Synthesis, study of the structure, and modification of the products of the reaction of 4-aryl-4-oxobut-2-enoic acids with thiourea

Article abstract of DOI:10.1007/s10593-020-02798-y

[Figure not available: see fulltext.] A number of previously undescribed derivatives of 2-amino-5-(2-aryl-2-oxoethyl)thiazol-4(5H)-one containing electron-donating substituents in the aromatic ring were synthesized by the reaction of (E)-4-aryl-4-oxobut-2

Full text of DOI:10.1007/s10593-020-02798-y

DOI 10.1007/s10593-020-02798-y
Chemistry of Heterocyclic Compounds 2020, 56(9), 1202–1209
Synthesis, study of the structure, and modification of the products of the
reaction of 4-aryl-4-oxobut-2-enoic acids with thiourea
Nadezhda N. Kolos1*, Nikolai V. Nazarenko1, Svetlana V. Shishkina1,2,
Andrey O. Doroshenko1, Elena G. Shvets1, Maksim A. Kolosov1, Fedor G. Yaremenko2
1 V. N. Karazin Kharkiv National University,
4 Svobody Sq., Kharkiv 61022, Ukraine; е-mail: kolos_n@ukr.net
2 State Scientific Institution '"'Institute for Single Crystals'',
National Academy of Sciences of Ukraine,
60 Nauky Ave., Kharkiv 61001, Ukraine
Translated from Khimiya Geterotsiklicheskikh Soedinenii,
2020, 56(9), 1202–1209
Submitted June 1, 2020
Accepted August 10, 2020
A number of previously undescribed derivatives of 2-amino-5-(2-aryl-2-oxoethyl)thiazol-4(5H)-one containing electron-donating
substituents in the aromatic ring were synthesized by the reaction of (E)-4-aryl-4-oxobut-2-enoic acids with thiourea. Reduction of the
reaction products with NaBH4 yielded diastereomeric alcohols, whereas bromination in AcOH was accompanied by elimination of HBr
and the formation of (Z)-2-amino-5-(2-aryl-2-oxoethylidene)thiazol-4(5H)-ones.
Keywords: 2-amino-5-(2-aryl-2-oxoethyl)thiazol-4(5H)-ones, 4-aryl-4-oxobut-2-enoic acids, thiourea, cyclocondensation, oxidative
bromination, reduction.
Derivatives of thiazolidin-4-ones exhibit various
physiological activity:1–3 analgesic and anti-inflammatory
drugs,4–6 fungicides,7 inhibitors of cyclooxygenase-2,8
anticancer and antiviral agents2,9,10 were found among
them. Synthetic approaches to 2-amino(imino)thiazolidin-
4-ones are based, as a rule, on the reactions of thiourea and
its derivatives with bielectrophilic reagents.4,7,11–14 Thus,
the reaction of 4-aryl-4-oxobut-2-enoic acids with thioureas
is a very convenient method for the formation of the
thiazolidine ring.15–20
Despite the fact that cyclocondensation of 3-benzoyl-
acrylic acid with thiourea was first carried out as early as in
1947,15 the structure of the molecules of the resulting
compounds has been a subject of discussion until recently.
Thus, the authors of studies describing the formation of
thiazol-4(5Н)-ones A in the reactions of 3-aroylacrylic
acids with thioureas by heating under reflux in EtOH with
additions of catalytic amounts of AcOH (Fig. 1)16,17
postulate the existence of the keto-enol equilibrium
with the participation of the endocyclic carbonyl group.
The formation of imino form B has been described
elsewhere,18–20 and the imino form becomes the only one
possible when N,N'-disubstituted thioureas are used in such
condensations.21 At the same time, heating the starting
reagents in AcOH under reflux leads to tetrahydro-
pyrimidine-2-thione22 or, when the reaction is carried out in
MeOH in the presence of EtONa, to its aromatized analog
C.23 Data from early studies,24,25 the authors of which
postulated the formation of thiohydantoins D, have been
convincingly refuted in later studies.
NH2
N
NH
NH
O
S
O
S
Ar
Ar
Ar
O
O
B
A
O
OH
NH
S
O
HN
NH
Ar
N
C
S
O
D
Figure 1. Structures of cyclocondensation products of 3-aroyl-
acrylic acids with thiourea proposed in the literature.
0009-3122/20/56(9)-1202©2020 Springer Science+Business Media, LLC
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Chemistry of Heterocyclic Compounds 2020, 56(9), 1202–1209
It is known that the first step of the reaction of
3-aroylacrylic acids with nucleophiles is the attack at the
α-position to the activated double bond with the formation
of Michael adducts, which is due to the higher electron-
withdrawing properties of the carbonyl group as compared
to the carboxy group.26–30 A similar mechanism follows
from the ease of formation of α-adducts in the reactions
with thiols and amines. For example, when 3-aroylacrylic
acids react with 1,3-diazine-2(1H)-thione derivatives,
which are formally cyclic thiourea derivatives, a Michael
adduct is always formed at the sulfur atom31 and not at the
endocyclic nitrogen atom, which is logically consistent
with the scale of nucleophilicity.
The aim of this work was to synthesize novel derivatives
of thiazol-4(5Н)-ones 3с–h as well as previously described
products 3a,b based on 4-aryl-4-oxobut-2-enoic acids 1а–h
and thiourea (2) and reliably establish their structures
(Scheme 1). The use in the reaction of 3-aroylacrylic acids
1а–h containing donor groups in the aromatic ring is due to
their higher synthetic availability. The target compounds
3а–h were obtained in good yields according to the well-
known literature methods: by heating the starting reagents
in glacial AcOH under reflux.14–18
Scheme 1
Figure 2. Molecular structure of compounds 3a and 4а according
to X-ray structural analysis data. Atoms are represented as
thermal vibration ellipsoids with 50% probability.
(amide), and C=O (ketone) groups. Thus, thiazol-4(5H)-
ones 3а–h, exist in the 2-amine tautomeric form according
to the obtained spectral data.
The X-ray structural study of compound 3а and its
reduced form 4а, the synthesis of which is described
below, was an additional confirmation of this fact (Fig. 2).
Two molecules of compound 3a (3aA and 3aB) were found
in the symmetrically independent part of the unit cell. The
reduced form of alcohol 4а exists in the solid state as a mono-
hydrate. An analysis of the bond lengths in these molecules
revealed a significant delocalization of the electron density
in the conjugated О(1)–С(1)–N(1)=C(3)–N(2) fragment.
The coordinates of the hydrogen atoms of the amino group
were revealed from the difference electron density
synthesis; their presence confirms the existence of
compounds 3а and 4а in the solid state in the amine
tautomeric form. At the same time, the formally single
exocyclic bond C(3)–N(2) turned out to be shorter than the
formally double bond N(1)–C(3) (Table 1) in molecules
3аB and 4а, in contrast to molecule 3аA, in which
conjugation in the О(1)–С(1)–N(1)=C(3)–N(2) fragment is
less pronounced. Based on such redistribution of electron
density, the structure of molecules 3aB and 4a can be
described as a superposition of two resonance structures,
neutral and zwitterionic (Scheme 2).
The synthesized products 3а–h are white powders with
low solubility in organic solvents. Their structure was
1
confirmed by IR, H, 13C NMR spectroscopy and mass
spectrometry. Noteworthy is the absence in the IR spectra
of absorption bands of stretching vibrations of the primary
amino group in the range of 3200–3500 cm–1, although a
band of variable intensity is observed in the 3200 cm–1
region. This absorption pattern may be due to the ability of
the molecules of cyclic amidines (2-aminoazolines and
2-aminoazines) to dimerize as a result of the formation of
short hydrogen contacts N–H···N between amidine
fragments.32 Mass spectra of compounds 3а–h are
characterized by the presence of a peak of the molecular
ion with low or medium intensity. The main direction of
fragmentation involves the elimination of the aroyl radical,
followed by the destruction of the thiazoline ring. In the
1H NMR spectra of products 3а–h, two broadened signals
of the amino group protons are observed at 8.72–8.78 and
8.93–9.01 ppm, which indicates hindered rotation of the
amino group. The 13C NMR spectra of compounds 3а–h
contain signals of the carbon atoms of the imine, C=O
The electron density distribution in the partially
hydrogenated aminothiazolone fragment of a molecule of
type 3 simulated by the density functional theory (DFT)
method fully corresponds to the resonance structure shown
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Chemistry of Heterocyclic Compounds 2020, 56(9), 1202–1209
Table 1. Selected bond lengths (Å) in molecules 3а and 4а
further biological screening. For this purpose, the reduction
of the carbonyl group was carried out. The reduction of the
carbonyl group of compounds 3а–c with NaBH4 in MeOH
gave the corresponding alcohols 4а–c in the form of
mixtures of two diastereomers with different relative
spatial orientations of the hydroxy group and the 5-СН
proton of the heterocycle (Scheme 3). According to the
according to X-ray structural analysis data
Molecule
Bond
Mean
3аА
3аВ
4а
С(1)–О(1)
C(1)–N(1)
N(1)–C(3)
C(3)–N(2)
1.213(6)
1.227(6)
1.225(8)
1.210
1.376
1.313
1.336
1.355(7)
1.307(6)
1.320(8)
1.337(7)
1.342(6)
1.298(8)
1.337(8)
1.325(7)
1.292(7)
1
data of H NMR spectroscopy, they are present in a 2:1
ratio, which may be due to different solubility during
recrystallization from a MeOH – H2O mixture.
To explain the violation of the expected equimolar ratio
of diastereomeric pairs, we performed quantum-chemical
modeling of the structure of the R,R- and R,S-isomers of
compound 4а which are formed upon reduction of the
carbonyl group of the R-enantiomer of compound 3а.
Another diastereomeric pair, S,R and S,S, have similar
characteristics. Both structures are characterized by the
presence of a strong intramolecular hydrogen bond
OH···O=C which is facilitated by the excess electron
density on the carbonyl oxygen atom (see above). The
energy of the discussed hydrogen bond, estimated within
the framework of R. Bader's theory of atoms in molecules
according to the recommendations,33 was 10–11 kcal/mol.
in Scheme 2: the negative charge on the amino nitrogen
atom is significantly decreased in absolute value, whereas
it is increased on the nitrogen atom of the thiazole ring and
carbonyl oxygen atom (see the calculated Mulliken charges
on the corresponding atoms in Scheme 2).
Scheme 2
–0,0474
NH2
NH2
S
S
–0,2019
N
N
R
R
O
O
–0,2189
Table 2. Geometric characteristics of intermolecular hydrogen
bonds in the solid state of compounds 3а and 4а
In the solid state, compound 3а exists in the form of
centrosymmetric dimers of the А–А and В–В types due to
N(2A)–H···N(1A) and N(2B)–H···N(1B) intermolecular
hydrogen bonds (Fig. 3). The dimers, in turn, are linked by
intermolecular hydrogen bonds N(2A)–H···O(1B) and
N(2B)–H···O(1A), forming chains along the crystallo-
graphic direction [0 1 0].
In the solid state, the molecules of compound 4a form
zigzag chains along the crystallographic direction [0 1 0]
due to the intermolecular hydrogen bond N(2)–H···N(1)
(Table 2). H2O molecules included in the crystal cell of
compound 4а are located between the chains and form
hydrogen bonds N(2)–H···O(1W), O(2)–H···O(1W),
O(1W)–H···O(1), and O(1W)–H···O(2) (Table 2).
Angle
Symmetry
operation
Length of
bond Н···А, Å
Hydrogen bond
D–H···A,
deg
Structure 3а
x, y, z
N(2A)–H···N(1B) 3 – x, 1 – y, 1 – z
N(2A)–H···O(1B)
1.95
2.09
2.08
1.96
163
169
173
166
N(2B)–H···N(1B)
N(2B)–H···O(1A)
2 – x, –y, 1 – z
x – 1, y – 1, z
Structure 4а
N(2)–H···O(1W) 0.5 + x, 1.5 – y, 1 – z
2.17
2.03
1.97
1.87
1.92
157
170
162
162
170
N(2)–H···N(1)
O(2)–H···O(1W)
O(1W)–H···O(1)
O(1W)–H···O(2)
1.5 – x, –0.5 + y, z
x, y – 1, z
x, y, z
0.5 – x, 0.5 + y, z
As noted earlier, the synthesized products 3а–h have
limited solubility in polar organic solvents, so we decided
to increase their solubility by modifying the structure for
Figure 3. Packing of molecules of compounds 3а (left) and 4а (right) in the solid state.
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Chemistry of Heterocyclic Compounds 2020, 56(9), 1202–1209
Scheme 3
It should be noted that the R,S-isomer turned out to be
somewhat more sterically hindered in comparison with the
R,R-isomer (Fig. 4) which led to a slightly higher energy
advantage of the latter, especially in solvents of higher
polarity. According to our DFT calculations in the PCM
approximation, the difference in the energies of the R,R-
and R,S-isomers in MeOH (in which the reduction of
compound 3а was carried out) is only 0.175 kcal/mol,
which nevertheless leads to the ratio of R,R/R,S ≈ 57:43
(according to Arrhenius). The deviation of the calculated
value from the value determined experimentally from the
1H NMR spectrum can be caused both by the disregard in
computer modeling of specific intermolecular interactions,
which play an important role for solutions in proton-donor
methanol, and by the different solubility of diastereomers.
Bromination of compounds 3а,b,e,f was carried out in
AcOH. It was assumed that the bromination of products of
type 3 would lead to the formation of the corresponding
α-bromocarbonyl derivatives, convenient two-carbon
synthons in the synthesis of five- and six-membered
heterocycles. It turned out that the reaction practically
cannot be stopped at the step of the formation of the
vinylene proton appears in the 7.65–7.90 ppm range,
whereas the signals of the protons of amino groups are
shifted downfield. In the 13C NMR spectra, the signals of
the carbon atoms of the double bond in the sp2-hybridized
state are recorded. The signals of the carbon atoms of the
imine, amide, and carbonyl groups are shifted upfield,
which indicates the presence of π-conjugation in the
system. The fragmentation pattern in the mass spectra of
ketones 5а–d is similar to that for thiazol-4(5Н)-ones 3a–h.
The question of the spatial configuration of 2-amino-
5-(2-aryl-2-oxoethylidene)thiazol-4(5H)-ones 5а–d was
difficult to solve using available physical research methods.
The use of NOE is impossible due to the absence of
spatially close hydrogen atoms in the studied molecule: the
distance between the vinylidene proton and the protons of
the amino group in position 2 of the thiazole ring is ~5 Å
and more.
This problem was solved using the methods of computer
simulation of molecule 5a by optimizing its molecular
geometry by the DFT method (B3LYP/cc-pVDZ, vacuum).
The initial approximation for both calculations was set flat,
the optimization was carried out without imposing
restrictions on the admissible ranges of bond lengths, bond
and torsion angles. In the initial planar E-configuration, the
oxygen atoms of the exo- and endocyclic carbonyl groups
turned out to be close to each other at a distance less than
the sum of their van der Waals radii; as a result, the
increased steric hindrances were eliminated by turning the
benzoyl fragment around the C–C single bond connecting
it with the methylidene group. Thus, the calculations
predicted a substantially nonplanar structure for the
E-isomer, making it energetically unfavorable compared to
the Z-isomeric form, which has a planar structure. The
calculated energy difference was about 11 kcal/mol, which
made it possible to exclude with a high probability the
formation of the E-configuration under the reaction
conditions.
α-bromo derivative, since dehydrobromination is
a
competing process in the reaction mixture. To obtain
individual compounds, the reaction mixture, after the
addition of a Br2 solution, was additionally heated under
reflux in AcOH, which made it possible to obtain yellow
5-arylethylidenediazol-4(5Н)-ones 5а–d in good yields
(Scheme 3). Note that even under the conditions of an
excess of Br2, no further bromination of the double bond in
products 5а–d under the described experimental conditions
was observed. The process of oxidative bromination was
previously described by us for 3-(2-aryl-2-oxoethyl)-3,4-di-
hydroquinoxalin-2(1H)-ones, the products of the reaction
of 3-aroylacrylic acids with o-phenylenediamine.34
The structure of ketones 5а–d is convincingly confirmed
1
by spectral characteristics. In the H NMR spectra of these
products, the typical ABX system of signals for the protons
of the thiazoline fragment disappears, but a signal for the
Similar conclusions were reached somewhat earlier by
other researchers who studied the benzylidene derivative of
Figure 4. The structure of the molecules of R,R- (left) and R,S-isomers (right) of compound 4а as calculated according to the B3LYP/cc-pVDZ
method. Shown are the critical points (–3, 1) of chemical bonds, estimated within the framework of R. Bader's atoms in molecules theory.
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Chemistry of Heterocyclic Compounds 2020, 56(9), 1202–1209
thiazolidin-4-one.10 Despite the absence of an exocyclic
3190, 1668 (C=O), 1607, 1490, 1383, 1356, 1284, 1222,
1
carbonyl group, the Z-configuration turned out to be more
preferable.
1175, 1138, 814. H NMR spectrum, δ, ppm (J, Hz): 2.38
2
3
(3Н, s, CH3); 3.45 (1H, dd, J = 18.7, J = 10.9) and 3.91
3
3
Thus, we have established that 5-substituted thiazol-4(5H)-
ones obtained from 3-aroylacrylic acids and thiourea exist
mainly in the 2-amine tautomeric form in solutions and in
the solid state. It was shown that the reduction of the
starting thiazol-4(5H)-ones with sodium borohydride forms
a mixture of diastereomeric alcohols in a 2:1 ratio, and
bromination in AcOH leads to 2-amino-5-(2-aryl-2-oxo-
ethylidene)thiazol-4(5H)-ones existing in the Z-configura-
tion, according to quantum-chemical modeling.
(1H, dd, 2J = 18.7, J = 3.0, CH2); 4.40 (1H, dd, J = 10.8,
3J = 3.0, CH); 7.34 (2Н, d, J = 8.1, H Ar); 7.88 (2Н, d,
J = 8.1, H Ar); 8.78 (1Н, br. s) and 9.00 (1Н, br. s, NH2).
13C NMR spectrum, δ, ppm: 21.7 (CH3); 43.1 (CH2); 51.2
(CH); 128.7, 129.8, 133.8, 144.6 (C Ar); 182.9 (C=N);
189.7 (C=O); 197.7 (C=O). Mass spectrum, m/z (Іrel, %):
248 [M]+ (31), 129 [M–ArCO]+ (100), 119 [ArCO]+ (64),
91 (47), 87 (23). Found, %: C 58.13; H 4.85; N 11.19.
C12H12N2O2S. Calculated, %: C 58.05; 4.87; N 11.28.
2-Amino-5-[2-(2,4-dimethylphenyl)-2-oxoethyl]thiazol-
4(5Н)-one (3c). Yield 1.39 g (53%), white powder, mp 224–
225°С (decomp., AcОН). IR spectrum, ν, cm–1: 3242,
2965, 1668 (C=O), 1609, 1495, 1391, 1269, 1218, 1147,
Experimental
IR spectra were registered on an Agilent Technologies
Cary 630 FT-IR spectrometer by the diffuse reflectance
1
1
technique in KBr pellets. H and 13C NMR spectra were
988, 823, 743. H NMR spectrum, δ, ppm (J, Hz): 2.29
2
acquired on a Varian MR-400 spectrometer (400 and
100 MHz, respectively) in DMSO-d6, with TMS as internal
standard. The assignment of signals of carbon atoms in the
13C NMR spectra was carried out according to a published
method.35 Mass spectra of compounds were recorded on a
Finnigan МАТ INCOS-50 mass spectrometer (EI
ionization, 70 eV). Elemental analysis was performed on a
EuroVector EA 3000 CHNS-analyzer. Melting points were
determined on a Kofler bench and are uncorrected.
Monitoring of the reaction progress and assessment of the
purity of synthesized compounds were done by TLC on
Silufol UV-254 plates, eluent СHCl3–MeOH, 9:1,
visualization with a phosphomolybdic acid solution in
2-PrOH.
(3Н, s, CH3); 2.38 (3Н, s, CH3); 3.37 (1H, dd, J = 18.4,
3J = 10.7) and 3.79 (1H, dd, 2J = 18.4, 3J = 3.2, CH2); 4.34
3
3
(1H, dd, J = 10.7, J = 3.2, CH); 7.09 (1H, s, H Ar); 7.11
(1Н, d, J = 8.4, H Ar); 7.75 (1Н, d, J = 8.4, H Ar); 8.74
(1Н, br. s) and 8.98 (1Н, br. s, NH2). 13C NMR spectrum,
δ, ppm: 21.4 (CH3); 21.7 (CH3); 45.4 (CH2); 51.5 (CH);
127.1, 130.2, 133.0, 133.9, 138.4, 142.6 (C Ar); 182.9 (C=N);
189.7 (C=O); 198.1 (C=O). Mass spectrum, m/z (Irel, %):
262 [M]+ (26), 133 [ArCO]+ (100), 129 [M–ArCO]+ (62), 105
(35), 87 (15), 79 (6). Found, %: C 59.41; H 5.30; N 10.43.
C13H14N2O2S. Calculated, %: C 59.52; H 5.38; N 10.68.
2-Amino-5-[2-(3,4-dimethylphenyl)-2-oxoethyl]thiazol-
4(5Н)-one (3d). Yield 1.97 g (75%), white powder, mp 243–
244°С (decomp., AcОН). IR spectrum, ν, cm–1: 3250,
2970, 1670 (C=O), 1607, 1504, 1445, 1409, 1373, 1279,
3-Aroylacrylic acids 1a–h were synthesized according
1
to literature methods.36
1208, 1117, 824, 751. H NMR spectrum, δ, ppm (J, Hz):
2
3
Synthesis of 2-amino-5-(2-aryl-2-oxoethyl)thiazol-
4(5Н)-ones 3a–h (General method). A mixture of acid 1a–h
(0.01 mol) and thiourea (2) (0.01 mol) in glacial AcOH
(10–15 ml) was heated under reflux for 0.5–1 h (the
reaction mixture became turbid, TLC control). After
cooling to room temperature, the formed precipitate was
filtered, washed with AcOH, then with MeOH (2×10 ml),
and dried.
2.26 (6H, s, 2CH3); 3.42 (1H, dd, J = 18.8, J = 11.0) and
2 3
3.88 (1H, dd, J = 18.8, J = 3.0, CH2); 4.37 (1H, dd,
3
3J = 11.0, J = 3.0, CH); 7.27 (1H, d, J = 7.9, H Ar); 7.69
(1H, d, J = 7.8, H Ar); 7.75 (1H, s, H Ar); 8.77 (1Н, br. s)
and 9.01 (1Н, br. s, NH2). 13C NMR spectrum, δ, ppm: 19.7
(CH3); 20.1 (CH3); 43.1 (CH2); 51.2 (CH); 126.2, 129.5,
130.3, 134.1, 137.3, 143.4 (C Ar); 182.8 (C=N); 189.7
(C=O); 197.8 (C=O). Mass spectrum, m/z (Irel, %): 262 [M]+
(30), 133 [ArCO]+ (100), 129 [M–ArCO]+ (70), 105 (37),
87 (15), 79 (18). Found, %: C 59.38; H 5.21; N 10.55.
C13H14N2O2S. Calculated, %: C 59.52; H 5.38; N 10.68.
2-Amino-5-[2-(2,5-dimethylphenyl)-2-oxoethyl]thiazol-
4(5Н)-one (3e). Yield 2.04 g (78%), white powder, mp 179–
2-Amino-5-(2-oxo-2-phenylethyl)thiazol-4(5Н)-one (3a).
Yield 1.56 g (67%), white powder, mp 240–241°С
(decomp., AcОН) (mp 221°С,15 mp >300°С20). IR spect-
rum, ν, cm–1: 3242, 2943, 1674 (C=O), 1488, 1387, 1287,
1
1215, 1141, 755, 685. H NMR spectrum, δ, ppm (J, Hz):
1
3.47 (1H, dd, 2J = 18.8, 3J = 10.8) and 3.92 (1H, dd, 2J = 18.8,
3J = 3.0, CH2); 4.38 (1H, dd, 3J = 10.8, 3J = 3.0, CH); 7.51
(2H, t, J = 7.8, H Ph); 7.63 (1H, t, J = 7.3, H Ph); 7.95 (2H,
d, J = 8.0, H Ph); 8.75 (1H, br. s) and 8.97 (1H, br. s, NH2).
13C NMR spectrum, δ, ppm: 47.9 (CH2); 55.9 (CH); 133.2,
134.0, 138.8, 141.0 (C Ph); 182.8 (C=N); 190.3 (C=O); 198.0
(C=O). Mass spectrum, m/z (Іrel, %): 234 [M]+ (24), 129
[M–PhCO]+ (100), 105 [PhCO]+ (64), 87 (22), 77 (50).
Found, %: C 56.22; H 4.15; N 11.86. C11H10N2O2S.
Calculated, %: C 56.40; H 4.30; N 11.96.
180°С (2-PrOH). H NMR spectrum, δ, ppm (J, Hz): 2.28
2
(3Н, s, CH3); 2.32 (3Н, s, CH3); 3.37 (1H, dd, J = 18.6,
3J = 10.6) and 3.78 (1H, dd, 2J = 18.6, 3J = 3.2, CH2); 4.34
3
3
(1H, dd, J = 10.6, J = 3.2, CH); 7.15 (1H, d, J = 7.8,
H Ar); 7.23 (1H, d, J = 7.8, H Ar); 7.64 (1H, s, H Ar); 8.74
(1Н, br. s) and 8.97 (1Н, br. s, NH2). 13C NMR spectrum,
δ, ppm: 20.9 (CH3); 21.0 (CH3); 45.7 (CH2); 51.4 (CH);
130.1, 132.1, 132.9, 134.8, 135.7, 136.8 (C Ar); 182.9
(C=N); 189.7 (C=O); 198.8 (C=O). Mass spectrum, m/z
(Irel, %): 262 [M]+ (30), 133 [ArCO]+ (97), 129 [M–ArCO]+
(100), 105 (52), 87 (22), 79 (20). Found, %: C 59.48;
H 5.27; N 10.48. C13H14N2O2S. Calculated, %: C 59.52;
H 5.38; N 10.68.
2-Amino-5-[2-oxo-2-(p-tolyl)ethyl]thiazol-4(5Н)-one
(3b). Yield 1.96 g (79%), white powder, mp 243–244°С
(decomp., AcОН) (mp 250°С22). IR spectrum, ν, cm–1: 3238,
1206

Chemistry of Heterocyclic Compounds 2020, 56(9), 1202–1209
2-Amino-5-[2-(4-ethylphenyl)-2-oxoethyl]thiazol-4(5Н)-
(MeOH–H2O, 1:1). IR spectrum, ν, cm–1: 3550 (ОН), 3235,
3013, 1647, 1529, 1383, 1273, 1142, 1057, 769, 729, 700.
1H NMR spectrum, δ, ppm (J, Hz): 1.76–1.92 (1H, m) and
one (3f). Yield 1.38 g (53%), white powder, mp 257–
258°С (decomp., AcОН). IR spectrum, ν, cm–1: 3246,
2962, 1670 (C=O), 1607, 1491, 1383, 1308, 1282, 1219,
3
2.44–2.54 (1H, m, CH2); 4.03 (0.33H, dd, J = 10.6,
1
1175, 1136, 993, 832, 752. H NMR spectrum, δ, ppm
3J = 2.8, CH B); 4.20 (0.67H, dd, 3J = 10.6, 3J = 2.8, CH A);
4.62 (0.65Н, dt, J = 8.1, J = 4.0, CHOH А); 4.74 (0.35H,
dt, J = 8.2, J = 4.0, CHOH В); 5.19 (0.34H, d, J = 3.2,
ОН В); 5.57 (0.66H, d, J = 3.2, ОН А); 7.25–7.34 (5H, m,
H, Ph); 8.71–8.90 (2Н, m, NH2). 13C NMR spectrum,
δ, ppm: 44.4 (CH2 В); 44.1 (CH2 А); 53.6 (CH); 72.0
(CHOH А); 72.1 (СНОН В); 126.3, 127.6, 128.6, 145.3
(C Ph); 182.5 (C=N В); 183.1 (C=N А); 190.4 (С=О).
Mass spectrum, m/z (Irel, %): 236 [M]+ (52), 219 (32), 156
(38), 151 (85), 129 (85), 97 (11), 87 (67). Found, %:
C 55.70; H 5.27; N 11.62. C11H12N2O2S. Calculated, %:
C 55.92; H 5.12; N 11.86.
(J, Hz): 1.15 (3H, t, J = 7.6, CH2CH3); 2.63 (2H, q, J = 7.6,
CH2CH3); 3.42 (1H, dd, 2J = 18.8, 3J = 11.0) and 3.88 (1H,
2
3
3
dd, J = 18.8, J = 3.0, CH2); 4.36 (1H, dd, J = 11.0,
3J = 3.0, CH); 7.32 (2H, d, J = 8.3, H Ar); 7.86 (2H, d,
J = 8.3, H Ar); 8.74 (1H, br. s) and 8.96 (1H, br. s, NH2).
13C NMR spectrum, δ, ppm: 15.7 (CH2CH3); 28.7
(CH3CH2); 43.1 (CH2); 51.2 (CH); 128.7, 128.8, 134.0,
150.6 (C Ar); 182.9 (C=N); 189.6 (C=O); 197.7 (C=O).
Mass spectrum, m/z (Irel, %): 262 [M]+ (34), 133 [ArCO]+
(98), 129 [M–ArCO]+ (100), 105 (61), 87 (63), 79 (5).
Found, %: C 59.48; H 5.35; N 10.80. C13H14N2O2S.
Calculated, %: C 59.52; H 5.38; N 10.68.
2-Amino-5-[2-hydroxy-2-(p-tolyl)ethyl]thiazol-4(5Н)-
ones (4b). Yield 1.22 g (49%), white powder, mp 209–
210°С (MeOH–H2O, 1:1). IR spectrum, ν, cm–1: 3553
(OH), 3239, 3026, 1650, 1489, 1377, 1281, 1138, 1059,
2-Amino-5-[2-(4-ethoxyphenyl)-2-oxoethyl]thiazol-
4(5Н)-one (3g). Yield 1.97 g (71%), white powder, mp 233–
235°С (decomp., AcОН). 1H NMR spectrum, δ, ppm
(J, Hz): 1.31 (3H, t, J = 6.9, CH3CH2); 3.39 (1H, dd,
1
813, 754, 719. H NMR spectrum, δ, ppm (J, Hz): 1.72–
3
2
3
2J = 18.6, J = 10.8) and 3.84 (1H, dd, J = 18.6, J = 3.2,
1.90 (1H, m, CH2); 2.30 (3H, s, CH3); 2.40–2.50 (1H, m,
CH2); 3.98 (0.34H, d, J = 8.4, CH B); 4.18 (0.67H, d,
J = 8.4, CH A); 4.57–4.62 (0.67H, m, CHOH A); 4.69–
4.73 (0.33Н, m, CHOH B); 5.42 (0.67H, d, J = 3.2, ОН A);
5.47 (0.33Н, d, J = 3.2, ОН B); 7.14 (2Н, d, J = 7.8, Н Ar);
7.22 (2Н, d, J = 7.8, Н Ar); 8.66 (1Н, br. s) and 8.90 (1Н,
br. s, NH2). 13C NMR spectrum, δ, ppm: 21.2 (CH3); 44.1
(CH2 B); 44.5 (CH2 A); 53.6 (CH); 71.8 (СНОН В); 71.9
(СНОН A); 126.3, 129.2, 136.5, 142.3 (C Ar); 183.0 (C=N
B); 182.5 (C=N A); 190.4 (C=O). Mass spectrum, m/z
(Irel, %): 250 [M]+ (31), 233 (42), 135 (27), 129 (22), 116
(100), 93 (26), 91 (32). Found, %: C 57.40; H 5.49;
N 11.10. C12H14N2O2S. Calculated, %: C 57.58; 5.64;
N 11.19.
CH2); 4.10 (2H, q, J = 6.9, CH2CH3); 4.35 (1H, dd,
3
3J = 10.8, J = 3.2, CH); 6.99 (2H, d, J = 8.0, H Ar); 7.91
(2H, d, J = 8.0, H Ar); 8.72 (1H, br. s) and 8.93 (1H, br. s,
NH2). 13C NMR spectrum, δ, ppm: 15.0 (CH2CH3); 42.9
(CH2); 51.3 (CH); 64.1 (OCH2CH3); 114.8, 129.0, 130.9,
163.3 (C Ar); 182.9 (C=N); 189.8 (C=O); 196.4 (C=O).
Mass spectrum, m/z (Irel, %): 278 [M]+ (45), 149 [ArCO]+
(88), 129 [M–ArCO]+ (100), 121 (90), 93 (24), 87 (24).
Found, %: C 56.06; H 5.15; N 9.89. C13H14N2O3S.
Calculated, %: C 56.10; H 5.07; N 10.07.
2-Amino-5-{2-[(4-methylsulfanyl)phenyl]-2-oxoethyl}-
thiazol-4(5Н)-one (3h). Yield 2.40 g (86%), white powder,
mp 255–256°С (decomp., AcОН). IR spectrum, ν, cm–1:
3256, 2988, 1674 (C=O), 1591, 1509, 1382, 1275, 1219,
1186, 1129, 1096, 991, 820, 753. 1H NMR spectrum,
δ, ppm (J, Hz): 2.47 (3H, s, SCH3); 3.41 (1H, dd, 2J = 18.7,
2-Amino-5-[2-(4-ethylphenyl)-2-hydroxyethyl]thiazol-
4(5H)-ones (4c). Yield 1.16 g (44%), white powder,
mp 204–205°С (MeOH–H2O, 1:1). IR spectrum, ν, cm–1:
3554 (OH), 3240, 3024, 2961, 1650, 1491, 1379, 1284, 1138,
3
3J = 10.8) and 3.86 (1H, dd, 2J = 18.7, J = 2.9, CH2); 4.35
3
3
1
(1H, dd, J = 10.8, J = 2.9, CH); 7.33 (2Н, d, J = 8.0,
H Ar); 7.86 (2Н, d, J = 8.0, H Ar); 8.73 (1Н, br. s) and 8.96
(1Н, br. s, NH2). 13C NMR spectrum, δ, ppm: 14.3 (SCH3);
42.9 (CH2); 51.1 (CH); 125.3, 129.0, 132.3, 146.5 (C Ar);
182.8 (C=N); 189.7 (C=O); 197.1 (C=O). Mass spectrum,
m/z (Irel, %): 280 [M]+ (61), 156 (38), 151 [ArCO]+ (85),
129 [M–ArCO]+ (85), 97 (11), 87 (67). Found, %: C 51.28;
H 4.43; N 9.67. C12H12N2O2S2. Calculated, %: C 51.41;
H 4.31; N 9.99.
1060, 830, 744. H NMR spectrum, δ, ppm (J, Hz): 1.16
(3H, t, J = 7.6, CH2CH3); 1.74–1.91 (1H, m) and 2.41–2.51
(1H, m, CH2); 2.58 (2H, q, J = 7.6, CH2CH3); 3.98–4.01
(0.34H, m, CH B); 4.18–4.22 (0.68H, m, CH A); 4.57–4.62
(0.67H, m, CHОН A); 4.67–4.71 (0.33H, m, CHОН B);
5.43 (0.33H, d, J = 2.8, OH B); 5.48 (0.67H, d, J = 2.8,
OH A); 7.17 (2H, d, J = 7.8, Н Ar); 7.25 (2H, d, J = 7.8,
H Ar); 8.70 (1H, br. s) and 8.95 (1H, s, NH2). 13C NMR
spectrum, δ, ppm: 16.1 (CH2CH3); 28.3 (CH2CH3); 44.0
(CH2 B); 44.4 (CH2 A); 53.7 (CH B); 53.8 (CH A); 71.8
(СНОН В); 71.9 (СНОН В); 126.3, 128.0, 142.5, 143.0
(C Ar); 182.5 (C=N B); 183.0 (C=N A); 190.3 (C=O).
Mass spectrum, m/z (Irel, %): 264 [M]+ (32), 247 (28), 149
(31), 135 (17), 116 (100), 97 (13), 91(12). Found, %:
C 59.28; H 6.19; N 10.36. C13H16N2O2S. Calculated, %:
C 59.07; H 6.10; N 10.60
Synthesis of 2-amino-5-[2-aryl-2-hydroxyethyl]thiazol-
4(5Н)-ones 4а–c (General method). NaBH4 (1.9 g, 0.05 mol)
was added to magnetically stirred and cooled (NaCl–ice)
slurry of thiazol-4(5H)-one 3a–c (0.01 mol) in MeOH (15 ml).
The mixture was left for 2 h at room temperature. The result-
ing solution was slowly poured into H2O (75 ml), the preci-
pitate that formed was filtered, washed with H2O, and crystal-
lized from 50% aqueous MeOH. The product was obtained
as a mixture of diastereomers A and B in a 2:1 ratio.
2-Amino-5-(2-hydroxy-2-phenylethyl)thiazol-4(5Н)-
ones (4a). Yield 1.63 g (69%), white powder, mp 207–208°С
Synthesis of (Z)-2-amino-5-(2-aryl-2-oxoethylidene)-
thiazol-4(5Н)-one 5a–d (General method). A solution of
Br2 (0.5 ml, 1 mmol) in AcOH (10 ml) was added in
portions to a magnetically stirred solution of 2-amino-
1207

Chemistry of Heterocyclic Compounds 2020, 56(9), 1202–1209
thiazol-4(5Н)-one 3a,b,e,f (1 mmol) in AcOH (10 ml).
Quantum-chemical calculations were carried out
within the framework of the DFT theory employing the
Gaussian 09 software package37 using the B3LYP38
electron density functional in the cc-pVDZ orbital basis.39
For the analysis of the wave function, elements of
R. Bader's atoms in molecules theory were used.40,41
After adding the entire amount of Br2, the mixture was
heated under reflux for 1 h and cooled to room
temperature. The formed precipitate was filtered off and
crystallized from AcOH.
(Z)-2-Amino-5-(2-oxo-2-phenylethylidene)thiazol-4(5Н)-
one (5a). Yield 0.16 g (69%), yellow powder, mp 279–
280°С (decomp., AcOH). IR spectrum, ν, cm–1: 3205,
3006, 1683 (C=O), 1643, 1597, 1504, 1447, 1383, 1286,
X-ray structural analysis of compounds 3а, 4а.
Crystals of compound 3a were obtained by recrystallization
from DMSO, triclinic system, C11H10N2О2S, at 293°С:
a 5.3108(8), b 11.509(2), c 18.476(3) Å; α 102.36(1),
1
1225, 1147, 1020, 743, 683. H NMR spectrum, δ, ppm
(J, Hz): 7.54 (2H, t, J = 7.6, H Ar); 7.66 (1H, t, J = 7.6,
H Ar); 7.94 (1H, s, CH); 8.09 (2H, d, J = 7.7, H Ar); 9.48
(1H, br. s) и 9.78 (1H, br. s, NH2). 13C NMR spectrum,
δ, ppm: 116.8 (C=CH); 128.3, 129.1, 133.7, 136.4 (C Ph);
147.9 (C=CH); 179.2 (C=N); 179.3 (C=O); 188.4 (C=O).
Mass spectrum, m/z (Irel, %): 232 [M]+ (100), 204 (14), 190
(99), 162 (53), 127 (39), 105 [ArCO]+ (94). Found, %:
C 56.52; H 3.29; N 12.17. C11H8N2O2S. Calculated, %:
C 56.89; H 3.47; N 12.06.
β
94.34(1),
γ
94.39(1)°;
V
1095.0(3)
Å3;
Mr 234.27; Z 4; P1¯ space symmetry group; dcalc 1.421 g/cm3;
μ(MoKα) 0.281 mm–1; F(000) 488. Unit cell parameters
and intensities of 7813 reflections (3874 independent,
Rint 0.078) were measured on an Xcalibur-3 diffractometer
(MoKα radiation, ССD-detector, graphite monochromator,
ω-scanning, 2θmax 50°). The structure was solved by the
direct method using the SHELXTL software package.42
H atom positions were found from difference electron
density synthesis and were refined according to the ''rider''
model with Uiso = 1.2Ueq for a non-hydrogen atom bonded
to given hydrogen atom. The structure was refined against
F2 by the least-squares technique in the full-matrix
anisotropic approximation for non-hydrogen atoms to wR2
0.147 over 3874 reflections (R1 0.072 over 1789 reflections
with F > 4σ(F), S 0.950). Atomic coordinates, as well as
complete tables of bond lengths and bond angles were
deposited at the Cambridge Crystallographic Data Center
(deposit CCDC 2005302).
(Z)-2-Amino-5-[2-oxo-2-(p-tolyl)ethylidene]thiazol-
4(5Н)-one (5b). Yield 0.21 g (85%), yellow powder,
1
mp >300°С (AcOH). H NMR spectrum, δ, ppm (J, Hz):
2.37 (3Н, s, CH3); 7.35 (2Н, d, J = 8.1, H Ar); 7.92 (1H, s,
CH); 8.00 (2Н, d, J = 8.1, H Ar); 9.44 (1Н, br. s) and 9.73
(1Н, br. s, NH2). 13C NMR spectrum, δ, ppm: 21.8 (CH3);
117.5 (C=CH); 129.1, 130.2, 134.6, 145.1 (C Ar); 148.2
(C=CH); 179.6 (C=N); 179.8 (C=O); 188.5 (C=O). Mass
spectrum, m/z (Irel, %): 246 [M]+ (99), 218 (35), 204 (100),
177 (30), 148 (37), 120 (87), 119 [ArCO]+ (90), 127 (39),
91 (92). Found, %:
C
58.40;
H
4.14; N 11.32.
Crystals of compound 4a suitable for X-ray structural
analysis were obtained by slow evaporation of the solution
in 2-PrOH, rhombic system, C11H12N2O2S·H2O, at 293°С:
a 12.130(1), b 8.1701(5), c 25.642(3) Å; V 2541.1(4) Å3;
Mr 254.30; Z 8; Рbca space symmetry group; dcalc 1.329 g/cm3;
μ(MoKα) 0.253 mm–1; F(000) 1072. Unit cell parameters and
intensities of 11159 reflections (2235 independent, Rint
0.095) were measured on an Xcalibur-3 (MoKα radiation,
ССD-detector, graphite monochromator, ω-scanning, 2θmax
50°). The structure was solved by the direct method using
the SHELXTL software package. H atom positions were
found from difference electron density synthesis and were
refined according to the ''rider'' model with
Uiso = nUeq for a non-hydrogen atom bonded to given
hydrogen atom (n = 1.5 for the hydroxy group and water
molecule and n = 1.2 for other hydrogen atoms). The
structure was refined against F2 by the least-squares
technique in the full-matrix anisotropic approximation for
non-hydrogen atoms to wR2 0.269 over 2235 reflections
(R1 0.097 over 1386 reflections with F > 4σ(F), S 1.097).
Atomic coordinates, as well as complete tables of bond
lengths and bond angles were deposited at the Cambridge
Crystallographic Data Center (deposit CCDC 2005303).
C12H10N2O2S. Calculated, %: C 58.52; H 4.09; N 11.37.
(Z)-2-Amino-5-[2-(2,5-dimethylphenyl)-2-oxoethylid-
ene]thiazol-4(5Н)-one (5c). Yield 0.16 g (62%), yellow
powder, mp 253–254°С (decomp., AcOH). 1H NMR
spectrum, δ, ppm (J, Hz): 2.31 (3Н, s, CH3); 2.36 (3Н, s,
CH3); 7.19 (1H, d, J = 7.8, H Ar); 7.27 (1H, d, J = 7.8,
H Ar); 7.65 (1H, s, CH); 7.89 (1H, s, H Ar); 9.50 (1Н,
br. s) and 9.75 (1Н, br. s, NH2). 13C NMR spectrum,
δ, ppm: 20.8 (CH3); 20.9 (CH3); 121.6 (C=CH); 130.3,
132.3, 133.7, 135.8, 136.0, 136.8 (C Ar); 144.7 (C=CH);
177.7 (C=N); 178.0 (C=O); 187.0 (C=O). Mass spectrum,
m/z (Irel, %): 260 [M]+ (99), 232 (5), 218 (78), 190 (99),
185 (75), 157 (97), 133 [ArCO]+ (98), 105 (100). Found,
%: C 59.49; H 4.49; N 10.60. C13H12N2O2S. Calculated, %:
C 59.98; H 4.65; N 10.76.
(Z)-2-Amino-5-[2-(4-ethylphenyl)-2-oxoethylidene]-
thiazol-4(5Н)-one (5d). Yield 0.17 g (65%), yellow
1
powder, mp >300°С (AcOH). H NMR spectrum, δ, ppm
(J, Hz): 1.19 (3H, t, J = 7.5, CH2CH3); 2.69 (2H, q, J = 7.5,
CH2CH3); 7.40 (2H, d, J = 8.1, H Ar); 7.88 (1H, s, CH);
8.05 (2H, d, J = 8.1, H Ar); 9.49 (1H, br. s) and 9.77 (1H,
br. s, NH2). 13C NMR spectrum, δ, ppm: 14.9 (CH2CH3);
28.1 (CH2CH3); 116.9 (C=CH); 128.4, 128.6, 134.3 (C Ar);
147.6 (C=CH); 150.5 (C Ar); 179.3 (C=N); 179.4 (C=O);
187.9 (C=O). Mass spectrum, m/z (Irel, %): 260 [M]+ (98),
232 (47), 218 (100), 191 (33), 189 (37), 162 (52), 133
[ArCO]+ (94), 105 (79). Found, %: C 59.86; H 4.57;
N 10.55. C13H12N2O2S. Calculated, %: C 59.98; H 4.65;
N 10.76.
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