Orthogonal arylations of 5-vinyl-1,2,4-triazoles

Article abstract of DOI:10.1016/j.tet.2020.130954

The preparation of 1,3,5-trisubstituted 1,2,4-triazoles is described using selective orthogonal arylation sequences. Ligand free Pd-catalyzed arylation allowed installing various (het)aryl units exclusively at the vinyl fragment of N1 substituted or N1-H precursors. Successful double arylations starting from ortho, meta and para bisiodobenzenes led to extended bistriazolyl derivatives. In contrast, Cu-catalyzed arylation using pyridylmethylamine as the ligand, led to N1-arylated triazoles keeping intact the vinyl moiety. Arylation process was compatible with electron donating groups in ortho, meta and para positions and tolerated electron withdrawing groups with a lesser extent. The strategy is general and spread the molecular diversity at the triazole core.

Full text of DOI:10.1016/j.tet.2020.130954

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Orthogonal arylations of 5-vinyl-1,2,4-triazoles
Safa Azzouni, Anne Gaucher, Damien Prim, Mohamed Lotfi Efrit
PII:
S0040-4020(20)30044-2
https://doi.org/10.1016/j.tet.2020.130954
TET 130954
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To appear in: Tetrahedron
Received Date: 17 November 2019
Revised Date: 7 January 2020
Accepted Date: 10 January 2020
Please cite this article as: Azzouni S, Gaucher A, Prim D, Efrit ML, Orthogonal arylations of 5-vinyl-1,2,4-
triazoles, Tetrahedron (2020), doi: https://doi.org/10.1016/j.tet.2020.130954.
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Orthogonal arylations of 5-vinyl-1,2,4-
triazoles
Leave this area blank for abstract info.
Safa Azzounia,b, Anne Gauchera, Damien Prima and Mohamed Lotfi Efritb
a Institut Lavoisier de Versailles, UVSQ, CNRS, Université Paris-Saclay, 78035 Versailles, Cedex, France. b Laboratoire de synthèse organique et
hétérocyclique sélective-Evaluation d’activité biologique, LR17ES01, Université de Tunis El Manar, Faculté des Sciences de Tunis, 2092 Tunis, Tunisia.

1
Tetrahedron
journal homepage: www.elsevier.com
Orthogonal arylations of 5-vinyl-1,2,4-triazoles
Safa Azzounia,b, Anne Gauchera, Damien Prima, and Mohamed Lotfi Efritb,
a Institut Lavoisier de Versailles, UVSQ, CNRS, Université Paris-Saclay, 78035 Versailles, Cedex, France.
b Laboratoire de synthèse organique et hétérocyclique sélective-Evaluation d’activité biologique, LR17ES01, Université de Tunis El Manar, Faculté des Sciences
de Tunis, Campus universitaire, 2092 Tunis, Tunisia.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
The preparation of 1,3,5-trisubstituted 1,2,4-triazoles is described using selective
orthogonal arylation sequences. Ligand free Pd-catalyzed arylation allowed installing
various (het)aryl units exclusively at the vinyl fragment of N1 substituted or N1-H
precursors. Successful double arylations starting from ortho, meta and para
bisiodobenzenes led to extended bistriazolyl derivatives. In contrast, Cu-catalyzed
arylation using pyridylmethylamine as the ligand, led to N1-arylated triazoles keeping
intact the vinyl moiety. Arylation process was compatible with electron donating groups
in ortho, meta and para positions and tolerated electron withdrawing groups with a
lesser extent. The strategy is general and spread the molecular diversity at the triazole
core.
Available online
Keywords:
1,2,4-triazole
C-C bond formation
C-N bond formation
Palladium
2009 Elsevier Ltd. All rights reserved
.
Copper
———
Corresponding author. e-mail: Damien.prim@uvsq.fr
Corresponding author. e-mail: medlotfi.efrit@fst.utm.tn

2
Tetrahedron
1. Introduction
Table 1. Determination of suitable arylation conditions of
vinyltriazole 1
.
The joint presence of three nitrogen and two carbon atoms in a
five-membered ring confers triazoles unique properties
combining different weak interactions, a characteristic basicity
and several coordination modes.1 Among them, 1,2,4-triazoles
hold a unique place in the broad class of heterocyclic compounds.
Indeed, the 1,2,4-triazole scaffold displays wide applications in
pharmaceutical,2 agricultural3 and material sciences fields.4
Moreover triazole derivatives exhibit corrosion inhibition5
properties and serves as ligand in catalytic transformations.6 Due
to the lasting interest of the scientific community for such
heterocycles and their properties, selective access to
polyfunctional triazoles remains a major challenge. In this
context, the 1,3,5-trisubstituted 1,2,4-triazole scaffold is of
special interest because modulation of properties mandatorily
arises from selective modification of the substitution pattern.
Although appealing preparation methods have been reported,7
effective control of the substitution pattern may represent a
hurdle especially when the triazole platform is substituted by
several transition metal reactive fragments. In this paper, we
describe the selective Pd- and Cu-catalyzed functionalization of
vinyl-triazoles. Our strategy allows installing aryl fragments at
the vinyl fragment and at the N1-H position. In addition, both
sites can be iteratively arylated spreading thus the molecular
diversity at the triazole core (Scheme 1).
Entry Cat. Syst.
Cond.
TBAI
(Y/N)
Time
(h)
X
1/4
Yield
(%)
1
2
Pd(OAc)2 (5%)
A
B
N
N
24
24
Br 1/4.3
62a
Pd(OAc)2
(10%)
I
I
I
1/1.7
1/0.9
1/0.4
3
4
Pd(OAc)2
(10%)
B
B
Y
N
24
24
Pd(OAc)2
(5%),
PPh3(40%)
5
6
Pd(OAc)2
(10%), PPh3
(40%)
B
B
N
N
24
24
I
I
1/1
PdCl2(dppf)
(5%)
1/0.2
7
Pd(OAc)2 (5%)
Pd(OAc)2 (5%)
Pd(OAc)2 (5%)
C
C
A
A
Y
Y
N
N
24
3
I
I
I
I
0/1
1/2.4
0/1
8
9
24
4
10
Pd(OAc)2
(5%)
0/1
78
Condition A: K3PO4 (2 eq.), DMF, 110°C. B: Et3N (2 eq.),
MeCN, 80°C. C: NaOAc (2.5 eq.), DMF 110°C.
Scheme 1. Selective Pd- and Cu-arylation of 5-vinyl-1,2,4-triazoles.
2. Results and discussion
Pd(OAc)2, PPh3 combinations as well as PdCl2(dppf) under
condition B, similarly afforded poor conversions (entries 4-6). In
contrast, under condition C in the presence of TBAI, using
NaOAc (2.5 eq) as the base at 110°C in DMF for 24h allowed
full conversion of the starting material (entry 7). Unfortunately,
under these conditions, the reaction time could not be reduced as
lower conversions were observed (compare entries 7 and 8).
Fortunately, Pd(OAc)2 (5%), K3PO4 (2 eq.) in DMF at 110 °C
revealed the most efficient conditions even in the absence of
TBAI (entry 9). Indeed, under these conditions a full conversion
of the starting material was observed in 24h. The reaction time
could be further reduced to 4h without any loss of conversion and
target triazole 4 could be isolated in 78% yield.
Vinyltriazole precursors used in the arylation sequences were
first prepared from imidate starting material according to our
recent publication.8 As shown in figure 1, triazoles 1-3 display a
substitution pattern including phenyl or isopropyl groups located
at position 3. N1 is substituted either by a phenyl group in
substrate 1 or remains unsubstituted in compounds 2 and 3.
Figure 1. 5-vinyl-1,2,4-triazole precursors.
With these conditions in hands, we further explored the
installation of various aryl groups at the vinyl fragment of
triazole 1 (figure 2).
We first experimented the arylation of triazole precursor 1, in
order to set suitable conditions (Table 1). We started to test
bromobenzene as the coupling partner. In this case, using
Pd(OAc)2 (5%) as the catalyst, K3PO4 (2 eq.) as the base in DMF
at 110 °C led to partial conversion even after 24h reaction course
(see ESI and preliminary result8). This prompted us to switch to
iodobenzene. Several catalytic systems and conditions were
tested in order improve the conversion. Condition B (Et3N (2 eq),
MeCN at 80°C) in the presence or absence of
tetrabutylammonium iodide (TBAI) led to disappointing results
even using 10% of Pd(OAc)2 (entries 2, 3).

3
Figure 3. Catalytic conditions suitable for the installation of EWG groups
We next envisioned the arylation of the vinyl fragment of
triazoles 2 and 3. In the latter compounds, the N1 atom remains
unsubstituted which may represent a challenging hurdle to
overcome for selective arylation. Indeed, in these cases, both
vinyl and N1 sites might be arylated under Pd-catalysis9 and lead
to mixtures of mono- and bis-arylated products (figure 4).
Further, the absence of substituent at the N 1 site could favor the
formation of Pd-triazole complexes and thus poison the catalytic
system.
First attempts were realized using conditions A, B, C and D.
Unfortunately, we were not able to isolate any of the potential
products, crude products mainly affording intractable mixtures.
However catalytic systems combining Pd(OAc)2 and XPhos,
afforded the expected compound 19 from triazole 2 and
iodobenzene. The latter could be isolated in a fair 51 % yield
using a Pd/L ratio of 1:2. Although N-arylated and bis-arylated
products cannot be ruled out, we were not able to evidence their
presence in the crude material. Triazoles 20-22 were obtained
using identical reaction condition E. The latter targets arose from
the reaction of precursor 2 and 3 and iodobenzene or o-
iodotoluene.
Figure 2. Access to variously substituted triazoles 4-14.
O- and m-iodotoluenes as well as 2-iodo-1,3-dimethylbenzene
were efficiently coupled to triazole 1 affording products 5-7 in 30
to 72 % yields. Similarly, triazoles 8 and 9 bearing o- and p-
methoxy groups could be obtained in 60 and 41% yields
respectively. Finally, triazoles 10 and 11 substitued by naphthyl
and thienyl groups were synthesized in yields in 60 and 35%
yields respectively. Precursor 1 was further reacted with
bisiodobenzenes under the aforementioned conditions.
Gratifyingly double coupling process afforded extended
architectures 12-14 based on a central benzene core and two
triazole units lying in ortho, meta and para fashion.
Ar
N
N
N
R
R
N
N
N
N
N
Ar
H
and/or
N
arylation
R
N
Ar
H
R
N
N
Ar
Condition E : Pd(OAc)2 (10 %), XPhos (20 %),
K2CO3 (2.0 eq), DMF, 140°C, 24h
The installation of aryl groups bearing electron withdrawing
substituents was next envisioned. Disappointingly, the use of the
aforementioned conditions A or B remained unsuccessful.
Indeed, under these conditions, no conversion was observed
(figure 3). Conditions C led to poor conversion and afforded
mainly degradation side products. In contrast, modified
conditions D using 3 eq. of TBAI as an additive allowed
minimizing the formation of unidentified degradation products
and finally isolating target triazoles 15-18. The latter comprise
nitrobenzene, trifluoromethylbenzene or cyanobenzene as well as
pyridyl fragments and were obtained in modest to low yields
ranging from 11 to 48%.
N
NH
N
19 51%
N
NH
N
20 56%
N
N
NH
N
NH
N
22 58%
21 48%
Figure4. Selective Pd-catalyzed arylation at the vinyl site of triazole 2
and 3.

4
Tetrahedron
Our next objective was the selective arylation of the N1 site
Selective N1 arylation sequence was successfully realized
with o-bromoiodobenzene affording triazole 25 in 57% yield.
Further, the procedure was extended to triazole 3 from which
targets 24 and 26 bearing a phenyl and a CF3 substituted phenyl
fragment have been isolated in 44 and 43% yield respectively.
Finally, N1-arylation was also successful when applied to
triazole 19.
of triazoles 2 and 3. To this end precursor 2 and iodobenzene
were choosen as model reaction and reacted under various
catalytic conditions.
As conditions A-E did not allow installing aryl groups at the
N1 reactive site, we moved to Cu- and Fe-catalyzed process.
Based on Buchwald, Bolm and Taillefer recent protocols,10
several Cu or Fe-based catalytic conditions were tested.
First CuI was experimented without ligand (Table 2, entry 1).
In this case the starting triazole 2 was recovered unchanged.
Combinations of CuI with various ligands were next tested.
Using L1 to L5 with Cs2CO3 in DMF at 130°C afforded various
ratio of the starting material 2 and the expected N-arylated
product 23 (entries 2-7). Similarly, to N-ligands, XPhos afforded
poor conversion (entry 8). Fe-based catalytic systems such as
Fe(acac)2/CuO or FeCl2 were found ineffective (entries 10-11).
Finally, Cu2O was tested in combination with L1 or L5 in the
presence of PEG-400 and Cs2CO3 (entries 12-14).
Figure 5. Selective Cu-catalyzed N-arylation of triazoles.
Table 2. Optimization of the N1 arylation reaction.
3. Conclusion
We succeeded in the preparation of 1,3,5-trisubstituted 1,2,4-
triazoles. Selective orthogonal Pd- and Cu-catalyzed sequences
are described allowing the installation of aryl groups at the vinyl
substituent or at the N1-site of triazole precursors. Precisely,
various (het)aryl units have been exclusively incorporated at the
triazole core using ligand free Pd-catalyzed process. Double
arylations starting from ortho, meta and para bisiodobenzenes
led to extended bistriazolyl derivatives. The N1 arylation was
realized using orthogonal Cu-catalysis. Combination of
pyridylmethylamine as the ligand and Cu2O led to N1-arylated
triazoles keeping intact the vinyl moiety. The strategy is general
and spread the molecular diversity at the triazole core.
Entry
Cat.a
Ligand
(20%)
Time
(h)
2/23
Yield (%)
1
2
3
4
5
6
7
8
9
CuI (3%)
CuI (3%)
CuI (3%)
CuI (3%)
CuI (3%)
CuI (3%)
CuI (3%)
CuI (3%)
---
24
24
24
30
30
30
24
48
30
1/0
L1
0.5/0.4
0.8/0.3
1/1
4. Experimental section
L1
General information
L2
Unless otherwise specified, reagents were obtained from
commercial sources and used without further purification.
Solvents were obtained from Fisher Scientific and dried by
standard methods. Reactions were monitored by thin-layer
chromatography (TLC) using ALUGRAM®Xtra SIL GUR Silica
Gel 60 F254 plates and visualized using UV light (254 nm).
Melting points were determined on a Kofler hotstaged apparatus
and were uncorrected. NMR spectra were recorded in CDCl3 as
the solvent with TMS as the internal standard on a Bruker-300
spectrometer. Chemical shifts are reported in ppm (δ) downfield
relative to TMS. Data are reported as follows: chemical shift,
multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, bs =
L3
1/0
L4
0.6/0.2
1/0.3
1/0.6
1/0
L5
XPhos
---
Fe(acac)2 (30%)
CuO(10%)11
10
11
12
13
FeCl2.4H2O (30%)11 ---
48
20
18
48
1/0
broad singlet,
m = multiplet), coupling constants (Hz),
Cu2O (20%)
Cu2O (20%)
Cu2O (20%)
L1/PEG
1/0.9
1/0
integration. High resolution mass spectra (HRMS) were
performed on a BrukermaXis Q-TOF spectrometer by electron
spray ionization (ESI) operating in positive mode. Triazoles 1-3
were prepared according to literature.8
---
L6/PEG
0.6/1
51
a Realized in DMF at 130°C.
General procedure for the Pd-catalyzed arylation of 5-
vinyl triazole (4-13)
Although complete conversions could not be reached, best
ratio 2/23 of 0.6/1 was observed using pyridylmethylamine12
L5/Cu2O/PEG-400 in the presence of Cs2CO3 (entry 14). Control
experiment showed that both L6 and PEG-400 were required
(entry 13). From the 0.6/1 ratio observed in the crude material,
the expected triazole 23 arising from a selective N-arylation
process could be isolated in 51% yield.
A 10 mL 2 dram screwed tube equipped with a magnetic
stirring bar was charged with 5-vinyl-1,2,4-triazole (0.17 mmol,
1.0 equiv), an organic halide (0.17 mmol, 1.0 equiv), and K3PO4
(108 mg, 0.32 mmol, 2.0 equiv); then Pd(OAc)2 (1.7 mg, 0.008
mmol) were added, followed by DMF (1.0 mL), which was
added to the mixture via syringe at r.t. under argon. The tube was
sealed and put into a preheated oil bath at 110 °C for 4 h. The

5
mixture was cooled to r.t quenched with H2O (20 mL). The layers
were separated and the aqueous layer was extracted with Diethyl
Ether (3 × 20 mL). The combined organic extracts were dried
(MgSO4), filtered, and concentrated in vacuo. The crude product
was then purified by preparative TLC (silica gel, EtOAc–PE,
3/7).
(E)-1,3-diphenyl-5-(2-(thiophen-2-yl)vinyl)-1H-1,2,4-
1
triazole (11): Yellow oil (35%). H NMR (300 MHz, CDCl3) δ
8.26 (dd, J = 7.9, 1.6 Hz, 2H), 8.06 (d, J = 15.7 Hz, 1H), 7.72 –
7.21 (m, 10H), 7.17 – 6.98 (m, 1H), 6.75 (d, J = 15.7 Hz, 1H).13C
NMR (75 MHz, CDCl3) δ 153.1, 140.8, 137.2, 129.6, 129.4,
129.2, 129.0, 128.6, 128.0, 126.8, 126.6, 125.4, 110.9. HRMS
(ESI): m/z calcd for C20H16N3S [M+H]+: 330.1065, found :
330.1074.
(E)-1,3-diphenyl-5-styryl-1H-1,2,4-triazole (4): Yellow
1
powder (78%), m.p. 132 °C. H NMR (300 MHz, CDCl3) δ 8.22
– 8.07 (m, 2H), 7.82 (d, J = 16.0 Hz, 1H), 7.52 – 7.17 (m, 13H),
6.82 (d, J = 16.0 Hz, 1H).13C NMR (75 MHz, CDCl3) δ 162.0,
153.4, 137.9, 137.3, 135.6, 130.8, 129.6, 129.4, 129.3, 129.1,
128.8, 128.6, 127.4, 126.7, 125.5, 111.9. HRMS (ESI): m/z calcd
for C22H18N3 [M+H]+: 324.1501, found : 324.1510.
1,4-bis((E)-2-(1,3-diphenyl-1H-1,2,4-triazol-5-
yl)vinyl)benzene (12): Yellow powder (24%), m.p. 194 °C. H
1
NMR (200 MHz, CDCl3) δ 8.23 (ddd, J = 7.6, 5.9, 2.0 Hz, 4H),
8.03 – 7.79 (m, 2H), 7.70 – 7.37 (m, 20H), 6.97 (t, J = 10.3 Hz,
2H). 13C NMR (75 MHz, CDCl3) δ 161.9, 160.0, 153.0, 136.0,
135.3, 129.6, 129,5, 129.2, 129.1, 128.8, 128.6, 128.0, 126.7,
125.5. HRMS (ESI): m/z calcd for C38H29N6 [M+H]+: 569.2454,
found : 569.2463.
(E)-5-(2-methylstyryl)-1,3-diphenyl-1H-1,2,4-triazole (5):
Brown powder (72%), m.p. 152 °C. 1H NMR (300 MHz, CDCl3)
δ 8.32 – 8.08 (m, 2H), 8.04 (d, J = 15.8 Hz, 1H), 7.59 – 7.23 (m,
9H), 7.29 – 7.01 (m, 3H), 6.75 (d, J = 15.8 Hz, 1H), 2.50 (s, 3H).
13C NMR (75 MHz, CDCl3) δ 162, 153.5, 137.1, 135.7, 134.7,
130.8, 130.7, 129.6, 129.4, 129.1, 129.0, 128.6, 126.6, 126.2,
125.7, 125.5, 113.2, 20.0. HRMS (ESI): m/z calcd for C23H20N3
[M+H]+: 338.1657, found: 338.1665.
1,2-bis((E)-2-(1,3-diphenyl-1H-1,2,4-triazol-5-
yl)vinyl)benzene (13): Yellow powder (21%), m.p. 195 °C. H
1
NMR (300 MHz, CDCl3) δ 8.22 (t, J = 10.5 Hz, 4H), 7.57 – 7.47
(m, 2H), 7.48 – 7.22 (m, 10H), 6.74 (d, J = 15.8 Hz, 2H). 13C
NMR (75 MHz, CDCl3) δ 164.9, 159.7, 153.0, 144.6, 137.1,
136.2, 129.7, 129.6, 129.2, 128.6, 127.9, 126.7, 125.4, 112.4.
HRMS (ESI): m/z calcd for C38H29N6 [M+H]+: 569.2454, found:
569.2463.
(E)-5-(3-methylstyryl)-1,3-diphenyl-1H-1,2,4-triazole (6):
Brown powder (38%), m.p. 117 °C. 1H NMR (300 MHz, CDCl3)
δ 8.27 (dd, J = 8.0, 1.4 Hz, 2H), 7.92 (d, J = 16.0 Hz, 1H), 7.65 –
7.25 (m, 11H), 7.20 (d, J = 7.3 Hz, 1H), 6.95 (d, J = 16.0 Hz,
1H), 2.41 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 162.0, 153.4,
138.5, 138.1, 137.3, 135.5, 130.8, 130.1, 129.6, 129.4, 129.0,
128.7, 128.6, 128.0, 126.6, 125.5, 124.6, 111.7, 21.4. HRMS
(ESI): calcd for C23H20N3 [M+H]+: 338.1657, found: 338.1648.
1,3-bis((E)-2-(1,3-diphenyl-1H-1,2,4-triazol-5-
yl)vinyl)benzene (14): Yellow powder (18%), m.p. 202 °C. H
1
NMR (300 MHz, CDCl3) δ 8.17 (d, J = 7.9 Hz, 4H), 7.86 (t, J =
14.7 Hz, 2H), 7.61 – 7.26 (m, 20H), 6.87 (d, J = 15.9 Hz, 2H).
13C NMR (75 MHz, CDCl3) δ 153.0, 137.2, 137.1, 136.2, 129.7,
129.6, 129.3, 129.2, 128.6, 127.9, 127.8, 126.7, 126.7, 125.4.
HRMS (ESI): m/z calcd for C38H29N6 [M+H]+: 569.2454, found:
569.2465.
(E)-5-(2,6-dimethylstyryl)-1,3-diphenyl-1H-1,2,4-triazole
1
(7): Brown powder (30%), m.p. 126 °C. H NMR (300 MHz,
CDCl3) δ 8.31 (d, J = 8.6 Hz, 2H), 8.02 (d, J = 16.3 Hz, 1H), 7.59
– 7.45 (m, 8H), 7.19 – 7.10 (m, 3H), 6.58 (d, J = 16.3 Hz, 1H),
2.42 (s, 6H). 13C NMR (75 MHz, CDCl3) δ 162.0, 153.2, 137.2,
136.5, 136.4, 135.3, 130.8, 129.5, 129.4, 129.1, 128.6, 128.2,
127.8, 126.7, 125.4, 117.9, 21.2. HRMS (ESI): calcd for
C24H22N3 [M+H]+: 352.1814, found : 352.1812.
General procedure for the Pd-catalyzed arylation of 5-
vinyl triazole (15-18)
A 10 mL 2 dram screwed tube equipped with a magnetic
stirring bar was charged with 5-vinyl-1,2,4-triazole (0.17 mmol,
1.0 equiv), an organic halide (0.17 mmol, 1.0 equiv), and NaOAc
(26.24 mg, 0.32 mmol, 2.0 equiv); TBAI (0.017 mmol, 6.27 mg);
then Pd(OAc)2 (1.7 mg, 0.008 mmol) were added, followed by
DMF (1.0 mL), which was added to the mixture via syringe at r.t.
under argon. The tube was sealed and put into a preheated oil
bath at 110 °C for 22 h. The mixture was cooled to r.t quenched
with H2O (20 mL). The layers were separated and the aqueous
layer was extracted with Diethyl Ether (3 × 20 mL). The
combined organic extracts were dried (MgSO4), filtered, and
concentrated in vacuo. The crude product was then purified by
preparative TLC (silica gel, EtOAc–PE, 3/7).
(E)-5-(2-methoxystyryl)-1,3-diphenyl-1H-1,2,4-triazole (8):
Yellow powder (60%), m.p. 120 °C. 1H NMR (200 MHz, CDCl3)
δ 8.28 (dd, J = 7.8, 1.8 Hz, 2H), 8.18 (d, J = 16.1 Hz, 1H), 7.67 –
7.22 (m, 10H), 7.12 (d, J = 16.1 Hz, 1H), 7.02 – 6.82 (m, 2H),
3.88 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 161.9, 158.0, 154.0,
137.5, 133.6, 131.0, 130.3, 129.4, 129.4, 128.9, 128.6, 126.7,
125.4, 125.4, 124.6, 120.7, 113.0, 111.1, 55.4. HRMS: (ESI :
calcd for C23H20N3O [M+H]+: 354.1616, found : 354.1606.
(E)-5-(4-methoxystyryl)-1,3-diphenyl-1H-1,2,4-triazole (9):
1
White powder (41%), m.p. 149 °C. H NMR (300 MHz, CDCl3)
δ 8.28 (dd, J = 7.9, 1.5 Hz, 2H), 7.91 (d, J = 15.9 Hz, 1H), 7.69 –
7.41 (m, 10H), 6.94 (d, J = 8.7 Hz, 2H), 6.83 (d, J = 15.9 Hz,
1H), 3.86 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 161.9, 160.6,
153.7, 137.5, 137.4, 130.9, 129.5, 129.0, 128.9, 128.6, 126.6,
125.5, 114.3, 109.6, 55.3. HRMS (ESI): m/z calcd for C23H20N3O
[M+H]+: 354.1616, found : 354.1601.
(E)-5-(4-nitrostyryl)-1,3-diphenyl-1H-1,2,4-triazole (15):
Yellow powder (48%), m.p. 182 °C. 1H NMR (300 MHz,
CDCl3) δ 8.32 – 8.23 (m, 4H), 8.00 (d, J = 16.0 Hz, 1H), 7.73 –
7.44 (m, 10H), 7.09 (d, J = 16.0 Hz, 1H). 13C NMR (75 MHz,
CDCl3) δ 162.2, 152.3, 141.8, 136.9, 135, 130.4, 129.7, 129.6,
129.4, 128.6, 127.8, 126.5, 125.4, 124.1, 115.9. HRMS (ESI):
m/z calcd for C22H17N4O2 [M+H]+: 369.1352, found: 369.1360.
(E)-5-(2-(naphthalen-2-yl)vinyl)-1,3-diphenyl-1H-1,2,4-
triazole (10): Yellow powder (60%), m.p. 203 °C. 1H NMR (300
MHz, CDCl3) δ 8.30 (dd, J = 8.0, 1.4 Hz, 2H), 8.13 (d, J = 15.9
Hz, 1H), 8.03 – 7.78 (m, 4H), 7.74 – 7.45 (m, 11H), 7.08 (d, J =
15.9 Hz, 1H). 13C NMR (75 MHz, CDCl3) δ 162.0, 153.4, 138.0,
137.3, 133.7, 133.4, 133.1, 130.8, 129.6, 129.4, 129.1, 128.7,
128.6, 128.5, 128.4, 127.7, 126.8, 126.6, 125.5, 123.3, 112.0.
HRMS (ESI): m/z calcd for C26H20N3 [M+H]+: 374.1657, found :
374.1656.
(E)-4-(2-(1,3-diphenyl-1H-1,2,4-triazol-5-yl)vinyl)pyridine
1
(16): Yellow powder (11%), m.p. 211 °C. H NMR (300 MHz,
CDCl3) δ 8.55 (d, J = 5.9 Hz, 2H), 8.21 – 8.13 (m, 2H), 7.77 (d, J
= 16.0 Hz, 1H), 7.59 – 7.35 (m, 8H), 7.29 (d, J = 5.9 Hz, 2H),
7.02 (d, J = 16.0 Hz, 1H). 13C NMR (75 MHz, CDCl3) δ 162.5,
152.3, 150.4, 134.9, 130.5, 129.7, 129.6, 129.4, 128.6, 126.6,

6
Tetrahedron
125.4, 121.3, 116.1. HRMS (ESI): m/z calcd for C21H17N4
126.1, 125.5, 117.3, 27.3, 21.3, 19.8. HRMS (ESI): m/z calcd for
[M+H]+: 325.1453, found: 325.1459.
C14H18N3 [M+H]+: 228.1501, found: 228.1496.
(E)-4-(2-(1,3-diphenyl-1H-1,2,4-triazol-5-
General procedure for the Cu-catalyzed arylation of 5-
vinyl triazole (23-27)
yl)vinyl)benzonitrile (17): Yellow powder (20%), m.p. 174 °C.
1H NMR (300 MHz, CDCl3) δ 8.28 – 8.25 (m, 2H), 7.95 (d, J =
16.0 Hz, 1H), 7.83 (d, J = 8.3 Hz, 1H), 7.67 (dt, J = 8.4, 6.6 Hz,
9H), 7.51 (d, J = 7.5 Hz, 2H), 7.04 (d, J = 15.9 Hz, 1H). 13C
NMR (75 MHz, CDCl3) δ 152.5, 139.9, 137.0, 135.5, 132.9,
132.6, 129.7, 129.6, 129.4, 128.6, 127.9, 127.7, 126.6, 125.4,
118.7, 115.2. HRMS (ESI): calcd for C23H17N4 : 349.1453,
found: 349.1451.
A 10 mL dram screwed tube equipped with a magnetic stirring
bar was charged with 5-vinyl-1,2,4- triazole (0.17 mmol, 1.0
equiv), the aryl halide (0.17 mmol, 1.0 equiv), and Cs2CO3 (110
mg, 0.32 mmol, 2.0 equiv) followed by Cu2O (4.8 mg, 0.034
mmol), 1,10-phenantroline (6,1 mg, 0.32 mmol) and DMF (1.0
mL). The tube was sealed and put into a preheated oil bath at 110
°C for 4 h under argon. The mixture was cooled to rt and
quenched with H2O (20 mL). The layers were separated and the
aqueous layer was extracted with diethyl ether (3×20 mL). The
combined organic extracts were dried over MgSO4, filtered and
concentrated in vacuo. The crude product was then purified by
preparative TLC (silica gel, EtOAc–PE, 3/7).
(E)-1,3-diphenyl-5-(4-(trifluoromethyl)styryl)-1H-1,2,4-
triazole (18): Yellow powder (38%), m.p. 146 °C. 1H NMR (300
MHz, CDCl3) δ 8.23 (d, J = 7.3 Hz, 2H), 7.93 (d, J = 16.0 Hz,
1H), 7.64 – 7.28 (m, 12H), 6.98 (d, J = 16.0 Hz, 1H) 13C NMR
(75 MHz, CDCl3) δ 162.1, 152.7, 138.9, 137.1, 136.0, 130.9,
130.5, 129.7, 129.6, 129.5, 129.2, 128.6, 127.4, 126.6, 125.8,
125.7, 125.4, 122.1, 114.3. HRMS (ESI): m/z calcd for
C23H17N3F3 [M+H]+: 392.1375, found: 392.1384.
1,3-diphenyl-5-vinyl-1H-1,2,4-triazole (23): Yellow powder
1
(51%), m.p. 82 °C. H NMR (300 MHz, CDCl3) δ 8.21 (dt, J =
8.4, 2.2 Hz, 2H), 7.54 – 7.41 (m, 8H), 6.68 – 6.49 (m, 2H), 5.67
(dd, J = 10.3, 2.2 Hz, 1H). 13C NMR (75 MHz, CDCl3) δ 161.8,
152.8, 137.0, 130.6, 129.4, 129.3, 129.0, 128.4, 126.5, 125.3,
123.6, 121.6. HRMS (ESI): m/z calcd for C16H14N3 [M+H]+:
248.1188, found: 248.1187.
General procedure for the Pd-catalyzed arylation of 5-
vinyl triazole (19-22)
A 10 mL 2 dram screwed tube equipped with a magnetic
stirring bar was charged with 5-vinyl-1,2,4-triazole (0.17 mmol,
1.0 equiv), o-dihaloarene (0.17 mmol, 1.0 equiv), and K2CO3 (70
mg, 0.51 mmol, 3.0 equiv); then Pd(OAc)2 (3.8 mg, 0.017 mmol)
and XPhos (16mg, 0.034 mmol) were added, followed by DMF
(1.0 mL), which was added to the mixture via syringe at r.t. under
argon. The tube was sealed and put into a preheated oil bath at
160 °C for 24 h. The mixture was cooled to r.t., quenched with
H2O (20 mL). The layers were separated and the aqueous layer
was extracted with Diethyl Ether (3 × 20 mL). The combined
organic extracts were dried (MgSO4), filtered, and concentrated
in vacuo. The crude product was then purified by preparatory
TLC (silica gel, Ether–PE, 7/3).
3-isopropyl-1-phenyl-5-vinyl-1H-1,2,4-triazole (24): Yellow
powder (44%), m.p 97°C . H NMR (300 MHz, CDCl3) δ 7.48 –
1
7.37 (m, 5H), 6.78 (dd, J = 17.6, 11.0 Hz, 1H), 6.34 (d, J = 17.6
Hz, 1H), 5.55 (dd, J = 27.4, 11.0 Hz, 1H), 3.12 – 3.07 (m, 1H),
1.35 (m, 6H). 13C NMR (75 MHz, CDCl3) δ 169.0, 151.9, 137.0,
129.2, 128.6, 125.1, 122.9, 121.7, 28.2, 21.5. HRMS (ESI): m/z
calcd for C13H16N3 [M+H]+: 214.1344, found : 214.1355.
1-(2-bromophenyl)-3-phenyl-5-vinyl-1H-1,2,4-triazole (25):
1
Yellow powder, m.p 134°C yield: 47%. H NMR (300 MHz,
CDCl3) δ 8.38 – 8.15 (m, 2H), 7.66 (dd,J = 7.9, 1.4 Hz, 2H),
7.56 – 7.16 (m, 5H), 6.98 (dd, J = 19.6, 8.0 Hz, 2H), 6.76 (t, J =
7.6 Hz, 1H). 13C NMR (75 MHz, CDCl3) δ 162.4, 155.8, 142.5,
130.6, 130.5, 130.1, 129.5, 128.8, 128.6, 128.5, 127.8, 127.6,
126.6, 125.0, 124.5, 118.6, 117.1. HRMS (ESI): m/z calculated
for C16H13N3Br [M+H]+: 326.0293, found: 326.0298.
3-Phenyl-5-styryl-1H-1,2,4-triazole (19): White solid (51%),
1
m.p. 110 °C. H NMR (300 MHz, CDCl3) δ 8.06 (m, J = 6.6,
2H), 7.61 (d, J = 16.3 Hz, 1H), 7.48 – 7.06 (m, 9H), 7.04 (d, J =
16.3 Hz, 1H). 13C NMR (75 MHz, CDCl3) δ 160, 158.1, 135.8,
135.6, 129.9, 128.9, 128.8, 128.7, 128.7, 128.4, 128.3, 127.1,
126.5, 114.4. HRMS (ESI): m/z calcd for C16H14N3 [M+H]+:
248.1188, found: 248.1185.
3-isopropyl-1-(4-(trifluoromethyl)phenyl)-5-vinyl-1H-
1
1,2,4-triazole (26): Yellow powder (43%), m.p 88 °C. H NMR
(300 MHz, CDCl3) δ 7.82 (dd, J = 8.3, 4.1 Hz, 2H), 7.63 (t, J =
8.6 Hz, 2H), 6.83 – 6.30 (m, 2H), 5.66 (ddd, J = 38.7, 10.8, 1.4
Hz, 1H), 3.17 (dt, J = 13.8, 6.9 Hz, 1H), 1.39 (d, J = 7 Hz, 3H),
1.34 (d, J = 7 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ 169.6,
161.7, 161.1, 152.5, 126.7, 126.6, 126.6, 126.3, 125.5, 125.2,
124.3, 121.3, 120 .3, 25.9, 21.6, 21.5. 9F NMR (282 MHz,
CDCl3) δ -62.60, -62.62. HRMS (ESI): m/z calcd for C14H15F3N3
[M+H]+: 282.1218, found: 282.1215.
(E)-5-(2-methylstyryl)-3-phenyl-1H-1,2,4-triazole
(20):
1
White solid (56%), m.p. 118 °C. H NMR (300 MHz, CDCl3) δ
8.05 (m, 2H), 7.93 (d, J = 16.2 Hz, 1H), 7.50 (m,1H), 7.42 (m,
3H), 7.18 (m, 4H), 6.95 (d, J = 16.2 Hz, 1H), 2.39 (s, 3H). 13C
NMR (75 MHz, CDCl3) δ 159.9, 136.7, 134.5, 133.6, 130.6,
129.9, 129.0, 128.8, 128.7, 126.5, 126.2, 125.5, 115.4, 19.8.
HRMS (ESI): m/z calcd for C17H16N3 [M+H]+: 262.1344, found:
262.1345.
(E)-1-(4-methoxyphenyl)-3-phenyl-5-styryl-1H-1,2,4-
1
triazole (27): Brown powder (41%) m.p. 159 °C. H NMR (300
(E)-3-isopropyl-5-styryl-1H-1,2,4-triazole (21): Yellow
oil (48%). H NMR (300 MHz, CDCl3) δ 7.57 (d, J = 16.3 Hz,
MHz, CDCl3) δ 8.24 (m, 2H), 7.92 (d, J = 16.0 Hz, 1H), 7.53 –
7.32 (m, 10H), 7.07 (d, J = 8.8 Hz, 2H), 6.86 (d, J = 16.0 Hz,
1H), 3.90 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 161.5, 160.0,
153.3, 137.8, 135.5, 130.6, 130.0, 129.4, 129.2, 128.8, 128.5,
127.3, 126.9, 126.6, 114.6, 111.6, 55.6. HRMS (ESI): m/z calcd
for C23H20N3O [M+H]+: 354.1606, found : 354.1601.
1
1H), 7.53 (d, J = 7 Hz, 2H), 7.37 – 7.26 (m, 3H), 7.05 (d, J =
16.3 Hz, 1H), 3.22 – 3.13 (m, 1H), 1.40 (d, J = 7.0 Hz, 6H). 13C
NMR (75 MHz, CDCl3) δ 136.1, 134.6, 128.7, 128.5, 128.3,
126.9, 126.8, 116.3, 27.3, 21.3. HRMS (ESI): m/z calcd for
C13H16N3 [M+H]+: 214.1344, found: 214.1346.
Acknowledgments
(E)-3-isopropyl-5-(2-methylstyryl)-1H-1,2,4-triazole (22):
Yellow oil (58%). H NMR (300 MHz, CDCl3) δ 7.80 (d, J =
16.2 Hz, 1H), 7.55 (m, 1H), 7.19 (m, 3H), 6.95 (d, J = 16.2 Hz,
1H), 3.17 (m, 1H), 2.39 (s, 3H), 1.39 (d, J = 7.0 Hz, 6H). 13C
NMR (75 MHz, CDCl3) δ 136.4, 135.1, 132.3, 130.5, 128.4,
1
The Universities of Versailles St-Quentin and Tunis El Manar,
the Tunisian Ministry of Higher Education and Scientific

7
Research and the CNRS are gratefully acknowledged for their
financial support.
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Highlights
TET-D-19-01386R1
•
•
•
•
Orthogonal arylations sequences lead to diversely substituted 1,2,4-triazoles
Selective C-arylation is realized using ligand free Pd-catalytic system
Cu/pyridylmethylamine catalytic system allow selective N-arylation of triazoles
Extended bistriazolyl derivatives arise from double arylation process

Declaration of interests
☒ The authors declare that they have no known competing financial interests or personal relationships
that could have appeared to influence the work reported in this paper.
☐The authors declare the following financial interests/personal relationships which may be considered
as potential competing interests: