Synthesis of [1,2,4]triazolo[4,3-a]pyrimidin-7(8H)-one derivatives by nucleophilic substitution of the methylmercapto group in 4-hydroxy-6-methyl-2-methylthiopyrimidine [3]

Full text of DOI:10.1023/A:1021277803841

Chemistry of Heterocyclic Compounds, Vol. 38, No. 9, 2002
a
SYNTHESIS OF [1,2,4]TRIAZOLO[4,3- ]PYRIMIDIN-
7(8H)-ONE DERIVATIVES BY NUCLEOPHILIC
SUBSTITUTION OF THE METHYLMERCAPTO GROUP
IN 4-HYDROXY-6-METHYL-2-METHYLTHIOPYRIMIDINE
V. A. Yanchenko, A. N. Gur'eva, A. R. Khairulin, and A. M. Demchenko
Keywords: 4-hydroxy-6-methyl-2-methylmercaptopyrimidine, [1,2,4]triazolo[4,3-a]pyrimidin-7(8H)-
one, nucleophilic substitution, spontaneous cyclization.
Triazolopyrimidines display anti-inflammatory [1], vasodilative [2], and bactericidal activity [3].
In previous work [4], we showed that heating 2-arylidenehydrazones of 4-hydroxy-6-methylpyrimidines
in nitrobenzene at reflux gives derivatives of [1,2,4]triazolo[4,3-a]pyrimidin-7(8H)-one. A method described in
the literature for obtaining this system involves the reaction of 4-hydroxy-6-methyl-2-methylthiopyrimidine (1)
with hydrazides of carboxylic acids in phenol [5, 6].
R
R
Me
Me
Me
O
ArCONHNH2
Me
N
N
N
N
NH
O
N
H
N
O
N
H
1
S
O
N
H
N
H
3a–d
2
3 a R = H; b R = Cl; c R = Me; d R = CMe3
We have found that the nucleophilic substitution upon fusing equimolar amounts of compound 1 and
hydrazides of aromatic carboxylic acids at 200°C does not stop at formation of 2-benzoylhydrazines of
4-hydroxy-6-methylpyrimidine (2) but proceeds with spontaneous cyclization to give derivatives of 3-aryl-5-
methyl[1,2,4]triazolo[4,3-a]pyrimidin-7(8H)-one (3). The NMR spectrum of compound 3b is completely
identical to the spectrum of the compound obtained by the oxidative cyclization of 2-(4-chlorobenzylidene)-
hydrazone of 4-hydroxy-6-methylpyrimidine in nitrobenzene [4].
1
The structures of the compounds synthesized were supported by H NMR spectral data obtained at
300 MHz, in DMSO-d6 with TMS as the internal standard.
a
5-Methyl-3-phenyl[1,2,4]triazolo[4,3- ]pyrimidin-7(8H)-one (3a)
1
. Mixture of compound (0.01 mol)
and benzoic acid hydrazide (0.01 mol) was heated for 1 h at 200°C. Upon cooling, the reaction mixture was
triturated in 2-propanol, filtered, and dried to give compound 3a in 78% yield; mp >300°C (DMF). IR spectrum,
1
ν, cm-1 (KBr pellets): 1610 (C=N); 1685 (C=O). H NMR spectrum, δ, ppm: 2.34 (3H, s, CH3); 5.69 (1H, s,
CH); 7.43-8.14 (5H, m, C6H5); 12.97 (1H, br. s, NH). Found, %: N 24.7. C12H10N4O. Calculated, %: N 24.8.
__________________________________________________________________________________________
T. G. Shevchenko Chernigov State University, 14038 Chernigov, Ukraine; e-mail: demch@cn.relc.com.
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 9, pp. 1296-1297, September, 2002. Original
article submitted April 27, 2002.
1138
0009-3122/02/3809-1138$27.00©2002 Plenum Publishing Corporation

a
was
obtained
3-(4-Chlorophenyl)-5-methyl[1,2,4]triazolo[4,3- ]pyrimidin-7(8H)-one
(3b)
analogously to compound 3a from equimolar amounts of pyrimidine 1 and 4-chlorobenzoic acid hydrazide. The
yield of compound 3b was 79%; mp >300°C (DMF). IR spectrum, ν, cm-1 (KBr pellets): 1600 (C=N); 1675
(C=O). 1H NMR spectrum, δ, ppm: 2.34 (3H, s, CH3); 5.85 (1H, s, CH); 7.56 and 8.11 (4H, dd, C6H4); 13.2 (1H,
br. s, NH). Found, %: N 21.3; Cl 13.3. C12H9ClN4O. Calculated, %: N 21.5; Cl 13.6.
a
was
obtained
5-Methyl-3-(4-methylphenyl)[1,2,4]triazolo[4,3- ]pyrimidin-7(8H)-one
(3c)
analogously to compound 3a from equimolar amounts of pyrimidine 1 and 4-methylbenzoic acid hydrazide. The
yield of compound 3c was 83%; mp >300°C (DMF). IR spectrum, ν, cm-1 (KBr pellets): 1600 (C=N); 1675
(C=O). 1H NMR spectrum, δ, ppm: 2.33 (3H, s, CH3); 2.37 (3H, s, CH3); 5.84 (1H, s, CH); 7.33 and 8.99 (4H,
dd, C6H4); 13.2 (1H, br. s, NH). Found, %: N 23.5. C13H12N4O. Calculated, %: N 23.3.
tert
a
was obtained
3-(4- -Butylphenyl)-5-methyl[1,2,4]triazolo[4,3- ]pyrimidin-7(8H)-one (3d)
analogously to compound 3a from equimolar amounts of pyrimidine 1 and 4-tert-butylbenzoic acid hydrazide.
The yield of compound 3d was 81%; mp >300°C (DMF). IR spectrum, ν, cm-1 (KBr pellets): 1600 (C=N); 1675
(C=O). 1H NMR spectrum, δ, ppm: 1.31 (9H, s, CH3); 2.04 (3H, s, CH3); 5.53 (1H, s, CH); 7.51 and 7.88 (4H,
dd, C6H4); 10.2 (1H, br. s, NH). Found, %: N 20.2. C16H17N4O. Calculated, %: N 19.9.
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