Tunable protic ionic liquids as solvent-catalysts for improved synthesis of multiply substituted 1,2,4-triazoles from oxadiazoles and organoamines

Article abstract of DOI:10.1016/j.tet.2012.03.114

More than green alternatives to traditional volatile molecular organic solvents, protic ionic liquids as dual solvent-catalysts have been successfully used to promote reactions of organoamines with oxadiazoles to afford sterically hindered 1,2,4-triazoles. Among the tested protic ionic liquids, pyridinium trifluoroacetate and acetate showed the highest efficiency for the reactions of arylamines and alkylamines, respectively, indicating that tunable catalysis could be readily effected with protic ionic liquid solvent-catalysts by simply tuning their cation and anion counterparts. A general and efficient approach has been developed for synthesis of multiply substituted 1,2,4-triazoles based on the tunable protic ionic liquid solvent-catalyst systems.

Full text of DOI:10.1016/j.tet.2012.03.114

Tetrahedron 68 (2012) 4813e4819
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Tunable protic ionic liquids as solvent-catalysts for improved synthesis of
multiply substituted 1,2,4-triazoles from oxadiazoles and organoamines
*
Xiaofeng Chen, Rui Liu, Yuan Xu, Gang Zou
Department of Fine Chemicals, East China University of Science and Technology, 130 Meilong Rd., Shanghai 200237, China
a r t i c l e i n f o
a b s t r a c t
Article history:
More than green alternatives to traditional volatile molecular organic solvents, protic ionic liquids as dual
solvent-catalysts have been successfully used to promote reactions of organoamines with oxadiazoles to
afford sterically hindered 1,2,4-triazoles. Among the tested protic ionic liquids, pyridinium tri-
fluoroacetate and acetate showed the highest efficiency for the reactions of arylamines and alkylamines,
respectively, indicating that tunable catalysis could be readily effected with protic ionic liquid solvent-
catalysts by simply tuning their cation and anion counterparts. A general and efficient approach has
been developed for synthesis of multiply substituted 1,2,4-triazoles based on the tunable protic ionic
liquid solvent-catalyst systems.
Received 9 January 2012
Received in revised form 22 March 2012
Accepted 30 March 2012
Available online 5 April 2012
Keywords:
Protic ionic liquid
1,2,4-Triazole
Oxadiazole
Ó 2012 Elsevier Ltd. All rights reserved.
Tunable catalysis
1. Introduction
a classic industrial process, production of -caprolactam, has also
3
been recognized to proceed in PIL of caprolactamium hydrogen
sulfate formed in situ.7 From the point view of organic chemistry,
PILs are, in fact, Brønsted acidebase salts that are well known in
organic synthesis as milder catalysts or promoters than bases or
acids themselves to give higher selectivities in some condensation
reactions in conventional organic solvents albeit often at cost of
efficacy,8 which could be compensated by use of stoichiometric or
a large excess amount of the salts. Therefore, there is no doubt
that PILs will increasingly attract interests as solvent-catalysts
to improve some organic reactions beside their environmental
advantages.9
Multiply substituted 1,2,4-triazoles are an important class of
heterocyclic compounds with wide applications in medicinal10 and
coordination chemistry.11 A number of methods have been de-
veloped for synthesis of multiply substituted 1,2,4-triazoles.12
Among these methods, the most important one involves cycliza-
tion of N-acylamidrazone formed in situ from reaction of amines
with activated amide derivatives. Oxadiazoles are more stable, thus
easy to handle, precursors of N-acylamidrazones than most of the
activated amide derivatives. Therefore, the approach through the
recyclization reaction of oxadiazoles with primary amines to mul-
tiply substituted 1,2,4-triazoles has been preferably adapted in re-
cent years.13 However, the reaction proved to be very sensitive to
both steric hindrance and electronic factors of substrates.12,14 For
example, when aromatic amines have an ortho-substituted aryl
group, the reaction would be sluggish giving the corresponding 4-
aryltriazoles in low yields even under harsh conditions, e.g., at
150e200 ꢀC, after long reaction time.13a,f,i,14
Ionic liquids (ILs) were reintroduced to chemical community
by Wilkes et al. as alternatives to conventional volatile molecular
organic solvents taking advantage of their negligible vapor pres-
sure and high polarity.1 Shortly later, a more critical aspect of ILs
as solvents, ready tunability of physical and chemical properties
by simply varying their cations and anions, the so-called ‘de-
signer’ solvents, has been recognized, which has led to an ex-
plosion in use of ILs as task-specific solvents in a wide range of
chemical processes2 and in many other nonsolvent applications.3
Among the wide applications of ILs as designer solvents, of
greater importance in organic synthesis is the control over re-
activity of solute materials to improve the corresponding re-
actions with respect to yields, rates, and/or selectivities, even to
make a synthesis feasible or possible, that is, difficult or impos-
sible in conventional organic solvents, taking advantage of the
inherent highly polarizing capability and/or a task-specific func-
tion of designed ILs.4 Protic ionic liquids (PILs), the most readily
available and practical subgroup of functional ILs, have attracted
increasing interests as green solvents in both laboratory and in-
dustrial processes.5 In fact, the first major industrial IL application,
BASIL (Biphasic Acid Scavenging utilizing Ionic Liquids) process by
BASF, is based on PIL of 1-alkylimidazolium chloride from scav-
enging the acid by-product with 1-alkylimidazole.6 Recently,
* Corresponding author. Tel.: þ86 21 64252390; e-mail address: zougang@
ecust.edu.cn (G. Zou).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2012.03.114

4814
X. Chen et al. / Tetrahedron 68 (2012) 4813e4819
Table 1
Herein, we report use of readily available protic ionic liquids of
Reaction of 2-phenyl-1,3,4-oxadiazole with mesitylamine in various ionic liquidsa
pyridinium trifluoroacetate and acetate, [PyH]þCF3CO2ꢁ and
[PyH]þOAcꢁ, as tunable solvent-catalysts to effect acidebase com-
bined catalysis for synthesis of multiply substituted 1,2,4-triazoles
from oxadiazoles and organoamines, especially the sterically hin-
dered ones that are difficult to obtain by the traditional acid-
catalysis.
N
N
N
Ph
solvent/catalyst
N
Ph
+ MesNH2
N
O
Mes
Entry
Solvent-catalyst
pH
T/ꢀC
Time
Yieldb (%)
2. Results and discussion
1
2
3
4
5
6
7
8
[HDABCO]þOAcꢁ
6e7
6e7
6e7
6e7
6e7
3
2
2
4
4
1
4
4
4
d
d
d
d
d
d
130
130
110
110
110
110
110
110
110
110
110
110
110
80
130
130
110
110
110
110
14 h
6 h
10 h
6 h
2 h
2 h
1 h
1 h
5 h
13 h
4 h
20 min
20 min
4 h
6 h
6 h
55
70
74
72
63
78
28
43
61
58
49
85
84
[PyH]þOAcꢁ
[PyH]þOAcꢁ
During our development of 1,2,4-triazolylidene transition metal
catalysis, we needed sterically demanding 1,2,4-triazoles, such as 3-
phenyl-4-mesityl-1,2,4-triazole. Unfortunately, all our initial at-
tempts met with failures in preparation of this target triazole by
adapting the acid-catalyzed procedures for synthesis of substituted
1,2,4-triazoles from arylamines and oxadiazoles due to the large
steric hindrance of mesitylamine although the reaction of aniline
readily gave the desired 1,2,4-triazole in good yields under similar
conditions (Scheme 1).
[HMIM]þOAcꢁ
[HMIM]þOTsꢁ
[HMIM]þCF3COꢁ2
[HMIM]þHSOꢁ4
[HMIM]þClꢁ
9
[HDABCO]þCF3COꢁ2
[HTEA]þCF3COꢁ2
10
11
12
13 c
14
15
16
17
18
19
20f
[HDMAc]þCF3COꢁ2
[PyH]þCF3COꢁ2
[PyH]þCF3COꢁ2
[PyH]þCF3COꢁ2
72
[BMIM]þBrꢁ/20 mol % TFAd
[Bpy]þBrꢁ/20 mol % TFAd
[Bpy]þBrꢁ/100 mol % TFAd
[Bpy]þBrꢁ/100 mol % AcOHd
[Bpy]þBrꢁ/100 mol % TsOHd
[Bpy]þBrꢁ/500 mol % AcOH
Tracee
<5e
46
N
4 h
N
5% CF3CO2H
N
O
Ph
N
12 h
10 h
6 h
21
31
17
ArNH2
+
Ph
o
sol. 120-150 C
N
Ar
a
Ar=Ph, Sol.= DCB or Py: 83-88%
Ar=Mes, Sol = DCB, DMF, Py: 0%
Reaction condition: oxadiazole (2.0 mmol), mesitylamine (3.0 mmol), PIL sol-
vent-catalysts (2.0 g).
b
Isolated yields.
Mesitylamine of 1.1 equiv used.
With respect to mesitylamine.
By TLC and some 2-phenyl-1,3,4-oxadiazole still detected.
Scheme 1. Steric effects of arylamines on their recyclization reaction with 2-phenyl-
1,3,4-oxadiazole.
c
d
e
f
We have recently observed that use of 1,4-diazabicyclo[2.2.2]
octane(DABCO) acetate [HDABCO]þOAcꢁ as solvent-catalyst in the
BayliseHillman reaction resulted in significant rate acceleration by
combination of the acidebase catalysis with the inherent highly
polarizing capability of PILs.15 Therefore, we conducted the reaction
of 2-phenyl-1,3,4-oxadiazole with mesitylamine in protic ionic
liquid of [HDABCO]þOAcꢁ and found that the reaction occurred to
offer the desired 3-phenyl-4-mesityl-1,2,4-triazole in modest yield
(55%) (Table 1, entry 1).
Acids of 5.0 equiv used with respect to oxadiazole and no desired triazole
detected for TFA and TsOH due to the decomposition of oxadiazole.
solvent-catalysts, the model reaction proceeded slower and gave
the triazole product in lower yields than that with N-methyl-
imidazolium trifluoroacetate (Table 1, entries 9e11). However,
when the model reaction was run in pyridinium trifluoroacetate,
the reaction completed in 20 min and offered the desired triazole in
85% isolated yield (Table 1, entry 12). Decrease in the loading of
mesitylamine to 1.1 from 1.5 equiv almost did not affect the re-
action while lowering the reaction temperature from 110 ꢀC to
80 ꢀC significantly slowed the reaction rate and led to slightly lower
yield of the triazole product (Table 1, entries 13 and 14). Therefore,
among the tested PILs, pyridinium trifluoroacetate [PyH]þCF3CO2ꢁ
was identified as the most efficient solvent-catalyst for the recyc-
lization reactions of oxadiazoles with arylamines.
To identify whether the acidebase catalysis or the inherent
highly polarizing capability of PILs that should be responsible for
the success in overcoming the steric obstacle of mesitylamine, the
model reaction was run in neutral ILs of N-butyl-N0-methyl-
imidazolium bromide ([BMIM]þBrꢁ) and N-butylpyridium bromide
([Bpy]þBrꢁ) as solvents in the presence 20 mol % CF3CO2H as cata-
lyst. The results showed that the reaction did occur but in very slow
rates in [Bpy]þBrꢁ(Table 1, entries 15 and 16). Further, the reaction
was conducted with 1 equiv amount of acids with respect to
mesitylamine, such as TFA, AcOH, and TsOH as catalysts and only
21e46% yields of the triazole product was obtained. When these
acids were used in excess amount, e.g., 5 equiv, as the amount of PIL
solvent-catalysts used, the substrate 2-phenyl-1,3,4-oxadiazole
decomposed completely with TFA and TsOH under the reaction
conditions and no 3-phenyl-4-mesityl-1,2,4-triazole was detected.
In the case of AcOH, 2-phenyl-1,3,4-oxadiazole disappeared after
6 h but the desired triazole was isolated only in 17% yield (Table 1,
entries 17e20). These results clearly indicate that both the acid and
base counterparts of PILs should contribute to the catalysis, namely,
Encouraged by this preliminary result, a series of protic ionic
liquids with respect to both the cation and anion counterparts were
screened to optimize the solvent-catalyst systems using the re-
action of 2-phenyl-1,3,4-oxadiazole with mesitylamine as model.
The model reaction proceeded faster and gave the triazole product
in higher yields (70e74%) in pyridinium ([PyH]þ) and N-methyl-
imidazolium ([HMIM]þ) acetate than in [HDABCO]þOAcꢁ even
under milder conditions (Table 1, entries 2e4). The anion coun-
terparts of the PILs also appeared to affect the reaction significantly.
For example, using N-methylimidazolium tosylate and tri-
fluoroacetate in placement of acetate, the model reaction com-
pleted in 2 h and gave the triazole product in 63% and 78% yields,
respectively, possibly benefiting from the stronger acidity of
p-toluenesulfonic acid (TsOH) and CF3CO2H (TFA) (Table 1, entries 5
and 6). Thus, we further tested N-methylimidazole salts of stronger
protic acids such as HCl and H2SO4 and found that 2-phenyl-1,3,4-
oxadiazole substrate completely disappeared within 1 h but gave
the desired triazole product in only 28% and 43% yields, re-
spectively, implying decomposition of 1,3,4-oxadiazole under the
reaction conditions (Table 1, entries 7 and 8). That is to say a deli-
cate balance between the cation and anion of PIL needs to be finely
tuned to control the reaction with respect to rate and selectivity.
Therefore, a series of nitrogen-based organic bases with various
basicities including amide, tertiary alkylamine, and pyridine were
screened for the most efficient PIL of trifluoroacetic acid salts in the
model reaction. With trifluoroacetic acid salts of DABCO, N,
N-dimethylacetamide (DMAc), and triethylamine (TEA) as PIL

X. Chen et al. / Tetrahedron 68 (2012) 4813e4819
4815
acidebase combined catalysis is more important than the inherent
highly polarizing capability of PILs in overcoming the obstacle in
reaction of mesitylamine with 2-phenyl-1,3,4-oxadiazole.
isopropyl groups while no reaction occurred for 2,5-diphenyl-1,3,4-
oxadiazole and mesitylamine (Table 2, entries 13 and 15). For
alkylamines, e.g., cyclohexylamine or butylamines, both alkyl and
aryl substituted 1,3,4-oxadiazoles reacted much slower and gave
the corresponding disubstituted triazoles in lower yields in
[PyH]þCF3COꢁ2 , especially for bulky tert-butylamine, from which
the product 3-phenyl-4-tert-butyl-1,2,4-triazole was isolated in
only 6% yield after 20 h (Table 2, entries 16e22), indicating that the
[PyH]þCF3COꢁ2 system might not be the most suitable solvent-
catalyst for alkylamines in this recyclization reaction.
Unlike traditional molecular solvents, ionic liquids, the so-called
designer solvents, are easily tailored for a specific task especially
with respect to protic ionic liquids. Considering the stronger ba-
sicity of alkylamines than anilines, the lower reactivity of alkyl-
amines (RNH2) could be attributed to their proton exchange with
[PyH]þCF3COꢁ2 forming the poorer nucleophiles [RNH3]þCF3COꢁ2 .
We anticipated that the reactions of 1,3,4-oxadiazoles with alkyl-
amines should be more efficiently promoted by PILs from weaker
acids than TFA, such as [PyH]þOAcꢁ, which had shown lower effi-
cacy than [PyH]þCF3CO2ꢁ in the model reaction of mesitylamine.
Therefore, reactions of alkylamines with 2-phenyl-1,3,4-oxadiazole
were tested in [PyH]þOAcꢁ. Just as expected, the reactions pro-
ceeded smoothly to offer the desired 1,2,4-triazoles in good yields,
even for bulky tert-butylamine (Table 3, entries 1e3).
Similarly, 2-alkyl-1,3,4-oxadiazoles also reacted better in
[PyH]þOAcꢁ than in [PyH]þCF3COꢁ2 giving the desired 3,4-dialkyl-
1,2,4-triazoles in 38e77% versus 7e28% (Table 3, entries 4e8 vs
Table 2 entries 18e21). These results clearly demonstrated that PIL
solvent-catalysts could be tuned to fit for different substrates.
Similar to arylamines in [PyH]þCF3COꢁ2 , for reaction of 2,5-aryl/al-
kyl-1,3,4-oxadiazoles with alkylamines, the steric hindrance af-
fected the product yields more remarkably. For example, yields of
the corresponding 3,4,5-substituted-1,2,4-triazoles in the reactions
of cyclohexylamine with 2-phenyl-5-alkyl-1,3,4-oxadiazoles de-
creased from 80% to 24% when the alkyl changed from methyl to
isopropyl groups (Table 3, entries 9 and 10). A similar trend was also
observed with respect to alkylamines in the reactions of 2-phenyl-
5-isopropyl-1,3,4-oxadiazole with butylamines (Table 3, entries 10
and 11).
The scope of PIL-promoted synthesis of the multiply substituted
1,2,4-triazoles was examined with respect to both oxadiazole and
amine substrates (Table 2). Similar to mesitylamine, even the more
bulky 2,6-diisopropylphenylaniline (i-PrNH2) also reacted with 2-
phenyl-1,3,4-oxadiazole to give 3-phenyl-4-(2,6-diisopropyl) phe-
nyl-1,2,4-triazole in 85% yield (Table 2, entry 1). For anilines with-
out steric hindrance, such as phenylamine and 4-methoxyaniline,
the reaction completed within 20 min giving triazoles in good
yields while for electron-deficient 4-nitroaniline, both the yield and
rate of the reaction decreased, consisting with the electronic effects
observed in traditional molecular solvents (Table 2, entries 2e4).
Alkyl substituted 1,3,4-oxadiazoles also reacted smoothly with
aromatic amines with various steric hindrance, but offering tri-
azoles just in modest yields, possibly due to their lower stability
than aryl analogues under the reaction conditions since the 1,3,4-
oxadiazole substrates disappeared very fast during the reaction
(Table 2, entries 5e10). The [PyH]þCF3CO2ꢁ-promoted reactions of
arylamines with 2,5-disubstituted 1,3,4-oxadiazoles were also ex-
amined for synthesis of trisubstituted 1,2,4-triazoles considering
their well-established importance in bioactive molecules.12 Aniline
reacted with 2,5-aryl/alkyl-1,3,4-oxadiazoles, such as 2,5-diphenyl-
1,3,4-oxadiazole, 2-isopropyl-5-phenyl-1,3,4-oxadiazole, and 2-
methyl-5-phenyl-1,3,4-oxadiazole smoothly to afford the corre-
sponding 3,4,5-trisubstituted 1,2,4-triazoles in good yields (Table 2,
entries 11, 12, and 14). However, the reactions of bulky arylamines
with 2,5-aryl/alkyl-1,3,4-oxadiazoles were affected more signifi-
cantly by the steric hindrance. For example, the yields of corre-
sponding 3,4,5-trisubstituted 1,2,4-triazoles decreased from 43% to
28% in reactions of mesitylamine with 2-alkyl-5-phenyl-1,3,4-
oxadiazoles when the alkyl changed from small methyl to bulky
Table 2
[PyH]þCF3COꢁ2 promoted synthesis of multiply substituted 1,2,4-triazoles from 1,3,4-
oxadiazoles and organoaminesa
N N
+
-
N N
O
[PyH] CF CO
3 2
R2
R1
R3NH2
+
o
N
R1
The widely accepted mechanism for the acid-catalyzed recycli-
zation reaction of 1,3,4-oxadiazole with organoamine consists of
the formation of oxadiazolium from oxadiazole and acid, followed
R2
110 C
R3
Entry
R1
R2
R3
Time
Yieldb (%)
1
2
3
4
5
6
7
8
Ph
Ph
Ph
Ph
H
H
H
H
H
H
H
H
i-Pr
Ph
4-MeOPh
20 min
20 min
20 min
5 h
15 min
15 min
15 min
15 min
15 min
10 min
12 h
2 h
8 h
5 h
12 h
10 h
20 h
10 h
12 h
85
95
86
50
70
65
66
55
65
68
81
92
43
85
28c
32c
6c
Table 3
[PyH]þOAcꢁ promoted synthesis of multiply substituted 1,2,4-triazoles from 1,3,4-
oxadiazoles and alkylaminesa
4-NO2Ph
Mes
Ph
i-Pr
i-Pr
i-Pr
Mes
Ph
Ph
Mes
Ph
Mes
Cy
t-Bu
Cy
p-MeOC6H4CH2CH2
p-MeOC6H4CH2CH2
p-MeOC6H4CH2CH2
CH3
PhCH2CH2
PhCH2CH2
Ph
Ph
Ph
Ph
Ph
Ph
N
N
+
-
N
N
[PyH] OAc
R3NH2
R1
R2
+
N
R1
110 C
o
R2
O
R3
9
H
H
Ph
CH3
CH3
Me2CH
Me2CH
H
H
H
H
H
H
Ph
10
11
12
13
14
15
16
17d
18
19
20d
21
22d
Entry
R1
R2
R3
Time (h)
Yield(%)b
1
2
3
4
5
6
7
8
Ph
Ph
Ph
H
H
H
H
H
H
H
H
Cy
10
15
2
84
53
87
77
63
55
58
38
80
24c
45c
t-Bu
n-Bu
Cy
Cy
t-Bu
Cy
t-Bu
Cy
Cy
p-MeOC6H4CH2CH2
12
20
20
10
10
12
12
12
PhCH2CH2
PhCH2CH2
CH3
CH3
Ph
Ph
p-MeOC6H4CH2CH2
PhCH2CH2
PhCH2CH2
CH3
23
15
7
Cy
t-Bu
Cy
12 h
10 h
12 h
9
10
11
CH3
Me2CH
Me2CH
28
15c
Ph
Ph
Ph
n-Bu
n-Bu
a
Reaction condition: oxadiazoles (2.0 mmol), organoamines (2.2 mmol),
[PyH]þCF3COꢁ2 solvent-catalyst (2.0 g).
a
In the cases with butylamines, the reaction was conducted in a sealed tube and
2.0 equiv amines due to their low bp.
b
Isolated yields.
Oxadiazole still detected by TLC.
In a sealed tube and 2.0 equiv of tert- or n-butylamines due to their low bp.
b
c
Isolated yields.
Oxadiazole still detected by TLC.
c
d

4816
X. Chen et al. / Tetrahedron 68 (2012) 4813e4819
by nucleophilic attraction of amine to generate N-acylamidrazone
intermediate, which recyclizes through dehydrationecondensation
to afford the final product 1,2,4-triazole.16 To explain the acidebase
combined catalysis in the recyclization reaction to offer 1,2,4-
triazoles more efficiently in PILs, a slightly modified mechanism
is illustrated using [PyH]þCF3COꢁ2 as example in Scheme 2.
lower nucleophilic activity of amine substrate and the corre-
sponding N-acylamidrazone intermediate, due to formation of
acidebase salts with the acid catalyst. Therefore, one needs acid
catalysts with different acidities to fit for different amine substrates
to reach the highest catalysis efficiency. The same should apply
equally to catalytic species of base in the PIL solvent-catalyst sys-
N N
N N
R1
R2
R1
R2
-
[PyH]+CF3CO2
O
N
R3
Py
Py
CF3CO2
R2
HN
N
HN N
CF3CO2
R1
R1
R2
O
N
R3
H2NR3
H2O
HN N
R2
R1
H2N N
CF3CO2
H2N
Py
O
R2
R3
R3
R1
HN
O
Py
[PyH]+CF3CO2
HN N
R2
R3
R1
[PyH]+CF3CO2
-
-
HN
O
Scheme 2. A slightly modified mechanism for the recyclization reaction of 1,3,4-oxadiazoles with organoamines in [PyH]þCF3CO2ꢁ PIL.
Initially, the active oxadiazolium salt forms via proton exchange
of oxadiazole with [PyH]þCF3CO2ꢁ, releasing free pyridine base that
will deprotonate N-acylamidrazone salt to generate free N-acyla-
midrazone intermediate, completing the ring-opening step and
regenerating [PyH]þCF3CO2ꢁ. An intramolecular nitrogen addition
to acyl group assisted by a proton from [PyH]þCF3CO2ꢁ followed by
dehydration affords a triazolium salt and free pyridine base again,
completing the recyclization step. A proton exchange between the
triazolium salt and free pyridine base offers the desired 1,2,4-
triazole and regenerates the solvent-catalyst [PyH]þCF3CO2ꢁ.
It can be seen from the modified mechanism that both acid and
base species from the PIL reservoir through equilibrium participate
in the reaction sequences, obviously promoting the reaction more
efficiently than acid or base catalyst alone, resulting in overcoming
the steric hindrance to a great degree. Of course, the presence of
large amount of [PyH]þCF3CO2ꢁ as solvent-catalyst surely acceler-
ates the process while the inherent highly polarizing capability of
PILs may not contribute much since no remarkable acceleration has
been observed in neutral ionic liquids of N-butyl-N0-methyl-
imidazolium bromide and N-butylpyridium bromide in the model
reaction.
The reason that reactions of aryl and alkylamines proceeds fa-
vorably in [PyH]þCF3CO2ꢁ and [PyH]þOAcꢁ, respectively, is easy to
understand based on the modified mechanism considering there
are proton exchanges between the substrate and intermediate
amines and the PIL solvent-catalysts. The activation of oxadiazole,
recyclization, and dehydration steps need the assistance from acid,
which are believed to be the rate-determining steps for the reaction
in the absence of an acid catalyst.16 Thus, the stronger acidity of an
acid catalyst has the faster these steps will be. However, the
stronger acidity of the acid catalyst in the system could result in the
tem. In fact, for most organic reactions, substrates with various
steric and electronic properties always behave differently although
chemists try all their best to develop a catalytic system as general as
possible. Therefore, ideally, one has a particular catalytic system for
each sort of substrates like enzyme catalysis to achieve the best
result. Our results clearly demonstrate the readily tunable basicity
and acidity of PILs by simply changing their cation and anion
counterparts could make the PIL-based acid and/or base catalysis to
fit for different substrates feasibly.
3. Conclusion
In summary, we have demonstrated that use of protic ionic
liquids as dual solvent-catalysts could successfully overcome the
obstacles in recyclization reactions of steric hindrance of organo-
amines with oxadiazoles by acidebase combined catalysis to afford
multiply substituted 1,2,4-triazoles, including those that are diffi-
cult to obtain with acid catalysis alone. Using protic ionic liquids,
[PyH]þCF3COꢁ2 and [PyH]þOAcꢁ, as solvent-catalysts for arylamines
and alkylamines, respectively, synthesis of multiply substituted
1,2,4-triazoles from oxadiazoles could be effected in up to excellent
yields, providing a general and efficient approach to the important
heterocyclic structures.
4. Experimental section
4.1. General
All manipulations were carried out in the air unless otherwise
stated. 2-Phenyl-1,3,4-oxadiazole,17 2-phenethyl-1,3,4-oxadiazole,18
2-methyl-1,3,4-oxadiazole,19 2,5-diphenyl-1,3,4-oxadiazole,20 and

X. Chen et al. / Tetrahedron 68 (2012) 4813e4819
4817
2-methyl-5-phenyl-1,3,4-oxadiazole21 were prepared according to
the previously reported procedures. Commercially available chem-
icals were used as received. The protic ionic liquids were prepared by
simply dropwise adding acids (1 equiv) to bases at 0 ꢀC. 1H and 13C
NMR spectra were recorded at ambient temperatures. Chemical
shifts are reported in parts per million (d), relative to the internal
standard of tetramethylsilane (TMS). ESI-MS spectra were recorded
on an LCT Premier XE instrument.
liquid (2 g). The mixture was stirred at 110 ꢀC and monitored by TLC
until oxadiazole was not detected unless otherwise stated. The
reaction mixture was diluted with CH2Cl2 (15 ml), followed by
washing twice with H2O (10 mlꢂ2), from which protic ionic liquid
could be recovered by rotavapor and recrystallization. The organic
layers were dried over anhydrous Na2SO4, filtered, and evaporated
under reduced pressure to give crude product, which was purified
by column chromatography on silica gel with CH2Cl2/MeOH to give
1,2,4-triazole.
4.2. Synthesis of oxadiazoles
4.3.2. 4-Mesityl-3-phenyl-4H-1,2,4-triazole. White
125e126 ꢀC; 1H NMR (500 MHz, CDCl3)
(ppm): 8.11 (s, 1H),
7.50e7.48 (m, 2H), 7.37e7.33 (m, 1H), 7.30e7.26 (m, 2H), 7.00 (s,
2H), 2.36 (s, 3H), 1.92 (s, 6H); 13C NMR (125 MHz, CDCl3)
(ppm):
152.8, 144.6, 140.0, 135.1, 130.6, 129.9, 129.8, 128.7, 126.9, 126.8, 21.1,
17.7; HRMS calcd for C17H18N3 [Mþ1]: 264.1501, found 264.1494.
solid;
mp
4.2.1. 2-(4-Methyoxyphenethyl)-1,3,4-oxadiazole. Methyl-3-(4-
methyoxyphenyl)-propanoate (2.91 g, 15 mmol), 80% hydrazine
monohydrate (4.69 g, 75 mmol), 15 ml ethanol were placed in
a 50 ml reaction flask equipped with a reflux condenser, and the
mixture was heated to reflux for 10 h, the resulting mixture was
allowed to cool to room temperature and evaporated in vacuo. The
residue was filtered and rinsed with hexane, the product, 3-(4-
methoxyphenyl)propanehydrazide, was used in the next step
without further purification.
d
d
4.3.3. 4-(2,6-Diisopropylphenyl)-3-phenyl-4H-1,2,4-triazole. White
solid; mp 114e115 ꢀC; 1H NMR (500 MHz, CDCl3)
d (ppm): 8.15 (s,
1H), 7.54e7.48 (m, 3H), 7.36e7.25 (m, 5H), 2.44e2.37 (m, 2H), 1.11
3-(4-Methoxyphenyl)propanehydrazide obtained above, p-
TsOH$H2O (3 mol%, 77 mg), and triethyl orthoformate (15 ml) were
placed in a two-necked reaction flask equipped with a reflux con-
denser under nitrogen atmosphere. The reaction mixture was
heated to 140 ꢀC and monitored by TLC until the starting material
was not detected. When the reaction completed, removal of the
ethanol and triethyl orthoformate under vacuum gave an oil resi-
due, which was purified by column chromatography on silica gel
with petroleum ether/ethyl acetate (5:1, v/v) to afford 2-(4-
methyoxyphenethyl)-1,3,4-oxadiazole as white solid in 72% yield
(two steps).
(d, J¼8.5 Hz, 6H), 0.91 (d, J¼8.5 Hz, 6H); 13C NMR (125 MHz, CDCl3)
d
(ppm): 153.4, 145.8, 130.9, 130.0, 129.9, 128.5, 127.2, 126.5, 124.7,
28.2, 24.9, 22.6; HRMS calcd for C20H23N3 [Mþ1]: 306.1970, found
306.1971.
4.3.4. 3,4-Diphenyl-4H-1,2,4-triazole.14c White
153e155 ꢀC; 1H NMR (500 MHz, CDCl3)
(ppm): 8.33 (s, 1H),
7.50e7.45 (m, 5H), 7.40e7.36 (m, 1H), 7.33e7.29 (m, 2H), 7.25e7.23
(m, 2H); 13C NMR (125 MHz, CDCl3)
(ppm): 153.17, 144.77, 134.65,
solid;
mp
d
d
129.98, 129.91, 129.47, 128.63, 128.57, 126.35, 125.74.
Mp: 45e46 ꢀC; 1H NMR (500 MHz, CDCl3)
7.11 (d, J¼11.0 Hz, 2H), 6.83 (d, J¼11.0 Hz, 2H), 3.78 (s, 3H), 3.18e3.15
(m, 2H), 3.08e3.05 (m, 2H); 13C NMR (125 MHz, CDCl3)
(ppm):
d
(ppm): 8.33 (s, 1H),
4.3.5. 4-(4-Methoxyphenyl)-3-phenyl-4H-1,2,4-triazole.22 Yellow
oil; 1H NMR (500 MHz, CDCl3)
d (ppm): 8.29 (s, 1H), 7.48 (d,
d
J¼9.0 Hz, 2H), 7.39e7.37 (m, 1H), 7.34e7.30 (m, 2H), 7.16 (d,
166.3, 158.3, 152.9, 131.4, 129.2, 114.1, 55.2, 31.6, 27.3; HRMS calcd
for C11H13N2O2 [Mþ1]: 205.0977, found 205.0970.
J¼11.0 Hz, 2H), 6.96 (d, J¼11.0 Hz, 2H), 3.86 (s, 3H); 13C NMR
(125 MHz, CDCl3) d (ppm): 160.2, 153.3, 145.1, 129.9, 128.6, 128.5,
127.2, 127.1, 126.3, 115.0, 55.6.
4.2.2. 2-Isopropyl-5-phenyl-1,3,4-oxadiazole. To a solution of ben-
zoylhydrazine (5.00 g, 36.7 mmol) and triethylamine (5.80 g,
57 mmol) in 20 ml THF was slowly added isobutyryl chloride
(4.71 g, 44 mmol) over 1 h at room temperature. The mixture
was refluxed for 3 h before the solvent was evaporated under
reduced pressure. The product, N’-(isobutyryl)benzohydrazide,
was recrystallized from water, which was used in the next step
directly.
4.3.6. 4-(4-Nitrophenyl)-3-phenyl-4H-1,2,4-triazole.23 White solid;
mp: 177e178 ꢀC; 1H NMR (500 MHz, CDCl3)
d (ppm): 8.42 (s, 1H),
8.35 (d, J¼11.0 Hz, 2H), 7.48e7.36 (m, 7H); 13C NMR (125 MHz,
CDCl3)
d (ppm): 153.0, 147.7, 144.1, 139.6, 130.5, 129.0, 128.8, 126.4,
125.5, 125.4.
4.3.7. 4-Mesityl-3-(4-methoxyphenethyl)-4H-1,2,4-triazole. Yellow
N’-(Isobutyryl)benzohydrazide (1.24 g, 6 mmol), TsCl (3.43 g,
18 mmol), and diisopropylethylamine (1.55 g 12 mmol) were dis-
solved in acetonitrile (60 ml), the resulting reaction mixture was
stirred at room temperature under nitrogen atmosphere for 12 h,
then it was poured into a 14% NH3 aqueous solution. The resulting
mixture was stirred at room temperature for 15e30 min, then
extracted with dichloromethane. The organic phase was washed
with water, dried over anhydrous Na2SO4, and concentrated in
vacuum to afford the crude product, which was then purified by
column chromatography on silica gel with petroleum ether/ethyl
acetate (10:1, v/v) to give 2-isopropyl-5-phenyl-1,3,4-oxadiazole as
oil; 1H NMR (500 MHz, CDCl3)
d (ppm): 8.01 (s, 1H), 7.03 (d,
J¼10.5 Hz, 2H), 6.98 (s, 2H), 6.78 (d, J¼10.5 Hz, 2H), 3.75 (s, 3H),
3.06e3.02 (m, 2H), 2.71e2.67 (m, 2H), 2.34 (s, 3H), 1.84 (s, 6H); 13C
NMR (125 MHz, CDCl3)
d (ppm): 157.1, 152.8, 142.1, 139.0, 134.2,
131.5, 128.5, 128.4, 128.2, 112.9, 54.2, 31.1, 25.7, 20.0, 16.3; HRMS
calcd for C20H24N3O [Mþ1]: 322.1919, found 322.1917.
4.3.8. 3-(4-Methoxyphenethyl)-4-phenyl-4H-1,2,4-triazole. Yellow
oil; 1H NMR (500 MHz, CDCl3)
d (ppm): 8.17 (s, 1H), 7.50e7.48 (m,
3H), 7.10e7.08 (m, 2H), 6.96 (d, J¼10.5 Hz, 2H), 6.76 (d, J¼10.5 Hz,
2H), 3.76 (s, 3H), 3.03e2.91 (m, 4H); 13C NMR (125 MHz, CDCl3)
colorless oil in 68% yield. 1H NMR (500 MHz, CDCl3)
d
(ppm):
d (ppm): 158.2, 153.7, 143.4, 133.7, 132.3, 129.9, 129.6, 129.3, 125.7,
8.06e8.02 (m, 2H), 7.53e7.49 (m, 3H), 3.31e3.24 (m, 1H), 1.46 (d,
113.9, 55.2, 32.9, 26.9; HRMS calcd for C17H18N3O [Mþ1]: 280.1450,
J¼9.0 Hz, 6H); 13C NMR (125 MHz, CDCl3)
d
(ppm): 170.8, 164.6,
found 280.1456.
131.4, 128.9, 126.7, 124.1, 26.4, 20.1; HRMS calcd for C11H13N2O
[Mþ1]: 189.1028, found 189.1030.
4.3.9. 4-(2,6-Diisopropylphenyl)-3-(4-methoxyphenethyl)-4H-1,2,4-
triazole. White solid; mp 200e202 ꢀC; 1H NMR (500 MHz, CDCl3)
4.3. Synthesis of multiply substituted triazoles
d
(ppm): 8.07 (s, 1H), 7.58 (t, J¼9.8 Hz, 1H), 7.28 (d, J¼10.0 Hz, 2H),
7.07 (d, J¼10.5 Hz, 2H), 6.80 (d, J¼10.5 Hz, 2H), 3.75 (s, 3H), 3.10 (t,
J¼10.3 Hz, 2H), 2.66 (t, J¼10.3 Hz, 2H), 2.28e2.21 (m, 2H), 1.12 (d,
J¼8.5 Hz, 6H), 1.08 (d, J¼8.5 Hz, 6H); 13C NMR (125 MHz, CDCl3)
4.3.1. General procedure. A 25 ml flask was charged with oxadia-
zole (2 mmol), primary amine (2.2e4.0 mmol), and protic ionic

4818
X. Chen et al. / Tetrahedron 68 (2012) 4813e4819
d
(ppm): 158.2, 154.5, 146.2, 144.0, 132.6, 130.8, 129.3, 128.5, 124.4,
(m, 3H), 1.37e1.23 (m, 3H); 13C NMR (125 MHz, CDCl3)
d (ppm):
114.0, 55.2, 32.0, 28.2, 27.0, 25.1, 23.0; HRMS calcd for C23H30N3O
153.5, 141.4, 130.0, 128.9,127.3, 55.1, 34.4, 35.3, 24.8; HRMS calcd for
[Mþ1]: 364.2389, found 364.2383.
C14H18N3 [Mþ1]: 228.1501, found 228.1500.
4. 3.10. 4-(2, 6-Diisopropylphenyl)-3-methyl-4H-1,2,4-
4.3.19. 4-tert-Butyl-3-phenyl-4H-1,2,4-triazole. White solid; mp
triazole. White solid; mp 123e124 ꢀC; 1H NMR (500 MHz, CDCl3)
155e156 ꢀC; 1H NMR (500 MHz, CDCl3)
d
(ppm): 8.33 (s, 1H),
d
(ppm): 8.05 (s, 1H), 7.50 (t, J¼9.8 Hz, 1H), 7.31 (d, J¼10.0 Hz, 2H),
7.53e7.29 (m, 5H), 1.49 (s, 9H); 13C NMR (125 MHz, CDCl3)
d
(ppm):
2.33e2.27 (m, 2H), 2.23 (s, 3H), 1.17 (d, J¼8.5 Hz, 6H), 1.11 (d,
153.7, 141.8, 130.6, 130.2, 129.8, 128.1, 57.3, 30.9; HRMS calcd for
C12H16N3 [Mþ1]: 202.1344, found 202.1343.
J¼8.5 Hz, 6H); 13C NMR (125 MHz, CDCl3)
d
(ppm): 151.8, 146.1,
144.0, 130.7, 128.7, 124.4, 28.1, 24.8, 23.1, 10.1; HRMS calcd for
C15H22N3 [Mþ1]: 244.1814, found 244.1815.
4.3.20. 4-Cyclohexyl-3-(4-methoxyphenethyl)-4H-1,2,4-
triazole. Colorless oil; 1H NMR (500 MHz, CDCl3)
d (ppm): 8.09 (s,
4.3.11. 4-(2,6-Diisopropylphenyl)-3-phenethyl-4H-1,2,4-
1H), 7.09 (d, J¼11.0 Hz, 2H), 6.83 (d, J¼10.5 Hz, 2H), 3.78 (s, 3H),
3.55e3.48 (m, 1H), 3.12e3.08 (m, 2H), 3.00e2.96 (m, 2H), 1.88e1.71
(m, 5H), 1.52e1.43 (m, 2H), 1.34e1.18 (m, 3H); 13C NMR (125 MHz,
triazole. White solid; mp 127e128 ꢀC; 1H NMR (500 MHz, CDCl3)
d
(ppm): 8.07 (s, 1H), 7.48 (t, J¼9.8 Hz, 1H), 7.29e7.23 (m, 4H),
7.20e7.13 (m, 3H), 3.18e3.14 (m, 2H), 2.71e2.67 (m, 2H), 2.30e2.20
(m, 2H), 1.13 (d, J¼8.5 Hz, 6H), 1.10 (d, J¼8.5 Hz, 6H); 13C NMR
CDCl3) d (ppm): 158.3, 152.9, 140.3, 132.6, 129.4, 114.0, 55.3, 54.6,
34.1, 33.2, 27.2, 25.5, 24.9; HRMS calcd for C17H24N3O [Mþ1]:
(125 MHz, CDCl3)
d
(ppm): 154.5, 146.2, 144.1, 140.6, 130.8, 128.6,
286.1919, found 286.1921.
128.3, 126.4, 124.4, 32.9, 28.2, 26.7, 25.2, 23.0; HRMS calcd for
C22H28N3 [Mþ1]: 334.2283, found 334.2278.
4.3.21. 4-Cyclohexyl-3-phenethyl-4H-1,2,4-triazole. Yellow oil; 1H
NMR (500 MHz, CDCl3)
d (ppm): 8.01 (s, 1H), 7.24e7.10 (m, 5H),
4.3.12. 4-Mesityl-3-phenethyl-4H-1,2,4-triazole. Colorless oil; 1H
3.47e3.40 (m, 1H), 3.09 (t, J¼9.8 Hz, 2H), 2.94 (t, J¼9.8 Hz, 2H),
NMR (500 MHz, CDCl3)
6.98 (s, 2H), 3.13e3.09 (m, 2H), 2.74e2.70 (m, 2H), 2.34 (s, 3H), 1.84
(s, 6H); 13C NMR (125 MHz, CDCl3)
(ppm): 153.66, 143.09, 140.42,
d (ppm): 8.02 (s, 1H), 7.25e7.10 (m, 5H),
1.79e1.69 (m, 5H), 1.44e1.36 (m, 2H), 1.24e1.06 (m, 3H); 13C NMR
(125 MHz, CDCl3)
d (ppm): 152.8, 140.6, 140.4, 128.7, 128.5, 126.5,
d
54.6, 34.1, 27.0, 25.5, 24.9; HRMS calcd for C16H22N3 [Mþ1]:
139.95, 135.17, 129.51, 129.12, 128.44, 128.37, 126.30, 32.92, 26.40,
21.03, 17.26; HRMS calcd for C19H22N3 [Mþ1]: 292.1814, found
292.1814.
256.1814, found 256.1810.
4.3.22. 4-tert-Butyl-3-phenethyl-4H-1,2,4-triazole. White solid; mp
76e77 ꢀC; 1H NMR (500 MHz, CDCl3)
d
(ppm): 8.17 (s, 1H),
7.33e7.21 (m, 5H), 3.32e3.28 (m, 2H), 3.19e3.15 (m, 2H), 1.60 (s,
9H); 13C NMR (125 MHz, CDCl3)
(ppm): 152.3, 140.4, 139.9, 127.6,
4.3.13. 3,4,5-Triphenyl-4H-1,2,4-triazole.24 White
>250 ꢀC; 1H NMR (500 MHz, CD3OD)
(ppm): 7.62e7.47 (m, 15H);
13C NMR (125 MHz, CD3OD)
(ppm): 155.5, 133.8, 133.4, 132.8,
131.6, 131.0, 130.3, 129.5, 123.1.
solid;
mp
d
d
d
127.4, 125.4, 55.2, 32.9, 29.1, 29.0; HRMS calcd for C14H20N3 [Mþ1]:
230.1657, found 230.1654.
4.3.14. 3-Methyl-4,5-diphenyl-4H-1,2,4-triazole.25 White solid; mp
165e166 ꢀC; 1H NMR (500 MHz, CDCl3)
(ppm): 7.52e7.51 (m, 3H),
7.40 (d, J¼9.5 Hz, 2H), 7.32 (t, J¼9.0 Hz, 1H), 7.28e7.19 (m, 4H), 2.36
(s, 3H). 13C NMR (125 MHz, CDCl3)
(ppm): 153.9, 152.7, 134.9,
4.3.23. 4-Cyclohexyl-3-methyl-4H-1,2,4-triazole.26 Yellow solid; mp
d
97e98 ꢀC; 1H NMR (500 MHz, CDCl3)
d (ppm): 8.13 (s, 1H),
3.84e3.78 (m, 1H), 2.46 (s, 3H), 2.07e2.04 (m, 2H), 1.97e1.94 (m,
2H), 1.81e1.78 (m, 1H), 1.65e1.55 (m, 2H), 1.49e1.38 (m, 2H),
d
130.1, 129.7, 129.5, 128.4, 128.2, 127.2, 127.0, 11.4.
1.33e1.25 (m, 1H); 13C NMR (125 MHz, CDCl3)
d (ppm): 150.0, 140.4,
54.7, 33.7, 25.3, 24.8, 10.5.
4.3.15. 4-Mesityl-3-methyl-5-phenyl-4H-1,2,4-triazole. Yellow
solid; mp 155e156 ꢀC; 1H NMR (500 MHz, CDCl3)
d
(ppm):
4.3.24. 4-Butyl-3,5-diphenyl-4H-1,2,4-triazole. White solid; mp
176e177 ꢀC; 1H NMR (500 MHz, CDCl3)
(ppm): 7.69e7.66 (m, 4H),
7.47e7.45 (m, 2H), 7.34e7.30 (m, 1H), 7.28e7.24 (m, 2H), 7.02 (s,
d
2H), 2.37 (s, 3H), 2.21 (s, 3H), 1.91 (s, 6H); 13C NMR (125 MHz,
7.54e7.53 (m, 6H), 4.09 (t, J¼9.5 Hz, 2H), 1.38e1.31 (m, 2H),
CDCl3) d (ppm): 152.9, 152.3, 140.0, 135.2, 130.5, 129.9, 129.6, 128.6,
1.04e0.95 (m, 2H), 0.63 (t, J¼9.3 Hz, 3H); 13C NMR (125 MHz,
127.3, 126.6, 21.2, 17.6, 10.6; HRMS calcd for C18H20N3 [Mþ1]:
CDCl3) d (ppm): 155.5,130.1,128.9,127.9, 44.6, 31.9,19.2,13.1; HRMS
278.1657, found 278.1656.
calcd for C18H20N3 [Mþ1]: 278.1657, found 278.1653.
4.3.16. 3-Isopropyl-4,5-diphenyl-4H-1,2,4-triazole. White solid; mp
4.3.25. 4-Butyl-3-phenyl-4H-1,2,4-triazole. Yellow oil; 1H NMR
(500 MHz, CDCl3) d (ppm): 8.26 (s,1H), 7.62e7.59 (m, 2H), 7.51e7.49
158e160 ꢀC; 1H NMR (500 MHz, CDCl3)
d
(ppm): 7.51e7.47 (m, 3H),
7.39e7.37 (m, 2H), 7.33e7.20 (m, 5H), 2.93e2.82 (m, 1H), 1.32 (d,
d (ppm): 160.5, 153.8,
134.9, 130.0, 129.7, 129.3, 128.4, 127.6, 127.1, 25.2, 21.3; HRMS calcd
for C17H18N3 [Mþ1]: 264.1501, found 264.1498.
(m, 3H), 4.03 (t, J¼9.3 Hz, 2H), 1.74e1.76 (m, 2H), 1.32e1.22 (m, 2H),
J¼9.0 Hz, 6H); 13C NMR (125 MHz, CDCl3)
0.86 (td, J1¼9.0 Hz, J2¼3.0 Hz, 3H); 13C NMR (125 MHz, CDCl3)
d¼153.8,144.1,129.9,128.8,128.6,126.9, 44.8, 32.4,19.4,13.3; HRMS
calcd for C12H16N3 [Mþ1]: 202.1344, found 202.1335.
4.3.17. 3-Isopropyl-4-mesityl-5-phenyl-4H-1,2,4-triazole. Yellow oil;
4.3.26. 4-tert-Butyl-3-methyl-4H-1,2,4-triazole.27 White solid; mp
1H NMR (500 MHz, CDCl3)
d
(ppm): 7.42e7.40 (m, 2H), 7.33e7.23
90e91 ꢀC; 1H NMR (500 MHz, CDCl3)
d (ppm): 8.16 (s, 1H), 2.63 (s,
(m, 3H), 7.00 (s, 2H), 2.62e2.52 (m, 1H), 2.36 (s, 3H), 1.90 (s, 6H),
3H), 1.64 (s, 9H); 13C NMR (125 MHz, CDCl3)
56.0, 29.8, 14.0.
d (ppm): 150.3, 141.6,
1.31 (d, J¼9.0 Hz, 6H); 13C NMR (125 MHz, CDCl3)
d (ppm): 160.3,
152.6, 139.9, 135.3, 130.3, 129.9, 129.4, 128.5, 127.4, 126.9, 25.2, 21.6,
21.2, 17.8; HRMS calcd for C20H24N3 [Mþ1]: 306.1967, found
306.1970.
4.3.27. 4-Cyclohexyl-3-methyl-5-phenyl-4H-1,2,4-triazole.28 Yellow
solid; mp 122e124 ꢀC; 1H NMR (500 MHz, CDCl3)
(ppm):
d
7.50e7.48 (m, 5H), 4.05e3.97 (m, 1H), 2.64 (s, 3H), 1.89e1.86 (m,
4.3.18. 4-Cyclohexyl-3-phenyl-4H-1,2,4-triazole. Yellow oil; 1H NMR
5H), 1.71e1.68 (m, 1H), 1.32e1.09 (m, 4H); 13C NMR (125 MHz,
(500 MHz, CDCl3)
d
(ppm): 8.32 (s, 1H), 7.58e7.52 (m, 5H),
CDCl3)
d (ppm): 155.2, 151.1, 129.9, 129.5, 128.7, 128.2, 56.4, 32.0,
4.06e4.00 (m, 1H), 2.09e2.05 (m, 2H), 1.91e1.88 (m, 2H), 1.75e1.61
25.8, 24.9, 13.4.

X. Chen et al. / Tetrahedron 68 (2012) 4813e4819
4819
6. (a) Seddon, K. R. Nat. Mater. 2003, 2, 363; (b) Rogers, R. D.; Seddon, K. R. Science
2003, 302, 792.
4.3.28. 4-Cyclohexyl-3-isopropyl-5-phenyl-4H-1,2,4-triazole. White
solid; mp 133e135 ꢀC; 1H NMR (500 MHz, CDCl3)
(ppm): 7.48 (m,
d
ꢀ
ꢀ
7. Fabos, V.; Lantos, D.; Bodor, A.; Balint, A.-M.; Mika, L. T.; Sielcken, O. E.; Cuiper,
5H), 4.03e3.96 (m, 1H), 3.26e3.16 (m, 1H), 1.89e1.73 (m, 6H), 1.49
(d, J¼9.0 Hz, 6H), 1.29e1.07 (m, 4H); 13C NMR (125 MHz, CDCl3)
ꢀ
A.; Horvath, I. T. ChemSusChem 2008, 1, 189.
8. (a) Vale, J. A.; Zanchetta, D. F.; Moran, P. J. S.; Rodrigues, J.; Augusto, R. Synlett
2009, 75; (b) Bugarin, A.; Jones, K. D.; Connell, B. T. Chem. Commun. 2010, 1715;
(c) Wang, B.; Zhou, S.; Sun, Y.; Xu, F.; Sun, R. Curr. Org. Chem. 2011, 15, 1392.
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Adv. Synth. Catal. 2003, 345, 959; (b) Moreau, C.; Finiels, A.; Vanoye, L. J. Mol.
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d
(ppm): 159.8, 154.1, 129.8, 129.8, 128.9, 128.5, 56.3, 32.7, 26.4, 26.0,
24.9, 22.4; HRMS calcd for C17H24N3 [Mþ1]: 270.1970, found
270.1969.
4.3.29. 4-Butyl-3-isopropyl-5-phenyl-4H-1,2,4-triazole. Yellow oil;
1H NMR (500 MHz, CDCl3)
d (ppm): 7.55e7.56 (m, 2H), 7.49e7.48
10. (a) Temple, C., Jr. The Chemistry of Heterocyclic Compounds: Triazoles 1,2,4; Wi-
ley: New York, NY, 1981; Vol. 37; (b) Al-Masoudi, I. A.; Al-Soud, Y. A.; Al-Salihi,
N. J.; Al-Masoudi, N. A. Chem. Heterocycl. Compd. 2006, 42, 1377; (c) Curtis, A.;
Jennings, N. In Comprehensive Heterocyclic Chemistry III; Katritzky, A. R.,
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2008; Vol. 5; (d) Shalini, K.; Kumar, N.; Drabu, S.; Sharma, P. K. Beilstein J. Org.
Chem. 2011, 7, 668; (e) Singhal, N.; Sharma, P. K.; Dudhe, R.; Kumar, N. J. Chem.
Pharm. Res. 2011, 3, 126.
(m, 3H), 3.91 (t, J¼10 Hz, 2H), 3.08e2.98 (m, 1H), 1.57e1.51 (m,
2H), 1.47 (dd, J1¼8.5 Hz, J2¼2.5 Hz, 6H), 1.24e1.16 (m, 2H), 0.81
(td, J1¼9.0 Hz, J2¼2.5 Hz, 3H); 13C NMR (125 MHz, CDCl3)
d
(ppm): 159.8, 154.2, 129.7, 128.8, 128.7, 127.9, 43.4, 32.6, 25.2,
21.7, 19.5, 13.3; HRMS calcd for C15H22N3 [Mþ1]: 244.1814, found
244.1817.
11. (a) Klingele, M. H.; Brooker, S. Coord. Chem. Rev. 2003, 241, 119; (b) Aromí, G.;
Barrios, L. A.; Roubeau, O.; Gamez, P. Coord. Chem. Rev. 2011, 255, 485; (c) Liu, K.;
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Acknowledgements
12. Moulin, A.; Bibian, M.; Blayo, A.-L.; Habnouni, S. E.; Martinez, J.; Fehrentz, J.-A.
Chem. Rev. 2010, 110, 1809.
Financial supports from the National Nature Science Foundation
of China (No. 20972049) are gratefully acknowledged.
13. (a) Olson, S.; Aster, S. D.; Brown, K.; Carbin, L.; Graham, D. W.; Hermanowski-
Vosatka, A.; LeGrand, C. B.; Mundt, S. S.; Robbins, M. A.; Schaeffer, J. M.;
Slossberg, L. H.; Szymonifka, M. J.; Thieringer, R.; Wright, S. D.; Balkovec, J. M.
Bioorg. Med. Chem. Lett. 2005, 15, 4359; (b) García, M. A.; Martín-Santamaría, S.;
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