Novel 6-azapteridines from bifunctional 1,2,4-triazines

Article abstract of DOI:10.1135/cccc20030965

The convergent synthesis of ethyl 5-chloro- and 5-amino-3-aryl-1,2,4-triazinecarboxylates 9a-9d and 10a-10d as well as of 5-amino-3-aryl-1,2,4-triazine-6-carboxamides 11a-11d is described. Compounds 9, 10 and 11 are powerful key compounds for cyclization reactions to the novel pyrimido[4,5-e][1,2,4]triazines 13d, 14c, 14d, 15c and 17a, 17d.

Full text of DOI:10.1135/cccc20030965

Novel 6-Azapteridines
965
NOVEL 6-AZAPTERIDINES FROM BIFUNCTIONAL 1,2,4-TRIAZINES
1,
2
Heinrich WAMHOFF * and Milena TZANOVA
Kekulé-Institut für Organische Chemie und Biochemie Universität Bonn, Gerhard-Domagk-Str. 1,
1
2
D-53121 Bonn, Germany; e-mail: wamhoff@uni-bonn.de, milenatzanova@hotmail.com
Received December 16, 2002
Accepted March 27, 2003
Dedicated to the memory of Professor Otakar Červinka.
The convergent synthesis of ethyl 5-chloro- and 5-amino-3-aryl-1,2,4-triazinecarboxylates
9a–9d and 10a–10d as well as of 5-amino-3-aryl-1,2,4-triazine-6-carboxamides 11a–11d is
described. Compounds 9, 10 and 11 are powerful key compounds for cyclization reactions
to the novel pyrimido[4,5-e][1,2,4]triazines 13d, 14c, 14d, 15c and 17a, 17d.
Keywords: Fused heterocycles; 1,2,4-Triazine; Pyrimido[4,5-e][1,2,4]triazine; 6-Azapteridine;
Amidrazone; Amidine; 5-Chloro-1,2,4-triazine; 5-Amino-1,2,4-triazine.
1,2,4-Triazines and pyrimido[1,2,4]triazines are considered as analogs of
naturally occurring N-heterocycles, especially of pyrimidine bases, purines
and pteridines. Several of them exhibit significant biological activities.
Pharmacological and biochemical activities of as-triazines1,2 and of
azapteridines3,4 are rather broad. Position of the introduced N atom leads to
a classification into pyrimido[4,5-e][1,2,4]triazine (named also 6-azapteri-
dines 2) and pyrimido[5,4-e][1,2,4]triazines (7-azapteridines 3), respectively.
6-Azapteridines have been much less investigated3,4 in comparison with the
7-azapteridines.
N
N
N
N
N
N
N
N
N
N
N
N
N
N
pteridine (1)
6-azapteridine (2)
7-azapteridine (3)
Synthetic approaches towards 6-azapteridines can start either from py-
rimidines, 1,2,4-triazines, or purines3. In this study, the annelation of py-
rimidine ring to the 1,2,4-triazine ring is realized in two different ways: by
[3+3] or [5+1] condensation. The 1,2,4-triazine derivatives required can be
obtained by [4+2] atom combination, i.e. by condenzation reaction of sym-
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doi:10.1135/cccc20030965

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Wamhoff, Tzanova:
metrically substituted 1,2-dicarbonyl compounds and hydrazidines, also
known as amidrazones1,2. This method can be carried out smoothly, as no
vigorous reaction conditions must be used, and the yields are rather high.
In order to obtain ethyl 5-oxo-4,5-dihydro-1,2,4-triazine-6-carboxylates
8a–8d, amidrazones 5a, 5b are required (Scheme 1), the latter being very
sensitive to light and oxygen, which cause fast dimerization reaction lead-
ing to red-violet tetrazines. Thus 5a, 5b must be prepared in situ. In any
case, several side products are formed and the method requires difficult sep-
aration5. Newly substituted amidrazones 5c, 5d are obtained in two differ-
ent ways (Scheme 1).
Route 1
NH2
NH2
N2H4·H2O
EtOH, RT
NH4Cl
+
N NH2
NH·HCl
R
R
5a, 5b
4
Route 2
4, 5, 6,
R
H
NH2
a) HCl/EtOH
b) N2H4·H2O
a
b
c
d
CN
3-NO2
4-Cl
4-OCH3
N NH2
R
R
5c, 5d
6
SCHEME 1
The amidrazones 5a, 5b generated from benzamidine hydrochloride 4 and
hydrazine (Scheme 1, route 1) are not isolated but transformed in situ by re-
action with diethyl oxomalonate (7) directly into the 1,2,4-triazin-5-ones
8a, 8b. This procedure looks quite simple, but offers only few advantages,
as the reaction conditions (polar solvent, high temperature) favor the for-
mation of side products, such as tetrazines and triazoles.
Synthesis of amidrazones 5a, 5b starting from benzonitriles proceeds via
several steps6,7 (Scheme 1, route 2) but proves to be much more effective as
the yields are high and the products are easier to isolate.
The in situ prepared (Scheme 1, route 1) amidrazones 5a, 5b and diethyl
oxomalonate (7) afford the 1,2,4-triazines 8a, 8b in ethanol as solvent, but
together with several side products5,6,8, while the other amidrazones 5c, 5d
(Scheme 1, route 2) react with the diethyl oxomalonate (7) smoothly in
propan-2-ol to afford 1,2,4-triazines7 8c, 8d.
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Novel 6-Azapteridines
967
The ethyl 5(4H)-oxo-1,2,4-triazine-6-carboxylates 8a–8d are colorless sol-
ids with high melting points and high stability. From them are obtained
the 5-chloro derivatives 9a–9d with phosphorus pentachloride8–10, but also
accessible with the aid of phosphorus oxychloride7,10 or thionyl chloride10,11
(Scheme 2). The nucleophilicity of the chloro-substituted C-5 of the 1,2,4-
triazine ring is similar to that of azalogous acid halides; thus, moisture hydro-
lyzes them back to the triazinones. However, nucleophiles such as ammo-
nia or primary amines convert them smoothly to amino derivatives8,10
.
O
CO2Et
R
N NH2
NH2
R
N N
CO2Et
+
- EtOH
- H2O
N
OEt
O
Cl
H
5a-5d
7
8a-8d
R
N N
N
OEt
R
N N
N
NH3
PCl5
CO2Et
O
H
Cl
N
H
10a, 10c, 10d
R
N N
N
NH2
O
NH3
5, 8-11
R
H
N
H
H
a
b
c
d
3-NO2
4-Cl
4-OCH3
11a, 11c, 11d
SCHEME 2
Synthesis of ethyl 5-amino-1,2,4-triazine-6-carboxylates 10a–10d from
chloro derivatives 9a–9d must be carried out cautiously in oder to avoid
side reactions; powdered triazines 10a–10d are suspended in ethanol satu-
rated with ammonia7. Monitoring the reaction time (optimum ca 30 min)
is essential to avoid the attack of ammonia on the ester carbonyl leading to
5-amino-1,2,4-triazine-6-carboxamides 11a–11d. Complete conversion to
11a–11d at room temperature is achieved after 20 h (Scheme 2).
Compounds 9c, 9d are converted in a one-step reaction with benz-
amidine (12) to the 6-azapteridines 14c, 14d (Scheme 3). We were able to
isolate and characterize an intermediate salt 13c, which is converted to
azapteridine 14c in boiling acetic acid. By treatment of 9c with benz-
amidrazone (5c) a nucleophilic displacement takes place on C-5 to afford
1
compound 15c, its constitution was proved by the H NMR spectroscopic
Collect. Czech. Chem. Commun. (Vol. 68) (2003)

968
Wamhoff, Tzanova:
data. The hydrazone protons form two singlets at 10.15 and 10.85 ppm,
suggesting a stable intramolecular H-bridge.
In analogy to the reaction of 9c, 9d with benzamidine (12), the reaction
of 9c with benzamidrazone 5c was expected to lead to a ring closure giving
a 6- or 7-membered heterocycle. However, despite varying the molar ratio
of the reactants, compound 15c remained the only product observed
(Scheme 3).
O
N
N
N
PhC(NH)NH2
NH2
NH2
(12)
N
N
9c, 9d
R
13c, 13d
AcOH
(R=Cl)
+ 5c
∆
OCH2CH3
O
N
O
N
N
N
N
H
H
N
N
N
N NH
N
H
C
R
R
14c, 14d
15c
Cl
13, 14, 15
R
c
d
Cl
CH3O
SCHEME 3
The 1,2,4-triazinecarboxamides 11a–11d possess two nucleophilic centers
in geometrically favorable positions, so their treatment with typical C-1
units should lead to fused pyrimidine systems. Pteridinone12 and several
pyrido[2,3-d]pyrimidin-4-ones13 have been obtained accordingly. In our
case, 11a, 11d and triethyl orthoformate (16) in the presence of acetic acid
afforded 6-azapteridinones 17a, 17d (Scheme 4).
Another [5+1] condensation of 11 is represented by the reaction of 11d
with benzaldehyde (18) leading under dehydration conditions to azapteri-
dine 14d (Scheme 4).
In conclusion, we present a novel, versatile and simple approach to
pyrimido[4,5-e][1,2,4]triazines. From the view of biological activities of sim-
ilar compounds, the systems obtained might be considered as potential new
structures deserving screening as drugs and/or crop protection agents.
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Novel 6-Azapteridines
969
O
N
N
N
H
H
N
N
HC(OEt)3
O
16
R
N
17a, 17d
N
NH2
NH2
N
O
N
H
R
N
N
11a, 11d
PhCHO
18
N
N
R
11, 14, 18
R
14d
c
d
H
CH3O
SCHEME 4
EXPERIMENTAL
Melting points are not corrected, Leitz microscope. IR (KBr; ν, cm–1): Perkin–Elmer FT-IR Par-
agon 500; UV: Beckman DU 640. MS: Kratos (A.E.I.) MS-30 and MS-50 (EI); Concept 1H
(FAB, mNBA as matrix). 1H, 13C NMR (DMSO-d6, TMS, δ 0, J in Hz): Bruker WM 300 (1H:
300 MHz; 13C: 75.0 MHz) and Bruker WM 400 (1H: 400 MHz; 13C: 100 MHz). Assignments
were partly based on DEPT-spectra. Elemental analyses: Microanalytical Department of the
Institute and Microanalytical Laboratory E. Pascher, Remagen. TLC: silica gel plates 60 F264
(Merck).
4-Chloro- and 4-Methoxybenzohydrazonamides 5c, 5d. General Procedure
Dry HCl stream was introduced into a solution of benzonitrile 6 (0.2 mol) in 200 ml of etha-
nol for 40 min under cooling with ice. The saturated ethanolic solution was kept at room
temperature overnight, then the solvent was evaporated. The solid residue was suspended in a
mixture of 5% aqueous KOH (250 ml) and diethyl ether (300 ml) and extracted, the aqueous
layer being extracted with another 150 ml of diethyl ether. The combined organic layers
were washed neutral with H2O and dried over molecular sieve 4Å. After evaporation of the
solvent to the half volume, a solution of 80% hydrazine monohydrate (12 ml; 0.2 mol) in
ethanol (30 ml) was added and the mixture was stirred at room temperature until it became
homogenous. After standing at 0 °C for 2 days, the solvent was removed in vacuo, and the
residual product dissolved in 50 ml of diisopropyl ether. The crystals formed after cooling
were filtered off and dried in vacuo.
4-Chlorobenzohydrazonamide8 (5c). White flakes, yield 67%, m.p. 64–65 °C (i-Pr2O). 1H NMR
(CDCl3): 4.60 (s, 2 H, NH2); 5.51 (s, 2 H, NNH2); 7.27 (d, 2 H, J = 7, 3-H); 7.45 (d, 2 H, J = 7,
4-H). 13C NMR (CDCl3): 126.9 (C-3), 128.8 (C-4), 133.1 (C-5), 135.4 (C-2), 150.5 (C-1).
IR (KBr): 3372.7, 3189.1 (NH2), 1645.5 (C=N). MS, m/z (rel.%): 169.1 (63, M+), 137.0 (100,
C7H4ClN+).
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Wamhoff, Tzanova:
4-Methoxybenzohydrazonamide (5d). White flakes, yield 62%, m.p. 85–87 °C (i-Pr2O). 1H NMR
(CDCl3): 3.89 (s, 3 H, CH3O); 4.95 (s, 2 H, NH2); 5.68 (s, 2 H, NNH2); 7.01 (d, 2 H, J = 7,
4-H); 7.77 (d, 2 H, J = 7, 3-H). 13C NMR (CDCl3): 54.9 (CH3O), 113.2 (C-4), 126.3 (C-5),
128.1 (C-3), 145.5 (C-2), 159.1 (C-1). IR (KBr): 3394.5, 3269.1 (NH2), 1639.8 (C=N). MS, m/z
(rel.%): 165.2 (100, M+).
Ethyl 5-Oxo-4,5-dihydro-1,2,4-triazine-6-carboxylates 8a, 8b. General Procedure
Benzamidine hydrochloride 4 (0.2 mol) was dissolved in 250 ml of ethanol and 80% hydra-
zine monohydrate ((12 ml, 0.2 mol) was added. The reaction mixture was stirred at ambient
temperature, then the precipitated ammonium chloride was filtered off, as well as new pre-
cipitates which might form during filtration. Then, diethyl oxomalonate (7; 31 ml, 0.2 mol)
was added under stirring and cooling with ice. The reaction mixture was stirred at room
temperature for additional 16 h and then refluxed for 4 h. The mixture was cooled and the
formed solid was filtered and crystallized from ethanol, the crystals were filtered and washed
with diethyl ether.
Ethyl 5-oxo-3-phenyl-4,5-dihydro-1,2,4-triazine-6-carboxylate (8a). White crystals, yield 53%,
m.p. 192–193 °C (EtOH); ref.8 m.p. 197–199 °C.
Ethyl 3-(3-nitrophenyl)-5-oxo-4,5-dihydro-1,2,4-triazine-6-carboxylate (8b). Light yellow crys-
tals, yield 49%, m.p. 182–183 °C (EtOH). For C12H10N4O5 (290.1) calculated: 49.66% C,
3.47% H, 19.30% N; found: 49.55% C, 3.48% H, 19.29% N. 1H NMR (DMSO-d6): 1.32 (t,
3 H, J = 7, CH3); 4.36 (q, 2 H, J = 7, CH2); 7.91 (t, 1 H, J = 8, 8-H); 8.49 (m, 2 H, 7-H, 9-H);
8.88 (s, 1 H, 5-H); 14.63 (s, 1 H, NH). 13C NMR (DMSO-d6): 14.3 (CH3), 62.3 (CH2), 123.3
(C-8), 127.6 (C-7), 131.2 (C-9), 132.3 (C-5), 134.7 (C-4), 144.5 (C-6), 148.4 (C-3), 157.6
(C-1), 158.9 (C-2), 162.5 (COO). IR (KBr): 3455.8, (NH),1736.4 (CO, ester), 1623.4 (CO,
lactam), 1533.3, 1349.5 (NO2). UV (EtOH): 220 (4.29). MS, m/z (rel.%): 290.2 (21, M+), 86.1
(100, C4H5O+).
Ethyl 5-Oxo-4,5-dihydro-1,2,4-triazine-6-carboxylates 8c, 8d. General Procedure
Benzohydrazonamide 5a, 5b (0.1 mol) was dissolved in 200 ml of propan-2-ol and an
equimolar amount of diethyl oxomalonate (7; 0.1 mmol, 15.5 ml) dissolved in the same al-
cohol was added under stirring and ice-cooling. Stirring was continued at room temperature
for 18 h, the obtained white precipitate was filtered, crystallized from ethanol and washed
with diethyl ether.
Ethyl 3-(4-chlorophenyl)-5-oxo-4,5-dihydro-1,2,4-triazine-6-carboxylate (8c). White crystals,
yield 68%, m.p. 244–246 °C (EtOH); ref.7 m.p. 244 °C.
Ethyl 3-(4-methoxyphenyl)-5-oxo-4,5-dihydro-1,2,4-triazine-6-carboxylate (8d). White crystals,
yield 66%, m.p. 216–218 °C (EtOH). For C13H13N3O4 (275.1) calculated: 56.72% C, 4.76% H,
15.27% N; found: 56.50% C, 4.73% H, 15.32% N. 1H NMR (DMSO-d6): 1.29 (t, 3 H, J = 7,
CH3); 3.86 (s, 3 H, CH3O); 4.33 (q, 2 H, J = 7, CH2); 7.15 (d, 2 H, J = 9, 6-H); 8.06 (d, 2 H,
J = 9, 5-H); 14.25 (s, 1 H, NH). 13C NMR (DMSO-d6): 13.8 (CH3), 55.5 (CH3O), 61.7 (CH2),
114.4 (C-6), 121.6 (C-7), 129.8.2 (C-5), 142.8 (C-4), 158.0 (C-3), 158.8 (C-1), 162.2 (C-2),
163.0 (COO). IR (KBr): 3452.0 (NH), 1734.9 (CO, ester), 1609.4 (CO, lactam). UV (EtOH):
327 (3.97). MS, m/z (rel.%): 275.2 (35, M+), 134.2 (100, C8H8NO+).
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Novel 6-Azapteridines
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Ethyl 5-Chloro-1,2,4-triazine-6-carboxylates 9a–9d. General Procedure
1,2,4-Triazin-5-one 8a–8d (0.1 mol) and PCl5 (31.2 g, 0.15 mol) were suspended in 500 ml
of absolute toluene and refluxed under argon for 1 h. After stirring at room temperature for
24 h, the dark yellow solution was washed three times with ice water and dried over anhy-
drous K2CO3. After evaporation, the obtained product was crystallized from diethyl ether.
Ethyl 5-chloro-3-phenyl-1,2,4-triazine-6-carboxylate (9a). Yellow crystals, yield 80%, m.p.
72–73 °C (Et2O); ref.8 m.p. 73–75 °C, ref.10 74–75 °C.
Ethyl 5-chloro-3-(4-chlorophenyl)-1,2,4-triazine-6-carboxylate (9c). Yellow crystals, yield 82%,
m.p. 111–112 °C (Et2O); ref.10 m.p. 135 °C. For C12H9Cl2N3O2 (297.0) calculated: 48.35% C,
3.04% H, 14.09% N; found: 48.06% C, 3.04% H, 13.82% N. 1H NMR (CDCl3): 1.41 (t, 3 H, J =
7, CH3); 4.47 (q, 2 H, J = 7, CH2); 7.48 (d, 2 H, J = 8, 5-H); 8.45 (d, 2 H, J = 8, 6-H). 13C NMR
(CDCl3): 14.1 (CH3), 63.4 (CH2), 129.6 (C-5), 130.6 (C-6), 131.1 (C-7), 139.9 (C-4), 148.8
(C-3), 155.7 (C-1), 161.9 (C-2), 163.2 (COO). IR (KBr): 1731.3 (CO). UV (CHCl3): 253 (4.17).
MS, m/z (rel.%): 297.0 (17, M+), 137.1 (100, C7H4ClN+).
Ethyl 5-chloro-3-(4-methoxyphenyl)-1,2,4-triazine-6-carboxylate (9d). Yellow crystals, yield
68%, m.p. 89–90 °C (Et2O). For C13H12ClN3O3 (293.1) calculated: 53.16% C, 4.12% H,
14.31% N; found: 48.06% C, 3.04% H, 13.82% N. 1H NMR (CDCl3): 1.44 (t, 3 H, J = 7, CH3);
3.82 (s, 3 H, CH3O); 4.58 (q, 2 H, J = 7, CH2); 6.93 (d, 2 H, J = 9, 6-H); 8.41 (d, 2 H, J = 9,
5-H). 13C NMR (CDCl3): 14.1 (CH3), 55.5 (CH3O), 63.7 (CH2), 114.2 (C-6), 126.6 (C-7), 130.8
(C-5), 140.4 (C-4), 160.7 (C-2), 162.2 (C-1), 163.2 (COO). IR (KBr): 1727.7 (CO). UV (CHCl3):
316 (4.28). MS, m/z (rel.%): 293.1 (32, M+), 133.1 (100, C8H7NO+).
Ethyl 5-Amino-1,2,4-triazine-6-carboxylates 10a–10d. General Procedure
Finely powdered 5-chloro-1,2,4-triazine 9a–9d (25 mmol) was suspended portionwise in
100 ml of ethanol saturated with ammonia by ice cooling. Stirring of the solution was con-
tinued at room temperature for 30 min. After evaporation, the product was crystallized from
ethanol.
Ethyl 5-amino-3-phenyl-1,2,4-triazine-6-carboxylate (10a). Yellow crystals, yield 90%, m.p.
177–178 °C (EtOH); ref.8 m.p. 190–193 °C.
Ethyl 5-amino-3-(4-chlorophenyl)-1,2,4-triazine-6-carboxylate (10c). Yellow crystals, yield
93%, m.p. 245–247 °C (EtOH). For C12H11ClN4O2 (278.1) calculated: 51.72% C, 3.98% H,
20.10% N; found: 51.88% C, 4.05% H, 20.24% N. 1H NMR (DMSO-d6): 1.35 (t, 3 H, J = 7,
CH3); 4.40 (q, 2 H, J = 7, CH2); 7.64 (d, 2 H, J = 8, 5-H); 7.85 (s, 1 H, NH); 8.36 (d, 2 H, J =
8, 6-H); 8.53 (s, 1 H, NH···O). 13C NMR (DMSO-d6): 14.3 (CH3), 61.9 (CH2), 129.6 (C-5),
130.2 (C-6), 133.1 (C-7), 133.8 (C-8), 137.4 (C-3), 155.4 (C-2), 161.5 (C-1), 164.9 (COO).
IR (KBr): 3452.0, 3266.8 (NH2), 1700.2 (CO). UV (EtOH): 332 (4.03). MS, m/z (rel.%):
278.1 (44, M+), 68.1 (100, C7H4ClN+).
Ethyl 5-amino-3-(4-methoxyphenyl)-1,2,4-triazine-6-carboxylate (10d). Yellow crystals, yield
92%, m.p. 224–225 °C (EtOH). For C13H14N4O3 (274.1) calculated: 56.93% C, 5.14% H,
20.43% N; found: 56.79% C, 5.44% H, 20.31% N. 1H NMR (DMSO-d6): 1.38 (t, 3 H, J = 7,
CH3); 3.83 (s, 3 H, CH3O); 4.38 (q, 2 H, J = 7, CH2); 7.01 (d, 2 H, J = 8, 6-H); 7.70 (s, 1 H,
NH); 8.21 (s, 1 H, NH···O); 8.34 (d, 2 H, J = 9, 5-H). 13C NMR (DMSO-d6): 14.3 (CH3), 55.6
(CH3O), 61.8 (CH2), 114.4 (C-6), 127.0 (C-7), 130.5 (C-5), 133.4 (C-4), 155.4 (C-2), 161.9
(C-3), 162.8 (C-1), 165.1 (COO). IR (KBr): 3443.7, 3279.1 (NH2), 1696.8 (CO). UV (EtOH):
341 (4.32). MS, m/z (rel.%): 274.1 (33, M+), 134.1 (100, C8H7NO+).
Collect. Czech. Chem. Commun. (Vol. 68) (2003)

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Wamhoff, Tzanova:
5-Amino-1,2,4-triazine-6-carboxamides 11a–11d. General Procedure
Finely powdered 5-chloro-1,2,4-triazine 9a–9d (25 mmol) was suspended portionwise in
100 ml of ethanol and saturated with ammonia. The resulting solution was stirred at room
temperature for 24 h. The residue after evaporation was crystallized from ethanol.
5-Amino-3-phenyl-1,2,4-triazine-6-carboxamide (11a). Yellow crystals, yield 79%, m.p.
271–272 °C (EtOH). For C10H9N5O (215.1) calculated: 55.81% C, 4.21% H, 32.54% N; found:
55.81% C, 4.08% H, 32.40% N. 1H NMR (DMSO-d6): 6.46 (m, 3 H, 6-H, 7-H); 6.79 (s, 1 H,
NH); 7.17 (s, 1 H, NH···O); 7.30 (d, 2 H, J = 8, 5-H); 7.41 (s, 2 H, NH2). 13C NMR (DMSO-d6):
127.4 (C-6), 128.0 (C-5), 130.9 (C-7), 134.3 (C-4), 134.6 (C-2), 154.7 (C-3), 161.9 (C-1),
166.5 (CO). IR (KBr): 3462.2, 3402.0 (NH2), 1672.5 (CO). UV (EtOH): 330 (3.98). MS, m/z
(rel.%): 215.1 (72, M+), 84.1 (100, C2H2N3O+).
5-Amino-3-chlorophenyl-1,2,4-triazine-6-carboxamide (11c). Yellow crystals, yield 77%, m.p.
297–298 °C (EtOH). For C10H8ClN5O (248.0) calculated: 48.11% C, 3.23% H, 28.05% N;
found: 48.04% C, 3.41% H, 27.87% N. 1H NMR (DMSO-d6): 7.62 (d, 2 H, J = 8, 5-H); 7.87 (s,
1 H, NH); 8.34 (d, 3 H, J = 8, 6-H; s, 1 H, NH···O included); 8.49 (s, 2 H, NH2). 13C NMR
(DMSO-d6): 129.2 (C-5), 130.0 (C-6), 134.3 (C-4), 135.4 (C-7), 136.8 (C-2), 155.4 (C-3), 161.8
(C-1), 167.2 (CO). IR (KBr): 3460.1, 3397.4 (NH2), 1673.5 (CO). UV (EtOH): 332 (4.08). MS,
m/z (rel.%): 248.0 (100, M+).
5-Amino-3-methoxyphenyl-1,2,4-triazine-6-carboxamide (11d). Yellow crystals, yield 83%,
m.p. 286–288 °C (EtOH). For C11H11N5O2 (245.1) calculated: 53.87% C, 4.52% H, 28.56% N;
found: 53.67% C, 4.32% H, 28.60% N. 1H NMR (DMSO-d6): 3.84 (s, 3 H, CH3O); 7.10 (d,
2 H, J = 9, 6-H); 7.86 (s, 1 H, NH); 8.26 (s, 1 H, NH···O); 8.32 (d, 2 H, J = 9, 5-H); 8.41 (s, 2 H,
NH2). 13C NMR (DMSO-d6): 55.3 (s, 3 H, CH3O), 114.0 (C-6), 114.4 (C-7), 127.2 (C-5), 129.6
(C-4), 134.3 (C-2), 154.9 (C-3), 162.0 (C-1), 166.9 (CO). IR (KBr): 3459.8, 3411.2 (NH2),
1676.6 (CO). UV (EtOH): 337 (4.13). MS, m/z (rel.%): 245.1 (100, M+).
3-(4-Chlorophenyl)-6-phenylpyrimido[4,5-e][1,2,4]triazin-8(7H)-one (14c)
5-Chloro-1,2,4-triazine 9c (0.3 g, 1 mmol) was mixed under ice cooling with benzamidine
(12; 0.6 g, 5 mmol). After heating at 120–130 °C for 1 h and cooling, the resulting precipi-
tate was powdered and suspended in 20 ml of acetic acid. After refluxing for 30 min, the
yellow precipitate was filtered off and crystallized from ethanol to provide 97% yield of yel-
low crystals, m.p. >400 °C (EtOH). For C17H10ClN5O (335.0) calculated: 60.81% C, 3.00% H,
20.86% N; found: 60.63% C, 2.98% H, 20.84% N. 1H NMR (DMSO-d6): 7.73 (m, 5 H, 11-,
12-, 13-H); 8.30 (d, 2 H, J = 8, 7-H); 8.60 (d, 2 H, J = 8, 8-H); 13.39 (s, 1 H, NH). 13C NMR
(DMSO-d6): 128.8 (C-13), 129.3 (C-12), 130.4 (C-11), 131.5 (C-10), 133.2 (C-8), 133.3 (C-6),
137.5 (C-9), 140.0 (C-3), 155.8 (C-5), 160.4 (C-4), 161.4 (C-2), 163.7 (C-1). IR (KBr): 3438.4
(NH), 1696.5 (CO). UV (EtOH): 348 (4.27). MS, m/z (rel.%): 335.0 (6, M+), 104.1 (C7H6N+).
Diamino(phenyl)methylium 3-(4-Methoxyphenyl)-6-phenylpyrimido[4,5-e][1,2,4]-
triazin-8-olate (13d)
5-Chloro-1,2,4-triazine 9d (0.6 g, 2 mmol) was mixed under ice cooling with benzamidine
(12; 1.19 g, 10 mmol). Heating at 120–130 °C for 1 h, followed by powdering of the precipi-
tate and twofold crystallization from ethanol provided 95% yield of yellow crystals, m.p.
>355 °C (decomp.) (EtOH). For C25H21N7O2 (451.2) calculated: 65.21% C, 4.82% H, 21.29% N;
found: 65.66% C, 4.54% H, 21.48% N. 1H NMR (DMSO-d6): 3.85 (s, 1 H, CH3O); 7.15 (d,
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Novel 6-Azapteridines
973
2 H, J = 9, 8-H); 7.48 (d, 4 H, J = 7, 11-H, 12-H included); 7.62 (t, 1 H, J = 7, 13-H); 7.75 (t,
1 H, J = 7, 18-H); 7.85 (d, 2 H, J = 7, 17-H); 8.45 (d, 2 H, J = 7, 16-H); 8.55 (d, 2 H, J = 9,
7-H); 9.25 (s, 1 H, NH2). 13C NMR (DMSO-d6): 55.3 (CH3O), 114.2 (C-8), 127.9 (C-12), 128.0
(C-9), 128.1 (C-10), 128.3 (C-13), 128.6 (C-11), 128.9 (C-18), 129.8 (C-17), 130.6 (C-16),
133.6 (C-8), 138.7 (C-6), 138.9 (C-5), 156.8 (C-3), 161.8 (C-2), 162.7 (C-4), 165.6 (C-1),
169.2 (C-15), 170.2 (C-14). IR (KBr): 3325.5 (NH2), 1684.3 (CO). UV (EtOH): 396 (4.21). MS,
m/z (rel.%): 452.2 (51, M + H+), 332.2 (C18H12N5O2 + H+).
3-(4-Methoxyphenyl)-6-phenylpyrimido[4,5-e][1,2,4]triazin-8(7H)-one (14d)
Compound 13d (0.45 mg, 1 mmol) was suspended in 20 ml of acetic acid and refluxed for
30 min. After cooling, the yellow precipitate was filtered off and crystallized from ethanol to
give 95% yield of yellow crystals, m.p. 357–359 °C (EtOH). For C18H13N5O2 (331.1) calcu-
lated: 65.25% C, 3.65% H, 21.14% N; found: 64.96% C, 3.94% H, 21.04% N. 1H NMR
(DMSO-d6): 3.93 (s, 3 H, CH3O); 7.20 (d, 2 H, J = 9, 8-H); 7.60 (d, 2 H, J = 7, 11-H); 7.70 (t, 1 H,
J = 7, 13-H); 8.28 (d, 2 H, J = 7, 12-H); 8.57 (d, 2 H, J = 9, 7-H); 13.31 (s, 1 H, NH). 13C NMR
(DMSO-d6): 55.5 (CH3O), 114.6 (C-8), 126.6 (C-9), 128.7 (C-12), 128.8 (C-11), 130.6 (C-13),
131.0 (C-10), 131.7 (C-7), 132.0 (C-6), 133.1 (C-5), 139.2 (C-3), 161.2 (C-2), 162.8 (C-4),
164.4 (C-1). IR (KBr): 3432.2 (NH), 1703.0 (CO). UV (EtOH): 323 (4.09). MS, m/z (rel.%):
331.1 (6, M+), 172.2 (100, C10H6N2O+).
Ethyl 5-(4-Chlorobenzohydrazonamido)-3-(4-chlorophenyl)-1,2,4-triazine-6-carboxylate (15c)
Finely powdered 5-chloro-1,2,4-triazine 9c (0.3 g, 1 mmol) was mixed with amidrazone 5c
(0.34 g, 2 mmol) and the dry powder was heated at 60 °C for 1 h. The formed orange mass
was suspended in 40 ml of dichloromethane and filtrated hot in order to remove excess
amidrazone hydrochloride. The dichloromethane filtrate was evaporated to a third of its vol-
ume, the crude product was removed by filtration and washed with ethanol to give 74%
yield of yellow crystals, m.p. 218–219 °C (CH2Cl2). For C19H16Cl2N6O2 (430.1) calculated:
52.91% C, 3.74% H, 19.49% N; found: 52.59% C, 3.72% H, 19.49% N. 1H NMR (DMSO-d6):
1.36 (t, 3 H, J = 7, CH3); 4.42 (q, 2 H, J = 7, CH2); 6.90 (s, 1 H, NH); 7.47 (d, 2 H, J = 8,
12-H); 7.52 (d, 2 H, J = 8, 6-H); 7.83 (d, 2 H, J = 8, 13-H); 8.29 (d, 2 H, J = 8, 7-H); 10.15 (s,
1 H, 9-H); 10.85 (s, 1 H, 9′-H). 13C NMR (DMSO-d6): 14.4 (CH3), 61.7 (CH2), 128.5 (C-11),
128.6 (C-12), 129.3 (C-6), 129.9 (C-13), 130.3 (C-7), 132.9 (C-5), 134.3 (C-14), 135.1 (C-8),
136.7 (C-10), 140.4 (C-4), 150.4 (C-3), 160.3 (C-2), 165.5 (C-1). IR (KBr): 3435.6 (NH),
3267.0 (NH2), 1674.1 (CO), 1636.5 (C=N). UV (CH2Cl2): 303 (4.45). MS, m/z (rel.%): 430.0
(100, M+).
3-Phenylpyrimido[4,5-e][1,2,4]triazin-8(7H)-ones 17a, 17d. General Procedure
1,2,4-Triazine 11a, 11d was suspended in excess of triethyl orthoformate (16) and acetic an-
hydride was added. After refluxing for 2 h, the solution was evaporated and the formed
solid was digested with chloroform. The crude product was filtered off and crystallized from
ethanol.
3-Phenylpyrimido[4,5-e][1,2,4]triazin-8(7H)-one monohydrate (17a). Yellow-green crystals,
yield 87%, m.p. >326 °C (decomp.) (EtOH). For C11H7N5O (225.1) calculated: 57.52% C,
3.29% H, 30.49% N; found: 57.78% C, 3.09% H, 30.20% N. 1H NMR (DMSO-d6): 7.65 (m,
3 H, 8-H, 9-H); 8.57 (m, 3 H, 7-H, 2-H included); 13.16 (s, 1 H, NH). 13C NMR (DMSO-d6):
Collect. Czech. Chem. Commun. (Vol. 68) (2003)

974
Wamhoff, Tzanova:
128.6 (C-8), 129.2 (C-9), 132.5 (C-7), 134.2 (C-6), 142.0 (C-5), 155.5 (C-2), 156.5 (C-3),
159.5 (C-4), 164.3 (C-1). IR (KBr): 3434.2 (NH), 1716.2 (CO), 1593.5 (C=N). UV (EtOH): 336
(4.07). MS, m/z (rel.%): 225.1 (6, M+), 169.1 (100, C9H5N4+).
3-(4-Methoxyphenyl)pyrimido[4,5-e][1,2,4]triazin-8(7H)-one monohydrate (17d). Yellow-green
crystals, yield 82%, m.p. >329 °C (decomp.) (EtOH). For C12H9N5O2 (255.1) calculated:
55.54% C, 3.81% H, 26.50% N; found: 54.66% C, 3.72% H, 26.20% N. 1H NMR (DMSO-d6):
3.90 (s, 3 H, CH3); 7.19 (d, 2 H, J = 9, 8-H); 8.52 (s, 1 H, 2-H); 8.57 (d, 2 H, J = 9, 7-H); 13.01
(s, 1 H, NH). 13C NMR (DMSO-d6): 55.9 (CH3), 115.2 (C-8), 126.9 (C-9), 131.1 (C-7), 141.0
(C-5), 155.6 (C-6), 156.5 (C-2), 159.7 (C-3), 163.4 (C-4), 164.7 (C-1). IR (KBr): 3438.0 (NH),
1718.9 (CO), 1602.9 (C=N). UV (EtOH): 335 (4.06). MS, m/z (rel.%): 255.1 (13, M+), 199.1
(100, C10H7N4O+).
3-(4-Methoxyphenyl)-6-phenylpyrimido[4,5-e][1,2,4]triazin-8(7H)-one (14d)
Finely powdered 5-amino-1,2,4-triazine 11d (245 mg, 1 mmol) was suspended in 5 ml of
benzaldehyde (18) and the mixture refluxed for 1.5 h. After cooling to room temperature,
the unreacted solid was filtered off. The filtrate was evaporated in vacuo and the residue was
treated with 20 ml of hot propan-2-ol and active carbon. After hot filtration and evapora-
tion of the solvent, the crude product was filtered off and crystallized three times from etha-
nol to give 12% yield of yellow crystals, m.p. 355 °C (EtOH). The identity of both products
formed either by the reaction from 9d via 13d or from 11d and 18, respectively, was con-
firmed by TLC, IR and 1H NMR spectra.
M. Tzanova thanks the Graduiertenförderung des Landes Nordrhein–Westfalen for a doctoral fel-
lowship.
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