Unusual intramolecular bridging reaction in thiacalix[4]arene series

Article abstract of DOI:10.1021/ol901812m

Thiacalix[4]arene immobilized In the cone conformation undergoes a direct formylation reaction giving unusual products in high yields. The Duff reaction (urotropine/TFA) leads to unprecedented intramolecularly bridged compounds possessing two formyl group

Full text of DOI:10.1021/ol901812m

ORGANIC
LETTERS
2009
Vol. 11, No. 18
4188-4191
Unusual Intramolecular Bridging
Reaction in Thiacalix[4]arene Series
Ondrej Kundrat,† Hana Dvorakova,§ Ivana Cisarova,‡ Michaela Pojarova,† and
Pavel Lhotak*,†
Department of Organic Chemistry and Laboratory of NMR Spectroscopy, Prague
Institute of Chemical Technology, Technicka 6, 166 28 Prague 6, Czech Republic, and
Department of Inorganic Chemistry, Charles UniVersity, HlaVoVa 8,
128 43 Prague 2, Czech Republic
lhotakp@Vscht.cz
Received August 5, 2009
ABSTRACT
Thiacalix[4]arene immobilized in the cone conformation undergoes a direct formylation reaction giving unusual products in high yields. The
Duff reaction (urotropine/TFA) leads to unprecedented intramolecularly bridged compounds possessing two formyl groups on the opposite
para- or para-/meta-positions. The comparison with the corresponding classical calix[4]arene analogues indicates an amazingly different reactivity
of the thiacalix[4]arene system.
Since their first appearance in 1997, thiacalix[4]arenes1 have
received considerable attention from the supramolecular
community. Incorporation of four sulfur atoms instead of
the common methylene bridges imparts many novel features
to the thiacalix[4]arene derivatives2 when compared to the
classical analogues. Thiacalix[4]arenes exhibit substantially
enhanced complexation capacities for transition metals,3
considerably different conformational behaviors/preferences,4
and novel types of chemistry5 (e.g., oxidation of sulfur
bridges) to mention at least some of their novel functions.
All these features make them very promising candidates for
the role of host molecules and/or building blocks with many
potential applications in supramolecular chemistry.
On the other hand, despite more than a decade of research
on thiacalixarenes, our knowledge of their chemistry is still
rather fragmented. Consequently, the broader application of
† Department of Organic Chemistry, Prague Institute of Chemical
Technology.
‡ Laboratory of NMR Spectroscopy, Prague Institute of Chemical
Technology.
(4) (a) Lang, J.; Dvorakova´, H.; Bartosova´, I.; Lhota´k, P.; Stibor, I.;
Hrabal, R. Tetrahedron Lett. 1999, 40, 373. (b) Lang, J.; Vlach, J.;
Dvorakova´, H.; Lhota´k, P.; Himl, M.; Hrabal, R.; Stibor, I. J. Chem. Soc.,
Perkin Trans. 2 2001, 576. (c) Cajan, M.; Lhota´k, P.; Lang, J.; Dvorakova´,
H.; Stibor, I.; Koca, J. J. Chem. Soc., Perkin Trans. 2 2002, 1922. (d)
Dvorakova´, H.; Lang, J.; Vlach, J.; Sykora, J.; Cajan, M.; Himl, M.;
Pojarova´, M.; Stibor, I.; Lhota´k, P. J. Org. Chem. 2007, 72, 7157.
(5) (a) Katagiri, H.; Hattori, T.; Morohashi, N.; Iki, N.; Miyano, S. J.
§ Department of Inorganic Chemistry, Charles University.
(1) Kumagai, H.; Hasegawa, M.; Miyanari, S.; Sugawa, Y.; Sato, Y.;
Hori, T.; Ueda, S.; Kamiyama, H.; Miyano, S. Tetrahedron Lett. 1997, 38,
3971.
(2) For recent reviews on thiacalixarenes, see: (a) Morohashi, N.;
Narumi, F.; Iki, N.; Hattori, T.; Miyano, S. Chem. ReV. 2006, 106, 5291.
(b) Lhotak, P. Eur. J. Org. Chem. 2004, 1675.
ˇ
(3) (a) Kajiwara, T.; Iki, N.; Yamashita, M. Coord. Chem. ReV. 2007,
251, 1734. (b) Morohashi, N.; Iki, N.; Sugawara, A.; Miyano, S. Tetrahedron
2001, 57, 5557. (c) Iki, N.; Morohashi, N.; Narumi, F.; Miyano, S. Bull.
Chem. Soc. Jpn. 1998, 71, 1597.
Org. Chem. 2007, 72, 8327. (b) Lhota´k, P.; Mora´vek, J.; Smejkal, T.; Stibor,
I.; Sy´kora, J. Tetrahedron Lett. 2003, 44, 7333. (c) Lhota´k, P. Tetrahedron
2001, 57, 4775. (d) Morohashi, N.; Iki, N.; Sugawara, A.; Miyano, S.
Tetrahedron 2001, 57, 5557.
10.1021/ol901812m CCC: $40.75
Published on Web 08/25/2009
 2009 American Chemical Society

thiacalixarenes in supramolecular chemistry is limited by the
absence of general derivatization methods that are otherwise
well established for classical methylene analogues.
Scheme 1. Regioselectivity of Duff Formylation in
Thiacalix[4]arene vs Classical Calix[4]arene Series
Although direct electrophilic substitution represents the
most common upper-rim derivatization method for the
classical series, the same reactions are scarcely used for
thiacalixarenes. Most electrophilic reactions carried out so
far (nitration, bromination) have been based either on the
lower-rim unsubstituted parent thiacalix[4]arenes6 or on
partly substituted derivatives.7 The weak point of this
approach is that the products are not immobilized in specific
conformations; hence, subsequent shaping of the molecule
(alkylation/acylation on the lower rim) is needed. Unfortu-
nately, these reactions frequently lead to unwanted conform-
ers, and in fact, no upper-rim substituted derivative of
thiacalix[4]arene immobilized in the cone conformation has
been reported so far.
In our previous work we have shown that the formylation
of thiacalix[4]arene in the 1,3-alternate conformation leads
surprisingly to meta-substituted products.8 In this paper, we
report unusual regio- or chemoselectivity of formylation
reactions carried out with the cone conformers. These
reactions clearly indicate a remarkably different reactivity
of the thiacalix[4]arene system compared to the classical
calix[4]arene analogue.
Starting compound 1 was prepared from the corresponding
dipropoxy derivative by a known procedure9 (PrI/NaH,
DMF), and its upper-rim substitution was carried out using
the Duff procedure: reaction of the aromatic compound with
hexamethylenetetramine (HMTA) in trifluoroacetic acid
(TFA) (Scheme 1). These reaction conditions are well-known
from classical calixarene chemistry where they are used in
the preparation of para-substituted formyl calix[4]arenes.10
Thus, tetraalkyloxy compounds can be smoothly transformed
into tetraformyl derivatives as documented by the transfor-
mation of compound 4 to derivative 5 in 87%.11
showed the presence of two products in an approximately
3:1 ratio which were separated using preparative TLC on
silica gel plates. The main product 2 (isolated in 51% yield)
possesses a rather simple H NMR spectrum, reflecting the
high symmetry of this compound (Figure 1).
1
The Duff formylation was carried out by reacting
thiacalix[4]arene 1 with an excess of urotropin in refluxing
CF3COOH overnight. Analysis of the crude reaction mixture
(6) (a) Lhota´k, P.; Mora´vek, J.; Stibor, I. Tetrahedron Lett. 2002, 43,
3665. (b) Shokova, E.; Taffenko, V.; Kovalev, V. Tetrahedron Lett. 2002,
43, 5153. (c) Hu, X.; Zhu, Z.; Shen, T.; Shi, X.; Ren, J.; Sun, Q. Can.
J. Chem. 2004, 82, 1266. (d) Desroches, C.; Parola, S.; Vocanson, F.; Perrin,
M.; Lamartine, R.; Letoffe, J. M.; Bouix, J. New. J. Chem. 2002, 26, 651.
(e) Desroches, C.; Lopes, C.; Kessler, V.; Parola, S. Dalton Trans. 2 2003,
2085. (f) Agrawal, Y. K.; Pancholi, J. P. Synth. Commun. 2008, 38, 2446.
(g) Kasyan, O.; Swierczynski, D.; Drapailo, A.; Suwinska, K.; Lipkowski,
J.; Kalchenko, V. Tetrahedron Lett. 2003, 44, 7167. (h) Lang, K.; Proskova,
P.; Kroupa, J.; Moravek, J.; Stibor, I.; Pojarova, M.; Lhota´k, P. Dyes
Pigments 2008, 77, 646.
Figure 1.
1H NMR spectrum of compound 2 (CDCl3, 298 K, 600
(7) (a) Lhota´k, P.; Himl, M.; Stibor, I.; Sy´kora, J.; Cisarova, I.
Tetrahedron Lett. 2001, 42, 7107. (b) Hu, X.; Shi, H.; Zhu, Z.; Sun, Q.; Li,
Y.; Yang, H. Bull. Chem. Soc. Jpn. 2005, 78, 138. (c) Kasyan, O.; Healey,
E. R.; Drapailo, A.; Zaworotko, M.; Cecillon, S.; Coleman, A. W.;
Kalchenko, V. J. Inclusion Phenom. Macrocycl. Chem. 2007, 58, 127. (d)
Kroupa, J.; Stibor, I.; Pojarova, M.; Tkadlecova, M.; Lhota´k, P. Tetrahedron
2008, 64, 10075.
MHz).
The presence of just two singlets (8.07 and 6.06 ppm) in
the aromatic part of the spectrum indicates that only para-
substituted aromatic rings are present. The reasonable
difference in their chemical shifts (2.0 ppm) is known as a
typical feature of the so-called pinched cone conformation.4c
The intensity of the singlet corresponding to the formyl
groups (9.98 ppm) points to the fact that only two carbonyl
(8) Kundrat, O.; Cisarova, I.; Bo¨hm, B.; Pojarova, M.; Lhotak, P. J.
Org. Chem. 2009, 74, 4592.
(9) Himl, M.; Pojarova, M.; Stibor, I.; Sykora, J.; Lhota´k, P. Tetrahedron
Lett. 2005, 46, 461.
(10) Lhotak, P.; Shinkai, S. Tetrahedron Lett. 1996, 37, 645.
(11) ondoni, A.; Marra, A.; Scherrmann, M. C.; Casnati, A.; Sansone,
F.; Ungaro, R. Chem.sEur. J. 1997, 3, 1774.
Org. Lett., Vol. 11, No. 18, 2009
4189

groups are present. Also, the presence of two different triplets
for the -OCH2- groups (4.27 and 3.86 ppm) is characteristic
of calix[4]arene derivatives possessing two perpendicular
symmetry plains. On the other hand, ESI+ MS of 2 shows a
signal at m/z ) 732.171 corresponding to the molecular peak
of the diformylated product having an additional -CH2-
group. Based on these observations, we finally assigned the
unexpected structure of derivative 2 with two distal formyl
groups and two opposite aromatic units bridged intramo-
lecularly by methylene group.
spectrum of this compound showed a more complicated
splitting pattern (Figure 3) than that of compound 2. Again,
The final unambiguous structural evidence was obtained
using X-ray crystallography, which proved that thiacalix[4]-
arene 2 adopts a pinched cone conformation enforced by the
short (methylene) bridge (Figure 2). In this conformation,
Figure 3.
1H NMR spectrum of compound 3 (CDCl3, 298 K, 600
MHz).
the presence of the methylene bridge can be documented by
singlet at 3.16 ppm. On the other hand, the presence of two
different formyl groups (singlets at 10.59 a 9.98 ppm)
indicated the lower symmetry of this molecule. Electrospray
MS of derivative 3 revealed a peak at m/z ) 732 corre-
sponding to the same molecular weight as compound 2.
These findings could be ascribed to the bridged structure
having one formyl group in para- and one formyl group in
meta-positions.
1
Unfortunately, even the H NMR spectrum measured at
higher frequency (CDCl3, 600 MHz, see Figure 3) did not
correspond with this assumption. Thus, the expected pair of
doublets with an interaction constant around 7-8 Hz (typical
value for aromatic ortho interactions), which should indicate
possible meta-substitution of thiacalixarene skeleton, are
missing as they coincidentally collapsed into the singlet at
8.10 ppm. As we did not succeed with growing of crystal
suitable for the X-ray analysis, we decided to prepare the
corresponding 2,4-dinitrophenyl hydrazone to invoke stronger
differentiation of these signals.
Figure 2. Crystallographic structure of compound 2.
the two opposite phenolic units bearing formyl groups are
pointing outward with an interplanar angle of approximately
128°. The remaining aromatic units are tilted toward each
other inside the cavity with an interplanar angle of 70°.
Although direct formylation represents a well-established
and frequently used procedure for the upper rim substitution
of classical calix[n]arenes, the formation of similar bridged
structures has never been observed. Hence, this unexpected
reaction is another illustrative example proving the dramati-
cally different reactivity of the thiacalix[4]arene system
compared to classical calix[4]arene analogues.12 The forma-
tion of diarylmethanes upon reaction of various phenols with
hexamethylene tetraamine (HMTA) is known in the litera-
ture, though the yields are usually low as they are formed
only as byproducts.13
Repeated TLC chromatography on silica gel led to the
1
isolation of pure byproduct 3 in 15% yield. The H NMR
(12) Methylene-bridged classical calix[4]arene was prepared in low yield
(10%) by the cyclization of the corresponding mono(hydroxymethyl)
derivative: Struck, O.; Van Duynhoven, J. P. M.; Verboom, W.; Harkema,
S.; Reinhoudt, D. N. Chem. Commun. 1996, 1517.
(13) See, e.g. : (a) Mo¨hrle, H.; Tro¨sten, K. Arch. Pharm. 1981, 314,
690. (b) Zinke, A.; Ziegler, E. Ber. 1944, 77, 264. (c) Hultzsch, K. Ber.
1949, 82, 16. (d) Gowan, J. E.; MacGiolla Riogh, S. P.; MacMahon, G. J.;
O’Cleirigh, S.; Philbin, E. M.; Wheeler, T. S. Tetrahedron 1958, 2, 116.
Figure 4
K, 600 MHz).
.
Partial 1H NMR spectrum of compound 3a (CDCl3, 298
4190
Org. Lett., Vol. 11, No. 18, 2009

The reaction of 2,4-dinitrophenyl hydrazine with 3 in
ethanol (2 days reflux) gave the corresponding hydrazone
3a, which was isolated by chromatography on silica gel in
78% yield. The splitting pattern of 1H NMR spectrum of 3a
is considerably different from that of derivative 3. As follows
from Figure 4, both hydrogens on the meta-substituted
aromatic ring are nicely split into a pair of doublets (7.71
and 7.93 ppm) with a typical ortho-interaction constant of
8.2 Hz.
To gain deeper insight into the mechanism of this reaction
we have carried out the Duff reaction using shorter reaction
times. Thus, the quenching of the reaction after 60 min gave
rather complicated reaction mixture from which the mono-
formyl-substituted methylene-bridged compound 6 was
isolated in 19% yield. Similarly, a shorter reaction time (30
min) enabled us to isolate the methylene-bridged derivative
7 in 9% yield (Figure 5). These findings indicate that the
in the last step of the sequence the remaining aromatic ring
is attacked either in the para or the meta positions leading
to isomers 2 or 3, respectively.
In conclusion, the results obtained from the Duff reaction
of thiacalix[4]arene in the cone conformation are dia-
metrically different from the same reaction carried out with
the 1,3-alternate thiacalix[4]arene analogue. As we have
shown in our previous paper,8 the formylation of 1,3-
alternate leads selectively to the formation of dialdehydes
with formyl groups attached exclusively in the meta positions
(para substitution was not observed at all). Our novel results
obtained with the cone conformation indicate that the
electronic effect of sulfur bridges is not the only factor
governing the regioselectivity of electrophilic substitution
in thiacalixarene series. Now it is obvious, that stereochem-
istry (conformation of the starting thiacalix[4]arene) repre-
sents another effect playing a crucial role in the process. To
the best of our knowledge, similar connection between the
conformation and the results of reaction (chemoselectivity,
regioselectivity) has never been observed in classical calix-
arene chemistry.
Acknowledgment. We thank the Grant Agency of the
Czech Republic (203/09/0691) and the Grant Agency of the
Academy of Sciences of the CR (IAAX08240901) for
financial support of this work.
Figure 5. Intermediates isolated from the Duff reaction.
Supporting Information Available: Synthetic procedures,
characterization of new compounds, and X-ray data of
compound 2. This material is available free of charge via
the Internet at http://pubs.acs.org.
bridging reaction is very fast and the reaction sequence goes
via bridged intermediate 7. This compound is subsequently
formylated in the para position to form compound 6. Finally,
OL901812M
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4191