Compounds Based on a Triethyl- or Trimethoxybenzene Scaffold Bearing Pyrazole, Pyridine, and Pyrimidine Groups: Syntheses and Representative Binding Studies towards Carbohydrates

Article abstract of DOI:10.1055/s-2016-1561449

Pyrazole-based artificial receptors have often been used in the recognition of ions, but in the area of sugar recognition the potential of pyrazole-based recognition groups has only been rarely examined. In this paper we describe the syntheses of twelve n

Full text of DOI:10.1055/s-2016-1561449

SYNTHESIS
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
© Georg Thieme Verlag Stuttgart · New York
2016, 48, A–K
feature
A
N. Koch et al.
Feature
Synthesis
Compounds Based on a Triethyl- or Trimethoxybenzene Scaffold
Bearing Pyrazole, Pyridine, and Pyrimidine Groups: Syntheses and
Representative Binding Studies towards Carbohydrates
Niklas Koch
H2
Wilhelm Seichter
N
C
CH3
H
X =
Monika Mazik*
N
N
H
N
N
N
N
N
H
O
N
H
Institut für Organische Chemie, Technische Universität
Bergakademie Freiberg, Leipziger Straße 29, 09599 Freiberg,
Germany
H3C
O
H
NH
N
X2
H
O
O
O
Y =
N
H
CH3
O
H
H
H
monika.mazik@chemie.tu-freiberg.de
X1
N
N
Y
N
H
N
CH3
R
X3
Y
R
O
Y =
N
H
R
Y
N
H
Y =
R = CH2CH3, OCH3
Received: 05.03.2016
Accepted after revision: 04.04.2016
Published online: 15.06.2016
ceptor systems based on these five-membered heterocyclic
groups either alone or in combination with other recogni-
tion units, including for instance 2-aminopyridine or -py-
rimidine7 groups as heterocyclic analogues of the asparag-
ine/glutamine primary amide side chain, represents a use-
ful strategy for the development of biomimetic receptors
with interesting binding preferences. It should be noted
that pyrazole-based receptors have often been used in the
recognition of ions,8 but in the area of sugar recognition the
potential of pyrazole-based recognition groups has only
been rarely examined.5 In this paper, we describe the syn-
theses of twelve new pyrazole-bearing compounds that en-
force a tripodal architecture based on a triethyl- (com-
pounds 1–10) or trimethoxybenzene (compounds 11 and
12) scaffold, as shown in Figure 1. The 1,3,5-substituted
2,4,6-triethylbenzene scaffold was used for the construc-
tion of both the symmetrical pyrazole-bearing compounds
and the unsymmetrical substituted derivatives, including
both pyrazole- and pyridine/pyrimidine-based recognition
groups (compounds 2–5 and 7–10). The pyrazole groups
were connected to the central benzene ring through
-CH2NHCH2- (compounds 1–5 and 11) or -CONHCH2-
linkers (compounds 6–10 and 12). As shown in our previ-
ous studies, the nature of the recognition units as well as of
the aromatic platform and the connected bridges/linkers
strongly influence the ability of the acyclic compounds to
act as carbohydrate receptors.1d,g,9–11
DOI: 10.1055/s-2016-1561449; Art ID: ss-2015-t0160-fa
Abstract Pyrazole-based artificial receptors have often been used in
the recognition of ions, but in the area of sugar recognition the poten-
tial of pyrazole-based recognition groups has only been rarely exam-
ined. In this paper we describe the syntheses of twelve new pyrazole-
bearing compounds, which are all potentially applicable for use as car-
bohydrate receptors. The prepared compounds enforce tripodal archi-
tecture and are based on a triethyl- or trimethoxybenzene scaffold.
Representative complexation studies with selected carbohydrates
showed interesting binding preferences of the new compounds.
Key words tripodal receptors, pyrazole groups, carbohydrate recogni-
tion, triethylbenzene scaffold, trimethoxybenzene scaffold
Introduction
Studies on the molecular recognition of carbohydrates
by artificial receptors are of particular current interest and
involve the design of both biomimetic systems,1 using non-
covalent interactions for sugar binding, and systems with
non-natural bonding interactions (reversible covalent
bonds based on boronic acids).2 The design of biomimetic
receptors aims, among other things, to develop model sys-
tems that should help us to better understand the molecu-
lar details of carbohydrate-based recognition processes,
and to provide carbohydrate-binding agents that can be
used for the detection and treatment of diseases.
The participation of heterocyclic groups such as the im-
idazole ring of His and the indole ring of Trp in biorecogni-
tion of carbohydrates3 has inspired us to design artificial
carbohydrate receptors consisting of imidazole- and indole-
based recognition units.4 It was also shown by our group
that other five-membered heterocycles, such as pyrazole5
or pyrrole4b,6 groups, are also valuable building blocks for
carbohydrate receptors. The construction of different re-
To compare the binding properties of the new com-
pounds with those of the previously studied tripodal deriv-
atives, octyl β-D-glucopyranoside and β-D-galactopyrano-
side were selected as substrates for the initial binding stud-
ies toward carbohydrates. The suitability of the pyrazole
groups to act as recognition units for carbohydrates as well
as the expected differences in the binding ability of ana-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–K

B
N. Koch et al.
Feature
Synthesis
logues incorporating either -CH2NHCH2- or -CONHCH2-
linkers were confirmed by the results of H NMR spectro-
scopic titrations.
tively. The conversion of 21/22 into the corresponding bis-
amines 25/26 was carried out via Gabriel synthesis, where-
as compounds 23/24 could be easily converted into the
amino derivatives 27/28 by treatment with a solution of
ammonia in methanol. Condensation of the mono- and bis-
amines 25–28 with carbaldehyde 18 provided the corre-
sponding imines 29–32, which were reduced with sodium
borohydride to give the target molecules 2–5, bearing one
(compounds 4 and 5) or two pyrazole groups (compounds 2
and 3) attached to the central benzene ring through a
-CH2NHCH2- unit. The reaction of 25–28 with 5-methyl-
1H-pyrazole-3-carboxylic acid (19) yielded the products 7–
10 with one (compounds 9 and 10) or two pyrazole groups
(compounds 7 and 8) connected to the central benzene ring
through a -CONHCH2- linker.
1
Syntheses of Compounds 1–12
The syntheses of compounds 1–10 started from 1,3,5-
tris(bromomethyl)-2,4,6-triethylbenzene (13) and are sum-
marized in Scheme 1. The reaction of 13 with potassium
phthalimide gave 16, which was converted into 1,3,5-
tris(aminomethyl)-2,4,6-triethylbenzene (17) by treatment
with hydrazine hydrate. Compound 17 was the starting
point for the synthesis of the symmetrical target molecules
1 and 6. The latter was prepared in 78% yield by reaction of
17 with 5-methyl-1H-pyrazole-3-carboxylic acid (19). The
condensation of 17 with 5(3)-methyl-1H-pyrazole-3(5)-
carbaldehyde (18) provided imine 20, which was further
reduced with sodium borohydride to give the product 1.
The reaction of 13 with 2-amino-4,6-dimethylpyridine (14)
or 2-amino-4,6-dimethylpyrimidine (15) provided the mo-
no- and disubstituted products 21/22 and 23/24, respec-
The basis for the synthesis of the symmetrical pyrazole-
bearing compounds 11 and 12, incorporating the trimeth-
oxybenzene scaffold, was 1,3,5-tris(aminomethyl)-2,4,6-
trimethoxybenzene (36),4c the preparation of which started
Biographical Sketches
Niklas Koch studied chemistry
at the Leibniz University of Han-
nover and the Technical Univer-
Monika Mazik in the field of mo-
lecular recognition, focusing on
the design and syntheses of ar-
tificial receptors for molecules
of biological relevance, and ob-
tained his Ph.D. in organic
chemistry at the Technical Uni-
versity of Freiberg (Germany) in
2014. Since 2015 he has been
working at Sulfotools GmbH in
Darmstadt (Germany) as a re-
search chemist on the develop-
ment of modified building
blocks and amino acids for
water-based peptide synthesis.
sity
of
Braunschweig
(Germany), where he received
his diploma degree in chemistry
in 2010. Afterwards he worked
under the supervision of Prof.
Wilhelm Seichter received his
diploma degree in organic
chemistry from the University
of Bonn (Germany). In the re-
search group of Prof. Edwin We-
ber, he obtained his Ph.D. in
1989. He moved to the Techni-
cal University of Freiberg (Ger-
many) in 1993. Currently he is
working in the research group
of Prof. Monika Mazik on struc-
tural characterization of artifi-
cial receptors and other
supramolecular systems.
Monika Mazik received her
Ph.D. in chemistry from the
Silesian Technical University at
Gliwice, and undertook post-
doctoral work with Prof. Reiner
Sustmann at the University of
Essen (Germany). After post-
doctoral research, she worked
on her habilitation (1998–2000)
at the University of Essen. In
2002 she became Professor at
the Technical University of
Braunschweig (Germany), and
since 2011 she has been Profes-
sor at the Technical University
of Freiberg and Director of the
Institute of Organic Chemistry.
Her research interests include
the design and synthesis of re-
ceptors for molecular recogni-
tion of biorelevant molecules,
self-assembly of organic com-
pounds, crystal engineering,
synthesis of heterocycles, as
well as the development of anti-
infective agents.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–K

C
N. Koch et al.
Feature
Synthesis
NH2
Br
b
NH2
a
Br
O
O
N
O
O
N
H2N
Br
13
17
O
14: X = C
15: X = N
X
16
N
f
H2N
N
O
O
O
c
d
OH
X
HN
N
HN
N
18
19
Br
X
N
NH
X
NH
N
N
H
N
+
N
N
6
H
21: X = C
22: X = N
23: X = C
24: X = N
N
Br
Br
N
N
h
NH
g
N
X
NH2
X
N
20
N
NH
X
N
N
H
HN
N
N
e
H
25: X = C
26: X = N
27: X = C
28: X = N
H2N
H2N
1
O
O
O
k
O
i
OH
OH
HN
N
HN
N
j
19
HN
N
18
l
19
HN
N
18
9: X = C
10: X = N
7: X = C
8: X = N
NH
N
X
N
NH
X
N
X
N
N
N
N
H
H
N
N
29: X = C
30: X = N
31: X = C
32: X = N
N
HN
N
HN
n
m
4: X = C
5: X = N
2: X = C
3: X = N
Scheme 1 Reagents and conditions: (a) potassium phthalimide (4.5 equiv), DMSO, 95 °C, 8 h (82%); (b) hydrazine hydrate, EtOH/PhMe, reflux, 19 h,
KOH (85%); (c) 5(3)-methyl-1H-pyrazole-3(5)-carbaldehyde (18; 6 equiv), THF, 4 d; (d) 5-methyl-1H-pyrazole-3-carboxylic acid (19; 3.3 equiv), HOB-
t·H2O, EDCI·HCl, DIPEA; DMF (78% of 6); (e) NaBH4 (9 equiv), 0 °C to r.t., 3 h (36% of 1); (f) 2-amino-4,6-dimethylpyridine (14; 2 equiv) or 2-amino-4,6-
dimethylpyrimidine (15; 2 equiv), THF/MeCN, K2CO3, r.t., up to 4 d (25% of 21, 19% of 23, 16% of 22, 20% of 24); (g) potassium phthalimide (3 equiv),
DMSO, 90 °C, 8–18 h; hydrazine hydrate, EtOH/PhMe, 90 °C (45% of 25, 58% of 26); (h) NH3 (7 N in MeOH), 2 d (82% of 27, 76% of 28); (i) 5-methyl-1H-
pyrazole-3-carboxylic acid (19; 2.2 equiv), HOBt·H2O, EDCI·HCl, DIPEA, DMF (53% of 7, 85% of 8); (j) 5(3)-methyl-1H-pyrazole-3(5)-carbaldehyde (18; 4
equiv), MeOH, 4 d; (k) 5-methyl-1H-pyrazole-3-carboxylic acid (19; 1.1 equiv), HOBt·H2O, EDCI·HCl, DIPEA, DMF (57% of 9, 73% of 10); (l) 5(3)-methyl-
1H-pyrazole-3(5)-carbaldehyde (18; 2 equiv), MeOH, 4 d; (m) NaBH4 (6 equiv), 0 °C to r.t., 3 h (65% of 2, 55% of 3); (n) NaBH4 (3 equiv), 0 °C to r.t., 3 h (87%
of 4, 98% of 5).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–K

D
N. Koch et al.
Feature
Synthesis
X
X
HN
X
HN
N
HN
N
N
NH
N
H
N
N
N
H
N
H
HN
N
HN
NH
NH
NH
N
N
X
N
NH
NH
1
NH
2: X = C
3: X = N
4: X = C
5: X = N
O
O
O
HN
X
HN
X
HN
N
N
N
NH
NH
N
N
N
H
N
N
H
H
N
HN
NH
NH
NH
N
N
N
O
O
NH
NH
O
NH
6
9: X = C
7: X = C
8: X = N
10: X = N
O
O
HN
O
O
O
O
HN
N
N
NH
NH
N
H
N
H
N
N
HN
HN
O
O
O
NH
NH
N
N
NH
NH
11
12
Figure 1 Structures of the new pyrazole-bearing compounds 1–12
from 1,3,5-trimethoxybenzene (33),12 as shown in Scheme
2. Compounds 11 and 12 were prepared by the reaction of
36 with 5(3)-methyl-1H-pyrazole-3(5)-carbaldehyde (18)
or 5-methyl-1H-pyrazole-3-carboxylic acid (19), respec-
tively.
molecular branches are arranged on the same side of the
central aromatic ring, whereas the ethyl groups are orient-
ed to the opposite side. A perspective view of the molecular
structure including atom labeling and ring specification (A–
D) is depicted in Figure 2.
The 5(3)-methyl-1H-pyrazole-3(5)-carbaldehyde (18),
used for the synthesis of 1–5 and 11, was prepared accord-
ing to a reported procedure,13 which was slightly modified
(see Scheme 3). Instead of hydrazine sulfate and aqueous
NaOH, hydrazine hydrate was used for the synthesis of
5(3)-diethoxymethylen-3(5)-methylpyrazole (40) (cycliza-
tion step b, Scheme 3). The reaction was carried out in a tol-
uene/methanol mixture and, after simple evaporation of
the solvents, compound 40 was obtained and directly con-
verted into the corresponding carbaldehyde in excellent
yield. This modification significantly simplified the synthe-
sis of 18.
Intramolecular hydrogen bonding is restricted to one
weak C–H···N contact with the nitrogen N(8) acting as an
acceptor [d(H···N) 2.59Å; see Figure 2 a]. The receptor mole-
cule exists in a less symmetric conformation. Although the
pyrimidine rings are nearly orthogonal [80.5(1), 87.9(1)°]
with regard to the benzene ring, the aminomethyl-pyrazole
moiety shows a strong twist, which is reflected by a torsion
angle of 54.7(2)° for the atomic sequence N(7)-C(28)-C(29)-
N(8) (see Figure 2 a). This value is correlated with a dihe-
dral angle of 54.9(1)° between the rings A and D. The basic
supramolecular entity of the crystal structure is represent-
ed by an inversion symmetric 2:2 host-guest (2 × 5∙CHCl3)
complex (Figure 3) held together by N–Hpyrazole···Npyrimidine
[N(9)–H(9)···N(2) 2.06(1) Å, 154(2)°] and N–Hamine···Npyrazole
hydrogen bonds [N(1)–H(1)···N(8) 2.14(1) Å, 162(2)°] (see
Figure 3 c and Tables S1–S3 in the Supporting Information).
Crystal Structure of 5
Crystallization of the tripodal compound 5, consisting of
one pyrazole and two pyrimidine groups, from CHCl3 gave a
1:1 solvent complex with triclinic space group P-1 (Z = 2).
In the solid-state structure, the heterocyclic rings of the
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–K

E
N. Koch et al.
Feature
Synthesis
O
O
O
O
Br
O
O
O
a
b
O
a
Br
b
O
O
O
O
O
O
38
39
Br
33
34
O
O
c
O
O
O
NH2
O
O
N
N
O
O
N
H
N
H2N
c
N
N
H
40
18
O
O
O
O
O
Scheme 3 Reagents and conditions: (a) acetone, NaH, PhMe/MeOH,
10 °C, 1 h (53%); (b) hydrazine hydrate, EtOH/PhMe, r.t., 12 h; (c) HCl
(1% solution), r.t., 24 h (96%).
NH2
36
N
35
O
O
For steric reasons, the amino hydrogen H(7) is excluded
from hydrogen bonding. In this complex, the solvent mole-
cules are associated through a relatively strong C–H···π bond
to the pyrazole ring [C(1A)–H(1A)···centroid(D) 2.48Å, 147°;
see Figure 2 a]. A view of the crystal structure along the a-
axis reveals that the molecular complexes are stacked in a
columnar fashion. Because of the hydrophobic surface of
the dimeric units, no directed noncovalent bonds are pres-
ent between them, neither in the direction of the stacking
axis (see Figure 4) nor along the other crystallographic
axes. Consequently, the stacking structure appears to be
primarily stabilized by van der Waals forces.
O
d
e
OH
HN
N
HN
N
19
18
11
12
Scheme 2 Reagents and conditions: (a) paraformaldehyde, HBr (33% in
HOAc), 70 °C, 3 h (29%); (b) potassium phthalimide (4.5 equiv), DMSO,
100 °C, 21 h (39%); (c) hydrazine hydrate, EtOH/PhMe, reflux, 20 h
(38%); (d) 5(3)-methyl-1H-pyrazol-3-carbaldehyde (18; 6 equiv), MeOH
(up to 4 d); NaBH4 (9 equiv), 0 °C to r.t., 4 h (64% of 11); (e) 5-methyl-
1H-pyrazole-3-carboxylic acid (19; 1.1 equiv), HOBt × H2O, EDCI × HCl,
DIPEA, DMF (54% of 12).
Representative Binding Studies
The complexation of selected carbohydrates by com-
pounds 2 and 7, consisting of one aminopyrimidine moiety
and two pyrazole groups attached to the central benzene
ring through -CH2NHCH2- or -CONHCH2- units, was investi-
1
gated by H NMR spectroscopic titrations in CDCl3. The ti-
tration experiments were carried out by addition of in-
creasing amounts of the tested carbohydrate, such as octyl
β-D-glucoside (37) and octyl β-D-galactoside (38), to a solu-
tion of the corresponding receptor. The complexation be-
tween the binding partners was evidenced by several
changes in the NMR spectra, as exemplified in the Support-
ing Information (Figure S1). The titration data were ana-
lyzed by using the WinEQNMR14 and HypNMR programs15
(representative plots are given in the Supporting Informa-
tion).
Our previous studies showed that the combination of
one 2-aminopyridine group with two imidazole4a units at-
tached to the benzene ring through -CH2NHCH2- linkers
represents a particularly valuable architecture for the rec-
ognition of β-glucoside and β-galactoside (K11> 100000 M–1
in CDCl3). The new pyrazole analogue 2 was established as
an effective receptor for the selected monosaccharides, but
less powerful than the previously studied imidazole-bear-
ing derivative (see Figure 5); for a discussion on hydrogen
bond basicity of nitrogen bases, including imidazole, 3-/5-
methylpyrazole (tautomeric forms) and other heterocycles,
see key references.16–18 The interactions of 2 with β-gluco-
Figure 2 (a) Perspective view of the 1:1 complex unit of 5 with CHCl3.
Thermal ellipsoids are drawn at the 50% probability level. Blue ellipsoids
represent nitrogen, green ellipsoids chlorine atoms. (b) Schematic rep-
resentation of the ababab conformation of 5 (a = above, b = below; for a
recent analysis of the conformations of pyrazole-bearing hexa-substi-
tuted benzene derivatives, see Koch et al.8f)
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–K

F
N. Koch et al.
Feature
Synthesis
Figure 3 (a) Packing excerpt of the crystal structure 5·CHCl3 (1:1). Blue circles represent nitrogen, green circles chlorine atoms. Hydrogen bonds are
marked as broken lines, C–H···π interactions as broken double lines. (b) Structure of the dimeric complex unit (2 × 5·CHCl3). (c) N–H···N hydrogen
bonds in the dimeric unit CHCl3·5 × 5·CHCl3
based receptor bearing three aminopyridine groups,7a,c but
its affinity toward β-galactoside was determined to be
stronger.
The replacement of the two -CH2NHCH2- bridges (as in
2) by -CONHCH2- units (as in 7) caused a significant de-
crease in the binding constants for the tested glycosides
(see Table 1 and Figure 6).
Table 1 Association Constantsa,b for Receptors 2 and 7 and Octyl Gly-
cosides 37 and 38
Receptor / substrate
K
11 / K12c or K21d [M–1
]
β12 or β21 [M–2
]
Figure 4 Space filling model of the stacking structure of the 2:2 com-
plex units (2 × 5·CHCl3). Nitrogen atoms are displayed as blue, chlorine
atoms as green circles
2 / β-glucoside 37
2 / β-galactoside 38
7 / β-glucoside 37
7 / β-galactoside 38
11 / β-glucoside 37
41000 / 90d
11800 / 135c
2240 / 110c
1290 / 140c
1950 / 80c
3.99 × 106
1.59 × 106
2.46 × 105
1.81 × 105
1.56 × 105
side 37 (K11 = 41000 M–1, K21 = 90 M–1; see Table 1) were
found to be more favorable than those with β-galactoside
38 (K11 = 11800 M–1, K12 = 135 M–1). The difference in the
complexation ability of 2 toward the two glycosides is
clearly visible by consideration of the complexation-
induced chemical shifts of the receptor signals after the ad-
dition of β-glucoside or β-galactoside, as illustrated in the
Supporting Information (Figures S1a and S1b). In the case
of the imidazole-bearing analogue, the binding preference
was reversed (preference for β-galactoside over β-gluco-
side). A preference for β-galactoside 38 over β-glucoside 37
was also observed in the case of the previously described 8-
hydroxyquinoline-bearing analogue (see Figure 5).9b It
should also be noted that 2 was found to be similar in affin-
ity toward β-glucoside to the symmetrical triethylbenzene-
a Average Ka values from multiple titrations.
b Errors were estimated at ≤10%.
c K12 corresponds to 1:2 receptor–sugar association constant titrations.
d K21 corresponds to 2:1 receptor–sugar association constant.
Compound 7 proved to be a less powerful receptor,
showing only a slight preference for β-glucoside over β-ga-
lactoside. According to the molecular modeling calcula-
tions, the geometry of 7 does not allow the pyrazole nitro-
gen atoms to participate in the binding process (see Figure
S10). In contrast, favorable interactions with the sugar sub-
strate are possible in the case of compound 2 (see Figure 7).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–K

G
N. Koch et al.
Feature
Synthesis
N
N
N
X =
N
H
H
N
N
N
N
H
OH
N
N
N
N
H
X
HN
binding affinity
X
β-Glucopyranoside
N
HN
β-Gal vs β-Glc
binding preference
β-Glc vs β-Gal
binding preference
NH
N
N
N
X =
N
N
N
H
H
N
N
OH
binding affinity
β-Galactopyranoside
Figure 5 Schematic illustration of the binding preferences of tripodal triethylbenzene-based receptors bearing different heterocyclic groups [unit X:
3(4)-substituted imidazole,4a 8-hydroxyquinoline,9b 4,6-dimethylpyridine,7c 3(5)-substituted 5(3)-methyl-1H-pyrazole, and 3-substituted 1-methylpyra-
zole5 groups] toward β-glucoside 37 and β-galactoside 38
Binding studies with the symmetrical pyrazole-bearing
compound 11, consisting of a trimethoxybenzene core and
-CH2NHCH2- bridges, revealed a relatively low binding af-
finity of 11 toward β-glucoside 37. As discussed in our pre-
vious work,4c the formation of intramolecular19 N–H···OCH3
hydrogen bonds (in the case of 11, both N–H···OCH3 and
pyrazole–NH···N-pyrazole hydrogen bonds, see Figure S11)
and a less favorable degree of preorganization than in the
case of the triethylbenzene-based systems adversely affect
the binding properties of the trimethoxybenzene-based
compounds.
and 7–10), were prepared and used for representative bind-
ing studies toward selected carbohydrates. Concerning the
syntheses of different precursors, the simplification of the
synthesis of 5(3)-methyl-1H-pyrazole-3(5)-carbaldehyde is
worthy of particular mention.
Conclusion
Tripodal triethylbenzene- or trimethoxybenzene-based
compounds 1–12, incorporating pyrazole groups either
alone (compounds 1, 6, 11 and 12) or in combination with
2-aminopyridine or -pyrimidine groups (compounds 2–5
H
N
N
H
N
N
Y
N
Y
NH
O
N
H
Y =
N
H
binding affinity
Figure 7 (a) Energy-minimized structure of the 1:1 complex formed
between 2 and methyl β-glucopyranoside (MacroModel V.9.8,
OPLS_2001 force field, MCMM, 50000 steps. Color code: receptor N,
blue; receptor C, gray; the sugar molecule is highlighted in orange). (b)
Examples of O–H·N, N–H·O and C–H·N hydrogen bonds in the 1:1 com-
plex.
β-Glucopyranoside
Figure 6 Schematic illustration of the binding strength of the meth-
ylpyrazole-bearing compounds 2 and 7 toward β-glucoside: increase in
binding affinity through replacement of the -CONHCH2- by the
-CH2NHCH2- units (unit Y).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–K

H
N. Koch et al.
Feature
Synthesis
The heterocyclic building blocks of compounds 1–12 (in
the case of 2–5 and 7–10 a combination of two types of het-
erocyclic groups) are able to act as recognition groups for
carbohydrates through participation in the formation of
both hydrogen bonds and CH–π interactions with a carbo-
hydrate substrate. It should be noted that the combination
of different types of recognition groups represents an effec-
tive binding strategy that is used by carbohydrate-binding
proteins and was also established by our previous studies
as a particularly valuable strategy for the construction of
powerful carbohydrate receptors. The connection between
the pyrazole groups and the central benzene ring was
realized by using -CH2NHCH2- (compounds 1–5 and 11) or
-CONHCH2- units (compounds 6–10 and 12), which are also
able to participate in the formation of hydrogen bonds. The
binding studies showed the suitability of the methylpyra-
zole-bearing compounds to act as carbohydrate receptors
and revealed the expected strong differences in binding af-
finity between the analogues consisting of either -CH2NHCH2-
or -CONHCH2- bridges. The previously observed relatively
low binding affinity of different trimethoxybenzene-based
compounds toward carbohydrates,4c,7a was also observed in
this study. The present studies allowed the identification of
interesting structure–activity relationships, which repre-
sent a valuable addition to results provided in our previous
studies. The design of artificial carbohydrate receptors with
predictable binding strength and selectivity20 constitutes
an enormous challenge. In this context, the identification of
characteristic structural features, having the ability to in-
fluence the binding properties in a predictable way, is of
particular importance.
1H NMR (400 MHz, CDCl3): δ = 6.50 (s, 1 H), 4.81 (s, 1 H), 3.54–3.76
(m, 4 H), 2.12 (s, 3 H), 1.25 (t, J = 7.1 Hz, 6 H).
13C NMR (100 MHz, CDCl3): δ = 192.46, 187.52, 99.49, 97.48, 62.22,
24.91, 14.87.
MS (EI, 70 eV): m/z = 103 [M – C4H5O2]+, 75 [M – C6H11O2]+.
5(3)-Diethoxymethylen-3(5)-methylpyrazole (40)
To a mixture of 1,1-diethoxy-2,4-pentandione (39; 1.00 g, 5.31 mmol)
in toluene–EtOH (2:1, 12 mL) at 0 °C, hydrazine hydrate (0.40 mL,
5.31 mmol; 64% solution) was added and the reaction mixture was
stirred for 12 h at r.t. The solvent was then removed and the resulting
yellow oil was used in the next step without further purification.
1H NMR (200 MHz, CDCl3): δ = 6.10 (s, 1 H), 5.59 (s, 1 H), 3.49–3.72
(m, 4 H), 2.30 (s, 3 H), 1.15–1.31 (m, 6 H).
5(3)-Methyl-3(5)-pyrazolecarbaldehyde (18)13b
5(3)-Diethoxymethylen-3(5)-methylpyrazole (40) was dissolved in
1% HCl (5 mL) and stirred for 24 h at r.t. The resulting precipitate was
filtered off and washed with distilled H2O (10 mL) and MeOH (10 mL)
and dried under vacuum.
Yield: 96% (0.56 g, 5.10 mmol); beige-colored solid; mp 177 °C.
1H NMR (400 MHz, DMSO-d6 + a drop of CF3COOD): δ = 9.98 (s, 1 H),
6.82 (s, 1 H), 2.52 (s, 3 H).
13C NMR (100 MHz, DMSO-d6 + a drop of CF3COOD): δ = 187.00,
151.26, 141.69, 103.73, 10.56.
MS (EI, 70 eV): m/z = 110 [M]+, 82 [M – CO]+, 67 [M – C2H4O]+, 53 [M –
CH2ON2]+.
Syntheses of 1–5 and 11; General Procedure
To a suspension of 5-methyl-1H-pyrazole-3-carbaldehyde (18; 2–6
equiv) in anhydrous THF (10 mL) (in the case of the synthesis of 1) or
MeOH (in the case of the synthesis of 2–5 and 11), the corresponding
derivative bearing one to three amino groups (17,21 25–289d,11 or 36,4c
see Scheme 1 and Scheme 2) (1 equiv), dissolved in anhydrous MeOH
(5 mL), was added. The resulting mixture was heated at reflux until a
clear solution resulted and then stirred at r.t. (up to 4 days, TLC analy-
sis). The resulting imines were reduced without further purification
by addition of NaBH4 (3–9 equiv) in portions. After complete addition
of the reducing agent, the reaction mixture was stirred for 24 h at r.t.
and then the solvent was removed under reduced pressure. The resi-
due was suspended in CHCl3–H2O (1:1, 10 mL) and stirred for 12 h at
r.t. The resulting suspension was extracted with CHCl3 (3 × 20 mL),
dried over MgSO4, and the solvent was removed. The crude product
was purified by column chromatography.
Analytical TLC was performed on commercial Merck plates coated
with silica gel (TLC Silica Gel 60 F254) and the silica gel used for flash
chromatography was Merck Kieselgel 60. Melting points are uncor-
rected.
1,1-Diethoxy-2,4-pentandione (39)13b
Under a nitrogen atmosphere, NaH (60% in mineral oil, 6.16 g, 0.15
mol) was added to a mixture of anhydrous toluene–MeOH (75:6, 81
mL) and cooled to –10 °C. A mixture of ethyl diethoxyacetate (38;
25.00 mL, 0.14 mol) and acetone (10.32 mL, 0.14 mol) was added
dropwise over a period of 3 h at this temperature. The reaction mix-
ture was then stirred at a temperature lower than 10 °C for 1 h and
then left overnight in the refrigerator at 10 °C. Under ice-cooling, the
mixture was poured into a mixture of glacial acetic acid–H2O (1:1, 40
mL). The resulting suspension was clarified by addition of Et2O and
the phases were separated. The aqueous layer was extracted with
Et2O (3 × 30 mL) and the combined organic phases were washed with
H2O (30 mL), aq NaHCO3 (until the organic phase was free from acid),
and again with H2O (20 mL). After drying over Na2SO4, the solvent was
removed and the crude product was distilled under reduced pressure.
1,3,5-Tris[(5-methyl-1H-pyrazol-3-yl-methyl)aminomethyl]-2,4,6-
triethylbenzene (1)
Obtained after purification by column chromatography (CHCl3–
MeOH, 1:2 v/v; incl. 1% 7 M NH3 in MeOH, Rf = 0.45).
Yield: 36% (0.15 g, 0.29 mmol); pale-yellow solid; mp 103 °C.
1H NMR (300 MHz, CDCl3): δ = 5.94 (s, 3 H), 3.78 (s, 6 H), 3.58 (s, 6 H),
2.42–2.60 (m, 6 H), 2.23 (s, 9 H), 1.00 (t, J = 7.0 Hz, 9 H).
13C NMR (75 MHz, CDCl3): δ = 142.24, 133.65, 103.82, 46.38, 45.98,
22.30, 16.69, 12.15.
HRMS (ESI): m/z [M + H]+ calcd for C30H46N9: 532.38707; found:
Yield: 53% (13.97 g, 74.25 mmol); light-yellow oil; bp 55 °C/0.18 mbar.
532.38738.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–K

I
N. Koch et al.
Feature
Synthesis
1-[(4,6-Dimethylpyridin-2-yl)aminomethyl]-3,5-bis[(5-methyl-
1H-pyrazol-3yl-methyl)-aminomethyl]-2,4,6-triethylbenzene (2)
1H NMR (400 MHz, CDCl3): δ = 6.31 (s, 2 H), 6.02 (s, 1 H), 5.96 (br s,
1 H), 4.52 (d, J = 3.8 Hz, 4 H), 3.79 (s, 2 H), 3.67 (s, 2 H), 2.75 (q, J =
7.5 Hz, 2 H), 2.64 (q, J = 7.2 Hz, 4 H), 2.31 (s, 12 H), 2.29 (s, 3 H), 1.19
(t, J = 7.4 Hz, 3 H), 1.12 (t, J = 7.2 Hz, 6 H).
13C NMR (100 MHz, CDCl3): δ = 167.33, 161.90, 143.52, 132.55,
109.36, 103.91, 46.22, 39.88, 24.00, 23.12, 22.63, 16.65, 11.73.
Obtained after purification by column chromatography (CHCl3–
MeOH, 7:1 v/v; incl. 1% 7 M NH3 in MeOH, Rf = 0.17).
Yield: 65% (0.20 g, 0.37 mmol); white solid; mp 154 °C.
1H NMR (400 MHz, CDCl3): δ = 6.32 (s, 1 H), 6.05 (s, 1 H), 5.98 (s, 2 H),
4.72 (br s, 1 H), 4.28 (d, J = 3.7 Hz, 2 H), 3.84 (s, 4 H), 3.67 (s, 4 H), 2.66
(q, J= 7.3 Hz, 4 H), 2.56 (q, J = 7.3 Hz, 2 H), 2.36 (s, 3 H), 2.27 (s, 6 H),
2.22 (s, 3 H), 1.14 (t, J = 7.4 Hz, 6 H), 1.04 (t, J =7.0 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 158.42, 156.59, 148.73, 142.92,
142.67, 134.00, 132.48, 113.56, 103.74, 103.36, 46.61, 46.57, 40.59,
30.95, 24.16, 22.69, 22.38, 21.15, 16.81, 16.74.
HRMS (ESI): m/z [M + H]+ calcd for C32H46N9: 556.38707; found:
556.38722.
Anal. Calcd for C32H45N9: C, 69.16; H, 8.16; N, 22.68. Found: C, 68.78;
H, 8.44; N, 22.43.
1,3,5-Tris[(5-methyl-1H-pyrazol-3-yl-methyl)aminomethyl]-2,4,6-
trimethoxybenzene (11)
HRMS (ESI): m/z [M + H]+ calcd for C32H47N8: 543.39182; found:
Obtained after purification by column chromatography (CHCl3–
543.39205.
MeOH, 5:1 v/v; incl. 1% 7 M NH3 in MeOH, Rf = 0.12).
Anal. Calcd for C32H46N8: C, 70.81; H, 8.54; N, 20.65. Found: C, 70.40;
H, 8.77; N, 20.53.
Yield: 64% (0.14 g, 0.26 mmol); white solid; mp 182 °C.
1H NMR (600 MHz, CDCl3): δ = 5.96 (s, 3 H), 3.80 (s, 6 H), 3.68 (s, 6 H),
1-[(4,6-Dimethylpyrimidin-2-yl)aminomethyl]-3,5-bis[(5-methyl-
2.25 (s, 9 H).
1H-pyrazol-3yl-methyl)aminomethyl]-2,4,6-triethylbenzene (3)
13C NMR (150 MHz, CDCl3): δ = 158.57, 122.90, 103.52, 62.41, 44.72,
Obtained after purification by column chromatography (CHCl3–
42.21, 12.26.
MeOH, 2:1 v/v; incl. 2% 7 M NH3 in MeOH, Rf = 0.84).
HRMS (ESI): m/z [M + H]+ calcd for C27H40N9O3: 538.32486; found:
Yield: 55% (0.22 g, 0.40 mmol); beige-colored solid; mp 191 °C.
538.32516.
1H NMR (400 MHz, CDCl3): δ = 6.32 (s, 1 H), 5.98 (s, 2 H), 4.49 (d, J =
3.8 Hz, 2 H), 3.82 (s, 4 H), 3.64 (s, 4 H), 2.66 (q, J = 7.5 Hz, 4 H), 2.47 (q,
J = 7.2 Hz, 2 H), 2.32 (s, 6 H), 2.27 (s, 6 H), 1.11 (t, J = 7.4 Hz, 6 H), 0.98
(t, J = 7.1 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 167.39, 161.87, 142.94, 132.49,
109.43, 103.87, 46.37, 46.12, 39.85, 23.97, 22.78, 22.42, 16.69, 12.08.
Syntheses of Compounds 6–10 and 12; General Procedure
To a solution of 5-methyl-1H-pyrazole-3-carboxylic acid (19; 1.1–3.3
equiv) in DMF (5 mL) were added EDCI·HCl (1.1–3.3 equiv), HOBt·H2O
(1.1–3.3 equiv) and DIPEA (1.1–3.3 equiv) at 0 °C and the resulting
mixture was stirred at this temperature for 30 min. The correspond-
ing derivative bearing one to three amino groups (17, 25–28 or 36; 1
equiv), dissolved in DMF (1 mL), was added and the reaction mixture
was stirred for 48 h at r.t. After this time, the reaction mixture was
poured into ice-water (30 mL) and the formed precipitate was filtered
off and washed thoroughly with small amounts of distilled H2O to
free it from DMF. After drying in a dessicator, the desired products
were obtained as white solids.
HRMS (ESI): m/z [M + H]+ calcd for C31H46N9: 544.38707; found:
544.38737.
Anal. Calcd for C31H45N9: C, 68.46; H, 8.34; N, 23.18. Found: C, 68.07;
H, 8.57; N, 23.43.
1,3-Bis[(4,6-dimethylpyridin-2-yl)aminomethyl]-5-[(5-methyl-
1H-pyrazole-3-yl-methyl)aminomethyl]-2,4,6-triethylbenzene (4)
Obtained after purification by column chromatography (CHCl3–
1,3,5-Tris[(5-methyl-1H-pyrazol-3-yl-carbonyl)aminomethyl]-
MeOH, 7:1 v/v; incl. 1% 7 M NH3 in MeOH, Rf = 0.35).
2,4,6-triethylbenzene (6)
Yield: 87% (0.21 g, 0.38 mmol); light-yellow solid; mp 189 °C.
Yield: 78% (0.11 g, 0.19 mmol); white solid; mp 178 °C (dec.).
1H NMR (400 MHz, CDCl3): δ = 6.32 (s, 2 H), 6.07 (s, 2 H), 5.99 (s, 1 H),
5.09 (br s, 2 H), 4.31 (d, J = 3.9 Hz, 4 H), 3.80 (s, 2 H), 3.67 (s, 2 H), 2.75
(q, J= 7.4 Hz, 2 H), 2.63 (q, J= 7.1 Hz, 4 H), 2.37 (s, 6 H), 2.29 (s, 3 H),
2.23 (s, 6 H), 1.20 (t, J= 7.5 Hz, 3 H), 1.14 (t, J= 7.4 Hz, 6 H).
13C NMR (100 MHz, CDCl3): δ = 158.43, 156.56, 148.67, 143.46,
142.84, 134.28, 113.49, 103.85, 103.45, 46.58, 46.40, 40.62, 24.19,
23.01, 22.54, 21.17, 16.84, 16.75.
1H NMR (400 MHz, CD3OD): δ = 6.50 (s, 3 H), 4.65 (s, 6 H), 2.85 (q, J =
7.5 Hz, 6 H), 2.29 (s, 9 H), 1.20 (t, J =7.5 Hz, 9 H).
13C NMR (100 MHz, CD3OD): δ = 164.63, 147.88, 145.72, 142.02,
133.02, 105.52, 38.75, 24.05, 16.67, 10.48.
HRMS (ESI): m/z [M + H]+ calcd for C30H40N9O3: 574.32486; found:
574.32506.
HRMS (ESI): m/z [M + H]+ calcd for C34H48N7: 554.39657; found:
554.39617.
1-[(4,6-Dimethylpyridin-2-yl)aminomethyl]-3,5-bis[(5-methyl-
1H-pyrazol-3-yl-carbonyl)aminomethyl]-2,4,6-triethylbenzene (7)
Anal. Calcd for C34H47N7: C, 73.74; H, 8.55; N, 17.70. Found: C, 73.37;
H, 8.46; N, 17.63.
Yield: 53% (0.12 g, 0.20 mmol); white solid; mp 211 °C.
1H NMR (400 MHz, CDCl3): δ = 7.05 (br s, 1 H), 6.53 (s, 2 H), 6.34 (s,
1 H), 6.22 (s, 1 H), 4.54 (s, 4 H), 4.27 (s, 2 H), 2.57–2.81 (m, 6 H), 2.33
(s, 3 H), 2.27 (s, 3 H), 2.16 (s, 6 H), 1.08–1.22 (m, 9 H).
13C NMR (100 MHz, CDCl3): δ = 162.43, 144.00, 131.59, 113.95,
105.04, 104.02, 40.71, 37.81, 23.08, 22.85, 16.37, 16.27, 14.13, 10.97.
1,3-Bis[(4,6-dimethylpyrimidin-2-yl)aminomethyl]-5-[(5-methyl-
1H-pyrazol-3-yl-methyl)aminomethyl]-2,4,6-triethylbenzene (5)
Obtained after purification by column chromatography (CHCl3–
MeOH, 5:1 v/v, Rf = 0.42).
HRMS (ESI): m/z [M + H]+ calcd for C32H43N8O2: 571.35035; found:
571.35063.
Yield: 98% (0.10 g, 0.18 mmol); yellow solid; mp 196 °C.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–K

J
N. Koch et al.
Feature
Synthesis
Anal. Calcd for C32H42N8O2: C, 67.34; H, 7.42; N, 19.63. Found: C,
66.97; H, 7.49; N, 19.34.
methods22 and were refined by full-matrix least-squares calculation
based on F2 for all reflections.23 With the exception of the amino hy-
drogen atoms H(1), H(4), H(7), and H(9) all other hydrogen atoms
were included in the models in calculated positions and were refined
as constrained to bonding atoms. Crystallographic data for the struc-
tures in this paper have been deposited with the Cambridge Crystal-
lographic Data Centre as supplementary publication number CCDC
1447955. These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
1-[(4,6-Dimethylpyrimidin-2-yl)aminomethyl]-3,5-bis[(5-methyl-
1H-pyrazol-3-yl-carbonyl)aminomethyl]-2,4,6-triethylbenzene (8)
Yield: 85% (0.18 g, 0.32 mmol); white solid; mp 167 °C.
1H NMR (400 MHz, CD3OD): δ = 6.52 (s, 1 H), 6.51 (s, 2 H), 4.65 (s,
4 H), 4.61 (s, 2 H), 2.83 (q, J= 7.6 Hz, 6 H), 2.32 (s, 6 H), 2.29 (s, 6 H),
1.20 (t, J = 7.4 Hz, 9 H).
13C NMR (100 MHz, CD3OD): δ = 145.63, 145.50, 133.68, 132.92,
110.82, 105.52, 40.98, 38.73, 23.99, 23.47, 16.76, 16.67.
HRMS (ESI): m/z [M + H]+ calcd for C31H42N9O2: 572.34559; found:
Acknowledgment
Financial support from the Deutsche Forschungsgemeinschaft is
gratefully acknowledged.
572.34590.
Anal. Calcd for C31H41N9O2: C, 65.13; H, 7.23; N, 22.05. Found: C,
64.77; H, 7.56; N, 22.13.
Supporting Information
1,3-Bis[(4,6-dimethylpyridin-2-yl)aminomethyl]-5-[(5-methyl-
1H-pyrazol-3-yl-carbonyl)aminomethyl]-2,4,6-triethylbenzene (9)
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0035-1561449.
S
u
p
p
ortiInfogrmoaitn
S
u
p
p
o
nrtogI
f
rmoaitn
Yield: 57% (0.10 g, 0.21 mmol); white solid; mp 150 °C.
1H NMR (400 MHz, CDCl3): δ = 6.88 (br s, 1 H), 6.58 (s, 1 H), 6.34 (s,
2 H), 6.09 (s, 2 H), 4.59 (d, J = 4.4 Hz, 2 H), 4.34 (d, J = 3.7 Hz, 4 H), 4.25
(br s, 2 H), 2.67–2.71 (m, 6 H), 2.32 (s, 6 H), 2.28 (s, 3 H), 2.23 (s, 6 H),
1.18–1.25 (m, 9 H).
13C NMR (100 MHz, CDCl3): δ = 158.24, 156.66, 148.92, 143.77,
133.15, 131.76, 113.96, 104.98, 103.53, 40.62, 37.79, 24.09, 22.92,
21.13, 16.80, 16.62.
References
(1) For examples of reviews on carbohydrate recognition with arti-
ficial receptors using noncovalent interactions, see: (a) Davis, A.
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(b) Mazik, M. ChemBioChem 2008, 9, 1015. (c) Walker, D. B.;
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M. Chem. Soc. Rev. 2009, 38, 935. (e) Davis, A. P. Org. Biomol.
Chem. 2009, 7, 3629. (f) Kubik, S. Angew. Chem. Int. Ed. 2009, 48,
1722. (g) Mazik, M. RSC Adv. 2012, 2, 2630.
(2) For examples of reviews on boronic acid-based receptors, see:
(a) James, T. D.; Phillips, M. D.; Shinkai, S. Boronic Acids in Sac-
charide Recognition; Royal Society of Chemistry: Cambridge,
2006. (b) Boronic Acids. Preparation and Applications in Organic
Synthesis and Medicine; Hall, D. G., Ed.; Wiley-VCH: Weinheim,
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(d) James, T. D.; Sandanayake, K. R. A. S.; Shinkai, S. Angew.
Chem., Int. Ed. Engl. 1996, 35, 1910.
(3) (a) Gabius, H. J. The Sugar Code – Fundamentals of Glycoscience;
Wiley-Blackwell: Weinheim, 2009. (b) Gabius, H.-J.; André, S.;
Jiménez-Barbero, J.; Romero, A.; Solis, D. Trends Biochem. Sci.
2011, 36, 298. (c) Lis, H.; Sharon, N. Lectins; Kluwer Academic
Publishers: Dordrecht, 2003. (d) Lis, H.; Sharon, N. Chem. Rev.
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(f) Weiss, W. I.; Drickamer, K. Annu. Rev. Biochem. 1996, 65, 441.
(4) (a) Mazik, M.; Hartmann, A. Beilstein J. Org. Chem. 2010, 6, No. 9.
(b) Mazik, M.; Kuschel, M. Chem. Eur. J. 2008, 14, 2405.
(c) Rosien, J.-R.; Seichter, W.; Mazik, M. Org. Biomol. Chem.
2013, 11, 6569. (d) Koch, N.; Rosien, J.-R.; Mazik, M. Tetrahedron
2014, 70, 8758. (e) For an example of benzimidazole-bearing
carbohydrate receptor, see: Mazik, M.; Cavga, H. J. Org. Chem.
2007, 72, 831.
HRMS (ESI): m/z [M + H]+ calcd for C34H46N7O: 568.37584; found:
568.37570.
1,3-Bis[(4,6-dimethylpyrimidin-2-yl)aminomethyl]-5-[(5-methyl-
1H-pyrazol-3-yl-carbonyl)aminomethyl]-2,4,6-triethylbenzene
(10)
Yield: 73% (0.10 g, 0.18 mmol); white solid; mp 146 °C.
1H NMR (400 MHz, CDCl3): δ = 6.74 (br s, 1 H), 6.57 (s, 1 H), 6.34 (s,
2 H), 4.78 (br s, 2 H), 4.60 (d, J = 4.4 Hz, 2 H), 4.57 (d, J = 4.5 Hz, 4 H),
2.70–2.74 (m, 6 H), 2.29 (s, 15 H), 1.19–1.23 (m, 9 H).
13C NMR (100 MHz, CDCl3): δ = 167.54, 161.74, 143.99, 143.77,
133.13, 131.71, 109.92, 104.91, 39.86, 37.78, 23.94, 22.97, 16.67,
16.55.
HRMS (ESI): m/z [M + H]+ calcd for C32H44N9O: 570.36633; found:
570.36599.
1,3,5-Tris[(5-methyl-1H-pyrazol-3-yl-carbonyl)aminomethyl]-
2,4,6-trimethoxybenzene (12)
Yield: 54% (0.12 g, 0.21 mmol); white solid; mp 192 °C.
1H NMR (400 MHz, DMSO-d6): δ = 12.89 (br s, 3 H), 7.67 (br s, 3 H),
6.39 (s, 3 H), 4.54 (s, 6 H), 3.80 (s, 9 H), 2.24 (s, 9 H).
13C NMR (100 MHz, DMSO-d6): δ = 161.19, 158.17, 146.53, 139.88,
121.42, 103.91, 62.01, 32.44, 10.21.
HRMS (ESI): m/z [M + Na]+ calcd for C27H33N9O6Na: 602.24460; found:
602.24488.
(5) For examples of carbohydrate receptors bearing pyrazole
groups, see ref. 4d and: Sonnenberg, C.; Hartmann, A.; Mazik,
M. Nat. Prod. Commun. 2012, 7, 321.
(6) Lippe, J.; Mazik, M. J. Org. Chem. 2015, 80, 1427.
X-ray Crystal Structure Determination
(7) (a) Lippe, J.; Seichter, W.; Mazik, M. Org. Biomol. Chem. 2015, 13,
11622. (b) Mazik, M.; Cavga, H.; Jones, P. G. J. Am. Chem. Soc.
2005, 127, 9045. (c) Mazik, M.; Radunz, W.; Boese, R. J. Org.
The intensity data of 5 were collected with a Kappa APEX II diffrac-
tometer (Bruker AXS) with Mo Kα radiation (λ = 0.71073 Å). Reflec-
tions were corrected for background, Lorentz and polarization effects.
Preliminary structure models were derived by application of direct
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–K

K
N. Koch et al.
Feature
Synthesis
Chem. 2004, 69, 7448. (d) Mazik, M.; Radunz, W.; Sicking, W.
Org. Lett. 2002, 4, 4579. (e) Mazik, M.; Sicking, W. Tetrahedron
Lett. 2004, 45, 3117.
(12) (a) Li, H.; Homan, E. A.; Lampkins, A. J.; Ghiviriga, I.; Castellano,
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–K