Reaction of 3-oxo-N-phenylbutanethioamide with 5-amino-1H-1,2,4-triazoles

Article abstract of DOI:10.1134/S1070428006100216

Reactions of 3-oxo-N-phenylbutanethioamide with 3-substituted 5-amino-1H-1,2,4-triazoles in acetic acid led to the formation of 5-methyl-7,8-dihydro[1,2,4]triazolo[1,5-a]pyrimidine-7-thiones, 7-methyl-5,8-dihydrol[1,2,4]triazolo[1,5-a]pyrimidine-5-thiones

Full text of DOI:10.1134/S1070428006100216

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2006, Vol. 42, No. 10, pp. 1516–1520. © Pleiades Publishing, Inc., 2006.
Original Russian Text © V.N. Britsun, A.N. Borisevich, L.S. Samoilenko, A.N. Chernega, M.O. Lozinskii, 2006, published in Zhurnal Organicheskoi Khimii,
2006, Vol. 42, No. 10, pp. 1529–1532.
Reaction of 3-Oxo-N-phenylbutanethioamide
with 5-Amino-1H-1,2,4-triazoles
V. N. Britsun, A. N. Borisevich, L. S. Samoilenko, A. N. Chernega, and M. O. Lozinskii
Institute of Organic Chemistry, National Academy of Sciences of Ukraine, ul. Murmanskaya 5, Kiev, 02660 Ukraine
e-mail: ioch@bpci.kiev.ua
Received June 30, 2005
Abstract—Reactions of 3-oxo-N-phenylbutanethioamide with 3-substituted 5-amino-1H-1,2,4-triazoles in
acetic acid led to the formation of 5-methyl-7,8-dihydro[1,2,4]triazolo[1,5-a]pyrimidine-7-thiones, 7-methyl-
5,8-dihydro[1,2,4]triazolo[1,5-a]pyrimidine-5-thiones and 7-methyl-5-phenylamino[1,2,4]triazolo[1,5-a]pyri-
1
midines. The structure of the products was proved by the H and 13C NMR spectra, X-ray diffraction data, and
chemical transformations.
DOI: 10.1134/S1070428006100216
We previously showed that 3-oxo-N-phenylbutane-
thioamide (I) possessing several reaction centers can
be used to synthesize various heterocyclic compounds,
such as thiazole [1], 1,2,4-dithiazolidine [2], pyrazole
[3], 1,3-thiazin-4-one, 6-thioxopiperidin-2-one, and
thiopyran-4-one derivatives [4]. In the present work we
examined reactions of 3-oxo-N-phenylbutanethioamide
(I) with 5-amino-1H-1,2,4-triazoles IIa and IIb, which
followed the [3+3]-cyclocondensation pattern. It
should be noted that each of the reactants (I and IIa or
IIb) possesses several potential reaction centers; there-
fore, the reaction could give rise to four compounds of
the [1,2,4]triazolo[1,5-a]pyrimidine series and four
compounds of the [1,2,4]triazolo[4,3-a]pyrimidine
series. Thus the main difficulty was to separate and
identify the products.
ity of these compounds. Therefore, we have developed
a procedure for the separation of mixtures IIIa/IVa
and IIIb/IVb, taking advantage of the better solubility
of compounds IIIa and IIIb in aqueous potassium hy-
droxide. According to the developed procedure, mix-
ture IIIa/IVa or IIIb/IVb was treated with an aqueous
solution of potassium hydroxide whose amount was
equimolar to the amount of compound IIIa or IIIb in
the mixture, the undissolved material (compound IVa
or IVb) was filtered off, and the filtrate was acidified
to precipitate triazolopyrimidine IIIa or IIIb. The
procedure is characterized by a good efficiency and
minimal losses of products III and IV.
The structure of triazolopyrimidines III–V cannot
be determined unambiguously on the basis of their
1H NMR spectra and elemental analyses. Therefore,
the structure of compound Vb was stidued by the
X-ray diffraction method. The results showed that
compound Vb is 7-methyl-2-methylsulfanyl-N-phenyl-
[1,2,4]triazolo[1,5-a]pyrimidin-5-amine. The general
view of molecule Vb is shown in figure. The N1–4C1–5
bicyclic system is planar within 0.009 Å. The C7–C12
benzene ring with that system forms a dihedral angle
of 49.3°. The bond length distribution in the bicyclic
fragment suggests essential delocalization of elec-
tron density. The N5 atom has a planar–trigonal bond
configuration (the sum of the bond angles at that atom
is 358.9°). Conjugation between the unshared electron
pair on the N5 atom and π-system of the bicyclic frag-
ment leads to a considerable shortening of the formally
We found that three types of triazolopyrimidines
III–V were formed in the reactions of 3-oxo-N-phenyl-
butanethioamide (I) with 5-amino-1H-1,2,4-triazoles
IIa and IIb in acetic acid at 100°C (Scheme 1). A mix-
ture of compounds III and IV separated from the solu-
tion on cooling to room temperature, and triazolo-
pyrimidines Va and Vb were isolated as individual
substances by treatment of the reaction mixture with
an aqueous solution of sodium hydrogen carbonate.
Mixtures IIIa/IVa and IIIb/IVb cannot be separat-
ed by recrystallization from water or organic solvents.
1
According to the H NMR data, their ratio did not
change after recrystallization. It was also difficult to
use chromatographic methods because of poor solubil-
1516

REACTION OF 3-OXO-N-PHENYLBUTANETHIOAMIDE
1517
Scheme 1.
Me
O
S
N
N
HN
N
N
+
R
Ph
–H2O, –H2S, –PhNH2
H2N
R
Me
N
N
H
S
N
H
I
IIa, IIb
IIIa, IIIb
S
NHPh
N
N
N
N
+
+
R
R
N
N
Me
N
Me
N
H
IVa, IVb
Va, Vb
Me
(1) KOH; (2) MeI
N
N
IIIa
N
MeS
N
VI
SMe
(1) KOH; (2) MeI
N
N
PhNH2, 160°C
N
IVa
Va
Me
N
VII
IIa–Va, R = H; IIb–Vb, R = MeS.
single N5–C5 bond [1.350(2) Å] against the standard
length of a single Nsp2–Csp2 bond (1.43–1.45 Å) [5, 6].
midines is located at δC 163–165 ppm, and that
belonging to C3–S in [1,2,4]triazolo[4,3-a]pyrimidines,
at δC ~143 ppm. We showed in [10, 11] that the C2
signals of methyl 7-oxo-2-phenyl-7H-[1,2,4]triazolo-
[5,1-b][1,3]thiazine-5-carboxylate and 5-phenyl-5,6-
dihydro-7H-[1,2,4]triazolo[5,1-b][1,3]thiazin-7-one
appear in the 13C NMR spectra in region δC 152–
153 ppm. We recorded the 13C NMR spectra of tri-
azolopyrimidines IIIa, IIIb, Va, and Vb. In the spectra
of Va and Vb (whose structure was proved by X-ray
According to the 1H NMR data, triazolopyrimidines
III and IV in neutral medium exist mainly in the
1
thione form. Their H NMR spectra contained broad-
ened singlets in a weak field (δ 14.06–14.95 ppm),
which should be assigned to NH rather than SH
proton; the latter is known [7] to appear in the δ region
3.5–5.0 ppm.
Compounds IIIa and IVa were subjected to alkyla-
tion by treatment with methyl iodide in alkaline
medium. Methylation products VI and VII showed in
C6
C3
1
the H NMR spectra singlets at δ 2.72–2.79 ppm from
N4
C2
C4
the SCH3 protons, which were absent in the spectra of
the initial compounds. Heating of triazolopyrimidine
VII with aniline at 160°C was accompanied by libera-
tion of methanethiol, and 5-phenylamino[1,2,4]tri-
azolo[1,5-a]pyrimidine (Va) was isolated. These data
unambiguously indicate that initial compounds IVa
and IVb are 7-methyl-5,8-dihydro[1,2,4]triazolo-
[1,5-a]pyrimidine-5-thiones.
C5
C9
N1
C1
C8
C7
N3
C10
N5
C13
N2
S1
C12
C11
According to published data [8, 9], the C2–S signal
Structure of the molecule of 7-methyl-2-methylsulfanyl-N-
phenyl[1,2,4]triazolo[1,5-a]pyrimidin-5-amine (Vb).
in the 13C NMR spectra of [1,2,4]triazolo[1,5-a]pyri-
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 42 No. 10 2006

BRITSUN et al.
1518
analysis), signals from the C2 atom were observed at
δC 154.4 (C–H) and 163.6 ppm (C–S), respectively,
which was consistent with the data of [6–9]. Taking
into account that the corresponding signals in the spec-
tra of triazolopyrimidines IIIa and IIIb were located at
δC 151.8 and 165.1 ppm, respectively, these com-
pounds were assigned the structure of 5-methyl-7,8-
dihydro[1,2,4]triazolo[1,5-a]pyrimidine-7-thiones.
crystals with the following unit cell parameters: a =
6.921(5), b = 10.718(5), c = 17.622(9) Å; β =
95.25(7)°; V = 1301.6 Å3; M = 271.3; Z = 4; dcalc
=
1.38 g/cm3; µ = 21.1 cm–1; F(000) = 570.6; space
group P21/n (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 [6]. The structure
refinement was performed using 2385 reflections with
I > 3σ(I) (225 refined parameters, 10.6 reflections per
parameter). All hydrogen atoms were visualized from
the difference synthesis of electron density, and their
positions were refined in isotropic approximation.
Chebyshev’s weight scheme [13] with five parameters
(0.72, –1.26, 0.08, –0.69, –0.02) was applied. The final
divergence factors were R = 0.037 and RW = 0.035,
GOF 1.142. The residual electron density from the
Fourier difference series was 0.18 and –0.22 e/Å3.
Absorption by the crystal was taken into account using
the azimuthal scanning technique [14]. The complete
set of crystallographic data for compound Vb was
deposited to the Cambridge Crystallographic Data
Center (entry no. CCDC 275142).
Thus 3-oxo-N-phenylbutanethioamide (I) reacts
with 5-amino-1H-1,2,4-triazoles IIa and IIb in acetic
acid to give mixtures of 5-methyl-7,8-dihydro[1,2,4]-
triazolo[1,5-a]pyrimidine-7-thiones III, 7-methyl-5,8-
dihydro[1,2,4]triazolo[1,5-a]pyrimidine-5-thiones IV,
and 7-methyl-N-phenyl[1,2,4]triazolo[1,5-a]pyrimidin-
5-amines V. Two reaction centers in triazoles IIa and
IIb (exocyclic amino group and the N1 atom) are in-
volved in this process, and their reactivities are ap-
proximately similar. 3-Oxo-N-phenylbutanethioamide
(I) reacts at the ketone carbonyl carbon atom and
carbon atom of the thioamide group; in the first case,
the departing molecule is only water, and in the
second, aniline and hydrogen sulfide are released.
The ratio of [1,2,4]triazolo[1,5-a]pyrimidines III,
IV, and V is 1.0:3.0:1.2 in the reaction with triazole
IIa and 2.8:1.4:1.0 in the reaction with IIb. This
means that the contribution of the cyclocondensation
pathway leading to the formation of [1,2,4]triazolo-
[1,5-a]pyrimidinethiones III and IV with elimination
of water and aniline is approximately twice as large
as that of the pathway leading to 7-methyl-5-phenyl-
amino[1,2,4]triazolo[1,5-a]pyrimidines V with elim-
ination of water and hydrogen sulfide. Unlike the first
reaction, the second pathway is regioselective. There-
fore, transamination of the thioamide group in com-
pound I with elimination of aniline occurs more
readily than its amination accompanied by elimination
of hydrogen sulfide. A probable reason is that the
double S=C1 bond is stronger than the single N–C1
bond, which is consistent with the energies of the
corresponding bonds reported in [12] (530 and
285 kJ/mol, respectively).
The NMR spectra were recorded from solutions in
DMSO-d6 on a Varian-300 spectrometer at 300 MHz
1
for H and 75 MHz for 13C; the chemical shifts were
measured relative to TMS as internal reference.
5-Methyl-7,8-dihydro[1,2,4]triazolo[1,5-a]pyri-
midine-7-thiones IIIa and IIIb, 7-methyl-5,8-dihy-
dro[1,2,4]triazolo[1,5-a]pyrimidine-5-thiones IVa
and IVb, and 7-methyl-N-phenyl-[1,2,4]triazolo-
[1,5-a]pyrimidin-5-amines Va and Vb (general
procedure). A solution of 1 g (5.2 mmol) of 3-oxo-N-
phenylbutanethioamide (I) and 6.0 mmol of 1H-1,2,4-
triazol-5-amine (IIa) or 3-methylsulfanyl-1H-1,2,4-tri-
azol-5-amine (IIb) in 5 ml of acetic acid was heated
for 5 h at 100°C. The mixture was cooled, and the
yellow precipitate containing compounds III and IV
was filtered off, washed on a filter with propan-2-ol
(2×3 ml), and dried. Yield of mixture IIIa/IVa 0.51 g,
1
ratio IIIa:IVa = 1:3 (according to the H NMR data).
Yield of IIIb/IVb 0.67 g, ratio IIIb:IVb = 2:1.
EXPERIMENTAL
The filtrate was adjusted to a weakly alkaline reac-
tion by adding 10% aqueous sodium hydrogen carbo-
nate, and the precipitate of compound Va or Vb was
filtered off, washed with water (2×5 ml), and dried.
Yield of Va 0.21 g (18%), mp 183–185°C (from
propan-2-ol). H NMR spectrum, δ, ppm: 2.42 s (3H,
7-CH3), 6.39 s (1H, 6-H), 7.31 m (1H, Harom), 7.48 m
(4H, Harom), 8.51 s (1H, 2-H), 10.21 s (1H, NH).
The X-ray diffraction data for a single crystal of
compound Vb (0.28×0.37×0.43 mm) were acquired
at room temperature on an Enraf–Nonius CAD-4 auto-
matic four-circle diffractometer (CuKα irradiation, λ =
1.54178 Å; scan rates ratio 2θ/ω = 1.2, θmax = 70°;
spherical segment 0 ≤ h ≤ 7, 0 ≤ k ≤ 13, –21 ≤ l ≤ 21).
Total of 2746 reflections were measured. Monoclinic
1
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 42 No. 10 2006

REACTION OF 3-OXO-N-PHENYLBUTANETHIOAMIDE
1519
13C NMR spectrum, δC, ppm: 24.6 (7-CH3), 89.1 (C6),
124.3 (Carom), 126.1 (Carom), 129.5 (Carom), 136.9
(Carom), 145.9 (C5), 154.4 (C2), 155.6 (C8a), 164.2 (C7).
Found, %: C 63.87; H 4.93; N 30.82. C12H11N5. Cal-
culated, %: C 63.99; H 4.92; N 31.09. Yield of Vb
0.20 g (14%), mp 178–180°C (from ethanol). 1H NMR
spectrum, δ, ppm: 2.39 s (3H, 7-CH3), 2.68 s (3H,
SCH3), 6.31 s (1H, 6-H), 7.28 m (1H, Harom), 7.43 m
(4H, Harom), 10.00 s (1H, NH). 13C NMR spectrum, δC,
ppm: 13.4 (SCH3), 24.6 (7-CH3), 89.0 (C6), 124.2
(Carom), 125.8 (Carom), 129.3 (Carom), 136.8 (Carom),
144.9 (C5), 155.9 (C8a), 163.6 (C2), 165.6 (C7). Found,
%: C 57.82; H 5.02; N 25.62; S 12.03. C13H13N5S. Cal-
culated, %: C 57.55; H 4.83; N 25.81; S 11.82.
was added dropwise to a solution of 0.83 g (5.0 mmol)
of compound IIIa and 0.28 g (5.0 mmol) of KOH in
5 ml of ethanol and 3 ml of water. The mixture was
stirred for 1 h at 30°C and evaporated to a volume of
3 ml, and the precipitate was filtered off. Yield 0.7 g
1
(78%), mp 187–190°C (from 75% ethanol). H NMR
spectrum, δ, ppm: 2.62 s (3H, 5-CH3), 2.72 s (3H,
SCH3), 7.19 s (1H, 6-H), 8.49 s (1H, 2-H). Found, %:
C 46.52; H 4.22; N 30.82; S 18.04. C7H8N4S. Cal-
culated, %: C 46.65; H 4.47; N 31.09; S 17.79.
7-Methyl-5-methylsulfanyl[1,2,4]triazolo[1,5-a]-
pyrimidine (VI) was synthesized in a similar way
from compound IVa. Yield 0.73 g (81%), mp 220–
1
222°C (from 75% ethanol). H NMR spectrum, δ,
Mixture IIIa/IVa, 0.51 g, was treated with a solu-
tion of 0.043 g (0.77 mmol) of potassium hydroxide in
8 ml of water, and the undissolved material (compound
IVa) was filtered off and dried. Yield 0.33 g (38%),
ppm: 2.58 s (3H, 7-CH3), 2.79 s (3H, SCH3), 6.99 s
(1H, 6-H), 9.12 s (1H, 2-H). Found, %: C 46.73;
H 4.33; N 31.19; S 17.94. C7H8N4S. Calculated, %:
C 46.65; H 4.47; N 31.09; S 17.79.
1
mp 295–297°C (from water). H NMR spectrum, δ,
Aminolysis of 7-methyl-5-methylsulfanyl[1,2,4]-
triazolo[1,5-a]pyrimidine (VII). A mixture of 0.45 g
(2.5 mmol) of compound VII and 0.31 g (3.3 mmol) of
aniline was heated for 1 h at 160°C. The mixture was
cooled and diluted with 5 ml of diethyl ether, and the
precipitate was filtered off and dried. Yield of Va
0.47 g (84%), mp 183–185°C (from propan-2-ol).
Found, %: C 64.12; H 5.07; N 30.93. C12H111N5. Cal-
culated, %: C 63.99; H 4.92; N 31.09. The H NMR
spectra of samples of Va obtained in the reaction of
3-oxobutanethioamide I with aminotriazole IIa and by
aminolysis of [1,2,4]triazolo[1,5-a]pyrimidine VIIa
were fully identical, and their mixture showed no
depression of the melting point.
ppm: 2.35 s (3H, 7-CH3), 6.91 s (1H, 6-H), 9.30 s
(1H, 2-H), 14.95 br.s (1H, N8H). Found, %: C 43.40;
H 3.71; N 33.90; S 19.19. C6H6N4S. Calculated, %:
C 43.36; H 3.64; N 33.71; S 19.29.
The filtrate was acidified with acetic acid, and the
precipitate was filtered off and dried. Yield of IIIa
1
0.10 g (12%), mp 323–325°C (from water). H NMR
spectrum, δ, ppm: 2.35 s (3H, 5-CH3), 6.89 s (1H,
6-H), 8.48 s (1H, 2-H), 14.24 br.s (1H, N8H). 13C NMR
spectrum, δC, ppm: 18.8 (5-CH3), 114.7 (C6), 146.9
(C8a), 147.9 (C5), 151.8 (C2), 177.9 (C7). Found, %:
C 43.13; H 3.50; N 33.62; S 19.06. C6H6N4S. Cal-
culated, %: C 43.36; H 3.64; N 33.71; S 19.29.
Mixture IIIb/IVb was separated in a similar way.
Yield of IVb 0.17 g (16%), mp 265–267°C (from
AcOH). H NMR spectrum, δ, ppm: 2.24 s (3H,
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