Synthesis and spatial structure of 4-(2-hydroxyethyl)-5-(2-hydroxyphenyl)- 2H-1,2,4-triazolo-3(4H)-thione

Article abstract of DOI:10.1134/S1070363209070226

By reaction of 2-vinyloxyethyl isothiocyanate with salicylic acid hydrazide a synthesis of the corresponding thiosemicarbazide was performed. Alkaline hydrolysis of the latter led to an intramolecular heterocyclization into 1,2,4-triazole derivative. When

Full text of DOI:10.1134/S1070363209070226

ISSN 1070-3632, Russian Journal of General Chemistry, 2009, Vol. 79, No. 7, pp. 1532–1536. © Pleiades Publishing, Ltd., 2009.
Original Russian Text © A.S. Alimbayeva, O.A. Nurkenov, A.Kh. Zhakina, I.V. Kulakov, D.M. Turdybekov, K.M. Turdybekov, 2009, published in Zhurnal
Obshchei Khimii, 2009, Vol. 79, No. 7, pp. 1175–1179.
Synthesis and Spatial Structure of 4-(2-Hydroxyethyl)-
5-(2-hydroxyphenyl)-2H-1,2,4-triazolo-3(4H)-thione
A. S. Alimbayevaa, O. A. Nurkenova, A. Kh. Zhakinaa,
I. V. Kulakova, D. M. Turdybekovb, and K. M. Turdybekovb
aInstitute of Organic Synthesis and Coal Chemistry of Republic of Kazakhstan,
ul. Alikhanova 1, Karaganda, 100008 Kazakhstan
e-mail: kulakov_iv@mail.ru
b Phytochemistry Scientific Production Centre, Karaganda, Kazakhstan
Received October 2, 2008
Abstract—By reaction of 2-vinyloxyethyl isothiocyanate with salicylic acid hydrazide a synthesis of the
corresponding thiosemicarbazide was performed. Alkaline hydrolysis of the latter led to an intramolecular
heterocyclization into 1,2,4-triazole derivative. When cyclization was carried out in the water-alkali medium, 2-
vinyloxyethyl fragment was shown to be hydrolyzed to form 4-(2-hydroxyethyl)-5-(2-hydroxyphenyl)-2H-
1,2,4-triazolo-3(4H)-thione, whose spatial structure was established by XRD analysis.
DOI: 10.1134/S1070363209070226
Salicylic acid is abundant in nature. Its derivatives,
in which it is predominantly bound to a glucose
residue, are contained in willow leaves and also in
essential oils of various plants. Salicylic acid is widely
used in medicine. It possesses antirheumatic, anti-
inflammatory, febrifugal, antimicrobial, antibacterial,
and antimycotic actions. Since 1876 o-oxybenzoic acid
derivatives (salicylates) has been introduces into the
clinic practice and are used everywhere to this day.
Sodium salicylate, salicylamide and acetylsalicylic
acid (aspirin) are employed as febrifugal, antir-
heumatic, anti-inflammatory and analgesic agents, and
phenyl salicylate is used as antiseptic, p-aminosalicylic
acid (PASK) and calcium p-benzoylaminosalicylate
(BEPASK), as tuberculocidal agents [1].
synthesic approach to thioureas and thiosemicar-
bazides. In this connection we attempted to prepare a
new thiosemicarbazide derivative proceeding from the
salicylic acid hydrazide and 2-vinyloxyethyl isothio-
cyanate. 2-Vinyloxyethyl isocyanate is of special
interest among isocyanates as a starting object. It is a
highly active bifunctional synthon combining unique
synthetic possibility of vinyl ethers and isothio-
cyanates. From 2-vinyloxyethyl isothiocyanate, isoni-
cotinic acid hydrazide and anabasine thiourea de-
rivatives were synthesized showing high antifungal
activity [8, 9].
Condensation of 2-vinyloxyethyl isothiocyanate
with salicylic acid hydrazide was carried out in alcohol
using equimolar reagents ratio.
Of particular interest is the synthesis of hydrazine-
containing derivatives of the salicylic acid since many
of hydrazine derivatives have a broad spectrum of
biological activity: analgesic, cardiovascular, anticon-
vulsive, antiviral, antimicrobial, tuberculocidal, etc.
[2–5]. It is also known that many of the thio-
semicarbaside and thioamide derivatives such as thio-
acetazone, p-aminobenzaldehyde thiosemicarbazone,
α-methylbenzylthiourea possess bacteriostatic and
antiviral activity [6, 7].
Reaction proceeds under mild conditions with
product I yield of 70%. The prepared compound I is
crystalline and well soluble in polar organic solvents.
In the IR spectrum of I there is an absorption band
in the region of 1310 сm–1 characteristic of NH-CS
moiety of the thiosemicarbazide fragment. The
absorption bands of amide C(O)NH and NH groups
appear at 1675 and 3390 сm–1 respectively.
In the 1Н NMR spectrum of I the signals of
aromatic ring protons are observed. Thus, signals of
The published data indicate that reaction of
isothicyanates with amines and hydrazides is the main
1532

SYNTHESIS AND SPATIAL STRUCTURE OF 4-(2-HYDROXYETHYL)-...
OH
1533
OH
O
O
CH2=CH−O−CΗ2−CH2−N=C=S
C
C
NHNH
NHNH2
C
S
O
CH CH2
NHCH2CH2
I
Н1–Н4 protons are registered in the downfield region: a
doublet at δ 6.97 (Н1), a triplet at 7.45 (Н2), a triplet at
6.92 (Н3), and a doublet at 7.87 ppm (Н4). Two triplets
at δ 3.70 and 3.80 ppm belong to the four methylene
protons Н8 and Н9 of the oxyethyl fragment. The vinyl
methine proton Н10 is observed at δ 6.50 ppm as a
doublet of doublets. Methylene protons Н11а and Н11b of
the vinyl fragment appear at δ 4.00 and 4.21 ppm.
Aromatic hydroxyl proton gives a singlet at δ
8.30 ppm. Amide and thioamide N–Н protons appear
as three singlets at δ 11.92 (Н5), 10.58 (Н6), and
9.55 ppm (Н7).
that belong to molecular ion 281 [М]+ (27%) and
fragment ions 248 (17%), 144 (28%), 121 (100%) and
86 (48%).
Thiosemicarbazides are known to be widely used in
organic chemistry as starting synthons for synthesis of
the nitrogen-containing heterocyclic compounds.
The prepared salicylic acid thiosemicarbazide
derivative I was subjected to an intramolecular
cyclization aiming at the preparation of new
biologically active substances. The promising in
respect to antibacterial properties are the derivatives of
1,2,4-triazole-3-thione, many of which are used in
pharmacology [10, 11] and agriculture [12–14].
OH
1
O
11а
H
2
C
5
6
10
9
7
8
The cyclization of salicylic acid thiosemicarbazide
derivative was carried out in the water-alkali medium
under heating the reaction mixture to 80–85ºС. In the
presence of alkali compound I transforms into a
thiolate. On further acidifying of the latter formed 5-
(2-hydroxyphenyl)-4-vinyloxyethyl-1,2,4-triazole-3-
thione II.
NHNH
C
S
O
CH C
NHCH2CH2
3
4
H
11b
I
In the mass-spectrum of compound I there are some
peaks with m/z values and relative intensities Irel (%)
OH
O δ−
OH
O
δ+
C
NH
KOH
C
NH
SK
C+
NHNH
C
NH C2H4OCH CH2
N
S
H2C=CH−CΗ2
I
C2H4OCH=CH2
N
CH2CH2OH
OH
OH
H+/H2O
N
C
S−K+
C
C=S
C
O
H
N
N
CH3
C
NH
N
Iа
II
Thioureas and thiosemicarbazides are weak SH-
acids. However, in a solution thione form prepredo-
minants, and the SH-form is present in a negligible
amount incapable to affect the further reaction course.
The alkali effect is based on the fact that these
compounds transform fully into thiolates at the high
alkali concentration resulting in a shift of the electronic
equilibrium and formation of conditions for intramo-
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 79 No. 7 2009

1534
ALIMBAYEVA et al.
observed absorption bands of hydroxy group in the
O2
range of 3370 сm–1. C=S group vibrations are observed
at 1265 сm–1.
C10
C5
C4
Peaks of molecular ion 237 [М]+ (51%) and ions
194 (59%), 193 (100%) and 120 (31%) were detected
in the mass-spectrum of II.
C6
C1
C9
N3
C3
1
In the Н NMR spectrum of II as distinct from
S1
C8
compound I some shift of aromatic Н4 proton is
observed. Thus, Н4 proton doublet is shifted upfield
from δ 7.87 (in compound I with adjacent carbonyl
group) to 7.31 ppm. There are a triplet of Н2 at δ 7.40,
a doublet of Н1 at 7.00, and a triplet of Н3 at 6.94 ppm.
Four methylene Н6 and Н7 and oxyethyl fragment
protons give two triplets at δ 3.49 and 3.90 ppm.
Aromatic and oxyethyl hydroxy protons appear as a
singlet at δ 10.25 ppm and as a broad singlet at δ
4.74 ppm respectively. Thioamide N–Н proton of
triazole cycle gives a narrow singlet in the downfield
region at δ 13.80 ppm.
C7
N1
C2
O1
N2
General view of the molecule of 4-(2-hydroxy-ethyl)-5-(2-
hydroxyphenyl)-2H-1,2,4-triazolo-3(4H)-thione II.
lecular cycle closure due to nucleophilic attack of the
nitrogen atom on the electron-deficient carbonyl carbon
giving a stable heterocyclic system.
The X-ray diffraction analysis was carried out to
establish the spatial structure of 4-(2-hydroxyethyl)-5-
(2-hydroxyphenyl)-2H-1,2,4-triazolo-3(4H)-thione II
(see figure).
However, on carrying out the intramolecular
heterocyclization we isolated not the expected com-
pound Ia, but its hydrolysis product, 4-(2-hyd-
roxyethyl)-5-(2-hydroxyphenyl)-2H-1,2,4-triazolo-3-
(4H)-thione II. The prepared compound II is a white
crystalline substance soluble in the polar organic
solvents. Formation of the derivative II was unam-
biguously confirmed using mass-spectrometry, IR, and
1Н NMR spectroscopy. In the IR spectrum of II we
Bond lengths and bond angles are close to the
standard values (Tables 1, 2) [15].
The five-membered triazole cycle N1N2N3C7C8 is
planar within 0.0028 Å. The deviation of the sulfur
Table 2. Bond angles (ω, deg) in structure II
Table 1. Bond lengths (d, Å) in molecule II
Angle
C8N3C7
C8N3C9
C7N3C9
C7N1N2
C8N2N1
C6C1C2
C6C1C7
C2C1C7
N2C8N3
N2C8S1
N3C8S1
N1C7N3
ω
Angle
N1C7C1
N3C7C1
O2C10C9
O1C2C3
O1C2C1
C3C2C1
N3C9C10
C4C3C2
C3C4C5
C6C5C4
C5C6C1
ω
Bond
S1–C8
d
Bond
d
107.58(12)
123.16(12)
128.46(12)
104.77(12)
112.99(12)
118.12(14)
123.25(13)
118.62(13)
104.35(12)
128.25(11)
127.36(11)
110.31(12)
121.56(13)
127.99(12)
112.72(12)
116.78(15)
122.72(15)
120.50(15)
113.64(12)
120.09(15)
120.35(16)
119.96(16)
120.86(15)
1.6821(15)
C1–C2
1.404(2)
O2–C10
N3–C8
1.4266(19)
1.3744(17)
C1–C7
1.4669(19)
1.513(2)
C10–C9
N3–C7
N3–C9
1.382118)
1.4709(17)
C2–O1
C2–C3
1.356(2)
1.384(2)
N1–C7
N1–N2
1.3110(18)
1.3685(18)
C3–C4
C4–C5
1.371(3)
1.383(3)
N2–C8
C1–C6
1.3344(19)
1.393(2)
C5–C6
1.380(2)
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 79 No. 7 2009

SYNTHESIS AND SPATIAL STRUCTURE OF 4-(2-HYDROXYETHYL)-...
Table 4. Atomic coordinates (×104, ×103 for Н) in II
1535
Table 3. Torsion angles (τ, deg) in molecule II
Angle
τ
Angle
τ
Atom
S1
x
y
z
C7N1N2C8
N1N2C8N3
N1N2C8S1
C7N3C8N2
C9N3C8N2
C7N3C8S1
0.48(18)
C2C1C7N3
C6C1C2O1
C7C1C2O1
C6C1C2C3
C7C1C2C3
C8N3C9C10
–142.35(16)
176.63(17)
–2.1(3)
3585(1)
9256(1)
5661(2)
3767(2)
2965(2)
6682(2)
4061(2)
5414(2)
8302(2)
5976(2)
7184(2)
7130(2)
8973(2)
9691(2)
8556(2)
4166(2)
364(4)
2350(1)
844(2)
317(1)
–1566(1)
–2231(1)
–3449(1)
–2110(1)
–4809(2)
–1342(2)
–3506(2)
–929(2)
O2
–0.74(17)
176.88(11)
0.69(16)
N3
2472(2)
1476(2)
1456(2)
2439(2)
2062(2)
2100(2)
2231(2)
3012(2)
3426(2)
3415(2)
3191(3)
2548(3)
2185(3)
3211(3)
27(4)
N1
–3.8(2)
N2
171.24(12)
–176.95(11)
177.46(14)
77.39(17)
C1
C8
C9N3C8S1
N2N1C7N3
–6.4(2)
C7N3C9C10
O2C10C9N3
–114.14(16)
66.15(16)
C7
0.00(16)
C10
C2
N2N1C7C1
–175.99(13)
O1C2C3C4
–177.93(18)
–6047(2)
–1879(2)
–7293(2)
–7336(2)
–6139(2)
–4886(2)
–6092(2)
–538(3)
C9
C8N3C7N1
C9N3C7N1
C8N3C7C1
–0.44(17)
–170.33(13)
175.22(14)
C1C2C3C4
C2C3C4C5
C3C4C5C6
2.5(3)
0.6(3)
C3
C4
–2.2(3)
C5
C9N3C7C1
C6C1C7N1
5.3(2)
C4C5C6C1
C2C1C6C5
0.8(3)
2.2(3)
C6
–145.82(17)
O1
HO1
HO2
C2C1C7N1
C6C1C7N3
32.9(2)
39.0(2)
C7C1C6C5
–179.14(17)
865(3)
–9(3)
–127(2)
atom from this plane is +0.079 Å. We believe that the
flattening of this cycle is due to the conjugation
between electron density of double bonds N1=N2 and
С8=S1. The benzene ring atoms are planar within
0.0012 Å, and the deviation of the atom О1 from this
plane is –0.074 Å. The phenyl plane is turned
equatorially relative to the triazole cycle. The cor-
responding torsion angle N1C7C1C2 is 32.84º (Table 3).
In this molecule the intramolecular hydrogen bond
O1HО1··· N1 is observed. The parameters of the
hydrogen bond are as follows: O1H···N1 2.694 Å,
О1–НО1···N1 1.991 Å, ∠О1–НО1···N1 147.62º that
influence considerably the turn of benzene ring relative
to the five-membered cycle. The todsion angle
N1C7C1C2 is 32.84º. The bulky substituent at the
N3 atom is equatorially oriented (torsion angle
N2C8N3C9 = 171.07º).
solution relative to internal TMS. The mass-spectra
were measured on a FINNIGAN MAT.INCOS 50
device (70 eV). Melting points were determined on a
Boetius device. TLC analysis was accomplished on a
Sorbfil plates using iodine vapor as a detecting agent.
Single crystal X-ray diffraction analysis. The unit
cell parameters and intensities of 2564 reflections were
measured on a BrukerP4 automatic four-circle diffracto-
meter (λMoKα radiation, graphite monochromator, θ/2θ
scanning). The crystals are triclinic, 2θ ≤ 56.9º, а 7.4320(4),
b 7.4873(3), c 9.9304(4) Å, α 79.959(3), β 81.189(4),
γ 88.543(4), V 537.70(4) Å3, Z 2(C12H13N3O2S), dcalc
1.626 g сm–3, space group Р1.
In the calculation we used 2358 independent
reflections with I > 2σ. The structure was solved by the
direct method and refined by the least-squares method
in the full-matrix anisotropic approximation for
nonhydrogen atoms. All the
H
atoms were
EXERIMENTAL
geometrically placed on the “rider” model, except for
the hydroxy hydrogen atoms at the О1 and О2 atoms,
which were revealed and refined in the anisotropic
1
The Н NMR spectra were recorded on a Bruker
DRX500 spectrometer (500 МHz) in DMSO-d6
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 79 No. 7 2009

1536
ALIMBAYEVA et al.
3. Gazaliev, А.М., Zhurinov, M.Zh., Nurkenov, О.А., and
Kulakov, I.V., Khimiya i farmakologiya gidrazidov
(Chemistry and Pharmacology of Hydrazides), Almaty:
Gylym, 2002, p. 132.
4. Glushkov, V.A., Mardanova, L.G., and Shavrina, T.V.,
Khim. Farm. Zh., 1995, no. 10, p. 12.
approximation. The final values of the divergence
factors are R 0.0359 and wR2 0.0985. The atomic
coordinates are given in Table 4. All the calculations
were performed using the SHELX-97 program
package.
Salicylic acid N-2-vinyloxyethylthiosemicarbazide
(I). To a solution of 1.52 g (0.01 mol) of salicylic acid
hydrazide in 25 ml of isopropyl alcohol was added
dropwise 1.29 g (0.01 mol) of 2-vinyloxyethyl
isothiocyanate dissolved in 5 ml of isopropyl alcohol at
room temperature. A mixture was stirred at 40–45ºС
for 2 h and then it was cooled. The white crystalline
precipitate was filtered off, dried and recrystalled from
anhydrous isopropyl alcohol. Yield 70%, mp 163–
165ºС.
5. Mashkovskii, M.D., Lekarstvennye sredstva (Pharma-
ceuticals), Мoscow: Novaya Volna, 2001, vol. 2, p. 306.
6. Mashkovskii, M.D., Lekarstva XX Veka (XX Century
Drugs), Мoscow: Novaya Volna, 1998, p. 320.
7. Dilanyan, E.R., Ovsenyan, T.R., Arsenyan, F.G., and
Agoronyan, А.А., Khim. Farm. Zh., 1999, vol. 33, no. 10,
p. 15.
8. Ibrayev, M.K., Takibayeva, А.T., Gazaliev, А.М.,
Nurkenov, О.А., and Fazylov, S.D., Zh. Prikl. Khim.,
2006, vol. 79, no. 2, p. 328.
9. Ibrayev, M.K., Turdybekov, D.M., Takibayeva, А.T.,
Nurkenov, О.А., Turdybekov, K.M., Gazaliev, А.М.,
and Adekenov, S.M., Zh. Obshch. Khim., 2006, vol. 76,
no. 4, p. 672.
10. Selezneva, Е.S., Belousova, Z.P., Ivanchina, A.I., and
Ten’gayev, E.I., Khim. Farm. Zh., 2006, vol. 40, no. 3,
p. 27.
11. Ivanskii, V.I., Khimiya Geterotsyklicheskich Soedinenii
(Chemistry of Heterocyclic Compounds), Moscow:
Vysshaya Shkola, 1978, p. 559.
4-(2-Hydroxyethyl)-5-(2-hydroxyphenyl)-2H-1,2,4-
triazolo-3(4H)-thione (II). To a water-alkali solution
of 0.56 g (0.01 mol) of КОН in 30 ml of the distilled
water was added 2.81 g (0.01 mol) of salicylic acid N-
(2-vinyloxyethyl)thiosemicarbazide I. The reaction
mixture was refluxed at 85ºС for 1 h, whereupon it
was cooled and acidified with hydrochloric acid to рН
3–4. The precipitate was filtered off and recrystalled
from 70% water ethanol. Yield 69%, mp 184–186ºС.
12. Berim, I.G., Khimicheskaya zashchita rastenii (Plant
Chemical Protection), Saint-Petersburg: Nauka, 1996,
p. 115.
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