Synthesis of 4-Acyl-5-aryl-3-hydroxy-1-(3-picolyl)-3-pyrroline-2-ones

Article abstract of DOI:10.1134/S1070363220040039

Abstract: Reaction of methyl esters of acylpyruvic acids with a mixture of aromatic aldehyde and 3-picolylamine gave 5-aryl-4-acyl-3-hydroxy-1-(3-picolyl)-3-pyrroline-2-ones, the structure of which was confirmed on the basis of ¹H NMR, ¹³C NMR, IR spectroscopy.

Full text of DOI:10.1134/S1070363220040039

ISSN 1070-3632, Russian Journal of General Chemistry, 2020, Vol. 90, No. 4, pp. 579–582. © Pleiades Publishing, Ltd., 2020.
Russian Text © The Author(s), 2020, published in Zhurnal Obshchei Khimii, 2020, Vol. 90, No. 4, pp. 508–512.
Synthesis
of 4-Acyl-5-aryl-3-hydroxy-1-(3-picolyl)-3-pyrroline-2-ones
V. L. Geina,*, N. V. Nosovaa, A. A. Cherepanova, L. F. Geinb, and K. D. Il’inaa
a Perm State Pharmaceutical Academy, Perm, 614990 Russia
b Perm State Medical University, Perm, 614990 Russia
e-mail: geinvl48@mail.ru
Received November 11, 2019; revised November 11, 2019; accepted November 14, 2019
Abstract—Reaction of methyl esters of acylpyruvic acids with a mixture of aromatic aldehyde and 3-picolylamine
gave 5-aryl-4-acyl-3-hydroxy-1-(3-picolyl)-3-pyrroline-2-ones, the structure of which was confirmed on the basis
of 1H NMR, 13C NMR, IR spectroscopy.
Keywords: methyl esters of acylpyruvic acids, aromatic aldehydes, 3-picolylamine, 5-aryl-4-acyl-3-hydroxy-
1-(3-picolyl)-3-pyrroline-2-ones
DOI: 10.1134/S1070363220040039
1,4,5-Trisubstituted 3-hydroxy-3-pyrrolin-2-ones
are available multifunctional heterocyclic compounds,
convenient for the synthesis of various fused heterocyclic
systems based on them [1–3]. Among the 1-substituted
5-aryl-4-acyl-3-hydroxy-3-pyrrolin-2-ones, substances
with antimicrobial, antifungal, antiviral activity, as well
as analgesic, anti-inflammatory, antipyretic and nootropic
activity have been previously found [1, 3–6]. It has been
shown that the nature of the substituent at position 1 of
the heterocycle has the greatest effect on the biological
activity of 3-pyrrolin-2-ones [1, 3].
reaction proceeded in dioxane with short-term heating to
form 5-aryl-4-acyl-3-hydroxy-1-(3-picolyl)-3-pyrrolin-
2-ones 1a–1l.
The obtained compounds 1a–1l are colorless
crystalline substances soluble in DMSO, DMF, sparingly
soluble in acetic acid, dioxane, and alcohol, insoluble in
water.
The IR spectra of compounds 1a–1l contain absorption
bands of the ketone carbonyl group (1624–1652 cm–1),
the lactam carbonyl group (1692–1710 cm–1) and the
enol OH group (3096–3200 cm–1). The 1H NMR spectra
of compounds 1a–1l, in addition to signals of aromatic
protons, contain a singlet of the methine proton at position
5 of the heterocycle in the region of 5.05–5.77 (1a–1e)
and 5.31–6.00 ppm (1f–1k), two doublets of enantiotopic
protons of the methylene group in the region of 3.80–
4.80 ppm (J = 15.8 Hz) and the singlet of protons of
the methyl group of the acetyl substituent (1a–1e) in at
2.25–2.30 ppm. The 13C NMR spectrum of compound 1a
contains signals at 191.4 (СО), 165.5 [С(О)N], 60.5 (СН),
41.5 (СН2), and 29.1 ppm (СН3). The 13C NMR spectra
of compounds 1b, 1c, 1f–1h are similar to the spectrum
of compound 1a and confirm the proposed structure.
Continuing the study of the effect of the nature of the
substituent at position 1 of the heterocycle on the chemical
properties and biological activity of 1-substituted 5-aryl-
4-acyl-3-hydroxy-3-pyrrolin-2-ones, it was of interest
to introduce a pyridinyl-3-methyl substituent at position
1. It is known that the pyridine fragment is a part of
natural biologically active substances, such as vitamin
B6, vitamin PP. In addition, it is scaffold of a number
of drugs, such as picamilon and pyriditol possessing
nootropic and vasodilating effects, non-steroidal synthetic
cardiotonic drugs amrinone and milrinone, as well as
anabasine alkaloid [7].
Continuing the studies on the chemistry of trisubstituted
3-hydroxy-3-pyrrolin-2-ones and the preparation of new
biologically active compounds, herein we reported the
reaction of acylpyruvic acid methyl ester with a mixture
of aromatic aldehyde and 3-picolylamine (Scheme 1). The
Based on the available literature data [1, 3], it can be
assumed that the formation of 5-aryl-4-acyl-3-hydroxy-1-
(3-picolyl)-3-pyrrolin-2-ones occurs according to a
known scheme. Apparently, the corresponding imine is
579

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GEIN et al.
Scheme 1.
Scheme 2.
formed in the first stage, which reacts with the acylpyruvic
acid ester to form intermediate A, which cyclizes to
3-hydroxy-3-pyrrolin-2-ones 1 (Scheme 2).
of new 5-aryl-4-acyl-3-hydroxy-1-(3-picolyl)-3-pyrrolin-
2-ones.
EXPERIMENTAL
All compounds obtained reacted with an alcoholic
solution of iron(III) chloride to form an intense violet-
purple solution. The spectral data and a qualitative
reaction indicate the existence of the obtained compounds
in the crystalline state and in solution mainly in enol
form, with an enolized carbonyl group in position 3 of
the heterocycle.
IR spectra were recorded on a Specord M-80
spectrometer from KBr pellets. 1H and 13C NMR spectra
were recorded on a Bruker Avance III HD spectrometer
(400 and 100 MHz, respectively) from DMSO-d6
solutions relative to internal TMS. Elemental analysis
was performed on a PerkinElmer 2400 instrument.
Melting points were determined on a Melting Point
M-565 instrument.
In summary, the three-component reaction of methyl
esters of acylpyruvic acids with aromatic aldehyde and
3-picolylamine is a convenient approach to the synthesis
4-Acetyl-3-hydroxy-5-phenyl-1-(3-picolyl)-3-
pyrrolin-2-one (1a). A mixture of 1.44 g (0.01 mol) of
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SYNTHESIS OF 4-ACYL-5-ARYL-3-HYDROXY-1-(3-PICOLYL)-3-PYRROLINE-2-ONES
581
4-Acetyl-3-hydroxy-5-(3-nitrophenyl)-1-(3-
picolyl)-3-pyrrolin-2-one (1d). Yield 2.40 g (67.9%),
mp 226–228°С (ethanol). IR spectrum, ν, cm–1: 1636
methyl ester of acetylpyruvic acid, 1.06 g (0.01 mol) of
benzaldehyde and 1.08 g (0.01 mol) of 3-picolylamine
was dissolved in 10 mLof dioxane at heating. The reaction
mixture was kept at room temperature until a precipitate
formed which was filtered off and recrystallized from
ethanol. Yield 1.8 g (58.5%), mp 208–210°С (ethanol). IR
spectrum, ν, cm–1: 1652 (С=О), 1710 (СОN), 3168 (OH).
1Н NMR spectrum, δ, ppm (J, Hz): 2.28 s (3Н, СН3СО),
3.88 d (1Н, СНАСНВ,J = 15.8 Hz), 4.73 d (1Н, СНАСНВ,
J = 15.8 Hz), 5.08 s (1H, C5H), 7.15 d (2Н, Ar, J =
8.3 Hz), 7.35 m (1Н, С5Н4N + 3Н,Ar), 7.50 t (1Н, С5Н4N,
J = 2.8 Hz), 8.25 s (1Н, С5Н4N), 8.44 d (1Н, С5Н4N, J =
2.8 Hz). 13С NMR spectrum, δС, ppm: 191.4 (СО), 165.5
[С(О)N], 154.6, 149.0, 148.0, 136.0, 135.1, 132.3, 128.4,
127.5, 127.0, 123.1, 120.0, 60.5 (СН), 41.5 (СН2), 29.1
(СН3). Found, %: С 70.37; Н 5.41; N 9.23. С18Н16N2О3.
Calculated, %: С 70.12; Н 5.23; N 9.09.
1
(С=О), 1708 (СОN), 3200 (OH). Н NMR spectrum,
δ, ppm: 2.27 s (3Н, СН3СО), 4.12 d (1Н, СНАСНВ, J =
15.8 Hz), 4.58 d (1Н, СНАСНВ, J = 15.8 Hz), 5.26 s
(1H, C5H), 7.16 d (1Н, С5Н4N, J = 2.8 Hz), 7.48 m (1Н,
С5Н4N + 3Н, Ar), 7.94 s (1Н, С5Н4N), 8.07 d (1Н, Ar),
8.21 d (1Н, С5Н4N, J = 2.8 Hz). Found, %: С 61.45; Н
4.42; N 12.13. С18Н15N2О5. Calculated, %: С 61.19; Н
4.28; N 11.89.
4-Acetyl-3-hydroxy-5-(2-nitrophenyl)-1-(3-
picolyl)-3-pyrrolin-2-one (1e). Yield 1.81 g (51.2%),
mp 211–213°C (dioxane). IR spectrum, ν, cm–1: 1642
(С=О), 1708 (СОN), 3180 (OH). 1Н NMR spectrum, δ,
ppm: 2.27 s (3Н, СН3СО), 4.06 d (1Н, СНАСНВ, J =
15.8 Hz), 4.78 d (1Н, СНАСНВ, J = 15.8 Hz), 5.77 s
(1H, C5H), 7.06 d (1Н, С5Н4N), 7.31 m (1Н, С5Н4N +
4Н, Аr), 7.78 s (1Н, С5Н4N), 8.27 d (1Н, С5Н4N, J =
2.7 Hz). Found, %: С 61.48; Н 4.06; N 11.72. С18Н15N2О5.
Calculated, %: С 61.19; Н 4.28; N 11.89.
Compounds 1b–1k were obtained similarly.
4-Acetyl-3-hydroxy-5-(4-methoxyphenyl)-1-(3-
picolyl)-3-pyrrolin-2-one (1b). Yield 1.78 g (52.7%), mp
216–218°С (ethanol). IR spectrum, ν, cm–1: 1648 (С=О),
1704(СОN), 3190(OH). 1НNMRspectrum, δ, ppm:2.25s
(3Н, СН3СО), 3.70 s (3Н, СН3О), 3.85 d (1Н, СНАСНВ,
J = 15.8 Hz), 4.70 d (1Н, СНАСНВ, J = 15.8 Hz), 5.05 s
(1H, C5H), 6.85 d (2Н, Ar, J = 8.3 Hz), 7.05 d (2Н, Ar,
J = 8.3 Hz), 7.30 d (1Н, С5Н4N, J = 2.8 Hz), 7.50 t (1Н,
С5Н4N, J = 2.8 Hz), 8.30 s (1Н, С5Н4N), 8.40 d (1Н,
С5Н4N, J = 2.8 Hz). 13С NMR spectrum, δС, ppm: 191.5
(СО), 165.5 [С(О)N], 158.3, 148.6, 148.0, 135.5, 132.3,
128.3, 127.5, 123.6, 120.0, 114.0, 60.0 (СН), 55.0, 41.8
(СН2), 29.3 (СН3). Found, %: С 67.74; Н 5.61; N 8.52.
С19Н18N2О4. Calculated, %: С 67.45; Н 5.36; N 8.28.
3-Hydroxy-4-(4-methoxyphenyl)-5-(3-nitro-
phenyl)-1-(3-picolyl)-3-pyrrolin-2-one (1f). Yield
2.80 g (65.0%), mp 227–229°С (decomp., ethanol). IR
spectrum, ν, cm–1: 1631 (С=О), 1696 (СОN), 3110 (OH).
1Н NMR spectrum, δ, ppm: 3.81 s (3Н, 4-СН3ОC6H4),
4.31 d (1Н, СНАСНВ, J = 16.0 Hz), 4.70 d (1Н, СНАСНВ,
J = 16.0 Hz), 5.62 s (1H, C5H), 6.96 d (2H, 4-CH3OC6H4,
J = 7.5 Hz), 7.25 t (1H, 3-NO2C6H4, J = 7.7 Hz), 7.51 m
(1Н, С5Н4N + 1H, 3-NO2C6H4), 7.71 d (1Н, С5Н4N, J =
2.7 Hz), 7.75 d (2H, 4-CH3OC6H4, J = 7.5 Hz), 8.06 m
(1Н, С5Н4N + 1H, 3-NO2C6H4), 8.28 s (1Н, С5Н4N),
8.40 d (1Н, С5Н4N, J = 2.7 Hz). 13С NMR spectrum, δС,
ppm: 187.2 (СО), 165.9 [С(О)N], 162.9, 150.8, 148.9,
148.2, 147.7, 138.6, 135.8, 134.4, 132.3, 131.2, 130.5,
130.0, 123.4, 123.1, 122.9, 119.4, 113.4, 60.9 (СН), 55.4
(СН2), 42.5 (СН3). Found, %: С 52.84; Н 4.48; N 6.62.
С24Н19N2О6. Calculated, %: С 52.90; Н 4.46; N 6.50.
4-Acetyl-3-hydroxy-5-(4-chlorophenyl)-1-(3-
picolyl)-3-pyrrolin-2-one (1c). Yield 1.53 g (44.6%),
mp 199–201°C (ethanol). IR spectrum, ν, cm–1: 1648
(С=О), 1708 (СОN), 3190 (OH). 1Н NMR spectrum, δ,
ppm: 2.30 s (3Н, СН3СО), 3.90 d (1Н, СНАСНВ, J =
15.8 Hz), 4.66 d (1Н, СНАСНВ, J = 15.8 Hz), 5.15 s (1H,
C5H), 7.15 d (2Н, Аr, J = 8.3 Hz), 7.25 d (2Н, С5Н4N,
J = 2.8 Hz), 7.30 s (1Н, Аr, J = 8.3 Hz), 7.45 t (1Н,
С5Н4N, J = 2.8 Hz), 8.30 s (1Н, С5Н4N), 8.40 d (1Н,
С5Н4N, J = 2.8 Hz). 13С NMR spectrum, δС, ppm: 191.0
(СО), 165.8 [С(О)N], 155.0, 148.6, 147.0, 135.2, 135.4,
133.0, 132.5, 129.6, 128.4, 123.6, 120.0, 59.5 (СН), 41.5
(СН2), 29.4 (СН3). Found, %: С 63.26; Н 4.63; Cl 10.28;
N 8.38. С18Н15ClN2О3. Calculated, %: С 63.07; Н 4.41;
Cl 10.34; N 8.17.
4-Benzoyl-3-hydroxy-5-phenyl-1-(3-picolyl)-3-
pyrrolin-2-one (1g). Yield 2.56 g (69.1%), mp 242–
244°C (decomp., dioxane). IR spectrum, ν, cm–1: 1628
(С=О), 1692 (СОN), 3106 (OH). 1Н NMR spectrum, δ,
ppm: 4.00 d (1Н, СНАСНВ, J = 15.8 Hz), 4.80 d (1Н,
СНАСНВ, J = 15.8 Hz), 5.40 s (1H, C5H), 7.26 s (5Н,
С6Н5), 7.45–7.60 m (6Н, С6Н5 + С6Н4N), 7.70 t (1Н,
С5Н4N, J = 2.8 Hz), 8.27 s (1Н, С5Н4N), 8.45 d (1Н,
С5Н, J = 2.8 Hz). 13С NMR spectrum, δС, ppm: 188.0
(СО), 165.0 [С(О)N], 149.0, 148.0, 138.0, 136.0, 135.0,
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GEIN et al.
133.0, 132.2, 132.5, 128.0, 127.5, 127.0, 126.0, 124.0,
119.0, 120.0, 62.0 (СН), 42.0 (СН2). Found, %: С 74.29;
Н 4.79; N 7.43. С23Н18N2О3. Calculated, %: С 74.58; Н
4.90; N 7.56.
3-NO2С6Н4), 8.17 s (1Н, С5Н4N), 8.28 d (1Н, С5Н4N,
J = 2.8 Hz). Found, %: С 66.69; Н 4.37; N 10.31.
С23Н176N3О5. Calculated, %: С 66.50; Н 4.12; N 10.12.
4-Benzoyl-3-hydroxy-5-(2-nitrophenyl)-1-(3-
picolyl)-3-pyrrolin-2-one (1k). Yield 3.21 g (77.0%),
mp 198–200°C (ethanol). IR spectrum, ν, cm–1: 1624
(С=О), 1696 (СОN), 3096 (OH). 1Н NMR spectrum, δ,
ppm: 4.22 d (1Н, СНАСНВ, J = 15.8 Hz), 4.77 d (1Н,
СНАСНВ, J = 15.8 Hz), 6.00 s (1H, C5H), 7.39 s (5Н,Ar),
7.50–7.63 m (4Н, Ar + 1Н, С5Н4N), 7.74 t (1Н, С5Н4N,
J = 2.8 Hz), 8.20 s (1Н, С5Н4N), 8.31 d (1Н, С5Н4N,
J = 2.8 Hz). Found, %: С 66.74; Н 3.93; N 10.29.
С23Н17N3О5. Calculated, %: С 66.50; Н 4.12; N 10.12.
4-Benzoyl-3-hydroxy-5-(4-methoxyphenyl)-1-(3-
picolyl)-3-pyrrolin-2-one (1h). Yield 2.5 g (62.4%), mp
233–235°С (decomp., dioxane). IR spectrum, ν, cm–1:
1628 (С=О), 1692 (СОN), 3120 (OH). 1Н NMR spectrum,
δ, ppm: 3.66 s (3Н, СН3О), 3.85 d (1Н, СНАСНВ,
J = 15.8 Hz), 4.80 d (1Н, СНАСНВ, J = 15.8 Hz),
5.33 s (1H, C5H), 6.78 d (2Н, СН3О С6Н4, J = 8.3 Hz),
7.15 d (2Н, СН3ОС6Н4, J = 8.3 Hz), 7.33 d (1Н, С5Н4N,
J = 2.8 Hz), 7.4–7.58 m (5Н, Аr), 7.71 t (1Н, С5Н4N,
J = 2.8 Hz), 8.30 s (1Н, С5Н4N, J = 2.8 Hz), 8.45 d (1Н,
С5Н4N, J = 2.8 Hz). 13С NMR spectrum, δС, ppm: 189.1
(СО), 165.6 [С(О)N], 158.8, 151.3, 149.1, 148.2, 137.8,
135.5, 132.5, 128.9, 128.7, 127.0, 126.3, 123.0, 120.0,
114.0, 60.5 (СН), 55.0 (OCH3), 41.5 (СН2). Found, %:
С 72.19; Н 5.28; N 7.32. С24Н20N2О4. Calculated, %: С
71.99; Н 5.03; N 7.00.
CONFLICT OF INTEREST
No conflict of interest was declared by the authors.
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4-Benzoyl-3-hydroxy-5-(4-chlorophenyl)-1-(3-
picolyl)-3-pyrrolin-2-one (1i). Yield 2.69 g (66.4%),
mp 242–244°C (decomp., ethanol). IR spectrum, ν, cm–1:
1624 (С=О), 1692 (СОN), 3120 (OH). 1Н NMR spectrum,
δ, ppm: 4.03 d (1Н, СНАСНВ, J = 15.8 Hz), 4.69 d
(1Н, СНАСНВ, J = 15.8 Hz), 5.31 s (1H, C5H), 7.21 s
(4Н, ClС6Н4), 7.33–7.45 m (6Н, Ar + С5Н4N), 7.61 t
(1Н, С5Н4N, J = 2.8 Hz), 8.19 s (1Н, С5Н4N), 8.30 d
(1Н, С5Н4N, J = 2.8 Hz). Found, %: С 68.13; Н 4.48; Cl
8.54; N 7.12. С23Н17 ClN2О3. Calculated, %: С 68.24; Н
4.23; Cl 8.76; N 6.92.
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4-Benzoyl-3-hydroxy-5-(3-nitrophenyl)-1-(3-
picolyl)-3-pyrrolin-2-one (1j). Yield 2.25 g (54.2%), mp
230–232°С (ethanol). 1Н NMR spectrum, δ, ppm: 4.15 d
(1Н, СНАСНВ, J = 15.8 Hz), 4.66 d (1Н, СНАСНВ, J =
15.8 Hz), 5.56 s (1H, C5H), 7.21–7.57 m (9Н, Ar +
С5Н4N), 7.91 t (1Н, С5Н4N, J = 2.8 Hz), 7.99 s (1Н,
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