Tetrahedron: Asymmetry 23 (2012) 415427

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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy

Preparation of pyridino-crown ether-based new chiral stationary phases

and preliminary studies on their enantiomer separating ability for chiral
protonated primary aralkylamines
Jzsef Kupai a, Sndor Lvai b, Kata Antal a,b, Gyrgy Tibor Balogh b, Tnde Tth a,c, Pter Huszthy a,c,
a

Department of Organic Chemistry and Technology, Budapest University of Technology and Economics, H-1521 Budapest, PO Box 91, Hungary
Compound Proling Laboratory, Chemical Works of Gedeon Richter Plc., H-1475 Budapest, PO Box 27, Hungary
c
Research Group for Alkaloid Chemistry of the Hungarian Academy of Sciences, H-1521 Budapest, PO Box 91, Hungary
b

a r t i c l e

i n f o

Article history:
Received 10 January 2012
Accepted 5 April 2012

a b s t r a c t
This paper reports the preparation and testing of three new pyridino-18-crown-6 ether-based chiral stationary phases (S,S)-CSP-12, (S,S)-CSP-17 and (S,S)-CSP-20. Secondary amine (S,S)-7 was rst transformed
to triethoxysilyl derivative (S,S)-11, which contains a urea unit by treating the former with 3-(triethoxysilyl)propyl isocyanate. Next, (S,S)-11 was heated with spherical HPLC quality silica gel in toluene to
obtain (S,S)-CSP-12. In order to acetylate the 3-aminopropylsilyl groups bonded to the silica gel during
immobilization of the triethoxysilyl derivative (S,S)-11, we pumped acetic anhydride and triethylamine
in DMF through the column to give the modied chiral stationary phase (S,S)-CSP-20.
Triate (S,S)-13 was rst transformed to a pyridino-18-crown-6 ether derivative (S,S)-15, which contains a 4-(methoxycarbonyl)phenyl substituent at the 4-position of the pyridine ring by a Suzuki carboncarbon coupling reaction. The hydrolysis of ester (S,S)-15 gave carboxylic acid (S,S)-21. Carboxylic
acid (S,S)-21 was reacted with an excess of thionyl chloride to form the appropriate acyl chloride, which
was treated with 3-(triethoxysilyl)propylamine in the presence of triethylamine in THF to furnish triethoxysilyl derivative (S,S)-16 containing an amide unit. Triethoxysilyl derivative (S,S)-16 was heated with
spherical HPLC quality silica gel in toluene to give the chiral stationary phase (S,S)-CSP-17.
The enantiomer separating ability of chiral stationary phases (S,S)-CSP-12, (S,S)-CSP-17 and (S,S)-CSP20 were tested by using mixtures of enantiomers of 1-(1-naphthyl)ethylamine hydrogen perchlorate
(1-NEA), 1-(2-naphthyl)ethylamine (2-NEA), 1-(4-bromophenyl)ethylamine (Br-PEA) and 1-(4-nitrophenyl)ethylamine hydrogen chloride (NO2-PEA). Chiral stationary phase (S,S)-CSP-17 showed the best
enantiomer separating ability for the mixtures of enantiomers of amine compounds amongst the pyridino-crown ether-based CSPs ever synthesized. The high enantioselectivity is probably due to the strong
pp interaction of the extended p system of the arylsubstituted pyridine unit.
2012 Elsevier Ltd. All rights reserved.

1. Introduction
A study of the enantiomeric recognition of chiral amines and
chiral protonated amines is of great signicance because these
compounds are basic building blocks of biological molecules and
therefore often used as guests.1,2 Cram et al. described the rst synthesis and characterization of a number of chiral crown ethers
capable of enantiomeric recognition towards the above mentioned
amino compounds.3,4 Cram et al. were also the rst to prepare and
utilize chiral stationary phases (CSPs) containing chiral crown
ethers for the resolution of primary amines, amino acids and amino
acid esters. They immobilized optically active bis(1,10 -binaphthyl)-

Corresponding author. Tel.: +36 1 463 1071; fax: + 36 1 463 3297.

E-mail address: huszthy@mail.bme.hu (P. Huszthy).
0957-4166/$ - see front matter 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2012.04.008

22-crown-6 ethers on silica gel5 and polystyrene resin6 by covalent

bonds.
Over the past three decades, optically active macrocycles containing pyridine subunits have become attractive hosts due to their
ability for chiral discrimination towards chiral organic ammonium
salts, amino acids and their derivatives.1,2,719 Bradshaw et al. reported the preparation of the rst CSP (S,S)-CSP-1 (Fig. 1) containing an optically active pyridino-18-crown-6 ether as a chiral
selector. They attached an enantiopure dimethylpyridino-18crown-6 ether derivative to ordinary silica gel by covalent bonds.20
By applying pure MeOH as an eluent they obtained an almost baseline separation of racemic 1-(1-naphthyl)ethylamine hydrogen
perchlorate (1-NEA) at atmospheric pressure.21
The pyridine subunit of these macrocycles was reported to be
important for the tripod hydrogen bonding formation with organic
ammonium salts,8,22,23 and also because of the pp interactions

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J. Kupai et al. / Tetrahedron: Asymmetry 23 (2012) 415427

N
R

O *

O
O

(S,S)-CSP-1: R=Me, X=O(CH2)3Si

O
O
O

ordinary
silica gel

(R,R)-CSP-2: R=tBu, X=O(CH2)3Si

O
O
O

ordinary
silica gel

(R,R)-CSP-3: R=tBu, X=OCH2CONH(CH2)3Si

O
O
O

HPLC quality
silica gel

(S,S)-CSP-4: R=Me, X=OCH2CONH(CH 2)3Si

O
O
O

spherical HPLC
silica gel

(S,S)-CSP-12: R=Me, X=N(Bu)CONH(CH2)3Si

O
O
O

spherical HPLC
silica gel

(S,S)-CSP-17: R=Me, X=(C6H4)-4-CONH(CH2)3Si

O
O
O

spherical HPLC
silica gel

Figure 1. Schematics of CSPs based on enantiopure pyridino-18-crown-6 ethers as selectors.

with the aromatic groups of the ammonium guests.1 These two

attractive interactions involving the pyridine ring result in rather
rigid conformations of the diastereomeric complexes of the macrocycles with guest enantiomers24,25 and thereby increase the degree
of enantiomeric recognition. The two attractive interactions pull
the host and the guest close and the margin of steric repulsion
caused by the different spatial arrangements in the two diastereomeric complexes becomes large resulting in appreciable enantiomeric discrimination.
Later on an enantiopure di-tert-butylpyridino-18-crown-6 ether
derivative was attached to ordinary silica gel, and the CSP so
obtained [(R,R)-CSP-2, see Fig. 1] separated effectively the enantiomers of racemic 1-NEA, 1-phenylethylamine hydrogen perchlorate
(PEA), phenylalanine methyl ester hydrogen perchlorate and phenylglycine methyl ester hydrogen perchlorate at atmospheric
pressure.26,27 Another optically active di-tert-butylpyridino-18crown-6 ether derivative was immobilized by covalent bonds on
HPLC quality silica gel; this CSP (R,R)-CSP-3 (Fig. 1) separated the
enantiomers of racemic 1-NEA and PEA under high pressure with
great efciency.28 Finally, an optically active dimethylpyridino18-crown-6 ether derivative was attached to spherical HPLC quality
silica gel; the CSP thus obtained (S,S)-CSP-4 (Fig. 1) separated the

enantiomers of racemic 1-NEA, 1-(2-naphthyl)ethylamine hydrogen perchlorate (2-NEA), aromatic a-amino acids and aliphatic aamino acids containing different aromatic side-chain protecting
groups very well by applying high pressure.29
In all of the above cases, the enantiopure pyridino-18-crown-6
ether derivatives were attached to silica gel20,21,2629 through an
oxygen atom at the 4-position of the pyridine ring. Our aim was
to work out a suitable synthetic route to such new pyridino-18crown-6 ether derivatives where the linking units at the 4-position
of the pyridine ring are attached through a nitrogen or a carbon
atom.
Herein we report a new route for the synthesis of the reported
enantiopure dimethyl30 (S,S)-5 (Scheme 1) and diisobutyl31 (S,S)-6
(Scheme 1) substituted pyridino-18-crown-6 ethers containing a
chlorine atom at the 4-position of the pyridine ring and also their
transformation into new enantiopure dimethyl- and diisobutylsubstituted pyridino-18-crown-6 ethers containing a butylamino
(S,S)-7 and (S,S)-8 (Scheme 2) or a benzylamino (S,S)-9 and (S,S)10, (Scheme 2) group at the 4-position of the pyridine ring. One
of these secondary amines (S,S)-7 was reacted with 3-(triethoxysilyl)propyl isocyanate to form a triethoxysilyl derivative (S,S)-11
(Scheme 3) containing a urea unit. The latter was immobilized by

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J. Kupai et al. / Tetrahedron: Asymmetry 23 (2012) 415427

Cl

N
H
R

A: (COCl)2, DCM
B: (COCl)2, CHCl3

C: SOCl2, DCM
D: SOCl2, CHCl3

O
(S,S)-5: R=Me (A:48%,B:10%,
C:74%,D:67%)
(S,S)-6: R=iBu (D:33%)

(S,S)-18: R=Me
(S,S)-19: R=iBu

Scheme 1. Synthesis of chloropyridino-crown ethers (S,S)-5 and (S,S)-6.

covalent bonds on spherical HPLC quality silica gel and this new
CSP (S,S)-CSP-12 (Fig. 1) was used for enantiomeric separation of

NHR'

N
(S,S)-5 or
(S,S)-6

R'-NH2
heating in
a sealed tube

O
(S,S)-7: R=Me, R'=Bu (98%)
(S,S)-8: R= iBu, R'=Bu (98%)
(S,S)-9: R=Me, R'=Bn (88%)
(S,S)-10: R= iBu, R'=Bn (69%)
Scheme 2. Preparation of pyridino-crown ethers containing a secondary amine
moiety (S,S)-7(S,S)-10.

mixtures of the enantiomers of primary amino compounds containing an aromatic moiety.

In order to obtain new pyridino-18-crown-6 ether derivatives
whereby the linking units at the 4-position of the pyridine ring
are attached through a carbon atom, we needed to apply a carboncarbon bond formatting reaction. One of the most straightforward methods for this type of reaction is the cross-coupling
reaction of organoboron reagents with organic halides or related
electrophiles such as triate (Suzuki reaction). The Suzuki reaction
proceeds under mild conditions, and was largely unaffected by the
presence of water, tolerating a broad range of functional groups,
and yielding nontoxic by-products.32 For the Suzuki reaction we
needed to synthesize the enantiopure dimethyl-substituted pyridino-18-crown-6 ether (S,S)-13 (Scheme 4) containing a trifluoromethylsulfonyloxy group at the 4-position of the pyridine
ring. We also transformed this into pyridino-18-crown-6 ether
(S,S)-14 (Scheme 5) containing an iodine atom at the 4-position
of the pyridine ring. Triate (S,S)-13 and iodide (S,S)-14, respectively, were reacted with 4-(methoxycarbonyl)phenylboronic acid
under Suzuki conditions to furnish 4-(methoxycarbonyl)phenyl
derivative (S,S)-15 (Scheme 6). The latter was converted in three
steps to a triethoxysilyl derivative (S,S)-16 (Schemes 7 and 8) containing an amide unit. Triethoxysilyl derivative (S,S)-16 was at-

O
OEt
Si OEt

Bu
N

OEt
OCN

Si OEt
OEt

N
H

OEt

N
Me

Me

(S,S)-7
heating in
a sealed tube

O
O

(S,S)-11 (36%)

spherical HPLC
silica gel
(S,S)-11

(S,S)-CSP-12
toluene
heat

Ac2O, TEA

(S,S)-CSP-20

DMF, 40 C

Scheme 3. Preparation and modication of the new chiral stationary phase (S,S)-CSP-12.

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J. Kupai et al. / Tetrahedron: Asymmetry 23 (2012) 415427

Me

OTf

N
H

Me

Me

Tf2O, TEA
DCM
r. t.

(S,S)-18

(S,S)-13 (98%)

Me

Scheme 4. Synthesis of pyridino-crown ether triate (S,S)-13.

COOH

N
NaI, CH3CN

Me

Me

(S,S)-13

HCl
r. t.

1)TMAH/H2O, MeOH

Me

Me

(S,S)-15
2) HOAc, rt

(S,S)-14 (57%)

O
O

Scheme 5. Synthesis of iodopyridino-crown ether (S,S)-14.

(S,S)-21 (96%)

tached to spherical HPLC quality silica gel and the new CSP (S,S)CSP-17 (Fig. 1) was used for enantiomeric separation of the mixtures of enantiomers of protonated primary amine compounds
containing an aromatic moiety.
We hoped that the CSPs prepared from the above mentioned
precursors will be more stable than their earlier analogues, and
their discriminating power for the enantiomers of protonated primary amines and amino acid derivatives would be greater. The
pyridine ring substituted with an aromatic linking unit provides
increased pp interactions with aromatic groups of the guest molecules, and by this is expected to increase the degree of enantiomeric recognition.

Scheme 7. Hydrolysis of ester (S,S)-7 to obtain (S,S)-11.

2. Results and discussion

2.1. Synthesis
The synthesis of chloropyridino-18-crown-6 ethers (S,S)-5 and
(S,S)-6, respectively, is outlined in Scheme 1. The reported33 dimethyl-substituted pyridono-crown ether (S,S)-18 was treated
with an excess of oxalyl chloride or thionyl chloride in boiling chlo-

COOMe

COOMe

B(OH)2
(S,S)-13 or
(S,S)-14

Pd(PPh3)4
K3PO4, KBr
dioxane
85 C

Me

Me

O
(S,S)-15 (68% from (S,S)-13
92% from (S,S)-14)

Scheme 6. Preparation of pyridino-crown ether (S,S)-15 containing a 4-(methoxycarbonyl)phenyl group at the 4-position of the pyridine ring.

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J. Kupai et al. / Tetrahedron: Asymmetry 23 (2012) 415427

CONH(CH2)3Si(OEt)3

N
1) SOCl2, 40 C

Me

Me

(S,S)-21
2) H2N(CH 2)3Si(OEt)3
TEA, THF
r. t.

O
O

(S,S)-16 (55%)
spherical HPLC
silica gel
(S,S)-16

toluene
heat

(S,S)-CSP-17

Scheme 8. Preparation of new chiral stationary phase (S,S)-CSP-17.

roform or dichloromethane (DCM) in the presence of a catalytic

amount of DMF to obtain the reported30 dimethyl-substituted
chloropyridino-crown ether (S,S)-5. We gained the best yield with
thionyl chloride using DCM as the solvent. The diisobutyl-substituted analogue (S,S)-6 was prepared in the same way as reported
in the literature31 starting from diisobutyl-substituted pyridonocrown ether (S,S)-19.
The preparation of pyridino-crown ethers (S,S)-7(S,S)-10 containing a secondary amino function is shown in Scheme 2. Heating
chloropyridino-crown ethers (S,S)-5 or (S,S)-6 with an excess of
benzylamine or butylamine in sealed tubes gave ligands (S,S)-7
(S,S)-10 in very good yields (Scheme 2). Our attempts to prepare
the diisobutyl-substituted pyridino-crown ether (S,S)-10 containing a benzylamino group at the 4-position of the pyridine ring
started from diisobutyl-substituted chloropyridono-crown ether
(S,S)-6 using either lithium benzylamidate or benzylamine and
applying microwave irradiation gave rather low yields.
Secondary amine (S,S)-7 was transformed into triethoxysilyl
derivative (S,S)-11 containing a urea unit by the addition of 3-(triethoxysilyl)propyl isocyanate, and then, according to the reported
method,29 the former was heated with spherical HPLC quality silica
gel to obtain (S,S)-CSP-12 (see Fig. 1 and Scheme 3).
However, during the immobilization of the pyridino-crown
ether derivative (S,S)-11 to silica gel, due to the long and harsh conditions (120 C, 4 days), a part of the urea units of the attached pyridino-crown ether was hydrolysed. In order to avoid interference of
the 3-aminopropylsilyl groups immobilized to silica gel with the
amino groups of the analytes, we acetylated the 3-aminopropylsilyl groups by pumping a DMF solution of acetic anhydride and triethylamine (TEA) through the column at 40 C. We obtained a
modied CSP (S,S)-CSP-20, which gave better enantioseparation
for the mixtures of enantiomers of aralkylamines.
The synthesis of pyridino-crown ether (S,S)-13 containing a triate group at the 4-position of the pyridine ring is shown in
Scheme 4. The reported33 dimethyl-substituted pyridono-crown
ether (S,S)-18 was treated with an excess of triuoromethanesulfonic anhydride (Tf2O) in dichloromethane (DCM) in the presence of
TEA to obtain triate (S,S)-13 in almost quantitative yield.
It is well known34 that the reactivity of electrophiles towards
organoboron compounds decreases in the order: Ar-I > ArBr > Ar-OTf > > Ar-Cl. Therefore triate (S,S)-13 was converted into
iodo derivative (S,S)-14 (Scheme 5) according to the procedure previously described35 for similar transformations.

We prepared 4-(methoxycarbonyl)phenyl-substituted pyridino-crown ether (S,S)-15 via a palladium-catalysed cross-coupling

reaction of triate (S,S)-13 with 4-(methoxycarbonyl)phenylboronic acid in the presence of K3PO4 in dioxane at an elevated temperature (Scheme 6). Suzuki et al. reported36,37 that for the
arylation of triates, boronic acids give better yields than the corresponding boronic esters. The addition of KBr is useful in preventing the decomposition of the catalyst (hydrolytic deboronation),
which is known to convert the extremely labile cationic palladium
species to the organopalladium bromide.37 Using iodo derivative
(S,S)-14, the Suzuki reaction gave a better yield than with triate
(S,S)-13, but the overall yield calculated for dimethylsubstituted
pyridono-crown ether (S,S)-18 was lower.
Ester (S,S)-15 was hydrolysed with aqueous tetramethylammonium hydroxide (TMAH) in MeOH, and then acidied with AcOH to
obtain carboxylic acid (S,S)-21 in very good yield (Scheme 7).
Heating carboxylic acid (S,S)-21 with an excess of thionyl chloride gave the corresponding acyl chloride, which was transformed
into triethoxysilyl derivative (S,S)-16 containing an amide unit via
addition of 3-(triethoxysilyl)propylamine. The product, according
to the reported method,29 was then heated with spherical HPLC
quality silica gel to give (S,S)-CSP-17 (Fig. 1 and Scheme 8).
2.2. High performance liquid chromatography
HPLC columns lled with (S,S)-CSP-12, its modied form (S,S)CSP-20 and (S,S)-CSP-17 were used for separating the enantiomers
of the test compounds listed in Figure 2. In the cases of (S,S)-CSP-12
and (S,S)-CSP-20, an isocratic elution was applied with a solvent
system of 0.05% HCOOH and 0.2% TEA in a 7:3 mixture of CH3CN/
MeOH (Tables 1 and 2), in the case of (S,S)-CSP-17 we applied a solvent system of 0.2% HCOOH and 0.1% TEA in a 1:4 mixture of
CH3CN/MeOH (Table 3). Optimum analysis times and effective
resolutions were achieved with the above eluents and a ow rate
of 1.0 mL/min at 25 C. An acidic modier (HCOOH) in the mobile
phase is necessary to form the protonated primary amino group
of the analytes38 Triethylamine in the mobile phase was used for
the deactivation of the free silanol groups.39
In the cases of (S,S)-CSP-12 and (S,S)-CSP-20, we used a mixture
of the (R)- and (S)-enantiomers in a ratio of 2:1, so that we could
determine the elution order of the enantiomers. In the case of
(S,S)-CSP-17 for 1-NEA and 2-NEA this ratio was 1:2; for NO2PEA the ratio was 2:1, and in the case of Br-PEA we used a racemic
mixture. The elution order of the enantiomers was determined by

NH3 +ClO4 -

1-(1-naphthyl)ethylamine
hydrogen perchlorate
1-NEA
NH2

Br
1-(4-bromophenyl)ethylamine
Br-PEA

NH 2

1-(2-naphthyl)ethylamine
2-NEA

NH 3+Cl-

NO2
1-(4-nitrophenyl)ethyamine
hydrogen chloride
NO2 -PEA

Figure 2. Structures of the aralkylamine analytes.

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J. Kupai et al. / Tetrahedron: Asymmetry 23 (2012) 415427

Table 1
Chromatographic data for the separation of mixtures of protonated primary aralkylamine enantiomers on (S,S)-CSP-12
Analytes

t (S) [min]

t (R) [min]

1-NEA
Br-PEA
NO2-PEA

4.61
3.61
2.70

6.22
4.23
2.91

RS

1.67
1.44
1.40

1.67
0.85
0.61

Isocratic conditions: 0.05% HCOOH and 0.2% TEA in a 7:3 mixture of CH3CN/MeOH
(ow rate: 1.0 mL/min).

Table 2
Chromatographic data for the separation of mixtures of protonated primary aralkylamine enantiomers on (S,S)-CSP-20
Analytes

t (S) (min)

t (R) (min)

1-NEA
2-NEA
Br-PEA
NO2-PEA

7.40
8.35
4.97
3.02

11.47
10.92
6.23
3.30

RS

1.78
1.42
1.46
1.35

4.54
1.60
1.00
0.95

Isocratic condition: 0.05% HCOOH and 0.2% TEA in a 7:3 mixture of CH3CN/MeOH
(ow rate: 1.0 mL/min).

Table 3
Chromatographic data for the separation of the mixtures of enantiomers of
protonated primary aralkylamines on (S,S)-CSP-17
Analytes

t (S) (min)

t (R) (min)

1-NEA
2-NEA
Br-PEA
NO2-PEA

16.22
15.79
15.91
16.12

37.79
25.07
23.09
21.86

RS

2.49
1.66
1.51
1.40

9.20
4.53
3.58
3.30

Isocratic conditions: 0.2% HCOOH and 0.1% TEA in a 1:4 mixture of CH3CN/MeOH
(ow rate: 1.0 mL/min).

the injection of standard (separately available) authentic enantiomers of Br-PEA.

It was found that the (S)-enantiomer eluted with a shorter
retention time than that of its antipode. This behaviour is in full
agreement with our earlier observations using CSPs containing
similar pyridino-crown ethers as chiral selectors attached to ordinary silica gel,20,21,26,27 HPLC quality silica gel28,29 or Merrield resin.33 The observed elution order can be explained by the
generally observed higher stability of the heterochiral complexes
[i.e., (R,R)-crown ether-(S)-aralkylammoniun salt or (S,S)-crown
ether-(R)-aralkylammonium salt] compared to that of homochiral
complexes [i.e., (S,S)-crown ether-(S)-aralkylammonium salt or
(R,R)-crown ether-(R)-aralkylammonium salt].14,40 The most retained analyte amongst our model compounds was 1-NEA, and
the enantioselectivity achieved was higher than in the cases of
Br-PEA or NO2-PEA (see Figs. 35; Tables 13).
The enantioseparation factors of the new chiral stationary
phase (S,S)-CSP-12 compared to the enantioseparation factors of
the reported pyridino-crown ether-based CSP (S,S)-CSP-429 indicate shorter retention times, and worse separation and resolution
factors for 1-NEA.
After acetylation of the 3-aminopropylsilyl groups of (S,S)-CSP12, the modied CSP (S,S)-CSP-20 was studied under the same
chromatographic conditions (isocratic elution, the same solvent
system, acidic and basic modier and ow rate). As a result of
the modications, retention times, separation (a) and resolution
(Rs) factors increased signicantly (Fig. 4a, c and d; Table 2). This
is because the acetylated 3-aminopropylsilyl groups probably did
not interfere with the enantiomers of the analytes. Furthermore,
these acetylated 3-aminopropylsilyl groups cannot be protonated,

Figure 3. Chromatograms of enantioseparations of the mixtures of enaniomers of

(a) 1-NEA, (b) Br-PEA, (c) NO2-PEA using (S,S)-CSP-12. Isocratic conditions: 0.05%
HCOOH and 0.2% TEA in a 7:3 mixture of CH3CN/MeOH (ow rate: 1.0 mL/min).

so electrostatic repulsion between the immobilized protonated 3aminopropylsilyl groups and the analytes does not take place.
Encouraged by the more efcient enantioseparations, we also tried
the chiral stationary phase (S,S)-CSP-20 for the separation of the
mixture of 2-NEA enantiomers. In this case, we also obtained an almost baseline separation (Fig. 4b). By comparing the resolution
data of 2-NEA and 1-NEA, it can be seen that the decrease of the
separation (a) and resolution (Rs) factors (Table 2) is due to the
unfavourable position of the naphthalene ring in the complex.14
The modied chiral stationary phase (S,S)-CSP-20 gives longer
retention times, and better separation and resolution factors for
1-NEA than the reported29 pyridino-crown ether-based (S,S)-CSP4.

J. Kupai et al. / Tetrahedron: Asymmetry 23 (2012) 415427

421

Figure 4. Chromatograms of enantioseparations of the mixtures of (a) 1-NEA, (b) 2-NEA, (c) Br-PEA, (d) NO2-PEA enantiomers using (S,S)-CSP-20. Isocratic conditions: 0.05%
HCOOH and 0.2% TEA in a 7:3 mixture of CH3CN/MeOH (ow rate: 1.0 mL/min).

Chiral stationary phase (S,S)-CSP-17 gave longer retention

times, and better separation and resolution factors for 1-NEA and
2-NEA than the reported29 pyridino-crown ether-based CSP (S,S)CSP-4. By comparing the resolution data of 2-NEA and 1-NEA
(see Fig. 5a and b; Table 3), it can also be seen that 1-NEA has
greater separation (a) and resolution (Rs) factors than 2-NEA.
We compared the resolution data of 1-NEA, 2-NEA, Br-PEA and
NO2-PEA on (S,S)-CSP-12, (S,S)-CSP-20 and (S,S)-CSP-17 (see Table 4). It can be seen that in all cases, (S,S)-CSP-17 showed the best
enantioseparation factors.
3. Conclusion
The synthesis and characterization of nine new (S,S)-7, (S,S)-8,
(S,S)-10, (S,S)-11, (S,S)-13(S,S)-16, (S,S)-21 and an earlier reported
(S,S)-9 pyridino-crown ether derivatives have been achieved. Pyridino-crown ethers containing a secondary amine unit have been obtained by reacting chloropyridino-crown ether (S,S)-5 or (S,S)-6 with
an excess of benzylamine or butylamine in a sealed tube at an elevated temperature. We found that butylamino-pyridino-crown
ether (S,S)-7 could be transformed into triethoxysilyl derivative
(S,S)-11 containing a urea unit. Using the latter pyridino-macrocycle
(S,S)-11, the preparation of the new pyridino-18-crown-6 etherbased CSP (S,S)-CSP-12 was accomplished.
Ester (S,S)-15 could be successfully transformed into a triethoxysilyl derivative (S,S)-16 containing an amide unit in three steps.
Using the latter pyridino-macrocycle (S,S)-16, the preparation of
the new pyridino-18-crown-6 ether-based CSP (S,S)-CSP-17 was
achieved.
We have demonstrated that chiral stationary phase (S,S)-CSP-12
and its modied form (S,S)-CSP-20, and (S,S)-CSP-17 separated the

mixtures of protonated primary aralkylamine enantiomers

efciently.
The modied CSP (S,S)-CSP-20 showed better enantioseparation
factors for the separation of the mixture of 1-NEA enantiomers
than (S,S)-CSP-12 and the reported29 pyridino-crown ether-based
CSP (S,S)-CSP-4.
Chiral stationary phase (S,S)-CSP-17 showed the best enantioseparation factors for the separation of the mixtures of enantiomers of 1-NEA and 2-NEA amongst all of the pyridino-crown
ether-based CSPs. In addition to the tripod-like hydrogen bonding,
which always occurs in the case of analogous crown ethers1,8,41 the
extended aromatic system of aryl-substituted pyridine unit, which
secures a strong pp interaction, also contributes greatly to the
stability of their complexes with organic ammonium salts containing aromatic moieties resulting in high selectivity towards the
enantiomers of the amine compounds studied.
Experiments are currently in progress to use (S,S)-CSP-17 and
(S,S)-CSP-20 for the enantioseparation of other mixtures of enantiomers of protonated primary amines, amino acids and their
derivatives and to prepare new CSPs starting from the other pyridino-crown ethers (S,S)-8(S,S)-10 containing a secondary amine
unit.
4. Experimental
4.1. General
Infrared spectra were recorded on a Bruker Alpha-T FT-IR
spectrometer. Optical rotations were taken on a Perkin-Elmer
241 polarimeter that was calibrated by measuring the optical
rotations of both enantiomers of menthol. NMR spectra were

422

J. Kupai et al. / Tetrahedron: Asymmetry 23 (2012) 415427

Figure 5. Chromatograms of enantioseparations of mixtures of (a) 1-NEA, (b) 2-NEA, (c) Br-PEA, (d) NO2-PEA enantiomers using (S,S)-CSP-17. Isocratic condition: 0.2%
HCOOH and 0.1% TEA in a 1:4 mixture of CH3CN/MeOH (ow rate: 1.0 mL/min).

Table 4
Comparison of chromatographic data for the separation of the mixtures of enantiomers of protonated primary aralkylamines on (S,S)-CSP-12, (S,S)-CSP-20 and (S,S)-CSP-17
Chiral stationary phase

Analytes

t (S) (min)

t (R) (min)

(S,S)-CSP-12
(S,S)-CSP-20
(S,S)-CSP-17
(S,S)-CSP-12
(S,S)-CSP-20
(S,S)-CSP-17
(S,S)-CSP-12
(S,S)-CSP-20
(S,S)-CSP-17
(S,S)-CSP-20
(S,S)-CSP-17

1-NEA
1-NEA
1-NEA
Br-PEA
Br-PEA
Br-PEA
NO2-PEA
NO2-PEA
NO2-PEA
2-NEA
2-NEA

4.61
7.40
16.22
3.61
4.97
15.91
2.70
3.02
16.12
8.35
15.79

6.22
11.47
37.79
4.23
6.23
23.09
2.91
3.30
21.86
10.92
25.07

RS

Eluent

1.67
1.78
2.49
1.44
1.46
1.51
1.40
1.35
1.40
1.42
1.66

1.67
4.54
9.20
0.85
1.00
3.58
0.61
0.95
3.30
1.60
4.53

A
A
B
A
A
B
A
A
B
A
B

A: Isocratic conditions: 0.05% HCOOH and 0.2% TEA in a 7:3 mixture of CH3CN/MeOH (ow rate: 1.0 mL/min).
B: Isocratic conditions: 0.2% HCOOH and 0.1% TEA in a 1:4 mixture of CH3CN/MeOH (ow rate: 1.0 mL/min).

recorded in CDCl3 either on a Bruker DRX-500 Avance spectrometer (at 500 MHz for 1H and at 125 MHz for 13C spectra) or on a
Bruker 300 Avance spectrometer (at 300 MHz for 1H and at
75 MHz for 13C spectra) and it is indicated in each individual
case. Mass spectra were recorded on an Agilent-1200 Quadrupole LC/MS instrument using ESI method. Elemental analyses
were performed in the Microanalytical Laboratory of the Department of Organic Chemistry, Institute for Chemistry, L. Etvs
Lornd University, Budapest, Hungary. Melting points were taken
on a Boetius micro-melting point apparatus and are uncorrected.
For the microwave irradiation, we used a CEM Discover (maxi-

mum magnetron power: 300 W) microwave reactor equipped

with a pressure controller. The packing of the HPLC column
was performed in Chiroquest Chiral Technologies Development
Ltd, Budapest, Hungary. Starting materials were purchased from
Aldrich Chemical Company unless otherwise noted. Silica gel 60
F254 (Merck) and aluminium oxide 60 F254 neutral type E
(Merck) plates were used for TLC. Aluminium oxide (neutral,
activated,
Brockman
I)
and
silica
gel
60
(70230 mesh, Merck) were used for column chromatography.
The ratios of the solvents for the eluents are given in volumes
(mL/mL). Solvents were dried and puried according to well

J. Kupai et al. / Tetrahedron: Asymmetry 23 (2012) 415427

423

established methods.42 Evaporations were carried out under reduced pressure unless otherwise stated.

yellow oil. Macrocycle (S,S)-6 obtained in this way had the same
spectroscopic data as that reported in the literature.31

4.2. Preparation, characterization and modication of (S,S)-CSP12

4.2.3. General procedure for the preparation of the pyridinocrown ethers containing a secondary amino group (S,S)-7(S,S)10 (see Scheme 2)
Chloropyridino-crown ether (S,S)-5 or (S,S)-6 (0.226 mmol) and
primary amine (0.677 mmol) were heated in a sealed tube at
160 C for 8 days. The excess of primary amine was evaporated,
the residue was taken up in DCM (5 mL), and the solution was
washed with 12.5% aqueous TMAH (5 mL). The aqueous layer
was extracted with DCM (3  5 mL). The combined organic phase
was dried over MgSO4, ltered and the solvent was evaporated.
The crude product was puried as described below for each compound to give the optically active pyridino-crown ethers (S,S)-7
(S,S)-10.

4.2.1. (4S,14S)-(+)-19-Chloro-4,14-dimethyl-3,6,9,12,15pentaoxa-21-azabicyclo [15.3.1]heneicosa-1(21),17,19-triene

(S,S)-5
4.2.1.1. From (S,S)-18 and oxalyl chloride in DCM (see
Scheme 1).
To a solution of dimethyl-substituted pyridonocrown ether (S,S)-18 (880 mg, 2.58 mmol) in pure and dry DCM
(30 mL) was added a catalytic amount of pure and dry DMF (two
drops) followed by oxalyl chloride (1.1 mL, 1.64 g, 12.89 mmol),
and the resulting mixture was stirred at reux temperature under
Ar for 1.5 h. The volatile components were removed and the residue was dissolved in a mixture of DCM (100 mL) and 12.5% aqueous tetramethylammonium hydroxide (TMAH) (30 mL). The
aqueous layer was then extracted with DCM (3  30 mL). The combined organic phase was dried over MgSO4, ltered, and the solvent was evaporated. The crude product was puried by column
chromatography on neutral aluminium oxide using EtOHtoluene
(1:120) mixture as an eluent to give (S,S)-5 (446 mg, 48%) as a pale
yellow oil. Macrocycle (S,S)-5 obtained this way had the same
spectroscopic data as that reported in the literature.30
4.2.1.2. From (S,S)-18 and oxalyl chloride in CHCl3 (see
Scheme 1).
Crown ether (S,S)-5 was prepared as described
above starting from dimethyl-substituted pyridono-crown ether
(S,S)-18 (500 mg, 1.46 mmol) and oxalyl chloride (3.2 mL, 4.61 g,
36.32 mmol) in CHCl3 (13 mL) with a catalytic amount of pure
and dry DMF (two drops). The crude product was puried as above
(A) to yield (S,S)-5 (52.7 mg, 10%). Macrocycle (S,S)-5 obtained this
way was identical in every aspect to that prepared by the previous
(A) procedure.
4.2.1.3. From (S,S)-18 and thionyl chloride in DCM (see
Scheme 1).
Crown ether (S,S)-5 was prepared as described
above starting from dimethyl-substituted pyridono-crown ether
(S,S)-18 (841.6 mg, 2.47 mmol) and thionyl chloride (0.9 mL,
1.47 g, 12.33 mmol) in DCM (30 mL) with a catalytic amount of
pure and dry DMF (two drops). The crude product was puried
as above (A) to yield (S,S)-5 (658.3 mg, 74%). Macrocycle (S,S)-5 obtained this way was identical in every aspect to that prepared by
the rst (A) procedure.
4.2.1.4. From (S,S)-18 and thionyl chloride in CHCl3 (see
Scheme 1).
Crown ether (S,S)-5 was prepared as described
above starting from dimethyl-substituted pyridono-crown ether
(S,S)-18 (95.6 mg, 0.28 mmol) and thionyl chloride (0.5 mL,
0.83 g, 6.98 mmol) in CHCl3 (3 mL) with a catalytic amount of pure
and dry DMF (one drop). The crude product was puried as above
(A) to yield (S,S)-5 (67.5 mg, 67%). Macrocycle (S,S)-5 obtained this
way was identical in every aspect to that prepared by the rst (A)
procedure.
4.2.2. (4S,14S)-()-19-Chloro-4,14-diisobutyl-3,6,9,12,15pentaoxa-21-azabicyclo [15.3.1]heneicosa-1(21),17,19-triene
(S,S)-6 (see Scheme 1)
Crown ether (S,S)-6 was prepared as described above starting
from diisobutyl-substituted pyridono-crown ether (S,S)-19
(221.3 mg, 0.52 mmol) and thionyl chloride (1.11 mL, 1.55 g,
13.0 mmol) in CHCl3 (5 mL) with a catalytic amount of pure and
dry DMF (two drops). The crude product was puried by column
chromatography on neutral aluminium oxide using EtOHtoluene
(1:160) mixture as an eluent to gain (S,S)-6 (76.2 mg, 33%) as a pale

4.2.3.1. (4S,14S)-(+)-N-Butyl-4,14-dimethyl-3,6,9,12,15-pentaoxa-21-azabicyclo[15.3.1]heneicosa-1(21)-17,19-triene-19-amine
(S,S)-7 (see Scheme 2).
Crown ether (S,S)-7 was prepared as
described above in the General procedure starting from dimethyl-substituted chloropyridino-crown ether (S,S)-5 (513.5 mg,
1.42 mmol) and butylamine (0.42 mL, 313 mg, 4.28 mmol). The
crude product was puried by column chromatography on neutral
aluminium oxide using EtOHtoluene (1:20) mixture as an eluent
to yield (S,S)-7 (554 mg, 98%) as a pale yellow oil. RF: 0.46 (alumina
TLC, EtOHtoluene = 1:10). a25
D 15:3 (c 0.91, DCM); IR (lm)
mmax 3244, 2957, 2929, 2863, 1606, 1523, 1258, 1351, 1102, 982,
921, 842 cm1; 1H NMR (500 MHz, CDCl3) d (ppm) 0.95 (t, 3H,
J = 7.5 Hz), 1.17 (d, 6H), 1.381.45 (m, 2H), 1.571.63 (m, 2H),
3.15 (q, 2H, J = 7 Hz), 3.433.65 (m, 13H), 3.783.84 (m, 2H), the
diastereotopic benzylic type protons give an AB quartet dA: 4.57
and dB: 4.65 (JAB = 13 Hz, 4H), 6.45 (s, 2H); 13C NMR (125 MHz,
CDCl3) d (ppm) 13.97, 17.16, 20.33, 31.36, 42.60, 70.65, 70.86,
71.95, 73.68, 75.76, 104.65, 155.11, 157.97; MS: 396.3 (M+1)+;
Anal. Calcd for C21H36N2O5: C, 63.61; H, 9.15; N, 7.06. Found: C,
63.31; H, 9.22; N, 7.03.
4.2.3.2. (4S,14S)-()-N-Butyl-4,14-diisobutyl-3,6,9,12,15-pentaoxa-21-azabicyclo[15.3.1]heneicosa-1(21)-17,19-triene-19amine (S,S)-8 (see Scheme 2).
Crown ether (S,S)-8 was prepared as described above in the General procedure starting from
diisobutyl-substituted chloropyridino-crown ether (S,S)-6 (34 mg,
0.0763 mmol) and butylamine (23 lL, 16.7 mg, 0.229 mmol). The
crude product was puried by column chromatography on neutral
aluminium oxide using EtOHtoluene (1:20) mixture as an eluent
to yield (S,S)-8 (36.1 mg, 98%) as a pale yellow oil. RF: 0.62 (alumina
TLC, EtOHtoluene = 1:10). a25
D 11:3 (c 0.73, DCM); IR (lm)
mmax 3246, 2953, 2926, 2868, 1674, 1606, 1524, 1466, 1365,
1351, 1260, 1189, 1091, 1040, 982, 950, 874, 842, 799, 668, 659,
597, 529, 440 cm1; 1H NMR (500 MHz, CDCl3) d (ppm) 0.89
0.94 (m, 15H), 1.191.26 (m, 2H), 1.391.66 (m, 6H), 1.721.81
(m, 2H), 3.153.22 (m, 2H), 3.513.69 (m, 15H), 4.604.70 (m,
4H), 6.47 (s, 2H); 13C NMR (125 MHz, CDCl3) d (ppm) 13.98,
20.39, 22.71, 23.45, 24.95, 29.90, 31.26, 41.06, 42.77, 70.66,
71.00, 74.68, 103.56, 154.42, 158.68; MS 480.4 (M+1)+; Anal. Calcd
for C27H48N2O5: C, 67.46; H, 10.07; N, 5.83. Found: C, 67.18; H,
10.36; N, 5.67.
4.2.3.3. (4S,14S)-(+)-N-Benzyl-4,14-dimethyl-3,6,9,12,15-pentaoxa-21-azabicyclo[15.3.1]heneicosa-1(21)-17,19-triene-19amine (S,S)-9 (see Scheme 2).
Crown ether (S,S)-9 was prepared as described above in the General procedure starting from
dimethyl-substituted chloropyridino-crown ether (S,S)-5 (50 mg,
0.139 mmol) and benzylamine (47 lL, 44.7 mg, 0.417 mmol). The
crude product was puried by column chromatography on neutral

424

J. Kupai et al. / Tetrahedron: Asymmetry 23 (2012) 415427

aluminium oxide using EtOHtoluene (1:20) mixture as an eluent

to yield (S,S)-9 (53 mg, 88%) as a pale yellow oil. RF: 0.75 (alumina
TLC, EtOHtoluene = 1:10).The product had the same spectral data
as those reported in the literature.30
4.2.3.4. (4S,14S)-()-N-Benzyl-4,14-diisobutyl-3,6,9,12,15-pentaoxa-21-azabicyclo[15.3.1]heneicosa-1(21)-17,19-triene-19amine (S,S)-10 (see Scheme 2).
4.2.3.4.1. From (S,S)-6 and benzyl amine heated in a sealed
tube. Crown ether (S,S)-10 was prepared as described above in
the General procedure starting from diisobutyl-substituted chloropyridino-crown ether (S,S)-6 (100 mg, 0.226 mmol) and benzylamine (74 lL, 72.5 mg, 0.677 mmol). The crude product was
puried by column chromatography on neutral aluminium oxide
using EtOHtoluene (1:20) mixture as an eluent to yield (S,S)-10
(80.3 mg, 69%) as a pale yellow oil. RF: 0.62 (alumina TLC, EtOH
toluene = 1:10). a25
D 17:6 (c 0.91, DCM); IR (lm) mmax 3345,
2953, 2918, 2867, 1604, 1519, 1495, 1467, 1453, 1402, 1385,
1351, 1327, 1288, 1262, 1246, 1205, 1111, 984, 939, 877, 841,
732, 696, 596, 552, 520, 504, 482, 458 cm1; 1H NMR (500 MHz,
CDCl3) d (ppm) 0.80 (d, 6H, J = 6 Hz), 0.83 (d, 6H, J = 6 Hz), 1.09
1.14 (m, 2H), 1.381.44 (m, 2H), 1.641.70 (m, 2H), 3.373.55
(m, 12 H), 3.57 (s, 1H), 3.583.63 (m, 2H), 4.30 (d, 2H, J = 5.5 Hz),
the diastereotopic benzylic type protons give an AB quartet dA:
4.58 and dB: 4.61 (JAB = 13 Hz, 4H), 6.44 (s, 2H), 7.207.29 (m,
5H); 13C NMR (125 MHz, CDCl3) d (ppm) 22.51, 23.58, 24.79,
41.27, 47.19, 70.73, 70.93, 72.55, 75.04, 75.94, 104.58, 127.52,
127.70, 128.94, 138.38, 154.59, 158.91; MS: 515.34 (M+1)+; Anal.
Calcd for C30H46N2O5: C, 70.01; H, 9.01; N, 5.44. Found: C, 69.89;
H, 9.13; N, 5.31.
4.2.3.4.2. From (S,S)-6 and benzyl amine heated in a microwave
reactor. Diisobutyl-substituted chloropyridino-crown ether (S,S)6 (100 mg, 0.226 mmol) and benzylamine (74 lL, 72.5 mg,
0.677 mmol) in a closed vial were irradiated in a CEM Discover
microwave reactor equipped with a pressure controller at 30 W
at 140 C for 10 hours. The excess benzylamine was evaporated,
the residue was taken up in DCM (5 mL), and the solution was
washed with 12.5% aqueous TMAH (5 mL). The aqueous layer
was extracted with DCM (3  5 mL). The combined organic phase
was dried over MgSO4, ltered and the solvent was evaporated.
The crude product was puried by column chromatography on
neutral aluminium oxide using EtOHtoluene (1:20) mixture as
an eluent to yield (S,S)-10 (8.2 mg, 7%) as a pale yellow oil. Macrocycle (S,S)-10 obtained in this way was identical in every aspect to
that prepared by the previous (A) procedure.
4.2.3.4.3. From (S,S)-6 and in situ prepared lithium-benzylamide. A mixture of dry THF (2 mL) and dry benzylamine (108
lL, 105.9 mg, 0.988 mmol) was cooled to 78 C and stirred under an Ar atmosphere. Next, 2.355 M n-butyllithium in n-hexane
(0.38 mL, 0.898 mmol) was slowly added dropwise. After the
addition was complete, the mixture was stirred at 0 C for 1 h.
The solution was transferred to a dropping funnel and added
to a mixture of (S,S)-6 (99 mg, 0.226 mmol) and dry THF
(2 mL) while being stirred at 0 C under Ar. After the addition
was complete, the reaction mixture was stirred for a further
2 h at room temperature. The volatile components were evaporated, the residue was taken up in DCM (30 mL), and the solution was washed with water (30 mL). The aqueous layer was
extracted with DCM (3  20 mL). The combined organic phase
was dried over MgSO4, ltered and the solvent was evaporated.
The crude product was puried by column chromatography on
neutral aluminium oxide using EtOHtoluene (1:20) mixture as
an eluent to yield (S,S)-10 (6.9 mg, 6%) as a pale yellow oil. Macrocycle (S,S)-10 obtained in this way was identical in every aspect to that prepared by the previous (A) procedure.

4.2.4. 1-Butyl-1-[(4S,14S)-(+)-4,14-dimethyl-3,6,9,12,15-pentaoxa-21-azabicyclo[15.3.1]heneicosa-1(21),17,19-triene-19-yl]3-(3-(triethoxysilyl)propyl)urea (S,S)-11 (see Scheme 3)

Butylamino-pyridino-crown ether (S,S)-7 (511.6 mg, 1.29
mmol) and 3-(triethoxysilyl)propyl isocyanate (3.2 mL, 3.2 g,
12.9 mmol) were heated in a sealed tube at 120 C for 5 days.
The crude product was puried by chromatography on silica gel
using dimethoxyethane (DME)toluene-mixture (1:2) as eluents
to give triethoxysilyl derivative (S,S)-11 (300 mg, 36%) as a pale
yellow oil. RF: 0.28 (silica gel TLC, DMEtoluene = 1:1). a25
D
3:6 (c 1.91, DME); IR (lm) mmax 2967, 2925, 2105, 1718, 1686,
1598, 1561, 1517, 1458, 1388, 1259, 1192, 1165, 1075, 1015,
956, 872, 794, 687, 668, 664, 483, 464, 438, 404 cm1; 1H NMR
(300 MHz, CDCl3) d (ppm) 0.540.65 (m, 2H), 0.89 (t, J = 7.5 Hz,
3H), 1.18 (t, J = 7 Hz, 9H), 1.22 (d, J = 7 Hz, 6H), 1.271.35 (m,
2H), 1.471.65 (m, 4H), 3.113.23 (m, 2H), 3.433.63 (m, 12H),
3.703.74 (m, 2H), 3.77 and 3.80 (q, J = 7 Hz, 6H), 3.833.87 (m,
2H), the diastereotopic benzylic type protons give an AB quartet
dA: 4.76 and dB: 4.81 (JAB = 14 Hz, 4H), 7.10 (s, 2H); 13C NMR
(75 MHz, CDCl3) d (ppm) 7.89, 13.96, 17.15, 18.46, 20.16, 23.80,
30.96, 43.63, 48.77, 58.59, 70.75, 70.95, 74.37, 76.26, 76.81,
118.01, 156.19, 158.41, 161.17; MS 644.4 (M+1)+; Anal. Calcd for
C31H57N3O9Si: C, 57.83; H, 8.92; N, 6.53. Found: C, 57.47; H, 8.97;
N, 6.47.
4.2.5. Chiral stationary phase (S,S)-CSP-12 (see Scheme 3)
The pyridino crown ether derivate containing the triethoxysilyl
group (S,S)-11 (98.5 mg, 0.153 mmol) in pure and dry toluene
(15 mL) was stirred (mechanical stirring) with HPLC quality spherical silica gel (Superspher Si 60, Cat. No. 119609, Merck; mean
particle size: 4 lm) (1.2666 g) under argon using an oil bath (bath
temperature: 120 C) for 4 days. The silica gel was ltered and
washed with 50% EtOH in toluene (3  15 mL), EtOH (15 mL),
50% MeOH in DCM (2  15 mL) and DCM (3  15 mL). The ltrate
and washings were evaporated to give 31.5 mg of a thick oil. All
of the physical (specic rotation) and spectroscopic (IR, 1H NMR,
13
C NMR, MS) data proved that this residue was the (S,S)-7 butylamino-substituted pyridino-crown ether, which was produced by
an urea bond cleavage as a result of the harsh reaction conditions.
It can be calculated that 0.0735 mmol crown ether was immobilized to the silica gel (0.058 mmol crown ether/1 g CSP). The silica
gel containing the bound crown ether was dried in a vacuum oven
at 80 C for 14 h to give 1.18 g of (S,S)-CSP-12. A sample of blank
silica gel was dried the same way and it gave a combustion analysis
of C, 1.06; H, 1.32; N, 0.00. The combustion analysis of (S,S)-CSP-12
gave C, 3.03; H, 1.62; N, 0.33. This result shows that each gram of
(S,S)-CSP-12 contained 0.058 mmol (by C%), 0.059 mmol (by H%)
and 0.058 mmol (by N%) of chiral crown ether.
4.2.6. Modied chiral stationary phase (S,S)-CSP-20 (Scheme 3)
A DMF solution of acetic anhydride (2.80 mol/L) and TEA
(2.55 mol/L) was pumped through a column (150  4 mm) lled
with (S,S)-CSP-12 (1,18 g) at 40 C with a 0.1 mL/min ow rate.
The acetylation was monitored by the DAD detector of the HPLC
system. The detector showed that the reaction nished after
60 min.
4.3. Preparation and characterization of (S,S)-CSP-17
4.3.1. (4S,14S)-(+)-4,14-Dimethyl-3,6,9,12,15-pentaoxa-21-azabicyclo[15.3.1]heneicosa-1(21),17,19-triene-19-yl triuoromethanesulfonate (S,S)-13 (see Scheme 4)
In a dry three-necked round-bottomed ask equipped with an
argon inlet, a solution of pyridono-crown ether (S,S)-18 (100 mg,
0.293 mmol) in DCM (2 mL) at 0 C was treated with TEA

J. Kupai et al. / Tetrahedron: Asymmetry 23 (2012) 415427

(81.7 lL, 59.3 mg, 0.59 mmol), after which Tf2O (98.7 lL, 165.3 mg,
0.59 mmol) was added dropwise via a syringe and a needle over 5
minutes. After warming the reaction mixture to room temperature,
it was stirred until TLC analysis (Al2O3 TLC; EtOHtoluene 1:40)
showed the total consumption of the starting material
(Rf(S,S)-18 = 0.07) and only one main spot (Rf(S,S)-13 = 0.50) for the
product (0.5 h). The reaction mixture was poured into ice-water
(10 mL) and the pH of the mixture was adjusted to 10 with 25%
aqueous tetramethyl ammonium hydroxide (TMAH). The mixture
was washed into a separating funnel with DCM (10 mL). The
resulting mixture was shaken well and separated. The aqueous
phase was shaken with DCM (3  10 mL). The combined organic
phase was dried over anhydrous MgSO4, ltered and the solvent
was evaporated. The dark purple coloured residue was puried
by column chromatography on silica gel using acetonetoluene
(1:1) mixture as an eluent to furnish triate (S,S)-13 (135.9 mg,
98%) as a pale brown oil. RF: 0.50 (alumina TLC, EtOHtoluene = 1:40). a25
D 11:8 (c 2.46, DCM); IR (lm) mmax 2970,
2870, 1596, 1579, 1424, 1375, 1351, 1335, 1295, 1242, 1211,
1136, 1114, 1031, 1014, 955, 924, 874, 817, 765, 669, 639, 604,
572, 516 cm1; 1H NMR (500 MHz, CDCl3) d (ppm) 1.19 (d, 6H,
J = 6 Hz, CH3 groups attached to the macro ring), 3.463.61 (m,
12H, OCH2), 3.813.87 (m, 2H, OCHCH3), 4.89 (s, 4H, benzylic type
CH2O), 7.24 (s, 2H, Pyr-H); 13C NMR (75 MHz, CDCl3) d (ppm) 17.18,
70.82, 71.11, 71.39, 74.53, 76.49, 112.29, 157.41, 162.93; MS: 474.4
(M+1)+; Anal. Calcd for C18H26F3NO8S: C, 45.66; H, 5.54; F: 12.04;
N, 2.96; S, 6.77. Found: C, 45.27; H, 5.72; F: 12.09; N, 2.81; S, 6.54.
4.3.2. (4S,14S)-(+)-19-Iodo-4,14-dimethyl-3,6,9,12,15-pentaoxa21-azabicyclo[15.3.1]heneicosa-1(21),17,19-triene (S,S)-14 (see
Scheme 5)
To a solution of triate (S,S)-13 (100 mg, 0.211 mmol) in CH3CN
(5 mL) was rst added NaI (158.3 mg, 1.056 mmol) followed by
30% aqueous HCl (30.8 mg, 0.253 mmol) and the resulting mixture
was stirred at room temperature until TLC analysis (Al2O3 TLC;
EtOHtoluene 1:40) showed the total consumption of the starting
material (Rf(S,S)-13 = 0.50) and only one main spot (Rf(S,S)-14 = 0.37)
for the product (5 h). The volatile components were evaporated,
the residue was diluted with water (5 mL), and the pH of the mixture was adjusted to 10 with 1 M NaOH. The mixture was washed
into a separating funnel with toluene (5 mL). The resulting mixture
was shaken well and separated. The aqueous phase was shaken
with toluene (3  5 mL). The combined organic phase was washed
with 5% aqueous Na2S2O3 (20 mL), 1 M NaOH (20 mL) and water
(3  20 mL). The organic phase was dried over anhydrous MgSO4,
ltered and the solvent was evaporated to give (S,S)-14 (95.2 mg,
57%) as a pale brown oil. RF: 0.37 (alumina TLC, EtOHtoluene = 1:40). a25
D 13:4 (c 2.09, DCM); IR (lm) mmax 2966,
2861, 1559, 1450, 1404, 1370, 1349, 1331, 1260, 1111, 924, 858,
799, 747, 660, 633, 599, 578, 550, 535, 514, 488 cm1; 1H NMR
(500 MHz, CDCl3) d (ppm) 1.17 (d, 6H, J = 6 Hz, CH3 groups attached
to the macroring), 3.443.63 (m, 12H, OCH2), 3.773.83 (m, 2H,
OCHCH3), 4.76 (s, 4H, benzylic type CH2O), 7.63 (s, 2H, Pyr-H);
13
C NMR (75 MHz, CDCl3) d (ppm) 17.20, 70.85, 71.07, 71.34,
74.23, 76.34, 106.51, 129.44, 159.73; MS: 452.2 (M+1)+; Anal. Calcd
for C17H26INO5: C, 45.24; H, 5.81; I: 28.12; N, 3.10. Found: C, 45.12;
H, 5.92; I: 28.07; N, 3.09.
4.3.3. Methyl 4-[(4S,14S)-()-4,14-dimethyl-3,6,9,12,15-pentaoxa-21-azabicyclo[15.3.1]heneicosa-1(21),17,19-triene-19-yl]benzoate (S,S)-15 (see Scheme 6)
4.3.3.1. Starting from triate (S,S)-13 (see Scheme 6).
A mixture of pyridino-crown ether triate (S,S)-13 (101.5 mg, 0.21
mmol), 4-(methoxycarbonyl)phenylboronic acid (42.5 mg, 0.236
mmol), Pd(PPh3)4 (6.2 mg, 0.0054 mmol), powdered K3PO4
(68.3 mg, 0.32 mmol) and KBr (28.1 mg, 0.236 mmol) in dioxane

425

(6 mL) was heated to 85 C under Ar until TLC analysis (Al2O3

TLC; EtOHtoluene 1:40) showed the total consumption of the
starting materials (Rf(S,S)-13 = 0.50; Rfboronic acid = 0.15) and only one
main spot (Rf(S,S)-15 = 0.22) for the product (5 h). Dioxane was evaporated, and the residue was diluted with toluene (5 mL), and treated with 25% aqueous TMAH (0.11 mL) and 30% aqueous H2O2
(0.11 mL) for 1 h at room temperature to oxidize the residual borane. The mixture was washed into a separating funnel with water
(5 mL). The resulting mixture was shaken well and separated. The
organic phase was shaken with water (2  5 mL) and dried over
anhydrous MgSO4, ltered and the solvent was evaporated. The
residue was puried by column chromatography on neutral
Al2O3 using an EtOHtoluene (1:80) mixture as an eluent to yield
ester (S,S)-15 (68.0 mg, 69%) as a pale brown oil. RF: 0.22 (alumina
TLC, EtOHtoluene = 1:40). a25
D 1:7 (c 1.21, DCM); IR (lm)
mmax 2863, 1721, 1602, 1577, 1552, 1435, 1396, 1371, 1351,
1314, 1276, 1185, 1104, 925, 887, 852, 818, 773, 721, 698, 672,
633, 592, 541, 490 cm1; 1H NMR (300 MHz, CDCl3) d (ppm) 1.13
(d, 6H, J = 6 Hz, CH3 groups attached to the macroring), 3.423.59
(m, 12H, OCH2), 3.773.84 (m, 2H, OCHCH3), 3.88 (s, 3H, COOCH3),
4.82 (s, 4H, benzylic type CH2O), 7.42 (s, 2H, Pyr-H), 7.65 and 8.07
(AA0 BB0 system, 22H, J = 8 Hz, Ph-H); 13C NMR (75 MHz, CDCl3) d
(ppm) 16.12, 51.25, 69.65, 69.84, 70.86, 72.94, 75.03, 117.37,
126.15, 127.40, 129.24, 142.08, 147.06, 158.34, 165.66; MS:
460.3 (M+1)+; Anal. Calcd for C25H33NO7: C, 65.34; H, 7.24; N,
3.05. Found: C, 65.12; H, 7.42; N, 2.81.
4.3.3.2. Starting from iodo derivative (S,S)-14 (see
Scheme 6).
Crown ether (S,S)-15 was prepared as described
above starting from iodopyridino-crown ether (S,S)-14 (45.8 mg,
0.101 mmol), 4-(methoxycarbonyl)phenylboronic acid (20.1 mg,
0.112 mmol), Pd(PPh3)4 (2.9 mg, 0.0025 mmol), powdered K3PO4
(32.3 mg, 0.152 mmol) and KBr (13.3 mg, 0.112 mmol) in dioxane
(1 mL). The crude product was puried as above (A) to yield
(S,S)-15 (42.6 mg, 92%). Macrocycle (S,S)-15 obtained in this way
was identical in every aspect to that prepared by the previous
(A) procedure.
4.3.4. 4-[(4S,14S)-()-4,14-Dimethyl-3,6,9,12,15-pentaoxa-21azabicyclo[15.3.1]heneicosa-1(21),17,19-triene-19-yl]-N-(3(triethoxysilyl)propyl)benzamide (S,S)-16 (see Scheme 8)
Carboxylic acid (S,S)-21 (0.25 g, 0.56 mmol) was converted into
the appropriate acyl chloride by stirring with SOCl2 (1.36 mL,
2.29 g, 19.2 mmol) under Ar at 40 C for 3 h. The volatile components were evaporated and the traces of SOCl2 were removed by
repeated distillation of toluene from the mixture. The white product was suspended in THF (5 mL), after which 3-(triethoxysilyl)propylamine (TSPA) (136 lL, 130.6 mg, 0.59 mmol) in the
presence of TEA (4.86 mL, 3.51 g, 34.6 mmol) in THF (2 mL) was
added dropwise at 0 C. After warming the reaction mixture to
room temperature it was stirred until the TLC analysis (silica gel
TLC; 100% DME) showed total consumption of the starting materials [Rf(S,S)-21 = 0.17; RfTSPA =0.12 (an alcoholic solution of phosphomolybdic acid was used for detecting the compounds on the TLC
plate)] and only one main spot (Rf(S,S)-16 = 0.58) for the product
(19 h). The volatile components were evaporated and DME
(5 mL) was added to the residue. Tetramethylammonium hydrogen
chloride was ltered off and the solvent was evaporated. The residue was puried by column chromatography on silica gel using
DMEtoluene (3:1) mixture as an eluent to yield amide (S,S)-16
(200.3 mg, 55%) as a pale yellow oil. RF: 0.58 (silica gel TLC, 100%
DME). a25
Hg365 2:0 (c 1.23, DCM); IR (lm) mmax 3311, 2963,
2870, 1721, 1638, 1604, 1573, 1547, 1509, 1450, 1397, 1372,
1351, 1302, 1259, 1193, 1015, 924, 850, 796, 723, 696, 670, 666,
561, 542 cm1; 1H NMR (500 MHz, CDCl3) d (ppm) 0.73 (t, 2H,
CH2CH2CH2Si), 1.20 (d, 6H, J = 6 Hz, CH3 groups attached to the

426

J. Kupai et al. / Tetrahedron: Asymmetry 23 (2012) 415427

macroring), 1.23 (t, 9H, J = 7 Hz, SiOCH2CH3), 1.761.82 (m, 2H,

CH2CH2CH2Si), 3.463.59 (m, 12H, OCH2), 3.603.65 (m, 4H,
CH2CH2CH2Si and OCHCH3), 3.84 (q, 6H, J = 7 Hz, SiOCH2CH3), the
diastereotopic benzylic type protons give an AB quartet dA: 4.86
and dB: 4.90; JAB = 13 Hz, 4H), 6.70 (br. s, 1H, CONH), 7.48 (s, 2H,
Pyr-H), 7.70 and 7.90 (AA0 BB0 system, 22H, J = 8 Hz, Ph-H); 13C
NMR (75 MHz, CDCl3) d (ppm) 8.05, 17.31, 18.49, 23.06, 42.47,
58.73, 70.83, 71.02, 72.04, 74.12, 76.19, 118.61, 127.42, 128.77,
132.34, 141.60, 148.41, 159.42, 167.05; MS: 649.1 (M+1)+; Anal.
Calcd for C33H52N2O9Si: C, 61.08; H, 8.08; N, 4.32. Found: C,
60.92; H, 8.17; N, 4.14.
4.3.5. Chiral stationary phase (S,S)-CSP-17 (see Fig. 1, Scheme 8)
The pyridino-crown ether derivate (S,S)-16 containing a triethoxysilyl end group (115.4 mg, 0.178 mmol) in pure, dry toluene (30 mL) was stirred (mechanical stirring) with HPLC quality
spherical silica gel (Superspher Si 60, Cat. No. 119609, Merck;
mean particle size: 4 lm) (1.4723 g) under Ar using an oil bath
(bath temperature: 120 C) for 20 h. The silica gel was ltered
and washed with 50% EtOH in toluene (3  13 mL), EtOH
(13 mL), 50% MeOH in DCM (2  13 mL) and DCM (3  13 mL).
The ltrate and washings were evaporated to give 34.0 mg of
thick oil. The silica gel containing the bound crown ether was
dried in a vacuum oven at 80 C for 14 h to give 1.3669 g of
(S,S)-CSP-17. A sample of blank silica gel was dried in the same
way and it gave a combustion analysis of C, 0.32; H, 1.28; N,
0.00. The combustion analysis of (S,S)-CSP-17 gave C, 1.79; H,
1.45; N, 0.13. This result shows that each gram of (S,S)-CSP-17
contained 0.045 mmol (by C%), 0.046 mmol (by H%) and
0.046 mmol (by N%) of chiral crown ether.
4.3.6. 4-[(4S,14S)-(+)-4,14-Dimethyl-3,6,9,12,15-pentaoxa-21azabicyclo[15.3.1]heneicosa-1(21),17,19-triene-19-yl]-benzoic
acid (S,S)-21 (see Scheme 7)
Ester (S,S)-15 (100 mg, 0.218 mmol) was dissolved in MeOH
(1.9 mL), water (0.9 mL) and 25% aqueous TMAH (0.11 mL,
0.261 mmol) and this solution was stirred at room temperature
for 20 hours. The volatile components were then evaporated. The
residue was dissolved in water (2 mL) and the pH of the mixture
was adjusted to 5 with AcOH. The mixture was washed into a separating funnel with EtOAc (5 mL). The resulting mixture was shaken well and separated. The aqueous phase was then shaken
with EtOAc (3  5 mL). The combined organic phase was dried over
anhydrous MgSO4, and ltered. The volatile components were
evaporated and the traces of AcOH were removed by repeated distillation of toluene from the mixture to give (S,S)-21 (93.1 mg, 96%)
as a colourless oil. RF: 0.22 (silica gel TLC, 100% DME). a25
D 19:9
(c 1.86, MeOH); IR (lm) mmax 3060, 2967, 2867, 1701, 1608, 1580,
1453, 1438, 1372, 1353, 1310, 1271, 1200, 1162, 1087, 1021, 1002,
925, 890, 851, 789, 774, 755, 722, 706, 694, 668, 540, 503, 491,
451 cm1; 1H NMR (300 MHz, MeOH-d4) d (ppm) 1.20 (d, 6H,
J = 6 Hz, CH3 groups attached to the macroring), 3.463.55 (m,
12H, OCH2), 3.793.89 (m, 2H, OCHCH3), 4.85 (s, 4H, benzylic type
CH2O), 7.69 (s, 2H, Pyr-H), 7.85 and 8.15 (AA0 BB0 system, 22H,
J = 8 Hz, Ph-H); 13C NMR (75 MHz, MeOH-d4) d (ppm) 17.30,
71.72, 71.95, 72.41, 75.52, 76.93, 120.26, 128.43, 130.21, 131.74,
133.28, 143.61, 150.45, 160.51; MS: 446.3 (M+1)+; Anal. Calcd for
C24H31NO7: C, 64.70; H, 7.01; N, 3.14. Found: C, 64.68; H, 7.03; N,
3.07.
4.4. Chromatography
Adsorbents (S,S)-CSP-12 and (S,S)-CSP-17 were packed into
150  4 mm stainless steel empty HPLC columns using the slurry
packing method. The packing was performed by using a Haskelpump at 500 bar. Chromatography was performed on a Hitachi

HPLC system, involving an L-2450 UV-detector, an L-2130 pump,

an L-2200 autosampler and an L-2300 column oven.
Acknowledgments
Financial support of the Hungarian Scientic Research Fund
(OTKA K81127 to P.H., PD71910 to T.T.) and Szab Zsuzsa Doctoral
Scholarship to J.K. is gratefully acknowledged. This work is connected to the scientic programme of the Development of quality-oriented and harmonized R+D+I strategy and functional
model at BME project, supported by the New Hungary Development Plan (Project ID: TMOP-4.2.1/B-09/1/KMR-2010-0002). This
paper was also supported by the Jnos Bolyai Research Scholarship
of the Hungarian Academy of Sciences. We gratefully acknowledge
Alajos Grn for his kind help in the microwave reaction. We wish
to thank Gbor Varga (Chiroquest Chiral Technologies Development Ltd) for packing the HPLC column.
References
1. Zhang, X. X.; Bradshaw, J. S.; Izatt, R. M. Chem. Rev. 1997, 97, 33133361.
2. Spth, A.; Knig, B. Beilstein J. Org. Chem. 2010, 6, 32.
3. Kyba, E. P.; Siegel, M. G.; Sousa, L. R.; Sogah, G. D. Y.; Cram, D. J. J. Am. Chem. Soc.
1973, 95, 26912692.
4. Kyba, E. B.; Koga, K.; Sousa, L. R.; Siegel, M. G.; Cram, D. J. J. Am. Chem. Soc. 1973,
95, 26922693.
5. Sousa, L. R.; Sogah, G. D. Y.; Hoffman, D. H.; Cram, D. J. J. Am. Chem. Soc. 1978,
100, 45694576.
6. Sogah, G. D. Y.; Cram, D. J. J. Am. Chem. Soc. 1979, 101, 30353042.
7. Jones, B. A.; Bradshaw, J. S.; Brown, P. R.; Christensen, J. J.; Izatt, R. M. J. Org.
Chem. 1983, 48, 26352639.
8. Izatt, R. M.; Zhu, C. Y.; Huszthy, P.; Bradshaw, J. S. Enantiomeric Recognition in
MacrocyclePrimary Ammonium Cation Systems. In Crown Compounds: Toward
Future Applications; Cooper, S. R., Ed.; VCH: New York, 1992. Chapter 12.
9. Somogyi, L.; Huszthy, P.; Bradshaw, J. S.; Izatt, R. M.; Hollsi, M. Chirality 1997,
9, 545549.
10. Dob, A.; Liptk, M.; Huszthy, P.; Vkey, K. Rapid Commun. Mass. Spectrom.
1997, 11, 889896.
11. Horvth, V.; Takcs, T.; Horvai, G.; Huszthy, P.; Bradshaw, J. S.; Izatt, R. M. Anal.
Lett. 1997, 30, 15911609.
12. Somogyi, L.; Huszthy, P.; Knts, Z.; Hollsi, M. Enantiomer 1998, 3, 439451.
} sy, A.; Neszmlyi, A. Tetrahedron:
13. Samu, E.; Huszthy, P.; Horvth, G.; Szllo
Asymmetry 1999, 10, 36153626.
14. Farkas, V.; Szalay, L.; Vass, E.; Hollsi, M.; Horvth, G.; Huszthy, P. Chirality
2003, 15, S65S73.
15. Gerencsr, J.; Bthori, N.; Czugler, M.; Huszthy, P.; Ngrdi, M. Tetrahedron:
Asymmetry 2003, 14, 28032811.
16. Kim, J.-K.; Kim, J.; Song, S.; Jung, O.-S.; Suh, H. J. Inclusion Phenom. Mol. Recognit.
Chem. 2007, 58, 187192.
17. Ozer, H.; Kocakaya, S
. O.; Akgun, A.; Hosgren, H.; Togrul, M. Tetrahedron:
Asymmetry 2009, 20, 15411546.
18. Turgut, Y.; Kocakaya, S. O. Tetrahedron: Asymmetry 2010, 21, 990996.
19. Deniz, P.; Turgut, Y.; Togrul, M.; Hosgren, H. Tetrahedron 2011, 67, 62276232.
20. Bradshaw, J. S.; Huszthy, P.; Wang, T. M.; Zhu, C. Y.; Nazarenko, A. Y.; Izatt, R.
M. Supramol. Chem. 1993, 1, 267275.
21. Huszthy, P.; Bradshaw, J. S.; Bodurov, A. V.; Izatt, R. M. ACH-Models Chem. 1994,
131, 445454.
22. Cram, D. J.; Helgeson, R. C.; Sousa, L. R.; Timko, J. M.; Newcomb, M.; Moreau, P.;
de Jong, F.; Gokel, G. W.; Hoffman, D. H.; Domeier, L. A.; Peacock, S. C.; Madan,
K.; Kaplan, L. Pure Appl. Chem. 1975, 43, 327349.
23. Vinogradov, S. N.; Linnell, K. H. Hydrogen Bonding; Van Nostrand Reinhold:
New York, 1971. Chapter 5.
24. Bailey, P. D.; Everitt, S. R. L.; Morgan, K. M.; Brewster, A. G. Tetrahedron 2001,
57, 13791386.
25. Wendelstorf, C.; Krmer, R. Angew. Chem., Int. Ed. 1997, 36, 27912793.
26. Knts, Z.; Huszthy, P.; Bradshaw, J. S.; Izatt, R. M. Tetrahedron: Asymmetry
1999, 10, 20872099.
27. Knts, Z.; Huszthy, P.; Bradshaw, J. S.; Izatt, R. M. Enantiomer 2000, 5, 561
566.
28. Horvth, G.; Huszthy, P.; Szarvas, S.; Szkn, G.; Redd, J. T.; Bradshaw, J. S.;
Izatt, R. M. Ind. Eng. Chem. Res. 2000, 39, 35763581.
29. Farkas, V.; Tth, T.; Orosz, G.; Huszthy, P.; Hollsi, M. Tetrahedron: Asymmetry
2006, 17, 18831889.
30. Tth, T.; Huszthy, P.; Kupai, J.; Nyitrai, J. Arkivoc 2008, iii, 6679.
31. Kupai, J.; Huszthy, P.; Szkely, K.; Tth, T.; Prknyi, L. Arkivoc 2011, ix, 7793.
32. Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 24572483.
33. Horvth, G.; Huszthy, P. Tetrahedron: Asymmetry 1999, 10, 45734583.
34. Ritter, K. Synthesis 1993, 735762.
35. Maloney, K. M.; Nwakpuda, E.; Kuethe, J. T.; Yin, J. J. Org. Chem. 2009, 74, 5111
5114.

J. Kupai et al. / Tetrahedron: Asymmetry 23 (2012) 415427

36.
37.
38.
39.
40.

Oh-e, T.; Miyaura, N.; Suzuki, A. Synlett 1990, 221223.

Oh-e, T.; Miyaura, N.; Suzuki, A. J. Org. Chem. 1993, 58, 22012208.
Hyun, M. H. J. Sep. Sci. 2003, 26, 242250.
Reta, M.; Carr, P. W. J. Chromatogr. A 1999, 855, 121127.
Izatt, R. M.; Wang, T. M.; Hathaway, J. K.; Zhang, X. X.; Curtis, J. C.; Bradshaw, J.
S.; Zhu, C. Y.; Huszthy, P. J. Inclusion Phenom. Mol. Recognit. Chem. 1994, 17,
157175.

427

} , G. M.; Samu, E.; Huszthy, P. Tetrahedron:

41. Grczei, T.; Bcskei, Z.; Keseru
Asymmetry 1999, 10, 19952005.
42. Riddick, J. A.; Burger, W. B.; Sakano, T. K., 4th ed. In Techniques of Chemistry;
Weissberger, A., Ed.; Wiley-Interscience: New York, 1986; Vol. 2,.