2.6- Dimethyl-4-nitropyridine

The synthesis of 5,7-dimethyl-l//-pyrrolo[2,3-c]pyridine (85) has been carried out starting with 4-chloro-2,6-dimethyl-3-nitropyridine (86) according to Scheme 35 <84H(22)1347>. 

In an abnormal von Richter rearrangement, 2,6-dimethyl-3-nitropyridine reacts with potassium cyanide in methanol to give a mixture of 3-methoxy-6-methylpyridine-2-carbonitrile 1-oxide and 6,8-dimcthylpyrido[3,4-ring carbon in the 2-position of the pyrido[3,4-e ]pyrimidine originates from the 2-methyl group of the educt.420... 

The ortho indirect deactivating effect of the two methyl groups in 2,6-dimethyl-4-nitropyridine 1-oxide (163) necessitates a much higher temperature (about 195°, 24 hr) for nucleophilic displacement of the nitro group by chloride (12iV HCl) or bromide ions N HBr) than is required for the same reaction with 4-nitropyridine 1-oxide (110°). With 5-, 6-, or 8-methyl-4-chloroquinolines, Badey observed 2-7-fold decreases in the rate of piperidino-dechlorination relative to that of the des-methyl parent (cf. Tables VII and XI, pp. 276 and 338, respectively). 

V-Alkylation of 3-hydroxypyridine results from direct treatment with an alkyl halide or dimethyl sulfate and alkali (59JA5140,57RTC58). Regioselectivity depends, however, on other substituents present as well as conditions. For example, 3-hydroxy-2-nitropyridine is exclusively O-alkylated with dimethyl sulfate and potassium carbonate (81MI20600) and 2-amino-3-hydroxypyridines are exclusively O-benzylated with benzyl chloride and alkali in a two phase system and phase transfer catalyst (Scheme 96) (81S971). 

Dimethyl 3,5,6-trichloro-2-pyridyl phosphate, known as Fospirate or Dowco 217, is an rnsechcide useful rn anlrllea collars for dogs and cats. The compound 4-aminopyridine, known as Avilrol 100, and 4-nitropyridine-N-oxide, known as Avitrol 200, are useful as bird repellents. 

Dimethyl-4-nitropyridine-N-oxide-dimethyl sulfate adduct... 

To a suspension of 3,5-dimethyl-4-nitropyridine-N-oxide (150 g, 0.80 mole) in acetone (450 ml) was added dimethyl sulfate (90 ml, 0.95 mole). The mixture was heated to reflux until a clear solution was obtained and then allowed to cool to ambient temperature. An off-white crystalline solid separated out, which was filtered, washed with acetone and dried to yield 220 g of the adduct. Yield was 83.8% of theoretical. 

Dimethyl-4-nitropyridine-N-oxide-dimethyl sulfate adduct (220 g, 0.75 mole) was dissolved in methanol (1.0 Itr) and the solution heated to reflux. A solution of ammonium persulfate (140 gm) in water (200 ml) was added dropwise over 4 hours after which reflux was continued for 4 hours. Methanol was distilled off under reduced pressure and the residue was basified to pH 10 by addition of caustic lye (105 ml). The mixture was extracted with dichloromethane (2 times 400 ml). The dichloromethane layer was dried over sodium sulfate and filtered. The product was used as its solution in dichloromethane for the next reaction. 

To the cooled dichloromethane solution of 3,5-dimethyl-2-hydroxymethyl-4-nitropyridine was added thionyl chloride (60 ml, 0.85 mole) dropwise over a period of 2 hours and stirring was continued for a further 2 hours. Methanol (10 ml) was added to destroy excess thionyl chloride and separated product was filtered under suction and washed with dichloromethane. The cake was dried in vacuum oven to yield 55 g of a cream colored product. Melting point was 124°-126°C. 

To a suspension of 5-methyl-2-mercaptobenzimidazole (36 g, 0.2 mole), 2-chloromethyl-3,5-dimethyl-4-nitropyridine hydrochloride (47.4 g, 0.2 mole) and triethyl benzylammonium chloride (5 g) in a dichloromethane (500 ml) was added dropwise a solution of NaOH (17.6 gm, 0.44 mole) in water (30 ml). The addition was exothermic and the temperature was observed to rise to 40°C with reflux of dichloromethane - the reaction mixture was stirred for further 6 hours at ambient temperature and filtered. The cake was washed with water and dried in vacuum oven to yield 55.8 g of cream color product. Yield 81.1% melting point 124°-128°C. 

Pyridine /V-oxide is nitrated in the 4-position as the free base (9.81) [64CI(L)1577] and/p has been estimated as between 2.1 x 10"3 and 4 x 10"6 [66JCS(B)870 67JCS(B)1213], up to 95% yields of 4-nitropyridine N-oxide have been reported (51RTC581). 4-Nitration on the free base also occurs for the 3,5-dimethyl and 2,6- and 3,5-dichloro derivatives (9.82-9.84) [67JCS(B)1213]. 

R = N02) is an intermediate in this transformation.98 This reaction has been exploited to synthesize 4-nitropyridine 2,6-dicarboxylic acid dimethyl ester (105) from dimethyl l,3,5-trinitropentane-l,5-dicarboxylate (104 R = C02Me, R = H).99 The suggested course of the reaction is as shown in Scheme 20. 

Methoxy-5-nitropyridine (126) reacts readily with Af,/V-dimethyl-ethylenediamine in boiling water to give 89% of 127 (85EUP136730). Analogously, 4-ethoxy-3-nitropyridine-hydrochloride (128), is heated at reflux for 8.5 hr with an aqueous solution of ammonium acetate to afford 87% of 3-nitro-4-aminopyridine (129) (85EUP149537). 

C5H4N203 2-hydroxy-5-nitropyridine 5418-51-9 25.00 1.4476 2 4464 C5H6Br2N202 1,3-dibromo-5,5-dimethyl-2,4-imidazolidinedi 77-48-5 25.00 2.0442 2... 

C7H8N203 2,3-dimethyl-4-nitropyridine-1-oxide 37699-43-7 463.98 40.434 2 10939 C7H9Br nortricyclyl bromide 695-02-3 350.15 29.695 1,2... 

C7H8N203 2,5-dimethyl-4-nitropyridine-1-oxide 21816-42-2 412.70 35.564 1,2 10940 C7H9CI 5-chloro-5-methyl-1-hexen-3-yne 819-44-3 413.41 35.630 2... 

C7H8N203 3,5-dimethyl-4-nitropyridine 1 -oxide 14248-66-9 515.25 45.351 1,2 10945 C7H9CIO 4,4-dlmethyi-2-pentynoyl chloride 52324-03-5 409.90 35.299 2... 

When aminopyridine N-nitroso derivatives 21 and 23 were treated with hydroxide or methoxide, ipso substitution occurred at the 2-position to give nitropyridines 22 and 24 (85MI2). Reactions of 3-azido-2-nitropyridine (25) and 4-azido-3-nitropyridine (27) with nucleophiles were studied. Pyridine 25 and sodium hydroxide gave pyridone 26. Morpholine and pyridine 27 gave the 3,4-disubstituted pyridine 28 (83KGS373). Treatment of 2-cyano-3,5-dimethyl-4-nitropyridine with sodium methoxide effects substitution at the... 

Pyrido[3,4-b]pyrazines substituted in the pyridine ring are available from the reactions of suitably substituted 3,4-diaminopyridines and the appropriate dicarbonyl compounds. No problems are encountered with diamines substituted with halogen or hydroxy groups. Similarly the pyridones 7 provide the oxo compounds 8 and 9. In contrast, 3,4-diamino-5-nitropyridine did not react with glyoxal, and only a low yield of 2,3-dimethyl-8-nitropyrido[3,4-b]pyrazine could be obtained using diacetyl. ... 

A new metabolite, 4-aminopyridine-2,3-dicarboxylic acid, was recently isolated from C. acromelalga in a yield of 0.000056% based on the weight of frozen fruiting bodies (41)5). A lethal effect of this compound on mice has not been observed however, bioactivity is still expected because of the similarity of its structure to the physiologicaUy active pyridine-2,3-dicarboxylic acid. The structure of this compound was deduced from H-NMR, C-NMR, and mass spectra, and the position of the substituents was assumed from comparison with clitidine, which contains a 4-aminopyridine-3-carboxylic acid moiety. The structural proposal was confirmed by synthesis from 2,3-dimethyl-4-nitropyridine 1-oxide (Scheme 91) when this compound was subjected to successive reduction and oxidation it yielded a product identical to the one occurring naturally. 

The nitro group in 4-nitro-l,3-dimethyl-IcP-2-one 412 was cleanly replaced by hydroxy and alkoxy groups when heated either with water or alcohols in the presence of alkali resulting in the formation of products 428-432 in a high yield (86KG97), as known to occur with 2- and 4-nitropyridine (61MI1). 

V-Nitrito-4-nitropyridinium salts are isomeric with the previously discussed W-nitropyridinium ions. Similarly, dimethylnitritosulfonium salts are isomeric with IV-nitrosulfonium ions, formed from nitronium salts and dimethyl sulfide. The nitro-onium salts are prepared from nitrosonium hexafluorophosphate with 4-nitropyridine-/V-oxide and dimethyl sulfoxide, respectively [131]. 

To a solution of 10.0 g 2-amino-4-methyl-5-nitropyridine (65.3 mmol) in 90 mL DMF was added 87.0 mL A, lV-dimethylformamide dimethyl acetal (653.0 mmol) in one portion. The deep red reaction mixture was heated at 110°C overnight and then cooled to room temperature and concentrated in vacuo to provide 17.7 g A, A -dimethyl-A -[4-(2-dimethylamino)vinyl)-5-nitropyridin-2-yl]formamidine as a red solid, in a yield of 100%. An analytical sample was purified by recrystallization from benzene, m.p. 149-151°C. 

The 3-nitropyridine compound (10 mmol) in dimethyl sulfoxide (30 mL) was added dropwise to a stirred solution of 4-amino-l,2,4-triazole (35 mmol) and potasium tert-butoxide (20 mmol) in dimethyl sulfoxide (60 mL) under nitrogen atmosphere. The reaction mixture was stirred for 5 h at room temperature and then poured into water (200 mL) saturated with NH4CI. The aqueous phase was extracted with CH2CI2 (3 X 100 mL), the combined organic phases evaporated, and the residue recrystallized from aqueous methanol to give the 2-amino-5-nitropyridine compound. 

Halo-4-nitropyridines and their A -oxides react at the C-nitro group when treated with bases or alkoxides to give XII-357 or MI-358 (X = Cl, Br, I). However, 3-fluoro-4-nitropyTidine and its 1-oxide form 4-nitro-3-pyridinols and 4-nitro-3-alkoxypyridines, respectivelyThe 3-alkoxy-4-nitropyridine-l-oxides have been converted to 3,4-dialkoxypyridine-l-oxides. Because of this marked reactivity of the 3-fluoro substituent, these studies have been extended to 3-fluoro-5-methyl-4-nitropyridine-l-oxide, 3-fluoro-2-methyl-4-nitropyri-dine-l-oxide, and 2,6-dimethyl-3-fluoro-4-nitropyridine-l-oxide. Several of these fluoronitropyridines have been extensively studied as potential reagents for formation of amino acid derivatives. 2-Fluoro-3,5-dinitropyridine, a typical example, is hydrolyzed by hot water and reacts with hot alcohols to form 2-alkoxy-3,5-dinitropyridines and reacts with amino acids and their derivatives to give well-defined products. The reactions of a number of fluoronitropyridines and their N-oxides have been summarized by Talik and Talik and the relative reactivities toward simple nucleophiles have been observed, as shown on p. 689. 

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