Synthesis and hererocyclizations of 3,4-dihydroquinazolin-2-yl guanidine in the search of new anticancer agents

Article abstract of DOI:10.3987/COM-09-11672

The cyclocondensations of 3,4-dihydroquinazolin-2-yl guanidine with a variety of electrophilic reagents viz. aldehydes, ketones, triethyl orthoformate, diethyl ethoxymethylenemalonate, carbon disulfide and trichloroacetonitrile were found to afford l,3,5-

Full text of DOI:10.3987/COM-09-11672

HETEROCYCLES, Vol. 78, No. 7, 2009
1761
HETEROCYCLES, Vol. 78, No. 7, 2009, pp. 1761 - 1775. © The Japan Institute of Heterocyclic Chemistry
Received, 2nd February, 2009, Accepted, 18th March, 2009, Published online, 19th March, 2009
DOI: 10.3987/COM-09-11672
SYNTHESIS
AND
HEREROCYCLIZATIONS
OF
3,4-DIHYDROQUINAZOLIN-2-YL GUANIDINE IN THE SEARCH OF
NEW ANTICANCER AGENTS1
Anton V. Dolzhenko, Mi Chelle Foo, Bee Jen Tan, Anna V. Dolzhenko,
Gigi Ngar Chee Chiu, and Wai Keung Chui*
Department of Pharmacy, Faculty of Science, National University of Singapore,
18 Science Drive 4, Singapore 117543, Singapore. E-mails: phacwk@nus.edu.sg;
phada@nus.edu.sg
Abstract – The cyclocondensations of 3,4-dihydroquinazolin-2-yl guanidine with
a variety of electrophilic reagents viz. aldehydes, ketones, triethyl orthoformate,
diethyl ethoxymethylenemalonate, carbon disulfide and trichloroacetonitrile were
found to afford 1,3,5-triazino[2,1-b]quinazolines. However, some unexpected
reactions were also observed. The structural properties such as tautomerism and
hinderance to conformational rotation were also investigated. The results of
biological testing suggested that the 1,3,5-triazino[2,1-b]quinazoline nucleus
could be a new promising scaffold for the development of potential anticancer
agents.
INTRODUCTION
In our previous studies2 we found that the heterocyclization of benzimidazol-2-yl guanidines (1) with
one-carbon inserting reagents afforded 1,3,5-triazino[1,2-a]benzimidazoles, particularly
2-amino-4,4-dimethyl-3,4-dihydro[1,3,5]triazino[1,2-a]benzimidazole (2) (Fig. 1), which was able to
inhibit one of the key enzymes in cellular methabolism, namely dihydrofolate reductase (DHFR).
Me Me
R
NH NH
NH NH
N
NH
NH2
N
N
N
H
NH2
N
H
NH2
N
N
1
2
3
Figure 1

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HETEROCYCLES, Vol. 78, No. 7, 2009
In order to extend this methodology to the synthesis of structurally similar 1,3,5-triazinoquinazolines with
potential anticancer activity, we report here the preparation of 3,4-dihydroquinazolin-2-yl guanidine (3)
(Fig. 1) and its reactions with a variety of elecrophiles.
Information on the synthesis of 1,3,5-triazinoquinazolines is limited. In general, three isomeric structures
are possible for quinazoline fused with 1,3,5-triazine nucleus, viz. 1,3,5-triazino[1,2-a]quinazoline (A),3
1,3,5-triazino[2,1-b]quinazoline (B)4 and 1,3,5-triazino[1,2-c]quinazoline (C)4a, 5 heterocyclic systems
(Fig. 2). The cyclization of 3,4-dihydroquinazolin-2-yl guanidine (3) might hypothetically result in the
formation of systems A or B. In previous study, we also found that cyclization of unsymmetrically
substituted in the phenylene fragment benzimidazol-2-yl guanidines (1, R ≠ H) with one-carbon inserting
reagents did not proceed regioselectively.2a Therefore, regioselectivity of the ring closure of 3 became one
of the important aspects of our investigation. With regards to DHFR inhibitory activity of 22 and
antiproliferative properties of other structurally related fused 1,3,5-triazines synthesized in our laboratory6,
we also report herein the results of the biological testing for the compounds prepared.
4
7
6
5
N
N
N
8
9
3
2
N
N
c
N
b
a
N
N
N
N
1
10 11
N
N
B
C
A
Figure 2
RESULTS AND DISCUSSION
Synthesis
3,4-Dihydroquinazolin-2-yl guanidine (3) was prepared using acid catalyzed cyclocondensation of
2-aminobenzylamine (4) and cyanoguanidine (Scheme 1).
i, ii
NH2
NH2
NH NH
N
NH
NH2
N
N
H
NH2
N
N
74%
H
H
4
3'
3
i: H2NC(=NH)NHCN, HCl, H2O, reflux, 18 h;
ii: 10 % NaOH, 80oC, 10 min
NH NH
NH2
N
N
H
3"
Scheme 1

HETEROCYCLES, Vol. 78, No. 7, 2009
1763
Broadening of the signals of C-2, C-4, C-8 and C-8a atoms observed in 13C NMR spectrum of 3 indicated
the existence of dihydroquinazolin-2-yl guanidine in equilibrium of two forms 3 and 3’ due to annular
tautomerism. The presence of tautomeric form 3’’ in the equilibrium was less probable as no broadening
for the signal of the guanidine group carbon atom in the 13C NMR spectrum was detected.
In our attempt to prepare an analogue of bioactive compound 2, 3,4-dihydroquinazolin-2-yl guanidine (3)
was heated in acetone under piperidine catalysis. The 1,3,5-triazine ring closure reaction resulted in the
formation of product with two geminal methyl groups for which two alternative structures 5 and 6 could
be attributed (Scheme 2). The formation of the dihydro-1,3,5-triazine ring with sp3 hybridized quarternary
13
carbon atom was confirmed by the presence of signals at 71.2 ppm in C NMR spectrum. 2D NOESY
experiments showed cross-peaks between the singlets of the gem-dimethyl groups and the methylenic
protons of dihydroquinazoline nucleus indicating their close proximity. These observations confirmed the
annelation of the triazine ring to side b of quinazoline and led to the assignment of the
2-amino-4,4-dimethyl-4,6-dihydro-1(3)(11)H-[1,3,5]triazino[2,1-b]quinazoline (5) structure for the
reaction product.
Me Me
N
NH
NH2
N
N
5, 62%
NH NH
NH2
acetone, piperidine, reflux, 18 h
N
N
H
N
3
N
N
Me
Me
N
NH2
H
6
Scheme 2
The reaction of 3,4-dihydroquinazolin-2-yl guanidine (3) with (het)arylaldehydes proceeded via (5+1)
heterocyclization with the formation of 2-amino-4-(het)aryl-4,6-dihydro-1(3)(11)H-[1,3,5]triazino-
[2,1-b]quinazolines (7) (Scheme 3). The reaction was found to be general and regioselective. The signal
13
of the sp3-hybridized carbon atom at 70-74 ppm in the C NMR spectra indicated the ring closure with
the formation of dihydro-1,3,5-triazine nucleus. Another evidence of the cyclization was a coupling
1
(Jgem ≈ 14.5 Hz) of the signals of methylenic protons of the dihydroquinazoline ring in H NMR spectra
of the products 7. These protons became diastereotopic and their signals appeared as two doublets of AM
system at 3.90-4.20 and 4.25-4.40 ppm. The dihydro-1,3,5-triazine ring fusion on side b of the
quinazoline was confirmed by cross-peaks found in 2D NOESY experiments for the signals of methylenic
protons and the singlet of proton at newly introduced sp3-hybridized carbon of the nucleus.

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HETEROCYCLES, Vol. 78, No. 7, 2009
R
N
RCHO, piperidine, EtOH, reflux, 4-18 h
NH NH
N
NH
NH2
N
N
H
NH2
N
3
7
Compound
Compound
R
Yield, %
85
R
Yield, %
58
4-MeOC6H4
4-Me2NC6H4
2-Thienyl
3-Py
7a
7b
7c
7d
Ph
7e
7f
4-ClC6H4
4-BrC6H4
4-MeC6H4
84
75
7g
7h
87
82
72
77
Scheme 3
The annular prototropic tautomerism was noticed in DMSO solution for compounds 5 and 7 viz. 1H-, 3H-
and 11H-tautomeric forms (Scheme 4). The prototropic interconversion between these tautomeric forms
was
postulated
based
on
broadening
observed
for
several
signals
of
13
4,6-dihydro-1(3)(11)H-[1,3,5]triazino[2,1-b]quinazoline heterocyclic system in the C NMR spectra of
compounds 5 and 7. The pattern of the signal broadening indicated that all three tautomeric forms were
involved in the proton transfer. The broadening of C-4 signal referred to the 1H- / 3H- equilibrium and
the broad signals of C-10a and C-10 indicated the 1H- / 11H- interconversion.
R1 R2
NH
R1 R2
N
N
N
N
N
NH2
N
N
NH2
H
3H-tautomer
1H-tautomer
R1 R2
N
N
N
N
NH2
H
11H-tautomer
Scheme 4
Heating cycloketones (e.g. cyclopentanone and cyclohexanone) with benzimidazol-2-yl guanidine (1,
R = H) in DMF has been shown to provide spiro-fused 1,3,5-triazines.2b, 7 When similar conditions were
applied for the reaction of 3 with these ketones, the formation of fused 1,3,5-triazines (8) with similar
structure was expected (Scheme 5). However, instead of dihydrotriazine ring closure, the reaction
furnished the formation of compounds 9 with pyrimidine ring constructed from guanidine moiety, two

HETEROCYCLES, Vol. 78, No. 7, 2009
1765
carbon atoms of cycloketone and one molecule of DMF, which was also involved in the reaction.
(CH2)n
N
NH
NH2
N
N
8
NH NH
NH2
(CH2)n
, DMF, reflux, 4 h
O
N
N
H
3
NH
N
(CH2)n
N
N
N
n = 1 (9a), 46%; 2 (9b), 62%
H
9
Scheme 5
Orthoesters are well known as one-carbon inserting reagents in heterocyclic chemistry for a long time.8
The reaction of 3 with triethyl orthoformate proceeded regioselectively with the 1,3,5-triazine ring closure
onto side b of the dihydroquinazoline affording 2-amino-6H-1,3,5-triazino[2,1-b]quinazoline (10)
(Scheme 6). This was confirmed by the observation of cross-peaks between the signals of methylenic
protons of quinazoline and methine proton of triazine ring in 2D NOESY experiment. 1H NMR spectrum
of 10 showed two separate D2O exchangeable signals at 7.20 and 7.24 ppm corresponding to the amino
group. The magnetic unequivalence of the amino group protons can be explained on the basis of strong
π-electrons delocalization of the amino group with the 1,3,5-triazine ring9 that resulted in increasing
rotational barrier. The activation energy (ΔG‡308) for the rotation around C-NH2 bond was found to be
70.6 kJ/mol as estimated by dynamic NMR experiments.
Diethyl ethoxymethylenemalonate as a potential triatomic synthon10 might theoretically react with
guanidine moiety providing 11 (Scheme 6). However, likewise in the reaction with benzimidazol-2-yl
guanidines (1),2 diethyl ethoxymethylenemalonate reacted with 3 playing a role of one-carbon inserting
reagent affording the formation of 10. The reaction proceeded with elimination of ethanol and diethyl
malonate and afforded the product (10) identical to the one obtained from the reaction of 3 with triethyl
orthoformate.
CO2Et
i
NH NH
NH2
N
N
NH
N
N
N
N
N
NH2
N
N
N
O
H
H
H
3
10
11
i : HC(OEt)3, DMF, reflux, 4 h (Method A), 63%; EtOCH=C(CO2Et)2, MeCN, reflux, 7 h (Method B), 82%
Scheme 6

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HETEROCYCLES, Vol. 78, No. 7, 2009
Carbon disulfide has been recognized as valuable reagent in organic chemistry, particularly useful for
thiocarbonylation reactions.11 The ring closure thiocarbonylation of 3 with carbon disulfide was
successfully achieved (Scheme 7) using the method described by Martin et al.7 for structurally related
benzimidazol-2-yl guanidine (1, R = H). The structure of the product (12) was confirmed by
spectroscopic data. The presence of the thioxo group at C-4 was supported with a significant stretching
13
absorption at 1186 cm-1 in the IR spectrum of compound 12 and signal at 182.8 ppm in the C NMR
spectrum for this atom. The anisotropic effect of the thioxo group caused a downfield shift of the signal of
1
methylenic protons (5.40 ppm) in H NMR spectrum, thus indicating the formation of the 1,3,5-triazine
ring onto side b of quinazoline.
S
CS2, pyridine, reflux, 5 h
NH NH
NH2
N
NH
NH2
N
N
N
N
52%
H
3
12
Scheme 7
Trichloroacetonitrile has been known as a useful synthon in heterocyclic chemistry,12 particularly it has
found an application as one-carbon inserting reagent for the construction of 1,3,5-triazine ring introducing
tricloromethyl or amino group.13 We found that 3 reacted with trichloroacetonitrile in ethanol with
elimination of chloroform, therefore providing the formation of diamine 15b (Scheme 8).
CCl3
X
N
N
N
N
NH2
X
14
NH NH
Cl3CCN, EtOH, reflux, 8 h
N
N
H
NH2
NH2
N
1, 3
X
N
N
N
NH2
H
N
15
NH2
H2NC(=NH)NHCN, 200oC, 0.5 h
N
13
HCl, H2O
NH2
N
X
N
X = - (1, 15a and 16a), CH2 (3, 15b and 16b)
16a, 72%; 16b, 68%
Cl-
NH2
N
N
H+
16
Scheme 8

HETEROCYCLES, Vol. 78, No. 7, 2009
1767
Similarly, benzimidazol-2-yl guanidine (1) under the same reaction conditions provided
2,4-diamino-1,3,5-triazino[1,2-a]benzimidazole (15a), which was identical to the compound prepared via
alternative synthetic pathway from 2-aminobenzimidazole (13) and cyanoguanidine according to the
method reported by Kreutzberger and Tantawy.14 The reactions of trichloroacetonitrile with
heterylguanidines (1 and 3) in ethanol were found to proceed chemo- and regioselectively affording with
good yields 15, exclusively; no traces of possible alternative product 14 were detected. Therefore,
trichloroacetonitrile could be considered as a safer replacement of cyanogen bromide used in this type of
reactions.7
Due to solubility problem, compounds 15 were converted into their hydrochloric salts. In both cases, the
protonation occurred at endocyclic nitrogen atom not belonging to the triazine ring that was confirmed by
2D NOESY experiment data (cross-peaks between signals of N+H and phenylene proton). Additionally,
for compound 16b, the cross-peaks observed between the singlet of methylenic protons at 5.12 ppm and
the signals of one of the amino groups at 7.76-7.78 ppm confirmed the regiochemistry of the triazine ring
closure to side b of quinazoline nucleus. The same cross-peaks also facilitated the assignments of signals
of the amino groups for this compound.
The hindered rotation was detected for the amino groups of 16. The activation energy (ΔG‡) of the
1
rotation around C(2)-NH2 bond was estimated for compounds 16 using dynamic H NMR spectroscopy.
For 2,4-diamino-1,3,5-triazino[1,2-a]benzimidazole hydrochloride (16a), the value of ΔG‡ was equal
333
71.4 kJ/mol; for 2,4-diamino-6H-1,3,5-triazino[2,1-b]quinazoline (10), ΔG‡
was found to be
320
73.6 kJ/mol.
Biological activity
The antiproliferative activity of the prepared 1,3,5-triazino[2,1-b]quinazolines against lung (A549) and
breast (MDA-MB-231) cancer cell lines was evaluated using MTT assay.15 4-(Het)aryl substituted
2-amino-4,6-dihydro-1(3)(11)H-[1,3,5]triazino[2,1-b]quinazolines (7) were the only group of compounds
which possessed antiproliferative activity in micromolar range (Table 1). This is the first time, anticancer
activity was reported for compounds with 1,3,5-triazino[2,1-b]quinazoline scaffold. The antiproliferative
activity of the compounds (7) seemed to depend on their lipophilicity. The more lipophilic halogen
substituted 7b and 7c showed higher antiproliferative effect.
In the enzyme assay, no significant effect on the human DHFR activity was observed in the presence of
the compounds at 100 μM. Therefore, the effect of the compounds on the growth of cancer cells was not
associated with DHFR inhibition.
CONCLUSION
New 1,3,5-triazino[2,1-b]quinazolines were effectively prepared via cyclocondensation of
3,4-dihydroquinazolin-2-yl guanidine (3) with variety of one-carbon inserting reagents. The reactions

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HETEROCYCLES, Vol. 78, No. 7, 2009
were found to be chemo- and regioselective. The 1,3,5-triazino[2,1-b]quinazoline nucleus was identified
as a new scaffold for the development of potential anticancer agents.
Table 1. Antiproliferative activity of some
2-amino-4-(het)aryl-4,6-dihydro-1(3)(11)H-[1,3,5]triazino[2,1-b]quinazolines (7)
Compound
R
GI50, μM
MDA-MB-231
A549
110
33
7a
7b
7c
7d
7e
7f
Ph
93
27
4-ClC6H4
4-BrC6H4
4-MeC6H4
4-MeOC6H4
4-Me2NC6H4
2-Thienyl
3-Py
17
15
61
33
98
40
53
27
7g
7h
92
104
> 100
> 100
EXPERIMENTAL
General Methods. Melting points (uncorrected) were determined on a Gallenkamp melting point
apparatus. The IR spectra were recorded with a Shimadzu IRPrestige-21 spectrophotometer using KBr
pellets. 1H and 13C NMR spectra were recorded on a Bruker DPX-300 spectrometer, using DMSO-d6 as a
solvent and TMS as an internal reference. The dynamic NMR experiments were performed using 0.5 M
solutions of the compounds in DMSO-d6.
1(3),4-Dihydroquinazolin-2-yl guanidine (3).
2-Aminobenzylamine (4, 5.0 g, 41 mmol) and cyanoguanidine (4.3 g, 51 mmol) were dissolved in 15 mL
of water with 8 mL of conc. HCl. The mixture was refluxed for 18 h, cooled and filtered. The
hydrochloride salt of 3 was dissolved in water on heating and the resulting solution was filtered hot and
basified with 5% NaOH solution. After stirring for 10 min and cooling, the precipitate was filtered and
washed with water. The product (3) was purified by reprecipitation from the hot solution in 5% HCl using
5% NaOH. The analytical sample was recrystallized from EtOH. Yield 74%; mp 198 °C (lit.,16 mp
202-204 °C).
1H NMR (300 MHz, DMSO-d6): δ 4.32 (2H, s, C(4)H2), 5.93 (1H, br s, NH), 6.67 (1H, d, J = 7.9 Hz,
H-8), 6.72 (1H, t, J = 7.5 Hz, H-6), 6.94 (4H, br s, NHC(=NH)NH2), 7.01 (1H, d, J = 7.2 Hz, H-5), 7.05
(1H, t, J = 7.5 Hz, H-7).

HETEROCYCLES, Vol. 78, No. 7, 2009
1769
13C NMR (75 MHz, DMSO-d6): δ 42.8 (br s, C-4), 120.3 (C-8), 120.6 (C-4a), 121.1 (br s, C-8), 125.0
(C-6), 127.0 (C-7), 145.3 (br s, C-8a), 159.5 (NHC(=NH)NH2), 159.9 (br s, C-2).
2-Amino-4,4-dimethyl-4,6-dihydro-1(3)(11)H-[1,3,5]triazino[2,1-b]quinazoline (5).
To suspension of 3,4-dihydroquinazolin-2-yl guanidine (3, 0.47 g, 2.5 mmol) in acetone (10 mL),
piperidine (0.2 mL) was added. The reaction mixture was heated under reflux for 18 h. After cooling, the
product (5) was filtered and recrystallized from a mixture of acetone and EtOH. Yield 62%; mp 246 °C.
1H NMR (300 MHz, DMSO-d6): δ 1.37 (6H, s, 2Me), 4.45 (2H, s, C(6)H2), 6.35 (2H, br s, NH2), 6.77
(1H, d, J = 7.9 Hz, H-10), 6.81 (1H, t, J = 7.5 Hz, H-8), 7.01 (1H, d, J = 7.9 Hz, H-7), 7.05 (1H, t, J = 7.5
Hz, H-9).
13C NMR (75 MHz, DMSO-d6): δ 27.0 (2Me), 42.7 (C-6), 71.2 (br s, C-4), 117.1 (br s, C-10), 119.7
(C-6a), 120.8 (C-8), 125.4 (C-9), 127.6 (C-7), 140.4 (br s, C-10a), 151.5 (C-2), 153.4 (br s, C-11a).
Anal. Calcd for C12H15N5: C, 62.86; H, 6.59; N, 30.54. Found: C, 62.75; H, 6.68; N, 30.37.
General Procedure for Synthesis of 2-Amino-4-(het)aryl-4,6-dihydro-1(3)(11)H-[1,3,5]triazino-
[2,1-b]quinazolines (7). To solution of 3,4-dihydroquinazolin-2-yl guanidine (3, 0.47 g, 2.5 mmol) in
EtOH (7 mL), appropriate aldehyde (2.5 mmol) and piperidine (0.2 mL) were added. After heating under
reflux for 4-18 h, the reaction mixture was cooled. The product (7) was filtered and recrystallized from a
suitable solvent.
2-Amino-4-phenyl-4,6-dihydro-1(3)(11)H-[1,3,5]triazino[2,1-b]quinazoline (7a).
Yield 85%; mp 219-220 °C (EtOH).
1H NMR (300 MHz, DMSO-d6): δ 3.97 (1H, d, Jgem = 14.3 Hz, HA-6), 4.34 (1H, d, Jgem = 14.3 Hz, HM-6),
5.50 (1H, s, H-4), 6.09 (2H, br s, NH2), 6.79 (1H, t, J = 7.3 Hz, H-8), 6.82 (1H, d, J = 7.3 Hz, H-10), 6.90
(1H, d, J = 7.3 Hz, H-7), 7.06 (1H, t, J = 7.3 Hz, H-9), 7.23-7.46 (5H, m, Ph).
13C NMR (75 MHz, DMSO-d6): δ 45.8 (C-6), 74.0 (br s, C-4), 117.0 (br s, C-10), 118.7 (C-6a), 121.3
(C-8), 125.5 (C-9), 126.4 (C-2’ and C-6’), 127.8, 127.9 (C-7 and C-4’), 128.5 (C-3’ and C-5’), 139.3 (br s,
C-10a), 142.6 (C-1’), 151.3 (C-2), 153.9 (br s, C-11a).
Anal. Calcd for C16H15N5: C, 69.29; H, 5.45; N, 25.25. Found: C, 69.02; H, 5.62; N, 25.03.
2-Amino-4-(4-chlorophenyl)-4,6-dihydro-1(3)(11)H-[1,3,5]triazino[2,1-b]quinazoline (7b).
Yield 84%; mp 156 °C (EtOH).
1H NMR (300 MHz, DMSO-d6): δ 3.95 (1H, d, Jgem = 14.3 Hz, HA-6), 4.33 (1H, d, Jgem = 14.3 Hz, HM-6),
5.53 (1H, s, H-4), 5.59 (2H, br s, NH2), 6.81 (1H, t, J = 7.2 Hz, H-8), 6.83 (1H, d, J = 7.5 Hz, H-10), 6.94
(1H, d, J = 7.2 Hz, H-7), 7.09 (1H, t, J = 7.3 Hz, H-9), 7.38 (2H, d, J = 8.3 Hz, H-2’ and H-6’), 7.43 (2H,
d, J = 8.3 Hz, H-3’ and H-5’), 9.51 (1H, br s, NH).

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13C NMR (75 MHz, DMSO-d6): δ 45.6 (C-6), 74.1 (br s, C-4), 116.1 (br s, C-10), 118.3 (C-6a), 121.3
(C-8), 125.6 (C-9), 127.9 (C-7), 128.2 (C-2’ and C-6’), 128.4 (C-3’ and C-5’), 132.2 (C-4’), 138.2 (br s,
C-10a), 142.0 (br s, C-1’), 151.3 (C-2), 154.4 (br s, C-11a).
Anal. Calcd for C16H14N5Cl: C, 61.64; H, 4.53; N, 22.46. Found: C, 61.52; H, 4.63; N, 22.35.
2-Amino-4-(4-bromophenyl)-4,6-dihydro-1(3)(11)H-[1,3,5]triazino[2,1-b]quinazoline (7c).
Yield 87%; mp 164 °C (EtOH).
1H NMR (300 MHz, DMSO-d6): δ 3.95 (1H, d, Jgem = 14.7 Hz, HA-6), 4.33 (1H, d, Jgem = 14.7 Hz, HM-6),
5.51 (1H, s, H-4), 5.68 (2H, br s, NH2), 6.80 (1H, t, J = 7.3 Hz, H-8), 6.83 (1H, d, J = 7.9 Hz, H-10), 6.93
(1H, d, J = 7.2 Hz, H-7), 7.08 (1H, t, J = 7.5 Hz, H-9), 7.32 (2H, d, J = 8.3 Hz, H-2’ and H-6’), 7.57 (2H,
d, J = 8.3 Hz, H-3’ and H-5’), 9.55 (1H, br s, NH).
13C NMR (75 MHz, DMSO-d6): δ 45.7 (C-6), 74.0 (br s, C-4), 116.3 (br s, C-10), 118.4 (C-6a), 120.8
(C-4’), 121.3 (C-8), 125.6 (C-9), 127.9 (C-7), 128.6 (C-2’ and C-6’), 131.3 (C-3’ and C-5’), 138.4 (br s,
C-10a), 142.4 (br s, C-1’), 151.3 (C-2), 154.3 (br s, C-11a).
Anal. Calcd for C16H14N5Br: C, 53.95; H, 3.96; N, 19.66. Found: C, 53.77; H, 3.98; N, 19.54.
2-Amino-4-(4-methylphenyl)-4,6-dihydro-1(3)(11)H-[1,3,5]triazino[2,1-b]quinazoline (7d).
Yield 72%; mp 179-180 °C (MeOH).
1H NMR (300 MHz, DMSO-d6): δ 2.28 (3H, s, Me), 3.94 (1H, d, Jgem = 14.3 Hz, HA-6), 4.30 (1H, d, Jgem
= 14.3 Hz, HM-6), 5.44 (1H, s, H-4), 5.68 (2H, br s, NH2), 6.78 (1H, t, J = 7.3 Hz, H-8), 6.80 (1H, d, J =
7.9 Hz, H-10), 6.90 (1H, d, J = 7.2 Hz, H-7), 7.06 (1H, t, J = 7.5 Hz, H-9), 7.17 (2H, d, J = 7.9 Hz, H-3’
and H-5’), 7.25 (2H, d, J = 7.9 Hz, H-2’ and H-6’), 9.38 (1H, br s, NH).
13C NMR (75 MHz, DMSO-d6): δ 20.6 (Me), 45.6 (C-6), 74.2 (br s, C-4), 116.6 (br s, C-10), 118.6 (C-6a),
121.2 (C-8), 125.5 (C-9), 126.3 (C-2’ and C-6’), 127.8 (C-7), 128.9 (C-3’ and C-5’), 137.0 (C-4’), 138.9
(br s, C-10a), 139.9 (br s, C-1’), 151.3 (C-2), 153.9 (br s, C-11a).
Anal. Calcd for C17H17N5: C, 70.08; H, 5.88; N, 24.04. Found: C, 69.89; H, 5.95; N, 23.86.
2-Amino-4-(4-methoxyphenyl)-4,6-dihydro-1(3)(11)H-[1,3,5]triazino[2,1-b]quinazoline (7e).
Yield 58%; mp 215-216 °C (AcOEt).
1H NMR (300 MHz, DMSO-d6): δ 3.73 (3H, s, OMe), 3.95 (1H, d, Jgem = 14.3 Hz, HA-6), 4.31 (1H, d,
Jgem = 14.3 Hz, HM-6), 5.42 (1H, s, H-4), 6.23 (2H, br s, NH2), 6.77 (1H, t, J = 8.3 Hz, H-8), 6.78 (1H, d,
J = 8.3 Hz, H-10), 6.88 (1H, d, J = 7.5 Hz, H-7), 6.93 (2H, d, J = 8.3 Hz, H-3’ and H-5’), 7.04 (1H, t, J =
7.3 Hz, H-9), 7.31 (2H, d, J = 8.3 Hz, H-2’ and H-6’), 9.35 (1H, br s, NH).
13C NMR (75 MHz, DMSO-d6): δ 45.8 (C-6), 55.0 (OMe), 73.4 (br s, C-4), 113.8 (C-3’ and C-5’),
117.4(br s, C-10), 118.9 (C-6a), 121.2 (C-8), 125.4 (C-9), 127.7 (C-2’ and C-6’), 127.8 (C-7), 134.6 (br s,

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C-1’), (br s, C-10), 118.9 (C-6a), 121.2 (C-8), 125.4 (C-9), 127.7 (C-2’ and C-6’), 127.8 (C-7), 134.6 (br s,
C-1’), 140.0 (br s, C-10a), 151.2 (br s, C-2), 153.6 (br s, C-11a), 159.0 (C-4’).
Anal. Calcd for C17H17N5O: C, 66.43; H, 5.58; N, 22.79. Found: C, 66.25; H, 5.82; N, 22.53.
2-Amino-4-[4-(N,N-dimethylamino)phenyl]-4,6-dihydro-1(3)(11)H-[1,3,5]triazino[2,1-b]quinazoline
(7f).
Yield 75%; mp 212-214 °C (EtOH).
1H NMR (300 MHz, DMSO-d6): δ 2.87 (6H, s, NMe2), 3.96 (1H, d, Jgem = 14.3 Hz, HA-6), 4.27 (1H, d,
Jgem = 14.3 Hz, HM-6), 5.32 (1H, s, H-4), 6.22 (2H, br s, NH2), 6.70 (2H, d, J = 8.7 Hz, H-3’ and H-5’),
6.75 (1H, t, J = 7.9 Hz, H-8), 6.76 (1H, d, J = 7.9 Hz, H-10), 6.86 (1H, d, J = 7.2 Hz, H-7), 7.03 (1H, t, J
= 7.3 Hz, H-9), 7.19 (2H, d, J = 8.7 Hz, H-2’ and H-6’), 9.37 (1H, br s, NH).
13C NMR (75 MHz, DMSO-d6): δ 40.0 (NMe2), 45.7 (C-6), 73.5 (br s, C-4), 112.1 (C-3’ and C-5’), 117.5
(br s, C-10), 119.0 (C-6a), 121.0 (C-8), 125.3 (C-9), 127.3 (C-2’ and C-6’), 127.7 (C-7), 129.7 (br s, C-1’),
141.0 (br s, C-10a), 150.2 (C-4’), 151.3 (br s, C-2), 153.5 (br s, C-11a).
Anal. Calcd for C18H20N6: C, 67.48; H, 6.29; N, 26.23. Found: C, 67.12; H, 6.49; N, 25.82.
2-Amino-4-(2-thienyl)-4,6-dihydro-1(3)(11)H-[1,3,5]triazino[2,1-b]quinazoline (7g).
Yield 82%; mp 214-215 °C (EtOH).
1H NMR (300 MHz, DMSO-d6): δ 4.17 (1H, d, Jgem = 14.3 Hz, HA-6), 4.40 (1H, d, Jgem = 14.3 Hz, HM-6),
5.81 (1H, s, H-4), 5.91 (2H, br s, NH2), 6.82 (1H, t, J = 7.2 Hz, H-8), 6.83 (1H, d, J = 7.5 Hz, H-10), 6.95
(1H, dd, J = 4.7, 3.7 Hz, H-4’), 6.98 (1H, d, J = 7.2 Hz, H-7), 7.08 (1H, t, J = 7.3 Hz, H-9), 7.10 (1H, d, J
= 3.7 Hz, H-3’), 7.43 (1H, d, J = 4.7 Hz, H-5’), 9.62 (1H, br s, NH).
13C NMR (75 MHz, DMSO-d6): δ 45.6 (C-6), 70.1 (br s, C-4), 116.2 (br s, C-10), 118.7 (C-6a), 121.4
(C-8), 124.8 (C-3’), 125.5, 125.6 (C-9 and C-5’), 126.1 (C-4’), 127.9 (C-7), 138.4 (br s, C-10a), 147.5 (br
s, C-2’), 150.9 (C-2), 155.0 (br s, C-11a).
Anal. Calcd for C14H13N5S: C, 59.34; H, 4.62; N, 24.72. Found: C, 59.09; H, 4.86; N, 24.57.
2-Amino-4-(3-pyridyl)-4,6-dihydro-1(3)(11)H-[1,3,5]triazino[2,1-b]quinazoline (7h).
Yield 77%; mp 215-217°C (EtOH).
1H NMR (300 MHz, DMSO-d6): δ 4.00 (1H, d, Jgem = 14.3 Hz, HA-6), 4.38 (1H, d, Jgem = 14.3 Hz, HM-6),
5.62 (1H, s, H-4), 5.68 (2H, br s, NH2), 6.82 (1H, t, J = 7.3 Hz, H-8), 6.85 (1H, d, J = 7.2 Hz, H-10), 6.95
(1H, d, J = 7.5 Hz, H-7), 7.10 (1H, t, J = 7.5 Hz, H-9), 7.40 (1H, dd, J = 7.7, 4.7 Hz, H-5’), 7.74 (1H, dd,
J = 7.5, 1.9 Hz, H-4’), 8.52 (1H, dd, J = 4.7, 1.5 Hz, H-6’), 8.57 (1H, d, J = 1.5 Hz, H-2’), 9.63 (1H, br s,
NH).

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13C NMR (75 MHz, DMSO-d6): δ 45.7 (C-6), 72.8 (br s, C-4), 116.1 (br s, C-10), 118.4 (C-6a), 121.4
(C-8), 123.8 (C-5’), 125.6 (C-9), 127.9 (C-7), 133.9 (C-4’), 138.1 (br s, C-10a), 138.2 (C-3’), 147.9
(C-2’), 149.1 (C-6’), 151.4 (C-2), 154.7 (C-11a).
Anal. Calcd for C15H14N6: C, 64.73; H, 5.07; N, 30.20. Found: C, 64.46; H, 5.43; N, 30.04.
Reaction of 3,4-dihydroquinazolin-2-yl guanidine (3) with cycloketones in DMF
To solution of 3,4-dihydroquinazolin-2-yl guanidine (3, 0.47 g, 2.5 mmol) in DMF (5 mL), appropriate
cycloketone (5.0 mmol) was added. After heating under reflux for 4 h, the reaction mixture was cooled
and evaporated to half of the volume. The product (9) was filtered and recrystallized from a suitable
solvent.
N-(6,7-Dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-3,4-dihydroquinazolin-2-amine (9a).
Yield 46%; mp > 300 °C (DMF).
1H NMR (300 MHz, DMSO-d6): δ 2.01 (2H, quintet, J = 7.5 Hz, C(6’)H2), 2.74-2.86 (4H, m, C(5’)H2 and
C(7’)H2), 4.52 (2H, s, C(6)H2), 6.89 (1H, t, J = 7.0 Hz, H-6), 6.90 (1H, d, J = 7.2 Hz, H-8), 7.08 (1H, d, J
= 7.5 Hz, H-5), 7.13 (1H, t, J = 7.5 Hz, H-7), 8.28 (1H, s, H-4’), 9.86 (2H, br s, 2NH).
13C NMR (75 MHz, DMSO-d6): δ 22.3 (C-6), 27.1 (CH2), 33.6 (CH2), 41.6 (C(6)H2), 115.0 (C-8), 118.6
(C-6a), 121.4 (C-6), 124.5 (C-4a’), 125.5 (C-7), 127.7 (C-5), 137.7 (C-8a), 151.3 (C-4’), 152.9 (C-2),
164.1 (C-7a’), 174.8 (C-2’).
Anal. Calcd for C15H15N5: C, 67.90; H, 5.70; N, 26.40. Found: C, 67.67; H, 5.96; N, 26.15.
N-(5,6,7,8-Tetrahydroquinazolin-2-yl)-3,4-dihydroquinazolin-2-amine (9b).
Yield 62%; mp 227 °C (EtOH).
1H NMR (300 MHz, DMSO-d6): δ 1.60-1.88 (4H, m, C(6’)H2 and C(7’)H2), 2.58 (2H, t, J = 6.0 Hz,
C(5’)H2), 2.69 (2H, t, J = 6.0 Hz, C(8’)H2), 4.51 (2H, s, C(6)H2), 6.88 (1H, d, J = 7.5 Hz, H-8), 6.89 (1H,
t, J = 7.2 Hz, H-6), 7.08 (1H, d, J = 7.5 Hz, H-5), 7.13 (1H, t, J = 7.5 Hz, H-7), 8.18 (1H, s, H-4’), 9.80
(2H, br s, 2NH).
13C NMR (75 MHz, DMSO-d6): δ 21.9 (CH2), 22.1 (CH2), 24.3 (CH2), 31.4 (CH2), 41.6 (C(6)H2), 114.9
(C-8), 118.6 (C-6a), 120.1 (C-4a’), 121.4 (C-6), 125.6 (C-7), 127.7 (C-5), 137.7 (C-8a), 152.9 (C-2),
157.2 (C-4’), 163.0 (C-8a’), 164.5 (C-2’).
Anal. Calcd for C16H17N5: C, 68.79; H, 6.13; N, 25.07. Found: C, 68.52; H, 6.28; N, 24.82.
2-Amino-6H-[1,3,5]triazino[2,1-b]quinazoline (10).
Method A. A solution of 3,4-dihydroquinazolin-2-yl guanidine (3, 0.47 g, 2.5 mmol) and triethyl
orthoformate (0.5 mL, 3 mmol) in DMF (5 mL) was heated under reflux for 4 h. After cooling, the yellow
precipitate was filtered, washed with EtOH and recrystallized from DMF.

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Method B. A mixture of 3,4-dihydroquinazolin-2-yl guanidine (3, 0.47 g, 2.5 mmol) and diethyl
ethoxymethylenemalonate (0.5 mL, 2.5 mmol) in MeCN (10 mL) was heated under reflux for 7 h. After
cooling, precipitated product was filtered, washed with EtOH and recrystallized from DMF to provide
compound identical to the sample obtained in Method A.
Yield 63% (Method A), 82% (Method B); mp 294-295 °C.
1H NMR (300 MHz, DMSO-d6): δ 4.99 (2H, s, C(6)H2), 6.80 (1H, d, J = 7.9 Hz, H-10), 6.85 (1H, t, J =
7.5 Hz, H-8), 6.98 (1H, d, J = 7.2 Hz, H-7), 7.08 (1H, t, J = 7.5 Hz, H-9), 7.20 (1H, s, NH), 7.24 (1H, s,
NH), 7.97 (1H, s, H-4).
13C NMR (75 MHz, DMSO-d6): δ 47.9 (C-6), 119.1 (C-6a), 121.7 (C-10), 122.6 (C-8), 124.9 (C-9), 128.0
(C-7), 143.9 (C-10a), 148.1 (C-2), 157.3 (C-4), 162.6 (C-11a).
Anal. Calcd for C10H9N5: C, 60.29; H, 4.55; N, 35.16. Found: C, 60.23; H, 4.58; N, 35.10.
2-Amino-6H-[1,3,5]triazino[2,1-b]quinazolin-4-thione (12).
3,4-Dihydroquinazolin-2-yl guanidine (3, 0.47 g, 2.5 mmol) and carbon disulphide (1.0 mL, 16 mmol)
were added to pyridine (4.0 mL) and refluxed for 5 h. After cooling, the product was filtered, washed
with MeOH and recrystallized from DMF. Yield 52%; mp > 300 °C.
IR (KBr, ν, cm-1): NH 3470, NH 3267, NH 3171, CHAr 3080, 1636, 1607, 1578, 1541, 1508, 1479, 1450,
1406, 1337, 1246, C=S 1186, 1111, 982, 820, 768, 758, 451.
1H NMR (300 MHz, DMSO-d6): δ 5.40 (2H, s, C(6)H2), 7.00 (1H, d, J = 7.9 Hz, H-10), 7.02 (1H, t, J =
7.5 Hz, H-8), 7.18 (1H, s, NH), 7.22 (1H, t, J = 7.9 Hz, H-9), 7.25 (1H, d, J = 7.5 Hz, H-7), 7.46 (1H, s,
NH), 10.65 (1H, s, NH).
13C NMR (75 MHz, DMSO-d6): δ 47.9 (C-6), 114.3 (C-10), 117.8 (C-6a), 123.2 (C-8), 126.3 (C-9), 128.3
(C-7), 133.8 (C-10a), 152.7 (C-2), 160.4 (C-11a), 182.8 (C-4).
Anal. Calcd for C10H9N5S: C, 51.93; H, 3.92; N, 30.28. Found: C, 51.71; H, 3.98; N, 30.09.
2,4-Diamino[1,3,5]triazino[1,2-a]benzimidazole hydrochloride (16a).
Benzimidazol-2-yl guanidine (1, 0.44 g, 2.5 mmol) and trichloroacetonitrile (0.35 mL, 3.5 mmol) was
added to EtOH (7 mL) and refluxed for 8 h. After cooling, the product (15a) was filtered and resuspended
in aqueous HCl (0.5 M, 5 mL). The solid was dissolved on heating and the resulting solution was filtered
hot. After cooling, the hydrochloride salt (16a) was filtered and recrystallized from water. Yield 72%; mp
> 300 °C.
1H NMR (300 MHz, DMSO-d6): δ 7.40 (1H, t, J = 7.3 Hz, H-7), 7.48-7.59 (2H, m, H-8, and H-9), 7.98
(1H, s, NH), 8.11 (1H, s, NH), 8.63 (1H, d, J = 7.3 Hz, H-6), 8.63 (2H, br s, NH), 13.83 (1H, s, NH+).
13C NMR (75 MHz, DMSO-d6): δ 111.9 (C-6), 114.0 (C-9), 122.7 (C-7), 124.0 (C-8), 126.6 (C-5a), 129.9
(C-9a), 151.6, 151.9 (C-2 and C-10a), 162.9 (C-4).

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Anal. Calcd for C9H9N6Cl: C, 45.68; H, 3.83; N, 35.51. Found: C, 45.53; H, 4.00; N, 35.28.
6H-[1,3,5]Triazino[2,1-b]quinazolin-2,4-diamine hydrochloride (16b).
3,4-Dihydroquinazolin-2-yl guanidine (3, 0.47 g, 2.5 mmol) and trichloroacetonitrile (0.35 mL, 3.5
mmol) was added to EtOH (7 mL) and refluxed for 8 h. After cooling, the product (15b) was filtered and
resuspended in EtOH (5 mL) and aqueous HCl (1.0 M, 2.5 mL). The solid was dissolved on heating and
the resulting solution was filtered hot. After cooling, the hydrochloride salt (16b) was filtered and
recrystallized from water. Yield 68%; mp > 300 °C.
1H NMR (300 MHz, DMSO-d6): δ 5.12 (2H, s, C(6)H2), 7.04-7.17 (3H, m, H-7, H-8 and H-10), 7.21-7.32
(1H, m, H-9), 7.76 (1H, s, NH), 7.78 (1H, s, NH), 8.38 (1H, br s, NH), 8.49 (1H, br s, NH), 11.21 (1H, s,
NH+).
13C NMR (75 MHz, DMSO-d6): δ 45.3 (C-6), 115.1 (C-10), 116.1 (C-6a), 123.7 (C-8), 125.7 (C-9), 128.7
(C-7), 132.6 (C-10a), 151.4 (C-2), 156.3 (C-4), 163.1 (C-11a).
Anal. Calcd for C10H11N6Cl: C, 47.91; H, 4.42; N, 33.52. Found: C, 47.74; H, 4.56; N, 33.38.
ACKNOWLEDGEMENTS
This work has been supported by the National Medical Research Council, Singapore
(NMRC/NIG/0019/2008 and NMRC/NIG/0020/2008).
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