Novel dendritic cores based on thiacalix[4]arene derivatives

Article abstract of DOI:10.1016/j.tetlet.2004.07.085

Thiacalix[4]arenes possessing carboxylic groups were used for the design of potential dendritic cores with amino surface groups. The known tetraacetic acid in the 1,3-alternate conformation gave the desired product in very low yield because of steric hind

Full text of DOI:10.1016/j.tetlet.2004.07.085

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 7145–7149
Novel dendritic cores based on thiacalix[4]arene derivatives
Dietmar Appelhans,a,* Vaclav Stastny,a,b Hartmut Komber,a Dieter Voigt,a Brigitte Voit,a
b
Pavel Lhotak and Ivan Stibor
b
´
aInstitute of Polymer Research Dresden, Hohe Strasse 6, 01069 Dresden, Germany
´
Department of Organic Chemistry, Institute of Chemical Technology, Technika 5, 166 28 Prague 6, Czech Republic
b
Received 27 May 2004; revised 29 June 2004; accepted 19 July 2004
Available online 14 August 2004
Abstract—Thiacalix[4]arenes possessing carboxylic groups were used for the design of potential dendritic cores with amino surface
groups. The known tetraacetic acid in the 1,3-alternate conformation gave the desired product in very low yield because of steric
hindrance on thiacalix[4]arene moiety. Therefore, synthetic strategy based on withdrawing of the carboxyl groups via benzylic
spacer from the thiacalix[4]arene moiety was successfully applied for the realization of novel thiacalix[4]arenes bearing two or four
protected lysine units.
Ó 2004 Elsevier Ltd. All rights reserved.
Since their discovery, thiacalixarenes1 have been attract-
ing considerable attention, as the presence of hetero
atoms results in many novel features compared with
Ôclassical calixarenesÕ.2 Hence, thiacalix[4]arenes exhibit
a broad range of interesting and potentially useful prop-
erties, such as excellent complexation ability toward
transition metals, chemical modification (oxidation) of
bridges or different conformational preferences.3 Calix-
arenes are commonly used in supramolecular chemistry
as building blocks and/or molecular scaffolds due to the
easily tunable calixarene scaffold. Among others, dend-
ritic-modified calixarenes were realized as supramolecu-
lar construction units.4 Until now the application of the
thiacalix[4]arenes in this role is still rather restricted by
the lack of generally applicable derivatization methods
to easily modify the outer spheres of thiacalix[4]arene
derivatives. In this letter we report on the design and
synthesis of novel thiacalix[4]arene-based systems with
Boc-protected amino surface groups potentially usable
as building block in the construction of dendritic deriv-
atives and other supramolecular assemblies.
alternate conformation, were converted into the carbo-
nyl chloride intermediates using the oxalyl chloride
method. These reactive intermediates were directly re-
acted (one pot procedure) with the mono-Boc-protected
1,2-diaminoethane and mono-Boc-protected 1,4-phenyl-
enediamine in the presence of triethylamine in DCM.
O
HO
HO
O
X
X
X
X
O
O
X
S
X
S
S
S
S
O
O
S
S
S
OH
X
X
HO
OH
OH
O
OH
O
OH
1a, X = H
2a, X = H
1b, X =But
2b, X =But
To our surprise, with the exception of 3 (isolated in low
yield after repeated column chromatography in Scheme
1) we were unable to obtain the desired compounds with
four Boc-protected amino groups in the exterior. The 1H
NMR spectra of the crude reaction products after trials
of the conversion of 2a and 2b indicated in all cases the
presence of partly unreacted carboxylic groups. Indeed,
compound 4 with two Boc-protected amino groups
(Scheme 1) was isolated from the reaction mixture as
the only product of the condensation with mono-Boc-
protected 1,4-phenylenediamine. The structure of 4
For the entry of general derivatization methods of the
thiacalix[4]arene 1a and 1b, the well established thia-
calix[4]arene tetraacids 2a5 and 2b,6 prepared by the
hydrolysis of the thiacalix[4]arene tetraacetates7 in 1,3-
Keywords: Thiacalixarenes; Benzylic spacer; Dendritic core; Amino
surface group.
*
Corresponding author. Tel.: +49 0351 4658353; fax: +49 0351
4658565; e-mail: applhans@ipfdd.de
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.07.085

7146
D. Appelhans et al. / Tetrahedron Letters 45 (2004) 7145–7149
R
N
R
N
HO
O
S
O
S
H
HO
O
O
H
O
O
O
O
3
(i)
H
N
S
S
S
O
S
-(CH2)2
S
R =
S
33%
O
O
O
O
O
R
H
O
OH
O
O
N
H
HO
N
O
R
2b
(ii)
O
H
O
25%
N
H
O
N
S
O
OH
O
O
4
S
S
S
O
O
H
O
N
O
HO
N
O
H
O
Scheme 1. Synthesis of thiacalix[4]arenes 3 and 4. Reagents and conditions: excess (COCl)2/CCl4, 3h under reflux; then (i) H2N–(CH2)2–NH–Boc/
Et3N, CH2Cl2, rt, 1d; (ii) p-H2N–Ph–NH–Boc/Et3N, CH2Cl2, rt, 1d.
was proved by 2D-NOESY experiments (Figs. 1 and 2 in
supplementary material). Its formation could be
ascribed to close arrangement between NH-amide
and carbonyl chloride groups resulting in H-bonding
interactions during the reaction. Thus, complete conver-
sion of the carboxylic groups in 2b was prevented. In
general, steric hindrance may be imposed to the used
structures of 2a and 2b during the conversion with func-
tionalized amino compounds caused by the possibility of
H-bonding interaction of adjacent functional groups on
the thiacalixarene moiety. Therefore, the free accessibil-
ity of nucleophiles for attacking the carbonyl chloride
groups on the thiacalixarene moiety is reduced.
for 5d in the presence of Cs2CO3 as a base. The desired
products 5a and 5b bearing four ester groups were
obtained after simple precipitation without additional
purification steps in 63% and 82% yield, respectively
(Scheme 2). Complete hydrolysis of the methyl esters
in 5a and 5b required 5d (Scheme 2) to isolate the cor-
responding tetraacid derivatives 6a and 6b after precipi-
tation in high yields. The compounds 5a, 5b, 6a, and 6b
were identified by 1D and 2D NMR, elemental analysis,
IR, and MALDI-TOF-MS. The proposed 1,3-alternate
conformation of the thiacalix[4]arene derivatives 5 and
6 was unambiguously confirmed by 2D-NOESY experi-
ments (Fig. 3 in supplementary material) that revealed
the interactions between the benzylic CH2 groups and
1
The results of the above reactions for 2a and 2b forced
us to change the synthetic strategy in such a way that
the reacting carboxylic groups have to be spaced more
apart from the thiacalix[4]arene moiety. Hence, the com-
mercially available methyl p-bromomethylbenzoate was
chosen as an alkylating agent, as this compound pos-
sesses the carboxylic for subsequent derivatization, and
aromatic protons. Very simple H NMR signal patterns
in the H NMR spectra of these compounds reflect the
1
high symmetry in the 1,3-alternate conformation (Fig.
4 in supplementary material).
In order to prepare thiacalix[4]arene derivatives suitable
as a dendritic core, we tested the general applicability of
well-known synthetic methods in the thiacalixarene ser-
ies (Scheme 2). In contrast with compound 2, the activa-
tion of carboxyl groups in 6a with CDI and subsequent
reaction with mono-Boc-protected 1,2-diaminoethane in
DCM led smoothly to the corresponding thiacalix-
[4]arene derivative 7 in very high yield (97%).
represents highly reactive benzyl halogenide. Moreover
7–11
during
the application of the metal template effect6b,
the alkylation of the parent thiacalixarenes 1a and 1b
should allow us to tune the conformational outcome
of the reaction.
In order to establish 1,3-alternate conformers (Scheme
2), thiacalix[4]arenes 1a and 1b were alkylated with
methyl p-bromomethylbenzoate in refluxing acetone
Similarly, the reaction of 6a with mono-Boc-protected
1,4-diaminobutane under the identical reaction condi-

D. Appelhans et al. / Tetrahedron Letters 45 (2004) 7145–7149
7147
X
X
X
X
R
R
N
N
H
H
OH
HO
O
O
O
O
S
S
S
S
OH
HO
OH
OH
X
X
1a, X = H
O
O
1b, X = But
O
O
(iii)
S
S
S
S
S
S
S
S
(i)
O
O
O
O
(ii)
X
X
O
O
O
O
H
H
O
N
R
N
O
X
X
O
OH
O
HO
R
O
O
6a, X = H 94%
7 (97%)
8 (74%)
9 (57%)
6b, X = But 99%
S
S
S
S
O
O
X
H
X
H
-(CH2)4
N
O
-(CH2)2
N
O
8, R =
7, R =
O
O
O
H
N
O
O
O
O
O
O
-(CH2)2
N
9, R =
5a, X = H 63%
5b, X = But 82%
N
O
H
H
O
O
H
O
H
H
N
(iv)
N
O
O
H2N-(CH2)2
10 (96%)H
N
O
N
O
O
N
O
O
H
10a
O
O
Scheme 2. Synthesis of thiacalix[4]arenes 7–9. Reagents and conditions: (i) p-BrCH2–Ph–CO2Me/Cs2CO3, acetone, 60°C, 5d; (ii) NaOH, H2O/
EtOH, 80°C, 5d, then 1N HCl; (iii) only for 6a: CDI, CH2Cl2, rt, 2h, then H2N–(CH2)x–NH–Boc (x = 2 or 4) or H2N–(CH2)2–NH–Lys(Boc)2 10,
rt, 1d; (iv) excess H2N–(CH2)2–NH2, MeOH, rt, 4d in the dark.
tions gave the desired thiacalix[4]arene derivative 8 in
74% yield (after column chromatography on silica gel).
The use of DMF as solvent for the activation of the
carboxyl groups in 6a and their amidation with primary
amines is not advantageous due to the problematic sep-
aration of DMF from the crude product.
The use of Na2CO3 as a base7b instead of Cs2CO3 led to
the cone conformer possessing two benzyl spacers bear-
ing carboxyl groups (Scheme 3). Thus, the thiacalix-
[4]arene 1b was alkylated with an excess of methyl
p-bromomethylbenzoate in refluxing acetone in the pres-
ence of 1equiv of Na2CO3 to give the disubstituted
methyl ester derivative 11 in 61% yield as pure com-
pound after precipitation. Interestingly, even the use of
more than 1equiv of the base gave only the disubstituted
product without any trace of tetraalkylated compound.
The cone conformation of the thiacalix[4]arene skeleton
in 11 was confirmed by 2D-NOESY experiments. The
observed interactions between the phenolic OH groups
and benzylic CH2 groups clearly supported the proposed
cone structure (see Fig. 6 in supplementary material). A
Amides 7 and 8 represent potential thiacalixarene-based
dendritic cores possessing the Boc-protected amino
groups on their exterior, suitable for the subsequent
transformations. To multiply the number of branching
units in the core unit, we have attempted the introduc-
tion of bis-Boc-protected L-lysine derivative 10,
obtained from aminolysis of bis-Boc-lysine methyl ester
10a12 using excess 1,2-diaminoethane (Scheme 2). The
reaction of CDI-activated carboxylic groups in 6a with
10 yielded the desired first generation thiacalix[4]arene
dendrimer 9 after column chromatography in 57% yield.
Thiacalix[4]arenes 7–9 were fully characterized by 1D
and 2D NMR, IR, and MALDI-TOF-MS. The 1H
NMR spectra of 8 and 9 are shown in Figure 5 (Supple-
mentary material) to outline the signal assignment of
each part structure in 8 and 9.
1
comparison of the H NMR spectra of the 1,3-alternate
conformers 5a and 5b and cone conformer 11 is given in
Figure 4 (Supplementary material) to depict the influ-
ence of the conformation on the chemical shifts of the
ether part structure in both conformers.
The hydrolysis of the methyl ester groups in 11 were
accomplished by the two days reflux with NaOH in

7148
D. Appelhans et al. / Tetrahedron Letters 45 (2004) 7145–7149
S
S
S
HO
S
OH
OH OH
1b
O
S
S
O
S
S
H
(i)
N
OH
O
O
OH
O
O
O
N
H
H
O
N
O
N
O
O
H
H
(iii)
O
N
H
N
O
O
38%
13
S
S
S
S
N
OH
O
O
OH
N
H
H
O
OR
O
OR
11, R = Me 61%
12, R =H 99%
(ii)
Scheme 3. Synthesis of thiacalix[4]arene 13. Reagents and conditions: (i) p-BrCH2–Ph–CO2Me/Na2CO3, acetone, 60°C, 4d; (ii) NaOH, H2O/EtOH,
80°C, 2d, then 1N HCl; (iii) CDI, CH2Cl2, rt, 2h, then H2N–(CH2)2–NH–Lys(Boc)2 10, rt, 1d.
aqueous ethanol (Scheme 3). The resulting carboxylic
acid 12 was isolated in quantitative yield after acidifica-
tion of the reaction mixture with 1N HCl. Finally, the
application of the CDI activation procedure under the
identical conditions as mentioned above and subsequent
reaction with amino-functionalized bis-Boc-lysine deriv-
ative 10 led to the desired product. The thiacalix[4]arene
derivative 13, as the first generation dendrimer, was
obtained in 38% yield after column chromatography
(Scheme 3). The 1H NMR spectrum exhibits the charac-
teristic features of the cone conformation (Fig. 7 in sup-
plementary material). The thiacalix[4]arenes 11–13 were
characterized by 1D and 2D NMR, elemental analysis,
IR, and MALDI-TOF-MS.
forschungsbereich 287 ÔReactive Polymers in Inhomoge-
neous Systems, in Melts and at InterfacesÕ for financial
support. The authors also wish to thank the Saxony Min-
istry of Science and Art for the financial support in the
frame work of ÔBiotechnologyÕ (7531-50-03-0370-01/4),
and the grant Agency of the Czech Republic for partial
financial support of this work (203/00/1011). We thank
Mrs. Adam and Mr. Schulze for carrying out IR investi-
gations and elemental analysis.
Supplementary data
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.
2004.07.085. Spectroscopic and analytical data, experi-
mental details for the compounds 3, 4, 5a, 5b, 6a, 6b,
7, 8, 9, 10, 11, 12, and 13, and Figures 1–7. This material
is available via the editorial office.
In conclusion, we have described a synthetic strategy for
the preparation of novel thiacalix[4]arene-based deriva-
tives potentially applicable as dendritic cores. To over-
come the problems with the steric hindrance on the
thiacalix[4]arene moiety, the aromatic spacer bearing
carboxyl groups can be used instead of common bromo-
acetate derivatives. The resulting carboxylic acid deriva-
tives preorganized in the 1,3-alternate or in the cone
conformations serve as a starting point for the synthesis
of novel amidic derivatives bearing amino groups on the
surface. These compounds represent the first examples of
thiacalix[4]arene derivatives potentially useful as dend-
ritic cores for the subsequent branching derivatization.
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