Cu/Pd-catalyzed, three-component click reaction of azide, alkyne, and aryl halide: One-pot strategy toward trisubstituted triazoles

Article abstract of DOI:10.1021/acs.orglett.5b01342

A Cu/Pd-catalyzed, three-component click reaction of azide, alkyne, and aryl halide has been developed. By using this Cu/Pd transmetalation relay catalysis, a variety of 1,4,5-trisubstituted 1,2,3-triazoles were quickly assembled in one step in high yield

Full text of DOI:10.1021/acs.orglett.5b01342

Letter
pubs.acs.org/OrgLett
Cu/Pd-Catalyzed, Three-Component Click Reaction of Azide, Alkyne,
and Aryl Halide: One-Pot Strategy toward Trisubstituted Triazoles
Fang Wei,†,∥ Haoyu Li,†,∥ Chuanling Song,† Yudao Ma,† Ling Zhou,§ Chen-Ho Tung,†
and Zhenghu Xu*,†,‡
†Key Lab for Colloid and Interface Chemistry of Education Ministry, School of Chemistry and Chemical Engineering, Shandong
University, Jinan 250100, China
‡State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
Shanghai 200032, China
§Department of Chemistry and Biochemistry, Miami University, Oxford, Ohio 45056, United States
S
* Supporting Information
ABSTRACT: A Cu/Pd-catalyzed, three-component click reaction of
azide, alkyne, and aryl halide has been developed. By using this Cu/Pd
transmetalation relay catalysis, a variety of 1,4,5-trisubstituted 1,2,3-
triazoles were quickly assembled in one step in high yields with
complete regioselectivity, just like assembling Lego bricks. Notably,
different from the well-established CuAAC click reactions only working on terminal alkynes, this reaction offers an alternative
solution for the problem of the click reaction of internal alkynes.
Scheme 1. Cu/Pd-Catalyzed Three-Component Click
Reaction
1,2,3-Triazoles are privileged heterocycles, serving as key
functional groups in many bioactive molecules and pharma-
ceuticals.1 Recently, they are widely used as ligands for
catalysis,2a directing groups for transition-metal-catalyzed C−
H activation,2b,c and versatile building blocks in organic
synthesis.3 The copper-catalyzed azide−alkyne cycloaddition
(CuAAC)4 is the major approach to this heterocycle and has
been widely extended into various research fields, such as
chemical biology and materials science.5 In the CuAAC
reaction, the copper(I) catalyst forming copper(I) acetylide
complexes with terminal alkynes is crucial to accelerate this
cycloaddition reaction and also deliver region selectivity.
Consequently, the CuAAC is limited to terminal alkynes.
Internal alkynes are far more difficult to react with azides to
synthesize fully substituted triazoles due to their weak reactivity
and difficulty in regiocontrol. This becomes a fundamental
problem of current click reactions.6−8
To access trisubstituted triazoles, a CuAAC reaction and
subsequent transition-metal-catalyzed direct arylation sequence
has been developed (Scheme 1A).9 In 2008, the Ackermann
group reported a copper-catalyzed, two-step, one-pot coupling
reaction of alkyne, azide, and aryl iodide at 140 °C for 20 h.9c
However, to cleave the inert C−H bond of the triazole ring,
usually very harsh conditions, such as very high temperature or
microwave, were required. To address this issue, we proposed a
new Cu/Pd transmetalation step to trap the vinylcopper
intermediate M2;10 thus, direct C−H bond cleavage was
avoided and very mild reaction conditions were possible
(Scheme 1B). By using this unprecedented Cu/Pd trans-
metalation relay catalysis,11 a modular synthesis of trisubstitued
triazoles12,13 from easily available materials was developed. This
reaction makes it possible to freely install three different
substituents onto the triazole ring in one step.
As illustrated in Scheme 1, the cycloaddition of copper(I)
acetylide M1 with azide 2 generates cuprate−triazole
intermediate M2. At the same time, oxidative addition of aryl
halide 3 to Pd(0) catalyst forms the palladium intermediate M3.
The transmetalation reaction between M2 and M3 followed by
Received: May 7, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b01342
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Letter
a
reductive elimination would produce the target trisubstituted
triazole 4 and regenerate Pd(0) catalyst. However, to achieve
this ideal catalytic cycle is an extremely challenging task because
of the two inevitable competing reactions: (1) Protonation of
the cuprate-triazole intermediate M2 produces the undesired
1,4-disubstituted 1,2,3-triazole 5 (path I). (2) Transmetalation
between copper(I) acetylide M1 and palladium intermediate M3
forms another byproduct 6, which is the traditional Sonogashira
coupling reaction (path II). To inhibit path I, we need to
reduce all of the possible proton sources and increase the
reaction rate of transmetalation. However, the facility of
transmetalation would also increase the amount of the
undesired Sonogashira coupling product (path II). This is the
most challenging issue of the proposed three-component
cycloaddition coupling reaction.
To validate this concept, phenylacetylene 1a, benzylazide 2a,
and iodobenzene 3a were chosen as the model substrates to
optimize the reaction conditions. When a catalytic amount of
copper catalyst was used, two major byproducts, the normal
click product 5 and diphenylacetylene 6 were the major
products, together with trace trisubstituted triazole 4aa. The
Lei group recently discovered that the Sonogashira coupling is a
first-order kinetic dependence on both [Cu] catalyst and [Pd]
catalyst;14a however, the Fokin group demonstrated the
CuAAC reaction is a second-order kinetic dependence on
[Cu] catalyst.14b,c Thus, increasing the concentration of [Cu]
would favor the designed click reaction pathway. We then
decided to screen the reaction conditions using 1 equiv of
copper catalyst (Table 1).
Table 1. Optimization of Reaction Conditions
b
yield (%)
entry
variation from “standard conditions”
4aa
5
1
none
93 (90)
3
2
PPh3 instead of XPhos
52
87
89
76
15
5
5
9
3
SPhos instead of XPhos
4
BrettPhos instead of XPhos
PdCl2(PPh3)2 instead of Pd2(dba)3 and XPhos
Et3N instead of K2CO3
10
8
5
6
44
6
7
t-BuOLi instead of K2CO3
toluene instead of DMF
8
0
23
29
17
6
9
dioxane instead of DMF
2
10
11
12
13
THF instead of DMF
7
Pd2(dba)3 (2.5 mol %)
71
78
62
CuCl (50 mol %), DMF (1 mL)
CuCl (25 mol %), DMF (0.5 mL)
PhBr 3a′ instead of PhI
10
13
11
15
c
14
d
87 (86)
15
PhBr 3a′ instead of PhI
73
a
Reaction conditions: a mixture of 1a (0.2 mmol), 2a (0.3 mmol), and
3a (0.3 mmol) in DMF (2 mL) was stirred at room temperature under
b
N2 atmosphere. Determined by 1H NMR using trimethoxybenzene as
the internal standard. The number in parentheses is the isolated yield.
CuCl (1 equiv), Pd2(dba)3 (2.5 mol %), XPhos (10 mol %), 70 °C, 5
h. CuCl (20 mol %), Pd2(dba)3 (0.5 mol %), XPhos (2 mol %), DMF
c
d
After a variety of reaction parameters were screened (for
details, see the Supporting Information), the desired three-
component cycloaddition coupling product 4aa was achieved in
93% yield under standard conditions: a mixture of CuCl (1
equiv), Pd2(dba)3 (1 mol %), XPhos (4 mol %) in DMF (2
mL) was stirred at room temperature under N2 atmosphere
overnight (Table 1, entry 1). The ligand XPhos greatly
accelerates the [Pd] cycle, which is very crucial for the success
of this reaction. When XPhos was replaced by PPh3, the yield of
4aa was low, and large amounts of byproduct 6 were observed
(entry 2). Base plays a very important role in this reaction, and
the use of Et3N or LiOBut in place of K2CO3 was not effective
(entries 6 and 7). Increasing the loading of palladium catalyst
led to decreased yield and selectivity, indicating the ratio of Cu/
Pd is highly important to realize this challenging reaction (entry
11). We then tried to lower the loading of copper catalyst
(entries 12 and 13). The yield slightly dropped to 78% with 50
mol % of copper. When CuCl (25 mol %) was employed, the
yield of 4aa further decreased to 62%. Even though reduced
yield was obtained when a catalytic amount of copper catalyst
was used, these results clearly demonstrated the feasibility of
the copper-catalyzed cycles.
Bromobenzene 3a′ is a cheaper aryl source but much less
reactive than iodobenzene. Thus, the application of bromo-
benzene instead of iodobenzene in the above three-component
coupling reaction is highly desirable but also very challenging.
After a detailed optimization of reaction conditions (see the
Supporting Information), the reaction of bromobenzene at 70
°C could also deliver the triazole 4aa in 86% yield (entry 14).
Notably, by using 20 mol % CuCl together with 0.5 mol % of
Pd2(dba)3 as catalysts, the desired triazoles could be isolated in
73% yield (entry 15). The reaction of disubstituted triazole 5
with iodobenzene or bromobenzene under standard conditions
could not afford any desired products 4aa, indicating 5 is not
(0.6 mL), MgSO4 (30 mg), 70 °C. XPhos = 2-dicyclohexylphosphino-
2′,4′,6′-triisopropylbiphenyl, SPhos =2-dicyclohexylphosphino-2′,6′-
dimethoxybiphenyl, BrettPhos =2-(dicyclohexylphosphino)-3,6-dime-
thoxy-2′-4′-6′-triisopropyl-1,1′-biphenyl.
the reaction intermediate. Thus, a stepwise reaction is not
likely, and vinylcopper to palladium transmetalation mechanism
is very possible.
We then started to investigate the scope of alkynes of this
reaction. To achieve better yields, we used the conditions using
1 equiv of cheap copper catalyst with very low precious
palladium catalyst loading. Both iodobenzene 3a and
bromobenzene 3a′ were used to react with benzyl azide and
various terminal alkynes under their optimized conditions
(Scheme 2). Both aromatic and aliphatic alkynes were suitable
substrates for this reaction, and a large variety of trisubstituted
triazoles were synthesized in good yields as the single
regioisomer. It was observed that the electron-withdrawing or
electron-donating groups at the para position of the aromatic
ring did not affect the reaction (entries 1−8). Notably,
thiophene- or ferrocene-substituted acetylenes were also
applicable in this transformation and gave the corresponding
trisubstituted triazoles in good yields, and the structure of
product 4ha was confirmed by single-crystal X-ray analysis
(entries 9−14). The reaction of aliphatic alkyne with
iodobenzene at room temperature was not successful. Raising
the reaction temperature to 60 °C could furnish the expected
three-component coupling products in very good yields
(conditions C). A series of functional groups such as hydroxyl,
cyclopropyl, and phenoxyl groups were well tolerated under
these conditions (entries 19−24). Electron-deficient alkynes
were similarly transformed into the corresponding products in
73−98% yields (entries 25−28).
B
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a
and position of the substituent groups (entries 5−20). Notably,
the styryl group could also be introduced onto the triazole ring
efficiently using styryl bromide as the reactant (entry 21).
The scope of the reaction with respect to azides was also
investigated (Scheme 4). All of the aliphatic azides tested were
Scheme 2. Substrate Scope of Alkynes
a
Scheme 4. Substrate Scope of Azides
a
b
Isolated yields were reported. A mixture of 1a (0.2 mmol), 2a (0.3
mmol), iodobenzene 3a (0.3 mmol), CuCl (1 equiv), Pd2(dba)3 (1
mol %), and XPhos (4 mol %) in DMF (2 mL) was stirred at room
temperature under N2 atmosphere overnight (Conditions A).
a
b
Isolated yields were reported. p-Bromoanisole (0.3 mmol), CuCl (1
b
equiv), Pd2(dba)3 (5 mol %), XPhos (20 mol %), 80 °C, overnight.
Pd2(dba)3 (2.5 mol %), X-Phos (10 mol %), other conditions as in
c
Conditions A. Bromobenzene 3a′ (0.3 mmol), CuCl (1 equiv),
Pd2(dba)3 (2.5 mol %), XPhos (10 mol %), 70 °C (Conditions B).
effective substrates, giving the corresponding triazoles in good
to excellent yields under standard conditions (entries 1−11).
Phthalimide-protected amine and the indole skeleton are both
tolerated under these mild conditions (entries 9 and 10).
Lysine-derived azide also worked well to give the trisubstituted
triazole 4h in 81% yield (entry 11). However, for the aromatic
azide the reaction is less efficient, generating the target
trisubstituted triazole in 36% yield (entry 12).
d
Iodobenzene 3a (0.3 mmol), CuCl (1 equiv), Pd2(dba)3 (2.5 mol %),
XPhos (10 mol %), 60 °C, overnight (Conditions C).
The scope of the various aryl halides was further investigated
(Scheme 3). Besides aryl iodides and bromides, phenyl
a
Scheme 3. Substrate Scope of Aryl Halides
The utility of this chemistry can be featured by the late-stage
click reaction on bioactive natural compounds and sugar and
amino acid derivatives (Scheme 5). Oleanolic acid, a naturally
Scheme 5. Synthetic Applications
a
b
Isolated yields were reported. Chlorobenzene (0.3 mmol), CuCl (1
equiv), Pd2(dba)3 (5 mol %), XPhos (20 mol %), 110 °C, overnight.
trifluoromethanesulfonate was also applicable for this trans-
formation under standard conditions to afford trisubstituted
triazoles in 66% yield (entry 3). The reaction also worked with
much less reactive chlorobenzene to produce the desired
product in 57% yield, albeit with increased catalyst loading and
higher temperature (entry 4). The reaction of various aromatic
bromides worked very well, regardless of the electronic nature
occurring triterpenoid, was found to exhibit anti-HIV and anti-
HCV activities, and a recent report indicated that its triazole
derivative showed increased potency.15 Its alkyne derivative 7
could be easily transformed into the trisubstituted triazole 8 in
80% yield, which showed great potential for drug late-stage
modification. Sugar derivative 9 bearing sensitive acetal- and
acetone-protecting groups was also tolerated and afforded the
C
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desired product 10 in 91% yield. The three-component click
reaction between p-iodoanisole, tyrosine, and lysine blocks was
also successful and produced the corresponding triazole 13 in
60% yield.
In summary, we have developed a Cu/Pd transmetalation
relay catalysis for the construction of trisubstituted triazoles
from azide, alkyne, and aryl halide. This method represents a
general modular synthesis of trisubstituted triazoles from easily
available materials. Application of this protocol led to the
bioactive triazole derivatives in a highly efficient and practical
manner. Because of the unique structure of the triazoles and the
notable features of this protocol, such as high atom and step
economy, mild conditions, high efficiency and regioselectivity,
and a broad substrate scope, we believe that this method should
be useful for drug discovery and development.
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental detailes, crystal structure of 4ha, and character-
ization data. The Supporting Information is available free of
charge on the ACS Publications website at DOI: 10.1021/
acs.orglett.5b01342.
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Duan, H.; Lu, W.; Petersen, J. L.; Shi, X. Org. Lett. 2008, 10, 1493.
(d) Zhou, F.; Tan, C.; Tang, J.; Zhang, Y.-Y.; Gao, W.-M.; Wu, H.-H.;
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AUTHOR INFORMATION
Corresponding Author
■
*E-mail: xuzh@sdu.edu.cn.
Author Contributions
∥These authors contributed equally to this work.
Notes
The authors declare no competing financial interest.
(15) Yu, F.; Wang, Q.; Zhang, Z.; Peng, Y.; Qiu, Y.; Shi, Y.; Zheng,
Y.; Xiao, S.; Wang, H.; Huang, X.; Zhu, L.; Chen, K.; Zhao, C.; Zhang,
C.; Yu, M.; Sun, D.; Zhang, L.; Zhou, D. J. Med. Chem. 2013, 56, 4300.
ACKNOWLEDGMENTS
We are grateful for the subject construction funds from
Shandong University (Nos. 2014JC008 and 104.205.2.5).
■
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