2-Amino-3- -1,8-naphthyridine

Naphth[2,l-d]oxazolium iodide, 2,3-dimethyl-reactions, 6, 215 Naphthyridine, amino-reactions, 2, 598 Naphthyridine, N-amino-reactions, 2, 596 Naphthyridine, 3-bromo-reactions... 

The 2,7-naphthyridine system 53 (Scheme 8.4.18) was combined with 2,4-dinitrochlorobenzene and 2-amino glycerol for in situ reaction of the resulting Zincke salt. The resulting naphthyridinium 54 was trapped by Bradsher cycloaddition with (Z)-vinyl ether 55, providing tetracycle 56 (X-ray) upon internal addition of one of the diastereotopic hydroxymethyl groups to the resulting iminium. This approach was also extended to the use of chiral 2,7-naphthyridinium salts, prepared via the analogous Zincke process. ... 

The amination of 2-bromo-l,5-naphthyridine also proceeds without rearrangement to yield 2-amino-1,5-naphthyridine (up to 80%) together with 1,5-naphthyridine (10%) and a substance (CgH8N4,10% yield) of unknown structure as by-products. Thus, here also it remains uncertain whether a 2,3-aryne is an intermediate. 

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... 

Several approaches to the synthesis of nitronaphthyridines and their derivatives are reported. Very common ones are those in which the construction of the nitronaphthyridine system was achieved by using nitro synthons (see Section II,A) or by nitration of the naphthyridine ring, although a successful nitration requires the presence of electron-donating substituents (see Section II,B). Furthermore, the oxidation of the amino group in aminonaphthyridines... 

In this method the nitro group in the aliphatic nitro compound is usually present on a carbon atom, which is also activated by CO-functioiiality (aldehyde, ester, arylketoiie). A successful application of this method is the Borsche modification of the Friedlander synthesis, involving condensation of A-(3-amino-4-picolylidene)-p-toluidine (17) with [Pg.289]

It was reported that the Niemeiitowski synthesis of 4-hydroxy-3-iiitro-7-pheiiyl-l,8-iiaphthyridiii-2(lH)-oiie (25) from ethyl 2-amiiio-6-pheiiyhii-cotiiiate (23) and ethyl nitroacetate (24) in the presence of sodium was unsuccessful, producing only traces of (25), while condensation of ethyl 2-amino-6-phenylnicotinate (23) with the less reactive ethyl acetate resulted in the formation of 4-hydroxy-7-phenyl-l,8-naphthyridin-2(lH)-one in good yield [66JCS(C)315]. It seems that the more reactive nitroacetate tends to precipitate rapidly from the reaction mixture as its sodio derivative, which explains the low yield of (25). 

Tlie condensation of nitromalonic aldehyde (26) with 2,6-diaminopyridine (27) in the presence of phosphoric acid, affording 2-amino-6-nitro-l,8-naphthyridine (28,37%) (77TL2087), is another example of a successful application of a nitro aliphatic compound in the synthesis of nitronaphthy-ridines. 

A low-temperature nitration of 2-amino-l,8-naphthyridine (59a) and 2-amino-l,5-naphthyridine (59b) yielded the 2-nitramino-l,8-naphthyridine (60a, 65%) (98MI3) and 2-nitramino-l,5-naphthyridine (60b, 70%) (63RTC988) respectively. Attempts to rearrange (60a) and (60b) to 2-amino-3- (or 6-) nitro-l,8-(or -1,5-) naphthyridines failed. 

Tlie products of nitration of 2-amino-5-phenyl-l,8-naphthyridin-7(8H)-one (63) vary depending on whether the reaction is carried out with nitric acid in sulfuric acid or in acetic anhydride (74GCI499). In sulfuric acid the phenyl ring was found to be nitrated more easily than the naphthyridine ring, yielding a mixture of 3- and 4-nitrophenyl derivatives (64) in acetic... 

Nitration of 2-amino-l,8-naphthyridin-5(8H)-one (67a) in acetic acid or in acetic anhydride does not occur in HNO3/H2SO4 the products obtained were difficult to separate (72GCI253). Hydrolysis of the amino group under nitration conditions has also been observed with 6- and 7-carboxy-2-aminonaphthyridin-5(8H)-ones (67b/67c), yielding the corresponding (68b/ 68c) (72GCI253). 

Oxidation of the 2-(S,S-dimethyl)sulhnylimine derivatives (74) of 2-amino-l,X-naphthyridines (73a-73c) (X = 5,6,8) with m-chloroperbenzoic... 

In all 3-nitronaphthyridines with an unsubstituted C-2 position (84a, 84f, and 84j) no traces of the corresponding 2-amino-3-nitro-l,X-naphthyridines (X = 5, 6, and 8) were obtained. As already mentioned, in the aminations of 2-R-3-nitronaphthyridines where R is a chloro or ethoxy group, no amino-dechlorination or amino-deethoxylation was observed. 

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. 

The compounds 87a and 87b are aminated at position 4, yielding the 4-amino compound (88a, 40%) and the 2,4-diamino compound (88b, 11%) respectively the 2-ethoxy compound (87c), however, undergoes amination at position 4 as well at position 5, giving a mixture of the 4-amino compound (88c, 20%) and the 5-amino compound (89a, 14%).Tlie 2-chloro compound (87d) yields a highly complex reaction mixture from which the 5-amino compound (89b), the 2,4-diamino derivative (88b), and 2,5-diamino-l,8-naphthyridine (89c) could be isolated. l-Ethyl-3-nitro-l,8-naphthyridin-2(lH)-one (90a) and 3,6-dinitro-l-ethyl-l,8-naphthyridin-2(lH)-one (90b) were aminated exclusively in the 4-position to give compounds 91a (62%) and 91b (45%), respectively (93LA471). 

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). 

In a similar manner 8-amino-5-nitro-l,7-naphthyridine (98,61%) was obtained from 8-ehloro-5-nitro-l,7-naphthyridine (97) (82MI1). 

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,... 

Similarly, a number of l-alkyl(aryl)-4-ehloro-3-nitro-l,8-naphthyridin-2 (IH)-ones (100) have been reported to reaet with ammonia or alkylamines to afford the eorresponding 4-amino eompounds [101, R = H, CH3, C2H5, CH(CH3)2, CH2 CfiHs] (91JHC2029, 91MI2 92JMC4866). 

Treatment of ethyl 4-chloro-7-diethylamino-6-nitro-l,8-naphthyridine 3-carboxylate (104) with the amines RH [R = N(CH2)s NH(CH2)N(C2Hs)2] gives the corresponding 4-amino derivatives [105, R = N(CH2)s, 74% and 105, R = NH(CH2)N(C2Hs)2, 50%]. With diethylamine the 7-chloro-6-nitro derivative of nalidixic acid (i.e., 106) yields the 7-diethylamino compound 107 (62%) (79YZ155). 

Catalytic hydrogenation (Pd/C) of 2-chloro-3-nitro-l,5-naphthyridine (125, R = Cl) in methanolic solution afforded 3-amino-l,5-naphthyridine (126, R = H, 74%) isolated in the form of its trihydrochloride (40MI1). Similar Pd/C hydrogenation of 2-ethoxy-3-nitro-l,5-naphthyridine (125, R = OEt) gave 3-amino-2-ethoxy-l,5-naphthyridine (126, R = OEt, 47%) (80RTC83). Reduction with tin(II) chloride in hydrochloric acid also leads to 126, (R = OEt, 73%) (63RTC997). 

Interestingly, no dehalogenation occurs when 2-chloro-3-nitro-l,8-naph-thyridine (127) is treated with tin(II) chloride in hydrochloric acid 3-amino-2-chloro-l,8-naphthyridine (128,33%) is the sole product (76S691). 

Tin(II) chloride reduction of both 4-chloro-3-nitro-l,8-naphthyridine (129, R = Cl) (79PJC1665) and 3-nitro-l,8-naphthyridine (129, R = H) (76S691) gave in 30-35% yield 3-amino-l,8-naphthyridine (130, R = H) reduction of the 4-amino-3-nitro compound (129, R = NH2) yielded 3,4-diamino-l,8-naphthyridine (130, R = NH2,37%) (79PJC1665). 

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). 

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