Palladium-catalyzed ortho-C-H alkenylation of 2-benzyl-1,2,3-triazoles

Article abstract of DOI:10.1039/c5ob00973a

A mild and efficient method for the direct alkenylation of 2-benzyl-1,2,3-triazoles via Pd-catalyzed C-H bond activation was developed. This protocol was compatible with various substrates and gave the corresponding products in good to excellent yields. Thus, the present study provides a novel and valuable method for the synthesis of 2-benzyl-1,2,3-triazole derivatives.

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Cite this: DOI: 10.1039/x0xx00000x
Palladium-catalyzed ortho-C-H Alkenylation of 2-
benzyl-1,2,3-triazoles
Received 00th January 2012,
Accepted 00th January 2012
Ping He,a Qingshan Tiana and Chunxiang Kuanga,b*
DOI: 10.1039/x0xx00000x
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A mild and efficient method for the direct alkenylation of 2-
benzyl-1, 2, 3-triazoles via Pd-catalyzed C–H bond activation
was developed. This protocol was compatible with various
substrates and gave the corresponding products in good to
excellent yields. Thus, the present work provides a novel and
valuable method for the synthesis of 2-benzyl-1, 2, 3-triazole
derivatives.
Scheme 1. C-H alkenylation of 2-benzyl-1,2,3-triazoles 1
We initiated our studies by exploring reactions between 2-benzyl-
1,2,3-triazole (1a) and alkene (2a) to identify suitable reaction
conditions (Table 1). First, the reaction was conducted with
Pd(OAc)2 as a catalyst, BQ as oxidant in DCE at 120 °C for 12h. To
our delight, the desired product 3a was generated in 21% yield. To
increase the yield of this reaction, some other generally used
oxidants, such as AgOAc, Cu(OAc)2, PhI(OAc)2, MnO2, and K2S2O8
were tested, in which K2S2O8 was found to be the most effective
which gives a yield of 83% (entries 2−6). Subsequently, we
investigated the effect of palladium catalysts on this reaction. The
results showed that PdCl2 and PdCl2(PPh3)2 could also prompt this
reaction but with relatively low yield (entries 8-9). No desired
product was observed when Pd(PPh3)4 was chosen as catalyst (entry
7). When the loading of Pd(OAc)2 was decreased to 5%, the yield of
3a also decreased synchronously to 59% (entry 12). An attempt to
increase the loading of Pd(OAc)2 to 20% did not give a significant
improvement on the yield. Moreover, the change of temperature to
80 °C and 140 °C let to 68% and 84% yield respectively (entries 10-
11). While a variety of other solvents such as DMSO, DMF, and
CH3CN were screened, DCE still appeared to be the best solvent
(entries 14-16). Thus, 10 mol% of Pd(OAc)2 , 2.0 equiv. of K2S2O8
and DCE as solvent were chosen as the optimized conditions for the
Pd-catalyzed reaction of 1a with 2a.
Since Fujiwara and Moritani reported the pioneering work on
Palladium-catalyzed oxidative coupling between arenes and olefins
in 1967, 1 C-H alkenylation has emerged as a powerful tool for the
synthesis of natural product and pharmaceutical precursors.2
However, low selectivity has restricted the practicality of this
transformation. In order to achieve regioselective C-H bond
functionalization, a large number of directing groups have been
reported. For instance, in 2011, the Yu group reported Pd-catalyzed
olefination of aromatic C-H bond using urea as a directing group.3a
In 2012, Zhang et al. reported Pd-catalyzed C-H alkenylation using
thioether as directing groups.3b Later, the Shi group described a Pd-
catalyzed oxidative olefination of phenol derivatives.3c More
recently, Pd-catalyzed ortho-C-H alkenylation of phenylalanine
derivatives has been developed by Carretero group.3d Despite these
significant progress achieved, those employing 1,2,3-triazoles as
directing groups remain underdeveloped.4
1,2,3-triazoles have widespread applications in diverse fields such as
material chemistry and medicinal chemistry.5 Over the last decades,
a large volume of research has been carried out on 1,2,3-triazoles
and their derivatives, which are present as core structural
components in an array of drug categories such as anticancer,6a
antibacterials6b and HIV Protease Inhibitors.6c The great medicinal
significance and broad applications of 1,2,3-triazoles prompted us to
develop new strategies to the access of various derivatives
containing this moiety. Recently, the Ackermann group reported a
Ru-catalyzed C–H cross-dehydrogenative alkenylation using 1,2,3-
triazole derivatives as versatile directing groups.7 However, the
substrates have only been limited to 1-substituted-1,2,3-triazoles. So
far, no example of the alkenylation of 2-substituted-1,2,3-triazoles
has been reported. Considering the important application of 2-
substituted-1, 2, 3-triazoles as pharmacophore and motivated by our
continuous interest in the C-H activation,8 herein we developed a
novel method to alkenylation of 2-benzyl-1,2,3-triazoles. (Scheme
1).
With the optimized reaction conditions in hand, we further
investigated the scope of substrates. As shown in Table 2, the
reaction tolerated a range of different electron-donating and electron-
withdrawing functional groups, including Me, F, Cl and MeO. The
corresponding ortho-alkenyl 2-benzyl-1, 2, 3-triazoles were obtained
in moderate to good yields. The substrates with a para-electron-
donating group (4-H, 4-MeO, and 4-Me) on the benzene rings
afforded the desired products in good yields (3a, 3e, 3j). On the
contrast, the reaction of 1 bearing a strong electron-withdrawing
NO2, CF3, or CN group at the para position provided the
corresponding product with slightly moderate yield (3i, 3k, 3l). The
regioselectivity of alkenylation with meta-substituted substrates may
be attributed to steric effects, delivering the product alkenylated at
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the less hindered ortho position (3f, 3h). The use of arenes bearing a
halogen group also provided good yields (3b, 3c, 3g). Moreover, the
present procedure was successfully extended to other acrylates.
Ethyl acrylate, butyl acrylate and methyl acrylate was all compatible
with this optimized conditions, which give the corresponding
products in good yields (3n, 3p). Besides, we found that when
acrylonitrile was subjected to the reaction, it afforded the product 3o
in 50% yield. Notably, N-tert-Butylacrylamide also
Table 2. Palladium-catalyzed alkenylation of 2-benzyl-1,2,3-triazoles with
alkenes.a
Table 1. Optimization of reaction conditions.a
Yield(
Entry
Catalyst (mol %)
Oxidant
BQ
Solvent
%)b
21
1
2
3
Pd(OAc)2(10)
Pd(OAc)2(10)
Pd(OAc)2(10)
DCE
DCE
DCE
AgOAc
17
0
Cu(OAc)
2
PhI(OAc)
2
4
Pd(OAc)2(10)
Pd(OAc)2(10)
Pd(OAc)2(10)
Pd(PPh3)4(10)
PdCl2(PPh3)2(10)
PdCl2(10)
DCE
DCE
18
0
5
MnO2
6
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
DCE
DCE
83
0
7
8
DCE
26
30
68
84
59
85
42
55
70
9
DCE
10c
11d
12
13
14
15
16
Pd(OAc)2(10)
Pd(OAc)2(10)
Pd(OAc)2(5)
Pd(OAc)2(20)
Pd(OAc)2(10)
Pd(OAc)2(10)
Pd(OAc)2(10)
DCE
DCE
DCE
DCE
DMSO
DMF
CH3CN
[a] Reaction conditions: 1a (0.2 mmol), 2a (0.4 mmol), palladium catalyst
(0.02 mmol) and oxidant (0.4 mmol) in solvent (2.0 mL), stirred at 120 °C
for 12 h. [b] Isolated yields. [c] Reaction temperature: 80 °C . [d] Reaction
temperature: 140 °C .
[a] Reaction conditions: 1a (0.2 mmol), 2 (0.4 mmol), Pd(OAc)2 (0.02 mmol)
and K2S2O8 (0.4 mmol) in DCE (2.0 mL), stirred at 120 °C for 12 h. Isolated
yields are given.
underwent this reaction in 53% yield. Interestingly, an attempt to use
2-benzyl-pyrazole as directing group failed to deliver the
corresponding product 3q. The tolerance of this reaction to substrates
with these functional groups indicated that it can be used for further
transformation of the products.
On the basis of these results we obtained and found in the previous
reports, 9 a plausible reaction mechanism that was proposed and is
shown in Scheme 2. First, coordination of 2-benzyl-1, 2, 3-triazole to
palladium acetate is followed by C−H activation to form a five-
membered cyclopalladated intermediate A, which has been
confirmed by previous research. Subsequently, olefin insertion takes
place followed by β-hydride elimination of the intermediate B,
furnishing the E-olefinated products C and liberate Pd(0). The Pd(II)
is regenerated from the oxidation of Pd(0) by K2S2O8.
Scheme 2. Plausible Reaction Mechanism.
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C. Kuang, Adv. Synth. Catal., 2014, 356, 1549; (d) Q. Tian, P. He, C.
Kuang, Org. Biomol. Chem., 2014, 12, 7474.
In conclusion, we have described a mild and efficient alkenylation of
2-benzyl-1,2,3-triazoles. This reaction occurs through ortho-C-H
alkenylation under Pd-catalyzed using K2S2O8 as an oxidant. This
approach provides a complementary method for the synthesis of 2-
benzyl-1,2,3-triazole derivatives which are important building blocks
in medicine and materials.
9 (a) A. R. Dick, M. S. Remy, J. W. Kampf, M. S. Sanford,
Organometallics, 2007, 26, 1365; (b) Y. Boutadla, O. Al-Duaij, D. L.
Davies, G. A. Griffith, K. Singh, Organometallics 2009, 28, 433; (c) L.
Li, W. Brennessel, W. D. Jones, J. Am. Chem. Soc. 2008, 130, 12414.
The present work was supported by the Natural Science Foundation
of China (No. 21272174), the Key Projects of Shanghai in
Biomedicine (No.08431902700), and the Scientific Research
Foundation of the State Education Ministry for Returned Overseas
Chinese Scholars. We thank Professor Yanghui Zhang for valuable
assistance. We also thank the Center for Instrumental Analysis,
Tongji University, China.
Notes and references
a
Department of Chemistry, Tongji University, Siping Road 1239,
Shanghai 200092, China
E-mail: kuangcx@tongji.edu.cn
Shanghai Key Lab of Chemical Assessment and Sustainability,
b
Department of Chemistry, Tongji University
† Electronic supplementary information (ESI) available. See DOI:
10.1039/ c000000x/
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