Controllable synthesis of bis(1,2,3-triazole)s and 5-alkynyl-triazoles via temperature effect on copper-catalyzed Huisgen cycloaddition

Article abstract of DOI:10.1016/j.tet.2013.09.093

A facile synthetic protocol has been developed for the controllable preparation of bis(1,2,3-triazole)s and 5-alkynyl-1,2,3-triazoles from alkyne and azide under different temperatures. Various azides and alkynes were used as substrates for the reactions and the successful applications in nucleoside analogues manifested the values of this method in syntheses of bioactive molecules. Besides, a possible temperature-guided triazolyl-copper intermediate aerobic oxidative coupling mechanism was proposed for this controllable reaction procedure.

Full text of DOI:10.1016/j.tet.2013.09.093

Accepted Manuscript
Controllable Synthesis of Bis(1,2,3-triazole)s and 5-Alkynyl-triazoles via Temperature
Effect on Copper-catalyzed Huisgen Cycloaddition
Lingjun Li, Xincui Fan, Yang Zhang, Anlian Zhu, Guisheng Zhang
PII:
S0040-4020(13)01527-5
10.1016/j.tet.2013.09.093
TET 24868
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 24 June 2013
Revised Date: 17 September 2013
Accepted Date: 27 September 2013
Please cite this article as: Li L, Fan X, Zhang Y, Zhu A, Zhang G, Controllable Synthesis of Bis(1,2,3-
triazole)s and 5-Alkynyl-triazoles via Temperature Effect on Copper-catalyzed Huisgen Cycloaddition,
Tetrahedron (2013), doi: 10.1016/j.tet.2013.09.093.
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ACCEPTED MANUSCRIPT
Controllable Synthesis of Bis(1,2,3-triazole)s and
5
-Alkynyl-triazoles via Temperature Effect on
Copper-catalyzed Huisgen Cycloaddition
*
*
Lingjun Li, Xincui Fan, Yang Zhang, Anlian Zhu, Guisheng Zhang
School of Chemistry and Chemical Engineering, Henan Normal University, Key
Laboratory of Green Chemical Media and Reactions, Ministry of Education, �
Xinxiang 453007, P. R. China
Lingjunlee@htu.cn, zgs@htu.cn
Abstract: A facile synthetic protocol has been developed for the controllable
preparation of bis(1,2,3-triazole)s and 5-alkynyl-1,2,3-triazoles from alkyne and azide
under different temperatures. Various azides and alkynes were used as substrates for
the reactions and the successful applications in nucleoside analogues manifested the
values of this method in syntheses of bioactive molecules. Besides, a possible
temperature-guided triazolyl-copper intermediate aerobic oxidative coupling
mechanism was proposed for this controllable reaction procedure.
Keywords: bis(1,2,3-triazole)s, 5-alkynyl-triazoles, nucleoside analogues

ACCEPTED MANUSCRIPT
1
. Introduction
[
1]
Since the concept of “click chemistry” was presented in 2001, the preparation and
[
2]
application of 1,2,3-triazoles have attracted wide interest in organic chemistry
,
[3]
[4]
medicinal chemistry and material sciences . Besides being applied as a simple
linkage to connect different building blocks, 1,2,3-triazole itself has been also
[5]
[6]
explored as bioisoster of peptide bonds , multi-functional ligands , and
[7]
supermolecular binding groups . Several synthetic protocols for the preparation of
1
,2,3-triazoles derivatives have been developed: (1) cycoloaddition between
[8]
substituted-alkyne and organic azide; (2) electrophilic trapping of triazolyl-copper
[
9]
[10]
intermediate; (3) C-H activation on 5-H of 1,2,3-triazole.
Bis(1,2,3-triazole)s (1) and 5-alkynyl-1,2,3-triazoles (2) were initially found as trace
by-products of the copper-catalyzed Huisgen cycloaddition reaction (CuAAC
[11]
reaction).
Recent researches showed functional perspectives of these two
1
,2,3-triazole derivatives in ligand design or as synthetic intermediates of fused
[12]
rings. Angell et al. developed the first preparative method for bis(1,2,3-triazole)s in
[13]
the presence of Na
2
CO
3
,
in which only propargyl ethers could lead to desirable
[13.14]
yields due to the sensitive steric effect.
Very recently, Xu et al. reported their
ligand-controlled synthesis of bis(1,2,3-triazole)s. Moderate to good yields of
bis(1,2,3-triazole)s could be achieved by using polysiloxane-supported secondary
[15]
amine as ligand.
As for 5-alkynyl-1,2,3-triazoles, the preparative method was
reported by Porco Jr et al in 2006, in which moderate yields were obtained through
additional co-oxidant together with ligand control. In this paper, based on temperature

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effect, a facile protocol for controllable syntheses of 1 and 2 has been developed
under ligand-free reaction conditions with CuBr as catalyst (Scheme 1). A wide scope
of substrates and tolerance of sensitive building blocks illustrate the potential
applications of this method in the design and synthesis of bioactive molecules.
Scheme 1. Temperature-regulated approaches for the preparation of
bis(1,2,3-triazole)s 1 and 5-alkynyl-1,2,3-triazoles 2 from alkynes and azides.
2
. Results and discussion
Temperature effect was accidently found during working on derivatization of
[
3d, 9b,c]
1
,2,3-triazole in drug design.
Under dry air, benzyl azide (3a, 0.16mmol) and
phenylacetylene (4a, 0.17 mmol) were added to a mixture of CuBr (0.016 mmol) and
NaOEt (0.32 mmol) in EtOH to immediately generate a yellow suspension. The
o
mixture was stirred at 0 C for 20 hours, all of the insoluble materials disappeared to
produce a light brown solution, and the staring material was completely comsumed by
1
TLC detection. The structure of product was determined by HNMR and LC-MS.
Unexpectedly, instead of click product 5, bis(1,2,3-triazole)s 1a was obtained in 91%
yield, which is much higher than 34% that was reported by Angell et al in 2009. More
o
interestingly, when the reaction temperature increased to 60 C, no 1a could be

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detected. Instead, 5-alkynyl-1,2,3-triazole 2a became the major product with 50%
yield slightly higher than click product 5a (41%) (Scheme 2). When the amount of
alkyne was increased to 2.5 equiv. of azide, 65% yield of 2a can be obtained.
Considering the same catalytic system and reactants, the reaction temperature might
play a role in regulation of the distributions of 1,2,3-triazole derivatives in oxidative
CuAAC reaction. Thus, we considered to develop a convenient synthetic protocol for
the controllable preparation of 1a and 2a from alkyne and azide through optimization
of the reaction temperature and other reaction conditions.
Scheme 2. CuAAC reaction products under different temperature conditions.
Initially, the temperature effect on the three products 1a, 2a and 5 was investigated
o
o
o
o
o
o
o
o
systemically under 0 C, 10 C, 20 C, 30 C, 40 C, 50 C, 60 C and 70 C with 10
mol% CuBr as catalyst, NaOEt as base, and EtOH as solvent. From the reaults in
Table 1, it could be concluded that 1a increased with the decrease of reaction
temperature, at the same time, 2a gradually increased with the increase of reaction
temperature. An exception was Entry 9, in which 55% yield of 2a was obtained at 70
o
o
o
C less than 65% at 60 C. Thus, 60 C was chosen as the best temperature in the
following optimization of reaction conditons for the preparation of 2a.
Table 1. Effect of temperature on the products of oxidative CuAAC reaction.

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Temperature
Isolated yield (%)
[a]
Entry
o
(
C)
1a
91
85
70
50
21
10
0
2a
0
0
5
5
1
2
3
4
5
6
7
0
10
20
30
40
50
60
60
70
10
18
32
55
50
41
31
42
7
10
18
35
50
65
55
[
b]
8
9
0
0
[
b]
[
a]
Reaction conditions: azide 3a (0.16 mmol), alkyne 4a (0.17mmol), CuBr (0.016
mmol), NaOEt (0.32 mmol) in 1.5 mL EtOH under dry air atmosphere for 20 h.
.40 mmol alkyne 4a was used.
[b]
0
The effect of copper salts on the products of CuAAC reaction was then investigated
Entry 1-3 in Table 2) by taking the reaction of 3a and 4a as an example. Among
(
three copper (I) salts, CuBr was the most effective catalyst for the preparation of
bis(1,2,3-triazole)s 1a and alkynyl-1,2,3-triazole 2a. CuI showed the best catalytic
activation for the preparation of 1,2,3-triazole 5. The solvent effect on the prodcuts of
CuAAC reaction was also investigated in the presence of 10 mol% CuBr as catalyst
o
o
(
Entry 4-11 in Table 2) at 0 C and 60 C respectively. For 1a, protic solvents such as
ethanol and methanol showed better results (91% and 83%) than aprotic solvents
o
CH CN and THF (42% and 38% ) at 0 C. In pure water, none of the three products
3
could be obtained with total recovery of starting materials. The investigation of
o
solvent effect on 2a was carried out under 60 C. In CH
3
CN, 61% yield of 2a was
obtained with 33% 5. In EtOH, 68% yield of 2a were obtained with 31% 5.

ACCEPTED MANUSCRIPT
Table 2 Effect of copper salt and solvent on the products of oxidative CuAAC
reaction.
Temperature
Isolated yield
[
a]
Entry
Solvent
Catalyst
o
(
C)
1a
18
38
5
35
42
91
83
NR
0
2a
0
10
5
5
5
0
0
NR
65
58
61
5
75
30
5
15
22
5
14
NR
31
35
33
1
2
3
4
5
6
7
8
25
THF
THF
THF
CuI
25
25
0
0
0
0
0
60
60
60
CuBr
CuCl
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CH
CH
EtOH
2
Cl
CN
2
3
[
b]
MeOH
[
c]
H
2
O
[
d]
9
1
1
EtOH
[
d]
[c]
0
1
THF
0
0
[
d]
[c]
CH CN
3
[
a]
Reaction conditions: azide 3a (0.16 mmol), alkyne 4a (0.17mmol), catalyst (0.016
mmol), NaOEt (0.32 mmol) in 1.5 mL solvent under dry air atmosphere for 20 h.
NaOMe (0.32 mmol) was used as base. NaOH (0.32 mmol) was used as base.
.40 mmol alkyne 4a was used.
[
b]
[
c]
[d]
0
The effect of base on the product of CuAAC reaction was studied by taking the
o
reaction of 1a and 2a as a model in the presence of 10 mol% CuBr in EtOH at 0 C
o
and 60 C respectively (Table 3). Angell et al. reported the effect of bases on the yield
[13]
of bis(1,2,3-triazole)s . Here we found that the strong base showed an effective
o
promotion on the yield of 1a at 0 C, but the effect of base was negligible at higher
o
reaction temperature. Using strong base NaOEt, 91% yield of 1a was obtained at 0 C.
o
However, for the same reaction, if the reaction temperature increased to 60 C, no 1a
could be detected, and in this case, 2a became major product. Thus, the reaction
temperature should take a more prominent role in the regulation of product

ACCEPTED MANUSCRIPT
distribution of oxidative CuAAC reaction. Additionally, NaOH was found as the best
o
base for the preparation of 5a at 60 C with 77% yield.
Table 3 Effect of base on the products of oxidative CuAAC reaction.
Temprature
Isolated yield
[a]
Entry
Base
CO
o
(
C)
0
1a
62
55
35
91
7
0
0
0
2a
15
30
10
0
40
44
77
65
5
1
2
3
4
K
2
3
17
10
35
5
41
43
21
31
0
0
0
60
60
60
60
Cs
2
CO
KOH
NaOEt
CO
CO
KOH
NaOEt
3
b
5
6
7
1
K
2
3
b
Cs
2
3
b
b
0
[
a]
Reaction conditions: azide 3a (0.16 mmol), alkyne 4a (0.17 mmol), CuBr (0.016
mmol), Base (0.32 mmol) in 1.5 mL EtOH under dry air atmosphere for 20 h. 0.40
[b]
mmol alkyne 4a was used.
The scope of the reaction of terminal alkynes with azides for the preparation of 1 was
o
investigated in the presence of 10 mol% CuBr, 0.2 equiv. NaOEt in EtOH under 0 C
(Table 4). Aromatic alkynes with both of electron-withdrawing and electron-donating
groups reacted smoothly with azide 3a to produce 1a-1d with yields of 68%-91%.
Aliphatic alkyne reacted with 3a to produce compound 1e with 84% yield. Phenethyl
azide also reacted well with terminal alkyne to produce 1f with 81% yield. Moreover,
this method was applied for the syntheses of bis(1,2,3-triazole)s nucleoside
derivatives. The ribosyl azide reacted with aromatic and aliphatic alkynes to give
nucleoside analogues 1g-1j with 61-70% yields.

ACCEPTED MANUSCRIPT
[
a,b]
Table 4. The scope of the preparation of bis(1,2,3-triazole)s
.
[
a]
Reaction conditions: azide 3 (0.16 mmol), alkyne 4 (0.17mmol), CuBr (0.016
o
mmol), NaOEt (0.32 mmol) in 1.5 mL EtOH under dry air atmosphere at 0 C for 20
h. Isolated yields. Reaction time was 48 h.
[
b]
[c]
[
a,b]
Table 5. The scope of the preparation of 5-alkynyl-1,2,3-triazoles
.

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R
Air
1
0 mol% CuBr
N
N
R
R' N3
+
R
N
2
.0 equiv. KOH
o
R'
3
4 (2.5 equiv.)
EtOH, 60 C
2
F
N
N
N
N
N
F
N
N
N
N
Bn
Bn
Bn
2a 77%
2b 68%
2c 76%
MeO
Ph
Ph
N
N
N
N
N
N
MeO
N
N
Bn
N
Bn
2d 71%
2e 75%
2f 75%
HO
HO
N
N
N
HO
N
O
N
N
N
N
N
Bn
O
O
Bn
2
g [c] 67%
2h 65%
2i 64%
[
a]
Reaction conditions: azide 3 (0.16 mmol), alkyne 4 (0.4 mmol), CuBr (0.016
o
mmol), KOH (0.32 mmol) in 1.5 mL EtOH under dry air atmosphere at 60 C for 20
h. Isolated yields. Reaction time was 20 h with NaOEt as base.
[
b]
[c]
The scope of our method for the preparation of 5-alkynyl-1,2,3-triazole 2 was
o
investigatd in the presence of 10 mol% CuBr, 0.2 equiv. KOH in EtOH under 60 C
as shown in Table 5. Aromatic alkynes with electron-withdrawing and
electron-donating substituent groups both reacted smoothly with 1a to produce 2a-2d
with high yields (68%-77%). Reactions of aliphatic alkynes 1-octyne and
pent-4-yn-1-ol with 3a produced compounds 2e, 2h with yields of 75%, and 65%,
respectively. Phenethyl azide reacted smoothly with terminal alkyne 4a to produc 2f

ACCEPTED MANUSCRIPT
with 75% yield. Ribosyl azide donor was also used for the preparation of 2, and a
triazole nucleoside 2g was obtained with 61% yield under the present condition. For
the more bulky 1-ethynylpyrene, the 64% yield of 2i was obtained.
Bn Bn
1
2
0 mol% CuBr,
equvi. NaOEt
Ph
N
N
N
N
N
N
N
N
N
2
o
EtOH, 0 C
Ph Ph
5
a
Bn
1a
Bn Bn
Ph
1
2
0 mol% CuBr,
equvi. NaOEt
N
N
N
N
N
N
N
N
Ph
+
BnN3
o
N
Bn
EtOH, 0 C
1
a
Ph Ph
Ph
2a
3a
10 mol% CuBr,
Ph
N
N
2 equvi. KOH
N
N
N
+
Ph
Ph
o
EtOH, 60 C
N
4a
2a
Bn
5a
Bn
Bn Bn
Ph
1
2
0 mol% CuBr,
equvi. KOH
N
N
N
N
N
N
N
N
Ph
Ph
+
Ph
or
BnN3
o
N
Bn
EtOH, 60 C
3a
Ph Ph
1a
2a
Scheme 3. The control experiments.
To elucidate the mechanism, some control experiments were carried out (Scheme 3).
Under the current reaction conditions, 5a could not react by self-coupling to 1a, and
2
a could not react with azide 3a to form 1a, which ruled out the possibilities of the
formation of 1a via 5a or 2a as intermediates. 5a could not react with alkyne 4a to
form 1a, which ruled out the possibility of the formation of 2a via 5a as intermediate.
Moreover, the 1,4-diphenyl-diyne could not react with azide 3a to form either 2a or
1
a, which ruled out the possibility of formation of 2a and 1a via cycloaddition of
Glaser coupling product 1,3-diyne. These control experiments indicated that the
cycloaddition step should take place before the oxidative coupling step. Additionally,

ACCEPTED MANUSCRIPT
when air was replaced by nitrogen atomsphere in the reaction of 3a and 4a , product
1
a and 2a could not be detected, instead, 5a was obtained in 92% yield. Thus the
formtion of 1,2,3-triazolyl-copper intermediate during this reaction proceedure should
be resonable.
Scheme 4. The possible reaction mechanism.
On the basis of these preliminary results, a possible mechanism of the
temperature-regulated oxidative CuAAC reaction was proposed (Scheme 4). The
current reaction might proceed through a tandem aerobic oxidative coupling reaction
of the triazolyl-copper complex intermediate 7 that was produced by CuAAC
[19]
o
reaction . At 0 C, the aerobic oxidative coupling reaction could take place
o
preferentially by Path A to produce 1. While at 60 C, the aerobic oxidative coupling
reaction could take place preferentially by Path B to produce 2. When the nitrogen
atomphere was used for this reaction, the oxidative coupling reaction was supressed,
and then the trapping proton on the intermediate 7 was prevailing to give 5 by Path C.

ACCEPTED MANUSCRIPT
A possible reason for this temperature-guided product distribution could be the effect
of temperature on the reactivity of triazolyl-copper complex 7 and 8. However, the
details of aerobic oxidative coupling machanism on complex 7 such as triazolyl
[20]
Cu-O intermediates are not clear at present.
2
3
. Conclusion
In conclusion, an effective controllable synthetic protocol has been developed for the
o
o
preparation of bis(1,2,3-triazole)s and 5-alkynyl-1,2,3-triazole at 0 C and 60 C
respectively. Various azides and alkynes can be used as the substrates for these
reactions, and the successful applications in syntheses of nucleoside analogues
manifest the values of this method in the design and synthesis of bioactive molecules.
Besides, a possible temperature-guided copper-catalyzed aerobic oxidative coupling
reaction mechanism is proposed, which provides an interesting example for the
development of temperature-guided synthetic protocol for other copper-catalyzed
coupling reactions. Further investigations to the reaction mechanism and application
of this oxidative CuAAC coupling reaction in functionalized 1,2,3-triazole derivatives
are still ongoing in our lab.
4
. Experimental section
General
2 2 2 3
Solvents were dried by refluxing for at least 12 h over CaH (CH Cl and CH CN),
sodium/benzophenone (THF), and freshly distilled prior to use. All reactions were
carried out under anhydrous conditions with freshly distilled solvents, unless
otherwise noted. Reactions were monitored by thin-layer chromatography (TLC) on

ACCEPTED MANUSCRIPT
silica gel GF254 precoated on plates. Spots were detected under UV light and/or by
charring with phosphomolybdic acid in ethanol solution. Solvents were evaporated
under reduced pressure and below 50 °C (water bath). High-resolution mass spectra
(HRMS) analyses were carried out using electrospray ionization time-of-flight mass
1
13
spectrometry (ESI-TOF/MS). H NMR and C NMR data were recorded with a
Avance 400/DPX (Bruker) spectrometer from CDCl solutions using the residual
3
solvent signal or TMS as reference. Chemical shifts are reported in parts per million.
All chemical shift values are quoted in ppm and coupling constants quoted in Hz.
Representative Procedure for the Preparation of compound 1a-j
Azide (0.16 mmol), alkyne (0.17mmol), and CuBr (2.3mg, 0.016mmol) were added
into 1.5 ml fresh ethanol solution of NaOEt (14.5mg, 0.64 mmol) under dry air
o
o
atmosphere at 0 C. The reaction mixture was stirred for 20 hours at 0 C, then the
solvent was evaporated, and the residue was partitioned between ethyl acetate and
H
2
O. The organic layer was washed with saturated NH
dried over anhydrous Na SO and evaporated. The residue was further purified by
silica gel column chromatography (ethyl acetate/petroleum ether) to give compound
4 2
Cl solution and H O, then
2
4
1
.
1
Compound 1a Isolated yield 33 mg (91%) as white amorphous solid. H NMR
(
CDCl
d, 2 H, J = 15 Hz), 4.62 (d, 2 H, J = 15 Hz); C NMR (CDCl
32.0, 128.4, 128.1, 127.92, 127.87, 127.82, 127.3, 124.9, 119.0, 51.8. HRMS
3
) δ 7.43 (d, 4 H, J = 8 Hz), 7.24-7.07 (m, 12 H), 6.79 (d, 4 H, J = 7 Hz), 4.68
13
(
3
, 100 MHz) δ 146.9,
1
+
+
(
25 6
ESI-TOF) m/z calculate for (M+H ) C30H N 469.2135, Found: 469.2196.

ACCEPTED MANUSCRIPT
1
Compound 1b Isolated yield 32.5 mg (81%) as white amorphous solid; H NMR
CDCl ) δ 7.35-7.31 (m, 4 H), 7.17-7.07 (m, 6 H), 6.87-6.80 (m, 8 H), 4.75 (d, 2 H, J
15 Hz) ,4.62 (d, 2 H, J = 15 Hz); C NMR (CDCl
31.9, 127.9, 127.2, 126.7, 126.6, 124.42, 124.39, 118.4, 115.2, 115.0, 51.9. HRMS
(
3
13
=
3
, 100 MHz) δ 163.3, 160.8, 146.2,
1
+
+
(
ESI) m/z calculate for (M+H ) C30
Compound 1c Isolated yield 28 mg (68%) as white amorphous solid; H NMR
CDCl ) δ 7.35 (d, 4 H, J =8 Hz), 7.15-7.05 (m, 6 H), 6.80 (d, 4 H, J = 8 Hz), 6.71 (d,
H, J = 8 Hz), 4.67 (d, 2 H, J = 15 Hz), 4.61 (d, 2 H, J = 15 Hz), 3.74 (s, 6 H); C
NMR (CDCl , 100 MHz) δ 159.1, 146.8, 132.2, 127.8, 127.7, 127.3, 126.3, 121.0 ,
23 2 6
H F N 505.1947, Found: 505.1903.
1
(
3
1
3
4
3
+
+
2
1
5
18.2, 113.5, 54.3, 51.7. HRMS (ESI) m/z calculate for (M+H ) C32
H
29
N
6
O
29.2347, Found: 529.2373.
1
Compound 1d Isolated yield 34 mg (86%) as white amorphous solid; H NMR
(
CDCl
Hz), 4.68 (d, 2 H, J = 15 Hz), 4.57 (d, 2 H, J = 15 Hz), 2.29 (s, 6 H); C NMR
CDCl , 100 MHz ) δ 147. 0, 137.9, 132.2, 128.8, 127.8, 127.6, 127.3, 125.6, 124.9,
3
, 400MHz) δ 7.32 (d, 4 H, J = 8 Hz), 7.13-6.99 (m, 10 H), 6.77 (d, 4 H, J = 8
13
(
3
+
+
6
1
4
18.7, 51.7, 20.3. HRMS (ESI) m/z calculate for (M+H ) C32
H
29
N
497.2448, Found:
97.2481.
1
Compound 1e Isolated yield 33 mg (84%) as white amorphous solid; HNMR
(
CDCl , 400 MHz) δ 7.26-7.25 (m, 6 H), 6.88-6.86 (m, 4 H), 4.89 (d, 2 H, J = 15 Hz),
3
5
1
.56 (d, 2 H, J = 15 Hz), 2.11-2.03 (m, 2 H), 1.95-1.87 (m, 2 H), 1.43-1.33 (m, 4 H),
1
3
3
.21-1.11 (m, 12 H), 084-0.80 ( t, 6 H, J = 8 Hz); C NMR (CDCl , 100 MHz) δ

ACCEPTED MANUSCRIPT
1
49.4, 133.2, 128.1, 127.8, 126.8, 119.3, 51.5, 30.5, 28.2, 27.7, 24.0, 21.6, 13.1.
+
+
HRMS (ESI) m/z calculate for (M+H ) C30
H
41
N
6
485.3387, Found: 485.3401.
1
Compound 1f Isolated yield 43 mg (81%) as white amorphous solid; HNMR
(
CDCl , 400 MHz) δ 7.52-7.48 (m, 4 H), 7.15-7.01 (m, 10 H), 6.81 (d, 4 H, J = 6.8
3
13
3
Hz), 3.76-3.72 (m, 4 H), 3.09-3.01 (m, 2 H), 2.75-2.68 (m, 2 H); C NMR (CDCl ,
1
1
5
00 MHz) δ 163.4, 161.0, 145.3, 135.4, 127.9, 127.6, 127.0, 126.9, 126.2, 124.6,
+
+
6
19.0, 115.6, 115.4, 48.7, 34.5. HRMS (ESI) m/z calculate for (M+H ) C32
H
27
F
2
N
33.2260, Found: 533.2252.
Compound 1g Isolated yield 32 mg (65% ) as white gum; The product as a mixture of
1
two isomers(the ratio is 2:1) HNMR (CDCl
3
, 400 MHz) δ 7.60-7.53 (m, 6 H),
7
.38-7.33 (m, 9 H), 5.71 (d, 1 H, J = 2 Hz), 5.52 ( d, 2 H, J = 1 Hz), 5.41-5.39 (m, 2
H), 5.18-5.16 (m, 1 H), 4.88-4.87 (m, 2 H), 4.71-4.68 (m, 1 H), 4.38-4.37 (m, 2 H),
4
2
1
9
.25-4.24 (m, 1 H), 3.72-3.63 (m, 3 H), 3.50-3.43 (m, 3 H), 3.21 (t, 2 H, J = 6 Hz),
13
.84 (t, 1 H, J = 7 Hz), 1.30-1.22 (m, 18 H); C NMR (CDCl , 100 MHz) δ 147.2,
3
28.7, 128.6, 128.4, 128.3, 127.8, 127.5, 125.41, 125.35, 119.1, 118.6, 113.5, 112.7,
2.5, 91.2, 89.2, 87.5, 83.9, 83.3, 80.3, 62.4, 62.2, 25.9, 25.8, 24.1, 23.9. HRMS (ESI)
+
+
36 6 8
m/z calculate for (M+Na ) C32H N NaO 655.2487, Found: 655.2499.
Compound 1h Isolated yield 34 mg (64% ) as white gum; The product as a mixture
1
of two isomers (the ratio is 1:3) HNMR (CDCl , 400 MHz) δ 7.53-7.47 (m, 5 H),
3
7
5
4
.05-6.98 (m, 5 H), 5.65 (d, 0.7 H, J = 2 Hz), 5.46 (s, 2 H), 5.34 (d, 2 H, J = 6 Hz),
.18-5.17 (m, 0.7 H), 4.85 (d, 2 H, J = 6 Hz), 4.76-4.75 (m, 0.7 H), 4.36-4.34 (m, 2 H),
.27 (d, 0.7 H, J = 2 Hz), 3.71-3.67 (m, 2.7 H), 3.50-3.49 (m, 2.7 H), 3.11(s, 2 H),

ACCEPTED MANUSCRIPT
1
3
2
1
9
3
.85 (s, 0.7 H), 1.29-1.21 (m, 16 H); C NMR (CDCl , 100 MHz) δ 163.8, 163.6,
61.3, 146.4, 127.34, 127.26, 123.7, 118.7, 115.8, 115.5, 115.3, 113.4, 112.8, 92.7,
1.5, 89.1, 87.7, 83.9, 83.4, 80.5, 80.4, 62.3, 62.2, 26.0, 25.8, 24.1. HRMS (ESI) m/z
+
+
calculate for (M+Na ) C H F N NaO 691.2298, Found: 691.2277.
32
34
2
6
8
Compound 1i Isolated yield 35 mg (63% ) as white gum; The product as a mixture of
1
two isomers (the ratio is 1:2) HNMR (CDCl
3
, 400 MHz) δ 7.52-7.45 (m, 6 H),
6
=
1
.89-6.84 (m, 6 H), 5.69 (s, 1 H), 5.53 (s, 2 H), 5.39 (d, 2 H, J = 4 Hz), 5.16 (d, 1 H, J
4 Hz), 4.88 (d, 2 H, 8Hz), 4.72 (d, 1 H, J = 4 Hz), 4.37-4.36 (m, 2 H), 4.27-4.26 (m,
H), 3.78 (d, 9 H, J =12 Hz), 3.71-3.68 (m, 3 H), 3.48-3.46 (m, 3 H), 3.20 (m, 2 H),
1
3
2
1
8
3
.95-2.91 (m, 1 H), 1.38-1.19 (m, 18 H); C NMR (CDCl , 100 MHz) δ 159.7, 159.6,
47.3, 147.1, 126.7, 120.3, 120.0, 118.2, 117.7, 113.9, 113.7, 113.4, 112.7, 92.6, 91.0,
9.3, 87.6, 84.0, 83.3, 80.4, 80.3, 62.4, 62.3, 54.4, 26.0, 25.8, 24.2, 24.0. HRMS (ESI)
+
+
m/z calculate for (M+Na ) C34
H
40
N
6
NaO10 715.2698, Found: 715.2711.
1
Compound 1j Isolated yield 36 mg (70% ) as white gum; H NMR (CDCl , 400
3
MHz) δ 5.57 (s, 2 H), 5.48-5.46 (m, 2 H), 4.95 (d, 2 H, J = 4 Hz), 4.44 (m, 2 H),
3
1
.76-3.74 (m, 2 H ), 3.52-3.50 (m, 4 H), 2.63-2.55 (m, 2 H), 2.49-2.41 (m, 2 H),
13
.62-1.57 (m, 4 H), 1.46 (s, 6H), 1.34 (s, 6 H), 1.24 (s, 12 H), 0.86-0.83 (m, 6H); C
3
NMR (CDCl , 100 MHz) δ 149.0, 119.8, 112.9, 91.5, 88.8, 83.9, 80.8, 62.5, 30.5,
+
2
8.1, 27.7, 26.0, 24.2, 24.1, 21.5, 13.1. HRMS (ESI) m/z calculate for (M+H )
+
C
32 53 6 8
H N O 649.3919, Found: 649.3935.
Representative Procedure for the Preparation of compound 2a-i
Azide (0.16 mmol), alkyne (0.4 mmol), CuBr (2.3 mg, 0.016 mmol), and KOH (17.7
mg, 0.32 mmol) were added to 1.5 ml ethanol at dry air atmosphere. The reaction

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mixture was stirred at 60 ºC for 20 h, and then cooled to room temperature. The
mixture was evaporated, and the residue was partitioned between ethyl acetate and
H
2
4 2
O. The organic layer was washed with saturated NH Cl solution and H O, then
dried over anhydrous Na SO and evaporated. The crude product was purified by
2
4
silica gel column chromatography (petroleum ether /ethyl acetate) to give compound
2
.
1
Compound 2a Isolated yield 37.5 mg (71%) as yellow amorphous solid; H NMR
CDCl , 400 MHz) δ 8.09 (d, 2 H, J = 8 Hz), 7.42-7.34 (m, 7 H), 7.27-7.21 (m, 4 H),
.66 (s, 2 H), 2.40 (d, 6H, J = 8 Hz); C NMR (CDCl
37.5, 133.9, 130.5, 128.52, 128.45, 127.9, 127.5, 127.2, 126.7, 125.2, 117.6, 116.2,
(
3
1
3
5
1
1
3
3
, 100 MHz) δ 147.2, 139.2,
+
+
3
01.6, 74.3, 52.0. HRMS (ESI) m/z calculate for (M+H ) C23
H
18
N
336.1495, Found:
36.1511.
1
Compound 2b Isolated yield 39 mg (68%) as yellow amorphous solid; H NMR
1
3
(
CDCl
NMR (CDCl
27.6, 127.2, 125.3, 120.5, 116.4, 101.6, 74.8, 52.1. HRMS (ESI) m/z calculate for
3
, 400MHz) δ 8.18 (d, 2 H, J = 8 Hz), 7.51-7.33 (m, 13 H), 5.68 (s, 2 H); C
3
, 100 MHz) δ 147.2, 133.9, 130.7, 129.5, 128.9, 128.0, 127.84, 127.75,
1
+
+
(
M+H ) C H N 364.1808, Found: 364.1811.
25 22 3
1
Compound 2c Isolated yield 45 mg (76%) as white amorphous solid; H NMR
(
CDCl , 400MHz) δ 8.15-8.13 (m, 2 H ), 7.48-7.45 (m, 2 H), 7.37-7.34 (m, 5 H),
3
13
7
.16-7.09 (m, 4 H), 5.66 (s, 2 H ); C NMR (CDCl
3
, 100 MHz) δ 163.7, 161.2, 146.5,
1
33.7, 132.8, 128.0, 127.7, 127.1, 125.6, 116.5, 116.0, 115.4, 115.2, 114.9, 114.7,
+
+
1
00.4, 74.2, 52.2. HRMS (ESI) m/z calculate for (M+H ) C H F N 372.1307,
23 16 2 3
Found: 372.1299.

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1
Compound 2d Isolated yield 45 mg (71%) as yellow amorphous solid; H NMR
CDCl , 400MHz) δ 8.12 (d, 2 H, J = 8 Hz), 7.44-7.30 (m, 7 H), 6.99-6.91 (m, 4
H),5.64 (s, 2 H), 3.84 (d, 6H, J = 4 Hz); C NMR (CDCl
(
3
13
3
, 100 MHz) δ 159.7, 158.9,
1
1
3
46.8, 134.0, 132.2, 127.9, 127.5, 127.2, 126.6, 122.2, 115.8, 113.4, 113.1, 112.6,
+
+
01.4, 73.7, 54.5, 54.4, 52.0. HRMS (ESI) m/z calculate for (M+H ) C25
H
22
N
3
O
2
96.1707, Found: 396.1713.
1
Compound 2e Isolated yield 42 mg (75%) as white amorphous solid; H NMR
3
(CDCl , 400 MHz) δ 7.32-7.28 (m, 5 H), 5.49 (s, 2 H), 2.68 (t, 2 H, J = 8 Hz), 2.44 (t,
2
H, J = 7 Hz), 1.73-1.66 (m, 2 H), 1.58-1.53 (m, 2 H), 1.30 (s, 12 H), 0.91-0.85 (m, 6
13
H); C NMR (CDCl
3
, 100 MHz) δ 134.3, 127.8, 127.3, 126.9, 118.3, 102.3, 65.4,
5
1.6, 30.6, 30.4, 28.0, 27.9, 27.6, 27.3, 24.7, 21.6, 18.7, 13.1. HRMS (ESI) m/z
+
+
calculate for (M+H ) C23
H
34
N
3
352.2747, Found: 352.2745.
1
Compound 2f Isolated yield 42 mg (75%) as white solid; H NMR (CDCl
3
, 400 MHz)
δ 8.14-8.10 (m, 2 H), 7.53-7.50 (m, 2 H), 7.30-7.22 (m, 3 H), 7.18-7.11 (m, 6 H), 4.70
13
(
t, 2 H, J = 7 Hz), 3.32 (t, 2 H, J = 16Hz); C NMR (CDCl
3
, 100 MHz) δ 146.1, 136.1,
1
9
32.8, 127.9, 127.2, 127.1, 126.2, 125.6, 116.5, 116.1, 115.4, 115.2, 114.9, 114.7,
+
+
20 3
9.8, 74.0, 49.6, 35.5. HRMS (ESI) m/z calculate for (M+H ) C24H N 350.1652,
Found: 350.1655.
1
Compound 2g Isolated yield 50 mg (67%) as white gum; H NMR (CDCl , 400
3
MHz) δ 8.06 (d, 2 H, J = 8 Hz), 7.48 (d, 2 H, J = 8 Hz), 7.29-7.22 (m, 4 H), 6.42 (d, 1
H, J = 2 Hz), 5.36-5.34 (m, 1 H), 5.11-5.10 (m, 1 H), 4.58 (s, 1 H), 3.92-3.88 (m, 1 H),
3
.77-3.68 (m, 1 H), 3.57-3.53 (m, 1H), 3.41(d, 6 H, J = 4 Hz), 1.64( s, 3 H), 1.40 (s, 3

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13
H); C NMR (CDCl
3
, 100 MHz) δ 146.9, 139.5, 138.0, 130.7, 128.5, 126.0, 125.3,
1
17.2, 116.7, 112.7, 102.6, 92.4, 88.4, 84.9, 81.2, 72.9, 62.7, 26.2, 24.3, 20.8, 20.4.
+
+
HRMS (ESI) m/z calculate for (M+H ) C26
H
27
3
N NaO
4
468.1894, Found: 468.1879.
1
Compound 2h Isolated yield 31 mg (65%) as white gum; H NMR (CDCl , 400
3
MHz) δ 7.37-7.23 (m, 5 H), 5.49 (s, 2 H), 3.73-3.66 (m, 4 H), 2.84-2.78 (m, 2 H),
13
2
.61-2.58 (m, 2 H), 1.98-1.89 (m, 2 H), 1.84-1.79 (m, 4 H); C NMR (CDCl
3
, 100
MHz) δ 134.0, 128.2, 127.9, 127.4, 127.1, 126.9, 102.0, 65.5, 60.9, 60.0, 51.8, 30.4,
+
+
2
2
9.8, 21.0, 15.3. HRMS (ESI) m/z calculate for (M+H ) C17
H
22
N
3
O
300.1707,
Found: 300.1721.
1
Compound 2i Isolated yield 60 mg (64%) as yellow amorphous solid; H NMR
(
CDCl
3
, 400MHz) δ 8.76 (d, 1 H, J = 8 Hz), 8.53 (d, 1 H, J = 8 Hz), 8.32 (d, 1 H, J =
8
Hz), 8.26 (d, 1 H, J = 8 Hz), 8.20-8.15 (m, 5 H), 8.08-7.97 (m, 7 H), 7.83 (d, 1 H, J
1
3
=
3
8 Hz), 7.62 (d, 2 H, J = 8 Hz), 7.49-7.40 (m, 4 H),5.97 (s, 2 H); C NMR (CDCl ,
1
1
1
00 MHz) δ141.9, 134.0, 131.2, 131.1, 131.0, 130.5, 130.2, 129.8, 128.5, 128.3,
28.2, 128.0, 127.7, 127.2, 127.0, 126.5, 126.1, 125.5, 125.2, 125.1, 124.7, 124.5,
+
24.4, 124.3, 123.8, 123.5, 114.4, 52.6. HRMS (ESI) m/z calculate for (M+H )
+
3
C
43
H
26
N
584.2121, Found: 584.2137.
Acknowledgments
This study was supported by the National Natural Sciences Foundation of China
(
21172058, 20802017, 21172056), HASTIT (2012HASTIT10), and PCSIRT
IRT1061).
(

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Notes and references
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Supporting Information
Controllable Synthesis of Bis(1,2,3-triazole)s and
5
-Alkynyl-triazoles via Temperature Effect on
Copper-catalyzed Huisgen Cycloaddition
*
*
Lingjun Li, Xincui Fan, Yang Zhang, Anlian Zhu, Guisheng Zhang
College of Chemistry and Chemical Engineering, Henan Normal University, Key
Laboratory of Green Chemical Media and Reactions, Ministry of Education,
XinXiang 123007, P. R. China
Contents
1
. Structures of azide donors used in the experiment-------------------------------S2
. X-ray structure of compound 2a------------------------------------------------------S2
2
3
4
1
13
Copies of H NMR and C NMR spectrum of compounds 1a-1j --------S3-S22
1
13
. Copies of H NMR and C NMR spectrum of compounds 2a-2i ------- S26-S10
S1

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Structures of azide donors used in the experiment:
1
Compound 3c were prepared with our previously reported methods. Unless
otherwise noted, all reagents were obtained from commercial suppliers and used
without further purification.
Figure 1. Organic azide compounds used in the preparation of
2
,2’-bis(1,2,3-triazole)s and 2-alkynyl-1,2,3-triazoles.
Reference
1
. L. Li, B. Lin, Z. Yang, L. Zhang and L. Zhang, Tetrahedron Lett. 2008, 19,
191-1193.
1
Figure 1. X-ray structure of compound 2a
S2

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1
a
S3

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1
a
S4

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1
b
S5

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1
b
S6