An Efficient Route to Ethyl 5-Alkyl- (Aryl)-1H-1,2,4-triazole-3-carboxylates

Article abstract of DOI:10.1002/jhet.1934

An efficient general route to the synthesis of 5-substituted 1H-1,2,4-triazole-3-carboxylates was developed. N-acylamidrazones were obtained from carboxylic acid hydrazides and ethyl thiooxamate or ethyl 2-ethoxy-2-iminoacetate hydrochloride and then were

Full text of DOI:10.1002/jhet.1934

Month 2014
An Efficient Route to Ethyl 5-Alkyl- (Aryl)-1H-1,2,4-triazole-3-
carboxylates
*
M. V. Chudinov, A. V. Matveev, N. I. Zhurilo, A. N. Prutkov, and V. I. Shvets
Biotechnology and Bionanotechnology Department, Lomonosov Moscow University of Fine Chemical Technology,
Vernadskogo pr. 86, Moscow, Russian Federation
*
E-mail: mikle@irims.ru
Received August 22, 2012
DOI 10.1002/jhet.1934
Published online 00 Month 2014 in Wiley Online Library (wileyonlinelibrary.com).
An efficient general route to the synthesis of 5-substituted 1H-1,2,4-triazole-3-carboxylates was devel-
oped. N-acylamidrazones were obtained from carboxylic acid hydrazides and ethyl thiooxamate or ethyl
2-ethoxy-2-iminoacetate hydrochloride and then were reacted with chloroanhydride of the same carboxylic
acid. As the next step, diacylamidrazones were cyclized to 5-substituted 1H-1,2,4-triazole-3-carboxylates
one pot in mild conditions.
J. Heterocyclic Chem., 00, 00 (2014).
INTRODUCTION
The acylamidrazone 1a cyclization in boiling acetic anhy-
dride leads to compound 2a with a high yield (71%). Under
the same reaction conditions, acylamidrazone 1b yields two
products, ethyl 5-ethyl-1H-1,2,4-triazole-3-carboxylate 2b
and ethyl 5-methyl-1H-1,2,4-triazole-3-carboxylate 2a, in
the ratio 2a : 2b= 85:15 (by LC/MS). We suggest that the
secondary acylation of compound 1b takes place followed
by diacylated amidrazone cyclization, and two routes are
possible (Scheme 1).
To examine this hypothesis, acylamidrazones 1a–h were
obtained by two routes (Table 1). Carboxylic acid hydrazides
reacted with either ethyl thiooxamate [10] or ethyl 2-ethoxy-
2-iminoacetate hydrochloride, obtained from ethyl cyanfor-
mate by Pinner method [11] (Scheme 2).
To study new nucleoside analogs that are under investiga-
tion in our laboratory, it was essential to synthesize a series
of 1H-1,2,4-triazole-3-carboxyesters with alkyl and aryl
substituents in the fifth position of the heterocyclic moiety.
To our astonishment, no general methods for the synthesis
of 5-alkyl/aryl-substituted 1H-1,2,4-triazole-3-carboxylic
acidderivatives were published to this date. The standard ways
of the triazole ring formation [1–4] were inefficient for our
goals, in particular for the carboxyl group in the 3(5) position.
RESULTS AND DISCUSSION
Most synthetic pathways proposed for these compounds
include the thermal cyclization of N-acylamidrazones 1. This
route is comparatively efficient only for ethyl 5-methyl-
1H-1,2,4-triazole-3-carboxylate 2a (44–52% yield) [5,6]
and possibly for some higher homologues [7,8]. Thus, we
found that heating induces sublimation or thermal decompo-
sition of N-acylamidrazones 1b–h. In this case, reaction
mixtures consisted of unconverted N-acylamidrazones
1b–h and unknown decomposition products, and triazoles
were not detected by LC/MS. Heating in the solvents (toluene,
o-xylene, DMF, or pyridine) also did not yield cyclization
products. Therefore, we were not able to apply this method
for 5-substituted 1H-1,2,4-triazole-3-carboxylates 2b–h synthe-
sis. The use of dehydrating agents, such as thionyl chlo-
ride, sulfuric acid, or trifluoroacetic anhydride, did not
yield the required triazoles. But the thermal cyclization
of compounds 1 with KOH in DMF, according to [9],
yields the corresponding triazole carboxylic acids and
potassium salts. However, this investigation does not
contain the structures characterization.
The acylamidrazones 1 were obtained with comparable
yields; however, the ethyl thiooxamate reaction is more
convenient for preparative synthesis. As these compounds
have low solubility, possible cyclization conditions are
limited. Reactions with acylchlorides in dry pyridine
appeared to be the optimal way. In the reaction of acylami-
drazones 1 with 1.1 equiv acylchloride in pyridine at room
temperature followed by reaction mixture boiling for
several hours, unstable ethyl 5-substituted 1-N-acyl-1,2,
4-triazole-3-carboxylates 3 were obtained with high yields;
the latter being readily hydrolyzed in situ after several
drops of water was added to the reaction mixture on the
final phase (Scheme 3).
The substituents R1 and R2 do not influence cyclization,
but the acylation agent excess is significant. The cyclization
efficiency was mainly affected by the acylation agent excess,
whereas the influence (contribution) of the substituents R1
and R2 was negligible (Table 2). Thus, acylation of com-
pound 1d with 1.1 equiv acetyl chloride (R1═iPr, R2═Me)
yields 2d (51%) and 2a (49%), but when 10 equiv acetyl
© 2014 HeteroCorporation

M. V. Chudinov, A. V. Matveev, N. I. Zhurilo, A. N. Prutkov, and V. I. Shvets
Vol 000
Scheme 1
Scheme 3
Table 2
Yields of ethyl 5-substituted-1H-1,2,4-triazole-3-carboxylates
2a–h (R1═R2).
2a (R═Me)
79%a
2b (R═Et)
2c (R═Pr)
2d (R═iPr)
2e (R═cyclo-Pr)
2f (R═iBu)
2g (R═t-Bu)
2h (R═Ph)
83%
69%
81%
66%
67%
30%b
38%c
Scheme 2
aCyclization in acetic anhydride.
bAfter additional hydrolysis of 3g.
cAfter column chromatography.
with the acylating agent followed by diacylamidrazones cycli-
zation one pot in mild conditions. Some of the intermediate
products, namely ethyl 1-N-acyl-1,2,4-triazole-3-carboxylates
3, were isolated and characterized by NMR.
Ethyl 5-substituted-1H-1,2,4-triazole-3-carboxylates
2a–h obtained herein were subsequently used for the synthe-
sis of 5-substituted Ribavirin analogs. These nucleoside ana-
log characteristics and bioactivity are currently being studied.
Table 1
Yields of acylamidrazones 1.
EXPERIMENTAL
a (%)
b (%)
All reactions were carried out under inert atmosphere in
glassware with magnetic stirring. Pyridine (Chimmed, Moscow,
Russia) was distilled from CaH2 (Chimmed, Moscow, Russia).
Other solvents and commercial reagents were used without addi-
tional purification. Unless otherwise noted, yields refer to chromato-
graphically and spectroscopically pure compounds. Visualization of
TLC (analytical TLC) was achieved by the use of UV light (254nm)
and treatment with phosphomolybdic acid followed by heating.
TLC was carried out on (OOO Imid, Krasnodar, Russia) Sorbfil
plates. Reaction mixtures were monitored by LC/MS detection us-
ing an Applied Biosystems (California, USA)/SCIEX API 150EX
LC/MS instrument equipped with the Turbo Ion Spray source.
HRMS were recorded using ESI-TOF on Agilent (Santa Clara,
1a (R═Me)
1b (R═Et)
1c (R═Pr)
1d (R═iPr)
1e (R═cyclo-Pr)
1f (R═iBu)
1g (R═t-Bu)
1h (R═Ph)
92
86
86
77
85
86
68
72
91
84
—
82
83
88
—
81
a: from ethyl thiooxamate; b: from ethyl ethoxy(imino)acetate).
chloride was used, 33% of 2d and 67% of 2a were obtained,
as monitored by LC/MS of the reaction mixture.
Thus, the efficient general route to the synthesis of com-
pounds 2 appeared to be the reaction of acyamidrazones 1
1
California, USA) 6224 LC/MS mass spectrometer. H NMR and
13C NMR were recorded on a 300-MHz (1H NMR at 300 MHz and
13C NMR at 75 MHz) Bruker (Billerica, Massachusetts, USA)
DPX300 spectrometer with solvent resonance as the internal standard
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2014
An Efficient Route to Ethyl 5-Alkyl (Aryl)-1H-1,2,4-triazole-3-carboxylates
(1H NMR: CDCl3 at 7.25 ppm, DMSO-d6 at 2.49 ppm; acetone-d6 at
2.04 ppm; 13C NMR: CDCl3 at 77.00 ppm, DMSO-d6 at 39.50 ppm).
NMR data are presented as follows: chemical shift in parts per million
(d ppm), multiplicity (s, singlet; d, doublet; t, triplet; q, quartet; and m,
multiplet), coupling constant in Hertz (Hz), and integration. Melting
points were reported uncorrected.
General procedure for the preparation of acylamidrazones (1)
Method A. Ethyl thiooxamate (25mmol) and hydrazide
(25mmol) were reacted in absolute ethanol (15 mL). The reaction
mixture was stirred for 12–72 h in a round-bottomed flask. The
resulting precipitate was filtered, washed with absolute ethanol
(2 Â 5 mL), and dried to give the acylamidrazone (1).
13.80; 13.58. HRMS: Calcd for C8H16N3O3 ([M + H]+): 202.1192.
Found: 202.1176. mp = 182–184ꢀC (with decomposition). Anal.
Calcd for C8H15N3O3: C, 47.75; H, 7.51; N, 20.88. Found:
C, 47.67; H, 7.48; N, 20.75.
Ethyl imino[2-(2-methylpropanoyl)hydrazino]acetate (1d).
Following Method A, isobutyric acid hydrazide 2.91 g (29 mmol) and
ethyl thiooxamate 3.79 g (29 mmol) were used and ethyl imino[2-(2-
methylpropanoyl)hydrazino]acetate (1d) was obtained (4.41 g, 77%).
Following Method B, isobutyric acid hydrazide 2.91 g (29 mmol)
and ethyl 2-ethoxy-2-iminoacetate hydrochloride 5.27 g (29 mmol)
were used to yield (1d) (4.70 g, 82%). 1H-NMR (DMSO-d6,
300 MHz) d (ppm): 9.68, 9.65 (2s, 1H); 6.47, 6.38 (2s, 2H); 4.22,
4.21 (2q, J= 7.1 Hz, 2H); 3.28, 2,44 (2m, 1H); 2.24, 2.23 (2t,
J= 7.1 Hz, 3H); 1.02, 1.01 (2d, J=6.8Hz, 6H). 13C-NMR (DMSO-
d6, 75MHz) d (ppm): 178.09; 172.50; 162.23; 161.52; 139.03;
135.76; 61.53; 61.41; 32.75; 28.93; 19.52; 18.61; 13.98. HRMS:
Calcd for C8H16N3O3 ([M + H]+): 202.1192. Found: 202.1186.
mp = 208–210ꢀC (with decomposition). Anal. Calcd for C8H15N3O3:
C, 47.75; H, 7.51; N, 20.88. Found: C, 47.72; H, 7.38; N, 20.93.
Ethyl [2-(cyclopropylcarbonyl)hydrazino](imino)acetate
(1e). Following Method A, cyclopropanecarboxylic acid
hydrazide 2.91 g (23 mmol) and ethyl thiooxamate 3.00 g
(23 mmol) were used and ethyl [2-(cyclopropylcarbonyl)hydrazino]
(imino)-acetate (1e) was obtained (3.81 g, 85%). Following Method
B, cyclopropanecarboxylic acid hydrazide 2.91 g (23 mmol) and
ethyl 2-ethoxy-2-iminoacetate hydrochloride 4.18 g (23 mmol) were
Method B. The solution of hydrazide (25mmol) in 10 mL of
absolute ethanol was added to ethyl 2-ethoxy-2-iminoacetate
hydrochloride (25 mmol) in 10 mL of absolute ethanol in a round-
bottomed flask, and the reaction mixture was stirred for 12–24 h at
room temperature and monitored by TLC (CHCl3–MeOH 9:1) for
the consumption of hydrazide and formation of N-acylamidrazone.
A 4M aqueous solution of sodium hydrocarbonate (10mL) was
then added. The reaction mixture was partially evaporated, and
white precipitate was washed with water (1 mL) and dried to give
the acylamidrazone (1).
Ethyl (2-acetylhydrazino)(imino)acetate (1a).
Following
Method A, acetic acid hydrazide (2.00 g, 27 mmol) and
ethyl thiooxamate (3.60 g, 27 mmol) were used and ethyl
(2-acetylhydrazino)(imino)acetate (1a) was afforded (4.30 g, 92%)
as a white solid. Following Method B, acetic acid hydrazide
(2.00 g, 27 mmol) and ethyl 2-ethoxy-2-iminoacetate hydrochloride
(4.90 g, 27 mmol) were used and 1a (4.25 g, 90%) was obtained.
1H-NMR (DMSO-d6, 300 MHz) d (ppm) 9.78, 9.75 (2s, 1H); 6.41,
6.36 (2s, 2H); 4.22, 4.20 (2q, J = 7.1Hz, 2H); 2.07, 1.89 (2s, 3H);
1.25, 1.24 (2t, J = 7.1Hz, 3H). 13C-NMR (DMSO-d6, 75MHz)
d (ppm) 172.1; 165.3; 162.3; 161.8; 138.8; 135.8; 61.5; 21.6;
20.1; 14.0. HRMS: Calcd for C6H12N3O3 ([M + H]+): 174.0879.
Found: 174.0873. mp= 196ꢀC (lit. 196.5–197.5 [3]). Anal. Calcd
for C6H11N3O3: C, 41.61; H, 6.40; N, 24.27. Found: C, 41.52;
H, 6.38; N, 24.35.
Ethyl imino(2-propionylhydrazino)acetate (1b). Following
Method A, propionic acid hydrazide (2.50 g, 28mmol) and
ethyl thiooxamate (3.78g, 28mmol) were used, and ethyl imino
(2-propionylhydrazino)acetate (1b) was afforded (4.57 g, 86%).
Following Method B, propionic acid hydrazide (2.50 g, 28mmol)
and ethyl 2-ethoxy-2-iminoacetate hydrochloride 5.09 g (28mmol)
were used to yield (1b) (4.46 g, 84%).1H-NMR (DMSO-d6,
300 MHz) d (ppm): 9.76, 9.65 (2s, 1H); 6.44, 6.37 (2s, 2H); 4.22,
4.21 (2q, J = 7.1Hz, 2H); 2.51, 2.16 (2q, J = 7.6 Hz, 2H); 1.24,
1.23 (2t, J = 7.1 Hz, 3H); 1.03, 1.00 (2t, J = 7.6 Hz, 3H). 13C-NMR
(DMSO-d6, 75MHz) d (ppm): 175.2; 169.2; 162.2; 161.8; 138.8;
135.7; 61.4; 27.3; 24.9; 14.0; 9.8; 8.6. HRMS: Calcd
for C7H14N3O3 ([M + H]+):188.1035. Found: 188.1030. mp =
216–218ꢀC (with decomposition). Anal. Calcd for C7H13N3O3:
C, 44.91; H, 7.00; N, 22.45. Found: C, 45.07; H, 6.88; N, 22.35.
Ethyl (2-butanoylhydrazino)(imino)acetate (1c). Following
Method A, butyric acid hydrazide 2.79 g (27 mmol) and
ethyl thiooxamate 3.64 g (27 mmol) were used and ethyl
(2-butyrylhydrazino)(imino)acetate (1c) was obtained (4.73 g, 86%).
1H-NMR (DMSO-d6, 300 MHz) d (ppm): 9.79, 9.67 (2s, 1H); 6.45,
6.37 (2s, 2H); 4.21, 4.20 (2q, J= 7.1 Hz, 2H); 2.47, 2.13
(2t, J= 7.2 Hz, 2H); 1.54 (m, J= 7.4 Hz, 2H); 1.24, 1.23
(2t, J= 7.1 Hz, 3H); 0.88, 0.86 (2t, J=7.4Hz, 3H). 13C-NMR
(DMSO-d6, 75MHz) d (ppm): 174.28; 168.19; 162.21; 161.76;
138.65; 135.68; 61.50; 61.41; 36.04; 33.50; 18.62; 17.38; 13.99;
1
used to yield (1e) (3.72 g, 83%). H-NMR (DMSO-d6, 300 MHz)
d
(ppm): 9.93, 9.90 (2s, 1H); 6.43, 6.41 (2s, 2H); 4.21
(q, J= 7.1 Hz, 2H); 2.51, 1.61 (2m, 1H); 1.24 (t, J=7.1Hz, 3H);
0.85–0.69 (m, 4H). 13C-NMR (DMSO-d6, 75MHz) d (ppm):
174.83; 169.20; 162.33; 161.88; 138.46; 136.25; 61.64; 61.59;
14.05; 12.85; 9.51; 7.95; 6.88. HRMS: Calcd for C8H14N3O3
([M + H]+): 200.1035. Found: 200.1184. mp = 230–232ꢀC (with
decomposition). Anal. Calcd for C8H13N3O3: C, 48.23; H, 6.58;
N, 21.09. Found: C, 48.02; H, 6.39; N, 21.23.
Ethyl imino[2-(3-methylbutanoyl)hydrazino]acetate (1f).
Following Method A, 3-methylbutanoic acid hydrazide
2.75 g (24 mmol) and ethyl thiooxamate 3.15 g (24 mmol)
were used and ethyl imino[2-(3-methylbutanoyl)hydrazino]
acetate (1f) was obtained (4.38 g, 86%). Following Method
B, cyclopropanecarboxylic acid hydrazide 2.75 g (24 mmol)
and ethyl 2-ethoxy-2-iminoacetate hydrochloride 4.00 g
(24 mmol) were used to yield (1f) (4.48 g, 88%). 1H-NMR
(DMSO-d6, 300 MHz) d (ppm): 9.79, 9.63 (2s, 1H); 6.45,
6.36 (2s, 2H); 4.21, 4.19 (2q, J = 7.1 Hz, 2H); 2.41–2.38
(m, 1H); 2.13–1.95 (m, 2H); 1.24, 1.23 (2t, J = 7.1 Hz, 3H); 0.89,
0.88 (2d, J =6.4 Hz, 6H). 13C-NMR (DMSO-d6, 75 MHz)
d (ppm): 173.79; 167.67; 162.23; 161.75; 138.71; 135.59; 61.53;
61.39; 43.31; 40.61; 25.52; 24.48; 22.51; 22.24; 13.99; 13.95.
HRMS: Calcd for C9H18N3O3 ([M + H]+): 216.1348. Found:
216.1499. mp = 210–212ꢀC (with decomposition). Anal. Calcd
for C9H17N3O3: C, 50.22; H, 7.96; N, 19.52. Found: C, 49.97;
H, 8.09; N, 19.63.
Ethyl [2-(2,2-dimethylpropanoyl)hydrazino](imino)acetate
(1g). Following Method A, pivalic acid hydrazide 3.00 g
(26 mmol) and ethyl thiooxamate 3.51g (26mmol) were used and
ethyl [2-(2,2-dimethylpropanoyl)hydrazino](imino)acetate (1g)
was obtained (3.78 g, 68%). 1H-NMR (DMSO-d6, 300 MHz)
d (ppm): 9.04 (s, 1H); 6.58 (s, 2H); 4.21 (q, J = 7.1 Hz, 2H); 1,24
(t, J = 7.1 Hz, 3H); 1.15 (s, 9H). 13C-NMR (DMSO-d6, 75 MHz)
d (ppm): 173.64; 162.28; 139.93; 61.45; 38.00; 27.23; 13.95.
HRMS: Calcd for C9H18N3O3 ([M + H]+): 216.1348. Found:
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

M. V. Chudinov, A. V. Matveev, N. I. Zhurilo, A. N. Prutkov, and V. I. Shvets
Vol 000
216.1391. mp = 188–190ꢀC (with decomposition). Anal. Calcd
for C9H17N3O3: C, 50.22; H, 7.96; N, 19.52. Found: C, 50.18;
H, 8.02; N, 19.50.
(t, J= 7.5 Hz, 2H); 1.79 (m, 2H); 1.37 (t, J=7.2Hz, 3H); 0.94
(t, J= 7.3 Hz, 3H). 13C-NMR (chloroform-d, 75MHz) d (ppm):
159.95; 159.20; 153.51; 61.60; 27.89; 21.02; 13.73; 13.18. HRMS:
Calcd for C8H14N3O2 ([M + H]+): 184.1086. Found: 184.1103.
mp = 128–130ꢀC. Anal. Calcd for C8H13N3O2: C, 52.45; H, 7.15;
N, 22.94. Found: C, 52.52; H, 7.12; N, 23.01.
Ethyl imino[2-(phenylcarbonyl)hydrazino]acetate (1h).
Following Method A, benzoic acid hydrazide 3.18 g (23mmol)
and ethyl thiooxamate 3.00g (23mmol) were used and ethyl
imino[2-(phenylcarbonyl)hydrazino]acetate (1h) was obtained
(3.98 g, 72%). Following Method B, benzoic acid hydrazide
3.18g (23 mmol) and ethyl 2-ethoxy-2-iminoacetate hydrochloride
3.83g (23 mmol) were used to yield (1h) (4.46 g, 81%). 1H-NMR
(DMSO-d6, 300MHz) d (ppm): 10.06 (s, 1H); 7.83–7.81 (m, 2H);
7.54–7.45 (m, 3H); 6.76 (s, 2H); 4.24 (q, J = 7.1 Hz, 2H); 1.27
(t, J = 7.1 Hz, 3H). 13C-NMR (DMSO-d6, 75 MHz) s (ppm):
163.60; 162.23; 140.93; 134.04; 131.37; 128.29; 127.74; 61.72;
14.04. HRMS: Calcd for C11H14N3O3 ([M + H]+): 236.1035.
Found: 236.1030. mp = 228–230ꢀC (with decomposition). Anal.
Calcd for C11H13N3O3: C, 56.16; H, 5.57; N, 17.86. Found:
C, 56.11; H, 5.52; N, 18.00.
Ethyl 5-methyl-1H-1,2,4-triazole-3-carboxylate (2a). A round-
bottomed flask was loaded with 1a (2.5g, 14 mmol) and acetic
anhydride (5 mL). The reaction mixture was refluxed for 3 h and
then evaporated to dryness under reduced pressure. The resulting
solid residue was triturated with 3 mL of Et2O then filtered and
dried to give the acylamidrazone 2a (1.77 g, 79%). 1H-NMR
(chloroform-d, 300 MHz) d (ppm): 4.44 (q, J = 7.1Hz, 2H); 2.61
(s, 3H); 1.38 (t, J = 7.1 Hz, 3H). 13C-NMR (chloroform-d,
75MHz): d (ppm) 160.41; 155.77; 154.12; 62.13; 14.17; 12.20.
HRMS: Calcd for C6H10N3O2 ([M + H]+): 156.0773. Found:
156.0780. mp = 186ꢀC. (lit. 185.5–186 [3]). Anal. Calcd for
C6H9N3O2: C, 46.45; H, 5.85; N, 27.08. Found: C, 46.40;
H, 5.82; N, 27.11.
General procedure for the preparation of 5-substituted-1H-
1,2,4-triazole-3-carboxylates (2b–2h). A 25-mL three-necked
flask, equipped with a magnetic stirrer, a condenser, and an
addition funnel, was loaded with 14mmol of compound 1 and
10mL of freshly distilled pyridine. A 16 mmol of acylchloride
was added over 10 min via the addition funnel, and the reaction
mixture was refluxed for 8–30 h. The reaction was monitored
by TLC (CHCl3–MeOH 95:5) for the depletion of 1. As the
full conversion was achieved, several drops of water were
added. Reaction mixture was refluxed for 1 h and then
evaporated to dryness under reduced pressure. The resulting
residue was dissolved in ethyl acetate (50 mL) and washed
with 1M HCl (10 mL) followed by 2M sodium hydrocarbonate
(10 mL). Organic layer was dried over anhydrous sodium
sulfate and concentrated at reduced pressure to give an oily
residue. The crude oil was triturated with 3 mL of Et2O and
filtered to give 2.
Ethyl 5-ethyl-1H-1,2,4-triazole-3-carboxylate (2b). Following
the general procedure, 1b (3 g, 16 mmol) and propionyl chloride
(1.61 mL, 18 mmol) were used to obtain 2b (2.25 g, 83%).
1H-NMR (chloroform-d, 300 MHz) d (ppm): 4.45 (q, J=7.2 Hz,
2H); 2.95 (q, J = 7.7 Hz, 2H); 1.38 (t, J= 7.2 Hz, 3H); 1.35
(t, J =7.7Hz, 3H). 13C-NMR (chloroform-d, 75MHz) d (ppm):
160.64; 160.36; 153.88; 62.04; 19.96; 14.11; 12.14. HRMS: Calcd
for C7H12N3O2 ([M + H]+): 170.0930. Found: 170.0954.
mp = 103–105ꢀC. Anal. Calcd for C7H11N3O2: C, 49.70; H, 6.55;
N, 24.84. Found: C, 49.61; H, 6.62; N, 24.71.
Ethyl 5-isopropyl-1H-1,2,4-triazole-3-carboxylate (2d).
Following the general procedure, 1d (3.5 g, 17 mmol) and
isobutyryl chloride (2.10 mL, 20 mmol) were used to yield 2d
1
(2.57 g, 81%). H-NMR (chloroform-d, 300MHz) d (ppm): 4.41
(q, J =7.1 Hz, 2H); 3.24 (m, J = 7.0Hz, 1H); 1.36 (d, J = 7.0 Hz,
6H); 1,33 (t, J = 7.1 Hz, 3H). 13C-NMR (chloroform-d, 75MHz)
d (ppm): 164.38; 160.19; 153.65; 61.97; 26.98; 20.99; 14.13.
HRMS: Calcd for C8H14N3O2 ([M + H]+): 184.1086. Found:
184.1092. mp= 102–104ꢀC. Anal. Calcd for C8H13N3O2: C,
52.45; H, 7.15; N, 22.94. Found: C, 52.61; H, 7.18; N, 22.76.
Ethyl 5-cyclopropyl-1H-1,2,4-triazole-3-carboxylate (2e).
Following the general procedure, 1e (3.0g, 15 mmol) and
cyclopropanecarbonyl chloride (1.57 mL, 17 mmol) were used
to yield 2e (1.80 g, 66%). 1H-NMR (chloroform-d, 300MHz)
d
(ppm): 4.45 (q, J = 7.1 Hz, 2H); 2.13 (m, 1H); 1.38
(t, J = 7.1 Hz, 3H); 1.18–1.05 (m, 4H). 13C-NMR (chloroform-d,
75MHz) d (ppm): 161.59; 160.24; 153.61; 62.03; 14.09; 8.98;
7.33. HRMS: Calcd for C8H12N3O2 ([M + H]+): 182.0930. Found:
182.0924. mp= 110–112ꢀC. Anal. Calcd for C8H11N3O2: C,
53.03; H, 6.12; N, 23.19. Found: C, 52.90; H, 6.18; N, 23.25.
Ethyl 5-(2-methylpropyl)-1H-1,2,4-triazole-3-carboxylate
(2f). Following the general procedure, 1f (3.0 g, 14 mmol) and
isovaleryl chloride (1.95 mL, 16mmol) were used to yield 2f
1
(1.85 g, 67%). H-NMR (chloroform-d, 300MHz) d (ppm): 4.44
(q, J = 7.1Hz, 2H); 2.79 (d, J =7.3 Hz, 2H); 2.18–2.05 (m, 1H);
1.37 (t, J = 7.1 Hz, 3H); 0.90 (d, J = 6.7 Hz, 6H). 13C-NMR
(chloroform-d, 75 MHz) d (ppm): 160.39; 159.04; 153.99; 62.07;
35.22; 28.21; 22.18; 14.20. HRMS: Calcd for C9H16N3O2
([M + H]+): 198.1243. Found: 198.1274. mp= 103–105ꢀC. Anal.
Calcd for C9H15N3O2: C, 54.81; H, 7.67; N, 21.30. Found: C,
54.80; H, 7.58; N, 21.51.
Ethyl 5-tert-butyl-1H-1,2,4-triazole-3-carboxylate (2g).
Following the general procedure, 1g (3.0 g, 14 mmol) and
pivaloyl chloride (1.97 mL, 16 mmol) were used to yield
crude 3g (1.44 g). The resulting solid was dissolved in 10-mL
ethanol–water mixture (5:1) and stirred for 1 h with NaHCO3
(0.5 g). The reaction mixture was evaporated to dryness
under reduced pressure, and the residue was triturated with
chloroform (5 mL). The mixture was filtered, and the filtrate
was concentrated to give 2g (0.82 g, 30%). 1H-NMR
(chloroform-d, 300 MHz) d (ppm): 4.38 (q, J = 7.1 Hz, 2H);
1.37 (s, 9H); 1.28 (t, J = 7.1 Hz, 3H). 13C-NMR (chloroform-d,
75 MHz) d (ppm): 167.00; 160.08; 153.65; 61.88; 32.46;
28.94; 14.13. HRMS: Calcd for C9H16N3O2 ([M + H]+):
198.1243. Found: 198.1275. mp = 184–186ꢀC. Anal. Calcd for
C9H15N3O2: C, 54.81; H, 7.67; N, 21.30. Found: C, 54.70;
H, 7.52; N, 21.38.
Ethyl 5-phenyl-1H-1,2,4-triazole-3-carboxylate (2h). Following
the general procedure, 1h (5.0 g, 21 mmol) and benzoyl
chloride (2.84 mL, 24mmol) were used to yield crude 2h. The
crude product was purified by column chromatography
(chloroform : methanol = 100:0 to 97:3, gradient elution) to give
2h (1.75 g, 38%). 1H-NMR (chloroform-d, 300 MHz) d (ppm):
8.05–8.01 (m, 2H); 7.43–7.36 (m, 3H); 4.40 (q, J = 7.2 Hz, 2H);
1.31 (t, J = 7.2Hz, 3H). 13C-NMR (chloroform-d, 75 MHz)
d (ppm): 159.62; 158.14; 153.39; 130.80; 128.98; 126.78; 62.31;
Ethyl 5-propyl-1H-1,2,4-triazole-3-carboxylate (2c). Following
the general procedure, 1c (4 g, 20 mmol) and butyryl chloride
(2.37 mL, 23 mmol) were used to yield 2c (2.51 g, 69%). 1H-NMR
(chloroform-d, 300 MHz) d (ppm): 4.44 (q, J= 7.1 Hz, 2H); 2.89
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2014
An Efficient Route to Ethyl 5-Alkyl (Aryl)-1H-1,2,4-triazole-3-carboxylates
14.02. HRMS: Calcd for C11H12N3O2 ([M + H]+): 218.0930.
Found: 218.0957. mp = 161–163ꢀC. Anal. Calcd for C11H11N3O2:
C, 60.82; H, 5.10; N, 19.34. Found: C, 60.76; H, 5.32; N, 19.13.
[2] Castanedo, G. M.; Seng, P. S.; Blaquiere, N.; Trapp, S.;
Staben, S. T. J Org Chem 2011, 76, 1177.
[3] Potts, K. T., Chem Rev, 1961, 61 (2), 87–127.
[4] Temple, C. In The chemistry of heterocyclic compounds.
Triazoles 1,2,4; Montgomery, J. A. Ed.; John Wiley & Sons: New York,
1981; Vol 37, pp 96–120.
[5] Oliver, J. E.; Sonnet, P. E. J Org Chem 1973, 38, 1437.
[6] McKillop, A.; Henderson, A.; Ray, P. S. Tet Lett 1982, 23, 3357.
[7] Cesar, J.; Sollner, M. Synth Commun 2000, 30, 4147.
[8] Borg, S.; Vollinga, R. C.; Labarre, M.; Payza, K.; Terenius, L.;
Luthman, K. J Med Chem 1999, 42, 4331.
Acknowledgments. This research was supported by the Russian
Foundation for Basic Research (grant 10-04-01020) and by the
State Contract No. P1085.
REFERENCES AND NOTES
[9] Dost, J.; Stein, J.; Heschel, M. Z Chem 1986, 26, 203.
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet