6-Amino-2-chloro-5-nitropyridine

Diaminopyridine has been prepared by reduction of 2-amino-3-nitropyridine with iron and aqueous acidified ethanol,3 tin and hydrochloric acid,6 or stannous chloride and hydrochloric acid,6 by catalytic reduction of 3-amino-2-nitropyridine,6 by reduction of 3-amino-2-nitropyridine,7 2-amino-5-chloro-3-nitro-pyridine,8 or 2-amino-5-bromo-3-nitropyridine 4 with sodium hydroxide solution and an aluminum nickel alloy, and by catalytic reduction of 2-amino-5-bromo-3-nitropyridine.4 Animation of... 

Nitropyridine yields a mixture of 2-, 4- and 6-amino-3-nitropyridines by this method142. An amino group is introduced into the 2-position of l,n-dinitronaphthalenes (.n = 3-8)143 and various 5- and 8-nitroquinolines, such as 8-methyl-5-nitroquinoline and 6-chloro-8-nitroquinoline, have been aminated adjacent to the nitro group144. Pteridines are converted into alkylarnino derivatives by the action of a solution of potassium permanganate in an alkylamine, e.g. equation 51145. 

Nitropyridine-2-sulfonic acid was utilized as starting material for the preparation of 2-alkoxy- and 2-amino-5-nitropyridines in fair to excellent yields. 2-Chloro-5-nitropyridine was also realized, whereas attempts with bromo, iodo, or cyano substituents were not successful <030BC2710>. 

Other pyridine derivatives have been aminated with alkali metal amides. Treatment of 2,3 -bipyridine (116) with sodium amide afforded the isomers shown in Scheme 46 (77MI1). In a similar fashion, 2,2 -bipyridine gave 6,6 -diamino-2,2 -bipyridine, 3,3 -bipyridine yielded 6-amino-3,3 -bipyridine, and 4,4 -bipyridine afforded 2,2 -diamino-4,4 -bipyridine upon treatment with sodium amide (78RCR1042). The amination of 2-chloro-5-nitropyridine gave the Chichibabin products 2-amino-6-chloro-3-nitropyridine and 4-amino-2-chloro-5-nitropyridine in low yields (<3% of each) on treatment with potassium amide in liquid ammonia. The main product was 2-amino-5-nitropyridine, obtained primarily by the S fANRORC) mechanism (85JOC484). 

Nucleophilic replacement of hydrogen is presumably being observed when reduction of a 3-nitropyridine to a 3-aminopyridine by stannous chloride and concentrated hydrochloric acid is accompanied by nuclear chlorina-tion so, 241a, 772-4, Thus, 4-amino-3-nitropyridine gives 3,4-diamino-2-chloropyridine soa and 4-ethoxy-3-nitropyridine yields 5-amino-2-chloro-4-ethoxypyridine24ia. Clearly, the pyridinium cations must be involved. 

Derivatives such as 3-fluoro-4-nitropyridine [13505-01 -6] (396) or the 1-oxide [769-54-0] (397) have been used to characteri2e amino acids and peptides. 5-Eluoro-3-pyridinemethanol [22620-32-2] has been patented as an antihpolytic agent (398). A promising antidepressant, l-(3-fluoro-2-pyridyl)pipera2ine hydrochloride [85386-84-1] is based on 2-chloro-3-fluoropyridine [17282-04-1] (399). 

Treatment of 2-amino-3-hydroxypyridine (185) with 2-chloro-3-nitropyridine (193) easily provided intermediate 194. Attempts to cyclize 194 with potassium hydroxide in aqueous ethanolic solutions failed, probably due to strong H-bonding. Similarly as with phenoxazines, the cyclization smoothly proceeded in DMSO to give low yield (31%) of 1,9-diazaphenoxazine (195) (Scheme 30) (74CC878, 76JHC107, 77H391). 

The hydrochloride of 3-amino-4-hydrazinopyridine 65 was prepared by reaction of the 4-chloro-3-nitropyridine derivative with ethoxycarbonyl-hydrazine in phenol to give the hydrochloride of ethyl 3-(3-nitro-4-pyridyl)carbazate 64 (R2 = OEt), which on successive heating in concentrated hydrochloric acid and hydrogenation over Pd/C gave 65. Its reaction with phenylacetic acid or with phenoxyacetic acid gave the hydrochloride... 

Dichloro-3-nitropyridine was reacted with N-ethoxycarbonylpiperazine to give 6-chloro-2-(4-ethoxycarbonyl-l-piperazinyl)-3-nitropyridine. The product, without purification, was heated with ethanolic ammonia in a sealed tube at 120°-125°C to give 6-amino-2-(4-ethoxycarbonyl-l-piperazinyl)-3-nitropyridine (mp 132°-134°C), which was treated with acetic anhydride in acetic acid to give 6-acetylamino-2-(4-ethoxycarbonyl-l-piperazinyl)-3-nitropyridine (mp 168°-169°C). This compound was catalytically hydrogenated in the presence of 5% palladium-carbon in acetic acid to yield 3-amino-6-acetylamino-2-(4-ethoxycarbonyl-l-piperazinyl)pyridine. The obtained 3-amino derivative, without further purification, was dissolved in a mixture of ethanol and 42% tetrafluoroboric acid, and to this solution was added a solution of isoamyl nitrite in ethanol at below 0°C with stirring 20 minutes later, ether was added to the solution. The resulting precipitate was collected by filtration and washed with a mixture of methanol and ether and then with chloroform to yield 6-acetylamino-2-(4-ethoxycarbonyl-l-piperazinyl)-3-pyridine diazonium tetrafluoroborate mp 117°-117.5°C (dec.). 

All these amination reactions show exclusive SNH substitution. There is hardly any indication for the formation of 3-nitropyridines, in which the chloro or methoxy group was replaced by an amino group, even when these leaving groups are present at the reactive a-position of the pyridine ring. It seems to be a characteristic feature of the oxidative amination... 

Chloro-3-nitropyridine undergoes SNH methylamination at C-6 as well as amino-dechlorination at C-2, 2,6-bis(methylamino)-3-nitropyridine being obtained (Scheme 7). 

The cyclization of 2-chloro-3-nitropyridines with 2-amino-3-hydroxy-pyridine proceeds in a similar way to afford the diazaphenoxazine 25 (Scheme 29) (74CC878 76JHC107 77H391 77JPS1349). 

As in benzene chemistry, electron-releasing amino groups facilitate electrophilic substitution, so that, for example, 2-aminopyridine undergoes 5-bromination in acetic acid even at room temperature this product can then be nitrated, at room temperature, forming 2-amino-5-bromo-3-nitropyridine. Bromina-tion of all three amino-pyridines is best achieved with iV-bromosuccinimide at room temperature, products being 2-amino-5-bromo-, 3-amino-2-bromo- and 4-amino-3-bromopyridines. Similarly, chlorination of 3-amino-pyridines affords 3-amino-2-chloro-pyridines. Nitration of amino-pyridines in acid solution is also relatively easy, with selective attack of 2- and 4-isomers at P-positions. A mechanistic study of dialkylamino-pyridines showed nitration to involve attack on the salts. ... 

A useful route for the unequivocal synthesis of complex derivatives of this ring system involves cyclization of compounds of general formula 63. These are readily prepared from the appropriate 2-chloro-3-nitropyridine and an aminoketone. If the requisite amino ketone is too unstable, the corresponding amino alcohol may be used and oxidized to the ketone after reaction with the chloropyridine. 

Structural studies presented by Chibata and by Kamiya included similar total syntheses of eritadenine, each consisting of the condensation of 4-amino-6-chloro-5-nitropyridine with 4-amino-4-deoxy-2,3-C)-isopropyli-dene-D-erythromic acid, followed by catalytic reduction of the ni-tro group and imidazole ring closure by formic acid or its amide. This can be exemplified by Kamiya s procedure (400) shown in Scheme 83. Soon improved syntheses were reported from both laboratories by Kawazu et al. (401) and Kamiya et al. (402), each starting from adenine and methyl 2,3-0-isopropylidene-5-0-tosyl-)8-D-ribofuranoside or d-erythronolactone acetonide, respectively (Schemes 84 and 85). Kamiya... 

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