Synthesis of substituted 5-nitro- 6-phenylpyridines by the cyclo- condensation of nitroacetophenone, ethyl orthoformate, and enamines

Abstract

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).

NitropyridineS. 9*. Synthesis of substituted 3-amino-5-nitropyridines

“…Sodium azide (0.43g, 6.6 mmol) was added by portions with stirring to a mixture of the corresponding 3-acetylpyridine (6 mmol) [10,11] in 3 ml conc. H 2 SO 4 .…”

“…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.…”

“…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] In the synthesis of 3-amino-4,6-dimethyl-5-nitropyridine (4) from the previously known nicotinamide 3a we successfully used the classical Hofmann reaction (NaOBr) [12]. Under these conditions the nitronicotinamides 3b,c and 7a,c, which are insoluble in aqueous alkali, did not rearrange to the corresponding 3-amino-5-nitropyridines.…”

Synthesis of pyridines by cyclocondensation of acetyl and benzoyl pyruvates with enamines

“…In one variant of the Hantzsch synthesis for the preparation of pyridines condensation of ethyl ethoxymethyleneacetoacetate (or other products of the reaction of β-dicarbonyl compounds with ethyl orthoformate) with enamines of β-dicarbonyl compounds is used [3]. We have previously successfully used a one-pot variant of this synthesis using methylene-activated nitroacetone and nitroacetophenone [4,5].…”