Convenient direct syntheses of selectively para-substituted di-, tri- and tetra-formylated thiacalix[4]arenes

Article abstract of DOI:10.1002/ejoc.201200252

An efficient direct method for di-, tri- and tetraformylation of thiacalix[4]arenes substituted on the para positions is described. Di- and triformylated thiacalix[4]arenes were obtained by formylation of partially propyl- or benzoyl-substituted thiacalix[4]arenes. Complete para-formylation was successfully achieved by formylation and dealkylation of tetraisopropoxythiacalix[4]arene conformers in one step. This experimental procedure is a simpler synthesis for completely formylated thiacalix[4]arene than the indirect method reported previously from brominated thiacalix[4]arene. Copyright

Full text of DOI:10.1002/ejoc.201200252

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FULL PAPER
DOI: 10.1002/ejoc.201200252
Convenient Direct Syntheses of Selectively para-Substituted Di-, Tri- and
Tetra-Formylated Thiacalix[4]arenes
Weiping Yang,[a] Wei Wang,[a] Rong Guo,[a] Linbo Gong,[a] and Shuling Gong*[a]
Keywords: Calixarenes / Regioselectivity / Formylation / Substituent effects / Synthetic methods
An efficient direct method for di-, tri- and tetraformylation of
thiacalix[4]arenes substituted on the para positions is de-
scribed. Di- and triformylated thiacalix[4]arenes were ob-
tained by formylation of partially propyl- or benzoyl-substi-
tuted thiacalix[4]arenes. Complete para-formylation was suc-
cessfully achieved by formylation and dealkylation of tetra-
isopropoxythiacalix[4]arene conformers in one step. This ex-
perimental procedure is a simpler synthesis for completely
formylated thiacalix[4]arene than the indirect method re-
ported previously from brominated thiacalix[4]arene.
triformylated thiacalix[4]arene derivertives through for-
mylation of partially propyl- or benzoyl-substituted thiaca-
lix[4]arenes. The synthesis of tetraformylated thiacalix[4]-
arene by using this method is not possible owing to unequal
electronic density distributions between the substituted and
unsubstituted phenol rings. According to our previous
study, isopropyl groups selectively dealkylate during the
Duff reaction of calix[4]arenes.[8] Thus, we decided to pre-
pare para-tetraformylthiacalix[4]arene derivatives by using
a “formylation and deprotection in one step” method.
Introduction
Thiacalix[4]arenes – in which all four methylene bridges
from the conventional calix[4]arene are replaced by sulfide
bonds – have attracted considerable interest in the broad
field of supramolecular chemistry since their first appear-
ance in 1997.[1] The presence of sulfur atoms makes thiaca-
lix[4]arenes very interesting molecules with properties that
are not present in the chemistry of classical calixarenes.[2]
However, after more than a decade of research, the use of
thiacalixarenes in supramolecular chemistry remains re-
stricted because of an absence of suitable methods for re-
gioselective or stereoselective substitution and functionali-
zation of the thiacalix[4]arene skeleton.[2]
Calixarenes formylated on the upper rims obtained
through the Gross or Duff reaction are well known and
provide useful intermediates for molecular receptors.[3,4] In
contrast, formylation of tetraalkoxythiacalix[4]arenes by
using conventional methods gives meta-substituted prod-
ucts only. The Gross formylation of tetrahydroxythiacalix-
[4]arene by treatment with TiCl4 gives no reaction.[5] To the
best of our knowledge, there is only one example of exclu-
sively para-formylated thiacalix[4]arenes, which uses an in-
direct method from brominated thiacalix[4]arene.[5a,6] The
method is a multistep reaction with strict conditions. There-
fore, a convenient method to prepare selectively para-for-
mylated thiacalix[4]arenes is needed. As reported, partially
substituted thiacalix[4]arenes could undergo an electro-
philic aromatic substitution reaction to give the corre-
sponding para-substituted derivertives (bromination and ni-
tration).[6,7] Therefore, we attempted to synthesize di- and
Results and Discussion
Dipropoxythiacalix[4]arene derivative 1[9] was prepared
according to a known procedure, and its upper rim substi-
tution was carried out by using the Duff reaction. Com-
pound 1 was treated with hexamethylenetetramine (HMTA)
in trifluoroacetic acid (TFA) for 72 h to afford a crude mix-
ture that was determined by TLC to be two products. The
main products, 1a and 1b, were isolated by column
chromatography on silica gel in 27 and 50% yields, respec-
tively (Scheme 1). The 1H NMR spectrum of compound 1a
(Figure 1) shows singlets at δ = 9.87 ppm (2 H), corre-
sponding to the formyl groups, and δ = 8.18 ppm (4 H),
corresponding to the H atoms of the aromatic rings, indi-
cating that two formyl groups were successfully introduced
at the para positions of the phenol rings. For compound 1b,
two singlets [δ = 8.21 (4 H) and 8.16 (2 H) ppm] in the
aromatic part of the spectrum indicate the presence of two
kinds of para-substituted aromatic rings. The structure was
further confirmed by the presence of two different triplets
for the –OCH2– groups (δ = 4.51 and 4.25 ppm) and two
singlets for the formyl groups (δ = 9.92 and 9.23 ppm).
[a] College of Chemistry and Molecular Sciences, Wuhan
University,
Wuhan, P. R. China
Fax: +86-27-68754067
E-mail: gongsl@whu.edu.cn
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201200252.
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W. Yang, W. Wang, R. Guo, L. Gong, S. Gong
FULL PAPER
pound 2a adopts a partial cone conformation in which one
of phenol rings linking with the alkylated ring is inverted
from top to bottom (Figure 2).
Figure 2. Crystallographic structure of compound 2a.
Scheme 1. Preparation of di- and triformylated thiacalix[4]arenes.
When the reaction was carried out with dibenzoxythia-
calix[4]arene 3 under reflux conditions for 24 h, 3a was iso-
lated in 69% yield as well as a small amount (19%) of
monobenzoyl compound 3b (Scheme 1). The solubilities of
compounds 3a and 3b differ greatly. Compound 3a dis-
solves easily in CHCl3, whereas 3b only dissolves in strong
polar solvents (e.g., methanol, acetone, DMF, and DMSO).
The structure of 3a was confirmed by 1H NMR spec-
troscopy. In addition, X-ray diffraction analysis confirmed
that 3a was para-formylated and adopts a pinched-cone
conformation (Figure 3). The two opposite phenol units
bearing formyl groups are pointing outward with an in-
terplanar angle of approximately 131°. The remaining aro-
matic units are tilted toward each other inside the cavity
with an interplanar angle of 39.6°.
Figure 1. 1H NMR spectra (300 MHz, CDCl3, 298 K) of com-
pounds 1a (top) and 1b (bottom).
Figure 3. Crystallographic structure of 3a. Disordered water mole-
In order to prepare di- and triformylated thiacalix[4]-
arenes more selectively, two partially substituted derivatives
2[7c] and 3[7a] were prepared (Scheme 1). When 2 was sub-
jected to formylation for 72 h only one product, triformyl
cules are omitted for clarity.
1
The H NMR and 13C NMR spectra of 3b showed very
derivative 2a, was isolated in 71% yield. The spectrum of complicated splitting patterns in the aromatic regions owing
2a displayed two characteristic broad singlets for the Ar– to the presence of five phenol rings in different chemical
OH protons in the ratio of 2:1. No distinct downfield shift or magnetic environments. According to the ESI-MS data,
for the resonance signals of Ar–OCH2– (Δδ = 0.02 ppm) which showed a peak at m/z = 683 in negative-ion mode,
was observed. Thus, 2a was a triformylated derivative in compound 3b was determined to be a triformylated mono-
which the alkylated phenol ring was not substituted. The benzoxythiacalix[4]arene. Because we were not able to ob-
structure of 2a was unequivocally confirmed by single-crys- tain suitable crystals for X-ray diffraction analysis to con-
tal X-ray diffraction analysis. Suitable crystals of 2a were firm the structure of 3b, we decided to hydrolyze the
obtained by slow crystallization from CHCl3/hexane. Com- benzoxy group. When heated to reflux with NaOH in eth-
2
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para-Substituted Formylated Thiacalix[4]arenes
anol for 12 h compound 3b afforded 3c in almost quantita- However, in reactions with compounds 1 and 2, even with
tive yield (Scheme 1). The 1H NMR spectral data of 3c prolonged reaction times, no dealkylation and further for-
(showing two singlets for the formyl groups at δ = 9.67 and mylation took place. According to our previous study, iso-
9.63 ppm in a ratio of 1:2) and ESI-MS data (m/z = 579.3 propyl groups on calix[4]arenes would dealkylate selectively
innegative-ionmode)provedthat3cwasatriformylatedthiacalix-under Duff reaction conditions.[8] In addition, the prepara-
[4]arene (Figure 4) and also confirmed the structure of 3b. tion of tetraalkylated thiacalix[4]arene was easier to achieve
Interestingly, when the reaction time for the formylation of than that of partially substituted derivatives. Therefore, tet-
3 was extended to 72 h, the yields of compounds 3a and 3b raisopropoxythiacalix[4]arene was prepared as the starting
changed to 31 and 48%, respectively. However, completely compound.
debenzoylated products were not isolated even when the re-
Compound 4 was treated with isopropyl iodide in ace-
action time was further prolonged. It is possible that the tone with K2CO3 as a base according to a literature pro-
esterification reaction is reversible under acidic conditions.
cedure (Scheme 2).[11] The crude products[12] were treated
with HMTA in TFA for 120 h without purification to give
tetraformylated tetrahydroxythiacalix[4]arene 4a success-
fully in 70% yield. The structure of 4a was confirmed by
1
the simple H NMR (Figure 4) and 13C NMR spectra and
the ESI-MS data (m/z = 607.1).
Scheme 2. Preparation of completely formylated thiacalix[4]arene
4a.
The formation of meta- or para-substituted products is
probably related to the activating abilities of the substitu-
ents on the benzene rings. The activating ability of the sulf-
ide bonds is stronger than that of methylene bridges of con-
ventional calix[4]arenes. Therefore, in the reactions of tetra-
Figure 4. 1H NMR spectra (300 MHz, [D6]DMSO, 298 K) of 3c propoxythiacalix[4]arenes, the sulfide bonds play a major
(top) and 4a (bottom).
role, and the formyl groups are introduced in the meta posi-
tions (ortho/para positions of the sulfide bonds). Whereas
Complete formylation of partially substituted thiacalix-
for the unsubstituted phenol rings, the activating ability of
[4]arenes is difficult to achieve directly, because the elec-
the –OH groups is stronger than both of the –OR groups
tronic density distributions are not equal between the sub-
and the sulfide bonds, resulting in formyl groups being in-
stituted and unsubstituted phenol rings. Considering the
troduced at the para positions of the –OH groups.
preference for meta substitution of tetraalkoxy thiacalix[4]-
arenes,[5] we attempted to prepare para-tetraformylated thi-
acalix[4]arene by using 4 as the starting compound. How-
ever, the Duff reaction did not work in our hands.
Conclusion
Inspired by the formylation of compound 3, we decided
Di- and triformylated thiacalix[4]arenes substituted on
to prepare a para-tetraformylthiacalix[4]arene derivative by the para positions were obtained by formylation of partially
a “formylation and deprotection in one step” method. As propyl- or benzoyl-substituted thiacalix[4]arenes. The
mentioned above, because of the reversible nature of the number of introduced formyl groups at the upper rims was
ester bond, a benzoyl group was not suitable. Monodemeth- influenced by the nature and number of the substituents
ylation and monodepropylation have been observed by tre- on the lower rims. Prolonged reaction times resulted in the
ating tetramethylated p-tert-butylcalix[4]arene under Duff hydrolysis of one of the benzoyl groups of dibenzoxythiaca-
reaction conditions[10] and tetrapropylated thiacalix[4]- lix[4]arene to give a triformylated product. Inspired by this,
arene under Gross reaction conditions,[5a] respectively. complete para-formylation was successfully achieved by for-
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W. Yang, W. Wang, R. Guo, L. Gong, S. Gong
FULL PAPER
H, OCH2), 4.25 (t, J = 6.3 Hz, 2 H, OCH2), 1.95–2.15 (m, 4 H,
CH2CH2), 1.20 (t, J = 7.5 Hz, 3 H, CH3), 1.16 (t, J = 7.5 Hz, 3 H,
CH3) ppm. 13C NMR (75 MHz, CDCl3): δ = 189.4, 189.1, 163.5,
162.4, 158.7, 139.1, 138.3, 137.3, 133.61, 133.55, 132.5, 131.8,
129.2, 127.3, 124.3, 122.9, 81.6, 76.6, 23.5, 23.0, 10.4, 1.0 ppm.
C33H28O7S4 (664.82): calcd. C 59.62, H 4.25, S 19.29; found C
59.59, H 4.56, S 19.21. ESI-MS: m/z = 663 [M – H]–, 685 [M +
Na+ – 2 H]–.
mylation and dealkylation of tetraisopropoxythiacalix[4]-
arene conformers in one step. This new direct formylation
method provides a new route to functionalized thiacalixar-
enes and may extend their use in synthetic procedures.
Experimental Section
General: All organic reagents were obtained from commercial sup-
pliers and used without further purification. Organic solvents and
inorganic reagents were purified according to standard drying
methods before use. TLC analysis was performed on precoated
glass plates. Column chromatography was performed on silica gel
(200–300 mesh). All NMR spectroscopic data was recorded with
an NMR spectrometer operating at 300 MHz for 1H nuclei and
75 MHz for 13C nuclei with TMS as an internal standard. Mass
spectra were recorded by using ESI technique. Samples for elemen-
tal analysis were dried in a desiccator with P2O5 under vacuum at
80 °C overnight.
Compound 2a: According to the General Procedure, 2 was allowed
to react for 72 h to give 2a (0.27 g, 71%) after purification (CHCl3/
acetone, 3:1, v/v). M.p. 211 °C. H NMR (300 MHz, CDCl3): δ =
1
9.84 (s, 2 H, CHO), 9.65 (s, 1 H, CHO), 9.09 (s, 2 H, ArOH), 9.78
(s, 1 H, ArOH), 8.21 (s, 4 H, ArH), 7.94 (s, 2 H, ArH), 7.62 (d, J
= 7.5 Hz, 2 H, ArH), 7.01 (t, J = 7.5 Hz, 1 H, ArH), 4.33 (t, J =
6.3 Hz, 2 H, OCH2), 2.11–2.29 (m, 2 H, CH2CH2), 1.25 (t, J =
7.5 Hz, 3 H, CH3) ppm. 13C NMR (75 MHz, CDCl3): δ = 189.3,
163.7, 162.9, 159.8, 140.3, 139.1, 130.6, 130.0, 127.7, 127.3, 122.2,
121.2, 81.5, 23.3, 10.7 ppm. C30H22O7S4 (622.74): calcd. C 57.86,
H 3.56, S 20.60; found C 57.55, H 3.60, S 20.29. ESI-MS: m/z =
621 [M – H]–.
Compound 2: Propyl iodide (1.08 g, 6.37 mmol, 0.62 mL) was added
to a suspension of 4 (0.8 g, 1.61 mmol) and K2CO3 (0.25 g,
1.81 mmol) in dry acetone (50 mL). The reaction mixture was
heated to reflux for 100 h. An HCl solution (ca. 15 mL, 1 m) was
added to the mixture (pH Ͻ 7). The aqueous layer was washed
with CHCl3 (3ϫ 20 mL). The combined organic fractions were
washed with water and dried with MgSO4. The solution was fil-
tered and the solvent removed under reduced pressure. After
recrystallization from acetone, 2 was obtained as white solid
(0.51 g, 60%). 1H NMR (300 MHz, CDCl3): δ = 8.77 (s, 3 H,
ArOH), 7.62 (d, J = 7.8 Hz, 4 H, ArH), 7.53 (d, J = 7.5 Hz, 2 H,
ArH), 7.44 (d, J = 7.5 Hz, 2 H, ArH), 6.90 (t, J = 7.5 Hz, 1 H,
ArH), 6.74 (t, J = 7.5 Hz, 2 H, ArH), 6.64 (t, J = 7.5 Hz, 1 H,
ArH), 4.31 (t, J = 6.6 Hz, 2 H, OCH2), 2.13–2.25 (m, 2 H,
CH2CH2), 1.25 (t, J = 7.2 Hz, 3 H, CH3) ppm. C27H22O4S4
(538.71): calcd. C 60.20, H 4.12, S 23.81; found C 60.01, H 3.91, S
23.52. ESI-MS: m/z = 537 [M – H]–.
Compound 3a: According to the General Procedure, 3 was allowed
to react for 24 h to give 3a (0.31 g, 69%) after purification (CHCl3).
M.p. Ͼ 250 °C. 1H NMR (300 MHz, [D6]DMSO): δ = 9.85 (s, 2
H, ArOH), 9.07 (s, 2 H, CHO), 7.92 (t, J = 7.2 Hz, 2 H, ArH),
7.84 (d, J = 7.2 Hz, 4 H, ArH), 7.71 (d, J = 7.2 Hz, 4 H, ArH),
7.56 (t, J = 7.2 Hz, 4 H, ArH), 7.43 (s, 4 H, ArH), 7.26 (t, J =
7.2 Hz, 2 H, ArH) ppm. C40H24O8S4 (760.86): calcd. C 63.14, H
3.18, S 16.86; found C 62.96, H 3.35, S 16.57. ESI-MS: m/z = 759
[M – H]–.
Compound 3b: According to the General Procedure, 3 was allowed
to react for 72 h to give 3b (0.20 g, 48%) after purification (CHCl3/
acetone, 3:1, v/v). M.p. Ͼ 250 °C. 1H NMR (300 MHz, [D6]-
DMSO): δ = 9.54–9.62 (m, 3 H, CHO), 6.90–8.20 (m, 14 H, ArH)
ppm. C34H20O8S4 (684.77): calcd. C 59.63, H 2.94, S 18.73; found
C 59.49, H 2.75, S 18.52. ESI-MS: m/z = 683 [M – H]–.
Compound 3c: A mixture of 3b (0.20 g, 0.29 mmol) and NaOH
(0.46 g, 11.5 mmol) in a mixture of EtOH (15 mL) and H2O (5 mL)
was heated to reflux for 12 h. After cooling, the solution was acidi-
fied to pH = 5–6 with HCl (1 m) to give a white precipitate. Pure
3c (0.16 g, 0.28 mmol, 97% yield) was collected by filtration and
washed with water. M.p. Ͼ 250 °C. 1H NMR (300 MHz, [D6]-
DMSO): δ = 9.67 (s, 1 H, CHO), 9.63 (s, 2 H, CHO), 8.11 (s, 2 H,
ArH), 8.02 (s, 4 H, ArH), 7.47 (d, J = 7.8 Hz, 2 H, ArH), 6.65 (t,
1 H, ArH) ppm. 13C NMR (75 MHz, [D6]DMSO): δ = 190.2,
169.9, 168.2, 160.2, 139.8, 139.2, 137.5, 127.5, 126.7, 124.0, 123.3,
122.7, 122.0, 120.2 ppm. C27H16O7S4 (580.66): calcd. C 55.85, H
2.78, S 22.09; found C 55.94, H 2.81, S 22.14. ESI-MS: m/z = 579.3
[M – H]–.
General Procedure for the Synthesis of 1–3a, 1b and 3b: Substituted
thiacalix[4]arene
(0.6 mmol)
and
hexamethylenetetramine
(18 mmol) were added to trifluoroacetic acid (50 mL), and the mix-
ture was heated to reflux. When the reaction was complete, it was
quenched with ice-cold water and the mixture extracted with
CHCl3. The organic layer was washed with water and dried with
MgSO4. The solution was filtered and the solvent removed under
reduced pressure. The residue was purified by using column
chromatography.
Compound 1a: According to the General Procedure, 1 was allowed
to react for 72 h to give 1a (0.10 g, 27%) after purification (CHCl3/
ethyl acetate, 60:1, v/v). M.p. Ͼ 250 °C. 1H NMR (300 MHz,
CDCl3): δ = 9.87 (s, 2 H, CHO), 8.49 (s, 2 H, ArOH), 8.18 (s, 4 H,
ArH), 7.08 (d, J = 7.5 Hz, 4 H, ArH), 6.65 (t, J = 7.5 Hz, 2 H,
ArH), 4.32 (t, J = 6.9 Hz, 4 H, OCH2), 2.01–2.13 (m, 4 H,
CH2CH2), 1.20 (t, J = 7.5 Hz, 6 H, CH3) ppm. 13C NMR (75 MHz,
CDCl3): δ = 189.7, 163.6, 159.3, 138.6, 136.7, 129.1, 128.7, 125.8,
123.9, 79.5, 29.9, 23.5, 10.7, 1.3 ppm. C32H28O6S4 (636.81): calcd.
C 60.35, H 4.43, S 20.14; found C 60.02, H 4.63, S 19.87. ESI-MS:
m/z = 635 [M – H]–.
Compound 4a: A mixture of 4 (0.67 g, 1.35 mmol), potassium car-
bonate (3.56 g, 26.18 mmol) and 2-iodopropane (2.7 mL, 27 mmol)
was stirred in acetone (35 mL) and heated to reflux for 48 h. The
reaction mixture was then poured into diluted HCl and extracted
with CHCl3. The organic layer was washed with water, dried with
MgSO4 and concentrated to yield the crude product. Without fur-
ther purification the crude product was allowed to react with
HMTA (5.68 g, 40.50 mmol) in TFA (50 mL) for 120 h. The reac-
tion was quenched with ice-cold water and the mixture filtered. The
crude mixture was added to CHCl3 (50 mL) and heated to reflux
Compound 1b: According to the General Procedure, 1 was allowed
to react for 72 h to give 1b (0.20 g, 50%) after purification (CHCl3/
ethyl acetate, 15:1, v/v). M.p. Ͼ 250 °C. 1H NMR (300 MHz, for 2 h. The suspension was filtered to give pure 4a (0.58 g, 70%
1
CDCl3): δ = 9.92 (s, 2 H, CHO), 9.23 (s, 1 H, CHO), 8.21 (s, 4 H, yield). M.p. Ͼ 250 °C. H NMR (300 MHz, [D6]DMSO): δ = 9.66
ArH), 8.16 (s, 2 H, ArH), 7.28 (d, J = 7.5 Hz, 2 H, ArH), 7.06 (s, (s, 4 H, CHO), 8.04 (s, 8 H, ArH) ppm. 13C NMR (75 MHz, [D6]-
2 H, ArOH), 6.83 (t, J = 7.5 Hz, 1 H, ArH), 4.51 (t, J = 6.6 Hz, 2 DMSO): δ = 190.5, 167.9, 139.3, 127.8, 123.2 ppm. C28H16O8S4
4
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para-Substituted Formylated Thiacalix[4]arenes
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Acknowledgments
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1
[12] The crude product was determined by H NMR spectroscopy
to be a mixture of conformers containing 1,2-alternate, partial-
cone, and 1,3-alternate compounds in a ratio of approximately
2:3:5.
Received: March 2, 2012
Published Online: ᭿
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5

Job/Unit: O20252
/KAP1
Date: 08-05-12 09:34:23
Pages: 6
W. Yang, W. Wang, R. Guo, L. Gong, S. Gong
FULL PAPER
Formylated Thiacalix[4]arenes
Di- and triformylated thiacalix[4]arenes
substituted on the para positions have been
synthesized by formylation of partially
propyl- or benzoyl-substituted thiacalix-
[4]arenes. The formylation of tetraiso-
propoxythiacalix[4]arene conformers gave
the completely dealkylated tetraformylthia-
calix[4]arene derivative. This result differs
from the formylation of propoxythiaca-
lix[4]arene.
W. Yang, W. Wang, R. Guo, L. Gong,
S. Gong* ........................................... 1–6
Convenient Direct Syntheses of Selectively
para-Substituted Di-, Tri- and Tetra-Form-
ylated Thiacalix[4]arenes
Keywords: Calixarenes / Regioselectivity /
Formylation / Substituent effects / Syn-
thetic methods
6
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Eur. J. Org. Chem. 0000, 0–0