Interaction of 3-(2-Aminophenyl)-6-R1-1,2,4-triazin-5-ones with Acylating Reagents: An Efficient Method for Preparation of 6-Substituted 3-R1-2H-[1,2,4]triazino[2,3-c]quinazolin-2-ones

Article abstract of DOI:10.1002/jhet.2120

The series of 6-substituted 3-R¹-2H-[1,2,4]triazino[2,3-c]quinazolin-2-one was prepared via condensation of 3-(2-aminophenyl)-6-R¹-1,2,4-triazin-5-ones with acylating reagents. Particularities of ¹H NMR spectra have been also discussed based on the comparison of experimental and theoretical results for 3-methyl-6-phenyl-2H-[1,2,4]triazino[2,3-c]quinazolin-2-one and its 4,3-isomer.

Full text of DOI:10.1002/jhet.2120

776
Interaction of 3-(2-Aminophenyl)-6-R1-1,2,4-triazin-5-ones with Acylating
Reagents: An Efficient Method for Preparation of 6-Substituted
3-R1-2H-[1,2,4]triazino[2,3-c]quinazolin-2-ones
Vol 53
a
a
b
a
b
*
Alexey Yu. Voskoboynik, Dmitriy Yu. Scorina, Tetiana Yu. Sergeieva, Sergiy I. Kovalenko, Sergiy I. Okovytyy,
Irina V. Omelchenko,c and Oleg V. Shishkinc,d
aOrganic and Bioorganic Chemistry Department, Zaporozhia State Medical University, Mayakovsky Avenue, 26,
Zaporozhye 69035, Ukraine
bOrganic Chemistry Department, Oles Honchar Dnipropetrovsk National University, 72 Gagarina Avenue,
Dnipropetrovsk 49050, Ukraine
cSSI “Institute for Single Crystals”, National Academy of Sciences of Ukraine, 60 Lenina Avenue, Kharkiv 61001, Ukraine
dV. N. Karazin Kharkiv National University, 4 Svobody Square, Kharkiv 61122, Ukraine
*
E-mail: kovalenkosergiy@gmail.com
Received April 22, 2013
DOI 10.1002/jhet.2120
Published online 2 June 2015 in Wiley Online Library (wileyonlinelibrary.com).
The series of 6-substituted 3-R1-2H-[1,2,4]triazino[2,3-c]quinazolin-2-one was prepared via condensation
1
of 3-(2-aminophenyl)-6-R1-1,2,4-triazin-5-ones with acylating reagents. Particularities of H NMR spectra
have been also discussed based on the comparison of experimental and theoretical results for 3-methyl-6-
phenyl-2H-[1,2,4]triazino[2,3-c]quinazolin-2-one and its 4,3-isomer.
J. Heterocyclic Chem., 53, 776 (2016).
INTRODUCTION
2-substituted-4-hydrazinoquinazolines with α-ketocarbo-
xilic acid esters. Unfortunately, LC–MS data showed that
refluxing of the mentioned compounds in acetic acid did
not lead to the formation of the expected products. Inabil-
ity of target compound formation can be explained by the
fact that the substituent in position 2 complicates the
ANRORC-rearrangement.
In continuation of our ongoing interest for the synthesis
of 6-substituted 3-R1-2H-[1,2,4]triazino[2,3-c]quinazolin-
2-ones, we proposed the alternative approach through
[5 + 1]-condensation. It is known that 3-R1-2H-[1,2,4]
triazino[2,3-c]quinazolin-2-ones under hydrazine hydrate
action undergo the nucleophilic cleavage, accompanied
by the formation of 3-(2-aminophenyl)-6-R1-1,2,4-triazin-
5-ones [6]. The products of the reaction were formed with
high yield and determined as NCCCN-binucleophiles.
Thus, they can be used like a starting compound for the
synthesis of 6-substituted 3-R1-2H-[1,2,4]triazino[2,3-c]
quinazolin-2-ones. During the studying of the [5 + 1]-
cyclocondensation, the acetic, propionic, succinic, and
glutaric anhydrides and benzoyl and chloracetic chlorides
were utilized as 1,1-bielectrophiles.
Triazino[c]quinazolines are heterocyclic compounds,
which have been proved to be very useful in the synthetic
chemistry, especially in various one-step heterocyclization
reactions. The most common among the extensively discussed
literature methods, which lead to the formation of such type of
heterocyclic systems, is [4 + 2]-cyclocondensation [1–3].
Especial attention should be given to the series of publica-
tions [4,5] describing the formation of 3-R1-2H-[1,2,4]
triazino[2,3-c]quinazolin-2-ones via condensation of 4-
hydrazinoquinazoline with α-ketocarboxylic acid esters.
Authors have found that the formation of the aforemen-
tioned substances proceeds through [4,3-с] systems in-
termediate resulted from specific Dimroth’s type
rearrangement. However, they obtained only 3-substituted
2H-[1,2,4]triazino[2,3-c]quinazolin-2-ones, despite the possi-
bility of compound formation with substitutions in other posi-
tions that greatly expand their potential particularly as
biologically active agents. Nevertheless, we synthesized an
unexpected series of the 6-substituted compounds. The main
purpose of the presented investigation is the elaboration of
preparative methods for 6-substituted 3-R1-2H-[1,2,4]
triazino[2,3-c]quinazolin-2-ones.
The obtained results indicated that refluxing of initial 3-
(2-aminophenyl)-6-R1-1,2,4-triazin-5-ones in acetic and
propionic anhydrides over 3 h has led to the corresponding
6-methyl(ethyl)-3-R1-2H-[1,2,4]triazino[2,3-c]quinazolin-
2-ones 3.1–3.4 (Scheme 1). Interactions of 2.1–2.9 with
cyclic anhydrides of dicarboxylic acids were performed
RESULT AND DISCUSSION
According to [4], we attempted to obtain 6-substituted 3-R1-
2H-[1,2,4]triazino[2,3-c]quinazolin-2-one via condensation of
© 2015 HeteroCorporation

May 2016
Interaction of 3-(2-Aminophenyl)-6-R1-1,2,4-triazin-5-ones with
Acylating Reagents
777
Scheme 1. Interaction of 3-(2-aminophenyl)-6-R1-1,2,4-triazin-5-ones with acylating agents.
in acetic acid. Refluxing of the afore mentioned compounds
over 4 h led to the formation of (3-R1-2-oxo-2H-[1,2,4]
triazino[2,3-c]quinazolin-6-yl)carboxylic acids 4.1–4.14
in high yields. Under similar conditions, the interaction
of 3-(2-aminophenyl)-6-methyl-1,2,4-triazin-5-one with
benzoylchloride resulted in the 6-phenyl-3-methyl-2H-
[1,2,4]triazino[2,3-c]quinazolin-2-one 5.1 formation. The
presence of two high reactive electrophilic centers in
the molecule of chloracetylchloride causes the necessity
of mild conditions during the reaction. Interaction of
chloracetylchloride with 3-(2-aminophenyl)-6-R1-1,2,
4-triazin-5-ones at 60°C in acetic acid yields to 6-
(chloromethyl)-3-R1-2H-[1,2,4]triazino[2,3-c]quinazolin-
2-ones 6.1 and 6.2.
ionization mechanism could also be applied to compounds
4.8–4.14. [F–CO2]+ (m/z 213), [F–COOH]+ (m/z 212), and
[F–CH2COOH]+ (m/z 198) ions formation resulted from
F+ ions with m/z 257. Elimination of CO and C2Н5 from
[F–CO2]+ and [F–COOH]+ gives an ion with maximal
intensity (m/z 185).
1Н NMR spectra of compounds 3.1–3.4, 4.1–4.14, 5.1,
6.1, and 6.2 were characterized by the presence of four sig-
nals belonging to the aromatic protons of triazinoquinazoline
system with the corresponding splitting [4]. The spectra of
compounds 3.1–3.4 contain the signals of an aliphatic substi-
tute that is observed in high field as a three-proton singlet
(3.1 and 3.2) or a combination of a three-proton triplet and
1
a two-proton quartet (3.3 and 3.4). The H NMR spectro-
The structures of the synthesized compounds were
scopic data of compounds 4.1–4.14 are also consistent with
the assigned structure. Triplet signals due to ethylene
fragment in compounds 4.1–4.7 are located at 3.63–3.55
and 3.03–2.98 ppm, and propylene fragment signals
(4.8–4.14) are observed at around 3.04, 2.47–2.30, and
1
proved by a complex of spectral methods: H NMR, 13С
NMR, EIMS, LC–MS, and X-ray analysis. The intensive
signals of molecular ions (MH+) are presented in the
LC–MS spectra of compounds 3.1–3.4, 4.1–4.14, 5.1,
6.1, and 6.2. The LC–MS spectra of compounds 3.2,
3.4, 4.7, and 4.14 also contain signals [M + 3] caused
by isotopic composition of the sulfur.
Mass spectra data for compounds 3.1, 4.1–4.14 and 5.1
show molecular ion instability. The main route for the
decomposition of triazine cycle is its degradation on
С(10b)–N(1) and N(3)–N(4) bonds. In the case of com-
pounds 4.1–4.7, breakdown of ions F+, detected after the
expansion of triazine ring, included formation of [F–Н2О]+
(m/z 225), [F–CO2]+ (m/z 199), [F–COOH]+ (m/z 198),
and [F–Н2О–CO]+ (m/z 197) ions, where [F–COOH]+
has the maximum intensity. The same dissociative
1
2.11–1.71 ppm, respectively. H NMR spectra of com-
pounds 6.1 and 6.2 prove the structure by the presence
of a two-proton singlet at 5.16–5.18 ppm, caused by the
chloromethylene group. The signals related to the substitutes
in position 3 are also presented in all 1H NMR spectra.
For better understanding of the particularities of 1H
NMR spectra of 2,3- and 4,3-isomers of quinazolin-2-ones,
1
we have performed quantum-chemical calculations of H
chemical shifts of isomeric 3-methyl-6-phenyl-2H-[1,2,4]
triazino[4,3-c]quinazolin-2-one (5.1) and 3-methyl-6-phenyl-
2H-[1,2,4]triazino[4,3-c]quinazolin-2-one that may be formed
as a result of possible tautomeric processes (Scheme 2).
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

778
A. Y. Voskoboynik, D. Y. Scorina, T. Y. Sergeieva, S. I. Kovalenko,
S. I. Okovytyy, I. V. Omelchenko, and O. V. Shishkin
Vol 53
Scheme 2. Theoretical formation of isomeric 3-methyl-6-phenyl-2H-[1,2,4]triazino[4,3-c]quinazolin-2-one as a result of tautomeric processes.
For the calculations, we have used a DFT approach with
pyrimidine ring. The N(1)–C(11) and N(2)–C(7) bonds
[1.278(1) and 1.377(1) Å, respectively] are shorter than the
С(1)–N(1) and N(2)–C(11) bonds [1.390(1) and 1.409(1) Å,
respectively]. The same effect was observed in the previously
studied structure [4]. The substituent at the С(11) atom has all-
trans conformation [the corresponding torsion angles are as
follows: С(11)-С(12)-С(13)-С(14) À175.98(9)°, С(12)-
С(13)-С(14)-С(15) 174.4(1)°, and С(13)-С(14)-С(15)-О(3)
166.72(9)°]. Such conformation of substituent is stabilized
by attractive intramolecular contacts: H(13B)…N(1) 2.62 Å,
H(12A)…N(3) 2.55 Å, and H(12B)…N(3) 2.65 Å (the sum
of van der Waals radii is 2.67 Å) [22]. Angular structure of
the tricyclic system causes formation of the H(5)…N(4) 2.53
Å (2.67 Å) attractive interaction that cannot be considered
as an intramolecular hydrogen bond because of the small
value of the C–H…N angle (100°).
B3LYP [7,8], PBE1PBE [9,10], and M06L [11] functionals
in combination with Continuous Set of Gauge Transforma-
tions (CSGT) [12] and Gauge-Independent Atomic Orbital
(GIAO) [13] techniques for geometry optimization at the
same levels of theory. Magnetically consistent 6–31G## (I)
basis set, proposed in [14] and tested for the calculations of
chemical shifts in [15–17], has been used herein. Taking into
account the effect of the solvent (DMSO), the calculations
were performed via the Polarizable continuum model
(PCM) method [18–20]. All calculations were performed
using Gaussian 09 program [21]. Chemical shifts were
obtained by subtracting the calculated magnetic shielding for
the corresponding nuclei of interest from the shielding of the
reference compound (TMS). As could be seen from Table 1,
the B3LYP and PBE1PBE functionals, in contrast to M06L,
give good agreement with the experiment and could be used
for signal assignments and identification of the structure of
such heterocyclic compounds. Calculations clearly demon-
strate that the difference of chemical shifts of ortho- and
meta-protons of the 6-phenyl fragment could be used for the
unambiguous assignment of isomers. Thus, in the case of
4,3-isomer, chemical shifts of those protons are almost equal,
while in the case of 2,3-isomer, the Δδo-m value in experimen-
tal spectrum reaches 0.24 ppm, which is very close to calcula-
tions with the B3LYP and PBE1PBE functionals. Analysis of
chemical shifts of protons at positions 8, 11 and 9, 10 reveals
in conclusion that protons H11 and H9 are more deshielded if
compared with H8 and H10, respectively.
CONCLUSIONS
The title synthetic protocol allowed the preparation of
hard accessible 6-substituted 3-R-2H-[1,2,4]triazino[2,3-c]
quinazolin-2-ones starting from proper 3-(2-aminophenyl)-6-
R-1,2,4-triazin-5-ones. The proposed method characterized
by good yields and purity of target products. Comparison
of experimental and theoretical results for 3-methyl-6-
phenyl-2H-[1,2,4]triazino[2,3-c]quinazolin-2-one and its
4,3-isomer and X-ray study confirm the formation of 2,3-
isomer series.
Formation of the aforementioned tricyclic system was
also confirmed by the carboxylic carbon signal at
174.77–173.67 ppm and the C6 atom signal at
153.95–151.34 ppm detected in the 13C NMR spectra
of compounds 4.1, 4.3, 4.8, and 4.10.
The complex of spectral data did not give us an ability to
determine the type of heterocyclic system that was formed.
Final conclusion about the structure of the synthesized
compounds was made on the basis of the results (Fig. 1)
of the XRD study of the compound (4.8).
Quinazoline fragment is planar within 0.021 Å. Triazinone
ring adopts a very flattened boat conformation. The deviations
of the N(2) and С(8) atoms from the mean plane of the
remaining atoms of ring are 0.03 and 0.04 Å, respectively.
There is a well-defined alternation of the bonds within the
EXPERIMENTAL
Melting points were determined using Stuart Scientific SMP30
apparatus (Stone, Staffordshire, UK). The elemental analyses (C, H,
N, and S) were performed using the Elementar vario EL cube ana-
lyzer (Hanau, Germany). Analyses were indicated by the symbols
of the elements or functions within 0.3% of the theoretical values.
IR spectra (4000–600 cm–1) were recorded on a Bruker ALPHA
FTIR spectrometer (Coventry, UK) using a module for measuring
ATR. 1H (400 MHz) and 13C NMR spectra (100 MHz): were
recorded on a Varian-Mercury 400 (Varian Inc., Palo Alto, CA)
spectrometer with TMS as internal standard in DMSO-d6 solution.
LC–MS data were recorded using a chromatography/mass spectro-
metric system that consists of an HPLC “Agilent 1100 Series” (Palo
Alto, CA) equipped with a diode-matrix and a mass-selective
detector “Agilent LC/MSD SL” (atmospheric pressure
chemical ionization). EIMS data were recorded on a Varian
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

May 2016
Interaction of 3-(2-Aminophenyl)-6-R1-1,2,4-triazin-5-ones with
Acylating Reagents
779
Table 1
Experimental 1H chemical shifts (ppm) for 3-methyl-6-phenyl-2H-[1,2,4]triazino[2,3-c]quinazolin-2-one (5.1), calculated values for (5.1) and its 4,3-
isomer, and parameters of the linear regression equation δexpt = A × δcalc + B.
B3LYP/6–31G## (I)
2,3-Isomer 4,3-Isomer
PBE1PBE/6–31G## (I)
2,3-Isomer 4,3-Isomer
M06L/6–31G## (I)
2,3-Isomer 4,3-Isomer
Experiment
2,3-Isomer
Atoms
CSGT
GIAO
CSGT
GIAO
CSGT
GIAO
CSGT
GIAO
CSGT
GIAO
CSGT
GIAO
2′, 6′
3′, 5′
4
8
9
10
11
1-CH3
Δδo-m
R1
7.80
7.56
7.56
7.93
8.02
7.78
8.57
2.22
0.24
7.97
7.74
7.77
8.08
8.18
7.88
8.89
2.28
0.23
0.991
0.87
0.85
8.10
7.85
7.92
8.21
8.31
8.03
9.06
2.28
0.25
0.990
0.84
0.97
7.72
7.67
7.70
8.05
8.08
7.86
9.06
2.52
0.05
0.970
0.69
2.37
7.82
7.78
7.85
8.16
8.22
8.02
9.27
2.49
0.04
0.963
0.64
2.64
8.08
7.82
7.86
8.16
8.25
7.96
8.99
2.28
0.26
0.989
0.86
0.87
8.23
7.94
8.01
8.30
8.40
8.11
9.18
2.28
0.29
0.988
0.82
1.06
7.82
7.75
7.79
8.14
8.17
7.94
9.17
2.53
0.07
0.971
0.68
2.39
7.94
7.86
7.93
8.26
8.32
8.11
9.39
2.50
0.08
0.968
0.63
2.65
8.08
7.69
7.71
7.96
8.06
7.80
8.77
2.34
0.39
0.965
0.90
0.67
8.51
7.71
7.97
8.44
8.59
8.17
9.31
2.44
0.8
7.73
7.61
7.65
7.98
8.03
7.80
8.98
2.59
0.12
0.977
0.71
2.19
8.06
7.73
7.90
8.32
8.10
7.97
9.50
2.74
0.33
0.952
0.56
3.30
0.963
0.65
2.46
A
B
Protons of methyl group have not been included to the correlation for better estimation of the region of aromatic protons.
Figure 1. Structure of 2h according to XRD data.
1200 L instrument at 70 eV. The purity of all obtained
2.77 (s, 3Н, 6-СН3), 7.70 (t, 1Н, J=8.1Hz, Н-10), 7.80 (d, 1Н,
J=8.1Hz, Н-8), 7.96 (t, 1Н, J=8.0Hz, Н-9), 8.48 (d, 1Н,
J=8.0Hz, Н-11); EIMS m/z (I rel, %) 227 (2.2), 226 (8.4), 186
(12.7), 185 (100.0), 145 (5.5), 144 (5.5), 102 (25.3), 90 (5.2), 76
(12.4), 75 (14.5); LC–MS m/z=227 [М+1]; Anal. Calcd for
С12H10N4O: C, 63.71; Н, 4.46; N, 24.76; Found: C, 63.74; Н, 4.52,
N, 24.77.
6-Methyl-3-(thiophen-2-yl)-2H-[1,2,4]triazino[2,3-c]quinazolin-
2-one (3.2). Yield:76.1%; mp 264–266°C; 1H NMR 2.89 (s, 3Н,
6-СН3), 7.31 (t, 1Н, J= 3.7 Hz, H-4 thioph), 7.74 (t, 1Н, J=7.8Hz,
Н-10), 7.86 (d, 1Н, J=7Hz.8, Н-8), 7.98 (m, 2Н, Н-9, H-5
thioph), 8.41 (d, 1Н, J=3.7Hz, Н-3 thioph), 8.54 (d, 1Н,
J=8.2Hz, Н-11); LC–MS m/z= 295 [М+1]; Anal. Calcd for
С15H10N4OS: C, 61.21; Н, 3.42; N, 19.04; Found: C, 61.23; Н,
3.43, N, 19.08.
compounds was checked by 1H NMR and LC–MS.
Substances 1.1–1.9 and 2.1–2.9 were synthesized according to
the reported procedures [4,6]. Other starting materials and sol-
vents were obtained from commercially available sources and
used without additional purification.
General method for the preparation of 6-alkyl-3-R1-2H-
[1,2,4]triazino[2,3-c]quinazolin-2-ones (3.1–3.4). The 5 mmol
of corresponded 3-(2-aminophenyl)-6-R-1,2,4-triazin-5(2H)-
one (2.1 and 2.9) was suspended in 15 mL of acetic or
propionic anhydride and refluxed during 3 h. The mixture was
cooled, and the formed precipitate was filtered off, washed with
propanol 2, and dried.
3,6-Dimethyl-2H-[1,2,4]triazino[2,3-c]quinazolin-2-one
(3.1). Yield:72.5%; mp 222–224°C; 1H NMR 2.36 (s, 3Н, 3-СН3),
Journal of Heterocyclic Chemistry
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A. Y. Voskoboynik, D. Y. Scorina, T. Y. Sergeieva, S. I. Kovalenko,
S. I. Okovytyy, I. V. Omelchenko, and O. V. Shishkin
Vol 53
6-Ethyl-3-methyl-2H-[1,2,4]triazino[2,3-c]quinazolin-2-one
(3.3).
Yield: 75.0%; mp 170–172°C; 1H NMR 1.36 (t, 3Н,
(10.8), 76 (6.1), 75 (6.1), 65 (7.5), 63 (6.5), 56 (6.3), 55 (14.4),
51 (8.9), 43 (5.8); LC–MS m/z = 362 ([M + 2]+), 361 (MH+);
Anal. Calcd for C20H16N4О3: C, 66.66; H, 4.48; N, 15.55;
Found: C, 66.64; H, 4.47; N, 15.54.
J = 7.4 Hz, 6-СН2СН3,), 2.36 (s, 3Н, 3-СН3), 3.16 (q, 2H,
J = 7.4 Hz, СН2СН3,), 7.70 (t, 1Н, J = 8.2 Hz, Н-10), 7.82
(d, 1Н, J = 8.2 Hz, Н-8), 7.96 (t, 1Н, J = 8.0 Hz, Н-9), 8.47
(d, 1Н, J = 8.0 Hz, Н-11); LC–MS m/z = 241 [М + 1]; Anal.
Calcd for С13H12N4O: C, 64.99; Н, 5.03; N, 23.32; Found:
C, 65.00; Н, 5.05, N, 23.32.
(3-Phenyl-2-oxo-2Н-[1,2,4]triazino[2,3-с]quinazolin-6-yl)
propanoic acid (4.3).
Yield: 89.2%; mp 280–282°C; 1H NMR
2.88 (t, 2H, J=6.8Hz, СН2СН2СООН), 3.51 (t, 2H, J=6.8Hz,
СН2СН2СООН), 7.60–7.53 (m, 3Н, Н-3′, 4′, 5′), 7.73 (t, 1Н,
J=8.1Hz, Н-10), 7.81 (d, 1Н, J=8.1Hz, Н-8), 7.98 (t, 1H,
J= 8.1 Hz, H-9), 8.25 (d, 2H, J=7.7Hz, Н-2′, 6′), 8.53 (d, 1H,
J=8.1Hz, Н-11), 12.30 (s, 1H, СООH); 13C NMR: δ = 28.21
(СН2СН2СООН), 30.25 (СН2СН2СООН), 119.64 (11a-C), 125.89
(8-C), 127.77 (11-C), 128.77 (10-C), 128.88 (4′-C), 129.76 (3′-C,
5′-C), 131.72 (2′-C, 6′-C), 132.56 (1′-C), 135.79 (9-C),
143.68 (3-C), 149.78 (11b-C), 151.34 (6-C), 153.56 (7а-C),
159.80 (2-C), 173.92 (СООН); IR (cmÀ1): 3011, 2916,
2848, 1733, 1663, 1639, 1630, 1615, 1602, 1573, 1544,
1498, 1474, 1448, 1420, 1343, 1331, 1317, 1293, 1247, 1179,
1163, 1100, 1015, 982, 945, 920, 874, 816, 802, 780, 755, 707,
690, 644, 631; EIMS m/z (I rel, %) = 347 ([M + 1]+, 1.3), 243
(30.0), 225 (6.2), 199 (44.0), 198 (100.0), 197 (19.3), 171 (24.9),
170 (7.0), 156 (5.3), 155 (43.1), 149 (6.4), 143 (12.9), 129 (11.2),
118 (8.8), 103 (22.1), 102 (16.5), 90 (5.5), 76 (11.6), 75 (5.5), 41
(6.6); LC–MS m/z= 348 ([MH + 2]+), 347 (MH+); Anal. Calcd for
C19H14N4О3: C, 65.89; H, 4.07; N, 16.18; Found: C, 65.91; H,
4.09; N, 16.20.
6-Ethyl-3-(thiophen-2-yl)-2H-[1,2,4]triazino[2,3-c]quinazolin-2-
1
one (3.4). Yield: 86.3%; mp 190–192°C; H NMR 1.36 (t, 3Н,
J=7.2Hz, 6-СН2СН3), 3.16 (q, 2Н, J=7.2Hz, 6-СН2СН3), 7.30
(1Н, J = 3.9 Hz, H-4 thioph,), 7.73 (t, 1Н, Н-10, J = 8.1 Hz),
7.88 (d, 1Н, J = 8.1 Hz, Н-8), 7.96 (m, 2Н, Н-9, H-5), 8.40
(d, 1Н, J=3.9Hz, Н-3 thioph,), 8.53 (d, 1Н, J=8.2Hz, Н -11);
LC–MS m/z = 309 [М + 1]; Anal. Calcd for С16H12N4OS: C,
62.32; Н, 3.92; N, 18.17; Found: C, 62.35; Н, 3.96, N,
18.18.
General procedure for the preparation of (3-R1-2-oxo-
2Н-[1,2,4]triazino[2,3-с]quinazolin-6-yl)carboxylic acids
(4.1–4.14). To
a
5 mmol of corresponding 6-R-3-(2-
aminophenyl)-[1,2,4]-triazin-5-ones (2.1–2.5, 2.7, and 2.9) in
10 mL of acetic acid, 5.25 mmol of succinic or glutaric anhydride
was added. The resulting mixture was refluxed for 4 h. The solvent
was removed in vacuum. After the addition of methanol, the solid
was filtered off and washed with ethyl ether. If necessary,
additional purification could be performed by crystallization from
acetic acid.
(3-(4′-Methylphenyl)-2-oxo-2Н-[1,2,4]triazino[2,3-с]quinazolin-
(3-Methyl-2-oxo-2Н-[1,2,4]triazino[2,3-с]quinazolin-6-yl)
6-yl)propanoic acid (4.4).
Yield: 89.5%; mp 262–264°C; 1H
1
propanoic acid (4.1).
Yield: 95.7; mp 234–236°C; H NMR
NMR 2.38 (s, 3Н, СН3), 2.87 (t, 2H, J=6.8Hz, СН2СН2СООН),
3.50 (t, 2H, J=6.8Hz, СН2СН2СООН), 7.35 (d, 3Н, J=7.7Hz, Н-
3′, 5′), 7.73 (t, 1Н, J=8.1Hz, Н-10), 7.81 (d, 1Н, J=8.1Hz, Н-8),
7.97 (t, 1H, J= 8.1 Hz, H-9), 8.19 (d, 2H, J=7.7Hz, Н-2′, 6′), 8.53
(d, 1H, J=8.1Hz, Н-11), 12.24 (s, 1H, СООH); IR (cmÀ1): 2973,
2917, 2848, 2668, 1745, 1626, 1603, 1570, 1546, 1494, 1469,
1389, 1362, 1341, 1308, 1284, 1264, 1239, 1214, 1180, 1162,
1142, 1110, 1015, 969, 944, 869, 835, 788, 777, 713, 699, 690,
678, 637, 623; EIMS m/z (I rel, %) = 361 ([M + 1]+, 2.4), 243
(31.6), 225 (5.3), 199 (42.9), 198 (100.0), 197 (14.9), 171 (25.4),
170 (7.3), 156 (6.0), 155 (48.5), 143 (16.5), 129 (14.2), 118 (13.4),
117 (18.6), 116 (20.5), 103 (5.6), 102 (21.0), 91 (5.0), 90 (16.1), 89
(11.8), 77 (6.4), 76 (5.0); LC–MS m/z= 362 ([MH + 2]+), 361
(MH+); Anal. Calcd for C20H16N4О3: C, 66.66; H, 4.48; N, 15.55;
Found: C, 66.61; H, 4.45; N, 15.52.
2.37 (s, 3H, СН3), 2.83 (t, 2H, J = 6.8 Hz, СН2СН2СООН),
3.38 (t, 2H, J = 6.8 Hz, СН2СН2СООН), 7.69 (t, 1H, J = 8.1 Hz,
H-10), 7.76 (d, 1Н, J=8.1Hz, Н-8), 7.95 (t, 1H, J= 8.1 Hz, H-9),
8.46 (d, 1H, J=8.1Hz, Н-11), 12.28 (s, 1H, СООH); 13C NMR:
δ = 18.34 (CH3), 28.26 (СН2СН2СООН), 30.27 (СН2СН2СООН),
119.93 (11a-C), 125.79 (8-C), 127.71 (11-C), 128.73 (10-C),
135.69 (9-C), 142.22 (3-C), 143.79 (11b-C), 152.28 (6-C), 153.34
(7а-C), 154.97 (2-C), 173.67 (СООН); IR (cmÀ1): 3106, 3003,
2922, 2859, 2779, 2677, 2601; 1702; 1660; 1625; 1592; 1568;
1510; 1464; 1421; 1408; 1359; 1335; 1286; 1273; 1259; 1222,
1204, 1181, 1155, 1129, 1104, 1081, 1036, 1018, 1005, 984, 967,
944, 873, 846, 777, 705, 689, 677, 668, 622; EIMS m/z (I rel,
%) = 284 (M+, 1.3), 244 (5.2), 243 (20.7), 225 (2.7), 199 (19.0),
198 (100.0). 171 (10.6), 170 (5.1), 155 (18.3), 143 (11.4), 129 (7.2),
118 (6.4), 102 (12.1), 90 (8.7), 76 (6.6). 75 (9.6); LC–MS m/z=286
([M + 2]+), 285 (MH+); Anal. Calcd for C14H12N4О3: C, 59.15;
H, 4.25; N, 19.71; Found: C, 59.16; H, 4.26; N, 19.71.
(3-Benzyl-2-oxo-2Н-[1,2,4]triazino[2,3-с]quinazolin-6-yl)
propanoic acid (4.2). Yield: 66.3%; mp 194–196°C; 1H NMR
2.76 (t, 2H, J=7.0Hz, СН2СН2СООН), 3.31 (t, 2H, J=7.0Hz,
СН2СН2СООН), 4.10 (s, 2Н, СН2), 7.23 (t, 1Н, J=7.6Hz, Н-4′),
7.31 (t, 2Н, J=7.6Hz, Н-3′, 5′), 7.38 (d, 2H, J=7.5Hz, Н-2′, 6′),
7.69 (t, 1Н, J = 8.1 Hz, Н-10), 7.77 (d, 1Н, J = 8.1 Hz, Н-8),
7.95 (t, 1H, J = 8.1 Hz, H-9), 8.48 (d, 1H, J = 8.1 Hz, Н-11),
12.25 (s, 1H, СООH); IR (cmÀ1): 2910, 2710, 2619, 2550,
1713, 1634, 1606, 1592, 1568, 1494, 1475, 1454, 1441,1425,
1349, 1334, 1295, 1268, 1247, 1227, 1178, 1158, 1102, 1076,
1029, 1003, 975, 917, 890, 873, 893, 829, 773, 748, 735, 697,
670, 657, 627, 605; EIMS m/z (I rel, %) = 361 ([M + 1]+, 5.3),
360 (M+, 22.0), 243 (4.7), 225 (2.8), 199 (23.0), 198 (100.0),
197 (11.5), 171 (20.5), 170 (6.6), 156 (7.6), 155 (51.6), 145
(6.3), 143 (19.3), 129 (17.0), 118 (12.9), 117 (19.7), 116
(24.2), 103 (6.0), 102 (25.9), 91 (18.5), 90 (25.1), 89 (17.7), 77
(3-(3′,4′-Dimethylphenyl)-2-oxo-2Н-[1,2,4]triazino[2,3-с]
quinazolin-6-yl)propanoic acid (4.5).
Yield: 97.3%; mp
240–244°C; 1H NMR: 2.28 (s, 3H, 4′-СН3); 2.24 (s, 3H,
3′–СН3), 2.87 (t, 2H, J=6.8Hz, СН2СН2СООН), 3.49 (t, 2Н,
J = 6.8 Hz, СН2СН2СООН), 7.27 (d, 1Н, J = 8.3 Hz, Н-5′),
7.73 (t, 1Н, J = 8.1 Hz, Н-10), 7.81 (d, 1H, J = 8.1 Hz, Н-8),
7.97 (t, 1H, J = 8.1 Hz, H-9), 8.01 (d, 1Н, J = 8.3 Hz, Н-6′),
8.03 (s, 1H, Н-2′), 8.51 (d, 1H, J = 8.1 Hz, Н-11), 12.34 (s, 1H,
СООH); IR (cmÀ1): 3020, 2916, 2848, 2752, 2651, 2565,
1700, 1662, 1630, 1604, 1573, 1574,1506, 1494, 1468, 1439,
1415, 1396, 1369, 1355, 1335, 1245, 1214, 1178, 1160, 1125,
1106, 1058, 1021, 995, 948, 911, 896, 857, 841, 829, 783, 745,
708, 686, 667, 625; EIMS m/z (I rel, %) = 375 ([M + 1]+, 1.4),
243 (27.8), 225 (5.2), 199 (40.5), 198 (100.0), 197 (15.1), 171
(22.7), 170 (5.8), 155 (40.5), 143 (12.6), 131 (9.5), 130 (7.9),
129 (10.8), 118 (8.1), 117 (6.8), 116 (25.0), 103 (6.7), 102
(13.3), 89 (5.2); LC–MS m/z = 376 ([MH + 2]+), 375 (MH+);
Anal. Calcd for C21H18N4О3: C, 67.37; H, 4.85; N, 14.66;
Found: C, 67.33; H, 4.80; N, 14.63.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

May 2016
Interaction of 3-(2-Aminophenyl)-6-R1-1,2,4-triazin-5-ones with
Acylating Reagents
781
(3-(4′-Methoxyphenyl)-2-oxo-2Н-[1,2,4]triazino[2,3-с]
quinazolin-6-yl)propanoic acid (4.6). Yield: 91.1%; mp 256–260;
1H NMR: δ = 2.87 (t, 2H, J = 6.8 Hz, СН2СН2СООН), 3.51
(t, 2H, J = 6.8 Hz, СН2СН2СООН), 3.83 (s, 3H, ОСН3),
7.09 (d, 2Н, J = 8.9 Hz, Н-3′, 5′), 7.72 (t, 1Н, J = 8.1 Hz, Н-10),
7.81 (d, 1Н, J = 8.1Hz, Н-8), 7.97 (t, 1H, J = 8.1 Hz, H-9), 8.33
(d, 2H, J = 9.0 Hz, Н-2′, 6′), 8.52 (d, 1H, J = 8.1 Hz, Н-11), 12.22
(s, 1H, СООH); IR (cmÀ1): 2914, 2839, 1725, 1655, 1627, 1599,
1570, 1537, 1489, 1470, 1438, 1410, 1347, 1312, 1256, 1168,
1143, 1113, 1041, 1019, 975, 943, 904, 884, 842, 815, 788, 776,
723, 705, 690, 678, 636, 621; EIMS m/z (I rel, %) = 376
(M+, 2.2), 243 (13.8), 225 (3.8), 198 (100.0), 197 (10.1),
185 (24.1), 171 (17.5), 170 (6.8), 156 (5.6), 155 (42.0), 149 (10.4),
145 (7.4), 144 (7.2), 143 (34.3), 134 (9.3), 133 (90.3), 131 (5.4),
130 (6.9), 129 (20.6), 118 (18.6), 117 (16.5), 116 (21.1), 115 (6.8),
111 (5.8), 104 (7.9), 103 (41.9), 102 (47.8), 91 (11.7), 90 (47.5), 89
(11.3), 87 (5.9), 83 (16.9), 81 (7.8), 77 (10.5), 76 (21.4), 75 (18.0),
74 (5.6), 73 (12.4), 71 (15.2), 70 (5.9), 69 (15.1), 67 (7.1), 65 (9.6),
64 (12.7), 63 (11.5), 60 (17.7), 57 (24.7), 56 (11.1), 55 (35.8), 54
(6.5), 51 (12.2), 50 (9.4), 45 (17.9), 43 (34.1), 42 (8.2), 41
(21.7); LC–MS m/z = 378 ([MH + 2]+), 377 (MH+); Anal.
Calcd for C20H16N4О4: C, 63.83; H, 4.28; N, 14.89; Found:
C, 63.81; H, 4.26; N, 14.86.
(3-(Tienyl-2)-2-oxo-2Н-[1,2,4]triazino[2,3-с]quinazolin-6-yl)
propanoic acid (4.7). Yield: 69.6%; mp 284–286°C; 1H NMR:
δ = 2.89 (t, 2Н, J = 7.0 Hz, СН2CH2COOH), 3.52 (t, 2Н,
J = 6.9 Hz, СН2CH2COOH), 7.30 (t, 1Н, J = 3.9 Hz, H-4′), 7.74
(t, 1Н, J = 8.1 Hz, Н-10), 7.84 (d, 1Н, J = 8.2 Hz, Н-8), 7.97
(m, 2Н, Н-9, 5′), 8.39 (d, 1Н, J = 3.9 Hz, Н-3′), 8.53 (d, 1Н,
J = 8.2 Hz, Н-11), 12.26 (s, 1Н, COOH); IR (cmÀ1): 2915,
1731, 1633, 1617, 1600, 1570, 1531, 1519, 1485, 1464,
1407, 1344, 1296, 1249, 1224, 1178, 1165, 1110, 1095,
1045, 993, 968, 928, 887, 852, 795, 772, 750, 736, 725,
691, 668, 626; EIMS m/z (I rel, %) = 352 (M+, 2.3), 244
(5.1), 243 (34.2), 225 (5.2), 199 (41.9), 198 (100.0), 197 (18.0),
171 (23.4), 170 (6.9), 156 (5.2), 155 (44.2), 145 (5.4), 143 (14.2),
129 (13.1), 118 (10.0), 117 (5.5), 103 (5.7), 102 (18.8), 97 (6.5), 90
(6.4), 85 (6.6), 83 (7.9), 76 (5.4), 71 (7.7), 69 (7.7), 57 (13.3), 56
(5.7), 55 (12.3), 45 (7.8), 43 (10.0), 41 (6.5); LC–MS m/z= 355
([MH + 3]+), 353 (MH+); Anal. Calcd for C17H12N4О3S: C, 57.95;
H, 3.43; N, 15.90; S, 9.10; Found: C, 57.93; H, 3.42; N,
15.87; S, 9.08.
89 (7.2), 85 (9.2), 83 (13.0), 77 (5.0), 76 (9.8), 75 (10.2), 60 (5.3),
56 (13.7), 55 (6.5), 45 (19.3), 43 (6.6), 42 (9.0), 41 (11.8); LC–MS
m/z= 300 ([MH + 2]+), 299 (MH+); Anal. Calcd for C15H14N4О3:
C, 60.40; H, 4.73; N, 18.78; Found: C, 60.43; H, 4.75; N, 18.79.
(3-Benzyl-2-oxo-2Н-[1,2,4]triazino[2,3-с]quinazolin-6-yl)
butanoic acids (4.9).
Yield: 72.9%; mp 152–154°C; 1H
NMR (q, 2H, J = 7.0 Hz, СН2СН2СН2СООН), 2.30 (t, 2H,
J = 7.0 Hz, СН2СН2СН2СООН), 3.04 (t, 2H, J = 7.0 Hz,
СН2СН2СН2СООН), 4.09 (s, СН2), 7.24 (t, 1Н, J=7.2Hz, Н-4′),
7.31 (t, 2Н, J=7.5Hz, Н-3′, 5′), 7.37 (d, 2H, J=7.5Hz, Н-2′, 6′),
7.68 (t, 1H, J = 8.1 Hz, H-10), 7.78 (d, 1Н, J = 8.1 Hz, Н-8),
7.92 (t, 1H, J = 7.7 Hz, H-9), 8.46 (d, 1H, J = 8.1 Hz, Н-11),
12.07 (s, 1H, СООH); IR (cmÀ1): 3061, 3026, 2971, 2907,
2671, 2575, 1700, 1663, 1627, 1607, 1590, 1508, 1467, 1414,
1377, 1351, 1332, 1317, 1288, 1249, 1224, 1184, 1164, 1150,
1124, 1098, 1071, 1025, 976, 922, 779, 754, 721, 700, 639,
614; EIMS m/z (I rel, %) = 375 ([M + 1]+, 6.9), 374 (M+, 26.1),
213 (4.0), 212 (28.0), 199 (11.6), 198 (83.3), 186 (12.8), 185
(100.0), 171 (4.0), 170 (4.2), 169 (11.7), 155 (23.6), 145
(12.7), 143 (18.9), 142 (10.9), 129 (11.4), 118 (5.4), 117
(15.9), 116 (18.1), 115 (5.2), 102 (17.4), 91 (13.6), 90 (15.3),
89 (11.4), 77 (6.1), 65 (5.0), 56 (9.2), 55 (8.7), 51 (5.0), 45
(5.0), 41 (9.8); LC–MS m/z = 376 ([MH + 2]+), 375 (MH+);
Anal. Calcd for C21H18N4О3: C, 67.37; H, 4.85; N, 14.96;
Found: C, 67.39; H, 4.87; N, 14.97.
(3-Phenyl-2-oxo-2Н-[1,2,4]triazino[2,3-с]quinazolin-6-yl)
butanoic acids (4.10).
Yield: 74.4%; mp 220–222°C; 1H
NMR: δ = 2.11 (q, 2H, J = 7.0 Hz, СН2СН2СН2СООН), 2.46
(t, 2H, J=7.0Hz, СН2СН2СН2СООН), 3.30 (t, 2H, J=7.1Hz,
СН2СН2СН2СООН), 7.60–7.53 (m, 3H, Н-3′, 4′, 5′), 7.74 (t, 1H,
J= 8.1 Hz, H-10), 7.86 (d, 1Н, J=8.1Hz, Н-8), 7.98 (t, 1H,
J= 8.1 Hz, H-9), 8.27 (d, 2Н, J=7.2Hz, Н-2′, 6′), 8.54 (d, 1H,
J=8.1Hz, Н-11), 12.10 (s, 1H, СООH); 13C NMR 21.67
(СН2СН2СН2СООН), 32.47 (СН2СН2СН2СООН), 33.30
(СН2СН2СН2СООН), 119.83 (11a-C), 125.89 (8-C), 127.86
(11-C), 128.82 (10-C), 128.87 (3′-C, 5′-C), 129.78 (2′-C, 6′-C),
131.72 (4′-C), 132.47 (1′-C), 135.62 (9-C), 143.95 (3-C), 149.47
(11b-C), 151.54 (6-C), 154.31 (7а-C), 159.96 (2-C), 174.77
(СООН); IR (cmÀ1): 3039, 2943, 2884, 2728, 2653, 2578, 1721,
1616, 1602, 1572, 1545, 1498, 1483, 1470, 1441, 1409, 1346,
1312, 1282, 1251, 1180, 1151, 1139, 1107, 1076, 1046, 1017, 999,
977, 946, 895, 844, 815, 778, 757, 693, 672, 649, 627, 615; EIMS
m/z (I rel, %) = 257 (11.8), 212 (19.8), 199 (10.1), 198 (75.8), 186
(13.0), 185 (100.0), 171 (3.1), 170 (3.9), 169 (8.8), 155 (21.8), 145
(11.2), 143 (19.0), 142 (11.2), 129 (12.9), 117 (8.1), 116 (7.1), 115
(5.7), 103 (18.8), 102 (19.8), 90 (6.2), 89 (6.6), 77 (7.9), 76 (13.2),
75 (5.5), 57 (5.6), 56 (10.3), 55 (8.0), 51 (5.3), 45 (6.8), 43 (5.0),
41 (11.9); LC–MS m/z= 362 ([MH + 2]+), 361 (MH+); Anal. Calcd
for C20H16N4О3: C, 66.66; H, 4.48; N, 15.55; Found: C, 66.63; H,
4.46; N, 15.53.
(3-Methyl-2-oxo-2Н-[1,2,4]triazino[2,3-с]quinazolin-6-yl)
butanoic acids (4.8).
Yield: 85.8%; mp 210–212°C; 1H
NMR 2.05 (q, 2H, J=7.0Hz, СН2СН2СН2СООН), 2.35 (s, 3H,
СН3), 2.42 (t, 2H, J=6.9Hz, СН2СН2СН2СООН), 3.16 (t, 2H,
J=7.0Hz, СН2СН2СН2СООН), 7.68 (t, 1H, J= 8.1 Hz, H-10),
7.78 (d, 1Н, J=8.1Hz, Н-8), 7.93 (t, 1H, J= 8.1 Hz, H-9), 8.44 (d,
1H, J=8.1Hz, Н-11), 12.08 (s, 1H, СООH); 13C NMR 18.35
(CH3), 21.61 (СН2СН2СН2СООН), 32.33 (СН2СН2СН2СООН),
33.29 (СН2СН2СН2СООН), 119.96 (C-11a), 125.70 (C-8), 127.69
(C-11), 128.60 (C-10), 135.58 (C-9), 143.92 (C-3), 152.30 (C-11b),
153.95 (C-6), 154.79 (C-7а), 160.74 (C-2), 174.66 (СООН); IR
(cmÀ1): 3052, 2985, 2916, 2846, 2602, 1698, 1657, 1631, 1608,
1593, 1572, 1505, 1467, 1435, 1409, 1379, 1362, 1339, 1291,
1277, 1247, 1226, 1206, 1132, 1106, 1088, 1059, 1021, 1003, 969,
931, 889, 797, 784, 740, 725, 691, 657, 624; EIMS m/z (I rel,
%) = 299 ([M + 1]+, 13.4), 298 (M+, 7.6), 258 (5.3), 257 (33.0), 213
(7.3), 212 (52.5), 199 (22.2), 198 (96.1), 186 (27.0), 185 (100.0),
171 (5.9), 170 (6.3), 169 (15.4), 156 (5.5), 155 (32.3), 145 (16.6),
144 (5.3), 143 (38.7), 142 (20.8), 129 (21.0), 118 (6.4), 117 (13.4),
116 (12.9), 115 (10.3), 105 (5.1), 103 (7.9), 102 (41.6), 90 (13.3),
(3-(4′-Methylphenyl)-2-oxo-2Н-[1,2,4]triazino[2,3-с]quinazolin-
6-yl)butanoic acids (4.11).
Yield: 83.5%; mp 226–228°C; 1H
NMR 2.11 (q, 2H, J=7.1Hz, СН2СН2СН2СООН), 2.36 (s, 3Н,
СН3), 2.45 (t, 2H, J=7.0Hz, СН2СН2СН2СООН), 3.28 (t, 2H,
J=7.1Hz, СН2СН2СН2СООН), 7.33 (d, 2H, J=8.0Hz, Н-3′, 5′),
7.72 (t, 1H, J = 8.1 Hz, H-10), 7.84 (d, 1Н, J = 8.1 Hz, Н-8),
7.96 (t, 1H, J = 8.1 Hz, H-9), 8.19 (d, 2Н, J = 8.0 Hz, Н-2′, 6′),
8.51 (d, 1H, J = 8.1 Hz, Н-11), 12.10 (s, 1H, СООH); IR
(cmÀ1): 3067, 3039, 2977, 2914, 2731, 2659, 2582, 1719,
1639, 1619, 1604, 1573, 1545, 1492, 1470, 1426, 1409, 1348,
1328, 1311, 1252, 1182, 1165, 1140, 1058, 1039, 1021, 947,
899, 838, 783, 772, 713, 692, 677, 660; 624; EIMS m/z (I rel,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

782
A. Y. Voskoboynik, D. Y. Scorina, T. Y. Sergeieva, S. I. Kovalenko,
S. I. Okovytyy, I. V. Omelchenko, and O. V. Shishkin
Vol 53
%) = 257 (11.8), 212 (19.4), 199 (11.2), 198 (82.0), 186 (12.9),
185 (100.0), 171 (3.6), 170 (3.4), 169 (9.1), 155 (19.6), 149
(5.0), 145 (10.4), 143 (18.7), 142 (8.8), 129 (10.3), 118 (6.1),
117 (16.2), 116 (16.6), 103 (5.1), 102 (17.5), 90 (11.8), 89
(8.7), 77 (5.9), 56 (7.6), 55 (6.5), 41 (9.1); LC–MS m/z = 376
([MH + 2]+), 375 (MH+); Anal. Calcd for C21H18N4О3: C,
67.37; H, 4.85; N, 14.96; Found: C, 67.38; H, 4.90; N, 14.97.
(3-(3′,4′-Dimethylphenyl)-2-oxo-2Н-[1,2,4]triazino[2,3-с]
366 (M+, 1.1), 257 (10.4), 212 (17.9), 199 (9.8), 198 (67.9), 186
(12.8), 185 (100.0), 169 (8.6), 155 (17.6), 145 (9.9), 143 (19.7),
142 (9.1), 129 (9.4), 117 (6.1), 109 (8.4), 102 (16.5), 69 (5.3), 56
(5.5), 41 (6.5); LC–MS m/z = 369 ([MH + 2]+), 367 (MH+); Anal.
Calcd for C18H14N4О3S: C, 59.01; H, 3.85; N, 15.29; S, 8.75;
Found: C, 59.03; H, 3.89; N, 15.27; S, 8.75.
Method for preparation of 3-methyl-6-phenyl-2H-[1,2,4]
triazino[2,3-c]quinazolin-2-one (5.1).
To a 5 mmol of 6-
quinazolin-6-yl)butanoic acids (4.12).
Yield: 91.2%; mp
methyl-3-(2-aminophenyl)-[1,2,4]-triazin-5-one (2.1) in 10 mL
of acetic acid, 5.25 mmol of benzoyl chloride was added. The
resulting mixture was refluxed for 4 h. The solvent was
removed in vacuum. After the addition of methanol, the solid
was filtered off and washed with ethyl ether. If necessary,
additional purification could be achieved by crystallization
from acetic acid.
3-Methyl-6-phenyl-2H-[1,2,4]triazino[2,3-c]quinazolin-2-one
(5.1). Yield:83.2%; mp 250–252°C; 1H NMR (400 MHz) 2.22
(s, 3Н, 3-СН3), 7.56 (m, 3Н, Н-3, Н-4, Н-5 Ph), 7.78 (t, 1Н,
J = 8.2 Hz, Н-10), 7.80 (d, 2Н, J = 8.2 Hz, Н-2, Н-6 Ph), 7.93
(d, 1Н, J = 8.2 Hz, Н-8), 8.02 (t, 1Н, J = 8.2 Hz, Н-9), 8.57
(d, 1Н, J = 8.2 Hz, Н-11); EIMS m/z (I rel, %) 288 (5.2),
248 (14.0), 247 (100.0), 206 (12.0), 205 (78.5), 103 (13.2),
102 (28.0), 90 (9.1), 77 (39.0), 76 (23.4); LC–MS m/z = 289
[М + 1]; Anal. Calcd for С17H12N4O: C, 70.82; Н, 4.20; N,
232–234°C; 1H NMR 2.10 (q, 2H, J=7.0Hz, СН2СН2СН2СООН),
2.17 (s, 3Н, 3′-СН3), 2.24 (s, 3Н, 4′-СН3), 2.46 (t, 2H, J=6.9Hz,
СН2СН2СН2СООН), 3.24 (t, 2H, J=7.0Hz, СН2СН2СН2СООН),
7.20 (d, 1Н, J=7.9Hz, Н-5′), 7.70 (t, 1Н, J=8.1Hz, Н-10), 7.82
(d, 1H, J = 8.1 Hz, Н-8), 8.01–7.93 (m, 3H, Н-2′, 6′, 9),
8.47 (d, 1H, J = 8.1 Hz, Н-11), 12.12 (s, 1H, СООH); IR
(cmÀ1): 3152, 3062, 2947, 2911, 1724, 1649, 1624, 1606,
1573, 1544, 1505, 1490, 1469, 1445, 1400, 1372, 1342,
1326, 1288, 1233, 1221, 1201, 1160, 1127, 1107, 1023, 996,
959, 899, 877, 861, 839, 772, 711, 688, 626; EIMS m/z
(I rel, %) = 257 (11.0), 212 (19.4), 199 (10.1), 198 (70.7),
186 (12.1), 185 (100.0), 169 (10.6), 159 (5.3), 155 (20.7),
149 (7.1), 145 (14.7), 143 (22.4), 142 (12.1), 131 (18.1),
130 (15.3), 129 (16.2), 118 (6.1), 117 (15.6), 116 (52.9),
115 (10.5), 104 (5.2), 103 (17.6), 102 (29.8), 97 (7.2), 91
(10.2), 90 (11.3), 89 (14.0), 85 (9.5), 83 (9.8), 79 (6.1), 77
(16.0), 76 (8.4), 75 (7.4), 73 (6.6), 71 (6.3), 70 (7.5), 69
(13.1), 65 (6.2), 60 (7.8), 57 (11.3), 56 (18.9), 55 (23.5), 51
(9.2), 50 (7.4), 45 (12.2), 43 (9.5), 41 (23.7); LC–MS m/z =390
([MH + 2]+), 389 (MH+); Anal. Calcd for C22H20N4О3:
C, 68.03; H, 5.19; N, 14.42; Found: C, 68.03; H, 5.20; N, 14.45.
(3-(4′-Methoxyphenyl)-2-oxo-2Н-[1,2,4]triazino[2,3-с]
19.43; Found: C, 70.85; Н, 4.22, N, 19.45.
General method for the preparation of 6-(chloromethyl)-
3-R1-2H-[1,2,4]triazino[2,3-c]quinazolin-2-ones (6.1 and
6.2).
The 5 mmol of corresponded 3-(2-aminophenyl)-6-R-
1,2,4-triazin-5(2H)-one (2.6 and 2.8) was suspended in
15 mL of acetic acid then 8.5 mmol of chloracetylchloride
was added and hold at 60°C during 30 min. The mixture
was cooled, and the formed precipitate was filtered off,
dried, and crystallized from acetone.
6-(Chloromethyl)-3-(4-isopropylphenyl)-2H-[1,2,4]triazino
[2,3-c]quinazolin-2-one (6.1). Yield:83.2%; mp 250–252°C;
1H NMR 1.33 (d, 6H, J = 6.8 Hz, CH(CH3)2), 3.04–2.97 (m, 1H,
CH(CH3)2), 5.16 (s, 2H, CH2Cl), 7.39 (d, 2H, J = 8.2 Hz, 2H, H-
3′, H-5′), 7.81 (t, 1H, J = 7.5 Hz, H-10), 7.92 (d, 1H, J = 7.0 Hz,
H-8), 8.02 (t, 1H, J = 7.2 Hz, H-9), 8.30 (d, 2H, J = 8.2 Hz, H-2′,
H-6′), 8.66 (d, 1H, J = 7.7 Hz, H-11); LC–MS m/z = 365 [М + 1];
Anal. Calcd for С20H17ClN4O: C, 65.84; Н, 4.70; N, 15.36;
Found: C, 65.87; Н, 4.71, N, 15.38.
6-(Chloromethyl)-3-(4-fluorophenyl)-2H-[1,2,4]triazino[2,3-c]
quinazolin-2-one (6.2). Yield:83.2%; mp 250–252°C; 1H NMR
(400 MHz) 5.18 (s, 2H, CH2Cl), 7.29 (t, 1H, J = 8.7 Hz, H-3′, H-5′),
7.81 (t, 1H, J= 7.4 Hz, H-10), 7.93 (d, 1H, J= 8.0 Hz, H-8), 8.03 (t,
1H, J= 7.1 Hz, H-9), 8.48 (dd, 2H, J= 8.7, 5.6 Hz, H-2′, H-6′), 8.66
(d, 1H, J=7.7Hz, H-11); EIMS m/z (I rel, %) = 221 (30.1). 220
(11.00). 219 (100.0), 185 (6.9), 184 (11.4), 177 (5.1), 143 (5.3),
142 (9.9), 122 (5.4), 121 (62.0), 116 (10.8), 115 (5.1), 107 (13.8),
102 (30.1), 95 (9.0), 94 (29.1), 90 (9.7), 89 (9.2), 88 (5.2), 81 (6.2),
76 (17.6), 75 (18.2), 64 (5.5), 63 (7.7), 57 (10.3), 56 (40.7), 51
(12.7), 50 (8.3), 49 (14.7); LC–MS m/z= 341 [М+1]; Anal. Calcd
for С17H10ClFN4O: C, 59.92; Н, 2.96; N, 16.44; Found: C, 59.98;
Н, 3.01, N, 16.48.
quinazolin-6-yl)butanoic acids (4.13).
Yield: 71.4%; mp
218–222°C; 1H NMR 2.11 (q, 2H, J2 = 14.4 Hz, J3 =7.2Hz,
СН2СН2СН2СООН), 2.46 (t, 2H, J=7.0Hz, СН2СН2СН2СООН),
3.29 (t, 2H, J=7.2Hz, СН2СН2СН2СООН), 3.83 (s, 3Н, ОСН3),
7.07 (d, 2H, J=8.9Hz, Н-3′, 5′), 7.71 (t, 1H, J= 7.7 Hz, H-10),
7.84 (d, 1Н, J = 8.1 Hz, Н-8), 7.96 (t, 1H, J = 7.7 Hz, H-9),
8.33 (d, 2Н, J = 8.9 Hz, Н-2′, 6′), 8.50 (d, 1H, J = 8.1 Hz, Н-11),
11.97 (s, 1H, СООH); IR (cmÀ1): 3171, 1741, 1642,
1624, 1603, 1571, 1537, 1514, 1488, 1471, 1455, 1417,
1400, 1372, 1347, 1332, 1305, 1290, 1268, 1218, 1175,
1111, 1098, 1061, 1026, 948, 906, 847, 814, 772, 750, 726,
689, 633, 622; EIMS m/z (I rel, %) = 391 ([M + 1]+, 2.4),
390 (M+, 2.4), 257 (9.0), 212 (16.7), 199 (8.6), 198 (63.1),
186 (14.9), 185 (100.0), 169 (6.7), 159 (5.8), 155 (13.0),
145 (8.1), 143 (32.2), 142 (6.5), 134 (6.8), 133 (64.7), 129
(7.8), 119 (4.5), 118 (8.1), 117 (5.2), 116 (5.3), 103 (18.5),
102 (21.2), 90 (19.6), 76 (8.2), 45 (10.5), 43 (5.7); LC–MS
m/z = 392 ([MH + 2]+), 391 (MH+); Anal. Calcd for
C21H18N4О4: C, 64.61; H, 4.65; N, 14.35; Found: C, 64.63;
H, 4.69; N, 14.37.
(3-(Thienyl-2)-2-oxo-2Н-[1,2,4]triazino[2,3-с]quinazolin-6-yl)
butanoic acids (4.14). Yield: 92.6%; mp 236–240°C; 1H NMR
1.71 (quintet, 2H, J = 7.1 Hz, СН2СН2СН2СООН), 2.47 (t, 2H,
J = 7.0 Hz, СН2СН2СН2СООН), 3.29 (t, 2H, J = 7.1 Hz,
СН2СН2СН2СООН), 7.59–7.71 (m, 2Н, Н-10, 4′), 7.86 (d, 1Н,
J = 8.1 Hz, Н-8), 8.00–7.96 (m, 2Н, Н-9, 5′), 8.41 (d, 1Н,
J = 3.3 Hz, Н-3′), 8.54 (d, 1Н, J = 8.1 Hz, Н-11), 12.11 (s, 1Н,
COOH); IR (cmÀ1): 3081, 2976, 2904, 1731, 1643, 1622, 1605,
1572, 1541, 1524, 1487, 1469, 1411, 1380, 1353, 1326, 1293,
1254, 1183, 1148, 1111, 1058, 994, 907, 876, 850, 772, 732,
714, 690, 665, 682; EIMS m/z (I rel, %) = 367 ([M + 1]+, 1.1),
X-ray diffraction study of 4.8.
Crystals are triclinic,
C13H14N4O3, at 20°С. a = 9.2355(4), b = 9.4258(4), c = 9.7498
(5) Å, α = 67.780(4)°, β = 75.948(4)°, γ = 66.363(4)°, V = 715.62
(6) Å3, Mr = 298.30, Z = 2, space group P1 , dsub = 1.384 g/sm3,
(MoK) = 0.100 mmÀ1, and F(000) = 312. Data collection was
performed on an “Xcalibur-3” diffractometer (MoK radiation,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

May 2016
Interaction of 3-(2-Aminophenyl)-6-R1-1,2,4-triazin-5-ones with
Acylating Reagents
783
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Atom coordinates and crystallographic parameters have been
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