Synthesis of mesoionic 1,2,4-triazolo[4,3-a]pyrimidin-5-ones and subsituted formamidines from diethyl (5-1-r-1h-1,2,4-triazol -3-yl)aminomethylenemalonates

Full text of DOI:10.1007/s10593-010-0642-7

Chemistry of Heterocyclic Compounds, Vol. 46, No. 9, 2010
SYNTHESIS OF MESOIONIC 1,2,4-TRIAZOLO[4,3-a]PYRIMIDIN-
5-ONES AND SUBSITUTED FORMAMIDINES FROM DIETHYL
(5-1-R-1H-1,2,4-TRIAZOL -3-YL)AMINOMETHYLENEMALONATES
A. V. Astakhov1 and V. M. Chernyshev1*
Keywords: amidines, aminomethylenemalonates, mesoionic 1,2,4-triazolo[4,3-a]pyrimidin-5-ones,
cyclization.
Hetaryl-substituted aminomethylenemalonates obtained by the condensation of aminoazoles with
2-alkoxymethylenemalonates are commonly used for the synthesis of biologically active azolopyrimidines [1, 2].
However, cyclization of hetaryl-substituted aminomethylenemalonates to give azolopyrimidines often proceeds
only at high temperature or under upon microwave activation [1] or by using special reagents [2]. In the present
work, we found that brief heating of diethyl aminomethylenemalonates 1a and 1b in ethanol in the presence of
sodium ethylate leads to the formation of mesoionic 1,2,4-triazolo[4,3-a]pyrimidin-5-ones 2a or 2b in high
yield. This reaction does not occur upon heating aminomethylenemalonates 1a or 1b with tertiary aliphatic
amines in ethanol at reflux. However, heating esters 1 with primary or secondary amines in ethanol or
acetonitrile at reflux leads to nucleophilic substitution of the malonate ester and formation of amidines 3a-c in
high yield.
8
–
5
1
N
O
N
R1
R2
7
EtO
O
+
–
H
N
EtO
EtOH
R1R2NH
MeCN
N
R
N
N
N
R
R
EtO
N
4
2
N
N
CH2(COOEt)2
N
3
+
6
N
N
NH2
O
O
NH2
OEt
NH2
3a–c
1a,b
2a,b
1a, 2a, 3 a, b R = Ph; 1b, 2b, 3c R = Bn; 3 a, c R1R2 = (CH2CH2)2O; b R1 = Bn, R2 = H
1
The structures of products 2 and 3 were confirmed by elemental analysis, mass spectrometry, H–1H
1
1
13
NOESY, H–13C HMBC, and HSQC correlation spectra. The H and C NMR spectra of pyrimidones 2a and 2b
are similar to the spectra of other mesoionic 2-substituted 3-amino-2H-1,2,4-triazolo[4,3-a]pyrimidin-5-ones [3].
The structure of amidines 3 was also unequivocally indicated by the X-ray diffraction structural analysis of 3a.
The H and 13C NMR spectra were taken on a Bruker Avance 600 spectrometer at 600 and 150 MHz,
1
respectively, in DMSO-d6 with TMS as the internal standard. The electron impact mass spectra were taken on a
Finnigan MAT Incos 50 mass spectrometer with direct sample inlet into the ion source and 70 eV ionization energy.
_______
* To whom correspondence should be addressed, e-mail: chern13@yandex.ru.
1South Russian State Technical University, Novocherkassk 346428, Russia.
__________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 9, pp. 1416-1418, September, 2010.
Original article submitted July 12, 2010.
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0009-3122/10/4609-1144©2010 Springer Science+Business Media, Inc.

3-Amino-6-ethoxycarbonyl-5-oxo-2-phenyl-5H-1,2,4-triazolo[4,3-a]pyrimidin-2-ium-8-ide
(2a).
Diester 1a (0.69 g, 2 mmol) was added to a solution of sodium (0.14 g, 6 mmol) in anhydrous ethanol (5 ml).
The mixture obtained was heated at reflux for 20 min, neutralized by adding acetic acid, and cooled. The
precipitate formed was filtered off to give 0.54 g (90%) compound 2a; mp 275-276°C (acetic acid–ethanol).
1H NMR spectrum, , ppm (J, Hz): 1.23 (3H, t, J = 7.1, CH3); 4.14 (2H, q, J = 7.1, CH2); 7.54-7.63 (5H, m,
C6H5); 8.50 (1H, s, CH); 8.60 (2H, s, NH2). 13C NMR spectrum, , ppm: 14.45 (OCH3CH3), 58.98 (OCH2CH3),
95.12 (C-6), 125.16, 129.62, 129.77, 134.40 (C6H5), 145.07 (C-3), 152.04 (C-8a), 157.60 (C-5), 162.72 (C-7),
164.90 (CO2Et). Mass spectrum, m/z (Irel, %): 299 [M]+ (8), 253 (100), 186 (27), 119 (16), 91 (29), 77 (78).
Found, %: C 55.86; H 4.76; N 23.11. C14H13N5O3. Calculated, %: C 56.18; H 4.38; N 23.40.
3-Amino-2-benzyl-6-ethoxycarbonyl-5-oxo-5H-1,2,4-triazolo[4,3-a]pyrimidin-2-ium-8-ide (2b) was
1
obtained in 78% yield (0.49 g) analogously to compound 2a; mp 209-210°C (ethanol). H NMR spectrum, ,
ppm (J, Hz): 1.22 (3H, t, J = 7.2, CH3); 4.12 (2H, q, J = 7.2, CH2); 5.23 (2H, s, CH2C6H5); 7.32-7.38 (5H, m,
C6H5); 8.43 (1H, s, CH); 8.71 (2H, s, NH2). Mass spectrum, m/z (Irel, %): 313 [M]+ (4), 91 (100), 65 (20). Found,
%: C 57.18; H 5.01; N 22.08. C15H15N5O3. Calculated, %: C 57.50; H 4.83; N 22.35.
N3-[(E)-Morpholin-4-ylmethylidene]-1-phenyl-1H-1,2,4-triazole-3,5-diamine (3a). A mixture of
diester 1a (0.69 g, 2 mmol), morpholine (0.37 g, 4.2 mmol), and acetonitrile (5 ml) was heated at reflux for 5 h
and then cooled. The precipitate formed was filtered off to give 0.46 g (84%) compound 3a; mp 208-208.5°C
(acetonitrile). 1H NMR spectrum, , ppm (J, Hz): 3.42-3.61 (8H, m, 4CH2); 6.21 (2H, s, NH2); 7.25-7.53 (5H, m,
C6H5); 8.26 (1H, s, CH). 13C NMR spectrum, , ppm: 42.52, 48.58, 65.44, 66.57, 121.68, 125.75, 129.16,
137.71, 153.59 (C-5 triazole), 155.03 (N–CH=N), 163.52 (C-3 triazole). Mass spectrum, m/z (Irel, %): 272 [M]+
(100), 241 (25), 186 (17), 175 (17), 77 (27). Found, %: C 57.35; H 5.94; N 30.88. C13H16N6O. Calculated, %:
C 57.34; H 5.92; N 30.86.
N'-(5-Amino-1-phenyl-1H-1,2,4-triazol-3-yl)-N-benzylimidoformamide (3b) was obtained in 80%
1
yield (0.47 g) analogously from compound 1a and benzylamine; mp 181-182°C (acetonitrile). H NMR
spectrum, , ppm (J, Hz): 4.47 (2H, d, J = 5.7, CH2); 6.25 (2H, s, NH2); 7.23-7.52 (10H, m, 2C6H5); 7.81 (1H,
m, NH); 8.37 (1H, d, J = 3.9, CH). 13C NMR spectrum, , ppm: 43.44 (CH2), 121.64, 125.68, 126.76, 127.35,
128.23, 129.14, 137.76, 139.05 (arom.), 153.36 (N–CH=N), 153.55 (C-5 triazole), 163.99 (C-3 triazole). Mass
spectrum, m/z (Irel, %): 292 [M]+ (8), 175 (49), 133 (35), 119 (32), 106 (35), 91 (100), 77 (81). Found, %:
C 65.48; H 5.50; N 29.02. C16H16N6. Calculated, %: C 65.74; H 5.52; N 28.75.
1-Benzyl-N3-[(E)-morpholin-4-ylmethylidene]-1H-1,2,4-triazole-3,5-diamine (3c) was obtained in
1
74% yield (0.42 g) from compound 2a and morpholine; mp 206-208°C (acetonitrile). H NMR spectrum, ,
ppm: 3.38-3.57 (8H, m, 4CH2); 4.97 (2H, s, CH2C6H5); 6.17 (2H, s, NH2); 7.17-7.32 (5H, m, C6H5); 8.17 (1H, s,
CH). Mass spectrum, m/z (Irel, %): 286 [M]+ (17), 125 (92), 91 (99), 65 (34), 54 (100). Found, %: C 58.49;
H 6.51; N 29.37. C14H18N6O. Calculated, %: C 58.73; H 6.34; N 29.35.
This work was carried out with the financial support of the Federal Education Agency of the Russian
Federation in the framework of the Federal Target Program for the Development of Scientists and Science
Teachers, Contract P302, Project NK-109P/2.
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