Cyclocondensation of N-aryl-3-oxobutanethioamides with 1H-1,2,4-triazol-5- amine

Article abstract of DOI:10.1134/S1070428008100229

Reactions of N-aryl-3-oxobutanethioamides with 1H-1,2,4-triazole-5-amine give mixtures of 7-arylamino-5-methyl[1,2,4]triazolo[1,5-a]pyrimidines, 5-methyl-4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidine-7-thione, 7-methyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrim

Full text of DOI:10.1134/S1070428008100229

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2008, Vol. 44, No. 10, pp. 1528–1531. © Pleiades Publishing, Ltd., 2008.
Original Russian Text © V.N. Britsun, 2008, published in Zhurnal Organicheskoi Khimii, 2008, Vol. 44, No. 10, pp. 1550–1553.
Cyclocondensation of N-Aryl-3-oxobutanethioamides
with 1H-1,2,4-Triazol-5-amine
V. N. Britsun
Institute of Organic Chemistry, National Academy of Sciences of Ukraine, ul. Murmanskaya 5, Kiev, 02660 Ukraine
e-mail: bvn1967@rambler.ru
Received January 25, 2008
Abstract—Reactions of N-aryl-3-oxobutanethioamides with 1H-1,2,4-triazole-5-amine give mixtures of
7-arylamino-5-methyl[1,2,4]triazolo[1,5-a]pyrimidines, 5-methyl-4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidine-
7-thione, 7-methyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidine-5-thione, and 5-arylamino-7-methyl[1,2,4]tri-
azolo[1,5-a]pyrimidines whose ratio depends on the substituent in the aryl group of initial N-aryl-3-oxobutane-
thioamide and solvent nature (the presence of a proton-donor solvent).
DOI: 10.1134/S1070428008100229
We recently showed [1] that N-phenyl-3-oxobu-
tanethioamide reacts with 3-amino-5-R-1,2,4-triazoles
(R = H, MeS) in acetic acid to give mixtures of
5-methyl-7-phenylamino-2-R-[1,2,4]triazolo[1,5-a]-
pyrimidines, 5-methyl-2-R-4,7-dihydro[1,2,4]triazolo-
[1,5-a]pyrimidine-7-thiones, and 7-methyl-2-R-4,5-di-
hydro[1,2,4]triazolo[1,5-a]pyrimidine-5-thiones whose
structure was confirmed by the 1H and 13C NMR spec-
tra and X-ray diffraction data. The reaction in the
absence of a proton-donor solvent was selective, and
the only products were the corresponding 5-methyl-7-
phenylamino-2-R-[1,2,4]triazolo[1,5-a]pyrimidines
[2]. However, the effect of substituents in the phenyl
ring of initial N-aryl-3-oxobutanethioamides on the
reaction direction in the presence of a proton-donor
solvent and in the absence of it was not studied. There-
fore, in the present work we examined the regioselec-
tivity in the cyclization of 1H-1,2,4-triazol-5-amine
with N-aryl-3-oxobutanethioamides having various
substituents in the benzene ring in acetic acid and
under solvent-free conditions with a view to supple-
ment and summarize our previous results [1, 2] and
elucidate the mechanism of the process.
The results of the reactions of N-aryl-3-oxobutane-
thioamides Ia–If with 1H-1,2,4-triazol-5-amine (II)
are collected in table (Scheme 1). The products were
the corresponding 7-arylamino-5-methyl[1,2,4]triazolo-
[1,5-a]pyrimidines IIIa–IIIf, 5-methyl-4,7-dihydro-
[1,2,4]triazolo[1,5-a]pyrimidine-7-thione (IV),
7-methyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidine-
5-thione (V), and 5-(4-nitrophenylamino)-7-methyl
[1,2,4]triazolo[1,5-a]pyrimidine (VIf).
Scheme 1.
NHAr
N
S
O
S
N
N
N
N
N
N
+
+
Ar
N
–H2O, –H2S (–ArNH2)
Me
N
NH2
N
H
Me
Me
N
Me
N
H
H
Ia–If
II
IIIa–IIIf
IV
Me
N
N
N
N
N
N
+
+
S
N
ArNH
N
H
V
VIf
Ar = Ph (a), 4-MeOC6H4 (b), 4-MeC6H4 (c), 3-ClC6H4 (d), 3-F3CC6H4 (e), 4-O2NC6H4 (f).
1528

CYCLOCONDENSATION OF N-ARYL-3-OXOBUTANETHIOAMIDES
1529
Reaction of N-aryl-3-oxobutanethioamides Ia–If with
1H-1,2,4-triazol-5-amine (ІІ)
As we showed previously on the basis of the X-ray
diffraction data [1, 3, 4], 1,2,4-triazole derivatives
react with electrophiles exclusively at the N2 atom.
Therefore, compound VIf was assigned the structure of
[1,2,4]triazolo[1,5-a]pyrimidine rather than isomeric
[1,2,4]triazolo[4,3-a]pyrimidine. Taking into account
that our experiments were performed with structurally
related initial compounds, the corresponding substit-
uent constants σ are given in table to estimate the
substituent effect. It is seen that the reactions carried
out in the absence of a proton-donor solvent were gen-
erally selective: the major products were 7-arylamino-
5-methyl[1,2,4]triazolo[1,5-a]pyrimidines IIIa–IIId
(run nos. 1–4, see table). In going to strong electron-
withdrawing substituents (such as trifluoromethyl and
nitro groups; Hammett constants σ +0.43 and +0.778,
respectively), the reaction becomes nonselective (run
nos. 5 and 6). The condensations in acetic acid were
not selective, and the products were mixtures of com-
pounds IIIa–IIIe, IV, V, and VIf. Obviously, the
regioselectivity of the process is controlled by both
substituent nature in the initial thioamide and proton-
donor solvent.
Yields of III, IV, and V, %
Run Initial com-
no. pound no.
Hammett
constant σ
AcOH
no solvent
62, 0, 0
50, 0, 0
70, 0, 0
68, 0, 0
64, 11, 0
40, 5, 0c
a1a
2
Ia
Ib
Ic
Id
Ie
If
18, 44, 15
0, 41, 30
31, 32, 16
43, 26, 11
33, 22, 80
41, 0, 0b
–0.000
–0.268
–0.170
+0.373
+0.430
+0.778
3
4
5
6
a
b
c
Data of [1, 2].
Compound VIf was also formed (yield 19%).
Compound VIf was also formed (yield 24%).
group of N-aryl-3-oxobutanethioamide Ia–If is the
preferred reaction path.
There are reasons to believe [5, 6] that thioamides
Ia–If react with aminotriazole II to form initially
enamino thioamides VIIa–VIIf and IXa–IXf and that
the latter are converted into tetrahedral intermediates
VIIIa–VIIIf and Xa–Xf, respectively [7]. These proc-
esses are reversible (Scheme 2). The direction of
further transformations of intermediates VIIIa–VIIIf
and Xa–Xf depends on the nature of substituent in the
benzene ring and proton-donor power of the solvent
(AcOH; Scheme 3).
The cyclocondensation of 1H-1,2,4-triazole-5-
amine (II) with N-aryl-3-oxobutanethioamides Ia–If
could involve attack by the exocyclic amino group in
II at both carbonyl and thiocarbonyl groups in sub-
strate Ia–If, followed by ring closure. Both in acetic
acid and without a solvent, the main reaction pathways
are those leading to [1,2,4]triazolo[1,5-a]pyrimidines
IIIa–IIIf and IV: their overall yield ranges from 41 to
75%. [1,2,4]Triazolo[1,5-a]pyrimidine derivatives V
and VIf are formed as minor products (overall yield 8–
30%). Thus the cyclization involving attack by the
amino group of aminotriazole II at the ketone carbonyl
Since the energy of C–S bond is lower than that of
the C–N bond (272 and 285 kJ/mol, respectively [8]),
high selectivity of the process in the absence of proton-
donor solvent for Ar = Ph, 4-MeOC6H4, 4-MeC6H4,
and 3-ClC6H4 may be rationalized assuming that inter-
mediate VIIIa–VIIId is transformed only through
Scheme 2.
Me
S
H
H
IIIa–IIIf
N
Me
N
–H2S
N
N
N
N
II
NH
HN
N
HS
NHAr
IV
Ar
VIIa–VIIf
–ArNH2
VIIIa–VIIIf
Ia–If
Me
Me
V
–ArNH2
–H2S
II
S
N
N
N
N
HN
NH2
SH
NHAr
N
Ar
N
N
VIf
H
IXa–IXf
Xa–Xf
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 44 No. 10 2008

BRITSUN
1530
Scheme 3.
H
N
H
Me
Me
N
N
N
N
N
2H+
N
N
IV
IIIa–IIIf
–ArNH2
–2H+
a
b
–H2S
X
X
HS
N
HS
N
H
H
H
H
XI
XIIa–XIIf
VIIIa–VIIIf
H
H
Me
Me
N
N
N
N
N
N
H+
N
N
IIIa, IIIc–IIIf
IV
–H2S, –H+
c
d
–ArNH2
X
X
HS
N
HS
N
H
H
H
XIII
XIV
transition state XІІa–XIId (path b). Fairly high elec-
tron density on the N–C5 bond therein makes that bond
strong, which favors dissociation of the C–S bond with
elimination of hydrogen sulfide and formation of
[1,2,4]triazolo[1,5-a]pyrimidine IIIa–IIId. Electron-
withdrawing substituents (X = CF3, NO2) reduce the
electron density on the N–C5 bond, thus favoring its
cleavage with elimination of arylamine and formation
of [1,2,4]triazolo[1,5-a]pyrimidine-5-thione (IV) (path
d, transition state XIV).
Thus we have shown that cyclocondensation of
N-aryl-3-oxobutanethioamides with 1H-1,2,4-triazol-5-
amine could give rise to four different products whose
ratio and yield may be controlled by varying the sol-
vent nature (using proton-donor solvents) and substit-
uent in the benzene ring of the initial thioamide.
EXPERIMENTAL
1
The H NMR spectra were recorded from solutions
in DMSO-d6 on a Varian-300 instrument (300 MHz)
In going to acid medium, the effect of substituent in
the benzene ring of N-aryl-3-oxobutanethioamides Ia–
If changes to the opposite. Depending on the substit-
uent nature, protonation of intermediate VIII in acetic
acid can occur either at both nitrogen atoms (N3 and
exocyclic, intermediate XІ) or only at N3 (intermediate
XIII). If the X substituent is electron-donating (the
most pronounced effect is observed for X = MeO),
protonation of the exocyclic nitrogen atom facilitates
elimination of aromatic amine with formation of thione
IV (path a). If X is an electron-withdrawing group,
elimination of hydrogen sulfide is likely to follow path
c through intermediate XІІІ. Presumably, the forma-
tion of triazolo[1,5-a]pyrimidines IIIa and IIIc–IIIf is
also favored to some extent by protonation of inter-
mediate XІІI at the sulfur atom.
In most cases, the transformation of intermediate
Xa–Xe in acid medium leads to formation of thione V
via elimination of arylamine, which may also be ex-
plained by protonation of the exocyclic nitrogen atom.
If the basicity of the latter is reduced (e.g., due to elec-
tron-withdrawing effect of the nitro group), interme-
diate Xf is stabilized through a transition state anal-
ogous to XIII.
using tetramethylsilane as internal reference.
General procedure for the reaction of N-aryl-3-
oxobutanethioamides Ia–If with 1H-1,2,4-triazol-5-
amine (II). a. A solution of 10 mmol of N-aryl-3-oxo-
butanethioamide Ia–If and 0.84 g (10 mmol) of amino-
triazole II in 5 ml of acetic acid was heated for 5 h at
100°C. The mixture was cooled, and the precipitate
(a mixture of compounds IV and V or IIIf and VIf)
was filtered off, washed on a filter with diethyl ether
(2×3 ml), and dried. The ratio of regioisomers IV and
1
V was determined from the H NMR spectra by com-
paring intensities of the 2-H and 6-H signals [1], and
the isomers were separated according to the procedure
described in [1]. The filtrate was evaporated in air to
isolate triazolo[1,5-a]pyrimidines IIIa–IIIe. Com-
pounds IIIf and VIf were separated by fractional crys-
tallization from benzonitrile. The yields of compounds
ІІІa–IIIf, ІV, V, and VIf are given in table.
b. A mixture of finely powdered N-aryl-3-oxobu-
tanethioamide Ia–If, 10 mmol, and 1H-1,2,4-triazol-5-
amine (II), 0.84 g (1 mmol), was thoroughly ground
and heated for 0.5 h at 130°C. The mixture was cooled
and treated with 4 ml of diethyl ether, and the precip-
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 44 No. 10 2008

CYCLOCONDENSATION OF N-ARYL-3-OXOBUTANETHIOAMIDES
1531
itate was filtered off. The products were separated and
identified as described above in a.
N 30.93. C12H10N6O2. Calculated, %: C 53.33; H 3.73;
N 31.10.
5-Methyl-N-phenyl[1,2,4]triazolo[1,5-a]pyrimi-
din-7-amine (ІІІa). mp 182–184°C (from propan-2-
ol); published data [1]: mp 183–185°C. The H NMR
5-Methyl-4,7-dihydro[1,2,4]triazolo[1,5-a]pyrim-
idine-7-thione (IV). mp 296–298°C; published data:
mp 295–297°C [1], 310°C [9]. The H NMR spectrum
1
1
spectrum of IIIa coincided with that given in [1].
Found, %: C 64.15; H 5.19; N 30.80. C12H11N5. Calcu-
lated, %: C 63.99; H 4.92; N 31.09.
of IV coincided with that reported in [1]. Found, %:
C 43.52; H 3.42; N 33.95. C6H6N4S. Calculated, %:
C 43.36; H 3.64; N 33.71.
7-Methyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrim-
idine-5-thione (V). mp 321–324°C; published data
[1]: mp 323–325°C. The 1H NMR spectrum of V coin-
cided with that reported in [1]. Found, %: C 43.10;
H 3.39; N 33.45. C6H6N4S. Calculated, %: C 43.36;
H 3.64; N 33.71.
N-(4-Methoxyphenyl)-5-methyl[1,2,4]triazolo-
[1,5-a]pyrimidin-7-amine (ІІІb). mp 188–190°C
(from ethanol). 1H NMR spectrum, δ, ppm: 2.34 s (3H,
CH3), 3.80 s (3H, CH3O), 6.16 s (1H, 6-H), 7.06 d (2H,
2′-H, 6′-H, J = 8.4 Hz), 7.32 d (2H, 3′-H, 5′-H, J =
8.4 Hz), 8.43 s (1H, 2-H), 10.05 s (1H, NH). Found,
%: C 60.96; H 4.87; N 27.62. C13H13N5O. Calculated,
%: C 61.17; H 5.13; N 27.43.
7-Methyl-N-(4-nitrophenyl)[1,2,4]triazolo[1,5-a]-
pyrimidin-5-amine (VIf). mp 350–355°C (from
1
PhCN). H NMR spectrum, δ, ppm: 2.24 s (3H, CH3),
5-Methyl-N-(4-methylphenyl)[1,2,4]triazolo-
[1,5-a]pyrimidin-7-amine (ІІІc). mp 197–199°C
(from ethanol). 1H NMR spectrum, δ, ppm: 2.35 s (3H,
4′-CH3), 2.40 s (3H, 5-CH3), 6.28 s (1H, 6-H), 7.27 d
(2H, 3′-H, 5′-H, J = 8.1 Hz), 7.31 d (2H, 2′-H, 6′-H,
J = 8.1 Hz), 8.44 s (1H, 2-H), 10.10 s (1H, NH).
Found, %: C 64.99; H 5.71; N 29.12. C13H13N5. Calcu-
lated, %: C 65.26; H 5.48; N 29.27.
5.76 s (1H, 6-H), 7.20 d (2H, 2′-H, 6′-H, J = 9.0 Hz),
8.20 d (2H, 3′-H, 5′-H, J = 9.0 Hz), 9.00 s (1H, 2-H),
10.76 br.s (1H, NH). Found, %: C 53.07; H 4.02;
N 31.16. C12H10N6O2. Calculated, %: C 53.33; H 3.73;
N 31.10.
REFERENCES
N-(3-Chlorophenyl)-5-methyl[1,2,4]triazolo-
[1,5-a]pyrimidin-7-amine (ІІІd). mp 238–240°C
(from DMSO). 1H NMR spectrum, δ, ppm: 2.45 s (3H,
CH3), 6.48 s (1H, 6-H), 7.31 m (1H, 5′-H), 7.43–
7.49 m (3H, 2′-H, 4′-H, 6′-H), 8.47 s (1H, 2-H), 10.31 s
(1H, NH). Found, %: C 55.25; H 3.70; N 27.19.
C12H10ClN5. Calculated, %: C 55.50; H 3.88; N 26.97.
1. Britsun, V.N., Borisevich, A.N., Samoilenko, L.S., Cher-
nega, A.N., and Lozinskii, M.O., Russ. J. Org. Chem.,
2006, vol. 42, p. 1516.
2. Britsun, V.N., Borisevich, A.N., and Lozinskii, M.O.,
Russ. J. Org. Chem., 2007, vol. 43, p. 1548.
3. Britsun, V.N., Esipenko, A.N., Chernega, A.N., and Lo-
zinskii, M.O., Russ. J. Org. Chem., 2005, vol. 41, p. 108.
4. Britsun, V.N., Esipenko, A.N., Chernega, A.N., Rusa-
nov, E.B., and Lozinskii, M.O., Khim. Geterotsikl.
Soedin., 2007, p. 1660.
5-Methyl-N-[3-(trifluoromethyl)phenyl][1,2,4]-
triazolo[1,5-a]pyrimidin-7-amine (ІІІe). mp 185–
187°C (from nitromethane). H NMR spectrum, δ,
ppm: 2.46 s (3H, CH3), 6.49 s (1H, 6-H), 7.59 m (1H,
6′-H), 7.70 m (1H, 5′-H), 7.77–7.83 m (2H, 2′-H,
4′-H), 8.49 s (1H, 2-H), 10.41 s (1H, NH). Found, %:
C 53.02; H 3.62; N 24.12. C13H10F3N5. Calculated, %:
C 53.25; H 3.44; N 23.88.
1
5. Borisevich, A.N. and Pel’kis, P.S., Zh. Org. Khim., 1967,
vol. 3, p. 1339.
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Russ. J. Org. Chem., 2007, vol. 43, p. 907.
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Moscow: Mir, 1987, vol. 2, p. 55.
8. Gauptman, Z., Grefe, Yu., and Remane, Kh., Orga-
nicheskaya khimiya, Moscow: Khimiya, 1979, p. 52.
5-Methyl-N-(4-nitrophenyl)[1,2,4]triazolo[1,5-a]-
pyrimidin-7-amine (ІІІf). mp 320–325°C (from
DMSO). 1H NMR spectrum, δ, ppm: 2.46 s (3H, CH3),
6.81 s (1H, 6-H), 7.70 d (2H, 2′-H, 6′-H, J = 9.0 Hz),
8.29 d (2H, 3′-H, 5′-H, J = 9.0 Hz), 8.53 s (1H, 2-H),
10.70 br.s (1H, NH). Found, %: C 53.58; H 3.70;
9. Allen, C.F., Beilfuss, H.R., Burness, D.M., and Rey-
nolds, G.A., J. Org. Chem., 1959, vol. 24, p. 787.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 44 No. 10 2008