Nitropyridines. 7*. Synthesis of nitropyridines from nitro-malonic dialdehyde

Article abstract of DOI:10.1007/s10593-009-0366-8

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 d

Full text of DOI:10.1007/s10593-009-0366-8

Chemistry of Heterocyclic Compounds, Vol. 45, No. 8, 2009
NITROPYRIDINES. 7*. SYNTHESIS
OF NITROPYRIDINES FROM NITRO-
MALONIC DIALDEHYDE
G. P. Sagitullina1**, A. K. Garkushenko1, E. O. Silina1, and R. S. Sagitullin1
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.
Keywords: enamines, nitromalonic dialdehyde, nitropyridines.
Aliphatic nitro compounds are widely used in the synthesis of nitropyridines unavailable by direct
nitration of pyridines and by other known methods [2-5]. Nitromalone dialdehyde is one of the most available of
the nitro ketones used but examples of nitropyridines obtained in this way are few [6-10].
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
R
X
O2N
H
CHO
OAc
H2N
CHO
_
O2N
H
O2N
X
R
Ac2O, Py
+
1a, 2a–d, 3a,b,e,f
Na
O
N
4a, 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 =
O
, e X = NO2, f X = CO2Et
_______
* For Communication 6 see [1].
** To whom correspondence should be addressed, e-mail: Sagitullina@orgchem.univer.omsk.su.
1F. M. Dostoevsky Omsk State University, Omsk 64077, Russia.
__________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 8, pp. 1193-1197, August, 2009. Original
article submitted October 3, 2008.
948
0009-3122/09/4508-0948©2009 Springer Science+Business Media, Inc.

convenient practically. The nitropyridines 4-6 were prepared in 40-85% yields. Lowering of the yield of the
nitropyridines is seen with an increase in the acceptor property of the X substituent in the enamine causing a
decrease in the nucleophilicity of the amino group. With use in the cyclocondensation of the nitroacetophenone
enamine the 3,5-dinitro-2-phenylpyridine (6e) was obtained in 40% yield but with the nitroacetone enamine the
2-methyl-3,5-dinitropyridine was not detected, even in trace amounts. A side reaction of the acylation of the
enamines can also affect the yield of the nitropyridines [11].
The structures of the compounds 2d, 4a, 5a,d, 6a and 6f synthesized for the first time were confirmed
from H NMR and IR spectroscopic (Table 1), from mass-spectrometric (Table 2) data and from elemental
1
analysis. The elemental analytical data is given in the Experimental section.
TABLE 1. Spectroscopic Characteristics of Compounds 2d, 4a, 5a,d, and 6a,f
Com-
pound
IR spectrum, ν, сm–1
1Н NMR spectrum, δ, ppm (J, Hz)
2d
1606 (C=C), 1659 (CO), 0.67-0.79 (2H, m, CH2); 0.91-0.96 (2H, m, CH2);
3297, 3142 (NH2)
1.68 (1H, m, СН); 5.00 (1Н, br. s, NH2); 5.18 (1Н, s, H-2);
9.65 (1H, br. s, NH2)
4a
5a
5d
1355, 1528 (NO2),
1654 (CO)
7.45–7.85 (5Н, m, COC6H5); 8.86 (1H, m, H-4);
9.29 (1H, d, J = 1.7, H-2), 9.62 (1H, d, J = 2.4, H-6)
1342, 1526 (NO2),
1658 (CO)
2.67 (3Н, s, СН3); 7.51-7.81 (5H, m, COC6H5);
8.42 (1Н, d, J = 2.4, Н-4); 9.44 (1Н, d, J = 2.4, Н-6)
1352, 1519 (NO2),
1682 (CO)
1.17-1.30 (2H, m, –CH2–); 1.34-1.42 (2H, m, CH2);
2.43 (1H, m, СН); 2.83 (3Н, s, СН3);
8.72 (1Н, d, J = 2.4, Н-4); 9.39 (1Н, br. s, Н-6)
6a
6f
1352, 1520 (NO2),
1666 (CO)
7.24-7.68 (10Н, m, C6H5, COC6H5);
8.62 (1H, d, J = 2.6, H-4); 9.61 (1H, d, J = 2.6, H-6)
1342, 1592 (NO2),
1710 (CO)
1.13 (3Н, t, J = 7.1, СН2–СН3);
4.24 (2Н, q, J = 7.1, СН2–СН3); 7.45-7.63 (5Н, m, C6H5);
8.86 (1Н, m, Н-4); 9.55 (1Н, d, J = 2.2, Н-6)
TABLE 2. Mass Spectra of Compounds 2d, 4a, 5a,d, and 6a,f
Com-
pound
m/z (I, %)*
2d
4a
125 [М]+• (47.63), 110 [М−CH3]+ (14.41), 84 [М−CH3−C2H2]+ (100), 42 (18.15)
228 [М]+▪ (34.86), 211 [М−OH]+ (25.89), 105 [C6H5CO]+ (100), 77 [C6H5]+ (69.91),
51 (15.84)
5a
5d
243 [М+1]+▪ (11.45), 242 [М]+▪ (64.02), 240 [М−H2]+▪ (65.95), 105 [C6H5CO]+ (100),
77 [C6H5]+ (97.67), 51 (24.69), 50 (16.17)
206 [М]+▪ (55.40), 191 [М−CH3]+ (33.68), 189 [М−OH]+ (11.78),
178 [М−CO]+▪ (25.57), 165 [М−CH3−C2H2]+ (100), 160 [М−NO2]+▪ (13.02),
153 (37.14), 91 (15.43), 69 (65.23), 63 (10.91), 50 (18.52), 41 (29.34), 39 (16.23)
6a
6f
305 [М+1]+▪ (13.33), 304 [М]+▪ (65.66), 276 [М−CO]+▪ (26.41),
258 [М−NO2]+▪ (19.68), 229 (14.44), 105 [C6H5CO]+ (88.00), 77 [C6H5]+ (100),
51 (20.98)
272 [М]+▪ (28.38), 244 [М−CO]+▪ (14.28), 243 [М−C2H5]+ (100),
227 [М−C2H5O]+ (13.42), 198 [М−CO−NO2]+▪ (10.03), 197 [М−C2H5−NO2]+ (38.16),
181 [М−C2H5O−NO2]+ (12.62), 153 [М−C2H5O−NO2−CO]+ (17.13), 127 (11.33),
77 [C6H5]+ (18.61), 29 [C2H5]+ (18.68), 28 [CO] (11.10)
_______
* I is the percentage of the maximum peak intensity and is quoted for peaks
with I > 10%.
949

The nitropyridines 4-6 obtained in this work are key compounds in the synthesis of nitroanilines and
indoles [12-14].
EXPERIMENTAL
1H NMR spectra were recorded on a Bruker AC-200 spectrometer (200 MHz) using CDCl3 solvent with
TMS as internal standard. IR spectra were obtained on a Specord IR-75 instrument in CHCl3. Mass spectra were
recorded on an Agilent 5973N mass spectrometer (electron ionization energy 70 eV, evaporator temperature
230-250ºC) and on a Finnigan MAT-8200 (electron ionization energy 70 eV, evaporator temperature 270-300ºC)
Molecular weights and elemental compositions for compounds 4a, 6a,f were determined mass spectrometrically.
Elemental analysis of the remaining compounds was performed on a Perkin-Elmer analyzer. Monitoring of the
reaction course and purity of the compounds obtained was carried out by TLC on Silufol UV-254 plates.
The Nitromalone dialdehyde Salt was prepared in two stages from furfural by the method given in
[15]. 3-Amino-1-phenyl-2-propen-1-one (1a), 3-amino-1-phenyl-2-buten-1-one (2a), 3-amino-1,3-diphenyl-
2-propen-1-one (3a), 4-amino-3-penten-2-one (2c), 3-amino-3-phenylacrylonitrile (3b), and ethyl 2-(3-amino-
3-phenyl)acrylate (3f), were synthesized by methods [16-21]. 2-Nitro-1-phenylethyleneamine (3e) was prepared
by transamination of N-(2-nitro-1-phenylvinyl)aniline [6, 22, 23]. The 3-amino-2-butenenitrile (2b) used in the
work was obtained from the Fluka company.
3-Amino-1-cyclopropyl-2-buten-2-one (2d). A mixture of 1-cyclopropyl-1,3-butanedione [24] (4.4 g,
35 mmol) and a saturated alcohol solution of ammonia (125 ml) was stirred at about 20ºC for 24 h. Solvent was
distilled off and the residue was recrystallized from CCl4. Yield 80%; mp 100-101 (CCl4). Found, %: C 67.03;
H 8.96; N 11.05. C7H11NO. Calculated, %: 67.17; H 8.86; N 11.19.
Nitropyridines 4-6 (General Method) A mixture of sodium nitromalone dialdehyde monohydrate (2.0 g,
12.7 mmol) and acetic anhydride (13 ml) was stirred for 30 min, pyridine (7.5 ml) was added, and the product was
stirred for a further 10 min. The corresponding enamine 1a, 2a-d, 3a,b,e,f (12.7 mmol) was added and stirred for
18 h. The mixture was poured into iced water and the precipitate formed was filtered off. The yields of
nitropyridines are given after column chromatographic purification (silica gel, Merck 60A, 0.060-0.200 mm, eluent
benzene).
3-Benzoyl-5-nitropyridine (4a). Yield 47%; mp 96-97ºC [petroleum ether (40-70ºC)]. Found: m/z
228.0549 [M]+. C12H8N2O3. Calculated: M 228.2036.
3-Benzoyl-2-methyl-5-nitropyridine (5a). Yield 85%; mp 55-56ºC (hexane). Found, %: C 64.82;
H 4.25. C13H10N2O3. Calculated, %: C 64.46; H 4.16.
3-Benzoyl-5-nitro-2-phenylpyridine (6a). Yield 55%; mp 113-114ºC [petroleum ether (40-70ºC)].
Found: m/z 304.0848 [M]+. C18H12N2O3. Calculated: M 304.2996.
2-Methyl-5-nitronicotinonitrile (5b). Yield 39%; mp 73-74ºC (hexane) (mp 73-74ºC [25]).
5-Nitro-2-phenylnicotinonitrile (6b). Yield 78%; mp 120-121ºC (alcohol) (mp 121-122ºC [25]).
3-Acetyl-2-methyl-5-nitropyridine (5c). Yield 52%; mp 64-65ºC (alcohol) (mp 63.5-64ºC [26]).
(2-Methyl-5-nitro-3-pyridyl)(cyclopropyl) ketone (5d). Eluent chloroform–ethyl acetate (9:1). Yield
62% as light-yellow crystals with mp 80-81ºC [petroleum ether (40-70ºC)]. Found, %: C 58.08; H 4.83;
N 13.26. C10H10N2O3. Calculated, %: C 58.25; H 4.89; N 13.59.
3,5-Dinitro-2-phenylpyridine (6e). Yield 40%; mp 84-85ºC (80% alcohol) (mp 83-85ºC [27]).
Ethyl 5-nitro-2-phenylnicotinate (6f). Yield 68%; mp 100-101ºC (alcohol). Found: m/z 272.0797
[M]+. C14H12N2O4. Calculated: M 272.2562.
This work was carried out with the financial support of the Russian Fund for Basic Research (grant No.
07-03-00783).
950

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