A fast access to non-symmetrically substituted 1,3-alternate conformers of calix[4]arenes

Article abstract of DOI:10.1002/ejoc.200400161

A simple and direct protocol is reported for the synthesis of the first non-symmetrically substituted 1,3-alternate conformers of calix[4]arenes by selective mono-deacylation of a tribenzoyl precursor under basic conditions, followed by dialkylation. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004.

Full text of DOI:10.1002/ejoc.200400161

FULL PAPER
A Fast Access to Non-Symmetrically Substituted 1,3-Alternate Conformers of
Calix[4]arenes
Arjan W. Kleij,[a][‡] Pilar Prados, and Javier de Mendoza*[a,b]
[a]
Keywords: Alkylation / Building blocks / Calixarenes / Conformation / Hydrolysis
A simple and direct protocol is reported for the synthesis of
( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
the first non-symmetrically substituted 1,3-alternate confor- Germany, 2004)
mers of calix[4]arenes by selective mono-deacylation of a
tribenzoyl precursor under basic conditions, followed by
dialkylation.
Introduction
of systems with adjacent, complementary features such as
catalytic groups or binding sites for molecular recognition.
Calixarenes[1] constitute one of the leading building Here we report that this can be easily achieved from triben-
[2]
blocks in supramolecular chemistry and are of wide- zoylcalix[4]arenes as starting compounds (Figure 1).
[3]
spread use for the preparation of anion receptors, molecu-
[
4]
[5]
lar capsules and catalysts. Since the molecular shapes of
the calixarenes strongly influence their properties, full con-
trol of the conformation behaviour during their synthesis
is essential.
Stable conformations of calix[4]arenes can be obtained
by a proper restriction of the ‘‘through-the-annulus’’ ro-
tation by O-alkylation or acylation/aroylation of the phenol
OH groups. On the other hand, the use of different cations
in the base-assisted O-functionalization has greatly contrib-
Figure 1. Schematic structure of non-symmetrically substituted 1,3-
uted to the selective formation of calix[4]arenes in the alternate calix[4]arenes
[
6]
[7]
cone, partial cone (paco), 1,2-alternate (1,2-alt), and 1,3-
[8]
alternate (1,3-alt) conformations. In the latter case, both
rims of the calixarene macrocycle usually bear identical
groups, though hetero-substitution of both rims can be
achieved starting from di- or tri-O-alkylated precursors in
a multi-step process.[ Thus, a direct procedure for the syn-
thesis of 1,3-alternate conformers carrying distinct groups
at the phenol rings, as well as a simple procedure for their
isolation, would be greatly beneficial for the construction
Results and Discussion
We have previously shown that the paco tribenzoyl de-
9]
[10]
rivative 1
is a good precursor for the synthesis of paco
1,2-anti-heterodisubstituted calix[4]arenes carrying an alkyl
and a benzoyl group; these products were isolated in a one-
[11]
pot, two-step sequence.
The process involves an in situ
alkylation with simultaneous partial deacylation. However,
the use of a less reactive alkyl halide, such as propyl bro-
mide, produced a more complex mixture of mono-O-propyl
derivatives and, interestingly, a minor amount (5%) of the
non-alkylated calix[4]arene 2. This compound, containing
two vicinal, anti oriented benzoyl groups, constitutes an
interesting building block for supramolecular studies.[
In order to optimize the yield of 2, we first studied the
influence of the reaction conditions on the product distri-
bution. Our earlier studies concerned an initial mixing of
all reactants, giving mono-alkylated products. When calix-
arene 1 was stirred for 15 min with an excess of sodium
[
a]
Departamento de Qu ´ı mica Org a´ nica, Universidad Aut o´ noma
de Madrid,
Cantoblanco, 28049 Madrid, Spain
Fax: ϩ 34-91-4973966
E-mail: javier.demendoza@uam.es
Institute of Chemical Research of Catalonia,
Avgda. Pa ¨ı sos Catalans s/n, 43007 Tarragona, Spain
Fax: ϩ 34-977-920226
[
b]
11a,12]
E-mail: jmendoza@iciq.es
[
‡] Current Address: van’t Hoff Institute for Molecular Sciences,
University of Amsterdam,
Nieuwe Achtergracht 166, 1018 WV Amsterdam, The
Netherlands
Fax: ϩ 31-20-5256422
E-mail: kleij@science.uva.nl
2848
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
DOI: 10.1002/ejoc.200400161
Eur. J. Org. Chem. 2004, 2848Ϫ2852

Non-Symmetrically Substituted 1,3-Alternate Conformers of Calix[4]arenes
FULL PAPER
Scheme 1. Synthesis of compounds 2Ϫ6 from the paco precursor 1
hydride (DMF, room temperature, Scheme 1) in the absence
Other alkylating agents produced analogous results.
of alkylating reagent, and subsequently quenched with cold Thus, use of 4-methylbenzyl bromide afforded calixarene 5
 HCl, the yield of 2 improved to 52% after crystalliza- in 28% yield, after work up. The NMR spectra of 5 is
1
tion. Longer mixing times (i.e. 2 hours) resulted in fully closely related to that of 3. The mother liquor of the tritu-
deacylated calix[4]arene 1 with 2 only present in minor ration step also contained an isomer of 5 but in a much
amounts.
higher amount and in a paco conformation (compound 6,
Propyl iodide (excess, neat) was therefore added to in situ 39% yield). The latter assignment was straightforward since
prepared 2 after 15 min stirring (vide supra).[ The crude both the H and C{ H} NMR spectra indicate a fully
product was triturated with MeOH at room temperature asymmetric species, as illustrated by the magnetic inequival-
and a solid material was obtained in 70% yield. An almost ence of all CH , OCH , ArCH and tBu groups. Further-
13]
1
13
1
2
2
3
1
pure single, symmetrical compound was detected in the H more, MALDI-TOF MS analysis provided decisive evi-
NMR spectrum (500 MHz). Two methylene CH groups dence for the presence of a dialkylated species.
2
emerge as two well-resolved doublets at δ ϭ 3.89 and
The starting point for the formation of 3Ϫ6 was the in
3
.69 ppm, whereas the other two CH groups appear as sin- situ prepared precursor 2 that contains two free phenol po-
2
glet peaks at δ ϭ 3.91 and 3.66 ppm, respectively. The sitions. Obviously, lower rim ‘‘through-the-annulus’’ ro-
1
3
1
[12]
C{ H} spectrum displays a set of three signals for these tation of the phenol groups
gives access to a predefined
CH groups at δ ϭ 39.8, 39.1 and 38.3 ppm, respectively, in number of possible dialkylated conformers. Remarkably, in
2
a 1:2:1 intensity ratio.[ These spectroscopic data account the case of alkylation with propyl iodide almost exclusive
for a 1,3-alternate conformation for 3 which, interestingly, formation of 1,3-alt 3 was observed, whereas treatment with
carries on both rims a propyl as well as a benzoyl group. 4-methylbenzyl bromide gave a significantly lower yield of
14]
2D NMR spectroscopy (NOESY and COSY, 500 MHz) the 1,3-alt product 5 and the paco isomer 6 was, in this case,
was additionally carried out for further structural assign- isolated as the major component. These differences can be
1
ment. In particular, the H NOESY spectrum shows explained in terms of reactivity rather than steric hindrance
through-space interactions between the propyl fragment of the alkyl iodide as compared to the aryl bromide.[ The
15]
and the benzoyl group on each rim (see Figure 2).
results seem to indicate that the alkylation procedure of in
A minor amount (3%) of an isomer of 3 was isolated situ prepared 2 follows a preferred route — first an anti-
from the mother liquor of the reaction (4, Scheme 1). Al- alkylation of one of the proximal positions followed by syn/
though the NMR spectra for both species are quite similar, anti introduction of the second alkyl unit to afford non-
the most striking differences were found for the CH and symmetrical 1,3-alt or paco calix[4]arenes.
2
propyl resonances. The protons of the propyl OCH groups
In conclusion, we have discovered a quick and accessible
2
[
16]
proved to be diastereotopic and give rise to two doublet- method for the preparation of non-symmetrically substi-
1
of-triplet patterns in the H NMR spectrum, whereas the tuted 1,3-alternate isomers of calix[4]arenes by alkylation of
1
3
1
C{ H} NMR spectrum shows, as for 3, three distinct sig- the readily available tribenzoyl precursor 1. Therefore, new
nals for the methylene groups at δ ϭ 40.0, 38.6 and pathways could be open towards the construction of tailor-
14]
3
0.6 ppm, respectively.[ These data are in agreement with made supramolecular architectures based on calixarene
a 1,2-alternate conformation for isomer 4, which was scaffolds with two complementary groups (i.e. func-
further corroborated by 2D NMR techniques. tionalized aryl/aroyl groups) directly placed in close prox-
Eur. J. Org. Chem. 2004, 2848Ϫ2852
www.eurjoc.org
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2849

A. W. Kleij, P. Prados, J. de Mendoza
FULL PAPER
Figure 2. NOESY spectrum for compound 3
imity and on the same rim of the calixarene. In particular, resultant two-phase mixture and the organic layer was separated,
2 4
washed with H O (2 ϫ 100 mL), dried over MgSO and filtered.
After concentration under reduced pressure, the oily product was
development of new catalytic systems that comprise cata-
lytic centers flanked by groups with recognition abilities
could be of widespread interest. Our future studies will be
focused on a further development of this protocol with a
focus on supramolecular synthesis.
triturated with MeOH to yield a white microcrystalline solid. Yield:
1
0
.19 g (52%). M.p. (crystals) 266Ϫ267 °C. H NMR (500 MHz,
CDCl
(
3
): δ ϭ 0.87 [s, 18 H, C(CH
s, 2 H, CH ), 3.89 (s, 2 H, CH ), 3.90 (s, 2 H, CH
), 6.77 (s, 2 H, ArH), 6.92 (s, 2 H, ArH), 7.04Ϫ6.93 (br. m, 8
3
)
3
], 1.07 [s, 18 H, C(CH
3 3
) ], 3.86
2
2
2
), 3.95 (s, 2 H,
CH
2
H, benzoyl-Horthoϩmeta), 7.07 (s, 2 H, ArH), 7.17 (s, 2 H, ArH), 7.31
s, 1 H, OH), 7.34 (t, J unresolved, 2 H, benzoyl-Hpara), 7.72 (s, 1
Experimental Section
(
1
3
1
H, OH) ppm. C{ H} NMR (126 MHz, CDCl
3
): δ ϭ 30.8, 31.3
All air-sensitive manipulations were carried out under an argon
atmosphere. Standard chemicals were purchased from Acros or Al-
drich and used as received. 25,26,27-Tris(benzoyloxy)-5,11,17,23-
tetrakis(1,1-dimethylethyl)-28-hydroxycalix[4]arene (1; symmetric
partial cone isomer) was prepared according to a previously re-
[
1
1
[
[
2 ϫ C(CH
3
)
3
], 32.4 (CH
2
), 33.8, 33.9 [2 ϫ C(CH ], 38.9 (CH ),
3
)
3
2
25.2, 125.6, 126.1, 126.3, 126.9, 127.9, 128.2, 128.3, 129.8, 131.5,
32.5, 132.8, 143.3, 144.2, 148.5, 149.0 (ArC, ArCH), 163.6
ArC(O)] ppm. MS (MALDI-TOF, ditranol ϩ KI): m/z ϭ 857.4
ϩ
ϩ
ϩ
M ϩ H] , 879.4 [M ϩ Na] , 895.4 [M ϩ K] . C58
64 6 2
H O ·1/2H O
[
11a]
1
13
1
ported method.
NMR spectroscopic experiments [ H, C{ H},
(
856.4): calcd. C 80.43, H 7.56; found C 80.52, H 7.70.
DEPT, COSY (H,H), HETCOR (C,H) and NOESY] were carried
out at 298 K on Bruker AMX 300 or 500 MHz spectrometers and
reported chemical shifts (δ) are externally referenced to SiMe and
4
given in ppm. MS measurements (MALDI-TOF method) were per-
formed on a REFLEX spectrometer. Elemental analyses were per-
formed on a LECO CHN 932 micro-analyser. Reported melting
points were measured in open capillaries and are uncorrected.
Alkylation with Propyl Iodide: A mixture of 1 (0.37 g, 0.39 mmol)
and NaH (0.54 g, 13.5 mmol) in dry DMF (12 mL) was stirred at
room temp. for 15 min, and propyl iodide (1.0 mL, 10.3 mmol) was
then added. Stirring was continued for 1.5 h and then the reaction
mixture was poured into cold 1  HCl (100 mL). The product was
extracted with CH
dried over MgSO
2
Cl
2 2
(100 mL) and washed with H O (100 mL),
4
, filtered and concentrated. Finally, the yellow
25,26-Bis(benzoyloxy)-5,11,17,23-tetrakis(1,1-dimethylethyl)-27,28-
oil obtained was triturated with MeOH to yield highly pure 3 as a
dihydroxycalix[4]arene (2): A mixture of tribenzoylcalix[4]arene 1
white solid as the first fraction. A second fraction (white solid) was
(
0.40 g, 0.42 mmol) and NaH (0.53 g, 13.3 mmol) in DMF (12 mL) obtained by cooling/concentration of the mother liquor and gave
was stirred for 20 min, after which it was quenched by addition of compound 4 as major component. Pure 4 could be isolated as white
an excess of cold 1  HCl. CH Cl (100 mL) was then added to the needles by crystallization from CH Cl /MeOH.
2
2
2
2
2850
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2004, 2848Ϫ2852

Non-Symmetrically Substituted 1,3-Alternate Conformers of Calix[4]arenes
FULL PAPER
,3-alt-25,26-Bis(benzoyloxy)-5,11,17,23-tetrakis(1,1-dimethyl- (dt, J ϭ 7.4, J ϭ 1.2 Hz, 2 H, benzoyl-Hpara) ppm. 13C{ H} NMR
3
4
1
1
ethyl)-27,28-bis(propyloxy)calix[4]arene (3): Yield: 0.25 g (70%).
(126 MHz, CDCl
): δ ϭ 0.83 [s, 18 H, 33.5, 33.7 [2 ϫ C(CH
], 0.90 (t, 3J ϭ 7.5 Hz, 6 H, 73.5 (ArCH
), 125.2, 125.8, 126.0, 126.7, 128.1, 128.7, 129.1, 130.3,
), 3.59 (m, 4 H, OCH ), 3.66 (s, 130.9, 131.8, 132.4, 132.9, 133.0, 133.9, 134.5, 138.2, 144.5, 146.1,
), 3.69 (d, J unresolved due to overlap with singlet at
3
): δ ϭ 21.4 (ArCH
3
), 30.9, 31.0 [2 ϫ C(CH
3 3
) ],
1
M.p. Ͼ 310 °C. H NMR (500 MHz, CDCl
C(CH ], 0.85 [s, 18 H, C(CH
CH CH ), 1.64 (m, 4 H, CH CH
H, CH
δ ϭ 3.66 ppm, 2 H, CH
with singlet at δ ϭ 3.91 ppm, 2 H, CH
3
3
)
3
], 38.3, 39.0, 39.4 (3 ϫ CH
2
, ratio 1:2:1),
3
)
3
3
)
3
2
2
3
2
3
2
2
2
2
147.1, 153.4 (ArC, ArCH), 164.2 [ArC(O)] ppm. MS (MALDI-
2
ϩ
2
), 3.89 (d, J unresolved due to overlap
), 3.91 (s, 2 H, CH ), 6.50
d, J ϭ 2.3 Hz, 2 H, ArH), 6.56 (d, J ϭ 2.1 Hz, 2 H, ArH), 7.00
TOF, ditranol ϩ KI): m/z ϭ 1013.3 [M Ϫ toluene ϩ K] , 1065.5
ϩ
ϩ
2
2
[M ϩ H] , 1103.5 [M ϩ K] . C74
80 6 2
H O ·H O (1064.5): calcd. C
4
4
(
(
(
82.03, H 7.63; found C 81.64, H 7.93.
4
4
d, J ϭ 2.2 Hz, 2 H, ArH), 7.06 (d, J ϭ 2.0 Hz, 2 H, ArH), 7.12
t, 3J ϭ 7.7 Hz, 4 H, benzoyl-Hmeta), 7.28 (d, 3J ϭ 7.2 Hz, 4 H,
paco-25,26-Bis(benzoyloxy)-5,11,17,23-tetrakis(1,1-dimethylethyl)-
27,28-bis(4-methylbenzyloxy)calix[4]arene (6): Yield: 166.1 mg
(39%). M.p. (crystals) 265Ϫ266 °C. H NMR (500 MHz, CDCl ):
δ ϭ 0.68 [s, 9 H, C(CH ], 0.74 [s, 9 H, C(CH ], 0.99 [s, 9 H,
C(CH ], 1.44 [s, 9 H, C(CH ], 2.26 (s, 3 H, ArCH ), 2.47 (s, 3 H,
ArCH
H, CH
benzoyl-Hortho), 7.41 (t, 3J ϭ 7.5 Hz, 2 H, benzoyl-Hpara) ppm.
1
1
3
1
3
C{ H} NMR (126 MHz, CDCl
CH CH ), 31.0 [(2 ϫ C(CH ], 33.5, 33.8 [2 ϫ C(CH
9.1, 39.8 (3 ϫ CH , ratio 1:2:1), 73.6 (OCH
3
): δ ϭ 9.9 (CH
2
CH
3
), 23.6
], 38.3,
3
)
3
3 3
)
(
2
3
3
)
3
3
)
3
3
)
3
3
)
3
3
2
3
1
1
2
2
), 125.4, 126.0, 126.1,
2
3
), 2.71 (d, J ϭ 12.7 Hz, 1 H, CH
2
), 3.05 (d, J ϭ 12.2 Hz, 1
), 3.44 (d, J ϭ 12.6 Hz, 1 H, CH ), 3.74 (m, 3 H, CH ),
), 4.31 (pseudo t, apparent J ϭ
26.7, 128.2, 129.1, 130.8, 132.1, 132.3, 132.6, 133.2, 133.40, 144.1,
46.2, 146.9, 155.0 (ArC, ArCH), 164.5 [ArC(O)] ppm. MS
2
2
2
2
2
2
ϩ
3.85 (d, J ϭ 17.1 Hz, 1 H, CH
13.2 Hz, 2 H, tolyl-CH ), 4.58 (d, J ϭ 11.6 Hz, 1 H, CH
2
(
MALDI-TOF, ditranol ϩ KI): m/z ϭ 941.6 [M ϩ H] , 963.6 [M
2
ϩ
ϩ
2
2
), 4.93
), 5.00 (d, J ϭ 11.5 Hz, 1 H, tolyl-
2
), 6.07 (d, J ϭ 7.9 Hz, 2 H, ArH), 6.40Ϫ6.17 (br. m, 2 H,
76 6 2 2
ϩ Na] , 979.6 [M ϩ K] . C64H O ·CH Cl (940.6): calcd. C
2
2
(
d, J ϭ 11.5 Hz, 1 H, tolyl-CH
2
76.08, H 7.66; found C 76.62, H 8.08.
3
CH
4
1
,2-alt-25,26-Bis(benzoyloxy)-5,11,17,23-tetrakis(1,1-dimethyl- benzoyl-Hmeta), 6.47 (d, apparent J ϭ 3.5 Hz, 2 H, ArH),
6.70Ϫ6.59 (br. m, 2 H, benzoyl-Hortho), 6.80 (d, J unresolved, 1 H,
ethyl)-27,28-bis(propyloxy)calix[4]arene (4): Yield: 9.3 mg (3%).
M.p. Ͼ 310 °C. H NMR (500 MHz, CDCl ): δ ϭ 0.26 (t, J ϭ ArH), 6.81 (d, J ϭ 8.0 Hz, 2 H, ArH), 6.94 (d, J unresolved, 1 H,
3
1
3
3
4
3
7
0
1
.4 Hz, 6 H, CH
.84Ϫ0.75 (m, 2 H, CH
8 H, C(CH ], 2.97 (dt, apparent J ϭ 5.4, J ϭ 10.6 Hz, 2 H, ArH), 7.28 (d, J ϭ 7.9 Hz, 2 H, ArH), 7.31 (m, 1 H, ArH), 7.35
2
CH
2
CH
3
), 0.67Ϫ0.58 (m, 2 H, CH
2
CH
2 3
CH ), ArH), 6.97 (d, J ϭ 2.2 Hz, 1 H, ArH), 7.10 (t, J ϭ 7.4 Hz, 1 H,
3
2
CH
2
CH ), 0.93 [s, 18 H, C(CH
3
3 3
) ], 1.49 [s, benzoyl-Hpara), 7.15 (m, 2 H, ArH), 7.22 (d, J ϭ 7.9 Hz, 2 H,
3
2
3
3 3
)
), 3.08 (dt, apparent J ϭ 5.3, 2J ϭ 10.4 Hz, 2 H,
3
(t, J ϭ 7.8 Hz, 2 H, benzoyl-Hmeta), 7.60 (t, J ϭ 7.5 Hz, 1 H,
3
3
CH
CH
CH
2
2
2
CH
CH
2
CH
CH
3
), 3.37 (d, 2J ϭ 12.8 Hz, 2 H, CH
), 3.90 (s, 2 H, benzoyl-Hpara), 8.14 (d, J ϭ 7.3 Hz, 2 H, benzoyl-Hortho) ppm.
3
2
3
2
2
13
1
), 3.99 (s, 2 H, CH
2
), 4.11 (d, J ϭ 12.7 Hz, 2 H, CH
2
), 6.76
C{ H} NMR (126 MHz, CDCl
], 31.4, 31.5 (2 ϫ CH
], 33.4, 33.6, 33.7, 34.4 [4 ϫ C(CH ], 38.7, 39.4 (2 ϫ
), 76.4, 76.6 (2 ϫ tolyl-CH ), 124.1, 124.9, 125.2, 125.5, 125.8,
benzoyl-Hpara), 7.37 (d, J ϭ 2.4 Hz, 2 H, ArH), 7.46 (d, J ϭ 125.9, 126.3, 127.8, 128.2, 128.3, 128.5, 129.0, 129.5, 129.9, 130.0,
3
): δ ϭ 21.1, 21.4 (2 ϫ ArCH
3
),
4
3
4
(d, J ϭ 2.1 Hz, 2 H, ArH), 7.05 (dt, J ϭ 7.8, J ϭ 0.7 Hz, 4 H, 30.7, 30.8, 31.1 [3 ϫ C(CH
3
)
3
2
), 31.7
3
benzoyl-Hmeta), 7.10 (br. d, J ϭ 7.7 Hz, 4 H, benzoyl-Hortho), 7.16
[C(CH
3
)
3
3 3
)
4
3
4
(d, J ϭ 2.3 Hz, 2 H, ArH), 7.35 (dt, J ϭ 7.3, J ϭ 1.2 Hz, 2 H, CH
2
2
4
4
13
1
2
.4 Hz, 2 H, ArH) ppm. C{ H} NMR (75 MHz, CDCl
CH CH CH ), 22.2 (CH CH CH ), 30.6 (CH ), 30.0, 31.6 [2 ϫ 134.72, 134.74, 135.6, 135.7, 137.4, 138.1, 144.4, 145.3, 145.5,
C(CH ], 33.8, 34.2 [2 ϫ C(CH ], 38.6, 40.0 (2 ϫ CH ), 75.2 146.1, 147.4, 147.5, 151.4, 152.6 (ArC, ArCH), 163.4, 165.3 [2 ϫ
CH CH CH ), 124.6, 125.5, 125.7, 127.2, 127.8, 128.9, 130.7, ArC(O)] ppm. MS (MALDI-TOF, ditranol ϩ KI): m/z ϭ 997.4 [M
31.5, 131.9, 132.9, 133.4, 133.8, 143.9, 144.9, 147.9, 154.3 (ArC,
80 6 2
ArCH), 165.0 [ArC(O)] ppm. MS (MALDI-TOF, ditranol ϩ KI): Na] , 1103.4 [M ϩ K] . C74H O ·1/2H O (1064.5): calcd. C
3
): δ ϭ 9.5
130.9, 131.4, 131.6, 131.7, 131.8, 132.4, 132.7, 132.8, 133.6, 133.7,
(
2
2
3
2
2
3
2
3
)
3
3
)
3
2
(
1
2
2
3
ϩ
ϩ
Ϫ toluene ϩ Na] , 1013.3 [M Ϫ toluene ϩ K] , 1087.5 [M ϩ
ϩ
ϩ
ϩ
ϩ
ϩ
m/z ϭ 941.6 [M ϩ H] , 963.5 [M ϩ Na] , 979.5 [M ϩ K] .
·1/2CH Cl (940.6): calcd. C 78.75, H 7.89; found C
8.36, H 8.01.
82.72, H 7.60; found C 82.37, H 7.94.
C
7
64
H
76
O
6
2
2
Alkylation with 4-Methylbenzyl Bromide: DMF (12 mL) was added
to a solid mixture of 1 (0.38 g, 0.40 mmol), NaH (0.59 g,
Acknowledgments
NWO (The Netherlands) and DGICYT (Spain) are kindly
acknowledged for a TALENT-stipendium (to A. W. K.) and for
financial support (grants PB1998-0088 and BQU2002-03536),
respectively.
1
4.8 mmol) and 4-methylbenzyl bromide (0.37 g, 2.00 mmol). The
resultant mixture was stirred for 1.5 h, quenched with excess cold
 HCl and worked up as reported for compounds 3 and 4 to
1
afford two fractions of product as white solids. The first fraction
contained virtually pure 5 whereas the second fraction consisted of
highly pure 6. Analytically pure materials were obtained by crystal-
[
1] [1a]
lization from a mixture of CH
2
Cl
2
and MeOH.
C. D. Gutsche, Calixarenes, The Royal Society of Chemis-
try, Cambridge, 1989. [ V. B öhmer, Angew. Chem. Int. Ed.
1b]
[1c]
1
,3-alt-25,26-Bis(benzoyloxy)-5,11,17,23-tetrakis(1,1-dimethyl-
Engl. 1995, 34, 713Ϫ745.
A. Ikeda, S. Shinkai, Chem. Rev.
1997, 97, 1713Ϫ1734. [ C. D. Gutsche, Calixarenes Revisited,
The Royal Society of Chemistry, Cambridge, 1998.
J.-M. Lehn, Supramolecular Chemistry. Concepts and Perspec-
tives, VCH, Weinheim, 1995.
1d]
ethyl)-27,28-bis(4-methylbenzyloxy)calix[4]arene (5): Yield:
17.0 mg (28%). M.p. (crystals) 271؊272 °C. H NMR (500 MHz,
CDCl ): δ ϭ 0.84 [s, 18 H, C(CH ], 0.88 [s, 18 H, C(CH ], 2.44
s, 6 H, ArCH ), 3.27 (s, 2 H, CH ), 3.38 (d, J ϭ 16.5 Hz, 2 H,
), 3.55 (d, J ϭ 16.5 Hz, 2 H, CH ), 3.72 (s, 2 H, CH ), 4.71
), 6.50 (d, J ϭ 2.4 Hz, 2 H, ArH), 6.58 (d, J ϭ
1
1
[
[
2]
3]
3
3
)
3
3 3
)
2
(
3
2
2
Calixarenes in Action (Eds.: L. Mandolini, R. Ungaro), Im-
perial College Press, London, 2000, and references cited ther-
ein.
CH
2
2
2
4
4
(
s, 4 H, ArCH
2
4
4
2
2
7
.1 Hz, 2 H, ArH), 6.89 (d, J ϭ 2.4 Hz, 2 H, ArH), 6.94 (d, J ϭ
[4]
J. de Mendoza, Chem. Eur. J. 1998, 4, 1373Ϫ1377.
3
3
.1 Hz, 2 H, ArH), 7.03 (d, J ϭ 8.0 Hz, 4 H, ArH), 7.15 (d, J ϭ
[5] [5a]
P. Molenveld, S. Kapsabelis, J. F. J. Engbersen, D. N. Rein-
.7 Hz, 4 H, ArH), 7.17 (t, J ϭ 7.8 Hz, 4J not resolved, 4 H,
3
[5b]
houdt, J. Am. Chem. Soc. 1997, 119, 2948Ϫ2949.
veld, J. F. J. Engbersen, D. N. Reinhoudt, J. Org. Chem. 1999,
P. Molen-
3
benzoyl-Hmeta), 7.28 (br. d, J ϭ 7.2 Hz, 4 H, benzoyl-Hortho), 7.43
Eur. J. Org. Chem. 2004, 2848Ϫ2852
www.eurjoc.org
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2851

A. W. Kleij, P. Prados, J. de Mendoza
FULL PAPER
[
5c]
[12]
[13]
6
4, 6337Ϫ6341.
F. Plourde, K. Gilbert, J. Gagnon, P. D.
The actual conformation of 2 remains unclear, although the
presence of four well-separated singlet lines for the methylene
Harvey, Organometallics 2003, 22, 2862Ϫ2875.
[
[
[
6]
7]
1
C. D. Gutsche, P. A. Reddy, J. Org. Chem. 1991, 56,
protons in the H NMR spectrum (500 MHz, CDCl
3
, room
4783Ϫ4791.
temp.) suggests a free rotation of the two free phenol sites. Note
that the structure is inherently chiral and 2 exists therefore as
a pair of enantiomers.
K. Iwamoto, K. Araki, S. Shinkai, J. Org. Chem. 1991, 56,
4
955Ϫ4962.
8] [8a]
For a recent example see: J. Guillon, J.-M. L e´ ger, P. Sonnet,
Although the 15 min reaction time is arbitrary, 2 was indeed
C. Jarry, M. Robba, J. Org. Chem. 2000, 65, 8283Ϫ8289. [
For a general synthetic protocol, see: W. Verboom, S. Datta,
Z. Asfari, S. Harkema, D. N. Reinhoudt, J. Org. Chem. 1992,
8b]
almost exclusively present after this time period in the
NMR spectrum of the crude mixture.
1
H
[14] 13
C NMR spectroscopy is a useful tool for the conformation
determination of calixarenes: C. Jaime, J. de Mendoza, P.
Prados, P. M. Nieto, C. S a´ nchez, J. Org. Chem. 1991, 56,
3372Ϫ3376.
If stereochemical considerations were to play a predominant
role, the 1,3-alt isomer 5 would be the major product in this
particular reaction. The difference in conformational outcome
for the alkylation process (propyl iodide vs. 4-methylbenzyl
bromide) could be interpreted as the result of a competition
between the rate of conformational interconversion and the
rate of derivatization.
57, 5394Ϫ5398.
[
9]
[9a]
For recent examples see:
J. S. Kim, W. K. Lee, W. Sim, J.
W. Ko, M. H. Cho, D. Y. Ra, J. W. Kim, J. Inclusion Phenom.
Macrocycl. Chem. 2000, 37, 359Ϫ370. [ A. Casnati, C. Mas-
sera, N. Pelizzi, I. Stibor, E. Pinkassik, F. Ugozzoli, R. Ungaro,
Tetrahedron Lett. 2002, 43, 7311Ϫ7314.
10]
9b]
[15]
[
[
The symmetrical tribenzoyl, partial cone isomer was employed.
For further details see ref. 11a.
11] [11a]
A. W. Kleij, B. Souto, C. J. Pastor, P. Prados, J. de Men-
doza, J. Org. Chem. 2003, 68, 8711Ϫ8714. [11b] For a recent
example of 1,2-disubstituted calix[4]arenes, see: F. Narumi, T.
Hattori, N. Morohashi, N. Matsumura, W. Yamabuki, H. Ka-
meyama, S. Miyano, Org. Biomol. Chem. 2004, 2, 890Ϫ898.
[16]
It has to be emphasized that only a single trituration step with
MeOH was needed to separate the different calixarene con-
formers from the crude mixture.
Received March 11, 2004
2852
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2004, 2848Ϫ2852