3- Amino-2-nitropyridine, oxidative

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). 

However, attempts to prepare 3-iiitro-l,8-iiaphthyridiiie (11) by the Skraup reaction—heating of 2-amino-5-nitropyridine with glycerol in the presence of an oxidant— were not successful (74YZ1328). 

N-Amination of amines by hydroxyl-amine-O-sulfonic add, 43, 1 p-Aminoacetanilide, oxidation to 4,4 -diaminoazobenzene, 40, 18 2-Amino-5-bromo-3-nitropyridine, 44,... 

In nitroamine oxides the nitro group may be reduced preferentially but usually both functions are affected. 5-Ethyl-2-methyl-4-nitropyridine A -oxide is converted quantitatively to 4-amino-5-ethyl-2-methylpyridine by hydrogen over 30% palladium on charcoal in ethanolic solution [737]. The outcome of the hydrogenation of a nitroamine oxide may be influenced by reaction conditions [736]. 

Dioximes of a-diketones such as benzil on oxidation with IBTA are converted into 1,2,5-oxadiazole-A-oxides (furoxans) in high yields (75S445) (Eq. 35). Benzo- (Scheme 46) and pyrido-oxadiazoles (Eq. 36) are formed when o-nitroaniline and 3-amino-2-nitropyridine are subjected to similar oxidation. 

Al-Jallo and Al-Biaty24 prepared 4-phenyl-2-oxo-2H-pyrido[l,2-c<]-pyrimidines from 2-aminopyridines and ethyl phenylpropiolate. When the reactions were carried out in deuterium oxide, the 3-deuterated derivatives were obtained. 2-Amino-5-nitropyridine failed to react. 

On addition of potassium permanganate the equilibrium shifts to the right, when the adducts are irreversibly oxidized into their respective amino-3-nitropyridines. Since the oxidation is assumed to be fast, the product composition probably reflects the kinetic composition of the three isomeric intermediates. 

Site specificity was found to be considerably higher in oxidative amino-dehydrogenation reactions with derivatives of 3-nitropyridine. 2-R-3-nitropyridine (R = C1, OMe) when treated with liquid ammonia and permanganate gives a reasonable yield of 6-amino-2-R-3-nitropyridine (R = C1, OMe) 6-R-3-nitropyridine yields 2-amino-6-R-3-nitropyridine (R = C1, OMe) (Scheme 4) (91LAC875). The corresponding 4-amino compounds are only obtained in small amounts. A similar observation was made on the low temperature oxidative amination of 2-amino-5-R-3-nitropyridines (R = H, Cl, Br). 

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... 

Oxidative amino-dehydrogenation of 2-, 4-, and 6-hydroxy-3-nitropyri-dines and of 4-amino- and 6-amino-3-nitropyridines met little success. 

Aminopyridines are especially convenient as a starting material for the preparation of nitropyridines by oxidizing the amino group. Kirpal and Bohm [214] have obtained 2-nitro- and 4-nitro-pyridines by this method. 

Whereas peroxyacetic acid oxidizes 2,6-dichloroaniline to 2,6-dichlo-ronitrosobenzene [/5J], peroxytrifluoroacetic acid carries the oxidation to the nitro compound. Refluxing 2,6-dichloroaniline with peroxytrifluoroacetic acid, which is prepared in situ from 90% hydrogen peroxide and trifluoroacetic anhydride in dichioromethane, gives 2,6-dichloronitroben-zene in 89-92% crude yields and 59-73% pure yields [290. 2-Amino-4-methylpyridine treated with 30% hydrogen peroxide in fuming sulfuric acid at 10-25 °C for 50 h yields 68% of 4-methyl-2-nitropyridine [203]. 

From the reaction of 2-chlorobenzoic acid and 2-amino-5-nitropyridine in the presence of potassium carbonate and copper powder or copper(II) oxide, Carboni and Pardi isolated the condensation product 210 (R = H, R -= 5-NO2), which was then cyclized with a strong concentrated acid to the pyrido[2,l-i)]quinazoline 211 (R= H, R = S-NOj). 

The combination of hydrogen peroxide with sulfuric acid serves well for oxidation of aminopyridines to nitropyridines. For example, a solution of 20 g. of 4-amino-2-methylpyridine in 100 ml. of cone, sulfuric acid is dropped into a mixture of 350 ml. of 15% fuming sulfuric acid and 175 ml. of 30% hydrogen peroxide at a temperature kept at 10-20°. The mixture is stirred at 20° for 1 hr., let stand for 2 days, and NH, NO,... 

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. 

Also carbanions of serine and threonine esters, protected in the form of oxazolines, are capable of addition to nitropyridines to form the corresponding adducts that can be oxidized into a-(nitropyridyl) amino acid derivatives [132]. It should be mentioned that addition of the carbanion of the protected threonine to nitropyridine proceeds with a high diastereoselectivity, which is controlled by the second chiral center present in the oxazoline ring (Scheme 38) [133],... 

In the series of azaaromatics pyridine appears to possess the least electron deficiency and cannot be aminated under these conditirms. In contrast, diazines, triazines, tetrazines, quinolines, quinoxalines, quinazolines, naphthiridines, polyazaaromatic compounds, and their nitro derivatives are able to undergo oxidative amination. Moreover, amination of highly Jt-deficient triazines, tetrazines, 3-nitropyridine, 3-nitroquinoline, etc. is possible to perform without KNH2, since ammonia itself serves as nucleophile in such cases (Scheme 6). However, the more electron deficiency of an azine substrate, the less regioselectivity of the reaction. Oxidative amination of 3-nitrop3ridine in Uquid ammonia with potassium permanganate affords a mixture of 2-amino-3-nitro- (33%), 4-amino-3-nitro- (24%), and... 

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