Efficient copper-catalyzed tandem oxidative iodination and alkyne-azide cycloaddition in the presence of glycine-type ligands

Article abstract of DOI:10.1016/j.tet.2020.131911

Tandem oxidative iodination and alkyne-azide cycloaddition reaction has provided one of the most widely used methods for preparation of 5-iodo-1,2,3-triazoles. However, stoichiometric copper salts are involved in this type of reaction in order to enhance

Full text of DOI:10.1016/j.tet.2020.131911

Tetrahedron 81 (2021) 131911
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Efficient copper-catalyzed tandem oxidative iodination and
alkyne-azide cycloaddition in the presence of glycine-type ligands
Donghe Yuan, Shilei Wang, Gongming Zhu**, Anlian Zhu, Lingjun Li*
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, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Tandem oxidative iodination and alkyne-azide cycloaddition reaction has provided one of the most
widely used methods for preparation of 5-iodo-1,2,3-triazoles. However, stoichiometric copper salts are
involved in this type of reaction in order to enhance the reaction effectiveness, which caused some
problems related to toxic metal contaminations and less sustainability. In this paper, we described that a
copper-catalyzed (10 mol%) tandem oxidative iodination and alkyne-azide cycloaddition could be
completed in the presence of the newly-found glycine-type ligands with low-cost NaI as the iodine
resource. In the novel reaction system, a wide range of terminal alkyne, organic azide and inexpensive
iodide could react effectively in one pot to give structurally diverse 5-iodo-1,4-subsitutied 1,2,3-triazoles.
Natural product derivatives and alkynyl pyridines that hardly react under traditional conditions could
also be transferred smoothly to the target products for the first time.
Received 6 October 2020
Received in revised form
20 December 2020
Accepted 23 December 2020
Available online 8 January 2021
Keywords:
5-iodo-1,2,3-triazole
CuAAC reaction
Oxidation iodination
Glycine-type ligands
© 2020 Elsevier Ltd. All rights reserved.
5-Iodo-1,2,3-triazoles represent a kind of intriguing fully-
substituted 1,2,3-triazoles, not only because of their flexibility to
transfer into variant 5-substituted 1,2,3-triazoles using metal-
coupling reactions [1], but also the unique properties of 5-iodo-
1,2,3-triazoles in the structural modifications of bioactive mole-
cules [2], supramolecular recognitions [3] and radioactive labeling
[4]. Current methods for syntheses of 5-iodo-1,2,3-triazoles can be
classified into four types based on the different starting materials
(Fig. 1): (1) multi-component syntheses of 5-iodo-1,2,3-triazoles
from terminal alkynes, organic azides and electrophonic iodine/
iodide reagents [1e8]; (2) cycloadditions of 1-iodo-alkyne or its
precursors and organic azides [9,10]; (3) transformations from 5-
NH2-1,2,3-triazoles by diazotization/iodination reactions [11]; (4)
direct iodination or metal-iodine exchange of triazoles [12,13]. The
multi-component reaction is the most convenient strategy
benefiting from easily accessible and stable starting materials, one-
pot operations with step economy and very mild reaction condi-
tions. However, it should be pointed out that the reported methods
of multi-component syntheses of 5-iodo-1,2,3-triazoles generally
involved stoichiometric copper salts such as CuI [6], CuCl2 [4] and
Cu(ClO5)2 [7], etc. in most cases. High ratios of copper salts are
disadvantageous to the complex reactants like biological molecules
[14,15], and also may cause the heavy metal residues in the prod-
ucts [16]. To address these problem, more efficient reaction systems
that can promote the syntheses of 5-iodo-1,2,3-triazoles in the
catalytic amount of copper would be highly appreciated.
In this paper, we reported that a copper-catalyzed (10 mol%)
tandem oxidative iodination and alkyne-azide cycloaddition could
be completed in the presence the newly-found glycine-type ligands
with low-cost NaI as the iodine resource. Through the effective
copper-catalyzed multi-component reactions, not only simple aryl
or alkyl alkynes and azides could react effectively to give various
1,4-disubstituted 5-iodo-1,2,3-triazoles in good yields, but also
structurally complicated alkynes bearing natural product motifs
and low-reactivity alkynyl pyridines could give the desirable
products smoothly.
The reaction between phenylacetylene and benzyl azide was
applied as the model (Table 1). In the presence of 10 mol% CuI as the
catalyst, 1.2 equivalent NaI as the iodine resource, we firstly
attempted the different oxidants for the multi-component reaction
(Entries 1 to 6 in Table 1). Our previously used oxidant NBS and
selectfluor proved less efficient to give 5-iodo-1,2,3-triazole under
the current conditions. A wider screening of ordinary organic
oxidant including mCPBA, DDQ, tBuOOH, Chloramine-T, then
* Corresponding author.
** Corresponding author.
E-mail addresses: zhugm1201@163.com (G. Zhu), lingjunlee@htu.cn (L. Li).
https://doi.org/10.1016/j.tet.2020.131911
0040-4020/© 2020 Elsevier Ltd. All rights reserved.

D. Yuan, S. Wang, G. Zhu et al.
Tetrahedron 81 (2021) 131911
we tried to optimize the solvents for the reaction (Entries 12 to 20
in Table 1). Among the ten solvents, THF was best one with 68%
yield of 5-iodo-1,2,3-triazole.
Traditional glycine derivatives, such as N,N-dimethylglycine and
N-methylglycine, have already been employed in copper(I)-
catalyzed organic reactions, such as Goldberg reaction [17], Ull-
mann coupling reaction [18,19], amine and halides coupling re-
actions [20,21], aryl halides and terminal alkynes coupling reaction
[22]. One the other hand, fine modifications on the amino acid
derivatives could offer the new ligands for more challenging CeH
activation transformations [23]. Inspired by these works, we syn-
thesized four glycine-type ligands as shown in Fig. 2, and attempted
them for promoting the multi-component synthesis of 5-iodo-
1,2,3-triazoles. The effects of ligands on the multicomponent re-
actions were investigated as shown in Entry 21 to.
Fig. 1. Synthetic methods of 5-iodo-1,2,3-triazoles.
Table 1
Optimization of the reaction conditions for the synthesis of 5-iodo-1,2,3-triazoles.
Entry 28 in Table 1. TBTA [24] and 1,10-phenanthroline (Phen)
[25] which were the classic ligands for CAAC reaction indicated
slightly and strongly inhibitory respectively for the production of 5-
iodo-1,2,3-triazole (Entry 20 and Entry 21 in Table 1). In contrast,
the glycine-type ligands didn’t show strongly inhibitory (Entry 22
to Entry 24 in Table 1). 5-iodo-1,2,3-triazoles. Interestingly, ligand
L4 had a promoting effect on the reaction to give the target product
with 76% yield at room temperature. Increasing reaction tempera-
ture to 50 ꢀC could further to enhance the yield to 86%. In order to
clarify the roles of L4 in the reaction, another control experiment
was conducted in the absence of ligang L4 under the same condi-
tions (Entry 27 in Table 1). However, a lower yield (74%) of 5-iodo-
1,2,3-triazole was obtained. A possible explanation is that the high
reaction temperature with the oxidant (here is Chloramine-T)
might cause a partial oxidation of Cu(I) to Cu (II), thus losing
some catalytic ability for the CuAAC reaction. To our best knowl-
edge, the glycine-type ligands are the first class of ligands that may
selectively promote the multicomponent preparations of 5-iodo-
1,2,3-triazoles from alkynes and azides.
The scope of the substrates was then investigated with the new
catalytic system. Alkynes and azides bearing various substituents
reacted smoothly with NaI under the optimized reaction conditions
(Table 2). Phenylacetylenes with electron-withdrawing and
electron-donating substituents reacted to give the corresponding
5-iodo-1,2,3-triazoles (Entries 1e7 in Table 2) 71e88% yield. Benzyl
azides with electron-withdrawing and electron-donating groups
were also effective substrates for the reaction, in which the corre-
sponding 5-iodo-1,2,3-triazoles could be obtained in yields of
67e84% (Entries 10e13). Alkyl azides were also effective in this
reaction to give 5-iodo-1,2,3-triazoles in 74% (3o) and 73% (3p)
yield respectively. These results suggested that this reaction was
very useful for the preparation 5-iodo-1,2,3-triazole derivatives of
small organic molecules. Inspired by the successful applications of
the proposed reaction to a wider scope of substrates, we next
investigated the potential of the reactions for the synthesis of more
structurally complex or low-reactivity compounds (Scheme 1).
Estrone derivatives bearing the 1,2,3-triazole motifs represented a
class of promising bioactive and functional molecules [26]. Here an
example is the azide-bearing estrone motifs 1h, which could act as
an effective substrate to provide the target 5-I-1,2,3-triazoles 3q in
76% yield. Besides, the yield of 3r could up to 87% when 3-alkynyl
pyridine 1j as substrate.
[a]
Entry
Catalyst
(10 mol%)
Oxidant
(1.2 eq)
Base
(1.2 eq)
Solvent
Product[b] (%)
1
2
3
4
5
6
7
8
CuCl
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
selectfluor
NBS
mCPBA
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
pyridine
DIPEA
DBU
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DMF
THF
MeCN
CH2Cl2
DMSO
CH3OH
Dioxane
CHCl3
THF
25
10
35
60
16
14
36
63
32
25
30
42
68
30
48
25
46
32
41
56
20
60
64
66
76
78
86
74
Chloramine-T
DDQ
tBuOOH
Chloramine-T
Chloramine-T
Chloramine-T
Chloramine-T
Chloramine-T
Chloramine-T
Chloramine-T
Chloramine-T
Chloramine-T
Chloramine-T
Chloramine-T
Chloramine-T
Chloramine-T
Chloramine-T
Chloramine-T
Chloramine-T
Chloramine-T
Chloramine-T
Chloramine-T
Chloramine-T
Chloramine-T
Chloramine-T
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
25[c]
26[d]
27[d]
DIPA
NaOH
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
CuI
CuI
TBTA/CuI
Phen/CuI
L1/CuI
L2/CuI
L3/CuI
L4/CuI
L4/CuI
L4/CuI
CuI
THF
THF
THF
THF
THF
THF
THF
THF
a
Otherwise noted, reactions were performed using azide (0.10 mmol), alkyne
(0.12 mmol), iodide source (0.12 mmol), oxidant (0.12 mmol), copper catalyst
(0.01 mmol), ligand (0.01 mmol), solvent (2 mL) at room temperature under N2
atmosphere.
b
Isolated yield.
c
Study at 40 ꢀC.
d
Study at 50 ꢀC.
showed Chloramine-T as the best one, by which 60% yield of target
compound could be obtained. Secondly, we investigated the effects
of bases on the reaction (Entries 7 to 11 in Table 1), and DIPEA
shown a little better than TEA to give 63% yield of 5-iodo-1,2,3-
triazole. Inorganic base and other organic bases were adverse for
the reaction with yields of target compound less than 36%. Thirdly,
A possible reaction pathway was suggested as shown in Scheme
1. Chloramine-T acts as a mild oxidant to oxidize the iodide of NaI to
electrophilic “Iþ”. In Route-A, the iodination might occur on the
reaction intermediate copper triazolide (II). While in Route-B, the
iodination might occur directly on alkyne to produce iodoalkyne
2

D. Yuan, S. Wang, G. Zhu et al.
Tetrahedron 81 (2021) 131911
Fig. 2. The structure of ligands.
Table 2
Table 2 (continued )
Preparations of various 5-iodo-1,2,3-triazoles.a
Entry Alkyne
Azide
Product
Isolated
yields
14
72
1e
2c
2f
3n
15
74
Entry Alkyne
Azide
Product
Isolated
yields
1e
3o
3p
1
BnN3 2a
86
80
83
88
82
71
73
89
71
67
84
70
71
16
73
1a
1e
3a
3b
3c
3d
3e
3f
2
BnN3 2a
BnN3 2a
BnN3 2a
BnN3 2a
BnN3 2a
BnN3 2a
BnN3 2a
BnN3 2a
2g
1b
a
The reactions were conducted under N2 atmosphere at 50 ꢀC temperature.
3
1c
(III) and then the proceed CuAAC reaction. To further investigate
the two pathway, two control experiments were conducted as
shown in Scheme 2. No iodoalkyne (III) could be effectively pre-
pared under the current reaction conditions. Besides, the trapping
experiment yielded 5-alkyl-1,2,3-triaozles, which suggested po-
tential existences of copper triazolide (II). As to possible interaction
mode of the ligand L4, we carried out DFT theoretical calculations
and the result indicated that the copper binding of ligand L4 is
similar to TBTA [22] in a tridentate model. The similar binding
models implied that L4 could stabilize the copper (I) species like
TBTA to some extent avoiding their oxidation to copper (II) and loss
catalytic properties for CuAAC reactions. The carboxyl group of L4
could effectively coordinate with Cu(I) where the distance of CueO
was 2.350 Å, which was dramatic longer than the distance of CueN
on triazolyl arms (2.035 Å) in the complex of TBTA:Cu(I) as shown
in Fig. 3. The structure of complex of L4 and copper (I) species thus
might be looser in the reaction in contrast to TBTA, which would be
helpful to the attack of “Iþ” for giving 5-iodo-1,2,3-triazole.
In conclusion, a novel copper(I)-catalyzed multi-component
reaction of 5-iodo-1,2,3-triazoles was developed in this work. In the
presence of catalytic CuI and L4, a wide range of terminal alkyne,
organic azide and inexpensive iodide could react effectively in one
pot to give structurally diverse 5-iodo-1,4-subsitutied 1,2,3-
triazoles. Natural product derivatives and low-reactivity alkynyl
pyridines could also be transferred smoothly to the target products.
Besides, the stabilization effects of glycine-type ligands on Cu(I)
catalysts were discussed, which suggested a new approach to
optimize reaction system toward the multicomponent preparations
of other 5-substituted 1,2,3-triazoles from terminal alkynes and
organic azides.
4
1d
5
1e
6
1f
7
1g
3g
3h
3i
8
1h
9
1i
10
1a
2b
2c
2d
2e
3j
11
1a
3k
3l
12
1a
13
1a
3m
(continued on next page)
3

D. Yuan, S. Wang, G. Zhu et al.
Tetrahedron 81 (2021) 131911
Scheme 1. Applications in complicated and low-activity reactants.
Scheme 2. Possible reaction mechanism and control experiments.
Science Foundation of China (nos. 21801257, 21778015 and
22077027), the 111 Project (No. D17007 to L. L.) and a start-up fund
from Henan Normal University (qd 18018).
Appendix A. Supplementary data
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tet.2020.131911.
Fig. 3. The DFT theoretical calculations for possible binding model of L4:Cu(I).
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