Aromatization and ring cyclization: A reasonable understanding on the ring cyclization mechanism of 3-amino-6-hydrazino-1,2,4-triazin-5(2H)-one reacted with one-carbon fragment reagents or nitrous acid

Article abstract of DOI:10.1002/jhet.5570430412

The cyclization mechanism for the title compound (2) reacting with one-carbon fragment reagents or nitrous acid to afford heterobicyclic compounds 6-amino-3-substituted-1,2,4-triazolo[3,4-f][1,2,4]triazin-8(7H)-ones (3a-d) or 6-amino-1,2,3,4-tetrazolo[5,1

Full text of DOI:10.1002/jhet.5570430412

Jul-Aug 2006
Aromatization and Ring Cyclization: A Reasonable Understanding on the
Ring Cyclization Mechanism of 3-Amino-6-hydrazino-1,2,4-triazin-5(2H)-one
Reacted with One-carbon Fragment Reagents or Nitrous Acid
889
Long-Chih Hwanga*, Chun-Hsien Tub and Jung-Hui Wangc
a Faculty of Medicinal and Applied Chemistry, Kaohsiung Medical University, Kaohsiung City 80708, Taiwan,
ROC E-mail: lnchhw@kmu.edu.tw
b Department of Psychiatry, Veterans Hospital of Longchuan, Pingtung 912, Taiwan, ROC
c Department of Pharmacy, Veterans General Hospital of Kaohsiung, Kaohsiung City 807, Taiwan, ROC
Received August 22, 2005
O
O
O
NHNH2
NHNH2
N
a, b, c, d, e
b, e
N
HN
H2N
N
O
N
N
N
N
X
R
N
H
N
H2N
N
H2N
a, HCOOH;
HO
b, CH COOH;
3
c, CNBr, H O;
2
3a~d : X = C
2
16
d, CS , C H N/H O;
e, NaNO , HCl.
2
5
5
2
R = H, CH , NH , SH
3
2
2
4
: X = N
O
O
N
O
N
NHNH2
R
N
N
N
N
a, b, c, e
a, b, c, e
N
N
N
N
X
R
N
H2N
H2N
H2N
10
H
O
O
N
H
O
NHNH2
N
N
N
CH3COOH
- H2O
HN
H2N
N
N
H
N
N
N
N
H2N
N
H
H2N
N
H3C
O
CH3
18
2
3b
The cyclization mechanism for the title compound (2) reacting with one-carbon fragment reagents or
nitrous acid to afford heterobicyclic compounds 6-amino-3-substituted-1,2,4-triazolo[3,4-f][1,2,4]triazin-
8(7H)-ones (3a~d) or 6-amino-1,2,3,4-tetrazolo[5,1-f][1,2,4]triazin-8(7H)-one (4), respectively, is explored
in this paper. When 3-amino-2-benzyl-6-hydrazino-1,2,4-triazin-5(2H)-one (10), the N-2 benzylated
derivative of 2, is treated under the same conditions, ring cyclization does not occur; instead, 3-amino-2-
benzyl-6-substituted-1,2,4-triazin-5(2H)-ones (11,12,14) and 2-N-(2-amino-1-benzyl-4-oxo-1,2,4-triazin-5-
yl)semicarbazide (13) are formed. Alternatively, when 3-amino-6-hydrazino-2-[(2-hydroxyethoxy)methyl]-
1,2,4-triazin-5(2H)-one (16), a compound bearing the 2-[(2-hydroxyethoxy)methyl] side-chain at N-2 of 2
by an N-C-O bond, reacts with glacial acetic acid or nitrous acid, the side-chain is cleaved through
acidolysis to affford the ring-closed compound 6-amino-3-methyl-1,2,4-triazolo[3,4-f][1,2,4]triazin-8(7H)-
one (3b) or compound 4, respectively. From these results, we suggest a cyclization mechanism that the ring
cyclization is dependent on the aromatization of the 1,2,4-triazine ring, which influence the reactivity and
reaction behavior of the ꢀ-deficient 1,2,4-triazine.
J. Heterocyclic Chem., 43, 889 (2006).
O
N
O
N
Introduction.
N
H
N
HN
H2N
HN
H2N
The 1,2,4-triazines and their condensed derivatives
form an important class of heteroaromatic compounds
with various biochemically interesting properties and
pharmacologically significant activities [1-5]. The
structure moiety of 6-amino-1,2,4-triazolo[3,4-f][1,2,4]-
triazin-8(7H)-one (1), the isosteric isomer of guanine, is a
tautomeric heterobicycle which may retain the Watson-
Crick type hydrogen bonding sites of the aglycon moiety.
N
N
N
H
1
Guanine
O
O
H
N
N
N
HN
N
N
N
N
H2N
N
N
H
H2N
N
H2N
CH3
5
2H-tautomer 6
7H-tautomer 7

890
L. C. Hwang, C. H. Tu and J. H. Wang
Vol 43
Derivatives of 1 may be prepared from suitably
substituted 1,2,4-triazoles as reported by Becker et al. [6].
acid, glacial acetic acid or cyanogen bromide) or nitrous
acid, expecting no observed ring cyclization.
Lovelette, however, described
a
more convenient
synthesis and facile ring closure reaction by reacting the
compound 3-amino-6-hydrazino-1,2,4-triazin-5(2H)-one
(2) with one-carbon fragment reagents (e.g. aliphatic
acids, orthoesters, cyanogen bromide or carbon disulfide)
or nitrous acid to afford 6-amino-3-substituted-1,2,4-
triazolo[3,4-f][1,2,4]triazin-8(7H)-ones (3a~d), 3-substi-
tuted derivatives 1, or 6-amino-1,2,3,4-tetrazolo[1,5-f]-
[1,2,4]triazin-8(5H)-one (4), respectively (Scheme 1) [7].
O
N
H
N
O
N
H
N
O
H
N
H
O
N
N
H
O
H
O
N
O
N
N
N
N
H2N
R
N
N
H2N
R
H2N
N
H
R
HO
Type I
Type II
Type III
Figure 1. Illustration on the electron resonance of three different structure types.
On the contrary, a side-chain on N-2 may undergo
bond-breaking and then the 1,2,4-triazine ring may be
aromatized by the electron pair resonating from N-2 to 5-
oxo (Figure 1. type III structure). In such a case, ring
cyclization will be observed. As we know, the chemical
character of methylene carbon in N-C-O bond is similar to
that in O-C-O bond, which could be acidolyzed in acidic
conditions. Accordingly, we synthesized the compound
3-amino-6-hydrazino-2-[(2-hydroxyethoxy)methyl]-
1,2,4-triazin-5(2H)-one (16) which contains a 2-[(2-
hydroxyethoxy)methyl] side-chain attached by an N-C-O
bond on N-2 of compound 2, then treated 16 with glacial
acetic acid or nitrous acid, trying to validate the
cyclization mechanism.
Scheme 1
O
N
O
NHNH2
N
a, b, c, d, e
HN
H2N
N
N
N
N
X
R
N
H
H2N
3a~d : X = C
R = H, CH3, NH2, SH
4 : X = N
2
a, HCOOH; b, CH3COOH; c, CNBr, H2O; d, CS2, C5H5N/H2O;
e, NaNO2, HCl.
Since the correct dominant tautomeric structure makes it
possible to properly interpret the detailed mechanisms of
reactions, the biological activities and the functions of
tautomeric heterocycles [8], we investigated on the
Kekulé structure which gave higher contribution to the
ground state of the basic structure 3-amino-1,2,4-triazine
(5) [9]. Additionally, we studied the prototropic tautom-
erism of 3-amino-1,2,4-triazin-5(2H)-one (6) and 6-
amino-3-ethyl-1,2,4-triazolo[3,4-f][1,2,4]triazin-8(7H)-
one (7) by X-ray crystallographic analysis [10,11], which
revealed the predominant tautomeric structure of
compound 6 as the 2H-tautomer and that of compound 7
as the 7H-tautomer (not the 5H-tautomer as speculated by
Lovelette [7]). These results inspired us to understand
more about the actual mechanism for this ring cyclization
of the compound 2 reacting with one-carbon fragment
reagents to afford tautomeric heterobicycles (3). One of
our previous study [12] has proved the hypothesis that the
ring cyclization is dependent on the resonance of the 2H-
5-one to the 5-ol on the 1,2,4-triazine ring (Figure 1. type
I structure). This is based on the fact that when 3-amino-
2-benzyl-6-hydrazino-1,2,4-triazin-5(2H)-one (10), an
N-2 benzylated derivative of 2, is treated with N,N-
dimethylformamide (DMF) and acetic acid to afford 3-
amino-2-benzyl-6-(2-formylhydrazino)-1,2,4-triazin-
5(2H)-one (11), no ring cyclization is observed since the
N-2 benzyl group prevents the prototropic tautomerism
required in the formation of the aromatic intermediate
(Figure 1. type II structure). Similar to the above way to
clarify the cyclization mechanism, in this paper we treated
compound 10 with one-carbon fragment reagents (formic
Results and Discussion.
We improved the product yield (>50%) of the requisite
compound 3-amino-2-benzyl-6-bromo-1,2,4-triazin-5(2H)-
one (9), which was prepared by a new method from 3-
amino-6-bromo-1,2,4-triazin-5(2H)-one (8) refluxed with
potassium carbonate and benzyl bromide in dry acetone
catalyzed by 18-crown-6-ether (Scheme 2). Compound 9
is identical in every respect with the corresponding
compound in our previous report [12]. Hydrazination of 9
gave compound 10 successfully by nucleophilic hetero-
aromatic substitution (the hydrazination mechanism as
illustrated in Scheme 2).
Scheme 2
O
O
Br
N
Br
K2CO3
N
N
H2N
N
N
C6H5CH2Br
H2N
N
H
8
9
NH2NH2
O
N
O
NHNH2
Br
NHNH2
N
N
N
N
H2N
H2N
N
10

Jul-Aug 2006
Aromatization and Ring Cyclization: Mechanism of
891
3-Amino-6-hydrazino-1,2,4-triazin-5(2H)-one
Scheme 3 shows that compound 10 reacts with one-
carbon fragment reagents or nitrous acid to afford
compounds 11-14, respectively. Compound 10 was
treated with hot formic acid to give 3-amino-2-benzyl-6-
cm-1, which was diagnostic for the existence of the 6-
azido functional group.
1
(2-formylhydrazino)-1,2,4-triazin-5(2H)-one (11). The H
nmr spectrum revealed a conformer mixture of 11 in a
ratio of about 2:1, and the same chemical shift was
observed between the major conformer and the product
from 10 reacted with DMF and acetic acid [12].
11 (MM2)
12 (MM2)
When compound 10 was treated with hot glacial acetic
acid,
3-amino-2-benzyl-6-(2-acetylhydrazino)-1,2,4-
triazin-5(2H)-one (12) was isolated. The 1H nmr spectrum
found a conformer mixture of 12 in a ratio of about 10:1,
and revealed ꢀ 1.81 (COCH3), 8.04 (NHNHCO) and 9.60
(NHNHCO) ppm for the acetylhydrazino group. The
structures of the major conformers of 11 and 12 were
derived from the MM2 and ab initio HF/6-31G
minimization calculations carried out by the CSGAMESS
suite of computer programs. Figure 2 shows the most
stable conformations and major/minor conformers of 11
and 12.
12 (HF/6-31G)
11 (HF/6-31G)
R
H
N
H
O
O
N
N
O
N
N
R
N
H
N
H
N
N
N
H N
2
H N
2
11 R = H
12 R = CH3
Scheme 3
major conformer
minor conformer
H
N
O
N
O
R
N
H
N
Figure 2
RCOOH
N
H2N
The existence of benzyl groups of these compounds
11-14 was shown by its 1H nmr spectrum. The ir spectra
of the carbonyl groups on 11-14 (i.e., 1666, 1639, 1679
and 1642 cm-1, respectively) suggested that these four
compounds did not undergo acidolysis and the ring
closure didn’t occur, because the intense ir absorption at
1719-1725 cm-1 (the carbonyl absorption for fused
triazines) indicated the occurrence of ring closure
[6,7,12]. This result proved that if tautermerism of the
2H-5-one to the 5-ol on the hydrazino-1,2,4-triazine did
not occur, no cyclization would be observed (Figure 1.
type II structure).
11 R = H
12 R = CH3
O
N
H
N
O
O
NHNH2
N
NH2
BrCN
H2O
N
H
N
N
H2N
N
N
H2N
10
13
O
N3
On the other hand, we prepared compound 16 by
refluxing 3-amino-6-bromo-2-[(2-hydroxyethoxy)methyl]-
1,2,4-triazin-5(2H)-one (15) [13] with hydrazine mono-
hydrate in ethanol (Scheme 4). The 6-hydrazino group of
N
NaNO2
HCl
N
N
H2N
1
14
16 was characterized by the H nmr spectrum at ꢀ 3.92
(NHNH2) and 7.30 (NHNH2) ppm. When 16 was treated
with hot glacial acetic acid, product 3b was isolated. The
1H and 13C nmr spectra confirmed that the 2-[(2-
hydroxyethoxy)methyl] side-chain was lost. The intense ir
absorption of 3b at 1729 cm-1 suggested the occurrence of
ring closure [6,7,12]. Furthermore, the mass spectrum and
the elemental analyses confirmed the formula as
C5H6N6O. Further confirmation of the structure of 3b via
alternative approach was to synthesize 3b by reacting 2
with hot glacial acetic acid, as described by Lovelette
Treatment of compound 10 with cyanogen bromide
refluxed in water led to 2-N-(2-amino-1-benzyl-4-oxo-
1,2,4-triazin-5-yl)semicarbazide (13). The 1H nmr
spectrum showed ꢀ 5.98 ppm corresponding to CONH2
and two singlets at ꢀ 7.41 and 7.71 ppm corresponding to
the NHNHCO and NHNHCO protons, respectively.
Reaction of compound 10 with nitrous acid at 0 °C gave
3-amino-6-azido-2-benzyl-1,2,4-triazin-5(2H)-one (14).
The ir spectrum exhibiting an intense absorption at 2122

892
L. C. Hwang, C. H. Tu and J. H. Wang
Vol 43
Scheme 4
O
O
O
N
Br
NHNH2
N
N
N
O
HN
H2N
CH3COOH
NH2NH2
N
N
N
N
N
H2N
N
H2N
O
HO
HO
CH3
15
3b
16
NaNO2/HCl
O
CH3COOH
O
O
O
Br
N3
NHNH2
NaN3
N
N
3 M HCl
N
N
HN
N
N
N
N
N
N
H2N
N
H
H2N
N
H
H2N
N
N
H
H2N
Na 2H2O
8
2
17
4
(Scheme 4) [7]. The most contributing prototropic
tautomerism of 3b was conjectured by the X-ray analysis
of 7 as the 7H-tautomer. Taking these evidences together,
the structure of 3b was assigned as 6-amino-3-methyl-
1,2,4-triazolo[3,4-f][1,2,4]triazin-8(7H)-one.
sodium bihydrate salt, was confirmed by elemental
analyses as C3H3N7O•Na+•2H2O. Compound 17 was then
stirred with 3 M hydrochloric acid at room temperature
overnight to give 4 (Scheme 4). From these results we
proved that the 2-[(2-hydroxyethoxy)methyl] side-chain
on N-2 underwent bond-breaking and then the ring
cyclization occurred (Figure 1. type III structure).
When compound 16 was treated with sodium nitrite in
hydrochloride solution, compound
4
was isolated
(Scheme 4). The H and 13C nmr spectra revealed the 2-
[(2-hydroxyethoxy)methyl] side-chain was lost. The mass
spectrum and the elemental analyses confirmed the
formula of 4 as C3H3N7O. The ir spectrum exhibited the
intense absorption of carbonyl group for similar fused
triazines but not of azido group. We checked the structure
of 4 by an alternative approach as described below.
Compound 8 refluxed with sodium azide in ethanol to
afford compound 17, which had an intense ir absorption
for 6-azido group at 2206 cm-1. The formula of 17, a
The product from fragment HOCH2CH2OCH2- of
compound 16 after reaction with hot glacial acetic acid
1
1
(Scheme 4) was isolated and characterized by the H nmr
(200 MHz) spectrum [ꢀH 2.08 (6H), 3.86 (2H), 4.24 (2H),
5.34 (2H)] and the 13C nmr (200 MHz) spectrum [ꢀC
20.63, 62.15, 70.29, 79.96, 174.73]. Additional supporting
evidence was the GC/MS spectrum [m/z 177 (M++1), 133
(M+ꢀCH3CO), 117, 101, 89, 87, 73, 59, 45, 43]. Taken
together, we assigned the product’s molecular formula as
CH3COOCH2OCH2CH2OCOCH3, acetic acid 2-acetoxy-
O
H
H
O
N
H
N
O
N
NHNH2
N
N
H
O
N
N
CH3COOH
- H2O
N
i
H
N
N
N
N
H2N
N
O
H2N
H3C
HO
H2N
O
H3C
O
AcO
O
CH3
H
O
16
18
H
H
N
O
N
O
O
N
N
N
ii
iii
H
iv
HN
N
N
N
N
N
N
- H2O
N
N
H2N
H2N
H2N
N
OH
H3C
CH3
CH3
3b
Figure 3. The proposed mechanism for the acidolysis and ring cyclization of compound 16 refluxed
with glacial acetic acid to form compound 3b. i, electron resonance and aromatization; ii,
deprotonation, £k-electron resonance and ring cyclization; iii, dehydration; iv, the most contributed
protropic tautomerism.

Jul-Aug 2006
Aromatization and Ring Cyclization: Mechanism of
893
3-Amino-6-hydrazino-1,2,4-triazin-5(2H)-one
cyclization mechanism will benefit us when synthesizing
new heterobicycles of 6-amino-3-substituted-1,2,4-
triazolo[3,4-f][1,2,4]triazin-8(7H)-ones from such as
3-amino-6-[2-alkylidenehydrazinyl]-1,2,4-triazin-5(2H)-
ones or 3-amino-6-[2-arylidenehydrazinyl]-1,2,4-triazin-
5(2H)-ones.
ethoxymethyl ester (MW 176.17).
A
reasonable
mechanism explaining the reaction mechanism for the
acidolysis and cyclization of 16 to form 3b is shown in
Figure 3. Initially the hydrazino group and the 2-[(2-
hydroxyethoxy)methyl] side-chain of 16 were acetylated.
The acetylated 2-[(2-acetoxyethoxy)methyl] side-chain
H
N
O
O
N
H
N
O
N
NHNH2
N
CH3COOH
HN
N
ii, iii, iv
i
H
N
N
- H2O
N
N
N
H2N
H2N
H2N
N
H
H3C
O
CH3
18
2
3b
Figure 4. The proposed mechanism for the ring cyclization of compound 2 refluxed
with glacial acetic acid to form compound 3b. The processes of i, ii, iii and iv are the
same as Figure 3.
EXPERIMENTAL
was then acidolyzed by glacial acetic acid. The N-2
electron pair then resonated to the 5-oxo to aromatize the
1,2,4-triazine ring, forming the important intermediate
3-amino-6-(2-acetyldrazino)-1,2,4-triazin-5-ol (18).
Sequentially, deprotonation of the N-1 hydrogen of the 6-
acetylhydrazino group gave the electron pair into 1,2,4-
triazine ring via ꢀ-electron resonance. The 1,2,4-triazine
ring then served as a nucleophile, allowing for the
intramolecular cyclization at N-1 of the intermediate 18,
followed by dehydration and tautomerization to the
predominant form 7H-tautomer 3b.
Figure 4 shows the proposed cyclization mechanism for
2 refluxed with glacial acetic acid to form the 7H-
tautomer 3b. This may serve as a typical cyclization
mechanism of 2 reacted with one-carbon fragment
reagents.
Melting points were measured on a YANACO micromelting
point apparatus and were uncorrected. The ir spectra were taken
with potassium bromide (KBr) discs on a Perkin-Elmer FTIR
1650 spectrophotometer and the uv absorption spectra were
recorded on a Shimadzu UV-Visible spectrophotometer. The 1H
and 13C nmr spectra were obtained in dimethylsulfoxide-d6
(DMSO-d6) on a Varian Gemini 200 (200 MHz) or a Varian
Unity 400 (400 MHz) spectrometer. Chemical shifts are
expressed in ppm (ꢀ) with tetramethylsilane (Me4Si) as an
internal standard. Coupling constants J are given in Hertz (Hz);
multiplicities were recorded as broad peaks (br), singlet (s),
doublets (d), triplets (t), quartets (q), and multiplets (m). Thin
layer chromatography (tlc) analyses were performed on silica
gel plates (Merck 60 F254, 0.2 mm thickness), and the
components were detected by uv light (254 nm). The ms and
hrms spectra were obtained on a Quattro VG-5022 spectrometer
and VG 70-250S GC/MS, respectively, with an ionization
potential of 70 eV. Elemental analyses were performed on a
Heraeus CHN-O-Rapid elemental analyzer. All the solvents
used were dried and distilled under argon prior to use.
Conclusions.
In this research we suggest that the mechanism for the
cyclization of 2 reacted with one-carbon fragment
reagents incorporates three important points: (1) the
tautomerism of the N-2 hydrogen with the C-5 oxo group
aromatizes the 1,2,4-triazine ring, (2) the aromatized
3-Amino-6-hydrazino-1,2,4-triazin-5(2H)-one (2) and 3-amino-
6-bromo-1,2,4-triazin-5(2H)-one (8)
Both compounds were prepared as described by Lovelette [7].
1,2,4-triazine ring supplies
a ꢀ-electron resonance
pathway, and (3) deprotonation of the N-1 hydrogen the
6-hydrozino group gives the electron pair into the
aromatic ꢀ-deficient 1,2,4-triazine ring, thus increases its
nucleophilicity which leads to the ring cyclization.
Briefly, the ring cyclization is dependent on the
aromatization of the 1,2,4-triazine ring, which influence
the reactivity and reaction behavior of the ꢀ-deficient
1,2,4-triazine. This reasonable understanding on the
3-Amino-2-benzyl-6-hydrazino-1,2,4-triazin-5(2H)-one (10) and
3-amino-6-bromo-2-[(2-hydroxyethoxy)methyl]-1,2,4-triazin-
5(2H)-one (15)
Both compounds were prepared as described by us [12,13].
3-Amino-2-benzyl-6-bromo-1,2,4-triazin-5(2H)-one (9)
A solution of 8 (0.57 g, 3 mmoles) in dry acetone (30 mL)
was mixed with anhydrous potassium carbonate (0.41 g, 3

894
L. C. Hwang, C. H. Tu and J. H. Wang
Vol 43
mmoles) and a catalytic amount of 18-crown-6-ether (0.08 g, 0.3
mmoles). Then benzyl bromide (0.51 g, 3 mmoles) was added
and refluxed for 24 hours. The solvent was evaporated to afford
a crude product which was then applied to a silica gel (230-400
mesh) column. The column was eluted with a mixed solvent of
chloroform and methanol (60:1) and the proper fractions were
combined and evaporated. The residue thus obtained was
recrystallized from dichloromethane and ethanol (5:1) to give a
white crystal compound 0.46 g (55%) of 9, which was a material
identical in every respect with the corresponding compound in
our previous research [12].
N HCl): ꢁmax nm (log ꢁ) 205 (3.86); (H2O): ꢁmax nm (log ꢁ) 266
(3.73); (0.1 N NaOH): ꢁmax nm (log ꢁ) 218 (3.37), 266 (3.54) ;
1H nmr (200 MHz): ꢀ 4.43 (d, 1H, J = 13.1, CHH-C6H5), 5.03 (d,
1H, J = 13.1, CHH-C6H5), 5.98 (s, 2H, CONH2), 6.49 (s, 2H, 2-
NH2). 7.22 (s, 5H, C6H5), 7.41 (s, 1H, NHNHCO), 7.71 (s, 1H,
NHNHCO); 13C nmr (200 MHz): ꢀ 53.22 (CH2), 141.02 (C-6),
156.56 (C-3), 157.39 (C-5), 158.56 (CO), 128.00, 128.36,
130.12, 135.02 (C6H5); ms: m/z (EI) 275 (M+, 1), 149 (30), 127
(24), 106 (98), 91 (100), 77 (20), 71 (4), 65 (21); hrms: m/z
Calcd. for C11H13N7O2: 275.1131. Found: 275.1131.
Anal. Calcd. for C11H13N7O2: C, 48.00; H, 4.76; N, 35.62.
Found: C, 47.73; H, 4.78; N, 35.41.
3-Amino-2-benzyl-6-(2-formylhydrazino)-1,2,4-triazin-5(2H)-
one (11).
3-Amino-6-azido-2-benzyl-1,2,4-triazin-5(2H)-one (14).
A solution of compound 10 (0.70 g, 3 mmoles) in 99% formic
acid (15 mL) was refluxed for 12 hours. Cooling separated white
crystal 0.42 g. The filtrate was evaporated to 3 mL to give 0.13
g. The total crude compound was recrystallized from ethanol to
afford 11 (0.41 g, 53%). The product was a white crystal with a
conformer mixture in a ratio of about 2:1. The major conformer
was a material identical in every respect with the corresponding
compound in our previous research [12]; and the minor
To a solution of compound 10 (0.70 g, 3 mmoles) in 6 M
hydrochloric acid (6 mL) under stirring at 0 °C, a solution of
sodium nitrite (0.24 g, 3.5 mmoles) in water (6 mL) was added
drop by drop. After the addition was complete, stirring was
continued for an additional 10 minutes and the precipitate was
collected. The solid precipitate was suspended in 15 mL of water
and was stirred at room temperature overnight. Collection of the
precipitate and recrystallization from ethanol produced 14 (0.45
g, 62%), mp 170-171 °C (from EtOH); ir: (ꢀ, cm–1) 3380, 3113,
2122 (N3), 1642 (C=O), 1535, 1374, 1271, 1152, 1081; uv: (0.1
N HCl): ꢁmax nm (log ꢁ) 206 (3.68), 238 (3.31), 296 (3.02), 298
(3.15); (H2O): ꢁmax nm (log ꢁ) 206 (3.95), 234 (3.94), 236 (3.52),
1
conformer showed the following spectral data: H nmr (400
MHz): ꢀ 5.00 (s, 2H, CH2), 7.02 (s, 2H, NH2), 7.22-7.37 (m, 5H,
C6H5), 7.92 (d, 1H, J = 10.8, NHNHCO), 8.75 (s, 1H, CHO),
9.27 (d, 1H, J = 10.8, NHNHCO); 13C nmr (200 MHz): ꢀ 54.95
(CH2), 146.58 (C-6), 154.58 (C-3), 158.28 (C-5), 167.55 (CO).
1
294 (3.34); (0.1 N NaOH): ꢁmax nm (log ꢁ) 239 (3.49); H nmr
(200 MHz): ꢀ 5.08 (s, 2H, CH2), 7.27-7.39 (m, 5H, C6H5), 7.46
(s, 2H, NH2); 13C nmr (400 MHz): ꢀ 55.34 (CH2), 142.73 (C-6),
154.96 (C-3), 158.70 (C-5), 127.24, 127.78, 128.61, 135.21
(C6H5); ms: m/z 243 (M+, 1), 217 (4), 129 (2), 106 (9), 91 (100),
77 (12), 69 (16), 65 (49); hrms: m/z Calcd. for C10H9N7O:
243.0869. Found: 243.0872.
3-Amino-2-benzyl-6-(2-acetylhydrazino)-1,2,4-triazin-5(2H)-
one (12).
A solution of compound 10 (0.70 g, 3 mmoles) in glacial
acetic acid (15 mL) was refluxed for 12 hours. Cooling
separated white crystal 0.61 g. The filtrate was evaporated to 3
mL to give 0.11 g. The total crude compound was recrystallized
from ethanol to afford 12 (0.61 g, 74%). The product was a
white crystal with a conformer mixture in a ratio of about 10:1;
mp > 300 °C (from EtOH); ir: (ꢀ, cm–1) 3366, 3190, 1639
(C=O), 1508, 1267, 1077; uv: (0.1 N HCl): ꢁmax nm (log ꢁ) 207
(4.01), 240 (3.80), 294 (3.55); (H2O): ꢁmax nm (log ꢁ) 222 (3.88),
285 (3.35); (0.1 N NaOH): ꢁmax nm (log ꢁ) 229 (4.41), 268
Anal. Calcd. for C10H9N7O: C, 49.38; H, 3.73; N, 40.31.
Found: C, 49.65; H, 3.66; N, 40.38.
3-Amino-6-hydrazino-2-[(2-hydroxyethoxy)methyl]-1,2,4-triazin-
5(2H)-one (16).
A solution of compound 15 (0.53 g, 2 mmoles) and hydrazine
monohydrate (0.4 g, 8 mmoles) in ethanol (30 mL) was refluxed
for 16 hours. Evaporating the solvent to 5 mL in vacuo afforded
a crude solid which was recrystallised from methanol to give
white crystal compound 16 (0.32g, 74%), mp 214-215 °C (from
MeOH); ir: (ꢀ, cm–1) 3397, 3362, 1677 (C=O), 1618, 1561,
1511, 1109, 1054; uv: (0.1 N HCl): ꢁmax nm (log ꢁ) 221 (4.25),
272 (3.73); (H2O): ꢁmax nm (log ꢁ) 224 (4.19), 288 (3.51); (0.1 N
1
(4.11), 332 (3.98); the major conformer H nmr (400 MHz): ꢀ
1.81 (s, 3H, CH3), 4.96 (s, 2H, CH2), 6.96 (s, 2H, NH2), 7.23-
7.37 (m , 5H, C6H5), 8.04 (d, 1H, J = 2.2, NHNHCO), 9.60 (d,
1H, J = 2.2, NHNHCO); 13C nmr (400 MHz): ꢀ 20.51 (CH3),
54.88 (CH2), 145.16 (C-6), 154.11 (C-3), 158.04 (C-5), 168.02
(CO), 127.13, 127.50, 128.44, 135.85 (C6H5); the minor
1
1
conformer H nmr (400 MHz): ꢀ 1.73 (s, 3H, CH3), 5.00 (s, 2H,
NaOH): ꢁmax nm (log ꢁ) 225 (4.31); H nmr (200 MHz): ꢀ 3.52-
CH2), 7.01 (s, 2H, NH2), 7.23-7.37 (m, 5H, C6H5), 7.35 (d, 1H, J
= 15.6, NHNHCO), 8.73 (d, 1H, J = 15.6, NHNHCO); ms: m/z
(EI) 274 (M+, 14), 232 (13), 141 (35), 91 (100), 69 (8), 65 (19);
hrms: m/z Calcd. for C12H14N6O2: 274.1178. Found: 274.1180.
Anal. Calcd. for C12H14N6O2: C, 52.55; H, 5.14; N, 30.64.
Found: C, 52.53; H, 5.17; N, 30.40.
3.58 (m, 4H, OCH2CH2O), 3.92 (s, 2H, NHNH2), 4.72 (t, 1H, 4'-
OH), 5.17 (s, 2H, NCH2O), 6.90 (s, 2H, NH2), 7.30 (s, 1H,
NHNH2); 13C nmr (200 MHz): ꢀ 60.31 (C-4'), 70.52 (C-3'),
81.88 (C-1'), 146.96 (C-6),154.69 (C-3), 158.87 (C-5); ms: m/z
216 (M+, 31), 153 (32), 142 (100), 113 (7), 91 (30), 85 (27), 69
(69).
Anal. Calcd. for C6H12N6O3: C, 33.33; H, 5.59; N, 38.87.
Found: C, 33.43; H, 5.62; N, 38.91.
2-N-(2-Amino-1-benzyl-4-oxo-1,2,4-triazin-5-yl)semicarbazide (13).
A solution of compound 10 (0.70 g, 3 mmoles) with cyanogen
bromide (0.64 g, 6 mmoles) in water (20 mL) was refluxed for
24 hours. Cooling separated a white crystal compound, which
was washed with ice water and then recrystallized from ethanol
to give product 13 (0.48 g, 58%), mp 263-265 °C (from EtOH);
ir: (ꢀ, cm–1) 3330, 3215, 1679 (C=O), 1589, 1451, 1089; uv: (0.1
6-Amino-3-methyl-1,2,4-triazolo[3,4-f][1,2,4]triazin-8(7H)-one (3b).
Method A. A solution of compound 16 (0.43 g, 2 mmoles) in
glacial acetic acid (10 mL) was refluxed for 12 hours (monitored
by tlc). Removal of excess acid in vacuo followed by
recrystallization from water afforded a white crystal compound

Jul-Aug 2006
Aromatization and Ring Cyclization: Mechanism of
895
3-Amino-6-hydrazino-1,2,4-triazin-5(2H)-one
3b (0.19 g, 57%), mp >300 °C (from water); ir: (ꢀ, cm–1) 3340,
3185, 1729 (C=O), 1625, 1517, 1408, 1283, 1131; uv: (0.1 N
HCl): ꢁmax nm (log ꢀ) 223 (4.24), 280 (3.41); (H2O): ꢁmax nm
(log ꢀ) 218 (4.13); (0.1 N NaOH): ꢁmax nm (log ꢀ) 228 (4.24); 1H
nmr (200 MHz): ꢁ 2.45 (s, 3H, CH3); 6.39 (s, 2H, NH2); 11.47
(br s, 1H, NH); 13C nmr (200 MHz): ꢁ 9.26 (CH3), 139.40 (C-
8a), 146.74 (C-3), 150.31 (C-6), 151.80 (C-8); ms: m/z 166 (M+,
35), 138 (3), 123 (5), 111 (8), 97 (6), 91 (4), 77 (5), 69 (24), 54
(32), 43 (100).
(log ꢀ) 223 (4.16), 252 (3.88); 1H nmr (200 MHz): ꢁ 6.89 (s, 2H,
NH2), 12.27 (br s, 1H, NH); 13C nmr (200 MHz): ꢁ 138.90 (C-
8a), 151.85 (C-6), 152.56 (C-8); ms: m/z 154 (M++1, 2), 127 (3),
125 (4), 97 (5), 85 (7), 82 (10), 69 (74), 54 (52), 43 (100).
Anal. Calcd. for C3H3N7O: C, 23.53; H, 1.98; N, 64.02.
Found: C, 23.37; H, 1.97; N, 64.05.
Method B. A solution of compound 17 (0.42 g, 2 mmoles) in 3
M hydrochloric acid (8 mL) was stirred at room temperature
overnight. Collection of the precipitate and recrystallization
from ethanol produced compound 4 (0.26 g, 85%).
Anal. Calcd. for C5H6N6O: C, 36.15; H, 3.64; N, 50.58.
Found: C, 36.10; H, 3.70; N, 50.74.
Acknowledgement.
Method B. Compound 2 (0.71 g, 5 mmoles) in glacial acetic
acid (15 mL) was refluxed for 12 hours. Cooling separated a
white crystal compound 0.56 g. The filtrate was evaporated to 3
mL to give 0.11 g. The total 0.67 g (81%) of the compound was
a material identical in every respect with compound 3b.
We are grateful to the National Science Council, Taiwan,
ROC, for support under grant NSC 89-2113-M-037-010.
REFERENCES
Sodium bihydrate 3-amino-6-azido-1,2,4-triazin-5(2H)-one (17).
A solution of compound 8 (0.95 g, 5 mmoles) and sodium
azide (0.36 g, 5.5 mmoles) in water (25 mL) was refluxed for 16
hours. Evaporating the solvent to 5 mL in vacuo afforded a
crude solid which was recrystallized from methanol to give
white crystal compound 17 (0.57 g, 54%), mp >300 °C; ir: (ꢀ,
cm–1) 3429, 2206 (N3), 1642, 1561, 1498, 1388, 1274, 1102;1H
nmr (200 MHz): ꢁ 5.69 (s, 2H, NH2); 13C nmr (200 MHz): ꢁ
137.62 (C-6), 160.06 (C-3), 162.39 (C-5).
[1] H. Neunhoeffer and P. F. Wiley, in Chemistry of 1,2,3-
Triazines and 1,2,4-Triazines, Tetrazines and Pentazines, A.
Weissberger and E. C. Taylor, eds, John Wiley and Sons, New York,
NY, 1978, pp 1001-1004.
[2] E. S. H. EL Ashry, N. Rashed, M. Taha and E. Ramadan,
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[4] R. M. Abdel-Rahman, Pharmazie, 56, 275 (2001).
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M. Abdel-Rahman, Pharmazie, 56, 376 (2001).
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[10] L. C. Hwang, J. H. Wang, C. C. Tzeng, G. H. Lee and S. M.
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[12] L. C. Hwang, R. R. Wu and C. H. Tu, J. Heterocyclic Chem.,
42, 851 (2005).
Anal. Calcd. for C3H3N7O•Na+•2H2O: C, 16.99; H, 3.33; N,
46.22. Found: C, 16.86; H, 3.23; N, 46.25.
6-Amino-1,2,3,4-tetrazolo[5,1-f][1,2,4]triazin-8(7H)-one (4).
Method A. To a solution of compound 16 (0.65 g, 3 mmoles)
in 6 M hydrochloric acid (6 mL) under stirring at 0 °C, a
solution of sodium nitrite (0.24 g, 3.5 mmoles) in water (6 mL)
was added drop by drop. After the addition was complete,
stirring was continued for an additional 10 minutes and was
stirred at room temperature overnight. Collection of the
precipitate and recrystallization from ethanol produced 4 (0.26
g, 57%), mp >300 °C (from EtOH); ir: (ꢀ, cm–1) 3392, 3313,
3210, 3175, 3086, 1742, 1716, 1641, 1474, 1390, 1300, 1085;
uv: (0.1 N HCl): ꢁmax nm (log ꢀ) 210 (4.17), 248 (3.71); (H2O):
ꢁmax nm (log ꢀ) 208 (4.04), 252 (3.55); (0.1 N NaOH): ꢁmax nm
[13] L. C. Hwang, D. C. Wei, M. C. Cheng, Y. Wang and C. C.
Tzeng, Nucleosides Nucleotides, 13, 2185 (1994).