Purine Unit as a Building Block of Artificial Receptors Designed for the Recognition of Carbohydrates

Article abstract of DOI:10.1002/ejoc.201901340

1,3,5-Substituted 2,4,6-triethylbenzene derivatives bearing pyridine/pyrimidine and purine units were synthesized and their potential to function as carbohydrate receptors was evaluated. Compounds consisting of 2-chloro-9H(7H)-purin-6-yl unit have the abi

Full text of DOI:10.1002/ejoc.201901340

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Accepted Article
Title: Purine unit as a building block of artificial receptors designed for
the recognition of carbohydrates
Authors: Stefan Kaiser, Christoph Geffert, and Monika Mazik
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10.1002/ejoc.201901340
European Journal of Organic Chemistry
Purine unit as a building block of artificial receptors designed for the
recognition of carbohydrates
Stefan Kaiser, Christoph Geffert, Monika Mazik*[a]
Stefan Kaiser, Dr. Christoph Geffert, Prof. Dr. Monika Mazik
[a] Institut für Organische Chemie, Technische Universität Bergakademie Freiberg, Leipziger Strasse 29,
09599 Freiberg, Germany; Tel.: 03731392389; Fax: 03731393170
e-mail: monika.mazik@chemie.tu-freiberg.de; http://tu-freiberg.de/fakultaet2/orgch
Keywords: Molecular Recognition / Carbohydrate Receptors / Tripodal Compounds / Noncovalent
Interactions
Abstract: 1,3,5-Substituted 2,4,6-triethylbenzene derivatives bearing pyridine/pyrimidine and
purine units were synthesized and their potential to function as carbohydrate receptors was
evaluated. Compounds consisting of 2-chloro-9H(7H)-purin-6-yl unit have the ability to act both
as carbohydrate-binding agents and as a basis for further functionalisation through the
nucleophilic displacement of the chlorine atom. Microwave-assisted reactions and/or the
application of sealed tubes allowed the preparation of derivatives with a varying substituent
pattern on the purine ring. The relatively drastic reaction conditions required for the successful
functionalisation reflect the unfavorable influence of the bulky C6-substituent on the
nucleophilic substitution at purine C2. Initial binding studies towards carbohydrates showed that
the properties of this type of purine-bearing compounds can be fine-tuned by the variation of the
C2-substituent of the purine ring and represents a valuable basis for the identification of new
structure-activity relationships. Such findings are of high importance for further developments in
the area of molecular recognition of carbohydrates by artificial receptors.
________________________________________________________________________________________
Introduction
Carbohydrates play a key role in a wide range of biological processes[1,2] and the detailed
understanding of the principles of their recognition by carbohydrate-binding proteins is of
particular interest for researchers. Crystallographic studies revealed that hydrogen bonds, CH∙∙∙
interactions and numerous van der Waals contacts are involved in selective carbohydrate
recognition by proteins.[2] The structural features of protein-carbohydrate interactions have
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inspired the design of artificial carbohydrate-binding agents (carbohydrate receptors).[3,4] The
representatives of such artificial receptors are regarded not only as model systems, which should
help us to enhance the knowledge on molecular details of carbohydrate-mediated recognition
processes, but also as compounds with potential valuable biological activities, including
antibacterial, antiviral and anticancer activities.
Within the scope of our studies in the area of sugar recognition by artificial receptors operating
by noncovalent interactions, we have developed both acyclic[5-8] and macrocyclic systems[9] (for
examples, see Figure 1) showing different interesting binding efficiencies and selectivities
towards carbohydrates in dependency of the type of the aromatic platform, the nature of the
recognition groups (units X in Figure 1) and the way of their connection (units L and Y) with the
aromatic core.
2
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Figure 1. Examples of acyclic[5-8] (a-c) and macrocyclic[9] (d) carbohydrate receptors reported by
our group (X = recognition groups, L / Y = linker / bridge units).
Systematic binding studies revealed that compounds bearing different types of recognition
groups (units X1-4, Figure 1a-c) are often more selective carbohydrate receptors than those that
consist of identical recognition units. Such a combination of different types of recognition
groups has been for example realised in the case of compounds bearing both 2-
aminopyrimidine/-pyridine units and pyrrole-, imidazole-, indole-, pyrazole-, quinoline-,
pyridinium-, phenanthroline- or isopropylamino-based recognition groups.
It is also worth noting that we have succeeded in obtaining single crystals of the receptor-
carbohydrate complexes suitable for X-ray structure analyses, which revealed the involvement of
hydrogen bonding (for examples, see Figure 2a), CH∙∙∙ interactions and van der Waals contacts
in the stabilization of these complexes,[5h] as in the case of protein-carbohydrate complexes.
Figure 2. (a) Examples of hydrogen bonds observed in the complexes of glycosides with
artificial receptors bearing 2-aminopyridine- (Z = CH) and 2-aminopyrimidine-based recognition
groups (Z = N; see, for example ref. 5h); (b,c) Examples of hydrogen bonds which can be
formed between purine units and carbohydrates (in the case of the 2-chloro-substituted purine
unit, the formation of the C-Cl∙∙∙O halogen bond could also be expected).
Our studies showed the enormous potential of the designed acyclic and macrocyclic receptor
architectures for versatile structural modifications, which enable the identification of interesting
3
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structure-activity relationships. The aim of this study was the synthesis of new 1,3,5-substituted
2,4,6-triethylbenzene derivatives[10,11] bearing beside the above mentioned 2-aminopyridine/-
pyrimidine units, which can be regarded as heterocyclic analogues of the asparagine/glutamine
primary amide side chain,[12] also purine unit(s), having the ability to participate in the formation
of hydrogen bonds (see Figure 2b and 2c) with the carbohydrate substrate. We were interested to
see how the incorporation of the purine-based recognition group(s) influences the binding
properties of this type of compounds (see structures 1-4, Figure 3). In addition, the integration of
the 2-chloro substituted purine unit (as in 2-4) offers the opportunity for further functionalisation
of the triethylbenzene-based compounds (see Figure 3). First tests in this direction have been
carried out using compounds 2 and 3 for reactions with selected amines, such as
cyclohexylamine, benzylamine, 2-picolylamine, 3-picolylamine and tryptamine, to obtain the
compounds 5-9.
Figure 3. Structures of the target compounds 1-9 considered in this study.
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The purine skeleton represents a highly important natural building block and has found also
broad applications in medicinal chemistry.[13,14] In addition, various organic derivatives
consisting of a purine subunit have been used as basis for the formation of different
supramolecular assemblies, liquid crystals and other supramolecular systems.[15-17]
Results and discussion
Synthesis of the target compounds 1-9.
Compounds 1 and 2 were prepared by the reaction of 1-aminomethyl-3,5-bis[(4,6-
dimethylpyridin-2-yl)aminomethyl]-2,4,6-triethylbenzene (10) with 6-chloropurine and 2,6-
dichloropurine, respectively, whereas the reaction of 1-aminomethyl-3,5-bis[(4,6-
dimethylpyrimidin-2-yl)aminomethyl]-2,4,6-triethylbenzene (11, the pyrimidine analoque of 10)
with 2,6-dichloropurine provided the derivative 3 (see Scheme 1). The basis for the synthesis of
compound 4, bearing two 2-chloropurine groups, was 1,3-bis(aminomethyl)-5-[(4,6-
dimethylpyridin-2-yl)aminomethyl]-2,4,6-triethylbenzene (12), as shown in Scheme 1.
The preparation of compounds 10-12 was carried out according to the procedure reported by us
previously[6b,6g] and is summarized in Scheme 2. This procedure comprises the synthesis of
compounds 15a/16a and 15b/16b bearing bromomethyl group(s) by a reaction of 1,3,5-
tris(bromomethyl)-2,4,6-triethylbenzene (14) with 2-amino-4,6-dimethylpyridine (Z = CH, see
Scheme 2) and 2-amino-4,6-dimethylpyrimidine (Z = N), respectively. Treatment of 16a and
16b with a solution of ammonia in methanol allows their facile convertion into the
corresponding aminomethyl derivatives 10 and 11, respectively, whereas the Gabriel synthesis
was used for the conversion of 15a into the educt 12 possessing two aminomethyl groups.
The reaction of 10 with 6-chloropurine (synthesis of 1; see Scheme 1) was accomplished
through conventional heating (110 °C, up to 16 hours), whereas the reactions of 10, 11 and 12
with 2,6-dichloropurine (syntheses of 2-4) were performed using conventional (80 - 110 °C, up
to 24 hours) and/or microwave heating (80 °C, approx. 1 hour). The higher reactivity in the 6-
position of the 2,6-dichloropurine[18] allows the sequential replacement of the chlorine atoms
and the synthesis of compounds bearing 2-chloropurine unit(s), as in the case of 2-4.
Compounds 1-4 were prepared with yields in the range of 25 % to 81 % (see Scheme 1). The
main advantage of the microwave procedure over the conventional method was the much shorter
reaction time (approx. 1 hour vs 24 hours).
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Scheme 1. Reaction conditions: (a) 6-Chloropurine or 2,6-dichloropurine, DIPEA, n-butanol,
80-110 °C, 16-24 h (45 % of 1, 78 % of 2); (b) 2,6-Dichloropurine, DIPEA, n-butanol,
microwave irradation, 80 °C, 1-1.25 h (81 % of 2, 75 % of 3); (c) 2,6-dichloropurine, DIPEA, n-
butanol, 110 °C, 24 h (25 % of 4); (d) Cyclohexylamine, n-butanol, sealed tube, 140 °C, 7 d (44
% of 5); (e) Benzylamine, n-butanol, sealed tube, 140 °C, 7 d (45 % of 6); (f) Benzylamine, n-
6
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butanol, microwave irradiation (180 W), 170 °C, 8 h (79 % of 6); (g) 2-Picolylamine, n-butanol,
sealed tube, 140 °C, 7 d (34 % of 7); (h) 3-Picolylamine, n-butanol, sealed tube, 125 °C, 6 d (25
% of 8); (i) 3-Picolylamine, n-butanol, microwave irradiation (200 W), 160 °C, 4 h (47 % of 8);
(j) Tryptamine, n-butanol, microwave irradiation (160 W), 170 °C, 6 h (42 % of 9).
Scheme 2. Reaction conditions: (a) 2-Amino-4,6-dimethylpyridine or -pyrimidine, K2CO3,
THF/acetonitrile, room temperature (in the case of the pyridine derivative) or 50 °C (in the case
of the pyrimidine analogue), 3 d (25 % of 15a, 28 % of 15b, 20 % of 16a, 16 % of 16b); (b) NH3
(7 N) in MeOH, room temperature, 2 d (69 % of 10, 38 % of 11); (c) Potassium phthalimide,
DMSO, 12 h, 95 °C; (d) N2H4H2O, EtOH/toluene, 20 h, 90 °C (37 % of 12).
After the replacement of the chlorine atom in the 6-position of the 2,6-dichloropurine by a
nitrogen nucleophile, the subsequent nucleophilic displacement in the 2-position requires more
drastic reaction conditions. Such nucleophilic displacement has often been explored,[19-21] but
not in the presence of as bulky group as that attached to the 6-position of the purine ring of
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compounds 2 and 3. The steric effect of such bulky group unfavourably affects the nucleophilic
substitution at purine C2.
The functionalisation of compounds 2 and 3 in the 2-position of the purine ring has been tested
by us with five selected amines, such as cyclohexylamine, benzylamine, 2-picolylamine, 3-
picolylamine and tryptamine (Scheme 1). The reactions were performed in n-butanol and N,N-
diisopropylethylamine (DIPEA) was used as a base. By carrying out the reaction of 2 with
cyclohexylamine, benzylamine 2-picolylamine and 3-picolylamine in a sealed tube at 125-140
°C, compounds 5, 6, 7 and 8 could be obtained with 44 %, 45 %, 34 % and 25 % yield,
respectively, but a long reaction time of several days was necessary. Through the use of
microwave heating the reaction time could be shortened from several days to 4-8 hours and the yields
increased significantly. The yield of 6 could be improved from 45 % to 79 % and that of 8 from 25 % to
47 %. The microwave-assisted reaction of compound 3 with tryptamine allowed the preparation of
9 with 42 % yield after 6 hours. Although the reaction time could be considerably shortened, the
required time is much longer than typically known[22] for microwave-assisted reactions. This fact
clearly reflects the reactivity problems at the C2-position and can be traced back to steric effects
caused by the large C6-substituent.
Exemplary binding studies towards selected carbohydrates.
1H NMR spectroscopic titrations of compounds 1 and 2 with selected glycosides (see Table 1,
Figure 4 and Supporting Information) revealed that these two compounds display similar
binding efficiency as the previously investigated symmetrical triethylbenzene-based compound
bearing three aminopyridine groups[5k] (see structure 17a in Scheme 2).
The binding preference for -glucoside versus -galactoside observed in the homogenous phase
was also confirmed by binding studies in two-phase systems. The extractions of methyl
glycosides from the solid state into a CDCl3 solution of the corresponding receptor (1 mM
solutions) showed that the extractability decreases in the sequence -glucoside > -galactoside ≈
-glucoside (see Table 2).
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1
Figure 4. Partial H NMR spectra (500 MHz, CDCl3) of compound 2 ([] = 1.01 mM) after
addition of (a) 0.00-4.56 equiv of octyl -D-glucoside and (b) 0.00-5.49 equiv of octyl β-D-
galactoside. Shown are the chemical shifts of the CH2NH and pyr-CH3 signals of 2.
Table 1. Association constantsa,b for the complexation of octyl -D-glucoside (glc) and octyl
1
-D-galactoside (gal) with compounds 1, 2 and 5-8 (results of H NMR spectroscopic
titrations, CDCl3, 20 °C).
Receptor/substrate
1 / glcd
2 / glc
K11 / K21c [M-1]
39300 / 680
34700 / 930
29900 / 350
42700 / 290
58200 / 290
33200 / 140
β21 = K11 x K21 [M-2]
2.67 x 107
3.23 x 107
1.05 x 107
1.24 x 107
5 / glc
6 / glc
7 / glc
1.69 x 107
4.65 x 106
8 / glc
----------
2 / gal
9800 / 170
7000
1.66 x 106
5 / gal
6 / gal
4500
aAverage Ka values from multiple titrations evaluated on the basis of different programs
(WinEQNMR,[23] HypNMR[24] and SupraFit[25]). bErrors were estimated at < 6 %. cK21 corresponds to 2:1
d
receptor−sugar association constant. For the previously investigated symmetrical analogue 17a the Ka
values were found to be 48630 M-1 (K11) and 1320 M-1 (K12) (for details see ref. 5k).
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Table 2. Solubilization of methyl glycosides in CDCl3 by compounds 1 and 2 (1 mM solutions).
Molar ratios sugar/receptor occurring in solutiona
Receptor
β-D-Glucoside
0.82
β-D-Galactoside
α-D-Glucoside
0.40
0.34
0.45
1
2
0.70
0.45
aThe 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.
Thus, the replacement of one pyridine-2-yl group by 9H(7H)-purin-6-yl or 2-chloro-9H(7H)-
purin-6-yl unit does not significantly affect the binding properties of the purine-bearing
analogues under the chosen titration and extraction conditions (see Table 1 and 2). However,
initial binding studies with compounds 5-9 confirmed our expectations that the binding
properties of this type of purine-bearing compounds can be fine-tuned by the variation of the C2-
substituent of the purine ring. For example, just such a small structural change as the
replacement of pyridine-2-yl (compound 7) by pyridine-3-yl unit (compound 8) is responsible
for a decrease in the binding capacity. Due to the purine tautomerism both the 9H- and 7H-
tautomer can participate in the binding process (see Figure 2b); however, the 9H-tautomer
represents the major form in the case of the examinated compounds. Through systematic
structural modifications of this type of architecture numerous compounds can be prepared,
which represent a valuable basis for studying the structure-activity relationships. Currently we
are synthesizing analogues of compounds 6-9 to study in detail the interactions between the -
and/or -face of the carbohydrate and the aromatic group(s) of the receptor molecule. The
structural modifications involve the variation of the aromatic group and the connecting bridge
(subunit Y, see Figure 5). In this connection it should be mentioned that the studies on aromatic-
sugar interactions[26] are of high current research interest.
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Figure 5. Schematic illustration of the binding mode of carbohydrates by purine-bearing
receptors, which are accessible by structural modifications of the basic chemical structure
described in this work.
Conclusion
New representatives of the class of 1,3,5-substituted 2,4,6-triethylbenzenes bearing beside 2-
aminopyridine/-pyrimidine unit(s) also purine-based recognition group(s) were prepared and
1
their ability to act as carbohydrate receptors was tested on the basis of H NMR spectroscopic
titrations and extraction experiments. Compounds 1-4, consisting of 9H(7H)-purin-6-yl or 2-
chloro-9H(7H)-purin-6-yl group(s), were prepared via reaction of 6-chloropurine or 2,6-
dichloropurine with the corresponding amino derivative, such as 1-aminomethyl-3,5-bis[(4,6-
dimethylpyridin-2-yl)aminomethyl]-2,4,6-triethylbenzene (10), 1-aminomethyl-3,5-bis[(4,6-
dimethylpyrimidin-2-yl)aminomethyl]-2,4,6-triethylbenzene (11) and 1,3-bis(aminomethyl)-5-
[(4,6-dimethylpyrimidin-2-yl)aminomethyl]-2,4,6-triethylbenzene (12).
Further functionalisation of the 2-chloropurine-bearing compounds 2 and 3 allowed the
preparation of derivatives 5-9 with a varying substituent pattern on the purine ring. The reactions
of 2 and 3 with selected amines, such as cyclohexylamine, benzylamine, 2-picolylamine, 3-
picolylamine and tryptamine, were performed using sealed tubes and/or microwave heating. The
unfavourable influence of the large C6-substituent has clearly been reflected by the relatively
drastic reaction conditions required for the nucleophilic displacement of the chlorine atom in the
C2-position of the purine ring and the successful synthesis of compounds 5-9.
Initial studies on carbohydrate-binding by compounds 5-8 confirmed our expectations and
showed that the properties of this type of purine-bearing compounds can be fine-tuned by the
variation of the C2-substituent. The results with compounds 1, 2 and 5-8 confirmed also our
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previous observations that in the case of 1,3,5-substituted 2,4,6-triethylbenzenes the
combination of two 2-aminopyridine/pyrimidine units with another recognition group seems to
be a particularly suitable architecture for the recognition of -glucoside, but represents a less
effective receptor architecture for -galactoside. In contrast, the combination of one 2-
aminopyrimidine/pyridine unit with two other recognition groups, such as isopropylamino-,
imidazole-, indole- or 8-hydroxyquinoline-based recognition group, was previously shown to
provide particularly powerful receptors for -galactoside.
The type of purine-bearing compounds studied here represents a valuable basis for systematic
structural modifications and provides through this the possibility of identification of new
structure-activity relationships, which are of high importance for the development of artificial
receptors with predictable binding properties. It should be noted that the exact prediction of the
binding strength and selectivity of artificial carbohydrate receptors has not yet been realised and
represents the basis of intensive research activities.
Experimental Section
Analytical TLC was performed on commercial Merck plates coated with silica gel 60 F254 and
the silica gel used for flash chromatography was Merck Kieselgel 60. Melting points are
uncorrected. 1H and 13C NMR spectra were recorded on Bruker Avance III 500, Bruker Nanobay
400 or Jeol Resonance ECZ500R NMR spectrometer using Me4Si as internal standard (strong
broadening of some NMR peaks of the purine-bearing compounds in CDCl3 results in missing
splitting; see Supporting Information). Mass spectra were recorded on Bruker amaZon SL and
JEOLAccuTOF 4G LC-Plus mass spectrometer as well as on Bruker solariX 15T (HRMS
measurements).
The titration experiments were carried out by addition of increasing amounts of the tested
carbohydrate to a solution of the corresponding receptor. In addition, inverse titrations were
performed in which the concentration of the sugar was held constant and that of the receptor was
varied (see Supporting Information). The titration data were analyzed by non-linear regression
analysis, using the programs WinEQNMR,[23] HypNMR[24] and SupraFit,[25] and the complex
stoichiometry was analysed on the basis of the mole ratio method[27] (see Supporting
Information).
Preparation of compounds 1-4 using conventional heating and/or microwave irradiation
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1-[(Purine-6-yl)-aminomethyl]-3,5-bis-[(4,6-dimethyl-pyridin-2-yl)-aminomethyl]-2,4,6-
triethylbenzene (1). Procedure A (conventional heating). A mixture of 6-chloropurine (0.03 g,
0.196 mmol), 1-aminomethyl-3,5-bis-[(4,6-dimethylpyridin-2-yl)aminomethyl]-2,4,6-triethyl-
benzene (9) (0.10 g, 0.22 mmol) and N,N-diisopropylethylamine (DIPEA) (0.06 mL, 0.37 mmol)
in n-butanol (15 ml) was stirred for 16 h at 110 °C. Afterwards, the solvent was removed by
rotary evaporation, the residue washed with water and the crude product was purified via column
chromatography [CHCl3/CH3OH incl. 1% 7 M NH3 in CH3OH, 15:1]. Yield 45 %. M.p. 99 °C.
1H-NMR (400 MHz, CDCl3):  = 1.15 (m, 6 H), 1.24 (t, J = 6.8 Hz, 3 H), 2.27 (s, 6 H), 2.41 (s,
6 H), 2.58 (m, 4 H), 2.77 (m, 2 H), 4.28 (br s, 2 H), 4.34 (s, 4 H), 4.74 (s, 2 H), 5.22 (br s, 1 H),
6.26 (s, 2 H), 6.36 (s, 2 H), 8.30 (s, 1 H), 8.50 (s, 1 H) ppm. 13C-NMR (100 MHz, CDCl3):  =
16.5, 16.8, 18.1, 2.4, 22.9, 23.1, 39.2, 40.8, 104.1, 113.8, 130.5, 131.9, 132.3, 143.9, 144.2,
145.5, 149.5, 151.3, 152.8, 152.9, 154.5 ppm. HRMS (ESI): calcd for C34H44N9: 578.37142
[M+H]+ and for C34H45N9: 289.68935 [M+2H]2+; found: 578.37147 [M+H]+, 289.68937
[M+2H]2+. Rf = 0.25 [CHCl3/CH3OH (15:1, v/v) incl. 1% 7 M NH3 in CH3OH].
1-[(2-Chloro-9H-purine-6-yl)-aminomethyl]-3,5-bis-[(4,6-dimethyl-pyridin-2-yl)-
aminomethyl]-2,4,6-triethylbenzene (2). Procedure A (conventional heating). A mixture of
2,6-dichloropurine (0.28 g, 1.5 mmol), 1-(aminomethyl)-3,5-bis-[(4,6-dimethylpyridin-2-
yl)aminomethyl]-2,4,6-triethylbenzene (9) (0.60 g, 1.31 mmol) and DIPEA (0.34 mL, 2.0 mmol)
in n-butanol (20 ml) was stirred for 24 h at 80 °C. Then, the solvent was removed by rotary
evaporation, the residue washed with water and the crude product was purified via column
chromatography [CHCl3/IPA incl. 2% 7 N NH3 in CH3OH]. Yield 78 % (0.63 g, 1.03 mmol).
Procedure B (microwave conditions). 2,6-Dichloropurine (0.25 g, 1.31 mmol) and compound 9
(0.60 g, 1.31 mmol) dissolved in n-butanol (20 ml) and DIPEA (0.24 mL, 1.41 mmol) were
placed in a microwave vessel. After purging with argon and closing of the microwave vessel, the
microwave irradiation (70 W) was applied for 1 h at 80 °C. Afterwards, the solvent was
removed by rotary evaporation, the residue washed with water and the crude product was
purified via column chromatography [CHCl3/IPA incl. 2% 7 N NH3 in CH3OH]. Yield 81 %
(0.65 g, 1.06 mmol). M.p. 131 °C. 1H-NMR (500 MHz, CDCl3/CD3OD 5:1):  = 1.27 (t, J = 7.4
Hz, 9 H), 2.28 (s, 6 H), 2.36 (s, 6 H), 2.79 (q, J = 7.6 Hz, 2 H), 2.80 (q, J = 7.5 Hz, 4 H), 4.39 (s,
4 H), 4.80 (s, 2 H), 6.25 (s, 2 H), 6.39 (s, 2 H), 7.88 (s, 1 H) ppm. 13C-NMR (125 MHz, CDCl3):
 = 16.4, 16.9, 21.2, 22.8, 23.0, 24.0, 39,2, 40.7, 103.8, 114.0, 118.0, 131.2, 132.9, 138.2, 138.6,
143.8, 143.9, 149.2, 150.8, 154.3, 154.5, 156.4, 158.3 ppm. HRMS (ESI): calcd for C34H43ClN9:
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612.332447 [M+H]+; found: 612.332451. Rf = 0.10 [CHCl3/CH3OH incl. 1% NH3 (7N) in
CH3OH, 10:1 v/v].
1-[(2-Chloro-9H-purine-6-yl)-aminomethyl]-3,5-bis-[(4,6-dimethyl-pyrimidin-2-yl)-amino-
methyl]-2,4,6-triethylbenzene (3). Procedure B (microwave conditions). 2,6-Dichloropurine
(0.15 g, 0.81 mmol) and 1-(aminomethyl)-3,5-bis-[(4,6-dimethylpyrimidin-2-yl)aminomethyl]-
2,4,6-triethylbenzene (10) (0.34 g, 0.73 mmol) dissolved in n-butanol (10 ml) and DIPEA (0.19
mL, 1.10 mmol) were placed in a microwave vessel. After purging with argon and closing of the
vessel, the microwave irradiation (75 W) was applied for 75 min at 80 °C. Afterwards, the
solvent was removed by rotary evaporation, the residue washed with water and the crude product
was purified via column chromatography [ethylacetate/ethanol incl. 2% 7 N NH3 in CH3OH,
10:1]. Yield 75 % (0.34 g, 0.55 mmol). M.p. 158 °C. 1H-NMR (500 MHz, CDCl3/CD3OD 5:1):
 = 1.26 (t, J = 7.5 Hz, 9 H), 2.33 (s, 12 H), 2.81 (q, J = 7.3 Hz, 6 H), 4.61 (s, 4 H), 4.80 (s, 2 H),
6.40 (s, 2 H), 7.85 (s, 1 H) ppm. 13C-NMR (125 MHz, CDCl3):  = 16.5, 16.6, 23.0, 23.0, 23.9,
39.5, 39.8, 109.8, 118.2, 131.2, 133.1, 138.5, 143.9, 144.3, 150.5, 154.2, 154.6, 161.8, 167.6
ppm. HRMS (ESI): calcd for C32H41ClN11: 614.322945 [M+H]+; found: 614.322947. Rf = 0.25
[ethylacetate/ethanol incl. 2% 7 N NH3 in CH3OH, 10:1].
1,3-bis-[(2-Chloro-9H-purine-6-yl)-aminomethyl]-5-[(4,6-dimethyl-pyridin-2-yl)-amino-
methyl]-2,4,6-triethylbenzene (4). Procedure A (conventional heating). A mixture of 2,6-
dichloropurine (0.05 g, 0.28 mmol), 1,3-bis-(aminomethyl)-5-[(4,6-dimethylpyridin-2-
yl)aminomethyl]-2,4,6-triethylbenzene (11) (0.05 g, 0.14 mmol) and DIPEA (0.08 mL, 0.43
mmol) in n-butanol (10 mL) was stirred for 24 h at 110 °C. Afterwards, the solvent was removed
by rotary evaporation, the residue washed with water and the crude product was purified via
column chromatography [CHCl3/CH3OH incl. 1% 7 M NH3 in CH3OH, 10:1]. Yield 25 %. M.p.
1
> 200 °C. H-NMR (400 MHz, CDCl3/CD3OD 7:1):  = 1.26 (t, J = 7.4 Hz, 9 H), 2.26 (s 2 H),
2.34 (s, 3 H), 2.81 (m, 6 H), 4.38 (s, 2 H), 4.81 (s, 4 H), 6.18 (s, 1 H), 6.36 (s, 1 H), 7.82 (br s, 2
H) ppm. 13C-NMR (100 MHz, CDCl3/CD3OD 7:1):  = 16.48, 16.66, 21.23, 23.21, 23.33, 39.43,
40.85, 104.38, 110.44, 114.29, 131.82, 133.20, 144.34, 144.54, 147.27, 149.23, 154.63, 156.32,
158.34, 161.80 ppm. HRMS (ESI): calcd for C32H36Cl2N12: 659.26412 [M+H]+; found:
659.26397. Rf = 0.10 [CHCl3/CH3OH incl. 1% NH3 7N in CH3OH, 10:1].
Preparation of compounds 5-8 using sealed tubes and/or microwave irradiation
General procedures. ProcedureꢀC (sealed tube). 1-[(2-Chloro-9H-purine-6-yl)-aminomethyl]-
3,5-bis-[(4,6-dimethylpyridin-2-yl)-aminomethyl]-2,4,6-triethylbenzene
(2)
and
the
14
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10.1002/ejoc.201901340
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corresponding amine in n-butanol (5 mL) were placed in a sealed tube. After purging with argon
and closing of the tube, the reaction mixture was stirred at 130 °C for 7 d. Then, the solvent was
removed by rotary evaporation, the residue washed with water and the crude product was
purified via column chromatography or by means of preparative HPLC (for details, see below).
Procedure D (microwave conditions). 1-[(2-chloro-9H-purine-6-yl)-aminomethyl]-3,5-bis-
[(4,6-dimethyl-pyridin-2-yl)-aminomethyl]-2,4,6-triethylbenzene (2) or 1-[(2-chloro-9H-purine-
6-yl)-aminomethyl]-3,5-bis-[(4,6-dimethyl-pyrimidin-2-yl)-amino-methyl]-2,4,6-triethylbenzene
(3) and the corresponding amine were dissolved in n-butanol (3 mL) in a microwave vessel.
After purging with argon and closing of the vessel, the microwave irradiation was applied for
several hours at 160 - 170 °C (for details, see below). Afterwards, the solvent was removed by
rotary evaporation, the residue washed with water and the crude product was purified via column
chromatography (for details, see below).
1-{[2-(Cyclohexylamino)-9H-purin-6-yl]aminomethyl}-3,5-bis[4,6-dimethylpyridin-2-
yl)aminomethyl]-2,4,6-triethylbenzene (5). ProcedureꢀC. Compound 5 was prepared from 2
(0.091 g, 0.14 mmol) and cyclohexylamine (0.17 mL, 1.5 mmol). Purification was performed by
means of preparative HPLC (Nucleodur 100-5 NH2 Macherey-Nagel, Isocratic CHCl3/ethanol
1
93:7, tR = 8.2 min). Yield 44 % (0.045 g, 0.065 mmol). M.p. 132 °C. H-NMR (500 MHz,
CDCl3): δꢀ 1.01 - 1.32 (m, 12 H), 1.60 (m, 1 H), 1.71 (m, 2 H), 1.83 (m, 2 H), 2.23 (s, 6 H), 2.36
(s, 6 H), 2.55 (q, J = 7.1 Hz, 4 H), 2.76 (q, J = 7.2 Hz, 2 H), 4.33 (s, 4 H), 4.53 (br s, 2 H), 4.70
(s, 2 H), 4.79 (br s, 1 H), 6.17 (s, 2 H), 6.35 (s, 2 H), 6.74 (s, 1 H), 7.65 (s, 1 H). 13C-NMR (125
MHz, CDCl3): δꢀ16.5, 16.8, 21.2, 22.8, 23.0, 24.1, 25.1, 25.7, 36.7, 39.3, 40.6, 50.5, 103.9,
114.0, 117.9, 131.3, 133.1, 138.9, 143.8, 144.0, 149.0, 151.2, 154.3, 154.5, 156.5, 158.3. HRMS
(ESI): calcd for C40H55N10: 675.460568 [M+H]+; found: 675.460567. Rf = 0.83 [CHCl3/IPA
(incl. 1% NH3 (7N) in CH3OH), 3:1].
1-[(2-Benzylamino-9H-purin-6-yl)aminomethyl]-3,5-bis-[(4,6-dimethylpyridin-2-
yl)aminomethyl]-2,4,6-triethylbenzene (6). Procedure C. Compound 6 was prepared from 2
(0.090 g, 0.146 mmol) and benzylamine (0.155 g, 1.46 mmol). Purification was performed by
means of preparative HPLC (Nucleodur 100-5 NH2 Macherey-Nagel, Isocratic CHCl3/IPA 91:9,
tR = 10.5 min). Yield 45 % (0.045 g, 0.066 mmol).
Procedure D. Compound 6 was prepared from 2 (0.107 g, 0.175 mmol) and benzylamine (0.37
g, 3.49 mmol). Microwave irradiation (180 W) was applied for 8 h at 170 °C. Purification was
performed by column chromatography [CHCl3/IPA incl. 2 % NH3 7N in CH3OH, 7:1]. Yield 79
% (0.094 g, 0.138 mmol). Rf = 0.44 [CHCl3/IPA incl. 2 % 7 N NH3 in CH3OH, 7:1]. M.p. 117
15
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European Journal of Organic Chemistry
°C. 1H-NMR (500 MHz, CDCl3/CD3OD 5:1): δꢀ 1.22 (t, J = 7.6 Hz, 6 H), 1.25 (t, J = 7.3 Hz, 3
H), 2.25 (s, 6 H), 2.34 (s, 6 H), 2.78 (m, 6 H), 4.38 (s, 4 H), 4.68 (s, 2 H), 4.73 (br s, 2 H), 6.19
(s, 2 H), 6.36 (s, 2 H), 7.24 (t, J = 7.3 Hz, 1 H), 7.32 (t, J = 7.6 Hz, 2 H), 7.40 (d, J = 7.4 Hz, 2
13
H), 7.54 (s, 1H). C-NMR (125 MHz, CDCl3): δꢀ16.5, 16.8, 21.2, 22.7, 22.9, 24.1, 38.4, 40.6,
45.8, 103.59, 113.7, 126.9, 128.5, 132.2, 132.8, 134.8, 143.6, 148.9, 151.4, 154.3, 156.6, 158.5,
159.8. HRMS (ESI): calcd for C41H51N10: 683.429268 [M+H]+; found: 683.429271.
1-{{2-[(Pyridin-2-yl)methylamino]-9H-purin-6-yl}aminomethyl}-3,5-bis-[(4,6-dimethyl-
pyridin-2-yl)aminomethyl]-2,4,6-triethylbenzene (7). Procedure C. Compound 7 was
prepared from 2 (0.08 g, 0.13 mmol) and 2-picolylamine (0.16 mL, 1.57ꢀmmol). Purification
was performed by column chromatography [CHCl3/IPA incl. 2 % NH3 7 N in CH3OH, 5:4].
Yield 34 % (0.03 g, 0.044 mmol). Rf = 0.57 [CHCl3/IPA incl. 2 % 7 N NH3 in MeOH, 5:4]. M.p.
155 °C. 1H-NMR (500 MHz, CDCl3/CD3OD 5:1): δꢀ=ꢀ 1.20 (t, J = 7.4 Hz, 6 H), 1.25 (t, J = 7.5
Hz, 3 H), 2.26 (s, 6 H), 2.35 (s, 6 H), 2.75 (q, J = 7.3 Hz, 4 H), 2.77 (q, J = 7.5 Hz, 2 H), 4.36 (s,
4 H), 4.66 (s, 2ꢀH), 4.80 (s, 2 H), 6.20 (s, 2 H), 6.36 (s, 2 H), 7.22 (m, 1 H), 7.38 (m, 1 H), 7.46
(d, J = 7.9 Hz, 1ꢀH), 7.57 (s, 1 H), 7.69 (td, Jꢀ=ꢀ7.7/1.7 Hz, 1ꢀH), 8.49 (m, 1ꢀH) ppm. 13C-NMR
(125 MHz, CDCl3/CD3OD): δꢀ=ꢀ 16.6, 16.8, 21.3, 23.1, 23.5, 24.9, 38.7, 40.8, 47.1, 104.2,
110.1, 114.1, 121.8, 122.3, 132.4, 132.8, 135.6, 137.3, 144.0, 144.0, 148.7, 149.9, 149.9, 154.1,
156.0, 158.3, 159.61, 159.7 ppm. HRMS (ESI): calcd for C41H51N10: 684.424517 [M+H]+;
found 684.424518.
1-{{2-[(Pyridin-3-yl)methylamino]-9H-purin-6-yl}aminomethyl}-3,5-bis-[(4,6-dimethyl-
pyridin-2-yl)aminomethyl]-2,4,6-triethylbenzene (8). Procedure C. Compound 8 was
prepared from 2 (0.080 mg, 0.13 mmol) and 3-picolylamine (0.070 mL, 0.68 mmol). The crude
product was purified by column chromatography [CHCl3/IPA incl. 1 % NH3 7N in CH3OH, 5:1].
Yield 25 % (0.024 g, 0.036 mmol).
Procedure D. Compound 8 was prepared from 2 (0.08 g, 0.13 mmol) and 3-picolylamine (0.13
mL, 1.28 mmol). Microwave irradiation (200 W) was applied for 4 h at 160 °C. Purification was
performed by column chromatography [CHCl3/IPA incl. 2 % NH3 7N in CH3OH, 5:1 ]. Yield 47
% (0.042 g, 0.061 mmol). Rf = 0.47 [CHCl3/IPA incl. 2 % NH3 7 N in CH3OH, 5:1]. M.p. 151
°C. 1H-NMR (500 MHz, CDCl3/CD3OD 5:1): δꢀ = 1.22 (t, J ꢀ=ꢀ 7.5 Hz, 6 H), 1.25 (t, J = 7.5 Hz,
3 H), 2.25 (s, 6 H), 2.34 (s, 6 H), 2.77 (q, J ꢀ=ꢀ 7.0 Hz, 6 H), 4.01 (s, 1 H), 4.37 (s, 4 H), 4.69
(brs, 4 H), 4.72 (s, 2 H), 6.19 (s, 2 H), 6.36 (s, 2 H), 7.33 (dd, J ꢀ=ꢀ 7.7 Hz / 5.0 Hz, 1 H), 7.55 (s,
1 H), 7.85 (d, J = 7.7 Hz, 1 H), 8.40 (dd, J ꢀ=ꢀ 4.8 Hz / 1.4 Hz, 1 H), 8.60 (d, J ꢀ=ꢀ 1.4 Hz, 1 H).
13C-NMR (125 MHz, CDCl3): δꢀ16.4, 16.8, 21.2, 22.6, 22.8, 24.0, 38.3, 40.7, 43.3, 103.4, 113.6,
16
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113.7, 123.2, 132.1, 132.5, 134.9, 135.3, 135.7, 143.3, 143.5, 148.2, 149.1, 149.3, 151.6, 154.2,
156.6, 158.6, 159.7. HRMS (ESI): calcd for C41H51N10: 684.424517 [M+H]+; found:
684.424519.
1-{{2-[(Indol-3-yl)ethylamino]-9H-purin-6-yl}aminomethyl}-3,5-bis-[(4,6-dimethyl-
pyrimidin-2-yl)aminomethyl]-2,4,6-triethylbenzene (9). Procedure D. Compound 9 was
prepared from 3 (0.10 g, 0.16 mmol) and tryptamine (0.26 g, 1.36 mmol). Microwave irradiation
(160 W) was applied for 6 h at 170 °C. Purification was performed by column chromatography
[CHCl3/IPA incl. 2 % NH3 7N in CH3OH, 2:1]. Yield 42 % (0.05 g, 0.07 mmol). Mp 165 °C.
1H-NMR (500 MHz, CDCl3/CD3OD 5:1): δꢀ = 1.24 (t, J ꢀ=ꢀ 7.4 Hz, 6 H), 1.26 (t, J = 8.4 Hz, 3
H), 2.32 (s, 12 H), 2.80 (q, J ꢀ=ꢀ 7.4 Hz, 2 H), 2.82 (q, J ꢀ=ꢀ 7.3 Hz, 4 H), 3.14 (t, J ꢀ=ꢀ 6.8 Hz, 2
H), 3.79 (t, J ꢀ=ꢀ 6.4 Hz, 2 H), 3.95 (br s, 1 H), 4.60 (s, 4 H), 4.78 (s, 2 H), 6.39 (s, 2 H), 6.94 (s,
1 H), 7.06 (m, 1 H), 7.12 (s, 1 H), 7.15 (m, 1 H), 7.39 (d, J = 8.1 Hz, 1 H), 7.53 (br s, 1 H), 7.66
(d, J = 7.8 Hz, 1 H) ppm. 13C-NMR (125 MHz, CDCl3): δꢀ16.5, 16.6, 22.8, 23.0, 23.9, 25.4,
38.4, 39.9, 42.3, 43.3, 109.7, 111.2, 113.6, 115.1, 118.82, 119.2, 121.9, 122.0, 127.5, 132.3,
132.7, 134.4, 136.4, 143.7, 143.7, 151.9, 154.9, 159.9, 162.0, 167.6 ppm. HRMS (ESI): calcd
for C41H51N10: 738.446315 [M+H]+; found: 738.446317.
Acknowledgments. This work was supported by the Deutsche Forschungsgemeinschaft.
1
Supporting Information Available. Description of the H NMR titrations (Tables S1 and S2).
1
Representative mole ratio plots (Figures S1a-d). Copies of the H and 13C NMR spectra of
compounds 1-9 in CDCl3/CD3OD and CDCl3 (Figures S2 – S25).
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10.1002/ejoc.201901340
European Journal of Organic Chemistry
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Graphical Abstract
Key Topics: Artificial Carbohydrate Receptors, Molecular Recognition
Short Text: Representatives of 1,3,5-substituted 2,4,6-triethylbenzenes consisting of 2-chloro-
purin-6-yl group(s) have the ability to act both as carbohydrate-binding agents and as a basis for
the preparation of derivatives with a varying substituent pattern on the purine ring.
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