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Article

Tetrahydropyridines’ Stereoselective Formation, How Lockdown Assisted in the Identification of the Features of Its Mechanism

by
Anatoly N. Vereshchagin
*,
Taigib M. Iliyasov
,
Kirill A. Karpenko
,
Radmir N. Akchurin
and
Mikhail E. Minyaev
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 47 Leninsky Prospect, 119991 Moscow, Russia
*
Author to whom correspondence should be addressed.
Molecules 2022, 27(14), 4367; https://doi.org/10.3390/molecules27144367
Submission received: 16 May 2022 / Revised: 21 June 2022 / Accepted: 30 June 2022 / Published: 7 July 2022
(This article belongs to the Section Organic Chemistry)
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Abstract

:
The multicomponent reaction of aldehydes, cyano-containing C-H acids, esters of 3-oxocarboxylic acid and ammonium acetate led to unexpected results. The boiling of starting materials in methanol for one to two hours resulted in the formation of polysubstituted 1,4,5,6-tetrahydropyridines with two or three stereogenic centers. During the 2020 lockdown, we obtained key intermediates of this six-step domino reaction. A number of fast and slow reactions occurred during the prolonged stirring of the reaction mass at rt. Sequence: 1. Knoevenagel condensation; 2. Michael addition; 3. Mannich reaction; 4. cyclization—fast reactions and cyclization of the product polysubstituted 2-hydroxypiperidine—was isolated after 40 min stirring at rt. Further monitoring proved the slow dehydration of 2-hydroxypiperidine to obtain 3,4,5,6-tetrahydropyridine after 7 days. Then, four-month isomerization occurred with 1,4,5,6-tetrahydropyridine formation. All reactions were stereoselective. Key intermediates and products structures were verified by X-ray diffraction analysis. Additionally, we specified conditions for the selective intermediates’ preparation.

1. Introduction

Six-membered heterocycles form the main subgroup of nitrogen-containing heterocycles. These compounds are well-known frameworks (piperidine, tetrahydropyridine, 1,4-dihydropyridine and pyridine) with a wide spectrum of biological activities [1,2]. Thus, piperidine derivatives display antihypertensive [3], neuroprotective [4,5], antibacterial [6], anticonvulsant [7] and anti-inflammatory [8] abilities, and are inhibitors of farnesyl transferase [9]. Additionally, substituted piperidines are important therapeutic agents in the treatment of influenza [10,11,12], diabetes [13,14], viral infections including AIDS [15,16,17], pulmonary embolism [18] and cancer metastases [19]. Tetrahydropyridines are known as insecticides [20], analgesics [21] and antimalarial agents [22]. Among medications, 4-phenylpiperidine derivatives are of great importance, because they resemble morphine pharmacophore [23,24].
The most common synthetic approaches to produce tetrahydropyridines include imines, in which the nitrogen atom is a source to construct nitrogen-containing six-membered rings. Diels–Alder reactions [25,26], using azadienophiles or azadienes, and domino addition–cyclization reactions involving imines were reported [27,28]. The latter reactions are multicomponent. For organic compounds’ preparation, domino and multicomponent syntheses are superior to two-component reactions in high atom efficiency [29,30], time, materials, energy saving, eco-friendliness and access to greater diversity [31,32,33,34,35,36]. Several publications describe the multicomponent synthesis of substituted tetrahydropyridines from aromatic aldehydes, C-H acids and aromatic amines [37,38], cyanoacetamide [39] or cyanothioacetamide [40].
We have carried out the multicomponent synthesis of substituted piperidines [41,42,43,44,45]. Ammonium acetate or aqueous ammonia were the nitrogen sources for piperidine cycles. Using this approach, we performed the stereoselective synthesis of substituted 1,4,5,6-tetrahydropyridines from electron-deficient olefins and aqueous ammonia [46] (three-component synthesis), or from alkylidenemaloninitriles, 3-oxopropanecarboxylates, aldehydes and ammonium acetate [47] (four-component synthesis) as a nitrogen source for the newly formed six-membered ring. The reaction was carried out by refluxing the starting compounds in methanol for 2–12 h. We hypothesized that the formation of tetrahydropyridine occurs through the following sequence of reactions: Michael addition to obtain 2-substituted 3-aryl-4,4-dicyanobutanoic acid ester A, Mannich reaction to give 2-substituted 5-amino-3,5-diaryl-4,4-dicyanopentanoic acid B, intramolecular cyclization yielding polysubstituted 2-hydroxypiperidine C, and dehydration (Scheme 1). Previously, Verboom et al. [48] studied the formation of close analogues of intermediate A from benzylidenemalononitriles and malononitrile, or ethyl cyanoacetate. However, the intermediates B and C have never been isolated or identified.
Subsequently, we studied the multicomponent synthesis of cyclic [49,50,51] and heterocyclic [52,53,54,55,56] compounds from carbonyls and C-H acids. The current research is dedicated to the pseudo-five-component synthesis of 1,4,5,6-tetrahydropyridines 4,5 directly from aromatic aldehydes 1 (both with electron-withdrawing and electron-donating substituents), cyano C-H acids 2 (malononitrile or ethyl cyanoacetate), esters of 3-oxocarboxylic acids 3 and ammonium acetate (Scheme 2, Table 1). Additionally, we examine the multicomponent process mechanism.

2. Results and Discussion

The refluxing of the starting compounds in MeOH led to the selective formation of esters of 2-alkyl(or aryl)-4,6-diaryl-5,5-dicyano-1,4,5,6-tetrahydropyridine-3-carboxylic acids 4 (X=CN) with two stereogenic centers, or diesters of 5-cyano-2,4,6-triaryl-1,4,5,6-tetrahydropyridine-5,3-carboxylates 5 (X=COOEt) with three stereogenic centers (Scheme 2, Table 1). This technique was developed in the study of the four-component synthesis of 1,4,5,6-tetrahydropyridines [47]. The new multicomponent reaction allows us to obtain 1,4,5,6-tetrahydropyridines 4, 5 in moderate to excellent yields in one step from cheap and available starting materials via the domino process with the formation of three C-C and two C-N bonds. All reactions were monitored via thin-layer chromatography (TLC). Product 4 was isolated in a 44–90% yield by simple filtration after freezing the reaction mixture. Product 5 was isolated by chromatography in moderate yields of 33% and 36%.
As the NMR spectra of compounds 4, 5 showed only a single set of signals, we assumed the stereoselective formation of individual diastereoisomers. The structure of 4r is shown in Figure 1. X-ray crystal diffraction data indicated that structure 4a with two stereogenic centers should be defined as ethyl (4SR,6RS)-5,5-dicyano-2-phenyl-4,6-bis(4-methoxy)phenyl-1,4,5,6-tetrahydropyridine-3-carboxylate. The structure of 5a is shown in Figure 2. X-ray indicated that structure 5a with three stereogenic centers had the conformation 4RS,5SR,6RS. In both 4r, 5a diastereomers, we observed bulky aryl substituents in sterically least-hindered positions relative to each other.
To validate the proposed mechanism (Scheme 1), we monitored the reaction between aldehydes 1, malononitrile 2a, aryl containing esters of 3-oxocarboxylic acids 3 and ammonium acetate in methanol at room temperature (Scheme 3, Table 2). In all cases, 40–45 min stirring of the reaction mass created a dense white precipitate. After filtration and drying, single compounds (by TLC and NMR) were obtained. The 1H and 13C NMR spectra of compounds 6 showed one set of signals, indicating the formation of a single diastereomer. The 6d structure is shown in Figure 3. X-ray crystal diffraction data indicated that the structure 6d with four stereogenic centers should be defined as methyl (2SR,3RS,4SR,6RS)-5,5-dicyano-2-(4-bromo)phenyl-2-hydroxy-4,6-bis(4-methyl)phenyl-piperidine-3-carboxylate.
It should be noted that the introduction of alkyl-substituted esters of 3-oxocarboxylic acid 3 (R1 = Alk) into this reaction did not result in the formation of 2-hydroxypiperidine 6. Apparently, the aryl substituent in position 2 is a “stabilizer” of the molecule as a whole. Thus, we found that 2-hydroxypiperidines 6 are formed as a result of a “fast” domino sequence: Knoevenagel condensation, Michael addition, Mannich reaction and intramolecular cyclization. This sequence of reactions takes only 40 min at rt. Unordinary results were found when one of the reaction mixtures was left for a long time without stirring due to isolation measures in spring 2020. The TLS monitoring of the reaction mixture containing 4-methylbenzaldehyde 1d, malononitrile 2a, methyl 3-(4-bromophenyl)-3-oxopropanoate 3f and ammonium acetate in methanol after one and a half months of standing at rt showed the presence of a new substance, different (according to TLS) from 2-hydroxypiperidine 6d and the final 1,4,5,6-tetrahydropyridine 4t. We monitored this reaction for 4.5 months. Every week, we took samples of the precipitate from the reaction mixture and analyzed it with 1H NMR spectroscopy (Figure 4).
We found the complete conversion of 2-hydroxypiperidine 6d within a week. A set of signals of the unknown compound 7 and 1,4,5,6-tetrahydropyridine 4t was observed in the reaction mixture precipitate. Further, over the course of 4 months, we observed the slow transformation of 7 into 4t. To isolate compound 7, we made the following assumption. Under reaction conditions, ammonium acetate dissociated into ammonia and acetic acid. Ammonia was consumed to form a six-membered nitrogen-containing ring, while acetic acid remained in the reaction mixture. Therefore, the dehydration of 6d to 7t should be carried out under acidification. The acidity of the reaction medium should influence the course of dehydration (Scheme 4, Table 3). Indeed, 6d refluxing in methanol for 2 h in the absence of the acid produced no conversion (Table 3, entry 1). When acidified with 2 eq. of acetic acid, the compound 6d was completely consumed after 2 h refluxing (Table 3, entry 2, TLC monitoring, eluting with hexane—ethyl acetate, 3:1). Additionally, we observed the formation of 7. The increase in the acid amount led to 4t (Table 3, entries 4–7).
The structure of 7 is shown in Figure 5a. X-ray crystal diffraction data indicated that structure 7 with three stereogenic centers should be defined as methyl (3RS,4SR,6RS)-5,5-dicyano-2-(4-bromo)phenyl-4,6-bis(4-methyl)phenyl-3,4,5,6-tetrahydropyridine-3-carboxylate. Structure 7 is the isomer of 4t. The Gibbs free energy of 4t is 15.64 kJ/mol lower than that of 7. DFT calculations were performed with the Gaussian 16 Rev C.01 quantum chemistry program [57].
Likewise, we studied the multicomponent reaction between 4-flurobenzaldehyde 1h, ethyl cyanoacetate 2b, methyl 3-(4-bromophenyl)-3-oxopropanoate 3f and ammonium acetate in methanol at rt (Scheme 5). TLC and 1H NMR monitoring allowed us to obtain the reaction intermediate 8 in 24%. The structure of 8 is shown in Figure 5b. X-ray crystal diffraction data indicated that structure 8 with four stereogenic centers should be defined as 5-ethyl 3-methyl (3SR,4RS,5SR,6SR)-6-(4-bromophenyl)-3-cyano-2,4-bis(4-fluorophenyl)-3,4,5,6-tetrahydropyridine-3,5-dicarboxylate. When ethyl cyanoacetate was introduced into the multicomponent reaction, the formation of an intermediate substituted 2-hydroxypiperidine was not observed.
Crystal data and the structure refinement of 4r, 5a, 6d, 7 and 8 are shown in Table 4.
Thus, the multicomponent reaction between aldehyde 1, cyano C-H acids 2 (malononitrile or ethyl cyanoacetate), esters of 3-oxocarboxylic acids 3 and ammonium acetate is a six-step domino process (Scheme 6). At the first stage, the Knoevenagel condensation between aldehydes and cyano C-H acid occurs. Ammonium acetate is a catalyst for this reaction. The formation of cyano olefins A under ammonium salts catalysis is already known [58]. The second step of the process is the Michael addition of C-H acid 3 to the electron-poor styrene A to form the Michael adduct B. The formation of close analogues of intermediate B from benzylidenemalononitriles and malononitrile or ethyl cyanoacetate was studied previously by Verboom et al. [48]. The subsequent Mannich reaction of B, aldehyde 1 (second equivalent) and ammonia, which is formed from ammonium acetate, leads to intermediate C. The latter undergoes intra-molecular cyclization with the formation of a substituted 2-hydroxypiperidine 6, which was identified and characterized in this work for the first time. A similar sequence of Knoevenagel condensation—Michael addition—Mannich reaction—intramolecular cyclization was described by Latypova et al. when studying the multicomponent reaction between 1,3-dicarbonyl compounds (two equiv.), formaldehyde and diamines with the formation of substituted bis-1,2,3,4-tetrahydropyridines [59]. None of the intermediates were isolated. Moreover, we tried to isolate C in the course of the work, but failed because in the reaction mass, after 10–30 min from the reaction start, there were many compounds (by TLC) that were almost impossible to isolate due to the rapid reaction rate. Polysubstituted 2-hydroxypiperidines 6 were isolated up to 87% even after stirring at rt for 40 min (see Table 2). The fifth step of the domino process is C dehydration. We established formation of 3,4,5,6-tetrahydropyridines 7, 8. A final isomerization produces 1,4,5,6-tetrahydropyridines 4, 5.

3. Experimental Procedure

3.1. General Information

All melting points were measured with a Stuart SMP30 melting point apparatus (Bibby Sterling Ltd., Granton, UK). 1H and 13C NMR spectra were recorded with a Bruker AM300 (Bruker, Bremen, Germany) and Bruker DRX 500 (Bruker BioSpin GmbH, Bremen, Germany) at ambient temperature in DMSO-d6 or CDCl3 solutions. Chemical shifts values are given in δ scale relative to Me4Si. The J values are given in hertz. Only discrete or characteristic signals for the 1H NMR are reported. IR spectra were recorded with a Bruker ALPHA-T FT-IR spectrometer (Bruker Corporation, Bremen, Germany) in KBr pellets. HR-ESI-MS were measured on a Bruker microTOF II instrument (Bruker Daltonik GmbH, Bremen, Germany); external or internal calibration was performed with electrospray calibrant solution (Fluka). All starting materials were obtained from commercial sources and used without purification. All reactions were monitored with thin-layer chromatography (TLC) and carried out with Merck precoated plates DC-AlufolienKieselgel60 F254 (Merck KGaA, Darmstadt, Germany). X-ray crystallographic analyses were performed with Bruker Quest D8 diffractometer (Bruker AXS GmbH, Bremen, Germany).

3.2. DFT Calculations

DFT calculations were performed with Gaussian 16 Rev C.01. B3LYP DFT (Gaussian Inc., Wallingford CT, USA, 2016) functional with GD3BJ empirical dispersion correction, and a Def2SVP basis set was used for geometry optimization and calculations of thermodynamics. Data from X-ray diffraction experiment for 7 were used as starting points for geometry optimizations. Cartesian coordinates are given in angstroms; absolute energies for all substances are given in hartrees. The analysis of vibrational frequencies was performed for all optimized structures. All compounds were characterized by only real vibrational frequencies. Wavefunction stability, using stable keyword, was also checked for each molecule. For more information see Supplementary Materials.
For the calculations of the optimized geometries, frequencies and thermodynamics with the following keywords were used:
# opt freq b3lyp nosymm def2svp empiricaldispersion = gd3bj test

3.3. X-ray Crystallographic Data and Refinement Details

X-ray diffraction data for all compounds were collected at 100 K on a Bruker Quest D8 diffractometer equipped with a Photon-III area detector, using graphite-monochromatized Mo Kα-radiation (0.71073 Å) and the shutterless φ- and ω-scan technique. Relying on the analysis of preliminary collected reflections with the Cell_Now program [60], all crystals of 8 from various batches contained over seven major domains with apparently chaotic orientations. This, along with a chiral space group, seriously impeded data analysis, resulting in six attempts to collect reflection data and to solve the structure. The intensity data were integrated by the SAINT program [61] and were semi-empirically corrected for absorption and decay, using SADABS [62] for 4r, 6d, 5a and 7 or using TWINABS [61] for 8. The structures were solved by direct methods using SHELXT [63] and refined by the full-matrix least-squares method on F2 using SHELXL-2018 [64]. The crystals of 6d and 7 were refined as inversion twins, for which the absolute structure parameter (Flack) was determined by classical fit [65]. The selected specimen of 8 was refined as a non-merohedral 2-component twin.
All non-hydrogen atoms were refined with individual anisotropic displacement parameters. The locations of atoms H1 (in 4r, 5a) and H1A, H1B (in 6d) were found from the electron density difference map; these H atoms were refined with individual isotropic displacement parameters. All other hydrogen atoms were placed in geometrically calculated positions and refined as riding atoms with relative isotropic displacement parameters. A rotating group model was applied for methyl groups. Mercury program [66] was used for molecular graphics. Crystal data, data collection and structure refinement details are summarized in Table 4.

3.4. Synthesis of 4–5

A mixture of aldehydes 1 (6 mmol), cyano C-H acid 2 (3 mmol), ester of 3-oxocarboxylic acids 3 (3 mmol) and ammonium acetate (6 mmol) was refluxed in methanol (10 mL) for 2 h. After the reaction completion, the mixture was maintained at –10 °C for 30 min for the complete precipitation of the product, the precipitate was collected by filtration and dried to obtain pure tetrahydropyridine 4. Compound 5 was purified by column chromatography.
Methyl (4SR,6RS)-5,5-dicyano-2-methyl-4,6-diphenyl-1,4,5,6-tetrahydropyridine-3-carboxylate (4a) Yield: 0.86 g (80%); white solid; m.p. 218–219 °C. (lit. [46] m.p. 218–219 °C); 1H-NMR (DMSO-d6, 300.13 MHz): δ = 7.63–7.7 (m, 2H, Ar), 7.52 (dd, 4 H, Ar, J1 = 5.9 Hz, J2 = 1.6 Hz), 7.34–7.28 (m, 4H, Ar + NH), 5.27 (s, 1H, CH), 4.83 (s, 1H, CH), 3.11 (s, 3H, OCH3), 2.32 (s, 3H, CH3).
Methyl (4SR,6RS)-5,5-dicyano-2-methyl-4,6-bis(2-methyl)phenyl-1,4,5,6-tetrahydropyridine-3-carboxylate (4b) Yield: 0.75 g (65%); white solid; m.p. 233–235 °C; 1H-NMR (CDCl3, 300.13 MHz): δ = 7.92–7.86 (m, 1H, Ar), 7.51–7.18 (m, 7H, Ar), 5.22 (s, 1H, CH), 5.09 (s, 1H, CH), 4.35 (s, 1H, NH), 3.26 (s, 3H, OCH3), 2.59 (s, 3H, CH3), 2.56 (s, 3H, CH3), 2.4 (s, 3H, CH3); 13C-NMR (CDCl3, 75.47 MHz): δ = 166.67, 151.99, 137.24, 136.92, 135.95, 131.95, 131.47, 130.69, 130.20, 128.03, 127.29, 126.49, 126.34, 126.22, 113.82, 112.61, 99.28, 57.54, 50.44, 46.09, 45.63, 20.04, 19.89; IR (KBr): 3343, 2249, 1686, 1460, 1247 cm−1; HRMS (ESI) m/z [M + H]+ calcd for C24H24N3O2+: 386.1863; found: 386.1857.
Methyl (4SR,6RS)-5,5-dicyano-2-methyl-4,6-bis(3-methyl)phenyl-1,4,5,6-tetrahydropyridine-3-carboxylate (4c) Yield: 0.88 g (76%); white solid; m.p. 191–193 °C; 1H-NMR (CDCl3, 300.13 MHz): δ = 7.11–7.48 (m, 8H, Ar), 4.72 (s, 1H, CH), 4.57 (s, 1H, CH), 4.43 (s, 1H, NH), 3.30 (s, 3H, OCH3), 2.44 (s, 3H, CH3), 2.42 (s, 3H, CH3), 2.38 (s, 3H, CH3); 13C-NMR (CDCl3, 75.47 MHz): δ = 166.92, 151.88, 139.25, 138.11, 137.65, 133.55, 131.46, 129.23, 129.17, 128.47, 128.39, 124.96 (s, 2C), 113.77, 111.91, 97.84, 61.92, 51.05, 50, 51, 47.99, 21.48 (s, 2C), 20.29; IR (KBr): 3422, 2252, 1655, 1453, 1248 cm−1; HRMS (ESI) m/z [M + H]+ calcd for C24H24N3O2+: 386.1863; found: 386.1857.
Methyl (4SR,6RS)-5,5-dicyano-2-methyl-4,6-bis(4-methyl)phenyl-1,4,5,6-tetrahydropyridine-3-carboxylate (4d) Yield: 0.83 g (72%); white solid; m.p. 208–210 °C. (lit. [47] m.p. 208–210 °C); 1H-NMR (DMSO-d6, 300.13 MHz): δ = 7.51 (d, J = 8.0 Hz, 2H, Ar), 7.44 (s, 1H, NH), 7.32 (d, J = 8.0 Hz, 2H, Ar), 7.21–7.14 (m, 4H, Ar), 5.19 (s, 1H, CH), 4.75 (s, 1H, CH), 3.13 (s, 3H, OCH3), 2.36 (s, 3H, CH3), 2.30 (s, 6H, 2CH3).
Methyl (4SR,6RS)-5,5-dicyano-2-methyl-4,6-bis(3-fluoro)phenyl-1,4,5,6-tetrahydropyridine-3-carboxylate (4e) Yield: 0.84 g (71%); white solid; m.p. 174–176 °C. (lit. [47] m.p. 174–176 °C); 1H-NMR (DMSO-d6, 300.13 MHz): δ = 7.7–7.13 (m, 8H, Ar + NH), 7.06 (d, J = 10.11 Hz, 1H, Ar), 5.32 (s, 1H, CH), 4.87 (s, 1H, CH), 3.17 (s, 3H, CH3), 2.34 (s, 3H, CH3).
Methyl (4SR,6RS)-5,5-dicyano-2-methyl-4,6-bis(3-chloro)phenyl-1,4,5,6-tetrahydropyridine-3-carboxylate (4f) Yield: 0.87 g (68%); white solid; m.p. 210–213 °C; 1H-NMR (DMSO-d6, 300.13 MHz): δ = 7.68 (d, J = 10.15 Hz, 2H, Ar), 7.63–7.25 (m, 7H, Ar + NH), 5.31 (s, H, CH), 4.86 (s, H, CH), 3.18 (s, 3H, OCH3), 2.34 (s, 3H, CH3); 13C-NMR (CDCl3, 75.47 MHz): δ = 166.39, 152.75, 139.74, 135.36, 135.19, 134.46, 131.06, 130.68, 129.9, 128.8, 128.07 (s, 2C), 126.27, 125,86, 113.22, 111.36, 97, 19, 61.22, 50.68, 50.46, 47, 48, 20.35; IR(KBr): 3411, 2240, 1712, 1458, 1247, 711 cm−1; HRMS (ESI) m/z [M + H]+ (for 35Cl) 426.0760 calcd for C22H18Cl2N3O2+: 426.0771, (for 35Cl and 37Cl) 428.0736 calcd for C22H18Cl2N3O2+: 428.0742.
Methyl (4SR,6RS)-5,5-dicyano-2-methyl-4,6-(3-pyridine)-1,4,5,6-tetrahydropyridine-3-carboxylate (4g) Yield: 0.67 g (62%); white solid; m.p. 200–203 °C; 1H-NMR (DMSO-d6, 300.13 MHz): δ = 8.81 (d, J = 8 Hz, 1H, Ar), 8.72 (dd, J = 4.8 Hz, J1 = 1.5 Hz, 1H, Ar), 8.56–8.53 (m, 2H, Ar), 8.03 (dt, J = 8 Hz, J1 = 1.7 Hz, 1H, Ar), 7.8 (s, 1H, NH), 7.68 (dt, J = 8 Hz, J1 = 1.6 Hz, 1H, Ar), 7.6 (dd, J = 8 Hz, J1 = 4.8 Hz, 1H, Ar), 7.43 (dd, J = 8 Hz, J1 = 4.8 Hz, 1H, Ar), 5.42 (s, 1H, CH), 4.95 (s, 1H, CH), 3.16 (s, 3H, OCH3), 2.36 (s, 3H, CH3); 13C-NMR (DMSO-d6, 125.76 MHz): δ = 166.01, 153.02, 152.28, 149.94, 149.60, 149.48, 135.23 (s, 2C), 133.51, 129.22, 124.2, 123.55, 112.85, 113.30, 96.97, 59.70, 50.82, 48.51, 47.55, 20.58; IR (KBr): 3204, 2248, 1651, 1459, 1263 cm−1; HRMS (ESI) m/z [M + H]+ calcd for C20H18N5O2+: 360.1455; found: 360.1456.
Ethyl (4SR,6RS)-5,5-dicyano-2-methyl-4,6-diphenyl-1,4,5,6-tetrahydropyridine-3-carboxylate (4h) Yield: 1.00Γ (90%); white solid; m.p. 200–202 °C; 1H-NMR (DMSO-d6, 500.13 MHz): δ = 7.72–7.31 (m, 11H, Ar + NH), 5.31 (s, 1H, CH), 4.86 (s 1HCH), 3.73–3.55 (m, 2H CH2), 2.36 (s, 3H, CH3), 0.57 (t, J = 7.12Hz, 3H, CH3); 13C-NMR (DMSO-d6, 75.47 MHz): δ =166.25, 154.33, 139.71, 134.84, 130.43, 129.06 (s, 2C), 128.82 (s, 2C), 128.63 (s, 2C), 128.33 (s, 3C), 114.44, 113.36, 94.9, 60.01, 58.61, 49.64, 48.2, 19.43, 13.79; IR (KBr): 3312, 2252, 1644, 1470, 1456, 1247 cm−1; HRMS (ESI) m/z [M + H]+ calcd for C23H22N3O2+: 372.1707; found: 372.1700.
Ethyl (4SR,6RS)-5,5-dicyano-2-methyl-4,6-bis(4-fluoro)phenyl-1,4,5,6-tetrahydropyridine-3-carboxylate (4i) Yield: 0.84 g (69%); white solid; m.p. 154–156 °C; 1H-NMR (DMSO-d6, 300.13 MHz): δ = 7.72–7.61 (m, 2H, Ar), 7.55 (s, 1H, NH), 7.44–7.3 (m, 4H, Ar), 7.29–7.16 (m, 2H, Ar), 5.31 (s, 1H, CH), 4.85 (s, 1H, CH), 3.77–3.54 (m, 2H, CH2), 2.32 (s, 3H, CH3), 0.61 (t, J = 7.19 Hz, 3H, CH3); 13C-NMR (DMSO-d6, 75.47 MHz): δ = 166.09, 163.44 (s, J1C-F = 246.7 Hz, 1C), 162.24 (s, J1C-F = 244.1Hz, 1C), 154.51, 135.08 (d, J4C-F = 2.9Hz, 2C), 131.01 (d, J3C-F = 8.7Hz, 2C), 130.05 (d, J3C-F = 8.6Hz, 2C), 116.06 (d, J2C-F = 21.8Hz, 2C), 115.54 (d, J2C-F = 21.6Hz, 2C), 114.28, 113.23, 94,81, 59.16, 58.69, 48.74, 48.31, 19.47, 13.87; IR (KBr): 3352, 2253, 1688, 1458, 1250, 1158 cm−1; HRMS (ESI) m/z [M + H]+ calcd for C23H20F2N3O2+: 408.1518; found: 408.1512.
Ethyl (4SR, 6RS)-5,5-dicyano-2-methyl-4,6-bis(4-nitro)phenyl-1,4,5,6-tetrahydropyridine-3-carboxylate (4j) Yield: 0.87Γ (63%); white solid; m.p. 242–243 °C; 1H-NMR (DMSO-d6, 300.13 MHz): δ = 8.43 (d, J = 8.66 Hz, 2H, Ar), 8.30 (d, J = 8.69 Hz, 2H, Ar), 7.92 (s, 1H, NH), 7.88 (d, J = 5.15 Hz, 2H, Ar), 7.61 (d, J = 8.31 Hz, 2H, Ar), 5.54 (s, H, CH), 5.09 (s, H, CH), 3.77–3.58 (m, 2H, OCH2), 0.62 (t, J = 7.07 Hz, 3H, CH3); 13C-NMR (DMSO-d6, 125.76 MHz): δ = 165.68, 155.48, 149.13, 147.75, 147.29, 141.16, 130.40 (s, 2C), 124.29 (s, 4C), 124.07 (s, 2C), 113.62, 112.65, 94.04, 59.04, 58.95, 48.76, 46.99, 19.76, 13.94; IR (KBr): 3372, 2250, 1689, 1348, 1242 cm−1; HRMS (ESI) m/z [M + H]+ calcd for C23H20N5O6+: 462.1408; found: 462.1402.
Methyl (4SR,6RS)-5,5-dicyano-2-ethyl-4,6-diphenyl-1,4,5,6-tetrahydropyridine-3-carboxylate (4k) Yield: 1.00 g (90%); white solid; m.p. 115–117 °C. (lit. [47] m.p. 115–117 °C); 1H-NMR (CDCl3 400.16 MHz): δ = 7.69–7.31 (m, 10H, Ar), 4.78 (s, 1H, CH), 4.63 (s, 1H, CH), 4.54 (s, 1H, NH), 3.27 (s, 3H, OCH3), 2.94–2.67 (m, 2H, CH2),1.35 (t, J = 7.5 Hz, 3H, CH3).
Methyl (4SR,6RS)-5,5-dicyano-2-ethyl-4,6-bis(4-methyl)phenyl-1,4,5,6-tetrahydropyridine-3-carboxylate (4l) Yield: 0.98 g (82%); white solid; m.p. 112–115 °C; 1H-NMR (CDCl3 300.13 MHz): δ = 7.53 (d, J = 8.1 Hz, 2H, Ar), 7.31 (d, J = 7.8 Hz, 4H, Ar), 7.17 (d, J = 8 Hz, 2H, Ar), 4.72 (s, 1H, CH), 4.58 (s, 1H, CH), 4.46 (s, 1H, NH), 3.30 (s, 3H, OCH3), 2.92–2.64 (m, 2H, CH2), 2.42 (s, 3H, CH3), 2.35 (s, 3H, CH3), 1.33 (t, J = 7.5 Hz, 3H, CH3); 13C-NMR (DMSO-d6, 75.47 MHz): δ = 166.59, 157.37, 140.84, 138, 134.79, 130.75, 130 (s, 2C), 129.27 (s, 2C), 127.71 (s, 4C), 113.92, 111.94, 61.47, 50.64, 50.53, 48.34, 26.92, 21.28, 21.18, 13.38; IR (KBr): 3354, 2254, 1695, 1466, 1261 cm−1; HRMS (ESI) m/z [M + H]+ calcd for C25H26N3O2+: 400.2020; found: 400.2014.
Methyl (4SR,6RS)-5,5-dicyano-2-ethyl-4,6-bis(4-bromo)phenyl-1,4,5,6-tetrahydropyridine-3-carboxylate (4m) Yield: 1.30 g (82%); white solid; m.p. 214–217 °C. (lit. [47] m.p. 214–217 °C); 1H-NMR (CDCl3 300.13 MHz): δ = 7.66 (d, J = 8.4 Hz, 2H, Ar), 7.54–7.49 (m, 4H, Ar), 7.3 (d, J = 8.4 Hz, 2H, Ar), 4.74 (s, 1H, CH), 4.59 (s, 1H, CH), 4.49 (s, 1H, NH), 3.33 (s, 3H, OCH3), 2.93–2.65 (m, 2H, CH2), 1.32 (t, J = 7.5 Hz, 3H, CH3).
Methyl (4SR, 6RS)-5,5-dicyano-2-ethyl-4,6-bis(4-nitro)phenyl-1,4,5,6-tetrahydropyridine-3-carboxylate (4n) Yield: 0.80 g (58%); white solid; m.p. 243–248 °C; IR (KBr): 3387, 2250, 1685, 1484, 1349, 1256 cm−1; 1H-NMR (DMSO-d6, 300.13 MHz): δ = 8.44 (d, J = 8.7 Hz, 2H, Ar), 8.3 (d, J = 8.8 Hz, 2H, Ar), 7.92 (s, 1H, NH), 7.9 (d, J = 8.9 Hz, 2H, Ar), 7.58 (d, J = 8.5 Hz, 2H, Ar), 5.52 (s, 1H, CH), 5.08 (s, 1H, CH), 3.16 (s, 3H, OCH3), 2.88–2.65 (m, 2H, CH2), 1.27 (t, J = 7.3Hz, 3H, CH3); 13C-NMR (DMSO-d6, 75.47 MHz): δ = 165.99, 161.28, 149.06, 147.65, 147.19, 141.04, 130.31 (s, 2C), 129.24 (s, 2C), 124.13 (s, 2C), 123.99 (s, 2C), 113.51, 112.45, 92.83, 58.88, 50.51, 48.47, 46.99, 26.19, 14.49; IR (KBr): 3387, 2250, 1685, 1484, 1349, 1256 cm−1; HRMS (ESI) m/z [M + H]+ calcd for C23H20N5O6+: 462.1408; found: 462.1401.
Methyl (4SR,6RS)-5,5-dicyano-2–4,6-triphenyl-1,4,5,6-tetrahydropyridine-3-carboxylate (4o) Yield: 0.95 g (76%); white solid; m.p. 223–225 °C. (lit. [47] m.p. 223–225 °C); 1H-NMR (CDCl3 300.13 MHz): δ = 7.73–7.33 (m, 15H, Ar), 4.98 (s, 1H, CH),4.78 (s, 1H, CH), 4.61 (s, 1H, NH), 3.15 (s, 3H, OCH3).
Methyl (4SR,6RS)-5,5-dicyano-2-phenyl-4,6-bis(3-fluoro)phenyl-1,4,5,6-tetrahydropyridine-3-carboxylate (4p) Yield: 0.69 g (52%); white solid; m.p. 191–193 °C; 1H-NMR (CDCl3 300.13 MHz): δ = 7.55–7.19 (m, 12H, Ar), 7.1 (t, J = 8Hz, 1H, Ar), 4.96 (s, 1H, CH), 4.77 (s, 1H, CH), 4.62 (s, 1H, NH), 3.19 (s, 3H, OCH3); 13C-NMR (CDCl3, 125.76 MHz): δ = 165.68, 162.93 (d, J1C-F = 249.7Hz, 1C), 162.77 (d, J1C-F = 247Hz, 1C), 154.36, 139.49 (d, J4C-F = 7.1 Hz, 1C), 136.07, 135.28 (d, J4C-F = 7.2 Hz, 1C), 131.27 (d, J3C-F = 8.3 Hz, 1C), 130.34 (d, J3C-F = 8.3 Hz, 1C), 129.99, 128.38 (s, 2C), 128.34 (s, 2C), 123.8 (d, J6C-F = 3 Hz, 2C), 118.08 (d, J2C-F = 21 Hz, 1C), 115.88 (d, J2C-F = 21.1 Hz, 1C), 115.25, 115.07, 113.21, 111.40, 98.68, 61.60, 50.80, 50.75, 47.64; IR(KBr): 3376, 2250, 1704, 1263, 1105 cm−1; HRMS (ESI) m/z [M + H]+ calcd for C27H20F2N3O2+: 456.1518; found: 456.1507.
Ethyl (4SR,6RS)-5,5-dicyano-2-phenyl-4,6-diphenyl-1,4,5,6-tetrahydropyridine-3-carboxylate (4q) Yield: 0.75 g (58%); white solid; m.p. 118–121 °C; IR(KBr): 3385, 2240, 1699, 1466, 1260 cm−1; 1H-NMR (CDCl3 300.13 MHz): δ = 7.72–7.34 (m, 15H, Ar), 4.98 (s, 1H, CH), 4.79 (s, 1H, CH), 4.6 (s, 1H, NH), 3.75–3.56 (m, 2H, CH2), 0.6 (t, J = 7.1 Hz, 3H, CH3); 13C-NMR (CDCl3, 75.47 MHz): δ = 165.37, 153.91, 137.29, 136.54, 133.33, 130.77, 129.66, 129.42 (s, 2C), 128.68 (s, 2C), 128.63, 128.51 (s, 2C), 128.24 (s, 4C), 127.93 (s, 2C), 113.66, 111.85, 99.18, 62.23, 59.53, 51.31, 48.17, 13.3; HRMS (ESI) m/z [M + H]+ calcd for C28H24N3O2+: 434.1863; found: 434.1850.
Ethyl (4SR,6RS)-5,5-dicyano-2-phenyl-4,6-bis(4-methoxy)phenyl-1,4,5,6-tetrahydropyridine-3-carboxylate (4r) Yield: 0.65 g (44%); white solid; m.p. 177–179 °C; 1H-NMR (CDCl3 300.13 MHz): δ = 7.58 (d, J = 8.6 Hz, 2H, Ar), 7.53–7.42 (m, 7H, Ar), 7 (d, J = 8.6 Hz, 2H, Ar), 6.94 (d, J = 8.6 Hz, 2H, Ar), 4.92 (s, 1H, CH), 4.72 (s, 1H, CH), 4.52 (s, 1H, NH), 3.84 (s, 3H, OCH3), 3.83 (s, 3H, OCH3), 3.72–3.59 (m, 2H, CH2), 0.64 (t, J = 7.1, 3H, CH3); 13C-NMR (CDCl3, 75.47 MHz): δ = 165.53, 161.29, 159.74, 153.50, 136.69, 129.54, 129.28 (s, 2C),129.18, 129.15 (s, 2C), 128.44 (s, 2C), 128.19 (s, 2C), 125.35, 114.74 (s, 2C), 114.06 (s, 2C), 113.94, 112.12, 99.42, 61.70, 59.50, 55.38, 55.22, 50.66, 48.77, 13.39; IR (KBr): 3345, 2256, 1699, 1445, 1252 cm−1; HRMS (ESI) m/z [M + H]+ calcd for C30H28N3O4+: 494.2074; found: 494.2062.
Methyl (4SR,6RS)-5,5-dicyano-2-(4-bromo)phenyl-4,6-diphenyl-1,4,5,6-tetrahydropyridine-3-carboxylate (4s) Yield: 0.92 g (62%); white solid; m.p. 167–170 °C. (lit. [47] m.p. 167–170 °C); 1H-NMR (CDCl3 300.13 MHz): δ = 7.69–7.33 (m, 14H, Ar), 4.96 (s, 1H, CH), 4.75 (s, 1H, CH), 4.57 (s, 1H, NH), 3.17 (s, 3H, OCH3).
Methyl (4SR,6RS)-5,5-dicyano-2-(4-bromo)phenyl-4,6-bis(4-methyl)phenyl-1,4,5,6-tetrahydropyridine-3-carboxylate (4t) Yield: 1.18 g (75%); white solid; m.p. 131–134 °C; 1H-NMR (CDCl3 300.13 MHz): δ = 7.59 (d, J = 8.2 Hz, 2H, Ar), 7.53 (d, J = 7.9 Hz, 2H, Ar), 7.42 (d, J = 6.3 Hz, 2H, Ar), 7,39 (d, J = 6.6 Hz, 2H, Ar), 7.3 (d, J = 9 Hz, 2H, Ar), 7.22 (d, J = 7.8 Hz, 2H, Ar), 4.90 (s, 1H, CH), 4.70 (s, 1H, CH), 4.54 (s, 1H, NH), 3.18 (s, 3H, OCH3), 2.41 (s, 3H, CH3), 2.38 (s, 3H, CH3); 13C-NMR (DMSO-d6, 75.47 MHz): δ =165.99, 154.72, 135.77, 136.24, 137.72, 139.86, 131.48 (s, 2C), 130.98 (s, 2C), 129.4 (s, 2C), 129.34 (s, 2C), 128.83 (c, 2C),128.13 (c, 3C), 122.64, 114.51, 113.34, 97.06, 60.43, 50.46, 49.47, 48.82, 21.26, 21.2; IR (KBr): 3484, 2255, 1690, 1433, 1262, 726 cm−1; HRMS (ESI) m/z [M + H]+ (for 79Br) 526.1128 calcd for C29H25BrN3O2+: 526.1125.
5-ethyl 3-methyl (4RS,5SR,6RS)-5-cyano-2-(4-bromo)phenyl-4,6-bis(4-bromo)phenyl-1,4,5,6-tetrahydropyridine-5,3-carboxylate (5a) Yield: 0.77 g (36%); white solid; m.p. 221–223 °C; 1H-NMR (CDCl3 300.13 MHz): δ = 7.62–7.18 (m, 12H, Ar), 4.87 (s, 1H, CH), 4.82 (s, 1H, CH),4.5 (s, 1H, NH), 3.93 (q, J = 7 Hz, 2H, OCH2), 3.17 (s, 3H, OCH3), 0.89 (t, J = 7,1 Hz, 3H, CH3); 13C-NMR (CDCl3, 75.47 MHz): δ = 166.14, 166.09, 152.55, 137.52, 135.69, 133.13, 132.33 (s, 2C),131.71, 131.59 (s, 2C), 131.44 (s, 2C), 130.14 (s, 2C), 129.46 (s, 2C), 129.34, 124.35, 123.86, 121.8, 114.87, 100.12, 63.14, 61.31, 57.65, 50.63, 49.16, 13.6; IR(KBr): 3334, 2247, 1737, 1259, 501 cm−1; HRMS (ESI) m/z [M + H]+ (for 79Br) 700.9281 calcd for C29H24Br3N2O4+: 700.9276.
5-ethyl 3-methyl (4RS,5SR,6RS)-5-cyano-2-(4-chloro)phenyl-4,6-bis(4-bromo)phenyl-1,4,5,6-tetrahydropyridine-5,3-carboxylate (5b) Yield: 0.61 g (33%); white solid; m.p. 205–208 °C; IR (KBr): 3333, 2247, 1739, 1259, 810, 500 cm−1; 1H-NMR (CDCl3 300.13MHz): δ = 7.59–7.21 (m, 12H, Ar), 4.87 (s, 1H, CH), 4.83 (s, 1H, CH), 4.48 (s, 1H, NH), 3.93 (q, J = 7 Hz, 2H, OCH2), 3.17 (s, 3H, OCH3), 0.89 (t, J = 7,1 Hz, 3H, CH3); 13C-NMR (CDCl3, 75.47 MHz): δ = 166.17, 166.1, 152.56, 137.55, 135.65, 135.18, 133.14, 132.34 (s, 2C), 131.6 (s, 2C), 129.91 (s, 2C), 129.47 (s, 2C), 129.33 (s, 2C), 128.48 (s, 2C), 124.35, 121.8, 114.89, 100.1, 63.15, 61.30, 57.67, 50.63, 49.15, 13.61; IR (KBr): 3333, 2247, 1739, 1259, 810, 500 cm−1; HRMS (ESI) m/z [M + H]+ (for 35Cl and 79Br) 656.9786 calcd for C29H24Br2ClN2O4+: 656.9776.

3.5. Synthesis of 6

A mixture of aldehyde 1 (6 mmol), malononitril 2a (3 mmol), ester of 3-oxocarboxylic acid 3 (3 mmol) and ammonium acetate (6 mmol) was stirred in methanol (7 mL) at rt for 40 min. The precipitate was collected by filtration and dried to obtain piperidine 6.
Ethyl (2SR,3RS,4SR,6RS)-5,5-dicyano-2-phenyl-2-hydroxy-4,6-diphenyl-piperidine-3-carboxylate (6a) Yield: 0.97 g (72%); white solid; m.p. 135–137 °C; 1H-NMR (DMSO-d6, 300.13 MHz): 7.72 (d, J = 7.2 Hz, 4H, Ar), 7.5–7.3 (m, 11H, Ar), 6.01 (s, OH), 5.14 (s, H, CH), 4.39 (d, J = 12.4 Hz, H, CH), 3.58 (s, NH), 3.52 (q, J = 7.1 Hz, 2H, CH2), 3.45 (d, J = 12.4 Hz, H, CH), 0.56 (t, J = 7.1 Hz, 3H, CH3); 13C-NMR (DMSO-d6, 75.47 MHz): 168.2, 144.7, 136.9, 136.2, 130.06, 129.3, 129.04 (s, 4C), 128.9 (s, 4C), 128.4, 128.3 (s, 2C), 126.5 (s, 2C), 114.1, 113.5, 84.4, 60.12, 59.5, 54.7, 49.2, 46.7, 13.7; IR (υmax) (KBr), ν/cm−1: 3503, 3317, 1711, 703 cm−1; HRMS (ESI) m/z [M + H]+ 452.1969 calcd for C28H26N3O3+: 452.1977.
Ethyl (2SR,3RS,4SR,6RS)-5,5-dicyano-2-phenyl-2-hydroxy-4,6-bis(4-methyl)phenyl-piperidine-3-carboxylate (6b) Yield: 0.88 g (61%); white solid; m.p. 130–132 °C; 1H-NMR (DMSO-d6, 300.13 MHz): 7.71 (d, J = 7.1 Hz, 2H, Ar), 7.59 (d, J = 8.1 Hz, 2H, Ar), 7.45–7.24 (m, 7H, Ar), 7.19 (d, J = 8.1 Hz, 2H, Ar), 6 (s, OH), 5.06 (s, H, CH), 4.31 (d, J = 12.4 Hz, H, CH), 3.51 (q, J = 7.1 Hz, 2H, CH2), 3.47 (s, NH), 3.41 (d, J = 12.4 Hz, H, CH), 2.31 (s, 3H, CH3), 2.28 (s, 3H, CH3), 0.58 (t, J = 7.1 Hz, 3H, CH3); 13C-NMR (DMSO-d6, 75.47MHz): 168.2, 144.8, 139.5, 138.6, 134, 133.3, 129.6 (s, 2C), 129.4 (s, 2C), 128.9 (s, 2C), 128.7 (s, 2C), 128.4, 128.3 (s, 2C), 126.5 (s, 2C), 114.2, 113.5, 84.4, 60.1, 59.2, 54.7, 49.5, 46.3, 21.3, 21.1, 13.7; IR (υmax) (KBr), ν/cm−1: 3498, 3320, 2224, 1713, 702 cm−1; HRMS (ESI) m/z [M + H]+ 480.2293 calcd for C30H30N3O3+: 480.2282.
Ethyl (2SR,3RS,4SR,6RS)-5,5-dicyano-2-phenyl-2-hydroxy-4,6-bis(4-chloro)phenyl-piperidine-3-carboxylate (6c) Yield: 0.87 g (56%); white solid; m.p. 126–128 °C; 1H-NMR (DMSO-d6, 300.13 MHz): δ = 7.72 (d, J = 8.6 Hz, 2H, Ar), 7.73–7.69 (m, 2H, Ar), 7.56 (d, J = 8.5 Hz, 2H, Ar), 7.48 (d, J = 2.4 Hz, 3H, Ar), 7.52–7.31 (m, 4H, Ar), 6.07 (s, OH), 5.17 (s, H, CH), 4.46 (d, J = 12.4 Hz, H, CH), 3.75 (s, NH), 3.54 (q, J = 7.1 Hz, 2H, CH2), 3.42 (d, J = 12.3 Hz, H, CH), 0.59 (t, J = 7.1 Hz, 3H, CH3); 13C-NMR (DMSO-d6, 75.47MHz): δ = 168, 144.5, 135.75, 135.27, 134.7, 134.1, 131.95 (s, 2C), 130.7 (s, 2C), 129.2 (s, 2C), 128.96 (s, 2C), 128.4, 128.3 (s, 2C), 126.6 (s, 2C), 113.8, 113.2, 84.5, 60.3, 58.7, 54.6, 48.98, 45.75, 13.7; IR (υmax) (KBr), ν/cm−1: 3501, 3317, 1711, 1494, 705 cm−1; HRMS (ESI) m/z [M + H]+ 520.1189 calcd for C28H24Cl2N3O3+: found: 520.1177.
Methyl (2SR,3RS,4SR,6RS)-5,5-dicyano-2-(4-bromo)phenyl-2-hydroxy-4,6-bis(4-methyl)phenyl-piperidine-3-carboxylate (6d) Yield: 1.42 g (87%); white solid; m.p. 144–146 °C; 1H-NMR (DMSO-d6, 300.13 MHz): δ = 7.56–7.7 (m, 4H, Ar), 7.58 (d, J = 8.1 Hz, 2H, Ar), 7.33–7.24 (m, 4H, Ar), 7.19 (d, J = 7.9 Hz, 2H, Ar), 6.15 (s, OH), 5.04 (s, H, CH), 4.32 (d, J = 12.4 Hz, 1H, CH), 3.63 (s, NH), 3.4 (d, J = 12.4Hz, H, CH), 3.09 (s, 3H, OCH3), 2.33 (s, 3H, CH3), 2.28 (s, 3H, CH3); 13C-NMR (DMSO-d6, 75.47 MHz): δ = 168.59, 144.36, 139.5, 138.67, 133.88, 133.22, 131.21 (s, 2C), 129.67 (s, 2C), 129.4 (s, 2C), 128.80 (s, 4C), 128.67 (s, 2C), 121.75, 114.15, 113.44, 84.20, 59.1, 54.6, 51.56, 49.4, 46.2, 21.26, 21.1; IR (υmax) (KBr), ν/cm−1: 3490, 3316, 2250, 1715, 512 cm−1; HRMS (ESI) m/z [M + H]+ (for 79Br) 544.1230 calcd for C29H27BrN3O3+: 544.1217.

3.6. Synthesis of 7

(2SR,3RS,4SR,6RS)-5,5-dicyano-2-(4-bromo)phenyl-2-hydroxy-4,6-bis(4-methyl)phenyl-piperidine-3-carboxylate 6d (1 mmol) and acetic acid (2 mmol) were refluxed in methanol (8 mL) for 2 h. The mixture was maintained at –10 °C for 30 min for the complete precipitation of the product. The precipitate was collected by filtration and dried to obtain pure 7.
Methyl (3RS,4SR,6RS)-5,5-dicyano-2-(4-bromo)phenyl-4,6-bis(4-methyl)phenyl-3,4,5,6-tetrahydropyridine-3-carboxylate (7) Yield: 0.18 g (90%); white solid; m.p. 235–237 °C; 1H-NMR (DMSO-d6, 300.13 MHz): δ = 7.86 (d, J = 8.6 Hz, 2H, Ar), 7.69 (d, J = 8.6 Hz, 2H, Ar), 7.54 (d, J = 8.1 Hz, 2H, Ar), 7.35–7.25 (m, 6H, Ar), 6.03 (d, J = 3 Hz, H, CH), 5 (dd, J1 = 11.2 Hz, J2 = 3 Hz, H, CH), 4.4 (d, J = 11.2 Hz, H, CH), 3.32 (s, 3H, OCH3), 2.35 (s, 6H, 2CH3); 13C-NMR (DMSO-d6, 75.47 MHz): δ = 169.97, 163.36, 139.4, 138.8, 136.74, 134.66, 131.96 (s, 2C), 131.93, 130.03 (s, 2C), 129.5 (s, 2C), 129.37 (s, 2C), 129.04 (s, 2C),128.72 (s, 2C), 125.20, 113.91, 112.69, 65.78, 53.25, 48.18, 47.16, 45.37, 21.22 (s, 2C); IR (υmax) (KBr), ν/cm−1: 2952, 2252, 1742, 1636, 1259, 500; HRMS (ESI) m/z [M + H]+ (for 79Br) 526.1125 calcd for C29H27BrN3O3+: 526.1118.

3.7. Synthesis of 8

4-flurobenzaldehyde 1h (6 mmol), ethyl cyanoacetate 2b (3 mmol), methyl 3-(4-bromophenyl)-3-oxopropanoate 3f (3 mmol) and ammonium acetate (6 mmol) in methanol (10 mL) were stirred at rt for 3 days. The solvent was evaporated under reduced pressure. Compound 8 was purified by column chromatography (eluent hexane/ethyl acetate = 3/1).
5-ethyl 3-methyl (3SR,4RS,5SR,6SR)-6-(4-bromophenyl)-3-cyano-2,4-bis(4-fluorophenyl)-3,4,5,6-tetrahydropyridine-3,5-dicarboxylate (8) Yield: 0.42 Γ (24%); white solid; m.p. 183–185 °C; 1H-NMR (DMSO-d6, 300.13 MHz): δ = 7.78 (d, J = 8.6 Hz, 2H, Ar), 7.67 (d, J = 8.6 Hz, 2H, Ar), 7.45–7.18 (m, 8H, Ar), 5.92 (d, J = 2.8 Hz, H, CH), 4.85 (dd, J1 = 11.2 Hz, J2 = 2.8 Hz, H, CH), 4.2 (d, J = 11.2 Hz, H, CH), 3.9 (q, J = 7.2 Hz, 2H, CH2), 3.32 (s, 3H, OCH3), 0.88 (t, J = 7.1 Hz, 3H, CH3); 13C-NMR (DMSO-d6, 75.47 MHz): δ = 170.88, 165.02, 162.84, 162.67 (d, J1C-F = 245.5 Hz, 2C), 162.38 (d, J1C-F = 245.5 Hz, 2C), 137.35, 134.77 (d, J4C-F = 2.9 Hz, 2C), 132.16 (d, J4C-F = 2.9 Hz, 2C), 131.96 (s, 2C), 131.23 (d, J3C-F = 8.5 Hz, 2C), 130.61 (d, J3C-F = 8.5 Hz, 2C), 129.15 (s, 2C), 124.65, 117.61, 116.3 (d, J2C-F = 21.5 Hz, 2C), 115.49 (d, J2C-F = 21.5 Hz, 2C), 65.85, 63.12, 54.01, 53.01, 48.26, 47.13, 13.81; IR (υmax) (KBr), ν/cm−1: 2250, 1734, 1230, 1009, 517 cm−1; HRMS (ESI) m/z [M + H]+ (for 79Br) 581.0884 calcd for C29H23BrF2N2O4+: 581.0882.

4. Conclusions

We developed a one-pot pseudo-five-component stereoselective synthesis of substituted 1,4,5,6-tetrahydropyridine, utilizing aldehydes (both with electron-withdrawing and electron-donating substituents), malononitrile or ethylcyanoacetate, esters of 3-oxocarboxylic acids and ammonium acetate, which played a dual role, acting as a base and as a nitrogen source for six-membered nitrogen-containing rings. Five bonds were formed as a result of the multicomponent process. Our method allows to obtain 2-substituted alkyl (4SR,6RS)-4,6-diaryl-5,5-dicyano-1,4,5,6-tetrahydropyridine-3-carboxylates with two stereogenic centers and 3,5-dialkyl (4RS, 5SR,6RS)-5-cyano-2,4,6-triaryl-1,4,5,6-tetrahydropyridine-5,3-carboxylates with three stereocenters. We established the formation mechanism of 1,4,5,6-tetrahydropyridines. These compounds were formed in a sequence of fast and slow reactions, including Knoevenagel condensation, Michael addition, Mannich reaction, intramolecular cyclization, dehydration and isomerization. The polysubstituted (4RS,6SR)-1,4,5,6-tetrahydropyridine was found to be more stable than the isomeric intermediate (3RS,4SR,6RS)-3,4,5,6-tetrahydropyridine. The conditions of all intermediates selective preparations were specified.

Supplementary Materials

The following are available online at https://www.mdpi.com/article/10.3390/molecules27144367/s1, Pages S2–S28: 1H and 13C NMR spectra of compounds 4–8; Pages S29–S32: 2D spectra of compounds 6d, 7; Pages S33–S37: DFT calculations.

Author Contributions

Conceptualization and methodology, A.N.V.; writing—original draft preparation, A.N.V. and T.M.I.; performed the synthesis, T.M.I., K.A.K. and R.N.A.; performed the X-ray analysis, M.E.M. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Acknowledgments

The authors are very grateful to Ivan Golovanov for performing the DFT calculations.

Conflicts of Interest

There authors declare no conflict of interest.

Sample Availability

Samples of the compounds 4–8 are available from the authors.

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Molecules 27 04367 sch001 550
Scheme 1. Presumed mechanism of the substituted 1,4,5,6-tetrahydropyridines’ formation.
Scheme 1. Presumed mechanism of the substituted 1,4,5,6-tetrahydropyridines’ formation.
Molecules 27 04367 sch001
Molecules 27 04367 sch002 550
Scheme 2. Pseudo-five-component transformation of aldehydes 1, C-H acids 2, esters of 3-oxocarboxylic acid 3 and ammonium acetate into 1,4,5,6-tetrahydropyridines 4,5.
Scheme 2. Pseudo-five-component transformation of aldehydes 1, C-H acids 2, esters of 3-oxocarboxylic acid 3 and ammonium acetate into 1,4,5,6-tetrahydropyridines 4,5.
Molecules 27 04367 sch002
Molecules 27 04367 g001 550
Figure 1. X-ray structure of the 4r 4SR,6RS configuration.
Figure 1. X-ray structure of the 4r 4SR,6RS configuration.
Molecules 27 04367 g001
Molecules 27 04367 g002 550
Figure 2. X-ray structure of the 5a 4RS,5SR,6RS configuration.
Figure 2. X-ray structure of the 5a 4RS,5SR,6RS configuration.
Molecules 27 04367 g002
Molecules 27 04367 sch003 550
Scheme 3. Pseudo-five-component transformation of aldehydes 1, malononitrile 2a, esters of 3-oxocarboxylic acid 3 and ammonium acetate into the substituted (2SR,3RS,4SR,6RS)-2-hydroxypiperidines 6.
Scheme 3. Pseudo-five-component transformation of aldehydes 1, malononitrile 2a, esters of 3-oxocarboxylic acid 3 and ammonium acetate into the substituted (2SR,3RS,4SR,6RS)-2-hydroxypiperidines 6.
Molecules 27 04367 sch003
Molecules 27 04367 g003 550
Figure 3. X-Ray structure of the 6d (2SR,3RS,4SR,6RS) configuration. Hydrogen bonding between the molecules of 6d and DMSO.
Figure 3. X-Ray structure of the 6d (2SR,3RS,4SR,6RS) configuration. Hydrogen bonding between the molecules of 6d and DMSO.
Molecules 27 04367 g003
Molecules 27 04367 g004 550
Figure 4. 1H NMR monitoring of the characteristic signals of 6d, unknown compound 7 and 4t over 4.5 months.
Figure 4. 1H NMR monitoring of the characteristic signals of 6d, unknown compound 7 and 4t over 4.5 months.
Molecules 27 04367 g004
Molecules 27 04367 sch004 550
Scheme 4. Dehydration of methyl (2SR,3RS,4SR,6RS)-5,5-dicyano-2-(4-bromo)phenyl-2-hydroxy-4,6-bis(4-methyl)phenyl-piperidine-3-carboxylate 6d.
Scheme 4. Dehydration of methyl (2SR,3RS,4SR,6RS)-5,5-dicyano-2-(4-bromo)phenyl-2-hydroxy-4,6-bis(4-methyl)phenyl-piperidine-3-carboxylate 6d.
Molecules 27 04367 sch004
Molecules 27 04367 g005 550
Figure 5. (a) X-ray structure of the 7 3RS,4SR,6RS configuration; (b) X-ray structure of the 8 3SR,4RS,5SR,6SR configuration.
Figure 5. (a) X-ray structure of the 7 3RS,4SR,6RS configuration; (b) X-ray structure of the 8 3SR,4RS,5SR,6SR configuration.
Molecules 27 04367 g005
Molecules 27 04367 sch005 550
Scheme 5. Stereoselective multicomponent synthesis of (3SR,4RS,5SR,6SR)-6-(4-bromophenyl)-3-cyano-2,4-bis(4-fluorophenyl)-3,4,5,6-tetrahydropyridine-3,5-dicarboxylate 8.
Scheme 5. Stereoselective multicomponent synthesis of (3SR,4RS,5SR,6SR)-6-(4-bromophenyl)-3-cyano-2,4-bis(4-fluorophenyl)-3,4,5,6-tetrahydropyridine-3,5-dicarboxylate 8.
Molecules 27 04367 sch005
Molecules 27 04367 sch006 550
Scheme 6. Verified mechanism of the substituted 1,4,5,6-tetrahydropyridines’ formation.
Scheme 6. Verified mechanism of the substituted 1,4,5,6-tetrahydropyridines’ formation.
Molecules 27 04367 sch006
Table
Table 1. Multicomponent synthesis of 1,4,5,6-tetrahydropyridines 4,5 a.
Table 1. Multicomponent synthesis of 1,4,5,6-tetrahydropyridines 4,5 a.
EntryAldehydeC-H AcidC-H AcidXArR1R2ProductYield b
1.1a2a3aCNC6H5MeMe4a80
2.1b2a3aCN2-MeC6H4MeMe4b65
3.1c2a3aCN3-MeC6H4MeMe4c76
4.1d2a3aCN4-MeC6H4MeMe4d72
5.1e2a3aCN3-FC6H4MeMe4e71
6.1f2a3aCN3-ClC6H4MeMe4f68
7.1g2a3aCN3-PyMeMe4g62
8.1a2a3bCNC6H5MeEt4h86
9.1h2a3bCN4-FC6H4MeEt4i69
10.1i2a3bCN4-NO2C6H4MeEt4j63
11.1a2a3cCNC6H5EtMe4k90
12.1d2a3cCN4-MeC6H4EtMe4l82
13.1j2a3cCN4-BrC6H4EtMe4m82
14.1i2a3cCN4-NO2C6H4EtMe4n58
15.1a2a3dCNC6H5C6H5Me4o76
16.1e2a3dCN3-FC6H4C6H5Me4p52
17.1a2a3eCNC6H5C6H5Et4q58
18.1k2a3eCN4-OMeC6H4C6H5Et4r44
19.1a2a3fCNC6H54-BrC6H4Me4s62
20.1d2a3fCN4-MeC6H44-BrC6H4Me4t75
21.1j2b3fCO2Et4-BrC6H44-BrC6H4Me5a73
22.1j2b3gCO2Et4-BrC6H44-ClC6H4Me5b66
a Reaction conditions: aldehyde 1 (6 mmol), cyano C-H acid 2 (3 mmol), ester of 3-oxocarboxylic acid 3 (3 mmol), NH4OAc (6 mmol) and methanol (10 mL), refluxing for 2 h. b Isolated yields.
Table
Table 2. Multicomponent synthesis of (2SR,3RS,4SR,6RS)-2-hydroxypiperidines 6 a.
Table 2. Multicomponent synthesis of (2SR,3RS,4SR,6RS)-2-hydroxypiperidines 6 a.
EntryAldehydeC-H AcidRR1R2ProductYield b
11a3eHC6H5Et6a72
21d3e4-MeC6H5Et6b61
31l3e4-ClC6H5Et6c56
41d3f4-Me4-BrC6H4Me6d87
a Reaction conditions: aldehyde 1 (6 mmol), malononitrile 2a (3 mmol), ester of 3-oxocarboxylic acid 3 (3 mmol), NH4OAc (6 mmol) and methanol (10 mL), rt, 40 min. b Isolated yields.
Table
Table 3. Dehydration of 6d a.
Table 3. Dehydration of 6d a.
EntryAcOH/mol.eq.Time, hTetrahydropyridineYield (%) b
102--
222790
342788
41027/4t = 1:190 c
51047/4t = 1:1.592 c
62527/4t = 1:288 c
75024t92
a 6d (1 mmol), MeOH (8 mL), refluxing. The progress of the reaction was monitored by TLC. b Isolated yields. c Total yield of tetrahydropyridines.
Table
Table 4. Crystal data and structure refinement.
Table 4. Crystal data and structure refinement.
Structure4r5a6d78
Empirical formulaC30H27N3O4C29H23Br3N2O4C29H26BrN3O3·C2H6OSC29H24BrN3O2C29H23BrF2N2O4
Formula weight493.54703.22622.56526.42581.40
Crystal systemMonoclinicMonoclinicMonoclinicOrthorhombicTriclinic
Space groupP21/nP21/cP21P212121 P 1 ¯
Unit cell parameters
a, Å13.5215(6)14.1399(5)9.3382(4)8.9278(2)7.9773(3)
b, Å14.4873(6)13.7544(4)17.1583(8)14.0848(3)15.5602(6)
c, Å13.6402(6)14.6488(5)10.1005(5)19.5522(4)21.8741(8)
α, °9090909091.0048(12)
β, °109.0602(13)107.0120(11)116.3107(12)9091.2217(12)
γ, °90909090103.2089(14)
Volume, Å32525.49(19)2724.32(16)1450.72(12)2458.62(9)2642.06(17)
Z44244
Density (calcd.), g/cm31.2981.7151.4251.4221.462
μ, mm−10.0874.4811.5301.7041.608
F (000)1040139264410801184
θ range, °2.58–30.002.07–33.732.43–30.502.51–33.742.32–31.53
Completeness to θmax0.9991.0001.0000.9990.995
Index ranges−19 < = h < = 15,
−20 < = k < = 20,
−19 < = l < = 19		−13 < = h < = 13,
−21 < = k < = 22,
−30 < = l < = 29		−13 < = h < = 13,
−24 < = k < = 24,
−14 < = l < = 14		−13 < = h < = 13,
−21 < = k < = 22,
−30 < = l < = 29		−11 < = h < = 11,
−22 < = k < = 22,
0 < = l < = 32
Reflections collected3732390656423078090320648
Independent reflections (R(int))7344 [0.0737]10,873 [0.0808]8837 [0.0539]9808 [0.0411]20,648 [-]
Observed reflections (I > 2σ(I))485269747570871711,148
Data, restraints, parameters7344, 0, 34110,873, 1, 3578837, 8, 3869808, 0, 32120,648, 0, 691
Goodness of fit on F21.0371.0191.0391.0501.019
Final R1, wR2 (I > 2σ(I))0.0523, 0.09420.0491, 0.10420.0328, 0.06370.0295, 0.06670.0593, 0.0984
Final R1, wR2 (all data)0.0951, 0.11710.0955, 0.12500.0454, 0.06930.0383, 0.07120.1452, 0.1219
Absolute structure parameter--0.016(6)0.388(6)-
Largest diff. peak, hole, e/Å30.321, −0.2820.993, −1.1760.377, −0.4880.348, −0.3780.595, −0.861
CCDC number19793092032519197918620116462011600
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Vereshchagin, A.N.; Iliyasov, T.M.; Karpenko, K.A.; Akchurin, R.N.; Minyaev, M.E. Tetrahydropyridines’ Stereoselective Formation, How Lockdown Assisted in the Identification of the Features of Its Mechanism. Molecules 2022, 27, 4367. https://doi.org/10.3390/molecules27144367

AMA Style

Vereshchagin AN, Iliyasov TM, Karpenko KA, Akchurin RN, Minyaev ME. Tetrahydropyridines’ Stereoselective Formation, How Lockdown Assisted in the Identification of the Features of Its Mechanism. Molecules. 2022; 27(14):4367. https://doi.org/10.3390/molecules27144367

Chicago/Turabian Style

Vereshchagin, Anatoly N., Taigib M. Iliyasov, Kirill A. Karpenko, Radmir N. Akchurin, and Mikhail E. Minyaev. 2022. "Tetrahydropyridines’ Stereoselective Formation, How Lockdown Assisted in the Identification of the Features of Its Mechanism" Molecules 27, no. 14: 4367. https://doi.org/10.3390/molecules27144367

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