Nitropyridines. 1. Hantzsch synthesis of nitropyridines and their quaternary salts

Article abstract of DOI:10.1023/A:1022174325051

Previously unknown 1,4-dihydropyridines containing acetyl, amide, benzoyl, ester, and cyano groups together with a nitro group were synthesized with preparative yields by a two-component Hantzsch synthesis based on 2-nitro-1,3-diphenylpropenone and variou

Full text of DOI:10.1023/A:1022174325051

Chemistry of Heterocyclic Compounds, Vol. 38, No. 11, 2002
NITROPYRIDINES. 1. HANTZSCH
SYNTHESIS OF NITROPYRIDINES
AND THEIR QUATERNARY SALTS
G. P. Sagitullina, L. V. Glizdinskaya, G. V. Sitnikov, and R. S. Sagitullin
Previously unknown 1,4-dihydropyridines containing acetyl, amide, benzoyl, ester, and cyano groups
together with a nitro group were synthesized with preparative yields by a two-component Hantzsch
synthesis based on 2-nitro-1,3-diphenylpropenone and various enamines. The nitrodihydropyridines
were aromatized with sodium nitrite in acetic acid. The quaternary salts of low-basicity pyridines were
produced with dimethyl sulfate and methyl fluorosulfonate.
Keywords: 5-nitro-1,4-dihydropyridines, nitropyridines, quaternary salts of nitropyridines.
1,4-Dihydropyridines with a nitro group in the pyridine ring have potential biological activity. Thus,
compounds that are effective antagonists for histamine H2- and H3-receptors [1, 2] and Ca antagonists [3-5] and
also possess cardiotonic and vasodilator activity [6, 7] and antitumor [8] and herbicidal [9] activity have been
found in the series of nitropyridines. Medicinal preparations based on substituted nitrodihydropyridines are used
for the treatment of blood circulation system and thrombosis [10], hypertension, atherosclerosis, and stenocardia
[11-13]. All this explains the interest in the production of new representatives of 1,4-dihydropyridines with a
nitro group in the pyridine ring.
Our interest in the synthesis of new 2-methyl-5-nitro-4,6-diphenylpyridines 4 arose from systematic
investigations into the recyclization of quaternary pyridinium salts [14, 15], which included study of the effect
of their structure on the direction of recyclization.
A two-component Hantzsch synthesis, based on separation of the Knoevenagel and Michael stages in
which separately prepared nitrochalcone 1 (acceptor) and enamines 2a-d (donors) are used, proved the most
suitable for the synthesis of unsymmetrical 1,4-dihydropyridines in that it eliminates the possibility of the
formation of cyclocondensation side products.
We found that the dihydropyridines 3a-d are formed with preparative yields if the reaction is conducted
in acetic acid at room temperature with the starting compounds 1 and 2 in a molar ratio of 1:1. Most of the
dihydropyridines are precipitated from the acetic acid on completion of the reaction.
1
In the H NMR spectra of these compounds the signal of the 4-H proton is in the region of
5.05-5.52 ppm, while that of the proton attached to the pyridine nitrogen atom is in the region of 6.04-6.44 ppm
(Table 1).
The dihydropyridines 3a,c,d are easily oxidized by sodium nitrite in acetic acid at 60-70°C. Compound
3b is oxidized by sodium nitrite at room temperature. 3-Carbamoyl-2-methyl-5-nitro-4,6-diphenylpyridine (4d)
was obtained by partial hydrolysis of the nitrocyanopyridine 4c in sulfuric acid. In the 1H NMR spectrum of the
__________________________________________________________________________________________
Omsk State University, Omsk 644077, Russia; e-mail: shkil@univer.omsk.su. Translated from Khimiya
Geterotsiklicheskikh Soedinenii, No. 11, pp. 1518-1524, November, 2002. Original article submitted
February 13, 2001.
1336
0009-3122/02/3811-1336$27.00©2002 Plenum Publishing Corporation

Ph
N
Me
5a–g
Ph
Ph
Ph
O
O2N
Ph
X
X
O2N
Ph
O2N
Ph
X
X
O2N
Ph
Me
A–
+
N
H
Me
N
4a–e
Me
H2N Me
2a–d
1
3a–d
2-5 a X = COMe, b X = COOCH2Me, c X = CN, d X = COPh; 4, 5 e X = CONH2;
5 f X = COMe, g X = COOCH2Me, a A = ClO4, b,c,e A = MeSO4, d,f,g A = FSO4
nitroamide 4e in the regions of 7.73 and 8.02 ppm it is easy to identify the signals of the cis and trans protons of
the amide group in the respective configurational isomers, which appear in the spectrum as broad singlets of
equal intensity.
Analysis of the mass spectra of compounds 4a-e showed the general character of the fragmentation of
the molecular ion, which does not depend on the functional group X. The main directions of the primary
dissociation of the molecular ion are elimination of the NO2, OH, CO, and CHO groups. All these processes are
connected with the presence of the phenyl substituent at the α-position to the pyridine nitrogen atom (Scheme 1,
Table 2). Another direction in the dissociation of the molecular ion is the ejection of NO, which is preceded by
partial isomerization of the molecular ion to the pyridyl nitrite ion [16].
The dehydrogenation process, accompanied by cyclization to a trinuclear structure, makes an
insignificant contribution to the general pattern of the dissociation of the molecular ion.
For the alkylation of the pyridines 4a-e with two accepting substituents on account of their extremely
low basicity we used dimethyl sulfate and methyl fluorosulfonate ("magic methyl"). When the pyridines 4a-c,e
are heated with an excess of dimethyl sulfate at 100°C for 20-24 h the corresponding pyridinium methyl sulfates
5b,c,e are formed with preparative yields.
Scheme 1
Ph
N
Ph
N
.
–Me
X
N
O
+
X
.
+
+
C17H10NX
Me
Me
Ph
.
.
–NO2
–OH
Ph
N
.
+
.
O
.
+
Ph
N
+
Ph
X
X
OH
X
NO2
Ph
O
N
O
Me
Me
N
Me
Ph
4a–e
.
.
–CHO
–NO
–CO
Ph
N
+
Ph
.
X
N
O
+
+
Ph
N
X
O
X
NOH
Me
Me
N
Ph
–CO
X
Me
Ph
–CO
.
–CHO
Me
N
+
Ph
+
C16H12N2X
1337

TABLE 1. The Characteristics of the 1,4-Dihydropyridines 3a-d, the Pyridines 4a-e, and the Pyridinium Salts 5a-g
Found, %
——————
Com-
Empirical
formula
Yield,
%
-1
1
ν
δ
mp, °C
IR spectrum, , cm
H NMR spectrum (CDCl3), , ppm, J (Hz)*
Calculated, %
pound
С
Н
1
3a
2
3
4
5
6
7
8
C20H18N2O3
71.60
71.84
5.28
5.43
88-89
3420, 3300 (NH), 1670 (C=O),
1470, 1305 (NO2)
2.24 (3H, s, 2-CH3); 2.39 (3H, s, –COCH3); 5.52 (1H, s, 4-H);
6.04 (1H, s, –NH–); 7.24-7.46 (10H, m, 4-, 6-Ph)
84
C21H20N2O4
69.45
5.71
147-148
3420, 3300 (NH), 1690 (C=O),
1.23 (3H, t, –COOCH2CH3, J = 7); 2.30 (3H, s, 2-CH3);
4.09 (2H, q, –COOCH2CH3, J = 7); 5.41 (1H, s, 4-H);
6.32 (1H, s, –NH–); 7.17-7.41 (10H, m, 4-, 6-Ph)
74
3b
69.22
5.53
1470, 1310 (NO2)
C19H15N3O2
С25Н20N2O3
C20H16N2O3
С21H18N2O4
71.45
71.91
4.91
4.76
95-97
160-161
132-133
84-85
3430, 3300 (NH), 2220 (CN),
1500, 1320 (NO2)
2.10 (3H, s, 2-CH3); 5.05 (1H, s, 4-H); 6.31 (1H, s, –NH–);
77
64
62
80
3с
3d
4a
4b
7.26-7.47 (10H, m, 4-, 6-Ph)
75.68
5.11
3420, 3300 (NH), 1640 (C=O),
1.72 (3Н, s, 2-CH3); 5.51 (1H, s, 4-Н); 6.44 (1H, s, –NH–);
75.74
5.09
1480, 1300 (NO2)
7.24-7.53 (15H, m, –COPh, 4-, 6-Ph)
72.46
72.28
4.70
4.85
1700 (C=O), 1530,1360 (NO2) 1.99 (3Н, s, 2-СН3); 2.65 (3H, s, –COCH3);
7.29-7.67 (10H, m, 4-, 6-Ph)
69.73
5.19
1720 (С=О), 1535, 1360 (NO2) 0.91 (3Н, t, –СООСН2СН3, J = 7.2); 2.72 (3Н, s, 2-СН3 );
69.60
5.01
4.03 (2Н, q, –СООСН2СН3, J = 7.2);
7.24-7.66 (10Н, m, 4-, 6-Ph)
С19Н13N3O2
C25H18N2O3
C19H15N3O3
72.33
72.37
4.15
4.16
149-150
148-149
283-284
2230 (CN), 1540, 1360 (NO2)
2.93 (3H, s, 2-CH3); 7.37-7.67 (10H, m, 4-, 6-Ph)
60
89
90
4c
4d
4e
75.86
4.68
1680 (С=О), 1540, 1360 (NO2) 2.57 (3Н, s, 2-СН3); 7.16-7.72 (15Н, m, 4-, 6-Ph, –COPh)
76.13
68.76
68.46
4.60
4.61
4.54
3525, 3400 (NH), 1690 (С=О),
2.65 (3Н, s, 2-СН3); 7.36-7.54 (10Н, m, 4-, 6-Ph);
1540, 1350 (NO2)
7.73 (1H, br. s, –CONH2, cis); 8.02 (1Н, br. s, –CONH2, trans)
C21H19ClN2O7
C23H24N2O8S
56.12
4.18
234-236
195-196
2.22 (3Н, s, 2-СН3); 2.85 (3Н, s, –СОСН3);
73
78
5a
5b
56.45
4.29
3.95 (3Н, s, 1-СН3); 7.37-7.70 (10Н, m, 4-, 6-Ph)
56.66
56.55
4.96
4.95
0.92 (3Н, t, –СООСН2СН3, J = 7.1); 2.96 (3Н, s, 2-СН3);
–
3.40 (3Н, s, СН3SO4 ); 3.96 (3Н, s, 1-СН3); 4.18 (2Н, q,
–СООСН2СН3, J = 7.1); 7.39-7.70 (10Н, m, 4-, 6-Ph)
–
C21H19N3O6S
57.17
57.14
4.36
4.34
202-203
3.22 (3H, s, 2-CH3); 3.37 (3H, s, CH3SO4 );
75
5c
4.01 (3H, s, 1-CH3); 7.55-7.78 (10H, m, 4-, 6-Ph)

TABLE 1 (continued)
1
2
3
4
5
6
7
8
C26H21FN2O6S
C21H21N3O7S
61.59
61.41
4.21
4.16
176-178
232-233
2.78 (3H, s, 2-CH3); 4.01 (3H, s, 1-CH3);
80
89
5d
7.19-7.87 (15H, m, 4-, 6-Ph, –СOPh)
–
54.93
4.61
2.93 (3H, s, 2-CH3); 3.39 (3H, s, CH3SO4 ); 3.95 (3H, s,
1-CH3); 7.38-7.72 (10H, m, 4-, 6-Ph); 8.17 (1Н, br. s,
–CONH2, cis); 8.23 (1Н, br. s, –CONH2, trans)
5e
54.89
4.60
C21H19FN2O6S
C22H21FN2O7S
56.27
56.50
4.17
4.29
206-208
2.23 (3H, s, 2-CH3); 2.86 (3H, s, –COCH3);
75
84
5f
3.96 (3H, s, 1-CH3); 7.35-7.72 (10H, m, 4-, 6-Ph)
55.67
4.51
178-179.5
0.93 (3H, t, –COOCH2CH3, J = 7.2); 2.97 (3H, s, 2-CH3);
3.96 (3H, s, 1-CH3); 4.18 (2H, q, –COOCH2CH3, J = 7.2);
7.35-7.74 (10H, m, 4-, 6-Ph)
5g
55.46
4.44
_______
* The 1H NMR spectra of compounds 4e and 5a-g were recorded in DMSO-d6.
TABLE 2. The Mass Spectra of the Nitropyridines 4a-c (m/z, Irel) (Intensities as % of the Intensity of the Maximum Peak)
Com-
M+·
[M–Н]+
[M–ОН]+
[M–СО]+·
[M–СНО]+
[M–NO]+
[M–NO2]+
[M–СO–CHO]+ [M–NO–CO]+ [M–NO2–CH3]+·
pound
332 (100.00)
362 (100.00)
315 (100.00)
394 (47.49)
333 (100.00)
331 (4.81)
361 (2.95)
314 (13.47)
393 (8.04)
332 (6.23)
315 (12.79)
345 (4.91)
298 (48.74)
377 (12.86)
316 (31.67)
304 (9.43)
334 (12.17)
287 (21.79)
366 (6.39)
305 (15.59)
303 (11.37)
333 (13.90)
286 (25.35)
365 (11.45)
304 (17.68)
302 (13.40)
332 (2.07)
285 (28.77)
364 (10.29)
303 (11.41)
286 (6.85)
316 (2.31)
269 (14.21)
348 (2.75)
287 (10.24)
275 (12.57)
305 (27.00)
258 (59.94)
337 (10.58)
276 (25.80)
274 (3.38)
304 (18.28)
257 (5.79)
336 (0.79)
275 (2.09)
271 (32.74)
301 (0.83)
254 (7.77)
333 (—)
272 (4.98)
4a
4b
4c
4d
4e

Pyridinium methyl sulfate 5a is formed as an oil, and it was therefore converted into the readily
crystallizing perchlorate by substitution of the anion. 3-Benzoyl-2-methyl-5-nitro-4,6-diphenylpyridine (4d) is
not alkylated by dimethyl sulfate, and methyl fluorosulfonate was therefore used for the production of its
quaternary salt. In addition to the methyl sulfates, the readily crystallizing fluorosulfonates 5g,f were also
obtained from the pyridines 4a,b.
It should be noted that the pyridines 4a-d that we synthesized from the nitro aliphatic precursors by the
Hantzsch reaction can probably not be obtained by other known methods.
EXPERIMENTAL
The 1H NMR spectra were recorded on a Bruker AC-200 spectrometer (200 MHz) with TMS as internal
standard. The IR spectra were obtained on a Specord IR-75 instrument (in chloroform). The mass spectra were
recorded on a Varian MAT 212C instrument with direct injection of the samples into the ion source at
ionization potential 70 eV. The reactions and the purity of the products were monitored by TLC on Silufol
UV-254 plates with 9:1 chloroform–ethyl acetate (compounds 3a-d), chloroform (compounds 4a-d), and 6:3:1
chloroform–ethyl acetate–ethanol (compound 4e) as eluents. The melting points of compounds 3a-d, 4a,c,d, and
5b,d,g were determined on a Boetius instrument, and the others were determined on an instrument for
determination of the melting points of crystalline substances.
Nitroacetophenone was obtained by the method in [17].
1,3-Diphenyl-2-nitropropenone (1). A mixture of nitroacetophenone (4.00 g, 25 mmol), benzaldehyde
(4.24 g, 40 mmol), β-alanine (0.188 g), and glacial acetic acid (4 ml) in benzene (40 ml) was boiled for 3 h in a
flask fitted with a Dean–Stark tube. The reaction mixture was washed with water (3 × 5 ml), the benzene was
removed under vacuum, and the product was recrystallized from ethanol. We obtained 3.85 g (63%) of the
1
nitrochalcone 1; mp 92°C [18]. H NMR spectrum (CDCl3), δ, ppm: 8.34 (1H, s, –CH), 7.98-7.35 (10H, m,
arom.).
General Procedure for the Production of Nitrodihydropyridines 3a-d (Table 1). A solution of
compound 1 (2.53 g, 10 mmol) and the respective enamine 2 (10 mmol) in glacial acetic acid (15 ml) was left at
room temperature for 20 h. The acetic acid was distilled under vacuum, and the residue was recrystallized from
ethanol. The nitrodihydropyridine 3a was purified by flash chromatography on a dry column (Silicagel
L 5/40 µ) with gradient elution (hexane, chloroform, 9:1 chloroform–ethyl acetate).
General Procedure for the Oxidation of Nitrodihydropyridines 3a-d to Nitropyridines 4a-d
(Table 2). To a suspension of the respective dihydropyridine 3a-d (2 mmol) in glacial acetic acid (6 ml) at 60-
70°C (at room temperature for 3b) with stirring we added in parts sodium nitrite (3 mmol). When all the
oxidizing agent had been added, the reaction mixture was stirred at the same temperature for a further 1 h,
cooled to room temperature, diluted four times with water and ice, and neutralized with ammonia. The crystals
of the pyridines 4a-d that separated were filtered off, washed with water, dried, and recrystallized from ethanol.
3-Carbamoyl-2-methyl-5-nitro-4,6-diphenylpyridine (4e). A solution of the pyridine 3c (0.63 g,
2 mmol) and concentrated sulfuric acid (10 ml) was heated on a water bath for 1 h. The mixture was cooled to
room temperature and poured into a mixture of water and ice. The precipitate was filtered off, dried, and
recrystallized from ethanol.
Nitropyridinium Methyl Sulfates (5a-c,e) (General Procedure for the Alkylation of Nitropyridines
with Dimethyl Sulfate). A mixture of the respective pyridine 4a-c,e (5 mmol) and freshly distilled dimethyl
sulfate (1.9 ml, 20 mmol) was heated at 100°C for 20-24 h. The mixture was cooled and washed with dry ether
(3 × 10 ml). The ether was decanted. If the oil did not crystallize (as in the case of 5a), the residue was dissolved
in water (5 ml), and a saturated aqueous solution of 1.5 g of sodium perchlorate was added. The crystallized salt
was filtered off, dried, and recrystallized from ethanol.
1340

Nitropyridinium Fluorosulfonates (5d,f,g) (General Procedure for the Alkylation with Methyl
Fluorosulfonate). A solution of the respective pyridine 4a,b,d (5 mmol) in chlorobenzene (15 ml) was cooled
to 0°C. A solution of methyl fluorosulfonate (15 mmol) in chlorobenzene (3 ml) was added drop by drop with
stirring. After 10 min the cooling was removed, and the reaction mixture was left at room temperature for 48 h.
The crystals that separated were filtered off, washed with dry ether, and recrystallized from ethanol.
The characteristics of the obtained salts 5a-g are given in Table 1.
The work was carried out with financial support from the Russian Fund for Fundamental Research
(grant No. 00-03-32832) and the Ministry of Education of Russia (grant No. 97-0-94-290).
REFERENCES
1.
2.
K. Agrawal, S. B. Tang, M. W. Wolowyk, and E. E. Knaus, Drug. Des. Deliv., 3, 297 (1988).
C. R. Ganellin, S. K. Hosseini, Y. S. Khalaf, W. Tertiuk, and J. M. Arrang, J. Med. Chem., 38, 3342
(1995).
3.
4.
5.
P. Krippeit-Drews, S. Britsch, F. Lang, and G. Drews, Adv. Exp. Med. Biol., 426, 355 (1997).
C. Linde, C. Luffler, C. Kessler, and U. Quast, Arch. Pharmacol.,356, 467 (1997).
P. Krippeit-Drews, S. Britsch, F. Lang, and G. Drews, Biochem. Biophys. Res. Commun., 200, 860
(1994).
6.
7.
R. Shan and E. E. Knaus, Bioorg. Med. Chem. Lett., 2613 (1999).
G. Luijtelaar, D. Wiaderna, C. Elants, and W. Scheenen, Eur. J. Pharmacol., 406, 381 (2000).
C. Temple, G. A. Rener, W. R. Waud, and P. E. Noker, J. Med. Chem., 35, 3686 (1992).
RF Patent Application No. 96102779/04 (1996); Byull. Izobr., No. 14, 57 (1998).
FRG Patent Application No. 3724909 (1989); Ref. Zh. Khim., 24O135P (1989).
FRG Patent Application No. 3601196 (1987); Ref. Zh. Khim., 6O65P (1988).
FRG Patent Application No. 3716652 (1988); Ref. Zh. Khim., 4O36P (1990).
FRG Patent Application No. 3732380 (1989); Ref. Zh. Khim., 3O44P (1990).
G. P. Shkil, V. Lusis, D. Muceniece, and R. S. Sagitullin, Tetrahedron, 51, 8599 (1995).
G. P. Shkil, L. V. Berdovich, V. Lusis, D. Muceniece, and R. S. Sagitullin, Khim. Geterotsikl. Soedin.,
86 (1995).
8.
9.
10.
11.
12.
13.
14.
15.
16.
P. B. Terent'ev and A. P. Stankyavichyus, Mass-Spectrometric Analysis of Biologically Active Nitrogen
Bases [in Russian], Mokslas, Vilnius (1987), p. 105.
17.
18.
L. Zalukaev, Izv. Akad. Nauk LatvSSR, 3, 107 (1953).
A. Dornow, A. Müller, and S. Lüpfert, Liebigs Ann., 594, 191 (1955).
1341