4-Methyl-2,6-naphthyridine

Whilst many alkaloids contain the pyridine ring system, the combination of two pyridine rings as exemplified in the naphthyridines is rather uncommon in nature. The alkaloid jasminine (436), a 2,7-naphthyridine derivative, has been isolated from Jasminium species (68AJC1321) whilst 4-methyl-2,6-naphthyridine (437) occurs in the aerial parts of Antirrhinum majus and aronticus (71P2849). 

Despite a general paucity of information on 2,6-naphthyridines, the system has been included in several reviews 50-52 57 58 61,265,436,1357 1430 1432 4-methyl-2,6-naphthyridine has been found to occur naturally in several Antirrhina species,226 241 267 and physical properties of the parent heterocycle (1) have been quite extensively studied, usually for comparison with those of the other unsubstituted naphthyridines (see Section 29.2.2). 

Hexaphenyl-2,6-naphthyridine 3-Hexyl-2,6-naphthyridine 3-Hexyl-2,6-naphthyridine 2-oxide 3-Hydroxy-2,6-naphthyridin-1 (2//)-one l-Isopropoxy-2,6-naphthyridi n-3-amine 3-Isopropoxy-2,6-naphthyridi n-1 -amine l-Isopropylamino-2,6-naphthyridin-3-amine l-Methoxy-4-methyl-2,6-naphthyridin-3-amine l-Methoxy-2,6-naphthyridin-3-amine... 

Methylbut-2-enyl)-l-phenyl-2,6-naphthyridin-3-amine ( ) 4-Methyl-2,6-naphthyridin-3-amine 4-Methyl-2,6-naphthyridine... 

In addition to 4-methyl-2,6-naphthyridine, an unknown alkaloid, C16H13N2O2, was isolated. ... 

Methyl-2,6-naphthyridine (46) has been isolated from the aerial parts.34 The structure was assigned on the basis of comparison of spectral data with that of known naphthyridines and related N-heterocycles. 

Methyl-2,6-naphthyridine (104) Neozeylanicine (70) 7-O-Nicotinoyl-strychnovoline (66) 7-O-Nicotinoyl-tetrahydrocantleyine (67)... 

Comparison of the H NMR data with those of both 2,6- and 2,7-naphthy-ridine was not possible, although 2,6-naphthyridine (106) shows resonances at 9.39 (H-l and H-5), 8.77 (H-3 and H-7), and 7.80 ppm (H-4 and H-6) (104,105). In addition, in the UV spectra of the two systems absorption beyond 330 nm is only observed for the 2,6-naphthyridine (105) system (104), 2,7-naphthyridine (105) shows a long-range maximum at 305 nm (106). On this basis, the compound was assigned the structure 4-methyl-2,6-naphthyridine (104) (57). However, the structure drawn in the paper is of 4-methyl-2,7-naphthyridine (107). Additional details of the isolation and spectroscopic properties were published subsequently (63), although no structures were presented in this paper. Further work by Taurins and Li (107) established the structure through synthesis (see Section III.D.l). 

Following their work on the synthesis of the parent compound 2,6-naphthyridine (105) (105). Taurins and Li reported their work in full (107) and at the same time reported a synthesis of the 4-methyl derivative 104, isolated by Harkiss and Swift (62). 4-Cyano-3-pyridyl-acetonitrile (275) was methylated (CFLI-NaOQHs) in the side chain to afford 2-(4-cyano-3-pyridyl)propionitrile (276), which was treated with hydrogen bromide in ether to afford 3-amino-l-bromo-4-methyl-2,6-naphthyridine (277). Diazo-tization/bromination and replacement of the bromine groups with hydrazine gave 278, and reaction with CuS04 in acetic acid afforded 4-methyl-2,6-naphthyridine (98) (Scheme 23) (107), whose spectroscopic properties were identical with those reported previously (62,63). 

Methyl-2,6-naphthyridine (104) may be derived as shown in Scheme 49. An iridodial such as 385 is cleaved in a manner similar to the formation of 2 to afford a seco-cyclopentano-dihydro-actinidine 386, which can be oxidized and decarboxylated to 104. 

The first known natural occurrence of a 2,6-naphthyridine has been reported. Thin-layer chromatography of an alcoholic extract of the plant above gave a base (CgHgNg mp 78°) whose spectral examination indicated that it is 4-methyl-2,6-naphthyridine (19). Other possible isomers were excluded on the basis of the NMR spectral data 14, 15). The same base was also isolated from A. orontium L. 16). 

Antirrhinum orontium L. (Misopates orontium Raf.) (Vol. 2, p. 281) 4-Methyl-2,6-naphthyridine (70) and choline were isolated and identified by comparison with authentic samples. Two other alkaloids, Base B (C15H9-N3O) and Base C, were obtained in sufficient quantity only for i.r., u.v., and mass spectral determination. 

There is only one study concerning the covalent animation of methyl-naphthyridines. It has been reported that both 2-methyl- (37a) and 4-methyl-1,8-naphthyridine (37c) after treatment with KNH2/NH, are not converted into 1 1 (7-adducts but instead into their conjugate bases 38 and 39, respec-... 

There is only one study concerning the covalent amination of methyl-naphthyridines. It has been reported that both 2-methyl- (37a) and 4-methyl-... 

Treatment of 7-acetamido-2,4-dimethyl-l,8-naphthyridine (139 R = NHAc, R = Me) with ethyl iodide at 110° for 24 hr gave an ethiodide the corresponding 4-phenyl compound and methyl iodide formed a methiodide. Both of these salts possess a reactive methyl group and are therefore the 1-salts (cf. 140). The easily formed... 

A methiodide of 6-chloro-2-methyl-l,5-naphthyridine has been 2irepared no structure was assigned, but it is probably the 1-salt (142). The 5-N atom of 1,6-dimethyl-2-naphthyridone undergoes... 

Covalent hydration has been demonstrated in the following families of compounds 1,6-naphthyridines, quinazolines, quinazoline. 3-oxides, four families of l,3,x-triazanapththalenes, both l,4,x-triazanaphthalenes, pteridines and some other tetraazanaphthalenes, and 8-azapurines these compounds are discussed in that order. In general, for any particular compound (e.g. 6-hydroxypteridine) the highest ratio of the hydrated to the anhydrous species follows the order cation > neutral species > anion. In some cases, however, anion formation is possible only when the species are hydrated, e.g. pteridine cf. 21 and N-methyl-hydroxypteridines (Section III, E, 1, d). Table V in ref. 10 should be consulted for the extent of hydration in the substances discussed here. 

Chloro-6-methyl-l,5-naphthyridine reacts readily with methano-lic methoxide (65°, 7 hr, 75% yield), but more vigorous conditions (180°, 2-7 hrs, 30-85% yield) were used for various aminations. The 4-chlorodiazanaphthalene reacted with a sec-alkylamine under less vigorous conditions (95%, 36 hr, 85% yield) and with ammonia-phenol (180°, 3 hr, 50% yield) gave the phenoxy derivative which was also alkylaminated (200°, 3 hr, 90% yield).The 3-bromo and 3-bromo-2-ethoxy derivatives of428 were aminated with copper sulfate and concentrated ammonia (170°, 40 hr, 75% yield). 

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... 

Tile same methodology as mentioned for the preparation of (9) was applied for the synthesis of 8-nitro-l,6-naphthyridines. Heating diethyl N- 3-nitropyridin-4-yl)aminomethylenemalonate (12) in diphenyl ether yields ethyl 8-nitro-l,6-naphthyridin-4(lH)-one 3-carboxylate (13) (63JCS4237, 30%) and acid treatment of 4-( y, y-diethoxypropylamino)-5-nitro-2-(/3,/3 -trifluoroethoxy)-pyridine (14) gives in a similar way 8-nitro-5-(/3, /3-triflu-oroethoxy)-l,2-dihydro-l,6-naphthyridine (15, 76%). Subsequent oxidation with chloranil, acid hydrolysis, and methylation with methyl iodide gives 8-nitro-6-methyl-l,6-naphthyridin-5(6H)-one (16,63%) (81JHC941). 

Tlie parent l,X-naphthyridines (X = 5, 6, 7, and 8) give with methyl iodide N-methyl naphthyridinium iodides. In 1,6- and 1,7-naphthyridine the... 

Anti-mycobacterium avium activity in vitro of 3-carboxy-7-methyl-6-nitro-l-ethyl-l,8-naphthyridin-4(lH)-one (6-nitro derivative of nalidixic acid) was demonstrated (93MI1). 

Whereas FVT of 3-methyl derivative of 131 at 700-830 °C (10 " mbar) afforded 1,3-dimethyl-4-hydroxy-1,2-dihydro-1,8-naphthyridin-2-one, FVT... 

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... 

Amide-induced pyridine-pyrimidine transformation is also reported with 2-bromo-l, 5-naphthyridine. 2-Methyl-4-amino-l, 3,5-triazanaphtha-lene is obtained, together with its 4-amino derivative The presence of the amino group at position 4 is certainly due to a SnH amino-dehydrogenation in preformed 2-methyl-l,3,5-triazanaphthalene (63RTC997, 73RC459, 94MI1). 

Chemical Name 1-ethYl-1,4-dihYdro-7-methyl-4-oxo-1,8-naphthyridine-3-carboxylic acid Common Name —... 

Abbreviations SB334867A, 1-(2-methyylbenzoxanzol-6-yl)-3-[1,5]naphthyridin-4-yl-urea hydrochloride SB408124, 1-(6,8-difluono-2-methy l-qu in ol in -4-y I )-3-(4-di methyl am ino-ph eny I )-urea aACT-078573 (Brisbare-Roch etal. Nat Med, 2007)... 

CsH, N02 103003-01-6) see Indeloxacine ( )-2-(hydroxymethyl)morphoIine see under 2-hydroxymethylmorpholine 4-hydroxy-7-methyl-l,8-naphthyridine-3-carboxylic acid (C,()HhN20 i 13250-97-0) see Nalidixic acid 4-hydroxy-7 melhyM,8-naphthyridine-3-carboxyIic acid ethyl ester... 

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