Synthesis of (thia)calix[4]arene oligomers: Towards calixarene-based dendrimers

Article abstract of DOI:10.1016/j.tet.2004.02.036

Thiacalix[4]arenes bearing two or four carboxylic functions on the lower rim served as starting compounds for the synthesis of novel calixarene oligomers connected by amidic functions. The cone conformers react smoothly with four molecules of 5-amino-calix[4]arene to yield the corresponding pentakis-calixarenes. On the other hand, because steric hindrance, the 1,3-alternate condenses only with two molecules leading thus to tris-calixarene, possessing a novel type of inherent chirality based on the 25,26-substitution pattern. The title compounds, which connect together 'classical' calixarene and thiacalixarene building blocks, represent a first step towards calixarene-based dendritic structures.

Full text of DOI:10.1016/j.tet.2004.02.036

Tetrahedron 60 (2004) 3383–3391
Synthesis of (thia)calix[4]arene oligomers:
towards calixarene-based dendrimers
a
Vaclav Stastny, Ivan Stibor, Hana Dvorakova and Pavel Lhotak
a
b
a
,
ˇ
*
´
ˇ´
´
´
´
aDepartment of Organic Chemistry, Prague Institute of Chemical Technology, Technicka 5, 166 28 Prague 6, Czech Republic
bLaboratory of NMR Spectroscopy, Institute of Chemical Technology, Technicka 5, 166 28 Prague 6, Czech Republic
Received 2 January 2004; revised 26 January 2004; accepted 19 February 2004
Abstract—Thiacalix[4]arenes bearing two or four carboxylic functions on the lower rim served as starting compounds for the synthesis of
novel calixarene oligomers connected by amidic functions. The cone conformers react smoothly with four molecules of 5-amino-
calix[4]arene to yield the corresponding pentakis-calixarenes. On the other hand, because steric hindrance, the 1,3-alternate condenses only
with two molecules leading thus to tris-calixarene, possessing a novel type of inherent chirality based on the 25,26-substitution pattern. The
title compounds, which connect together ‘classical’ calixarene and thiacalixarene building blocks, represent a first step towards calixarene-
based dendritic structures.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
The overall shape of hyperbranched polymers or dendritic
structures1 can be controlled by using an appropriate
multivalent core. The geometry of this core determines
the direction of branching while the number of its functional
groups controls the number of branches. The chemistry of
calix[n]arenes and thiacalix[n]arenes offers us broad
variations in the structural and geometrical features of
calixarene derivatives, making the calixarenes ideal candi-
dates for the core moieties of dendrimers. The shape of the
core can be changed depending on the conformation used.
Particularly, we can control the size (calix[4]arene,
calix[6]arene, calix[8]arene), the multiplicity of function-
ality (e.g., number of hydroxyl groups could be from 4 to 8)
Figure 1. Dendritic structures based on the various calix[4]arene
conformations (schematically): (a) cone, (b) partial cone, (c) 1,3-alternate.
and the conformation of molecules (Fig. 1).
Thiacalixarene2 1 has appeared recently as a novel member
Tetraalkylation of the phenolic functions (lower rim) is a
of the well-known calixarene3 family. The presence of four
common procedure for the shaping of the thiacalixarene
sulfur atoms results in many novel features4 compared with
skeleton.3 Recently, several groups5 have studied the
‘classical’ calixarenes, such as different complexation
conformational preferences during the alkylation reaction
ability with sulfur contribution, easy chemical modification
of thiacalixarenes 1 and 2 with ethyl bromoacetate in
(oxidation) of bridges, different size and different confor-
acetone. It was found that thiacalixarenes exhibit a
mational behaviour of this novel macrocycle. Hence,
pronounced template effect, and the conformer distribution
thiacalix[4]arene exhibits a broad range of interesting
depends strictly on the reaction conditions used. Thus, using
functions, which make this compound a good candidate
different bases M2CO3 (M¼Naþ, Kþ and Csþ), the reaction
for many applications in supramolecular chemistry.
yields selectively the corresponding tetraacetates in various
conformations (cone, partial cone, 1,3-alternate). As the
products are readily isolable in multi-gram amounts without
chromatographic purification, the tetraacetates represent
suitable building blocks for the construction of more
sophisticated molecules.
Keywords: Calixarenes; Dendrimers; Conformational analysis.
*
Corresponding author. Tel.: þ420-2-2435-4280; fax: þ420-2-2435-4288;
e-mail address: lhotakp@vscht.cz
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.02.036

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In this paper we report on the first example of systems
combining both types of building blocks (classical calix[4]-
arenes and thiacalix[4]arenes) within one molecule. These
oligocalixarenes are preorganised in defined conformations
and could be potentially used as the core molecules for the
construction of various dendritic6 structures.
of mono- to tetra-amides). Surprisingly, using an excess of
DCC (10, 20, and 40 equiv.) did not significantly improve
the outcome. The plausible explanation could be based on
steric reasons: the DCC is too bulky for the activation of all
four carboxylic functions at the same time. Hence, we
focused on the second method. The preparation of acid
chlorides was accomplished by stirring the starting acids
with an excess of oxalyl chloride in CCl4 under reflux. The
crude acid chlorides 3c, 4c, 7c, and 8c were obtained in
almost quantitative yield and used without purification in
the next step due to their presumed instability. Subsequent
condensation with 4-aminotoluene (5 equiv., dichloro-
methane or THF, rt) in the presence of Et3N gave the
corresponding tetraamides both in the cone 5 (88%), 6
(41%), and in the 1,3-alternate 9 (71%), and 10 (20%)
conformations (Scheme 1).
2. Results and discussion
2.1. Synthesis of conjugates
The synthesis started from parent thiacalixarenes 1 and 2,
which were transformed into the corresponding tetraacetates
by alkylation with ethyl bromoacetate in refluxing acetone
using Na2CO3 (3a, 75%; 4a, 55% yield) or Cs2CO3 (7a,
68%; 8a, 48% yield) as a base. These esters were hydrolysed
with NaOH in aqueous ethanol under reflux to yield
tetracarboxylic acids 3b, 4b, 7b, and 8b in quantitative
yields. Before coupling with the corresponding amino-
calix[4]arene, we tested the general applicability of the
synthetic methods in the thiacalixarene series using a model
aromatic amine (4-aminotoluene). Two methods were
selected for the screening: (i) a direct reaction of carboxylic
acids with 4-aminotoluene using dicyclohexylcarbodiimide
as a coupling agent, and (ii) reaction of the corresponding
acyl chlorides with 4-aminotoluene (Scheme 1).
Similar reaction conditions were applied for the synthesis of
oligocalixarenes combining within the molecule both
common building blocks: ‘classical’ calixarene and thia-
calixarene. Thus, monoamino derivative 11 immobilised in
the cone conformation, reacted smoothly with central cone
acid tetrachloride moieties 3c and 4c to give the correspond-
ing pentakis-calixarenes 12 and 13 in 25 and 52% yields,
respectively. On the other hand, the reaction of chlorides 7c
and 8c revealed that steric hindrance of the central 1,3-
alternate unit plays a key role in the condensation. While the
corresponding pentakis-calixarene 15 was obtained in 11%
yield after preparative TLC of a very complicated reaction
mixture, the similar product 14 bearing tert-butyl groups on
the upper rim of the 1,3-alternate core was not isolated at all.
Instead, tris-calixarene 16 was obtained in 21% yield
The reactions with DCC/4-aminotoluene were carried out in
dichloromethane solution. The coupling accomplished with
5 equiv. of DCC led to a complicated mixture of several
products corresponding to the incomplete reaction (mixture
Scheme 1. (i) BrCH2COOEt/Na2CO3, acetone, reflux (3a, 75%; 4a, 55%); (ii) NaOH, EtOH/water, reflux (3b, 99%; 4b, 99%); (iii) oxalyl chloride/CCl4, reflux
(3c, 4c, quant.); (iv) 4-aminotoluene/Et3N/CH2Cl2, rt (5, 88%; 6, 41%); (v) BrCH2COOEt/Cs2CO3, acetone, reflux (7a, 68%; 8a, 48%); (vi) NaOH, EtOH/
water, reflux (7b, 99%; 8b, 99%); (vii) oxalyl chloride/CCl4, reflux (7c, 8c, quant.); (iv) 4-aminotoluene/Et3N/CH2Cl2, rt (9, 71%; 10, 20%).

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Scheme 2. (i) 3c/Et3N/CH2Cl2, rt (12, 25%); (ii) 4c/Et3N/CH2Cl2, rt (13, 52%); (iii) 8c/Et3N/CH2Cl2, rt (15, 11%); (iv) 7c/Et3N/CH2Cl2, rt (16, 21%).
(Scheme 2). It is obvious, that the presence of bulky groups on
the upper rim prevents the complete condensation of both acid
chlorides at the same side of the molecule. The acid
tetrachloride can react only with two amines 11 leading thus
to derivative 16 after quenching of the reaction mixture. This
compound represents a novel type of inherent7 chirality in the
calixarene family. The symmetry of 1,3-alternate structure is
broken by a 25,26-substitution pattern which gives rise to a
chiral derivative never described in calixarene literature.8
Unfortunately, all our attempts to separate the racemate using
chiral HPLC columns (Chiralpack, Wheelk-O) failed.
troscopy (ESI-MS or FAB MS). As the synthesis started
from the conformationally immobilised compounds of
known structures, proved by one-dimensional DPFGSE-
NOE experiments,9 the conformation assignment of pro-
1
ducts was not necessary. Thus, the H NMR spectrum of
derivative 15 (Fig. 2) reflects several characteristic features
of both thiacalix[4]arene and calix[4]arene systems: (i) the
presence of two doublets due to the equatorial protons of
Ar–CH2–Ar bridging groups (3.08 and 3.12 ppm) with the
geminal coupling constant of 13.2 Hz being clear evidence
for a mono-substituted cone conformation (coming from
amine units); (ii) the presence of two singlets of amidic NH
and bridging –CO–CH2– groups at 8.28 and 4.81 ppm,
respectively; (iii) typical doublet of aromatic protons (meta)
of thiacalixarene part (7.51 ppm, J¼7.7 Hz), all in accord-
ance with proposed S4 symmetry of the whole system. The
2.2. Structure assignments and NMR study
The structures of the novel tetraamides were proved using a
combination of 1H NMR spectroscopy and mass spec-

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3386
Figure 2. 1H NMR spectrum of pentakis-calixarene 15 (300 MHz, CDCl3, 298 K).
FAB MS spectrum shows the two most intense signals at
m/z¼3090.7 and 2440.3 corresponding to the molecular
peak [Mþ1]þ and to the fragment without one calix-CO–
CH2– moiety, respectively.
usually observable only at very low temperatures,10 the
situation in the thiacalixarene series is notably different. As
we have shown in our previous study,11 this phenomenon in
Interesting behaviour was found in the case of tetraamides 6
and 13 possessing a central thiacalix[4]arene moiety in the
cone conformation without tert-butyl groups on the upper
1
rim. The H NMR spectrum of 6 measured in CDCl3 at
room temperature showed duplicate multiplicity with a
substantial line broadening indicating a dynamic process
ascribed to the pinched cone–pinched cone interconversion
(Fig. 3). It is known, that the C4v symmetry usually observed
in the NMR spectra of classical calix[4]arene cone
derivatives is a time-averaged signal due to fast chemical
exchange between the two conformers with lower C2v
symmetry.3 While the coalescence phenomenon of this
interconversion in tetraalkylated classical calix[4]arenes is
Figure 4. The partial 1H NMR spectra of 6 (500 MHz, CDCl2CDCl2):
measured at (a) 398 K; (b) 308 K; (c) 248 K.
Figure 3. Pinched cone–pinched cone interconversion of 6.

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Figure 5. The partial 1H NMR spectra of 5 (500 MHz, a,b¼CD2Cl2; c,d,e¼CD2Cl2/CD3OD¼4:1v/v): measured at (a) 298 K; (b) 203 K; (c) 203 K; (d) 183 K;
(e) 173 K; pdenotes the solvents.
the thiacalix[4]arene series exhibits much higher coales-
cence temperatures if compared with classical calixarenes.
gas constant, Dn is the chemical shift difference of the
exchanging signals at zero rate of chemical exchange).
DG#0 ¼ RTc½22:96 þ lnðTc=DnÞꢀ
ð1Þ
The conformational behaviour of tetraamide derivative 6
was studied in the range of 213–398 K using CDCl2CDCl2
as a solvent. As shown in Figure 4, a simple set of signals
corresponding to C4v symmetry (e.g., singlets at
d¼9.11 ppm (NH) and 4.92 ppm (–COCH2–)) appeared
at 398 K because of fast chemical exchange of C2v
conformers. Subsequent lowering the temperature led to
the appearance of new signals, already well visible at
ambient temperature, and corresponding to the presence of
two conformers having C2v symmetry (Fig. 4(b)).
The activation free energy DG#0¼60.5 kJ mol21
(^1 kJ mol21) computed from independent signals
(DNH¼1206 Hz, Tc¼333 K; D– COCH –¼462 Hz, Tc¼
2
323 K) and the corresponding coalescence temperatures
are the highest ever observed in the thiacalixarene series. As
the coalescence temperature of –CO–CH2– groups in
starting tetraester 4a (Tc¼263 K) is much lower, the
substitution pattern on the lower rim obviously plays an
important role in the overall energy barrier of this process.
On the other hand, the activation free energy DG#0 of
derivative 13 was found to be essentially the same as that of
6. It indicates that the presence of four calix[4]arene units in
The coalescence temperature Tc of the above exchange
process was used to calculate the activation free energy of
the process by means of the Eq. 1 (where R is the universal

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3388
the amidic part of the molecule has almost no influence on
the dynamics of the whole system.
Zeiss Jena, Germany) and are not corrected. The IR spectra
were measured on an FT-IR spectrometer Nicolet 740 in
CHCl3 and/or in KBr. 1H NMR spectra were recorded on a
Varian Gemini 300 spectrometer, the temperature depen-
dant spectra were recorded on a Bruker AMX3 400 and
Bruker DRX 500 Avance spectrometers using tetramethyl-
silane as an internal standard. Dichloromethane and CCl4
used for the reaction were dried with CaH2 and P2O5,
respectively, and stored over molecular sieves. The purity of
the substances and the courses of reactions were monitored
by TLC using TLC aluminium sheets with Silica gel 60 F254
(Merck). Preparative TLC chromatography was carried out
on 20£20 cm glass plates covered by Silica gel 60 GF254
(Merck).
The temperature-dependent NMR study on derivative 5
revealed a dramatic influence of the tert-butyl groups on the
dynamic behavior of thiacalixarenes. The spectra measured
in CDCl2CDCl2 corresponded to C4v symmetry in the whole
temperature range with considerable line broadening at the
lowest temperatures (<213 K) indicating additional motion.
Surprisingly, the low temperature 1H NMR in CD2Cl2
reflected unexpected asymmetry of the system. Figure 5(a)
and (b) shows the situation where the originally simple
spectrum (room temp.) gradually becomes very complicated
at 203 K. Obviously, the singlet of the OCH2– group at
4.95 ppm is split into at least eight new signals at low
temperature, and the same tendency is well observable for
all other signals. As the exact assignment of spectrum is
extremely difficult we can only speculate that this
phenomenon corresponds to the formation of asymmetric
hydrogen bonding array(s) on the lower rim (amidic
functions), probably with simultaneous appearance of the
pinched cone interconversion. This assumption is further
supported by the fact that addition of CD3OD into the
sample leads to the interruption of hydrogen bonds array
and to the reappearance of proposed C2 symmetry at lower
temperature (Fig. 5(c)). The coalescence temperature
(213 K) corresponds to the activation free energy
DG#0¼38^1 kJ mol21 as computed from the NH signals.
While the NH signals (2 singlets) and the aromatic part of
spectrum (6 signals) exactly reflect the proposed C2
symmetry at 290 8C (Fig. 5(d)), the CH2 region surprisingly
reveals another coalescence phenomenon. This is clearly
apparent at 2100 8C (Fig. 5(e)) where several novel signals
appeared if compared with original C2 symmetry (desig-
nated by arrows).
Starting esters 3a, 4a, 7a and 8a were prepared according to
known procedures12 by the reaction of 1 and 2 with ethyl
bromoacetate in boiling acetone in the presence of Na2CO3
or Cs2CO3.
It is known that the elemental analyses of the calixarene
derivatives are sometimes ambiguous.13 The EA usually
resulted in C values 1–3% lower than the calculated values.
There are two possible and widely accepted explanations: (i)
cavity-possessing compounds contain the molecules of
solvents/reagents which are extremely difficult to eliminate;
(ii) the incomplete combustion of these high-melting
compounds under the standardized conditions of the
elemental analysis. We believe that the structures of the
calixarenes are sufficiently documented by the spectral
evidence or by the subsequent chemical transformations.
3.1.1. Synthesis of 5,11,17,23-tetra-tert-butyl-
25,26,27,28-tetrakis(carboxymethoxy)-2,8,14,20-tetra-
thia-calix[4]arene (cone) 3b. Tetraester 3a (2.0 g,
1,88 mmol) was dissolved in 150 ml of EtOH and a solution
of NaOH (1.5 g, 37.5 mmol) in 10 ml of distilled water was
added. The reaction mixture was stirred for 6 days at reflux.
Ethanol was then removed on vacuum evaporator, the
residue was dissolved in water and acidified by 1 M HCl.
The white precipitate was collected by filtration and dried in
vacuum to yield the title compound in quantitative yield.
Mp 333–334 8C (lit.14 mp 293.4–294.8 8C). 1H NMR
(CDCl3, 300 MHz) d: 7.40 (s, 8H, H-arom), 5.03 (s, 8H,
–O–CH2–CO–), 1.12 (s, 36H, But). IR (KBr) nmax (cm21):
1758 (CvO), 3462 (O–H). MS-ESI m/z¼975.1 [MþNa]þ.
As the cone tetraacetates are known12 for their complex-
ation ability towards alkali metal cations, we tested the
influence of sodium cation on the dynamic behaviour of
compounds 5 and 6. As expected, the addition of 2 equiv. of
Kobayashi reagent (tetrakis[3,5-bis(trifluoromethyl)-
phenyl]boron sodium) led to the formation of 1:1 complexes
with tetraamides 5 and 6. As a consequence, only the spectra
reflecting the C4v symmetry of the complex formed were
observable in CD2Cl2 with no indications of intra/inter-
molecular hydrogen bonding or pinched cone–pinched
cone interconversion down to 40 8C.
3.1.2. Synthesis of 25,26,27,28-tetrakis(carboxy-
methoxy)-2,8,14,20-tetrathiacalix[4]arene (cone) 4b.
The preparation was analogous to that described for 3b,
quantitative yield of white precipitate. Mp 287–288 8C. 1H
NMR (DMSO-d6, 300 MHz) d: 6.93 (bs, 8H, H-arom), 6.84
(t, 4H, H-arom, J¼7.14 Hz), 5.04 (s, 8H, –O–CH2–CO).
IR (KBr) nmax (cm21): 1738 (CvO). EA Calcd for
C32H24O12S4: C, 52.74; H, 3.32; S, 17.60. Found: C,
52.82; H, 3.52; S, 17.12.
In conclusion, we have shown that thiacalix[4]arene
tetraacetates can be used as a starting point in the synthesis
of multiple calixarenes connecting together ‘classical’
calixarene and thiacalixarene building blocks. These
compounds, representing a first step towards calixarene-
based dendritic structures, exhibit interesting dynamic
behaviour because of multiple hydrogen bonding
interactions.
3.1.3. Synthesis of 5,11,17,23-tetra-tert-butyl-
25,26,27,28-(carboxymethoxy)-2,8,14,20-tetrathia-
calix[4]arene (1,3-alternate) 7b. The preparation was
analogous to that described for 3b, quantitative yield of
3. Experimental
3.1. General
1
white precipitate. Mp 325–326 8C (lit.15 325–327 8C). H
NMR (CDCl3, 300 MHz) d: 7.39 (s, 8H, H-arom), 4.66 (s,
Melting points were determined on a Boetius block (Carl

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8H, –O–CH2–CO–), 1.25 (s, 36H, But). IR (KBr) nmax
(cm21): 1695 (CvO). MS-ESI m/z¼975.1 [MþNa]þ.
CH3). IR (CHCl3) nmax (cm21): 3409, 3314 (N–H), 1680
(CvO). MS-ESI m/z¼1107.2 [MþNa]þ.
3.1.4. Synthesis of 25,26,27,28-tetrakis(carboxy-
methoxy)-2,8,14,20-tetrathiacalix[4]arene (1,3-alternate)
8b. The preparation was analogous to that described
for 3b, quantitative yield of white precipitate. Mp 309–
310 8C (lit.16 290 8C (decomp.)). 1H NMR (DMSO-d6,
300 MHz) d: 7.60 (d, 8H, H-arom, J¼7.69 Hz), 6.81 (t, 4H,
H-arom, J¼7.14 Hz), 4.53 (s, 8H, –O–CH2–CO–). IR
(KBr) nmax (cm21): 1743 (CvO). MS-ESI m/z¼751.0
[MþNa]þ.
3.2.4. Synthesis of 5,11,17,23-tetra-tert-butyl-
25,26,27,28-tetrakis[(4-methylphenyl)carbamoyl-meth-
oxy]-2,8,14,20-tetrathiacalix[4]arene (1,3-alternate) 9.
The reaction was carried out analogously to the procedure
described for 5 using tetrachloride 7c as starting compound.
The crude product was purified by precipitation from
CHCl3/methanol mixture to yield derivative 9 (71%) as a
1
white powder with mp 295–296 8C (CHCl3–MeOH). H
NMR (CDCl3, 300 MHz) d: 8.45 (s, 4H, –NH), 7.47 (s, 8H,
H-arom), 7.40 (d, 8H, J¼8.2 Hz, H-arom), 7.15 (d, 8H,
J¼8.8 Hz, H-arom), 4.86 (s, 8H, –O–CH2–CO–), 2.32 (s,
12H, Ar-CH3), 0.70 (s, 36H, But). IR (CHCl3) nmax (cm21):
3394, 3283 (N–H), 1679 (CvO). EA Calcd for
C76H84N4O8S4: C, 69.69; H, 6.46; N, 4.28; S, 9.79; C,
69.66; H, 6.55; N, 3.78; S, 10.19.
3.2. Synthesis of model compounds
3.2.1. Preparation of acid chloride. A mixture of tetraacid
(76 mmol) and (COCl)2 (0.13 ml; 1.52 mmol) in 5 ml of
anhydrous CCl4 was stirred under reflux for 3 h (3c) to 3
days (8c). The end of reaction was indicated by the
formation of the clear yellowish solution. The solvent and
the residual oxalyl chloride were distilled off, the residue
was treated with anhydrous CH2Cl2 (5 ml) and the solvent
was again evaporated under reduced pressure. The resulting
solid was then dried in a vacuum (5 Torr) for 2 h to yield the
corresponding acyl chlorides 3c, 4c, 7c, and 8c in almost
quantitative yield. These reactive intermediates were used
in the next step without subsequent characterisation and
purification.
3.2.5. Synthesis of 25,26,27,28-tetrakis[(4-methyl-phe-
nyl)-carbamoylmethoxy]-2,8,14,20-tetrathia-calix[4]-
arene (1,3-alternate) 10. The reaction was carried out
analogously to the procedure described for 5 using
tetrachloride 8c as starting compound. The crude product
was purified by preparative TLC chromatography on silica
gel using CHCl3 as eluent to yield derivative 10 (20%) as a
beige solid with mp 256–257 8C (CHCl3–MeOH). 1H
NMR (CDCl3, 300 MHz) d: 8.22 (s, 4H, –NH), 7.53 (d, 8H,
J¼7.7 Hz, H-arom), 7.28 (d, 8H, J¼8.8 Hz, H-arom), 7.17
(d, 8H, J¼8.2 Hz, H-arom), 6.56 (t, 4H, J¼7.7 Hz, H-arom),
4.95 (s, 8H, –O–CH2–CO–), 2.35 (s, 12H, Ar-CH3). IR
(CHCl3) nmax (cm21): 3388, 3298 (N–H), 1686 (CvO).
MS-ESI m/z¼1107.2 [MþNa]þ.
3.2.2. Synthesis of 5,11,17,23-tetra-tert-butyl-
25,26,27,28-tetrakis[(4-methylphenyl)carbamoyl-meth-
oxy]-2,8,14,20-tetrathiacalix[4]arene (cone) 5. A solution
of 4-aminotoluene (0.11 g, 1.05 mmol) in 5 ml of dry DCM
was added dropwise at room temperature to a stirred
solution of tetrachloride 3c (0.215 g, 0.21 mmol) and Et3N
(0.3 ml, 2.1 mmol) in 5 ml of dry DCM. The reaction
mixture was stirred overnight and the solvent was removed
in a reduced pressure. The residue was dissolved in CHCl3
(30 ml) and washed with 1 M HCl and then with water. The
separated organic layer was dried over MgSO4. The volume
of solution was reduced to 5 ml and product (190 mg, 88%)
was obtained by precipitation with methanol as beige solid
3.2.6. Synthesis of pentakis-calixarene 12. A solution of
aminocalixarene 11 (75 mg, 0.123 mmol) in 3 ml of dry
CH2Cl2 was added at room temperature under a nitrogen
atmosphere to a stirred solution of tetrachloride 3c
(24.6 mg, 0.024 mmol) and Et3N (0.1 ml, 0.72 mmol) in
3 ml of dry CH2Cl2. The reaction mixture was stirred for
22 h and the solvent was distilled off. The residue was
dissolved in CHCl3 (20 ml) and thoroughly washed with
1 M HCl. The organic layer was separated and the aqueous
layer was extracted twice with small amount of CHCl3. The
collected organic layers were dried over MgSO4 end
evaporated to dryness. The residue was purified by repeated
preparative TLC on silica gel using CHCl3–ethyl
acetate¼250:1 and petroleum-ether–CHCl3¼5:1 mixtures
as eluents. The title compound was obtained as yellowish
powder (20 mg, 25%) with mp 195–196 8C (CHCl3–
MeOH). 1H NMR (CDCl3, 300 MHz) d: 9.12 (s, 4H,
–NH), 7.39 (s, 8H, H-arom), 7.06 (s, 8H, H-arom), 6.66–
6.38 (m, 36H, H-arom), 4.98 (s, 8H, –O–CH2–CO–), 4.41,
4,30 (2d, 16H, J¼13.5 Hz, Ar-CH2-Ar ax.), 3.84–3.73 (m,
32H, –O–CH2–CH2–), 3.09, 3.01 (2d, 16H, J¼13.2 Hz,
Ar-CH2-Ar eq.), 1.90–1.80 (m, 32H, –CH2–CH3), 1.14 (s,
36H, But), 1.20–0.90 (m, 48H, –CH2–CH3). IR (CHCl3)
nmax (cm21): 3308 (N–H), 1678 (CvO). MS-ESI
1
with mp 272–273 8C (CHCl3–MeOH). H NMR (CDCl3,
300 MHz) d: 9.28 (s, 4H, –NH), 7.43 (d, 8H, H-arom,
J¼8.2 Hz), 7.38 (s, 8H, H-arom), 6.97 (d, 8H, H-arom,
J¼8.2 Hz), 4.95 (s, 8H, –O–CH2–CO–), 2.24 (s, 12H, Ar-
CH3), 1.13 (s, 36H, But). IR (CHCl3) nmax (cm21): 3307
(N–H), 1678 (CvO). EA Calcd for C76H84N4O8S4: C,
69.69; H, 6.46; N, 4.28; S, 9.79. Found: C, 70.41; H, 6.75;
N, 4.32; S, 10.23.
3.2.3. Synthesis of 25,26,27,28-tetrakis[(4-methyl-phe-
nyl)-carbamoylmethoxy]-2,8,14,20-tetrathia-calix[4]-
arene (cone) 6. The reaction was carried out analogously to
the procedure described for 5 using tetrachloride 4c as
starting compound. The crude product was purified by
preparative TLC chromatography on silica gel using
CHCl3–acetone (10:1) mixture to yield derivative 6
1
(41%) as a white powder with mp 289–290 8C. H NMR
m/z¼3335.2 [MþNa]þ, 1679,5 [Mþ2Na]2þ
.
(CDCl2–CDCl2, 135 8C, 500 MHz) d (ppm): 9.11 (s, 4H,
–NH), 7.52 (d, 8H, J¼7.2 Hz, H-arom), 7.20 (brd, 8H,
H-arom), 7.07 (d, 8H, J¼7.3 Hz, H-arom), 6.92 (t, 4H,
H-arom), 4.92 (s, 8H, –O–CH2–CO–), 2.32 (s, 12H, Ar-
3.2.7. Synthesis of pentakis-calixarene 13. Reaction was
carried out analogously to the procedure described for 12
using tetrachloride 4c as starting compound. The product

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3390
J., Tomalia, D. A., Eds.; Wiley: London, 2001. (d) Recent
Developments in Dendrimer Chemistry, Special Issue of
Tetrahedron, 2003, 59(22), 3787–4024.
was obtained as a beige solid (52%) after preparative TLC
chromatography on silica gel using CHCl3 as an eluent. Mp
197–199 8C (CHCl3–MeOH). H NMR (CDCl2–CDCl2,
1
135 8C, 500 MHz) d: 8.58 (s, 4H, –NH), 6.84 (s, 8H,
H-arom), 6.24–6.52 (m, 36H, H-arom), 4.68 (s, 8H, –O–
CH2–CO–), 4.34, 4.26 (2d, 16H, J¼13.5 Hz, Ar-CH2-Ar
ax.), 3.71 (m, 32H, O–CH2–CH2–), 3.00, 2.92 (2d, 16H,
J¼13.2 Hz, Ar-CH2-Ar eq.), 1.85–1.95 (m, 32H, –CH2–
CH3), 0.80–1.00 (m, 48H, –CH2–CH3). IR (CHCl3) nmax
(cm21): (N–H), (CvO). MS-ESI (CH3CN) m/z¼3111
2. Kumagai, H.; Hasegawa, M.; Miyanari, S.; Sugawa, Y.; Sato,
Y.; Hori, T.; Ueda, S.; Kamiyama, H.; Miyano, S. Tetrahedron
Lett. 1997, 38, 3971–3972.
3. For books on calixarenes see: (a) In Calixarenes 2001; Asfari,
¨
Z., Bohmer, V., Harrowfield, J., Vicens, J., Eds.; Kluwer
Academic: Dordrecht, 2001. (b) In Calixarenes in action;
Mandolini, L., Ungaro, R., Eds.; Imperial College: London,
2000. (c) Gutsche, C. D. In Calixarenes revisited. Monographs
in supramolecular chemistry; Stoddart, J. F., Ed.; The Royal
Society of Chemistry: Cambridge, 1998; Vol. 6. (d) In
Calixarenes 50th aniversary: commemorative issue; Vicens,
J., Asfari, Z., Harrowfield, J. M., Eds.; Kluwer Academic:
Dordrecht, 1994. (e) In Calixarenes: a versatile class of
[MþNa]þ, 1567 [Mþ2Na]2þ
.
3.2.8. Synthesis of pentakis-calixarene 15. The reaction
was carried out analogously to the procedure described for
12 using tetrachloride 8c as starting compound. The product
was obtained as a white solid (11%) after repeated
preparative TLC chromatography on silica gel using
CHCl3 and then petroleum-ether–ethyl acetate¼10:1 as
an eluent. Mp 214–216 8C (CHCl3–MeOH). 1H NMR
(CDCl3, 300 MHz) d: 8.28 (s, 4H, –NH), 7,51 (d, 8H,
J¼7.7 Hz, H-arom), 6.79 (s, 8H, H-arom), 6.65–6.50 and
6.32 (2m, 40H, H-arom), 4.81 (s, 8H, –O–CH2–CO–),
4.43 (d, 16H, J¼13.2 Hz, Ar-CH2-Ar ax.), 3.86–3.71 (m,
32H, O–CH2–CH2–), 3.12, 3.08 (2d, 16H, J¼13.2 Hz, Ar-
CH2-Ar eq.), 1.90 (m, 32H, –O–CH2–CH2–), 0.99 (m,
48H, CH2–CH3). IR (CHCl3) nmax (cm21): 3399, 3288
(N–H), 1677 (CvO). MS-FAB m/z (int.%)¼3090.7
(100%) [MH]þ, 2440.3 (98%) [M2(calix-CO–CH2–)]þ.
¨
macrocyclic compounds; Vicens, J., Bohmer, V., Eds.; Kluwer
Academic: Dordrecht, 1991.
4. For recent reviews on thiacalixarenes see: (a) Iki, N.; Miyano,
S. J. Inclusion Phenom. Macrocycl. Chem. 2001, 41, 99–105.
(b) Hosseini, M. W. Calixarenes 2001; 2001; pp 110–129.
(c) For books on calixarenes see: (a). In Calixarenes 2001;
¨
Asfari, Z., Bohmer, V., Harrowfield, J., Vicens, J., Eds.;
Kluwer Academic: Dordrecht, 2001. (d) Morohashi, N.; Iki,
N.; Miyano, S. J. Synth. Org. Chem. Jpn 2002, 60, 550–561,
(in Japanese). (e) Iki, N.; Miyano, S. Nippon Kagaku Kaishi
2001, 11, 609–622, (in Japanese). (f) Shokova, E. A.;
Kovalev, V. V. Russian J. Org. Chem. 2003, 39, 1–28.
(g) Lhotak, P. Eur. J. Org. Chem. 2004, in press.
3.2.9. Synthesis of tris-calixarene 16. Reaction was carried
out analogously to the procedure described for 12 using
tetrachloride 7c as starting compound. The product was
obtained as a white solid (21%) after several times repeated
preparative TLC chromatography on silica gel (CHCl3–
acetone¼50:1, petroleum-ether–ethyl acetate¼5:2). Mp
206–208 8C (CHCl3–MeOH). 1H NMR (CDCl3,
300 MHz) d: 8.60 (s, 2H, –NH), 7.70 (d, 2H, J¼2.8 Hz,
H-arom), 7.54 (d, 2H, J¼2.2 Hz, H-arom), 7.33 (d, 2H,
J¼2.2 Hz, H-arom), 7.19 (d, 2H, J¼2.2 Hz, H-arom), 6.80
(d, 4H, J¼7.7 Hz, H-arom), 6.59 (t, 2H, J¼7.4 Hz, H-arom),
6.44–6.39 (m, 16H, H-arom), 4.71, 4.58, 4.37, 4.22 (4d, 8H,
–O–CH2–CO–), 4.46, 4.42 (2d, 8H, Ar-CH2-Ar), 3,95–
3,71 (m, 16H, O–CH2–CH2–), 3.17, 3.13 (2d, 8H, Ar-CH2-
Ar), 1.88 (m, 16H, –CH2–CH3), 1.20, 1,13 (2s, 36H, But),
1.09–0.92 (m, 24H, CH2–CH3). IR (CHCl3) nmax (cm21):
3451, 3387, 3302 (N–H), 1786 (CvO). MS-FAB
m/z¼2131.5 [Mþ].
5. (a) Iki, N.; Narumi, F.; Fujimoto, T.; Morohashi, N.; Miyano,
S. J. Chem. Soc., Perkin Trans. 2 1998, 2745–2750. (b) Akdas,
H.; Mislin, G.; Graf, E.; Hosseini, M. W.; DeCian, A.; Fischer,
´
J. Tetrahedron Lett. 1999, 40, 2113–2116. (c) Lhotak, P.;
´ ´
Stastny, V.; Zlatuskova, P.; Stibor, I.; Michlova, V.;
´
Tkadlecova, M.; Havlicek, J.; Sykora, J. Collect. Czech.
Chem. Commun. 2000, 65, 757–771.
6. For multicalixarenes or dendritic structures based on
´
calixarenes see e.g.: (a) Lhotak, P.; Shinkai, S. Tetrahedron
1995, 51, 7681–7696. (b) Mogck, O.; Parzuchowski, P.;
¨
Nissinen, M.; Bohmer, V.; Rokicki, G.; Rissanen, K.
´
Tetrahedron 1998, 54, 10053–10068. (c) Lhotak, P.;
Kawaguchi, M.; Ikeda, A.; Shinkai, S. Tetrahedron 1996,
´
52, 12399–12408. (d) Budka, J.; Dudic, M.; Lhotak, P.;
Stibor, I. Tetrahedron 1999, 55, 12647–12654. (e) Szemes, F.;
Drew, M. G. B.; Beer, P. D. Chem. Commun. 2002,
1228–1229. (f) Xu, H.; Kinsel, G. R.; Zhang, J.; Li, M.;
Rudkevich, D. M. Tetrahedron 2003, 59, 5837–5848.
¨
7. (a) Bohmer, V.; Kraft, D.; Tabatabai, M. J. Inclusion Phenom.
1994, 19, 17–39. (b) Otsuka, H.; Shinkai, S. Supramol. Sci.
¨
1996, 3, 189–205. (c) Vysotsky, M.; Schmidt, C.; Bohmer, V.
Acknowledgements
Advances in supramolecular chemistry; 2000; Vol. 7. pp 139–
233. (d) Yamakawa, Y.; Ueda, M.; Nagahata, R.; Takeuchi,
K.; Asai, M. J. Chem. Soc., Perkin Trans. 1 1998, 4135–4139.
(e) Haba, O.; Haga, K.; Ueda, M.; Morikawa, O.; Konishi, H.
Chem. Mater. 1999, 11, 427–432.
We thank the Grant Agency of the Czech Republic for
financial support (No. 203/03/0926).
8. Similar dissymetrisation of a 1,3-alternate skeleton via the
upper rim was described: Sharma, S. K.; Gutsche, C. D. J. Org.
Chem. 1999, 64, 3507–3512.
References and notes
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´ ˇ´ ´
9. Dudic, M.; Lhotak, P.; Stibor, I.; Dvorakova, H.; Lang, K.
¨
Moorefield, C. N.; Vogtle, F. Dendritic molecules; VCH:
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¨
Vogtle, F. Dendrimers and dendron; VCH: Weinheim, 2001.
(c) In Dendrimers and other dendritic polymers; Frechet, J. M.

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´
´ ´
(b) Lhotak, P.; Himl, M.; Stibor, I.; Sykora, J.; Dvorakova, H.;
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Lang, J.; Petrickova, H. Tetrahedron 2003, 59, 7581–7585.
´ ´
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´
V.; Tkadlecova, M.; Havlicek, J.; Sykora, J. Collect. Czech.
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¨ ¨
13. (a) Bohmer, V.; Jung, K.; Schon, M.; Wolff, A. J. Org. Chem.