Phase-transfer-catalysed Preparation of N-Alkylated Trihydroxamic Acids

Article abstract of DOI:10.1039/a700300e

We describe a synthetic route involving phase transfer catalysis leading to a series of tripodal N-alkylated hydroxamic acids as models of desferrioxamine; iron(III) exchange reactions between their iron complexes and EDTA were investigated.

Full text of DOI:10.1039/a700300e

View Article Online / Journal Homepage / Table of Contents for this issue
218 J. CHEM. RESEARCH (S), 1997
J. Chem. Research (S),
1997, 218–219†
Phase-transfer-catalysed Preparation of N-Alkylated
Trihydroxamic Acids†
Pascal Hoffmann, Jean-Baptiste Doucet, Wenhao Li, Laurent Vergnes and
Serge Labidalle*
Laboratoire de Synthe`se, Physico-Chimie et Radiobiologie, JE 175, Universite´ Paul Sabatier,
Faculte´ des Sciences Pharmaceutiques, 35, chemin des Maraˆıchers, 31062 Toulouse cedex 04,
France
We describe a synthetic route involving phase transfer catalysis leading to a series of tripodal N-alkylated hydroxamic
acids as models of desferrioxamine; iron(III) exchange reactions between their iron complexes and EDTA were
investigated.
Naturally occurring hydroxamic acids act variously as growth
factors, antibiotics, tumour inhibitors, cell division factors or
lipoxygenase inhibitors, and play a major role as iron transfer
agents.1 Most of these biological activities are due to their
complexing properties towards transition metal ions, particu-
larly with iron(III). Desferrioxamine, a natural trihydroxamic
acid, is used therapeutically for the treatment of iron-over-
loaded patients,2 particularly in patients with AIDS, but the
lack of oral activity and its short biological half-life limits its
use. Otherwise, iron chelation by desferrioxamine, and other
chelators, protects against the cytotoxic and reactivating
effects of hydrogen peroxide,3 and thus decreases NF-kB
activation due to oxidative stress, and subsequent activa-
tion of HIV-1 transcription. The natural products with an
iron(III)trihydroxamate centre form a class comprised of
many known members. When three hydroxamate functions
are present in the same molecule with an appropriate spacing
between the hydroxamic acid units, the complex tends to
retain the 1:1 structure, even at low pH.
In this work, we report the synthesis of a series of N-H or
N-alkylated tripodal hydroxamic acids 4 (Scheme 1) as simple
models of desferrioxamine. We use phase transfer catalysis4
(PTC) on the one hand to access the triester 1, and on the
other hand to perform the N-alkylation reactions. The rela-
tive stabilities of the iron(III) complexes were investigated.
PTC was used for the first step to synthesize the triester 1,
a building block that is often used as a starting material for
dendrimeric macromolecule synthesis.5 Michael-type addi-
tion of nitromethane to methyl acrylate, without added
organic solvent but in the presence of potassium carbonate
and with benzyltriethylammonium chloride as phase-transfer
reagent, followed by saponification of the triester 1 afforded
the triacid 2. Condensation of O-protected hydroxylamines
with the triacid chloride gave the O-benzylated trihydroxamic
acid 3a, and the O-tritylated trihydroxamic acid 3؅a. As the
deprotection conditions of the benzyl group are often incom-
patible with the presence of other functional groups, we used
two different protective groups for the synthesis of com-
pounds 3. Although synthetic methods for hydroxamic acids
are well documented,6 direct acylation of O-protected
hydroxylamine derivatives with acid chlorides remains the
most commonly used method. A direct condensation with
unprotected hydroxylamine gave a mixture of N- and O-
acylated products. Hydroxamic acids have been alkylated
with a large variety of electrophiles. Phase-transfer catalysis
in the N-alkylation of organic molecules seems to be effective
especially when the nitrogen atom has a low basicity which
renders it less reactive towards alkylating agents. Here, we
used PTC in the absence of solvent for the N-alkylation4c of
3a with methyl iodide, n-butyl bromide, and n-octyl bromide
in the presence of potassium tert-butoxide and Aliquat 336
(tricaprylylmethylammonium chloride) to yield respectively
the N-alkylated-O-protected hydroxamic acids 3b–d. Finally,
deprotection of the benzylated derivatives 3a–d by catalytic
hydrogenation with ammonium formate and 10% pal-
ladium–carbon gave the amino hydroxamic acids 4a–d in
moderate yields (20–35%), while removal of the trityl group
of compounds 3؅a in acidic diethyl ether gave the nitro deriv-
ative 4؅a. The N-n-octylated product (4d) was isolated by
chromatography on silica gel, whereas 4a–c and 4؅a were
purified by reversed-phase preparative TLC with a mixture of
methanol and water as eluent.
All final hydroxamic acids gave a deep red colour in the
presence of Fe3ǹ with a wide characteristic absorption band
CO2Me
+
OBn
OBn
OH
N
O2N-Me
iii
iv
v
N
H
N
R
O2N
O2N
H2N
i
C
O
C
O
C
O
R
3
3
3
OMe
OH
O2N
O2N
ii
3a
3b–d
4a–d
C
O
C
O
a R = H
OTr
OH
3
3
iii'
v'
b R = Me
c R = Bun
N
H
N
1
2
O2N
O2N
C
O
C
O
H
d R = n-C8H17
3
3
3'a
4'a
Scheme 1 Reagents and conditions: i, PTC: benzyltriethylammonium chloride, K2CO3, RT; ii, NaOH–methanol, reflux; iii, SOCl2, reflux;
O-benzylhydroxylamine, Et3N–THF, RT; iii؅, SOCl2, reflux; O-tritylhydroxylamine, Et3N–THF, RT; iv, PTC: methyl iodide, n-butyl bromide
or n-octyl bromide, Aliquat 336, potassium tert-butoxide, 50 °C (reflux for methyl iodide, 42 °C); v, ammonium formate, 10% Pd/C–
methanol, reflux; v؅, HCl–diethyl ether, RT (RT = room temperature)
in the visible range with a maximum located between 420 and
*To receive any correspondence.
440 nm.
†This is a Short Paper as defined in the Instructions for Authors,
Section 5.0 [see J. Chem. Research (S), 1997, Issue 1]; there is there-
fore no corresponding material in J. Chem. Research (M).
In order to investigate the relative stabilities of the iron
complexes, the pseudo-first-order constants for iron(III
)

View Article Online
J. CHEM. RESEARCH (S), 1997 219
exchange reactions between the FeIII–4 complexes and
EDTA were determined by following the decrease in absorb-
ance at 425 nm in the presence of a large excess of EDTA.
The relative stability constants of the iron(III) complexes of
TLC and 4d on silica gel. 4a (yield: 59%), solid (hygroscopic): dH
([2H6]DMSO) 1.75–2.18 (14 H, m, CH2CH2ǹNH2), 5.02 (3 H, br s,
OH), 7.35 (3 H, s, NH). 4b (yield: 70%), oil dH ([2H6]DMSO)
2.02–2.27 (14 H, m, CH2CH2ǹNH2), 3.02 (9 H, s, NCH3), 7.87
(3 H, br s, OH). 4c (yield: 95%), oil: dH ([2H6]DMSO) 0.82–0.88
(9 H, t, CH3), 1.19–1.34 (6 H, m, CH2), 1.42–1.53 (6 H, m, CH2),
2.05–2.32 (14 H, m, CH2CH2ǹNH2), 3.43–3.48 (6 H, t, NCH2),
6.70 (3 H, br s, OH). 4d (yield: 79%), oil, dH ([2H6]DMSO)
0.85–0.87 (9 H, t, CH3), 1.26–1.33 (36 H, m, CH2), 2.10–2.30
(14 H, m, CH2CH2ǹNH2), 3.51–3.59 (6 H, t, NCH2), 8.43 (3 H, br
s, OH). RF values on reversed-phase TLC (C18): 4a 0.75
(H2O–MeOH, 80:20); 4b 0.62 (H2O–CH3OH, 60:40); 4c: 0.17
(H2O–MeOH, 40:60). RF value on silica gel TLC: 4d: 0.20
(CH2Cl2–MeOH, 95:5).
4؅a, 4a, 4b, 4c and 4d were respectively 0.8Å10ꢀ2, 1.5Å10ꢀ2
,
1.0Å10ꢀ2, 0.2Å10ꢀ2 and 0.4Å10ꢀ2 sꢀ1, suggesting that the
lipophilic compounds 4c and 4d hold iron a little more tightly
than do the other ligands. However, the order of magnitude
of the observed constants indicates that the tripodal ligands 4
form much less stable complexes than does desferrioxamine,
a linear trihydroxamic acid that has an optimal nine-atom
spacing between hydroxamate moieties, and whose exchange
constant towards EDTA is 6.5Å1ꢀ6 sꢀ1 under the same
experimental conditions. The shape of the molecule (linear
or tripodal) and the spacing between the hydroxamic acid
Compound 4؅a. To a solution of 3؅a (5.6 g, 5.34 mmol) in
dichloromethane (190 ml) was added a solution of hydrochloric
acid (1.1 ) in diethyl ether (30 ml). The solution was stirred for
M
2 h at room temperature. The precipitate was filtered off, washed
with dichloromethane and dried under reduced pressure. The resi-
due was dissolved in water, filtered and lyophilised to give 4؅a
(yield: 74%), solid (hygroscopic); dH ([2H6]DMSO) 1.92–2.10
(12 H, m, CH2CH2), 9.90 (3 H, br s, OH), 10.66 (3 H, s, NH).
RF = 0.70 [reversed-phase TLC (C18); H2O–MeOH, 80:20].
Iron-exchange Reactions with EDTA.sThe exchange reactions
between the iron complexes and EDTA were carried out by UV
spectroscopy, noting the decrease in the absorbance at 425 nm in
the presence of an excess of EDTA as previously described.7
units seem to play a major role in creating stable iron(III
)
complexes.
The final hydroxamic acids will be tested as potent antiviral
agents in future work; moreover, as part of a program to
develop novel chelators for the radioimaging of organs and
tumours, the affinity of the trihydroxamic acids 4 towards
gallium(III) and indium(III) will be measured.
Experimental
NMR spectra were recorded on a Bruker AC 250 instrument at
250 MHz and UV spectra with a UVIKON 931 spectrometer
(Kontron instruments).
Received, 13th January 1997; Accepted, 28th February 1997
Paper E/7/00300E
Compound 1. Yield: 97%, oil; dH (CDCl3) 2.26–2.28 (12 H, m,
CH2CH2), 3.66 (9 H, s, CH3).
Compound 2. Yield: 65%, solid, mp 175 °C; dH [2H6]DMSO)
2.16–2.17 (12 H, m, CH2CH2), 12.31 (3 H, s, COOH).
Compound 3a. Yield: 77%, solid, mp 107 °C; dH ([2H6]DMSO)
1.93–2.13 (12 H, m, CH2CH2), 4.78 (6 H, s, PhCH2), 7.34–7.40
(15 H, m, C6H5), 11.09 (3 H, s, NH).
References
1 J. B. Neilands, Science, 1967, 156, 1443; R. J. Bergeron, Chem.
Rev., 1984, 84, 587.
2 R. J. Bergeron, C. Z. Liu, J. S. McManis, M. X. B. Xia, S. E. Algee
and J. Weigand, J. Med. Chem., 1994, 37, 1411.
3 C. Sappey, J. R. Boelaert, S. Legrand-Poels, C. Forceille, A.
Favier and J. Piette, AIDS Res. Hum. Retroviruses, 1995, 11,
1049.
Compound 3؅a. Yield: 58%, oil; dH ([2H6]DMSO) 1.88–2.08
(12 H, m, CH2CH2), 7.25–7.48 (15 H, m, C6H5), 10.89 (3 H, s,
NH).
General Procedure for PTC N-alkylation.sTo a dry mixture of 3a
(9 mmol) and potassium tert-butoxide (45 mmol) was added Ali-
quat 336 (0.1 g). After 2 h under stirring at 50 °C, methyl iodide,
n-butyl or n-octyl bromide (5–10 mol equiv.) were added and the
mixture was stirred for 2 h at 50 °C. Chromatography on silica gel
with a silica gel with a mixture of dichloromethane and methanol as
eluent (ranging from 99:1 to 95:5) provided the desired com-
pounds. 3b (yield: 67%), oil, dH (CDCl3 2.15–2.20 (12 H, m,
CH2CH2), 3.17 (9 H, s, NCH3), 4.77 (6 H, s, PhCH2), 7.36 (15 H, s,
C6H5). 3c (yield: 55%), oil, dH (CDCl3) 0.87–0.93 (9 H, t, CH3),
1.25–1.35 (6 H, m, CH2), 1.54–1.63 (6 H, m, CH2), 2.08–2.27
(12 H, m, CH2CH2), 3.58–3.64 (6 H, t, NCH2), 4.75 (6 H, s, PhCH2),
7.36 (15 H, s, C6H5). 3d (yield: 48%) oil 0.87 (9 H, s, CH3),
1.25–1.30 (36 H, m, CH2), 2.08–2.23 (12 H, m, CH2CH2), 3.56–3.60
(6 H, t, NCH2), 4.75 (6 H, s, PhCH2), 7.36 (15 H, s, C6H5).
General Procedure for Debenzylation.sTo a solution of 3a–d (9
mmol) in methanol (50 ml) was added under argon 10% Pd–C
(2.5 g) and a solution of ammonium formate (90 mmol) in metha-
nol (100 ml). The mixture was heated at 65 °C for 12 h under argon.
After cooling, the mixture was filtered through a Celite pad. The
palladium was washed three times with methanol, and the filtrate
was evaporated. 4a–c were chromatographed on reversed-phase
4 (a) E. V. Dehmlow, Angew. Chem., Int. Ed. Engl., 1977, 16, 493; (b)
for Michael addition via PTC, see for example: V. Dryanska, K.
Popandova and C. Ivanov, Synth. Commun., 1987, 17, 211; G.
Bram, H. Galons, S. Labidalle, A. Loupy, M. Miocque, A. Petit, P.
Pigeon and J. Sansoulet, Bull. Soc. Chim. Fr., 1989, 247; (c) for
PTC N-alkylation, see for example: R. J. M. Nolte and D. J. Cram,
J. Am. Chem. Soc., 1984, 106, 1416; E. V. Dehmlow and Y. R. Rao,
Synth. Commun., 1988, 18, 487.
5 G. R. Newkome, C. N. Moorefield and G. R. Baker, Aldrichim.
Acta, 1992, 25, 31.
6 A. M. Lobo, M. M. Marques, S. Prabhakar and H. S. Rzepa, J. Org.
Chem., 1987, 52, 2925; R. J. Bergeron and J. S. McManis, Tetra-
hedron, 1990, 46, 5881; J. M. Altenburger, C. Mioskowski, H.
d’Orchymont, D. Schirlin, C. Schalk and C. Tarnus, Tetrahedron
Lett., 1992, 33, 5055; M. A. Staszak and C. W. Doecke, Tetrahedron
Lett., 1994, 35, 6021; J. Zhu, S. Robin, C. Goasdou´e, A. Loupy and
H. Galons, Synth. Commun., 1995, 25, 2515; S. S. Nikam, B. E.
Kornberg, D. R. Johnson and A. M. Doherty, Tetrahedron Lett.,
1995, 36, 197.
7 M. Akiyama, A. Katoh and T. Ogawa, J. Chem. Soc., Perkin Trans.
2, 1989, 1213.