Monosubstituted lower rim thiacalix[4]arene derivatives

Article abstract of DOI:10.1016/j.tetlet.2012.02.037

A clean and partially green route to monoalkyled thiacalix[4]arenes has been demonstrated. We have discovered that tetraalkylammonium halide can cleave selectively one of the two aryl alkyl ethers of dialkylated para-tert- butylthiacalix[4]arenes. Thus, p-tert-butyl thiacalix[4]arenes differently monoalkyled at the lower rim with acetyl, propyl, and benzyl group were synthesized in good yield.

Full text of DOI:10.1016/j.tetlet.2012.02.037

Tetrahedron Letters 53 (2012) 2088–2090
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Tetrahedron Letters
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Monosubstituted lower rim thiacalix[4]arene derivatives
Meriem Lamouchi a,b, Erwann Jeanneau a, Rodica Chiriac a, Didier Ceroni a, Faouzi Meganem b,
Arnaud Brioude a, Anthony W. Coleman a, Cédric Desroches a,
⇑
a Laboratoire des Multimatériaux et Interfaces (UMR 5615), Université Claude Bernard Lyon1, Campus de La Doua, 69622 Villeurbanne Cedex, France
b Laboratoire de Synthèse Organique, Faculté de Sciences de Bizerte, Jarzouna, 7021 Bizerte, Tunisia
a r t i c l e i n f o
a b s t r a c t
Article history:
A clean and partially green route to monoalkyled thiacalix[4]arenes has been demonstrated. We have
discovered that tetraalkylammonium halide can cleave selectively one of the two aryl alkyl ethers of
dialkylated para-tert-butylthiacalix[4]arenes. Thus, p-tert-butyl thiacalix[4]arenes differently monoalky-
led at the lower rim with acetyl, propyl, and benzyl group were synthesized in good yield.
Ó 2012 Elsevier Ltd. All rights reserved.
Received 14 December 2011
Revised 2 February 2012
Accepted 8 February 2012
Available online 15 February 2012
Keywords:
Thiacalix[4]arene
Synthesis
Disubstitution
Monosubstitution
Solid state structure
In 1997 Miyano et al. described the first synthesis of para-
tert-butylthiacalix[4]arene, with sulfur atom bridges between the
phenolic units instead of the CH2 groups.1 Their ease of preparation
and their high potential for numerous applications has increased
the popularity of this class of macrocycles.2 The first investigations
on the chemistry of thiacalix[4]arenes concerned essentially
modifications at the lower rim. The Williamson synthesis of ethers,
using alkyl halides and a base, is general and the commonly used
derivatization for such modifications of thiacalixarenes. Depending
on reaction conditions and the ratio of thiacalixarenes to alkylation
reagent and base, the reaction provides essentially 1,3-di or tetra-
substituted products. Dialkylation of thiacalixarenes leads nor-
mally to distally (1,3-)di-substituted products.3 Nevertheless, a
few reactions relate to the synthesis of mono or tri substituted
macrocycles.4 Initially, we carried out a study on the mono-
alkylation of thiacalix[4]arenes using alkyl halides. In this Letter,
we report a general synthetic method with several alkyl halides
to obtain in high yield monoalkyled thiacalix[4]arenes.
of the base was studied. Several types of bases were studied
including carbonate, bicarbonate alkaline salts, fluoride, basic
oxides (Al2O3).
The proportion of base to macrocycle has been varied from 0.1 to
10. Each reaction was followed by silica gel TLC with tetraalkylated
and dialkylated para-tert-butylthiacalix[4]arenes as references.
Even at low ratios of bases/macrocycle it was difficult to observe
other products than the di or tetra-substituted. Indeed all these
tests yielded either the di-alkylated compound, or a varied mixture
of tetra, dialkylated, and non-substituted para-tert-butylthiaca-
lix[4]arene. Of this set of manipulation, one was to be retained.
With KF as the base and an excess of alkyl halide, in contrast to
the reaction on calix[4]arene which leads to monoalkylated deriva-
tives,5 only the 25,27-dialkyoxy compound is obtained. This repre-
sents a very simple method for a high yield synthesis of the 25,27-
dialkyoxy thiacalix[4]arenes.
In further investigations to obtain monoalkylated thiacalixa-
renes, other classes of bases were investigated. Initially our at-
tempts at the preparation of mono-substituted thiacalixarene
using various amine bases, mixture of dialkyled products, and
starting materials were isolated. However after prolonged stirring
of the reaction mixture, the 25,27-dialkyoxy product disappeared
and mono-substituted thiacalixarene was obtained. After different
trials, it was shown that treatment of the mixture of 25,27-dialky-
oxy thiacalixarene with tetraalkylammonium chloride or bromide
salts in a polar solvent such as DMF yields the mono-alkylated
thiacalixarene (70–95%). Excess of tetrabutylammonium increased
the reaction speed (Scheme 1). Suitable tetraalkylammonuim
halides can be used as both reagent and solvent (at a temperature
This study initially used ethyl 2-bromoacetate as the alkyl-
ation reagent. O-alkylation by ethyl 2-bromoacetate is of partic-
ular interest as the ester function introduced is
a versatile
starting unit for further modifications: hydrolysis, aminolysis,
reduction to aldehydes and alcohols, preparation of acylchlo-
rides. The general synthesis uses various ratios of thiacalixa-
renes/ethyl 2-bromoacetate/alkaline carbonate salts in refluxing
acetone. So, in the first place only the nature and proportion
⇑
Corresponding author. Tel.: +33 472448166; fax: +33 472440618.
E-mail address: cedric.desroches@univ-lyon1.fr (C. Desroches).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2012.02.037

M. Lamouchi et al. / Tetrahedron Letters 53 (2012) 2088–2090
2089
Scheme 1. Synthesis of di and mono-substituted thiacalixarene.11,12
superior to the melting point of the salt). With per-O-tetra-alkyl-
ated thiacalixarene the reaction does not occur. A hypothesis about
these unexpected reactions can be given. It is well-know that the
high nucleophilicity of halide ions can be used for the nucleophilic
displacement of an alkyl group to regenerate phenol from the
corresponding aryl alkyl ether.6 Nucleophilic substitution reactions
are solvent dependent, so our reaction media, melting salt, or
dimethylformamide, allow obtention of the enhanced halide nucle-
ophilicity necessary for the selective removal of one substitution
group from dialkylated thiacalixarene.7 Moreover, a driving-force
could be the symbiotic phenomena between soft base (thiacalixa-
rene) and soft acid (tetrabutylammonium).8
Figure 1. Structure of 1a complex (left) and a view demonstrating intramolecular
hydrogen bonds (right). Hydrogen atoms are omitted for clarity.10
The salt is stable and the addition of acidic reagent is necessary
to reprotonate the phenolate group. Different alkylammonium
halide salts have been tested with more and less efficiencies. The
best salt is tetraalkylammonium (ethyl, propyl or butyl) chloride
or bromide. This reaction has been validated with other 25,27-dial-
kyoxy thiacalixarene (Table 1).
The structure of compound 1a was solved using single crystal X-
ray diffraction. Suitable crystals for diffraction were obtained by
slow diffusion of methanol into a dichloromethane solution of
1a.10 The compound is obtained as the tetrabutylammonium salt.
The conformation is a distorted pinched cone. The phenolate anion
is stabilized by a strong hydrogen bond (dH91-O4 = 1.70 Å, dH331-
O4 = 1.79 Å; (O9-H31-O4) = 170°, (O33-H331-O4) = 164°) (Fig. 1).
Another interesting feature of the derivative 1a complex is repre-
sented by its molecular packing. Figure 2a shows that along the c
axis they pack as anti-parallel columns and along the b-axis as
head to head to bilayers, with the polar O substituents forming
the interior of the bilayers. The presence of the tert-butyl head
groups precludes insertion of the short alkyl chains into the
macrocylic cavity as observed for the de-tert-butyl-calix[4]arene
analogues.9 The integrity of the structure is assured by two
CH(ammonium)–O(phenolic) contacts and one bifurcated
CH(ammonium)–S.
Figure 2. Crystal packing of 1a complex: (a) view along the c-axis, and (b) view
along the b-axis. Tetrabutylammonium cations are omitted for clarity. Each atom is
depicted as follows: S, yellow; O, red; C, gray.
In conclusion, a clean and partially green route to monoalkylat-
ed thiacalix[4]arenes has been demonstrated. Work is underway to
extend the studies to acylated analogues.
Acknowledgments
Table 1
De-alkylation of dialkylated thiacalix[4]arenes using the tetraBuCl/DMF system
The structure measurements were performed at the ‘Centre de
Diffractométrie Longchambon’ of the University of Lyon. The
authors thank R. Vera for performing the X-ray diffraction analysis.
We thank F. Albrieux, C. Duchamp and N. Henriques from the
Centre Commun de Spectrométrie de Masse (ICBMS UMR-5246),
Compounds
Y
Ri
Yield (%)
1a
1b
2
tBu
H
tBu
tBu
–CH2COOEt
–CH2COOEt
–CH2–C6H5–
–CH2CH2CH3
95
71
78
75
3

2090
M. Lamouchi et al. / Tetrahedron Letters 53 (2012) 2088–2090
The yellow solution was stirred for 6 h at 120 °C and hydrolyzed with 1 M HCl
solution (50 mL). The resulting precipitate was filtered and was taken up in
CHCl3 (50 mL). The organic phase was extracted and washed with water
(50 mL) and with brine (50 mL). The organic layer was dried over MgSO4, and
the solvent was evaporated. The product was obtained by precipitation from
methanol. Recrystallization from acetone gave pure 25-monoalkylated
thiacalix[4]arene (70–95%) as white powder.
Method B: A mixture of dialkylated thiacalix[4]arenes TTBi or TDBi (4.82 mmol)
and tertrabutylammonium chloride or bromide (14 mmol) was dissolved in
minimum of CH2Cl2 to give solution. CH2Cl2 was removed and the solid was
heated at 120 °C during 6 h. The mixture was taken up in CHCl3 (50 mL). The
organic phase was extracted and washed with water (50 mL) and with brine
(50 mL). The organic layer was dried over MgSO4, and the solvent was
evaporated. The product was obtained by precipitation from methanol.
Recrystallization from acetone gave pure 25-monoalkylated thiacalix[4]arene
(70–95%) as white powder.
Synthesis of 5,11,17,23-tetra-tert-butyl-25-(ethoxycarbonyl)methoxy-2,8,14,20-
tetrathiacalix[4]arene (1a): mp: 320 °C. 1H NMR (300 MHz, CDCl3): dH (ppm):
9.53 (s, 2H, –OH), 9.23 (s, 1H, –OH), 7.58 (2s, 2H, Ar), 7.62 (m, 6H, Ar), 5.21 (s,
2H, –O–CH2), 4.45 (q, 2H, J = 7.05 Hz, –O–CH2–CH3), 1.42 (t, 3H, J = 7.3Hz, –
CH2–CH3), 1.22 (s, 9H, C–CH3), 1.21 (s, 18H, C–CH3), 1.18 (s, 9H, C–CH3) 13C
NMR (75 MHZ, CDCl3.): dC (ppm) 169.6 (O@C–O), 158.06 (Ar C–O–Acetate),
157.7, 156.73 (Ar C–OH), 137.12, 136.5, 136.27(Ar CH), 128.47 (Ar C–S), 121.65,
121.07, 121.02 (Ar C–tertbutyl), 72.47 (Ar-O–CH2), 62.02 (O–CH2–C), 34.75,
34.45, 34.4 (tert-butyl C), 31.6, 31.57, 31.33 (tert-butyl CH3),14.66 (–CH3). IR
mmax (cmÀ1) 3332, 2958, 1751, 1447, 1211, 1095, 893, 743, 553 (s). MS-ESI:
calcd for C44H54O6S4: 806, found ESI (+) m/z = 807 [M+H]+,1635.5[2M+Na]+;
ESI(-) 805[MÀH]À.
for the assistance and access to the Mass Spectrometry facilities.
We thank Pr. Parola S. for his joviality.
References and notes
1. Kumagai, H.; Hasegawa, M.; Miyanari, S.; Sugawa, Y.; Sato, Y.; Hori, T.; Ueda, S.;
Kamiyama, H.; Miyano, S. Tetrahedron Lett. 1997, 8, 3971–3972.
2. For review on thiacalixarenes: (a) Morohashi, N.; Narumi, F.; Iki, N.; Hattori, T.;
Miyano, S. Chem. Rev. 2006, 106, 5291–5316; (b) Iki, N.; Miyano, S. J. Inclusion
Phenom. Macrocyclic Chem. 2001, 41, 99–105; (c) Hosseini, M. W. Calixarenes
2001, 110–129; (d) Shokova, E. A.; Kovalev, V. V. Russ. J. Org. Chem. 2003, 39, 1–
28; (e) Parola, S.; Desroches, C. C. Czech. Chem. Commun. 2004, 69, 966–983; (f)
Lhotak, P. Eur. J. Org. Chem. 2004, 1675–1692.
3. (a) Iki, N.; Narumi, F.; Fujimoto, T.; Morohashi, N.; Miyano, S. J. Chem. Soc.,
Perkin Trans. 1 1998, 2745–2750; (b) Akdas, H.; Mislin, G.; Graf, E.; Hosseini, M.
W.; DeCian, A.; Fisher, J. Tetrahedron Lett. 1999, 40, 2113–2116; (c) Iki, N.;
Morohashi, N.; Narumi, F.; Fujimoto, T.; Suzuki, T.; Miyano, S. Tetrahedron Lett.
1999, 40, 7337–7341; (d) Didic, M.; Lhotak, P.; Stibor, I.; Dvorakova, H.; Lang, K.
Tetrahedron 2002, 58, 5475–5482; (e) Himl, M.; Pojarova, M.; Stibor, I.; Korab, J.
S.; Lhotak, P. Tetrahedron Lett. 2005, 46, 461–464.
4. (a) Kovalev, V.; Shokova, E.; Vatsouro, I.; Khomich, E.; Motomaya, A.; SL14,
CALIX 8th International Conference on Calixarenes, Prague, 25–29 July 2005.;
(b) Antipin, I. S.; Stoikov, I. I.; Solovieva, S. E.; Konovalov, A. I.; P6, CALIX 8th
International Conference on Calixarenes, Prague, 25–29 July 2005.; (c) Kon, N.;
Iki, N.; Sano, Y.; Ogawaa, S.; Kabutob, C.; Miyano, S. Collect. Czech. Chem.
Commun. 2004, 69, 1080–1096; (d) Omran, A. O. Molecules 2009, 14, 1755–
1761; (e) Zhang, C.-L.; Jin, Y.; Gong, S.-L.; Zhang, X.-F.; Chen, Y.-Y. J. Chem. Res.
2006, 9, 596–599.
Synthesis of 25-(ethoxycarbonyl)methoxy-2,8,14,20-tetrathiacalix[4]arene (1b):
mp: 219 °C 1H NMR (300 MHz, CDCl3): dH (ppm) 9.04 (m, 3H, –OH), 7.6 (m, 6H,
Ar), 7.51 (m, 2H, Ar), 6.92 (t, 1H, Ar), 6.7(m, 3H, Ar), 5.21 (s, 2H, –O–CH2), 4.46
(q, 2H, J = 7.2 Hz –O–CH2–CH3), 1.445 (t, 3H, J, –CH2–CH3). 13C NMR (75 MHZ,
CDCl3.): dC (ppm) 169.09 (O@C–O), 159.89 (Ar C–O-Acetate), 158.77, 158.08
(Ar C–OH), 139.22,138.55, 138.39 (Ar CH), 128.83 (Ar C–S), 126.57, 121.52,
121.11 (Ar C–H), 72.24 (Ar-O–CH2–), 61.73 (O–CH2–C),14.16 (–CH3). IR mmax
(cmÀ1) 3280, 1745, 1414, 1190, 825, 730. MS-ESI: calcd for C28H22O6S4: 582;
found: ESI(+) m/z = 583 [M+H]+, 605[M+Na]+, 621[M+K].
5. Mbemba, C.; Sigaud, K.; Perret, F.; Suwinska, K.; Shkurenko, O.; Coleman, A. W.
J. Inclusion Phenom. 2008, 58, 29–40.
6. (a) Boovanahalli, S. K.; Kim, D. W.; Chi, D. Y. J. Org. Chem. 2004, 69, 3340–3344;
(b) Kemperman, G. J.; Roeters, T. A.; Hilberink, P. W. Eur. J. Org. Chem. 2003,
1681–1686.
7. Mc Mullan, R.; Jeffery, G. A. J. Chem. Phys. 1959, 31, 1231–1234.
8. (a) Pearson, R. G. Science 1966, 151, 172; (b) Pearson, R. G.; Sobel, H.; Songstad,
J. J. Am. Chem. Soc. 1968, 90, 319.
Synthesis of 5,11,17,23-tetra-tert-butyl-25-(benzoyl)methoxy-2,8,14,20-tetrathi
acalix[4]arene (2): mp: 247.8 °C 1H NMR (300 MHz, CDCl3): dH (ppm) 8.89 (s,
1H, –OH), 7.7 (m, 2H, Ar) 7.55 (m, 4H, Ar) 7.49 (m, 4H, Ar), 7.4 (m, 3H, Ar), 5.34
(s, 2H, –O–CH2), 1.12 (m, 36H, C–CH3). 13C NMR (75 MHZ, CDCl3.): dC (ppm)
157.49 (C–O–Benzyl), 156.64, 156.04, (Ar C–OH), 136.54, 135.82, 135.66(Ar C–
H), 129.4 (Ar C–S), 128.72, 128.63, 128.58(Benz C–H),122.19 (Ar C–CH2),
120.24, 120.64, 120.83 (Ar C-tertbutyl), 79.67 (O–CH2), 34.42, 34.10, 34.05
9. Suwinska, K.; Shkurenko, O.; Mbemba, C.; Leydier, A.; Jebors, S.; Coleman, A.
W.; Matar, R.; Falson, P. New J. Chem. 2008, 32, 1988–1998.
10. Crystallographic data: C60H89N1O6S4, fw = 1048.63, monoclinic, P 1 21/c 1 (14),
a = 20.307(2) Å ꢀ, b = 13.913(9) Å ꢀ, c = 21.853(1) Å, b = 94.574(6)° 6154.49
(400) Å3, Z = 4, 14992 independent reflections, 10903 reflections were
observed (I >2.0r(I)), R1 = 0.055, wR2 = 0.166 (observed). Crystallographic
data reported in this Letter have been deposited with the Cambridge
Crystallographic Data Centre as supplementary publication No. CCDC 847210.
11. Dialkylation of thiacalixarene 10—To a suspension of thiacalix[4]arenes or
para-tert-butylthiacalix[4]arenes (5.55 mmol) and KF (34 mmol) in dry
acetone (100 mL) was added propyl iodide or benzyl bromide or ethyl 2-
bromoacetate (70 mmol). The reaction mixture was refluxed for 72 h and then
allowed to cool to room temperature. After evaporation of the solvent with a
rotary evaporator, the mixture was taken up in CHCl3 (50 mL) and washed with
1 M HCl solution (50 mL) and with brine (50 mL). The organic layer was dried
over MgSO4, and the solvent was evaporated. Recrystallization from acetone
gave pure 25,27-dialkylated thiacalix[4]arene (60–80%) as white crystals.
12. De-alkylation of 25,27-dialkyoxy thiacalix[4]arenes, Method A: A mixture of
25,27-dialkyoxy thiacalix[4]arenes (4.82 mmol) and tertrabutylammonium
chloride or bromide (14 mmol) was dissolved in 6 mL of dimethylformamide.
(tert-butyl C–), 31.74, 31.69, 31.51 (tert-butyl CH3). IR m
max (cmÀ1) 3332, 2961,
1457, 1236, 887, 746, 550. MS-ESI calcd for C47H54S4O4: 810; found ESI(+) m/
z = 811 [M+H]+, 833 [M+Na]+.
Synthesis of 5,11,17,23-tetra-tert-butyl-25-propoxy-2,8,14,20-tetrathiacalix[4]
3arene (3): mp: 247.8 °C 1H NMR (300 MHz, CDCl3): dH (ppm) 9.27 (s, 1H, –
OH), dH 9.14 (s, 1H, –OH), 7.56 (m, 4H, Ar), 7.51 (m, 4H, Ar), 4.28 (t, 2H,
J = 6.6Hz, –O–CH2), 2.139 (m, 2H CH2–CH3), 1.59 (m, 39H, –CH3). 13C NMR
(75 MHZ, CDCl3.): dC (ppm) 157.12 (Ar C–O-propyl), 149.38, 143.98 (Ar C–OH),
136.49, 136.24, 136.14 (Ar CH), 128.86 (Ar C–S), 121.28, 121.17, 120.84 (Ar C-
tertbutyl) 80.49 (O–CH2), 34.84, 34.56, 34.5 (tert-butyl C–), 31.73, 31.67, 31.48
(tert-butyl CH3), 23.53 (CH2), 10.9 (propyl CH3). IR mmax (cmÀ1) 3286, 2952,
1457, 1248, 988, 890, 743. MS-ESI calcd for C43H54S4O4: 762; found ESI (+) m/
z = 763.3 [M+H]+, 785.3[M+Na]+, ESI(-) 761.3[MÀH]À.