Reaction of 1-hetaryl-4-phenylthiosemicarbazides with N,N- dicyclohexylcarbodiimide

Article abstract of DOI:10.1134/S1070428009090127

1,2,4-Triazolo[3,4-b][1,3]benzothiazole, 1,2,4-triazolo[4,3-a]pyrimidine, and thieno[3,2-e][1,2,4]-triazolo[4,3-a]pyrimidine derivatives were synthesized by reactions of 1-hetaryl-4-phenylthiosemicarbazides with N,N- dicyclohexylcarbodiimide.

Full text of DOI:10.1134/S1070428009090127

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2009, Vol. 45, No. 9, pp. 1386–1389. © Pleiades Publishing, Ltd., 2009.
Original Russian Text © R.I. Vas’kevich, P.V. Savitskii, Yu.L. Zborovskii, V.I. Staninets, 2009, published in Zhurnal Organicheskoi Khimii, 2009, Vol. 45,
No. 9, pp. 1399–1402.
Reaction of 1-Hetaryl-4-phenylthiosemicarbazides
with N,N′-Dicyclohexylcarbodiimide
R. I. Vas’kevich, P. V. Savitskii, Yu. L. Zborovskii, and V. I. Staninets
Institute of Organic Chemistry, National Academy of Sciences of Ukraine, ul. Murmanskaya 5, Kiev, 02660 Ukraine
e-mail: vaskevich@ioch.kiev.ua
Received November 19, 2008
Abstract—1,2,4-Triazolo[3,4-b][1,3]benzothiazole, 1,2,4-triazolo[4,3-a]pyrimidine, and thieno[3,2-e][1,2,4]-
triazolo[4,3-a]pyrimidine derivatives were synthesized by reactions of 1-hetaryl-4-phenylthiosemicarbazides
with N,N′-dicyclohexylcarbodiimide.
DOI: 10.1134/S1070428009090127
We previously showed that heterocyclization of
1-(1,3-benzothiazol-2-yl)-4-phenylthiosemicarbazide
with methyl iodide in ethanol in the presence of
sodium acetate leads to the formation of 2,2′-dithiobis-
[N-(3-methylsulfanyl-4-phenyl-1,2,4-triazol-5-yl)ani-
line] [1] and that 1-(4-methyl-6-oxo-1,6-dihydropyrim-
idin-2-yl)-4-arylthiosemicarbazides under analogous
conditions are converted into 3-arylamino-7-methyl-5-
oxo-1H-1,2,4-triazolo[4,3-a]pyrimidines [2]. 1-(4,6-Di-
methylpyrimidin-2-yl)-4-arylthiosemicarbazides give
rise to 2-arylamino-5,7-dimethyl-1,2,4-triazolo[1,5-a]-
pyrimidines, and the reaction is accompanied by
Dimroth rearrangement. Likewise, substituted 1-(thi-
eno[2,3-d]pyrimidin-2-yl)-4-arylthiosemicarbazides
reacted with methyl iodide to give fused heterocyclic
compounds, derivatives of thienotriazolopyrimidine
[3]. The regioselectivity of this reaction is the same as
in the formation of 3-arylamino-7-methyl-5-oxo-1H-
1,2,4-triazolo[4,3-a]pyrimidines, where the N3 atom in
the pyrimidine ring is involved in triazole ring closure.
The pyrimidine ring in the compounds examined by
us previously contains two atoms accessible for intra-
molecular electrophilic attack leading to cyclization;
these are the N1 and N3 atoms. Insofar as the above
cyclizations occurred at the N3 atom in the pyrimidine
ring, it was interesting to force the cyclization (triazole
ring closure) to involve more basic N1 atom. For this
purpose, we made an attempt to convert the thiosemi-
carbazide fragment in the substrate into a more reac-
tive carbodiimide fragment via elimination of hydro-
gen sulfide by the action of N,N′-dicyclohexylcarbo-
diimide. Analysis of published data [4–7] showed that
carbodiimides are quite applicable for such transforma-
tion. Intermediate carbodiimide thus generated seems
Scheme 1.
Ph
HN
N
N
DCC, toluene
H
H
N
N
N
N
S
N
H
Ph
S
S
I
II
O
N
Ph
Ph
Me
O
N
HN
HN
NH
DCC, dioxane
N
N
H
H
+
N
N
N
N
Me
N
Ph
N
N
O
N
H
Me
H
H
S
III
IV
V
DCC is N,N′-dicyclohexylcarbodiimide.
1386

REACTION OF 1-HETARYL-4-PHENYLTHIOSEMICARBAZIDES
1387
Scheme 2.
CH2
H
O
N
O
N
O
N
N
N
N
BrCH2CH=CH2
DCC, dioxane
N
NH
N
N
H
H
N
N
S
N
Ph
HN
HN
S
S
Ph
Ph
H
S
VI
VII
IX
O
CH2
DCC, dioxane
N
IX
H
H
N
N
S
N
N
Ph
H
S
VIII
to be capable of being involved in closure of triazole
ring with participation of the N1 atom in the pyrimi-
dine ring.
mide in DMF in the presence of potassium carbonate
afforded the corresponding 4-allyl derivative IX which
was also obtained by reaction of 1-allylpyrimidine
VIII with N,N′-dicyclohexylcarbodiimide in dioxane.
The same product was synthesized previously [3] by
cyclization of compound VIII via reaction with methyl
iodide in the presence of sodium acetate in ethanol.
We found that, unlike our previous results [1], the
cyclization of compound I in the presence of N,N′-di-
cyclohexylcarbodiimide in toluene yields triazoloben-
zothiazole II (Scheme 1). In analogous reaction of
thiosemicarbazide III with N,N′-dicyclohexylcarbodi-
imide in dioxane, the cyclization to form triazole ring
involved both N1 and N3 in the pyrimidine ring, and
the products were triazolopyrimidines IV and V which
were isolated from the reaction mixture at a ratio of
5:1. These data differ from the results obtained with
the use of methyl iodide and sodium acetate; in the
latter case the cyclization regioselectively occurred
only at the N3 atom of the pyrimidine ring [2].
Thus the formation of compound IX in the alkyla-
tion of thienotriazolopyrimidine VII with allyl bro-
mide and in the cyclization of thiosemicarbazide VIII
by the action of N,N′-dicyclohexylcarbodiimide unam-
biguously indicates that the hydrogen atom in mole-
cule VII is attached to N4 and that the triazole ring is
formed with participation of the N1 atom in VI.
Cyclization products II, IV, V, VII, and IX were
characterized by different chemical shifts of the NH
protons in the 1H NMR spectra, which depended on the
regioselectivity of cyclization. Compound IV dis-
The cyclization of benzothienopyrimidine VI by
the action of N,N′-dicyclohexylcarbodiimide in dioxane
involved the N1 atom in the pyrimidine ring to give
angular thienotriazolopyrimidine VII as the only prod-
uct (Scheme 2). The alkylation of VII with allyl bro-
1
played in the H NMR spectrum a singlet from the
PhNH proton at δ 8.29 ppm, whereas the correspond-
ing signal of isomeric triazolopyrimidine V appeared
Scheme 3.
O
O
N
NH
NH
H
DCC
N
N
NH
N
N
N
VI
VII
Ph
–DCT
·
N
H
S
NHPh
NPh
Ph
A
B
DCT is N,N′-dicyclohexylthiourea.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 45 No. 9 2009

VAS’KEVICH et al.
1388
of dioxane was heated for 40 min under reflux (oil bath
temperature 115–120°C). The resulting solution was
cooled and evaporated to 1/3 of the initial volume, the
precipitate of compound IV was filtered off, washed
on a filter with diethyl ether, and recrystallized from
alcohol. The filtrate was evaporated to dryness, 5 ml of
alcohol was added to the residue, and the mixture was
heated for 10 min under reflux. The undissolved mate-
rial (compound V) was filtered off and washed with
alcohol and diethyl ether.
at δ 9.43 ppm. Likewise, the second NH proton in IV
resonated at δ 12.54 ppm, and the second NH group in
V gave a singlet at δ 13.17 ppm. Differences were also
observed in the IR spectra of compounds IV and V.
The stretching vibration frequencies of the carbonyl
groups in triazolopyrimidines IV and V were 1675 and
1710 cm–1, respectively.
Our results suggest the following mechanism of the
reactions of hetaryl-substituted thiosemicarbazides I,
III, VI, and VIII with N,N′-dicyclohexylcarbodiimide
(Scheme 3). In the first step, addition of the sulfur
atom in the thiosemicarbazide fragment of I, III, VI,
or VIII to the central carbon atom of N,N′-dicyclo-
hexylcarbodiimide gives bis-carbamimidoyl sulfide
intermediate A which decomposes into new carbodi-
imide B and N,N′-dicyclohexylthiourea. The subse-
quent intramolecular cyclization of intermediate B
with participation of more basic N1 atom in the pyrimi-
dine ring yields final product VII.
5-Methyl-3-phenylamino[1,2,4]triazolo[4,3-a]py-
rimidin-7(8H)-one (IV). Yield 0.32 g (66%), mp 258–
260°C (from EtOH). IR spectrum, ν, cm–1: 3200, 3020,
2920, 1675 (C=O), 1600, 1550, 1490, 1410, 1380,
1
1350, 1250, 880, 760. H NMR spectrum, δ, ppm:
2.44 s (3H, CH3), 5.91 s (1H, CH), 6.82–6.89 m (3H,
Harom), 7.22 t (2H, Harom, J = 7.8 Hz), 8.29 s (1H, NH),
12.54 br.s (1H, NH). Found, %: C 59.63; H 4.54;
N 28.96. C12H11N5O. Calculated, %: C 59.74; H 4.60;
N 29.03.
EXPERIMENTAL
7-Methyl-3-phenylamino[1,2,4]triazolo[4,3-a]-
pyrimidin-5(1H)-one (V). Yield 0.06 g (12%),
mp >320°C (from EtOH–DMSO). IR spectrum, ν, cm–1:
The IR spectra were recorded in KBr on a UR-20
1
1
spectrometer. The H NMR spectra were measured
3320, 1710 (C=O), 1660, 1620, 1585. H NMR spec-
on a Varian VXR-300 spectrometer (300 MHz) in
DMSO-d6 using tetramethylsilane as internal refer-
ence. Compounds I [1], III [2], and VI and VIII [3]
were reported previously.
trum, δ, ppm: 2.23 s (3H, CH3), 5.60 s (1H, CH), 7.00 t
(1H, Harom, J = 7.5 Hz), 7.35 t (2H, Harom, J = 7.5 Hz),
7.61 d (2H, Harom, J = 8.7 Hz), 9.42 s (1H, NH),
13.20 br.s (1H, NH). Found, %: C 59.67; H 4.56;
N 28.93. C12H11N5O. Calculated, %: C 59.74; H 4.60;
N 29.03.
N-Phenyl[1,2,4]triazolo[3,4-b][1,3]benzothiazol-
3-amine (II). A mixture of 0.60 g (2 mmol) of thio-
semicarbazide I and 0.52 g (2.5 mmol) of N,N′-dicy-
clohexylcarbodiimide in 15 ml of toluene was heated
for 1.5 h under reflux (oil bath temperature 115–
120°C). The mixture was cooled, and the precipitate
was filtered off and washed on a filter with toluene and
petroleum ether. Yield 0.22 g (41%), mp 269–271°C
(from EtOH–DMSO). IR spectrum, ν, cm–1: 1600,
1-Phenylamino-6,7,8,9-tetrahydrobenzo[b]thi-
eno[3,2-e][1,2,4]triazolo[4,3-a]pyrimidin-5(4H)-one
(VII) was synthesized in a similar way from com-
pound VI. Yield 0.49 g (73%), mp 261–262°C (from
EtOH). IR spectrum, ν, cm–1: 2950, 1670 (C=O), 1600,
1
1550, 1500, 1400, 1310, 760. H NMR spectrum, δ,
ppm: 1.75 m (4H, CH2), 2.66–2.87 m (4H, CH2), 6.80–
6.87 m (3H, Harom), 7.20 t (2H, Harom, J = 7.8 Hz),
8.67 s (1H, NH), 12.58 s (1H, NH). Found, %:
C 60.59; H 4.41; N 20.57; S 9.53. C17H15N5OS. Calcu-
lated, %: C 60.52; H 4.48; N 20.76; S 9.50.
1
1550, 1490, 1450, 1260, 760. H NMR spectrum, δ,
ppm: 6.94 t (1H, Harom, J = 6.9 Hz), 7.23–7.32 m (4H,
Harom), 7.43–7.53 m (2H, Harom), 7.80 d (1H, Harom, J =
7.5 Hz), 8.02 d (1H, Harom, J = 7.8 Hz), 9.13 s (1H,
NH). Found, %: C 63.02; H 3.65; N 21.03; S 11.99.
C14H10N4S. Calculated, %: C 63.14; H 3.78; N 21.04;
S 12.04.
4-Allyl-1-phenylamino-6,7,8,9-tetrahydrobenzo-
[b]thieno[3,2-e][1,2,4]triazolo[4,3-a]pyrimidin-
5(4H)-one (IX). a. Compound IX was synthesized
from thiosemicarbazide VIII as described above for
triazolopyrimidine VII.
Reaction of 1-(4-methyl-6-oxo-1,6-dihydropy-
rimidin-2-yl)-4-phenylthiosemicarbazide (III) with
N,N′-dicyclohexylcarbodiimide. A suspension of
0.56 g (2 mmol) of thiosemicarbazide III and 0.52 g
(2.5 mmol) of N,N′-dicyclohexylcarbodiimide in 20 ml
b. Allyl bromide, 0.1 ml (1.2 mmol), was added to
a mixture of 0.34 g (1 mmol) of compound VII and
0.17 g (1.2 mmol) of potassium carbonate in 5 ml of
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 45 No. 9 2009

REACTION OF 1-HETARYL-4-PHENYLTHIOSEMICARBAZIDES
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RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 45 No. 9 2009