Calix[4]quinones III: The synthesis of p-hydroxycalix[4]arenes by Wolff-Kishner reduction

Article abstract of DOI:10.1002/jccs.200400091

The Wolff-Kishner reduction of the half-protected ketal calix[4]monoquinone 3 and its basic hydrolysis product 4 produced a partially reducing product 5. When the same reduction conditions were applied to the calix[4]quinone benzoates 1 and 2, the corresponding title compounds, p-hydroxycalix[4]arenes (6 and 7), were afforded in one step.

Full text of DOI:10.1002/jccs.200400091

Journal of the Chinese Chemical Society, 2004, 51, 607-611
607
Calix[4]quinones III: The Synthesis of p-Hydroxycalix[4]arenes by
Wolff-Kishner Reduction
Ching-Yu Tsoo (
Wen-You Wang (
Institute of Applied Chemistry, Chinese Culture University, Taipei, Taiwan, 11114, R.O.C.
), Rong-Fua Chen (
) and Lee-Gin Lin* (
),
)
The Wolff-Kishner reduction of the half-protected ketal calix[4]monoquinone 3 and its basic hydrolysis
product 4 produced a partially reducing product 5. When the same reduction conditions were applied to the
calix[4]quinone benzoates 1 and 2, the corresponding title compounds, p-hydroxycalix[4]arenes (6 and 7),
were afforded in one step.
Keywords: Calix[4]quinone; p-Hydroxycalix[4]arene; Chlorine dioxide oxidation; Wolff-Kishner re-
duction.
INTRODUCTION
The calixarenes are divided into two sub-classes, endo-
ing to the same synthetic route.7 During the course of the syn-
thesis, we noted that the two carbonyl groups on the quinones
moieties were differentiated, in which only the less hindered
“upper rim” carbonyl groups were protected in the ketal for-
mation step.6,7 Therefore, it is reasonable to propose that the
Wolff-Kishner reduction followed by a removal of the “upper
rim” ketal protecting group may transform the calix[4]qui-
none monoketals into non-substituted exo-calix[4]arenes, as
shown in Scheme I.
calixarenes and exo-calixarenes, based on the position of
their phenolic hydroxy groups. The endo-calixarenes, which
possess hydroxy groups on their “lower rim”, are well dem-
onstrated in the literature;1,2 whereas, only a few research
studies report on the “upper rim” hydroxy containing exo-
calixarenes.2-5
It is well understood that, due to the strong ortho- and
para- directing ability of the phenolic hydroxy group, the
exo-calixarenes which had their phenolic hydroxy moieties
meta to the methylene linkage were unable to be prepared in
either a simple one-step condensation or in a stepwise con-
densation procedure.5 However, we have demonstrated in our
earlier work that an oxygen atom was able to be introduced
onto the calixarenes’ para-position in a chlorine dioxide oxi-
dation reaction, and the mono-substituted p-hydroxycalix-
[4]arene was derived following a six-step conversion.6 In this
paper, we report that the transformation of calix[4]quinone
benzoates to the partial p-hydroxy substituted calix[4]arenes
can be simplified into a single step procedure by way of
Wolff-Kishner reduction conditions.
Partial reduced calix[4]quinone 5
When the Wolff-Kishner reaction conditions were per-
formed on monoketal 3, a reddish solid material was attained
after a chromatographic separation. All of the spectral data of
this reddish solid material, instead of the expected totally re-
duced product, was shown to be a known partially reduced
compound 5. Compound 5, which was prepared differently in
our earlier work,6 was fully characterized and possessed a
partially reduced “lower rim” tetrahedral carbinol structure.
It is believed that the formation of the “lower rim” hydrazone
moieties was hindered by the steric structure of monoketal 3,
and subsequently, the possibility of producing the totally re-
duced product as well as the exo-calix[4]arene in this Wolff-
Kishner reduction condition was negated. However, the reac-
tion conditions of hydrazine with strong base (which sup-
plied the reducing power for the “lower rim” carbonyl groups)
and the basic refluxing conditions (which removed all the
benzoate moieties from the starting materials) provided the
reaction conditions for the formation of the partially reduced
compound 5.
RESULTS AND DISCUSSION
In our earlier work,6 we established a six-step synthetic
route for the mono-substituted p-hydroxycalix[4]arene. Un-
fortunately, due to the intramolecular Michael-addition, the
p-1,3-dihydroxycalix[4]arene could not be produced accord-
Upon examining the structure of compound 3, we noted

608 J. Chin. Chem. Soc., Vol. 51, No. 3, 2004
Tsoo et al.
Scheme I A proposed synthetic route for exo-calix[4]arenes
that either the structure of calix[4]arene itself or the three
bulky benzoate groups could cause the failure of the “lower
rim” hydrazones formation. In order to identify the origin of
this failure, the basic hydrolysis compound 4 was chosen for
the same reduction conditions. This resulted in a similar
quantity of product 5 and indicated that the structure of
calix[4]arene itself possessed a highly hindered “lower rim”,
and the tetrahedral carbon structure with larger substituents
on the “lower rim” was not possible even in the intermediate
stage.
product 6. In the original six-step synthetic route, NaBH4 was
applied to reduce calix[4]monoquinone to yield product 6 in
the final stage; the same product was attained in higher yield
when the Wolff-Kishner reduction reactions were employed
instead. Nevertheless, the partially reduced Wolff-Kishner
reaction conditions were able to modify and reduce the origi-
nal synthetic route for p-monohydroxycalix[4]arene (6) to
three-steps.
As mentioned earlier, calix[4]diquinone 2 underwent
an intramolecular Michael-addition in basic conditions, and
the original six-step synthetic route for p-1,3-dihydroxy-
calix[4]arene (7) was disturbed. Therefore, the Wolff-
Kishner reduced reaction conditions, which simultaneously
removed the benzoate groups and reduced the “lower rim”
carbonyl moieties in the calix[4]monoquinone case, were
performed on calix[4]diquinone 2 and were expected to gen-
erate the partially reduced product 7. In the actual reduction
reaction, a very fine pinkish powder was obtained during the
worked-up procedure. Unlike its monohydroxy counterpart
6, this pinkish solid was soluble in methanol and the recrys-
p-Hydroxycalix[4]arenes 6 and 7
On the Wolff-Kishner partial reduction of monoketal 3,
both the removal of the benzoate groups and the reduction of
the “lower rim” carbonyl moieties were achieved in a simple
one-step reaction. We speculated that the same reaction con-
ditions may also transform the calix[4]monoquinone triben-
zoate 1 into a partial reduction with a benzoate removing
product. When compound 1 was treated under Wolff-Kishner
reaction conditions, a reddish solid material was produced as
in previous cases. The spectral data indicated that the reddish
solid product was the expected compound, p-monohydroxy-
calix[4]arene (6). The color of the product, which did not
agree with reports in the literature,5 was maintained through-
out the recrystallization process. However, the reddish color
material possessed a very low Rf value, and a short column
chromatography revealed the off-white appearance of the
1
tallization was achieved in acetone and n-hexane. The H-
NMR spectrum of this pinkish powder 7 displayed two broad
singlets, which vanished upon treating with D2O, at 9.89 and
7.72 ppm at the ratio of 2:1, respectively. This spectral data
indicated that a total of six phenolic hydroxy moieties were
presented, and the four “lower rim” phenolic hydroxy groups
were different from the other two “upper rim” hydroxy

Calix[4]quinones III
J. Chin. Chem. Soc., Vol. 51, No. 3, 2004 609
Scheme II The reaction paths of the calix[4]quinones
groups. With the support of other spectral data, the structure
of pinkish powder 7 was assigned to be the title compound,
p-1,3-dihydroxycalix[4]arene (7).
vide valuable information for the structure of calix[4]arenes,
if one could establish a correlation between the chemical shift
and the distance between the phenolic hydroxy groups.
The same 1H-NMR spectral feature was also observed
in the p-monohydroxycalix[4]arene (6) case, in which two
broad singlets at 10.09 and 4.40 ppm with a 4:1 integral ratio
were displayed. This chemical shift could possibly indicate
the overall strength of the calixarene’s intramolecular hydro-
gen bond. We believe that these 1H-NMR spectra would pro-
EXPERIMENTAL8
General Procedure
A portion of 5 mL of hydrazine hydrate was added to a

610 J. Chin. Chem. Soc., Vol. 51, No. 3, 2004
Tsoo et al.
solution of 1.00 mmol of sample in 15 mL of diethylene gly-
col, and a solution of 2.30 g of KOH in 20 mL of ethylene gly-
col was then added. The reaction mixture was refluxed for 4
hours with a Dean-Stark trap to remove excess hydrazine.
The solution was cooled to room temperature, and a large ex-
cess of diluted HCl was added to induce a solid material. The
purification procedure for an individual product is described
separately.
149.8, 149.0, 148.7, 142.4, 129.3, 129.1, 129.0, 128.9, 128.2,
128.1, 128.0, 122.3, 122.1, 115.5, 31.8, 31.7; FAB-MS m/z:
440 (M+). Anal. Calcd for C28H24O5: C, 76.36; H, 5.45.
Found: C, 74.30; H, 5.34.
Method B: from 25,26,27-trihydroxy-28-calix[4]monoqui-
none
A red solid was collected from a sample of 0.44 g (1.00
mmol) of 25,26,27-trihydroxy-28-calix[4]monoquinone. A
short column chromatographic separation followed by re-
crystallization from CHCl3 and n-hexane afforded 0.41 g
(93%) of pale yellow solid 6. This product is identical with
the product produced in method A.
28-Hydro-25,26,27,28-tetrahydroxycalix[4]monoquinone-
17-ethylene ketal (5). Method A: from 25,26,27-tribenzo-
yloxy-28-calix[4]monoquinone-17-ethylene ketal (3)
A deep red solid was collected from a sample of 0.80 g
(1.00 mmol) of 3. Chromatographic separation (eluent:
EtOAc:n-hexane = 1:2) followed by recrystallization from
CHCl3 and CH3OH afforded 0.18 g (37%) of deep red solid 8:
mp 300-302 °C (Lit.6 274-276 °C; after recrystallization from
5,17,25,26,27,28-Hexahydroxycalix[4]arene (7)
A pink solid was collected from a sample of 0.66 g
(1.00 mmol) of 25,27-dibenzoyloxy-26,28-calix[4]diqui-
none (2). The solid material was recrystallized from acetone
and n-hexane to afford 0.23 g (50%) of pinkish powder: mp
1
CHCl3 and n-hexane); H-NMR9 (CDCl3) d 10.10 (s, 4H,
ArOH), 7.01-7.06 (m, 6H, ArH), 6.68-6.75 (m, 3H, ArH),
6.60 (s, 2H, ArH), 4.25 (bs, 4H, ArCH2Ar), 3.90-3.93 (m, 2H,
OCH2-C), 3.81-3.86 (m, 2H, OCH2-C), 3.51 (bs, 2H,
ArCH2Ar), 3.47 (bs, 2H, ArCH2Ar); 13C-NMR (CDCl3) d
153.0, 149.0, 148.6, 142.7, 139.7, 129.2, 129.0, 128.9, 128.8,
128.2, 127.9, 122.3, 122.1, 114.9, 69.5, 61.5, 32.0, 31.7;
FAB-MS m/z: 484 (M+). Anal. Calcd for C30H28O6: C, 74.38;
H, 5.79. Calcd for C30H28O6×3/2H2O: C, 70.45; H, 6.07.
Found: C, 70.70; H, 5.87.
1
222-224 °C; H-NMR (acetone-D6) d 9.89 (bs, 4H, ArOH),
7.72 (bs, 2H, ArOH), 7.13-7.14 (d, J = 7.5Hz, 4H, m-ArH),
6.69-6.72 (t, J = 7.5 Hz, 2H, p-ArH), 6.62 (s, 4H, ArH), 3.50-
4.10 (bs, 8H, ArCH2Ar); 13C-NMR (acetone-D6) d 152.4,
149.9, 141.8, 129.9, 129.7, 129.1, 122.5, 116.0, 31.7; FAB-
MS m/z: 456 (M+). Anal. Calcd for C28H24O6: C, 73.66; H,
5.30. Calcd for C28H24O6×3/2H2O: C, 69.57; H, 5.59. Found:
C, 69.57; H, 5.49.
Method B: from 25,26,27-trihydroxy-28-calix[4]monoqui-
none-17-ethylene ketal (4)
ACKNOWLEDGMENT
A deep red solid was collected from a sample of 0.48 g
(1.00 mmol) of 4. Chromatographic separation following by
recrystallization from CHCl3 and CH3OH afforded 0.12 g
(25%) of deep red solid. The physical and the spectral proper-
ties of this product were identical to the product which was
produced in Method A.
Financial support of this work from the National Sci-
ence Council of the Republic of China (Grant NSC-91-2113-
M034-002) is gratefully acknowledged.
Received September 9, 2003.
5,25,26,27,28-Pentahydroxycalix[4]arene (6). Method A:
from 25,26,27-tribenzoyloxy-28-calix[4]monoquinone (1)
A red solid was collected from a sample of 0.75 g (1.00
mmol) of 1. A short column chromatographic separation (col-
umn height 10 cm; eluent: CHCl3:n-hexane = 3:1) followed
by recrystallization from CHCl3 and n-hexane afforded 0.24
g (55%) of pale yellow solid 6: mp 309-311 °C (Lit.6 310-312
°C); 1H-NMR (CDCl3) d 10.09 (bs, 4H, ArOH), 7.00-7.06 (m,
6H, ArH), 6.68-6.73 (m, 3H, ArH), 6.50 (s, 2H, ArH), 4.40
(bs, 1H, ArOH), 4.22 (bs, 4H, ArCH2Ar), 3.51 (bs, 2H,
ArCH2Ar), 3.42 (bs, 2H, ArCH2Ar); 13C-NMR (CDCl3) d
REFERENCES
1. For books on calixarenes, (a) Asfari, Z.; B`hmer, V.
Calixarenes 2001; Harrowfield, J., Ed.; Kluwer Academic:
Dordrecht, 2001. (b) Gutsche, C. D. Calixarenes Revisited:
Monographs in Supramolecular Chemistry; Stoddart, J. F.,
Ed. The Royal Society of Chemistry: Cambridge, 1998. (c)
Vicens, J.; Asfari, Z. Calixarenes 50th Anniverary: Com-
memorative Issue; Harrowfield, J. M., Ed.; Kluwer Aca-
demic: Dordrecht, 1994. (d) Vicens, J. Calixarenes: A Versa-

Calix[4]quinones III
J. Chin. Chem. Soc., Vol. 51, No. 3, 2004 611
tile Class of Macrocyclic Compounds; B`hmer, V., Ed.;
Kluwer Academic: Dordrecht, 1991. (e) Gutsche, C. D.
Calixarenes: Monographs in Supramolecular Chemistry;
Stoddart, J. F., Ed.; The Royal Society of Chemistry: Cam-
bridge, 1989.
L.-G. Tetrahedron 2001, 57, 8101.
8. All reagents were obtained from commercial chemical com-
panies and used without further purification. Melting points
were taken in capillary tubes on a Mel-Temp apparatus (Lab-
oratory Devices, Cambridge, MA) and are uncorrected.
1H-NMR spectra are recorded on Bruker DMX-300 WB
and/or Bruker DMX-500 SB spectrometers, and chemical
shifts are reported as d values in ppm relative to TMS (d =
0.00) as an internal standard. FAB-MS spectra were taken on
a JOEL JMS-HX 102 spectrometer and elemental analyses
were taken on a Perkin-Elmer 240C analyzer. Chromato-
graphic separations were performed with Merck silica gel
(230-400 mesh ASTM) on columns of 25 mm diameter filled
to a height of 150 mm. TLC analyses were carried out on
Merck aluminum back silica gel 60 F254 plates (absorbant
thickness 0.2 mm).
9. In the 1H-NMR spectrum of compound 5, we were not able to
assign the proton signal for the carbon-28’s hydrogen which
was located on tetrahedral carbinol carbon. It was speculated
that a free rotation around the methylene linkage in calix-
[4]arene system constantly altered the magnetic environ-
ments for 28-hydro-, and therefore, a sharp proton signal for
28-hydro- was not observed.
2. For selected reviews, (a) Ikeda, A.; Shinkai, S. Chem. Rev.
1997, 97, 1713. (b) Timmerman, P.; Verboom, W.;
Reinhoudt, D. N. Tetrahedron 1996, 52, 2663. (c) B`hmer,
V. Angew. Chem. Int. Ed. Engl. 1995, 34, 713. (d) Shinkai, S.
Tetrahedron 1993, 49, 8933.
3. Chasar, D. W. J. Org. Chem. 1985, 50, 545.
4. (a) Isorrell, T. N.; Yuan, H. J. Org. Chem. 1997, 62, 1899. (b)
Sartori, G.; Porta, C.; Bigi, F.; Maggi, R.; Peri, F.; Marzi, E.;
Lanfranchi, M.; Pellinghelli, M. A. Tetrahedron 1997, 53,
3287. (c) Biali, S. E.; B`hmer, V.; Brenn, J.; Frings, M.;
Thondorf, I.; Vogt, W.; W`hnert, J. Angew. J. Org. Chem..
1997, 62, 8350.
5. With three methyls as blocking groups, the exo-calixarenes
with their phenolic hydroxy moieties meta to the methylene
linkage were synthesized. Pappalardo, S.; Ferguson, G.;
Gallagher, J. F. J. Org. Chem. 1992, 57, 7102.
6. Lee, M.-D.; Yang, K.-M.; Tsoo, C.-Y.; Shu, C.-M.; Lin, L.-G.
Tetrahedron 2001, 57, 8095.
7. Yang, K.-M.; Lee, M.-D.; Chen, R.-F.; Chen, Y.-L.; Lin,