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Article

Multicomponent Synthesis of Unsymmetrical Derivatives of 4-Methyl-Substituted 5-Nitropyridines

by
Daria M. Turgunalieva
1,
Alena L. Stalinskaya
2,
Ilya I. Kulakov
3,
Galina P. Sagitullina
3,
Victor V. Atuchin
4,5,6,7,*,
Andrey V. Elyshev
1 and
Ivan V. Kulakov
1,*
1
Center for Nature-Inspired Engineering, University of Tyumen, 625003 Tyumen, Russia
2
Institute of Environmental and Agricultural Biology (X-Bio), University of Tyumen, 625003 Tyumen, Russia
3
Chemical Faculty, Omsk F. M. Dostoevsky State University, 644077 Omsk, Russia
4
Laboratory of Optical Materials and Structures, Institute of Semiconductor Physics, 630090 Novosibirsk, Russia
5
Research and Development Department, Kemerovo State University, 650000 Kemerovo, Russia
6
Department of Industrial Machinery Design, Novosibirsk State Technical University, 630073 Novosibirsk, Russia
7
R&D Center “Advanced Electronic Technologies”, Tomsk State University, 634034 Tomsk, Russia
*
Authors to whom correspondence should be addressed.
Processes 2023, 11(2), 576; https://doi.org/10.3390/pr11020576
Submission received: 30 January 2023 / Revised: 10 February 2023 / Accepted: 10 February 2023 / Published: 14 February 2023
(This article belongs to the Section Chemical Processes and Systems)
Browse Figures
Versions Notes

Abstract

:
The multicomponent reaction of 2-nitroacetophenone (or nitroacetone), acetaldehyde diethyl acetal, β-dicarbonyl compound, and ammonium acetate in an acetic acid solution allowed the acquisition of previously undescribed 4-methyl-substituted derivatives of 5-nitro-1,4-dihydropyridine in satisfactory yields. The oxidation of the obtained 5-nitro-1,4-dihydropyridine derivatives resulted in the corresponding 2,4-dimethyl-5-nitropyridines. In addition, for the first time in the synthesis of unsymmetrical 1,4-dihydropyridines by the Hantzsch reaction acetaldehyde, diethyl acetal was used as a source of acetaldehyde. The use of more volatile and sufficiently reactive acetaldehyde in this reaction did not lead to a controlled synthesis of unsymmetrical 5-nitro-1,4-dihydropyridines. The proposed multicomponent approach to the synthesis of 4-methyl-substituted 5-nitro-1,4-dihydropyridines and their subsequent aromatization into pyridines made it possible to obtain previously undescribed and hardly accessible substituted 5(3)-nitropyridines.

Graphical Abstract

1. Introduction

Currently, the use of green chemistry technology is one of the most actively developing area of study in modern organic chemistry. This is especially true for the pharmaceutical industry and syntheses of pharmacologically important heterocyclic derivatives, because it is the synthesis of drugs that still belong to the “dirtiest” processes regarding many key indicators of “green chemistry” [1,2,3,4,5,6]. In this regard, special attention should be paid to the study and application of multicomponent reactions (MCR) [7,8,9,10,11,12,13,14,15,16]. MCR entirely fit into the general concept of green chemistry, and they appear to be a promising area of chemistry for the future [17,18,19,20,21,22]. According to many indicators, MCR meet the criteria of environmental sustainability, as well as the requirements of atomic and stage efficiency, which is why they are often considered close to ideal syntheses [23,24].
By means of using multicomponent reactions, it is possible to synthesize a large number of heterocyclic derivatives in one step (a library of various compounds with different functional substituents) and often with good yields, which is highly important for further studies of the structure–activity relationship.
Despite the abundance and huge variety of the multicomponent reactions described in the literature, our attention was focused on the multicomponent Hantzsch reaction. One of the first examples of successfully implemented multicomponent reactions was the synthesis of pyridines or 1,4-dihydropyridines, that was discovered by A.R. Hantzsch in 1881 [25]. Nowadays, this reaction of dihydropyridine synthesis has been thoroughly and extensively investigated, the reaction mechanism has been established by using NMR spectroscopy [26] and mass spectrometry [27,28]; optimal conditions, limitations and examples of the reaction have been found, including the ones under the action of microwaves [29,30,31], ultrasound [32,33,34], green solvents [35,36,37] and effective catalysts [38,39,40,41,42,43]. All this combined made it possible to raise the yields in the Hantzsch synthesis to almost a quantitative amount.
It is worth noting that some derivatives of 1,4-dihydropyridines (1,4-DHP) belong to the class of antihypertensive drugs (for example, nifedipine 1, nitrendipine 2, etc.), which serve as calcium channel blockers [44,45,46,47,48,49,50]. The most effective drugs based on 1,4-dihydropyridine derivatives were synthesized back in the 1980s and 1990s. By now, they represent a huge pharmaceutical block of highly effective vasodilators and antihypertensive agents. For example, in 1990, Nifedipine held fourth place in terms of the total world market sales of pharmaceuticals with USD 1.95 billion, and in 2020, the estimation of the total world sale was USD 856.66 million [51]. The 3-nitrophenyl fragment in the fourth position is a specific characteristic of 1,4-DHP [52]. In 5-nitro-1,4-dihydropyridines of type 3 (Figure 1) similar characteristics were found [53,54,55], which increases the relevance of research pertaining to the creation of previously undescribed synthesis techniques and the search for potent medications in a variety of 5-nitro-1,4-dihydropyridine derivatives. So, more than 20 years ago while searching for more effective antihypertensive agents in the range of 1,4-dihydropiridine derivatives, a neuroprotective drug, cerebrocrast 4 (Figure 1), was unexpectedly discovered.
It has been shown that cerebrocraste not only has a high affinity for DHP-receptors, but also enhances brain functions. It has a nootropic effect, improving cognitive abilities and memory, as well as neuroprotective activity (correcting age-related, antihypoxic and anti-alcohol disorders in neurons) [56,57].
As it has already been mentioned, the synthesis of symmetric 1,4-dihydropyridines by the Hantzsch [58,59,60] reaction does not cause any major issues. Moreover, not only are standard dicarbonyl compounds (1,3-diketones, ketoenols, ketoesters, ketoamides, etc.) used in syntheses, but so are ketones with activated methylene groups. Thus, as an example, the symmetric 3,5-dinitro-1,4-DHP 5 is formed within 2 h [61] from nitroacetone, benzaldehyde and ammonium acetate according to Scheme 1, which is provided in this study:
However, the traditional Hantzsch reaction is coupled with considerable challenges in producing and isolating an individual product for the synthesis of unsymmetrical 1,4-DHP. It is caused by the variable reactivity of the carbonyl compounds used in the process [62]. Therefore, such reactions are described in the literature only in isolated examples [63], which makes research in this area highly relevant.
Basically, the equivalent nitrochalcone 6 and enamines of β-dicarbonyl compounds 7 are combined to produce the unsymmetrical 5-nitro-1,4-DHP (Scheme 2) [64]. This preparation method requires the preliminary synthesis of the initial nitrochalcone 6 and enamines 7 [65], a large expenditure of time and energy, and 5-nitro-1,4-DHP 8 is obtained with relatively low total yield. By using sodium nitrite in acetic acid, 5-nitro-1,4-DHP 8 was further oxidized into the corresponding 5-nitropyridine 9 [64].
Additionally, functionally substituted 1,4-DHP formation is a crucial step in the traditional pyridine preparation process, since these intermediates are excellent precursors in the synthesis of hardly accessible 3-(or 5-)-aminopyridines.
For example, there is a multicomponent one-step preparation method of 4-unsubstituted 5-nitro-6-phenylpyridines 10a–c, based on nitroacetophenone (or nitroacetone), enamine β-dicarbonyl compounds 7a–c and triethyl orthoformate [66,67,68] (Scheme 3). In the synthesis of the alkaloid Quindoline, its structural analogues and the substituted β-carbolines, these pyridines 10 were found to be effective precursors [69] (Scheme 3).
This method, from our point of view, also has significant drawbacks in comparison to the traditional method of obtaining pyridines through an intermediate stage of 1,4-DHP formation: the total reaction time ranges from 50 [66] to 122 h [67], including prolonged heating at 30 and 80 °C, the use of an inert gas, an additional stage of preliminary preparation of enamine β-dicarbonyl compounds 7a–c, the use of a more expensive triethyl orthoformate and a relatively low total yield of the reaction.
However, according to an analysis of the data of the literature, despite the simplicity of the 1,4-DHP synthesis, methods for obtaining 4-unsubstituted 5-nitro-6-phenylpyridines 10a–c by oxidation of the corresponding 1,4-DHP, unfortunately, have not yet been described.
Previously, we have successfully tested [70,71] the methods of the four-component synthesis of both unsymmetrical 4-furyl-substituted 11a–c and 4-unsubstituted 5-nitro-1,4-DHP 11a–c based on the 2-nitroacetophenone, β-dicarbonyl compounds 7a–c, aromatic aldehyde furfural (and urotropin, a source of formaldehyde), taken in equivalent molar quantities and some excess ammonium acetate (Scheme 4). Additionally, the optimal conditions for the oxidation of the obtained 1,4-DHP 8, 11a–c with previously unused potassium nitrate in the presence of catalytic amounts of copper (II) nitrate to the corresponding pyridines 9, 10a–c with yields of up to 95% were shown.
The synthesis of pyridines 10a–c through the stage of multicomponent synthesis of 1,4-DHP and their subsequent oxidation compared to the described method presented in the literature [64] allowed us to reduce the number of stages from four to two, increase the total yield of pyridines 10 from 24% to 38% and significantly reduce the total reaction time from 40 h to 1 h [70].
In the literature there are also original methods for the multicomponent synthesis of 1,4-dihydropyridine-3,5-dicarbonitriles [72] based on 2,6-dichlorobenzaldehyde with a double fold of malononitrile and morpholine. In this case, hardly accessible unsymmetric 2-amino-1,4-dihydropyridine with substituents in the 2-, 6-positions are formed.

2. Results and Discussion

In the continuation of our work on the synthesis and study of new examples of multicomponent reactions for the synthesis of unsymmetrical 5-nitro-1,4-DHP, we conducted a study on the possible synthesis of 5-nitro-1,4-DHP containing an alkyl (in particular, methyl) substituent in the fourth position of the molecule. It is widely known that aromatic aldehydes smoothly undergo the Hantzsch reaction. More reactive and more volatile aliphatic aldehydes (for example, acetaldehyde and propanal) give very satisfactory yields of the corresponding symmetric 1,4-DHP [73]. The aliphatic aldehydes application in the process of obtaining unsymmetrical 5-nitro-1,4-DHP is almost not available.
It is known that acetals are often used as a source of aldehydes, for example, in reactions with nitrogenous nucleophiles [74]. Since acetals are stable in alkaline environments but are easily hydrolyzed with water in acidic ones, an acid catalyst or solvent is required for their use in the reaction. To test the course of a possible multicomponent reaction in the synthesis of 4-methyl-substituted 5-nitro-1,4-DHP, we selected its acetal as a source of acetaldehyde. The replacement of highly volatile and reactive acetaldehyde with its higher boiling source of diethyl acetal acetaldehyde, in our opinion, should lead to a more controlled reaction process, also contributing to the dosed and gradual release of acetaldehyde as a result of acetal hydrolysis. It should also be noted that in the literature, there are few examples of the use of acetals of aromatic aldehydes in the Hantzsch reaction [75]. However, there are no certain examples of the use of acetals of aliphatic aldehydes, and in particular, acetaldehyde in the Hantzsch reaction.
To carry out a new four-component reaction, the aromatic nitroacetophenone was used as a nitrocarbonyl compound, as well as additionally synthesized nitroacetone [76], dicarbonyl compounds (acetylacetone, ethyl ether of acetoacetic acid, benzoylacetone and 2-thiophenoylacetone) in molar amounts equivalent to nitroketone, a 2-fold excess of diethyl acetal acetaldehyde and 3-fold excess of ammonium acetate. Acetic acid was used as a solvent, which not only dissolves all four components, but also creates an acidic environment for acetal hydrolysis (Scheme 5). Synthesis optimization was tested on the example of compound 13a. The following parameters were chosen as optimization criteria: temperature and reaction time. The monitoring of the reaction course was carried out by thin-layer chromatography.
The best results were obtained at a reaction temperature of 60 °C. At a lower temperature (<50 °C), the reaction time increased and at a higher temperature (>70 °C) a significant tarring of the reaction mixture occurred, which made it difficult to isolate the product and lowered its yield. An excess of diketone or acetaldehyde diethyl acetal led to the additional formation of a certain amount of symmetrical 3,5-diacetyl-2,6-dimethyl-1,4-DHP in the reaction mixture. It should be noted that the use of a more volatile and sufficiently reactive acetaldehyde in this reaction did not lead to a controlled synthesis of unsymmetrical 5-nitro-1,4-dihydropyridines 12a–d.
In general, the isolation and purification of 1,4-dihydropyridines 12a–d did not cause any difficulties, and the yields of products was up to 50–63%. In an attempt to synthesize a similar 1,4-dihydropyridines 13a–d based on nitroacetone according to the method described above, we encountered a number of difficulties. For example, in the case of a 4-component reaction of nitroacetone with acetylacetone, acetaldehyde diethyl acetal and ammonium acetate at 60 °C, the reaction mixture was tarred, and the main product of this reaction was 3,5-diacetyl-2,6-dimethyl-1,4-DHP, which was confirmed by the signals of the corresponding protons in the 1H NMR spectrum. Changing the order of the reagents’ addition to each other (it is important that acetylacetone is added last), as well as reducing the reaction temperature to 50 °C allowed us to isolate the unsymmetrical 1,4-dihydropyridine 13a with a yield of 41%.
By monitoring the reaction course of nitroacetone with acetoacetic ether, acetaldehyde diethyl acetal and ammonium acetate by thin-layer chromatography, it was found out that even at 50 °C, two products are formed—minor symmetric diethyl 2,4,6-trimethyl-1,4-dihydropyridine-3,5-dicarboxylate and major unsymmetrical 5-nitro-1,4-dihydropyridine 13b. The target product, 13b, was purified from the symmetric by-product with the use of column chromatography (eluent—EtOAc-hexane 1:3), yield 40%.
A feature of the 4-component reaction (following the order of reagents addition to each other) of nitroacetone, benzoylacetone, acetaldehyde diethyl acetal and ammonium acetate at 50 °C is the formation of a single product—unsymmetrical 1,4-dihydropyridine 13c—with a yield of 45%. A similar result was obtained for the example of 2-thiophenoylacetone—the reaction led only to the formation of an unsymmetrical 1,4-dihydropyridine 13d with a yield of 49%. Apparently, such reactions are associated with the comparable reactivity of dicarbonyl compounds (acetylacetone and acetoacetic ether) and nitroacetone; therefore, multicomponent reactions involving it led to minor condensation by-products—symmetrical 1,4-dihydropyridines. In the case of less reactive benzoylacetone and 2-thiophenoylacetone, only the formation of target unsymmetrical 1,4-dihydropyridines 13c,d occurs.
The formation of derivatives 12 and 13(a–d) was proved by 1H and 13C NMR spectroscopy (Figures S8–S23 Supporting Information) and mass spectrometry high-resolution (LC/Q-TOF, Figures S24–S30 Supporting Information). For example, in the 1H NMR spectra of all unsymmetrical 1,4-dihydropyridine, the CH3-CH multiplet system is clearly seen, consisting of a duplet and a quartet with a spin–spin coupling constant J = 6.4 Hz (Figures S8–S15 Supporting Information).
At the next stage, 5-nitro-1,4-dihydropyridines 12, 13a–d were oxidized to the corresponding 5-nitropyridines 14, 15a–d according to the standard method—chromium (VI) oxide in acetic acid solution—with sufficiently high yields (70–91%) (Scheme 5).
The use of sodium nitrite or hydrogen peroxide in the oxidative aromatization reaction led to the slightly reduced yields, but the reaction time was increased significantly.

3. Conclusions

Thus, we have shown a fairly simple and effective method for obtaining acyl 4-methyl-substituted 5-nitro-1,4-DHP and their subsequent aromatization products—pyridines—based on acetaldehyde diethyl acetal as a source of acetaldehyde which has not been described in the literature. The reaction was tested with two examples of nitroketones, as for each we varied four dicarbonyl derivatives. The selection of optimal conditions allowed us to obtain eight unsymmetrical 5-nitro-1,4-DHP with satisfactory yields at the first stage and eight oxidized products—5-nitropyridines—with good yields at the second stage. The obtained positive results throughout this work will make it possible to quickly synthesize a range of the derivatives for subsequent chemical modifications, as well as conduct further studies of their biological properties.

4. Materials and Methods

1H and 13C NMR spectra were recorded on a Bruker DRX400 (400 and 100 MHz, respectively), Bruker AVANCE 500 (500 and 126 MHz, respectively) and Magritek spinsolve 80 carbon ultra (81 and 20 MHz, respectively) instruments using CDCl3, CCl4 or CD2Cl2 the internal standard was residual solvent signals (7.26 and 77.0 ppm for 1H and 13C nuclei in CDCl3, 5.32 ppm for 1H nuclei in CD2Cl2; 96.1 ppm for 13C nuclei in CCl4).
Samples were analyzed by HPLC-MS with the use of an Agilent 1260 Infinity II chromatograph linked to an Agilent 6545 LC/Q-TOF high-resolution mass spectrometer equipped by a Dual AJS ESI ionization source working in a positive ion mode with the following parameters: capillary voltage 4000 V; spray pressure 20 (psi); drying gas 10 L/min; gas temperature 325 °C; sheathed gas flow 12 L/min; shielding gas temperature 400 °C; nozzle voltage 0 V; fragmentation voltage 180 V; skimmer voltage 45 V; octopole RF 750 V. The mass spectra were recorded with LC/MS accuracy over the range of 100–1000 m/z and the scan rate was 1.5 spectrum/s. Chromatographic separation was implemented on an ZORBAX RRHD Eclipse Plus C18 (2.1 × 50 mm2, particle size 1.8 µm) columns. During the analysis, the column temperature was maintained at 35 °C. The mobile phase was prepared by eluents A and B. In the positive ionization mode, 0.1% formic acid solution in deionized water was applied as eluent A, and 0.1% formic acid solution in acetonitrile as eluent B. The chromatographic separation was carried out with elution according to the following scheme: 0–10 min 95% A, 10–13 min 100% B and 13–15 min 95% A. The mobile phase flow was maintained at the level of 400 µL/min in the analysis. In the experiments, the sample injection volume was 1 µL. The sample was prepared by dissolving the entire sample (in 1000 µL) in methanol (for HPLC). The sample dilution was carried out just before the analysis. The Agilent MassHunter 10.0 software (Agilent Technologies, Santa Clara, CA, USA) was applied for the recorded data processing using.
Chromato-mass spectrometric studies were carried out on a Trace GC Ultra chromatograph with a DSQ II mass-selective detector in the electron ionization mode (70 eV) on a Thermo TR-5 MS quartz capillary column, 15 m long, 0.25 mm inner diameter, with a film thickness of the stationary phase of 0.25 μm. The splitless input mode was used and a carrier gas discharge of 20 mL/min. The velocity of the carrier gas (helium) was 1 mL/min. The evaporator temperature was 200 °C, the transition chamber temperature was 200 °C, the ion source temperature was 200 °C. The temperature of the column thermostat was changed according to the program: from 15 (5 min delay) to 220 °C at a rate of 20 °C per minute, to 290 °C at a rate of 15 °C per minute. The total analysis time was 30 min. The volume of the injected sample was 1 μL. Chromatograms were recorded in TIC mode. The range of mass scanning was 30–450 amu.
Melting points were determined using a Stuart SMP10 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.

Synthesis of Compounds

1,4-Dihydropyridines 12(a–d) (general method). A mixture of 2-nitroacetophenone (330 mg, 2.0 mmol), 1,1-diethoxyethane (472 mg, 4.0 mmol), the β-dicarbonyl compound (2.0 mmol) and ammonium acetate (462 mg, 6.0 mmol) in glacial acetic acid (4 mL) was stirred at 60 °C for 2.5 h. The reaction batch was cooled, poured into water (40 mL) and extracted from CH2Cl2 (3 × 10 mL). The combined organic layers were dried over the anhydrous Na2SO4 and, then, they were evaporated in vacuum. The residue was recrystallized from CH2Cl2–hexane (1:5).
1,4-Dihydropyridines 13(a–d) (general method). 1,1-diethoxyethane (472 mg, 4.0 mmol), appropriate β-dicarbonyl compound (2.0 mmol) and ammonium acetate (462 mg, 6.0 mmol) were added to the solution of nitro-2-propanone (206 mg, 2.0 mmol) in glacial acetic acid (4 mL). The reaction batch was stirred at 50 °C for 2.5 h; then, it was cooled, poured into water (40 mL) and extracted from CH2Cl2 (3 × 10 mL). The combined organic layers were dried with the use of anhydrous Na2SO4, and, then, the product was evaporated in a vacuum. The residue was purified and recrystallized from CH2Cl2–hexane (1:5).
1-(2,4-Methyl-5-nitro-6-phenyl-1,4-dihydropyridin-3-yl)ethan-1-one 12a. Yield: 300 mg (55%); mp 193–194 °C. 1H NMR (400 MHz, CDCl3) δ ppm 1.25 (d, J = 5.9 Hz, 3H, 4-CH3), 2.28 (s, 3H, -C(O)CH3), 2.35 (s, 3H, 2-CH3), 4.34 (q, J = 6.1 Hz, 1H, H-4), 6.07 (br. s, 1H, -NH), 7.33 (d, J = 6.8 Hz, 2H, H-2,6 Ph), 7.45–7.48 (m, 3H, H-3,4,5 Ph). 13C NMR (101 MHz, CDCl3) δ ppm 19.8, 21.6, 29.2, 31.0, 115.9, 127.5, 127.6 (2C), 129.2 (2C), 130.4, 134.1, 141.7, 145.1, 198.4. MS (Q-TOF) m/z: calcd for C15H16N2O3+ [M + H]+: 273.1194; found: 272.9125.
Ethyl 2-(2,4-dimethyl-5-nitro-6-phenyl-1,4-dihydropyridin-3-yl)-2-oxoacetate 12b. Yield: 380 mg (63%); mp 150–153 °C. 1H NMR (500 MHz, CDCl3) δ ppm 1.24 (d, J = 6.6 Hz, 3H, 4-CH3), 1.33 (t, J = 7.1 Hz, 3H, -OCH2CH3), 2.31 (s, 3H, 2-CH3), 4.18–4.19–4.27 (m, 2H, -OCH2CH3), 4.34 (q, J = 6.4 Hz, 1H, -CH), 6.00 (s, 1H, -NH), 7.30 (dd, J = 7.7, 1.3 Hz, H-2,6 Ph), 7.41–7.48 (m, 3H, H-3,4,5 Ph). 13C NMR (126 MHz, CDCl3) δ ppm 14.3, 18.8, 21.2, 30.2, 60.3, 107.8, 127.4 (3C), 128.9 (2C), 130.2, 134.3, 142.9, 145.0, 166.6. MS (Q-TOF) m/z: calcd for C16H18N2O4+ [M + H]+: 303.1300; found: 303.1349.
(2,4-Dimethyl-5-nitro-6-phenyl-1,4-dihydropyridin-3-yl)(phenyl)methanone 12c. Yield: 334 mg (50%); mp 188–190 °C. 1H NMR (81 MHz, CDCl3) δ ppm 1.21 (d, J = 6.5 Hz, 3H, 2-CH3), 1.85 (s, 3H, 4-CH3), 4.36 (q, J = 6.4 Hz, 1H, -CH), 6.42 (s, 1H, -NH), 7.30–7.63 (m, 8H, H-3,4,5 Ph, H-2′,3′,4′,5′,6′), 7.71–7.83 (m, 2H, H-2,6 Ph). 13C NMR (20 MHz, CDCl3) δ ppm 18.1, 21.4, 32.5, 117.6, 127.6 (3C), 128.9 (6C), 130.2, 132.7, 134.5, 137.6, 138.8, 146.1, 197.3. MS (Q-TOF) m/z: calcd for C20H18N2O3+ [M + H]+: 335.1351; found: 335.2410.
(2,4-Dimethyl-5-nitro-6-phenyl-1,4-dihydropyridin-3-yl)(thiophen-2-yl)methanone 12d. Yield: 401 mg (59%); mp 205–207 °C. 1H NMR (81 MHz, CDCl3) δ ppm 1.28 (d, J = 6.4 Hz, 3H, 4-CH3), 1.96 (s, 3H, 2-CH3), 4.48 (q, J = 6.4 Hz, 1H, -CH), 6.01 (br. s, 1H, -NH), 7.14 (t, J = 4.4 Hz, 1H, H-4 thiothenyl), 7.37–7.44 (m, 5H, Ph), 7.68 (d, J = 4.4 Hz, 2H, H-3,5 thiothenyl). 13C NMR (20 MHz, CDCl3) δ ppm 17.8, 21.5, 33.1, 118.0, 124.2, 127.4 (2C), 128.2, 128.5, 129.0 (2C), 130.1, 133.2, 134.1, 134.9, 144.3, 146.1, 186.8. MS (Q-TOF) m/z: calcd for C20H18N2O3+ [M + H]+: 341.0915; found: 341.2039.
1-(2,4,6-Trimethyl-5-nitro-1,4-dihydropyridin-3-yl)ethan-1-one 13a. Yield: 172 mg (41%); mp 120–121 °C. 1H NMR (81 MHz, CDCl3) δ ppm 1.10 (d, J = 6.4 Hz, 3H, 4-CH3), 2.26 (s, 3H, -C(O)CH3), 2.33 (s, 3H, 2-CH3), 2.50 (s, 3H, 6-CH3), 4.29 (q, J = 6.5 Hz, 1H, -CH), 6.59 (br. s, 1H, -NH). 13C NMR (20 MHz, CDCl3) δ ppm 19.4, 21.2 (2C), 29.2, 30.6, 116.6, 128.6, 141.9, 145.9, 198.6. MS (Q-TOF) m/z: calcd for C10H14N2O3+ [M + H]+: 211.1038; found: 211.0291.
Ethyl 2-oxo-2-(2,4,6-trimethyl-5-nitro-1,4-dihydropyridin-3-yl)acetate 13b. Yield: 192 mg (40%); mp 146–148 °C. 1H NMR (81 MHz, CDCl3) δ ppm 1.10 (d, J = 6.3 Hz, 3H, 4-CH3), 1.30 (t, J = 7.1 Hz, 3H, -OCH2CH3), 2.30 (s, 3H, 2-CH3), 2.48 (s, 3H, 6-CH3), 4.20 (2 q, J = 6.5 Hz, 3H, -CH, -OCH2CH3), 6.52 (br. s, 1H, -NH). 13C NMR (20 MHz, CDCl3) δ ppm 14.4, 18.7, 20.8, 21.2, 30.0, 60.3, 108.5, 128.4, 143.0, 146.2, 166.9. MS (Q-TOF) m/z: calcd for C11H16N2O4+ [M + H]+: 241.1144; found: 241.2583.
Phenyl(2,4,6-trimethyl-5-nitro-1,4-dihydropyridin-3-yl)methanone 13c. Yield: 245 mg (45%); mp 150–152 °C. 1H NMR (81 MHz, CDCl3) δ ppm 1.09 (d, J = 6.4 Hz, 3H, 4-CH3), 1.87 (s, 3H, 2-CH3), 2.54 (s, 3H, 6-CH3), 4.31 (q, J = 6.4 Hz, 1H, -CH), 6.29 (br. s, 1H, -NH), 7.42–7.57 (m, 3H, H-3,4,5 Ph), 7.75 (dd, J = 7.7, 2.0 Hz, H-2,6 Ph). 13C NMR (20 MHz, CDCl3) δ ppm 18.0, 20.9, 21.4, 32.2, 118.1, 127.5, 128.8 (2C), 128.9 (2C), 132.7, 137.6, 138.9, 146.8, 197.5. MS (Q-TOF) m/z: calcd for C15H16N2O3+ [M + H]+: 273.1194; found: 273.6470.
Thiophen-2-yl(2,4,6-trimethyl-5-nitro-1,4-dihydropyridin-3-yl)methanone 13d. Yield: 272 mg (49%); mp 179–180 °C. 1H NMR (81 MHz, CDCl3) δ ppm 1.14 (d, J = 6.4 Hz, 3H, 4-CH3), 1.93 (s, 3H, 2-CH3), 2.54 (s, 3H, 6-CH3), 4.39 (q, J = 6.4 Hz, 1H, -CH), 6.54 (br. s, 1H, -NH), 7.12 (dd, J = 3.9, 3.9 Hz, 1H, H-4 thiophenyl), 7.51–7.79 (m, 2H, H-3,5 thiophenyl). 13C NMR (20 MHz, CDCl3) δ ppm 17.5, 20.9, 21.5, 32.7, 118.4, 126.9, 128.2, 133.2, 134.1, 134.7, 144.2, 146.8, 189.0. MS (Q-TOF) m/z: calcd for C13H14N2O3S+ [M + H]+: 279.0759; found: 279.2496.
Pyridines 14, 15(a–d) (general method). A solution of CrO3 (40 mg, 0.4 mmol) in H2O (0.5 mL) was added dropwise to a mixture of 1,4-dihydropyridine 12, 13 (0.2 mmol) in glacial acetic acid (1 mL) cooled to 0 °C, at such a rate that the reaction mixture temperature did not exceed 10 °C. Stirring was maintained for 2 h after CrO3 was all added, then poured into an ice–water mixture (20 mL) and extracted from EtOAc 3 × 5 mL). The combined organic layers were dried by the anhydrous Na2SO4 and evaporation in vacuum. The residue was purified and recrystallized from hexane.
1-(2,4-Dimethyl-5-nitro-6-phenylpyridin-3-yl)ethan-1-one 14a. Yield: 76 mg (70%); mp 83–84 °C. 1H NMR (400 MHz, CDCl3) δ ppm 2.25 (s, 3H, -COCH3), 2.57 (s, 3H, 2-CH3), 2.58 (s, 3H, 4-CH3), 7.42–7.47 (m, 3H, H-3,4,5 Ph), 7.54–7.59 (m, 2H, H-2,6 Ph). 13C NMR (101 MHz, CDCl3) δ ppm 14.5, 23.0, 32.3, 128.0 (2C), 129.0 (2C), 130.1, 135.4, 135.6, 136.7, 146.2, 150.1, 154.1, 203.7. MS (EI) m/z (Irel, %): [M]+ 270.01 (20), 181.03 (15), 139.00 (14), 80.97 (54), 42.99 (100). Anal. calcd for C15H14N2O3: C, 66.66; H, 5.22; N, 10.36; found: C, 66.47; H, 5.39; N, 10.15.
Ethyl 2-(2,4-dimethyl-5-nitro-6-phenylpyridin-3-yl)-2-oxoacetate 14b. Yield: 92 mg (77%); mp 67–69 °C. 1H NMR (81 MHz, CD2Cl2) δ ppm 1.47 (t, J = 7.1 Hz, 3H, -OCH2CH3), 2.35 (s, 3H, 2-CH3), 2.66 (s, 3H, 4-CH3), 4.46 (q, J = 7.1 Hz, 2H, -OCH2CH3), 7.30–7.65 (m, 5H, Ph). 13C NMR (20 MHz, CCl4) δ ppm 14.2, 14.6, 23.1, 61.3, 128.0 (2C), 128.3 (2C), 128.5, 129.6, 135.5, 136.8, 146.0, 149.7, 155.7, 165.9. MS (EI) m/z (Irel, %): [M]+ 238.21 (4), 208.20 (70), 163.18 (55), 135.18 (66), 134.13 (100), 120.16 (34), 93.16 (48), 77.15 (50), 65.16 (60). Anal. calcd for C16H16N2O4: C, 63.99; H, 5.37; N, 9.33; found: C, 63.76; H, 5.19; N, 9.10.
(2,4-Dimethyl-5-nitro-6-phenylpyridin-3-yl)(phenyl)methanone 14c. Yield: 98 mg (74%); mp 121–123 °C. 1H NMR (81 MHz, CDCl3) δ ppm 2.16 (s, 3H, 2-CH3), 2.46 (s, 3H, 4-CH3), 7.33–7.75 (m, 8H, H-3,4,5 Ph, H-2′,3′,4′,5′,6′ Ph), 7.88 (dd, J = 7.8, 2.0 Hz, 2H, H-2,6 Ph). 13C NMR (20 MHz, CDCl3) δ ppm 14.9, 23.3, 128.1 (2C), 129.0 (2C), 129.5 (2C), 129.6 (3C), 130.1, 135.1, 135.7, 136.0, 137.2, 146.3, 150.3, 155.9, 195.9. MS (EI) m/z (Irel, %): [M]+ 332.15 (12), 301.37 (100), 273.15 (21), 105.02 (33), 76.82 (47). Anal. calcd for C20H16N2O3: C, 72.28; H, 4.85; N, 8.43; found: C, 72.50; H, 4.67; N, 8.59.
(2,4-Dimethyl-5-nitro-6-phenylpyridin-3-yl)(thiophen-2-yl)methanone 14d. Yield: 107 mg (79%); mp 115–117 °C. 1H NMR (81 MHz, CDCl3) δ ppm 2.36 (s, 3H, 2-CH3), 2.67 (s, 3H, 4-CH3), 7.35 (dd, J = 4.8, 1.3 Hz, 1H, H-3 thiophenyl), 7.50–7.81 (m, 6H, Ph, H-4 thiophenyl), 7.99 (dd, J = 4.9, 1.3 Hz, 1H, H-5 thiophenyl). 13C NMR (20 MHz, CDCl3) δ ppm 14.9, 23.3, 128.1 (2C), 129.0 (2C), 129.1 (2C), 130.2, 134.3, 135.7 (2C), 137.1 (2C), 143.5, 150.5, 155.9, 187.7. MS (EI) m/z (Irel, %): [M]+ 338.19 (1), 308.19 (6), 83.12 (20), 77.20 (19). Anal. calcd for C18H14N2O3S: C, 63.89; H, 4.17; N, 8.28; found: C, 63.71; H, 4.33; N, 8.49.
1-(2,4,6-Trimethyl-5-nitropyridin-3-yl)ethan-1-one 15a. Yield: 76 mg (91%); mp 58–60 °C. 1H NMR (81 MHz, CDCl3) δ ppm 2.18 (s, 3H, -COCH3), 2.47 (s, 3H, 2-CH3), 2.51 (s, 6H, 4,6-CH3). 13C NMR (20 MHz, CDCl3) δ ppm 14.4, 153.8, 149.5, 136.1, 134.8, 105.3, 32.2, 22.8, 20.7, 203.6. MS (EI) m/z (Irel, %): [M]+ 208.21 (8), 193.18 (26), 178.22 (84), 135.16 (100), 118.16 (54), 108.17 (54), 94.17 (61), 81.19 (46), 65.13 (52). Anal. calcd for C10H12N2O3: C, 57.69; H, 5.81; N, 13.45; found: C, 57.90; H, 5.61; N, 13.64.
Ethyl 2-oxo-2-(2,4,6-trimethyl-5-nitropyridin-3-yl)acetate 15b. Yield: 83 mg (87%); mp 64–65 °C. 1H NMR (81 MHz, CDCl3) δ ppm 1.38 (t, J = 7.1 Hz, 3H, -OCH2CH3), 2.24 (s, 3H, 2-CH3), 2.51 (s, 3H, 4-CH3), 2.53 (s, 3H, 6-CH3), 4.41 (q, J = 7.1 Hz, 2H, -OCH2CH3). 13C NMR (20 MHz, CDCl3) δ ppm 14.2, 14.9, 20.7, 23.2, 62.2, 128.5, 137.0, 146.8, 149.9, 156.3, 167.0. MS (EI) m/z (Irel, %): [M]+ 238.21 (4), 208.20 (70), 163.18 (55), 135.18 (66), 134.13 (100), 120.16 (34), 93.16 (48), 77.15 (50), 65.16 (60). Anal. calcd for C11H14N2O4: C, 55.46; H, 5.92; N, 11.76; found: C, 55.65; H, 5.73; N, 11.90.
Phenyl(2,4,6-trimethyl-5-nitropyridin-3-yl)methanone 15c. Yield: 78 mg (72%); mp. 72–74 °C. 1H NMR (81 MHz, CDCl3) δ ppm 1H NMR (81 MHz, CDCl3) δ ppm 2.08 (s, 3H, 2-CH3), 2.35 (s, 3H, 4-CH3), 2.58 (s, 3H, 6-CH3), 7.34–7.70 (m, 3H, H Ph), 7.80 (dd, J = 7.8, 1.9 Hz, 2H, H-2,6 Ph). 13C NMR (20 MHz, CDCl3) δ ppm 14.8, 20.8, 23.1, 129.5 (2C), 129.6 (2C), 133.7, 134.9, 136.1, 136.6, 146.9, 149.8, 155.6, 196.0. MS (EI) m/z (Irel, %): [M]+ 270.13 (32), 253.04 (36), 239.57 (100), 222.03 (35), 211.08 (34), 192.89 (34), 135.02 (33), 105.12 (86), 77.10 (89). Anal. calcd for C15H14N2O3: C, 66.66; H, 5.22; N, 10.36; found: C, 66.81; H, 5.39; N, 10.19.
Thiophen-2-yl(2,4,6-trimethyl-5-nitropyridin-3-yl)methanone 15d. Yield: 88 mg (80%); mp 66–68 °C. 1H NMR (81 MHz, CDCl3) δ ppm 2.17 (s, 3H, 2-CH3), 2.44 (s, 3H, 4-CH3), 2.58 (s, 3H, 6-CH3), 7.16 (dd, J = 4.8, 3.9 Hz, 1H, H-4 thiophenyl), 7.39 (dd, J = 3.9, 1.2 Hz, 1H, H-3 thiophenyl), 7.83 (dd, J = 4.8, 1.2 Hz, 1H, H-5 thiophenyl). 13C NMR (20 MHz, CDCl3) δ ppm 14.7, 20.8, 23.0, 129.0, 133.6, 135.5, 136.6, 136.9, 143.6, 146.7, 149.9, 155.6, 187.7. 276.13 (36), 246.13 (44), 212.97 (53), 110.71 (100), 82.96 (47), 65.02 (43). MS (EI) m/z (Irel, %): [M]+ 276.13 (36), 246.13 (44), 212.97 (53), 110.71 (100), 82.96 (47), 77.02 (40), 66.05 (37). Anal. calcd for C13H12N2O3S: C, 56.51; H, 4.38; N, 10.14; found: C, 56.69; H, 4.55; N, 10.28.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/pr11020576/s1. S2–S7, Experimental Procedures; S8–S23, 1H and 13C NMR spectra; S24–S30, Mass spectra.

Author Contributions

Conceptualization, G.P.S. and I.V.K.; methodology, I.V.K. and G.P.S.; software, A.L.S.; validation, V.V.A., I.V.K., and A.L.S.; formal analysis, D.M.T., A.L.S., I.I.K., and G.P.S.; investigation, D.M.T., A.L.S., I.I.K.; resources, A.V.E., I.V.K.; data curation, D.M.T., A.L.S., I.I.K., and I.V.K.; writing—original draft preparation, I.V.K.; writing—review and editing, I.V.K. and G.P.S.; visualization, I.V.K. and V.V.A.; supervision, I.V.K., A.V.E.; project administration, A.V.E. and I.V.K.; funding acquisition, A.V.E. All authors have read and agreed to the published version of the manuscript.

Funding

This research was conducted with the support of the Ministry of Science and Higher Education of the Russian Federation: “Priority 2030” in the Center of Nature-Inspired Engineering.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Data are available from the authors on request.

Acknowledgments

Spectrophotometric studies were carried out using the equipment of the Center for Collective Use “Rational Nature Management and Physicochemical Research” of the University of Tyumen.

Conflicts of Interest

The authors declare no conflict of interest.

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Processes 11 00576 g001 550
Figure 1. The structural formulas of biologically active 1,4-DHP.
Figure 1. The structural formulas of biologically active 1,4-DHP.
Processes 11 00576 g001
Processes 11 00576 sch001 550
Scheme 1. Four-component synthesis of symmetric 3,5-dinitro-1,4-dihydropyridines.
Scheme 1. Four-component synthesis of symmetric 3,5-dinitro-1,4-dihydropyridines.
Processes 11 00576 sch001
Processes 11 00576 sch002 550
Scheme 2. Stagewise synthesis of 4-furyl 5-nitro-6-phenylpyridines.
Scheme 2. Stagewise synthesis of 4-furyl 5-nitro-6-phenylpyridines.
Processes 11 00576 sch002
Processes 11 00576 sch003 550
Scheme 3. One-step synthesis of 4-unsubstituted 5-nitropyridines.
Scheme 3. One-step synthesis of 4-unsubstituted 5-nitropyridines.
Processes 11 00576 sch003
Processes 11 00576 sch004 550
Scheme 4. Synthesis of 4-unsubstituted and 4-furylsubstituted 5-nitro-6-phenylpyridines.
Scheme 4. Synthesis of 4-unsubstituted and 4-furylsubstituted 5-nitro-6-phenylpyridines.
Processes 11 00576 sch004
Processes 11 00576 sch005 550
Scheme 5. Synthesis of 5-nitro-pyridines 14, 15(a–d).
Scheme 5. Synthesis of 5-nitro-pyridines 14, 15(a–d).
Processes 11 00576 sch005
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Turgunalieva, D.M.; Stalinskaya, A.L.; Kulakov, I.I.; Sagitullina, G.P.; Atuchin, V.V.; Elyshev, A.V.; Kulakov, I.V. Multicomponent Synthesis of Unsymmetrical Derivatives of 4-Methyl-Substituted 5-Nitropyridines. Processes 2023, 11, 576. https://doi.org/10.3390/pr11020576

AMA Style

Turgunalieva DM, Stalinskaya AL, Kulakov II, Sagitullina GP, Atuchin VV, Elyshev AV, Kulakov IV. Multicomponent Synthesis of Unsymmetrical Derivatives of 4-Methyl-Substituted 5-Nitropyridines. Processes. 2023; 11(2):576. https://doi.org/10.3390/pr11020576

Chicago/Turabian Style

Turgunalieva, Daria M., Alena L. Stalinskaya, Ilya I. Kulakov, Galina P. Sagitullina, Victor V. Atuchin, Andrey V. Elyshev, and Ivan V. Kulakov. 2023. "Multicomponent Synthesis of Unsymmetrical Derivatives of 4-Methyl-Substituted 5-Nitropyridines" Processes 11, no. 2: 576. https://doi.org/10.3390/pr11020576

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