Synthesis and X-ray structures of iodothiacalix[4]arenes

Article abstract of DOI:10.1016/j.tetlet.2007.05.150

Mono-, di-, and tetraiodothiacalix[4]arenes 13-16 have been successfully synthesized for the first time by the Griess reaction of diazonium salts of the corresponding aminothiacalix[4]arenes 4-7. X-ray crystallography reveals that monoiodinated compound 1

Full text of DOI:10.1016/j.tetlet.2007.05.150

Tetrahedron Letters 48 (2007) 5293–5296
Synthesis and X-ray structures of iodothiacalix[4]arenes
Shinya Tanaka, Hiroshi Katagiri, Naoya Morohashi,*
Tetsutaro Hattori* and Sotaro Miyano
Department of Environmental Studies, Graduate School of Environmental Studies, Tohoku University, 6-6-11 Aramaki-Aoba, Aoba-ku,
Sendai 980-8579, Japan
Received 23 April 2007; revised 17 May 2007; accepted 18 May 2007
Available online 29 May 2007
Abstract—Mono-, di-, and tetraiodothiacalix[4]arenes 13–16 have been successfully synthesized for the first time by the Griess reac-
tion of diazonium salts of the corresponding aminothiacalix[4]arenes 4–7. X-ray crystallography reveals that monoiodinated com-
pound 13 adopts a distorted pinched cone conformation, in which the three hydroxy groups and the iodine atom form a pseudo-
cyclic hydrogen bonding. On the other hand, tetraiodinated compound 16 adopts a 1,3-alternate conformation presumably due to
the steric hindrance and dipole repulsion between the iodine atoms.
Ó 2007 Elsevier Ltd. All rights reserved.
Calix[4]arenes are one of the most popular building
blocks in the field of supramolecular chemistry.1 Among
a large number of calixarene derivatives, halogenated
ones such as iodine derivatives (e.g., 1) are especially
useful as an intermediate for the elaboration of sophisti-
cated molecular hosts by using various reactions includ-
ing transmetallations and transition metal-catalyzed
coupling reactions. Although a number of papers have
dealt with the introduction of halo-substituents into
the upper rim of calixarenes (para to the hydroxy group)
and their successive transformation into other func-
tional groups,2 it is quite recent that a calixarene bearing
iodo-substituents at the lower rim (2) has appeared in
the literature for the first time as an accidental by-prod-
uct of the palladium-catalyzed Sonogashira coupling
reaction of 1,3-bistriflate of calix[4]arene.3,4 This is due
to the difficulty of replacing hydroxy groups on the
benzene nuclei of calixarenes with other functions by
cleaving the aryl-oxygen bond particularly in the case
of calixarenes of small ring size.6 In addition, thiacalix-
arenes (e.g., 3), having epithio groups instead of methy-
lene bridges in the conventional calixarenes, often show
different reactivity and/or selectivity from those of the
methylene-bridged counterparts in the modification
reactions and the palladium-catalyzed iodination was
found to be inapplicable to 1,3-bistriflate of thiaca-
lix[4]arene 3. In our continuing efforts to develop novel
functions of thiacalixarenes,7 we have recently suc-
ceeded in the synthesis of tetraaminothiacalix[4]arene 4
via a chelation-assisted nucleophilic aromatic substitu-
tion (SNAr) reaction8 of tetra-O-methylsulfinylcalix-
[4]arene of rtct configuration9 8(rtct) with lithium benz-
ylamide, followed by debenzylation of the resulting
tetra(benzylamino)sulfinylcalix[4]arene and successive
reduction of the sulfinyl functions.10 In the solvent
extraction experiment, while thiacalixarene 3 can extract
soft to intermediate metal ions by cooperative coordina-
tion of the bridging sulfur with two neighboring pheno-
lates to the metal center,11 aminothiacalixarene 4
selectively extracted gold and palladium ions,12 which
are classified as the softest among metal ions. This was
attributed to the softer nature of the amino nitrogen
than hydroxy oxygen, which realized selective coordina-
tion to these softest metal ions. On the other hand, it
goes without saying that the amino group is pivotal in
aromatic synthesis as it can be easily converted into var-
ious functions via diazonium salts.13 Therefore, amino-
thiacalixarene 4 does not only present attractive
features not attainable by phenol-based calixarenes as
a host molecule but is also expected to serve as a useful
precursor of highly elaborated synthetic receptors. Here-
in, we wish to report the first synthesis of iodothiacalix-
arenes, in which all or a part of the hydroxy groups of
thiacalixarene 3 are replaced with iodine atoms, by
iodination of diazonium salts prepared from amino-
thiacalixarenes 4–7.
Keywords: Calixarene; Griess reaction; Amination; Nucleophilic
aromatic substitution.
*
Corresponding authors. Tel.: +81 22 795 7262; fax: +81 22 795 7293
(T.H.); e-mail addresses: morohashi@orgsynth.che.tohoku.ac.jp;
hattori@orgsynth.che.tohoku.ac.jp
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.05.150

5294
S. Tanaka et al. / Tetrahedron Letters 48 (2007) 5293–5296
compound could be prepared by changing the reaction
conditions and/or employing the other stereoisomer9
of compound 8. Removal of the benzyl moieties (10)
from 910 followed by demethylation with a sodium
thioalkoxide and subsequent reduction of the sulfinyl
14
functions with LiAlH4–TiCl4 delivered the desired
monoaminothacalixarene 5.15 On the other hand, direct
reduction of debenzylated compound 10 gave O-methyl
protected monoamine 6.15 O-Methyl protected diamine
7 was also obtained from diaminosulfinylcalixarene 11
by applying the same procedure as used for the prepara-
tion of monoamine 6.15
Monoamine 5 was diazotized with nitrous acid in acetic
acid by stirring the mixture for 4 h to give a clear solu-
tion of the diazonium salt, which was treated with KI
and I2 to give monoiodinated compound 13 in 11%
yield,16,17 accompanied by the formation of many
unidentified by-products (Scheme 2). The identity of
1
13 was confirmed by FAB-MS [m/z 830 (M+)] and H
NMR spectrum, which showed three singlets for the
tert-butyl protons (9H, 9H, and 18H) and two singlets
(each 2H) and two doublets (each 2H) for the aromatic
protons, being consistent with a symmetric structure
with a r-plane. Biali and co-workers reported that the
thermal dediazoniation of a diazonium salt of mono-
aminocalix[5]arene afforded a xanthene-type compound
by an intramolecular cyclization between the in situ-gen-
erated phenyl cation and an adjacent hydroxy group.5
Such a cyclization could be a cause of reducing the yield
in the present iodination. We then tried the reaction of
O-methyl protected amines 6 and 7. To our pleasure,
they gave the corresponding mono- and diiodinated
compounds 14 and 15,17 respectively, in good yields.
Iodination of compound 4, having four amino groups
to be converted, was difficult but gave tetraiodinated
compound 16 in a meaningful yield.17 It should be noted
that this is the first successful synthesis of a calix-type
compound in which all the hydroxy groups at the lower
rim are replaced with halogen atoms. The 1H NMR
Prerequisite tetraaminothiacalixarene 4 was prepared
according to our previously reported procedure.10 We
have found that mono- and diaminothiacalixarenes 5–
7 can also be prepared by a similar procedure by using
tetra-O-methylsulfinylcalixarene of rctt configuration9
8(rctt) as a starting material (Scheme 1). Thus, the SNAr
reaction of 8(rctt) with 8.0 mol equiv of lithium benzyl-
amide in THF gave 1,3-diaminosulfinylcalixarene 11 in
48% yield with concomitant formation of a small
amount of monoamino counterpart 9, which was in turn
obtained in substantial yield by reducing the reaction
time (Scheme 1). On the other hand, no triaminated
O
O
S
O
S
But
But
But
O
But
O
But
O
But
O
But
O
But
O
S
S
X X
X
X X
X
X X
X
X X
X
i
iv, v, vi
25%
ii, iii
S
S
S
S
S
S
S
S
X
2 min, 22 %
77%
S
S
S
S
But
But
But
But
But
But
But
But
O
O
O
8(rctt): X = OCH3
9: X = OCH3, R = CH2Ph
10: X = OCH3
5: X = OH
v, vi
77%
i
5 min, 48%
O
S
O
But
O
But
But
But
O
But
But
But
But
But
S
S
S
v, vi
60%
ii, iii
X
X
X X
X
X
S
S
S
O
O
S
S
S
S
S
X
X
89%
X
S
S
S
S
But
But
But
But
But
But
But
O
O
11: X = OCH3, R = CH2Ph
12: X = OCH3
7: X = OCH3
6: X = OCH3
Scheme 1. Reagents and conditions: (i) PhCH2NHLi, THF, rt; (ii) NBS, BPO, benzene, reflux; (iii) 6 M HCl, benzene, reflux; (iv) NaH,
CH3(CH2)7SH, THF, reflux; (v) LiAlH4, TiCl4, THF, rt; (vi) Bu4NF, THF, rt.

S. Tanaka et al. / Tetrahedron Letters 48 (2007) 5293–5296
5295
But
But
But
But
S
S
i, ii
X X
X
X X
S
S
S
S
X
I
S
S
But
But
But
But
But
But
But
5: X = OH
13: X = OH (11%)
6: X = OCH3
14: X = OCH3 (55%)
But
S
X
S
i, ii
I
X
X
I
S
S
S
S
X
45%
S
S
But
But
But
But
But
But
But
But
7: X = OCH3
15: X = OCH3
S
S
i, ii
X X
I
I
I
I
S
S
S
S
X
X
9%
S
S
But
But
But
But
4: X = NH2
16
Figure 1. X-ray structure of compound 13. (a) Side view; (b) top view.
Hydrogen atoms except of OH are omitted for clarity.
Scheme 2. Reagents and conditions: (i) NaNO2, H2SO4, CH3CO2H,
rt; (ii) KI, I2, rt.
spectrum of 16 showed one singlet each for the tert-butyl
and aromatic protons, indicating that the compound
adopted either cone or 1,3-alternate conformation. The
latter conformation is the same as that in the crystals
and more feasible in the solution, considering the steric
hindrance and dipole repulsion between the iodine
atoms (vide infra).
X-ray crystallographic analyses of compounds 13 and 16
were carried out to examine the influence of the iodine
substituent(s) on the conformation of the calixarene
framework.18 Single crystals of 13 and 16 were obtained
by slow diffusion of ethanol or hexane to a chloroform
solution of each compound. Compound 13 adopted a
distorted pinched cone conformation, in which the benz-
ene ring bearing the iodine atom was almost parallel to
the facing benzene ring and tilted so as to put the bulky
iodine atom outside the macrocycle, the dihedral angles
between the facing benzene rings being 3.97(15)° for the
A–C pair and 87.83(8)° for the B–D pair, respectively
(Fig. 1). No solvent was included in the cavity due to
the distorted structure. The conformation was stabilized
by a pseudo-cyclic hydrogen bonding among the three
hydroxy groups and the iodine atom as evidenced by
Figure 2. X-ray structure of 16. Hydrogen atoms and solvent are
omitted for clarity.
each other, the deviations form the trigonal plane
defined by the improper torsion angles being 1.20° for
I1, I1* and 1.43° for I2, I2*, respectively.
In conclusion, we have synthesized mono-, di-, and tetra-
iodothiacalix[4]arenes for the first time by the Griess
reaction of diazonium salts of the corresponding amino-
thiacalix[4]arenes, which could be prepared by using a
chelation-assisted SNAr reaction of tetra-O-methyl-
sulfinylcalix[4]arenes with lithium benzylamide as a
key step. X-ray crystallographic analyses of two iodin-
ated compounds revealed that their conformations were
affected by the bulkiness, electronegativity, and hydro-
gen-bonding acceptor nature of the iodine atoms. The
structural information is potentially useful for a further
derivatization of these compounds.
˚
the interatomic distances between O1–O2 (2.828 A),
˚
˚
˚
O2–O3 (3.182 A), O3–I (3.841 A), and I–O1 (4.081 A)
atoms. On the other hand, compound 16 adopted 1,3-
alternate conformation with C2 symmetry, which would
be the result of minimizing the dipole moment of the
molecule and avoiding the steric hindrance between
the iodine atoms (Fig. 2). It is of interest to note here
that the trigonal planar geometry of four aromatic car-
bons bearing an iodine atom was warped outside the
macrocycle to place the facing iodine atoms apart from
References and notes
1. Reviews: (a) Gutsche, C. D. Calixarenes. In Monographs
in Supramolecular Chemistry; Stoddart, J. F., Ed.; The

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S. Tanaka et al. / Tetrahedron Letters 48 (2007) 5293–5296
Royal Society of Chemistry: Cambridge, 1989; (b) Ikeda,
12. Katagiri, H.; Iki, N.; Matsunaga, Y.; Kabuto, C.; Miyano,
S. Chem. Commun. 2002, 2080.
A.; Shinkai, S. Chem. Rev. 1997, 97, 1713; (c) Gutsche, C.
D. Calixarenes Revisited. In Monographs in Supramole-
cular Chemistry; Stoddart, J. F., Ed.; The Royal Society of
Chemistry: Cambridge, 1998; (d)Calixarenes in Action;
Mandolini, L., Ungaro, R., Eds.; Imperial College Press:
London, 2000; (e) Calixarenes 2001; Asfari, Z., Bo¨hmer,
V., Harrowfield, J. M., Vicens, J., Eds.; Kluwer Academic:
Dordrecht, 2001.
13. (a) The Chemistry of Diazonium and Diazo Groups; Patai,
S. Ed.; Wiley: New York, 1978; (b) Zollinger, H. Diazo
Chemistry I: Aromatic and Heteroaromatic Compounds;
John Wiley & Sons: New York, 1994; (c) Roglans, A.;
Quintana, A. P.; Manas, M. M. Chem. Rev. 2006, 106,
4622.
14. Drabowicz, J.; Mikolajczyk, M. Synthesis 1976, 527.
15. Compound 5: 1H NMR (500 MHz, CDCl3): d 1.20 (s, 9H,
C(CH3)3), 1.23 (s, 9H, C(CH3)3), 1.23 (s, 18H, C(CH3)3),
7.60 (d, 2H, J = 2.5 Hz, ArH), 7.63 (s, 2H, ArH), 7.65 (s,
2H, ArH), 7.66 (d, 2H, J = 2.5 Hz, ArH); FAB MS (m/z)
719 (M+). Compound 6: 1H NMR (500 MHz, CDCl3,
333 K): d 1.09 (s, 18H, C(CH3)3), 1.28 (s, 9H, C(CH3)3),
1.36 (s, 9H, C(CH3)3), 3.69 (s, 6H, OCH3), 3.76 (s, 3H,
OCH3), 5.19 (br, 2H, NH2), 7.26 (d, 2H, J = 2.4 Hz,
ArH), 7.42 (d, 2H, J = 2.4 Hz, ArH), 7.54 (s, 2H, ArH),
7.60 (s, 2H, ArH); FAB MS (m/z) 761 (M+). Compound 7:
1H NMR (500 MHz, CDCl3): d 0.90 (s, 18H, C(CH3)3),
1.29 (s, 18H, C(CH3)3), 4.03 (s, 6H, OCH3), 5.61 (br, 4H,
NH2), 7.19 (s, 4H, ArH), 7.59 (s, 4H, ArH); FAB MS
(m/z) 846 (M+).
2. For iodination of the upper rim of calixarenes, see: (a) van
Loon, J.-D.; Arduini, A.; Coppi, L.; Verboom, W.;
Pochini, A.; Ungaro, R.; Harkema, S.; Reinhoudt, D. N.
J. Org. Chem. 1990, 55, 5639; (b) Arduini, A.; Pochini, A.;
Rizzi, A.; Sicuri, A. R.; Ungaro, R. Tetrahedron Lett.
1990, 31, 4653; (c) Timmerman, P.; Verboom, W.;
Reinhoudt, D. N.; Arduini, A.; Grandi, S.; Sicuri, A. R.;
Pochini, A.; Ungaro, R. Synthesis 1994, 185; (d) Aruduini,
A.; McGregor, W. M.; Pochini, A.; Secchi, A.; Ugozzoli,
F.; Ungaro, R. J. Org. Chem. 1996, 61, 6881; (e) Arduini,
A.; McGregor, W. M.; Paganuzzi, D.; Pochini, A.; Secchi,
A.; Ugozzoli, F.; Ungaro, R. J. Chem. Soc., Perkin Trans.
2 1996, 839; (f) Pinkhassiki, E.; Stibor, I.; Casnati, A.;
Ungaro, R. J. Org. Chem. 1997, 62, 8654; (g) Barbour, L.
J.; Orr, G. W.; Atwood, J. M. Chem. Commun. 1997, 1439;
(h) van Wageningen, A. M. A.; Timmerman, P.; van
Duynhoven, J. P. M.; Verboom, W.; van Veggel, F. C. J.
M.; Reinhoudt, D. N. Chem. Eur. J. 1997, 3, 639; (i)
Klenke, B.; Friedrichsen, W. J. Chem. Soc., Perkin Trans.
1 1998, 3377.
16. Typical procedure for the iodination: To a solution of
amine 6 (100 mg, 0.139 mmol) in acetic acid (10 ml) was
added NaNO2 (20.0 mg, 0.290 mmol) in concd sulfuric
acid (3 ml) and the mixture was stirred at room temper-
ature. After 4 h, the excess of NaNO2 was decomposed by
the addition of urea (15.7 mg, 0.261 mmol). To the
mixture was added a mixed solution of KI (348 mg,
2.10 mmol) and I2 (33.2 mg, 0.131 mmol) in water (7 ml)
and the resulting mixture was stirred for a further 12 h.
The mixture was quenched with 10% NaHSO3 and
extracted with chloroform. The extract was dried over
MgSO4 and evaporated to leave a residue, which was
chromatographed on silica gel with chloroform–hexane
(1:2) as an eluent to give iodide 14 (57.1 mg, 55%).
17. Compound 13: 1H NMR (500 MHz, CDCl3): d 0.51 (s, 9H,
C(CH3)3), 1.12 (s, 9H, C(CH3)3), 1.33 (s, 18H, C(CH3)3),
6.64 (s, 2H, ArH), 7.36 (s, 2H, OH), 7.42 (s, 2H, ArH), 7.67
(d, 2H, J = 2.4 Hz, ArH), 7.69 (d, 2H, J = 2.4 Hz, ArH),
8.44 (br, 1H, OH); FAB MS (m/z) 830 (M+). Compound
3. Al-Saraierh, H.; Miller, D. O.; Georghiou, P. E. J. Org.
Chem. 2005, 70, 8273.
4. It was also reported that a diazonium salt of monoamino-
calix[5]arene on treatment with tetrabutylammonium
iodide in chloroform afforded a practically unisolable
mixture of monochloro- and monoiodocalix[5]arene. See
Ref. 5.
5. Van Gelder, J. M.; Aleksiuk, O.; Biali, S. E. J. Org. Chem.
1996, 61, 8419.
6. For transformation of the hydroxy group of calixarenes
into other functions, see: (a) Gibbs, C. G.; Sujeeth, P. K.;
Rogers, J. S.; Stanley, G. G.; Krawiec, M.; Watson, W.
H.; Gutsche, C. D. J. Org. Chem. 1995, 60, 8394; (b)
Ohseto, F.; Murakami, H.; Araki, K.; Shinkai, S. Tetra-
hedron Lett. 1992, 33, 1217; (c) Aleksiuk, O.; Grynszpan,
F.; Biali, S. E. J. Org. Chem. 1993, 58, 1994.
7. Morohashi, N.; Narumi, F.; Iki, N.; Hattori, T.; Miyano,
S. Chem. Rev. 2006, 106, 5291, and references cited
therein.
8. For representative examples of the chelation-assisted
SNAr reaction, see: (a) Hattori, T.; Hotta, H.; Suzuki,
T.; Miyano, S. Bull. Chem. Soc. Jpn. 1993, 66, 613; (b)
Hattori, T.; Suzuki, T.; Hayashizaka, N.; Koike, N.;
Miyano, S. Bull. Chem. Soc. Jpn. 1993, 66, 3034; (c)
Hattori, T.; Sakamoto, J.; Hayashizaka, N.; Miyano, S.
Synthesis 1994, 199; (d) Hattori, T.; Suzuki, M.; Tomita,
N.; Takeda, A.; Miyano, S. J. Chem. Soc., Perkin Trans. 1
1997, 1117; (e) Hattori, T.; Takeda, A.; Suzuki, K.; Koike,
N.; Koshiishi, E.; Miyano, S. J. Chem. Soc., Perkin Trans.
1 1998, 3661; (f) Hattori, T.; Shimazumi, Y.; Goto, H.;
Yamabe, O.; Morohashi, N.; Kawai, W.; Miyano, S. J.
Org. Chem. 2003, 68, 2099.
1
14: H NMR (500 MHz, CDCl3, 333 K): d 1.19 (br s, 9H,
C(CH3)3), 1.25 (s, 9H, C(CH3)3), 1.29 (s, 18H, C(CH3)3),
3.19 (br s, 3H, OCH3), 3.66 (s, 6H, OCH3), 7.44 (s, 2H,
ArH), 7.47 (d, 2H, J = 2.5 Hz, ArH), 7.58 (br s, 2H, ArH),
7.60 (d, 2H, J = 2.5 Hz, ArH); FAB MS (m/z) 872 (M+).
Compound 15: 1H NMR (500 MHz, CDCl3): d 1.26
(s, 18H, C(CH3)3), 1.29 (s, 18H, C(CH3)3), 3.68 (s,
6H, OCH3), 7.58 (s, 4H, ArH), 7.66 (s, 4H, ArH); FAB
1
MS (m/z) 968 (M+). Compound 16: H NMR (500 MHz,
CDCl3): d 1.31 (s, 36H, C(CH3)3), 7.90 (s, 8H, ArH); FAB
MS (m/z) 1160 (M+).
18. Crystallographic data for 13: C40H47IO3S4, fw = 830.92,
ꢀ
˚
˚
triclinic, P1, a = 9.6635(13) A, b = 10.1568(14) A, c =
˚
21.158(3) A,
a = 77.237(3)°,
b = 88.701(3)°,
c =
3
˚
82.817(3)°, V = 2009.4(5) A , Z = 2, 9175 independent
reflections, 7426 reflections were observed (I > 2r(I)),
R1 = 0.0392, wR2 = 0.1041 (observed), R1 = 0.0488,
wR2 = 0.1079 (all data). Crystallographic data for
16ÆCHCl3: C41H45Cl3I4S4, fw = 1279.96, orthorhombic,
˚
˚
9. For stereoisomers of sulfinylcalix[4]arene, see: Morohashi,
N.; Katagiri, H.; Iki, N.; Yamane, Y.; Kabuto, C.;
Hattori, T.; Miyano, S. J. Org. Chem. 2003, 68,
2324.
10. Katagiri, H.; Iki, N.; Hattori, T.; Kabuto, C.; Miyano, S.
J. Am. Chem. Soc. 2001, 123, 779.
Pbcn,
a = 15.198(2) A,
b = 22.152(3) A,
c =
3
˚
˚
13.4696(17) A, V = 4534.7(10) A , Z = 4, 5238 indepen-
dent reflections, 3499 reflections were observed (I > 2r(I)),
R1 = 0.0242, wR2 = 0.0421 (observed), R1 = 0.0444,
wR2 = 0.0438 (all data). Crystallographic data reported
in this Letter have been deposited with the Cambridge
Crystallographic Data Centre as supplementary publica-
tion Nos. CCDC 644542 and 644543.
11. Morohashi, N.; Iki, N.; Sugawara, A.; Miyano, S.
Tetrahedron 2001, 57, 5557.