Unexpected Single-Step Formation of 1,2-anti-Heterodisubstituted Calix[4]arenes upon Alkylation of a Tribenzoyl Precursor

Article abstract of DOI:10.1021/jo035150h

The selective preparation and complete structural characterization of a small series of 1,2-anti-hetero-disubstituted calix[4]arenes has been accomplished. These compounds were obtained in two steps from unsubstituted p-tert-butylcalix[4]arene by tribenzo

Full text of DOI:10.1021/jo035150h

1,2-disubstituted versions have been reported, but full
conformational evidence was not provided in these par-
ticular cases.10 In this note we wish to report the selective
formation of 1,2-anti-heterodisubstituted calix[4]arenes
and a detailed conformational study of these derivatives
and of their tribenzoyl precursor.
Un exp ected Sin gle-Step F or m a tion of
1,2-a n ti-Heter od isu bstitu ted Ca lix[4]a r en es
u p on Alk yla tion of a Tr iben zoyl P r ecu r sor
Arjan W. Kleij,*,†,§ Beatriz Souto,‡ Ce´sar J . Pastor,‡
Pilar Prados,† and J avier de Mendoza*,†
Chawla et al.11 first reported the tribenzoylation of
p-tert-butylcalix[4]arene 1 (Scheme 1) (benzoyl chloride
(4 equiv)/pyridine, 1 M calixarene). The isolated product
(87% yield) was described as two conformationally dif-
ferent tribenzoyl derivatives (cone and partial cone
conformations) in a ca. 1:3 ratio. For larger-scale prepa-
ration, we decided to use a much higher dilution (32.5
mM) and a different workup. The isolated crude material
(13.49 g, 84% overall yield) was partially dissolved in
methanol upon trituration. Both the resulting solid and
the solution were found to contain the same three
components in different ratios (84:15:1 for the solid (10.05
g) and 1:88:11 in solution (3.44 g) by NMR integration).
Overall, the three components were present in a 63:34:3
ratio. The major components of both fractions were
obtained as pure materials by a single crystallization
step. The identity of the third, not isolated minor
Universidad Auto´noma de Madrid, Departamento de
Quı´mica Orga´nica, C-I and Universidad Auto´noma de
Madrid, Servicio Interdepartamental de Investigacio´n,
Cantoblanco, 28049-Madrid, Spain
javier.demendoza@uam.es; kleij@science.uva.nl
Received August 5, 2003
Abstr a ct: The selective preparation and complete struc-
tural characterization of a small series of 1,2-anti-hetero-
disubstituted calix[4]arenes has been accomplished. These
compounds were obtained in two steps from unsubstituted
p-tert-butylcalix[4]arene by tribenzoylation and a subsequent
one-pot, two-step sequence involving alkylation with simul-
taneous partial deacylation, resulting in heterodisubstituted
calixarenes carrying an alkyl and an aroyl group. The mono-
alkyl-tribenzoyl intermediate, prior to in situ deprotection,
could also be isolated.
(3) (a) Mogck, O.; Paulus, E. F.; Bo¨hmer, V.; Thondorf, I.; Vogt, W.
Chem. Commun. 1996, 2533-2534. (b) McGillivray, L. R.; Atwood, J .
L. Nature 1997, 389, 469-472. (c) Rinco´n, A. M.; Prados, P.; de
Mendoza, J . J . Am. Chem. Soc. 2001, 123, 3493-3498. (d) Shivanyuk,
A.; Rebek, J ., J r. J . Am. Chem. Soc. 2002, 124, 12074-12075. (e) Far,
A. R.; Shivanyuk, A.; Rebek, J ., J r. J . Am. Chem. Soc. 2002, 124, 2854-
2855. (f) Corbellini, F.; Fiammengo, R.; Timmerman, P.; Crego-Calama,
M.; Versluis, K.; Heck, A. J . R.; Luyten, I.; Reinhoudt, D. N. J . Am.
Chem. Soc. 2002, 124, 6569-6575.
(4) (a) Ferguson, G.; Gallagher, J . F.; Pappalardo, S. Acta Crystal-
logr. 1993, C49, 1537-1540. (b) Beer, P. D.; Drew, M. G. B.; Gale, P.
A.; Leeson, P. B.; Ogden, M. I. J . Chem. Soc., Dalton Trans. 1994,
3479-3485. (c) Verboom, W.; Bodewes, P. J .; van Essen, G.; Timmer-
man, P.; van Hummel, G. J .; Harkema, S.; Reinhoudt, D. N. Tetrahe-
dron 1995, 51, 499-512. (d) Pappalardo, S.; Petringa, A.; Parisi, M.
F.; Ferguson, G. Tetrahedron Lett. 1996, 37, 3907-3910.
(5) For illustrative examples of this interconversion, see: (a) Araki,
K.; Iwamoto, K.; Shinkai, S.; Matsuda, T. Chem. Lett. 1989, 1747-
1750. (b) Iwamoto, K.; Araki, K.; Shinkai, S. J . Org. Chem. 1991, 56,
4955-4962.
(6) (a) Iwamoto, K.; Araki, K.; Shinkai, S. Tetrahedron 1991, 47,
4325-4342. (b) Groenen, L. C.; Rue¨l, B. H. M.; Casnati, A.; Verboom,
W.; Pochini, A.; Ungaro, R.; Reinhoudt, D. N. Tetrahedron 1991, 47,
8379-8384. (c) Casnati, A.; Arduini, A.; Ghidini, E.; Pochini, A.;
Ungaro, R. Tetrahedron 1991, 47, 2221-2228.
Functionalized calixarenes1 are useful building blocks
and molecular platforms for supramolecular applications
such as molecular recognition2 and formation of capsular
entities.3 To achieve these goals, however, full control
over the calixarene conformations by means of selective
introduction of functional groups is an essential require-
ment. Conformations of calix[4]arenes (cone, partial cone,
1,3-alternate, and 1,2-alternate) have been extensively
studied.4 Introduction of bulky groups or chains longer
than ethyl on the phenol positions at the lower rim
effectively prevents a “through-the-annulus” intercon-
version between the different conformer families.5
The lower rim O-functionalization of calix[4]arenes has
been well-developed, and simple synthetic procedures are
known for monosubstituted,6 1,3-syn-disubstituted,7 and
fully substituted analogues.8 Selective proximal homo-
1,2-dialkylation of calix[4]arenes can also be achieved,9
though significantly fewer examples are known as com-
pared with the case of their 1,3-distal-alkylated regio-
isomers. A rather limited number of examples of hetero-
(7) (a) Dijkstra, P. J .; Brunink, J . A. J .; Bugge, K.-E.; Reinhoudt,
D. N.; Harkema, S.; Ungaro, R.; Ugozolli, F.; Ghidini, E. J . Am. Chem.
Soc. 1989, 111, 7567-7575. (b) van Loon, J . D.; Arduini, A.; Verboom,
W.; Ungaro, R.; van Hummel, G. J .; Harkema, S.; Reinhoudt, D. N.
Tetrahedron Lett. 1989, 30, 2681-2684.
† Universidad Autono´ma de Madrid, Departamento de Qu´ımica
Orga´nica.
(8) Sharma, S. K.; Gutsche, C. D. Tetrahedron 1994, 50, 4087-4104.
(9) (a) Bottino, F.; Giunta, L.; Pappalardo, S. J . Org. Chem. 1989,
54, 5407-5409. (b) Arduini, A.; Casnati, A.; Dodi, L.; Pochini, A.;
Ungaro, R. J . Chem. Soc., Chem. Commun. 1990, 1597-1598. (c)
Groenen, L. C.; Rue¨l, B. H. M.; Casnati, A.; Timmerman, P.; Verboom,
W.; Harkema, S.; Pochini, A.; Ungaro, R.; Reinhoudt, D. N. Tetrahedron
Lett. 1991, 32, 2675-2678. (d) Groenen, L. C.; van Loon, J .-D.;
Verboom, W.; Harkema, S.; Casnati, A.; Ungaro, R.; Pochini, A.;
Ugozolli, F.; Reinhoudt, D. N. J . Am. Chem. Soc. 1991, 113, 2385-
2392. (e) Pappalardo, S. New J . Chem. 1996, 20, 465-472.
(10) Only two examples of hetero-1,2-dialkylation are known, though
these compounds were obtained after several steps involving protection/
deprotection sequences: (a) Iwamoto, K.; Shimizu, H.; Araki, K.;
Shinkai, S. J . Am. Chem. Soc. 1993, 115, 3997-4006. (b) Narumi, F.;
Morohashi, N.; Matsumura, N.; Iki, N.; Kameyama, H.; Miyano, S.
Tetrahedron Lett. 2002, 43, 621-625.
‡ Universidad Autono´ma de Madrid, Servicio Interdepartamental
de Investigacio´n.
§ Current Address: Institute of Molecular Chemistry, University of
Amsterdam, Nieuwe Achtergracht 166, 1018 WV, Amsterdam, The
Netherlands.
(1) (a) Gutsche, C. D. Calixarenes; The Royal Society of Chemistry:
Cambridge, 1989. (b) Bo¨hmer, V. Angew. Chem., Int. Ed. Engl. 1995,
34, 713-745. (c) Gutsche, C. D. Calixarenes Revisited; The Royal
Society of Chemistry: Cambridge, 1998. (d) Calixarenes in Action;
Mandolini, L., Ungaro, R., Eds.; Imperial College Press: London, 2000
and references therein.
(2) Anion receptor systems: (a) Beer, P. D.; Drew, M. G. B.;
Hazlewood, C.; Hesek, D.; Hodacova, J .; Stokes, S. E. J . Chem. Soc.,
Chem. Commun. 1993, 229-231. (b) Beer, P. D.; Drew, M. G. B.; Hesek,
D.; Nam, K. C. Chem. Commun. 1997, 107-108. (c) Atwood, J . L.;
Steed, J . W.; Hancock, K. S. B.; Holman, K. T.; Staffilani, M.; J uneja,
R. K.; Burkhalter, R. S. J . Am. Chem. Soc. 1997, 119, 6324-6335.
(11) Chawla, H. M.; Pathak, M. Bull. Soc. Chim. Fr. 1991, 128, 232-
243. A partial cone isomer was suggested as the major product on the
basis of the NMR spectrum.
10.1021/jo035150h CCC: $25.00 © 2003 American Chemical Society
Published on Web 10/01/2003
J . Org. Chem. 2003, 68, 8711-8714
8711

observed in the 1H and 13C{1H} NMR spectra. This latter
observation suggested that the three benzoyl groups
should occupy both rims of this calixarene in either a
(u,u,d) or (d,d,u) fashion.13 The NOESY spectrum showed
clear NOE interactions with two Ho protons from distinct
benzoyl groups as well with both Heq and Hax protons of
one of the methylene AB systems. The observation of
additional well-defined through-space contacts was com-
plicated due to strong overlap of signals. Nevertheless,
the simplicity of the tert-butyl region in the 1H and
13C{1H} spectra of 3 suggested either the presence of a
single asymmetric species or a fast equilibrium between
a partial cone and a 1,2-alternate conformation. Likely,
the equilibrium takes place by rotation of the free phenol
ring through the annulus.
F IGURE 1. Structures of the tribenzoyl derivatives 2 and 3.
SCHEME 1. Syn th esis of Ca lixa r en e Com p ou n d s
2-6
The inherent chirality of the two proposed con-
formers was established by H NMR (CDCl3, 500 MHz)
1
by addition of an excess of Pirkle’s chiral shift reagent
((R)-(-)-2,2,2-trifluoro-1-(9-anthracyl)ethanol) to 3, which
caused splitting of the OH group, the benzoyl protons,
and the AB patterns corresponding to the methylene
fragments. One of the tert-butyl signals was also split.
Benzylation of 2 with 4-iodobenzyl bromide (NaH,
DMF, rt) and subsequent workup under acidic conditions
yielded a mixture of three components in a 78:15:7 ratio
(4-6, Scheme 1). The major component 4 was isolated
in a 30% yield as a pure, microcrystalline solid.
1
The H NMR spectrum of 4 displayed a nonsymmetric
structure (four distinct signals for the CH2 and tert-butyl
groups) and revealed the presence of a single benzoyl
group and two free phenol rings (singlet resonances at δ
) 8.91 and 7.89 ppm). Clearly, two benzoyl groups were
hydrolyzed during the benzylation process. A NOESY
experiment showed a strong contact between OHB and
OHC protons, implying a syn orientation of both adjacent
phenol rings. Furthermore, additional strong contacts
were observed for OHB and both benzylic CH2 protons
(H3 and H4) as well as with the aromatic H5 proton, a
fact that provided evidence that the benzyl substituent
resides on the same face of the calixarene framework as
the phenol hydrogens. As for 2, the benzoyl protons Ho,
Hm, and Hp displayed medium to weak NOE contacts
with the tBuA, tBuB, and tBuC groups, which indicated
again that the benzoyl moiety is pointing toward the
(upper rim) cavity (Figure 2). The 13C{1H} NMR spectrum
of 4 showed two methylene carbon resonances in the
region around 39 ppm, indicating that the remaining
aromatic ring of the calixarene system carrying the ben-
zoyl group must be in an anti orientation14 with respect
to the benzyl and the hydroxyl groups. Thus, a partial
cone assignment was fully supported by the NMR data.
1
component, could not be established. The H NMR and
NOESY spectra at 500 MHz indicated that the major
component was the symmetric partial cone isomer 2
(Scheme 1), whereas the earlier reported partial cone
isomer11 showed much resemblance with the minor iso-
lated component (Scheme 1, 3). In contrast to the results
obtained under Chawla’s conditions,11 no cone isomer
could be detected.12
For compound 2, medium to strong NOE contacts were
observed between the tBuB group and benzoyl pro-
tons Ho′, Hm′, and Hp′, whereas tBuA showed contacts
only with Hm′, suggesting that this benzoyl group is
partially included into the cavity (Figure 1). On the other
hand, strong NOEs were noted between benzoyl hydro-
gens Ho, Hm, and Hp and the tBuC group. Finally, the free
phenol hydrogen showed a strong through-space contact
with the benzoyl proton Ho, a fact that unambiguously
confirms the structure of 2 as a symmetric partial cone
conformation.
A definite confirmation of the proposed structure for 4
was obtained by X-ray crystallography. The benzoyl
group is pointing inside the upper rim cavity, in agree-
ment with the high-field shifts found for the Ho and Hm
(12) In our hands, at
1 M calixarene concentration (Chawla’s
conditions), a mixture of the symmetrical partial cone isomer 2 (49%),
the asymmetric partial cone isomer 3 (26%), and the cone isomer (25%)
in an 83% isolated yield was obtained.
(13) u ) up, d ) down: Gutsche, C. D.; Dhawan, B.; Levine, J . A.;
No, K. H.; Bauer, L. J . Tetrahedron 1983, 39, 409-426.
(14) 13C NMR constitutes a useful tool to determine the conformation
of calixarenes: J aime, C.; de Mendoza, J .; Prados, P.; Nieto, P. M.;
Sa´nchez, C. J . Org. Chem. 1991, 56, 3372-3376.
The minor component 3 was identified as an asym-
metric species, since four distinct tert-butyl groups were
8712 J . Org. Chem., Vol. 68, No. 22, 2003

reactivity of the anchored groups may be used to furnish
a number of predefined calixarene structures with con-
formational features potentially useful as building blocks
in supramolecular chemistry.
Exp er im en ta l Section
Gen er a l Sta tem en ts. The presence of solvent molecules in
the analytical samples was supported by 1H NMR spectroscopy.
Melting points were measured in open capillaries and are
uncorrected.
Syn th esis of Tr iben zoyla ted p-ter t-Bu tylca lix[4]a r en e.
To a solution of p-tert-butylcalix[4]arene 1 (10.53 g, 16.2 mmol)
in pyridine (500 mL) was slowly added benzoyl chloride (28 mL,
33.9 g, 241 mmol) at ambient temperature. The homogeneous,
salmon-colored reaction mixture was stirred for 72 h, after which
the solvent was largely removed under reduced pressure. To the
residue was added CH2Cl2 (200 mL) and H2O (200 mL), and the
layers were separated. The aqueous layer was once more
extracted with CH2Cl2 (200 mL), and the combined organic
layers were washed with three portions of H2O (200 mL), dried
on MgSO4, filtered, and concentrated to leave a yellowish oil.
Trituration at rt with MeOH yielded a first fraction of a white
solid (10.05 g). Concentration and cooling (-30 °C) of the MeOH
layer furnished a second fraction (3.44 g) of product. Total
yield: 13.49 g (14.0 mmol, 84%). Recrystallization of both
fractions yielded 2 and 3 as pure materials with spectroscopic
and analytical data as given below.
F IGURE 2. Structures of the products 4-6 obtained after
alkylation of 2.
protons in NMR. Furthermore, as earlier suggested by
the NMR study, the two phenol OHs are linked by a
hydrogen bond (see Supporting Information).
The structures of isolated 5 and 6 (Figure 2) could be
readily assigned by 1D and 2D NMR spectroscopy. Thus,
data for 5 agreed with a 1,3-alternate conformation, as
evidenced by the 13C NMR spectrum, which showed two
signals for the calixarene CH2 groups at 38.9 and 38.4
ppm, respectively,14 while the 1H NMR spectrum dis-
played two different AB systems for these groups. Fur-
thermore, MALDI-TOF mass spectrometric analysis con-
firmed the presence of three benzoyl groups in 5. On the
contrary, 6 was fully depleted of benzoyl groups and
showed a cone conformation. Its structure was assigned
by comparison with previously published data.15
Other alkylating agents produced a comparable set of
derivatives from 2, also yielding 1,2-anti-heterodisubsti-
tuted products as the major component. Thus, treatment
of 2 with benzyl bromide yielded the desired monoben-
zyl-monobenzoyl product 7 in 47% after crystallization
(Scheme 1). With propyl iodide, however, a mixture of
components resulted. The identity of all components,
isolated by column chromatography, was established by
NMR and MALDI-TOF-MS to be compounds 8-11
(Scheme 1). Interestingly, the two main products in this
propylation reaction were 816 and the nonalkylated, fully
deacylated starting material 1 (both isolated in 27%
yield), whereas the other (minor) products 9-1117,18 were
isolated in 13, 5, and 3% yield, respectively.
CPK model inspection suggests that the formation of
species 4, 7, and 9 is related to the faster hydrolysis of
the benzoyl moieties in their more crowded, tribenzoyl
compounds. On the other hand, the less reactive halides
(i.e., propyl iodide) give rise to more complex mixtures.
Although the mechanism for the formation of 4, 7, and 9
remains unclear, there are some precedents of base-
induced cleavage and/or rearrangement processes that
involve aroyl substituents in calixarene compounds.19
More details about the mechanistic aspects of the above
transformations are currently under investigation.
In summary, we have described the selective formation
of 1,2-anti-heterodisubstituted calix[4]arenes carrying
both benzyl/alkyl and benzoyl groups. The difference in
Sym m etr ica l P a r tia l Con e 5,11,17,23-Tetr a k is(1,1-d im -
eth yleth yl)-25,25,27-tr is(ben zoyloxy)-28-(h yd r oxy)ca lix[4]-
a r en e (2). Mp (crystals): 310-312 °C. 1H NMR (500 MHz,
3
4
CDCl3): δ ) 8.10 (d, J ) 8.3 Hz, J ) 1.2 Hz, 4H, benzoyl-Ho),
7.55 (t, 3J ) 7.5 Hz, 4J ) 1.2 Hz, 2H, benzoyl-Hp), 7.29 (s, 2H,
3
3
4
ArH), 7.21 (t, J ) 7.8 Hz, benzoyl-Hm), 7.16 (t, J ) 7.1 Hz, J
4
) 1.7 Hz, 1H, benzoyl-Hp), 6.99 (d, J ) 2.4 Hz, 1H, ArH), 6.95
(s, 1H, ArH), 6.65 (d, 4J ) 2.4 Hz, 1H, ArH), 6.64 (s, 1H, OH,
D2O exchangeable), 6.55-6.60 (dd+d, 4H, benzoyl-Ho+m), 4.21
(d, 2J (A-B) ) 13.5 Hz, 2H, CH2), 4.06 (d, 2J (A-B) ) 16.6 Hz,
2
2
2H, CH2), 3.86 (d, J (A-B) ) 16.7 Hz, 2H, CH2), 3.50 (d, J (A-
B) ) 13.6 Hz, 2H, CH2), 1.45 (s, 9H, C(CH3)3), 0.86 (s, 9H,
C(CH3)3), 0.73 (s, 18H, C(CH3)3). 13C{1H} NMR (75 MHz,
CDCl3): δ ) 164.9, 163.2 (2 × ArC(O) ), 150.0, 148.5, 148.0,
145.9, 144.1, 142.9, 133.0, 132.5, 132.4, 132.0, 131.7, 130.3, 129.9,
129.4, 129.0, 128.3, 127.84, 127.80, 126.5, 126.0, 125.53, 125.47
(all ArC), 38.9 (CH2), 34.1, 33.8, 33.7 (3 × C(CH3)3, ratio 1:1:2),
32.3 (CH2), 31.8, 30.9, 30.6 (3 × C(CH3)3, ratio 1:1:2). MALDI-
TOF-MS (ditranol + KI): m/z ) 961.4 (M + H)+ (calcd 961.5),
999.4 (M + K)+ (calcd. 999.5). Anal. Calcd for C65H68O7‚1/2H2O:
C, 80.46; H, 7.17. Found: C, 80.70; H, 7.07.
Non sym m etr ica l P a r tia l Con e/1,2-Alter n a te r a c-5,11,17,-
23-Tetr a k is(1,1-d im eth yleth yl)-25,25,27-tr is(ben zoyloxy)-
28-(h yd r oxy)ca lix[4]a r en e (3). Mp (crystals): 286-288 °C. 1H
NMR (500 MHz, CDCl3): δ ) 7.57 (d, 4J ) 2.1 Hz, 1H, ArH),
7.45 (t, 3J ) 7.5 Hz, 1H, benzoyl-Hp), 7.43 (d, 4J ) 2.7 Hz, 1H,
ArH), 7.37 (t, 3J ) 7.3 Hz, 1H, benzoyl-Hp), 7.31 (d, 4J ) 2.1 Hz,
4
3
1H, ArH), 7.30 (d, J ) 2.0 Hz, 1H, ArH), 7.25 (d, J ) 7.5 Hz,
2H, benzoyl-Ho), 7.20 (d, 3J ) 7.7 Hz, 2H, benzoyl-Ho), 7.19-
7.13 (m, 6H, one ArH + benzoyl-H), 7.04 (t, 3J ) 7.7 Hz, 2H,
benzoyl-Hm), 6.84 (d, 4J ) 1.9 Hz, 1H, ArH), 6.82 (d, 4J ) 1.8
Hz, 1H, ArH), 6.80 (d, 4J ) 1.8 Hz, 1H, ArH), 6.64 (t, 3J ) 7.6
2
Hz, 2H, benzoyl-Hm), 5.16 (s, 1H, OH), 4.02 (d, J (A-B) ) 16.7
2
2
Hz, 1H, CH2), 3.95 (d, J (A-B) ) 16.8 Hz, 1H, CH2), 3.92 (d, J
not resolved due to strong overlap with other signals, 1H, CH2),
3.91 (s, 2H, CH2), 3.89 (d, 2J (A-B) ) 14.2 Hz, 1H, CH2), 3.58
(d, 2J (A-B) ) 13.6 Hz, 1H, CH2), 3.52 (d, 2J (A-B) ) 14.0 Hz,
1H, CH2), 1.43 (s, 9H, C(CH3)3), 1.18 (s, 9H, C(CH3)3), 0.98 (s,
(17) A 1,2-proximal dibenzoyl calix[4]arene has been reported:
Dospil, G.; Schatz, J . Tetrahedron Lett. 2001, 42, 7837-7840. However,
in these studies the syn conformer was employed.
(18) Iwamoto, K.; Araki, K.; Shinkai, S. Tetrahedron 1991, 47, 4325-
4342.
(19) See, K. A.; Fronczek, F. R.; Watson, W. A.; Kashyap, R. P.;
Gutsche, C. D. J . Org. Chem. 1991, 56, 7256-7268.
(15) Santoyo-Gonza´lez, F.; Torres-Pinedo, A.; Sa´nchez-Ortega. A. J .
Org. Chem. 2000, 65, 4409-4414.
(16) Compound 8 was actually isolated as a mixture of a 1,3-
alternate and a partial cone isomer, which could not be separated by
crystallization or column chromatography.
J . Org. Chem, Vol. 68, No. 22, 2003 8713

9H, C(CH3)3), 0.94 (s, 9H, C(CH3)3). 13C{1H} NMR (75 MHz,
CDCl3): δ ) 165.4, 165.0, 164.2 (3 × ArC(O)), 150.4, 148.8, 148.3,
148.1, 144.9, 144.6, 144.5, 142.3, 134.4, 133.7, 132.9, 132.6, 132.4,
131.9, 131.5, 129.9, 129.6, 128.7, 128.5, 128.3, 128.2, 128.0, 127.8,
126.4, 126.3, 126.00, 125.95, 125.9, 125.8, 125.6, 125.3, 124.3
(all ArC), 38.8, 36.8 (2 × CH2), 34.4, 34.0, 33.9, 33.7 (4 ×
C(CH3)3), 32.5 (CH2), 31.5, 31.4, 31.0, 30.8 (4 × C(CH3)3), 30.5
(CH2). MALDI-TOF-MS (ditranol + KI): m/z ) 961.3 (M + H)+
(calcd 961.5), 999.3 (M + K)+ (calcd 999.5). Anal. Calcd for
Hz, 1H, OCH2), 4.29 (d, 2J (A-B) ) 16.6 Hz, 1H, CH2), 4.14 (d,
2
2J (A-B) ) 13.3 Hz, 1H, CH2), 4.12 (d, J (A-B) ) 17.5 Hz, 1H,
CH2), 4.02 (d, 2J (A-B) ) 17.4 Hz, 1H, CH2), 3.89 (d, apparent
2
2J (A-B) ) 14.6 Hz, 2H, 2 × CH2), 3.48 (d, J (A-B) ) 13.5 Hz,
1H, CH2), 3.35 (d, 2J (A-B) ) 13.3 Hz, 1H, CH2), 1.42 (s, 9H,
C(CH3)3), 1.34 (s, 9H, C(CH3)3), 0.75 (s, 9H, C(CH3)3), 0.66 (s,
9H, C(CH3)3). 13C{1H} NMR (75 MHz, CDCl3): δ ) 163.3 (ArC-
(O)), 149.7, 149.6, 148.2, 148.11, 148.09, 146.0, 143.3, 142.3,
135.1, 133.9, 132.6, 131.64, 131.55, 130.7, 129.6, 129.3, 128.7,
128.5, 128.1, 127.7, 127.6, 127.3, 126.9, 126.4, 126.3, 125.6,
125.03, 124.96, 124.8, 124.6 (all ArC), 75.5 (OCH2), 39.2, 39.1
(2 × CH2), 34.3, 34.1, 33.6, 33.1 (4 × C(CH3)3), 32.7, 32.4 (2 ×
CH2), 31.7, 31.5, 30.8, 30.7 (4 × C(CH3)3). MALDI-TOF-MS
(ditranol + KI): m/z ) 881.6 (M + K)+ (calcd 881.5). Anal. Calcd
for C58H66O5: C, 82.62; H, 7.89. Found: C, 82.67: H, 8.27.
P a r tia l Con e 1,2-a n ti-Heter od isu bstitu ted 5,11,17,23-
Tetr akis(1,1-dim eth yleth yl)-25-(pr opyloxy)-26-(ben zoyloxy)-
27,28-bis(h yd r oxy)ca lix[4]a r en e (9). Yield (Rf ) 0.74): 45.5
mg (13%). 1H NMR (500 MHz, CDCl3): δ ) 9.47 (s, 1H, OH),
8.00 (s, 1H, OH), 7.32 (s, 1H, ArH), 7.27 (s, 1H, ArH), 7.18 (s, 4J
C
65H68O7‚H2O: C, 79.72; H, 7.21. Found: C, 79.58; H, 7.49.
P a r tia l Con e 1,2-a n ti-Heter od isu bstitu ted 5,11,-
1 7 ,2 3 -T e t r a k i s (1 ,1 -d i m e t h y l e t h y l )-2 5 -(4 -i o d o b e n -
zyloxy)-26-(ben zoyloxy)-27,28-bis(h ydr oxy)calix[4]ar en e (4).
Yield (after crystallization of the crude product): 30%. Mp
(crystals): 258-260 °C (turns brown). 1H NMR (500 MHz,
CDCl3): δ ) 8.91 (s, 1H, OH), 7.89 (s, 1H, OH), 7.70 (d, 3J ) 8.3
Hz, 2H, ArH iodoaryl group), 7.45 (d, 4J ) 1.7 Hz, 1H, ArH),
4
4
7.26 (d, J ) 2.3 Hz, 1H, ArH), 7.17 (d, J ) 2.3 Hz, 1H, ArH),
7.14 (d, 4J ) 1.6 Hz, 1H, ArH), 6.95 (t, 3J ) 7.4 Hz, 1H, benzoyl-
Hp), 6.93 (d, 4J ) 2.2 Hz, 1H, ArH), 6.73 (d, 4J ) 2.3 Hz, 1H,
3
4
3
ArH), 6.66 (d, J ) 8.3 Hz, 2H, ArH iodoaryl group), 6.61 (d, J
) 2.1 Hz, 1H, ArH), 7.16 (s, 1H, ArH), 6.92 (t, J ) 7.2 Hz, 1H,
) 2.1 Hz, 1H, ArH), 6.58 (d, 4J ) 2.1 Hz, 1H, ArH), 6.30-6.50
benzoyl-Hp), 6.86 (s, 1H, ArH), 6.73 (s, 1H, ArH), 6.53 (s, 1H,
ArH), 6.52 (s, 1H, ArH), 6.45-6.10 (br, 4H, benzoyl-Ho+m), 4.25
(d, 2J (A-B) ) 13.4 Hz, 1H, CH2), 4.16 (d, 2J (A-B) ) 16.6 Hz,
1H, CH2), 4.01-3.78 (m, 5H, CH2 + OCH2), 3.66 (dd, apparent
2
(br, 4H, benzoyl-Ho+m), 5.20 (d, J (A-B) ) 11.1 Hz, 1H, OCH2),
4.56 (d, 2J (A-B) ) 11.1 Hz, 1H, OCH2), 4.28 (d, 2J (A-B) ) 16.6
Hz, 1H, CH2), 4.17 (d, 2J (A-B) ) 13.4 Hz, 1H, CH2), 4.08 (d,
2J (A-B) ) 17.6 Hz, 1H, CH2), 4.01 (d, J (A-B) ) 17.6 Hz, 1H,
3J (A-B) ) 8.3 Hz, 1H, OCH2), 3.51 (d, J (A-B) ) 13.7 Hz, 1H,
2
2
CH2), 3.89 (d, 2J (A-B) ) 16.6 Hz, 1H, CH2), 3.87 (d, 2J (A-B) )
CH2), 3.39 (d, 2J (A-B) ) 13.5 Hz, 1H, CH2), 1.42 (s, 9H,
C(CH3)3), 1.41 (s, 9H, C(CH3)3), 0.68 (s, 9H, C(CH3)3), 0.63 (s,
9H, C(CH3)3). 13C{1H} NMR (75 MHz, CDCl3): δ ) 163.2 (ArC-
(O)), 149.7, 149.4, 148.2, 147.9, 147.7, 145.9, 143.6, 142.5, 133.5,
132.4, 131.7, 131.6, 130.4, 129.8, 129.3, 128.2, 127.8, 127.3, 126.8,
126.4, 125.7, 125.4, 125.0, 124.8, 124.7 (all ArC), 75.6 (OCH2),
39.2, 39.0 (2 × CH2), 34.4, 34.2, 33.6, 33.2 (4 × C(CH3)3), 32.7,
32.5 (2 × CH2), 31.8, 31.7, 30.9, 30.7 (4 × C(CH3)3). MALDI-
TOF-MS (ditranol + KI): m/z ) 833.7 (M + K)+ (calcd 833.5).
Anal. Calcd for C54H66O5‚1/2H2O: C, 80.66; H, 8.40. Found: C,
81.21; H, 9.00.
13.6 Hz, 1H, CH2), 3.50 (d, 2J (A-B) ) 13.7 Hz, 1H, CH2), 3.38
2
(d, J (A-B) ) 13.5 Hz, 1H, CH2), 1.43 (s, 9H, C(CH3)3), 1.30 (s,
9H, C(CH3)3), 0.75 (s, 9H, C(CH3)3), 0.67 (s, 9H, C(CH3)3). 13C-
{1H} NMR (75 MHz, CDCl3): δ ) 163.3 (ArC(O)), 149.7, 149.2,
148.3, 148.0, 146.0, 143.5, 142.3, 137.8, 134.8, 134.0, 132.6, 131.6,
131.5, 130.7, 129.6, 129.2, 129.1, 128.1, 127.5, 127.3, 126.8, 126.4,
125.6, 125.1, 125.0, 124.7, 124.7 (all ArC), 94.2 (ArC-I), 74.4
(OCH2), 39.2, 39.1 (2 × CH2), 34.3, 34.1, 33.6, 33.2 (4 × C(CH3)3),
32.5, 32.4 (2 × CH2), 31.7, 31.5, 30.8, 30.7 (4 × C(CH3)3). MALDI-
TOF-MS (ditranol + KI): m/z ) 969.3 (M + H)+ (calcd 969.4),
1007.2 (M + K)+ (calcd 1007.4). Anal. Calcd for C58H65IO5‚1/
2H2O: C, 71.23; H, 6.80. Found: C, 71.00; H, 6.67.
Ackn owledgm en t. We thank CICYT (Grant PB1998-
0088) for financial support. A.W.K. thanks The Neth-
erlands Organization for Scientific Research for a
TALENT fellowship.
P a r tia l Con e 1,2-a n ti-Heter od isu bstitu ted 5,11,17,23-
Tetr akis(1,1-dim eth yleth yl)-25-(ben zyloxy)-26-(ben zoyloxy)-
27,28-bis(h yd r oxy)ca lix[4]a r en e (7). This compound was
prepared under nearly identical conditions as reported for 4
using benzyl bromide as reagent. Yield (after crystallization of
Su p p or tin g In for m a tion Ava ila ble: The ORTEP dia-
1
1
the crude product): 47%. Mp (crystals): 247-248 °C. H NMR
gram for the X-ray molecular structure of 4, copies of H and
(500 MHz, CDCl3): δ ) 8.98 (s, 1H, OH), 7.88 (s, 1H, OH), 7.47
(s, 1H, ArH), 7.39-7.36 (m, 3H, ArH benzyl), 7.24 (s, 1H, ArH),
7.22 (s, 1H, ArH), 7.16 (s, 1H, ArH), 6.97-6.95 (m, 3H, ArH
benzyl + benzoyl-Hp), 6.92 (s, 1H, ArH), 6.73 (s, 1H, ArH), 6.62
(s, 1H, ArH), 6.57 (s, 1H, ArH), 6.50-6.14 (br, 4H, benzoyl-Ho+m),
5.30 (d, 2J (A-B) ) 10.6 Hz, 1H, OCH2), 4.58 (d, 2J (A-B) ) 10.6
NOESY (500 MHz) spectra for 2-4, experimental/analytical
details and/or workup procedures for 4, 5, and 7-10, and CIF
file for the X-ray structural data of 4. This material is available
free of charge via the Internet at http://pubs.acs.org.
J O035150H
8714 J . Org. Chem., Vol. 68, No. 22, 2003