Condensation of 5-(4-methylphenyl)-2,4-dihydro-3H-1,2,4-triazole-3-thione with haloacetic acids

Article abstract of DOI:10.1007/s11172-012-0299-8

Reactions of triazolethiones with haloacetic acids were studied with 5-(4-methylphenyl)-2,4-dihydro-3H-1,2,4-triazole-3-thione as an example. It was proved for the first time by X-ray diffraction that the cyclocondensation of these compounds proceeds regiospecifically to give 2-(4-methylphenyl)[1,3] thiazolo[3,2-b][1,2,4]triazol-6(5H)-one rather than its isomer 3-(4-methylphenyl)[1,3]thiazolo[2,3-c][1,2,4]triazol-5(6H)-one.

Full text of DOI:10.1007/s11172-012-0299-8

Russian Chemical Bulletin, International Edition, Vol. 61, No. 11, pp. 2133—2136, November, 2012
2133
Condensation of 5ꢀ(4ꢀmethylphenyl)ꢀ2,4ꢀdihydroꢀ
3Hꢀ1,2,4ꢀtriazoleꢀ3ꢀthione with haloacetic acids
A. A. Rzhevskii,a N. P. Gerasimova,a E. M. Alov,a O. S. Kozlova,a A. S. Danilova,a
S. A. Khapova,b and K. Yu. Suponitskiic
aYaroslavl State Technical University,
88 Moskovskii pr., 150023 Yaroslavl, Russian Federation.
Fax: +7 (485 2) 44 1310. Eꢀmail: rzhevskiyaa@ystu.ru
bYaroslavl State Academy of Agriculture,
58 Tutaevskoe sh., 150042 Yaroslavl, Russian Federation.
Eꢀmail: khapovas@mail.ru
cA. N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences,
28 ul. Vavilova, 119991 Moscow, Russian Federation.
Eꢀmail: kirshik@yahoo.com
Reactions of triazolethiones with haloacetic acids were studied with 5ꢀ(4ꢀmethylphenyl)ꢀ
2,4ꢀdihydroꢀ3Hꢀ1,2,4ꢀtriazoleꢀ3ꢀthione as an example. It was proved for the first time by Xꢀray
diffraction that the cyclocondensation of these compounds proceeds regiospecifically to
give 2ꢀ(4ꢀmethylphenyl)[1,3]thiazolo[3,2ꢀb][1,2,4]triazolꢀ6(5H)ꢀone rather than its isomer
3ꢀ(4ꢀmethylphenyl)[1,3]thiazolo[2,3ꢀc][1,2,4]triazolꢀ5(6H)ꢀone.
Key words: 1,2,4ꢀtriazoleꢀ3ꢀthiones, haloacetic acids, cyclocondensation, bicyclic ring sysꢀ
tems, Xꢀray diffraction study.
Interest in the chemistry of 1,2,4ꢀtriazoleꢀ3ꢀthiones is
due to the broad spectrum of biological and physiological
(antiviral, woundꢀhealing, hepatoprotective, antidepresꢀ
sant, antifungal, etc.) activity exhibited by their derivaꢀ
tives.1—3 These compounds show fungicidal, insecticidal,
and herbicidal properties.4,5
oxymethylation of triazolethiones with haloacetic acids)
has been reported1,2,12 to yield [1,3]thiazolo[3,2ꢀb][1,2,4]ꢀ
triazolꢀ6(5H)ꢀones. Condensation of these compounds
with aldehydes affords the corresponding 5ꢀylidene[1,3]ꢀ
thiazolo[3,2ꢀb][1,2,4]triazolꢀ6(5H)ꢀones.13 However, these
data are in conflict with the reported3,14—16 formation of
the isomeric compounds [1,3]thiazolo[2,3ꢀc][1,2,4]triꢀ
azolꢀ5(6H)ꢀones and 6ꢀylidene[1,3]thiazolo[2,3ꢀc][1,2,4]ꢀ
triazolꢀ5(6H)ꢀones in the same reactions. The goal of the
present work was to study condensation reactions of triꢀ
azolethiones with haloacetic acids and determine the correct
structures of the bicyclic products by Xꢀray diffraction.
We employed 5ꢀ(4ꢀmethylphenyl)ꢀ2,4ꢀdihydroꢀ3Hꢀ
1,2,4ꢀtriazoleꢀ3ꢀthione (1) as a model compound. It had
been prepared by acylation of thiosemicarbazide with
pꢀtoluyl chloride followed by intramolecular cyclization of
the acyl derivative in the presence of 10% aqueous NaOH
according to a known procedure17 (Scheme 1). Ringꢀclosꢀ
ing reactions of triazolethione 1 with ClCH2COOH and
BrCH2COOH were carried out in one and two steps (in the
latter case, through the intermediate formation of {[5ꢀ(4ꢀ
methylphenyl)ꢀ1Hꢀ1,2,4ꢀtriazolꢀ3ꢀyl]sulfanyl}acetic acid
(2)). The best yields of compound 2 were achieved when
triazolethione 1 was refluxed with ClCH2COOH (30 min)
and BrCH2COOH (15 min) in glacial acetic acid (74 and
81%, respectively).
The presence of the fragment NC(S)N in the triazoꢀ
lethione molecule allows modification its structure, inꢀ
volving both one and two nucleophilic centers: the exoꢀ
cyclic S atom and the endocyclic N atoms. Reactions of
1,2,4ꢀtriazoleꢀ3ꢀthiones with various ambident electroꢀ
philic reagents (such as haloacetic acids, ꢀhalo ketones,
epichlorohydrin, etc.) initially occurs at the S atom beꢀ
cause this is the most nucleophilic and sterically accesꢀ
sible center. Then the formation of a bicyclic product can
involve the N atom in position 2 or 4. The former position
appears to be more likely since N(2) is more nucleophilic
than N(4). The syntheses of bicyclic systems from triazoꢀ
lethiones according to both the former6,7 and latter pathꢀ
ways8,9 have been reported; both bicyclic isomers can also
be formed simultaneously in comparable amounts.10 It
should be noted that structural identification of the isoꢀ
mers only by spectroscopic methods and an independent
synthesis leads, in some cases, to contradictory concluꢀ
sions about the reaction products.11 For instance, cycloꢀ
dehydration of sulfanylacetic acids (formed by Sꢀcarbꢀ
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 11, pp. 2116—2119, November, 2012.
1066ꢀ5285/12/6111ꢀ2133 © 2012 Springer Science+Business Media, Inc.

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Rzhevskii et al.
Cyclodehydration of acid 2 involved 30ꢀmin reflux in
both Ac2O and POCl3. The oneꢀstep synthesis of the bicyꢀ
clic product from triazolethione 1 and haloacetic acid was
carried out in the boiling system AcOH—Ac2O. The reflux
time was 2.5 h for ClCH2COOH and 2 h for BrCH2COOH.
Both the oneꢀ and twoꢀstep methods afforded 2ꢀ(4ꢀ
methylphenyl)[1,3]thiazolo[3,2ꢀb][1,2,4]triazolꢀ6(5H)ꢀ
one (3) rather than its isomer 3ꢀ(4ꢀmethylphenyl)[1,3]ꢀ
thiazolo[2,3ꢀc][1,2,4]triazolꢀ5(6H)ꢀone (4). This was conꢀ
firmed by spectroscopic, physicochemical, and Xꢀray difꢀ
fraction data. The yields of compound 3 were 63—67 (in
one step), 80 (in two steps with Ac2O), and 61% (in two
steps with POCl3).
Scheme 1
Structure 3 imaged from Xꢀray diffraction data is shown
in Fig. 1. The independent part of its unit cell in the crysꢀ
tal comprises one molecule.
Structure 3 is planar; the C(1)—C(8) bond (1.464(2) Å)
is even somewhat shorter than its average value for conjuꢀ
gated systems (1.476 Å).18 This suggests a ꢀconjugation
between the cyclic moieties of the molecule. Apparently,
the planar structure is due to the crystal packing: moleꢀ
cules are stacked along the crystallographic axis a. The
stacking is characterized by considerable overlap of the
ꢀsystems (Fig. 2); the shortest distances are 3.389(2)
and 3.313(2) Å for the contacts C(6)...C(11)A and
C(4)...N(1)A, respectively. The crystal packing is addiꢀ
tionally stabilized by weak C—H...O and van der Waals
interactions.
As noted above, different structures are assigned1,3,12—16
to both bicyclic products derived from triazolethiones and
haloacetic acids and products of their condensation with
aldehydes through the methylene group. That is why we
found it necessary to carry out the above reactions with
aldehydes in two ways involving (1) threeꢀcomponent conꢀ
densation in AcOH—Ac2O and (2) twoꢀcomponent conꢀ
densation of thiazolotriazolone 3 with the proved strucꢀ
ture (Xꢀray diffraction). For instance, a reaction of comꢀ
pound 3 with benzaldehyde in the presence of an equimoꢀ
lar amount of AcONa in AcOH—Ac2O gave 5ꢀbenzylꢀ
ideneꢀ2ꢀ(4ꢀmethylphenyl)[1,3]thiazolo[3,2ꢀb][1,2,4]triꢀ
azolꢀ6(5H)ꢀone (5) in 78% yield. Its structure was deterꢀ
mined using spectroscopic methods (Scheme 2). The same
product was obtained in one step via threeꢀcomponent
condensation between triazolethione 1, haloacetic acid,
and benzaldehyde in the presence of an equimolar amount
of AcONa in AcOH—Ac2O. The yields of compound 5
Reagents and conditions: i. HalCH2COOH, AcOH, Ac2O, reꢀ
flux, 2.5 (Hal = Cl) or 2 h (Hal = Br); ii. HalCH2COOH, AcOH,
reflux, 30 (Hal = Cl) or 15 min (Hal = Br); iii. Ac2O, reflux,
30 min; iv. POCl3, reflux, 30 min.
C(3)
N(3)
S(1)
C(10)
C(9)
N(2)
C(4)
C(8)
C(2)
C(1)
C(7)
C(5)
C(11)
O(1)
N(1)
C(6)
Fig. 1. General view of structure 3 with atomic displacement
ellipsoids (p = 50%).
S(1A)
S(1)
C(4)
C(11A)
N(1A)
C(6)
Fig. 2. Fragment of the  stacking in the crystal packing of compound 3. The shortest intermolecular contacts are indicated with
dashed lines.

Condensation of 1,2,4ꢀtriazoleꢀ3ꢀthiones
Russ.Chem.Bull., Int.Ed., Vol. 61, No. 11, November, 2012 2135
Calculated (%): C, 53.00; H, 4.45; N, 16.86; S, 12.86. IR, /cm–1
3174 (NH), 3171—2728 (OH), 1682 (C=O), 882 (OH). 1H NMR,
: 2.38 (s, 3 H, Me); 3.94 (s, 2 H, CH2); 7.28 (d, 2 H, CHtolyl
J = 7.8 Hz); 7.83 (d, 2 H, CHtolyl, J = 7.8 Hz); 12.81 (br.s, 1 H,
COOH); 14.24 (br.s, 1 H, NH).
2ꢀ(4ꢀMethylphenyl)[1,3]thiazolo[3,2ꢀb][1,2,4]triazolꢀ6(5H)ꢀ
one (3). A. A solution of compound 1 (0.96 g, 5 mmol) and
HalCH2COOH (0.49 (Hal = Cl) or 0.73 g (Hal = Br), 5 mmol)
in a mixture of AcOH (5 mL) and Ac2O (2 mL) was refluxed for
2.5 (Hal = Cl) or 2 h (Hal = Br). The reaction mixture was left
for 16 h. The precipitate that formed was filtered off and dried.
The yield was 63 (Hal = Cl) or 67% (Hal = Br).
:
were 67 and 76% (with ClCH2COOH and BrCH2COOH,
respectively). The fact that both the synthetic routes lead
to the same compound provides another piece of eviꢀ
dence for the correct formulation of structure 5 as
5ꢀbenzylideneꢀ2ꢀ(4ꢀmethylphenyl)[1,3]thiazolo[3,2ꢀb]ꢀ
[1,2,4]triazolꢀ6(5H)ꢀone rather than its isomer 6ꢀbenzylꢀ
ideneꢀ3ꢀ(4ꢀmethylphenyl)[1,3]thiazolo[2,3ꢀc][1,2,4]triꢀ
azolꢀ5(6H)ꢀone.
,
Scheme 2
B. A solution of compound 2 (1 g, 4 mmol) in POCl3 (5 mL)
or Ac2O (5 mL) was refluxed for 30 min. The reaction mixture
was cooled and slowly poured onto ice (stirring was provided to
avoid overheating). The precipitate that formed was filtered off,
washed with cold water, dried, and recrystallized from acetone
(with Ac2O as a dehydrating agent, the workup of the precipitate
followed procedure A). Yield 80%, m.p. 197—198 C. Found (%):
C, 56.53; H, 4.21; N, 18.02; S, 13.79. C11H9N3OS. Calculatꢀ
ed (%): C, 57.13; H, 3.92; N, 18.17; S, 13.86. IR, /cm–1: 1762
(C=O). 1H NMR, : 2.40 (s, 3 H, Me); 4.69 (s, 2 H, CH2); 7.33
(d, 2 H, CHtolyl, J = 7.8 Hz); 8.00 (d, 2 H, CHtolyl, J = 7.8 Hz).
5ꢀBenzylideneꢀ2ꢀ(4ꢀmethylphenyl)[1,3]thiazolo[3,2ꢀb][1,2,4]ꢀ
triazolꢀ6(5H)ꢀone (5). A. A solution of compound 1 (0.96 g,
5 mmol), HalCH2COOH (0.49 (Hal = Cl) or 0.73 g (Hal = Br),
5 mmol), benzaldehyde (0.53 mL, 0.52 mmol), and AcONa
(0.86 g, 10 mmol) in a mixture of AcOH (4 mL) and Ac2O
(3 mL) was refluxed for 3 (Hal = Cl) or 2.5 h (Hal = Br). The
reaction mixture was left for 16 h. The precipitate that formed
was filtered off, washed with cold water, and dried. The yield
was 67 (Hal = Cl) or 76% (Hal = Br).
Reagents and conditions: i. HalCH2COOH, PhCHO, AcOH,
Ac2O, AcONa, reflux, 3 (Hal = Cl) or 2.5 h (Hal = Br);
ii. PhCHO, AcOH, Ac2O, AcONa, reflux, 1.5 h.
We examined sulfanylacetic acid 2 as a potential plant
growth regulator. To estimate its growthꢀpromoting acꢀ
tivity, we pretreated four times summer wheat seed (Lada
brand) with an aqueous solution of acid 2 (C = 0.01 wt.%).
The pretreated seed showed higher (by 16%) germinating
power against a control (waterꢀtreated) group. Other benꢀ
efits include longer roots and greater leaf areas.
B. A solution of compound 3 (0.93 g, 4 mmol), benzaldeꢀ
hyde (0.43 mL, 4.2 mmol), and AcONa (0.33 g, 4 mmol) in
a mixture of AcOH (4 mL) and Ac2O (1 mL) was refluxed for
1.5 h. Further workup followed procedure A. Yield 78%, m.p.
228—230 C. Found (%): C, 67.12; H, 4.37; N, 13.03; S, 9.89.
C18H13N3OS. Calculated (%): C, 67.69; H, 4.10; N, 13.16;
S, 10.04. IR, /cm–1: 1736 (C=O). 1H NMR, : 2.38 (s, 3 H, Me);
7.34 (d, 2 H, CHtolyl, J = 7.8 Hz); 7.99 (d, 2 H, CHtolyl, J = 7.8 Hz);
7.60—7.74 (m, 5 H, Ph); 8.24 (s, 1 H, =CH—).
To sum up, our studies demonstrated that reactions of
haloacetic acids with triazolethiones (with compound 1 as
an example) proceed regiospecifically, involving the S and
N(2) atoms of the heterocycle. The structure of bicyclic
product 3 was proved by spectroscopic methods and Xꢀray
diffraction. Triazolylsulfanylacetic acid 2, an intermediꢀ
ate product in the synthesis of compound 3, revealed itself
as a growth promoter for summer wheat seed treated with
it prior to sowing.
Xꢀray diffraction study. The single crystals of compound 3
(C11H9N3OS, M = 231.27) are triclinic; at 100 K, a = 6.1854(5) Å,
b = 8.2313(6) Å, c = 10.3245(8) Å,  = 79.3630(10),
Experimental
3
 = 89.2300(10),  = 76.1150(10), V = 501.27(7) Å , Z = 2,
space group P–1,  = 0.301 mm–1, dcalc = 1.532 g cm–3. The
intensities of 5112 reflections were measured on a SMART
APEX2 CCD diffractometer ((MoꢀK) = 0.71073 Å, graphite
monochromator,  scan mode, 2 < 54°). The initial array of
measured reflection intensities was processed with the SAINT
and SADABS programs from the APEX2 software.19 The strucꢀ
ture was determined by the direct methods and refined anisotroꢀ
pically on F2hkl by the fullꢀmatrix leastꢀsquares method for nonꢀ
hydrogen atoms. The H atoms were located geometrically and
refined using a riding model. In the refinement, 2189 indepenꢀ
dent reflections (Rint = 0.0183) were used. Final residuals are
wR2 = 0.0961 (for all independent reflections) and R1 = 0.0353
for 1992 reflections with I > 2(I), GOOF = 0.993. All calculaꢀ
tions were performed on an IBM PC AT with the SHELXTL
program package.20 Structure 3 has been deposited with the Camꢀ
bridge Crystallographic Data Center (CCDC No. 879591).
1
H NMR spectra were recorded on a Bruker AMꢀ300 instruꢀ
ment (300 MHz) in DMSOꢀd6—CCl4 with Me4Si as the internal
standard. IR spectra were recorded on a Spectrum RX1 FTIR
spectrometer (Perkin Elmer) in Nujol.
Single crystals of compound 3 for Xꢀray diffraction were
obtained by its recrystallization from acetone.
{[5ꢀ(4ꢀMethylphenyl)ꢀ1Hꢀ1,2,4ꢀtriazolꢀ3ꢀyl]sulfanyl}acetic
acid (2). A solution of compound 1 (0.96 g, 5 mmol) and
HalCH2COOH (0.49 (Hal = Cl) or 0.73 g (Hal = Br), 5 mmol)
in AcOH (10 mL) was refluxed for 30 (Hal = Cl) or 15 min
(Hal = Br). The reaction mixture was cooled, poured into water,
and kept for 16 h. The precipitate that formed was filtered off,
washed with cold water, dried, and recrystallized from benzene. The
yield was 74 (Hal = Cl) or 81% (Hal = Br), m.p. 149.5—150.5 C.
Found (%): C, 52.57; H, 4.57; N, 16.73; S, 12.72. C11H11N3O2S.

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Rzhevskii et al.
10. T. Cablewski, C. L. Francis, A. J. Liepa, Aust. J. Chem.,
2008, 61, 332.
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Received May 25, 2012;
in revised form November 6, 2012