Formation of calix[4]arenes with acyloxycarboxylate functions

Article abstract of DOI:10.1016/j.tet.2020.131395

Calix[4]arenes are an exciting class of multifunctional compounds. Their ability to bind small molecules and ions actively makes them useful tools for many applications. While looking for a suitable chelating agent, a particular modification of the calix[4]arene led to an unexpected side reaction. In this work, we will describe the selective formation of the observed acyloxyacetate derivatives. The according yields can be regulated by controlling the water content of the solvent system. All new compounds were obtained in yields higher than 45percent and fully characterized by NMR, MS, EA, and X-ray crystallography. By performing and analyzing several reactions with different calix[4]arenes and monomeric derivatives, an explanation for the reaction mechanism was postulated. Further, we report on the modification of reaction conditions which were investigated to verify our findings’ veracity. In total, three acyloxyacetate derivatives were synthesized and characterized to support our conclusions.

Full text of DOI:10.1016/j.tet.2020.131395

Tetrahedron 76 (2020) 131395
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Formation of calix[4]arenes with acyloxycarboxylate functions
,
,
b
c
a, b, *
David Bauer a b, Sergej Stipurin a , Martin Kockerling , Constantin Mamat
€
a Institut für Radiopharmazeutische Krebsforschung, Helmholtz-Zentrum Dresden-Rossendorf, Bautzner Landstraße 400, 01328 Dresden, Germany
Fakultat Chemie und Lebensmittelchemie der TU Dresden, 01062 Dresden, Germany
Institut für Chemie, Anorganische Festkorperchemie der Universitat Rostock, Albert-Einstein-Straße 3a, 18059 Rostock, Germany
b
€
c
€
€
a r t i c l e i n f o
a b s t r a c t
Article history:
Calix[4]arenes are an exciting class of multifunctional compounds. Their ability to bind small molecules
and ions actively makes them useful tools for many applications. While looking for a suitable chelating
agent, a particular modification of the calix[4]arene led to an unexpected side reaction. In this work, we
will describe the selective formation of the observed acyloxyacetate derivatives. The according yields can
be regulated by controlling the water content of the solvent system. All new compounds were obtained
in yields higher than 45% and fully characterized by NMR, MS, EA, and X-ray crystallography. By per-
forming and analyzing several reactions with different calix[4]arenes and monomeric derivatives, an
explanation for the reaction mechanism was postulated. Further, we report on the modification of re-
action conditions which were investigated to verify our findings’ veracity. In total, three acyloxyacetate
derivatives were synthesized and characterized to support our conclusions.
Received 30 March 2020
Received in revised form
6 July 2020
Accepted 8 July 2020
Available online 11 July 2020
Keywords:
Calix[4]arenes
Esterification
O-alkylation
© 2020 Elsevier Ltd. All rights reserved.
Complexation
Selective bromination
1. Introduction
diacetates and found an unexpected and regioselective reaction by
using different alkylation agents. In this publication, the synthesis
Compounds based on calix[4]arenes arise from the field of su-
pramolecular chemistry and consist of four phenolic units linked by
methylene bridges [1e3]. This arrangement creates a cavity that
forms inclusion complexes with small neutral molecules or ions
[4e8]. One major field of application is their use as extraction
agents/chelators for nuclear waste treatment [9e12], since they
interact particularly strongly with heavy group 2 metals [13e17].
Modifying their backbone modulates the cavity properties, allow-
ing for an appropriate alignment for the required task. Remarkably,
the regioselective alkylation of the phenolic hydroxy groups pro-
vides for an accessible introduction of various moieties to optimize
a host-guest interaction. Additionally, the upper rim can be func-
tionalized, e.g., by the introduction of halogen or nitro groups to
of these compounds is described, and the supposed side reaction
illuminated. Additionally, varying the reaction conditions allowed
control over the ratio between the expected compound and the O-
alkylated side product.
2. Results and discussion
We aimed to synthesize a variety of multimodal calix[4]arenes
that offer oxygen donors with proton-ionizable groups to bind ions
of heavy alkaline earth metals strongly, and further contain func-
tional groups (e.g., bromine) at the upper rim for additional
modifications.
A common method to add more donor atoms to the calix
backbone is to alkylate the phenolic hydroxy groups, e.g., with ethyl
bromoacetate, followed by saponification of the ester to obtain
carboxylate donors. Therefore, 1a and 1b were reacted with a high
excess of ethyl bromoacetate (40 equiv.) under basic conditions,
which led to the exhaustedly alkylated products 2a and 2b in high
yields [21e23].
access multimodal calix[4]arenes [1e3]. Multimodality is
a
requirement for the use of these class of molecules, e.g., as carrier
system for radiometals in a radiopharmaceutical context.
During our search for suitable ligands for heavy alkaline earth
metals, primarily for the radiopharmaceutical-relevant nuclide
radium-223 [18e20], we modified various dibromocalix[4]
The compounds 2a and 2b, and e after saponification e their
corresponding acids, provide hard donor atoms. The next
contemplated step to produce a calix[4]arene-based radiophar-
maceutical relevant precursor, is to functionalize the upper calix-
rim of these compounds by mono- or dibromination. This would
* Corresponding author. Institut für Radiopharmazeutische Krebsforschung,
Helmholtz-Zentrum Dresden-Rossendorf, Bautzner Landstraße 400, 01328, Dres-
den, Germany.
E-mail address: c.mamat@hzdr.de (C. Mamat).
https://doi.org/10.1016/j.tet.2020.131395
0040-4020/© 2020 Elsevier Ltd. All rights reserved.

2
D. Bauer et al. / Tetrahedron 76 (2020) 131395
Table 1
allow to couple the chelator with a suitable targeting molecule (e.g.,
by Suzuki reaction). However, it was found to be disadvantageous
to brominate the calix[4]arene at this stage. Notably, a straight-
forward, regioselective mono- or dibromination of 2a or 2b is not
described in the literature, since the reactivity for all four phenolic
units is equal [1e3].
Reaction conditions for the conversion of the starting material 4 to the calix-
compounds 5 and 6.
Entry
Solvent
Base
Water
Yield 5
Yield 6
1
2
3
4
5
6
7
8
DMF
DMF
DMF
DMF
THF
THF
THF
THF
DMF
DMF
DMF
DMF
K2CO3
KOtBu
NaH
NaOH
K2CO3
KOtBu
NaH
NaOH
K2CO3
KOtBu
NaH
e
45%
e
e
e
e
e
55%
21%
39%
e
e
Nevertheless,
a regioselective alternating dibromination is
e
e
possible by taking additional steps [24e29]. Regioselectively alky-
lated calix[4]arenes 3a and 3b were obtained in yields of approx.
90%, when using a stoichiometric amount (1e1.5 equiv. per OH
group) of ethyl bromoacetate instead of 40 equiv [21,30e32]. The
regioselective alkylation of 1a and 1b (Scheme 1) is provided by
intramolecular hydrogen bonds and the resulting gradation of the
hydroxy-pKa values [33]. Due to the þI inductive effect of alkyl
groups, the alkylated phenolic units in 3a and 3b will not undergo
the bromination reaction with elemental bromine, as reported in
the literature [34e36]. Accordingly, bromination led to a rapid and
quantitative formation of compound 4 [37]. After the selective
modification of the upper rim, the two remaining hydroxy groups
of 4 can be easily functionalized using alkylation or acylation re-
actions. Since the synthesis of compound 5 by alkylation with ethyl
bromoacetate is not described in the literature, the reaction con-
ditions were chosen according to the preparation of comparable
derivatives [38].
e
e
e
e
e
27%
12%
<1%
e
e
e
e
9
0.1%
0.1%
0.1%
0.1%
6%
e
10
11
12
2%
5%
28%
40%
NaOH
Table 2
Crystal data and structure refinement for compounds 2b and 6.
Compound
Formula
2b
6
C60H80O12
x
C48H50Br2O16
0.35(CH3OH)
1004.61
123
Formula weight (g$molꢁ1
Temperature (K)
Crystal system
)
1024.70
123
triclinic
triclinic
Space group
P1
P1
Unit cell dimensions
2.1. Side reactions
a (Å)
b (Å)
c (Å)
12.1337(7)
14.8610(8)
16.966(1)
102.438(2)
102.204(2)
95.184(2)
2890.2(3), 2
18500/21/708
157057
15.7713(8)
15.9458(8)
19.448(1)
96.369(2)
101.698(2)
99.172(3)
4675.8(4), 4
18388/0/1189
200461
During the synthesis route mentioned above, an unexpected
side reaction attracted our interest. After the reaction of compound
4 with an excess of ethyl bromoacetate according to conditions iv in
Scheme 1 (Table 1, entry 12), two compounds were isolated. The
desired product 5 gave a yield of only 5%. The main product (40%
yield) could initially not be identified. Mass spectrometry revealed
an additional mass of 116 u compared to compound 5, which
a
b
g
(ꢀ)
(ꢀ)
(ꢀ)
Volume (Å3), Z
Data/restraints/param.
Measured reflections
qmax (ꢀ)
31.09
26.0
GoF on F [2]
1.03
1.06
R1 [I > 2
wR2 (all data)b
Larg. diff. peak/hole (e$Å3)
s
(I)]a
0.051
0.053
0.139
0.139
0.77/-0.69
1.94/-1.06
strongly correlates with two extra ethyl acetate units. However, a
crystal structure was required to identify the molecular structure of
compound 6 unambiguously (Fig. 1) (see Table 2).
Interestingly, a selective saponification and alkylation of the
ester moieties attached to the unbrominated phenolic units have
occurred in the reaction from compound 4 to product 6. In general,
the formation of the acyloxyacetate moiety itself is reported
[39e42]. However, there are only a few reports in the literature on
examples for the selectivity [43], which was observed for com-
pound 6.
Hereafter, the reaction conditions were optimized to produce
either product 5 or 6 in high yields. The alkylation of compound 4
was forced by an excess of 8 equiv. ethyl bromoacetate with various
bases like K2CO3, NaH or KOtBu. In both anhydrous solvents THF or
DMF, the fourfold alkylated product 5 was isolated as the main
product; no formation of calix 6 was obtained. However, when
traces of water were present in DMF, product 6 was formed. All
reaction conditions and yields are summarized in Table 1.
Worthy of mention is the absence of products 5 or 6 when using
KOtBu as a base (Table 1, entries 2, 6, and 10). Compound 5 was
obtained in yields of 45% and 55%, respectively, when using anhy-
drous DMF with K2CO3 or NaH as base (Table 1, entries 1 and 3).
Compound 6 was obtained in the highest yield of 40% using NaOH
as base (Table 1, entry 12). Since an appropriate protocol to syn-
thesize the acyloxyacetic acid ethyl ester was found, it had to be
Scheme 1. Reagents and conditions. i) BrCH2COOEt (40 equiv.), K2CO3, KI, ACN, reflux,
2 d; ii) BrCH2COOEt (2 equiv.), K2CO3, ACN, reflux, 1 d; iii) Br2, DCM, 30 min; iv)
BrCH2COOEt (8 equiv.), NaOH, DMF, 90 ꢀC, 1 d.

D. Bauer et al. / Tetrahedron 76 (2020) 131395
3
Scheme 2. Alkylation of compound 4 with different substrates. Reaction conditions: i)
BrCH2C6H4COOEt, NaOH, DMF (þ0.1% water), 90 ꢀC; ii) Br(CH2)3COOEt, NaOH, DMF
(þ0.1% water), 90 ꢀC.
no chain-elongated product was observed.
These results lead to the assumption that this reaction is
somehow promoted by the molecular structure of compound 4,
and is influenced to a lesser degree by the alkylation agent.
Fig. 1. Molecular structure of the two symmetry-independent conformers 6A and 6B
in crystals of 6.
2.3. Evaluation of the crystal structures
further investigated whether other alkylating agents react with
compound 4 to produce analogs of product 6.
The essential step in the identification of compound 6 was the
elucidation of its crystal structure. Crystals of both calix[4]arenes
2b and 6 were grown using slow evaporation from a solvent
mixture of dichloromethane and methanol, and analyzed by single
crystal X-ray crystallography. Both NMR and mass spectra
confirmed the results.
The structure of acyloxyacetate compound 6 (Fig.1) is composed
of two symmetry-independent molecules 6A and 6B. These two
conformers (ratio 1:1) are not superimposable and differ signifi-
cantly, as visible in Fig. 1. In both conformers 6A and 6B also in the
calixarene 2b, the four methylene-bridged phenyl rings are not
arranged symmetrically. They form a cage with the shape of a
bucket or trapezoid prism. Thereby, two different groups of oppo-
site phenyl rings exist; one with almost parallel phenyl rings (an-
gles between the mean planes through all carbon atoms of the
opposite phenyl rings: 13.6ꢀ and 24.2ꢀ), and one set with two
strongly tilted phenyl rings (105.2ꢀ and 120.8ꢀ). The two con-
formers differ in which phenolic rings are facing each other: the
brominated ones (6A) or the unbrominated ones (6B).
2.2. Investigations of the side reaction with different substrates
Traces of water combined with basic conditions seem to be
required to form the acyloxyacetate moiety. It is evident that an
intramolecular transesterification combined with saponification
are part of the reaction mechanism. However, it has to be clarified
why this reaction selectively takes place on both non-brominated
phenolic units, and if a specific alkylation agent determines the
outcome of the reaction. To further elaborate on and verify this type
of reaction, additional alkyl bromides were used as substrates. As
shown in Scheme 2, compound 4 was reacted with ethyl 4-
bromobutyrate and ethyl 4-(bromomethyl)benzoate under the
conditions according to entry 12 in Table 1. All reactions were
worked-up identically, and all compounds were isolated and
analyzed.
When using ethyl 4-(bromomethyl)benzoate, product 7, as well
as acyloxyacetate derivative 8, were isolated in yields of 13% and
52%, respectively. In contrast, when using ethyl 4-bromobutyrate,
compound 9 was not observed. Instead, the acyloxyacetate deriv-
ative 10 was isolated in a yield of 47%. These findings prove that the
formation of the acyloxy ester reproducibly takes place exclusively
on the unbrominated phenolic units. Additionally, compounds 2a,b
and, 5 were treated under the conditions of entry 12 in Table 1, but
Calixarenes are known for their pseudopolymorphisms [44e46]
where the two different isomers are the result from the interaction
with solvent molecules. For compound 6, true polymorphism was
observed. This fact is supported by 1H NMR spectra of this com-
pound recorded at 25 ꢀC and ꢁ26 ꢀC in CDCl3 (see SI). At temper-
atures below ꢁ20 ꢀC, most of the proton signals moved and started
to broaden, revealing the existence of the two conformers 6A and

4
D. Bauer et al. / Tetrahedron 76 (2020) 131395
6B. The same behavior might be anticipated for the other calix[4]
arenes.
However, the conformer 6A is peculiar. We assume that due to
intramolecular interactions between the bromines (van der Waals
force) the phenolic rings are strongly inclined. This pinch in the
upper rim leads to a significantly enlarged cavity at the lower rim.
Since the NMR study supports the change in the molecular struc-
ture, this might also apply for compound 6 in solution. Conformer
6A might possess a particular arrangement, which could be one of
the reasons why the ester moieties of the non-brominated phenyl
rings readily undergo alkylation. To confirm the necessity of this
arrangement for the observed reaction, additional experiments
were performed.
Scheme 3. Alkylation of the monomeric compounds 11a,b. Reaction conditions: i)
BrCH2COOEt, NaOH, DMF (þ0.1% water), 90 ꢀC.
Almost rectangular relations exist between the phenyl rings in
crystals of 2b. Two of them are inclined by 2.6ꢀ (practically parallel)
selectively took place on only those two opposing ester moieties
attached to the non-brominated phenol units.
t
and the other two by 92.5ꢀ. One of the Bu groups of 2b shown in
Fig. 2 is disordered. This has been modeled by a split refinement.
Bond lengths and angles are within expected ranges.
To investigate the influence of the bromine atoms attached at
the para-position of two opposing phenols (cf. compounds 6, 8 and
10), the alkylation with ethyl bromoacetate was tested on the non-
brominated compounds 2a and 2b, as well as on the fourfold
alkylated calix[4]arene 5. Although identical conditions were used
for the synthesis of compound 6 (entry 12 in Table 1), no formation
of the corresponding acyloxyacetic derivatives was observed with
these molecules. It should also be noted that no saponified products
were found. Even the monomeric species 11a,b did not deliver the
acyloxyacetic derivatives 14a,b, but delivered saponified products
13a,b partly. This leads to the assumption that compound 4 is
mandatory as the starting material.
According to these results, we suggest a possible mechanism,
which is illustrated in Scheme 4. The first step could be the
saponification of the present ethyl ester of 4. The formed acetate I
undergoes a nucleophilic reaction with ethyl bromoacetate, which
is used in excess to form the observed acyloxyacetic moiety, fol-
lowed by the deprotonation of the remaining free phenolic OH
2.4. Alkylation of a simplified, “monomeric” system
To find a reasonable explanation for the formation of the acy-
loxyacetate derivatives, the influence of the calixarene skeleton was
investigated. Therefore, the two compounds 2,6-dimethylphenol
11a and 4-bromo-2,6-dimethylphenol 11b, which can be seen as
monomeric calixarenes units, were reacted with ethyl bromoace-
tate (Scheme 3) under the above elaborated conditions (entry 12 in
Table 1). Resultantly, the reaction of compounds 11a/b with ethyl
bromoacetate was performed to give the expected alkylated
products 12a/b in yields of 57% and 46%, respectively. Furthermore,
both saponified products 13a and 13b were isolated in yields of 21%
and 24%. However, the acyloxyacetic acid ethyl esters 14a and 14b
were not obtained.
Thus, it must be concluded that the observed reaction is not
exclusively dependent on the esters themselves, but rather on the
arrangement of the phenolic rings in the rigid calix[4]arene back-
bone of compound 4. Based on this investigation, a mechanism was
formulated to explain the observed results of these various
reactions.
2.5. Proposed mechanism
The formation of the acyloxyacetic derivative 6, as well as of
compound 8 and 10 was rather unexpected, since the reaction
Fig. 2. Molecular structure of 2b, without showing the co-crystallized solvent mole-
cules (only one of the two disordered tBu groups is shown).
Scheme 4. Suggested mechanism for the formation of compound 6.

D. Bauer et al. / Tetrahedron 76 (2020) 131395
5
groups of II. Due to the bromine atom in para-position, these
groups are slightly more acidic. In the final step, the two phenolate
units of III react with ethyl bromoacetate to form compound 6.
Calix[4]arene derivatives with free carboxylate groups or with an
intramolecular formed lactone moiety were not observed.
arene (3a, 3.0 g, 5.03 mmol) was dissolved in dichloromethane
(100 mL) and a solution of elemental bromine (2.03 g, 12.70 mmol)
in dichloromethane (10 mL) was slowly added at rt. After stirring
for 30 min, the reaction was quenched by adding an aqueous so-
lution of Na2S2O5 (approx. 15 mL) until the color of the solution
disappeared. Next, the organic layer was washed with water
(20 mL) and dried over Na2SO4 to yield compound 4 as a colorless
solid (3.79 g, >99%) after removal of the solvent. Rf ¼ 0.7 (petroleum
ether/ethyl acetate 1:2); m.p. 246e248 ꢀC; 1H NMR (400 MHz,
3. Conclusion
During our investigation, we found that reacting the calix[4]
arene derivative 4 with ethyl bromoacetate an unexpected regio-
selective side reaction occured, leading to the acyloxyacetic acid
ester derivative 6. Various reaction conditions were tested to con-
trol the yield ratio between the expected and novel products.
Finally, reproducible protocols were established for the synthesis of
the desired compounds 6, 8, and 10.
When using the “monomeric phenolic units” 2,6-
dimethylphenol (11) and 4-bromo-2,6-dimethylphenol (11b)
instead of calix[4]arene 4, the O-alkylation was not viable. The same
applies to the fourfold alkylated compounds 2a,b, and 5. This
mechanism requires a specific chemical environment provided by
the restricted calix[4]arene skeleton formed by brominated and
non-brominated phenolic units of calix 4 in contrast to the
monomeric molecules.
CDCl3):
d
¼ 1.35 (t, 3J ¼ 7.2 Hz, 6H, CH3), 3.33 (d, 2J ¼ 13.2 Hz, 4H,
CH2), 4.33 (q, 3J ¼ 7.2 Hz, 4H, OCH2), 4.43 (d, 2J ¼ 13.2 Hz, 4H, CH2),
4.70 (s, 4H, CH2C]O), 6.81 (t, 3J ¼ 7.5 Hz, 2H, ArH), 6.93 (d,
3J ¼ 7.5 Hz, 4H, ArH), 7.15 (s, 4H, ArH), 7.73 ppm (s, 2H, OH); 13C
NMR (101 MHz, CDCl3):
d
¼ 14.3 (CH3), 31.4 (CH2), 61.6 (OCH2), 72.5
(CH2C]O), 110.8 (Cq), 126.0 (p-CH), 129.6 (m-CH), 130.3 (Cq), 131.0
(m-CH), 132.7 (Cq), 152.2 (Cq), 152.6 (Cq), 168.9 ppm (C]O); MS
(ESIþ): m/z (%): 779 (11) [MþþNa,81Br], 777 (23) [MþþNa,79/81Br],
775 (12) [MþþNa,79Br], 757 (52) [MþþNa,81Br], 755 (100)
[MþþH,79/81Br], 753 (50) [MþþH,79Br]; elemental analysis calcd (%)
for C36H34Br2O8: C 57.31, H 4.54; found: C 57.58, H 4.44.
4.2.2. 5,17-Dibromo-25,26,27,28-tetra((ethoxycarbonyl)methoxy)
calix[4]arene (5)
Calix[4]arene 4 (250 mg, 0.33 mmol) was dissolved in anhy-
drous DMF (10 mL), NaH (132 mg, 3.31 mmol, 60% in mineral oil)
and ethyl bromoacetate (443 mg, 2.65 mmol) were added and the
resulting mixture was stirred at 90 ꢀC overnight. After cooling to rt,
the solvent was removed. The crude product was dissolved in
dichloromethane (20 mL) and washed with 10% HCl (2 ꢂ 20 mL)
and water (2 ꢂ 20 mL). The organic layer was dried over Na2SO4, the
solvent was removed and the crude product was purified via col-
umn chromatography (first column: DCM/MeOH 0 / 4%, second
column: petroleum ether/ethyl acetate 5:1 / 2:1) to give 5 as a
colorless solid (169 mg, 55%). Rf ¼ 0.51 (petroleum ether/ethyl ac-
4. Experimental section
4.1. General
All chemicals were purchased from commercial suppliers and
used without further purification, unless otherwise specified.
Anhydrous THF and DMF was purchased from Acros and deuterated
solvents were purchased from deutero GmbH. Compounds 2a, 2b
[21], 3a and 3b [32] were prepared according to the literature.
Spectra of compounds 12a and 13a are in accordance with those,
previously published [47]. 1H and 13C NMR spectra were recorded
on Agilent DD2 NMR spectrometers (400 or 600 MHz) with Pro-
beOne at 298 K. Chemical shifts of the spectra were reported in
parts per million (ppm) using TMS as internal standard. Mass
spectrometric (MS) data were obtained on a Xevo TQ-S mass
spectrometer (Waters) by using electrospray ionization (ESI). The
melting points were determined on a Galen III melting point
apparatus (Cambridge Instruments & Leica) and are uncorrected.
Microanalyses were carried out with an LECO CHNS 932 elemental
analyzer. Diffraction data were collected with a Bruker Nonius Apex
Kappa-II CCD diffractometer, using graphite-monochromated MoKa
etate 2:1); m.p. 136 ꢀC; 1H NMR (400 MHz, CDCl3):
d
¼ 1.29 (t,
3J ¼ 7.2 Hz, 12H, CH3), 3.20 (d, 2J ¼ 13.7 Hz, 4H, CH2), 4.20 (q,
3J ¼ 7.2 Hz, 8H, OCH2), 4.67 (s, 4H, CH2C]O), 4.72 (s, 4H, CH2C]O),
4.84 (d, 2J ¼ 13.7 Hz, 4H, CH2), 6.64 (s, 6H, ArH), 6.85 ppm (s, 4H,
ArH); 13C NMR (151 MHz, CDCl3):
d
¼ 14.3 (m, CH3), 31.4 (CH2), 60.7
(OCH2), 60.8 (OCH2), 71.4 (CH2C]O), 71.5 (CH2C]O), 115.8 (Cq),
123.5 (p-CH), 128.9 (m-CH), 131.3 (m-CH), 133.8 (Cq), 137.1 (Cq),
155.3 (Cq), 155.7 (Cq), 170.0 (C]O), 170.1 ppm (C]O); MS (ESI þ):
m/z ¼ 951 [MþþNa; 81Br], 949 [MþþNa; 79/81Br], 947 [MþþNa;
79Br]; elemental analysis calcd (%) for C44H46Br2O12: C 57.03, H
5.00; found: C 56.96, H 5.10.
radiation (
l
¼ 0.71073 Å) and the measurement was performed
at ꢁ150 ꢀC. The structure was solved by direct methods and refined
against F2 by full-matrix least-squares using the program suites
from G. M. Sheldrick [48e50]. All non-hydrogen atoms were
refined anisotropically; all hydrogen atoms were placed on
geometrically calculated positions and refined by using riding
models. CCDC 1904616 and 1906961 contain the supplementary
crystallographic data for compounds 2b and 6. The crystallographic
data for this paper can be obtained free of charge from The Cam-
bridge Crystallographic Data Centre. Preparative column chroma-
tography was carried out with silica gel 60 (Merck, particle size
0.040e0.063 mm), petroleum ether (Fisher Scientific, bp 40e60 ꢀC,
analytical reagent grade), methanol, chloroform, and ethyl acetate
(Fisher Scientific, HPLC grade).
4.2.3. 5,17-Dibromo-25,27-bis(((ethoxycarbonyl)methoxy-
carbonyl)methoxy)-26,28-bis((ethoxycarbonyl)methoxy)calix[4]-
arene (6)
Calix[4]arene 4 (250 mg, 0.33 mmol) was dissolved in DMF
(10 mL), NaOH (132 mg, 3.31 mmol), a few drops of water and ethyl
bromoacetate (443 mg, 2.65 mmol) were added and the resulting
mixture was stirred at 90 ꢀC overnight. After cooling to rt, the
solvent was removed. The crude product was dissolved in
dichloromethane (20 mL) and washed with 10% HCl (2 ꢂ 20 mL)
and water (2 ꢂ 20 mL). The organic layer was dried over Na2SO4, the
solvent was removed and the crude product was purified via col-
umn chromatography (first column: DCM/MeOH 0 / 4%, second
column: petroleum ether/ethyl acetate 5:1 / 2:1) to give 6 as a
colorless solid (138 mg, 40%). Rf ¼ 0.34 (petroleum ether/ethyl ac-
etate 2:1); m.p. 117e118 ꢀC; 1H NMR (400 MHz, CD3CN):
4.2. Syntheses
d
¼ 1.18e1.32 (m, 12H, CH3), 3.26 (d, 2J ¼ 13.7 Hz, 4H, CH2),
4.2.1. 5,17-Dibromo-25,27-bis((ethoxycarbonyl)methoxy)-26,28-
dihydroxycalix[4]arene (4)
4.11e4.25 (m, 8H, OCH2), 4.59 (s, 4H, CH2C]O), 4.66 (s, 4H, CH2C]
O), 4.77 (d, 2J ¼ 13.7 Hz, 4H, CH2), 4.95 (s, 4H, CH2C]O), 6.66 (s, 4H,
ArH), 6.86 (t, 3J ¼ 7.5 Hz, 2H, ArH), 7.50 ppm (d, 3J ¼ 7.5 Hz, 4H,
25,27-Bis((ethoxycarbonyl)methoxy)-26,28-dihydroxycalix[4]

6
D. Bauer et al. / Tetrahedron 76 (2020) 131395
ArH); 13C NMR (101 MHz, CD3CN):
d
¼ 14.4 (CH3), 14.5 (CH3), 31.8
4H, CH2), 4.34e4.41 (m, 12H, CH2þOCH2), 4.59 (s, 4H, CH2C]O),
4.98 (s, 4H, CH2C]O), 5.07 (s, 4H, CH2C]O), 6.67 (s, 4H, ArH),
6.69e6.75 (m, 6H, ArH), 7.26 (d, 3J ¼ 8.2 Hz, 4H, ArH), 7.45 (d,
3J ¼ 8.2 Hz, 4H, ArH) 7.94e8.00 ppm (m, 8H, ArH); 13C NMR
(CH2), 61.7 (CH2C]O), 61.8 (OCH2), 62.2 (OCH2), 71.7 (CH2C]O),
72.4 (CH2C]O), 116.1 (Cq), 124.4 (p-CH), 130.2 (m-CH), 131.6 (m-
CH), 135.9 (Cq), 137.7 (Cq), 155.5 (Cq), 157.0 (Cq), 168.6, 170.4,
170.8 ppm (3 x C]O); MS (ESIþ): m/z ¼ 1045 [MþþH; 81Br], 1043
[MþþH, 79/81Br], 1041 [MþþH; 79Br], 1067 [MþþNa, 81Br], 1065
[MþþNa, 79/81Br], 1063 [MþþNa; 79Br]; elemental analysis calcd (%)
for C48H50Br2O16: C 55.29, H 4.83; found: C 55.16, H 4.90.
(151 MHz, CDCl3):
d
¼ 14.4, 14.5 (2 x CH3), 31.3 (CH2), 61.2 (OCH2),
65.8, 70.9, 76.6 (3 x CH2C]O), 115.9 (Cq), 123.7 (CHAr), 127.8 (CHAr),
129.2 (CHAr), 129.6 (CHAr), 129.9 (CHAr), 130.4 (Cq), 130.6 (Cq), 131.1
(CHAr), 134.2, 136.9, 140.2, 142.0, 154.2, 155.6 (6 x Cq), 166.2, 166.4,
169.4 ppm (3 x C]O); MS (ESIþ): m/z (%): 1156 (20) [MþþH; 81Br],
1054 (100) [MþþH,79/81Br], 1052 (49) [MþþH,79Br]; elemental
analysis calcd (%) for C56H66Br2O16: C 58.24, H 5.76; found: C 58.50,
H 5.79.
4.2.4. 5,17-Dibromo-25,27-bis((ethoxycarbonyl)methoxy)-26,28-
bis((ethoxycarbonyl)benzyloxy)calix[4]arene (7) and 5,17-dibromo-
25,27-bis(((ethoxycarbonyl)benzyloxycarbonyl)-methoxy)-26,28-
bis((ethoxycarbonyl)benzyloxy)calix[4]arene (8)
Calix[4]arene 4 (250 mg, 0.33 mmol) was dissolved in DMF
(10 mL), NaOH (132 mg, 3.31 mmol), a few drops of water and ethyl
4-(bromomethyl)benzoate (2.03 g, 2.65 mmol) were added and the
resulting mixture was stirred at 90 ꢀC overnight. After cooling to rt,
the solvent was removed. The crude product was dissolved in
dichloromethane (20 mL) and washed with 10% HCl (2 ꢂ 20 mL)
and water (2 ꢂ 20 mL). The organic layer was dried over Na2SO4, the
solvent was removed and the crude product was purified via col-
umn chromatography (first column: DCM/MeOH 0 / 4%, second
column: petroleum ether/ethyl acetate 5:1 / 2:1) to give 7 (46 mg,
13%) and 8 (232 mg, 52%) both as a colorless solids. Compound 7:
Rf ¼ 0.75 (petroleum ether:ethyl acetate 2:1); 1H NMR (600 MHz,
4.2.6. Ethyl 2-(2,6-dimethylphenoxy)acetate (12a) and 2-(2,6-
dimethyl phenoxy)acetic acid (13a)
2,6-Dimethylphenol (11a, 300 mg, 2.46 mmol) was dissolved in
DMF (15 mL), NaOH (491 mg, 12.3 mmol), a few drops of water and
ethyl bromoacetate(1.64 g, 9.8 mmol) were added and the resulting
mixture was stirred at 90 ꢀC overnight. After cooling to rt, the
solvent was removed. The crude product was dissolved in
dichloromethane (40 mL) and washed with 10% HCl (2 ꢂ 40 mL)
and water (2 ꢂ 40 mL). The organic layer was dried over Na2SO4, the
solvent was removed and the crude product was purified via col-
umn chromatography (petroleum ether/ethyl acetate 5:1 /1:1) to
give 12a (291 mg, 57%) and 13a (93 mg, 21%) both as a colorless oil.
NMR and MS data are in accordance with the previously published
[16].
CDCl3):
d
¼ 1.24 (t, 3J ¼ 7.2 Hz, 6H, CH3), 1.40 (t, 3J ¼ 7.1 Hz, 6H, CH3),
3.04 (d, 2J ¼ 13.7 Hz, 4H, CH2), 4.15 (q, 3J ¼ 7.2 Hz, 4H, OCH2),
4.36e4.41 (m, 8H, CH2þOCH2), 4.44 (s, 4H, CH2C]O), 5.14 (s, 4H,
CH2C]O), 6.60e6.67 (m, 6H, ArH), 6.78 (s, 4H, ArH), 7.50 (d,
3J ¼ 8.2 Hz, 4H, ArH), 7.99 ppm (d, 3J ¼ 8.2 Hz, 4H, ArH); 13C NMR
4.2.7. Ethyl 2-(4-bromo-2,6-dimethylphenoxy)acetate (12b) and 2-
(4-bromo-2,6-dimethylphenoxy)acetic acid (13b)
(151 MHz, CDCl3):
d
¼ 14.3, 14.5 (2 x CH3), 31.3 (CH2), 60.8, 61.1 (2 x
4-Bromo-2,6-dimethylphenol (11b, 500 mg, 2.49 mmol) was
dissolved in DMF (15 mL), NaOH (497 mg, 12.4 mmol), a few drops
of water and ethyl bromoacetate(1.66 g, 9.95 mmol) were added
and the resulting mixture was stirred at 90 ꢀC overnight. After
cooling to rt, the solvent was removed. The crude product was
dissolved in dichloromethane (40 mL) and washed with 10% HCl
(2 ꢂ 40 mL) and water (2 ꢂ 40 mL). The organic layer was dried over
Na2SO4, the solvent was removed and the crude product was pu-
rified via column chromatography (petroleum ether/ethyl acetate
5:1 /1:1) to give 12b (328 mg, 46%) and 13b (154 mg, 24%) both as
colorless oil. Compound 12b: Rf ¼ 0.65 (DCM:MeOH 16:1); 1H NMR
(400 MHz, CDCl3): 1H NMR (400 MHz, CDCl3): 1.31 (t, 3J ¼ Hz, 3H,
CH3), 2.26 (s, 6H, ArCH3), 4.28 (q, 3J ¼ Hz, 2H, CH2), 7.11 ppm (s, 2H,
OCH2), 71.0, 76.5 (2 x CH2C]O), 115.7 (Cq), 123.5 (p-CH), 129.0 (m-
CH), 129.5 (CHAr), 129.7 (CHAr), 130.3 (), 131.2 (m-CH), 133.9, 137.4,
142.2, 154.5, 155.5 (5 x Cq), 166.6, 169.7 ppm (2 x C]O); MS (ESIþ):
m/z (%): 1080 (47) [MþþH,81Br], 1078 (95) [MþþH,79/81Br], 1076
(48) [MþþH,79Br]; elemental analysis calcd (%) for C56H53Br2O12: C
62.40, H 4.96; found: C 62.58, H 4.81; Compound 8: Rf ¼ 0.49
(petroleum ether:ethyl acetate 2:1)1H NMR (400 MHz, CDCl3):
d
¼ 1.34e1.42 (m, 12H, CH3), 3.02 (d, 2J ¼ 13.4 Hz, 4H, CH2),
4.33e4.41 (m, 12H, CH2O þ CH2), 4.58 (s, 4H, CH2C]O), 4.98 (s, 4H,
CH2C]O), 5.06 (s, 4H, CH2C]O), 6.66e6.73 (m, 8H, ArH), 7.25 (d,
3J ¼ 8.1 Hz, 4H, ArH), 7.45 (d, 3J ¼ 8.1 Hz, 4H, ArH), 7.93e8.00 ppm
(m, 8H, ArH); 13C NMR (101 MHz, CDCl3):
d
¼ 14.4, 14.5 (2 x CH3),
31.3 (CH2Ar), 61.2, 65.8, 70.9, 76.6 (4 x CH2), 115.9 (Cq), 123.7 (p-CH),
127.8 (CHAr), 129.2 (m-CH), 129.5 (CHAr), 129.6 (CHAr), 129.9 (CHAr),
130.4 (Cq), 130.6 (Cq), 131.2 (m-CH), 154.2 (Cq), 155.6 (Cq), 166.2,
166.4, 169.4 ppm (3 x C]O); MS (ESIþ): m/z (%): 1049 (47)
[MþþH,81Br], 1047 (95) [MþþH,79/81Br], 1045 (47) [MþþH,79Br];
elemental analysis calcd (%) for C72H66Br2O16: C 64.20, H 4.94;
found: C 64.28, H 4.90.
ArH); 13C NMR (101 MHz, CDCl3):
d
¼ 14.3 (CH3), 16.2 (ArCH3), 61.4,
69.2 (2 x CH2), 117.1 (Cq), 131.6 (CHAr), 133.0 (CHAr), 154.6 (Cq),
168.8 ppm (C]O); MS (ESIþ): m/z (%): 108 (20) [Mþ], 107 (60)
[MþꢁH], 91 (100) [C7Hþ7 ]; elemental analysis calcd (%) for
C
12H15BrO3: C 50.19, H 5.27; found: C 50.00, H 5.29. Compound 13b:
Rf ¼ 0.1 (DCM:MeOH 16:1); 1H NMR (400 MHz, CDCl3): 2.26 (s, 6H,
CH3), 4.42 (s, 2H, CH2), 7.15 ppm (s, 2H, ArH); 13C NMR (101 MHz,
CDCl3):
d
¼ 16.3 (CH3), 68.5 (CH2), 117.7 (Cq), 131.9 (CHAr), 132.9
4.2.5. 5,17-Dibromo-25,27-bis(((ethoxycarbonyl)butoxycarbonyl)
methoxy)-26,28-bis((ethoxycarbonyl)butoxy)calix[4]arene (10)
Calix[4]arene 4 (250 mg, 0.33 mmol) was dissolved in DMF
(10 mL), NaOH (132 mg, 3.31 mmol), a few drops of water and ethyl
4-bromobutanoate (559 mg, 2.65 mmol) were added and the
resulting mixture was stirred at 90 ꢀC overnight. After cooling to rt,
the solvent was removed. The crude product was dissolved in
dichloromethane (20 mL) and washed with 10% HCl (2 ꢂ 20 mL)
and water (2 ꢂ 20 mL). The organic layer was dried over Na2SO4, the
solvent was removed and the crude product was purified via col-
umn chromatography (first column: DCM/MeOH 0 / 4%, second
column: petroleum ether/ethyl acetate 5:1 / 2:1) to give 10 as a
colorless solid (180 mg, 47%). Rf ¼ 0.65 (DCM:MeOH 16:1); 1H NMR
(CHAr), 153.9 (Cq), 172.2 ppm (C]O); MS (ESIþ): m/z (%): 108 (20)
[Mþ], 107 (60) [MþꢁH], 91 (100) [C7Hþ7 ]; elemental analysis calcd
(%) for C10H11BrO3: C 46.36, H 4.28; found: C 46.34, H 4.20.
Declaration of competing interest
The authors declare that they have no known competing
financial interests or personal relationships that could have
appeared to influence the work reported in this paper.
Acknowledgments
This work is part of the master thesis of Sergej Stipurin (TU
Dresden, Faculty of Chemistry and Food Chemistry).
(600 MHz, CDCl3):
d
¼ 1.36e1.41 (m, 12H, CH3), 3.02 (d, 2J ¼ 13.7 Hz,

D. Bauer et al. / Tetrahedron 76 (2020) 131395
7
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