Synthesis, structure and the binding properties of the amide-based anion receptors derived from 1H-indole-7-amine

Article abstract of DOI:10.1016/j.tet.2007.11.012

Indole-7-amine was investigated as an alternative to aniline in construction of amide-based anion receptors. Replacement of aniline with indolamine introduces additional binding site-indolyl NH, which can enhance anion binding for more than five times. The molecular modelling of indole-containing receptors revealed the correlation between their conformational preferences and their affinity towards anions.

Full text of DOI:10.1016/j.tet.2007.11.012

Available online at www.sciencedirect.com
Tetrahedron 64 (2008) 568e574
www.elsevier.com/locate/tet
Synthesis, structure and the binding properties of the amide-based
anion receptors derived from 1H-indole-7-amine
Tomasz Zieli n´ ski , Pawe1 Dydio , Janusz Jurczak a,b,*
a
a,b
a
Institute of Organic Chemistry, Polish Academy of Sciences, Kasprzaka 44/52, 01-224 Warsaw, Poland
b
Department of Chemistry, Warsaw University, Pasteura 1, 02-093 Warsaw, Poland
Received 23 July 2007; received in revised form 17 October 2007; accepted 1 November 2007
Available online 6 November 2007
Abstract
Indole-7-amine was investigated as an alternative to aniline in construction of amide-based anion receptors. Replacement of aniline with
indolamine introduces additional binding sitedindolyl NH, which can enhance anion binding for more than five times. The molecular modelling
of indole-containing receptors revealed the correlation between their conformational preferences and their affinity towards anions.
Ó 2007 Elsevier Ltd. All rights reserved.
Keywords: Anion recognition; Indole; Hydrogen bond; Amides
1
. Introduction
by conversion of amide or urea groups into their thio-ana-
4
,5,11
logues.
Also fusion of pyrrole with a benzene ring leads
to an increased acidity of pyrrolic NH, as expressed by values
Coordination chemistry of anions is one of the most active
1
fields of supramolecular chemistry. In this research area, con-
struction of neutral hosts for anions is especially attractive due
of pK for pyrrole, indole and carbazole in DMSO: 23.0, 20.9
a
1
7
and 19.9, respectively. Moreover, the indole moiety has
been a part of binding sites in some natural systems, mainly
2
to the many possible applications of such receptors. Binding
by uncharged ligands is generally achieved by the usage of
1
8
as the tryptophan residue. These aspects make benzopyrroles
an important subject of studies, and there are published exam-
ples of successful application of benzopyrroles as building
3
hydrogen bond formed by amide, thioamide, urea, thio-
4,5
6,7
8
e11
12
and hydroxyl groups or a pyrrole moiety.
13,14
urea
A
1
9
single hydrogen bond is weak and thus multiple such interac-
tions must be applied for efficient complexation of anions.
However, the groups mentioned above consist of both hydro-
gen bond donor and acceptor fragments, and as a result, they
often participate in intramolecular hydrogen bonds that must
be broken upon complexation, which decrease the affinity of
hosts towards anions. The pyrrole subunit is exceptional be-
cause it can only act as a hydrogen bond donor, and due to this
feature, the construction of pyrrole-based receptors is of great
blocks for anion receptors. In this communication, we would
like to present our studies of the amides 1e3 derived from in-
2
0
dole-7-amine (Scheme 1). Independently Gale has published
2
1
in Chem. Commun. his studies on similar derivatives of 2,3-
dimethyl-indole-7-amine. We hope that readers will find our re-
sults complementary to those reported by Gale and co-workers.
1
5
2. Results and discussion
1
3,14
interest.
In order to improve anion binding, the acidity of hydrogen
bond donor groups can be increased. It has been achieved by
There are many known ligands the binding sites of which
are derived from aniline, usually in the form of amides or
7
,9,14
7
,8,16
ureas.
By replacement of the aniline subunit with
the introduction of electron-withdrawing substituents
or
indole-7-amine, a new hydrogen bond donor, namely indole
NH, can be introduced into such systems, and thus an in-
creased affinity towards anions may be expected. To check
*
Corresponding author. Tel.: þ48 22 632 05 78; fax: þ48 22 632 66 81.
E-mail address: jurczak@icho.edu.pl (J. Jurczak).
0040-4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.11.012

T. Zieli n´ ski et al. / Tetrahedron 64 (2008) 568e574
569
O
O
N
H
O
O
N
NH
NH
HN
HN
O
O
NH
NH
HN
HN
NH
NH
Scheme 1.
HN
HN
1
2
3
this assumption we decided to investigate aromatic bisamides
e3 (Scheme 1) derived from indole-7-amine and compare
Table 1
The binding constants (M ) for the formation of 1:1 complexes of model
ꢀ1
1
a
ligands with various anions in DMSO-d
6
þ0.5% H
2
O at 296 K
them with their aniline-based analogues 10e12. As building
blocks for ligands’ construction, we chose pyrrole-, azulene-
and pyridine-dicarboxylic acids for the following reasons.
5
10
23
11
1
2
3
12
ꢀ
b
PhCO2
NH pyrrole
NH indole
NH amide
NH pyrrole
NH indole
NH amide
NH pyrrole
NH indole
NH amide
1
327
33
d
2
2
Ligand 1 derived from 2,5-pyrroledicarboxylic acid contains
five hydrogen bond donors in its structure, and in conse-
quence, strong anion binding could be expected. The 1,3-azu-
526
544
28
24
83
b
d
80
b
d
105
496
3.4
9.5
ꢀ
H
2
PO
4
35
84
11
2400
2300
164
100
2
3
lenedicarboxylic acid offers an arrangement of hydrogen
bond donors similar to its pyrrole analogue due to the five-
membered ring geometry, but ligand 2 can bind only by four
such interactions. The derivatives of dipicolinic acid are often
203
ꢀ
Cl
5.2
d
d
5.7
5.2
36
50
2.5
1.7
c
3.8
9.3
2
4
a
used for construction of anion receptors and this building
block is well known for its preorganisation in the synesyn
conformation.
Determined by H NMR titration. Errors estimated to be <10%. TBA salts
were used as a source of anions.
b
Cannot be determined due to disappearing of the pyrrole NH signal.
Error 15%, too small value of chemical shift.
Interaction to weak to be measured.
c
Indole-7-amine (6) was easily prepared by the catalytic
reduction (H , Pd/C 5%) of 7-nitroindole (5), which is
commercially available, or can be synthesised by the Bartoli
d
2
2
5
method from 1,2-dinitrobenzene (4). The desired amides
e3 and 10e12 were obtained by reactions of the correspond-
ing acetic dichlorides 7e9 with indolyl-7-amine (6) or aniline
oxoanions over halogens and all complexes are formed with
1:1 stoichiometry. The replacement of the aniline subunit
with indoleamine does not influence remarkably the relative
selectivity towards anions.
1
(
Scheme 2).
Contrary to our predictions, the replacement of aniline moi-
ety with indoleamine 6 in pyrrole-based ligand 1 failed to
increase its affinity towards anions (Table 1). Moreover, the
values of binding constants differ depending on which type
of protons was used for calculations. The highest values
were determined for the pyrrole NH, and the lowest values
were for the indole NHs. It may seem that the indolyl NH is
too far away to participate in the anion binding, similarly as
was observed by Gale for a pyrrole-based ligand with pendant
NO2
MgBr
NO2
H2, Pd/C
NH2
NO2
NH
NH
Ar
4
6
5
O
Ar
O
O
O
NH HN
O
Ar
O
aniline
6
NH HN
Cl
Cl
NH HN
2
6
arms. However, our structural studies suggest a different
explanation.
1
2
3
Ar = 2,5-pyrrole
Ar = 1,3-azulene
Ar = 2,6-pyridine
7 Ar = 2,5-pyrrole
8 Ar = 1,3-azulene
9 Ar = 2,6-pyridine
10 Ar = 2,5-pyrrole
11 Ar = 1,3-azulene
12 Ar = 2,6-pyridine
The azulene-based ligand 2, which also contains a five-
membered aromatic scaffold, turned out to bind anions fairly
strongly. Its affinity towards anions is almost five times higher
than for the aniline derivative 11 (Table 1). There is a good
agreement between the values of binding constants determined
for amide and indolyl protons. In contrast to its pyrrole-based
analogue 1, the azulene derivative 2 is able to bind anions by
concerted hydrogen bonds formed by both amide groups and
indole NH.
The introduction of two additional binding sites has a posi-
tive effect on anion binding also in the case of the dipicolinic
acid derivative 3 (Table 1). The indole-containing ligand 3 is
a better receptor than its aniline analogue 12. Moreover, the
binding constants calculated for indolyl NHs are higher than
determined on the basis of amide groups.
Scheme 2.
To determine the anion binding properties of our ligands we
1
used H NMR titration technique with DMSOþ0.5% H O as
2
a solvent. Although this is a very competitive medium, it
will allow further comparison with known ligands. Upon addi-
tion of tetrabutylammonium salts, the signals of the amide and
pyrrole-type protons were shifted downfield and used to calcu-
late the values of binding constants (Table 1). Interactions of
all the ligands with bromide were too weak to determine asso-
ciation constants. Although the K values obtained for interac-
a
tion with the chloride anion are small, they are reliable, and
since they were measured in the same conditions, they can
be used for comparison. We observed typical selectivity for

570
T. Zieli n´ ski et al. / Tetrahedron 64 (2008) 568e574
The results for amides 2 and 3 confirmed that the replace-
ment of the aniline subunit with the indole-7-amine (6) can
lead to over five times stronger interaction with anions. How-
ever, the interesting question is why no such improvement is
observed for the pyrrole-containing ligand 1. Molecular mod-
elling gave us some insight into this problem.
We performed a conformational search for ligands 1e3 us-
ing semi-empirical AM1 method. The resulting conformations
could be sorted according to two attributes: the syn or anti
orientation of the amide groups, and the presence or absence
of the intramolecular hydrogen bond between indolyl NH and
carbonyl group. As could be predicted, the structures with
this intramolecular interaction have the lowest energy. For fur-
ther studies, we chose conformations with the inner hydrogen
bond, and investigated the influence of orientation of carbonyl
groups on energy using DFT B3LYP method at the 6-31G level.
The pyrrole derivative 1 prefers the conformation in which
carbonyl groups are in the antieanti orientation (Table 2), the
same preference was observed for simple pyrrole-based bisa-
5
mide. The intramolecular hydrogen bonds between indolyl
and pyrrolic NHs and carbonyl groups assure that aromatic
rings are coplanar and as a result the ligand 1 is completely
flat (Fig. 1a). To bind anions with convergent hydrogen bonds
that originate from amide groups and pyrrole NHs, the ligand
1
must adopt the synesyn conformation. In the synesyn
conformation, carbonyl groups of 1 are tilted, thus two con-
formers are possible: one with amides on the same side of
pyrrole plane (denoted as þþ), and the other in which amides
point to opposite directions (denoted as þꢀ). Both synesyn
conformers have energy higher by more than 40 kJ/mol than
antieanti one (Table 2). This strong preference for the antie
anti conformation was also observed in solution, since the
NOESY experiment in DMSO shows the NOE effect between
amide NH and pyrrole CH.
On the contrary to pyrrole derivative 1, the azulene-based
ligand 2 is already preorganised in the favourable synesyn
conformation (Table 2). The carbonyl groups are deviated
from the plane of azulene ring, thus two structures are possi-
ble: one in which the amide groups occupy the same side of
azulene (noted as synesynþþ, Fig. 1c) and the other in which
the carbonyl groups point in opposite directions (noted as
synesynþꢀ, Fig. 1b). Both conformers have similar energy.
Figure 1. The conformers of ligands 1e3 having the lowest energy as calcu-
lated with DFT B3LYP/6-31G method. (a) 1; (b) 2; (c) 2; (d) 3.
Again, the ligand structure is induced by the preferences of
the building block used for its construction, since such a pref-
erence for the synesyn conformation was found for simple
2
3
azulene-based bisamide.
The dipicolinic acid derivatives are known for their prefer-
ence for advantageous synesyn conformation, thus it is not
surprising that the carbonyl groups adopt the synesyn orienta-
tion in the ligand 3 (Fig. 1d; Table 2). The structure is flat due
to the presence of intramolecular hydrogen bonds.
In all ligands studied (1e3), the introduced additional bind-
ing sitedindole NH is involved in hydrogen bonding with the
carbonyl groups. We decided to determine the strength of this
bond using DFT B3LYP method. We optimised the structures
of conformations in which the carbonyl groups adopted the
synesyn orientation, but one of the indole subunits was
twisted and its NH was directed into the binding cleft and
thus one hydrogen bond was broken. Then we compared the
energies of such conformers with the undisturbed ones. The
breaking of the hydrogen bond and changing position of indole
subunit require 31 kJ/mol in the case of pyrrole-based ligand
Table 2
The relative energies (kJ/mol) for the conformers of ligands 1e3
a
1
2
3
b
E
E
E
antieanti
syneanti
0
27.4 (þꢀ)
112.0
2
9.4 (þþ)
17.2
10.7 (þꢀ)
36.8
0
1
1.5 (þþ)
0 (þꢀ)
synesyn
47.0 (þꢀ)
44.0 (þþ)
1.1 (þþ)
Calculations in the gas phase using DFT B3LYP/6-31G method and basis
a
1, and this value is higher than the corresponding values for
azulene and pyridine derivatives 2 and 3: 29 and 27 kJ/mol,
respectively. It should be noted that if the energy differences
o
of about 3 kJ contributed to the DG of complexation, the
values of binding constants would be three times higher.
sets. In the considered conformers, the indole NH was involved in hydrogen
bond with the carbonyl group, the syn, anti attributes concern orientation of
the carbonyl groups.
b
(
þꢀ) denotes energy for the antieantiþꢀ conformation, (þþ) marks
energy for the antieantiþþ conformation, similarly for other conformers.

T. Zieli n´ ski et al. / Tetrahedron 64 (2008) 568e574
571
solvent oxygen, also indole moieties are tilted from the plane
of pyridine ring.
We also simulated the structures of the complexes of our
ligands with a chloride anion. However, interpretation of cal-
culations for anion complexes must always be taken very care-
fully. Interactions of anions with solvent molecules are crucial
for the complexation process that takes place in solution and
are more critical than for the coordination chemistry of cat-
2
7
ions. Therefore, consideration of energies obtained for the
gas phase is irrelevant to the complexation in solution. How-
ever, time-consuming computations for anionic species with
either continuum solvation model or explicit solvent approach
2
8
also lack accuracy. Thus, computation of the anion com-
plexes should be rather limited to the structural investigations
like geometric fit, strain present, etc. We decided to base such
analysis only on gas phase modelling, since for non-macrocy-
clic ligands, without anion encapsulation, shape disturbance
invoked by solvation sphere should be negligible.
We calculated the structure of the chloride anion complex
with pyrrole-containing ligand 1. The anion is bound by five
hydrogen bonds that involve all NH protons. The complex is
flat and symmetrical (Fig. 3a). The hydrogen bond lengths
Figure 2. Crystal structure of acetone solvate of ligand 3. (a) Different views of
the independent part; (b) different views of ligand dimer (the acetone has been
removed for clarity).
We obtained diffraction-grade single crystal of 3 by slow
evaporation of its acetone solution. However, the structural
analysis revealed that receptor 3 binds one solvent molecule
˚
(distance between N and Cl) are about 3.2 A for both pyr-
˚
rolyl/indolyl NHs and 3.5 A for amide groups, thus dismissing
(
Fig. 2), so we cannot compare this structure directly with the
the hypothesis that the indolyl binding sites are too far to
interact with anions (Table 3). However, this is not the struc-
ture with lowest energy, we found another, the energy of which
was lower by 0.6 kJ/mol. This complex is also planar, but the
chloride anion is bound by two amide groups, NHs from pyr-
role ring and only one of the indole moieties (Fig. 3b). In this
calculated one. In the solid state, the indole moieties are tilted
and as a result the ligand is not flat. An acetone molecule
occupies the centre of the binding cleft and is bound by two
hydrogen bonds formed by amide groups (NeO distances
are 2.94 and 3.02 A). The indole NHs are engaged in hydrogen
bonds with carbonyl groups (NeO distances are 2.84 and
˚
˚
.88 A), however, contrary to the modelled structure, the
hydrogen bonds involve carbonyl groups belonging to the
neighbouring molecule, and the ligands actually form a dimer
2
Table 3
The calculated distances between hydrogen bond donors and chloride anion
a
for ligands 1e3 complexes
(
Fig. 2, bottom). The distance between ligands’ pyridine rings
b
1
2
3
˚
is 3.2 A, the rings are parallel to each other and shifted in
such a manner that the pyridine nitrogen is almost at the mid-
dle of the neighbouring aromatic ring, thus it seems likely
that not only hydrogen bonds stabilise the dimer structure
but also p-stacking. This structure resembles the one pub-
d Amide NHeCl
d Indole NHeCl
3.55
3.25
3.17
3.61
3.20
3.36
3.50
3.16
3.47
c
d XeCl
a
Calculations in gas phase using DFT B3LYB/6-31G method.
Distances for the complex with five hydrogen bonds with anions (Fig. 3a).
The X stands for the central atom in aromatic ring between carbonyl
b
c
2
1
lished by Gale for the DMSO solvate of analogue 3. In
both structures amide groups form hydrogen bonds with
groups: X¼N in 1, 3 and X¼2-C in 2.
ꢀ
ꢀ
ꢀ
Figure 3. Calculated structures of chloride anion complexes with ligands 1e3 by DFT B3LYP/6-31G method. (a) and (b) 1$Cl ; (c) 2$Cl ; (d) 3$Cl .

572
T. Zieli n´ ski et al. / Tetrahedron 64 (2008) 568e574
structure, one of the indole subunits does not rotate to interact
with anions but is still engaged in hydrogen bond with the
carbonyl group. Both structures of 1$Cl are energetically
3. Conclusions
ꢀ
To summarise, indole-7-amine (6) is an interesting alterna-
tive to aniline for the construction of anion receptors. Intro-
duction of indole NH as an additional binding site can
improve anion binding more than five times as was demon-
strated by azulene- and pyridine-based bisamides 2 and 3.
However, the advantageous presence of the additional hydro-
gen bond donor can be diminished by strong intramolecular
hydrogen bonds and unfavourable ligand preorganisation as
exemplified by receptor 1. Molecular modelling seems to be
able to predict the case, which would take place and save
the synthetic effort.
almost equivalent, and as we stated above, they do not
necessarily reflect the complex behaviour in solution. How-
ever, this surprising result is in good agreement with titration
experiments. The values of the association constants deter-
mined on the basis of indolyl NH are the lowest. Probably,
the indole group switches between two hydrogen bonds:
with the anion or with the carbonyl group, since both interac-
tions are similarly attractive.
A different binding mode was obtained for the chloride
complex with the azulene-based ligand 2 (Fig. 3c). The anion
is located above the azulene ring, the side chainsdindole moi-
eties are tilted, and the chloride anion is anchored by two pairs
of hydrogen bonds: involving indole moieties (NeCl distance
4. Experimental
˚
˚
3
are summarised in Table 3.
.2 A), and amide groups (NeCl distance 3.6 A). The results
4.1. General remarks
Calculations reveal that pyridine containing ligand 3 also
forms a non-planar complex with the chloride anion
The details concerning structural analysis and determina-
tion of binding constants are provided in the Supplementary
data. Crystallographic data (excluding structure factors) for
the structures discussed in this paper have been deposited
with the Cambridge Crystallographic Data Centre as supple-
mentary publication number CCDC 654083. Copies of the
data can be obtained, free of charge, on application to CCDC,
12 Union Road, Cambridge CB2 1EZ, UK (fax: þ44 1223
336033 or e-mail: deposit@ccdc.cam.ac.uk) .
(
Fig. 3d). The side chains are twisted even more than in the
case of amide 2, so the anion is farther from the pyridine
plane, probably in order to minimise the repulsion with the
electron pair of pyridine nitrogen. This modelled structure is
in good agreement with the crystal structure of the chloride
complex published by Gale for the dipicolinic bisamide of
2
1
2
,3-dimethyl-indole-7-amine. The main difference is that
the indole pendant arms are tilted with different angles in
the solid state, and as a result the ligand structure is unsym-
metrical, also the hydrogen bonds are slightly shorter, and
the chloride anion is closer to the pyridine scaffold.
The aniline-containing ligands 10e12 were prepared by
reaction of the appropriate acetic dichlorides 7e9 with ani-
line. The 7-nitroindole (5) is commercially available or
can be synthesised from 1,2-dinitrobenzene (4) according to
5
,23
There is a correlation between length of hydrogen bonds in
the all three calculated chloride complexes with ligands 1e3.
The bond formed by indole NH is longest for the pyrrole-
based ligand 1, whereas the distance between chloride and
the aromatic ring is shortest. In the case of pyridine-based
ligand 3, the distance between chloride and aromatic ring is
longest and hydrogen bond involving indole is shortest (Table
the procedure given in the Supplementary data.
4.2. 1H-Indole-7-amine (6)
7-Nitroindole 5 (1.1 g, 6.8 mmol) was dissolved in metha-
nol (50 ml) and 5% palladium on charcoal was added
(0.2 g). The mixture was vigorously stirred under hydrogen
atmosphere. The reaction was monitored by TLC, and after
completion (about 2 h), the catalyst was filtered off on Celite.
The solvent was evaporated, and the solid residue was recrys-
3
). It is understandable, since in the complex of ligand 1 chlo-
ride anion is attracted by pyrrole NH in 1, whereas it is pushed
out by the free electron pair of ligand 3.
For azulene and pyridine ligands 2 and 3 we also optimised
the complex structures in which one of the hydrogen bond
between indole NH and carbonyl group was preserved. On
the contrary to the pyrrole-based ligand 1, such complexes
have higher energies: about 6 kJ/mol for azulene-containing
tallised from hot CHCl to which a small amount of pentane
3
was added after cooling down. This yields 0.71 g (80%) of
ꢁ
the desired amine 6 as colourless crystals, mp 94e95 C.
1
H NMR (200 MHz, DMSO) d¼10.64 (br s, 1H, NH-
indole), 7.25 (t, 1H, J ¼2.8 Hz), 6.76 (m, 2H), 6.35 (d, 1H, J ¼
1
1
2
and 8 kJ/mol for the derivative of pyridine 3.
On the basis of this conformational analysis, it is apparent
1.4 Hz), 6.31 (t, 1H, J ¼2.6 Hz, J ¼2.4 Hz), 5.01 (br s, 2H,
1
2
1
3
NH ); C NMR (50 MHz, DMSO) d¼134.2, 128.7, 126.1,
2
that the pyrrole derivative 1 has a structure that is poorly suit-
able for anion recognition. It is the only ligand studied that
upon anion complexation must accomplish rotation of its car-
bonyl groups. The intramolecular hydrogen bonds between
indolyl NHs and carbonyl groups are the strongest in 1, and
these bonds must be broken in order to coordinate anions.
Moreover, computation showed that binding of the chloride
anion by five and by only four hydrogen bonds is energetically
similar for the ligand 1, at least in the gas phase.
124.2, 120.4, 109.1, 105.1, 102.0; HR EI calcd for C H N
8
8
2
þ
M : 132.06875, found: 132.06863.
4.3. 1H-Pyrrole-2,5-dicarboxylic acid bis-[(1H-indol-
7-yl)-amide] (1)
Into the suspension of amine 6 (1.9 g, 14.4 mmol) in dry
CH Cl (40 ml), N,N-dimethylaniline was added (1.8 ml,
2
2
5
14.4 mmol), then the solution of acetic dichloride 7 (0.92 g,

T. Zieli n´ ski et al. / Tetrahedron 64 (2008) 568e574
573
4
.8 mmol) in CH Cl (8 ml) was added dropwise over 20 min.
2
THF yielding 0.68 g (87%) of slightly yellow crystals of the
ꢁ
2
The stirring was continued for 2 h, then the precipitated amine
hydrochloride was filtered off, and the solvent was removed in
vacuo. The residue was dissolved in ethyl acetate (100 ml) and
washed with water (2ꢂ25 ml), 1 M HCl (2ꢂ25 ml) and brine
amide 3, mp 295e297 C (with dec).
1
H NMR (500 MHz, DMSO) d¼11.19 (s, 2H, NH ), 11.01
(s, 2H, NH-indole), 8.44 (d, 2H, J ¼7.7 Hz, 3,5-CH-pyridine),
1
8.32 (m, 1H, 4-CH-pyridine), 7.49 (d, 2H, J ¼7.7 Hz, 4-CH ),
1
(
25 ml). The organic layer was dried over MgSO , the solvent
7.38 (dd, 2H, J ¼J ¼5.5 Hz, 2-CH ), 7.26 (d, 2H, J ¼7.4 Hz,
4
1
1
1
was removed, and the crude product crystallised from ethanol/
pentane and then recrystallised from hot 1,2-dichloroethane, to
which a small amount of pentane was added after cooling
down. Yield 1.6 g (85%) of the amide 1 as slightly yellow
6-CH ), 7.05 (dd, 2H, J ¼J ¼7.6 Hz, 5-CH ), 6.50 (m, 2H, 3-
1
1
1
3
CH ); C NMR (125 MHz, CDCl ) d¼162.4, 149.4, 140.2,
3
131.5, 129.7, 125.9, 125.5, 122.4, 119.1, 118.7, 118.2, 101.9;
HR ESI calcd for C H N O Na [MþNa] : 418.1280, found:
þ
2
3 17 5 2
ꢁ
crystals, mp 232 C.
1
418.1271. Anal. Calcd for C H N O : C 69.86, H 4.33, N
23 17 5 2
H NMR (500 MHz, DMSO) d¼12.28 (br s, 1H, NH-pyr-
17.71, found: C 69.81, H 4.53, N 17.52.
role), 10.85 (s, 2H, NH-indole), 10.02 (s, 2H, NH ), 7.42 (d,
2
7
7
H, J ¼7.7 Hz, 4-CH ), 7.37e7.34 (m, 4H, 2-CHþ6-CH ),
1
Supplementary data
.14 (d, 2H, J ¼1.2 Hz, CH-pyrrole), 7.02 (dd, 2H, J ¼J ¼
1
1
2
1
.7 Hz, 5-CH ), 6.48 (m, 2H, 3-CH ); C NMR (125 MHz,
3
Details concerning binding studies and structural analysis
as well the synthetic procedure for compound 5 are available.
Supplementary data associated with this article can be found
in the online version, at doi:10.1016/j.tet.2007.11.012.
CDCl ) d¼158.8, 130.0, 129.8, 129.7, 125.7, 123.1, 119.29,
3
1
17.7, 115.9, 113.5, 102.0; HR ESI calcd for C H N O Na
22 17 5 2
þ
[MþNa] : 406.1280, found: 406.1287. Anal. Calcd for
C H N O : C 68.92, H 4.47, N 18.27, found: C 69.06, H
2
2 17 5 2
4
.58, N 18.19.
References and notes
4
amide] (2)
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A procedure analogous to that for the amide 1 was per-
3
formed using the diacid dichloride 8 (0.45 g, 1.8 mmol),
2
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2
but the reaction was left overnight. Then the solid was filtered
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3
crude product was purified by flushing over silica gel with
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ꢁ
let-red crystals, mp 276e279 C.
1
4
. Inoue, Y.; Kanbara, T.; Yamamoto, T. Tetrahedron Lett. 2003, 44, 5167e
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5
169; Hossain, M. A.; Kang, S. O.; Llinares, J. M.; Powell, D.; Bowman-
1
9
0.14 (s, 2H, NH ), 9.76 (d, 2H, J ¼9.8 Hz, 4-CH-azulene),
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1
5
. Zieli n´ ski, T.; Jurczak, J. Tetrahedron 2005, 61, 4081e4089.
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1
6
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1
1
2
7
H, J ¼7.8 Hz, 6-CH ), 7.43e7.37 (m, 4H, 3-CHþ4-CH ),
1
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1
1
þ
HR ESI calcd for C H N O Na [MþNa] : 467.1484, found:
2
8 20 4 2
7
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4
67.1482. Anal. Calcd for C H N O : C 75.66, H 4.54, N
28 20 4 2
1
2.60, found: C 75.32, H 4.64, N 12.48.
8
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4
amide] (3)
.5. Pyridine-2,6-dicarboxylic acid bis-[(1H-indol-7-yl)-
9
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1
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(
the mixture was cooled to 0 C, and then the solution of di-
2
2
ꢁ
acetic dichloride 9 (0.5 g, 2.1 mmol) in CH Cl (2 ml) was drop-
2
2
wise added. Stirring was continued for 4 h, then the solid was
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4
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