Synthesis of N,7-diaryl-5-methyl-4,7-dihydro-1,2,4-triazolo[1,5-a]- pyrimidine-6-carboxamides

Article abstract of DOI:10.1134/S1070363214010125

Reaction of N-arylamides of acetoacetic acid with aromatic aldehyde and 3-amino-1,2,4-triazole derivatives has resulted in N,7-diaryl-5-methyl-4,7- dihydro-1,2,4-triazolo[1,5-a]pyrimidine-6-carboxamides.

Full text of DOI:10.1134/S1070363214010125

ISSN 1070-3632, Russian Journal of General Chemistry, 2014, Vol. 84, No. 1, pp. 82–85. © Pleiades Publishing, Ltd., 2014.
Original Russian Text © V.L. Gein, T.M. Zamaraeva, M.I. Vakhrin, 2014, published in Zhurnal Obshchei Khimii, 2014, Vol. 84, No. 1, pp. 86–89.
Synthesis of N,7-Diaryl-5-methyl-4,7-dihydro-1,2,4-triazolo[1,5-а]-
pyrimidine-6-carboxamides
V. L. Gein, T. M. Zamaraeva, and M. I. Vakhrin†
Perm State Pharmaceutical Academy, ul. Polevaya 2, Perm, 614990 Russia
e-mail: geinvl48@mail.ru
Received February 21, 2013
Abstract―Reaction of N-arylamides of acetoacetic acid with aromatic aldehyde and 3-amino-1,2,4-triazole
derivatives has resulted in N,7-diaryl-5-methyl-4,7-dihydro-1,2,4-triazolo[1,5-а]pyrimidine-6-carboxamides.
DOI: 10.1134/S1070363214010125
Various modifications of the Biginelli reaction [1]
are promising for synthesis of carbonyl-containing
heterocyclic systems [1]. Using the aminoheterocycles
as heterocyclic analogues of urea, the annulated
pyrimidines, in particular, azolopyrimidines, can be
prepared [2–4].
The presence of two nonequivalent nitrogen atoms
(N2 and N4) in the 3-amino-1,2,4-triazole molecule
suggested possible formation of two reaction products.
However, compounds I–XIII were formed predo-
minantly, seemingly, due to higher basicity and
nucleophilicity of the N2 atom.
The three-component reaction of benzoylpiruvic
acid methyl esters with 3-amino-1,2,4-triazole hydro-
chloride and an aromatic aldehyde has given 4-aryl-3-
benzoyl-2-methoxycarbonyl-1,4-dihydropyrimido[1,2-
b]triazoles [5]. The three-component condensation of
3-amino-5-alkylthio-1,2,4-triazoles with aromatic al-
dehydes and acetoacetamides has been known as well
[6].
Carboxamides I–XIII were colorless crystalline
solids, soluble in DMF, DMSO, acetic acid, and
ethanol and insoluble in water.
IR spectra of I–XIII contained the absorption bands
assigned to stretching vibrations of the amide groups
(1660–1680 cm–1), the N–H bond (3150–3200 cm–1),
and the C=C bond (1600–1620 cm–1).
Along with the signals of aromatic ring protons and
of the corresponding substituents, the singlets of
methyl (1.66–2.21 ppm), methine (6.36–7.51 ppm),
and NH (8.83–9.69 and 9.78–10.30 ppm) protons were
observed in 1H NMR spectra of the prepared
compounds.
Previously, we studied the reaction of N-arylamides
of acetoacetic acid with aromatic aldehyde and 5-
aminotetrazole monohydrate resulting in N,7-diaryl-5-
methyl-4,7-dihydrotetrazolo[1,5-а]pyrimidine-6-carbox-
amides [7].
In this work we obtained N,7-diaryl-5-methyl-4,7-
dihydro-1,2,4-triazolo[1,5-а]pyrimidine-6-carboxamides
I–XIII via the three-component reaction of N-aryl-
amides of acetoacetic acid with aromatic aldehyde and
3-amino-1,2,4-triazole (see Scheme 1).
The mass spectrum of IX contained the peaks of
[М
–
(СН3)2С6Н3NHCO]+ (m/z 256), [М
–
(СН3)2С6Н3NHCO – С2Н5OC6H4]+ (m/z 135), and
[(СН3)2С6Н3NH]+ (m/z 121), [Ph]+ (m/z 77). The
structure of VIII was confirmed by the presence of the
The syntheses were performed in the absence of
solvent and without any catalyst, at 120–150°C during
5 min using equimolar amounts of acetoacetanilide,
aromatic aldehyde, and 3-amino-1,2,4-triazole.
[М
–
(СН3)2С6Н3NHCO]+ (m/z 268), [М
–
(СН3)2С6Н3NHCO – (СH3)3CC6H4]+ (m/z 135), and
[Ph]+ (m/z 77) fragments.
EXPERIMENTAL
IR spectra were registered with Specord M-80
spectrophotometer in mineral oil. H NMR spectra
1
†
Deceased.
82

83
SYNTHESIS OF N,7-DIARYL-5-METHYL-4,7-DIHYDRO-1,2,4-TRIAZOLO[1,5-a]PYRIMIDINE...
Scheme 1.
R1
O
N
H
NH
N
N
N
NH2
R2
R1
N
O
O
O
I−XIII
+
+
N
H
R1
N
R2
N
H
H
O
N
H
NH
N
N
N
R2
R1 = H, R2 = 3-NO2 (I); R1 = H, R2 = 2-OMe (II); R1 = 2-Me, R2 = 4-OH (III); R1 = 2-Me, R2 = 3-NO2 (IV); R1 = 2,4-(Me)2,
R2 = 2-OMe (V); R1 = 2,4-(Me)2, R2 = 4-NO2 (VI); R1 = 2,4-(Me)2, R2 = 3-NO2 (VII); R1 = 2,4-(Me)2, R2 = 4-t-Bu (VIII);
R1 = 2,4-(Me)2, R2 = 4-OEt (IX); R1 = 2,4-(Me)2, R2 = 4-OH (X); R1 = 4-Cl, R2 = 2-OMe (XI); R1 = 4-Cl, R2 = 3-NO2
(XII); R1 = 4-Cl, R2 = H (XIII).
were recorded with Bruker 500 (500.13 MHz) instru-
ment using DMSO-d6 as solvent and TMS as internal
reference. Mass spectra were recorded with Finnigan
MAT INCOS-50 spectrometer (70 eV). Melting points
were determined with M-565 instrument.
NMR spectrum, δ, ppm: 2.09 s (3Н, СН3), 3.58 s (3H,
CH3O), 6.67 s (1Н, СН), 6.76–7.49 m (9Н, С6Н5,
CH3OC6H4), 9.61 s (1Н, NН), 9.96 s (1Н, N4H).
Found, %: С 66.37, 66.52; Н 5.19, 5.39; N 19.30, 19.43.
C20H19N5O2. Calculated, %: С 66.47; Н 5.30; N 19.38.
5-Methyl-7-(3-nitrophenyl)-N-phenyl-4,7-dihydro-
1,2,4-triazolo[1,5-а]pyrimidine-6-carboxamide (I).
A mixture of 0.01 mol of acetoacetanilide, 0.01 mol of
3-nitrobenzaldehyde, and 0.01 mol of 3-amino-1,2,4-
triazole was incubated in the absence of solvent at
120–150°C during 5 min until gas evolving ceased.
After cooling, the residue was treated with ethanol,
filtered off, and recrystallized from ethanol. Yield 2.25 g
(68%), mp 267–269°C. IR spectrum, ν, cm–1: 1600
7-(4-Hydroxyphenyl)-5-methyl-N-(2-methylphe-
nyl)-4,7-dihydro-1,2,4-triazolo[1,5-а]pyrimidine-6-
carboxamide (III). Yield 2.26 g (62%), mp 260–262°С.
IR spectrum, ν, cm–1: 1620 (C=C), 1680 (CON), 3190
1
(NH). H NMR spectrum, δ, ppm: 1.83 s (3Н, СН3),
2.19 s (3H, СН3C6H4), 6.32 s (1Н, СН), 6.58–7.52 m
(8Н, СН3С6Н4, HOC6H4), 9.03 s (1Н, NН), 9.94 s (1H,
HO), 9.97 s (1Н, N4H). Found, %: С 66.38, 66.54; Н
5.24, 5.37; N 19.27, 19.47. C20H19N5O2. Calculated,
%: С 66.47; Н 5.30; N 19.38.
1
(C=C), 1680 (CON), 3160 (NH). H NMR spectrum,
δ, ppm: 2.19 s (3Н, СН3), 6.62 s (1Н, СН), 6.91–8.07
m (9Н, С6Н5, NO2C6H4), 9.66 s (1Н, NН), 10.23 s
(1Н, N4H). Found, %: С 60.55, 60.76; Н 4.23, 4.39; N
22.21, 22.41. C19H16N6O3. Calculated, %: С 60.63; Н
4.28; N 22.33.
5-Methyl-N-(2-methylphenyl)-7-(3-nitropenyl)-
4,7-dihydro-1,2,4-triazolo[1,5-а]pyrimidine-6-car-
boxamide (IV). Yield 2.81 g (72%), mp 248–250°С.
IR spectrum, ν, cm–1: 1620 (C=C), 1680 (CON), 3190
1
(NH). H NMR spectrum, δ, ppm: 1.81 s (3Н, СН3),
Compounds II–XIII were obtained similarly.
2.25 s (3H, СН3C6H4), 6.59 s (1Н, СН), 6.80–8.24 m
(8Н, СН3С6Н4, NO2C6H4), 9.24 s (1Н, NН), 10.24 s
(1Н, N4H). Found, %: С 61.47, 61.65; Н 4.59, 4.75; N
21.42, 21.62. C20H18N6O3. Calculated, %: С 61.53; Н
4.65; N 21.53.
5-Methyl-7-(2-methoxyphenyl)-N-phenyl-4,7-di-
hydro-1,2,4-triazolo[1,5-а]pyrimidine-6-carboxamide
(II). Yield 2.41 g (66%), mp 226–228°С. IR spectrum,
1
ν, cm–1: 1620 (C=C), 1680 (CON), 3180 (NH). H
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84
GEIN et al.
5-Methyl-N-(2,4-dimethylphenyl)-7-(2-methoxy-
CH3CH2O, J 7.0 Hz), 1.78 s (3Н, СН3), 2.18 s and
2.20 s [6Н, (СН3)2C6H3], 3.97 q (2H, CH3CH2O, J
7.0 Hz), 6.36 s (1Н, СН), 6.73–7.50 m [7Н,
(СН3)2С6Н3, CH3CH2OC6H4], 8.99 s (1Н, NН), 9.97 s
(1Н, N4H). Found, %: С 68.35, 68.55; Н 6.17, 6.32; N
17.27, 17.46. C23H25N5O2. Calculated, %: С 68.47; Н
6.25; N 17.36.
phenyl)-4,7-dihydro-1,2,4-triazolo[1,5-а]pyrimidine-
6-carboxamide (V). Yield 3.03 g (78%), mp 228–
230°С. IR spectrum, ν, cm–1: 1620 (C=C), 1680
(CON), 3190 (NH). 1H NMR spectrum, δ, ppm: 1.80 s
(3Н, СН3), 2.15 s and 2.19 s [6Н, (СН3)2C6H3], 3.66 s
(3H, CH3O), 6.67 s (1Н, СН), 6.81–7.36 m [7Н,
(СН3)2С6Н3, CH3OC6H4], 8.83 s (1Н, NН), 9.78 s (1Н,
N4H). Found, %: С 67.73, 67.97; Н 5.88, 6.03; N
17.88, 18.07. C22H23N5O2. Calculated, %: С 67.85; Н
5.95; N 17.98.
7-(4-Hydroxyphenyl)-N-(2,4-dimethylphenyl)-5-
methyl-4,7-dihydro-1,2,4-triazolo[1,5-а]pyrimidine-
6-carboxamide (X). Yield 2.96 g (79%), mp 253–
255°С. IR spectrum, ν, cm–1: 1620 (C=C), 1680
(CON), 3190 (NH). 1H NMR spectrum, δ, ppm: 1.79 s
(3Н, СН3), 2.18 s and 2.20 s [6Н, (СН3)2C6H3], 6.32 s
(1Н, СН), 6.58–7.49 m [7Н, (СН3)2С6Н3, HOC6H4],
9.09 s (1Н, NН), 9.97 s (1H, HO), 9.94 s (1Н, N4H).
Found, %: С 67.06, 67.27; Н 5.57, 5.74; N 18.54,
18.75. C21H21N5O2. Calculated, %: С 67.18; Н 5.64; N
18.65.
5-Methyl-N-(2,4-dimethylphenyl)-7-(4-nitrophe-
nyl)-4,7-dihydro-1,2,4-triazolo[1,5-а]pyrimidine-6-
carboxamide (VI). Yield 4.14 g (76%), mp 274–276°С.
IR spectrum, ν, cm–1: 1620 (C=C), 1680 (CON), 3190
1
(NH). H NMR spectrum, δ, ppm: 1.79 s (3Н, СН3),
2.19 s and 2.22 s [6Н, (СН3)2C6H3], 6.54 s (1Н, СН),
6.79–8.12 m [7Н, (СН3)2С6Н3, NO2C6H4], 8.99 s (1Н,
NН), 10.12 s (1Н, N4H). Found, %: С 62.24, 62.41; Н
4.87, 5.07; N 20.69, 20.87. C21H20N6O3. Calculated,
%: С 62.37; Н 4.98; N 20.78.
5-Methyl-7-(2-methoxyphenyl)-N-(4-chlorophe-
nyl)-4,7-dihydro-1,2,4-triazolo[1,5-а]pyrimidine-6-
carboxamide (XI). Yield 3.40 g (86%), mp 241–243°С.
IR spectrum, ν, cm–1: 1620 (C=C), 1680 (CON), 3190
5-Methyl-N-(2,4-dimethylphenyl)-7-(3-nitrophe-
nyl)-4,7-dihydro-1,2,4-triazolo[1,5-а]pyrimidine-6-
carboxamide (VII). Yield 4.41 g (81%), mp 273–275°С.
IR spectrum, ν, cm–1: 1620 (C=C), 1680 (CON), 3190
1
(NH). H NMR spectrum, δ, ppm: 2.21 s (3Н, СН3),
3.68 s (3H, CH3O), 6.56 s (1Н, СН), 7.09–8.21 m (8Н,
ClС6Н4, CH3OC6H4), 9.57 s (1Н, NН), 9.76 s (1Н,
N4H). Found, %: С 60.62, 60.81; Н 4.47, 4.68; N
17.58, 17.76. C20H18ClN5O2. Calculated, %: С 60.69;
Н 4.58; N 17.69.
1
(NH). H NMR spectrum, δ, ppm: 1.66 s (3Н, СН3),
2.07 s and 2.20 s [6Н, (СН3)2C6H3], 6.57 s (1Н, СН),
6.65–8.04 m [7Н, (СН3)2С6Н3, NO2C6H4], 9.13 s (1Н,
NН), 10.16 s (1Н, N4H). Found, %: С 62.13, 62.39; Н
4.90, 5.05; N 20.65, 20.89. C21H20N6O3. Calculated,
%: С 62.37; Н 4.98.; N 20.78.
5-Methyl-7-(3-nitrophenyl)-N-(4-chlorophenyl)-
4,7-dihydro-1,2,4-triazolo[1,5-а]pyrimidine-6-car-
boxamide (XII). Yield 3.04 g (74%), mp 252–254°С.
IR spectrum, ν, cm–1: 1620 (C=C), 1680 (CON), 3190
N-(2,4-Dimethylphenyl)-7-(4-tert-butylphenyl)-5-
methyl-4,7-dihydro-1,2,4-triazolo[1,5-а]pyrimidine-
6-carboxamide (VIII). Yield 2.78 g (67%), mp 220–
222°С. IR spectrum, ν, cm–1: 1620 (C=C), 1680
(CON), 3190 (NH). 1H NMR spectrum, δ, ppm: 1.23 s
(9H, (CH3)3CC6H4), 1.68 s (3Н, СН3), 2.18 s and 2.36
s [6Н, (СН3)2C6H3], 6.35 s (1Н, СН), 6.81–7.51 m
[7Н, (СН3)2С6Н3, (CH3)3CC6H4], 8.99 s (1Н, NН),
9.99 с (1Н, N4H). Found, %: С 72.19, 72.38; Н 6.98,
7.13; N 16.73, 16.92. C25H29N5O. Calculated, %: С
72.26; Н 7.03; N 16.85.
1
(NH). H NMR spectrum, δ, ppm: 2.21 s (3Н, СН3),
6.61 s (1Н, СН), 7.09–8.21 m (8Н, ClС6Н4, NO2C6H4),
9.69 s (1Н, NН), 10.29 s (1Н, N4H). Found, %: С
55.46, 55.67; Н 3.60, 3.76; N 20.34, 20.51.
C19H15ClN6O3. Calculated, %: С 55.55; Н 3.68; N
20.46.
5-Methyl-7-phenyl-N-(4-chlorophenyl)-4,7-dihydro-
1,2,4-triazolo[1,5-а]pyrimidine-6-carboxamide (XIII).
Yield 2.53 g (69%), mp 241–243°С. IR spectrum, ν,
1
cm–1: 1612 (C=C), 1680 (CON), 3200 (NH). H NMR
N-(2,4-Dimethylphenyl)-5-methyl-7-(4-ethoxyphe-
nyl)-4,7-dihydro-1,2,4-triazolo[1,5-а]pyrimidine-6-
carboxamide (IX). Yield 2.54 g (63%), mp 229–231°С.
IR spectrum, ν, cm–1: 1620 (C=C), 1680 (CON), 3190
(NH). 1H NMR spectrum, δ, ppm: 1.34 t (3H,
spectrum, δ, ppm: 1.77 s (3Н, СН3), 6.57 s (1Н, СН),
7.09–7.60 m (9Н, ClС6Н4, C6H5), 9.65 s (1Н, NН),
10.30 s (1Н, N4H). Found, %: С 62.27, 62.45; Н 4.34,
4.50; N 19.04, 19.23. C19H16ClN5O. Calculated, %: С
62.38; Н 4.41; N 19.14.
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SYNTHESIS OF N,7-DIARYL-5-METHYL-4,7-DIHYDRO-1,2,4-TRIAZOLO[1,5-a]PYRIMIDINE...
4. Desenko, S.M., Gladkov, E.S., and Nenaidenko, V.G.,
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