Novel synthesis of 5-iodo-1,2,3-triazoles using an aqueous iodination system under air

Article abstract of DOI:10.1016/j.tetlet.2018.08.039

A novel aqueous iodination system was developed for the synthesis of 5-iodo-1,2,3-triazoles under air. This reaction system has high efficiency and excellent chemo-selectivity with wide functional group tolerance. In addition, this method can be utilized

Full text of DOI:10.1016/j.tetlet.2018.08.039

Accepted Manuscript
Novel synthesis of 5-iodo-1,2,3-triazoles using an aqueous iodination system
under air
Lingjun Li, Xiaofang Xing, Chi Zhang, Anlian Zhu, Xincui Fan, Changpo Chen,
Guisheng Zhang
PII:
S0040-4039(18)31031-1
https://doi.org/10.1016/j.tetlet.2018.08.039
TETL 50214
DOI:
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
20 June 2018
13 August 2018
20 August 2018
Please cite this article as: Li, L., Xing, X., Zhang, C., Zhu, A., Fan, X., Chen, C., Zhang, G., Novel synthesis of 5-
iodo-1,2,3-triazoles using an aqueous iodination system under air, Tetrahedron Letters (2018), doi: https://doi.org/
1
0.1016/j.tetlet.2018.08.039
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2
Graphical Abstract
Novel synthesis of 5-iodo-1,2,3-triazoles using
an aqueous iodination system under air
Leave this area blank for abstract info.
Lingjun Li*, Xiaofang Xing, Chi Zhang, Anlian Zhu*, Xincui Fan, Changpo Chen and Guisheng Zhang*.

Tetrahedron Letters
Novel synthesis of 5-iodo-1,2,3-triazoles using an aqueous iodination system
under air
Lingjun Li*, Xiaofang Xing, Chi Zhang, Anlian Zhu*, Xincui Fan, Changpo Chen and Guisheng Zhang*.
Collaborative Innovation Center of Henan Province for Green Manufacturing of Fine Chemicals, Key Laboratory of Green Chemical Media and Reactions,
Ministry of Education, Henan Key Laboratory of Organic Functional Molecule and Drug Innovation, School of Chemistry and Chemical Engineering, Henan
Normal University, Xinxiang, Henan 453007, P. R. China.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A novel aqueous iodination system was developed for the synthesis of 5-iodo-1,2,3-triazoles
under air. This reaction system has high efficiency and excellent chemo-selectivity with wide
functional group tolerance. In addition, this method can be utilized for the modification of
biomolecules such as riboses and nucleosides, and for the double labeling of biomolecules when
coupled with other reaction types such as the Sonogashira reaction. 2009 Elsevier Ltd. All rights
reserved.
Available online
Keywords:
Iodination in water
5
-iodo-1,2,3-triazoles
Nucleosides
1
,2,3-Triazoles are important pharmacophores which
1,2
have been widely used in medicinal chemistry. Among
them, 5-functionalized 1,2,3-triazoles show many privileged
properties and have been utilized as high-affinity Hsp90
inhibitors, potent antileukemic lead compounds, and chiral
ligands. 5-Iodo-1,2,3-triazoles also display biological
activities (Fig. 1A), and have also been used as platform
molecules for further functionalization. Numerous efforts
have been made for the synthesis of various functionalised
-iodo-1,2,3-triazoles.
involving copper-catalyzed alkyne/azide cycloaddition
CuAAC) have shown high regiospecificity at the 5-position
3
4
5
6
7
,8
9
-11
5
Multicomponent
syntheses
(
of the 1,2,3-triazole, as well as high atom- and step-
economy, but the key intermediate copper triazolides are
1
2-
easily attacked by water or oxidized by oxygen (Fig. 1B).
1
4
Therefore, these reactions are typically conducted under
1
5-17
an inert atmosphere with anhydrous reaction conditions,
and in some cases utilise expensive ligands for the control of
1
8,19
reaction selectivity.
In the past few years, researchers have investigated the
multicomponent syntheses of 5-iodo-1,2,3-triazoles in
2
0, 21
water.
These methods have advantages such as readily
accessible starting materials and clean reaction media, but
they still suffer from narrow substrate scope, high reaction
temperatures, use of additive agents, and limited iodine
_
_________________
Corresponding authors at: Department of Chemistry, Henan Normal
University, Xinxiang, Henan 453007, P. R. China.
Phone: 86-3733326335
E-mail addresses: lingjunlee@htu.cn (L. Li),
alzhuchem@126.com (A. Zhu),
Figure 1. 5-iodo-1,2,3-triazoles and their synthesis.
zgs@htu.cn (G. Zhang).

2
sources. Herein, we report that the iodine source has a significant
influence on the chemoselectivity for the synthesis of 5-iodo-
alkynes bearing either electron-donating groups or electron-
withdrawing groups reacted with azide 2a to afford the
corresponding products in good to high yields (Table 2, entries 1-
4). Aliphatic alkyne 1e also gave the target 5-iodo-1,2,3-triazole
3e in satisfactory yield (Table 2, entry 5). The substrate tolerance
with respect to the azide (Table 2, entries 6-11), showed that
alkyl azides, phenyl azides and benzyl azides were all suitable
substrates, and that the substituent on the benzyl ring had no
significant influence on their reactivity.
1
,2,3-triazoles. When Et NI was used as the iodine source, the
4
target 5-iodo-1,2,3-triazoles were obtained in good to high
isolated yields in aqueous solutions under air, and potential side-
reactions, including the protonation and oxidation of copper
triazolides, are effectively inhibited (Fig. 1C)
.
The model reaction between benzyl azide 1a and
phenylacetylene 2a was selected to study the influence of the
iodine source (Table 1). When sodium iodide was used the
protonation product of copper triazolides, 5-H-1,2,3-triazole 4a,
was the main product (60%) and the target compound 5-iodo-
Nucleosides bearing 1,2,3-triazole motifs are widely used
6,22
in medicinal chemistry. Therefore, our aqueous reaction
system was expanded to the modification of riboses and
nucleosides with the iodo-1,2,3-triazole motif (Table 2).
Azide substituted uridines and riboses with different
protecting groups reacted with phenylacetylene 1a to give
the corresponding 5-iodo-1,2,3-triazole nucleosides, with the
ribose ring and the protecting groups remaining intact.
Alkyne substituted uridines, with or without protecting
groups, also reacted effectively with benzyl azide 2a (Table
2, entries 15 and 16). These results demonstrated that
nucleosides bearing either azide or alkyne groups could be
converted to the corresponding 5-iodo-1,2,3-triazole
derivatives, implying that this method could provide broad
classes of nucleoside derivatives as candidate compounds
for drug discovery.
1
1
,2,3-triazole 3a was only obtained in 32% yield (Table 1, entry
). When quaternary ammonium iodides were utilized the
20
yields of 3a was significantly increased (Table 1, entries 2-6).
Specifically, with Et NI the target compound 3a was obtained in
4
8
2% yield. However, quaternary ammonium iodides bearing
propyl and butyl groups showed a slight decrease in the yield of
3
a. The influence of bases (Table 1, entries 7, 8), oxidants (Table
1
, entries 9-19) and catalysts (Table 1, entries 20, 21) were also
studied. The influence of the temperature was also investigated
o
(
Table 1, entries 1, 22, 23) and 30 C was found to be optimal.
The results in Table 1 also indicated that the replacement of
water with methanol as the solvent completely inhibited the
formation of triazole 3a (Table 1, entry 24).
The optimized reaction conditions were then utilized for the
synthesis of various 5-iodo-1,2,3-triazoles (Table 2). Aryl
a
Table 1. Optimization of the reaction conditions for the synthesis of 5-iodo-1,2,3-triazoles in an aqueous solvent.

3
o
b
Entry
Iodide source
NaI
Base
Oxidant
Catalyst
Temp ( C)
Time (h)
Yield
a (%) 4a (%)
3
1
2
3
4
5
6
7
8
9
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
Selectfluor
Selectfluor
Selectfluor
Selectfluor
Selectfluor
Selectfluor
Selectfluor
Selectfluor
ChloramineT
NIS
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuBr
CuCl
CuI
CuI
CuI
30
30
30
30
30
30
30
30
30
30
30
30
30
30
30
30
30
30
30
30
30
10
50
30
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
24
3
3
32
65
70
82
60
58
22
52
68
36
45
18
29
48
5
60
31
25
14
32
37
33
31
25
51
36
76
54
36
69
68
72
79
62
35
26
31
33
NH
Me NI
Et
4
I
4
4
NI
Pr
4
NI
Bu
4
NI
NI
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
4
2 3
Cs CO
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
NI
NI
NI
NI
NI
NI
NI
NI
NI
NI
NI
NI
NI
NI
NI
NI
NI
2 3
K CO
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
1
0
1
1
NBS
1
1
1
1
1
1
1
1
2
2
2
2
2
2
3
4
5
6
7
8
9
0
1
2
3
4
DDQ
m-CPBA
TBHP
DTBP
DCP
3
BPO
5
CuCl2
10
25
31
20
60
54
-
NaClO
Selectfluor
Selectfluor
Selectfluor
Selectfluor
Selectfluor
c
-
a
Reagents and conditions: alkyne 1a (0.1 mmol), azide 2a (0.11 mmol), iodide source (0.11 mmol), oxidant (0.12 mmol), copper catalyst (0.01
b
c
2
mmol), H O (0.5 mL). Isolated yield. Methanol was used as the solvent under air.
Table 2. Multi-component synthesis of 5-iodo-1,2,3-triazoles.

4
giving the double labelled nucleoside 5a in 78% overall
yield (Scheme 1). This application indicated our method is
potentially appropriate for the modification of structurally
complicated biomolecules with multi-functionalised groups.
Scheme 1. Fluorescent and photo-cross-linking dual labelling of a
nucleoside based on 5-iodo-1,2,3-triazoles.
A series of control experiments were then conducted to
investigate the plausible mechanism. Two separate
mechanistic pathways proceeding via the 1-iodoalkyne or
the triazolide copper species were suggested (Route A and B,
2
3
Scheme 2). We first investigated whether the triazolide
copper species existed in the current reaction system. After
the addition of allyl bromide (4.0 equiv.), 5-allyl-1,2,3-
triazole was obtained in 25% yield (Eq 1, Scheme 2),
suggesting the existence of an intermediate triazolide copper
2
3a
species. Next, we studied the possibility of 1-iodoalkyne
as a reaction intermediate. When the azide component was
omitted from the optimized reaction conditions, 1-
iodoalkyne was obtained in 88% yield (Eq 2, Scheme 2).
After benzyl azide was added again, the formed 1-
iodoalkyne reacted to give 5-iodo-1,2,3-triazole in 86%
yield (Eq 3, Scheme 2). Based on the results of Eq 2 and Eq
3
, Route B represents the most reasonable pathway.
In addition, we investigated the roles of water and the
quaternary ammonium iodide. When Et NI added to a
4
mixture of the alkyne, azide and catalyst in an aqueous
solvent, a suspension was formed from the formerly
biphasic mixture (Image A and B, Scheme 2). After reaction
completion, the mixture again turned bi-phasic (Image C,
Scheme 2). This suggested that a micro-hydrophobic core
might be formed around the catalytic Cu(I) species in the
suspension, which could increase its stability and promote
the cycloaddition reaction between the alkyne or 1-
iodoalkyne and the azide in water. When methanol was
added to the aqueous reaction to break-up the formed
suspension, no 5-H-1,2,3-triazole or 5-iodo-1,2,3-triazole
was detected (Eq 4, Scheme 2), The UV spectrum of the
methanol-water reaction mixture further showed an
absorption at 700 nm, indicating that Cu(I) had been
2
3a
oxidised into Cu(II).
a
Reagents and conditions: alkyne (0.1 mmol), azide (0.11 mmol), Et
4
NI (0.11
In summary, an efficient oxidative iodination system was
developed for the synthesis of 5-iodo-1,2,3-triazoles in water.
This method showed excellent functional group tolerance and
could be utilized for the modification of biomolecules such as
nucleosides and riboses. Further utilization in the double labeling
of biomolecules suggested that this method can also be coupled
with other type of reactions such as the Sonagashira reaction to
allow multi-functional modifications.
mmol), Selectfluor (0.12 mmol), DIPEA (0.12 mmol), CuI (0.01 mmol), H
2
O
o
b
c
(0.5 mL), 3-5 h , 30 C. Isolated yield. β-isomer.
The successful utilization of our reaction system in
riboses and nucleosides promoted us to investigate its use in
the double labelling of representative nucleoside.
Propargyl uridine 1f was first reacted with fluorescent 9-
azidomethyl)anthracene 2k to give the fluorescent
a
(
compound 3q. Next, an alkyne with a photo-cross-linking
group 5a was reacted with 3q via the Sonagashira reaction,
Scheme 2. Possible reaction mechanism.

5
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This work was supported by the National Natural Science
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6
Highlights
Multi-component iodination reaction in water under
open air.
Syntheses of 5-iodo-1,2,3-triazoles from
inexpensive and simple starting materials.
Quaternary ammonium iodide (QAI) regulates
chemoselectivity.
Modification and labeling of biomolecules.