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

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.

1. Introduction

The incorporatiopan class="Chemical">n of n class="Chemical">fluorine into organic compounpan>ds has become a commonclass="Chemical">pan>ly used tool in medicinal chemistry and agrochemistry. The presenpan>ce of n class="Chemical">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 n class="Chemical">are becoming more significant in a number of disciplines, in particular, the pharmaceutical industry, materials science and agriculture [1,2,3].

The electrophilic fluoripan class="Chemical">nation of n class="Chemical">aromatic heterocycles has beenpan> less studied than the fluorinationclass="Chemical">pan> of n class="Chemical">arenes. However, a number of n class="Chemical">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 papan class="Chemical">n class="Chemical">pyridines has beenpan> extended by the developmenpan>t of many signpan>ificant transformations, such as addition, addition-elimination, elimination-addition and ring openpan>ing, as well as proton abstraction reactions followed by nucleophilic substitution. The nature of the n class="Chemical">pyridine rings and bases employed plays an important role in the course of reactions [23].

It should also be noted that, despite the pan class="Chemical">fact that n class="Chemical">fluorine- and n class="Chemical">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 pan class="Chemical">new electrophilic fluorination reaction of n class="Chemical">1,4-dihydropyridines, providing an approach to previously unpan>known n class="Chemical">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 n class="Chemical">1,2-dihydropyridinespan> n class="Chemical">are known in pn class="Chemical">articular 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 opan class="Chemical">f our knowledge, there n class="Chemical">are no previous studies on the fluorinpan>ation reactions of n class="Chemical">1,2-dihydropyridines. In this paper, we studied the electrophilic fluorination reaction of 1,2-dihydropyridines 1a–k with Selectfluor® (Table 1).

Table 1

The reaction of 1,2-dihydropyridines 1a–k with Selectfluor®.

Comp.	R	Alk	R′	R″	Ar	The Ratio of Diastereomers, % 1	Yield, %2
2a	Me	Me	H	NO2	Ph	45:55	94
2b	Me	Me	H	NO2	Ph-Ph	40:60	96
2c	Me	Me	H	NO2	o-OMe-Ph	45:55	90
2d	Me	Me	H	NO2	3,4,5-OMe-Ph	20:80	90
2e	Et	Me	H	NO2	o-OMe-Ph	50:50	97
2f	Me	Me	H	NO2	p-NO2-Ph	50:50	94
2g	Me	Me	H	NO2	m-F-Ph	50:50	88
2h	Me	Me	H	NO2	1,3-Ph-1H-pyrazol-4-yl	10:90	89
2k	Me	Et	Me	COOEt	Ph	15:85	82

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.

2. Results and Discussion

Stn class="Chemical">arpan>ting n class="Chemical">2-methyl-5-nitro-1,2-dihydropyridines 1 were obtained by the cyclisation of corresponding nitrodienamines with n class="Chemical">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 opan class="Chemical">f diastereomers was determined according to the n class="Chemical">19F, n class="Chemical">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).

Table 2

The formation of pyridines 3a–k from 3-fluoro-3,6-dihydropyridines 2a–k after the elimination of hydrogen fluoride.

Comp.	R	Alk	R′	R″	Ar	Yield, %1
3a	Me	Me	H	NO2	Ph	91
3b	Me	Me	H	NO2	Ph-Ph	85
3c	Me	Me	H	NO2	o-OMe-Ph	72
3d	Me	Me	H	NO2	3,4,5-OMe-Ph	84
3e	Et	Me	H	NO2	o-OMe-Ph	82
3f	Me	Me	H	NO2	p-NO2-Ph	93
3g	Me	Me	H	NO2	m-F-Ph	87
3h	Me	Me	H	NO2	1,3-Ph-1H-pyrazol-4-yl	79
3k	Me	Et	Me	COOEt	Ph	85

1 Isolated yields are given.

It was foupan class="Chemical">nd that after the storage of n class="Chemical">3-fluoro-3,6-dihydropyridines 2a–k in n class="Chemical">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 efpan class="Chemical">fect of vn class="Chemical">arious factors on the course of this reaction, such as the solvenpan>t, the order of addition of reagenpan>ts, temperature and dilution, was studied. n class="Chemical">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 n class="Chemical">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 onen class="Chemical">-dimenpan>sional n class="Chemical">1H, 19F, 13C and two-dimensional {1H−1H} COSY, {13C−1H} HSQC and {13C−1H} HMBC NMR spectral data (Table 3).

Table 3

The general NMR spectral characteristics of 3-fluoro-3,6-dihydropyridines 2a–k.

Comp.	The Ratio of Diastereo-mers, %1	δ C6H Proton for Both Diastereomers in 1H-NMR Spectra, ppm		δ F for both Diastereomers in 19F-NMR Spectra, ppm		Homoallylic Coupling Constant 5JH-F(F-H) for Both Diastereomers, Hz2		3JH-F(F-H) for Both Diastereomers, Hz2		Allylic Coupling Constant 4JH-H for both Diastereomers, Hz3
		Minor	Major	Minor	Major	Minor	Major	Minor	Major	Minor	Major
2a	45:55	6.09	5.79	−140.6	−142.4	15.4	12.1	9.4	5.6	1.3	1.2
2b	40:60	6.22	5.94	−140.3	−142.4	15.4	12.1	9.3	5.6	1.2	1.2
2c	45:55	6.70	6.22	−139.9	−144.3	16.6	12.6	9.0	6.2	1.4	1.6
2d	20:80	5.79	6.02	−141.5	−140.4	12.2	15.8	5.4	9.2	1.1	1.2
2e	50:50	6.72	6.21	−140.5	−145.1	17.0	12.6	9.1	6.5	1.2	1.6
2f	50:50	6.26	5.94	−141.6	−143.0	14.4	11.4	9.5	5.7	1.1	1.3
2g	50:50	6.16	5.85	−140.7	−142.8	14.9	11.8	9.4	5.6	1.1	1.2
2h	10:90	6.05	6.30	−144.2	−142.6	11.9	14.0	5.8	9.5	1.5	1.1
2k	15:85	5.38	5.70	−150.4	−145.9	12.0	15.5	-	-	-	-

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.

The correlations opan class="Chemical">f the protons at 5.4−6.2 ppm in the {n class="Chemical">13C−n class="Chemical">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 opan class="Chemical">f compounds 2a–k, the n class="Chemical">fluorine atom and n class="Chemical">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 papan class="Chemical">n class="Chemical">19F-NMR spectra of compounpan>ds 2a–k, a signpan>al of the n class="Chemical">fluorine atom appen class="Chemical">ars 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 ipan class="Chemical">nteresting fact is that compounds 2a–k in the n class="Chemical">1H and n class="Chemical">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 betweepan class="Chemical">n the n class="Chemical">fluorine atom and C6H proton, heteronclass="Chemical">pan>uclen class="Chemical">ar spin decoupling was used. Figure 1 shows the effect of the heteronuclen class="Chemical">ar 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.

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}).

Our attempts to explain the origipan class="Chemical">n of the ln class="Chemical">arge coupling constanpan>t 5J (n class="Chemical">19F,n class="Chemical">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 opan class="Chemical">f through-space proton–n class="Chemical">fluorine interactions in compounpan>ds 2a–k, ab initio calculations were cn class="Chemical">arried out and the data are presented in Table 4.

Table 4

Quantum chemical calculation data for compounds 2a–k.

Comp.	d(H…F), Å		d(C6 to N1-C2-C4-C5 plane), Å		d(C3 to N1-C2-C4-C5 plane), Å		The angle between C6-N1-C2-C3 and C6-C5-C4-C3 Planes, °
	cis	trans	cis	trans	cis	trans	cis	trans
2a	4.60	4.73	0.11	0.11	0.12	0.13	169.38	168.88
2b	4.60	4.85	0.11	0.02	0.13	0.05	169.18	178.46
2c	4.59	4.85	0.10	0.01	0.13	0.08	169.72	175.66
2d	4.61	4.72	0.12	0.12	0.13	0.15	168.90	167.86
2e	4.57	4.77	0.09	0.07	0.12	0.07	170.45	173.73
2f	4.59	4.85	0.10	0.03	0.13	0.10	169.74	174.07
2g	4.60	4.85	0.11	0.01	0.13	0.08	169.40	175.94
2h	4.63	4.77	0.13	0.08	0.14	0.08	167.81	172.97
2k	4.98	4.80	0.30	0.02	0.42	0.05	148.20	176.79

According to the quapan class="Chemical">ntum chemical calculations, the angles between the n class="Disease">C6-N1-C2-C3 and C6-C5-C4-C3 planes n class="Chemical">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].

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.

The distance betweepan class="Chemical">n the proton and the n class="Chemical">fluorine in cis conformer is shorter than in tranpan>s for n class="Chemical">5-nitro-substituted n class="Chemical">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 representatiopan class="Chemical">n of the optimised moleculn class="Chemical">ar geometry for both diastereomers of compounpan>d 2a, obtained with denpan>sity−functional theory (DFT) calculations, is shown in Figure 2.

The data show that n class="Chemical">3,6-dihydropyridinespan> 2 are nen class="Chemical">arly 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 ln class="Chemical">arpan>ge homoallyl long-range HH couplings have beenpan> previously observed for n class="Chemical">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-H is greater (9.6−11.0 Hz) than the 5JH-H (7.5−8.4 Hz) [49]. Based on these data, we can also suggest that the cis diastereomer of compounds 2a–k has a ln class="Chemical">arger homoallylic coupling constant 5JF-H than the corresponding trans diastereomer.

We can propose the pan class="Chemical">following scheme for the formation of n class="Chemical">3-fluoro-3,6-dihydropyridines 2a–k. At the first stage of the reaction, n class="Chemical">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).

Scheme 1

Supposed scheme for the formation of 3-fluoro-3,6-dihydropyridines 2a–k and pyridines 3a–k.

The reaction opan class="Chemical">f n class="Chemical">3-fluoro-2-methyl-5-nitro-3,6-dihydropyridines 2a,c,f,g with n class="Chemical">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).

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.

Comp.	Ar	Ratio 3:5, %1		Yields, %2
		Method A	Method B	Comp. 3	Comp. 5
3a, 5a	Ph	50:50	55:45	44	32
3c, 5b	o-OMe-Ph	60:40	55:45	52	21
3f, 5c	p-NO2-Ph	15:75	20:80	10	38
3g, 5d	m-F-Ph	50:50	50:50	36	43

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.

It is knowpan class="Chemical">n that N-F fluorinating agents and, in pn class="Chemical">articuln class="Chemical">ar 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).

Scheme 2

Supposed scheme for the formation of methyl 2-(fluoromethyl)-5-nitro-6-arylnicotinates 5a–d.

On the other hapan class="Chemical">nd, n class="Chemical">2-methylpyridines 3a,c,f,g can be formed as a result of the eliminationclass="Chemical">pan> of n class="Chemical">hydrogen fluoride from n class="Chemical">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 n class="Chemical">arpan>e very limited data in the literature about straightforward methods for the preparation of n class="Chemical">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 prepn class="Chemical">arpan>ation of n class="Chemical">2- or 4-(fluoromethyl)pyridines was realised with N-fluorobis(trifluoromethanesulfonyl)imide from corresponding n class="Chemical">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 class="Chemical">pan class="Chemical">N-Fluorobis(trifluoromethanesulfonyl)imide, n class="Chemical">(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 fluoripan class="Chemical">nation reactions of n class="Chemical">1,2-dihydropyridines 1 and n class="Chemical">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 pan class="Chemical">from Acros Organics (Geel, Belgium), n class="Disease">Sigma-Aldrich/Merck KGaA (Dn class="Chemical">armstadt, 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 opan class="Chemical">f n class="Chemical">Selectfluor® (0.170 g, 0.5 mmol) in dry n class="Chemical">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 n class="Chemical">yellow oil. Yield 0.137 g (94%). Mixture of diastereomers (the ratio is 45:55 according to the pan> class="Chemical">19F and 1H-NMR spectra). n class="Chemical">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 n class="Chemical">yellow oil. Yield 0.177 g (96%). Mixture of diastereomers (the ratio is 40:60 according to the pan> class="Chemical">19F and 1H-NMR spectra). n class="Chemical">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)

n class="Chemical">Yellow oil. Yield 0.145 g (90%). Mixture of diastereomers (the ratio is 45:55 according to the pan> class="Chemical">19F and 1H-NMR spectra). n class="Chemical">1H-NMR (CDCl3): δ 2.18−2.20 (m, 6H, CH3 of both diastereomers), 3.85 (s, 3H, COOCH of minor diastereomer), 3.89 (s, 3H, COOCH 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)

n class="Chemical">Yellow brown oil. Yield 0.172 g (90%). Mixture of diastereomers (the ratio is 20:80 according to the pan> class="Chemical">19F and 1H-NMR spectra). n class="Chemical">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)

n class="Chemical">Yellow oil. Yield 0.163 g (97%). Mixture of diastereomers (the ratio is 50:50 according to the pan> class="Chemical">19F and 1H-NMR spectra). n class="Chemical">1H-NMR (CDCl3): δ 1.08−1.14 (m, 6H, 2 × CH2CH of both diastereomers); 2.34−2.44 (m, 2H, CHCH3), 2.51−2.64 (m, 2H, CHCH3), 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)

n class="Chemical">Yellow oil. Yield 0.169 g (94%). Mixture of diastereomers (the ratio is 50:50 according to the pan> class="Chemical">19F and 1H-NMR spectra). n class="Chemical">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)

n class="Chemical">Yellow oil. Yield 0.136 g (88%). Mixture of diastereomers (the ratio is 50:50 according to the pan> class="Chemical">19F and 1H-NMR spectra). n class="Chemical">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)

n class="Chemical">Yellow brown oil. Yield 0.150 g (89%). Mixture of diastereomers (the ratio is 10:90 according to the pan> class="Chemical">19F and 1H-NMR spectra). n class="Chemical">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 n class="Chemical">yellow oil. Yield 0.142 g (82%). Mixture of diastereomers (the ratio is 15:85 according to the pan> class="Chemical">19F and 1H-NMR spectra). n class="Chemical">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 n class="Chemical">deuterochloropan class="Chemical">form solutionclass="Chemical">pan> (3 mL) of n class="Chemical">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. n class="Chemical">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 papan class="Chemical">n class="Chemical">ethanol). Rf: 0.54 (petroleum ether – ethyl acetate 4:1). Anclass="Chemical">pan>al. calcd for C14n class="Species">H12N2O4: C, 61.76; H, 4.44; N, 10.29; found: C, 61.85; H, 4.55; N, 10.16. n class="Chemical">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; founpan>d: C, 69.02; H, 4.71; N, 7.96. pan> class="Chemical">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 (class="Chemical">pan> class="Chemical">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 (pan class="Chemical">from ethanol). Rf: 0.29 (petroleum ether – ethyl acetate 4:1). IR νmax (Film) 3006, 2945, 2840, 1731, 1592, 1554, 1455, 1424, 1334. pan> class="Chemical">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 n class="Chemical">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 pan> class="CellLine">C16H16N2O5: C, 60.76; H, 5.10; N, 8.86; found: C, 60.84; H, 5.19; N, 8.75. 1H-NMR (n class="Chemical">CDCl3): δ 1.36 (t, 3JH-H = 7.4 Hz, 3H, CH2CH), 3.33 (t, 3JH-H = 7.4 Hz, 2H, CHCH3), 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 n class="Chemical">ethanol). Rf: 0.39 (petroleum ether–ethyl acetate 4:1). IR νmax (Film) 3086, 2995, 1719, 1553, 1517, 1443, 1358, 1345. class="Chemical">pan> class="Chemical">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. class="Chemical">pan> class="Chemical">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). class="Chemical">pan> class="Chemical">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 n class="Chemical">yellow oil. Yield 0.093 g (85%). Rf: 0.60 (petroleum ether–ethyl acetate 4:1). n class="Chemical">1H-NMR (n class="Chemical">CDCl3): δ 0.99 (t, 3JH-H = 7.1 Hz, 3H, COOCH2CH), 1.42 (t, 3JH-H = 7.1 Hz, 3H, COOCH2CH), 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 opan class="Chemical">f n class="Chemical">3-fluoro-5-nitro-3,6-dihydropyridines 2a,c,f,g (0.5 mmol) in dry n class="Chemical">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 opan class="Chemical">f n class="Chemical">1,2-dihydropyridines 1a,c,f,g (0.5 mmol) in dry npan> class="Chemical">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 n class="Chemical">2-(fluoromethyl)pyridines pan> class="Chemical">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 n class="Chemical">yellow oil. Yield 0.046 g (32%). Rf: 0.45 (petroleum ether–ethyl acetate 4:1). Anal. calcd for pan> class="Chemical">C14H11FN2O4: C, 57.93; H, 3.82; N, 9.65; found: C, 58.06; H, 3.93; N, 9.52. 1H-NMR (n class="Chemical">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 n class="Chemical">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. Anclass="Chemical">pan>al. calcd for n class="Chemical">C15H13FN2O5: C, 56.25; H, 4.09; N, 8.75; found: C, 56.39; H, 4.19; N, 8.64. n class="Chemical">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. class="Chemical">pan> class="Chemical">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. class="Chemical">pan> class="Chemical">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 pan class="Chemical">new n class="Chemical">fluorinated 3,6-dihydropyridines 2a–k can be obtained by the reactionclass="Chemical">pan> of n class="Chemical">1,2-dihydropyridines 1a–k with n class="Chemical">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.