Of 3-nitropyridine

Direct aminadon of 3-nitropyridines v/ith methoxyamine in the presence of zinc chloride under basic conthdons proceeds to give 3-amino amino-3-nitropyridines fEq 9 51 ... 

Besides being presently the most efficient method for site-directed interchain disulfide bridging of two different cysteine peptides, this procedure is also recommended for a controlled peptide-protein conjugation by reacting Npys-protected cysteine peptides with properly thiol-functionalized protein carriers. 1761 In this conjugation procedure the amount of peptide grafted to the protein is quantitatively determined by measuring spectro-photometrically at 430 nm the amount of 3-nitropyridine-2(l//)-thione liberated in the reaction. An example of this approach is outlined in Scheme 18. 

The mechanism of the formation of 3-nitropyridine from pyridine on reaction with dinitrogen pentaoxide in the presence of sulfur dioxide has been partially elucidated,... 

Amination of 3-nitropyridine with potassium permanganate in liquid ammonia, or an aliphatic amine, affords the 2-amino-pyridine 157 (Equation 83) <1999JPR75>. The nitropyridine 158 is aminated at C-6 with O-methylhy-droxylamine in the presence of ZnCl2 to give 159 in high yield (Equation 84) <1998CC1519>. 

To prepare 2-aminopyridine by treatment of pyridine with potassium amide in liquid ammonia at —33 °C and using permanganate as oxidant was not successful. No reaction takes place under these conditions. The aromaticity of the pyridine ring is too high to allow nucleophilic amide addition. It was surprisingly observed that treatment of a solution of 3-nitropyridine in liquid ammonia (thus without the presence of potassium amide) with potassium permanganate, gave after work-up a mixture of... 

In general solutions of azines in liquid ammonia are homogeneous, making it possible to detect by 1H- and 13C-NMR spectroscopy the occurrence of intermediary compounds (see Section IV). In case of 3-nitropyridine the NMR spectrum in liquid ammonia did not feature any indication for intermediary covalent er-adducts. 

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... 

H-NMR spectroscopy of a solution of 3-nitropyridine in liquid methylamine shows an upheld shift of 5.33 ppm for H-4, clearly showing... 

The triazinone derivatives (325a-c) were prepared by the reaction of 3-nitropyridine with KCN in methanol, followed by treatment with diazomethane <83YZ1129>. 

Nitro compounds are easily reduced, catalytically or chemically, to amino compounds. Incomplete reduction can lead to a hydroxylamino derivative or to binuclear azo, azoxy, and hydrazo compouds, e.g., 789 790, 791. Examples include reduction of 3-nitropyridines using aqueous sodium hydrosulfite at room temperature <2005JME5104> and of 2-nitropyridine by transfer hydrogenation in the presence of 10% Pd/G and recyclable polymer-supported formate, prepared from aminomethylpolystyrene resin and ammonium formate <2005SC223>. A nitro group can be reduced in the presence of an A-oxidc group, e.g., 784 782. 

Vicarious nucleophilic substitution (3.3.3) permits the introduction of amino groups para (or ortho if para blocked) to nitro groups by reaction with methoxyamine or 1-amino-l,2,4-triazole. In contrast, VNS substitution of 3-nitropyridine with benzyl chloroacetate proceeds at C-4. °... 

The copper-catalyzed amination of bromopyridine 29 was reported by workers at Merck on route to the synthesis of muscarinic (M3) antagonist 31 <01TL3251>. Interestingly, an uncatalyzed amination of 3-nitropyridines has also been reported <01JCS(P1)376>. Other metal mediated processes have been used to access pyridines with important biological activity as well <0lJOC605x01TL6811>. 

Scheme 5 Palladium-catalyzed and metal-free amination of 3-nitropyridine...

The nitro group in the ortho- or para-positions is one of the strongest electron-withdrawing substituent, activating an aromatic ring for a nucleophilic attack [5]. No wonder that a great deal of both oxidative and eliminative Sn reactions have been observed in the series of nitroaromatic compounds [11, 15-18, 25, 27, 28, 30-32, 36, 37, 97-100]. The VNS protocol has been particularly effective for the Sn reactions of a large number of nitro-substituted aromatic and heteroaromatic compounds [11-18, 25, 27, 28, 30-32, 36, 37, 45, 98-100], as illustrated by nucleophilic alkylation of 3-nitropyridine with vicarious methyl chloroacetate (Scheme 22) [100]. 

Oxidative amination of 3-nitropyridine with ammonia, alkyl- and dialkylamines, and KMn04 as oxidant was reported by Bakke (Scheme 49) [60]. 

A similar VNS cyanomethylation of 3-nitropyridine and subsequent hydrogena-ti(Mi of the so-formed ort/io-nitropyridyl-substituted acetonitriles provided 4- and 6-azaindoles. The VNS of hydrogen in 2-methoxy-5-nitropyridine with the carb-anion of aiyloxyacetonitrile leads to pyridylacetonitrile. Alkylation of the latter with hromoacetOTiitrile followed by a two-step reduction efficiently results in the formation of 5-azamelatonin (Scheme 69) [187]. Condensation of pyridyl-substituted acetonitriles with aromatic aldehydes followed by catalytic reduction gave 3-benzyl-4-azaindoles [187],... 

Scheme 11 Oxidative aUtylamination of 3-nitropyridine in DMSO solution...

In order to improve the solubility of KMn04 in alkylamines, especially secondary ones, polar solvents were used. For instance, treatment of 3-nitropyridine with diethylamine and KMn04 in DMSO gave 6-diethylamino derivative in 60% yield, while without DMSO the reaction did not occur at aU (Scheme 11) [59]. As isolation of the target product in the presence of DMSO is rather complicated, alkylamination of l,2,4-triazine-4-oxides with dialkylamines (such as MeaNH, EtaNH, pyrrolidine, piperidine, and morpholine) and KMn04 can be carried out in acetone, as co-solvent [60]. 

In order to understand this phenomenon, the mechanism of oxidative alkylamination of 3-nitropyridine, 1,3-dinitrobenzene, and quinazoline with butylamine and pyrrolidine has been investigated [88]. 

Pyridine itself can be converted into 3-nitropyridine only inefficiently by direct nitration even with vigorous conditions, however a pair of methyl groups facilitate electrophilic substitution sufficiently to allow nitration to compete with side-chain oxidation. Steric or/and inductive inhibition of A-nitration allows C-substitution using nitronium tetrafluoroborate, an example is 2,6-dichloropy-ridine dehalogenation of 2,6-dichloro-3-nitropyridine provides a practicable preparation of 3-nitropyridine. ... 

The preparation of 3-fluoro-4-nitropyridine can be effected by oxidation of the aminofluoro compound with persulfuric acid. A similar reaction yields 4-nltrotetrafluoropyridine from the corresponding amino precursor. 4-Nitrotetrafluoropyridine is a liquid whose boiling point (152 to 154°) is appreciably lower than that of 2-nitropyridine (256°), or of 3-nitropyridine (216°). 

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