Copper-catalyzed one-pot synthesis of 1,2,4-triazoles from nitriles and hydroxylamine

Article abstract of DOI:10.1021/jo502709t

A simple and efficient copper-catalyzed one-pot synthesis of substituted 1,2,4-triazoles through reactions of two nitriles with hydroxylamine has been developed. The protocol uses simple and readily available nitriles and hydroxylamine hydrochloride as th

Full text of DOI:10.1021/jo502709t

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Article
Copper-Catalyzed One-Pot Synthesis of 1,2,4-
Triazoles from Nitriles and Hydroxylamine
Hao Xu, Shuang Ma, Yuanqing Xu, Longxiang Bian, Tao
Ding, Xiaomin Fang, Wenkai Zhang, and Yanrong Ren
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo502709t • Publication Date (Web): 07 Jan 2015
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Copper-Catalyzed One-Pot Synthesis of 1,2,4-Triazoles from Nitriles
and Hydroxylamine
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Hao Xu,* Shuang Ma, Yuanqing Xu,* Longxiang Bian, Tao Ding, Xiaomin Fang, Wenkai Zhang, and
Yanrong Ren
Institute of Fine Chemistry and Engineering, Henan Engineering Laboratory of Flame-retardant and
Functional Materials, College of Chemistry and Chemical Engineering, Henan University, Kaifeng
475004, P. R. China.
E-mail : xuhao@henu.edu.cn; xuyuanqing@henu.edu.cn
ABSTRACT: A simple and efficient copper-catalyzed one-pot synthesis of substituted 1,2,4-triazoles
has been developed through reactions of two nitriles with hydroxylamine. The protocol uses simple and
readily available nitriles and hydroxylamine hydrochloride as the starting materials, inexpensive
Cu(OAc)2 as the catalyst, and the corresponding 1,2,4-triazole derivatives were obtained in moderate to
good yields. The reactions underwent sequential intermolecular addition of hydroxylamine to one nitrile
to provide amidoxime, copper-catalyzed treatment of the amidoxime with another nitrile and intramole-
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cular dehydration cyclization. This finding provides a new and useful strategy for synthesis of 1,2,4-
triazole derivatives.
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INTRODUCTION
Substituted 1,2,4-triazoles and their derivatives are key skeletons of many biologically active molecu-
lers and important organic compounds, and they exhibit wide applications in pesticides, medicines,
functional materials and organocatalysts.1,2 In addition, a number of natural products contain a 1,2,4-
triazole motif.3 Owing to their important properties and applications, various methods for synthesis of
1,2,4-triazole derivatives have been developed.4 In the previous methods, intramolecular cyclization of
N-acylamidorazones obtained from hydrazines and carboxylic acid derivatives is a common strategy.5
However, the method often involves tedious synthetic procedures and low yields. Therefore, developing
a simple and practical procedure to access 1,2,4-triazole derivatives is still highly desirable. Currently,
the transition-metal-catalyzed formation of N-heterocycles continues to be an active field,6 but the tran-
sition-metal-catalyzed synthesis of 1,2,4-triazoles from readily available starting materials is relatively
rare.7 Furthermore, there remain some limitations such as inconvenient starting materials, harsh reaction
conditions and low yields in the reported transition-metal-catalyzed procedures. In 2009, Nagasawa’s
group developed a simple and efficient copper-catalyzed synthesis of 1,2,4-triazole derivatives via
coupling of amidines with nitriles,7a which was the first example for the transition-metal-catalyzed syn-
thesis of 1,2,4-triazole derivatives using readily available starting materials. Subsequently, we reported a
convenient and efficient copper-catalyzed one-pot synthesis of 1,2,4-triazoles via sequential coupling
and aerobic oxidative dehydrogenation of amidines.7b Very recently, Beifuss’s group has developed a
novel and efficient copper-catalyzed cascade reaction between imidates and ammonium carbonate for
the synthesis of symmetrically substituted 3,5-diaryl-1,2,4-triazoles.7d The methods above were efficient,
but most of them used amidines or imidatates as the substrates that are usually prepared from nitriles8.
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In an attempt to use simple nitriles as the substrates for improving the previous procedures, Ma and co-
workers have first reported a simply copper-mediated one-pot three-component synthesis of symmetri-
cally substituted 1,2,4-triazoles from amines and arylnitriles under microwave assistance.7f Unfortunate-
ly, the reaction needed two equivalents of Cu salts, and the yields of cyclization products were 12-55%.
This prompted us to study the feasibility of synthesizing 1,2,4-triazoles from nitriles or other simple
substrates under copper catalysis. On the basis of the coordination ability of transition metals to activate
nitriles9 and great achievements in copper-catalyzed couplings and synthesis of N-heterocycles10, herein,
we report a simple and efficient copper-catalyzed one-pot synthesis of symmetrically and unsymmetri-
cally substituted 1,2,4-triazoles from nitriles and hydroxylamine.
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RESULTS AND DISCUSSION
At first, sequential reactions of cyclopropanecarbonitrile (1h) with hydroxylamine hydrochloride and
4-methyl- benzonitrile (1b) were chosen as the model to optimize conditions including the catalysts,
bases and solvents. As shown in Table 1, the one-pot synthesis of 3-cyclopropyl-5-(p-tolyl)-1H-1,2,4-
triazole (2j) underwent sequential two-step procedures: the first-step nucleophilic addition of hydrox-
ylamine
to
cyclopropanecarbonitrile
(1h)
was
performed
to
provide
N-
hydroxycyclopropanecarboxamidine (A) in the presence of triethylamine (TEA) at 80 oC for 18 h with-
out exclusion of air. The second-step copper-catalyzed cascade reaction, including intermolecular coupl-
ing of A with 4-methylbenzonitrile (1b) and intramolecular dehydration cyclization, was carried out at
120 oC for 24 h. Nine copper catalyst (0.2 equiv) were tested by using anhydrous t-BuOH as the solvent
in the first step, 3 equiv of Cs2CO3 as the base (relative to amount of 1b) and anhydrous DMSO as the
solvent in the second step (Table 1, entries 1-9), Cu(OAc)2 showed the highest activity (Table 1, entry 8).
No target product (2j) was observed in the absence of copper catalyst or using 20 mol% of p-
toluenesulfonic acid (PTSA) as the catalyst without addition of base (Table 1, entry 10-11). We at-
tempted various anhydrous solvents (Table 1, entries 8, 12-18), t-BuOH as the solvent in the first step
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and DMSO as the solvent in the second step were the best choice (Table 1, entry 8). The effect of bases
in the second step was also investigated (Table 1, compare entries 8, 19-21), and the Cs2CO3 provided
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the highest yield. We tried different temperature (Table 1, compare entries 8, 22-23), and 120 C was
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suitable. The yield decreased because of hydrolysis of an extra amount of 4-methylbenzonitrile (1b)
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when temperature was raised to 140 C (Table 1, entry 23). The second step was performed under O2
(Table 1, entry 24), and a low yield was afforded. When the second step was performed under N2 (Table
1, entry 25), a 60% yield was provided. The result proved that the second-step reaction could furnish the
desired product without requirement of O2. In addition, the reaction did not need additional ligands or
additives, and the result implied that the substrates cyclopropanecarbonitrile (1h) and 4-
methylbenzonitrile (1b) could act as ligands, and the nitriles as the ligands were reported in the previous
research.11
Table 1. Copper-Catalyzed One-Pot Synthesis of 3-Cyclopropyl-5-(p-tolyl)-1H-1,2,4-triazole (2j) via Sequential
Reaction of Cyclopropanecarbonitrile (1h) with Hydroxylamine and 4-Methylbenzonitrile (1b) and: Optimiza-
tion of Conditions.a
Solvent-1/ Sol-
Entry
Cu Cat.
Base
Temp (oC) Yield of 2j (%)b
vent-2
1
2
3
4
5
6
CuI
CuBr
CuCl
Cu2O
CuO
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
t-BuOH/DMSO
t-BuOH/DMSO
t-BuOH/DMSO
t-BuOH/DMSO
t-BuOH/DMSO
t-BuOH/DMSO
120
120
120
120
120
120
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25
16
19
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CuCl2
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CuSO4
Cu(OAc)2
Cu
Cs2CO3
Cs2CO3
Cs2CO3
-
t-BuOH/DMSO
t-BuOH/DMSO
t-BuOH/DMSO
t-BuOH/DMSO
t-BuOH/DMSO
EtOH/DMSO
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
100
140
120
120
5
61
35
0
9
9
10c
11
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23
24d
25e
PTSA
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-
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K2CO3
Na2CO3
K3PO4
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
0
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
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5
CH3OH/DMSO
THF/DMSO
6
i-PrOH/DMSO
t-BuOH/DMF
t-BuOH/Xylene
t-BuOH/DCB
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48
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13
23
19
45
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60
t-BuOH/DMSO
t-BuOH/DMSO
t-BuOH/DMSO
t-BuOH/DMSO
t-BuOH/DMSO
t-BuOH/DMSO
t-BuOH/DMSO
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a
Reaction conditions: without exclusion of air. For the first step, cyclopropanecarbonitrile (1h) (0.45 mmol), hydrox-
ylamine hydrochloride (0.5 mmol), triethylamine (TEA) (0.9 mmol), anhydrous solvent-1 (1.5 mL), temperature (80
oC), time (18 h). For the second step, 4-methylbenzo-nitrile (1b) (0.3 mmol), catalyst (0.06 mmol), base (0.9 mmol),
anhydrous solvent-2 (1.0 mL), anhydrous sodium sulfate (2.1 mmol), temperature (120 oC), time (24 h) in the sealed
Schlenk tube. b Isolated yield. c using 20 mol% of PTSA (p-toluenesulfonic acid) as catalyst without addition of base. d
Under O2 for the two steps. e Under N2 for the two steps.
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The scope of copper-catalyzed one-pot synthesis of 1,2,4-triazole derivatives was investigated under
the optimized condition. As shown in Table 2, most of the substrates examined provided moderate to
good yields. Delightfully, homogeneous reactions of aromatic nitriles were performed well (Table 2 en-
tries 1-6), various electron-donating groups (EDG) (Me, OMe; Table 2, entries 2, 5) and electron-
withdrawing groups (EWG) (Cl, NO2; Table 2, entries 3, 4) in the substituents, even the N-heterocyclic
nitriles (Table 2, entries 6), were completely tolerated in this transformation. Reactions between aromat-
ic nitriles and aliphatic nitriles could give heterogeneous products in moderate yields (Table 2 entries 7-
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19). Generally, the steric hindrance of the substrates could lower the yields (Table 2, entries 12, 14-15,
18). Furthermore, the position of the substituents on the aryl group (para and meta position) affected the
yields of 2, and the para-substituted substrates could give relatively higher yields (Table 2, compare en-
tries 10 and 19). In the copper-catalyzed one-pot couplings, no ligand or additive was required. The me-
thods could tolerate various functional groups in the substrates including ether (Table 2, entry 5), C-Cl
bond (Table 2, entry 3, 11-15), nitro (Table 2, entry 4, 16-18), and N-heterocycle (Table 2, entry 6).
Table 2. Copper-Catalyzed One-Pot Synthesis of Substituted 1,2,4-Triazoles.
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Yield
(%)b
R1-CN (1)
R2-CN (1)
2
Entry
N
1
2
63
N
N
H
2a
Me
N
62
66
73
Me
N
N
N
N
H
2b
Cl
N
3
4
5
Cl
N
H
2c
NO2
N
O2N
N
H
2d
82
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7
8
1a
1a
1b
1b
1c
1c
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65
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9
1g
1h
1g
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1h
1c
1c
68
48
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1c
45
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1g
1d
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1h
1j
1d
1d
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1h
a Reaction conditions：without exclusion of air. For the first step, R1-CN (1) (0.45 mmol), hydroxylamine hydrochlo-
ride (0.5 mmol), triethylamine (TEA) (0.9 mmol), anhydrous t-BuOH (1.5 mL), temperature (80 oC), time (18 h). For
the second step, R2-CN (1) (0.3 mmol), Cu(OAc)2 (0.06 mmol), Cs2CO3 (0.9 mmol), anhydrous DMSO (1 mL), an-
hydrous sodium sulfate (2.1 mmol), temperature (120 oC), time (24 h) in the sealed Schlenk tube. b Isolated yield.
Interestingly, under acidic condition, reaction of amidoximes with nitriles could afford 1,2,4-
oxadiazoles by using PTSA-ZnCl2 as the catalysts, and the result was reported by Augustine and co-
workers in 2009.12 However, under basic condition, 1,2,4-triazoles were synthesized from nitriles and
amidoximes which was obtained by the reaction of nitriles with hydroxylamine in our work. The struc-
ture of compound 2h was confirmed by X-ray crystallography (See Figure S1 in Supporting Informa-
tion).
A possible mechanism was proposed for synthesis of 1,2,4-triazoles (Scheme 1). At first, intermolecu-
lar nucleophilic addition of amino in hydroxylamine to cyano of R1-CN in the presence of TEA leads to
amidoxime (I),13 and then coupling of I with copper-complex (II) of R1-CN affords intermediate III.7f,14
Finally, intramolecular dehydration cyclization of III gives the desired target product (2) releasing Cu(II)
catalyst.
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Scheme 1 Possible Mechanism for Synthesis of 1,2,4-Triazoles
CONCLUSION
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We have developed a simple and efficient copper-catalyzed one-pot method for synthesis of 1,2,4-
triazole derivatives. The protocol uses simple and readily available nitriles and hydroxylamine hydro-
chloride as the starting materials and inexpensive Cu(OAc)2 as the catalyst, and the catalytic cycle was
achieved without protection of inert gas. The one-pot reactions underwent sequential intermolecular ad-
dition of hydroxylamine to one nitrile to amidoxime, copper-catalyzed treatment of the amidoxime with
another nitrile and intramolecular dehydration cyclization without the addition of ligand and additive,
and the corresponding 1,2,4-triazole derivatives were obtained in moderate to good yields. The present
method can tolerate various functional groups, including ether, C-Cl bond, nitro, and N-heterocycle, and
shows economical and practical advantages over the previous methods, so it provides opportunity for
construction of diverse and useful molecules. Considering the easy availability of starting materials and
potential of the products,1,2 the method will have a promising application in the synthesis for the 1,2,4-
triazole drugs or organocatalysts.
EXPERIMENTAL SECTION
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General experimental procedures: All reactions were carried out under air. Proton and carbon mag-
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netic resonance spectra (1H NMR and C NMR) were recorded using tetramethylsilane (TMS) in the
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solvent of d6-DMSO as the internal standard (1H NMR: TMS at 0.00 ppm, DMSO at 2.50 ppm; 13C
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NMR: DMSO at 39.52 ppm).
General procedure for synthesis of 1,2,4-triazoles (2a-s). The first nitrile (1) (0.45 mmol), hydro-
xylamine hydrochloride (0.5 mmol, 34.7 mg), triethylamine (0.9 mmol, 126 μL), anhydrous t-BuOH
(1.5 mL) were added to a 25 mL Schlenk tube charged with a magnetic stirrer. The reaction mixture was
o
stirred at 80 C for 18 h without exclusion of air for the first step. The second nitrile (1) (0.3 mmol),
Cu(OAc)2 (0.06 mmol 12 mg), Cs2CO3 (0.9 mmol, 293 mg), anhydrous DMSO (1.0 mL), anhydrous
sodium sulfate (2.1 mmol, 0.3 g) were added to the Schlenk tube, and the mixture was stirred at 120 oC
for another 24 h in the sealed Schlenk tube for the second step. The resulting solution was concentrated
by a rotary evaporator, and the residue was purified by column chromatography on silica gel using pe-
troleum ether/ethyl acetate as the eluent to give the desired target product (2a-s).
3,5-Diphenyl-4H-1,2,4-triazole (2a).7a Eluent: petroleum ether/ethyl acetate (6:1). Yield 42 mg (63%).
White solid, mp 190.2-191.0 oC (lit.7a m.p. 190-191 oC). 1H NMR (d6-DMSO, 400 MHz, 25 oC) δ 14.62
(s, 1H), 8.36-8.06 (s, 4H), 7.67-7.21 (m, 6H). 13C NMR (d6-DMSO, 100 MHz, 25 oC) δ = 162.2, 155.6,
131.9, 130.6, 129.5, 129.2, 127.8, 126.6. ESI-MS [M+H]+ m/z 222.1.
3,5-Di-p-tolyl-4H-1,2,4-triazole (2b).7b Eluent: petroleum ether/ethyl acetate (6:1). Yield 46 mg
(62%). White solid, mp 259.5-259.6 oC (lit.7b m.p. 249-251 oC). 1H NMR (d6-DMSO, 400 MHz, 25 oC)
δ = 14.37 (s, 1H), 8.04-7.91 (m, 4H), 7.46-7.21 (m, 4H), 2.44-2.30 (m, 6H). 13C NMR (d6-DMSO, 100
o
MHz, 25 C) δ 162.0, 155.4, 140.4, 138.8, 130.1, 129.7, 129.1, 126.5, 126.3, 125.0, 21.4. ESI-MS
[M+H]+ m/z 250.1.
3,5-Bis(4-chlorophenyl)-4H-1,2,4-triazole (2c).7b Eluent: petroleum ether/ethyl acetate (6:1). Yield
57 mg (63%). White solid, mp 288.4-288.8 oC (lit.7b m.p. 292-294 oC). 1H NMR (d6-DMSO, 400 MHz,
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25 oC) δ = 14.69 (s, 1H), 8.21-7.95 (m, 4H), 7.71-7.46 (m, 4H). 13C NMR (d6-DMSO, 100 MHz, 25 oC)
δ 161.2, 154.8, 135.0, 134.8, 130.2, 129.9, 129.4, 128.8, 128.2, 126.6. ESI-MS [M+H]+ m/z 290.0.
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3,5-Bis(4-nitrophenyl)-4H-1,2,4-triazole (2d).7c Eluent: petroleum ether/ethyl acetate (6:1). Yield 68
mg (73%). Yellow solid, mp 250.0-252.0 oC (lit.7c m.p. 246-248 oC). 1H NMR (d6-DMSO, 400 MHz, 25
oC) δ = 14.56 (s, 1H), 8.46-8.13 (m, 8H). 13C NMR (d6-DMSO, 100 MHz, 25 oC) δ 157.5, 148.4, 135.1,
127.6, 124.7. ESI-MS [M+H]+ m/z 312.5.
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3,5-Bis(4-methoxyphenyl)-4H-1,2,4-triazole (2e).15 Eluent: petroleum ether/ethyl acetate (6:1). Yield
69 mg (82%). White solid, mp 193-195 oC (lit.13 m.p. 196-197 oC). 1H NMR (d6-DMSO, 400 MHz, 25
oC) δ = 14.16 (s, 1H), 7.98 (d, J = 8.7 Hz, 4H), 7.17-6.93 (m, 4H), 3.79 (s, 6H). 13C NMR (d6-DMSO,
100 MHz, 25 oC) δ = 161.8, 161.1, 160.3, 155.2, 134.7, 128.2, 127.8, 124.6, 120.4, 116.9, 114.9, 114.5,
55.8, 55.6. ESI-MS [M+H]+ m/z 282.3, [M+Na]+ m/z 304.2.
3,5-Di(pyridin-3-yl)-4H-1,2,4-triazole (2f).16 Eluent: ethyl acetate. Yield 56 mg (83%). White solid,
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mp 230.0-233.2 C (lit.14 m.p. 231-232 C). H NMR (d6-DMSO, 400 MHz, 25 C) δ = 14.96 (s, 1H),
9.30 (s, 2H), 8.83-8.58 (m, 2H), 8.49-8.40 (m, 2H), 7.61 (s, 2H). 13C NMR (d6-DMSO, 100 MHz, 25 oC)
δ = 174.4, 167.0, 160.0, 153.7, 152.3, 150.9, 149.1, 147.5, 135.6, 133.9, 127.2, 124.5. ESI-MS [M+H]+
m/z 224.2, [M+Na]+ m/z 246.2.
3-Phenyl-5-propyl-4H-1,2,4-triazole (2g).17 Eluent: petroleum ether/ethyl acetate (6:1). Yield 29 mg
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(52%). White solid, mp 75.1-78.3 C (lit.15 m.p. 71-72 C). 1H NMR (d6-DMSO, 400 MHz, 25 C) δ =
13.71 (s, 1H), 8.03 (d, J = 7.1 Hz, 2H), 7.59-7.29 (m, 3H), 2.73 (t, J = 6.9 Hz, 2H), 1.83-1.68 (m, 2H),
0.95 (t, J = 7.4 Hz, 3H). 13C NMR (d6-DMSO, 100 MHz, 25 oC) δ = 161.2, 157.7, 132.2, 129.0, 126.2,
40.6, 28.2, 21.3, 14.0. ESI-MS [M+H]+ m/z 188.1.
3-Cyclopropyl-5-phenyl-4H-1,2,4-triazole (2h).7b Eluent: petroleum ether/ethyl acetate (6:1). Yield
36 mg (65%). White solid, mp 201.4-201.5 oC (lit.7b m.p. 202-204 oC). 1H NMR (d6-DMSO, 400 MHz,
o
25 C) δ = 14.11-13.58 (m, 1H), 7.95 (d, J = 7.2, 2H), 7.66-7.28 (m, 3H), 2.19-1.89 (s, 1H), 1.26-0.68
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(m, 4H). 13C NMR (d6-DMSO, 100 MHz, 25 oC) δ = 161.3, 159.8, 132.4, 130.2, 129.1, 126.2, 8.5, 7.6.
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ESI-MS [M+H]+ m/z 186.1.
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3-Propyl-5-(p-tolyl)-4H-1,2,4-triazole (2i).7b Eluent: petroleum ether/ethyl acetate (6:1). Yield 30 mg
(50%). White solid, mp 112.4-114.2 oC (lit.7b m.p. 140-142 oC). 1H NMR (d6-DMSO, 400 MHz, 25 oC)
δ = 14.01-13.57 (m, 1H), 7.92-7.79 (m, 2H), 7.37-7.17 (m, 2H), 2.75-2.57 (m, 2H), 2.33 (s, 3H), 1.78-
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1.65 (m, 2H), 0.93 (t, J = 7.4, 3H). C NMR (d6-DMSO, 100 MHz, 25 C) δ = 161.3, 157.6, 138.4,
129.6, 129.5, 126.1, 28.2, 21.4, 21.3, 14.0. ESI-MS [M+H]+ m/z 202.1.
3-Cyclopropyl-5-(p-tolyl)-4H-1,2,4-triazole (2j).7b Eluent: petroleum ether/ethyl acetate (6:1). Yield
31 mg (52%). White solid, mp 188.6-191.5 oC (lit.7b m.p. 186-188 oC). 1H NMR (d6-DMSO, 400 MHz,
o
25 C) δ = 14.21-13.21 (m, 1H), 7.84 (d, J = 8.0, 2H), 7.39-7.07 (m, 2H), 2.33 (s, 3H), 2.12-1.93 (m,
o
1H), 1.12-0.74 (m, 4H). 13C NMR (d6-DMSO, 100 MHz, 25 C) δ = 161.2, 159.7, 138.5, 129.7, 126.2,
21.4, 8.5, 7.6. ESI-MS [M+H]+ m/z 200.1.
3-(4-Chlorophenyl)-5-propyl-4H-1,2,4-triazole (2k). Eluent: petroleum ether/ethyl acetate (6:1).
Yield 37 mg (55%). White solid, mp 123.0-124.1oC. 1H NMR (d6-DMSO, 400 MHz, 25 oC) δ = 14.20-
13.68 (m, 1H), 8.04-7.87 (m, 2H), 7.65-7.40 (m, 2H), 2.79-2.57 (m, 2H), 1.81-1.64 (m, 2H), 1.02-0.78
(m, 3H). 13C NMR (d6-DMSO, 100 MHz, 25 oC) δ = 160.3, 158.4, 133.7, 131.1, 129.2, 127.8, 28.7, 21.2,
14.0. HR-MS [M+H]+ m/z calcd for C11H13ClN3 222.0798, found 222.0799.
3-(4-Chlorophenyl)-5-undecyl-4H-1,2,4-triazole (2l). Eluent: petroleum ether/ethyl acetate (6:1).
Yield 43 mg (43%). White solid, mp 98.6-99.4 oC. 1H NMR (d6-DMSO, 400 MHz, 25 oC) δ = 13.75 (s,
1H), 8.01 (d, J = 8.4 Hz, 2H), 7.48 (d, J = 8.4 Hz, 2H), 2.80-2.62 (m, 2H), 1.78-1.57 (m, 2H), 1.37-1.08
o
(m, 16H), 0.82 (t, J = 6.7 Hz, 3H). 13C NMR (d6-DMSO, 100 MHz, 25 C) δ = 160.3, 158.0, 133.6,
131.1, 129.0, 127.8, 31.8, 29.5, 29.4, 29.3, 29.2, 29.0, 27.8, 26.2, 22.6, 14.3. HR-MS [M+H]+ m/z calcd
for C19H29ClN3 334.2050, found 334.2056.
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3-(4-Chlorophenyl)-5-cyclopropyl-4H-1,2,4-triazole (2m).7b Eluent: petroleum ether/ethyl acetate
(6:1). Yield 45 mg (68%). White solid, mp 200.5-200.6 oC (lit.7b m.p. 202-203 oC). 1H NMR (d6-DMSO,
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400 MHz, 25 C) δ = 14.23-13.55 (m, 1H), 7.96 (d, J = 8.5 Hz, 2H), 7.58-7.41 (m, 2H), 2.14-2.00 (m,
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1H), 1.14-0.86 (m, 4H). 13C NMR (d6-DMSO, 100 MHz, 25 C) δ = 160.1, 160.0, 133.7, 130.9, 129.1,
127.9, 8.6, 7.5. ESI-MS [M+H]+ m/z 220.1.
7b
3-(tert-Butyl)-5-(4-chlorophenyl)-4H-1,2,4-triazole (2n).
Eluent: petroleum ether/ethyl acetate
(8:1). Yield 34 mg (48%). White solid, mp 191.6-192.5 oC(lit.7b m.p. 165-167 oC). 1H NMR (d6-DMSO,
400 MHz, 25 C) δ 14.17-13.60 (m, 1H), 8.02 (d, J = 8.5 Hz, 2H), 7.62-7.35 (m, 2H), 1.36 (s, 9H).13C
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NMR (d6-DMSO, 100 MHz, 25 C) δ 165.6, 159.8, 133.7, 131.1, 129.1, 127.9, 32.2, 29.5. ESI-MS
[M+H]+ m/z 236.1.
3-(4-Chlorophenyl)-5-cyclopentyl-4H-1,2,4-triazole (2o). Eluent: petroleum ether/ethyl acetate (6:1).
Yield 33 mg (45%). White solid, mp 187.2-189.4 oC. 1H NMR (d6-DMSO, 400 MHz, 25 oC) δ = 14.16-
13.62 (m, 1H), 8.13-7.91 (m, 2H), 7.64-7.39 (m, 2H), 3.29-3.05 (m, 1H), 2.12-1.91 (m, 2H), 1.89-1.53
(m, 6H). 13C NMR (d6-DMSO, 400 MHz, 25 oC) δ = 161.8, 160.1, 133.7, 131.0, 129.1, 127.9, 37.0, 32.2,
25.5. HR-MS [M+H]+ m/z calcd for C13H15ClN3 248.0955, found 248.0953.
3-(4-Nitrophenyl)-5-propyl-4H-1,2,4-triazole (2p). Eluent: petroleum ether/ethyl acetate (6:1). Yield
36 mg (51%). Light yellow solid, mp 148.5-149.0 oC. 1H NMR (d6-DMSO, 400 MHz, 25 oC) δ = 14.53-
13.74 (m, 1H), 8.22 (d, J = 8.8 Hz, 2H), 8.16 (d, J = 8.9 Hz, 2H), 2.71 (t, J = 7.5 Hz, 2H), 1.79-1.64 (m,
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2H), 0.90 (t, J = 7.4 Hz, 3H). C NMR (d6-DMSO, 100 MHz, 25 C) δ = 159.6, 158.5, 147.7, 138.1,
127.0, 124.4, 28.1, 21.2, 13.9. HR-MS [M+H]+ m/z calcd for C11H13N4O2 233.1039, found 233.1036.
3-Cyclopropyl-5-(4-nitrophenyl)-4H-1,2,4-triazole (2q). Eluent: petroleum ether/ethyl acetate (6:1).
Yield 38 mg (55%). Light yellow solid, mp 218.3-221.1oC. 1H NMR (d6-DMSO, 400 MHz, 25 C) δ =
o
14.05 (s, 1H), 8.27 (d, J = 9.0 Hz, 2H), 8.16 (d, J = 9.0 Hz, 2H), 2.16-2.04 (m, 1H), 1.11-0.92 (m, 4H).
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13C NMR (d6-DMSO, 100 MHz, 25 oC) δ = 161.1, 158.8, 147.8, 137.7, 127.1, 127.0, 124.4, 124.3, 8.7,
8.6, 7.6, 7.5. HR-MS [M+H]+ m/z calcd for C11H11N4O2 231.0882, found 231.0881.
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3-(tert-Butyl)-5-(4-nitrophenyl)-4H-1,2,4-triazole (2r). Eluent: petroleum ether/ethyl acetate (6:1).
Yield 34 mg (75%). Yellow solid, mp 158.7-159.4 oC. 1H NMR (d6-DMSO, 400 MHz, 25 oC) δ = 13.98
(s, 1H), 8.27 (d, J = 8.7 Hz, 2H), 8.20 (d, J = 8.9 Hz, 2H), 1.41-1.33 (m, 9H). 13C NMR (d6-DMSO, 100
o
MHz, 25 C) δ = 166.2, 159.1, 147.7, 138.2, 127.1, 124.4, 32.3, 29.4. HR-MS [M+H]+ m/z calcd for
C12H15N4O2 247.1195, found 247.1192.
3-Cyclopropyl-5-(m-tolyl)-4H-1,2,4-triazole (2s). Eluent: petroleum ether/ethyl acetate (6:1). Yield
25 mg (75%). White solid, mp 151.5-152.6 oC. 1H NMR (d6-DMSO, 400 MHz, 25 oC) δ = 14.25-13.08
(m, 1H), 7.87-7.64 (m, 2H), 7.45-7.05 (m, 2H), 2.35 (s, 3H), 2.16-1.94 (m, 1H), 1.13-0.78 (m, 4H). 13C
o
NMR (d6-DMSO, 100 MHz, 25 C) δ = 165.7, 161.1, 159.7, 154.6, 138.7, 138.1, 132.0, 131.0, 129.7,
129.3, 128.9, 127.8, 126.9, 126.7, 123.5, 123.3, 21.5, 21.3, 9.3, 8.5, 7.9, 7.5. HR-MS [M+H]+ m/z calcd
for C12H14N3 200.1188, found 200.1188.
ASSOCIATED CONTENT
13
Supporting Information. General experimental procedures, characterization data, and 1H, C NMR
spectra of these synthesized compounds. This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
* E-mail: xuhao@henu.edu.cn; xuyuanqing@henu.edu.cn
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGEMENTS
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The authors wish to thank the Young Scientific Talent Seed-foundation of Henan University (No.
0000A40477), PhD Scientific Research Starting Foundation of Henan University (No. B2012048), Na-
tional Natural Science Foundation of China (No. 51403051).
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