p-(Benzyloxy)calix[8]arene: One-Pot Synthesis and Functionalization

Article abstract of DOI:10.1021/jo970620r

The condensation of hydroquinone monobenzyl ether in the presence of several bases gives a mixture of cyclic oligomers. Using p-benzyloxyphenol, paraformaldehyde, and NaOH in 45:82:1 molar ratio in refluxing xylene, p-(benzyloxy)calix[8]arene (2) was sele

Full text of DOI:10.1021/jo970620r

6236
J . Org. Chem. 1997, 62, 6236-6239
p-(Ben zyloxy)ca lix[8]a r en e: On e-P ot Syn th esis a n d
F u n ction a liza tion
Alessandro Casnati, Riccardo Ferdani, Andrea Pochini, and Rocco Ungaro*
Dipartimento di Chimica Organica e Industriale dell’Universita`, Viale delle Scienze, I-43100 Parma, Italy
Received April 7, 1997X
The condensation of hydroquinone monobenzyl ether in the presence of several bases gives a mixture
of cyclic oligomers. Using p-benzyloxyphenol, paraformaldehyde, and NaOH in 45:82:1 molar ratio
in refluxing xylene, p-(benzyloxy)calix[8]arene (2) was selectively produced in 48% isolated yield.
Compound 2 was also functionalized at the lower rim with acetoxy, methyl, pentyl, [(ethyloxy)car-
bonyl]methyl, and [(N,N-diethylamino)carbonyl]methyl groups. Replacement of the benzyl groups
on these compounds allowed for the first time the high-yield syntheses of calix[8]hydroquinone
and its derivatives.
In tr od u ction
because the quinone or hydroquinone nuclei can be easily
functionalized,7,8 thus allowing the synthesis, inter alia,
of inherently chiral “meta”-substituted calixarenes. Until
now no direct synthesis of calixhydroquinones or calix-
quinones has been reported. We report here for the first
time the one-pot synthesis of p-(benzyloxy)calix[8]arene
(2) and its functionalization at both rims, allowing the
obtainment of new host molecules potentially useful in
supramolecular chemistry.
The cyclic phenol-formaldehyde oligomers, called calix-
arenes,1 occupy a well-established place in supramolecu-
lar chemistry as versatile building blocks for the synthe-
sis of more complex receptors. This is due to their high-
yield synthesis from cheap reagents and to the possibility
of their functionalization both at the aromatic nuclei
(upper rim) and at the phenolic OH groups (lower rim).2,3
In the case of calix[4]- and calix[6]arenes, well-estab-
lished procedures for their selective functionalization have
been developed during the last 20 years.3,4 In several
cases a good control of stereochemical properties of these
macrocycles has also been achieved.
For the synthesis of calixarenes two general procedures
are available: (i) the one-pot synthesis via the base-
catalyzed condensation of para-substituted phenols (usu-
ally having alkyl or phenyl groups)2 and (ii) the stepwise
procedure from acyclic phenol-formaldehyde precursors.5
An interesting class of calixarenes is that of calixquinones
and calixhydroquinones, obtained so far through indirect
procedures from native calixarenes.6,7 These macrocycles
have attracted the attention of several research groups
because of their redox6b,e,f and binding6f,g properties and
Resu lts a n d Discu ssion
On e-p ot Syn th esis of p-(Ben zyloxy)ca lix[8]a r en e.
The one-pot synthesis of calixarenes via the base-
catalyzed condensation of phenols and formaldehyde has
so far been limited to p-alkyl2a-m and p-phenyl deriv-
atives.2n Usually the yields of p-tert-butylcalixarenes are
higher than with other p-alkyl groups.
In order to have a direct access to calixhydroquinone
derivatives, we first explored (Scheme 1) the base-
catalyzed condensation of hydroquinone 1a and p-meth-
oxyphenol (1b) under the classical conditions used to
obtain p-alkylcalixarenes. In the case of 1a , a black
insoluble material was produced, whereas, with 1b, a
complex mixture of oligomeric compounds, cyclic and
acyclic, was obtained.
X Abstract published in Advance ACS Abstracts, August 1, 1997.
(1) (a) Gutsche, C. D. Calixarenes. In Monographs in Supramolecu-
lar Chemistry; Stoddard, J . F., Ed.; Royal Society of Chemistry; London,
1989. (b) Bo¨hmer, V. Angew. Chem. Int. Ed. Engl. 1995, 34, 713. (c)
Pochini, A.; Ungaro, R. In Comprehensive Supramolecular Chemistry;
Vo¨gtle, F., Ed.; Pergamon Press: New York, 1996; Vol. 2, pp 103.
(2) (a) Gutsche, C. D.; Iqbal M. Organic Syntheses; Wiley: New York,
1993; Collect. Vol. VIII, p 75. (b) Gutsche, C. D.; Dhawan, B.; Leonis,
M.; Steward, D. Organic Syntheses; Wiley: New York, 1993; Collect.
Vol. VIII, p 77. (c) Munch, J . H.; Gutsche, C. D. Organic Syntheses;
Wiley: New York, 1993; Collect. Vol. VIII, p 80. (d) Stewart, D. R.;
Gutsche, C. D. OPPI Briefs 1993, 25, 137. (e) Gutsche C. D.; Dhawan,
B.; No, K. H.; Muthukrishnam, R. J . Am. Chem. Soc. 1981, 103, 3782.
(f) Gutsche, C. D.; Iqbal, M.; Stewart, D. J . Org. Chem. 1986, 51, 742.
(g) Lubitov, I. E.; Shikova, E. A.; Kovalev, V. V. Synlett 1993, 647. (h)
Patrick, T. B.; Egan, P. A. J . Org. Chem. 1977, 42, 382. (i) Izatt, S. R.;
Hawkins, R. T.; Christensen, J . J .; Izatt R. M. J . Am. Chem. Soc. 1985,
107, 63. (j) Dhawan, B.; Chen S.-I.; Gutsche C. D. Makromol. Chem.
1987, 188, 921. (k) Asfari Z.; Vicens, J . Makromol. Chem., Rapid
Commun. 1989, 10, 181. (l) Nakamoto, Y.; Kozu, T.; Oya, S.; Ishida,
S. Netsu. Kokasei J ushi 1985, 6, 73 (Chem. Abstr. 1986, 105, 6301g).
(m) Asfari Z.; Vicens, J . Tetrahedron Lett. 1988, 29, 2659. (n) Gutsche,
C. D.; Pagoria, P. F. J . Org. Chem. 1985, 50, 5795.
(3) Arduini, A.; Casnati, A. Calixarenes In Macrocyclic Synthesis:
a Practical Approach; Oxford University Press: Oxford, 1996; pp 145,
and references therein.
(4) van Loon, J .-D.; Verboom, W.; Reinhoudt, D. N. Org. Prep.
Proced. Int. 1992, 24, 437-462 and references therein. 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. Casnati,
A.; Domiano, L.; Pochini, A.; Ungaro, R.; Carramolino, M.; Magrans,
J . O.; Nieto, P. M.; Lo´pez-Prados, J .; de Mendoza, J .; J anssen, R. G.;
Verboom, W.; Reinhoudt, D. N. Tetrahedron 1995, 51, 12699.
We then studied more systematically the reaction of
p-(benzyloxy)phenol (1c) and formaldehyde in the pres-
ence of a base (Scheme 1). Since the crude reaction
product appeared to be insoluble in most organic solvents,
it was analyzed after complete acetylation with CH3COCl/
(5) (a) Bo¨hmer, V.; Chhim, P.; Ka¨mmerer, H. Makromol. Chem.,
1979, 180, 2503. (b) Bo¨hmer, V.; Merkel, L.; Kunz, U. J . Chem. Soc.,
Chem. Commun. 1987, 896. (c) Tabatabai, M.; Vogt, W.; Bo¨hmer, V.
Tetrahedron Lett. 1990, 31, 3295. (d) Sartori, G.; Maggi, R.; Bigi, F.;
Arduini, A.; Pastorio, A.; Porta, C. J . Chem. Soc., Perkin Trans. 1 1994,
1657. (e) Gru¨tten, C.; Bo¨hmer, V.; Vogt, W.; Thondorf, I.; Biali, S. E.;
Grynszpan, F. Tetrahedron Lett. 1994, 35, 6267.
(6) (a) Marita, Y.; Agawa, T.; Kay, Y.; Kanehisa, N.; Kasai, N.;
Nomura, E.; Taniguchi, H. Chem. Lett. 1989, 1349. (b) Suga, K.;
Fujihira, M.; Marita, Y.; Agawa, T. J . Chem. Soc., Faraday Trans.
1991, 87, 1575. (c) Reddy, P. A.; Kashyap, R. P.; Watson, W. H.;
Gutsche, C. D. Isr. J . Chem. 1992, 32, 89. (d) Marita, Y.; Agawa, T. J .
Org. Chem. 1992, 57, 3658. (e) Casnati, A.; Comelli, E.; Fabbi, M.;
Bocchi, V.; Mori, G.; Ugozzoli, F.; Manotti-Lanfredi, A. M.; Pochini,
A.; Ungaro, R. Recl. Trav. Chim. Pays-Bas 1993, 112, 384. (f) Kaifer,
M. G.; Reddy, P. A.; Gutsche, C. D.; Echegoyen, L. J . Am. Chem. Soc.
1994, 116, 2580. (g) P. D. Beer, Z. Chen, M. G. B. Drew, P. A. Gale, J .
Chem. Soc., Chem. Commun. 1994.
(7) (a) Arduini, A.; Mirone, L.; Paganuzzi, D.; Pinalli A.; Pochini,
A.; Secchi, A.; Ungaro, R. Tetrahedron, 1996, 52, 6011. (b) Mascal, M.;
R. T. Naven; R. Warmuth Tetrahedron Lett. 1995, 36, 9361.
(8) Reddy, P. A.; Gutsche, C. D. J . Org. Chem. 1993, 58, 3245.
S0022-3263(97)00620-8 CCC: $14.00 © 1997 American Chemical Society

Synthesis of p-(Benzyloxy)calix[8]arene
J . Org. Chem., Vol. 62, No. 18, 1997 6237
Sch em e 1
Sch em e 2
Ta ble 1. In flu en ce of th e Ba se Used on th e Cyclic
P r od u ct Distr ibu tion in th e Rea ction of 1c a n d
P a r a for m a ld eh yd ea
% relative yield
base
calix[6]arene (4) calix[7]arene (3) calix[8]arene (2)
LiOH
NaOH
KOH
20
10
7
17
6
21
63
84
72
Sch em e 3
a
Mean values of three runs. Relative yields determined by
HPLC (reverse phase C18, methanol/water ) 96/4).
pyridine. The compounds were identified by mass spec-
tra and 1H NMR after isolation by preparative HPLC
(reverse phase C18, CH3OH/H2O 96/4).
After several efforts, conditions were found where only
the cyclic compounds are produced in the reaction
mixture. They were identified as the p-(benzyloxy)-
calix[8]arene (2), and the corresponding calix[7]- (3) and
calix[6]arene (4). The ratio between the three compounds
depended on the base used in the condensation, although
the cyclic octamer 2 was always the main reaction
product (Table 1).
Interestingly, no trace of cyclic tetramer was detected,
in sharp contrast with the behavior of p-tert-butylphenol
under similar conditions.2f
The highest yield of cyclic octamer 2 was obtained
using p-(benzyloxy)phenol (1c), paraformaldehyde, and
NaOH in 45:82:1 molar ratio in refluxing xylene. The
pure compound 2 can be isolated in 48% yield by simple
filtration from hot CH2Cl2. This result is interesting
because calix[8]hydroquinone derivatives are unknown
compounds and have so far not been synthesized even
using indirect procedures.
The high insolubility of 2, which allows its easy
purification from the reaction mixture, nevertheless
makes its characterization more difficult. NMR spectra
can only be taken in a DMSO solution, where, as
expected, compound 2 shows a complete conformational
freedom, as deduced from the presence of a singlet for
the ArCH2Ar protons at 3.80 ppm. The molecular peak
(M) in the mass spectra was only visible using negative
CI, easily showing the loss of benzyl groups (M-91).
Compound 2 can be almost quantitatively converted to
the octacetoxy derivative (5a ), whereas complete alkyl-
ation can be obtained by reaction with the appropriate
alkyl halide and Cs2CO3 in dry DMF at 80 °C to yield
compounds 5b-e in 40-60% yield (Scheme 2). All these
compounds show a mobile structure in solution, as
inferred from the temperature independent (-65/25 °C)
1H NMR spectra.
H2), even at high temperature and under 3-4 atm
pressure, often fails, and therefore, different methods
have been used by us and others to cleave the ArO-
CH2Ph bond. Among these methods, we have often
successfully used bromotrimethylsilane at room temper-
ature in CHCl3, which is very efficient and selective to
cleave ArO-CH2Ph bonds over other ethereal bonds
ArO-R (R ) CH2CH3, (CH2CH2O)n, CH2COX).9 How-
ever, the treatment of compounds 5a -e with a large
excess of bromotrimethylsilane, or of the more reactive
iodotrimethylsilane also in refluxing CHCl3, gives mix-
tures of products where the benzyl groups are only
partially removed. Complete debenzylation of com-
pounds 5a and 5e (76% and 80% yields respectively) was
achieved by treating a chloroform solution of these
products with dimethyl sulfide and boron trichloride (1
M solution in heptane) at room temperature (Scheme 3).10
However, debenzylation of 5b and 5c under the same
reaction conditions was not complete, and this prompted
us to look for a more efficient method. We eventually
found the use of Pd(OH)2/C (20%, Pearlsman’s catalyst)
and cyclohexene in refluxing ethanol11 to be a very
effective and general method to obtain all compounds 6
Deben zyla tion a n d F u r th er F u n ction a liza tion .
In order to make the upper rim of the calix available for
further functionalization, it was necessary to find an easy
and general method for the debenzylation of compounds
5a -e. The removal of benzyl groups from calixarenes
has never been simple. Catalytic hydrogenation (Pd/C,
(9) Casnati, A.; Arduini, A.; Ghidini, E.; Pochini, A.; Ungaro, R.
Tetrahedron 1991, 47, 2221. Casnati, A.; Pochini, A.; Ungaro, R.;
Bocchi, C.; Ugozzoli, F.; Egberink, R. J . M.; Reinhoudt, D. N. Chem.
Eur. J . 1996, 2, 436.
(10) Fuji K.; Ichigawa, K.; Node, M.; Fujita, E. J . Org. Chem. 1979,
44, 1661.
(11) Hanessian, S.; Liak, T. J .; Vanasse, B. Synthesis, 1981, 396.

6238 J . Org. Chem., Vol. 62, No. 18, 1997
Casnati et al.
ganMAT 90 (FAB, NBA). Infrared spectra were recorded with
a Perkin-Elmer model 298 spectrometer. Melting points were
obtained in a nitrogen-sealed capillary on Electrothermal
Apparatus. All compounds gave satisfactory elemental analy-
ses. All reactions were performed with efficient stirring in a
nitrogen atmosphere. Petroleum ether refers to the fraction
boiling at 40-60 °C.
Sch em e 4
5,11,17,23,29,35,41,47-Oct a k is(b en zyloxy)-49,50,51,52,
53,54,55,56-octa h yd r oxyca lix[8]a r en e (2). A 20.0 g (0.1
mol) sample of p-(benzyloxy)phenol (1c) (purchased from
Fluka, purum, >99%) was dissolved in 400 mL of xylene in a
1 L round-bottomed flask equipped with a Dean & Stark water
collector. The solution was heated to 100 °C, then 1.1 mL (2
mmol) of 2 N NaOH aqueous solution and 5.4 g (179.8 mmol)
of paraformaldehyde were added. After 2 h the temperature
was increased to 150 °C and a precipitate began to form. The
reaction mixture was refluxed for 48 h and then cooled and
filtered on a Buchner funnel. The resulting solid was washed
with diethyl ether and then transferred to a 250 mL round-
bottomed flask and suspended in 200 mL of methylene cloride.
This heterogeneous solution was refluxed for 3 h and then hot
filtered on a Buchner funnel to yield 10.2 g (48%) of white
compound 2: mp >300 °C; 1H NMR (DMSO-d6) δ 8.63 (s, 8H),
7.29 (s, 40H), 6.60 (s, 16H), 4.80 (s, 16H), 3.80 (s, 16H); MS
(CI-) m/ z 1697 (M-); 13C NMR (DMSO-d6) δ 151.0, 146.6,
137.6, 128.9, 128.1, 127.6, 69.7, 32.0; MS (CI-) 1696 (M+);
Anal. Calcd for C112H96O16: C, 79.23; H, 5.69. Found: C,
79.11; H, 5.80.
in very good yields (80-90%). These compounds, which
bear free OH groups at the upper rim, unlike their
benzylated precursor are not very soluble in organic
solvents, which indicates that strong intermolecular
hydrogen bonds are operating among these molecules.
NMR spectra can only be recorded in DMSO-d6 or
mixtures CDCl3-CD3OD. Interestingly, compound 6e is
soluble in water solution (5 × 10-3-10-2 M) when at least
16 equiv of NaOH are added. NMR spectra in D2O
clearly indicate that the calixarene assumes a rigid
conformation in these conditions, since only two doublets
at 4.11 and 3.20 ppm appear for the methylene bridge
protons. The spectrum results as being very simple and
symmetrical; also, the OCH2CO protons become dias-
terotopic, originating an AX system (3.94 and 3.20 ppm,
An a lysis of P r od u cts Distr ibu tion in th e On e-P ot
Con d en sa tion of p-(Ben zyloxy)p h en ol a n d F or m a ld e-
h yd e. The crude solid resulting from condensation reaction
in xylene, once filtered on a Buchner and washed with diethyl
ether, was submitted to acetylation reaction. A 0.2 g sample
of this solid (mixture of calix[8]-, -[7]- and -[6]arenes) was
dissolved in hot pyridine (5 mL) and 0.4 mL of acetyl chloride
was slowly added. After stirring at room temperature for 24
h, 50 mL of 1 N HCl was added and the precipitate filtered
under suction. A sample of this solid was dissolved in the
minimum amount of chloroform and then an excess of metha-
nol was added. This solution was analyzed by HPLC (reverse
phase C18, eluent methanol/water ) 96/4, flux 1.5 mL/min).
Samples of the eluate were collected in correspondence of the
single peaks and analyzed by mass spectrometry: hexamer,
tR ) 7.31 min, MS (CI+) m/ z 1526.1 [(M + 1)]+; heptamer, tR
J
) 14.7 Hz), while the aromatic protons give two
doublets with typical meta coupling (J ) 2.6 Hz). Since
the cone conformation (C8 symmetry) cannot explain the
presence of diastereotopicity for the OCH2CO and the
nonequivalence of the ArH protons, we propose for this
salt of 6e a 1,3,5,7-alternate conformation (u, d, u, d, u,
d, u, d),1 where the oxygens of both the chelating chains
and the phenoxide anions interact with sodium cations.
The octahydroxyoctakis[[[(N,N-diethylamino)carbon-
yl])methyl]oxy]calix[8]arene (6e) has several noteworthy
properties and potentialities: (1) it possesses eight cation
binding groups at the lower rim and can be further
functionalized at the upper rim with long alkyl chains
in order to increase the lipophilicity of the ionophore and
(2) binding groups of the same type or different from
those present at the lower rim can be introduced on the
free OH groups, thus creating ionophores with a channel-
like structure or various types of ditopic receptors.
As an example of one of these types of functionalization
at the upper rim, we synthesized (Scheme 4) the hexa-
decamide derivative (7b ) by reaction of 6e with Cl-
CH2CON(C2H5)2 in the presence of Cs2CO3.
)10.66 min, MS (CI+) m/ z 1779.6 [(M + 1)]+; octamer, tR
)
17.21 min, MS (CI-) m/ z 2033.0 (M)-.
5,11,17,23,29,35,41,47-Oct a k is(b e n zyloxy)-49,50,51,
52,53,54,55,56-octa a cetoxyca lix[8]a r en e (5a ). A 0.2 g (0.12
mmol) sample of 2 was dissolved in the minimum amount (∼5
mL) of hot pyridine, then 0.4 mL of acetyl chloride was slowly
added. The solution was stirred at room temperature for 24
h, then 50 mL of 1 N HCl was added to the reaction mixture,
causing the precipitation of a white solid which was filtered,
dissolved in CH2Cl2, and precipitated with hexane (95%
yield): mp 137-138 °C; IR (KBr) 1760 cm-1; 1H NMR (CDCl3)
δ 7.26 (s, 40H), 6.55 (s, 16H), 4.80 (s, 16H), 3.56 (s, 16H), 1.95
(s, 24H); 13C NMR δ 169.0, 156.3, 140.9, 136.6, 132.8, 128.3,
127.8, 127.5, 115.0, 69.9, 31.5, 20.0; MS (CI-) m/ z 2033 (M-).
Anal. Calcd for C128H112O24: C, 75.58; H, 5.54. Found: C,
75.43; H, 5.62.
Gen er a l P r oced u r e for th e Alk yla tion of Com p ou n d
2. A solution of 0.65 g (0.38 mmol) of compound 2 was
dissolved in 20 mL of dry DMF and stirred with 13.3 mmol of
Cs2CO3 and 22.8 mmol of alkyl halide at 90 °C. After 10-20
h, the cooled reaction mixture was quenched with 1 N HCl
(75 mL) and the crude product was filtered on a Buchner
funnel and washed with water. After drying, pure products
5b-e were purified as reported below.
Finally, we prepared (Scheme 3) calix[8]hydroquinone
(7a ) following two different debenzylation procedures
(iodotrimethylsilane in chloroform or Pd(OH)2/C and
cyclohexene in ethanol and DMF).
Exp er im en ta l Section
Gen er a l P r oced u r es. Most of the solvents and all re-
agents were obtained from commercial supplies and used
without further purification. DMF was freshly distilled and
stored over 4 Å molecular sieves. Proton and carbon nuclear
magnetic resonance spectra (1H NMR and 13C NMR) were
recorded on a Bruker AC100, Bruker AC300 and Bruker
AMX400 spectrometers. Chemical shifts are reported as δ
values in ppm from tetramethylsilane (δ 0.0) as internal
standard. Analytical thin-layer chromatography was carried
out on silica gel plates (SiO2, Merk 60 F254). Mass spectra were
performed with Finnigan MAT SSQ 710 (CI, CH4) and Finni-
5b. Methyl iodide was used as alkylating agent. The crude
product was dissolved in CH2Cl2 and precipitated with CH3OH
to give 0.28 g (yield 40%) of pure product: mp ) 104-5 °C;
1H NMR (CDCl3) δ 7.19 (m, 40H), 6.51 (s, 16H), 4.72 (s, 16H),
3.92 (s, 16H), 3.41 (s, 24H); 13C NMR (CDCl3) δ 154.6, 150.5,
137.1, 134.8, 128.4, 127.7, 127.5, 115.0, 70.0, 60.8, 33.1; MS
(FAB) m/ z 1809 (M+). Anal. Calcd for C120H112O16: C, 79.63;
H, 6.23. Found: C, 79.81; H, 6.34.

Synthesis of p-(Benzyloxy)calix[8]arene
J . Org. Chem., Vol. 62, No. 18, 1997 6239
5c. In this reaction pentyl iodide was the alkylating agent.
The crude product was dissolved in CH2Cl2 and purified by
column chromatography (SiO2) using petroleum ether/THF (7/
3) as eluent: yield ) 60%; mp 98-100 °C; 1H NMR (CDCl3) δ
7.11 (s, 40H), 6.50 (s, 16H), 4.61 (s, 16H), 3.97 (s, 16H), 3.58
(t, 16H), 1.55 (m, 16H), 1.31 (m, 32H), 0.84 (m, 24H); 13C NMR
(CDCl3) δ 154.6, 149.4, 137.3, 135.0, 128.2, 127.5, 127.4, 115.0,
73.6, 69.7, 30.5, 30.0, 28.4, 22.6, 14.0; MS (CI+) m/ z 2257 (M+).
Anal. Calcd for C152H176O16: C, 80.82; H, 7.85. Found: C,
80.87; H, 7.92.
7a . In the workup of the reaction, solutions containing the
product may easily darken, owing to the oxidation of some
hydroquinone nuclei of the macrocycle. The crude product was
therefore dissolved in CHCl3 and stirred under a nitrogen
atmosphere with a 1% solution of Na2S2O4 for 2 h. Then the
yellow solid was filtered under nitrogen and collected: mp
1
>300 °C; IR (KBr) 1660 cm-1; H NMR (DMSO-d6) δ 8.59 (s,
8H), 8.36 (s, 8H), 6.36 (s, 16H), 3.70 (s, 16H); 13C NMR (DMSO-
d6) δ 150.4, 143.6, 128.8, 114.6, 31.0; MS (CI+) m/ z 920 [(M -
2CO)]+. Anal. Calcd for C56H48O16: C, 68.85; H, 4.95. Found:
C, 68.98; H, 5.02.
5d . The alkylating agent was 2-bromoethyl acetate. The
crude product was dissolved in CH2Cl2 and precipitated with
CH3OH (50% yield): mp >300 °C; 1H NMR (CDCl3) δ 7.20 (m,
40H), 6.53 (s, 16H), 4.68 (s, 16H), 4.21 (s, 16H), 4.01 (m, 32H),
1.05 (t, J ) 7.1 Hz, 24H); 13C NMR (CDCl3) δ 168.7, 155.1,
148.7, 136.9, 134.3, 128.2, 127.5, 127.4, 115.0, 70.2, 69.6, 60.8,
30.6, 13.8; MS (FAB) m/ z 2385 (M+). Anal. Calcd for
C144H144O32: C, 72.47; H, 6.07. Found: C, 72.39; H, 6.26.
5e. 2-Chloro-N,N-diethylacetamide was the alkylating agent.
The crude product was dissolved in CH2Cl2, then CH3OH was
added to the solution which was left for 10 h at -10 °C. The
filtration gave 0.61 g (61% yield) of pure product: mp >300
°C; IR (KBr) 1645 cm-1; 1H NMR (CDCl3) δ 7.13 (m, 40H), 6.54
(s, 16H), 4.54 (s, 16H), 4.42 (s, 16H), 4.04 (s, 16H), 3.25 (q, J
) 7 Hz, 16H), 3.12 (q, J ) 7 Hz, 16H), 0.99 (t, J ) 7 Hz, 24H),
0.93 (t, J ) 7 Hz, 24H); 13C NMR (CDCl3) δ 166.9, 155.0, 149.2,
137.0, 134.5, 128.0, 127.5, 127.4, 115.0, 72.1, 69.4, 41.1, 39.9,
30.5, 14.1, 12.7; MS (FAB) m/ z 2601 (M+). Anal. Calcd for
C160H184O24N8: C, 73.83; H, 7.12; N, 4.30. Found: C, 73.71;
H, 7.19; N, 4.48.
Compounds 5a and 5e were also debenzylated in good yields
to 6a (76%) and 6e (80%) also using the following procedure.
A sample of 0.33 mmol of compound 5a or 5e was dissolved
in 10 mL of CHCl3 and treated with 3.4 mL of dimethyl sulfide
(46.2 mmol) and 23.1 mL (23.1 mmol) of a BCl3 solution (1 M
in CH2Cl2) at room temperature. After 4 h, the solvent and
the excess of dimethyl sulfide were removed by evaporation
under vacuum and the remaining solid was treated with water.
The resulting solid was separated by filtration and slowly
crystallized from CHCl3/CH3OH ) 3/1.
5,11,17,23,29,35,41,47,49,50,51,52,53,54,55,56-H e xa -
d eca h yd r oxyca lix[8]a r en e (7a ). Meth od A: a suspension
of 0.14 g (0.08 mmol) of 2 in 5 mL of CHCl3 was treated with
0.5 mL (3.51 mmol) of iodotrimethylsilane and stirred at 60
°C. After 12 h, 5 mL of CH3OH was added and then the
solvent removed, giving 0.07 g (0.07 mmol) (87.5%) of a dark
solid which became ink-blue when treated with water. This
product was suspended in 5 mL of CHCl3 and treated with 5
mL of a 1% solution of Na2S2O4. The mixture was stirred
under an argon atmosphere at room temperature for 2 h and
then the product was isolated by filtration under flushing
nitrogen (yield 80%).
Gen er a l P r oced u r e for th e Deben zyla tion of Ca lix[8]-
a r en es 5 a n d 2. A sample (0.1 mmol) of compound 5a -c,e
or 2 was dissolved in hot ethanol (50 mL) and stirred in an
inert atmosphere at 90 °C with 18 mL of cyclohexene and 0.7
g of Pd(OH)2/C (20%, Pearlman’s catalyst) per gram of com-
pound. After 15-18 h, the carbon was removed by filtration
and the liquid was evaporated under vacuum, leaving the
crude product in nearly quantitative yields (>90%). The
product was purified by crystallization.
Meth od B: see above, General Procedure for the Deben-
zylation of Calix[8]arenes 5 and 2.
5,11,17,23,29,35,41,47,49,50,51,52,53,54,55,56-H exa d e-
c a k i s [[[(N ,N -d i e t h y la m i n o )c a r b o n y l]m e t h y l]o x y ]-
ca lix[8]a r en e (7b). A 0.23 g (0.12 mmol) sample of 6e was
dissolved in 10 mL of dry DMF and to this solution were added
3.2 g (9.8 mmol) of Cs2CO3 and 1.1 mL (10.4 mmol) of 2-chloro-
N,N-diethylacetamide. After 10 h of stirring at 80 °C, the
reaction was quenched with 50 mL of 1 N HCl. CH2Cl2 (30
mL) was added and the organic layer was separated and
extracted several times with 1 N HCl. The final organic layer
was evaporated under reduced pressure till a volume of 5 mL
was reached and the product precipitated with petroleum
ether: 1H NMR (CDCl3) δ 6.42 (s, 16H), 4.37 (s, 16H), 4.23 (s,
16H), 3.82 (s, 16H), 3.32-3.26 (m, 64H), 1.0-0.85 (m, 96H);
13C NMR (CDCl3) δ 166.9, 154.6, 134.6, 115.1, 71.5, 66.8, 41.4,
40.2, 31.1, 14.3, 12.9; MS (FAB+) m/ z 2809 [(M + Na)]+, 2825
[(M + K)]+. Anal. Calcd for C152H224O32N16: C, 65.49; H, 8.09;
N, 8.04. Found: C, 65.37; H, 8.17; N, 8.15.
1
6a . Yield ) 76%, mp 235 °C (dec); H NMR (DMSO-d6) δ
9.25 (s, 8H), 6.39 (s, 16H), 3.34 (s, 16H), 1.97 (s, 24H); 13C NMR
(DMSO-d6) δ 173.9, 159.6, 144.5, 137.9, 120.2, 24.8, 18.7; MS
(FAB) m/ z 1312 (M+). Anal. Calcd for C72H64O24: C, 65.85;
H, 4.91. Found C, 65.77; H, 4.98.
6b. Yield ) 90%; mp >300 °C; 1H NMR (DMSO-d6) δ 8.93
(s, 8H), 6.31 (s, 16H), 3.79 (s, 16H), 3.58 (s, 24H); 13C NMR
(DMSO-d6) δ 152.8, 148.6, 134.2, 115.0, 60.3, 29.4; MS (CI+)
m/ z 1088 (M+). Anal. Calcd for C64H64O16: C, 70.58; H, 5.92.
Found: C, 70.49; H, 6.00.
6c. Yield ) 90%; mp 347-9 °C; 1H NMR (DMSO-d6) δ 8.75
(s, 8H), 6.27 (s, 16H), 3.79 (s, 16H), 3.50 (t, 16H), 1.56 (t, 16H),
1.30 (t, 16H), 1.24 (t, 16H), 0.77 (q, 24H); 13C NMR (DMSO-
d6) δ 152.6, 147.6, 134.1, 115.0, 72.8, 29.4, 27.8, 22.0, 13.7;
Ack n ow led gm en t. We thank the C.N.R. (Progetto
Strategico Tecnologie Chimiche Innovative: Sottopro-
getto A) and the Human Capital and Mobility Pro-
gramme (Contracts no. CHRX-CT94-0484) for financial
support. We thank C.I.M. (Centro Interdipartimentale
Misure) dell’Universita` di Parma for the NMR and Mass
facilities.
MS (CI+) m/ z 1537 (M+). Anal. Calcd for C96H128O16
: C,
74.97; H, 8.38. Found: C, 75.06; H, 8.47.
1
6e. Yield ) 80%: mp >300 °C; H NMR (CDCl3/CD3OD )
3/1) δ 6.38 (s, 16H), 4.41 (s, 16H), 3.93 (s, 16H), 3.16 (d, J ) 7
Hz, 16H), 3.13 (d, J ) 7 Hz, 16H), 1.04 (t, J ) 7 Hz, 24H),
0.94 (t, J ) 7 Hz, 24H); 13C NMR (CDCl3/CD3OD ) 3/1) δ 168.7,
153.9, 148.6, 135.3, 116.1, 72.0, 42.1, 41.0, 30.9, 14.2, 12.9; MS
(FAB+) m/ z 1880.7 (M+). Anal. Calcd for C104H136O24N8: C,
66.37; H, 7.27; N, 5.95. Found: C, 66.45; H, 7.39; N, 6.07.
J O970620R