Next Article in Journal
Super Secondary Structures of Proteins with Post-Translational Modifications in Colon Cancer
Next Article in Special Issue
Asymmetric Preparation of α-Quaternary Fluorinated β-keto Esters. Review
Previous Article in Journal
Metabolic Current Production by an Oral Biofilm Pathogen Corynebacterium matruchotii
Previous Article in Special Issue
Molecular Structure Modulated Trap Distribution and Carrier Migration in Fluorinated Epoxy Resin
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Molecules
Volume 25
Issue 14
10.3390/molecules25143143
molecules-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Article

Synthesis of Fluorinated 3,6-Dihydropyridines and 2-(Fluoromethyl)pyridines by Electrophilic Fluorination of 1,2-Dihydropyridines with Selectfluor®

by
Nadiia V. Pikun
1,*,
Arkadij Sobolev
1,
Aiva Plotniece
1,
Martins Rucins
1,
Brigita Vigante
1,
Marina Petrova
1,
Ruslan Muhamadejev
1,
Karlis Pajuste
1 and
Yuriy G. Shermolovich
2
1
Latvian Institute of Organic Synthesis, Aizkraukles Str. 21, LV-1006 Riga, Latvia
2
Institute of Organic Chemistry NAS of Ukraine, Murmanska Str. 5, 02660 Kyiv, Ukraine
*
Author to whom correspondence should be addressed.
Molecules 2020, 25(14), 3143; https://doi.org/10.3390/molecules25143143
Submission received: 4 June 2020 / Revised: 8 July 2020 / Accepted: 8 July 2020 / Published: 9 July 2020
(This article belongs to the Special Issue Fluorine Chemistry)
Browse Figures
Versions Notes

Abstract

:
New fluorinated 3,6-dihydropyridines were obtained by the electrophilic fluorination of 1,2-dihydropyridines with Selectfluor®. These 3-fluoro-3,6-dihydropyridines were easily converted to corresponding pyridines by the elimination of hydrogen fluoride under mild conditions. A new approach to the synthesis of methyl 2-(fluoromethyl)-5-nitro-6-arylnicotinates by the fluorination of 3-fluoro-2-methyl-5-nitro-3,6-dihydropyridines or 1,2-dihydropyridines with Selectfluor® has been developed.

Graphical Abstract

1. Introduction

The incorporation of fluorine into organic compounds has become a commonly used tool in medicinal chemistry and agrochemistry. The presence of fluorine may result in substantial changes in the biological, as well as physicochemical, properties of organic compounds. The incorporation of fluorine into a drug structure can drastically influence its physicochemical properties, such as bond strength, lipophilicity, bioavailability, conformation, electrostatic potential, dipole moment, pKa, etc. The fluorination of organic compounds also significantly affects their pharmacological properties and toxicology [1,2,3]. The majority of currently marketed modern drugs have heterocyclic fragments in their structures. The fluorinated heterocycles are becoming more significant in a number of disciplines, in particular, the pharmaceutical industry, materials science and agriculture [1,2,3].
The electrophilic fluorination of aromatic heterocycles has been less studied than the fluorination of arenes. However, a number of fluoropyrroles [4,5], furans [6], thiophenes [7], pyrrolo[2,3-d]pyrimidines [8,9], quinolines [10,11,12] and indoles [13,14,15,16,17,18,19,20,21,22] have been prepared either by direct fluorination or by fluorodecarboxylation using mainly Selectfluor® and N-fluorobenzenesulfonimide.
The chemistry of the pyridines has been extended by the development of many significant transformations, such as addition, addition-elimination, elimination-addition and ring opening, as well as proton abstraction reactions followed by nucleophilic substitution. The nature of the pyridine rings and bases employed plays an important role in the course of reactions [23].
It should also be noted that, despite the fact that fluorine- and trifluoromethyl-substituted pyridines have been very extensively studied, there are very limited data on 2- and 4-(fluoromethyl)pyridines in the literature [24,25,26,27,28,29], which makes these compounds attractive for investigations.
In our previous works, we reported a new electrophilic fluorination reaction of 1,4-dihydropyridines, providing an approach to previously unknown fluorinated 2,6-heptanediones as useful synthons for the preparation of fluorine-containing compounds. The use of 2,6-heptanediones in reactions with ammonia, amines or hydrazine hydrate offered new fluorine-containing carbocycles and heterocycles, such as 3-acetyl-5-(alkyloxycarbonyl)-3,5-difluoro-2,6-dioxo-4-phenylcyclohexan-1-ides, 2-oxa-6-azabicyclo[2.2.2]octanes and pyrazolinone derivatives [30,31].
The 1,2-dihydropyridines are known in particular for their ability to readily undergo oxidation to the pyridines [32]. Thus, isomerisation involving hydride transfer was shown to convert 1,2-dihydropyridines into their 1,4-isomers in the presence of the transition metal complex RhCl(PPh3)2 [33]. Polysubstituted 1,2-dihydropyridines have been found to undergo [4+2] cycloaddition as reactive dienes with maleic anhydride, dimethyl fumarate and methyl acrylate, leading to the formation of 2-azabicyclo[2.2.2]oct-7-enes [34]. The regiospecific 1,3-dipolar cycloaddition reaction of 1,2-dihydropyridines with cyanogen azide and per(poly)fluoroalkanesulfonyl azides has afforded corresponding 2,7-diazabicyclo[4.1.0]hept-4-enes and N-(1,2,3,6-tetrahydropyridylidene)fluoroalkanesulfonylamides [35,36]. The alkylation and acylation reactions of 2-alkyl(phenyl)-1-lithio-1,2-dihydropyridines has also been investigated [37,38,39,40].
It has to be noted that, to the best of our knowledge, there are no previous studies on the fluorination reactions of 1,2-dihydropyridines. In this paper, we studied the electrophilic fluorination reaction of 1,2-dihydropyridines 1a–k with Selectfluor® (Table 1).

2. Results and Discussion

Starting 2-methyl-5-nitro-1,2-dihydropyridines 1 were obtained by the cyclisation of corresponding nitrodienamines with aldehydes [41]. We show that 1,2-dihydropyridines 1a–k reacted with Selectfluor® at 0 °C in dry acetonitrile under an argon atmosphere to form a series of new 3-fluoro-3,6-dihydropyridines 2a–k (Table 1).
Products 2a–k were isolated as mixtures of two diastereomers. The ratio of diastereomers was determined according to the 19F, 1H-NMR spectra of compounds 2a–k (Table 1). The attempts to separate the diastereomers by column chromatography failed, as during separation the formation of corresponding pyridines 3a–k occurred as a result of the removal of hydrogen fluoride (according to LC–MS data) (Table 2).
It was found that after the storage of 3-fluoro-3,6-dihydropyridines 2a–k in deuterochloroform solution at room temperature for 2−4 days, hydrogen fluoride was eliminated, leading to the formation of corresponding pyridines 3a–k (Table 2). Compounds 3a–k were isolated by column chromatography in 72−91% yields (Table 2).
The effect of various factors on the course of this reaction, such as the solvent, the order of addition of reagents, temperature and dilution, was studied. Acetonitrile turned out to be the best solvent for the preparation of 3-fluoro-3,6-dihydropyridines 2a–k. Finally, the optimal reaction conditions for the synthesis of fluorinated 3,6-dihydropyridines 2a–k were when the solution of Selectfluor® in acetonitrile was slowly added to the solution of 1,2-dihydropyridines 1a–k in acetonitrile under an argon atmosphere at 0 °C. Compounds 2a–k obtained by this method were further used without additional purification. In other cases, a mixture of 3-fluoro-3,6-dihydropyridines 2a–k and pyridines 3a–k as products of the elimination of hydrogen fluoride from 3-fluoro-3,6-dihydropyridines 2 was formed, according to LC–MS data.
The structures of compounds 2a–k were established and confirmed on the base of one-dimensional 1H, 19F, 13C and two-dimensional {1H−1H} COSY, {13C−1H} HSQC and {13C−1H} HMBC NMR spectral data (Table 3).
The correlations of the protons at 5.4−6.2 ppm in the {13C−1H} HMBC spectra with the ipso and orto carbon atoms and aryl substituent for both diastereomers of compounds 2a–k indicate that the mentioned proton and aryl substituent are located at the same C6 carbon atom.
In both diastereomers of compounds 2a–k, the fluorine atom and ester moiety are located at the same C3 carbon atom, as is evidenced by the large values of the constants 1JC3-F = 189.1−194.2 Hz for the C3 carbon atom at 84.7−87.0 ppm and 2JC-F = 26.2−30.7 Hz for the carbonyl carbon atom at 165.5−166.7 ppm according to the 13C-NMR spectra.
In the 19F-NMR spectra of compounds 2a–k, a signal of the fluorine atom appears as a doublet doublet in the range of −139.9 ppm to −145.9 ppm with the constants 5JF-H = 14.0−17.0 Hz and 3JF-H = 9.0−9.5 Hz for one diastereomer and in the field of −141.5 ppm to −150.4 ppm with the constants 5JF-H = 11.4−12.6 Hz and 3JF-H = 5.4−6.5 Hz for another diastereomer (Table 3).
An interesting fact is that compounds 2a–k in the 1H and 19F-NMR spectra have unusually large coupling constants between the fluorine atom and C6H proton, which are separated by five bonds (5J (19F,1H)). The case of considerably large coupling across five bonds is unusual, however, it can be observed under favourable circumstances [42]. The value of this constant is almost two times higher than the constant between the fluorine nuclei and C4H protons separated by only three bonds (3JF-H = 5.4−9.5 Hz) (3J (19F,1H) in compounds 2a–h (Table 3).
To prove the coupling between the fluorine atom and C6H proton, heteronuclear spin decoupling was used. Figure 1 shows the effect of the heteronuclear spin decoupling of the 19F nucleus on the C6H and C4H proton signals of compound 2a. In the below spectrum (Figure 1), the signals of the C4H protons are presented as two doublet doublets coupled with the fluorine atom and C6H proton (4JH-H ~ 1.3 Hz). The C6H proton is coupled with the fluorine atom through five bonds (Table 3), as well as with the C4H and C2CH3 protons (4JH-H < 1.9 Hz). In the above spectrum (Figure 1), the fluorine atom is irradiated and the doublet of doublets of the C4H and the multiplet of C6H are collapsed to broaden singlets. The C4H and C6H proton signal broadening results from long-range coupling with the mentioned protons. The main information obtained from the 19F decoupling is the confirmation of the coupling between the fluorine atom and C4H and C6H protons.
Our attempts to explain the origin of the large coupling constant 5J (19F,1H) value in compounds 2a–k were initially based on the hypothesis of through-space coupling for the spatially proximate C6H proton and F nuclei. The evidence for the through-space mechanism in HF couplings was known previously [43,44,45]. The through-space mechanism is possible for compounds where the fluorine and a coupled proton are separated by a distance which does not exceed the sum of their van der Waals radii (~2.6 Å).
To ascertain the possibility of through-space proton–fluorine interactions in compounds 2a–k, ab initio calculations were carried out and the data are presented in Table 4.
According to the quantum chemical calculations, the angles between the C6-N1-C2-C3 and C6-C5-C4-C3 planes are 167.8−178.5° for compounds 2a–k (Figure 2, Table 4), which indicate that the 3,6-dihydropyridine ring is planar or near planar. According to Table 3, the only non-planar conformer was 2k cis (α = 148.2°). It has already been established that the 1,4-cyclohexadiene ring is also relatively flat and for various cyclohexadiene derivatives α = 166−172° [46,47,48,49].
The distance between the proton and the fluorine in cis conformer is shorter than in trans for 5-nitro-substituted 3,6-dihydropyridines 2a–h. The distance from the C3 and C6 carbons to the N1-C2-C4-C5 plane is larger in its cis conformer (except 2a and 2d compounds) (Table 4).
The graphical representation of the optimised molecular geometry for both diastereomers of compound 2a, obtained with density−functional theory (DFT) calculations, is shown in Figure 2.
The data show that 3,6-dihydropyridines 2 are nearly planar and the distance between the two coupled atoms (C6H proton and F) greatly exceeds the sum of the van der Waals radii varying in the interval 4.6−5.0 Å for compounds 2a–k (Table 4). Consequently, we can claim that the transfer of spin–spin interaction through-space is rather problematic for compounds 2. The hypothesis about homoallyl long-range coupling transmitted through π-electrons across a double bond of the heterocycle in compounds 2a–k seems to be more likely as compared with through-space interaction. The homoallylic coupling occurs over five bonds and attains a maximum value when the bonds to the coupled atoms are nearly parallel. The coupling is optimal when both C-H and C-F bonds are aligned with the π-orbital of an intervening double bond (perpendicular to the plane of the double bond) [49].
Extremally large homoallyl long-range HH couplings have been previously observed for 1,4-cyclohexadienes and related structures, where there were two paths for the coupling [50]. For planar 1,4-cyclohexadienes and their derivatives, the value of the 5JH-Hcis is greater (9.6−11.0 Hz) than the 5JH-Htrans (7.5−8.4 Hz) [49]. Based on these data, we can also suggest that the cis diastereomer of compounds 2a–k has a larger homoallylic coupling constant 5JF-H than the corresponding trans diastereomer.
We can propose the following scheme for the formation of 3-fluoro-3,6-dihydropyridines 2a–k. At the first stage of the reaction, Selectfluor® is probably attached to the double bond of 1,2-dihydropyridines 1a–k with the formation of ammonium salts 4. The decomposition of these salts 4 under mild conditions results in the formation of 3-fluoro-3,6-dihydropyridines 2a–k (Scheme 1).
The reaction of 3-fluoro-2-methyl-5-nitro-3,6-dihydropyridines 2a,c,f,g with Selectfluor® was also investigated. It was found that this reaction with 2 equiv. of Selectfluor® led to the formation of a mixture of new methyl 2-(fluoromethyl)-5-nitro-6-arylnicotinates 5a–d and 2-methylpyridines 3a,c,f,g (Table 5, Method A). The compounds 5a–d and compounds 3a,c,f,g were isolated by column chromatography in 21−43% and 10–52% yields, respectively. Our attempts to optimise the reaction conditions, such as the solvent, the order of addition of reagents, temperature and dilution, did not lead to an increase in the yields of compounds 5a–d. The one-pot reaction of 1,2-dihydropyridines 1a,c,f,g with 3 equiv. of Selectfluor®, in this case omitting the isolation of 3,6-dihydropyridines 2a,c,f,g, directly formed 2-(fluoromethyl)pyridines 5a–d and 2-methylpyridines 3a,c,f,g (Table 5, Method B). The ratios of compounds 3a,c,f,g and 5a–d were determined according to the 1H-NMR spectra and the LC–MS data of the reaction mixture were similar to those obtained by Method A (Table 5).
It is known that N-F fluorinating agents and, in particular Selectfluor®, are also strong oxidants, and competition between fluorofunctionalisation and oxidation can occur. The selectivity of fluorination reactions may thereby be decreased if the structure of the substrate contains oxidisable functional groups or heteroatoms. In our case, the reaction of 3-fluoro-2-methyl-5-nitro-3,6-dihydropyridines 2a,c,f,g with Selectfluor® can proceed in two competitive directions. Tautomers of 3-fluoro-3,6-dihydropyridines 2 with an enamine-like structure are probably fluorinated by Selectfluor® on the methylene site of the enamine to form ammonium salts 6 (Scheme 2, Path B). The decomposition of these salts 6, followed by the elimination of hydrogen fluoride, leads to the formation of 2-(fluoromethyl)pyridines 5a–d (Scheme 2).
On the other hand, 2-methylpyridines 3a,c,f,g can be formed as a result of the elimination of hydrogen fluoride from 3-fluoro-2-methyl-5-nitro-3,6-dihydropyridines 2a,c,f,g. (Scheme 2, Path A). Under similar conditions, pyridines 3 did not react with Selectfluor®.
There are very limited data in the literature about straightforward methods for the preparation of 2- or 4-(fluoromethyl)pyridines. When direct fluorination was performed on 4-picoline by F2/N2, 2-fluoro-4-methylpyridine was the main product [24]. Additionally, 4-(fluoromethyl)pyridine was prepared from 4-(chloromethyl)pyridine using activated tetrabutylammonium fluoride (TBAF) [25].
The preparation of 2- or 4-(fluoromethyl)pyridines was realised with N-fluorobis(trifluoromethanesulfonyl)imide from corresponding methylpyridines in dichloromethane at room temperature. In these reactions, the presence of sodium carbonate is necessary to suppress the formation of unreactive pyridinium salts, which are generated by the strongly acidic bis(trifluoromethanesulfonyl)imide co-product [26,27].
N-Fluorobis(trifluoromethanesulfonyl)imide, (CF3SO2)2NF, is a very attractive fluorinating agent because of its favourable physical properties and high reactivity, but it is not commercially available. In the reaction of 2-(chloromethyl)pyridine with potassium fluoride, 2-(fluoromethyl)pyridines can be also obtained (Finkelstein reaction, SN2 reaction that involves the exchange of one halogen atom for another) [28] or in the reaction of 2-pyridinylmethanol derivatives with (diethylamino)sulfur trifluoride [29].
Thus, the electrophilic fluorination reactions of 1,2-dihydropyridines 1 and 3-fluoro-2-methyl-5-nitro-3,6-dihydropyridines 2 with a commercially available Selectfluor® can be used as a convenient approach for the preparation of 2-(fluoromethyl)pyridines 5.

3. Materials and Methods

3.1. General Methods

All reagents were purchased from Acros Organics (Geel, Belgium), Sigma-Aldrich/Merck KGaA (Darmstadt, Germany), or Alfa Aesar (Lancashire, UK) and used without further purification. TLC was performed on silica gel 60 F254 aluminium sheets 20 × 20 cm (Merck KGaA, Darmstadt, Germany). Silica gel of particle size 35−70 µm (Merck KGaA, Darmstadt, Germany) was used for column chromatography. Melting points were recorded on an OptiMelt digital melting point apparatus (Stanford Research Systems, Sunnyvale, CA, USA) and were uncorrected. One-dimensional 1H, 13C, 19F and two-dimensional {1H-1H} COSY, {13C-1H} HMBC and {13C-1H} HSQC-NMR spectra were recorded on a Bruker Avance Neo 400 MHz (Bruker Biospin Gmbh, Rheinstetten, Germany) with a double resonance broadband CryoProbe Prodigy (1H 399.96 MHz, 13C 100.58 MHz, 19F 376.30 MHz). Inverse gate decoupling experiments for 19F on 1H were recorded on a Bruker Avance Neo 600 MHz (Bruker Biospin Gmbh, Rheinstetten, Germany) with a quadrupole resonance CryoProbe (CP QCI 600S3 H/F-C/N-D-05 Z) (1H 599.93 MHz, 19F 564.44 MHz). Chemical shifts of the hydrogen, carbon and fluorine atoms are presented in parts per million (ppm) and refer to the residual signals of the deuterated CDCl3 (δ: 7.26) solvent for the 1H-NMR spectra and CDCl3 (δ: 77.16) solvent for the 13C-NMR, respectively. For the 19F-NMR experiments, indirect referencing (Bruker standard referencing) was used. Coupling constants J are reported in hertz (Hz). Multiplicities are abbreviated as s = singlet; d = doublet; t = triplet; q = quartet, m = multiplet; br = broad; dd = double doublet; dm = double multiplet; td = triple doublet; ddd = double double doublet. Low resolution mass spectra (MS) were determined on an Acquity UPLC system (Waters, Milford, MA, USA) connected to a Waters SQ Detector-2 operating in the electrospray ionisation (ESI) positive or negative ion mode on a Waters Acquity UPLC® BEH C18 column (1.7 µm, 2.1 × 50 mm, using gradient elution with acetonitrile (0.01% formic acid) in water (0.01% formic acid). High resolution mass spectra (HRMS) were determined on an Acquity UPLC H-Class system (Waters, Milford, MA, USA) connected to a Waters Synapt G2-Si operating in the ESI positive or negative ion mode on a Waters Acquity UPLC® BEH C18 column (1.7 µm, 2.1 × 50 mm, using gradient elution with acetonitrile (0.01% formic acid) in water (0.01% formic acid). Infrared spectra were recorded with a Prestige-21 FTIR spectrometer (Shimadzu, Kyoto, Japan). Elemental analyses were determined on an Elemental Combustion System ECS 4010 (Costech International S.p.A., Milano, Italy) at the Laboratory of Chromatography of the Latvian Institute of Organic Synthesis. All quantum chemical calculations were performed with Gaussian 09 [51]. Geometry optimisation and vibrational calculations were performed with 6-311++G(d2,p2) basis set using DFT B97D3 functional with Grimme’s empirical dispersion D3 correction [52]. All geometries were optimised using the polarisable continuum model (PCM) solvation model for chloroform. For all optimised geometries, vibrational harmonic frequencies were calculated at the same level of theory, all the obtained harmonic frequencies were positive. Planes, distances to planes and angles between planes were calculated with the Mercury 3.1 program by Cambridge Crystallographic Data Centre (CCDC) (https://www.ccdc.cam.ac.uk/solutions/csd-system/components/mercury/).

3.2. General Procedure for the Synthesis of 3-Fluoro-3,6-dihydropyridines 2a–k

A solution of Selectfluor® (0.170 g, 0.5 mmol) in dry acetonitrile (5 mL) was slowly added dropwise to a solution of 1,2-dihydropyridines 1a–k (0.5 mmol) in dry acetonitrile (5 mL) in the presence of 3 Å molecular sieves at 0°C under an argon atmosphere. The reaction mixture was stirred for 10 min at 0 °C, after which the temperature was slowly raised to room temperature. The reaction mixture was concentrated in vacuo to dryness, then diluted with diethyl ether (15 mL) and filtered. The filtrate was evaporated in vacuo to give compounds 2a–k as oils in 82−97% yields. Compounds 2a–k obtained by this method were further used without additional purification.

3.2.1. Methyl 3-fluoro-2-methyl-5-nitro-6-phenyl-3,6-dihydropyridine-3-carboxylate (2a)

Pale yellow oil. Yield 0.137 g (94%). Mixture of diastereomers (the ratio is 45:55 according to the 19F and 1H-NMR spectra). 1H-NMR (CDCl3): δ 2.20 (d, 4JH-F = 2.1 Hz, 3H, CH3 of major diastereomer), 2.22 (dd, 4JH-F = 1.8 Hz, 5JH-H = 1.5 Hz, 3H, CH3 of minor diastereomer), 3.87 (s, 3H, COOCH3 of minor diastereomer), 3.89 (s, 3H, COOCH3 of major diastereomer), 5.77−5.81 (dm, 5JH-F = 12.1 Hz, 1H, C6H of major diastereomer), 6.06−6.11 (dm, 5JH-F = 15.4 Hz, 1H, C6H of minor diastereomer), 7.09 (dd, 3JH-F = 5.6 Hz, 4JH-H = 1.2 Hz, 1H, C4H of major diastereomer), 7.18 (dd, 3JH-F = 9.4 Hz, 4JH-H = 1.3 Hz, 1H, C4H of minor diastereomer), 7.22−7.24 (m, 1H, CH, Ph), 7.24−7.26 (m, 1H, CH, Ph), 7.30−7.38 (m, 8H, CH, Ph of both diastereomers). 19F-NMR (CDCl3): δ −140.6 (dd, 5JF-H = 15.4 Hz, 3JF-H = 9.4 Hz, 1F, CF of minor diastereomer), −142.4 (dd, 5JF-H = 12.1 Hz, 3JF-H = 5.6 Hz, 1F, CF of major diastereomer). 13C-NMR (CDCl3): δ 20.7 (s, CH3 of minor diastereomer), 20.9 (s, CH3 of major diastereomer), 54.1 (s, COOCH3 of minor diastereomer), 54.2 (s, COOCH3 of major diastereomer), 61.9 (d, 4JC-F = 3.2 Hz, C6H of major diastereomer), 62.5 (d, 4JC-F = 2.7 Hz, C6H of minor diastereomer), 84.8 (d, 1JC-F = 189.9 Hz, CF of major diastereomer), 87.0 (d, 1JC-F = 191.2 Hz, CF of minor diastereomer), 120.9 (d, 2JC-F = 27.3 Hz, C4H of major diastereomer), 122.3 (d, 2JC-F = 25.9 Hz, C4H of minor diastereomer), 128.0 (s, 2×CH, Ph of major diastereomer), 128.2 (s, 2×CH, Ph of minor diastereomer), 128.8 (s, CH, Ph of minor diastereomer), 128.9 (s, CH, Ph of major diastereomer), 129.0 (s, 2×CH, Ph of minor diastereomer), 129.3 (s, 2×CH, Ph of major diastereomer), 135.5 (d, 5JC-F = 6.9 Hz, Cq, Ph of major diastereomer), 135.8 (d, 5JC-F = 4.1 Hz, Cq, Ph of minor diastereomer), 154.7 (d, 3JC-F = 8.7 Hz, C5 of minor diastereomer), 155.7 (d, 3JC-F = 8.4 Hz, C5 of major diastereomer), 156.8 (d, 2JC-F = 20.9 Hz, C2 of major diastereomer), 157.3 (d, 2JC-F = 19.8 Hz, C2 of minor diastereomer), 165.5 (d, 2JC-F = 28.8 Hz, C=O of minor diastereomer), 165.9 (d, 2JC-F = 29.3 Hz, C=O of major diastereomer). HRMS (ESI+): Calcd for C14H13FN2O4 [M + H]: 293.0946; found 293.0938.

3.2.2. Methyl 6-([1,1′-biphenyl]-4-yl)-3-fluoro-2-methyl-5-nitro-3,6-dihydropyridine-3-carboxylate (2b)

Pale yellow oil. Yield 0.177 g (96%). Mixture of diastereomers (the ratio is 40:60 according to the 19F and 1H-NMR spectra). 1H-NMR (CDCl3): δ 2.23−2.24 (dm, 4JH-F = 1.8 Hz, 3H, CH3 of major diastereomer), 2.24−2.25 (dm, 4JH-F = 1.5 Hz, 3H, CH3 of minor diastereomer), 3.91 (s, 3H, COOCH3 of minor diastereomer), 3.92 (s, 3H, COOCH3 of major diastereomer), 5.91−5.96 (dm, 5JH-F = 12.1 Hz, 1H, C6H of major diastereomer), 6.20−6.25 (dm, 5JH-F = 15.4 Hz, 1H, C6H of minor diastereomer), 7.13 (dd, 3JH-F = 5.6 Hz, 4JH-H = 1.2 Hz, 1H, C4H of major diastereomer), 7.23 (dd, 3JH-F = 9.3 Hz, 4JH-H = 1.2 Hz, 1H, C4H of minor diastereomer), 7.23−7.37 (m, 4H, CH, Ar of both diastereomers), 7.41−7.46 (m, 6H, CH, Ar of both diastereomers), 7.54−7.60 (m, 8H, CH, Ar of both diastereomers). 19F-NMR (CDCl3): δ −140.3 (dd, 5JF-H = 15.4 Hz, 3JF-H = 9.3 Hz, 1F, CF of minor diastereomer), −142.4 (dd, 5JF-H = 12.1 Hz, 3JF-H = 5.6 Hz, 1F, CF of major diastereomer). 13C-NMR (CDCl3): δ 20.9 (s, CH3 of minor diastereomer), 21.0 (s, CH3 of major diastereomer), 54.2 (s, COOCH3 of minor diastereomer), 54.3 (s, COOCH3 of major diastereomer), 61.7 (d, 4JC-F = 3.2 Hz, C6H of major diastereomer), 62.3 (d, 4JC-F = 2.7 Hz, C6H of minor diastereomer), 84.8 (d, 1JC-F = 189.1 Hz, CF of major diastereomer), 86.1 (d, 1JC-F = 191.4 Hz, CF of minor diastereomer), 121.2 (d, 2JC-F = 24.3 Hz, C4H of major diastereomer), 122.5 (d, 2JC-F = 26.3 Hz, C4H of minor diastereomer), 127.25 (s, Ar of minor diastereomer), 127.29 (s, Ar of major diastereomer), 127.7 (s, Ar of minor diastereomer), 127.9 (s, Ar of minor diastereomer), 128.1 (s, Ar of major diastereomer), 128.5 (s, Ar of major diastereomer), 128.6 (s, Ar of minor diastereomer), 128.9 (s, Ar of major diastereomer), 134.4 (d, 5JC-F = 7.0 Hz, Cq, Ar of major diastereomer), 134.8 (d, 5JC-F = 3.8 Hz, Cq, Ar of minor diastereomer), 140.5 (s, Cq, Ar of both diastereomers), 141.8 (s, Cq, Ar of minor diastereomer), 142.0 (s, Cq, Ar of major diastereomer), 154.7 (d, 3JC-F = 9.0 Hz, C5 of minor diastereomer), 155.7 (d, 3JC-F = 8.7 Hz, C5 of major diastereomer), 157.1 (d, 2JC-F = 20.8 Hz, C2 of major diastereomer), 157.6 (d, 2JC-F = 20.0 Hz, C2 of minor diastereomer), 165.8 (d, 2JC-F = 28.8 Hz, C=O of minor diastereomer), 166.1 (d, 2JC-F = 29.4 Hz, C=O of major diastereomer). HRMS (ESI+): Calcd for C20H17FN2O4 [M + H]: 369.1251; found 369.1264.

3.2.3. Methyl 3-fluoro-6-(2-methoxyphenyl)-2-methyl-5-nitro-3,6-dihydropyridine-3-carboxylate (2c)

Yellow oil. Yield 0.145 g (90%). Mixture of diastereomers (the ratio is 45:55 according to the 19F and 1H-NMR spectra). 1H-NMR (CDCl3): δ 2.18−2.20 (m, 6H, CH3 of both diastereomers), 3.85 (s, 3H, COOCH3 of minor diastereomer), 3.89 (s, 3H, COOCH3 of major diastereomer), 3.91 (s, 3H, OCH3 of minor diastereomer), 3.96 (s, 3H, OCH3 of major diastereomer), 6.21−6.26 (dm, 5JH-F = 12.6 Hz, 1H, C6H of major diastereomer), 6.69−6.75 (dm, 5JH-F = 16.6 Hz, 1H, C6H of minor diastereomer), 6.84−6.89 (m, 1H, CH, Ar), 6.90−6.94 (m, 2H, 2 × CH, Ar of both diastereomers), 6.96−7.00 (m, 2H, CH, Ar of both diastereomers), 7.03−7.05 (m, 1H, CH, Ar), 7.07 (dd, 3JH-F = 6.2 Hz, 4JH-H = 1.6 Hz, 1H, C4H of major diastereomer), 7.22 (dd, 3JH-F = 9.0 Hz, 4JH-H = 1.4 Hz, 1H, C4H of minor diastereomer); 7.27−7.31 (m, 2H, CH, Ar of both diastereomers). 19F-NMR (CDCl3): δ −139.9 (dd, 5JF-H = 16.6 Hz, 3JF-H = 9.0 Hz, 1F, CF of minor diastereomer), −144.3 (dd, 5JF-H = 12.6 Hz, 3JF-H = 6.2 Hz, 1F, CF of major diastereomer). 13C-NMR (CDCl3): δ 20.8 (s, 2 × CH3 of both diastereomers), 54.2 (s, COOCH3 of minor diastereomer), 54.3 (s, COOCH3 of major diastereomer), 55.7 (s, OCH3 of major diastereomer), 55.9 (d, 4JC-F = 2.6 Hz, C6H of minor diastereomer), 56.2 (s, OCH3 of minor diastereomer), 56.8 (d, 4JC-F = 3.2 Hz, C6H of major diastereomer), 86.16 (d, 1JC-F = 190.1 Hz, CF of major diastereomer), 86.23 (d, 1JC-F = 191.3 Hz, CF of minor diastereomer), 120.86 (s, Ar of minor diastereomer), 120.90 (d, 2JC-F = 24.8 Hz, C4H of major diastereomer), 121.3 (s, CH, Ar of major diastereomer), 122.6 (d, 2JC-F = 26.6 Hz, C4H of minor diastereomer), 123.6 (s, Ar of major diastereomer), 125.6 (s, Ar of minor diastereomer), 127.6 (s, Ar of minor diastereomer), 129.03−129.06 (m, Cq, Ar of minor diastereomer), 130.52−130.56 (m, Cq, Ar of major diastereomer), 144.7 (s, C-OCH3, Ar of both diastereomers), 155.13−155.31 (m, C5 of both diastereomers), 157.3 (s, C2 of major diastereomer), 157.4 (s, C2 of minor diastereomer), 166.0 (d, 2JC-F = 30.7 Hz, C=O of both diastereomers). MS: m/z = 323 [M + 1] (100%).

3.2.4. Methyl 3-fluoro-2-methyl-5-nitro-6-(3,4,5-trimethoxyphenyl)-3,6-dihydropyridine- 3-carboxylate (2d)

Yellow brown oil. Yield 0.172 g (90%). Mixture of diastereomers (the ratio is 20:80 according to the 19F and 1H-NMR spectra). 1H-NMR (CDCl3): δ 2.21 (d, 4JH-F = 1.7 Hz, 3H, CH3 of minor diastereomer), 2.24 (t, 4JH-F = 1.4 Hz, 3H, CH3 of major diastereomer), 3.81 (s, 6H, OCH3, Ar of both diastereomers), 3.83 (s, 6H, 2 × OCH3, Ar of minor diastereomer), 3.85 (s, 6H, 2 × OCH3, Ar of major diastereomer), 3.91 (s, 3H, COOCH3 of minor diastereomer), 3.94 (s, 3H, COOCH3 of major diastereomer), 5.77−5.81 (dm, 5JH-F = 12.2 Hz, 1H, C6H of minor diastereomer), 6.02−6.07 (dm, 5JH-F = 15.8 Hz, 1H, C6H of major diastereomer), 6.43 (s, 2H, 2 × CH, Ar of minor diastereomer), 6.62 (s, 2H, 2 × CH, Ar of major diastereomer), 7.08 (dd, 3JH-F = 5.4 Hz, 4JH-H = 1.1 Hz, 1H, C4H of minor diastereomer), 7.14 (dd, 3JH-F = 9.2 Hz, 4JH-H = 1.2 Hz, 1H, C4H of major diastereomer). 19F-NMR (CDCl3): δ −140.3 (dd, 5JF-H = 15.8 Hz, 3JF-H = 9.2 Hz, 1F, CF of major diastereomer), −141.6 (dd, 5JF-H = 12.2 Hz, 3JF-H = 5.4 Hz, 1F, CF of minor diastereomer). 13C-NMR (CDCl3): δ 21.0 (s, CH3 of major diastereomer), 21.1 (s, CH3 of minor diastereomer), 54.3 (s, COOCH3, Ar of minor diastereomer), 54.4 (s, COOCH3, Ar of major diastereomer), 56.27 (s, 2 × OCH3 of minor diastereomer), 56.33 (s, 2 × OCH3 of minor diastereomer), 60.9 (s, OCH3 of both diastereomers), 62.1 (d, 4JC-F = 3.4 Hz, C6H of minor diastereomer), 62.7 (d, 4JC-F = 2.8 Hz, C6H of major diasteeomer), 85.7 (d, 1JC-F = 189.2 Hz, CF of minor diastereomer), 86.1 (d, 1JC-F = 194.2 Hz, CF of major diastereomer), 105.2 (s, CH, Ar of minor diasrereomer), 105.7 (s, CH, Ar of major diastereomer), 121.0 (d, 2JC-F = 24.1 Hz, C4H of minor diastereomer), 121.8 (d, 2JC-F = 25.4 Hz, C4H of major diastereomer), 130.8 (d, 5JC-F = 7.0 Hz, Cq, Ar of minor diastereomer), 131.0 (d, 5JC-F = 4.3 Hz, Cq, Ar of major diastereomers), 138.4 (s, C-OCH3, Ar of major diastereomer), 138.5 (s, C-OCH3, Ar of minor diastereomer), 153.7 (s, 2 × C-OCH3, Ar of major diastereomer), 153.9 (s, 2 × C-OCH3, Ar of minor diastereomer), 155.1 (d, 3JC-F = 9.0 Hz, C5 of major diastereomer), 155.8 (d, 3JC-F = 8.4 Hz, C5 of minor diastereomer), 157.2 (d, 2JC-F = 20.5 Hz, C2 of minor diastereomers), 157.5 (d, 2JC-F = 19.6 Hz, C2 of major diastereomer), 166.0 (d, 2JC-F = 29.0 Hz, C=O of minor diastereomer); 166.4 (d, 2JC-F = 27.5 Hz, C=O of minor diastereomer). MS: m/z = 383 [M + 1] (100%).

3.2.5. Methyl 2-ethyl-3-fluoro-6-(2-methoxyphenyl)-5-nitro-3,6-dihydropyridine-3-carboxylate (2e)

Yellow oil. Yield 0.163 g (97%). Mixture of diastereomers (the ratio is 50:50 according to the 19F and 1H-NMR spectra). 1H-NMR (CDCl3): δ 1.08−1.14 (m, 6H, 2 × CH2CH3 of both diastereomers); 2.34−2.44 (m, 2H, CH2CH3), 2.51−2.64 (m, 2H, CH2CH3), 3.84 (s, 3H, OCH3), 3.87 (s, 3H, COOCH3), 3.89 (s, 3H, OCH3), 3.95 (s, 3H, COOCH3), 6.20−6.25 (dm, 5JH-F = 12.6 Hz, 1H, C6H), 6.71−6.77 (dm, 5JH-F = 17.0 Hz, 1H, C6H), 6.84−7.06 (m, 6H, 6 × CH, Ar), 7.00 (dd, 3JH-F = 6.5 Hz, 4JH-H = 1.6 Hz, 1H, C4H), 7.16 (dd, 3JH-F = 9.1 Hz, 4JH-H = 1.2 Hz, 1H, C4H), 7.26−7.30 (m, 2H, 2 × CH, Ar of both diastereomers). 19F-NMR (CDCl3): δ −140.5 (dd, 5JF-H = 17.0 Hz, 3JF-H = 9.1 Hz, 1F, CF), −145.1 (dd, 5JF-H = 12.6 Hz, 3JF-H = 6.5 Hz, 1F, CF). 13C-NMR (CDCl3): δ 10.8 (s, CH2CH3), 10.9 (s, CH2CH3), 27.0 (s, CH2CH3), 27.1 (s, CH2CH3), 54.0 (s, COOCH3), 54.1 (s, COOCH3), 55.7 (s, OCH3, Ar), 55.9 (d, 4JC-F = 2.6 Hz, C6H), 56.3 (s, OCH3, Ar), 56.9 (d, 4JC-F = 3.4 Hz, C6H), 86.3 (d, 1JC-F = 190.0 Hz, CF), 86.4 (d, 1JC-F = 190.3 Hz, CF), 111.85 (s, CH, Ar), 111.91 (s, CH, Ar), 120.7 (s, CH, Ar), 121.0 (d, 2JC-F = 25.4 Hz, C4H), 121.2 (s, CH, Ar), 122.4 (d, 2JC-F = 25.7 Hz, C4H), 124.3 (d, 5JC-F = 6.3 Hz, Cq, Ar), 124.9 (d, 5JC-F = 3.9 Hz, Cq, Ph), 127.8 (s, CH, Ar), 129.2 (s, CH, Ar), 130.1 (s, CH, Ar), 130.2 (s, CH, Ar), 155.7 (d, 3JC-F = 10.1 Hz, C5), 157.5 (d, 3JC-F = 5.8 Hz, C5), 160.4 (d, 2JC-F = 19.4 Hz, C2 of both diastereomers), 166.2 (d, 2JC-F = 29.1 Hz, C=O), 166.7 (d, 2JC-F = 30.2 Hz, C=O). MS: m/z = 337 [M + 1] (100%).

3.2.6. Methyl 3-fluoro-2-methyl-5-nitro-6-(4-nitrophenyl)-3,6-dihydropyridine-3-carboxylate (2f)

Yellow oil. Yield 0.169 g (94%). Mixture of diastereomers (the ratio is 50:50 according to the 19F and 1H-NMR spectra). 1H-NMR (CDCl3): 2.22 (dd, 4JH-F = 1.9 Hz, 4JH-H =0.9 Hz, 3H, CH3), 2.23−2.24 (dm, 4JH-F = 1.6 Hz, 3H, CH3), 3.91 (s, 3H, COOCH3), 3.92 (s, 3H, COOCH3), 5.91−5.96 (dm, 5JH-F = 11.4 Hz, 1H, C6H), 6.24−6.28 (dm, 5JH-F = 14.4 Hz, 1H, C6H), 7.21 (dd, 3JH-F = 5.7 Hz, 4JH-H = 1.3 Hz, 1H, C4H), 7.30 (dd, 3JH-F = 9.5 Hz, 4JH-H = 1.1 Hz, 1H, C4H), 7.41−7.44 (dm, 3JH-H = 8.7 Hz, 2H, 2×CH, Ar), 7.54−7.58 (dm, 3JH-H = 8.7 Hz, 2H, 2×CH, Ar), 8.20−8.25 (m, 4H, 2 × CH, Ar of both diastereomers). 19F-NMR (CDCl3): δ −141.6 (dd, 5JF-H = 14.4 Hz, 3JF-H = 9.5 Hz, 1F, CF), −143.0 (dd, 5JF-H = 11.4 Hz, 3JF-H = 5.7 Hz, 1F, CF). 13C-NMR (CDCl3): δ 20.9 (s, CH3), 21.1 (s, CH3), 54.5 (s, 2 × COOCH3 of both diastereomers), 61.1 (d, 4JC-F = 3.3 Hz, C6H), 61.9 (d, 4JC-F = 2.7 Hz, C6H), 85.8 (d, 1JC-F = 190.2 Hz, CF), 86.2 (d, 1JC-F = 194.1 Hz, CF), 122.7 (d, 2JC-F = 24.6 Hz, C4H), 123.9 (d, 2JC-F = 26.4 Hz, C4H), 124.3 (s, Ar), 124.5 (s, Ar), 129.2 (s, Ar), 129.4 (s, Ar), 142.86 (d, 5JC-F = 6.9 Hz, Cq, Ar), 142.92 (d, 5JC-F = 4.0 Hz, Cq, Ar), 148.1 (s, C−NO2, Ar), 148.2 (s, C−NO2, Ar), 153.4 (d, 3JC-F = 8.6 Hz, C5), 154.4 (d, 3JC-F = 8.4 Hz, C5), 158.6 (d, 2JC-F = 20.9 Hz, C2), 159.0 (d, 2JC-F = 20.0 Hz, C2), 165.6 (d, 2JC-F = 28.6 Hz, C=O of both diastereomers). MS: m/z = 338 [M + 1] (100%).

3.2.7. Methyl 3-fluoro-6-(3-fluorophenyl)-2-methyl-5-nitro-3,6-dihydropyridine-3-carboxylate (2g)

Yellow oil. Yield 0.136 g (88%). Mixture of diastereomers (the ratio is 50:50 according to the 19F and 1H-NMR spectra). 1H-NMR (CDCl3): δ 2.20−2.21 (dm, 4JH-F = 1.8 Hz, 3H, CH3), 2.22−2.23 (dm, 4JH-F = 1.5 Hz, 3H, CH3), 3.90 (s, 3H, COOCH3), 3.91 (s, 3H, COOCH3), 5.82−5.87 (dm, 5JH-F = 11.8 Hz, 1H, C6H), 6.14−6.18 (dm, 5JH-F = 14.9 Hz, 1H, C6H), 6.93−6.96 (dm, 3JH-F = 9.5 Hz, 1H, CH, Ar), 7.00−7.06 (m, 4H, CH, Ar of both diastereomers), 7.12 (dd, 3JH-F = 5.6 Hz, 4JH-H = 1.2 Hz, 1H, C4H), 7.17−7.20 (dm, 3JH-F = 7.7 Hz, 1H, CH, Ar ), 7.22 (dd, 3JH-F = 9.4 Hz, 4JH-H = 1.1 Hz, 1H, C4H), 7.31−7.37 (m, 2H, CH, Ar of both diastereomers). 19F-NMR (CDCl3): δ −111.46 −(−111.52) (m, 1F, CF, Ar), −111.73−(−111.79) (m, 1F, CF, Ar), −140.7 (dd, 5JF-H = 14.9 Hz, 3JF-H = 9.5 Hz, 1F, CF), −142.8 (dd, 5JF-H = 11.8 Hz, 3JF-H = 5.6 Hz, 1F, CF). 13C-NMR (CDCl3): δ 20.8 (s, CH3), 21.0 (s, CH3), 54.3 (s, COOCH3), 54.4 (s, COOCH3), 61.4 (dd, 4JC-F = 3.2 Hz, 4JC-F = 2.0 Hz, C6H), 62.0 (t, 4JC-F = 2.2 Hz, C6H), 84.7 (d, 1JC-F = 190.7 Hz, CF), 86.0 (d, 1JC-F = 191.9 Hz, CF), 115.2 (d, 2JC-F = 23.2 Hz, CH, Ar), 115.3 (d, 2JC-F = 22.4 Hz, CH, Ar), 115.9 (d, 2JC-F = 21.1 Hz, CH, Ar), 116.1 (d, 2JC-F = 21.1 Hz, CH, Ar), 121.7 (d, 2JC-F = 24.2 Hz, C4H), 122.9 (d, 2JC-F = 26.4 Hz, C4H), 123.8 (d, 4JC-F = 3.0 Hz, CH, Ar), 124.3 (d, 4JC-F = 3.1 Hz, CH, Ar), 130.7 (d, 3JC-F = 8.5 Hz, CH, Ar), 130.9 (d, 3JC-F = 8.2 Hz, CH, Ar), 137.91−138.06 (dm, 5JC-F = 7.0 Hz, Cq, Ar), 138.2 (dd, 5JC-F = 4.1 Hz, 3JC-F = 7.4 Hz, Cq, Ar), 154.2 (d, 3JC-F = 9.0 Hz, C5), 155.2 (d, 3JC-F = 8.5 Hz, C5), 157.7 (d, 2JC-F = 20.7 Hz, C2), 158.1 (d, 2JC-F = 19.8 Hz, C2), 163.0 (d, 1JC-F = 246.2 Hz, CF, Ar), 163.1 (d, 1JC-F = 247.6 Hz, CF, Ar), 165.5 (d, 2JC-F = 29.0 Hz, C=O), 165.9 (d, 2JC-F = 29.6 Hz, C=O). MS: m/z = 311 [M + 1] (100%).

3.2.8. Methyl 6-(1,3-diphenyl-1H-pyrazol-4-yl)-3-fluoro-2-methyl-5-nitro-3,6-dihydropyridine- 3-carboxylate (2h)

Yellow brown oil. Yield 0.150 g (89%). Mixture of diastereomers (the ratio is 10:90 according to the 19F and 1H-NMR spectra). 1H-NMR (CDCl3): δ 2.18−2.20 (dm, 4JH-F = 1.8 Hz, 3H, CH3), 2.25−2.26 (dm, 4JH-F = 1.5 Hz, 3H, CH3), 3.97 (s, 3H, COOCH3), 3.98 (s, 3H, COOCH3), 6.03−6.07 (dm, 5JH-F = 11.9 Hz, 1H, C6H of minor diastereomer), 6.27−6.32 (dm, 5JH-F = 14.0 Hz, 1H, C6H of major diastereomer), 7.02 (dd, 3JH-F = 5.8 Hz, 4JH-H = 1.5 Hz, 1H, C4H), 7.19 (dd, 3JH-F = 9.5 Hz, 4JH-H = 1.1 Hz, 1H, C4H), 7.42−7.48 (m, 8H, CH, Ph of both diastereomers), 7.50−7.55 (m, 4H, CH, Ph of both diastereomers), 7.66−7.69 (m, 4H, CH, Ph of both diastereomers), 7.87 (s, 2H, CH, pyrazolyl of both diastereomers), 8.01−8.04 (m, 4H, CH, Ph of both diastereomers). 19F-NMR (CDCl3): δ −142.6 (dd, 5JF-H = 14.0 Hz, 3JF-H = 9.5 Hz, 1F, CF of major diastereomer), −144.2 (dd, 5JF-H = 11.9 Hz, 3JF-H = 5.8 Hz, 1F, CF of minor diastereomer). 13C-NMR (CDCl3): δ 20.8 (s, CH3 of major diastereomer), 21.1 (s, CH3 of minor diastereomer), 53.7 (d, 4JC-F = 2.4 Hz, C6H of major diastereomer), 54.3 (s, COOCH3 of minor diastereomer), 54.5 (s, COOCH3 of major diastereomer), 86.6 (d, 1JC-F = 193.8 Hz, CF of major diastereomer), 117.2 (d, 5JC-F = 4.1 Hz, pyrazolyl of major diastereomer), 119.2 (s, Ph, of major diastereomer) 122.1 (d, 2JC-F = 26.3 Hz, C4H of major diastereomer), 126.9 (s, Ph of both diastereomers), 128.7 (s, CH, pyrazolyl of both diastereomers), 128.8 (s, Ph of both diastereomers), 128.9 (s, Ph of both diastereomers), 129.6 (s, Ph of both diastereomers), 132.6 (s, Cq, Ph of both diastereomers), 132.6 (s, Cq, Ph of both diastereomers), 139.9 (s, Cq, Ph of both diastereomers), 153.0 (s, C−Ph, pyrazolyl of both diastereomers), 154.8 (d, 3JC-F = 8.7 Hz, C5 of major diastereomer), 157.1 (d, 2JC-F = 20.2 Hz, C2 of major diastereomer), 166.2 (d, 2JC-F = 29.6 Hz, C=O of major diastereomer). MS: m/z = 338 [M + 1] (100%).

3.2.9. Diethyl 5-fluoro-4,6-dimethyl-2-phenyl-2,5-dihydropyridine-3,5-dicarboxylate (2k)

Pale yellow oil. Yield 0.142 g (82%). Mixture of diastereomers (the ratio is 15:85 according to the 19F and 1H-NMR spectra). 1H-NMR (CDCl3): δ 0.89 (t, 3JH-H = 7.4 Hz, 3H, COOCH2CH3 of minor diastereomer), 1.01 (t, 3JH-H = 7.4 Hz, 3H, COOCH2CH3 of major diastereomer), 1.13 (t, 3JH-H = 6.9 Hz, 3H, FCOOCH2CH3 of minor diastereomer), 1.23 (t, 3JH-H = 7.4 Hz, 3H, FCOOCH2CH3 of major diastereomer), 1.94 (d, 4JH-F = 2.1 Hz, 3H, CH3 of minor diastereomer), 2.02 (d, 4JH-F = 1.9 Hz, 3H, CH3 of major diastereomer), 2.07 (dd, 4JH-F = 1.8 Hz, 5JH-H = 1.4 Hz, 3H, CH3C=N of major diastereomer), 2.09 (dd, 4JH-F = 2.4 Hz, 5JH-H = 1.9 Hz, 3H, CH3C=N of minor diastereomer), 3.84−3.93 (m, 4H, 2 × COOCH2CH3 of both diastereomers), 4.07−4.16 (m, 4H, 2 × COOCH2CH3 of both diastereomers), 5.24−5.30 (dm, 5JH-F = 12.0 Hz, 1H, C6H of minor diastereomer), 5.57−5.62 (dm, 5JH-F = 15.5 Hz, 1H, C6H of major diastereomer), 7.11−7.34 (m, 10H, CH, Ph of both diastereomers). 19F-NMR (CDCl3): δ −145.9 (d, 5JF-H = 15.6 Hz, 1F, CF of major diastereomer), −150.4 (d, 5JF-H = 12.2 Hz, 1F, CF of minor diastereomer). 13C-NMR (CDCl3): δ 13.5 (d, 3JC-H = 4.5 Hz, CH3 of both diastereomers), 14.0 (s, COOCH2CH3 of both diastereomers), 14.1 (s, COOCH2CH3 of both diastereomers), 21.2 (s, CH3C=N of both diastereomers), 61.1 (s, COOCH2CH3 of both diastereomers), 63.2 (s, COOCH2CH3 of both diastereomers), 64.5 (d, 4JC-F = 2.5 Hz, C6H of minor diastereomer), 65.3 (d, 4JC-F = 1.8 Hz, C6H of major diastereomer), 84.65 (d, 1JC-F = 183.8 Hz, CF of major diastereomer), 127.8 (s, CH, Ph), 128.0 (s, CH, Ph), 128.3 (s, 2×CH, Ph), 128.4 (s, 2×CH, Ph), 128.5 (s, 2×CH, Ph), 128.6 (s, 2×CH, Ph), 130.7 (d, 2JC-F = 22.1 Hz, C4 of minor diastereomer), 132.0 (d, 2JC-F = 21.6 Hz, C4 of major diastereomer), 133.8 (d, 5JC-F = 4.8 Hz, Cq, Ph of major diastereomer), 134.2 (d, 5JC-F = 5.1 Hz, Cq, Ph of minor diastereomer), 138.8 (d, 3JC-F = 4.8 Hz, C5 of major diastereomer), 139.2 (d, 3JC-F = 5.4 Hz, C5 of minor diastereomer), 157.4 (d, 2JC-F = 22.7 Hz, C2 of major diastereomer), 158.5 (d, 2JC-F = 20.4 Hz, C2 of minor diastereomer), 165.9 (s, C=O), 166.2 (s, C=O), 166.5 (d, 2JC-F = 29.7 Hz, C=O, CH3CH2COOCF). MS: m/z = 348 [M + 1] (100%).

3.3. General Procedure for the Synthesis of Pyridines 3a–k

A deuterochloroform solution (3 mL) of 3-fluoro-3,6-dihydropyridines 2a–k (0.3 mmol) was maintained for 2 days in the case of compounds 2c,d,e,h,k and for 4 days in the case of compounds 2a,b,f,g at room temperature, after which the solvent was evaporated in vacuo. Pyridines 3a–k were isolated by column chromatography in 72–91% yields.

3.3.1. Methyl 2-methyl-5-nitro-6-phenylnicotinate (3a)

White powder. Yield 0.074 g (91%). Mp 93−94 °C (from ethanol). Rf: 0.54 (petroleum ether – ethyl acetate 4:1). Anal. calcd for C14H12N2O4: C, 61.76; H, 4.44; N, 10.29; found: C, 61.85; H, 4.55; N, 10.16. 1H-NMR (CDCl3): δ 2.98 (s, 3H, CH3), 3.98 (s, 3H, COOCH3), 7.47−7.49 (m, 3H, 3×CH, Ph), 7.59−7.61 (m, 2H, 2×CH, Ph), 8.69 (s, 1H, C4H). 13C-NMR (CDCl3): δ 25.4 (s, CH3), 53.0 (s, COOCH3), 123.8 (s, C3), 128.5 (s, CH, Ph), 129.0 (s, CH, Ph), 130.5 (s, CH, Ph), 135.1 (s, Cq, Ph), 135.9 (s, C4H), 143.9 (s, C5), 154.5 (s, C6), 163.5 (s, C2), 165.0 (s, C=O). MS: m/z = 273 [M + 1] (100%).

3.3.2. Methyl 6-([1,1′-biphenyl]-4-yl)-2-methyl-5-nitronicotinate (3b)

Colorless viscous oil. Yield 0.089 g (85%). Rf: 0.50 (petroleum ether – ethyl acetate 4:1). Anal. calcd for C20H16N2O4: C, 68.96; H, 4.63; N, 8.04; found: C, 69.02; H, 4.71; N, 7.96. 1H-NMR (CDCl3): δ 3.00 (s, 3H, CH3), 4.00 (s, 3H, COOCH3), 7.36−7.50 (m, 3H, Ar), 7.62−7.65 (m, 2H, Ar), 7.70 (s, 4H, Ar), 8.71 (s, 1H, C4H). MS: m/z = 349 [M + 1] (100%).

3.3.3. Methyl 6-(2-methoxyphenyl)-2-methyl-5-nitronicotinate (3c)

Colorless viscous oil. Yield 0.065 g (72%). Rf: 0.63 (petroleum ether–ethyl acetate 4:1). 1H-NMR (CDCl3): δ 2.98 (s, 3H, CH3), 3.71 (s, 3H, OCH3), 3.98 (s, 3H, COOCH3), 6.91 (d, 3JH-H = 8.4 Hz, 1H, CH, Ar), 7.16 (td, 3JH-H = 7.6 Hz, 4JH-H = 1.0 Hz, 1H, CH, Ar), 7.46 (ddd, 3JH-H = 7.6 Hz, 3JH-H = 8.4 Hz, 4JH-H = 1.7 Hz, 1H, CH, Ar), 7.73 (dd, 3JH-H = 7.6 Hz, 4JH-H = 1.7 Hz, 1H, CH, Ar), 8.74 (s, 1H, C4H). HRMS (ESI+): Calcd for C15H14N2O5 [M + H]: 303.0981; found 303.0985.

3.3.4. Methyl 2-methyl-5-nitro-6-(3,4,5-trimethoxyphenyl)nicotinate (3d)

Red brown powder. Yield 0.091 g (84%). Mp 172−173°C (from ethanol). Rf: 0.29 (petroleum ether – ethyl acetate 4:1). IR νmax (Film) 3006, 2945, 2840, 1731, 1592, 1554, 1455, 1424, 1334. 1H-NMR (CDCl3): δ 2.97 (s, 3H, CH3), 3.89 (s, 6H, 2×OCH3, Ar), 3.90 (s, 3H, OCH3, Ar), 3.98 (s, 3H, COOCH3), 6.82 (s, 2H, 2×CH, Ar), 8.63 (s, 1H, C4H). 13C-NMR (CDCl3): δ 25.4 (s, CH3), 53.0 (s, COOCH3), 56.4 (s, 2 × OCH3, Ar), 61.1 (s, OCH3, Ar), 105.8 (s, 2 × CH, Ar), 123.7 (s, C3), 130.8 (s, Cq, Ar), 134.9 (s, CH), 140.3 (s, C−OCH3, Ar), 144.0 (s, C5), 153.7 (s, 2 × OCH3, Ar), 153.8 (s, C6), 163.3 (s, C2), 164.9 (s, C=O). HRMS (ESI+): Calcd for C17H18N2O7 [M + H]: 363.1192; found 363.1201.

3.3.5. Methyl 2-ethyl-6-(2-methoxyphenyl)-5-nitronicotinate (3e)

Pale yellow oil. Yield 0.078 g (82%). Rf: 0.61 (petroleum ether–ethyl acetate 4:1). IR νmax (Film) 3082, 2977, 2840, 1733, 1598, 1456, 1354. Anal. calcd for C16H16N2O5: C, 60.76; H, 5.10; N, 8.86; found: C, 60.84; H, 5.19; N, 8.75. 1H-NMR (CDCl3): δ 1.36 (t, 3JH-H = 7.4 Hz, 3H, CH2CH3), 3.33 (t, 3JH-H = 7.4 Hz, 2H, CH2CH3), 3.72 (s, 3H, OCH3), 3.98 (s, 3H, COOCH3), 6.92 (d, 3JH-H = 8.6 Hz, 1H, CH, Ar), 7.13−7.18 (m, 1H, CH, Ar), 7.43−7.50 (m, 1H, CH, Ar), 7.76 (dd, 3JH-H = 7.6 Hz, 3JH-H = 1.7 Hz, 1H, CH, Ar), 8.70 (s, 1H, C4H). MS: m/z = 317 [M + 1] (100%).

3.3.6. Methyl 2-methyl-5-nitro-6-(4-nitrophenyl)nicotinate (3f)

White powder. Yield 0.088 g (93%). Mp 167−168 °C (from ethanol). Rf: 0.39 (petroleum ether–ethyl acetate 4:1). IR νmax (Film) 3086, 2995, 1719, 1553, 1517, 1443, 1358, 1345. 1H-NMR (CDCl3): δ 2.99 (s, 3H, CH3), 4.01 (s, 3H, COOCH3), 7.73−7.75 (dm, 3JH-H = 9.1 Hz, 2H, 2×CH, Ar), 8.32−8.34 (dm, 3JH-H = 9.1 Hz, 2H, 2×CH, Ar), 8.80 (s, 1H, C4H). 13C-NMR (CDCl3): δ 25.4 (s, CH3), 53.2 (s, COOCH3), 124.0 (s, 2×CH, Ar), 125.2 (s, C−COOCH3), 129.7 (s, 2×CH, Ar), 135.5 (s, CH), 142.2 (s, Cq, Ar), 143.7 (s, C5), 148.9 (s, C−NO2, Ar), 152.5 (s, C6), 164.2 (s, C2), 164.6 (s, C=O). HRMS (ESI+): Calcd for C14H11N3O6 [M + H]: 318.0726; found 318.0731.

3.3.7. Methyl 6-(3-fluorophenyl)-2-methyl-5-nitronicotinate (3g)

White powder. Yield 0.076 g (87%). Mp 105−107 °C (from ethanol). Rf: 0.61 (petroleum ether–ethyl acetate 4:1). IR νmax (Film) 3094, 2963, 2848, 1726, 1595, 1533, 1515, 1442, 1304. 1H-NMR (CDCl3): δ 2.98 (s, 3H, CH3), 4.00 (s, 3H, COOCH3), 7.20 (tdd, 3JH-F = 8.4 Hz, 3JH-H = 2.6 Hz, 4JH-H = 1.0 Hz, 1H, CH, Ar), 7.30−7.33 (dm, 3JH-H = 7.7 Hz, 1H, CH, Ar), 7.35−7.38 (dm, 3JH-F = 9.4 Hz, 1H, CH, Ar), 7.43 (td, 3JH-H = 8.0 Hz, 4JH-H = 5.6 Hz, 1H, CH, Ar), 8.71 (s, 1H, C4H); 19F-NMR (CDCl3): δ −111.8− (−111.9) (m, 1F, CF, Ar). 13C-NMR (CDCl3): δ 25.3 (s, CH3), 53.1 (s, COOCH3), 115.8 (d, 2JC-F = 23.7 Hz, CH, Ar), 117.5 (d, 2JC-F = 21.5 Hz, CH, Ar), 124.1 (d, 4JC-F = 3.1 Hz, CH, Ar), 124.4 (s, C3), 130.5 (d, 3JC-F = 8.1 Hz, CH, Ar), 135.2 (s, C4H), 137.9 (s, d, 3JC-F = 7.8 Hz, Cq, Ar), 143.8 (s, C5), 153.1 (d, 4JC-F = 2.6 Hz, C6), 162.9 (d, 1JC-F = 247.4 Hz, CF, Ar), 163.7 (s, C2), 164.8 (s, C=O). HRMS (ESI+): Calcd for C14H11FN2O4 [M + H]: 291.0781; found 291.0788.

3.3.8. Methyl 6-(1,3-diphenyl-1H-pyrazol-4-yl)-2-methyl-5-nitronicotinate (3h)

Red yellow powder. Yield 0.098 g (79%). Mp 160−162 °C (from ethanol). Rf: 0.41 (petroleum ether–ethyl acetate 4:1). 1H-NMR (CDCl3): δ 2.95 (s, 3H, CH3), 3.98 (s, 3H, COOCH3), 7.32−7.40 (m, 6H, CH, Ph), 7.48−7.52 (m, 2H, CH, Ph), 7.82−7.85 (m, 2H, CH, Ph), 8.39 (s, 1H, CH, pyrazolyl), 8.67 (s, 1H, C4H); 13C-NMR (CDCl3): δ 25.3 (s, CH3), 53.0 (s, COOCH3), 118.4 (s, Cq, pyrazolyl), 119.6 (s, Ph), 122.6 (s, C3), 127.3 (s, Ph), 127.9 (s, Ph), 128.7 (s, Ph), 128.8 (s, Ph), 129.4 (s, CH, pyrazolyl), 129.70 (s, Ph), 132.53 (s, Cq, Ph), 135.5 (s, C4H), 139.7 (s, Cq, Ph), 143.3 (s, C5), 148.3 (s, C6), 152.4 (s, C−Ph, pyrazolyl), 164.1 (s, C2), 164.9 (s, C=O). HRMS (ESI+): Calcd for C23H18N4O4 [M + H]: 415.1406; found 415.1408.

3.3.9. Diethyl 2,4-dimethyl-6-phenylpyridine-3,5-dicarboxylate (3k)

Pale yellow oil. Yield 0.093 g (85%). Rf: 0.60 (petroleum ether–ethyl acetate 4:1). 1H-NMR (CDCl3): δ 0.99 (t, 3JH-H = 7.1 Hz, 3H, COOCH2CH3), 1.42 (t, 3JH-H = 7.1 Hz, 3H, COOCH2CH3), 2.36 (s, 3H, CH3), 2.61 (s, 3H, CH3), 4.11 (q, 3JH-H = 7.1 Hz, 2H, COOCH2CH3), 4.45 (q, 3JH-H = 7.1 Hz, 2H, COOCH2CH3), 7.40−7.42 (m, 3H, 3×CH, Ph), 7.55−7.57 (m, 2H, 2×CH, Ph). 13C-NMR (CDCl3): δ 13.7 (s, COOCH2CH3), 14.4 (s, COOCH2CH3), 17.0 (s, CH3), 23.3 (s, CH3), 61.7 (s, COOCH2CH3), 61.9 (s, COOCH2CH3), 127.4 (s, C−COOCH2CH3), 128.4 (s, 2×CH, Ph), 128.5 (s, 2×CH, Ph), 128.6 (s, C−COOCH2CH3), 129.0 (s, CH, Ph), 139.8 (s, Cq, Ph), 143.0 (s, C−CH3), 155.4 (s, C6), 156.6 (s, C−CH3), 168.50 (s, C=O), 168.53 (s, C=O); MS: m/z = 364 [M + 1] (100%). HRMS (ESI+): Calcd for C19H19F2NO4 [M + H]: 364.1360; found 364.1366.

3.4. General Procedure for the Synthesis of Methyl 2-(fluoromethyl)-5-nitro-6-arylnicotinates 5a–d

Method A: To a stirred solution of 3-fluoro-5-nitro-3,6-dihydropyridines 2a,c,f,g (0.5 mmol) in dry acetonitrile (5 mL) in the presence of 3 Å molecular sieves cooled to 0 °C, a solution of Selectfluor® (0.340 g, 1 mmol) in dry acetonitrile (10 mL) was added in portions under an argon atmosphere. The reaction mixture was stirred for 10 min at 0 °C, after which the temperature was slowly raised to room temperature. The reaction mixture was stirred for 48 h at room temperature under an argon atmosphere, then volatile compounds were evaporated in vacuo, diethyl ether (15 mL) was added to the residue and the precipitate was filtered. According to the LC–MS data, the filtrate contained a mixture of 2-(fluoromethyl)pyridines 5a–d and pyridines 3a,c,f,g. The filtrate was evaporated in vacuo and the residue was separated by column chromatography to give methyl 2-(fluoromethyl)-5-nitro-6-arylnicotinates 5a–d in 21−43% yields and 2-methylpyridines 3a,c,f,g in 10–52% yields.
Method B: To a stirred solution of 1,2-dihydropyridines 1a,c,f,g (0.5 mmol) in dry acetonitrile (5 mL) in the presence of 3 Å molecular sieves cooled to 0 °C, a solution of Selectfluor® (0.53 g, 1.5 mmol) in dry acetonitrile (10 mL) was added dropwise under an argon atmosphere. The reaction mixture was stirred for 10 min at 0 °C, after which the temperature was slowly raised to room temperature. The reaction mixture was stirred for 48 h at room temperature under an argon atmosphere. Then the reaction mixture was evaporated in vacuo, diluted with diethyl ether (15 mL) and the insoluble precipitate was filtered. The filtrate was evaporated in vacuo to give a mixture of 2-(fluoromethyl)pyridines 5a–d and pyridines 3a,c,f,g in similar ratios as in Method A according to the 1H-NMR spectra and LC–MS data (Table 5).
Isolated yields for 2-(fluoromethyl)pyridines 5a–d and pyridines 3a,c,f,g obtained by Method A are given.

3.4.1. Methyl 2-(fluoromethyl)-5-nitro-6-phenylnicotinate (5a)

Pale yellow oil. Yield 0.046 g (32%). Rf: 0.45 (petroleum ether–ethyl acetate 4:1). Anal. calcd for C14H11FN2O4: C, 57.93; H, 3.82; N, 9.65; found: C, 58.06; H, 3.93; N, 9.52. 1H-NMR (CDCl3): δ 4.02 (s, 3H, COOCH3), 5.93 (d, 2JH-F = 46.9 Hz, 2H, CH2F), 7.49−7.51 (m, 3H, 3×CH, Ph), 7.65−6.67 (m, 2H, 2×CH, Ph), 8.71 (d, 5JH-F = 1.1 Hz, 1H, C4H). 19F-NMR (CDCl3): δ −219.4 (t, 2JF-H = 46.9 Hz, 1F, FCH2). 13C-NMR (CDCl3): δ 53.4 (s, COOCH3), 82.9 (d, 1JC-F = 174.4 Hz, FCH2), 123.1 (s, C−COOCH3), 128.7 (s, Ph), 129.1 (s, Ph), 131.0 (s, Ph), 135.15 (s, Cq, Ph), 135.20 (s, C4H), 144.9 (s, C5), 154.8 (s, C6), 159.2−156-4 (m, C2), 164.1 (s, C=O). MS: m/z = 291 [M + 1] (100%).

3.4.2. Methyl 2-(fluoromethyl)-6-(2-methoxyphenyl)-5-nitronicotinate (5b)

White powder. Yield 0.034 g (21%). Mp 143−145 °C (from ethanol). Rf: 0.38 (petroleum ether–ethyl acetate 4:1). IR νmax (Film) 3095, 2953, 2924, 2848, 1736, 1595, 1562, 1521, 1494, 1466, 1437, 1351, 1304. Anal. calcd for C15H13FN2O5: C, 56.25; H, 4.09; N, 8.75; found: C, 56.39; H, 4.19; N, 8.64. 1H-NMR (CDCl3): δ 3.72 (s, 3H, OCH3), 4.01 (s, 3H, COOCH3), 5.92 (d, 2JH-F = 46.9 Hz, 2H, CH2F), 6.90−6.92 (m, 1H, CH, Ar), 7.15−7.19 (m, 1H, CH, Ar), 7.46−7.50 (m, 1H, CH, Ar), 7.80−7.82 (m, 1H, CH, Ar), 8.77 (d, 5JH-F = 1.1 Hz, 1H, C4H). 19F-NMR (CDCl3): δ −219.1 (t, 2JF-H = 46.9 Hz, 1F, FCH2); 13C-NMR (CDCl3): 53.3 (s, COOCH3), 55.10 (s, OCH3), 82.9 (d, 1JC-F = 173.91 Hz, FCH2), 110.8 (s, CH, Ar), 121.8 (s, CH, Ar), 123.1 (s, C3), 125.3 (s, Cq, Ar), 131.4 (s, CH, Ar), 131.5 (s, CH, Ar), 134.6 (s, C4H), 145.9 (s, C5), 152.6 (s, C6), 156.7 (s, C−OMe, Ar), 159.2 (d, 2JC-F = 15.4 Hz, C2), 164.3 (s, C=O). MS: m/z = 321 [M + 1] (100%).

3.4.3. Methyl 2-(fluoromethyl)-5-nitro-6-(4-nitrophenyl)nicotinate (5c)

White powder. Yield 0.049 g (38%). Mp 150−151 °C (from ethanol). Rf: 0.43 (petroleum ether–ethyl acetate 4:1). IR νmax (Film) 3101, 2958, 2860, 1728, 1596, 1555, 1522, 1437, 1351, 1300. 1H-NMR (CDCl3): δ 4.04 (s, 3H, COOCH3), 5.94 (d, 2JH-F = 46.6 Hz, 2H, CH2F), 7.79−7.82 (m, 2H, 2×CH, Ar), 8.33−8.37 (m, 2H, 2×CH, Ar), 8.83 (d, 5JH-F = 1.1 Hz, 1H, CH). 19F-NMR (CDCl3): δ −220.1 (t, 2JF-H = 46.6 Hz, 1F, FCH2). 13C-NMR (CDCl3): δ 53.6 (s, COOCH3), 82.6 (d, 1JC-F = 175.8 Hz, FCH2), 124.1 (s, 2×CH, Ar), 124.6 (s, C3), 129.9 (s, 2×CH, Ar), 135.6 (s, C4H), 141.4 (s, C5), 145.0 (s, Cq, Ar), 149.1 (s, C−NO2, Ar), 152.8 (s, C6), 159.8 (d, 2JC-F = 15.0 Hz, C2), 163.6 (s, C=O); MS: m/z = 336 [M + 1] (100%). HRMS (ESI+): Calcd for C14H10FN3O6 [M + H]: 336.0632; found 336.0634.

3.4.4. Methyl 2-(fluoromethyl)-6-(3-fluorophenyl)-5-nitronicotinate (5d)

White powder. Yield 0.057 g, (43%). Mp 107−109 °C (from ethanol). Rf: 0.42 (petroleum ether–ethyl acetate 4:1). IR νmax (Film) 3098, 2976, 2919, 2861, 1714, 1597, 1557, 1519, 1436, 1351, 1309. 1H-NMR (CDCl3): δ 4.02 (s, 3H, COOCH3), 5.93 (d, 2JH-F = 46.6 Hz, 2H, CH2F), 7.20−7.25 (m, 1H, CH, Ar), 7.36−7.48 (m, 3H, 3×CH, Ar), 8.73 (d, 5JH-F = 0.6 Hz, 1H, CH). 19F-NMR (CDCl3): δ −111.45–−111.51 (m, 1F, CF, Ar), −219.6 (t, 2JF-H = 46.6 Hz, 1F, FCH2). 13C-NMR (CDCl3): δ 54.5 (s, COOCH3), 82.7 (d, 1JC-F = 174.7 Hz, FCH2), 116.0 (d, 2JC-F = 23.5 Hz, CH, Ar), 118.0 (d, 2JC-F = 20.9 Hz, CH, Ar), 123.8 (s, CH, Ar), 124.3 (d, 3JC-F = 3.2 Hz, C3), 130.7 (d, 3JC-F = 8.2 Hz, CH, Ar), 135.3 (s, CH), 137.2 (d, 3JC-F = 7.1 Hz, Cq, Ar), 145.0 (s, C5), 153.4 (d, 4JC-F = 3.1 Hz, C6), 159.3 (d, 2JC-F = 15.9 Hz, C2), 163.0 (d, 1JC-F = 247.4 Hz, CF, Ar), 163.9 (s, C=O). MS: m/z = 309 [M + 1] (100%). HRMS (ESI+): Calcd for C14H10F2N2O4 [M + H]: 309.0687; found 309.0692.

4. Conclusions

A series of new fluorinated 3,6-dihydropyridines 2a–k can be obtained by the reaction of 1,2-dihydropyridines 1a–k with Selectfluor®. According to quantum chemical calculations, the 3,6-dihydropyridine ring of 3-fluoro-3,6-dihydropyridines 2a–k was shown to be planar or near planar. The large values of the long-range 5J (1H,19F) coupling constants registered in the 1H and 19F-NMR spectra of compounds 2 were apparently due to the homoallyl long-range coupling transmitted through π-electrons across a double bond of the heterocycle rather than by through-space interaction. The elimination of hydrogen fluoride under mild conditions can easily convert 3-Fluoro-3,6-dihydropyridines 2a–k to corresponding pyridines 3a–k. A new approach to the synthesis of methyl 2-(fluoromethyl)-5-nitro-6-arylnicotinates 5a–d by the reaction of 3-fluoro-2-methyl-5-nitro-3,6-dihydropyridines 2a,c,f,g or 1,2-dihydropyridines 1a,c,f,g with Selectfluor® has been also proposed.

Supplementary Materials

The following are available online: one-dimensional 1H, 19F, 13C and two-dimensional {1H−1H} COSY, {13C−1H} HSQC, {13C−1H} HMBC-NMR spectral data of compounds 2a–k, 3a–k and 5a–d (file type pdf), the optimised structures of compounds 2a–k are provided in Gaussian output files.

Author Contributions

N.V.P., Y.G.S. and A.S. conceived and designed the experiments; N.V.P., B.V., M.R., and A.P. performed the experiments; N.V.P., K.P., M.P., R.M. analysed the data; K.P., and A.S. contributed reagents/materials/analysis tools; and N.V.P., and Y.G.S. wrote the paper. All authors have read and agreed to the published version of the manuscript.

Funding

This research was supported by the PostDoc project Nr.1.1.1.2/VIAA/2/18/373 of N. Pikun entitled as “Electrophilic fluorination as an effective tool for the synthesis of new bioactive molecules and studies of fluorine substitution effects on the physicochemical properties of obtained compounds”.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Petrov, V.A. Fluorinated Heterocyclic Compounds: Synthesis, Chemistry, and Applications; Wiley: Hoboken, NJ, USA, 2009; pp. 1–432. ISBN 9780470452110. [Google Scholar]
  2. Gakh, A.A.; Kirk, K.L. Fluorinated Heterocycles. In ACS Symposium Series; American Chemical Society: Washington, DC, USA, 2009; Volume 1003, pp. 3–20. ISBN 9780841269538. [Google Scholar]
  3. Nenajdenko, V. Fluorine in heterocyclic chemistry: Volume 2: 6-Membered heterocycles. In Fluorine in Heterocyclic Chemistry: Volume 2: 6-Membered Heterocycles; Springer International Publishing: Berlin, Germany, 2014; pp. 1–760. ISBN 9783319044354. [Google Scholar]
  4. Wang, J.; Scott, A.I. Fluoro-decarboxylation of pyrrolecarboxylic acids by F–TEDA–BF4—A convenient general synthesis of fluoropyrroles. J. Chem. Soc. Chem. Commun. 1995, 23, 2399–2400. [Google Scholar] [CrossRef]
  5. Hiramatsu, K.; Tamamura, H. A Mild Method for the Direct Fluorination of Pyrroles by Using a Lipophilic Anionic Phase-Transfer Catalyst. European J. Org. Chem. 2016, 2016, 3491–3494. [Google Scholar] [CrossRef]
  6. Forrest, A.K.; O’Hanlon, P.J. The preparation and lithiation of bromofluorofurans via a novel fluorodecarboxylation. Tetrahedron Lett. 1995, 36, 2117–2118. [Google Scholar] [CrossRef]
  7. Kobarfard, F.; Kauffman, J.M.; Boyko, W.J. Attempted syntheses of aminofluorothiophenes. J. Heterocycl. Chem. 1999, 36, 1247–1251. [Google Scholar] [CrossRef]
  8. Wang, X.; Seth, P.P.; Ranken, R.; Swayze, E.E.; Migawa, M.T. Synthesis and Biological Activity of 5-Fluorotubercidin. Nucleosides Nucleotides Nucleic Acids 2004, 23, 161–170. [Google Scholar] [CrossRef]
  9. Thiyagarajan, A.; Salim, M.T.A.; Balaraju, T.; Bal, C.; Baba, M.; Sharon, A. Structure based medicinal chemistry approach to develop 4-methyl-7-deazaadenine carbocyclic nucleosides as anti-HCV agent. Bioorganic Med. Chem. Lett. 2012, 22, 7742–7747. [Google Scholar] [CrossRef]
  10. O’Neill, P.M.; Storr, R.C.; Park, B.K. Synthesis of the 8-aminoquinoline antimalarial 5-fluoroprimaquine. Tetrahedron 1998, 54, 4615–4622. [Google Scholar] [CrossRef]
  11. Tang, P.; Ritter, T. Silver-mediated fluorination of aryl silanes. Tetrahedron 2011, 67, 4449–4454. [Google Scholar] [CrossRef] [Green Version]
  12. Gu, Q.; Vessally, E. N-Fluorobenzenesulfonimide: A useful and versatile reagent for the direct fluorination and amination of (hetero)aromatic C–H bonds. RSC Adv. 2020, 10, 16756–16768. [Google Scholar] [CrossRef]
  13. Takeuchi, Y.; Tarui, T.; Shibata, N. A novel and efficient synthesis of 3-fluorooxindoles from indoles mediated by Selectfluor. Org. Lett. 2000, 2, 639–642. [Google Scholar] [CrossRef]
  14. Bisht, G.S.; Gnanaprakasam, B. Transition-metal-free addition reaction for the synthesis of 3-(aminobenzylidene/aminoalkylidene)indolin-2-ones and its synthetic applications. J. Org. Chem. 2019, 84, 13516–13527. [Google Scholar] [CrossRef] [PubMed]
  15. Shibata, N.; Tarui, T.; Doi, Y.; Kirk, K.L. Synthesis of fluorogypsetin and fluorobrevianamide E by a novel fluorination - Cyclization of cyclo-L-Trp-L-AAs. Angew. Chemie Int. Ed. 2001, 40, 4461–4463. [Google Scholar] [CrossRef]
  16. Yuan, X.; Yao, J.F.; Tang, Z.Y. Decarboxylative Fluorination of Electron-Rich Heteroaromatic Carboxylic Acids with Selectfluor. Org. Lett. 2017, 19, 1410–1413. [Google Scholar] [CrossRef] [PubMed]
  17. Hodson, H.F.; Madge, D.J.; Slawin, A.N.Z.; Widdowson, D.A.; Williams, D.J. Electrophilic fluorination in the synthesis of new fluoroindoles. Tetrahedron 1994, 50, 1899–1906. [Google Scholar] [CrossRef]
  18. Jiang, X.; Wang, H.; He, H.; Wang, W.; Wang, Y.; Ke, Z.; Yeung, Y.-Y. Enantioseletive Fluorination of 3-Functionalized Oxindoles Using Electron-rich Amino Urea Catalyst. Adv. Synth. Catal. 2018, 360, 4710–4714. [Google Scholar] [CrossRef]
  19. Baudoux, J.; Salit, A.; Cahard, D.; Plaquevent, J.C. Ionic liquids as solvents of choice for electrophilic fluorination: Fluorination of indoles by F-TEDA-BF4. Tetrahedron Lett. 2002, 43, 6573–6574. [Google Scholar] [CrossRef]
  20. Yang, Q.; Dai, G.L.; Yang, Y.M.; Luo, Z.; Tang, Z.Y. Solvent Effects: Syntheses of 3,3-Difluorooxindoles and 3-Fluorooxindoles from Hydrazonoindolin-2-one by Selectfluor. J. Org. Chem. 2018, 83, 6762–6768. [Google Scholar] [CrossRef]
  21. Li, J.; Cai, Y.; Chen, W.; Liu, X.; Lin, L.; Feng, X. Highly enantioselective fluorination of unprotected 3-substituted oxindoles: One-step synthesis of BMS 204352 (MaxiPost). J. Org. Chem. 2012, 77, 9148–9155. [Google Scholar] [CrossRef] [PubMed]
  22. Shibata, N.; Suzuki, E.; Asahi, T.; Shiro, M. Enantioselective fluorination mediated by cinchona alkaloid derivatives/Selectfluor combinations: Reaction scope and structural information for N-fluorocinchona alkaloids. J. Am. Chem. Soc. 2001, 123, 7001–7009. [Google Scholar] [CrossRef]
  23. Abramovitch, R.A. The Chemistry of Heterocyclic Compounds, 14, Parts 1-4, Supplement: Pyridine and Its Derivatives. In The Chemistry of Heterocyclic Compounds; John Wiley & Sons: Hoboken, NJ, USA, 2007; ISBN 9780470188132. [Google Scholar]
  24. Van Der Puy, M. Direct fluorination of substituted pyridines. Tetrahedron Lett. 1987, 28, 255–258. [Google Scholar] [CrossRef]
  25. Anders, E.; Opitz, A.; Bauer, W. Remote Controlled Nucleophilicity, 21: Lithiated Cα-Substituted 4-Methylpyridines. Synthesis (Stuttg) 1991, 1991, 1221–1227. [Google Scholar] [CrossRef]
  26. Ying, W.; DesMarteau, D.D.; Gotoh, Y. N-fluoro-bis[(trifluoromethyl)sulfonyl]imide: Electrophilic fluorination of imines and some methyl-substituted pyridines. Tetrahedron 1996, 52, 15–22. [Google Scholar] [CrossRef]
  27. Baudoux, J.; Cahard, D. Electrophilic Fluorination with N-F Reagents. In Organic Reactions; John Wiley & Sons, Inc.: Hoboken, NJ, USA, 2008; pp. 1–326. [Google Scholar]
  28. Moberg, C.; Adolfsson, H.; Wärnmark, K.; Norrby, P.-O.; Marstokk, K.-M.; Møllendal, H. Conformational Preference of 2-(Halomethyl)- and 2-(Oxymethyl)Pyridines: Microwave Spectrum, Ab Initio, and MM3 Studies of 2-(Fluoromethyl)Pyridine. Chem. A Eur. J. 1996, 2, 516–522. [Google Scholar] [CrossRef]
  29. Andrews, S.P.; Brown, G.A.; Congreve, M.S.; Mason, J.S.; Richardson, C.M. 1,2,4-Triazine-4-amine derivatives. PCT Int. Appl. WO2011095625 A, 2011. [Google Scholar]
  30. Pikun, N.V.; Kolesnyk, N.V.P.; Rusanov, E.B.; Plotniece, A.; Rucins, M.; Sobolev, A.; Shermolovich, Y.G. Synthesis of fluorinated 2,6-heptanediones and 2-oxa-6-azabicyclo[2.2.2]octanes from 1,4-dihydropyridines. Tetrahedron 2018, 74, 2884–2890. [Google Scholar] [CrossRef]
  31. Pikun, N.V.; Kolesnyk, N.V.P.; Rusanov, E.B.; Plotniece, A.; Sobolev, A.; Domracheva, I.; Shermolovich, Y.G. Contrasting reactivity of fluorinated 2,6-heptanediones towards amines and ammonia, leading to cyclohexanediones or 2-oxa-6-azabicyclo[2.2.2]octanes and evaluation of their cytotoxicity. New J. Chem. 2019, 43, 10537–10544. [Google Scholar] [CrossRef]
  32. Ananthakrishnan, R.; Gazi, S. [Ru(bpy)3]2+ aided photocatalytic synthesis of 2-arylpyridines via Hantzsch reaction under visible irradiation and oxygen atmosphere. Catal. Sci. Technol. 2012, 2, 1463–1471. [Google Scholar] [CrossRef]
  33. Eisner, U.; Sadeghi, M.M. Isomerisation of dihydropyridines. Tetrahedron Lett. 1978, 19, 299–302. [Google Scholar] [CrossRef]
  34. Reine, I.; Muceniece, D.; Lusis, V.; Kemme, A. 2-Azabicyclo[2.2.2]oct-7-enes. 1. Synthesis from polysubstituted 1,2-dihydropyridines. Heterocycl. Commun. 2002, 8, 173–178. [Google Scholar] [CrossRef] [Green Version]
  35. Ondrus, T.A.; Knaus, E.E.; Ciam, C.S. Some reactions of 1,2-dihydropyridines with cyanogen azide. Synthesis of üiazabieyclo[4.1.0]hept-4-enes. J. Heterocycl. Chem. 1979, 16, 409–410. [Google Scholar] [CrossRef]
  36. Xu, Y.; Wang, Y.; Zhu, S.; Zhu, G.; Jia, Y.; Huang, Q. Synthesis of N-(1,2,3,6-tetrahydropyridylidene)-fluoroalkanesulfonylamides from reactions of per(poly)fluoroalkanesulfonyl azides with 1,2-dihydropyridines. J. Fluor. Chem. 2000, 106, 133–138. [Google Scholar] [CrossRef]
  37. Francis, R.F.; Crews, C.D.; Scott, B.S. Identification of 2,5-Dihydropyridine Intermediates in the Reactions of 2-Alkyl(Phenyl)-1-lithio-1,2-dihydropyridines with Alkyl Halides. J. Org. Chem. 1978, 43, 3227–3230. [Google Scholar] [CrossRef]
  38. Giam, C.S.; Knaus, E.E.; Pasutto, F.M. Carbon vs. Nitrogen Acylation in Reactions of Organolithium-Pyridine Adducts with Acid Chlorides and Esters. J. Org. Chem. 1974, 39, 3565–3568. [Google Scholar] [CrossRef]
  39. Giam, C.S.; Knaus, E.E.; Lockhart, R.A.; Keener, I.G. Some Reactions of 1-Lithio-2-phenyl-1,2-dihydropyridine. IV. Synthesis of β-Substituted Pyridines. Can. J. Chem. 1975, 53, 2305–2310. [Google Scholar] [CrossRef]
  40. Ondrus, T.A.; Pasutto, F.M.; Knaus, E.E.; Giam, C.S. Some reactions of 2- n -butyl(phenyl)-1,2-dihydropyridines with isocyanates, pyridyl esters, and diethyl chlorophosphate. Can. J. Chem. 1978, 56, 1913–1918. [Google Scholar] [CrossRef]
  41. Vigante, B.; Plotniece, A.; Rucins, M.; Petrova, M.; Muhamadejev, R.; Pajuste, K.; Belyakov, S.; Shermolovich, Y.G.; Sobolev, A. An efficient synthesis of multisubstituted 4-nitrobuta-1,3-dien-1-amines and application in cyclisation reactions. Tetrahedron 2018, 74, 2596–2607. [Google Scholar] [CrossRef]
  42. Hennig, M.; Munzarová, M.L.; Bermel, W.; Scott, L.G.; Sklenář, V.; Williamson, J.R. Measurement of long-range 1H-19F scalar coupling constants and their glycosidic torsion dependence in 5-fluoropyrimidine- substituted RNA. J. Am. Chem. Soc. 2006, 128, 5851–5858. [Google Scholar] [CrossRef] [Green Version]
  43. Hilton, J.; Sutcliffe, L.H. The “through-space” mechanism in spin spin coupling. Prog. Nucl. Magn. Reson. Spectrosc. 1975, 10, 27–39. [Google Scholar] [CrossRef]
  44. Myhre, P.C.; Edmonds, J.W.; Kruger, J.D. Long-Range Spin-Spin Coupling in Alkylfluorobenzenes. The Stereochemical Requirements for Coupling of Fluorine and Hydrogen Separated by Five Bonds. J. Am. Chem. Soc. 1966, 88, 2459–2466. [Google Scholar] [CrossRef]
  45. Abraham, R.J.; Mobli, M. Modelling H-NMR Spectra of Organic Compounds: Theory, Applications and NMR Prediction Software. In Modelling H-NMR Spectra of Organic Compounds: Theory, Applications and NMR Prediction Software; John Wiley & Sons: Hoboken, NJ, USA, 2008; pp. 1–380. ISBN 9780470723012. [Google Scholar]
  46. Grossel, M.C.; Cheetham, A.K.; Newsam, J.M. The effect of bulky substituents on the conformation of cyclohexa-1,4-diene. Tetrahedron Lett. 1978, 19, 5229–5232. [Google Scholar] [CrossRef]
  47. Atkinson, D.J.; Perkins, M.J. A comment on the magnitude of homoallylic coupling and the conformation of 1,4-cyclohexadiene. Tetrahedron Lett. 1969, 10, 2335–2338. [Google Scholar] [CrossRef]
  48. Grossel, M.C.; Cheetham, A.K.; Hope, D.A.O.; Lam, K.P.; Perkins, M.J. The preferred conformation of cis-1,4-dihydro-4-tritylbiphenyl: A flexible cyclohexa-1,4-diene. Tetrahedron Lett. 1979, 20, 1351–1354. [Google Scholar] [CrossRef]
  49. Cheetham, A.K.; Newsam, J.M.; Grossel, M.C. Conformational Studies of Dihydrotetraphenylmethanes. 1. X-ray Crystallographic and Solution 1H-NMR Studies of trans-1,4-Dihydro-4-tritylbiphenyl and Its 4’-Bromo Derivative: Boat-Boat Inversion in a Congested Cyclohexa-1,4-diene. J. Am. Chem. Soc. 1981, 103, 5363–5372. [Google Scholar] [CrossRef]
  50. Garbisch, E.W.; Griffith, M.G. The Conformation of 1,4-Cyclohexadiene from Stereoisomeric Allylic-Allylic Proton Couplings. J. Am. Chem. Soc. 1968, 90, 3590–3592. [Google Scholar] [CrossRef]
  51. Frisch, M.J.; Trucks, G.W.; Schlegel, H.B.; Scuseria, G.E.; Robb, M.A.; Cheeseman, J.R.; Scalmani, G.; Barone, V.; Mennucci, B.; Petersson, G.A.; et al. Gaussian 09; revision D.01; Gaussian, Inc.: Wallingford, CT, USA, 2013. [Google Scholar]
  52. Grimme, S.; Antony, J.; Ehrlich, S.; Krieg, H. A consistent and accurate ab initio parametrization of density functional dispersion correction (DFT-D) for the 94 elements H-Pu. J. Chem. Phys. 2010, 132. [Google Scholar] [CrossRef] [Green Version]
Sample Availability: Samples of the compounds 3a,c,e and 5a,d are available from the authors.
Molecules 25 03143 g001 550
Figure 1. The 600 MHz 1H-NMR spectrum of 2a in CDCl3 (red—spectra without decoupling, cyan—with 19F decoupled irradiated 19F atoms (1H-{19F}).
Figure 1. The 600 MHz 1H-NMR spectrum of 2a in CDCl3 (red—spectra without decoupling, cyan—with 19F decoupled irradiated 19F atoms (1H-{19F}).
Molecules 25 03143 g001
Molecules 25 03143 g002 550
Figure 2. The structure of 2a optimised by density−functional theory (DFT) calculations. The optimised structures of 2b–k are provided in the Supplementary Materials as Gaussian output files.
Figure 2. The structure of 2a optimised by density−functional theory (DFT) calculations. The optimised structures of 2b–k are provided in the Supplementary Materials as Gaussian output files.
Molecules 25 03143 g002
Molecules 25 03143 sch001 550
Scheme 1. Supposed scheme for the formation of 3-fluoro-3,6-dihydropyridines 2a–k and pyridines 3a–k.
Scheme 1. Supposed scheme for the formation of 3-fluoro-3,6-dihydropyridines 2a–k and pyridines 3a–k.
Molecules 25 03143 sch001
Molecules 25 03143 sch002 550
Scheme 2. Supposed scheme for the formation of methyl 2-(fluoromethyl)-5-nitro-6-arylnicotinates 5a–d.
Scheme 2. Supposed scheme for the formation of methyl 2-(fluoromethyl)-5-nitro-6-arylnicotinates 5a–d.
Molecules 25 03143 sch002
Table
Table 1. The reaction of 1,2-dihydropyridines 1a–k with Selectfluor®.
Table 1. The reaction of 1,2-dihydropyridines 1a–k with Selectfluor®.
Molecules 25 03143 i001
Comp.RAlkR′R″ArThe Ratio of Diastereomers, % 1Yield, %2
2aMeMeHNO2Ph45:5594
2bMeMeHNO2Ph-Ph40:6096
2cMeMeHNO2o-OMe-Ph45:5590
2dMeMeHNO23,4,5-OMe-Ph20:8090
2eEtMeHNO2o-OMe-Ph50:5097
2fMeMeHNO2p-NO2-Ph50:5094
2gMeMeHNO2m-F-Ph50:5088
2hMeMeHNO21,3-Ph-1H-pyrazol-4-yl10:9089
2kMeEtMeCOOEtPh15:8582
1 The ratio of diastereomers is determined according to the 19F, 1H-NMR spectra of compounds 2a–k. 2 The yields of 2a–k after extraction with diethyl ether are given.
Table
Table 2. The formation of pyridines 3a–k from 3-fluoro-3,6-dihydropyridines 2a–k after the elimination of hydrogen fluoride.
Table 2. The formation of pyridines 3a–k from 3-fluoro-3,6-dihydropyridines 2a–k after the elimination of hydrogen fluoride.
Molecules 25 03143 i002
Comp.RAlkR′R″ArYield, %1
3aMeMeHNO2Ph91
3bMeMeHNO2Ph-Ph85
3cMeMeHNO2o-OMe-Ph72
3dMeMeHNO23,4,5-OMe-Ph84
3eEtMeHNO2o-OMe-Ph82
3fMeMeHNO2p-NO2-Ph93
3gMeMeHNO2m-F-Ph87
3hMeMeHNO21,3-Ph-1H-pyrazol-4-yl79
3kMeEtMeCOOEtPh85
1 Isolated yields are given.
Table
Table 3. The general NMR spectral characteristics of 3-fluoro-3,6-dihydropyridines 2a–k.
Table 3. The general NMR spectral characteristics of 3-fluoro-3,6-dihydropyridines 2a–k.
Comp.The Ratio of Diastereo-mers, %1δ C6H Proton for Both Diastereomers in 1H-NMR Spectra, ppmδ F for both Diastereomers in 19F-NMR Spectra, ppmHomoallylic Coupling Constant 5JH-F(F-H) for Both Diastereomers, Hz23JH-F(F-H) for Both Diastereomers, Hz2Allylic Coupling Constant 4JH-H for both Diastereomers, Hz3
MinorMajorMinorMajorMinorMajorMinorMajorMinorMajor
2a45:556.095.79−140.6−142.415.412.19.45.61.31.2
2b40:606.225.94−140.3−142.415.412.19.35.61.21.2
2c45:556.706.22−139.9−144.316.612.69.06.21.41.6
2d20:805.796.02−141.5−140.412.215.85.49.21.11.2
2e50:506.726.21−140.5−145.117.012.69.16.51.21.6
2f50:506.265.94−141.6−143.014.411.49.55.71.11.3
2g50:506.165.85−140.7−142.814.911.89.45.61.11.2
2h10:906.056.30−144.2−142.611.914.05.89.51.51.1
2k15:855.385.70−150.4−145.912.015.5----
1 The ratio of diastereomers is determined according to the 19F, 1H-NMR spectra of compounds 2a–k. 2 Determined according to the 19F, 1H-NMR spectra of compounds 2a–k. 3 Determined according to the 1H-NMR spectra of compounds 2a–k.
Table
Table 4. Quantum chemical calculation data for compounds 2a–k.
Table 4. Quantum chemical calculation data for compounds 2a–k.
Comp.d(H…F), Åd(C6 to N1-C2-C4-C5 plane), Åd(C3 to N1-C2-C4-C5 plane), ÅThe angle between C6-N1-C2-C3 and C6-C5-C4-C3 Planes, °
cistranscistranscistranscistrans
2a4.604.730.110.110.120.13169.38168.88
2b4.604.850.110.020.130.05169.18178.46
2c4.594.850.100.010.130.08169.72175.66
2d4.614.720.120.120.130.15168.90167.86
2e4.574.770.090.070.120.07170.45173.73
2f4.594.850.100.030.130.10169.74174.07
2g4.604.850.110.010.130.08169.40175.94
2h4.634.770.130.080.140.08167.81172.97
2k4.984.800.300.020.420.05148.20176.79
Table
Table 5. Reactions of 3-fluoro-2-methyl-5-nitro-3,6-dihydropyridines 2a,c,f,g or 1,2-dihydropyridines 1a,c,f,g with Selectfluor®, leading to the formation of a mixture of methyl 2-(fluoromethyl)-5-nitro-6-arylnicotinates 5a–d and 2-methylpyridines 3a,c,f,g.
Table 5. Reactions of 3-fluoro-2-methyl-5-nitro-3,6-dihydropyridines 2a,c,f,g or 1,2-dihydropyridines 1a,c,f,g with Selectfluor®, leading to the formation of a mixture of methyl 2-(fluoromethyl)-5-nitro-6-arylnicotinates 5a–d and 2-methylpyridines 3a,c,f,g.
Molecules 25 03143 i003
Comp.ArRatio 3:5, %1Yields, %2
Method A Method B Comp. 3Comp. 5
3a, 5aPh50:5055:454432
3c, 5bo-OMe-Ph60:4055:455221
3f, 5cp-NO2-Ph15:7520:801038
3g, 5dm-F-Ph50:5050:503643
1 The ratio of compounds 3a,c,f,g to 5a–d were determined according to the 1H-NMR spectra and LC–MS data of the reaction mixture. 2 Isolated yields obtained by Method A are given.

Share and Cite

MDPI and ACS Style

Pikun, N.V.; Sobolev, A.; Plotniece, A.; Rucins, M.; Vigante, B.; Petrova, M.; Muhamadejev, R.; Pajuste, K.; Shermolovich, Y.G. Synthesis of Fluorinated 3,6-Dihydropyridines and 2-(Fluoromethyl)pyridines by Electrophilic Fluorination of 1,2-Dihydropyridines with Selectfluor®. Molecules 2020, 25, 3143. https://doi.org/10.3390/molecules25143143

AMA Style

Pikun NV, Sobolev A, Plotniece A, Rucins M, Vigante B, Petrova M, Muhamadejev R, Pajuste K, Shermolovich YG. Synthesis of Fluorinated 3,6-Dihydropyridines and 2-(Fluoromethyl)pyridines by Electrophilic Fluorination of 1,2-Dihydropyridines with Selectfluor®. Molecules. 2020; 25(14):3143. https://doi.org/10.3390/molecules25143143

Chicago/Turabian Style

Pikun, Nadiia V., Arkadij Sobolev, Aiva Plotniece, Martins Rucins, Brigita Vigante, Marina Petrova, Ruslan Muhamadejev, Karlis Pajuste, and Yuriy G. Shermolovich. 2020. "Synthesis of Fluorinated 3,6-Dihydropyridines and 2-(Fluoromethyl)pyridines by Electrophilic Fluorination of 1,2-Dihydropyridines with Selectfluor®" Molecules 25, no. 14: 3143. https://doi.org/10.3390/molecules25143143

Article Metrics

Back to TopTop