Synthesis and disproportionation of ABAC-type oxacalix[4]arenes

Article abstract of DOI:10.1016/j.tetlet.2007.02.118

An efficient method to prepare ABAC-type oxacalix[4]arenes by a '3+1' fragment synthesis and their CsF-catalyzed disproportionation producing an equilibrium mixture of three oxacalix[4]arenes are described.

Full text of DOI:10.1016/j.tetlet.2007.02.118

Tetrahedron Letters 48 (2007) 3029–3032
Synthesis and disproportionation of ABAC-type oxacalix[4]arenes
Hisatoshi Konishi,* Takayuki Mita, Osamu Morikawa and Kazuhiro Kobayashi
Department of Materials Science, Faculty of Engineering, Tottori University, 4-101 Koyama-minami, Tottori 680-8552, Japan
Received 28 December 2006; revised 19 February 2007; accepted 26 February 2007
Available online 1 March 2007
Abstract—An efficient method to prepare ABAC-type oxacalix[4]arenes by a ‘3+1’ fragment synthesis and their CsF-catalyzed dis-
proportionation producing an equilibrium mixture of three oxacalix[4]arenes are described.
Ó 2007 Elsevier Ltd. All rights reserved.
Replacement of the methylene bridges between the
aromatic units of calixarenes by heteroatoms such as
sulfur,1 nitrogen,2 and oxygen3 forms heteroatom-
bridged calixarenes.4 Since this replacement modifies
the size, conformational mobility and molecular recog-
nition properties of the macrocycles, these modified
calixarenes have attracted considerable research interest
as molecular building blocks for constructing supra-
molecular architectures.
Figure 1. Schematic representation of the syn- and anti-isomers of
ABAB-type oxacalix[4]arenes.
Generally, heteroatom-bridged calixarenes have been
obtained by a single-step reaction. For example, oxaca-
lixarenes have been prepared by the reaction of acti-
vated 1,3-dihalobenzenes and 1,3-dihydroxybenzenes.
This process produces ABAB-type macrocycles in which
two different aromatic units are incorporated in an alter-
nating order. As far as we are aware, three different aro-
matic units have not previously been incorporated into
these macrocycles.
product distribution. On the other hand, although the
reaction catalyzed by CsF in DMF produced a mixture
of cyclic compounds, the product distribution depended
upon the reaction time, that is, the C–O bond formation
is a reversible process. Analogous ether bond cleavage of
aromatic polyethers bearing electron-withdrawing
groups catalyzed by the fluoride ion in aprotic solvents
was reported.6 Thus, CsF-catalyzed the conversion of
the anti-isomer and the hexamer to the syn-isomer in this
solvent, which is selectively prepared in good yields in
the CsF/DMF system. These data established that the
syn-isomer of oxacalix[4]arene is the thermodynamically
favored product.
Recently, we demonstrated the kinetically and thermo-
dynamically controlled synthesis of oxacalix[4]arenes
1.5 Thus, the triethylamine-catalyzed nucleophilic aro-
matic substitution of 1,5-difluoro-2,4-dinitrobenzene 2
with 2-propylresorcinol 3b in a 1:1 molar ratio in aceto-
nitrile produced a mixture of two oxacalix[4]arenes (syn-
and anti-isomers, Fig. 1) and oxacalix[6]arene. In this
reaction, the reaction time had little effect on the prod-
uct distribution. Furthermore, these cyclic compounds
did not interconvert in the presence of triethylamine.
Hence, it is concluded that this nucleophilic aromatic
substitution mostly results in kinetically controlled
We have now applied the kinetically controlled condi-
tions to obtain a linear trimer with an ABA-sequence,
and have prepared ABAC-type oxacalixarenes by a
‘3+1’ fragment synthesis.7,8 Furthermore, we have
developed the disproportionation of the ABAC-type
macrocycles into ABAB- and ACAC-type ones under
thermodynamically controlled conditions.
Keywords: Oxacalixarene; Metacyclophane; Disproportionation.
*
The triethylamine-catalyzed reaction of 2 with resor-
cinol 3a (3:1 molar ratio) in MeCN produced linear
Corresponding author. Fax: +81 857315331; e-mail: konis@chem.
tottori-u.ac.jp
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.02.118

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H. Konishi et al. / Tetrahedron Letters 48 (2007) 3029–3032
Scheme 1. Synthesis of ABAC-type oxacalix[4]arenes.
trimer 4 in 71% yield (Scheme 1).ꢀ This indicates that the
remaining fluorine atom of 4 is much less reactive than
that of 2. The macrocyclization of linear trimer 4 with
resorcinols 3b–d (1:1 molar ratio) sufficiently took place
in Et3N/MeCN, and the ABAC-type oxacalix[4]arenes
5b–d were obtained in 69–78% yields.ꢁ In DMSO-d6 at
50 °C, the ABAC-type oxacalix[4]arenes 5b, 5c and 5d
display the signals of their intra-annular aromatic pro-
tons of the dinitrobenzene units (Hin) at 5.53, 5.79 and
5.58 ppm, respectively. The up-field shifts of these sig-
nals, by 0.8–1.1 ppm compared to those of the corre-
sponding signals of 1a that have no substituents at the
intra-annular position, can be accounted for by the ring
current effect of the neighboring resorcinol rings. Since
the Hin protons of syn-1b and anti-1b appear at 5.34
and 5.63 ppm, respectively, it is suggested that the pre-
ferred conformations of these oxacalix[4]arenes bearing
one or two substituents at the intra-annular positions
are similar. In the solid state, the conformation of syn-
1b and anti-1b is schematically represented as ‘boat (or
1,3-alternate)’ and ‘chair’, respectively (Fig. 1).5 For
both isomers, the two resorcinol rings are almost
perpendicular to the plane formed by the four bridging
oxygen atoms and the Hin protons are located in the
shielding region of the neighboring resorcinol rings.
Since the syn-isomer is thermodynamically more stable
than the anti-isomer, we estimate that the preferred con-
formations of these ABAC-type oxacalix[4]arenes are
boat (or 1,3-alternate) in solution.
ꢀ Preparation of linear trimer 4: To a solution of 1,5-difluoro-2,4-
dinitrobenzene 2 (612 mg, 3 mmol) and resorcinol 3a (110 mg,
1 mmol) in MeCN (5 ml) was added Et3N (122 mg, 1.1 mmol) under
an argon atmosphere. The solution was stirred at 60 °C for 6 h. After
most of the solvent was removed under reduced pressure, the residue
was dissolved in CHCl3, and then washed with dil hydrochloric acid,
dried over anhydrous Na2SO4, filtered, and concentrated in vacuo.
The crude product was recrystallized from CHCl3–hexane to yield 4
(340 mg, 71%). Mp 162 °C. Calcd. for C18H8N4O10: C, 54.92; H, 3.05;
N, 9.49. Found: C, 54.52; H, 3.23; N, 9.44. 400 MHz. 1H NMR
(DMSO-d6, 50 °C) d 7.27 (dd, 2H, J = 2.2 Hz, 8.1 Hz), 7.32 (t, 1H,
J = 2.2 Hz), 7.54 (d, 2H, J = 12.8 Hz), 7.66 (t, 1H, J = 8.1 Hz), 8.93
(d, 2H, J = 8.1 Hz). (CDCl3) d 6.86 (d, 2H, J = 10.6 Hz), 7.00 (t, 1H,
J = 2.2 Hz), 7.15 (dd, 2H, J = 2.6 Hz, 8.2 Hz), 7.65 (t, 1H,
J = 8.2 Hz), 8.88 (d, 2H, J = 7.3 Hz).
ꢁ Synthesis of ABAC-type oxacalixarene: General reaction conditions.
Under an argon atmosphere, linear trimer 4 (0.5 mmol) and resor-
cinol 3 (0.5 mmol) were dissolved in MeCN (2.5 ml). To this was
added Et3N (0.5 mmol), and the mixture was stirred at 70 °C for 8 h.
After cooling, the reaction mixture was poured into a mixture of
water (5 ml) and MeOH (5 ml). The precipitated crude product was
collected by filtration, washed with MeOH, dried in vacuo, and
recrystallized from appropriate solvents. Compound 5b: 69%. Mp
256 °C (from CHCl3–hexane). Anal. Calcd for C27H18N4O12: C,
45.19; H, 1.67; N, 11.72. Found: C, 45.12; H, 1.82; N, 11.65. 1H
NMR (400 MHz, DMSO-d6, 50 °C) d 0.75 (t, 2H, J = 7.2 Hz,
CH2CH2CH3), 1.48 (sext, 2H, J = 7.2 Hz, CH2CH2CH3), 2.04 (t,
3H, J = 7.2 Hz, CH2CH2CH3), 5.53 (s, 2H, Hin), 7.25 (d, 2H,
J = 8.0 Hz), 7.26 (d, 2H, J = 8.0 Hz), 7.40 (t, 1H, J = 2.0 Hz), 7.47 (t,
1H, J = 8.0 Hz), 7.64 (t, 1H, J = 8.0 Hz), 8.96 (s, 2H, Hout). MS
(FAB) 591.1 ([M+1]+). Compound 5c: 78%. Mp 310 °C (dec) (from
DMF–MeOH). Anal. Calcd for C24H11N5O14: C, 48.57; H, 1.85; N,
11.80. Found: C, 48.43; H, 1.90; N, 11.72. 1H NMR (400 MHz,
DMSO-d6, 50 °C) d 5.79 (s, 2H, Hin), 7.30 (m, 3H), 7.67 (t, 1H,
J = 8.8 Hz), 7.72 (d, 2H, J = 8.8 Hz), 7.96 (t, 1H, J = 8.8 Hz), 8.95 (s,
2H, Hout). Compound 5d: 71%. Mp 320 °C (dec) (from DMF). Anal.
Calcd for C24H11N4O14BrÆH2O: C, 44.72; H, 2.02; N, 8.67. Found: C,
44.95; H, 1.90; N, 8.51. 1H NMR (400 MHz, DMSO-d6, 50 °C) d 5.58
(s, 2H, Hin), 7.28 (m, 3H), 7.51 (d, 2H, J = 8.0 Hz), 7.66 (m, 2H), 8.99
(s, 2H, Hout).
It is noteworthy that the CsF-catalyzed reaction of 2
with resorcinol 3a (3:1 molar ratio) in DMF produces
oxacalix[4]arene 1a as the major product and trimer 4
only in trace amounts. Under these conditions, the C–
O bond formation is a reversible process, therefore,
the thermodynamically most stable product 1a selec-
tively forms. From these results, it could be expected
that the ABAC-type macrocycles should convert to the
ABAB- and ACAC-type ones in the presence of CsF.
To determine whether it is possible for the product dis-
tribution to reach its thermodynamic equilibrium, the
disproportionation experiment of 5b was done in an
NMR tube in DMSO-d6 in the presence of CsF at
1
80 °C.§ The H NMR spectral spectra were recorded at
regular time intervals. The spectral changes in the region
of Ha signals are shown in Figure 2. The signal for 5b
gradually decreased and new signals assigned to 1a
§ Determination of the disproportionation of the oxacalix[4]arenes.
Oxacalix[4]arene 5b (5 mg) and CsF (1 mg) were placed in an NMR
tube under an argon atmosphere. To this was added DMSO-d6
(0.5 ml). The sample was heated to 80 °C and its 1H NMR spectra
were determined at 20-min intervals. The isomer ratio was determined
from the integrals of the Ha signals. The 1H NMR spectra that are
shown in Figure 2 are normalized to the signal height of the residual
protons of the solvent.

H. Konishi et al. / Tetrahedron Letters 48 (2007) 3029–3032
3031
Figure 3. Hydrolysis products of syn-1b.
On the other hand, the CsF-catalyzed reaction of 5c did
not produce an equilibrium mixture of macrocycles.
Under the same conditions, the signal of 5c decreased.
1
However, the H NMR spectrum indicated the forma-
tion of a small amount of the ABAB-type oxaca-
lix[4]arenes 1a and 1c and a complex mixture of linear
oligomers. Similarly, the CsF-catalyzed reaction of 5d
also produced an ambiguous mixture of oligomers.
These observations can be explained as follows. For
5b, the fluoride anion attacks the dinitrobenzene carbon
that is attached to the bridging oxygen atom, and
cleaves the macrocycles. The phenolate terminal group
generated by the bond cleavage acts as a nucleophile,
and also attacks the dinitrobenzene core. Thus, the fluo-
ride ion and phenolate cleave the C–O bond, affording
linear oligomers with a dinitrofluorobenzene terminal
group and/or a phenolate terminal group. Finally, the
reaction between these species produces an equilibrium
mixture of oxacalix[4]arenes. On the other hand, in the
case of 5c and 5d, the resorcinol units have an elec-
tron-withdrawing group, therefore, the ipso-attack of
nucleophiles may occur on both the dinitrobenzene ring
and the resorcinol ring. That is, the ether bonds are non-
selectively cleaved to afford various types of oligomers.
Therefore, a further reaction between the oligomers
resulted in the formation of only a small amount of
the calix[4]arenes and a large amount of a complex
mixture of oligomers.
Figure 2. Changes in the 1H NMR spectra with time for the
disproportionation of 5b in the presence of CsF in DMSO-d6 at
80 °C. The region of Hin protons for 5b, 1a and syn-1b is shown.
and syn-1b appeared. After 1 h, the spectral changes
almost ceased and the ratio of 5b, 1a and syn-1b was
approximately 1:1:1. Moreover, treatment of a 1:1 mix-
ture of 1a and syn-1b under the same conditions resulted
in the formation of a 1:1:1 mixture of 5b, 1a and syn-1b.
These results clearly indicate that an equilibrium be-
tween the three oxacalix[4]arenes is reached in the pres-
ence of CsF in DMSO (see Scheme 2). However, it was
found that prolonged heating of the DMSO solution
gradually resulted in the hydrolysis of the cyclic tetra-
mer. Indeed, the heating of the DMSO solution of
syn-1b in the presence of excess CsF yielded a complex
mixture, from which linear tetramer 6 and dimer 7 that
have hydroxyl groups at both ends were isolated as ma-
jor products (see Fig. 3). It can therefore be presumed
that the minor signals, which appeared in the 1H
NMR spectrum after 80 min, were assigned to analo-
gous oligomers.
In conclusion, we have developed an efficient method to
prepare ABAC-type oxacalix[4]arenes by a ‘3+1’ frag-
ment synthesis. The CsF-catalyzed disproportionation
of the ABAC-type oxacalix[4]arenes bearing an alkyl
group on the resorcinol unit produced an equilibrium
Scheme 2. The CsF-catalyzed disproportionation of 5b to form 1a and syn-1b.

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H. Konishi et al. / Tetrahedron Letters 48 (2007) 3029–3032
W.; Van Hecke, K.; Van Meervelt, L.; Dehaen, W. Org.
Lett. 2006, 8, 4161–4164.
mixture of three oxacalix[4]arenes. On the other hand,
when the resorcinol unit is substituted with an elec-
tron-withdrawing group, the ether bonds are randomly
broken to afford a complex mixture of oligomers.
4. (a) Ko¨nig, B.; Fonseca, M. H. Eur. J. Inorg. Chem. 2000,
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5. Konishi, H.; Tanaka, K.; Teshima, Y.; Mita, T.; Morikawa,
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