25-Alkoxy-26-benzoyloxycalix[4]arenes: The reaction mechanism of benzoyl migration

Article abstract of DOI:10.1016/j.tetlet.2012.04.138

In the presence of K₂CO₃ as reaction base, the 25-alkoxy-27-benzoyloxy-calix[4]arenes were converted into 25-alkoxy-26- benzoyloxy derivatives by benzoyl-migration. A benzoyl-migrated reaction mechanism with a cyclic orthobenzoate-like intermediate was proposed, and the mechanism was supported by the identical reaction results on the conversion of 25-ethoxy-27-benzoyloxycalix[4]arene to 25-ethoxy-26-benzoyloxycalix[4]arene, and vice versa.

Full text of DOI:10.1016/j.tetlet.2012.04.138

Tetrahedron Letters 53 (2012) 3510–3513
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
25-Alkoxy-26-benzoyloxycalix[4]arenes: the reaction mechanism of benzoyl
migration
Lee-Gin Lin a, , Pi-Guey Su a, Jun-Ren Huang a, Cheng-Han Kuo a, Chien-Hung Lin a, Chi-Peng Dai a,
⇑
Tahsin J. Chow b
a Institute of Applied Chemistry, Chinese Culture University, Taipei 11114, Taiwan, ROC
b Institute of Chemistry, Academy Sinica, Taipei 11529, Taiwan, ROC
a r t i c l e i n f o
a b s t r a c t
Article history:
In the presence of K2CO3 as reaction base, the 25-alkoxy-27-benzoyloxy-calix[4]arenes were converted
into 25-alkoxy-26-benzoyloxy derivatives by benzoyl-migration. A benzoyl-migrated reaction mecha-
nism with a cyclic orthobenzoate-like intermediate was proposed, and the mechanism was supported
by the identical reaction results on the conversion of 25-ethoxy-27-benzoyloxycalix[4]arene to
25-ethoxy-26-benzoyloxycalix[4]arene, and vice versa.
Received 15 March 2012
Revised 17 April 2012
Accepted 28 April 2012
Available online 3 May 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Calix[4]arene
Disubstituted calix[4]arenes
Benzoyl-migration
Cyclic orthobenzoate-like intermediate
It is known that, with only two special exceptions,1,2 the intro-
duction of the second substituent onto the calix[4]arene ‘lower
rim’ yielded the 1,3-disubstituted calix[4]arene derivatives.3–6 It
is generally believed that the formation of the second substitu-
ent-linkage at the distant 3-position rather than the more available
proximal 2-positions was due to the steric hindrance effect. Hence,
the inherent steric hindrance problem of the proximal positions
has to be solved first in order to achieve the preparation of the
1,2-disubstituted calix[4]arenes.
To aim the goal of preparing the 1,2-disubstituted calix[4]are-
nes, several multi-step synthetic routes5–7 had been explored in
the past few years. In one of the synthetic routes for the 25,26-dial-
koxycalix[4]arenes, it was observed that the benzoyl moieties were
migrated in several alkyl halide cases.6 In order to illustrate the for-
mation of the unexpected 25,27-dialkoxy-26-benzoyloxy products,
a benzoyl-migration reaction mechanism with cyclic orthobenzo-
ate-like intermediate was then proposed. Additionally, with the
purpose of further comprehending the migration behavior of the
benzoyl moieties, a weaker base K2CO3, which was shown to en-
hance the migration behavior,5 was selected in this investigation.
In this Letter we will utilize the benzoyl migration behavior to
convert the easily accessible 25-alkoxy-27-benzoyloxycalix[4]are-
nes into 25-alkoxy-26-benzoyloxycalix[4]arenes, a new set of
calix[4]arene derivatives have not been reported in the literature.
We will also demonstrate that the benzoyl moiety is migrated
via cyclic orthobenzoate-like intermediate as in our earlier pro-
posed mechanism.6
Results and discussion
It was reported6 that the etherification of 25-alkoxy-27-ben-
zoyloxycalix[4]arenes yielded two isomeric dialkoxy-products,
25,26-dialkoxy-27-benzoyloxycalix[4]arenes and 25,27-dialkoxy-
26-benzoyloxycalix[4]arenes, in approximately equal amounts.
To elucidate the formation of the unexpected 25,27-dialkoxy-26-
benzoyloxycalix[4]arenes, a benzoyl-migrated reaction mecha-
nism with a cyclic orthobenzoate-like anionic intermediate was
proposed as shown in Figure 1.
Preparation of 25-alkoxy-26-benzoyloxycalix[4]arenes via
benzoyl-migration route
In our proposed mechanism, we speculated that the alkyl
halides were probably more favorable to approach the cyclic ortho-
benzoate-like anionic intermediate from the less hindered 3-posi-
tion side, as shown in Figure 1, and yielded the benzoyl-migrated
25,27-dialkoxy-26-benzoyloxy products. We also anticipated that,
with or without the presence of alkyl halides, the breaking of cyclic
orthobenzoate ring would occur eventually and afford either the
starting materials or the corresponding benzoyl-migrated deriva-
tives. Therefore, the refluxing reaction conditions of 25-alkoxy-
27-benzoyloxy-calix[4]arenes 1–4 with K2CO3 in CH3CN were
⇑
Corresponding author.
E-mail address: lglin@faculty.pccu.edu.tw (L.-G. Lin).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.04.138

L.-G. Lin et al. / Tetrahedron Letters 53 (2012) 3510–3513
3511
CH2
CH2
R=
CH2
CH2
C
C
O
OH
OR
OH
OH
O
OH
O
C=O
Ph
O
O
CH2
CH2
RO
CH2
RO
-CH2CH3
-CH2CH2CH3
-CH2CH2CH2CH3
-CH2Ph
CH2
1
2
3
4
CH2
CH2
CH2
CH2
OH
base
OH
base
CH3CN
K2CO3, CH3CN
reflux for 16h
CH3CN
-
-
C
C
O
O
O
O
O
O
CH2
CH2
RO
CH2
RO
CH2
CH2
CH2
CH2
CH2
O
CH2
CH2
OR
OH
OH
C=O
Ph
CH2
CH2
OH
OH
-CH2CH3
5
6
7
8
R=
-CH2CH2CH3
-CH2CH2CH2CH3
-CH2Ph
formation of cyclic
orthobenzoate-like
intermediate
formation of cyclic
orthobenzoate-like
intermediate
-
O
C
Scheme 1. Synthetic scheme for 25-alkoxy-26-benzoyloxycalix[4]arenes 5–8.
R-X and/or H2O
more favor to approach
from less hindered side
O
O
CH2
RO
CH2
component 5. The isolation of the new product 5 was performed
in a two-stage recrystallization procedure. The symmetrical start-
ing material 1 was crystallized as the first crop, and a further evap-
oration of the mother solution yielded the second crop with
product 5 as predominant component. Further recrystallization of
the second crop yielded the product 5 in pure form.8 Although
the spectral integral ratio of product 5 indicated that no proton-
containing moiety was introduced and/or removed during the
refluxing periods, but the resulting proton NMR spectrum was sub-
stantially different from its starting material 1, as shown in Figure
2. A total of eight sets of doublets (d 3.2–4.5) for the eight different
calix[4]arene’s methylene protons strongly suggested that the
structure of the product 5 contained no symmetry elements. The
upfield shift of 0.60 ppm for the ethoxy’s methyl protons also indi-
cated that the magnetic environment for the ethoxy moiety had
been changed. An intramolecular migration of benzoyl moiety
from distant 3-position to proximal 2-position seemed to be the
only reasonable explanation for the chemical shift of the ethoxy’s
methyl protons and a complete vanishing of the symmetry ele-
ment on product 5. Based on the benzoyl-migrated assumption
and the spectral evidences, the molecular structure of product 5
was easy to assign as 25-ethoxy-26-benzoyloxycalix[4]arene.
All the other 25-alkoxy-27-benzoyloxycalix[4]arenes 2–4
yielded the similar crude product mixtures, and the corresponding
benzoyl-migrated 25-alkoxy-26-benzoyloxy products 6–8 were
characterized with the isolating yields of 20–28%.9 It was interest-
ing to notice that such proximal structural isomers had never been
reported in the literature.
CH2
ring-opening of
orthobenzoate-like
intermediate with R-X
ring-opening of
orthobenzoate-like
intermediate without R-X
CH2
OH
C
C
OR
O
OH
O
O
O
CH2
CH2
RO
CH2
RO
CH2
CH2
CH2
CH2
CH2
OH
OH
+
+
C
OH
OR
C
O
O
O
O
CH2
CH2
RO
CH2
RO
CH2
CH2
CH2
CH2
CH2
OH
OH
Figure 1. A proposed benzoyl-migrated reaction mechanism.
Benzoyl-migration behavior of 25-ethoxy-27-benzoyloxycalix
[4]arene and 25-ethoxy-26-benzoyloxycalix[4]arene
undertaken to investigate the unusual benzoyl-migration behavior.
(Scheme 1).
In the most accessible 25-ethoxy-27-benzoyloxy case, the
TLC analysis of the reaction crude products indicated that the
product mixtures contained, along with the starting material 1, a
small amount of known hydrolyzed compound and a new major
In our proposed reaction mechanism, the benzoyl-migrated
products were afforded by ring-opening of the cyclic orthobenzo-
ate-like intermediates. The proposed mechanism also suggested
that both of the 25-alkoxy-27-benzoyloxycalix[4]arenes and
25-alkoxy-26-benzoyloxy-calix[4]arenes produced the same cyclic

3512
L.-G. Lin et al. / Tetrahedron Letters 53 (2012) 3510–3513
Figure 2. The 1H NMR spectrum of 25-ethoxy-26-benzoyloxycalix[4]arene 5.
intermediates. Therefore, it is reasonable to anticipate that the
benzoyl-migrated reaction of 25-alkoxy-27-benzoyloxycalix[4]
arenes and/or 25-alkoxy-26-benzoyloxy-calix[4]arenes will yield
the same product mixtures. The isolation of 25-alkoxy-26-benzoyl-
oxy-calix[4]arenes in the previous section provided an opportunity
to verify the proposed reaction mechanism.
Acknowledgment
We thank Ms. L.-M. Hsu of the NSC Instrumental Center in
Taichung for taking all the FAB-MS measurements. A private finan-
cial support of this work from Ms. Jenny Chen is gratefully
acknowledged.
In a preliminary study of the ethoxy case, both of the 25-eth-
oxy-27-benzoyloxycalix[4]arene (1) and 25-ethoxy-26-ben-
zoyloxycalix[4]arene (5) were refluxed with K2CO3 in acetonitrile
for 16 h. When the proton NMR spectra of those reaction crude
product mixtures were taken10, two almost identical proton NMR
spectra were attained.11 A semi-quantitative analysis by spectral
integration of the ethoxy’s methyl proton (displayed as a triplet
at 1.79 ppm for compound 1, at 1.17 ppm for compound 5, and
at 1.86 ppm for hydrolyzed compound) indicated that the ratio of
the amount of compound 1 to compound 5 was identical in both
crude product mixtures, and the discrepancy between two spectra
were arisen only from a slight difference in the amount of the
hydrolyzed compound. Since the formation of compound 1 and/
or compound 5 involved both chemical bond-breaking and bond-
forming, therefore, the benzoyl-migrated reactions starting either
from 25-ethoxy-27-benzoyloxycalix[4]arene (1) or 25-ethoxy-26-
benzoyloxycalix[4]arene (5) should have possessed a common
reaction intermediate in order to produce an identical product
mixtures. This result strongly supported our proposed benzoyl-mi-
Supplementary data
Supplementary data (copies of 1H NMR spectra of 25-alkoxyca-
lix[4]arenes and compounds 1–8; and copies of 13C NMR spectra of
compounds 5, 7, and 8 are available.) associated with this article
can be found, in the online version, at http://dx.doi.org/10.1016/
j.tetlet.2012.04.138.
References and notes
1. Shu, C.-M.; Yuan, T.-S.; Ku, M.-C.; Ho, Z.-C.; Liu, W.-C.; Tang, F.-S.; Lin, L.-G.
Tetrahedron 1996, 52, 9805–9818. and references therein.
2. (a) Groenen, L. C.; Ruël, B. H. M.; Casnati, A.; Timmerman, P.; Verboom, W.;
Harkema, S.; Pochini, A.; Ungaro, R.; Reinhoudt, D. N. Tetrahedron Lett. 1991, 32,
2675–2678; (b) Shimizu, S.; Moriyama, A.; Kito, K.; Sasaki, Y. J. Org. Chem. 2003,
68, 2187–2194. and references therein.
3. For 25,27-dialkoxycalix[4]arenes: (a) van Loon, J.-D.; Arduini, A.; Verboom, W.;
Ungaro, R.; van Hummel, G. J.; Harkema, S.; Reinhoudt, D. N. Tetrahedron Lett.
1989, 30, 2681–2684; (b) van Loon, J.-D.; Arduini, A.; Coppi, L.; Verboom, W.;
Pochini, A.; Ungaro, R.; Harkema, S.; Reinhoudt, D. N. J. Org. Chem. 1990, 55,
5639–5646. and references therein.
grated reaction mechanism with
intermediate.
a cyclic orthobenzoate-like
4. For 25,27-dibenzoylxycalix[4]arenes: Shu, C.-M.; Liu, W.-C.; Ku, M.-C.; Tang, F.-
S.; Yeh, M.-L.; Lin, L.-G. J. Org. Chem. 1994, 59, 3730.
5. For 25-acetoxy-27-alkoxycalix[4]arenes: Wu, F.-Y.; Chang, K.-F.; Kuo, C.-H.;
Chen, K.-C.; Lee, K.-C.; Huang, C.-S.; Chiang, Y.-S.; Lin, L.-G. Tetrahedron 2011,
67, 3238–3247.
6. For 25-alkoxy-27-benzoyloxycalix[4]arenes: Kuo, C.-H.; Huang, J.-R.; Chen, H.-
R.; Chen, P.-Y.; Lin, C.-H.; Lin, L.-G. Tetrahedron 2011, 67, 3936–3944.
7. Narumi, F.; Hattori, T.; Morohashi, N.; Matsumura, N.; Yamabuki, W.;
Kameyama, H.; Miyan, S. Org. Biomol. Chem. 2004, 2, 890. and references
therein.
With all the results from this study on the benzoyl-migration
phenomena in calix[4]arene system, we concluded that the
benzoyl moieties not only provide ‘neighborhood group effect’
to stabilize the cyclic reaction intermediate, but also set up a
stage for the migration to occur. We believe that such acyl-migra-
tory behavior also occurs in the nature, and the acyl migration
may then create a vast varieties of alkylated and/or acylated poly-
hydroxy-derivatives in the plant kingdom. Furthermore, one can
even imagine that the phosphated carbohydrate systems, for
example ribose phosphate, may possess the cyclic phosphate
diester analog, and the parallel phosphate-migratory behavior
will have the chance to evolve into an enormous amount of
species in the nature.
8. 25-Ethoxy-26-benzoyloxy-27,28-dihydroxycalix[4]arene (5):
a
colorless
crystals, isolated yield 56%; mp 185–190 °C; 1H NMR (CDCl3) d 9.70 (s, 1H,
ArOH), 9.14 (s, 1H, ArOH), 8.62–8.64 (d, 2H, Ar0H), 7.59–7.70 (t, 3H, ArH and
Ar0H), 6.59–7.28 (m, 12H, ArH), 4.29–4.39 (2d, 2H, ArCH2Ar), 4.01–4.16 (m, 3H,
ArCH2Ar and OCH2CH3), 3.83–3.88 (m, 1H, OCH2CH3), 3.45–3.55 (dd, 3H,
ArCH2Ar), 3.29–3.33 (d, J = 12.8 Hz, 1H, ArCH2Ar), 1.21–1.25 (t, 3H, OCH2CH3);
13C NMR (CDCl3) d 166.4, 152.2, 152.0, 149.5, 144.9, 135.6, 133.7, 133.4, 133.3,
133.3, 130.8, 130.2, 130.1, 129.7, 129.5, 129.3, 129.1, 129.0, 128.6, 128.5, 128.4,
128.0, 127.7, 127.4, 127.4, 126.2, 126.0, 121.7, 119.8, 72.9, 32.7, 31.9, 31.7, 30.4,

L.-G. Lin et al. / Tetrahedron Letters 53 (2012) 3510–3513
3513
14.8; FAB-MS m/e: 557 (M++1); HRMS (FAB) m/e: Calcd for C37H32O5+H+:
557.2329; Found: 557.2333.
pattern and the exact molecular structure was unable to assign accurately
without any doubt.
9. Thethreebenzoyl-migratedproducts6,7,and8wereisolatedinasameprocedure
as ethoxy case with a slight difference in solvent system (products 6: EtOAc–
CH3OH,isolatedyield20%;products7and8:CHCl3–CH3OH,isolatedyield26%and
28%, respectively). The25-allyloxy-27-benzoyloxycalix[4]arene also migrated to
its benzoyl-migrated derivative, 25-allyloxy-26-benzoyloxycalix[4]arene.
However, the isolation of 25-allyloxy-26-benzoyloxycalix[4]arene required
chromatographic separation. With a lack of molecular symmetry, 25-allyloxy-
26-benzoyloxycalix[4]arene displayed a very complex proton NMR spectral
10. The NMR spectral samples of those benzoyl-migrated reactions were prepared
by removing the solvent and adding CDCl3 to retrieve the reaction crude
product mixtures.
11. Copies of the benzoyl-migrated 1H NMR spectra of 25-ethoxy-27-
benzoyloxycalix[4]arene (1) and 25-ethoxy-26-benzoyloxycalix[4]arene (5)
and copies of the benzoyl-migrated time-interval 1H NMR spectra of 25-
ethoxy-27-benzoyloxycalix[4]arene (1) are attached as part of the
Supplementary data.