Xanthone receptors as oxyanion-hole mimics in artificial enzymes

Article abstract of DOI:10.1002/hlca.200590133

Different xanthone-based receptors (2-10) for lactones and lactams have been prepared, and the feasibility of these compounds to mimic the known enzymatic 'oxyanion-hole' structure is discussed. The self-association of the receptors was found to pose a serious drawback for complex formation. X-Ray crystal structures of receptor dimers allowed us to understand the reasons for their self-association and to improve the design of the catalysts. The catalytic activity of the receptors has been tested towards the nucleophilic addition of pyrrolidine to unsaturated lactones. Since the resulting complexes were very weak in organic solvents, new receptors were developed for lactams, which showed better stabilities, and their catalytic activities were studied.

Full text of DOI:10.1002/hlca.200590133

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Xanthone Receptors as Oxyanion-Hole Mimics in Artificial Enzymes
by Luis Simo¬na), Francisco M. Munƒiza), Silvia Sa¬eza), Ce¬sar Raposob), Francisca Sanzc),
and JoaquÌn R. Mora¬n*a)
a) Organic Chemistry Department, Universidad de Salamanca, Plaza de los CaÌdos, 37008Salamanca, Spain
b) Mass Spectrometry Service, Universidad de Salamanca, Plaza de los CaÌdos, 37008Salamanca, Spain
c) X-Ray Diffraction Service, Universidad de Salamanca, Plaza de los CaÌdos, 37008Salamanca, Spain
Dedicated to Professor Rolf Huisgen on the occasion of his 85th birthday
Different xanthone-based receptors (2 10) for lactones and lactams have been prepared, and the
feasibility of these compounds to mimic the known enzymatic −oxyanion-hole× structure is discussed. The self-
association of the receptors was found to pose a serious drawback for complex formation. X-Ray crystal
structures of receptor dimers allowed us to understand the reasons for their self-association and to improve the
design of the catalysts. The catalytic activity of the receptors has been tested towards the nucleophilic addition of
pyrrolidine to unsaturated lactones. Since the resulting complexes were very weak in organic solvents, new
receptors were developed for lactams, which showed better stabilities, and their catalytic activities were studied.
Introduction. H-Bonds play an important role in enzymatic catalysis [1]. Over the
last decade, the so-called oxyanion hole has frequently been found as a structural motif
in hydrolase-like enzymes [2]. The oxyanion hole consists of two or more H-bond
donors (usually two peptide NH groups from the backbone of the enzyme) oriented
towards an O-atom in the substrate (usually a CˆO group), which accumulates
electron density as the enzymatic reaction takes place. The increased stability of the H-
bonds in the transition state reduces the energy barrier of the reaction, enhancing
catalysis. In the search for organic receptors able to mimic the behavior of enzymes, it
would be of great interest to design structures that could play the role of the oxyanion
hole.
Enzymes such as proteases, lipases, esterases, dehalogenases, peroxidases, and
epoxide hydrolases display the oxyanion-hole structure, and it has been suggested that
this structural similarity may imply that these enzymes may have had a common
ancestor [2]. Enoyl CoA hydratase belongs to this family of enzymes. Bahnson et al.
[3] described the X-ray structure of rat liver enoyl CoA hydratase bound to 4-(N,N-
dimethylamino)cinnamoyl CoA (PDB entry 1EY3). Selected amino acids at the
active site and the substrate are shown in Fig. 1 (left). This author also discussed the
important role of the oxyanion hole in catalysis in another article [4].
The structure of the xanthone receptor 1 is known from an X-ray study (vide infra).
In Fig. 1 (right), we have overlaid this structure with that of the enoyl CoA hydratase
active site. Besides the structural similarity, aromatic amides are expected to give
stronger H-bonds than aliphatic ones, which should increase the catalytic activity.
Nevertheless, synthetic availability, stability under the reaction conditions, solubility
¹ 2005 Verlag Helvetica Chimica Acta AG, Z¸rich

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Fig. 1. Structure of the active center of the enoyl CoA hydratase complex. On the right, the structure is overlaid
with the xanthone-based receptor 1.
problems, and receptor self-association all need to be considered, as we attempt to do in
this paper.
Results and Discussion. 1. Preparation and Properties of Xanthone Receptors for
Lactones. In a recent paper [5], we described the synthesis of a receptor suitable for
association of amino acids. Receptor 2 is based on the same skeleton, but its synthesis
(Scheme 1) has been modified to include a diisopropylamide group. Bulky groups in the
non H-bonding region of the receptor are desirable to prevent solubility problems due
to p-stacking. The urea functional group provides a third H-bond in the association of
lactones.
1H-NMR spectra of receptor 2 in CDCl3 showed broad signals, but the addition of
CD3OD or (D6)DMSO led to sharp signals (Fig. 2). This effect indicates that 2 forms
aggregates in CDCl3 solution that are broken in the presence of more-polar solvents.
After slow evaporation of a CH2Cl2/undecane solution of 2, it was possible to
obtain crystals suitable for X-ray-diffraction analysis. The crystalline structure of 2
shows that this compound readily self-associates, forming dimers (Fig. 3). This
aggregate is stabilized by two intramolecular H-bonds between the urea and the O-
atom of the acetamide, and an intermolecular H-bond between the NH of the
acetamide and the CˆO group of the diisopropylamide. The structure is also stabilized
by p-stacking and the anti-parallel orientation of the molecular dipoles.

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Scheme 1. Synthesis of Receptor 2, and Its Binding Mode with Furan-2(5H)-one
i) HNO3, H2SO4. ii) PCl5, SOCl2. iii) (i-Pr)2NH (1 equiv.), Et3N, CCl4, À 308. iv) i-PrOH (excess). v) Potassium
4-tert-butyl-2-nitro-phenolate, DMF. vi) Fe, AcOH, MeOH. vii) MeSO3H, P2O5. viii) Cl2CˆO in toluene,
CH2Cl2. ix) 2,4,4-Trimethylpentan-2-amine (excess), toluene. x) H2, Pd/C, AcOH. xi) AcCl, THF.
Owing to its high value, dilution experiments did not provide an assessment of the
dimerization constant of 2. The stability of this dimer is a severe drawback for
association of neutral molecules. A 25 mm solution of 2 was prepared in CDCl3, and an
1
absolute H-NMR titration [6] with butyrolactone (ˆdihydrofuran-2(3H)-one) as
guest was performed. Although some 1H-NMR signals were deshielded due to complex

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Fig. 2. 1H-NMR Spectra of 2 in CDCl3 (top), and in mixtures of CDCl3/CD3OD (left) vs. CDCl3/(D6)DMSO
(right)
Fig. 3. Schematic representation of the dimeric structure of 2 in the solid state (left), and X-ray crystal structure of
the monomer (thermal ellipsoids; right)
formation as the guest was added, we were unable to reproduce the conventional
1
saturation of the H-NMR shifts. Instead, deshielding continued after the addition of
more than 35 equiv. of guest, indicating that some complex had been formed, but that
the association constant was too small to be determined by this method.
A slight modification of the synthetic route yielded xanthone 3 (Scheme 2), in
which the positions of the urea and acetamido groups are exchanged; this should
1
prevent the formation of an aggregate similar to dimeric 2. Nevertheless, broad H-
NMR signals were observed again, and the addition of CD3OD or (D6)DMSO had a
effect similar to that seen for 2. It was impossible to obtain suitable crystals of 3, but
this was possible for receptor 4 with a similar structure (Fig. 4).

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Scheme 2. Synthesis of Receptors 3 and 4, and Their Binding Mode with Furan-2(5H)-one
i) AcCl, THF. ii) H2, Pd/C, AcOH. iii) Cl2CˆO in toluene, CH2Cl2. iv) 2,4,4-trimethylpentan-2-amine (excess),
toluene. v) BuNH2 (excess), toluene.
Again, dimer formation was observed, with the CˆO O-atom of the diisopropyl
group of 4 fitting into the cleft of another molecule. One of every two molecules had
the acetamide group twisted to establish a H-bond with the urea O-atom of a molecule
belonging to a different dimer. In solution, the acetamide group is probably oriented
towards the O-atom of the diisopropylamide, so that this dimer is stabilized by six H-
bonds.

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Fig. 4. Schematic representation of the dimeric structure of 4 in the solid state (left), and X-ray crystal structure of
the monomer (thermal ellipsoids; right)
Since the diisopropylamide was involved in both dimer structures, this group was
replaced with a butyl ester in receptor 5. The planar structure of the butyl ester should
prevent the establishment of intermolecular H-bonds, since, with this geometry, it
should be unable to fit into the cleft of another molecule. The synthesis of this receptor
is shown in Scheme 3.
Although xanthone 5 is considerably less soluble in chloroform than receptors 2 and
3, 1H-NMR analysis in CDCl3 revealed less aggregation than for the previous receptors.
Moreover, a value of 11 l/mol for the association constant with butyrolactone was
calculated by means of a titration experiment.
Slow evaporation of a MeOH/benzene solution of 5 yielded crystals suitable for
structural determination by X-ray diffraction (Fig. 5). The structure is made of chains
of monomers in which the O-atoms of acetamide groups fit into the cleft of another
receptor. Two independent chains are packed, and no H-bond interaction is observed
between them. The urea conformation is changed from cis (as in 2 and 4) to the less-
stable trans, probably due to higher packing densities.
In an attempt to study the ability of these receptors in catalysis as oxyanion-hole
mimics, we chose the Michael addition of pyrrolidine to an unsaturated lactone, furan-
2(5H)-one. This reaction is expected to proceed via a transition state with high electron
density on the CˆO O-atom and could be similar to the reaction catalyzed by enoyl
CoA hydratase. The experiments were carried out at 293 K at a concentration of
pyrrolidine and lactone of 0.1m each. Finally, in the catalytic experiments, 5% of
receptor was added. The resulting half-lives of the reactions are summarized in Table 1.
The best catalytic activity was obtained with receptor 5, which is easily rationalized by
means of the higher association constant. Nevertheless, in our opinion, these small
association constants do not allow better results, and the solubility of 5 was still a
problem.

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Scheme 3. Synthesis of Receptor 5, and Its Binding Mode with Furan-2(5H)-one
i) Fe, AcOH, MeOH. ii) HBr. iii) P2O5, MeSO3H. iv) SOCl2 (cat.), BuOH. v) Cl2CˆO in toluene, CH2Cl2. vi)
2,4,4-Trimethylpentan-2-amine (excess), toluene. vii) H2, Pd/C, AcOH. viii) AcCl, THF.
2. Preparation and Properties of Xanthone Receptors for Lactams. Since self-
association hinders complex formation with lactones, lactams were chosen as the guests.
Amide CˆO groups are better H-bond acceptors [7], and should, thus, show a higher
affinity for the xanthone receptors. The structure of the receptor had to be modified to
accommodate the lactam NH, and, hence, structure 6 was designed (Scheme 4).
Receptors sharing the same skeleton have already been used for the complexation of
carboxylic acids [8] and diketopiperazines [9], and high association constants were

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Fig. 5. Schematic representation of the dimeric structure of 5 in the solid state (left), and X-ray crystal structure of
the monomer (thermal ellipsoids; right)
Table 1. Half-Lives (t1/2) of the Michael Addition Reaction between Pyrrolidine and Furan-2(5H)-one in the
Presence of Different Receptors. Conditions: solvent, CDCl3; temperature, 298K; receptor, 5 mol-%.
Receptor
t1/2 [min]
None
305
133
243
54
2
3
5
obtained. Different N-substituents were introduced to study the effect of NH acidity on
catalysis, and reduction of the CˆO group would allow the preparation of xanthene
receptors with less-acidic NH groups. The synthesis of these receptors (6 10) is shown
in Scheme 4.
The lactam guest 11 (ˆ 5,6-dihydropyridin-2(1H)-one) was prepared according to
Scheme 5. Wineman et al. [10] have reported the synthesis of monobromide 12 by
partial hydrogenation of dibromide 13, but, instead, we used a more-suitable method
with Ph3P, followed by dithiocarbamate formation to 14 and then thermal elimination
to 11. The association constant of 6 with lactam 11 was determined in C6D6, monitoring

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Scheme 4. Synthesis of Receptors 6 10, and Their Binding Mode with Lactam 11
i) Decanoyl chloride, THF. ii) Trifluoroacetyl chloride, THF. iii) MeSO2Cl, THF. iv) Sn, EtOH. v) Decanoyl
chloride, Et3N, THF. vi) MeSO2Cl, Et3N, THF.

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the deshielding of the HÀC(10)1) 1H-NMR signal of the host as the lactam was added.
The value obtained (1.8 Â 103 l/mol) was much higher than the low values obtained for
the association of lactones. For receptors 7 10, a competitive titration was performed
to derive relative association constants with respect to 6. The results are summarized in
Table 2. As expected, less-acidic NH groups, and, therefore, less-stable H-bonds,
correspond to lower association constants.
Scheme 5
‡
i) Ph3P, MeOH/H2O 10 :1. ii) Me2NC(S)SÀMe2NH2 . iii) 2608, 1 Torr.
Table 2. Absolute and Relative (rel) Association Constants K for the Complexation of Lactam 11 by Different
Receptors. The K values of 7 10 were calculated from Krel obtained by indirect titrations (see text). Conditions:
solvent, C6D6; temperature, 298K; 1H-NMR titration (see text).
Receptor
K [l/mol]
Krel
6
7
8
9
10
1800a)
2700
9360
160
1.00
1.5
5.2
0.089
1.6
2880
a
1
) Determined by direct H-NMR titration.
The catalytic activity of the lactam receptors was also tested by Michael addition of
pyrrolidine to the unsaturated lactam 11. This reaction is considerably slower than the
Michael addition of pyrrolidine to a,b-unsaturated lactones. Under the reaction
conditions, pyrrolidine can be alkylated by CHCl3 or CH2Cl2, yielding pyrrolidinium
chloride, which may act as a general-acid catalyst. The presence of ClÀ may also block
the receptor cleft, preventing its catalytic activity. Thus, we preferred to use C6D6 as
solvent. To reduce the half-lives of the reaction, the pyrrolidine concentration was
increased to 3.0m, and the lactam concentration was fixed at 0.80m. The temperature
during the kinetic experiments was 293 K, and in the catalytic experiments, 5% of
receptor was added. The half-lives obtained are summarized in Table 3. A plot of t1/2 vs.
relative association constant Krel is shown in Fig. 6. In this plot, a clear correlation is
observed between the association constants in benzene and the catalytic activity of the
receptors. Nevertheless, there seems to be a saturation effect that does not allow the
catalytic activities to be improved simply by increasing the association constants.
1
)
Arbitrary numbering, see Fig. 7. For systematic names, see Exper. Part.

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Fig. 6. Plot of half-lives of the Michael addition between pyrrolidine and lactam 11 in the presence of different
receptors vs. relative association constants for the corresponding 1:1 complexes between the receptors and 11.
Conditions: solvent, C6D6, temperature, 293 K; 5 mol-% of receptor.
Table 3. Half-Lives (t1/2) of the Addition Reaction between Pyrrolidine and Lactam 11 in the Presence of
Different Receptors. Conditions: solvent, C6D6; temperature, 293 K; 5 mol-% receptor; 1H-NMR titration (see
text).
Receptor
t1/2 [min]
None
6
7
305
84
57
8
48
9
10
179
69
This saturation effect could be rationalized by taking into account that the different
association constants depend on the acidity of the NH groups. Pyrrolidine is basic and a
good H-bond acceptor. In the competition between pyrrolidine and the substrate, a
receptor with acidic NH groups should favor the association of pyrrolidine, since H-
bonds between acceptors and donors with similar pKa values are known to be very
strong [11].
To study the influence of pyrrolidine on the association constants, a new experiment
was performed. Successive portions of pyrrolidine were added to a C6D6 solution of the
complexes of receptors 6, 8, and 10 with lactam 11. The 1H-NMR spectra revealed shifts
in the receptor signals that could be attributed to the breakage of the lactam complexes
(Fig. 7). It may be seen that the receptor with the most-acidic NH groups shows the
greatest sensitivity to the addition of pyrrolidine. We, therefore, conclude that the
receptor H-bond donor should not be too acidic.

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Fig. 7. Addition of increasing amounts of complex-breaking pyrrolidine in an 1H-NMR titration of the complexes
6, 8, and 10 with the guest 11. The chemical shifts of HÀC(10) and HÀC(8) (trivial numbering) of the receptors
were followed upon addition of pyrrolidine to the complexes. Conditions: solvent, C6D6, temperature, 298K.
Since it is clear that pyrrolidine competes with the lactam for receptor H-bonds, it is
very important to estimate the actual association constant under the reaction
1
conditions. An attempt to perform an H-NMR titration in 3m pyrrolidine solution
failed, because it was very difficult to follow the low degree of shielding of the receptor
signals under these conditions. Since it was not possible to carry out direct measure-
ment of the association constant, a different guest, 15, with a similar association
constant was used. The advantage of 2-[(2-ethylhexyl)oxy]naphthalene-1-carboxa-
mide (15; see Fig. 8) is its strong shielding of the HÀC(10) receptor 1H-NMR signal1) in
the complex, which makes titrations specially easy. Based on CPK models, this large
shift probably arises since HÀC(10) lies in the anisotropic shielding cone of the guest

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Fig. 8. Complex between receptor 6 and guest 15, and corresponding 1H-NMR-titration signals upon addition of
increasing amounts of guest to a C6D6 soln. of the receptor at 298 K
naphthalene ring in the complex (Fig. 8). The association constant under the conditions
applied was found to be 11 l/mol.
A competitive titration with receptor 6 in C6D6 afforded an association constant
3.85-fold higher for 11 than for 15. Since the presence of pyrrolidine will probably
reduce this ratio, we evaluated the association constant of the lactam under the reaction
conditions to lies somewhere between 11 and 40 l/mol. This range ensures that most
(90%) of the receptor is complexed under the reaction conditions.
The skeleton of xanthone 6 is, in our opinion, a good choice for the design of
artificial enzymes mimicking an oxyanion hole. As in natural enzymes, where the
oxyanion hole is only one part of the active site, our skeleton must be completed with
other active groups able to collaborate in the stabilization of the transition state. In
further work, we hope to include this kind of catalytic group to improve the catalytic
activity of our receptors, and to obtain asymmetric induction in the addition products.
Experimental Part
1. General. THF was distilled from Na/benzophenone. Melting points (m.p.) were measured on a Stuart
Scientific SMP3 device. IR Spectra were recorded on a BOMEM MB-100 FT-IR spectrometer; in cmÀ1. 1H- and
13C-NMR Spectra were acquired on Bruker Avance DRX-400 (400/100 MHz) or Varian 200 Mercury VX 2000
(200/50 MHz) spectrometers; d in ppm, J in Hz. Mass spectra were recorded on a Waters ZQ4000 quadrupole
spectrometer, with positive electrospray ionization (3.5 kV). For X-ray crystallographic data, see Sect. 8 and
Table 4.
2. Synthesis of Receptor 2. 2.1. 4-Bromo-5-nitroisophthalic Acid (16). 4-Bromoisophthalic acid (100 g,
410 mmol) was dissolved in 98% H2SO4 (2 l) and heated to 1008. To this soln., fuming HNO3 (42 ml, 1.013 mol)
was slowly added. After 30 min, the soln. was added to H2O, and colorless crystals of compound 16 (100 g, 84%)
were filtered off. M.p. 124 1268. IR: 3441 3256, 1732, 1640, 1597, 1537, 1262, 1192, 1165, 1140, 1098, 1038.
1H-NMR (CDCl3): 8.44 (d, J ˆ 1.9, 1 H); 8.33 (d, J ˆ 1.9, 1 H). 13C-NMR (CDCl3): 164.6 (C); 163.4 (C); 152.1
‡
‡
(C); 136.2 (C); 133.2 (C); 130.6 (C); 126.9 (CH); 117.6 (CH). ESI-MS: 312 ([M ‡ Na] ), 290 ([M ‡ H] ). Anal.
calc. for C8H4BrNO6: C 33.13, H 1.39, N 4.83; found: C 33.35, H 1.26, N 4.83.
2.2. Isopropyl 2-Bromo-5-[(diisopropylamino)carbonyl]-3-nitrobenzoate (17). Compound 16 (100 g,
346 mmol) was dissolved in CH2Cl2 (400 ml), and PCl5 (144 g, 692 mmol) was added with external cooling.
Once the exothermic reaction was over, the solvent was evaporated under vacuum. The intermediary acid

Helvetica Chimica Acta Vol. 88 (2005)
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dichloride was then dissolved in CCl4 (500 ml), and a soln. of (i-Pr)2NH (49 ml) and Et3N (55 ml) in CCl4
(500 ml) was added dropwise at 08 (ice bath). When the addition was complete, i-PrOH (150 ml) was added, the
solvent was evaporated under vacuum, and the residue was washed with AcOEt and 4% aq. Na2CO3 soln. The
residue was subjected to column chromatography (CC) on SiO2 to afford 17 (112 g, 78%). M.p. 124 1268. IR:
3000, 1732, 1640, 1597, 1537, 1454, 1373, 1339, 1285, 1262, 1192, 1165, 1140, 1098, 1038, 936. 1H-NMR (CDCl3):
7.73 (d, J ˆ 2.0, 1 H); 7.69 (d, J ˆ 2.0, 1 H); 5.36 5.24 (m, 1 H); 3.72 3.54 (m, 2 H); 1.59 (d, J ˆ 6.0, 6 H); 1.50
1.20 (m, 12 H). 13C-NMR (CDCl3): 166.0 (C); 151.6 (C); 140.1 (C); 138.7 (C); 136.9 (C); 129.7 (CH); 123.6
‡
‡
(CH); 112.4 (C); 70.6 (CH); 62.9 (CH); 21.5 (Me); 20.4 (Me). ESI-MS: 437 ([M ‡ Na] ), 415 ([M ‡ H] ).
Anal. calc. for C17H23BrN2O5: C 49.17, H 5.58, N 6.75; found: C 49.06, H 5.65, N 6.89.
2.3. Isopropyl 2-(4-tert-Butyl-2-nitrophenoxy)-5-[(diisopropylamino)carbonyl]-3-nitrobenzoate (18). Com-
pound 17 (20.2 g, 48.8 mmol) and potassium 4-tert-butyl-2-nitrophenolate (13.6 g, 58.3 mmol) were suspended in
DMF (20 ml), and then heated to 908 for 2 h. The mixture was poured over a 2% aq. NaOH soln. cooled
externally with ice. Crystals were then filtered off to yield 18 (23.1 g, 90%). M.p. 149 1518. IR: 2926, 1709, 1638,
1530, 1493, 1462, 1408, 1377, 1337, 1279, 1208, 1150, 1105, 1038, 924. 1H-NMR (CDCl3): 8.15 (d, J ˆ 1.8, 1 H); 8.09
(d, J ˆ 1.8, 1 H); 8.01 (d, J ˆ 2.1, 1 H); 7.43 (dd, J ˆ 8.8, 2.1, 1 H); 6.54 (d, J ˆ 8.8, 1 H); 5.02 4.86 (m, 1 H);
3.86 3.18 (m, 2 H); 1.55 1.15 (m, 12 H); 1.30 (s, 9 H); 0.98( d, J ˆ 6.0, 6 H). 13C-NMR (CDCl3): 166.4 (C);
162.2 (C); 149.2 (C); 146.3 (C); 145.4 (C); 144.3 (C); 138.4 (C); 137.0 (C); 133.7 (CH); 131.0 (CH); 128.8 (C);
126.6 (CH); 122.7 (CH); 115.3 (CH); 70.4 (CH); 62.4 (CH); 34.4 (C); 31.0 (Me); 21.0 (Me); 20.6 (Me). ESI-
‡
MS: 552 ([M ‡ Na] ). Anal. calc. for C27H35N3O8: C 61.23, H 6.66, N 7.93; found: C 61.11, H 6.52, N 7.98.
2.4. Isopropyl 3-Amino-2-(4-tert-butyl-2-nitrophenoxy)-5-[(diisopropylamino)carbonyl]benzoate (19).
Compound 18 (20 g, 38mmol) was dissolved in a mixture of MeOH (200 ml), AcOH (45 ml), and CH 2Cl2
(50 ml). After the addition of Fe powder (60 g, 1.07 mol) under mechanical stirring, the mixture was warmed to
358 for 30 min. The excess Fe was filtered off, and the solvent was evaporated under vacuum. The resulting
residue was dissolved in MeOH (100 ml), and this soln. was slowly poured over 2m aq. HCl soln. The resulting
crystals were filtered off, dried, and percolated with SiO2 to eliminate Fe salts. Yield of 19: 13.9 g (74%). M.p.
154 1568. IR: 3443, 3335, 2922, 1703, 1620, 1591, 1532, 1462, 1377, 1312, 1269, 1208, 1155, 1101, 1042, 1001, 903.
1H-NMR (CDCl3): 7.82 (d, J ˆ 2.0, 1 H); 7.35 (dd, J ˆ 2.0, 8.9, 1 H); 7.14 (d, J ˆ 1.2, 1 H); 6.93 (d, J ˆ 1.2, 1 H);
6.58( d, J ˆ 8.9, 1 H); 5.08 4.98 (m, 1 H); 3.75 3.60 (m, 1 H); 3.51 3.47 (m, 1 H); 1.40 1.35 (m, 12 H); 1.42
1.20 (m, 9 H); 0.91 (d, J ˆ 6.2, 6 H). 13C-NMR (CDCl3): 175.4 (C); 169.7 (C); 147.2 (C); 146.4 (C); 143.8(C);
137.7 (C); 136.9 (C); 129.6 (CH); 128.8 (CH); 122.9 (C); 121.1 (C); 116.8 (CH); 114.7 (CH); 111.3 (CH); 76.9
‡
‡
(CH); 41.0 (CH); 35.1 (C); 31.1 (Me); 21.8(Me); 20.6 (Me). ESI-MS: 538([ M ‡ K] ), 522 ([M ‡ Na] ), 500
‡
([M ‡ H] ). Anal. calc. for C27H37N3O6: C 64.91, H 7.46, N 8.41; found: C 64.76, H 7.58, N 8.29.
2.5. 4-Amino-7-tert-butyl-N,N-diisopropyl-5-nitro-9-oxo-9H-xanthene-2-carboxamide (20). P2O5 (2.0 g,
14.1 mmol) was added to MeSO3H (20 ml), and this mixture was stirred overnight. Compound 19 (10 g,
20 mmol) was then added, and the mixture was heated to 858 for 4 h. The soln. was added to cold H2O with
strong stirring, which resulted in crystals of 20 (8.34 g, 95%). M.p. 173 1758. IR: 3360, 2926, 1672, 1630, 1532,
1
1462, 1377, 1312, 1287, 1206, 1157, 1123, 1044. H-NMR (CDCl3): 8.63 (d, J ˆ 2.2, 1 H); 8.53 (d, J ˆ 2.2, 1 H);
7.56 (d, J ˆ 1.9, 1 H); 7.15 (d, J ˆ 1.9, 1 H); 3.91 3.45 (m, 2 H); 1.44 (s, 9 H); 1.63 1.13 (m, 12 H). 13C-NMR
(CDCl3): 169.3 (C); 163.9 (C); 148.5 (C); 145.1 (C); 141.3 (C); 138.6 (C); 138.3 (C); 136.8 (C); 130.8 (CH); 127.1
(C); 125.7 (C); 121.9 (CH); 117.1 (CH); 115.1 (CH); 38.6 (CH); 34.2 (C); 30.9 (Me); 21.0 (Me); 20.4 (Me). ESI-
‡
‡
MS: 462 ([M ‡ Na] ), 440 ([M ‡ H] ). Anal. calc. for C24H29N3O5: C 65.59, H 6.65, N 9.56; found: C 65.38, H
6.53, N 9.69.
2.6. 7-tert-Butyl-N,N-diisopropyl-5-nitro-9-oxo-4-({[(1,1,3,3-tetramethylbutyl)amino]carbonyl}amino)-9H-
xanthene-2-carboxamide (21). Compound 20 (5 g, 11.4 mmol) was dissolved in CH2Cl2 (50 ml). A 0.6m
phosgene soln. in toluene (3.0 ml) was added, and the mixture was refluxed for 20 min. The solvent was
evaporated under vacuum, and the residue was co-evaporated with toluene (30 ml). The dry residue was
dissolved in toluene (20 ml), and this soln. was added to a toluene soln. (30 ml) of 2,4,4-trimethylpentan-2-
amine (−tert-octylamine×; 3.0 g, 23.2 mmol) with magnetic stirring at r.t. Then, the solvent was evaporated, and
the residue was washed with AcOEt and 2m aq. HCl soln. The crude product from the org. layer was
recrystallized from MeOH/H2O to afford 21 (6.35 g, 94%). M.p. 215 2178. IR: 3399, 3324, 2924, 1709, 1672,
1616, 1599, 1532, 1462, 1375, 1343, 1298, 1273, 1252, 1217, 1200, 1155, 1101, 1042. 1H-NMR (CDCl3): 8.42 (d, J ˆ
2.5, 1 H); 8.13 (d, J ˆ 1.5, 1 H); 8.02 (d, J ˆ 2.5, 1 H); 7.13 (d, J ˆ 1.5, 1 H); 3.95 3.81 (m, 1 H); 3.60 3.42 (m,
1 H); 1.79 (s, 2 H); 1.60 (d, J ˆ 6.6, 6 H); 1.45 (s, 15 H); 1.11 (d, J ˆ 6.6, 6 H); 1.04 (s, 9 H). 13C-NMR (CDCl3):
173.4 (C); 169.2 (C); 153.4 (C); 147.2 (C); 145.4 (C); 144.8 (C); 138.5 (C); 137.7 (C); 134.2 (C); 128.7 (CH);
128.1 (CH); 125.3 (CH); 121.7 (C); 119.1 (C); 113.3 (CH); 54.3 (C); 51.4 (CH2); 34.9 (C); 31.5 (CH); 31.3 (Me);

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Helvetica Chimica Acta Vol. 88 (2005)
‡
‡
30.9 (Me); 29.8(Me); 20.6 (Me); 20.5 (C). ESI-MS: 617 ([ M ‡ Na] ), 595 ([M ‡ H] ). Anal. calc. for
C33H46N4O6: C 66.64, H 7.80, N 9.42; found: C 66.47, H 7.93, N 9.33.
2.7. 5-(Acetylamino)-7-tert-butyl-N,N-diisopropyl-9-oxo-4-({[(1,1,3,3-tetramethylbutyl)amino]carbonyl}-
amino)-9H-xanthene-2-carboxamide (2). Compound 21 (1.0 g, 1.68mmol) was dissolved in AcOH (10 ml),
and 10% Pd/C (0.1 g) was added. The mixture was hydrogenated overnight under a pressure of 4 atm of H2. The
catalyst was filtered off, and washed several times with AcOEt. After evaporation of the solvent, the residue was
dissolved in anh. THF (5.0 ml), and AcCl (1.0 ml) was added. The acylation reaction was completed within
15 min at r.t. Then, the solvent and excess AcCl were evaporated, and the remaining solid was recrystallized
from MeOH/H2O to afford crystalline 2 (0.52 g, 97%). M.p. 173 1758. IR: 3360, 2926, 1672, 1630, 1532, 1462,
1377, 1312, 1287, 1206, 1157, 1123, 1044. 1H-NMR (CDCl3): 8.84 (d, J ˆ 1.6, 1 H); 8.74 (d, J ˆ 1.6, 1 H); 8.46 (d,
J ˆ 2.0, 1 H); 8.16 (d, J ˆ 2.0, 1 H); 4.44 4.28( m, 1 H); 4.09 3.92 (m, 1 H); 2.72 (s, 3 H); 2.23 (s, 2 H); 1.98
1.83 (m, 6 H); 1.8 6 (s, 6 H); 1.8 1 (s, 9 H); 1.67 1.33 (m, 6 H); 1.45 (s, 9 H). 13C-NMR (CDCl3): 175.0 (C); 172.1
(C); 169.0 (C); 153.3 (C); 147.5 (C); 145.1 (C); 144.2 (C); 132.6 (C); 129.6 (C); 126.6 (CH); 126.1 (CH); 121.7
(C); 120.7 (C); 120.3 (C); 118.0 (CH); 114.1 (CH); 54.4 (C); 51.7 (CH); 51.4 (CH2); 46.1 (CH); 34.9 (C); 31.4
‡
‡
(Me); 31.2 (Me); 30.0 (Me); 24.2 (Me); 20.7 (Me); 20.4 (C). ESI-MS: 629 ([M ‡ Na] ), 607 ([M ‡ H] ). Anal.
calc. for C35H50N4O5: C 69.28, H 8.31, N 9.23; found: C 69.02, H 8.55, N 9.42.
3. Syntheses of Receptors 3 and 4. 3.1. 4-(Acetylamino)-7-tert-butyl-N,N-diisopropyl-5-nitro-9-oxo-9H-
xanthene-2-carboxamide (22). Compound 20 (1.0 g, 2.3 mmol) was dissolved in anh. THF (5.0 ml), and AcCl
(1.0 ml) was added. The mixture was maintained at r.t. for 15 min. Then, the solvent and excess reagent were
evaporated, and the residue was recrystallized from MeOH/H2O to afford 22 (1.076 g, 98%). M.p. 260 2628.
IR: 3397, 2934, 1705, 1672, 1626, 1572, 1537, 1462, 1418, 1377, 1327, 1294, 1277, 1209, 1157, 1105, 1092, 1044.
1H-NMR (CDCl3): 8.73 (d, J ˆ 1.7, 1 H); 8.64 (d, J ˆ 2.2, 1 H); 8.59 (d, J ˆ 2.2, 1 H); 7.93 (d, J ˆ 1.7, 1 H);
3.90 3.70 (m, 1 H); 3.66 3.45 (m, 1 H); 2.35 (s, 3 H); 1.59 1.40 (m, 6 H); 1.43 (s, 9 H); 1.23 1.11 (m, 6 H).
13C-NMR (CDCl3): 174.5 (C); 169.3 (C); 168.9 (C); 147.8 (C); 146.0 (C); 145.1 (C); 137.6 (C); 135.5 (C); 129.7
(CH); 129.3 (CH); 128.2 (C); 123.8(CH); 122.7 (C); 120.8(C); 117.4 (CH); 51.4 (CH); 46.3 (CH); 35.3 (C);
‡
‡
31.2 (Me); 24.7 (Me); 20.7 (Me); 20.6 (Me). ESI-MS: 504 ([M ‡ Na] ), 482 ([M ‡ H] ). Anal. calc. for
C26H31N3O6: C 64.85, H 6.49, N 8.73; found: C 64.73, H 6.35, N 8.84.
3.2. 4-(Acetylamino)-5-amino-7-tert-butyl-N,N-diisopropyl-9-oxo-9H-xanthene-2-carboxamide (23). Com-
pound 22 (1.0 g, 2.1 mmol) was reduced with H2 on Pd/C, as described for the reduction of 21, to afford 23
(0.88 g, 94% yield). M.p. 237 2398. IR: 3381, 2924, 1701, 1663, 1603, 1541, 1464, 1377, 1333, 1294, 1250, 1204,
1157, 1103, 1042. 1H-NMR (CDCl3): 9.24 (d, J ˆ 1.9, 1 H); 7.90 (d, J ˆ 1.9, 1 H); 7.27 (d, J ˆ 2.2, 1 H); 7.04 (d,
J ˆ 2.2, 1 H); 3.99 3.84 (m, 1 H); 3.68 3.55 ( m, 1 H); 2.26 (s, 3 H); 2.07 (d, J ˆ 8.2, 6 H); 1.48 (s, 9 H); 1.16 (d,
J ˆ 6.4, 6 H). 13C-NMR (CDCl3): 175.5 (C); 171.6 (C); 169.6 (C); 148.1 (C); 145.5 (C); 142.5 (C); 138.4 (C);
132.4 (C); 127.4 (C); 123.5 (CH); 121.4 (C); 120.3 (C); 116.9 (CH); 112.3 (CH); 109.3 (CH); 52.1 (CH); 46.3
‡
‡
(CH); 35.2 (C); 31.7 (Me); 30.8(Me); 24.4 (Me); 20.9 (Me). ESI-MS: 474 ([ M ‡ Na] ), 452 ([M ‡ H] ). Anal.
calc. for C26H33N3O4: C 69.16, H 7.37, N 9.31; found: C 69.33, H 7.25, N 9.44.
3.3. 4-(Acetylamino)-7-tert-butyl-N,N-diisopropyl-9-oxo-5-({[(1,1,3,3-tetramethylbutyl)amino]carbonyl}-
amino)-9H-xanthene-2-carboxamide (3). Compound 23 (0.5 g, 1.11 mmol) was dissolved in CH2Cl2 (15 ml),
and a 0.6m phosgene soln. in toluene (1.0 ml) was added. The mixture was refluxed for 20 min, the solvent was
evaporated under vacuum, and the residue was co-evaporated with toluene (10 ml). The anh. residue was
dissolved in toluene (15 ml), and this soln. was added to a soln. of 2,4,4-trimethylpentan-2-amine (−tert-
octylamine×; 1 g) in toluene (15 ml) with stirring. When the addition was complete, the solvent was evaporated,
and the residue was taken up in AcOEt and washed with 2m aq. HCl soln. The org. layer was dried (Na2SO4),
and evaporated under vacuum. The residue was recrystallized from MeOH/H2O to afford 3 (0.65 g, 96%). M.p.
186 1888. IR: 3312, 2924, 1707, 1670, 1607, 1551, 1530, 1462, 1377, 1333, 1300, 1258, 1211, 1157, 1107, 1040.
1H-NMR (CDCl3): 8.80 (s, 1 H); 8 .46 (s, 1 H); 7.8 0 (s, 1 H); 7.78 (s, 1 H); 3.95 3.82 (m, 1 H); 3.77 3.62 (m,
1 H); 2.40 (s, 3 H); 1.77 (br. s, 2 H); 1.64 (d, J ˆ 6.4 H, 6 H); 1.46 (s, 6 H); 1.25 (s, 9 H); 1.16 (d, J ˆ 6.4, 6 H);
1.04 (s, 9 H). 13C-NMR (CDCl3): 175.0 (C); 172.4 (C); 168.8 (C); 160.7 (C); 153.2 (C); 147.9 (C); 145.1 (C);
144.1 (C); 132.5 (C); 129.8(C); 126.6 (C); 126.1 (CH); 120.7 (CH); 120.3 (C); 118.0 (CH); 113.8(CH); 54.5
(C); 52.0 (CH); 51.3 (CH2); 46.1 (CH); 35.0 (C); 31.5 (Me); 31.3 (Me); 30.1 (Me); 22.6 (C); 20.9 (Me); 20.6
‡
‡
(Me); 14.0 (Me). ESI-MS: 629 ([M ‡ Na] ), 607 ([M ‡ H] ). Anal. calc. for C35H50N4O5: C 69.28, H 8.31, N
9.23; found: C 69.40, H 8.21, N 9.20.
3.4. 4-(Acetylamino)-7-tert-butyl-5-{[(butylamino)carbonyl]amino}-N,N-diisopropyl-9-oxo-9H-xanthene-
2-carboxamide (4). Compound 23 (0.4 g, 0.89 mmol) was dissolved in CH2Cl2 (15 ml), and a 0.6m phosgene
soln. in toluene (1.0 ml) was added. The mixture was refluxed for 20 min. Then, the solvent was evaporated
under vacuum, and the residue was co-evaporated with toluene (10 ml). The anh. residue was dissolved in

Helvetica Chimica Acta Vol. 88 (2005)
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toluene (15 ml), and this soln. was added to a soln. of BuNH2 (1 g) in toluene (15 ml) with stirring. When the
addition was complete, the solvent was evaporated, and the residue was taken up in AcOEt, and extracted with
2m aq. HCl soln. The org. layer was dried (Na2SO4), and evaporated under vacuum to afford, after
recrystallization from MeOH/H2O, compound 4 (0.43 g, 88%). M.p. 262 2648. IR: 3383, 2926, 1697, 1655, 1607,
1534, 1458, 1418, 1375, 1325, 1294, 1250, 1208, 1157, 1103, 1042. 1H-NMR (CDCl3): 8.35 (d, J ˆ 1.8, 1 H); 8.12 (d,
J ˆ 2.3, 1 H); 7.83 (d, J ˆ 1.8, 1 H); 7.72 (d, J ˆ 2.3, 1 H); 3.87 3.75 (m, 1 H); 3.59 3.41 (m, 1 H); 3.06 (t, J ˆ
7.0, 2 H); 2.28( s, 3 H); 1.57 1.35 (m, 6 H); 1.32 (s, 9 H); 1.15 1.02 (m, 10 H); 0.85 (t, J ˆ 7.2, 3 H). 13C-NMR
(CDCl3): 176.1 (C); 170.2 (C); 169.5 (C); 159.6 (C); 149.5 (C); 148.8 (C); 145.7 (C); 134.7 (C); 133.2 (CH);
133.0 (C); 127.9 (C); 124.3 (CH); 122.2 (C); 122.0 (CH); 121.3 (C); 118.4 (CH); 41.4 (CH); 40.9 (CH2); 37.5
‡
(Me); 35.2 (C); 31.5 (Me); 29.7 (CH2); 20.8(Me); 20.0 (CH 2); 13.7 (Me). ESI-MS: 573 ([M ‡ Na ), 551 ([M ‡
‡
H] ). Anal. calc. for C31H42N4O5: C 67.61, H 7.69, N 10.17; found: C 67.53, H 7.60, N 10.22.
4. Synthesis of Receptor 5. 4.1. Dimethyl 4-(4-tert-Butyl-2-nitrophenoxy)-5-nitroisophthalate (24). Prepared
in analogy to 18, starting from dimethyl 4-bromo-5-nitroisophthalate (120 g, 377.4 mmol). Yield: 156.1 g (96%).
M.p. 112 1148. 1H-NMR (CDCl3): 7.97 (d, J ˆ 2.4, 1 H); 7.90 (d, J ˆ 2.4, 1 H); 7.67 (d, J ˆ 2.5, 1 H); 7.40 (dd,
‡
J ˆ 8.8, 2.5, 1 H); 6.60 (d, J ˆ 8.8, 1 H); 3.91 (s, 3 H); 3.70 (s, 3 H); 1.30 (s, 9 H). ESI-MS: 455 ([M ‡ Na] ), 433
‡
([M ‡ H] ). Anal. calc. for C20H20N2O9: C 55.56, H 4.66, N 6.48; found: C 55.39, H 4.56, N 6.34.
4.2. Dimethyl 5-Amino-4-(4-tert-butyl-2-nitrophenoxy)isophthalate (25). Compound 24 (116 g, 269 mmol)
was dissolved in a mixture of MeOH (1000 ml), AcOH (300 ml), and benzene (300 ml). Then, Fe powder
(350 g, 6.25 mol) was added, and the mixture was vigorously (mechanically) stirred for 2 h, the temp. being kept
at 308 with an external cooling bath. Excess Fe was filtered off, and most of the solvent was evaporated under
vacuum. The residue was dissolved in AcOEt and washed with H2O. The org. layer was dried (Na2SO4) and
evaporated, and the resulting residue was percolated over SiO2 to separate it from Fe salts. Yield of 25: 90.52 g
1
(84%). M.p. 112 1148. H-NMR (CDCl3): 7.81 (d, J ˆ 2.2, 1 H); 7.77 (d, J ˆ 2.2, 1 H); 7.61 (d, J ˆ 2.5, 1 H);
7.41 (dd, J ˆ 8.8, 2.5, 1 H); 6.54 (d, J ˆ 8.8, 1 H); 3.98 (s, 3 H); 3.96 (s, 3 H); 1.20 (s, 9 H). ESI-MS: 425
‡
‡
([M ‡ Na] ), 403 ([M ‡ H] ). Anal. calc. for C20H22N2O7: C 59.70, H 5.51, N 6.96; found: C 59.52, H 5.56, N
6.84.
4.3. 4-Amino-7-tert-butyl-5-nitro-9-oxo-9H-xanthene-2-carboxylic Acid (26). Compound 25 (40.6 g,
101 mmol) was suspended in 48% HBr (400 ml). The mixture was refluxed for 3 h, whereupon a homogeneous
soln. resulted. Ice was added, and crystals of the diacid were filtered from the cold suspension (35.8g,
95.7 mmol, 95%). Once dried, the intermediary diacid was added to a suspension of P2O5 (10 g) in MeSO3H
(100 ml), which had previously been stirred overnight. The mixture was heated to 908 for 2 h, and then added to
cold H2O to afford crystalline 26 (33.2 g, 97% (second step)). M.p. 280 2828. IR: 2924, 1696, 1618, 1535, 1476,
1287, 1196, 1055. 1H-NMR (CDCl3): 8.52 (d, J ˆ 2.5, 1 H); 8.42 (d, J ˆ 2.5, 1 H); 7.90 (d, J ˆ 2.0, 1 H); 7.38( d,
‡
‡
J ˆ 2.0, 1 H); 1.34 (s, 9 H). ESI-MS: 379 ([M ‡ Na] ), 357 ([M ‡ H] ). Anal. calc. for C18H16N2O6: C 60.67, H
4.53, N 7.86; found: C 60.53, H 4.39, N 7.94.
4.4. Butyl 4-Amino-7-tert-butyl-5-nitro-9-oxo-9H-xanthene-2-carboxylate (27). Acid 26 (15 g, 42.1 mmol)
was suspended in BuOH (250 ml), and SOCl2 (3.0 ml) was carefully added. The mixture was refluxed for 3 h,
whereupon the starting material completely dissolved. The solvent was partially evaporated under vacuum, and
hexane (300 ml) was added to induce the crystallization of 27 (16.1 g, 93%). M.p. 188 1908. IR: 3483, 3368,
2924, 1717, 1665, 1622, 1570, 1537, 1464, 1377, 1310, 1285, 1252, 1225, 1113, 1053, 1017. 1H-NMR (CDCl3): 8.62 (d,
J ˆ 2.3, 1 H); 8.51 (d, J ˆ 2.3, 1 H); 8.25 (d, J ˆ 1.6, 1 H); 7.72 (d, J ˆ 1.6, 1 H); 4.33 (t, J ˆ 6.6, 2 H); 1.89 1.74
(m, 2 H); 1.56 1.43 (m, 2 H); 1.44 (s, 9 H); 0.98( t, J ˆ 7.3, 3 H). 13C-NMR (CDCl3): 175.2 (C); 165.5 (C); 147.6
(C); 146.0 (C); 138.3 (C); 137.7 (C); 136.6 (C); 129.6 (CH); 128.8 (CH); 127.5 (C); 122.9 (C); 121.0 (C); 119.0
(CH); 116.5 (CH); 65.3 (CH2); 35.1 (Me); 31.0 (CH2); 30.7 (C); 19.2 (CH2); 13.7 (Me). ESI-MS: 435 ([M ‡
‡
‡
Na] ), 413 ([M ‡ H] ). Anal. calc. for C22H24N2O6: C 64.07, H 5.87, N 6.79; found: C 64.01, H 5.89, N 6.68.
4.5. Butyl 7-tert-Butyl-5-nitro-9-oxo-4-({[(1,1,3,3-tetramethylbutyl)amino]carbonyl}amino)-9H-xanthene-2-
carboxylate (28). Prepared by reaction with a 0.6m phosgene soln. in toluene, as described for 17. Yield of 28:
95%. M.p. 236 2388. IR: 3445, 3403, 2924, 2855, 1724, 1672, 1618, 1574, 1534, 1464, 1377, 1344, 1317, 1285, 1248,
1198, 1107, 1061. 1H-NMR (CDCl3): 9.10 (d, J ˆ 1.8, 1 H); 8.62 (d, J ˆ 2.4, 1 H); 8.56 (d, J ˆ 2.4, 1 H); 8.49 (d,
J ˆ 1.8, 1 H); 4.36 (t, J ˆ 6.8, 2 H); 1.82 (s, 2 H); 1.90 1.73 (m, 2 H); 1.51 (s, 6 H); 1.57 1.41 (m, 2 H); 1.44 (s,
9 H); 1.07 (s, 9 H); 0.98( t, J ˆ 7.3, 3 H). 13C-NMR (CDCl3): 174.9 (C); 165.5 (C); 152.9 (C); 148.2 (C); 146.6
(C); 146.2 (C); 137.3 (C); 130.4 (CH); 129.9 (C); 129.4 (CH); 128.0 (C); 124.6 (CH); 123.1 (C); 120.5 (CH);
120.4 (C); 65.7 (CH2); 55.5 (C); 52.2 (CH2); 35.4 (C); 31.7 (Me); 31.3 (Me); 30.9 (CH2); 29.8(Me); 20.5 (C);
‡
‡
19.4 (CH2); 14.0 (Me). ESI-MS: 590 ([M ‡ Na] ), 568([ M ‡ H] ). Anal. calc. for C31H41N3O7: C 65.59, H 7.28,
N 7.40; found: C 65.48, H 7.39, N 7.24.

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4.6. Butyl 5-Amino-7-tert-butyl-9-oxo-4-({[(1,1,3,3-tetramethylbutyl)amino]carbonyl}amino)-9H-xanthene-
2-carboxylate (29). Prepared in analogy to the synthetic path leading to 2, but starting from 28. Yield of 29: 92%.
M.p. 127 1298. IR: 3376, 2928, 2855, 1715, 1655, 1626, 1605, 1539, 1464, 1377, 1314, 1283, 1246, 1219, 1155, 1101,
1061, 768, 721. 1H-NMR (CDCl3): 8.68 (br. s, 1 H); 7.71 (d, J ˆ 2.2, 1 H); 7.18( d, J ˆ 2.2, 1 H); 6.87 (br. s, 1 H);
4.36 (t, J ˆ 6.6, 2 H); 1.79 (s, 2 H); 1.76 1.59 (m, 2 H); 1.46 (s, 6 H); 1.34 (s, 9 H); 1.41 0.96 (m, 14 H).
13C-NMR (CDCl3): 177.7 (C); 165.9 (C); 154.6 (C); 148.8 (C); 148.4 (C); 142.2 (C); 138.3 (C); 136.2 (C); 129.2
(C); 125.8(CH); 121.7 (CH); 121.0 (C); 120.9 (C); 117.8(CH); 110.5 (CH); 65.4 (CH 2); 54.8(C); 51.7 (CH 2);
34.6 (C); 31.4 (Me); 31.1 (Me); 30.7 (CH2); 29.8(Me); 20.5 (C); 19.1 (CH 2); 13.6 (Me). ESI-MS: 560
‡
‡
([M ‡ Na] ), 538([ M ‡ H] ). Anal. calc. for C31H43N3O5: C 69.25, H 8.06, N 14.88; found: C 69.19, H 8.12, N
14.81.
4.7. Butyl 5-(Acetylamino)-7-tert-butyl-9-oxo-4-({[(1,1,3,3-tetramethylbutyl)amino]carbonyl}amino)-9H-
xanthene-2-carboxylate (5). Prepared in analogy to the synthetic path leading to 2, but starting from 29. Yield
of 5: 98%. M.p. 198 2008. IR: 3343, 3293, 3187, 3063, 2926, 1723, 1705, 1642, 1605, 1539, 1466, 1375, 1300, 1277,
1
1242, 1221, 1105, 1072, 1024. H-NMR (CDCl3): 8.47 (br. s, 1 H); 8.36 (br. s, 1 H); 7.96 (br. s, 1 H); 7.31 (br. s,
1 H); 4.31 (t, J ˆ 6.7, 2 H); 2.37 (s, 3 H); 1.75 (s, 2 H); 1.79 1.70 (m, 2 H); 1.49 1.39 (m, 2 H); 1.42 (s, 6 H); 1.34
(s, 9 H); 0.99 (s, 9 H); 0.96 (t, J ˆ 7.4, 3 H). 13C-NMR (CDCl3): 176.5 (C); 169.8(C); 165.6 (C); 154.2 (C); 147.9
(C); 144.6 (C); 138.8(C); 129.1 (C); 126.7 (CH); 126.3 (C); 125.8(CH); 123.1 (CH); 121.7 (CH); 120.9 (C);
120.7 (C); 118.2 (CH); 65.4 (CH2); 54.5 (C); 51.4 (CH2); 34.9 (C); 31.3 (Me); 31.0 (Me); 30.6 (CH2); 29.7 (Me);
‡
23.9 (Me); 20.7 (C); 19.1 (CH2); 13.6 (Me). ESI-MS: 602 ([M ‡ Na] ). Anal. calc. for C33H45N3O6: C 68.37, H
7.82, N 7.25; found: C 68.32, H 7.89, N 7.37.
5. Syntheses of Receptors 6 8. 5.1. Ethyl 3,3-Dibutyl-11-(decanoylamino)-2,3,4,7-tetrahydro-2,4,7-trioxo-
1H-[1]benzopyrano[3,2-h]quinoline-9-carboxylate (6). Amine 30 (1.0 g, 2.09 mmol) was dissolved in anh. THF
(5.0 ml), and decanoyl chloride (1.2 g, 6.3 mmol) was added. The reaction was complete after 10 min at r.t. H2O
(0.3 ml) was added, and the mixture was heated to 508 for 30 min to hydrolyze the excess decanoyl chloride. The
solvent was evaporated, and the residue was subjected to CC (SiO2) to afford 6 (1.15 g, 87%). M.p. 194 1968.
IR: 3403, 3248, 2926, 1713, 1682, 1651, 1609, 1584, 1537, 1464, 1377, 1285, 1246, 1213, 1099, 1022. 1H-NMR
(CDCl3): 9.25 (d, J ˆ 2.1, 1 H); 8.82 (d, J ˆ 2.1, 1 H); 8.14 (d, J ˆ 8.4, 1 H); 7.97 (d, J ˆ 8.4, 1 H); 4.47 (q, J ˆ
7.1, 2 H); 2.61 (t, J ˆ 7.3, 2 H); 2.18 2.03 ( m, 2 H); 1.94 1.80 (m, 4 H); 1.46 (t, J ˆ 7.1, 3 H); 1.42 1.38( m,
12 H); 1.30 1.17 (m, 8 H); 0.89 (t, J ˆ 6.6, 3 H); 0.79 (t, J ˆ 6.4, 6 H). 13C-NMR (CDCl3): 196.5 (C); 178.5 (C);
175.2 (C); 172.9 (C); 165.5 (C); 149.4 (C); 143.7 (C); 130.9 (CH); 130.5 (C); 128.6 (C); 126.5 (C); 124.5 (CH);
123.3 (C); 122.6 (C); 122.3 (CH); 122.0 (C); 117.3 (CH); 62.9 (CH2); 62.4 (C); 41.4 (CH2); 37.6 (CH2); 32.4
(CH2); 30.2 (CH2); 28.2 (CH2); 26.0 (CH2); 23.6 (CH2); 23.2 (CH2); 14.9 (Me); 14.5 (Me); 14.3 (Me); 14.0
‡
‡
‡
(Me). ESI-MS: 671 ([M ‡ K] ), 655 ([M ‡ Na] ), 633 ([M ‡ H] ). Anal. calc. for C37H48N2O7: C 70.23, H 7.65,
N 4.43; found: C 70.17, H 7.75, N 4.49.
5.2. Ethyl 3,3-Dibutyl-2,3,4,7-tetrahydro-11-{[(trifluoromethyl)carbonyl]amino}-2,4,7-trioxo-1H-[1]benzo-
pyrano[3,2-h]quinoline-9-carboxylate (7). Compound 30 (0.4 g, 0.84 mmol) was reacted in anh. THF with an
excess of trifluoroacetic anhydride (2 ml) under conditions similar to those used to prepare 6. When the reaction
was complete, and the excess of reagent was hydrolyzed, the solvent was evaporated under vacuum, and the
residue was taken up in AcOEt and washed with a dilute soln. of aq. Na2CO3. The org. layer was dried (Na2SO4),
the solvent was evaporated, and the residue was recrystallized from CH2Cl2/Et2O to afford 7 (0.42 g, 87%). M.p.
152 1548. IR: 3248, 3067, 2926, 1738, 1699, 1657, 1605, 1584, 1555, 1501, 1462, 1377, 1283, 1244, 1215, 1155, 1067,
1024. 1H-NMR (CDCl3): 9.00 (d, J ˆ 1.8, 1 H); 8.93 (d, J ˆ 1.8, 1 H); 8.13 (d, J ˆ 8.4, 1 H); 7.97 (d, J ˆ 8.4,
1 H); 4.51 (q, J ˆ 7.1, 2 H); 2.11 1.93 (m, 4 H); 1.49 (t, J ˆ 7.1, 3 H); 1.01 0.78( m, 8H); 0.53 0.24 ( m, 6 H).
13C-NMR (CDCl3): 195.9 (C); 177.2 (C); 174.0 (C); 163.8(C); 155.8(C); 149.1 (C); 143.0 (C); 130.5 (C); 129.8
(CH); 127.1 (C); 125.8(C); 125.5 (CH); 124.3 (C); 122.6 (C); 121.9 (C); 121.6 (CH); 120.9 (CH); 62.0 (C); 40.6
‡
‡
(CH2); 27.1 (CH2); 22.7 (CH2); 14.1 (Me); 13.0 (Me). ESI-MS: 597 ([M ‡ Na] ), 575 ([M ‡ H] ). Anal. calc.
for C29H29F3N2O7: C 60.62, H 5.09, N 4.88; found: C 60.65, H 4.99, N 4.96.
5.3. Ethyl 3,3-Dibutyl-2,3,4,7-tetrahydro-11-[(methylsulfonyl)amino]-2,4,7-trioxo-1H-[1]benzopyrano[3,2-
h]quinoline-9-carboxylate (8). Prepared, in analogy to 7, from 30 (0.4 g, 0.84 mmol) and excess of
methanesulfonic acid chloride (2 ml). Yield of 8: 0.428g (92%). M.p. 144 146 8. IR: 3260, 2926, 1715, 1674,
1651, 1603, 1495, 1464, 1377, 1283, 1208, 1157, 1144, 1047, 1024. 1H-NMR (CDCl3): 8.86 (d, J ˆ 2.1, 1 H); 8.77 (d,
J ˆ 2.1, 1 H); 8.12 (d, J ˆ 8.4, 1 H); 8.01 (d, J ˆ 8.4, 1 H); 4.46 (q, J ˆ 7.1, 2 H); 3.30 (s, 3 H); 2.18 1.86 ( m,
4 H); 1.45 (t, J ˆ 7.1, 3 H); 1.16 0.93 (m, 8H); 0.59 ( t, J ˆ 5.7, 6 H). 13C-NMR (CDCl3): 196.3 (C); 176.4 (C);
174.6 (C); 164.3 (C); 149.2 (C); 143.1 (C); 138.8(C); 131.0 (C); 127.6 (CH); 126.8(C); 125.6 (CH); 124.7 (C);
122.9 (C); 122.1 (CH); 120.4 (CH); 118.0 (C); 62.5 (C); 61.8 (CH2); 40.5 (Me); 39.5 (CH2); 27.1 (CH2); 22.7

Helvetica Chimica Acta Vol. 88 (2005)
1699
‡
‡
(CH2); 14.1 (Me); 13.3 (Me). ESI-MS: 579 ([M ‡ Na] ), 557 ([M ‡ H] ). Anal. calc. for C28H32N2O8S: C 60.42,
H 5.79, N 5.03, S 5.76; found: C 60.35, H 5.99, N 4.85, S 5.73.
6. Syntheses of Receptors 9 and 10. 6.1. Ethyl 11-Amino-3,3-dibutyl-2,3,4,7-tetrahydro-2,4-dioxo-1H-
[1]benzopyrano[3,2-h]quinoline-9-carboxylate (31). Compound 30 (2.0 g, 4.18mmol) was dissolved in anh.
EtOH (100 ml), and ground Sn (4 g, 33.7 mmol) was added. The mixture was vigorously stirred at refluxed.
When TLC analysis indicated that the reaction was complete, 35% HCl soln. (60 ml) was added. The EtOH was
partially evaporated at reduced pressure, and the resulting mixture was added to cold H2O, whereupon 31 (1.8g,
93%) crystallized. Anal. calc. for C27H32N2O5: C 69.81, H 6.94, N 6.03; found: C 69.72, H 6.85, N 6.15.
6.2. Ethyl 3,3-Dibutyl-11-(decanoylamino)-2,3,4,7-tetrahydro-2,4-dioxo-1H-[1]benzopyrano[3,2-h]quino-
line-9-carboxylate (9). Compound 31 (1.0 g, 2.16 mmol) were dissolved in anh. THF (20 ml), and an excess of
Et3N (1 ml) and decanoyl chloride (0.41 g, 2.15 mmol) was added. The mixture was heated to 508 during 1 h, and
then the solvents were evaporated under vacuum. The residue was dissolved in AcOEt, washed with 2m aq. HCl
soln., and the org. layer was dried and evaporated. The resulting residue was subjected to CC (SiO2) to afford 9
(1.10 g, 83%). M.p. 212 2148. IR: 3408, 3235, 2926, 1707, 1670, 1647, 1632, 1541, 1464, 1377, 1314, 1217, 1024.
1H-NMR (CDCl3): 8.83 (d, J ˆ 1.8, 1 H); 7.71 (d, J ˆ 1.8, 1 H); 7.70 (d, J ˆ 8.1, 1 H); 7.03 (d, J ˆ 8.1, 1 H); 4.40
(q, J ˆ 7.1, 2 H); 4.14 (br. s, 2 H); 2.56 (t, J ˆ 7.2, 2 H); 2.14 1.97 (m, 2 H); 1.87 1.74 (m, 4 H); 1.65 1.55 (m,
4 H); 1.42 (t, J ˆ 7.1, 3 H); 1.39 1.36 (m, 4 H); 1.24 1.17 (m, 12 H); 0.89 (t, J ˆ 6.6, 3 H); 0.79 (t, J ˆ 6.4, 6 H).
13C-NMR (CDCl3): 197.1 (C); 178.3 (C); 173.2 (C); 166.4 (C); 144.6 (C); 138.8 (C); 138.7 (C); 129.7 (C); 127.3
(C); 126.5 (C); 126.3 (CH); 124.5 (CH); 123.6 (CH); 122.5 (CH); 120.3 (C); 119.4 (C); 62.2 (CH2); 61.8(C);
41.6 (CH2); 37.5 (CH2); 32.4 (CH2); 30.2 (CH2); 28.2 (CH2); 23.7 (CH2); 23.2 (CH2); 15.0 (Me); 14.5 (Me); 14.1
‡
‡
(Me). ESI-MS: 641 ([M ‡ Na] ), 619 ([M ‡ H] ). Anal. calc. for C37H50N2O6: C 71.82, H 8.14, N 4.53; found: C
71.92, H 8.08, N 4.63.
6.3. Ethyl 3,3-Dibutyl-2,3,4,7-tetrahydro-11-[(methylsulfonyl)amino]-2,4-dioxo-1H-[1]benzopyrano[3,2-
h]quinoline-9-carboxylate (10). Prepared in analogy to 9, from 31 (1 g, 2.16 mmol) and methanesulfonic acid
chloride (3 ml). The excess reagent was hydrolyzed by adding H2O (1 ml). After evaporation of the solvent at
reduced pressure, the residue was dissolved in AcOEt, and washed with 4% aq. Na2CO3 soln. The org. layer was
evaporated to afford 10 (1.08g, 92%). M.p. 127 129 8. IR: 3217, 2926, 2855, 1707, 1647, 1605, 1466, 1377, 1341,
1290, 1213, 1192, 1157, 1076, 1024. 1H-NMR (CDCl3): 8.26 (d, J ˆ 1.9, 1 H); 7.79 (d, J ˆ 1.9, 1 H); 7.72 (d, J ˆ
8.1, 1 H); 7.02 (d, J ˆ 8.1, 1 H); 4.39 (q, J ˆ 7.0, 2 H); 4.39 (br. s, 2 H); 3.16 (s, 3 H); 2.11 1.93 (m, 4 H); 1.78
1.62 (m, 4 H); 1.41 (t, J ˆ 7.0, 3 H); 1.15 0.99 (m, 4 H); 0.60 (t, J ˆ 6.0, 6 H). 13C-NMR (CDCl3): 196.6 (C);
176.8(C); 165.1 (C); 145.6 (C); 138.5 (C); 137.8(C); 129.7 (C); 127.5 (C); 127.1 (CH); 126.8(C); 125.5 (C);
124.1 (CH); 123.1 (CH); 122.1 (CH); 119.8(C); 61.8(CH 2); 61.2 (C); 40.1 (Me); 39.7 (CH2); 28.1 (CH2); 27.1
‡
‡
(CH2); 22.8(CH 2); 14.2 (Me); 13.4 (Me). ESI-MS: 565 ([M ‡ Na] ), 543 ([M ‡ H] ). Anal. calc. for
C28H34N2O7S: C 61.97, H 6.32, N 5.16, S 5.91; found: C 61.84, H 6.23, N 5.04, S 6.01.
7. Synthesis of the Guest 11. 7.1. 3-Bromopiperidin-2-one (12). Dibromide 13 (10 g, 39 mmol) was dissolved
in a mixture of MeOH (45 ml) and H2O (5.0 ml). To this soln., Ph3P (10.2 g, 39 mmol) was slowly added,
keeping the temp. below 408 with external cooling. When the phosphine was completely dissolved, ca. half of the
solvent was evaporated under vacuum, and H2O was slowly added to induce crystallization of Ph3PˆO, which
was separated by filtration. The filtrate was extracted several times with mixtures of AcOEt and THF, the
extraction being facilitated by adding salt to the aq. layer. The org. layers were evaporated to afford 12 (5.5 g,
1
79%). M.p. 123 1258. IR: 3256, 2926, 1655, 1462, 1377, 1165, 1113, 1090, 1049. H-NMR (CDCl3): 4.51 (t, J ˆ
4.2, 1 H); 3.47 3.27 (m, 2 H); 2.34 2.20 (m, 2 H); 1.88 1.73 (m, 2 H). 13C-NMR (CDCl3): 168.6 (C); 44.6
‡
‡
(CH); 41.7 (CH2); 31.2 (CH2); 18.5 (CH2). ESI-MS: 200 ([M ‡ Na] ), 178([ M ‡ H] ). Anal. calc. for
C5H8BrNO: C 33.73, H 4.53, N 7.87; found: C 33.64, H 4.61, N 7.89.
7.2. 2-Oxopiperidin-3-yl Dimethyldithiocarbamate (14). Compound 12 (10 g, 56 mmol) was dissolved in
MeOH (100 ml), and dimethylammonium dimethyldithiocarbamate (9.30 g, 56 mmol) was added with external
cooling. Most of the solvent was evaporated at reduced pressure, and H2O was added to induce the
crystallization of 14 (11.5 g, 96%). Anal. calc. for C8H14N2OS2: C 44.01, H 6.46, N 12.83, S 29.37; found: C 43.94,
H 6.52, N 12.77, S 29.29.
7.3. 5,6-Dihydropyridin-2(1H)-one (11). Compound 14 was heated to 2608 at 1 Torr. Under these conditions,
product 11 sublimed, but was still contaminated with small amounts of the reagent, which was removed by CC
(SiO2). Yield of 11: 68%. Liquid at r.t. IR: 3202, 2926, 1670, 1603, 1458, 1377, 1341, 1314, 1263, 1202, 1142, 1115,
1059, 1001. 1H-NMR (CDCl3): 6.62 (td, J ˆ 4.2, 9.5, 1 H); 5.87 (dt, J ˆ 10.5, 1.8, 1 H); 3.44 3.33 (m, 2 H); 2.37
2.23 (m, 2 H). 13C-NMR (CDCl3): 166.9 (C); 141.7 (CH); 125.0 (CH); 39.7 (CH2); 24.0 (CH2). ESI-MS: 120
‡
([M ‡ Na] ). Anal. calc. for C5H7NO: C 61.84, H 7.27, N 14.42; found: C 61.77, H 7.32, N 14.35.

1700
Helvetica Chimica Acta Vol. 88 (2005)
8. X-Ray Diffraction Studies2). Crystallographic data were collected on a four-circle Seifert XRD 3003 SC
diffractometer, with CuKa radiation (l ˆ 1.54180 ä) and graphite monochromator at ambient temperature in
the w-2q scan mode. A summary of the X-ray and refinement data of compounds 2, 4, and 5 is given in Table 4.
Table 4. Crystal Data and Structure Refinement for Compounds 2, 4, and 5
2
4
5
Empirical formula
Formula weight
Temperature [K]
Wavelength [ä]
Crystal system, space group
Unit cell dimensions: a [ä]
b [ä]
C35H50N4O5
606.79
293(2)
C33H45N3O6
579.72
293(2)
C63H88N8O11
1133.41
293(2)
1.54180
1.54180
1.54180
≈
Trigonal, R3
27.100(4)
27.100(4)
25.133(5)
90
Orthorhombic, P212121
8.857(2)
23.073(5)
31.756(6)
90
Monoclinic, C2/c
36.912(7)
14.761(3)
26.859(5)
90
c [ä]
a [8]
b [8]
g [8]
90
120
90
90
92.17(3)
90
Volume [ä3]
15985.3(45)
6489.6(23)
14623.8(51)
Z
188
8
Density (calc.) [Mg/m3]
Absorption coefficient [mmÀ1
F(000)
1.135
0.607
5904
1.187
1.030
]
0.6580.572
2496
4880
Crystal size [mm]
V Range for data collection
Limiting indexes
0.1 Â 0.08 Â 0.06
2.58 59.98 8
À 20 ꢀ h ꢀ 20,
À 30 ꢀ k ꢀ 0,
À 7 ꢀ l ꢀ 27
4722 (1769)
Full-matrix
least-squares
on F2
0.1 Â 0.09 Â 0.07
2.37 60.068
0 ꢀ h ꢀ 9,
0.08 Â 0.06 Â 0.05
2.40 60.038
À 35 ꢀ h ꢀ 35,
À 14 ꢀ k ꢀ 0,
À 26 ꢀ l ꢀ 0
À 1 ꢀ k ꢀ 23,
À 6 ꢀ l ꢀ 30
5148(685)
Reflections collect. (obs.)
Refinement method
9958(2526)
Full-matrix
least-squares
on F2
Full-matrix
least-squares on F2
Data, restraints, parameters
Goodness-of-fit on F2
4721, 0, 446
0.922
5144, 1, 344
0.651
9948, 7, 752
0.954
Final R indexes [I > 2s(I)]
R1 ˆ 0.0750,
wR2 ˆ 0.2206
R1 ˆ 0.1616,
wR2 ˆ 0.2550
1.059 and À 0.242
R1 ˆ 0.0700,
wR2 ˆ 0.0934
R1 ˆ 0.2902,
wR2 ˆ 0.1696
0.297 and À 0.263
R1 ˆ 0.1494,
wR2 ˆ 0.3910
R1 ˆ 0.2810,
wR2 ˆ 0.4600
0.952 and À 0.353
R Indexes (all data)
Largest diff. peak and hole [e äÀ3
]
The unit-cell parameters were determined by least-squares refinement on the 2q values of 25 strong, well-
centered reflections in the range 168 < 2q < 408. Scattering factors for neutral atoms and anomalous dispersion
correction for C-, N-, and O-atoms were taken from the literature [12]. The structures of 2, 4, and 5 were solved
by direct methods. All calculations were performed with the CRYSOM software [13] for data collection, with
2
)
Crystallographic data (excluding structure factors) for the structures reported in this paper have been
deposited with the Cambridge Crystallographic Data Centre as supplementary publication numbers
CCDC-264634 (2), -264635 (4), and -264636 (5). These data can be obtained, free of charge, via the
internet at http://www.ccdc.cam.ac.uk/data_request/cif.

Helvetica Chimica Acta Vol. 88 (2005)
1701
XRAY8O [14] for data reduction, and with SHELXTL [15] to resolve and refine the structures, and to prepare
the graphical material for publication.
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Received March 8, 2005