Palladium-Catalyzed 2H-1,2,3-Triazole-Directed Oxidative Alkoxylation of Arenes with Alcohols

Article abstract of DOI:10.1002/cjoc.201400462

A palladium catalyzed ortho-alkoxylation of aryl C-H bond was accomplished with primary and secondary alcohols as alkoxylation reagents and with triazole as new directing group. This transformation has a good functional group tolerance and is not sensitive to moisture and air. A palladium catalyzed ortho-alkoxylation of aryl C-H bond with alcohols was described. Trizaole was used as new directing group. A series of functional groups could be tolerated and the reaction is not sensitive to moisture and air.

Full text of DOI:10.1002/cjoc.201400462

COMMUNICATION
DOI: 10.1002/cjoc.201400462
Palladium-Catalyzed 2H-1,2,3-Triazole-Directed Oxidative
Alkoxylation of Arenes with Alcohols†
Wenjuan Shia and Zhangjie Shi*,a,b
a Beijing National Laboratory of Molecular Sciences (BNLMS) and Key Laboratory of Bioorganic Chemistry and
Molecular Engineering of Ministry of Education, College of Chemistry, Peking University, Beijing 100871, China
b State Key Laboratory of Organometallic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China
A palladium catalyzed ortho-alkoxylation of aryl C－H bond was accomplished with primary and secondary
alcohols as alkoxylation reagents and with triazole as new directing group. This transformation has a good func-
tional group tolerance and is not sensitive to moisture and air.
Keywords triazole, alkoxylation, palladium, C－H activation
Introduction
preparation by click chemistry,[10] and its wide applica-
tion as a nitrogen ligand.[11] In addition, this directing
group could be remained after the alkoxylation reaction
as it is a widespread applied structure in medicinal
chemistry (Scheme 1),[12] such as an orexin receptor
antagonist (MK4305), and an inhibitor of syk protein
kinase. To explore such chemistry, we reported the
2H-1,2,3-triazole directed C(sp2)－H oxidative alkoxy-
lation with alcohols.[13]
Ethers are fundamental function groups in biologi-
cally active molecules and functional materials.[1]
Therefore, the formation of C－O bond is of high de-
mand. Traditional approaches to alkyl ethers include
acid-catalyzed condensation of alcohols, Williamson
synthesis and mercury catalyzed electrophilic addition
of alcohols to alkenes, [2] as well as Buchwald-Hartwig
etheration.[3] Some drawbacks of current synthetic
methods hampered their applications, including the use
of strong base, toxic reagents and high temperature. In
contrast, direct oxidative alkoxylation of C－H bonds is
appealing, resulting from its high efficiency and atom-
economy.
As a valuable and atom-economical strategy to con-
struct various C－C, C－N, and C－O bonds, transi-
tion-metal catalyzed oxidative cross-couplings have
drawn great attention over the recent decades.[4] There
are several challenges for the C－O bond formation,
especially when alcohols are used as alkoxylation re-
agents:[5] first, the energy gap between LUMO of Pd－
C bond and HOMO of Pd－O bond is very large. Sec-
ond, Pd－O bond is an ionic bond. Third, the in situ
generated palladium alkoxide weakens the eletrophilic-
ity of Pd(II). Fourth, the palladium alkoxide intermedi-
ates are prone to undergo β-elimination to form the cor-
responding ketones or carboxylic acids. Although C－H
bonds acetoxylation and hydroxylation have been re-
ported with remarkable successes based on the ortho
directing group assistance strategy,[6] the C－H alkoxy-
lation remained challenging.[7-9] Herein, we considered
the triazole motif as a new directing group, owing to its
Scheme 1 Applications of triazole motifs
N
N
N
N
N
O
N
MeO
O
N
N
N
NH
N
O
Me
Cl
N
NH2
Me
N
H
MK-4305
NH2
Results and Discussion
We initiated our investigation by examining the
alkoxylation of 2-phenyl-2H-1,2,3-triazole with ethanol
as alkoxylating reagents in the presence of PdCl2 (5.0
mol%), PhI(OAc)2 in a series of solvents. Gratifyingly,
under acidic condition, we obtained the desired product
in 11% yield (entry 1). The use of HOAc as the solvent
promoted the yield to 42% (entry 2).[14] Screening of
several oxidants showed that only the high iodine re-
agents worked well, while oxone, highlighted by San-
ford group[7b] gave a trace amount of product. Many
*
E-mail: zshi@pku.edu.cn; Tel.: 0086-010-62760890; Fax: 0086-010-62760890
Received July 9, 2014; accepted September 12, 2014; published online September 29, 2014.
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/cjoc.201400462 or from the author.
Dedicated to Professor Chengye Yuan and Professor Li-Xin Dai on the occasion of their 90th birthdays.
†
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Chin. J. Chem. 2014, 32, 974—980

Palladium-Catalyzed 2H-1,2,3-Triazole-Directed Oxidative Alkoxylation of Arenes with Alcohols
kinds of palladium catalysts possessed comparable ac-
tivities to Pd(OAc)2. And the catalyst loading and tem-
perature could be reduced to 5.0 mol% and 70 ℃
without obvious decrease of the yield (entries 6－7).
Notably, the reaction was not sensitive to moisture and
air (entries 10－13) .
maceuticals (3r). The naphthyl substrate showed high
efficiency (3s). To be noted that, when the 2-(m-tolyl)-
2H-tetrazole was utilized as substrate, no product was
observed.
To our delight, this transformation was compatible
with a variety of primary and secondary alcohols (Table
3). Both primary and secondary alcohols showed good
reactivity (2a－2d, 2g－2h). The easily removable
benzyl ether can also be obtained in a good yield (2e).
To our interest, the diol directly gave the acetylated
product (2f).
To gain insights into the mechanism, we conducted
experiments to study an intermolecular kinetic isotopic
effect (KIE) (Scheme 2). The intermolecular kinetic
isotopic effect value was 1.38, suggesting that the C－H
bond cleavage may not be involved in the rate deter-
mined step.
Based on these studies and other reported reac-
tions[7-9] we proposed a mechanism as Scheme 3. First, a
five-membered palladacycle (I) was generated by the
C－H bond cleavage step. After the oxidation of the
cyclopalladated species to the key palladium(IV) spe-
cies (II), alcohol coordinated to the Pd center via ligand
exchange. Finally, the intramolecular reductive elimina-
tion formed the desired alkoxylated product company-
ing the regeneration of the Pd(II) catalyst to fulfill the
catalytic cycle.[9b]
With the best condition in hand, we firstly investi-
gated the substrate scope of triazoles (Table 2). With a
meta-substituted methyl group, the yield improved from
67% to 81% compared with the non-substituted arene
(3a－3b). Compared to meta-substitution, the para-
substitution led to relatively lower yields, resulting from
the di-alkoxylaiton byproduct (comparing 3b with 3c,
3e with 3f). It is worth noting that the reaction is not
sensitive to the steric effect. The ortho-methyl and
3,5-dimethyl substrates could afford the products in ex-
cellent yields (3d, 3g－3h). Electronneutral groups in
different positions such as Et, i-Pr, Ph gave the corre-
sponding products in good yields (3i－3k). In the pres-
ence of halo-substituents, good to moderate yields could
be obtained, which offered an opportunity for further
functionalization (3l－3o). In addition, ketone could
also be tolerated (3p). Moreover, the strong electron-
withdrawing nitro group was tolerated under the reac-
tion conditions, which could be a complement to the
traditional electrophilic reaction of nitro compounds
(3q). The trifluoromethyl group could also be used,
which was very promising for the application in phar-
Table 1 Optimization of reaction conditions
N
N
N
N
Pd cat., oxidant
N
N
+
EtOH
H
OEt
solvent,
120 oC, N2, 24 h
1
3
Entry
1
Pd/mol%
Oxidant/equiv.
PhI(OAc)2 (2.0)
PhI(OTFA)2 (2.0)
PhI(OTFA)2 (2.0)
PhI(OTFA)2 (2.0)
PhI(OTFA)2 (2.0)
PhI(OTFA)2 (2.0)
PhI(OTFA)2 (2.0)
PhI(OTFA)2 (2.0)
PhI(OTFA)2 (2.0)
PhI(OTFA)2 (2.0)
PhI(OTFA)2 (2.0)
PhI(OTFA)2 (1.5)
PhI(OTFA)2 (1.2)
Solvent/mL
Yielda/%
11
PdCl2 (5.0%)
HOAc∶TFEol (1.0∶0.8)
HOAc∶TFEol (1.0∶0.8)
HOAc (1.0)
2
PdCl2 (5.0%)
21
3
PdCl2 (10%)
42
4
Pd(OAc)2 (10%)
Pd(OAc)2 (10%)
Pd(OAc)2 (10%)
Pd(OAc)2 (10%)
Pd(OAc)2 (10%)
Pd(OAc)2 (10%)
Pd(OAc)2 (10%)
Pd(OAc)2 (10%)
Pd(OAc)2 (10%)
Pd(OAc)2 (10%)
HOAc (1.0)
57
5
Propionic acid (1.0)
HOAc (2.0)
50
84b
6
7
HOAc (1.8)
86b,c
88b,d
87b,e
85b,e,f
87b,e,f,g
90 (74)b,e,f
77b,e,f
8
HOAc (1.8)
9
HOAc (1.8)
10
11
12
13
HOAc (1.8)
HOAc (2.7)
HOAc (1.8)
HOAc (1.8)
1
a Conditions: 2H-1,2,3-triazole (1a) (0.2 mmol), EtOH (0.4 mL), catalyst, oxidant, solvent, 120 ℃, 12 h, N2. And H NMR yields were
given using CH2Br2 as the internal standard and isolated yield was shown in parentheses. 2,2,2-TFEol＝trifluoroethan-1-ol. b 2-(m-Tolyl)-
e
2H-1,2,3-triazole (1b) was used as the substrate. c 70 ℃ instead of 120 ℃. d 130 ℃ instead of 120 ℃. air (1×105 Pa) instead of N2.
f 12 h instead of 24 h. g EtOH (0.6 mL) was used.
Chin. J. Chem. 2014, 32, 974—980
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COMMUNICATION
Table 2 Substrate scope of triazoles
N
N
N
N
Pd(OAc)2 (10 mol%)
PhI(OTFA)2 (1.5 equiv.)
N
N
H
OMe
R
MeOH : HOAc = (0.4 mL : 1.8 mL)
120 oC, air, 12 h
R
N
1
3
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
OMe
OMe
OMe Me
OMe
OMe
OMe Me
OMe
Me
MeO
Me
OMe
3f, 55%
Me
3g, 82%
3a, 67%
3b, 81%
3c, 58%
3d, 77%
3e, 62%
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
F
OMe
OMe
OMe
OMe
OMe
OMe
Me
Me
Et
Me
iPr
3j, 54%
Ph
F
3h, 45%
3i, 85%
3k, 55%
3l, 47%
3m, 58%
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
OMe
OMe
OMe
OMe
OMe
OMe
Cl
F3C
Cl
COPh
3p, 47%
NO2
3q, 28%
3n, 61%
3o, 45%
3r, 33%
3s, 85%
Condition: 1 (0.2 mmol), Pd(OAc)2 (10 mol%), PhI(OTFA)2 (1.5 equiv.), MeOH (0.4 mL), HOAc (1.8 mL), air, 120 oC, 12 h.
Table 3 Substrate scope of alcohols
N
N
N
N
N
Pd(OAc)2 (10 mol%)
PhI(OTFA)2 (1.5 equiv.)
N
OR2
H
R1
R2OH : HOAc = (0.4 mL : 1.8 mL)
120 oC, air, 12 h
R1
2
1
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
O
O
O
O
O
O
OAc
Me
Me
Me
Me
Me
Me
2e, 54%
2f, 48%
2a, 74%
2b, 68%
2c, 76%
2d, 74%
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
O
O
O
Me
O
O
Me
Me
MeO
Me
2j, 46%
2g, 60%
2h, 62%
2k, 49%
2i, 58%
Condition: 1 (0.2 mmol), Pd(OAc)2 (10 mol%), PhI(OTFA)2 (1.5 equiv.), alcohol (0.4 mL), HOAc (1.8 mL), air, 120 oC, 12 h.
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Palladium-Catalyzed 2H-1,2,3-Triazole-Directed Oxidative Alkoxylation of Arenes with Alcohols
Scheme 2 Deuterium-labeling experiment
performed on silica gel 200－300 mesh. Otherwise, all
reactions were carried out under air atmosphere.
N
N
Pd(OAc)2 (10 mol%)
PhI(OTFA)2 (1.5 equiv.)
N
N
N
General experimental procedure
N
D
D
D
D
General procedure for the palladium catalyzed
alkoxylation To an oven-dried 25 mL Schlenk tube,
Pd(OAc)2 (4.5 mg, 0.02 mmol), PhI(OTFA)2 (172 mg,
0.3 mmol) triazole (1b) (31.8 mg, 0.2 mmol), alcohol
(0.4 mL), HOAc (1.8 mL) were added under air. Then
the sealed tube was placed in a 120 ℃ parallel reactor
and stirred for 12 h. After cooled to room temperature,
the reaction mixture was concentrated under reduced
pressure. The residue was purified by silica gel chro-
matography (EtOAc/petroleum ether: 50∶1 to 30∶1)
to yield the product (30.6 mg, 81%).
MeOH : HOAc = (0.4 mL : 1.8 mL)
120 oC, air, 1 h
D
KIE = 1.38
(0.1 mmol)
(0.1 mmol)
1a
1aa
N
N
N
D
N
N
N
D
D
OMe
D
OMe
3a
3aa
2-(2-Methoxyphenyl)-2H-1,2,3-triazole
(3a)
1
Yield 67%, yellow oil; H NMR (400 MHz, CDCl3) δ:
7.85 (s, 2H), 7.52 (d, J＝7.8 Hz, 1H), 7.43 (t, J＝7.8 Hz,
1H), 7.12－7.03 (m, 2H), 3.86 (s, 3H); 13C NMR (100
MHz, CDCl3) δ: 153.5, 135.1, 130.4, 129.8, 127.1,
120.7, 112.8, 56.3; HRMS ([M ＋ H]), calcd for
C9H10N3O, 176.08184, found 176.08190.
Scheme 3 Plausible mechanism
2-(2-Methoxy-5-methylphenyl)-2H-1,2,3-triazole
1
(3b) Yield 81%, yellow oil; H NMR (400 MHz,
CDCl3) δ: 7.83 (s, 2H), 7.34 (d, J＝1.9 Hz, 1H), 7.21
(dd, J＝8.4, 1.7 Hz, 1H), 6.97 (d, J＝8.4 Hz, 1H), 3.82
(s, 3H), 2.33 (s, 3H); 13C NMR (100 MHz, CDCl3) δ:
151.3, 135.1, 130.7, 130.3, 129.4, 127.4, 112.8, 56.4,
20.3; HRMS ([M ＋ H]), calcd for C10H12N3O,
190.09749, found 190.09758
2-(2-Methoxy-4-methylphenyl)-2H-1,2,3-triazole
1
(3c) Yield 58%, white solid; H NMR (400 MHz,
CDCl3) δ: 7.83 (s, 2H), 7.38 (d, J＝7.9 Hz, 1H), 6.91－
6.83 (m, 2H), 3.84 (s, 3H), 2.42 (s, 3H); 13C NMR (100
MHz, CDCl3) δ: 153.2, 140.8, 135.0, 127.5, 126.7,
121.2, 113.4, 56.2, 21.7; HRMS ([M＋H]), calcd for
C10H12N3O, 190.09749, found 190.09748
Conclusions
In summary, we have developed a palladium-cata-
lyzed C(sp2)-H alkoxylation with primary and secon-
dary alcohols with a new directing group, 2H-1,2,3-
triazole. The arene substrates scope was broad and even
the ortho-substitute and strong electron-withdrawing
groups can be tolerated. The transformation is not sensi-
tive to moisture and air. Further application of this
methodology and new reactions with this directing
group was underway.[13]
2-(2-Methoxy-6-methylphenyl)-2H-1,2,3-triazole
1
(3d) Yield 77%, yellow oil; H NMR (400 MHz,
CDCl3) δ: 7.86 (s, 2H), 7.34 (t, J＝8.0 Hz, 1H), 6.89 (dd,
J＝12.0, 8.0 Hz, 2H), 3.74 (s, 3H), 1.97 (s, 3H); 13C
NMR (100 MHz, CDCl3) δ: 155.7, 137.8, 134.9, 130.7,
129.2, 122.4, 109.5, 56.1, 17.0; HRMS ([M＋H]), calcd
for C10H12N3O, 190.09749, found 190.09753.
2-(2,5-Dimethoxyphenyl)-2H-1,2,3-triazole
(3e)
Yield 62%, white solid; 1H NMR (400 MHz, CDCl3) δ:
7.84 (s, 2H), 7.13 (s, 1H), 7.03 (d, J＝9.1 Hz, 1H), 6.99
－6.96 (m, 1H), 3.81 (s, 3H), 3.80 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ: 153.6, 147.5, 135.2, 130.0, 115.9,
114.5, 112.2, 57.1, 55.9; HRMS ([M＋H]), calcd for
C10H12N3O2, 206.09240, found 206.09235.
Experimental
General experimental methods
All of the reagents were used directly as obtained
commercially. Pd(OAc)2, PhI(OTFA)2 were purchased
from Sinocompound Technology Co., Ltd., Alfa Aesar.
NMR spectra were recorded on Bruker 400 M spec-
2-(2,4-Dimethoxyphenyl)-2H-1,2,3-triazole
(3f)
Yield 55%, white solid; 1H NMR (400 MHz, CDCl3) δ:
7.75 (s, 2H), 7.34 (d, J＝8.7 Hz, 1H), 6.54 (s, 1H), 6.48
(d, J＝8.7 Hz, 1H), 3.77 (s, 3H), 3.74 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ: 161.3, 154.8, 134.9, 127.9, 123.5,
104.4, 99.7, 56.1, 55.6; HRMS ([M＋H]), calcd for
C10H12N3O2, 206.09240, found 206.09227.
1
trometers, operating at 400 MHz for H NMR and 100
MHz for 13C NMR using CDCl3 and TMS as the inter-
nal standard. High-resolution mass spectra (HRMS)
were recorded on a Bruker Apex IV FTMS mass spec-
trometer (ESI) in the State-authorized Analytical Center
in Peking University. Column chromatography was
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COMMUNICATION
2-(2-Methoxy-4,6-dimethylphenyl)-2H-1,2,3-tria-
zole (3g) Yield 82%, yellow solid; H NMR (400
CDCl3) δ: 7.85 (s, 2H), 7.57 (d, J＝2.6 Hz, 1H), 7.38
(dd, J＝8.9, 2.6 Hz, 1H), 7.02 (d, J＝8.9 Hz, 2H), 3.86
(s, 3H); 13C NMR (100 MHz, CDCl3) δ: 152.0, 135.5,
130.2, 130.0, 126.9, 125.5, 114.0, 56.6; HRMS ([M＋
H]), calcd for C9H9N3OCl, 210.04287, found
210.04257.
1
MHz, CDCl3) δ: 7.85 (s, 2H), 6.70 (d, J＝15.6 Hz, 2H),
3.73 (s, 3H), 2.38 (s, 3H), 1.93 (s, 3H); 13C NMR (100
MHz, CDCl3) δ: 155.3, 140.9, 137.3, 134.8, 126.8,
123.0, 110.2, 56.0, 21.8, 16.9; HRMS ([M＋H]), calcd
for C11H14N3O, 204.11314, found 204.11257.
2-(4-Chloro-2-methoxyphenyl)-2H-1,2,3-triazole
1
2-(2-Methoxy-3,5-dimethylphenyl)-2H-1,2,3-tria-
(3o) Yield 45%, white solid; H NMR (400 MHz,
1
zole (3h) Yield 45%, yellow oil; H NMR (400 MHz,
CDCl3) δ: 7.85 (s, 2H), 7.47 (d, J＝8.3 Hz, 1H), 7.11－
7.01 (m, 2H), 3.87 (s, 3H); 13C NMR (100 MHz, CDCl3)
δ: 153.9, 135.8, 135.4, 128.4, 127.8, 120.8, 113.4, 56.6;
HRMS ([M＋H]), calcd for C9H9N3OCl, 210.04287,
found 210.04308.
(3-Methoxy-4-(2H-1,2,3-triazol-2-yl)phenyl)(phe-
nyl)methanone (3p) Yield 47%, yellow solid; 1H
NMR (400 MHz, CDCl3) δ: 7.88 (s, 2H), 7.82 (d, J＝
8.1 Hz, 2H), 7.67 (d, J＝8.1 Hz, 1H), 7.64－7.57 (m,
2H), 7.50 (t, J＝7.6 Hz, 2H), 7.42 (dd, J＝8.1, 1.6 Hz,
1H), 3.94 (s, 3H); 13C NMR (100 MHz, CDCl3) δ: 195.4,
153.1, 138.9, 137.2, 135.7, 132.8, 132.5, 130.0, 128.4,
126.3, 122.9, 114.0, 56.6; HRMS ([M＋H]), calcd for
C16H14N3O2, 280.10805, found 280.10805.
CDCl3) δ: 7.85 (s, 2H), 7.23 (s, 1H), 7.09 (s, 1H), 3.51
(s, 3H), 2.33 (s, 3H), 2.32 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ: 149.9, 135.2, 133.5, 133.3, 132.7, 132.5,
124.5, 60.9, 20.6, 16.1; HRMS ([M＋H]), calcd for
C11H14N3O, 204.11314, found 204.11316.
2-(5-Ethyl-2-methoxyphenyl)-2H-1,2,3-triazole (3i)
1
Yield 85%, yellow oil; H NMR (400 MHz, CDCl3) δ:
7.84 (s, 2H), 7.36 (d, J＝2.2 Hz, 1H), 7.24 (dd, J＝8.5,
2.2 Hz, 1H), 7.00 (d, J＝8.5 Hz, 1H), 3.83 (s, 3H), 2.65
(q, J＝7.6 Hz, 2H) 1.24 (t, J＝7.6 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ: 151.4, 136.8, 135.1, 129.6, 129.5,
126.3, 112.8, 56.4, 27.8, 15.5; HRMS ([M＋H]), calcd
for C11H14N3O, 204.11314, found 204.11315.
2-(4-Isopropyl-2-methoxyphenyl)-2H-1,2,3-tria-
zole (3j) Yield 54%, yellow oil; H NMR (400 MHz,
2-(2-Methoxy-4-nitrophenyl)-2H-1,2,3-triazole (3q)
Yield 28%, yellow solid; 1H NMR (400 MHz, CDCl3) δ:
7.97－7.93 (m, 2H), 7.90 (s, 2H), 7.80 (dd, J＝7.7, 1.4
Hz, 1H), 4.00 (s, 3H); 13C NMR (100 MHz, CDCl3) δ:
153.2, 148.2, 136.2, 134.1, 126.8, 116.0, 108.3, 57.0;
HRMS ([M＋H]), calcd for C9H9N4O3, 221.06692,
found 221.06644.
1
CDCl3) δ: 7.82 (s, 2H), 7.42 (d, J＝8.5 Hz, 1H), 6.94－
6.90 (m, 2H), 3.85 (s, 3H), 2.96 (dt, J＝13.8, 6.9 Hz,
1H), 1.29 (d, J＝6.9 Hz, 6H); 13C NMR (100 MHz,
CDCl3) δ: 153.4, 151.9, 135.0, 127.6, 126.9, 118.5,
111.0, 56.2, 34.4, 23.9; HRMS ([M＋H]), calcd for
C12H16N3O, 218.12879, found 218.12874.
2-(3-Methoxy-[1,1'-biphenyl]-4-yl)-2H-1,2,3-tria-
zole (3k) Yield 55%, white solid; 1H NMR (400 MHz,
CDCl3) δ: 7.86 (s, 2H), 7.61 (t, J＝8.2 Hz, 3H), 7.46 (t,
J＝7.4 Hz, 2H), 7.39 (t, J＝7.3 Hz, 1H), 7.28－7.26 (m,
2H), 3.92 (s, 3H); 13C NMR (100 MHz, CDCl3) δ: 153.5,
143.7, 140.3, 135.3, 128.9, 128.0, 127.3, 127.2, 119.5,
111.7, 56.4; HRMS ([M＋H]), calcd for C15H14N3O,
252.11314, found 252.11335.
2-(2-Methoxy-5-(trifluoromethyl)phenyl)-2H-1,2,
1
3-triazole (3r) Yield 33%, white solid; H NMR (400
MHz, CDCl3) δ: 7.88 (s, 2H), 7.85 (d, J＝2.1 Hz, 1H),
7.70 (dd, J＝8.7, 2.1 Hz, 1H), 7.18 (d, J＝8.7 Hz, 1H),
3.94 (s, 3H); 13C NMR (100 MHz, CDCl3) δ: 155.8,
135.7, 129.6, 127.5 (q, J＝3.7 Hz), 124.5 (q, J＝3.7 Hz),
123.7 (q, J＝269.7 Hz), 123.1 (q, J＝33.8 Hz), 112.8,
56.6; HRMS ([M ＋ H]), calcd for C10H9N3OF3,
244.06922, found 244.06851.
2-(2-Fluoro-6-methoxyphenyl)-2H-1,2,3-triazole
(3l) Yield 47%, yellow oil; 1H NMR (400 MHz,
CDCl3) δ: 7.90 (s, 2H), 7.47－7.37 (m, 1H), 6.91－6.80
(m, 2H), 3.80 (s, 3H); 13C NMR (100 MHz, CDCl3) δ:
158.8 (d, J＝253.7 Hz), 156.7 (d, J＝3.1 Hz), 135.6,
131.4 (d, J＝10.3 Hz), 118.6 (d, J＝15.0 Hz), 108.4 (d,
J＝19.9 Hz), 107.6 (d, J＝3.2 Hz), 56.6; HRMS ([M＋
H]), calcd for C9H9N3OF, 194.07242, found 194.07255.
2-(4-Fluoro-2-methoxy-5-methylphenyl)-2H-1,2,
2-(3-Methoxynaphthalen-2-yl)-2H-1,2,3-triazole (3s)
Yield 85%, white solid; 1H NMR (400 MHz, CDCl3) δ:
8.02 (s, 1H), 7.89 (s, 2H), 7.77 (t, J＝9.2 Hz, 2H), 7.49
(t, J＝7.2 Hz, 1H), 7.37 (t, J＝7.2 Hz, 1H), 7.30 (s, 1H),
3.93 (s, 3H); 13C NMR (100 MHz, CDCl3) δ: 151.6,
135.4, 134.3, 130.4, 128.1, 127.8, 127.6, 126.6, 126.4,
124.8, 107.7, 56.2; HRMS ([M ＋ H]), calcd for
C13H12N3O, 226.09749, found 226.09687.
2-(2-Ethoxy-5-methylphenyl)-2H-1,2,3-triazole (2a)
1
1
3-triazole (3m) Yield 58%, white solid; H NMR
Yield 74%, yellow oil; H NMR (400 MHz, CDCl3) δ:
(400 MHz, CDCl3) δ: 7.83 (s, 2H), 7.34 (d, J＝8.0 Hz,
1H), 6.77 (d, J＝11.0 Hz, 1H), 3.82 (s, 3H), 2.25 (d, J＝
1.7 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ: 161.6 (d,
J＝247.9 Hz), 152.8 (d, J＝10.4 Hz), 135.1, 129.4 (d,
J＝7.5 Hz), 125.5 (d, J＝3.5 Hz), 116.7 (d, J＝19.0 Hz),
100.6 (d, J＝27.9 Hz), 56.5, 13.5 (d, J＝2.8 Hz); HRMS
([M＋H]), calcd for C10H11N3OF, 208.08807, found
208.08812.
7.82 (s, 2H), 7.32 (d, J＝1.5 Hz, 1H), 7.19 (dd, J＝8.4,
1.6 Hz, 1H), 6.97 (d, J＝8.4 Hz, 1H), 4.05 (q, J＝7.0 Hz,
2H), 2.33 (s, 3H), 1.29 (t, J＝7.0 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ: 150.8, 134.9, 130.7, 130.4, 130.0,
127.5, 114.5, 65.3, 20.3, 14.6; HRMS ([M＋H]), calcd
for C11H14N3O, 204.11314, found 204.11324.
2-(5-Methyl-2-propoxyphenyl)-2H-1,2,3-triazole
1
(2b) Yield 68%, yellow oil; H NMR (400 MHz,
2-(5-Chloro-2-methoxyphenyl)-2H-1,2,3-triazole
(3n) Yield 61%, white solid; H NMR (400 MHz,
CDCl3) δ: 7.82 (s, 2H), 7.32 (s, 1H), 7.19 (d, J＝8.4 Hz,
1H), 6.96 (d, J＝8.4 Hz, 1H), 3.93 (t, J＝6.5 Hz, 2H),
1
978
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© 2014 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2014, 32, 974—980

Palladium-Catalyzed 2H-1,2,3-Triazole-Directed Oxidative Alkoxylation of Arenes with Alcohols
2.33 (s, 3H), 1.77－1.61 (m, 2H), 0.88 (t, J＝7.4 Hz,
3H); 13C NMR (100 MHz, CDCl3) δ: 151.1, 134.8,
130.7, 130.3, 130.0, 127.4, 114.4, 22.4, 20.3, 10.2;
HRMS ([M＋H]), calcd for C12H16N3O, 218.12879,
found 218.12864.
6.9 Hz, 3H), 1.23 (dd, J＝11.8, 5.0 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ: 149.9, 134.8, 131.4, 130.7, 130.7,
127.5, 117.4, 77.6, 31.4, 25.5, 23.1, 20.3; HRMS ([M＋
H]), calcd for C15H20N3O, 258.16009, found 258.16053.
2-(2-Ethoxy-6-methylphenyl)-2H-1,2,3-triazole (2i)
1
2-(2-Butoxy-5-methylphenyl)-2H-1,2,3-triazole
Yield 58%, yellow oil; H NMR (400 MHz, CDCl3) δ:
1
7.85 (s, 2H), 7.31 (d, J＝8.0 Hz, 1H), 6.88 (dd, J＝10.5,
8.0 Hz, 2H), 3.99 (q, J＝7.0 Hz, 2H), 1.98 (s, 3H), 1.21
(t, J＝7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ:
155.2, 137.7, 134.7, 130.6, 129.8, 122.2, 110.8, 64.6,
17.0, 14.5; HRMS ([M＋H]), calcd for C11H14N3O,
204.11314, found. 204.11346.
(2c) Yield 76%, yellow oil; H NMR (400 MHz,
CDCl3) δ: 7.79 (s, 2H), 7.30 (d, J＝2.0 Hz, 1H), 7.16
(dd, J＝8.4, 2.2 Hz, 1H), 6.94 (d, J＝8.4 Hz, 1H), 3.94
(t, J＝6.5 Hz, 2H), 2.30 (s, 3H), 1.66－1.59 (m, 2H),
1.35－1.26 (m, 2H), 0.84 (t, J＝7.4 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ: 151.1, 134.8, 130.7, 130.2, 130.0,
127.4, 114.4, 69.3, 31.1, 20.3, 19.0, 13.7; HRMS ([M＋
H]), calcd for C13H18N3O, 232.14444, found 232.14447.
2-(5-Methyl-2-(pentyloxy)phenyl)-2H-1,2,3-tria-
2-(2-Ethoxy-4-methylphenyl)-2H-1,2,3-triazole (2j)
1
Yield 46%, yellow oil; H NMR (400 MHz, CDCl3) δ:
7.81 (s, 2H), 7.36 (d, J＝7.9 Hz, 1H), 6.91－6.81 (m,
2H), 4.06 (q, J＝7.0 Hz, 2H), 2.40 (s, 3H), 1.30 (q, J＝
7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ: 140.8,
134.8, 128.0, 126.8, 121.2, 114.9, 64.9, 21.7, 14.6;
HRMS ([M＋H]), calcd for C11H14N3O, 204.11314,
found 204.11334.
1
zole (2d) Yield 74%, yellow oil; H NMR (400 MHz,
CDCl3) δ: 7.81 (s, 2H), 7.31 (d, J＝1.9 Hz, 1H), 7.19
(dd, J＝8.4, 1.9 Hz, 1H), 6.96 (d, J＝8.4 Hz, 1H), 3.96
(t, J＝6.6 Hz, 2H), 2.33 (s, 3H), 1.67 (dd, J＝16.9, 10.0
Hz, 2H), 1.34－1.18 (m, 4H), 0.85 (t, J＝7.1 Hz, 3H);
13C NMR (100 MHz, CDCl3) δ: 151.1, 134.8, 130.7,
130.2, 130.0, 127.4, 114.4, 69.7, 28.7, 27.9, 22.3, 20.3,
13.9; HRMS ([M ＋ H]), calcd for C14H20N3O,
246.16009, found 246.16018.
2-(2-Ethoxy-5-methoxyphenyl)-2H-1,2,3-triazole
1
(2k) Yield 49%, yellow oil; H NMR (400 MHz,
CDCl3) δ: 7.84 (s, 2H), 7.10 (d, J＝3.0 Hz, 1H), 7.03 (d,
J＝9.1 Hz, 1H), 6.96 (dd, J＝9.1, 3.0 Hz, 1H), 4.01 (q,
J＝7.0 Hz, 2H), 3.80 (s, 3H), 1.28 (t, J＝7.0 Hz, 3H);
13C NMR (100 MHz, CDCl3) δ: 153.7, 146.9, 135.1,
130.9, 116.8, 116.1, 112.0, 66.3, 55.9, 14.8; HRMS ([M
＋ H]), calcd for C11H14N3O, 220.10805, found
220.10825.
2-(2-(Benzyloxy)-5-methylphenyl)-2H-1,2,3-tria-
1
zole (2e) Yield 54%, yellow oil; H NMR (400 MHz,
CDCl3) δ: 7.85 (s, 2H), 7.36 (d, J＝1.9 Hz, 1H), 7.31－
7.22 (m, 5H), 7.16 (dd, J＝8.4, 1.7 Hz, 1H), 6.99 (d,
J＝8.4 Hz, 1H), 5.10 (s, 2H), 2.33 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ: 150.4, 136.7, 135.1, 131.0, 130.7,
128.4, 127.7, 127.5, 126.9, 115.3, 71.3, 20.3; HRMS
([M ＋ H]), calcd for C16H16N3O, 266.12879, found
266.12922.
Acknowledgement
Support of this work by the “973” Project from the
MOST of China (2015CB856600) and NSFC (No.
21332001) is gratefully acknowledged.
5-(4-Methyl-2-(2H-triazol-2-yl)phenoxy)pentyl
1
acetate (2f) Yield 48%, yellow oil; H NMR (400
MHz, CDCl3) δ: 7.80 (s, 2H), 7.30 (d, J＝1.9 Hz, 1H),
7.19 (dd, J＝8.4, 1.9 Hz, 1H), 6.94 (d, J＝8.4 Hz, 1H),
4.02－3.93 (m, 4H), 2.32 (s, 3H), 2.01 (s, 3H), 1.72－
1.64 (m, 2H), 1.62－1.51 (m, 2H), 1.41－1.31 (m, 2H);
13C NMR (100 MHz, CDCl3) δ: 171.1, 151.0, 134.9,
130.8, 130.5, 130.0, 127.5, 114.4, 69.3, 64.3, 28.6, 28.2,
22.3, 21.0, 20.3; HRMS ([M ＋ H]), calcd for
C16H22N3O3, 304.16557, found 304.16597.
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2-(2-Isopropoxy-5-methylphenyl)-2H-1,2,3-tria-
1
zole (2g) Yield 60%, yellow oil; H NMR (400 MHz,
CDCl3) δ: 7.81 (s, 2H), 7.31 (d, J＝2.0 Hz, 1H), 7.18
(dd, J＝8.4, 2.0 Hz, 1H), 7.00 (d, J＝8.4 Hz, 1H), 4.33
(hept, J＝6.1 Hz, 1H), 2.32 (s, 3H), 1.20 (d, J＝6.1 Hz,
6H); 13C NMR (100 MHz, CDCl3) δ: 150.1, 134.8,
131.4, 130.9, 130.7, 127.6, 117.6, 73.0, 22.0, 20.3;
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found 218.12859.
2-(2-(Cyclohexyloxy)-5-methylphenyl)-2H-1,2,3-
1
triazole (2h) Yield 62%, yellow oil; H NMR (400
MHz, CDCl3) δ: 7.81 (s, 2H), 7.31 (d, J＝1.9 Hz, 1H),
7.18 (dd, J＝8.4, 1.9 Hz, 1H), 7.00 (d, J＝8.4 Hz, 1H),
4.16－4.08 (m, 1H), 2.33 (s, 3H), 1.78 (dd, J＝12.1, 6.1
Hz, 2H), 1.65－1.54 (m, 2H), 1.46 (ddd, J＝12.9, 10.6,
Chin. J. Chem. 2014, 32, 974—980
© 2014 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
979

Shi & Shi
COMMUNICATION
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[14] When HOAc was used as the solvent, the side reactions, such as
di-alkoxylation, and even acetoxylation, hydroxylation could be
minimized. And when t-BuOH was the solvent, only the hydrolytic
product was observed.
(Zhao, X.)
980
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© 2014 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2014, 32, 974—980