Naphthyridines substitution

The 8-position of the quinolone nucleus can often be advantageously substituted by fluorine (58) or chlorine (59) to give compounds with improved antibacterial potency over hydrogen in this position. With 1,8-naphthyridines, activity is reported to be approximately equivalent to the quinolone bearing a hydrogen in this position (60). As an example of this, see the data for norfloxacin (8) and enoxacin (7) in Table 2. 

When two fused six-membered rings (naphthalene analogues) are considered, possibilities become very numerous, partly on account of the reduced symmetry of naphthalene, compared with benzene, and also because of the larger number of positions available for substitution. Thus, there are two monoazanaphthalenes, quinoline (8) and isoquinoline (9), four benzodiazines [cinnoline (10), phthalazine (11), quinazoline (12) and quinoxaline(13)], with the two nitrogen atoms in the same ring, and six naphthyridines (e.g. (14), named and... 

No kinetic data or semi-quantitative comparisons among themselves or with other diazines are available. The most reactive derivative is expected to be the 4-substituted-l,6-naphthyridine (425), with 2-substituted-1,6- and l-substituted-2,7-naphthyridines (426) somewhat less reactive, all three positions being activated by two ring-nitrogens by resonance. Other positions also activated in this way... 

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. 

Methoxylation of l-chloro-3-methyl-2,7-naphthyridine occurs exothermically on addition to methanolic methoxide (20°). The 1-chloro or l-chloro-3-methyl derivatives are substituted with... 

A great number of N-substituted 4-hydroxy-3-nitro-l,8-naphthyridin-2 (IH)-ones are obtained by reaction of N-substituted azaisatoic anhydrides with ethyl nitroacetate carbanion (Section II,A,4,a). A very specific method, more recently developed, is that of the inverse Diels-Alder method, involving the reactions of enamines with 5-nitropyrimidine (Section II,A,4,b). 

Many reports deal with the preparation of numerous hydroxynitronaph-thyridones and nitronaphthyridinediones. By the nitration of 4-hydroxy-l,X-naphthyridin-2(lH)-ones (X = 5,6,7, and 8) (51a-51d) using nitric acid in acetic acid, the corresponding 3-nitro substituted compounds (52a-52d) were obtained in reasonable-to-good yield (75JMC726 77MI1 96MI1). 

Tile easy availability of (di)nitronaphthyridones, in which the lactam part can easily be converted into an iminochloride, has successfully led to preparation of the parent (di)nitronaphthyridines by removal of the chloro atom. For that purpose the chloro atom in the 2- and 4-chloro derivative of the 3-nitro-l,5-, -1,6-, and -1,8-naphthyridines (78a-78e) was first substituted with tosylhydrazine to give the corresponding tosyl-hydrazide, which then was hydrolyzed in alkaline solution into the corresponding 3-nitro-l,5-, -1,6-, and -1,8-naphthyridines (79a, 79b, and 79c). 

Nitro-l,5-, -1,6-, and -1,8-naphthyridines (75a-75c) are very reluctant to undergo SnH substitution when treated with liquid ammonia/potassium... 

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]

As discussed before, in liquid ammonia/potassium permanganate nucleo-phugal substituents at C-2, such as ones present in the naphthyridines (84c, 84e, 84h, 84i, 841, and 84m), could not be replaced by the amino group only SnH substitution takes place. However, it has been observed that in the reaction of the 2-chloro-3-nitro-l,8-naphthyridine (92c) with liquid methylamine/potassium permanganate S H substitution as well as methylamino-dechlorination takes place, yielding 2,4-bis-(methylamino)-3-nitro-l,8-naphthyridine (93c). 

Taking into account the high reactivity of the ehloro atoms in 2-ehloro-3-nitro- (99a, 99d, and 99f), 7-ehloro-3-nitro- (99e and 99g), 2,7-diehloro-3-nitro- (99c), and 2-ehloro-3,6-dinitro-l,8-naphthyridines (99b), a great variety of 2- (or 7-) substituted amino produets [99, = NHCH3, N(CH3)Ph,... 

A number of 1-substituted 4-chloro-3-nitro-l,8-naphthyridin-2(lH)-ones (122) (R are the same substituents as in the scheme in Section II,A,4,a) were obtained from the corresponding 4-hydroxy-l,8-naphthyridin-2(lH)-ones (30) (91JHC2029,91MI2 92JMC4866). 

Sodium hydrosulfite successfully reduced the iiitro group in a number of l-A -alkyl(aryl) 4-(substituted) amino-3-nitro-l,8-naphthyridin-2(lH)-ones (143) to give the corresponding 3-amino derivatives (144) (91JHC2029, 91MI2 92JMC4866). Tliese products could not be purified but were used in their crude form for further annelation into imidazonaphthyridin-4(5H)-ones (see Section III,G). 

Also, the observed highly regioselective course in the SnFI substitutions in 2-R-3-nitro-l, 8-naphthyridines (R = FI, OFI, Cl, NFI2, OEt) with the anion of chloromethyl phenyl sulfone was explained by MNDO quantum-chemical calculations showing that, like in the aminations, the interaction of FIOMO of the nucleophile with LUMO of the nitronaphthyridines controls the regioselectivity (91JFIC1075). 

Heating diethyl (2-pyridylamino)methylenemalonates 304 (R = COOEt, = Me, OH) in AcOH afforded 4-oxo-4//-pyrido[l, 2-n]pyrimidine-3-carboxylates 305 (R = Me, OH) (96JHC1041). Flash vacuum thermolysis of 2-substituted 3-(2-pyridylamino)acrylates 304 (R = CN, COOEt, R = H) through a packed silica tube (530 °C, 0.01 mmHg) gave 3-substituted 4//-pyrido[l,2-n]pyrimidm-4-ones 306 (R = CN, COOEt) (94AJC1263). Ethyl 7-methyl-4-oxo-l, 4-dihydro-1,8-naphthyridine-3-carboxylate (79%) was... 

A series of 6-substituted 8,9-dimethoxy-2,3-methylenedioxy-6ff-dibenzo[c,h] [2,6] naphthyridin-5-ones (IX) was synthesized and evaluated for topo I-targeting activity as well as for cytotoxicity against different cell lines by Zhu et al. [53]. From the topo I-mediated DNA cleavage data of these compounds (IX), we developed Eq. 7 (Table 5) ... 

Besides the domino Michael/SN processes, domino Michael/Knoevenagel reactions have also been used. Thus, Obrecht, Filippone and Santeusanio employed this type of process for the assembly of highly substituted thiophenes [102] and pyrroles [103]. Marinelli and colleagues have reported on the synthesis of various 2,4-disubstituted quinolines [104] and [l,8]naphthyridines [105] by means of a domino Michael addition/imine cyclization. Related di- and tetrahydroquinolines were prepared by a domino Michael addition/aldol condensation described by the Hamada group [106]. A recent example of a domino Michael/aldol condensation process has been reported by Brase and coworkers [107], by which substituted tetrahydroxan-thenes 2-186 were prepared from salicylic aldehydes 2-184 and cycloenones 2-185 (Scheme 2.43). 

Formation of the central six-membered ring is the key to the synthesis of the highly substituted irnidazo[4,5-r]-[2,7]naphthyridines, 67 and 68 (Equations 15 and 16) the bicyclic precursors 65 and 66 are themselves the products of Hantzsch pyridine syntheses <1999PHA814>. 

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