Practical synthesis of regioisomeric 5(7)-amino-6,7(4,5)-dihydro[1,2,4]triazolo[1,5-a][1,3,5]triazines

Article abstract of DOI:10.1016/j.tet.2007.10.046

A convenient and efficient synthesis of new 5-azapurine derivatives was developed. The regioisomeric 5-amino-6,7-dihydro- and 7-amino-4,5-dihydro[1,2,4]triazolo[1,5-a][1,3,5]triazines were prepared in 3-4 steps from benzhydrazide via complementary and reg

Full text of DOI:10.1016/j.tet.2007.10.046

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Tetrahedron 63 (2007) 12888–12895
Practical synthesis of regioisomeric 5(7)-amino-6,7(4,5)-
dihydro[1,2,4]triazolo[1,5-a][1,3,5]triazines*
b
a
Anton V. Dolzhenko,a, Anna V. Dolzhenko and Wai-Keung Chui
*
aDepartment of Pharmacy, Faculty of Science, National University of Singapore, 18 Science Drive 4, Singapore 117543, Singapore
bPerm State Pharmaceutical Academy, 48 Lenin Street, Perm 614990, Russian Federation
Received 25 July 2007; revised 25 September 2007; accepted 11 October 2007
Available online 13 October 2007
Abstract—A convenient and efficient synthesis of new 5-azapurine derivatives was developed. The regioisomeric 5-amino-6,7-dihydro- and
7-amino-4,5-dihydro[1,2,4]triazolo[1,5-a][1,3,5]triazines were prepared in 3–4 steps from benzhydrazide via complementary and regiospe-
cific routes as a part of our lead finding program. The molecular structures and tautomeric preferences of the compounds obtained were
investigated using NMR spectral data and X-ray crystallography.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
interested in the aza-analogues of the purine system that
carries a bridge nitrogen, particularly the 1,2,4-triazolo[1,5-a]-
[1,3,5]triazines (5-azapurines).1 The 1,2,4-triazolo[1,5-a]-
[1,3,5]triazine derivatives have been shown to possess a
wide range of biological activities.5 However, antifolate
activity of the compounds with this heterocyclic scaffold
has not been investigated.
Dihydrofolate reductase (DHFR) plays an essential role in
cellular biochemistry and has been a well-recognized drug
target for half a century. Antifolate drugs have been devel-
oped as anticancer, antibacterial, antifungal, and antipara-
sitic agents.2 4,6-Diamino-1,2-dihydro-1,3,5-triazines (e.g.,
antimalarial drug cycloguanil and WR 99210) are known
to be potent inhibitors of DHFR.2a,b Recently, dihydro-
1,3,5-triazino[1,2-a]benzimidazoles (1) (Fig. 1) have also
been found to possess antifolate activity.3 Reports on other
examples of fused dihydro-1,3,5-triazine with DHFR inhi-
bitory activity are limited.
There are some common structural features, which are
unique to the triazine antifolates: (1) one of the carbon atoms
of triazine ring should be in sp3 hybridization (gem-dimethyl
substitution is usually preferred); (2) the other two carbon
atoms ought to be connected with nitrogen atoms of amino
group or fused ring; (3) lypophilic aromatic moiety is required
at the distal part of molecule. In this report we describe new
practical synthesis of derivatives of 5-azapurine system, viz.
As a continuation to our investigation on fused 1,3,5-
triazines as potential inhibitors of DHFR,3a,4 we became
R
Cl
Me
N
Me
NH
Me Me
Me Me
Cl
Cl
O
O
R
N
N
N
N
N
NH2
Cl
H2N
N
NH2
N
H2N
N
NH2
1, R = H, Me
Cycloguanil
WR 99210
R1 R2
R1 R2
HN
N
N
N
N
NH
N
N
NH2
N
N
NH2
2
3
Figure 1. Selected antifolate 1,3,5-triazines and the compounds of interest.
*
Part 8 in the series ‘Fused heterocyclic systems with s-triazine ring’, for part 7 see Ref. 1.
Keywords: Hydrazides; 1,2,4-Triazoles; Fused 1,3,5-triazines; Triazolotriazines; 5-Azapurines; Tautomerism.
* Corresponding author. Tel.: +65 6516 2657; fax: +65 6779 1554; e-mail: phada@nus.edu.sg
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.10.046

A. V. Dolzhenko et al. / Tetrahedron 63 (2007) 12888–12895
12889
hitherto unknown regioisomeric 5-amino-6,7-dihydro- and
7-amino-4,5-dihydro[1,2,4]triazolo[1,5-a][1,3,5]triazines
(2 and 3). These compounds contain in the structure pharma-
cophoric fragments (Fig. 1) of the triazine DHFR inhibitors
and potentially may interact with this enzyme.
isolated. The signal of sp3-hybridized carbon atom in 13C
NMR spectra at 62–80 ppm indicated that the triazine ring
closure had occurred. The formation of theoretically possi-
ble regioisomeric structure 10 was excluded based on 2D
NOESY experiments (no cross-peaks were found between
R1 or R2 and phenyl group) and X-ray crystallography of
compound 2h (Fig. 2).6
We designed a 3–4 step synthesis of dihydro[1,2,4]tria-
zolo[1,5-a][1,3,5]triazines 2 and 3 from benzhydrazide (4)
with the subsequent formation of the 1,2,4-triazole and the
1,3,5-triazine rings using simple procedures, inexpensive
and readily available reagents that make this synthetic ap-
proach very practical. The final step that leads to the annula-
tion of the 1,3,5-triazine nucleus, can be successfully achieved
via cyclization of the suitably substituted 1,2,4-triazoles, i.e.,
5-guanidino-3-phenyl-1,2,4-triazole (5) and 5-amino-1-gua-
nyl-3-phenyl-1,2,4-triazole (6) with aldehydes or ketones 7
to generate the libraries for biological screening (Scheme 1).
R1 R2
N
N
NH
Ph
N
N
2
NH2
R1
R2
NH
N
NH
N
i
N
NH
NH2
Ph
N
H
NH2
N
Ph
N
N
N
N
5
9
Ph
N
N
R1
NH2
N
H
R1 R2
NH2
N
R2
N
N
N
N
N
NH
N
10
Ph
R1
R2
Ph
N
NH2
N
H
Scheme 3. Reagents and conditions: (i) 7a–g (1 equiv) or 7i,j (2 equiv),
EtOH, piperidine (0.4 equiv), 3–24 h, reflux (72–96%); for 2h acetone,
piperidine (0.4 equiv), 18 h, reflux (98%).
2
3
R1
R2
Table 1. 5-Amino-6,7-dihydro[1,2,4]triazolo[1,5-a][1,3,5]triazines (2)
O
HN
N
2
R1
R2
Yield (%)
NH2
NH2
NH
7
N
NH
N
a
b
c
d
e
f
g
h
i
H
H
H
H
H
H
H
Me
Ph
92
91
90
73
76
72
78
98
96
72
NH2
Ph
N
H
4-MeO–C6H4
4-Me–C6H4
4-Cl–C6H4
4-F–C6H4
2-Furyl
4-Py
Ph
N
N
5
6
NHNH2
Ph
O
Me
–(CH2)4–
–(CH2)5–
4
j
Scheme 1. Design of the 5(7)-amino-6,7(4,5)-dihydro[1,2,4]triazolo-
[1,5-a][1,3,5]triazines synthesis.
2. Results and discussion
The reactions of benzhydrazide (4) with cyanoguanidine in
the presence of hydrochloric acid gave N-benzamidobigua-
nide (8) (Scheme 2). The treatment of N-benzamidobigua-
nide (8) with aqueous alkali resulted in 1,2,4-triazole ring
closure and provided 5-guanidino-1,2,4-triazole 5.
The heating of 5-guanidino-1,2,4-triazole 5 with carbonyl
compounds 7 in ethanol in the presence of piperidine gave
5-amino-6,7-dihydro[1,2,4]triazolo[1,5-a][1,3,5]triazines 2
(Scheme 3, Table 1). This heterocyclization was found to
proceed smoothly with a variety of aldehydes and ketones.
The reaction was regioselective and afforded only the prod-
ucts of the ring closure to nitrogen atom N-1 of the triazole 5;
the products of the ring closure to nitrogen atom N-4 (com-
pounds 10) as well as possible intermediates 9 were not
Figure 2. X-ray crystal structure of 2h.
The synthesis of the regioisomeric 7-amino-4,5-dihydro-
[1,2,4]triazolo[1,5-a][1,3,5]triazines (3) was also initiated
from benzhydrazide (4). The reactions of 4 with S-methyl iso-
thiourea gave N0-benzamidoguanidine (11) (Scheme 4). The
NH2
HN
N
NH
HN NH2
H2N
NH
HN
O
N
NH
i
ii
Ph
NH
Ph
NH
NH2
+
Ph
N
H
HCl
N
O
N
NH2
4
8
5
Scheme 2. Reagents and conditions: (i) cyanoguanidine (1.1 equiv), HCl (1 equiv), EtOH, 4 h, reflux (80%); (ii) 10% NaOH, 6 h, 80 ꢀC (68%).

12890
A. V. Dolzhenko et al. / Tetrahedron 63 (2007) 12888–12895
HN NH2
HN
O
N
N NH
HN
N
i
ii
Ph
Ph
NH2
Ph
NH2
Ph
NH2
N
N
O
4
NH2
11
12
12'
+
N
N
SMe
NH2
1
Ph
NH2
/
H2SO4
2
N
HN
HN NH
H
12''
Ph
NH2
O
NH
11'
Scheme 4. Reagents and conditions: (i) S-methylisothiouronium sulfate (0.5 equiv), NaOH (1 equiv), H2O, 72 h, rt, 3 h, 50 ꢀC (86%); (ii) H2O, 4 h, reflux
(97%).
1
Table 2. 7-Amino-4,5-dihydro[1,2,4]triazolo[1,5-a][1,3,5]triazines (3)
two signals of NH2 groups in H NMR spectra of the com-
pound 11 indicated that tautomeric form 11, ratherz than
3
R1
R2
Yield (%)
form 110, was preferred in DMSO solution ðDG316
¼
a
b
c
d
e
f
g
h
i
H
H
H
H
H
H
H
Me
Ph
78
87
72
70
78
70
68
65
62
73
67:6 kJÞ. N-Benzamidoguanidine (11) was found to be stable:
it could be recrystallized from water or aqueous ethanol and
no changes were observed after drying at 140 ꢀC under
vacuum for 24 h.
4-MeO–C6H4
4-Me–C6H4
4-Cl–C6H4
4-F–C6H4
2-Furyl
4-Py
In general, N-benzamidoguanidine (11) could be cyclized to
aminotriazoles with elimination of water molecule. The
reported methods7 required heating of 11 to above its mp
(220 ꢀC) or refluxing with sodium ethoxide. We found that
the ring closure could be achieved easier and with higher
yield. When N-benzamidoguanidine (11) was heated in wa-
ter, the triazole 12 was obtained in almost quantitative yield
(Scheme 4). The reaction was found to be clean and afforded
Me
–(CH2)4–
–(CH2)5–
j
J value was small and not always detectable, 2D NOESY
experiments clearly indicated that NH proton located in the
vicinity of sp3-hybridized carbon. The same tautomeric
preferences were found in solid state as confirmed by
X-ray crystallography of 2h and 3h (Figs. 2 and 3).1,6 Inter-
estingly, two almost identical individual molecules with the
intermediate between a twist boat and a half-boat conforma-
tion were identified for compound 3h in the crystal (Fig. 3).
1
12 with excellent purity. H NMR spectroscopy studies of
the 1,2,4-triazoles 12 in DMSO solution concluded that 5-
amino-3-phenyl-1,2,4-triazole (12) was predominant in the
equilibrium, while 3-amino-5-phenyl-1,2,4-triazole (120) was
found to exist in minor proportion (KT¼8.2, DG298
¼
ꢁ5.2 kJ molꢁ1), whereas the 4H-form 1200 was not detected.
3. Conclusion
Benzotriazole has been shown to be a very effective auxi-
liary8 and we attempted to apply 1-guanylbenzotriazole hy-
drochloride9 as a guanylating agent10 in the reaction with
12. It was found that the guanylbenzotriazole selectively at-
tacked endocyclic nitrogen N-1 of the triazole 12 affording
6 as hydrochloride, which was converted to the base using so-
dium carbonate. The target 7-amino-4,5-dihydro[1,2,4]tri-
azolo[1,5-a][1,3,5]triazines (3) were prepared in good yields
via (5+1) heterocyclization of 6 using aldehydes or ketones
7 as one-carbon inserting reagents (Scheme 5, Table 2).
In summary, the synthesis of 1,2,4-triazolo[1,5-a][1,3,5]tri-
azines with potential antifolate activity was successfully
developed and their structures were investigated. The prep-
aration method is practical: it required simple and easily
available starting materials and provided derivatives of the
interesting 5-azapurine system in 3–4 steps starting from
benzhydrazide.
4. Experimental section
4.1. General
Both 5-amino-6,7-dihydro- and 7-amino-5,6-dihydro[1,2,4]-
triazolo[1,5-a][1,3,5]triazines (2 and 3) might be involved in
the annular tautomerism (Scheme 6). However, the indicated
forms were found to be predominant. The coupling of proton
at sp3-hybridized carbon and NH proton in 1H NMR spectra
was observed for several compounds (J¼0–1.5 Hz). Despite
Melting points (uncorrected) were determined on a Gallen-
kamp melting point apparatus. Analytical TLC were carried
out on aluminum plates coated with Silica gel 60 F254
HN
HN
NH2
NH2
NH2
NH2
N
N
N
NH
N N
N
N
i, ii
iii
N
N
R1
R2
Ph
N
HCl
+
Ph
NH2
Ph
N
N
N
H
3
12
6
Scheme 5. Reagents and conditions: (i) guanylbenzotriazole hydrochloride (1 equiv), EtOH, 30 min, reflux 62%; (ii) 10% Na2CO3, 25 ꢀC (92%); (iii) 7a–g
(1 equiv) or 7i,j (2 equiv), EtOH, piperidine (0.4 equiv), 2–15 h, reflux (62–87%); for 3h acetone, piperidine (0.4 equiv), 12 h, reflux (65%).

A. V. Dolzhenko et al. / Tetrahedron 63 (2007) 12888–12895
12891
NOE
NH2
N
R1 R2
N
N
R1 = H, 3J = 0-1.5 Hz
N
N
N
R1
R2
N
NH
Ph
Ph
N
H
N
2
NH2
3
NOE
R1 R2
R1 R2
NH2
N
NH2
N
H
N
N
N
N
N
N
N
N
N
N
N
Ph
Ph
R1
R2
R1
R2
Ph
Ph
N
H
N
H
NH2
N
NH2
N
H
N
N
N
R1 R2
H
N
N
N
N
Ph
N
NH2
Scheme 6. Tautomerism in 5(7)-amino-6,7(4,5)-dihydro[1,2,4]triazolo[1,5-a][1,3,5]triazines.
(4.62 g, 55 mmol) were added. The reaction mixture was
heated under reflux with stirring for 4 h. After cooling on
ice,theproductwasfiltered, washedwithcoldEtOH,anddried
to give white powder. White crystalline powder; yield
1
80%; mp 172–173 ꢀC (EtOH) [lit.11 mp 169–170 ꢀC]. H
NMR (300 MHz, DMSO-d6): d 7.10 (br s, 4H, NH–
C(]NH)NH2), 7.51 (t, 2H, J¼7.3 Hz, H-3 and H-5), 7.60
3
3
(t, 1H, J¼7.2 Hz, H-4), 7.67 (br s, 2H, NH2), 7.97 (d, 2H,
3J¼7.2 Hz, H-2 and H-6), 9.37 (br s, 1H, NH), 10.74 (br s,
1H, CONH).
4.3. N-(3-Phenyl-1H-1,2,4-triazol-5-yl)guanidine (9)12
N-Benzamidobiguanide hydrochloride (8, 5.13 g, 20 mmol)
was heated at 80 ꢀC in 10% aqueous sodium hydroxide solu-
tion (10 ml) for 6 h. After cooling, the product was filtered,
washed with cold water, and dried. White crystalline powder;
yield 68%; mp 242–243 ꢀC [lit.12 mp 244–246 ꢀC]. TLC (sil-
1
ica gel, EtOH): Rf 0.16. H NMR (300 MHz, DMSO-d6):
d 6.58 (br s, 4H, NH–C(]NH)NH2), 7.33 (t, 1H,
3
3J¼7.1 Hz, H-40), 7.41 (t, 2H, J¼7.1 Hz, H-30 and H-50),
3
7.96 (d, 2H, J¼7.1 Hz, H-20 and H-60), 12.40 (br s, 1H,
NH). 13C NMR (75 MHz, DMSO-d6): d 125.2 (2C), 128.0,
128.3 (2C), 139.2, 157.0, 157.7, 160.5.
Figure 3. X-ray crystal structure of 3h.
4.4. N-Benzamidoguanidine (11)7
(Merck) with detection by UV light. Mass spectra were ob-
tained on a Finnigan MAT LCQ LC–MS mass spectrometer
using atmospheric pressure chemical ionization (APCI)
mode. IR spectra were recorded in KBr pellets using a Shi-
The mixture of benzhydrazide (1, 13.6 g, 100 mmol) and S-
methylisothiouronium sulfate (13.9 g, 50 mmol) in 1%
aqueous sodium hydroxide solution (400 ml) was stirred at
rt for 72 h and then heated to 50 ꢀC for another 3 h. After
cooling, the precipitated product was filtered, washed with
ice-cold water, and dried. White powder; yield 86%; mp
1
madzu IRPrestige-21 FTIR spectrophotometer. H and 13C
NMR spectra were recorded on a Bruker DPX-300 spec-
trometer using DMSO-d6 as a solvent and TMS as an inter-
nal reference. The energy of activation (DGz) for the
equilibrium between 11 and 110 was estimated at the temper-
1
176 ꢀC [lit.7 mp 184 ꢀC]. H NMR (300 MHz, DMSO-d6):
d 6.97 (br s, 2H, NH2), 7.16 (br s, 2H, NH2), 7.23–7.35
(m, 3H, H-3, H-4 and H-5), 7.89–8.01 (m, 2H, H-2 and
H-6), 11.01 (br s, 1H, NH). 13C NMR (75 MHz, DMSO-d6):
d 126.5 (2C), 127.3 (2C), 128.0, 138.5, 152.9, 160.5.
1
ature of coalescence using dynamic H NMR experiments
(0.1 M solution in DMSO-d6). The tautomeric preferences
for 12 were investigated using 1H NMR spectral data
(0.1 M solution in DMSO-d6 at 27 ꢀC).
4.5. 3(5)-Phenyl-1,2,4-triazol-5(3)-amine (12)13
4.2. N-Benzamidobiguanide hydrochloride (8)11
N-Benzamidoguanidine (11, 8.90 g, 50 mmol) was heated
under reflux in 80 ml of water for 4 h. After cooling, the pre-
cipitated amino-1,2,4-triazole 12 was filtered, washed with
Tothesolutionofbenzhydrazide(1, 6.80 g, 50 mmol)inEtOH
(35 ml), concd HCl (5 ml, 50 mmol) and cyanoguanidine

12892
A. V. Dolzhenko et al. / Tetrahedron 63 (2007) 12888–12895
ice-cold water, and dried. Colorless crystals; yield 97%; mp
186–187 ꢀC [lit.13 mp 186–187 ꢀC]. TLC (silica gel, EtOH):
Rf 0.59. H NMR (300 MHz, DMSO-d6): d 5.29* and 6.05
(7–10 ml) was heated under reflux for 3–18 h. After cooling,
the product was filtered, washed with cold EtOH, dried, and
recrystallized from EtOH, DMF or their mixture.
1
(two br s, 2H, NH2), 7.32 (t, 1H, 3J¼7.2 Hz, H-40), 7.39 (t,
3
3
2H, J¼7.2 Hz, H-30 and H-50), 7.89 (d, 2H, J¼6.8 Hz,
H-20 and H-60), 12.04 and 13.20* (two br s, 1H, NH). 13C
NMR (75 MHz, DMSO-d6): d 125.2 (2C), 128.0, 128.2
(2C), 132.3, 157.2, 158.3. *, Signals of the minor tautomeric
form.
4.9.1. 2,7-Diphenyl-6,7-dihydro[1,2,4]triazolo[1,5-a]-
[1,3,5]triazin-5-amine (2a). White crystalline powder;
yield 92%; mp 300–301 ꢀC. TLC (silica gel, EtOH): Rf
0.57. LC–MS (APCI) m/z 291 (MH+). Anal. Calcd for
C16H14N6: C, 66.19; H, 4.86; N, 28.95. Found: C, 66.02;
H, 4.95; N, 28.73%. IR (KBr): n 3461, 3311, 3237, 3135,
1653, 1646, 1597, 1548, 1522 (m), 1474, 1460, 1444,
4.6. 1-Guanylbenzotriazole hydrochloride14
1434, 1411, 1371, 764, 747, 713, 691 cmꢁ1 1H NMR
.
To the stirred mixture of benzotriazole (8.9 g, 75 mmol) and
cyanamide (6.3 g, 150 mmol) at 100 ꢀC, concd HCl (8.5 ml,
85 mmol) was added. After initial vigorous reaction, the
mixture was heated for 15 min at 100 ꢀC. Then, 1 M HCl
(12 ml) was added. After cooling, the precipitated 1-guanyl-
benzotriazole hydrochloride was filtered, washed with ice-
cold 1 M HCl, and dried. White powder; yield 68%; mp
(300 MHz, DMSO-d6): d 6.42 (s, 2H, NH2), 6.69 (s, 1H,
H-7), 7.29–7.47 (m, 8H, H-30, H-40, H-50 and 5-Ph), 7.86
3
4
(dd, 2H, J¼7.9, J¼1.5 Hz, H-20 and H-60), 7.93 (d, 1H,
3J¼1.5 Hz, NH). 13C NMR (75 MHz, DMSO-d6): d 68.3,
125.3 (2C), 126.2 (2C), 128.3 (2C), 128.4, 128.7 (2C),
129.0, 131.7, 140.4, 155.5, 156.4, 159.2.
1
194–196 ꢀC [lit.14 mp 195–197 ꢀC]. H NMR (300 MHz,
4.9.2. 7-(4-Methoxylphenyl)-2-phenyl-6,7-dihydro-
[1,2,4]triazolo[1,5-a][1,3,5]triazin-5-amine (2b). White
crystalline powder; yield 91%; mp 291 ꢀC. TLC (silica
gel, EtOH): Rf 0.54. LC–MS (APCI) m/z 321 (MH+). Anal.
Calcd for C17H16N6O: C, 63.74; H, 5.03; N, 4.99. Found:
C, 63.70; H, 5.12; N, 4.91%. IR (KBr): n 3451, 3309,
3227, 3110, 1653, 1647, 1594, 1523 (m), 1477, 1435,
3
DMSO-d6): d 7.67 (t, 1H, J¼7.7 Hz, H-3), 7.87 (t, 1H,
3
3J¼7.7 Hz, H-5), 8.08 (d, 1H, J¼8.3 Hz, H-4), 8.32 (d,
3
1H, J¼8.3 Hz, H-7), 10.23 (s, 4H, C(]NH)NH2$HCl).
13C NMR (75 MHz, DMSO-d6): d 112.8, 120.2, 126.5,
130.4, 130.5, 145.6, 152.1.
1
4.7. 1-Guanyl-3-phenyl-1,2,4-triazol-5-amine hydro-
chloride (6$HCl)9b
1409, 1369, 1254, 1178, 815, 746, 688 cmꢁ1. H NMR
(300 MHz, DMSO-d6): d 3.75 (s, 3H, OMe), 6.39 (s, 2H,
NH2), 6.63 (d, 1H, 3J¼0.8 Hz, H-7), 6.97 (d, 2H,
3
To the solution of 3(5)-phenyl-1,2,4-triazol-5(3)-amine (12,
6.80 g, 40 mmol) in EtOH (35 ml), 1-guanylbenzotriazole
hydrochloride (7.88 g, 40 mmol) was added. The reaction
mixture was heated under reflux with stirring for 30 min. Af-
ter cooling, the product was filtered, washed with cold
EtOH, and dried. White crystalline powder; yield 62%; mp
3J¼8.7 Hz, H-300 and H-500), 7.28 (d, 2H, J¼8.7 Hz, H-200
3
and H-600), 7.35 (t, 2H, J¼7.5 Hz, H-30 and H-50), 7.37 (t,
3
3
1H, J¼7.5 Hz, H-40), 7.86 (d, 2H, J¼7.5 Hz, H-20 and
H-60), 7.87 (s, 1H, NH). 13C NMR (75 MHz, DMSO-d6):
d 55.1, 68.0, 114.0 (2C), 125.3 (2C), 127.6 (2C), 128.3
(2C), 128.4, 131.8, 132.5, 155.5, 156.3, 159.1, 159.7.
1
212 ꢀC [lit.9b mp 210 ꢀC]. H NMR (300 MHz, DMSO-
d6): d 7.46–7.56 (m, 3H, H-30, H-40 and H-50), 7.71 (s, 2H,
4.9.3. 7-(4-Methylphenyl)-2-phenyl-6,7-dihydro[1,2,4]-
triazolo[1,5-a][1,3,5]triazin-5-amine (2c). White crystal-
line powder; yield 90%; mp 281 ꢀC. TLC (silica gel,
EtOH): Rf 0.57. LC–MS (APCI) m/z 305 (MH+). Anal. Calcd
for C17H16N6: C, 67.09; H, 5.30; N, 27.61. Found: C, 66.92;
H, 5.34; N, 27.55%. IR (KBr): n 3462, 3311, 3231, 3111,
1652, 1648, 1599, 1522 (m), 1477, 1444, 1435, 1409,
3
4
NH2), 8.00 (dd, 2H, J¼6.4, J¼3.0 Hz, H-20 and H-60),
9.47 (s, 4H, C(]NH)NH2$HCl). 13C NMR (75 MHz,
DMSO-d6): d 126.4 (2C), 128.7 (2C), 129.4, 130.3, 151.9,
157.0, 160.8.
4.8. 1-Guanyl-3-phenyl-1,2,4-triazol-5-amine (6)9b
1
1365, 805, 745, 689 cmꢁ1. H NMR (300 MHz, DMSO-
The sodium carbonate solution (10%, 30 ml) was added to
the solution of 1-guanyl-3-phenyl-1,2,4-triazol-5-amine hy-
drochloride (6$HCl, 5.95 g, 25 mmol) in water (15 ml). Af-
ter cooling, the product was filtered, washed with cold water,
and dried. White powder; yield 92%; mp 168 ꢀC [lit.9b mp
165 ꢀC]. TLC (silica gel, EtOH): Rf 0.59. 1H NMR
(300 MHz, DMSO-d6): d 6.36 (s, 1H, NH), 6.54 (s, 2H,
NH2), 7.37–7.53 (m, 3H, H-30, H-40 and H-50), 7.88 (s, 2H,
d6): d 2.29 (s, 3H, Me), 6.40 (s, 2H, NH2), 6.65 (d, 1H, 3J¼
1.5 Hz, H-7), 7.20–7.25 (m, 4H, H-200, H-300, H-500 and
H-600), 7.32–7.41 (m, 3H, H-30, H-40 and H-50), 7.86 (dd,
3
4
3
2H, J¼8.1, J¼1.7 Hz, H-20 and H-60), 7.89 (d, 1H, J¼
1.5 Hz, NH). 13C NMR (75 MHz, DMSO-d6): d 20.7, 68.2,
125.3 (2C), 126.2 (2C), 128.3 (2C), 128.4, 129.2 (2C),
131.8, 137.6, 138.5, 155.5, 156.3, 159.1.
3
4
NH2), 7.98 (dd, 2H, J¼7.3, J¼1.7 Hz, H-20 and H-60).
13C NMR (75 MHz, DMSO-d6): d 125.9 (2C), 128.4 (2C),
129.2, 130.7, 152.7, 156.6, 156.8.
4.9.4. 7-(4-Chlorophenyl)-2-phenyl-6,7-dihydro[1,2,4]-
triazolo[1,5-a][1,3,5]triazin-5-amine (2d). White crystal-
line powder; yield 73%; mp 290 ꢀC. TLC (silica gel,
EtOH): Rf 0.56. LC–MS (APCI) m/z 325, 327 (MH+).
Anal. Calcd for C16H13ClN6: C, 59.17; H, 4.03; N, 25.88.
Found: C, 59.02; H, 4.19; N, 25.73%. IR (KBr): n 3446,
3309, 3237, 3111, 1653, 1647, 1595, 1525 (m), 1472,
4.9. General method for preparation of 7-(het)aryl-2-
phenyl-6,7-dihydro[1,2,4]triazolo[1,5-a][1,3,5]triazin-5-
amines (2a–g)
1433, 1396, 1363, 745, 689 cmꢁ1 1H NMR (300 MHz,
.
The solution of N-(3-phenyl-1H-1,2,4-triazol-5-yl)guani-
dine (5, 0.50 g, 2.5 mmol), appropriate aldehyde (7a–g,
2.5 mmol), and piperidine (0.10 ml, 1.0 mmol) in EtOH
DMSO-d6): d 6.48 (s, 2H, NH2), 6.74 (s, 1H, H-7), 7.29–
7.44 (m, 5H, H-200, H-600, H-30, H-40 and H-50), 7.51 (d,
3
3
2H, J¼8.3 Hz, H-300 and H-500), 7.87 (d, 2H, J¼7.5 Hz,

A. V. Dolzhenko et al. / Tetrahedron 63 (2007) 12888–12895
12893
H-20 and H-60), 7.97 (s, 1H, NH). 13C NMR (75 MHz,
DMSO-d6): d 67.6, 125.4 (2C), 128.2 (2C), 128.3 (2C),
128.5, 128.8 (2C), 131.7, 133.6, 139.3, 155.4, 156.4, 159.4.
1651, 1616, 1559, 1528 (m), 1476, 1460, 1444, 1420,
1362, 1172, 748, 699, 691, 476 cmꢁ1. 1H NMR (300 MHz,
DMSO-d6): d 1.64 (s, 6H, Me2), 6.21 (s, 2H, NH2), 7.36–
7.40 (m, 3H, H-30, H-40 and H-50), 7.58 (s, 1H, NH), 7.92
4
4.9.5. 7-(4-Fluorophenyl)-2-phenyl-6,7-dihydro[1,2,4]-
triazolo[1,5-a][1,3,5]triazin-5-amine (2e). White crystal-
line powder; yield 76%; mp 280–281 ꢀC. TLC (silica gel,
EtOH): Rf 0.56. LC–MS (APCI) m/z 309 (MH+). Anal. Calcd
for C16H13FN6: C, 62.33; H, 4.25; N, 27.26. Found: C,
62.21; H, 4.34; N, 27.19%. IR (KBr): n 3469, 3310, 3236,
3112, 1653, 1647, 1601, 1524 (m), 1476, 1436, 1409,
(dd, 2H, 3J¼8.3, J¼1.5 Hz, H-20 and H-60). 13C NMR
(75 MHz, DMSO-d6): d 28.7 (2C), 70.1, 125.3 (2C), 128.3
(3C), 132.1, 155.5, 155.8, 158.7.
4.10. General method for preparation of the spiro
derivatives of 2-phenyl-6,7-dihydro[1,2,4]triazolo-
[1,5-a][1,3,5]triazin-5-amines (2i,j)
1363, 1239, 821, 746, 688 cmꢁ1 1H NMR (300 MHz,
.
DMSO-d6): d 6.45 (s, 2H, NH2), 6.73 (s, 1H, H-7), 7.27
The solution of N-(3-phenyl-1H-1,2,4-triazol-5-yl)guani-
dine (9, 0.50 g, 2.5 mmol), appropriate cyclic ketone (7i,j,
5.0 mmol), and piperidine (0.10 ml, 1.0 mmol) in EtOH
(8 ml) was heated under reflux for 16–24 h. After cooling,
the product was filtered, washed with cold EtOH, dried,
and recrystallized from EtOH/DMF.
3
3
(dd, 2H, JHF¼8.9, J¼8.9 Hz, H-300 and H-500), 7.32–7.47
(m, 5H, H-30, H-40, H-50, H-200 and H-600), 7.86 (d, 2H, 3J¼
3
7.5 Hz, H-20 and H-60), 7.94 (d, 1H, J¼1.5 Hz, NH). 13C
NMR (75 MHz, DMSO-d6): d 67.6, 115.6 (d, 2JCF¼21.8 Hz,
2C), 125.4 (2C), 128.3 (2C), 128.5, 127.5 (d, 3JCF¼8.8 Hz,
4
2C), 131.7, 136.7 (d, JCF¼2.9 Hz), 155.5, 156.4, 159.4,
162.3 (d, 1JCF¼245.2 Hz).
4.10.1. 20-Phenyl-60H-spiro[cyclopentane-1,70-[1,2,4]tri-
azolo[1,5-a][1,3,5]triazin]-50-amine (2i). White crystalline
powder; yield 96%; mp 300 ꢀC. TLC (silica gel, EtOH): Rf
0.54. LC–MS (APCI) m/z 269 (MH+). Anal. Calcd for
C14H16N6: C, 62.67; H, 6.01; N, 31.32. Found: C, 62.46;
H, 6.17; N, 31.19%. IR (KBr): n 3471, 3280, 3204, 3123,
2962, 1653, 1635, 1630, 1598, 1523 (m), 1473, 1435,
4.9.6. 7-(2-Furyl)-2-phenyl-6,7-dihydro[1,2,4]triazolo-
[1,5-a][1,3,5]triazin-5-amine (2f). Beige crystalline pow-
der; yield 72%; mp 272 ꢀC. TLC (silica gel, EtOH): Rf
0.56. LC–MS (APCI) m/z 281 (MH+). Anal. Calcd for
C14H12N6O: C, 59.99; H, 4.32; N, 29.98. Found: C, 59.78;
H, 4.43; N, 29.89%. IR (KBr): n 3472, 3448, 3313, 3232,
3105, 1655, 1651, 1603, 1523 (m), 1477, 1436, 1395,
1
1419, 1362, 753, 703 cmꢁ1. H NMR (300 MHz, DMSO-
d6): d 1.71–1.97 (m, 6H, (CH2)2, H-2a and H-5a), 2.21–
2.37 (m, 2H, H-2e and H-5e), 6.20 (s, 2H, NH2), 7.34 (t,
1
1364, 830, 750, 693 cmꢁ1. H NMR (300 MHz, DMSO-
3
3
3
3
d6): d 6.45 (s, 2H, NH2), 6.47 (dd, 1H, J¼3.1, J¼1.7 Hz,
1H, J¼7.0 Hz, H-40), 7.46 (t, 2H, J¼7.2 Hz, H-30 and
3
3
H-400), 6.54 (d, 1H, J¼3.1 Hz, H-300), 6.81 (s, 1H, H-7),
H-50), 7.73 (s, 1H, NH), 7.92 (d, 2H, J¼7.2 Hz, H-20 and
7.30–7.45 (m, 3H, H-30, H-40 and H-50), 7.68 (d, 1H,
H-60). 13C NMR (75 MHz, DMSO-d6): d 23.0 (2C), 39.6
(2C), 79.6, 125.3 (2C), 128.3 (3C), 132.0, 155.5, 156.2,
158.7.
3
4
3J¼1.7 Hz, H-500), 7.88 (dd, 2H, J¼7.5, J¼1.5 Hz, H-20
and H-60), 7.92 (s, 1H, NH). 13C NMR (75 MHz, DMSO-
d6): d 62.2, 108.7, 110.5, 125.4 (2C), 128.3 (2C), 128.5,
131.7, 143.8, 151.5, 155.5, 156.3, 159.3.
4.10.2. 20-Phenyl-60H-spiro[cyclohexane-1,70-[1,2,4]tri-
azolo[1,5-a][1,3,5]triazin]-50-amine (2j). White crystalline
powder; yield 72%; mp 283 ꢀC. TLC (silica gel, EtOH): Rf
0.58. LC–MS (APCI) m/z 283 (MH+). Anal. Calcd for
C15H18N6: C, 63.81; H, 6.43; N, 29.77. Found: C, 63.72; H,
6.65; N, 29.58%. IR (KBr): n 3463, 3363, 3309, 3134,
2933, 1653, 1647, 1636, 1587, 1558, 1534, 1521 (m), 1473,
4.9.7. 2-Phenyl-7-(4-pyridyl)-6,7-dihydro[1,2,4]triazolo-
[1,5-a][1,3,5]triazin-5-amine (2g). Yellowish crystalline
powder; yield 78%; mp 242–244 ꢀC. TLC (silica gel,
EtOH): Rf 0.30. LC–MS (APCI) m/z 292 (MH+). Anal. Calcd
for C15H13N7: C, 61.84; H, 4.50; N, 33.66. Found: C, 61.63;
H, 4.62; N, 33.50%. IR (KBr): n 3447, 3324, 3107, 3079,
1653, 1647, 1624, 1606, 1521 (m), 1437, 1420, 1362,
.
1444, 1409, 1356, 753, 710, 693 cmꢁ1 1H NMR
(300 MHz, DMSO-d6): d 1.22–1.71 (m, 8H, (CH2)3, H-2a
and H-6a), 2.00–2.18 (m, 2H, H-2e and H-6e), 6.28 (s, 2H,
NH2), 7.30–7.45 (m, 3H, H-30, H-40 and H-50), 7.45 (s, 1H,
1295, 741, 685 cmꢁ1 1H NMR (300 MHz, DMSO-d6):
.
d 6.56 (s, 2H, NH2), 6.77 (s, 1H, H-7), 7.23–7.48 (m, 5H,
3
3
4
H-200, H-600, H-30, H-40 and H-50), 7.89 (d, 2H, J¼7.5 Hz,
NH), 7.92 (dd, 2H, J¼8.0, J¼1.5 Hz, H-20 and H-60). 13C
NMR (75 MHz, DMSO-d6): d 20.8 (2C), 24.0, 36.4 (2C),
71.2, 125.3 (2C), 128.3 (3C), 132.1, 155.5, 155.8, 158.5.
3
H-20 and H-60), 8.06 (s, 1H, NH), 8.64 (d, 2H, J¼5.3 Hz,
H-300 and H-500). 13C NMR (75 MHz, DMSO-d6): d 67.0,
120.9 (2C), 125.4 (2C), 128.3 (2C), 128.6, 131.6, 148.2,
150.2 (2C), 155.5, 156.4, 159.6.
4.11. General method for preparation of 5-(het)aryl-2-
phenyl-4,5-dihydro[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-
amines (3a–g)
4.9.8. 7,7-Dimethyl-2-phenyl-6,7-dihydro[1,2,4]triazolo-
[1,5-a][1,3,5]triazin-5-amine (2h). The mixture of N-(3-
phenyl-1H-1,2,4-triazol-5-yl)guanidine (5, 0.50 g, 2.5 mmol)
and piperidine (0.10 ml, 1.0 mmol) in acetone (7 ml) was
heated under reflux for 18 h. After cooling, the precipitated
product was filtered, washed with acetone, dried, and recrys-
tallized from EtOH. White crystalline powder; yield 98%;
mp 294 ꢀC. TLC (silica gel, EtOH): Rf 0.50. LC–MS
(APCI) m/z 243 (MH+). Anal. Calcd for C12H14N6: C,
59.49; H, 5.82; N, 34.69. Found: C, 59.45; H, 5.86; N,
34.64%. IR (KBr): n 3473, 3308, 3230, 3055, 2977, 1654,
The solution of 1-guanyl-3-phenyl-1,2,4-triazol-5-amine (6,
0.50 g, 2.5 mmol), appropriate aldehyde (7a–g, 2.5 mmol),
and piperidine (0.10 ml, 1.0 mmol) in EtOH (7–10 ml) was
heated under reflux for 2–12 h. After cooling, the product
was filtered, washed with cold EtOH, dried, and recrystal-
lized from EtOH, DMF or their mixture.
4.11.1. 2,5-Diphenyl-4,5-dihydro[1,2,4]triazolo[1,5-a]-
[1,3,5]triazin-7-amine (3a). White crystalline powder;

12894
A. V. Dolzhenko et al. / Tetrahedron 63 (2007) 12888–12895
yield 78%; mp 204–205 ꢀC. TLC (silica gel, EtOH): Rf 0.62.
LC–MS (APCI) m/z 291 (MH+). Anal. Calcd for C16H14N6:
C, 66.19; H, 4.86; N, 28.95. Found: C, 66.05; H, 5.07; N,
28.73%. IR (KBr): n 3437, 3231, 3133, 1706, 1697, 1626,
EtOH): Rf 0.63. LC–MS (APCI) m/z 309 (MH+). Anal. Calcd
for C16H13FN6: C, 62.33; H, 4.25; N, 27.26. Found: C,
62.02; H, 4.47; N, 27.11%. IR (KBr): n 3441, 3225, 3134,
1706, 1697, 1627, 1601, 1532, 1507, 1496, 1449, 1436,
1531, 1495, 1450, 1434, 1340, 1026, 730, 701, 685 cmꢁ1
.
1340, 1227, 1034, 771, 736, 687 cmꢁ1 1H NMR
.
1H NMR (300 MHz, DMSO-d6): d 5.91 (s, 1H, H-5), 6.60
(s, 2H, NH2), 7.25–7.53 (m, 8H, H-30, H-40, H-50 and 5-
Ph), 8.00 (dd, 2H, 3J¼7.3, 4J¼2.4 Hz, H-20 and H-60), 8.68
(s, 1H, NH). 13C NMR (75 MHz, DMSO-d6): d 68.2,
126.2 (2C), 126.3 (2C), 127.7, 128.1 (2C), 128.5 (2C),
129.6, 130.5, 142.9, 143.4, 156.1, 159.8.
(300 MHz, DMSO-d6): d 5.93 (s, 1H, H-5), 6.63 (s, 2H,
3
3
NH2), 7.20 (dd, 2H, JHF¼8.9, J¼8.9 Hz, H-300 and H-500)
7.43–7.54 (m, 5H, H-30, H-40, H-50, H-200 and H-600), 8.00
3
4
(dd, 2H, J¼7.3, J¼2.4 Hz, H-20 and H-60), 8.68 (s, 1H,
NH). 13C NMR (75 MHz, DMSO-d6): d 67.6, 114.9 (d,
3
2JCF¼21.8 Hz, 2C), 126.2 (2C), 128.4 (d, JCF¼8.2 Hz,
4
2C), 128.5 (2C), 129.6, 130.5, 139.1 (d, JCF¼2.9 Hz),
4.11.2. 5-(4-Methoxyphenyl)-2-phenyl-4,5-dihydro-
[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-amine (3b). White
crystalline powder; yield 87%; mp 212 ꢀC. TLC (silica
gel, EtOH): Rf 0.55. LC–MS (APCI) m/z 321 (MH+). Anal.
Calcd for C17H16N6O: C, 63.74; H, 5.03; N, 4.99. Found:
C, 63.60; H, 5.23; N, 4.81%. IR (KBr): n 3439, 3231,
3126, 1706, 1697, 1624, 1534, 1511, 1499, 1451, 1437,
143.6, 156.1, 159.9, 161.6 (d, 1JCF¼243.4 Hz).
4.11.6. 5-Furyl-2-phenyl-4,5-dihydro[1,2,4]triazolo[1,5-a]-
[1,3,5]triazin-7-amine (3f). Beige crystalline powder; yield
70%; mp 210 ꢀC. TLC (silica gel, EtOH): Rf 0.62. LC–MS
(APCI) m/z 281 (MH+). Anal. Calcd for C14H12N6O: C,
59.99; H, 4.32; N, 29.98. Found: C, 59.83; H, 4.46; N,
29.84%. IR (KBr): n 3305, 3240, 3159, 1702, 1698, 1637,
1343, 1252, 1036, 737, 690 cmꢁ1 1H NMR (300 MHz,
.
1
DMSO-d6): d 3.74 (s, 3H, OMe), 5.84 (s, 1H, H-5), 6.54
1529, 1457, 1438, 1342, 1233, 1015, 755 cmꢁ1. H NMR
3
3
(s, 2H, NH2), 6.92 (d, 2H, J¼8.7 Hz, H-300 and H-500),
(300 MHz, DMSO-d6): d 5.94 (d, 1H, J¼1.1 Hz, H-5),
3
3
7.37 (d, 2H, J¼8.7 Hz, H-200 and H-600), 7.42–7.52 (m,
6.29 (d, 1H, J¼3.0 Hz, H-500), 6.40 (dd, 1H, 3J¼3.0,
3H, H-30, H-40 and H-50), 7.98 (dd, 2H, 3J¼7.2, 4J¼
2.3 Hz, H-20 and H-60), 8.58 (s, 1H, NH). 13C NMR
(75 MHz, DMSO-d6): d 55.0, 67.8, 113.4 (2C), 126.2 (2C),
127.5 (2C), 128.5 (2C), 129.6, 130.5, 135.0, 143.4, 156.1,
158.7, 159.8.
3J¼1.8 Hz, H-400), 6.63 (s, 2H, NH2), 7.41–7.52 (m, 3H,
3
H-0, H-40 and H-50), 7.59 (d, 1H, J¼1.8 Hz, H-300), 7.99
3
4
(dd, 2H, J¼7.3, J¼2.4 Hz, H-20 and H-60), 8.74 (d, 1H,
3J¼1.1 Hz, NH). 13C NMR (75 MHz, DMSO-d6): d 62.3,
105.8, 110.1, 126.1 (2C), 128.5 (2C), 129.6, 130.4, 142.4,
144.2, 154.9, 155.5, 159.6.
4.11.3. 5-(4-Methylphenyl)-2-phenyl-4,5-dihydro[1,2,4]-
triazolo[1,5-a][1,3,5]triazin-7-amine (3c). White crystal-
line powder; yield 72%; mp 213–214 ꢀC. TLC (silica gel,
EtOH): Rf 0.58. LC–MS (APCI) m/z 305 (MH+). Anal. Calcd
for C17H16N6: C, 67.09; H, 5.30; N, 27.61. Found: C, 66.86;
H, 5.52; N, 27.53%. IR (KBr): n 3440, 3224, 3125, 1702,
1696, 1624, 1532, 1496, 1452, 1437, 1343, 1034, 758,
4.11.7. 2-Phenyl-5-(4-pyridyl)-4,5-dihydro[1,2,4]tri-
azolo[1,5-a][1,3,5]triazin-7-amine (3g). Yellowish crystal-
line powder; yield 68%; mp 333–335 ꢀC. TLC (silica gel,
EtOH): Rf 0.38. LC–MS (APCI) m/z 292 (MH+). Anal. Calcd
for C15H13N7: C, 61.84; H, 4.50; N, 33.66. Found: C, 61.63;
H, 4.76; N, 33.52%. IR (KBr): n 3442, 3230, 3126, 1705,
1697, 1625, 1533, 1496, 1453, 1436, 1416, 1340, 1036,
1
735, 686 cmꢁ1. H NMR (300 MHz, DMSO-d6): d 2.29 (s,
3H, Me), 5.86 (s, 1H, H-5), 6.56 (s, 2H, NH2), 7.17 (d, 2H,
771, 735, 685 cmꢁ1 1H NMR (300 MHz, DMSO-d6):
.
3
3J¼7.9 Hz, H-300 and H-500), 7.32 (d, 2H, J¼7.9 Hz, H-200
d 5.96 (s, 1H, H-5), 6.72 (s, 2H, NH2), 7.39–7.54 (m, 5H,
and H-400), 7.41–7.51 (m, 3H, H-30, H-40 and H-50), 7.98
H-30, H-40, H-50, H-200 and H-600), 8.00 (dd, 2H, 3J¼7.0, 4J¼
3
4
3
4
(dd, 2H, J¼7.2, J¼2.2 Hz, H-20 and H-60), 8.61 (s, 1H,
NH). 13C NMR (75 MHz, DMSO-d6): d 20.6, 68.0, 126.1
(2C), 126.2 (2C), 128.5 (2C), 128.6 (2C), 129.6, 130.5,
136.8, 140.0, 143.4, 156.1, 159.8.
2.4 Hz, H-20 and H-60), 8.59 (dd, 2H, J¼4.7, J¼1.3 Hz,
H-300 and H-500), 8.81 (s, 1H, NH). 13C NMR (75 MHz,
DMSO-d6): d 67.1, 121.3 (2C), 126.2 (2C), 128.5 (2C),
129.7, 130.4, 143.8, 149.7 (2C), 151.1, 155.9, 159.9.
4.11.4. 5-(4-Chlorophenyl)-2-phenyl-4,5-dihydro[1,2,4]-
triazolo[1,5-a][1,3,5]triazin-7-amine (3d). White crystal-
line powder; yield 70%; mp 220–221 ꢀC. TLC (silica gel,
EtOH): Rf 0.60. LC–MS (APCI) m/z 325, 327 (MH+).
Anal. Calcd for C16H13ClN6: C, 59.17; H, 4.03; N, 25.88.
Found: C, 58.94; H, 4.32; N, 25.62%. IR (KBr): n 3444,
3228, 3124, 1705, 1697, 1628, 1533, 1498, 1490, 1454,
4.11.8. 5,5-Dimethyl-2-phenyl-4,5-dihydro[1,2,4]tri-
azolo[1,5-a][1,3,5]triazin-7-amine (3h). The mixture of
1-guanyl-3-phenyl-1,2,4-triazol-5-amine (6, 0.50 g, 2.5 mmol)
and piperidine (0.10 ml, 1.0 mmol) in acetone (7 ml) was
heated under reflux for 12 h. After cooling, the precipitated
product was filtered, washed with acetone, dried, and recrys-
tallized from EtOH. White crystalline powder; yield 65%;
mp 210 ꢀC. TLC (silica gel, EtOH): Rf 0.55. LC–MS
(APCI) m/z 243 (MH+). Anal. Calcd for C12H14N6: C,
59.49; H, 5.82; N, 34.69. Found: C, 59.31; H, 6.03; N,
34.56%. IR (KBr): n 3414, 3388, 3072, 2965, 1705, 1698,
1624, 1522, 1495, 1448, 1431, 1380 (d, gem-Me2), 1340,
913, 740, 705, 694 cmꢁ1. 1H NMR (300 MHz, DMSO-d6):
d 1.37 (s, 6H, Me2), 6.30 (s, 2H, NH2), 7.42–7.51 (m, 3H,
1437, 1343, 1018, 773, 737, 689 cmꢁ1
.
1H NMR
(300 MHz, DMSO-d6): d 5.92 (s, 1H, H-5), 6.62 (s, 2H,
NH2), 7.39–7.54 (m, 7H, H-30, H-40, H-50, H-200, H-300, H-
3
4
500 and H-600), 7.99 (dd, 2H, J¼7.2, J¼1.9 Hz, H-20 and
H-60), 8.67 (s, 1H, NH). 13C NMR (75 MHz, DMSO-d6):
d 67.6, 126.2 (2C), 128.1 (2C), 128.2 (2C), 128.5 (2C),
129.6, 130.4, 132.2, 141.9, 143.6, 156.0, 159.9.
3
4
H-30, H-40 and H-50), 7.98 (dd, 2H, J¼7.2, J¼1.9 Hz,
H-20 and H-60), 8.25 (s, 1H, NH). 13C NMR (75 MHz,
DMSO-d6): d 30.5 (2C), 68.8, 126.1 (2C), 128.5 (2C),
129.5, 130.7, 141.5, 155.4, 159.5.
4.11.5. 5-(4-Fluorophenyl)-2-phenyl-4,5-dihydro[1,2,4]-
triazolo[1,5-a][1,3,5]triazin-7-amine (3e). White crystal-
line powder; yield 78%; mp>360 ꢀC. TLC (silica gel,

A. V. Dolzhenko et al. / Tetrahedron 63 (2007) 12888–12895
12895
4.12. General method for preparation of the spiro
derivatives of 2-phenyl-4,5-dihydro[1,2,4]triazolo-
[1,5-a][1,3,5]triazin-7-amines (3i,j)
000-069-112). The authors thank Tan Geok Kheng and
Koh Lip Lin for the X-ray crystallography study.
The solution of 1-guanyl-3-phenyl-1,2,4-triazol-5-amine
(6, 0.50 g, 2.5 mmol), appropriate cyclic ketone (7i,j,
5.0 mmol), and piperidine (0.10 ml, 1.0 mmol) in EtOH
(8 ml) was heated under reflux for 10–15 h. After cooling,
the product was filtered, washed with cold EtOH, dried,
and recrystallized from EtOH.
References and notes
1. Dolzhenko, A. V.; Tan, G. K.; Koh, L. L.; Dolzhenko, A. V.;
Chui, W. K. Acta Crystallogr. 2007, E63, o2797.
2. (a) Chan, D. C. M.; Anderson, A. C. Curr. Med. Chem.
2006, 13, 377–398; (b) Kompis, I. M.; Islam, K.; Then,
R. L. Chem. Rev. 2005, 105, 593–620; (c) Gangjee, A.;
Jain, H. D.; Kupur, S. Anti-Cancer Agents Med. Chem.
2007, 7, 524–542.
3. (a) Dolzhenko, A. V.; Chui, W. K. J. Heterocycl. Chem. 2006,
43, 95–100; (b) Toyoda, T.; Brobey, R. K. B.; Sano, G.-I.; Horii,
T.; Tomioka, N.; Itai, A. Biochem. Biophys. Res. Commun.
1997, 235, 515–519.
4. Dolzhenko, A. V.; Chui, W. K.; Dolzhenko, A. V.; Chan, L. W.
J. Fluorine Chem. 2005, 126, 759–763.
5. For review, see: Dolzhenko, A. V.; Dolzhenko, A. V.; Chui,
W. K. Heterocycles 2006, 68, 1723–1759.
6. Dolzhenko, A. V.; Tan, G. K.; Koh, L. L.; Dolzhenko, A. V.;
Chui, W. K. Acta Crystallogr. 2007, E63, o2796.
7. Hoggarth, E. J. Chem. Soc. 1950, 612–614.
4.12.1. 20-Phenyl-40H-spiro[cyclopentane-1,50-[1,2,4]tri-
azolo[1,5-a][1,3,5]triazin]-70-amine (3i). White crystalline
powder; yield 62%; mp 206–207 ꢀC. TLC (silica gel, EtOH):
Rf 0.60. LC–MS (APCI) m/z 269 (MH+). Anal. Calcd for
C14H16N6: C, 62.67; H, 6.01; N, 31.32. Found: C, 62.50;
H, 6.22; N, 31.16%. IR (KBr): n 3389, 3246, 3074, 2959,
1702, 1698, 1628, 1527, 1494, 1452, 1436, 1374, 1344,
1
743, 690 cmꢁ1. H NMR (300 MHz, DMSO-d6): d 1.62–
1.87 (m, 8H, (CH2)4), 6.30 (s, 2H, NH2), 7.39–7.52 (m,
3H, H-30, H-40 and H-50), 7.98 (dd, 2H, 3J¼7.5, 4J¼
1.9 Hz, H-20 and H-60), 8.33 (s, 1H, NH). 13C NMR
(75 MHz, DMSO-d6): d 22.2 (2C), 41.0 (2C), 78.9, 126.1
(2C), 128.5 (2C), 129.5, 130.7, 141.7, 155.9, 159.6.
8. For recent reviews, see: (a) Katritzky, A. R.; Manju, K.; Singh,
S. K.; Meher, N. K. Tetrahedron 2005, 61, 2555–2581; (b)
Katritzky, A. R.; Rogovoy, B. V. Chem.—Eur. J. 2003, 9,
4586–4593.
9. For applications of 1-guanylbenzotriazole hydrochloride as
a guanylating agent, see: (a) Zahariev, S.; Guarnaccia, C.;
Lamba, D.; Cemazar, M.; Pongor, S. Tetrahedron Lett. 2004,
45, 9423–9426; (b) Bokaldere, R. P.; Grinsteins, V. Ya. Khim.
Geterotsikl. Soedin. 1970, 563–564.
10. For recent review on guanylating agents, see: Katritzky, A. R.;
Rogovoy, B. V. ARKIVOC 2005, 4, 49–87.
11. Mamalis, P.; Green, J.; McHale, D. J. Chem. Soc. 1960, 229–
238.
4.12.2. 20-Phenyl-40H-spiro[cyclohexane-1,50-[1,2,4]tri-
azolo[1,5-a][1,3,5]triazin]-70-amine (3j). White crystalline
powder; yield 73%; mp 216–217 ꢀC. TLC (silica gel, EtOH):
Rf 0.59. LC–MS (APCI) m/z 283 (MH+). Anal. Calcd for
C15H18N6: C, 63.81; H, 6.43; N, 29.77. Found: C, 63.57;
H, 6.53; N, 29.64%. IR (KBr): n 3374, 3287, 3072, 2936,
2922, 1702, 1698, 1635, 1527, 1491, 1451, 1430, 1354,
1
746, 692 cmꢁ1. H NMR (300 MHz, DMSO-d6): d 1.25–
1.81 (m, 10H, (CH2)5), 6.31 (s, 2H, NH2), 7.39–7.54 (m,
3H, H-30, H-40 and H-50), 7.99 (dd, 2H, 3J¼7.3, 4J¼
1.7 Hz, H-20 and H-60), 8.20 (s, 1H, NH). 13C NMR
(75 MHz, DMSO-d6): d 21.3 (2C), 25.0, 38.9 (2C), 70.3,
126.1 (2C), 128.5 (2C), 129.5, 130.7, 141.2, 155.6, 159.6.
12. Logemann, W.; Artini, D.; Canavesi, L.; Tosolini, G. Chem.
Ber. 1963, 96, 2909–2913.
Acknowledgements
13. Dolzhenko, A. V.; Dolzhenko, A. V.; Chui, W. K. Heterocycles
2007, 71, 429–436.
This work is supported by the Academic Research Fund
from the National University of Singapore (WBS R-148-
14. Grinsteins, V. Ya.; Veveris, A. P. USSR Patent 215225, 1968;
Chem. Abstr. 1968, 69, 59251.