Palladium-catalyzed selective ortho C–H alkoxylation at 4-aryl of 1, 4-disubstituted 1, 2, 3-triazoles

Article abstract of DOI:10.1016/j.tet.2020.130985

The ortho- C–H bonds at C(4)-aryl of 1, 4-disubstituted 1, 2, 3-triazoles were regioselectively alkoxylated in good to excellent yields with under the directing of the triazole ring. Some products were found to exhibit strong antifungal capacity to fight against root-rot disease of Panax notoginseng by testing the minimum inhibitory concentration (MIC).

Full text of DOI:10.1016/j.tet.2020.130985

Tetrahedron xxx (xxxx) xxx
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Palladium-catalyzed selective ortho CeH alkoxylation at 4-aryl of 1, 4-
disubstituted 1, 2, 3-triazoles
a
a
c
b
,
**
, Tiebo Xiao a
, ***
Yongsheng Ren , Yaowen Liu , Shulin Gao , Xian Dong
Yubo Jiang
a
,
a, *
Faculty of Science, Kunming University of Science and Technology, Kunming, 650500, China
College of Pharmaceutical Sciences, Yunnan University of Chinese Medicine, Kunming, 650500, China
School of Chemistry and Chemical Engineering, Kunming University, Kunming, 650214, China
b
c
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 14 December 2019
Received in revised form
The ortho- CeH bonds at C(4)-aryl of 1, 4-disubstituted 1, 2, 3-triazoles were regioselectively alkoxylated
in good to excellent yields with under the directing of the triazole ring. Some products were found to
exhibit strong antifungal capacity to fight against root-rot disease of Panax notoginseng by testing the
minimum inhibitory concentration (MIC).
23 January 2020
Accepted 29 January 2020
Available online xxx
©
2020 Elsevier Ltd. All rights reserved.
Keywords:
Palladium-catalyzed
Triazole-directed
CeH alkoxylation
1, 4-Disubstituted 1, 2, 3-Triazoles
Antifungal properties
1
. Introduction
Chen groups have demonstrated Pd-catalyzed regioselective ary-
lation and alkenylation of CeH bonds on C(5) position of the tri-
azole ring respectively (Scheme 1a) [8]. The ortho- CeH bond on
N(1)-aryl can also be functionalized through Ru-catalyzed alkeny-
lation and arylation processes [9] (Scheme 1b). While efforts were
also paid to the modification of ortho- CeH on C(4)-aryl of 1, 4-
diaryl 1, 2, 3-triazoles including mono- CeH functionalizations
(nitration halogenation, acylation, and acyloxylation) [10] and di-
CeH transformations (arylation and alkenylation) with the use of
Pd, Ru or Rh as a catalyst (Scheme 1c) [11]. Recently, triazole-
assisted CeH formylation, alkylation and alkoxycarbonylation
were also demonstrated [12]. Despite these remarkable advances, a
general method for direct ortho- CeH alkoxylation of 1, 4-
disubstituted 1, 2, 3- triazoles unfortunately proved elusive.
Herein, we would like to report an efficient protocol for direct
ortho- CeH alkoxylation of 1, 4-disubstituted 1, 2, 3-triazoles using
alcohol as the alkoxyl source. Moreover, the alkoxylated products
obtained have been demonstrated to exhibit strong antifungal ca-
pacity to fight against root-rot disease of Panax notoginseng, a
traditional Chinese medicine material (Scheme 1d).
Since the Huisgen 1, 3-dipolar cycloaddition of azides and al-
kynes was developed into the “click chemistry” by Sharpless at the
beginning of this century [1], the 1, 2, 3-triazole derivatives have
been widely employed in various fields such as organic synthesis
[
2], materials science [3], medicinal chemistry [4], biological tech-
nology [5], and agricultural area [6]. These extensive applications
and current new emerging problems have vigorously promoted the
explorations for constructions of new type of 1, 2, 3-triazoles,
especially by means of direct CeH functionalization process. In the
past few years, Kuang group has mainly modified 2-
monosubstituted 1, 2, 3-triazoles through CeH activation [7].
Meanwhile, great efforts have been recently devoted to the regio-
selective modification of 1, 4-disubstituted 1, 2, 3-triazoles, which
are more challenging owing to the plenty CeH bonds available from
different region [N(1)-aryl, C(4)-aryl, and C(5)-H]. Ackermann and
*
Corresponding author.
*
*
* Corresponding author.
** Corresponding author.
E-mail addresses: dongxian_1655129@163.com (X. Dong), xiaotb@kust.edu.cn
(
T. Xiao), ybjiang@kust.edu.cn (Y. Jiang).
https://doi.org/10.1016/j.tet.2020.130985
040-4020/© 2020 Elsevier Ltd. All rights reserved.
0
Please cite this article as: Y. Ren et al., Palladium-catalyzed selective ortho CeH alkoxylation at 4-aryl of 1, 4-disubstituted 1, 2, 3-triazoles,
Tetrahedron, https://doi.org/10.1016/j.tet.2020.130985

2
Y. Ren et al. / Tetrahedron xxx (xxxx) xxx
oxidants including (NH
Table 1, entries 4e7). Next, the amount of Pd(OAc)
and it turned out that the efficiency was affected upon reducing the
loading of Pd(OAc) (Table 1, entry 8). Subsequently, the amount of
was examined and changing the amount of K to 2 or 4
4
)
2
S
2
O
8
and TBHP were used instead
(
2
was examined,
2
K
2
S
2
O
8
2 2 8
S O
equiv. Both led to a reduction of the yield (Table 1, entries 9e10).
The amount of MeOH is another factor that affects the conversion.
More MeOH like 50 equivalent used had no obvious contribution to
the product while 30 equivalents of MeOH generated a much lower
yield (Table 1, entries 11e12). Raising or decreasing the reaction
temperature also affected the methoxylation process remarkably
(Table 1, entries 13e15).
With the optimal conditions in hand (Table 1, entry 1), we firstly
examined the scope of 1, 4-disubstituted 1, 2, 3-triazoles. The re-
actions of methanol 2a with various 1, 4-disubstituted 1, 2, 3-
triazoles 1 proceeded smoothly to generate the desired products
3
in good to excellent yields (Table 2, 3a-3t). The 1, 2, 3-triazoles
that have CH , OH, or Br at meta- or para-position of the N(1)-
aryl produced higher yields in comparison with those containing
3
Scheme 1. Triazole-directed CeH activation of 1, 4-diaryl 1,2,3-triazoles.
the substituents at ortho-position (Table 2, 3a and 3d vs. 3c; 3j vs.
2
. Results and discussion
Table 2
Scope of 1, 4-disubstituted 1, 2, 3-triazolesa,b,c.
We initiated our investigation by treating 4-phenyl-1-(p-tolyl)-
1
H-1, 2, 3-triazole 1a (0.3 mmol) and methanol 2a (12 mmol) as
ꢀ
both reactant and solvent with Pd catalyst at 100 C (Table 1). The
effects of catalyst, oxidant, temperature, and the amount of MeOH
were explored respectively. We were delighted to find that the
desired product 3a was obtained in 83% yield in the presence of
2 2 2 8
10 mmol % Pd(OAc) as the catalyst, 3.0 equiv of K S O as the
oxidant, and 40 equiv MeOH as both the methoxyl source and
solvent for 12 h (Table 1, entry 1). The molecular structure of
product 3a was unambiguously confirmed by a X-ray study (CCDC:
1814595). Not surprisingly, the reaction did not occur in absence of
catalyst or oxidant (Table 1, entries 2e3). Inferior performance was
also observed when other Pd such as PdCl
2
and Pd
2
(dba)
3
, or other
Table 1
a
Optimization of the reaction conditions .
Entry
Conditions changed
Yield(%)b
1
2
3
4
5
6
7
8
9
e
83
0
0
no Pd(OAc)
no K
PdCl
Pd (dba)
(NH
TBHP instead of K
5 mol % Pd(OAc)
2.0 equiv K
4.0 equiv K
50 equiv MeOH
2
2
S
2
O
8
2
instead of Pd(OAc)
2
45
23
34
0
35
52
74
82
63
54
69
74
2
3
instead of Pd(OAc)
2 2 8
instead of K S O
2
4
)
2
S
2
O
8
2 2 8
S O
2
2
S
S
2
O
O
8
10
11
12
13
14
15
2
2
8
30 equiv MeOH
80
90
ꢀ
ꢀ
C
C
ꢀ
120
C
a
a
Reaction conditions: 1, 4-disubstituted 1, 2, 3-triazoles 1 (0.3 mmol), Pd(OAc)
2
Reaction conditions unless noted: 4-phenyl-1-(p-tolyl)-1H-1, 2, 3-triazole 1a
ꢀ
(
10 mol %) and K
2
S
2
O
8
(0.9 mmol) , MeOH (12 mmol) at 100 C for 12 h
(
1
0.3 mmol), MeOH 2a (12 mmol), Pd(OAc)
2
(10 mol %), and K
2
S
2
O
8
(0.9 mmol) at
b
ꢀ
Yield of isolated product.
Yield from substrate bear an ortho-OMe on C(4) aryl.
00 C for 12 h.
c
b
Yield of isolated product.
Please cite this article as: Y. Ren et al., Palladium-catalyzed selective ortho CeH alkoxylation at 4-aryl of 1, 4-disubstituted 1, 2, 3-triazoles,
Tetrahedron, https://doi.org/10.1016/j.tet.2020.130985

Y. Ren et al. / Tetrahedron xxx (xxxx) xxx
3
3
i). Moreover, the substrates with an electron-donating group (OH,
Table 4
Scope of other substratesa,b.
2
CH OH) seem superior to those with electron-withdrawing group
(
Br) on the N(1)-aryl (Table 2, 3g and 3h vs. 3i and 3j). Obviously,
this process exhibits good tolerance of bromine, phenol hydroxyl,
and alcohol hydroxyl. To our delighted, the substrates regardless
with an electron-donating or electron-withdrawing substituent on
N(4)-aryl could all generate the corresponding products in good
yields (Table 2, 3f-3k, 3p). It is worth noted that mono-methoxy-
lated product could be delivered when the substrate contained an
ortho- or meta-substituent on the C(4)-aryl (Table 2, 3l, 3q-3t). And
substituent on C(4)-aryl seems no obvious affections on the yield.
Additionally, 1-benzyl 1, 2, 3-triazoles were also suitable for this
system and could all generate the expected products in good yields
(
Table 2, 3m-3p).
We next turned our attention to explore the scope of alcohols
Table 3). A variety of 1, 4-disubstituted 1, 2, 3-triazoles could be
a
5
(0.3 mmol), Pd(OAc)
2
(10 mol %), MeOH (12 mmol), and K
2
S
2
O
8
(0.9 mmol) at
ꢀ
(
100 C for 12 h.
b
Yield of isolated product.
coupled with primary and secondary alcohols smoothly, and for
most cases the alkoxylated products were obtained in good yields
n
(
Table 3, 4a-4j). For primary alcohols such as ethanol and PrOH,
F. oxysporum, F. solani, and C. destrutans which are mainly accom-
panied with root-rot disease of Panax notoginseng, a traditional
Chinese medicinal material with high-valued functions of acti-
vating blood circulation and alleviating pain with great medicinal
and economic significance [14]. As a result, compounds 3a, 3b, 3f,
and 4i exhibited excellent inhibitory activities toward all the strains
and showed higher antifungal activities compared to commercial
agricultural chemical of Propamocarb. Additionally, compounds 3c
and 3p have good inhibitory effect on F. oxysporum and F. solani.
Compounds 3s and 3t could inhibit F. oxysporum and C. destrutans
growth efficiently. It should be noted that product 3b possesses
the corresponding dialkoxylated molecule could selectively ac-
quired and no mono-methoxylated product were observed (Table 3,
a-4f). While bulkier alcohols including BuOH, BuOH, and cyclo-
hexanol specifically delivered mono-alkoxylated molecule in good
yields (Table 3, 4g-4j).
To expand the applications of the method and prove the
directing role of the 1, 2, 3-triazole ring, we investigated some other
substrates 5 (Table 4). When using 2-pyridyl as the directing group,
the dimethoxylated product 6a from 2-phenylpyridine 5a was ob-
tained with an excellent of 91% (Tables 4 and 6a). As to 1-phenyl-
pyrazole 5b, the methoxylation process could also go smoothly
i
s
4
amazing activity against F. solani (MIC value: 9.4 ± 0.0 mg/mL) and is
0
with 65% yield (Tables 4 and 6b). For substrate of 1, 1 -biphenyl 5c
more competent compared to commercial agricultural chemicals
like Flutriafol, Grondverbeteraar, Hymexazol and Propamocarb.
To obtain further insight into the reaction mechanisms, we have
carried out the kinetic isotope effect experiments between 4-
without a directing group, the corresponding alkoxylated product
was not detected, which means that the triazole-ring was supposed
to act as a directing group in the alkoxylation process (Tables 4 and
6
c).
In our searching for fungicides, the antifungal activities of the
products were evaluated by microbroth dilution technique
Table 5) [13], toward the three fungal strains including
phenyl-1-(p-tolyl)-1H-1, 2, 3-triazole 1a and 1a-d . This intermo-
5
lecular kinetic isotope effect (KIE) study showed that the k /kD of
H
3a to 3a-d3 was determined to be 4.88, indicating that the CeH
bond cleavage should be involved in the rate-limiting step
(
(
Scheme 2).
Table 3
Based on our studies and previous reports [7b,11d,15], we pro-
Scope of alcoholsa,b.
posed a possible Pd(II)/Pd(IV) mechanism for this ortho- CeH
Table 5
The MIC values (
m
g/mL) of the compounds.
Product
F. oxysporum
F. solani
C. destructans
3
3
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
a
b
c
f
h
j
n
o
p
m
s
t
d
f
g
h
j
75 ± 0.0
113 ± 21.7
105 ± 18.4
45 ± 7.5
>150
>150
>150
>150
150 ± 0.0
>150
150 ± 0.0
150 ± 0.0
>150
>150
>150
>150
>150
47 ± 9.0
50 ± 13.0
37.5 ± 0.0
75 ± 0.0
9.4 ± 0.0
49.8 ± 12.6
28.1 ± 5.4
>150
75 ± 0.0
>150
>150
56.3 ± 10.8
>150
>150
>150
>150
>150
>150
>150
>150
26.3 ± 4.6
12.5 ± 3.1
135 ± 15.0
>150
113 ± 21.0
120 ± 18.4
>150
105 ± 18.4
>150
>150
>150
>150
>150
>150
51.6 ± 14.1
46.7 ± 9.4
>150
>150
>150
>150
150 ± 0.0
100 ± 25.0
12.5 ± 3.1
3.8 ± 0.6
75 ± 0.0
150 ± 0.0
i
a
Hymexazol
Flutriafol
Grondverbeteraar
Propamocarb
a
a
Reaction conditions: Reaction conditions: 1, 4-disubstituted 1, 2, 3-triazoles 1
a
>150
150 ± 0.0
(
1
2 2 2 8
0.3 mmol), alcohols 2 (12 mmol), Pd(OAc) (10 mol %), and K S O (0.9 mmol) at
a
o
>150
00 C for 12 h.
b
Yield of isolated product.
a
A positive control.
Please cite this article as: Y. Ren et al., Palladium-catalyzed selective ortho CeH alkoxylation at 4-aryl of 1, 4-disubstituted 1, 2, 3-triazoles,
Tetrahedron, https://doi.org/10.1016/j.tet.2020.130985

4
Y. Ren et al. / Tetrahedron xxx (xxxx) xxx
4. Experimental
4.1. General information
1H and 13C NMR spectra were recorded with a Bruker ACF
spectrometer (400 MHz, 500 MHz and 600 MHz) in CDCl with TMS
3
as an internal standard. All reactions were monitored by TLC with
HuanghaiGF 254 silica gel coated plates. Column chromatography
was carried out using 300e400 mesh silica gel at medium pressure.
Infrared spectra were taken on a Bruker Vertex Series FTIR (KBr)
ꢁ1).
and are reported in reciprocal centimeters (cm
Melting points
were obtained using a Büchi melting point apparatus and are un-
corrected. HRMS spectra were recorded on Waters Micromass
Premier Q-TOF spectrometer. Determination of minimum inhibi-
tory concentrations (MIC) were carried out in 96-well plates and
the absorbance of each well was measured at 595 nm by using
microplate reader (Thermo. Model:1510).
Scheme 2. KIE study.
4.2. General procedure for the target products 3, 4, and 6
1
, 4-Disubstituted 1, 2, 3-triazole 1 (0.3 mmol), Pd(OAc)
2
(
0.03 mmol, 10 mol%), alcohol 2 (12 mmol), and K (0.9 mmol)
2 2 8
S O
were sequentially added to a 15 mL pressure tube. The tube was
ꢀ
sealed, and the resulting mixture was stirred at 100 C for 12 h.
After consumption of the 1, 4-disubstitued 1, 2, 3-triazole moni-
tored by TLC analysis, the mixture was diluted with EtOAc (50 mL)
and filtered. The combined organic layers were washed with brine
(
3 ꢂ 5 mL) and dried with Na
2 4
SO . After filtration, the mixture was
concentrated under reduced pressure to afford the crude product.
Purification by column chromatography on silica gel [EtOAc/pe-
troleum ether (PE), 1:4] afforded the desired product 3 and 4. And
the procedure for the target molecule of 6 is similar to 3 and 4.
4.3. General procedures for intermolecular kinetic isotope effect
Scheme 3. Possible Mechanism.
4
-Phenyl-1-(p-tolyl)-1H-1, 2, 3-triazole (1a) (47 mg, 0.2 mmol),
-4-phenyl-1-(p-tolyl)-1H-1, 2, 3-triazole (1a-d (48 mg,
.2 mmol), Pd(OAc) (8.5 mg, 0.04 mmol), MeOH (16 mmol) and
(324 mg, 1.2 mmol) were sequentially added to a 15 mL
d
0
5
5
)
alkoxylation on C(4)-aryl of 1, 4-disubstituted 1, 2, 3-triazoles
Scheme 3). Firstly, selective coordination of electron-richer N(3)
in 1, 2, 3-triazole 1a to the Pd(II) species A combined with CeH
activation forms a five-membered palladacycle B [16]. Next, the
Pd(II) intermediate B was oxidized to Pd(IV) intermediate C by
2
(
2 2 8
K S O
pressure tube. The tube was sealed, and the resulting mixture was
ꢀ
stirred at 100 C for 3 h. The mixture was diluted with EtOAc
(
50 mL) and filtered. The combined organic layers were washed
2 2 8
K S O and followed by ligand exchange with methanol 2a to form
with brine (3 ꢂ 5 mL) and dried with Na
2
SO . After filtration, the
mixture was concentrated under reduced pressure to afford the
4
D. Subsequently, the intermediate D underwent a reductive elimi-
nation process, regenerating Pd(II) and producing the mono-
alkoxylation intermediate E, which then might transform to dia-
lkoxylated product 3a by another similar catalytic cycle.
crude product. Purification by column chromatography on silica gel
[
EtOAc/petroleum ether (PE), 1:4] afforded the desired product 3a
and 3a-d . The ratio of 3a/(3a-d ) was determined to be 0.83/0.17
/k
¼ 4.88) by H NMR spectroscopy.
3
3
1
(
k
H
D
4.4. Determination of minimum inhibitory concentrations (MIC)
3
. Conclusion
The concentrations of conidial suspensions were adjusted to be
We have developed a Pd(OAc)
efficient method for the directed CeH alkoxylation on C(4)-aryl of 1,
-disubstituted 1, 2, 3-triazoles using alcohols as alkoxylating re-
agents. Directed by N(3) of 1, 2, 3-triazole ring, di- or mono-
alkoxylation process can be facilely achieved and various etherified
, 4-disubstituted 1, 2, 3-triazole derivatives were obtained in good
to excellent yields. Antifungal evaluation discloses that products 3a,
b, 3f and 4i possess a broad spectrum of antifungal properties
against the three agricultural pathogenic fungi of F. oxysporum,
F. solani, and C. destrutans, indicating its potential for developing
into the antifungal agents for the treatment of root-rot disease of
Panax notoginseng. Some molecules showed higher potency than
commercial products.
2
catalyzed regioselective and
1 ꢂ 104 spores/mL for each fungus in a 1/4 liquid PDA growth
medium. Each compound was dissolved in DMSO with the initial
4
concentration of 6 mg/mL. A mixture formed from 4
156 L conidial suspensions in the first row of a 96-cell microtiter
plate, and then diluted two-fold with the same solution to adjust
the concentration to 150e0.29 g/mL. Hymexazol, flutriafol,
mL samples and
m
1
m
grondverbeteraar and propamocarb were used as positive controls.
3
The plates, securely sealed with a polyester sealing film (VWR)
ꢀ
were incubated in a fungal incubator at 28 C for 36 h, and the
absorbance of each well was measured at 595 nm by an enzyme-
labeled instrument. The MIC was defined as the lowest concen-
tration of the compound producing complete inhibition of visible
growth.
Please cite this article as: Y. Ren et al., Palladium-catalyzed selective ortho CeH alkoxylation at 4-aryl of 1, 4-disubstituted 1, 2, 3-triazoles,
Tetrahedron, https://doi.org/10.1016/j.tet.2020.130985

Y. Ren et al. / Tetrahedron xxx (xxxx) xxx
5
Acknowledgements
4459e4465;
(
(
(
c) P. He, Q. Tian, C. Kuang, Org. Biomol. Chem. 13 (2015) 7146e7148;
d) W. Liu, Y. Li, B. Xu, C. Kuang, Org. Lett. 15 (2013) 2342e2345;
e) Z. Wang, C. Kuang, Adv. Synth. Catal. 356 (2014) 1549e1554;
We gratefully acknowledge the National Natural Science Foun-
dation of China (Nos. 21662020, 21262020 and 81660626) for the
financial support.
(f) S. Shi, C. Kuang, J. Org. Chem. 79 (2014) 6105e6112.
8] (a) L. Ackermann, A. Althammer, S. Fenner, Angew. Chem. Int. Ed. 48 (2009)
01e204;
b) L. Ackermann, R. Jeyachandran, H. Potukuchi, P. Novak, L. Buttner, Org.
Lett. 12 (2010) 2056e2059;
c) H. Jiang, Z. Feng, A. Wang, X. Liu, Z. Chen, Eur. J. Org Chem. (2010)
227e1230.
[
[
2
(
Appendix A. Supplementary data
(
1
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tet.2020.130985.
9] (a) C. Tirler, L. Ackermann, Tetrahedron 71 (2015) 4543e4551;
(b) L. Ackermann, R. Vicente, A. Althammer, Org. Lett. 10 (2008) 2299e2302.
[
10] (a) F. Zhao, Z. Chen, Y. Liu, K. Xie, Y. Jiang, Eur. J. Org Chem. 2016 (2016)
971e5979;
b) F. Zhao, Z. Chen, X. Ma, S. Huang, Y. Jiang, Tetrahedron Lett. 58 (2017)
14e617;
5
(
6
References
[1] (a) V.V. Rostovtsev, L.G. Green, V.V. Fokin, K.B. Sharpless, Angew. Chem. Int.
(c) Y. Jiang, X. Ma, F. Zhao, C. Han, Synlett 28 (2017) 713e718;
(d) F. Zhao, Z. Chen, S. Huang, Y. Jiang, Synthesis 48 (2016) 2105e2111;
(e) A. Goitia, E. G oꢀ mez-Bengoa, A. Correa, Org. Lett. 19 (2017) 962e965.
Ed. 41 (2002) 2596e2599;
(
2
b) H.C. Kolb, M.G. Finn, K.B. Sharpless, Angew. Chem. Int. Ed. 40 (2001)
004e2021.
[11] (a) S. Zhao, R. Yu, W. Chen, M. Liu, H. Wu, Org. Lett. 17 (2015) 2828e2831;
(b) X.G. Li, K. Liu, G. Zou, P.N. Liu, Eur. J. Org Chem. 2014 (2014) 7878e7888;
(c) Z. Shen, G. Cera, T. Haven, L. Ackermann, Org. Lett. 19 (2017) 3795e3798;
(d) F. Zhao, Y. Liu, S. Yang, K. Xie, Y. Jiang, Org. Chem. Front. 4 (2017)
1112e1115;
(e) A. Irastorza, J.M. Aizpurua, A. Correa, Org. Lett. 18 (2016) 1080e1083.
[12] (a) X. Ma, W. Du, W. Liu, Y. Liu, T. Xiao, Y. Jiang, J. Chem. Sci. 131 (2019) 1e7;
(b) I. Guerrero, A. Correa, Eur. J. Org Chem. 2018 (2018) 6034e6049;
(c) H. Wang, X. Yi, Y. Cui, W. Chen, Org. Biomol. Chem. 16 (2018) 8191e8195;
(d) Z. Yu, C. Zhang, J. Li, Y. Liu, X. Yu, L. Guo, G. Li, Y. Wu, Tetrahedron Lett. 59
(2018) 2816e2819;
(e) R. Sang, Y. Zheng, H. Zhang, X. Wu, Q. Wang, L. Hai, Y. Wu, Org. Chem.
Front. 5 (2018) 648e652.
[13] (a) Y. Ma, F. Xu, C. Chen, Q. Li, M. Wang, Y. Cheng, X. Dong, Ind. Crop. Prod. 133
(2019) 185e192;
(b) C. Ajay G, R. Utpal, D. Gunaseelan, S. Ramkrishna, N. Sushma, Front.
Microbiol. 6 (2015), 1335-1335.
[14] T. Dong, X. Cui, Z. Song, K. Zhao, Z. Ji, K. Lo, K. Tsim, J. Agric. Food Chem. 51
(2003) 4617e4623.
[2] (a) Y. Zhao, H. van Nguyen, L. Male, P. Craven, B. Buckley, J. Fossey, Organo-
metallics 37 (2018) 4224e4241;
(b) K. Lal, P. Yadav, A. Kumar, Med. Chem. Res. 25 (2016) 644e652;
(c) X. Yu, Q. Ma, S. Lv, J. Li, C. Zhang, L. Hai, Q. Wang, Y. Wu, Org. Chem. Front. 4
(2017) 2184e2190.
[
[
3] (a) S. Garg, J. Shreeve, J. Mater. Chem. 21 (2011) 4787e4795;
b) M. Nguyen, J. Byun, S. Kim, J. Hyun, K. Hur, T. Shin, B. Cho, Angew. Chem.
Int. Ed. 58 (2019) 2749e2753.
4] (a) Q. Shen, H. Deng, S. Wang, Y. Tian, Z. Quan, Eur. J. Med. Chem. 173 (2019)
(
1
(
e14;
b) E. Bonandi, M. Christodoulou, G. Fumagalli, D. Perdicchia, G. Rastelli,
D. Passarella, Drug Discov. Today 22 (2017) 1572e1581;
c) M. Giroud, B. Kuhn, S. Saint-Auret, C. Kuratli, R. Martin, et al., J. Med. Chem.
1 (2018) 3370e3388.
(
6
[
[
5] (a) F. Pagliai, T. Pirali, E. Del Grosso, R. Di Brisco, G.C. Tron, G. Sorba,
A. Genazzani, J. Med. Chem. 49 (2006) 467e470;
(
b) P. Yadav, K. Lal, L. Kumar, A. Kumar, A. Kumar, A. Paul, R. Kumar, Eur. J.
Med. Chem. 155 (2018) 263e274.
6] (a) J. He, H. He, L. Zhao, L. Zhang, G. You, L. Feng, J. Wan, H. He, Bioorg. Med.
Chem. 23 (2015) 1395e1401;
[15] (a) P. Gandeepan, K. Parthasarathy, C. Cheng, J. Am. Chem. Soc. 132 (2010)
8569e8571;
(b) X. Chen, K.M. Engle, D. Wang, J. Yu, Angew. Chem. Int. Ed. 48 (2009)
5094e5115.
[16] T. Mindt, H. Struthers, L. Brans, T. Anguelov, C. Schweinsberg, V. Maes,
D. Tourwe, R. Schibli, J. Am. Chem. Soc. 128 (2006) 15096e15097.
(
b) W. Yan, X. Wang, K. Li, T. Li, J. Wang, K. Yao, L. Cao, S. Zhao, Y. Ye, Pestic.
Biochem. Physiol. 156 (2019) 160e169;
(
(
c) S. Yu, L. Wang, Y. Wang, Y. Song, Y. Cao, Y. Jiang, Q. Sun, Q. Wu, RSC Adv. 3
2013) 13486e13490.
[7] (a) S. Shi, W. Liu, P. He, C. Kuang, Org. Biomol. Chem. 12 (2014) 3576e3580;
(
b) X. Yu, Z.D. Huang, W. Liu, S.P. Shi, C.X. Kuang, Org. Biomol. Chem. 13 (2015)
Please cite this article as: Y. Ren et al., Palladium-catalyzed selective ortho CeH alkoxylation at 4-aryl of 1, 4-disubstituted 1, 2, 3-triazoles,
Tetrahedron, https://doi.org/10.1016/j.tet.2020.130985