Nitropyridines. 2*. Hantzsch synthesis of nitro- and dinitropyridines

Article abstract of DOI:10.1007/s10593-005-0214-4

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

Full text of DOI:10.1007/s10593-005-0214-4

Chemistry of Heterocyclic Compounds, Vol. 41, No. 6, 2005
NITROPYRIDINES. 2*. HANTZSCH SYNTHESIS
OF NITRO- AND DINITROPYRIDINES
G. P. Sagitullina, L. V. Glizdinskaya, and R. S. Sagitullin
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.
Keywords: 3,5-dinitrodihydropyridines, 5-nitro-1,4-dihydropyridines, nitro ketones, nitropyridines,
nitrochalcones.
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].
__________________________________________________________________________________________
Department of Organic Chemistry, Omsk State University, Omsk 644077, Russia; e-mail:
sagitullina@orgchem.univer.omsk.su. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 6, pp. 858-
863, June, 2005. Original article submitted August 19, 2003.
0009-3122/05/4106-0739©2005 Springer Science+Business Media, Inc.
739

Scheme 1
Ph
O
CO2Et
Me
O2N
Me
+
+
A
B
Ph
H2N
O2N
Me
CO2Et
Me
1a
Ph
N
H
O2N
Me
CO2Et
Me
3d
NH2
O
2f
[9], the condensation product of dimethylacetamide diethylacetal with nitromethane, is a more difficultly
available compound compared with benzylidenenitroacetone 1a even allowing for the low yield of the latter. We
therefore used variant A for cyclocondensation in the synthesis of 2,6-dimethyl-1,4-dihydropyridines 3a-e.
R1
R1
R1
X
O2N
R
O2N
R
X
O2N
R
X
+
H2N
Me
N
Me
N
Me
O
H
2a–f
1a,f,h,i
4a–i
3a–i
1a, 3, 4 a–e R1 = Ph, R = Me; 1f, 3, 4 f, g R1 = R = Ph; 1, 3, 4 h R1 = 4-MeOC6H4, R = Ph;
i R1 = 2-Fu, R = Ph; 2–4 a X = COMe; b X = COPh; c X = CONHPh; d X = COOEt;
e X = CN; f X = NO2, 3, 4 g X = CONHPh; h, i X = COOEt
When using the two-component Hantzsch synthesis 1,4-dihydropyridines 3b-i begin to precipitate from
the reaction mixture after a few hours. Their yield at a reaction time of 15-20 h is 50-70%. Chromatographic
purification was required only for the isolation of 2-acetyl-5-nitro-1,4-dihydropyridine (3a), the remaining
1,4-dihydropyridines were purified by recrystallization. Aromatization was carried out with NaNO2 in acetic
acid at 60-70°C. The spectral characteristics and yields of the compounds synthesized are given in Table 1.
The mass spectra of nitropyridines 4a-c,e,g (Table 2) were characterized by high, and in some cases
maximal intensity for the M+· ion peaks. Fragmentation of the molecular ions leads to the appearance of ions
both for nitropyridines and of ions formed by decomposition of the functional substituent. Peaks for [M-OH]+,
[M-OH-NO]+·, and [M-NO2-CH3]+· ions were common in the mass spectra of these compounds. Characteristic of
nitropyridines 4c,g was fission of the functional substituent from the molecular ion with the formation of the [M-
C6H5NH]+ ion of high intensity, decomposition of which occurs with elimination of ions common for this series
of compounds.
On the basis of the data obtained by us it is possible to draw a conclusion on the preparative availability
of nitropyridines synthesized according to Hantzsch. These are key compounds in the synthesis of indoles
[10, 11] and m-terphenyls [12].
740

741

742

TABLE 2. Mass Spectra of Nitropyridines 4a-c,e,g (I, % of the intensity of
the maximum peak)
Com-
pound
m/z (I, %)*
4a
270 [M]+·, (100), 255 [M–CH3]+ (41), 253 [M–OH]+ (22), 225 [M–CH3–NO] +· (26),
223 [M–NO–OH] +· (21), 209 [M–NO2–CH3]+· (17), 208 [M–CH3–OH–NO]+ (82),
181 (17), 180 (20), 153 (11), 139 (21), 43 [CH3CO]+ (73)
4b
4c
332 [M]+· (88), 331 [M–H]+ (43), 315 [M–OH]+ (11), 284 [M–NO2–H2]+ (16),
208 [M–NO–OH–C6H5]+ (13), 105 [C6H5CO]+ (100), 77 [C6H5]+ (56)
347 [M]+· (62), 256 (13), 255 [M–C6H5NH]+ (82), 225 [M–C6H5NH–NO]+· (32), 209 (23),
208 [M–C6H5NH–NO–OH]+ (100), 181 (22), 180 [M–C6H5NH–NO–OH–CO]+ (26),
153 (17), 140 (11), 139 (20), 77 [C6H5]+ (12)
4e
253 [M]+· (100), 236 [M–OH]+ (24), 225 [M–H2CN]+ (66), 224 [M–CHO]+ (34),
223 [M–NO]+ (16), 208 [M–OH–NO]+· (11), 197 (13), 196 [M–CO–CHO]+ (38),
192 [M–NO2–CH3]+· (22), 183 (19), 180 (14), 165 (11), 164 (16), 156 (13), 155 (18),
153 (11), 152 (12), 140 (32), 139 (27), 127 [C6H5C≡C–CN]+ (17), 115 (15), 77 [C6H5]+
(16), 76 (11), 63 (11), 51 (12), 43 (24), 42 (11), 39 (12)
4g
409 [M] +· (39), 318 (21), 317 [M–C6H5NH]+ (100), 272 [M–C6H5NH–NO–CH3]+ (16),
271 [M–C6H5NH–NO2] +· (63), 270 [M–C6H5NH–NO–OH]+ (16)
_______
* Peaks with I > 10% are given.
EXPERIMENTAL
The 1H NMR spectra were recorded on a Bruker AC 200 (200 MHz) spectrometer in solution in CDCl3,
DMSO-d6, and CD3CN, internal standard was TMS. The IR spectra were recorded on a Specord IR 75
instrument in chloroform. Mass spectra were obtained on a Varian MAT 212C instrument using direct insertion
of samples into the ion source, ionizing voltage was 70 eV. A check on the progress of reactions and the purity
of the compounds obtained was carried out by TLC on Silufol UV 254 plates, eluent was benzene (for
compound 4f), chloroform (for compounds 4d,e,h,i), chloroform–ethyl acetate, 9 : 1 (for compounds 3e-g,
4a,b,g), and chloroform–ethyl acetate, 1:1 (for compounds 3a-d, 3h-i, 4c). The melting points of all compounds
except 3c and 4c were determined on a Boetius hot stage, for 3c and 4c in capillaries to determine the melting
point of the crystalline substance.
Nitroisopropanol was obtained as described in [3], nitroacetophenone by the procedure of [5], the
chalcones of nitroacetophenone by the method of [6, 1], 2-amino-1-nitro-1-propene 2f by the method of [8], and
nitropyridine 4d was described in [13].
Nitroacetone. A solution of conc. H2SO4 (19.6 ml) in water (9.8 ml) was added dropwise to a mixture of
nitroisopropanol (20.0 g, 0.19 mol) and Na2Cr2O7 (30.0 g, 0.11 mol) in water (20 ml) cooled to 0°C, at such a
rate that the temperature of the reaction mixture did not exceed 10°C. After adding all the acid, the mixture was
stirred a further 2 h, then water (60 ml) was added, and the mixture extracted with CHCl3 (3 × 20 ml). The
extract was washed with saturated NaCl solution, and dried over MgSO4. After removing the solvent in vacuum,
nitroacetone (15.7 g, 80%) was obtained, which crystallized on cooling, was then diluted with absolute ether,
and filtered off. The snow-white crystals had mp 47°C [3,4]. Crystalline nitroacetone was stored in the
refrigerator for 2 weeks.
2-Nitro-1-phenyl-1-buten-3-one (1a). Nitroacetone (5.15 g, 0.05 mol) was added to a solution of
benzylidenebutylamine (8.1 g, 0.05 mol) in acetic anhydride (25 ml) with cooling. The precipitated white
crystals went back into solution again after a short time. The reaction mixture was left for 1 day at ~20°C, and
then poured into water. The precipitated oil crystallized on cooling for several hours. The crystals were washed
with a small quantity of CCl4, and filtered off. Compound 1a (2.48 g, 26%) of mp 106°C was obtained [7].
743

Nitrodihydropyridines 3a-i (General Procedure). A solution of nitrochalcone 1 (10 mmol) and the
appropriate enamine 2 (10 mmol) in glacial CH3COOH (15 ml) was left at room temperature for 15-20 h. The
acetic acid was distilled in vacuum, and the residue recrystallized from ethanol. Nitrodihydropyridine 3a was
purified by flash chromatography on a dry column [14] (Silicagel L 5/40 µ sorbent).
Oxidation of Nitrodihydropyridines 3a-i into Nitropyridines 4a-i (General Procedure). Sodium
nitrite (3 mmol) was added in portions with stirring to a suspension of the appropriate dihydropyridine 3a-i in
glacial CH3COOH (6 ml) at 60-70°C. After adding all the oxidizing agent the reaction mixture was stirred for
1 h further at the same temperature. The reaction mixture was cooled to room temperature, and diluted to
4 volumes with water and ice. The precipitated crystals of pyridines 4a-i were filtered off, washed with water,
dried, and recrystallized from ethanol.
The work was carried out with the financial support of the Russian Fund for Fundamental Investigations
(grant No. 00-03-32832).
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