First synthesis of lower-rim-substituted aryl ethers of p-tert-butylcalix[4]arene

Article abstract of DOI:10.1021/jo015622x

With the use of S_NAr or Ullmann reactions, the synthesis of the first lower-rim aryl ether derivatives of tert-butylcalix[4] arene is reported, as are some of their conformational properties, ¹H NMR spectra, and X-ray crystal structures. The lower-rim aryl pendants reported herein provide for new scaffolds upon which a host of other new molecular architectures can be constructed, thus extending the capability of the versatile calix[4]arenes even further.

Full text of DOI:10.1021/jo015622x

J . Org. Chem. 2001, 66, 6257-6262
6257
F ir st Syn th esis of Low er -Rim -Su bstitu ted Ar yl Eth er s of
p-ter t-Bu tylca lix[4]a r en e
Sultan Chowdhury and Paris E. Georghiou*
Department of Chemistry, Memorial University Newfoundland,
St. J ohn’s, Newfoundland A1B 3X7, Canada
parisg@mun.ca
Received March 7, 2001
With the use of SNAr or Ullmann reactions, the synthesis of the first lower-rim aryl ether derivatives
of tert-butylcalix[4]arene is reported, as are some of their conformational properties, 1H NMR spectra,
and X-ray crystal structures. The lower-rim aryl pendants reported herein provide for new scaffolds
upon which a host of other new molecular architectures can be constructed, thus extending the
capability of the versatile calix[4]arenes even further.
In tr od u ction
of lower-rim-substituted aryl ethers of p-tert-butylcalix-
[4]arene (4).
In recent years, much attention has been devoted to
the synthesis and study of the properties of functionalized
calix[4]arenes because of their potential utility as supra-
molecular hosts for neutral guest molecules such as
[60]fullerene and as selective ionophores for various
cations or anions.1 Calix[4]arenes, 1 (see Chart 1), can
be readily functionalized at either their lower or their
upper rim or both. Functional groups such as amides,
esters, poly(ethylene glycol) units, alkyl ethers, and
benzyl ethers are most often introduced at the lower rims
of the calix[4]arene scaffold. However, no lower-rim aryl
ether derivatives of calix[4]arenes, such as 2 and 3, have
been reported although such derivatives could be useful
lower-rim cavitands2 in which the aryl pendant groups
define an additional hydrophobic cavity. Furthermore,
because the pendant aryl groups themselves can easily
be modified, such calix[4]arene aryl ethers can provide
additional scaffolds for constructing desirable molecular
architectures.
While lower-rim O-alkylated and lower-rim O-benz-
ylated calix[4]arenes are easily formed via simple Will-
iamson-type nucleophilic substitution reactions of the
corresponding calixarenes with alkyl or benzyl halides,
the synthesis of O-aryl ether analogues has not been
reported. A single publication by Gutsche3 exists which
describes the mono-, di-, and hexa-2,4-dinitrophenyl ether
derivatives of the larger and conformationally more
flexible tert-butylcalix[8]arenes. To the best of our knowl-
edge, this is the only published report of any lower-rim
aryl ether derivatives of a calixarene. As part of our
studies on developing methods to functionalize the lower
rim of calix[4]arenes4 and calix[4]naphthalenes5 to create
new target molecules, we report herein the first syntheses
Resu lts a n d Discu ssion
The endeavors required for the synthesis and study of
the vancomycin group of antibiotics have necessitated
development of mild methods for macrocyclization of 16-
membered ring systems in which, essentially, a diaryl
ether is formed.6 Recently, Chan7 and Evans8 reported
methods for relatively mild Cu(II) acetate-promoted
arylation of phenols with arylboronic acids. However, the
use of their methodology with 4 and phenylboronic acid
in our hands failed to produce any of the corresponding
phenyl ethers, affording only unreacted starting materi-
als. Normal Ullmann conditions also failed with simple
aryl halides and 4. In this regard, these findings were
consistent with our earlier observations that the lower-
rim Suzuki-Miyaura coupling reactions with phenyl-
boronic acids and p-tert-butylcalix[4]arene triflates were
unsuccessful, presumably because of steric crowding of
the intermediates that lead to product formation.4
On the other hand, when a nucleophilic aromatic
substitution (SNAr)-based reaction was employed using
2 equiv of the readily available 4-fluoro-3-nitrobenz-
aldehyde (5) with 4 in the presence of K2CO3/DMF (Table
1, entry 1), the monoaryl ether 3a was formed in 58%
isolated yield. The 1H NMR spectrum in acetone-d6
revealed it to be exclusively in a cone conformation,
although when the solvent was changed to CDCl3 or C6D6
the presence of another conformer was observed. VT-1H
NMR experiments on 3a over the range of 223-323 K
revealed only that the relative concentration of the minor
component increased with increasing temperature, but
we were unable to isolate and unequivocally assign a
structure to it. The closely related corresponding hy-
droxymethyl compound 6 (vide infra) however did not
(1) Gutsche, C. D. Calixarenes Revisited; Stoddart, J . F., Ed.;
Monographs in Supramolecular Chemistry; The Royal Society of
Chemistry: Cambridge, U.K., 1998 and references therein.
(2) For a recent overview of cavitands, see: Tucci, F. C.; Rudkevich,
D. M.; Rebek, J ., J r. J . Org. Chem. 1999, 64, 4555 and references
therein.
(3) Muthukrishnan, R.; Gutsche, C. D. J . Org. Chem. 1979, 44, 3962.
(4) Chowdhury, S.; Bridson, J . N.; Georghiou, P. E. J . Org. Chem.
2000, 65, 3299.
(6) For a recent review of these macrocyclization reactions directed
toward the synthesis of vancomycin, see: Nicolaou, K. C.; Boddy, C.
N.; Bra¨se, S.; Winssinger, N. Angew. Chem., Int. Ed. 1999, 38, 2096
and references therein.
(7) Chan, D. T.; Monaco, K. L.; Wang, R.-P.; Winters, M. P.
Tetrahedron Lett. 1998, 39, 2933.
(5) Georghiou, P. E.; Ashram, M.; Clase, H. J .; Bridson, J . N. J . Org.
Chem. 1998, 63, 1819.
(8) Evans, D. A.; Katz, J . L.; West, T. R. Tetrahedron Lett. 1998,
39, 2937.
10.1021/jo015622x CCC: $20.00 © 2001 American Chemical Society
Published on Web 08/21/2001

6258 J . Org. Chem., Vol. 66, No. 19, 2001
Chowdhury and Georghiou
Ch a r t 1
Ta ble 1. Rea ction of Va r iou s Ar yl Ha lid es w ith 4 a n d 7
entry
1
substrates
conditions
product(s)
4-fluoro-3-nitrobenzaldehyde
K2CO3/DMF or
K2CO3/CuO/pyridine
K2CO3/DMF
K2CO3/DMF
NaH/DMF
K2CO3/DMF
K2CO3/CuO/pyridine
K2CO3/CuO/pyridine
3a -c
2
3
4
5
6
7
1,3-dinitro-2-fluorobenzene
4-fluorobenzaldehyde
4-fluoro-3-nitrobenzaldehyde
3-fluorobenzaldehyde
ethyl 4-fluoro-3-nitrobenzoate
4-fluoro-1-nitrobenzene
no reaction
no reaction
8
no reaction
9a and 9b
10 and 11
show similar behavior in the different solvents. The
pattern of the methylene proton signals observed for 3a
is consistent with those typically found in lower-rim-
substituted tert-butylcalix[4]arenes existing in a cone
conformation. Further confirmation for the assignment
of 3a was obtained by NOED experiments in both C6D6
and in acetone-d6. A single-crystal X-ray structure of 3a
crystallized from benzene solution clearly reveals its cone
conformation in the solid state9 and reveals that it is a
clathrate with three molecules of benzene contained in
the lattice. One of the benzene molecules is situated
within the cavity (or basket) of 3a , and the other two are
situated outside the cavity.
Reaction of 4 with larger amounts of 5 produced
mixtures of the di- and triaryl ethers 3b and 3c which
could not be separated, although (+) FAB MS indicated
the presence of 3c but not of the corresponding tetraaryl
ether 3d . Table 1 lists several other aryl halides, which
contain electron-withdrawing substituents and which
were evaluated for their reactivities with 4. The aryl
halides listed in entries 2, 3, and 5 of Table 1 failed to
produce the corresponding aryl ethers with 4. To deter-
mine whether steric crowding due to the presence of four
aryl groups on the lower rim of the calixarene might have
been a factor inhibiting the formation of tri- or tetraaryl
ethers, the 1,3-di-O-benzylated tert-butylcalixarene 710
was treated with 5 using NaH in DMF (Table 1, entry 4)
to successfully afford in 53% yield the di-O-benzyl-di-O-
aryl ether 8, which was determined by NMR to be in a
cone conformation. It is thus possible to functionalize the
lower rim of 4 with two aryl ether and two benzyl ether
pendants using SNAr-type reaction conditions, and there-
fore, steric crowding should not be a factor inhibiting
potential tetraarylation.
1
The H NMR spectrum of 8 shows that there is a large
upfield shift for the axial and equatorial protons of the
methylene bridges in the calixarene ring, from δ 3.20 and
4.22 ppm in the parent calixarene 7 to δ 2.86 and 3.98
ppm in compound 8 for the axial and equatorial protons,
respectively (correlated with the 13C NMR signal at δ 31.3
ppm). This can be explained by assuming that the
observed shielding effect occurs as a result of the presence
of the aryl ether group in close proximity to the meth-
ylene protons. NOED experiments on 8 confirmed this
hypothesis; irradiation of the signal centered at δ 2.86
ppm (equatorial methylene proton) enhances the signals
at δ 3.98 ppm, 6.39 ppm (proton meta to the nitro group
in the aryl substituent), and δ 6.97 ppm (proton ortho to
the benzyl methylene) by 19%, 3%, and 4%, respectively,
while the signal centered at δ 3.98 ppm (axial methylene
proton) enhanced the signal at δ 2.86 ppm, 5.47 ppm
(benzyl methylene protons), and δ 6.99 ppm (calixarene
aromatic protons) by 14%, 4%, and 1%, respectively. The
downfield shift for the benzylic protons from δ 5.00 (in
7) to 5.46 ppm (in 8) can be explained by assuming that
the deshielding effect is likely due to the anisotropic
effects of the neighboring nitro-aryl ring. The 1,3-
alternate structure would not likely have resulted in this
observed downfield shift. Furthermore, the single 13C
signal at δ 31.3 ppm due to the methylene bridges (“de
Mendoza rule”1,11) supports the assignment of a cone
conformation.
(9) Atomic coordinates of the structures of 3a and 3e have been
deposited with the Cambridge Crystallographic Data Centre. These
are available on request from the Director, Cambridge Crystallographic
Data Centre, 12 Union Road, Cambridge CB2 1EK, U.K.
(11) J aime, C.; de Mendoza, J .; Prados, P.; Nieto, P. D.; Sa`nchez, C.
(10) Ikeda, A.; Shinkai, S.; Tetrahedron 1991, 47, 4325.
J . Org. Chem. 1991, 56, 3372.

Aryl Ethers of p-tert-Butylcalix[4]arene
J . Org. Chem., Vol. 66, No. 19, 2001 6259
Sch em e 1
F igu r e 1. Stereoview of 3e in a partial cone conformation.
One of the aryl ether pendants is sandwiched between two
adjacent tert-butyl-bearing phenyl rings within the calix[4]-
arene cavity.
NMR spectrum of 10 in CD2Cl2 shows the presence of
three signals at δ 1.14, 1.44, and 1.63 ppm in a 1:2:1 ratio,
which are assigned to the three different tert-butyl
groups. Two AB quartets due to the methylene bridge
protons are centered at δ 3.25 and 3.34 ppm with geminal
coupling constants of J ) 13 and 15 Hz, respectively. The
13C NMR spectrum shows a pattern that is consistent for
a partial cone conformation and shows eight upfield
resonances due to the quaternary carbons (δ 34.7, 35.1,
and 35.4 ppm), the methyl carbons of the tert-butyl
groups (δ 31.7, 31.9, and 32.5 ppm), and the methylene
carbons (δ 31.0 and 37.4 ppm). The methylene carbon
signals at δ 31.0 and 37.4 ppm deviate only slightly from
the positions typically found at δ 31.1 and 37.0 ppm as
described by de Mendoza for calix[4]arenes in partial cone
conformations. The downfield resonances consisting of 22
signals arising from the aromatic carbons are in agree-
ment with the predicted structure. Additional support for
the assigned structure was obtained by CI MS analysis,
which showed a molecular ion peak at the expected value
of m/z ) 1132.
The use of Ullmann ether conditions (K2CO3/CuO/
pyridine, reflux)12 with 5 and other aryl halides that were
previously found to be reactive was then evaluated, and
in general, workup was found to be more convenient.
With the use of 3 equiv of 5, both monoaryl ether 3a and
the distal diaryl ether 3b were formed in 38% yield each
(Table 1, entry 1) and could be easily separated by
1
chromatography. The H NMR spectrum of 3b revealed
two AB systems centered at δ 3.22 and 4.00 ppm (geminal
coupling constant of J ) 13.6 Hz) due to the methylene
bridge protons of the calixarene ring. The corresponding
13C methylene carbons were at δ 31.0 and 31.5 ppm, re-
spectively, a feature which, according to the de Mendoza
rule, is typical for 1,3-substituted calix[4]arenes in the
cone conformation.
It was surprising therefore to see that the X-ray
structure of a single crystal obtained from what was
presumed to be entirely 3b showed it to be proximally
(i.e., 1,2-) disubstituted and in a partial cone conforma-
tion (Figure 1).9 The two aryl groups are trans to each
other, with one being “sandwiched” between two adjacent
tert-butyl-bearing phenyl rings within the calixarene
cavity. The other aryl pendant is twisted outside of the
cavity. The most likely explanation for the X-ray crystal
structure, which is not in accord with the NMR assign-
ments, is that it is due to a minor contaminant, 3e,
formed alongside 3b which was not detected in the NMR
spectra.
With 2 equiv of ethyl-4-fluoro-3-nitrobenzoate (5b), the
corresponding mono- and diaryl ethers, 9a and 9b, were
obtained in 37% and 24% yields, respectively (Table 1,
entry 6). With 4 equiv, again only 9a and 9b could be
isolated, although this time in 73% and 21% yields,
respectively, with no evidence of any of the tri- or
tetrasubstituted aryl ethers having been formed. Analysis
of both the 1H and 13C NMR spectra is in agreement with
the proposed structures for each of 9a and 9b being in
cone conformations.
To obtain tetraaryl ethers of 4, the efficacy of both
Ullmann and SNAr conditions was evaluated using 4
equiv of 4-fluoro-1-nitrobenzene. As depicted in Scheme
1 (Table 1, entry 7), 10 was obtained as the major product
(46%) and 11 as a minor product (16%). Compound 10
was unambiguously confirmed by NMR analysis and
mass spectrometry to be the expected tetraaryl ether
derivative of 4 in a partial cone conformation. The 1H
The minor product 11 is also a tetraaryl ether deriva-
tive of 4 that exists in the 1,2-alternate conformation in
solution. Its structure was determined by NMR analysis,
1
and its molecular mass was confirmed by CI MS. The H
NMR spectrum of 11 in CD2Cl2 was very simple, showing
a singlet at δ 1.25 ppm due to the tert-butyl protons, a
pair of doublets centered at δ 3.20 and 3.57 ppm (J )
12.5 Hz), and a singlet at δ 3.40 ppm for the methylene
protons indicating that 11 has C2h symmetry and is in a
1,2-alternate conformation. The doublet at δ 5.98 ppm
(J ) 9 Hz) is due to the aromatic protons ortho to the
oxygen atoms on the aryl ether groups, and it is coupled
with the doublet at δ 7.83 ppm. A proton ortho to a
strongly electron-withdrawing group, such as the nitro
group, would be expected to appear further downfield
than δ 7.83 ppm. In the case of 11 however, these protons
are shielded by the aromatic units of the calixarene and
therefore appear upfield. The 13C NMR spectrum exhibits
signals at δ 30.4 and 38.5 ppm due to the methylene
carbons, while the signals at δ 31.9 and 34.9 ppm are
due to the methyl and quaternary carbons of the tert-
butyl groups, respectively. The chemical shifts of the
methylene carbons are consistent for calix[4]arenes hav-
ing a 1,2-alternate conformation.11
With these lower-rim aryl ethers in hand, experiments
aimed at the coupling of two such arylated calix[4]arene
molecules via a spacer molecule such as 1,2-dibromo-
ethane were conducted. Reduction of 3a with NaBH4
afforded, in 85% yield, the corresponding alcohol 6 which
could serve as a direct precursor toward 12 as outlined
in Scheme 2. The structure of 6 was determined in the
usual manner to be in a cone conformation, and as
(12) (a) Ullmann, F. Ber. Dtsch. Chem. Ges. 1904, 37, 853. (b)
Ullmann, F.; Sponagel, P. Ber. Dtsch. Chem. Ges. 1905, 38, 2211.

6260 J . Org. Chem., Vol. 66, No. 19, 2001
Chowdhury and Georghiou
Sch em e 3
Sch em e 2
one of the propoxy groups. The triplet centered at the
exceptionally high field position of δ 0.04 ppm (J ) 7.3
Hz) coupled to the multiplet at δ 0.92 ppm (J ) 7.3 Hz)
is assigned to the methyl and to the vicinal methylene
protons of the propoxy group. There are a total of four
sets of quartets centered at δ 2.39, 2.55, 3.60, and 4.11
ppm that all have the same geminal coupling constant
(J ) 9 Hz). These clearly indicate that the protons on
each of these methylene groups are diastereotopic be-
cause of the different magnetic environments experienced
by these protons when the molecule is in a 1,2-alternate
conformation. The unusual upfield shifts experienced by
one propoxy group, and to a lesser extent by the second
propoxy group (triplet at δ 1.02 ppm, multiplet at δ 1.90
ppm, and the two sets of AB quartets centered at δ 2.39
and 2.55 ppm), indicate that one of the propoxy groups
is strongly shielded by the neighboring calixarene aro-
matic ring which bears the aryl ether pendant, as shown
in the structure depicted in Scheme 3. Such diastereo-
topicity for the protons of simple propoxy-bearing calix-
[4]arenes has not been noted by others but has been
observed with the propyl and other alkyl ether deriva-
tives of tert-butylcalix[4]naphthalenes and calix[4]naph-
thalenes.13
referred to previously, none of the complex behavior seen
with 3a in the different deuterated solvents was observed
for 6. Reaction of 6 with 1,2-dibromoethane in the
presence of NaH in THF, however, has thus far failed to
unambiguously afford the expected double calix[4]arene
product 12. The NMR analysis of the product obtained
did not provide any conclusive evidence to allow for the
determination of its structure. It was therefore thought
necessary to first protect the free phenolic groups in 3a
before attempting the coupling reaction. Through the use
of excess 1-iodopropane in the presence of K2CO3 in
acetonitrile with 3a , the mono-O-aryl-O-dipropoxy-tert-
butylcalix[4]arene 13a and the mono-O-aryl-O-propoxy-
tert-butylcalix[4]arene 13b were obtained in 36% and
32% yields, respectively (Scheme 3). The structures of
13a and 13b were determined in the usual manner.
The spectra of 13b are relatively straightforward;
1
however, the H NMR spectrum of 13a is more complex
and revealing. The eight methylene bridge protons of the
calixarene scaffold appear as a set of six one-proton
doublets due to three clearly defined AB systems and a
two-proton apparent broad singlet at δ 3.94 ppm. Each
of the doublets is centered at δ 2.99, 3.36, 3.53, 3.86, and
3.97 ppm (the latter consisting of a pair of overlapping
doublets) having typical geminal coupling constants (J
≈ 13-15.5 Hz). The signal at δ 3.94 ppm is due to the
methylene protons, which bridge the pair of propoxy-
bearing aromatic rings of the calixarene, which are trans
to each other. These protons would therefore be pseudo-
axial and pseudoequatorial and thus would have rela-
tively small chemical shift differences. Thus, the com-
pound is proximally dipropoxy-substituted and exists in
a 1,2-alternate conformation. There are four signals at δ
31.3, 32.9, 39.1, and 39.6 ppm that can be assigned to
the methylene bridges, their positions being consistent
with the 13C NMR signal patterns for 1,2-alternate
conformations of calix[4]arenes,9 the signals at δ 39.1 and
39.6 ppm being more deshielded than the value of δ 38.2
ppm generally reported. The 1H NMR spectrum also
reveals a strong upfield shift for the methyl protons of
In conclusion, either SNAr or Ullmann ether conditions
can be used to functionalize the lower rim of tert-
butylcalix[4]arene (4) in synthetically useful yields. It has
been shown that all four free hydroxyl groups of 4 can
be derivatized with several readily available aryl fluo-
rides containing electron-withdrawing groups, which,
once coupled to the calix[4]arenes, can be further modi-
fied. Particularly interesting structural features were
1
revealed in the H NMR spectrum of 13a , which shows
a very strong upfield signal at δ 0.04 ppm for the methyl
group of one of the propoxy ether groups, indicating that
the molecule is in a partial cone conformation. In addi-
tion, diastereotopicity of the propoxy protons can be
clearly seen. Overall, because compounds such as 10 and
(13) Chowdhury, S. Ph.D. Dissertation, Memorial University of
Newfoundland, St. J ohn’s, Newfoundland, Canada, 2001.

Aryl Ethers of p-tert-Butylcalix[4]arene
J . Org. Chem., Vol. 66, No. 19, 2001 6261
with water, dried over anhydrous MgSO4, and filtered. The
solvent was evaporated, and the crude product was purified
by column chromatography eluting with EtOAc/hexane 20:80
to afford 3a (0.15 g, 38%) and 3b (0.19 g, 38%): mp 252-254
11 could be produced, thus showing that all the hydroxyl
groups can be arylated at the lower rim, these findings
may open up many new possibilities for calixarene
structural modifications. Ongoing experiments are being
conducted in an attempt to find the optimal conditions
required for the synthesis of double calixarenes envi-
sioned as a result of the findings which have been
described herein.
1
°C (dec). H NMR: δ 0.92 (s, 18H), 1.31 (s, 18H), 3.22 (d, J )
13.6 Hz, 4H), 4.00 (d, J ) 13.6 Hz, 4H), 5.90 (s, 2H), 6.79 (s,
2H), 6.87 (d, J ) 8.5 Hz, 2H), 7.06 (s, 4H), 7.97-7.99 (dd, J )
1.9, 8.8 Hz, 2H), 8.95 (d, J ) 1.9 Hz, 2H), 9.99 (s, 2H). 13C
NMR: δ 30.9, 31.0, 31.5, 34.8, 125.2, 126.3, 127.3, 129.0, 130.1,
131.6, 134.0, 139.9, 142.0, 144.5, 149.1, 150.1, 150.4, 156.7,
188.8. FAB MS (m/z), relative intensity (%): 946 (M+, 100),
931 (28), 874 (20); calcd for C58H62O10N2, 946.4400.
Exp er im en ta l Section
X-r a y cr ysta l d a ta for 3e: crystal (benzene) mp 252-254
°C, C58H62O10N2‚3H2O, triclinic, space group P1h (No. 2), Z )
2, a ) 10.9363(7) Å, b ) 12.6808(8) Å, c ) 20.501(1) Å, R )
89.837(1)°, â ) 83.837(1)°, γ ) 78.003(1)°, V ) 2764.4(3) Å3,
Dcalcd ) 1.203 g cm-3, crystal size ) 0.60 × 0.44 × 0.14 mm.
Intensity data were measured at 193 K on a Bruker P4/CCD
diffractometer with graphite monochromated Mo KR (λ )
0.710 73 Å) radiation to 2θmax ) 52.8°; 15 875 reflections
converged to a final Rint ) 0.026 for 11 133 reflections with I
> 2.00σ(I). Final R1 and wR2 values were 0.098 and 0.324,
respectively, with GOF ) 1.05.9
All reactions were performed under argon unless otherwise
indicated. Pyridine was distilled over KOH, and DMF was
distilled over MgSO4 under argon. Organic solvents were
removed under reduced pressure using a rotary evaporator.
Flash column chromatography was performed according to the
procedure of Still14 using MERCK silica gel 230-400 mesh,
60 Å. Preparative layer chromatography (PLC) plates were
made from Scientific Adsorbents Inc. silica gel (TLC standard
grade 2-25 µm) with calcium sulfate as a binder. Thin-layer
chromatography was performed using precoated silica gel 60
F
254 plates. Unless otherwise indicated, 1H NMR and 13C NMR
5,11,17,23-Te t r a -t er t -b u t yl-25-(4-h yd r oxym e t h yl-2-
n it r op h en oxy)ca lix[4]a r en e-26,27,28-t r iol (Con e Con -
for m er ) (6). To a solution of 3a (258 mg, 0.33 mmol) in
methanol (10 mL) was added in one portion NaBH4 (65 mg,
0.25 equiv, based on starting material). The reaction slurry
was stirred at room temperature for 2 h. The solvent was
evaporated, the residue was diluted with CH2Cl2 (25 mL), and
the resulting solution was washed with aqueous saturated
NH4Cl (3 × 10 mL). The organic solution was dried over
anhydrous MgSO4 and filtered. After the solvent was evapo-
rated, the crude yellow product was purified by column
chromatography eluting with EtOAc/hexane 30:70 to afford 6
(0.23 g, 87%): mp 160-162 °C. 1H NMR (C6D6): δ 0.78 (s, 9H),
0.87 (s, 9H), 1.16 (br, 1H, D2O exchangeable), 1.40 (s, 18H),
3.23 (d, J ) 13.2 Hz, 2H), 3.32 (d, J ) 14.0 Hz, 2H), 4.04 (s,
2H), 4.16 (d, J ) 13.3 Hz, 2H), 4.52 (d, J ) 14.0 Hz, 2H), 6.46
(d, J ) 8.5 Hz, 1H), 6.82 (m, 3H), 7.17 (m, 6H), 7.71 (s, 1H),
9.11 (s, 2H, D2O exchangeable), 9.88 (s, 1H, D2O exchangeable).
13C NMR: δ 31.0, 31.5, 32.3, 32.6, 33.3, 33.9, 34.3, 34.5, 62.5,
116.5, 125.1, 125.9, 126.5, 126.8, 127.5, 127.7, 128.5, 128.8,
132.8, 133.3, 136.5, 140.0, 143.2, 144.2, 145.2, 147.2, 149.8,
150.4, 151.9. FAB MS (m/z), relative intensity (%): 799 (100,
M+), 798 (75), 781 (5), 764 (15), 743 (12), 708 (8); calcd for
spectra were conducted using CDCl3 as solvent and were
recorded at 500 and 125 MHz, respectively, using TMS as an
internal standard.
5,11,17,23-Tetr a-ter t-bu tyl-25-(4-for m yl-2-n itr oph en oxy)-
ca lix[4]a r en e-26,27,28-tr iol (Con e Con for m er ) (3a ). A
mixture of 4 (1.01 g, 1.57 mmol), 4-fluoro-3-nitrobenzaldehyde
(0.53 g, 3.13 mmol), and powdered anhydrous K2CO3 (1.73 g,
12.5 mmol) in anhydrous DMF (15.7 mL) was stirred at room
temperature for 5 days. The black mixture was diluted with
EtOAc (50 mL), and the precipitate was removed by filtration.
The organic layer was washed with aqueous 10% HCl and
brine, dried over anhydrous MgSO4, and filtered. The organic
solvent was evaporated, and the residue was purified by
column chromatography eluting with EtOAc/hexane 20:80 to
afford 3a (0.97 g, 58%) as a light yellow solid: mp 178-180
1
°C. H NMR (acetone-d6): δ 1.2 (s, 9H), 1.14 (s, 9H), 1.23 (s,
18H), 3.53 (d, J ) 13.3 Hz, 2H), 3.59 (d, J ) 13.7 Hz, 2H),
4.04 (d, J ) 13.1 Hz, 2H), 4.25 (d, J ) 13.7 Hz, 2H), 6.86 (d,
J ) 8.7 Hz, 1H), 7.21 (s, 2H), 7.27 (d, J ) 1.9 Hz, 2H), 7.32 (d,
J ) 1.9 Hz, 2H), 7.44 (s, 2H), 8.19 (dd, J ) 1.8, 8.7 Hz, 1H),
8.42 (s, 2H, D2O exchangeable), 8.74 (d, J ) 1.8 Hz, 1H), 10.11
(s, 1H, D2O exchangeable). 13C NMR (C6D6): δ 30.9, 31.4, 31.6,
32.0, 32.3, 32.4, 33.3, 33.9, 34.3, 34.5, 117.1, 121.0, 125.8, 126.6,
127.0, 127.8, 129.6, 131.2, 132.8, 133.6, 139.9, 143.4, 144.2,
144.9, 147.1, 150.3, 156.4, 188.2. FAB MS (m/z), relative
intensity (%): 797 (100, M+), 782 (20), 740 (15), 630 (72), 611
(25); calcd for C51H59NO7, 797.4291.
C
51H61NO7, 799.4448.
5,11,17,23-Tet r a -ter t-b u t yl-25,27-d i-(4-for m yl-2-n it r o-
p h en oxy)-26,28-d i-[(4-m et h ylb en zyl)oxy]ca lix[4]a r en e
(Con e Con for m er ) (8): A mixture of 710 (373 mg, 0.43 mmol),
5 (333 mg, 1.97 mmol), and NaH (60% suspension in oil, 114
mg, 2.96 mmol) in DMF (5 mL) was stirred at room temper-
ature for 3 days. The dark reaction mixture was diluted with
EtOAc, washed with two portions of water and with aqueous
saturated NH4Cl, dried over anhydrous MgSO4, and filtered.
After the solvent was evaporated, the crude product was
purified by preparative TLC eluting with EtOAc/hexane 20:
80 to obtain 8 (264 mg, 53%): mp 275-277 °C. 1H NMR: δ
0.89 (s, 18H), 1.29 (s, 18H), 2.18 (s, 6H), 2.86 (d, J ) 14.1 Hz,
4H), 3.98 (d, J ) 12.9 Hz, 4H), 5.46 (s, 4H), 6.39 (d, J ) 8.9
Hz, 2H), 6.53 (s, 4H), 6.81 (d, J ) 7.8 Hz, 4H), 6.97-6.99 (m,
8H), 7.77 (dd, J ) 1.8, 8.4 Hz, 2H), 8.45 (d, J ) 1.8 Hz, 2H),
9.95 (s, 2H). 13C NMR: δ 21.2, 31.1, 31.3, 31.7, 33.9, 34.0, 74.6,
125.6, 125.7, 127.9, 128.1, 129.4, 130.4, 131.9, 133.7, 134.3,
135.3, 137.0, 139.7, 145.2, 146.0, 147.4, 151.7, 157.6, 188.8.
MS CI (m/z), relative intensity (%): 1153 (M+ - 1, 30), 1099
(92), 1042 (31), 992 (15), 958 (78), 903 (45), 901 (30); calcd for
X-r a y cr ysta l d a ta for 3a : crystal (benzene) mp 178-180
°C, C51H59NO7‚3C6H6, monoclinic, space group P21/c (No. 14),
Z ) 4, a ) 19.281(1) Å, b ) 15.153(1) Å, c ) 20.866(1) Å, â
)101.249(2)°, V ) 5979.0(6) Å3, Dcalcd ) 1.147 g cm-3, crystal
size ) 0.35 × 0.24 × 0.07 mm. Intensity data were measured
at 193 K on a Bruker P4/CCD diffractometer with graphite
monochromated Mo KR (λ ) 0.710 73 Å) radiation to 2θmax
)
52.9°; 34 213 reflections converged to a final Rint of 0.102 for
12 254 reflections with I > 2.00σ(I). Final R1 and wR2 values
were 0.073 and 0.210, respectively, and GOF ) 0.90.9
5,11,1 7,23-T e t r a -t e r t -b u t y l -2 5 ,26 -d i (4-fo r m y l -2 -
n itr oph en oxy)calix[4]ar en e-27,28-diol (P ar tial Con e Con -
for m er ) (3b). Pyridine (10 mL) was added to a mixture of 4
(324 mg, 0.50 mmol), 4-fluoro-3-nitrobenzaldehyde (169 mg,
1.0 mmol), K2CO3 (278 mg, 1.0 mmol), and CuO (158 mg, 1.0
mmol). The resultant black mixture was heated at reflux for
24 h. TLC plates showed the presence of the monoaryl ether
product 3a , so an additional equivalent of 5 was added, and
the reaction was continued at reflux for a further 24 h. The
mixture was cooled to room temperature, and the precipitate
was removed by filtration. The organic layer was diluted with
CH2Cl2 (50 mL), washed with aqueous 10% NaHSO4 and then
C
74H78N2O10, 1154.5656.
5,11,17,23-Te t r a -t er t -b u t yl-25-[4-(e t h ylc a r b oxy)-2-
n it r op h en oxy]ca lix[4]a r en e-26,27,28-t r iol (Con e Con -
for m er ) (9a ) a n d 5,11,17,23-Tetr a -ter t-bu tyl-25,27-d i-(4-
et h ylfor m a t e-2-n it r op h en oxy)ca lix[4]a r en e-26,28-d iol
(Con e Con for m er ) (9b). A flask containing 4 (0.32 g, 0.5
mmol), ethyl 4-fluoro-3-nitrobenzoate (0.21 g, 1.0 mmol), K2CO3
(0.56 g, 4.0 mmol), and CuO (0.32 g, 4.0 mmol) was flushed
(14) Still, W. C.; Kahn, M.; Mitra, A. J . Org. Chem. 1978, 43, 2923.

6262 J . Org. Chem., Vol. 66, No. 19, 2001
Chowdhury and Georghiou
with Ar, and then pyridine (10 mL) was added. The resulting
black mixture was refluxed for 48 h. The reaction mixture was
cooled to room temperature, and the solid was filtered off. The
organic layer was diluted with EtOAc (25 mL), washed with
aqueous 10% NaHSO4 and then with water, dried over
anhydrous MgSO4, and filtered. The solvent was evaporated,
and the crude product was purified by column chromatography
eluting with EtOAc/hexane 20:80 to afford 9a (243 mg, 57%)
5,11,17,23-Tetr a-ter t-bu tyl-25-(4-for m yl-2-n itr oph en oxy)-
26,27-d ip r op oxyca lix[4]a r en e-28-ol (1,2-Alter n a te Con -
for m er ) (13a) an d 5,11,17,23-Tetr a-ter t-bu tyl-25-(4-for m yl-
2-n itr oph en oxy)-27-pr opoxycalix[4]ar en e-26,28-diol (Con e
Con for m er ) (13b). A mixture of 3a (459 mg, 0.576 mmol),
1-iodopropane (0.22 mL, 2.30 mmol), and K2CO3 (640 mg, 4.60
mmol) in CH3CN (25 mL) was refluxed for 28 h. The reaction
mixture was cooled to room temperature and filtered, and then
the solvent was evaporated. The organic layer was extracted
with CH2Cl2, washed with aqueous saturated NH4Cl solution,
dried over anhydrous MgSO4, and filtered. After the solvent
was evaporated, the crude product was purified by column
chromatography using EtOAc/hexane 10:90 to afford 13a (156
mg, 32%) and 13b (175 mg, 36%). Compound 13a was obtained
1
as a colorless solid: mp 199-201 °C. H NMR: δ 1.18 (s, 9H,
tert-butyl), 1.22 (s, 27 H, tert-butyl), 1.40 (t, J ) 7.1 Hz, 3H),
3.30 (d, J ) 13.3 Hz), 3.45 (d, J ) 13.8 Hz), 3.94 (d, J ) 13.3
Hz, 2H), 4.32 (d, J ) 13.8 Hz, 2H), 4.41 (q, J ) 7.1 Hz, 2H),
6.67 (d, J ) 8.8 Hz, 1H), 7.01 (s, 2H), 7.02 (s, 2H), 7.04 (s,
2H), 7.12 (s, 2H), 8.15 (d, J ) 8.7 Hz, 1H), 8.37 (s, 2H), 8.78
(s, 1H), 9.83 (s, 1H, D2O exchangeable). 13C NMR: δ 14.3, 31.1,
31.4, 31.5, 32.8, 33.9, 34.0, 34.4, 61.7, 116.4, 124.8, 125.3, 125.7,
126.1, 126.5, 126.9, 127.4, 128.2, 132.6, 135.6, 138.8, 143.0,
143.3, 147.6, 147.6, 148.6, 150.0, 155.5. Compound 9b (101 mg,
19%) was obtained as a light yellow solid: mp 270-272 °C.
1H NMR: δ 0.91 (s, 18H), 1.30 (s, 18H), 1.41 (t, J ) 7.2 Hz,
6H), 3.20 (d, J ) 13.6 Hz, 4H), 4.01 (d, J ) 13.6 Hz, 4H), 4.39-
4.43 (q, J ) 7.2 Hz, 4H), 5.97 (s, 2 × OH), 6.78 (m, 6H), 7.05
(s, 4H), 8.09-8.11 (dd, J ) 2.1, 8.8 Hz, 2H), 8.75 (d, J ) 2.0
Hz, 2H). 13C NMR: δ 14.3, 30.9, 31.3, 31.7, 33.8, 33.9, 61.6,
124.0, 125.2, 126.2, 127.4, 131.7, 135.2, 138.5, 141.7, 144.6,
150.5, 155.7, 164.5. MS CI (m/z), relative intensity (%): 1036
(M+ + 4, 60), 1035 (M+ + 3, 100), 1034 (M+ + 2, 78), 391 (75),
279 (38); calcd for C53H60N2O8, 1032.4768.
1
as a light yellow solid: mp 202-204 °C. H NMR (CD2Cl2): δ
0.04 (t, J ) 7.3 Hz, 3H), 0.87-0.95 (m, 2H), 1.02 (t, J ) 7.3
Hz, 3H), 1.18 (s, 9H), 1.20 (s, 9H), 1.27 (s, 18H), 1.28 (s, 3H),
1.81-1.98 (m, 2H), 2.39 (q, J ) 7.3 Hz, 1H), 2.55 (q, J ) 7.8
Hz, 1H), 2.99 (d, J ) 12.3 Hz, 1H), 3.36 (d, J ) 13.5 Hz, 1H),
3.53 (d, J ) 15.4 Hz, 1H), 3.60 (q, J ) 9.0 Hz, 1H), 3.86 (d, J
) 15.5 Hz, 1H), 3.94 (s, 2H), 3.97 (d, J ) 13.5 Hz, 2H), 4.11
(m, 1H), 6.64 (d, J ) 8.5 Hz, 1H), 7.01 (d, J ) 2.3 Hz, 1H),
7.04 (s, 1H), 7.06 (d, J ) 2.3 Hz, 2H), 7.10 (d, J ) 3.6 Hz, 2H),
7.25 (d, J ) 2.2 Hz, 1H), 7.47 (s, 1H), 7.89-7.92 (dd, J ) 2.2,
8.7 Hz, 1H), 8.45 (s, 1H), 9.94 (s, 1H). 13C NMR (CD2Cl2): δ
9.8, 10.2, 24.2, 24.3, 31.3, 31.5, 31.6, 31.8, 32.0, 32.9, 34.3, 34.4,
34.6, 34.7, 39.1, 39.6, 125.5, 126.3, 126.8, 127.1, 128.0, 128.1,
128.2, 128.4, 128.5, 129.1, 129.9, 133.3, 133.5, 133.8, 133.9,
134.0, 134.6, 139.8, 141.9, 145.3, 147.2, 147.8, 148.4, 151.1,
151.8, 154.9, 157.3, 189.9. MS CI (m/z), relative intensity (%):
883 (M+ + 1, 38), 882 (M+, 75), 880 (M+ - 1, 100), 879 (95),
849 (30), 838 (28), 732 (30), 647 (60); calcd for C57H71NO7,
881.5227.
5,11,17,23-T e t r a -t er t -b u t y l-25,26,27,28-t e t r a k is -(4-
n itr op h en oxy)ca lix[4]a r en e (P a r tia l Con e Con for m er )
(10) a n d 5,11,17,23-Tetr a -ter t-bu tyl-25,26,27,28-tetr a k is-
(4-n itr oph en oxy)calix[4]ar en e (1,2-Alter n ate Con for m er )
(11). A mixture of 4 (324 mg, 0.50 mmol), 4-fluoro-1-nitroben-
zene (0.21 mL, 2.0 mmol), K2CO3 (278 mg, 2.0 mmol), and CuO
(159 mg, 2.0 mmol) in pyridine was refluxed for 3 days. After
the reaction mixture was cooled to room temperature, the
mixture was filtered, and the organic layer was partitioned
between EtOAc and aqueous 10% Na2HPO4. The organic layer
was washed with brine, dried over anhydrous MgSO4, and
filtered. The solvent was evaporated, and the crude product
was purified by preparative TLC, eluting with hexane/benzene
5:95. The yellow solid obtained was purified further by
preparative TLC using the same solvent mixture to afford 10
(159 mg, 46%) as the major product and 11 (90 mg, 16%) as a
Compound 13b was obtained as a colorless solid: mp 151-
153 °C. 1H NMR: δ 0.84 (s, 9H), 1.00 (s, 9H), 1.29 (s, 21H),
2.12-2.24 (m, J ) 6.8 Hz, 2H), 3.12 (d, J ) 13.0 Hz, 2H), 3.40
(d, J ) 13.6 Hz, 2H), 4.04-4.13 (m, 6H), 6.72 (s, 2H), 6.80 (s,
1H), 6.82 (s, 2H), 6.87 (s, 2H), 7.05 (s, 2H), 7.09-7.94 (dd, J )
2.0, 8.7 Hz, 1H), 8.46 (d, J ) 2.0 Hz, 1H), 9.95 (s, 1H). 13C
NMR (CDCl3): δ 10.9, 23.3, 30.8, 31.0, 31.2, 31.7, 33.8, 33.9,
34.0, 79.3, 116.6, 124.8, 125.1, 125.7, 126.2, 126.4, 127.9, 129.3,
131.9, 132.3, 133.9, 139.6, 141.5, 146.4, 147.7, 147.9, 148.5,
150.5, 157.4, 188.9. MS CI (m/z), relative intensity (%): 840
(M+ + 1), 838 (M+ - 2, 27), 732 (30), 647 (62); calcd for
1
minor product. Data for 10: mp >360 °C. H NMR (CD2Cl2):
C
54H65NO7, 839.4798.
δ 1.14 (s, 18H), 1.44 (s, 9 H), 1.63 (s, 9 H), 3.10 (d, J ) 13.0
Hz, 2H), 3.30 (d, J ) 15.0 Hz, 2H), 3.38 (d, J ) 15.0 Hz, 2H),
3.40 (d, J ) 13.0 Hz, 2H), 6.47 (d, J ) 9.0 Hz, 4H), 6.53 (br,
H), 6.64 (d, J ) 2.0 Hz, 2H), 7.02 (d, J ) 2.0 Hz, 2H), 7.26 (s,
2H), 7.39 (s, 2H), 8.05 (d, J ) 9.5 Hz, 4H), 8.19 (br, 2H). 13C
NMR (CD2Cl2): δ 31.0, 31.7, 31.9, 32.5, 34.7, 35.1, 35.4, 37.4,
115.2, 126.5, 126.9, 128.0, 128.1, 132.4, 132.9, 134.5, 135.4,
142.5, 142.6, 142.8, 147.1, 147.6, 148.1, 149.3, 150.4, 162.1,
Ack n ow led gm en t. This work was supported by the
Natural Sciences and Engineering Research Council of
Canada and Memorial University of Newfoundland. We
thank Dr. Bob McDonald, University of Alberta, for the
X-ray data collection and Mr. David Miller of the X-ray
Crystallographic Unit, Memorial University of New-
foundland. We also thank Dr. Youchu Wang, Depart-
ment of Chemistry, Memorial University of Newfound-
land, for valuable discussions on diaryl systems.
163.9, 164.1. MS CI (m/z), relative intensity(%): 1133 (M+
+
1, 40), 431 (28), 391 (100); calcd for C68H68N4O12, 1132.4829.
Compound 11 was obtained as a light yellow solid: mp >300
1
°C. H NMR (CD2Cl2): δ 1.25 (s, 36H), 3.20 (d, J ) 12.5 Hz,
2H), 3.40 (s, 4H), 3.57 (d, J ) 12.5 Hz, 2H), 5.98 (d, J ) 9 Hz,
8H), 6.60 (d, J ) 2.0 Hz, 4H), 7.74 (d, J ) 2.0 Hz, 4H), 7.83 (d,
J ) 9 Hz, 8H). 13C NMR (CD2Cl2): δ 30.4, 31.9, 34.9, 38.5,
126.1, 127.1, 127.4, 131.8, 134.3, 142.2, 147.6, 148.9, 163.2.
MS CI (m/z), relative intensity (%): 1132 (M+, 60), 391 (100);
calcd for C68H68N4O12, 1132.4829.
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
spectra of compounds 3a , 3b, 6, 8-11, 13a , and 13b and an
ORTEP figure for 3a . This material is available free of charge
via the Internet at http://pubs.acs.org.
J O015622X