Visible-Light-Mediated Click Chemistry for Highly Regioselective Azide–Alkyne Cycloaddition by a Photoredox Electron-Transfer Strategy

Article abstract of DOI:10.1002/chem.202000252

Click chemistry focuses on the development of highly selective reactions using simple precursors for the exquisite synthesis of molecules. Undisputedly, the Cu^I-catalyzed azide–alkyne cycloaddition (CuAAC) is one of the most valuable examples of click chemistry, but it suffers from some limitations as it requires additional reducing agents and ligands as well as cytotoxic copper. Here, we demonstrate a novel strategy for the azide–alkyne cycloaddition reaction that involves a photoredox electron-transfer radical mechanism instead of the traditional metal-catalyzed coordination process. This newly developed photocatalyzed azide–alkyne cycloaddition reaction can be performed under mild conditions at room temperature in the presence of air and visible light and shows good functional group tolerance, excellent atom economy, high yields of up to 99 %, and absolute regioselectivity, affording a variety of 1,4-disubstituted 1,2,3-triazole derivatives, including bioactive molecules and pharmaceuticals. The use of a recyclable photocatalyst, solar energy, and water as solvent makes this photocatalytic system sustainable and environmentally friendly. Moreover, the azide–alkyne cycloaddition reaction could be photocatalyzed in the presence of a metal-free catalyst with excellent regioselectivity, which represents an important development for click chemistry and should find versatile applications in organic synthesis, chemical biology, and materials science.

Full text of DOI:10.1002/chem.202000252

A Journal of
Accepted Article
Title: Visible-Light-Mediated Click Chemistry for Highly Regioselective
Azide-Alkyne Cycloaddition via Photoredox Electron-Transfer
Strategy
Authors: Zheng-Guang Wu, Xiang-Ji Liao, Li Yuan, Yi Wang, You-
Xuan Zheng, Jing-Lin Zuo, and Yi Pan
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To be cited as: Chem. Eur. J. 10.1002/chem.202000252
Link to VoR: http://dx.doi.org/10.1002/chem.202000252
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10.1002/chem.202000252
Chemistry - A European Journal
RESEARCH ARTICLE
Visible-Light-Mediated Click Chemistry for Highly Regioselective
Azide-Alkyne Cycloaddition via Photoredox Electron-Transfer
Strategy
Zheng-Guang Wu†[a], Xiang-Ji Liao†[a], Li Yuan,[a] Yi Wang,[a] You-Xuan Zheng,*[a] Jing-Lin Zuo,[a] and
Yi Pan[a]
Dedicated to the 100th anniversary of the School of Chemistry and Chemical Engineering, Nanjing University
[a]
Dr. Z.-G. Wu, Mr. X.-J. Liao, Miss. L. Yuan, Prof. Y. Wang, Prof. Y.-X, Zheng, Prof. J.-L. Zuo, and Prof. Y. Pan
State Key Laboratory of Coordination Chemistry, Collaborative Innovation Center of Advanced Microstructures Institution
School of Chemistry and Chemical Engineering
Nanjing University, Nanjing, 210023, P. R. China
E-mail: yxzheng@nju.edu.cn
†Wu and Liao have same contributions to this paper
Abstract: “Click” chemistry is focused on the development of highly
selective reactions utilizing simple precursors for the exquisite
synthesis of molecules. Undisputedly, the Cu(I)-catalyzed azide–
alkyne cycloaddition (CuAAC) is one of the most valuable examples
of click chemistry, but there are still some limitations as needing
additional reducing agents and ligands as well as the toxicity of copper
in cell or body. Here, we demonstrate a novel strategy of photoredox
electron-transfer radical cation pattern for AAC reaction instead of
traditional metal-catalyzed coordination process. This newly-
developed photocatalyzed azide–alkyne cycloaddition (PcAAC) could
be performed in mild conditions of room temperature, air and visible
light with good functional group tolerance, excellent atom economy,
high yield up to 99%, and absolute regioselectivity, affording variety
of 1,4-disubstituted 1,2,3-triazole derivatives including bioactive
has been established as one of the most useful and valuable
examples of click chemistry.[2a,2b]
Triazoles are not only the important structural motifs in
biologically active compounds (Figure 1a),[3] but also widely
applied in a broad range of disciplines including biomolecular
ligation, chemical sensors, supramolecular and polymeric
materials.[4] A pioneer work for the triazole synthesis is a thermal
1,3-diploar cycloaddition between azides and alkynes (Fig 1b),
which was investigated by Huisgen in the 1960s.[5] Due to the high
activation barrier, the reaction yields are generally low and the
regioselectivity is poor with a mixture of regioisomeric 1,4- and
1,5-disubstituted 1,2,3-triazoles. Ever since the groups of Meldal
and Sharpless independently reported their pioneering works on
the CuAAC reaction for 1,4-disubstituted-1,2,3-triazole
regioisomer with excellent regioselectivity and high yields (Fig.
1b), which represents a powerful tool for preparing this class of
heterocycles, the development and application of this reaction
received enormous attention.[6] In light of this, besides copper,
click reactions involving other metals for AAC reaction have also
been developed in full swing, including ruthenium (RuAAC),[7] zinc
(ZnAAC),[8] silver (AgAAC),[9] gold (AuAAC)[10] and Raney-Ni
(RaneyNiAAC)[11] catalyzed AAC reactions.
molecules and pharmaceuticals. The use of
a
recyclable
photocatalyst, solar energy and water makes this photocatalytic
system sustainable and environmentally friendly. Moreover, the
metal-free photocatalyzed AAC reaction with excellent regioselectivity
was also implemented for the first time, representing an important
development for click chemistry, which should find versatile
applications in organic synthesis, chemical biology and materials
science.
As is known, the metal-catalyzed AAC reactions usually
involve the formation of π-alkynyl complex with metal at first. The
next step is the complexation of the azide by metal of the π-
coordinated triple bond. After cyclization produces the
metallacycle and then reductive elimination affords the respective
1,4-disubstituted 1,2,3-triazole (Fig. 1b). However, in this
transformation, the metal acetylide complex and the intermediate
metallacycle would lead some side reactions, such as oxidative
coupling for formation of diacetylene, bistriazole and 5-alkynyl
triazole.[12] Additionally, most of these click reaction processes
have their own necessities such as additional suitable bases,
reducing agents like sodium ascorbate, different solvents, harsh
reaction conditions, modified substrates, and catalysts.[13]
Besides, due to the toxicity of copper in cell or body, the trials for
achieving ‘copper-free’ click chemistry are in progress, which is
highly attractive to biological or biomedical researchers.[14]
Therefore, the development of efficient, selective, green, and
sustainable method for triazole synthesis has always been a
greatly significant work.
Introduction
Inventing new chemical reactions to promote the development of
organic synthesis chemistry is a long-standing passion of
chemists. Click chemistry as one of the most powerful paradigms
in organic synthesis, drug chemistry, materials and biology
science, have attracted an enormous amount of interest over the
past decade.[1] The term “click” chemistry proposed in 2001 by
Sharpless et al, is addressing a set of powerful, highly reliable,
and selective reactions for the rapid and exquisite synthesis of
molecules. The required process is featured of high efficiency,
excellent atom economy, readily available starting materials, mild
reaction conditions and easy purification or isolation. Several
reactions have been identified as good candidates for click
chemistry,[2] but without doubt the Cu(I)-catalyzed azide–alkyne
cycloaddition (CuAAC) leading to 1,4-disubstituted 1,2,3-triazoles
1
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10.1002/chem.202000252
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RESEARCH ARTICLE
Figure 1. Structures of 1,4-disubstituted 1,2,3-triazoles and their synthetic strategies. [a] Bioactive molecules and pharmaceuticals based on 1,4-triazole core; [b]
The reported synthetic methods for 1,4-trizole and the mechanism for traditional metal-catalyzed AAC reaction; [c] Our designed strategy for AAC reaction through
photoredox electron-transfer cyclization and its advantages and features, as well as the proposed mechanism.
In recent years, visible-light-induced photoredox catalysis for
Results and Discussion
the synthesis of high value added chemicals has been a hot topic
of research for chemists due to the inherent green character of
Firstly, we investigated the reaction of benzyl azide (1a) with
light, high reactivity, and good functional group tolerance. Several
phenylacetylene (2a) in the presence of various photocatalysts
recent studies have revealed that the some unsaturated
with very simple conditions under room temperature (r.t.), air and
compounds, including alkene, alkyne and imine, et al, could
visible light irradiation. From Table 1 it can be found that the
undergo a single electron transfer (SET) process to afford the
.
widely
used
photocatalysts
of
Ru(bpy)3Cl2 6H2O,
corresponding radical, radical cation or radical anion by an
oxidative or reductive quenching cycle of the excited state of the
photocatalyst (PC).[15] Inspired by this, we speculate that this AAC
reaction would be realized through a photoredox electron-transfer
radical strategy instead of traditional metal-catalyzed coordination
with alkynes. The proposed mechanism is described in Fig 1c. A
single electron-oxidation of alkyne generates radical cation A in
the presence of the excited state of the PC.[16] The intermediate
A combines with the azide to form the intermediate B, which
undergoes cycloaddition to afford intermediate C. Finally, a
single-electron reduction of C by PC- provides the desired 1,4-
disubstituted 1,2,3-triazole with the concurrent regeneration of the
PC for the next cycle. Therefore, a new pathway employing the
visible-light-induced AAC reaction via radical strategy is brought
up.
(dfppy)2Ir(dtbpy)PF6, Ir(ppy)3, FIrpic and EosinY were explored for
this reaction (Table 1, entries 1-7, the structures of photocatalysts
are supplied in SI). Fortunately, the photocatalysts of
(piq)2Ir(acac) or TPPT-Cl do indeed catalyze the formation of 1,4-
disubstituted 1,2,3-triazoles, and the resulting reaction product
was then analyzed by NMR and XRD, illustrating absolutely
regioselective 1, 4-triazole, without any 1,5-triazole isomer.
Though the reaction efficiency and yield of this photocatalyzed
click cycloaddition are low, the results confirm our hypothesis that
the AAC reaction could be realized via a photoredox electron-
transfer radical strategy with excellent regioselectivity.
Inspired by this, the further investigation of solvents effect was
conducted, and the results demonstrated that DCM was the
optimal choice with an enhanced yield of 83% (EtOH: 26%,
Acetone: 75%, EA: 40%, THF: trace, Toluene: 62%) (Table 1,
entries 8-13). When the reaction was performed under blue LED,
the yield became lower due to the slight degradation of azide
under high irradiation energy (Table 1, entry 14). Furthermore,
with the increase of reaction time, the yield could be further
improved to 98% (Table 1, entry 15). The control experiments
demonstrated that no product was observed without photocatalyst
Here, we present a visible light-mediated click reaction of
azide and alkyne: the photocatalyzed AAC (PcAAC) reaction for
formation of 1,4-disubstituted 1,2,3-triazole via photoredox
electron-transfer strategy with excellent efficiency and
regioselectivity, which is an important complementarity and
development of click chemistry.
2
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10.1002/chem.202000252
Chemistry - A European Journal
RESEARCH ARTICLE
or light (in the dark), thus supporting our proposed mechanism
(Table 1, entries 16, 17). Besides, a radical inhibition experiment
with 2 equiv of DMPO or BHT entirely stopped the reaction,
therefore suggesting a radical pathway (Table 1, entries 18, 19).
The optimization results demonstrate this PcAAC reaction can be
performed under air, r.t. and visible light irradiation with high
efficiency and absolute regioselectivity.
internal alkyne, affording 4r in 60% yield. In addition, single-
crystal X-ray crystallographic analyses determined the structures
of the 1,4-disubstituted 1,2,3-triazoles 3f and 4l.
To expand the versatility of the PcAAC, this reaction was also
explored to bioactive molecules and pharmaceuticals. 1,4-
Triazole hybrids modified with coumarin (5a, 5b),[17] acridinone
(5c),[18] indole (5),[19] oxazolinone (5e)[20] and amino acid (5f)[21]
structures possess promising anti-bacterial, anti-cancer and anti-
viral activity, were synthesized smoothly with moderate to
excellent yields of 65~98% and absolute regioselectivity.
Furthermore, glucal-derived triazoles are important in
carbohydrate-based biochemistry and organic synthesis.[22]
Glucosidase inhibitor derivatives featured of anti-bacterial activity
could be obtained with high efficiency using this photocatalyzed
click pattern (5g, 5h, 5i). Clodinafop-propargyl with herbicidal
activity was employed to react with 1a, generating 5j with 80%
yield.[23] This methodology was also applied in the derivatization
of Erlotinib (5k), which is often used for molecular targeted
therapy. As observed in almost all cases, the PcAAC reaction
showed excellent selectivity, conversions and yields, which
represents an important finding to prepare 1,4-substituted 1,2,3-
triazoles without the use of copper.[24]
In addition, to illustrate the practicability of reaction protocol,
the PcAAC reaction could be scaled up to a 1 g of 0.5 mol with a
satisfying yield of 88% (Fig. 3a). The recycling of the photocatalyst
was also evaluated and the results demonstrate the photocatalyst
is air- and moisture-tolerant and can be readily recovered after
use and reused several times. Fig. 3b showed that the
photocatalyst retains its own catalytic activity during the
continuous recycling experiments (4 cycles) with considerable
selectivity and efficiency.
Table 1. Optimization of the reaction conditions[a]
Entry
Catalyst
Solvent
Time/Atmosphere
Yield[b]
.
1
2
Ru(bpy)3Cl2 6H2O
DMF
DMF
DMF
DMF
DMF
DMF
DMF
EtOH
Acetone
EA
4h/r.t., Air, White LED
4h/r.t., Air, White LED
4h/r.t., Air, White LED
4h/r.t., Air, White LED
4h/r.t., Air, White LED
4h/r.t., Air, White LED
4h/r.t., Air, White LED
4h/r.t., Air, White LED
4h/r.t., Air, White LED
4h/r.t., Air, White LED
4h/r.t., Air, White LED
4h/r.t., Air, White LED
4h/r.t., Air, White LED
4h/r.t., Air, Blue LED
6h/r.t., Air, White LED
6h/r.t., Air, in dark
trace
NR
(dfppy)2Ir(dtbpy)PF6
Ir(ppy)3
3
NR
4
(piq)2Ir(acac)
FIrpic
20%
trace
NR
5
6
EosinY
7
TPPT-Cl
11%
26%
75%
40%
83%
trace
62%
70%
98%
trace
NR
8
(piq)2Ir(acac)
(piq)2Ir(acac)
(piq)2Ir(acac)
(piq)2Ir(acac)
(piq)2Ir(acac)
(piq)2Ir(acac)
(piq)2Ir(acac)
(piq)2Ir(acac)
(piq)2Ir(acac)
-
9
10
11
12
13
14
15
16
17
18[c]
19[d]
DCM
THF
toluene
DCM
DCM
DCM
DCM
DCM
DCM
6h/r.t., Air, White LED
6h/r.t., Air, White LED
6h/r.t., Air, White LED
(piq)2Ir(acac)
(piq)2Ir(acac)
NR
NR
[a] Reaction condition: benzyl azide (1a) (0.2 mmol), phenylacetylene (2a) (0.2
mmol), photocatalyst (5 mol%), solvent (2.0 mL), under an ambient atmosphere
and irradiation (26 W white LED or blue LED). [b] Isolated yield. [c] With DMPO
(5,5-Dimethyl-1-pyrroline-N-oxide). [d] With BHT (butylated hydroxytoluene).
With the optimized reaction conditions, the substrate scope
and generality of the method were investigated and the products
were summarized in Fig.2. First, the scope of the reaction was
explored with respect to the azide component, and the reactions
of various azides produced the corresponding 1,4-disubstituted
1,2,3-triazoles in moderate to excellent isolated yields (53−99%)
with excellent regioselectivity. Various functional groups of azide,
including halogens (fluorine and bromine) (3c, 3l), trifluoromethyl
(3d), hydroxyl (3m, 3r), ester (3f, 3n, 3q), and ketone (3o) as well
as heterocycle moieties (thiophene and quinoline) (3g, 3h), were
compatible with the reaction conditions. Notably, the borate
moiety (3e) remained intact during the photocatalyzed process,
which could be employed for further functionalization.
For the scope of organic alkyne partner, a variety of aromatic
and aliphatic alkynes with diverse functional groups, including
halogens (4a-4d), borate (4g), ether (4f, 4l), amide (4m, 4n, 4p),
BOC (4q), were employed to react with 1a, giving the
corresponding products with excellent yields and regioselectivity.
Interestingly, the PcAAC reaction was also very efficient for
Figure 3. A graphical guide to the PcAAC reaction and recycling experiment.
[a] Equipment and TLC analysis of large-scale reaction: azides (0.5 mol), alkyne
(0.5 mol), photocatalyst (3 mol%), DCM (25 mL), r.t., air, 6 h and white LED
irradiation. [b] The photocatalyst could be reused several times with the
corresponding yields of 96% for cycle 1, 90% for cycle 2 , 83% for cycle 3, 75%
for cycle 4.
3
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10.1002/chem.202000252
Chemistry - A European Journal
RESEARCH ARTICLE
Figure 2. Scope of PcAAC reaction. Standard reaction conditions: azides (0.2 mmol), alkyne (0.2 mmol), photocatalyst (5 mol%), DCM (2.0 mL), r.t., air, 6-12 h and
26W white LED irradiation.
The click chemistry is widely used in bioorthogonal reaction
The development of solar synthesis for organic
photochemistry is a greatly significant event[25] because sunlight
is effectively an inexhaustible energy source. In light of this, the
photocatalyzed click reaction was also performed in the sunlight.
Satisfyingly, this solar-click pattern achieved excellent efficiency
and regioselectivity in the air even without stirring (Fig. 4a). We
also employed our optimized solar-click reaction process for the
synthesis at the one gram scale of one triazole-based anti-cancer
activity pharmaceutical 5c, resulted in good yield of 71% (Fig. 4b).
under aqueous conditions for labelling of biomolecules inside
living cells and even in animals.[26] Therefore, we employed water
or phosphate buffer saline (PBS) as the solvent for the developed
PcAAC reaction, and the results indicate the feasibility of
aqueous-based PcAAC reaction with moderate yield of ~40% (Fig.
4c), which would have important and potential applications for
chemical biology. Particularly, organic chemists have attempted
to remove the toxic copper catalyst from the representative click
reaction CuAAC.45-47 Therefore, the preliminary attempt for
screening metal-free AAC reaction was also conducted by us, and
4
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RESEARCH ARTICLE
the corresponding 1,4-disubstituted 1,2,3-triazole was Conclusion
successfully obtained with excellent regioselectivity by using
TPPT-Cl as the photocatalyst with visible light irradiation under an
ambient atmosphere for 12 h, despite of the medium yield.
Several substrates with different functional groups were
employed for this metal-free AAC reaction, generating various
1,4-disubstituted 1,2,3-triazoles with excellent regioselectivity,
which well proves the universality and feasibility of it (Fig. 4c). This
is the first time for implement of regioselective AAC reaction by
metal-free photoredox electron-transfer strategy. Our trials
resulted in ‘copper-free’ click chemistry by developing metal-free
PcAAC reaction, which is highly attractive to biological or
biomedical researchers.
In summary, we devised
a
highly efficient method for
regioselective azide−alkyne cycloaddition under photocatalytic
conditions by using photoredox electron-transfer strategy. The
alkenyl radical cation formed by photocatalyst could rapidly ligate
with azide component to generate 1,4-disubstituted 1,2,3-triazole
with excellent regioelectivity. The new reaction is air and
moisture-tolerant, and the photocatalyst can be readily recovered
after use and reused several times, which are applied to a broad
range of substrates with high efficiency of yield up to 99%,
including the expedient synthesis of various biaocative molecules
and pharmaceuticals. Furthermore, the solar-click pattern also
achieved excellent efficiency and regioselectivity in the air even
without stirring. The metal-free photocatalyzed AAC concept was
also put forward first time, and the preliminary attempt indicate the
feasibility of it. The novel design strategy for AAC reaction by
visible light catalysis via photoredox electron-transfer process
would promote the development of click chemistry and enrich the
click family, which should find application in organic synthesis,
medicinal chemistry, chemical biology and materials science.
Acknowledgements
This work was supported by the National Natural Science
Foundation of China (51773088, 21975119).
Keywords: click chemistry • photoredox reaction • photocatalysis
• cycloaddition • regioselectivity
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10.1002/chem.202000252
Chemistry - A European Journal
RESEARCH ARTICLE
Entry for the Table of Contents
The novel design strategy for azide-alkyne cycloaddition reaction by visible light catalysis via photoredox electron-transfer process
was brought up for first time, representing an important development for click chemistry.
7
This article is protected by copyright. All rights reserved.