No abstract
The interaction of α,β-unsaturated nitro ketones and various enamines leads to the synthesis of 5-nitro-1,4-dihydropyridines containing acetyl, amide, benzoyl, ester, and cyano groups in position 3, and also unsymmetrical 3,5-dinitro-1,4-dihydropyridines. Aromatization of the nitrodihydropyridines was carried out with sodium nitrite in acetic acid.The synthesis of nitropyridines by the Hantzsch reaction is effected by the cyclocondensation of α,β-unsaturated nitro ketones (condensation products of aromatic aldehydes with nitroacetone and nitroacetophenone) with various enamines.The availability of nitroacetone and nitroacetopheone enables them to be considered as valuable raw materials in the synthesis of nitropyridines [2], possessing potential biological activity.Nitroacetone [3,4] and nitroacetophenone [5] used in the work were obtained by the condensation of nitromethane with acetaldehyde and benzaldehyde (the Anri reaction). The nitroalcohols obtained were oxidized with sodium dichromate.The condensation of nitroacetophenone with aromatic aldehydes proceeds readily and the corresponding nitrochalcones 1 are formed in preparative yield [6].Nitroacetone may interact with aromatic aldehydes at both the methyl and the methylene group. Under alkaline catalysis conditions the aldol condensation product is formed only at the methyl group. To obtain condensation products at the methylene group a less reactive Schiff's base of the aromatic aldehyde is used. In this way condensation products at the methylene group are formed in good yield only in the reaction of nitroacetone with Schiff's bases of an aromatic aldehyde containing an acceptor group in the nucleus [7], the yield of 2-nitro-1-phenyl-1-buten-3-one 1a was only 26%. Because of the low yield of chalcone 1a, the cyclocondensation of benzylideneacetoacetic ester with the enamine of nitroacetone 2f was used for the synthesis of nitrodihydropyridine 3d (variant B) (Scheme 1).The condensation of benzylidenenitroacetone 1a with aminocrotonic ester (variant A) in acetic acid at room temperature and an equimolar ratio of initial reactants leads to nitrodihydropyridine 3d in 56% yield. On condensation by variant B under analogous conditions pyridine 3d is formed with a yield of 40%. We also note that the enamine of nitroacetone 2f [8], obtained by the transamination of 2-dimethylamino-1-nitro-1-propene _______ * For Part 1 see [1]. __________________________________________________________________________________________
Previously unreported nitriles of 5-nitronicotinic acid were synthesized by various types of cyclocondensation using nitrocarbonyl compounds and their derivatives. The partial hydrolysis of these nitriles in concentrated sulfuric acid and in alkali solution in the presence of hydrogen peroxide leads to nitronicotinamides.Most substituted nicotinamides containing a nitro group at various positions of the pyridine ring display anticoccidial activity and are heterocyclic analogs of coccidine, an effective means against various types of bird-parasite coccidia [2,3]. Substituted 2-nitro-and 5-nitronicotinamides display the greatest anticoccidial activity [4].In the present work, a synthesis is described for previously unreported nitriles of 5-nitronicotinic acid and 5-nitronicotinamides.A one-pot cyclocondensation of nitroacetone, ethyl orthoformate, and enamines 1a,b described in our previous work [5] was used to prepare 3-cyano-5-nitropyridines 2a,b. Me O O 2 N N H 2 R CN N R Me O 2 N CN N R Me O 2 N CONH 2 H 2 SO 4 1-3 a R = Me, b R = Ph AcOH, N 2 30°C, 48 h 90°C, 3 h 1a,b 2a,b 3a,b HC(OEt) 3 +When nitroacetone is replaced by nitroacetophenone, the cyclocondensation with ethyl orthoformate and 3-aminocrotononitrile 1a does not give the expected nitrile of 2-methyl-5-nitro-6-phenylnicotinic acid (9c), but rather leads to complete conversion to tar. Hence, nitropyridine 9c was obtained in two steps by the Hantsch
3-Cyanopyridines containing an acetyl, ester, nitro, or cyano group in the 5-position were synthesized via various versions of the Hantzsch reaction. Recyclization of quaternary pyridinium salts by the action of aqueous-alcoholic alkali afforded 2-methylaminopyridine derivatives and 6-methylamino-3-nitro-2,4-diphenylbenzonitrile. R = 4-ClC 6 H 4 (a), 4-MeOC 6 H 4 (b), 2,4-(MeO) 2 C 6 H 3 (c), 2-furyl (d), Me (e).In continuation of our studies on recyclization of pyridinium salts having a cyano group in position 3 [1-3] we synthesized previously unknown cyanopyridines IIa-IIg with a view to examine the effect of structural and electronic factors on the direction of recyclization of quaternary salts derived therefrom. Symmetrically substituted 3,5-dicyanopyridines IIaIIe were obtained by cyclocondensation of 3-amino-2-butenenitrile with various aldehydes (HantzschMeyer-Mohr reaction), by analogy with the synthesis of 3,5-dicyanopyridines reported previously [4-6]. 1,4-Dihydropyridines Ia-Ie were oxidized with sodium nitrite in acetic acid. Both stages in the synthesis of pyridines IIa-IIe (Scheme 1) were characterized by fairly high yields. 5-Acetyl-6-methyl-2-phenylpyridine-3-carbonitrile (IIf) was prepared by three-component condensation of benzoylacetonitrile, triethyl orthoformate, and 4-amino-3-penten-2-one at a ratio of 1 : 3 : 1 at 70°C. Under these conditions, addition of the β-carbon atom in the enamine fragment of 4-amino-3-penten-2-one to ethoxymethylene derivative of benzoylacetonitrile gave rise to a new carbon-carbon bond and closure of pyridine ring [7, 8] (Scheme 2). The synthesis of ethyl 5-cyano-2-methyl-4-phenylpyridine-3-carboxylate (IIg) included structural modification of previously described ethyl 5-cyano-2-methyl-6-oxo-4-phenyl-1,6-dihydropyridine-3-carboxylate [9] via nucleophilic replacement of the hydroxy group by chlorine and subsequent reductive dechlorination (Scheme 3). NitroMe 2 SO 4 , NaClO 4 N NC Me CN Me R IIIa-IIIe Me ClO 4 RCHO + 2 CN H 2 N Me N H NC Me CN Me R NaNO 2 , AcOH N NC Me CN Me R Ia-Ie IIa-IIe Scheme 1.
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