Reaction of 1-substituted 3-(2-hydroxyethylamino)quinoline-2,4(1H,3H)-diones with isothiocyanic acid

Article abstract of DOI:10.1007/s10593-020-02701-9

[Figure not available: see fulltext.] 3-Chloroquinoline-2,4-diones react with ethanolamine to form 3-(3-hydroxyethylamino)quinoline-2,4-diones. These compounds afford, depending on substituents in positions 1 and 3, four different products from their reac

Full text of DOI:10.1007/s10593-020-02701-9

DOI 10.1007/s10593-020-02701-9
Chemistry of Heterocyclic Compounds 2020, 56(5), 566–571
Reaction of 1-substituted 3-(2-hydroxyethylamino)quinoline-
2,4(1H,3H)-diones with isothiocyanic acid
Antonín Klásek1*, Antonín Lyčka2, Michal Rouchal1, Radek Bartošík1
1 Department of Chemistry, Faculty of Technology, Tomas Bata University,
CZ-76272 Zlín, Czech Republic; e-mail: klasek@utb.cz
2 Research Institute for Organic Syntheses (VUOS),
CZ-533 54 Pardubice, Czech Republic; e-mail: Antonin.Lycka@vuos.com
Submitted November 7, 2019
Accepted after revision January 30, 2020
Published in Khimiya Geterotsiklicheskikh Soedinenii,
2020, 56(5), 566–571
3-Chloroquinoline-2,4-diones react with ethanolamine to form 3-(3-hydroxyethylamino)quinoline-2,4-diones. These compounds afford,
depending on substituents in positions 1 and 3, four different products from their reaction with isothiocyanic acid: 3-(2-hydroxy-
ethyl)-2-thioxo-3,3a-dihydro-1H-imidazo[4,5-c]quinolin-4(5H)-ones, 9b-hydroxy-3-(2-hydroxyethyl)-2-thioxo-3,3a,5,9b-tetrahydro-1H-
imidazo[4,5-c]quinolin-4(2H)-ones, 3-(2-hydroxyethyl)-2-thioxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-4(5H)-ones, or 1'-methyl-7a-phenyl-
5-thioxo-3,5,6,7a-tetrahydro-2H-spiro[imidazo[5,1-b]oxazole-7,3'-indolin]-2'-one.
Keywords: isocyanic acid, isothiocyanic acid, 2-thioxo-1H-imidazo[4,5-c]quinolin-4(2H)-ones, 2-thioxo-1H-imidazo[4,5-c]quinolin-
4(5H)-ones, quinoline-2,4-diones, nuclear magnetic resonance, rearrangement.
The chemistry of quinolinediones, and in particular,
3-aminoquinoline-2,4-diones have been of interest to our
group for a long time.1 In the literature, two derivatives of
3-aminoquinoline-2,4-diones are mentioned in connection
with their biological activity. 3-Amino-3-(4-fluorophenyl)-
1H-quinoline-2,4-dione is effective against oxidative stress-
related diseases2 and inhibits cisplatin-induced hearing
loss through suppression of reactive oxygen species.3,4
Later we found that the preferable source of isocyanic acid
is sodium cyanate and that an acceptable source of
isothiocyanic acid is potassium thiocyanate, both in acetic
acid solution. Under these conditions, we prepared new
heterocycles, e. g., spiro-linked imidazoline-2-thiones and
thioxo derivatives of imidazo[1,5-c]quinazolin-5-ones and
imidazo[4,5-c]quinolin-4-ones.1g
In an effort to discover an influence of other substituents
in the molecule of the amine, we chose ethanolamine as an
easily accessible and inexpensive reagent. In our last
paper,1h we described its reaction with 3-chloroquinoline-
2,4-diones 1. According to expectations, 3-(2-hydroxy-
ethylamino)quinoline-2,4-diones 2 were obtained and their
reaction with isocyanic acid afforded mainly 5-hydroxy-
1-(2-hydroxyethyl)-1H-spiro[imidazolidine-4,3'-indole]-2,2'-
diones 3, but also 3-(2-hydroxyethyl)-3,3a-dihydro-2H-
imidazo[4,5-c]quinoline-2,4-(5H)-diones 4 (Scheme 1).
In this paper, the analogous reaction of compounds 2
with isothiocyanic acid is described. The starting com-
pounds 2a–f were reacted with isothiocyanic acid
generated in situ from potassium thiocyanate in acetic acid.
The composition of products from this reaction was
A
similar effect is exhibited by 3-amino-6-fluoro-
3-(4-fluorophenyl)-1H-quinoline-2,4-dione.4 Therefore, we
tried to prepare some 3-aminoquinoline-2,4-dione deriva-
tives with the 3-amino group fixed in a fused ring structure.
3-Aminoquinoline-2,4(1H,3H)-diones were prepared in our
laboratory from 3-chloroquinoline-2,4-diones and ammonia
or primary amines.1a We found, that these compounds
undergo molecular rearrangements when reacting with
isocyanic acid that is formed from urea in boiling acetic
acid. Through this synthetic route, 2,6-dihydroimidazo[1,5-c]-
quinolone-2,4-diones and rearranged 3,3a-dihydro-5H-
imidazo[4,5-c]quinazoline-3,5-diones, 3-(3-acylureido)-2,3-
dihydro-1H-indol-2-ones, and 4-alkylidene-1'H-spiro-
[imidazolidine-5,3'-indole]-2,2'-diones were prepared.1b,c
0009-3122/20/56(5)-0566©2020 Springer Science+Business Media, LLC
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Chemistry of Heterocyclic Compounds 2020, 56(5), 566–571
Scheme 1
different from that with isocyanic acid and comprised three
different N-hydroxyethyl-substituted 2-thioxo-1H-imidazo-
[4,5-c]quinolin-4-ones 5a,c,d,f, 6a,b,d,e,f, and 7b,e, and, in
one case, a product of molecular rearrangement 8c with
spiro[imidazo[5,1-b]oxazole-7,3'-indolin]-2'-one structure
(Scheme 1, Table 1). It is noteworthy that the respective
noncyclized thioureas derived of compounds 2 were never
isolated.
It can be expected, that compounds 3 and 5 can probably
arise from hydroxyethyl derivative 2 by known Marckwald
synthesis.5 However, no strong acid is present in the
reaction mixture. Therefore, we offer another inter-
pretation, based on the formation of isocyanic or isothio-
cyanic acids during the reaction. With moderately strong
isocyanic acid (pKa 3.7),6 arising from the isomerization of
weak cyanic acid (pKa 5.4),7 compounds 2a,b,d–f react to
form1h compounds 3a,b and 4d–f. However, isothiocyanic
acid is a very strong acid (pKa –1.3)7,8 and arises from the
isomerization of weak thiocyanic acid (pKa 5.4).7 Its
reaction with 3-aminoquinoline-2,4(1H,3H)-diones 2 afforded
not only compounds 5a,c,d,f which are thio analogs of
products 4, obtained by the reaction with isocyanic acid,
but also new structures containing sulfur atom, such as
dealkylated products 7b,e, due to the influence of strong
isothiocyanic acid.
Table 1. Products of the reactions
of compounds 2a–f with HNCS
Starting
R1
R2
Product (yield, %)
material
2a
Me
Me
Me
Ph
Bu
Bn
Ph
Bu
Bn
Ph
5a (24), 6a (16), 2a* (26), N-methylisatin (7)
6b (8), 7b (8)
2b
5c (11), 8c (49)
2c
5d (30), 6d (9), 2d* (33), N-phenylisatin (3)
6e (27), 7e (8)
2d
Ph
2e
Ph
5f (31), 6f (23), N-phenylisatin (6)
2f
* Recovered starting material.
different alkyl substituent at N-3 atom.1i On the other hand,
compounds 6 can also be an antecedent of compounds 5.1g
Indeed, yellow compounds 5a,f were prepared in high
yields through the dehydration of colorless 6a,f upon
treatment with P2O5 (Scheme 2). However, the same treat-
ment of compound 6e does not result in compound 5e,
instead, colorless compound 9e was isolated with 39%
yield (Scheme 2). It is likely that this new compound must
originate from C-debenzylation and subsequent S-benzylation
with benzyl cation.
Scheme 2
The explanation of the origin of the obtained compounds
was based on the NMR spectroscopy. Yellow or orange
compounds 5a,c,d,f were produced in moderate yield from
compounds 2a,c,d,f through the reaction with HNCS. The
signals of NCH2 protons resonate more downfield than the
signals of OCH2 protons. It was surprising, however, the
location was proved by 2D NMR (mainly HSQC and
HSQC–TOCSY). Protons are situated on the periphery of a
molecule and their resonance can be relatively easily
influenced by different neighbouring groups.
When compound 5a was kept for one month in DMSO-d6
the NMR spectrum indicated conversion into compound
6a, the product of a nucleophilic attack on compound 5a by
H2O, with a yield of about 65%. Typical 13C chemical
shifts in the spectra of this condensation product agree with
those in oxa analog of compound 6a, except that it has a
In the first-order positive-ion ESI-MS spectra of
compounds 5a,c,d,f, we observed three singly charged
signals, which we assigned to [M+H]+, [M+Na]+, and
[M+K]+. In the first-order negative-ion ESI-MS spectra of
compounds 6, singly charged signals assigned to [M–H]–,
[M+Cl]–, and [2M–H]– were detected. Moreover, singly
charged ion with m/z 150 in the mass spectra of compounds
6a,b and m/z 212 in the mass spectra of compounds 6d,e,f
were observed in the negative ionization mode. We
567

Chemistry of Heterocyclic Compounds 2020, 56(5), 566–571
S
S
N
Scheme 3
H+
HO
O
H
N
R2
HN
HN
(From 2b,e)
HNSC
OH
OH
N
OH
CH2Ph
O
N
Me
2b,c,e
O
N
Me
N
Me
O
6b,e
7b,e
(From 2c)
HNSC
S
S
S
H+
HO
OH
N
HN
N
N
C
OH
HN
N
HN
O
Ph
O
Ph
Ph
O
O
N
N
Me
Me
Me
6c
8c
assigned these ions to 1-[2-(methylamino)phenyl]ethanolate
and 1-[2-(phehylamino)phenyl]ethanolate, respectively.
We propose that these ions are products of in-source
fragmentation of deprotonated molecular ion [M–H]–.
The only product of molecular rearrangement is
compound 8c, having two aliphatic quaternary carbons,
unlike its isomer 5c. In agreement with our preceding
results, this compound must originate from the molecular
rearrangement of compound 6c (Scheme 3). In three cases
(Table 1), the corresponding isatins were isolated in
addition to the main product, which is indicative of the
extensive degradation of the starting compound 2 by
isothiocyanic acid. Compounds 7b,e (Scheme 3) arise from
the debenzylation of starting compounds 2b,e, bearing a
benzyl group at position 3. Such reaction, resulting from
the presence of strongly acidic isothiocyanic acid, has been
observed before.1a
In conclusion, we would like to emphasize that our
results provide new information about the behavior of
reactive quinoline-2,4-dione systems. 3-(2-Hydroxyethyl-
amino)quinolinediones, prepared from 3-chloroquinoline-
dione and ethanolamine, react with isothiocyanic acid to
form four different heterocyclic structures: three related
imidazo[4,5-c]quinolin-4-ones and spiro[imidazo[5,1-b]-
oxazole-7,3'-indolin]-2'-one, a new tetracyclic spiro system
that has not been previously described. Unfortunately, the
latter compound arises in only one case and our
experiments on the preparation of other similar spiro
compounds were so far unsuccessful. This study also
demonstrated a new example of benzyl group migration
from carbon to sulfur atom. An important result is also
dehydration of 9b-hydroxy-2-thioxo-4H-imidazo[4,5-c]-
quinolin-4-ones to 2-thioxo-4H-imidazo[4,5-c]quinolin-
4-ones enabling preparation of these compounds as the
only product by the two-step reaction from starting
3-aminoquinoline-2,4-diones. The prepared compounds are
suitable for biological testing as well as further synthetic
elaboration.
50 MHz, respectively) in DMSO-d6; the 1H and 13C
chemical shifts are given with respect to internal standard
TMS; for 15N spectra, MeNO2 was used as external
standard in a coaxial capillary; signal assignments were
carried out using APT and 2D experiments (gradient-selected
1
(gs) H–1H COSY, gs-1H–1H TOCSY, gs-1H–13C HMQC,
gs-1H–13C HMQC-RELAY, gs-1H–13C HMBC, gs-1H–15N
HMBC, and HSQC-TOCSY).9–11 Mass spectra were
recorded on a Bruker Daltonics amaZon X ion-trap mass
spectrometer, equipped with an ESI source; individual
samples were injected into the ESI source as MeOH–H2O
solutions (concentration 500 ng/ml) via a syringe pump
with a constant flow rate of 3 ml/min; m/z range 50–1500,
electrospray voltage 4.2 kV, drying gas temperature
220°C, drying gas flow rate 6.0 dm3/min, nebulizer
pressure 55.16 kPa, capillary exit voltage 140 V; N2 was
used as both nebulizing and drying gas. Elemental analysis
was carried out on a Thermo Fisher Scientific Flash EA 1112
elemental analyzer. Melting points were determined using a
Kofler block. TLC was performed using Macherey-Nagel
Alugram® SIL G/UV254 foil plates; elution with PhH–
AcOEt, 4:1, CHCl3–EtOH, 9:1, or CHCl3–AcOEt, 7:3.
Column chromatography was carried out on Merck silica
gel (grade 60, 70–230 mesh); elution with CHCl3, then
CHCl3–EtOH, 99:1→8:2, or PhH, then PhH–AcOEt,
99:1→8:2.
Compounds 2a–f were prepared from the respective
compounds 1a–f and ethanolamine.1a
Reaction of compounds 2a–f with HNCS (General
method). KSCN (0.874 g, 9 mmol) was added to a solution
of compound 2a–f (1.5 mmol) in AcOH (4.5 ml), and the
mixture was stirred for 3 h at 50°C. The course of the
reaction was monitored by TLC. After cooling, the mixture
was poured onto crushed ice (20 ml) and extracted with
CHCl3 (5×15 ml) and then with AcOEt (5×15 ml). The
combined extracts were dried with anhydrous Na2SO4 and
evaporated to dryness. The residue was separated by
column chromatography.
3a-Butyl-3-(2-hydroxyethyl)-5-methyl-2-thioxo-2,3,3a,5-
tetrahydro-4H-imidazo[4,5-c]quinolin-4-one (5a) was
prepared from compound 2a. Yield 0.137 g (24%). Orange
solid. Mp 135–137°C (PhH–cyclohexane). IR spectrum,
ν, cm–1: 3376, 2961, 2932, 2875, 1690, 1661, 1609, 1589,
1471, 1439, 1389, 1334, 1287, 1255, 1230, 1211, 1178,
Experimental
IR spectra were recorded on
a Smart OMNI-
Transmission Nicolet iS10 spectrophotometer in KBr
pellets. H, 13C, and 15N NMR spectra were recorded on a
1
Bruker Avance III HD 500 spectrometer (500, 125, and
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Chemistry of Heterocyclic Compounds 2020, 56(5), 566–571
1160, 1110, 1072, 1050, 990, 967, 775, 758, 730, 699, 683,
413 [2M+Ca]2+ (11), 394 [M+H]+ (15). Found, %: C 67.05;
H 6.10; N 10.65; S 8.02. C22H23N3O2S. Calculated, %:
C 67.15; H 5.89; N 10.68; S 8.15.
1
671, 608, 520. H NMR spectrum, δ, ppm (J, Hz): 0.68
(3Н, t, J = 7.3, 4-CH3 Bu); 0.66–0.76 (2Н, m, 2-CH2 Bu);
1.02–1.13 (2Н, m, 3-CH2 Bu); 1.81–1.90 (1H, m) and 2.33–
2.41 (1H, m, 1-CH2 Bu); 3.32 (3H, s, 5-CH3); 3.78–3.88
(3H, m, CH2O, NCH2); 4.03–4.10 (1H, m, NCH2); 4.90
(1H, br. s, OH); 7.32–7.37 (1Н, m, H-7); 7.43–7.47 (1Н, m,
H-9); 7.74–7.79 (1Н, m, H-8); 7.90–7.94 (1Н, m, H-6).
13C NMR spectrum, δ, ppm: 13.6 (C-4 Bu); 21.1 (C-3 Bu);
24.2 (C-2 Bu); 29.9 (5-CH3); 36.5 (C-1 Bu); 47.2 (NCH2);
56.8 (CH2O); 81.2 (C-3a); 116.0 (C-5a); 116.8 (C-9); 124.1
(C-7); 125.8 (C-6); 135.7 (C-8); 141.7 (C-9a); 166.6 (C-4);
183.8 (C-9b); 194.5 (C-2). Mass spectrum, m/z (Irel, %):
685 [2M+Na]+ (5), 370 [M+K]+ (10), 354 [M+Na]+ (100),
351 [2M+Ca]2+ (9), 332 [M+H]+ (12). Found, %: C 61.45;
H 6.60; N 12.79; S 9.64. C17H21N3O2S. Calculated, %:
C 61.61; H 6.39; N 12.68; S 9.67.
3-(2-Hydroxyethyl)-3a,5-diphenyl-2-thioxo-2,3,3a,5-
tetrahydro-4H-imidazo[4,5-c]quinolin-4-one (5f) was
prepared from compound 2f. Yield 0.192 g (31%). Orange
solid. Mp 178–180°C (PhH–cyclohexane). IR spectrum,
ν, cm–1: 3451, 3061, 2361, 1702, 1608, 1587, 1492, 1466,
1449, 1394, 1359, 1309, 1289, 1246, 1229, 1165, 1140,
1060, 1037, 1003, 953, 771, 733, 721, 703, 694, 671, 611,
1
594, 568, 516. H NMR spectrum, δ, ppm (J, Hz): 3.10–
3.19 (1H, m) and 3.59–3.66 (1H, m, CH2O); 3.49–3.58
(1H, m) and 3.79–3.86 (1H, m, NCH2); 4.68 (1H, t, J = 5.7,
OH); 6.29–6.34 (1Н, m, H-9); 7.17–7.26 (3H, m, H-7,
H-2,6 3a-Ph); 7.39–7.69 (9H, m, H-8, H 5-Ph, H-3,4,5
3a-Ph); 7.97–8.02 (1Н, m, H-6). 13C NMR spectrum,
δ, ppm: 47.3 (NCH2); 56.1 (CH2O); 83.6 (C-3a); 116.6
(C-5a); 117.4 (C-9); 124.4 (C-7); 126.1 (C-2,6 3a-Ph); 126.3
(C-6); 128.9 (C-2,6 5-Ph); 130.1 (C-4 5-Ph); 130.3 (C-3,5
3a,5-Ph); 130.5 (C-4 3a-Ph); 131.5 (C-1 5-Ph); 135.1
(C-8); 136.8 (C-1 3a-Ph); 142.3 (C-9a); 165.2 (C-4); 182.9
(C-9b); 195.0 (C-2). Mass spectrum, m/z (Irel, %): 849
[2M+Na]+ (8), 452 [M+K]+ (8), 436 [M+Na]+ (100), 433
[2M+Ca]2+ (21), 414 [M+H]+ (16). Found, %: C 69.81;
H 4.75; N 10.18; S 7.74. C24H19N3O2S. Calculated, %:
C 69.71; H 4.63; N 10.16; S 7.75.
3-(2-Hydroxyethyl)-5-methyl-3a-phenyl-2-thioxo-2,3,3a,5-
tetrahydro-4H-imidazo[4,5-c]quinolin-4-one (5c) was
prepared from compound 2c. Yield 0.058 g (11%). Yellow
solid. Mp 170–177°C (PhH–hexane). IR spectrum, ν, cm–1:
3556, 3056, 2937, 2897, 1678, 1608, 1588, 1491, 1468,
1447, 1400, 1361, 1326, 1284, 1222, 1168, 1143, 1123,
1050, 1001, 968, 952, 934, 809, 760, 724, 695, 664, 610,
1
571, 529. H NMR spectrum, δ, ppm (J, Hz): 3.17–3.29
(1H, m) and 3.62–3.74 (1H, m, CH2O); 3.44 (3H, s,
5-CH3); 3.47–3.59 (1H, m) and 3.68–3.80 (1H, m, NCH2);
4.73 (1H, t, J = 5.7, OH); 6.98–7.02 (2Н, m, H-2,6 Ph);
7.23–7.28 (1Н, m, H-7); 7.36–7.43 (4Н, m, H-9, H-3,4,5
Ph); 7.62–7.66 (1Н, m, H-8); 7.82–7.92 (1Н, m, H-6).
13C NMR spectrum, δ, ppm: 30.4 (5-CH3); 47.4 (NCH2);
56.2 (CH2O); 83.4 (C-3a); 116.7 (C-5a); 116.8 (C-9); 124.1
(C-7); 125.9 (C-2,6 Ph); 126.1 (C-6); 130.1 (C-3,5 Ph);
130.4 (C-4 Ph); 131.6 (C-1 Ph); 135.5 (C-8); 141.2 (C-9a);
165.0 (C-4); 183.1 (C-9b); 195.0 (C-2). Mass spectrum, m/z
(Irel, %): 725 [2M+Na]+ (9), 390 [M+K]+ (7), 374 [M+Na]+
(100), 371 [2M+Ca]2+ (8), 352 [M+H]+ (17). Found, %:
C 64.86; H 4.91; N 11.77; S 9.00. C19H17N3O2S. Calculated, %:
C 64.94; H 4.88; N 11.96; S 9.12.
3a-Butyl-9b-hydroxy-3-(2-hydroxyethyl)-5-methyl-2-thi-
oxo-1,2,3,3a,5,9b-hexahydro-4H-imidazo[4,5-c]quinolin-
4-one (6a) was prepared from compound 2a. Yield 0.096 g
(16%). Colorless solid. Mp 203–217°C (AcOEt). IR spectrum,
ν, cm–1: 3418, 3226, 2958, 2933, 2871, 1662, 1605, 1478,
1436, 1365, 1303, 1255, 1205, 1170, 1122, 1054, 1005,
989, 956, 939, 910, 865, 843, 757, 721, 691, 623, 590, 518,
490. 1H NMR spectrum, δ, ppm (J, Hz): 0.68 (3Н, t, J = 7.3,
4-CH3 Bu); 0.70–0.76 (1H, m) and 0.92–1.01 (1H, m,
2-CH2 Bu); 1.07–1.15 (2Н, m, 3-CH2 Bu); 1.95 (2H, m,
1-CH2 Bu); 3.29 (3H, s, 5-CH3); 3.57–3.65 (2H, m, CH2O);
3.83–3.90 (2H, m, NCH2); 4.60 (1H, t, J = 6.4, OH); 6.87
(1H, s, 9b-OH); 7.12–7.20 (2H, m, H-6,8); 7.38–7.43 (1H,
m, H-7); 7.72–7.79 (1H, m, H-9); 9.14 (1H, s, NH).
13C NMR spectrum, δ, ppm: 13.5 (C-4 Bu); 22.5 (C-3 Bu);
24.1 (C-2 Bu); 29.4 (5-CH3); 31.3 (C-1 Bu); 46.4 (NCH2);
59.0 (CH2O); 72.3 (C-3a); 84.7 (C-9b); 114.5 (C-6); 123.3
(C-8); 123.7 (C-9a); 126.3 (C-9); 130.0 (C-7); 136.2 (C-5a);
168.6 (C-4); 181.3 (C-2). 15N NMR spectrum, δ, ppm (J, Hz):
3a-Butyl-3-(2-hydroxyethyl)-5-phenyl-2-thioxo-2,3,3a,5-
tetrahydro-4H-imidazo[4,5-c]quinolin-4-one (5d) was
prepared from compound 2d. Yield 0.177 g (30%). Yellow
solid. Mp 161–166°C (PhH–hexane). IR spectrum, ν, cm–1:
3454, 3066, 2962, 2929, 2871, 1689, 1608, 1590, 1490,
1467, 1432, 1385, 1340, 1322, 1281, 1245, 1225, 1164,
1108, 1066, 1033, 1004, 962, 859, 777, 754, 733, 696, 633,
610, 582, 516. 1H NMR spectrum, δ, ppm (J, Hz): 0.78
(3Н, t, J = 7.3, 4-CH3 Bu); 0.75–0.85 (2Н, m, 2-CH2 Bu);
1.07–1.23 (2Н, m, 3-CH2 Bu); 2.15–2.27 (1H, m) and 2.48–
2.55 (1H, m, 1-CH2 Bu); 3.73–3.88 (3H, m, CH2O, NCH2);
4.05–4.11 (1H, m, NCH2); 4.83 (1H, t, J = 5.3, OH); 6.39–
6.44 (1Н, m, H-9); 7.27–7.34 (3H, m, H-7, H-2,6 Ph); 7.47–
7.64 (4H, m, H-8, H-3,4,5 Ph); 7.96–8.01 (1Н, m, H-6).
13C NMR spectrum, δ, ppm: 13.6 (C-4 Bu); 21.1 (C-3 Bu);
24.4 (C-2 Bu); 36.4 (C-1 Bu); 47.2 (NCH2); 56.8 (CH2O);
81.5 (C-3a); 115.7 (C-9); 117.3 (C-5a); 124.1 (C-7); 125.9
(C-6); 129.4 (C-2,6 Ph); 129.9 (C-4 Ph); 130.3 (C-3,5 Ph);
130.4 (C-1 Ph); 136.8 (C-8); 142.8 (C-9a); 166.9 (C-4);
183.7 (C-9b); 194.9 (C-2). Mass spectrum, m/z (Irel, %):
809 [2M+Na]+ (5), 432 [M+K]+ (11), 416 [M+Na]+ (100),
1
–237.9 (d, J = 95.6, 1-NH); –252.6 (N-5); –253.3 (N-3).
Mass spectrum, m/z (Irel, %): 721.2 [2M+Na]+ (5), 388
[M+K]+ (11), 372 [M+Na]+ (100), 369 [2M+Ca]2+ (26),
350 [M+H]+ (6). Mass spectrum, m/z (Irel, %): 697 [2M–H]–
(66), 384 [M+35Cl]– (23), 348 [M–H]– (100), 150 (86).
Found, %: C 58.36; H 6.74; N 11.86; S 8.98. C17H23N3O3S.
Calculated, %: C 58.43; H 6.63; N 12.02; S 9.18.
3a-Benzyl-9b-hydroxy-3-(2-hydroxyethyl)-5-methyl-
2-thioxo-1,2,3,3a,5,9b-hexahydro-4H-imidazo[4,5-c]-
quinolin-4-one (6b) was prepared from compound 2b.
Yield 0.046 g (8%). Colorless solid. Mp 205–215°C (PhH–
cyclohexane). IR spectrum, ν, cm–1: 3244, 2937, 2887,
1662, 1606, 1477, 1410, 1369, 1304, 1249, 1197, 1132,
1075, 1034, 1016, 961, 944, 896, 832, 790, 756, 740, 701,
621, 596, 550, 526, 456. 1H NMR spectrum, δ, ppm
569

Chemistry of Heterocyclic Compounds 2020, 56(5), 566–571
(J, Hz): 3.18 (1H, d, J = 16.0) and 3.36 (1H, d, J = 16.0,
(1H, m, H-9); 9.39 (1H, s, NH). 13C NMR spectrum,
δ, ppm: 36.3 (CH2Ph); 46.9 (NCH2); 59.2 (CH2O); 73.3
(C-3a); 85.1 (C-9b); 115.1 (C-6); 123.0 (C-8); 123.1 (C-9a);
126.5 (C-9); 127.1 (C-4 5-Ph); 127.3 (C-3,5 5-Ph); 128.6
(C-3,5 CH2Ph); 129.1 (C-4 CH2Ph); 130.0 (C-7); 130.8
(C-2,6 CH2Ph); 132.4 (C-1 CH2Ph); 136.8 (C-5a); 137.1
(C-1 5-Ph); 167.9 (C-4); 181.8 (C-2). Mass spectrum, m/z
(Irel, %): 913 [2M+Na]+ (8), 484 [M+K]+ (27), 468 [M+Na]+
(100), 465 [2M+Ca]2+ (7), 446 [M+H]+ (10). Mass spectrum,
m/z (Irel, %): 889 [2M–H]– (21), 480 [M+35Cl]– (43), 444 [M–H]–
(22), 212 (100). Found, %: C 67.36; H 5.28; N 9.24; S 7.27.
C25H23N3O3S. Calculated, %: C 67.40; H 5.20; N 9.43; S 7.20.
9b-Hydroxy-3-(2-hydroxyethyl)-3a,5-diphenyl-2-thioxo-
1,2,3,3a,5,9b-hexahydro-4H-imidazo[4,5-c]quinolin-4-one
(6f) was prepared from compound 2f. Yield 0.149 g (23%).
Colorless solid. Mp 228–235°C (AcOEt). IR spectrum,
ν, cm–1: 3230, 2957, 1685, 1661, 1605, 1594, 1491, 1464,
1431, 1390, 1341, 1307, 1260, 1195, 1140, 1077, 996, 945,
930, 863, 832, 759, 735, 704, 691, 630, 606, 589, 574, 532,
513. 1H NMR spectrum, δ, ppm (J, Hz): 3.27–3.40 (1H, m,
NCH2); 3.60–3.74 (2H, m, NCH2, OCH2); 3.87–3.99 (2H,
m, OCH2); 4.55 (1H, t, J = 5.7, OH); 6.29–6.33 (1H, m,
H-6); 7.00 (1H, s, 9b-OH); 7.07–7.13 (1H, m, H-8); 7.20–
7.26 (1H, m, H-7); 7.27–7.50 (7H, m, H-2,6 5-Ph,
H-2,3,4,5,6 3a-Ph); 7.53–7.58 (1H, m, H-4 5-Ph); 7.61–7.69
(2Н, m, H-9, H-3,5 5-Ph); 9.55 (1H, s, NH). 13C NMR
spectrum, δ, ppm: 48.7 (NCH2); 58.4 (CH2O); 79.0 (C-3a);
86.5 (C-9b); 116.2 (C-6); 122.5 (C-9a); 123.5 (C-8); 128.0
(C-9); 128.2 (C-2,6 3a-Ph); 128.8 (C-3,5 3a-Ph, C-2,6 5-Ph);
129.9 (C-7); 130.3 (C-3,5 5-Ph); 131.8 (C-1 3a-Ph); 137.4
(C-5a); 137.6 (C-1 5-Ph); 168.0 (C-4); 184.5 (C-2). Mass
spectrum, m/z (Irel, %): 885 [2M+Na]+ (4), 470 [M+K]+
(15), 454 [M+Na]+ (100), 451 [2M+Ca]2+ (9), 432 [M+H]+
(5). Mass spectrum, m/z (Irel, %): 861 [2M–H]– (4), 466
[M+35Cl]– (20), 430 [M–H]– (59), 212 (100). Found, %:
C 66.64; H 4.93; N 9.53; S 7.68. C24H21N3O3S. Calculated, %:
C 66.80; H 4.91; N 9.74; S 7.43.
CH2Ph); 3.35 (3Н, s, 5-CH3); 3.65–3.81 (2H, s, CH2O);
4.04–4.08 (2H, m, NCH2); 4.65 (1H, t, J = 6.3, OH); 6.54–
6.56 (1H, m, H-6); 6.81–6.93 (5H, m, H Ph); 6.97–7.02
(1H, m, H-8); 7.07–7.12 (1H, m, H-7); 7.15 (1H, s,
9b-OH); 7.64–7.67 (1H, m, H-9); 9.19 (1H, s, NH).
13C NMR spectrum, δ, ppm: 29.0 (5-CH3); 36.2 (CH2Ph);
46.9 (NCH2); 59.2 (CH2O); 72.9 (C-3a); 84.7 (C-9b); 113.6
(C-6); 122.6 (C-8); 123.0 (C-9a); 126.1 (C-9); 126.7 (C-4 Ph);
126.8 (C-3,5 Ph); 129.2 (C-7); 130.0 (C-2,6 Ph); 132.2 (C-1
Ph); 135.6 (C-5a); 168.1 (C-4); 181.8 (C-2). 15N NMR
1
spectrum, δ, ppm (J, Hz): –237.9 (d, J = 95.6, 1-NH);
–250.3 (N-5); –254.0 (N-3). Mass spectrum, m/z (Irel, %):
789 [2M+Na]+ (10), 422 [M+K]+ (13), 406 [M+Na]+ (100),
403 [2M+Ca]2+ (15), 384 [M+H]+ (4). Mass spectrum, m/z
(Irel, %): 765 [2M–H]– (47), 418 [M+35Cl]– (9), 382 [M–H]–
(100), 150 (57). Found, %: C 62.83; H 5.51; N 10.84;
S 8.53. C20H21N3O3S. Calculated, %: C 62.64; H 5.52;
N 10.96; S 8.36.
3a-Butyl-9b-hydroxy-3-(2-hydroxyethyl)-5-phenyl-2-thi-
oxo-1,2,3,3a,5,9b-hexahydro-4H-imidazo[4,5-c]quinolin-
4-one (6d) was prepared from compound 2d. Yield 0.055 g
(9%). White solid. Mp 220–226°C (PhH). IR spectrum,
ν, cm–1: 3283, 3169, 2958, 2932, 2872, 1654, 1606, 1596,
1464, 1430, 1398, 1356, 1304, 1257, 1207, 1127, 1070,
1051, 1006, 966, 945, 857, 754, 720, 699, 681, 649, 628,
1
586, 511. H NMR spectrum, δ, ppm (J, Hz): 0.78 (3Н, t,
J = 7.0, 4-CH3 Bu); 1.12–1.31 (4H, m, 2,3-CH2 Bu); 1.99–
2.12 (2H, m, 1-CH2 Bu); 3.59–3.67 (2H, m, CH2O); 3.75–
3.81 (1H, m) and 3.86–3.93 (1H, m, NCH2); 4.60 (1H, t,
J = 6.2, OH); 6.14–6.17 (1H, m, H-6); 7.00 (1H, s, 9b-OH);
7.11–7.24 (4H, m, H-7,8, H-2,6 Ph); 7.50–7.54 (1H, m,
H-4 Ph); 7.57–7.62 (2Н, m, H-3,5 Ph); 7.81–7.84 (1H, m,
H-9); 9.28 (1H, s, NH). 13C NMR spectrum, δ, ppm: 13.5
(C-4 Bu); 22.5 (C-3 Bu); 24.3 (C-2 Bu); 31.7 (C-1 Bu);
46.6 (NCH2); 59.0 (CH2O); 72.5 (C-3a); 85.1 (C-9b); 115.5
(C-6); 123.4 (C-8,9a); 126.8 (C-9); 128.3 (C-2,6 Ph); 128.7
(C-4 Ph); 129.6 (C-7); 130.2 (C-3,5); 137.1 (C-5a); 137.4
(C-1 Ph); 168.9 (C-4); 181.5 (C-2). 15N NMR spectrum,
3-(2-Hydroxyethyl)-5-methyl-2-thioxo-1,2,3,5-tetrahydro-
4H-imidazo[4,5-c]quinolin-4-one (7b) was prepared from
compound 2b. Yield 0.033 g (8%). Yellowish solid.
Mp 295–310°C (cyclohexane–AcOEt). IR spectrum, ν, cm–1:
3347, 3074, 2925, 2842, 2730, 1670, 1635, 1587, 1524,
1483, 1427, 1393, 1358, 1327, 1261, 1211, 1164, 1115,
1074, 1063, 1043, 1009, 969, 884, 863, 768, 754, 733, 677,
1
δ, ppm (J, Hz): –231.0 (N-5); –237.7 (d, J = 96.0, 1-NH);
–254.6 (N-3). Mass spectrum, m/z (Irel, %): 845 [2M+Na]+
(7), 450 [M+K]+ (20), 434 [M+Na]+ (100), 431 [2M+Ca]2+
(12), 412 [M+H]+ (3). Mass spectrum, m/z (Irel, %): 821
[2M–H]– (21), 446 [M+35Cl]– (27), 410 [M–H]– (29), 212
(100). Found, %: C 64.14; H 6.28; N 9.98; S 7.85.
C22H25N3O3S. Calculated, %: C 64.21; H 6.12; N 10.21;
S 7.79.
1
626, 585, 520. H NMR spectrum, δ, ppm (J, Hz): 3.66
(3H, s, CH3); 3.71 (2H, t, J = 6.6, CH2O); 4.56 (2H, t,
J = 6.6, NCH2); 4.84 (1H, br. s, OH); 7.31–7.36 (1H, m,
H-8); 7.52–7.62 (1H, m, H-6,7); 8.05–8.09 (1H, m, H-9);
13.75 (1H, s, NH). 13C NMR spectrum, δ, ppm: 28.9 (CH3);
46.3 (NCH2); 58.4 (CH2O); 110.0 (C-3a); 115.7 (C-6);
117.7 (C-9a); 122.0 (C-8); 122.5 (C-9); 129.4 (C-7); 131.5
(C-9b); 136.8 (C-5a); 153.2 (C-2); 167.1 (C-4). 15N NMR
spectrum, δ, ppm (J, Hz): –220.3 (N-3); –223.1 (d, 1J = 97.5,
1-NH); –240.0 (N-5). Mass spectrum, m/z (Irel, %): 573
[2M+Na]+ (73), 432.5 [3M+Ca]2+ (11), 314 [M+K]+ (9),
298 [M+Na]+ (100), 276 [M+H]+ (21). Mass spectrum,
m/z (Irel, %): 571 [2M–2H+Na]– (12), 274 [M–H]– (100).
Found, %: C 56.48; H 4.66; N 15.01; S 11.84.
C13H13N3O2S. Calculated, %: C 56.71; H 4.76; N 15.26;
S 11.65.
3a-Benzyl-9b-hydroxy-3-(2-hydroxyethyl)-5-phenyl-
2-thioxo-1,2,3,3a,5,9b-hexahydro-4H-imidazo[4,5-c]-
quinolin-4-one (6e) was prepared from compound 2e.
Yield 0.180 g (27%). Colorless solid. Mp 243–247°C
(AcOEt). IR spectrum, ν, cm–1: 3387, 3192, 2933, 1652,
1598, 1491, 1475, 1432, 1397, 1358, 1303, 1239, 1199,
1134, 1067, 1038, 970, 854, 811, 755, 744, 717, 701, 608,
1
545, 524. H NMR spectrum, δ, ppm (J, Hz): 3.28 (1H, d,
J = 16.0) and 3.54 (1H, d, J = 16.0, CH2Ph); 3.63–3.69
(1H, m) and 3.71–3.77 (1H, m, CH2O); 3.97–4.06 (2H, m,
NCH2); 4.67 (1H, t, J = 6.3, OH); 5.59–5.64 (1H, m, H-6);
6.70–6.85 (2H, m, H Ph); 6.90–7.15 (7H, m, H-7,8, H Ph);
7.38 (1H, s, 9b-OH); 7.38–7.53 (3H, m, H Ph); 7.75–7.80
570

Chemistry of Heterocyclic Compounds 2020, 56(5), 566–571
1
3-(2-Hydroxyethyl)-5-phenyl-2-thioxo-1,2,3,5-tetrahydro-
4H-imidazo[4,5-c]quinolin-4-one (7e) was prepared from
compound 2e. Yield 0.040 g (8%). Colorless solid. Mp 275–
290°C (AcOEt). IR spectrum, ν, cm–1: 3426, 3056, 2924,
2740, 1668, 1634, 1591, 1569, 1521, 1480, 1463, 1434, 1394,
1341, 1324, 1267, 1238, 1210, 1164, 1121, 1072, 1029,
989, 860, 786, 753, 732, 699, 683, 608, 563, 515. 1H NMR
spectrum, δ, ppm (J, Hz): 3.71 (2H, td, J = 6.7, J = 5.7,
CH2O); 4.56 (2H, t, J = 6.7, NCH2); 4.88 (1H, t, J = 5.7, OH);
6.56–6.61 (1H, m, H-6); 7.31–7.45 (4H, m, H-7,8, H-2,6 Ph);
7.55–7.68 (3H, m, H-3,4,5 Ph); 8.16–8.20 (1H, m, H-9);
13.95 (1H, s, NH). 13C NMR spectrum, δ, ppm: 46.4 (NCH2);
58.5 (CH2O); 110.1 (C-3a); 116.5 (C-6); 117.9 (C-9a);
122.1 (C-9); 122.8 (C-8); 129.0 (C-4 Ph); 129.3 (C-7); 129.4
(C-2,6 Ph); 130.1 (C-3,5 Ph); 132.4 (C-9b); 137.2 (C-5a);
138.3 (C-1 Ph); 152.5 (C-2); 167.4 (C-4). 15N NMR spectrum,
δ, ppm (J, Hz): –219.1 (N-5); –220.3 (N-3); –223.9 (d,
1J = 96.6, 1-NH). Mass spectrum, m/z (Irel, %): 697
[2M+Na]+ (14), 376 [M+K]+ (11), 360 [M+Na]+ (100), 338
[M+H]+ (16). Mass spectrum, m/z (Irel, %): 336 [M–H]– (100).
Found, %: C 63.95; H 4.50; N 11.98; S 9.27. C18H15N3O2S.
Calculated, %: C 64.08; H 4.48; N 12.45; S 9.50.
757, 702, 681, 666, 607, 563, 546. H NMR spectrum,
δ, ppm (J, Hz): 3.64–3.69 (2H, m, CH2O); 4.32–4.36 (2H,
m, NCH2); 4.64 (2H, s, SCH2); 4.96 (1H, t, J = 6.9, OH);
6.55–6.59 (1Н, m, H-6); 7.24–7.37 (7H, m, H-7,8,
H-2,3,4,5,6 5-Ph); 7.47–7.51 (2H, m, H-2,6 CH2Ph); 7.58–
7.62 (1H, m, H-4 CH2Ph); 7.62–7.66 (2H, m, H-3,5
CH2Ph); 8.23–8.27 (1H, m, H-9). 13C NMR spectrum,
δ, ppm: 36.5 (SCH2); 48.0 (NCH2); 60.1 (CH2O); 116.0 (C-9a);
116.3 (C-6); 121.1 (C-3a); 121.8 (C-9); 122.6 (C-8); 127.5
(C-4 5-Ph); 128.2 (C-7); 128.5 (C-2,6 5-Ph); 128.8 (C-4
CH2Ph); 129.0 (C-2,6 CH2Ph); 129.6 (C-3,5 5-Ph); 130.0
(C-3,5 CH2Ph); 137.4 (C-1 CH2Ph); 137.6 (C-1 5-Ph);
138.4 (C-5a); 143.9 (C-9b); 152.5 (C-2); 154.1 (C-4).
15N NMR spectrum, δ, ppm: –137.2 (N-1); –217.6 (N-3);
–220.9 (N-5). Mass spectrum, m/z (Irel, %): 877 [2M+Na]+
(5), 466 [M+K]+ (8), 450 [M+Na]+ (63), 428 [M+H]+
(100). Mass spectrum, m/z (Irel, %): 426 [M–H]– (100).
Found, %: C 70.46; H 5.09; N 9.56; S 7.47. C25H21N3O2S.
Calculated, %: C 70.24; H 4.95; N 9.83; S 7.50.
Supplementary information file containing 1H, 13C, and 1H–15N
HMBC NMR spectra of the synthesized compounds is available
at the journal website at http://link.springer.com/journal/10593.
1'-Methyl-7a-phenyl-5-thioxo-2,3,5,6-tetrahydro-7aH-
spiro[imidazo[5,1-b]oxazole-7,3'-indolin]-2'-one (8c) was
prepared from compound 2c. Yield 0.258 g (49%). White
solid. Mp 221–224°C (hexane–AcOEt). IR spectrum, ν, cm–1:
3289, 3058, 3033, 2968, 2901, 1710, 1612, 1472, 1356,
1293, 1260, 1233, 1193, 1154, 1127, 1093, 1072, 1052,
1024, 1005, 991, 948, 915, 857, 784, 753, 703, 687, 653,
A. K. and M. R. thank for financial support from the
internal grant of TBU in Zlín (No. IGA/FT/2019/010),
funded from the resources of specific university research.
The authors thank Mrs. H. Geržová (Faculty of Technology,
Tomas Bata University in Zlín) for technical help.
1
623, 588, 532. H NMR spectrum, δ, ppm: 2.67 (3H, s,
References
CH3); 3.22–3.30 (1H, m, 2-CH2); 3.40–3.46 and 3.86–3.93
(2H, m, 3-CH2); 4.51–4.56 (2H, m, 2-CH2); 6.94–7.01 (3Н,
m, H-7', H Ph); 7.14–7.18 (1H, m, H-5'); 7.20–7.32 (3H, m,
H Ph); 7.43–7.48 (1H, m, H-6'); 7.53–7.56 (1H, m, H-4');
9.98 (1H, s, NH). 13C NMR spectrum, δ, ppm: 25.8 (CH3);
47.9 (C-3); 62.8 (C-2); 71.7 (C-7); 102.9 (C-7a); 108.6
(C-7'); 121.6 (C-3a'); 122.4 (C-5'); 126.0 (C-2,6); 127.7
(C-3,5); 127.9 (C-4'); 129.0 (C-4 Ph); 130.8 (C-6'); 134.2
(C-1 Ph); 144.2 (C-7'); 172.0 (C-2'); 191.9 (C-5). 15N NMR
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1
spectrum, δ, ppm (J, Hz): 244.7 (N-4); –246.9 (d, J = 96.6,
6-NH); –252.0 (N-1'). Mass spectrum, m/z (Irel, %): 352
[M+H]+ (100). Mass spectrum, m/z (Irel, %): 350 [M–H]– (100).
Found, %: C 65.12; H 5.01; N 11.72; S 9.28. C19H17N3O2S.
Calculated, %: C 64.94; H 4.88; N 11.96; S 9.12.
Conversion of compounds 6a,e,f to compounds 5a,f and
9e. P2O5 (43 mg, 0.30 mmol) was added portionwise to a
stirred solution of compound 6a,e,f (0.20 mmol) in CHCl3
(4.0 ml) at room temperature. After 45 min, the yellow
solution was filtered through a short column of silica gel. The
filtrate was evaporated to dryness, and the residue was crystal-
lized. From compounds 6a,f, compounds 5a (yield 0.047 g
(59%)) and 5f (yield 0.060 g (73%)) were obtained, identical
to those prepared from compounds 2a,f, respectively. From
compound 6e, compound 9e (yield 0.033 g (39%)) was
obtained besides compound 7e (yield 3.4 mg (5%)).
2-(Benzylsulfanyl)-3-(2-hydroxyethyl)-5-phenyl-3,5-
dihydro-4H-imidazo[4,5-c]quinolin-4-one (9e). Colorless
solid. Mp 182–186°C (hexane–benzene). IR spectrum, ν, cm–1:
3317, 3061, 3031, 2962, 1670, 1575, 1492, 1456, 1430,
1359, 1309, 1247, 1223, 1163, 1128, 1056, 1036, 947, 852,
8. Chiang, Y.; Kresge, A. J. Can. J. Chem. 2000, 78, 1627.
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Practical Course; Wiley-VCH: Weinheim, 2004, 3rd ed.
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Organic Chemistry; Elsevier: Amsterdam, 2016, 3rd ed.
11. Marek, R.; Lyčka, A.; Kolehmainen, E.; Sievanen, E.;
Toušek, J. Curr. Org. Chem. 2007, 11, 1154.
571