An Improved Protocol for Synthesis of 3-Substituted 5-Arylidene-2-thiohydantoins: Two-step Procedure Alternative to Classical Methods

Article abstract of DOI:10.1002/jhet.2464

A novel method for the direct synthesis of 5-arylidene-2-thiohydantoins from thioureas and aromatic aldehydes in the presence of base in ethanol was developed. Application of this efficient method allowed preparing thiohydantoins, which are difficult to s

Full text of DOI:10.1002/jhet.2464

Month 2015
An Improved Protocol for Synthesis of 3-Substituted 5-Arylidene-2-
thiohydantoins: Two-step Procedure Alternative to Classical Methods
Olga Yu Kuznetsova,a Roman L. Antipin,a Anna V. Udina,a Olga O. Krasnovskaya,a Elena K. Beloglazkina,a
Vladimir I. Terenin,a Victor E. Koteliansky,a Nikolay V. Zyk,a and Alexander G. Majougaa,b
*
aDepartment of Chemistry, M. V. Lomonosov Moscow State University, Leninskie Gory 1/3, Moscow 119992, Russia
bNational University of Science and Technology MISiS, Leninsky Ave 4, Moscow 119049, Russia
*
E-mail: alexander.majouga@gmail.com
Additional Supporting Information may be found in the online version of this article.
Received February 22, 2015
DOI 10.1002/jhet.2464
Published online 00 Month 2015 in Wiley Online Library (wileyonlinelibrary.com).
A novel method for the direct synthesis of 5-arylidene-2-thiohydantoins from thioureas and aromatic
aldehydes in the presence of base in ethanol was developed. Application of this efficient method allowed
preparing thiohydantoins, which are difficult to synthesis by traditional methods.
J. Heterocyclic Chem., 00, 00 (2015).
INTRODUCTION
of N-acylthiourea with aromatic aldehydes in the presence
of acetic anhydride and sodium acetate results in the forma-
tion of 5-arylmethyl-2-thiohydantoins. But the acidity of the
reaction media and high temperature make this method
unsuitable for the substrates having labile functional groups.
On the other hand, development of the novel condensation
reactions in basic media under mild conditions allows syn-
thesizing the compounds with different functional groups.
Herein, we describe a novel synthetic protocol for the
preparation of the 5-arylidene-2-thiohydantoin derivatives
via one-pot, two-step condensation–cyclization procedure
starting from ethyl isothiocyanatoacetate, amine, and
aldehyde.
During the past decade, chemistry, synthesis, and trans-
formation of five-membered heterocyclic compounds have
received considerable attention because of their wide appli-
cation. The five-membered heterocycles and in particular
the thiohydantoin are currently proposed in medicinal
chemistry as “privileged scaffolds”. The 3-substituted 5-
arylidene-2-thiohydantoin moiety (Fig. 1) is known to be
a biologically active heterocyclic core in areas of
antimycobacterial [1], fungicidal [2], antiviral [3], antitu-
mor [4], and anti-inflammatory [5] activities and anticon-
vulsant indications [6], for the treatment of schistosomiasis
infections [7], Alzheimer’s disease [8], and antiarrhythmics
drugs [9].
For the synthesis of substituted 5-arylidene-2-
thiohydantoins, the condensation of 2-thiohydantoins with
aldehydes in acidic [10–14] or basic [15] conditions is typ-
ically applied (Scheme 1). Another method for the synthe-
sis of 2-thiohydantoin derivatives, that is, three-component
condensation of α-amino acid derivatives, aromatic alde-
hydes, and potassium thiocyanates, was also reported [15].
The disadvantages of these methods included inaccessibility
of some substituted isothiocyanates, which is limited by the
complexity of their preparation (using of CSCl2 or CS2) [16]
and poor yields of target products in the case of three-
component condensation.
RESULTS AND DISCUSSION
The synthetic approach to 3-substituted 5-arylidene-2-
thiohydantoins was based on exploration of thiourea con-
densation with aromatic or heteroaromatic aldehydes. The
starting thioureas 1a–i containing different substituents
were obtained using the respective amine and ethyl
isothiocyanatoacetate (Scheme 2), which was synthesized
according to literature procedure [16]. The reactions were
carried out under room temperature in diethyl ether.
Products were obtained in high yields and did not require
purification before using in the next step. Yields for com-
pounds 1a–i are presented in Table 1.
Among the publications devoted to the 2-
thiohydantoins, we were interested in the work by Johnson
and co-workers [17]. The authors showed that condensation
We have found that thioureas 1a–i react with aromatic or
heteroaromatic aldehydes in the presence of potassium
© 2015 HeteroCorporation

Vol 000
O. Y. Kuznetsova, R. L. Antipin, A. V. Udina, O. O. Krasnovskaya, E. K. Beloglazkina,
V. I. Terenin, V. E. Koteliansky, N. V. Zyk, and A. G. Majouga
Figure 1. Structural analogues of compounds related to 3-substituted 5-arylidene-2-thiohydantoins investigated for potential biological activity.
Scheme 1. Synthetic methodologies for 3-substituted 5-arylidene-2-thiohydantoins synthesis.
ethyl group in NMR spectra area typical to ethanol in
Scheme 2. Preparation of thioureas 1a–i.
CD3OD assumes that the cyclization step takes place
[18]. After addition of 2-pyridine carboxaldehyde, we
observed signal of proton at 6.44 that corresponds to
vinyl proton.
We expect that the key point in the proposed mechanism
(Scheme 4) is cyclization of initial thiourea to
thiohydantoine and further condensation with 2-
pyridinecarboxaldehyde.
hydroxide in ethanol and after acidification with hydro-
chloric acid, apparently gives thiohydantoins 2a–r
(Scheme 3). In contrast to previously described procedures
for the synthesis of substituted thiohydantoins, the
proposed method includes application of ethyl
isothiocyanatoacetate and commercially available amines
as starting material. This method allows varying both 5-
arylidene fragments and substituents at the third position
of heterocyclic core. 5-Arylidene-2-thiohydantoins were
obtained with high yield (Table 2) and characterized by
1H NMR, IR, and elemental analysis.
Exploration of novel and efficient method for the prepa-
ration of thiohydantoin derivatives allows us to synthesize
imidazolones with acid-sensitive substituents like tert-
butoxycarbonyl (BOC) and cyclopropyl groups. To study
cyclization mechanism, we carry out model reaction of thio-
urea 1d and 2-pyridine carboxaldehyde in the presence of
potassium hydroxide (KOH) in deutero methanol (CD3OD)
by 1H NMR spectroscopy (Supporting Information).
Addition of one equivalent of KOH to thiourea 1d
results in changes in 1H NMR spectra: a small shift of aro-
matic ring protons and disappearance of methylene group
correspond to ethyl isothiocyanate fragment obviously
because of enolization process. Appearance of protons of
To compare our method with previously published pro-
cedures [19], we studied reaction of model thiourea 1i with
different pyridine carboxaldehydes. Previously, we have
showed that yield of the products 2m–o (Table 3) with
the different pyridine carboxaldehydes strongly depends
on reaction conditions (Scheme 5) [20,21].
We compare the yields of the pyridyl-substituted 2-
thiohydantoins, which was previously synthesized using
condensation under basic (method A) or acidic (methods
B and C) conditions.
The protocol developed in this work allows obtaining re-
action products with high yields, compared with previously
described.
CONCLUSIONS
In conclusion, an efficient and simple approach for the
synthesis of 3-substituted 5-arylidene-2-thiohydantoins,
based on condensation of thioureas with aromatic and
heteroaromatic aldehydes, has been developed. Easy
workup procedure, good to high yields, and the possibility
of using of easy available amines instead of
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2015
An Improved Protocol for Synthesis of 3-Substituted 5-Arylidene-2-thiohydantoins:
Two-step Procedure Alternative to Classical Methods
Table 1
Thioureas 1a–i synthesized in this work.
Entry
Amine
Compound
Yield (%)
1a
72
89
1b
1c
1d
88
95
76
1e
1f
89
1g
1h
1i
83
85
65
isothiocyanates for the target compound synthesis are the
advantages of the present method.
cold Et2O (3 × 15mL), and dried. In the case of
compound 1h, reaction was carried in H2O/EtOH 1:1
mixture under heating.
EXPERIMENTAL
Scheme 3. Synthesis of 3-substituted 5-arylidene-2-thiohydantoins.
Typical reaction procedure for the synthesis of compounds
1a–i. Equimolar amounts of ethyl isothiocyanatoacetate
and appropriate amine in minimum amount of
ethoxyethane were mixed and stirred for 4h at room
temperature. The precipitate was filtered, washed with
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O. Y. Kuznetsova, R. L. Antipin, A. V. Udina, O. O. Krasnovskaya, E. K. Beloglazkina,
V. I. Terenin, V. E. Koteliansky, N. V. Zyk, and A. G. Majouga
Table 2
3-Substituted 5-arylidene-2-thiohydantoins 2a–q synthesized in this work.
Entry
Thiourea
Aldehyde
Compound
Yield (%)
2a
1a
78
43
2b
1b
2c
1b
1c
47
93
2d
2e
2f
1c
1c
81
89
2g
2h
1d
1d
92
89
92
2i
2j
1d
1e
85
(Continued)
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Month 2015
An Improved Protocol for Synthesis of 3-Substituted 5-Arylidene-2-thiohydantoins:
Two-step Procedure Alternative to Classical Methods
Table 2
(Continued)
Entry
Thiourea
Aldehyde
Compound
Yield (%)
86
2k
1f
2l
1g
81
2m
2n
2o
1h
1h
1h
81
56
84
2p
2q
1i
1i
28
35
Ethyl 12,12-dimethyl-11-oxo-4-thioxo-10-oxa-3,5,9-triazatridecan-
1-oate (1a).
Anal. Calcd for C12H25N3O3S: C, 46.90; H, 8.14; N,
13.68; S, 10.42. Found: C, 46.98; H, 8.21; N, 13.83; S,
10.65.
White solid, yield 72%, mp 110–112°C; IR
(KBr, cmÀ1): 1750, 1690 ;1H NMR (400MHz,
DMSO-d6) δ, ppm: 1.32 (t, 3H, J =7.26 Hz), 1.45 (s, 9H),
1.77 (m, 2H), 3.20 (m, 2H), 3.61 (m, 2H), 4.22 (q, 2H,
J =7.26 Hz), 4.38 (s, 2H), 4.90 (br, s, 1H), 6.75 (br, s,
1H), 8.33 (br, s, 1H); Anal. Calcd for C12H25N3O3S: C,
46.90; H, 8.14; N, 13.68; S, 10.42. Found: C, 46.98; H,
8.21; N, 13.83; S, 10.65.
Ethyl 2-(3-dimethylphenyl)thioureido)acetate (1c). White
solid, yield 88%, mp 118–120°C: IR (KBr, cmÀ1): 1753,
1
1695; H NMR (400MHz, CDCl3) δ, ppm: 1.30 (t, 3H,
J=7.04Hz), 2.35 (s, 6H), 4.23 (q, 2H, J=7.24Hz,
J=21.52Hz), 4.45 (s, 2H), 6.63–6.71 (br, s, 1H), 6.86–
6.90 (s, 2H), 6.93–6.94 (s, 1H), 7.82–8.05 (br, s, 1H);
Anal. Calcd for C13H18N2O2S: C, 58.62; H, 6.81; N,
Ethyl 2-(3-cyclopropylthioureido)acetate (1b).
White
solid, yield 89%, mp 101–103°C; IR (KBr, cmÀ1): 3429,
2960, 1752; 1H NMR (400 MHz, DMSO-d6) δ, ppm:
1.26–1.30 (m, 2H), 1.44–1.52 (m, 2H), 1.97(t, 3H,
J =7.04 Hz), 3.27–3.29 (m, 1H), 4.84–4.89 (m, 2H), 4.98–
5.02 (m, 2H), 8.51–8.59 (br, s, 1H), 8.92–8.98 (br, s, 1H);
10.52. Found: C, 58.74; H, 6.93; N, 10.63.
Ethyl 2-(3-(3,4-dimethylbenzyl)thioureido)acetate (1d). White
solid, yield 95%, mp 123–125°C; IR (KBr, cmÀ1): 1748,
1
1692; H NMR (400MHz, CDCl3) δ, ppm: 1.28 (t, 3H,
J= 7.24Hz), 2.26 (s, 6H), 4.18 (q, 2H, J=7.04Hz,
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Vol 000
O. Y. Kuznetsova, R. L. Antipin, A. V. Udina, O. O. Krasnovskaya, E. K. Beloglazkina,
V. I. Terenin, V. E. Koteliansky, N. V. Zyk, and A. G. Majouga
Scheme 4. Proposed mechanism of reaction.
(t, 3H, J= 7.14 Hz), 4.13 (q, 2H, J=7.04Hz, J=21.32Hz),
4.22–4.31 (m, 2H), 7.14–7.21 (m, 1H), 7.35–7.46 (m, 1H),
7.64–7.72 (m, 1H), 8.07–8.14 (m, 1H), 10.01 (s, 1H);
Anal. Calcd for C11H12F2N2O2S: C, 48.17; H, 4.41; N,
Table 3
Yields of 2-thiohydantoins 2m–o.
Yield of 2n–p compound (%)
10.21. Found: C, 48.27; H, 4.50; N, 10.35.
Thiohydantoin
This work Method A Method B Method C
Ethyl 2-(3-(4-trifluoromethyl)phenyl)thioureido)acetate (1f).
White solid, yield 89%, mp 126–128°C; IR (KBr, cmÀ1):
2m
2n
2o
81
56
84
95
7
11
Traces
50
75
Traces
61
60
1
1753, 1689; H NMR (400MHz, CDCl3) δ, ppm: 1.33 (t,
3H, J =7.24), 4.26 (q, 2H, J =7.04, J =21.32), 4.48 (s,
2H), 6.76–6.92 (br, s, 1H), 7.44 (d, 2H, J =8.22), 7.71 (d,
2H, 8.02), 8.12–8.23 (br, s, 1H); Anal. Calcd for
C12H13F3N2O2S: C, 47.05; H, 4.28; N, 9.15. Found: C,
J = 21.32 Hz), 4.36 (s, 2H), 4.49–4.58 (br, s, 2H),
7.03–7.15 (m, 3H); Anal. Calcd for C14H20N2O2S: C,
59.97; H, 7.19; N, 9.99. Found: C, 60.05; H, 7.26; N, 10.13.
47.13; H, 4.37; N, 9.34.
Ethyl 2-(3-(3-morpholinopropyl)thioureido)acetate (1g).
White solid, yield 83%, mp 137–139°C; IR (KBr, cmÀ1):
1768, 1698; 1H NMR (400 MHz, CDCl3) δ, ppm: 1.25 (t,
3H, J = 7.04 Hz), 1.91 (quin, 2H, J = 7.04, J = 14.28,
J=28.56), 2.44–2.54 (m, 6H), 3.67–3.77 (m, 6H), 3.85–3.91
Ethyl 2-(3-(3,4-difluorophenyl)thioureido)acetate (1e). White
solid, yield 76% mp 138–140°C; IR (KBr, cmÀ1): 1763,
1674; 1H NMR (400MHz, DMSO-d6) δ, ppm: 1.22
Scheme 5. Synthesis of 2-thiohydantoines with different substituents in position 5. [Color figure can be viewed in the online issue, which is available at
wileyonlinelibrary.com.]
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2015
An Improved Protocol for Synthesis of 3-Substituted 5-Arylidene-2-thiohydantoins:
Two-step Procedure Alternative to Classical Methods
(t, 2H, J=7.04), 4.07 (s, 2H); Anal. Calcd for C12H23N3O3S:
C, 49.08; H, 8.01; N, 14.52. Found: C, 49.14; H, 8.09; N,
14.73.
2H), 7.12–7.16 (m, 1H), 7.41–7.43 (m, 1H), 7.79–7.83 (m,
1H), 7.91–7.94 (m, 1H), 8.79–8.82 (m, 1H), 11.67–12.07 (br,
s, 1H); Anal. Calcd for C17H15N3OS: C, 66.00; H, 4.89; N,
Ethyl 2-(3-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)thioureido)
acetate (1h). White solid, yield 79%, mp 154–156°C; IR (KBr,
13.58. Found: C, 66.15; H, 4.97; N, 13.73.
3-(3,5-Dimethylphenyl)-(5Z)-5((4-brombenzylidene)-2-ylmethylene)-
2-thioxoimidazolin-4-one (2e). Yellow solid, yield 81%, mp
cmÀ1): 2918, 1768, 1700, 1312; 1H NMR (400 MHz, CDCl3)
δ, ppm: 1.20 (t, 3H, J=7.09), 4.10 (q, 2H, J=7.09,
J= 21.27), 4.21 (d, 2H, J=5.38), 7.91–8.13 (br, s, 1H),
8.29–8.44 (br, s, 1H), 10.73–10.89 (br, s, 1H), 11.30–11.48
(br, s, 1H); Anal. Calcd for C9H12N4O4S: C, 39.70; H,
4.44; N, 20.58. Found: C, 39.84; H, 4.52; N, 20.87.
199–201°C; IR (KBr, cmÀ1): 3192, 1754, 748; H NMR
1
(400MHz, DMSO-d6) δ, ppm: 2.31 (s, 6H), 6.61–6.70 (m,
1H), 6.96 (s, 2H), 7.10 (s, 1H), 7.59 (d, 1H, J=8.61Hz), 7.65
(d, 1H, J=8.41Hz), 7.78 (d, 1H, J= 8.22 Hz), 7.99 (d, 1H,
J=8.41Hz); Anal. Calcd for C18H15BrN2OS: C, 55.82; H,
Ethyl 2-(3-phenylthioureido)acetate (1i).
White solid,
3.90; N, 7.23. Found: C, 55.95; H, 4.12; N, 7.43.
yield 85%, mp 86–87°C; IR (KBr, cmÀ1): 1760, 1695;
1H NMR (400 MHz, CDCl3) δ, ppm: 1.33 (t, 3H,
J =7.24), 4.26 (q, 2H, J= 7.04, J = 21.32), 4.53 (s, 2H),
7.25–7.33 (m, 3H), 7.42–7.47 (m, 2H); Anal. Calcd for
C11H14N2O2S: C, 55.44; H, 5.92; N, 11.76. Found: C,
55.56; H, 6.03; N, 11.87.
3-(3,5-Dimethylphenyl)-(5Z)-5((4-methylbenzylidene)-2-ylmethy
lene)-2-thioxoimidazolin-4-one (2f). Yellow solid, yield 89%,
mp 172–174°C; IR (KBr, cmÀ1): 3198, 1768, 761; 1H
NMR (400MHz, DMSO-d6) δ, ppm: 2.32 (s, 6H), 2.36 (s,
3H), 6.62 (s, 1H), 6.96–6.98 (m, 2H), 7.10–7.13 (m, 1H),
7.27 (d, 2H, J=7.70Hz), 7.76 (d, 2H, J=7.70Hz),
12.45–12.54 (br, s, 1H); Anal. Calcd for C19H18N2OS: C,
Typical reaction procedure for the synthesis of compounds
2a–q. To a solution of 0.1 mmol of thioureas (1a–i) in
70.78; H, 5.63; N, 8.69. Found: C, 70.86; H, 5.71; N, 8.75.
3-(4-Dimethylbenzyl)-(5Z)-5((4-methylbenzylidene)-2-ylmethy
15mL of 2% KOH in ethanol was added dropwise an
equimolar amount of aldehyde. The reaction mixture was
stirred at room temperature for 6 h, and then 10% HCl
was slowly added. The precipitate was collected by
filtration and washed with water until neutral and dried
lene)-2-thioxoimidazolin-4-one (2g).
Yellow solid, yield
92%, mp 173–175°C; IR (KBr, cmÀ1): 3197, 1763, 748;
1H NMR (400MHz, DMSO-d6) δ, ppm: 2.18 (s, 6H),
2.35 (s, 3H), 4.94 (s, 2H), 6.63 (s, 1H), 6.96–7.13 (m,
3H), 7.27 (d, 2H, J=7.58), 7.71 (d, 2H, J=8.07),
12.37–12.45 (br, s, 1H); Anal. Calcd for C20H20N2OS: C,
under vacuum.
3-(3-Tert-butylpropylcarbamate)-(5Z)-5(pyridine-2-ylmethylene)-
2-thioxoimidazolin-4-one (2a). Yellow solid, yield 78%, mp
71.40; H, 5.99; N, 8.33. Found: C, 71.58; H, 6.05; N, 8.45.
3-(3,4-Dimethylbenzyl)-(5Z)-5((4-brombenzylidede)-2-ylmeth
ylene)-2-thioxoimidazolin-4-one (2h). Yellow solid, yield
1
185–187°C; IR (KBr, cmÀ1): 3150, 2931 (br), 1786; H
89%, mp 191–193°C; IR (KBr, cmÀ1): 3195, 1768, 764;
1H NMR (400 MHz, DMSO-d6) δ, ppm: 2.18 (s, 6H),
4.92 (d, 2H, J = 15.06), 6.64 (d, 1H, J = 14.56 Hz), 7.00–
7.12 (m, 3H), 7.57–7.65 (m, 2H), 7.73–7.75 (m, 1H),
7.99–8.02 (m, 1H), 12.50 (br, s, 1H); Anal. Calcd for
C19H17BrN2OS: C, 56.86; H, 4.27; N, 6.98. Found: C,
NMR (400MHz, CDCl3) δ, ppm: 1.47 (s, 9H), 1.93 (quin,
2H, J=6.33Hz, J=12.74Hz, J=25.31Hz), 3.16 (d, 2H,
J= 5.62 Hz), 4.02 (t, 2H, J=6.42), 5.10–5.20 (br, s, 1H),
6.57 (s, 1H), 7.25–7.31 (m, 1H), 7.43 (d, 1H, J=7.82Hz),
7.76 (t, 1H, J=7.64Hz), 8.67–8.71 (m, 1H), 11.41–11.52
(br, s, 1H); Anal. Calcd for C17H22N4O3S: C, 56.33; H,
6.12; N, 15.46. Found: C, 56.48; H, 6.19; N, 15.63.
3-Cyclopropyl-(5Z)-5((1-methyl-1H-imidazol-2-ylmethylene))-
2-thioxoimidazolin-4-one (2b). Yellow solid, yield 43%, mp
56.98; H, 4.41; N, 7.34.
3-(3,4-Dimethylbenzyl)-(5Z)-5(pyridine-2-ylmethylene)-2-
thioxoimidazolin-4-one (2i). Yellow solid, yield 92%, mp
1
139–141°C; IR (KBr, cmÀ1): 3180 (br), 1737, 1650; H
156–158°C; IR (KBr, cmÀ1): 3185, 1729, 785; H NMR
1
NMR (400MHz, DMSO-d6)δ, ppm: 0.98–1.06 (m, 4Н),
2.77–2.89 (m, 1Н), 3.80 (s, 3Н), 6.57 (s, 1Н), 7.26 (s,
1Н), 7.39 (s, 1Н); Anal. Calcd for C11Н12N4SO* H2O: C,
49.62; H, 5.26; N, 21.05; S, 12.03. Found: C, 49.30; H,
(400MHz, DMSO-d6) δ, ppm: 2.18 (s, 6H), 4.95 (s, 2H),
6.77 (s, 1H), 7.02–7.12 (m, 3H), 7.37–7.43 (m, 1H), 7.73–
7.79 (m, 1H), 7.87–7.94 (m, 1H), 8.74–8.78 (m, 1H), 11.67–
11.95 (br, s, 1H); Anal. Calcd for C18H17N3OS: C, 66.85; H,
5.30; N, 12.99; S, 9.9. Found: C, 66.97; H, 5.41; N, 13.14.
3-(3,4-Difluorophenyl)-(5Z)-5(pyridine-2-ylmethylene)-2-
thioxoimidazolin-4-one (2j). Yellow solid, yield 85%, mp
4.51; N, 20.46; S, 11.87.
3-Cyclopropyl-(5Z)-5((1H-imidazol-2-yl)methylene-2-ylmethy
lene))-2-thioxoimidazolin-4-one (2c). Yellow solid, yield
1
190–192°C; IR (KBr, cmÀ1): 3178, 1781, 756; H NMR
61%, mp 159–161°C; IR (KBr, cmÀ1): 3170 (br), 1730,
1670, 1473; 1H NMR (400 MHz, DMSO-d6) δ, ppm:
0.97–1.07 (br, s, 4Н), 2.77–2.87 (m, 1Н), 6.36 (s, 1Н),
7.34 (s, 2Н); Anal. Calcd for C10Н10N4SO: C, 51.27; H,
(400 MHz, DMSO-d6) δ, ppm: 6.76 (s, 1H), 7.27–7.45
(m, 2H), 7.52–7.70 (m, 2H), 7.91 (s, 2H), 8.76 (s, 1H),
11.69–12.43 (br, s, 1H); Anal. Calcd for C15H9F2N3OS: C,
56.78; H, 2.86; N, 13.24. Found: C, 56.84; H, 2.98; N, 13.43.
4.30; N, 23.91. Found: C, 51.41; H, 4.43; N, 24.13.
3-(3,5-Dimethylphenyl)-(5Z)-5(pyridine-2-ylmethylene)-2-thioxoi
midazolin-4-one (2d). Yellow solid, yield 93%, mp 163–165°C;
3-(4-(Trifluoromethyl)phenyl)-(5Z)-5(4-bromobenzylidene-2-
ylmethylene)-2-thioxoimidazolin-4-one (2k).
Yellow solid,
yield 86%, mp 196–198°C; IR (KBr, cmÀ1): 3179, 1752;
1H NMR (400 MHz, CDCl3) δ ppm: 6.71 (s, 1H), 7.60
1
IR (KBr, cmÀ1): 3185, 1731, 770; H NMR (400 MHz,
DMSO-d6) δ, ppm: 2.32 (s, 6H), 6.79 (s, 1H), 7.00–7.05 (m,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Vol 000
O. Y. Kuznetsova, R. L. Antipin, A. V. Udina, O. O. Krasnovskaya, E. K. Beloglazkina,
V. I. Terenin, V. E. Koteliansky, N. V. Zyk, and A. G. Majouga
REFERENCES AND NOTES
(d, 2H, J =7.63 Hz), 7.68 (d, 2H, J = 8.02Hz), 7.91 (d, 2H,
[1] Kiec-Kononowicz, K.; Szymanska, E. Farmaco 2002, 57, 909.
[2] Sun, Y. Ding Ming-Wu; Phosphorus, Sulfur and Silicon 2003,
178, 2137–2145.
[3] Khodair, A. I. Phosphorus Sulfur Silicon 1997, 122, 9.
[4] Khodair, A. I.; El-Subbagh, H. I.; Al-Obaid, A. M. Phosphorus
Sulfur Silicon 1998, 140, 159.
[5] Curran, A, C. W. U. S. Pat. 1976, 3,984,430.
[6] Mehta, N.; Risiger, C. A.; Soroko, F. E. J Med Chem 1981, 24,
465.
[7] Albuquerque, M. C. P. A.; Silva, T. G.; Pitta, M. G. R.; Silva,
A. C. A.; Silva, P. G.; Malagueno, E.; Santana, J. V.; Wanderley, A. G.;
Lima, M. C. A.; Galdino, S. L.; Barbe, J.; Pitta, I. R. Pharmazie 2005,
60, 13.
[8] Ono, M.; Hayashi, S.; Matsumura, K.; Kimuru, H.; Okamoto, Y.;
Ihara, M.; Takahashi, R.; Mori, H.; Saji, H. ACS Chem Neurosci 2011, 2,
269.
[9] Knabe, J.; Ahlhem, A. Pharmazie 1997, 52, 912.
[10] Kiec-Kononowicz, K.; Karolak-Wojciechowska, J.; Michalak,
B.; Pekala, E.; Schumacher, B.; Muller C.E. Eur J Med Chem 2004, 39,
205.
[11] Ates-Alagoz, Z.; Altanlar, N.; Buyukbingol, E. J Heterocycl
Chem 2009, 46, 1375.
[12] Khodair, A. I. Carbohydr Res 2001, 331, 445.
[13] Kiec-Kononowicz, K.; Muller, C.E.; Pekala, E.; Karolak-
Wojciechowska, J.; Handzlik, J.; Lazewska, D. J Heterocycl Chem
2002, 39, 243.
J =8.61 Hz), 7.99 (d, 2H, J = 8.02Hz); Anal. Calcd for
C17H10BrF3N2OS: C, 47.79; H, 2.36; N, 6.56. Found: C,
47.85; H, 2.54; N, 6.78.
3-(4-(3-Morpholinopropyl)-(5Z)-5(pyridine-2-ylmethylene)-
2-thioxoimidazolin-4-one (2l).. Yellow solid, yield 81%,
1
mp 168–170°C; IR (KBr, cmÀ1): 3183, 1755; H NMR
(400 MHz, CDCl3) δ ppm: 1.94 (quin, 2H, J = 6.85Hz,
J =13.89 Hz, J = 27.78 Hz), 2.41–2.49 (m, 6H), 3.67 (t,
4H, J = 4.69Hz), 4.03 (t, 2H, J= 7.04Hz), 6.54 (s, 1H),
7.23–7.29 (m, 1H), 7.40 (d, 1H, J =7.83 Hz), 7.71–7.78
(m, 1H), 8.65–8.70 (m, 1H), 11.19–11.61 (br, s, 1H);
Anal. Calcd for C16H20N4O2S: C, 57.81; H, 6.06; N,
16.85. Found: C, 57.96; H, 6.15; N, 16.98.
3-(o-Tolyl)-(5Z)-5(cyclohexylmethylene)-2-thioxoimidazolin-4-one
(2p).
White solid, yield 28%, mp 214–218°C; IR (KBr,
cmÀ1): 3187, 1755, 1690; 1H NMR (400 MHz, DMSO-d6) δ,
ppm: 1.13–1.38 (m, 5H), 1.59–1.78 (m, 5H), 2.66–2.76 (m,
1H), 5.74 (d, 1H, J= 5.73 Hz), 7.18–7.25 (m, 1H), 7.27–7.41
(m, 4H), 12.35–12.52 (br, s, 1H); Anal. Calcd for
C17H20N2OS: C, 67.97; H, 6.71; N, 9.32. Found: C, 68.14;
H, 6.83; N, 9.48.
[14] Aly, Y. L. J Sulfur Chem 2007, 28, 371.
[15] Porwal, S.; Kumar, R.; Maulik, P.R. Chauhan Tetrahedron
Lett, 2006, 47, 5863.
[16] Floch, L.; Kovac, S. Collect Czech Chem Commun 1975, 40,
2845.
2-Cyclohexylidene-4-(2-methylphenyl)-5-thioxopyrrolidin-3-one
(2q). Yellow solid, yield 35%, mp 196–198°C; IR (KBr,
cmÀ1): 3182, 1693; 1H NMR (400MHz, DMSO-d6) δ,
ppm: 1.21–1.35 (m, 5H), 1.62–1.72 (m, 5H), 2.06 (c, 3H),
5.74 (d, 1H, J=5.72Hz), 7.21 (m, 1H), 7.35–7.45 (m, 3H);
Anal. Calcd for C16H18N2OS: C, 67.71; H, 6.29; N, 9.79.
Found: C, 67.98; H, 6.47; N, 9.98.
[17] Wheler, H. L.; Nicolet, B. H.; Johnson, T. B. Am Chem J
1911, 456.
[18] Fulmer, G. R.; Miller, A. J. M.; Sherden, N. H.; Gottlieb, H. E.;
Nudelman, A.; Stoltz, B. M.; Bercaw, J. E.; Goldberg, K. I. Organometallics,
2010, 29, 2176.
[19] Majouga, A. G.; Beloglazkina, E. K.; Vatsadze, S. Z.; Frolova,
N. A.; Zyk, N. V. Russian Chem Bull Int Edn 2004, 53, 2850.
[20] Majouga, A. G.; Udina, A. V.; Beloglazkina, E. K.; Skvortsov,
D. A.; Zvereva, M. I.; Dontsova, O. A.; Zyk, N. V.; Zefirov, N. S. Tetra-
hedron Lett 2012, 53, 51.
Acknowledgments. We are thanking RSF (14-34-00017), financial
support in part from the Ministry of Education and Science of the
Russian Federation in the framework of Increase Competitiveness
Program of NUST “MISiS” (No. K1-2014-022).
[21] Beloglazkina, E. K.; Kuznetsova, O. Y.; Majouga, A. G.;
Moiseeva, A. A.; Zyk, N. V. Mendeleev Commun 2014, 24, 37.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet