A general synthesis of tris-indole derivatives as potential iron chelators

Article abstract of DOI:10.3390/10020488

The development of a novel route for the synthesis of a new class of compounds is described. The first tripodal, tris-indole amines are prepared by straightforward routes.

Full text of DOI:10.3390/10020488

Molecules 2005, 10, 488-491
molecules
ISSN 1420-3049
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A General Synthesis of Tris-Indole Derivatives as Potential Iron
Chelators
R. Bryan Sears, Russell A. Carpenter and Christine R. Whitlock*
Department of Chemistry, Georgia Southern University, P. O. Box 8064, Statesboro, Georgia 30460,
USA. Tel. (+1) 912 681-5682, Fax (+1) 912 681-0699
* Author to whom correspondence should be addressed; e-mail cwhitlock@georgiasouthern.edu
Received: 1 August 2004; in revised form 27 December 2004 / Accepted: 29 December 2004 /
Published: 28 February 2005
Abstract: The development of a novel route for the synthesis of a new class of compounds
is described. The first tripodal, tris-indole amines are prepared by straightforward routes.
Keywords: Indole, TRENSOX, iron chelation.
Introduction
Recent research in the area of oral iron-chelation therapy centers on the TRENSOX drugs. Both
N-TRENSOX (1) [1] and O-TRENSOX (2) [2] have shown promising results in iron binding and
water solubility studies [3]. These novel compounds contain three quinoline units which each contain
two oxygen functional groups. The oxygen atoms are located in such a way to provide the six
electron-donating ligands required to chelate an iron ion in an octahedral configuration.
SO3Na
SO3Na
N
O
N
O
OH
NH
NH
NH
O
N
NH
O
OH
N
N
O
N
O
OH
NH
NH
OH
NaO3S
OH
OH
N
NaO3S
N
NaO3S
NaO3S
1
2

Molecules 2005, 10
489
Due to their wide range of biological activities, indole and its derivatives continue to serve as
important synthetic targets [4]. 3-Substituted indoles [5], particularly 3-acylindoles [6], are commonly
found in pharmaceutical agents and are important synthetic intermediates.
Results and Discussion
Here, we describe the preliminary results toward the synthesis of two new TRENSOX derivatives,
containing indole units in place of the quinolines. We have previously shown that indole-3-glyoxalyl
chloride (3) will react with tris(2-aminoethyl)amine (TREN) to produce a 3-armed, claw-like structure
(4) (Scheme 1) [7]. The tripodal amine appears to be fluxional in solution, as seen by NMR, and
tightly closed as a solid, as seen by x-ray diffraction. To prepare the derivative, indole was first reacted
with oxalyl chloride, and the resulting glyoxalyl chloride was added to TREN and triethylamine (TEA)
in THF. After 24 hours, the resulting slurry was filtered, crystallized from methanol and filtered again
to provide 4 as a beige powder.
Scheme 1.
NH
O
O
O
N
O
NH
O
NH2
N
NH
NH2
C-C-Cl
O O
NH
O
N
O
ClC-CCl
ether
NH2
H
N
H
N
O
TEA, THF
H
N
H
3
4
Having established the success in the preparation of the first member in this new class of
compounds, a related tripodal amine (5) with one carbonyl unit per arm was also been prepared by a
modification of the above procedure. As seen in Scheme 2, indole-3-carboxylic acid was reacted with
thionyl chloride to produce the acyl chloride 6, which was then reacted with TREN and TEA in THF.
Scheme 2.
H
N
O
N
NH
O
NH2
N
NH
NH2
CO2H
C-Cl
N
H
NH
O
O
SOCl2
THF
NH2
N
N
TEA, THF
H
H
HN
6
5

Molecules 2005, 10
490
The temperature of the reactions at the point when TREN is added seems to have a significant
impact on the success of the reactions. Several attempts to add TREN at room temperature resulted in
dark-colored gums, while additions in an ice bath gave relatively clean products. The rapidity of the
addition of TREN is also critical, as the acyl chloride derivatives initially prepared are moisture
sensitive.
Conclusions
We have developed a facile method for the synthesis of two novel tris-indolyl amines. These
tripodal compounds are important intermediates in the development of new drugs with potential iron-
chelating abilities. As efforts to improve the water-solubility of these compounds are underway, the
success in their preparation should provide a general route to a new class of compounds.
Experimental
General
1
Melting points are uncorrected. H-NMR spectra were obtained using a Bruker 250 MHz multi-
nuclear spectrometer. MS were measured using a Shimadzu QP 5050A instrument.
Tris(2-[indole-3-glyoxylamido]ethyl)amine (4). To indole (10.07 g, 86.1 mmol) in ether (200 mL) was
added dropwise oxalyl choride (14.6 g, 114.6 mmol) over 15 mins. After stirring for 30 min, the
solution was filtered to yield 3 as a yellow solid, which was rapidly dissolved in THF (50 mL). To 3
in THF at 0°C was added a solution of TREN (6.14 g, 42.0 mmol) and TEA (42.3 mmol) in THF (10
mL). After stirring at 0°C for 1 h, the solution was filtered and the filtrate was evaporated to yield 4 as
a beige solid which crystallized from MeOH. Yield 5.93 g (31.4%); mp > 250°C. 1H-NMR (250 MHz,
DMSO-d6) 8.75 (s, 3H, H2), 8.65 (t, J=5.29 Hz, 3H, H1), 8.14 (d, J=6.9 Hz, 3H, H4), 7.47 (d, J=7.1
Hz, 3H, H7), 7.22 (t, J=7.0 Hz, 3H, H5 or H6), 7.16 (t, J=7.0 Hz, 3H, H6 or H5), 3.31 (m, 6H, Ha), 2.71
(bt, 6H, Hb); MS (M+1)+ = 660 for C36H33N7O6
Tris(2-[indole-3-amido]ethyl)amine (5). Indole-3-carboxylic acid (0.56 g, 3.4 mmol) dissolved in
SOCl2 (6 mL) was stirred at 0°C. After 1.5 h, the solution was rotary evaporated, and to the resulting
oil was added TREN (0.62 g, 4.2 mmol) and TEA (0.46 g, 4.6 mmol) in THF (25 mL). After stirring
at 0°C for 30 min, the solution was vacuum filtered to yield 5 as a beige solid which was recrystallized
1
from MeOH. Yield 0.28 g (43.0%); mp > 250°C. H-NMR (250 MHz, DMSO-d6) 7.98 (s, 3H, H2),
7.44 (m, 3H, H1), 7.17 (m, 3H, H4), 7.15 (d, 3H, H7), 7.14 (m, 3H, H5 or H6), 7.12 (m, 3H, H6 or H5),
3.40 (m, 12H, Ha and Hb); MS (M+1)+ = 576 for C33H33N7O3.
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Molecules 2005, 10
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Sample availability: Not available.
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