Pd-catalyzed ligand-free C(5)–H arylation of 1,4-disubstituted 1,2,3-triazoles promoted by microwaves

Article abstract of DOI:10.1080/00397911.2016.1222441

Pd(OAc)₂-catalyzed regioselective C(5)–H arylation of 1,4-disubstituted 1,2,3-triazoles was achieved without ligand under microwave conditions in 1 h, generating 1,4,5-trisubstituted 1,2,3-triazoles with good to excellent yields. The obtained molecules can be easily converted into 4,5-disubstituted 1,2,3-triazoles through the debenzylation process with one-pot manipulation.

Full text of DOI:10.1080/00397911.2016.1222441

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
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Pd-Catalyzed Ligand-Free C(5)–H Arylation of
1,4-disubstituted 1,2,3-triazoles Promoted by
Microwave
Fen Zhao, Wen-Hai Tian, Fang Luo, Hui-Ling Cheng, Yu-Bo Jiang & Zhen Chen
To cite this article: Fen Zhao, Wen-Hai Tian, Fang Luo, Hui-Ling Cheng, Yu-Bo Jiang & Zhen
Chen (2016): Pd-Catalyzed Ligand-Free C(5)–H Arylation of 1,4-disubstituted 1,2,3-triazoles
Promoted by Microwave, Synthetic Communications
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Date: 25 August 2016, At: 01:57

Pd-catalyzed ligand-free C(5)–H arylation of 1,4-disubstituted 1,2,3-triazoles
promoted by microwave
Fen Zhao1, Wen-Hai Tian2, Fang Luo1, Hui-Ling Cheng1, Yu-Bo Jiang1, Zhen Chen1
1Faculty of Science, Kunming University of Science and Technology, Kunming,
China,2Department of Architectural Engineering, Huaibei Vocational and Technical
College, Huaibei, China
Address correspong Authors:
Yu-bo Jiang: Faculty of Science, Kunming University of Science and Technology,
Kunming 650500, China. E-mail: ybjiang@kmust.edu.cn
Zhen Chen: Faculty of Science, Kunming University of Science and Technology,
Kunming 650500, China. E-mail: chenzhen69@qq.com
Abstract
Pd(OAc)2-catalyzed regioselective C(5)–H arylation of 1,4-disubstituted 1,2,3-triazoles
was achieved without ligand under microwave conditions in 1 h, generating
1,4,5-trisubstituted 1,2,3-triazoles with good to excellent yields. The obtained molecules
can be easily converted into 4,5-disubstituted 1,2,3-triazoles through the debenzylation
process with one-pot manipulation.
Graphical Abstract
1

Pd(OAc)2-catalyzed regioselective C–H arylation on the C-5 position of 1,4-disubstituted
1,2,3-triazoles was achieved without ligand under microwave conditions in 1 hour,
generating 1,4,5-trisubstituted 1,2,3-triazoles with good to excellent yields. The obtained
molecules can be converted into 4,5-disubstituted 1,2,3-triazoles facilely by
debenzylation process in one pot.
KEYWORDS: Pd-catalyzed, ligand-free, C–H arylation, 1,2,3-triazoles, microwave
INTRODUCTION
With recent developments in the synthesis of various 1,2,3-triazole derivatives, these
heterocycles have varied applications in many fields, including biological science as HIV
protease inhibitors,[1,2] anticancer,[3,4] antituberculosis,[5–7] and antibacterial drugs,[8,9] as
well as materials, such as energetic materials,[10,11] dyes,[12–14] ionic liquids,[15–17] liquid
crystal,[18,19] and transition metal ligands.[20,21] The three types of 1,2,3-triazole
derivatives mainly contain monosubstituted, disubstituted, and trisubstituted
1,2,3-triazoles. The monosubstituted and disubstituted 1,2,3-triazoles are prepared from
azides and terminal alkynes catalyzed by Cu(I),[22–24] Ru(I),[25–27] and organic
catalysts.[28,29] Three kinds of methodologies for the construction of trisubstituted
1,2,3-triazoles have been the focus of considerable attention in the past five years
(Scheme 1). The first method employs the cycloaddition of organic azides with
methylene ketones and internal alkynes and alkenes, using Cu, Fe, and organic catalysts
(Scheme 1, a).[30–33] The second process employed to construct triazoles depends on
2

trapping the 5-Cu(I)-1,2,3-triazole intermediate in the CuAAC reaction by an exogenous
electrophile (Scheme 1, b).[34–36] The third technique utilized to access this trisubstituted
heterocycle involves the direct modification of 1,4-disubstituted 1,2,3-triazoles through
Pd-catalyzed C–H functionalization, in which expensive phosphorous ligands are usually
used (Scheme 1, c).[37,38] Some of aforementioned methods have high efficiency and good
functional group compatibility. However, most of these methods have a long reaction
time. In this study, we propose a microwave (10 W)-promoted efficient method to form
1,4,5-trisubstitued 1,2,3-triazoles from 1,4-disubstituted 1,2,3-triazoles, using Pd(OAc)2
as the catalyst under ligand-free conditions for 1 h (Scheme 1, d).
RESULTS AND DISCUSSION
Our initial investigations focused on the model cross-coupling reaction of
1-benzyl-4-phenyl-1H-1,2,3-triazole 1a with 1-iodo-4-methylbenzene 2a, which was
conducted under microwave conditions at 10 W for 1 h, generating the target molecule
1,4,5-trisubstituted 1,2,3-triazole 3a. The C(5)–H bond of the triazole ring can be
arylated, producing 3a with 27% yield when the reaction was catalyzed by Pd(PPh3)4
(10%) under the influence of K2CO3 in solvent of H2O (Table 1, entry 1). Further base
screening indicated that Cs2CO3 favored the activation of the C(5)–H bond of
1,2,3-triazole, producing 3a with 36% yield (Table 1, entry 2). When bases, such as
tBuOK and Ag2CO3, were used, the product can be obtained, but with low yields ( Table
1, entries 3 and 4). However, no target molecules of 3a were detected when Na2CO3,
K3PO4, or KH2PO3 was used as a base (Table 1, entries 5 to 7). When the reaction was
performed with Pd(OAc)2-PPh3 as the catalyst system instead of Pd(PPh3)4, no expected
3

product was obtained (Table 1, entry 8). Further explorations indicate that the coupling
was remarkably affected by the reaction medium. Aprotic organic solvents, such as
DMSO, DMF, DMA, DCE, and DEA are favored for the construction of
1,4,5-trisubstituted 1,2,3-triazoles (Table 1, entries 9 to 13). A moderate yield of 58%
was achieved when the reaction was conducted in DMA catalyzed by Pd(OAc)2, using
Cs2CO3 as the base (Table 1, entry 11). By contrast, no target molecules of 3a were
detected when PhMe or TFA was used as solvent (Table 1, entries 14 and 15). A better
yield of 85% was obtained when PPh3 was selected as a ligand for the aforementioned
reaction (Table 1, entry 16). However, changing the ligand to S-Phos, X-Phos, or TCHP
instead of PPh3 resulted in lower yields (Table 1, entries 17 to 19). Notably, an excellent
yield of 94% was achieved when the ligand of PPh3 was replaced by trimethylacetic acid
(tBuCO2H) (Table 1, entry 20). Trimethylacetic acid (tBuCO2H) may be used as
cocatalyst in the basic reaction conditions.[39] Only a low yield of 46% was obtained
when DMA-H2O mixture (1:1 in volume) was applied as the solvent (Table 1, entry 21).
Further explorations indicate that increasing or decreasing microwave power did not
favor the reaction (Table 1, entries 22 to 23). If the amount of catalyst was decreased to
5%, then only a 72% yield of the product could be obtained (Table 1, entry 24).
Conventional heating seems inefficient, as the yield reached only 55% when the reaction
was conducted under 120 °C for 24 h (Table 1, entry 25). Thus, the optimized condition
was achieved when the reaction of 1-benzyl-4-phenyl-1H-1,2,3-triazole 1a (0.3 mmol)
with 1-iodo-4-methylbenzene 2a (0.36 mmol) was conducted in DMA catalyzed by
Pd(OAc)2 (0.03 mmol), using Cs2CO3 (0.6 mmol) as the base and tBuCO2H (0.06 mmol)
as the additive under 10 W microwave conditions for 1 h (Table 1, entry20).
4

The versatility and functional group tolerance of the C(5)–H arylation of triazoles 1 was
investigated under the optimized reaction conditions. Table 2 shows that a variety of
substituents, such as Me, OMe, F, Cl, and Br, on the substrates were tolerated and had no
significant effect on the reactions, but obtained good to excellent yields in most cases.
Halides and alkyl groups on ortho, meta, and para positions of aryl iodides were all
suitable for this transformations. Notably, electron-rich iodides were observed to be more
efficient for C–C coupling, producing higher yields than electron-poor iodides (Table 2,
3b–d vs 3e–f, 3h–i vs 3j, 3l–n vs 3o, and 3q–r vs 3s). The use of aryl bromides instead
of iodides for this system were explored, and the reactions proceeded smoothly with
excellent yields (as shown in parentheses in Table 2, 3a–c, 3g, and 3k–l).
According to recent literature,[40] the proposed Pd(0)/Pd(II) catalytic cycle for the C(5)–H
arylation of 1,4-disubstituted 1,2,3-triazoles to form 1,4,5-triazoles is shown in Scheme 2.
The aryl palladium intermediate A is generated through oxidative addition of aryl iodide
1 to active species Pd(0), which was produced from the reduction of Pd(II) in situ. Then,
the coordination of the base to intermediate A generates the Pd intermediate B, in which
C–H bond activation will occur via the CMD pathway to yield the tricoordinated Pd
intermediate C. Aryl triazole-4-yl palladium species D is formed through the release of a
molecule of CsHCO3. In the final step, reductive elimination of intermediate D yields the
desired C–C coupling C(5) arylated product of 1,4,5-trisubstituted 1,2,3-triazole 3
through the release of the Pd(0) species to complete the catalytic cycle.
5

In addition, the applications of synthesized products were investigated. One of the most
important processes is to transform the obtained trisubstituted molecules to
4,5-disubstituted 1,2,3-triazoles through the debenzylation process with one-pot
manipulation. According to the reported methods,[41–43] we conducted some experiments
by adding relevant reagents to the system for the next step of the debenzylation process
under the same microwave conditions when C(5)–H arylation was completed. The
tBuOK-DMSO combination is a good choice for this transformation. When the reaction
for the synthesis of 1,4,5-triazoles is completed, 2 equiv of tBuOK and 1 mL of DMSO
were added to the system for the subsequent debenzylation reaction. After the mixture
was promoted under 10 W microwave for another 0.5 h, good to excellent yields of
4,5-disubstuted 1,2,3-triazoles 4 were obtained (Table 3).
CONCLUSION
In conclusion, we developed a highly efficient method for the synthesis of
1,4,5-trisubstituted 1,2,3-triazoles through C(5)–H activation of 1,4-disubstituted
1,2,3-triazoles under 10 W microwave conditions for 1 h catalyzed by Pd(OAc)2.
Moreover, the system can be easily used to prepare 4,5-disubstituted 1,2,3-triazoles
through the debenzylation process with one-pot manipulation under similar conditions for
another 0.5 h.
6

EXPERIMENTAL
All reactions were conducted using the CEM Discover-SP microwave instrument. 1H and
13C NMR spectra were recorded with a MercuryPlus 300 (300 MHz) or a Bruker ACF400
spectrometer (400 MHz) in d6-DMSO or CDCl3 with TMS as an internal standard. All
reactions were monitored by TLC analysis with HuanghaiGF 254 silica gel-coated plates.
Column chromatography was conducted using 300 to 400 mesh silica gel at medium
pressure. Infrared spectra were recorded on the Bruker Vertex Series FTIR (KBr) and
were reported in reciprocal centimeters (cm−1). Melting points were obtained using the
Büchi melting point apparatus and were uncorrected. HRMS spectra were recorded on
the Waters Micromass Premier Q-TOF spectrometer.
General Procedures For The Synthesis Of Compound 3a
1-Benzyl-4-phenyl-1H-1,2,3-triazole 1a (0.3 mmol), iodobenzene 2a (0.36 mmol, 1.2
equiv), Pd(OAC)2 (7 mg, 0.03 mmol, 10 mol%), tBuCO2H (6 mg, 0.06 mmol, 20 mol%),
Cs2CO3 (195 mg, 0.6 mmol, 2.0 equiv), and DMA (2.0 mL) were added to a 5 mL
microwave reaction tube. The mixture was promoted under 10 W microwave for 1 h. After
consumption of the 1-benzyl-4-phenyl-1H-1,2,3-triazole monitored by TLC analysis, the
mixture was added with H2O (15 mL) and extracted with EtOAc (3 × 15 mL). The
combined organic layer was washed with brine (3 × 5 mL), dried over Na2SO4, and
concentrated under reduced pressure to yield a crude product. Purification by column
7

chromatography on silica gel yielded the desired 1-benzyl-4,5-diphenyl-1H-1,2,3-triazole
3a.
Formation Of Compound 4a By The Debenzylation Process With One-Pot
Manipulation
1-Benzyl-4-phenyl-1H-1,2,3-triazole 1a (0.3 mmol), 1-iodo-4-methylbenzene 2a (0.36
mmol, 1.2 equiv), Pd(OAC)2 (7 mg, 0.03 mmol, 10 mol%), tBuCO2H (6 mg, 0.06 mmol, 20
mol%), Cs2CO3 (195 mg, 0.6 mmol, 2.0 equiv), and DMA (2.0 mL) were added to a 5 mL
microwave reaction tube. The mixture was promoted under 10 W microwave for 1 h. After
consumption of 1a monitored by TLC analysis, the mixture was added with 2 equiv of
tBuOK and 1 mL DMSO and promoted under 10 W microwave for another 0.5 h until the
debenzylation process was completed. Then, the system was added with H2O (15 mL) and
extracted with EtOAc (3 × 15 mL). The combined organic layer was washed with brine (3
× 5 mL), dried over Na2SO4, and concentrated under reduced pressure to yield a crude
product. Purification by column chromatography on silica gel yielded the desired
4-phenyl-5-(p-tolyl)-1H-1,2,3-triazole 4a.
Spectral Data For The Selected Compounds
Compound 3f: Brown solid; mp 89 °C to 91 °C; 1H NMR (400 MHz, DMSO): δ = 7.59
(d, J = 7.7 Hz, 1H), 7.51 (d, J = 7.7 Hz, 1H), 7.48-7.39 (m, 3H), 7.36 to 7.23 (m, 7H),
8

6.98 (d, J = 5.1 Hz, 2H), 5.50 (s, 2H); 13C NMR (100 MHz, DMSO): δ = 143.2, 134.9,
133.2, 132.0, 130.5, 129.9, 129.3, 129.1, 128.8, 128.3, 128.1, 128.1, 127.4, 126.7, 126.7,
125.8, 51.0; IR (KBr) = 3,418, 3,128, 2,308, 1,602, 1,568, 1,498, 1,349, 1,130, 1,096,
990, 814, 777, 693 cm−1; HRMS calculated for [C21H16ClN3+H]+ = 346.1106, Found =
346.1108.
Compound 3i: Light brown oil; 1H NMR (400 MHz, DMSO): δ = 7.43 to 7.32 (m, 4H),
7.31 to 7.22 (m, 3H), 7.16 to 7.04 (m, 4H), 7.04 to 6.91 (m, 2H), 5.43 (s, 2H), 2.28 (s,
3H), 2.24 (s, 3H); 13C NMR (100 MHz, DMSO): δ = 142.8, 138.0, 136.5, 135.2, 133.1,
129.8, 129.8, 128.6, 128.5, 128.4, 128.0, 127.5, 127.3, 126.7, 126.5, 125.6, 50.7, 20.3,
20.2; IR (KBr) = 3,419, 3,129, 1,610, 1,514, 1,000, 823, 731, 703, 687, 521 cm−1; HRMS
calculated for [C23H21N3+H]+ = 340.1808, Found = 340.1809.
Compound 3j: Light brown oil; 1H NMR (400 MHz, CDCl3): δ = 7.46 to 7.35 (m, 4H),
7.28 to 7.23 (m, 3H), 7.18 to 6.93 (m, 6H), 5.40 (s, 2H), 2.30 (d, J = 4.8 Hz, 3H); 13C
NMR (100 MHz, CDCl3): δ = 144.8, 137.7, 135.8, 135.2, 132.2, 131.4, 129.4, 129.2,
128.7, 128.2, 127.6, 127.3, 126.6, 126.0, 52.0, 21.1; IR (KBr) = 3,419, 3,129, 1,621,
1,515, 1,480, 1,091, 984, 824, 734, 517 cm−1; HRMS calculated for [C22H18ClN3+H]+ =
360.1262, Found = 360.1260.
Compound 3m: Light yellow solid; mp 108 °C to 110 °C; 1H NMR (400 MHz, CDCl3): δ
= 7.53 to 7.44 (m, 2H), 7.32 to 7.22 (m, 5H), 7.07 to 6.99 (m, 2H), 6.94 (d, J = 7.1 Hz,
1H), 6.87 (s, 1H), 6.84 to 6.72 (m, 2H), 5.37 (s, 2H), 3.76 (s, 3H), 2.29 (s, 3H); 13C NMR
9

(100 MHz, CDCl3): δ = 159.1, 144.2, 138.8, 135.5, 133.2, 130.6, 130.2, 128.9, 128.5,
128.0, 127.8, 127.8, 127.5, 127.1, 123.6, 113.8, 55.1, 52.0, 21.2; IR (KBr) = 3,419, 3,131,
2,956, 2,835, 1,614, 1,562, 1,455, 1,352, 1,175, 1,109, 1,038, 996, 841, 815, 794, 705,
675, 594, 576 cm−1; HRMS calculated for [C23H21N3O+H]+ = 356.1757, Found =
356.1755.
FUNDING
We are grateful for the financial support provided by the National Natural Science
Foundation of China (Grant No. 51464021) and the Science and Technology Planning
Project of Yunnan Province (Grant No. KKSY201307056).
SUPPORTING INFORMATION
Full experimental detail, 1H and 13C NMR spectra. This material can be found via the
“Supplementary Content” section of this article’s webpage.
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Table 1 Optimization of the reaction conditions.a
Entry
Cat.
Additive
Base
Solvent
H2O
H2O
H2O
H2O
3a (%)b
27
1
2
3
4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
–
–
–
–
K2CO3
Cs2CO3
tBuOK
Ag2CO3
36
22
15
5
6
7
8
Na2CO3
K3PO4
H2O
H2O
H2O
H2O
DMSO
DMF
DMA
DCE
0
0
0
Pd(PPh3)4
–
–
–
PPh3
–
–
–
–
–
Pd(PPh3)4
Pd(PPh3)4
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
KH2PO4
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
0
9
42
48
58
32
30
0
10
11
12
13
14
15
16
17
18
19
20
21
22c
23d
24e
25f
DEA
PhMe
TFA
–
–
PPh3
0
DMA
DMA
DMA
DMA
DMA
DMA-H2O
DMA
DMA
DMA
DMA
85
34
45
32
94
46
68
70
72
55
TCHP
X-Phps
S-Phps
tBuCO2H
tBuCO2H
tBuCO2H
tBuCO2H
tBuCO2H
tBuCO2H
aReaction conditions unless noted: 1-benzyl-4-phenyl-1H-1,2,3-triazole 1a (0.3 mmol),
1-iodo-4-methylbenzene 2a (0.36 mmol), palladium catalyst (0.03 mmol), additive (0.06
mmol), and base (0.6 mmol) were added to 2 mL of solvent and the reaction was
conducted under 10 W microwave conditions for 1 h.
bIsolated yields.
cMicrowave 5 W used.
dMicrowave 10 W used.
e5% Pd(OAc)2 was used.
fConducted under120 °C by conventional heating for 20 h.
14

Table 2 Synthesis of 1,4-disubstituted 1,2,3-triazoles 3 by expanding aromatic
nitrocompounds.a,b
15

aReaction conditions: 1 (0.3 mmol), 2 (0.36 mmol), Pd(OAc)2 (0.03 mol), tBuCO2H (0.06
mmol), and Cs2CO3 (0.6 mmol) were added to 2 mL of DMA and the reaction was
conducted under 10 W microwave for 1 h.
bYield of isolated product after column chromatography.
cIsolated yields using aryl bromides instead of aryl iodides.
16

Table 3 Formation of 4,5-disubstuted 1,2,3-triazoles through the debenzylation process
with one-pot manipulation.a,b
t
aReaction conditions: 1 (0.3 mmol), 2 (0.36 mmol), Pd(OAC)2 (0.03 mmol), BuCO2H
(0.06 mmol), and Cs2CO3 (0.6 mmol) were added to 2 mL of DMA and the reaction was
conducted under 10 W microwave for 1 h. Then, the system was added with 2 equiv of
tBuOK and 1 mL of DMSO and the reaction was conducted under 10 W microwave for
another 0.5 h.
bIsolated yields.
17

Scheme 1. Methods employed to construct trisubstituted 1,2,3-triazoles
18

Scheme 2. Proposed mechanism
19