Pyridin-2(1H)-ones are the privileged scaffolds in medicinal chemistry. The structural motif of pyridin-2(1H)-ones is widely represented in natural compounds.1,2,–3 Compounds of this type include biologically active molecules that have shown anticancer,4, 5 antiviral (including antiHIV),6, 7 cardiotonic,8 anticonvulsant,9 and other types of biological effects.10, 11 For this reason, it is important to continue the development of new methods for the preparation of pyridin-2(1Н)-ones.

We have previously reported that intramolecular cyclization of N-(3-oxoalkyl)amides and N-(3-oxoalkenyl)amides provides a convenient method for the synthesis of pyridin-2(1Н)-ones functionalized at position 3,12,13,14,–15 as well as their hydrogenated derivatives.16,17,–18 The aforementioned method was used to obtain various compounds of this class,14, 15, 19, 20 including 3-tosyl-3,4-dihydropyridin-2(1Н)-ones.21

This approach was used to synthesize only one 3-tosylsubstituted pyridin-2(1Н)-one.15 During the nucleophilic substitution of halide with a tosyl group in N-(3-oxoalkenyl)chloroacetamide 2, an intramolecular cyclization of p-toluenesulfonyl derivative 3 occurred with the formation of the corresponding pyridin-2(1Н)-one 4. It is important to note that the earlier method for the preparation of 3-arylsulfonylpyridin-2(1Н)-ones was based on the condensation of arylsulfonylacetonitrile with β-enaminoketones 1 (Scheme 1).22, 23 These approaches complement each other by allowing to convert the same starting β-enaminoketone into the isomeric pyridin-2(1H)-ones with different arrangement of the R1 and R3 substituents in the ring.

scheme 1

Scheme 1.

For the purpose of studying the limitations of N-(3-oxoalkenyl)chloroacetamide reactions with sodium p-toluenesulfinate (TsNa), we performed the synthesis of 3-tosylpyridin-2(1H)-ones both with the previously known compounds 2а–с12,15,24 and the new N-(3-oxoalkenyl)chloroacetamides 2d–f, which were obtained in 25–81% yields according to a published procedure15 by acylation of the respective enaminoketones 1 with chloroacetyl chloride. Compounds 2e,f lacking a substituent at the α-position relative to the nitrogen atom were formed as mixtures of isomers (84:16 ratio of isomers (Z)/(Е)-2f and 63:37 ratio of isomers (Z)/(Е)-2e). At the same time, for N-(3-oxoalkenyl)chloroacetamide 2d containing the methyl group (R3 = Me) in the α-position to the nitrogen atom, unlike its structural isomer 2e, no formation of the (E)-configuration was observed. The individual (Z)- and (Е)-isomers 2е were isolated by silica gel column chromatography. The (Е)-isomer was separated by crystallizing a mixture of (Z)- and (Е)-isomers of compound 2f from EtOAc (Scheme 2).

scheme 2

Scheme 2.

The composition and structure of the obtained products were confirmed by data of elemental analysis, 1Н, 13С NMR and IR spectroscopy. The (Z)-isomers of compounds 2а–f showed a broad absorption band in IR spectra at 3150–3250 cm−1 due to the stretching vibrations of the hydrogen-bonded N–H group. The NH proton was observed in 1Н NMR spectra of compounds 2а–f in CDCl3 solution in the range of 12.1–13.4 ppm as a result of intramolecular hydrogen bond with the oxygen atom of carbonyl group, confirming its (Z)-configuration. At the same time, IR spectra of (E)-isomers featured a narrow absorption band at 3410 cm−1 due to the stretching vibrations of N–H bond, while 1Н NMR spectra showed the NH proton signal at 8.3 ppm. These observations were in a good agreement with literature data on (E)- and (Z)-isomers of N-acyl-β-enaminoketones.25

The experiments regarding nucleophilic substitution of chloride in N-(3-oxoalkenyl)chloroacetamides 2a–d with a tolylsulfonyl group by the action of TsNa showed that the obtained 3-tosylacetamides 3a–d cyclized under the reaction conditions, forming 3-tosylpyridin-2(1Н)-ones 4а–d already at room temperature according to TLC data. Performing the reaction in the presence of K2CO3 in DMF for 1–2 days allowed to obtain 3-tosylpyridin-2(1Н)-ones 4а–с in 51–71% yields (Scheme 3).

scheme 3

Scheme 3.

At the same time, the reaction of chloroacetamide 2d with TsNa under these conditions did not proceed to completion according to TLC analysis. It could be completed by subsequent heating of the reaction mixture to 70°С for 5 h or by performing the reaction at room temperature for 4 days. The longer reaction time required in the case of compound 2d was apparently associated with the lower activity of carbonyl group in the five-membered ring.

Attempts to convert N-(3-oxoalkenyl)chloroacetamides (Z)-2e,f to the corresponding 3-(tolylsulfonyl)pyridin-2-ones 4e,f were unsuccessful neither by heating in the presence of K2CO3 nor by treatment with potassium tertbutoxide. The only major products of the reaction were the (E)-isomers of tosylacetamides 3e,f, obtained in 62 and 79% yields, respectively. Decreasing the steric bulk of the substituent R3 at the α-position relative to the nitrogen atom in N-(3-oxoalkenyl)amide should stabilize the (E)-isomer by minimizing the steric interaction with carbonyl group at the double bond. On the other hand, increasing the steric bulk of substituent R3 favored the (Z)-isomer via additional stabilization by intramolecular hydrogen bond.

Deprotonation of the nitrogen atom by the action of bases resulted in the control of equilibrium between the isomers (tautomers) only through steric factors, increasing the stability of (E)-isomers in the case of compounds 3e,f (R3 = H), the cyclization of which is impossible (Scheme 4). We observed a similar substituent effect during the cyclization of N-(3-oxoalkenyl)arylacetamides to 6-arylpyridin-2(1Н)-ones.13

scheme 4

Scheme 4.

Thus, intramolecular cyclization of N-(3-oxoalkenyl)-tosylacetamides can be successfully used for the synthesis of 3-tosylpyridin-2-ones, including derivatives with alicyclic rings fused at the С(4)–С(5) and С(5)–С(6) bonds. At the same time, this method failed to provide 3-tosylpyridin-2(1Н)-ones lacking substituents at the С(6) position. However, the diversity of suitable starting materials and the simple experimental procedure make N-(3-oxoalkenyl)chloroacetamides convenient precursors for the preparation of 3-tosyl-substituted pyridin-2-ones.

Experimental

IR spectra were recorded on an Infralum FT-801 spectrometer in KBr pellets. 1Н and 13C NMR spectra were acquired on a Bruker DRX-400 spectrometer (400 and 100 MHz, respectively) in CDCl3 solution, with TMS as internal standard. 13С NMR spectra were acquired in JMOD mode. Elemental analysis was performed on a Carlo Erba EA 1106 automatic CHN-analyzer. The reaction progress and purity of the obtained compounds were controlled by TLC method on Sorbfil AF-A-UF plates, visualization with iodine vapor and under UV light. The separation and purification of the obtained compounds were performed by column chromatography, using L 40/100 silica gel or alumina as the stationary phase.

The starting β-enaminoketones 1a–d26 and 1e,f27 were obtained according to published procedures. The synthesis of N-(3-oxoalkenyl)chloroacetamides 2a–c was described in our earlier work.24

Synthesis of N-(3-oxoalkenyl)chloroacetamides 2d–f (General method). A solution of enaminoketone 1d–f (11 mmol) in anhydrous CHCl3 (15 ml) and pyridine (1.58 g, 20 mmol) was cooled and treated by dropwise addition of chloroacetyl chloride (1.9 g, 17 mmol) solution in CHCl3 (5 ml). The reaction mixture was stirred for 5 h at room temperature and left overnight. The solution was then washed with aqueous 10% HCl solution, several times with H2O, dried over anhydrous Na2SO4, and the solvent was removed by evaporation at reduced pressure.

2-Chloro- N -[1-(2-oxocyclopentylidene)ethyl]acetamide (2d). The product was purified by column chromatography (Al2O3, CH2Cl2–hexane, 5:1). Yield 1.97 g (89%), light-yellow oil. IR spectrum, ν, cm−1: 3200–3100 (NH), 1692 (С=О), 1675 (С=О), 1613 (NС=О). 1H NMR spectrum, δ, ppm (J, Hz): 1.89–1.98 (2H, m, H-4); 2.39 (3H, s, CH3); 2.42 (2H, t, 3J = 7.9, H-5); 2.61–2.67 (2H, m, H-3); 4.08 (2H, s, СH2Cl); 12.61 (1H, br. s, NH). 13C NMR spectrum, δ, ppm: 18.3 (CH3); 19.7 (C-4); 27.2 (C-5); 39.6 (C-3); 43.2 (CH2); 116.3 (C-1); 146.2 (CCH3); 165.7 (NHCO); 208.3 (COCH3). Found, %: C 53.75; H 5.76; N 6.72. C9H12ClNO2. Calculated, %: C 53.61; H 6.00; N 6.95.

2-Chloro- N -[(2-oxocyclohexylidene)methyl]acetamide (2e) (a mixture of (Z)- and (Е)-isomers). The dark residue was purified by silica gel flash chromatography (CHCl3–EtOAc, 1:1). Chloroacetamide 2e was obtained as a light-yellow oil (0.55 g, 25%) containing a mixture of (Z)- and (E)-isomers at 84:16 ratio according to the data of 1Н NMR spectroscopy. The individual isomers were isolated by silica gel column chromatography, using 1:1 CHCl3–EtOAc as eluent.

Compound ( Z )-2e. Colorless crystals, mp 62–64°C (hexane). Rf 0.56 (CHCl3–EtOAc, 1:1). IR spectrum, ν, cm−1: 3254 (NH), 1697 (C=O), 1663, 1587 (NC=O). 1H NMR spectrum, δ, ppm (J, Hz): 1.71–1.88 (4H, m), 2.41–2.54 (4H, m, (CH2)4); 4.13 (2Н, s, CH2Cl); 7.19 (1H, dt, 3J = 10.6, 4J = 1.5, CHNH); 12.16 (1Н, m, NH). 13C NMR spectrum, δ, ppm: 22.3; 23.3; 28.9; 39.6 (4CH2); 42.3 (CH2Cl); 115.4 (C=СHN); 132.2 (СНN); 165.7 (NHCO); 203.9 (С=О). Found, %: C 53.87; H 6.29; N 6.71. C9H12ClNO2. Calculated, %: C 53.61; H 6.00; N 6.95.

Compound ( E )-2e. Colorless crystals, mp 115–117°C (EtOAc). Rf 0.56 (CHCl3–EtOAc, 1:1). IR spectrum, ν, cm−1: 3411 (NH), 1710 (C=O), 1687, 1598 (NC=O). 1H NMR spectrum, δ, ppm (J, Hz): 1.80–1.89 (4H, m), 2.32–2.57 (4H, m, (CH2)4); 4.20 (2Н, s, CH2Cl); 7.90 (1Н, d, 3J = 12.1, CHNH); 8.28 (1H, d, 3J = 12.1, NH). 13C NMR spectrum, δ, ppm: 22.6; 22.7; 24.5; 39.6 (4CH2); 42.6 (CH2Cl); 118.6 (C=СHN); 128.4 (СНN); 163.8 (NHCO); 199.1 (С=О). Found, %: C 53.93; H 5.72; N 7.26. C9H12ClNO2. Calculated, %: C 53.61; H 6.00; N 6.95.

2-Chloro- N -[1-(2-oxocyclopentylidene)methyl]acetamide (2f) (mixture of (Е)- and (Z)-isomers). The obtained dark residue (1.68 g, 81%) containing a mixture of (Z)- and (E)-isomers of chloroacetamide 2f (63:37 ratio according to the data of 1Н NMR spectroscopy) was first purified by silica gel flash chromatography (CHCl3–EtOAc, 1:1), followed by removal of the solvent and recrystallization from EtOAc. The product was pure (E)-isomer of chloroacetamide 2f (300 mg, 15% yield) isolated as light-yellow crystals. The evaporation of mother liquors afforded viscous yellow oil containing the (Z)-isomer with a small amount of the (E)-isomer.

Compound ( E )-2f. Light-yellow crystals, mp 164–165°С. Rf 0.45 (EtOAc–hexane, 1:1). IR spectrum, ν, cm−1: 3408 (NH), 1710 (С=О), 1632 (NС=О). 1Н NMR spectrum, δ, ppm (J, Hz): 1.99–2.07 (2H, m, 4-CH2); 2.38 (2H, t, 3J = 8.0, 5-CH2); 2.63 (2H, td, 3J = 7.3, 4J = 2.7, 3-CH2); 4.19 (2H, s, CH2Cl); 7.78 (1H, dt, 3J = 11.9, 4J = 2.5, CHNH); 8.31 (1H, br. d, 3J = 11.0, NH). 13C NMR spectrum, δ, ppm: 19.8 (C-4); 25.4 (C-5); 38.6 (C-3); 42.4 (CH2Cl); 119.9 (C-1); 125.3 (CHN); 164.4 (NHCO); 206.8 (C-2). Found, %: С 51.59; Н 5.74; N 7.18. C8H10ClNO2. Calculated, %: С 51.21; Н 5.37; N 7.47.

Compound ( Z )-2f. Yellow oil. Rf 0.65 (EtOAc–hexane, 1:1). 1Н NMR spectrum, δ, ppm (J, Hz): 1.99–2.07 (2H, m, 4-CH2); 2.41 (2H, t, 3J = 7.8, 5-CH2); 2.67 (2H, td, 3J = 7.3, 4J = 1.8, 3-CH2); 4.15 (2H, s, CH2Cl); 7.26 (1H, dt, 3J = 10.5, 4J = 2.1, CHNH); 11.77 (1H, br. s, NH). 13C NMR spectrum, δ, ppm (obtained by subtracting the signals of (E)-isomer from the spectrum of isomer mixture): 21.1 (C-4); 27.4 (C-5); 39.5 (C-3); 42.2 (CH2Cl); 117.7 (C-1); 127.9 (CHN); 165.1 (NHCO); 210.2 (C-2).

Synthesis of (4-methylphenyl)sulfonylpyridones 4a–d (General method). A mixture of compound 2 (1.0 mmol), K2CO3 (207 mg, 1.5 mmol), TsNa monohydrate (294 mg, 1.5 mmol), and KI (17 mg, 0.10 mmol) in anhydrous DMF (3 ml) was stirred for 2 days at room temperature, then poured into cold water (12 ml). The precipitate was filtered off and recrystallized.

4,6-Dimethyl-3-[(4-methylphenyl)sulfonyl]-2(1 H )-one (4а). Yield 70%, colorless crystals, mp 268–270°С (decomp.). 1H NMR spectrum, δ, ppm (J, Hz): 2.16 (3H, s, 4-CH3); 2.36 (3H, s, 6-CH3); 2.62 (3H, s, ArCH3); 6.07 (1H, s, 5-H); 7.33–7.80 (2Н, m, Н Ar); 12.01 (1Н, br. s, NH). 13C NMR spectrum, δ, ppm: 18.37 (6-CH3); 20.91 (4-CH3); 21.14 (ArCH3); 109.15 (C-5); 122.70 (C-3); 127.55; 128.68; 139.46; 142.95 (С Ar); 151.29 (C-6); 156.33 (C-4); 158.29 (C-2). 1H and 13С NMR spectra, as well as melting point were in agreement with the previously reported data for compound 4а.15

6-Methyl-3-[(4-methylphenyl)sulfonyl]-4-phenylpyridin-2(1 H )-one (4b). Yield 205 mg (60%), colorless crystals, mp 244–245°С (EtOH). IR spectrum, ν, cm−1: 3250 (NH), 1643, 1617 (C=O), 1308, 1149 (SO2). 1H NMR spectrum, δ, ppm (J, Hz): 2.32 (3H, s, 6-CH3); 2.39 (3H, s, ArCH3); 6.06 (1H, s, H-5); 7.17–7.24 (2H, m, H Ar); 7.33–7.53 (5H, m, H Ph); 7.78–7.90 (2H, m, H Ar); 13.41 (1H, br. s, NH). 13C NMR spectrum, δ, ppm: 19.0 (6-CH3); 21.6 (ArCH3); 110.9 (C-5); 124.0 (C-3); 127.3; 127.7; 128.5; 128.6 (2C); 128.8 (2C); 138.1; 138.8; 143.5; 150.3 (C-4); 159.1 (C-6); 161.3 (C-2). Found, %: C 67.49; H 5.21; N 4.38. C19H17NO3S. Calculated, %: С 67.24; H 5.05; N 4.13.

4-Methyl-3-[(4-methylphenyl)sulfonyl]-5,6,7,8-tetrahydroquinolin-2(1 H )-one (4c). Yield 226 mg (71%), colorless crystals, mp 237–238°С (EtOH). IR spectrum, ν, cm−1: 3300–3240 (NH), 1639, 1614 (NC=O), 1304, 1156 (SO2). 1H NMR spectrum, δ, ppm (J, Hz): 1.69–1.85 (4H, m, 2CH2); 2.38 (3H, s, ArCH3); 2.42–2.51 (4H, m, 2CH2); 2.71 (3H, s, 4-CH3); 7.18–7.23 (2H, m, H Ar); 7.83–7.89 (2H, m, H Ar); 12.95 (1Н, br. s, NH). 13C NMR spectrum, δ, ppm: 16.1 (4-CH3); 20.8 (CH2); 21.6 (ArCH3); 22.6, 24.5, 27.5 (3CH2); 115.6 (C-4a); 124.9 (C-3); 128.1 (2C Ar); 128.5 (2C Ar); 140.1 (C Ar); 143.1 (C Ar); 148.6 (C-4); 157.5 (C-8a); 159.7 (C-2). Found, %: C 64.04; H 5.86; N 4.63. C17H19NO3S. Calculated, %: С 64.33; H 6.03; N 4.41.

1-Methyl-4-[(4-methylphenyl)sulfonyl]-2,5,6,7-tetrahydro-3 H -cyclopenta[ с ]pyridin-3-one (4d) was obtained according to the general method, but after stirring for 1 day at room temperature the reaction mixture was heated to 70°С and maintained for 5 h. Yield 154 mg (51%), colorless crystals, mp 262–263°С (EtOH). IR spectrum, ν, cm−1: 3290–3240 (NH), 1631 (NC=O), 1317, 1151 (SO2). 1H NMR spectrum, δ, ppm (J, Hz): 2.05–2.14 (2H, m, CH2); 2.22 (3H, s, 1-CH3); 2.38 (3H, s, ArCH3); 2.63–2.69 (2H, m), 3.50 (2H, t, 3J = 7.7, 2CH2); 7.19–7.23 (2H, m, H Ar); 7.88–7.92 (2H, m, H Ar). 13C NMR spectrum, δ, ppm: 17.3 (1-CH3); 21.6 (ArCH3); 24.8, 28.0, 34.5 (3СH2); 121.7 (C-4); 122.6 (C-7a); 128.5 (2C Ar); 128.7 (2C Ar); 139.0 (C Ar); 143.6 (C Ar); 145.4 (C-4a); 160.9 (C-1); 164.2 (C-3). Found, %: C 63.65; H 5.84; N 4.48. C16H17NO3S. Calculated, %: С 63.34; H 5.65; N 4.62.

( E )-2-[(4-Methylphenyl)sulfonyl]- N -[(2-oxocyclohexylidene)methyl]acetamide (3e) was obtained according to the general method for the synthesis of compounds 4. Yield 199 mg (62%), colorless crystals, mp 142–143°C (EtOH–H2O). IR spectrum, ν, cm−1: 3263 (NH), 1714 (C=O), 1678, 1570 (NC=O), 1330, 1152 (SO2). 1H NMR spectrum, δ, ppm (J, Hz): 1.76–1.99 (4H, m), 2.42–2.46 (2H, m, 3CH2); 2.47 (3H, s, CH3); 2.51–2.57 (2H, m, CH2); 4.13 (2H, s, СH2SO2); 7.37–7.41 (2H, m, H Ar); 7.72–7.76 (2H, m, H Ar); 7.84–7.90 (1H, m, СНNH); 8.69 (1H, m, NH). 13C NMR spectrum, δ, ppm: 21.8 (CH3); 22.6, 22.7, 24.6, 39.7 (4CH2); 61.9 (CH2SO2); 118.7; 128.0 (2C Ar); 128.5 (CНN); 130.5 (2C Ar); 134.6 (C Ar); 146.4 (C Ar); 158.7 (NHCO); 199.3 (С=О). Found, %: C 59.55; H 5.71; N 4.59. C16H19NO4S. Calculated, %: C 59.79; H 5.96; N 4.36.

( E )-2-[(4-Methylphenyl)sulfonyl]- N -[(2-oxocyclopentylidene)methyl]acetamide (3f). A solution of acetamide (E)-2f (150 mg, 0.8 mmol) in i-PrOH (5 ml) was treated by the addition of TsNa hydrate (230 mg, 1.2 mmol) and refluxed for 24 h. The precipitated salt was filtered off, the solvent was evaporated, the residue was triturated with hexane, and the amorphous hygroscopic powder was recrystallized three times from 1:1 mixture of H2O–EtOH. Yield 195 mg (79%), white crystals, mp 152–153°С. IR spectrum, ν, cm−1: 3275 (NH); 1697 (C=O), 1607, 1526 (NC=O), 1323, 1153 (SO2). 1Н NMR spectrum, δ, ppm (J, Hz): 1.96–2.06 (2H, m, 4-CH2); 2.38 (2H, t, 3J = 7.8, 5-CH2); 2.43 (3H, s, CH3); 2.65 (2H, td, J = 7.2, J = 2.6, 3-CH2); 4.20 (2H, s, CH2SO2); 7.39 (2H, d, J = 7.9, H-3,5); 7.69–7.77 (3H, m, СНNH, H-2,6); 8.75 (1H, br. d, J = 11.6, NH). 13C NMR spectrum, δ, ppm: 19.9 (C-4); 21.8 (СН3); 25.6 (C-5); 38.8 (C-3); 62.1 (CH2SO2); 120.3 (C-1); 125.4 (CHN); 128.1 (2C Ar); 130.3 (2C Ar); 134.8 (C Ar); 146.2 (C Ar); 159.5 (NHCO); 207.3 (C-2). Found, %: С 58.97; Н 5.85; N 4.88. C15H17NO4S. Calculated, %: С 58.61; Н 5.57; N 4.56.