One-pot esterification-click (CuAAC) and esterification-acetylene coupling (Glaser/Eglinton) for functionalization of Wang polystyrene resin

Article abstract of DOI:10.1016/j.tetlet.2013.07.034

We report three new sets of one-pot reactions for functionalization of Wang polystyrene resin and its derivatives. We first show that it is possible to combine esterification and CuAAC (Copper-Catalyzed Alkyne-Azide Cycloaddition) in a one-pot reaction wi

Full text of DOI:10.1016/j.tetlet.2013.07.034

Tetrahedron Letters 54 (2013) 5056–5060
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Tetrahedron Letters
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One-pot esterification-click (CuAAC) and esterification–acetylene
coupling (Glaser/Eglinton) for functionalization of Wang polystyrene
resin
⇑
⇑
Sagi Eppel , Moshe Portnoy
School of Chemistry, Raymond and Beverly Sackler Faculty of Exact Sciences, Tel Aviv University, Tel Aviv 69978, Israel
a r t i c l e i n f o
a b s t r a c t
Article history:
We report three new sets of one-pot reactions for functionalization of Wang polystyrene resin and its
derivatives. We first show that it is possible to combine esterification and CuAAC (Copper-Catalyzed
Alkyne-Azide Cycloaddition) in a one-pot reaction with a very high yield. We also demonstrate for the
first time that it is possible to combine esterification with either Glaser or Eglinton acetylene-couplings
in a one-pot reaction. Finally, we show that the esterification, CuAAC, and Glaser-coupling reactions are
all compatible with each other, and it is possible to run in parallel esterification/CuAAC and esterification/
Glaser coupling in a single vessel. All reactions are performed at room temperature while the only sep-
aration method required is filtering and washing the resin.
Received 3 February 2013
Revised 22 June 2013
Accepted 5 July 2013
Available online 15 July 2013
Keywords:
One-pot reactions
Click chemistry
Esterification
Ó 2013 Elsevier Ltd. All rights reserved.
Glaser coupling
Eglinton coupling
Solid-phase synthesis
Introduction
as the base promoter. The only separation method required, for
all cases, was filtration and washing of the resin, making this pro-
The use of one-pot reactions for the functionalization of poly-
mers and other purposes has received significant attention.1,2 By
allowing more than one reaction to be performed simultaneously
or consecutively in the same vessel, the one-pot method makes it
possible to concurrently functionalize polymers with several dif-
ferent groups,1,2 as well as to synthesize relatively complex struc-
tures in a single step, thereby saving both time and effort.3 It has
also been shown that the use of such one-pot reactions can facili-
tate new growth and polymerization processes.4,5
cedure very simple to carry out.
Asfarasweknow, one-potesterification–acetylenecoupling10–12
(Glaser3/Eglinton13), and one-pot esterification/CuAAC/Glaser reac-
tions have not been demonstrated so far in any medium. One-pot
esterification–CuAAC (Click)2 with carboxylic acids has been
reported on two occasions.4,14 However, in both these cases, differ-
ent reagents were used and the reactions were performed in
different mediums.
In this Letter we report three new one-pot reactions: (a) ester-
ification–CuAAC (Copper-Catalyzed Alkyne-Azide Cycloaddition);
(b) esterification–Glaser coupling and esterification–Eglinton cou-
pling; (c) parallel esterification–CuAAC/esterification–Glaser
coupling.
All of the reactions were used to functionalize Wang polysty-
rene or the first-generation dendronized Wang polystyrene sup-
port, and were performed at room temperature with DMF as the
solvent, HBTU6–9 as the esterification reagent, copper(I) iodide as
the catalyst/reagent for the CuAAC/Glaser reactions, and DIPEA10
One-pot esterification-CuAAC (click) reaction
Recently, Shao et al.,15,16 reported the use of a carboxylic acid,
DIPEA, and copper(I) iodide to promote the CuAAC (Click)2 reaction
in non-polar solvents. We noted that these conditions were nearly
the same as those used for HBTU-promoted esterification reac-
tions,6–9 and could be used to combine the esterification and
CuAAC reactions in a one-pot method. This method could be very
useful for the functionalization of polymers, frequently executed
by our group.17,18 We examined such a reaction using the carbox-
ylic acid both as a promoter for the CuAAC reaction and as a re-
agent for the esterification reaction (Scheme 1), DIPEA as the
base for both reactions, copper(I) iodide as the catalyst for the
CuAAC reaction, and HBTU as the reagent for the esterification
⇑
Corresponding authors. Tel.: +972 3640 6517; fax: +972 3640 9293.
E-mail addresses: sagieppel@gmail.com (S. Eppel), portnoy@post.tau.ac.il (M.
Portnoy).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.07.034

S. Eppel, M. Portnoy / Tetrahedron Letters 54 (2013) 5056–5060
5057
Scheme 1. The esterification-CuAAC one-pot reactions were all performed in a closed vessel, at room temperature for 24 h with DIPEA (0.23 ml), copper(I) iodide
(0.079 mmol), HBTU (0.53 mmol), DMF (1 ml), and Wang polystyrene resin (0.89 mmol/g, 0.053 mmol) or G1 resin (0.5 mmol/g, 0.03 mmol). The identity and yield of the
products were determined by acidolytic cleavage from the resin, followed by 1H NMR spectroscopy in the cleavage solution with an internal reference (1,1,2,2
tetrachloroethane). PS = Polystyrene. G1 is a first-generation dendronized Wang PS. Reaction d produces two products on the resin; however, once cleaved from the resin both
products converge to a single species. Hence, the yield measured by NMR in the cleavage solution is a combined yield of the two products.
reaction. The reaction was performed on Wang polystyrene resin
or on the first-generation dendronized Wang polystyrene (G1,
Scheme 1 reactions e–h),17,18 with both carrying free OH groups,
as the alcohol reactant, with a carboxylic acid functionalized with
an azide or alkyne as the second reactant, and an alkyne or azide as
the third reacting component (Scheme 1). DMF was used as the
solvent. The reaction gave a nearly perfect yield after 24 h at room
temperature in a closed vessel. All building blocks functionalized
with a carboxylic acid, which were attached to the support during
the esterification reaction, underwent the CuAAC stage of the one-
pot process. Thus, the efficiency of the CuAAC (Click) stage on the
support was excellent. Accordingly, the yield indicated in Scheme 1
(with the exception of process h) refers to the percent of the ester-
ification–click products on the resin, relative to the maximum pos-
sible amount, based on the initial resin loading and weight, and can
also be considered as a measure of the esterification efficiency.
As mentioned above, the one-pot esterification-CuAAC with
carboxylic acids has been reported twice, but in solution only.4,14
Rolfe et al.,14 reported a yield of about 50%, while the yield of
Gao and Zheng was not reported. To our knowledge, the method
reported herein is the first to functionalize polymers or any solid
support and also the most efficient reaction of this type to date.
We also tried to apply the same reaction conditions to a system
with an azide reagent, but without an alkyne partner (Scheme 1,
reaction h). The results did not show any side reactions occurring
at the azide functionality under these conditions.
One-pot esterification-Glaser and esterification-Eglinton
coupling reactions
We noted that when the above esterification-CuAAC reaction
conditions were run with little or no azide present, a Glaser cou-
pling reaction tended to occur between alkynes. This is not surpris-
ing given that the Glaser coupling10–12 is promoted by both
copper(I) and bases, similarly to the CuAAC-click reaction,10,11
and the CuAAC reaction is known to sometimes be accompanied
by Glaser coupling side products.16,19,20 However, given that a
one-pot combination of esterification and Glaser coupling has not
been previously reported in the literature, we decided to further
examine this reaction. The Glaser coupling is much slower than
the CuAAC reaction and, therefore, insignificant when an azide is
present. However with no azide and with additional copper(I) io-
dide, the Glaser coupling can be brought to completion without a
substantial reduction in the esterification yield (Table 1). Given

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S. Eppel, M. Portnoy / Tetrahedron Letters 54 (2013) 5056–5060
Table 1
One-pot esterification–Glaser and esterification–Eglinton coupling reactionsa,b,c
a
Esterification–Glaser reactions were all performed at room temperature in a closed vessel, with DIPEA (0.23 ml), Wang resin (0.89 mmol/g, 0.044 mmol), copper(I) iodide
(0.21 mmol) and HBTU (0.53 mmol) in DMF (1.1 ml) for 24–48 h.
b
All esterification–Eglinton reactions were run under similar conditions with addition of py (0.2 ml) and copper(II) chloride dihydrate (0.12 mmol) and were run for 48 h.
c
The identity and yield of the products were determined following acidolytic cleavage from the resin, followed by 1H NMR spectroscopy of the cleavage solution with an
internal reference (1,1,2,2 tetrachloroethane).
d
Eglinton coupling conditions.
Glaser coupling conditions.
e
f The acetylene-coupling yield is the molar fraction of resin-bound molecules that have participated in the acetylene-coupling reaction, as observed by 1H NMR spectroscopy
of the cleavage solution.
g The total yield refers to the percent of the esterification–acetylene coupling products on the resin, relative to the maximum amount, based on the initial resin loading and
weight.
that the Glaser coupling is a reaction between identical functional
groups, all reactions that involve two different alkynes will create
some distribution of symmetric and non-symmetric products
(Table 1). However, by using an excess of the carboxyl-free alkyne
in the mixture (R–CBCH, Table 1), the reaction could be carried out
in such a way that the product of the non-symmetric Glaser reac-
tion dominated on the resin. While for some reactions the Glaser
conditions [Cu(I), DIPEA] led to good coupling yields, in other cases,
mainly those involving more sterically hindered reactants, the Gla-
ser coupling was very slow. Addition of Cu(II) (CuCl2) and pyridine
(to create the Eglinton coupling conditions13,21) allowed the alkyne
coupling reaction to reach completion in these cases, thus creating
a one-pot esterification-Eglinton reaction. Besides its role as a pro-
moter for the Eglinton coupling, pyridine is also essential for dis-
solving CuCl2 in DMF. While in most cases the building blocks
tethered to the resin via esterification also underwent the alkyne
coupling to yield a non-symmetric or a symmetric two stage prod-
uct (Table 1), in some cases a small amount of the carboxylate-con-
taining alkyne underwent esterification, but not alkyne coupling.
Accordingly, the total yield of the reaction indicated in Table 1 re-
flects the yield of both processes and is equal to or lower than the
yield of the esterification process (Total yield = [Esterification
yield] Â [Acetylene-coupling yield]).
One-pot, parallel esterification-CuAAC, and esterification-Glaser
reactions
Based on the previous results, it is apparent that CuAAC, ester-
ification, and Glaser reactions are all compatible with each other,
and can all be carried out in a one-pot manner. Since such a com-
bination has never been reported previously, we decided to dem-
onstrate this possibility. This was accomplished by carrying out
the esterification-CuAAC and esterification-Glaser reactions in the
same vessel in a parallel manner. Despite the fact that such an
experiment can only lead to a distribution of products on the sup-
port, parallel immobilization of two moieties, one equipped with
an azido functionalized group and another with an alkynyl group,
can benefit from such an approach.
The CuAAC and Glaser reactions both compete for the alkyne
group. Since the CuAAC reaction is much faster than the Glaser cou-
pling, under most conditions the CuAAC process will consume all
the alkyne, leading to an insignificant amount of the Glaser product.

S. Eppel, M. Portnoy / Tetrahedron Letters 54 (2013) 5056–5060
5059
Table 2
One-pot, parallel esterification-CuAAC/esterification-Glaser reactions
a
The alkyne R1C„CH was added in excess compared to the azide.
b
The azide R2-N3 was added after 8.5 h.
c The acetylene-coupling yield is the molar fraction of resin-bound molecules that have participated in the acetylene-coupling reaction, as observed by 1H NMR spectroscopy
of the cleavage solution.
d
The CuAAC yield is the molar fraction of resin-bound molecules that have participated in the CuAAC-click reaction, as observed by 1H NMR spectroscopy of the cleavage
solution.
e The total yield refers to the percent of the esterification-CuAAC/acetylene coupling products on the resin, relative to the maximum amount, based on the initial resin loading
and weight.
There are two ways to avoid this: (1) using a small ratio of azide to
alkyne, in such a way that the CuAAC reaction will consume all the
azide, leaving a large enough fraction of unreacted alkyne that will
then react via the slower Glaser coupling; or (2) starting the
reaction with all the reagents present except for the azide, and add-
ing the azide after the appropriate amount of time such that a frac-
tion of the alkyne undergoes the Glaser coupling before the CuAAC
reactions starts. Both methods were used successfully, demonstrat-
ing that it was possible to combine the CuAAC and Glaser coupling
with esterification in a one-pot manner (Table 2).
form multiple attachment points (Scheme 2, reaction b). For all
the reactions in Scheme 2, the products that were actually cleaved
from the resins indicated perfect yields of the Glaser and CuAAC
stages.
Summary
We have demonstrated two new sets of one-pot reactions on
solid support: esterification-CuAAC and esterification-acetylene
coupling (Glaser and Eglinton). We showed that both one-pot reac-
tions can be further combined and used in parallel in a single reac-
tion vessel. The esterification-CuAAC process shows nearly perfect
yields for both the CuAAC and esterification steps. The one-pot
esterification-acetylene coupling shows very good yields for the
acetylene-coupling, but apparently only moderate to good yields
in the product attachment to the resin via the esterification
reaction. Though further research on this outcome is needed, we
suspect that this phenomenon is related to cross-linking of the
resin by double or multiple attachments of the products, which
prevents the products from being observed via cleavage and
NMR analysis.
Reduction of the observed yield for products with multiple
attachment points to the resin
The identity and yields of the products were determined by
their cleavage from the resin under acidic conditions and measur-
ing their 1H NMR spectra in solution, using an internal reference,
via a standard procedure as detailed in the Supplementary data.
The accuracy of this method, however, depends on the ability of
all the products to dissociate from the resin into the cleavage solu-
tion, which was not always the case.
Performing the esterification-acetylene coupling on G1 polymer
or with a dialkyne reactant (Scheme 2, reactions a and c), resulted
in a very low apparent yield, as observed by 1H NMR analysis of the
cleavage solution. We strongly suspect that this is a result of the
formation of products with multiple attachment points to the resin
(Scheme 2). Such multiple attachment points can reduce the prob-
ability of the product being cleaved from the resin into the cleav-
age/NMR solution, and hence reduce the amount of material
observed by NMR. Such an effect is also likely to reduce the appar-
ent yield of the symmetric products in all esterification-Glaser/Egl-
inton reactions (Scheme 2, reaction d). Similar reduction of the
yield was observed in esterification-CuAAC processes that could
Typical procedures
Esterification-CuAAC (Scheme 1, reaction a, product 1)
DIPEA (0.25 ml, 1.43 mmol, 26.9 equiv), 3-azidomethylbenzoic
acid (40 mg, 0.23 mmol, 4.2 equiv), and dimethyl 5-(prop-2-ynyl-
oxy)isophthalate (150 mg, 0.6 mmol, 11.3 equiv) were added to a
suspension of Wang resin (60 mg, 0.89 mmol/g, 0.053 mmol,
1 equiv) in dry DMF (0.6 ml). CuI (15 mg, 0.079 mmol, 1.47 equiv)
and HBTU (200 mg, 0.53 mmol, 9.87 equiv) were then added to
the resin along with dry DMF (0.4 ml), and the mixture was stirred

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S. Eppel, M. Portnoy / Tetrahedron Letters 54 (2013) 5056–5060
Scheme 2. Formation of products with multiple attachment points to the polymer support. The total yield is based on the products observed in the NMR spectra of the
cleavage solution, and hence do not account for the products that fail to dissociate from the polymer into this solution. For the yields of the reactions d, see Table 1.
in a sealed vessel for 24 h at room temperature. Subsequently, the
resin was separated from the solution using vacuum filtration, and
the resin was washed with 1,2-diaminoethane/THF (1:1), water/
THF (1:1), DMF/water (1:1), DMF, THF/water (1:1), THF, and CHCl3,
and was left overnight to dry. Loading = 0.64 mmol/g, CuAAC
yield = 100%, total yield = 97%.
Supplementary data
Supplementary data (experimental procedures and analytical
data for all the new compounds) associated with this article can
be found, in the online version, at http://dx.doi.org/10.1016/j.
tetlet.2013.07.034. These data include MOL files and InChiKeys of
the most important compounds described in this article.
1H NMR of the cleavage solution (400 MHz, CDCl3/TFA, 1:1): d
8.44 (m, 1H), 8.25 (m, 3H); 7.94 (m, 2H), 7.76 (m, 1H), 7.67 (m,
1H), 5.88 (s, 2H), 5.48 (s, 2H), 4.05 (s, 6H).
References and notes
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Esterification-Glaser (Table 1, entry 13)
DIPEA (0.23 ml, 1.32 mmol, 29 equiv), 4-(prop-2-ynyloxy)ben-
zoic acid (40 mg, 0.23 mmol, 5.1 equiv), and 1-hexyne (0.12 ml,
1.04 mmol, 23.5 equiv) were added to a suspension of Wang resin
(50 mg, 0.89 mmol/g, 0.044 mmol, 1 equiv) in dry DMF (0.6 ml).
CuI (40 mg, 0.21 mmol, 4.7 equiv) and HBTU (200 mg, 0.53 mmol,
11.8 equiv) were then added to the resin along with dry DMF
(0.5 ml), and the reaction vessel was closed and the contents stir-
red for 48 h at room temperature. Subsequently, the resin was sep-
arated from the solution using vacuum filtration. The resin was
washed with 1,2-diaminoethane/THF (1:1), water/THF (1:1),
DMF/water (1:1), DMF, THF/water (1:1), THF, and CHCl3, and was
left overnight to dry. Loading = 0.28 mmol/g, esterification
yield = 52%, acetylene coupling yield = 100%, total yield = 52%
(non-symmetric to symmetric ratio = 4:1).
1H NMR of the cleavage solution (400 MHz, CDCl3/TFA, 1:1):
Non-symmetric product: d 8.10 (m, 2H), 7.06 (m, 2H), 4.87 (m,
2H), 2.28 (t, J = 6.4 Hz, 2H), 1.49 (m, 2H), 1.41 (m, 2H), 0.91 (t,
J = 6.7 Hz, 3H).
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Symmetric product: d 8.10 (m, 4H), 7.06 (m, 4H), 4.87 (m, 4H).
Acknowledgment
This work was supported by the Israel Science Foundation
(Grants No. 955/10 and No. 410/08).