2.6- Dichloro-1,5-naphthyridine

X-NaphthvridinvloxvDhenoxvDropanoic Acids. The final naphthyri-dinylox3rphenoxypropanoic acids 1-4 were assembled by condensation of the 2-chloronaphthyridines with a 2-(4-hydroxyphenoxy)propanoic acid derivative. Thus, reaction of 2,6-dichloro-1,5-naphthyridine (5) with the dianion of acid 22 (excess K2CO3, DMSO, 105 C) smoothly led to 63% of the desired aryloxyphenoxypropanoic acid la (Scheme 6). Similarly, condensation of 2-chloro-l,6-naphthyridine (6), 2,6-di-chlor0-1,7-naphthyridine (7) and 2,6-dichloro-1,8-naphthyridine (8) with the methyl ester of 2-(4-hydroxyphenoxy)propanoic acid (23)... 

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... 

When more than one oxo (hydroxy) group is present, a mixture of chloro-hydroxy- and dichloro-naphthyridines is usually formed.Thus, reflux of 3-nitro-l,8-naphthyridin-2,7(lH,8H)-dione (114) with phosphorus oxychloride gives the three halogeno compounds (115,116, and 117), the ratio being dependent on the reaction time (94EJMC735). 

Several 3-fiuoropyridine derivatives are employed to produce enoxacia, tosufioxacia, and other naphthyridine antibacterials (Table 14). Examples of such iatermediates iaclude 2,6-dichloro-5-fiuoronicotiQonitrile (429), ethyl 2,6-dichloro-5-fiuoronicotiQate (430), 2-chloro-3-fiuoropyridine (393), 6-acetyl-2-(4-acetyl-l-piperaziQyl)-3-fiuoropyridine (431), and 5-fiuoro-2,6-dihydroxynicotiQamide (394). 

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. ... 

Reaction of 2,4-dichloro-l,5-naphthyridine with ammonia (170°, 20 hr), hydrazine (100°, 16 hr), or aqueous hydrochloric acid (100°, 3 hr) was shown to yield the 2-amino- (47% yield) and 2-hydroxy-4-chloro derivatives (66% yield), but 2-hydrazino substitution (68% yield) was assumed. Disubstitution with ammonia (190°, 4 hr), hydrazine (100°, 48 hr), and ammonia-phenol (180°, 6 hr) occurred in high yield. Displacement of the 4-oxo group in 2,4-dioxo-l,5-naphthyridine occurs with aniline plus its hydrochloride (180°, 12 hr, 88% yield) to yield 429. Oxo groups in the 2- or 4-positions were... 

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. 

Subjecting 8-chloro-5-iiitro-l,7-iiaphthyridiiie (97) to reduction with tin(II) chloride leads, besides loss of the chloro atom and reduction of the nitro group, i.e., formation of 5-amino-l,7-naphthyridine (131, 22%), to the formation of small amounts of 5-amino-6,8-dichloro- (132, 1.5%) and 5-amino-6-(or 8-)chloro-l,7-naphthyridine (133, 2.5%) (88PJC305). 

The synthesis of the corresponding naphthyridone scaffold was carried out according to the methods reported by Chu et al. [12] and Sanchez et al. [13]. Namely, the hydrolysis of ethyl 2,6-dichloro-5-fluoronicotinate (3) [14] followed by reaction with thionyl chloride results in the formation of 2,6-dichloro-5-fluoronicotinyl chloride (4). Treatment of this compound with monoethyl malonate in THF under n-butyllithium followed by acidification and decarboxylation gives rise to ethyl 2,6-dichloro-5-fluoronicotinylacetate (5). Reaction of compound 5 with ethyl orthoformate in acetic acid followed by cyclopropylamine results in the formation of 3-cyclopropylamino-2-(2,6-dichloro-5-fluoronicotinyl)acrylate (6), the cyclization reaction of which under NaH/THF gives rise to the required ethyl l-cyclopropyl-6-fluoro-7-chloro-l,4-dihydro-4-oxo-l,8-naphthyridine-3-carboxylate (7), as shown in Scheme 3. 

The N-acylation product of the reaction of enaminones with either 2-chloronicotinoyl chloride or 2,6-dichloro-5-fluoronicotinoyl chloride readily undergoes cyclization (either directly or on treatment with sodium hydride) to give high yields of 8-acyl-7-alkyl[l,6]naphthyridin-5(6//)-ones, which themselves are attractive precursors for elaboration to naphtho[2,3-, ][l,6]naphthyridin-5-ones and pyrido[2,3-f][l,6]naphthyridin-6-ones <2002T58>. 

It has been demonstrated that the 2-chlorine atom in 2,4-dichloro-1,5-naphthyridine can be preferentially displaced by water, ammonia, and hydrazine. With phenol, aniline, and benzylamine, both chlorine atoms are replaced. The selective reactivity of the 2-chlorine atom is in agreement with approximate quantum mechanical calculations.25... 

Chloro-,26 8-chloro-,10,25 8-bromo-,2s 5,8-dichloro, and 5,8-dibromo-1,7-naphthyridine (25a-e)27 with KNH2/NH3 give an exclusive addition at C-2, yielding the 2-aminochloro- and 2-aminobromodihydro-l,7-naph-... 

Phosphorus oxychloride converts 1,6-naphthyridine 1,6-dioxide to a mixture of 2,5-dichloro-, 3,5-dichloro-, 4,5-dichloro-, and 5-chloro-l,X-naphthyridines (121, 120, 122, and 123, respectively). The 3,5- and 2,5-dichloro isomers are formed as the major products. 

Nitro-l,5-naphthyridin-2 (T//)-one (18) gave a 1 1 mixture of 2-chloro-3-nitro-(19, R = N02) and 2,3-dichloro-l, 5-naphthyridine (19, R = Cl) (PC15, POCl3, reflux, 2.5 h 40% of a mixture that afforded 10% yield of each product after separation) 818 thus neat POCl3 was better (see preceding example). 

Dichloro-l,5-naphthyridine (48) gave 2-methoxy-4-chloro-l,5-naphthyri-dine (47) (limited MeONa, MeOH, reflux, 1 h 65%).1151 or 2,4-diphe-noxy-l,5-naphthyridine (49) (excess PhOH, reflux, 6h 89%).1023... 

Also macrocyclic products from 2,6-dichloro-l,5-naphthyridine and triethylene glycol or the like.389... 

The nontautomeric oxo substrate, 6-methyl-l,6-naphthyridin-5(6//)-one (16) with phosphoryl chloride gave only 5-chloro-l,6-naphthyridine (17) (reactants, 170°C, sealed, 20 h 63% reflux, 12 h 0%) but with phosphorus pentachloride and phosphoryl chloride gave a separable mixture of the same product (17), 5,8-dichloro-l,6-naphthyridine (18), and 8-chloro-6-methyl-1,6-naphthyridin-5(6//-one (19) (reactants, reflux, 24 h 2%, 24%, and 14%, respectively) 299... 

Naphthyridine 1,6-dioxide (22) likewise gave a mixture of chlorinated products from which the main constituents, 2,5- and 3,5-dichloro-l, 6-naphthyridine (23), appear to have been isolated.1069... 

Dichloro-3-[2-ethoxycarbonyl-3-(thiazol-2-ylamino)acryloyl]-5-fluoropyri-dine (13) gave ethyl 7-chloro-6-fluoro-4-oxo-l-(thiazol-2-yl)-l,4-dihydro-l,8-naphthyridine-3-carboxylate (14) (Bu OK/dioxane 63%).143... 

Dichloro-3-ethoxycarbonylacetyl-5-fluoropyridine (52) with triethyl orthoformate and subsequently cyclopropylamine gave 7-chloro-l-cyclopropyl-6-fluoro-4-oxo-l,4-dihydro-l,8-naphthyridine-3-carboxylic acid (53) ( 60% note hydrolysis of the ester group).487... 

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