Selective crown ether based macrocyclization: a model case study from N,N-bis(2-hydroxyalkylbenzyl)alkylamine

Article abstract of DOI:10.1016/j.tet.2009.04.093

A model case of selective crown ether based macrocycles, i.e., [1+1] or [2+2] macrocycles, obtained from a simple reaction of N,N-bis(2-hydroxyalkylbenzyl)alkylamine, HBA, and ditosylated compounds is proposed. For HBA with the methyl group at ortho and p

Full text of DOI:10.1016/j.tet.2009.04.093

Tetrahedron 65 (2009) 5855–5861
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Selective crown ether based macrocyclization: a model case study
from N,N-bis(2-hydroxyalkylbenzyl)alkylamine
,
b
,
a
a
Suwabun Chirachanchai a , Thitiporn Rungsimanon , Suttinun Phongtamrug ,
*
Mikiji Miyata c, Apirat Laobuthee d
a The Petroleum and Petrochemical College, Chulalongkorn University, Pathumwan, Bangkok 10330, Thailand
b Center for Petroleum, Petrochemicals, and Advanced Materials, Chulalongkorn University, Pathumwan, Bangkok 10330, Thailand
c Division of Advanced Science and Biotechnology, Graduate School of Engineering, Osaka University, Suita, Osaka 565-0871, Japan
d Department of Materials Engineering, Faculty of Engineering, Kasetsart University, Chatuchak, Bangkok 10900, Thailand
a r t i c l e i n f o
a b s t r a c t
Article history:
A model case of selective crown ether based macrocycles, i.e., [1þ1] or [2þ2] macrocycles, obtained from
a simple reaction of N,N-bis(2-hydroxyalkylbenzyl)alkylamine, HBA, and ditosylated compounds is
proposed. For HBA with the methyl group at ortho and para positions, and at N atom, 1, the reaction
between this derivative and the ditosylated compound with three, four, five, or eight atom chain length
gives only a [1þ1] macrocycle. For HBA with the methyl group at ortho and para positions, but a cyclo-
hexyl group at N atom, 2, the reaction gives both [1þ1] and [2þ2] macrocyclic types when reacting with
the ditosylated compound. The present work indicates that the structure of HBA induces selective
macrocyclization to provide both [1þ1] and [2þ2] macrocycles.
Received 26 September 2008
Received in revised form 1 April 2009
Accepted 23 April 2009
Available online 7 May 2009
Keywords:
Benzoxazine
Macrocycle
N,N-Bis(2-hydroxyalkylbenzyl)alkylamine
Ditosylated compound
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
macrocycle, with modest yields (22–68%). However, in such cases,
purification, especially column chromatography, was needed.
In general, macrocycles are obtained by the cyclization of two or
more different molecules under dilute conditions and/or the use of
a metal template.1–4 For example, 18-crown-6 and 15-crown-5
were obtained by using potassium and sodium ions as a template.3
Hydrogen bond networks of pyridazine- and naphthyridine-con-
taining macrocycles were carried out via condensation.4
Previously, our group focused on N,N-bis(2-hydroxy-
alkylbenzyl)alkylamine (HBA) obtained from benzoxazine de-
rivatives and phenol compounds as a unit for macrocyclization
(Scheme 1).9–12 Considering the structure of these derivatives, the
single crystal X-ray analysis demonstrated the unique structures
with an inter- and intramolecular hydrogen bond network to pro-
vide an asymmetric reaction and molecular assembly frame-
work.13–16 Recently, we found that the reaction of HBA with
a ditosylated compound not only gives a [1þ1] macrocycle but also
a [2þ2] one, depending on the HBA derivatives.17 At this stage, the
questions yet to be answered are (i) what are the factors that
control the selectivity? (ii) How does the reaction give only [1þ1]
and/or [2þ2] macrocycles without oligomers or polymers? (iii)
What is the possible mechanism?
Among many reports on the macrocyclization of crown ethers,
cyclization with tosyl derivatives in the presence of a base is a good
approach to obtain macrocycles.5–8 For example, Charbonniere and
`
Ziessel proposed the synthesis of novel crown ethers, i.e., cyclic
di[(o-polyethyleneglycoxy)phenyl]amine by treating diarylamine
with ditosylated tri-, tetra-, and penta-ethyleneglycol using Cs2CO3
as the base.7 Agai et al. reported on the preparation of dibenzo-
´
monoaza crown ethers from the cyclization of phenol-aza-phenol
derivatives with an appropriate ditosylated compound in the
presence of K2CO3.8 In both cases it should be noted that the cy-
clization of the crown ring with various chain lengths of ditosylated
compounds gave only a single type of macrocycle, i.e., [1þ1]
The present work, therefore, focuses on an investigation of the
selective crown ether based macrocyclization of HBA with
* Corresponding author. Tel.: þ66 2218 4134; fax: þ66 2215 4459.
E-mail address: csuwabun@chula.ac.th (S. Chirachanchai).
Scheme 1. N,N-Bis(2-hydroxyalkylbenzyl)alkylamine (HBA).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.04.093

5856
S. Chirachanchai et al. / Tetrahedron 65 (2009) 5855–5861
Scheme 2. Feasible products of reaction of 1 and 1,3-bis(tosyloxy)propane.
ditosylated compounds by varying the chain lengths of ditosylated
compounds, as well as the HBA derivatives, to determine the factors
involved in the selectivity of macrocyclization.
Figure
1c
shows
the
parent
peak
(MþHþ)
at
m/z¼340.23, which indicates the structure of 3c. The elemental
analysis result also confirms the most appropriate structure of 3c. All
results indicate that the reaction of 1 with 1,3-bis(tosyloxy)propane
gives only [1þ1] macrocycle, 3c, in high yield (80%) after re-
crystallization. It is possible that other 20% yields were by-products,
as shown in Scheme 2. However, it should be noted that the [1þ1]
compound obtained did not show any minor peaks belonging to the
by-products, in either the NMR or the MALDI-TOF MS spectra. The
calculated data were equal to that of the found data in EA, including
the same single crystal results even though we randomly used dif-
ferent crystals. This implies that the reaction yielded a single type of
cyclic product with some unreacted species. In order to identify how
the reaction provides the [1þ1] macrocycle, various chain lengths of
the available commercially ditosylated compounds were used.
When 1 was reacted with four, five, or eight atomic chain lengths of
the ditosylated compound, the reaction gave a single type of [1þ1]
cyclic compounds, i.e., 4, 5, and 6, respectively (Table 1). This sug-
gests that [1þ1] macrocyclization is selectively derived from the
structure of 1 itself rather than from the chain lengths of the dito-
sylated compounds. In order to confirm that the structure of HBA
induces the selective macrocyclization, 2 was used instead of 1.
2. Results and discussion
2.1. Structural characterization
In order to initiate a nucleophilic reaction between the phenol
and tosyl groups, an excess amount of base, i.e., NaOH (2.1 mmol),
was added. Compound 1 provides various possible products, i.e., 3a,
3b, 3c, and 3d, when it was reacted with 1,3-bis(tosyloxy)propane
(Scheme 2). Compound 1 showed the broad peak of the hydroxyl
group and the C–N stretching at 3399 and 1243 cm
3, the FTIR spectrum shows the disappearance of the hydroxyl group
at 3300–3500 cmꢀ1, the peak shift of C–N stretching to 1213 cmꢀ1
.
ꢀ116 In the case of
,
referring to the change in vibrational mode, and the new ether peak
at 1053 cmꢀ1, implying successful etherification (Fig. 1a). The 1H
NMR spectrum (Fig. 1b) indicates the chemical shifts of the methy-
lene protons of CH2–CH2–CH2 and O–CH2–CH2 at 2.11 and 4.11, re-
spectively. This shows that the etherification was successful at the
two hydroxyl groups of 1 and the possible products are 3a–3d.
Figure 1. Structural characterization of 3c; (a) FTIR spectrum, (b) 1H NMR spectrum, and (c) MALDI-TOF mass spectrum.

S. Chirachanchai et al. / Tetrahedron 65 (2009) 5855–5861
5857
Table 1
Macrocyclic compounds obtained when 1 or 2 reacts with various ditosylated compounds
Ditosylated compound
HBA
No cyclization
No cyclization
Ethylene di(p-toluene sulfonate)
atomic chain lengths¼2
1,3-Bis(tosyloxy)propane
atomic chain lengths¼3
1,4-Bis(tosyloxy)butane
atomic chain lengths¼4
Ditosylated diethylene glycol
atomic chain lengths¼5
Ditosylated triethylene glycol
atomic chain lengths¼8
No cyclization
Ditosylated tetraethylene glycol
No cyclization
atomic chain lengths¼11
Actually, the reaction of 2 was done using the same procedures as in
the cases of 1. However, [2þ2] macrocycles, (7 and 8), were obtained
when 2 was reacted with three or four atomic chain lengths of the
ditosylated compound (Table 1). In addition, Table 1 demonstrates
that [1þ1] macrocycle, 10, was achieved by the reaction of 2 with
a ditosylated chain length of eight. This implies that 2, the structure
of which consists of a bulky group at the N atom, provides both types
of macrocycles, i.e., [1þ1] and [2þ2]macrocycles. Theresult from the
single crystal analysis shows that 9 was obtained by the reaction of 2
with five ditosylated chain lengths (Fig. 2). This implies unsuccessful
macrocyclization. Combining the results of 1 and 2, we may con-
clude that the structure of HBAinduces selectivemacrocyclization to
obtain either [1þ1] or [2þ2] macrocycles. (See a further discussion in
effect of HBA derivatives to selective macrocyclization.) Although the
macrocyclization of HBA derivatives with three, four, five, or eight
atomic chain lengths of the ditosylated compounds was successful,
that of HBA derivatives with two or eleven atomic chain lengths of
the ditosylated compounds was not successful (Table 1). This might
be because (i) the preparation conditions are not suitable for these
cases, and (ii) the chain lengths of the ditosylated compounds are too
short or too long for macrocyclization.
2.2. Single crystal analysis
In order to identify the macrocyclic structure, single crystal analysis
was applied. The single crystals of products derived from 1 or 2 were

5858
S. Chirachanchai et al. / Tetrahedron 65 (2009) 5855–5861
2.3. Effect of HBA derivatives to selective macrocyclization
To study the selective macrocyclization of the HBA derivative
systematically, we controlled the basic structure of HBA by using
a phenol derivative with methyl groups at ortho and para posi-
tions, but varying the substitutional group at N atom. Here, we
chose 1 and 2, of which the substitutional group at N atom is
methyl and cyclohexyl groups, respectively, as representative
compounds for the study. Table 1 shows that 1 gives only [1þ1]
macrocycles (3–6), even though it was reacted with three, four,
five, or eight ditosylated chain lengths. This implies that the
chain lengths of the ditosylated compound are not the main
factor to induce the selective macrocyclization. In other words,
the structure of HBA itself controls the reaction to provide only
a single type of macrocycle. It is important to note that the se-
lective macrocycles are obtained in high yield (70–80%) via
simple reaction without complicated purification steps. This
simple, effective, and selective macrocyclization might be due to
the synergistic effects of hydrogen-bonded HBA and the metal
template used in the reaction.18 In addition, Table 1 demon-
strates that 2 gives both [1þ1] and [2þ2] macrocycles. For ex-
ample, the reaction of 2 with three or four ditosylated chain
lengths gives [2þ2] macrocycle, (7 and 8), whereas [1þ1] mac-
rocycle, 10, was obtained in the case of eight ditosylated chain
lengths. Although it is difficult to prove how the reaction gives
[1þ1] or [2þ2] cyclic compounds, since there are no in-
termediates during the one-pot reaction, we speculate that the
reaction between 2 and short chain lengths of the ditosylated
compound prefers to form [2þ2] macrocycles due to the com-
bined effects of (i) the bulkiness of the cyclohexyl group and (ii)
the shortness and stiffness of the ditosylated chain leading to the
obstruction of [1þ1] macrocyclization. In the past, we also pro-
posed the unique structures of the inter- and intramolecular
hydrogen bond network of HBA caused asymmetric reactions.13,14
Taking this into consideration, we suspect a mechanism (Scheme 3)
in which only one hydroxyl group of HBA might be conjugated
with the ditosylated compound, whereas another hydroxyl group
still maintains the intramolecular hydrogen bond leading to in-
termediate compounds. Consequently, two intermediate com-
pounds were reacted together to form [2þ2] macrocycles (7 and
8). On the other hand, in the case of 10, [1þ1] macrocyclization
Figure 2. ORTEP drawing of 9. Hydrogen atoms are omitted for clarity.
obtained by slowly cooling over a few days at room temperature under
the mixed solvent of isopropanol and chloroform with 2:1 or 3:2 v/v,
respectively. For the reaction of 1 with the ditosylated compound, the
single crystallographic analysis reveals that cyclic compounds (3, 4,
and 6) consist of one molecule of 1 linked with one molecule of
ditosylated compound to be a single type of [1þ1] macrocycle (Fig. 3).
Macrocycles 3, 4, and 6 are the 12-, 13-, and 17-membered ring, re-
spectively (Fig. 3a–c). Even though all macrocycles are [1þ1] cyclic
compounds, their crystal systems are different. The structure of 3 is
triclinic, space group P1 (no. 2); that of 4 is monoclinic, space group
P21 (no. 4); and that of 6 is orthorhombic, space group Pna21 (no. 33).
For the reaction of 2 with the ditosylated compound, the single crys-
tallographic analysis demonstrates that 7 and 8 consist of two mole-
cules of 2 linked with two molecules of ditosylated oxyalkane to form
[2þ2] macrocycles (Fig. 3d and e), whereas 10 contains one molecule
of 2 linked with one molecule of ditosylated triethylene glycol to form
the [1þ1] macrocycle (Fig. 3f). All macrocyclic compounds are triclinic,
space group P1 (no. 2). This suggests that the reaction of 2 with three,
four, or eight ditosylated chain lengths provides both types of mac-
rocycles, i.e., [1þ1] and [2þ2] macrocycles. In the case of the reaction
of 2 with ditosylated diethylene glycol, the crystallographic data
indicate that 9 forms a combination of a fragment of 2 and the
ditosylated group of ditosylated diethylene glycol through ionic
bond (Fig. 2). This implies that the macrocyclization of fraction 2
with five atomic chain lengths of the ditosylated compound under
the presence of NaOH in acetonitrile was not successful.
Figure 3. ORTEP drawings of (a) 3, (b) 4, (c) 6, (d) 7, (e) 8, and (f) 10. Hydrogen atoms are omitted for clarity.

S. Chirachanchai et al. / Tetrahedron 65 (2009) 5855–5861
5859
4. Experimental
4.1. Chemicals
Paraformaldehyde, methylamine, cyclohexylamine, 2,4-dime-
thylphenol, sodium sulfate anhydrous, diethylene glycol, tri-
ethylene glycol ditosylated, and p-toluenesulfonyl chloride were
purchased from Fluka, Switzerland. The 1,3-bis(tosyloxy)propane
and 1,4-butanediol were obtained from TCI, Japan. Sodium
hydroxide and isopropanol were obtained from Carlo Erba, Italy.
Diethyl ether, 1,4-dioxane, acetonitrile, chloroform, dichloro-
methane, and tetraethylene glycol ditosylated were obtained from
Labscan, Ireland. Deuterated chloroform and ethylene di(p-tolue-
nesulfonate) were purchased from Aldrich, Germany. All chemicals
were used as received.
4.2. Instruments and equipment
Melting points were measured by a YANACO micro melting
point apparatus. Fourier transform infrared spectra (FTIR) were
recorded by a HORIBA FT-720 infrared spectrophotometer in the
range 4000–400 cmꢀ1 at a resolution of 4 cmꢀ1. Proton nuclear
magnetic resonance spectra (1H NMR) were obtained from a Varian
Mercury-400BB spectrometer. Mass spectra were analyzed by
a PerSeptive Biosystems/Vestec matrix-assisted laser desorption
ionization time-of-flight mass spectrometer (MALDI-TOF MS) or
a JEOL JMS-HX100 fast atom bombardment mass spectrometer
(FAB MS). Elemental analysis was carried out using a YANACO CHN
Corder MT-5. Single crystal X-ray analysis was done by using
a Rigaku RAXIS-RAPID imaging-plate diffractometer and the Crys-
talStructure3.8 crystallographic software package.
4.3. Synthesis
Scheme 3. Proposed mechanism of [2þ2] macrocyclization.
4.3.1. HBA derivatives (1 and 2)
N,N-Bis(2-hydroxy-3,5-dimethylbenzyl)methylamine, 1, and
N,N-bis(2-hydroxy-3,5-dimethylbenzyl)cyclohexylamine, 2, were
prepared from 3,4-dihydro-3,6,8-trimethyl-2H-1,3-benzoxazine
and 3,4-dihydro-6,8-dimethyl-3-cyclohexyl-2H-1,3-benzoxazine,
respectively, via the ring-opening reaction with 2,4-dimethyl
phenol.16,19
was satisfied. This might be because the appropriate chain
lengths, i.e., eight atomic chain lengths, together with four oxygen
atoms of the ditosylated compound, provide a flexible chain to
exactly match one molecule of 2 and one molecule of the dito-
sylated compound, leading to the [1þ1] macrocyclization (Fig. 3f).
It should be noted that when the ditosylated compound has five
atomic chain lengths, the cyclization was not accomplished, as
seen in the case of 9 (Table 1). A possible explanation for this is
that the five-ditosylated chain lengths are flexible but too short
for the [1þ1] macrocyclization of 2. Therefore, the structure of
macrocycle might be distorted, resulting in cleavage of the mac-
rocycle giving the final product of 9 (Fig. 2). Combining the results
derived from 1 and 2, we identify that both types, [1þ1] and
[2þ2] macrocycles, were controlled by the structure of HBA. For
HBA consisting of methyl groups at ortho and para positions, and
at N atom, the reaction gives only the [1þ1] macrocycle. For HBA
with the methyl group at ortho and para position, but a cyclohexyl
group at N atom, the reaction gives both [1þ1] and [2þ2]
macrocycles.
4.3.2. [1þ1] Macrocycles (3–6)
[1þ1] Macrocycles (3–6) were obtained by the etherification of 1
with ditosylated derivatives as follows: 1,3-bis(tosyloxy)propane
(0.385 g, 1 mmol) was dropwisely added into the solution of 1
(0.299 g, 1 mmol) with sodium hydroxide (0.084 g, 2.1 mmol) in
acetonitrile (150 mL) and refluxed at 105 ꢁC for 3 days. The solvent
was removed to obtain the crude product, 3, which was recrystal-
lized in a mixed solvent of isopropanol and chloroform (2:1, v/v).
The single crystals were characterized by X-ray single crystal
analysis.20 Similarly, 4, 5, and 6 were prepared by using the same
procedures as 3.17,21 However, 1,4-bis(tosyloxy)butane (0.398 g,
1 mmol), ditosylated diethylene glycol (0.414 g, 1 mmol), and
ditosylated triethylene glycol (0.458 g, 1 mmol) were used instead
of 1,3-bis(tosyloxy)propane (0.385 g, 1 mmol) to obtain 4, 5, and 6,
respectively. The products were analyzed by FTIR, 1H NMR, MALDI-
TOF MS, EA, and X-ray single crystal analysis.
3. Conclusion
Compound 3: 80% yield; mp¼123–125 ꢁC; FTIR (KBr, cmꢀ1):
1480 (vs, tri-substituted benzene), 1213 (vs, C–N stretching), 1053
(s, C–O–C); 1H NMR (400 MHz, CDCl3, ppm): dH 1.94 (3H, s, N–CH3),
2.11 (2H, t, CH2–CH2–CH2, J¼7.98 Hz), 2.25 (12H, s, Ar–CH3), 3.62
(4H, s, Ar–CH2–N), 4.11 (4H, t, Ar–O–CH2, J¼7.98 Hz), 6.79 (2H, s, Ar–
H), 6.91 (2H, s, Ar–H); 13C NMR (100 MHz, CDCl3, ppm): dC 16.26,
20.58, 31.38, 39.85, 62.45, 76.77, 130.02, 130.90, 131.01, 131.30,
132.16, 154.16. MALDI-TOF MS: m/z 340.23 (MþHþ). Anal. Calcd for
The present work presents the achievement of the selective
crown ether based macrocyclization of HBA with ditosylated
compounds to obtain selective macrocycles in high yield via
a simple reaction. The structure of HBA is a key factor to induce
selective macrocycles. An understanding of the effect of the
substituted group of HBA on the selective macrocyclization will
help in molecular design to obtain the as-desired macrocycles.

5860
S. Chirachanchai et al. / Tetrahedron 65 (2009) 5855–5861
C22H29NO2: C, 77.84; H, 8.61; N, 4.13; O, 9.42%. Found: C, 77.63; H,
8.40; N, 4.12%. Crystal data for 3: C22H29NO2, M¼339.48, triclinic,
Compound 8: 65% yield; mp¼219–220 ꢁC; FTIR (KBr, cmꢀ1):
1473 (s, tri-substituted benzene), 1209 (vs, C–N stretching), 1051 (s,
C–O–C); 1H NMR (400 MHz, CDCl3, ppm): dH 1.97 (4H, m, CH2), 2.01
(8H, m, O–CH2–CH2), 2.22–2.34 ((24H, s, Ar–CH3) and (16H, m,
CH2)), 2.46 (2H, m, CH), 3.56 (8H, s, Ar–CH2–N), 4.02 (8H, m, O–CH2–
CH2), 6.85 (4H, s, Ar–H), 6.92 (4H, s, Ar–H). MALDI-TOF MS: m/z
844.55 (MþHþ). Anal. Calcd for C56H78N2O4: C, 79.76; H, 9.32; N,
3.32; O, 7.59%. Found: C, 77.27; H, 9.03; N, 3.39%. Crystal data for 8:
C56H78N2O4, M¼843.24, triclinic, a¼10.1109(5) Å, b¼11.2701(5) Å,
a¼9.2230(3) Å, b¼10.2768(3) Å, c¼11.4606(4) Å,
a
¼111.6953(10)ꢁ,
b
¼95.7124(11)ꢁ,
g
¼99.7462(10)ꢁ, V¼979.04(5) Å3, T¼296 K, space
group P1 (no. 2), Z¼2,
m
(Mo K
a
)¼0.726 cmꢀ1, 3491 reflections
measured, 599 unique (Rint¼0.025), which were used in all calcu-
lations. The final R1¼0.0336 and wR2¼0.0999.
Compound 4: 76% yield; mp¼171–173 ꢁC; FTIR (KBr, cmꢀ1):
1481 (vs, tri-substituted benzene), 1213 (vs, C–N stretching), 1076
(vs, C–O–C); 1H NMR (400 MHz, CDCl3, ppm): dH 1.96 (3H, s, N–
CH3), 2.00 (4H, t, O–CH2–CH2, J¼7.92 Hz), 2.25 (12H, s, Ar–CH3), 3.55
(4H, s, Ar–CH2–N), 4.01 (4H, t, O–CH2–CH2, J¼7.92 Hz), 6.85 (2H, s,
Ar–H), 6.92 (2H, s, Ar–H). MALDI-TOF MS: m/z 354.13 (MþHþ). Anal.
Calcd for C23H31NO2: C, 78.15; H, 8.84; N, 3.96; O, 9.05%. Found: C,
77.35; H, 8.82; N, 3.88%. Crystal data for 4: C23H31NO2, M¼353.50,
monoclinic, a¼8.8186(3) Å, b¼8.9144(3) Å, c¼12.8234(4) Å,
c¼11.9581(6) Å,
a
¼104.883(3)ꢁ,
b
¼90.099(3)ꢁ,
g
¼109.335(3)ꢁ,
V¼1237.01(10) Å3, T¼213 K, space group P1 (no. 2), Z¼1,
m(Cu
Ka
)¼5.381 cmꢀ1
, 12,796 reflections measured, 4399 unique
(Rint¼0.089), which were used in all calculations. The final
R1¼0.1060 and wR2¼0.2719.
4.3.4. Compound 9
b
¼92.9630(17)ꢁ, V¼1006.73(5) Å3, T¼213 K, space group P21 (no.
Compound 9 was achieved by using the same procedures as 7,
but using ditosylated diethylene (0.414 g, 1 mmol) instead of 1,3-
bis(tosyloxy)propane (0.385 g, 1 mmol) as the starting compound.
Compound 9: 90% yield; mp¼223–225 ꢁC; FTIR (KBr, cmꢀ1):
3312 (w, –NH–), 1484 (vs, tri-substituted benzene), 1364 (s,
O]S]O), 1221 (s, C–N stretching), 1177 (vs, O]S]O); 1H NMR
(400 MHz, CDCl3, ppm): dH 0.70 (4H, m, CH2), 0.95 (4H, m, CH2), 1.15
(2H, m, CH2), 1.68 (2H, m, CH2), 2.20 (3H, s, Ar–CH3), 2.32 (3H, s,
Ar–CH3), 2.38 (3H, s, S–Ar–CH3), 2.69 (1H, m, CH), 3.52 (2H, t, CH2–
CH2–O, J¼3.69 Hz), 3.88 (2H, s, Ar–CH2–N), 4.02 (2H, t, S–O–CH2,
J¼3.84 Hz), 6.72 (1H, s, Ar–H), 6.85 (1H, s, Ar–H), 7.18 (2H, d, S–Ar–
H, J¼1.59 Hz), 7.30 (2H, d, S–Ar–H, J¼1.59 Hz), 7.70 (4H, m, S–Ar–H).
FAB MS: m/z 234.2. Anal. Calcd for C22H31NSO4: C, 65.15; H, 7.70; N,
3.45; O, 15.78; S, 7.91%. Found: C, 64.74; H, 7.69; N, 3.36; S, 7.05%.
Crystal data for 9: C22H31NSO4, M¼405.55, monoclinic,
4), Z¼2,
m
(Cu K
a
)¼5.708 cmꢀ1, 10,556 reflections measured, 3577
unique (Rint¼0.068), which were used in all calculations. The final
R1¼0.1097 and wR2¼0.3422.
Compound 5: 70% yield; mp 90–91 ꢁC; FTIR (KBr, cmꢀ1): 1481
(vs, tri-substituted benzene), 1221 (vs, C–N stretching), 1053 (s, C–
O–C); 1H NMR (400 MHz, CDCl3, ppm): dH 2.10 (3H, s, N–CH3), 2.30
(12H, s, Ar–CH3), 3.79 (4H, s, Ar–CH2–N), 3.95 (4H, t, CH2–O–CH2,
J¼3.52 Hz), 4.07 (4H, t, Ar–O–CH2, J¼3.52 Hz), 6.84 (2H, s, Ar–H),
6.93 (2H, s, Ar–H); 13C NMR (100 MHz, CDCl3, ppm): dC 16.32, 20.79,
39.76, 58.03, 72.06, 77.06, 130.84, 131.01, 131.28, 131.33, 132.44,
154.41. MALDI-TOF MS: m/z 370.32 (MþHþ). Anal. Calcd for
C23H31NO3: C, 74.47; H, 8.40; N, 3.79; O, 13.34%. Found: C, 74.47; H,
8.41; N, 3.87%.
Compound 6: 80% yield; mp¼97–100 ꢁC; FTIR (KBr, cmꢀ1): 1489
(vs, tri-substituted benzene), 1209 (vs, C–N stretching), 1057 (s, C–
O–C); 1H NMR (400 MHz, CDCl3, ppm): dH 2.17 (3H, s, N–CH3), 2.24
(12H, s, Ar–CH3), 3.71 (4H, s, Ar–CH2–N), 3.80–3.83 (8H, m, CH2–O–
CH2), 3.95–3.99 (4H, m, Ar–O–CH2), 6.84 (2H, s, Ar–H), 7.12 (2H, s,
Ar–H); 13C NMR (100 MHz, CDCl3, ppm): dC 16.29, 20.76, 41.96,
55.25, 70.81, 72.37, 77.00, 128.96, 130.19, 130.25, 132.10, 133.15,
153.84. MALDI-TOF MS: m/z 414.26 (MþHþ). Anal. Calcd for
C25H35NO4: C, 72.61; H, 8.53; N, 3.39; O, 15.47%. Found: C, 72.41; H,
8.38; N, 3.38%. Crystal data for 6: C25H35NO4, M¼413.56, ortho-
a¼25.1142(6) Å, b¼10.0918(3) Å, c¼16.3733(4) Å,
b
¼94.3394(15)ꢁ,
V¼4137.88(17) Å3, T¼123 K, space group C2/c (no. 15), Z¼8,
m(Cu
K
a
)¼16.164 cmꢀ1
, 20,057 reflections measured, 3777 unique
(Rint¼0.104), which were used in all calculations. The final
R1¼0.0885 and wR2¼0.2845.
4.3.5. [1þ1] Macrocycle 10
[1þ1] Macrocycle, 10 was achieved by using the same pro-
cedures as 6, but using 2 (0.367 g, 1 mmol) instead of 1 (0.299 g,
1 mmol) as the starting compound. The crude product was
recrystallized by the mixed solvent of isopropanol and chloroform
(3:2, v/v).
rhombic,
a¼18.0895(4) Å,
b¼8.9394(2) Å,
c¼14.4691(3) Å,
V¼2339.79(9) Å3, T¼296 K, space group Pna21 (no. 33), Z¼4,
m(Mo
K
a
)¼0.783 cmꢀ1
,
7677 reflections measured, 388 unique
(Rint¼0.019), which were used in all calculations. The final
Compound 10: 79% yield; mp¼115–118 ꢁC; FTIR (KBr, cmꢀ1):
1479 (s, tri-substituted benzene), 1209 (vs, C–N stretching), 1058 (s,
C–O–C); 1H NMR (400 MHz, CDCl3, ppm): dH 1.12 (2H, m, CH2), 1.36
(2H, m, CH2), 1.58 (2H, m, CH2), 1.75 (2H, m, CH2), 1.98 (2H, m, CH2),
2.22 (6H, s, Ar–CH3), 2.26 (6H, s, Ar–CH3), 2.44 (1H, m, CH), 3.75 (4H,
s, Ar–O–CH2–CH2–O–CH2), 3.78 (4H, s, Ar–CH2–N), 3.82 (4H, m, Ar–
O–CH2–CH2), 3.92 (4H, m, Ar–O–CH2), 6.79 (2H, s, Ar–H), 7.25 (2H, s,
Ar–H); 13C NMR (100 MHz, CDCl3, ppm): dC 16.01, 20.53, 24.96,
25.99, 28.01, 47.47, 58.78, 70.25, 72.14, 77.00, 128.88, 129.77, 130.57,
130.69, 133.05, 153.61. MALDI-TOF MS: m/z 483.21 (MþHþ). Anal.
Calcd for C30H43NO4: C, 74.81; H, 9.00; N, 2.91; O, 13.29%. Found: C,
71.23; H, 8.57; N, 4.28%. Crystal data for 10: C30H43NO4, M¼481.67, tri-
R1¼0.0290 and wR2¼0.0804.
4.3.3. [2þ2] Macrocycles (7 and 8)
[2þ2] Macrocycles (7 and 8) were prepared from the same
procedures as 3 and 4, respectively, but using 2 (0.367 g, 1 mmol)
instead of 1 (0.299 g, 1 mmol) as the starting compound. The crude
product was recrystallized by the mixed solvent of isopropanol and
chloroform (3:2, v/v).
Compound 7: 68% yield; mp¼206–207 ꢁC; FTIR (KBr, cmꢀ1):
1481 (vs, tri-substituted benzene), 1209 (vs, C–N stretching), 1056
(s, C–O–C); 1H NMR (400 MHz, CDCl3, ppm): dH 1.26 (4H, m, CH2),
1.90 (4H, m, CH2–CH2–CH2), 2.20–2.27 ((24H, s, Ar–CH3) and (16H,
m, CH2)), 2.44 (2H, m, CH), 3.66 (8H, s, Ar–CH2–N), 3.88 (8H, t, Ar–
O–CH2, J¼6.75 Hz), 6.82 (4H, s, Ar–H), 7.33 (4H, s, Ar–H). FAB MS: m/z
408.4 (MþHþ). Anal. Calcd for C54H74N2O4: C, 79.56; H, 9.15; N, 3.44;
O, 7.85%. Found: C, 77.27; H, 9.01; N, 3.99%. Crystal data for 7:
C54H74N2O4, M¼815.19, triclinic, a¼9.8551(3) Å, b¼9.8809(4) Å,
clinic, a¼10.2934(5) Å, b¼11.0830(5) Å, c¼13.8177(6) Å,
a
¼70.900(3)ꢁ,
b
¼79.973(3)ꢁ,
g
¼74.412(3)ꢁ, V¼1428.34(11) Å3, T¼273 K, space group
P1 (no. 2), Z¼2,
m
(Cu K
a
)¼5.771 cmꢀ1, 14,840 reflections measured,
5091 unique (Rint¼0.392), which were used in all calculations. The
final R1¼0.1699 and wR2¼0.5297.
c¼13.7754(4) Å,
a
¼90.004(2)ꢁ,
b
¼99.8559(18)ꢁ,
g
¼115.8896(16)ꢁ,
Acknowledgements
V¼1184.74(7) Å3, T¼213 K, space group P1 (no. 2), Z¼1,
m(Cu
K
a
)¼5.464 cmꢀ1
,
12,516 reflections measured, 4229 unique
The authors acknowledge the financial support from the Thai-
land Research Fund (Royal Golden Jubilee Ph.D. Program, Grant No.
PHD/0068/2548 and Research Scholar Award, Grant No.
(Rint¼0.102), which were used in all calculations. The final R1¼0.1297
and wR2¼0.4090.

S. Chirachanchai et al. / Tetrahedron 65 (2009) 5855–5861
5861
3. Laidler, D. A.; Stoddart, J. F. In Crown Ethers and Analogs; Patai, S., Rappoport, Z.,
Eds.; John Wiley & Sons: New York, NY, 1989; pp 1–57.
4. Xing, L.; Ziener, U.; Sutherland, T. C.; Cuccia, L. A. Chem. Commun. 2005, 5751–
5753.
5. Zhang, L.-J.; Lin, H.-K.; Bu, X.-H.; Chen, Y.-T.; Liu, X.-L.; Miao, F.-M. Inorg. Chim.
Acta 1995, 240, 257–262.
RSA4680025). The authors thank Assoc. Prof. Norimitsu Tohnai and
Asst. Prof. Ichiro Hisaki, Division of Advanced Science and Bio-
technology, Graduate School of Engineering, Osaka University, Ja-
pan, for 13C NMR measurements and their valuable discussions.
Appreciation is also extended to Prof. Kohji Tashiro, Department of
Future Industry-Oriented Basic Science and Materials, Graduate
School of Engineering, Toyota Technological Institute, Japan, for
some single crystal analysis works.
6. Demirel, N.; Bulut, Y. Tetrahedron: Asymmetry 2003, 14, 2633–2637.
7. Charbonnie`re, L. J.; Ziessel, R. F. Tetrahedron Lett. 2000, 41, 2373–2376.
´
´
¨
¨
8. Agai, B.; Nemeth, V.; Bocskei, Z.; Simon, K.; Bitter, I.; Toke, L. Tetrahedron 1996,
52, 6713–6724.
9. Laobuthee, A.; Ishida, H.; Chirachanchai, S. J. Inclusion Phenom. Macrocyclic
Chem. 2003, 47, 179–185.
Supplementary data
10. Laobuthee, A.; Chirachanchai, S. Chem. Lett. 2002, 31, 614–615.
11. Chirachanchai, S.; Phongtamrug, S.; Laobuthee, A. Chem. Lett. 2003, 32,
432–433.
Crystallographic data (excluding structure factors) for the
structures in this paper have been deposited with the Cambridge
Crystallographic Data Centre as supplementary publication num-
bers CCDC 671193 (3), 671194 (4), 671195 (6), 701834 (7), 701835 (8),
701836 (9), and 701837 (10). Copies of the data can be obtained, free
of charge, on application to CCDC, 12 Union Road, Cambridge CB2
1EZ, UK, (fax: þ44 1223 336033 or e-mail: deposit@ccdc.cam.ac.uk).
Supplementary data associated with this article can be found in the
online version, at doi:10.1016/j.tet.2009.04.093.
12. Phongtamrug, S.; Chirachanchai, S.; Tashiro, K. Macromol. Symp. 2006, 242,
40–48.
13. Laobuthee, A.; Chirachanchai, S.; Ishida, H.; Tashiro, K. J. Am. Chem. Soc. 2001,
123, 9947–9955.
14. Phongtamrug, S.; Pulpoka, B.; Chirachanchai, S. Supramol. Chem. 2004, 16,
269–278.
15. Phongtamrug, S.; Miyata, M.; Chirachanchai, S. Chem. Lett. 2005, 34, 634–635.
16. Phongtamrug, S.; Tashiro, K.; Miyata, M.; Chirachanchai, S. J. Phys. Chem. B 2006,
110, 21365–21370.
17. Rungsimanon, T.; Laobuthee, A.; Miyata, M.; Chirachanchai, S. J. Inclusion Phe-
nom. Macrocyclic Chem. 2008, 62, 333–338.
18. Chirachanchai, S.; Phongtamrug, S.; Rungsimanon, T. Tetrahedron Lett. 2008, 49,
3181–3184.
19. Laobuthee, A. Ph.D. Thesis in Polymer Science, The Petroleum and Petro-
chemical College, Chulalongkorn University, Bangkok, Thailand, 2002.
20. CrystalStructure 3.8: Crystal Structure Analysis Package, Rigaku and Rigaku/
MSC(2000–2006). 9009 New Trails Dr. The Woodlands TX 77381, USA.
21. Rungsimanon, T.; Laobuthee, A.; Miyata, M.; Chirachanchai, S. Chem. Lett. 2008,
37, 1108–1109.
References and notes
1. Dietrich, B. In Encyclopedia of Supramolecular Chemistry; Atwood, J. L., Steed,
J. W., Eds.; Marcel Dekker: New York, NY, 2004; Vol. 1, pp 830–844.
2. Dietrich, B.; Viout, P.; Lehn, J.-M. Macrocyclic Chemistry: Aspects of Organic and
Inorganic Supramolecular Chemistry; VCH: New York, NY, 1992; pp 65–71.