Improved synthesis of 2-amino-1,2,4-triazolo[1,5-a]pyrimidines

Article abstract of DOI:10.1134/S1070427206070172

An improved procedure is suggested for preparing 2-amino-1,2,4-triazolo[1, 5-a]pyrimidines from 3,5-diamino-1,2,4-triazole and unsaturated aromatic ketones, with acetyl protection of the amino group in the step of oxidation of 2-amino-4,7-dihydro-1,2,4-tr

Full text of DOI:10.1134/S1070427206070172

ISSN 1070-4272, Russian Journal of Applied Chemistry, 2006, Vol. 79, No. 7, pp. 1134 1137. Pleiades Publishing, Inc., 2006.
Original Russian Text
pp. 1144 1147.
V.M. Chernyshev, A.N. Sokolov, V.A. Taranushich, 2006, published in Zhurnal Prikladnoi Khimii, 2006, Vol. 79, No. 7,
ORGANIC SYNTHESIS
AND INDUSTRIAL ORGANIC CHEMISTRY
Improved Synthesis of 2-Amino-1,2,4-triazolo[1,5-a]pyrimidines
V. M. Chernyshev, A. N. Sokolov, and V. A. Taranushich
South-Russian State Technical University, Novocherkassk, Rostov oblast, Russia
Received May 4, 2006
Abstract An improved procedure is suggested for preparing 2-amino-1,2,4-triazolo[1,5-a]pyrimidines from
3,5-diamino-1,2,4-triazole and unsaturated aromatic ketones, with acetyl protection of the amino group in the
step of oxidation of 2-amino-4,7-dihydro-1,2,4-triazolo[1,5-a]pyrimidines.
DOI: 10.1134/S1070427206070172
2-Amino-1,2,4-triazolo[1,5-a]pyrimidines exhibit a
R1
R1
N
+
broad spectrum of biological activity and can be used
as analgetics [1], blood pressure regulators [2], anti-
bacterial agents [3], and herbicides [4, 5]. The pres-
ence of a reactive amino group makes these com-
pounds valuable building blocks in syntheses of bio-
logically active compounds [6, 7].
(1) H
NBS or
O
N
N
N
N
(2) NH
N
Br
2
3
N
,
H2N
N
H
R2
R2
N
XVI XXII
IX XV
1
2
2
1
2
where R = Ph, R = Me (II, IX, XVI); R = p-Cl
C H , R = Ph (III, X, XVII); R = Ph, R = p-Cl
C H (IV, XI, XVIII); R = p-MeC H , R = Ph (V,
XII, XIX); R = Ph, R = p-MeC H (VI, XIII, XX);
One of the most convenient routes to 2-amino-
1,2,4-triazolo[1,5-a]pyrimidines is the cyclocondensa-
tion of 3,5-diamino-1,2,4-triazole I with , -unsatu-
rated ketones [1, 7 11] followed by heteroaromatiza-
tion of the resulting 2-amino-4,7-dihydro-1,2,4-tri-
azolo[1,5-a]pyrimidines with bromine or N-bromosuc-
cinimide (NBS) [11, 12]. An advantage of this route,
compared to other methods for forming triazolopyri-
midine core, is high regioselectivity and availability
of the starting compounds [8, 9]. However, an experi-
mental check showed that the oxidation of the dihydro
derivatives is accompanied by formation of a large
amount of impurities (presumably azo derivatives),
probably because of side oxidation of the amino
group. Separation of these impurities involves major
loss of the desired 2-amino-1,2,4-triazolo[1,5-a]pyri-
midines, so that their yield does not exceed 25 30%.
We believe that this procedure can be improved by
acetyl protection of the amino group in the oxidation
step. This possibility was examined in the present
study with a series of 2-amino-1,2,4-triazolo[1,5-a]-
pyrimidines:
1
6
4
1
2
6
4
6 4
4
1
2
6
1
2
1
R = p-MeOC H , R = Ph (VII, XIV, XXI); R =
6
4
6 4
2
R
= p-MeC H (VIII, XV, XXII).
The first step of the suggested scheme involves the
condensation of diamine I with unsaturated ketones
to obtain 2-amino-4,7-dihydro-1,2,4-triazolo[1,5-a]-
pyrimidines. Since it was difficult to isolate and puri-
fy the majority of the dihydro derivatives because of
their high solubility, acetyl derivatives II VIII were
prepared by adding acetic anhydride to the reaction
mixture after the condensation completion. The yield
of II VIII in the one-pot process was 52 90% (see
table). These compounds were not described previous-
1
ly and were identified by elemental analysis, H NMR
spectroscopy, and mass spectrometry.
2-Acetylamino-1,2,4-triazolo[1,5-a]pyrimidines
IX XV were obtained in 84 95% yields (see table)
by oxidation of II VIII with N-bromosuccinimide in
ethanol at 50 60 C or with bromine in acetic acid at
15 20 C. In this step, it is very important to maintain
the required temperature and reactant ratio. Performing
the oxidation at higher temperatures or with excess
oxidant results in formation of difficult-to-separate
impurities identified by mass spectrometry as bromi-
nated derivatives of IX XV. Acid hydrolysis of acetyl
derivatives IX XV gave the desired 2-amino-1,2,4-
triazolo[1,5-a]pyrimidines XVI XXII in almost quan-
R1
N
1
NH
2
N
N
R
CH=CH COR
H
2N
N
H2N
N
H2
N
I
R2
N
R1
H
O
N
N
Ac O
2
N
H
R2
N
N
H
II VIII
1134

IMPROVED SYNTHESIS OF 2-AMINO-1,2,4-TRIAZOLO[1,5-a] PYRIMIDINES
Yields and properties of II XXII
1135
Com-
pound
Yield, %
86
mp, C
Formula*
1H NMR spectrum, , ppm (J, Hz)
II
244 245 C14H15N5O
1.91 s (3H, CH3), 2.00 s (3H, CH3), 4.46 d (1H, CH, J = 3.2), 5.59 d
(1H, CH, J = 3.2), 7.18 7.38 m (5H, arom.), 9.50 s (1H, NH), 9.91 s
(1H, NH)
III
IV
55
76
296 298 C19H16N5ClO 2.00 s (3H, CH3), 5.07 d (1H, CH, J = 3.3), 6.12 d (1H, CH, J = 3.3),
7.21 7.64 m (9H, arom.), 10.00 s (1H, NH), 10.10 s (1H, NH)
257 259 C19H16N5ClO 1.94 s (3H, CH3), 5.24 d (1H, CH, J = 3.5), 6.10 d (1H, CH, J = 3.5),
7.21 7.38 m (5H, Ph), 7.46 d (2H, arom., J = 8.5), 7.61 d (2H,
arom., J = 8.5), 10.05 s (1H, NH), 10.12 s (1H, NH)
V
90
61
52
264 266 C20H19N5O
228 230 C20H19N5O
1.95 s (3H, CH3), 2.26 s (3H, CH3), 5.16 d (1H, CH, J = 3.5), 6.04 d
(1H, CH, J = 3.5), 7.16 m (4H, arom.), 7.40 m (3H, arom.), 7.59 m
(2H, arom.), 9.98 s (1H, NH), 10.12 s (1H, NH)
1.94 s (3H, CH3), 2.30 s (3H, CH3), 5.15 d (1H, CH, J = 3.5), 6.08 d
(1H, CH, J = 3.5), 7.19 7.49 m (9H, arom.), 9.98 s (1H, NH),
10.17 s (1H, NH)
VI
VII
259 261 C20H19N5O2 1.95 s (3H, CH3), 3.71 s (3H, CH3O), 5.15 d (1H, CH, J = 3.5),
6.04 d (1H, CH, J = 3.5), 6.91 d (2H, arom., J = 8.5), 7.20 d (2H,
arom., J = 8.5), 7.39 7.58 m (5H, arom.), 9.97 s (1H, NH), 10.12 s
(1H, NH)
VIII
81
273 274 C21H21N5O
1.96 s (3H, CH3), 2.26 s (3H, CH3), 2.31 s (3H, CH3), 5.12 d (1H,
CH, J = 3.7), 6.03 d (1H, CH, J = 3.7), 7.12 7.22 m (6H, arom.),
7.47 d (2H, arom., J = 8.2), 9.94 s (1H, NH), 10.11 s (1H, NH)
2.14 s (3H, CH3), 2.63 s (3H, CH3), 7.45 s (1H, CH), 7.60 m (3H,
arom.), 8.17 m (2H, arom.), 10.86 s (1H, NH)
IX
X
95 (b)
92 (a)
236 237 C14H13N5O
314 315 C19H14N5ClO 2.20 s (3H, CH3), 7.44 7.70 m (5H, arom.), 8.00 s (1H, CH), 8.32
8.44 m (4H, arom.), 10.86 s (1H, NH)
XI
XII
90(a), 88(b) 272 274 C19H14N5ClO 2.18 s (3H, CH3), 7.58 7.71 m (5H, arom), 8.06 s (1H, CH), 8.32
8.42 m (4H, arom.), 10.92 s (1H, NH)
88 (a)
302 304 C20H17N5O
2.18 s (3H, CH3), 2.43 s (3H, CH3), 7.44 d (2H, arom., J = 8.0),
7.57 7.59 m (3H, arom.), 8.04 s (1H, CH), 8.24 8.36 m (4H, arom.),
10.94 s (1H, NH)
XIII
XIV
XV
91(a), 90(b) 276 277 C20H17N5O
2.18 s (3H, CH3), 2.39 s (3H, CH3), 7.38 d (2H, arom., J = 8.0),
7.57 7.69 m (3H, arom.), 8.02 s (1H, CH), 8.25 8.28 m (4H, arom.),
10.93 s (1H, NH)
84 (a)
278 280 C20H17N5O2 2.18 s (3H, CH3), 3.88 s (3H, CH3O), 7.19 d (2H, arom., J = 8.9),
7.59 m (3H, arom.), 8.04 s (1H, CH), 8.35 8.42 m (4H, arom.),
10.94 s (1H, NH)
90(a), 87(b) 305 306 C21H19N5O
2.18 s (3H, CH3), 2.40 s (3H, CH3), 2.43 s (3H, CH3), 7.36 7.45 m
(4H, arom.), 8.00 s (1H, CH), 8.22 8.27 m (4H, arom.), 10.92 s
(1H, NH)
XVI
94
90
89
93
249 250** C12H11N5
2.53 s (3H, CH3), 6.34 s (2H, NH2), 7.16 s (1H, CH), 7.58 m (3H,
arom.), 8.12 m (2H, arom.)
XVII
XVIII
XIX
207 209 C17H12N5Cl 6.52 s (2H, NH2), 7.54 m (3H, arom.), 7.69 d (2H, arom., J = 8.1),
7.84 s (1H, CH), 8.30 8.33 m (4H, arom.)
220
C17H12N5Cl 6.52 s (2H, NH2), 7.59 7.62 m (5H, arom.), 7.83 s (1H, CH), 8.24
221***
244 245 C18H15N5
8.27 m (2H, arom.), 8.24 d (2H, arom., J = 8.6)
2.42 s (3H, CH3), 6.47 s (2H, NH2), 7.43 d (2H, arom., J = 8.1),
7.53 m (3H, arom.), 7.78 s (1H, CH), 8.21 d (2H, arom., J = 8.1),
8.28 m (2H, arom.)
XX
95
217
219****
C18H15N5
2.38 s (3H, CH3), 6.45 s (2H, NH2), 7.35 d (2H, arom., J = 8.0),
7.59 m (3H, arom.), 7.76 s (1H, CH), 8.18 8.24 m (4H, arom.)
RUSSIAN JOURNAL OF APPLIED CHEMISTRY Vol. 79 No. 7 2006

1136
CHERNYSHEV et al.
Table. (Contd.)
Com-
Yield, %
mp, C
Formula*
1H NMR spectrum, , ppm (J, Hz)
pound
XXI
91
92
238 240 C18H15N5O
187 188 C19H17N5O
3.87 s (3H, CH3O), 6.46 s (2H, NH2), 7.15 d (2H, arom., J = 8.9),
7.55 m (3H, arom.), 7.77 s (1H, CH), 8.27 8.35 m (4H, arom.)
2.38 s (3H, CH3), 2.42 s (3H, CH3), 6.51 s (2H, NH2), 7.35 d (2H,
arom., J = 8.1), 7.41 d (2H, arom., J = 8.1), 7.74 s (1H, CH), 8.18 d
(2H, arom., J = 8.1), 8.19 d (2H, arom., J = 8.1)
XXII
* The results of the C, H, N analysis were consistent with the calculated composition within 0.32%; the mass spectra of all
+
the compounds contain a strong [M + H] peak.
** mp 245 250 C [4].
*** mp 210 211 C [11].
**** mp 220 222 C [11].
titative yield (see table). The overall yield of XVI
XXII based on I was 40 70%. Compounds IX XXII
were identified by elemental analysis, H NMR spec-
(b) To a solution of 0.003 mol of II, IV, VII, or
VIII and 0.27 g (0.0044 mol) of sodium acetate in
1
10 15 ml of acetic acid, 0.48 g (0.003 mol) of Br
2
troscopy, and mass spectrometry (see table).
was added dropwise over a period of 5 min at 15
20 C. The solution was stirred for 30 min and diluted
with 15 20 ml of water. The precipitate was filtered
off, washed with water (20 ml), and crystallized from
DMF ethanol (1 : 3).
EXPERIMENTAL
1
The H NMR spectra were recorded on a Varian
Unity-300 spectrometer (300 MHz, DMSO-d , inter-
6
2-Amino-1,2,4-triazolo[1,5-a]pyrimidines XVI
XXII. Concentrated HCl (1 ml) was added to a sus-
pension of 0.0014 mol of IX XV in 10 ml of ethanol;
the mixture was refluxed for 40 min, the solvent was
distilled off, and the residue was neutralized with
nal reference TMS). The mass spectra were taken on
a Finnigan LCQ Deca XP MAX device in the electro-
spray mode with positive polarization at direct inlet of
1
0.5 mg ml solutions of the compounds in acetoni-
trile. Elemental analysis was performed with a Perkin
Elmer 2400 analyzer. The melting points were deter-
mined by the capillary method with a PTP device.
aqueous NH to pH 6 8. The precipitate was filtered
3
off and crystallized from DMF ethanol, 1 : 3.
2-Acetylamino-4,7-dihydro-1,2,4-triazolo[1,5-a]-
pyrimidines II VIII. A mixture of 1 g (0.01 mol) of
I, 0.01 mol of appropriate unsaturated ketone, and
4 ml of anhydrous DMF was refluxed for 20 min,
CONCLUSIONS
(1) Successive reactions of 3,5-diamino-1.2.4-tri-
azole with , -unsaturated aromatic ketones and ace-
tic anhydride allow one-pot synthesis of 2-acetyl-
amino-4,7-dihydro-1,2,4-triazolo[1,5-a]pyrimidines in
52 90% yield.
after which 1.39 g (0.0136 mol) of Ac O was added,
2
and the mixture was refluxed for an additional 3 min.
Then the mixture was cooled, 4 ml of acetonitrile was
added, and the precipitate of the target product was
filtered off and washed with 20 ml of acetone. Com-
pounds II VIII were purified by twofold refluxing
with 5 ml of acetonitrile.
(2) The acetyl protection of the amino group in
2-amino-4,7-dihydro-1,2,4-triazolo[1,5-a]pyrimidines
in the step of their oxidation with N-bromosuccin-
imide or bromine prevents oxidation of the amino
group and allows the overall yield of 2-amino-1,2,4-
triazolo[1,5-a]pyrimidines to be increased to 40 70%
based on 3,5-diamino-1,2,4-triazole.
2-Acetylamino-1,2,4-triazolo[1,5-a]pyrimidines
IX XV. (a) To a stirred mixture of 0.003 mol of ace-
tyl derivative III VIII and 0.27 g (0.0044 mol) of
sodium acetate in 20 ml of ethanol, 0.52 g (0.003 mol)
of N-bromosuccinimide was added in 0.1-g portions
over a period of 10 min at 50 60 C. Then the mixture
was refluxed for 15 min and diluted with 15 20 ml of
water; the precipitate was filtered off, washed with
20 ml of water, and crystallized from DMF ethanol
(1 : 3).
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IMPROVED SYNTHESIS OF 2-AMINO-1,2,4-TRIAZOLO[1,5-a] PYRIMIDINES
1137
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