A-21·CuI as a catalyst for Huisgen's reaction: About iodination as a side-reaction

Article abstract of DOI:10.1016/j.tetlet.2015.05.079

The polymer-supported catalyst Amberlyst A-21·CuI has found many applications in copper(I)-catalyzed Huisgen's (CuAAC) and other reactions. This catalyst was found to be efficient and reusable for the formation of 1,4-disubstituted 1,2,3-triazoles. It was

Full text of DOI:10.1016/j.tetlet.2015.05.079

Tetrahedron Letters 56 (2015) 4339–4344
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A-21ÁCuI as a catalyst for Huisgen’s reaction: about iodination
as a side-reaction
⇑
Riadh Slimi, Shiva Kalhor-Monfared, Baptiste Plancq, Christian Girard
Unité de Technologies Chimiques et Biologiques pour la Santé—Equipe Synthèse, Electrochimie, Imagerie et Systèmes Analytiques pour le Diagnostique, UMR 8258 CNRS, U
1022 INSERM, Chimie ParisTech—PSL, Ecole Nationale Supérieure de Chimie de Paris, 11 rue Pierre et Marie Curie, 75005 Paris, France
a r t i c l e i n f o
a b s t r a c t
Article history:
The polymer-supported catalyst Amberlyst A-21ÁCuI has found many applications in copper(I)-catalyzed
Huisgen’s (CuAAC) and other reactions. This catalyst was found to be efficient and reusable for the forma-
tion of 1,4-disubstituted 1,2,3-triazoles. It was used with success in several usual procedures, as well as in
automated and continuous-flow approaches. However, in a few instances, this heterogeneous catalyst
gave a few percentages of the 5-iodotriazole derivative, like it was observed under homogeneous condi-
tions. Since the iodination process was scarcely encountered and that we did not, to the best of our
knowledge, observed this side-product before, we became interested in studying the possible causes of
this side-reaction. The preparation of the catalyst, and to a lesser extent the purity of the reagents, as well
as the substrate and the amount of catalyst used were found to be the cause of iodination up to 12% but
kept below 0.5% with the right procedure.
Received 6 March 2015
Revised 20 May 2015
Accepted 22 May 2015
Available online 29 May 2015
Keywords:
Huisgen
Copper(I)-catalyzed
A-21ÁCuI
CuAAC
Ó 2015 Elsevier Ltd. All rights reserved.
Iodination
Introduction
However, in a few instances, a side-reaction was reported in
low percentage: namely iodination at the 5-position of the 1,4-iso-
Copper(I)-catalyzed azide alkyne cycloaddition (CuAAC) is the
catalyzed version of Huisgen’s reaction (Scheme 1).1,2 Initially con-
ducted under thermal conditions, the reaction was leading to 1,4
and 1,5 isomers of 1,2,3-triazole, usually under harsh conditions.
The CuAAC offers the possibility to conduct the reactions at low
temperature, in several solvents and even in biological environ-
ment, and is giving exclusively the 1,4-isomer. The reaction can
be conducted under homo- and heterogeneous conditions, the lat-
ter giving the opportunity of a simple work-up and reuse of the
catalytic systems.3
mer of the formed 1,2,3-triazole.7–10 Since this iodination was
observed in a few cases, and that we did not detect it to the best
of our knowledge, we became interested in identifying the origins
of this side-reaction. We made the hypotheses that the iodination
may be due to different reagents and providers, catalyst prepara-
tion, substrate, or reaction conditions. We thus decided to study
these factors and their influence on the results on model reactions
using the publish procedure for CuAAC in methylene chloride. We
report herein our findings.
In 2006, we published the first polymer-supported copper(I)
catalyst for the CuAAC reaction. This catalyst was prepared from
dry Amberlyst A-21 after incubation with a copper(I) iodide in ace-
tonitrile: Amberlyst A-21ÁCuI.4
Results and discussion
The original procedure was giving indications on the treatment
of commercial Amberlyst A-21 and its incubation with cuprous
iodide for the preparation of the catalyst (Scheme 2). Shortly,
wet commercial Amberlyst A-21 (ca. 50%w water) was soaked in
methanol (3 times) to remove water and then in purified methy-
lene chloride (distilled from P2O5, 3 times) to remove methanol,
before being dried under vacuum in a rotary evaporator (50 °C,
10 mm Hg) and finally overnight under vacuum in a desiccator
(10 mm Hg, with P2O5). The dried polymer was incubated in a
CuI solution in acetonitrile overnight before being filtrated and
rinsed with acetonitrile, methylene chloride, and finally dried
under vacuum (40 °C, 0.01 mm Hg) overnight to give Amberlyst
A-21ÁCuI.
This catalyst has proved its efficiency in regular synthetic pro-
cedures, even in solvent-free reactions and automated and contin-
uous flow approaches.5 The catalyst gives exclusively the pure 1,4-
isomer of substituted 1,2,3-triazole, usually in high yields, after
simple filtration/evaporation procedures, and can be recycled a
number of times. The scope of the catalyst is large and it has been
used in different reaction types and other metals with success.6
⇑
Corresponding author. Tel.: +33 144 276 748; fax: +33 144 276 496.
E-mail address: christian.girard@enscp.fr (C. Girard).
http://dx.doi.org/10.1016/j.tetlet.2015.05.079
0040-4039/Ó 2015 Elsevier Ltd. All rights reserved.

4340
R. Slimi et al. / Tetrahedron Letters 56 (2015) 4339–4344
R1
N
However, the incubation with the CuI solution and drying of the
Huisgen's
reaction
R1
catalyst were made with light protection (aluminum foil) as we
proceeded for the catalyst preparation (unwritten but common
while working with iodide derivatives). The catalyst was isolated
as white beads with a loading of 1.37 mmol CuIÁgÀ1. Finally, entries
9 and 10 followed the same procedure with light protection at the
end, with the same CuI (S.-A.) and both A-21 (Acr and Ald), but
using HPLC grade CH3CN, in one case as such (entry 9) and in the
other degassed prior to use (entry 10). Catalysts were isolated with
R2
R1
N
N
+
R1
Δ
Cu (I)
4
+
CuAAC
R2
N
N
N3 R2
N
1
5
1,4-isomer
Alkyne
Azide
R2
N
N
N
1
1,4 and 1,5
isomers
a
light green and blue color, with loadings of 1.39 and
1.33 mmol CuIÁgÀ1, respectively.
Scheme 1. Thermal (regular) and copper(I)-catalyzed (CuAAC) Huisgen’s reaction
leading to substituted 1,2,3-triazoles.
In order to test the different catalysts prepared, we selected our
usual model reactions and conducted them in purified methylene
chloride at room temperature during 18 h, as previously published
(Scheme 3).
In order to reproduce some possible mistakes in the procedure,
due to lack of details in our published procedure, or reagent origin;
we decided first to check out the influence of commercial sources
of reagents and some obvious details that were not clearly stated.
We thus decided to prepare some versions of the catalyst by the
variation of misreading and possibly unclear details (Table 1,
Fig. 1).
For entries 1–3, the same source of A-21 (Acr) was selected and
magnetic agitation was used during the soaking steps instead of
swirling occasionally, while the polymer was in the solvents.
Untreated methylene chloride was used for soaking in all cases.
In entry 2, the first wash was done using acetonitrile instead of
methanol, to simulate a misreading. The same was done for the
first drying step in entry 1, in which the polymer was pre-dried
in air in an oven. In entries 2 and 3, the polymer was pre-dried
in a rotary evaporator under vacuum as written in the procedure.
For incubation, the same source of CuI (S.-A.) was used, the solu-
tion made using analytic grade CH3CN, and the incubation was
done in a glass round bottom flask overnight and drying in a
Büchi oven, both without protection from light. The catalyst
obtained in entry 1 was yellow colored beads with a loading of
1.06 mmol CuIÁgÀ1. In entries 2 and 3, the catalysts were isolated
as dark yellow powders with loadings of 1.30 and
1.20 mmol CuIÁgÀ1, respectively.
The results and conditions for the reactions are indicated in
Table 2 and the corresponding 1H NMR spectra depicted in
Figure 2. Percentages of the iodination product 5 were evaluated
using the methylene of the N-benzyl substituent, respectively at
5.58 for 4, and 5.72 ppm for 5. In order to circumvent any artifacts,
the products were analyzed as crude mixtures. Broadening in NMR
signals (e.g., in the aromatic proton region and for H-5 around
7.7 ppm) is due to copper(I) presence. In some cases, the excess
azide is still present (4.4 ppm). In the case of phenylacetylene
(2), the use of A-21ÁCuI number 1–3 (entries 1–3), for which unpu-
rified CH2Cl2 was used, soaking done with magnetic agitation, mis-
takes made for one wash (CH3CN instead of MeOH) and for pre-
drying (in an oven), preparing the catalyst and doing the reaction
without light protection; the 5-iodotriazole 5 was present at 9–
12%. Residual azide 1 was also isolated with triazoles 4 and 5 (8–
15%). Using catalysts number 4–7 (entries 4–7), prepared this time
using purified CH2Cl2 with manual agitation during soaking, two
different sources of A-21 and CuI, and without light protection
for the catalyst preparation and CuAAC; 1–5% of the iodination pro-
duct 5 was present, without trace of azide 1. For the catalyst 8
(entries 8 and 9), freshly prepared with all the correct details and
protecting from light for the catalyst preparation; when the reac-
tion was conducted with or without light protection, less than
0.5% of iodination took place, once again without azide 1 left.
Using the same catalyst, but a one-year old sample (entries 10
and 11), the reactions gave higher contents of 5-iodated derivative
5 being or not protected from light (1.8% and 2.4%, respectively).
Changing from analytic grade CH3CN to HPLC one (entries 4–7)
for the catalyst preparation while protected from light gave low
iodination. Using the solvent as such (entries 12 and 13) gave a
slightly higher content of iodotriazole 5 when the reaction was
conducted in the presence (1.8%) or the absence (1.1%) of light.
When the CH3CN was degassed prior to use, iodination levels went
down, as for the catalyst in entries 8 and 9, giving only 0.8% of 5 in
the presence or the absence of light.
In entries 4–7, the preparations were conducted under identical
conditions. The different A-21 were soaked with manual agitation
using purified methylene chloride this time, pre-dried in an evap-
orator under vacuum, incubated with two different quality of CuI
in analytic grade CH3CN, and dried in a Büchi oven, without light
protection. In entries 4 and 5, the same A-21 (Acr) was used with
two different CuI (S.-A., P99.5% and A.-C., 98%) giving beige beads
with respective loadings of 1.43 and 1.41 mmol CuIÁgÀ1. In entries
6 and 7, the A-21 was changed (Ald) and treated with the two CuI
(S.-A. and A.-C.). The catalysts were isolated as beige beads and
similar loadings (entry 6: 1.36 mmol CuIÁgÀ1
,
entry 7:
1.40 mmol CuIÁgÀ1).
In entry 8, A-21 (Acr) and CuI (S.-A.) were used and following
the same protocol and using the same solvents as entries 4–7.
The reaction was also conducted on methyl propiolate (3) using
what we thought to be the catalysts an average chemist would
have prepared while reading our procedure: that is, A-21ÁCuI num-
bers 4–7, and conducting the reactions without protection from
the light (entries 16–19). In these cases, only the 5-protiotriazole
MeOH washes
CH2Cl2 washes
NMe2•nH2O
6
was present, the iodo derivative 7 was never observed.
However, in these reactions, some residual azide 1 was present
with the cycloaddition product (8–13%). This may be an indication
that the iodination reaction can be substrate-dependent.10
Drying in two steps
Commercial (ca. 50 %w water)
From the results gathered here, for phenylacetylene (2), it
seems that mistakes made for the catalysts 1–3 (entries 1–3) have
quite deleterious effects on the catalyst’s performances. The high-
est ratios of iodination were observed while using them. Changing
the source of A-21 (Catalysts 4 and 5 vs 6 and 7, entries 4–7) does
not seem to have a great impact on the iodination levels, neither
does the purity of the copper(I) iodide used (Catalysts 4 and 6 vs
CuI
CH3CN
NMe2
NMe2
CuI
Drying
Dried Amberlyst A-21
Amberlyst A-21•CuI
Scheme 2. Amberlyst A-21ÁCuI catalyst preparation.

R. Slimi et al. / Tetrahedron Letters 56 (2015) 4339–4344
4341
Table 1
Preparation of versions of Amberlyst A-21ÁCuI by variation of different parameters
Entry
A-21
Washes
Drying (50 °C)c
CuI
Incubation
(light)e
Drying
(light)e
Loading
Aspect
sourcea
(agitation)b
sourced
(mmol CuIÁgÀ1
)
1
2
3
4
5
6
7
8
9
10
Acr
Acr
Acr
Acr
Acr
Ald
Ald
Acr
Acr
Ald
MeOH (MAG)
Oven, air, overnight
S.-A.
S.-A.
S.-A.
S.-A.
A.-C.
S.-A.
A.-C.
S.-A.
S.-A.
S.-A.
CH3CNh
Büchi
1.06
1.30
1.20
1.43
1.41
1.36
1.40
1.37
1.39
1.33
Yellow beads
Yellow powder
Yellow powder
Beige beads
Beige beads
Beige beads
Beige beads
White beads
f
CH2Cl2 (MAG)
(+h
CH3CNh
(+h
CH3CNh
(+h
CH3CNh
(+h
CH3CNh
(+h
CH3CNh
(+h
CH3CNh
(+h
CH3CNh
(Àh
CH3CNi
(Àh
CH3CNj
(Àh
m)
(+h
Büchi
(+h
Büchi
(+h
Büchi
(+h
Büchi
(+h
Büchi
(+h
Büchi
(+h
Büchi
(Àh
Büchi
(Àh
Büchi
(Àh
m)
CH3CN (MAG)
Evaporator, 10 mm Hg
Evaporator, 10 mm Hg
Evaporator, 10 mm Hg
Evaporator, 10 mm Hg
Evaporator, 10 mm Hg
Evaporator, 10 mm Hg
Evaporator, 10 mm Hg
Evaporator, 10 mm Hg
Evaporator, 10 mm Hg
f
CH2Cl2 (MAG)
m)
m)
MeOH (MAG)
f
CH2Cl2 (MAG)
m)
m)
MeOH (MAN)
g
CH2Cl2 (MAN)
m)
m)
MeOH (MAN)
g
CH2Cl2 (MAN)
m)
m)
MeOH (MAN)
g
CH2Cl2 (MAN)
m)
m)
MeOH (MAN)
g
CH2Cl2 (MAN)
m)
m)
MeOH (MAN)
g
CH2Cl2 (MAN)
m
)
m)
MeOH (MAN)
Light green beads
Light blue beads
g
CH2Cl2 (MAN)
m
)
m)
MeOH (MAN)
g
CH2Cl2 (MAN)
m
)
m)
a
The source of the polymer does not mean that one is of better quality than the other. Both companies gave the same specifications. Acr: Acros Organics, lot A0270131. Ald:
Sigma–Aldrich, older sample, lot MS08728JR.
b
Type of agitation during the washes: MAN: manual, MAG: magnetic.
Before being dried (10 mm Hg) and kept in a desiccator containing P2O5.
The source of CuI does not mean that one is of better quality than the other, except for the purity analysis. S.-A.: Sigma–Aldrich, Purum P99.5%, lot SZBB211AV. A.-C.:
c
d
Aldrich–Chemie, old sample, 98%, lot 4011940.
e
The light indication is relative to protection from light by aluminum foil (Àh
m
) and non protection (+h
m
) for incubation and drying in vials (40 °C, 0.01 mm Hg, Büchi
oven).
f
g
h
i
Untreated CH2Cl2.
CH2Cl2 distilled from P2O5.
Analytic grade acetonitrile, SDS (France), lot 17119901.
HPLC PLUS Gradient grade acetonitrile Carlo-Erba (France), lot D1 M043141M.
HPLC grade acetonitrile, degassed before use.
j
1
6
2
7
3
8
4
9
5
10
Figure 1. Amberlyst A-21ÁCuI catalysts prepared (Table 1).
R2
R1
to be due to light protection during the preparation as seen for the
A-21•CuI
8 mol%
N3
Ph
catalysts 4 (entry 4) and 8 (entry 8), where the iodination level
drops below 0.5% instead of 1–5%. For the catalyst 8 (entries 8
and 9), protection from light during the reaction does not seem
important. However, most of our reactions were conducted in the
back of a fume hood during the night. Aging of the catalyst (entries
8 and 9 vs 10 and 11), increases the iodination level from <0.5% to
around 2%. Absence of light protection and aging of the catalyst
seem to be responsible for more iodination, this may be caused
by more iodine presence, or another species, that can give the iodo-
triazole. Another factor seems to be the type of CH3CN used.
Changing from analytic grade (entries 8 and 9) to HPLC (entries
12–15) also increased the iodination from <0.5% to 0.8–1.8%.
With HPLC grade CH3CN, degassing the solvent seems to help a lit-
tle since the level was only of 0.8% with the degassed one (entries
Ph
1
N
N
CH2Cl2
R.T., 18 h
N
+
R1
4: R1= Ph, R2= H
2: R1= Ph
5: R1= Ph, R2= I
3: R1= CO2Me
6: R1= CO2Me, R2= H
7: R1= CO2Me, R2= I
Scheme 3. Model reactions tested with samples of A-21ÁCuI for quantification of
iodination products.
5 and 7). The iodination levels were in the same range, between 1%
and 5%, but maybe somehow lower with a better CuI (entries 4 and
5: 1% and 5%, entries 6 and 7: 2% and 3%). The big difference seems

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R. Slimi et al. / Tetrahedron Letters 56 (2015) 4339–4344
Table 2
Reactions of alkynes 2 and 3 with benzyl azide (1) with samples of A-21ÁCuI and percentage of 5-iodotriazolesa
Entry
A-21ÁCuI
Alkyne
h
mb
5-Hc (%)
5-Ic (%)
Entry
A-21ÁCuI
Alkyne
h
+
mb
5-Hc (%)
5-Ic (%)
1
2
3
4
5
6
7
8
9
1
2
3
4
5
6
7
8
2
2
2
2
2
2
2
2
+
+
+
+
+
+
+
+
4 (91)d
4 (88)d
4 (88)d
4 (99)
4 (95)
4 (98)
4 (97)
4 (>99.5)
4 (>99.5)
5 (9)
10
11
12
13
14
15
16
17
18
19
8e
2
4 (97.6)
4 (98.2)
4 (98.2)
4 (98.9)
4 (99.2)
4 (99.2)
6 (100)d
6 (100)d
6 (100)
6 (100)d
5 (2.4)
5 (1.8)
5 (1.8)
5 (1.1)
5 (0.8)
5 (0.8)
7 (0)
7 (0)
7 (0)
7 (0)
5 (12)
5 (12)
5 (1)
5 (5)
5 (2)
5 (3)
5 (<0.5)
5 (<0.5)
À
9
2
2
+
À
+
10
À
4
5
6
7
3
3
3
3
+
+
+
+
À
a
b
c
0.5 mmol alkyne/0.55 mmol azide/2 mL CH2Cl2.
Protected from light (À) or not (+).
By NMR 1H.
Residual azide (8–15%).
One year old sample.
d
e
the total absence of copper(I) into this catalyst. As a matter of fact,
the standard electrochemical potentials for copper (E°
Cu2+/Cu+ = 0.15 V) and iodine (E° I2/IÀ = 0.62 V) indicate that
copper(I) will be oxidized into copper(II) by iodine.11
Finally, we studied the influence of the amount of catalyst used
onto the iodination process. In order to conduct the reaction under
good conditions due to the large amount of catalyst to be added,
these reactions had to be conducted in more solvent (5 mL instead
of 2) and the results are presented in Table 3, entries 5–11. Under
these conditions, the use of 10 mol % of A-21ÁCuI (entry 5) gave 94%
yield with 0.9% of iodotriazole 5. By increasing the amount of cat-
alyst to 25 (entry 6) and 50 mol % (entry 7), yields are still good but
the iodination reaches 2% (99/1.8% and 97/2.0%, respectively).
When increasing again the amount of catalyst to 75% and to the
stoichiometry (100%), the yields are maintained (98% and 99%),
but the iodination still increases to 2.3% and 2.9% (entries 8 and
9). The use of 150 mol % (entry 10) gave a good yield of 96% but
with the presence of 3.3% of 5-iodotriazole 5. The highest incorpo-
ration of iodine onto the triazole was reached with the use of
200 mol % of the catalyst (entry 11), with 4.3% of iodotriazole 5
and a yield of 97%. From these results, it seems obvious that
increasing the catalyst far beyond the catalytic level, the iodination
process can even become complete.8
Figure 2. NMR spectra (300 MHz, CDCl3) of protonated triazole
iodotriazole 5 (bottom) and intermediate compositions (Table 2).
4
(top) and
Even if it is difficult to clearly make a link between hetero- and
homogeneous catalysis, iodination as a side-reaction was some-
times observed in solution. By reading the literature, it seems that
the iodination while using copper(I) iodide is a multi-factor reac-
tion, as for all chemical reactions we should say. It may be influ-
enced by the solvent nature, the concentration of alkyne and/or
azide, the temperature, the length of the reaction, the amount of
copper(I) iodide, as well as the amount and nature of the base
used.12 To make a story short, increasing the amount of CuI over
the catalytic levels and far beyond stoichiometric amounts, with
excess of organic base (amine), and the use of solvent such as ace-
tonitrile, tetrahydrofuran, and organo-aqueous mixtures, usually
lead to moderate to complete iodination. By selecting carefully
all parameters, it is even possible to make the iodination reaction
the main one in order to produce 5-iodo-1,2,3-triazoles.12,13
The iodination process is itself unclear. The results extracted
from the literature seem in favor an ionic mechanism in which
‘I+’, under the form of iodine or other, could be responsible for
the iodination of the transient 5-cuprotriazole.14 The fact that
residual amounts of azide, or even the diyne, are present at the
end of the reaction can be indicative of an oxido-reductive mecha-
nism initiating the side-reaction (Glaser coupling). Addition of
haloreagents such as NBS and NCS in stoichiometric amounts in
CuAAC gave good yields of the iodinated triazole.15 However, in
14 and 15) versus 1.1–1.8 for the normal one (entries 12 and 13).
The main difference between analytical and HPLC grade CH3CN is
that the latter is filtered. This step can increase the content in oxy-
gen of the solvent, and can explain both the light blue to green
color of the catalyst due to copper oxidation. For methyl propiolate
(3), the reaction seems to be insensitive to lower quality catalysts
(entries 16–19) and, as previously said, no 5-iodotriazole 7 was
observed, but some azide 1 was present.
We then decided to test the hypothesis of iodine presence onto
the outcome of the reaction. In order to do so, we prepared cata-
lysts with iodine added during the copper chelation process in
CH3CN (Table 3, entries 1–4). Introduction of 1.6–10% iodine based
on the copper(I) (entries 1 and 2) does not change the results of the
reaction, both catalysts, used at 10 mol % here, giving quantitative
yield and iodination at a level between 1.0% and 1.2%. However,
when 50% iodine was added (entry 3), the yield dropped to 9% with
a similar but a little higher 5-iodotriazole (1.5%). The addition of
100% of iodine (entry 4) completely killed the catalyst, the reaction
not even taking place. These results seem to indicate that iodine
itself plays a little role in the iodination process but maybe not
on this form. The fact that the addition of 100% iodine in respect
to the copper is giving an inactive catalyst maybe attributed to

R. Slimi et al. / Tetrahedron Letters 56 (2015) 4339–4344
4343
Table 3
Reactions of phenylacetylene (2) with benzyl azide (1) with increasing amounts of added iodine and of A-21ÁCuI and their influence on the yield in triazole 4 and percentage of 5-
iodotriazole 5a
5-I 5c (%)
Entry
A-21ÁCuI
Alkyne
I2
Yield
(%)
5-I 5c
(%)
b
b
Entry
A-21ÁCuI
Alkyne
I2 (%)
Yield
(%)
(mol %)
(mol %)
(%)
1
2
3
4
5
10
10
10
10
10d
2
2
2
2
2
1.6
10
50
100
—
99
100
9
0
94
1.2
1.0
1.5
0
6
7
8
9
10
11
25d
2
2
2
2
2
2
—
—
—
—
—
—
99
97
98
99
96
97
1.8
2.0
2.3
2.9
3.3
4.3
50d
75d
100d
150d
200d
0.9
a
b
c
0.5 mmol alkyne/0.55 mmol azide/2 mL CH2Cl2.
Iodine added during the catalyst preparation in CH3CN.
By NMR 1H.
d
In 5 mL CH2Cl2.
this study the addition of iodine was deleterious to the catalyst.
When working with organocopper reagents, the chemist is aware
of the polymeric nature of those reagents that can occur or be dis-
rupted during the reaction. Polymerization degree and species are
ruled by ligand exchanges with the reagents, additives, solvents,
and dilutions. According to the suggested mechanisms of the
CuAAC,2,16 we thus cannot rule out the possibility of a mechanism
of radical or oxido-reductive nature, passing through suggested di-
copper species, polymeric or not, or even copper(III) intermediates,
that can ultimately lead to the observed products after reductive
elimination and insertion of one of the ligand, especially iodine,
like in the case of cuprate derivatives.17
For the difference observed between phenylacetylene (2) and
methyl propiolate (3), the iodination reaction also seems to be sub-
strate-dependent. When an activating functional group is present
on the alkyne, like a carbonyl group (activated alkyne), the iodina-
tion does not take place, while when an unactivated alkyne is used,
iodination was observed. This behavior was also reported by others
while working in solution. The reactivity difference can be attribu-
ted to the availability of charge on the different reaction
intermediates.15
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2015.05.
079.
References and notes
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In this study about the preparation of Amberlyst A-21ÁCuI, the
highest iodination levels were attained when the polymer was
air-dried, unpurified methylene chloride used, and light protection
not in place. In these cases, we think that amine oxidation onto the
polymer, impurities in the solvent, and light influence can produce
some iodonium reacting onto the cupriotriazole, or species influ-
encing the fate of the copper intermediates, that can explain the
higher levels observed. In the cases where the catalyst was cor-
rectly prepared, and since the reaction is using a polymer sup-
ported catalyst at defined concentrations of all reagents, the very
low iodination seems to be inherent to CuAAC in this system on
this scale and using this procedure. Using the catalyst over stoi-
chiometric amounts leads to more iodine incorporation in relation
to the amount of A-21ÁCuI, thus to the amount of amine and
copper(I) iodide. At last, important things to point out are that by
changing the substrate, the concentrations, the solvent, the
amount of catalyst, and the reaction temperature, the iodination
levels could be different.
6. (a) Jiang, H.-F.; Wang, A.-Z.; Liu, H.-L.; Qi, C.-R. Eur. J. Org. Chem. 2008, 2309–
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‘iodine incorporation’, without stating the level.
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Quéneau, Y. Bioorg. Med. Chem. 2011, 19, 926–938.
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derivatives bearing an hydroxyl group at the 2-position, giving around 4%
iodination, indicating an obvious influence of the substrate.
11. Standard Potentials in Aqueous Solution; Bard, A. J., Parson, R., Jordan, J., Eds.;
Marcel Dekker: New York, 1985.
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When working using the same procedure and using the clear
catalyst preparation procedure that we leave to the readers, the
levels of iodination can be kept at a minimum level.18 We hope
that this catalyst will still find useful applications in the future.
Acknowledgments
18. Preparation of Amberlyst A-21ÁCuI: Wet commercial Amberlyst A-21 (250 g, ca.
50%w water) was soaked in methanol (250 mL) with occasional swirling during
0.5 h. The process was repeated 2 other times after decantation of the resin.
After this cycle, the filtrated polymer was soaked in purified methylene
chloride (250 mL, distilled over P2O5 after 1 h reflux) for 0.5 h with manual
This work was made possible by the Grants UMR 8151 CNRS, U
1022 INSERM, AFM 15768 and the French and Tunisian Ministries
of Education. We thank Pr Y. Quéneau for useful discussion onto
their experimental procedures.

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R. Slimi et al. / Tetrahedron Letters 56 (2015) 4339–4344
Dry Amberlyst A-21 (2.0 g, 9.6 mmol amine) was added to
agitation from time to time. Two other soakings were done the same way
a
solution of
before the A-21 was filtrated on a sintered glass funnel. The resin was the
transferred in a round-bottom flask and dried on a rotary evaporator (40 °C,
10 mm Hg, with rotation) until free flowing. The polymer was then placed in a
desiccator, over P2O5, and further dried under vacuum (10 mm Hg) for the
night. Dry Amberlyst A-21 was obtained as electrostatic amine-smelling beads
(ca. 125 g, depending on the amount of water) and was kept in a closed vial in a
desiccator (P2O5). Specifications from the manufacturer indicated 4.8 mmol
amine/g of dry polymer.
copper(I) iodide (762 mg, 4.00 mmol) in acetonitrile (15 mL) and gently shaken
on an orbital stirrer for 17 h with protection from light (aluminum foil). The
solvent was drawn off and the resin washed with CH3CN (2 Â 30 mL), CH2Cl2
(2 Â 30 mL) and dried in vacuum (0.01 mm Hg) at 40 °C (with light protection,
aluminum foil). The weight increase was of 0.706 g (3.71 mmol CuI), which
gave a loading of 1.37 mmol CuIÁgÀ1. The catalyst is kept in dark brown bottles
(or protected with aluminum foil) inside a closed cupboard protected from
moisture and oxygen.