Nitropyridines as 2π-Partners in 1,3-Dipolar Cycloadditions with N-Methyl Azomethine Ylide: An Easy Access to Condensed Pyrrolines

1,3-Dipolar cycloaddition reactions of 2-substituted 5-R-3-nitropyridines and isomeric 3-R-5-nitropyridines with N-methyl azomethine ylide were studied. The effect of the substituent at positions 2 and 5 of the pyridine ring on the possibility of the [3+2]-cycloaddition process was revealed. A number of new derivatives of pyrroline and pyrrolidine condensed with a pyridine ring were synthesized.


Introduction
Pyridine derivatives of both natural and synthetic origin are one of the promising classes of heterocyclic compounds, which have a great synthetic potential and are of interest for the synthesis of biologically active substances. It is known that a large number of pyridine derivatives possess antimicrobial, antiviral, anticancer, analgesic, and antioxidant activities [1][2][3][4][5]. Recently, there has been a rapid development of approaches to the synthesis (including industrial) of condensed pyridines with various types of useful biological activity [6][7][8][9][10][11][12].
Earlier, we reported on the development of a method for the synthesis of pyrrolidine and pyrroline derivatives condensed with a pyridine ring on the basis of 2-R-3,5-dinitropyridines [19,20]. It was shown that, depending on the nature of 2-R, annulation of either two pyrrolidine rings or one pyrroline ring is possible [20], Scheme 1.

Introduction
Pyridine derivatives of both natural and synthetic origin are one of the promising classes of heterocyclic compounds, which have a great synthetic potential and are of interest for the synthesis of biologically active substances. It is known that a large number of pyridine derivatives possess antimicrobial, antiviral, anticancer, analgesic, and antioxidant activities [1][2][3][4][5]. Recently, there has been a rapid development of approaches to the synthesis (including industrial) of condensed pyridines with various types of useful biological activity [6][7][8][9][10][11][12].
Earlier, we reported on the development of a method for the synthesis of pyrrolidine and pyrroline derivatives condensed with a pyridine ring on the basis of 2-R-3,5-dinitropyridines [19,20]. It was shown that, depending on the nature of 2-R, annulation of either two pyrrolidine rings or one pyrroline ring is possible [20], Scheme 1.

Synthesis of Starting 2-Substitutied 5-R-3nitropyridines 2a-q
In this work we studied the effect of the substituent at position 5 of the pyridine ring on the [3+2]-cycloaddition process. We used available 2-chloro-5-R-3-nitropyridines 1 as starting compounds. The mobile chlorine atom in these compounds is capable of being replaced by the action of nucleophiles under mild conditions. As a result of reaction 1 with thiols, amines, and phenols, compounds 2a-q were synthesized (Scheme 2, Table 1). on the [3+2]-cycloaddition process. We used available 2-chloro-5-R-3-nitropyridines 1 as starting compounds. The mobile chlorine atom in these compounds is capable of being replaced by the action of nucleophiles under mild conditions. As a result of reaction 1 with thiols, amines, and phenols, compounds 2a-q were synthesized (Scheme 2, Table 1).

[3+2]-Cycloaddition of Nitropyridines 2
We studied pyridines 2a-q in 1,3-dipolar cycloaddition reactions with an excess of N-methyl azomethine ylide 3, which was generated in situ from sarcosine and paraformaldehyde under reflux in toluene. In the case of pyridines 2a,b,d,e,g-i,k-m,o-q, a dipole was added at the C=C-NO2 bond followed by elimination of the HNO2 molecule  on the [3+2]-cycloaddition process. We used available 2-chloro-5-R-3-nitropyridines 1 as starting compounds. The mobile chlorine atom in these compounds is capable of being replaced by the action of nucleophiles under mild conditions. As a result of reaction 1 with thiols, amines, and phenols, compounds 2a-q were synthesized (Scheme 2, Table 1).

[3+2]-Cycloaddition of Nitropyridines 2
We studied pyridines 2a-q in 1,3-dipolar cycloaddition reactions with an excess of N-methyl azomethine ylide 3, which was generated in situ from sarcosine and paraformaldehyde under reflux in toluene. In the case of pyridines 2a,b,d,e,g-i,k-m,o-q, a dipole was added at the C=C-NO2 bond followed by elimination of the HNO2 molecule  on the [3+2]-cycloaddition process. We used available 2-chloro-5-R-3-nitropyridines 1 as starting compounds. The mobile chlorine atom in these compounds is capable of being replaced by the action of nucleophiles under mild conditions. As a result of reaction 1 with thiols, amines, and phenols, compounds 2a-q were synthesized (Scheme 2, Table 1).

[3+2]-Cycloaddition of Nitropyridines 2
We studied pyridines 2a-q in 1,3-dipolar cycloaddition reactions with an excess of N-methyl azomethine ylide 3, which was generated in situ from sarcosine and paraformaldehyde under reflux in toluene. In the case of pyridines 2a,b,d,e,g-i,k-m,o-q, a dipole was added at the C=C-NO2 bond followed by elimination of the HNO2 molecule on the [3+2]-cycloaddition process. We used available 2-chloro-5-R-3-nitropyridines 1 as starting compounds. The mobile chlorine atom in these compounds is capable of being replaced by the action of nucleophiles under mild conditions. As a result of reaction 1 with thiols, amines, and phenols, compounds 2a-q were synthesized (Scheme 2, Table 1).

[3+2]-Cycloaddition of Nitropyridines 2
We studied pyridines 2a-q in 1,3-dipolar cycloaddition reactions with an excess of N-methyl azomethine ylide 3, which was generated in situ from sarcosine and paraformaldehyde under reflux in toluene. In the case of pyridines 2a,b,d,e,g-i,k-m,o-q, a dipole was added at the C=C-NO2 bond followed by elimination of the HNO2 molecule on the [3+2]-cycloaddition process. We used available 2-chloro-5-R-3-nitropyridines 1 as starting compounds. The mobile chlorine atom in these compounds is capable of being replaced by the action of nucleophiles under mild conditions. As a result of reaction 1 with thiols, amines, and phenols, compounds 2a-q were synthesized (Scheme 2, Table 1).

[3+2]-Cycloaddition of Nitropyridines 2
We studied pyridines 2a-q in 1,3-dipolar cycloaddition reactions with an excess of N-methyl azomethine ylide 3, which was generated in situ from sarcosine and paraformaldehyde under reflux in toluene. In the case of pyridines 2a,b,d,e,g-i,k-m,o-q, a dipole was added at the C=C-NO2 bond followed by elimination of the HNO2 molecule on the [3+2]-cycloaddition process. We used available 2-chloro-5-R-3-nitropyridines 1 as starting compounds. The mobile chlorine atom in these compounds is capable of being replaced by the action of nucleophiles under mild conditions. As a result of reaction 1 with thiols, amines, and phenols, compounds 2a-q were synthesized (Scheme 2, Table 1).

[3+2]-Cycloaddition of Nitropyridines 2
We studied pyridines 2a-q in 1,3-dipolar cycloaddition reactions with an excess of N-methyl azomethine ylide 3, which was generated in situ from sarcosine and paraformaldehyde under reflux in toluene. In the case of pyridines 2a,b,d,e,g-i,k-m,o-q

[3+2]-Cycloaddition of Nitropyridines 2
We studied pyridines 2a-q in 1,3-dipolar cycloaddition reactions with an excess of Nmethyl azomethine ylide 3, which was generated in situ from sarcosine and paraformaldehyde under reflux in toluene. In the case of pyridines 2a,b,d,e,g-i,k-m,o-q, a dipole was added at the C=C-NO 2 bond followed by elimination of the HNO 2 molecule and rearomatization of the system with the formation of pyrroline derivatives 4, Scheme 3. and rearomatization of the system with the formation of pyrroline derivatives 4, Scheme 3.
Thus, pyridines containing a donor substituent (Me or H) at position 5 do not undergo a [3+2]-cycloaddition reaction. In addition, in the presence of an amine moiety in position 2 (compounds 2c, 2j, 2n, 2q), the reaction also does not proceed. This reactivity is most likely associated with the electron-donor effect of the amino group, which reduces the overall electrophilicity of the starting compound [20,21]. The target product was isolated only for compound 2f where conversion of the starting pyridine was about 50% according to the NMR spectroscopy data.
The reaction of pyridine 2o with azomethine ylide 3 deserves special attention (Scheme 4). We found that this reaction resulted in the addition of two molecules of a dipole to the pyridine nucleus with the formation of compound 5. It is known that, in similar reactions, the addition of a dipole occurs from the opposite sides of the benzene (pyridine) ring, providing trans-cycloadducts [19,20,22,23]. However there are examples of the formation of cis-cycloadducts [24]. The cycloaddition of 3 to pyridine 2o can in principle provide two isomeric products 5 and 6, Figure 1. We carried out a detailed study of the cycloaddition adduct using various NMR experiments (COSY, 1 H- 13 C HMBC, 1 H- 13 C HSQC, NOESY). The full assignment of hydrogen and carbon atoms in NMR spectra was made. The 1 H-1 H NOESY spectrum of 5 contains a characteristic cross-peak corresponding to the interaction of spatially close H(1) and H(6)  2c, 2j, 2n, 2q), the reaction also does not proceed. This reactivity is most likely associated with the electron-donor effect of the amino group, which reduces the overall electrophilicity of the starting compound [20,21]. The target product was isolated only for compound 2f where conversion of the starting pyridine was about 50% according to the NMR spectroscopy data.
The reaction of pyridine 2o with azomethine ylide 3 deserves special attention (Scheme 4). We found that this reaction resulted in the addition of two molecules of a dipole to the pyridine nucleus with the formation of compound 5. and rearomatization of the system with the formation of pyrroline derivatives 4, Scheme 3.
Thus, pyridines containing a donor substituent (Me or H) at position 5 do not undergo a [3+2]-cycloaddition reaction. In addition, in the presence of an amine moiety in position 2 (compounds 2c, 2j, 2n, 2q), the reaction also does not proceed. This reactivity is most likely associated with the electron-donor effect of the amino group, which reduces the overall electrophilicity of the starting compound [20,21]. The target product was isolated only for compound 2f where conversion of the starting pyridine was about 50% according to the NMR spectroscopy data.
The reaction of pyridine 2o with azomethine ylide 3 deserves special attention (Scheme 4). We found that this reaction resulted in the addition of two molecules of a dipole to the pyridine nucleus with the formation of compound 5. It is known that, in similar reactions, the addition of a dipole occurs from the opposite sides of the benzene (pyridine) ring, providing trans-cycloadducts [19,20,22,23]. However there are examples of the formation of cis-cycloadducts [24]. The cycloaddition of 3 to pyridine 2o can in principle provide two isomeric products 5 and 6, Figure 1. We carried out a detailed study of the cycloaddition adduct using various NMR experiments (COSY, 1 H- 13  It is known that, in similar reactions, the addition of a dipole occurs from the opposite sides of the benzene (pyridine) ring, providing trans-cycloadducts [19,20,22,23]. However there are examples of the formation of cis-cycloadducts [24]. The cycloaddition of 3 to pyridine 2o can in principle provide two isomeric products 5 and 6, Figure 1. We carried out a detailed study of the cycloaddition adduct using various NMR experiments (COSY, 1 H- 13 C HMBC, 1 H- 13 C HSQC, NOESY). The full assignment of hydrogen and carbon atoms in NMR spectra was made. The 1 H-1 H NOESY spectrum of 5 contains a characteristic crosspeak corresponding to the interaction of spatially close H(1) and H(6) protons, Figure 1. At the same time, the interaction between H(1) and H(5) was not observed. These data allowed us to unambiguously confirm trans-cycloaddition and the formation of compound 5. protons, Figure 1. At the same time, the interaction between H(1) and H(5) was not observed. These data allowed us to unambiguously confirm trans-cycloaddition and the formation of compound 5.

General Information
All chemicals were of commercial grade and used directly without purification. Melting points were measured on a Stuart SMP 20 apparatus (Stuart (Bibby Scientific), UK). 1 H and 13 C NMR spectra were recorded on a Bruker AM-300 (at 300.13 and 75.13 MHz, respectively, Bruker Biospin, Germany) and a Bruker Avance DRX 500 (at 500 and 125 MHz, respectively, Bruker Biospin, Germany) in DMSO-d6 or CDCl3. HRMS spectra were recorded on a Bruker micrOTOF II mass spectrometer (Bruker micrOTOF II mass spectrometer) using ESI. All reactions were monitored by TLC analysis using ALUGRAM SIL G/UV254 plates, which were visualized by UV light (see Supplementary Materials). 2a, 2d, 2g, 2h, 2k, 2l, 2o An appropriate thiol (1 mmol) and Et3N (0.14 mL, 1 mmol) were added to a solution of 1 mmol of appropriate chloride in methanol (30 mL). The reaction mixture was stirred at room temperature for 0.5-2 h until the starting compound was completely consumed (TLC). Then mixture was poured into water and acidified with HCl to a pH of 4. The precipitate that formed was filtered off, washed with water, and dried in air.

General Information
All chemicals were of commercial grade and used directly without purification. Melting points were measured on a Stuart SMP 20 apparatus (Stuart (Bibby Scientific), UK). 1 H and 13 C NMR spectra were recorded on a Bruker AM-300 (at 300.13 and 75.13 MHz, respectively, Bruker Biospin, Germany) and a Bruker Avance DRX 500 (at 500 and 125 MHz, respectively, Bruker Biospin, Germany) in DMSO-d 6 or CDCl 3 . HRMS spectra were recorded on a Bruker micrOTOF II mass spectrometer (Bruker micrOTOF II mass spectrometer) using ESI. All reactions were monitored by TLC analysis using ALUGRAM SIL G/UV254 plates, which were visualized by UV light (see Supplementary Materials). 2a, 2d, 2g, 2h, 2k, 2l, 2o An appropriate thiol (1 mmol) and Et 3 N (0.14 mL, 1 mmol) were added to a solution of 1 mmol of appropriate chloride in methanol (30 mL). The reaction mixture was stirred at room temperature for 0.5-2 h until the starting compound was completely consumed (TLC). Then mixture was poured into water and acidified with HCl to a pH of 4. The precipitate that formed was filtered off, washed with water, and dried in air.   13 2b, 2e, 2i, 2m, 2p 4-Nitrophenol 0.14g (1 mmol) and Na 2 CO 3 (0.106 g, 1 mmol) were added to a solution of appropriate chloride (1 mmol) in acetonitrile (15 mL). The reaction mixture was refluxed for 2 h until the starting compound was completely consumed (monitoring by TLC), poured into a five-fold excess of water, and acidified with HCl to a pH of 2. The precipitate that formed was filtered off, washed with water, and dried in air.  13 13 2c, 2f, 2j, 2n, 2q Pyrrolidine 0.16 mL (2 mmol) was added to a solution of appropriate chloride (1 mmol) in methanol (15 mL). The reaction mixture was stirred at room temperature for 2 h (monitoring by TLC), poured into an excess of water, and acidified with HCl to a pH of 2. The precipitate that formed was filtered off, washed with water, and dried.