Stepwise Construction of Some Hexahomooxacalix[3]arenes and Their Conformations in Solid State

Article abstract of DOI:10.1021/jo971945a

Hexahomooxacalix[3]arenes 1 bearing different substituents on their upper rim were synthesized from the corresponding linear trimers 2 by the acid-catalyzed cyclization. The X-ray crystallographic analyses of 1 (R¹ = R³ = H, R² = t-Bu, and R¹ = Et, R² = t-Bu, R³ = i-Pr) revealed that they adopt a cone conformation, owing to an intramolecular hydrogen-bonded network in the solid state.

Full text of DOI:10.1021/jo971945a

3260
J . Org. Chem. 1998, 63, 3260-3265
Step w ise Con str u ction of Som e Hexa h om ooxa ca lix[3]a r en es a n d
Th eir Con for m a tion s in Solid Sta te
Kazunori Tsubaki,† Tadamune Otsubo,† Kiyoshi Tanaka,† and Kaoru Fuji*,†
Institute for Chemical Research, Kyoto University, Uji, Kyoto 611-0011, J apan
Takayoshi Kinoshita‡
Basic Research Laboratories, Fujisawa Pharmaceutical Co., Ltd., Kashima, Yodogawa,
Osaka 532-8514, J apan
Received October 21, 1997
Hexahomooxacalix[3]arenes 1 bearing different substituents on their upper rim were synthesized
from the corresponding linear trimers 2 by the acid-catalyzed cyclization. The X-ray crystallographic
analyses of 1 (R1 ) R3 ) H, R2 ) t-Bu, and R1 ) Et, R2 ) t-Bu, R3 ) i-Pr) revealed that they adopt
a cone conformation, owing to an intramolecular hydrogen-bonded network in the solid state.
Ch a r t 1
In tr od u ction
Since the pioneering work on the one-step synthesis
of p-tert-butylcalix[4,6,8]arenes (Chart 1) by Gutsche and
co-workers,1 a considerable amount of attention has been
paid to these molecules from the viewpoint of host-guest
chemistry. Calixarenes were prepared by the base-
induced condensation of 4-tert-butylphenol with 37%
formaldehyde under strictly controlled conditions. Con-
trary to calixarenes, hexahomooxacalix[3]arenes have
received little attention2 despite their unique structural
features such as a cavity composed of an 18-membered
ring, C3 symmetry, and a limited number of possible
conformations (i.e., cone and partial cone). Only a few
methods for the synthesis of hexahomooxacalix[3]arenes
have been available so far. These include the methods
reported by Gutsche et al.,3 Vicens et al.,4 and Hampton
et al.5 All involve cyclotrimerization using 2,6-bis-
(hydroxymethyl)phenols as a monomer unit. Conse-
quently, these procedures can only give symmetrical
hexahomooxacalix[3]arenes bearing the same substitu-
ents on the upper rim of the molecules. On the other
hand, desymmetrization of the molecules by the intro-
duction of different substituents into the upper rim leads
to chiral host molecules, which realize enantioselective
molecular recognition, if their conformation is fixed.
Calixarenes having para substituents other than tert-
butyl have been synthesized by a reverse Friedel-Crafts
reaction6 of tert-butylcalixarenes followed by electrophilic
substitution with a variety of electrophiles.1e,g,i However,
this approach is not applicable to hexahomooxacalix[3]-
arenes because it is difficult to selectively remove the
para substituents by the reverse Friedel-Crafts reaction
due to the presence of three dibenzyl ethereal linkages.
Therefore, a prior introduction of the specified para
substituents is necessary. In this paper, we report the
* The corresponding author: Kyoto University, Uji, Kyoto 611,
J apan. Phone: +81-774-38-3190. FAX: +81-774-38-3197. E-mail:
fuji@scl.kyoto-u.ac.jp.
† Kyoto University.
‡ Fujisawa Pharmaceutical Co., Ltd.
(1) (a) Gutsche, C. D.; Dhawan, B.; No, K. H.; Muthukrishnan, R.
J . Am. Chem. Soc. 1981, 103, 3782. (b) Gutsche, C. D.; Iqbal, M.
Organic Syntheses; Wiley: New York, 1993; Collect. Vol. VIII, 75. (c)
Gutsche, C. D.; Dhawan, B.; Leonis, M.; Stewart D. Organic Syntheses;
Wiley: New York, 1993, Collect. Vol. VIII, 77. (d) Munch, J . H.;
Gutsche, C. D. Organic Syntheses Wiley: New York, 1993; Collect. Vol.
VIII, 81. For reviews on calixarenes, see: (e) Gutsche, C. D. Calixare-
nes, Royal Society of Chemistry; Cambridge. (f) Gutsche, C. D. Acc.
Chem. Res. 1983, 16, 161. (g) Bo¨hmer, V. Angew. Chem., Int. Ed. Engl.
1995, 34, 713. (h) Shinkai, S. Tetrahedron 1993, 49, 8933. (i) Gutsche,
C. D. Aldrichimica Acta 1995, 28, 3.
(2) (a) Daitch, C. E.; Hampton, P. D.; Duesler, E. N.; Alam, T. M. J .
Am. Chem. Soc. 1996, 118, 8, 7769. (b) Daitch, C. E.; Hampton, P. D.;
Duesler, E. N. Inorg. Chem. 1995, 34, 5641. (c) Hampton, P. D.; Daitch,
C. E.; Alam, T. M.; Bencze, Z.; Rosay, M. Inorg. Chem. 1994, 33, 4750.
(d) Masci, B.; Tetrahedron 1995, 51, 5459. (e) Araki, K.; Inaba, K.;
Otsuka, H.; Shinkai, S. Tetrahedron 1993, 49, 9465. (f) Matsumoto,
H.; Nishio, S.; Takeshita, M.; Shinkai, S. Tetrahedron 1995, 51, 4647.
(g) Takeshita, M.; Shinkai, S. Chem. Lett. 1994, 125. (h) Araki, K.;
Hashimoto, N.; Otsuka, H.; Shinkai, S. J . Org. Chem. 1993, 58, 5958.
(i) Araki, K.; Inada, K.; Shinkai, S. Angew. Chem., Int. Ed. Engl. 1996,
35, 72. (j) Khrifi, S.; Guelzim, A.; Baert, F. Acta Crystallogr. 1995, C51,
153. (k) Hampton, P. D.; Daitch, C. E.; Duesler, E. N. New J . Chem.
1996, 20, 427. (l) Suzuki, K.; Minami, H.; Yamagata, Y.; Fujii, S.;
Tomita, K. Acta Crystallogr. 1992, C48, 350.
(4) Zerr, P.; Mussrabi, M.; Vicens, J . Tetrahedron Lett. 1991, 32,
1879.
(5) Hampton, P. D.; Bencze, Z.; Tong, W.; Daitch, C. E. J . Org. Chem.
1994, 59, 4838.
(6) (a) Gutsche, C. D.; Lin, L.-G. Tetrahedron 1986, 42, 1633. (b)
Bocchi, V.; Foina, D.; Pochini, A.; Ungaro, R. Tetrahedron 1982, 38,
373.
(3) Dhawan, B.; Gutsche, C. D. J . Org. Chem. 1983, 48, 1536.
S0022-3263(97)01945-2 CCC: $15.00 © 1998 American Chemical Society
Published on Web 04/16/1998

Stepwise Construction of Hexahomooxacalix[3]arenes
J . Org. Chem., Vol. 63, No. 10, 1998 3261
Ta ble 1. Cycliza tion of Lin ea r Tr im er s to
Hexa h om ooxa ca lix[3]a r en es
Sch em e 1
entry linear trimer
R1
R2
R3
product % yielda
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
H
Me
Et
i-Pr
t-Bu
H
Me
Et
i-Pr
t-Bu
Me
Et
H
H
H
H
H
Me
Et
i-Pr
t-Bu
H
Me
Et
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
37
38
22
44
42
42
54
22
43
50
54
48
45
53
20
51
0
H
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
H
i-Pr
t-Bu
Et
t-Bu
i-Pr
OMe OMe OMe
t-Bu
Br
Br
Br
Br
t-Bu
Br
t-Bu
Bu
t-Bu
Br
34b
4
Br
a
b
Isolated yield. 13 h for the reaction time.
with 4b 22b with 4c, and 22c with 4g, gave the trimers
15, 16, and 20, respectively.
Linear trimers 5-21 gave the desired hexahomooxa-
calix[3]arenes 23-38 after treatment with HClO410 under
high-dilution conditions in CHCl3. Pretreatment of
CHCl3 with H2O is indispensable for this cyclization.
Thus, commercially available CHCl3 was washed with
water, allowed to stand for at least 6 h in a separatory
funnel, and then separated. This process is required to
supply H2O for the deprotection as well as to remove trace
amounts of ethanol added as a stabilizer. If nontreated
CHCl3 was used, byproducts originating from the addi-
tion of ethanol formed to some extent. No effective
cyclization proceeded in CHCl3 or CH2Cl2 containing
amylene as a stabilizer. The additives KClO4 and Na-
ClO4 did not exert any template effect on the reaction.
The results of the cyclization to a variety of hexahomo-
oxacalix[3]arenes 23-38 are summarized in Table 1.
Constant and moderate chemical yields were observed,
and among the R2 substituents on the central ring of the
linear trimers, tert-butyl, hydrogen, and bromine resulted
in almost the same yield. In the case of R1 ) R3 ) H,
somewhat lower yields were obtained (entries 1 and 6).
Cyclization was extremely suppressed for trimers with
R1 ) R3 ) Br (entries 15 and 17). Thus, the attempted
cyclization of a linear trimer 19 gave deprotected prod-
ucts 39-41 in 18%, 31%, and 40% yields, respectively.
first stepwise synthesis of a variety of hexahomooxacalix-
[3]arenes 23-38 having different substituents on their
upper rim. We report elucidation of their conformations
in the solid state; the synthesis is based on the cyclization
of the corresponding linear trimers under acidic high-
dilution conditions.
Resu lts a n d Discu ssion
Syn th esis of Hexa h om ooxa ca lix[3]a r en es 23-38.
The starting 2,6-bis-(hydroxymethyl)phenols 15,7 were
treated with 2,2-dimethoxypropane in the presence of
p-TsOH to afford the acetonides 3,8 which were bromi-
nated with CBr4-PPh3, yielding the corresponding ben-
zylbromides 4. Separately, the coupling partners, diols
2, were prepared by the reaction of 1 with MOMCl using
Adogen464 as a phase-transfer catalyst.9 Alkylation of
2 with 2.2 equiv of bromides 4 provided the linear trimers
(5-14, 17-19, and 21) having the same substituent for
R1 and R3 (Scheme 1). Monoalkylation of 2a , 2e, and 2g
with 4c, 4d , and 4e, respectively, gave the dimers 22a ,
22b, and 22c. The second alkylation of the dimer 22a
(7) Freeman, J . H. J . Am. Chem. Soc. 1952, 74, 6257.
(8) Clark, D. A.; Riccardis, F. D.; Nicolaou, K. C. Tetrahedron 1994,
50, 11391.
(9) (a) Kelly, T. R.; J agoe, C. T.; Li, Q. J . Am. Chem. Soc. 1989, 111,
4522. (b) van Heerden, F. R.; van Zyl, J . J .; Rall, G. J . H.; Brandt, E.
V.; Roux, D. G. Tetrahedron Lett. 1978, 661.

3262 J . Org. Chem., Vol. 63, No. 10, 1998
Tsubaki et al.
Sch em e 2
F igu r e 1. (a) Crystal structure of 28 in two conformations, A
and B, showing the atom-labeling scheme for the oxygens. (b)
Side view to emphasize their one conformation. Hydrogen
atoms are excluded for clarity.
Contrary to these results, the desired product 37 was
obtained from 20 in 34% yield.
It is especially worthwhile to note that the isolation of
the products from the reaction mixture was quite easy
in these reactions. The cyclized products 23-25, 32, and
33 were isolated from MeOH in an extremely pure form
without any chromatographic separation. Simple puri-
fication by short column chromatography on silica gel
with CHCl3 as an eluent made it possible to isolate other
products with a high degree of purity.
The formation of hexahomooxacalix[3]arenes from the
corresponding linear trimers presumably involves the
initial protonation at the aliphatic ethereal oxygen to give
an oxonium species a (Scheme 2). The following proto-
nation at the aromatic ethereal oxygen creates a dioxo-
nium species b. The cyclic ether is formed by the
intramolecular attack of the primary hydroxyl group to
the benzylic position, as shown in b, or to the correspond-
ing benzylic cation. According to this mechanism, both
of the oxygen atoms in the ketal ring should be proto-
nated. This explains why 37 was obtained from 20 but
not from 19. Protonation at the phenolic oxygen shown
in a is less favorable for 19 due to an electron-withdraw-
ing group on the phenyl ring, while this process occurs
easily with 20.
Con for m a tion of Hexa h om ooxa ca lix[3]a r en es in
th e Solid Sta te. The X-ray crystallographic analysis of
some hexahomooxacalix[3]arene derivatives such as metal
complexes,2a,b O-alkylated2i,j or O-silylated2k compounds
of the phenolic hydroxyl group, and 322l have been
reported, and only two conformations had been observed
to date. Among them, it was reported that 32 adopts a
cone conformation owing to three intramolecular hydro-
gen bondings between each phenolic hydroxy group;
however, the positions of the involving hydrogens are not
specified.2l. It is interesting to investigate the conforma-
tion of the newly prepared hexahomooxacalix[3]arenes
which have different substituents on their upper rim.
Thus, the X-ray analyses of 28 and 34 were undertaken.
The crystals of hexahomooxacalix[3]arene 28 are trigo-
nal and are classified as belonging to the space group
P31. The compound 28 exists in two conformations, A
Ta ble 2. Dista n ces (Å) a n d An gles (d eg) of
In tr a m olecu la r Hyd r ogen Bon d in g of 28a
D-A
(Å)
D-H
(Å)
H‚‚A
(Å)
D-H‚‚‚A
(deg)
donor hydrogen acceptor
O28a H(O28a)
O28a H(O28a)
O33a H(O33a)
O33a H(O33a)
O34a H(O34a)
O34a H(O34a)
O26a
O34a
O8a
O28a
O17a
O33a
2.821(8) 0.86(5) 2.06(5)
2.828(8) 0.86(5) 2.27(8)
2.77(1) 0.8(1) 2.12(8)
2.920(9) 0.8(1) 2.2(1)
2.800(9) 0.81(8) 2.2(1)
2.890(5) 0.81(8) 2.22(5)
147(6)
122(6)
135(6)
140(6)
136(7)
140(8)
O28b H(O28b)
O28b H(O28b)
O33b H(O33b)
O33b H(O33b)
O34b H(O34b)
O34b H(O34b)
O26b
O34b
O8b
O28b
O17b
O33b
2.75(1) 1.09(7) 1.99(9)
2.828(4) 1.09(7) 1.90(6)
2.831(7) 1.02(8) 1.98(9)
2.832(8) 1.02(8) 2.4(1)
2.867(8) 1.09(9) 2.33(7)
123(5)
139(7)
139(9)
102(9)
108(3)
163(5)
2.879
1.09(9) 1.82(8)
a
1. The symmetry operations are applied to the acceptors. 2.
Estimated standard deviations (esd’s) are shown in the parenthe-
ses. They are not calculated when one of the atoms has an esd )
0.0. 3. Estimated hydrogen positions are located at 1 Å away from
the donors.
and B, in the crystalline state (Figure 1a), and the both
adopt the cone conformation in the solid state (Figure
1b). Of particular interest is that all the phenolic
hydrogen atoms are geometrically fixed. Furthermore,
it has become apparent from the X-ray analysis that 28
forms an extended network of six intramolecular hydro-
gen bondings. Each phenolic hydrogen atom is shared
with two oxygen atoms (the phenolic oxygen and the
dibenzyl ethereal oxygen); therefore the angles of O-H‚‚‚O
are not 180° (linear form) but between 102° and 163°.
The pattern of the intramolecular hydrogen bonding in
conformations A and B in terms of distances and angles
is shown in Table 2. Thus, hexahomooxacalix[3]arenes
adopt a cone conformation with a bifurcate-arranged
intramolecular hydrogen bonds network, whose strong
hydrogen bondings are supported by bond distances of
approximately 2 Å. In addition, an astonishing feature
is that 28 exists in an optically active form in the
crystalline package despite being an achiral molecule.11
The crystals of hexahomooxacalix[3]arene 34 are orthor-
hombic and belong to the space group Pna21. The crystal
structure of 34 is shown in Figure 2. It was also clarified
(10) Particular caution should be taken when handling perchloric
acid and related compounds; it must, especially be kept in mind that
heating the reaction mixture might cause a hazardous explosion.

Stepwise Construction of Hexahomooxacalix[3]arenes
J . Org. Chem., Vol. 63, No. 10, 1998 3263
reduced pressure to afford the diol 2e (24.7 g, 68%) as pale
yellow powder, which was recrystallized from EtOAc (75%).
2a : 52% yield. 2f: 38% yield. 2g: 54% yield.
Gen er a l P r oced u r e for th e P r ep a r a tion of Aceton id es
3. The acetonides 3 were prepared from the corresponding
2,6-bis-(hydroxymethyl)phenols 15,7 according to the procedure
of Nicolaou.8 The preparation of the acetonide 3e is typical.
To a stirred solution of 4-tert-butyl-2,6-bis-(hydroxymethyl)-
phenol (78.7 g) and 2,2-dimethoxypropane (160 mL) in acetone
(80 mL) was added p-TsOH (0.5 g) at room temperature for 3
h. The solution was neutralized by the addition of excess solid
sodium bicarbonate. The mixture was concentrated under
reduced pressure, diluted with EtOAc, and washed with water
(four times). The organic extract was evaporated under
reduced pressure, and HOAc (60 mL, 50% v/v aqueous solu-
tion) was added to the residue. The mixture was allowed to
stand for 0.5 h before being diluted with ethyl ether. The
organic layer was washed successively with water (2 times),
aqueous NaHCO3 (two times), water (two times), and brine
and dried. Evaporation under reduced pressure left the
acetonide 3e (80.3 g, 86%), which was directly used for the
next step without further purification. A part of the sample
was subjected to the further purification by PTLC to give an
analytical sample.
F igu r e 2. Crystal structure of 34 in two conformations, C
and D. Hydrogen atoms are excluded for clarity.
that 34 consists of two individual cone conformations C
and D in the crystalline state. The existence of a network
due to hydrogen bondings in 34 in the solid state is
strongly indicated by the distances both between each
phenolic oxygen atom and between phenolic and dibenzyl
ethereal oxygen atoms (2.70-2.98 Å), which are compa-
rable to those of 28 (2.77-2.92 Å).
Con clu sion
3a : 93% yield. 3b: 90% yield. 3c: 83% yield. 3d : 99% yield.
3g: 82% yield.
In the present study, the construction of a number of
hexahomooxacalix[3]arene derivatives 23-38 was achieved
by an acid-catalyzed cyclization of the corresponding
linear trimers under high-dilution conditions in yields
of 4-54%. It appeared that the newly prepared hexa-
homooxacalix[3]arenes adopt the cone conformation in
the crystalline state by virtue of a network of bifurcated
intramolecular hydrogen bonds. The present method not
only is an alternative to previous methods but also has
opened a new synthetic pathway to hexahomooxacalix-
[3]arenes bearing and a variety of substituents on their
upper rim, which has been difficult to achieve by the
previously available approach. We believe that this
method is practical and useful, especially for the synthe-
sis of unsymmetrical hexahomooxacalix[3]arenes, and
might contribute to the field of host-guest chemistry.
The interaction of 32 and 38 prepared by this method
with fullerene has been examined,12 and other complex-
ations of these hexahomooxacalix[3]arenes with various
guest molecules are now in progress.
Gen er a l P r oced u r e for th e P r ep a r a tion of Ben zylbr o-
m id es 4. The conversion of the acetonide 3e to the benzyl-
bromide 4e is typical. To a stirred solution of the acetonide
3e (13.4 g) and triphenylphosphine (28.1 g) in CH2Cl2 (270 mL)
was added portionwise carbon tetrabromide (26.6 g) at room
temperature. The solution was stirred for 6.5 h and evapo-
rated under reduced pressure. Hexane was added to the
residue, and triphenylphosphineoxide was filtered off. The
filtrate was evaporated under reduced pressure, and the
residue was purified by column chromatography on silica gel
with hexane/EtOAc ) 10:1 as an eluent to afford the benzyl-
bromide 4e (6.05 g, 36%).
4a : 65% yield. 4b: 65% yield. 4c: 56% yield. 4d : 66% yield.
4f: 43% yield. 4g: 36% yield.
Gen er a l P r oced u r e for th e P r ep a r a tion of Lin ea r
Tr im er s 5-21. To a solution of the diol 2 in DMF (10 mL for
1.00 g of diol 2) was added portionwise sodium hydride (2.5
equiv) at 0 °C, and the suspension was further stirred for 20
min at room temperature. A solution of the benzylbromide 4
(2.2 equiv) in DMF (10 mL for 1.00 g of diol 2) was added
dropwise to the suspension, and the resulting mixture was
stirred for 10 h at ambient temperature. The reaction mixture
was poured into ice-cold water and extracted with EtOAc. The
organic layer was washed with water (four times) and brine
and dried. Concentration of the extract under reduced pres-
sure gave the residue, which was subjected to silica gel column
chromatography with hexane/EtOAc ) 5:1 to afford the linear
trimer 5-21.
5: 95% yield from 4a and 2a . 6: 85% yield from 4b and 2a .
7: 80% yield from 4c and 2a . 8: 89% yield from 4d and 2a . 9:
84% yield from 4e and 2a . 10: 83% yield from 4a and 2e. 11:
86% yield from 4b and 2e. 12: 85% yield from 4c and 2e. 13:
87% yield from 4d and 2e. 14: 87% yield from 4e and 2e. 15:
84% yield from 4b and the dimer 22a . 16: 61% yield from 4c
and the dimer 22b. 17: 84% yield from 4f and 2f. 18: 83%
yield from 4e and 2g. 19: 75% yield from 4g and 2e. 20: 56%
yield from 4g and the dimer 22c. 21: 78% yield from 4g and
2g.
Gen er a l P r oced u r e for th e P r ep a r a tion of Dim er s 22.
To a stirred solution of the diol 2 in DMF (10 mL for 1.00 g of
diol 2) was added portionwise sodium hydride (1.1 equiv) at 0
°C, and the mixture was stirred for 20 min at room temper-
ature. A solution of benzylbromide 4 (1.0 equiv) in DMF (10
mL for 1.00 g of diol 2) was added dropwise to the above
suspension, and the mixture was stirred at ambient temper-
ature for 10 h. The reaction mixture was poured into ice-cold
water and extracted with EtOAc. The organic layer was
washed with water (4 times) and brine and dried. Evaporation
under reduced pressure gave the residue, which was purified
Exp er im en ta l Section
Gen er a l. Melting points are uncorrected. Nuclear mag-
netic resonance (NMR) spectra were taken at 200 or 400 MHz
in CDCl3 with chemical shifts being reported as δ ppm from
tetramethylsilane as an internal standard, and couplings are
expressed in hertz. All extractive organic solutions were dried
over anhydrous sodium sulfate. Flash column chromatography
was carried out with silica gel 60 spherical (150-325 mesh).
Gen er a l P r oced u r e for th e P r ep a r a tion of Diols 2.9
The preparation of the diol 2e is typical. To a stirred solution
of 4-tert-butyl-2,6-bis(hydroxymethyl)phenol (30.0 g) and
Adogen464 (6.6 g) in CH2Cl2 (260 mL) and 2 N aqueous NaOH
(130 mL) was added dropwise methoxymethyl chloride (13 mL)
at room temperature. The resulting solution was stirred for
10 h, and then the organic layer was separated, washed with
aqueous 0.5 N HCl, aqueous 0.5 N NaOH, water (two times),
and brine. The extract was dried and concentrated under
(11) (a) Sakamoto, M. Chem. Eur. J . 1997, 3, 684. (b) Azumaya, I.;
Yamaguchi, K.; Okamoto, I.; Kagechika, H.; Shudo, K. J . Am. Chem.
Soc. 1995, 117, 9083. (c) Koshima, H.; Hayashi, E.; Matsuura, T.;
Tanaka, K.; Toda, F.; Kato, M.; Kiguchi, M. Tetrahedron Lett. 1997,
38, 5009.
(12) The complexations of 32 and 28 with fullerene including their
X-ray analyses will appear in a preliminary form in J . Chem. Soc.,
Chem. Commun.

3264 J . Org. Chem., Vol. 63, No. 10, 1998
Tsubaki et al.
by column chromatography on silica gel with a solvent system
of hexane/EtOAc ) 5/1 to afford the corresponding dimer 22.
22a : 40% yield; 22b: 34% yield; 22c: 39% yield.
3H); HRMS calcd for C32H40O6 (M+) 520.2825, found 520.2828.
Anal. Calcd for C32H40O6: C, 73.82; H, 7.74. Found: C, 73.63;
H, 7.93.
31: mp 191-192 °C (from CHCl3-MeOH); IR (KBr) 3367,
2957, 2869, 1612, 1487, 1211, 1084, and 879 cm-1; 1H NMR δ
1.16 (d, J ) 6.9, 12H), 1.24 (s, 9H), 2.78 (hep, J ) 6.9, 2H),
4.71 (brs, 12H), 6.98 (s, 4H), 7.13 (s, 2H), 8.58 (s, 3H); HRMS
calcd for C34H44O6 (M+) 548.3138, found 548.3129. Anal.
Calcd for C34H44O6: C, 74.42; H, 8.08. Found: C, 74.25; H,
8.17.
Gen er a l P r oced u r e for t h e P r ep a r a t ion of H exa h o-
m ooxa ca lix[3]a r en es 23-38. To a stirred solution of the
linear trimer in CHCl3 saturated with H2O (for the prepara-
10
tion, see text; 200 mL) was added 60% HClO4 (0.20 mL for
1.00 g of the trimer). The reaction mixture was stirred at room
temperature for 4 h, and then water was added to the solution.
The organic layer was separated, dried, and evaporated under
reduced pressure to leave the residue, which was triturated
with MeOH (10 mL for 1.00 g of the linear trimer), and the
mixture was allowed to stand overnight. When white solids
were precipitated (23-25, 32, and 33), the precipitates were
filtered off, washed with MeOH, and dried in vacuo to afford
hexahomooxacalix[3]arenes. In the case of no precipitation,
the solvent was removed under reduced pressure, and the
residue was purified by column chromatography on silica gel
with chloroform to afford hexahomooxacalix[3]arenes. In this
way, each hexahomooxacalix[3]arene was obtained from the
corresponding linear trimer in the yield indicated in Table 1.
23: mp 135-136 °C (from CHCl3-MeOH); IR (KBr) 3354,
3047, 2851, 1616, 1600, 1469, 1356, 1242, 1206, 1070, and 749
cm-1; 1H NMR δ 4.73 (s, 12H), 6.80 (t, J ) 7.5, 3H), 7.13 (d, J
) 7.5, 6H), 8.80 (s, 3H); HRMS calcd for C24H24O6 (M+)
408.1573, found 408.1565. Anal. Calcd for C24H24O6•2/3
H2O: C, 68.56; H,6.07. Found: C, 68.39; H, 6.04.
32:3,4,5 This compound was identified by a comparison with
the reported physical data.
33: mp 183-184 °C (from CHCl3-MeOH); IR (KBr) 3341,
2961, 2855, 1602, 1488, 1358, 1205, 1158, 1077, 1011 867, 778,
1
and 749 cm-1; H NMR δ 1.15 (t, J ) 7.7, 3H), 2.22 (s, 3H),
2.52 (q, J ) 7.7, 2H), 4.70 (brs, 12H), 6.79 (t, J ) 7.6, 1H),
6.93 (s, 2H), 6.95 (s, 2H), 7.12 (d, J ) 7.6, 2H), 8.56 (s, 1H),
8.57 (s, 1H), 8.80 (s, 1H); HRMS calcd for C27H30O6 (M+)
450.2043, found 450.2061. Anal. Calcd for C27H30O6: C, 71.98;
H, 6.71. Found: C, 71.82; H, 6.73.
34: mp 177-178 °C (from CHCl3-MeOH); IR (KBr) 3366,
2957, 2868, 1613, 1488, 1209, 1084, and 877 cm-1; 1H NMR δ
1.10-1.25 (m, 3H), 1.16 (d, J ) 6.9, 6H), 1.24 (s, 9H), 2.51 (q,
J ) 7.3, 2H), 2.79 (hep, J ) 6.9, 1H), 4.70 (brs, 12H), 6.95 (s,
2H), 6.98 (s, 2H),7.13 (s, 2H), 8.58 (s, 3H); HRMS calcd for
C
C
33H42O6 (M+) 534.2981, found 534.3003. Anal. Calcd for
33H42O6: C, 74.13; H, 7.92. Found: C, 73.79; H, 8.10.
35: mp 160 °C (from CHCl3-MeOH); IR (KBr) 3358, 2838,
24: mp 189-190 °C (from CHCl3-MeOH); IR (KBr) 3343,
2858, 1602, 1488, and 1076 cm-1; 1H NMR δ 2.22 (s, 6H), 4.67
(s, 4H), 4.69 (s, 4H), 4.71 (s, 4H), 6.79 (t, J ) 7.4, 1H), 6.93 (s,
4H), 7.12 (d, J ) 7.4, 2H), 8.56 (s, 2H), 8.79 (s, 1H); HRMS
calcd for C26H28O6 (M+) 436.1886, found 436.1876. Anal.
Calcd for C26H28O6‚1/3CHCl3: C, 66.41; H, 6.00. Found: C,
66.18; H, 6.02.
1611, 1489, 1359, 1320, 1252, 1193, 1156, 1082, 1053, 854, 778,
and 750 cm-1; H NMR δ 3.73 (s, 9H), 4.68 (s, 12H), 6.72 (s,
1
6H), 8.39 (s, 3H); HRMS calcd for C27H30O9 (M+) 498.1890,
found 498.1877. Anal. Calcd for C27H30O9‚1/2H2O: C, 63.90;
H, 6.16. Found: C, 63.92; H, 5.99.
36: mp 103-105 °C (from H2O-MeOH); IR (KBr) 3364,
2956, 1614, 1489, 1362, 1213, 1079, 1011, 879, and 732 cm-1
;
25: mp 158-160 °C (from CHCl3-MeOH); IR (KBr) 3331,
1H NMR δ 1.25 (s, 18H), 4.66 (s, 4H), 4.71 (s, 4H), 4.73 (s,
4H), 7.14 (brs, 4H), 7.24 (brs, 2H), 8.49 (s, 2H), 8.87 (s, 1H);
HRMS calcd for C32H39Br*O6 (M+) 598.1930, found 598.1933,
calcd for C32H39Br*O6 (M+) 600.1910, found 600.1902. Anal.
Calcd for C32H39BrO6‚H2O: C, 62.24; H, 6.69. Found: C, 62.42;
H, 6.39.
1
2962, 2870, 1601, 1488, and 1077 cm-1; H NMR δ 1.15 (t, J
) 7.6, 6H), 2.52 (q, J ) 7.6, 4H), 4.70 (brs, 12H), 6.79 (t, J )
7.5, 1H), 6.95 (s, 4H), 7.12 (d, J ) 7.5, 2H), 8.58 (s, 2H), 8.80
(s, 1H); HRMS calcd for
C
28H32O6 (M+) 464.2199, found
464.2187. Anal. Calcd for C28H32O6: C, 72.39; H, 6.94.
Found: C, 72.18; H, 6.94.
37: mp 142-144 °C (from CHCl3-MeOH); IR (KBr) 3346,
2959, 2860, 1471, 1353, 1242, 1200, 1079, 1010, 881, and 729
26: mp 142-143 °C (from CHCl3-MeOH); IR (KBr) 3348,
2955, 2866, 1604, 1487, 1359, 1207, 1178, 1079, 881, and 748
1
cm-1; H NMR δ 1.25 (s, 9H), 4.64 (s, 4H), 4.66 (s, 4H), 4.71
cm-1 1H NMR δ 1.17 (d, J ) 7.0, 12H), 2.79 (hep, J ) 7.0,
;
(s, 4H), 7.14 (s, 2H), 7.24 (s, 2H), 7.25 (s, 2H), 8.40 (s, 1H),
8.77 (s, 2H); HRMS calcd for C28H30Br2*O6 (M+) 620.0409,
found 620.0425, calcd for C28H30Br2*O6 (M+) 622.0389, found
622.0409, calcd for C28H30Br2*O6 (M+) 624.0369, found 624.0388.
Anal. Calcd for C28H30Br2O6: C, 54.04; H, 4.86. Found: C,
54.30; H, 4.95.
2H), 4.72 (s, 12H), 6.78 (t, J ) 7.6, 1H), 6.98 (s, 4H), 7.12 (d,
J
C
C
) 7.6, 2H), 8.58 (s, 2H), 8.81 (s, 1H); HRMS calcd for
30H36O6 (M+) 492.2512, found 492.2512. Anal. Calcd for
30H36O6: C, 73.15; H, 7.37. Found: C, 72.90; H, 7.34.
27: mp 178-179 °C (from CHCl3-MeOH); IR (KBr) 3377,
2957, 2859, 1602, 1490, 1469, 1362, 1306, 1214, 1076, and 879
38: mp 220-221 °C (from CHCl3-MeOH); IR (KBr) 3328,
cm-1
7.4, 1H), 7.12 (d, J ) 7.4, 2H), 7.14 (s, 4H), 8.59 (s, 2H), 8.81
(s, 1H); HRMS calcd for
32H40O6 (M+) 520.2825, found
32H40O6: C, 73.82; H,7.74.
;
1H NMR δ 1.24 (s, 18H), 4.73 (brs, 12H), 6.78 (t, J )
2856, 1471, 1352, 1241, 1077, 1010, 866, and 728 cm-1 1H
;
NMR δ 4.64 (s, 12H), 7.25 (s, 6H), 8.68 (s, 3H); HRMS calcd
C
for C24H21Br3*O6 (M+) 641.8888, found 641.8936, calcd for
520.2847. Anal. Calcd for
Found: C, 73.57; H, 7.83.
C
C
24H21Br3*O6 (M+) 643.8868, found 643.8906, calcd for C24H21
-
Br3*O6 (M+) 645.8847, found 645.8845, calcd for C24H21Br3*O6
(M+) 647.8826, found 647.8854. Anal. Calcd for C24H21
Br3O6: C, 44.68; H, 3.28. Found: C, 44.44; H, 3.24.
-
28: mp 183-185 °C (from CHCl3-MeOH); IR (KBr) 3342,
2960, 2864, 1602, 1469, 1356, 1269, 1207, 1075, 1006, and 755
cm-1; 1H NMR δ 1.25 (s, 9H), 4.72 (brs, 12H), 6.79 (t, J ) 7.5,
2H), 7.13 (d, J ) 7.5, 4H), 7.15 (s, 2H), 8.58 (s, 1H), 8.81 (s,
2H); HRMS calcd for C28H32O6 (M+) 464.2198, found 464.2170.
Anal. Calcd for C28H32O6: C, 72.39; H, 6.94. Found: C, 72.40;
H, 7.05.
29: mp 100-102 °C (from H2O-MeOH); IR (KBr) 3352,
2954, 2859, 1612, 1488, 1357, 1306, 1210, 1159, 1078, 1000,
863, 824, 783, 756, 570, and 408 cm-1; 1H NMR δ 1.24 (s, 9H),
2.21 (s, 6H), 4.66 (s, 4H), 4.69 (s, 4H), 4.71 (s, 4H), 6.92 (s,
4H), 7.13 (s, 2H), 8.56 (s, 3H); HRMS calcd for C30H36O6 (M+)
492.2512, found 492.2540. Anal. Calcd for C30H36O6: C, 73.15;
H, 7.37. Found: C, 72.96; H, 7.45.
Attem p ted Cycliza tion of 19. To a stirred solution of the
linear trimer 19 (145.5 mg) in CHCl3 saturated with H2O (for
the preparation, see text; 29.1 mL) was added 60% HClO4 (29
µL). The reaction mixture was stirred at room temperature
for 4 h, and then water was added to the solution. The organic
layer was separated, dried, and evaporated under reduced
pressure. The residue was purified by PTLC with a solvent
system of hexane/EtOAc ) 1:1 to afford 39 (24.3 mg, 18%), 40
(39.6 mg, 31%), and 41 (48.1 mg, 40%), respectively.
39: IR (CHCl3) 3386, 3014, 2963, 2846, 1463, 1376, 1245,
1
and 1137 cm-1; H NMR δ 1.29 (s, 9H), 1.54 (s, 12H), 4.57 (s,
4H), 4.70 (s, 4H), 4.81 (s, 4H), 7.05 (brs, 2H), 7.18 (s, 2H), 7.41
(brs, 2H), 7.53 (s, 1H); HRMS calcd for C34H40Br2*O7 (M+)
718.1141, found 718.1151, calcd for C34H40Br2*O7 (M+) 720.1121,
found 720.1124, calcd for C34H40Br2*O7 (M+) 722.1100, found
722.1077.
30: mp 153-154 °C (from CHCl3-MeOH); IR (KBr) 3363,
1
2960, 1612, 1488, 1208, and 1082 cm-1; H NMR δ 1.14 (t, J
) 7.6, 6H), 1.24 (s, 9H), 2.51 (q, J ) 7.6, 4H), 4.69 (s, 4H),
4.70 (s, 4H), 4.72 (s, 4H), 6.95 (s, 4H), 7.13 (s, 2H), 8.58 (s,

Stepwise Construction of Hexahomooxacalix[3]arenes
J . Org. Chem., Vol. 63, No. 10, 1998 3265
40: IR (CHCl3) 3386, 2964, 1466, 1376, 1247, and 1065 cm-1
;
Dcalcd ) 1.138 g cm-3, λ (Cu KR) ) 1.541 78 Å, T ) 298 K, R )
0.098, Rw ) 0.086 for 5601 reflections. Further details of the
crystal structure investigation are available on request from
the Director of the Cambridge Crystallographic Data Center.
1H NMR δ 1.27 (s, 9H), 1.57 (s, 6H), 4.59 (s, 2H), 4.68 (brs,
6H), 4.74 (s, 2H), 4.83 (s, 2H), 7.07 (d, J ) 2.4, 1H), 7.10 (d, J
) 2.4, 1H), 7.14 (d, J ) 2.4, 1H), 7.18 (d, J ) 2.4, 1H), 7.27 (d,
J ) 2.4, 1H), 7.34 (d, J ) 2.4, 1H), 7.72 (s, 1H), 8.15 (s, 1H);
HRMS calcd for C31H36Br2*O7 (M+) 678.0828, found 678.0808,
calcd for C31H36Br2*O7 (M+) 680.0807, found 680.0814, calcd
for C31H36Br2*O7 (M+) 682.0787, found 682.0843.
Ack n ow led gm en t. The authors are sincerely grate-
ful to Mr. T. Nakajima (Fujisawa Pharmaceutical Co.,
Ltd.) for referring to the Chemical Abstracts Service file
for the related compounds.
41: IR (CHCl3) 3369, 3013, 2964, 1611, 1488, 1470, 1364,
1255, 1072, and 870 cm-1; 1H NMR δ 1.26 (s, 9H), 4.64 (s, 4H),
4.68 (s, 4H), 4.69 (s, 4H), 7.11 (s, 2H), 7.17 (d, J ) 2.4, 2H),
7.21 (d, J ) 2.4, 2H), 8.08 (s, 1H), 8.59 (s, 2H); HRMS calcd
for C28H32Br2*O7 (M+) 638.0515, found 638.0551, calcd for
Su p p or tin g In for m a tion Ava ila ble: The X-ray crystal-
lographic analysis data for 28 and 34, 1H NMR, IR, MS
spectral, and elemental analysis data of intermediates, 2a ,e-
g, 3a -e,g, 4a -g, 5-21, and 22a -c, and 1H NMR spectra of
3a ,b, 4c,d , 8, 10, 18-21, 22b, and 39-41 lacking elemental
analyses (21 pages). This material is contained in libraries
on microfiche, immediately follows this article in the microfilm
version of the journal, and can be ordered from the ACS; see
any current masthead page for ordering information.
C
28H32Br2*O7 (M+) 640.0494, found 640.0509.
X-r a y Cr ysta llogr a p h ic An a lyses of 28 a n d 34. Crystal
data for 28 (C28H32O6): trigonal, space group P31, a
)
18.6231(7) Å, c ) 12.142(1) Å, V ) 3646.9(4) Å3, Z ) 6, Dcalcd
) 1.269 g cm-3, λ (Cu KR) ) 1.541 78 Å, T ) 298 K, R ) 0.061,
Rw
) 0.088 for 4588 reflections. Crystal data for 34
(C33H42O6): orthorhombic, space group Pna21, a ) 12.986(1)
Å, b ) 28.047(2) Å, c ) 17.130(4) Å, V ) 6238(2) Å3, Z ) 8,
J O971945A