Facile One-Pot Synthesis of Methyl 1-Aryl-1H-1,2,4-triazole-3-carboxylates from Nitrilimines with Vilsmeier Reagent

Article abstract of DOI:10.1002/ejoc.201801808

Two convenient and effective one-pot methods have been developed to synthesize methyl 1-aryl-1H-1,2,4-triazole1–3-carboxylates by using hydrazonoyl hydrochlorides (nitrilimines) with Vilsmeier reagent. The first, a direct one-pot method, involved the reac

Full text of DOI:10.1002/ejoc.201801808

A Journal of
Accepted Article
Title: Facile One-Pot Synthesis of Methyl 1-Aryl-1H-1,2,4-triazole-3-
carboxylates from Nitrilimines with Vilsmeier Reagent
Authors: Shuo-En Tsai, Kun-Heng Chiang, Ching-Chun Tseng, Nai-
Wei Chen, Fung Fuh Wong, and Ching-Yuh Chern
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201801808
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10.1002/ejoc.201801808
European Journal of Organic Chemistry
FULL PAPER
Facile One-Pot Synthesis of Methyl 1-Aryl-1H-1,2,4-triazole-3-
carboxylates from Nitrilimines with Vilsmeier Reagent
Shuo-En Tsai,[a,b] Kun-Heng Chiang,[a] Ching-Chun Tseng,[a,b] Nai-Wei Chen,[c] Ching-Yuh Chern,*[d]
and Fung Fuh Wong*[a]
Abstract: Two convenient and effective one-pot methods have been
developed to synthesize methyl 1-aryl-1H-1,2,4-triazole1-3-
carboxylates by using hydrazonoyl hydrochlorides (nitrilimines) with
Vilsmeier reagent. The first, a direct one-pot method, involved the
reaction between nitrilimines and Vilsmeier reagent at ~85C for ~0.5
h. Another one-pot two-step cascade method proceeded via
nucleophilic substitution with bis(trimethylsilyl)amine [NH(SiMe3)2]
and subsequent intramolecular cycloaddition reaction with Vilsmeier
reagent. Substrate scope, multicomponent examples, and
mechanistic insights are discussed.
addition, Vilsmeier reagents provides some advantages such as
high yield and purity of products, functional group tolerance, and
simple manipulation.[20] Herein, we report two convenient and
effective one-pot methods to synthesize methyl 1-aryl-1H-1,2,4-
triazole-3-carboxylates 2a–n from nitrilimines using the Vilsmeier
reagent (HCONH2/POCl3). The first is a direct method involving
the reaction between 2-chloro-2-(2-phenylhydrazono)acetate
nitrilimines 1a–n and the Vilsmeier reagent. The other one is a
two-step cascade method that gave methyl 2-amino-2-(2-
phenylhydrazono)acetate 4 in the first step, via nucleophilic
substitution reaction with bis(trimethylsilyl)amine [NH(SiMe3)2].
This was followed by an intramolecular cycloaddition reaction with
the Vilsmeier reagent (HCONH2/POCl3) to form the corresponding
1,2,4-triazoles 2a–n in good isolated yields (73–91%). Both
approaches to the preparation of methyl 1-aryl-1H-1,2,4-triazole1-
3-carboxylates are presented in Scheme 1.
Introduction
1,2,4-Triazoles constitute an important class of heterocyclic
compounds, having various biological activities,[1] such as
[4]
antibacterial,[2]
antifungal,[3]
anti-inflammatory,
antituberculosis,[5] anticancer,[6] antioxidant[7] and InhA inhibitory
activity.[8] Therefore, the development of simple and efficient
synthetic methods of pharmaceutically active 1,2,4-triazoles is
important to drug discovery.[9]
Scheme 1
Syntheses of substituted 1,2,4-triazoles have been reported in the
Results and Discussion
literature.[10]
These included dehydrative cyclization of
acylamidrazone intermediates[11] and formation of the 1,2,4-
triazole motif from hydrazides and activated nitriles or amides
including imidates and thioamides.[12] We have also successfully
developed a number of syntheses to afford substituted 1,2,4-
triazoles by reacting nitrilimines with aldehydes, nitriles, imidate
hydrochlorides, oxime hydrochlorides, and carbodiimides via a
We reckoned that an intramolecular cyclization reaction between
Vilsmeier reagents and hydrazonoyl hydrochlorides (nitrilimines)
is highly feasible. To investigate the reactivity of such reactions,
we
prepared
a
series
of
methyl
2-chloro-2-(2-
arylhydrazono)acetate 1a–n as the starting material by literature
methods.[13,21] To evaluate the reaction conditions, methyl 2-
chloro-2-(2-phenylhydrazono)acetate 1a was used as a model
reactant with the Vilsmeier reagent (HCONH2/3.0 equiv of POCl3)
under various reaction temperatures including ~25, 55, 75, 85,
125C, and at reflux (see Scheme 1 and Table 1). We also studied
the reaction time from 0.5 to 72 h and followed the reactions by
TLC (see Table 1).
1,3-dipolar
cycloaddition
methodology.[13]
Additional
methodologies for the preparation of 1-aryl-1,2,4-triazoles have
been developed. Examples included the direct condensation of
hydrazine derivatives,[14,15] transition metal catalyzed C–N bond
coupling,[16] and SNAr-type chemistry of a halogenated arene with
1,2,4-triazole as a nucleophile.[17]
The Vilsmeier reagent is a versatile and widely-used synthetic
agent. This reagent and its analogues have been used to achieve
and
heterocyclization[20] in organic and medicinal chemistry. In
Table 1
amindination,[18]
formylation,[18,19]
formyloxylation,[19]
Based on the results, we concluded that the intramolecular
cyclization reaction required heating above 55C even with
reaction times as long as 72 h (see entry 1 and 2). Higher reaction
temperatures (75–85C) gave the desired product 1-aryl-1H-
1,2,4-triazole 2a and the minor decarboxylated product 3a in
72%/90% and 14%/4%, respectively (see entry 3 and 4 of Table
1). When the reaction temperature increased to 125C, formation
of the decarboxylated product 3a was promoted (see entry 5 of
Table 1). Consequently, when we carried out the reaction under
reflux (~175C) for the same reaction time, 3a predominated and
was produced in 86% yield (see entry 6 of Table 1). Overall, the
best reaction condition was 80-90C and the reaction time was
about 0.5 h (see Table 1 and Figure 1). To evaluate the generality
of these conditions, we further prepared ethyl 2-chloro-2-(2-
[a]
[b]
Prof. F. F. Wong*, S.-E. Tsai, K.-H. Chiang and C.-C. Tseng
School of Pharmacy, China Medical University, No. 91, Hsueh-Shih
Rd., Taichung 40402, Taiwan, R.O.C
E-mail: ffwong@mail.cmu.edu.tw; wongfungfuh@yahoo.com.tw
http://webap.cmu.edu.tw/TchEportfolio/index_1/ffwong
S.-E. Tsai and C.-C. Tseng
The Ph.D. Program for Biotech Pharmaceutical Industry, China
Medical University, No. 91 Hsueh-Shih Rd., Taichung 40402,
Taiwan, R.O.C.
[c]
[d]
N.-W. Chen
Master Program for Pharmaceutical Manufacture, China Medical
University, No. 91, Hsueh-Shih Rd., Taichung, 40402, Taiwan
C.-Y. Chern*
Department of Applied Chemistry, National Chia-Yi University, Chia-
Yi, 60004, Taiwan
E-mail: cychern@mail.ncyu.edu.tw
http://www.ncyu.edu.tw/chem/content.aspx?site_content_sn=5158
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10.1002/ejoc.201801808
European Journal of Organic Chemistry
FULL PAPER
phenylhydrazono)acetate as the starting material. A similar
reaction with the Vilsmeier reagent gave the corresponding 1-aryl-
1H-1,2,4-triazole product 2b in 74% yield. For economic and
arylhydrazono)acetates 4a, 4d–g, 4i, and 4k in high crude yields
(>95%, see Scheme 2).
reaction
efficiency
reasons,
methyl
2-chloro-2-(2-
Scheme 2
phenylhydrazono)acetates 1a-n were chosen as the substrates in
further studies.
Our strategy intended to skip all the intermediate isolations.
Compound
1
was treated with bis(trimethylsilyl)amine
Figure 1
[NH(SiMe3)2] under the above reaction conditions. When the
amination reaction was complete, fresh Vilsmeier reagent (2.0 mL
of HCONH2/3.0 equiv of POCl3) [18–20] was added to the resulting
solution and the mixture was heated to ~85C for ~0.5 h. As
expected, the corresponding 1-phenyl-1H-1,2,4-triazole-3-
carboxylates 2a, 2d–g, 2i, and 2k were successfully afforded in
73–91% goods yields (see Scheme 2 and Table 4). Compared to
the direct one-pot method, no decarboxylation was found with this
two-step cascade strategy. However, this cascade procedure was
more tedious and troublesome than the straightforward one-pot
process.
Reliability of the optimized procedure was demonstrated with 2-
chloro-2-(2-arylhydrazono)acetate 1b–n. Despite various
substituents including o-, m-, p-CF3, o-, m-, p-F, m-, p-Cl, m-, p-
Me, p-Br, p-OMe, and 3,4-di-Cl, the one-pot intramolecular
heterocyclization reaction proceeded smoothly at ~85C for ~0.5
h to give the corresponding methyl 1-aryl-1H-1,2,4-triazole-3-
carboxylates 2b–n in good to excellent yields (82–95%, see Table
2). All 1-aryl-1H-1,2,4-triazoles 2a–n were fully characterized by
spectroscopic methods. For example, compound 2a presented
two singlet peaks at δ 8.61 ppm for the1,2,4-triazolic ring and δ
4.01 ppm for the –OMe group in the H NMR. In the 13C NMR
1
Table 4
spectrum, compound 2a showed characteristic absorption at δ
160.1 ppm for the carboxylate carbon O=13COMe. The structure
of methyl 1-phenyl-1H-1,2,4-triazole-3-carboxylate 2a was further
charactered by X-rays crystallographic analysis and a single-
crystal X-ray diffraction study (ORTEP) was presented in Figure
2.
To interpret the reactivity difference between the direct method
and the two-step cascade strategy in terms of formation of methyl
1-phenyl-1H-1,2,4-triazole-3-carboxylate 2a, we proposed
a
mechanism as shown in Scheme 3. Methyl 2-Chloro-2-(2-
phenylhydrazono)acetate 1a and Vilsmeier reagent belonged to
the acidic species and they can be simultaneously reacted at
~85C to give imine intermediate 5. Subsequently, intramolecular
cycloaddition reaction happened effectively under heating
condition. The expected product 2a was smoothly provided in
good yields. For two-step cascade method, methyl 2-chloro-2-(2-
phenylhydrazono)acetate 1a in THF solution was reacted with
bis(trimethylsilyl)amine [NH(SiMe3)2] in presence of excess
amount of TEA. The amination reaction was carried out to give
methyl 2-(2-phenylhydrazono)acetate 4a. When fresh Vilsmeier
reagent was added towards the resulting solution, compound 4a
was transferred into intermediate 6. Because the protonated
bis(trimethylsilyl)amino group was also a leaving group,[22] the
intramolecular cyclization reaction could smoothly and gradually
occur at ~85C to obtain the desired methyl 1-phenyl-1H-1,2,4-
triazole-3-carboxylate product 2a without the detectable
decarboxylated product 3a (see Scheme 3). To prove the
mechanism of two-step cascade one-pot reaction, we tried to
isolate the intermediate methyl 2-(2-phenylhydrazono)acetate 4a.
Then crude intermediate 4a was directly reacted towards
Vilsmeier reagent at ~85C. The expected result was obtained
under the same reaction condition. Therefore, it provided the
strong evidence for demonstrating our plausible mechanism.
Table 2
Figure 2
For further investigation into the reaction temperature effect, 2-
chloro-2-(2-arylhydrazono)acetates substituted with o-, m-, p-CF3,
o-, m-, p-F, m-, p-Cl, or m-, p-Me 1a–k were allowed to react with
Vilsmeier reagent (HCONH2/3.0 equiv of POCl3) at reflux. The
corresponding decarboxylated products 3a–k predominated as a
single product in 82–94% yields (see Table 3). The
decarboxylated 1-aryl-1H-1,2,4-triazoles 3a–k were identified by
spectroscopic methods. Compound 3a exhibited two singlet
peaks at δ 7.99 and 8.47 ppm for the 1,2,4-triazole ring in the 1H
NMR spectrum. Furthermore, compound 1-(4-Fluorophenyl)-1H-
1,2,4-triazole 3g was further identified by X-ray crystallography as
shown in Figure 3. Following the above results (Table 2 and Table
3), we assumed that 1-aryl-1H-1,2,4-triazole-3-carboxylates 2
were unstable and readily decarboxylated to give 3 under acidic
condition and high temperature (> 125C).
Table 3
Scheme 3
Figure 3
To evaluate alternative ways for the synthesis of 1-aryl-1H-1,2,4-
triazole-3-carboxylates 2, we developed another one-pot strategy
by treating 2-chloro-2-(2-arylhydrazono)acetates 1a, 1d–g, 1i and
1k with 3.0 equiv of bis(trimethylsilyl)amine [NH(SiMe3)2] in THF Conclusions
solution at 60C (see Scheme 2). When the starting materials 1a,
1d–g, 1i and 1k were fully consumed as shown by TLC, the
reaction mixtures were worked up with saturated aqueous
NaHCO3 solution to give the corresponding 2-(2-
We have developed two simple one-pot methods for synthesis of
methyl 3-carboxylate-1-aryl-1H-1,2,4-triazoles, which involved
the direct one-pot reaction and two-step cascade synthetic
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10.1002/ejoc.201801808
European Journal of Organic Chemistry
FULL PAPER
procedure. Under the normal heating condition, methyl 3-
carboxylate-1-aryl-1H-1,2,4-triazoles 2 was able to be generated
successfully in presence of Vilsmeier reagent and nitrilimines.
Compare with these two methods, we conceived the
straightforward one-pot method was more efficient and economic.
On the other hand, we observed that methyl 1-aryl-1H-1,2,4-
triazole-3-carboxylates
2
were unstable under the high
temperature (> 125C) and gradually converted to the
decarboxylated 1-aryl-1H-1,2,4-triazole products 3.
Scheme 1. Two convenient and effective one-pot methods for synthesis of
methyl 1-aryl-1H-1,2,4-triazole-3-carboxylates 2a–n from nitrilimines 1a–n or 4
with Vilsmeier reagent.
Figure 1. (a) The reaction condition started at ~25C (□: 1H NMR of the
hydrazonoyl hydrochloride starting material 1a), (b) The reaction condition was
at ~55C for 0.5 h, (c) The reaction condition was at ~85C for 0.5 h (∆:1H NMR
of 1-phenyl-1H-1,2,4-triazole-3-carboxylate 2a), (d) The reaction condition was
at ~175C for 0.5 h (○: 1H NMR of 1-phenyl-1H-1,2,4-triazole 3a).
Scheme 2. The new developed one-pot two-step cascade method for synthesis
of methyl 1-aryl-1H-1,2,4-triazole-3-carboxylates 2.
Figure 2. The ORTEP diagram of methyl 1-phenyl-1H-1,2,4-triazole-3-
carboxylate 2a (CCDC 1865434).
Scheme 3. The plausible mechanism of two new developed one-pot methods
for synthesis of methyl 3-carboxylate-1-aryl-1H-1,2,4-triazole 2a.
Figure 3. The ORTEP diagram of 1-(4-Fluorophenyl)-1H-1,2,4-triazole 3g
(CCDC 1865435).
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10.1002/ejoc.201801808
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Table 1. The reaction condition study for synthesis of 1,2,4-triazole-3-
carboxylate 2a and 1,2,4-triazole 3a.
Table 3. The reaction result for synthesis of 1-aryl-1H-1,2,4-triazoles 3a–n
Nitrilimines
Yields (%)[a]
Reaction
temperature
Entry
Entry
3a–k
Yields (%)
Reaction Time
1a–k
1a
X
Compound 2a
Compound 3a
~ 25 C
~ 55 C
~ 75 C
> 72 h
24 h
N/A[b]
N/A[b]
1
2
3
4
H
1
2
3
4
3a
3b
3c
3d
3e
3f
86
82
87
88
82
89
93
94
84
83
85
16
72
10
14
1b
1c
o-CF3
m-CF3
p-CF3
o-F
~0.5 h
90
66
4
1d
1e
~ 85 C
~0.5 h
~0.5 h
5
6
33
5
6
~ 125 C
1f
m-F
~ 175 C
86
~0.5 h
N/A
7
1g
1h
p-F
3g
3h
3i
(at reflux)
8
[a] The results were identified by the isolated yields.
[b] The starting material 1a was recovered.
m-Cl
p-Cl
m-Me
p-Me
9
1i
1j
Table 2. The reaction result for synthesis of 1,2,4-triazole-3-carboxylates 2a–n
10
11
3j
1k
3k
Table 4. The reaction result for synthesis of 1,2,4-triazole-3-carboxylates 2a,
2d–g, 2i, and 2k
Nitrilimines
Entry
2a–n
Yields (%)
1a–n
1a
X
H
1
2
3
4
2a
2b
2c
2d
2e
2f
90
89
1b
1c
o-CF3
m-CF3
p-CF3
o-F
Nitrilimines
Entry
91
Compounds 2
Yields (%)
1a, 1d–g, 1i, and 1k
X
H
1d
1e
93
82
1
2
3
4
1a
2a
2d
2e
2f
73
91
88
5
6
1d
1e
1f
o-CF3
o-F
1f
m-F
85
85
92
94
95
92
87
95
88
7
1g
1h
p-F
2g
2h
8
m-Cl
p-Cl
m-F
p-F
87
83
9
1i
1j
2i
2j
5
6
7
1g
1i
2g
2i
10
11
12
13
14
m-Me
p-Me
p-Br
p-Cl
p-Me
79
86
1k
1l
2k
2l
1k
2k
1m
1n
p-OMe
3,4-di-Cl
2m
2n
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10.1002/ejoc.201801808
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2H, ArH), 7.94 (d, J = 7.6 Hz, 1H, ArH), 8.03 (s, 1H, ArH), 8.70 (s, 1H,
triazole-H). 13C NMR (100 MHz, CDCl3): δ 53.04, 117.53, 123.25 (q, J =
513.0 Hz), 123.45, 125.79, 130.70, 132.70 (q, J = 33.3 Hz), 136.78, 142.36,
155.79, 159.79. IR (KBr): 2359, 1726, 1458, 1329, 1317, 1159, 1115, 1069
cm–1. EIMS m/z: 271 (M+, 47), 240 (100), 213 (61), 207 (50), 172 (31), 159
(38), 145 (39). HRMS calcd. for C11H8F3N3O2: 271.0569; found: 271.0561.
Experimental Section
General
All chemicals were reagent grade and used as purchased except methyl
2-chloro-2-(2-arylhydrazono)acetate 1a–n synthesized by the previously
report methods.[13,21] All reactions were carried out under nitrogen
atmosphere and monitored by TLC analysis. Flash column
chromatography purification of compounds was carried out by gradient
elution using hexanes in ethyl acetate (EA) unless otherwise stated.
Commercially available reagents were used without further purification
Methyl 1-[4-(trifluoromethyl)phenyl]-1H-1,2,4-triazole-3-carboxylate
(2d). The residue solution was purified by column chromatography on
silica gel to give methyl 1-[4-(trifluoromethyl)phenyl]-1H-1,2,4-triazole-3-
carboxylate 2d as light yellow solid (252 mg, 93%); mp 171–172 C
(hexane–EtOAc). 1H NMR (CDCl3, 400 MHz): δ 4.04 (s, 3H, OCH3), 7.80
(d, J = 8.8 Hz, 2H, ArH), 7.90 (d, J = 8.4 Hz, 2H, ArH), 8.69 (s, 1H, triazole-
H). 13C NMR (100 MHz, CDCl3): δ 53.05, 120.42 (2 × C), 123.36 (q, J =
272.5 Hz), 123.37, 127.25 (q, J = 3.4 Hz) , 131.13 (q, J = 32.7 Hz), 138.81,
142.35, 155.85, 159.77. IR (KBr): 3105, 2359, 1721, 1341, 1155, 1112 cm–
1. EIMS m/z: 271 (M+, 48), 240 (100), 213 (54), 172 (26), 159 (28), 145
(31). HRMS calcd. for C11H8F3N3O2: 271.0569; found: 271.0568.
unless otherwise noted. 1H NMR was recorded at 400 or 500 MHz and 13
C
NMR recorded at 100 or 125 MHz, in CDCl3. The standard abbreviations
s, d, t, q, and m refer to singlet, doublet, triplet, quartet, and multiplet,
respectively. Coupling constant (J), whenever discernible, have been
reported in Hz. Infrared spectra (IR) were recorded as neat solutions or
solids; and mass spectra were recorded using electron impact or
electrospray ionization techniques. The wavenumbers reported are
referenced to the polystyrene 1601 cm–1 absorption. High-resolution mass
Methyl 1-(2-fluorophenyl)-1H-1,2,4-triazole-3-carboxylate (2e).[24] The
residue solution was purified by column chromatography on silica gel to
give methyl 1-(2-fluorophenyl)-1H-1,2,4-triazole-3-carboxylate 2e as
yellow solid (181 mg, 82%); mp 81–82 C (hexane–EtOAc). 1H NMR
(CDCl3, 400 MHz): δ 4.01 (s, 3H, OCH3), 7.26–7.32 (m, 2H, ArH), 7.38–
7.42 (m, 1H, ArH), 7.92 (dd, J = 8.0, 16.0 Hz, 1H, ArH), 8.68 (s, 1H,
triazole-H). 13C NMR (100 MHz, CDCl3): δ 52.92, 117.00 (d, J = 20.0 Hz),
124.66 (2 × C), 125.41 (d, J = 3.2 Hz), 130.26 (d, J = 7.9 Hz), 145.22 (d, J
= 12.55 Hz), 153.74 (d, J = 250.6 Hz), 154.85, 159.89. IR (KBr): 1744,
1514, 1462, 1252, 1202, 1171, 751 cm–1. EIMS m/z: 221 (M+, 66), 190
(100), 163 (87), 122 (32), 109 (84), 95 (24), 83 (21). HRMS calcd. for
C10H8FN3O2: 221.0601; found: 221.0608.
spectra were obtained by means of
spectrometer.
a JEOL JMS-HX110 mass
Method 1: Standard Procedure of the Directed One-Pot Method for
Synthesis of Methyl 1-Aryl-1H-1,2,4-triazole-3-carboxylates 2a–n.
The reliable procedure involved the treatment of methyl 2-chloro-2-(2-
phenylhydrazono)acetates (1a–n, 1.0 equiv), with POCl3 (~3.0 equiv) in
formamide solution (5 mL) at ~ 85 C within 0.5 h. When the reaction was
completed, the reaction mixture was added to water (15 mL) and extracted
with dichloromethane (15 mL × 3). The combined organic layer was
washed sodium bicarbonate (15 mL × 3), dried over MgSO4, filtered, and
concentrated under reduced pressure. The residue solution was purified
by column chromatography on silica gel to give the corresponding methyl
1-aryl-1H-1,2,4-triazole-3-carboxylates 2a–n in 82–95% yields.
Methyl 1-(3-fluorophenyl)-1H-1,2,4-triazole-3-carboxylate (2f). The
residue solution was purified by column chromatography on silica gel to
give methyl 1-(3-fluorophenyl)-1H-1,2,4-triazole-3-carboxylate 2f as brown
1
solid (188 mg, 85%); mp 144–145 C (hexane–EtOAc). H NMR (CDCl3,
400 MHz): δ 4.01 (s, 3H, OCH3), 7.11–7.16 (m, 1H, ArH), 7.45–7.53 (m,
3H, ArH), 8.63 (s, 1H, triazole-H). 13C NMR (100 MHz, CDCl3): δ 52.97,
108.40 (d, J = 26.0 Hz), 115.67, 116.10 (d, J = 21.0 Hz), 131.36 (d, J = 9.0
Hz), 137.54 (d, J = 10.0 Hz), 142.27, 155.56, 159.84, 163.13 (d, J = 284.0
[23]
Methyl 1-phenyl-1H-1,2,4-triazole-3-carboxylate (2a).
The residue
solution was purified by column chromatography on silica gel to give
methyl 1-phenyl-1H-1,2,4-triazole-3-carboxylate 2a as brown solid (183
mg, 90%); mp 93–94 C (hexane–EtOAc). 1H NMR (CDCl3, 400 MHz): δ
4.01 (s, 3H, OCH3), 7.41–7.45 (m, 1H, ArH), 7.49–7.53 (m, 2H, ArH), 7.69–
7.72 (m, 2H, ArH), 8.61 (s, 1H, triazole-H). 13C NMR (100 MHz, CDCl3): δ
52.88, 120.51 (2 × C), 129.11, 129.86 (2 × C), 136.38, 142.20, 155.38,
160.03. IR (KBr): 2342, 1735, 1460, 1254, 1204, 1171, 758, 673 cm–1.
EIMS m/z: 203 (M+, 91), 172 (100), 145 (52), 104 (20), 91 (58), 77 (23).
HRMS calcd. for C10H9N3O2: 203.0695; found: 203.0690.
Hz). IR(KBr): 3132, 1727, 1606, 1471, 1274, 1218, 867, 774, 672 cm–1
.
EIMS m/z: 221 (M+, 67), 190 (100), 163 (68), 122 (29), 109 (66), 95 (41),
83 (17), 81 (17), 75 (15). HRMS calcd. for C10H8FN3O2: 221.0601; found:
221.0597.
Methyl 1-(4-fluorophenyl)-1H-1,2,4-triazole-3-carboxylate (2g). The
residue solution was purified by column chromatography on silica gel to
give methyl 1-(4-fluorophenyl)-1H-1,2,4-triazole-3-carboxylate 2g as white
1
Methyl 1-[2-(trifluoromethyl)phenyl]-1H-1,2,4-triazole-3-carboxylate
(2b). The residue solution was purified by column chromatography on
silica gel to give methyl 1-[2-(trifluoromethyl)phenyl]-1H-1,2,4-triazole-3-
carboxylate 2b as brown liquid (241 mg, 89%). 1H NMR (CDCl3, 400 MHz):
δ 3.98 (s, 3H, OCH3), 7.53 (d, J = 7.6 Hz, 1H, ArH), 7.64–7.73 (m, 2H,
ArH), 7.82 (d, J = 7.6 Hz, 1H, ArH), 8.37 (s, 1H, triazole-H). 13C NMR (100
MHz, CDCl3): δ 52.86, 122.45 (q, J = 274.0 Hz), 126.39 (q, J = 32.0 Hz),
127.27 (q, J = 4.8 Hz), 129.23, 130.82, 133.15, 133.95, 146.16, 155.36,
159.76. IR (KBr): 3116, 2956, 1743, 1460, 1317, 1247, 1189, 1134, 1118,
815, 773, 675 cm–1. EIMS m/z: 271 (M+, 27), 240 (100), 213 (81), 207 (25),
172 (29), 159 (30), 145 (34). HRMS calcd. for C11H8F3N3O2: 271.0569;
found: 271.0574.
solid (187 mg, 85%); mp 152–153 C (hexane–EtOAc). H NMR (CDCl3,
400 MHz): δ 4.02 (s, 3H, OCH3), 7.21 (dd, J = 8.0, 20.0 Hz, 2H, ArH), 7.70
(dd, J = 4.4, 12.0 Hz, 2H, ArH), 8.56 (s, 1H, triazole-H). 13C NMR (100MHz,
CDCl3): δ 52.94, 116.91 (d, J = 23.4 Hz, 2 × C), 122.63 (d, J = 8.7 Hz, 2 ×
C), 132.62, 142.28, 155.49, 159.93, 162.58 (d, J = 250.0 Hz). IR (KBr):
2922, 1728, 1514, 1470, 1258, 1209, 1177, 839 cm–1. EIMS m/z: 221 (M+,
100), 190 (100), 163 (39), 149 (39), 135 (14), 122 (32), 109 (65), 95 (34),
83 (18), 75 (13), 57 (16). HRMS calcd. for C10H8FN3O2: 221.0601; found:
221.0593.
Methyl 1-(3-chlorophenyl)-1H-1,2,4-triazole-3-carboxylate (2h).[25] The
residue solution was purified by column chromatography on silica gel to
give methyl 1-(3-chlorophenyl)-1H-1,2,4-triazole-3-carboxylate 2h as
yellow solid (218 mg, 92%); mp 136–137 C (hexane–EtOAc). 1H NMR
(CDCl3, 400 MHz): δ 4.01 (s, 3H, OCH3), 7.39–7.46 (m, 2H, ArH), 7.61 (dt,
J = 1.6, 7.5 Hz, 1H, ArH), 7.79 (t, J = 1.9 Hz, 1H, ArH), 8.63 (s, 1H, triazole-
H). 13C NMR (100 MHz, CDCl3): δ 53.00, 118.27, 120.79, 129.21, 130.92,
135.84, 137.19, 142.26, 155.56, 159.82. IR (KBr): 3132, 2358, 1726, 1267,
Methyl 1-[3-(trifluoromethyl)phenyl]-1H-1,2,4-triazole-3-carboxylate
(2c). The residue solution was purified by column chromatography on silica
gel to give methyl 1-[3-(trifluoromethyl)phenyl]-1H-1,2,4-triazole-3-
carboxylate 2c as yellow solid (247 mg, 91%); mp 146–147 C (hexane–
EtOAc). 1H NMR (CDCl3, 400 MHz): δ 4.02 (s, 3H, OCH3), 7.65–7.72 (m,
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201801808
European Journal of Organic Chemistry
FULL PAPER
669 cm–1. EIMS m/z: 239 (M+ + 2, 24), 237 (M+, 75), 208 (44), 207 (68),
206 (100), 182 (29), 179 (82), 151 (12), 138 (31), 133 (12), 127 (20), 125
(61), 111 (31), 105 (13), 90 (27), 75 (21), 69 (14), 63 (16). HRMS calcd.
for C10H8ClN3O2: 237.0305; found: 237.0312.
202 (20), 121 (50). HRMS calcd. for C11H11N3O3: 233.0800; found:
233.0797.
Methyl 1-(3,4-dichlorophenyl)-1H-1,2,4-triazole-3-carboxylate (2n).
The residue solution was purified by column chromatography on silica gel
to give methyl 1-(3,4-dichloro phenyl)-1H-1,2,4-triazole-3-carboxylate 2n
as light yellow solid (240 mg, 88%); mp 169–170 C (hexane–EtOAc). 1H
NMR (CDCl3, 400 MHz): δ 4.03 (s, 3H, OCH3), 7.60 (s, 2H, ArH), 7.92 (s,
1H, ArH), 8.62 (s, 1H, triazole-H). 13C NMR (100 MHz, CDCl3): δ 53.07,
119.24, 122.35, 131.60, 133.42, 134.35, 135.39, 142.21, 155.76, 159.72.
IR (KBr): 3108, 1720, 1458, 1347, 999, 666, 437 cm–1. EIMS m/z: 273 (M+
+ 2, 64), 271 (100), 244 (23), 242 (61), 240 (95), 215 (57), 213 (90), 185
(13), 174 (25), 172 (38), 161 (50), 159 (71), 149 (16), 147 (17), 145 (26),
133 (15), 126 (19), 124 (56), 109 (20), 97 (13), 59 (17). HRMS calcd. for
C10H7Cl2N3O2: 270.9915; found: 270.9922.
Methyl 1-(4-chlorophenyl)-1H-1,2,4-triazole-3-carboxylate (2i).[26] The
residue solution was purified by column chromatography on silica gel to
give methyl 1-(3-chlorophenyl)-1H-1,2,4-triazole-3-carboxylate 2i as light
yellow solid (222 mg, 94%); mp 182–183 C (hexane–EtOAc). 1H NMR
(CDCl3, 400 MHz): δ 3.99 (s, 3H, OCH3), 7.46 (dt, J = 2.0, 8.5, Hz, 2H,
ArH), 7.67 (dt, J = 1.9, 8.9 Hz, 2H, ArH), 8.61 (s, 1H, triazole-H). 13C NMR
(100 MHz, CDCl3): δ 52.90, 121.63 (2 × C), 130.02 (2 × C), 134.84, 134.91,
142.19, 155.49, 159.84. IR (KBr): 2359, 1722, 1456, 1348, 1261, 1074,
887, 667 cm–1. EIMS m/z: 239 (M+ + 2, 26), 237 (M+, 75), 208 (21), 206
(61), 195 (21), 181 (17), 179 (52), 151 (11), 138 (24), 127 (38), 125 (100),
111 (27), 99 (15), 90 (30), 75 (22), 63 (18). HRMS calcd. for C10H8ClN3O2:
237.0305; found: 237.0304.
Method 2: Standard Procedure of the One-Pot Two-Step Cascade
Method for Synthesis of Methyl 1-Aryl-1H-1,2,4-triazole-3-
carboxylates 2a, 2d–g, 2i, and 2k.
Methyl 1-(3-methylphenyl)-1H-1,2,4-triazole-3-carboxylate (2j). The
residue solution was purified by column chromatography on silica gel to
give methyl 1-(3-methyl phenyl)-1H-1,2,4-triazole-3-carboxylate 2j as
yellow solid (222 mg, 95%); mp 119–120 C (hexane–EtOAc). 1H NMR
(CDCl3, 400 MHz): δ 2.40 (s, 3H, CH3), 4.00 (s, 3H, OCH3), 7.22 (d, J =
7.6 Hz, 1H, ArH), 7.36 (t, J = 7.8 Hz, 1H, ArH), 7.47 (d, J = 8.1 Hz, 1H,
ArH), 7.55 (s, 1H, ArH), 8.58 (s, 1H, triazole-H). 13C NMR (100 MHz,
CDCl3): δ 21.27, 52.83, 117.38, 121.13, 129.57, 129.81, 136.29, 140.23,
142.17, 155.25, 160.04. IR (KBr): 3121, 1724, 1464, 1267, 1207, 1173,
775, 671 cm–1. EIMS m/z: 217 (M+, 100), 186 (90), 159 (37), 118 (25), 105
(52), 104 (24), 91 (23). HRMS calcd. for C11H11N3O2: 217.0851; found:
217.0842.
The reliable procedure involved the treatment of 2-chloro-2-(2-
phenylhydrazono)acetate (1a, 1d–g, 1i, and 1k, 1.0 equiv) and 3.0
equivalent of triethylamine was stirred in THF solution (5 mL) at room
temperature
for
0.5–1
h.
Consequently,
aminating
agent
bis(trimethylsilyl)amine (NH(SiMe3)2, 3.0 equiv) was added into the
resulting mixture and heated at 60 C for 3–5 h. When the starting material
1a, 1d–g, 1i, or 1k was fully completed (monitored by TLC), the resulting
mixture was added to water (15 mL) and extracted with dichloromethane
(15 mL × 3). The organic extracts were washed with saturate sodium
bicarbonate (15 mL × 2), dried over MgSO4, filtered, and concentrated
under reduced pressure. The residue solution was treated with POCl3
(~3.0 equiv) in formamide solution (5 mL) at ~ 85 C within 0.5 h. When
the reaction was completed, the reaction mixture was added to water (15
mL) and extracted with dichloromethane (15 mL × 3). The combined
organic layer was washed sodium bicarbonate (15 mL × 3), dried over
MgSO4, filtered, and concentrated under reduced pressure. The residue
solution was purified by column chromatography on silica gel to give the
corresponding methyl 1-aryl-1H-1,2,4-triazole-3-carboxylates 2a, 2d–j, 2i,
and 2k in 73–91% yields.
Methyl 1-(4-methylphenyl)-1H-1,2,4-triazole-3-carboxylate (2k).[26] The
residue solution was purified by column chromatography on silica gel to
give methyl 1-(3-methyl phenyl)-1H-1,2,4-triazole-3-carboxylate 2k as
brown solid (222 mg, 95%); mp 151–152 C (hexane–EtOAc). 1H NMR
(CDCl3, 400 MHz): δ 2.38 (s, 3H, CH3), 4.00 (s, 3H, OCH3), 7.28 (d, J =
8.2 Hz, 2H, ArH), 7.57 (d, J = 8.4 Hz, 2H, ArH), 8.55 (s, 1H, triazole-H).
13C NMR (100 MHz, CDCl3): δ 21.03, 52.80, 120.40 (2 × C), 130.32 (2 ×
C), 134.09, 139.31, 142.08, 155.20, 160.07. IR (KBr): 3111, 2358, 1740,
1468, 1258, 1207, 1175 cm–1. EIMS m/z: 217 (M+, 100), 186 (62), 159 (39),
118 (26) , 105 (81), 104 (20), 91 (26), 77 (22). HRMS calcd. for C11H11N3O2:
217.0851; found: 217.0844.
Methyl 1-phenyl-1H-1,2,4-triazole-3-carboxylate (2a).[23] The residue
solution was purified by column chromatography on silica gel to give
methyl 1-phenyl-1H-1,2,4-triazole-3-carboxylate 2a as brown solid (148
mg, 73%).
Methyl 1-(4-bromophenyl)-1H-1,2,4-triazole-3-carboxylate (2l). The
residue solution was purified by column chromatography on silica gel to
give methyl 1-(4-bromo phenyl)-1H-1,2,4-triazole-3-carboxylate 2l as
white solid (245 mg, 87%); mp 188–189 C (hexane–EtOAc). 1H NMR
(CDCl3, 400 MHz): δ 4.00 (s, 3H, OCH3), 7.59–7.65 (m, 4H, ArH), 8.61 (s,
1H, triazole-H). 13C NMR (100 MHz, CDCl3): δ 52.94, 121.85 (2 × C),
122.81, 133.02 (2 × C), 135.34, 142.14, 155.54, 159.85. IR (KBr): 3111,
2359, 1724, 1459, 1348, 1260 cm–1. EIMS m/z: 283 (M+ + 2, 99), 282 (12),
281 (M+, 100), 252 (64), 250 (65), 225 (60), 223 (223), 184 (24), 182 (25),
171 (69), 169 (68), 157 (24), 155 (24), 143 (34), 116 (18), 90 (64), 76 (25),
75 (24), 63 (35). HRMS calcd. for C10H8BrN3O2: 280.9800; found:
280.9796.
Methyl 1-[4-(trifluoromethyl)phenyl]-1H-1,2,4-triazole-3-carboxylate
(2d) The residue solution was purified by column chromatography on silica
gel to give methyl 1-[4-(trifluoromethyl)phenyl]-1H-1,2,4-triazole-3-
carboxylate 2d as light yellow solid (246 mg, 91%).
Methyl 1-(2-fluorophenyl)-1H-1,2,4-triazole-3-carboxylate (2e). [24] The
residue solution was purified by column chromatography on silica gel to
give methyl 1-(2-fluorophenyl)-1H-1,2,4-triazole-3-carboxylate 2e as
yellow solid (194 mg, 88%).
Methyl 1-(3-fluorophenyl)-1H-1,2,4-triazole-3-carboxylate (2f). The
residue solution was purified by column chromatography on silica gel to
give methyl 1-(3-fluorophenyl)-1H-1,2,4-triazole-3-carboxylate 2f as brown
solid (192 mg, 87%).
Methyl 1-(4-methoxyphenyl)-1H-1,2,4-triazole-3-carboxylate (2m).[26]
The residue solution was purified by column chromatography on silica gel
to give methyl 1-(4-methoxylphenyl)-1H-1,2,4-triazole-3-carboxylate 2m
as light yellow solid (221 mg, 95%); mp 134–135 C (hexane–EtOAc). 1H
NMR (CDCl3, 400 MHz): δ 3.83 (s, 3H, OCH3), 4.00 (s, 3H, OCH3), 6.99
(td, J = 2.2, 9.4 Hz, 2H, ArH), 7.60 (dt, J = 2.2, 9.1 Hz, 2H, ArH), 8.50 (s,
1H, triazole-H). 13C NMR (100 MHz, CDCl3): δ 52.87, 55.65, 114.90 (2 ×
C), 122.28 (2 × C), 129.75, 142.15, 155.16, 160.10, 160.15. IR (KBr): 3121,
2922, 1738, 1520, 1482, 1252, 1204, 1171 cm–1. EIMS m/z: 233 (M+, 100),
Methyl 1-(4-fluorophenyl)-1H-1,2,4-triazole-3-carboxylate (2g). The
residue solution was purified by column chromatography on silica gel to
give methyl 1-(4-fluorophenyl)-1H-1,2,4-triazole-3-carboxylate 2g as white
solid (183 mg, 83%).
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201801808
European Journal of Organic Chemistry
FULL PAPER
Methyl 1-(4-chlorophenyl)-1H-1,2,4-triazole-3-carboxylate (2i).[26] The
residue solution was purified by column chromatography on silica gel to
give methyl 1-(3-chlorophenyl)-1H-1,2,4-triazole-3-carboxylate 2i as light
yellow solid (187 mg, 79%).
1-(2-Fluorophenyl)-1H-1,2,4-triazole (3e). The residue solution was
purified by column chromatography on silica gel to give methyl 1-(2-
fluoromethylphenyl)-1H-1,2,4-triazole 3e as yellow liquid (134 mg, 82%);
1H NMR (CDCl3, 500 MHz): δ 7.20–7.25 (m, 3H, ArH), 7.28–7.33 (m, 1H,
ArH), 7.80–7.84 (m, 1H, ArH), 8.06 (s, 1H, triazole-H), 8.61 (d, 1H, J = 2.8
Hz). 13C NMR (125 MHz, CDCl3): δ 116.85, 116.69, 124.02 , 125.13 (d, J
= 3.5 Hz), 129.06 (d, J = 7.9 Hz), 143.77 (d, J = 12.7 Hz), 151.78, 153.41
(d, J = 249.7 Hz). IR (KBr): 3120, 1517, 1281, 1227, 1145, 759 cm–1. EIMS
m/z: 163 (M+, 88), 136 (21), 109 (100), 82 (16). HRMS calcd. for C8H6FN3:
163.0546; found: 163.0542.
Methyl 1-(4-methylphenyl)-1H-1,2,4-triazole-3-carboxylate (2k).[26] The
residue solution was purified by column chromatography on silica gel to
give methyl 1-(3-methyl phenyl)-1H-1,2,4-triazole-3-carboxylate 2k as
brown solid (200 mg, 86%).
Standard Procedure of the Directed One-Pot Method for Synthesis of
1-Aryl-1H-1,2,4-triazoles 3a–n.
1-(3-Fluorophenyl)-1H-1,2,4-triazole (3f).[29] The residue solution was
purified by column chromatography on silica gel to give methyl 1-(3-
fluoromethylphenyl)-1H-1,2,4-triazole 3f as brown solid (145 mg, 89%);
The reliable procedure involved the treatment of 2-chloro-2-(2-
phenylhydrazono)acetate (1a–n, 1.0 mmol), with POCl3 (3.0 mmol) in
formamide solution (5 mL) at reflux within 0.5 h. When the reaction was
completed, the reaction mixture was added to water (15 mL) and extracted
with dichloromethane (15 mL × 3). The combined organic layer was
washed sodium bicarbonate (15 mL × 3), dried over MgSO4, filtered, and
concentrated under reduced pressure. The residue solution was purified
by column chromatography on silica gel to give the corresponding 1-aryl-
1H-1,2,4-triazoles 3a–n in 82–94% yields.
1
mp 69–70 C (hexane–EtOAc). H NMR (CDCl3, 400 MHz): δ 7.04–7.09
(m, 1H, ArH), 7.43–7.44 (m, 3H, ArH), 8.07 (s, 1H, triazole-H), 8.54 (s, 1H,
triazole-H). 13C NMR (100 MHz, CDCl3): δ 107.79 (d, J = 26.0 Hz), 114.91,
115.11, 131.15 (d, J = 8.9 Hz), 138.15 (d, J = 10.0 Hz), 140.88, 152.70,
163.12 (d, J = 246.9 Hz). IR (KBr): 3107, 1607, 1518, 866, 669 cm–1. EIMS
m/z: 163 (M+, 79), 109 (100), 105 (13), 82 (16), 77 (15). HRMS calcd. for
C8H6FN3: 163.0546; found: 163.0538.
1-(4-Fluorophenyl)-1H-1,2,4-triazole (3g).[29] The residue solution was
purified by column chromatography on silica gel to give methyl 1-(4-
fluoromethylphenyl)-1H-1,2,4-triazole 3g as brown solid (151 mg, 93%);
mp 73–74 C (hexane–EtOAc). 1H NMR (CDCl3, 400 MHz): δ 7.14–7.20
(m, 2H, ArH), 7.60–7.64 (m, 2H, ArH), 8.06 (s, 1H, triazole-H), 8.47 (s, 1H,
triazole-H). 13C NMR (100 MHz, CDCl3): δ 116.56, 116.79, 121.99, 122.07,
133.24, 140.86, 152.63, 162.00 (d, J = 248.18 Hz). IR (KBr): 1524, 1275,
1275, 1234, 831, 675, 514 cm–1. EIMS m/z: 163 (M+, 85), 136 (16), 109
(100), 82 (16). HRMS calcd. for C8H6FN3: 163.0546; found: 163.0541.
1-Phenyl-1H-1,2,4-triazole (3a). [26] The residue solution was purified by
column chromatography on silica gel to give methyl 1-phenyl-1H-1,2,4-
triazole 3a as brown liquid (125 mg, 86%). H NMR (CDCl3, 400 MHz): δ
7.23–7.27 (m, 1H, ArH), 7.36 (dd, J = 7.6, 15.2 Hz, 2H, ArH), 7.56 (d, J =
8.0 Hz, 2H, ArH), 7.99 (s, 1H, triazole-H), 8.48 (s, 1H, triazole-H). 13C NMR
(100 MHz, CDCl3): δ 119.65 (2 × C), 127.81, 129.40 (2 × C), 136.67,
140.60, 152.22. IR (KBr): 3420, 3117, 1569, 1512, 1279, 1217, 1146, 758,
673 cm–1. EIMS m/z: 145 (M+, 96), 118 (21), 91 (100), 64 (19). HRMS calcd.
for C8H7N3: 145.0640; found: 145.0642.
1
1-(3-Chlorophenyl)-1H-1,2,4-triazole (3h).[30] The residue solution was
purified by column chromatography on silica gel to give methyl 1-(3-
chloromethylphenyl)-1H-1,2,4-triazole 3h as brown solid (168 mg, 94%);
mp 82–83 C (hexane–EtOAc). 1H NMR (CDCl3, 400 MHz): δ 7.35 (d, J =
8.0 Hz, 1H, ArH), 7.41 (t, J = 8.0 Hz , 1H, ArH), 7.55 (d, J = 8.0 Hz, 1H,
ArH), 7.71 (s, 1H, ArH), 8.08 (s, 1H, triazole-H), 8.54 (s, 1H, triazole-H).
13C NMR (100 MHz, CDCl3): δ 117.83, 120.33, 128.23, 130.80, 135.62,
137.83, 140.88, 152.77. IR (KBr): 3094, 1599, 1514, 1493, 880, 775, 669
cm–1. EIMS m/z: 181 (M+ + 2, 26), 179 (M+, 93), 154 (13), 152 (44), 127
(31), 125 (100), 90 (36), 75 (13), 69 (17), 63 (21). HRMS calcd. for
C8H6ClN3: 179.0250; found: 179.0257.
1-[2-(Trifluoromethyl)phenyl]-1H-1,2,4-triazole (3b).[28] The residue
solution was purified by column chromatography on silica gel to give
methyl 1-[2-(trifluoromethyl)phenyl]-1H-1,2,4-triazole 3b as yellow liquid
(175 mg, 82%); 1H NMR (CDCl3, 400 MHz): δ 7.47 (d, J = 8.00 Hz, 1H,
ArH), 7.58–7.69 (m, 2H, ArH), 7.79 (d, J = 7.6 Hz, 1H, ArH), 8.07 (s, 1H,
triazole-H), 8.28 (s, 1H, triazole-H). 13C NMR (100 MHz, CDCl3): δ 122.57
(q, J = 273.5 Hz), 126.22 (q, J = 31.7 Hz), 127.22 (d, J = 4.9 Hz), 128.95,
130.08, 132.99, 134.69, 144.66, 152.32. IR (KBr): 1514, 1318, 1277, 1180,
1134, 1117, 1076, 1040, 772 cm–1. EIMS m/z: 213 (M+, 95), 186 (31), 159
(100), 132 (17), 109 (37). HRMS calcd. for C9H6F3N3: 213.0514; found:
213.0505.
1-(4-Chlorophenyl)-1H-1,2,4-triazole (3i).[30] The residue solution was
purified by column chromatography on silica gel to give methyl 1-(4-
chlorophenyl)-1H-1,2,4-triazole 3i as brown solid (150 mg, 84%); mp 108–
109 C (hexane–EtOAc). 1H NMR (CDCl3, 400 MHz): δ 7.42–7.46 (m, 2H,
ArH), 7.58–7.61 (m, 2H, ArH), 8.06 (s, 1H, triazole-H), 8.51 (s, 1H, triazole-
H). 13C NMR (100 MHz, CDCl3): δ 121.15 (2 × C), 129.87 (2 × C), 133.83,
135.44, 140.75, 152.70. IR (KBr): 2359, 1514, 1275, 824, 675 cm–1. EIMS
m/z: 181 (M+ + 2, 33), 179 (M+, 96), 152 (27), 127 (33), 125 (100), 90 (24),
75 (15), 63 (24). HRMS calcd. for C8H6ClN3: 179.0250; found: 179.0255.
1-[3-(Trifluoromethyl)phenyl]-1H-1,2,4-triazole (3c).[28] The residue
solution was purified by column chromatography on silica gel to give
methyl 1-[3-(trifluoromethyl)phenyl]-1H-1,2,4-triazole 3c as brown solid
(185 mg, 87%); mp 50–51 C (hexane–EtOAc). 1H NMR (CDCl3, 400 MHz):
δ 7.62–7.66 (m, 2H, ArH), 7.86–7.89 (m, 1H, ArH), 7.97 (s, 1H, ArH), 8.12
(s, 1H, triazole-H), 8.61 (s, 1H, triazole-H). 13C NMR (100 MHz, CDCl3): δ
117.01 (q, J = 3.7 Hz), , 122.90, 123.31 (q, J = 271.1 Hz) 124.81 (q, J =
3.3 Hz), 130.54, 132.49 (q, J = 33.2 Hz), 137.34, 140.95, 152.99. IR (KBr):
1514, 1325, 1279, 1173, 1128 cm–1. EIMS m/z: 213 (M+, 100), 186 (16),
159 (84), 109 (17), 105 (60). HRMS calcd. for C9H6F3N3: 213.0514; found:
213.0511.
1-(3-Methylphenyl)-1H-1,2,4-triazole (3j).[30] The residue solution was
purified by column chromatography on silica gel to give methyl 1-(3-
methylphenyl)-1H-1,2,4-triazole 3j as brown liquid(132 mg, 83%); 1H NMR
(CDCl3, 400 MHz): δ 7.15 (d, J = 7.6 Hz, 1H, ArH), 7.32 (t, J = 7.8, 1H,
ArH), 7.40 (d, J = 8.0 Hz, 1H, ArH), 7.45 (s, 1H, ArH), 8.04 (s, 1H, triazole-
H), 8.50 (s, 1H, triazole-H). 13C NMR (100 MHz, CDCl3): δ 21.27, 116.97,
120.63, 128.86, 129.42, 136.81, 139.91, 140.77, 152.33. IR (KBr): 3117,
1690, 1593, 1506, 1279, 1215, 1146, 783, 675 cm–1. EIMS m/z: 159 (M+,
100), 132 (17), 106 (12), 105 (80), 104 (37), 78 (17), 77 (17), 65 (11).
HRMS calcd. for C9H9N3: 159.0796; found: 159.0802.
1-[4-(Trifluoromethyl)phenyl]-1H-1,2,4-triazole (3d).[28] The residue
solution was purified by column chromatography on silica gel to give
methyl 1-[4-(trifluoromethyl)phenyl]-1H-1,2,4-triazole 3d as brown solid
(187 mg, 88%); mp 96–97 C (hexane–EtOAc). 1H NMR (CDCl3, 500 MHz):
δ 7.78 (dd, J = 32.0, 8.7 Hz, 4H, ArH), 8.1 1 (s, 1H, triazole-H), 8.62 (s,
1H, triazole-H). 13C NMR (125 MHz, CDCl3): δ 119.82, 123.52 (q, J = 338.1
Hz), 127.08, 127.12, 130.14 (q, J = 270.6 Hz), 139.40, 140.97, 153.03. IR
(KBr): 2359, 1130, 845, 669 cm–1. EIMS m/z: 213 (M+, 88), 186 (19), 159
(100), 139 (22). HRMS calcd. for C8H6FN3: 271.0569; found: 213.0506.
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10.1002/ejoc.201801808
European Journal of Organic Chemistry
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1-(4-Methylphenyl)-1H-1,2,4-triazole (3k).[31] The residue solution was
purified by column chromatography on silica gel to give methyl 1-(4-
methylphenyl)-1H-1,2,4-triazole 3k as brown solid (135 mg, 85%); mp 57–
58 C (hexane–EtOAc). 1H NMR (CDCl3, 400 MHz): δ 7.21 (d, J = 8.0 Hz,
2H, ArH), 7.47 (d, J = 8.6 Hz, 2H, ArH), 8.01 (s, 1H, triazole-H), 8.45 (s,
1H, triazole-H). 13C NMR (100 MHz, CDCl3): δ 20.81, 119.78 (2 × C),
130.03 (2 × C), 134.48, 138.03, 140.58, 152.17. IR (KBr): 3445, 1526,
1277, 812, 673 cm–1. EIMS m/z: 159 (M+, 100), 91 (59), 77 (31), 57 (39).
HRMS calcd. for C9H9N3: 159.0796; found: 159.0792.
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China (MOST 107-2113-M-039-006) for financial support.
Keywords: 1,2,4-Triazole •Nitrilimines • Vilsmeier reagent •
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FULL PAPER
The selectively convenient one-pot
methods have been developed for
synthesis of 1,2,4-triazoles and methyl
Heterocylclization*
Shuo-En Tsai,[a,b] Kun-Heng Chiang,[a]
Ching-Chun Tseng,[a,b] Nai-Wei Chen,[c]
Ching-Yuh Chern,*[d] and Fung Fuh
Wong*[a]
1H-1,2,4-triazole-3-carboxylates
by
using hydrazonoyl hydrochlorides
(nitrilimines) with Vilsmeier reagent. 2-
Amino-2-(2-arylhydrazono)acetates
were prepared from 2-chloro-2-(2-
Page No. – Page No.
Facile One-Pot Synthesis of Methyl 1-
Aryl-1H-1,2,4-triazole-3-carboxylates
from Nitrilimines with Vilsmeier
Reagent
arylhydrazono)acetates
with
bis(trimethylsilyl)amine [NH(SiMe3)2]
as the isolated intermediates for the
further mechanistic study.
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