'Green' synthesis of 1,4-disubstituted 5-iodo-1,2,3-triazoles under neat conditions, and an efficient approach of construction of 1,4,5-trisubstituted 1,2,3-triazoles in one pot

Article abstract of DOI:10.1016/j.tetlet.2014.10.128

An environmentally friendly and efficient method for synthesis of 1,4-disubstituted 5-iodo-1,2,3-triazoles through [Cu(phen)(PPh₃)₂]NO₃-catalyzed cycloaddition of organic azides and iodoalkynes under solvent-free condition

Full text of DOI:10.1016/j.tetlet.2014.10.128

Accepted Manuscript
“Green” synthesis of 1,4-disubstituted 5-iodo-1,2,3-triazoles under neat condi-
tions, and an efficient approach of construction of 1,4,5-trisubstituted 1,2,3-
triazoles in one pot
Dong Wang, Si Chen, Baohua Chen
PII:
S0040-4039(14)01835-8
DOI:
http://dx.doi.org/10.1016/j.tetlet.2014.10.128
TETL 45357
Reference:
Tetrahedron Letters
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Received Date:
Revised Date:
Accepted Date:
10 September 2014
17 October 2014
24 October 2014
Please cite this article as: Wang, D., Chen, S., Chen, B., “Green” synthesis of 1,4-disubstituted 5-iodo-1,2,3-triazoles
under neat conditions, and an efficient approach of construction of 1,4,5-trisubstituted 1,2,3-triazoles in one pot,
Tetrahedron Letters (2014), doi: http://dx.doi.org/10.1016/j.tetlet.2014.10.128
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“Green” synthesis of 1,4-disubstituted
5-iodo-1,2,3-triazoles under neat conditions, and an
efficient approach of construction of 1,4,5-trisubstituted 1,2,3-triazoles
in one-pot
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Dong Wang, Si Chen, and Baohua Chen*
2
R
I
[Cu(phen)(PPh ) ]NO (3mol%)
3 2
3
1
2
R
N
3
+
I
R
neat, r.t.
N
N
1
R
N
3
R
3
R
1. [Cu(phen)(PPh ) ]NO (3mol%)
2
3 2
3
R
2
1
I
N +
3
R
+
B(OH)
2
R
2. PdCl (PPh ) (5 mol%)
2
3 2
N
N
1
R
N

Tetrahedron Letters
journal homepage: www.elsevier.com
“Green” synthesis of 1,4-disubstituted 5-iodo-1,2,3-triazoles under neat conditions,
and an efficient approach of construction of 1,4,5-trisubstituted 1,2,3-triazoles in one
pot
Dong Wang,§ Si Chen,§ and Baohua Chen
State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou, 730000, P. R. China; Key Laboratory of
Nonferrous Metal Chemistry and Resources Utilization of Gansu Province, Lanzhou, 730000, P. R. China
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
An environmentally friendly and efficient method for synthesis of 1,4-disubstituted 5-iodo-
1,2,3-triazoles through [Cu(phen)(PPh3)2]NO3-catalyzed cycloaddition of organic azides and
iodoalkynes under solvent-free conditions was developed. Based on this, a one-pot method for
the synthesis of fully substituted 1,2,3-triazoles via cycloaddition/Suzuki reactions was also
demonstrated in this report.
Available online
2014 Elsevier Ltd. All rights reserved.
Keywords:
solvent-free
5-iodo-1,2,3-triazoles
one-pot synthesis
1,4,5-trisubstituted 1,2,3-triazoles
The copper-catalyzed alkyne-azide cycloadition reaction
(CuAAC)1, 2 yielding 1,2,3-triazoles under mild conditions with
high efficiency is undoubtedly the premier example of a “click
chemistry” to date,3 it has been widely applied in various fields
including chemical synthesis, biology, medical science and
material science.4 However, CuAAC is limited to terminal
alkynes with the production of 1,4-disubstituted triazoles. Until
now only a few methods,5 for example, ruthenium-catalyzed
cycloaddition of internal alkynes with organic aizdes,5a were
developed for the synthesis of fully substituted (trisubstituted)
1,2,3-triazoles, which possess various promising applications as
multifunctional bioactive molecules, and in material science.
These reported methods are not really modeled reactions, only
partially address deficiency of CuAAC. Therefore, a general
method for synthesis of fully substituted 1,2,3-triazoles would be
a valuable addition to existing strategies.
1,2,3-triazoles;8 c) copper-catalyzed cycloaddition of 1-
iodoalkynes with organic azides.9 The latter is the most efficient,
economical, easy-to-operate, highly selective synthetic strategy
comparing with the former two. It should be pointed out that the
reported methods of copper-catalyzed cycloaddition of 1-
iodoalkynes with organic azides generally involve organic
solvents such as DMSO, THF and CH3CN. Owing to the
environmental harmfulness of organic solvents, it is highly
desirable to develop more environmentally friendly and
economic methodologies for synthesizing 5-iodo-triazoles.
2
2
R
R
a) [I]
H
Iodination reaction
c) [Cu]
I
2
1
N
N
R
I +
R
N
3
N
N
Cycloaddition
[I] = I , ICl, NaI, CuI
2
N
N
1
1
R
R
b)
NIS
Due to the existence of highly reactive 5-iodo fragment, 5-
iodo-triazoles are versatile synthetic intermediates that provide
the possibility of straightforward introduction of another
functionalized fragment into 1,2,3-triazoles unit.6 Several known
methods for the synthesis of 5-iodo-triazoles can be classified
into three types (Scheme 1): a) iodination of 1,4-disubstituted
1,2,3-triazoles;7 b) iodination of 1,4-disubstituted 5-alumino-
———
2
R
Me Al
2
N
N
N
1
R
Scheme 1. General strategy for the synthesis of 1,4-disunstituted
5-iodo-1,2,3-triazoles.
§ Both authors contributed equally to this work.
 Corresponding author. Tel.: +86-139-198-15840; fax: +86-931-891-2582; e-mail: chbh@lzu.edu.cn

We recently demonstrated the remarkable activity of
[Cu(phen)(PPh3)2]NO3 complex (phen=1,10-phenanthroline) in
the Huisgen cycloaddition of terminal alkynes with organic
azides.10 Herein, we report that 1-iodoalkynes are also suitable
cycloaddition partners taking the place of terminal alkynes in the
presence of [Cu(phen)(PPh3)2]NO3 complexes under “green”
solvent-free conditions, offering 5-iodo-1,2,3-triazoles. In
addition, fully substituted 1,2,3-triazoles can be successfully
synthesized through cycloaddition/Suzuki reactions of organic
azides and iodoalkynes, and borophenylic acid in one pot.
In the initial survey of experimental conditions, iodoethynyl-
benzene 1a and benzyl azide 2a were chosen as the model
substrates, and the cycloaddition was conducted at room
temperature in air under solvent-free conditions for 24 h in the
presence of several Cu(I) salts and complexes with 1mol% of
catalytic amount. It was observed that Cu(I) salts CuBr and CuI
were not effective for this transformation, the desired product 3a
was obtained in nearly 0 and 7% yields, respectively (Table 1,
entries 5 and 6). The uses of Cu(I) complexes including
and the reactivity of aliphatic alkyne (Table 2, entry 9) was
somewhat lower than aromatic ones (entries 1, 4, 5, 7). The
reaction of the heteroatomcontaining alkynes 3-ethylthiopheen
with benzyl azide proceeded efficiently, the corresponding 1,4-
disubstituted-5-iodo-1,2,3-triazoles 3g was isolated in 91% yield
(entry 7). The substrate scope of organic azides was also
examined. The results indicated that aliphatic azides including
benzyl, n-octyl, n-dodecyl, and 4-nitrobenzyl groups were
successfully employed, and the reactivities of both n-octyl and n-
dodecyl azides were lower than the azides containing benzyl
group. In addition, the longer chain of aliphatic azide can slow
down the process (entries 2 and 3). Unfortunately, only trace
product was obtained when the phenyl azide was employed
(entry 10).
Table 2
Screening of catalysts for cycloaddition reaction between 1-
iodoalkynes and organic azides.a
R1
I
[Cu(phen)(PPh3)2]NO3 (3 mol%)
R1
I
+
R2 N3
N
N
R2
neat, r.t., 36 h
N
Cu(PPh3)3Br,
Cu(PPh3)3Cl,
Cu(PPh3)2NO3,
1
2
3
[Cu(phen)(PPh3)2]NO3 provided 29-54% yields, and among of
them, [Cu(phen)(PPh3)2]NO3 showed superior catalytic activity
(entries 1-4). The yields increased gradually with raising the
catalyst loadings or reaction time (entries 7-9). When the reaction
was carried out in the presence of 3 mol% [Cu(phen)(PPh3)2]NO3
within 36 hours, the corresponding 5-iodo-1,2,3-triazole 3a was
isolated with 86% yield and 100% selectivity (entry 9). In
addition, we found that the catalytic system was successfully and
reproducibly applied up to 10 mmol-scale synthesis, allowing the
isolation of 2.63 g (73% yield) of 3a (entry 10).
Entry
R1
Ph
Ph
Ph
R2
Product
3a
Yield (%)b
1
PhCH2
C8H17
86
2
3b
3c
57
3
C12H25
PhCH2
PhCH2
4-NO2PhCH2
PhCH2
C8H17
32
4
4-CH3Ph
3d
3e
76
5
4-CH3OPh
4-CH3OPh
Thiophen-3-yl
Thiophen-3-yl
C4H9
77
6
3f
88
7
3g
91
Table 1
8
3h
3i
87
Screening of catalysts for cycloaddition reaction between
iodoethynyl-benzene and benzyl azide.a
9
PhCH2
Ph
69
I
10
Ph
3j
Trace
[Cu], neat, r.t.
N
I +
a
N
The reaction was carried out using 1 (0.5 mmol) and 2 (0.5 mmol) in the
N
N3
presence of [Cu(phen)(PPh3)2]NO3at room temperature within 36 h in air.
Isolated yields after column chromatography.
3a
1a
2a
b
Entry Catalyst (mol%)
Time (h)
24
Yield (%)b
The cascade reaction strategy offers significant advantages
over classical stepwise methods and has widely been used as a
powerful protocol in organic synthesis, because it offers rapid
and convergent construction of molecules without the need of
isolation and purifications of any intermediates.11 Suzuki-
Miyaura cross-coupling reaction has proven to be a powerful tool
for assembling two fragments into one molecular through the
formation of carbon-carbon bonds under milder conditions. In
this context, a three-component one-pot process was explored
through cycloaddition/Suzuki-Miyaura reactions of organic
azides, iodoalkynes, and borophenylic acid (Scheme 2). This
sequential process was conducted nicely in the presence of 3
mol% of [Cu(phen)(PPh3)2]NO3 and 5 mol% of PdCl2(PPh3)2
using KOH as base in refluxing THF. The desired 1,4,5-
trisubstituted 1,2,3-triazoles 4a-4d bearing various groups were
obtained in 74-83% yields.
1
Cu(PPh3)3Br (1)
Cu(PPh3)3Cl (1)
Cu(PPh3)2NO3 (1)
29
2
24
31
3
24
37
4
[Cu(phen)(PPh3)2]NO3 (1)
CuBr (1)
24
54
5
24
Trace
7
6
CuI (1)
24
7
[Cu(phen)(PPh3)2]NO3 (2)
[Cu(phen)(PPh3)2]NO3 (3)
[Cu(phen)(PPh3)2]NO3 (3)
[Cu(phen)(PPh3)2]NO3 (3)
24
65
8
24
75
9
36
86
10
36
73c
a
The reaction was carried out using 1a (0.5 mmol) and 2a (0.5 mmol) in the
presence of a catalyst at room temperature in air.
Isolated yields after column chromatography.
b
c
3
R
The reaction is carried out in 10 mmol of scale.
3
OH
OH
R
1
1. [Cu(phen)(PPh ) ]NO (3 mol%)
3
2
3
R
1
2
B
+
R
I +
R
N
3
2. PdCl (PPh ) (5 mol%)
2
3 2
Encouraged by the efficiency of the reaction protocol
described above, we investigated the substrate scope. A series of
terminal alkynes were investigated to be reacted with benzyl
azide under the optimized conditions. As shown in Table 2, both
aromatic and aliphatic alkynes were suitable cycloaddition
partners, the corresponding 1,4-disubstituted 5-iodo-1,2,3-
triazoles were synthesized with the yields in the range of 69-91%,
N
N
R
2
KOH, THF, reflux
N
4
1
2
3
4a: R = Ph, R = PhCH , R = H; yield = 78%
2
1
2
3
4b: R = Ph, R = PhCH , R = 4-CH ; yield = 74%
2
3
1
2
3
4c: R = Ph, R = C H , R = H; yield = 80%
6
7
1
2
3
4d: R = C H , R = PhCH , R = H; yield = 83%
4
9
2
Scheme 2. Synthesis of 1,4,5-trisubstituted-1,2,3-triazoles in
“one-pot”.

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In summary, an environmentally friendly method for synthesis
1,4-disubstituted 5-iodo-1,2,3-triazoles through
[Cu(phen)(PPh3)2]NO3-catalyzed cycloaddition of organic azides
and iodoalkynes under solvent-free conditions were developed.
Nine 1,4-disubstituted 5-iodo-1,2,3-triazoles were produced in up
to 91% yields. On the basis of this neat synthesis, a series of fully
of
substituted 1,2,3-triazoles were readily obtained through
a
sequential process involving cycloaddition and Suzuki reaction.
The procedures reported in this work are economical and
performed easily, making them possibly acceptable for industrial-
scale production. The presented method will be perhaps applied
in the syntheses of modified 1,2,3-triazolyl bioactive molecules,
1,2,3-triazolyl multi-functional materials, and multi-dentate
organic ligands containing 1,2,3-triazole.
Acknowledgments
We are grateful to the project sponsored by the National
Science Foundation of P. R. of China (No. 21372102) and the
Project of National Science Foundation of Gansu Province P. R.
China (No. 1208RJZA266).
Supplementary data
Supplementary data associated with this article can be found,
in the online version, at
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