Calix[4]arene-based receptors with hydrogen-bonding groups immersed into a large cavity

Article abstract of DOI:10.1021/jo9804543

A one-pot procedure, which combines the Ritter and Friedel-Crafts reactions, produced the first members of a new type of calix[4]arene-based receptors. The cavity in these receptors is formed by a calix[4]arene framework fixed in the cone conformation and

Full text of DOI:10.1021/jo9804543

9
644
J . Org. Chem. 1998, 63, 9644-9651
Ca lix[4]a r en e-Ba sed Recep tor s w ith Hyd r ogen -Bon d in g Gr ou p s
Im m er sed in to a La r ge Ca vity
Evgueni Pinkhassik, Vladimir Sidorov, and Ivan Stibor*
Department of Organic Chemistry, Institute of Chemical Technology, Technick a´ 5,
1
6628 Prague, The Czech Republic
Received March 10, 1998
A one-pot procedure, which combines the Ritter and Friedel-Crafts reactions, produced the first
members of a new type of calix[4]arene-based receptors. The cavity in these receptors is formed
by a calix[4]arene framework fixed in the cone conformation and bulky adamantyl or (and)
phenylacetylene moieties. Amido and amino groups were used as potential hygrogen bond donors.
Preliminary studies revealed interesting complexation properties, in particular, the tetrahedral
recognition of water molecules performed by one of the receptors.
In tr od u ction
Hydrogen bonds are the most important of all nonco-
Sch em e 1
valent bond types in biochemistry.1 They play an es-
sential role in the formation of biological macromolecules
such as the globular proteins and the DNA double helix
and in the mechanism of enzyme-substrate recognition.1
Formation of hydrogen bonds as a driving force of the
molecular recognition has also been widely used in
artificial receptors.2 Complexation of calix[4]arene de-
rivatives with neutral molecules has always been the
subject of special attention.3 Early works demonstrated
the ability of calix[4]arenes to form inclusion complexes
in the solid state, while more recent publications deal
4
with complexation in aqueous and apolar media. Sev-
eral hydrogen bonding calix[4]arenes have been recently
5
described. In some cases, such receptors tend toward
self-association.5 One may speculate that the immersion
c
of H-bond active groups into a large cavity should
disfavor the self-association in favor of the coordination
of a substrate. In this paper, we report our results in
the design and synthesis of a series of calix[4]arene-based
receptors with hydrogen-bonding groups immersed into
a large cavity as well as the preliminary complexation
study.
(
1) J effrey, G. A.; Saenger, W. Hydrogen Bonding in Biological
Structures; Springer: Berlin, 1991.
2) (a) Inclusion Compounds; Atwood, J . L., Davies, J . E. D.,
MacNicol, D. D., Eds.; Oxford University Press: Oxford, 1991; Vol. 4.
b) Hamilton, A. D. In Advances in Supramolecular Chemistry; Gokel,
G. W., Ed.; J AI Press Inc.: London, 1990; Vol. 1, pp 1-64. (c) van
Doorn, A. R.; Verboom, W.; Reinhoudt, D. N. In Advances in Supramo-
lecular Chemistry; Gokel, G. W., Ed.; J AI Press Inc.: London, 1993;
Vol. 3, pp 169-206.
3) (a) Gutsche, C. D. Calixarenes. Monographs in Supramolecular
Chemistry; The Royal Society of Chemistry: Cambridge, 1989; Vol. 1.
b) Calixarenes: A Versatile Class of Macrocyclic Compounds; Vincens,
(
(
Resu lts a n d Discu ssion
(
Design . According to the proposed concept, the recep-
tor is made of a calix[4]arene framework, a hydrogen-
bonding group, and a bulky moiety. Calix[4]arene fixed
in the cone conformation predetermines the shape of the
cavity and to a great extent the conformational mobility.
By choosing the proper substitution at the lower rim, one
may vary the conformational features of the calix[4]arene
framework.6 This task can be accomplished using both
noncovalent fixation by means of intramolecular hydro-
gen bonds or covalent fixation by a properly chosen rigid
bridge. Both approaches are used below. H-bond active
groups are attached to the upper rim of calix[4]arene.
Their role is supposed to be the hydrogen bond formation
(
J ., Boehmer, V., Eds.; Kluwer Academic: Dordrecht, 1991. (c) Pochini,
A.; Ungaro, R. In Comprehensive Supramolecular Chemistry; Atwood,
J . L., Davies, J . E. D., MacNicol, D. D., Vogtle, F., Eds.; Pergamon:
Oxford, 1996; Vol. 2, pp 103-142.
(
4) Solid-state complexes are treated in the following: (a) Andreetti,
G. D.; Ugozzoli, F. In Calixarenes: A Versatile Class of Macrocyclic
Compounds; Vincens, J ., Boehmer, V., Eds.; Kluwer Academic: Dor-
drecht, pp 87-123. (b) Brouwer, E. B.; Ripmeester, J . A.; Enright, G.
D. J . Incl. Phenom. 1996, 24, 1-17. Complexes in apolar media are
regarded in the following: (c) Arduini, A.; McGregor, W. A.; Paganuzzi,
D.; Pochini, A.; Secchi, A.; Ugozzoli, F.; Ungaro, R. J . Chem. Soc.,
Perkin Trans. 2 1996, 839-846. (d) Kousaku, Y.; Yoshimasa, F.
Tetrahedron Lett. 1996, 37, 1435-1438. (e) Smirnov, S.; Sidorov, V.;
Pinkhassik, E.; Havl ´ı cˇ ek, J .; Stibor, I. Supramol. Chem. 1997, 8, 187-
1
96. (f) Smirnov, S.; Sidorov, V.; Pinkhassik, E.; Ko cˇ a, J .; Stibor, I.
Supramol. Chem., in press. (g) Sidorov, V.; Pinkhassik, E.; Smirnov,
S.; Stibor, I.; Kovalev, V.; Khomich, A.; Shokova, E. Supramol. Chem.,
in press.
(6) (a) Iwamoto, K.; Araki, K.; Shinkai, S. J . Org. Chem. 1991, 56,
4955. (b) Groenen, L. C.; Steinwender, E.; Lutz, B. T. G.; van der Maas,
J . H.; Reinhoudt, D. N. J . Chem. Soc., Perkin Trans. 2 1992, 1893. (c)
Ikeda, A.; Tsuzuki, H.; Shinkai, S. J . Chem Soc., Perkin Trans. 2 1994,
2073. (d) Arduini, A.; Fabbi, M.; Mantovani, M.; Mirone, L.; Pochini,
A.; Secchi, A.; Ungaro, R. J . Org. Chem. 1995, 60, 1454.
(
5) (a) van Loon, J . P.; Heida, J . F.; Verboom, W.; Reinhoudt, D. N.
Recl. Trav. Chim. Pays-Bas 1992, 111, 353. (b) Murakami, H.; Shinkai,
S. J . Chem. Soc., Chem. Commun. 1993, 1533. (c) van Loon, J .-D.;
J anssen, R. G.; Verboom, W.; Reinhoudt, D. N. Tetrahedron Lett. 1992,
3
3, 5125.
1
0.1021/jo9804543 CCC: $15.00 © 1998 American Chemical Society
Published on Web 11/26/1998

Calix[4]arene-Based Receptors
J . Org. Chem., Vol. 63, No. 26, 1998 9645
Sch em e 2
Sch em e 3
with a substrate. The number, nature, and placement
of hydrogen-bonding groups can be varied. The receptor
design is completed by bulky moieties. They extend the
cavity of the calix[4]arene skeleton and shield the sub-
strate from the solvent molecules. Moreover, they can
possibly be involved in the additional binding of a
substrate. The preference has been given to the ada-
mantyl unit for several reasons: this is a bulky and
highly symmetric structure; a number of readily available
and cheap adamantyl-containing intermediates makes
the introduction of adamantyl moiety to the receptor
7
relatively easy; the adamantyl unit has several positions
for the attachment of the additional substituents that
opens the road to the further development of this type of
receptors (possible fine-tuning of selectivity, formation
of chiral cavity, etc.). Another possible candidate for the
enlargement of the cavity is a rigid π-electron-containing
unit that can be involved in π-π interactions between
the cleftlike receptor and a substrate.8
Syn th esis. Among many suitable reactions leading
to the formation of an amide function, the Ritter reaction9
attracted our attention due to the possibility to combine
it with the Friedel-Crafts alkylation that promises the
shortest way to the proposed type of receptors. Indeed,
the adamantylation10 of the dicyanocalix[4]arene 1 in the
presence of trifluoroacetic acid led to the desired product
Obviously, 7 seems to be also attractive for the receptor
synthesis. However, the adamantylation of 7 performed
in several runs gave no desired product.
The reduction of 4 with BH
amino groups as potential hydrogen bond donors (Scheme
).
Compound 11 bearing four amido groups has been
3
‚THF produced 5 with
1
3
in 42% yield (Scheme 1). This way, the construction
synthesized according to Scheme 3. The reaction path-
way consisted of exhaustive bromination of tetrapropoxy-
calix[4]arene 8 by N-bromosuccinimide, introduction of
the cyano functions, and the subsequent adamantylation
of tetracyanocalix[4]arene 10.
of a large cavity and the introduction of H-bond active
groups there occurred simultaneously in a one-pot pro-
cedure.
It was shown in the previous reports that the substitu-
tion pattern in the lower rim of calix[4]arene strongly
affects its binding properties.4 Thus, for example, calix-
The idea of using π-π aromatic interactions in the
c
1
1
receptors adopted from nature proved to be very fruitful.
[4]arenes with two hydroxyl groups in the distal positions
We may apply it to our system by keeping two amido
functions with bulky adamantyl units and modifying the
two remaining positions with the substituents of aromatic
nature. To form a stable cleftlike structure, these sub-
stituents should be coplanar with the phenolic units of
calix[4]arene skeleton. One of the most promising can-
didates for this role is the phenylacetylene moiety. Its
attachment to the calix[4]arene framework via the cor-
responding iodo derivative has been discussed else-
where.12 Adamantylation of diiododicyanocalix[4]arene
at the lower rim reveal stronger binding of simple organic
molecules than tetrahydroxy or tetraalkoxy calix[4]-
arenes.4 It is interesting therefore to compare 3 with
its analogue dialkylated in the lower rim. For this
purpose, we need the corresponding intermediates5,11-
dicyano-25,27-dihydroxy-26,28-dipropoxycalix[4]arene. The
exchange of bromine for a cyano function in the reaction
of 6 with cuprous cyanide gave the desired calix[4]arene
c
2
in 58% yield together with an unexpected coproduct 7
(16%) (Scheme 2), apparently due to the reduction by
1
2 produced 13, and the subsequent exchange of iodine
monovalent copper. The adamantylation of 2 led to the
target structure 4 in 44% yield (Scheme 1). As follows
to phenylacetylene led to 14 (Scheme 4). As a result of
the bulk and polarizability of iodine, 13 may be of interest
not only as an intermediate for the preparation of
phenylacetylene derivatives but also as a potential recep-
tor for the coordination of electron deficient substrates.
1
from the H NMR spectrum, the calix[4]arene moiety in
4
is fixed in the flattened cone conformation by the array
of intramolecular hydrogen bonds in the lower rim.
(
7) Kovalev, V.; Shokova, E.; Khomich, A.; Luzikov, Y. New J . Chem.
1
996, 20, 483 and references therein.
(11) (a) Burley, S. K.; Petsko, G. A. Science 1985, 229, 23. (b)
Diederich, F. Angew. Chem., Int. Ed. Engl. 1988, 27, 362.
(8) Hunter, C. A. Chem. Soc. Rev. 1994, 101.
(
9) Krimer, L. I.; Cota, D. J . In Organic Reactions, 17; J ohn Wiley
(12) Pinkhassik, E.; Stibor, I.; Casnati, A.; Ungaro, R. J . Org. Chem.
1997, 62, 8654. The synthesis described therein was performed using
the Stephens-Castro reaction.
&
Sons: 1969; pp 213-325.
1
3
(10) Khomich, A.; Shokova, E.; Kovalev, V. Synlett 1994, 1027.

9
646 J . Org. Chem., Vol. 63, No. 26, 1998
Pinkhassik et al.
Sch em e 4
Sch em e 5
Another option for the synthesis of such a type of
mantylation: exchange of iodine for phenylacetylene
moiety w introduction of a bridge w adamantylation w
iodination of dicyanodihydroxycalix[4]arene 2. Iodination
of 2 was performed in the same way as mentioned above
for 16; adamantylation of 19 has produced diamide 20.
The reaction of 20 with 2-iodoethyl ether/NaH in DMF
introduced the ethereal bridge. The final step in the
synthetic sequence was the coupling of 21 with cuprous
phenylacetylide, which gave 22. This strategy was
successful, and the desired compound 22 was isolated in
6% overall yield from 2 (Scheme 6).
receptors is the rigidification of the cavity by capping of
calix[4]arene with the rigid bridge in the lower rim. In
this case, calix[4]arene is fixed in the pinched cone
conformation by the covalent linkage.6d Initially, the
following retrosynthetic approach to the proposed com-
pound has been chosen: coupling with cuprous phenyl-
acetylide w adamantylation w iodination w exchange of
bromine for cyano group w introduction of a bridge to
dibromodipropoxycalix[4]arene (Scheme 5). The intro-
duction of the short bridge to the calix[4]arene 6 was
performed according to the recently published protocol
using 2-iodoethyl ether as an alkylating agent and NaH
as a base in DMF.6d Subsequent exchange of bromine
for cyano functions in 15 was performed by the standard
One more factor to change is the placement (and
nature) of the amido function. To accomplish this, the
cyano groups in 12 were reduced (BH ‚THF) to aminom-
3
ethyl functions and the resulting compound 23 was
coupled with adamantylcarbonyl chloride to give diamide
24 followed by exchange of iodine for the phenylacetylene
moiety (Scheme 7). The product 25 possesses the re-
versed orientation of amido groups compared with those
present in the previous series of receptors.
1
4
method (with CuCN in N-methylpyrrolidinone). The
iodination of 16 followed a recently published procedure
1
5
using iodine with silver trifluoroacetate in chloroform.
However, the adamantylation of the bridged calix[4]arene
7 led together with the desired amide formation, to the
1
undesired ring opening in the lower rim. No expected
product was isolated from the reaction mixture. The
possible reason for this can be the action of strong
trifluoroacetic acid on the strained ethereal system.
Therefore, we have changed the approach to the desired
compound, with the bridge being introduced after ada-
To reveal the role of amido groups in this type of
receptors, we have synthesized two model compounds,
the structural analogues of 3 and 4. The syntheses of
27 and 28, performed according to standard procedures,
required exhaustive and selective alkylation of 26, re-
spectively (Scheme 8).16
Com p lexa tion Stu d ies. The preliminary complex-
ation studies were performed with guests traditionally
(
(
(
13) Stephens, R. D.; Castro, C. E. J . Org. Chem. 1963, 28, 3313.
14) Gutsche, C. D.; Pagoria, P. F. J . Org. Chem. 1985, 50, 5795.
15) Arduini, A.; Pochini, A.; Sicuri, A. R.; Secchi, A.; Ungaro, R.
(16) van Loon, J .-D.; Verboom, W.; Reinhoudt, D. N. Org. Prep.
Proced. Int. 1992, 24, 437.
Gazz. Chim. Ital. 1994, 124, 129.

Calix[4]arene-Based Receptors
Sch em e 6
J . Org. Chem., Vol. 63, No. 26, 1998 9647
part) prove the 1:1 stoichiometry of the formed complex,
3
‚H
2
O, which indicates the binding of a single molecule
of water and not the water associate. We performed the
NOE difference experiment with a solution of this
complex in CCl
4
.
Irradiating protons of water, we
observed NOE peaks with the protons of aromatic units
bearing directly attached adamantyl moieties (Figure 1).
The downfield complexation-induced shift (CIS) of the
amide proton (0.6 ppm) indicates that the amido groups
act as hydrogen bond donors forming the bonds with the
oxygen lone pairs. According to the NOE experiment,
the water molecule is held inside the cavity. Usually the
encapsulation of the guest into the aromatic cavity causes
a large upfield shift of its protons.18 However, the signal
of water protons undergoes the moderate downfield CIS
(0.3 ppm). We suppose that this is the result of the
superposition of two factors: shielding by the aromatic
cavity (large upfield CIS expected) and the presence of
O-H‚‚‚π interactions (large downfield CIS expected). On
the basis of these data, the geometry of the complex is
supposed to be as shown in Figure 1. The water molecule
is bound by N-H‚‚‚O hydrogen bonds and fixed inside
the cavity by O-H‚‚‚p interactions. Although we cannot
allege the four-point caption of the water molecule, which
can as well oscillate between the mentioned binding sites,
its averaged position is clear and indicates the tetrahe-
dral recognition of an H
2
O molecule by 3.19
Interestingly, a lower rim disubstituted analogue of 3
compound 4) reveals no affinity toward water. As the
(
chemical nature of the cavity in both compounds seems
to be the same, the different behavior is caused by the
difference in their geometry. Lower rim 1,3-disubstituted
calix[4]arenes are known to exist in a stable pinched cone
conformation in solution, with the aromatic units bearing
hydroxyl groups being perpendicular.20 Tetraalkoxycalix-
[
4]arens undergo fast interconversion between two pinched
6
c
cone conformations. Evidently, 3 can adopt the geom-
etry suitable for the accommodation of water, while in
4
, the amido groups are kept apart by the array of
hydrogen bonds in the lower rim, and the change of
geometry for this compound is inevitably accompanied
by a loss of energy. Compound 27, the analogue of 3
without amido groups, also does not show the binding of
H O, which indicates that OH‚‚‚π interactions alone are
2
not sufficient for the capture of the water molecule within
the cavity.
Thus, we see that all the structural elements of 3 are
essential for binding of the water molecule: the presence
of two amido groups in the upper rim, flexibility of calix-
[4]arene framework provided by the substitution pattern
in the lower rim, and the shielding from the solvent
molecules by bulky adamantyl moieties.
capable of hydrogen bond formation like, for example,
water and those known to form stable inclusion com-
plexes with some calix[4]arene derivatives in apolar
media. The results are summarized in Table 1.
Compound 3 forms strong complex with water, which
is inevitably present in every solvent and complicates the
correct description of the complexation.17 The H NMR
Considering guests unable to form strong hydrogen
bonds, it is remarkable that 4 reveals the similar binding
properties with 28. Consequently, in the cases when
amido groups do not form hydrogen bonds with the guest,
the complexation is not altered by their presence. At the
same time, 4 binds pyrazine and DMF contrary to 28 that
evidences the positive role of amido groups.
1
4
spectrum of a CCl solution of the linear analogue of 3,
N-(1-adamantyl)benzamide, did not exhibit any changes
upon saturation with water; therefore, complexation of
water by 3 could hardly be confined to simple water-
amide interactions.
(
18) Diederich, F. In Cyclophanes, Monographs in Supramolecular
Chemistry; Stoddart, J . F., Ed.; RSC: Cambridge 1991; Vol. 3, p 82.
19) For several other receptors capable of tetrahedral recognition
Taking this into account, we undertook a more detailed
study of the complex of 3 with H
direct and reversed H NMR titrations (see experimental
2
O. The results of the
(
1
of water, see: (a) Chand, D. K.; Ragunathan, K. G.; Mak, T. C. W.;
Bharadwaj, P. K. J . Org. Chem. 1996, 61, 1169. (b) Dixon, D. A.; Dobbs,
K. D. J . Phys. Chem. 1994, 98, 13435.
(
17) Connors, K. A. Binding Constants; Wiley & Sons: New York,
(20) Timmerman, P.; Boerrigter, H.; Verboom, W.; Reinhoudt, D.
N. Recl. Trav. Chim. Pays-Bas 1995, 114, 103.
1
987; p 410.

9
648 J . Org. Chem., Vol. 63, No. 26, 1998
Pinkhassik et al.
Sch em e 7
Sch em e 8
Friedel-Crafts reactions in a one-pot procedure. Com-
pound 3 revealed the tetrahedral recognition of the water
molecule. In several cases, the difference between the
complexation by the amide-containing receptors (3, 4) and
their analogues (27, 28) was attributed to the positive
role of the amido groups.
Exp er im en ta l Section
Melting points are uncorrected. Column chromatography
was performed with silica gel (0.040-0.100 mm). Preparative
Ta ble 1
3
4
14
22 27
28
H2O
DMSO
pyradazine
pyrazine
CH3CN
270 ( 52 NC
138 ( 12 NC NC NC
a
NC
NC
NC
NC
29 ( 2
104 ( 9 34 ( 6
NC
NC NC NC
a
a
a
a
NC NC 78 ( 20
NC NC NC
NC NC 134 ( 3
NC 84 ( 2
13 ( 1
108 ( 12 28 ( 6
ClCH2CH2CN NC
68 ( 24
a
Due to the presence of water in CCl4, NC corresponds to K <
-
1
1
0 M .
1
4 can be considered an analogue of 3 where two
adamantyl groups are substituted by phenylacetylene
moieties. Unlike 3, it complexes acetonitrile and py-
ridazine, which indicates the presence of host-guest π-π
interactions. 22 seems to be too rigid to bind any of the
guests studied so far.
The majority of complexes reported herein are of
moderate stability. It is known that the systems with
multipoint binding are very sensitive to the precise
mutual correspondence between host and guest. Further
development of this type of receptor and the search for
appropriate host-guest pairs are the subjects of future
work.
Con clu sion s
A new type of calix[4]arene-based receptors with
hydrogen-bonding groups immersed into a large cavity
has been proposed and synthesized. Syntheses of 3 and
4
were achieved by the combination of the Ritter and
F igu r e 1.

Calix[4]arene-Based Receptors
J . Org. Chem., Vol. 63, No. 26, 1998 9649
Ta ble 2. Con cen tr a tion of Wa ter in Sa tu r a ted CCl4 Solu tion (M × 10-5) a t 298 K
1
H NMR
gravimetry
ref comp
concH2
ClCH2CN
376
CH3NO2
365
CH2Cl2
357
C6H5NO2
383
ClC2H4Cl
371
no.
1
2
3
O
330
412
353
thin-layer chromatography was performed with silica gel
Merck, 60 PF254). Chemicals were of reagent grade purchased
from Aldrich and were used without further purification. CH
Cl and DMF were distilled from CaH and were stored over
molecular sieves (4 Å). THF was distilled from K/benzophe-
none. CH CN was dried over molecular sieves (4 Å) prior to
All titration series with moisture-sensitive ligands were
performed using freshly dried equipment and agents. Samples
were prepared in the AtmosBag filled with dry argon. NMR
tubes, vessels, and solid ligands were dried under vacuum and
increased temperature (>200 °C) for 3-4 h. Syringes were
dried by the attachment to the vacuum line in the flow of dry
(
2
-
2
2
3
use. Petroleum ether refers to the fraction with bp 40-60 °C.
Reactions with moisture- and air-sensitive reagents were
performed in a dry nitrogen atmosphere.
argon and washed several times with freshly distilled CCl
4
before use. NMR measurements were accomplished within 1
h after preparation of the samples.
NMR spectra were recorded on a Varian Gemini 300 HC
spectrometer. The resonance frequency was 300.08 MHz for
the H measurements and 75.02 MHz for the C measure-
The NOE difference experiments were performed with the
number of transients accumulated from 640 to 2048, depending
on the pulse width. Sensitivity-enhancing weighting with LB
) 0.5 was applied. Samples were degassed by conventional
1
13
ments. Determination of stability constants was performed
1
23
by H NMR titration at 298 K in CCl
4
solutions. A capillary
methods. To separate the Overhauser effect from the pos-
filled with D
2
O was placed along the axis of the NMR tube
sible exchange of protons, the NOE difference experiments
were performed with different pulse widths and acquisition
and delay times. The similarity of the obtained spectra
demonstrates the validity of ascribing the signals to NOE. The
NOE difference experiment performed for the 4-water mix-
ture, where the water signal was irradiated, did not result in
any reasonable response; this gives additional proof of the
correctness of the above-discussed experiments.
and was used for system lock and shimming. Measurements
were done with scan numbers varying from 16 through 2048
depending on the solution concentrations. Sensitivity-enhanc-
ing weighting was applied with LB ) 0.2 Hz.
Concentrations of the components in the titration series
were adjusted by sequential planning in order to cover the
range from 40 to 90% of minor component saturation and to
have equidistant positions of experimental points on the
Scatchard plot that was used with the Fisher test for model
Compounds 1, 6, 8, 12, 23, 26, and 2810 were
15
15
20
12
12
4g
synthesized according to the literature procedures.
1
7
consistence testing. Binding constants and CIS values were
computed with the original nonlinear regression curve-fitting
Com p ou n d 3. A mixture of 1 (322 mg, 0.5 mmol), 1-ada-
mantanol (609 mg, 4 mmol), trifluoroacetic acid (1 mL), and
chloroform (1 mL) was refluxed for 24 h. The reaction mixture
was quenched with 10 mL of 2 N KOH and extracted with
dichloromethane. The organic layer was separated, washed
with water, and dried, and the solvent was evaporated. The
residue was submitted to column chromatography (silica gel,
2
1
program. Typically, binding constants were estimated from
data obtained for different protons and compared for self-
consistency of the result. As a rule, calixarene protons were
monitored in the presence of an excess of the guest. When
possible, guest and host concentrations were reversed and
guest protons were monitored and the results were compared.16
The evaluation of the stability constants of the water
complexes was performed in the following way,
CH
2
Cl
2
) to give 255 mg (42%) of white solid. mp 193-6 °C.
1
H NMR (CDCl
3
): δ ) 7.07 (s, 4H), 6.69 (s, 4H), 5.73 (s, 2H),
4
7
.45 and 3.16 (2d, 8H, J ) 13 Hz), 3.98 and 3.67 (2t, 8H, J )
Hz), 2.16-1.6 (m, 68H), 1.07 and 0.92 (2t, 12H, J ) 7 Hz).
1
. The concentration of water in the water-saturated CCl
4
was determined both gravimetrically and by comparison of the
peak squares of different reference compounds of known
concentration and water in 1H NMR spectra. To determine
the water solubility gravimetrically, three independent por-
13
3
C NMR (CDCl ): 168.22, 158.29, 155.44, 146.22, 135.75,
1
3
34.18, 131.13, 127.18, 125.94, 52.37, 46.04, 44.17, 42.21,
7.55, 37.13, 36.78, 36.41. MS (FAB) m/z 1215.6. Anal. Calcd
for 3‚2H
.91%.
Rea ction of 6 w ith Cu CN. A mixture of 6 (1.00 g, 1.50
2
O: C, 78.68%; H, 8.86%. Found: C, 78.49%; H,
tions of saturated CCl
refluxed for 48 h over P
4
(at 25 °C) of known weight were
5
O powder of known weight in the
8
2
apparatus, isolated from the atmosphere by a silicon bulb
playing the role of pressure buffer, and placed in the Atmos-
mmol) and CuCN (0.47 g, 5.25 mmol) in dry N-methylpyrro-
lidinone (20 mL) was refluxed with stirring for 5 h. The
reaction mixture was cooled to 100 °C and poured into a
2
2
2 5
Bag filled with dry argon. To avoid the release of P O dust,
the top of the weighted flask was equipped with pore-glass
membrane. Then the solvent was removed under reduced
pressure on the oil pump until a constant weight was reached.
The increase in the weights were ascribed to the capture of
solution of FeCl
40 mL). It was stirred at 100-110 °C for 1 h. The precipitate
was then filtered off, dried, and submitted to column chroma-
tography (silica gel, CH Cl /petroleum ether, 1:1 v/v, then CH
Cl ) to give 2 (360 mg, 58%) and 7 (129 mg, 16%).
3
‚6H
2
O (2 g) and concd HCl (6 mL) in water
(
2
2
2
-
1
water from the solvent and averaged with the results of H
2
-
3
NMR measurements (Table 2) to give (3.70 ( 0.12) × 10
M
1
a . Ca lixa r en e 2. mp 232-4 °C. H NMR (CDCl
.16 (s, 2H), 7.39 (s, 4H), 6.98-6.81 (m, 6H), 4.26 and 3.42
2d, 8H, J ) 13 Hz), 4.00 (t, 4H, J ) 6 Hz), 2.14-2.01 (m, 4H),
3
): δ )
of water solubility in CCl
The portion of CCl
4
4
at 298 K.
was dried in two steps. (a) The
powder for 24 h in the
9
(
1
2
.
2 5
solvent was refluxed over P O
+
.32 (t, 6H, J ) 6 Hz). MS (CI) m/z 558.3 (M ). Anal. Calcd:
C, 77.40%; H, 6.13%. Found: C, 77.23%; H, 6.21%.
b. Ca lixa r en e 7. mp 195 °C. H NMR (CDCl
apparatus, isolated from the atmosphere by silicon bulb, and
placed in the AtmosBag filled with dry argon. (b) Then the
solvent was distilled into the flask containing the fresh
phosphorus pentoxide and refluxed for 48 h more.
The distillation of solvent was always done directly before
preparation of samples.
1
3
): δ ) 9.24
(
s, 1H), 8.24 (s, 1H), 7.38 (s, 2H), 7.07, 6.97, 6.89 (3d, 6H, J )
7
.5 Hz), 6.80 (t, 2H, J ) 7.5 Hz), 6.66 (t, 1H, J ) 7.5 Hz), 4.30
and 4.29 (2d, 4H, J ) 13 Hz), 4.07-3.91 (m, 4H), 3.40 (d, 4H,
J ) 13 Hz), 2.08 (m 4H), 1.32 (t, 6H, J ) 7 Hz). MS (CI) m/z
3
.
The titration series of 3-water and 14-water was
prepared by the mixing of certain amounts of the solution of
dry ligand in the dry solvent and water-saturated CCl . The
+
5
33.5 (M ). Anal. Calcd: C, 78.77%; H, 6.61%; N, 2.62%.
Found: C, 78.54%; H, 6.72%; N, 2.43%.
4
Ca lixa r en e 4. A mixture of 2 (279 mg, 0.5 mmol), 1-ada-
mantanol (609 mg, 4 mmol), trifluoroacetic acid (1 mL), and
chloroform (1 mL) was stirred at the reflux for 24 h. The
reaction mixture was cooled, quenched with 10 mL of 2 N KOH
final amount of water in the samples was controlled by the
1
comparison of H NMR peaks of water and reference compound
(TMS) of known concentration.
(
21) The detailed description of the titration method and supple-
mentary software is available at our address upon request.
22) Purchased from Aldrich Chemical Co.
(23) Derome, A. Modern NMR Technique for Chemical Research;
Organic Chemistry Series, 6; Pergamon Press: New York, 1987.
(

9
650 J . Org. Chem., Vol. 63, No. 26, 1998
Pinkhassik et al.
and extracted with dichloromethane. The organic layer was
separated, washed with water, and dried, and the solvent was
evaporated. The residue was submitted to column chroma-
8H, J ) 13 Hz), 4.04 and 3.68 (2t, 8H, J ) 7 Hz), 2.26-1.68
1
3
(m, 38H), 1.07 and 0.87 (2t, 12H, J ) 7 Hz).
C NMR
3
(CDCl ): 167.04, 160.62, 156.19, 137.40, 136.45, 136.22,
tography (silica gel/CH
mp 224 °C. H NMR (CDCl
2
Cl
2
) to give 232 mg (41%) of white solid.
): δ ) 8.91 (s, 2H), 7.40 (s, 4H),
.98 (s, 4H), 5.52 (s, 2H), 4.32 and 3.41 (2d, 8H, J ) 13 Hz),
.97 (t, 4H, J ) 6.5 Hz), 2.21-1.48 (m, 64H), 1.28 (t, 6H, J )
130.70, 128.29, 86.99, 42.45, 37.19, 31.59, 30.31, 24.04, 23.56,
11.31, 10.52. MS (FAB) m/z 1199.4 (M + 1). Anal. calcd for
2
13‚1.5H O: C, 60.73%; H, 6.49%. Found: C, 60.83%; H, 6.51%.
Ca lixa r en e 14. A mixture of 13 (100 mg, 0.083 mmol),
cuprous phenylacetylide (41 mg, 0.250 mmol), and dry pyridine
(1 mL) was stirred at the reflux in an inert atmosphere for 24
h. The reaction mixture was cooled, poured into 10 mL of 1 N
HCl, and extracted with dichloromethane (2 × 10 mL). The
organic layer was washed with 1 N HCl and water and dried,
and the solvent was evaporated. The residue was submitted
1
3
6
3
6
+
2
.5 Hz). MS (CI) m/z 1130.6 (M ). Anal. Calcd for 4‚H O:
C, 80.67%; H, 8.37%; N, 2.48%. Found: C, 80.34%; H, 8.54%;
N, 2.23%.
Ca lixa r en e 5. To a solution of 4 (40 mg, 0.035 mmol) in
dry THF (5 mL) was added dropwise BH
3
(1 M in THF, 1 mL,
1
mmol) under nitrogen. The reaction mixture was then
heated at 70 °C for 7 h. After being cooled, the solution was
carefully hydrolyzed by the addition of water, and the mixture
was stirred for 30 min at room temperature. The solvent was
then distilled off, and the solid residue was heated to reflux
for 3 h in 6 N HCl (5 mL). After being cooled, the acidic
solution was evaporated to dryness in vacuo, 2 N NaOH (5
mL) was added to the reaction flask, and the product was
to preparative TLC to furnish 65 mg (68%) of 14. mp 184-
1
186 °C. H NMR (CDCl
3
): δ ) 7.37 (s, 4H), 7.34-7.01 (m,
10H), 6.68 (s, 4H), 5.81 (s, 2H), 4.45 and 3.22 (2d, 8H, J ) 13
Hz), 4.02 and 3.76 (2t, 8H, J ) 7 Hz), 2.22-1.64 (m, 38H),
1
3
3
1.05 and 0.92 (2t, 12H, J ) 7 Hz). C NMR (CDCl ): 167.46,
160.20, 156.53, 136.09, 134.05, 132.07, 132.00, 130.74, 128.43,
128.05, 127.89, 124.16, 117.96, 51.37, 42.21, 37.01, 31.60,
30.14, 23.85, 23.54, 11.07, 10.51. MS (FAB) m/z 1147.6 (M +
1). Anal. Calcd: C, 80.38%; H, 7.61%; N, 2.40%. Found: C,
80.09%; H, 7.83%; N, 2.26%.
extracted with CH
layer was dried over MgSO
to dryness to give 32 mg (82%) of 5. mp >170 °C (decomp).
2
Cl
2
(2 × 10 mL). The combined organic
4
, and the solvent was evaporated
1
H NMR (CDCl
.29 and 3.34 (2d, 8H, J ) 12.5 Hz), 3.99-3.50 (m, 10H), 2.11-
.18 (m, 70H). MS (CI) m/z 1102.9 (M ).
3
): δ ) 8.24 (s, 2H), 7.27 and 6.91 (2s, 8H),
Ca lixa r en e 15. To a suspension of 6 (1.50 g, 2.25 mmol)
and NaH (60% in oil, 1 g, 25 mmol, washed twice with hexane)
in dry DMF (100 mL) was added dropwise a solution of
2-iodoethyl ether (1.47 g, 4.5 mmol) in dry DMF (10 mL). The
reaction mixture was heated at 80 °C for 24 h and then
4
1
+
Ca lixa r en e 9. A solution of 8 (5.93 g, 10 mmol) and
N-bromosuccinimide (17.8 g, 100 mmol) in ethylmethyl ketone
200 mL) was stirred at room temperature for 24 h. The
mixture was then mixed with 150 mL of 10% Na and
(
evaporated to dryness. The residue was dissolved in CH
(50 mL), washed with 1 N HCl (2 × 50 mL) and water, and
dried over MgSO , and the solvent was evaporated to dryness.
The residue was purified by column chromatography (silica
gel, CH Cl /petroleum ether 2:1 v/v) and gave 0.56 g (34%) of
15. mp 240-242 °C. H NMR (CDCl
2 2
Cl
2
2 5
S O
stirred for 15 min. The organic layer was separated, washed
with water, and dried, and the solvent was evaporated. The
4
solid yellow residue was recrystallized from CHCl
give 6.96 g (77%) of white crystals. mp 181-183 °C. H NMR
CDCl ): δ ) 6.81 (s, 8H), 4.35 and 3.08 (2d, 8H, J ) 13.5
Hz), 3.81 (t, 8H, J ) 7.5 Hz), 1.82 (seq, 8H, J ) 7.5 Hz), 0.97
3
/CH
3
OH to
2
2
1
1
3
): δ ) 7.30 (s, 4H), 6.27
(
3
(t, 2H, J ) 7.5 Hz), 6.06 (d, 4H, J ) 7.5 Hz), 4.33 and 3.14
(2d, 8H, J ) 13.5 Hz), 4.18 and 3.98 (2t, 8H, J ) 4 Hz), 3.44
(t, 4H, J ) 7 Hz), 1.92-1.77 (m, 4H), 1.08 (t, 6H, J ) 7 Hz).
+
(
t, 12H, J ) 7.5 Hz). MS (CI) m/z 908.4 (M ). Anal. Calcd
for C40 : C, 52.89%; H, 4.88%; Br, 35.18%. Found: C,
2.55%; H, 5.07%; Br, 34.92%.
Ca lixa r en e 10. A mixture of 9 (6.0 g, 6.6 mmol) and CuCN
3.6 g, 40 mmol) in N-methylpyrrolidinone (120 mL) was
1
3
H
44Br
4
O
4
3
C NMR (CDCl ): 153.48, 155.52, 139.88, 133.07, 132.43,
5
128.15, 123.05, 115.46, 77.73, 73.89, 71.01, 31.28, 24.19, 11.60.
+
MS (CI) m/z 734.4 (M ). Anal. Calcd: C, 61.97%; H, 5.47%.
(
Found: C, 61.62%; H, 5.56%.
refluxed with stirring in a nitrogen atmosphere for 5 h. The
reaction mixture was cooled to 100 °C and poured into a
Ca lixa r en e 16. A mixture of 15 (680 mg, 0.92 mmol),
CuCN (330 mg, 3.69 mmol), and dry N-methylpyrrolidinone
(10 mL) was refluxed with stirring in an inert atmosphere for
5 h. The reaction mixture was cooled to 100 °C and poured
into a solution of FeCl (2 g), concd HCl (5 mL), and water (25
3
mL). The mixture was stirred at 100 °C for 1 h, and the
precipitate was filtered off, dried, and submitted to column
solution of FeCl
250 mL). It was stirred at 100-110 °C for 1 h. The
precipitate was then filtered off, dried, and submitted to
column chromatography (silica gel, CH Cl ) to give 2.8 g (61%)
): δ ) 7.00 (s, 8H), 4.45 and 3.26 (2d,
H, J ) 13.5 Hz), 3.91 (t, 8H, J ) 7.5 Hz), 1.89 (seq, 8H, J )
3
‚6H
2
O (15 g) and concd HCl (40 mL) in water
(
2
2
1
of 10. H NMR (CDCl
3
8
7
chromatography (silica gel, CH
2 2
Cl /petroleum ether 2:1 v/v)
+
.5 Hz), 1.00 (t, 12H, J ) 7.5 Hz). MS (CI) m/z 692.1 (M ).
: C, 76.28%; H, 6.40%; N, 8.09%.
to give 354 mg (61%) of 16 as a white solid. mp 212-216 °C.
1
Anal. Calcd for C44
H
44
N
4
O
4
3
H NMR (CDCl ): δ ) 7.49 (s, 4H), 6.26 (t, 2H, J ) 7.5 Hz),
Found: C, 75.79%; H, 6.78%; N, 7.82%.
Ca lixa r en e 11. A mixture of 10 (100 mg, 0.144 mmol),
5.98 (d, 4H, J ) 7.5 Hz), 4.39 and 3.24 (2d, 8H, J ) 13.5 Hz),
4.17 and 4.05 (2t, 8H, J ) 4 Hz), 3.66 (t, 4H, J ) 7 Hz), 1.92-
1
-adamantanol (200 mg, 4 mmol), trifluoroacetic acid (1 mL),
1.78 (m, 4H), 1.10 (t, 6H, J ) 7 Hz). 13C NMR (CDCl
3
): 163.16,
and chloroform (1 mL) was stirred at the reflux for 24 h. The
reaction mixture was cooled, quenched with 10 mL of 2 N
KOH, and extracted with dichloromethane. The organic layer
was separated, washed with water, and dried, and the solvent
was evaporated. The residue was submitted to column chro-
155.53, 139.14, 133.81, 132.55, 128.28, 123.28, 120.09, 106.46,
77.90, 73.89, 70.79, 31.23, 24.18, 11.58. MS (CI) m/z 628.6
+
(M ). Anal. Calcd: C, 76.41%; H, 6.41%. Found: C, 76.14%;
H, 6.71%.
Ca lixa r en e 17. To a suspension of CF
2.39 mmol) in CHCl (30 mL) was added a solution of 16 (300
mg, 0.477 mmol) in CHCl (20 mL), and the cloudy solution
was refluxed for 25 min, and then I (605 mg, 2.39 mmol) was
added. After 1 h, the precipitated AgI was filtered off and the
solution was treated with a 20% aqueous Na solution (50
mL) until the violet color had disappeared. The organic layer
was separated, washed twice with water, dried over Na SO
and evaporated to afford the diiodo calix[4]arene 17 as a yellow
solid, which was purified by crystallization (CH Cl /CH OH),
yield 374 mg (89%). mp 234-238 °C. H NMR (CDCl ): δ )
3
COOAg (527 mg,
matography (silica gel/CH
solid. mp 210-212 °C. H NMR (CDCl
5
2
Cl
2
) to give 232 mg (41%) of white
): δ ) 7.08 (s, 8H),
.84 (s, 4H), 4.46 and 3.24 (2d, 8H, J ) 13 Hz), 3.88 (t, 8H, J
3
1
3
3
2
)
7.5 Hz), 2.14-1.42 (m, 68 H), 0.98 (t, 12H, J ) 7.5 Hz). MS
+
(
CI) m/z 1302.4 (M + 1). Anal. Calcd for 11‚2H
2
O: C,
2 2 5
S O
7
6.27%; H, 8.15%. Found: C, 76.51%; H, 8.19%.
Ca lixa r en e 13. A mixture of 12 (250 mg, 0.294 mmol),
2
4
,
1
-adamantanol (255 mg, 1.68 mmol), trifluoroacetic acid (1
mL), and chloroform (1 mL) was stirred at the reflux for 24 h.
The reaction mixture was cooled, quenched with 10 mL of 2
N KOH, and extracted with dichloromethane. The organic
layer was separated, washed with water, and dried, and the
solvent was evaporated. The solid residue was submitted to
2
2
3
1
3
7.49 (s, 4H), 6.48 (s, 4H), 4.32 and 3.22 (2d, 8H, J ) 13.5 Hz),
4.20 and 4.03 (2t, 8H, J ) 4 Hz), 3.64 (t, 4H, J ) 7 Hz), 1.93-
1.78 (m, 4H), 1.08 (t, 6H, J ) 7 Hz). 13C NMR (CDCl
): 162.7,
3
column chromatography (silica gel/CH
46%) of white solid product. mp 198 °C. H NMR (CDCl
δ ) 7.43 (s, 4H), 6.64 (s, 4H), 5.79 (s, 2H), 4.38 and 3.18 (2d,
2
Cl
2
1
) to give 154 mg
155.6, 138.3, 137.4, 134.9, 133.9, 107.4, 86.88, 78.4, 74.1, 71.3,
+
(
3
):
30.85, 24.08, 11.45. MS (CI) m/z 881.0 (M + 1). Anal.
Calcd: C, 54.56%; H, 4.35%. Found: C, 54.21%; H, 4.32%.

Calix[4]arene-Based Receptors
J . Org. Chem., Vol. 63, No. 26, 1998 9651
Ad a m a n tyla tion of 17. A mixture of 17 (150 mg, 0.215
mmol), 1-adamantanol (131 mg, 0.860 mmol), trifluoroacetic
acid (1 mL), and chloroform (1 mL) was stirred at the reflux
for 24 h. The reaction mixture was cooled, quenched with 10
mL of 2 N KOH, and extracted with dichloromethane. The
organic layer was separated, washed with water, and dried,
and the solvent was evaporated. The solid residue was
HCl, and extracted with dichloromethane (2 × 10 mL). The
organic layer was washed with 1 N HCl and water and dried,
and the solvent was evaporated. The residue was submitted
to preparative TLC (silica gel, CH
2
Cl
2
) to furnish 27 mg (69%)
of 22. 1H NMR (CDCl
): δ ) 7.64-7.14 (m, 18H), 5.89 (s, 2H),
3
4.39 and 3.31 (2d, 8H, J ) 13.5 Hz), 4.20 and 3.98 (2 br s,
8H), 3.67 (t, 4H, J ) 7 Hz), 2.26-1.58 (m, 34H), 1.08 (br t,
+
submitted to preparative TLC (silica gel/CH
mg (27%) of white solid product 18. H NMR (CDCl
2
Cl
2
) to give 70
): δ )
6H, J ) 7 Hz). MS (CI) m/z 1133.4 (M + 1). Anal. Calcd:
1
3
C, 79.27%; H, 7.18%. Found: C, 78.93%; H, 7.21%.
7
3
1
.67, 7.53, 6.76, 6.39 (4s, 8H), 7.14 (s, 2H), 5.86 (s, 2H), 4.58-
Ca lixa r en e 24. 1-Adamantanecarbonyl chloride (40 mg,
.98 (m, 14H), 3.72 (t, 4H, J ) 7 Hz), 3.38-3.16 (m, 4H), 2.23-
0.20 mmol) in dry CH Cl2 (5 mL) was added dropwise to a
2
.68 (m, 34H), 1.09 (t, 6H, J ) 7.5 Hz). MS (CI) m/z 1202.7
solution of 23 (90 mg, 0.10 mmol) and DMAP (27 mg, 0.22
mmol) in dry CH Cl (5 mL) at room temperature in an inert
+
(
M ). Anal. Calcd for 18‚2H
2
O: C, 58.16%; H, 6.18%.
2
2
Found: C, 57.91%; H, 6.26%.
atmosphere. The reaction mixture was stirred at room tem-
Ca lixa r en e 19. To a suspension of CF
mmol) in CHCl (100 mL) was added a solution of 2 (3.50 g,
.26 mmol) in CHCl (50 mL). The cloudy solution was
refluxed for 25 min, and then I (6.35 g, 25.0 mmol) was added.
After 1 h, the precipitated AgI was filtered off and the solution
was treated with a 20% aqueous Na solution (50 mL)
until the violet color had disappeared. The organic layer was
separated, washed twice with water, dried over Na SO , and
evaporated to afford calix[4]arene 19 as a yellow solid, which
was purified by crystallization (CH Cl : CH OH), yield 4.27 g
84%). mp 192-194 °C. H NMR (CDCl ): δ ) 9.02 (s, 2H),
3
COOAg (5.53 g, 25.0
perature overnight, washed with 1 N HCl (2 × 10 mL) and
3
water (10 mL), dried over MgSO and evaporated to dryness.
4
6
3
The solid residue was submitted to preparative TLC (silica gel,
CH Cl /petroleum ether, 2:1 v/v) to give 93 mg (76%) of 24.
2
2
2
1
mp 165-168 °C. H NMR (CDCl ): δ ) 7.21 (s, 4H), 6.46 (br
3
2
S
2
O
5
t, 2H), 6.18 (s, 4H), 4.34 and 3.05 (2d, 8H, J ) 13 Hz), 4.04 (br
d, 4H), 3.92 and 3.67 (2t, 8H, J ) 7 Hz), 2.18-1.68 (m, 38H),
1
3
2
4
1.03 and 0.91 (2t, 12H, J ) 7 Hz). C NMR (CDCl ): 178.44,
3
157.8, 155.1, 139.1, 137.7, 133.9, 132.9, 126.2, 86.03, 78.11,
77.61, 42.51, 41.45, 40.19, 37.41, 31.50, 29.10, 24.09, 23.75,
2
2
3
1
+
(
3
11.32, 10.75. MS (CI) m/z 1227.4 (M + 1). Anal. Calcd for
24‚H O: C, 61.73%; H, 6.64%. Found: C, 62.04%; H, 6.61%.
7
3
7
1
1
4
.39 (s, 4H), 7.28 (s, 4H), 4.17 and 3.39 (2d, 8H, J ) 13 Hz),
.97 (t, 4H, J ) 7.5 Hz), 2.14-1.98 (m, 4H), 1.30 (t, 6H, J )
2
Ca lixa r en e 25. A mixture of 24 (50 mg, 0.041 mmol),
cuprous phenylacetylide (27 mg, 0.163 mmol), and dry pyridine
1
3
3
.5 Hz). C NMR (CDCl ): 158.22, 152.48, 139.19, 135.09,
33.61, 128.78, 120.10, 103.24, 90.44, 79.67, 31.49, 24.08,
(1 mL) was stirred at the reflux in an inert atmosphere for 24
+
1.51. MS (CI) m/z 810.8 (M ). Anal. Calcd: C, 57.93%; H,
h. The reaction mixture was cooled, poured into 10 mL of 1 N
HCl, and extracted with dichloromethane (2 × 10 mL). The
organic layer was washed with 1 N HCl and water and dried,
and the solvent was evaporated. The residue was submitted
to preparative TLC (silica gel, CH Cl ) to furnish 33 mg (69%)
.32%. Found: C, 57.61%; H, 4.39%.
Ca lixa r en e 20. A mixture of 19 (400 mg, 0.494 mmol),
-adamantanol (304 mg, 2.0 mmol), trifluoroacetic acid (2 mL),
1
and chloroform (2 mL) was stirred at reflux for 24 h. The
reaction mixture was cooled, quenched with 10 mL of 2 N
KOH, and extracted with dichloromethane. The organic layer
was separated, washed with water, and dried, and the solvent
was evaporated. The solid residue was submitted to column
2
2
1
of 25. mp 180-182 °C. H NMR (CDCl ): δ ) 7.66-7.08 (m,
3
18H), 6.51 (br t, 2H), 4.27 and 3.16 (2d, 8H, J ) 13 Hz), 4.09
(br s, 4H), 3.94 and 3.75 (2t, 8H, J ) 7 Hz), 2.20-1.68 (m,
38H), 1.09 and 0.95 (2t, 12H, J ) 7 Hz). MS (CI) m/z 1175.4
chromatography (silica gel/CH
2
Cl
2
) to give 187 mg (34%) of
(M + 1). Anal. Calcd for 25‚1.5H O: C, 79.90%; H, 7.79%.
+
2
1
2
0 as a white solid product. mp 172 °C. H NMR (CDCl
3
): δ
Found: C, 80.12%; H, 7.74%.
)
8.53 (s, 2H), 7.46 (s, 4H), 7.26 (s, 4H), 5.73 (br s, 2H), 4.20
and 3.39 (2d, 8H, J ) 13 Hz), 3.95 (t, 4H, J ) 7 Hz), 2.24-
Ca lixa r en e 27. To a suspension of 26 (300 mg, 0.312 mmol)
and NaH (60% in oil, 100 mg, 2.50 mmol) in dry DMF (20 mL)
was added dropwise propyl iodide (0.25 mL, 2.50 mmol). The
reaction mixture was heated at 80 °C for 24 h and then
1
.58 (m, 34H), 1.28 (t, 6H, J ) 7 Hz). MS (CI) m/z 1115.3
+
2
(M ). Anal. Calcd for 20‚1.5H O: C, 58.90%; H, 5.91%.
Found: C, 58.58%; H, 6.01%.
2 2
evaporated to dryness. The residue was dissolved in CH Cl
Ca lixa r en e 21. To a suspension of 20 (120 mg, 0.11 mmol)
and NaH (60% in oil, 50 mg, 1.25 mmol) in dry DMF (15 mL)
was added dropwise a solution of 2-iodoethyl ether (82 mg,
(
20 mL), washed with 1 N HCl (2 × 20 mL) and water, and
dried over MgSO
The residue was purified by crystallization (CH
to furnish 260 mg (74%) of 27. H NMR (CDCl
8
Hz), 2.16-1.52 (m, 68H), 1.00 (t, 12H, J ) 7.5 Hz). MS (CI)
m/z 1129.1 (M ). Anal. Calcd: C, 85.06%; H, 9.28%. Found:
4
, and the solvent was evaporated to dryness.
Cl /CH OH)
): δ ) 6.82 (s,
2
2
3
0
.25 mmol) in dry DMF (5 mL). The reaction mixture was
heated at 80 °C for 24 h and then evaporated to dryness. The
residue was dissolved in CH Cl (20 mL), washed with 1 N
HCl (2 × 20 mL) and water, and dried over MgSO , and the
solvent was evaporated to dryness. The residue was purified
by preparative TLC (silica gel, CH Cl /petroleum ether 2:1 v/v)
1
3
H), 4.42 and 3.13 (2d, 8H, J ) 12 Hz), 3.81 (t, 8H, J ) 7.5
2
2
+
4
C, 84.81%; H, 9.33%.
2
2
N-(1-a d a m a n tyl)ben za m id e. A mixture of benzonitrile (1
mL, 9.79 mmol) and 1-adamantanol (3.73 g, 24.50 mmol, 2.5-
fold excess) was dissolved in trifluoroacetic acid (10 mL) and
stirred for 15 h at 55 °C. Then, the solvent was removed under
reduced pressure and the solid residue was dissolved in
and gave 40 mg (31%) of 21, all of which was used in the
subsequent reaction with cuprous phenylacetylide. mp 212
1
°
2
C. H NMR (CDCl
3
): δ ) 7.54 (s, 4H), 6.52 (s, 4H), 5.86 (s,
H), 4.32 and 3.22 (2d, 8H, J ) 13.5 Hz), 4.19 and 3.97 (2 br
s, 8H), 3.64 (t, 4H, J ) 7 Hz), 2.26-1.58 (m, 34H), 1.08 (t, 6H,
dichloromethane and washed with 0.1 M K
The organic layer was separated, dried over MgSO
2
CO
3
and water.
, and
+
J ) 7 Hz). MS (CI) m/z 1185.2 (M + 1).
4
Ca lixa r en e 22. A mixture of 21 (40 mg, 0.034 mmol),
evaporated to give the crude solid consisted of mainly N-(1-
adamantyl)benzamide and an excess of adamantanol. Sub-
mission to column chromatography (silica gel, CH Cl ) afforded
2 2
cuprous phenylacetylide (22 mg, 0.136 mmol), and dry pyridine
(1 mL) was stirred at the reflux in an inert atmosphere for 24
h. The reaction mixture was cooled, poured into 10 mL of 1 N
the pure product (2.18 g, 8.54 mmol, 87% yield). The analytical
and spectral data of N-(1-adamantyl)benzamide obtained
2
4
(
24) (a) Kreutzberger, A.; Schr o¨ ders, H. H. Tetrahedron Lett. 1970,
correspond to those available from the literature.
4
1
523. (b) Isaev, S. D.; Novoselov, E. F.; Yurchenko, A. G. Zh. Org. Khim.
985, 21, 114.
J O9804543