Synthesis of 5-functionalized-1,2,3-triazoles via a one-pot aerobic oxidative coupling reaction of alkynes and azides

Article abstract of DOI:10.1016/j.cclet.2014.03.004

In this paper, an efficient synthesis of 5-alkynyl-1,2,3-triazoles through a one-pot aerobic oxidative coupling reaction of various alkynes and azides has been developed. Further derivatization of 5-alkynyl-1,2,3-triazoles readily yielded 5-carbonyl-1,2,3-triazoles, 5-carboxylic-1,2,3-triazole, 5-hydroxyalkyl-1,2,3-triazoles and 5-quinoxaline-1,2,3-triazole, which provided an entry into structurally diverse 5-functionalized-1,2,3-triazoles.

Full text of DOI:10.1016/j.cclet.2014.03.004

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CCLET-2888; No. of Pages 4
Chinese Chemical Letters xxx (2014) xxx–xxx
Contents lists available at ScienceDirect
Chinese Chemical Letters
journal homepage: www.elsevier.com/locate/cclet
Original article
Synthesis of 5-functionalized-1,2,3-triazoles via a one-pot aerobic
oxidative coupling reaction of alkynes and azides
*
*
Ling-Jun Li , Yu-Qin Zhang, Yang Zhang, An-Lian Zhu, Gui-Sheng Zhang
School of Chemistry and Chemical Engineering, Key Laboratory of Green Chemical Media and Reactions, Ministry of Education,
Collaborative Innovation Center of Henan Province for Green Manufacturing of Fine Chemicals, Henan Normal University, Xinxiang 453007, China
A R T I C L E I N F O
A B S T R A C T
Article history:
In this paper, an efficient synthesis of 5-alkynyl-1,2,3-triazoles through a one-pot aerobic oxidative
coupling reaction of various alkynes and azides has been developed. Further derivatization of 5-alkynyl-
1,2,3-triazoles readily yielded 5-carbonyl-1,2,3-triazoles, 5-carboxylic-1,2,3-triazole, 5-hydroxyalkyl-
1,2,3-triazoles and 5-quinoxaline-1,2,3-triazole, which provided an entry into structurally diverse 5-
functionalized-1,2,3-triazoles.
Received 19 November 2013
Received in revised form 26 January 2014
Accepted 17 February 2014
Available online xxx
ß 2014 Ling-Jun Li and Gui-Sheng Zhang. Published by Elsevier B.V. on behalf of Chinese Chemical
Society. All rights reserved.
Keywords:
Alkyne
Azide
1,2,3-Triazole
Copper catalysis
1. Introduction
tools for the triazole-based drug discovery [6,13]. In this paper, we
report our recent progress in synthesizing 5-alkynyl-1,2,3-
Recently, triazole derivatives have attracted considerable
attention not only because of their importance as effective and
convenient linkages in biological conjugation chemistry [1,2] and
polymer chemistry [3], but also their potentials as pharmaco-
phores in medicinal chemistry [4,5]. Besides classic 1,4-disubsti-
tuted-1,2,3-triazoles, the modifications on the 5-position of 1,2,3-
triazoles proved an alternative effective approach in drug design
[6,7]. Thus simple and effective synthetic methodologies for the
derivatization on the 5-position of 1,2,3-triazoles are in great need.
Several protocols have been reported to address this issue
including the cycloaddition reactions between substituted-alkynes
and organic azides [8], electrophilic trapping of triazolyl copper
intermediate [9] and C–H activation of the 5-H in 1,2,3-triazoles
[10]. But these methods require the synthesis of the unstable 1-
iodoalkynes, expensive palladium reagents and complex ligands,
or have narrow structural diversity on both reactants and
substituents, which limit their further applications in the synthesis
of structurally complex compounds and drugs. During our
exploration of 1,2,3-triazoles as nucleobase mimics [11], we have
developed a series of multi-component reactions to synthesize 5-
substituted-1,2,3-triazoles [9b,c,e,12], providing usful synthetic
triazoles through a one-pot aerobic oxidative coupling reaction
of various alkynes and azides, and their conversion to other 5-
functionalized-1,2,3-triazoles via oxidation, reduction and con-
densation reactions.
Traditional methods for the preparation of 5-alkynyl-1,2,3-
triazoles use a two-step sequence involving the synthesis of 5-
iodo-1,2,3-triazole followed by
terminal alkynes. Porco et al. reported the ligand effects on the
oxidative-CuAAC reaction and developed ligand-controlled
a Sonogashira reaction with
a
synthesis of 5-alkynyl-1,2,3-triazoles using NMO as an oxidant
[14]. During our preparation of this paper, Alonso and coworkers
also reported their work of constructing 1-benzyl-5-alkynyl-1,2,3-
triazoles from benzyl bromide, azide sodium and alkynes [15]. In
our work, we found the simple temperature regulation could
dramatically improve the yields of 5-alkynyl-1,2,3-triazoles using
azides and alkynes as starting materials. Furthermore, this
methodology showed a wider scope of substrates such as ribosyl
azide, which could not be prepared directly from simple halide.
2. Experimental
The 1H NMR and 13C NMR spectra were recorded at 400 MHz
and 100 MHz, respectively. Chemical shifts were reported in ppm
from the residual solvent signal or tetramethylsilane (TMS) as an
internal standard. Multiplicity was indicated as follows: s (singlet);
*
Corresponding authors.
E-mail addresses: lingjunlee@htu.cn (L.-J. Li), zgs@htu.cn (G.-S. Zhang).
http://dx.doi.org/10.1016/j.cclet.2014.03.004
1001-8417/ß 2014 Ling-Jun Li and Gui-Sheng Zhang. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
Please cite this article in press as: L.-J. Li, et al., Synthesis of 5-functionalized-1,2,3-triazoles via a one-pot aerobic oxidative coupling
reaction of alkynes and azides, Chin. Chem. Lett. (2014), http://dx.doi.org/10.1016/j.cclet.2014.03.004

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Table 2
d (doublet); t (triplet); m (multiplet); dd (doublet of doublets), etc.
and coupling constants were given in Hz. The conversion of
starting materials was monitored by thin layer chromatography
(TLC) analysis using silica gel plates (silica gel 60 F254, 0.25 mm)
and components were visualized by observation under UV light
(254 and 365 nm). Experimental procedures and spectroscopic
data are detailed in the supporting information.
Synthesis of 5-alkynyl-1,2,3-triazoles 3.a
R2
CuBr, KOH
R1 N3
N
N
R2
R2
+
60 oC, MeOH
N
R1
1
2
3
Preparation of 5-alkynyl-1,2,3-triazole 3a: Benzyl azide (21 mg,
0.16 mmol), phenylacetylene (40.2 mg, 0.4 mmol), CuBr (2.3 mg,
0.016 mmol), and KOH (17.7 mg, 0.32 mmol) were added to 1.5 mL
of ethanol. The reaction mixture was stirred at 60 8C for 10 h and
cooled to room temperature. The solvent was evaporated and the
residue was partitioned between ethyl acetate and H2O. The
organic layer was washed with saturated NH4Cl solution and H2O,
then dried over anhydrous Na2SO4 and evaporated. The crude
product was purified by silica gel column chromatography (5:1,
petroleum ether/ethyl acetate) to give compound 3a as a yellow
solid (37.5 mg, 71%).
Entry
R1
R2
Product
Isolated yield (%)
1
2
3
4
5
6
7
8
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Ph
3a
3b
3c
3d
3e
3f
77
68
76
71
64
75
65
75
4-MeC6H4
4-FC6H4
4-MeOC6H4
pyrenyl
n-hexyl
HOCH2CH2CH2
Ph
3g
3h
phenethyl
HO
O
9
Ph
3i
67
O
O
Preparation of 1-(1-benzyl-4-phenyl-1H-1,2,3-triazol-5-yl)-2-
phenylethane-1,2-dione 4: A 50 mL flask, immersed in a water
bath at 25 8C, was charged with acetone (10 mL) and 1-benzyl-4-
phenyl-5-(phenylethynyl)-1H-1,2,3-triazole (33.5 mg, 0.1 mmol).
To this mixture was added a solution of NaHCO3 (13.6 mg,
0.162 mmol) and MgSO4 (136 mg, 0.552 mol) in water (6 mL). The
mixture was stirred with a magnetic stirrer. Powdered potassium
permanganate (60 mg, 0.39 mmol) was added in one portion, and
the mixture was stirred for 8 h. The unreacted permanganate and
the precipitated MnO2 were reduced to soluble Mn2+ ions by
adding a minimum quantity of NaNO2 (19 mg) and 10% H2SO4
(1 mL). The solution was transferred to a 50 mL separating funnel,
saturated with NaCl, and extracted with a hexane-ether mixture.
The organic solvents were removed using a rotary evaporator. The
residue was dissolved in ether (5 mL) and extracted with a dilute
5% NaOH solution to remove any carboxylic acids present. The
ether layer was washed with a saturated solution of NaCl and dried
(anhydrous Na2SO4, and the solvent was removed in a rotary
evaporator to produce a yellow solid (29.4 mg, 80%).
a
Reaction conditions: azide
1
(0.16 mmol), alkyne
2
(0.4 mmol), CuBr
(0.016 mmol), KOH (0.32 mmol) in 1.5 mL solvent at 60 8C for 20 h.
was the best inorganic base. In the presence of 10 mol% CuBr and
KOH, phenylacetylene 2a and benzyl azide 1a reacted at 60 8C to
yield 5-alkynyl-1,2,3-triazole 3a in 77% yield. Regioselectivity of
this reaction was confirmed by the X-ray diffraction (XRD) analysis
of compound 3a as shown in Fig. S1 in Supporting information,
which showed the regioselective alkynyl substitution on the 5-
position of 1,4-disubstituted-1,2,3-triazole.
The different azides and terminal alkynes were applied to
investigate the scope of this method (Table 2). Substituted
aromatic alkynes with both electron-withdrawing and electron-
donating substituents reacted smoothly to produce 5-alkynyl-
1,2,3-triazoles in high yields (68%–71%). For the more bulky 1-
ethynylpyrene, a 64% yield of 5-alkynyl-1,2,3-triazole 3e was still
obtained. Aliphatic alkyne reacted with 1a to produce compounds
3f and 3g in 75% and 65% yields, respectively. Phenethyl azide as
3. Results and discussion
Through the optimization of reaction temperatures, catalysts,
solvents and bases (Table 1), 60 8C was found to be the best
reaction temperature, CuBr was the best copper catalyst, and KOH
Scheme 1. Synthesis of 5-dicarbonly-1,2,3-triazole 4.
Table 1
Optimization of reaction conditions for the synthesis of 5-alkynyl-1,2,3-triazole
3a.a
Ph
Copper salt, Base
Solvent
N
N
BnN3
Ph
.
+
Ph
N
Bn
2a
1a
3a
Entry
Cat. (10 mol%)
Base (2 equiv.)
Temp (8C)
Isolated yield (%)
Scheme 2. Synthesis of 5-hydroxyalkyl-1,2,3-triazole
triazoles 6.
5 and 5-carboxyl-1,2,3-
1
2
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuI
KOH
0
50
60
70
60
60
60
60
60
60
0
55
77
61
79
41
65
44
60
15
KOH
3
KOH
4
KOH
6b
7
KOH
K2CO3
EtONa
CsCO3
KOH
8
9
10
11
Cu2O
KOH
a
Reaction conditions: 1a (0.16 mmol), 2a (0.4 mmol), copper catalyst
(0.016 mmol) in 1.5 mL solvent for 20 h under air atmosphere.
Scheme 3. Synthesis of 5-quinoxaline-1,2,3-triazole 7.
b
Under 1 atm. O2 atmosphere.
Please cite this article in press as: L.-J. Li, et al., Synthesis of 5-functionalized-1,2,3-triazoles via a one-pot aerobic oxidative coupling
reaction of alkynes and azides, Chin. Chem. Lett. (2014), http://dx.doi.org/10.1016/j.cclet.2014.03.004

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3
Scheme 4. The possible reaction mechanism.
the azide donor reacted smoothly with a terminal alkyne to
produce 5-alkynyl-1,2,3-triazole 3h in 75% yield. Unnatural
nucleosides are valuable biological tools and bioactive molecules
[16]. Connection of ribosyl azide and designed alkynyl building
blocks by CuAAC reaction provided an effective approach to this
kind of compounds [4b]. Herein we found that ribosyl azide donor
was also an effective substrate for the preparation of 5-alkynyl-
1,2,3-triazolyl nucleoside 3i in 67% yield under standard condi-
tions.
With 5-alkynyl-1,2,3-triazoles in hand, we explored next the
potential of 5-alkynyl-1,2,3-triazoles as precursors to other 5-
functionalized-1,2,3-triazoles (Schemes 1–3). It was difficult to
introduce an electron-withdrawing group on the 5-position of
1,2,3-triaozle by the CuAAC reactions. Here we could successfully
transform 5-alkynyl-1,2,3-triazole 3a to 5-dicarbonly-1,2,3-tria-
zole 4 via an oxidative reaction in presence of KMnO4 (Scheme 1).
And then, the 5-hydroxyalkyl-1,2,3-triazole 5, 5-carboxyl-1,2,3-
triazoles 6 could be prepared from 4 in excellent yields, by an
oxidation and a reduction reaction, respectively (Scheme 2).
Quinoxaline is a classic pharmacophore in current drug design. 5-
Quinoxaline-1,2,3-triazole 7 could also be effectively prepared by a
condensation reaction between 5-dicarbonly-1,2,3-triazole 4 and
benzene-1,2-diamine (Scheme 3).
4. Conclusion
In conclusion, a simple, efficient and ligand-free synthesis of 5-
alkynyl-1,2,3-triazoles has been developed using a one-pot aerobic
oxidative CuAAC reactions at 60 8C. Various azides and alkynes can
be used as the substrates in these reactions to achieve chemical
diversity. In particular, the successful application of the CuBr/Base
catalytic system in sugar indicates the value of this method in the
synthesis of designed unnatural nucleoside. Furthermore, the
transformation of 5-alkynyl-1,2,3-triazoles to other structurally
diverse 5-functionalized-1,2,3-triazoles illustrates the potential of
our methods in the triazole-based drug design.
Acknowledgments
We are grateful to the NSFC (Nos. 21172058, 20802017),
HASTIT (No. 2012HASTIT10), PCSIRT (No. IRT1061) and Key
Technologies
R
&
D
Program of Henan Province (No.
112102310319) for financial support.
Appendix A. Supplementary data
For the mechanism of the formation of 5-alkynal-1,2,3-triazoles
from alkynes and azides, three possible routes (A, B, and C) showed
in Scheme 4 based on the mechanisms of the Cu(I) mediated click
reaction and Glaser reaction of alkynes in the literatures [8a,17]
can be envisioned. Two additional experiments were also
performed (Scheme 4): under the current reaction conditions,
compound 8 cannot react with 2a to form 5-alkynyl-1,2,3-triazole
3a, and Glaser coupling product 1,4-diphenyl-1,3-diyne 9 cannot
either react with azide 1a to form 3a, which rule out the
possibilities of forming 3 via 8 as an intermediate (Mechanism C) or
via Cu(I) mediated Glaser coupling of an alkyne to a 1,3-diyne
followed by the click reaction with azide 2 (Mechanism A). These
results revealed that the CuAAC reaction should precede the
oxidative coupling reaction in the sequence. Thus it seems that the
reaction proceeds through the aerobic coupling of the carbanion
intermediate 80 of the CuAAC reaction with the copper acetylide 20
to afford the corresponding 3 (mechanism B). In this procedure, the
temperature might play a role to regulate reaction pathways. At
60 8C, aerobic oxidative coupling reaction preferentially takes
place between intermediate 80 and copper acetylide 20 to produce
5-alkynly-1,2,3-triaozle 3 chemoselectively.
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.cclet.2014.03.004.
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reaction of alkynes and azides, Chin. Chem. Lett. (2014), http://dx.doi.org/10.1016/j.cclet.2014.03.004