphthyridines required 7-chloro-6-formyl-3-ethyl ester as the precursor that was obtained by the Stephen reduction of the corresponding aromatic nitrile. The solution of the aromatic nitrile in chloroform was added to the solution of SnC /dry HCI gas in ether. After two days of stirring, the aldimine hexachlorostannane product was treated with warm water to obtain the desired aromatic aldehyde in modest yield. Heating of the aldehyde with methyl hydrazine afforded the pyrazole derivative. 

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