Copper(II)-catalyzed aerobic oxidative synthesis of substituted 1,2,3- and 1,2,4-triazoles from bisarylhydrazones via C-H functionalization/C-C/N-N/C-N bonds formation

Article abstract of DOI:10.1021/jo300592t

An unprecedented copper(II)-catalyzed aerobic oxidative synthesis of 2,4,5-triaryl-1,2,3-triazoles and 1,3,5-triaryl-1,2,4-triazoles from bisarylhydrazones as the common starting precursor has been achieved via cascade C-H functionalization/C-C/N-N/C-N bonds formation under mild reaction conditions. One of the enthralling outcomes of this strategy is the copper(II)-catalyzed room temperature C-H functionalization/C-N bond formation in presence of air, which has been accomplished during the synthesis of substituted 1,2,4-triazoles. This new class of compounds could give prospective luminescence as an iconic component in the area of pharmaceutical and biological sciences. The intermediates for both the processes have been isolated to elucidate the mechanistic scenario.

Full text of DOI:10.1021/jo300592t

Article
pubs.acs.org/joc
Copper(II)-Catalyzed Aerobic Oxidative Synthesis of Substituted
1,2,3- and 1,2,4-Triazoles from Bisarylhydrazones via C−H
Functionalization/C−C/N−N/C−N Bonds Formation
Murali Mohan Guru and Tharmalingam Punniyamurthy*
Department of Chemistry, Indian Institute of Technology Guwahati, Guwahati 781039, India
S
* Supporting Information
ABSTRACT: An unprecedented copper(II)-catalyzed aerobic
oxidative synthesis of 2,4,5-triaryl-1,2,3-triazoles and 1,3,5-triaryl-
1,2,4-triazoles from bisarylhydrazones as the common starting
precursor has been achieved via cascade C−H functionalization/
C−C/N−N/C−N bonds formation under mild reaction con-
ditions. One of the enthralling outcomes of this strategy is the
copper(II)-catalyzed room temperature C−H functionalization/
C−N bond formation in presence of air, which has been accomplished during the synthesis of substituted 1,2,4-triazoles. This
new class of compounds could give prospective luminescence as an iconic component in the area of pharmaceutical and
biological sciences. The intermediates for both the processes have been isolated to elucidate the mechanistic scenario.
On the other hand, 1,2,4-triazoles have received considerable
attention in biological and pharmaceutical fields, as they display
potent biological properties such as antibacterial7f and
antifungal7g activities. Furthermore, N-1-aryl-1,2,4-triazoles
such as ICL670 (deferasirox), an orally active iron chelator, is
very useful in iron overload therapy.7e There are only a few
studies available for the synthesis of substituted 1,2,4-
triazoles.14 A particularly interesting scaffold of these hetero-
cycles is 1,3,5-trisubstituted 1,2,4-triazoles that could be
constructed either by heterocyclization of primary amidines
via acylamidine intermediate15 or through oxidative cyclization
of triazenes.16 Pertinent to the present research, there appears
hardly any precedent for the catalytic one-pot regioselective
synthesis of fully substituted triazoles from the same starting
precursor under aerobic conditions. The present method uses
the readily accessible bisarylhydrazones as only substrate and
offers a new route for the regioselective synthesis of both 2,4,5-
triaryl-1,2,3-triazoles and 1,3,5-triaryl-1,2,4-triazoles via a
cascade copper(II)-catalyzed aerobic oxidative C−H function-
alization/C−C/N−N/C−N bonds formation (Scheme 1).
INTRODUCTION
■
The functionalization of C−H bonds has emerged to be a
powerful strategy for its increased efficiency and ideality of new
synthetic routes. The most alluring aspect in this context is the
construction of the heterocyclic compounds through transition-
metal-catalyzed C−H activation.1 Although for the most part,
rhodium-,2 ruthenium-,3 and palladium-based4 catalysts are
contributing to the dramatic resurgence of interest in carbon−
carbon or carbon−heteroatom bond formation by the cleavage
of ubiquitous C−H bonds, the use of copper5 catalysts can also
be beneficial for achieving the same, a pivotal advantage with
respect to cost and toxicity. Our contribution in this field has
been modest,5h,i and our contention was to extend this strategy
for the synthesis of heterocycles, such as substituted triazoles,
which have found versatile applications in biological, material,
and medicinal sciences.6,7
1,2,3-Triazoles are an important class of heterocycles because
of their pharmacological properties like antifungal,6i antiviral,6j
and anticoccidiostatic activities.6k Because of limitations of the
traditional Huisgen azide−alkyne dipolar cycloaddition (AAC)
processes,8 metal-catalyzed AAC reactions9 have enabled the
assembly of diversely N-1-substituted 1,2,3-triazoles under
relatively mild reaction conditions. However, the synthesis of
another subset N-2-substituted 1,2,3-triazoles, widely used as
biologically active compounds such as orexin receptor
antagonist (MK-4305),6d SYK kinase inhibitors,6l and ALK5
inhibitors,6m has remained a challenging task to the scientific
endeavor.10 To get N-2-aryl-1,2,3-triazoles, the usual strategy
involves N-arylation of 1,2,3-triazoles, which are limited
because of the regioselectivity problem.6e,l,11 Recently, the
C−N cross-coupling reactions of aryl halides with 1,2,3-
triazoles has been employed for N-2 selective arylation of 1,2,3-
triazoles by incorporating C-4- and C-5-substituents on the
heteroarenes12 or by using bulky ligand.13
RESULTS AND DISCUSSION
■
In our recent study5i and from the literature reports,17 we have
found that bisarylhydrazones are unstable at elevated temper-
ature. With this finding, when we initiated our new approach
with the reaction of bisarylhydrazone 1a in presence of 20 mol
% Cu(OAc)2·H2O in toluene at 60 °C under air, gratifyingly,
we got 1,2,3-triazole 2a in 75% yield after 6 h (see the
Supporting Information). Other reaction parameters were
examined with 1a as a model substrate. Anhydrous Cu(OAc)2
Received: March 21, 2012
© XXXX American Chemical Society
A
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solvents such as dioxane, DMSO, and THF, the product 2a was
obtained in trace to moderate yield. Use of molecular oxygen
led to the formation of 2a in 74% yield, while the reaction
utilizing aqueous 30% H2O2 afforded 2a in 65% yield. In
contrast, under nitrogen atmosphere, the yield of the target
compound 2a was reduced to 30%. A similar result was
observed when either the reaction temperature (40 °C) or the
amount of the copper source (10 mol %) was reduced. Control
experiment confirmed that without the copper source, the
product 2a was not obtained. In brief, condition A provided the
best results for the synthesis of 2,4,5-triaryl-1,2,3-triazoles
(Scheme 1).
Scheme 1. Cu(II)-Catalyzed C−H Functionalization of
Bisarylhydrazones
During further investigation of the reaction conditions,
intriguingly, we found that bisarylhydrazone 1a could readily
undergo reaction with an organic base such as Et3N in toluene
at 60 °C for 30 h under air to give an intermediate that could
was found to be slightly less efficient than the hydrated one,
whereas other copper salts gave inferior results. In polar
a c
−
Table 1. Copper(II)-Catalyzed Synthesis of 2,4,5-Triaryl-1,2,3-Triazoles
a
b
Conditions: Bisarylhydrazones 1a−n (0.5 mmol) and Cu(OAc)2·H2O (20 mol %) were stirred in toluene (2 mL) at 60 °C under air. Aldehydes
c
(5−10%) were obtained as byproduct. Isolated yield.
B
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Scheme 2. Copper(II)-Catalyzed Synthesis of Unsymmetrically Substituted 1,2,3-Triazole
a c
−
Table 2. Copper(II)-Catalyzed Synthesis of 1,3,5-Triaryl-1,2,4-Triazoles
a
Conditions: Bisarylhydrazones 1a−l and 1o−r (0.5 mmol) in the presence of DABCO (1 equiv) were stirred in dioxane (2 mL) at 60 °C for 30 h
under air, the resulting mixture was treated with Cu(OAc)2·H2O (10 mol %) at rt under air, and the stirring was continued for the appropriate time.
b
c
Aldehydes (2−10%) were obtained as byproduct. Isolated yield.
proceed reaction further with 10 mol % Cu(OAc)2·H2O at
room temperature to afford 1,3,5-triaryl-1,2,4-triazole 3a in 55%
yield (see the Supporting Information). Having this important
result in our hand, we went on further to screen the other
reaction parameters with 1a as a model substrate. Employing
other organic bases and solvents led to find DABCO and
dioxane as the choice of base and solvent, respectively. In
contrast, the reactions with inorganic bases were found to be
ineffective. The catalytic activity of the other copper sources
such as Cu(OAc)2, CuCl2, Cu(OTf)2, CuCl, and CuI was
C
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Scheme 3. Copper(II)-Catalyzed Synthesis of Unsymmetrically Substituted 1,2,4-Triazole
examined, and Cu(II) salts were found to be superior to Cu(I)
salts to afford the product 3a in high yield. When the amount of
the copper source (5 mol %) or quantity of the base (0.5 equiv)
was reduced, the yield of 3a was significantly dropped. Control
experiment revealed that in the absence of the copper source,
no cyclization was observed to give the target heterocycle 3a.
As a whole, condition B was fascinated to be the best for the
synthesis of 1,3,5-triaryl-1,2,4-triazoles (Scheme 1).
3n,o, respectively, in 61−82% yield. Bisarylhydrazone 1i with
both electron-donating and -withdrawing substituents on the
aryl ring cyclized to give 1,2,4-triazole 3i in 72% yield. In
addition, bisarylhydrazones 1l and 1o having trimethoxy
substituents in the aromatic rings could be converted into the
corresponding substituted 1,2,4-triazoles 3l and 3m in 58−68%
yield. Furthermore, the substrates 1j and 1k underwent reaction
to give substituted 1,2,4-triazoles 3j and 3k, respectively, in 85−
86% yield. The single crystal of the compound 3c obtained
from acetonitrile solution was analyzed by X-ray analysis (see
the Supporting Information).
Synthesis of Unsymmetrically Substituted 1,2,4-
Triazole. The reaction condition B could also be readily
employed for the synthesis of unsymmetrical 1,3,5-triaryl-1,2,4-
triazoles. For an example, a 1:1 mixture of hydrazones 1a and
1c underwent reaction to give the corresponding unsym-
metrical 1,2,4-triazole 3q in 68% yield along with the
symmetrical 1,2,4-triazoles 3a and 3c as minor products
(Scheme 3).
Substrate Scope for the Synthesis of 1,2,3-Triazoles
(Condition A). Having the optimal conditions in hand, we set
out to explore the scope of the reactions of a wide range of
readily accessible bisarylhydrazones by employing condition A.
The reaction was general, and a series of substrates readily
proceeded cyclization to give the target molecules in moderate
to high yields. For example, bisarylhydrazones 1a−n underwent
reaction to give the substituted 1,2,3-triazoles 2a−n in 45−90%
yields (Table 1). Bisarylhydrazones 1b−e, 1h, and 1m bearing
electron-withdrawing substituents on the arenes led to give
2b−e, 2h, and 2m in 56−90% yields. While bisarylhydrazones
1a, 1f, and 1n having electron-donating substituents on the aryl
rings proceeded cyclization to afford the corresponding
heterocycles 2a, 2f, and 2n in 45−87% yield. Furthermore,
bisarylhydrazone 1i having both electron-withdrawing and
electron-donating substituents on the arenes could afford the
target heterocycle 2i in 66% yield. The substrate 1g with
unsubstituted arenes afforded 2g in 85% yield. The substrate 1l
bearing trimethoxy substituents on the aryl ring underwent
reaction to provide the substituted 1,2,3-triazole 2l in 66%
yield. Arylhydrazones 1j and 1k containing furanyl and
thiophenyl moieties also proceeded cyclization to provide the
target heterocycles 2j and 2k, respectively, in moderate yield.
Under this condition, alkyl arylhydrazones were not stable and
underwent decomposition to give aldehydes. For structural
confirmation, the single crystal of the compound 2f, grown
from acetonitrile solution, was analyzed by single crystal X-ray
analysis (see the Supporting Information).
Synthesis of Unsymmetrically Substituted 1,2,3-
Triazole. The reaction condition A was also compatible for
the synthesis of unsymmetrical 2,4,5-triaryl-1,2,3-triazoles. For
an example, bisarylhydrazones 1a and 1c readily proceeded in
reaction to give the unsymmetrical 2,4,5-triaryl-1,2,3-triazole 2o
in 70% yield along with the symmetrically substituted 1,2,3-
triazoles 2a and 2c as minor products (Scheme 2).
Substrate Scope for the Synthesis of 1,2,4-Triazoles
(Condition B). Next, we explored the scope for the synthesis
of 1,3,5-triayl-1,2,4-triazoles 3a−p with optimal condition B
(Table 2). Bisarylhydrazones 1b−e, 1h, and 1r bearing
electron-withdrawing groups on the aryl rings proceeded
cyclization to give the corresponding substituted triazoles
3b−e, 3h, and 3p in 61−94% yield. Furthermore, the substrates
1a, 1f,g, and 1p,q bearing H or electron-donating substituents
on the aryl rings afforded the target heterocycles 3a, 3f,g and
Mechanistic Studies of the Synthesis of 1,2,3-
Triazoles 2a−n. During the transformation of bisarylhydra-
zone 1a to give the substituted 1,2,3-triazole 2a, we were able to
isolate the intermediate 1a′ (eq 1) as crystals, a dimer of 1a,
whose structure was confirmed by single crystal X-ray analysis
(see the Supporting Information). Next, to get insight about
whether the reaction involves a radical pathway, a radical
inhibition test was carried out. When TEMPO, an effective
radical scavenger, was added to the reaction mixture, the
progress of the reaction was significantly slowed and a mixture
of 2a (7%) and unreacted 1a (55%) was isolated (see the
Supporting Information). This result clearly suggests that the
reaction may involve radical intermediate.
On the basis of the above experimental observations and
literature reports,18 a plausible pathway for the synthesis of
substituted 1,2,3-triazoles has been proposed (Scheme 4).
Thus, bisarylhydrazones 1a−n may transform into the radical
cation C via single-electron transfer (SET) to Cu(II)X2. The
intermediate C could then transform into D by the elimination
of HX. Dimerization of D could lead to the formation of E,
which could isomerize to afford the intermediate F. The latter
could form a radical cation G by reductive elimination of
elemental copper through SET process. The generation of
D
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Scheme 4. Proposed Catalytic Cycle for the Synthesis of Substituted 1,2,3-Triazoles
metallic copper(0) was confirmed by powder XRD analysis
(Figure 1). The sharp peaks at 43.20°, 50.29°, and 73.98°
oxidation under air to give the more stable azo compound K,
which was confirmed by single crystal X-ray analysis of 2h′ (see
the Supporting Information), a byproduct, formed during the
transformation of 1h to 2h (eq 2). The reduced copper(0)
species may be reoxidized by air to regenerate the active
copper(II) species to complete the catalytic cycle.5h,14e
Figure 1. Powder XRD analysis of the recovered copper(0) species.
correspond to the (111), (200), and (220) planes of face-
centered cubic copper(0) (with space group Fm3m, JCPDS 03-
1005).19 Elimination of HX followed by cyclization of G may
lead to the formation of H, which could afford the target
heterocycles 2a−n via elimination of the radical intermediate I.
Dimerization of I may give J, which could readily undergo
Mechanistic Studies of the Synthesis of 1,2,4-
Triazoles 3a−p. To demonstrate the mechanism for the
synthesis of 1,2,4-triazoles 3a−p, the intermediate 1K′, formed
from 1k in presence of organic base (eq 3), was isolated, and its
E
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structure was confirmed by single crystal X-ray analysis (see the
Supporting Information). To our delight, the intermediate 1c″
has also been isolated from 1c when it was treated with organic
base for 30 h followed by the addition of copper catalyst in
presence of air (eq 4). Furthermore, the keto imine
heterocycle 3k. These results clearly suggest that DABCO is
not only acting as a base but also playing a crucial role of an
effective ligand for the copper(II)-catalyzed oxidative cycliza-
tion to give the target heterocycles 3a−p.
The literature reports on copper-catalyzed aerobic oxidative
transformations developed by Chiba20 and Stahl21 facilitate to
unravel the mechanistic route for the synthesis of substituted
1,2,4-triazoles. Observed experimental results and the literature
precedent on copper-catalyzed aerobic oxidative processes22
suggest that the base may mediate the dimerization of
bisarylhydrazones 1a−l and 1o−r to give P via C−N bond
formation (Scheme 5). The aerobic oxidation of P could give
Q, which may lead to the formation of the radical cation R by
single-electron transfer to copper(II) complex derived from
copper(II)-salt with DABCO. The radical intermediate R may
react with copper(I) complex to give copper(II) species S by
elimination of HX. Aerobic oxidation of S may provide the
copper(III)-superoxo species T. Heterocyclization of T may
lead to the formation of benzylic radical U, which may further
be converted into copper(II)-peroxo species V.20a Rearrange-
ment of V could form the intermediate W, which with
elimination of nirosoarenes23 and copper(I) complex may
afford keto imine intermediate X by abstracting hydrogen either
intermediate 1c″, whose structure was confirmed by X-ray
analysis (see the Supporting Information), readily proceeded
with cyclization to give the substituted 1,2,4-triazole 3c when
the reaction was prolonged. To see whether DABCO has any
role in the cyclization step, the reaction of the dimeric
intermediate 1K′ was investigated with 10 mol % Cu-
(OAC)2·H2O in dioxane at room temperature under air.
However, no cyclization was observed, and the intermediate
1K′ was isolated intact. In contrast, when DABCO was added,
the reaction proceeded efficiently to afford the target
Scheme 5. Plausible Catalytic Cycle for the Synthesis of Substituted 1,2,4-Triazoles
F
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Typical Procedure for Gram Scale Synthesis of 2,4,5-
Triphenyl-1,2,3-Triazole 2g. Bisphenylhydrazone 1g (10 mmol,
1.96 g) and Cu(OAc)2·H2O (20 mol %, 0.40 g) were stirred at 60 °C
in toluene (40 mL) under air for 9 h. After cooling to room
temperature, the reaction mixture was passed through a short pad of
silica gel using hexane followed by a mixture of ethyl acetate and
hexane as eluent to afford the target 2,4,5-tripenyl-1,2,3-triazole 2g in
75% (1.11 g) yield.
4,5-Bis(4-methoxyphenyl)-2-phenyl-2H-1,2,3-triazole 2a.
Analytical TLC on silica gel, 1:19 ethyl acetate/hexane Rf = 0.40;
colorless solid: yield 75% (67.0 mg); mp 134−135 °C (lit.24 mp 133
°C); 1H NMR (400 MHz, CDCl3) δ 8.21 (d, J = 8.4 Hz, 2H), 7.62 (d,
J = 8.8 Hz, 4H), 7.50 (t, J = 8.0 Hz, 2H), 7.34 (t, J = 7.6 Hz, 1H), 6.95
(d, J = 8.8 Hz, 4H), 3.81 (s, 6H); 13C NMR (100 MHz, CDCl3) δ
160.0, 145.6, 139.9, 129.8, 129.3, 127.1, 123.4, 118.6, 114.1, 55.33,
55.27; FT-IR (KBr) 2966, 2934, 1614, 1598, 1526, 1493, 1459, 1443,
1435, 1300, 1274, 1248, 1177, 1027 cm−1; m/z (ESI-MS) 358.16 [M +
H]+. Anal. Calcd for C22H19N3O2: C, 73.93; H, 5.36; N, 11.76. Found:
C, 73.86; H, 5.34; N, 11.81.
from water generated during the reaction or from intermediate
Q. The Lewis acid assisted heterocyclization of X may lead to
the target azaheterocycles 3a−p via Y and Z. The active
copper(II) complex could be regenerated by the aerobic
oxidation of copper(I) complex in presence of HX.
Finally, the scale up of the conditions A and B were studied
with 1g as a substrate (Scheme 6). As anticipated, the reactions
were efficient and afforded the corresponding target hetero-
cycles 2g and 3g in 75 and 77% yield, respectively, with slightly
longer reaction time.
Scheme 6. Gram Scale Synthesis of Substituted Triazoles
4,5-Bis(4-bromophenyl)-2-phenyl-2H-1,2,3-triazole 2b. Ana-
lytical TLC on silica gel, 1:49 ethyl acetate/hexane Rf = 0.50; colorless
1
solid: yield 88% (100.0 mg); mp 159−160 °C; H NMR (400 MHz,
CDCl3) δ 8.15 (d, J = 8.0 Hz, 2H), 7.55−7.42 (m, 10H), 7.38 (t, J =
7.2 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 144.9, 139.6, 132.0,
130.0, 129.6, 129.4, 127.8, 123.2, 118.9; FT-IR (KBr) 2917, 1651,
1597, 1497, 1486, 1455, 1392, 1372, 1309, 1284, 1262, 1078, 1072,
1013 cm−1; m/z (ESI-MS) 453.96, 455.97, 457.96 [M + H]+. Anal.
Calcd for C20H13Br2N3: C, 52.78; H, 2.88; N, 9.23. Found: C, 52.87;
H, 2.87; N, 9.18.
4,5-Bis(4-chlorophenyl)-2-phenyl-2H-1,2,3-triazole 2c. Ana-
lytical TLC on silica gel, 1:49 ethyl acetate/hexane Rf = 0.60; colorless
solid: yield 90% (82.4 mg); mp 156−157 °C; H NMR (400 MHz,
1
CONCLUSIONS
■
CDCl3) δ 8.15 (d, J = 7.6 Hz, 2H), 7.55 (d, J = 8.8 Hz, 4H), 7.50 (t, J
= 7.6 Hz, 2H), 7.38−7.35 (m, 5H); 13C NMR (100 MHz, CDCl3) δ
144.9, 139.6, 135.0, 129.8, 129.4, 129.1, 127.8, 118.9; FT-IR (KBr)
1637, 1598, 1496, 1456, 1396, 1372, 1310, 1285, 1264, 1092, 1071,
1016 cm−1; m/z (ESI-MS) 366.06 [M + H]+. Anal. Calcd for
C20H13Cl2N3: C, 65.59; H, 3.58; N, 11.47. Found: C, 65.66; H, 3.60;
N, 11.42.
4,5-Bis(4-carbomethoxyphenyl)-2-phenyl-2H-1,2,3-triazole
2d. Analytical TLC on silica gel, 1:4 ethyl acetate/hexane Rf = 0.50;
colorless solid: yield 66% (68.2 mg); mp 160−161 °C; 1H NMR (400
MHz, CDCl3) δ 8.18 (d, J = 8.4 Hz, 2H), 8.07 (d, J = 8.0 Hz, 4H),
7.70 (d, J = 8.0 Hz, 4H), 7.53 (t, J = 8.0 Hz, 2H), 7.40 (t, J = 7.6 Hz,
1H), 3.93 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 166.8, 145.1,
139.3, 134.8, 130.2, 129.9, 129.3, 128.3, 127.9, 118.8, 52.2; FT-IR
(KBr) 2945, 2923, 1717, 1614, 1593, 1497, 1432, 1404, 1311, 1277,
1176, 1103, 1015 cm−1; m/z (ESI-MS) 414.16 [M + H]+. Anal. Calcd
for C24H19N3O4: C, 69.72; H, 4.63; N, 10.16. Found: C, 69.65; H,
4.64; N, 10.19.
In summary, the intriguing chemistry of copper(II)-catalyzed
oxidative C−H functionalization of bisarylhydrazones for the
regioselective synthesis of 2,4,5-triaryl-1,2,3-triazoles and 1,3,5-
triaryl-1,2,4-triazoles have been exploited under aerobic
conditions. This strategy, carried out under mild reaction
conditions, could be explored in large synthetic scope with wide
functional group compatibility from the readily accessible
substrates. The ground breaking feature with this protocol
involves the synthesis of 1,3,5-triaryl-1,2,4-triazoles by copper-
(II)-catalyzed C−H functionalization at room temperature
using aerobic oxygen as an oxidant. This could introduce a new
incarnation to the scientific endeavor for copper-catalyzed
room temperature C−H functionalization. Although we have
isolated the reactive intermediates to unravel the mechanistic
ubiquity, the detailed mechanism of each elementary step is still
to be illuminated.
4,5-Bis(4-fluorophenyl)-2-phenyl-2H-1,2,3-triazole 2e. Ana-
lytical TLC on silica gel, 1:19 ethyl acetate/hexane Rf = 0.60; colorless
solid: yield 84% (70.0 mg); mp 147−148 °C; H NMR (400 MHz,
EXPERIMENTAL SECTION
■
1
General Procedure for Copper(II)-Catalyzed Synthesis of
2,4,5-Triaryl-1,2,3-Triazoles. Bisarylhydrazones 1a−n (0.5 mmol)
and Cu(OAc)2·H2O (20 mol %, 20.0 mg) were stirred at 60 °C in
toluene (2 mL) under air. After stirring for the appropriate time, the
reaction mixture was cooled to room temperature and passed through
a short pad of silica gel using hexane followed by a mixture of ethyl
acetate and hexane as eluent to accomplish the target 2,4,5-triaryl-
1,2,3-triazoles 2a−n in analytically pure form.
Typical Procedure for Copper(II)-Catalyzed Synthesis of
Unsymmetrical 2,4,5-Triaryl-1,2,3-Triazole 2o. Bisarylhydrazones
1a (0.25 mmol, 56.6 mg) and 1c (0.25 mmol, 57.7 mg) with
Cu(OAc)2·H2O (20 mol %, 20.0 mg) were stirred at 60 °C in toluene
(2 mL) under air. After stirring for 6 h, the reaction mixture was
cooled to room temperature and passed through a short pad of silica
gel using hexane followed by a mixture of ethyl acetate and hexane as
eluent to accomplish the target 2,4,5-triaryl-1,2,3-triazole 2o in 70%
(63.3 mg) yield along with symmetrical 2,4,5-triaryl-1,2,3-triazoles 2a
and 2c in 8% (7.1 mg) and 7% (6.4 mg) yield, respectively.
CDCl3) δ 8.16 (d, J = 8.4 Hz, 2H), 7.61−7.57 (m, 4H), 7.51 (t, J = 8.0
Hz, 2H), 7.37−7.33 (m, 1H), 7.11−7.07 (m, 4H); 13C NMR (100
MHz, CDCl3) δ 164.4, 162.0, 145.0, 139.7, 130.4, 130.3, 129.4, 127.7,
126.9, 118.8, 116.0, 115.8; FT-IR (KBr) 3067, 1605, 1594, 1522, 1498,
1456, 1263, 1225, 1156, 1070 cm−1; m/z (ESI-MS) 334.14 [M + H]+.
Anal. Calcd for C20H13F2N3: C, 72.06; H, 3.93; N, 12.61. Found: C,
72.13; H, 3.92; N, 12.56.
2-Phenyl-4,5-di-p-tolyl-2H-1,2,3-triazole 2f. Analytical TLC on
silica gel, 1:19 ethyl acetate/hexane Rf = 0.50; colorless solid: yield
87% (70.8 mg); mp 144−145 °C (lit.25 mp 145−146 °C); H NMR
1
(400 MHz, CDCl3) δ 8.17 (d, J = 8.4 Hz, 2H), 7.54 (d, J = 8.0 Hz,
4H), 7.50 (t, J = 8.0 Hz, 2H), 7.35−7.31 (m, 1H), 7.20 (d, J = 8.4 Hz,
4H), 2.38 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 146.0, 139.9,
138.5, 129.4, 129.3, 128.5, 128.1, 127.3, 118.8, 21.5; FT-IR (KBr)
3034, 3019, 2912, 1615, 1596, 1496, 1455, 1372, 1288, 1266, 1070
cm−1; m/z (ESI-MS) 326.17 [M + H]+. Anal. Calcd for C22H19N3: C,
81.20; H, 5.89; N, 12.91. Found: C, 81.15; H, 5.90; N, 12.95.
G
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2,4,5-Triphenyl-2H-1,2,3-triazole 2g. Analytical TLC on silica
gel, 1:19 ethyl acetate/hexane Rf = 0.45; colorless solid: yield 85%
2-(4-Methoxyphenyl)-4,5-diphenyl-2H-1,2,3-triazole26 2n.
Analytical TLC on silica gel, 1:9 ethyl acetate/hexane Rf = 0.70;
colorless solid: yield 45% (36.8 mg); mp 103−104 °C (lit.26 mp 101−
(63.2 mg); mp 123−124 °C (lit.25 mp 124−125 °C); H NMR (400
1
1
MHz, CDCl3) δ 8.27 (d, J = 8.4 Hz, 2H), 7.74−7.72 (m, 4H), 7.55 (t,
J = 8.0 Hz, 2H), 7.47−7.43 (m, 6H), 7.40 (t, J = 7.6 Hz, 1H); 13C
NMR (100 MHz, CDCl3) δ 146.1, 139.9, 130.9, 129.4, 128.7, 128.6,
127.5, 118.8; FT-IR (KBr) 1632, 1597, 1496, 1458, 1441, 1375, 1322,
1289, 1266, 1074 cm−1; m/z (ESI-MS) 298.15 [M + H]+. Anal. Calcd
for C20H15N3: C, 80.78; H, 5.08; N, 14.13. Found: C, 80.73; H, 5.10;
N, 14.17.
102 °C); H NMR (400 MHz, CDCl3) δ 8.08 (d, J = 8.8 Hz, 2H),
7.63−7.61 (m, 4H), 7.39−7.37 (m, 6H), 7.00 (d, J = 9.2 Hz, 2H), 3.86
(s, 3H); 13C NMR (100 MHz, CDCl3) δ 159.2, 145.7, 128.8, 128.7,
128.6, 124.5, 120.4, 114.5, 114.3, 55.7; FT-IR (KBr) 2963, 2928, 1603,
1577, 1511, 1459, 1440, 1294, 1260, 1176, 1144, 1102, 1024 cm−1; m/
z (ESI-MS) 328.15 [M + H]+. Anal. Calcd for C21H17N3O: C, 77.04;
H, 5.23; N, 12.84. Found: C, 77.11; H, 5.21; N, 12.81.
2-(4-Chlorophenyl)-4,5-diphenyl-2H-1,2,3-triazole 2h. Ana-
4-(4-Chlorophenyl)-5-(4-methoxyphenyl)-2-phenyl-2H-
1,2,3-triazole 2o. Analytical TLC on silica gel, 1:19 ethyl acetate/
hexane Rf = 0.40; colorless solid: yield 70% (63.3 mg); mp 98−99 °C;
1H NMR (400 MHz, CDCl3) δ 7.97 (d, J = 7.6 Hz, 2H), 7.40−7.33
(m, 4H), 7.28−7.26 (m, 2H), 7.16−7.11 (m, 3H), 6.73−6.71 (m, 2H),
3.59 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 160.2, 145.9, 144.5,
139.7, 134.6, 129.8, 129.7, 129.5, 129.3, 128.9, 127.4, 122.9, 118.7,
114.2, 55.3; FT-IR (KBr) 2962, 1614, 1599, 1497, 1458, 1251, 1175,
1092, 1032 cm−1; m/z (ESI-MS) 362.12 [M + H]+. Anal. Calcd for
C21H16ClN3O: C, 69.71; H, 4.46; N, 11.61. Found: C, 69.80; H, 4.44;
N, 11.58.
General Procedure for Copper(II)-Catalyzed Synthesis of
1,3,5-Triaryl-1,2,4-Triazoles. Bisarylhydrazones 1a−l and 1o−r (0.5
mmol) with DABCO (1 equiv, 56.1 mg) were stirred in dioxane (2
mL) at 60 °C for 30 h under air. After cooling to room temperature,
Cu(OAc)2·H2O (10 mol %, 10.0 mg) was added in the same pot, and
the stirring was continued for the appropriate time at room
temperature under air. After completion of the reaction, the solvent
was concentrated under reduced pressure, and the residue was purified
by column chromatography on silica gel using ethyl acetate and hexane
as eluent to afford the desired heterocycles 3a−p in analytically pure
form.
lytical TLC on silica gel, 1:19 ethyl acetate/hexane Rf = 0.70; colorless
1
solid: yield 56% (46.5 mg); mp 95−96 °C; H NMR (400 MHz,
CDCl3) δ 8.14 (d, J = 9.2 Hz, 2H), 7.66−7.63 (m, 4H), 7.47 (d, J = 8.8
Hz, 2H), 7.41−7.39 (m, 6H); 13C NMR (100 MHz, CDCl3) δ 146.4,
138.4, 133.1, 130.7, 129.5, 129.0, 128.8, 128.6, 120.1; FT-IR (KBr)
3054, 2917, 1492, 1456, 1439, 1410, 1371, 1286, 1263, 1088, 1067
cm−1; m/z (ESI-MS) 332.08 [M + H]+. Anal. Calcd for C20H14ClN3:
C, 72.40; H, 4.25; N, 12.66. Found: C, 72.49; H, 4.23; N, 12.61.
4,5-Bis(4-chlorophenyl)-2-(4-methoxyphenyl)-2H-1,2,3-tria-
zole 2i. Analytical TLC on silica gel, 1:19 ethyl acetate/hexane Rf =
0.60; colorless solid: yield 66% (65.4 mg); mp 127−128 °C; 1H NMR
(400 MHz, CDCl3) δ 8.05 (d, J = 9.2 Hz, 2H), 7.54−7.52 (m, 4H),
7.37−7.35 (m, 4H), 7.00 (d, J = 8.8 Hz, 2H), 3.86 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ 159.3, 144.5, 134.8, 133.5, 129.8, 129.3, 129.1,
120.4, 114.5, 55.7; FT-IR (KBr) 2962, 2923, 1632, 1603, 1510, 1451,
1393, 1297, 1258, 1163, 1093, 1030 cm−1; m/z (ESI-MS) 396.09 [M +
H]+. Anal. Calcd for C21H15Cl2N3O: C, 63.65; H, 3.82; N, 10.60.
Found: C, 63.74; H, 3.83; N, 10.55.
4,5-Di(furan-2-yl)-2-phenyl-2H-1,2,3-triazole 2j. Analytical
TLC on silica gel, 1:19 ethyl acetate/hexane Rf = 0.60; yellow solid:
1
yield 58% (40.2 mg); mp 75−76 °C; H NMR (400 MHz, CDCl3) δ
8.23 (d, J = 8.4 Hz, 2H), 7.654−7.652 (m, 2H), 7.56−7.44 (m, 2H),
7.43−7.30 (m, 1H), 7.09−7.08 (m, 2H), 6.61−6.60 (m, 2H); 13C
NMR (100 MHz, CDCl3) δ 145.1, 143.3, 139.5, 137.4, 129.4, 128.0,
119.2, 111.7, 110.8; FT-IR (KBr) 2963, 1594, 1513, 1491, 1425, 1369,
1294, 1261, 1095, 1030 cm−1; m/z (ESI-MS) 278.07 [M + H]+. Anal.
Calcd for C16H11N3O2: C, 69.31; H, 4.00; N, 15.15. Found: C, 69.39;
H, 3.98; N, 15.11.
Typical Procedure for Copper(II)-Catalyzed Synthesis of
Unsymmetrical 1,3,5-Triaryl-1,2,4-Triazole 3q. Bisarylhydrazones
1a (0.25 mmol, 56.6 mg) and 1c (0.25 mmol, 57.7 mg) with DABCO
(1 equiv, 56.1 mg) were stirred in dioxane (2 mL) at 60 °C for 30 h
under air. After cooling to room temperature, Cu(OAc)2·H2O (10 mol
%, 10.0 mg) was added in the same pot, and the stirring was continued
for 3 h at room temperature under air. After completion of the
reaction, the solvent was concentrated under reduced pressure, and the
residue was purified by column chromatography on silica gel using
ethyl acetate and hexane as eluent to afford unsymmetrical 1,3,5-
triaryl-1,2,4-triazole 3q in 68% (61.5 mg) yield along with symmetrical
1,3,5-triaryl-1,2,4-triazoles 3a and 3c in 10% (8.9 mg) and 8% (7.3
mg) yield, respectively.
Typical Procedure for Gram Scale Synthesis of 1,3,5-
Triphenyl-1,2,4-Triazole 3g. Bisphenylhydrazone 1g (10 mmol,
1.97 g) and DABCO (10 mmol, 1.12 g) were stirred in dioxane (40
mL) at 60 °C for 48 h under air. After cooling to room temperature,
Cu(OAc)2·H2O (10 mol %, 0.20 g) was added in the same pot, and
the stirring was continued for 3.5 h at room temperature under air.
The solvent was concentrated under reduced pressure, and the residue
was purified by column chromatography on silica gel using ethyl
acetate and hexane as eluent to afford 1,3,5-triphenyl-1,2,4-triazole 3g
in 77% (1.14 g) yield.
3,5-Bis(4-methoxyphenyl)-1-phenyl-1H-1,2,4-triazole 3a.
Analytical TLC on silica gel, 1:9 ethyl acetate/hexane Rf = 0.40;
colorless solid: yield 72% (64.3 mg); mp 132−133 °C; 1H NMR (400
MHz, CDCl3) δ 8.17 (d, J = 8.0 Hz, 2H), 7.44 (d, J = 8.0 Hz, 2H),
7.34−7.31 (m, 5H), 6.94 (d, J = 8.0 Hz, 2H), 6.77 (d, J = 8.0 Hz, 2H),
3.72 (s, 3H), 3.65 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 161.4,
160.7, 160.5, 154.3, 138.4, 130.3, 129.2, 128.5, 127.8, 125.3, 123.5,
120.2, 113.8, 55.0; FT-IR (KBr) 2939, 2837, 1611, 1577, 1531, 1498,
1482, 1465, 1426, 1390, 1345, 1301, 1255, 1172, 1108, 1031 cm−1; m/
z (ESI-MS) 358.18 [M + H]+. Anal. Calcd for C22H19N3O2: C, 73.93;
H, 5.36; N, 11.76. Found: C, 74.01; H, 5.35; N, 11.73.
2-Phenyl-4,5-di(thiophen-2-yl)-2H-1,2,3-triazole 2k. Analyti-
cal TLC on silica gel, 1:19 ethyl acetate/hexane Rf = 0.70; orange
1
solid: yield 47% (36.4 mg); mp 80−81 °C; H NMR (400 MHz,
CDCl3) δ 8.14 (d, J = 8.8 Hz, 2H), 7.50−7.40 (m, 5H), 7.37 (d, J = 7.6
Hz, 2H), 7.10−7.08 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 140.6,
139.5, 131.6, 129.7, 129.4, 127.8, 127.7, 127.1, 119.0; FT-IR (KBr)
2961, 1593, 1494, 1421, 1261, 1093, 1026 cm−1; m/z (ESI-MS) 310.05
[M + H]+. Anal. Calcd for C16H11N3S2: C, 62.11; H, 3.58; N, 13.58; S,
20.73. Found: C, 62.02; H, 3.56; N, 13.63; S, 20.79.
4,5-Bis(2,4,5-trimethoxyphenyl)-2-phenyl-2H-1,2,3-triazole
2l. Analytical TLC on silica gel, 1:1 ethyl acetate/hexane Rf = 0.60;
1
brown solid: yield 66% (78.8 mg); mp 138−139 °C; H NMR (400
MHz, CDCl3) δ 8.06 (d, J = 8.4 Hz, 2H), 7.33−7.29 (m, 2H), 7.16−
7.12 (m, 1H), 6.98 (s, 2H), 6.37 (s, 2H), 3.73 (s, 6H), 3.69 (s, 6H),
3.25 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 151.4, 149.7, 144.9,
142.7, 139.6, 128.9, 126.6, 118.3, 113.6, 112.6, 97.4, 56.2, 55.8; FT-IR
(KBr) 2935, 2842, 1614, 1596, 1527, 1497, 1461, 1436, 1399, 1379,
1291, 1261, 1210, 1175, 1102, 1029 cm−1; m/z (ESI-MS) 478.21 [M +
H]+. Anal. Calcd for C26H27N3O6: C, 65.40; H, 5.70; N, 8.80. Found:
C, 65.31; H, 5.69; N, 8.85.
4,5-Bis(3-nitrophenyl)-2-phenyl-2H-1,2,3-triazole 2m. Analyt-
ical TLC on silica gel, 1:1 ethyl acetate/hexane Rf = 0.50; colorless
1
solid: yield 65% (62.9 mg); mp 152−153 °C; H NMR (400 MHz,
CDCl3) δ 8.55−8.54 (m, 2H), 8.29−8.27 (m, 2H), 8.20 (d, J = 8.4 Hz,
2H), 7.92−7.90 (m, 2H), 7.62−7.52 (m, 4H), 7.44 (t, J = 7.6 Hz, 1H);
13C NMR (100 MHz, CDCl3) δ 148.7, 143.9, 139.2, 134.0, 131.9,
130.1, 129.8, 129.6, 128.5, 123.9, 123.3, 119.0; FT-IR (KBr) 1595,
1537, 1509, 1488, 1466, 1374, 1347, 1303, 1262, 1168, 1100, 1072,
1023 cm−1; m/z (ESI-MS) 388.12 [M + H]+. Anal. Calcd for
C20H13N5O4: C, 62.01; H, 3.38; N, 18.08. Found: C, 62.09; H, 3.37;
N, 18.05.
3,5-Bis(4-bromophenyl)-1-phenyl-1H-1,2,4-triazole 3b. Ana-
lytical TLC on silica gel, 1:19 ethyl acetate/hexane Rf = 0.50; gummy
liquid: yield 94% (106.9 mg); 1H NMR (400 MHz, CDCl3) δ 8.08 (d,
J = 8.8 Hz, 2H), 7.59 (d, J = 8.8 Hz, 2H), 7.49−7.37 (m, 9H); 13C
H
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Article
NMR (100 MHz, CDCl3) δ 161.1, 153.7, 138.0, 131.81, 131.75, 130.4,
129.6, 129.5, 129.1, 128.1, 126.7, 125.3, 124.7, 123.7; FT-IR (KBr)
2961, 1638, 1597, 1497, 1470, 1456, 1416, 1404, 1339, 1262, 1173,
1139, 1094, 1070, 1012 cm−1; m/z (ESI-MS) 453.96, 455.93, 457.95
[M + H]+. Anal. Calcd for C20H13Br2N3: C, 52.78; H, 2.88; N, 9.23.
Found: C, 52.72; H, 2.89; N, 9.25.
3,5-Bis(4-chlorophenyl)-1-(4-methoxyphenyl)-1H-1,2,4-tria-
zole 3i. Analytical TLC on silica gel, 1:19 ethyl acetate/hexane Rf =
0.50; colorless solid: yield 72% (71.3 mg); mp 191−192 °C; 1H NMR
(400 MHz, CDCl3) δ 8.14 (d, J = 8.8 Hz, 2H), 7.49 (d, J = 8.8 Hz,
2H), 7.42 (d, J = 8.4 Hz, 2H), 7.33−7.28 (m, 4H), 6.96 (d, J = 8.8 Hz,
2H), 3.84 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 160.8, 160.1,
153.9, 136.4, 135.5, 130.6, 130.2, 128.92, 128.86, 128.5, 127.8, 126.9,
125.9, 114.7, 55.5; FT-IR (KBr) 2955, 2928, 1599, 1509, 1469, 1459,
1424, 1406, 1307, 1251, 1170, 1137, 1102, 1087, 1027, 1013 cm−1; m/
z (ESI-MS) 396.08 [M + H]+. Anal. Calcd for C21H15Cl2N3O: C,
63.65; H, 3.82; N, 10.60. Found: C, 63.55; H, 3.83; N, 10.64.
3,5-Di(furan-2-yl)-1-phenyl-1H-1,2,4-triazole 3j. Analytical
TLC on silica gel, 1:5 ethyl acetate/hexane Rf = 0.30; gummy liquid:
yield 85% (58.9 mg); 1H NMR (400 MHz, CDCl3) δ 7.63 (d, J = 8.4
Hz, 1H), 7.53−7.45 (m, 5H), 7.36−7.32 (m, 1H), 7.11−7.10 (m, 1H),
6.52−6.51 (m, 2H), 6.41−6.39 (m, 1H); 13C NMR (100 MHz,
CDCl3) δ 156.1, 155.0, 144.3, 144.1, 143.2, 137.4, 129.4, 129.1, 128.7,
125.8, 119.9, 113.1, 111.5, 109.9; FT-IR (KBr) 2963, 1599, 1508,
1497, 1437, 1319, 1261, 1094, 1075, 1016 cm−1; m/z (ESI-MS) 278.11
[M + H]+. Anal. Calcd for C16H11N3O2: C, 69.31; H, 4.00; N, 15.15.
Found: C, 69.23; H, 4.01; N, 15.19.
3,5-Bis(4-chlorophenyl)-1-phenyl-1H-1,2,4-triazole 3c. Ana-
lytical TLC on silica gel, 1:19 ethyl acetate/hexane Rf = 0.50; colorless
1
solid: yield 88% (80.6 mg); mp 133−134 °C; H NMR (400 MHz,
CDCl3) δ 8.15 (d, J = 8.4 Hz, 2H), 7.48−7.38 (m, 9H), 7.33 (d, J = 8.4
Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 161.0, 153.8, 138.0, 136.3,
135.4, 130.2, 129.6, 129.2, 128.9, 128.7, 127.9, 127.2, 126.2, 125.4,
112.7; FT-IR (KBr) 1644, 1598, 1498, 1471, 1455, 1408, 1337, 1178,
1136, 1086, 1014 cm−1; m/z (ESI-MS) 366.07 [M + H]+. Anal. Calcd
for C20H13Cl2N3: C, 65.59; H, 3.58; N, 11.47. Found: C, 65.68; H,
3.56; N, 11.44.
3,5-Bis(4-carbomethoxyphenyl)-1-phenyl-1H-1,2,4-triazole
3d. Analytical TLC on silica gel, 1:4 ethyl acetate/hexane Rf = 0.30;
colorless solid: yield 61% (63.1 mg); mp 135−136 °C; 1H NMR (400
MHz, CDCl3) δ 8.30 (d, J = 8.4 Hz, 2H), 8.13 (d, J = 8.4 Hz, 2H),
8.02 (d, J = 8.4 Hz, 2H), 7.63 (d, J = 8.4 Hz, 2H), 7.46−7.43 (m, 2H),
7.42−7.37 (m, 3H), 3.92 (s, 3H), 3.90 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 166.8, 166.3, 161.3, 154.1, 137.9, 134.8, 131.9, 131.5, 130.9,
130.0, 129.8, 129.7, 129.4, 129.0, 126.5, 125.5, 52.4, 52.2; FT-IR (KBr)
2923, 2851, 1719, 1637, 1613, 1497, 1434, 1418, 1341, 1277, 1138,
1108, 1017 cm−1; m/z (ESI-MS) 414.17 [M + H]+. Anal. Calcd for
C24H19N3O4: C, 69.72; H, 4.63; N, 10.16. Found: C, 69.64; H, 4.61;
N, 10.21.
1-Phenyl-3,5-di(thiophen-2-yl)-1H-1,2,4-triazole 3k. Analyti-
cal TLC on silica gel, 1:4 ethyl acetate/hexane Rf = 0.50; gummy
liquid: yield 86% (66.5 mg); 1H NMR (400 MHz, CDCl3) δ 7.80 (d, J
= 3.6 Hz, 1H), 7.54−7.49 (m, 5H), 7.39−7.36 (m, 2H), 7.12−7.10 (m,
1H), 7.08 (d, J = 4.0 Hz, 1H), 6.96−6.94 (m, 1H); 13C NMR (100
MHz, CDCl3) δ 157.1, 149.0, 136.6, 132.3, 129.1, 128.8, 128.3, 128.0,
126.9, 126.8, 126.0, 125.9; FT-IR (KBr) 3090, 3071, 1594, 1549, 1499,
1469, 1451, 1434, 1393, 1314, 1229, 1107, 1075 cm−1; m/z (ESI-MS)
310.02 [M + H]+. Anal. Calcd for C16H11N3S2: C, 62.11; H, 3.58; N,
13.58; S, 20.73. Found: C, 62.19; H, 3.57; N, 13.54; S, 20.70.
3,5-Bis(2,4,5-trimethoxyphenyl)-1-phenyl-1H-1,2,4-triazole
3l. Analytical TLC on silica gel, 1:1 ethyl acetate/hexane Rf = 0.20;
3,5-Bis(4-fluorophenyl)-1-phenyl-1H-1,2,4-triazole 3e. Ana-
lytical TLC on silica gel, 1:19 ethyl acetate/hexane Rf = 0.45; colorless
1
solid: yield 79% (65.8 mg); mp 101−102 °C; H NMR (400 MHz,
CDCl3) δ 8.21−8.17 (m, 2H), 7.55−7.51 (m, 2H), 7.45−7.38 (m,
5H), 7.15 (t, J = 8.8 Hz, 2H), 7.06 (t, J = 8.8 Hz, 2H); 13C NMR (100
MHz, CDCl3) δ 164.3, 161.8, 160.4, 153.2, 137.5, 130.5, 130.4, 128.9,
128.6, 128.4, 128.0, 127.9, 126.4, 124.8, 123.5, 115.3, 115.12, 115.06,
114.9; FT-IR (KBr) 3061, 1604, 1599, 1529, 1499, 1483, 1462, 1451,
1422, 1385, 1343, 1217, 1159, 1141, 1098 cm−1; m/z (ESI-MS) 334.13
[M + H]+. Anal. Calcd for C20H13F2N3: C, 72.06; H, 3.93; N, 12.61.
Found: C, 72.13; H, 3.94; N, 12.57.
1
gummy liquid: yield 58% (69.2 mg); H NMR (400 MHz, CDCl3) δ
7.57 (s, 1H), 7.35−7.26 (m, 5H), 7.17 (s, 1H), 6.61 (s, 1H), 6.33 (s,
1H), 3.90−3.88 (m, 9H), 3.85 (s, 6H), 3.19 (s, 3H); 13C NMR (100
MHz, CDCl3) δ 170.6, 159.6, 152.1, 151.4, 151.1, 150.2, 142.9, 142.7,
138.8, 128.3, 127.3, 122.9, 113.7, 113.5, 111.4, 108.3, 98.1, 96.7, 59.9,
56.7, 56.1, 55.6, 54.9, 53.3; FT-IR (KBr) 2933, 2840, 1612, 1504,
1465, 1437, 1375, 1276, 1214, 1171, 1028 cm−1; m/z (ESI-MS) 478.18
[M + H]+. Anal. Calcd for C26H27N3O6: C, 65.40; H, 5.70; N, 8.80.
Found: C, 65.50; H, 5.68; N, 8.76.
1-Phenyl-3,5-di-p-tolyl-1H-1,2,4-triazole 3f. Analytical TLC on
silica gel, 1:19 ethyl acetate/hexane Rf = 0.40; colorless solid: yield
80% (65.1 mg); mp 115−116 °C (lit.27 mp 116.5−117 °C) ; 1H NMR
(400 MHz, CDCl3) δ 8.16 (d, J = 8.0 Hz, 2H), 7.46−7.41 (m, 7H),
7.28 (d, J = 8.0 Hz, 2H), 7.16 (d, J = 8.0 Hz, 2H), 2.40 (s, 3H), 2.35
(s, 3H); 13C NMR (100 MHz, CDCl3) δ 161.6, 154.4, 139.8, 138.9,
138.2, 129.1, 128.99, 128.96, 128.6, 128.3, 127.9, 126.3, 125.1, 124.9,
21.14, 21.05; FT-IR (KBr) 3025, 2919, 2857, 1613, 1595, 1499, 1478,
1462, 1417, 1389, 1344, 1262, 1178, 1139, 1021 cm−1; m/z (ESI-MS)
326.19 [M + H]+. Anal. Calcd for C22H19N3: C, 81.20; H, 5.89; N,
12.91. Found: C, 81.12; H, 5.92; N, 12.96.
3,5-Bis(3,4,5-trimethoxyphenyl)-1-phenyl-1H-1,2,4-triazole
3m. Analytical TLC on silica gel, 2:3 ethyl acetate/hexane Rf = 0.40;
1
gummy liquid: yield 68% (81.2 mg); H NMR (400 MHz, CDCl3) δ
7.38−7.28 (m, 7H), 6.64−6.60 (m, 2H), 3.79−3.66 (m, 12H), 3.52−
3.47 (m, 6H); 13C NMR (100 MHz, CDCl3) δ 161.1, 154.2, 153.1,
152.7, 139.1, 138.8, 138.0, 129.1, 128.7, 125.8, 125.5, 122.3, 106.0,
103.3, 60.4, 55.8, 55.5; FT-IR (KBr) 2932, 2846, 1590, 1497, 1486,
1463, 1418, 1347, 1234, 1127, 1004 cm−1; m/z (ESI-MS) 478.17 [M +
H]+. Anal. Calcd for C26H27N3O6: C, 65.40; H, 5.70; N, 8.80. Found:
C, 65.48; H, 5.71; N, 8.75.
1,3,5-Triphenyl-1H-1,2,4-triazole 3g. Analytical TLC on silica
gel, 1:19 ethyl acetate/hexane Rf = 0.65; colorless solid: yield 82%
(61.0 mg); mp 105−106 °C (lit.28 mp 104−105 °C); H NMR (400
1
3,5-Bis(2-methoxyphenyl)-1-phenyl-1H-1,2,4-triazole 3n.
Analytical TLC on silica gel, 2:3 ethyl acetate/hexane Rf = 0.40;
MHz, CDCl3) δ 8.29 (d, J = 7.2 Hz, 2H), 7.52 (d, J = 8.4 Hz, 2H),
7.42−7.20 (m, 11H); 13C NMR (100 MHz, CDCl3) δ 161.7, 154.5,
138.1, 130.7, 129.8, 129.3, 129.2, 128.8, 128.6, 128.5, 128.4, 127.8,
126.4, 125.2; FT-IR (KBr) 3062, 2923, 1594, 1517, 1496, 1478, 1442,
1397, 1352, 1272, 1262, 1172, 1138, 1070, 1027 cm−1; m/z (ESI-MS)
298.14 [M + H]+. Anal. Calcd for C20H15N3: C, 80.78; H, 5.08; N,
14.13. Found: C, 80.85; H, 5.06; N, 14.09.
1
gummy liquid: yield 61% (54.5 mg); H NMR (400 MHz, CDCl3) δ
8.03 (d, J = 7.6 Hz, 1H), 7.66 (d, J = 7.6 Hz, 1H), 7.42−7.26 (m, 7H),
7.06−7.00 (m, 3H), 6.78 (d, J = 8.4 Hz, 1H), 3.93 (s, 3H), 3.29 (s,
3H); 13C NMR (100 MHz, CDCl3) δ 160.2, 157.5, 156.5, 151.9,
138.9, 131.8, 131.4, 131.0, 130.4, 128.6, 127.7, 123.2, 120.8, 120.4,
111.9, 111.7, 111.6, 111.2, 55.7, 54.6; FT-IR (KBr) 2923, 1629, 1603,
1583, 1498, 1462, 1250, 1160, 1105, 1023 cm−1; m/z (ESI-MS) 358.13
[M + H]+. Anal. Calcd for C22H19N3O2: C, 73.93; H, 5.36; N, 11.76.
Found: C, 73.85; H, 5.37; N, 11.81.
1-(4-Chlorophenyl)-3,5-diphenyl-1H-1,2,4-triazole 3h. Ana-
lytical TLC on silica gel, 1:19 ethyl acetate/hexane Rf = 0.35; colorless
1
solid: yield 62% (51.4 mg); mp 114−115 °C; H NMR (400 MHz,
3,5-Diphenyl-1-m-tolyl-1H-1,2,4-triazole 3o. Analytical TLC
CDCl3) δ 8.21 (d, J = 6.8 Hz, 2H), 7.54 (d, J = 6.8 Hz, 2H), 7.45−7.34
(m, 10H); 13C NMR (100 MHz, CDCl3) δ 162.1, 154.8, 136.8, 134.5,
130.6, 130.2, 129.6, 129.0, 128.8, 128.7, 127.8, 126.6, 126.5; FT-IR
(KBr) 3066, 2923, 1519, 1494, 1478, 1443, 1396, 1352, 1171, 1141,
1094, 1016 cm−1; m/z (ESI-MS) 332.08 [M + H]+. Anal. Calcd for
C20H14ClN3: C, 72.40; H, 4.25; N, 12.66. Found: C, 72.31; H, 4.24; N,
12.71.
on silica gel, 1:9 ethyl acetate/hexane Rf = 0.40; colorless liquid: yield
1
76% (59.2 mg); H NMR (400 MHz, CDCl3) δ 8.25 (d, J = 6.8 Hz,
2H), 7.58 (d, J = 6.8 Hz, 2H), 7.49−7.22 (m, 9H), 7.14 (d, J = 8.0 Hz,
1H), 2.38 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 161.9, 154.8,
139.8, 138.3, 130.9, 130.0, 129.7, 129.5, 129.2, 129.1, 128.7, 128.6,
128.2, 126.7, 126.1, 122.7, 21.4; FT-IR (KBr) 3064, 2956, 2917, 1610,
I
dx.doi.org/10.1021/jo300592t | J. Org. Chem. XXXX, XXX, XXX−XXX

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Article
1591, 1517, 1491, 1478, 1443, 1395, 1352, 1262, 1173, 1137, 1071,
1027, 1012 cm−1; m/z (ESI-MS) 312.17 [M + H]+. Anal. Calcd for
C21H17N3: C, 81.00; H, 5.50; N, 13.49. Found: C, 81.08; H, 5.48; N,
13.44.
Hasegawa, C.; Hiroya, K.; Doi, T. Org. Lett. 2008, 10, 5147.
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Am. Chem. Soc. 2010, 132, 9602. (v) Ackermann, L. Chem. Rev. 2011,
111, 1315.
1-(4-Fluorophenyl)-3,5-diphenyl-1H-1,2,4-triazole 3p. Analyt-
ical TLC on silica gel, 1:19 ethyl acetate/hexane Rf = 0.40; orange
1
solid: yield 71% (56.0 mg); mp 100−101 °C; H NMR (400 MHz,
(2) For examples of Rh-catalyzed reactions, see: (a) Stokes, B. J.;
Dong, H.; Leslie, B. E.; Pumphrey, A. L.; Driver, T. G. J. Am. Chem.
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Maxwell, A. C.; Williams, J. M. J. Org. Lett. 2010, 12, 3856. (b) Murai,
S.; Kakiuchi, F.; Sekine, S.; Tanaka, Y.; Kamatani, A.; Sonoda, M.;
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CDCl3) δ 8.22 (d, J = 6.8 Hz, 2H), 7.54−7.47 (m, 2H), 7.46−7.34 (m,
8H), 7.14−7.10 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 163.7,
162.1, 161.3, 155.0, 134.5, 130.7, 130.3, 129.7, 129.1, 128.81, 128.76,
127.9, 127.5, 127.4, 126.7, 116.7, 116.4; FT-IR (KBr) 2923, 2851,
1637, 1509, 1478, 1440, 1399, 1352, 1219, 1155, 1097, 1067 cm−1; m/
z (ESI-MS) 316.13 [M + H]+. Anal. Calcd for C20H14FN3: C, 76.18;
H, 4.47; N, 13.33. Found: C, 76.11; H, 4.45; N, 13.39.
5-(4-Chlorophenyl)-3-(4-methoxyphenyl)-1-phenyl-1H-
1,2,4-triazole 3q. Analytical TLC on silica gel, 1:9 ethyl acetate/
hexane Rf = 0.40; colorless solid: yield 68% (61.5 mg); mp 149−151
1
°C; H NMR (400 MHz, CDCl3) δ 8.14 (d, J = 9.2 Hz, 2H), 7.48−
7.40 (m, 7H), 7.33 (d, J = 8.8 Hz, 2H), 6.98 (d, J = 9.2 Hz, 2H), 3.85
(s, 3H); 13C NMR (100 MHz, CDCl3) δ 160.7, 153.4, 138.0, 136.1,
130.2, 129.44, 129.37, 128.9, 128.8, 128.0, 127.8, 125.4, 123.2, 114.0,
55.2; FT-IR (KBr) 2991, 1613, 1596, 1499, 1471, 1440, 1424, 1250,
1169, 1092, 1027 cm−1; m/z (ESI-MS) 362.09 [M + H]+. Anal. Calcd
for C21H16ClN3O: C, 69.71; H, 4.46; N, 11.61. Found: C, 69.60; H,
4.48; N, 11.64.
ASSOCIATED CONTENT
* Supporting Information
■
(4) For some examples, see: (a) Dai, H.-X.; Stepan, A. F.; Plummer,
M. S.; Zhang, Y.-H.; Yu, J.-Q. J. Am. Chem. Soc. 2011, 133, 7222.
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D.-H.; Engle, K. M.; Shi, B.-F.; Yu, J.-Q. Science 2010, 327, 315.
S
General information, optimization tables, crystal structures and
data (CIF), and NMR (1H and 13C) spectra of 2a−o and 3a−q.
This material is available free of charge via the Internet at
http://pubs.acs.org.
́
(d) Garcia-Rubia, A.; Arrayas, R. G.; Carretero, J. C. Angew. Chem., Int.
Ed. 2009, 48, 6511. (e) Cho, S. H.; Hwang, S. J.; Chang, S. J. Am.
Chem. Soc. 2008, 130, 9254. (f) Daugulis, O.; Do, H,-Q.; Shabashov,
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Chem. Rev. 2010, 110, 1147. (h) Chen, X.; Engle, K. M.; Wang, D.-H.;
Yu, J.-Q. Angew. Chem., Int. Ed. 2009, 48, 5094. (i) Zhang, H.; Ferreira,
E. M.; Stoltz, B. M. Angew. Chem., Int. Ed. 2004, 43, 6144.
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AUTHOR INFORMATION
Corresponding Author
*E-mail: tpunni@iitg.ernet.in.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
(5) For some examples, see: (a) Wendlandt, A. E.; Suess, A. M.;
Stahl, S. S. Angew. Chem., Int. Ed. 2011, 50, 11062. (b) Xiong, T.; Li,
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(c) Bellina, F.; Rossi, S. Adv. Synth. Catal. 2010, 352, 1223. (d) Wei,
Y.; Zhao, H.; Kan, J.; Su, W.; Hong, M. J. Am. Chem. Soc. 2010, 132,
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(g) Chen, X.; Hao, X. S.; Goodhue, C. E.; Yu, J.-Q. J. Am. Chem. Soc.
2006, 128, 6790. (h) Guru, M. M.; Ali, M. A.; Punniyamurthy, T. Org.
Lett. 2011, 13, 1194. (i) Guru, M. M.; Ali, M. A.; Punniyamurthy, T. J.
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Meacham Harrell, C.; Murphy, K. L.; Garson, S. L.; Doran, S. M.;
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We gratefully acknowledge the Department of Science and
Technology, New Delhi, and the Council of Scientific and
Industrial Research, New Delhi, for financial support.
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