Selective functionalization of a single methylene bridge of a Calix[6]arene

Article abstract of DOI:10.1021/jo1005476

The monohydroxycalix[6]arene derivative 4a was prepared via photochemical bromination of hexamethoxycalix[6]arene 3a in aq THF. Monohydroxycalix[6]arene 4a and its chloro derivative 5 are useful synthetic intermediates for the preparation of structurally diverse calix[6]arenes functionalized at a single methylene bridge.

Full text of DOI:10.1021/jo1005476

pubs.acs.org/joc
Selective Functionalization of a Single Methylene Bridge
of a Calix[6]arene
Norbert Itzhak and Silvio E. Biali*
Institute of Chemistry, The Hebrew University of Jerusalem, Jerusalem 91904, Israel
silvio@vms.huji.ac.il
Received March 23, 2010
The monohydroxycalix[6]arene derivative 4a was prepared via photochemical bromination of
hexamethoxycalix[6]arene 3a in aq THF. Monohydroxycalix[6]arene 4a and its chloro derivative 5
are useful synthetic intermediates for the preparation of structurally diverse calix[6]arenes function-
alized at a single methylene bridge.
Introduction
been achieved only for the calix[4]arene scaffold and, nota-
bly, both synthetic methods reported involved metalation of
a methylene bridge. The first method reported involved a
homologous anionic ortho Fries rearrangement.4 In this
approach, a carbamate group originally attached to the
lower rim of the calixarene is transferred to a lithiated
methylene bridge via a five-membered intermediate. The
second approach, developed by Fantini and co-workers,
involved the monolithiation of a tetramethoxycalix[4]arene
followed by reaction of the lithiated macrocycle with an
alkylation agent such as primary alkyl halides or carbon
dioxide.5,6
The functionalization of the scaffold of the calixarenes is of
interest since the introduction of substituents may affect the
conformational preferences of the macrocycle, its rigidity, and
the physical and chemical properties of the molecule.1 Most
synthetic modifications have been conducted on the aryl rings
(the walls surrounding the cavity)1,2 and, to a much lesser
extent, at the methylene bridges.
Monosubstitution of a single methylene bridge is of inter-
est in the case where a minimal or gradual modification of the
properties of the macrocycle is desirable. Monofunction-
alized calixarenes have been prepared either by cycloconden-
sation of suitable fragments (the fragment condensation
method)3 or in straightforward fashion by direct modifica-
tion of the macrocycle. So far, the latter transformation has
(1) For recent reviews on calixarenes, see: (a) Calixarenes in Action;
Mandolini, L., Ungaro, R., Eds.; Imperial College Press: London, 2000. (b)
We have recently reported7,8 that the calixarenes incor-
porating bromine atoms at all bridges 1a-c are useful
starting materials for the preparation of a wide array of
€
Bohmer, V. In The Chemistry of Phenols; Rappoport, Z., Ed.; Wiley: Chichester,
2003; Chapter 19. (c) Gutsche, C. D. Calixarenes: an Introduction; Royal Society
of Chemistry: Cambridge, 2008.
(2) For recent examples, see: (a) Troisi, F.; Mogavero, L.; Gaeta, C.;
Gavuzzo, E.; Neri, P. Org. Lett. 2007, 9, 915. (b) Troisi, F.; Citro, L; Gaeta,
C.; Gavuzzo, E.; Neri, P. Org. Lett. 2008, 10, 1393.
(4) Middel, O.; Greff, Z.; Taylor, N. J.; Verboom, W.; Reinhoudt, D. N.;
Snieckus, V. J. Org. Chem. 2000, 65, 667.
€
(3) (a) Tabatabai, M.; Vogt, W.; Bohmer, V. Tetrahedron Lett. 1990, 31,
3295. (b) Sartori, G.; Maggi, R.; Bigi, F.; Arduini, A.; Pastorio, A.; Porta, C.
(5) (a) Scully, P. A.; Hamilton, T. M.; Bennett, J. L. Org. Lett. 2001, 3,
2741. (b) Hertel, M. P.; Behrle, A. C.; Williams, S. A.; Schmidt, J. A. R.; Fantini,
J. L. Tetrahedron 2009, 65, 8657. J. L. Fantini previously published as J. L.
Bennett. (c) For a recent study of the conformation behavior of a calix[4]arene with
a single methylene group substituted by a carboxyl functionality, see: Gruber, T.;
Gruner, M.; Fischer, C.; Seichter, W.; Bombicz, P.; Weber, E. New J. Chem. 2010,
34, 250. (d) For agostic and methylene hydride complexes of calix[4]arene, see:
Buccella, D.; Parkin, G. J. Am. Chem. Soc. 2006, 128, 16358.
€
J. Chem. Soc., Perkin Trans. 1 1994, 1657. (c) Biali, S. E.; Bohmer, V.; Cohen,
S.; Ferguson, G.; Gruttner, C.; Grynszpan, F.; Paulus, E. F.; Thondorf, I.;
€
Vogt, W. J. Am. Chem. Soc. 1996, 118, 2261. (d) Bergamaschi, M.; Bigi, F.;
Lanfranchi, M.; Maggi, R.; Pastorio, A.; Pellinghelli, M. A.; Peri, F.; Porta,
C.; Sartori, G. Tetrahedron 1997, 53, 13037. (e) For a review on the synthesis
of calixarenes via the stepwise and fragment condensation methods, see:
€
Bohmer, V. Liebigs Ann./Recueil 1997, 2019.
DOI: 10.1021/jo1005476
r
Published on Web 04/26/2010
J. Org. Chem. 2010, 75, 3437–3442 3437
2010 American Chemical Society

Itzhak and Biali
JOCArticle
calixarenes with all the methylene bridges monofunction-
alized. Replacement of the bromine atoms was conducted
under SN1 conditions, simply by refluxing a solution of the
bromocalixarene and the nucleophile in an ionizing solvent
such as 2,2,2-trifluoroethanol (TFE) or hexafluoro-2-propa-
nol (HFIP) (e.g., eq 1).9
all the methylene bridges of 3a, we conducted the photo-
chemical reaction using 15 equiv of NBS. Unexpectedly,
examination of the 1H NMR spectrum of the crude product
indicated the presence of a ca. 1:1 mixture of starting
material and a new compound, as well as γ-butyrolactone.
The new compound displayed six doublets for the methylene
protons in 2:2:2:2:1:1 ratio, a pattern indicating mirror
symmetry and consistent with a calix[6]arene derivative
with a single bridge monofunctionalized. On the basis of
the presence of a pair of doublets (J = 5.1 Hz) at 6.39 and
2.30 ppm (assigned to the methine and OH protons of the
CHOH unit, respectively) the product was assigned to the
monohydroxy calix[6]arene derivative 4a. The formation of
4a probably involves monobromination of the calixarene at a
single methylene bridge followed by hydrolysis of the formed
benzhydrylic-type bromine under the reaction conditions.
It seems likely that the abstraction of a hydrogen atom by
a bromine radical is slower in calixarene 3a than in the
bispropellane 2 due to steric hindrance, and therefore, reac-
tion with the THF solvent molecules successfully competes
with the bromination of 3a.
Attractive features of this route are the simplicity of the
reaction conditions (no Lewis acids, inert atmosphere, or dry
solvents are required) and its versatility (O-, N- S-, and
C-nucleophiles can be attached to the bridges by this route).
In this paper, we describe a simple route for the selective
monofunctionalization of the calix[6]arene skeleton.10
Results and Discussion
Methylene-Functionalized Monohydroxy Calix[6]arene
Derivative. Recently, Fitjer and co-workers reported the
oxidation of a single methylene group of the bispropellane
2 using NBS in a THF/water/CaCO3 mixture (eq 2).11
Additional attempts to improve the yield of the monohy-
droxy derivative proved unsuccessful. For example, as
shown by 1H NMR spectroscopy, increasing the number of
equivalents of NBS decreased the amount of unreacted
starting material but resulted in the concomitant formation
of additional products. In retrospect, the ratio of reagents
chosen for our initial attempted “oxidation” reaction proved
to be the best for the preparation of the monosubstituted
product. Although the reaction yields a mixture of 4a
and unreacted 3a, a 5 g mixture of the two compounds can
be easily separated by flash chromatography due to their
significantly different Rf values, and if necessary 3a can be
recycled for an additional reaction. We also attempted
to achieve selective functionalization of two bridges by
decreasing the amount of THF by half or by conducting
the reaction on the monohydroxy derivative 4a. However, in
both cases, a complex mixture of products was obtained as
shown by 1H NMR spectroscopy. Apparently, the function-
alization of the second bridge does not proceed in regiose-
lective fashion.
We examined also the reaction of 3b and 3c to test whether
the reaction conditions found for 3a are applicable also for
the selective functionalization of a single methylene bridge of
larger and smaller ring calixarenes. The attempted re-
actions were conducted using amounts of reagents (1.05 g
of calixarene, 2.67 g of NBS, 1.2 g of CaCO3, and 20 mL of
THF containing 5% water) identical to those used for 3a.
Although samples of identical weight of the calixarenes 3a-c
Because of our continued interest in ketocalixarenes,12 we
decided to attempt the analogous reaction on the hexa-
methoxy calix[6]arene 3a (eq 3). In an attempt to oxidize
(6) For examples of calixarenes modified at two or all bridges, see, for
€
€
example: (a) Gormar, G.; Seiffarth, K.; Schultz, M.; Zimmerman, J.; Flamig,
G. Makromol. Chem. 1990, 191, 81. (b) Agbaria, K.; Biali, S. E. J. Am. Chem.
Soc. 2001, 123, 12495. (c) Kuno, L.; Seri, N.; Biali, S. E. Org. Lett. 2007, 9,
1577. (d) For a recent example of an optically active methylene-substituted
calix[4]arene, see: Gopalsamuthiram, V.; Predeus, A. V.; Huang, R. H.;
Wulff, W. D. J. Am. Chem. Soc. 2009, 131, 18018.
€
(7) (a) Klenke, B.; Nather, C.; Friedrichsen, W. Tetrahedron Lett. 1998,
39, 8967. (b) Kumar, S. K.; Chawla, H. M.; Varadarajan, R. Tetrahedron
Lett. 2002, 43, 7073.
(8) (a) Columbus, I.; Biali, S. E. Org. Lett. 2007, 9, 2927. (b) Columbus, I.;
Biali, S. E. J. Org. Chem. 2008, 73, 2598. (c) Kogan, K.; Columbus, I.; Biali, S.
E. J. Org. Chem. 2008, 73, 7327. (d) Kogan, K.; Biali, S. E. J. Org. Chem.
2009, 74, 7172.
(9) For examples of silver-mediated substitutions in bromodienone calix-
arene derivatives, see: Troisi, F.; Pierro, T.; Gaeta, C.; Neri, P. Org. Lett.
2009, 11, 697.
(10) Several calix[5]arenes monosubstituted at a single bridge have been
€
prepared by the fragment condensation method. See: Biali, S. E.; Bohmer,
V.; Columbus, I; Ferguson, G.; Gruttner, C.; Grynszpan, F.; Paulus, E. F.;
€
Thondorf, I. J. Chem. Soc., Perkin Trans. 2 1998, 2261.
(11) Justus, K.; Beck, T.; Noltemeyer, M.; Fitjer, L. Tetrahedron 2009, 65,
5192.
(12) (a) Seri, N.; Thondorf, I.; Biali, S. E. J. Org. Chem. 2004, 69, 4774. (b)
Kogan, K.; Biali, S. E. Org. Lett. 2007, 9, 2393.
3438 J. Org. Chem. Vol. 75, No. 10, 2010

Itzhak and Biali
JOCArticle
obviously differ in the total number of molecules, they
possess an identical total number of methylene groups.
If the reactivities of the methylene groups of the different
calixarenes are similar, it could be expected that monofunc-
tionalized calixarenes (in addition to unreacted starting
material and γ-butyrolactone) should be obtained in all
cases.
1
Reaction of 3c afforded, as judged from H NMR of
the crude product, almost exclusively starting material
and γ-butyrolactone. The lower reactivity of 3c under
the reaction conditions (as compared to 3a) indicates that
a methylene group of 3c is significantly less reactive toward
the bromine radical than the corresponding group
in 3a. The difference in reactivity may be due to the dec-
reased conformational flexibility of the smaller calix-
arene. Ideally, in the transition state of the hydrogen
abstraction step by the bromine radical, the π clouds
of two rings geminal to the reacting methylene bridge
should overlap with the orbital of the developing carbon
radical. This arrangement can be more easily attainable
for the larger calix[6]arene, thus the lower reactivity of 3c.
For the larger calix[8]arene 3b, the reactivity under the
reaction conditions was essentially identical to that of 3a
and afforded a ca. 1:1 mixture of starting material and its
monohydroxy derivative 4b.13 This compound displayed in
the 1H NMR spectrum four t-Bu signals, eight doublets for
the methylene protons in 2:2:2:2:2:2:1:1 ratio, and a pair of
doublets (J = 4 Hz) at 6.45 and 2.71 ppm for the CHOH
moiety.
FIGURE 1. Crystal structure of the monohydroxycalix[6]arene 4a.
between two enantiomeric conformations of C1 symmetry
(an enantiomerization process, Figure 2).14
Preparation and Reactions of the Chloro Derivative 5.
Calixarene 4a can provide a synthetic entry into a wide array
of calix[6]arenes monofuntionalized at a single group by
means of the SN1 route utilized for the bromocalixarenes.
To be on more familiar grounds, monohydroxycalix[6]arene
was treated with SOCl2 to afford the monochloro derivative 5.
To test whether this compound is reactive toward O-nucleo-
philes under solvolytic conditions, 5 was heated in solution at
reflux temperature with either TFE or 2-propanol. In both
cases, the corresponding ethers (6a and 6b, respectively) were
obtained in practically quantitative yield15 (eq 4). As in the
case of 1a-c,8 most likely the substitution reaction proceeds
via a SN1 mechanism involving a carbocation.
Crystal Structure of 4a and Conformation in Solution. A
single crystal of 4a was grown from chloroform and sub-
mitted to X-ray crystallography (Figure 1). The molecule
adopts a 1,2,3-alternate conformation with four methoxy
groups oriented “out” and a pair of methoxy groups oriented
“in”. In the crystal conformation the substituent is located
between a pair of rings oriented syn. The OH group is
intermolecularly hydrogen bonded to the oxygen of one of
the methoxy groups oriented “in” (O3) of a neighboring
molecule.
Ideally, in the absence of the substituent at the bridge, the
1,2,3-alternate conformation should possess Ci symmetry.
However, its presence lowers the symmetry to C1, rendering
the conformation chiral. The pattern of signals observed in
the 1H NMR spectrum at room temperature indicates a
structure of Cs symmetry, but if indeed the solution con-
formation is similar to the conformation found in the crystal,
the pattern observed may be the result of fast exchange
The solvolytic Friedel-Crafts reaction8,16 of 5 was also
examined. Reactions with the electron-rich thymol and
p-tert-butylphenol were conducted in a mixture of TFE/CHCl3
containing a drop of concd HBr.17 For the less nucleophilic
mesitylene, HFIP was used as the ionizing solvent yielding 7e.
Since HFIP is relatively expensive, we also examined “classical”
Friedel-Crafts reaction conditions using a Lewis acid instead
(14) Lowering the temperature of a sample of 4a in CD2Cl2 to 188 K
resulted in extensive broadening of all signals, but no decoalescence was
observed.
(15) In contrast to 1c, the reaction of 5 with aniline (in HFIP) proceeds in
nonregioselective fashion and affords a mixture of two products, derived
from N-alkylation and C-alkylation of aniline.
(16) Hofmann, M.; Hampel, N.; Kanzian, T.; Mayr, H. Angew. Chem.
Int. Ed. 2004, 43, 5402.
(17) In principle, reaction of the carbocation with TFE could results in the
formation of 6a. However, if the trifluoroethoxy group of 6a is reversibly
cleaved under the acidic reaction conditions, but the electrophilic substitu-
tion reaction on the aromatic ring is irreversible, only the Friedel-Crafts
product should be obtained.
(13) The use of 4b as a starting material for the preparation of methylene-
functionalized calix[8]arenes is currently under investigation and will be
reported in due course.
J. Org. Chem. Vol. 75, No. 10, 2010 3439

Itzhak and Biali
JOCArticle
FIGURE 2. Up-down rotation of the rings A and B in the left structure results in enantiomerization. When these rotations are fast (on the
NMR time scale) a signals pattern consistent with an average Cs symmetry should be observed.
of the ionizing solvent. The reaction of 5 with m-xylene
catalyzed by boron trifluoride etherate proceeded readily and
yielded the derivative 7d (eq 5).
trifluoride etherate yielded the monoacetylacetonyl deriva-
tive 8 (eq 6).18
In contrast to 3, the t-Bu, methylene, and methoxy signals
of the 7a-d displayed some broadening in the NMR
spectrum at room temperature. This broadening was parti-
cularly marked for the mesityl derivative 7e. It seems likely
that this broadening is due to restricted rotation. At 373 K,
sharp signals were observed for 7e with a signal pattern
indicating an average (dynamic) Cs symmetry, as observed
for 4a at rt.
The OH group can be utilized for the incorporation of
other groups at the bridge. The OH group of aliphatic
alcohols can be replaced by fluorine by treatment with the
deoxofluorinating reagent DAST (Et2NSF3).19 Reaction of
4a with DAST proceeded readily and afforded 9 (eq 7), the
first calixarene derivative in which a fluorine atom has been
incorporated into a bridge. The incorporation of a fluorine
1
atom was readily evident in the H NMR and 13C NMR
spectra of 9, since in both spectra doublets indicating cou-
plings with the fluorine atom were observed for the proton
(2J = 47 Hz) and carbon (1J = 166 Hz) of the functionalized
methylene group. In addition, a fluorine signal was observed
in the 19F NMR (δ -165.6 ppm).
Direct Replacement of the OH Group of 4a. The possibility
of conducting the reaction directly on the hydroxy deriva-
tive, rather than on the chloro derivative (whose preparation
requires an additional synthetic step), was also examined.
No reaction was observed when a solution of 4a and
m-xylene in HFIP was heated at reflux, indicating that,
although the ionizing solvent is relatively acidic, its presence
alone in not sufficient to generate the calixarene carboca-
tion. However, in the presence of a Lewis acid the OH group
at the bridge can be cleaved heterolytically. Treatment of a
solution of 4a and 1,3-pentadienone in CH2Cl2 with boron
Conclusions
In summary, we have shown that the monohydroxy and
monochloro derivatives 4a and 5 are readily synthetically
available and are useful precursors for the preparation of a
wide array of monofunctionalized calix[6]arenes. Interest-
ingly, the present approach and the method developed by
Fantini and co-workers involve the introduction of opposite
charges (positive and negative) at a single methylene bridge.
Electron-rich substituents, which can be incorporated by the
SN1 route, are not accessible via the lithiation/alkylation
(18) For recent reports of the Lewis acid-catalyzed alkylation of benzhy-
dryl cations with compounds possessing active methylenes, see: (a) Bisaro,
F.; Prestat, G.; Vitale, M.; Poli, G. Synlett 2002, 1823. (b) Jana, U.; Biswas,
S.; Maiti, S. Tetrahedron Lett. 2007, 48, 4066. (c) Sanz, R.; Miguel, D.;
Martinez, A.; Alvarez-Gutierrez, J. M.; Rodriguez, F. Org. Lett. 2007, 9,
2027.
(19) Middleton, W. J. J. Org. Chem. 1975, 40, 574.
3440 J. Org. Chem. Vol. 75, No. 10, 2010

Itzhak and Biali
JOCArticle
route and vice versa (primary alkyl groups, readily available
by the lithiation route cannot be incorporated by the present
approach), and therefore, the two synthetic methodologies
are complementary.
signals, 6H), 6.95 (br s, 3H), 4.40 (d, J = 15.6 Hz, 2H), 4.24 (d,
J = 15.2 Hz, 2H), 4.16 (d, J = 14.8 Hz, 1H), 3.79 (d, J = 14.4
Hz, 1H), 3.68 (d, J = 15.2 Hz, 2H), 3.55 (d, J = 14.8 Hz, 2H),
3.09 (s, 6H), 3.05 (s, 6H), 2.98 (s, 6H), 1.16 (s, 18H), 1.12 (s,
18H), 1.10 (s, 18H); 13C NMR (125 MHz, CDCl3) δ 153.8, 152.7,
146.1, 145.8, 133.9, 133.7, 133.4, 133.3, 132.8, 128.0, 126.0,
125.9, 125.8, 125.7, 124.5, 65.1, 60.5, 60.0, 53.4, 34.3, 34.1,
31.4, 31.3, 30.3, 30.0, 15.3; HRMS (ESI) m/z 1055.7123 (M -
Cl), calcd for C72H95O6 (M - Cl) 1055.7129. Anal. Calcd for
C72H95ClO6: C, 79.19; H, 8.77. Found: C, 79.07; H, 8.71.
General Procedure for the Preparation of Monoalkoxy Calix-
[6]arene Derivatives. A solution of 5 (0.10 g, 0.09 mmol) in 4 mL
of chloroform and 10 mL of the appropriate alcohol was heated
to reflux overnight. The solvents were evaporated under vacuum
to afford the corresponding derivatives in quantitative yield. A
small amount was recrystallized from CHCl3/MeOH for analy-
tical purposes.
5,11,17,23,29,35-Hexa-tert-butyl-37,38,39,40,41,42-hexam-
ethoxy-2-(2,2,2-trifluoroethoxy)calix[6]arene (6a): mp 210 °C;
1H NMR (CDCl3, 400 MHz) δ 7.20 (d, J = 2.4 Hz, 2H), 7.13 (d,
J = 2.4 Hz, 2H), 7.00 (br m, 2H), 6.97 (br m, 6H), 6.22 (s, 1H),
4.42 (d, J = 15.2 Hz, 2H), 4.22 (d, J = 14.8 Hz, 2H), 4.15 (d, J =
15.6 Hz, 1H), 3.79 (m, 3H), 3.67 (d, J = 15.2 Hz, 2H), 3.53 (d,
J = 15.6 Hz, 2H), 3.04 (s, 6H), 3.00 (s, 6H), 2.97 (s, 6H), 1.13 (s,
18H), 1.12 (s, 18H), 1.11 (s, 18H); 13C NMR (125 MHz, CDCl3)
δ 133.7, 133.6, 133.5, 133.4, 133.0, 132.0, 128.0, 126.0, 125.9,
125.8, 123.8, 73.5, 66.6, 66.3, 60.0, 59.97, 34.3, 34.1, 31.39, 31.38,
31.3, 30.4, 30.2, 30.0; HRMS (ESI) m/z 1177.7079 (M þ Naþ),
calcd for C74H97F3O7Na 1177.7084. Anal. Calcd for C74H97-
F3O7: C, 76.91; H, 8.46. Found: C, 77.20; H, 8.45.
Experimental Section
5,11,17,23,29,35-Hexa-tert-butyl-2-hydroxy-37,38,39,40,41,42-
hexamethoxycalix[6]arene (4a). A mixture of 3a20 (1.05 g, 1.0
mmol), NBS (2.67 g, 15 mmol), CaCO3 (1.2 g, 12 mmol), and
THF containing 5% water (20 mL) was heated at reflux over-
night while being irradiated with a spotlight (150 W). After
evaporation of the solvent, the residue was dissolved in chloro-
form (30 mL) and washed with brine, diluted aq HCl, and brine.
The organic phase was dried (Na2SO4) and evaporated. The
crude product was recrystallized from methanol to give 0.6 g
(60%) of a ca. 1:1 mixture of 3 and 4a, as judged by 1H NMR.
The mixture was separated by flash chromatography (eluent,
100:6 CH2Cl2/ethyl acetate) to afford 250 mg (23%) of pure 4a:
mp 315 °C dec; 1H NMR (400 MHz, CDCl3) δ 7.31 (d, J = 2.4
Hz, 2H), 7.08 (d, J = 2.4 Hz, 2H), 7.03 (d, J = 2.4 Hz, 2H), 7.01
(d, J = 2.4 Hz, 2H), 6.99 (d, J = 2.4 Hz, 2H), 6.97 (d, J = 2.4 Hz,
2H), 6.39 (d, J = 5.1 Hz, 1H), 4.30 (d, J = 15.2 Hz, 2H), 4.16 (d,
J = 14.8 Hz, 2H), 4.10 (d, J = 14.8 Hz, 1H), 3.84 (d, J = 14.8
Hz, 1H), 3.76 (d, J = 15.2 Hz, 2H), 3.63 (d, J = 15.2 Hz, 2H),
3.00 (s, 6H), 2.97 (s, 6H), 2.93 (s, 6H), 2.30 (d, J = 5.1 Hz, 1H,
exchanges with D2O), 1.16 (s, 18H), 1.14 (s, 18H), 1.13 (s, 18H);
13C NMR (125 MHz, CDCl3) δ 153.9, 153.8, 153.3, 146.1, 145.8,
145.7, 136.2, 133.6, 133.48, 133.45, 133.39, 133.29, 133.0, 127.5,
126.0, 125.5, 123.0, 60.5, 60.4, 60.0, 59.9, 34.3, 34.1, 34.0, 31.4,
31.3, 31.0, 30.5, 30.3, 30.2; HRMS (ESI) m/z 1095.7048 (M þ
Naþ), calcd for C72H96O7Na 1095.7054.
5,11,17,23,29,35-Hexa-tert-butyl-2-isopropoxy-37,38,39,40,41,42-
1
hexamethoxycalix[6]arene (6b): mp 178 °C; H NMR (CDCl3,
400 MHz) δ 7.24 (br s, 2H), 7.07 (d, J = 2.4 Hz, 2H), 7.00 (d, J =
2.4 Hz, 2H), 6.97 (br s, 6H), 6.23 (s, 1H), 4.44 (d, J = 15.2 Hz,
2H), 4.28 (d, J = 14.8 Hz, 2H), 4.20 (d, J = 15.6 Hz, 1H), 3.75
(d, J = 15.6 Hz, 1H), 3.63 (d, J = 15.2 Hz, 2H), 3.58 (h, J = 6.0
Hz, 1H), 3.52 (d, J = 15.2 Hz, 2H), 3.02 (br s, 6H), 3.01 (br s,
6H), 2.96 (s, 6H), 1.23 (d, J = 6.0 Hz, 6H), 1.12 (s, 36H), 1.11 (s,
18H); 13C NMR (125 MHz, CDCl3) δ 154.1, 153.9, 153.8, 145.7,
145.68, 134.1, 133.5, 133.45, 133.38, 133.34, 133.2, 127.3, 126.0,
125.9, 125.8, 124.4, 69.7, 69.1, 60.7, 60.01, 59.99, 41.3, 34.2,
34.1, 31.4, 31.38, 30.9, 30.5, 30.3, 30.2, 30.0, 29.0, 22.6, 22.4;
HRMS (ESI) m/z 1137.7518 (M þ Naþ), calcd for C75H102O7Na
1137.7523.
5,11,17,23,29,35,41,47-Octa-tert-butyl-2-hydroxy-49,50,51,52,
53,54,55,56-octamethoxycalix[8]arene (4b). A mixture of 3b (2.81
g, 2.0 mmol), NBS (5.34 g, 30 mmol), CaCO3 (2.4 g, 24 mmol),
and 45 mL of THF (containing 5% water) was stirred and heated
under reflux overnight while being irradiated with a spotlight
(150 W). After vacuum evaporation of the solvent, theresidue was
dissolved in chloroform (50 mL) and washed successively with
brine, diluted aq HCl, and brine. The organic phase was dried
(Na2SO4) and evaporated. The crude product was recrystallized
from CHCl3/MeOH to give 1.8 g (63%) of a ca. 40:60 mixture of
4b and 3b, as judged by NMR. The mixture was separated by flash
chromatography (eluent: 100:6 methylene chloride/ethyl acetate)
1
Reaction of 5 with Thymol and p-tert-Butylphenol. To a
solution of 5 (0.10 g, 0.009 mmol) in 7.5 mL of TFE and 2.5
mL of CHCl3 was added one drop of concentrated HBr and 0.03
mmol of the appropriate arene derivative. The mixture was
heated to reflux overnight. The solvents were evaporated under
vacuum. The residue was dissolved in chloroform (10 mL) and
washed with brine and the organic phase dried on Na2SO4 and
evaporated. Recrystallization from CHCl3/MeOH afforded the
pure compound.
to afford 620 mg (22%) of pure 4b: mp 288 °C; H NMR (400
MHz, CDCl3) δ 7.25 (d, J = 2.4 Hz, 2H), 7.00 (d, J = 2.4 Hz, 2H),
6.96-6.92 (overlapping d, 6H), 6.90-6.89 (overlapping d, 4H),
6.85 (d, J = 2.4 Hz, 2H), 6.45 (d, J = 4.4 Hz, 1H), 4.25 (d, J= 16.0
Hz, 2H), 4.19 (d, J = 15.6 Hz, 2H), 4.14 (d, J = 14.4 Hz, 2H), 4.05
(d, J = 16.0 Hz, 1H), 3.93 (d, J = 16.0 Hz, 1H), 3.91 (d, J = 14.4
Hz, 2H), 3.87 (d, J = 16.4 Hz, 2H), 3.81 (d, J = 16.0 Hz, 2H), 3.44
(s, 6H), 3.43 (s, 6H), 3.40 (br s, 12H), 2.71 (d, J = 4.0 Hz, 1H), 1.12
(s, 18H), 1.08 (s, 18H), 1.07 (s, 18H), 1.03 (s, 18H); 13C NMR (125
MHz, CDCl3) δ 154.4, 153.9, 146.3, 146.0, 145.97, 145.93, 135.7,
133.1, 133.0, 132.7, 127.5, 125.9, 123.2, 61.1, 60.5, 60.4, 34.3, 34.1,
31.6, 31.3; HRMS (ESI) m/z 1448.9482 (M þ Naþ), calcd for
C96H128O9Na 1448.9490.
1
7a: yield 35 mg (32%); mp 182 °C; H NMR (CDCl3, 400
MHz) δ 7.00 (br s, 10H), 6.85 (s, 2H), 6.78 (s, 1H), 6.50 (s, 1H),
6.29 (s, 1H), 4.58 (s, 1H), 4.44 (d, J = 15.2 Hz, 2H), 4.32 (d, J =
15.6 Hz, 2H), 4.25 (d, J = 14.8 Hz, 1H), 3.72 (d, J = 14.8 Hz,
1H), 3.64 (d, J = 15.2 Hz, 2H), 3.48 (d, J = 15.2 Hz, 2H), 3.20
-2.87 (13H), 2.77 (br s, 6H), 1.23-1.08 (60 H); 13C NMR (125
MHz, CDCl3) δ 153.9, 153.8, 153.6, 150.3, 145.7, 145.6, 145.2,
136.3, 135.5, 134.9, 133.5, 133.45, 133.38, 133.0, 130.9, 130.5,
128.8, 127.0, 126.1, 126.0, 125.9, 125.7, 123.4, 117.2, 60.6, 60.1,
60.0, 59.96, 59.90, 39.3, 34.3, 34.13, 34.12, 34.0, 31.4, 31.3, 30.5,
30.3, 30.2, 29.9, 29.7, 26.5, 22.8, 19.1; HRMS (ESI) m/z
1227.7987 (M þ Naþ), calcd for C82H108O7Na 1227.7993.
5,11,17,23,29,35-Hexa-tert-butyl-2-chloro-37,38,39,40,41,42-
hexamethoxycalix[6]arene (5). A mixture of 4a (0.5 g, 0.47
mmol) in thionyl chloride (5 mL) was heated at reflux for 1 h.
The solution was evaporated to dryness to afford quantitatively
almost pure 5. Recrystallization from ether gave 0.38 g (74%)
pure 5: mp 295 °C dec; 1H NMR (400 MHz, CDCl3) δ 7.39 (d,
J = 2.4 Hz, 2H), 7.11 (d, J = 2.4 Hz, 2H), 6.98 (overlapping
1
7b: yield 40 mg (38%); mp 182 °C; H NMR (CDCl3, 400
(20) Janssen, R. G.; Verboom, W.; Reinhoudt, D. N.; Casnati, A.;
Freriks, M.; Pochini, A.; Ugozzoli, F.; Ungaro, R.; Nieto, P. M.
Carramolino, M.; Cuevas, F.; Prados, P.; de Mendoza, J. Synthesis 1993, 380.
MHz) δ 7.08 (dd, J = 8.0, 2.4 Hz, 1H), 7.06 (d, J = 2.4 Hz, 2H),
7.01 (br s, 4H), 6.99 (br s, 2H), 6.97 (br s, 2H), 6.94 (d, J = 2.8 Hz,
J. Org. Chem. Vol. 75, No. 10, 2010 3441

Itzhak and Biali
JOCArticle
1H), 6.93 (d, J = 2.4 Hz, 2H), 6.71(d, J = 8 Hz, 1H), 6.38(s, 1H),
4.79 (s, 1H), 4.43 (d, J = 14.8 Hz, 2H), 4.27 (J = 15.2 Hz, 2H),
4.19 (d, J = 15.2 Hz, 1H), 3.76 (d, J = 15.6 Hz, 1H), 3.67 (d, J =
15.6 Hz, 2H), 3.50 (d, J = 15.2 Hz, 2H), 3.06 (br s, 6H), 2.99 (br s,
6H), 2.84 (s, 6H), 1.17 (s, 9H), 1.13 (s, 18H), 1.12 (s, 18H), 1.08 (s,
18H); 13C NMR (125 MHz, CDCl3) δ 153.8, 153.6, 151.1, 145.71,
145.69, 145.58, 142.6, 134.9, 133.6, 133.47, 133.42, 133.25. 129.9,
127.0, 126.3, 126.1, 125.9, 125.8, 125.6, 123.9, 115.3, 60.17, 60.02,
59.99, 37.13, 34.17, 34.12, 34.0, 31.47, 31.41, 31.30, 30.4, 30.3,
30.0; HRMS (ESI) m/z 1205.8169 (M þ Hþ), calcd for C82H109O7
(M þ Hþ) 1205.8173.
2.78 (s, 6H), 2.23 (s, 3H), 2.15 (s, 6H), 1.25 (s, 18H), 1.24 (s,
18H), 1.14 (s, 18H); 13C NMR (125 MHz, C2D2Cl4, 400 K) δ
154.2, 153.8, 145.54, 145.51, 144.8, 137.9, 137.2, 134.8, 133.4,
133.2, 133.14, 133.13, 132.9, 129.9, 126.5, 125.7, 60.4, 59.9, 59.8,
59.6, 41.1, 34.0, 33.85, 33.84, 33.80, 31.24, 31.12, 30.68, 30.41,
29.8, 21.9, 20.4; HRMS (ESI) m/z 1197.7882 (M þ Naþ), calcd
for C81H106O6Na 1197.7887.
5,11,17,23,29,35-Hexa-tert-butyl-37,38,39,40,41,42-hexam-
ethoxy-2-(2,4-pentanedion-3-yl)calix[6]arene (8). To a solution
of 4a (0.1 g, 0.093 mmol) in dry CH2Cl2 (10 mL) were added 1,3-
pentanedione (0.5 mL) and BF3 OEt2 (50 μL). The mixture
3
Reaction of 5 with 4-Methylanisole. To a solution of 5 (0.1 g,
0.009 mmol) in TFE (8 mL) and CHCl3 (1.5 mL) was added 1
drop of concd HBr and 4-methylanisole (0.1 mL). The mixture
was heated to reflux overnight. After evaporation of the sol-
vents, the residue was dissolved in CHCl3 (15 mL) and washed
with brine. The organic phase was dried on Na2SO4, and the
solvent was evaporated. The crude product was recrystallized
from MeOH to afford pure 7c: yield 35 mg (33%); mp 202 °C; 1H
NMR (CDCl3, 500 MHz) δ 7.13-6.92 (overlapping peaks,
11H), 6.84 (s, 2H), 6.80-6.72 (overlapping peaks, 2H), 6.56 (s,
1H), 4.45 (d, J = 15.0 Hz, 2H), 4.31 (d, J = 15.0 Hz, 2H), 4.23
(d, J = 15.0 Hz, 1H), 3.76 (d, J = 14.5 Hz, 1H), 3.68 (d, J = 15.0
Hz, 2H), 3.65 (s, 3H), 3.51 (d, J = 15.0 Hz, 2H), 3.06 (s, 6H), 3.03
was stirred overnight at room temperature, the solvents were
evaporated and the residue dissolved in CH2Cl2 (15 mL) and
washed with a saturated solution of NaHCO3 (5 mL) and brine.
The organic layer was dried (Na2SO4) and evaporated. The
crude product was recrystallized from methanol to afford pure
8: yield 45 mg (43%); mp 262 °C; 1H NMR (500 MHz, CDCl3,
318 K) δ 7.13 (d, J = 2.0 Hz, 2H), 7.12 (br s, 2H), 7.04 (d, J = 2.0
Hz, 2H), 6.97 (br s, 2H), 6.93 (d, J = 2.0 Hz, 2H), 6.92 (br s, 2H),
5.29 (d, J = 11.5 Hz, 1H), 4.77 (d, J = 11.7 Hz, 1H), 4.12 (d, J =
14.5 Hz, 2H), 3.99 (overlapping d, J = 14.0 Hz, 3H), 3.88 (d, J =
14.5 Hz, 1H), 3.81 (d, J = 14.5 Hz, 2H), 3.69 (d, J = 14.5 Hz,
2H), 3.16 (s, 6H), 3.13 (s, 6H), 2.74 (s, 6H), 1.98 (s, 6H), 1.17 (s,
18H), 1.15 (s, 36H); 13C NMR (125 MHz, CDCl3, 318 K) δ
204.2, 154.1, 154.07, 154.00, 153.9, 145.8, 145.7, 145.6, 133.8,
133.7, 133.5, 133.4, 132.6, 126.7, 126.4, 126.2, 126.1, 125.5,
124.7, 60.1, 59.9, 59.8, 34.2, 34.14, 34.08, 31.4, 31.3, 30.4, 30.2,
29.9; HRMS (ESI) m/z 1177.7467 (M þ Naþ), calcd for
C77H108O8Na 1177.7472. Anal. Calcd for C77H108O8: C,
80.03; H, 8.90. Found: C, 79.87; H, 8.79.
(s, 6H), 2.93 (s, 6H), 2.22 (s, 3H), 1.16 (s, 36H), 1.08 (s, 18H); 13
C
NMR (125 MHz, CDCl3) δ 155.2, 153.8, 145.7, 145.6, 145.0,
136.6, 133.5, 133.4, 133.3, 133.1, 132.9, 130.7, 128.9, 127.4,
125.8, 125.7, 111.2, 60.04, 59.96, 56.07, 37.1, 34.1, 31.4, 31.3,
30.4, 30.2, 30.0, 20.8; HRMS (ESI) m/z 1199.7674 (M þ Naþ),
calcd for C80H104O7Na 1199.7680.
5,11,17,23,29,35-Hexa-tert-butyl-2-(2,4-dimethylphenyl)-
37,38,39,40,41,42-hexamethoxycalix[6]arene (7d). A mixture of
5 (0.05 g, 0.045 mmol), dry m-xylene (2 mL), and BF3 OEt2
5,11,17,23,29,35-Hexa-tert-butyl-2-fluoro-37,38,39,40,41,42-
hexamethoxycalix[6]arene (9). To a cold solution (-18 °C) of 4a
(0.1 g, 0.093 mmol) in dry CH2Cl2 (10 mL) was added, during 10
min under an inert atmosphere, 0.1 mL (0.73 mmol) of diethy-
laminosulfur trifluoride (DAST). The temperature of the solu-
tion was raised slowly to room temperature, and the mixture was
stirred overnight. The excess DAST was quenched with 5 mL of
water, and the organic phase was separated, washed several
times with brine, dried (Na2SO4), and evaporated. The residue
was recrystallized from CHCl3/MeOH: yield 20 mg (19%); mp
260 °C dec; 1H NMR (500 MHz, CDCl3) δ 7.24 (d, J = 2 Hz,
2H), 7.16 (d, J = 2 Hz, 2H), 7.10 (d, J = 47 Hz, 1H), 6.99
(overlapping d, J = 2 Hz, 6H), 6.97 (d, J = 2 Hz, 2H), 4.34 (d, J
= 15.1 Hz, 2H), 4.18 (d, J = 14.7 Hz, 2H), 4.08 (d, J = 14.7 Hz,
1H), 3.81 (d, J = 14.7 Hz, 1H), 3.72 (d, J = 14.7 Hz, 2H), 3.57
(d, J = 15.3 Hz, 2H), 3.08 (s, 6H), 3.01 (s, 6H), 2.97 (s, 6H), 1.16
(s, 18H), 1.13 (s, 18H), 1.11 (s, 18H); 13C NMR (125 MHz,
CDCl3) δ 153.86, 153.80, 153.55, 153.52, 146.1, 145.76, 145.68,
133.6, 133.5, 133.4, 133.0, 132.3, 132.1, 128.4, 126.0, 125.9,
125.7, 123.04, 122.99, 86.05, 84.7, 60.9, 60.0, 59.9, 34.3, 34.1,
31.4, 31.37, 31.34, 30.4, 30.2, 30.1; HRMS (ESI) m/z 1097.7007
(M þ Naþ), calcd for C72H95FO6Na 1097.7010.
3
(20 μL) was heated for 2 h to 80 °C. The solvent was evaporated
and the residue dissolved in CH2Cl2 (15 mL). The solution was
dried (Na2SO4) and evaporated to afford 7d. The crude product
was recrystallized form methanol: yield 20 mg (38%); mp 160 °C;
1H NMR (CDCl3, 500 MHz) δ 7.07-6.98 (overlapping peaks,
10H), 6.92 (s, 1H), 6.86 (d, J = 8.0 Hz, 1H), 6.84 (br s, 2H), 6.78
(d, J = 8.0 Hz, 1H), 6.32 (s, 1H), 4.42 (d, J = 15.0 Hz, 2H), 4.27
(d, J = 15.0 Hz, 2H), 4.19 (d, J = 15.0 Hz, 1H), 3.78 (d, J = 15.0
Hz, 1H), 3.69 (d, J = 15.0 Hz, 2H), 3.51 (d, J = 15.0Hz, 2H), 3.31
(s, 6H), 3.04 (s, 6H), 2.81 (s, 6H), 2.27 (s, 3H), 2.13 (s, 3H), 1.16 (s,
18H), 1.14 (s, 18H), 1.09 (s, 18H); 13C NMR (125 MHz, CDCl3) δ
153.8, 153.7, 145.71, 145.68, 145.3, 140.1, 136.4, 136.3, 135.2,
133.6, 133.5, 133.4, 133.2, 133.0, 131.1, 128.7, 125.92, 125.88,
60.06, 60.03, 59.9, 39.8, 34.15, 34.12, 31.42, 31.41, 31.36, 30.3,
30.2, 29.8, 29.5, 20.9, 19.6; HRMS (ESI) m/z 1183.7725 (M þ
Naþ), calcd for C80H104O6Na 1183.7731.
5,11,17,23,29,35-Hexa-tert-butyl-37,38,39,40,41,42-hexam-
ethoxy-2-mesitylcalix[6]arene (7e). To a solution of 5 (0.1 g,
0.009 mmol) in 8 mL of CHCl3 and 2 mL of HFIP was added 0.2
mL of mesitylene and the mixture heated to reflux for 3 h. After
the solvents were evaporated, the residue was dissolved in
chloroform (15 mL) and the solution was washed with brine.
The organic phase was dried (Na2SO4) and evaporated. Recrys-
tallization from CHCl3/MeOH afforded the pure product: yield
45 mg (41%); mp 218 °C; 1H NMR (500 MHz, C2D2Cl4, 400 K)
δ 7.18-7.04 (overlapping peaks, 10H), 6.94 (s, 2H), 6.80 (s, 2H),
6.40 (s, 1H), 4.35 (d, J = 15.0 Hz, 2H), 4.26 (d, J = 14.5 Hz, 2H),
4.19 (d, J = 15.0 Hz, 1H), 3.86 (d, J = 15.0 Hz, 1H), 3.81 (d, J =
15.0 Hz, 2H), 3.63 (d, J = 15.0 Hz, 2H), 3.23 (s, 6H), 3.20 (s, 6H),
Acknowledgment. We thank Dr. Shmuel Cohen (Hebrew
University) for the crystal structure determination. This
research was supported by the Israel Science Foundation
(Grant No. 257/07).
Supporting Information Available: Experimental details and
1H and 13C spectra of compounds 4-8. This material is available
free of charge via the Internet at http://pubs.acs.org.
3442 J. Org. Chem. Vol. 75, No. 10, 2010