Structural studies and binding properties of pendant diazacoronands-precursors to macrocyclic compounds of planar chirality

Article abstract of DOI:10.1016/j.tet.2006.04.024

Structural studies of pendant diazacoronands having an N-benzoyl, N-acetyl, O-benzyl or O-benzoyl side arm were performed by means of X-ray and temperature-dependent ¹H NMR experiments. The energies of macroring flipping process were determined

Full text of DOI:10.1016/j.tet.2006.04.024

Tetrahedron 62 (2006) 5905–5914
Structural studies and binding properties of pendant
diazacoronands—precursors to macrocyclic compounds
of planar chirality
Jaros1aw Kalisiak,a Ewa Kalisiakb and Janusz Jurczaka,b,
*
aInstitute of Organic Chemistry, Polish Academy of Sciences, Kasprzaka 44/52, 01-224 Warsaw, Poland
bDepartment of Chemistry, University of Warsaw, Pasteura 1, 02-093 Warsaw, Poland
Received 10 February 2006; revised 21 March 2006; accepted 6 April 2006
Available online 2 May 2006
Abstract—Structural studies of pendant diazacoronands having an N-benzoyl, N-acetyl, O-benzyl or O-benzoyl side arm were performed
by means of X-ray and temperature-dependent 1H NMR experiments. The energies of macroring flipping process were determined for three
pendant diazacoronands. The complexation properties of pendant diazacoronands toward the alkali metal cations (Na+, K+, and Rb+) were
estimated by ESI-MS experiments.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
jump through it; (2) the presence of a non-symmetric moiety
in the molecule (Scheme 1).
The design and synthesis of macrocyclic compounds are
closely related to the supramolecular chemistry and host–
guest interactions.1 However, up to now, no special effort has
been made to prepare receptors of planar chirality.2 Among
the known macrocyclic compounds of planar chirality,
most of them are based on a [2.2]paracyclophane framework
having small, rigid macroring structure.3 For these reasons,
they cannot be efficient receptors for supramolecular appli-
cations. Hitherto, only several examples of such chiral com-
pounds having a larger macroring have been published.4 This
is probably caused by the difficult preparation sequence re-
quiring non-commercially available substrates. In addition,
contrary to the [2.2]paracyclophane derivatives, the chiral
compounds having larger macroring are conformationally
flexible, thus their structural analysis and determination of
energy barrier of deformation are indispensable to the design
and synthesis of stable atropoisomers.5
R
R
Scheme 1. The source of planar chirality in the pendant macrocyclic
compounds.
The intraannular arm is an essential part of the presented
planar–chiral system. Its size strongly affects the stability
of such enantiomers and additionally it could modify the
binding properties of the macrocyclic compounds. There-
fore, the synthesis of efficient and stable macrocyclic recep-
tors of planar chirality requires initial structural studies for
simpler, non-chiral pendant diazacoronands. Additionally,
knowledge of the influence of the type of intraannular group
on the binding properties makes it possible to design appro-
priate chiral receptors.
Recently, our attention has been focused on the synthesis
of diazacoronands of planar chirality, as potential receptors
for supramolecular applications.6 To the existence of such
atropoisomers, two independent requirements are indispens-
able: (1) the presence of a large pendant arm, which is
located on only one side of the macroring and cannot easily
In this contribution, we would like to present the conforma-
tional analysis of pendant diazacoronands investigated by
variable temperature 1H NMR spectroscopy and X-ray anal-
ysis. The binding properties of pendant diazacoronands
toward alkali metal cations (Na+, K+, and Rb+) were esti-
mated by the electrospray ionization mass spectrometry
(ESI-MS) experiments.
Keywords: Binding properties; Diazacoronands; ESI-MS; Supramolecular
chemistry.
* Corresponding author. Tel.: +48 22 632 05 78; fax: +48 22 632 66 81;
e-mail: jurczak@icho.edu.pl
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.04.024

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J. Kalisiak et al. / Tetrahedron 62 (2006) 5905–5914
O
O
2. Results and discussion
N
N
O
O
O
O
2.1. Synthesis
H
H
O
O
O
O
H /Pd
2
OH
O
MeOH
For the preparation of the title compounds, the double-
amidation reaction was applied. In this reaction, originally
introduced by Tabushi,7 and developed in our laboratory,8 di-
methyl a,u-dicarboxylates react with a primary a,u-diamine
in the presence of MeOꢀ under non-high dilution conditions.
For example, diazacoronand 3 was prepared via the reaction
of the appropriate diester 19 with diamine 210 in moderate
yield (15%). To assess the influence of pendant arm on bind-
ing properties, two types of diazacoronands were compared,
namely (1) those having a pendant arm, i.e., 4–7,11 9,6a 10,12
13, and (2) their analogs, compounds 3 and 8,13 unsubstituted
at the intraannular position (Scheme 2).
H
N
H
N
O
O
10 (43%)
11 (90%)
MeI
3
PhCOCl
Py
K CO , CH CN
2
3
O
O
N
N
O
O
O
H
H
O
O
O
O
OMe
O
O
H
N
H
N
O
O
O
OMe
N
O
O
H2N
H2N
O
O
O
H
O
O
O
O
O
MeONa
MeOH
12 (54%)
13 (42%)
+
O
O
H
N
OMe
N
N
O
O
H
H
O
O
O
O
O
O
MeI
3 (15%)
OMe
1
2
OH
O
K CO , CH CN
2
3
3
H
N
H
N
O
O
O
O
N
N
N
O
O
O
O
O
O
O
H
H
H
O
O
O
N
O
O
O
14 (78% from 6)
15 (93%)
N
H
N
H
O
O
O
Scheme 3. Modifications of macrocyclic phenols 11 and 14.
H
N
H
N
H
N
O
O
O
O
methyl bromoacetate. Diester 18 was then examined in
macrocyclization reactions with the diamino-ethers 210 and
19 to afford macrocyclic compounds 20 and 21, respectively
4 (30%)
5 (37%)
6 (54%)
O
O
O
N
H
N
N
H
O
O
O
O
O
H
O
O
O
O
O
O
O
O
O
N
H
OMe
OH
NO2
O
O
O
H
N
H
N
H
N
O
OH
O
O
1) H /Pd/C
2
BrCH COOMe
2
N
H
OH
N
H
O
O
O
K CO
2) CH COCl
3
2
3
7 (70% from 6)
8 (24%)
9 (23%)
OH
OMe
Scheme 2. Pendant diazacoronands 4–7, 9 and their unsubstituted analogs 3
and 8.
O
17 (55%)
18 (80%)
16
An advantage of compounds 6 and 10 is their chemical ver-
satility resulting from the presence of the O-benzyl group.
Starting from diazacoronand 10, the intraannular function
was easily removed by hydrogenation to form the hydroxy
derivative 11 in good yield (90%). Compound 11 could be
modified invarious ways, including alkylation and acylation,
and it was easily transformed into the O-methyl derivative 12
as well as into the O-benzoyl compound 13, in satisfactory
yields of 80% and 42%, respectively (Scheme 3). The alkyl-
ation of phenol 1411 was performed analogously and the ref-
erence O-methyl compound 1514 was isolated in good yield.
H2N
H2N
O
O
O
O
H2N
H2N
2
19
O
O
N
N
H
O
O
O
O
O
O
H
O
O
O
O
N
H
N
H
The syntheses of the reference compounds having the less
sterically demanding N-acetyl intraannular group, were per-
formed via the reaction sequence shown in Scheme 4.
Starting from 2-nitroresorcinol 16, after catalytic reduc-
tion and acylation of the resulting amino group, we obtained
compound 17, which in turn was elongated by means of
H
N
H
N
O
O
20 (19%)
21 (30%)
Scheme 4. The synthesis of N-acetyl diazacoronands 20 and 21.

J. Kalisiak et al. / Tetrahedron 62 (2006) 5905–5914
5907
(Scheme 4). Interestingly, the isolated yields of these com-
pounds are comparable to the yields of N-benzoyl deriva-
tives 4 and 9, although the N-acetyl side arm is sterically
less demanding. Furthermore, the compounds with no intra-
annular group (3 and 8) were synthesized in even lower
yields (15% and 24%, respectively). This proves that the
intraannular group plays an important role in the macro-
cyclization step.
2.2. Structural analysis
2.2.1. Structural analysis of N-substituted compounds.
Diazacoronands 4, 5, and 9 having N-type side arm readily
crystallized from methanolic solutions in a vapor diffusive
system (n-pentane or diethyl ether). X-ray analysis of 4 dis-
played the presence of two types of hydrogen bonds:
Figure 2. X-ray analysis of 5 reveals a ‘molecular zipper’.
Structural analysis of compound 9 reveals a similar shape to
the aliphatic analogs 4 and 5; however, two intramolecular
hydrogen bonds are observed (Fig. 3A). Additionally, the
benzamide function participates in the intermolecular inter-
actions, forming a network of hydrogen bonds with the
methanol molecules (Fig. 3B).
(1) intramolecular between the oxygen atom of the benz-
amide group and the amide function (Fig. 1A);
(2) intermolecular between the proton of the benzamide
group and the oxygen atom from the other molecule
(Fig. 1B).
In addition, the macroring adopts a U-shaped arrange-
ment with the intraannular function turned away from the
macroring.
2.2.2. 1H NMR studies of N-substituted compounds. The
conformational studies of pendant diazacoronands in solu-
tion were performed by means of H NMR spectroscopy.
1
The temperature-dependent experiment was designed to
establish the transition state free energy at the coalescence
temperature (DG#c), which represents the energy barrier of
a macroring flipping process. According to the structural
studies of compounds 4, 5, and 9 in the solid state, the length
of the intraannular group is greater than the diameter of the
macroring, thus the pendant arm cannot easily jump through
it. Therefore, diazacoronands 4, 5, and 9 should exhibit a sat-
isfactory structural stability also in solution. In fact, at room
The solid-state analysis of compound 5 reveals analogous
intra- and intermolecular hydrogen bonds. The pendant
arm is turned out of the macroring as well. The characteristic
crystal packing, observed also for compound 4, is a ‘molec-
ular zipper’. Two chains of molecules of 5 make sides of the
‘zipper’, which are linked together by intermolecular p–p
interactions of the pyridine moieties (Fig. 2).
Figure 1. X-ray analysis of compound 4. (A) Intramolecular hydrogen bond
and (B) intermolecular hydrogen bond.
Figure 3. X-ray analysis of compound 9. (A) Intramolecular hydrogen
bonds and (B) a network of hydrogen bonds.

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J. Kalisiak et al. / Tetrahedron 62 (2006) 5905–5914
The free energy of activation for the macroring flipping pro-
cess (DG#c) was determined by Eyring15 equations using the
experimentally found coalescence temperature Tc.
À
Á
1=2
kc ¼ p=21=2 Dn2 þ 6J2
ð1Þ
ð2Þ
À
Á
DG#c ¼ 2:303RTc 10:32 þ log Tc ꢀ log kc
where kc is a rate constant, Dn is the shift difference at low
temperature and J is a coupling constant. According to
Eq. 2, the values of DG#c were calculated and amounted
to 73.0 kJ/mol for 4, 80.2 kJ/mol for 5, and 77.1 kJ/mol for
21 (Table 1).
To find the reason for the significantly higher structural sta-
bility of diazacoronands with an additional benzene ring (9
and 20), NOESY experiment was carried out for compound
9 (Fig. 5). Strong cross peaks were observed between ali-
phatic and aromatic protons close to the macroring (A and
B in Fig. 5). These findings indicate that the macroring
system is not planar, and it probably adopts a U-shaped con-
formation. The absence of any cross peak between the
N-benzoyl group (dotted line) and the macrocycle protons
suggests that the intraannular function is located out of the
macrocyclic cavity. This assumption is additionally sup-
ported by the fact that chemical shift related to intraannular
NH proton is concentration dependent. This implies involve-
ment of amide NH’s in the intermolecular hydrogen bond-
ing. The result of the NOESY experiment agrees well with
the result of the X-ray analysis for the solid state and gives
no explanation of the higher conformational stability of
compound 9 over compound 4.
Figure 4. The temperature-dependent 1H NMR spectrum of isolated CHaHb
protons of compound 4 in DMSO-d6.
temperature, the protons Ha, Hb of the isolated methylene
group appear as an AB quartet and they are diastereotopic.
The 1H NMR experiment for compound 4 at various temper-
atures revealed coalescence of the AB-type signal at 353 K
(Fig. 4).
To establish the influence of the pyridine moiety on the
structural stability, an analogous experiment was carried
out for compound 5 and the conformational stability was de-
termined to be higher than that of compound 4. The AB-type
signal coalesces only at 390 K.
Considering the similar structural results for diazacoronands
4 and 9, and because the N-benzoyl function is turned away
from the macrocyclic cavity, we proposed the following route
of the macroring flipping process in compound 4 (Fig. 6).
According to our suggestions, not the intraannular group but
the hydrogen atom at para position jumps through the mac-
roring plane. Due to high flexibility of the macroring in com-
pound 4, the N-benzoyl side arm can easily rotate and cross
the plane defined by macroring. In the case of compound 9,
which bears an additional benzene ring, the macroring is
more rigid and such deformation is more energy demanding.
This assumption is additionally supported by the fact that the
reference diazacoronands 20 and 21 with smaller N-acetyl
intraannular function possess comparable conformational
stability as N-benzoyl derivatives 4 and 9. Surprisingly,
according to these findings, the flexibility of the macroring
rather than the size of the intraannular group seems to
have the major influence on the conformational stability of
such diazacoronands. Therefore, the further synthesis of
To verify the influence of the size of the intraannular func-
tion on the conformational stability, an analogous 1H
NMR experiment was carried out for the reference N-acetyl
compound 21. Surprisingly, the AB-type signal coalesces at
373 K, even higher than that of the N-benzoyl derivative 4.
This suggests that the size of the side arm has a minor in-
fluence on the conformational stability of N-substituted
diazacoronands.
1
The H NMR experiments for compounds 9 and 20 have
shown that the widths of the AB-type signals at 373 K are
close to these widths at room temperature. Due to limitation
of the NMR apparatus, we could not establish DG#c for them,
but, from the viewpoint of this work, we could assume that if
the signal of the methylene group did not coalesce at 373 K,
then the pendant diazacoronand possessed conformational
stability sufficient for the further purposes. Our assumption
was also supported by our earlier results where enantiomers
of a non-symmetrical diazacoronand based on the frame-
work of compound 9 retained their enantiomeric purity for
at least six months at room temperature and even extended
boiling of solutions in acetonitrile (24 h) did not lead to
any racemization.6a
Table 1. Thermodynamic parameters determined for diazacoronands 4, 5,
and 21
Tc [K]
Dn [Hz]
J [Hz]
kc [Hz]
DG#c [kJ/mol]
4
5
21
353
390
373
35.0
55.0
39.4
16.1
16.0
16.1
116.7
150.0
123.8
73.0
80.2
77.1

J. Kalisiak et al. / Tetrahedron 62 (2006) 5905–5914
5909
Figure 5. 2D 1H NMR NOESY spectrum of compound 9; signals from N-benzoyl group (dotted line).
a stable, chiral compound with N-benzoyl side arm requires
the presence of a rigid macroring structure.
O-substituents, do not reveal a typical AB-type signal. These
findings show that the structures of the O-substituted deriva-
tives are completely different from the N-substituted diaza-
coronands 4, 5, 21, 9, and 20. To support our proposal, a
NOESYexperiment was carried out for compound 6, and re-
vealed cross peaks between protons of the benzyl function
and the macroring (Fig. 8, A and B). This suggested that
the intraannular group was oriented inwards the macroring,
which was additionally proved for compound 10.12 The
2.2.3. Structural analysis of O-substituted compounds.
Attempts to obtain suitable single crystals of O-substituted
compounds were unsuccessful, thus the structural studies
of these compounds were carried out only in solution. The
1
temperature-dependent H NMR experiments carried out
for the O-substituted compounds 6, 7, 10, and 13 have shown
stabilities significantly higher than for the N-substituted dia-
zacoronands. The diastereotopic protons of O-benzyl deriva-
tive 6 do not coalesce at 373 K. Furthermore, the width of the
AB-type signals is almost independent of the temperature
(Fig. 7).
Comparable 1H NMR results were observed for the deriva-
tive 7 as well as for 10 and 13 with an additional benzene
1
ring. H NMR spectra for the reference compounds 12 and
1514 with an O-methyl side arm, the smallest of the possible
Ph
O
HN
H
353K
O
H
N
Ph
H
Figure 7. The temperature-dependent 1H NMR spectrum of isolated CHaHb
protons of compound 6 in DMSO-d6.
Figure 6. Proposed way of macroring flipping process in compound 4.

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J. Kalisiak et al. / Tetrahedron 62 (2006) 5905–5914
Figure 8. 2D 1H NMR NOESY spectrum of compound 6.
flipping process is significantly more energy demanding than
in the case of the aliphatic N-benzoyl derivative 4. Therefore,
in the case of compound 6, the size and structure of the
O-benzyl group ensure sufficient conformational stability.
used. Although complexation experiments are typically
carried out by means of NMR, potentiometry, extraction or
UV–vis techniques, these conventional methods are more
time-consuming and require up to 1000 times more analyte
than ESI-MS. Up to now, several studies have evaluated the
use of ESI-MS for the applications involving non-covalent
host–guest interactions,16 and revealed that this approach is
suitable for quick, initial characterization of the considered
host.
According to the presented results, the type of the intraannu-
lar group strongly affects the structural stability of pendant
diazacoronands. In the case of compounds 4, 5, and 21, the
coalescence temperatures and DG#c were measurable. The
rest of the presented diazacoronands 6, 7, 9, 10, 13, and 20
have significantly higher conformational stability, thus we
assume that they are sufficiently stable for our further pur-
poses. The O-substituted compounds have higher stability
than the N-substituted derivatives 4, 5, and 21. Surprisingly,
in the case of the latter group of compounds, rigidity of the
macroring, and not the size of intraannular function has
the main effect on the conformational stability. The O-sub-
stituted diazacoronands 6 and 7, although having an aliphatic
macroring, reveal a substantial structural stability and the
signal from diastereotopic protons do not coalesce at
373 K. Summing up, further synthesis of stable macrocycles
of planar chirality requires the presence of additional benz-
ene ring in the case of N-substituted derivatives. On the
contrary, chiral O-substituted diazacoronands can possess
an aliphatic macroring.
Our investigations focused on checking competition
between two ligands toward one alkali metal cation. It is
well known from the ESI-MS technique that the response
factor depends on the solvation energy of the given ions.
In order to perform a quantitative analysis of the results,
one should introduce the corresponding coefficients for cor-
relation of the different ligand response factors. Such a pro-
cedure is possible but quite tedious and unnecessary from the
viewpoint of this work. For our purposes, it is reasonable to
assume that the peak intensity ratios higher than 4:1 are
indicative for the stronger complexing properties of one
out of the two complexing ligands. To verify how structural
changes of diazacoronands affect their binding properties,
three ESI-MS experiments were carried out.
(1) Effect of the intraannular group: Table 2 shows six pairs
consisting of the pendant diazacoronands and the unsub-
stituted reference compounds 3 and 8. The peak ratio is
the highest in the case of derivatives 4 and 6 (entries 1
and 2). No differences were observed for the pair 7/8
2.3. Binding properties (ESI-MS)
To estimate the influence of the intraannular group on the
binding properties of pendant diazacoronands, ESI-MS was

J. Kalisiak et al. / Tetrahedron 62 (2006) 5905–5914
5911
Table 2. The ratio of signal intensities (ESI-MS spectra) for two ligands and
one alkali metal cation
Table 4. The ratio of signal intensities (ESI-MS spectra) for two ligands and
one alkali metal cation
Entry
Ligands
Signal intensities ratio in ESI-MS
spectra [L1+M+]/[L2+M+]
Entry
Ligands
Signal intensities ratio in ESI-MS
spectra [L1+M+]/[L2+M+]
L1
L2
Na+
K+
Rb+
L1
L2
Na+
K+
Rb+
1
2
3
4
5
6
4
6
7
9
10
13
8
8
8
3
3
3
2.5
2.6
1.0
0.7
1.0
0.3
3.4
4.2
1.3
0.3
0.8
0.1
5.7
7.6
2.0
0.2
0.71
0.1
11
12
13
14
15
5
4
4
9
10
4
6
7
13
13
2.7
2.7
9.1
4.8
8.8
3.5
3.0
7.1
4.5
12.5
4.3
2.3
6.4
3.9
19.4
The values given in the table are averages of three measurements repro-
ducible within ꢁ10%.
The values given in the table are averages of three measurements repro-
ducible within ꢁ10%.
(entry 3). Similar experiments carried out for diazacoro-
nands 9, 10, and 13 possessing additional benzene ring
revealed surprisingly weaker affinity to alkali metal
cations than compound 3 (entries 4–6).
(2) Effect of the rigidity of the macroring: In order to
thoroughly explore the effect of rigidity of the macro-
ring, four further experiments were carried out. Each
diazacoronand with aliphatic macroring was subjected
to ESI-MS investigation with an appropriate compound
possessing additional benzene ring (Table 3).
Figure 9. Color changes of Cu2+ solution induced by the addition of
compounds 4 or 5. Cu2+¼free salt; 4¼4+Cu2+; 5¼5+Cu2+
.
In all of the examined pairs, the aliphatic diazacoronands are
better receptors for cations than their aromatic analogs. This
is probably caused by the higher rigidity of the macroring
structure in compounds 3, 9, 10, and 13, which prevents their
geometry from adapting to the guest molecule. In the case
of compound 13, the highest ratio of signal intensities was
observed and amounted to 34.2 (entry 10).
the influence of counterions on color changes. Typically,
an appropriate diazacoronand (2 mg in 1 ml of MeOH)
was added to an appropriate copper salt solution (ca. 3 mg
in 1 ml of MeOH).
Color changes were observed only in the case of compound 5,
although its mixture with CuCl2 gave a slight difference. The
derivative 4, although structurally very similar to 5, did not
give any visible results. This simple experiment demon-
strated that a minor change in the structure of diazacoronands
can result in different and interesting binding properties.
(3) Comparison of the type of intraannular groups: To deter-
mine which pendant arm modifies the binding properties
best, direct comparison of two pendant diazacoronands
was carried out (Table 4). The best receptors are com-
pounds 4 and 5 with N-substituted side arm and only
slightly weaker ligand is the derivative 6 possessing
the O-benzyl function (entries 11 and 12). On the con-
trary, the weakest receptors are compounds 7 and 12
with O-benzoyl side arm (entries 13–15).
3. Conclusions
In this paper, we presented the structural studies and initial
binding properties of pendant diazacoronands. Here, the
intraannular group plays a double role: (1) it ensures a suffi-
cient conformational stability, indispensable in the case of
further synthesis of stable atropoisomers and (2) it is an extra
binding side, slightly modifying the complexation properties
of the macrocyclic receptors. The structural studies per-
formed by means of the X-ray analysis and the variable tem-
As expected, derivative 5 with a pyridine moiety is a slightly
more efficient host than its benzene analog 4. An apparent
experiment showing another advantage of diazacoronad 5
over 4 consists in inducing color changes of Cu2+ solutions
(Fig. 9). Several typical copper salts were used to exclude
1
perature H NMR experiments show that the O-substituted
Table 3. The ratio of signal intensities (ESI-MS spectra) for two ligands and
one alkali metal cation
compounds exhibit higher conformational stability than
the N-substituted analogs. On the contrary, initial binding
experiments (ESI-MS) show that the N-substituted diaza-
coronands are slightly better receptors than the O-substituted
diazacoronands. The main advantage of the presented sys-
tem is a diversity of intraannular groups, which can be intro-
duced into the diazacoronand framework, and the possibility
of almost unlimited modifications. Application of the above-
presented synthetic approach to preparation of macrocycles
with planar chirality as well as their use in asymmetric
synthesis is in progress.
Entry
Ligands
Signal intensities ratio in ESI-MS
spectra [L1+M+]/[L2+M+]
L1
L2
Na+
K+
Rb+
7
8
9
10
8
4
6
7
3
9
10
13
7.0
15.9
10.1
23.1
6.6
15.2
7.6
4.7
24.8
8.6
31.1
34.2
The values given in the table are averages of three measurements repro-
ducible within ꢁ10%.

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J. Kalisiak et al. / Tetrahedron 62 (2006) 5905–5914
4. Experimental
4.1. General methods
7.5 mmol) were added. The reaction mixture was stirred
at rt for 12 h. Next, a second portion of MeI (0.5 ml,
12.5 mmol) was added and the reaction was carried out for
the subsequent 12 h. After filtration, the solvent was evapo-
rated and the residuewas crystallized in a vapor diffusive sys-
tem (MeOH/CHCl3, 1:1/n-pentane), to give white crystals
(0.56 g, 54%), mp 239.8–241.0 ꢂC. 1H NMR 500 MHz
(DMSO): d¼7.94 (br t, 2H, CONH); 7.07–6.99 (m, 3H,
ArH); 6.91–6.87 (m, 4H, ArH); 4.63 (s, 4H, OCH2CO);
4.07 (br t, 4H, CH2O); 3.72 (s, 3H, OMe); 3.60 (br q, 4H,
CH2N). 13C NMR 125 MHz (DMSO): d¼167.9 (CONH),
152.4, 147.8, 140.2, 124.9, 121.0, 112.9, 112.1, 70.8,
67.4, 61.5, 38.2, ESI HRMS (MeOH) m/z calcd for
C21H24N2O7Na [M+Na]+: 439.1476; found: 439.1480.
Anal. Calcd for C21H24N2O7: C, 60.57; H, 5.76; N, 6.73.
Found: C, 60.60; H, 5.93; N, 6.74%.
Melting points were determined using a Boetius M HMK
¨
hot-stage apparatus and were uncorrected. 1H and 13C
NMR spectra were recorded using a Bruker AM 500 or
Varian BB 200 spectrometer. Chemical shifts are reported
as d values relative to TMS peak defined at d¼0.00. The
mass spectral analysis was performed by the ESI-TOF tech-
nique on a Mariner mass spectrometer from PerSeptive
Biosystem. Column chromatography was performed on
silica gel (Kieselgel-60, 200–400 mesh).
4.1.1. 2,8,15,21-Tetraoxa-5,18-diazatricyclo[20.3.1.09,14
]
hexacosa-1(25),9(14),10,12,22(26),23-hexaene-4,19-dione
(3). Procedure A: An appropriate diester (39 mmol) was dis-
solved in dry MeOH (300 ml) and added to diamino-ether 2
or 19 (39 mmol) in dry MeOH (100 ml). Then, a solution of
MeONa (5.4 g, 100 mmol) in dry MeOH (100 ml) was
added to the mixture. The mixture was left at ambient
temperature for a period of 2–7 days (TLC monitored).
Subsequently, the solvent was evaporated and the residue
was purified by column chromatography (silica gel; AcOEt/
MeOH, 9:1 or CHCl3/MeOH, 95:5 in the case of 20 and 21,
respectively) to give the desired product. Yield (15%), crys-
tallization in a vapor diffusive system (MeOH/CHCl3, 2:3/
4.1.4. Benzoic acid 4,19-dioxo-2,8,15,21-tetraoxa-5,18-di-
aza-tricyclo[20.3.1.09,14]hexacosa-1(25),9(14),10,12,
22(26),23-hexaen-26-yl ester (13). To phenol 11 (1g,
2.5 mmol) dissolved in pyridine (10 ml) and cooled (0 ꢂC),
benzoyl chloride (0.34 ml, 3.0 mmol) was added dropwise.
The reaction mixture was stirred overnight at rt and subse-
quently acidified with 1 M aq HCl. After extraction with
AcOEt (3ꢃ100 ml), the organic layers were combined, dried
over MgSO4, filtered and evaporated. The residue was puri-
fied by column chromatography (silica gel; AcOEt) to give
the desired product (42%, 0.53 g). Crystallization in a vapor
diffusive system (MeOH/Et2O) gave white needles, mp
1
Et2O) gives white crystals, mp 224.3–225.4 ꢂC. H NMR
500 MHz (DMSO): d¼7.93 (br t, 2H, CONH); 7.19 (t,
1H, J¼8.2, ArH); 7.02–6.98 (m, 2H, ArH); 6.93–6.88 (m,
2H, ArH); 6.58 (dd, 2H, J1¼8.2, J2¼2.3, ArH); 6.47
(t, 1H, J¼2.3, ArH); 4.51 (s, 4H, OCH2CO); 4.07 (br t,
4H, CH2O); 3.52 (br q, 4H, CH2N), 13C NMR 125 MHz
(DMSO): d¼167.8 (CONH), 158.7, 148.1, 130.1, 121.3,
114.3, 107.8, 101.1, 67.1, 66.8, 38.2, ESI HRMS (MeOH)
m/z calcd for C20H22N2O6Na [M+Na]+: 409.1370; found:
409.1394. Anal. Calcd for C20H22N2O6: C, 62.34; H, 5.45;
N, 7.27. Found: C, 62.32; H, 5.63; N, 7.22%.
1
203.4–204.6 ꢂC. H NMR 500 MHz (CDCl3): d¼8.22 (br
d, 2H, CONH); 7.66 (t, 1H, J¼7.5, ArH); 7.48 (t, 2H,
J¼7.5, ArH); 7.10 (br s, 2H, ArH); 6.91–6.78 (m, 5H,
ArH); 6.53 (d, 2H, J¼7.5, ArH); 4.69 (dAB, 2H, J¼16.5,
OCH2CO); 4.64 (dAB, 2H, J¼16.5, OCH2CO); 4.20–4.14
(m, 2H, CH2O); 3.90–3.83 (m, 4H, CH2O+CH2N); 3.46–
3.40 (m, 2H, CH2N); 13C NMR 125 MHz (CDCl3): d¼
168.2 (CONH), 150.1, 148.0, 134.3, 130.6, 128.8, 128.2,
127.1, 120.8, 111.8, 66.8, 65.8, 39.1, ESI HRMS (MeOH)
m/z calcd for C27H26N2O8Na [M+Na]+: 529.1581; found:
529.1552. Anal. Calcd for C27H26N2O8: C, 64.03; H, 5.17;
N, 5.53. Found: C, 63.81; H, 5.34; N, 5.42%.
4.1.2. 26-Hydroxy-2,8,15,21-tetraoxa-5,18-diaza-tri-
cyclo[20.3.1.09,14]hexacosa-1(25),9(14),10,12,22(26),23-
hexaene-4,19-dione (11). A mixture of compound 10 (3 g,
6.1 mmol) and Pd/C (0.5 g, 10%) in MeOH (200 ml) was
stirred overnight under an atmosphere of hydrogen (balloon
pressure) at rt. The reaction mixture was filtered through
Celite and the resulting solution was evaporated. Crystalliza-
tion from MeOH (120 ml) gave light purple crystals (2.2 g,
4.1.5. 22-Methoxy-2,8,11,17-tetraoxa-5,14-diaza-bicyclo-
[16.3.1]docosa-1(21),18(22),19-triene-4,15-dione (15).
Procedure B: (93%), mp 108.2–109.9 ꢂC, lit.14 mp 109–
1
111 ꢂC. H NMR 500 MHz (DMSO): d¼7.59 (br t, 2H,
CONH); 7.03 (t, 1H, J¼8.4, ArH); 6.79 (d, 2H, J¼8.4,
ArH); 4.58 (s, 4H, OCH2CO); 3.85 (s, 3H, OMe); 3.47–
3.42 (m, 8H, CH2O); 3.33–3.28 (m, 4H, CH2N), 13C NMR
125 MHz (DMSO): d¼167.8 (CONH), 151.9, 139.5, 124.3,
110.3, 70.1, 69.6, 68.9, 61.2, 38.7, ESI HRMS (MeOH) m/z
calcd for C17H24N2O7Na [M+Na]+: 391.1476; found:
391.1471.
1
90%), mp 168.9–171.4 ꢂC. H NMR 500 MHz (DMSO):
d¼9.74 (br s, 1H, OH); 8.30 (br t, 2H, CONH); 6.95–6.91
(m, 2H, ArH); 6.88–6.84 (m, 2H, ArH); 6.81–6.78 (m, 2H,
ArH); 6.75–6.71 (m, 1H, ArH); 4.58 (s, 4H, OCH2CO);
4.01 (t, 4H, J¼4.9); 3.55 (q, 4H, J¼4.9, CH2N); 13C NMR
125 MHz (DMSO): d¼168.6 (CONH), 148.0, 147.6, 137.8,
121.0, 119.3, 113.5, 111.3, 70.5, 67.1, 38.3, ESI HRMS
(MeOH) m/z calcd for C20H22N2O7Na [M+Na]+: 425.1319;
found: 425.1304. Anal. Calcd for C20H22N2O7: C, 59.70;
H, 5.51; N, 6.96. Found: C, 59.57; H, 5.77; N, 6.91%.
4.1.6. N-(2,6-Dihydroxyphenyl)acetamide (17). A mixture
of compound 16 (10 g, 64 mmol) and Pd/C (1 g, 10%) in
MeOH (200 ml) was stirred at rt under an atmosphere of hy-
drogen (balloon pressure) for 2 days. The catalyst was filtered
off on Celite. Then, the solution was cooled to ꢀ20 ꢂC and
acetyl chloride was added dropwise. The reaction mixture
was stirred at ꢀ20 ꢂC/rt overnight. After evaporation of
the solvent, the residue was crystallized from EtOH to give
gray crystals (5.9 g, 55% overall yield), mp 95.5–97.1 ꢂC.
4.1.3. 26-Methoxy-2,8,15,21-tetraoxa-5,18-diaza-tri-
cyclo[20.3.1.09,14]hexacosa-1(25),9(14),10,12,22(26),23-
hexaene-4,19-dione (12). Procedure B: To phenol 11 (1 g,
2.5 mmol) dissolved in MeCN (150 ml), 5 equiv of MeI
(0.5 ml, 12.5 mmol) and 3 equiv of anhydrous K2CO3 (1 g,

J. Kalisiak et al. / Tetrahedron 62 (2006) 5905–5914
5913
1H NMR 200 MHz (CDCl3): d¼7.53 (br s, 1H, NHCOMe);
4.2. ESI-MS comparison measurements
6.94 (t, 1H, J¼8.3, ArH); 6.49 (d, 2H, J¼8.3, ArH); 2.30
(s, 3H, Me), 13C NMR 50 MHz (CDCl3): d¼168.1
(NHCO), 147.8, 129.8, 124.8, 120.9, 25.6, ESI HRMS
(MeOH) m/z calcd for C8H9NO3Na [M+Na]+: 190.1556;
found: 190.1563. Anal. Calcd for C8H9NO3: C, 57.48; H,
5.43; N, 8.38. Found: C, 57.68; H, 5.54; N, 8.26%.
All electrospray ionization mass spectra were recorded on
a Micromass instrument equipped with an ESI source. The
needle potential for the methanol solution was set to 4.0 kV
for all experiments. Each spectrum taken was an average of
25–30 scans.
4.1.7. Methyl [2-(acetylamino)-3-(2-methoxy-2-oxo-
ethoxy)phenoxy]acetate (18). To a mixture of 17 (10 g,
149 mmol), and anhydrous K2CO3 (40 g, 290 mmol) in an-
hydrous 2-butanone (300 ml), methyl bromoacetate (26 ml,
290 mmol) was added. The reaction mixture was stirred at
80 ꢂC for 2 days under an argon atmosphere. After cooling
the suspension to room temperature, the insoluble inorganic
salts were removed by filtration. Then, the solvent was
evaporated and the residue was purified by column chroma-
tography (silica gel; AcOEt) to give the desired product
(14.9 g, 80%), mp 92.6–93.4 ꢂC. 1H NMR 500 MHz
(CDCl3): d¼7.33 (br s, 1H, NHCO); 7.12 (t, 1H, J¼8.3,
ArH); 6.55 (d, 2H, J¼8.3, ArH); 4.67 (s, 4H, OCH2CO);
3.77 (s, 6H, OMe); 2.18 (br s, 3H, COMe), 13C NMR
125 MHz (CDCl3): d¼169.5 (CO); 168.8 (NHCO); 154.2,
127.5, 117.6, 108.3, 66.9, 52.2, 23.3, ESI HRMS (MeOH)
m/z calcd for C14H17NO7Na [M+Na]+: 334.2839; found:
334.2845. Anal. Calcd for C14H17NO7: C, 54.02; H, 5.50;
N, 4.50. Found: C, 54.15; H, 5.44; N, 4.55%.
All solutions were prepared in methanol. The solutions con-
taining chloride salt and two hosts had the concentration
ratios of 1:1:1, and the host concentrations were 1ꢃ10ꢀ4 M
for each host.
4.3. The X-ray structure investigations
The intensity data were collected on a Kuma KM4CCD dif-
fractometer with a graphite-monochromated Mo Ka radia-
˚
tion (l¼0.71073 A). The crystal was positioned at 65 mm
from the KM4CCD camera, 600 frames were measured at
1ꢂ intervals with a counting time of 15 s. The data were cor-
rected for Lorentz and polarization effects. No absorption
correction was applied. The structure was solved by the di-
rect method and refined by full-matrix least squares on F2 us-
ing SHELXL 97. The H atoms were located in geometrically
calculated positions and were allowed to ride on their parent
atom. CCDC data sets No. 264711, 264712, and 264713 for
4, 9, and 5, respectively, contain the supplementary crystal-
lographic data for this paper. These data can be obtained free
of charge via www.ccdc.cam.ac.uk/conts/retrieving.html (or
from the Cambridge Crystallographic Data Center, 12,
Union Road, Cambridge CB2 1EZ, UK; fax: (+44) 1223-
336-033; or deposit@ccdc.cam.ac.uk).
4.1.8. N-(4,19-Dioxo-2,8,15,21-tetraoxa-5,18-diaza-
tricyclo[20.3.1.09,14]hexacosa-1(25),9(14),10,12,22(26),
23-hexaen-26-yl)-acetamide (20). Procedure A: (19%)
Crystallization in a vapor diffusive system (MeOH/n-pen-
1
tane) gives white needles, mp 221.3–221.9 ꢂC. H NMR
500 MHz (DMSO): d¼9.44 (s, 1H, NHCO); 7.54 (br t, 2H,
CONH); 6.95 (t, 1H, J¼8.5, ArH); 6.82 (s, 4H, ArH); 6.57
(d, 2H, J¼8.5, ArH); 4.74 (dAB, 2H, J¼16.3, OCH2CO);
4.66 (dAB, 2H, J¼16.3, OCH2CO); 3.87–3.80 (m, 2H,
CH2O); 3.75–3.63 (m, 4H, CH2O+CH2N); 3.13–3.05 (m,
2H, CH2N); 2.09 (s, 3H, COMe), 13C NMR 125 MHz
(DMSO): d¼169.9 (NHCO), 168.1 (CONH), 153.2, 148.3,
127.7, 121.0, 114.9, 113.9, 105.0, 67.0, 66.4, 38.5, 22.6,
ESI HRMS (MeOH) m/z calcd for C22H25N3O7Na
[M+Na]+: 466.1585; found: 466.1562. Anal. Calcd for
C22H25N3O7: C, 59.59; H, 5.64; N, 9.48. Found: C, 59.68;
H, 5.73; N, 9.43%.
Crystal data for 4: Crystals obtained in a vapor diffusive
system MeOH/CHCl3, 1:1/n-pentane; C23H29N3O8, Mr¼
475.5, monoclinic, P2(1)/n, a¼8.4650(17), b¼20.425(4),
c¼13.845(3) A, a¼90ꢂ, b¼96.36(3)ꢂ, g¼90ꢂ, V¼
˚
3
3
˚
2379.1(8) A , Z¼4, Dc¼1.338 g/cm , F000¼1008, T¼
293(2) K, m¼0.101 mmꢀ1, 4176 reflections collected, 2921
unique. Final GOF¼1.129, R1¼0.0577, wR2¼0.1892 (all
data).
Crystal data for 5: Crystals obtained in a vapor diffusive sys-
tem MeOH/Et2O; C22H28N4O8, Mr¼476.5, monoclinic,
˚
P2(1)/n, a¼8.3978(17), b¼20.422(4), c¼13.885(3) A, a¼
3
ꢂ
ꢂ
ꢂ
˚
90 , b¼96.41(3) , g¼90 , V¼2366.1(8) A , Z¼4, Dc¼
4.1.9. N-(4,15-Dioxo-2,8,11,17-tetraoxa-5,14-diaza-bicy-
clo[16.3.1]docosa-1(21),18(22),19-trien-22-yl)-acetamide
(21). Procedure A: (30%) Crystallization in a vapor diffusive
system (MeOH/n-pentane), gives white needles, mp 174.3–
174.6 ꢂC. 1H NMR 500 MHz (DMSO): d¼9.39 (s, 1H,
NHCO); 7.72 (br q, 2H, CONH); 7.15 (t, 1H, J¼8.5, ArH);
6.58 (d, 2H, J¼8.5, ArH); 4.67 (dAB, 2H, J¼16.1,
OCH2CO); 4.58 (dAB, 2H, J¼16.1, OCH2CO); 3.56–3.48
(m, 2H, CH2O); 3.41–3.35 (m, 2H, CH2O); 3.25–3.19 (m,
2H, CH2O); 3.11–3.04 (m, 2H, CH2O); 2.96–2.81 (m,
4H, CH2N); 2.10 (s, 3H, COMe), 13C NMR 125 MHz
(DMSO): d¼169.0 (NHCO), 167.8 (CONH), 153.1,
127.3, 114.7, 104.9, 69.8, 68.6, 66.7, 39.3, 22.8, ESI
HRMS (MeOH) m/z calcd for C18H25N3O7Na [M+Na]+:
418.1585; found: 418.1605. Anal. Calcd for C18H25N3O7:
C, 54.68; H, 6.33; N, 10.63. Found: C, 54.69; H, 6.40;
N, 10.74%.
1.337 g/cm3, F000¼1008, T¼150(2) K, m¼0.103 mmꢀ1
,
17,400 reflections collected, 4157 unique. Final
GOF¼0.890, R1¼0.0424, wR2¼0.0832 (all data).
Crystal data for 9: Crystals obtained in a vapor diffusive
system MeOH/CHCl3, 1:1/n-pentane; C28H31N3O8, Mr¼
537.5, monoclinic, P2(1)/c, a¼11.4801(7), b¼14.5891(8),
c¼16.5399(3) A, a¼90ꢂ, b¼95.23(4)ꢂ, g¼90ꢂ, V¼
˚
3
3
˚
2758.6(3) A , Z¼4, Dc¼1.294 g/cm , F000¼1136, T¼
293(2) K, m¼0.096 mmꢀ1, 38,138 reflections collected,
4318 unique. Final GOF¼1.138, R1¼0.0530, wR2¼0.1675
(all data).
Acknowledgements
Financial support from the State Committee for Scientific
Research (project T09A 087 21) is gratefully acknowledged.

5914
J. Kalisiak et al. / Tetrahedron 62 (2006) 5905–5914
6. (a) Pia˛tek, P.; Kalisiak, J.; Jurczak, J. Tetrahedron Lett. 2004,
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