A new method for the synthesis of 1-aryl-1,2,4-triazole derivatives

Article abstract of DOI:10.1055/s-0030-1260026

A new and convenient one-step recyclization method for the synthesis of ethyl 1-aryl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxylates is reported. Various ethyl chloro(2-arylhydrazinylidene)ethanoates react with thiazolidine-2,4-dione in the presence of potassium hydroxide to produce the 1-aryl-1,2,4-triazole derivatives in moderate to good yields. The procedure is economical, environmentally friendly and simple to perform. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0030-1260026

PAPER
1799
A New Method for the Synthesis of 1-Aryl-1,2,4-triazole Derivatives
S
ynthesis of 1-Ary
a
l-1,2,4-tria
z
s
oles yl S. Matiychuk,a Mykhaylo A. Potopnyk,a Roman Luboradzki,b Mykola D. Obushak*a
a
Department of Organic Chemistry, Ivan Franko National University of Lviv, Kyryla i Mefodiya St. 6, 79005 Lviv, Ukraine
Institute of Physical Chemistry, Polish Academy of Sciences, ul. Kasprzaka 44/52, 01-224 Warsaw, Poland
Fax +38(32)2971668; E-mail: obushak@in.lviv.ua
b
Received 6 February 2011; revised 22 March 2011
EtOOC
Cl
Abstract: A new and convenient one-step recyclization method for
the synthesis of ethyl 1-aryl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-
3-carboxylates is reported. Various ethyl chloro(2-arylhydrazi-
nylidene)ethanoates react with thiazolidine-2,4-dione in the pres-
ence of potassium hydroxide to produce the 1-aryl-1,2,4-triazole
derivatives in moderate to good yields. The procedure is economi-
cal, environmentally friendly and simple to perform.
N2+\Cl–
N
O
O
NH
NaOAc⋅3H2O
+
R
OEt
R
Cl
2
1a–k
3a–k
Key words: 1,2,4-triazoles, diazonium salts, ring-opening, thiazo-
lidine-2,4-dione, heterocyclization
Scheme
ro)ethanoates 3a–k
1
Preparation of ethyl (2-arylhydrazinylidene)(chlo-
It is known that the chlorine atom in compounds 3 is labile
and can be easily displaced using nucleophiles such as
amines17 and thiols.18 Thus we investigated the reaction of
compounds 3 with 1,3-thiazolidine-2,4-dione (4). The re-
action takes place via nucleophilic attack of the anion of
the thiazolidinedione, generated in the presence of a base,
followed by heterocyclization with rearrangement to af-
ford ethyl 1-aryl-5-oxo-4,5-dihydro-1H-[1,2,4]triazole-3-
carboxylates 5a–k as stable crystalline solids in 47–70%
yield (Table 1). The reaction proceeded in boiling ethanol
in the presence of potassium hydroxide. The structures of
5a–k were established from their spectral data and by el-
emental analysis. Single crystal X-ray structure determi-
nation confirmed unambiguously the structure of
compound 5f (Figure 1).19
Substituted 1,2,4-triazoles play an important role in or-
ganic chemistry due to their presence as key structural
units in pharmaceuticals and biologically active com-
pounds. For example, fluconazole and itraconazole are
used for the treatment and prevention of superficial and
systemic fungal infections. Vorozole, letrozole, fadrozole
and anastrozole are nonsteroidal drugs used to treat of es-
trogen-dependent breast cancer.1 Compounds possessing
the 1,2,4-triazole moiety have been reported as inhibitors
of HIV-integrase,2 cyclin-dependent kinase,3 hormone-
sensitive lipase4 and methionine aminopeptidase-2,5 as
antagonists of cannabinoid receptors6 and the corticotro-
pin-releasing factor-1 receptor,7 and to display antimicro-
bial and antituberculosis activity.8 In addition, substituted
1,2,4-triazoles have been reported as organic materials for
organic light-emitting diodes.9
1,2,4-Triazoles can also be employed as versatile synthet-
ic intermediates or building blocks for the synthesis of a
wide range of organic compounds.10 General synthetic
strategies for the preparation of 1,2,4-triazoles include the
cyclization reactions of semicarbazide2 or thio-
semicarbazide11 derivatives, and the cycloaddition of re-
active cumulenes with nitrile precursors.12 Other reported
methods include recyclization reactions,13 solid-phase
synthesis14 and microwave irradiation.15
Herein, we report a simple one-pot method for the prepa-
ration of alkyl 1-aryl-5-oxo-4,5-dihydro-1H-[1,2,4]tria-
zole-3-carboxylates 5. Our synthesis began with the
preparation of ethyl (2-arylhydrazinylidene)(chloro)eth-
anoates 3a–k from diazonium salts 1a–k and ethyl 2-chlo-
ro-3-oxobutanoate (2) according to the literature method
(Scheme 1).16
SYNTHESIS 2011, No. 11, pp 1799–1803
x
x.
x
x
.
2
0
1
1
Advanced online publication: 05.05.2011
DOI: 10.1055/s-0030-1260026; Art ID: Z18011SS
Figure 1 X-ray crystal structure (ORTEP plot) of compound 5f
© Georg Thieme Verlag Stuttgart · New York

1800
V. S. Matiychuk et al.
PAPER
Table 1 Synthesis of Ethyl 1-Aryl-5-oxo-4,5-dihydro-1H-1,2,4-tri-
azole-3-carboxylates 5a–k.
In summary, we have developed a new and very simple
method for the synthesis of ethyl 1-aryl-5-oxo-4,5-dihy-
EtOOC
dro-1H-1,2,4-triazole-3-carboxylates.
This
method
EtOOC
Cl
NH
should enable the preparation of other aromatic-substitut-
ed 1,2,4-triazole derivatives.
O
N
N
O
N
NH
KOH
NH
+
EtOH
O
S
4
R
R
Melting points were obtained for samples in capillary tubes using a
Thiele apparatus and are uncorrected. NMR spectra were recorded
on Varian Mercury 400 (at 400 MHz for 1H NMR spectra) or Varian
Gemini (at 200 MHz and 50 MHz for 1H and 13C NMR spectra, re-
spectively) spectrometers using CDCl3 or DMSO-d6 as the solvent
and TMS as the internal standard. Elemental analyses were obtained
using a Perkin-Elmer 2400 CHN analyzer.
5a–k
3a–k
Entry
R
Product
Yield (%)a
1
2
H
5a
5b
5c
5d
5e
5f
64
69
66
54
64
57
70
47
62
68
60
4-MeO
Ethyl (2-Arylhydrazinylidene)(chloro)ethanoates 3; General
Procedure
3
3,4-Me2
4-F
A soln of the corresponding aromatic amine (5 mmol) in dilute aq
HCl (2 mL, 1:1) was cooled to 0 °C, and a soln of NaNO2 (380 mg,
5.5 mmol) in H2O (3 mL) was added dropwise and the mixture
stirred for 15 min. The resulting diazonium salt 1a–k was added
dropwise to a cold soln of 2-chloro-4-oxobutanoate (2) (823 mg, 5
mmol) and NaOAc·3H2O (2.04 g, 15 mmol) in EtOH–H2O (15 mL,
9:1). The mixture was stirred for 4 h at 0 °C and then added to H2O
(50 mL). The resulting precipitate was filtered, dried and recrystal-
lized from EtOH. Compounds 3a–f and 3h are reported in the liter-
ature.16
4
5
3-Cl
6
4-Cl
7
4-Br
5g
5h
5i
8
3-F3C
2,4-Cl2
3,4-Cl2
2,5-Cl2
9
Ethyl [2-(4-Bromophenyl)hydrazinylidene](chloro)ethanoate
(3g)
Yield: 1.14 g (75%); mp 158 °C.
10
11
5j
5k
1H NMR (200 MHz, CDCl3): d = 1.40 (t, J = 7.2 Hz, 3 H, CH3),
4.38 (q, J = 7.2 Hz, 2 H, CH2), 7.11 (d, J = 8.8 Hz, 2 H, ArH), 7.42
(d, J = 8.8 Hz, 2 H, ArH), 8.36 (s, 1 H, NH).
a Yield after purification
A plausible mechanism for this one-pot reaction is shown
in Scheme 2. The first step involves alkylation of 1,3-thi-
azolidine-2,4-dione (4) with hydrazine 3 to produce the
intermediate A. Next, nucleophilic attack on the more
electrophilic carbonyl group (C-2) of A, followed by ring-
13C NMR (50 MHz, CDCl3): d = 14.21, 62.88, 115.41, 115.99,
116.78, 132.30, 140.63, 159.44.
Anal. Calcd for C10H10BrClN2O2: C, 39.31; H, 3.30; N, 9.17.
Found: C, 39.10; H, 3.19; N, 9.06.
opening and subsequent elimination of mercaptoacetic EthylChloro[2-(2,4-dichlorophenyl)hydrazinylidene]ethanoate
(3i)
acid from thiol C yields the products 5.
Yield: 1.23 (84%); mp 89 °C.
1H NMR (200 MHz, CDCl3): d = 1.41 (t, J = 7.2 Hz, 3 H, CH3),
4.40 (q, J = 7.2 Hz, 2 H, CH2), 7.23 (dd, J = 8.7, 2.4 Hz, 1 H, ArH),
7.33 (d, J = 2.4 Hz, 1 H, ArH), 7.53 (d, J = 8.7 Hz, 1 H, ArH), 8.71
(s, 1 H, NH).
13C NMR (50 MHz, CDCl3): d = 14.17, 62.98, 116.43, 119.11,
119.29, 127.53, 128.26, 128.92, 136.50, 159.08.
O
O
HN
K+ –
N
+
KOH
O
O
S
S
4
4a
O
O
S
EtOOC
Anal. Calcd for C10H9Cl3N2O2: C, 40.64; H, 3.07; N, 9.48. Found:
C, 40.33; H, 3.19; N, 9.35.
EtOOC
Cl
N
EtOOC
4a
– KCl
N
O
N
S
N
N
••
NH
Ar
NH
N
OH
EthylChloro[2-(3,4-dichlorophenyl)hydrazinylidene]ethanoate
(3j)
Yield: 1.18 g (80%); mp 148 °C.
1H NMR (200 MHz, CDCl3): d = 1.41 (t, J = 7.2 Hz, 3 H, CH3),
4.40 (q, J = 7.2 Hz, 2 H, CH2), 7.05 (dd, J = 8.6, 2.6 Hz, 1 H, ArH),
7.37 (d, J = 8.6 Hz, 1 H, ArH), 7.37 (d, J = 2.6 Hz, 1 H, ArH), 8.34
(s, 1 H, NH).
Ar
Ar
3
A
B
O
EtOOC
EtOOC
SH
N
NH
HO–/H2O
N
N
O
O
N
N
HSCH2CO2H
13C NMR (50 MHz, CDCl3): d = 14.20, 63.06, 113.77, 116.10,
117.67, 126.08, 130.94, 133.42, 141.02, 159.26.
Ar
C
Ar
5
Anal. Calcd for C10H9Cl3N2O2: C, 40.64; H, 3.07; N, 9.48. Found:
C, 40.76; H, 3.15; N, 9.19.
Scheme 2 A plausible mechanism for the formation of ethyl 1-aryl-
5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxylates 5a–k
Synthesis 2011, No. 11, 1799–1803 © Thieme Stuttgart · New York

PAPER
Synthesis of 1-Aryl-1,2,4-triazoles
1801
EthylChloro[2-(2,5-dichlorophenyl)hydrazinylidene]ethanoate
(3k)
Yield: 1.26 (86%); mp 79 °C.
1H NMR (400 MHz, DMSO-d6): d = 1.39 (t, J = 7.2 Hz, 3 H, CH3),
4.38 (q, J = 7.2 Hz, 2 H, CH2), 7.21 (t, J = 8.4 Hz, 2 H, ArH), 7.95
(dd, JHH = 8.4 Hz, JHF = 4.8 Hz, 2 H, ArH), 12.92 (br s, 1 H, NH).
1H NMR (200 MHz, CDCl3): d = 1.42 (t, J = 7.1 Hz, 3 H, CH3),
4.42 (q, J = 7.1 Hz, 2 H, CH2), 6.93 (dd, J = 8.5, 2.4 Hz, 1 H, ArH),
7.25 (d, J = 8.5 Hz, 1 H, ArH), 7.60 (d, J = 2.4 Hz, 1 H, ArH), 8.73
(s, 1 H, NH).
13C NMR (50 MHz, CDCl3): d = 14.19, 63.13, 115.59, 117.12,
119.71, 122.95, 130.18, 134.09, 138.47, 159.08.
13C NMR (100 MHz, DMSO-d6): d = 14.88, 62.12, 116.83 (d,
JC-F = 23.1 Hz, 2 C), 121.92 (d, JC-F = 7.7 Hz, 2 C), 134.60 (d, JC-F
=
2.6 Hz, 1 C), 138.49, 153.04, 157.33, 160.75 (d, JC-F = 242.5 Hz, 1 C).
Anal. Calcd for C11H10FN3O3: C, 52.59; H, 4.01; N, 16.73. Found:
C, 52.44; H, 4.08; N, 16.53.
Ethyl 1-(3-Chlorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazole-
3-carboxylate (5e)
Yield: 343 mg (64%); mp 184 °C.
Anal. Calcd for C10H9Cl3N2O2: C, 40.64; H, 3.07; N, 9.48. Found:
C, 40.41; H, 3.02; N, 9.57.
Ethyl 1-Aryl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxy-
lates 5; General Procedure
1H NMR (400 MHz, DMSO-d6): d = 1.39 (t, J = 7.2 Hz, 3 H, CH3),
4.39 (q, J = 7.2 Hz, 2 H, CH2), 7.25 (d, J = 8.0 Hz, 1 H, ArH), 7.45
(t, J = 8.0 Hz, 1 H, ArH), 7.90 (d, J = 8.0 Hz, 1 H, ArH), 8.01 (s, 1
H, ArH), 13.02 (br s, 1 H, NH).
13C NMR (50 MHz, DMSO-d6): d = 13.95, 62.27, 116.83, 117.90,
125.54, 130.92, 133.47, 137.97, 138.42, 152.06, 156.27.
KOH (123 mg, 2.2 mmol) was added to a soln of 1,3-thiazolidine-
2,4-dione (4)20 (258 mg, 2.2 mmol) in EtOH (10 mL) and the mix-
ture heated at reflux temperature for 1 h. Next, a soln of compound
3 (2 mmol) in EtOH (10 mL) was added dropwise and the mixture
heated at reflux temperature for 1.5 h. About half of the solvent was
removed under reduced pressure and the remainder was diluted with
H2O (5 mL). The resulting precipitate was filtered and recrystal-
lized from EtOH.
Anal. Calcd for C11H10ClN3O3: C, 49.36; H, 3.77; N, 15.70. Found:
C, 49.51; H, 3.58; N, 15.57.
Ethyl 1-(4-Chlorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazole-
3-carboxylate (5f)
Yield: 304 mg (57%); mp 203 °C.
Ethyl 5-Oxo-1-phenyl-4,5-dihydro-1H-1,2,4-triazole-3-carbox-
ylate (5a)
1H NMR (400 MHz, DMSO-d6): d = 1.38 (t, J = 7.2 Hz, 3 H, CH3),
4.39 (q, J = 7.2 Hz, 2 H, CH2), 7.45 (d, J = 8.4 Hz, 2 H, ArH), 7.96
(d, J = 8.4 Hz, 2H, ArH), 12.96 (br s, 1 H, NH).
13C NMR (50 MHz, DMSO-d6): d = 13.96, 62.21, 120.13, 129.08,
129.85, 136.12, 137.79, 152.05, 156.31.
Yield: 298 mg (64%); mp 193–194 °C.
1H NMR (400 MHz, DMSO-d6): d = 1.39 (t, J = 7.2 Hz, 3 H, CH3),
4.39 (q, J = 7.2 Hz, 2 H, CH2), 7.24 (t, J = 8.0 Hz, 1 H, PhH), 7.44
(t, J = 8.0 Hz, 2 H, PhH), 7.93 (d, J = 8.0 Hz, 2 H, PhH), 12.88 (br
s, 1 H, NH).
13C NMR (50 MHz, DMSO-d6): d = 13.99, 62.16, 118.81, 125.97,
129.14, 137.22, 137.58, 152.15, 156.41.
Anal. Calcd for C11H10ClN3O3: C, 49.36; H, 3.77; N, 15.70. Found:
C, 49.04; H, 3.65; N, 15.61.
Anal. Calcd for C11H11N3O3: C, 56.65; H, 4.75; N, 18.02. Found: C,
56.49; H, 4.68; N, 17.90.
Ethyl 1-(4-Bromophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazole-
3-carboxylate (5g)
Yield: 437 mg (70%); mp 210 °C.
Ethyl 1-(4-Methoxyphenyl)-5-oxo-4,5-dihydro-1H-1,2,4-tria-
zole-3-carboxylate (5b)
Yield: 363 mg (69%); mp 179 °C.
1H NMR (400 MHz, DMSO-d6): d = 1.38 (t, J = 7.2 Hz, 3 H, CH3),
3.80 (s, 3 H, CH3), 4.37 (q, J = 7.2 Hz, 2 H, CH2), 6.96 (d, J = 9.2
Hz, 2 H, ArH), 7.78 (d, J = 9.2 Hz, 2 H, ArH), 12.80 (br s, 1 H, NH).
1H NMR (200 MHz, DMSO-d6): d = 1.32 (t, J = 7.0 Hz, 3 H, CH3),
4.37 (q, J = 7.0 Hz, 2 H, CH2), 7.66 (d, J = 8.4 Hz, 2 H, ArH), 7.87
(d, J = 8.4 Hz, 2 H, ArH), 12.95 (br s, 1 H, NH).
13C NMR (50 MHz, DMSO-d6): d = 13.96, 62.22, 118.06, 120.42,
132.01, 136.55, 137.83, 152.04, 156.31.
13C NMR (50 MHz, CDCl3): d = 14.06, 55.48, 62.90, 114.08,
121.65, 130.07, 136.85, 153.26, 156.47, 158.19.
Anal. Calcd for C11H10BrN3O3: C, 42.33; H, 3.23; N, 13.46. Found:
C, 42.12; H, 3.34; N, 13.67.
Anal. Calcd for C12H13N3O4: C, 54.75; H, 4.98; N, 15.96. Found: C,
54.61; H, 5.04; N, 15.72.
Ethyl 5-oxo-1-[3-(Trifluoromethyl)phenyl]-4,5-dihydro-1H-
1,2,4-triazole-3-carboxylate (5h)
Yield: 283 mg (47%); mp 187 °C.
Ethyl 1-(3,4-Dimethylphenyl)-5-oxo-4,5-dihydro-1H-1,2,4-tria-
zole-3-carboxylate (5c)
Yield: 345 mg (66%); mp 188 °C.
1H NMR (200 MHz, DMSO-d6): d = 1.33 (t, J = 7.2 Hz, 3 H, CH3),
4.37 (q, J = 7.2 Hz, 2 H, CH2), 7.62 (d, J = 7.6 Hz, 1 H, ArH), 7.72
(t, J = 7.8 Hz, 1 H, ArH), 8.18 (d, J = 7.8 Hz, 1 H, ArH), 8.25 (s, 1
H, ArH), 13.10 (br s, 1 H, NH).
13C NMR (50 MHz, DMSO-d6): d = 13.94, 62.31, 114.50 (q, J = 4.0
Hz), 122.01, 122.06 (q, J = 4.0 Hz), 126.55, 129.78 (q, J = 31.7 Hz),
130.63, 137.87, 138.22, 152.25, 156.31.
1H NMR (400 MHz, DMSO-d6): d = 1.39 (t, J = 7.2 Hz, 3 H, CH3),
2.28 (s, 3 H, CH3), 2.30 (s, 3 H, CH3), 4.38 (q, J = 7.2 Hz, 2 H, CH2),
7.16 (d, J = 8.0 Hz, 1 H, ArH), 7.62 (d, J = 8.0 Hz, 1 H, ArH), 7.66
(s, 1 H, ArH), 12.80 (br s, 1 H, NH).
13C NMR (50 MHz, DMSO-d6): d = 13.99, 18.92, 19.59, 62.09,
116.34, 119.81, 129.87, 134.07, 135.08, 137.04, 137.19, 152.05,
156.42.
Anal. Calcd for C12H10F3N3O3: C, 47.85; H, 3.35; N, 13.95. Found:
C, 47.69; H, 3.31; N, 13.76.
Anal. Calcd for C13H15N3O3: C, 59.76; H, 5.79; N, 16.08. Found: C,
59.94; H, 5.71; N, 16.24.
Ethyl 1-(2,4-Dichlorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-tria-
zole-3-carboxylate (5i)
Yield: 375 mg (62%); mp 206 °C.
Ethyl 1-(4-Fluorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazole-
3-carboxylate (5d)
Yield: 272 mg (54%); mp 206 °C.
1H NMR (200 MHz, DMSO-d6): d = 1.30 (t, J = 7.0 Hz, 3 H, CH3),
4.35 (q, J = 7.0 Hz, 2 H, CH2), 7.55–7.69 (m, 2 H, ArH), 7.88 (s, 1
H, ArH), 12.97 (br s, 1 H, NH).
Synthesis 2011, No. 11, 1799–1803 © Thieme Stuttgart · New York

1802
V. S. Matiychuk et al.
PAPER
13C NMR (50 MHz, DMSO-d6): d = 13.92, 62.21, 128.42, 129.83,
ARKIVOC 2006, (ix), 59. (c) Al-Masoudi, I. A.; Al-Soud, Y.
A.; Al-Salihi, N. J.; Al-Masoudi, N. A. Chem. Heterocycl.
Compd. 2006, 42, 1377. (d) Balasubramanian, M.; Keay, J.
G.; Scriven, E. F. V.; Shobana, N. Heterocycles 1994, 37,
1951. (e) Kofman, T. P. Russ. J. Org. Chem. 2002, 38, 1231;
Zh. Org. Khim. 2002, 38, 1289.
131.27, 132.29, 132.51, 134.88, 138.43, 152.53, 156.36.
Anal. Calcd for C11H9Cl2N3O3: C, 43.73; H, 3.00; N, 13.91. Found:
C, 43.51; H, 2.91; N, 14.05.
Ethyl 1-(3,4-Dichlorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-tria-
zole-3-carboxylate (5j)
Yield: 411 mg (68%); mp 209 °C.
1H NMR (200 MHz, DMSO-d6): d = 1.32 (t, J = 7.4 Hz, 3 H, CH3),
4.33 (q, J = 7.4 Hz, 2 H, CH2), 7.64 (dd, J = 8.6, 2.3 Hz, 1 H, ArH),
7.72 (d, J = 8.6 Hz, 1 H, ArH), 7.79 (d, J = 2.3 Hz, 1 H, ArH), 13.13
(br s, 1 H, NH).
(11) Mustafa, S. M.; Nair, V. A.; Chittoor, J. P.; Krishnapillai, S.
Mini-Rev. Org. Chem. 2004, 1, 375.
(12) Yamazaki, C.; Sakai, M.; Miyamoto, Y.; Suzuki, N.
J. Chem. Soc., Perkin Trans. 1 1987, 1567.
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Chem. Heterocycl. Compd. 2007, 43, 996. (b) Roy, R. U.;
Desai, A. R.; Desai, K. R. E-J. Chem. 2005, 2, 1.
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M. C.; Watson, K. Org. Lett. 1999, 1, 1189. (b) Boeglin,
D.; Cantel, S.; Heitz, A.; Martinez, J.; Fehrentz, J.-A. Org.
Lett. 2003, 5, 4465. (c) Larsen, S. D.; DiPaolo, B. A. Org.
Lett. 2001, 3, 3341. (d) Theoclitou, M.-E.; Delaet, N. G. J.;
Robinson, L. A. J. Comb. Chem. 2002, 4, 315.
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Commun. 2003, 33, 113. (b) Yeung, K.-S.; Farkas, M. E.;
Kadow, J. F.; Meanwell, N. A. Tetrahedron Lett. 2005, 46,
3429.
(16) Matiichuk, V. S.; Potopnyk, M. A.; Obushak, N. D. Russ. J.
Org. Chem. 2008, 44, 1352; Zh. Org. Khim. 2008, 44, 1368.
(17) (a) Peng, Y.; Zhang, Q.; Arora, S.; Keenan, S. M.;
Kortagere, S.; Wannemacher, K. M.; Howells, R. D.; Welsh,
W. J. Bioorg. Med. Chem. 2009, 17, 6442. (b) Krauth, F.;
Friedemann, R.; Rüttinger, H.-H.; Frohberg, P. ARKIVOC
2009, (vii), 150. (c) Catarzi, D.; Colotta, V.; Varano, F.;
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13C NMR (50 MHz, DMSO-d6): d = 13.93, 62.32, 118.28, 119.50,
127.73, 131.18, 131.51, 136.93, 138.16, 152.00, 156.19.
Anal. Calcd for C11H9Cl2N3O3: C, 43.73; H, 3.00; N, 13.91. Found:
C, 43.57; H, 2.85; N, 13.78.
Ethyl 1-(2,5-Dichlorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-tria-
zole-3-carboxylate (5k)
Yield: 363 mg (60%); mp 205 °C.
1H NMR (200 MHz, DMSO-d6): d = 1.30 (t, J = 7.0 Hz, 3 H, CH3),
4.36 (q, J = 7.0 Hz, 2 H, CH2), 7.63 (dd, J = 8.6, 2.3 Hz, 1 H, ArH),
7.73 (d, J = 8.6 Hz, 1 H, ArH), 7.79 (d, J = 2.3 Hz, 1 H, ArH), 13.01
(br s, 1 H, NH).
13C NMR (50 MHz, DMSO-d6): d = 13.93, 62.26, 129.84, 130.04,
131.06, 131.62, 132.05, 134.49, 138.48, 152.51, 156.36.
Anal. Calcd for C11H9Cl2N3O3: C, 43.73; H, 3.00; N, 13.91. Found:
C, 43.62; H, 2.74; N, 13.85.
(d) Awadallah, A. M.; Zahra, J. A. Molecules 2008, 13, 170.
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(g) Catarzi, D.; Colotta, V.; Varano, F.; Filacchioni, G.;
Galli, A.; Costagli, C.; Carlà, V. J. Med. Chem. 2001, 44,
3157.
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(19) A colorless crystal of approximate dimensions 1.0 × 0.05 ×
0.05 mm was used. Diffraction data were collected at 100 K
using a Bruker Kappa CCD diffractometer with graphite
monochromated MoKa radiation (0.71073 Å). Lorentz-
polarization correction was employed, but not for
absorptions. The structure was solved by direct methods
(SHELXS-97)21 and refined on F2 using the full-matrix
least-squares method (SHELXL-97).21 Formula:
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C11H10ClN3O3, orthorhombic, space group = P212121,
a = 4.3850 (2), b = 10.5690 (7), c = 24.8990 (16) Å,
V = 1153.95 (12) Å3, R1 = 0.0804 [I>2s(I)], wR2 = 0.2070
for all data. The hydrogen atoms were added geometrically
and refined with the riding model. The crystallographic data
for compound 5f have been deposited with the Cambridge
Crystallographic Data Centre as supplementary publication
number CCDC 804995. These data can be obtained free of
charge via www.ccdc.cam.ac.uk, or on application to the
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK.
Synthesis 2011, No. 11, 1799–1803 © Thieme Stuttgart · New York

PAPER
Synthesis of 1-Aryl-1,2,4-triazoles
1803
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Synthesis 2011, No. 11, 1799–1803 © Thieme Stuttgart · New York