Synthesis of 1-[2-(1H-Indol-3-yl)ethyl]-4-acetyl-3-hydroxy-5-phenyl-1H-pyrrol-2(5H)-ones

Article abstract of DOI:10.1134/S1070363218060373

1-[2-(1H-indol-3-yl)ethyl]-4-acetyl-3-hydroxy-5-phenyl-1H-pyrrole-2(5H)-ones were synthesized by the short heating of a mixture of tryptamine, aromatic aldehyde, and methyl acetylpyruvate followed by stirring at room temperature for one day.

Full text of DOI:10.1134/S1070363218060373

ISSN 1070-3632, Russian Journal of General Chemistry, 2018, Vol. 88, No. 6, pp. 1270–1272. © Pleiades Publishing, Ltd., 2018.
Original Russian Text © O.E. Nasakin, M.I. Kazantseva, L.I. Varkentin, V.L. Gein, 2018, published in Zhurnal Obshchei Khimii, 2018, Vol. 88, No. 6,
pp. 1048–1050.
LETTERS
TO THE EDITOR
Synthesis of 1-[2-(1H-Indol-3-yl)ethyl]-4-acetyl-3-hydroxy-
5-phenyl-1H-pyrrol-2(5H)-ones
O. E. Nasakina, M. I. Kazantsevaa, L. I. Varkentinb, and V. L. Geinb*
a Ulyanov Chuvash State University, Cheboksary, Russia
b Perm State Pharmaceutical Academy, ul. Polevaya 2, Perm, 614990 Russia
*e-mail: geinvl48@mail.ru
Received December 14, 2017
Abstract—1-[2-(1H-indol-3-yl)ethyl]-4-acetyl-3-hydroxy-5-phenyl-1H-pyrrole-2(5H)-ones were synthesized
by the short heating of a mixture of tryptamine, aromatic aldehyde, and methyl acetylpyruvate followed by
stirring at room temperature for one day.
Keywords: N,N-tryptamine heterocyclic analogues, 1-[2-(1H-indol-3-yl)ethyl]-4-acetyl-3-hydroxy-5-phenyl-1H-
pyrrole-2(5H)-ones
DOI: 10.1134/S1070363218060373
Dimethyltryptamine is unique in that it occurs in
both animal and plant world [1]. It is an endogenous
mediator of the central nervous system, a structural
analog of serotonin produced by the epiphysis during
the fast sleep phase. Dimethyltryptamine is formed
from L-tryptophan by its decarboxylation and sub-
reagents dissolution followed by stirring in dioxane for
24 h at room temperature gave rise to 1-[2-(1H-indol-3-
yl)ethyl]-4-acetyl-3-hydroxy-5-phenyl-1H-pyrrole-2(5H)-
ones 1a–1j (Scheme 1).
Compounds 1a–1j are pale yellow crystalline sub-
stances soluble in DMF and DMSO, in ethanol when
heated and insoluble in water.
sequent
transmethylation
of
tryptamine.
In
pharmacognosy dimethyltryptamine is known as a
structural component of the alkaloids of some plants,
for example, Mimosa tenuiflora [2–4].
Synthesis of heterocyclic derivatives of dimethyl-
tryptamine analogs is of interest. To this end, the
reaction of tryptamine with an aromatic aldehyde and
methyl acetylpyruvate was performed by the known
procedure [5].
In the IR spectra of the compounds obtained there
were bands of stretching vibrations of the carbonyl
group (1626–1667 cm–1), C=C bonds (1595–1615 cm–1),
CON (1676–1710 cm-–1), OH (3085–3185 cm–1), and
NH groups (3259–3436 cm–1).
In the 1H NMR spectra compounds 1a–1j, in
addition to the signals of aromatic protons and
associated groups, there were a singlet of three protons
of the acetyl group (2.25 ppm), multiplets of C1HAHB
The short heating of a mixture of tryptamine,
aromatic aldehyde, and methyl acetylpyruvate till the
Scheme 1.
R
O
H
O
O
O
20°C, 24 h
dioxane
+
O
+
NH2
N
OH
HN
HN
O
R
O
1a−1j
R = 4-ОH (а), 3-ОH (b), 3-OMe (c), 3,4-OMe (d), 4-OН + 3-OMe (e), 4-Et (f), 4-iPr (g), 4-Br (h), 4-Cl (i), 3-F (j).
1270

SYNTHESIS OF 1-[2-(1H-INDOL-3-YL)ETHYL]-4-ACETYL-3-HYDROXY-...
1271
(2.60–2.78 ppm), C1HAHB (3.75–3.80) and C2H2
protons (2.87 ppm), as well as singlets of the C5H atom
(5.0–5.10 ppm) and the NH group (10.70–10.80 ppm).
These spectra indicate that the compounds obtained
exist predominantly in the enol form, which was
confirmed by the reaction with an alcohol solution of
ferric chloride.
1-[2-(1H-Indol-3-yl)ethyl]-4-acetyl-3-hydroxy-5-
(3,4-dimethoxyphenyl)-1H-pyrrole-2(5H)-one (1d).
Yield 2.32 g (55.7%), mp 175–177°C. IR spectrum, ν,
cm–1: 1611 (С=С), 1639 (С=О), 1676 (СON), 3085
1
(OH), 3420 (NН). Н NMR spectrum (DMSO-d6), δ,
ppm: 2.25 s (3Н, СН3СО), 2.70 m (1Н, С1НАНВ), 3.80
m (1Н, С1НАНВ), 2.87 m (2H, C2H2), 3.68 s and 3.73 2
s (6Н, 3,4-ОСН3), 5.05 s (1Н, С5Н), 6.66–7.38 m (8Н,
Ar), 10.75 s (1Н, NH). Found, %: С 68.92; Н 5.87; N
6.47. С24Н24N2O5. Calculated, %: С 68.56; Н 5.75; N
6.65.
The proposed procedure for the synthesis of 1-[2-
(1H-indol-3-yl)ethyl]-4-acetyl-3-hydroxy-5-phenyl-1H-
pyrrole-2(5H)-ones is simple and allows to obtain the
final products in good yields.
1-[2-(1H-Indol-3-yl)ethyl]-4-acetyl-3-hydroxy-5-
(4-hydroxy-3-methoxyphenyl)-1H-pyrrole-2(5H)-
one (1e). Yield 3.1 g (76%), mp 173–175°C. IR
spectrum, ν, cm–1: 1610 (С=С), 1650 (С=О), 1685
1-[2-(1H-Indol-3-yl)ethyl]-4-acetyl-3-hydroxy-5-
(4-hydroxyphenyl)-1H-pyrrol-2(5H)-one (1a). To a
mixture of 0.01 mol of aromatic aldehyde and
0.01 mol of tryptamine in 50 mL of dioxane was added
0.01 mol of methyl acetylpyruvate. The mixture was
heated till the reagents dissolution and then stirred at
room temperature for 1 day. The formed precipitate
was filtered off and recrystallized from ethanol. Yield
2.64 g (71%), mp 206–208°C. IR spectrum, ν, cm–1:
1595 (С=С), 1626 (С=О), 1677 (СON), 3118 (OH),
1
(СON), 3150 (OH), 3390 (NН). Н NMR spectrum
(DMSO-d6), δ, ppm: 2.25 s (3Н, СН3СО), 2.65 m (1Н,
С1НAНB), 3.75 m (1Н, С1НAНB), 2.87 m (2H, C2H2),
3.68 s (3Н, 3-ОСН3), 5.03 s (1Н, С5Н), 6.50–7.40 m
(8Н, Ar), 8.90 s (1Н, ОH), 10.80 s (1Н, NH). Found,
%: С 68.02; Н 5.77; N 6.49. С23Н22N2O5. Calculated,
%: С 67.97; Н 5.46; N 6.89.
1
3426 (NН). Н NMR spectrum (DMSO-d6), δ, ppm:
1-[2-(1H-Indol-3-yl)ethyl]-4-acetyl-3-hydroxy-5-
(4-ethylphenyl)-1H-pyrrole-2(5H)-one (1f). Yield
2.58 g (64.4%), mp 169–171°C. IR spectrum, ν, cm–1:
1601 (С=С), 1668 (С=О), 1701 (СON), 3163 (OH),
2.30 s (3Н, СН3СО), 2.72 m (1Н, С1НАНВ), 3.77 m
(1Н, С1НАНВ), 2.87 m (2H, C2H2), 5.00 s (1Н, С5Н),
6.60–7.46 m (8Н, Ar), 9.40 s (1Н, ОH), 10.8 s (1Н,
NH). Found, %: С 69.92; Н 5.53; N 7.27. С22Н20N2O4.
Calculated, %: С 70.20; Н 5.36; N7.44.
1
3385 (NН). Н NMR spectrum (DMSO-d6), δ, ppm:
1.15 s (5Н, 4-CH2CH3), 2.25 s (3Н, СН3СО), 2.60 m
(1Н, С1НАНВ), 3.75 m (1Н, С1НАНВ), 2.87 m (2H,
C2H2), 5.09 s (1Н, С5Н), 6.85–7.45 m (8Н, Ar), 10.70
s (1Н, NH). Found, %: С 69.72; Н 5.75; N 7.49.
С22Н20N2O4. Calculated, %: С 70.20; Н 5.36; N7.44.
Compounds 1b–1j were obtained similarly.
1-[2-(1H-Indol-3-yl)ethyl]-4-acetyl-3-hydroxy-5-
(3-hydroxyphenyl)-1H-pyrrole-2(5H)-one (1b). Yield
2.53 g (67%), mp 217–219°C. IR spectrum, ν, cm–1:
1603 (С=С), 1630 (С=О), 1683 (СON), 3120 (OH),
1-[2-(1H-Indol-3-yl)ethyl]-4-acetyl-3-hydroxy-5-
(4-isopropylphenyl)-1H-pyrrole-2(5H)-one (1g). Yield
3.38 g (85%), mp 186–188°C. IR spectrum, ν, cm–1:
1595 (С=С), 1663 (С=О), 1708 (СON), 3153 (OH),
1
3436 (NН). Н NMR spectrum (DMSO-d6), δ, ppm:
2.25 s (3Н, СН3СО), 2.70 m (1Н, С1НАНВ), 3.77 m
(1Н, С1НАНВ), 2.87 m (2H, C2H2), 5.05 s (1Н, С5Н),
6.50–7.41 m (8Н, Ar), 9.30 s (1Н, ОH), 10.7 s (1Н,
NH). Found, %: С 69.92; Н 5.53; N 7.27. С22Н20N2O4.
Calculated, %: С 70.20; Н 5.36; N 7.44.
1
3371 (NН). Н NMR spectrum (DMSO-d6), δ, ppm:
1.15 s [7Н, СН(СН3)2], 2.25 s (3Н, СН3СО), 2.78 m
(1Н, С1НAНB), 3.75 m (1Н, С1НAНB), 2.87 m (2H,
C2H2), 5.09 s (1Н, С5Н), 6.85–7.45 m (8Н, Ar), 10.70
s (1Н, NH). Found, %: С 74.42; Н 6.77; N 6.59.
С25Н26N2O3. Calculated, %: С 74.60; Н 6.50; N 6.96.
1-[2-(1H-Indol-3-yl)ethyl]-4-acetyl-3-hydroxy-5-
(3-methoxyphenyl)-1H-pyrrole-2(5H)-one (1c). Yield
2.60 g (67.5%), mp 212–214°C. IR spectrum, ν, cm–1:
1610 (С=С), 1663 (С=О), 1709 (СON), 3110 (OH),
1-[2-(1H-Indol-3-yl)ethyl]-4-acetyl-3-hydroxy-5-
(4-bromophenyl)-1H-pyrrole-2(5H)-one (1h). Yield
3.00 g (68%), mp 214–216°C. IR spectrum, ν, cm–1:
1610 (С=С), 1650 (С=О), 1710 (СON), 3180 (OH),
1
3259 (NН). Н NMR spectrum (DMSO-d6), δ, ppm:
2.25 s (3Н, СН3СО), 2.70 m (1Н, С1НАНВ), 3.77 m
(1Н, С1НАНВ), 2.87 m (2H, C2H2), 3.68 s (3H,
3-OCH3), 5.10 s (1Н, С5Н), 6.65–7.35 m (8Н, Ar),
10.75 s (1Н, NH). Found, %: С 70.92; Н 5.57; N 7.47.
С23Н22N2O4. Calculated, %: С 70.75; Н 5.68; N 7.17.
1
3415 (NН). Н NMR spectrum (DMSO-d6), δ, ppm:
2.25 s (3Н, СН3СО), 2.70 m (1Н, С1НАНВ), 3.75 m
(1Н, С2НАНВ), 2.87 m (2H, C2H2), 5.09 s (1Н, С5Н),
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 88 No. 6 2018

1272
NASAKIN et al.
6.90–7.50 m (8Н, Ar), 10.75 s (1Н, NH). Found, %: С
60.42; Н 4.77; N 6.56. С22Н19BrN2O3. Calculated, %:
С 60.15; Н 4.36; N 6.38.
analysis was performed on a Perkin Elmer 2400 analyzer.
Melting points were determined on a Melting Point M-
565 apparatus. The reaction progress and individuality
of the obtained compounds were monitored by TLC on
Silufol UV-254 plates, eluting with a CHCl3–AcOH
(9 : 1) and detecting with UV irradiation.
1-[2-(1H-Indol-3-yl)ethyl]-4-acetyl-3-hydroxy-5-
(4-chlorophenyl)-1H-pyrrole-2(5H)-one (1i). Yield
2.8 g (71%), mp 222–224°C. IR spectrum, ν, cm–1:
1615 (С=С), 1667 (С=О), 1715 (СON), 3185 (OH),
ACKNOWLEDGMENTS
1
3413 (NН). Н NMR spectrum (DMSO-d6), δ, ppm:
2.25 s (3Н, СН3СО), 2.78 m (1Н, С1НAНB), 3.75 m
(1Н, С1НAНB), 2.87 m (2H, C2H2), 5.10 s (1Н, С5Н),
6.85–7.40 m (8Н, Ar), 10.80 s (1Н, NH). Found, %: С
66.42; Н 4.77; N 6.57. С22Н19СlN2O3. Calculated, %:
С 66.92; Н 4.85; N 7.09.
This work was financially supported by the Russian
Science Foundation (project no. 15-13-10029).
REFERENCES
1. Dai, L., Shu, P., Wang, Z., Li, Q., Yu, Q., Shi, Y., and
Rong, L., Synthesis, 2017, no. 49, p. 637. doi 10.1055/s-
0036-1588605
1-[2-(1H-Indol-3-yl)ethyl]-4-acetyl-3-hydroxy-5-
(4-fluorophenyl)-1H-pyrrole-2(5H)-one (1j). Yield
3.04 g (81.3%), mp 179–181°C. IR spectrum, ν, cm–1:
1613 (С=С), 1665 (С=О), 1709 (СON), 3163 (OH),
2. Hong, A.Y. and Vanderwall, C.D., Terahedron, 2017,
1
no. 73, p. 4160. doi 10.1016/j.tet.2016.11.004
3370 (NН). Н NMR spectrum (DMSO-d6), δ, ppm:
2.25 s (3Н, СН3СО), 2.78 m (1Н, С1НAНB), 3.75 m
(1Н, С1НAНB), 2.87 m (2H, C2H2), 5.10 s (1Н, С5Н),
6.80–7.40 m (8Н, Ar), 10.80 s (1Н, NH). Found, %: С
69.42; Н 4.79; N 7.57. С22Н19FN2O3. Calculated, %: С
69.83; Н 5.06; N 7.40.
1H NMR spectra were recorded on a Bruker DRX-
500 (500.13 MHz) spectrometer from solution in
DMSO-d6. IR spectra were registered on a Specord
M-80 spectrometer from KBr pellets. Elemental
3. Giustiniano, M., Pellicia, S., Sangaletti, L., Meneghetti, F.,
Amato, J., Novellino, E., and Tron Gian, C.,
Terahedron Lett., 2017, no. 58, p. 4264. doi 10.1016/
j.tetlet.2017.09.076
4. Singh, V.K., Dubey, R., Upadhyay, A., Sharma, L.K.,
and Singh, R.K.P., Terahedron Lett., 2017, no. 58,
p. 4227. doi 10.1016/j.tetlet.2017.09.003
5. Gein, V.L., Tetragidropirrol- i tetragidrofuran-2,3-
diony (Tetrahydropyrrole- and Tetrahydrofuran-2,3-dione),
Perm: PGFA, 2004.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 88 No. 6 2018