Reaction with 2-chloro-3-nitropyridine

The parent heterocycle of pyrido[2,3-e][l,2,4]triazine and its phenyl derivative 39 were prepared (89JHC475) by cyclization with polyphos-phoric acid of 3-acyIhydrazino-2-aminopyridines 36, obtained by reduction of the corresponding 3-acylhydrazino-2-nitropyridines 35. Compounds 35 were obtained from 3-fluoro-2-nitropyridine 34 either by reaction with benzoylhydrazine or by reaction with hydrazine and subsequent for-mylation of the initially formed 3-hydrazino-2-nitropyridine 38. Attempts to prepare 38 from 3-chloro-2-nitropyridine gave 2-hydrazino-3-chloropyridine 37. These results could be explained by semiempirical calculations (CNDO and MNDO calculations). 

The hydrochloride of 3-amino-4-hydrazinopyridine 65 was prepared by reaction of the 4-chloro-3-nitropyridine derivative with ethoxycarbonyl-hydrazine in phenol to give the hydrochloride of ethyl 3-(3-nitro-4-pyridyl)carbazate 64 (R2 = OEt), which on successive heating in concentrated hydrochloric acid and hydrogenation over Pd/C gave 65. Its reaction with phenylacetic acid or with phenoxyacetic acid gave the hydrochloride... 

It has been proposed that the reaction of 2-chloro-5-nitropyridine (183) with the anions of benzotriazole, imidazole, pyrrole and phthalimide in DMF occurs by the S l mechanism. Thus, the reaction of 183 with the anion of benzotriazole gives 95% of the substitution product 184 (equation 125)229. 

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. 

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>. 

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. 

Nitro derivatives of a variety of heteroaromatic compounds enter the VNS reactions with alkyl hydroperoxide anions to produce the expected hydroxylation products [41, 137-139]. For instance, the VNS hydroxylation of 2-chloro-5-nitropyridine with ferf-butylhydroperoxide was shown to give 2-chloro-5-nitro-6-hydroxypytidine that exists in its tautomeric form of pyridone [41] (Scheme 44). It should be stressed that the SNAr of chlorine located in the highly activated position 2 was not competing with the VNS. 

Ompoimd (13) has been prepared ftom 2-chloro-3-nitropyridine by a four-step sequence (treatment with NaHS, reduction with tin(Q)chloride, diazotization with nitrous acid and treatment with carbon disulfide at 220°Q[72],[85]. Compound (14) has been prepared by treatment of disodium 5-cyanoisotiilaz-oledithiolate with thiophosgene [83], [86]. Con unds (15)-(17) have beai prepared by a two-step sequence (treatment with KHS or NaHSe and reaction with thiophosgene) [78],[82]. Reactions with phosgene yielded the corresponding -2-ones [78],[82],[83],[86]. Compounds (15),(17) have been prepared also by treatment of 2,3-dichloropyrazine and 2,3-dichloro-5,6-dimethylpyrazine respe vely, with potassium tiithiocarbonate [78]. 

The amino function in 4-amino-3-halopyridines belraves unexceptionally. Thus 4-amino-3-diloropyridine gives the 3-chloro-4-pyridinediazonium salt dien treated with nitrous acid the diazonium salt decomposes in the presence of potassium iodide to yield 3-chloro-4-iodopyridine. 4-Amino-2,3,5,6-tetrafluoropyridine is a very weak base but it can be diazotized in 80% hydrofluoric acid. The diazonium salt is converted to 4-bromo-2,3,5,6-tetrabromopyridine with cuprous bromide, but its reaction with water or with A, lV-dimethylaniline are complex. 4-Amino-2-chloro-3-nitropyridine is not converted to 2-chloro-3-nitro-4-pyridone (K-97) on diazotization with mineral acids and sodium nitrite or with isoamyl nitrite in glacial acetic acid with the latter reagent 2-chloro-3-nitropyri-dine (K-98) is formed." Nitrous acid reacts with 4-amlno-2-pyridone to give 4-amino-3-nitroso-2-pyridone instead of the diazonium salt. ... 

Table 5.19, Reactions with 2-Chloro-5 -nitropyridine in 99 8 per cent Ethanol at 25 ...

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