Multicomponent synthesis of 4-unsubstituted 5-nitropyridine derivatives

Article abstract of DOI:10.1080/00397911.2020.1780261

Multicomponent reaction of 2-nitroacetophenone, urotropine (or paraformaldehyde), β-dicarbonyl compound and ammonium acetate afforded five new 4-unsubstituted 5-nitro-6-phenyl-1,4-dihydropyridine derivatives, oxidation of which provided the corresponding

Full text of DOI:10.1080/00397911.2020.1780261

Synthetic Communications
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ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: https://www.tandfonline.com/loi/lsyc20
Multicomponent synthesis of 4-unsubstituted 5-
nitropyridine derivatives
Ivan V. Kulakov, Alena L. Oleshchuk, Vladislav A. Koveza & Irina V.
Palamarchuk
To cite this article: Ivan V. Kulakov, Alena L. Oleshchuk, Vladislav A. Koveza & Irina V.
Palamarchuk (2020): Multicomponent synthesis of 4-unsubstituted 5-nitropyridine derivatives,
Synthetic Communications, DOI: 10.1080/00397911.2020.1780261
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https://doi.org/10.1080/00397911.2020.1780261
Multicomponent synthesis of 4-unsubstituted
5-nitropyridine derivatives
Ivan V. Kulakova , Alena L. Oleshchuka,b, Vladislav A. Kovezab, and
Irina V. Palamarchuka
b
aInstitute of Chemistry, Tyumen State University, Tyumen, Russia; Faculty of Chemistry, Omsk F. M.
Dostoevsky State University, Omsk, Russia
ABSTRACT
ARTICLE HISTORY
Received 22 December 2019
Multicomponent reaction of 2-nitroacetophenone, urotropine (or paraf-
ormaldehyde), b-dicarbonyl compound and ammonium acetate
afforded five new 4-unsubstituted 5-nitro-6-phenyl-1,4-dihydropyridine
derivatives, oxidation of which provided the corresponding 5-nitro-6-
phenylpyridines. The proposed approach for the synthesis of 4-unsub-
stituted 5-nitro-6-phenyl-1,4-dihydropyridines and their subsequent
aromatization into pyridines made it possible to reduce the total reac-
tion time by more than 200 times and the overall yield of 5-nitro-6-
phenylpyridine by 2 times compared with the known methods.
KEYWORDS
Green chemistry;
5-nitro-1,4-dihydropyridines;
5-nitropyridines; multicom-
ponent reaction
GRAPHICAL ABSTRACT
Introduction
Currently, multicomponent reactions (MCR),[1,2] are one of the modern trends of organic
chemistry. They not only correspond to the general concept of green chemistry as one of
the promising areas of the future chemistry[3] but also meet the criteria of environmental
friendliness, atom and step efficiency, which brings them close to perfect syntheses.
Multicomponent reactions make it possible to synthesize a large number of various
heterocyclic compounds in one step and with good yields, including the symmetric 1,4-
dihydropyridines (1,4-DHP) by the Hantzsch reaction.[4] However, the synthesis of
non-symmetric 1,4-DHP through to the classical by the Hantzsch method is associated
with significant difficulties in the preparation and isolation of an individual reaction
CONTACT Ivan V. Kulakov
i.v.kulakov@utmn.ru
Institute of Chemistry, Tyumen State University, Tyumen
625003, Russia.
Supplemental data for this article is available online at publisher’s website.
ß 2020 Taylor & Francis Group, LLC

2
I. V. KULAKOV ET AL.
Figure 1. Biologically active 1,4-dihydropyridines.
product due to the different reactivity of the used carbonyl compounds.[5] There are
only few examples on the synthesis of non-symmetric 1,4-DHP by this method.[6]
In this regard, research in this area is an urgent task.
Note some 1,4-DHP derivatives are used as antihypertensive drugs (for example, nifedi-
pine 1, nitrendipine 2, etc.), which are calcium channel blockers.[7] A distinctive feature of
these compounds is the presence of a 3-nitrophenyl fragment in the position 4 of the dihy-
dropyridine ring.[8] Similar properties were found in 5-nitro-1,4-dihydropyridines 3,[9] that
also increase the relevance of research related to the development of new synthesis meth-
ods and the search for new effective drugs in the series of 5-nitro-1,4-dihydropyridine
derivatives (Figure 1).
Thus, an example of multicomponent synthesis of symmetric 3,5-dinitro-1,4-DHP 4
has been reported in Vigante et al.[10] (Scheme 1).
However, there are no examples of the synthesis of unsymmetrical 3(5)-nitro-1,4-
DHP according to the scheme similar to the above. Generally, non-symmetric 5-nitro-
1,4-DHP can be synthesized by the reaction of the corresponding nitrochalcone 6 and
enamines of b-dicarbonyl compounds 8 (Scheme 2).[11] This method requires prelimin-
ary synthesis of nitrochalcone 6[12] and enamines 8,[13] as well as a lot of time and
energy. Moreover, the overall yield of the target 5-nitro-1,4-DHP 9 is low. Further oxi-
dation of 5-nitro-1,4-DHP 9 with sodium nitrite in glacial acetic acid furnished the cor-
responding 5-nitropyridine 10.[11]
In addition, functionally substituted 1,4-DHPs are important intermediates in the classical
method for preparation of pyridines, including 3- or 5-nitropyridines, which in turn are
excellent precursors in the synthesis of unavailable 3- or 5-aminopyridines. So, for example,
there is a three-component one-step method for producing 4-unsubstituted 5-nitro-6-phe-
nylpyridines 11a–c starting from nitroacetophenone 5, enamines 8a–c and triethyl orthofor-
mate[14,15] (Scheme 3). The obtained pyridines 11 turned out to be good precursors in the
synthesis of alkaloid quindoline, its structural analogues and substituted d-carbolines.[16]
In our opinion, this method also has significant drawbacks compared to the classical
method of obtaining pyridines through the intermediate stage of 1,4-DHP formation:
the total duraꢀtion of all reactions is from 50[14] to 122 h,[15] including prolonged heating
at 30 and 80 ‘, the use of inert gas, the additional stage of the preliminary preparation
of b-dicarbonyl compounds enamines 8a–c, the use of more expensive triethyl orthofor-
mate, as well as a relatively low total reaction yield. At the same time, unfortunately,
analysis of literature data showed that despite the ease of synthesis of 1,4-DHPs there
are no data on the methods for producing 4-unsubstituted 5-nitro-6-phenylpyridines
11a–c by oxidation of the corresponding 1,4-DHPs.
Recently,[17] we have reported the four-component synthesis of 1,4-DHPs 9a–c based
on the reaction of 2-nitroacetophenone 5[18] with equimolar amounts of b-dicarbonyl

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Scheme 1. Synthesis of symmetric 3,5-dinitro-1,4- dihydropyridines.
Scheme 2. Three step synthesis of 4-substituted 5-nitro-6-phenylpyridines.
Scheme 3. Synthesis of 4-unsubstituted 5-nitro-6-phenylpyridines.
compounds 7a–c and furfural in the presence of an excess of ammonium acetate. The
optimal conditions for oxidation of the obtained 1,4-DHPs 9a–c with potassium nitrate
in the presence of catalytic amounts of copper(II) nitrate to the corresponding pyridines
10a–c with yields of up to 85% have been also shown. Compared to the method
reported in,[11] the preparation of pyridines 10a–c through the multicomponent synthe-
sis of 1,4-DHPs and their subsequent oxidation allowed us to reduce the number of
stages from 4 to 2, increase the total pyridine yield from 24% to 38% and significantly
reduce the total reaction time from 40 to 1 h.[17]
Results and discussion
Therefore, it was of interest to study the possibility of obtaining in this way non-symmetric
4-unsubstituted 5-nitro-6-phenylpyridines 11a–c by the classical method, i.e., through the

4
I. V. KULAKOV ET AL.
Scheme 4. Synthesis of 4-unsubstituted 5-nitro-6-phenylpyridines.
stage of multicomponent synthesis of intermediate 1,4-DHPs and their further aromatiza-
tion into pyridines.
The four-component reactions were performed using equimolar amounts of nitroace-
tophenone 5, the corresponding b-dicarbonyl compound 7a–e, formaldehyde, and an
excess of ammonium acetate (Scheme 4).
Various sources of formaldehyde (formalin, urotropine and paraformaldehyde) were
used. Acetic acid, which dissolves all 4 components, was used as a solvent. To select
optimal conditions, the synthesis of compound 12a was used as the model reaction. The
formaldehyde source, reaction temperature, an excess of acetylacetone 7a and ammo-
nium acetate, as well as the solvent were varied. Acetates or chlorides of Cu2þ, Ni2þ
,
Zn2þ, Mn2þ (10–20 mol%) were screened as possible reaction catalysts.
The best results were obtained when the reaction was performed at 60–70 ꢀC and
using urotropine (or paraformaldehyde) as a formaldehyde source. At a lower tempera-
ture (<60ꢀ‘), the reaction time increased, and at a higher temperature (>70ꢀ‘) a sig-
nificant grinding of the reaction mixture occurred, which made it difficult to isolate the
reaction product and reduced its yield. The use of formalin immediately led to the resin-
ification of the reaction mixture, probably due to its uncontrolled excess. An excess of
diketone 7a or urotropine led to the additional formation of a certain amount of sym-
metric 3,5-diacetyl-2,6-dimethyl-1,4-DHP. It should be noted that the reaction progress
was monitored both by TLC and visually by the precipitation of a red-orange fine-crys-
1
talline precipitate. The crystalline product was filtered off, dried and analyzed. By 
NMR data, it did not require further purification. Isolation of an additional amount of
compound 12a from the mother liquor proved to be very laborious and added only
2–3% to the total yield; therefore, it was neglected.
When changing acetic acid with other solvents (benzene, 2-propanol, ethanol, DFA),
the desired product 12a did not precipitate from the reaction mixture, which
significantly complicated its isolation and reduced yields to 15–20%. The best yields
(up to 63%) and reaction time (3–6 min) were obtained using 3(or 5)-fold excess of
ammonium acetate and about 10-fold molar excess of the solvent. The use of a smaller

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5
amount of the solvent made it difficult to dissolve the starting components, whereas a
large dilution did not lead to complete precipitation of the reaction product. The use of
acetates or chlorides of the above metals as possible reaction catalysts did not practically
affect the increase in yield and the reaction rate (Table 1).
The resulting 5-nitro-1,4-dihydropyridines 12a–e were further oxidized to 5-nitropyri-
dines 11a–e by procedure developed by us previously[17] using potassium nitrate instead of
toxic sodium nitrite in the presence of 5 mol% of copper(II) nitrate (or acetate) in acetic
acid, which also led to high yields (up to 95%) and the purity of the corresponding
Table 1. Optimization of synthesis methods on the example of compound 12a.
Entry
Catalyst (mol %)
Solvent
Eq. AcONH4 Eq. AcOH Temp. (ꢀC) Reaction time (min)a Yield (%)
1.
2.
3.
4.
5.
6.
7.
8.
–
–
–
–
–
–
–
–
–
–
–
–
AcOH
AcOH
AcOH
EtOH
DFA
5
5
5
5
5
5
5
5
2
3
5
3
3
3
3
3
3
3
3
3
3
20
20
20
–
40
70
80
60
60
60
60
60
60
60
60
60
60
60
60
60
60
60
60
60
60
15
–
–
–
–
–
–
5
–
5,5
1,5
2,5
7
3,5
6
4
2
4
2
45
43
20
18
22
20
25
51
32
47
63
63
49
56
59
46
61
58
53
59
52
–
AcOH/H2O, 1:1
AcOH/ EtOH, 1:1
AcOH
10
10
20
20
20
10
10
20
10
20
20
10
10
20
10
20
9.
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
a
Cu(AcO)2ꢁ H2O (10)
Cu(AcO)2ꢁ H2O (10)
Cu(AcO)2ꢁ H2O (20)
ZnCl2 (10)
ZnCl2 (10)
ZnCl2 (20)
Mn(AcO)2 4H2O (10)
Mn(AcO)2 4H2O (10)
Mn(AcO)2 4H2O (20)
1,5
8
AcOH
The time of precipitation of the reaction product from the reaction mixture.
Scheme 5. Proposed oxidation mechanism of 5-nitro-1,4-dihydropyridines 12a–e to 5-nitropyri-
dines 11a–e.

6
I. V. KULAKOV ET AL.
Table 2. Comparison of the methods for the synthesis of compound 12a.
Reaction parameters
Method MCR
Literature method[14]
Step number
Overall yield, %
Overall reaction time, h
2
63
0.25
2
31
52
pyridines. Although the oxidation only with potassium nitrate, without copper catalysis, pro-
vides the desired product, it significantly increases the reaction time (almost 3 times) and
reduces the yield to 70–80%. In this regard, we suggested that copper(II) cations coordi-
nated with nitrogen atom of 1,4-DHP significantly accelerate the electron transfer in corre-
sponding redox reaction, reducing to Cu(I). Then nitrate ions easily oxidize Cu(I) to Cu(II),
and the oxidation process of 1,4-DH repeats again (Scheme 5).
A comparative analysis of the synthesis method developed by us (method MCR) and
those described earlier[14] is given in Table 2.
Conclusions
In summary, we developed a simple, universal, economic, and efficient method for the syn-
thesis of 4-unsubstituted 5-nitro-6-phenylpyridines, which in many respects satisfies the
principles of green chemistry and significantly exceeds the method described in the litera-
ture in terms of overall yield and reaction time. The obtained positive results will allow
relatively quickly synthesizing the libraries of such derivatives for subsequent modifications.
Experimental
1
IR spectra were recorded on an Infralum FT-801 spectrometer for KBr pellets. H and
13C NMR spectra were recorded on a Bruker DRX400 instrument (400 and 100 MHz,
respectively) using DMSO-d6 (compound 12d,e) or CDCl3 (remaining compounds) the
internal standard was TMS or residual solvent signals (7.25 and 77.0 ppm in the case of
CDCl3 for 1 and 13C nuclei, respectively, and 39.9 ppm for 13C nuclei in DMSO-d6).
The MALDI TOF (matrix-assisted laser desorption/ionization) mass-spectra were obtained
on a Ultraflex-II mass spectrometer (Bruker Daltonics) in a positive ion mode using
reflection mode (20mV target voltage) with 4-hydroxybenzoic acid (and sodium 4-
hydroxybenzoate) matrix. Elemental analysis was performed on a Carlo Erba 1106 CHN
instrument. Melting points were determined using a Koffler hot bench. Monitoring of the
reaction course and the purity of the products was carried out by TLC on Sorbfil plates
and visualized using iodine vapor or UV light.
The physicochemical and spectral characteristics of compounds 12a–c matched the
literature data.[14]
Preparation of 5-nitro-6-phenyl-1,4-dihydropyridine derivatives 12a–e
(general method)
A mixture of 2-nitroacetophenone (5) (0.83 g, 5.0 mmol), hexamethylenetetramine
(0.18 g, 1.25 mmol), the appropriate b-dicarbonyl compound 7a–e (5.0 mmol), aꢀnd
ammonium acetate (1.16 g, 15.0 mmol) in glacial acetic acid (3 ml) was stirred at 60 ‘

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7
for 3–10 min. The reaction mixture containing crystalline precipitate that formed after
the completion of reaction was cooled to 0–5ꢀ‘, filtered, washed first with 40% aqueous
solution of ethanol, and dried. Recrystallized from 2-propanol (or ethanol).
Preparation of 5-nitro-6-phenylpyridine derivatives 11a–e (general method)
A mixture of 1,4-dihydropyridine 12a–e (10.0 mmol), potassium nitrate (1.01 g,
10.0 mmol), and copper(II) nitrate trihydrate (121 mg, 0.5 mmol) in glacial acetic acid
ꢀ
(20 ml) was stirred at 70 ‘ for 10–15 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 ꢂ 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 hexane
(or ethanol).
Full experimental details, 1H and 13C NMR spectra can be found via the
“Supplementary Content” section of this article’s webpage.
Acknowledgments
Spectrophotometric studies were performed on the basis of the Research Resource Center
“Natural Resource Management and Physico-Chemical Research” Institute of Chemistry, Tyumen
State University (with the financial support of the Ministry of Science and Higher Education of
the Russian Federation (contract no. 05.594.21.0019, unique identification number
RFMEFI59420X0019)).
Funding
The reported study was funded by RFBR according to the research project [No. 19-03-00376].
ORCID
Ivan V. Kulakov
http://orcid.org/0000-0001-5772-2096
References
[1] Multicomponent Reactions (Synthesis of Bioactive Heterocycles), 1st ed.; Ameta, K. L.,
Dandia, A.; CRC Press – Taylor & Francis Group: Baco Raton, FL, 2017.
[2] Domling, A.; Wang, W.; Wang, K. Chem. Rev. 2012, 112, 3083–3135. DOI: 10.1021/
cr100233r.
[3] Cioc, R. C.; Ruijter, E.; Orru, R. V. Green Chem. 2014, 16, 2958–2975. DOI: 10.1039/
C4GC00013G.
[4] (a) Allais, C.; Grassot, J.-M.; Rodriguez, J.; Constantieux, T. Chem. Rev. 2014, 114,
10829–10868. DOI: 10.1021/cr500099b. (b) Sharma, G. V.; Reddy, K. L.; Lakshmi, P. S.;
Krishna, P. R. Synthesis 2006, 2006, 55–58. DOI: 10.1055/s-2005-921744. (c) Debache, A.;
Boulcina, R.; Belfaitah, A.; Rhouati, S.; Carboni, B. Synlett 2008, 2008, 509–512. DOI: 10.
1055/s-2008-1032093. (d) Kumar, A.; Maurya, R. A. Synlett 2008, 2008, 883–885. DOI: 10.
1055/s-2008-1042908.

8
I. V. KULAKOV ET AL.
[5] Multicomponent Reactions; Herrera, R. P.; Marquez-Lopez, E., Eds.; Wiley-VCH:
Weinheim, 2015, p 477.
[6] (a) Zhou, Y.; Kijima, T.; Kuwahara, S.; Watanabe, M.; Izumi, T. Tetrahedron Lett. 2008,
49, 3757–3761. DOI: 10.1016/j.tetlet.2008.04.027. (b) Memarian, H. R.; Abdoli-Senejani,
€
€
M.; Dopp, D. Zeitschrift Fur Naturforschung B 2006, 61, 50–56. DOI: 10.1515/znb-2006-
0110.
[7] Brown, A. M.; Kunze, D. L.; Yatani, A. Nature 1984, 311, 570–572. DOI: 10.1038/
311570a0.
[8] Takahashi, D.; Oyunzul, L.; Onoue, S.; Ito, Y.; Uchida, S.; Simsek, R.; Gunduz, M. G.;
Safak, C.; Yamada, S. Biol. Pharm. Bull. 2008, 31, 473–479. DOI: 10.1248/bpb.31.473.
ꢀ
[9] (a) Garaliene, V.; Barsys, V.; Macys, A.; Vigante, B.; Krauze, A. Eur. J Med Chem.
2011, 46, 4441–4447 DOI: 10.1016/j.ejmech.2011.07.018. (b) Shan, R.; Velazquez, C.;
Knaus, E. E. J. Med. Chem. 2004, 47, 254–261. DOI: 10.1021/jm030333h. (c) Visentin, S.;
Rolando, B.; Di Stilo, A.; Fruttero, R.; Novara, M.; Carbone, E.; Roussel, C.; Vanthuyne,
N.; Gasco, A. J. Med. Chem. 2004, 47, 2688–2693. DOI: 10.1021/jm031109v.
[10] Vigante, B. A.; Terekhova, M. I.; Ozols, Y. Y.; Petrov, E. S.; Dubur, G. Y. Chem.
Heterocycl. Compd. 1989, 25, 1028–1031. DOI: 10.1007/BF00487303.
[11] Sagitullina, G. P.; Glizdinskaya, L. V.; Sagitullin, R. S. Russ. J. Org. Chem. 2007, 43,
602–606. DOI: 10.1134/S1070428007040197.
[12] Berestovitskaya, V. M.; Aboskalova, N. I.; Ishmaeva, E. A.; Bakhareva, S. V.; Berkova,
G. A.; Vereshchagina, Y. A.; Fel’gendler, A. V.; Fattakhova, G. R. Russ. J. Gen. Chem.
(Engl. Transl.) 2001, 71, 1942–1949. DOI: 10.1023/A:1014200612456.
[13] Baraldi, P. G.; Simoni, D.; Manfredini, S. Synthesis 1983, 1983, 902–903. DOI: 10.1055/s-
1983-30557.
[14] Sagitullina, G. P.; Garkushenko, A. K.; Sagitullin, R. S. Chem. Heterocycl. Comp. 2009, 45,
1147–1148. DOI: 10.1007/s10593-009-0395-3.
[15] Zobenko, Y. A.; Pozhidaeva, S. A.; Kuratova, A. K.; Glyzdinskaya, L. V.; Vorontsova,
M. A.; Sagitullina, G. P. Chem. Heterocycl. Comp. 2017, 53, 1014–1025. DOI: 10.1007/
s10593-017-2164-z.
[16] Shuvalov, V. Y.; Rupp, A. S.; Fisyuk, A. S.; Kuratova, A. K.; Nefedov, A. A.; Sagitullina,
G. P. ChemistrySelect 2019, 4, 1696–1699. DOI: 10.1002/slct.201803515.
[17] Koveza, V. A.; Kulakov, I. V.; Shulgau, Z. T.; Seilkhanov, T. M. Chem. Heterocycl. Comp.
2018, 54, 1127–1130. DOI: 10.1007/s10593-019-02403-x.
[18] Gavrilin, G. F.; Bykova, L. U.; Rogachkova, T. D. Pharm. Chem. J. (Engl. Transl.) 1973, 7,
173.