Simple synthesis of 2-amino-4-(het)aryl-4,6-dihydro-1(3)(11)H-[1,3,5] triazino[2,1-b]quinazolin-6-ones [1]

Article abstract of DOI:10.1002/jhet.5570450119

(Chemical Equation Presented) The 2-amino-4-(het)aryl-4,6-dihydro-1(3)(11) H-[1,3,5]triazino[2,1-b]quinazolin-6-ones were prepared readily by cyclocondensation of anthranilic acid derived 4-oxo-3,4-dihydroquinazolinyl-2- guanidine with a variety of aldehydes. The structures of the compounds were confirmed by nmr spectroscopy, including 2D NOESY experiments.

Full text of DOI:10.1002/jhet.5570450119

Jan-Feb 2008
173
Simple Synthesis of 2-Amino-4-(het)aryl-4,6-dihydro-1(3)(11)H-
[1,3,5]triazino[2,1-b]quinazolin-6-ones [1]
Anton V. Dolzhenko,* Anna V. Dolzhenko and Wai-Keung Chui
Department of Pharmacy, National University of Singapore, 18 Science Drive 4, Singapore
117543, Singapore. E-mail phada@nus.edu.sg
Received May 10, 2007
NH
N
O
O
N
O
N
R
N
N
NH2
RCHO
H
OH
NH2
NH NH
NH2
N
NH
NH2
N
H
The 2-amino-4-(het)aryl-4,6-dihydro-1(3)(11)H-[1,3,5]triazino[2,1-b]quinazolin-6-ones were prepared
readily by cyclocondensation of anthranilic acid derived 4-oxo-3,4-dihydroquinazolinyl-2-guanidine with a
variety of aldehydes. The structures of the compounds were confirmed by nmr spectroscopy, including 2D
NOESY experiments.
J. Heterocyclic Chem., 45, 173 (2008).
Scheme 1
INTRODUCTION
O
O
NH
NH2
Naturally occurring and synthetic quinazolinone
derivatives, including fused systems, are known to
possess a wide range of biological activities [2-4].
Three isomeric structures are possible for quinazo-
line fused with 1,3,5-triazine nucleus, viz. 1,3,5-tria-
zino[1,2-a]quinazoline, 1,3,5-triazino[1,2-c]quinazo-
line and 1,3,5-triazino[2,1-b]quinazoline hetero-
cyclic systems. The known methods of the synthesis
of these compounds are limited. The system with
[1,2-a] ring junction has been prepared via (2+2+2)
cycloaddition of two isocyanate molecules to the
side ‘a’ of quinazolines [5,6] or by (3+3) hetero-
cyclization of 2-aminoquinazolines with chlorocar-
bonyl isocyanate [7]. The annulation of 1,3,5-
triazine ring onto the side ‘c’ of the quinazolines
with the formation of 1,3,5-triazino[1,2-c]quinazo-
lines was also reported [8-11].
N
OH
NH NH
NH2
+
N
H
NH2
N
N
H
1
2
The reaction of 4-oxo-3,4-dihydroquinazolinyl-2-
guanidine (2) with aldehydes in DMF proceeded via (5+1)
heterocyclization and resulted in the formation of hitherto
unknown 2-amino-4-(het)aryl-4,6-dihydro-1(3)(11)H-
[1,3,5]triazino[2,1-b]quinazolin-6-ones (3) (Scheme 2).
Scheme 2
O
R
N
N
NH
NH2
N
3
Among the methods of 1,3,5-triazino[2,1-b]-
quinazolines synthesis [8,12-14], only one annu-
lation of 1,3,5-triazine ring onto an existing quina-
zoline skeleton has been reported [8] using thermal
ring closure of 2-benzamido-3-cyano-3,4-dihydro-
quinazolin-4-one. As a continuation of our investi-
gations [1,15-18] of fused 1,3,5-triazines syntheses
via the reactions of hetarylguanidines with
aldehydes, we describe herein the reaction of 4-oxo-
3,4-dihydroquinazolinyl-2-guanidines with benz-
aldehydes and hetarylaldehydes.
O
O
NH NH
NH2
NH
O
R
+
N
N
H
N
N
H
4
H2N
N
R
2
O
N
5
N
N
R
N
H
NH2
RESULTS AND DISCUSSION
The structures of the products were established using
data of nmr and ir spectroscopy. The formation of the
dihydro-s-triazine ring in the reaction was suggested by
The 4-oxo-3,4-dihydroquinazolinyl-2-guanidine (2)
was prepared by cyclocondensation of anthranilic acid (1)
with cyanoguanidine (Scheme 1) using the reported
method [19].
1
the singlet of H-4 observed at 6.90-7.04 ppm in the H

174
A. V. Dolzhenko, A. V. Dolzhenko and W.-K. Chui
Vol 45
nmr spectra of 3, together with the signal of C-4 at 60.4-
61.0 ppm in the 13C nmr spectra. This strong evidence of
the sp3 hybridization of C-4 ruled out the structure of the
possible Schiff base-like compounds 4. The alternative
structure 5 might arise in case of the ring closure to the
side ‘a’ of the quinazolone. The carbonyl group C=O
vibrations in ir spectra of the compounds obtained were
observed at a considerably lower frequency compared to
C=O signal of 2. These results indicated that the nitrogen
atom adjacent to the C=O group might be involved in the
ring closure. The 1,3,5-triazino[1,2-a]quinazolines (5)
would show in 2D NOESY nmr experiments cross-peaks
between the singlet of proton located at sp3 hybridized
carbon atom and one of the doublets of the phenylene part
of the molecule. As there were no cross-peaks found for
these signals, the structure of 1,3,5-triazino[2,1-b]quina-
zolines (3) was assigned for the prepared compounds.
Annular prototropic tautomerism was observed in
dimethyl sulfoxide solution for compounds 3 (viz. 1H-,
3H- and 11H- tautomeric forms) (Scheme 3).
Scheme 3
O
R
7
4
6
5
8
9
N
NH
3
N
N
NH2
2
10
11
1
A
O
R
O
R
N
N
N
N
N
N
N
H
NH2
N
H
NH2
B
C
In conclusion, we developed a simple method for the
fusion of the 1,3,5-triazine ring to the side ‘b’ of quinazo-
lines with the formation of 2-amino-4-(het)aryl-4,6-
dihydro-1(3)(11)H-[1,3,5]triazino[2,1-b]quinazolin-6-ones.
EXPERIMENTAL
The prototropic interconversion between these tauto-
meric forms was postulated based on the broadening of
the several signals of 4,6-dihydro-1(3)(11)H-[1,3,5]-
triazino[2,1-b]quinazolin-6-one heterocyclic system in the
13C nmr spectra of compounds 3. The pattern of the
broadening of signals indicated that all the three forms (A,
B and C) were involved in the proton transfer. The
broadening of C-4 signal referred to A-B equilibrium and
the broad signals of C-10a indicated B-C interconversion.
At the same time, the broadening of C-10a signals also
confirmed the structure 3, since in the alternative structure
5 this phenylene carbon atom would not be in close
proximity with the nitrogen atoms involved in the
tautomerization.
Melting points (uncorrected) were determined on
a
Gallenkamp melting point apparatus. Nmr spectra were recorded
on a Bruker DPX-300 spectrometer, using dimethyl sulfoxide-d6
as a solvent and TMS as an internal reference. The assignments
were made using 2D COSY, NOESY and HMQC experiments.
Ir spectra were performed on a Jasco FT-IR-430 spectro-
photometer in potassium bromide pellets. The course of the
reactions was monitored by tlc on Silica gel 60 F254 plates
(Merck, Germany).
Preparation of 4-oxo-3,4-dihydroquinazolinyl-2-guanidine
(2). Anthranilic acid (1) (6.9 g, 50 mmole) was dissolved on
heating in 50 mL of 10% sulfuric acid and cyanoguanidine (6.3
g, 75 mmole) was added. The reaction mixture was heated for
20 min and then 10 mL of 50% sodium hydroxide solution was
Table 1
2-Amino-4-(het)aryl-4,6-dihydro-1(3)(11)H-[1,3,5]triazino[2,1-b]quinazolin-6-ones
Compound
R
Mp
(°C)
Yield
%
Molecular
Formula
Analysis %, Calcd./Found
H
C
N
3a
3b
3c
3d
3e
3f
Ph
302-303
248-251
246-248
257-258
263-264
267-269
280
61
52
55
62
63
74
60
58
82
C16H13N5O
65.97
65.63
66.87
66.58
63.54
63.09
62.13
61.86
58.99
58.72
51.91
51.60
59.78
59.41
56.55
56.17
61.64
61.30
4.50
4.72
4.95
4.90
4.71
4.83
3.91
4.18
3.71
4.03
3.27
3.52
3.94
4.23
3.73
3.36
4.14
4.02
24.04
23.89
22.94
22.87
21.79
21.62
22.64
22.45
21.50
21.37
18.92
18.67
24.90
24.65
23.55
23.42
28.75
28.55
C6H4Me-4
C6H4OMe-4
C6H4F-4
C17H15N5O
C17H15N5O2
C16H12FN5O
C16H12ClN5O
C16H12BrN5O
C14H11N5O2
C14H11N5OS
C15H12N6O
C6H4Cl-4
C6H4Br-4
Furyl-2
3g
3h
3i
Thienyl-2
Pyridyl-3
297
285-286

Jan-Feb 2008
2-Amino-4-(het)aryl-4,6-dihydro-1(3)(11)H-[1,3,5]triazino[2,1-b]quinazolin-6-ones
175
Table 2
Spectral Data of 2-Amino-4-(het)aryl-4,6-dihydro-1(3)(11)H-[1,3,5]triazino[2,1-b]quinazolin-6-ones
Compound
ir, potassium bromide,
ꢁ (cm-1)
1H nmr (300 MHz)
dimethyl sulfoxide-d6/TMS, ꢀ (ppm)
13C nmr (75 MHz)
dimethyl sulfoxide-d6/TMS, ꢀ (ppm)
3a
NH 3464, NH 3331,
CH 3069, C=O 1680,
1654, 1613, 1575,
1527, 1468, 1417,
1272, 764, 694
6.98 (br s, 2H, NH2), 7.00 (s, 1H, H-4), 7.17 (t, J =
7.5 Hz, 1H, H-8), 7.24-7.40 (m, 6H, H-10 and Ph),
60.9 (br s, C-4), 117.7 (C-6a), 122.4 (C-8), 125.3 (C-
10), 125.5 (C-2' and -6'), 126.2 (C-7), 128.4 (C-3' and
7.62 (td, J = 7.7, 1.5 Hz, 1H, H-9), 7.94 (dd, J = 7.9, -5'), 128.6 (C-4'), 134.2 (C-9), 140.2 (C-1'), 149.9 (br
1.5 Hz, 1H, H-7), 8.32 (s, 1H, NH)
s, C-10a), 150.5 (br s, C-11a), 156.8 (br s, C-2), 160.4
(C-6)
3b
3c
NH 3446, NH 3329,
CH 3061, C=O 1683, NH2), 7.10-7.23 (m, 5H, H-8, -2', -3', -5' and -6'),
2.24 (s, 3H, Me), 6.97 (s, 1H, H-4), 7.03 (br s, 2H, 20.5 (Me), 61.0 (br s, C-4), 117.7 (C-6a), 122.4 (C-
8), 125.2 (C-10, -2' and -6'), 126.2 (C-7), 129.1 (C-
1655, 1611, 1573,
1527, 1467, 1417,
1267, 774, 694
7.32 (d, J = 7.9 Hz, 1H, H-10), 7.62 (t, J = 7.5 Hz, 3' and -5'), 134.2 (C-9), 137.3 (C-1'), 137.8 (C-4'),
1H, H-9), 7.94 (d, J = 7.9 Hz, 1H, H-7), 8.42 (br s, 149.8 (br s, C-10a), 150.2 (br s, C-11a), 156.6 (br s,
1H, NH)
3.70 (s, 3H, OMe), 6.90 (d, J = 8.7 Hz, 2H, H-2'
C-2), 160.3 (C-6)
NH 3463, NH 3341,
CH 3070, C=O 1676, and -6'), 6.95 (s, 1H, H-4), 6.97 (br s, 2H, NH2),
1656, 1611, 1574,
1514, 1467, 1421,
1268, 1257, 1176,
1031, 761, 694
NH 3457, NH 3332,
CH 3070, C=O 1683, 7.2 Hz, 1H, H-8), 7.20 (dd, J = 8.5 Hz, 3JHF = 8.5
1654, 1604, 1575,
1528, 1467, 1414,
1268, CF 1236, 765,
693
55.0 (OMe), 60.6 (br s, C-4), 113.9 (C-3' and -5'),
117.7 (C-6a), 122.3 (C-8), 125.4 (C-10), 126.2 (C-
7), 126.7 (C-2' and -6'), 132.4 (C-1'), 134.2 (C-9),
149.8 (br s, C-10a), 150.4 (br s, C-11a), 156.9 (br s,
C-2), 159.2 (C-4'), 160.3 (C-6)
7.16 (t, J = 7.5 Hz, 1H, H-8), 7.21 (d, J = 8.7 Hz,
2H, H-3' and -5'), 7.31 (d, J = 8.3 Hz, 1H, H-10),
7.61 (t, J = 7.5 Hz, 1H, H-9), 7.93 (d, J = 7.9 Hz,
1H, H-7), 8.26 (br s, 1H, NH)
3d
3e
3f
7.00 (s, 1H, H-4), 7.01 (br s, 2H, NH2), 7.18 (t, J = 60.4 (br s, C-4), 115.5 (d, 2JCF = 21.8 Hz, C-3' and -
5'), 117.7 (C-6a), 122.4 (C-8), 125.5 (C-10), 126.2
(C-7), 127.5 (d, 3JCF =8.2 Hz, C-2' and -6'), 134.3
(C-9), 136.6 (d, 4JCF = 2.4 Hz, C-1'), 149.7 (br. s, C-
10a), 150.5 (br s, C-11a), 156.8 (br s, C-2), 160.4
(C-6), 161.9 (d, 1JCF = 244.6 Hz, C-4')
Hz, 2H, H-3' and -5'), 7.27-7.38 (m, 3H, H-10, -2'
and -6'), 7.63 (td, J = 7.9, 1.1 Hz, 1H, H-9), 7.94
(dd, J = 7.9, 1.1 Hz, 1H, H-7), 8.30 (s, 1H, NH)
NH 3458, NH 3336,
7.01 (s, 1H, H-4), 7.02 (br s, 2H, NH2), 7.18 (t, J = 60.4 (br s, C-4), 117.7 (C-6a), 122.5 (C-8), 125.5
CH 3065, C=O 1680, 7.5 Hz, 1H, H-8), 7.29 (d, J = 8.3 Hz, 2H, H-2' and (C-10), 126.2 (C-7), 127.3 (C-2' and -6'), 128.7 (C-
1653, 1611, 1573,
1531, 1466, 1414,
1270, CCl 1093, 772, H-9), 7.94 (d, J = 7.9 Hz, 1H, H-7), 8.32 (br s, 1H, C-2), 160.4 (C-6)
759
3458 (NH, st), 3339
(NH, st), 3064 (CH,
m), 1683 (C=O, st),
1651, 1611, 1577,
1530, 1467, 1423,
-6' ), 7.32 (d, J = 7.9 Hz, 1H, H-10), 7.44 (d, J =
8.3 Hz, 2H, H-3' and -5'), 7.63 (t, J = 7.5 Hz, 1H,
3' and -5'), 133.1 (C-4'), 134.3 (C-9), 139.2 (C-1'),
149.6 (br s, C-10a), 150.4 (br s, C-11a), 156.8 (br s,
NH)
6.99 (s, 1H, H-4), 7.04 (br s, 2H, NH2), 7.18 (t, J = 60.5 (br s, C-4), 117.6 (C-6a), 121.6 (C-4'), 122.4
7.7 Hz, 1H, H-8), 7.22 (d, J = 8.3 Hz, 2H, H-2' and (C-8), 125.5 (C-10), 126.2 (C-7), 127.6 (C-2' and -
-6' ), 7.33 (d, J = 7.9 Hz, 1H, H-10), 7.58 (d, J =
8.3 Hz, 2H, H-3' and -5'), 7.63 (t, J = 7.9 Hz, 1H,
6'), 131.6 (C-3' and -5'), 134.3 (C-9), 139.6 (C-1'),
149.6 (br s, C-10a), 150.4 (br s, C-11a), 156.7 (br s,
H-9), 7.94 (d, J = 7.9 Hz, 1H, H-7), 8.31 (br s, 1H, C-2), 160.4 (C-6)
1270, 1011 (CBr, st), NH)
771, 761
3g
3h
3i
NH 3451, CH 3020,
C=O 1681, 1651,
1632, 1611, 1578,
1520, 1469, 1417,
6.28 (d, J = 3.0 Hz, 1H, H-3'), 6.40 (dd, J = 3.0,
56.1 (br s, C-4), 107.2 (C-3'), 110.4 (C-4'), 117.7
(C-6a), 122.5 (C-8), 125.4 (C-10), 126.2 (C-7),
134.3 (C-9), 143.1 (C-5'), 149.2 (br s, C-10a), 150.2
(br s, C-11a), 151.6 (C-2'), 156.7 (br s, C-2), 159.9
(C-6)
1.5 Hz, 1H, H-4'), 7.05 (s, 1H, H-4), 7.06 (br s,
2H, NH2), 7.19 (t, J = 7.3 Hz, 1H, H-8), 7.32 (d, J
= 7.9 Hz, 1H, H-10), 7.60 (d, J = 1.5 Hz, 1H, H-
1271, 1011, 799, 769 5'), 7.63 (t, J = 7.5 Hz, 1H, H-9), 7.95 (d, J = 7.9
Hz, 1H, H-7), 8.32 (1H, s, NH)
6.96 (dd, J = 4.9, 3.5 Hz, 1H, H-4'), 7.04 (d, J =
3.5 Hz, 1H, H-3'), 7.14 (br s, 2H, NH2), 7.19 (t, J
NH 3466, CH 3020,
C=O 1679, 1651,
1628, 1610, 1570,
1533, 1518, 1468,
1414, 1271, 768, 702
57.8 (br s, C-4), 117.7 (C-6a), 122.4 (C-8), 125.2
(C-3'), 125.5 (C-10), 126.2 (C-7 and -5'), 126.4 (C-
= 7.5 Hz, 1H, H-8), 7.24 (s, 1H, H-4), 7.31 (d, J = 4'), 134.3 (C-9), 143.1 (C-2'), 149.1 (br s, C-10a),
8.3 Hz, 1H, H-10), 7.44 (d, J = 4.9 Hz, 1H, H-5'),
7.62 (t, J = 7.5 Hz, 1H, H-9), 7.97 (d, J = 7.9 Hz,
1H, H-7), 8.36 (s, 1H, NH)
7.08 (s, 1H, H-4), 7.09 (br s, 2H, NH2), 7.20 (t, J
= 7.3 Hz, 1H, H-8), 7.34 (d, J = 7.9 Hz, 1H, H-
150.4 (br s, C-11a), 156.9 (br s, C-2), 160.1 (C-6)
NH 3363, NH 3327,
CH 3060, C=O 1683,
1671, 1607, 1582,
1527, 1471, 1416,
1270, 1025, 764
59.5 (br s, C-4), 117.6 (C-6a), 122.6 (C-8), 123.8
(C-5'), 125.5 (C-10), 126.2 (C-7), 133.0 (C-4'),
10), 7.40 (dd, J = 7.9, 4.9 Hz, 1H, H-5'), 7.62 (dd, 134.4 (C-9), 135.8 (C-3'), 147.0 (C-2'), 149.6 (br s,
J = 7.9, 1.8 Hz, 1H, H-6'), 7.64 (td, J = 8.1, 0.8
Hz, 1H, H-9), 7.95 (dd, J = 7.9, 0.8 Hz, 1H, H-7),
8.36 (s, 1H, NH), 8.54 (dd, J = 4.9, 1.5 Hz, 1H,
H-4'), 8.56 (d, J = 2.3 Hz, 1H, H-2')
C-10a), 149.7 (C-6'), 150.4 (br s, C-11a), 156.8 (br
s, C-2), 160.4 (C-6)
1
added. After heating for additional 15 min, the reaction
mixture was cooled, the solid collected by filtration and
washed with water. The prepared compound was sufficiently
pure and was used without further purification. After
recrystallization from 5% sodium hydroxide solution mp of the
product (2) did not change and was 317 ºC (lit. [19] mp 316-
317 ºC); yield 70%; H nmr (300 MHz) dimethyl sulfoxide-
d6/TMS, ꢀ (ppm): 7.18 (t, J = 7.3 Hz, 1H, H-6), 7.37 (d, J =
7.9 Hz, 1H, H-8), 7.60 (t, J = 7.5 Hz, 1H, H-7), 7.83 (br s, 4H,
NH-C(=NH)NH2), 7.95 (d, J = 7.9 Hz, 1H, H-5), 11.37 (br s,
1H, N(3)H); 13C nmr (75 MHz) dimethyl sulfoxide-d6/TMS, ꢀ
(ppm): 118.1 (C-4a), 122.3 (C-6), 124.2 (br s, C-8), 125.7 (C-

176
A. V. Dolzhenko, A. V. Dolzhenko and W.-K. Chui
Vol 45
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T
5), 133.5 (C-7), 149.2 (br s, C-8a), 156.1 (C-2), 159.4 (NH-
C(=NH)NH2), 165.4 (C=O); ir (porassium bromide): NH 3402,
NH 3340, CH 3048, C=O 1702, 1669, 1624, 1585, 1502, 1456,
1315, 767 cm-1.
General Procedure for the Synthesis of 2-Amino-4-
(het)aryl-4,6-dihydro-1(3)(11)H-[1,3,5]triazino[2,1-b]quina-
zolin-6-ones (3). A mixture of 4-oxo-3,4-dihydroquinazolinyl-2-
guanidine (2) (0.51 g, 2.5 mmole) and appropriate arylaldehyde
(5.0 mmole) in DMF (5 mL) was heated under reflux for 2-10 h
and concentrated under vacuum. The product (3) was filtered,
washed with ethanol and recrystallized from DMF.
Acknowledgement. This work is supported by the Academic
Research Fund (WBS R-148-000-069-112) from the National
University of Singapore.
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[1] Part
9 in the series “Fused heterocyclic systems with
s-triazine ring”, for part 8 see Dolzhenko, A. V.; Dolzhenko, A. V.;
Chui, W. K. Tetrahedron, in press.
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