Substituted 3-hydroxy-3-pyrrolin-2-ones are five-membered nitrogen-containing heterocyclic compounds that are components of a number of biologically active substances and drugs, which determines their interest for medicine and pharmacy [1, 2].

They are of interest in organic synthesis due to possibility to react with various nucleophiles owing to the presence of two carbonyl groups at position 3 of the heterocycle and a side chain at position 4, which allows the formation of various heterocyclic fused systems [1, 2].

Previously, it has been found that the substituent at position 1 of the heterocycle significantly affects the biological activity and reactivity of 1,4,5-trisubstituted 3-hydroxy-3-pyrrolin-2-ones [1, 3].

Cyano group is a part of a number of currently used drugs [4]. Therefore, it was of interest to introduce a cyanomethyl group into the position 1 of the heterocycle and further evaluate its effect on the reactivity and biological activity of newly synthesized compounds. The synthesis of 5-aryl-4-aroyl-3-hydroxy-1-cyanomethyl-3-pyrrolin-2-ones has been previously described in [5]. In order to assess the effect of the halogen in the para-position of aroylpyruvic acid methyl ester on the reactivity and biological activity of the obtained compounds, we studied the three-component reaction of p-halobenzoylpyruvic acids methyl esters with a mixture of aromatic aldehyde and 2-aminoacetonitrile sulfate. The reaction proceeds upon short-term heating of an equimolar amount of reagents in the presence of anhydrous sodium acetate in glacial acetic acid to form 5-aryl-4-(-4-halogenaroyl)-3-hydroxy-1-cyanomethyl-3-pyrrolin-2-ones 1–10 (Scheme 1).

Scheme
scheme 1

1.

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2-Aminoacetonitrile, which does not exist in free form under normal conditions, was obtained in situ by reacting 2-aminoacetonitrile sulfate with anhydrous sodium acetate in acetic acid medium. Presumably, the reaction proceeds with the formation of an intermediate Schiff base. Further addition of methyl p-halobenzoylpyruvate followed by cyclization of the intermediate 4-aryl-4-amino-2-oxobutanoic acid ester furnished the corresponding 3-hydroxy-3-pyrrolin-2-ones 1–10 (Scheme 2).

Scheme
scheme 2

2.

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The obtained compounds 1–10 are crystalline substances, soluble in DMSO, DMF, in ethanol and glacial acetic acid with heating, and insoluble in water. The IR spectra of compounds 1–10 show absorption bands of the lactam carbonyl group at 1696–1664 cm–1 and a strong absorption band of the enol hydroxyl group at 3200–3040 cm–1. The absorption band of the side chain carbonyl group is observed at 1632–1604 cm–1.

It should be noted that we were unable to detect the absorption band of the C≡N group in the IR spectra of compounds 1–10. Apparently, this is explained by the fact that the introduction of an oxygen-containing group into the molecule leads to a significant decrease in the intensity of the C≡N absorption band [6], and the effect of this group is greater when it is attached to the same carbon atom as the nitrile, and can be indistinguishable at all.

The 1Н NMR spectra of compounds 1–10 contain signals of aromatic protons (6.35–8.46 ppm), a characteristic singlet of the methine proton at position 5 of the heterocycle (5.36–5.69 ppm), two doublets of cyanomethyl group protons at the nitrogen atom of the heterocycle (3.96–4.54 ppm, J = 16.7–18.6 Hz) and the signal of the OH-group proton in position 3 of the heterocycle (11.98–12.31 ppm). The signal of the OH group proton in position 3 of the heterocycle in the spectra of compounds 1–10 is strongly broadened due to deuterium exchange [2].

In order to study the reactivity of the obtained compounds 1–10, we performed their reactions with p-toluidine and hydrazine hydrate [7, 8]. Thus, the reaction of 5-phenyl-4-(4-chlorobenzoyl)-3-hydroxy-1-cyanomethyl-3-pyrrolin-2-one 5 with p-toluidine upon refluxing in acetic acid for 2 h yielded 5-phenyl-4-(4-chlorobenzoyl)-3-(4-methylphenylamino)-1-cyanomethyl-3-pyrrolin-2-one 11 (Scheme 3). Structure of compound 11 was confirmed by 1H NMR data.

Scheme
scheme 3

3.

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The 1Н NMR spectrum of compound 11 contains signals of aromatic protons in the range of 6.78– 7.33 ppm, a singlet of the methine proton at the C5 atom at 5.64 ppm, and two doublets of methylene group protons in the α-position of the cyanomethyl substituent at 4.20, 4.24 ppm (CαHAHB) and 4.48, 4.53 ppm (CαHAHB). The NH-proton of the aminotolyl substituent in position 3 of the heterocycle resonates at 9.04 ppm; the singlet at 1.92 ppm corresponds to the protons of the p-methyl group.

5-Aryl-4-(4-halogenaroyl)-3-hydroxy-1-cyanomethyl-3-pyrrolin-2-ones have two reaction sites at positions 3 and 4 of the pyrrole ring. Therefore, reactions of these compounds with such a binucleophilic agent as hydrazine hydrate allows to obtain a fused heterocyclic system [8]. So, the reaction of 5-phenyl-4-bromobenzoyl-3-hydroxy-1-cyanomethyl-3-pyrrolin-2-one 1 and hydrazine hydrate in glacial acetic acid produced 6-p-bromophenyl-5-phenyl-4-cyanomethyl-3,5-dihydropyrrolo[3,4-c]pyrazol-3-one 12 (Scheme 3).

Structure of compound 12 was confirmed by 1H NMR spectroscopy data. The 1Н NMR spectrum of compound 12 contains signals of aromatic protons in the range of 7.26–7.54 ppm, a singlet of the NH proton at 13.88– 13.96 ppm, a singlet of the methine proton at the C5 atom in the range of 6.0 ppm, as well as two doublets of the methylene protons at the α-position of the cyanomethyl substituent at 4.56, 4.52 ppm (CαHAHB) and 4.20, 4.15 ppm (CαHAHB).

Thus, the introduction of a halogen at the p-position of aroylpyruvic acid methyl ester does not significantly affect the formation of a fused heterocyclic system and the reactivity of the carbonyl group at position 3 of the heterocycle.

EXPERIMENTAL

IR spectra were recorded on a Specord M-80 spectrometer from KBr pellets. 1H NMR spectra were registered on a Bruker AM-300 (300 MHz) instrument from DMSO-d6 solutions relative to internal TMS.

General procedure for the preparation of compounds 1–10. To a solution of 0.05 mol of aminoacetonitrile hydrogen sulfate in acetic acid was added 0.1 mol of sodium acetate. The resulting mixture was stirred until complete dissolution. Then a mixture of 0.1 mol of aromatic aldehyde and 0.01 mol of 4-aroylpyruvic acid methyl ester in dioxane was added. The resulting mixture was heated until the components dissolved and kept at room temperature for 1 day. The precipitate formed upon cooling was filtered off and recrystallized from ethanol.

4-Bromobenzoyl-3-hydroxy-5-phenyl-1-cyanomethyl-3-pyrrolin-2-one (1). Yield 77%, mp 252–256°С. IR spectrum, ν, cm–1: 3160 (OH), 1698 (CON), 1638 (CO). 1Н NMR spectrum, δ, ppm: 4.36 d (НАНВ, CH2CN, J = 17.6 Hz), 4.21 d (НАНВ, CH2CN, J = 17.6 Hz), 5.43 s (1H, С5Н), 7.27–7.55 m (9Н, CHAr), 11.62 s (1Н, OH). Found, %: C 57.45; H 3.30; N 7.05. C19H13BrN2O3. Calculated, %: C 57.15; H 3.00; N 6.75.

4-Bromobenzoyl-3-hydroxy-5-(4-methoxyphenyl)-1-cyanomethyl-3-pyrrolin-2-one (2). Yield 59%, mp 234–236°С. IR spectrum, ν, cm–1: 3176 (OH), 1698 (CON), 1638 (CO). 1Н NMR spectrum, δ, ppm: 3.66 s (3Н, ОСН3), 4.33 d (НАНВ, CH2CN, J = 17.7 Hz), 4.19 d (НАНВ, CH2CN, J = 17.6 Hz), 5.37 s (1H, С5Н), 6.75– 7.55 m (8Н, CHAr), 12.15 s (1Н, OH). Found, %: C 56.22; H 3.54; N 6.56. C20H15BrN2O4. Calculated, %: C 55.92; H 3.24; N 6.26.

4-Bromobenzoyl-3-hydroxy-1-cyanomethyl-5-(4-ethoxyphenyl)-3-pyrrolin-2-one (3). Yield 64%, mp 230–234°С. IR spectrum, ν, cm–1: 3180 (OH), 1698 (CON), 1638 (CO). 1Н NMR spectrum, δ, ppm: 1.34 t (5Н, ОСН2СН3), 3.96 q (5Н, ОСН2СН3), 4.33 d (НАНВ, CH2CN, J = 18.6 Hz), 4.19 d (НАНВ, CH2CN, J = 16.7 Hz), 5.37 s (1H, С5Н), 6.75–7.56 m (8Н, CHAr), 12.09 s (1Н, OH). Found, %: C 57.16; H 3.88; N 6.35. C21H17BrN2O4. Calculated, %: C 56.86; H 3.58; N 6.05.

4-Bromobenzoyl-3-hydroxy-5-(4-hydroxy-3-ethoxyphenyl)-1-cyanomethyl-3-pyrrolin-2-one (4). Yield 70%, mp 239–242°С. IR spectrum, ν, cm–1: 3054 (OH), 1712 (CON), 1632 (CO). 1Н NMR spectrum, δ, ppm: 4.32 d (СНАНВ, CH2CN, J = 17.6 Hz), 4.21 d (НАНВ, CH2CN, J = 17.6 Hz), 5.33 s (1H, С5Н), 6.69–7.58 m (7Н, CHAr), 11.40 s (1Н, OH). Found, %: C 55.16; H 3.75; N 6.13. C21H17BrN2O5. Calculated, %: C 54.86; H 3.45; N 5.83.

3-Hydroxy-5-phenyl-4-chlorobenzoyl-1-cyanomethyl-3-pyrrolin-2-one (5). Yield 68%, mp 217–226°С. IR spectrum, ν, cm–1: 3176 (OH), 1696 (CON), 1638 (CO). 1Н NMR spectrum, δ, ppm: 4.35 d (НАНВ, CH2CN, J = 17.6 Hz), 4.20 d (НАНВ, CH2CN, J = 18.5 Hz), 5.41 s (1H, С5Н), 7.26–7.68 m (9Н, CHAr), 11.49 s (1Н, OH). Found, %: C 64.69; H 3.71; N 7.94. C19H13ClN2O3. Calculated, %: C 64.39; H 3.41; N 7.64.

3-Hydroxy-5-(4-methoxyphenyl)-4-chlorobenzoyl-1-cyanomethyl-3-pyrrolin-2-one (6). Yield 62%, mp 205–210°С. IR spectrum, ν, cm–1: 3160 (OH), 1700 (CON), 1636 (CO). 1Н NMR spectrum, δ, ppm: 3.67 s (3Н, ОСН3), 4.33 d (НАНВ, CH2CN, J = 17.4 Hz), 4.17 d (НАНВ, CH2CN, J = 16.7 Hz), 5.36 s (1H, С5Н), 7.17–7.69 m (8Н, CHAr), 11.28 s (1Н, OH). Found, %: C 62.75; H 3.95; N 7.32. C20H15ClN2O4. Calculated, %: C 62.45; H 3.65; N 7.02.

3-Hydroxy-4-chlorobenzoyl-1-cyanomethyl-5-(4-ethoxyphenyl)-3-pyrrolin-2-one (7). Yield 52%, mp 210–215°С. IR spectrum, ν, cm–1: 3180 (OH), 1700 (CON), 1636 (CO). 1Н NMR spectrum, δ, ppm: 1.26 t (5Н, ОСН2СН3), 3.88 q (5Н, ОСН2СН3), 4.33 d (НАНВ, CH2CN, J = 17.7 Hz), 4.20 d (НАНВ, CH2CN, J = 17.6 Hz), 5.38 s (1H, С5Н), 6.73–7.69 m (8Н, CHAr), 11.37 s (1Н, OH). Found, %: C 63.56; H 4.32; N 7.06. C21H17ClN2O4. Calculated, %: C 63.26; H 4.02; N 6.76.

3-Hydroxy-5-phenyl-4-fluorobenzoyl-1-cyanomethyl-3-pyrrolin-2-one (8). Yield 71%, mp 223–227°С. IR spectrum, ν, cm–1: 3056 (OH), 1712 (CON), 1625 (CO). 1Н NMR spectrum, δ, ppm: 4.36 d (НАНВ, CH2CN, J = 17.6 Hz), 4.22 d (НАНВ, CH2CN, J = 17.6 Hz), 5.43 s (1H, С5Н), 7.07–7.73 m (9Н, CHAr), 11.57 s (1Н, OH). Found, %: C 67.85; H 3.90; N 8.33. C19H13FN2O3. Calculated, %: C 67.55; H 3.60; N 8.03.

3-Hydroxy-5-(4-methoxyphenyl)-4-fluorobenzoyl-1-cyanomethyl-3-pyrrolin-2-one (9). Yield 94%, mp 210–214°С. IR spectrum, ν, cm–1: 3064 (OH), 1712 (CON), 1607 (CO). 1Н NMR spectrum, δ, ppm: 3.68 s (3Н, ОСН3), 4.34 d (НАНВ, CH2CN, J = 17.6 Hz), 4.20 d (НАНВ, CH2CN, J = 17.6 Hz), 5.40 s (1H, С5Н), 6.75–7.91 m (8Н, CHAr), 11.64 s (1Н, OH). Found, %: C 65.57; H 4.13; N 7.65. C20H15FN2O4. Calculated, %: C 65.27; H 3.83; N 7.35.

3-Hydroxy-4-fluorobenzoyl-1-cyanomethyl-5-(4-ethoxyphenyl)-3-pyrrolin-2-one (10). Yield 85%, mp 201–206°С. IR spectrum, ν, cm–1: 3168 (OH), 1712 (CON), 1604 (CO). 1Н NMR spectrum, δ, ppm: 1.26 t (5Н, ОСН2СН3), 3.96 q (5Н, ОСН2СН3), 4.34 d (НАНВ, CH2CN, J = 17.6 Hz), 4.21 d (НАНВ, CH2CN, J = 17.6 Hz), 5.39 s (1H, С5Н), 6.74–7.80 m (8H, CHAr), 12.29 s (1Н, OH). Found, %: C 66.31; H 4.50; N 7.36. C21H17FN2O4. Calculated, %: C 66.01; H 4.2; N 7.06.

3-(4-Methylphenylamino)-5-phenyl-4-(4-chlorobenzoyl)-1-cyanomethyl-3-pyrrolin-2-one (11). To a solution of 0.002 mol of compound 5 in 10 mL of glacial acetic acid was added 0.004 mol of p-toluidine. The resulting mixture was refluxed for 2 h. The precipitate that formed upon cooling was filtered off and recrystallized from acetic acid. Yield 35%, mp 150–156°С. 1Н NMR spectrum, δ, ppm: 1.92 s (3H, CH3), 4.22 d (НАНВ, CH2CN, J = 20.0 Hz), 4.51 d (НАНВ, CH2CN, J = 16.0 Hz), 5.64 s (1H, С5Н), 6.78–7.33 m (14H, CHAr), 11.82 s (1Н, OH), 9.04 s (1H, NH). Found, %: C 70.67; H 4.56; N 9.51. C26H20ClN3O2. Calculated, %: C 70.37; H 4.26; N 9.21.

6-(4-Bromophenyl)-5-phenyl-4-cyanomethyl-3,5-dihydropyrrolo[3,4-с]pyrazol-3-one (12). To a solution of 0.002 mol of compound 1 in 10 mL of glacial acetic acid was added 0.002 mol of hydrazine hydrate. The resulting mixture was refluxed for 2 h. The precipitate that formed upon cooling was filtered off and recrystallized from acetic acid. Yield 57%, mp 265–267°С. 1Н NMR spectrum, δ, ppm: 4.18 d (НАНВ, CH2CN, J = 16.0 Hz), 4.54 d (НАНВ, CH2CN, J = 20.0 Hz), 6.0 s (1H, С5Н), 7.26–7.54 m (9H, CHAr). Found, %: C 58.03; H 3.33; N 14.25. C19H13BrN4O. Calculated, %: C 57.73; H 3.03; N 13.95.