8-Nitro pyridine, from reduction

Introduction of a trifluoroethyl group at the a-carbon of the nitro group of 280 by a sequence of reactions - (l,5-diazabicyclo[4.3.0]non-5-ene) (DBU)-catalyzed alkylation with trifluoroacetaldehyde hemiacetal in MeCN, dehydration with acetic anhydride-pyridine, and reduction of the C-C double bond with NaBH4 - produces 281. 6-Trifluoroethyl-L-lysine 282 can be prepared from 281 (see Scheme 9.60) [88]. 

Nitration of 2,6-dichloropyridine-l-oxide (IX-188) gives 2,6-dichloro-4-nitro-pyridine-1-oxide (IX-189), which, on catalytic reduction using Raney nickel as the catalyst, gives 4-amino-2,6-dichloropyridine (IX-190). From the amino compound, the 2,6-dichloro-4-nitraminopyridine (IX-191) is readily formed and rearranges to IX-192. Catalytic reduction of IX-192 gives an almost quantitative yield of 2,6-dichloro-3,4-diaminopyridine (IX-193). ... 

Amino-2- and -6-methylpyridine have been prepEired by catalytic hydrogenation of the corresponding 4-chloro-3-nitropicoline l-oxides3 <, and 2-amino-3,5-diethoxypyridine from the nitro-oxide by reduction with iron and acetic acid but, of course, the use of pyridine 1-oxides as a source of aminopyridines has become of importance only since the discovery that nitration occurs readily at C(4) (p. 174). 4-Nitropyridine 1-oxides have been reduced to 4-aminopyridine 1-oxides by ammonium sulphide and by catalytic hydrogenation " 40i , 637 and to 4-aminopyridines by... 

Treatment of a 3-aminotriazolopyridine with acid gave the imidazopyridine 242 (81T1787), also obtained from the 3-nitro derivative by catalytic reduction (83AHC79). Quaternary salts derived from compound 2, when treated with tri-ethylamine and subsequently heated give 2-pyridylcyanamides 243 or 2-(oxazol-l-yl)pyridines 244 depending on the alkyl group (86H(24)2563) the ylides are presumably intermediates (see also Section IV.I). 

The majority of analgesics can be classified as either central or peripheral on the basis of their mode of action. Structural characteristics usually follow the same divisions the former show some relation to the opioids while the latter can be recognized as NSAlD s. The triamino pyridine 17 is an analgesic which does not seem to belong stmcturally to either class. Reaction of substituted pyridine 13 (obtainable from 12 by nitration ) with benzylamine 14 leads to the product from replacement of the methoxyl group (15). The reaction probably proceeds by the addition elimination sequence characteristic of heterocyclic nucleophilic displacements. Reduction of the nitro group with Raney nickel gives triamine 16. Acylation of the product with ethyl chlorofor-mate produces flupirtine (17) [4]. 

Scheme 4. The compounds and intermediates on the rear plane of the bicubic system (farthest from the reader) are protonated on the pyridine nitrogen atom those on the front plane (nearest the reader) are not. Laviron s work has shown that the reduction of 14 and its corresponding N-oxide34, and indeed probably most aryl nitro compounds, proceeds by an ECEC sequence leading to the neutral N,N-dihydroxy [ArN(OH)2] intermediate at all proton concentrations from Ho = —6 to pH 9.6. This substance then loses water to form the nitroso compound, which then undergoes a second sequence leading to the arylhydroxylamine.

A concerted elimination-cyclization mechansim, involving a sulfenyl halide in a 1,3-butadiene-1-thio system, is the most probable mechanism for the formation of benzo[6 Jthiophenes from cinnamic acids or 4-aryl-2-butanones by treatment with thionyl chloride. The reactions shown in Scheme 5 have been carefully worked out, and the intermediates isolated (75JOC3037). The unique aspect of this synthesis is the reduction of the sulfinyl chloride (a) by thionyl chloride to form the sulfenyl chloride (b). The intermediate (b) was isolated and converted in pyridine to the 3-chlorobenzo[6]thiophene-2-carbonyl chloride in 36% yield (73TL125). The reaction is probably initiated by a sulfenyl ion attack on the aromatic ring, since it is promoted by electron-releasing groups para to the site of ring closure. For example, when X in (36) was N02, a 23% yield of (37), a mixture of 5-and 7-nitro derivatives, was obtained, but when X in (36) was OMe, a 54% yield of (37) was obtained, contaminated with some 3,4-dichloro-5-methoxybenzo[6]thiophene-2-carboxylic acid. 

The results of nitration reactions depend on reagents and the acidity of the medium. Thus fuming nitric acid in concentrated sulfuric acid converts (410a) to the 3-nitro derivative while with acetyl nitrate reaction occurs exclusively at C-4 (equation 50). The nitration in the 4-position can also conveniently be done with nitronium tetrafluoroborate. The reduction of these nitro compounds by hydrazine in the presence of palladium on charcoal provides a versatile route to 4-amino-7,6-borazarothieno[3,2-c]pyridines (75ACS(B)46l>. In the nitration of 4,5-borazarothieno[2,3-c]pyridines (e.g. 409a), peri effects from the substituents on the boron atom lead to formation of a considerable amount of the 2-nitro derivatives. 

The corresponding V-nitro derivatives behave similarly306-308 in acid solution the hydrazines are produced in a six-electron reaction, in alkaline medium the first two-electron reduction results in the formation of the A7-nitroso derivatives which at a more negative potential are further reduced. iV-Nitropyrazole behaves slightly differently as the reduction in acid solution also results in a cleavage of the N-N bond with formation of nitrous acid. 2-Nitraminopyri-dine309 in acid solution is reduced to the hydrazine. In alkaline solution the anion is reducible, in contradistinction to most nitramines derived from primary amines. The four-electron reduction yields 2-aminopyridine. Pyridine 1-nitroimide is reduced to pyridine.309... 

If, on the other hand, an amino group can be introduced ortho to the nitro group, reduction of 202 or 203 makes available the starting materials for fused heterocycles. One example is the synthesis of imidazo[4,5-c]pyridines 205 from diamino pyridines such as 204. 

Compared with the isomeric pyrido [2,3-h]pyrazines, relatively little work has been done on this ring system. All the syntheses of the heterocycle so far reported start from pyridine intermediates. A key intermediate for the preparation of pyrido[3,4-h]pyrazines is 3,4-diaminopyridine, which is prepared by nitration of 4-aminopyridine, followed by reduction of the 4-amino-3-nitro derivative using either sodium sulfide or hydrogen over palladium on charcoal, Reduction of... 

---