No abstract

The discovery of bacteriostatic activity of Sulfidine was the stimulus for the study of the chemistry of isomeric aminopyridines with the objective of converting them into promising sulfamide preparations [2].Aminopyridines with nitrogroups on the pyridine nucleus have been insufficiently well studied, which is explained by their low accessibility. Exceptions are 2-amino-3-nitro-and 5-nitropyridines and their derivatives, which are accessible thanks to the activity of 2-aminopyridine to electrophilic substitution [3]. The number of publications connected with the preparation of substituted 3-amino-5-nitropyridines is limited to those describing the synthesis of 3-amino-5-nitropyridine [4-7], 3-amino-2-methyl-5-nitropyridine [8], and 3-amino-5-nitrocollidine [9].The objective of the present work was the synthesis of the previously unknown 3-amino-5-nitropyridines 2a,b, 4, 6b,c, and 9a-c based on the available nitropyridines 1a,b, 3a-c, and 7a-c which contain acetyl, amide, and carboxyl groups at position 3 of the pyridine nucleus, The choice of the variant of the sextet rearrangement in the synthesis of 3-amino-5-nitropyridines was determined by the availability of the corresponding 5-nitropyridines. 3-Amino-5-nitropyridines 2a,b were obtained by the Schmidt reaction starting from 3-acetyl-5-nitropyridines 1a,b by a one-stage synthesis which we had developed earlier [10,11]: N Ac O 2 N Me R N NH 2 R Me O 2 N 1. NaN 3 , H 2 SO 4 2. H 2 O,  1a,b 2a,b 1,2 a R = Me, b R = Ph

We have previously developed a simple method for the synthesis of substituted 2,6-dimethyl-5-nitropyridines and 3,5-dinitropyridines by the cyclocondensation of nitroacetone and ethyl orthoformate with various enamines [1]. Replacing nitroacetone with nitroacetophenone permitted us to make available nitropyridines 2a-d with a phenyl substituent in the pyridine ring. These nitropyridines may be used in theThe IR spectra were taken on a Specord IR-75 spectrometer in CHCl 3 . The 1 H NMR spectra were taken on a Bruker AC-200 spectrometer at 200 MHz in CDCl 3 with TMS as the internal standard. The mass spectra were taken on an Agilent 5973N mass spectrometer.2-Nitro-1-phenylethanone was obtained according to Gavrilin [3]. The synthesis of 3-amino-1-cyclopropyl-2-buten-1-one (1b) was described in our previous work [1].Nitropyridines 2 (General Method). A solution of nitroacetophenone (0.99 g, 6 mmol), corresponding enamine 1a-d (6 mmol), and ethyl orthoformate (3 ml, 18 mmol) in acetic acid (5 ml) was stirred for 48 h in an inert gas atmosphere at 30°C. The excess of the reagents was distilled off in vacuum. The residue was heated at reflux with activated charcoal in 20 ml ethanol and filtered. After cooling, the crystalline precipitate was filtered off. Nitropyridines 2a-d were recrystallized from petroleum ether (40-70°C).

Substituted 5-nitro-2-ethynylpyridines were synthesized by the Sonogashira reaction of 2-bromo-5-5-nitropyridine with terminal acetylenes. Desilylation, oxidative decarbonylation, and the retro-Favorskii reaction of the cross-coupling products of 2-bromo-5-nitropyridine with trimethylsilylacetylene, prop-2-ynyl alcohol, and 2-methylbut-3-yn-2-ol, respectively, gave 2-ethynyl-5-nitropyridine. The hydration of 2-ethynyl-5-nitropyridine and 5-nitro-2-(phenylethynyl)pyridine according to Kucherov afforded 2-acetyl-5-nitropyridine and 5-nitro-2-phenacylpyridine, respectively.

Cyclocondensation of sodium nitromalone dialdehyde with different enamines gave 3-acetyl (benzoyl, cyano, cyclopropanoyl, carbethoxy)-2-methyl(phenyl)-5-nitropyridines. With the aim of increasing the yield of pyridines we have activated the nitromalonic dialdehyde through acylation of its enol form.Aliphatic nitro compounds are widely used in the synthesis of nitropyridines unavailable by direct nitration of pyridines and by other known methods [2][3][4][5]. Nitromalone dialdehyde is one of the most available of the nitro ketones used but examples of nitropyridines obtained in this way are few [6][7][8][9][10].The aim of this work was to synthesize 5-nitropyridines by cyclocondensation of nitromalone dialdehyde with different enamines.Analysis of the experimental work has shown that an activated form of the nitromalone dialdehyde is most efficiently used in the cyclocondensation. With this in view, tosylation and acetylation of its enol form have been carried out [9,10]. We have checked both variants of the acylation of nitromalone dialdehyde in the synthesis of nitropyridines experimentally and found that use of acetic anhydride for elimination of a molecule of water from the sodium malone dialdehyde monohydrate salt with simultaneous acetylation is more H O CHO O 2 N Ac 2 O, Py H OAc CHO O 2 N X R N H 2 N X R O 2 N O _ 1a, 2a-d, 3a,b,e,f4a, 5a-d, 6a,b,e,f 1, 4 R = H, 2, 5 R = Me, 3, 6 R = Ph a X = COPh, b X = CN, c X = COMe, d X = , e X = NO 2 , f X = CO 2 Et Na +