A facile one-pot synthesis of 3-imidazolyl 1,2,4-triazoles and 1,2,4-oxa-diazolones

Article abstract of DOI:10.1055/s-0030-1258820

5-(5-Aminoimidazol-4-yl)-1,2,4-triazol-3-ones were obtained under mild experimental conditions from 5-amino-4-(N-ethoxycarbonyl) cyanoformimidoyl imidazoles and hydrazine in a rapid one-pot reaction. When hydroxylamine hydrochloride was used, in the presence of base, the corresponding 1,2,4-oxadiazol-5-ones were isolated. An equally fast reaction occurred when 5-amino-4-(N-acetyl/benzoyl) cyanoformimidoyl imidazoles were combined with hydrazine to give 5-(5-aminoimidazol-4-yl)-1,2,4-triazoles.

Full text of DOI:10.1055/s-0030-1258820

2792
LETTER
A Facile One-Pot Synthesis of 3-Imidazolyl 1,2,4-Triazoles and 1,2,4-Oxa-
diazolones
S
ynthesis of 3-Imi
l
dazolyl
i
1,2, 4-T
c
riazoles an
e
d
1,2,4-Oxadiazo
M
lones . Dias,* Isabel M. Cabral, A. Sofia Vila-Chã, Daniela P. Cunha, Nádia Senhorães, Sandra M. Nobre, Cristina
E. Sousa, M. Fernanda Proença
Departamento de Química, Universidade do Minho, Campus de Gualtar, 4710-057 Braga, Portugal
Fax +351(253)678983; E-mail: ad@quimica.uminho.pt
Received 11 August 2010
To the best of our knowledge there are only three reports
Abstract: 5-(5-Aminoimidazol-4-yl)-1,2,4-triazol-3-ones were ob-
tained under mild experimental conditions from 5-amino-4-(N-
ethoxycarbonyl) cyanoformimidoyl imidazoles and hydrazine in a
rapid one-pot reaction. When hydroxylamine hydrochloride was
on the synthesis of 5-(5-aminoimidazolyl)-1,2,4-triazoles.
An indirect synthesis involving ring opening of triazo-
lo[3,4-i]purines or triazolo[5,1-i]purines, which were ob-
used, in the presence of base, the corresponding 1,2,4-oxadiazol-5- tained upon treatment of 6-hydrazinopurine and 6-(1-
ones were isolated. An equally fast reaction occurred when 5-ami-
no-4-(N-acetyl/benzoyl) cyanoformimidoyl imidazoles were com-
bined with hydrazine to give 5-(5-aminoimidazol-4-yl)-1,2,4-
cyanoimidazoles with triethylorthoformate followed by
triazoles.
benzylhydrazino)purine with dimethoxymethyl acetate
and, more recently, from the reaction of 5-amino-4-
condensation with hydrazines and acylhydrazines at high
temperature.11
Key words: heterocycles, cyclization, ring closure, imidazole,
1,2,4-triazole, 1,2,4-oxadiazole
In our research group, 5-amino-4-cyanoformimidoyl imi-
dazoles 1 have been used as versatile precursors for nitro-
gen heterocycles linked or fused with the imidazole ring.12
Azole heterocycles are present in a wide range of biolog-
In previous work, imidazoles 1 were reacted with ethyl
chloroformate. The acylation occurs on the imine nitrogen
leading to the formation of compounds 212g,13 (Table 1).
ically active molecules. The growing number of patents
describing 1,2,4-triazole derivatives with biological prop-
erties reveals the importance of this heterocycle.1 The bi-
ological activities displayed by 1,2,4-triazoles and 1,2,4-
triazolones include antibacterial,2 antifungal,3 antitumor,4
anti-inflammatory,5 and adenosine receptor antagonist ef-
fects.6 1,2,4-Oxadiazoles have also been well documented
throughout the literature due to their pharmacological im-
portance. Indeed, the 1,2,4-oxadiazole nucleus can be
found in potent agonist or antagonist receptor ligands and
in enzyme inhibitors.7 Additionally, both triazole and ox-
adiazole moieties have often been used as amide and ester
bioisosteres in order to improve the bioavailability of the
parent bioactive molecules. The use of these surrogates is
particularly important for peptide chemistry and for the
development of peptidomimetics.6,8 The synthesis of
1,2,4-triazoles was recently reviewed.1 The most used
method to synthesize 1,2,4-triazoles and 1,2,4-oxadiaz-
oles involves a cylodehydration of N-acylamidrazone or
O-acylamidoxime, respectively, at high temperatures.1
These intermediates have been preferably obtained from
activated amide or nitrile derivatives such as imidate and
thioamide precursors. In general, these procedures require
high temperature and/or long reaction times and usually
result in low yields of the product.1,9a–c Some reactions
were performed at room temperature in the presence of
mercury(II) acetate,1 and more recently, silver benzoate.9d
More specific methods were also reported.10
These compounds were combined with methyl and benzyl-
amine under mild conditions and a fast nucleophilic attack
occurred at the imine carbon atom with substitution of the
cyano group.13 As an extension of this work, we now
present the results of the reaction of intermediates 2 with
hydrazine and hydroxylamine.
When hydrazine monohydrate was added to a suspension
of 2 in DMF or ethanol, the bright yellow color of the
starting material disappeared instantly leading to a white
solid which was identified as the imidazolyl 1,2,4-triaz-
olone 3. Most of the products 3 were isolated in excellent
yield after 5–40 minutes of reaction.14 This one-pot for-
mation of the 1,2,4-triazolone ring can only be rational-
ized on the basis of a two-steps reaction sequence: the
elimination of HCN followed by the elimination of etha-
nol (Scheme 1).
These results prompted us to investigate the reaction of in-
termediates 2 with hydroxylamine. For this purpose, hy-
droxylamine hydrochloride was neutralized in situ with an
aqueous 1 M KOH solution, and the resulting mixture was
added to a suspension of imidazole 2 in dichloromethane.
A slow reaction occurred at room temperature leading to
the 1,2,4-oxadiazolone 4a after 29 hours, which was iso-
lated as a light yellow solid in an excellent yield. Attempts
to reproduce this procedure with differently substituted
imidazoles 2 failed. Alternatively, triethylamine was add-
ed to a suspension of hydroxylamine hydrochloride in ac-
etonitrile giving the desired products after two days at
room temperature in moderate yields.15 The assignment of
SYNLETT 2010, No. 18, pp 2792–2796
x
x
.x
x
.2
0
1
0
Advanced online publication: 08.10.2010
DOI: 10.1055/s-0030-1258820; Art ID: G23810ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of 3-Imidazolyl 1,2,4-Triazoles and 1,2,4-Oxadiazolones
2793
Table 1 Synthesis of Compounds 3–5, 8, and 9
R1
R1
N
R1
N
R1
N
H2N N
Y
NH2
NH2
NH2
NH2
NH
(R2CO)2O
N
ClCO2OEt
H
R2
OEt
N
OEt
N
N
N
N
N
N
O
6, R2 = Me
7, R2 = Ph
N
O
O
CN
NH2NH2
CN
CN
N
2
1, R1 = alkyl, aryl,
Y
NH2XH
R1
hydroxyalkyl
5a, Y = CH2
5b, Y = NMe
R1
N
NH2
NH2
N
N
N
N
N
X
NH
8, R2 = Me
9, R2 = Ph
HN
N
3, X = NH
4, X = O
R2
O
Compound
R1
X/Y/R2
NH
NHXH (equiv)
Reaction conditions
Yield (%)
3a
3b
3c
3d
3e
4-MeOC6H4
4-CNC6H4
4-FC6H
2.0
2.0
2.0
2.0
2.0
DMF, 5 min, r.t.
DMF, 30 min, r.t.
EtOH, 40 min, 0 °C
EtOH, 30 min, r.t.
EtOH, 30min, r.t.
99
83
98
37
92
NH
NH
Me
NH
CH2CH2OH
NH
O
3f
NH
2.0
EtOH, 5 min, 0 °C
78
O
4a
4b
4c
4-MeOC6H4
O
O
O
3.0
2.0
1.2
KOH (aq) 1 M (3 equiv), CH2Cl2, 29 h, r.t.
Et3N (3 equiv), MeCN, 2 d, r.t.
99
50
58
4-FC6H4
CH2CH2OH
O
Et3N (3 equiv), MeCN, 2 d, r.t.
4d
O
2.0
Et3N (3 equiv), MeCN, 2 d, r.t.
17
O
5a
5b
8a
8b
8c
8d
8e
9a
9b
9c
9d
4-MeOC6H4
CH2
NMe
Me
1.2
1.3
2.0
1.2
1.2
1.2
2.0
2.0
1.2
1.2
1.2
CH2Cl2, 15 min, r.t.
EtOH, 15 min, r.t.
EtOH, 5 min, 0 °C
EtOH, 5 min, 0 °C
EtOH, 5 min, 0 °C
EtOH, 5 min, 0 °C
EtOH, 5 min, 0 °C
EtOH, 5 min, 0 °C
EtOH, 5 min, 0 °C
EtOH, 5 min, 0 °C
EtOH, 5 min, 0 °C
66
65
61
85
82
82
56
66
76
63
79
4-MeOC6H4
4-MeOC6H4
Ph
Me
Me
Me
CH2CH2OH
Me
CH2CHOHCH2OH Me
4-MeOC6H4
4-FC6H4
Ph
Ph
Ph
Ph
Ph
Me
structure 4 was well supported by their IR spectra show- sponding carbonyl stretching vibration was observed at
ing a carbonyl band at ca. 1780 cm–1. This result was con- 1715 cm–1 as was expected for a cyclic urea.
sistent with the presence of a urethane unit in a five-
membered ring. For the 1,2,4-triazolones 3 the corre-
Imidazoles 2 were also combined with N,N-disubstituted
hydrazines, in order to establish the reaction mechanism.
When aminopiperidine and 1-amino-4-methylpiperazine
Synlett 2010, No. 18, 2792–2796 © Thieme Stuttgart · New York

2794
A. M. Dias et al.
LETTER
R1
N
R1
N
R1
N
NH2
NCO2Et
NH2
NHCO2Et
NHXH
NH2
NH2XH
H
(– HCN)
OEt
N
N
N
N
NC
2
O
XH
CN
N
10
11
R1
N
R1
N
NH2
NH2
H
H
(– EtOH)
OEt
N
N
N
N
OH
O
N
N
X
X
3, X = NH
4, X = O
12
Scheme 1 Proposed mechanism for the one-pot formation of 1,2,4-triazolones 3 and 1,2,4-oxadiazolones 4
were reacted with imidazole 2, only products 5 were In conclusion, a general and efficient one-pot reaction was
formed, after 45–50 minutes at room temperature.16
developed to prepare imidazolyl 1,2,4-triazolones 3 and
1,2,4-triazoles 8 and 9. These compounds were formed at
room temperature or 0 °C from the easily accessible acy-
lated imidazole (2, 6, and 7) and hydrazine. An equally
simple method was developed for the synthesis of the cor-
responding 3-imidazolyl 1,2,4-oxadiazolones starting
from the same precursor 2 upon reaction with hydroxyl-
amine. The acylated imidazoles 2, 6, and 7 were obtained
in very good yields from the versatile imidazoles 1 and an-
hydrides or ethyl chloroformate. These compounds are
not easy to prepare by other methods.
These results agree with previous studies on the reactivity
of the imidazoles 2 with primary amines,13 supporting the
postulated mechanism outlined in Scheme 1. The reaction
is initiated by a nucleophilic attack of the amino group in
the hydrazine/hydroxylamine to the imine carbon atom. A
tetrahedral intermediate 10 must be formed and evolves to
the amidrazone 11 by elimination of HCN. The free hy-
drazine amino group is still a strong nucleophile and an
easy and prompt intramolecular cyclization occurs, upon
attack to the carbonyl carbon atom. The triazolone ring is
formed by elimination of ethanol from the cyclic interme-
diate 12.
Acknowledgment
The amidoxime unit, with a less reactive hydroxy group at
an equivalent position, requires basic medium to be con-
verted on the target 1,2,4-oxadiazolone ring through a
similar pathway.
The authors gratefully acknowledge the financial support by the
University of Minho and Fundação para a Ciência e Tecnologia
(project PRAXIS/C/QUI/45391/2002).
The same synthetic sequence must be followed for the
preparation of 1,2,4-triazoles 8 and 9 starting from the
corresponding acetylated and benzoylated imidazole pre-
cursors 6 and 7. Imidazoles 6 were prepared by a previ-
ously reported method involving acetylation of
imidazoles 1 with acetic anhydride under mild experimen-
tal conditions.12g Benzoylation of 1 was carried out under
similar experimental conditions. Acetonitrile was used as
solvent and the products 7 were obtained after two to four
hours at room temperature or 0 °C in good to excellent
yields.17 Treatment of precursors 6 and 7 with a slight ex-
cess of hydrazine monohydrate (2.0–1.2 equiv) resulted in
an equally facile and fast one-pot, two-steps reaction, pro-
viding the desired 1,2,4-tiazoles 8 and 9 after five minutes
at 0 °C. The products were isolated as off-white solids in
good to very good yields.18 The higher electron-withdraw-
ing effect of the acetyl and benzoyl groups when com-
pared to the oxycarbonyl counterpart may be responsible
for the faster and milder reaction conditions. The intramo-
lecular cyclization will also be facilitated due to the higher
electrophilicity of the amide group.
References and Notes
(1) For a recent review, see: Moulin, A.; Bibian, M.; Blayo,
A.-L.; El Habnouni, S.; Martinez, J.; Fehrentz, J.-A. Chem.
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(2) (a) Patel, N. B.; Khan, I. H.; Rajani, S. D. Eur. J. Med. Chem.
2010, 45, 4293. (b) Bayrak, H.; Demirbas, A.; Karaoglu,
S. A.; Demirbas, N. Eur. J. Med. Chem. 2009, 44, 1057.
(c) Isloor, A. M.; Kalluraya, B.; Shetty, P. Eur. J. Med.
Chem. 2009, 44, 3784. (d) Bayrak, H.; Demirbas, A.;
Demirbas, N.; Karaoglu, S. A. Eur. J. Med. Chem. 2009, 44,
4362.
(3) Katica, C. R.; Vesna, D.; Vlado, K.; Dora, G. M.;
Aleksandra, B. Molecules 2001, 6, 815.
(4) (a) Demirbas, N.; Ugurluoglu, R.; Demirbas, A. Bioorg.
Med. Chem. 2002, 10, 3717. (b) Romagnoli, R.; Baraldi,
P. G.; Cruz-Lopez, O.; Cara, C. L.; Carrion, M. D.; Brancale,
A.; Hamel, E.; Chen, L.; Bortolozzi, R.; Basso, G.; Viola, G.
J. Med. Chem. 2010, 53, 4248.
(5) Abdel-Megeed, A. M.; Abdel-Rahman, H. M.; Alkaramany,
G.-E. S.; El-Gendy, M. A. Eur. J. Med. Chem. 2009, 117.
(6) Alanine, A.; Anselm, L.; Steward, L.; Thomi, S.; Vifian, W.;
Groaning, M. D. Bioorg. Med. Chem. Lett. 2004, 14, 817.
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Eur. J. Med. Chem. 2007, 42, 823. (b) Farooqui, M.; Bora,
R.; Patil, C. R. Eur. J. Med. Chem. 2009, 794.
Synlett 2010, No. 18, 2792–2796 © Thieme Stuttgart · New York

LETTER
Synthesis of 3-Imidazolyl 1,2,4-Triazoles and 1,2,4-Oxadiazolones
2795
(8) Borg, S.; Vollinga, R. C.; Labarre, M.; Payza, K.; Terenius,
L.; Luthman, K. J. Med. Chem. 1999, 42, 4331.
(15) General Procedure for the Synthesis of 1,2,4-
Oxadiazolones 4
(9) (a) Yeung, K.-S.; Farkas, M. E.; Kadow, J. F.; Meanwell,
N. A. Tetrahedron Lett. 2005, 46, 3429. (b) Amarasinghe,
K. K. D.; Maier, M. B.; Srivastavab, A.; Graya, J. L.
Tetrahedron Lett. 2006, 47, 3629. (c) Katritzky, A. R.;
Khashab, N. M.; Kirichenko, N.; Singh, A. J. Org. Chem.
2006, 71, 9051. (d) Bibian, M.; Blayo, A.-L.; Moulin, A.;
Martinez, J.; Fehrentz, J.-A. Tetrahedron Lett. 2010, 51,
2660.
(10) (a) Su, Y.; Jiang, Z.; Hong, D.; Lu, P.; Wang, Y.; Lin, X.
Tetrahedron 2010, 66, 2427. (b) Kurz, T.; Lolak, N.;
Geffken, D. Tetrahedron Lett. 2007, 48, 2733. (c) Yin, P.;
Ma, W.-B.; Chen, Y.; Huang, W.-C.; Deng, Y.; He, L. Org.
Lett. 2009, 11, 5482. (d) Ueda, S.; Nagasawa, H. J. Am.
Chem. Soc. 2009, 131, 15080. (e) Wang, Y.; Miller, R. L.;
Sauer, D. R.; Djuric, S. W. Org. Lett. 2005, 7, 925. (f) Lin,
S.; Lang, J. r. Y.-iA.; Lovell, M. F.; Perkinson, N. A. J. Org.
Chem. 1979, 44, 4160. (g) Saleem, R. S. Z.; Tepe, J. J.
J. Org. Chem. 2010, 75, 4330. (h) Perez, M. A.; Dorado,
C. A.; Soto, J. L. Synthesis 1983, 483.
A yellow suspension of 2 (0.29–1.85 mmol) in CH2Cl2 (for
4a, 15.0 mL) or in MeCN (for 4b–d, 3.0–5.0 mL) was added
to a solution of hydroxylamine hydrochloride (for 4a, 3.0
equiv; for 4b–d, 2.0 equiv; for 4c, 1.2 equiv) in aq 1 M KOH
(for 4a, 3.0 equiv) or to a solution of Et3N (for 4b–d, 3.0
equiv) in MeCN. The mixture was stirred at r.t., and after
29–72 h the starting material was totally consumed. The
light yellow solid was filtered and washed with EtOH,
MeCN, and Et2O to give compounds 4 in 17–99% yield. The
structure of the products was confirmed by elemental
analysis, 1H NMR and 13C NMR spectroscopy.
3-[5-Amino-1-(4-methoxyphenyl)-1H-imidazol-4-yl]-
1,2,4-oxadiazol-5 (4H)-one (4a)
Mp 261–264 °C. 1H NMR (300 MHz, DMSO-d6):
d = 13.00–10.00 (br s, 1 H), 7.49 (s, 1 H), 7.42 (d, J = 8.7 Hz,
2 H), 7.11 (d, J = 8.7 Hz, 2 H), 5.46 (s, 2 H), 3.81 (s, 3 H).
13C NMR (75 MHz, DMSO-d6): d = 159.54, 159.30, 155.30,
140.73, 132.66, 126.78, 126.75, 114.96, 103.15, 55.56.
Anal. Calcd for C12H11N5O3: C, 52.75; H, 4.06; N, 25.63.
Found: C, 52.85; H, 4.13; N, 25.57. IR (mull): 3414, 3317,
3128, 1787 (CO), 1633 cm–1.
(11) (a) Temple, C. Jr.; Kussner, C. L.; Montgomery, J. A. J. Org.
Chem. 1965, 30, 3601. (b) Temple, C. Jr.; Kussner, C. L.;
Montgomery, J. A. J. Org. Chem. 1967, 32, 2241.
(c) Okamura, T.; Kurogi, Y. J. Med. Chem. 2002, 45, 3703.
(d) Hosmane, R. S.; Lim, B. B.; Burnett, F. N. J. Org. Chem.
1988, 53, 382.
(16) General Procedure for the Synthesis of 5
A suspension of aminopiperidine or 1-amino-4-
metilpiperazine (1.2–1.3 equiv) and imidazole 2 (0.98–1.20
mmol) in CH2Cl2 (0.5 mL) or EtOH (2.0 mL) was stirred at
r.t.. After 45–50 min the yellow suspension evolved to a
white solid precipitate that was filtered and washed with
EtOH and Et2O. The structure of the products obtained was
confirmed by elemental analysis, 1H NMR and 13C NMR
spectroscopy.
Ethyl [5-Amino-1-(4-methoxyphenyl)-1H-imidazol-4-
yl](piperidin-1-ylimino)methylcarbamate (5a)
Mp 165–166 °C. 1H NMR (300 MHz, DMSO-d6): d = 8.06
(s, 1 H), 7.38 (d, J = 8.7 Hz, 2 H) 7.38 (s, 1 H), 7.10 (d,
J = 8.7 Hz, 2 H), 5.69 (br s, 2 H), 3.81 (s, 3 H), 3.98 (q,
J = 7.2 Hz, 2 H), 2.50–3.50 (br s, 4 H), 1.50 (br s, 6 H), 1.20
(t, J = 7.2 Hz, 3 H). 13C NMR (75 MHz, DMSO-d6):
d = 162.35, 159.04, 149.28, 141.60, 130.05, 59.95, 55.55,
55.03, 26.69, 25.27, 14.28. Anal. Calcd for C19H26N6O3: C,
59.05; H, 6.78; N, 21.75. Found: C, 59.08; H, 6.68; N, 21.69.
IR (mull): 3359, 3287, 3162, 3112, 3066, 1698 (CO), 1618,
1571 cm–1.
(12) (a) Alves, M. J.; Booth, B. L.; Freitas, A. P.; Proença, M. F.
J. Chem. Soc., Perkin Trans. 1 1992, 913. (b) Booth, B. L.;
Dias, A. M.; Proença, M. F. J. Chem. Soc., Perkin Trans. 1
1992, 2119. (c) Alves, M. J.; Booth, B. L.; Proença, M. F.
J. Heterocycl. Chem. 1994, 31, 345. (d) Booth, B. L.;
Coster, R. D.; Proença, M. F. Synthesis 1988, 389.
(e) Alves, M. J.; Booth, B. L.; Carvalho, M. A.; Pritchar d,
R. G.; Proença, M. F. J. Heterocycl. Chem. 1997, 739.
(f) Al-Azmi, A.; Booth, B. L.; Carpenter, R. A.; Carvalho,
M. A.; Marrelec, E.; Pritchard, R. G.; Proença, M. F. J.
Chem. Soc., Perkin Trans. 1 2001, 2532. (g) Booth, B. L.;
Cabral, I. M.; Dias, A. M.; Freitas, A. P.; Matos-Beja, A. M.;
Proença, M. F.; Ramos-Silva, M. J. Chem. Soc., Perkin
Trans. 1 2001, 1241. (h) Carvalho, M. A.; Esteves, T. M.;
Proença, M. F.; Booth, B. L. Org. Biomol. Chem. 2004, 2,
1019. (i) Carvalho, M. A.; Álvares, Y.; Zaki, M. E.; Proença,
M. F.; Booth, B. L. Org. Biomol. Chem. 2004, 2, 2340.
(13) Dias, A. M.; Cabral, I. M.; Vila-Chã, A. S.; Proença, M. F.
Synlett 2007, 1231.
(17) General Procedure for the Synthesis of 6 and 7
Acetic or benzoic anhydride (2.0 equiv) was added to a
suspension of 1 (1.0–4.0 mmol) in MeCN (1.0–5.0 mL) at 0
°C, and the mixture was stirred at r.t. until the starting
material was totally consumed (2–4 h). The bright yellow/
orange solid was filtered and washed with MeCN and Et2O
to give compounds 6 and 7 in 13–99% yields. The structure
of the products was confirmed by elemental analysis, 1H
NMR and 13C NMR spectroscopy.
5-Amino-1-(4¢-fluorophenyl)-4-[(N-benzoyl)cyano-
formimidoyl]-1H-imidazole (7, R1 = 4-FC6H4, R2 = Ph)
Mp 167–168 °C. 1H NMR (300 MHz, DMSO-d6): d = 8.34
(br s, 2 H), 8.08 (d, J = 7.2 Hz, 2 H), 7.77 (s, 1 H), 7.64 (t,
J = 7.2 Hz, 1 H), 7.55 (dd, J = 9.0, 4.8 Hz, 2 H), 7.54 (t,
J = 7.2 Hz, 2 H), 7.44 (t, J = 9.0 Hz, 1 H). 13C NMR (75
MHz, DMSO-d6): d = 174.93, 160.06 (d, J = 243 Hz),
151.23, 138.60, 135.38, 134.74, 132.81, 131.57 (d, J = 3
Hz), 129.41, 128.51, 125.08 (d, J = 8 Hz), 122.51, 116.31 (d,
J = 22 Hz), 112.14. Anal. Calcd for C12H11N5O3·0.1H2O: C,
64.51; H, 3.67; N, 20.90. Found: C, 64.40; H, 3.81; N, 20.86.
IR (mull): 3342, 2232 (CN), 1629, 1603, 1529 cm–1.
(18) General Procedure for the Synthesis of 8 and 9
Hydrazine monohydrate (2.0 or 1.2 equiv) was added to a
(14) General Procedure for the Synthesis of 1,2,4-Triazolones
3
Hydrazine monohydrate (2.0 equiv) was added to a
suspension of imidazole 2 (0.52–1.95 mmol) in DMF (for 3a
and 3b, 2.0 mL) or EtOH (for 3c–f, 1.0–5.0 mL). The
mixture was stirred at r.t. for 5–30 min (for 3a,b and 3d–e),
and at 0 °C for 40 min (for 3c and 3f). The resulting
suspension was filtered and washed with EtOH and Et2O to
give compounds 3 (78–99%). The structure of the products
was confirmed by elemental analysis, 1H NMR and 13
NMR spectroscopy.
C
5-[5-Amino-1-(4-methoxyphenyl)-1H-imidazol-4-yl]-2,4-
dihydro-3H-1,2,4-triazol-3-one (3a)
Mp >316 °C (dec.). 1H NMR (300 MHz, DMSO-d6):
d = 11.20 (s, 1 H), 7.42 (d, J = 8.7 Hz, 2 H), 7.39 (s, 1 H),
7.09 (d, J = 8.7 Hz, 2 H), 5.22 (s, 2 H), 3.81 (s, 3 H). 13
C
NMR (75 MHz, DMSO-d6): d = 158.98, 155.64, 144.33,
137.91, 130.96, 127.36, 126.31, 114.85, 108.10, 55.52.
Anal. Calcd for C12H12N6O2: C, 52.94; H, 4.44; N, 30.87.
Found: C, 52.75; H, 4.60; N, 30.88. IR (mull): 3428, 3331,
3102, 1715 (CO), 1634 cm–1.
Synlett 2010, No. 18, 2792–2796 © Thieme Stuttgart · New York

2796
A. M. Dias et al.
LETTER
(mull): 3354, 3276, 3170, 3104, 2725, 1616, 1571 cm–1.
1-(4-Fluorophenyl)-4-(5-phenyl-4H-1,2,4-triazol-3-yl)-
1H-imidazol-5-amine (9b)
suspension of imidazole 6 (0.78–1.36 mmol) or 7 in EtOH
(1.5–2.0 mL) at 0 °C leading to a homogeneous solution.
After 5 min a white solid precipitated out of solution and was
filtered and washed with EtOH and Et2O. The structure of
the products was confirmed by elemental analysis, 1H NMR
and 13C NMR spectroscopy.
Mp >250 °C (dec.). 1H NMR (300 MHz, DMSO-d6):
d = 13.94 (br s, 1 H), 8.06 (dt, J = 6.6, 1.5 Hz, 2 H), 7.64 (dd,
J = 9.0, 4.8 Hz, 2 H), 7.55 (s, 1 H) 7.43 (t, J = 9.0 Hz, 2 H),
7.48–7.40 (m, 3 H), 5.75 (br s, 2 H). 13C NMR (75 MHz,
DMSO-d6): d = 161.48 (d, J = 244 Hz), 160.16, 152.27,
138.98, 131.58, 131.15, 128.65, 128.58, 127.11 (d, J = 9
Hz), 125.76, 116.58 (d, J = 23 Hz), 108.89. Anal. Calcd for
C17H13N6F·0.1H2O: C, 63.39; H, 4.13; N, 26.08. Found: C,
63.26; H, 4.18; N, 26.01. IR (mull): 3407, 3276, 3318, 3127,
1634, 1603, 1518 cm–1.
Characterization of 1-Methyl-4-(5-methyl-4H-1,2,4-
triazol-3-yl)-1H-imidazol-5-amine (8c)
Mp >233 °C (dec.). 1H NMR (300 MHz, DMSO-d6):
d = 13.15 (br s, 1 H), 7.20 (s, 1 H), 5.51 (br s, 2 H), 3.44 (s,
3 H), 2.23 (s, 3 H). 13C NMR (75 MHz, DMSO-d6):
d = 158.43, 152.03, 139.21, 141.98, 139.87, 131.61, 108.53,
29.76, 13.76. Anal. Calcd for C8H9N5O·0.1H2O: C, 46.71; H,
5.71; N, 46.69. Found: C, 46.65; H, 5.86; N, 46.25. IR
Synlett 2010, No. 18, 2792–2796 © Thieme Stuttgart · New York

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