Synthesis of 1,3-dialkyl-4-[(arylmethylidene)amino]glycolurils

Article abstract of DOI:10.1007/s10593-021-02963-x

[Figure not available: see fulltext.] A method for the synthesis of 1,3-dialkyl-4-[(arylmethylidene)amino]glycolurils was developed based on nucleophilic substitution of the sulfur atom with the oxygen atom in the corresponding thioglycolurils via alkylation of the latter followed by acid hydrolysis of alkylsulfanyl derivatives of thioglycolurils, both with the isolation of alkylsulfanyl intermediates and by the one-pot method. The structure of the synthesized compounds was confirmed by X-ray structural analysis of several examples.

Full text of DOI:10.1007/s10593-021-02963-x

DOI 10.1007/s10593-021-02963-x
Chemistry of Heterocyclic Compounds 2021, 57(6), 646–655
Synthesis of 1,3-dialkyl-4-[(arylmethylidene)amino]glycolurils
Sergei А. Serkov1, Marina А. Es'kova1,2, Natalya V. Sigay1, Natalya N. Kostikova1,
Tatyana N. Volkhina2,3, Natalya G. Kolotyrkina1, Galina А. Gazieva1*
1 N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences,
47 Leninsky Ave., Moscow 119991, Russia; e-mail: gaz@ioc.ac.ru
2 A. N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences,
28 Vavilova St., Moscow 119991, Russia; e-mail: marinaeskovskaya@gmail.com
3 D. Mendeleev University of Chemical Technology of Russia,
9 Miusskaya Sq., Moscow 125047, Russia; e-mail: tanya.volhina.99@mail.ru
Translated from Khimiya Geterotsiklicheskikh Soedinenii,
Submitted February 16, 2021
2021, 57(6), 646–655
Accepted after revision April 16, 2021
A method for the synthesis of 1,3-dialkyl-4-[(arylmethylidene)amino]glycolurils was developed based on nucleophilic substitution of the
sulfur atom with the oxygen atom in the corresponding thioglycolurils via alkylation of the latter followed by acid hydrolysis of alkyl-
sulfanyl derivatives of thioglycolurils, both with the isolation of alkylsulfanyl intermediates and by the one-pot method. The structure of
the synthesized compounds was confirmed by X-ray structural analysis of several examples.
Keywords: 5-[(4-bromobenzyl)sulfanyl]-3,3a,6,6a-tetrahydroimidazo[4,5-d]imidazol-2(1H)-ones, glycolurils, 5-methylsulfanyl-3,3a,6,6a-
tetrahydroimidazo[4,5-d]imidazol-2(1H)-ones, tetrahydroimidazo[4,5-d]imidazole-2,5(1H,3H)-diones, thioglycolurils, 5-thioxohexa-
hydroimidazo[4,5-d]imidazol-2(1H)-ones, S-alkylation, hydrolysis.
Amides and thioamides, including cyclic ones, are
widely used in medicinal chemistry.1 Depending on the
availability of the corresponding amides or thioamides, it
becomes necessary to replace the amide oxygen atom with
a sulfur atom1c–e,2 or desulfurize thioamides.3 Glycolurils
(tetrahydroimidazo[4,5-d]imidazole-2,5(1H,3H)-diones) are
an important class of cyclic amides that exhibit a wide
spectrum of neurotropic activity.4 1,3,4,6-Tetraalkyl-
glycolurils are recommended for the treatment of
neuroses.4a,b N-(Carboxyalkyl)glycolurils showed neuro-
protective activity.4c Nootropic and anxiolytic effects of
N-(2-acetylaminoethyl)glycolurils were revealed.4d At the
same time, substituted N-aminothioglycolurils have
antiproliferative, fungicidal,5 and sedative6 effects, while
N-aminoglycolurils are practically inaccessible.
The replacement of the thioxo group with the oxo group
is based on two main approaches: nucleophilic
substitution3d,e,5b,7 and oxidation.3a–c Earlier, we showed by
several examples the possibility of synthesizing 1,3-di-
alkyl-4[(E)-((E)-3-phenylallylidene)amino]glycolurils by
alkylation of the corresponding thioglycolurils with MeI
followed by hydrolysis of the resulting methylsulfanyl
derivatives; isolation of the methylsulfanyl derivatives
afforded higher yields (62–81%) of the target glycolurils as
compared to the one-pot process (48–69% yields of
glycolurils).5b The literature data also confirmed the
efficiency of the method of the synthesis of imidazolidin-
2-ones via hydrolysis of imidazolidine-2-thione alkyl-
sulfanyl derivatives.7
In this regard, the aim of this work was to develop a
method for the synthesis of 1,3-dialkyl-4-[(arylmethyl-
idene)amino]glycolurils by alkylation of the corresponding
thioglycolurils followed by hydrolysis of alkylsulfanyl
derivatives.
1,3-Dialkyl-4-[(arylmethylidene)amino]thioglycolurils
1a–j were obtained according to a previously developed
procedure8 by the reaction of octahydroimidazo[4,5-e]-
[1,2,4]triazines 2a,b with (hetero)aromatic aldehydes 3a–e
(Scheme 1). 5-Methylsulfanyl derivatives 4a–k were
synthesized by alkylation of thioglycolurils 1a–j by the
action of MeI in the presence of an equimolar amount of
K2CO3 similarly to the known procedure.5 The yields of
compounds 4a–j were 83–98%, the yield of product 4k
was 15% (Scheme 2).
0009-3122/21/57(6)-0646©2021 Springer Science+Business Media, LLC
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Chemistry of Heterocyclic Compounds 2021, 57(6), 646–655
Scheme 1
carbon atom which is observed in compounds 4b,g,k
at 156.2–161.7 ppm. For comparison, the signal of a
similar carbon atom in the spectrum of sodium 4-nitro-
phenoxide is observed at 178.6 ppm.9 Alkylation of 1,3-di-
ethyl-substituted thioglycoluril 1h at a molar ratio of
K2CO3:1h = 1:1 gave a mixture of potassium salt 4h and
hydroxy derivative 4k, the separation of which by
fractional crystallization from EtOH led to a decrease in the
total yield of S-alkylation products from ~80 to ~41%. An
increase in the molar ratio of K2CO3:1h to 1.2:1 made it
possible to obtain potassium salt 4h in 85% yield.
Alkylation of thioglycoluril 1g containing a hydroxy-
benzylidene moiety resulted in the formation of trace
amounts of the O-methylation product. The 1Н NMR
spectrum of the reaction mixture showed a minor signal of
the methoxy group at 3.85 ppm; in the high-resolution
mass spectrum, along with the molecular ion peak [M+H]+
of compound 4g (m/z 348.1493), a peak corresponding to
the molecular ion [M+H]+ of compound 4l (m/z 362.1648),
methylated both at the sulfur atom and at the oxygen atom,
was present (Fig. 1).
Scheme 2
1
Generally, in the H NMR spectra of alkylation products
4a–k, in comparison with the spectra of thioglycolurils 1a–j,
the signal of the NH proton disappears (singlet in the
region of 9.94–10.44 ppm)8 and the signal of protons of the
SCH3 group emerges (singlet in the region 2.40–2.46 ppm).
In the 13C NMR spectra, the signal of the carbon atom of
the C=S group disappears in the 178.2–179.7 ppm range8
and the signals of the carbon atoms of the SCH3 and N=CS
groups appear in the 12.9–13.0 and 166.0–167.2 ppm
ranges, respectively.
Compound 4f was chosen as a model for studying the
hydrolysis of alkylsulfanylglycolurils. The reactions were
carried out in MeOH in the presence of an equivalent
amount of concentrated HCl. The progress of the reactions
was monitored by 1H NMR spectroscopy. At room
temperature, the hydrochloride of the starting compound
1
4f·HCl was formed (Table 1). According to the H NMR
spectrum of the reaction mixture, the conversion of
hydrochloride 4f·HCl was about 5% after 24 h (entries 1
and 2). When heating to 40°С, the yield of the target
compound 5f reached 50% after 1.5 h, after which its
amount did not increase, and the formation of byproducts
began 5.5 h after the start of the reaction (entries 3–5).
Upon heating under reflux in MeOH, already 15 min
after the start of the reaction, the signals of the target
1
product 5f were recorded in the H NMR spectrum, along
with the signals of hydrochloride 4f·HCl (Table 1, entry 6).
After 1 h, about 10% of compound 4f·HCl remained,
As shown by the data of elemental analysis and NMR
spectroscopy, the alkylation of compound 1c containing
hydroxy and nitro groups in the phenyl substituent resulted
in the formation of the potassium salt of S-methyl-
sulfanylglycoluril 4c in high yield (93%). The most
characteristic feature of the 13C NMR spectrum of salt 4c is
the downfield shift of the signal of the aromatic carbon
atom directly bonded to the oxygen atom, which is
observed at 178.1 ppm, in contrast to the signal of a similar
Figure 1. Byproduct 4l of alkylation of thioglycoluril 1g.
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Chemistry of Heterocyclic Compounds 2021, 57(6), 646–655
Table 1. Optimization of the reaction conditions
of the hydrolysis of S-methyl derivative 4f*
Ph
Ph
N
N
Et
N
N
Et
HCl
N
N
O
S
O
S
Me
N
N
Me
N
N
Et
H
Cl
4f·HCl
Et
4f
Ph
HCl
H2O
N
N
Et
N
Ph
N
Ph
N
Figure 2. O,S-Alkylation product 7k and potassium salt of
thioglycoluril 1k obtained by alkylation of compound 1h.
MeOH
O
O
6a
Side product
N
N
H
Et
5f
O,S-alkylation product 7k and the potassium salt of
thioglycoluril 1k (Fig. 2) were isolated in 2 and 8% yields,
respectively, and characterized.
Yield,** %
Amount of
HCl, equiv
Temperature,
Time,
h
Entry
°С
4f·HCl
5f
In the 1H NMR spectra of the alkylation products
7a,b,d–g,i,j, in comparison with the spectra of
thioglycolurils 1a,b,d–g,i,j, the NH proton signal
disappears (singlet in the 9.94–10.44 ppm region)8 and
proton signals of the SCH2 group (singlet in the range of
4.25–4.29 ppm) and the 4-bromophenyl fragment (two
doublets in the range of 7.38–7.52 ppm) appear. In the
13C NMR spectra of compounds 7a,b,d–g,i,j, the signal of
the carbon atom of the C=S group disappears in the range
of 178.2–179.7 ppm,8 accompanied with the appearance of
signals of the (4-bromobenzyl)sulfanyl group (the most
characteristic signals at 33.1–33.2, 131.2–131.3, and 131.3–
131.4 ppm) and the N=CS group at 164.9–165.6 ppm.
Hydrolysis of 4-bromobenzyl derivatives 7a,b,d–g,i,j
was carried out by heating with an equivalent amount of
HCl under reflux in MeOH for 1 or 6 h (the progress of the
1
2
3
4
5
6
7
8
9
1
1
20
20
1
24
0.5
1.5
5.5
0.25
1
100
95
67
50
20
93
10
5
0
5
1
40
33
50
50
6
1
40
1
40
1
Reflux
Reflux
Reflux
Reflux
1
60
43***
0
1
3
0.1
2
0
* Amounts of reagents: glycoluril 4f (331 mg, 1 mmol), MeOH (30 ml).
** According to 1H NMR spectroscopy data.
*** Yield of isolated product.
while, along with the signals of the target glycoluril 5f
(about 60% yield, entry 7), signals of byproducts, apparently,
decomposition products (for example, 1,2-di((E)-benzyl-
idene)hydrazine (6a), about 15%), emerged. After 3 h, the
conversion of compound 4f·HCl reached 95%; however,
along with an increase in the relative integral intensity of
the signals from glycoluril 5f, the intensity of signals from
the degradation products also increased. Glycoluril 5f was
isolated in 43% yield (entry 8). When the amount of HCl
was decreased to 0.1 equiv, neither glycoluryl 5f nor
hydrochloride 4f·HCl was formed from methylsulfanyl
derivative 4f (entry 9).
Considering the obtained results, glycolurils 5a–j were
synthesized by heating compounds 4a–j with an equivalent
amount of HCl under reflux in MeOH for 1 or 6 h (the
course of reactions was monitored by 1H NMR
spectroscopy) in 19–58% yields (Scheme 2). For the
hydrolysis of potassium salts 4c,h, 2 equiv of HCl was
used. Since the yields of the target glycolurils 5a–j are far
from quantitative, we attempted to obtain them via the
(4-bromobenzyl)sulfanyl derivatives of thioglycolurils
7a,b,d–g,i,j. Compounds 7a,b,d–g,i,j were prepared by
alkylation of thioglycolurils 1a,b,d–g,i,j with 4-bromo-
benzyl bromide in DMSO in the presence of K2CO3 at
room temperature for 5 h. Yields of compounds 7a,b,d–g,i,j
amounted to 62–96% (Scheme 2). Alkylation of
compounds 1c,h led to a mixture of S- and O,S-alkylation
products, as well as a mixture of potassium salts of the
starting thioglycolurils 1c,h and S-alkylation products. The
1
reactions was monitored by H NMR spectroscopy). The
yields of target glycolurils 5a,e,f,j were 37–58% (Scheme 2).
The hydrolysis of compounds 7b,d,g,i was more severe
with the formation of a mixture of products that was
difficult to identify.
Next, the possibility of accessing glycolurils 5a–j by the
reaction of N-aminothioglycolurils 1a–j with an excess of
MeI in a H2O–MeOH, 1:80 mixture was investigated
(Scheme 2). Heating the reaction mixture under reflux for
5 h using a fourfold excess of MeI resulted in a mixture of
the starting thioglycoluril 1a–j with a small amount of the
target glycoluril 5a–j. An increase in the degree of
conversion of the starting thioglycolurils 1a–j to 90–100%
1
(according to H NMR spectroscopy) was achieved by
increasing the amount of MeI to 7 equiv, and in some cases
also by increasing the reaction time to 8–10 h. The yields
of glycolurils 5a–j were 20–62%. Due to the low solubility
of thioglycolurils 1c,h in MeOH, their reactions with MeI
were also carried out in a DMF–H2O, 10:1 mixture both at
room temperature and at 60°С, but this did not lead to a
significant increase in the yields of glycolurils 5c,h (20–
22%). In general, the moderate yields of glycolurils 5a–j
are explained by hydrolysis in an alternative direction
leading to the formation, in particular, of the above-
mentioned N,N'-dibenzylidenehydrazines 6. In addition to
1H NMR spectroscopy data, the structure of compound 6b
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Chemistry of Heterocyclic Compounds 2021, 57(6), 646–655
(Ar
= 2-HO-5-O2NC6H3) was confirmed by mass
spectroscopy.
1
In the H NMR spectra of glycolurils 5a–j, an upfield
shift of the signal of the NH proton (8.41–8.55 ppm) is
observed in comparison with the signal of the same proton
in the spectra of thioglycolurils 1a–j (9.94–10.44 ppm). In
the 13C NMR spectra of glycolurils 5a–j, the signal of the
C=O group at 155.7–156.6 ppm appears instead of the
signal of the C=S group in the spectra of thioglycolurils
1a–j at 178.2–179.7 ppm.
The structures of compounds 4j and 5g,h were
confirmed by X-ray structural analysis of their single
crystals (Figs. 3–5), which, in the case of compound 5h,
contained one solvate MeOH molecule per one molecule of
the target product. According to the data obtained in this
way, compounds 4j and 5g,h have the E-configuration of
the C=N bond and the molecular geometry expected for
this class of compounds,8,10 including the planar
conformation of the heterocyclic rings in the glycoluryl
fragment, the angle between which is 60.76(6), 60.77(9),
and 59.37(10)°, respectively. In addition, the rings of
the thiophene and phenol substituents and the
corresponding heterocycle are practically in the same plane
as indicated by the angle between their rms planes of
15.07(7)–21.62(6)°. In the case of glycolurils 5g,h, such a
planar configuration is additionally stabilized by intra-
molecular hydrogen bonds O–H···N (distance O···N:
2.6559(18) and 2.5591(13) Å, angle O–H···N: 144.72(10)
and 148.96(6)°, respectively) with the hydroxy group of the
phenol substituent. On the contrary, the NH group in
compounds 5g,h, which is absent in sulfanylglycoluril 4j,
participates in the formation of intermolecular hydrogen
bonds N–H···O (distance N···O: 2.8494(19) and 2.8377(13) Å,
angle N–H···O: 168.87(10) and 165.27(7)°, respectively)
either with the neighboring molecule of the target product,
as in glycoluril 5g, or with the MeOH solvate molecule, as
in glycoluril 5h. In the first case, this leads to the
appearance of centrosymmetric dimers in the solid state, or,
in the second, infinite chains formed by the O–H···O hydrogen
bond (distance O···O: 2.7106(12) Å, angle O–H···O:
171.10(6)°) between the indicated MeOH molecule and the
O(2) oxygen atom of the glycoluryl fragment.
Figure 3. The molecular structure of compound 4j with atoms
represented as thermal vibration ellipsoids of 50% probability.
Hydrogen atoms are not shown for clarity.
Figure 4. The molecular structure of compound 5g with atoms
represented as thermal vibration ellipsoids of 50% probability.
Hydrogen atoms (with the exception of those belonging to the NH
and OH groups) are not shown for clarity. The dotted line shows
the O–H···N hydrogen bond.
The synthesized glycolurils 5f,g and methylsulfanyl
derivatives 4i,j were tested for cytotoxicity against human
rhabdomyosarcoma (RD), lung carcinoma (A549), and
intestinal carcinoma (HCT116) cell lines. It was shown that
compounds 5f,g and 4i,j do not possess cytotoxicity, which
is a positive result for potential neurotropically active
compounds.
To conclude, methods for the synthesis of 1,3-dialkyl-
4-[(arylmethylidene)amino]glycolurils were developed
based on nucleophilic substitution of the sulfur atom with
the oxygen atom in the corresponding thioglycolurils by
alkylation of the latter and acid hydrolysis of alkylsulfanyl
derivatives of thioglycolurils. The one-pot method
involving alkylation of thioglycolurils at the sulfur atom
with an excess of MeI followed by hydrolysis of the
resulting methylsulfanyl derivatives by the released HI can
be considered as a general and convenient approach to the
synthesis of the target glycolurils.
Figure 5. The molecular structure of compound 5h with atoms
represented as thermal vibration ellipsoids of 50% probability.
Hydrogen atoms (with the exception of those belonging to the NH
and OH groups) and the MeOH solvate molecule are not shown
for clarity. The dotted line shows the O–H···N hydrogen bond.
649

Chemistry of Heterocyclic Compounds 2021, 57(6), 646–655
Experimental
Synthesis of methylsulfanylglycolurils 4a–k (General
method). MeI (125 μl, 2 mmol) was added with stirring to a
suspension of thioglycoluril 1a–j (1 mmol) and K2CO3
(138 mg, 1 mmol) (166 mg, 1.2 mmol for the synthesis of
salt 4h) in MeOH (30 ml). The resulting mixture was
stirred at 60°C for 2 h, then concentrated under reduced
pressure. The residue was triturated with MeOH (for salts
4c,h), H2O (for compounds 4a,d–f,i,j), or Me2CO (for
compounds 4b,g); the formed precipitate was filtered off,
washed with H2O (5 ml) (2×1 ml for salts 4c,h) and air-
dried.
IR spectra were registered on a Bruker ALPHA Fourier
1
transform spectrometer in KBr pellets. H and 13C NMR
spectra (300 and 75 MHz, respectively) were acquired on a
Bruker AM-300 spectrometer in DMSO-d6 with TMS as
internal standard. High-resolution mass spectra were
recorded on a Bruker micrOTOF II mass spectrometer with
electrospray ionization in the positive ion registration mode
(capillary voltage 4500 V). Scanning range m/z 50–3000,
external or internal calibration (Fluka Electrospray Calibrant
Solution). Syringe injection was used for solutions of
compounds in MeCN or MeOH, flow rate 3 μl/min. N2 was
used as spray gas (flow rate 4 l/min), interface temperature
180°C. The mass spectrum of compound 6b was registered
on a Finnigan MAT INCOS-50 mass spectrometer (EI, 70 eV).
Elemental analysis was performed on a Perkin Elmer Series
II 2400 CHN-analyzer. Melting points were determined on
a Boetius heating bench.
(E)-4-Benzylideneamino-1,3-dimethyl-5-methylsulfanyl-
3,3a,4,6a-tetrahydroimidazo[4,5-d]imidazol-2(1H)-one
(4a). Yield 288 mg (95%), white powder, mp 189–191°С
(MeOH). IR spectrum, ν, cm–1: 1695 (C=O), 1564, 1492,
1
1449, 1397, 1215, 1089, 1032. H NMR spectrum, δ, ppm
(J, Hz): 2.43 (3H, s, SCH3); 2.83 (3H, s, NCH3); 2.92 (3H,
s, NCH3); 5.59 (1H, d, J = 7.8, CH); 5.94 (1H, d,
J = 7.9, CH); 7.38–7.46 (3H, m, H Ph); 7.68 (2H, d,
J = 7.2, H Ph); 8.10 (1H, s, N=CH). 13C NMR spectrum,
δ, ppm: 12.9; 28.3; 30.5; 72.2; 80.0; 126.4 (2С); 128.7
(2С); 129.4; 134.4; 138.1; 157.6; 166.8. Found, m/z:
304.1236 [M+H]+. C14H18N5OS. Calculated, m/z:
304.1227.
(E)-4-[(2-Hydroxybenzylidene)amino]-1,3-dimethyl-
5-methylsulfanyl-3,3a,4,6a-tetrahydroimidazo[4,5-d]-
imidazol-2(1H)-one (4b). Yield 313 mg (98%), white
powder, mp 157–159°С (Me2CO). IR spectrum, ν, cm–1:
3401 (OH), 3202, 1704 (C=O), 1670, 1607, 1572, 1499,
1455, 1410, 1260, 1212, 1192, 1169, 1042. 1H NMR
spectrum, δ, ppm (J, Hz): 2.45 (3H, s, SCH3); 2.83 (3H, s,
NCH3); 2.92 (3H, s, NCH3); 5.58 (1H, d, J = 7.8, CH); 5.94
(1H, d, J = 7.8, CH); 6.86–6.91 (2H, m, H Ar); 7.24 (1H, t,
J = 7.5, H Ar); 7.58 (1H, d, J = 7.6, H Ar); 8.30 (1H, s,
N=CH); 10.12 (1H, br. s, OH). 13C NMR spectrum, δ, ppm:
13.0; 28.4; 30.8; 72.7; 80.0; 116.2; 119.4; 119.8; 127.1;
130.8; 137.3; 156.3; 157.7; 166.4. Found, m/z: 320.1176
[M+H]+. C14H18N5O2S. Calculated, m/z: 320.1176.
(E)-2-{[(4,6-Dimethyl-2-methylsulfanyl-5-oxo-4,5,6,6a-
tetrahydroimidazo[4,5-d]imidazol-1(3aH)-yl)imino]-
methyl}-4-nitrophenol, potassium salt (4c). Yield 374 mg
(93%), orange powder, mp >300°С (MeOH). IR spectrum,
ν, cm–1: 3449 (br, H2O), 1707 (C=O), 1597, 1559 (NO2),
1489, 1444, 1416, 1339 (NO2), 1283, 1220, 1043. 1H NMR
spectrum, δ, ppm (J, Hz): 2.41 (3H, s, SCH3); 2.81 (3H, s,
NCH3); 2.88 (3H, s, NCH3); 5.52 (1H, d, J = 8.0, CH); 5.83
(1H, d, J = 8.0, CH); 6.05 (1H, d, J = 9.5, H Ar); 7.73 (1H,
dd, J = 9.5, J = 3.1, H Ar); 8.26 (1H, d, J = 3.2, H Ar); 8.28
(1H, s, N=CH). 13C NMR spectrum, δ, ppm: 12.9; 28.4;
31.2; 73.1; 79.9; 121.0; 121.3; 122.3; 127.3; 128.5; 138.0;
157.9; 167.2; 178.1. Found, m/z: 365.1019 [M+H]+.
C14H17N6O4S. Calculated, m/z: 365.1027. Found, %:
С 39.47; H 4.03; N 19.51. C14H15KN6O4S·H2O. Calculated,
%: С 39.99; H 4.08; N 19.99.
Synthesis of thioglycolurils 1a–j (General method).
Aldehyde 3a–e (2.05 mmol) and concentrated HCl (2 drops)
were added to a suspension of imidazotriazine 2a,b
(2.00 mmol) in MeOH (30 ml). The resulting mixture was
stirred and heated under reflux for 1.5–2 h, then cooled to
room temperature. After 4–48 h, the formed precipitate was
filtered off, washed with MeOH (5 ml), and air-dried.
Compound 1b was recrystallized from MeOH.
Yields, melting points, and 1H NMR spectra of
thioglycolurils 1a,b,d–g,i,j correspond to the previously
published.8
(E)-4-[(2-Hydroxy-5-nitrobenzylidene)amino]-1,3-di-
methyl-5-thioxohexahydroimidazo[4,5-d]imidazol-2(1H)-
one (1c). Yield 315 mg (45%), yellowish powder, mp 281–
283°С (decomp., MeOH). IR spectrum, ν, cm–1: 3436
(OH), 3139 (NH), 1798, 1693 (C=O), 1625, 1576 (C=N),
1529 (NO2), 1497, 1477, 1451, 1340 (NO2), 1275, 1207.
1H NMR spectrum, δ, ppm (J, Hz): 2.78 (3H, s, NCH3);
2.96 (3H, s, NCH3); 5.51 (1H, d, J = 8.3, CH); 6.13 (1H, d,
J = 8.3, CH); 7.13 (1H, d, J = 9.1, H Ar); 8.20 (1H, dd,
J = 9.1, J = 2.9, H Ar); 8.63 (1H, d, J = 2.9, H Ar); 8.96
(1H, s, N=CH); 10.44 (1H, s, NH); 12.28 (1H, s, OH).
13C NMR spectrum, δ, ppm: 28.2; 30.8; 69.0; 72.3; 117.5;
119.0; 125.3; 126.6; 139.9; 143.7; 157.4; 162.4; 179.6.
Found, m/z: 351.0862 [M+H]+. C13H15N6O4S. Calculated,
m/z: 351.0870.
(E)-1,3-Diethyl-4-[(2-hydroxy-5-nitrobenzylidene)-
amino]-5-thioxohexahydroimidazo[4,5-d]imidazol-2(1H)-
one (1h). Yield 423 mg (56%), yellowish powder, mp 255–
256°С (decomp., MeOH). IR spectrum, ν, cm–1: 3448
(OH), 3231 (NH), 1700, 1688 (C=O), 1624, 1574 (C=N),
1519 (NO2), 1478, 1452, 1342 (NO2), 1290, 1254, 1200,
1
1182. H NMR spectrum, δ, ppm (J, Hz): 1.01–1.12 (6Н,
m, 2CH3); 3.10–3.52 (4H, m, 2NCH2); 5.60 (1H, d, J = 8.3,
CH); 6.15 (1H, d, J = 8.3, CH); 7.14 (1H, d, J = 9.1, H Ar);
8.20 (1H, dd, J = 9.1, J = 2.9, H Ar); 8.62 (1H, d, J = 2.9,
H Ar); 9.12 (1H, s, N=CH); 10.31 (1H, s, NH); 12.12 (1H,
s, OH). 13C NMR spectrum, δ, ppm: 12.9; 13.7; 36.0; 37.9;
67.0; 72.3; 117.4; 119.5; 124.3; 126.9; 140.0; 144.8; 156.9;
162.5; 179.2. Found, m/z: 379.1181 [M+H]+. C15H19N6O4S.
Calculated, m/z: 379.1183.
(E)-4-[(Furan-2-ylmethylidene)amino]-1,3-dimethyl-
5-methylsulfanyl-3,3a,4,6a-tetrahydroimidazo[4,5-d]-
imidazol-2(1H)-one (4d). Yield 252 mg (86%), white
powder, mp 187–189°С (MeOH). IR spectrum, ν, cm–1:
1719 (C=O), 1563, 1484, 1443, 1412, 1382, 1211, 1040.
1H NMR spectrum, δ, ppm (J, Hz): 2.41 (3H, s, SCH3);
650

Chemistry of Heterocyclic Compounds 2021, 57(6), 646–655
2.82 (3H, s, NCH3); 2.88 (3H, s, NCH3); 5.57 (1H, d,
178.2. Found, m/z: 393.1336 [M+H]+. C16H21N6O4S.
J = 7.8, CH); 5.90 (1H, d, J = 7.8, CH); 6.61 (1H, dd,
J = 3.3, J = 1.8, H Ar); 6.80 (1H, d, J = 3.3, H Ar); 7.80
(1H, s, H Ar); 8.00 (1H, s, N=CH). 13C NMR spectrum,
δ, ppm: 13.0; 28.3; 30.4; 72.2; 79.8; 112.0; 112.5; 128.9;
144.5; 149.4; 157.6; 166.5. Found, m/z: 294.1023 [M+H]+.
C12H16N5O2S. Calculated, m/z: 294.1019.
Calculated, m/z: 393.1340.
(E)-1,3-Diethyl-4-[(furan-2-ylmethylidene)amino]-
5-methylsulfanyl-3,3a,4,6a-tetrahydroimidazo[4,5-d]-
imidazol-2(1H)-one (4i). Yield 270 mg (84%), white
powder, mp 133–135°С (MeOH). IR spectrum, ν, cm–1:
1694 (C=O), 1582, 1486, 1475, 1439, 1396, 1377, 1292,
1
(E)-1,3-Dimethyl-5-methylsulfanyl-4-[(thiophen-2-yl-
methylidene)amino]-3,3a,4,6a-tetrahydroimidazo[4,5-d]-
imidazol-2(1H)-one (4e). Yield 257 mg (83%), white
powder, mp 190–193°С (MeOH). IR spectrum, ν, cm–1:
1718, 1697 (C=O), 1564, 1490, 1443, 1392, 1218, 1194,
1244, 1233, 1211, 1197, 1185, 1064. H NMR spectrum,
δ, ppm (J, Hz): 0.98 (3H, t, J = 6.9, CH3); 1.13 (3H, t,
J = 7.0, CH3); 2.40 (3H, s, SCH3); 3.17–3.46 (4H, m,
2NCH2); 5.68 (1H, d, J = 7.7, CH); 5.96 (1H, d, J = 7.8,
CH); 6.61 (1H, s, H Ar); 6.81 (1H, d, J = 3.0, H Ar); 7.80
(1H, s, H Ar); 7.85 (1H, s, N=CH). 13C NMR spectrum,
δ, ppm: 13.0; 13.3; 13.8; 36.1; 37.6; 70.7; 78.5; 112.0;
112.3; 128.4; 144.6; 149.3; 157.0; 166.1. Found, m/z:
322.1321 [M+H]+. C14H20N5O2S. Calculated, m/z:
322.1332.
(E)-1,3-Diethyl-5-methylsulfanyl-4-[(thiophen-2-yl-
methylidene)amino]-3,3a,4,6a-tetrahydroimidazo[4,5-d]-
imidazol-2(1H)-one (4j). Yield 304 mg (90%), white
powder, mp 150–157°С (MeOH). IR spectrum, ν, cm–1:
1686 (C=O), 1573, 1471, 1453, 1439, 1386, 1360, 1313,
1
1042. H NMR spectrum, δ, ppm (J, Hz): 2.41 (3H, s,
SCH3); 2.82 (3H, s, NCH3); 2.90 (3H, s, NCH3); 5.57 (1H,
d, J = 7.8, CH); 5.88 (1H, d, J = 7.9, CH); 7.11 (1H, t,
J = 4.2, H Ar); 7.41 (1H, d, J = 3.2, H Ar); 7.59 (1H, d,
J = 5.0, H Ar); 8.31 (1H, s, N=CH). 13C NMR spectrum,
δ, ppm: 13.0; 28.3; 30.4; 72.5; 80.0; 127.8; 127.9; 129.6;
133.9; 139.4; 157.6; 166.5. Found, m/z: 310.0795 [M+H]+.
C12H16N5OS2. Calculated, m/z: 310.0791.
(E)-4-(Benzylideneamino)-1,3-diethyl-5-methylsulfanyl-
3,3a,4,6a-tetrahydroimidazo[4,5-d]imidazol-2(1H)-one
(4f). Yield 321 mg (97%), white powder, mp 136–138°С
(MeOH). IR spectrum, ν, cm–1: 1693 (C=O), 1581, 1570,
1
1248, 1224, 1197, 1180, 1064. H NMR spectrum, δ, ppm
(J, Hz): 0.99 (3H, t, J = 7.0, CH3); 1.14 (3H, t, J = 7.1,
CH3); 2.41 (3H, s, SCH3); 3.17–3.49 (4H, m, 2NCH2); 5.68
(1H, d, J = 7.8, CH); 5.94 (1H, d, J = 7.8, CH); 7.11 (1H,
dd, J = 4.8, J = 3.6, H Ar); 7.41 (1H, d, J = 3.4, H Ar); 7.59
(1H, d, J = 4.9, H Ar); 8.18 (1H, s, N=CH). 13C NMR
spectrum, δ, ppm: 12.9; 13.3; 13.9; 36.1; 37.6; 71.1; 78.5;
127.8; 127.9; 129.5; 133.4; 139.2; 156.9; 166.0. Found, m/z:
338.1100 [M+H]+. C14H20N5OS2. Calculated, m/z:
338.1104.
(E)-1,3-Diethyl-4-[(2-hydroxy-5-nitrobenzylidene)-
amino]-5-methylsulfanyl-3,3a,4,6a-tetrahydroimidazo-
[4,5-d]imidazol-2(1H)-one (4k). Yield 59 mg (15%), beige
powder, mp 200–202°С (EtOH). IR spectrum, ν, cm–1:
1703 (C=O), 1592, 1569 (NO2), 1470, 1436, 1341, 1325
(NO2), 1295, 1285, 1244, 1185. 1H NMR spectrum, δ, ppm
(J, Hz): 1.05 (3H, t, J = 6.6, CH3); 1.15 (3H, t, J = 6.9,
CH3); 2.46 (3H, s, SCH3); 3.16–3.54 (4H, m, 2NCH2); 5.69
(1H, d, J = 7.8, CH); 6.03 (1H, d, J = 7.8, CH); 7.07 (1H, d,
J = 9.0, H Ar); 8.11–8.14 (2H, m, H Ar, N=CH); 8.48 (1H,
d, J = 2.5, H Ar). 13C NMR spectrum, δ, ppm: 13.0; 13.3;
13.7; 36.2; 37.7; 70.8; 78.6; 116.7; 121.1; 121.2; 126.0;
132.3; 139.9; 156.9; 161.7; 166.0. Found, m/z: 415.1167
[M+Na]+. C16H20N6NaO4S. Calculated, m/z: 415.1159.
(E)-1,3-Diethyl-4-[(2-methoxybenzylidene)amino]-
5-methylsulfanyl-3,3a,4,6a-tetrahydroimidazo[4,5-d]-
imidazol-2(1H)-one (4l). Found, m/z: 362.1648 [M+H]+.
C17H24N5O2S. Calculated, m/z: 362.1645.
1
1473, 1450, 1405, 1357, 1319, 1230, 1195, 1064. H NMR
spectrum, δ, ppm (J, Hz): 1.00 (3H, t, J = 7.0, CH3); 1.14
(3H, t, J = 7.2, CH3); 2.42 (3H, s, SCH3); 3.17–3.52 (4H,
m, 2NCH2); 5.70 (1H, d, J = 7.9, CH); 6.00 (1H, d, J = 7.9,
CH); 7.39–7.47 (3H, m, H Ph); 7.67 (2H, d, J = 7.0, H Ph);
7.95 (1H, s, N=CH). 13C NMR spectrum, δ, ppm: 12.9;
13.3; 13.9; 36.1; 37.6; 70.7; 78.5; 126.4 (2С); 128.8 (2С);
129.4; 134.3; 137.6; 157.0; 166.3. Found, m/z: 332.1535
[M+H]+. C16H22N5OS. Calculated, m/z: 332.1540.
(E)-1,3-Diethyl-4-[(2-hydroxybenzylidene)amino]-
5-methylsulfanyl-3,3a,4,6a-tetrahydroimidazo[4,5-d]-
imidazol-2(1H)-one (4g). Yield 313 mg (90%), white
powder, mp 94–96°С (Me2CO). IR spectrum, ν, cm–1: 3401
(OH), 3174, 1696 (C=O), 1575, 1470, 1388, 1299, 1245,
1
1193, 1064. H NMR spectrum, δ, ppm (J, Hz): 1.02–1.17
(6H, m, 2CH3); 2.44 (3H, s, SCH3); 3.18–3.53 (4H, m,
2NCH2); 5.68 (1H, d, J = 7.8, CH); 6.00 (1H, d, J = 7.8,
CH); 6.85–6.91 (2H, m, H Ar); 7.23 (1H, t, J = 7.5, H Ar);
7.59 (1H, d, J = 7.4, H Ar); 8.18 (1H, s, N=CH); 10.20
(1H, br. s, OH). 13C NMR spectrum, δ, ppm: 13.0; 13.3;
13.7; 36.2; 37.6; 70.8; 78.6; 116.1; 119.4; 119.8; 126.6;
130.8; 136.2; 156.2; 156.9; 166.1. Found, m/z: 348.1493
[M+H]+. C16H22N5O2S. Calculated, m/z: 348.1489.
(E)-2-{[(4,6-Diethyl-2-methylsulfanyl-5-oxo-4,5,6,6a-
tetrahydroimidazo[4,5-d]imidazol-1(3aH)-yl)imino]methyl}-
4-nitrophenol, potassium salt (4h). Yield 366 mg (85%),
orange powder, mp >255°С (decomp., MeOH). IR spect-
rum, ν, cm–1: 1699 (C=O), 1571 (NO2), 1474, 1441, 1318
(NO2), 1290, 1241, 1193, 1069. 1H NMR spectrum, δ, ppm
(J, Hz): 1.01 (3H, t, J = 7.0, CH3); 1.13 (3H, t, J = 7.1,
CH3); 2.40 (3H, s, SCH3); 3.10–3.48 (4H, m, 2NCH2); 5.62
(1H, d, J = 8.0, CH); 5.89 (1H, d, J = 8.0, CH); 6.07 (1H, d,
J = 9.5, H Ar); 7.73 (1H, dd, J = 9.5, J = 3.2, H Ar); 8.19
(1H, s, N=CH); 8.27 (1H, d, J = 3.2, H Ar). 13C NMR
spectrum, δ, ppm: 13.0; 13.3; 13.8; 36.2; 37.7; 71.2; 78.5;
121.0; 121.4; 122.3; 127.4; 128.7; 137.6; 157.2; 166.9;
Synthesis of 5-[(4-bromobenzyl)sulfanyl]glycolurils
7a,b,d–g,i,j,k and potassium salt 1k (General method).
4-Bromobenzyl bromide (255 mg, 1.02 mmol) was added
with stirring to a solution of thioglycoluril 1a,b,d–g,i,j
(1.00 mmol) and K2CO3 (152 mg, 1.1 mmol) in DMSO
(5 ml). The resulting mixture was stirred at room
temperature for 5 h, then poured into ice-cold H2O (50 ml)
and kept in the refrigerator overnight. The precipitate that
formed was filtered off, washed with H2O (5 ml), and air-
dried. The product was recrystallized from MeOH.
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Chemistry of Heterocyclic Compounds 2021, 57(6), 646–655
Compounds 7k and 1k were obtained by fractional
crystallization from MeOH of the precipitate isolated
during the alkylation of thioglycoluril 1h.
(E)-4-Benzylideneamino-5-[(4-bromobenzyl)sulfanyl]-
1,3-diethyl-3,3a,4,6a-tetrahydroimidazo[4,5-d]imidazol-
2(1H)-one (7f). Yield 355 mg (73%), white powder, mp 129–
131°С. IR spectrum, ν, cm–1: 1694 (C=O), 1576, 1460,
(E)-4-Benzylideneamino-5-[(4-bromobenzyl)sulfanyl]-
1,3-dimethyl-3,3a,4,6a-tetrahydroimidazo[4,5-d]imidazol-
2(1H)-one (7a). Yield 422 mg (92%), white powder,
mp 178–179°С. IR spectrum, ν, cm–1: 1696 (C=O), 1582,
1
1388, 1300, 1246, 1229, 1191, 1064. H NMR spectrum,
δ, ppm (J, Hz): 1.00 (3H, t, J = 6.2, CH3); 1.16 (3H, t,
J = 6.8, CH3); 3.18–3.52 (4H, m, 2NCH2); 4.28 (2H, s,
SCH2); 5.73 (1H, d, J = 7.6, CH); 5.99 (1H, d, J = 7.6,
CH); 7.38–7.44 (5H, m, H Ar); 7.52 (2H, d, J = 7.8, H Ar);
7.65 (2H, d, J = 6.5, H Ar); 7.94 (1H, s, N=CH). 13C NMR
spectrum, δ, ppm: 13.3; 13.9; 33.1; 36.3; 37.7; 70.6; 78.8;
120.3; 126.4 (2С); 128.8 (2С); 129.5; 131.2 (2C); 131.3
(2C); 134.3; 137.2; 137.8; 157.0; 165.2. Found, m/z:
486.0954 [M+H]+. C22H25BrN5OS. Calculated, m/z:
486.0958.
1
1568, 1489, 1448, 1412, 1398, 1285, 1206, 1040. H NMR
spectrum, δ, ppm (J, Hz): 2.84 (3H, s, NCH3); 2.90 (3H, s,
NCH3); 4.27 (2H, s, SCH2); 5.63 (1H, d, J = 7.7, CH); 5.94
(1H, d, J = 7.7, CH); 7.38–7.42 (5H, m, H Ar); 7.52 (2H, d,
J = 8.1, H Ar); 7.66 (2H, d, J = 7.0, H Ar); 8.09 (1H, s,
N=CH). 13C NMR spectrum, δ, ppm: 28.3; 30.5; 33.1; 72.1;
80.1; 120.4; 126.5 (2С); 128.8 (2С); 129.5; 131.2 (2C);
131.4 (2C); 134.4; 137.3; 138.3; 157.6; 165.6. Found, m/z:
458.0635 [M+H]+. C20H21BrN5OS. Calculated, m/z:
458.0645.
(E)-5-[(4-Bromobenzyl)sulfanyl]-1,3-diethyl-4-[(2-
hydroxybenzylidene)amino]-3,3a,4,6a-tetrahydroimidazo-
[4,5-d]imidazol-2(1H)-one (7g). Yield 337 mg (67%),
white powder, mp 198–201°С. IR spectrum, ν, cm–1: 1684
(C=O), 1568, 1483, 1455, 1298, 1249, 1224, 1193, 1067.
1H NMR spectrum, δ, ppm (J, Hz): 1.04 (3H, t, J = 7.0,
CH3); 1.15 (3H, t, J = 7.2, CH3); 3.13–3.52 (4H, m,
2NCH2); 4.29 (2H, s, SCH2); 5.70 (1H, d, J = 7.9, CH);
6.00 (1H, d, J = 7.9, CH); 6.83–6.89 (2H, m, H Ar); 7.22
(1H, t, J = 7.7, H Ar); 7.40 (2H, d, J = 8.4, H Ar); 7.51
(2H, d, J = 8.4, H Ar); 7.57 (1H, d, J = 7.7, H Ar); 8.16
(1H, s, N=CH); 10.06 (1H, s, OH). 13C NMR spectrum,
δ, ppm: 13.4; 13.8; 33.2; 36.4; 37.7; 70.7; 78.9; 116.2;
119.5; 119.9; 120.4; 126.4; 130.9; 131.3 (2C); 131.4 (2C);
136.1; 137.2; 156.2; 157.0; 165.1. Found, m/z: 502.0893
[M+H]+. C22H25BrN5O2S. Calculated, m/z: 502.0907.
(E)-5-[(4-Bromobenzyl)sulfanyl]-1,3-diethyl-4-[(furan-
2-ylmethylidene)amino]-3,3a,4,6a-tetrahydroimidazo-
[4,5-d]imidazol-2(1H)-one (7i). Yield 381 mg (80%),
white powder, mp 136–138°С. IR spectrum, ν, cm–1: 1710
(C=O), 1580, 1556, 1485, 1470, 1433, 1376, 1293, 1237,
1188, 1065. 1H NMR spectrum, δ, ppm (J, Hz): 0.97 (3H, t,
J = 6.1, CH3); 1.15 (3H, t, J = 6.6, CH3); 3.16–3.49 (4H, m,
2NCH2); 4.25 (2H, s, SCH2); 5.70 (1H, d, J = 7.1, CH);
5.95 (1H, d, J = 7.1, CH); 6.60 (1H, br. s, H Fur); 6.81 (1H,
br. s, H Fur); 7.39 (2H, d, J = 7.8, H Ar); 7.50 (2H, d,
J = 7.8, H Ar); 7.79 (1H, s, H Fur); 7.84 (1H, s, N=CH).
13C NMR spectrum, δ, ppm: 13.3; 13.9; 33.1; 36.3; 37.6;
70.7; 78.7; 112.1; 112.5; 120.3; 128.5; 131.2 (2С); 131.3
(2С); 137.3; 144.7; 149.2; 157.0; 165.0. Found, m/z:
476.0760 [M+H]+. C20H23BrN5O2S. Calculated, m/z:
476.0750.
(E)-5-[(4-Bromobenzyl)sulfanyl]-4-[(2-hydroxybenzyl-
idene)amino]-1,3-dimethyl-3,3a,4,6a-tetrahydroimidazo-
[4,5-d]imidazol-2(1H)-one (7b). Yield 294 mg (62%),
white powder, mp 203–205°С. IR spectrum, ν, cm–1: 1695
(C=O), 1610, 1579, 1489, 1412, 1399, 1285, 1268, 1199,
1
1041. H NMR spectrum, δ, ppm (J, Hz): 2.84 (3H, s,
NCH3); 2.91 (3H, s, NCH3); 4.29 (2H, s, SCH2); 5.62 (1H,
d, J = 7.3, CH); 5.94 (1H, d, J = 7.3, CH); 6.85–6.90 (2H,
m, H Ar); 7.23 (1H, t, J = 7.4, H Ar); 7.43–7.52 (5H, m,
H Ar); 8.26 (1H, s, N=CH); 10.07 (1H, s, OH). 13C NMR
spectrum, δ, ppm: 28.3; 30.9; 33.1; 72.6; 80.1; 116.2;
119.5; 119.8; 120.4; 126.9; 130.9; 131.2 (2C); 131.4 (2C);
137.1; 137.2; 156.2; 157.6; 165.3. Found, m/z: 474.0602
[M+H]+. C20H21BrN5O2S. Calculated, m/z: 474.0594.
(E)-5-[(4-Bromobenzyl)sulfanyl]-4-[(furan-2-ylmethyl-
idene)amino]-1,3-dimethyl-3,3a,4,6a-tetrahydroimidazo-
[4,5-d]imidazol-2(1H)-one (7d). Yield 291 mg (65%),
white powder, mp 192–193°С. IR spectrum, ν, cm–1: 1695
(C=O), 1577, 1488, 1413, 1397, 1286, 1205, 1177, 1042.
1H NMR spectrum, δ, ppm (J, Hz): 2.83 (3H, s, NCH3);
2.87 (3H, s, NCH3); 4.25 (2H, s, SCH2); 5.60 (1H, d,
J = 7.8, CH); 5.89 (1H, d, J = 7.9, CH); 6.59 (1H, dd,
J = 3.0, J = 1.8, H Fur); 6.79 (1H, d, J = 3.0, H Fur); 7.37
(2H, d, J = 8.3, H Ar); 7.51 (2H, d, J = 8.3, H Ar); 7.78
(1H, s, H Fur); 7.98 (1H, s, N=CH). 13C NMR spectrum,
δ, ppm: 28.3; 30.5; 33.1; 72.1; 80.0; 112.1; 112.7; 120.3;
129.0; 131.2 (2С); 131.4 (2С); 137.3; 144.6; 149.3; 157.5;
165.4. Found, m/z: 448.0438 [M+H]+. C18H19BrN5O2S.
Calculated, m/z: 448.0437.
(E)-5-[(4-Bromobenzyl)sulfanyl]-1,3-dimethyl-4-[(thio-
phen-2-ylmethylidene)amino]-3,3a,4,6a-tetrahydroimidazo-
[4,5-d]imidazol-2(1H)-one (7e). Yield 446 mg (96%),
white powder, mp 188–190°C. IR spectrum, ν, cm–1: 1695
(C=O), 1576, 1488, 1442, 1412, 1397, 1380, 1285, 1202,
(E)-5-[(4-Bromobenzyl)sulfanyl]-1,3-diethyl-4-[(thio-
phen-2-ylmethylidene)amino]-3,3a,4,6a-tetrahydroimid-
azo[4,5-d]imidazol-2(1H)-one (7j). Yield 345 mg (70%),
white powder, mp 222–223°С. IR spectrum, ν, cm–1: 1711
(C=O), 1575, 1470, 1438, 1383, 1291, 1244, 1223, 1188,
1
1174, 1040. H NMR spectrum, δ, ppm (J, Hz): 2.83 (3H,
1
s, NCH3); 2.88 (3H, s, NCH3); 4.25 (2H, s, SCH2); 5.61
(1H, d, J = 7.7, CH); 5.88 (1H, d, J = 7.7, CH); 7.10 (1H, t,
J = 4.0, H Th); 7.40–7.42 (3H, m, H Ar, H Th); 7.51 (2H,
d, J = 8.2, H Ar); 7.58 (1H, d, J = 4.7, H Th); 8.31 (1H, s,
N=CH). 13C NMR spectrum, δ, ppm: 28.3; 30.5; 33.1; 72.5;
80.0; 120.4; 127.8; 128.0; 129.8; 131.2 (2С); 131.4 (2С);
134.1; 137.3; 139.3; 157.5; 165.3. Found, m/z: 464.0204
[M+H]+. C18H19BrN5OS2. Calculated, m/z: 464.0209.
1065. H NMR spectrum, δ, ppm (J, Hz): 0.98 (3H, t,
J = 6.8, CH3); 1.15 (3H, t, J = 6.8, CH3); 3.18–3.48 (4H, m,
2NCH2); 4.25 (2H, s, SCH2); 5.71 (1H, d, J = 7.8, CH);
5.94 (1H, d, J = 7.8, CH); 7.10 (1H, t, J = 4.1, H Th); 7.38–
7.41 (3H, m, H Ar, H Th); 7.50 (2H, d, J = 8.1, H Ar); 7.58
(1H, d, J = 4.9, H Th); 8.17 (1H, s, N=CH). 13C NMR
spectrum, δ, ppm: 13.4; 13.9; 33.1; 36.3; 37.7; 71.0; 78.8;
120.4; 127.8; 128.1; 129.7; 131.2 (2С); 131.3 (2С); 133.7;
652

Chemistry of Heterocyclic Compounds 2021, 57(6), 646–655
137.3; 139.2; 157.0; 164.9. Found, m/z: 492.0524 [M+H]+.
C20H23BrN5OS2. Calculated, m/z: 492.0522.
compounds 5a,e,f,j was filtered off, washed with a H2O–
MeOH, 1:1 mixture (5 ml), and air-dried.
(E)-4-({2-[(4-Bromobenzyl)oxy]-5-nitrobenzylidene}-
amino)-5-[(4-bromobenzyl)sulfanyl]-1,3-diethyl-3,3a,4,6a-
tetrahydroimidazo[4,5-d]imidazol-2(1H)-one (7k). Yield
12 mg (2%), white powder, mp 200–202°С (MeOH).
IR spectrum, ν, cm–1: 1729, 1702 (C=O), 1584, 1567
(NO2), 1488, 1466, 1340 (NO2), 1284, 1270, 1134, 1073.
1H NMR spectrum, δ, ppm (J, Hz): 0.68 (3H, br. s, CH3);
1.13 (3H, br. s, CH3); 2.90–3.01 (1H, m) and 3.20–3.49
(3H, m, 2NCH2); 4.29 (2H, s, SCH2); 5.31 (2H, s, OCH2);
5.69 (1H, d, J = 7.4, CH); 5.93 (1H, d, J = 7.4, CH); 7.42–
7.64 (9H, m, H Ar); 7.99 (1H, s, H Ar); 8.26 (1H, d,
J = 3.2, H Ar); 8.46 (1H, s, N=CH). 13C NMR spectrum,
δ, ppm: 13.2 (2C); 33.1; 36.3; 37.7; 70.2; 70.8; 78.9; 113.6;
120.1; 120.3; 121.8; 123.3; 126.0; 130.6; 130.7 (2C); 131.2
(2C); 131.3 (2C); 131.5 (2C); 134.9; 137.3; 141.2; 156.9;
160.6; 165.0. Found, m/z: 715.0332 [M+H]+.
C29H29Br2N6O4S. Calculated, m/z: 715.0332.
Method III. MeI (435 μl, 7 mmol) and H2O (0.5 ml)
were added dropwise with stirring to a suspension of
thioglycoluril 1a–j (1 mmol) in MeOH (40 ml). The
resulting mixture was stirred and heated under reflux for 5–
10 h, then concentrated under reduced pressure to half the
initial volume, and cooled to room temperature. The
formed precipitate of glycoluril 5a–j was filtered off and
air-dried. Compounds 5c,h were recrystallized from
Me2CO. First, hydrazine 6b precipitates, followed by
glycoluril 5c,h.
(E)-4-(Benzylideneamino)-1,3-diethyl-5-methylsulfanyl-
3,3a,4,6a-tetrahydroimidazo[4,5-d]imidazol-2(1H)-one
hydrochloride (4f·HCl). 1H NMR spectrum, δ, ppm
(J, Hz): 0.97 (3H, t, J = 6.9, CH3); 1.15 (3H, t, J = 7.0,
CH3); 2.80 (3H, s, SCH3); 3.15–3.62 (4H, m, 2NCH2); 6.03
(1H, d, J = 8.2, CH); 6.63 (1H, d, J = 8.2, CH); 7.52–7.54
(3H, m, H Ph); 7.80–7.83 (2H, m, H Ph); 8.62 (1H, s,
N=CH). 13C NMR spectrum, δ, ppm: 13.0; 14.1; 14.2; 36.5;
48.6; 72.2; 72.4; 127.7 (2С); 129.3 (2С); 131.7; 132.5;
148.9; 156.8; 172.4.
(E)-4-(Benzylideneamino)-1,3-dimethyltetrahydroimid-
azo[4,5-d]imidazole-2,5(1H,3H)-dione (5a). Yield 112 mg
(41%, method I), 101 mg (37%, method II), 169 mg (62%,
method III, 10 h), white powder, mp 252–254°С (MeOH).
IR spectrum, ν, cm–1: 3246 (NH), 1725, 1690 (C=O), 1417,
1404, 1390, 1375, 1367, 1227, 1187, 1042. 1H NMR
spectrum, δ, ppm (J, Hz): 2.71 (3H, s, NCH3); 2.85 (3H, s,
NCH3); 5.24 (1H, d, J = 8.2, CH); 5.61 (1H, d, J = 8.2,
CH); 7.42–7.47 (3H, m, H Ph); 7.68–7.71 (2H, m, H Ph);
8.42 (1H, s, NH); 8.98 (1H, s, N=CH). 13C NMR spectrum,
δ, ppm: 27.8; 29.2; 64.3; 72.6; 126.7 (2C); 128.7 (2C);
129.9; 134.8; 148.4; 156.0; 157.8. Found, m/z: 296.1123
[M+Na]+. C13H15N5NaO2. Calculated, m/z: 296.1118.
(E)-4-[(2-Hydroxybenzylidene)amino]-1,3-dimethyl-
tetrahydroimidazo[4,5-d]imidazole-2,5(1H,3H)-dione (5b).
Yield 168 mg (58%, method I), 90 mg (31%, method III,
5 h), beige powder, mp 188–189°С (MeOH). IR spectrum,
ν, cm–1: 3433 (OH), 3246 (NH), 1738, 1715 (C=O), 1620,
1495, 1454, 1402, 1377, 1275, 1218, 1038. 1H NMR
spectrum, δ, ppm (J, Hz): 2.71 (3H, s, NCH3); 2.85 (3H, s,
NCH3); 5.25 (1H, d, J = 8.2, CH); 5.68 (1H, d, J = 8.2,
CH); 6.87–6.92 (2H, m, H Ar); 7.27 (1H, t, J = 7.6, H Ar);
7.58 (1H, d, J = 7.6, H Ar); 8.47 (1H, s, NH); 9.02 (1H, s,
N=CH); 10.49 (1H, s, OH). 13C NMR spectrum, δ, ppm:
27.9; 29.4; 64.5; 72.1; 116.2; 119.3; 119.6; 128.1; 131.2;
148.0; 156.0; 156.8; 157.8. Found, m/z: 290.1241 [M+H]+.
C13H16N5O3. Calculated, m/z: 290.1248.
(E)-2-{[(4,6-Diethyl-5-oxo-2-thioxohexahydroimidazo-
[4,5-d]imidazol-1(2H)-yl)imino]methyl}-4-nitrophenol,
potassium salt (1k). Yield 33 mg (8%), orange powder,
mp 208–210°С (MeOH). IR spectrum, ν, cm–1: 1711
(C=O), 1594, 1535 (NO2), 1483, 1431, 1358 (NO2), 1307,
1
1281, 1241. H NMR spectrum, δ, ppm (J, Hz): 1.00–1.09
(6Н, m, 2CH3); 3.10–3.19 (2H, m, NCH2); 3.26–3.34 (2H,
m, NCH2); 5.45 (1H, d, J = 8.4, CH); 5.94 (1H, d,
J = 8.4, CH); 6.07 (1H, d, J = 9.6, H Ar); 7.75 (1H, dd,
J = 9.6, J = 3.2, H Ar); 8.42 (1H, d, J = 3.2, H Ar); 9.05
(1H, s, N=CH); 9.66 (1H, s, NH). 13C NMR spectrum,
δ, ppm: 12.8; 13.4; 35.8; 37.2; 66.1; 74.5; 120.3; 121.7;
123.8; 127.9; 128.5; 155.0; 156.9; 178.4; 178.7. Found,
m/z: 379.1182 [M+H]+. C15H19N6O4S. Calculated, m/z:
379.1183.
Synthesis of glycolurils 5a–j. Method I. Concentrated
HCl (34.31%, d 1.1706 g/cm3) (91 μl, 1 mmol) (182 μl,
2 mmol for salts 4c,h) was added with stirring to a solution
of methylsulfanylglycoluril 4a–j (1 mmol) in MeOH
(30 ml). The resulting solution was heated under reflux for
1 h (for compounds 4a,f), 3 h (for compounds 4b,d,e,g), or
6 h (for compounds 4c,h–j), then cooled to room
temperature (for compounds 5a,c,e–h,j). The formed
precipitate of compounds 5a,e,f,g,j was filtered off, washed
with a H2O–MeOH, 1:1 mixture (5 ml), and air-dried.
Glycolurils 5g,j were recrystallized from Me2CO. For
compounds 5c,h, the precipitate of KCl was filtered,
washed with MeOH (5 ml) and Me2CO (5 ml). The solvent
from the filtrate was evaporated under reduced pressure,
the residue was recrystallized from a H2O–MeOH, 3:7
mixture. To obtain compounds 5b,d,i, the solvent from the
reaction mixture was evaporated to dryness under reduced
pressure. Product 5b was recrystallized from Me2CO.
Glycolurils 5d,i were precipitated with H2O, filtered off,
washed with Et2O (5 ml) and Me2CO (2 ml).
(E)-4-[(2-Hydroxy-5-nitrobenzylidene)amino]-1,3-di-
methyltetrahydroimidazo[4,5-d]imidazole-2,5(1H,3H)-
dione (5c). Yield 170 mg (51%, method I), 100 mg (30%,
method III, 10 h), beige powder, mp 273–276°С (Me2CO).
IR spectrum, ν, cm–1: 3492 (OH), 3266 (NH), 1725, 1682
(C=O), 1604, 1514 (NO2), 1443, 1405, 1341 (NO2), 1290,
Method II. Concentrated HCl (34.31%, d 1.1706 g/cm3)
(91 μl, 1 mmol) was added with stirring to a solution of
S-(4-bromobenzyl) derivative 7a,e,f,j (1 mmol) in MeOH
(30 ml). The resulting solution was heated under reflux for
1 h (for compounds 7a,e,j) or 6 h (for compound 7f), then
cooled to room temperature. The formed precipitate of
1
1220, 1041. H NMR spectrum, δ, ppm (J, Hz): 2.72 (3H,
s, NCH3); 2.87 (3H, s, NCH3); 5.27 (1H, d, J = 8.2, CH);
5.70 (1H, d, J = 8.2, CH); 7.10 (1H, d, J = 9.1, H Ar); 8.15
(1H, dd, J = 9.0, J = 2.7, H Ar); 8.53–8.55 (2H, m, H Ar,
NH); 9.14 (1H, s, N=CH); 11.81 (1H, s, OH). 13C NMR
653

Chemistry of Heterocyclic Compounds 2021, 57(6), 646–655
spectrum, δ, ppm: 27.9; 29.5; 64.5; 72.0; 116.9; 121.2;
Yield 69 mg (19%, method I), 72 mg (20%, method III, 10 h),
beige powder, mp 144–146°С (Me2CO). IR spectrum, ν, cm–1:
3467 (OH), 3229 (NH), 1742, 1681 (C=O), 1618, 1521
(NO2), 1482, 1460, 1396, 1342 (NO2), 1289, 1242, 1199,
121.9; 126.3; 139.9; 142.3; 155.7; 157.7; 162.2. Found, m/z:
335.1094 [M+H]+. C13H15N6O5. Calculated, m/z: 335.1098.
(E)-4-[(Furan-2-ylmethylidene)amino]-1,3-dimethyl-
tetrahydroimidazo[4,5-d]imidazole-2,5(1H,3H)-dione (5d).
Yield 66 mg (25%, method I), 76 mg (29%, method III,
5 h), white powder, mp 202–204°С (MeOH). IR spectrum,
ν, cm–1: 1738, 1692 (C=O), 1508, 1480, 1455, 1420, 1384,
1229, 1176, 1042. 1H NMR spectrum, δ, ppm (J, Hz): 2.70
(3H, s, NCH3); 2.81 (3H, s, NCH3); 5.22 (1H, d, J = 7.9,
CH); 5.55 (1H, d, J = 8.0, CH); 6.62 (1H, dd, J = 3.3,
J = 1.8, H Ar); 6.88 (1H, d, J = 3.4, H Ar); 7.80 (1H, s,
H Ar); 8.42 (1H, s, NH); 8.87 (1H, s, N=CH). 13C NMR
spectrum, δ, ppm: 28.4; 29.6; 64.8; 73.2; 112.5; 114.1;
139.3; 145.4; 150.1; 156.6; 158.3. Found, m/z: 264.1097
[M+H]+. C11H14N5O3. Calculated, m/z: 264.1091.
(E)-1,3-Dimethyl-4-[(thiophen-2-ylmethylidene)amino]-
tetrahydroimidazo[4,5-d]imidazole-2,5(1H,3H)-dione (5e).
Yield 61 mg (22%, method I), 128 mg (46%, method II),
117 mg (42%, method III, 10 h), white powder, mp 251–
253°С (MeOH). IR spectrum, ν, cm–1: 1717, 1678 (C=O),
1506, 1438, 1409, 1242, 1214, 1189, 1037. 1H NMR
spectrum, δ, ppm (J, Hz): 2.70 (3H, s, NCH3); 2.82 (3H, s,
NCH3); 5.21 (1H, d, J = 8.2, CH); 5.54 (1H, d, J = 8.2,
CH); 7.12 (1H, t, J = 4.3, H Ar); 7.45 (1H, d, J = 3.1,
H Ar); 7.62 (1H, d, J = 4.9, H Ar); 8.44 (1H, s, NH); 9.16
(1H, s, N=CH). 13C NMR spectrum, δ, ppm: 27.8; 29.1;
64.3; 72.7; 127.9; 128.4; 130.6; 139.8; 144.1; 156.0; 157.8.
Found, m/z: 280.0869 [M+H]+. C11H14N5O2S. Calculated,
m/z: 280.0863.
1
1128, 1068. H NMR spectrum, δ, ppm (J, Hz): 1.05–1.12
(6H, m, 2CH3); 3.08–3.43 (4H, m, 2NCH2); 5.38 (1H, d,
J = 8.4, CH); 5.78 (1H, d, J = 8.4, CH); 7.09 (1H, d,
J = 9.1, H Ar); 8.14 (1H, dd, J = 9.1, J = 2.9, H Ar); 8.53
(2H, br. s, H Ar, NH); 9.22 (1H, s, N=CH); 11.74 (1H, s,
OH). 13C NMR spectrum, δ, ppm: 12.9; 13.3; 35.7; 36.6;
62.7; 71.1; 116.9; 121.3; 121.7; 126.4; 140.0; 143.1; 155.8;
157.0; 162.0. Found, m/z: 363.1412 [M+H]+. C15H19N6O5.
Calculated, m/z: 363.1411.
(E)-1,3-Diethyl-4-[(furan-2-ylmethylidene)amino]-
tetrahydroimidazo[4,5-d]imidazole-2,5(1H,3H)-dione (5i).
Yield 105 mg (36%, method I), 93 mg (32%, method III,
5 h), white powder, mp 134–136°С (MeOH). IR spectrum,
ν, cm–1: 3249 (NH), 1716, 1690 (C=O), 1484, 1456, 1448,
1
1399, 1342, 1243, 1199, 1074. H NMR spectrum, δ, ppm
(J, Hz): 1.03–1.10 (6H, m, 2CH3); 3.08–3.45 (4H, m,
2NCH2); 5.34 (1H, d, J = 8.3, CH); 5.63 (1H, d, J = 8.3,
CH); 6.62 (1H, dd, J = 3.3, J = 1.8, H Ar); 6.88 (1H, d,
J = 3.3, H Ar); 7.81 (1H, d, J = 1.8, H Ar); 8.42 (1H, s,
NH); 8.90 (1H, s, N=CH). 13C NMR spectrum, δ, ppm:
13.0; 13.4; 35.7; 36.5; 62.6; 71.8; 112.1; 113.7; 139.5;
145.0; 149.6; 156.2; 157.1. Found, m/z: 292.1400 [M+H]+.
C13H18N5O3. Calculated, m/z: 292.1404.
(E)-1,3-Diethyl-4-[(thiophen-2-ylmethylidene)amino]-
tetrahydroimidazo[4,5-d]imidazole-2,5(1H,3H)-dione (5j).
Yield 77 mg (25%, method I), 148 mg (48%, method II),
187 mg (61%, method III, 8 h), white powder, mp 183–
185°С (MeOH). IR spectrum, ν, cm–1: 1715, 1688 (C=O),
1487, 1456, 1447, 1397, 1338, 1253, 1241, 1225, 1201,
(E)-4-(Benzylideneamino)-1,3-diethyltetrahydroimid-
azo[4,5-d]imidazole-2,5(1H,3H)-dione (5f). Yield 133 mg
(44%, method I), 175 mg (58%, method II), 157 mg (52%,
method III, 5 h), white powder, mp 194–196°C (MeOH).
IR spectrum, ν, cm–1: 3217 (NH), 1728, 1684 (C=O), 1486,
1
1185, 1072. H NMR spectrum, δ, ppm (J, Hz): 1.03–1.11
(6H, m, 2CH3); 3.06–3.33 (4H, m, 2NCH2); 5.33 (1H, d,
J = 8.1, CH); 5.62 (1H, d, J = 8.1, CH); 7.12 (1H, t, J = 4.2,
H Ar); 7.45 (1H, d, J = 2.7, H Ar); 7.62 (1H, d, J = 4.7,
H Ar); 8.42 (1H, s, NH); 9.20 (1H, s, N=CH). 13C NMR
spectrum, δ, ppm: 12.9; 13.2; 35.7; 36.5; 62.6; 71.6; 127.9;
128.5; 130.6; 139.8; 144.7; 156.1; 157.1. Found, m/z: 330.0985
[M+Na]+. C13H17N5NaO2S. Calculated, m/z: 330.0995.
1,2-Di((E)-benzylidene)hydrazine (6a). 1H NMR
spectrum, δ, ppm: 7.49–7.52 (6Н, m, H Ph); 7.87–7.90
(4Н, m, H Ph); 8.72 (2Н, s, 2N=CH).
1
1470, 1398, 1388, 1336, 1240, 1196. H NMR spectrum,
δ, ppm (J, Hz): 1.05–1.11 (6H, m, 2CH3); 3.11–3.38 (4H,
m, 2NCH2); 5.36 (1H, dd, J = 8.3, J = 1.6, CH); 5.69 (1H,
d, J = 8.3, CH); 7.42–7.47 (3H, m, H Ph); 7.67–7.71 (2H,
m, H Ph); 8.41 (1H, s, NH); 9.03 (1H, s, N=CH). 13C NMR
spectrum, δ, ppm: 12.9; 13.2; 35.7; 36.5; 62.6; 71.6; 126.6
(2C); 128.8 (2C); 129.9; 134.7; 149.3; 156.0; 157.1. Found,
m/z: 324.1431 [M+Na]+. C15H19N5NaO2. Calculated, m/z:
324.1431.
(E)-1,3-Diethyl-4-[(2-hydroxybenzylidene)amino]tetra-
hydroimidazo[4,5-d]imidazole-2,5(1H,3H)-dione (5g). Yield
60 mg (19%, method I), 159 mg (50%, method III, 5 h),
white crystals, mp 215–217°С (MeOH). IR spectrum, ν, cm–1:
3245 (NH), 1731, 1712 (C=O), 1617, 1601, 1487, 1470, 1415,
2,2'-[(1E,1'E)-Hydrazine-1,2-diylidenebis(methanyl-
ylidene)]bis(4-nitrophenol) (6b). Yield 38 mg (23%, from
compound 1c), 48 mg (29%, from compound 1h), beige
1
powder, mp >320°С (MeOH). H NMR spectrum, δ, ppm
(J, Hz): 7.15 (2H, d, J = 9.1, H Ar); 8.24 (2H, dd, J = 9.1,
J = 2.4, H Ar); 8.67 (2H, d, J = 2.4, H Ar); 9.06 (2H, s,
2N=CH); 12.04 (2H, br. s, 2OH). Mass spectrum, m/z
(Irel, %): 330 [M]+ (100).
X-ray structural analysis of compounds 4j and 5g,h
was performed at 120K on a Bruker Apex II diffractometer
(CCD-detector, MoKα radiation, λ 0.71073 Å, graphite
monochromator). The structures were solved using the
SHELXT11 program and refined by the full-matrix least-
squares technique using the OLEX212 program in the
anisotropic approximation for non-hydrogen atoms.
Hydrogen atoms of NH and OH groups were localized
1
1406, 1362, 1268, 1242, 1198. H NMR spectrum, δ, ppm
(J, Hz): 1.07 (6H, t, J = 7.0, 2CH3); 3.09–3.40 (4H, m,
2NCH2); 5.37 (1H, d, J = 8.3, CH); 5.75 (1H, d, J = 8.3, CH);
6.86–6.92 (2H, m, H Ar); 7.27 (1H, t, J = 7.6, H Ar); 7.59
(1H, d, J = 7.6, H Ar); 8.45 (1H, s, NH); 9.08 (1H, s,
N=CH); 10.38 (1H, s, OH). 13C NMR spectrum, δ, ppm:
12.9; 13.3; 35.8; 36.6; 62.8; 71.4; 116.3; 119.4; 119.7; 127.8;
131.3; 149.2; 156.2; 156.9; 157.1 Found, m/z: 340.1381
[M+Na]+. C15H19N5NaO3. Calculated, m/z: 340.1380.
(E)-1,3-Diethyl-4-[(2-hydroxy-5-nitrobenzylidene)amino]-
tetrahydroimidazo[4,5-d]imidazole-2,5(1H,3H)-dione (5h).
654

Chemistry of Heterocyclic Compounds 2021, 57(6), 646–655
Ser. Khim. 2021, 383.] (c) Bao, X.; Wei, S.; Qian, X.; Qu, J.;
from differential Fourier syntheses of electron density, the
positions of the remaining hydrogen atoms were calculated
geometrically, the positions of all hydrogen atoms were
refined in the isotropic approximation according to the rider
model. The full sets of X-ray structural data for compounds
4j and 5g,h were deposited at the Cambridge
Crystallographic Data Center (deposits CCDC 2062628,
CCDC 2062629, CCDC 2062630, respectively).
The study of the cytotoxicity of compounds 4i,j and
5f,g was performed in vitro using the MTT assay against
human rhabdomyosarcoma (RD), lung carcinoma (A549),
and intestinal carcinoma (HCT116) cell lines according to
the described method.5b,c
Wang, B.; Zou, L.; Ge, G. Org. Lett. 2018, 20, 3394.
(d) Beloglazkina, A.; Barashkin, A.; Polyakov, V.; Kotovsky, G.;
Karpov, N.; Mefedova, S.; Zagribelny, B.; Ivanenkov, Y.;
Kalinina, M.; Skvortsov, D.; Tafeenko, V.; Zyk, N.; Majouga, A.;
Beloglazkina, E. Chem. Heterocycl. Compd. 2020, 56, 747.
[Khim.
Geterotsikl.
Soedin.
2020,
56,
747.]
(e) Perevoshchikova, A. N.; Eroshenko, D. V.; Dmitriev, M. V.;
Grishko, V. V.; Shklyaev, Yu. V. J. Heterocycl. Chem. 2019,
56, 1634.
4. (a) Mashkovskii, M. D. Lekarstvennye sredstva (Drugs [in
Russian]); Moscow: Novaya volna, 2016, Vol. 1, p. 89.
(b) Anikina, L. V.; Vikharev, Yu. B.; Baranov, V. V.;
Malyshev, O. R.; Kravchenko, A. N. Mendeleev Commun.
2018, 28, 317. (c) Vikharev, Yu. B.; Anikina, P. V.;
Chikunov, I. E.; Sigachev, А. S.; Kravchenko, А. N.;
Shklyaev, Yu. V.; Makhova, N. N. Vopr. Biol. Med. Farm.
Khimii 2006, (2), 12. (d) Anikina, L. V.; Gazieva, G. A.;
Kravchenko, A. N. Russ. Chem. Bull., Int. Ed. 2020, 69, 563.
[Izv. Akad. Nauk, Ser. Khim. 2020, 563.] (e) Bakibaev, A. A.;
Akhmedzhanov, R. R.; Yagovkin, A. Yu.; Novozheeva, T. P.;
Filimonov, V. D.; Saratikov, A. S. Pharm. Chem. J. 1993, 27, 401.
[Khim. Farm. Zh. 1993, 27(6), 29.] (f) Kamburg, R. US Patent
20080227838; Chem. Abstr. 2008, 149, 347537.
(g) Berlyand, A. S.; Prokopov, A. A. Pharm. Chem. J. 2014,
48, 347. [Khim. Farm. Zh. 2014, 48(5), 47.]
5. (a) Gazieva, G. A.; Nechaeva, T. V.; Kostikova, N. N.;
Sigay, N. V.; Serkov, S. A.; Popkov, S. V. Russ. Chem. Bull.,
Int. Ed. 2018, 67, 1059. [Izv. Akad. Nauk, Ser. Khim. 2018,
1059.] (b) Gazieva, G. A.; Anikina, L. V.; Nechaeva, T. V.;
Pukhov, S. A.; Karpova, T. B.; Popkov, S. V.; Nelyubina, Yu. V.;
Kolotyrkina, N. G.; Kravchenko, A. N. Eur. J. Med. Chem.
2017, 140, 141. (c) Gazieva, G. A.; Anikina, L. V.;
Pukhov, S. A.; Karpova, T. B.; Nelyubina, Yu. V.;
Kravchenko, A. N. Mol. Diversity 2016, 20, 837.
6. Gazieva, G. A.; Vikharev, Yu. B.; Anikina, L. V.; Karpova, T. B.;
Kravchenko, A. N.; Permyakov, E. A.; Svitanko, I. V.
Mendeleev Commun. 2013, 23, 202.
7. (a) Khan, S.; Tyagi, V.; Mahar, R.; Bajpai, V.; Kumar, B.;
Chauhan, P. M. S. Synthesis 2013, 2405. (b) Izquierdo, J.;
Etxabe, J.; Duñabeitia, E.; Landa, A.; Oiarbide, M.; Palomo, C.
Chem.–Eur. J. 2018, 24, 7217. (c) Izquierdo, J.; Demurget, N.;
Landa, A.; Brinck, T.; Mercero, J. M.; Diner, P.; Oiarbide, M.;
Palomo, C. Chem.–Eur. J. 2019, 25, 12431.
8. (a) Gazieva, G. A.; Poluboyarov, P. A.; Popov, L. D.;
Kolotyrkina, N. G.; Kravchenko, A. N.; Makhova, N. N.
Synthesis 2012, 3366. (b) Gazieva, G. A.; Karpova, T. B.;
Popov, L. D.; Nelyubina, Yu. V.; Kravchenko, A. N.
J. Heterocycl. Chem. 2015, 52, 1390.
9. SDBSWeb. http://sdbs.db.aist.go.jp (National Institute of
Advanced Industrial Science and Technology, SDBS
№ 2699CDS-12-319). Accessed May 14, 2020.
Supplementary information file containing 1H and 13C NMR
spectra of compounds 1c,h,k, 4a–k, 4f·HCl, 7a,b,d–g,i–k,
5a–j, 1Н NMR spectrum of compound 6b, as well as X-ray
structural analysis data for compounds 4j and 5g,h is
available at the journal website at http://link.springer.com/
journal/10593.
The authors express their gratitude to the program for
the development of scientific schools of N. D. Zelinsky
Institute of Organic Chemistry of the Russian Academy of
Sciences.
The authors are grateful to PhD (Biology) L. V. Anikina
(Institute of Physiologically Active Compounds, Russian
Academy of Sciences) for conducting the cytotoxic activity
assays.
X-ray structural analysis was carried out with the
support of the Ministry of Science and Higher Education of
the Russian Federation using the scientific equipment of
the X-ray Structural Center of the A. N. Nesmeyanov
Institute of Organoelement Compounds of the Russian
Academy of Sciences.
References
1. (a) Thakral, S.; Singh, V. Curr. Bioact. Compd. 2019, 15,
316. (b) Suresh, A. S.; Baburajan, P.; Ahmed, M. Tetrahedron
Lett. 2015, 56, 4864. (c) Boström, J.; Olsson, R. I.; Tholander, J.;
Greasley, P. J.; Ryberg, E.; Nordberg, H.; Hjorth, S.; Cheng, L.
Bioorg. Med. Chem. Lett. 2010, 20, 479. (d) Sun, H.-K.; Pang, A.;
Farr, D. C.; Mosaiab, T.; Britton, W. J.; Anoopkumar-Dukie, S.;
Grice, I. D.; Kiefel, M. J.; West, N. P.; Grant, G. D.; Houston T. A.
Aust. J. Chem. 2018, 71, 716. (e) Verma, H.; Khatri, B.;
Chakraborti, S.; Chatterjee, J. Chem. Sci. 2018, 9, 2443.
2. (a) Fathalla, W.; Ali, I. A. I.; Pazdera, P. Beilstein J. Org.
Chem. 2017, 13, 174. (b) Wiget, P. A.; Manzano, L. A.;
Pruet, J. M.; Gao, G.; Saito, R.; Monzingo, A. F.; Jasheway, K. R.;
Robertus, J. D.; Anslyn, E. V. Bioorg. Med. Chem. Lett.
2013, 23, 6799.
10. Panshina, S. Yu.; Ponomarenko, O. V.; Bakibaev, A. A.;
Malkov, V. S. J. Struct. Chem. 2020, 61, 1315. [Zh. Strukt.
Khim. 2020, 61, 1389.]
11. Sheldrick, G. M. Acta Crystallogr., Sect. A: Found. Adv.
2015, A71, 3.
12. Dolomanov, O. V.; Bourhis, L. J.; Gildea, R. J.; Howard, J. A. K.;
Puschmann, H. J. Appl. Crystallogr. 2009, 42, 339.
3. (a) Xu, N.; Jin, X.; Suzuki, K.; Yamaguchi, K.; Mizuno, N. New J.
Chem. 2016, 40, 4865. (b) Polushina, A. V.; Zavarzin, I. V.;
Krayushkin, M. M.; Rodionova, G. M.; Yarovenko, V. N.
Russ. Chem. Bull., Int. Ed. 2021, 70, 383. [Izv. Akad. Nauk,
655