Intramolecular direct arylation in an A,C-functionalized calix[4]arene

Article abstract of DOI:10.1039/b713357j

A recently developed efficient method for intramolecular direct arylation is employed on a doubly functionalized calix[4]arene fixed in the cone conformation. The reaction takes place in high yield leading to meta substituted calix[4]arenes. The functionalities are located at two opposite aromatic rings and the two possible diastereomers 1a and 1b are obtained in a 1: 1 ratio. Full sets of data including crystal structures for both isomers are presented. The NMR data reveal that even at temperatures up to 120 °C both isomers are fixed in a flattened cone conformation with the substituted aromatic units pointing outwards. The Royal Society of Chemistry 2008.

Full text of DOI:10.1039/b713357j

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PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
Intramolecular direct arylation in an A,C-functionalized calix[4]arene†
Olaf G. Barton,a B. Neumann,b H.-G. Stammlerb and Jochen Mattay*a
Received 30th August 2007, Accepted 25th October 2007
First published as an Advance Article on the web 16th November 2007
DOI: 10.1039/b713357j
A recently developed efficient method for intramolecular direct arylation is employed on a doubly
functionalized calix[4]arene fixed in the cone conformation. The reaction takes place in high yield
leading to meta substituted calix[4]arenes. The functionalities are located at two opposite aromatic rings
and the two possible diastereomers 1a and 1b are obtained in a 1 : 1 ratio. Full sets of data including
crystal structures for both isomers are presented. The NMR data reveal that even at temperatures up to
120 ◦C both isomers are fixed in a flattened cone conformation with the substituted aromatic units
pointing outwards.
aromatic unit B. In the C2-symmetric isomer 1b each of the newly
formed rings points to a different unfunctionalized aromatic unit.
Introduction
Phenolcalixarenes are well-established aromatic macrocycles.1
1b represents a racemic mixture of inherently chiral calixarenes.
Their electron-rich aromatic systems provide good conditions for
We were interested in the question of whether the first ring closure
aromatic electrophilic substitution reactions with a regiochemistry
directs the orientation of the second ring closure. In that case one
governed by the para directing effect of the activating phenol
of the isomers 1a or 1b should be formed in excess.
group, whereas the ortho positions are blocked by the methylene
moieties bridging the aromatic units. Therefore the vast majority
of phenolcalixarenes functionalized at the wide rim are substituted
Results and discussion
at the para position. However, phenolcalixarenes functionalized at
the meta position are rare. Of special interest are systems with fused
Synthesis
The synthetic route to 1a and 1b is outlined in Scheme 1. It
starts with the dibromocalix[4]arene 3 which could be prepared
according to reported protocols.7 Compound 3 is fixed in a
cone conformation due to O-alkylation of the phenolic groups
with propyl groups which are bulky enough to prevent inver-
sion of the aromatics.8 Lithiation, arylboronate formation and
oxidative carbon–boron bond cleavage led to the formation of
dihydroxycalix[4]arene 4 in a yield of 85%. This transformation
has been reported before, however without experimental data.9
Here, we present an experimental procedure with complete
characterization. Alkylation of 4 at the phenol groups on the wide
rim with benzyl bromide 5 via a Williamson ether synthesis with
Cs2CO3 in acetone produced dibenzyl ether 2 in a yield of 65%.
Subsequent direct arylation using Fagnou’s protocol afforded the
meta substituted calix[4]arenes 1a and 1b in a 1 : 1 ratio in 94%
yield.6 These diastereomers were separated after careful multiple
chromatography. In the first flash column chromatography (silica
gel, 95% cyclohexane–5% ethyl acetate), most of the impurities
were removed, a second flash column chromatography (75%
chloroform–25% cyclohexane) yielded slightly impure 1b, a mixed
fraction of 1a and 1b and a fraction containing pure 1a. A final
purification step using HPLC (88% cyclohexane–6% chloroform–
6% diethyl ether) gave pure 1b. The ratio of the diastereomers was
gathered from the masses of the pure fractions and the 1H NMR
spectrum of the mixed fraction.
rings because they should expand the calixarene cavity. So far only
calix[4]arenes with the expansion of one of the four aromatic units
have been described. These systems are inherently chiral, which
explains the interest in developing their chemistry. The first system
of that kind was synthesized in 1996 by transforming a mono-
formylcalix[4]arene into a naphthalene-containing calix[4]arene.2
Recently, inherently chiral calix[4]quinolines were prepared start-
ing from monoaminocalix[4]arenes.3 A ring expansion employing
metal coordination was achieved by the complexation of MnIII
and UO2 with salen calix[4]arene ligands, which were generated
from meta-formylated monohydroxycalix[4]arenes.4 Very recently,
oxidative photocyclization on monostyrylcalix[4]arenes resulting
in the formation of phenanthrene-containing calix[4]arenes was
investigated.5
In this paper, we present the first application of intramolecular
direct arylation to a calixarene system. For this purpose, we
adopted a procedure developed by Fagnou et al.6 As a substrate
we used the doubly functionalized calix[4]arene 2 fixed in the cone
conformation (Scheme 1). The reaction centres are located at two
opposite aromatic rings, the remaining two aromatic rings bear
no functional groups. Therefore ring closure could lead to two
diastereomers 1a and 1b. In the achiral Cs-symmetric isomer 1a
both newly formed rings reside near the same unfunctionalized
aOrganische Chemie I, Universita¨t Bielefeld, Universita¨tsstr. 25, 33501
Bielefeld, Germany. E-mail: oc1jm@uni-bielefeld.de; Fax: +49 521 106
6417; Tel: +49 521 106 2072
NMR studies
bAbteilung fu¨r Ro¨ntgenstrukturanalyse, Anorganische Chemie II, Universita¨t
Bielefeld, Universita¨tsstr. 25, 33501 Bielefeld, Germany
The two isomers isolated by column chromatography could be
easily distinguished in 1H as well as 13C NMR spectroscopy. Isomer
1b was first eluted during the purification process. It is expected
† Electronic supplementary information (ESI) available: NMR spectra of
all isolated compounds. See DOI: 10.1039/b713357j
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Scheme 1 Synthesis of 1a and 1b; indices of protons according to calixarene nomenclature are given in the experimental section.
that its C2 symmetry generates two sets of signals for two sets of
propoxy groups in a 1 : 1 ratio. In the H NMR spectrum two
done on the basis of 1H–1H COSY, ROESY, HMQC and HMBC
experiments. The assignment is facilitated by the fact that the
signals of the two types of methylene bridges, close to the fused
rings and at a distance from the fused rings, are different from
each other. The latter ones show shifts which are common for
calix[4]arenes in the cone conformation. In the 1H NMR spectrum
of each isomer, two pairs of AB doublets (|2J| = 13–14 Hz)
appear. In each case, one pair of doublets lies in the common
region, whereas the other pair is noticeably shifted downfield with
1
well separated triplet signals at 1.17 ppm and 0.94 ppm caused
by protons of the terminal methyl groups are easily recognized
(Fig. 1b). In contrast the Cs symmetric isomer 1a gives rise to
three sets of signals for the three sets of propoxy groups in a
1 : 1 : 2 ratio. Again the proton signals of the terminal methyl
groups at 1.15 ppm, 1.08 ppm, and 0.89 ppm can be found easily
(Fig. 1a). Complete assignment of all proton and carbon signals is
Fig. 1 1H NMR spectra of (a) 1a in C2D2Cl4 at 55 ◦C and (b) 1b in C2D2Cl4 at rt, residual solvent signals are marked with an asterisk, signals for the
two pairs of diastereomeric protons of the methylene bridges are marked with symbols (ꢀ: close to the annealed rings, ᭜: distant to the annealed rings).
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an extreme shift of the doublet for the equatorial protons. This is
explained by the ring current effect of the closely fused aromatics.
The corresponding 13C NMR signals are also shifted unusually
and appear at a higher field (27.91 ppm for 1b and 27.38 ppm
for 1a) than the signals of the bridges remote to the fused rings
(31.33 ppm for 1b and 30.88 ppm for 1a), which again fall in the
common region for calix[4]arenes adopting the cone conformation
(Fig. 2).10 These tentative assignments are confirmed by HMBC
experiments, which show coupling between the bridging carbons
and the correct meta protons of the phenolic rings. Further support
is a NOE contact between the strongly shifted equatorial protons
and the bay region proton of the fused ring in each isomer.
symmetric isomer 1b should not be taken as a hint for any confor-
mational dynamics. Their resonances at low temperature shifted
by D = 0.11 ppm slightly more downfield than the signals did on
average (D = 0.05 ppm). This led to a separation from the signals
for the para protons H11/23. However, a separation was also seen at
room temperature when C2D2Cl4 as solvent was applied (Fig. 3).
Another example of small differences caused by the solvent are
the resonances of the diastereotopic benzylic methylene protons of
isomer 1a. From −80 ◦C to room temperature in CD2Cl2 they are
isochronous, from room temperature to 55 ◦C in CDCl3 they are
slightly split, whereas in C2D2Cl4 at room temperature as well as
120 ◦C they are clearly divided. All minor changes observed in the
experiments at low temperature could be attributed to restrictions
of local degrees of freedom. The only minor change displayed
in the low temperature spectra of the Cs symmetric isomer 1a
concerned the multiplet for the methylene group a to the methyl
group of the propoxy chains on rings A and C. This multiplet
became broader with new peaks appearing which indicates a split-
ting of two overlying multiplets consistent with two diastereotopic
methylene protons. A similar but more pronounced change is
observed in isomer 1b. Here, both methylene groups of the propoxy
chains on rings A and C were affected. The multiplets of the
diastereotopic protons became completely separated at −40 ◦C
(Fig. 4). Additionally the signals of the diastereotopic benzylic
methylene protons started to split up at low temperature (Fig. 3).
Fig. 2 Partial 13C NMR spectra of (a) 1a in C2D2Cl4 at 55 ◦C and (b) 1b
in CD2Cl2 at rt showing the signals for the propoxy groups. The symbols
᭜ and ꢀ indicate signals from the methylene bridge carbons distant and
close to the annealed rings, respectively.
Due to the ring current effect of the fused benzene rings, the
proton signals of the unfunctionalized aromatics which lie in
proximity to the fused benzene rings are shifted upfield. In the
case of the C2 symmetric isomer 1b, a highfield shifted doublet
at 5.77 ppm can be assigned to the meta protons H10/22 near the
fused benzene rings, whereas the signals of the other meta protons
H12/24 overlap with resonances for the para protons H11/23 at 6.20–
6.15 ppm. In the Cs symmetric isomer 1a signals for the protons
of ring B, which is framed by the fused rings, emerge at higher
field than the signals for the protons of ring D. The meta protons
H10/12 on ring B resonate at 5.76 ppm compared to 6.22 ppm for
the meta protons H22/24 on ring D.
1H NMR experiments at low and high temperatures were carried
out to examine the conformational dynamics of both isomers. In
the range of −80 ◦C to room temperature, CD2Cl2 was used as the
◦
solvent and experiments from room temperature to 120 C were
conducted in C2D2Cl4. Surprisingly the spectra were basically un-
changed from −80 ◦C to 120 ◦C. This means that the conformation
of the calix[4]arene skeleton is fixed over the whole temperature
range. A possible equilibrium between two flattened cone confor-
mations can be ruled out. In that case, resonances for the protons
experiencing ring current effects should be shifted markedly,
because the shielding and deshielding is sensitive to geometrical
changes. In fact all relevant signals stayed the same. A minor
change regarding the meta protons H12/24 of rings B and D of the C2
Fig. 3 Partial 1H NMR spectra of 1b at variable temperatures in CD2Cl2
(top) and at rt in C2D2Cl4 (bottom), residual solvent signals are marked
with asterisks.
X-Ray analysis
Crystals of isomers 1a and 1b suitable for single crystal X-ray
structural analysis were grown from chloroform–ethanol and
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In isomer 1b, both unsubstituted rings B and D are clearly tilted.
The dihedral angles for rings A, B, C and D to the O4 plane are
127.9◦, 77.7◦, 149.8◦ and 77.3◦, respectively. The phenolic rings A
and C together with their substituents can be regarded as bridged
biphenyl moieties to which axial chirality can be ascribed. For
isomer 1a, the descriptor is Sa for ring A with an inter-ring torsion
angle of 28.9◦ and Ra for ring C with an interplanar angle of
30.5◦. The aromatic rings, which were attached to the calix[4]arene
scaffold, are turned so that they stand steeper on the O4 plane
than the phenolic rings. As a consequence, the bay region carbon
atom lies under the plane of the corresponding phenolic ring and
the carbon atom of the bridging methylene group is the upmost
atom of the calixarene. In contrast, the attached aromatic rings of
isomer 1b are arranged more flat to the O4 plane than the phenolic
rings. Thus, the bay region carbon atom lies above the plane of the
corresponding phenolic ring and the bridging methylene group
points sidewards. The descriptor of axial chirality for the enan-
tiomer shown in Fig. 5c and d is Ra for rings A and C with inter-
ring torsion angles of 23.1◦ and 28.0◦. An important result of the
geometry of both isomers 1a and 1b in the solid state is the fact that
there is no cavity large enough to include guest molecules. This can
be illustrated by the short distance between the para carbon atoms
Fig. 4 Partial 1H NMR spectra of 1b at variable temperatures in CD2Cl2;
marked signals indicate equatorial methylene bridge protons close to (ꢀ)
and remote from (᭜) the annealed rings.
chloroform–dichloromethane–methanol. Fig. 5 shows the molec-
ular structures inthesolid state. No solventmolecules are included.
The most prominent feature of both compounds is their flattened
cone conformation in which the unsubstituted aromatic rings B
and D are bent towards each other whereas the meta substituted
phenolic rings A and C are directed away from each other. In case
of isomer 1a, the unsubstituted ring D, which is most removed
from the fused rings, is almost perpendicular to the plane defined
by the four oxygen atoms of the propoxy groups (O4 plane) with
a dihedral angle of 89.2◦. The unsubstituted ring B lying between
the fused rings is tilted towards ring D, its dihedral angle to the O4
plane is 76.1◦. The substituent bearing phenolic rings A and C are
flattened with dihedral angles of 136.1◦ and 151.3◦ to the O4 plane.
˚
˚
of the upstanding rings A and C of 4.07 A and 4.52 A, respectively.
Intramolecular direct arylation in a fourfold functionalized
calix[4]arene
The fixed flattened cone conformations in 1a and 1b raises the
question of whether a fourfold arylation would be possible or ster-
ically hindered. Therefore, we synthesised the appropriate probe
molecule 6 (Scheme 2). It was treated under the same conditions
Fig. 5 ORTEP view of 1a: (a) top view, (b) side view and 1b: (c) top view, (d) side view. Thermal ellipsoids are drawn at the 50% probability level,
disorder in two propoxy groups of 1a is shown, hydrogen atoms are omitted for clarity.
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Scheme 2 Synthesis of probe molecule 6.
that led successfully to the doubly meta substituted calix[4]arenes.
Experimental
Synthesis began from the known tetra iodinated calix[4]arene 7.11
It was transformed into the benzyl protected phenol derivative 8
under recently reported conditions for Ullmann reactions.12 The
benzyl protecting groups were removed under standard conditions
yielding the known tetrahydroxycalix[4]arene 9.13 Contrary to
dihydroxycalix[4]arene 4, the subsequent alkylation with benzyl
bromide 5 was incomplete in boiling acetone and had to be carried
out in boiling acetonitrile to achieve completion. Tetrabenzyl ether
6 was subjected to direct arylation. The end of this reaction was
indicated, like in the case of the A,C-functionalized calix[4]arene 2,
by a colour change from yellow to gray. The crude product mixture
and its TLC spots were examined by MALDI-ToF spectrometry.
Masses corresponding to two, three and four times intramolecular
arylation could be detected, as well as signals indicating one and
two times hydrodehalogenation. Three different TLC spots include
molecules with masses corresponding to fourfold intramolecular
arylation. This is a hint that of the four possible isomers at least
three were formed. However, none of the isomers could be isolated.
Judging roughly from the HPLC trace these isomers constitute at
most 5% of the product mixture.
General
Melting points were measured in open capillaries with a Bu¨chi
B-540 melting point apparatus and are uncorrected. H and 13C
NMR spectra were recorded on a Bruker DRX 500, chemical shifts
were calibrated to the residual proton and carbon resonance of the
solvent (CD2Cl2: dH = 5.32 ppm, dC = 53.80 ppm; CDCl3: dH
1
=
7.24 ppm, dC = 77.00 ppm; C2D2Cl4: dH = 5.91 ppm, dC = 73.70
ppm). J values are given in Hz. MALDI-ToF mass spectra were
obtained with a PerSeptive Biosystems Voyager-DE spectrometer
using 2,5-dihydroxybenzoic acid as the matrix, a Bruker Esquire
3000 was used to record ESI mass spectra and exact masses were
measured on a Bruker APEX III (FT-ICR). Elemental analyses
were determined with a Perkin Elmer 240 instrument. X-Ray
crystal structures were determined from data collected with a
Nonius Kappa CCD area detector diffractometer, using graphite
monochromatized Mo-Ka radiation. Analytical thin-layer chro-
matography was performed on silica gel 60 F254 (Merck),
flash column chromatography on silica gel MN 60, 40–63 lm
(Macherey-Nagel) and HPLC on a Nucleosil 100-7 silica gel col-
umn 250-20 mm (CS-Chromatographie). All reagents were reagent
grade quality and used as received from commercial suppliers.
Calix[4]arenes 3 and 7 were prepared according to the literature.7,11
Conclusions
We examined the direct intramolecular arylation of an A,C-
functionalized calix[4]arene with respect to the regioselectivity of
the reaction. Both possible isomers were formed in a 1 : 1 ratio,
with an overall yield of 94%. Therefore, no regioselectivity was
observed. From NMR and X-ray analysis, we conclude that both
isomers are fixed in a flattened cone conformation. This is a hint
that an expansion of the calix[4]arene cavity cannot be achieved
by annealing four arene rings in the described way. Accordingly,
an experiment with the ABCD-functionalized calix[4]arene led to
very poor results (<5% yield). We suppose that the steric crowding
which is imposed by the first fused rings is the reason for a strongly
diminished reactivity in further intramolecular arylations.‡
5,17-Dihydroxy-25,26,27,28-tetra(1-propyloxy)calix[4]arene (4)
n-BuLi (1.6 M in hexanes, 2.00 mL, 3.20 mmol, 2.4 eq.) was
added dropwise to a stirred solution of di-bromo compound 3
(1.00 g, 1.33 mmol) in THF (50 mL) under argon at −78 ◦C. The
reaction mixture was stirred at that temperature for 20 min and
then B(OMe)3 (0.75 mL, 6.7 mmol, 5 eq.) was added. The mixture
was allowed to warm to room temperature and stirred for 18 h.
Then the reaction flask was placed in an ice-water bath and the
reaction mixture was treated with an ice-cold solution of 30%
H2O2 (2.7 mL, 26 mmol, 20 eq.) in 3 N aqueous NaOH solution
(4.4 mL, 13 mmol, 10 eq.). After stirring the mixture at room
temperature for 6 h, H2O (100 mL) was added and the aqueous
layer was extracted with a mixture of diethyl ether (100 mL) and
dichloromethane (20 mL). The organic layer was washed with
H2O (2 × 100 mL) and brine (100 mL) and dried over MgSO4.
Chromatographic purification (flash column, silica gel, CHCl3–
3% MeOH) and drying under high vacuum afforded a colourless
oil (707 mg, 1.13 mmol, 85%). Found: C, 76.34; H, 7.73. C40H48O6
‡ In a preliminary experiment similar to ref. 5, we conducted oxidative
photocyclization under standard diluted conditions with an ABCD styryl
functionalized calix[4]arene. Mass analysis of the crude product mixture
indicated that the reaction took place on only two positions. This
result further supports the assumption that building up rings with a
phenanthrene connectivity comprising the calix[4]arene para and meta
positions is strongly sterically hindered.
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requires C, 76.89; H, 7.74%; dH(500 MHz, CDCl3) 7.02 (4 H, d,
J 7.5), 6.81 (2 H, t, J 7.5), 6.29 (2 H, s), 5.53 (4 H, s), 4.39 (4 H,
d, J 13.2), 3.96 (4 H, t, J 8.2), 3.61 (4 H, t, J 6.6), 3.06 (4 H, d,
J 13.2), 1.94–1.80 (8 H, m), 1.09 (6 H, t, J 7.4), 0.84 (6 H, t, J
7.5); dC(125 MHz, CDCl3) 160.0, 149.8, 149.2, 136.7, 134.6, 128.9,
121.8, 114.2, 76.9, 76.4, 31.1, 23.4, 22.9, 10.8, 9.76; m/z (MALDI-
ToF) 624 (M•+), 647 ([M + Na]+), 663 ([M + K]+); ESI-HRMS: m/z
calc. for C40H52NO6: 642.37891 ([M + NH4]+); found: 642.37820;
for C40H48NaO6: 647.33431 ([M + Na]+); found: 647.33439.
For crystallisation the oil was dissolved in dichloromethane.
Under heating, MeOH was added and dichloromethane was
allowed to evaporate. After cooling, colourless small needles
were collected and dried under high vacuum (217 mg, yield
suitable for single crystal X-ray structural analysis were grown
from chloroform–ethanol. A mixed fraction of 1a and 1b was
concentrated in vacuo and dried under high vacuum, the ratio of
isomers was determined from 1H NMR spectroscopy (22.5 mg 1a
and 3.0 mg 1b). Purification of the residual material by HPLC
(88% cyclohexane–6% chloroform–6% diethyl ether) and drying
under high vacuum yielded isomer 1b (70.4 mg), and crystals
suitable for single crystal X-ray structural analysis were grown
from chloroform–dichloromethane–methanol.
Isomer 1a (75.7 mg, 0.0944 mmol, 48%)
1
not optimised; according to H NMR spectroscopy no solvent
molecules included), mp 265 ◦C.
5,17-Di(2-bromo-benzyloxy)-25,26,27,28-
tetra(1-propyloxy)calix[4]arene (2)
A mixture of dihydroxy-calixarene 4 (379 mg, 0.606 mmol), 2-
bromobenzyl bromide (333 mg, 1.33 mmol) and caesium carbon-
ate (433 mg, 1.33 mmol) in acetone (25 mL) was refluxed for 24 h.
After cooling, the mixture was partitioned between water (100 mL)
and diethyl ether (100 mL). The organic layer was washed with wa-
ter (two times 100 mL) and brine (100 mL), dried over MgSO4 and
concentrated in vacuo. Chromatographic purification (flash col-
umn, silica gel, 50% cyclohexane–50% chloroform) and drying un-
der high vacuum afforded a colourless solid (378 mg, 0.393 mmol,
Mp 282 ◦C (decomp.); found: C, 80.68; H, 7.09. C54H56O6 requires
C, 80.97; H, 7.05%; dH(500 MHz, CDCl3) 7.72 (2 H, d, J 7.5,
H6ꢀ/13ꢀ), 7.38–7.34 (2 H, m, H5ꢀ/12ꢀ), 7.31–7.26 (4 H, m, H3ꢀ/10ꢀ,
H4ꢀ/11ꢀ), 6.88 (2 H, s, H4/18), 6.33–6.31 (1 H, m, H23), 6.26 (2
H, d, J 7.5, H22/24), 6.00 (1 H, t, J 7.5, H11), 5.73 (2 H, d, J 7.5,
H10/12), 5.01 (2 H, d, J 13.0, H1ꢀ/8ꢀ), 4.99 (2 H, d, J 13.0, H1ꢀ/8ꢀ),
4.53 (2 H, d, J 14.4, H8ax./14ax.), 4.42 (2 H, d, J 13.3, H2ax./20ax.),
4.08 (2 H, d, J 13.6, H8eq./14eq.), 4.05 (4 H, m, O–CH2 (A/C)),
3.71 (2 H, t, J 6.6, O–CH2 (B)), 3.64 (2 H, t, J 6.6, O–CH2 (D)),
3.14 (2 H, d, J 13.4, H2eq./20eq.), 2.07–1.97 (4 H, m, CH2 (A/C)),
1.96–1.91 (2 H, m, CH2 (B)), 1.90–1.84 (2 H, m, CH2 (D)), 1.19
(3 H, t, J 7.5, CH3 (B)), 1.11 (3 H, t, J 7.5, CH3 (D)), 0.91 (6 H,
t, J 7.5, CH3 (A/C)); dC(125 MHz, C2D2Cl4, 55 ◦C) 155.0 (C27),
154.9 (C25), 154.3 (C26/28), 150.6 (C5/17), 137.7 (C3/19), 134.3
(C7/15), 133.6 (C9/13, C2ꢀ/9ꢀ), 132.3 (C1/21), 130.8 (C7ꢀ/14ꢀ),
127.8 (C5ꢀ/12ꢀ), 127.1 (C22/24), 126.4 (C4ꢀ/11ꢀ), 126.3 (C10/12,
C6ꢀ/13ꢀ), 124.9 (C3ꢀ/10ꢀ), 122.7 (C6/16), 122.4 (C11), 122.2 (C23),
116.5 (C4/18), 76.6 (O–CH2 (D)), 76.5 (O–CH2 (A/C)), 76.1 (O–
CH2 (B)), 69.3 (C1ꢀ/8ꢀ), 30.9 (C2/20), 27.4 (C8/14), 23.5 (CH2
(B)), 23.3 (CH2 (D)), 22.7 (CH2 (A/C)), 10.8 (CH3 (B)), 10.7
(CH3 (D)), 9.7 (CH3 (A/C)); m/z (ESI, CHCl3–MeOH) 801.4
([M + H]+).
◦
65%). Mp 58 C; found: C, 67.32; H, 6.19. C54H58Br2O6 requires
C, 67.36; H, 6.07; Br, 16.60; O, 9.97%; dH(500 MHz, CDCl3) 7.47
(2 H, dd, J 1.1, 7.9), 7.38 (2 H, dd, J 1.2, 7.5), 7.19 (2 H, dt, J 1.0,
7.5), 7.06 (2 H, dt, J 1.7, 7.6), 6.66 (4 H, d, J 7.2), 6.61–6.58 (2 H,
m), 6.26 (4 H, s), 4.76 (4 H, s), 4.43 (4 H, d, J 13.3), 3.86 (4 H, t,
J 7.5), 3.78 (4 H, t, J 7.44), 3.10 (4 H, d, J 13.3), 1.97–1.87 (8 H,
m), 1.01–0.97 (12 H, m); dC(125 MHz, CDCl3) 156.6, 153.0, 150.9,
137.0, 135.7, 135.0, 132.2, 128.6, 128.2, 127.3, 122.1, 121.8, 114.5,
76.8, 76.7, 69.7, 31.2, 23.21, 23.19, 10.4, 10.3; m/z (MALDI-ToF)
983 ([M + Na]+), 999 ([M + K]+), 1093 ([M + Cs]+).
Isomers 1a and 1b
A mixture of calixarene 2 (190 mg, 0.197 mmol) and potassium
carbonate (109 mg, 0.789 mmol) in N,N-dimethylacetamide
(DMA, 2 mL) in a screw-cap vial equipped with a magnetic stirrer
was carefully degassed and argon-saturated by two freeze-and-
pump cycles. After the addition of Pd(OAc)2 (4.4 mg, 0.020 mmol)
and PCy3–HBF4 (14.5 mg, 0.0394 mmol), two more degassing
cycles were carried out. The reaction mixture was heated to
130 ◦C for 24 h. At the end of the reaction the colour had
changed from yellow to grey. After cooling to room temperature,
the mixture was partitioned between water (100 mL) and diethyl
ether (100 mL)–dichloromethane (20 mL). The organic layer was
washed with water (100 mL) and brine (100 mL), dried over
MgSO4 and concentrated in vacuo. The first chromatographic
purification (flash column, silica gel, 95% cyclohexane–5% ethyl
acetate) gave a mixture of three compounds. Collection of the last
band of a second chromatography (flash column, silica gel, 75%
chloroform–25% cyclohexane) and drying under high vacuum
afforded isomer 1a as a colourless solid (53.2 mg), crystals
Isomer 1b (73.4 mg, 0.0916 mmol, 46%)
Mp 282 ◦C (decomp.); found: C, 80.86; H, 7.13. C54H56O6 requires
C, 80.97; H, 7.05%; dH(500 MHz, CD2Cl2) 7.77 (2 H, d, J 7.8,
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H6ꢀ/13ꢀ), 7.42–7.37 (2 H, m, H5ꢀ/12ꢀ), 7.31–7.30 (4H, m, H3ꢀ/10ꢀ,
H4ꢀ/11ꢀ), 6.88 (2 H, s, H4/16), 6.20–6.15 (4 H, m. H11/23,
H12/24), 5.87 (2 H, dd, J 2.2, 6.9, H10/22), 5.036 (2 H, d, J
12.7, H1ꢀ/8ꢀ), 5.020 (2 H, d, J 12.7, H1ꢀ/8ꢀ), 4.55 (2 H, d, J 14.1,
H8ax./20ax.), 4.45 (2 H, d, J 13.5, H2ax./14ax.), 4.14 (2 H, d, J 14.3,
H8eq./20eq.), 4.13–4.03 (4 H, m, O–CH2 (A/C)), 3.74–3.65 (4 H, m,
O–CH2 (B/D)), 3.14 (2 H, d, J 13.6, H2eq./14eq.), 2.12–1.98 (4 H,
m, CH2 (A/C)), 1.97–1.90 (4 H, m, CH2 (B/D)), 1.17 (6 H, t, J
7.4, CH3 (B/D)), 0.94 (6 H, t, J 7.5, CH3 (A/C)); dC(125 MHz,
C2D2Cl4) 155.5 (C25/27), 155.1 (C26/28), 151.3 (C5/17), 138.3
(C3/15), 134.9 (C7/19), 134.33 (C9/21), 134.28 (C2ꢀ/9ꢀ), 132.9
(C1/13), 131.4 (C7ꢀ/14ꢀ), 128.2 (C5ꢀ/12ꢀ), 127.2 (C12/24), 127.0
(C10/22, C4ꢀ/11ꢀ), 126.9 (C6ꢀ/13ꢀ), 125.3 (C3ꢀ/10ꢀ), 123.3 (C6/18),
122.8 (C11/23), 117.0 (C4/16), 77.4 (O–CH2 (A/C)), 77.0 (O–
CH2 (B/D)), 69.8 (C1ꢀ/8ꢀ), 31.3 (C2/14), 27.9 (C8/20), 24.0 (CH2
(B/D)), 23.3 (CH2 (A/C)), 11.1 (CH3 (B/D)), 10.0 (CH3 (A/C));
m/z (ESI, CHCl3–MeOH) 801.4 ([M + H]+).
HPLC (80% chloroform–20% cyclohexane) and drying under high
vacuum afforded a colourless oil (138 mg, 0.103 mmol, 61% over
two steps). Found: C, 61.27; H, 5.25; C68H68Br4O8 requires C,
61.28; H, 5.14%; dH(500 MHz, CDCl3) 7.45 (4 H, dd, J 1.3, 8.0),
7.42 (4 H, dd, J 1.5, 7.6), 7.21 (4 H, dt, J 1.3, 7.5), 7.04 (4 H, dt,
J 1.8, 7.7), 6.32 (8 H, s), 4.77 (8 H, s), 4.41 (4 H, d, J 13.2), 3.77
(8 H, t, J 7.2), 3.05 (4 H, d, J 13.2), 1.94–1.87 (8 H, m), 0.97 (12 H,
t, J 7.5); dC(125 MHz, CDCl3) 153.2, 150.9, 137.0, 135.6, 132.2,
128.6, 128.5, 127.3, 121.7, 114.3, 76.9, 69.7, 31.4, 23.2, 10.3; m/z
(ESI, CHCl3–MeOH) 1333 [M + H]+.
Direct intramolecular arylation of 6
A mixture of calixarene 6 (138 mg, 0.104 mmol) and potassium car-
bonate (115 mg, 0.828 mmol) in N,N-dimethylacetamide (DMA,
2.8 mL) in a screw-cap vial equipped with a magnetic stirrer was
carefully degassed and argon-saturated by two freeze-and-pump
cycles. After the addition of Pd(OAc)2 (4.7 mg, 0.021 mmol)
and PCy3–HBF4 (15.3 mg, 0.0414 mmol), two more degassing
cycles were carried out. The reaction mixture was heated to
130 ◦C. After 24 h, its colour had changed from yellow to brown
and after a further 12 h to black. Subsequently it was cooled to
room temperature and the mixture was partitioned between water
(100 mL) and diethyl ether (100 mL)–dichloromethane (20 mL).
The organic layer was washed with water (100 mL) and brine
(100 mL), dried over MgSO4 and concentrated in vacuo.
5,11,17,23-Tetrabenzyloxy-25,26,27,28-
tetra(1-propyloxy)calix[4]arene (8)
Tetraiodocalix[4]arene 7 (547 mg, 0.500 mmol) was combined
with copper(I) iodide (38 mg, 0.20 mmol), 1,10-phenanthroline
(76 mg, 0.42 mmol), caesium carbonate (1.30 g, 4.00 mmol),
benzyl alcohol (4.33 g, 40.0 mmol) and toluene (4.1 mL). The
reaction tube was sealed and the mixture was stirred at 110 ◦C for
48 h. The resulting suspension was cooled to room temperature
and filtered through a pad of silica gel, eluting with diethyl ether.
The filtrate was concentrated in vacuo. Purification of the residue
by flash chromatography (silica gel, 95–90% cyclohexane, 5–10%
ethyl acetate) and subsequent trituration with dichloromethane–
methanol provided a colourless solid (173 mg, 0.170 mmol, 34%).
Mp 151 ◦C; found: C, 80.22; H, 7.25; C68H72O8 requires C, 80.28;
H, 7.13%; dH(500 MHz, CDCl3) 7.33–7.27 (16 H, m), 7.24–7.21
(4 H, m), 6.30 (8 H, s), 4.74 (8 H, s), 4.41 (4 H, d, J 13.2), 3.77
(8 H, t, J 7.5), 3.03 (4 H, d, J 13.2), 1.94–1.87 (8 H, m), 0.97
(12 H, t, J 7.5); dC(125 MHz, CDCl3) 153.5, 150.8, 137.8, 135.6,
128.4, 127.6, 127.3, 114.2, 76.8, 70.2, 31.4, 23.1, 10.3; m/z (ESI,
CHCl3–MeOH) 1017.4 ([M + H]+).
Crystal structure determination§
Crystal data for 1a. C54H56O6, M = 800.99, monoclinic, a =
◦
˚
17.3668(7), b = 11.4423(3), c = 23.2936(9) A, b = 108.9726(17) ,
3
˚
V = 4377.3(3) A , T = 100 K, space group P21/c, Z = 4, l(Mo-
Ka) = 0.078 mm−1, 41 011 reflections measured, 9820 unique
(Rint = 0.056) which were used in all calculations. The final wR(F2)
was 0.1447 (all data). CCDC 657956.
Crystal data for 1b. C54H56O6, M = 800.99, triclinic, a =
˚
11.5936(2), b = 11.6506(3), c = 17.2247(3) A, a = 73.0552(11),
◦
3
˚
b = 75.3562(13) c = 77.6072(12) , V = 2128.35(8) A , T =
−1
¯
100 K, space group P1, Z = 2, l(Mo-Ka) = 0.080 mm , 59 242
reflections measured, 12 396 unique (Rint = 0.068) which were used
in all calculations. The final wR(F2) was 0.1271 (all data). CCDC
657957.
5,11,17,23-Tetra(2-bromo-benzyloxy)-25,26,27,28-tetra(1-
propyloxy)calix[4]arene (6)
Acknowledgements
A solution of calix[4]arene 8 (171 mg, 0.168 mmol) in CHCl3–
MeOH (1 : 1, 50 mL) was subjected to hydrogenolysis over 10%
palladium (134 mg) on activated carbon and under a high pressure
of H2 (2 bar) for 20 h. The mixture was filtered over celite, the solid
was washed with CHCl3–MeOH (1 : 1) and the combined filtrate
was concentrated under reduced pressure to afford 5,11,17,23-
tetrahydroxy-25,26,27,28-tetra(1-propyloxy)calix[4]arene 9 which
was used in the following step without further purification.
A mixture of crude tetrahydroxycalix[4]arene 9, 2-bromobenzyl
bromide (253 mg, 1.01 mmol) and caesium carbonate (331 mg,
1.01 mmol) in acetonitrile (25 mL) was refluxed for 24 h. After
cooling, the mixture was partitioned between water (100 mL)
and diethyl ether (100 mL). The organic layer was washed with
water (two times 100 mL) and brine (100 mL), dried over
MgSO4 and concentrated in vacuo. Purification by flash column
chromatography (silica gel, 95% cyclohexane–5% ethyl acetate),
This work was supported by the Deutsche Forschungsgemein-
schaft (DFG). We thank Bayer Industry Services for the gift of
chemicals. O. G. B. thanks Dr. Tina Kasper for discussing the
manuscript.
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§ CCDC 657956 and 657957. For crystallographic data in CIF or other
electronic format, see DOI: 10.1039/b713357j
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