Multicomponent synthesis of unsymmetrical 5-nitropyridines

Article abstract of DOI:10.1007/s10593-019-02403-x

[Figure not available: see fulltext.] Reaction of 2-nitroacetophenone, furfurol, β-dicarbonyl compounds, and ammonium acetate led to 3-substituted 4-(2-furyl)-5-nitro-6-phenyl-1,4-dihydropyridines, which were oxidized with potassium nitrate in the presenc

Full text of DOI:10.1007/s10593-019-02403-x

DOI 10.1007/s10593-019-02403-x
Chemistry of Heterocyclic Compounds 2018, 54(12), 1127–1130
Multicomponent synthesis
of unsymmetrical 5-nitropyridines
Vladislav A. Koveza1, Ivan V. Kulakov2,3*,
Zarina T. Shulgau3, Tulegen M. Seilkhanov4
1 F. M. Dostoevskii Omsk State University,
55a Mira Ave., Omsk 644077, Russia; е-mail: koveza.vladislav@yandex.ru
2 Institute of Chemistry, Tyumen State University,
15a Perekopskaya St., Tyumen 625003, Russia, e-mail: i.v.kulakov@utmn.ru
3 Republican State Enterprise ''National Center for Biotechnology'' under
the Science Committee of Ministry of Education and Science of the Republic of Kazakhstan,
13/5 Kurgalzhinskoye Rd., Astana 010000, Kazakhstan; e-mail: shulgau@biocenter.kz
4 Sh. Ualikhanov Kokshetau State University,
76 Abaya St., Kokshetau 020000, Kazakhstan; e-mail: tseilkhanov@mail.ru
Translated from Khimiya Geterotsiklicheskikh Soedinenii,
2018, 54(12), 1127–1130
Submitted September 4, 2018
Accepted November 15, 2018
Reaction of 2-nitroacetophenone, furfurol, β-dicarbonyl compounds, and ammonium acetate led to 3-substituted 4-(2-furyl)-5-nitro-
6-phenyl-1,4-dihydropyridines, which were oxidized with potassium nitrate in the presence of copper(II) nitrate (10 mol %), leading to
the respective 5-nitro-6-phenylpyridines. The performed multicomponent reactions met the general principles of green chemistry.
Synthesis of these unsymmetrical 5-nitro-6-phenylpyridines via the formation of 1,4-dihydropyridine intermediates under the conditions
of multicomponent reaction significantly shortened the overall reaction time, decreased the number of steps, and improved the yield.
Keywords: 5-nitro-1,4-dihydropyridines, 5(3)-nitropyridines, green chemistry, multicomponent reaction.
One of the most important topics in contemporary
organic chemistry is the study of multicomponent reactions
(MCR).1,2 This topic is aligned with the overall concept of
green chemistry as one of the promising future directions in
advanced chemical research.3 MCR generally meet the
criteria of low environmental impact, atom economy, and
small number of steps, allowing to approach perfection in
synthetic process development.
The currently known multicomponent syntheses provide
single-step access to good yields of many different
heterocyclic derivatives, including symmetrical 1,4-di-
hydropyridines (1,4-DHP) via the Hantzsch reaction.4
However, the synthesis of unsymmetrical 1,4-DHP
according to the classical Hatzsch reaction encountered
significant difficulties in the preparation and isolation of
individual products due to the different reactivity of the
employed carbonyl compounds,5 therefore only isolated
examples of such reactions are reported in the literature6
and it is quite interesting to continue studies in this
direction.
Some 1,4-DHP derivatives relate to an important class
of antihypertensive drugs (for example, nifedipine 1,
nitrendipine 2, Fig. 1), which act as calcium channel
blockers.7
A distinctive structural feature of these
compounds is the 3-nitrophenyl substituent at position 4.8
Analogous properties were also observed in the case of
5-nitro-1,4-dihydropyridine 3,9 which additionally empha-
sizes the importance of studies aimed at the development of
new synthetic methods and search for new, effective drugs
in the series of 5-nitro-1,4-dihydropyridine derivatives.
Thus, an example of multicomponent synthesis of
symmetrical 3,5-dinitro-1,4-dihydropyridines 4 over the
0009-3122/18/54(12)-1127©2018 Springer Science+Business Media, LLC
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Chemistry of Heterocyclic Compounds 2018, 54(12), 1127–1130
NO2
NO2
with sodium nitrite in acetic acid gave the corresponding
5-nitropyridines 10.11
The purpose of this work was to develop a simple and
effective method for the preparation of 5-nitro-1,4-di-
hydropyridine 9. In order to accomplish this, we used the
example of compound 9a to develop and optimize a four-
component reaction of 2-nitroacetophenone (5) (obtained
according to a published procedure15), acetylacetone (7а),
and furfurol in equimolar amounts, in the presence of a
moderate excess of ammonium acetate (Scheme 3). The
parameters selected for optimization were: the choice of
solvent, reaction temperature, and the excess of ammonium
acetate.
MeO2C
Me
CO2Me EtO2C
CO2Me
Me
N
H
1
Me
Me
N
H
2
F3C
O2N
CO2Me
Me
Me
N
H
3
Scheme 3
Figure 1. The structural formulas of biologically active 1,4-DHP.
course of 2 h has been reported in the literature
(Scheme 1).10 Readily available starting materials were
used in this process: benzaldehyde, nitroacetone, and
ammonium acetate.
Scheme 1
The best yields and highest purity of the product were
obtained by using acetic acid as solvent and a 5-fold excess
of ammonium acetate. The optimal reaction temperature
was found to be 50–60°С. 5-Nitro-1,4-dihydropyridine 9а
was formed at these conditions in a relatively high yield for
multicomponent reactions, with the reaction duration as
short as 30 min. It should be noted that the reaction
duration was controlled both by TLC and by the
precipitation of bright-orange, fine crystalline solids, which
were collected by filtration and did not require additional
purification, as 1Н NMR spectrum indicated that the
product was analytically pure compound 9а. The isolation
of an additional amount of compound 9а from the mother
liquors was quite laborious and improved the overall yield
only by 1–3%, thus it was deemed to be unnecessary.
Performing the reaction at lower temperature (<50°С)
significantly prolonged the reaction time, while higher
temperature (>60°С) led to pronounced resinification of the
reaction mixture, complicating the isolation of product and
decreasing its yield. In other solvents (benzene, 2-propanol,
ethanol), the target product failed to precipitate from the
reaction mixture, complicating its isolation and decreasing
the yield to 10–15%.
However, no reports have been published on the
synthesis of unsymmetrical 3,5-dinitro-1,4-dihydro-
pyridines according to a scheme analogous to that
described above. In general, unsymmetrical 5-nitro-
1,4-dihydropyridines are synthesized by a reaction of the
respective nitrochalcone 6 and enamines 8 derived from
β-dicarbonyl compounds (Scheme 2).11,12 This preparative
procedure requires preliminary synthesis of the starting
nitrochalcone 613 and enamines 8,14 takes considerable time,
and consumes significant amounts of energy, while 5-nitro-
1,4-dihydropyridine 9 is formed in relatively low overall
yields. Further oxidation of 5-nitro-1,4-dihydropyridine 9
Scheme 2
It should be noted that only the use of furfurol in this
MCR resulted in precipitation of 1,4-DHP 9a as pure
crystals from the reaction mixture. The attempts to use
other aromatic aldehydes (benzaldehyde, thiophenecarb-
aldehyde) also resulted in the formation of the respective
1,4-dihydropyridines, albeit in lower yields (10–25%).
Furthermore, the procedure involved additional steps for
the isolation of pure products, which did not precipitate
from the reaction mixture, unlike in the case of compound
9a. When analogous reactions were performed at the
optimized conditions by replacing acetylacetone (7a) with
acetoacetic ester (7b) or benzoylacetone (7c), the products
were 1,4-dihydropyridines 9b,c.
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Chemistry of Heterocyclic Compounds 2018, 54(12), 1127–1130
Since the oxidation of the obtained 5-nitro-1,4-
spectrometer (400 and 100 MHz, respectively), the internal
standard was TMS or residual solvent signals (7.25 and
dihydropyridines 9а–с to the respective 5-nitropyridines
10а–с with sodium nitrite in acetic acid gave low yields
(approximately 60%),11 we were interested in improving
these yields. It was considered worthwhile to replace
sodium nitrite with less toxic oxidants, such as nitrates.16 It is
known that nitrates of some metals, such as Cu(NO3)2,17a
Fe(NO3)3,17b Fe(NO3)3–Cu(NO3)2,17c Zr(NO3)4,17d Bi(NO3)3,17e
(NH4)2Ce(NO3)6,17f have been successfully used for the
oxidation of 1,4-dihydropyridines to pyridines in moderate
to high yields. However, we did not find any literature
sources using potassium nitrate for such purposes and our
attempt to use it for the oxidation of 1,4-dihydropyridines
9a–c was not successful. At the same time, the oxidation of
1,4-dihydropyridines 9a–c with 0.5–1.0 equiv of potassium
nitrate in combination with 5–10 mol % of copper(II) nitrate
in acetic acid not only significantly improved the yields of
oxidation products to 85%, but also allowed to obtain
pyridines 10а–с in better purity (the melting points of
pyridines 10а–с were higher than the literature values11 by
several degrees), which was beneficial for their subsequent
purification by recrystallization (Scheme 4). The
characteristics of both methods are compared in Table 1.
1
77.0 ppm in the case of CDCl3 for Н and 13C nuclei,
respectively, and 39.9 ppm for 13C nuclei in DMSO-d6).
The signals of 13С nuclei were assigned using APT method
by taking into account the chemical shift range of carbon
atoms belonging to functional groups. The reaction
progress and purity of the obtained compounds were
controlled using TLC method on Sorbfil AF-A-UF plates,
eluent AcOEt–hexane–AcOH, 5:5:0.1. Visualization was
performed in iodine vapor chamber and under UV light.
The physicochemical and spectral characteristics of
compounds 9, 10 a–c matched the literature data.11
Preparation of 5-nitro-6-phenyl-1,4-dihydropyridine
derivatives 9a–c (General method). A mixture of 2-nitro-
acetophenone (5) (4.95 g, 30.0 mmol), furfurol (2.88 g,
30.0 mmol), the appropriate β-dicarbonyl compound 7a–c
(30.0 mmol), and ammonium acetate (11.55 g, 150 mmol)
in glacial acetic acid (25 ml) was stirred at 50–60°С for 0.5–
1 h. The reaction mixture containing crystalline precipitate
that formed after the completion of reaction was cooled to
0–5°С, filtered, washed first with 50% aqueous solution of
2-propanol, then washed with water, and dried.
1-[4-(Furan-2-yl)-2-methyl-5-nitro-6-phenyl-1,4-dihydro-
pyridin-3-yl]ethan-1-one (9a). Yield 4.34 g (45%), fine
bright-orange crystals, mp 187–189°С (EtOH) (mp 189–
190°С11). IR spectrum, ν, cm–1: 1204, 1328, 1444, 1483,
Scheme 4
O
KNO3 (0.5–1.0 equiv)
O
O
O
Cu(NO3)2 (5–10 mol %)
1
1637 (С=О), 3284 (N–H). H NMR spectrum (CDCl3),
O2N
Ph
O2N
Ph
R
R
AcOH, H2O
50–60°C, 0.5 h
80–84%
δ, ppm (J, Hz): 2.34 (6H, s, 2CH3); 5.65 (1H, s, 4-CH);
6.19 (1H, d, J = 2.6, H-3 Fur); 6.32 (1H, br. s, H-4 Fur);
6.35 (1H, br. s, NH); 7.29–7.36 (3H, m, H-5 Fur, H-3,5
Ph); 7.40–7.50 (3H, m, H-2,4,6 Ph). 13C NMR spectrum
(CDCl3), δ, ppm: 19.7 (2-CH3); 29.4 (COCH3); 35.6 (C-4);
106.4 (C-3 Fur); 110.5 (C-4 Fur); 111.8; 123.5; 127.5
(C-2,6 Ph); 128.9 (C-3,5 Ph); 130.3 (C-4 Ph); 133.7; 142.2
(C-5 Fur); 142.7; 145.4; 154.8; 197.8 (С=О).
N
H
Me
N
Me
9a–c
10a–c
a R = Me, b R = OEt, c R = Ph
Table 1. Our MCR for the preparation of 1,4-DHP 9a
and pyridine 10a as compared with a literature method
Ethyl 4-(furan-2-yl)-2-methyl-5-nitro-6-phenyl-1,4-di-
hydropyridine-3-carboxylate (9b). Yield 4.34 g (44%),
fine bright-yellow crystals, mp 157–159°С (EtOH) (mp 157–
159°С11). IR spectrum, ν, cm–1: 1215, 1263, 1317, 1484,
Reaction parameters
Our MCR
Literature method11
Synthesis of 1,4-DHP 9а
Number of steps
1
3
1
1703 (С=О), 3292 (N–H). H NMR spectrum (CDCl3),
Overall yield of 1,4-DHP, %
45
36
39
δ, ppm (J, Hz): 1.29 (3H, br. t, J = 6.9, OCH2CH3); 2.32
(3H, s, CH3); 4.18 (2H, m, OCH2CH3); 5.61 (1H, s, 4-CH);
6.17 (1H, d, J = 2.9, H-3 Fur); 6.30 (1H, br. s, H-4 Fur); 6.44
(1H, br. s, NH); 7.24–7.32 (3H, m, H-5 Fur, H-3,5 Ph);
7.36–7.45 (3H, m, H-2,4,6 Ph). 13C NMR spectrum
(CDCl3), δ, ppm: 14.2 (CH3CH2); 18.7 (2-CH3); 34.6 (C-4);
60.4 (ОCH2); 104.3; 105.9 (C-3 Fur); 110.5 (C-4 Fur);
122.9; 127.4 (C-2,6 Ph); 128.8 (C-3,5 Ph); 130.1 (C-4 Ph);
133.8; 141.5 (C-5 Fur); 143.6; 146.1; 155.4; 166.2 (С=О).
[4-(Furan-2-yl)-2-methyl-5-nitro-6-phenyl-1,4-dihydro-
pyridin-3-yl](phenyl)methanone (9с). Yield 4.34 g (37%),
fine bright-orange crystals, mp 219–221°С (EtOH) (mp 219–
221°С11). IR spectrum, ν, cm–1: 1227, 1277, 1314, 1454,
1494, 1637 (С=О), 3304 (N–H). 1H NMR spectrum
(CDCl3), δ, ppm (J, Hz): 1.91 (3H, s, CH3); 5.75 (1H, s,
4-CH); 5.97 (1H, br. s, NH); 6.10 (1H, d, J = 2.5, H-3 Fur);
6.25 (1H, br. s, H-4 Fur); 7.25–7.30 (3H, m, H-5 Fur, H-3,5
Ph); 7.42–7.54 (6H, m, H-2,4,6 Ph, H-3,4,5 PhCO); 7.68
Combined duration of reactions, h
0.5
Synthesis of pyridine 10а
Number of steps
2
4
Overall yield of pyridine, %
38
24
40
Combined duration of reactions, h
1.0
Thus, we have developed a relatively simple, econo-
mical, and effective method for the preparation of 4-furyl-
substituted 5-nitro-6-phenylpyridines, which in many ways
(better overall yield, shorter reaction time, small number of
steps) is superior to the previously published methods.
Experimental
IR spectra were recorded on an Infralum FT-801
spectrometer for samples in KBr pellets. Н and 13C NMR
1
spectra were acquired on
a Jeol JNM-ECA 400
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Chemistry of Heterocyclic Compounds 2018, 54(12), 1127–1130
(2H, d, J = 7.6, H-2,6 PhCO). 13C NMR spectrum (DMSO-d6),
128.0 (C-2,6 Ph); 128.9 (C-3,5 Ph); 129.0 (2 signals, C-2,6
PhCO); 129.1 (C-3,5 PhCO); 130.1 (C-4 Ph); 131.1; 134.2;
135.3; 135.9; 141.9; 143.2; 145.3 (C-5 Fur); 150.9; 157.0;
195.2 (С=О).
δ, ppm: 17.5 (2-CH3); 36.5 (C-4); 105.2 (C-3 Fur); 110.7
(C-4 Fur); 113.3; 119.7; 128.2 (C-2,3,5,6 Ph); 128.5 (C-2,6
PhCO); 128.9 (C-3,5 PhCO); 129.8; 132.5 (C-4 Ph); 133.8;
139.1; 139.8; 142.3 (C-5 Fur); 148.5; 155.4; 196.2 (С=О).
Preparation of compounds 10а–с (General method).
A mixture of 1,4-dihydropyridine 9a–c (1.0 mmol),
potassium nitrate (101 mg, 1.0 mmol), and copper(II)
nitrate trihydrate (24 mg, 0.1 mmol) in glacial acetic acid
(10 ml) and water (0.5 ml) was stirred at 50–60°С for
30 min (control by TLC). When the reaction was complete,
the solution was cooled, poured into ice–water mixture
(100 ml), and salted out using NaCl. The obtained
precipitate was filtered off, washed with water, and dried.
The filtrate was additionally extracted with ethyl acetate
(2×10 ml). The extract was dried over Na2SO4, and the
solvent was removed by distillation. The crystals isolated
from the extract were combined with the precipitate and
recrystallized from ethanol.
This work received financial support from the
Committee for Science, Ministry of Education and Science,
Republic of Kazakhstan (grant No. AP05131602).
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1-[4-(Furan-2-yl)-2-methyl-5-nitro-6-phenylpyridin-3-yl]-
ethan-1-one (10a). Yield 268 mg (84%), beige crystals,
mp 126–128°С (ethanol) (mp 124–126°С11). IR spectrum,
1
ν, cm–1: 1249, 1353, 1566, 1709, 3131. H NMR spectrum
(CDCl3), δ, ppm (J, Hz): 2.24 (3H, s, CH3); 2.62 (3H, s,
CH3); 6.55 (1H, br. s, H-4 Fur); 6.77 (1H, d, J = 4.4, H-3
Fur); 7.45–7.50 (3H, m, H-5 Fur, H-3,5 Ph); 7.58–7.63
(3H, m, H-2,4,6 Ph). 13C NMR spectrum (CDCl3), δ, ppm:
23.0 (2-CH3); 30.9 (COCH3); 112.8 (C-3 Fur); 114.6 (C-4
Fur); 127.7; 128.0 (C-2,6 Ph); 128.9 (C-3,5 Ph); 130.1 (C-4
Ph); 133.2; 135.2; 142.0; 143.2; 145.7 (C-5 Fur); 150.5;
155.7; 202.3 (С=О).
Ethyl 4-(furan-2-yl)-2-methyl-5-nitro-6-phenylnicoti-
nate (10b). Yield 290 mg (83%), beige crystals, mp 117–
118°С (ethanol) (mp 116–117°С11). IR spectrum, ν, cm–1:
1273, 1360, 1536, 1598, 1726, 2982, 3143. 1H NMR
spectrum (CDCl3), δ, ppm (J, Hz): 1.27 (3H, t, J = 6.8,
OCH2CH3); 2.71 (3H, s, CH3); 4.34 (2H, q, J = 6.4,
OCH2CH3); 6.53 (1H, br. s, H-4 Fur); 6.78 (1H, br. s, H-3
Fur); 7.43–7.49 (3H, m, H-5 Fur, H-3,5 Ph); 7.54–7.63
(3H, m, H-2,4,6 Ph). 13C NMR spectrum (CDCl3), δ, ppm:
14.0 (CH3CH2); 23.1 (2-CH3); 62.3 (ОCH2); 112.4 (C-3
Fur); 113.7 (C-4 Fur); 126.0; 128.0 (C-2,6 Ph); 128.8
(C-3,5 Ph); 129.0; 130.1 (C-4 Ph); 135.2; 142.1; 143.7;
145.3 (C-5 Fur); 150.9; 157.2; 166.7 (С=О).
[4-(Furan-2-yl)-2-methyl-5-nitro-6-phenylpyridin-3-yl]-
(phenyl)methanone (10с). Yield 310 mg (80%), beige
crystals, mp 102–103°С (mp 101–103°С11). IR spectrum,
1
ν, cm–1: 1267, 1351, 1536, 1675, 2925. H NMR spectrum
(CDCl3), δ, ppm (J, Hz): 2.53 (3H, s, CH3); 6.30 (1H, br. d,
J = 5.1, H-4 Fur); 6.62 (1H, d, J = 4.5, H-3 Fur); 7.30 (1H,
br. s, H-5 Fur); 7.42–7.51 (5H, m, H-2–6 Ph); 7.58 (1H, t,
J = 7.5, H-4 PhCO); 7.62–7.69 (2H, m, H-3,5 PhCO); 7.79
(2H, d, J =7.8, H-2,6 PhCO). 13C NMR spectrum (CDCl3),
δ, ppm: 23.3 (2-CH3); 112.3 (C-3 Fur); 114.8 (C-4 Fur);
1130