A novel synthetic route to new 1,2,4-triazolo-1,3,5-triazin-4-ones derivatives

Article abstract of DOI:10.1080/10426500500269380

The reaction of ethyl chloroformate with iminoesters derived from 3-aminotriazole, followed by amine or phenyl hydrazine condensation, leads to a variety of 1,2,4-triazolo-1,3,5-triazin-4-ones in a 60-85% overall yield. Copyright Taylor & Francis Group, L

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Phosphorus, Sulfur, and Silicon
and the Related Elements
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A Novel Synthetic Route to
New 1,2,4-Triazolo-1,3,5-
triazin-4-ones Derivatives
Raoudha Abderrahim a
a Département de Chimie, Faculté des Sciences de
Bizerte , Tunis Campus Universitaire , Zarzouna,
Tunisie
Published online: 01 Feb 2007.
To cite this article: Raoudha Abderrahim (2006) A Novel Synthetic Route to New
1,2,4-Triazolo-1,3,5-triazin-4-ones Derivatives, Phosphorus, Sulfur, and Silicon and the
Related Elements, 181:3, 581-585, DOI: 10.1080/10426500500269380
To link to this article: http://dx.doi.org/10.1080/10426500500269380
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Phosphorus, Sulfur, and Silicon, 181:581–585, 2006
Copyright © Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500500269380
A Novel Synthetic Route to New
1,2,4-Triazolo-1,3,5-triazin-4-ones Derivatives
Raoudha Abderrahim
De´partement de Chimie, Faculte´ des Sciences de Bizerte, Tunis Campus
Universitaire, Zarzouna, Tunisie
The reaction of ethyl chloroformate with iminoesters derived from 3-aminotriazole,
followed by amine or phenyl hydrazine condensation, leads to a variety of 1,2,4-
triazolo-1,3,5-triazin-4-ones in a 60–85% overall yield.
Keywords 1,2,4-triazolo-1,3,5-triazin-4-ones; 3-amino-triazole; amine; Ethylchlorofor-
mate; iminoesters; phenyl hydrazine
INTRODUCTION
Its important to note here that triazolo-triazines and its derivatives
are known for their useful properties, ranging from pharmacologi-
cal and biological activities.1–3 For instance, in recent years, some
triazolo–triazine compounds have shown potent antitumor and antivi-
ral activity.4–8 Our interest for theses compounds is due to the well-
known, interesting pharmaceuticals properties.
A variety of methods were used to obtain triazolo–triazine
derivatives.8–12
RESULT AND DISCUSSION
We have successfully obtained substituted triazolo-triazine 3 or 4 start-
ing from iminoesters 1 in a two-step transformation. Iminoesters 1
were treated with an equivalent of ethyl chloroformate in the pres-
ence of a small excess of pyridine in order to form N-3- (4-carbethoxy)
triazolyl imidate 2. Furthermore, the mixture of an excess of amine
and compound 2 was heated under reflux for 4 h to transform them
into triazolo-triazine 3, presumably via the intermediate A (Scheme 1).
Received March 10, 2005; accepted May 10, 2005.
Address correspondence to Raoudha Abderrahim, De´partement de Chimie, Faculte´
Des Sciences de Bizerte, Tunis Campus Universitaire, Zarzouna, 7021 Tunisie. E-mail:
abderrahim raoudha@yahoo.fr
581

582
R. Abderrahim
SCHEME 1
The condensation of phenyl hydrazine with compound 2 at r.t. leads to
triazolo-triazine 4 after 5 days.
The structure of compound 2 was deduced from their IR and 1H NMR
spectra.
The structural features of our target compounds 3 or 4 were eluci-
dated by IR and 1H and 13C spectral data.
The formation of compound 3 was confirmed by the IR spectra show-
ing a strong band in the region of 1720–1740 cm−1 assigned to the

New 1,2,4-Triazolo-1,3,5-triazin-4-ones Derivatives
583
carbonyl group and another band in the region 1620 cm−1 assigned for
C N. The IR and 1H NMR data confirm the structure of compound 4.
The IR spectrum of 4 exhibited absorption bands for NH, C N, and
C O groups. 1H NMR spectrum recorded in DMSO—d6 revealed a sin-
glet in the region of δ = 7.5–7.8, attributed to the NH proton.
The 13C NMR spectra display the characteristic signals of all carbons.
From a mechanistic viewpoint, we have isolated one intermediate
A. The attack of the carbon of the carbamate group by the nitro-
gen atom of the amine forms A. The latter undergoes intramolecu-
lar nucleophilic cyclization to give the derivatives of triazolotriazines 3
(Scheme 1).
The condensation of phenyl hydrazine and compound 2 at r.t. gives
4; we could not isolate intermediate B.
EXPERIMENTAL
IR spectra were run in a CHCl3 solution on a Perkin Elmer Paragon
1000 PC spectrometer.
1H and 13C NMR spectra were recorded with CDCl3 or (CD3)2SO as
a solvent containing TMS on a Bruker 300 spectrometer. The chemical
shifts are reported in ppm relative to TMS (internal reference). For the
H NMR, the multiplicities of signals are indicated by the following ab-
breviations: s: singlet; d: doublet; t: triplet; q: quartet; and m: multiplet.
Melting points were obtained using a Bu¨chi melting point apparatus.
Synthesis of Imidates Type 1
Imidates type 1 was obtained from the condensation of 3-amino-1,2,4-
triazole with an excess of orthoester in the presence of acetic acid. The
mixture was refluxed for 3 h; the solvent was evaporated under reduced
pressure. The solid product so formed was filtered according to the pub-
lished procedure.13–15
Synthesis of Imidates Type 2
To a mixture of 0.011 mol of imidate 1 and 0.012 mole of pyridine in
50 mL of anhydrous ether, 0.011 mol of ethyl chloroformate was added
drop wise at 0◦C. The mixture was stirred for 3 h. The pyridinium
chlorhydrate obtained was filtered, and the solvent was removed un-
der reduced pressure. The resulting solid was washed three times with
anhydrous Et2O and then used for further steps.

584
R. Abderrahim
2a: Yield: 90%, m.p. = 110, IR (CHCl3) νCO = 1770 cm−1, νCN = 1660
cm−1, NMR 1H (CDCl3): 8.7(s, 1H), 4.5(q, 4H), 1.4(t, 6H), 2.2(s, 3H).
2b: Yield: 80%, m.p. = 127◦C, IR (CHCl3) νCO = 1770 cm−1, νCN = 1660
cm−1, NMR 1H (CDCl3): 8.7(s, 1H), 4.5(q, 4H), 1.4(t, 9H), 2.5(q, 2H).
2c: Yield: 85%, m.p. = 63◦C, IR (CHCl3) νCO = 1770 cm−1, νCN = 1660
cm−1, NMR 1H (CDCl3): 8.5(s, 1H), 4.5(q, 4H), 1.4(t, 6H), 7.3(s, 5H).
Synthesis of Triazolo-Triazinones 3 and 4
Synthesis of 1,2,4-Triazolo-1,3,5-triazine-4-ones 3
The treatment of compound 2 with an excess of amine using methanol
as a solvent and heating the mixture under reflux for 4 h gave 3. The sol-
vent was removed under reduced pressure; the solid product so formed
was collected by filtration, dried, and recrystallized from ethanol to give
3.
Intermediate A: Yield = 50% m.p. = 160◦C, IR (CHCl3 ν(cm−1)):
1
νNH = 3460; νC
= 1650, νC
= 1750, H NMR (CDCl3): 4. 7(1, 2H);
N
O
7.3–7.6(mu, 9H); 9.8(s, 1H); 8.5(1, 1H); 1.4(t, 3H); 4.3(q, 2H).
3a: Yield = 60%, m.p. = 190◦C, IR (CHCl3 ν(cm−1)): νC
= 1610,
N
1
νC
= 1710, H NMR (CDCl3): 2.4(s, 3H); 7–7.4(mu, 5H); 10(s, 1H,
O
13C NMR (CDCl3): 15.7; 124; 138; 129; 131; 141.5; 148; 159.5; 160.
3b: Yield = 67%, m.p. = 160◦C, IR (CHCl3, ν(cm−1)): νC
= 1615,
N
1
νC
= 1710, H NMR (CDCl3): 1.2(t, 3H); 2.4(q, 2H); 7–7.4(mu, 5H);
O
10(s, 1H). 13C NMR (CDCl3): 10.5; 30; 124; 129.5; 138; 140; 141.2; 147;
157.5; 160.
3c: Yield = 63%, m.p. = 210◦C, IR (CHCl3, ν(cm−1)): νC
= 1610,
N
νC
= 1710, 1H NMR (CDCl3): 2.2(s, 3H); 4.6(1, 2H); 7.2–7.4(mu, 5H);
O
10 (s, 1H). 13C NMR (CDCl3): 17.5; 46; 128; 129; 130.7; 136.4; 141.2;
151; 157.5; 161.
Analyze Calcd.: %C = 55.6 % H = 4.5 % N = 29.0
Found: %C = 55.0 % H = 4.3 % N = 28.7
3d: Yield = 65%, m.p. = 172◦C, IR (CHCl3 ν(cm−1)): νC
= 1610,
N
νC
= 1710, 1H NMR (CDCl3): 2.2(q, 2H); 4.6(1, 2H); 7.2–7.4(mu, 5H);
O
10(s, 1H). 13C NMR (CDCl3): 12.5; 29; 46; 128; 129; 130.7; 136.4; 141.2;
151; 157.5; 161.
3e: Yield = 60%, m.p. = 212◦C, IR (CHCl3, ν(cm−1)): νC
= 1610,
N
νC
= 1720, 1H NMR (CDCl3: 4.6(1, 2H); 7.2–8.6(mu, 10H); 9.6(s, 1H).
O
13C NMR (CDCl3): 47; 125; 128; 129; 130.7; 136.4; 141.2; 151; 156; 157.5;
164.
3f: Yield = 78% m.p. = 175◦C, IR (CHCl3, ν(cm−1)): νC
= 1620,
N
νC
= 1725, 1H NMR (CDCl3): 2.4(s, 3H); 4.7(1,2H); 7.2–7.6.(mu, 4H);
O
10(s, 1H).

New 1,2,4-Triazolo-1,3,5-triazin-4-ones Derivatives
585
3g: Yield = 75%, m.p. = 185◦C, IR (CHCl3 ν(cm−1)): νC
= 1620,
N
1
νC
= 1725, H NMR (CDCl3); 4.7(1, 2H); 7.2–7.6. (mu, 10H); 9.7(s,
O
1H).
Synthesis of Triazolo-Triazine 4
Treatment of iminoesters 2 with an excess of phenyl hydrazine at r.t.
for 5 days in methanol gave 4. The solvent was removed under reduced
pressure, and the solid was crystallized in methanol.
4a Yield = 70%, m.p. = 225◦C, IR (KBr, ν(cm−1)): νNH = 3360,
νC
= 1630, νC
= 1725, 1H NMR ((CD3)2SO): 2.1(s, 3H), 7–7.2(mu,
N
O
5H); 7.7(s 1H); 7.8(mu, 1H); 9.7(s, 1h).
4b Yield = 75%, m.p. = 205◦C, IR (KBr ν(cm−1)): νNH = 3360
νC
1630, νC
1725, 1H NMR ((CD3)2SO): 2.55(q, 2H), 1.2(t, 3H)
O
N
7–7.2 (mu, 5H); 7.7(s, 1H); 7.8(mu, 1H); 9.7(s, 1H).
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