Design and synthesis of new ethylenediamine or propylenediamine diacetic acid derivatives for Re(I) organometallic chemistry

Article abstract of DOI:10.1016/j.tet.2003.11.058

A general synthetic approach for a novel range of bifunctional chelating agent (BCA) for the 'fac-[M(CO)₃]⁺' core (M= ^99mTc, ⁹⁹Tc or Re) has been developed. The strategy includes the facile preparation of these tridentate ligands possessing a tertiary amine bearing two carboxylic acid functions as coordinating site and an aromatic amino group for coupling to a biovector. First complexation study has shown that these compounds act exclusively as tridentate ligands (via the two acids and the tertiary amine functions). The convenient synthesis of these new ligands coupled with their high affinity for Re(I) make them quite promising for biomedical applications.

Full text of DOI:10.1016/j.tet.2003.11.058

Tetrahedron 60 (2004) 1167–1174
Design and synthesis of new ethylenediamine or propylenediamine
diacetic acid derivatives for Re(I) organometallic chemistry
b
a
b
Mustapha Allali,a,b Eric Benoist,a Nouzha Habbadi, Marie Gressier, Abdelaziz Souizi
,
*
a
`
and Michele Dartiguenave
a
´
Laboratoire de Chimie Inorganique, Universite Paul Sabatier, Bat. IIR1, 118, route de Narbonne, 31062 Toulouse, France
´ ´
Laboratoire de Chimie Organique et d’Agrochimie, Universite Ibn Tofail, Faculte des sciences, Kenitra, Morocco
b
Received 4 August 2003; revised 3 November 2003; accepted 20 November 2003
Abstract—A general synthetic approach for a novel range of bifunctional chelating agent (BCA) for the ‘fac-[M(CO)3]þ‘ core (M¼99mTc,
99Tc or Re) has been developed. The strategy includes the facile preparation of these tridentate ligands possessing a tertiary amine bearing
two carboxylic acid functions as coordinating site and an aromatic amino group for coupling to a biovector. First complexation study has
shown that these compounds act exclusively as tridentate ligands (via the two acids and the tertiary amine functions). The convenient
synthesis of these new ligands coupled with their high affinity for Re(I) make them quite promising for biomedical applications.
q 2003 Elsevier Ltd. All rights reserved.
1. Introduction
radiopharmaceutical application, should contain one or
more amine functionalities (preferentially aromatic
N-heterocycles) in combination with a carboxylic acid
function.11 Recently, Schibli and co-workers12 have com-
pared the in vivo and in vitro behaviours of different
99mTc(I)-tricarbonyl complexes with various bi- and
tridentate ligand systems. They have concluded that
for the radiolabelling with fac-[99mTc(CO)3]þor fac-
The technetium-99m is the most important radionuclide in
diagnostic nuclear medicine. This preferential use of
99mTc-radiopharmaceuticals reflects the ideal nuclear
properties of the isotope (T1/2¼6 h, 140 keV gamma
emitter), as well as its low cost and its convenient
availability from commercial generators. Consequently, it
is of high priority to develop efficient molecules with a
chelating group specific for this radionuclide.1 Efforts to
design new chelate systems for this nuclide and rhenium for
subsequent use, respectively, in diagnostic and therapy have
led to the development of new Tc or Re-specific ligands.
[
186/188Re(CO)3]þ, tridentate chelating systems were
preferable since they formed organometallic compounds
with more favourable pharmacokinetics.
We here provide a facile and convenient synthetic approach
for the tridentate bifunctional chelating agent (BCA) which
incorporates the design features illustrated in Figure 1; these
include: (i) a tridentate coordinating site for low oxidation
state metal carbonyls, (ii) a linking site to a biomolecule via
the amino functionality (iii) a tethering moiety (an ethylene
or propylene bridge) between the linking and coordinating
sites. The enhancement of bridge size should limit the
possible interaction between the secondary aromatic amine
Whereas in the past, the Tc or Re compounds bore
preferentially N,S tetradentate ligands2 which form stable
technetium(V) or rhenium(V) complexes,3 over the last 20
years, organometallic technetium and rhenium complexes in
low oxidation states have gained considerable attention in
the development of novel target-specific radiopharma-
ceuticals.4–9 Because of the high kinetic inertness and
their ease of preparation, Tc(I)/Re(I)-tricarbonyl
complexes are attractive for use in labelling site-specific
biomolecules.10
Previous in vitro studies on the macroscopic and n.c.a (non
carrier added) level suggested that ideal chelating systems
for the ‘fac-[M(CO)3]þ’ core, in respect of a potential
Keywords: Bifunctional chelating agent; Imino diacetic acid; Rhenium(I).
*
Corresponding author. Tel.: þ33-561-556-104; fax: þ33-561-556-118;
e-mail address: benoist@chimie.ups-tlse.fr
Figure 1. Design features of novel Re(I) ligands.
0040–4020/$ - see front matter q 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2003.11.058

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M. Allali et al. / Tetrahedron 60 (2004) 1167–1174
and the iminodiacetic acid group during the complexation
reaction. In this paper, we describe the synthesis of a range
of new ethylenediamine diacetic acid derivatives (EDDA)
and propylenediamine diacetic acid derivatives (PDDA)
which, on preliminary examination, exhibits significant
Re(I)-specificity.
derivatives (NO2Ph-EDDA) were performed in three steps
as described in Scheme 1. The key step was the introduction
of the nitro group (future linking site) during the synthesis of
the chelating moiety.
For ortho and para-NO2Ph-EDDA ligands, we used an
elegant and rapid route to synthesise nitrophenyldiamine
intermediates.14 By refluxing o- or p-chloronitrobenzene
with an excess of ethylenediamine, we obtained 1 and 6
respectively in 93 and 85% yield. This one-step substitution
reaction gave better yields than the Gabriel two-steps
synthesis using 2-bromoethylphtalimide as starting
material. Another advantage of this first step was the rapid
access to the triamine 2 by reduction of the nitro group using
SnCl2 as reducing agent in acidic conditions. This
compound 2 obtained in two steps with an overall yield of
86% was a versatile intermediate in the synthesis of
Ph-DTPA, (phenyleneetylenetriamine pentaacetic acid) a
potent ligand for radioimmunotherapy. This method
proved more suitable than that described by Gouin et al.15
2. Results and discussion
Amino polycarboxylic acid based ligand systems like
iminodiacetic acid react readily with the fac-[M(CO)3]þ
core to form complexes which have a stable octahedral
coordination sphere, where substitution reaction via a
dissociative or an associative mechanism is unlikely.12,13
Our synthetic strategy offers a simple method for generating
aminodiacetic acid derivatives bearing an aromatic amino
group for coupling to biomolecules.
The syntheses of nitrophenylethylenediaminediacetic acid
Scheme 1. o,m,p-NO2Ph-EDDA ligand synthesis Reagents and conditions: (i) ethylenediamine, 100 8C, 1 h–1 h 30 min 85–93% (ii) (a) SnCl2, HCl, 100 8C,
1 h (b) H2S 92% (iii) BrCH2COOEt, K2CO3, KI, ACN, 60 8C, 12 h, 83–90% (iv) 6 N HCl, 110 8C, 1 day, 70% (v) 2 N NaOH/EtOH, 70 8C, 3 h then 2 N HCl
78–90% (vi) Ref. 19, 62% (vii) 9, K2CO3, KI, ACN, 60 8C, 3 h, 60%.

M. Allali et al. / Tetrahedron 60 (2004) 1167–1174
1169
which uses a classical three-step sequence (peptidic
coupling–amine deprotection–amide reduction) providing
an overall yield of no more than 73%.
material.19 Basic hydrolysis of the ester followed by
acidification step afforded the ligand 11 in 90% yield.
The three o-, p-, m-NO2Ph-EDDA derivatives were
achieved respectively in 67, 55 and 33% yield and the
yields of each step, especially the amine alkylation step,
were not affected by the position of the nitro group on the
aromatic ring.
The second step was the dialkylation of the primary amine
function of 1 and 6. According to the classical alkylation
method,16 diethyl esters 3 and 7 were obtained with good
yields through the action of two equivalents of ethyl-
bromoacetate in the presence of a catalytic amount of KI
and a slight excess of K2CO3 in acetonitrile. Even with a
large excess of ethylbromoacetate, the desactivating nitro
group did not allowed the alkylation of the aromatic amine
function. Recently, a report has been published on N,N-
dialkylation of p-nitroaniline using CsF-Celite/alkyl
halides/acetonitrile combination17 but in our case, these
conditions afforded mainly the dialkylated ester and the
trialkylated ester only in minor proportion (.5%).
Using the same versatile route than for the ligands 5 and 8,
we also synthesized the o- and p-NO2Ph-PDDA substituting
ethylenediamine by 1,3-diaminopropane as starting material
in the first step (Scheme 2). These two ligands 16 and 17,
having one carbon more between the linking and chelating
moieties, have been obtained respectively in 67 and 60%
yield.
For rapid functionalization of a biomolecule, the introduc-
tion of the nitro group is a decisive advantage of the
presented synthetic strategy. For example, as shown in
Scheme 3, bifunctional chelating agent 19 was achieved in
40% yield by catalytic hydrogenation of the nitro group of 5.
Nevertheless, 19 was obtained with a better overall yield in
two steps, starting from 3 (56%). We found that it was
easier to purify intermediates using reduction then basic
hydrolysis sequence than the opposite. The aromatic amine
function allows e.g. in the case of 19, the coupling to a
carboxylic acid of a biomolecule. The same synthetic
procedure of functionalization could be applied to all our
ligands.
Attempts to prepare and obtain pure ortho-NO2Ph-EDDA
by the direct acid hydrolysis of 3 failed and resulted in the
formation of the six-membered azalactam 4 in 70% yield.
Genik–Sas–Berezowsky et al.18 have already noticed that
cyclization of the non-fully substituted EDDA derivatives
took place quite readily under acid conditions. To
circumvent this lactamisation, compounds 3 and 7 were
hydrolysed in smooth basic conditions followed by
acidification step providing easily the corresponding pure
hydrochloride salts of diacids 5 and 8 in 80% yield.
An alternative pathway was investigated to obtain the meta-
NO2Ph-EDDA 11. m-nitroaniline was converted to the
dialkylated ester 10 after alkylation reaction with compound
9. This intermediate was first prepared by a well-known
two-steps synthesis using ethanolamine as starting
The coordination chemistry behaviour of one of our
ligands has also been investigated. When reacted with the
Re(CO)5Cl precursor in methanol and in the presence of
Scheme 2. o,p-NO2Ph-PDDA derivatives Reagents and conditions: (i) (a) 1,3-diaminopropane, 100 8C, 1 h 92% (ii) BrCH2COOEt, K2CO3, KI, ACN, 60 8C,
12 h, 83–90% (iii) 2 N NaOH/EtOH, 70 8C, 3 h then 2 N HCl, 80%.
Scheme 3. BCA synthesis.

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M. Allali et al. / Tetrahedron 60 (2004) 1167–1174
Scheme 4. Re(I) complex formation.
triethylamine, the ligand 5 formed almost quantitatively a
well-defined species with a metal-to-ligand ratio of 1:1 as
evident by proton NMR spectroscopy and mass spectra
(Scheme 4).
performed using precoated Kieselgel 60 plates F254 (TLC
plates, Merck) and was visualized by UV or iodine.
NMR spectra were recorded on a Bruker AC 200
(50.323 MHz for 13C and 200.133 MHz for 1H), 250
(62.896 MHz for 13C and 250.133 MHz for 1H) or 300
In the free ligand, the two methylene groups appear as an
unique singlet (3.59 ppm). After complexation with
Re(CO)5Cl, the singlet splits into two doublets forming
the pattern of two AB-spin systems at 3.48 and 3.65 ppm
(J¼16 Hz). This feature is in accordance with the proposed
tridentate coordination via the tertiary amine and the two
carboxylic acids. The complex was a NHEtþ3 salt as evident
by elemental analysis. This is confirmed by the negative
Electrospray spectrum that presents two prominent ion
peaks with an isotope distribution pattern consistent with the
monomeric anion [Re(CO)3(NO2Ph-EDDA)]2. The IR
spectrum revealed firstly the presence of N–H stretching
band of secondary aromatic amine and secondly three bands
in the carbonyl stretching region (2029–1887 cm21) which
is characteristic of a fac-octahedral tricarbonyl metal
moiety.20 This proved the tridentate coordination of the
metal-tricarbonyl core via the EDDA ligand. The complex
is soluble in all polar organic solvents and is stable to aerial
oxidation.
1
apparatus (75.467 MHz for 13C and 300.13 MHz for H).
Chemical shifts are indicated in d values (ppm) downfield
from internal TMS, and coupling constants (J) are given in
Hertz (Hz). Multiplicities were recorded as s (singlet), d
(doublet), t (triplet) q (quadruplet), qt (quintuplet) and m
(multiplet). For aromatic ring NMR assignments, the
protons (or carbons) were numbered from 1 to 6 starting
from carbon bearing the secondary aromatic amine and
turning clockwise. Infrared spectrum was recorded as KBr
pellets on a BRUKER Vector 22 spectrophotometer in the
range 4000–400 cm21. Electrospray or DCI-Mass spectra
were obtained on a NERMAG R 10–10 mass spectrometer.
Microanalysis was performed by the microanalytical
´
department of the Ecole Nationale Superieure de Chimie
de Toulouse. Melting points were determinated on a stuart
melting point SMP3 apparatus and are uncorrected.
4.1. Synthesis of EDDA derivatives
4.1.1. N-(2-Nitrophenyl)ethylenediamine (1). 2-Nitro-
chlorobenzene (10 g, 0.063 mol) and ethylenediamine
(40 g, 0.67 mol) were stirred 1 h under reflux. After
distillation of the excess of ethylenediamine, the crude
was acidified at pH 6 with 2 N HCl, then heated and filtrated.
After cooling, 13.02 g of N-(2-nitrophenyl)ethylenediamine
hydrochloride were collected as yellow needles.
3. Conclusion
A versatile way to produce tridentate chelating systems for
low oxidation state metal carbonyls like M(CO)3 fragment
(M¼Tc or Re) was presented. While still maintaining a
simplicity of synthesis and high overall yield, we have
developed a new range of amino diacetic acid derivatives. A
decisive advantage of the presented synthetic strategy is that
this kind of molecules already possesses a linking site for
future coupling to biomolecule. First complexation study
has shown that these compounds act exclusively as
tridentate ligands (via the two acids functions and the
tertiary amine). The convenient synthesis of this new range
of molecules coupled with their high affinity for Re(I) make
them promising candidates for radiopharmaceuticals.
Rhenium(I) and technetium(I) chemistry of all our ligands
are currently in progress.
The product was dissolved in water (10 mL). The solution
was basified at pH 12 and extracted twice with chloroform
(15 mL). The organic layer was dried with sodium sulfate,
filtered and concentrated to dryness under reduce pressure to
give 1 as an orange oil (10.60 g, 93%)
1H NMR (200 MHz, CDCl3) dH (ppm): 1.32 (bs, 2H, NH2);
3.04 (m, 2H, CH2); 3.35 (m, 2H, CH2); 6.62 (m, 1H, H-5);
6.85 (m, 1H, H-3); 7.41 (m, 1H, H-4); 8.13 (m, 1H, H-6);
8.24 (s, 1H, NH); 13C NMR (50.3 MHz, CDCl3) dC (ppm):
40.8 (CH2); 45.7 (CH2); 113.6 (C-3); 115.3 (C-5); 127.0
(C-6); 133.0 (C-2); 136.3 (C-4); 145.6 (C-1); MS
(DCI/NH3): 182 (MþHþ); 199 (MþNH4þ); mp¼261 8C;
Anal.: found (as hydrochloride salt): C, 44.2; H, 5.6; N,
19.7%; C8H12N3O2Cl requires: C, 44.2; H, 5.6; N, 19.3%.
4. Experimental
All chemicals were of the highest purity commercially
available. Solvents were purified by standard methods
before use and stored over 0.3 nm molecular sieves. Silica
gel (0.060–0.200 nm) was purchased from Acros. TLC was
4.1.2. N-(2-Aminophenyl)ethylenediamine trihydro-
chloride (2). 3.00 g (16.6 mmol) of
1 and 13.5 g

M. Allali et al. / Tetrahedron 60 (2004) 1167–1174
1171
(59.8 mmol) of SnCl2.2H2O were heated at 100 8C in
concentrated chlorhydric acid (30 mL). After 1 h, the
mixture was cooled and filtrated. The residue was dissolved
in water and H2S gas was bubbled into the solution to
precipitate tin salt. After filtration, the filtrate was
concentrated to dryness under reduce pressure to give 2 as
pale yellow crystals (3.97 g, 92%).
4 8C. The obtained precipitate was filtered and dried under
vacuum to give 5 as yellow powdery product (267 mg, 80%).
1H NMR (250 MHz, DMSO-d6) dH (ppm): 3.02 (m, 2H,
NCH2); 3.43 (m, 2H, NCH2); 3.59 (s, 4H, 2NCH2); 6.67 (m,
1H, H-5); 7.06 (m, 1H, H-3); 7.52 (m, 1H, H-4); 8.03 (m,
1H, H-6); 8.33 (bs, 1H, NH); 13C NMR (62.9 MHz, DMSO-
d6) dC (ppm): 40.6 (NCH2); 51.8 (NCH2); 54.3 (NCH2);
114.5 (C-3); 115.0 (C-5); 126.0 (C-6); 130.9 (C-2); 136.4
(C-4); 144.9 (C-1); 171.8 (2CO); MS (DCI/NH3): 298
(MþHþ). Anal.: found (as hydrochloride salt): C, 43.4; H,
4.8; N, 12.2%; mp¼219 8C; C12H16N3O6Cl requires: C,
43.2; H, 4.8; N, 12.6%.
1H NMR (200 MHz, D2O) dH (ppm): 3.13 (m, 2H, CH2);
3.44 (m, 2H, CH2); 6.77–6.87 (m, 2H, ArH); 7.17–7.33 (m,
2H, ArH); 13C NMR (50.3 MHz, D2O) dC (ppm): 40.7
(CH2); 42.4 (CH2); 116.8 (C-5); 120.4 (C-3); 122.0 (C-6);
126.7 (C-4); 134.0 (C-1); 143.0 (C-2); MS (DCI/NH3): 152
[(M23HCl)þHþ]; mp¼214 8C; Anal.: found (as trihydro-
chloride salt): C, 37.0; H, 6.3; N, 15.8%; C8H16N3Cl3
requires: C, 36.9; H, 6.1; N, 16.1%.
4.1.6. N-(4-Nitrophenyl)ethylenediamine (6). 4-nitro-
chlorobenzene (10 g, 0.063 mol) and ethylenediamine
(40 g, 0.67 mol) were stirred 1 h and half under reflux.
After distillation of the excess of ethylenediamine, the crude
was taken in hot distillated water (150 mL) and filtrated.
After cooling, 6 was collected as an orange solide (9.70 g,
85%).
4.1.3. N-(2-Nitrophenyl)ethylenediamine-N0,N0-diethyl-
diacetate (3). A mixture of 1 (785 mg, 4.34 mmol),
potassium iodide (1.44 g, 0.87 mmol), potassium carbonate
(9.00 g, 6.51 mmol) and ethyl bromoacetate (1.00 mL,
9.02 mmol) in acetonitrile (100 mL), over an atmosphere
of nitrogen, was boiled one night at 60 8C. The insoluble
materials were filtered off and the solvent was removed
under reduced pressure. The crude material was purified by
column chromatography on silica gel (eluent: CH2Cl2 then
CH2Cl2/AcOEt: 4/6) to give 3 as an orange oil (1.38 g, 90%).
1H NMR (200 MHz, CDCl3) dH (ppm): 1.36 (s, 2H, NH2);
3.01 (m, 2H, CH2); 3.25 (m, 2H, CH2); 5.29 (s, 1H, NH);
6.66 (d, 2H, J¼9.4 Hz, H-2, H-6); 8.05 (d, 2H, J¼9.4 Hz,
H-3, H-5); 13C NMR (50.3 MHz, CDCl3) dC (ppm): 40.5
(CH2); 45.2 (CH2); 111.1 (C-2, C-6); 126.5 (C-3, C-5);
137.8 (C-4); 154.4 (C-1); MS (DCI/NH3): 182 (MþHþ),
199 (MþNHþ4 ); mp¼142 8C, Anal.: found: C, 52.8; H, 6.0;
N, 22.7%; C8H11N3O2 requires: C, 52.7; H, 6.0; N, 23.1%.
1H NMR (200 MHz, CDCl3) dH (ppm): 1.24 (t, 6H,
J¼7.1 Hz, 2CH3); 3.13 (m, 2H, NCH2); 3.37 (m, 2H,
NCH2); 3.60 (s, 4H, 2NCH2); 4.15 (q, 4H, J¼7.1 Hz,
2OCH2); 6.63 (m, 1H, H-5); 6.82 (m, 1H, H-3); 7.40 (m, 1H,
H-4); 8.15 (m, H, H-6); 8.35 (bs, 1H, NH); 13C NMR
(50.3 MHz, CDCl3) dC (ppm): 14.2 (CH3); 41.0 (NCH2);
52.1 (NCH2); 55.5 (2NCH2); 60.8 (2 OCH2); 113.9 (C-3);
115.1 (C-5); 126.8 (C-6); 136.1 (C-2); 139.0 (C-4); 145.2
(C-1); 171.0 (2CO); MS (DCI/NH3): 354 (MþHþ).
4.1.7. N-(4-Nitrophenyl)ethylenediamine-N0,N0-diethyl-
diacetate (7). Using the same procedure than 3, 786 mg
of 6 gave 7 as an orange oil (1.27 g, 83%).
1H NMR (250 MHz, CDCl3) dH (ppm): 1.28 (t, 6H,
J¼7.1 Hz, 2CH3); 3.00 (m, 2H, NCH2); 3.13 (m, 2H,
NCH2); 3.52 (s, 4H, 2NCH2); 4.12 (q, 4H, J¼7.1 Hz,
2OCH2); 6.41 (bs, 1H, NH); 6.82 (d, 2H, J¼9.2 Hz, H-2,
H-6); 8.01 (d, 2H, J¼9.2 Hz, H-3, H-5); 13C NMR
(50.3 MHz, CDCl3) dC (ppm): 13.9 (CH3); 40.5 (NCH2);
51.9 (NCH2); 54.9 (2NCH2); 60.9 (2 OCH2); 110.7 (C-2,
C-6); 126.5 (C-3, C-5); 137.2 (C-4); 153.8 (C-1); 171.7
(2CO); MS (DCI/NH3): 354 (MþHþ).
4.1.8. N-(4-Nitrophenyl)ethylenediamine-N0,N0-diacetic
acid hydrochloride salt (8). Using the same procedure
than 5, 353 mg of compound 7 gave 8 as orange powdery
product (260 mg, 78%).
4.1.4. 4-(2-Nitrophenyl)-3-oxopiperazin-1-yl acetic acid
(4). 1.12 g (3.17 mmol) of compound 3 into 10 mL of 6 N
HCl were refluxed during 24 h. After cooling, the solvent
was removed under reduced pressure. The crude product
was taken in 10 mL of ethyl acetate and the organic layer
was washed twice with water (30 mL), dried with sodium
sulfate and concentrated under vacuum to give 4 as a yellow
solid (620 mg, 70%).
1H NMR (200 MHz, D2O) dH (ppm): 3.70 (m, 2H, NCH2);
4.16 (m, 4H, 2NCH2); 4.26 (m, 2H, NCH2); 7.50 (m, 1H,
H-6); 7.70 (m, 1H, H-4); 7.84 (m, 1H, H-5); 8.16 (m, 1H,
H-3); 13C NMR (50.3 MHz, D2O) dC (ppm): 46.3 (NCH2);
51.4 (NCH2); 55.5 (NCH2); 58.5 (NCH2); 126.5 (C-3);
131.6 (C-5); 133.7 (C-6); 134.7 (C-2); 136.5 (C-4); 147.3
(C-1); 165.7 (CO); 169.8 (COOH); MS (DCI/NH3): 280
(MþHþ); 297 (MþNHþ4 ). Anal.: found (as hydrochloride
salt): C, 41.0; H, 4.7; N, 11.4%; mp¼204 8C;
C12H15N3O5Cl2 requires: C, 40.9; H, 4.3; N, 11.9%.
1H NMR (250 MHz, DMSO-d6) dH (ppm): 2.93 (,t, 2H,
J¼6.2 Hz, NCH2); 3.23 (,t, 2H, J¼6.2 Hz, NCH2); 3.50 (s,
4H, 2NCH2); 6.65 (d, 2H, J¼9.3 Hz, H-2, H-6); 7.30 (bs,
1H, NH); 8.03 (d, 2H, J¼9.3 Hz, H-3, H-5); 13C NMR
(62.9 MHz, DMSO-d6) dC (ppm): 40.4 (NCH2); 52.1
(NCH2); 54.6 (NCH2); 110.7 (C-2, C-6); 126.1 (C-3, C-5);
135.5 (C-4); 154.2 (C-1); 172.3 (2CO); MS (DCI/NH3): 298
(MþHþ). Anal.: found (as hydrochloride salt): C, 43.3; H,
4.6; N, 12.7%; mp¼186 8C; C12H16N3O6Cl requires: C,
43.2; H, 4.8; N, 12.6%.
4.1.5. N-(2-Nitrophenyl)ethylenediamine-N0,N0-diacetic
acid hydrochloride salt (5). 353 mg (1 mmol) of diester
3 in 10 mL of a 2 N NaOH/ethanol (1/1) solution were
heated at 70 8C for 3 h. After cooling, the solution was
acidified with 2 N HCl until pH was 1 and left a few hours at
4.1.9. N-(3-Nitrophenyl)ethylenediamine-N0,N0-diethyl-
diacetate (10). In an atmosphere of nitrogen, a mixture of

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M. Allali et al. / Tetrahedron 60 (2004) 1167–1174
3-nitroaniline (310 mg, 2.24 mmol), potassium iodide
(310 mg, 1.87 mmol), potassium carbonate (514 mg,
3.73 mmol) and compound 9 (663 mg, 2.24 mmol) in
acetonitrile (100 mL) was boiled under reflux for 3 h. The
insoluble materials were filtered off and the solvent was
removed under reduced pressure. The crude material was
purified by column chromatography on silica gel, eluting
with CH2Cl2 to give 10 as a brown oil (474 mg, 60%).
55.1; H, 6.7; N, 21.3%; mp¼94 8C; C9H13N3O2 requires: C,
55.1; H, 6.6; N, 21.4%.
4.2.3. N-(2-Nitrophenyl)propylenediamine-N0,N0-diethyl-
diacetate (14). Using the same procedure than 3, 846 mg of
compound 12 gave 14 as an orange oil (1.44 g, 90%).
1H NMR (250 MHz, CDCl3) dH (ppm): 1.19 (t, 6H,
J¼7.0 Hz, 2CH3); 1.81 (qt, J¼6.7 Hz, 2H, CH2); 2.81 (m,
2H, NCH2); 3.45 (m, 2H, NCH2); 3.55 (s, 4H, 2NCH2); 4.15
(q, 4H, J¼7.0 Hz, 2OCH2); 6.55 (m, 1H, H-5); 6.86 (m, 1H,
H-3); 7.35 (m, 1H, H-4); 8.09 (m, 1H, H-6); 8.19 (bs, 1H,
NH); 13C NMR (50.3 MHz, CDCl3) dC (ppm): 13.9 (CH3);
27.0 (CH2); 40.8 (NCH2); 51.5 (NCH2); 55.1 (2NCH2); 60.5
(2 OCH2); 113.7 (C-3); 115.1 (C-5); 126.7 (C-6); 131.7
(C-2); 136.2 (C-4); 145.6 (C-1); 171.1 (2CO); MS
(DCI/NH3): 368 (MþHþ).
1H NMR (250 MHz, CDCl3) dH (ppm): 1.27 (m, 6H, 2CH3);
3.15 (m, 4H, 2NCH2); 3.57 (s, 4H, NCH2); 4.19 (s, 4H,
2OCH2); 5.60 (bs, 1H, NH); 6.90 (m, 1H, H-6); 7.35 (m, 3H,
H-2, H-4, H-5); 13C NMR (62.9 MHz, CDCl3) dC (ppm):
13.9 (CH3); 42.2 (NCH2); 52.7 (NCH2); 55.2 (2NCH2); 60.8
(2 OCH2); 105.4 (C-2); 110.6 (C-6); 118.4 (C-4); 129.5
(C-5); 148.2 (C-3); 149.2 (C-1); 171.7 (2CO); MS
(DCI/NH3): 354 (MþHþ).
4.1.10. N-(3-Nitrophenyl)ethylenediamine-N0,N0-diacetic
acid (11). Using the same procedure than 5, 353 mg of
compound 10 gave 11 as brown crystals (267 mg, 90%).
4.2.4. N-(4-Nitrophenyl)propylenediamine-N0,N0-diethyl-
diacetate (15). Using the same procedure than 3, 846 mg of
compound 13 gave 15 as an orange oil (1.33 g, 83%).
1H NMR (250 MHz, DMSO-d6) dH (ppm): 2.88 (,t, 2H,
J¼6.3 Hz, NCH2); 3.15 (,t, 2H, J¼6.3 Hz, NCH2); 3.51 (s,
4H, 2NCH2); 6.35 (bs, 1H, NH); 6.98 (m, 1H, H-6); 7.33 (m,
3H, H-2, H-4, H-5); 13C NMR (50.3 MHz, DMSO-d6) dC
(ppm): 41.0 (NCH2); 52.3 (NCH2); 54.7 (NCH2); 105.1
(C-2); 109.6 (C-6); 118.2 (C-4); 129.9 (C-5); 148.7 (C-3);
149.7 (C-1); 172.7 (2CO); MS (DCI/NH3): 298 (MþHþ);
mp¼150 8C; Anal.: found: C, 48.0; H, 5.2; N, 13.9%;
C12H15N3O6 requires: C, 48.5; H, 5.0; N, 14.1%.
1H NMR (250 MHz, CDCl3) dH (ppm): 1.23 (t, 6H,
J¼7.0 Hz, 2CH3); 1.69 (m, 2H, CH2); 2.78 (m, 2H,
NCH2); 3.35 (m, 2H, NCH2); 3.49 (s, 4H, 2NCH2); 4.17
(q, 4H, J¼7.0 Hz, 2OCH2); 6.51 (d, 2H, J¼9.4 Hz, H-2,
H-6); 7.72 (bs, 1H, NH); 8.00 (d, 2H, J¼9.4 Hz, H-3, H-
5); 13C NMR (62.9 MHz, CDCl3) dC (ppm): 14.4 (CH3);
25.3 (CH2); 41.9 (NCH2); 52.4 (NCH2); 54.9 (2NCH2);
60.8 (2 OCH2); 110.6 (C-2, C-6); 126.5 (C-3, C-5); 136.4
(C-4); 154.2 (C-1); 171.3 (2CO); MS (DCI/NH3): 368
(MþHþ).
4.2. Synthesis of PDDA derivatives
4.2.5. N-(2-Nitrophenyl)propylenediamine-N0,N0-diacetic
acid hydrochloride salt (16). Using the same procedure
than 5, 367 mg of compound 14 gave 16 as a yellow powder
(278 mg, 80%).
4.2.1. N-(2-Nitrophenyl)propylenediamine (12). Using
the same procedure than 1 and substituting ethylenediamine
by 1,3-diaminopropane (46.62 g, 0.63 mol), we obtained
after purification 12 as an orange-red oil (11.42 g, 93%).
1H NMR (250 MHz, DMSO-d6) dH (ppm): 1.47 (m, 2H,
CH2); 2.77 (m, 2H, NCH2); 3.48 (m, 6H, 3NCH2); 6.70 (m,
1H, H-5); 7.09 (m, 1H, H-3); 7.56 (m, 1H, H-4); 8.02 (m, H,
H-6); 8.30 (bs, 1H, NH); 13C NMR (62.9 MHz, DMSO-d6)
dC (ppm): 26.2 (CH2); 40.6 (NCH2); 51.0 (NCH2); 54.5
(NCH2); 114.3 (C-3); 114.8 (C-5); 126.1 (C-6); 130.7 (C-2);
136.4 (C-4); 145.1 (C-1); 172.2 (2CO); MS (DCI/NH3): 312
(MþHþ). Anal.: found (as hydrochloride salt): C, 44.6; H,
5.1; N, 12.4%; mp¼158 8C; C13H18N3O6Cl requires: C,
44.9; H, 5.2; N, 12.1%.
1H NMR (250 MHz, CDCl3) dH (ppm): 1.20 (bs, 2H, NH2);
1.82 (q, 2H, J¼7.0 Hz, CH2); 2.82 (t, J¼7.0 Hz, 2H, NCH2);
3.33 (m, 2H, NCH2); 6.56 (m, 1H, H-5); 6.80 (m, 1H, H-3);
7.35 (m, 1H, H-4); 8.04 (m, 1H, H-6); 8.11 (bs, 1H, NH);
13C NMR (62.9 MHz, CDCl3) dC (ppm): 32.3 (CH2);
39.8 (NCH2); 41.0 (NCH2); 113.9 (C-3); 115.7 (C-5);
126.9 (C-6); 131.8 (C-2); 136.4 (C-4); 145.7 (C-1);
MS (DCI/NH3): 196 (MþHþ); 213 (MþNH4þ);
mp¼174 8C; Anal.: found (as hydrochloride salt): C, 46.8;
H, 6.2; N, 18.2%; C9H14N3O2Cl requires: C, 46.7; H, 6.1; N,
18.2%.
4.2.6. N-(4-Nitrophenyl)propylenediamine-N0,N0-diacetic
acid hydrochloride salt (17). Using the same procedure
than 5, 367 mg of compound 15 gave 17 as an hydroscopic
orange powder (274 mg, 79%).
4.2.2. N-(4-Nitrophenyl)propylenediamine (13). Using
the same procedure than 6 and substituting ethylenediamine
by 1,3-diaminopropane (46.62 g, 0.63 mol), we obtained
after purification 13 as an orange solide (11.30 g, 92%).
1H NMR (250 MHz, DMSO-d6) dH (ppm): 1.67 (q,
J¼6.6 Hz, 2H, CH2); 2.77 (t, 2H, J¼6.6 Hz, NCH2); 3.20
(m, 2H, NCH2); 3.44 (s, 4H, 2NCH2); 6.64 (d, 2H,
J¼9.5 Hz, H-2, H-6); 7.50 (bs, 1H, NH); 7.56 (d, 2H,
J¼9.5 Hz, H-3, H-5); 13C NMR (62.9 MHz, DMSO-d6) dC
(ppm): 26.2 (CH2); 40.6 (NCH2); 51.4 (NCH2); 54.6
(NCH2); 110.6 (C-2, C-6); 126.2 (C-3, C-5); 135.2 (C-4);
154.5 (C-1); 172.4 (2CO); MS (DCI/NH3): 312 (MþHþ);
mp¼130 8C; Anal.: found (as hydrochloride salt): C, 40.7;
1H NMR (200 MHz, CDCl3) dH (ppm): 1.40 (s, 2H, NH2);
1.75 (m, 2H, CH2); 2.89 (m, 2H, CH2); 3.30 (m, 2H, CH2);
5.76 (bs, 1H, NH); 6.92 (d, 2H, J¼9.4 Hz, H-2, H-6); 7.21
(d, 2H, J¼9.4 Hz, H-3, H-5); 13C NMR (50.3 MHz, CDCl3)
dC (ppm): 31.3 (CH2); 40.5 (CH2); 42.5 (CH2); 110.8 (C-2,
C-6); 126.5 (C-3, C-5); 140.8 (C-6); 153.7 (C-1); MS
(DCI/NH3): 196 (MþHþ); 213 (MþNHþ4 ); Anal.: found: C,

M. Allali et al. / Tetrahedron 60 (2004) 1167–1174
1173
H, 4.9; N, 11.2% C13H18N3O6Cl.2H2O requires: C, 40.7; H,
5.7; N, 11.0%.
concentrated to dryness under reduce pressure. The crystal-
lisation step was repeated twice. In these conditions,
produced Et3NHCl staid in the filtrate and 20 was obtained
as a yellow powder (triethylamine hydrochloride salt,
180 mg, 90%).
4.3. Synthesis of bifunctional chelating agent
4.3.1. N-(2-Aminophenyl)ethylenediamine-N0,N0-diethyl-
diacetate (18). Catalytic hydrogenation of 3 (0.54 g,
1.53 mmol) in methanol (25 mL) over 10% Pd/C (20%
w/w) was carried out at atmospheric pressure. After 30 min,
the catalyst was filtered off (Celite), and the solvent was
removed under reduced pressure. The crude material was
purified by column chromatography on silica gel, eluting
with methanol to give 18 as a brown oil (0.37 g, 75%).
NMR 1H (300 MHz, DMSO-d6) dH (ppm): 1.07 (t, 9H,
J¼7.1 Hz, CH3); 3.01 (q, 6H, J¼7.1 Hz, NCH2); 3.39 (m,
2H, NCH2); 3.48 (AB system, 2H, J¼16.0 Hz, CH2CO);
3.59 (m, 2H, NCH2); 3.65 (AB system, 2H, J¼16.0 Hz,
CH2CO); 6.63 (m, 1H, H-6); 7.17 (d, 1H, J¼8.5 Hz, H-4);
7.50 (m, 1H, H-5); 8.00 (dd, 1H, J¼8.5 and 1.5 Hz, H-3);
8.13 (t, J¼6,0 Hz, 1H, NH).13C NMR (75.5 MHz, DMSO-
d6) dC (ppm): 9.17 (CH3); 38.5 (NCH2); 46.2 (NCH2); 63.2
(CH2CO); 67.2 (NCH2); 114.9 (C-6); 116.0 (C-4); 126.8
(C-3); 131.8 (C-2); 137.2 (C-5); 145.0 (C-1); 178.8 (2CO);
199.1, 199.4 (3CO), IR (KBr): 3369 br, 2029 s, 1917 s, 1887
s, 1666 s cm21; MS (ES2): 564 (60), 566 (100) [M2];
mp¼217 8C; Anal.: found: C, 38.1; H, 4.3; N, 8.4%;
C21H29N4O9Re requires: C, 37.8; H, 4.3; N, 8.4%.
1H NMR (250 MHz, CDCl3) dH (ppm): 1.24 (t, 6H,
J¼7.1 Hz, 2CH3); 3.07 (m, 4H, 2NCH2); 3.55 (s, 4H,
2NCH2); 4.13 (q, 4H, J¼7.1 Hz, 2OCH2); 6.57–6.67 (m,
4H, ArH); 13C NMR (62.9 MHz, CDCl3) dC (ppm): 14.2
(CH3); 41.6 (NCH2); 53.0 (NCH2); 55.1 (2NCH2); 60.7 (2
OCH2); 111.2 (C-3); 115.6 (C-5); 118.0 (C-6); 119.8 (C-2);
134.6 (C-4); 137.3 (C-1); 171.7 (2CO); MS (DCI/NH3): 324
(MþHþ).
4.3.2. N-(2-Aminophenyl)ethylenediamine-N0,N0-diacetic
acid dihydrochloride salt (19). Method A: 200 mg
(0.62 mmol) of diester 18 in 10 mL of a 2 N NaOH/ethanol
(1/1) solution was heated at reflux for 3 h. After cooling, the
solution was acidified until pH was 1 with 2 N HCl. The
solution was concentrated and the residue was taken twice
with acetone (20 mL). After filtration, the filtrate was
evaporated, dried under vacuum to afford a brown solid
(168 mg, 75%).
Acknowledgements
´
The authors thank the C.M.I.F.M. (Comite Mixte Inter
Universitaire Franco-Marocain) for financial support
(project MA/02/35).
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1H NMR (200 MHz, D2O) dH (ppm): 2.74 (m, 2H, NCH2);
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55.9 (NCH2); 61.5 (2NCH2); 116.2 (C-6); 118.9 (C-4);
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