Heterocyclizations of 1-(Benzothiazol-2-yl)-4-phenylthiosemicarbazide

Article abstract of DOI:10.1007/s11178-008-3015-2

1-(Benzothiazol-2-yl)-4-phenylthiosemicarbazide reacted with methyl iodide in the presence of sodium acetate in boiling ethanol to give 2,2′-dithiobis[N-(5-methylsulfanyl-4-phenyl-4H-1,2,4-triazol-3-yl) -benzenamine]. The reaction of the title compound wi

Full text of DOI:10.1007/s11178-008-3015-2

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2008, Vol. 44, No. 3, pp. 402–406. © Pleiades Publishing, Ltd., 2008.
Original Russian Text © P.V. Savitskii, R.I. Vas’kevich, Yu.L. Zborovskii, V.I. Staninets, S.A. But, A.N. Chernega, 2008, published in Zhurnal Organicheskoi
Khimii, 2008, Vol. 44, No. 3, pp. 407–410.
Heterocyclizations of 1-(Benzothiazol-2-yl)-
4-phenylthiosemicarbazide
P. V. Savitskii, R. I. Vas’kevich, Yu. L. Zborovskii, V. I. Staninets,
S. A. But, and A. N. Chernega
Institute of Organic Chemistry, National Academy of Sciences of Ukraine, ul. Murmanskaya 5, Kiev, 02660 Ukraine
e-mail: savitsky@bpci.kiev.ua
Received July 19, 2007
Abstract—1-(Benzothiazol-2-yl)-4-phenylthiosemicarbazide reacted with methyl iodide in the presence of
sodium acetate in boiling ethanol to give 2,2′-dithiobis[N-(5-methylsulfanyl-4-phenyl-4H-1,2,4-triazol-3-yl)-
benzenamine]. The reaction of the title compound with dimethyl acetylenedicarboxylate in dioxane led to
the formation of methyl 3-(benzothiazol-2-yl)-2-(2-methoxy-2-oxoethyl)-2,3-dihydro-1,3,4-thiadiazole-
2-carboxylate.
DOI: 10.1134/S1070428008030159
Thiosemicarbazides possess nitrogen and sulfur
atoms that are capable of being involved in hetero-
cyclization processes; therefore, they can be used in
syntheses of nitrogen- and sulfur-containing hetero-
cycles. We previously showed [1] that 1-(4-oxo-3,4-
dihydrothieno[2,3-d]pyrimidin-2-yl)-4-arylthiosemi-
carbazides react with dimethyl acetylenedicarboxylate
in dioxane to give derivatives of 2-(2-arylamino-4,5-
dihydro-1,3,4-thiadiazol-4-yl)-3,4-dihydrothieno-
[2,3-d]pyrimidin-4-ones and that an analogous reaction
Scheme 1.
Ph
H
N
N
SMe
SMe
S
NCS
N
MeI, NaOAc
EtOH, Δ
N
N
N
N
HN
N
S
PhH, Δ
S
S
+
NHNH2
NH HN Ph
S
R
N
N
H
Ph
II
IIIa–IIIc
I
V
EtOH, Δ
MeI, NaOAc
EtOH, Δ
EtOH, Δ
HN
N
S
S
NH
N
R = H
N
N
NH HN
R
R
S
S
IVa–IVc
R = H (a), MeO (b), EtOCO (c).
402

HETEROCYCLIZATIONS OF 1-(BENZOTHIAZOL-2-YL)-4-PHENYLTHIOSEMICARBAZIDE
403
Scheme 2.
H
N
S
NH
N
N
[O]
NH
S
I
IVa
N
N
H
H
N
S
Ph
SH
Ph
A
Ph
O
H
N
H
Ph
N2H4
N
S
N
NH
NH
N
N
S
H
Ph
SH
VI
VII
[O]
Ph
Ph
NH
S
S
HN
HN
NH
N
N
VIII
in methanol leads to the formation of N′-(4-oxo-3,4-
dihydrothieno[2,3-d]pyrimidin-2-yl)-3-aryl-5-
methoxycarbonylmethylidene-4-oxo-1,3-thiazolidin-2-
one hydrazones. Cyclization of 4-aryl-1-(pyrimidin-2-
yl)thiosemicarbazides by the action of methyl iodide
[2, 3] provides a synthetic route to arylamino-substi-
tuted [1,2,4]triazolo[1,5-a]- or [1,2,4]triazolo[4,3-a]-
pyrimidines.
2-sulfanylanilines requires strongly alkaline medium
and elevated temperature, we presumed that in our
case mild cleavage of the thiazole ring occurs as
recyclization of I according to synchronous donor–
acceptor mechanism through intermediate spirocyclic
complex A (Scheme 2). This assumption is consistent
with the data of [5] where hydrazinolysis of 2-phen-
acylbenzothiazole (VI) was shown to involve inter-
mediate formation of unstable spiro structure VII; the
latter was also converted into disulfide derivative of
2-sulfanylaniline (compound VIII) in dioxane at room
temperature.
In the present work we used as substrate for hetero-
cyclization 1-(benzothiazol-2-yl)-4-phenylthiosemicar-
bazide (I) which was prepared by heating benzo-
thiazol-2-ylhydrazine (II) with phenyl isothiocyanate
(IIIa) in benzene. Our attempts to synthesize thiosemi-
carbazide I, as well as its analogs having a substituent
in the para position of the benzene ring, by reaction of
hydrazine II with the corresponding aryl isothiocy-
anates IIIa–IIIc in boiling ethanol according to the
procedure described in [4] resulted in the formation of
2,2′-dithiobis[N-(4-aryl-5-thioxo-4,5-dihydro-1H-
1,2,4-triazol-3-yl)anilines] IVa–IVc instead of the ex-
pected thiosemicarbazides (Scheme 1).
Although compound I tends to undergo recycliza-
tion, it reacts with dimethyl acetylenedicarboxylate in
a way similar to thiosemicarbazides of the pyrimidine
series [1] with formation of dihydrothiadiazole deriv-
ative IX (Scheme 3).
The structure of the isolated compounds was con-
firmed by the analytical and 1H NMR data. In addition,
Scheme 3.
MeO
O
Thiosemicarbazide I reacted with methyl iodide
and sodium acetate in boiling ethanol to give substi-
tuted 1,2,4-triazole V. Analogous thiosemicarbazides
of the pyrimidine series were converted into triazolo-
pyrimidine derivatives under similar conditions [2, 3].
Compound V was also obtained by treatment of IVa
with methyl iodide in the presence of sodium acetate.
I
+
O
OMe
N
NHPh
N
S
N
S
Dioxane, Δ
O
O
OMe
IX
Taking into account that hydrolysis of the thiazole
ring in benzothiazole derivatives with formation of
OMe
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 44 No. 3 2008

SAVITSKII et al.
Molecules IVb in crystal are linked to centro-
404
H3
C4
N2
C4
C5
3
N3
N2
C18
symmetric dimers through fairly strong [8] hydrogen
bonds N3–H3 ···S3′ [N–H 0.93(4), N···S 3.225(3),
H···S 2.31(4) Å; ∠NHS 169(2)°]. Analogous dimers
are also formed through N7–H7···S4′ hydrogen bonds
with participation of the other half of the molecule
[N–H 0.83(4), N · · · S 3.253(3), H · · · S 2.44(4) Å;
∠NHS 166(2)°]. As a result, infinite zigzag chains are
formed (Fig. 2).
N
3
C3
C5
C6
C
C18
C19
C8
C8
C19
7
17
C17
C7
C
C
C2
N1
3
S3
S
C2
NC1 6
N4
C20
C20
N4
C9
16
C16
1
C
C1
C
1
H1
H
C9
C21
C21
CC1414
C10
C11
3
S2
C10
C11
N5
N
S2
N6 N6
S1 S1
EXPERIMENTAL
22
C22
C
3
H5
H
7
1
C13
H
H7
The H NMR spectra were recorded on a Varian
8
C13
N8
N
VXR-300 spectrometer (300 MHz) from solutions in
DMSO-d6 using TMS as internal reference.
N7
C25
C12
O1
C25
N7
C12
C24
26
C26
C
C24
C29
23
C
C23
The X-diffraction data for a 0.38×0.39×0.49-mm
single crystal of compound IVb were acquired at room
temperature on an Enraf–Nonius CAD-4 automatic
O1
O2
C29
C15
S4
C27
C28
C27
O2
C28
C30
S4
diffractometer (CuKα irradiation, λ = 1.54178 Å, θmax
=
Fig. 1. Structure of the molecule of 2,2′-dithiobis{N-[4-(4-
methoxyphenyl)-5-thioxo-4,5-dihydro-1H-1,2,4-triazol-3-
yl]aniline} (IVb) according to the X-ray diffraction data.
Principal bond lengths (Å) and bond angles (deg): S1–S2
2.102(1), S1–C1 1.764(3), S2–C16 1.761(3), N1–C6 1.401(3),
N1–C7 1.350(3), N2–N3 1.395(3), N2–C7 1.306(3), N3–C8
1.333(3), N4–C7 1.384(3), N4–C8 1.379(3), N5–C21 1.395(3),
N5–C22 1.357(3), N6–N7 1.386(3), N6–C22 1.304(3), N7–C23
1.328(3), N8–C22 1.385(3), N8–C23 1.383(3); S2S1C1
100.31(9), S1S2C16 101.28(9).
65°, 0 ≤ h ≤ 16, 0 ≤ k ≤ 16, –20 ≤ l ≤ 19). Total of 5942
reflections were measured, 5430 of which were inde-
pendent (Rint = 0.014). Monoclinic crystals with the
following unit cell parameters: a = 13.754(4), b =
14.033(6), c = 17.137(3) Å; β = 104.9(2)°; V =
3195 Å3; M 658.9; Z = 4; dcalc = 1.37 g/cm3; μ =
30.77 cm–1; F(000) = 1368; space group P21/c (no. 14).
The structure was solved by the direct method and was
refined by the least-squares procedure in full-matrix
anisotropic approximation using CRYSTALS software
package [9]; 4035 reflections with I > 3σ(I) were used
in the refinement (413 refined parameters, 9.8 reflec-
tions per parameter). All hydrogen atoms were
visualized from the difference synthesis of electron
density and were involved in the refinement procedure
with fixed positional and thermal factors (only the H1,
H3, H5, and H7 atoms were refined in isotropic approx-
imation). Chebyshev’s weight scheme [10] was applied
with the following five parameters: 1.28, –0.78, 0.42,
–0.05, and –0.21. The final divergence factors were
R = 0.042 and RW = 0.046; goodness of fit 1.004. The
final electron density from the Fourier difference series
was –0.25 and 0.23 e/Å3. Absorption by the crystal was
taken into account by the azimuthal scanning tech-
nique [11]. The complete set of crystallographic data
for compound IVb was deposited to the Cambridge
Crystallographic Data Center (entry no. CCDC
651601).
the structure of IVb was unambiguously proved by
X-ray analysis (Fig. 1). Molecule IVb is essentially
nonplanar: the torsion angle C1S1S2C16 reaches 50.2°,
the dihedral angle between the C1–C6 and C16–C21 ring
planes is 29.5°, the dihedral angles between the C1–C6
and N2N3N4C7C8 planes is 16.6°, and the C16–C21 ben-
zene ring with the N6N7N8C22C23 plane forms a di-
hedral angle of 21.6°. The C1–C6 and C16–C21 rings are
turned relative to the N2N3N4C7C8 and N6N7N8C22C23
heterorings, respectively, through dihedral angles of
65.6 and 65.9°. The N2N3N4C7C8 and N6N7N8C22C23
heterorings are planar within 0.009 and 0.006 Å, re-
spectively. Their geometric parameters indicate con-
siderable delocalization of electron density therein.
The N1 and N5 atoms are characterized by planar–
trigonal bond configuration within the experimental
error: the sums of the bond angles at these atoms are
equal to 360°. Effective conjugation of lone electron
pairs on the N1 and N5 atoms with π systems of the
N2N3N4C7C8 and N6N7N8C22C23 heterorings makes the
N1–C7 [1.350(3) Å] and N5–C22 bonds [1.357(3) Å]
considerably shorter than the distance 1.43–1.45 Å
typical of standard single N(sp2)–C(sp2) bond [6, 7].
1-(Benzothiazol-2-yl)-4-phenylthiosemicarbazide
(I). Phenyl isothiocyanate, 2.0 ml (0.017 mol), was
added to a suspension of 2.30 g (0.014 mol) of
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 44 No. 3 2008

HETEROCYCLIZATIONS OF 1-(BENZOTHIAZOL-2-YL)-4-PHENYLTHIOSEMICARBAZIDE
405
4
S4
SS33
S
S4
S4
compound II in 100 ml of benzene. The mixture was
stirred for 1.5 h on heating on a water bath at a bath
temperature of 70–75°C. The precipitate was filtered
off from the hot mixture and washed first with benzene
and then with diethyl ether. Yield 2.96 g (71%),
1
mp 171–172°C. H NMR spectrum, δ, ppm: 7.15 m
b
b
(2H, Harom), 7.33 m (3H, Harom), 7.51 m (3H, Harom),
7.82 m (1H, Harom), 10.11 br.s (1H, NH), 10.24 br.s
(2H, NH). Found, %: C 56.22; H 3.88; N 18.42;
S 21.24. C14H12N4S2. Calculated, %: C 55.98; H 4.03;
N 18.65; S 21.35.
3
S
4
S3
S3
S3
S4
S4′
S
S3′
S3′
S3'
S3'
S4'
2,2′-Dithiobis[N-(4-aryl-5-thioxo-4,5-dihydro-
1H-1,2,4-triazol-3-yl)anilines] IVa–IVc (general pro-
cedure). Compound II, 1.00 g (6 mmol), was dissolved
in 75 ml of ethanol on heating, a solution of 9 mmol of
aryl isothiocyanate IIIa–IIIc in 15 ml of ethanol was
added, and the mixture was heated for 1 h under reflux.
After cooling, the finely crystalline product was
filtered off, washed with diethyl ether, and dried at
70–80°C.
c
c
0 0
a a
S3′
S4′
S4′
S4'
S3'
S4'
Fig. 2. Packing of 2,2′-dithiobis{N-[4-(4-methoxyphenyl)-5-
thioxo-4,5-dihydro-1H-1,2,4-triazol-3-yl]aniline} (IVb)
molecules in crystal (the p-methoxyphenyl substituents are
not shown). Intermolecular hydrogen bonds N–H···S are
shown with dotted lines.
2,2′-Dithiobis[N-(4-phenyl-5-thioxo-4,5-dihydro-
1H-1,2,4-triazol-3-yl)aniline] (IVa). Yield 1.46 g
1
(81%), mp 265–268°C. H NMR spectrum, δ, ppm:
6.96 m (1H, Harom), 7.19 m (1H, Harom), 7.36 m (1H,
H
arom), 7.43 m (2H, Harom), 7.59 m (4H, Harom), 7.80 s
(1 mmol) of compound I, 0.12 g (1.5 mmol) of sodium
acetate, 0.1 ml (1.5 mmol) of methyl iodide, and 25 ml
of ethanol was heated for 1 h under reflux. After
cooling, the precipitate was filtered off and washed in
succession with water, ethanol, and diethyl ether. Yield
0.115 g (19%), mp 229–231°C (from DMF–ethanol).
1H NMR spectrum, δ, ppm: 2.56 s (3H, CH3), 6.82 m
(1H, Harom), 7.03 m (1H, Harom), 7.35 m (1H, Harom),
7.43 m (2H, Harom), 7.58 m (3H, Harom), 7.68 s (1H,
NH), 7.76 m (1H, Harom). Found, %: C 57.61; H 4.29;
N 17.66; S 20.38. C30H26N8S4. Calculated, %: C 57.48;
H 4.18; N 17.88; S 20.46.
(1H, NH), 13.49 s (1H, NH). Found, %: C 55.98;
H 3.81; N 18.83; S 21.49. C28H22N8S4. Calculated, %:
C 56.16; H 3.70; N 18.71; S 21.42.
2,2′-Dithiobis{N-[4-(4-methoxyphenyl)-5-thioxo-
4,5-dihydro-1H-1,2,4-triazol-3-yl]aniline} (IVb).
Yield 1.17 g (59%), mp 252–254°C. H NMR spec-
trum, δ, ppm: 3.85 s (3H, CH3), 6.95 m (1H, Harom),
7.10 d (2H, Harom, J = 8.9 Hz), 7.22 m (1H, Harom),
7.30 d (2H, Harom, J = 8.9 Hz), 7.36 m (1H, Harom),
7.62 m (1H, Harom), 7.71 s (1H, NH), 13.43 s
(1H, NH). Found, %: C 54.51; H 4.14; N 17.17;
S 19.55. C30H26N8O2S4. Calculated, %: C 54.69;
H 3.98; N 17.01; S 19.47.
1
b. A mixture of 0.96 g (1.6 mmol) of compound
IVa, 0.4 g (4.9 mmol) of sodium acetate, 0.3 ml
(4.8 mmol) of methyl iodide, and 50 ml of ethanol was
heated for 1.5 h under reflux. After cooling, the finely
crystalline product was filtered off and washed with
water and ethanol. Yield 0.27 g (26%). The product
was identical to a sample prepared from compound I
as described above in a.
2,2′-Dithiobis{N-[4-(4-ethoxycarbonylphenyl)-5-
thioxo-4,5-dihydro-1H-1,2,4-triazol-3-yl]aniline}
(IVc). Yield 1.16 g (52%), mp 153–155°C. H NMR
spectrum, δ, ppm: 1.33 t (3H, CH3, J = 7.2 Hz), 4.36 q
(2H, CH2, J = 7.2 Hz), 6.95 m (1H, Harom), 7.20 m (1H,
Harom), 7.28 m (1H, Harom), 7.40 m (1H, Harom), 7.60 d
(2H, Harom, J = 8.6 Hz), 8.04 s (1H, NH), 8.10 d
(2H, Harom, J = 8.6 Hz), 13.50 s (1H, NH). Found, %:
C 55.21; H 4.26; N 15.03; S 17.18. C34H30N8O4S4. Cal-
culated, %: C 54.97; H 4.07; N 15.08; S 17.26.
1
Methyl 3-(benzothiazol-2-yl)-2-(2-methoxy-2-
oxoethyl)-2,3-dihydro-1,3,4-thiadiazole-2-carbox-
ylate (IX). A mixture of 0.3 g (1 mmol) of compound I
and 0.15 ml (1.2 mmol) of dimethyl acetylenedicar-
boxylate in 20 ml of dioxane was stirred for 25 h at
2,2′-Dithiobis[N-(5-methylsulfanyl-4-phenyl-4H-
1,2,4-triazol-5-yl)aniline] (V). a. A mixture of 0.30 g
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 44 No. 3 2008

SAVITSKII et al.
406
3. Vas’kevich, R.I., Savitskii, P.V., Zborovskii, Yu.L.,
Staninets, V.I., Rusanov, E.B., and Chernega, A.N.,
Russ. J. Org. Chem., 2006, vol. 42, p. 1403.
18–25°C. The solvent was removed under reduced
pressure (15–20 mm), the residue was ground with
a small amount of acetone, and the finely crystalline
product was filtered off and washed on a filter with
acetone and hexane. Yield 0.31 g (70%), mp 186–
188°C (MeOH). 1H NMR spectrum, δ, ppm: 3.63 s and
3.70 s (3H each, OCH3), 3.62 d and 4.29 d (1H each,
CH2, J = 16.5 Hz), 7.04 m (1H, Harom), 7.15 m (1H,
Harom), 7.30–7.41 m (3H, Harom), 7.53 m (3H, Harom),
7.87 m (1H, Harom), 9.86 s (1H, NH). Found, %:
C 54.16; H 4.21; N 12.53; S 14.58. C20H18N4O4S2. Cal-
culated, %: C 54.28; H 4.10; N 12.66; S 14.49.
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