Direct Access to 1,3,5-Trisubstituted 1 H -1,2,4-Triazoles from N -Phenylbenzamidines via Copper-Catalyzed Diamination of Aryl Nitriles

Article abstract of DOI:10.1055/s-0035-1562490

A copper-catalyzed formation of C-N/N-N bonds using N-phenylbenzamidines with aryl nitriles has been developed and affords a route to 1,3,5-trisubstituted 1H-1,2,4-triazoles in moderate to excellent yields. The method is operationally simple and environme

Full text of DOI:10.1055/s-0035-1562490

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2016, 48, A–G
paper
A
L. Zhang et al.
Paper
Synthesis
Direct Access to 1,3,5-Trisubstituted 1H-1,2,4-Triazoles from
N-Phenylbenzamidines via Copper-Catalyzed Diamination of Aryl
Nitriles
Lutao Zhanga
Dong Tanga
Jing Gaoa
Jing Wanga
Ping Wua
R2
Cu(I) catalyst
Lewis acid
ligand
CN
NH
R1
N
+
N
N
R2
under air
H
N
R1
R3
25 examples
yields up to 96%
Xu Mengb
Baohua Chen*a
R3
a State Key Laboratory of Applied Organic Chemistry, Lanzhou University,
Lanzhou 730000, P. R. of China
b State Key Laboratory for Oxo Synthesis and Selective Oxidation, Lanzhou
Institute of Chemical Physics, Chinese Academy of Sciences, Lanzhou
730000, P. R. of China
chbh@lzu.edu.cn
Received: 11.04.2016
Accepted after revision: 17.05.2016
Published online: 28.06.2016
icity, this type of reaction is highly appealing to modern
chemists.7,8 Recently, Zhang and co-workers have raised the
possibility of producing various 1,2,3-triazoles from N-to-
sylhydrazones and anilines.9 Following the successful trials
on 1,2,4-triazoles, Nagasawa’s group has further contribut-
ed the synthesis of [1,2,3]triazolo[1,5-a]pyridines from
acylpyridines.10 Our group has also reported some facile
methods for the preparation of substituted 1,2,3-triazoles
by means of copper-catalyzed tandem cyclization.11 Addi-
tionally, we discovered certain diamination processes of al-
dehydes,12 as well as acetyl compounds,13 to form different
imidazole skeletons. Herein, we report the synthesis of
1,3,5-trisubstituted 1H-1,2,4-triazoles from readily avail-
able N-phenylbenzamidines and aryl nitriles. The corre-
sponding triazoles were obtained with high regioselectivity
under mild conditions. The reaction involves the sponta-
neous formation of a C–N bond and an N–N bond through
N–H bond cleavage.
We began our observations by taking N-phenylbenz-
amidine (1a) and benzonitrile (2a) as the model substrates.
The results are summarized in Table 1. Our initial attempt
was carried out employing a combination of CuI (10 mol%),
ZnI2 (10 mol%) and phenanthroline (Phen) (10 mol%) in o-
dichlorobenzene (ODCB) at 130 °C under air atmosphere;
the desired product (3aa) was obtained in 36% yield (Table
1, entry 1). The yield dropped when the reaction was car-
ried out at higher or lower temperature. When 2,2′-bipyri-
dine (Bipy) (10 mol%) was used instead of phenanthroline,
the yield was decreased by half (Table 1, entry 2). Other
common solvents, such as DMSO and chlorobenzene, were
tested; reaction in chlorobenzene gave similar results to
that in ODCB solution (Table 1, entries 1, 3, 4). Considering
DOI: 10.1055/s-0035-1562490; Art ID: ss-2016-f0248-op
Abstract A copper-catalyzed formation of C–N/N–N bonds using N-
phenylbenzamidines with aryl nitriles has been developed and affords a
route to 1,3,5-trisubstituted 1H-1,2,4-triazoles in moderate to excellent
yields. The method is operationally simple and environmentally benign
with a large substrate scope available and represents an economical
path for numerous C–N/N–N bond formations.
Key words amination, copper, heterocycles, ring closure, tandem re-
action
1,2,4-Triazoles and their derivatives are mostly used as
polymers, agricultural chemicals and pharmaceuticals.1
General methods for their synthesis have gained booming
attention.2 Traditionally, 1,2,4-triazoles were synthesized
by means of the Einhorn–Brunner reaction or the Pellizzari
reaction.1 Subsequently, they have commonly been pre-
pared by the cyclization of substituted hydrazones with
other nitrogen-containing organic compounds.3 1,2,4-Tri-
azoles have also been reported as products from the reac-
tions of amidines with carboxylic acids4 or DMF.5 In 2009,
Ueda and Nagasawa presented a copper-catalyzed oxidative
process performed by aminopyridines or amidines with ni-
triles.6 However, the building blocks for triazoles often lead
to disubstituted species. Certain approaches for synthesiz-
ing sterically bulky 1,3,5-trisubstituted 1,2,4-triazoles are
somewhat limited, probably on account of unfavorable re-
action conditions.
Copper-catalyzed tandem addition/oxidative cyclization
has become one of the most focused strategies for the gen-
eration of heterocycles. Because of its low cost and low tox-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–G

B
L. Zhang et al.
Paper
Synthesis
Table 1 Optimization of the Reaction Conditionsa
reduced to 64% yield with an amplified temperature of
140 °C (Table 1, entries 17, 18). The presence of side prod-
ucts was not observed.
Ph
NH
N
N
Ph
PhCN
+
With the optimized reaction conditions in hand, the
substrate scope with respect to different kinds of N-phenyl-
benzamidines with various substituents on one or both
phenyl rings was examined (Scheme 1). This reaction could
tolerate N-phenylbenzamidines with electron-donating or
electron-withdrawing moieties. Presumably as a result of
steric hindrance, reagent 1 with alkyl substituent(s) at the
para position(s) provided the desired products in moderate
Ph
Ph
N
H
N
Ph
1a
2a
3aa
Entry Catalyst (equiv)
Additive
Ligand
Solvent
Yieldb (%)
1
2
CuI (0.1)
ZnI2
ZnI2
ZnI2
ZnI2
ZnI2
TBHP
ZnI2
ZnI2
ZnI2
ZnI2
ZnI2
ZnI2
BF3
Phen
Bipy
ODCB
ODCB
PhCl
DMSO
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
36
19
37
16
0
CuI (0.1)
3
CuI (0.1)
Phen
Phen
Phen
–
4
CuI (0.1)
R2
5
AgOAc (0.1)
I2 (0.1)
6
0
CuI (50 mol%)
NH
ZnI2 (10 mol%)
R1
7
CuI (0.5)
Phen
Phen
Phen
Phen
Phen
Phen
Phen
Phen
Phen
Phen
Phen
Phen
56
41
33
19
33
54
46
26
28
55
74
64
N
+
PhCN
N
R2
N
H
8
CuI (1.0)
Phen (10 mol%)
PhCl, 130 °C, 36 h
under air
N
R1
9
Cu(OAc)2 (0.5)
Cu(OTf)2 (0.5)
CuBr (0.5)
CuCl (0.5)
CuI (0.5)
1
2a
3
10
11
12
13
14
15
16c
17d
18e
N
N
N
N
N
N
N
CuI (0.5)
FeCl3
I2
N
N
CuI (0.5)
3aa 74%
3ba 69%
3ca 43%
CuI (0.5)
ZnI2
ZnI2
ZnI2
CuI (0.5)
CuI (0.5)
N
N
N
N
N
N
N
a Reaction conditions: 1a (0.2 mmol), 2a (2.0 equiv), additive (10 mol%),
ligand (10 mol%), solvent (1 mL), 130 °C, 24 h; reactions performed under
N
N
air.
b Isolated yield.
c 4 Å MS (100 mg) were added.
d 36 h.
3da 53%
3ea 36%
3fa 62%
OCH3
e 140 °C, 36 h.
N
N
N
N
N
N
N
OCH3
F
N
N
the reduced effort required for reaction workup, chloroben-
zene is a more suitable solvent than ODCB. The use of
AgOAc or I2 without the presence of copper catalyst result-
ed in none of the desired product 3aa (Table 1, entries 5, 6).
When the amount of CuI was increased to 50 mol%, 3aa was
formed in 56% yield; however, higher equivalents of CuI
proved to be detrimental (Table 1, entries 7, 8). Various cop-
per catalysts were examined, including Cu(OAc)2, Cu(OTf)2,
CuBr and CuCl (Table 1, entries 7, 9–12), with the result that
CuI performed best among the copper compounds tested.
Of the Lewis acid additives that were evaluated (ZnI2, BF3,
FeCl3), ZnI2 provided the best outcome (Table 1, entries 7,
13, 14). Interestingly, a 28% yield of 3aa was obtained when
I2 was employed as an additive (Table 1, entry 15). Addition
of 4 Å molecular sieves had no significant effect on the yield
(Table 1, entry 16). The yield of 3aa was further improved to
74% with an increased reaction time of 36 hours, but was
3ga 59%
3ha 62%
3ia 47%
Cl
N
N
N
N
N
N
N
Cl
N
Br
N
3ja 58%
3ka 30%
3la 67%
N
N
N
Br
3ma 36%
Scheme 1 Substrate scope of N-phenylbenzamidines
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–G

C
L. Zhang et al.
Paper
Synthesis
to high yields, higher than with 2-alkyl-substituted reac-
tants (products 3ba to 3fa). Reactants 1 with a 4-methoxy
group were also tested, yielding 3ga and 3ha in 59% and
62%, respectively. Halogen-containing N-phenylbenzami-
dines were also tolerated in the reaction. Fluoro-substitut-
ed 3ia was obtained in 47% yield. Chlorinated product 3ja
was obtained in a yield similar to the corresponding me-
thoxy-substituted 3ga, while 3ka was produced in a much
lower yield than 3ha. Reactants 1 with multiple methyl and
bromo substituents gave 3la and 3ma with significantly
different yields, with 3ma lower than 3la.
We then explored the feasibility of the reaction with re-
spect to the aryl nitrile component. Under the standard
conditions, substrates 2 containing various substituents
also performed well (Scheme 2). Nitriles bearing an alkyl or
methoxy group gave a lower yield of product than nitriles
with nitro or halogen substituents. The sterically hindered
ortho-substituted benzonitriles furnished triazoles 3ab and
3ah in lower yield than the para-substituted products;
however, triazoles 3ac and 3ai with the corresponding sub-
stitution at the meta position were attained in the highest
yields. To our delight, 3,4-dichlorobenzonitrile gave a su-
perb 96% yield of 3ak. Additionally, we tested the accessi-
bility of nicotinonitrile in the reaction which resulted in a
73% yield of 3am, similar to the original 3aa. Following the
successful trials with aryl nitriles, we undertook further ex-
periments involving reactants with saturated hydrocarbon
moieties, such as acetonitrile and cyclopropylnitrile. Unfor-
tunately, those attempts did not provide the desired prod-
ucts.
N
CuI (50 mol%)
NH
ZnI2 (10 mol%)
N
Ph
+
N
Ph
N
Phen (10 mol%)
PhCl, 130 °C, 36 h
under air
H
N
R1
R1
1a
2
3
To elucidate the mechanism of this reaction, some con-
trol experiments were carried out (Scheme 3). When the
radical marker TEMPO (2.0 equiv) was added to 1a and 2a
under the otherwise standard conditions, a major reduc-
tion in yield was not detected; hence, a radical process is
unlikely to be implicated (equation A). No product 3aa was
formed in the absence of the ligand phenanthroline, where-
as a 51% yield was obtained without ZnI2, thus proving the
importance of the presence of a ligand (equations B and C).
There was no significant decrease in the yield of 3aa when
the reaction was tested under O2 atmosphere whilst it
dropped to 19% under inert N2, thereby indicating probable
stoichiometric oxidative procedures (equation D).
N
N
N
N
N
N
N
N
N
3ab 26%
3ac 54%
3ad 48%
OCH3
NO2
F
N
N
N
N
N
N
N
N
N
CuI (50 mol%)
ZnI2 (10 mol%)
Phen (10 mol%)
Ph
NH
N
N
(A)
Ph
Ph
+
+
PhCN
3ag 62%
3ae 57%
3af 69%
Ph
Ph
Ph
Ph
N
H
TEMPO
PhCl, 130 °C, 36 h
N
Cl
Ph
Ph
1a
2a
3aa 59%
Cl
N
N
CuI (50 mol%)
Phen (10 mol%)
Ph
Cl
NH
N
N
N
N
N
N
N
N
N
PhCN
(B)
N
H
PhCl, 130 °C, 36 h
N
1a
2a
3aa 51%
CuI (50 mol%)
ZnI2 (10 mol%)
NH
3ah 47%
3ai 81%
3aj 72%
Ph
Ph
+
+
PhCN
(C)
(D)
3aa 0%
Cl
Cl
Br
Ph
Ph
N
H
N
PhCl, 130 °C, 36 h
1a
2a
N
N
N
N
Ph
N
NH
N
N
N
N
standard conditions
N
N
PhCN
Ph
N
H
N
Ph
1a
2a
3aa
under O2 atmosphere
under N2 atmosphere
65%
19%
3ak 96%
3al 87%
3am 73%
Scheme 2 Substrate scope of aryl nitriles
Scheme 3 Control experiments
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–G

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L. Zhang et al.
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Synthesis
A reaction mechanism is proposed on the basis of the
experimental studies and related work in the literature
(Scheme 4).14 Taking the production of 3aa as a model, the
process begins with Cu(I)-promoted activation of N-phenyl-
benzamidine (1a) to form intermediate 1I. Then, via tau-
tomerization, 1II is delivered after release of the proton ad-
jacent to the phenyl-substituted nitrogen. Simultaneously,
benzonitrile (2a) coordinates with Cu(I) to provide 2I and
subsequently 2II. Then, 2II combines with 1II to give inter-
mediate III. Nucleophilic attack of the nitrile by the amidine
results in the formation of intermediate IV, then affords ad-
duct V. Reductive elimination of V delivers the final cyclic
product 3aa. Detached Cu(0) is oxidized to Cu(I) to com-
plete the catalytic cycle; it would further be oxidized to
Cu(II), also catalytically active.8,15 The ligand phenanthro-
line likely provides a linkage between Cu(I) catalysts, as is
shown in Scheme 4. ZnI2, usually employed as a facile Lewis
acid,16 may assist the initial coordination with nitrile.
By way of conclusion, we have developed an efficient
and regioselective access to 1,3,5-trisubstituted 1H-1,2,4-
triazoles from N-phenylbenzamidines and nitriles. This
new route via copper-catalyzed tandem addition/oxidative
cyclization employs easily available substances and toler-
ates a broad range of functional groups.
matography was carried out with Merck silica gel 60 (63–200 mesh).
Analytical TLC was performed with Merck silica gel 60 F254 plates,
and the products were visualized by UV detection. 1H NMR (300
MHz) and 13C NMR (75 MHz) spectra were recorded in CDCl3 on an
Agilent Mercury plus 300 BB spectrometer. Chemical shifts (δ) are re-
ported in ppm using TMS as internal standard. Melting points were
determined on an LJ-XLC microscopic apparatus. HRMS data were re-
corded on a ThermoFisher LTQ Orbitrap XL ETD.
Several compounds are known: 3aa,2e 3ab,18 3ad,18 3ae,18 3ah,18 3aj,18
3am,18 3ga,2e 3ja.17
N-Phenylbenzamidines 1; General Procedure
A 100-mL round-bottomed two-neck flask was charged with an ani-
line (12.0 mmol), a nitrile (10.0 mmol) and NaH (11.0 mmol). The
flask was then evacuated and flushed with N2. DMSO (10 mL) was in-
jected into the mixture at 0 °C. If reactants are liquids, they may be
added subsequently. The mixture was stirred at 0 °C for 45 min, then
at room temperature for 60 min, and was monitored by TLC until re-
action completion. Then, the reaction was quenched with ice–water.
Crystals separated and were collected using a sintered glass funnel.
The crystals were washed multiple times in the funnel with petro-
leum ether, then were ground into a powder and oven-dried. The
powder was further purified by washing with petroleum ether.
1,3,5-Triphenyl-1H-1,2,4-triazole (3aa); Typical Procedure
A sealed tube equipped with a stirrer bar was charged with N-phenyl-
benzamidine (1a; 0.0393 g, 0.2 mmol), benzonitrile (2a; 41 μL, 0.40
mmol), CuI (0.0190 g, 0.10 mmol), ZnI2 (0.0063 g, 0.02 mmol),
phenanthroline (0.0040 g, 0.02 mmol) and chlorobenzene (1 mL). The
All reactions were carried out in oven-dried flasks. Commercially
available reagents were used without further purification. Flash chro-
N
N
CuI
CuI
H
N
CuI
CuI
N
Ph
H
N
C
N
Ph
N
Ph
N
N
III
Ph
IV
N
Ph
Ph
– H+
N
N
CuI
Ph
N
C
2II
Ph
CuI
N
H
N
N
– H+
N
CuI
CuI
N
Ph
N
N
N
Ph
1II
CuI
Ph
N
V
N
Ph
C
CuI
H
Ph
2I
N
2a
CuI
H
N
Ph
1I
N
Ph
3aa
N
CuI
1a
N
N
N
N
Cu0
Cu0
2 CuI
2 Cu0
[O]
N
N
Scheme 4 Possible reaction mechanism
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–G

E
L. Zhang et al.
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Synthesis
resulting mixture was stirred at 130 °C for 36 h. After reaction com-
pletion, the residue was directly purified by flash column chromatog-
raphy (EtOAc–petroleum ether) to afford pure product 3aa.
1H NMR (300 MHz, CDCl3): δ = 8.23 (d, J = 6.4 Hz, 2 H), 7.49–7.39 (m, 5
H), 7.30 (d, J = 8.3 Hz, 2 H), 7.22 (d, J = 8.3 Hz, 2 H), 7.15 (d, J = 8.0 Hz,
2 H), 2.40 (s, 3 H), 2.36 (s, 3 H).
White solid; yield: 44 mg (74%); mp 100–105 °C.
13C NMR (75 MHz, CDCl3): δ = 161.86, 154.96, 140.25, 139.02, 136.15,
131.08, 130.11, 129.40, 129.01, 128.70, 126.75, 125.49, 125.37, 21.60,
21.39.
IR: 3430.2, 1592.1, 1517.8, 1496.1, 1476.3, 1441.6, 1397.9, 1350.4,
1271.9, 1138.5, 1070.7, 1025.8, 990.4, 923.3, 848.4, 771.7, 728.5,
695.3 cm–1
.
HRMS (ESI): m/z [M + H]+ calcd for C22H20N3+: 326.1657; found:
326.1656.
1H NMR (300 MHz, CDCl3): δ = 8.24 (dd, J = 7.9, 1.5 Hz, 2 H), 7.56 (dd,
J = 8.0, 1.4 Hz, 2 H), 7.52–7.32 (m, 11 H).
5-(4-Methoxyphenyl)-1,3-diphenyl-1H-1,2,4-triazole (3ga)
13C NMR (75 MHz, CDCl3): δ = 162.12, 154.93, 138.47, 130.91, 130.18,
129.58, 129.17, 129.00, 128.76, 128.20, 126.78, 125.61.
Yellow solid; yield: 39 mg (59%); mp 97–98 °C.
1H NMR (300 MHz, CDCl3): δ = 8.24 (d, J = 6.5 Hz, 2 H), 7.52–7.36 (m,
10 H), 6.84 (d, J = 8.8 Hz, 2 H), 3.77 (s, 3 H).
HRMS (ESI): m/z [M + H]+ calcd for C20H16N3+: 298.1344; found:
298.1344.
13C NMR (75 MHz, CDCl3): δ = 161.86, 160.96, 154.76, 138.60, 130.98,
130.58, 129.51, 129.43, 128.85, 128.67, 126.68, 125.61, 120.42,
114.10, 55.40.
HRMS (ESI): m/z [M + H]+ calcd for C21H18N3O+: 328.1450; found:
328.1449.
1,3-Diphenyl-5-p-tolyl-1H-1,2,4-triazole (3ba)
White solid; yield: 43 mg (69%); mp 92–97 °C.
1H NMR (300 MHz, CDCl3): δ = 8.24 (dd, J = 8.0, 1.6 Hz, 2 H), 7.49–7.39
(m, 10 H), 7.15 (d, J = 8.1 Hz, 2 H), 2.36 (s, 3 H).
13C NMR (75 MHz, CDCl3): δ = 162.03, 155.07, 140.38, 138.61, 131.00,
129.55, 129.45, 129.05, 128.92, 128.73, 126.77, 125.65, 125.29, 21.62.
HRMS (ESI): m/z [M + H]+ calcd for C21H18N3+: 312.1501; found:
312.1500.
1-(4-Methoxyphenyl)-3,5-diphenyl-1H-1,2,4-triazole (3ha)
Yellow solid; yield: 41 mg (62%); mp 128–130 °C.
1H NMR (300 MHz, CDCl3): δ = 8.24 (d, J = 6.6 Hz, 2 H), 7.56 (d, J = 6.2
Hz, 2 H), 7.49–7.29 (m, 8 H), 6.91 (d, J = 8.9 Hz, 2 H), 3.80 (s, 3 H).
13C NMR (75 MHz, CDCl3): δ = 162.07, 160.17, 155.06, 131.70, 131.24,
3,5-Diphenyl-1-o-tolyl-1H-1,2,4-triazole (3ca)
129.50, 129.19, 128.95, 128.73, 128.43, 127.47, 126.95, 115.06, 56.09.
HRMS (ESI): m/z [M + H]+ calcd for C21H18N3O+: 328.1450; found:
328.1445.
White solid; yield: 27 mg (43%); mp 73–75 °C.
1H NMR (300 MHz, CDCl3): δ = 8.25 (d, J = 6.6 Hz, 2 H), 7.55 (d, J = 6.9
Hz, 2 H), 7.50–7.28 (m, 10 H), 2.06 (s, 3 H).
13C NMR (75 MHz, CDCl3): δ = 162.14, 155.53, 137.92, 135.56, 131.67,
131.06, 130.15, 129.55, 128.77, 128.34, 127.96, 127.90, 127.37,
126.77, 17.78.
HRMS (ESI): m/z [M + H]+ calcd for C21H18N3+: 312.1501; found:
312.1501.
5-(4-Fluorophenyl)-1,3-diphenyl-1H-1,2,4-triazole (3ia)
White solid; yield: 30 mg (47%); mp 98–101 °C.
1H NMR (300 MHz, CDCl3): δ = 8.22 (dd, J = 7.9, 1.7 Hz, 2 H), 7.59–7.51
(m, 2 H), 7.50–7.39 (m, 8 H), 7.05 (t, J = 8.7 Hz, 2 H).
13C NMR (75 MHz, CDCl3): δ = 165.49, 162.14, 154.05, 138.35, 131.33,
131.21, 130.81, 129.71, 129.67, 129.20, 128.80, 126.76, 125.66,
124.41, 116.15, 115.86.
HRMS (ESI): m/z [M + H]+ calcd for C20H15FN3+: 316.1250; found:
316.1252.
3,5-Diphenyl-1-p-tolyl-1H-1,2,4-triazole (3da)
White solid; yield: 33 mg (53%); mp 106–110 °C.
1H NMR (300 MHz, CDCl3): δ = 8.24 (d, J = 6.5 Hz, 2 H), 7.56 (d, J = 8.2
Hz, 2 H), 7.49–7.27 (m, 8 H), 7.22 (d, J = 8.4 Hz, 2 H), 2.40 (s, 3 H).
13C NMR (75 MHz, CDCl3): δ = 161.97, 154.83, 139.12, 136.02, 131.00,
130.14, 130.08, 129.51, 129.14, 128.72, 128.28, 126.76, 125.45, 21.41.
HRMS (ESI): m/z [M + H]+ calcd for C21H18N3+: 312.1501; found:
312.1503.
5-(4-Chlorophenyl)-1,3-diphenyl-1H-1,2,4-triazole (3ja)
White solid; yield: 39 mg (58%); mp 122–125 °C.
1H NMR (300 MHz, CDCl3): δ = 8.22 (d, J = 7.0 Hz, 2 H), 7.53–7.37 (m,
10 H), 7.33 (d, J = 8.5 Hz, 2 H).
13C NMR (75 MHz, CDCl3): δ = 162.24, 153.90, 138.29, 136.44, 130.75,
130.45, 129.76, 129.71, 129.29, 129.10, 128.81, 126.77, 126.64,
125.67.
HRMS (ESI): m/z [M + H]+ calcd for C20H15ClN3+: 332.0955; found:
332.0954.
1-(2-Ethylphenyl)-3,5-diphenyl-1H-1,2,4-triazole (3ea)
White solid; yield: 23 mg (36%); mp 61–65 °C.
1H NMR (300 MHz, CDCl3): δ = 8.25 (d, J = 6.0 Hz, 2 H), 7.55 (d, J = 6.5
Hz, 2 H), 7.50–7.27 (m, 10 H), 2.42 (q, J = 7.6 Hz, 2 H), 1.05 (t, J = 7.8
Hz, 3 H).
13C NMR (75 MHz, CDCl3): δ = 161.95, 155.59, 141.26, 137.40, 131.08,
130.40, 130.12, 130.01, 129.54, 128.77, 128.74, 128.47, 128.06,
127.90, 127.25, 126.77, 24.21, 14.22.
HRMS (ESI): m/z [M + H]+ calcd for C22H20N3+: 326.1657; found:
326.1659.
1-(4-Chlorophenyl)-3,5-diphenyl-1H-1,2,4-triazole (3ka)
White solid; yield: 20 mg (30%); mp 105–110 °C.
1H NMR (300 MHz, CDCl3): δ = 8.22 (d, J = 8.2 Hz, 2 H), 7.55 (d, J = 6.5
Hz, 2 H), 7.51–7.34 (m, 10 H).
13C NMR (75 MHz, CDCl3): δ = 162.35, 155.03, 136.96, 134.78, 130.72,
130.44, 129.78, 129.19, 128.95, 128.82, 127.99, 126.80, 126.72.
3-Phenyl-1,5-di-p-tolyl-1H-1,2,4-triazole (3fa)
White solid; yield: 40 mg (62%); mp 133–136 °C.
HRMS (ESI): m/z [M + H]+ calcd for C20H15ClN3+: 332.0955; found:
332.0953.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–G

F
L. Zhang et al.
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Synthesis
5-(4-Bromophenyl)-3-phenyl-1-p-tolyl-1H-1,2,4-triazole (3la)
13C NMR (75 MHz, CDCl3): δ = 161.99, 160.83, 154.77, 138.51, 130.11,
129.55, 129.16, 128.89, 128.74, 128.28, 128.22, 125.59, 123.64,
114.13, 55.49.
HRMS (ESI): m/z [M + H]+ calcd for C21H18N3O+: 328.1450; found:
328.1452.
White solid; yield: 52 mg (67%); mp 150–155 °C.
1H NMR (300 MHz, CDCl3): δ = 8.21 (d, J = 6.4 Hz, 2 H), 7.59–7.36 (m, 7
H), 7.32–7.25 (m, 4 H), 2.42 (s, 3 H).
13C NMR (75 MHz, CDCl3): δ = 162.13, 153.87, 139.52, 135.82, 132.02,
131.12, 130.83, 130.63, 130.34, 129.64, 129.04, 128.79, 127.18,
126.76, 125.52, 124.70, 21.45.
3-(4-Nitrophenyl)-1,5-diphenyl-1H-1,2,4-triazole (3af)
White solid; yield: 47 mg (69%); mp 169–174 °C.
1H NMR (300 MHz, CDCl3): δ = 8.45–8.36 (m, 2 H), 8.35–8.26 (m, 2 H),
HRMS (ESI): m/z [M + H]+ calcd for C21H17BrN3+: 390.0606; found:
390.0609.
7.59–7.53 (m, 2 H), 7.42 (m, 8 H).
5-(3-Bromo-4-methylphenyl)-3-phenyl-1-p-tolyl-1H-1,2,4-tri-
azole (3ma)
13C NMR (75 MHz, CDCl3): δ = 160.13, 155.57, 148.47, 138.16, 137.03,
130.55, 129.72, 129.42, 129.12, 128.88, 127.65, 127.40, 125.53,
124.13.
HRMS (ESI): m/z [M + H]+ calcd for C20H15N4O2+: 343.1195; found:
343.1195.
White solid; yield: 29 mg (36%); mp 127–130 °C.
1H NMR (300 MHz, CDCl3): δ = 8.21 (d, J = 6.2 Hz, 2 H), 7.54–7.35 (m, 4
H), 7.34–7.24 (m, 5 H), 7.16 (d, J = 8.0 Hz, 1 H), 2.42 (s, 3 H), 2.40 (s, 3
H).
3-(4-Fluorophenyl)-1,5-diphenyl-1H-1,2,4-triazole (3ag)
13C NMR (75 MHz, CDCl3): δ = 162.03, 153.40, 140.16, 139.43, 135.82,
132.90, 130.84, 130.26, 129.60, 128.78, 127.67, 126.77, 125.52, 23.13,
21.46.
White solid; yield: 39 mg (62%); mp 114–119 °C.
1H NMR (300 MHz, CDCl3): δ = 8.22 (dd, J = 8.7, 5.5 Hz, 2 H), 7.55 (dd,
J = 7.9, 1.2 Hz, 2 H), 7.46–7.32 (m, 8 H), 7.14 (t, J = 8.7 Hz, 2 H).
HRMS (ESI): m/z [M + H]+ calcd for C22H19BrN3+: 404.0762; found:
13C NMR (75 MHz, CDCl3): δ = 165.48, 162.20, 161.34, 155.00, 138.40,
130.25, 129.61, 129.14, 129.07, 128.79, 128.75, 128.63, 128.09,
127.17, 125.58, 115.90, 115.62.
404.0766.
1,5-Diphenyl-3-o-tolyl-1H-1,2,4-triazole (3ab)
HRMS (ESI): m/z [M + H]+ calcd for C20H15FN3+: 316.1250; found:
White solid; yield: 16 mg (26%); mp 73–78 °C.
1H NMR (300 MHz, CDCl3): δ = 8.08 (dd, J = 5.3, 2.1 Hz, 1 H), 7.57 (d,
J = 7.5 Hz, 2 H), 7.47–7.27 (m, 11 H), 2.73 (s, 3 H).
316.1250.
3-(2-Chlorophenyl)-1,5-diphenyl-1H-1,2,4-triazole (3ah)
13C NMR (75 MHz, CDCl3): δ = 153.98, 138.58, 137.52, 131.35, 130.13,
White solid; yield: 31 mg (47%); mp 94–99 °C.
129.82, 129.52, 129.24, 129.14, 128.85, 128.76, 125.95, 125.50, 22.09.
1H NMR (300 MHz, CDCl3): δ = 8.02 (dd, J = 6.0, 3.5 Hz, 1 H), 7.57 (d,
J = 6.7 Hz, 2 H), 7.52 (dd, J = 5.9, 3.4 Hz, 1 H), 7.47–7.33 (m, 10 H).
HRMS (ESI): m/z [M + H]+ calcd for C21H18N3+: 312.1501; found:
312.1500.
13C NMR (75 MHz, CDCl3): δ = 160.68, 154.32, 138.34, 133.18, 131.85,
131.68, 130.52, 130.10, 129.80, 129.36, 129.01, 128.00, 127.07,
126.62, 125.81, 125.37.
HRMS (ESI): m/z [M + H]+ calcd for C20H15ClN3+: 332.0955; found:
332.0956.
1,5-Diphenyl-3-m-tolyl-1H-1,2,4-triazole (3ac)
White solid; yield: 34 mg (54%); mp 100–103 °C.
1H NMR (300 MHz, CDCl3): δ = 8.08 (d, J = 0.6 Hz, 1 H), 8.04 (d, J = 8.1
Hz, 1 H), 7.57 (t, J = 1.4 Hz, 1 H), 7.54 (d, J = 1.7 Hz, 1 H), 7.43–7.32 (m,
10 H), 2.43 (s, 3 H).
3-(3-Chlorophenyl)-1,5-diphenyl-1H-1,2,4-triazole (3ai)
13C NMR (75 MHz, CDCl3): δ = 162.24, 154.89, 138.43, 130.74, 130.39,
130.16, 129.58, 129.17, 128.99, 128.75, 128.69, 128.21, 127.35,
125.62, 123.92, 21.59.
White solid; yield: 53 mg (81%); mp 138–141 °C.
1H NMR (300 MHz, CDCl3): δ = 8.28–8.24 (m, 1 H), 8.14–8.10 (m, 1 H),
7.56–7.54 (m, 1 H), 7.53 (dd, J = 1.7, 0.5 Hz, 1 H), 7.43–7.34 (m, 10 H).
HRMS (ESI): m/z [M + H]+ calcd for C21H18N3+: 312.1501; found:
13C NMR (75 MHz, CDCl3): δ = 160.91, 155.08, 138.30, 134.81, 132.70,
130.30, 130.06, 129.61, 129.11, 128.79, 127.93, 126.82, 125.54,
125.35, 124.80.
312.1505.
1,5-Diphenyl-3-p-tolyl-1H-1,2,4-triazole (3ad)
HRMS (ESI): m/z [M + H]+ calcd for C20H15ClN3+: 332.0955; found:
White solid; yield: 30 mg (48%); mp 138–142 °C.
1H NMR (300 MHz, CDCl3): δ = 8.13 (d, J = 8.1 Hz, 2 H), 7.55 (dd, J = 7.8,
332.0954.
1.3 Hz, 2 H), 7.43–7.26 (m, 10 H), 2.40 (s, 3 H).
3-(4-Chlorophenyl)-1,5-diphenyl-1H-1,2,4-triazole (3aj)
13C NMR (75 MHz, CDCl3): δ = 162.20, 154.81, 139.54, 138.50, 130.13,
129.56, 129.48, 129.30, 129.18, 128.93, 128.74, 128.26, 128.11,
126.70, 125.61, 21.66.
White solid; yield: 48 mg (72%); mp 126–130 °C.
1H NMR (300 MHz, CDCl3): δ = 8.21–8.18 (m, 1 H), 8.17–8.15 (m, 1 H),
7.55 (t, J = 1.4 Hz, 1 H), 7.53 (t, J = 2.0 Hz, 1 H), 7.45–7.32 (m, 10 H).
HRMS (ESI): m/z [M + H]+ calcd for C21H18N3+: 312.1501; found:
13C NMR (75 MHz, CDCl3): δ = 161.19, 155.05, 138.34, 135.47, 130.53,
130.30, 130.06, 129.83, 129.59, 129.47, 129.32, 129.12, 129.01,
128.90, 128.78, 128.06, 128.00, 125.78.
312.1499.
3-(4-Methoxyphenyl)-1,5-diphenyl-1H-1,2,4-triazole (3ae)
HRMS (ESI): m/z [M + H]+ calcd for C20H15ClN3+: 332.0955; found:
Yellow solid; yield: 37 mg (57%); mp 109–114 °C.
1H NMR (300 MHz, CDCl3): δ = 8.17 (d, J = 8.4 Hz, 2 H), 7.55 (d, J = 7.5
Hz, 2 H), 7.47–7.31 (m, 8 H), 6.99 (d, J = 8.5 Hz, 2 H), 3.86 (s, 3 H).
332.0957.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–G

G
L. Zhang et al.
Paper
Synthesis
3-(3,4-Dichlorophenyl)-1,5-diphenyl-1H-1,2,4-triazole (3ak)
(2) (a) Xu, H.; Ma, S.; Xu, Y.; Bian, L.; Ding, T.; Fang, X.; Zhang, W.;
Ren, Y. J. Org. Chem. 2015, 80, 1789. (b) Liu, X.; Wang, D.; Chen,
B. Tetrahedron 2013, 69, 9417. (c) Lee, J.; Hong, M.; Jung, Y.; Cho,
E. J.; Rhee, H. Tetrahedron 2012, 68, 2045. (d) Al-Soud, Y. A.;
Heydel, M.; Hartmann, R. W. Tetrahedron Lett. 2011, 52, 6372.
(e) Su, W.; Yang, D.; Li, J. Synth. Commun. 2005, 35, 1435.
(3) (a) Ito, S.; Tanaka, Y.; Kakehi, A.; Fukuyama, T.; Osawa, N.; Sayo,
N. Bull. Chem. Soc. Jpn. 1983, 56, 545. (b) Hoque, A. K. M. M.;
Kovelesky, A. C.; Wang-Keun, L.; Shine, H. J. Tetrahedron Lett.
1985, 26, 5655. (c) Staben, S. T.; Blaquiere, N. Angew. Chem. Int.
Ed. 2010, 49, 325. (d) Guru, M. M.; Punniyamurthy, T. J. Org.
Chem. 2012, 77, 5063.
White solid; yield: 70 mg (96%); mp 65–70 °C.
1H NMR (300 MHz, CDCl3): δ = 8.36 (d, J = 1.5 Hz, 1 H), 8.06 (dd, J = 8.4,
1.9 Hz, 1 H), 7.57–7.50 (m, 3 H), 7.46–7.33 (m, 8 H).
13C NMR (75 MHz, CDCl3): δ = 160.18, 155.24, 138.25, 133.52, 133.09,
131.00, 130.81, 130.42, 129.67, 129.26, 129.11, 128.84, 128.60,
127.82, 125.90, 125.55.
HRMS (ESI): m/z [M + H]+ calcd for C20H14Cl2N3+: 366.0565; found:
366.0561.
3-(4-Bromophenyl)-1,5-diphenyl-1H-1,2,4-triazole (3al)
(4) Castanedo, G. M.; Seng, P. S.; Blaquiere, N.; Trapp, S.; Staben, S.
T. J. Org. Chem. 2011, 76, 1177.
(5) Huang, H.; Guo, W.; Wu, W.; Li, C. J.; Jiang, H. Org. Lett. 2015, 17,
2894.
White solid; yield: 65 mg (87%); mp 147–151 °C.
1H NMR (300 MHz, CDCl3): δ = 8.11 (d, J = 8.5 Hz, 2 H), 7.58 (d, J = 8.5
Hz, 2 H), 7.54 (d, J = 6.7 Hz, 2 H), 7.44–7.32 (m, 8 H).
13C NMR (75 MHz, CDCl3): δ = 161.21, 155.05, 138.32, 137.88, 131.92,
130.28, 129.91, 129.60, 129.11, 128.78, 128.44, 128.32, 127.97,
125.54, 123.80.
(6) Ueda, S.; Nagasawa, H. J. Am. Chem. Soc. 2009, 131, 15080.
(7) Liao, Q.; Yang, X.; Xi, C. J. Org. Chem. 2014, 79, 8507.
(8) Li, J.; Neuville, L. Org. Lett. 2013, 15, 1752.
(9) Chen, Z.; Yan, Q.; Liu, Z.; Xu, Y.; Zhang, Y. Angew. Chem. Int. Ed.
2013, 52, 13324.
(10) Hirayama, T.; Ueda, S.; Okada, T.; Tsurue, N.; Okuda, K.;
Nagasawa, H. Chem. Eur. J. 2014, 20, 4156.
(11) (a) Zhang, Y.; Li, X.; Li, J.; Chen, J.; Meng, X.; Zhao, M.; Chen, B.
Org. Lett. 2012, 14, 26. (b) Wang, D.; Li, N.; Zhao, M.; Shi, W.; Ma,
C.; Chen, B. Green Chem. 2010, 12, 2120.
(12) Liu, X.; Wang, D.; Chen, Y.; Tang, D.; Chen, B. Adv. Synth. Catal.
2013, 355, 2798.
HRMS (ESI): m/z [M + H]+ calcd for C20H15BrN3+: 376.0449; found:
376.0448.
3-(1,5-Diphenyl-1H-1,2,4-triazol-3-yl)pyridine (3am)
White solid; yield: 44 mg (73%); mp 107–111 °C.
1H NMR (300 MHz, CDCl3): δ = 9.47 (s, 1 H), 8.66 (d, J = 4.8 Hz, 1 H),
8.49 (d, J = 7.9 Hz, 1 H), 7.58–7.53 (m, 2 H), 7.45–7.36 (m, 9 H).
13C NMR (75 MHz, CDCl3): δ = 159.79, 155.21, 150.44, 148.21, 138.23,
133.97, 130.38, 129.64, 129.22, 129.10, 128.81, 127.81, 126.96,
125.54, 123.60.
(13) Qu, J.; Wu, P.; Tang, D.; Meng, X.; Chen, Y.; Guo, S.; Chen, B. New
J. Chem. 2015, 39, 4235.
(14) (a) Allen, S. E.; Walvoord, R. R.; Padilla-Salinas, R.; Kozlowski, M.
C. Chem. Rev. 2013, 113, 6234. (b) Song, L.; Tian, X.; Lv, Z.; Li, E.;
Wu, J.; Liu, Y.; Yu, W.; Chang, J. J. Org. Chem. 2015, 80, 7219.
(c) Zheng, Z.; Ma, S.; Tang, L.; Zhang-Negrerie, D.; Du, Y.; Zhao,
K. J. Org. Chem. 2014, 79, 4687. (d) Sun, M.; Chen, C.; Bao, W. RSC
Adv. 2014, 4, 47373. (e) Wang, L.-Y.; Tsai, H. J.; Lin, H.-Y.; Kaneko,
K.; Cheng, F.-Y.; Shih, H.-S.; Wong, F. F.; Huang, J.-J. RSC Adv.
2014, 4, 14215. (f) Tam, A.; Armstrong, I. S.; La Cruz, T. E. Org.
Lett. 2013, 15, 3586. (g) Wang, Y.; Wang, H.; Peng, J.; Zhu, Q. Org.
Lett. 2011, 13, 4604.
HRMS (ESI): m/z [M + H]+ calcd for C19H15N4+: 299.1297; found:
299.1299.
Acknowledgment
Our gratitude goes to the National Natural Science Foundation of Chi-
na (No. 21372102 and 21403256) who sponsored the project.
(15) Meng, X.; Yu, C.; Zhao, P. RSC Adv. 2014, 4, 8612.
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2015, 80, 2972. (b) Mishra, S.; Monir, K.; Mitra, S.; Hajra, A. Org.
Lett. 2014, 16, 6084. (c) Aschwanden, P.; Frantz, D. E.; Carreira,
E. M. Org. Lett. 2000, 2, 2331.
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0035-1562490.
S
u
p
p
ortiInfogrmoaitn
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u
p
p
ortioInfgrmoaitn
(17) Perez, M.; Dorado, C.; Soto, J. Synthesis 1983, 6, 483.
(18) Wang, F.; You, Q.; Wu, C.; Min, D.; Shi, T.; Kong, Y.; Zhang, W.
RSC Adv. 2015, 5, 78422.
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–G