Convenient synthesis of 5-substituted 2-amino[1,2,4]triazolo[1,5- a ][1,3,5]triazin-7(6 H)-ones from N -triazolide imidates and 1,2,4-Triazole-3,5- diamine

Article abstract of DOI:10.1055/s-0029-1218718

A convenient and efficient synthesis of previously unreported N-triazolide imidates and their reaction with 1,2,4-triazole-3,5-diamine to give regioselectively 5-substituted 2-amino[1,2,4]triazolo[1,5-a][1,3,5]triazin-7(6H) -ones is described. The structure of the reported bicyclic compounds has been unambiguously proven by X-ray crystallography. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0029-1218718

PAPER
1645
Convenient Synthesis of 5-Substituted 2-Amino[1,2,4]triazolo-
[1,5-a][1,3,5]triazin-7(6H)-ones from N-Triazolide Imidates and
1,2,4-Triazole-3,5-diamine
5
-Substituted 2-Amino
e
[1,2, 4]triaz
h
olo[1,5-
a
][1,
d
3,5]triazin-7
i
(6
H
)-ones Khankischpur, Finn K. Hansen, Detlef Geffken*
Institute of Pharmacy, University of Hamburg, Bundesstr. 45, 20146 Hamburg, Germany
Fax +49(40)428386573; E-mail: geffken@chemie.uni-hamburg.de
Received 17 December 2009; revised 10 February 2010
viously unknown N-triazolide imidates 3a–f in 50–81%
yield after either column chromatography or recrystalliza-
tion from appropriate solvents (Scheme 1, Table 1).
Abstract: A convenient and efficient synthesis of previously unre-
ported N-triazolide imidates and their reaction with 1,2,4-triazole-
3,5-diamine to give regioselectively 5-substituted 2-ami-
no[1,2,4]triazolo[1,5-a][1,3,5]triazin-7(6H)-ones is described. The
structure of the reported bicyclic compounds has been unambigu-
ously proven by X-ray crystallography.
O
Cl–
N
+
NH
NH2
N
K2CO3
CDT
N
Key words: imidates, heterocycles, cyclizations, triazolotriazines,
ring-closure
N
R
O
R
O
1
2
R
O
3
Scheme 1 Synthesis of N-triazolide imidates 3
Fused heterocyclic 1,3,5-triazine derivatives have attract-
ed considerable attention in medicinal chemistry because
of their bioisosteric relationship with purine derivatives.1
Particular interest has been devoted to 5-azapurines as
antagonists of adenosine receptors. For example, 5,7-di-
amino[1,2,4]triazolo[1,5-a][1,3,5]triazines have been
identified as highly active and selective non-xanthine A2A
adenosine receptor inhibitors.2
The IR spectra of compounds 3 are characterized by two
sharp absorption bands at 1718–1732 cm–1 and 1630–
1685 cm–1.
Table 1 N-Triazolide Imidates 3
Compound
R
Yield (%)
Very recently, derivatives of 5-amino[1,2,4]triazolo[1,5-
a][1,3,5]triazines have also been found to possess antipro-
liferative activity,3 and 7-oxo[1,2,4]triazolo[1,5-
a][1,3,5]triazines, which are structurally related to xan-
thine, have been described as xanthine oxidase inhibitors.4
3a
3b
3c
3d
3e
3f
cyclohexyl
4-ClC6H4
81
50
77
75
76
79
4-ClC6H4CH2
3,4-Cl2C6H3CH2
3,4-(MeO)2C6H3CH2
Ph(CH2)2
N-Functionalized imidates represent useful building
blocks in heterocyclic chemistry and have been already
utilized for the preparation of substituted 1,2,4-triazo-
lo[1,3,5]triazines.5–7 However, only a few synthetic pro-
cedures exist for the preparation of 7-oxo-substituted
1,2,4-triazolo[1,5-a][1,3,5]triazines and relatively long
reaction times are described.5
Subsequent reaction of the N-triazolide imidates 3 with
1H-1,2,4-triazole-3,5-diamine in boiling methanol fur-
nished exclusively 5-substituted 2-amino[1,2,4]triazo-
lo[1,5-a][1,3,5]triazin-7(6H)-ones 4a–f in 52–78% yield
and not the theoretically possible isomers of type 5
(Scheme 2, Table 2). Structural proof for compounds 4
was obtained by X-ray crystal structure analysis of com-
pound 4f, which clearly shows the [1,5-a] anellation with
allocation of the oxo-group at position 7 of the bicyclic
system (Figure 1).10 Heterocycles 4 demonstrated strong
C=O absorption bands in the IR spectra at 1735–1752
cm–1.
We disclose here a facile and rapid method for the synthe-
sis
of
5-substituted
2-amino[1,2,4]triazolo[1,5-
a][1,3,5]triazin-7(6H)-ones (4), employing readily avail-
able N-triazolide imidates 3 as suitable precursors.
Imidate hydrochlorides 1, which are accessible by the
Pinner reaction8 from the corresponding nitriles, were
converted into the imidate bases 2 by treatment with a sat-
urated aqueous solution of potassium carbonate
(Scheme 1). Without further purification, the imidates 2
were reacted directly with 1.1 equivalents of 1,1¢-carbon-
yl-di(1,2,4-triazole) (CDT)9 to smoothly produce the pre-
The structural assignment of the target compounds 4 was
deduced from the IR, 1H and 13C NMR spectra and from
microanalytical data.
SYNTHESIS 2010, No. 10, pp 1645–1648
x
x.
x
x
.
2
0
1
0
Advanced online publication: 26.03.2010
DOI: 10.1055/s-0029-1218718; Art ID: T23609SS
© Georg Thieme Verlag Stuttgart · New York

1646
M. Khankischpur et al.
PAPER
Heraeus CHN-O-Rapid instrument. HRFAB-MS analysis was per-
formed with an Agilent TOF LC/MS spectrometer. IR spectra were
O
N
N
N
1
recorded with a Varian 800 FT-IR. H NMR (400 MHz) and 13C
HN
N
NH2
NMR (100 MHz) spectra were recorded with a Bruker AMX 400
spectrometer using TMS as an internal standard and DMSO-d6 as
solvent. X-ray crystal analysis was performed on a Bruker Smart
APEX CCD diffractometer with Mo-Ka radiation at 100 K. CDT
was purchased from Fluka Chemicals.
R
H
N
4
O
H2N
NH2
N
N
N
N
N
N
R
O
R
Preparation of 3a–f; General Procedure
3
N
N
Imidate hydrochlorides 1a–f were prepared according to the Pinner
protocol.8 Without further purification, the crude imidate hydro-
chlorides 1 (3 mmol) were converted into the corresponding imidate
bases 2 by treatment with ice-cold, sat. aq K2CO3 (20 mL) and sub-
sequent extraction with Et2O (3 × 15 mL). During the reaction, the
formation of imidate bases 2 were determined by IR spectroscopy
[IR: 1635–1660 (C=N) cm–1] and by TLC. The organic layer was
dried over MgSO4, filtered, and the solvent was removed under re-
duced pressure. The remaining oil was dissolved in anhydrous
CH2Cl2 (15 mL). CDT (542 mg, 3.3 mmol) was added at 5 °C and
the reaction mixture was stirred at r.t. for 1 h. The resulting suspen-
sion was washed with H2O (3 × 10 mL), dried over MgSO4 and fil-
tered. The solvent was removed and the remaining residue was
either crystallized (Et2O–n-hexane) to afford compounds 3a–d as
solid products, or purified by filtration through a short silica gel col-
umn (3 cm; CH2Cl2) to afford compounds 3e–f as colorless oils.
N
N
NH2
O
N
H
5
Scheme 2 Synthesis of 5-substituted 2-amino[1,2,4]triazolo[1,5-
a][1,3,5]triazin-7(6H)-ones 4
Ethyl N-(1H-1,2,4-Triazol-1-ylcarbonyl)cyclohexanecarbox-
imidoate (3a)
Yield: 608 mg (81%); colorless crystals; mp 67.0 °C.
IR (KBr): 1726, 1663 cm–1.
1H NMR (DMSO-d6): d = 1.15–1.82 (m, 10 H, CH2), 1.31 (t, J = 7.1
Hz, 3 H, OCH2CH3), 2.61 (tt, J = 11.7, 3.2 Hz, 1 H, CH), 4.31 (q,
J = 7.1 Hz, 2 H, OCH2CH3), 8.25 (s, 1 H, ArH), 9.27 (s, 1 H, ArH).
13C NMR (DMSO-d6): d = 13.5, 24.7, 25.0, 42.5, 64.3, 152.5, 153.3,
166.4, 174.6.
Figure 1 X-ray crystal structure of compound 4f. Hydrogen atoms
have been omitted for clarity. Selected distances [Å] and angles [°]:
O1–C3 1.214(15), N1–C4 1.368(15), N3–C3 1.376(16), N3–C2
1.378(15), N3–N4 1.383(14), N2–C4 1.309(16), N5–C2 1.314(16);
C3–N3–C2 123.8(10), C2–N3–N4 110.4(10), C2–N5–C1 102.7(10),
C1–N4–N3 100.3(10), N4–C1–N5 116.4(11), N2–C4–N1 122.5(11),
N5–C2–N3 110.1(11).
Anal. Calcd for C12H18N4O2: C, 57.57; H, 7.25; N, 22.38. Found: C,
57.66; H, 7.41; N, 22.25.
Ethyl 4-Chloro-N-(1H-1,2,4-triazol-1-ylcarbonyl)benzenecar-
boximidoate (3b)
Yield: 418 mg (50%); colorless solid; mp 80.2 °C.
Table 2 5-Substituted 2-Amino[1,2,4]triazolo[1,5-a][1,3,5]triazin-
7(6H)-ones 4
IR (KBr): 1723, 1685 cm–1.
Compound
R
Yield (%)
1H NMR (DMSO-d6): d = 1.44 (t, J = 7.1 Hz, 3 H, OCH2CH3), 4.50
(q, J = 7.1 Hz, 2 H, OCH2CH3), 7.56–7.63 (m, 4 H, ArH), 8.23 (s,
1 H, ArH), 9.33 (s, 1 H, ArH).
13C NMR (DMSO-d6): d = 13.6, 65.7, 129.2, 129.8, 137.7, 152.0,
153.4, 164.2, 168.2.
4a
4b
4c
4d
4e
4f
cyclohexyl
4-ClC6H4
74
60
75
78
52
67
4-ClC6H4CH2
3,4-Cl2C6H3CH2
3,4-(MeO)2C6H3CH2
Ph(CH2)2
Anal. Calcd for C12H11ClN4O2: C, 51.72; H, 3.98; N, 20.10. Found:
C, 51.63; H, 4.03; N, 19.80.
Ethyl (1Z)-2-(4-Chlorophenyl)-N-(1H-1,2,4-triazol-1-yl-carbo-
nyl)ethanimidoate (3c)
Yield: 676 mg (77%); colorless solid; mp 60.5 °C.
IR (KBr): 1722, 1639 cm–1.
In conclusion, we have successfully elaborated a new and
efficient synthetic method for 5-substituted 2-ami-
no[1,2,4]triazolo[1,5-a][1,3,5]triazin-7(6H)-ones 4, by
cyclization of readily available N-triazolide imidates 3
with 1H-1,2,4-triazole-3,5-diamine.
1H NMR (DMSO-d6): d = 1.27 (t, J = 7.1 Hz, 3 H, OCH2CH3), 3.94
(s, 2 H, CH2), 4.35 (q, J = 7.1 Hz, 2 H, OCH2CH3), 7.27 (d, J = 8.5
Hz, 2 H, ArH), 7.34 (d, J = 8.3 Hz, 2 H, ArH), 8.24 (s, 1 H, ArH),
9.21 (s, 1 H, ArH).
13C NMR (DMSO-d6): d = 13.5, 38.0, 64.8, 128.3, 131.1, 131.8,
132.6, 152.5, 153.3, 170.8.
Melting points (uncorrected) were determined with an Electrother-
mal 9100 apparatus. Elemental analyses were carried out with a
Anal. Calcd for C13H13ClN4O2: C, 53.34; H, 4.48; N, 19.14. Found:
C, 52.96; H, 4.57; N, 18.76.
Synthesis 2010, No. 10, 1645–1648 © Thieme Stuttgart · New York

PAPER
5-Substituted 2-Amino[1,2,4]triazolo[1,5-a][1,3,5]triazin-7(6H)-ones
1647
Ethyl (1Z)-2-(3,4-Dichlorophenyl)-N-(1H-1,2,4-triazol-1-ylcar-
bonyl)ethanimidoate (3d)
Yield: 736 mg (75%); colorless solid; mp 62.5 °C.
2-Amino-5-(4-chlorophenyl)[1,2,4]triazolo[1,5-a][1,3,5]triazin-
7(6H)-one (4b)
Yield: 315 mg (60%); colorless solid; mp 356.0 °C (dec.).
IR (KBr): 1718, 1671 cm–1.
IR (KBr): 3448, 1736, 1655 cm–1.
1H NMR (DMSO-d6): d = 1.27 (t, J = 7.1 Hz, 3 H, OCH2CH3), 3.99
(s, 2 H, CH2), 4.36 (q, J = 7.1 Hz, 2 H, OCH2CH3), 7.27 (dd,
J = 8.3, 2.0 Hz, 1 H, ArH), 7.53 (d, J = 1.8 Hz, 1 H, ArH), 7.56 (d,
J = 8.3 Hz, 1 H, ArH), 8.25 (s, 1 H, ArH), 9.23 (s, 1 H, ArH).
13C NMR (DMSO-d6): d = 13.4, 37.8, 64.9, 129.7, 129.9, 130.4,
131.3, 134.7, 152.5, 153.3, 170.3.
1H NMR (DMSO-d6): d = 6.31 (br s, 2 H, NH2), 7.66 (d, J = 8.6 Hz,
2 H, ArH), 8.15 (d, J = 8.6 Hz, 2 H, ArH), 13.08 (br s, 1 H, NH).
13C NMR (DMSO-d6): d = 128.8, 130.0, 137.3, 143.6, 156.1, 156.8.
Anal. Calcd for C10H7ClN6O: C, 45.73; H, 2.69; N, 32.00. Found:
C, 45.67; H, 2.87; N, 32.29.
Anal. Calcd for C13H12Cl2N4O2: C, 47.73; H, 3.70; N, 17.12. Found:
C, 47.73; H, 3.80; N, 16.94.
2-Amino-5-(4-chlorobenzyl)[1,2,4]triazolo[1,5-a][1,3,5]triazin-
7(6H)-one (4c)
Yield: 416 mg (75%); colorless solid; mp 323.8 °C (dec.).
Ethyl (1Z)-2-(3,4-Dimethoxyphenyl)-N-(1H-1,2,4-triazol-1-yl-
carbonyl)ethanimidoate (3e)
Yield: 726 mg (76%); colorless oil.
IR (film): 1731, 1664 cm–1.
1H NMR (DMSO-d6): d = 1.29 (t, J = 7.1 Hz, 3 H, OCH2CH3), 3.66
(s, 3 H, OCH3), 3.69 (s, 3 H, OCH3), 3.82 (s, 2 H, CH2), 4.33 (q,
J = 7.1 Hz, 2 H, OCH2CH3), 6.69–6.74 (m, 1 H, ArH), 6.78 (d,
J = 1.8 Hz, 1 H, ArH), 6.79–6.82 (m, 1 H, ArH), 8.21 (s, 1 H, ArH),
9.16 (s, 1 H, ArH).
13C NMR (DMSO-d6): d = 13.5, 38.3, 55.3, 55.4, 64.6, 111.8, 113.0,
121.5, 125.6, 148.0, 148.5, 152.5, 153.2, 171.0.
IR (KBr): 3447, 3337, 1750 cm–1.
1H NMR (DMSO-d6): d = 3.94 (s, 2 H, ArCH2), 6.20 (s, 2 H, NH2),
7.35–7.43 (m, 4 H, ArH), 12.98 (br s, 1 H, NH).
13C NMR (DMSO-d6): d = 39.0, 128.3, 131.1, 131.7, 134.2, 143.0,
157.1, 160.9, 165.3.
Anal. Calcd for C11H9ClN6O: C, 47.75; H, 3.28; N, 30.38. Found:
C, 47.65; H, 3.56; N, 30.61.
2-Amino-5-(3,4-dichlorobenzyl)[1,2,4]triazolo[1,5-a][1,3,5]tri-
azin-7(6H)-one (4d)
Yield: 485 mg (78%); colorless solid; mp 292.5 °C (dec.).
IR (KBr): 3464, 3350, 1746, 1638 cm–1.
1H NMR (DMSO-d6): d = 3.97 (s, 2 H, ArCH2), 6.20 (s, 2 H, NH2),
7.32–7.69 (m, 3 H, ArH), 12.95 (br s, 1 H, NH).
13C NMR (DMSO-d6): d = 38.6, 129.7, 129.8, 130.4, 130.8, 131.4,
136.2, 143.0, 157.1, 160.4, 165.3.
HRMS-FAB: m/z [M + Na]+ calcd for C15H18N4NaO4: 341.1220;
found: 341.1222.
Ethyl (1Z)-3-Phenyl-N-(1H-1,2,4-triazol-1-ylcarbonyl)propan-
imidoate (3f)
Yield: 645 mg (79%); colorless oil.
IR (film): 1732, 1630 cm–1.
1H NMR (DMSO-d6): d = 1.30 (t, J = 7.1 Hz, 3 H, OCH2CH3), 2.90
(s, 4 H, PhC2H4), 4.34 (q, J = 7.1 Hz, 2 H, OCH2CH3), 7.15–7.25
(m, 5 H, ArH), 8.24 (s, 1 H, ArH), 9.11 (s, 1 H, ArH).
13C NMR (DMSO-d6): d = 13.5, 31.2, 34.2, 64.5, 126.3, 128.1,
128.3, 139.5, 152.7, 153.3, 173.6.
Anal. Calcd for C11H8Cl2N6O: C, 42.47; H, 2.59; N, 27.01. Found:
C, 42.41; H, 2.78; N, 27.09.
2-Amino-5-(3,4-dimethoxybenzyl)[1,2,4]triazolo[1,5-
a][1,3,5]triazin-7(6H)-one (4e)
Yield: 315 mg (52%); colorless solid; mp 241.5 °C (dec.).
IR (KBr): 3344, 1752, 1599 cm–1.
1H NMR (DMSO-d6): d = 3.73 (s, 3 H, CH3), 3.75 (s, 3 H, CH3),
3.84 (s, 2 H, ArCH2), 6.15 (s, 2 H, NH2), 6.84–7.01 (m, 3 H, ArH),
12.84 (br s, 1 H, NH).
13C NMR (DMSO-d6): d = 39.7, 55.5, 55.5, 111.9, 113.1, 121.2,
127.6, 143.4, 147.9, 148.6, 157.3, 161.9, 165.3.
HRMS-FAB: m/z [M + Na]+ calcd for C14H16N4NaO2: 295.1165;
found: 295.1167.
Preparation of 4a–f; General Procedure
A solution of the respective N-triazolide imidate 3 (2 mmol) and
1H-1,2,4-triazole-3,5-diamine (218 mg, 2.2 mmol) in anhydrous
MeOH (10 mL) was heated at reflux for 30 min. The reaction mix-
ture was allowed to cool to 40–50 °C and the precipitate was filtered
and washed with cold MeOH (2 × 5 mL). Compounds 4a, 4e, and
4f were purified by recrystallization (MeOH); compounds 4b–d
were treated with boiling MeOH (10 mL), filtered and washed with
cold MeOH (2 × 5 mL).
Anal. Calcd for C13H14N6O3: C, 51.65; H, 4.67; N, 27.80. Found: C,
51.43; H, 4.76; N, 27.83.
2-Amino-5-(2-phenylethyl)[1,2,4]triazolo[1,5-a][1,3,5]triazin-
7(6H)-one (4f)
Yield: 345 mg (67%); colorless solid; mp 289.8 °C (dec.).
IR (KBr): 3490, 1736, 1602 cm–1.
2-Amino-5-cyclohexyl[1,2,4]triazolo[1,5-a][1,3,5]triazin-7(6H)-
one (4a)
Yield: 349 mg (74%); colorless solid; mp 270.2 °C.
IR (KBr): 3498, 2931, 1735 cm–1.
1H NMR (DMSO-d6): d = 2.83–2.93 (m, 2 H, CH2), 3.01 (t, J = 7.8
Hz, 2 H, CH2), 6.21 (s, 2 H, NH2), 7.17–7.35 (m, 5 H, ArH), 12.78
(br s, 1 H, NH).
13C NMR (DMSO-d6): d = 31.8, 35.5, 126.1, 128.2, 128.3, 140.1,
143.0, 157.1, 162.0, 165.4.
1H NMR (DMSO-d6): d = 1.13–1.93 (m, 10 H, CH2), 2.49–2.62 (m,
1 H, CH), 6.16 (s, 2 H, NH2), 12.60 (br s, 1 H, NH).
13C NMR (DMSO-d6): d = 25.1, 25.2, 29.9, 42.3, 143.3, 157.4,
165.4, 166.1.
Anal. Calcd for C12H12N6O: C, 56.24; H, 4.72; N, 32.79. Found: C,
56.15; H, 4.85; N, 33.05.
Anal. Calcd for C10H14N6O: C, 51.27; H, 6.02; N, 35.87. Found: C,
51.28; H, 6.25; N, 36.20.
Synthesis 2010, No. 10, 1645–1648 © Thieme Stuttgart · New York

1648
M. Khankischpur et al.
PAPER
(6) Bekircan, O.; Küxük, M.; Kahveci, B.; Kolayli, S. Arch.
Pharm. (Weinheim, Ger.) 2005, 338, 365.
(7) Chabchoub, F.; Rekik, A.; Salem, M. Synth. Commun. 2005,
35, 2467.
Acknowledgment
The authors thank Miss Isabelle Nevoigt for her valuable help in the
preparation of the X-ray crystal structure.
(8) Pinner, A. Die Imidoäther und ihre Derivate; Oppenheim:
Berlin, 1892.
(9) (a) Staab, H. A.; Bauer, H.; Schneider, K. M. Azolides in
Organic Synthesis and Biochemistry; Wiley-VCH:
Weinheim, 1998. (b) Kurz, T.; Khankischpur, M. Synthesis
2009, 4068.
(10) CCDC-755847 contains the supplementary crystallographic
data for the deposited structure. These data can be obtained
free of charge from the Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif. Crystal
data for compound 4f: Empirical formula: C12H12N6O;
Mr = 256.28; Crystal system = monoclinic; Space group
P21/n; Unit cell dimensions a = 11.6229(9), b = 9.8793(8),
c = 10.1094(8) Å; b = 94.834(3)°; V = 1156.69(16) Å3;
T = 100 K; Z = 4; D(calcd) = 1.472 Mg·m–3; m = 0.10 mm–1;
l (Mo Ka) = 0.71073 Å; F(000) = 536; 2636 independent
reflections (Rint = 0.027), 2254 reflections with I > 2σ(I);
refinement method full-matrix least-squares refinement on
F2; R[F2>2σ(F2)] = 0.037, wR(F2) = 0.094, S = 1.05.
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Synthesis 2010, No. 10, 1645–1648 © Thieme Stuttgart · New York