Трикомпонентна циклізація як підхід до створення комбінаторної бібліотеки 2Н-спіро[хромено[2,3-с]пірол-1,3'-індолін]-2',3,9-трионів
A versatile and efficient three-component cyclization of methyl 4-(o-hydroxyphenyl)-2,4-dioxobutanoates 1, N-substituted isatins 2, and primary amines 3 was explored to synthesize of 2H-spiro[chromeno[2,3-c]pyrrole-1,3'-indoline]-2',3,9-triones. We obtained a library of 122 derivatives wit...
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V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the National Academy of Sciences of Ukraine
2020
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| author | Vydzhak, Roman N. Kachaeva, Maryna V. Pilyo, Stepan G. Moskvina, Viktoriia S. Shablykina, Olga V. Kozytskiy, Andriy V. Brovarets, Volodymyr S. |
| author_facet | Vydzhak, Roman N. Kachaeva, Maryna V. Pilyo, Stepan G. Moskvina, Viktoriia S. Shablykina, Olga V. Kozytskiy, Andriy V. Brovarets, Volodymyr S. |
| author_institution_txt_mv | [
{
"author": "Roman N. Vydzhak",
"institution": "V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the NAS of Ukraine, 1 Murmanska St., Kyiv, 02094, Ukraine"
},
{
"author": "Maryna V. Kachaeva",
"institution": "V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the NAS of Ukraine, 1 Murmanska St., Kyiv, 02094, Ukraine"
},
{
"author": "Stepan G. Pilyo",
"institution": "V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the NAS of Ukraine, 1 Murmanska St., Kyiv, 02094, Ukraine"
},
{
"author": "Viktoriia S. Moskvina",
"institution": "Taras Shevchenko National University of Kyiv, 60 Volodymyrska St., Kyiv, 01601, Ukraine"
},
{
"author": "Olga V. Shablykina",
"institution": "Taras Shevchenko National University of Kyiv, 60 Volodymyrska St., Kyiv, 01601, Ukraine"
},
{
"author": "Andriy V. Kozytskiy",
"institution": "L.V. Pisarzhevskii Institute of Physical Chemistry of the NAS of Ukraine, 31 Nauky Ave., Kyiv, 03028, Ukraine"
},
{
"author": "Volodymyr S. Brovarets",
"institution": "V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the NAS of Ukraine, 1 Murmanska St., Kyiv, 02094, Ukraine"
}
] |
| author_sort | Vydzhak, Roman N. |
| baseUrl_str | https://bioorganica.com.ua/index.php/journal/oai |
| collection | OJS |
| datestamp_date | 2026-07-19T14:56:52Z |
| description | A versatile and efficient three-component cyclization of methyl 4-(o-hydroxyphenyl)-2,4-dioxobutanoates 1, N-substituted isatins 2, and primary amines 3 was explored to synthesize of 2H-spiro[chromeno[2,3-c]pyrrole-1,3'-indoline]-2',3,9-triones. We obtained a library of 122 derivatives with an indolin-2-one motif as an important structural fragment in natural alkaloids. This method is practical and useful strategy for constructing dihydrochromeno[2,3-c]pyrrole-3,9-diones. Most of the obtained products also have functional groups for easy and further diversification by classical reactions.   |
| doi_str_mv | 10.15407/bioorganica2020.01.026 |
| first_indexed | 2025-07-17T12:19:47Z |
| format | Article |
| fulltext |
ISSN 1814-9758. Ukr. Bioorg. Acta, 2020, Vol. 15, N 1
UDC 547.756 + 547.812 + 547.816.8
DOI: https://doi.org/10.15407/bioorganica2020.01.026
26
RESEARCH ARTICLE
Three-component cyclization as an approach to a combinatorial library
of 2H-spiro-[chromeno[2,3-c]pyrrole-1,3'-indoline]-2',3,9-triones
Roman N. Vydzhak1, Maryna V. Kachaeva1, Stepan G. Pilyo1, Viktoriia S. Moskvina1,2*,
Olga V. Shablykina1,2, Andriy V. Kozytskiy3,4 and Volodymyr S. Brovarets1
1 V. P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the NAS of Ukraine, 1 Murmanska St., Kyiv, 02094, Ukraine
2 Taras Shevchenko National University of Kyiv, 60 Volodymyrska St., Kyiv, 01601, Ukraine
3 L. V. Pisarzhevskii Institute of Physical Chemistry of the NAS of Ukraine, 31 Nauky Ave., Kyiv, 03028, Ukraine
4 Enamine Ltd. (www.enamine.net), 78 Chervonotkatska St., Kyiv, 02094, Ukraine
Abstract: A versatile and efficient three-component cyclization of methyl 4-(o-hydroxyphenyl)-2,4-dioxobutanoates 1, N-substituted
isatins 2, and primary amines 3 was explored to synthesize of 2H-spiro[chromeno[2,3-c]pyrrole-1,3'-indoline]-2',3,9-triones. We obtained
a library of 122 derivatives with an indolin-2-one motif as an important structural fragment in natural alkaloids. This method is а practical
and useful strategy for constructing dihydrochromeno[2,3-c]pyrrole-3,9-diones. Most of the obtained products also have functional
groups for easy and further diversification by classical reactions.
Keywords: isatin, multicomponent reactions, chromenes, combinatorial library.
Introduction
The synthesis of privileged heterocyclic compounds has
become one of the prime areas of research in the field of
synthetic and medicinal chemistry as most of the
compounds with biological activity are derived from
heterocyclic structures [1, 2].
Natural products are important privileged scaffolds that
serve as important, biologically pre-validated platforms for
the design of compound libraries in the search for new drug
candidates [3]. The structural motif of indolin-2-ones is an
important scaffold for medicinal chemistry and can be
found in many naturally occurring compounds related to
indole alkaloids [4]. Spirocyclic indolenines have
significant therapeutic potential, and these structural motifs
Received:
Revised:
Accepted:
Published online:
27.04.2020
11.05.2020
16.05.2020
30.06.2020
Corresponding author. Tel.: +380-44-239-3342;
e-mail: v.moskvina@gmail.com (V. S. Moskvina)
ORCID: 0000-0001-5556-9147
are present in a number of biologically active natural
products. Examples of such spiro[indoline-3,2'-pyrroles] are
Horsfiline [5], Coerulescine [6], and Elacomine [7] as well
as polyfused Spirotryptostatin A [8] and Strychnofoline [9]
(Figure 1).
Figure 1. Examples of natural compounds with indolin-2-one
motif.
© Vydzhak R. N. et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted
use, distribution, and reproduction in any medium, provided the original author and source are credited.
Ukrainica Bioorganica Acta
www.bi oorgan ica .org .ua
mailto:v.moskvina@gmail.com
https://orcid.org/0000-0001-5556-9147
ISSN 1814-9758. Ukr. Bioorg. Acta, 2020, Vol. 15, N 1
27
The most numerous representatives of polyfused indolin-
2-ones are spiro[indoline-3,6'-pyrano[3,4-f]indolizins]. The
members of this group differ mostly in the configuration of
specific asymmetric centers (like alkaloids Mitraphylline,
Formosanine, and Pteropodine, Figure 2) and the presence
of substituents in the benzol ring (e.g., mono- and
dimethoxy derivativs – Vinerine and Elegantissine
(Herboxine) [10].
According to the literature, spiro[indoline-3,6'-pyrano-
[3,4-f]indolizin] alkaloids are widely represented in plants
that have long been used in traditional medicine [11, 12]. It
is not surprising therefore that according to the recent data,
these and similar structures can find practical use in
medicine. For example, Pteropodine has manifested
antigenotoxic, antioxidant and lymphocyte induction effects
[13], while Mitraphylline has shown anti-inflammatory
activity [14]. Several synthetic spiroheterocycles containing
both indole and pyran heterocycles possess anticonvulsant
and analgesic [15], antimicrobial [16], and herbicidal
activities [17].
Figure 2. Examples of natural spiro[indoline-3,6'-pyrano[3,4-f]-
indolizin] alkaloids.
In most cases, the synthesis of these compounds is a
challenging task comprising of multiple synthetic steps
[18]. One of the main goals of modern synthetic organic
chemistry is the rapid construction of target drug-like
compound libraries, characterized by several important
features, for example, the complexity and variety of
molecules, high variability, and easy access from relatively
simple and commercially available reagents.
Results and Discussion
In our previous works, several examples of 1,2-
dihydrochromeno[2,3-c]pyrrole-3,9-diones were obtained in
a three-component condensation of methyl 4-(o-hydroxy-
phenyl)-2,4-dioxobutanoate with aromatic aldehydes and
heterocyclic amines [19] or aromatic amines [20], aliphatic
amines [21] (Scheme 1). Alternative routes to the synthesis
of 2-phenyl-5,6-dihydropyrano[2,3-c]pyrrole-4,7-diones
[22] and 1-aryl-2-[2-(dimethylamino)ethyl]-1,2-dihydro-
chromeno[2,3-c]pyrrole-3,9-diones [23] were also
developed.
Scheme 1. Synthesis of 1,2-dihydrochromeno[2,3-c]pyrrole-3,9-
diones (previous work).
Only two examples of 1,2-dihydrochromeno[2,3-
c]pyrrole-3,9-dione spiro derivatives were obtained in our
previous research when N-methylisatin was used as the
carbonyl component [24].
The goal of the present research was to study a one-pot
three-component condensation of methyl 4-(o-hydroxy-
phenyl)-2,4-dioxobutanoate, N-substituted isatins, and
primary amines, as well as the applicability of this reaction
in the combinatorial synthesis. The utility and scope of this
method were tested on a wide range of commercially
available substrates.
The substrate scope in this condensation was
subsequently explored by employing various methyl 4-(o-
hydroxyphenyl)-2,4-dioxobutanoates 1{1-5} (5 examples)
with N-substituted isatins 2{1-8} (8 examples), and primary
amines 3{1-24} (24 examples) (Scheme 2). The
representative substrates – methyl 4-(o-hydroxyphenyl)-2,4-
dioxobutanoates (1{1-5}), N-substituted isatins 2{1-8}, and
primary amines 3{1-24} are listed in Figure 3.
Scheme 2. The 1-аryl-1,2-dihydrochromeno[2,3-c]pyrrole-3,9-
dione 4 library generation.
First, the compatibility of different N-substituted isatins
and primary amines in the present transformation was
examined. To our delight, a wide range of alkyl groups in
the case of N-substituted isatins, including methyl, ethyl,
propyl, butyl, allyl, and benzyl, were well compatible in this
transformation. It should be mentioned that the substituted
primary amines were also suitable for the transformation,
and synthesis of 2H-spiro[chromeno[2,3-c]pyrrole-1,3'-
indoline]-2',3,9-triones was conducted in МеОН (for
3{1-10, 13-15, 24}), EtОН (for 3{11}), i-PrOH (for 3{12})
at 35-40 °C, or acetic acid (for 3{16-23}) under reflux.
Methyl 4-(o-hydroxyphenyl)-2,4-dioxobutanoates with
methyl, chloro, and fluoro substituents were also tolerated
in this one-pot three-component procedure. As the
R. N. Vydzhak., M. V. Kachaeva, S. G. Pilyo et al.
28
Figure 3. Scope of 4-(2-hydroxyphenyl)-2,4-dioxobutanoates 1{1-5}, isatins 2{1-13} and primary amines 3{1-24}.
result, spiro[chromeno[2,3-c]pyrrole-1,3'-indoline]-2',3,9-
triones (87% success rate) with good purity ( > 95%
according MS) (Table 1). In most cases, the yields were in
the range of 48-81%, and for more than 50% of the
representative set, the yield was over 70%.
1H NMR spectra of products 4 corresponded to the
proposed structures. However, because the skeleton of the
molecules is complex, 13C NMR spectra were also
measured to prove the structure of the compounds, and for
several compounds, COSY, HMBS, and HSQC
experiments were performed.
Figure 4. Important HMBC correlations for 4{1-1-10} and
4{4-2-13}.
In 13C NMR spectra of library members 4{1-1-10} and
4{4-2-13}, signals at 163.0-163.1 ppm are attributed to the
C-3 atom, signals at 171.3 and 172.1 ppm are attributed to
the C-9 atom and signals at 169.9-170.3 ppm are attributed
to the C-2' atom. Carbon atom at 67.5, and 67.8 ppm
assigned to spirocarbon of pyrrole-1,3'-indoline moiety.
Figure 4 shows the assignments and the most important
HMBC correlations for 4{1-1-10} and 4{4-2-13} between
signals in the 13С NMR spectra (blue) and 1Н NMR spectra
(green) upon which the assignments were based (red
arrow).
The IR spectra of products 4 contain fairly intense
absorption bands of carbonyl groups at 1735-1715 cm-1 and
1670-1660 cm-1, as well as rather an intensive absorption of
the unsaturated fragments conjugated with them, at
approximately 1610 cm-1.
Conclusions
In conclusion, we have developed an efficient protocol
for the rapid synthesis of 2H-spiro[chromeno[2,3-c]pyrrole-
1,3'-indoline]-2',3,9-triones using N-substituted isatins and
primary amines in a one-pot three-component cyclo-
condensation. This protocol was found to be compatible
with a wide range of substituents and paves the way for the
practical synthesis of 2H-spiro[chromeno[2,3-c]pyrrole-
1,3'-indoline]-2',3,9-triones with a broad range of
substituents under mild conditions.
ISSN 1814-9758. Ukr. Bioorg. Acta, 2020, Vol. 15, N 1
29
Table 1. Scope of the products 4.
4{1-1-1} 4{1-1-21}a 4{1-3-5} 4{1-5-8} 4{2-1-13} 4{2-7-10} 4{3-1-13} 4{3-5-10} 4{4-5-9}
4{1-1-3} 4{1-1-22} 4{1-3-7} 4{1-5-9} 4{2-2-13} 4{2-7-12}a 4{3-2-9}a 4{3-5-12} 4{4-5-10}
4{1-1-4} 4{1-1-23} 4{1-3-8}a 4{1-5-10} 4{2-3-7} 4{2-7-13} 4{3-2-10} 4{3-5-13}a 4{4-5-12}a
4{1-1-5} 4{1-2-4} 4{1-3-9} 4{1-5-11} 4{2-3-10}a 4{2-7-17} 4{3-2-12} 4{4-1-5} 4{4-5-21}
4{1-1-6} 4{1-2-5} 4{1-3-10} 4{1-5-12} 4{2-3-9} 4{2-7-18}a 4{3-2-13} 4{4-1-10} 4{5-1-21}a
4{1-1-7} 4{1-2-7} 4{1-3-13} 4{1-5-13} 4{2-3-13} 4{2-7-19} 4{3-3-7}a 4{4-1-12} 4{5-2-5}
4{1-1-8} 4{1-2-8} 4{1-3-11} 4{1-5-17} 4{2-3-17} 4{2-7-20}a 4{3-3-9} 4{4-2-10} 4{5-3-17}a
4{1-1-9} 4{1-2-9} 4{1-3-12} 4{1-6-4}a 4{2-5-7} 4{2-7-21} 4{3-3-10} 4{4-2-12} 4{5-5-5}a
4{1-1-10}a 4{1-2-10} 4{1-3-24}a 4{1-6-11} 4{2-5-8} 4{2-7-22} 4{3-3-12} 4{4-2-13}a 4{5-5-7}
4{1-1-11} 4{1-2-11} 4{1-4-11} 4{1-6-17} 4{2-5-9} 4{3-1-7} 4{3-3-13} 4{4-3-10} 4{5-5-19}
4{1-1-12} 4{1-2-12} 4{1-4-24}a 4{2-1-7} 4{2-5-10} 4{3-1-8} 4{3-3-21} 4{4-3-12} 4{5-5-23}
4{1-1-13} 4{1-2-13} 4{1-5-2} 4{2-1-8} 4{2-5-12} 4{3-1-9} 4{3-5-8} 4{4-3-13} 4{5-6-6}a
4{1-1-14} 4{1-2-22}a 4{1-5-5} 4{2-1-10} 4{2-5-13}a 4{3-1-10}a 4{3-5-9} 4{4-3-16}a 4{5-8-10}a
4{1-1-15} 4{1-3-4} 4{1-5-7}a 4{2-1-12} 4{2-7-9}
a The method of the synthesis, physicochemical properties, NMR and LCMS spectra are described in the experimental section.
Experimental section
The solvents were purified according to the standard
procedures. All starting materials such as substituted methyl
4-(o-hydroxyphenyl)-2,4-dioxobutanoates, N-substituted
isatins, and primary amines were obtained from Enamine,
Ltd. All materials were purchased from commercial sources
and used without further purification. The success rate was
calculated as the number of successful experiments divided
by the total number of experiments. 1H NMR spectra were
recorded on a Varian VXR-300 spectrometer (300 MHz)
or Bruker 170 spectrometer (500 MHz) and
13C NMR spectra were recorded at Bruker 170 spectrometer
(125 MHz) spectra in DMSO-d6 or CF3CO2D or CDCl3
solution. Chemical shifts are reported in ppm downfield
from TMS as internal standards. Mass spectra were
recorded on an LC-MS instrument with chemical ionization
(CI). LC-MS data were acquired on an Agilent 1200 HPLC
system equipped with DAD/ELSD/LCMS-6120 diode
matrix and mass-selective detector. Melting points were
measured on a MPA100 OptiMelt automated melting point
system. Elemental analyses were performed at the
Laboratory of Organic Analysis, Department of Chemistry,
Taras Shevchenko National University of Kyiv.
The Experimental Section describes 25 compounds
selected in a random manner, which corresponds to
generally accepted approaches in combinatorial chemistry
(according to ACS standards).
A representative procedure for the synthesis of 1'-methyl-
2-phenethyl-2H-spiro[chromeno[2,3-c]pyrrole-1,3'-indoline]-
2',3,9-trione (4{1-1-21}).
To a suspension of 0.01 mol of N-methylisatin 2{1} in
15 mL of glacial acetic acid, 0.01 mol of 2-phenyl-
ethylamine 3{21} and 0.01 mol of methyl-o-hydroxy-
benzoylpyruvate 1{1} were added. The reaction mixture
was refluxed for 1 h, cooled, and evaporated. The
residues were purified by crystallization from ethanol.
Yield: 335 mg, 77%. 1H NMR (500 MHz, DMSO-d6) δ 7.98
(d, J 7.5 Hz, 1H), 7.92-7.82 (m, 2H), 7.56-7.44 (m, 2H),
7.27-7.10 (m, 5H), 7.07-6.96 (m, 3H), 3.35 (s, 3H), 3.33-
3.23 (m, 2H), 2.68 (t, J 7.3 Hz, 2H). IR (KBr) ν 3063, 3020,
2934, 1729 (vs), 1715 (vs), 1664 (vs), 1611, 1495, 1457,
1385, 1369, 1341, 1283, 1199, 1184, 1128, 1105, 1085,
938, 888, 751, 699, 690. MS (CI) m/z (M+H)+ 437.
2-(3-Methoxypropyl)-1'-methyl-2H-spiro[chromeno-
[2,3-c]pyrrole-1,3'-indoline]-2',3,9-trione (4{1-1-10}).
Yield: 310 mg, 77%. 1H NMR (500 MHz, DMSO-d6) δ
7.97 (d, J 7.9 Hz, 1H), 7.94-7.83 (m, 2H), 7.54 (t, J 6.6 Hz,
1H), 7.47 (t, J 7.7 Hz, 1H), 7.25 (t, J 6.6 Hz, 2H), 7.07 (t,
J 7.5 Hz, 1H), 3.32 (s, 3H), 3.29-3.00 (m, 7H), 1.66-1.45
(m, 2H). 13C NMR (125 MHz, CDCl3) δ 172.1, 170.3,
163.0, 156.5, 155.7, 145.0, 134.7, 131.3, 126.2, 125.9,
125.9, 125.4, 123.9, 123.6, 121.7, 119.2, 109.6, 69.7, 67.5,
58.4, 39.2, 28.0, 27.3. IR (KBr) ν 2976, 2931, 2894, 2832,
2808, 1735 (vs), 1712 (vs), 1665 (vs), 1611, 1463, 1374,
1304, 1279, 1200, 1106, 943, 873, 755, 692. MS (CI) m/z
(M+H)+ 405.
1'-Ethyl-2-(4-methoxyphenethyl)-2H-spiro[chromeno-
[2,3-c]pyrrole-1,3'-indoline]-2',3,9-trione (4{1-2-22}).
Yield: 360 mg, 75%. 1H NMR (500 MHz, DMSO-d6) δ
7.99 (d, J 7.9 Hz, 1H), 7.95-7.83 (m, 2H), 7.59-7.51 (m,
1H), 7.47 (t, J 7.6 Hz, 1H), 7.30 (d, J 7.8 Hz, 1H), 7.18 (d,
J 7.3 Hz, 1H), 7.03 (t, J 7.4 Hz, 1H), 6.89 (d, J 8.5 Hz, 2H),
6.74 (d, J 8.5 Hz, 2H), 3.90 (q, J 6.7 Hz, 2H), 3.69 (s, 3H),
3.35-3.09 (m, 2H), 2.59 (t, J 7.9 Hz, 2H), 1.31 (t, J 7.0 Hz,
3H). IR (KBr) ν 3073, 3046, 2976, 2932, 2840, 1727 (vs),
1664, 1610, 1513, 1492, 1463, 1365, 1307, 1284, 1245,
1187, 1134, 1026, 884, 833, 757, 688. MS (CI) m/z (M+H)+
480.
2-(3-Hydroxypropyl)-1'-propyl-2H-spiro[chromeno[2,3-c]-
pyrrole-1,3'-indoline]-2',3,9-trione (4{1-3-8}).
R. N. Vydzhak., M. V. Kachaeva, S. G. Pilyo et al.
30
Yield: 305 mg, 73%. 1H NMR (500 MHz, DMSO-d6) δ
7.98 (d, J 7.8 Hz, 1H), 7.95-7.83 (m, 2H), 7.59-7.49 (m,
1H), 7.44 (t, J 7.7 Hz, 1H), 7.30-7.19 (m, 2H), 7.05 (t,
J 7.5 Hz, 1H), 4.30 (br s, 1H), 3.86-3.68 (m, 2H), 3.35-2.99
(m, 4H), 1.75 (m, 2H), 1.55-1.38 (m, 2H), 1.00 (t, J 7.4 Hz,
3H). IR (KBr) ν 3512 (vs, br), 3063, 2955, 2934, 2877,
1728 (vs), 1664 (vs), 1610, 1490, 1462, 1361, 1312, 1284,
1191, 1135, 1107, 1069, 942, 871, 759, 690. MS (CI) m/z
(M+H)+ 419.
2-(1,1-Dioxidotetrahydrothiophen-3-yl)-1'-propyl-2H-
spiro[chromeno[2,3-c]pyrrole-1,3'-indoline]-2',3,9-trione
(4{1-3-24}).
Yield: 349 mg, 73%. 1H NMR (500 MHz, DMSO-d6) δ
7.97 (d, J 7.9 Hz, 1H), 7.94-7.83 (m, 2H), 7.53 (ddd, J 8.2,
6.0, 2.3 Hz, 1H), 7.47 (t, J 7.8 Hz, 1H), 7.39 (t, J 8.2 Hz,
1H), 7.27 (d, J 7.9 Hz, 1H), 7.06 (t, J 7.5 Hz, 1H), 3.92-3.55
(m, 3.5H), 3.49-3.27 (m, 1.5H), 3.17-2.95 (m, 1.5H), 2.92-
2.59 (m, 1.5H), 2.28-2.13 (m, 0.4H), 2.13-1.98 (m, 0.6H),
1.85-1.67 (m, 2H), 1.00 (t, J 7.3 Hz, 3H). IR (KBr) ν 3069,
3036, 2963, 2942, 2875, 1732 (vs), 1718 (vs), 1666 (vs),
1610, 1486, 1463, 1414, 1349, 1320, 1287, 1215, 1192,
1127, 1089, 940, 875, 757, 688, 654, 572. MS (CI) m/z
(M+H)+ 479.
1'-Butyl-2-(1,1-dioxidotetrahydrothiophen-3-yl)-2H-
spiro[chromeno[2,3-c]pyrrole-1,3'-indoline]-2',3,9-trione
(4{1-4-24}).
Yield: 373 mg, 76%. 1H NMR (500 MHz, DMSO-d6) δ
7.98 (d, J 8.0 Hz, 1H), 7.94-7.83 (m, 2H), 7.54 (ddd, J 8.1,
5.8, 2.4 Hz, 1H), 7.47 (t, J 7.7 Hz, 1H), 7.43-7.35 (m, 1H),
7.25 (d, J 7.9 Hz, 1H), 7.06 (t, J 7.5 Hz, 1H), 3.95-3.55 (m,
3.5H), 3.50-3.25 (m, 1.5H), 3.18-2.94 (m, 1.5H), 2.89-2.59
(m, 1.5H), 2.27-2.13 (m, 0.5H), 2.11-1.97 (m, 0.5H), 1.78-
1.64 (m, 2H), 1.51-1.35 (m, 2H), 0.97 (t, J 7.3 Hz, 3H).
IR (KBr) ν 3100, 3069, 3038, 3020, 2961, 2936, 2875, 1732
(vs), 1667 (vs), 1610, 1488, 1464, 1411, 1351, 1322, 1306,
1288, 1189, 1126, 1106, 1089, 942, 756, 690, 573. MS (CI)
m/z (M+H)+ 493.
1'-Allyl-2-(2-hydroxyethyl)-2H-spiro[chromeno[2,3-c]-
pyrrole-1,3'-indoline]-2',3,9-trione (4{1-5-7}).
Yield: 309 mg, 77%. 1H NMR (500 MHz, DMSO-d6) δ
8.00 (d, J 7.8 Hz, 1H), 7.98-7.90 (m, 2H), 7.64-7.54 (m,
1H), 7.46 (t, J 7.8 Hz, 1H), 7.36 (d, J 7.4 Hz, 1H), 7.17 (d,
J 7.9 Hz, 1H), 7.08 (t, J 7.5 Hz, 1H), 6.00-5.87 (m, 1H),
5.49 (d, J 17.4 Hz, 1H), 5.25 (d, J 10.4 Hz, 1H), 4.76 (br s,
1H), 4.54 (d, J 16.9 Hz, 1H), 4.39 (d, J 17.1 Hz, 1H), 3.42-
3.07 (m, 4H). IR (KBr) ν 3477 (s, br), 2966, 2932, 2886,
1725 (vs), 1659 (vs), 1610, 1490, 1459, 1361, 1285, 1178,
1055, 933, 888, 756, 691. MS (CI) m/z (M+H)+ 403.
1'-Benzyl-2-propyl-2H-spiro[chromeno[2,3-c]pyrrole-
1,3'-indoline]-2',3,9-trione (4{1-6-4}).
Yield: 336 mg, 75%. 1H NMR (500 MHz, DMSO-d6) δ
7.98 (d, J 7.6 Hz, 1H), 7.94-7.81 (m, 2H), 7.58-7.49 (m,
1H), 7.45 (t, J 7.7 Hz, 1H), 7.30-7.19 (m, 2H), 7.05 (t,
J 7.4 Hz, 1H), 3.94-3.77 (m, 2H), 3.26-3.10 (m, 1H), 2.98
(dt, J 14.1, 7.0 Hz, 1H), 1.40-1.21 (m, 2H), 0.77 (t, J 7.3
Hz, 3H). IR (KBr) ν 3095, 3064, 3042, 2963, 2932, 2875,
1720 (vs), 1666 (vs), 1610, 1488, 1467, 1367, 1342, 1286,
1198, 1152, 1135, 1097, 946, 832, 775, 756, 689. MS (CI)
m/z (M+H)+ 451.
2-(3-Methoxypropyl)-7-methyl-1'-propyl-2H-spiro-
[chromeno[2,3-c]pyrrole-1,3'-indoline]-2',3,9-trione (4{2-
3-10}).
Yield: 343 mg, 77%. 1H NMR (500 MHz, DMSO-d6) δ
7.78-7.72 (m, 2H), 7.68 (dd, J 8.8, 2.0 Hz, 1H), 7.44 (td,
J 7.8, 1.1 Hz, 1H), 7.28-7.21 (m, 2H), 7.04 (t, J 7.4 Hz,
1H), 3.87-3.69 (m, 2H), 3.28-3.15 (m, 3H), 3.15-2.99 (m,
4H), 2.42 (s, 3H), 1.83-1.66 (m, 2H), 1.65-1.47 (m, 2H),
1.00 (t, J 7.4 Hz, 3H). IR (KBr) ν 3055, 3029, 2980, 2942,
2888, 2878, 2827, 2745, 1721 (vs), 1664 (vs), 1611, 1479,
1469, 1367, 1321, 1281, 1204, 1113, 1095, 1027, 945, 926,
909, 886, 825, 796, 749, 689, 658. MS (CI) m/z (M+H)+
447.
1'-Allyl-7-methyl-2-((tetrahydrofuran-2-yl)methyl)-2H-
spiro[chromeno[2,3-c]pyrrole-1,3'-indoline]-2',3,9-trione
(4{2-5-13}).
Yield: 351 mg, 77%. 1H NMR (500 MHz, DMSO-d6) δ
7.82 (d, J 8.4 Hz, 1H), 7.80-7.71 (m, 2H), 7.43 (t, J 7.4 Hz,
1H), 7.29 (t, J 7.4 Hz, 1H), 7.15-7.02 (m, 2H), 5.98-5.85
(m, 1H), 5.52 (d, J 15.6 Hz, 1H), 5.24 (d, J 13.4Hz, 1H),
4.52 (br d, J 15.0 Hz), 4.36 (m, 1H), 3.70-3.54 (m, 2H),
5.55-3.37 (m, 2H), 3.00 (dd, J 14.4, 4.8 Hz, 0.7H), 2.91 (dd,
J 14.4, 7.5 Hz, 0.3H), 2.42 (s, 3H), 1.82-1.63 (m, 3H), 1.62-
1.35 (m, 1H). IR (KBr) ν 3075, 3057, 3025, 2981, 2965,
2918, 2869, 1729 (vs), 1664 (vs), 1612, 1479, 1467, 1362,
1282, 1191, 1091, 993, 948, 923, 819, 750, 736. MS (CI)
m/z (M+H)+ 457.
1'-(2-Fluorobenzyl)-2-(3-isopropoxypropyl)-7-methyl-
2H-spiro[chromeno[2,3-c]pyrrole-1,3'-indoline]-2',3,9-
trione (4{2-7-12}).
Yield: 410 mg, 76%. 1H NMR (500 MHz, DMSO-d6) δ
7.82-7.74 (m, 2H), 7.70 (dd, J 8.7, 1.9 Hz, 1H), 7.55 (t,
J 7.7 Hz, 1H), 7.43-7.32 (m, 2H), 7.29 (d, J 6.9 Hz, 1H),
7.26-7.14 (m, 2H), 7.10-7.01 (m, 2H), 5.14 (d, J 16.4 Hz,
1H), 5.04 (d, J 16.3 Hz, 1H), 3.44-3.02 (m, 5H), 2.45 (s,
3H), 1.56-1.40 (m, 2H), 0.99 (t, J 6.3 Hz, 6H). IR (KBr) ν
3058, 2972, 2932, 2864, 1732 (vs), 1723 (vs), 1662 (vs),
1614, 1491, 1469, 1409, 1360, 1341, 1311, 1284, 1228,
1201, 1172, 1146, 1099, 943, 921, 828, 816, 758, 748, 690.
MS (CI) m/z (M+H)+ 541.
2-(Benzo[d][1,3]dioxol-5-ylmethyl)-1'-(2-fluorobenzyl)-
7-methyl-2H-spiro[chromeno[2,3-c]pyrrole-1,3'-indoline]-
2',3,9-trione (4{2-7-18}).
Yield: 430 mg, 75%. 1H NMR (500 MHz, DMSO-d6) δ
7.82-7.74 (m, 2H), 7.70 (dd, J 8.7, 1.9 Hz, 1H), 7.47 (t,
J 7.7 Hz, 1H), 7.40-7.26 (m, 2H), 7.24-7.08 (m, 3H), 6.99-
6.86 (m, 2H), 6.59 (d, J 7.9 Hz, 1H), 6.48 (d, J 1.4 Hz, 1H),
6.32 (dd, J 7.9, 1.4 Hz, 1H), 5.92 (s, 2H), 4.92 (d, J 16.6
Hz, 1H), 4.78 (d, J 16.5 Hz, 1H), 4.42 (d, J 15.1 Hz, 1H),
4.13 (d, J 15.1 Hz, 1H), 2.43 (s, 3H). IR (KBr) ν 3098,
3060, 3027, 2926, 2890, 2782, 1722 (vs), 1663 (vs), 1611,
1491, 1467, 1448, 1367, 1308, 1285, 1253, 1228, 1187,
ISSN 1814-9758. Ukr. Bioorg. Acta, 2020, Vol. 15, N 1
31
1099, 1042, 946, 823, 771, 754, 687. MS (CI) m/z (M+H)+
575.
1'-(2-Fluorobenzyl)-2-(furan-2-ylmethyl)-7-methyl-2H-
spiro[chromeno[2,3-c]pyrrole-1,3'-indoline]-2',3,9-trione
(4{2-7-20}).
Yield: 390 mg, 75%. 1H NMR (500 MHz, DMSO-d6) δ
7.78 (d, J 8.5 Hz, 2H), 7.71 (dd, J 8.7, 2.0 Hz, 1H), 7.55 (t,
J 7.2 Hz, 1H), 7.41-7.27 (m, 3H), 7.28-7.13 (m, 3H), 6.98
(t, J 7.5 Hz, 1H), 6.92 (d, J 7.9 Hz, 1H), 6.17 (dd, J 3.0,
1.9 Hz, 1H), 5.87 (d, J 3.1 Hz, 1H), 4.96 (d, J 16.7 Hz, 1H),
4.81 (d, J 16.6 Hz, 1H), 4.62 (d, J 15.8 Hz, 1H), 4.20 (d,
J 15.8 Hz, 1H), 2.44 (s, 3H). IR (KBr) ν 3048, 2923, 1730
(vs), 1660 (vs), 1612, 1491, 1472, 1424, 1361, 1288, 1229,
1204, 1182, 1146, 1102, 1080, 1010, 942, 828, 767, 753,
733, 689. MS (CI) m/z (M+H)+ 521.
2-(3-Methoxypropyl)-1',6,7-trimethyl-2H-spiro[chromeno-
[2,3-c]pyrrole-1,3'-indoline]-2',3,9-trione (4{3-1-10}).
Yield: 311 mg, 72%. 1H NMR (500 MHz, DMSO-d6) δ
7.66 (s, 1H), 7.61 (s, 1H), 7.45 (td, J 8.7, 1.1 Hz, 1H), 7.22
(d, J 8.5 Hz, 2H), 7.06 (t, J 7.9 Hz, 1H), 3.32 (s, 3H), 3.29-
3.15 (m, 3H), 3.13 (s, 3H), 3.11-2.98 (m, 1H), 2.40 (s, 3H),
2.31 (s, 3H), 1.67-1.44 (m, 2H). IR (KBr) ν 3061, 3047,
3029, 2973, 2928, 2876, 2834, 1733 (vs), 1719 (vs), 1662
(vs), 1611, 1467, 1414, 1367, 1350, 1284, 1195, 1133,
1113, 1084, 1020, 942, 754, 690. MS (CI) m/z (M-H)- 430.
1'-Ethyl-2-(2-methoxyethyl)-6,7-dimethyl-2H-spiro-
[chromeno[2,3-c]pyrrole-1,3'-indoline]-2',3,9-trione (4{3-
2-9}).
Yield: 320 mg, 74%. 1H NMR (500 MHz, DMSO-d6) δ
7.68 (s, 1H), 7.62 (s, 1H), 7.43 (td, J 7.8, 1.1 Hz, 1H), 7.21
(d, J 7.8 Hz, 1H), 7.18 (d, J 6.7 Hz, 1H), 7.03 (t, J 7.3 Hz,
1H), 3.98-3.70 (m, 2H), 3.50-3.36 (m, 1H), 3.31-3.09 (m, 6H),
3.03 (s, 3H), 2.40 (s, 3H), 2.31 (s, 3H), 1.30 (t, J 7.1 Hz,
3H). IR (KBr) ν 3060, 3031, 2986, 2935, 2886, 2832, 1727
(vs), 1664 (vs), 1611, 1493, 1467, 1414, 1373, 1303, 1194,
1160, 1123, 1093, 1008, 873, 765, 690. MS (CI) m/z
(M+H)+ 433.
2-(2-Hydroxyethyl)-6,7-dimethyl-1'-propyl-2H-spiro-
[chromeno[2,3-c]pyrrole-1,3'-indoline]-2',3,9-trione
(4{3-3-7}).
Yield: 311 mg, 72%. 1H NMR (500 MHz, CF3CO2D) δ
7.98 (s, 1H), 7.64 (s, 2H), 7.37-7.18 (m, 3H), 4.64-4.39 (m,
1H), 4.15-3.90 (m, 3H), 3.90-3.69 (m, 1.5H), 3.63-3.46 (m,
0.5H), 2.55 (s, 3H), 2.45 (s, 3H), 2.08-1.88 (m, 2H), 1.15 (t,
J 7.2 Hz, 3H). IR (KBr) ν 3500 (vs, br), 3052, 2966, 2934,
2876, 1726 (vs), 1667 (vs), 1610 (vs), 1489, 1468, 1410,
1367, 1305, 1285, 1193, 1139, 1095, 1054, 943, 852, 763,
690. MS (CI) m/z (M+H)+ 433.
1'-Allyl-6,7-dimethyl-2-((tetrahydrofuran-2-yl)methyl)-
2H-spiro[chromeno[2,3-c]pyrrole-1,3'-indoline]-2',3,9-
trione (4{3-5-13}).
Yield: 357 mg, 76%. 1H NMR (500 MHz, CF3CO2D) δ
7.98 (s, 1H), 7.73-7.56 (m, 2H), 7.39-7.18 (m, 3H), 6.16-5.93
(m, 1H), 5.58 (dd, J 17.3, 4.9 Hz, 1H), 5.47 (d, J 10.4 Hz,
1H), 4.82-4.68 (m, 1H), 4.67-4.50 (m, 1H), 4.43-4.32 (m,
0.6H), 4.32-4.21 (m, 0.4H), 4.11-3.89 (m, 2H), 3.82 (dd,
J 15.1, 5.3 Hz, 0.6H), 3.66-3.34 (m, 1.4H), 2.56 (s, 3H),
2.45 (s, 3H), 2.26-1.98 (m, 3H), 1.97-1.78 (m, 1H). IR (KBr) ν
3092, 3056, 2971, 2952, 2924, 2854, 1731 (vs), 1662 (vs),
1609, 1489, 1467, 1436, 1408, 1360, 1303, 1275, 1182,
1132, 1067, 941, 864, 825, 764, 692, 675. MS (CI) m/z
(M+H)+ 469.
1'-Ethyl-7-fluoro-2-((tetrahydrofuran-2-yl)methyl)-2H-
spiro[chromeno[2,3-c]pyrrole-1,3'-indoline]-2',3,9-trione
(4{4-2-13}).
Yield: 363 mg, 81%. 1H NMR (500 MHz, DMSO-d6) δ
8.07 (dd, J 9.3, 4.2 Hz, 1H), 7.91-7.78 (m, 1H), 7.68 (dd,
J 8.3, 3.1 Hz, 1H), 7.46 (t, J 7.8 Hz, 1H), 7.33-7.22 (m,
2H), 7.06 (t, J 7.5 Hz, 1H), 3.92-3.71 (m, 2H), 3.71-3.53
(m, 1H), 3.52-3.30 (m, 3H), 3.05 (dd, J 14.7, 4.9 Hz, 0.3H),
2.92 (dd, J 14.4, 7.4 Hz, 0.7H), 1.85-1.59 (m, 3H), 1.59-
1.33 (m, 1H), 1.25 (t, J 7.1 Hz, 3H). 13C NMR (125 MHz,
CDCl3) δ (as a mixture of two diastereomers (1:2.5), signals
of the main isomer) 171.3, 169.9, 163.1, 160.0 (d, JC-F 249.0
Hz), 155.5, 152.6, 144.4, 131.2, 126.7 (d, JC-F 7.4 Hz),
125.9, 124.1, 123.1, 122.8 (d, JC-F 25.4 Hz), 121.4, 121.3 (d,
JC-F 8.2 Hz), 111.07 (d, JC-F 24.1 Hz), 109.5, 76.6, 67.8,
45.1, 35.9, 29.5, 28.3, 25.2, 12.4. IR (KBr) ν 3068, 2978,
2949, 2876, 1726 (vs), 1670 (vs), 1609, 1475, 1362, 1282,
1258, 1191, 1140, 1110, 1056, 932, 897, 834, 764, 750,
689. MS (CI) m/z (M+H)+ 449.
2-Benzyl-7-fluoro-1'-propyl-2H-spiro[chromeno[2,3-c]-
pyrrole-1,3'-indoline]-2',3,9-trione (4{4-3-16}).
Yield: 355 mg, 76%. 1H NMR (500 MHz, DMSO-d6) δ
8.09 (dd, J 9.3, 4.2 Hz, 1H), 7.86 (ddd, J 9.2, 8.0, 3.2 Hz,
1H), 7.68 (dd, J 8.3, 3.1 Hz, 1H), 7.40 (t, J 7.7 Hz, 1H),
7.25-7.11 (m, 5H), 7.00-6.88 (m, 3H), 4.49 (d, J 15.4 Hz,
1H), 4.17 (d, J 15.4 Hz, 1H), 3.52 (t, J 6.9 Hz, 2H), 1.66-
1.47 (m, 2H), 0.89 (t, J 7.4 Hz, 3H). IR (KBr) ν 3091, 3056,
3043, 2967, 2935, 2919, 2876, 1727 (vs), 1667, 1609, 1580,
1470, 1376, 1354, 1326, 1285, 1256, 1189, 1140, 1086,
940, 883, 832, 735, 704, 687. MS (CI) m/z (M+H)+ 469.
1'-Allyl-7-fluoro-2-(3-isopropoxypropyl)-2H-spiro[chro-
meno[2,3-c]pyrrole-1,3'-indoline]-2',3,9-trione (4{4-5-12}).
Yield: 366 mg, 77%. 1H NMR (500 MHz, DMSO-d6) δ
8.00 (dd, J 9.3, 4.2 Hz, 1H), 7.82-7.71 (m, 1H), 7.65 (dd,
J 8.2, 3.1 Hz, 1H), 7.43 (t, J 7.3 Hz, 1H), 7.27 (d, J 7.2 Hz,
1H), 7.13 (d, J 7.9 Hz, 1H), 7.06 (t, J 7.5 Hz, 1H), 5.90
(ddd, J 15.1, 10.2, 5.0 Hz, 1H), 5.45 (d, J 17.3 Hz, 1H),
5.24 (d, J 10.4 Hz, 1H), 4.51 (dd, J 16.8, 4.4 Hz, 1H), 4.39
(dd, J 16.8, 4.7 Hz, 1H), 3.45-3.01 (m, 5H), 1.60-1.44 (m,
2H), 1.00 (t, J 6.2 Hz, 3H). IR (KBr) ν 3083, 3061, 3044,
3035, 3028, 2974, 2932, 2885, 2843, 1729 (vs), 1660 (vs),
1610, 1471 (vs), 1368, 1335, 1286, 1258, 1189, 1141, 1087,
977, 922, 886, 838, 756, 705, 691, 561. MS (CI) m/z
(M+H)+ 477.
7-Chloro-1'-methyl-2-phenethyl-2H-spiro[chromeno-
[2,3-c]pyrrole-1,3'-indoline]-2',3,9-trione (4{5-1-21}).
Yield: 371 mg, 79%. 1H NMR (500 MHz, CF3CO2D) δ
8.18 (d, J 1.1 Hz, 1H), 7.91 (dd, J 9.1, 1.1 Hz, 1H), 7.79 (d,
R. N. Vydzhak., M. V. Kachaeva, S. G. Pilyo et al.
32
J 9.1 Hz, 1H), 7.65 (t, J 7.8 Hz, 1H), 7.33-7.18 (m, 5H),
7.08-6.97 (m, 3H), 3.74-3.50 (m, 3H), 3.03-2.85 (m, 2H).
IR (KBr) ν 3074, 3024, 2937, 1730 (vs), 1714 (vs), 1665
(vs), 1609, 1494, 1461, 1367, 1349, 1282, 1177, 1114,
1087, 942, 823, 757, 700, 688, 655. MS (CI) m/z (M+H)+
471.
7-Chloro-2-(4-methoxybenzyl)-1'-propyl-2H-spiro[chro-
meno[2,3-c]pyrrole-1,3'-indoline]-2',3,9-trione (4{5-3-17}).
Yield: 386 mg, 75%. 1H NMR (500 MHz, DMSO-d6) δ
7.99-7.93 (m, 1H), 7.93-7.87 (m, 2H), 7.39 (t, J 7.7 Hz,
1H), 7.12 (d, J 7.9 Hz, 1H), 7.08 (d, J 7.3 Hz, 1H), 6.94 (t,
J 7.5 Hz, 1H), 6.79 (d, J 8.6 Hz, 2H), 6.65 (d, J 8.6 Hz, 2H),
4.49 (d, J 15.0 Hz, 1H), 4.03 (d, J 15.0 Hz, 1H), 3.70 (s,
3H), 3.57-3.38 (m, 2H), 1.69-1.49 (m, 2H), 0.92 (t, J 7.4
Hz, 3H). IR (KBr) ν 3088, 3076, 2958, 2932, 2873, 2841,
1736 (vs), 1725 (vs), 1668 (vs), 1609 (vs), 1512, 1488,
1463, 1436, 1365, 1313, 1281, 1265, 1247, 1201, 1180,
1139, 1111, 1087, 1024, 942, 902, 825, 765, 687, 656. MS
(CI) m/z (M+H)+ 515.
1'-Allyl-2-butyl-7-chloro-2H-spiro[chromeno[2,3-c]-
pyrrole-1,3'-indoline]-2',3,9-trione (4{5-5-5}).
Yield: 313 mg, 70%. 1H NMR (500 MHz, CF3CO2D) δ
7.98 (s, 1H), 7.69-7.56 (m, 2H), 7.36-7.21 (m, 3H), 6.04
(ddt, J 15.9, 10.4, 5.3 Hz, 1H), 5.54 (d, J 17.3 Hz, 1H), 5.47
(d, J 10.3 Hz, 1H), 4.68 (qd, J 16.4, 5.4 Hz, 2H), 3.64-3.45
(m, 1H), 3.45-3.25 (m, 1H), 2.56 (s, 3H), 2.46 (s, 1H), 1.63-
1.48 (m, 2H), 1.41-1.23 (m, 2H), 0.87 (t, J 7.3 Hz, 3H). IR
(KBr) ν 3058, 3048, 3029, 2960, 2931, 2874, 2860, 1731
(vs), 1718 (vs), 1663 (vs), 1621, 1610, 1487, 1467, 1438,
1410, 1391, 1360, 1306, 1285, 1192, 1136, 1104, 954, 868,
752, 692. MS (CI) m/z (M+H)+ 449.0.
2-Allyl-1'-benzyl-7-chloro-2H-spiro[chromeno[2,3-c]-
pyrrole-1,3'-indoline]-2',3,9-trione (4{5-6-6}).
Yield: 347 mg, 72%. 1H NMR (500 MHz, CF3CO2D) δ
8.23 (br s, 1H), 7.94 (br d, J 9.1 Hz, 1H), 7.81 (d, J 9.1 Hz,
1H), 7.59-7.34 (m, 6H), 7.31-7.18 (m, 3H), 5.76-5.58 (m,
1H), 5.23 (d, J 15.4 Hz, 1H), 5.08 (d, J 15.4 Hz, 1H), 4.96
(d, J 10.1 Hz, 1H), 4.88 (d, J 17.0 Hz, 1H), 4.43 (dd, J 15.3,
5.4 Hz, 1H), 3.80 (dd, J 15.4, 8.0 Hz, 1H). IR (KBr) ν 3092,
3073, 3025, 2984, 2932, 2907, 1730 (vs), 1661 (vs), 1608,
1489, 1461, 1368, 1350, 1282, 1256, 1200, 1177, 1114,
944, 928, 829, 756, 698, 657. MS (CI) m/z (M+H)+ 483.
7-Chloro-1'-(4-fluorobenzyl)-2-(3-methoxypropyl)-2H-
spiro[chromeno[2,3-c]pyrrole-1,3'-indoline]-2',3,9-trione
(4{5-8-10}).
Yield: 372 mg, 70%. 1H NMR (500 MHz, CF3CO2D) δ
8.22 (br s, 1H), 7.94 (br d, J 9.1 Hz, 1H), 7.81 (d, J 9.1 Hz,
1H), 7.62-7.47 (m, 3H), 7.33-7.23 (m, 3H), 7.13 (t, J 8.2
Hz, 2H), 5.27 (d, J 15.5 Hz, 1H), 5.16 (d, J 15.6 Hz, 1H),
3.63 (t, J 5.9 Hz, 2H), 3.59-3.42 (m, 5H), 1.98-1.77 (m,
2H). IR (KBr) ν 3071, 2984, 2929, 2868, 2826, 2805, 1728
(vs), 1667 (vs), 1608, 1509, 1489, 1462, 1374, 1360, 1323,
1287, 1258, 1225, 1202, 1174, 1118, 1095, 944, 907, 839,
826, 763, 687, 676, 663. MS (CI) m/z (M+H)+ 533.
Notes
Acknowledgments. Authors are grateful to ENAMINE
Ltd., Kyiv for financial support and for providing NMR
spectra.
The authors declare no conflict of interest.
Author contributions. R. N. V.: synthesis of
compounds, investigation, formal analysis, editing.
M. V. K.: synthesis of compounds, investigation, formal
analysis. S. G. P.: synthesis of compounds, investigation,
formal analysis, editing. V. S. M.: investigation, formal
analysis, writing of the most part of the manuscript, editing.
O. V. S.: formal analysis, writing experimental section,
editing. A. V. K.: NMR correlation experiment. V. S. B.
conceptualization, supervision, writing - review & editing.
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Трикомпонентна циклізація як підхід до створення комбінаторної бібліотеки 2Н-
спіро[хромено[2,3-с]пірол-1,3'-індолін]-2',3,9-трионів
Р. Н. Виджак1, М. В. Качаєва1, С. Г. Пільо1, В. С. Москвіна1,2*, О. В. Шабликіна1,2, А. В. Козицький3,4,
В. С. Броварець1
1 Інститут біоорганічної хімії та нафтохімії ім. В.П. Кухаря НАН України, вул. Мурманська, 1, Київ, 02094, Україна
2 Київський національний університет імені Тараса Шевченка, вул. Володимирська, 60, Київ, 01601, Україна
3 Інститут фізичної хімії ім. Л. В. Пісаржевського НАН України, просп. Науки, 31, Київ, 03028, Україна
4 ТОВ НВП «Єнамін», вул. Червоноткацька, 78, Київ, 02094, Україна
Резюме: Представлено дослідження трикомпонентної циклізації метилових естерів 4-(о-гідроксифеніл)-2,4-діоксобутанових кислот 1,
N-заміщених ізатинів 2 та первинних амінів 3, що веде до утворення 2Н-спіро[хромено[2,3-c]пірол-1,3'-індолін]-2',3,9-трионів. Спіроциклічні
індолін-2-они досить широко представлені серед природних біоактивних сполук, зокрема, у складі алкалоїдів, молекули яких містять систему
спіро[індолін-3,6'-пірано[3,4-f]індолізину]. Зараз є доведеним, що деякі популярні в традиційній медицині лікарські рослини зобов'язані своїм
цілющим властивостям саме алкалоїдам цієї групи. Разом із тим, синтез таких похідних досить складний, що обмежує можливості їх
використання на практиці. Альтернативною стратегією є високоефективний трикомпонентний одностадійний синтез близьких за будовою
структур, зокрема, 2Н-спіро[хромено[2,3-c]пірол-1,3'-індолін]-2',3,9-трионів, з можливістю варіації в широких межах замісників і
функціональних груп. В ході досліджень було підтверджено, що вказана трикомпонентна гетероциклізація дійсно є універсальним та ефективним
інструментом синтезу 2Н-спіро[хромено[2,3-c]пірол-1,3'-індолін]-2',3,9-трионів. На основі естерів 4-(о-гідроксифеніл)-2,4-діоксобутанових
кислот, ізатинів із алкільними, алільним та бензильними замісниками в положенні 1, а також широкого набору аліфатичних амінів (в тому числі з
активними функціональними групами, ароматичними та гетероциклічними фрагментами) було створено комбінаторну бібліотеку з 122 похідних,
причому синтетична ефективність склала 87%, а виходи більш ніж 50% представників бібліотеки перевищували 70%. Синтетична процедура є
простою у виконанні, допускає варіацію розчинників і придатна для автоматизації. ЯМР дослідження синтезованих сполук, а саме 1Н та 13С
спектри ЯМР, а також (для окремих представників) – COSY, HMBS та HSQC, дозволили не лише однозначно підтвердити структуру речовин, але
й встановити характеристичні сигнали в спектрах 1Н та 13С ЯМР, зокрема сигнал спіроатома карбону – близько 67 м.ч. Сигнали карбонільних
груп в ІЧ спектрах виявляються двома широкими та інтенсивними смугами – 1735-1715 та 1670-1660 см-1.
Ключові слова: ізатин, трикомпонентна циклізація, 1,2-дигідрохромено[2,3-с]пірол-3,9-діони, комбінаторна бібліотека.
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| id | oai:ojs2.bioorganica.com.ua:article-5 |
| institution | Ukrainica Bioorganica Acta |
| keywords_txt_mv | keywords |
| language | English |
| last_indexed | 2026-07-20T01:01:12Z |
| publishDate | 2020 |
| publisher | V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the National Academy of Sciences of Ukraine |
| record_format | ojs |
| resource_txt_mv | bioorganicacomua/d5/b70539250d915edbe9598f51993161d5.pdf |
| spelling | oai:ojs2.bioorganica.com.ua:article-52026-07-19T14:56:52Z Three-component cyclization as an approach to a combinatorial library of 2H-spiro-[chromeno[2,3-c]pyrrole-1,3'-indoline]-2',3,9-triones Трикомпонентна циклізація як підхід до створення комбінаторної бібліотеки 2Н-спіро[хромено[2,3-с]пірол-1,3'-індолін]-2',3,9-трионів Vydzhak, Roman N. Kachaeva, Maryna V. Pilyo, Stepan G. Moskvina, Viktoriia S. Shablykina, Olga V. Kozytskiy, Andriy V. Brovarets, Volodymyr S. isatin multicomponent reactions chromenes combinatorial library Ізатин трикомпонентна циклізація 1,2-дигідрохромено[2,3-с]пірол-3,9-діони комбінаторна бібліотека A versatile and efficient three-component cyclization of methyl 4-(o-hydroxyphenyl)-2,4-dioxobutanoates 1, N-substituted isatins 2, and primary amines 3 was explored to synthesize of 2H-spiro[chromeno[2,3-c]pyrrole-1,3'-indoline]-2',3,9-triones. We obtained a library of 122 derivatives with an indolin-2-one motif as an important structural fragment in natural alkaloids. This method is practical and useful strategy for constructing dihydrochromeno[2,3-c]pyrrole-3,9-diones. Most of the obtained products also have functional groups for easy and further diversification by classical reactions.   Представлено дослідження трикомпонентної циклізації метилових естерів 4-(о-гідроксифеніл)-2,4-діоксобутанових кислот 1, N-заміщених ізатинів 2 та первинних амінів 3, що веде до утворення 2Н-спіро[хромено[2,3-c]пірол-1,3'-індолін]-2',3,9-трионів. Спіроциклічні індолін-2-они досить широко представлені серед природних біоактивних сполук, зокрема, у складі алкалоїдів, молекули яких містять систему спіро[індолін-3,6'-пірано[3,4-f]індолізину]. Зараз є доведеним, що деякі популярні в традиційній медицині лікарські рослини зобов'язані своїм цілющим властивостям саме алкалоїдам цієї групи. Разом із тим, синтез таких похідних досить складний, що обмежує можливості їх використання на практиці. Альтернативною стратегією є високоефективний трикомпонентний одностадійний синтез близьких за будовою структур, зокрема, 2Н-спіро[хромено[2,3-c]пірол-1,3'-індолін]-2',3,9-трионів, з можливістю варіації в широких межах замісників і функціональних груп. В ході досліджень було підтверджено, що вказана трикомпонентна гетероциклізація дійсно є універсальним та ефективним інструментом синтезу 2Н-спіро[хромено[2,3-c]пірол-1,3'-індолін]-2',3,9-трионів. На основі естерів 4-(о-гідроксифеніл)-2,4-діоксобутанових кислот, ізатинів із алкільними, алільним та бензильними замісниками в положенні 1, а також широкого набору аліфатичних амінів (в тому числі з активними функціональними групами, ароматичними та гетероциклічними фрагментами) було створено комбінаторну бібліотеку з 122 похідних, причому синтетична ефективність склала 87%, а виходи більш ніж 50% представників бібліотеки перевищували 70%. Синтетична процедура є простою у виконанні, допускає варіацію розчинників і придатна для автоматизації. ЯМР дослідження синтезованих сполук, а саме 1Н та 13С спектри ЯМР, а також (для окремих представників) – COSY, HMBS та HSQC, дозволили не лише однозначно підтвердити структуру речовин, але й встановити характеристичні сигнали в спектрах 1Н та 13С ЯМР, зокрема сигнал спіроатома карбону – близько 67 м.ч. Сигнали карбонільних груп в ІЧ спектрах виявляються двома широкими та інтенсивними смугами – 1735-1715 та 1670-1660 см-1 V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the National Academy of Sciences of Ukraine 2020-06-30 Article Article application/pdf https://bioorganica.com.ua/index.php/journal/article/view/5 10.15407/bioorganica2020.01.026 Ukrainica Bioorganica Acta; Vol. 15 No. 1 (2020): Ukrainica Bioorganica Acta; 26-33 Ukrainica Bioorganica Acta; Том 15 № 1 (2020): Ukrainica Bioorganica Acta; 26-33 1814-9766 1814-9758 10.15407/bioorganica2020.01 en https://bioorganica.com.ua/index.php/journal/article/view/5/7 Copyright (c) 2020 Roman N. Vydzhak, Maryna V. Kachaeva, Stepan G. Pilyo, Viktoriia S. Moskvina, Olga V. Shablykina, Andriy V. Kozytskiy, Volodymyr S. Brovarets https://creativecommons.org/licenses/by/4.0 |
| spellingShingle | Ізатин трикомпонентна циклізація 1,2-дигідрохромено[2,3-с]пірол-3,9-діони комбінаторна бібліотека Vydzhak, Roman N. Kachaeva, Maryna V. Pilyo, Stepan G. Moskvina, Viktoriia S. Shablykina, Olga V. Kozytskiy, Andriy V. Brovarets, Volodymyr S. Трикомпонентна циклізація як підхід до створення комбінаторної бібліотеки 2Н-спіро[хромено[2,3-с]пірол-1,3'-індолін]-2',3,9-трионів |
| title | Трикомпонентна циклізація як підхід до створення комбінаторної бібліотеки 2Н-спіро[хромено[2,3-с]пірол-1,3'-індолін]-2',3,9-трионів |
| title_alt | Three-component cyclization as an approach to a combinatorial library of 2H-spiro-[chromeno[2,3-c]pyrrole-1,3'-indoline]-2',3,9-triones |
| title_full | Трикомпонентна циклізація як підхід до створення комбінаторної бібліотеки 2Н-спіро[хромено[2,3-с]пірол-1,3'-індолін]-2',3,9-трионів |
| title_fullStr | Трикомпонентна циклізація як підхід до створення комбінаторної бібліотеки 2Н-спіро[хромено[2,3-с]пірол-1,3'-індолін]-2',3,9-трионів |
| title_full_unstemmed | Трикомпонентна циклізація як підхід до створення комбінаторної бібліотеки 2Н-спіро[хромено[2,3-с]пірол-1,3'-індолін]-2',3,9-трионів |
| title_short | Трикомпонентна циклізація як підхід до створення комбінаторної бібліотеки 2Н-спіро[хромено[2,3-с]пірол-1,3'-індолін]-2',3,9-трионів |
| title_sort | трикомпонентна циклізація як підхід до створення комбінаторної бібліотеки 2н-спіро[хромено[2,3-с]пірол-1,3'-індолін]-2',3,9-трионів |
| topic | Ізатин трикомпонентна циклізація 1,2-дигідрохромено[2,3-с]пірол-3,9-діони комбінаторна бібліотека |
| topic_facet | isatin multicomponent reactions chromenes combinatorial library Ізатин трикомпонентна циклізація 1,2-дигідрохромено[2,3-с]пірол-3,9-діони комбінаторна бібліотека |
| url | https://bioorganica.com.ua/index.php/journal/article/view/5 |
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