On triazoles XLV [1]. Synthesis of 5,7-diamino-1,2,4-triazolo[1,5-a][1,3,5]triazines

Article abstract of DOI:10.1002/jhet.5570390214

The reaction of differently substituted 5-amino-1,2,4-triazoles (5) with isothiourea derivatives (3) to yield isomeric 5,7-diamino-1,2,4-triazolo[1,5-a][1,3,5]triazines (6 and 7), previously described as not proceeding in melt, was performed in different solvents as well as in the melt at 150-160°. It was proved that the above reaction had rather general validity. The structure of isomers 6 and 7 were proved spectroscopically. The structure of 6/5 (Q = ethylamino) was corroborated with single crystal X-ray diffraction determination, as well.

Full text of DOI:10.1002/jhet.5570390214

On Triazoles XLV [1]. Synthesis of
327
Mar-Apr 2002
5,7-Diamino-1,2,4-triazolo[1,5-a][1,3,5]triazines
Gábor Berecz, László Pongó, István Kövesdi and József Reiter
EGIS Pharmaceuticals Ltd., P.O.Box 100, H-1475 Budapest, Hungary
Received July 11, 2001
th
Dedicated to Professor András Messmer on the occasion of his 80 birthday
The reaction of differently substituted 5-amino-1,2,4-triazoles (5) with isothiourea derivatives (3) to yield
isomeric 5,7-diamino-1,2,4-triazolo[1,5-a][1,3,5]triazines (6 and 7), previously described as not proceeding
in melt, was performed in different solvents as well as in the melt at 150-160°. It was proved that the above
reaction had rather general validity. The structure of isomers 6 and 7 were proved spectroscopically. The
structure of 6/5 (Q = ethylamino) was corroborated with single crystal X-ray diffraction determination, as
well.
J. Heterocyclic Chem., 39, 327 (2002).
The synthesis of 5-amino-3-(substitutedamino)-1,2,4-
1 2
derivatives (5, Q = NR R ) as their starting materials were
required to enable their synthesis for biological screening.
During the large scale preparation of 5-amino-3-(ethyl-
amino and n-octylamino)-1,2,4-triazoles (5, Q = ethylamino
and n-octylamino, respectively) a small amount (3 and 4 %,
respectively) of byproducts (6 or 7, Q = ethylamino and
n-octylamino, respectively, Scheme 2) could be isolated
from the mother liquors. The ms and nmr data of products
recorded corroborated their 5,7-diamino-1,2,4-triazolo-
[1,5-a][1,3,5]triazine structure 6 or 7 but owing to the
unusual symmetry of the isomeric molecules could not
differentiate between them. To verify their structure X-ray
diffraction analysis of the ethyl derivative was performed
proving its structure 6/5 (Q = ethylamino, Scheme 3, Table
I) [7]. The full analogy of the cmr data measured for the
1,2,4-triazolo[1,5-a][1,3,5]triazine skeleton of the ethyl and
n-octyl derivatives, respectively, proved also the structure of
derivative 6/7 (Q = n-octylamino)(Scheme 2, Table I).
1
2
triazoles (5, Q = NR R ) by the reaction of dimethyl
N-cyanimidodithiocarbonate (1) with primary or
1
2
secondary amines (2, R , R = hydrogen, alkyl, aralkyl,
aryl) through the isothiourea derivatives (3) (which can be
either isolated or not isolated using a one pot procedure)
[2-3] and hydrazine hydrate (4) is well known in the
literature [4-5](Scheme 1).
Scheme 3
Perspective view of 6/5. Atomic thermal ellipsoids are on 50% probability
level.
As some of our tricyclic cycloalka- and heterocyclocalka-
1,2,4-triazolo[1,5-a]pyrimidine derivatives possessed
excellent cardiovascular activity [6] large quantities of
Recently, Caulkett and coworkers [8] happened to
synthesise analogous 5-amino-7-alkylamino-1,2,4-tria-
zolo[1,5-a][1,3,5]triazine derivatives 12 (Scheme 4)

328
G. Berecz, L. Pongó, I. Kövesdi and J. Reiter
Vol. 39

Mar-Apr 2002
On Triazoles XLV. Synthesis of 5,7-Diamino-1,2,4-triazolo[1,5-a][1,3,5]triazines
329
starting from the corresponding 5-amino-3-substituted-
1,2,4-triazole derivatives 5 and dimethyl N-cyanimi-
dodithiocarbonate (1) to yield a mixture of isomeric
derivatives 8 and 9. After their separation the reactive
methylthio group of 9 was transformed with the
corresponding amines (10) leading to derivatives 12.
However, even though it seemed to be straightforward, the
corresponding derivative 12 could not be obtained by the
reaction of the triazole 5 (Q = 2-furyl) and the
corresponding type 3 isothiourea 11, even by performing
the reaction at 200° in melt [8](Scheme 4).
On the other hand, the analogous isourea derivative 13
[R = 2-(4-hydroxyphenyl)ethyl] reacted readily at room
temperature with 5 (Q = 2-furyl) in acetonitrile to give a
1-N-substituted-5-amino-1,2,4-triazole 14 [Q = 2-furyl,
R = 2-(4-hydroxyphenyl)ethyl] that proved to be the
intermediate of the reaction leading to 12 [Q = 2-furyl,
R = 2-(4-hydroxyphenyl)ethyl] as shown by its refluxing
in ethanol [8](Scheme 5).
Even though it was stated [8], that the type 3
isothioureas 11 did not react with the type 5 5-amino-
1,2,4-triazole (5, Q = 2-furyl) in melt we came to the
decision that our type 6 derivatives could only have
formed during the synthesis of triazoles 5 in ethanol by the
route mentioned above, i.e. by the reaction of the triazoles
5 once formed with the isothioureas (3) most probably
through the not isolated type 15 intermediates (Scheme 6).
For this reason we tried to react derivatives 3 with
derivatives 5 using different solvents and temperatures. The
reaction - even though it was rather sluggish requiring long
reaction times - proceeded acceptably in many high boiling
solvents, such as n-amylalcohol, benzylalcohol, dimethyl-
formamide, but surprisingly, from the reaction mixtures
obtained by long refluxing of the reactants in n-butanol
products 6 crystallised in pure state in 22-48 % yield
(Scheme 6, Table I, for their spectral data see Table II).

330
G. Berecz, L. Pongó, I. Kövesdi and J. Reiter
Vol. 39
Table II
Pmr and cmr Spectral Data of Compounds 6
pmr (DMSO-d ), δ, ppm
cmr (DMSO-d ), δ, ppm
6
6
1
2
1
2
Compounds NH
Q
NH
R + R
C-2
C-7
C-5
C-3a
Q
R + R
2
6/1
6/2
6/3
6.97 bs
7.03 bs
7.04 bs
8.06 s
8.61 s
1.74 (qi, 2H)
2.14 (s, 6H)
2.28 (t, 2H)
154.2 149.2 162.7 158.8
154.4 149.5 162.7 159.0
165.0 148.4 161.8 161.3
-
26.5
39.2 (NHCH )
45.3 (NMe )
57.1 (NCH )
43.3
127.2 (p), 127.5
128.5, 138.6 (s)
2
2
3.45 (q, 2H)
4.65 (d, J = 5.4 Hz)
7.25 - 7.4 (m, 5H)
2
8.10 s
9.07
(t, J = 5.4 Hz)
-
2.53 s
2.58 s
-
3.73 (t, 4H, OCH )
4.13 (bs, 4H, NCH )
13.2
13.4
46.7 (NCH )
2
65.9 (OCH )
2
2
2
6/4
[a]
6/5
[a]
6/6
7.01 bs
6.68 bs
8.31 bs
1.18 (t, 3H)
3.44 (m, 2H)
1.15 (t, 3H)
3.41 (qi, 2H)
165.2 148.2 162.6 159.3
165.6 148.2 162.3 158.4
165.9 148.5 162.3 158.7
14.6 (CH )
3
35.1 (CH )
15.0 (CH )
34.9 (CH )
2
1.13 (t, 3H)
3.20 (qi, 2H)
6.32 (t, NH-2)
7.68 (t, NH-7)
15.2
37.0
45.7
3
2
6.77 bs 4.44 (d, J = 6.3 Hz) 7.00 (t, J = 6.3 Hz, 4.58 (d, J = 6.0 Hz)
43.1
7.2-7.4 (m, 5H)*
NH-2)
8.29 (t, J = 6.0 Hz,
NH-7)
7.2-7.4 (m, 5H)*
140.7 (s)
139.1 (s)
126.7, 127.7 (p)
127.3, 127.5,
128.3, 128.4 (o + m)
6/7
6.59 bs
0.86 (t, 3H)*
1.25 (m, 10H)*
1.55 (m, 2H)*
3.16 (q, 2H)
6.25 (t, NH-2)
7.53 (t, NH-7)
0.86 (t, 3H)*
1.25 (m, 10H)*
1.55 (m, 2H)*
3.36 (q, 2H)
5.15 bs
[b]
0.9 (m, 3H)*
1.28 (m, 10H)*
1.63 (m, 2H)*
3.30 (q, 2H)
4.52 (t, NH-2)
5.89 (t, NH-7)
0.9 (m, 3H)*
1.28 (m, 10H)*
1.63 (m, 2H)*
3.50 (q, 2H)
164.8 148.6 162.4 157.8
[c]
31.8
42.9
14.1 (two peaks)
31.9
41.0
22.7 (two peaks)
26.8-29.6 (8 peaks)
6/8
6/9
6.70 bs
6.68 bs
2.16 (s, 6H)
2.40 (t, 6H)
3.25 (q, 2H)
1.67 (m, 2H)
2.11 (s, 6H)
2.25 (t, 2H)
3.19 (q, 2H)
6.15 (t, NH-2)
7.35 (t, NH-7)
2.18 (s, 6H)
2.45 (t, 2H)
3.46 (q, 2H)
1.71 (m, 2H)
2.14 (s, 6H)
2.27 (t, 2H)
3.41 (q, 2H)
165.6 148.3 162.3 158.4
165.7 148.3 162.3 158.3
37.8
45.3*
57.9
27.3
45.4
40.8
57.2
45.7
65.8
40.4 (NHCH )
2
45.4* (NMe )
2
58.5 (NCH )
2
6.37 (t, NH-2)
7.93 (t, NH-7)
26.6
39.1 (NHCH )
2
45.3 (NMe )
2
57.2 (NCH )
2
6/10
6.83 bs 3.35 (m, 4H, NCH )
-
3.70 (t, 4H, OCH )
4.11 (bs, 4H, NCH )
165.5 148.5 161.6 160.7
46.5
66.0
2
2
3.66 (t, 4H, OCH )
2
2
[a] Assignment checked by 2D-NMR; [b] Taken in deuteriochloroform; [c] Taken in a mixture of deuteriochloroform and deuteriomethanol.
To study the scope of the above reaction it was
It is worth mentioning that in the reaction of 5-amino-
3-methylthio-1H-1,2,4-triazole (5/4, Q = methylthio)
and N-cyano-N'-ethyl-S-methylisothiourea (3/5,
performed with differently substituted isothioureas 3, such
1
as the mono-N-substituted derivatives 3 (R = ethyl,
1
2
n-octyl, benzyl, 2-dimethylaminoethyl and 3-dimethyl-
NR R = ethylamino) besides the expected derivative
6/4 (Q = methylthio) the isomeric 7/4 (Q = methylthio)
was also formed that could be isolated by column
chromatography of the mother liquor evaporated to
dryness (Scheme 7). The formation of 7/4 (Q =
methylthio) could be deduced from the intermediate
17/4 (Q = methylthio) formed either directly from 5/4
2
aminopropyl, respectively, R = H), the di-N-substituted
1
2
derivatives 3 (NR R = morpholin-4-yl) as well as
different 5-amino-1,2,4-triazoles such as 5 (Q = H), 5 (Q =
methylthio), and 5-amino-3-monosubstitutedamino-1,2,4-
triazoles such as 5 (Q = ethylamino, n-octylamino, benzyl-
amino, 2-dimethylaminoethylamino, 3-dimethylamino-
propylamino) and 5-amino-3-disubstitutedamino-1,2,4-
triazoles such as 5 (Q = morpholin-4-yl), respectively,
(Table I) giving in each case the expected type 6
derivatives. These experiments showed the rather general
validity of the above reaction.
1
2
(Q = methylthio) and 3/5 (NR R = ethylamino) or by
thermal rearrangement of the intermediate 16/4 (Q =
methylthio). An analogous rearrangement of 1-acyl,
1-carbamoyl and 1-thiocarbamoyl-5-amino-1,2,4-
triazoles was observed previously [9-10].

Mar-Apr 2002
On Triazoles XLV. Synthesis of 5,7-Diamino-1,2,4-triazolo[1,5-a][1,3,5]triazines
331
5-Amino-3-ethylamino-1H-1,2,4-triazole (5/5, Q = ethylamino)
and 5-Amino-2,7-bis(ethylamino)-1,2,4-triazolo[1,5-a]-
[1,3,5]triazine (6/5, Q = ethylamino).
To a stirred hot suspension of 83.1 g (0.58 mole) of N-cyano-
1
2
N'-ethyl-S-methylisothiourea (3/5, NR R = ethylamino) [12] in
200 ml of 2-propanol 35.0 g (34 ml, 0.7 mole) of 100 %
hydrazine hydrate was added dropwise within 1.5 hours (during
the reaction methylthiol was evolved that was trapped in sodium
hydroxyde solution). The reaction was completed by refluxing
for a further 2 hours. After cooling 300 ml of diethyl ether was
added to the reaction mixture, the crystals that precipitated were
isolated by filtration and washed with a 1:1 mixture of ether and
2-propanol to yield 51.0 g (69 %) of 5-amino-3-ethylamino-1H-
1,2,4-triazole (5/5, Q = ethylamino), mp 152-154°. An analytical
sample was recrystallised from a mixture of CH CN and 2-PrOH,
3
mp 156-157.5° (Lit. [11] mp 116-118°, Lit. [13] mp 120-123°;
[14]). The mother liquor was evaporated in vacuo to dryness and
the residue dry column flash chromatographed on Kieselgel 60
H, eluent chloroform-methanol 100:1 to yield 2.2 g (3 %) of
5-amino-2,7-bis(ethylamino)-1,2,4-triazolo[1,5-a][1,3,5]triazine
(6/5, Q = ethylamino), mp 280-285° (for its spectral data see
Table II). Continuing the chromatography with a 9:1 mixture of
chloroform and methanol a further 13.3 g (18 %) crop of (5/5)
was obtained, mp 153-155°.
5-Amino-3-(n-octyl)amino-1H-1,2,4-triazole (5/7, Q = n-octyl-
amino) and 5-Amino-2,7-bis(n-octylamino)-1,2,4-triazolo-
[1,5-a][1,3,5]triazine (6/7, Q = n-octylamino).
To a stirred hot suspension of 84.2 g (0.37 mole) of N-cyano-
1
2
N'-(n-octyl)-S-methylisothiourea (3/7, NR R = n-octylamino)
[15] in 200 ml of 2-propanol 22.2 g (21.5 ml, 0.44 mole) of
100 % hydrazine hydrate was added dropwise within 1.5 hours
(during the reaction methylthiol was evolved that was trapped in
sodium hydroxyde solution). The reaction was completed by
refluxing for a further 2 hours. After cooling 300 ml of diethyl
ether was added to the reaction mixture, the crystals precipitated
were isolated by filtration and washed with a 1:1 mixture of ether
and 2-propanol to yield 51.5 g (66 %) of 5-amino-3-(n-
octyl)amino-1H-1,2,4-triazole (5/7, Q = n-octylamino), mp
135-137°. An analytical sample was recrystallised from
After the success of the above reactions we tried to
perform them also in melt. Surprisingly, from the reaction
1
2
mixture of 5/4 (Q = methylthio) and 3/5 (NR R = ethyl-
amino) 69 % of 6/4 (Q = methylthio) and 3.7 % of 7/4 (Q =
methylthio) could be isolated by chromatography.
Analogously, from the reaction mixture of 5/5 (Q = ethyl-
+
acetonitrile, mp 138.5-139.5°; ms (ES): 212 (MH ); pmr
(DMSO-d ): δ, ppm 0.86 (t, J = 6.5 Hz, 3H, CH ), 1.25 (bs, 10H,
6
3
CH -3',4',5',6',7'), 1.45 (m, 2H, CH -2'), 2.98 (q, J = 6.5 Hz, 2H,
2
2
NHCH ), 5.2 (bs, 3H, NH and NH ), 10.65 (bs, 1H, triazole NH);
2
2
1
2
amino) and 3/5 (NR R = ethylamino) 52 % of 6/5 (Q =
ethylamino) and 1.8 % of 7/5 (Q = ethylamino) was
obtained.
cmr (DMSO-d ): δ, ppm 14.1 (CH ), 22.2, 26.7, 28.9, 29.0, 29.6,
6
3
31.4 (CH ), 43.0 (NHCH ), 160 (bm, triazole C and C ) (a mix-
2
2
3
5
ture of 1H and 2H tautomeric forms).
The mother liquor was evaporated in vacuo to dryness and
triturated with ether to yield after filtration 3.4 g of crude
5-amino-2,7-bis(n-octylamino)-1,2,4-triazolo[1,5-a][1,3,5]-
triazine (6/7, Q = n-octylamino), mp 194-197°. After recrystalli-
sation from 2-propanol 3.0 g (4 %) of pure 6/7 was obtained mp
196-196.5° (for its spectral data see Table II).
EXPERIMENTAL
Melting points were determined on a Kofler-Boëtius micro
apparatus and are uncorrected. The infrared spectra were
obtained as potassium bromide pellets using Perkin-Elmer 882
spectrophotometer. The pmr and the cmr measurements were
performed on Bruker WM-250 and Varian Unity Inova 400
(400 MHz) instruments. To confirm the assignments in some
cases standard Varian HSQC and HMBC 2D-nmr programs were
used. The ms spectra were recorded on a Kratos MS25RFA
instrument using direct inlet probe in EI or CI mode, as well as on
a VG Quattro instrument (ES).
N-Cyano-N'-(2-dimethylaminoethyl)-S-methylisothiourea (3/8,
1
2
NR R = 2-dimethylaminoethylamino).
To a suspension of 14.62 g (0.1 mole) of dimethyl N-cyan-
imidodithiocarbonate (1) (Fluka) in 150 ml of diethyl ether the
solution of 9.70 g (0.11 mole) of N,N-dimethylaminoethylamine
(Fluka) in 50 ml of diethyl ether was added dropwise with stirring

332
G. Berecz, L. Pongó, I. Kövesdi and J. Reiter
Vol. 39
at room temperature within 20 minutes. (The methylthiol liber-
ated was trapped in sodium hydroxide solution.) The thick
suspension obtained was stirred at room temperature overnight.
The crystals precipitated were isolated by filtration and washed
with diethyl ether to yield 17.2 g (92 %) of N-cyano-N'-(2-
5-Amino-3-(3-dimethylaminopropyl)amino-1H-1,2,4-triazole
(5/9, Q = 3-dimethylaminopropylamino).
To a stirred suspension of 16.02 g (0.08 mole) of N-cyano-N'-
1
2
(3-dimethylaminopropyl)-S-methylisothiourea (3/9, NR R =
3-dimethylaminopropylamino) in 80 ml of acetonitrile 3.84 g
(0.12 mole) of anhydrous hydrazine was added and the reaction
mixture stirred at room temperature for 23 hours (during the
reaction methylthiol was evolved that was trapped in sodium
hydroxyde solution). The crystals that precipitated were isolated
by filtration and washed with acetonitrile to yield 12.7 g (86 %)
of 5-amino-3-(3-dimethylaminopropyl)amino-1H-1,2,4-triazole
(5/9, Q = 3-dimethylaminopropylamino), mp 107-109°. An
1
2
dimethylaminoethyl)-S-methylisothiourea (3/8, NR R
=
2-dimethylaminoethylamino), mp 98-99°. An analytical sample
was recrystallised from a mixture of diisopropyl ether and ethyl
-1
acetate, mp 99.5-100.5°; ir ν (CN): 2173 cm ; ms (ES): 187
+)
(MH ; pmr (deuteriochloroform): δ, ppm 2.26 (s, 6H, NCH ),
3
2.52 (t, J = 6.2 Hz, 2H, NCH ), 2.57 (s, 3H, SCH ), 3.45 (bs, 2H,
2
3
NHCH ), 7.0 (bs, 1H, NH); cmr (deuteriochloroform): δ, ppm
2
14.1 (SCH ), 40.4 (NHCH ), 44.8 (NCH ), 56.2 (NCH ), 115.9
3
2
3
2
analytical sample was recrystallised from CH CN, mp
3
(CN), 169.7 (C=N).
+
105.5-107.5°; ms (ES): 185 (MH ); pmr (DMSO-d ): δ, ppm
6
Anal. Calcd. for C H N S (MW 186.28): C, 45.14; H, 7.58;
7
14 4
1.62 (qui, J = 7.0 Hz, 2H, CCH C), 2.13 (s, 6H, NCH ), 2.24
2
3
N, 30.08; S, 17.21. Found: C, 45.08; H, 7.64; N, 29.94; S, 17.30.
(t, J = 7.0 Hz, 2H, NCH ), 3.04 (q, J = 6.5 Hz, 2H, NHCH ), 5.3
2
2
5-Amino-3-(2-dimethylaminoethyl)amino-1H-1,2,4-triazole
(5/8, Q = 2-dimethylaminoethylamino).
(bs, 2H, NH ), 5.6 (bs, 1H, NH), 10.8 (bs, 1H, triazole NH); cmr
2
(DMSO-d ): δ, ppm 27.4 (CCH C), 41.4 (NHCH ), 45.1
6
2
2
(NCH ), 57.1 (NCH ), 158.4 (C-3), 160.0 (C-5)
3
2
To a stirred suspension of 9.32 g (0.05 mole) of N-cyano-N'-(2-
Anal. Calcd. For C H N (MW 184.25): C, 45.63; H, 8.75; N,
7
16 6
1
2
dimethylaminoethyl)-S-methylisothiourea (3/8, NR R
=
45.61. Found: C, 45.55; H, 8.88; N, 45.61.
2-dimethylaminoethylamino) in 50 ml of acetonitrile 2.40 g
(0.075 mole) of anhydrous hydrazine was added and the reaction
mixture stirred at room temperature for 27 hours (during the
reaction methylthiol was evolved that was trapped in sodium
hydroxyde solution). The crystals that precipitated were isolated
by filtration and washed with acetonitrile to yield 8.3 g (97 %) of
5-amino-3-(2-dimethylaminoethyl)amino-1H-1,2,4-triazole (5/8,
Q = 2-dimethylaminoethylamino), mp 159-160°. An analytical
General Method for the Direct Synthesis of Derivatives 6
A solution of 0.01 mole of the appropriate isothiourea
derivative 3 and 0.01 mole of the appropriate 5-amino-1,2,4-
triazole 5 in 10 ml of n-butanol was refluxed for the time given in
Table I. After cooling the product that precipitated was isolated
by filtration and washed with acetonitrile. For preparative
conditions and physical data of products see Table I, for their
spectral data see Table II.
sample was recrystallised from a mixture of CH CN and EtOH,
3
+
mp 159.5-161°; ms (ES): 171 (MH ); pmr (DMSO-d ): δ, ppm
6
2.14 (s, 6H, NCH ), 2.35 (t, J = 6.7 Hz, 2H, NCH ), 3.09 (q, J =
3
2
5-Amino-7-ethylamino-2-methylthio-1,2,4-triazolo[1,5-a]-
[1,3,5]triazine (6/4, Q = methylthio) and 7-Amino-5-ethylamino-
2-methylthio-1,2,4-triazolo[1,5-a][1,3,5]triazine (7/4, Q =
methylthio) – in n-Butanol.
6.7 Hz, 2H, NHCH ), 4.5-6.5 (bs, 3H, NH and NH ), 10.75 (bs,
2
2
1H, triazole NH); cmr (DMSO-d ): δ, ppm 41.0 (NHCH ), 45.4
6
2
(NCH ), 58.7 (NCH ), 160 (bm, triazole C and C ) (a mixture of
3
2
3
5
1H and 2H tautomeric forms).
Anal. Calcd. for C H N (MW 170.22): C, 42.34; H, 8.28; N,
A mixture of 9.76 g (0.075 mole) of 5-amino-3-methylthio-
1H-1,2,4-triazole (5/4, Q = methylthio) [16] and 10.75 g
(0.075 mole) of N-cyano-N'-ethyl-S-methylisothiourea (3/5,
6
14 6
49.37. Found: C, 42.24; H, 8.42; N, 49.28.
N-Cyano-N'-(3-dimethylaminopropyl)-S-methylisothiourea (3/9,
1
2
NR R = ethylamino) [12] and 75 ml of n-butanol was refluxed
with stirring for 96 hours. After cooling the product that
crystallised was isolated by filtration and washed with
acetonitrile to yield 6.6 g (39 %) of raw 5-amino-7-ethylamino-2-
methylthio-1,2,4-triazolo[1,5-a][1,3,5]triazine (6/4, Q =
methylthio) (mp 222-231°), that after recrystallisation from
160 ml of a 1:1 mixture of acetonitrile and ethanol yielded 5.4 g
(32 %) of pure 6/4 (Table I), mp 229-231°. (For its spectral data
see Table II).
1
2
NR R = 3-dimethylaminopropylamino).
To a suspension of 14.62 g (0.1 mole) of dimethyl N-cyan-
imidodithiocarbonate (1) (Fluka) in 150 ml of diethyl ether the
solution of 11.24 g (0.11 mole) of N,N-dimethyl-1,3-propane-
diamine (Fluka) in 50 ml of diethyl ether was added dropwise
with stirring at room temperature within 20 minutes. (The
methylthiol liberated was trapped in sodium hydroxide solution.)
The thick suspension obtained was stirred at room temperature
overnight. The precipitated crystals were isolated by filtration
and washed with diethyl ether to yield 18.1 g (90 %) of N-cyano-
The combined mother liquors were evaporated in vacuo to
dryness and the residue was twice dry column flash
chromatographed on Kieselgel 60 H (Merck). The elution with
dichloromethane resulted in 2.6 g (24 %) of unreacted isothiourea
1
2
N'-(3-dimethylaminopropyl)-S-methylisothiourea (3/9, NR R =
3-dimethylaminopropylamino), mp 90-91°. An analytical sample
was recrystallised from a mixture of diisopropyl ether and ethyl
1
2
3/5 (NR R = ethylamino). Continuing the chromatography with
100:1 and 100:2 mixtures of dichloromethane and methanol
resulted in a mixture of 6/4 (Q = methylthio) and 7/4 (Q =
methylthio), that was chromatographed again using a 1:1 mixture
of cyclohexane and ethyl acetate. This way 0.64 g (3.8 %) of
7-amino-5-ethylamino-2-methylthio-1,2,4-triazolo[1,5-a]-
[1,3,5]triazine (7/4) was obtained that after recrystallisation from
-1
+
acetate, mp 90-91°; ir ν (CN): 2176 cm ; ms (ES): 201 (MH );
pmr (deuteriochloroform): δ, ppm 1.73 (qui, J = 5.5 Hz, 2H,
CCH C), 2.28 (s, 6H, NCH ), 2.44 (s, 3H, SCH ), 2.54 (t, J = 5.4
2
3
3
Hz, 2H, NCH ), 3.50 (t, 2H, NHCH ), 9.4 (bs, 1H, NH); cmr
2
2
(deuteriochloroform): δ, ppm 13.4 (SCH ), 23.6 (CCH C), 44.5
3
2
(NHCH ), 44.5 (NCH ), 58.4 (NCH ), 115.5 (CN), 169.7 (C=N).
2
3
2
+
Anal. Calcd. For C H N S (MW 200.31): C, 47.97; H, 8.05;
acetonitrile melted at 203-205°; ms (EI): 225 (M ); pmr
8
16 4
N, 27.97; S, 16.01. Found: C, 48.11; H, 8.30; N, 27.86; S, 15.99.
(DMSO-d ): δ, ppm 1.09 (t, J = 7.0 Hz, 3H, CCH ), 2.56 (s, 3H,
6
3

Mar-Apr 2002
On Triazoles XLV. Synthesis of 5,7-Diamino-1,2,4-triazolo[1,5-a][1,3,5]triazines
333
SCH ), 3.26 (qui, J = 6.4 Hz , 2H, NHCH ), 7.35 (t, J = 5.5 Hz,
bis(ethylamino)-1,2,4-triazolo[1,5-a][1,3,5]triazine (7/5, Q =
3
2
1H, NH), 7.95 (bs, 2H, NH ); cmr (DMSO-d ): δ, ppm 13.35
ethylamino) was obtained that after washing with ether melted at
2
6
+
(SCH ), 14.7 (CH ), 35.5 (NHCH ), 149.4 (C-7), 159.4 (C-3a),
202-205°. ms (EI): 222 (M ); pmr (DMSO-d ): δ, ppm 1.09
3
3
2
6
161.0 (C-5), 165.2 (C-2).
Anal. Calcd. for C H N S (MW 225.28): C, 37.32; H, 4.92;
(t, J = 7.2 Hz, 3H, CCH -5), 1.13 (t, J = 7.1 Hz, 3H, CCH -2),
3
3
3.26 (m, 4H, NHCH
-2,5), 6.29 (t, J = 5.7 Hz, 1H, NH-2), 7.03
2
7
11 7
(t, 1H, NH-5), 7.44 (bs, 2H, NH ); cmr (DMSO-d ): δ, ppm 14.9
N, 43.52; S, 14.23. Found: C, 37.30; H, 5.03; N, 43.48; S, 14.19.
Continuing the chromatography with pure ethyl acetate a sec-
ond 1.26 g (7.5 %) crop of 6/4 (Q = methylthio) was obtained, mp
226-228° (acetonitrile/ethanol).
2
6
(CH -5), 15.2 (CH -2), 35.4 (NHCH -5), 36.9 (NHCH -2),
3
3
2
2
149.4 (C-7), 158.6 (C-3a), 160.9 (C-5), 165.6 (C-2).
Anal. Calcd. for C H N (MW 222.25): C, 43.23; H, 6.35; N,
8
14 8
50.42. Found: C, 43.30; H, 6.45; N, 50.38.
5-Amino-7-ethylamino-2-methylthio-1,2,4-triazolo[1,5-
a][1,3,5]triazine (6/4, Q = methylthio) and 7-Amino-5-ethyl-
amino-2-methylthio-1,2,4-triazolo[1,5-a][1,3,5]triazine (7/4, Q =
methylthio) – in Melt.
Crystal Structure Analysis of 6/5 [7].
Crystal data: C
H
N , Fwt.: 222.27, monoclinic, space
14 8
8
group P 2 /n, a = 7.240(2)Å, b = 13.315(2)Å, c = 11.009(1)Å, β
1
3
A mixture of 3.90 g (0.03 mole) of 5-amino-3-methylthio-1H-
1,2,4-triazole (5/4, Q = methylthio) [16] and 4.32 g (0.03 mole)
= 90.42(1)°, V = 1061.3(3) Å , T = 293(2)K, Z = 4, F(000) = 472,
3
-1
Dx =1.391Mg/m , µ = 0.097mm . crystal size: 0.40 x 0.22 x
0.10 mm. Intensities of 4677 reflections (4407 unique, 2191 >
2σ(I)) were collected on an Enraf-Nonius CAD4 diffractometer
with graphite monochromated Mo-Kα radiation, λ = 0.71070 Å)
at 293(2)K in the range 2.40° ≤ θ ≤ 34.22° using ω/θ scans. No
absorption correction was applied. The structure was solved by
direct methods and refined in anisotropic approximation by full-
1
2
of N-cyano-N'-ethyl-S-methyl-isothiourea (3/5, NR R = ethyl-
amino) [12] was melted at 150° for 6 hours. After cooling 30 ml
of acetonitrile was added to the melt obtained, the product that
crystallised was isolated by filtration and washed with
acetonitrile to yield 4.75 g of raw 5-amino-7-ethylamino-2-
methylthio-1,2,4-triazolo[1,5-a][1,3,5]triazine (6/4, Q =
methylthio) that was dry column flash chromatographed on
Kieselgel 60 H (Merck), eluent a 97:3 mixture of
dichloromethane and methanol. After collecting and evaporating
the appropriate fractions and triturating the residue with
acetonitrile 4.30 g (63.5 %) of pure 5-amino-7-ethylamino-2-
methylthio-1,2,4-triazolo[1,5-a][1,3,5]triazine (6/4, Q =
methylthio) was obtained, mp 222-227° that was identical (ir,
pmr) with that 6/4 obtained above.
2
matrix least-squares refinement on F for all non-hydrogen atoms
to R1 = 0.075 and wR2 = 0.234 for I>2σ(I) (R1 = 0.1836 and
wR2 = 0.312 for all intensity data, goodness-of-fit = 1.007; the
maximum and mean shift/esd 0.136 and 0.005). Number of
parameters = 147. The maximum and minimum residual electron
density in the final difference map was 0.534 and -0.438e/ Å .
Hydrogen atomic positions were located from assumed
geometries, but were not refined.
3
Evaporating the mother liquor of raw 6/4 to dryness and dry
column flash chromatography of the residue on Kieselgel 60 H
using the method described in the previous experiment 0.25 g
(3.7 %) of 7-amino-5-ethylamino-2-methylthio-1,2,4-tria-
zolo[1,5-a][1,3,5]triazine (7/4, Q = methylthio) was obtained that
after recrystallisation from acetonitrile melted at 203-205°. The
product is identical (ir, pmr) with that of 7/4 obtained in the
previous experiment.
Acknowledgement
The authors wish to express their thanks to Dr. Gyula Argay
and Dr. Alajos Kálmán for performing the crystal structure
analysis, to Mrs. Sándorné Sólyom for recording the ir spectra, to
Mrs. Magdolna Nagy for recording the nmr spectra, to Mr.
Kálmán Újszászy, Dr. Éva Szabó and Dr. Péter Slégel for
recording the ms spectra, to Mrs. Magdolna Hirkóné-Csík for
performing the elemental analyses and to Mrs. Erika Korenné-
Ausländer and Mr. Tibor Merczel for technical assistance.
Continuing the chromatography with pure ethyl acetate a
second 0.38 g (5.5 %) crop of 6/4 (Q = methylthio) was obtained.
5-Amino-2,7-bis(ethylamino)-1,2,4-triazolo[1,5-a][1,3,5]triazine
(6/5, Q = ethylamino) and 7-Amino-2,5-bis(ethylamino)-1,2,4-
triazolo[1,5-a][1,3,5]triazine (7/5, Q = ethylamino) – in Melt.
REFERENCES AND NOTES
A mixture of 2.54 g (0.02 mole) of 5-amino-3-ethylamino-1H-
1,2,4-triazole (5/5, Q = ethylamino) and 2.86 g (0.02 mole) of
[1] For Part XLIV see G. Berecz, J. Reiter, Gy. Argay and
A. Kálmán, J. Heterocyclic Chem., 39, 319 (2002).
[2] J. Reiter, T. Somorai, E. Kasztreiner, L. Toldy, T. Somogyi and
T. Balogh, Hung. Pat. No. 181743; Chem. Abstr. 99, 70405d (1983).
[3] Houben-Weyl: Methoden der organischen Chemie, Band E4
(1983), p. 1296.
[4] J. Reiter, L. Pongó, T. Somorai and P. Dvortsák,
J. Heterocyclic Chem., 23, 401 (1986).
[5] Houben-Weyl: Methoden der organischen Chemie, Band E8d
(1994), p. 518.
1
2
N-cyano-N'-ethyl-S-methyl-isothiourea (3/5, NR R = ethylamino)
[12] was melted at 160° for 1 hour. After cooling 20 ml of
acetonitrile was added to the melt obtained, the product that
crystallised was isolated by filtration and washed with acetonitrile
to yield 3.17 g of raw 5-amino-2,7-bis(ethylamino)-1,2,4-tria-
zolo[1,5-a][1,3,5]triazine (6/5, Q = ethylamino) that was dry
column flash chromatographed on Kieselgel 60 H (Merck), eluent
a 95:5 mixture of dichloromethane and methanol. After collecting
and evaporating the appropriate fractions 2.32 g (52 %) of pure
5-amino-2,7-bis(ethylamino)-1,2,4-triazolo[1,5-a][1,3,5]triazine
(6/5, Q = ethylamino) was obtained, mp 270-281° that was
identical (ir, pmr) with that of 6/5 obtained above.
"
[6] J. Reiter, G. Berecz, G. Zsila, L. Petocz, M. Fekete, G. Gigler,
"
"
M. Csörgo, F. Görgényi, M. Szécseyné Hegedu s, L. Rohácsné
Zamkovaja, E. Szirtné Kiszelly, Hung. Pat. No. 208693; Chem. Abstr.
118, 234093q (1993).
Evaporating the mother liquor of raw 6/5 to dryness and dry
column flash chromatography of the residue on Kieselgel 60 H
using ethyl acetate as eluent 0.08 g (1.8 %) of 7-amino-2,5-
[7] Crystallographic data for compound 6/5 reported in this paper
have been deposited at the Cambridge Crystallographic Data Center
(deposition number CCDC 173153).

334
G. Berecz, L. Pongó, I. Kövesdi and J. Reiter
Vol. 39
[8] P. W. R. Caulkett, G. Jones, M. McPartlin, N. D. Renshaw,
[14] We have repeated the experiment described in [11] leading to
S. K. Stewart and B. Wright, J. Chem. Soc. Perkin Trans. 1, 801 (1995).
[9] J. Reiter, L. Pongó and P. Dvortsák, J. Heterocyclic Chem., 24,
127 (1987).
5/5 (Q = ethylamino) but obtained for 5/5 a mp 155-156° with spectral
+
data: ms (EI): 127 (M ); pmr (DMSO-d ): δ, ppm 1.07 (t, J = 7.1 Hz, 3H,
6
CH ), 3.04 (qi, J = 6.5 Hz, 2H, CH ), 5.3 (bs, 2H, NH ), 5.6 (bs, 1H, NH),
3
2
2
[10] J. Reiter, L. Pongó and P. Dvortsák, J. Heterocyclic Chem., 24,
1685 (1987).
10.8 (bs, 1H, triazole NH); cmr (DMSO-d ): δ, ppm 15.4 (CH ), 37.6
6 3
(CH ), 156.1 (C-3), 162.4 (C-5).
2
1
2
[11] T. Okabe, B. Bhooshan, T. Novinson, I. W. Hillyard,
G. E. Garner and R. K. Robins, J. Heterocyclic Chem., 20, 735 (1983).
[15] Compound 3/7 (NR R = n-octylamino) was prepared
+
according to [2], mp 115-116° (2-PrOH); ms (ES): 228 (MH ); ir: ν
1
2
-1
[12] Compound 3/5 (NR R = ethylamino) was synthesised
(CN): 2170 cm ; pmr (DMSO-d ): δ, ppm 0.86 (t, J = 6.5 Hz, 3H, CH ),
6
3
according to [2]. Lit. [11] mp 160°, our mp 163-164° (2-PrOH); ms (EI):
1.25 (bs, 10H, CH -3',4',5',6',7'), 1.51 (qui, J = 6.5 Hz, 2H, CH -2'), 2.56
2 2
(s, 3H, SCH ), 3.26 (t, J = 7.0 Hz, 2H, NHCH ), 8.34 (bs, 1H, NH); cmr
3 2
+
-1
143 (M ); ir: ν (CN): 2171 cm ; pmr (DMSO-d ): δ, ppm 1.10 (t, J = 7.1
6
Hz, 3H, CH ), 2.56 (s, 3H, SCH ), 3.31 (q, J = 7.1 Hz, 2H, CH ), 8.34
(DMSO-d ): δ, ppm 14.05 (CH ), 14.17 (SCH ), 22.2, 26.3, 28.2, 28.72,
6 3 3
3
3
2
(bs, 1H, NH); cmr (DMSO-d ): δ, ppm 13.6 (SCH ), 14.0 (CH ), 38.2
28.74, 31.4 (CH ), 43.3 (NHCH ), 116.1 (CN), 169.7 (C=N).
2 2
6
3
3
(CH ), 115.6 (CN), 169.6 (C=N).
[16] J. Reiter, T. Somorai, Gy. Jerkovich and P. Dvortsák,
J. Heterocyclic Chem., 19, 1157 (1982).
2
˘
[13] J. Zmitek, Vestn. Slov. Kem. Drus., 39, 497 (1992).