8-Hydroxyquinoline as a building block for artificial receptors: Binding preferences in the recognition of glycopyranosides

Article abstract of DOI:10.1039/c0ob00960a

8-Hydroxyquinoline-based receptors 1-3, containing a trisubstituted triethylbenzene core, were prepared and their binding properties towards glycosides were evaluated. ¹H NMR and fluorescence titrations as well as binding studies in two-phase s

Full text of DOI:10.1039/c0ob00960a

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PAPER
8-Hydroxyquinoline as a building block for artificial receptors: binding
preferences in the recognition of glycopyranosides†
Monika Mazik* and Christoph Geffert
Received 31st October 2010, Accepted 21st December 2010
DOI: 10.1039/c0ob00960a
8-Hydroxyquinoline-based receptors 1–3, containing a trisubstituted triethylbenzene core, were
prepared and their binding properties towards glycosides were evaluated. 1H NMR and fluorescence
titrations as well as binding studies in two-phase systems, such as dissolution of solid carbohydrates in
apolar media and phase transfer of sugars from aqueous into organic solvents, revealed b- vs. a-anomer
binding preferences in the recognition of glycosides. Compared to the previously described three-armed
aminopyridine-based receptor, compounds 1 and 2 showed significantly increased affinity to
b-galactoside. Receptor 2, incorporating two 8-hydroxyquinoline units, was shown to be the most
effective receptor for b-galactoside. Compound 3, bearing one 8-hydroxyquinoline group, was found to
be a highly effective receptor for b-glucoside and shown to be a more powerful receptor than the
quinoline-based compound 4, indicating an important role of the quinoline hydroxy group in the
complex formation.
potential of this unit has not been evaluated.7 As first representa-
tives of this group we have prepared compounds 1–3 (see Fig. 2),
containing one to three 8-hydroxyquinoline units. The recognition
Introduction
Artificial carbohydrate receptors using noncovalent interactions
for sugar binding1–3 provide valuable model systems to study the
properties of these compounds towards monosaccharides 5–8
underlying principles of carbohydrate-based molecular recogni-
were compared with those of the previously studied receptors. In
tion processes and may serve as a basis for the development
of saccharide sensors or new therapeutics.4 Although effective
receptor systems have been developed, the exact prediction of
the binding preferences of the artificial receptors is still further
addition, the properties of the 8-hydroxyquinoline-based receptor
3 were compared with those of the quinoline-based compound 4.
away and it is hoped that systematic studies towards effective
recognition motifs for carbohydrates will contribute significantly
Results and discussion
Synthesis of the receptors
to the solution of this problem. Our previous studies showed that
acyclic receptors,5 such as compounds containing a trisubstituted
trialkylbenzene core, represent particularly interesting objects
for such systematic studies. Depending on the nature of the
recognition units (see Fig. 1) and connecting bridges used as
the building blocks, a variety of receptors with different binding
properties could be obtained.
The aim of the present study was to evaluate the potential
of 8-hydroxyquinoline-based receptors in the complexation of
carbohydrates. The 8-hydroxyquinoline unit has been extensively
used for the construction of metal ion ligands.6 In the area of sugar
recognition by receptors employing noncovalent interactions the
The synthesis of compounds 1–4 started from 1,3,5-
tris(bromomethyl)-2,4,6-triethylbenzene (9) and is summarised
in Scheme 1. The reaction of 9 with potassium phthalimide gave
1,3,5-tris(phthalimidomethyl)-2,4,6-triethylbenzene (10),8 which
was converted into 1,3,5-tris(aminomethyl)-2,4,6-triethylbenzene
(11). Compound 11 was allowed to react with 8-hydroxyquinoline-
2-carbaldehyde (12) to give the imine 13, which was subsequently
reduced with sodium borohydride to yield the product 1. 1,3-
Bis(bromomethyl)-5-[(4,6-dimethylpyridin-2-yl)aminomethyl]-2,
4,6-triethylbenzene (15) and 1-bromomethyl-3,5-bis[(4,6-dim-
ethylpyridin-2-yl)aminomethyl]-2,4,6-triethylbenzene (16) were
prepared via a reaction of 9 with 2-amino-4,6-dimethylpyridine
(14); the separation of 15 and 16 was carried out by column
chromatography.5g The reaction of 15 with potassium phthalimide
gave 1,3-bis(phthalimidomethyl)-5-[(4,6-dimethylpyridin-2-yl)-
Institut fu¨r Organische Chemie der Technischen Universita¨t Braunschweig,
Hagenring 30, 38106, Braunschweig, Germany. E-mail: m.mazik@tu-bs.de;
Fax: +49 531 391 8185; Tel: +49 531 391 5266
aminomethyl]-2,4,6-triethylbenzene
(17),5c
which
was
† Electronic supplementary information (ESI) available: Descriptions of
the 1H NMR and fluorescence titration experiments (Tables S1–S5),
converted into 1,3-bis(aminomethyl)-5-[(4,6-dimethylpyridin-2-
yl)aminomethyl]-2,4,6-triethylbenzene (18). The condensation
of 18 with 8-hydroxyquinoline-2-carbaldehyde (12), followed by
1
changes in chemical shift observed for selected signals during H NMR
titrations (Table S6), and example of a fluorescence titration (Figure S1).
See DOI: 10.1039/c0ob00960a
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Fig. 1 Examples of recognition units that have been used for the construction of acyclic carbohydrate receptors.5
Fig. 2 Structures of receptors and sugars investigated in this study.
reduction of the corresponding imine 19, yielded the product 2.
Treatment of 16 with aqueous ammonia gave 1-aminomethyl-3,5-
bis[(4,6-dimethylpyridin-2-yl)aminomethyl]-2,4,6-triethylbenzene
(20), which was the base for the synthesis of compounds 3
and 4.
Binding studies in two-phase systems: liquid–solid and liquid–liquid
extractions
Extractions of methyl pyranosides, such as b-glucoside 5b, a-
glucoside 6b, b-galactoside 7b and a-galactoside 8, from the
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Scheme 1 Reaction conditions: (a) potassium phthalimide, dimethyl sulfoxide, 100 ◦C, 8 h (90%);8 (b) hydrazine hydrate, ethanol/toluene, reflux, 20 h,
KOH (93%);8 (c) 3 equiv. of 12, CH2Cl2, reflux, 48 h; (d) NaBH4, CH3OH, 0 ◦C to room temperature (45% of 1); (e) 2 equiv. of 2-amino-4,6-dimethylpyridine,
CH3CN/THF, K2CO3, room temperature, 3 d (20% of 15, 30% of 16);5g (f) potassium phthalimide, dimethyl sulfoxide, 95 ◦C, 8 h, (57%);5c (g) hydrazine
hydrate, ethanol/toluene, reflux, 20 h, KOH (43%);5c (h) 2 equiv. of 12, CH2Cl2, reflux, 24 h; (i) NaBH4, CH3OH, 0 ◦C to room temperature (46% of 2);
(j) NH3/H2O (25% solution), 12 h (72%);5g (k) 1 equiv. of 8-hydroxyquinoline-2-carbaldehyde (12) or quinoline-2-carbaldehyde (21), CH2Cl2, reflux, 16 h
in the case of 12 and 8 h in the case of 21; (l, m) NaBH4, CH3OH, 0 ◦C to r. t. (44% of 3, 49% of 4).
Table 1 Solubilization of sugars in CDCl3 by receptors 1–4 (1 mM
the extractability decreased in the sequence b-galactoside 7b >
b-glucoside 5b > a-galactoside 8 > a-glucoside 6b (see Table
1; control experiments were performed in the absence of the
receptor). The preference of 1 and 2 for b- over a-glucoside
(5b vs. 6b) as well as for b-galactoside over b-glucoside (7b
vs. 5b) indicated by liquid–solid extractions was further con-
solutions)
Sugar
Sugar/1a
Sugar/2a
Sugar/3a
Sugar/4a
b-D-glucoside 5b
a-D-glucoside 6b
b-D-galactoside 7b
a-D-galactoside 8
0.65
0.18
0.73
0.25
0.87
0.30
0.92
0.35
0.98
0.31
0.45
0.27
0.65
0.18
0.30
0.29
1
firmed by H NMR spectroscopic titrations (see below). Com-
pared to the previously studied symmetrical aminopyridine-based
receptor,5q the extraction experiments indicated a significantly
higher affinity of 1 and 2 towards b-galactoside. In the case
of receptor 3, containing one 8-hydroxyquinoline unit and two
aminopyridine10 moieties, the extractability decreased in the
sequence b-glucoside 5b > b-galactoside 7b > a-glucoside 6b >
a-galactoside 8. Compared to the quinoline-based compound
4, the extraction experiments indicated a higher affinity of the
8-hydroxyquinoline-based receptor 3 to the substrates 5b, 6b,
and 7b.
a Molar ratios sugar/receptor occurring in solution (the 1H NMR signals
of the corresponding sugar were integrated with respect to the receptor’s
signals to provide the sugar–receptor ratio; control experiments were
performed in the absence of the receptor).
solid state into a CDCl3 solution9 of the corresponding receptor
(1 mM) provided evidence for stronger complexation of the b-
anomers 5b and 7b (see Table 1). In the case of receptors 1 and 2,
bearing three and two 8-hydroxyquinoline moieties, respectively,
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1
Fig. 3 (a) Partial H NMR spectra (400 MHz; CDCl3) of receptor 2 before (bottom) and after the addition of b-galactoside 7a; shown are chemical
shifts of the pyridine CH3 and quinoline CH resonances of 2. [2] = 0.88 mM, equiv. of 7a: 0.00–3.90. (b) Chemical shifts of the pyridine CH3 resonances of
the previously described symmetrical aminopyridine-based receptor5q (1,3,5-tris[(4,6-dimethylpyridin-2-yl)aminomethyl]-2,4,6-triethylbenzene, 0.90 mM)
after the addition of 0.00–5.20 equiv. of b-galactoside 7a (500 MHz; CDCl3).
Fig. 4 Partial 1H NMR spectra (400 MHz; CDCl3) of receptor 3 before (bottom) and after the addition of b-glucoside 5a; shown are chemical shifts of
the pyridine CH3 and N-CH2 resonances of 3; [3] = 1.00 mM, equiv. of 5a: 0.00–3.44.
Studies of the extraction of methyl b-D-glucoside (5b) and
methyl b-D-galactoside (7b) from aqueous solution into chloro-
form (using the procedure described by Davis et al., see refs 11a,b;
see also ref. 5c) revealed that compound 2 (1 mM chloroform
solution) is capable to extract 0.15 equiv of b-glucoside 5b and
0.25 equiv of b-galactoside 7b from 1 M aqueous solutions (control
experiments were performed in the absence of the receptor). In the
case of compound 3, about 0.19 equiv of b-glucoside 5b could be
extracted from the aqueous solution.
receptor (see Supporting Information). In addition, inverse titra-
tions were performed in which the concentration of the sugar
was held constant and that of the receptor was varied. The
complexation between the receptors 1–4 and monosaccharides
was evidenced by several changes in the NMR spectra; examples
are given in Fig. 3a and 4 as well as in Table S6 (see Supporting
1
Information). The H NMR titration data were analyzed using
the Hostest 5.612 and EQNMR13 program; the binding constants
are summarised in Table 1. In all cases, the curve fitting of the
titration data suggested the existence of 1 : 1 and 2 : 1 receptor–
sugar complexes in CDCl3 solutions, with stronger association
constant for 1 : 1 binding and a weaker association constant for
2 : 1 receptor–sugar complex; this model was further supported by
the mole ratio plots14 (see Fig. 5).
Binding studies in homogeneous media
The interactions of the receptors and carbohydrates were inves-
1
tigated by H NMR and fluorescence spectroscopic titrations in
The interactions of 1–3 with b-glucoside 5a were shown to be
more effective than those with the a anomer 6a. In comparison
to the previously described three-armed aminopyridine-based
receptor,5q compounds 1 and 2 showed significantly increased
organic media (CDCl3, DMSO-d6/CDCl3 mixtures or CHCl3).
The H NMR titration experiments with octyl b-glucoside 5a,
a-glucoside 6a and b-galactoside 7a were carried out by adding
increasing amounts of the sugar to a solution of the corresponding
1
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Fig. 5 Mole ratio plots: (a) Titration of receptor 2 with b-galactoside 7a (analysis of the complexation-induced shift of the quinoline CH of 2). (b)
Titration of receptor 3 with b-glucoside 5a(analysis of the complexation-induced shift of the pyridine CH3 of 3). [2] = 0.88 mM, equiv. of 7a: 0.00–4.10;
[3] = 1.00 mM, equiv. of 5a: 0.00–3.40.
Table 2 Association constantsa,b for receptors 1–4 and carbohydrates 5a,
binding affinity toward b-galactoside 7a. The differences in the
6a and 7a
complexation ability of the receptors 1/2 and the previously
described receptor are clearly visible by the comparison of the
Host–guest
K11 [M-1
]
K21 [M-1
]
b21 = K11K21
chemical shifts of the receptor signals after the addition of b-
galactoside 7a, as illustrated in Fig. 3a and 3b for the pyridine CH3
signals. It is noteworthy that the strong enhancement of the bind-
ing affinity of 1 and 2 towards b-galactoside was achieved through
a relatively simple variation of the receptor structure. The presence
of three (as in 1) or two (as in 2) 8-hydroxyquinoline units seems to
be favourable for the recognition of b-galactoside. It should be also
noted that the previously described imidazole/aminopyridine-
and indole/aminopyridione-based receptors, bearing two 4(5)-
substituted imidazole or 3-substituted indole units,5b were also
found to display significantly higher binding affinity for b-
galactoside than the symmetrical aminopyridine-based receptor
(In contrast to 1–3 and the indole/imidazole-based5b receptors,
the previously described phenanthroline/aminopyridine-based
receptors5c,e were shown to display a high binding affinity towards
a-galactoside as well as a strong a- versus b anomer binding
preference). The binding affinity of 1–3 towards b-galactoside
decrease in the sequence 2 > 1 > 3. Compound 3, bearing
one hydroxyquinoline and two aminopyridine units, was found
to be similar in affinity to b-galactoside as the three-armed
aminopyridine-based receptor. In the case of b-glucoside 5a the
situation is reversed; the binding affinity of 1–3 towards 5a
decrease in the sequence 3 > 2 > 1. Compound 3 was shown to be
the most effective receptor for this monosaccharide. Interestingly,
compound 3 was also shown to be a more powerful receptor for
b-glucoside that the quinoline-based compound 4. These results
indicate an important contribution of the quinoline hydroxy group
to the complex formation with b-glucoside.
c
complex
Solvent
1·5a
1·6a
1·7a
2·5a
CDCl3
CDCl3
CDCl3
CDCl3
5% DMSO-d6/CDCl3
CDCl3
CDCl3
5% DMSO-d6/CDCl3
CDCl3
5% DMSO-d6/CDCl3
CDCl3
19500
3300
24700
69500
4300
6810
148700
8600
160200
8300
4150
6130
20700
4830
1380
270
1320
1060
300
100
1580
770
860
520
430
340
190
220
2.69 ¥ 107
8.91 ¥ 105
3.26 ¥ 107
7.37 ¥ 107
1.29 ¥ 106
6.81 ¥ 105
2.34 ¥ 108
6.62 ¥ 106
1.37 ¥ 108
4.32 ¥ 106
1.78 ¥ 106
2.08 ¥ 106
3.93 ¥ 106
1.06 ¥ 106
2·6a
2·7a
3·5a
3·6a
3·7a
4·5a
4·7a
CDCl3
CDCl3
CDCl3
a Average Ka values from multiple titrations (the high values of the binding
constants for 2·5a, 2·7a, and 3·5a determined on the base of the 1H NMR
spectroscopic titrations in CDCl3 were confirmed by fluorescence titrations
in CHCl3). b Errors in Ka are less than 20%. K21 corresponds to 2 : 1
c
receptor–sugar association constant.
and show a preference of 2 for b-galactoside over b-glucoside (as
already indicated by the 1H NMR titrations in CDCl3).
Inverse titrations provided further information about the in-
teractions, which contribute to the stabilization of the receptor–
carbohydrate complexes. During the titration of b-glucoside 5a
or b-galactoside 7a with the receptor 1–3 in CDCl3 the signals
due to the OH protons of the sugar shifted downfield with strong
broadening and became almost indistinguishable from the base
line after the addition of only 0.1 equiv of the receptor, whereas the
CH signals of 5a/7a moved upfield. The spectral changes indicate
the participation of the OH groups of 5a/7a in the formation
of intermolecular hydrogen bonds and the involvement of the
sugar CHs in CH ◊ ◊ ◊ p interactions17 with the aromatic rings of
the receptor.18,19
In the case of 2·5a, 2·7a and 3·5a the binding constants in
CDCl3 were too large to be accurately determined by the NMR
spectroscopic method (for a review discussing the limitations of
the NMR method, see ref. 15). To compare the binding capability
of the receptors 2 and 3, additional 1H NMR titrations in a more
polar solvent (DMSO-d6/CDCl3 mixture) were carried out. As
expected, the affinity of 2 and 3 significantly decreased as solvent
polarity increased;16 the binding constants are given in Table 2
The formation of complexes was also detected by means of
fluorescence spectroscopy (in the case of 2·5a, 2·7a, 3·5a, and
4·5a). The fluorescence titration experiments were carried out by
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adding increasing amounts of the sugar to a CHCl3 solution of
the receptor (for examples, see Table S4 and S5 in the Supporting
Information). On addition of the sugar the fluorescence emission
was enhanced, as shown in the Supporting Information (see Figure
S1). Analysis of the titration data by curve fitting (Hyperquad
2006 program20) yielded binding constants, which are in good
agreement with the values obtained through 1H-NMR titrations.
Among the tested compounds, compound 3 was shown to be
the most powerful receptor for b-glucoside, whereas 2 was found
to be the most effective receptor for b-galactoside.
with CHCl3 (3 ¥ 15 mL). The organic phase was further washed
with water (3 ¥ 30 mL), dried over MgSO4, and the solvent was
removed through rotary evaporation. The crude product was
purified via column chromatography [CHCl3/CH3OH (incl. 1% 7
◦
1
M NH3 in CH3OH), 7 : 1]. Yield 45%. M.p. 69–70 C. H-NMR
(400 MHz, CDCl3): d = 1.08 (t, J = 7.6 Hz, 9 H), 2.81 (q, J = 7.6
Hz, 6 H), 3.75 (s, 6 H), 4.21 (s, 6 H), 7.17 (dd, J = 7.5/1.1 Hz, 3
H), 7.31 (dd, J = 8.5/1.2, 3 H), 7.42 (m, 3 H), 7.55 (d, J = 8.5
Hz, 3 H); 8.13 (d, J = 8.5 Hz, 3 H) ppm. 13C-NMR (100 MHz,
CDCl3): d = 16.76, 22.72, 47.33, 56.19, 110.13, 117.7, 121.48,
127.13, 127.49, 133.98, 136.51, 137.49, 142.54, 151.95, 158.46
ppm. HR-MS (ESI) calcd for C45H49N6O3: 721.38606 [M + H]+;
found: 721.38619. Rf 0.20 [chloroform/methanol (incl. 1% NH3),
3 : 1]. Anal. calcd for C45H48N6O3: C, 74.97; H, 6.71; N, 11.66;
found: C, 74.89; H, 6.84; N, 11.55%.
Conclusion
Compounds 1–3, bearing one to three 8-hydroxyquinoline-based
recognition units, were established as powerful carbohydrate
receptors and shown to display interesting binding preferences.21
1H NMR and fluorescence titrations as well as binding studies
in two-phase systems, such as dissolution of solid carbohydrates
in apolar media and phase transfer of sugars from aqueous into
organic solvents, revealed b- vs. a-anomer binding preferences in
the recognition of glycosides. Compound 3 has been established
as a highly effective receptor for b-glucoside 5. In comparison
to 3, receptors 1 and 2 showed significantly increased affinity
to b-galactoside 7, but decreased affinity to b-glucoside 5. It
should be noted that compounds 1 and 2, containing three and
two 8-hydroxyquinoline units, respectively, were shown to be
more powerful carbohydrate receptors for b-galactoside than the
previously described symmetrical aminopyridine-based receptor.
In particular, compound 2 has been established as a highly effective
receptors for b-galactoside. It has been shown that both hydrogen
bonding and interactions of the carbohydrate CH units with the
aromatic rings of the receptors contribute to the stabilization of
the receptor–carbohydrate complexes. The binding affinity of 1–
3 towards b-galactoside 7a and b-glucoside 5a decreases in the
sequence 2 > 1 > 3 and 3 > 2 > 1, respectively. Compound
3, containing the 8-hydroxyquinoline moiety, was shown to be
a more effective carbohydrate receptor than the quinoline-based
compound 4, indicating an important role of the quinoline hydroxy
group in the complex formation.
1,3-Bis-[(8-hydroxyquinolin-2-yl-methyl)aminomethyl]-5-[(4,6-
dimethyl-pyridin-2-yl)-aminomethyl]-2,4,6-triethylbenzene (2)
1,3-Bis(aminomethyl)-5-[(4,6-dimethylpyridin-2-yl)aminome-
thyl]-2,4,6-triethylbenzene (18) (0.15 g, 0.42 mmol) dissolved in
5 mL CH2Cl2 was added to a solution of 8-hydroxyquinoline-2-
carbaldehyde (12) (0.22 g, 1.27 mmol) in CH2Cl2 (15 mL) and
the resulting mixture was refluxed for 24 h. Then, dry methanol
(10 mL) was added, the solution was cooled to 0 ◦C and NaBH4
(0.16 g, 4.24 mmol) was slowly added. The reaction mixture was
stirred for 2 h, the solvent was removed by rotary evaporation
and 30 mL water were added. The mixture was stirred for 4
h and extracted with CHCl3. The organic phase was further
washed with water (3 ¥ 30 mL), dried over MgSO4 and the
solvents were removed. The crude product was purified via column
chromatography [CHCl3/CH3OH (incl. 1% 7 M NH3 in CH3OH),
7 : 1]. Yield 46%. M.p. 80–81 ◦C. 1H-NMR (400 MHz, CDCl3): d =
1.11 (t, J = 7.5 Hz, 3 H), 1.14 (t, J = 7.5 Hz, 6 H), 2.22 (s, 6 H), 2.35
(s, 6 H), 2.76 (q, J = 7.5 Hz, 4 H), 2.84 (q, J = 7.5 Hz, 2 H), 3.78 (s, 4
H), 4.17 (s, 1 H), 4.22 (s, 4 H), 4.33 (d, J = 4.1 Hz, 2 H), 6.05 (s, 1 H),
6.33 (s, 1 H), 7.16 (dd, J = 7.5/1.2 Hz, 2 H), 7.32 (dd, J = 8.2/1.2
Hz, 2 H), 7.42 (m, 2 H), 7.56 (d, J = 8.4 Hz, 2 H), 8.13 (d, J = 8.4
Hz, 2 H) ppm. 13C-NMR (100 MHz, CDCl3): d = 16.80, 21.09,
22.76, 24.22, 40.61, 47.34, 56.27, 103.44, 110.09, 113.73, 117.72,
121.51, 127.15, 127.49, 132.66, 134.30, 136.54, 137.49, 142.77,
142.91, 148.62, 151.90, 156.62, 158.25, 158.56 ppm. HR-MS (ESI)
calcd for C42H49N6O2: 669.39115 [M + H]+; found: 669.39140. Rf
0.38 [chloroform/methanol (incl. 1% NH3), 7 : 1]. Anal. calcd for
C42H48N6O2: C, 75.42; H, 7.23; N, 12.56; found: C, 75.29; H, 8.01;
N, 12.70%.
Experimental section
Analytical TLC was carried out on silica gel 60 F254 plates employ-
ing chloroform/methanol mixtures as the mobile phase. Melting
points are uncorrected. Sugars 5–8 are commercially available. The
binding studies are described in Supporting Information.
1,3,5-Tris-[(8-hydroxyquinolin-2-yl-methyl)aminomethyl]-2,4,6-
triethylbenzene (1)
General procedure for the synthesis of compounds 3 and 4
To
a solution of 8-hydroxyquinoline-2-carbaldehyde (12)
1,3,5-Tris(aminomethyl)-2,4,6-triethylbenzene (11) (0.11 g,
0.44 mmol) dissolved in 5 mL CH2Cl2 was added to a solution
of 8-hydroxyquinoline-2-carbaldehyde (12) (0.25 g, 1.44 mmol)
in CH2Cl2 (15 mL) and the resulting mixture was allowed to
reflux for 48 h. Afterward, dry methanol (10 mL) was added,
or quinoline-2-carbaldehyde (21) (0.38 mmol) in CH2Cl2
(10 mL) was added 1-aminomethyl-3,5-bis[(4,6-dimethylpyridin-
2-yl)aminomethyl]-2,4,6-triethylbenzene (20) (0.30 mmol) dis-
solved in 5 mL CH2Cl2. The reaction mixture was allowed to reflux
for 16 h in the case of 12 and for 8 h in the case of 21. Afterward,
dr◦y methanol (5 mL) was added, the solution was cooled to
0 C and solid NaBH4 (1.64 mmol) was added in portions. The
reaction mixture was stirred for 1 h, the solvents were removed
by rotary evaporation and water (30 mL) was added. The mixture
◦
the mixture was cooled to 0 C and NaBH4 (0.20 g, 5.29 mmol)
was slowly added. The reaction mixture was stirred for 2 h, the
solvents were removed through rotary evaporation, and water
(50 mL) was added. The mixture was stirred for 4 h and extracted
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was stirred for 2 h and extracted with CHCl3. The organic phase
was washed with water (3 ¥ 30 mL), dried over MgSO4, and the
solvent was removed. The crude product was purified via column
chromatography [CHCl3/CH3OH (incl. 1% 7 M NH3 in CH3OH),
7 : 1 or 20 : 1 v/v].
D. James, Chem. Commun., 2009, 6557–6559; For a recent discussion
on o-hydroxymethyl phenylboronic acid binding capability, see: (d) M.
Berube, M. Dowlut and D. G. Hall, J. Org. Chem., 2008, 73, 6471–6479.
3 For some recent examples of carbohydrate receptors operating through
noncovalent interactions (earlier examples are given in ref. 1), see ref.
5a–p and: (a) E. Klein, M. P. Crump and A. P. Davis, Angew. Chem.,
Int. Ed., 2005, 44, 298–302; (b) H. Abe, Y. Aoyagi and M. Inouye,
Org. Lett., 2005, 7, 59–61; (c) M. G. J. Ten Cate, D. N. Reinhoudt and
M. Crego-Calama, J. Org. Chem., 2005, 70, 8443–8453; (d) H. Abe,
N. Masuda, M. Waki and M. Inouye, J. Am. Chem. Soc., 2005, 127,
16189–16196; (e) H.-P. Yi, X.-B. Shao, J.-L. Hou, C. Li, X.-K. Jiang
and Z.-T. Li, New J. Chem., 2005, 29, 1213–1218; (f) O. Francesconi,
A. Ienco, G. Moneti, C. Nativi and S. Roelens, Angew. Chem., Int. Ed.,
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1-[(8-Hydroxyquinolin-2-yl-methyl)aminomethyl]-3,5-bis[(4,6-
dimethylpyridin-2-yl)-aminomethyl]-2,4,6-triethylbenzene (3)
Yield 44%. M.p. 84–85 ◦C. 1H-NMR (400 MHz, CDCl3): d = 1.17
(t, J = 7.5 Hz, 6 H), 1.20 (t, J = 7.5 Hz, 3 H), 2.23 (s, 6 H), 2.35 (s, 6
H), 2.71 (q, J = 7.5 Hz, 2 H), 2.78 (q, J = 7.5 Hz, 4 H), 3.79 (s, 2 H),
4.15 (s, 2 H), 4.22 (s, 2 H), 4.35 (d, J = 4.2 Hz, 4 H), 6.07 (s, 2 H),
6.33 (s, 2 H), 7.16 (dd, J = 7.5/1.3 Hz, 1 H), 7.32 (dd, J = 8.3/1.2
Hz, 1 H), 7.41 (m, 1 H), 7.57 (d, J = 8.4 Hz, 1 H), 8.14 (d, J = 8.5
Hz, 1 H) ppm. 13C-NMR (100 MHz, CDCl3): d = 16.81, 21.09,
22.82, 24.22, 40.62, 47.25, 56.25, 103.45, 110.10, 113.81, 117.73,
121.51, 127.16, 127.48, 132.91, 134.49, 136.56, 137.48, 143.05,
143.22, 148.69, 151.87, 156.72, 158.25, 158.49 ppm. HR-MS (ESI)
calcd for C39H49N6O: 617.39623 [M + H]+; found: 617.39611. Rf
0.50 [chloroform/methanol (incl. 1% NH3), 7 : 1]. Anal. calcd for
C39H48N6O: C, 75.94; H, 7.84; N, 13.62; found: C, 75.80; H, 7.96;
N, 13.67%.
1-[(Quinolin-2-yl-methyl)aminomethyl]-3,5-bis[(4,6-
dimethylpyridin-2-yl)aminomethyl]-2,4,6-triethylbenzene (4)
4 (a) A. P. Davis, Org. Biomol. Chem., 2009, 7, 3629–3638; (b) S.
Kubik, Angew. Chem., Int. Ed., 2009, 48, 1722–1725; (c) M. Mazik,
ChemBioChem, 2008, 9, 1015–1017.
Yield 49%. M.p. 70–71 ◦C. 1H-NMR (400 MHz, CDCl3): d = 1.16
(t, J = 7.5 Hz, 6 H), 1.21 (t, J = 7.5 Hz, 3 H), 2.23 (s, 6 H), 2.35 (s, 6
H), 2.72 (q, J = 7.5 Hz, 2 H), 2.84 (q, J = 7.5 Hz, 4 H), 3.81 (s, 2 H),
4.17 (s, 2 H), 4.23 (s, 2 H), 4.36 (d, J = 4.2 Hz, 4 H), 6.07 (s, 2 H),
6.33 (s, 2 H), 7.51 (m, 1H), 7.54 (d, J = 8.2 Hz), 7.70 (m, 1 H), 7.81
(dd, J = 8.2/1.2 Hz, 1 H), 8.08 (d, J = 8.4 Hz, 1 H), 8.14 (d, J =
8.3 Hz, 1 H) ppm. 13C-NMR (100 MHz, CDCl3): d = 16.83, 21.09,
22.77, 24.19, 40.66, 47.29, 56.53, 103.50, 113.76, 120.68, 126.04,
127.32, 127.56, 129.03, 129.44, 132.85, 134.74, 136.38, 142.96,
143.36, 147.74, 148.71, 156.68, 158.28, 160.43 ppm. HR-MS (ESI)
calcd for C39H49N6: 601.40132 [M + H]+; found: 601.40143. Rf
0.30 [chloroform/methanol (incl. 1% NH3), 7 : 1]. Anal. calcd for
C39H48N6: C, 77.96; H, 8.05; N, 13.98; found: C, 77.85; H, 8.13; N,
14.02.
5 (a) M. Mazik and C. Sonnenberg, J. Org. Chem., 2010, 75, 6416–6423;
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6 For some recent examples of 8-hydroxyquinoline-based chelators, see:
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Acknowledgements
This work was supported by the Deutsche Forschungsgemein-
schaft.
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