Modification of the upper rim of homooxacalix[3]arenes and complexation between a nitrohomooxacalix[3]arene derivative and n-hexylamine

Article abstract of DOI:10.1021/jo026152p

Several functional groups were introduced on the upper rim of (lower rim free) homooxacalix[3]-arene for the first time. The swinging nitrohomooxacalix[3]arene host 1 was fixed in the cone conformation by complexation with n-hexylamine.

Full text of DOI:10.1021/jo026152p

Mod ifica tion of th e Up p er Rim of Hom ooxa ca lix[3]a r en es a n d
Com p lexa tion betw een a Nitr oh om ooxa ca lix[3]a r en e Der iva tive
a n d n -Hexyla m in e†
Kazunori Tsubaki,* Tadamune Otsubo, Tatsuya Morimoto, Hiromi Maruoka, Mika Furukawa,
Yashima Momose, Muhong Shang, and Kaoru Fuji*
Institute for Chemical Research, Kyoto University, Uji, Kyoto 611-0011, J apan
tsubaki@fos.kuicr.kyoto-u.ac.jp
Received J uly 8, 2002
Several functional groups were introduced on the upper rim of (lower rim free) homooxacalix[3]-
arene for the first time. The swinging nitrohomooxacalix[3]arene host 1 was fixed in the cone
conformation by complexation with n-hexylamine.
In tr od u ction
best of our knowledge, only two papers have been
reported concerning the transformation of functional
groups for lower rim (phenolic hydroxy group) protected
homooxacalix[3]arenes.2g,4f We investigated a stepwise
construction of homooxacalix[3]arenes based on the cy-
clization of the corresponding linear trimers to overcome
those difficulties.1e Although this method is appropriate
to construct homooxacalix[3]arenes bearing different
substituents or functional groups on their upper rims,
the types of functional groups on their upper rims are
limited. Here, we report for the first time the transfor-
mation of functional groups on the upper rim in the
presence of the phenolic hydroxy group on the lower rim
of homooxacalix[3]arenes as well as functions of the
chromogenic nitrohomooxacalix[3]arene receptor 1 (Fig-
ure 1).
Homooxacalix[3]arene is related to calix[4]arene and
18-crown-6 ether with unique structural features, such
as a cavity composed of an 18-membered ring, C3-
symmetry, and a limited number of possible conforma-
tions (i.e., cone and partial cone).1 The most striking
structural difference between homooxacalix[3]arene and
18-crown-6 ether is that homooxacalix[3]arene has a
three-dimensional cavity. These features have awakened
supramolecular chemists to make receptors for metal
cations,2 ammonium cations,3 and fullerene derivatives.4
Due to the presence of three fragile dibenzyl etheral
linkages, many difficulties, however, arose in the trans-
formation of functional groups on the upper rim. To the
† Dedicated to Emeritus Professor Soichi Misumi on the occasion of
his 77th birthday.
(1) For reviews on oxacalixarene, see: (a) Ibach, S.; Prautzsch, V.;
Vo¨gtle, F.; Chartroux, C.; Gloe, K. Acc. Chem. Res. 1999, 32, 2. 729-
740. (b) Dhawan, B.; Gutsche, C. D. J . Org. Chem. 1983, 48, 1536-
1539. (c) Zerr, P.; Mussrabi, M.; Vicens, J . Tetrahedron Lett. 1991, 32,
1879-1880. (d) Hampton, P. D.; Bencze, Z.; Tong, W.; Daitch, C. E. J .
Org. Chem. 1994, 59, 4838-4843. (e) Tsubaki, K.; Otsubo, T.; Tanaka,
K.; Fuji, K.; Kinoshita, T. J . Org. Chem. 1998, 63, 3260-3265. (f)
Tsubaki, K.; Mukoyoshi, K.; Otsubo, T.; Fuji, K. Chem. Pharm. Bull.
2000, 48, 882-884. (g) Masci, B. J . Org. Chem. 2001, 66, 1497-1499.
(h) Masci, B. Tetrahedron 2001, 57, 2841-2845. (i) Ashram, M.;
Mizyed, S.; Georghiou, P. E. J . Org. Chem. 2001, 66, 1473-1479. (j)
Komatsu, N.; Chishiro, T. J . Chem. Soc., Perkin Trans. 1 2001, 1532-
1537.
(2) (a) Araki, K.; Hashimoto, N.; Otsuka, H.; Shinkai, S. J . Org.
Chem. 1993, 58, 5958-5963. (b) Araki, K.; Inada, K.; Otsuka, H.;
Shinkai, S. Tetrahedron 1993, 49, 9465-9478. (c) Matsumoto, H.;
Nishio, S.; Takeshita, M.; Shinkai, S. Tetrahedron 1995, 51, 4647-
4654. (d) Daitch, C. E.; Hampton, P. D.; Duesler, E. N.; Alam, T. A. J .
Am. Chem. Soc. 1996, 118, 7769-7773. (e) Ohkanda, J .; Shibui, H.;
Katoh, A. Chem. Commun. 1998, 375-376. (f) Yamato, T.; Haraguchi,
M.; Nishikawa, J .; Ide, S.; Tsuzuki, H. Can. J . Chem. 1998, 76, 989-
996. (g) Araki, K.; Hayashida, H. Tetrahedron Lett. 2000, 41, 1807-
1810.
Resu lts a n d Discu ssion
Im p r oved Syn t h et ic R ou t e for Lin ea r Tr im er s.
The synthetic route for key intermediates (11a and 11b)
is depicted in Scheme 1. 11a and 11b were prepared from
the corresponding linear trimers 10a and 10b by the
previously reported method.1e The synthetic routes of the
linear trimers were modified as follows: (1) On the basis
of recent work of Crisp et al.,5 nitrobenzyl alcohol 5 was
synthesized through the Mannich reaction. (2) Benzyl
bromide 9 was afforded from benzyl alcohol 8 by meth-
anesulfonylation and bromination instead of using PPh3
and CBr4.
(4) (a) Ikeda, A.; Yoshimura, M.; Shinkai, S. Tetrahedron Lett. 1997,
38, 2107-2110. (b) Ikeda, A.; Suzuki, Y.; Yoshimura, M.; Shinkai, S.
Tetrahedron 1998, 54, 2497-2508. (c) Tsubaki, K.; Tanaka, K.; Fuji,
K.; Tanaka, K.; Kinoshita, T. Chem. Commun. 1998, 895-896. (d)
Atwood, J . L.; Barbour, L. J .; Nichols, P. J .; Raston, C. L.; Sandoval,
C. A. Chem.-Eur. J . 1999, 5, 990-996. (e) Ikeda, A.; Yoshimura, M.;
Udzu, H.; Fukuhara, C.; Shinkai, S. J . Am. Chem. Soc. 1999, 121,
4296-4297. (f) Ikeda, A.; Nobukuni, S.; Udzu, H.; Zhong, Z.; Shinkai,
S. Eur. J . Org. Chem. 2000, 3287-3293. (g) Ikeda, A.; Hatano, T.;
Shinkai, S.; Akiyama, T.; Yamada, S. J . Am. Chem. Soc. 2001, 123,
4855-4856. (h) Mizyed, S.; Ashram, M.; Miller, D. O.; Georghiou, P.
E. J . Chem. Soc., Perkin Trans. 2 2001, 1916-1919.
(3) (a) Takeshita, M.; Shinkai, S. Chem. Lett. 1994, 125-128. (b)
Masci, B. Tetrahedron 1995, 51, 5459-5464. (c) Takeshita, M.;
Inokuchi, F.; Shinkai, S. Tetrahedron Lett. 1995, 36, 3341-3344. (d)
Araki, K.; Inada, K.; Shinkai, S. Angew. Chem., Int. Ed. Engl. 1996,
35, 72-74. (e) Odashima, K.; Yagi, K.; Tohda, K.; Umezawa, Y. Bioorg.
Med. Chem. Lett. 1999, 9, 2375-2378. (f) Ikeda, A.; Udzu, H.; Zhong,
Z.; Shinkai, S.; Sakamoto, S.; Yamaguchi, K. J . Am. Chem. Soc. 2001,
123, 3872-3877. (g) Tsubaki, K.; Otsubo, T.; Kinoshita, T.; Kawada,
M.; Fuji, K. Chem. Pharm. Bull. 2001, 49, 507-509.
(5) Crisp. G. T.; Turner, P. D. Tetrahedron 2000, 56, 407-415.
10.1021/jo026152p CCC: $22.00 © 2002 American Chemical Society
Published on Web 10/22/2002
J . Org. Chem. 2002, 67, 8151-8156
8151

Tsubaki et al.
SCHEME 2a
F IGURE 1. Homooxacalix[3]arenes and hosts 1 and 2.
SCHEME 1a
a
Reaction conditions: (a) NaH, MeI; (b) Pd(OAc)2, PPh3,
HCO2H, triethylamine; (c) dimethylamine, formalin, acetic acid
then methyl iodide; (d) NaCN; (e) NaN3; (f) sodium methoxide; (g)
potassium phthalimide; (h) imidazole; (i) NH4NO3, acetic anhy-
dride.
activated phenyl acetate part was selectively removed by
DMAP and methanol followed by protection with a MOM
group and hydrolysis of acetate on both sides with sodium
hydroxide to give the nitrobenzyl alcohol 5 in 62% overall
yield. The phenolic hydroxy group of bis(hydroxymethyl)-
phenol 61e was protected by allyl bromide followed by
chlorination of benzylic alcohols with thionyl chloride to
produce dibenzyl chloride 7 in 63% yield in two steps.
On the other hand, benzyl alcohol 81e was treated with
methanesulfonyl chloride followed by bromination with
lithium bromide to give benzyl bromide 91e in 61% yield.
Reaction of 5 and benzyl bromide 9 provided the linear
trimer 10a in 65% yield. The key nitrohomooxacalix[3]-
arene 11a was synthesized from the linear trimer 10a
by a previously reported procedure in 55% yield.1e Benzyl
alcohol 8 was treated with sodium hydride followed by
condensation with dibenzyl chloride 7 to give the corre-
sponding linear trimer 10b in 98% yield. After deprotec-
tion of the allyl group in 10b by palladium and sodium
borohydride,6 10b was converted to another key bromo-
homooxacalix[3]arene 11b1e in 51% yield.
Up p er Rim F u n ction a liza tion . Several functional
group transformations on the upper rim of key homo-
oxacalix[3]arenes 11a and 11b were examined (Scheme
2). Selective debromination of 11b in the presence of the
dibenzyl ether part was accomplished under formic acid
reduction conditions to give 12 in 94% yield.7 In the field
of calixarene chemistry, the p-quinone methide or Man-
nich route is one of the most useful functionalization
a
Reaction conditions: (a) formalin, morpholine; (b) acetic
anhydride; (c) DMAP, MeOH; (d) K2CO3, MOMCl; (e) NaOH; (f)
allyl bromide, K2CO3; (g) thionyl chloride; (h) MsCl, triethylamine;
(i) LiBr; (j) NaH; (k) HClO4; (l) PdCl2(PPh3)2, NaBH4.
4-Nitrophenol (3) was treated with morpholine and
formalin in acetic acid to form bis(morpholinomethyl)-
phenol, and then the crude Mannich base was converted
to its triacetate 4 in 78% overall yield in two steps. The
(6) (a) Beugelmans, R.; Bourdet, S.; Bigot, A.; Zhu, J . Tetrahedron
Lett. 1994, 35, 4349-4350. (b) Bois-Choussy, M.; Neuville, L.; Beugel-
mans, R.; Zhu, J . J . Org. Chem. 1996, 61, 9309-9322.
(7) Cacchi, S.; Ciattini, P. G.; Morera, E.; Ortar, G. Tetrahedron Lett.
1986, 27, 5541-5544.
8152 J . Org. Chem., Vol. 67, No. 23, 2002

Modification of the Upper Rim of Homooxacalix[3]arenes
F IGURE 2. X-ray structure of host 1 (stereoview). Hydrogen
atoms are excluded for clarity.
methods on the upper rim.8 Thus, we investigated the
Mannich reaction on homooxacalix[3]arene 12. The cor-
responding Mannich base could be easily prepared by
treatment of 12 with formalin and dimethylamine in
acetic acid at 80 °C and then converted to the trimethyl
quaternary ammonium salt followed by treatment with
various nucleophiles to produce substituted homooxacalix-
[3]arenes 13-17. Because of the difficulty of purification
of the Mannich base due to its zwitterionic character,
introduction of functional groups on the upper rim was
achieved by successive reactions from 12 (i.e., the Man-
nich reaction, exhaustive methylation, p-quinone methide
formation, and nucleophilic substitution). The transfor-
mations on the upper rim were adapted to O-, N-, and
C-nucleophiles, and the desired products were obtained
in moderate overall yields in four steps. The nucleophiles
and yields of functional group transformations are as
follows: sodium cyanide (13, 59% yield), sodium azide
(14, 57% yield), sodium methoxide (15, 55% yield),
potassium phthalimide (16, 57% yield), imidazole (17,
45% yield). Transformations other than the Mannich
reaction route on the upper rim have not been effective.
For example, nitration at the para position of 12 took
place in very low yields (16% yield, from 12 to 11a );
therefore, we synthesized 11a by a stepwise route vide
supra.
Nitrohomooxacalix[3]arene 11a is an especially attrac-
tive candidate compound from the perspective of host-
guest chemistry because the nitrophenol part itself has
chromogenic character and could potentially be converted
to other chromogenic moieties such as an azophenol.9 Due
to their strong intramolecular hydrogen-bonding net-
work,1e,10 lower rim free homooxacalix[3]arenes have a
negligible affinity for cations; therefore, we have designed
host molecule 1 such that two methyl groups are selec-
tively introduced on p-tert butylphenolic oxygens. Nitro-
homooxacalix[3]arene 11a was treated with methyl iodide
(10 equiv) and sodium hydride (10 equiv) to produce host
1 in 67% yield. The structure of host 1 was confirmed by
the results of X-ray analysis (Figure 2). On account of
cutting off the intramolecular hydrogen-bonding network
among three phenolic hydroxy groups by replacement of
two methyl groups, the conformation of 1 should be
predominantly inclined to the partial cone. This is the
first example that swinging homooxacalix[3]arene is fixed
in the partial cone conformation in the solid state.
F IGURE 3. 1H NMR (400 MHz) spectra of (a) n-hexylamine,
(b) n-hexylamine hydrochloride, (c) 1:1 mixture of host 1 and
n-hexylamine, [host 1] ) [n-hexylamine] ) 6.6 × 10-2 M, and
(d) host 1 in CDCl3 at -20 °C (for b) or -40 °C (for a, c, and
d).
Com p lexa tion w ith n -Hexyla m in e in Solu tion .
Although some examples of the complexation between
cone and/or partial cone fixed homooxacalix[3]arenes and
ammonium ions have been reported,3a,c,d it is interesting
to investigate the mode of complexation between swing-
ing homooxacalix[3]arenes and amine/ammonium guest
molecules. Therefore, we chose host 1 and n-hexylamine,
and the complexation between them was investigated.
With the addition of n-hexylamine to a solution of host 1
at 25.0 °C, the absorption at around 410 nm was
gradually increased. Association constants (Ka) between
host 1 and n-hexylamine in various solvents at 25 °C
were determined by UV-vis titration and analyzed by
the Rose-Drago method.11 The association constants
are: Ka ) 251 ( 2 (chloroform), Ka ) 1116 ( 6 (metha-
nol), Ka ) 133 ( 1 (THF), Ka ) 627 ( 17 (acetonitrile),
Ka > 105 (DMSO). Association constants are affected by
the acidity of nitrophenolic OH of host 1 and by the
degree of stabilization of the generated phenolate/am-
monium ionic host-guest complex with solvents. With
the exception of DMSO, it was actually observed that
association constants roughly correlated to the ET(30)
values that are used as empirical parameters of solvent
polarities.12
(8) For reviews on calixarenes, see: (a) Gutsche, C. D. Calixarenes;
The Royal Society of Chemistry: Cambridge; 1989. (b) Gutsche, C. D.
Calixarenes Revisited; The Royal Society of Chemistry: Cambridge;
1998. (c) Gutsche, C. D.; Nam, K. C. J . Am. Chem. Soc. 1988, 110,
6153-6162.
(9) We recently reported a homooxacalix[3]arene possessing pyri-
dinium N-phenolate dye (Reichardt dye ET1). Tsubaki, K.; Morimoto,
T.; Otsubo, T.; Fuji, K. Org. Lett. 2002, 4, 2301-2304.
(10) Suzuki, K.; Minami, H.; Yamagata, Y.; Fujii, S.; Tomita, K.;
Asfari, Z.; Vicens, J . Acta Crystallogr. Sect. C: Cryst. Struct. Commun.
1992, C48, 350-352.
To understand the mode of complexation, NMR studies
of 1 and n-hexylamine were carried out (Figure 3).
(11) (a) Rose, N. J .; Drago, R. S. J . Am. Chem. Soc. 1959, 81, 6138-
6145. (b) Hirose, K. J . Inclusion Phenom. 2001, 39, 193-209.
(12) Reichardt, C. Angew. Chem., Int. Ed. Engl. 1979, 18, 98-110.
J . Org. Chem, Vol. 67, No. 23, 2002 8153

Tsubaki et al.
TABLE 1. 1H-CIS Va lu es (p p m ) for n -h exyla m m on iu m
Ca tion u p on Com p lexa tion w ith Hosts 1 a n d 2a
host
NH R-CH2 â-CH2 γ-CH2 δ-CH2 ꢀ-CH2 ú-CH3
1b
-2.23 -2.42 -1.93 -1.05 -0.72 -0.39 -0.21
-2.23 -2.82 -2.08 -1.06 -0.56 -0.38 -0.20
-1.24 -1.08 -0.62d -0.37 -0.09d -0.12d -0.04
cone-2c
partial
cone-2c
a
400 MHz 1H NMR spectra in CDCl3. 1H-CIS (complexation-
induced shifts) ) δ (complex) - δ (guest)). b 1H-CIS values were
calculated based on a set of chemical shifts of n-hexylamine
hydrochloride as guest.13 c Association constant is estimated. See
d
ref 13. Peaks are not resolved; therefore, CIS values are esti-
mated by cross-peaks of the corresponding COSY spectrum.
F IGURE 4. Proposed possible complex structures.
Shinkai and co-workers reported that ring inversion of
homooxacalix[3]arene occurred through the oxygen-
through-the-annulus rotation and that cone/partial cone
ring inversion was allowed for O-trimethylated homooxa-
calix[3]arene.2b In fact, in the 1H NMR spectrum of 1 even
at -40 °C, the signals of the methoxy protons are a
singlet and those of benzylic protons composed 18-
membered ring are also a (broad) singlet. This result
indicates that the ring inversion is faster than the NMR
time scale (Figure 3d). In contrast, a drastic change was
observed in the mixture of 1 and n-hexylamine in a 1:1
ratio, as the signals ascribed to n-hexylamine were
dramatically shifted to higher magnetic field (Figure 3c).
1
The H-CIS (complexation-induced shifts ) δ (complex)
- δ (guest)) values of guest n-hexylamine are sum-
marized in Table 1. The magnitude of higher magnetic
shifts of guest signals grows fainter with increasing
distance from the amino group. On the basis of these
observations, it is clear that the amino group approaches
the π-cavity composed of the aromatic rings of host 1.
Furthermore, the benzylic protons on the 18-membered
ring of host 1 changed from a broad singlet to three (not
six) AB quartets in a ratio of 1:1:1. Thus, the flexible
homooxacalix[3]arene skeleton should be fixed to one
symmetric conformation by complexation through n-
hexylamine. Among the possible complexes, the following
two candidates could be proposed. Complex A: the guest
amine approaches the cone shape 1 from the upper rim
side. Complex B: the guest amine approaches the
inverted nitrophenol part of the partial cone shape 1 from
the tert-butyl substituent side (Figure 4).
Since NOESY and ROESY spectra did not provide any
useful information concerning the shape of the complex,
the CIS values of host 1 and n-hexylamine were com-
pared with those of the cone or partial cone fixed
homooxacalix[3]arenes 2 and n-hexylamine hydrochlo-
ride.2c,3a,d The 1H NMR charts between the cone and
partial cone-2 and n-hexylamine hydrochloride are shown
in Figure 5, and the CIS values are also given in Table
1. Taking together, the behavior of host 1 and n-
hexylamine is very similar to that of cone-2 and n-
hexylamine hydrochloride. Thus, these data clearly in-
F IGURE 5. 1H NMR (400 MHz) spectra of (a) partial cone 2,
(b) 1:1 mixture of partial cone 2 and n-hexylamine hydrochlo-
ride, [partial cone 2] ) [n-hexylamine hydrochloride] ) 5.4 ×
10-2 M (c) n-hexylamine hydrochloride, (d) 1:1 mixture of cone
2 and n-hexylamine hydrochloride, [cone 2] ) [n-hexylamine
hydrochloride] ) 7.1 × 10-2 M, and (e) cone 2 in CDCl3 at
-20 °C (for c, d, and e) or -40 °C (for a and b).
dicate that the guest amine approaches the cone shape
1 from the upper rim side (Figure 4, complex A).
In this study, the upper rim functionalization of
homooxacalix[3]arene was achieved through the Mannich
route. This method should be suitable for synthesis of
more functionalized homooxacalix[3]arene derivatives.
Furthermore, the determination of the mode of complex-
ation between host 1 and primary amines should be a
base for the development of more complicated host-guest
systems.
(13) Due to the host-guest exchange rate is very slow compared to
the NMR time scale, NMR spectrum of the mixture of host and guest
gives peaks for host, guest, and complex separately. Therefore, the
association constant can be estimated on the basis of the integration
of the corresponding peaks. The association constants are: Ka ) 1.1 ×
104 mol-1 (cone 2 and n-hexylamine hydrochloride, CDCl3, -40 °C).
Ka > 9 × 104 mol-1 (partial cone 2 and n-hexylamine hydrochloride,
CDCl3, -40 °C, Even in the mixture of partial cone 2 (1.0 × 10-3 M)
and n-hexylamine (1.0 × 10-3 M), only the peaks ascribed to the host-
guest complex were observed).
Exp er im en ta l Section
Gen er a l Meth od s. Melting points are uncorrected. Nuclear
magnetic resonance (NMR) spectra were taken at 200 MHz
8154 J . Org. Chem., Vol. 67, No. 23, 2002

Modification of the Upper Rim of Homooxacalix[3]arenes
with chemical shifts being reported as δ ppm from tetrameth-
of ethyl acetate and water. The organic layer was separated,
washed successively with water, and brine. The organic layer
was dried over magnesium sulfate and evaporated in vacuo.
The residue was purified by column chromatography (SiO2,
n-hexane/ethyl acetate ) 10/1) to afford 9 as a white powder
(8.93 g, 61% yield). The characterization data are reported.1e
ylsilane as an internal standard.
4. Mannich base was prepared from nitrophenol (3) accord-
ing to the procedure of Crisp.5 A solution of nitrophenol (3)
(25.0 g, 180 mmol) and morpholine (36 mL, 413 mmol) in acetic
acid (36 mL) and formalin (45 mL) was stirred for 18 h at 80
°C. Solvent was evaporated under reduced pressure to give a
residue. The residue was dissolved in acetic anhydride (300
mL), and the mixture was stirred for 23 h at 100 °C. The
solvent was evaporated in vacuo, and the residue was directly
purified by column chromatography (SiO2, n-hexane/ethyl
acetate ) 2/1) followed by recrystallization from ethyl acetate
and n-hexane to afford 4 as pale yellow needles (36.7 g, 63%
yield). Additional 4 (8.5 g, 15% yield) was obtained from the
mother liquors: mp 74-75 °C (from ethyl acetate/n-hexane);
10a . To a solution of 5 (1.63 g, 6.7 mmol) in DMF (35 mL)
and THF (10 mL) was added portionwise sodium hydride (60%
mineral oil dispersion, 1.10 g, 26.7 mmol), and the reaction
mixture was stirred for 15 min at 0 °C. A solution of 9 (4.4 g,
14 mmol) in THF (5 mL) was added dropwise to the reaction
mixture. After being stirred for 1 h at room temperature, the
mixture was poured into the mixed solvent of ethyl acetate
and water. The organic layer was separated and washed
successively with water and brine. The organic layer was dried
over magnesium sulfate and evaporated in vacuo. The residue
was purified by column chromatography (SiO2, n-hexane/ethyl
acetate ) 10/1) to afford 10a as a pale yellow oil (3.03 g, 65%
yield): IR (neat) 2960, 2865, 1739, 1594, 1526 cm-1; 1H NMR
(200 MHz, CDCl3) δ 1.29 (s, 18H), 1.54 (s, 12H), 3.52 (s, 3H),
4.62 (s, 4H), 4.67 (s, 4H), 4.85 (s, 4H), 5.07 (s, 2H), 6.93 (d,
J ) 2.4 Hz, 2H), 7.31 (d, J ) 2.4 Hz, 2H), 8.35 (s, 2H); HRMS
calcd for C40H53NO10 (M+), 707.3670, found 707.3661. Anal.
Calcd for C40H53NO10: C, 67.87; H, 7.55; N, 1.98. Found: C,
67.58; H, 7.48; N, 1.79
IR (KBr) 3071, 1740, 1539, 1352, 1242 cm-1 1H NMR (200
;
MHz, CDCl3) δ 2.13 (s, 6H), 2.41 (s, 3H), 5.10 (s, 4H), 8.33 (s,
2H); HRMS calcd for C14H15NO8 (M+) 325.0798, found 325.0802.
Anal. Calcd for C14H15NO8: C, 51.70; H, 4.65; N, 4.31. Found:
C, 51.64; H, 4.60; N, 4.28
5. To a mixture of 4 (32.5 g, 100 mmol) and 4-(dimethy-
lamino)pyridine (610 mg, 5 mmol) in DMF (150 mL) were
added methanol (8.0 mL, 200 mmol) and potassium carbonate
(27.6 g, 200 mmol), and the mixture was stirred for 4 h at room
temperature. Chloromethyl methyl ether (15.2 mL, 200 mmol)
was added to the reaction mixture and stirred for 39 h at room
temperature. Chloromethyl methyl ether (8.0 mL, 107 mmol)
and potassium carbonate (13.0 g, 94 mmol) were added, and
the reaction mixture was stirred for a further 1.5 h. Aqueous
sodium hydroxide solution (2.5 M, 300 mL) was added and the
mixture stirred for 5 h. The precipitate was collected by
filtration, washed with water, and air dried at room temper-
ature to afford 5 (15.0 g, 62% yield): mp 125-126 °C (from
10b. A solution of 8 (25.0 g, 100 mmol) in THF (100 mL)
was added dropwise to a suspension of sodium hydride (60%
mineral oil, 6.0 g, 150 mmol) in THF (50 mL) at 0 °C. A
solution of 7 (35.5 g, 50 mmol) in DMF (150 mL) was added to
the reaction mixture and stirred for 17 h. The mixture was
poured into the mixed solvent of ethyl acetate and water. The
organic layer was separated and washed successively with
water (twice) and brine. The organic layer was dried over
sodium sulfate and evaporated in vacuo. The residue was
purified by column chromatography (SiO2, n-hexane/ethyl
acetate ) 4/1) to afford 10b as pale yellow oil (36.2 g, 98%
yield): IR (CHCl3) 2964, 2253, 1485, 1375 cm-1; 1H NMR (200
MHz, CDCl3) δ 1.28 (s, 18H), 1.54 (s, 12H), 4.35 (ddd, J ) 5.6,
1.6, 1.6 Hz, 2H), 4.58 (s, 4H), 4.60 (s, 4H), 4.84 (s, 4H), 5.21
(ddt, J ) 10.3, 1.6, 1.6 Hz, 1H), 5.33 (ddt, J ) 17.2, 1.6, 1.6
Hz, 1H), 5.99 (ddt, J ) 17.2, 10.3, 5.6 Hz, 1H), 6.92 (d, J ) 2.2
Hz, 2H), 7.30 (d, J ) 2.2 Hz, 2H), 7.57 (s, 2H); HRMS calcd
for C41H53Br79O7 (M+) 736.2975, found 736.2979; calcd for
toluene-ethanol); IR (KBr) 3385, 2933, 1523, 1439, 1349 cm-1
;
1H NMR (200 MHz, DMSO) δ 3.51 (s, 3H), 4.63 (d, J ) 5.2
Hz, 4H), 5.08 (s, 2H), 5.52 (t, J ) 5.2 Hz, 2H), 8.23 (s, 2H);
HRMS calcd for C10H13NO6 (M+) 246.0742, found 243.0742.
Anal. Calcd for C10H13NO6: C, 49.38; H, 5.39; N, 5.76. Found:
C, 49.45; H, 5.42; N, 5.69.
7. Allyl bromide (10.3 mL, 119 mmol) was dropwise added
to a mixture of 6 (25.0 g, 107 mmol) and potassium carbonate
(22.0 g, 159 mmol) in DMF (120 mL) at 0 °C. The mixture
was stirred for 24 h and poured into the mixed solvent of ethyl
acetate and water. The organic layer was separated and
washed successively with water (twice) and brine. The organic
layer was dried over sodium sulfate and evaporated in vacuo
to give a residue as white powder. Thionyl chloride (23.0 mL,
315 mmol) was dropwise added to a solution of the residue in
DMF (1 mL) and dichloromethane (200 mL) at 0 °C. The
mixture was stirred for 17 h at room temperature. The solvent
was evaporated in vacuo, and the residue was directly purified
by column chromatography (SiO2, n-hexane/ethyl acetate )
10/1) to afford 7 as a white powder (21.0 g, 63% yield for two
steps): mp 90-92 °C (white needle from n-hexane); IR (CHCl3)
3155, 2253, 1793, 1466, 1381 cm-1; 1H NMR (200 MHz, CDCl3)
δ 4.55 (ddd, J ) 5.3, 1.3,1.3 Hz, 2H), 4.59 (s, 4H), 5.34 (ddt,
J ) 10.5, 1.3, 1.3 Hz, 1H), 5.49 (ddt, J ) 17.2, 1.3, 1.3 Hz,
1H), 6.12 (ddt, J ) 17.2, 10.5, 5.3 Hz, 1H), 7.55 (s, 2H); HRMS
calcd for C11H11Br79Cl352O (M+) 307.9371, found 307.9371; calcd
for C11H11Br79Cl35Cl37O (M+) 309.9341, found 309.9329; calcd
for C11H11Br81Cl352O (M+) 309.9350, found 309.9368; calcd for
C
41H53Br81O7 (M+) 738.2954, found 738.2964.
11a . Sta r tin g fr om 10a . Compound 11a was synthesized
from the corresponding linear trimer 10a by reported proce-
dure (55% yield):1e mp 159-160 °C; IR (KBr) 3301, 2961, 1602,
1
1523, 1489 cm-1; H NMR (200 MHz, CDCl3) δ 1.26 (s, 18H),
4.75 (s, 12H), 7.14 (d, J ) 2.6 Hz, 2H), 7.16 (d, J ) 2.6 Hz,
2H), 8.07 (s, 2H), 8.39 (s, 2H), 9.83 (s, 1H); HRMS calcd for
C
C
32H39NO8 (M+) 565.2675, found 565.2673. Anal. Calcd for
32H39NO8: C, 67.95; H, 6.95; N, 2.48. Found: C, 67.81; H,
6.96; N, 2.52
Sta r tin g fr om 12. To a solution of homooxacalix[3]arene
12 (97 mg, 0.19 mmol) in acetic anhydride (2.0 mL) was added
ammonium nitrate (16 mg, 0.20 mmol) under nitrogen atmo-
sphere and the mixture stirred for 5 h at 60 °C. Aqueous
sodium hydrogen carbonate solution was carefully added to
the reaction mixture at 0 °C and extracted with ethyl acetate
(three times). The organic layers were collected and washed
with brine and evaporated in vacuo. The residue was purified
by PTLC (n-hexane/ethyl acetate ) 9/1) to afford 11a (17 mg,
16% yield).
C
C
11H11Br79Cl352O (M+) 311.9312, found 311.9323; calcd for
11H11Br81Cl35Cl37O (M+) 311.9321, found 311.9323. Anal.
11b.1e Sodium borohydride (1.8 g, 47.4 mmol) was added to
a mixture of 10b (35.0 g, 47.4 mmol) and dichlorobis(triphen-
ylphosphine)palladium (350 mg, 0.7 mmol) in THF (150 mL)
and stirred for 10 h at room temperature. The solvent was
evaporated, and the residue was dissolved in ethyl acetate.
The organic layer was washed successively with hydrochloric
acid (twice), water, and brine. The organic layer was dried over
sodium sulfate and evaporated in vacuo to give crude depro-
tection of the allyl group derivative [ca. 34 g; 1H NMR (200
Calcd for C11H11BrCl2O: C, 42.64; H, 3.58. Found: C, 42.80;
H, 3.50.
9.1e To a solution of 81e (10.0 g, 39.9 mmol) and triethylamine
(23 mL, 160 mmol) in ethyl acetate (300 mL) was added
methanesulfonyl chloride (6.2 mL, 80 mmol) dropwise at 0 °C.
After 2 h, white precipitate was filtered off, and LiBr‚H2O (42
g, 399 mmol) and DMF (100 mL) were added to the filtrate.
The reaction mixture was stirred for 30 min at room temper-
ature. The reaction mixture was poured into the mixed solvent
J . Org. Chem, Vol. 67, No. 23, 2002 8155

Tsubaki et al.
MHz, CDCl3) δ 1.28 (s, 18H), 1.56 (s, 12H), 4.58 (s, 4H), 4.66
(s, 4H), 4.85 (s, 4H), 6.93 (d, J ) 2.6 Hz, 2H), 7.25 (d, J ) 2.6
Hz, 2H), 7.30 (s, 2H), 7.89 (s, 1H)]. The residue (5.0 g) was
converted to 11b by reported procedure (51% yield).1e The
characterization data were also reported.
(s, 2H), 4.70 (s, 4H), 4.72 (s, 4H), 4.73 (s, 4H), 7.07 (s, 2H),
7.13 (d, J ) 2.4 Hz, 2H), 7.14 (d, J ) 2.4 Hz, 2H), 8.50 (s, 2H),
8.92 (s, 1H); HRMS calcd for C34H41NO6 (M+), 559.2933 found
559.2939. Anal. Calcd for C34H41NO6: C, 72.96; H, 7.38; N,
2.50. Found: C, 72.80; H, 7.46; N, 2.47.
12. A mixture of bromohomooxacalix[3]arene 11b (7.0 g, 11.7
mmol), palladium acetate (50 mg, 0.2 mmol), triphenylphos-
phine (125 mg, 0.5 mmol), and formic acid (0.95 mL, 25.2
mmol) in triethylamine (5.0 mL) and DMF (25.0 mL) was
stirred for 7.5 h at 50 °C under nitrogen atmosphere. The
mixture was poured into ethyl acetate and washed successively
with hydrochloric acid, water (twice), and brine. The organic
layer was dried over sodium sulfate and evaporated in vacuo.
The residue was purified by column chromatography (SiO2,
n-hexane/ethyl acetate ) 6/1) to afford 12 (5.71 g, 94% yield).
The characterization data were reported.1e
14: 57% yield from 12 and sodium azide. 15: 55% yield from
12 and sodium methoxide. 16: 57% yield from 12 and
potassium phthalimide. 17: 45% yield from 12 and imidazole.
Host 1. To a solution of homooxacalix[3]arene 11a (100 mg,
0.18 mmol) in DMF (1.0 mL) was added sodium hydride (60%
mineral oil dispersion, 77 mg, 1.8 mmol) and the mixture
stirred for 10 min at 0 °C. Methyl iodide (0.11 mL, 1.8 mmol)
was added to the reaction mixture, and the reaction mixture
was stirred for 40 min at 0 °C. The mixture was poured into
the mixed solvent of ethyl acetate and hydrochloric acid. The
organic layer was separated and washed successively with
water (twice) and brine. The organic layer was dried over
magnesium sulfate, and evaporated in vacuo. The residue was
purified by PTLC (n-hexane/ethyl acetate ) 5/1) to afford 1
(70 mg, 67% yield) as a white powder: mp 205-209 °C (from
ethyl acetate); IR (KBr) 3334, 1600, 1521 cm-1; 1H NMR (200
MHz, CDCl3) δ 1.33 (s, 18H), 3.33 (s, 6H), 4.52 (s, 4H), 4.56 (s,
4H), 4.58 (s, 4H), 7.30 (d, J ) 2.4 Hz, 2H), 7.46 (d, J ) 2.4 Hz,
2H), 8.12 (s, 2H) 8.36 (s, 1H); HRMS calcd for C34H43NO8 (M+)
593.2988, found 593.2969. Anal. Calcd for C34H43NO8: C,
68.78; H, 7.30; N, 2.36. Found: C, 68.76; H, 7.41; N, 2.27
F u n ct ion a liza t ion on Up p er R im t h r ou gh Ma n n ich
Rea ction . The preparation of 13 is typical. A solution of
dimethylamine (40% in water, 13.0 mL) and formalin (37% in
water, 8.0 mL) in acetic acid (7.0 mL) was stored for overnight
as a stock solution. A solution of 12 (1.0 g, 1.92 mmol) and
the stock solution (4.0 mL) in acetic acid (6.0 mL) was stirred
for 17 h at 80 °C. The mixture was poured into ethyl acetate
and washed successively with aqueous sodium hydrogen
carbonate solution, water (twice), and brine. The organic layer
was dried over sodium sulfate and evaporated in vacuo to give
a residue (1.4 g). Methyl iodide (179 µL) was added to a
solution of the residue (1.4 g) in DMSO (10 mL) and stirred
for 40 min at room temperature. Sodium cyanide (470 mg) was
added to the solution and stirred for 4 h at 50 °C. The mixture
was poured into ethyl acetate and washed successively with
sodium hydrogen carbonate solution, water (twice), and brine.
The organic layer was dried over sodium sulfate and evapo-
rated in vacuo. The residue was purified by column chroma-
tography (SiO2, n-hexane/ethyl acetate ) 4/1) to afford 13 as
pale yellow powder (680 mg, 59% yield): mp 198-199 °C
(white powder from Et2O); IR (CHCl3) 3358, 1488, 1220, 1209,
Su p p or tin g In for m a tion Ava ila ble: Characterization
data for 14-17. 1H NMR spectra for compounds 10b, 11a , 13-
17, and Figures 3a-d and 5a-e. COSY spectra for n-hexyl-
amine hydrochloride, host
1 + n-hexylamine, cone 2 +
n-hexylamine hydrochloride, and partial cone 2 + n-hexyl-
amine hydrochloride. Crystallographic information file (CIF)
of host 1. This material is available free of charge via the
Internet at http://pubs.acs.org.
1
1076 cm-1; H NMR (200 MHz, CDCl3) δ 1.25 (s, 18H), 3.62
J O026152P
8156 J . Org. Chem., Vol. 67, No. 23, 2002