En route to inherently chiral tetraoxacalix[2]arene[2]triazines

Article abstract of DOI:10.1016/j.tet.2007.05.129

This paper describes our attempts to synthesize inherently chiral heteroatom-bridged calixaromatics. Based on a stepwise fragment-coupling approach using a chiral 3,5-dihydroxybenzamide or benzoate, 2,4-dihydroxyacetophenone, and cyanuric chloride as reac

Full text of DOI:10.1016/j.tet.2007.05.129

Tetrahedron 63 (2007) 10801–10808
En route to inherently chiral tetraoxacalix[2]arene[2]triazines
*
Bao-Yong Hou, Qi-Yu Zheng, De-Xian Wang and Mei-Xiang Wang
Beijing National Laboratory for Molecular Sciences, Laboratory of Chemical Biology, Institute of Chemistry,
Chinese Academy of Sciences, Beijing 100080, China
Received 25 April 2007; revised 26 May 2007; accepted 30 May 2007
Available online 20 July 2007
Abstract—This paper describes our attempts to synthesize inherently chiral heteroatom-bridged calixaromatics. Based on a stepwise frag-
ment-coupling approach using a chiral 3,5-dihydroxybenzamide or benzoate, 2,4-dihydroxyacetophenone, and cyanuric chloride as reactants,
chiral tetraoxacalix[2]arene[2]triazine derivatives 16 and 17 were synthesized in good yields. Subsequent macrocyclic condensation with a
diamine 6 furnished efficiently the pairs of diastereomers of inherently chiral tetraoxacalix[2]arene[2]triazine azacrowns 18 and 19.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
configurations, and can have different degrees of conjuga-
tion with adjacent aromatic rings. These features can give
rise to slight variations in both the bond lengths and the
bond angles, yielding a range of macrocycles of varied
conformational structures and of different size. This has
been well demonstrated7a,k by aza- and/or oxacalix[2]-
arene[2]triazines, which give a series of differently sized
macrocyclic molecules. Furthermore, heteroatom-bridged
calixaromatics are fluxional in solution and interconversion
of conformers is rapid. This flexibility allows the host mole-
cules to self-regulate their conformation and cavity struc-
ture in order to achieve strongest interaction with the guest
species in presence.8d–f For example, when treated with dif-
ferent acids,8e mono- and diols,10 azacalix[4]pyridine was
found to adjust its conformational structure to form stable
inclusion complexes.
Owing to their easy availability, interesting conformational
and cavity structures, and versatile recognition properties
and functions, calix[n]arenes constitute an important and
indispensable tool of supramolecular chemistry.1 While
development of the synthesis of diverse calix[n]arene deri-
vatives2 and other calixaromatics3 continues, there is also
a fast growing interest in the construction of heteroatom-
bridged calixaromatics.4 Compared to conventional calixaro-
matics in which all aromatic units are linked by methylene
units, introduction of heteroatoms into the bridge positions
has led to a wide variety of novel macrocyclic mole-
cules.5–9 For example, as reported by Miyano et al. in
1997, heating a mixture of p-tert-butylphenol and elemental
sulfur at 230 ꢀC in the presence of NaOH yielded tetrathia-
calix[4]arene in 54% yield.5 This practical preparation
has paved the way to the extensive study of sulfur-bridged
calixarenes.6 A few years ago, we started our program in
supramolecular chemistry, and found that the stepwise frag-
ment-coupling strategy provided an efficient method for the
synthesis of azacalix[m]arene[n]pyridines (n¼2, 4)8d and
azacalix[n]pyridines (n¼4, 8).8e Later, we established a
very convenient, cost-effective, and high-yielding synthetic
route to diverse nitrogen and/or oxygen-bridged calix[2]-
arene[2]triazines.7a Recently, Katz et al. have reported a
useful one-pot reaction for the preparation of symmetric
tetraoxacalixarene derivatives.7
Heteroatom-bridged calixaromatics also provide a unique
and versatile platform for further elaboration and functional-
ization. As with calixarenes, a range of functional groups can
be introduced onto the aromatic rings of the heteroatom-
bridged calixaromatics.11 In addition, the bridging atoms
of the macrocyclic rings can be derivatized and functionali-
zed.7k The reactions of both the aromatic segments and the
bridging units should render heteroatom-bridged calix-
aromatics useful in the fabrication of sophisticated synthetic
receptors.
Inherently chiral molecules are important and intriguing
chemical entities in terms of creation of chiral spaces for
enzyme mimics and chiral recognition.12 A challenging task,
synthesis of inherently chiral forms of macrocyclic mole-
cules such as calixarenes, remains largely unexplored.13
Very recently, inherently chiral calixarene crown derivatives
have been synthesized and isolated in enantiomerically pure
forms through the formation of diastereomers using a chiral
Being different from the conventional calixarenes,1–3 het-
eroatom-bridged calixaromatics exhibit unique conforma-
tional structures and a fine-tunable cavity. Heteroatoms,
particularly nitrogen, can have either sp2 or sp3 electronic
* Corresponding author. Tel.: +86 10 62565610; fax: +86 10 62564723;
e-mail: mxwang@iccas.ac.cn
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.05.129

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B.-Y. Hou et al. / Tetrahedron 63 (2007) 10801–10808
auxiliary.14 Success in the efficient preparation of hetero-
atom-bridged calix[2]arene[2]triazines from the stepwise
fragment-coupling approach7a,k prompted us to attempt the
synthesis of inherently chiral heteroatom-bridged calix-
aromatics. We envisaged that the fragment-coupling strategy
employing unsymmetrically substituted aromatic com-
pounds would allow us to readily construct the desired inher-
ently chiral macrocycles.
essential to freeze the conformation of macrocyclic mole-
cule. We then decided to take advantage of the two reactive
chlorotriazine moieties in the molecule by transforming
compound 5 into the crown derivative 7, in order to restrict
the rotation of two triazine rings around the meta–meta axes
or through the annulus. Very recently, we have demonstrated
that dichlorinated tetraoxacalix[2]arene[2]triazines derived
from 1,3-benzenediols bearing a large substituent at 5-
position were able to react with diamines to give symmetric
calixazacrown compounds. However, because of the con-
jugation of the amino groups with the triazine rings, most
2. Results and discussion
We started our investigation with the preparation of racemic
inherently chiral tetraoxacalix[2]arene[2]triazine azacrown
7 using 2,4-dihydroxyacetophenone 1 as an unsymmetrical
fragment. As depicted in Scheme 1, 2,4-dihydroxyaceto-
phenone 1 reacted with 2 equiv of cyanuric chloride 2 at
0 ꢀC in the presence of diisopropyl(ethyl)amine as an acid
scavenger to give intermediate 3 in 67% yield. A (macro)-
cyclocondensation reaction of 3 with benzyl 3,5-dihydroxy-
benzoate 4 took place at room temperature to afford the
desired target molecule 5, albeit in 29% yield. It should be
noted that the unsymmetrically substituted tetraoxacalix[2]-
arene[2]triazine 5 is not an inherently chiral molecule. It is
known that sterically less hindered heteroatom-bridged calix-
aromatics are fluxional in solution and that they undergo
very rapid conformation interconversions.7 As illustrated
in Scheme 2, the ‘enantiomers’ of tetraoxacalix[2]arene[2]-
triazine 5 are actually interconvertible due to the rapid
conformational inversion. To obtain the inherently chiral
tetraoxacalix[2]arene[2]triazine derivatives, it is therefore
mirror
OCH2Ph
PhH2CO
O
O
O
O
O
O
O
O
O
O
O
N
O
N
N
N
N
N
N
N
N
N
N
N
N
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
inversion
N
inversion
N
N
N
N
N
N
N
N
O
N
O
NO
O
O
O
O
O
O
O
O
O
OCH2Ph
PhH2CO
mirror
Scheme 2. Inversion of 1,3-alternate conformers.
CO2CH2Ph
COMe
O
COMe
COMe
DIPEA
THF
0 °C
O
HO
OH
O
O
HO
OH
1
N
N
N
4
N
N
+
Cl
N
N
Cl
N
N
Cl
DIPEA/acetone, rt
29%
67%
Cl
N
N
Cl
N
O
O
N
N
Cl
Cl
2
3
Cl
N
Cl
CO2CH2Ph
5
2
OCH2Ph
PhH2CO
O
O
O
O
Me
Me
O
O
O
O
O
O
+
O
N
O
N
N
N
N
N
N
N
N
N
N
O
N
H
H
H
O
O
H
NH2
O
NH2
N
N
N
N
O
O
O
O
O
4
6
A'
PhH2CO
A
K2CO3, THF, reflux
91%
O
O
OCH2Ph
O
O
Me
Me
O
N
O
O
O
O
O
+
O
N
O
N
N
+
N
N
N
N
N
N
N
O
N
H
H
H
O
O
H
O
N
N
N
N
O
O
O
O
B'
B
7
Scheme 1. Synthesis of tetraoxacalix[2]arene[2]triazine 5 and its anti-azacrown-7 derivative.

B.-Y. Hou et al. / Tetrahedron 63 (2007) 10801–10808
10803
tetraoxacalix[2]arene[2]triazine azacrowns were found to
exist as a mixture of syn- and anti-isomer. Only with the in-
corporation of a diamine 6 derived from 3,6,9,12-tetraoxate-
tradecane-1,14-diol did the calixazacrown products adopt an
exclusively anti-isomeric structure.15 To avoid the complex-
ity of forming both syn- and anti-isomer in our inherently
chiral molecules, diamine 6 was employed. In the presence
of K2CO3, dichlorinated tetraoxacalix[2]arene[2]triazine 5
reacted with diamine 6 in refluxing tetrahydrofuran (THF)
to furnish tetraoxacalix[2]arene[2]triazine azacrown 7 in
91% yield (Scheme 1). The structure of 7 is worth address-
ing. Since two benzene rings in the macrocycle 5 are differ-
ently substituted, the anti-configured azacrown product 7
might in theory give rise to two isomeric forms A and B
and their enantiomers A0 and B0 (Scheme 1). Very interest-
employed because of their easy availability. The pre-
parations of chiral building blocks 11 and 13 were rather
straightforward. Starting with 3,5-dihydroxybenzoic acid,
protection of two hydroxyl groups by THP, followed by
amidation or esterification and deprotection yielded chiral
amide 11 or ester 13 in high yields (Scheme 3). Under sim-
ilar reaction conditions as for the preparation of 3, reaction
of 11 and 13 with 2 equiv of cyanuric chloride 2 produced
the corresponding intermediates 14 and 15 in yields of
70% and 42%, respectively. Chiral tetraoxacalix[2]arene[2]-
triazine products 16 and 17 were successfully obtained in
fairly good yields from macrocyclic coupling reactions
between 2,4-dihydroxyacetophenone 1 and intermediates
14 and 15. Further reaction of 16 and 17 with the diamine
6, following the reaction conditions for the synthesis of 5,
led efficiently to chiral tetraoxacalix[2]arene[2]triazine
azacrowns 18 and 19 (Scheme 4).
1
ingly, in its H (Fig. 1) and 13C NMR spectra, tetraoxa-
calix[2]arene[2]triazine azacrown 7 gave only one set of
proton and carbon resonance signals, respectively. This indi-
cated that product 7 existed as a single anti-isomer, or more
probably that isomers A and B equilibrate rapidly on the
NMR time scale (Scheme 1). We attempted the resolution
of racemic tetraoxacalix[2]arene[2]triazine azacrown 7 by
means of HPLC, using commercially available chiral col-
umns such as Diacel AD, OD, and OJ and Cyclobond.
Unfortunately, no resolution was achieved.
The structures of all chiral products were established on
the basis of spectroscopic data and microanalyses. To estab-
lish the chiral tetraoxacalix[2]arene[2]triazine structure be-
yond doubt, the X-ray single crystal structure of 1716 was
determined (Fig. 2). Like most of the heteroatom-bridged
calixaromatics,7a compound 17 adopted a 1,3-alternate con-
formation. The introduction of a chiral auxiliary and an
unsymmetrically substituted benzene ring did not change
the 1,3-alternate conformation of macrocyclic ring. The
two differently substituted benzene rings are face-to-face
and almost parallel, whereas the two triazines are nearly
edge-to-edge oriented, giving the distances between C(11)
and C(31), and C(16) and C(30) around 4.946 and
An alternative strategy was then applied utilizing a chiral
auxiliary. It was hoped that the introduction of a chiral aux-
iliary into the inherently chiral heteroatom-bridged calix-
aromatics would result in the formation of a pair of
diastereomers, which would therefore facilitate the separa-
tion. To test this approach, enantiomerically pure R-(+)-a-
phenylethylamine and (1R,2S,5R)-(ꢁ)-menthol were
˚
8.841 A, respectively. The bond lengths and bond angles
(see the caption of Fig. 2) of bridging oxygen atoms indicate
7
2.5
ppm
18
2.5
ppm
1.7
ppm
ppm
0.80
19
2.5
ppm
4.0
7.5
7.0
6.5
6.0
5.5
5.0
4.5
3.5
3.0
2.5
2.0
1.5
1.0 ppm
Figure 1. Partial 1H NMR spectra of compounds 7, 18, and 19.

10804
B.-Y. Hou et al. / Tetrahedron 63 (2007) 10801–10808
H
N
H
O
R-(+)-α-phenylethylamine
COOH
CO2H
DCC/HOBT
CH2Cl2, rt
74%
THPO
OTHP
HO
OH
THPO
PPTS
OTHP
8
(-)-menthol
9
10
DCC/DMAP
CH2Cl2, rt
C2H5OH 96%
55 °C
60%
PPTS
C2H5OH
55 °C
H
H
O
O
N
O
O
O
95%
HO
OH
THPO
OTHP
HO
OH
12
13
11
Scheme 3. Preparation of chiral building blocks 11 and 13.
conjugation of the linking oxygen atoms with triazine rings
rather than benzene rings. It is very interesting to note that
chiral product 17 existed actually as a single diastereomeri-
cally pure isomer in this crystal (Fig. 2). It should be noted,
however, that diastereomers were not detected for products
16 and 17 in solution, as both their 1H and 13C NMR spectra
showed only one set each of proton and carbon signals. Such
spectroscopic characteristics are most likely attributable to
the rapid conformation inversion in solution (Scheme 2) as
we discussed previously. Therefore, the presence of only a
single diastereomer in the crystal is most probably an effect
of lattice forces.
proton and carbon resonance signals, chiral anti-tetraoxaca-
lix[2]arene[2]triazine azacrowns 18 and 19 existed as a pair
of diastereomers. For example, in contrast to the spectrum of
compound 7, there are two singlet peaks (2.44–2.48 ppm)
1
corresponding to the acetyl methyl protons in the H NMR
spectrum of 18 and 19 (Fig. 1). In addition, two sets of dou-
blet signals at 1.65–1.68 ppm and two sets of doublet signals
at 0.76–0.79 ppm were observed for chiral amido- and ester-
bearing azacrown products 18 and 19, respectively. The di-
astereomer ratio in both cases was around 1:1, as determined
roughly by the integration of the intensity of two peaks
(Fig. 1). It is quite clear that by the introduction of unsym-
metrically substituted aromatic rings and inhibition of the
conformational inversion, stable, inherently chiral hetero-
atom-bridged calixaromatics may be obtained. We have
As shown by the 1H (Fig. 1) and 13C NMR spectra of prod-
ucts 18 and 19, which displayed, respectively, two sets of
R*
O
Cl
Cl
Cl
N
DIPEA
THF, 0 °C
11
13
1, DIPEA/acetone, rt
Cl
N
N
N
N
N
N
+
2
Cl
N
2
Cl
Cl
O
N
O
14, R* = (R)-NHCH(Me)Ph, 70%
15, R* = O-(-)-menthyl, 42%
*R
R*
O
O
O
O
Me
Me
6, K2CO3, THF, reflux
O
O
O
O
+
O
O
O
N
N
O
N
N
N
N
N
N
N
N
N
N
Cl
Cl
Cl
A'
Cl
A
16, R* = (R)-NHCH(Me)Ph, 53%
17, R* = O-(-)-menthyl, 38%
R*
*R
O
O
O
O
Me
Me
O
O
O
O
O
O
+
O
N
O
N
N
N
N
N
N
N
N
N
N
O
N
H
H
H
O
O
H
O
N
N
N
N
O
O
O
O
A'
A
18, R* = (R)-NHCH(Me)Ph, 75%
19, R* = O-(-)-menthyl, 63%
Scheme 4. Synthesis of inherently chiral tetraoxacalix[2]arene[2]triazines and their azacrown derivatives.

B.-Y. Hou et al. / Tetrahedron 63 (2007) 10801–10808
10805
˚
Figure 2. X-ray molecular structure of 17: top (left) and side (middle and right) views. Selected interatomic distances [A]: N(2)/N(5) 4.601, C(16)/C(30)
9.209, Cl(1)/Cl(2) 12.246, C(14)/C(25) 4.453, C(11)/C(31) 4.946, N(2)/C(25), 3.244, C(25)/N(5) 3.137, N(5)/C(14) 3.267, C(14)/N(2) 3.158.
˚
Selected bond lengths [A]: C(13) /O(7) 1.340, O(7)/C(27) 1.408, C(29)/O(6) 1.395, O(6) /C(26) 1.335, C(21) /O(3) 1.344, O(3) /C(23) 1.402,
C(22) /O(5) 1.420, O(5) /C(12) 1.339. Selected bond angles: C(13)–O(7)–C(27) 117.5ꢀ, C(29)–O(6)–C(26) 117.7ꢀ, C(21)–O(3)–C(23) 118.2ꢀ, C(22)–
O(5)–C(12) 117.1ꢀ.
attempted separation of diastereomers of 18 and 19 using
various chromatographic methods but have as yet been
unsuccessful.
diisopropyl(ethyl)amine hydrochloride by filtration, the
filtrate was concentrated and chromatographed on a silica
gel column (100–200 mesh) with a mixture of petroleum
ether and acetone as the mobile phase to give pure 3
(7.50 g, 67%) as pale yellow solid: mp 113–114 ꢀC; IR
1
3. Conclusions
(KBr) n 1687, 1536 cmꢁ1; H NMR (300 MHz, CDCl3)
d 8.04 (1H, d, J¼8.6 Hz), 7.35 (1H, dd, J¼2.3, 8.6 Hz),
7.16 (1H, d, J¼2.3 Hz), 2.58 (3H, s); 13C NMR (75 MHz,
CDCl3) d 195.5, 173.4, 173.1, 170.9, 170.3, 154.0, 150.2,
132.4, 128.4, 120.0, 117.0, 29.0; MS (ESI) m/z (%) 447.1
(M+H+, 100), 445.1 (94), 443.1 (74), 449.1 (67), 469.0
(M+Na+, 82), 467.0 (80), 465.0 (81), 471.0 (38), 485.0
(M+K+, 31), 482.0 (25), 479.0 (27). HRMS (ESI) m/z
446.9340. C14H6O3N6Cl4 requires 446.9328.
In summary, we have developed a rather efficient and
straightforward strategy for the construction of inherently
chiral heteroatom-bridged calixaromatics. Two pairs of
diastereomers of inherently chiral tetraoxacalix[2]arene[2]-
triazine azacrowns have been synthesized conveniently
using R-(+)-a-phenylethylamine and (1R,2S,5R)-(ꢁ)-menthol
as chiral auxiliaries. Although the separation of the diastereo-
mers, which are the precursors to enantiomerically pure
inherently chiral tetraoxacalix[2]arene[2]triazine azacrowns,
is yet to be achieved, we are confident that the strategy is
correct and worth pursuing. Searching for separable diastereo-
mers of inherently chiral heteroatom-bridged calixaromatics
using other effective chiral auxiliaries is being actively
investigated in this laboratory.
4.3. Synthesis of 5
At room temperature, solutions of benzyl 3,5-dihydr-
oxybenzoate (4.0 mmol) in acetone (200 mL) and 3
(4.0 mmol) in acetone (200 mL) were added dropwise si-
multaneously and at the same rate to a solution of diisopro-
pyl(ethyl)amine (1.24 g, 9.6 mmol) in acetone (1400 mL).
After addition of the two reactants, which took about
12 h, the resulting mixture was stirred at room temperature
for another 24 h. The solvent was then removed under
vacuum, and the residue was chromatographed on a silica
gel column (200–300 mesh) with a mixture of petroleum
ether and acetone as the mobile phase to give pure 5
(0.72 g, 29%) as white solid: mp 230–231 ꢀC; IR (KBr) n
4. Experimental
4.1. General information
1H and 13C NMR spectra were recorded on Bruker Avance
300 and 600 spectrometers. Chemical shifts are reported in
parts per million with either tetramethylsilane or the residual
solvent resonance peak as an internal standard. Melting
points are uncorrected. Elemental analyses were performed
at the Analytical Laboratory of the Institute. All chemicals
were dried or purified according to standard procedures prior
to use.
1729, 1695, 1551 cmꢁ1 1H NMR (600 MHz, CDCl3)
;
d 7.63 (1H, d, J¼8.4 Hz), 7.58 (2H, t, J¼1.8 Hz), 7.44–
7.40 (5H, m), 6.96 (1H, dd, J¼1.8, 8.4 Hz), 6.91 (1H, t,
J¼1.8 Hz), 6.77 (1H, d, J¼2.4 Hz), 5.34 (2H, s), 2.42
(3H, s); 13C NMR (75 MHz, CDCl3) d 195.2, 175.0,
174.9, 172.5, 172.3, 172.1, 163.8, 154.1, 151.7, 151.4,
150.4, 135.2, 133.5, 132.0, 128.8, 128.6, 121.0, 120.9,
120.5, 119.9, 117.8, 67.6, 29.3; MS (MALDI-TOF) m/z
(%) 618.8 (M+H+, 100), 619.8 (32), 620.8 (71), 621.8
(21), 622.8 (13), 623.8 (6), 640.7 (M+Na+, 24), 641.7
(8), 642.7 (15), 643.7 (6), 644.7 (4), 656.8 (M+K+, 6),
657.8 (5), 658.8 (4). Anal. Calcd for C28H16O7N6Cl2: C,
54.30; H, 2.60; N, 13.57. Found: C, 54.25; H, 2.65;
N, 13.35.
4.2. Synthesis of 3
To an ice-cooled solution of cyanuric chloride 2 (9.23 g,
50 mmol) in THF (100 mL) was added dropwise a mixture
of
1 (3.80 g, 25 mmol) and diisopropyl(ethyl)amine
(8.06 g, 62.5 mmol) in THF (80 mL) over 1 h. The resulting
mixture was stirred for another 1 h. After removal of

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B.-Y. Hou et al. / Tetrahedron 63 (2007) 10801–10808
4.4. Synthesis of 7
10.8 Hz), 2.11–2.06 (1H, m), 1.96–1.89 (1H, m), 1.74–
1.70 (2H, m), 1.57–1.48 (2H, m), 1.14–1.02 (2H, m),
0.97–0.86 (7H, m), 0.78 (3H, d, J¼6.9 Hz); 13C NMR
(75 MHz, MeOD-d3) d 167.8, 159.8, 133.6, 108.8, 108.2,
76.0, 42.1, 35.5, 32.7, 27.8, 24.8, 22.4, 21.0, 16.9; MS (EI)
m/z (%) 292 (M+, 7), 154 (40), 138 (94), 137 (100), 95
(67), 81 (42). Anal. Calcd for C17H24O4: C, 69.84; H,
8.27. Found: C, 69.48; H, 8.45.
Solutions of a diamine 6 (1.0 mmol) in THF (200 mL) and a
dichlorinated tetraoxacalix[2]arene[2]triazine 5 (1.0 mmol)
in THF (200 mL) were added dropwise simultaneously
and at the same rate to a refluxing suspension of K2CO3
(2.76 g, 20 mmol) in THF (480 mL). After addition of the
reactants, which took about 10 h, the resulting mixture was
refluxed for another 12 h. Filtration removed the solids and
the filtrate was concentrated under vacuum. The residue
was then chromatographed on a silica gel column (200–
300 mesh) with a mixture of petroleum ether and acetone
as the mobile phase to give pure product 7 (0.71 g, 91%)
as white solid: mp 204–205 ꢀC; IR (KBr) n 3280, 3150,
4.7. Synthesis of 14
Following the same procedure for preparation of 3, pure 14
(70%) was obtained as white solid: mp 92–93 ꢀC; IR (KBr) n
3311, 1645, 1527 cmꢁ1; 1H NMR (300 MHz, CDCl3) d 7.59
(2H, d, J¼2.2 Hz), 7.39–7.28 (5H, m), 7.22 (1H, t,
J¼2.2 Hz), 6.28 (1H, d, J¼7.4 Hz), 5.31 (1H, quin,
J¼7.1 Hz), 1.63 (3H, d, J¼6.9 Hz); 13C NMR (75 MHz,
CDCl3) d 173.4, 170.6, 163.8, 151.5, 142.4, 138.1, 128.9,
127.8, 126.3, 118.6, 118.0, 49.8, 21.5; MS (EI) m/z (%)
551 (M+, 60), 552 (21), 553 (82), 554 (22), 555 (39), 556
(8), 557 (10), 558 (2), 435 (50), 433 (100), 431 (75), 104
(93). Anal. Calcd for C21H13N7O3Cl4: C, 45.59; H, 2.37;
N, 17.72. Found: C, 45.99; H, 2.58; N, 17.43.
1717, 1692, 1590 cmꢁ1 1H NMR (600 MHz, CDCl3)
;
d 7.69 (1H, d, J¼8.6 Hz), 7.56–7.54 (2H, m), 7.42–7.38
(4H, m), 7.36–7.34 (1H, m), 6.90 (1H, d, J¼7.9 Hz), 6.76
(1H, br s), 6.61–6.58 (1H, m), 6.05–5.95 (2H, m), 5.34
(1H, d, J¼12.3 Hz), 5.31 (2H, d, J¼12.3 Hz), 4.35–4.34
(2H, m), 3.76–3.73 (4H, m), 3.62–3.46 (12H, m), 3.16–
3.14 (2H, m), 2.42 (3H, s); 13C NMR (75 MHz, CDCl3)
d 195.8, 171.9, 171.5, 170.0, 164.6, 155.3, 152.4, 151.7,
135.6, 132.6, 131.5, 128.7, 128.5, 128.3, 120.6, 120.1,
120.0, 119.3, 117.3, 71.2, 70.8, 70.5, 70.1, 67.3, 40.8, 30.3;
MS (MALDI-TOF) m/z 783.0 (M+H+), 805.0 (M+Na+),
821.0 (M+K+). Anal. Calcd for C38H38O11N8: C, 58.31; H,
4.89; N, 14.32. Found: C, 58.06; H, 5.13; N, 14.13.
4.8. Synthesis of 15
Following the same procedure for preparation of 3, 15 (42%)
was obtained as white solid: mp 46–47 ꢀC; IR (KBr) n 1719,
4.5. Synthesis of 10 and 12
1529 cmꢁ1 1H NMR (300 MHz, CDCl3) d 7.87 (2H,
;
d, J¼2.2 Hz), 7.29 (2H, t, J¼2.2 Hz), 4.96–4.95 (1H,
m), 2.14–2.11 (1H, m), 1.95–1.94 (1H, m), 1.76–1.72 (2H, m),
1.58–1.52 (3H, m), 1.15–1.08 (2H, m), 0.95–0.91 (6H, m),
0.82–0.79 (3H, m); 13C NMR (75 MHz, CDCl3) d 173.4,
170.6, 163.5, 151.3, 134.3, 121.9, 119.2, 76.3, 47.2, 40.8,
34.2, 31.4, 26.5, 23.6, 22.0, 20.8, 16.5; MS (EI) m/z (%)
588 (M++2, 5), 590 (2), 437 (5), 436 (5), 435 (27), 434
(10), 433(61), 432 (8), 431(51), 138 (100), 95 (53). Anal.
Calcd for C23H22N6O4Cl4: C, 46.96; H, 3.77; N, 14.29.
Found: C, 47.03; H, 4.12; N, 14.22.
At room temperature, to a solution of 9 (4.83 g, 15 mmol)
and R-(+)-a-phenylethylamine (1.82 g, 15 mmol) or (ꢁ)-
menthol (2.34 g, 15 mmol) in dry CH2Cl2 (200 mL) were
added DCC (3.09 g, 15 mmol) and HOBT (2.03 g,
15 mmol) or DMAP (0.18 g, 1.5 mmol). The resulting
mixture was stirred for 24 h. After removal of solid through
filtration, the filtrate was concentrated and chromatographed
on a silica gel column (200–300 mesh) with a mixture of
petroleum ether and ethyl acetate as the mobile phase to
give pure 10 (4.72 g, 74%) as a colorless oil or 12 (4.14 g,
60%) as a yellow oil.
4.9. Synthesis of 16
4.6. Synthesis of 11 and 1317
Following the same reaction procedure for preparation of 5,
pure 16 (53%) was obtained as white solid: mp 154–155 ꢀC;
[a]2D5 5.4 (c 1.0, CHCl3); IR (KBr) n 3351, 1690, 1662,
At room temperature, to a solution of 10 (8.50 g, 20 mmol)
or 12 (9.2 g) in EtOH (200 mL) was added PPTS (1.00 g,
4 mmol). The resulting mixture was stirred at 55 ꢀC for
4 h. After removal of EtOH under vacuum, the residue was
chromatographed on a silica gel column (200–300 mesh)
with a mixture of petroleum ether and acetone as the mobile
phase to give pure 11 (4.93 g, 96%) or 13 (5.55 g, 95%) both
as pale yellow foam. Compound 11: mp 75–76 ꢀC; IR (KBr)
1
1552 cmꢁ1; H NMR (600 MHz, CDCl3) d 7.41–7.36 (5H,
m), 7.32–7.30 (2H, m), 7.15 (1H, s), 6.91 (1H, d, J¼
8.4 Hz), 6.78 (1H, s), 6.74 (1H, s), 6.60 (1H, d, J¼7.8 Hz),
5.29 (1H, quin, J¼7.2 Hz), 2.45 (3H, s), 1.63 (3H, d,
J¼7.2 Hz); 13C NMR (75 MHz, CDCl3) d 197.0, 174.9,
172.4, 172.3, 172.2, 164.0, 154.2, 151.8, 151.79, 150.1,
142.7, 138.4, 131.5, 130.0, 128.8, 127.7, 126.3, 120.3,
119.1, 118.5, 118.2, 117.4, 49.6, 29.6, 21.4; MS (EI) m/z
(%) 631 (M+, 37), 632 (13), 633 (26), 634 (8), 635 (6),
636 (2), 511 (71), 512 (20), 513 (49), 514 (13), 515 (10),
516 (3), 120 (93), 104 (100), 103 (50). Anal. Calcd for
C29H19N7O6Cl2: C, 55.08; H, 3.03; N, 15.50. Found: C,
54.94; H, 3.09; N, 15.18.
n 3415, 3251, 1644, 1595 cmꢁ1 1H NMR (300 MHz,
;
MeOD-d3) d 7.43–7.23 (5H, m), 6.74 (2H, d, J¼2.2 Hz),
6.43 (1H, t, J¼2.2 Hz), 5.21 (1H, q, J¼7.0 Hz), 3.38 (2H,
s), 1.56 (3H, d, J¼7.1 Hz); 13C NMR (75 MHz, d3-MeOD)
d 170.0, 159.8, 145.4, 138.2, 129.5, 128.0, 127.1, 106.9,
106.6, 50.6, 22.3; MS (EI) m/z (%) 257 (M+, 23), 56 (84),
43 (100). Anal. Calcd for C15H15NO3: C, 70.02; H, 5.88;
N, 5.44. Found: C, 69.47; H, 6.10; N, 5.57. Compound 13:
4.10. Synthesis of 17
mp 70–71 ꢀC; IR (KBr) n 3395, 1686, 1604 cmꢁ1 1H
;
NMR (300 MHz, CDCl3) d 7.15 (2H, d, J¼2.2 Hz), 6.59
Following the same reaction procedure for preparation of 5,
pure 17 (38%) was obtained as white solid: mp 290–291 ꢀC;
(1H, t, J¼2.1 Hz), 5.57 (2H, s), 4.90 (1H, dt, J¼4.4,

B.-Y. Hou et al. / Tetrahedron 63 (2007) 10801–10808
10807
[a]2D5 ꢁ23.4 (c 1.0, CHCl3); IR (KBr) n 1713, 1691,
for C41H50N8O11: C, 59.27; H, 6.07; N, 13.49. Found: C,
59.17; H, 6.11; N, 13.46.
1
1553 cmꢁ1; H NMR (600 MHz, CDCl3) d 7.72 (1H, d,
J¼8.4 Hz), 7.53 (2H, d, J¼1.8 Hz), 6.99 (1H, dd, J¼
2.4 Hz, 8.4 Hz), 6.89 (1H, t, J¼2.4 Hz), 6.78 (1H, d,
J¼2.4 Hz), 4.91–4.87 (1H, m), 2.47 (3H, s), 2.07–2.05
(1H, m), 1.84–1.81 (1H, m), 1.74–1.72 (2H, m), 1.55–1.49
(2H, m), 1.12–1.04 (2H, m), 0.94–0.88 (7H, m), 0.77 (3H,
d, J¼6.6 Hz); 13C NMR (75 MHz, CDCl3) d 195.1, 174.9,
172.5, 172.3, 172.2, 163.5, 154.1, 151.7, 151.4, 150.4,
134.2, 131.8, 128.8, 120.8, 120.7, 120.1, 119.9, 117.9,
76.1, 47.1, 40.8, 34.1, 31.4, 29.3, 26.6, 23.6, 22.0, 20.7,
16.6; MS (MALDI-TOF) m/z (%) 667.6 (M+H+, 100),
668.6 (37), 669.6 (71), 670.6 (25), 671.6 (16), 672.6 (5),
673.6 (1). Anal. Calcd for C31H28O7N6Cl2: C, 55.78; H,
4.23; N, 12.59. Found: C, 55.82; H, 4.36; N, 12.27. X-ray
quality single crystals were obtained by slow evaporation
of the solvent from 17 solvent in a mixture of ethyl acetate
and n-hexane.
Acknowledgements
We thank the National Natural Science Foundation of China,
Ministry of Science and Technology, Chinese Academy of
Sciences for financial support.
Supplementary data
Preparations of starting materials, copies of H and 13C
NMR spectra of all products. Supplementary data associated
with this article can be found in the online version, at
doi:10.1016/j.tet.2007.05.129.
1
References and notes
4.11. Synthesis of 18
Following the same procedure for the synthesis of 7, pure 18
(75%) was obtained as white solid: mp 179–180 ꢀC; [a]D25
ꢁ1.6 (c 1.0, CHCl3); IR (KBr) n 3388, 3282, 3154,
1. (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.
2. (a) Calixarenes in Action; Mandolini, L., Ungaro, R., Eds.;
Imperial College: London, 2000; (b) Lumetta, G. J.; Rogers,
R. D.; Gopalan, A. S. Calixarenes for Separation; ACS:
Washington, DC, 2000; (c) Calixarenes 2001; Asfari, Z.,
1
1590 cmꢁ1; H NMR (600 MHz, CDCl3) d 7.55 (1H, t,
J¼7.6 Hz), 7.45 (2H, d, J¼7.6 Hz), 7.39–7.35 (2H, m),
7.30–7.28 (1H, m), 7.24 (1H, br s), 7.09 (1H, br s), 6.88–
6.76 (2H, m), 6.60–6.55 (2H, m), 5.87–5.78 (2H, m),
5.36–5.32 (1H, m), 4.36–4.34 (2H, m), 3.73 (4H, br s),
3.60–3.41 (12H, m), 3.15–3.13 (2H, m), 2.48 (1.67H, s),
2.44 (1.27H, s), 1.68 (1.27H, d, J¼7.0 Hz), 1.65 (1.70H, d,
J¼6.9 Hz); 13C NMR (150 MHz, CDCl3) d 7.9, 197.7,
172.2, 172.0, 171.9, 171.7, 171.4, 172.0, 170.1, 165.3,
165.1, 155.5, 152.6, 152.5, 151.5, 151.3, 143.2, 143.1,
137.8, 137.6, 130.6, 128.7, 128.6, 127.5, 127.4, 126.5,
126.3, 120.1, 118.6, 118.5, 118.4, 118.3, 117.5, 117.4,
117.2, 117.1, 71.1, 70.8, 70.5, 70.1, 69.9, 49.6, 49.3, 40.7,
30.3, 21.8, 21.1; MS (MALDI-TOF) m/z 796.6 (M+H+),
818.6 (M+Na+), 834.6 (M+K+). Anal. Calcd for
C39H41N9O10: C, 58.86; H, 5.19; N, 15.84. Found: C,
58.52; H, 5.24; N, 15.77.
€
Bohmer, V., Harrowfield, J., Vicens, J., Saadioui, M., Eds.;
Kluwer Academic: The Netherlands, 2001.
3. For reviews on calixpyrroles, see: (a) Gale, P. A.; Anzenbacher,
P.; Sessler, J. L. Coord. Chem. Rev. 2001, 222, 57; (b) Sliwa, W.
Heterocycles 2002, 57, 169; For examples on calixpyridines,
ꢀ
see: (c) Kral, V.; Gale, P. A.; Anzenbacher, P.; Jursikova, K.;
Lynch, V.; Sessler, J. L. Chem. Commun. 1998, 9; (d) Sessler,
ꢀ
ꢀ
J. L.; Cho, W.-S.; Lynch, V.; Kral, V. Chem.—Eur. J. 2002, 8,
1134; (e) Newkome, G. R.; Joo, Y. J.; Fronczek, F. R.
J. Chem. Soc., Chem. Commun. 1987, 854; For other recent
examples, see: (f) Guillard, J.; Meth-Cohn, O.; Rees, C. W.;
White, A. J. P.; Williams, D. J. Chem. Commun. 2002, 232;
€
(g) Vogel, E.; Pohl, M.; Herrmann, A.; Wiss, T.; Konig, C.;
Lex, J.; Gross, M.; Gisselbrecht, J. P. Angew. Chem., Int. Ed.
1996, 35, 1520; (h) Black, D. S.; Craig, D. C.; Rezaie, R.
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Torre, G. L.; Parisi, M. F.; Nascone, R. P.; White, A. J. P.;
Williams, D. J. Chem.—Eur. J. 2002, 8, 3148; (k) Cafeo, G.;
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Nascone, R. P.; Williams, D. J. Tetrahedron 2004, 60, 1895;
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4.12. Synthesis of 19
Following the same procedure for the synthesis of 7, pure 19
(63%) was obtained as white solid: mp 213–214 ꢀC; [a]D25
ꢁ20.9 (c 1.0, CHCl3); IR (KBr) n 3280, 3150, 1717, 1692,
1
1590 cmꢁ1; H NMR (600 MHz, CDCl3) d 7.72 (1H, dd,
J¼1.7, 8.4 Hz), 7.51–7.50 (2H, m), 6.92–6.90 (1H, m),
6.75 (1H, br s), 6.60 (1H, br s), 5.96–5.95 (2H, m), 4.86
(1H, br s), 4.34 (2H, br s), 3.76–3.74 (4H, m), 3.62–3.46
(12H, m), 3.16–3.14 (2H, m), 2.46 (1.28H, s), 2.45 (1.67H,
s), 2.10 (1H, br s), 1.87–1.85 (1H, m), 1.73–1.71 (2H, m),
1.54–1.48 (2H, m), 1.14–1.03 (2H, m), 0.94–0.89 (7H, m),
0.79 (1.32H, d, J¼6.9 Hz), 0.76 (1.78H, d, J¼6.9 Hz); 13C
NMR (150 MHz, CDCl3) d 195.84, 195.8, 172.0, 171.9,
171.8, 171.4, 171.3, 169.9, 164.2, 155.2, 152.3, 152.1,
152.0, 151.7, 151.5, 133.3, 133.2, 131.4, 128.6, 128.5,
120.4, 120.1, 119.9, 119.8, 119.7, 119.3, 119.1, 117.6,
117.4, 117.3, 75.7, 75.67, 71.1, 70.8, 70.5, 70.1, 70.0,
69.8, 69.6, 47.1, 40.8, 40.7, 34.2, 31.4, 30.4, 30.3, 26.6,
23.6, 22.0, 20.7, 20.67, 16.6, 16.5; MS (MALDI-TOF) m/z
831.4 (M+H+), 853.4 (M+Na+), 869.4 (M+K+). Anal. Calcd
4. For a useful overview on heteroatom-bridged calixarenes, see:
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Konig, B.; Fonseca, M. H. Eur. J. Inorg. Chem. 2000, 2303.
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Wang, M.-X.; Yang, H.-B. J. Am. Chem. Soc. 2004, 126, 15412;
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Meervelt, L.; Dehaen, W. Org. Lett. 2006, 8, 4161; (f) Hao,
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A. R.; Khalil, A.; Richmond, P.; Sandford, G.; Yufit, D. S.;
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Chambers, R. D.; Hoskin, P. R.; Khalil, A.; Richmond, P.;
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C. L. D.; Gibb, B. C. J. Am. Chem. Soc. 2003, 125, 650; (j)
Yang, F.; Yan, L.-W.; Ma, K.-Y.; Yang, L.; Li, J.-H.; Chen,
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Ed. Engl. 1995, 34, 661; (c) Yoshida, M.; Goto, M.;
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10. Gong, H.-Y.; Wang, D.-X.; Xiang, J.-F.; Zheng, Q.-Y.; Wang,
M.-X. Chem.—Eur. J., in press.
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12. Scarso, A.; Rebek, J., Jr. Supramolecular Chirality; Crego-
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13. For a general review on chiral calixarenes, see: Vysotsky,
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8. For recent examples on nitrogen-bridged calixaromatics, see:
(a) Ito, A.; Ono, Y.; Tanaka, K. New J. Chem. 1998, 779; (b)
Ito, A.; Ono, Y.; Tanaka, K. J. Org. Chem. 1999, 64, 8236;
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14. (a) Cao, Y.-D.; Zheng, Q.-Y.; Chen, C.-F.; Wang, M.-X.;
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16. Crystal data of compound 17: C31H28Cl2N6O7, M¼667.49,
˚
tetragonal, P43, a¼12.0356(5), c¼22.8066(16) A, V¼
3
3303.7(3) A , Z¼4, m(Mo Ka)¼0.251 mmꢁ1. Final residuals
˚
(415 parameters) R1¼0.0446 for 2981 reflections with
I>2s(I), and R1¼0.0584, wR2¼0.1053, GooF¼1.002 for all
3766 data.
9. For examples on other heteroatoms-bridged calixaromatics,
17. Miyashita, M.; Yoshikoshi, A.; Grieco, P. A. J. Org. Chem.
1977, 42, 3772.
€
see: (a) Konig, B.; Rodel, M.; Bubenitschek, P.; Jones, P. G.;
€