2-Chloro-5-nitropyridine

Chloro-3-nitropyridine [5470-18-8] M 158.5, m 100-103°, 101-102°, 103-104° (sublimes), pK -2.6. Forms needles from H2O. Purified by continuous sublimation over a period of 2 weeks at 50-60°/0.1mm [Barlin J Chem Soc 2150 1964]. The N-oxide has m 99-100°(from CH2Cl2-Et20). [Taylor and Driscoll J Org Chem 25 1716 I960-, Ochiai and Kaneko Chem Pharm Bull Jpn 8 28 I960.]... 

Halopyridines undergo self-quaternization on standing while the less reactive 2-halo isomers do not. However, more is involved here than the relative reactivity at the ring-positions. The reaction rate will depend on the relative riucleophilicity of the attack-ing pyridine-nitrogens (4-chloropyridine is more basic) and on the much lower steric hindrance at the 4-position. Related to this self-quatemization are the reactions of pyridine and picolines as nucleophiles with 4-chloro- and 2-chloro-3-nitropyridines. The 4-isomer (289) is. again the more reactive by 10-30-fold (Table VII, p. 276). 

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). 

Reaction of disodium salt of pyridine-2,3-dithiol (385) with l-chloro-2-nitrobenzene provided in 45% yield the corresponding aza analog 386 (82JHC1441). Similar treatment with 2-chloro-3-nitropyridine (193) provided... 

A special, isotope-labeled case of the azide-tetrazole equilibrium was studied by Cmoch et al. <2000JP0480>, and the results are shown in Scheme 23. 2-Chloro-3-nitropyridine 86 was treated with potassium azide containing a doubly labeled (15NN15N) azide anion. The authors detected formation of two differently labeled tetrazolopyridines the 2,4- 87 and the 1,3-labeled 88 derivatives. 

Trudell and co-workers reported the N-arylation with 2-chloro-3-nitropyridine of [l,2,3]triazolines fused onto [4,5-dpyridazine (Scheme 5) and [4,5-,yjpyrimidine (Scheme 6) <2000JHC1597>. Substitution at the 2-position of the pyridine ring was confirmed by X-ray crystallographic analysis of products 8 and 9. Similarly, [l,2,3]triazolo[4,5-,yjpyrimidine gave 10 in low yield, after nucleophilic substitution of the chloro substituent activated by the nitro group in 2-chloronitrobenzene (Scheme 6). 

In the reaction with imidazole anion (71% of product) and with pyrrole anion (67% of product), the substitution occurs only on nitrogen. The reaction of benzotriazole anion with 2-chloro-3-nitropyridine is slower compared with that of the 5-nitro isomer. This reaction was ESR active, and it was completely inhibited by FeCl3229. 

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 iV-hydroxytriazolopyridines are generally obtained by intramolecular cyclization of hydra-zinonitropyridines. Treatment of 2-chloro-3-nitropyridine and 2-nitro-3-fluoropyridine with excess... 

Reaction of 2-chloro-3-nitropyridine (316) with TV -phenylbenzothiohydrazide and Et3N gave 1,3-diphenyl-17/-pyrido[2,3-e]-l,3,4-thiadiazine (317) (70%). The pyridine (316) reacted with dithizone under identical conditions to deliver the pyridothiadiazine (52) (75%). Compounds (317) and (52) are believed to be formed via a Smiles rearrangement <80JOC3677>. 

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). 

An interesting synthesis of these C-nucleosides utilized the easily accessible 5-(j3-D-ribofuranosyl)tetrazoles 235 as masked C-glycosyl-diazometh-ane. Reacting 235 with 2-chloro-3-nitropyridine gave a mixture of 1,2,4-triazolo[4,3-fl]pyridin-3-yl (236) and l,2,4-triazolo[l,5-a]pyridin-2-yl (237) C-nucleosides. The latter (237) resulted from thermally induced Dimroth-like rearrangement of the former (236) (86MI9) (Scheme 70). Compounds 236 and 237 possess considerable cytotoxic effect (86MI9). 

Treatment of the isoquinoline Reissert compound (2) with sodium hydride in dimethylformamide,96 with 50% aqueous sodium hydroxide-TEBA chloride,61 or with 50% aqueous sodium hydroxide-TBA chloride963 and an activated aryl halide, such as 2,4-dinitrofluorobenzene,96 2-bromo-3-nitropyridine,96 4-nitrochlorobenzene,61 t-butyl 2-chloro-5-nitrobenzoate,61 2-chloro-3-nitropyridine,963 4-chloro-3-nitropyridine,96a or 9-chloroacri-dine96b leads to the arylation product 43. Arylation of the quinoline Reissert compound (1) with 4-nitrofluorobenzene in the presence of sodium hydride in dimethylformamide leads to 44.96 It should be noted that alkylation of... 

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