Sequestering agent for uranyl chelation: a new family of CAMS ligands

Article abstract of DOI:10.1016/j.tet.2008.05.021

The synthesis of new dipodal bis-sulfocatecholamide uranophiles is presented. Their binding abilities for uranyl cation were determined by UV spectrophotometry in aqueous media under various pH conditions and further studied by ¹H NMR analysis of the resonance signal of both aromatic protons of the sulfocatecholamide groups. The results showed that the efficiency of these hydrosoluble chelating agents depends on the nature of the spacers. Each ligand shows a more or less pronounced affinity for uranium. The best receptor is the ligand CYCAMS 5d obtained as a mixture of cis/trans isomers, which achieves the best compromise between rigidity and steric hindrance.

Full text of DOI:10.1016/j.tet.2008.05.021

Tetrahedron 64 (2008) 6662–6669
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Sequestering agent for uranyl chelation: a new family of CAMS ligands
a
b
a
,
a
*
´
´
Antoine Leydier , Delphine Lecercle , Stephane Pellet-Rostaing , Alain Favre-Reguillon ,
b
a
´ ´
Frederic Taran , Marc Lemaire
a
`
´
´
Laboratoire de Catalyse et Synthese Organique, ICBMS, Institut de Chimie et Biochimie Moleculaires et Supramoleculaires,
CNRS, UMR 5246, Universite´ Claude Bernard LYON-1, 69622 Villeurbanne, France
b Service de Chimie Bio-organique et de Marquage, iBiTec-S, CEA-Saclay 91191 Gif sur Yvette, France
a r t i c l e i n f o
a b s t r a c t
Article history:
The synthesis of new dipodal bis-sulfocatecholamide uranophiles is presented. Their binding abilities for
uranyl cation were determined by UV spectrophotometry in aqueous media under various pH conditions
and further studied by 1H NMR analysis of the resonance signal of both aromatic protons of the sulfo-
catecholamide groups. The results showed that the efficiency of these hydrosoluble chelating agents
depends on the nature of the spacers. Each ligand shows a more or less pronounced affinity for uranium.
The best receptor is the ligand CYCAMS 5d obtained as a mixture of cis/trans isomers, which achieves the
best compromise between rigidity and steric hindrance.
Received 18 March 2008
Received in revised form 2 May 2008
Accepted 7 May 2008
Available online 11 May 2008
Keywords:
CAMS
Dipodal ligands
Chelates
Ó 2008 Elsevier Ltd. All rights reserved.
Uranium
1. Introduction
Although sought for many years, there are only a few ligands
that are able to strongly bind U(VI) in vivo, promote its excretion
Uranium is the second most common naturally occurring
actinide (after thorium), and is more widely used than thorium.
Uranium is most commonly used as nuclear fuel in fission reactors
for civilian purpose. The hexavalent uranyl ion (UO22þ, U(VI)) was
proved to be the most stable form in aqueous solutions and in vivo1
at physiological pH.
When actinides such as uranium are introduced in the body in
the case of internal contamination or in the event of a nuclear
accident by ingestion, inhalation or through wounds, they are
chelated in the blood by complexing agents such as proteins or
carbonates. After chelation, toxic species are distributed and
retained in target organs such as kidneys, liver or bones.2 This can
induce cancer and chemical intoxication in the case of heavy
contamination.3
To avoid these effects, heavy metals must be eliminated from
the body by administering non-toxic chelating agents. Non-toxic
chelating agents can form highly stable complex so that the body
can rapidly excrete the poison from blood and target organs. Fur-
thermore, the uranyl-ligand complexes must be soluble and stable
in physiological fluids in a pH range of 2–9 to be subsequently
eliminated from the body after crossing the renal or hepatic bar-
riers. Thus uranyl concentrations and radiation doses, and sub-
sequently tumour risks may be reduced.
and efficiently prevent or reduce deposition in kidneys and bones,
the two main target organs of U(VI).
During the past 30 years, several effective uranyl ligands were
synthesised, based on different complexing functions. Phosphorus
containing molecules, especially bisphosphonates, were found to
be very effective uranyl ligands,4–7 but few significant decorpora-
tion works have been reported so far concerning the decorporation
efficacy of EHBP.8–11
Decorporation with bidentate methylterphthalimide (MeTAM)-
based chelating ligands was also studied, which did not suit for
biological decorporation due to their high toxicity.12
Sulfocatechol Tiron, which forms a stable U(VI) complex within
the physiological pH range,13 was injected promptly, reducing sig-
nificantly tissue uranium concentration in mice.14 However, a molar
ratio greater than 200 was required to reduce U(VI) deposition in
kidneys, offering only modest encouragement with regard to its
possible therapeutic potential.15,16 Nevertheless, the modest suc-
cessful reduction of acute U(VI) toxicity and reduction of body U(VI)
with Tiron and the favourable stability constant of U(VI)–catechol
(log KML¼15.9) suggested that multidentate ligands containing
sulfocatecholamide (CAMS) or structurally analogous hydroxyl-
pyridone (HOPO) units would be effective for in vivo chelation of
U(VI).17,18
A rational design of uranyl-sequestering agents based on 3-
hydroxy-2(1H)-pyridinone (3,2-HOPO) and sulfocatecholamide
(CAMS) ligands resulted in the first effective agent for mammalian
* Corresponding author. Tel.: þ33 (0) 4 72 44 85 07; fax: þ33 (0) 4 72 43 14 08.
E-mail address: pellet@univ-lyon1.fr (S. Pellet-Rostaing).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.05.021

A. Leydier et al. / Tetrahedron 64 (2008) 6662–6669
6663
H
N
H
N
2. Results and discussion
2.1. Synthesis
O
O
O
OH
O
HO
O
Based on Raymond’s procedure,18,19 the first step of the syn-
thesis involved the reaction of an excess of oxalyl chloride with the
protected catechol 2 in dichloromethane assisted by a catalytic
amount of DMF to afford the corresponding acid chloride in-
termediate in a quantitative yield. Addition of the acid chloride on
diamines 1a–h in the presence of Et3N gave the bis-catecholamides
analogues 3a–h in good yields (Scheme 1).
N
N
5-LIO(Me-3,2-HOPO)
HN NH
O
O
OH
OH
HO
HO
HO3S
SO3H
5-LI-CAMS
C5
O
OH
NH
O
HN
O
Figure 1. Low-toxicity uranyl complexants.
O
1) (COCl)2, CH2Cl2
O
O
O
O
2) CH2Cl2, N(Et)3
1a-h
uranyl decorporation. Raymond found that both non-toxic ligands
5-LICAM(S) and 5-LIO(Me-3,2-HOPO) (Fig. 1) efficiently chelate
circulating U(VI) in the body.18 5-LICAM(S) is able to divert to ex-
cretion a significant fraction of the U(VI) already deposited in bone
when injected promptly (5–30 min) after contamination. Sufficient
5-LICAM(S) was orally bioavailable to reduce kidney U(VI),12 but
5-LIO(Me-3,2-HOPO) was the most effective for the reduction of
U(VI) in that organ.18
O
2
3a-h (73-98%)
C5
BBr3
CH2Cl2
NH
O
HN
O
OH HO
OH HO
Structure–activity relationship19 underscores that the linear
tetradentate ligands were generally more effective for reducing
whole body and kidney uranium than the higher denticity ligands
with branched chains. The in vivo results also indicated that both
the chain length and the number of the substituents on the linear
aliphatic diamine linker of these tetradentate ligands play impor-
tant roles in toxicity and in vivo U(VI) chelation efficiency. The best
results were obtained with a five-unit backbone for low toxicity and
high efficacy of U(VI) in vivo chelation.
So, our goal was to optimise these structures in order to increase
the affinity of the ligand for the uranyl ion in physiological medium.
Thus we present here the synthesis and the chelating properties of
a family of CAMS derivatives containing different branched (1b and
c), rigidified (1d–g) or chelating (1h) five-unit backbones.
The first part in this project involved the synthesis of a series of
bis-catechol ligands linked by various substituted linear five-unit
backbone diamines as platforms (Fig. 2).
4a-g (77-90%)
Scheme 1. General synthesis of CAMS derivatives.
Depending on the nature of the starting diamines, 3b and 3h
were obtained as racemic mixtures of enantiomers and 3d and 3g
as mixtures of cis/trans stereoisomers.
Deprotection of the hydroxyl groups was achieved using BBr3 in
dichloromethane rather than TMSI that often leads to partial
conversions.20
However, total deprotection of catechol methoxy and ethyl ester
could not be achieved when 1h was used as backbone, even when
the ester was first saponified (3i), decomposition products being
recovered. In order to obtain the desired product 4h, it was nec-
essary to use benzylated catechol 7, which can be deprotected
under mild conditions (Scheme 2). Condensation of 7 with oxalyl
Commercially available diamines 1a and 1c, racemic mixtures of
branched diamines 1b and 1h, cis/trans isomers mixtures of cyclic
diamine 1d or 1g and aromatic derivatives 1e–f were selected as
linker.
The second part concerned the comparative evaluation of the
complexation constants with uranyl ions in water with 5-LICAM(S)
as reference, using SCP method.4
R
O
OH
NH
O
HN
O
1) (COCl)2,
CH2Cl2
O
O
O
O
O
Bn
Bn
Bn Bn
Bn Bn
2) CH2Cl2,
NEt3
1h
O
7
3h': R = COOEt
3i': R = COOH
55%
LiOH, THF/H2O
92%
C5
H2N
NH2
O
OH
H2, Pd/C,
THF
99%
NH
O
HN
O
H2N
NH2
NH2
H2N
H2N
NH2H2N
NH2
OH
OH
HO
HO
1a
1b
1c
BBr3
CH2Cl2
4h
NH2
H2N
H2N
O
OH
NH2
1d
1e
1f
HN
NH
O
O
LiOH,
THF/H2O
80%
CO2Et
O
O
O
3h
Me Me
Me Me
H2N
NH2
H2N
NH2
O
1g
1h
3i
Figure 2. Diamine backbones.
Scheme 2. Synthesis of LysCAM 4h.

6664
A. Leydier et al. / Tetrahedron 64 (2008) 6662–6669
chloride and coupling with diamine 1h afforded 3h0 in 55% yield.
Saponification followed by hydrogenolysis of 3h0 led to 4h as a ra-
cemic mixture of enantiomers in 91% overall yield.
Sulfonation of 4a–d in 20% oleum followed by precipitation
in diethylether gave the desired pure disulfonated compounds
5a–d in good yields. Trisulfonated CAMS 5e and 5f were also
obtained in good yields under these conditions. Unfortunately,
these conditions caused the degradation of 4g and 4h. Compound
5h was finally obtained by sulfonation in H2SO4 at 60 ꢀC in 88%
yield (Fig. 3).
Water-soluble CAMS ligands 5a–f,h were fully characterised by
1H NMR, 13C NMR, mass spectroscopy and elemental analyses.
Resonance signals of the catechol protons of symmetrical 5-LICAMS
5a and 3-MeCAMS 5c in D2O were, respectively, identified as two
doublets at 7.32 ppm and 7.62 ppm (J¼2.08 Hz) and two singlets at
7.27 ppm and 7.57 ppm.
Aromatic protons of 5b were characterised by a broad doublet at
7.28 ppm and two overlapped doublets at 7.58 ppm and 7.59 ppm
demonstrating the expected dissymmetry of the structure of the
ligand. Dissymmetric 5h ligand was also characterised by a well
defined spectrum with two pairs of doublets at 7.64/7.54 ppm and
7.27/7.24 ppm corresponding to the aromatic protons. A cis/trans
isomer mixture of CYCAMS 5d in an 80:20 ratio was confirmed by
the presence of two pairs of doublets located at 7.36 ppm and
7.64 ppm (J¼1.9 Hz) and at 7.31 ppm and 7.62 ppm (J¼2.07 Hz).
Dissymetric structures of m-BENZCAMS 5e and p-BENZCAMS
5f were established on the basis of 2D COSY experiments. Thus
aromatic protons of the catechol moiety of 5f were observed as two
overlapped doublets at 7.23 ppm (J¼2.08 Hz) and two doublets
at 7.59 ppm and 7.55 ppm (J¼2.08 Hz). Resonance signals of the
aromatic protons of the central ring were observed as a singlet
at 7.74 ppm and a large multiplet at 7.31 ppm. Finally, aromatic
protons of catechol moiety of 5e were observed as two overlapped
doublets at 7.27 ppm (J¼2.07 Hz) and two doublets at 7.58 ppm and
7.64 ppm (J¼2.07 Hz). A doublet at 7.83 ppm (J¼8.3 Hz), a broad
singlet at 7.63 ppm and a multiplet at 7.30 ppm were allocated
to the resonance signals of protons of the central aromatic ring.
2.2. Complexation studies
The complexation behaviour of the water-soluble CAMS– de-
rivatives 5a–f,h towards uranyl cation was studied by the spec-
trophotometric method developed by Taran et al.,4 based on
competitive uranium binding by using sulfochlorophenol SCP as
chromogenic chelate, which was found highly suitable for a rapid
screening of putative uranium ligand library.
Comparison of the results obtained with dipodal bis-cat-
echolamides 5a–f showed the influence of the nature of the spacer
separating the two chelating moieties. Globally, the CAMS ligands
exhibit high Kcond enhancement in basic conditions in accordance
with the previous findings.21 The best uranyl-binding performance
independent of pH was observed with CYCAMS 5d (Table 1). At pH
5.5, all CAMS derivatives showed better constant than the reference
5-LICAMS 5a18 except LysCAMS 5h, which was not able to displace
more than 10% of the SCP/UO2 complex.4 Whatever the pH, aro-
matic CAMS 5e and 5f exhibited lower complexation efficiency
towards UO22þ suggesting that these ligands are too rigid.
Theabilityofligands5a–dtocomplexUO22þ was also studied by 1H
NMR spectroscopy. Figure 4 shows the NMR spectra of variable
amount of uranyl nitrate hexahydrate in the presence of LICAMS 5a
and CYCAMS 5d in a binary mixture of D2O/NaOD at room tempera-
ture with sodium nitrate (0.05 mol Lꢁ1). After each addition of
UO2(NO3)2$6H2O, the pH of the deuterated solution was adjusted to
12 by addition of NaOD. In the absence of uranyl nitrate, the doublets
assigned to the H1 and H2 protons of the catechol moieties of 5a
shiftedfrom7.32 ppmand7.62 ppminD2Oto6.85ppmand7.49 ppm
in D2O/NaOD (Fig. 4a and a1). Both pairs of doublets at 7.36/7.64 ppm
and 7.31/7.62 ppm in D2O corresponding to the resonance signals of
the catechol protons of the cis/trans mixture of 5d shift as two
overlapped doublets at 6.88 ppm and 7.51 ppm in D2O/NaOD (Fig. 4b
and b1). Addition of increasing amount of UO2(NO3)2$6H2O (Fig. 4a2–
a5 and 4b2–b5) led to appreciable changes and downfield shifts of the
aromatic proton resonances of the phenol rings (Table 2). Upon ad-
ditionofUO2(NO3)2$6H2Oinadeuteratedsolutioncontaining5a, two
new doublets appear, respectively, at 7.09 ppm and 7.68 ppm
(Fig. 4a2–a4), whose signal intensities (Dd¼0.24 ppm and 0.19 ppm)
depend on the concentration of the ligand. Similarly, the changes in
the level of the signals of the protons of the alkyl chains were also
indicative due to the proximityof the uranyl cation nearby the altered
protons. Thus, the triplet at 3.45 ppm assigned to the CH2NC(O)
protons of the free ligand was located at 3.62 ppm and both multi-
plets corresponding to the resonance signals of CH2CH2CH2 chain
shift from 1.57 ppm and 1.72 ppm to 1.89 ppm as a broad singlet.
When uranyl nitrate hexahydrate was added to a deuterated
solution of 5d, we assumed that UO22þ was simultaneously chelated
by cis and trans stereoisomers, based on the appearance of two
doublets at 7.64 ppm (Dd¼0.13 ppm) and 7.70 ppm (Dd¼0.19 ppm)
of similar integration corresponding to the resonance signals of the
H1 protons of the uranyl complexes (Fig. 4b2). Resonance signals of
H2 shifts from 6.88 ppm to 7.10 ppm (Dd¼0.22 ppm) as two over-
lapped doublets.
4a-f
H2SO4, SO3
C5
O
HN
NH
O
OH
OH
HO
HO
HO3S
SO3H
5a-f
5-LICAMS: 5a (79%)
2-MeCAMS: 5b (77%)
3-MeCAMS: 5c (79%)
Table 1
Kcond of ligand–UO22þat several pH values (ꢂ0.1)
SO3H
pH
log Kcond (U–L)/(pH)
SO3H
5.5
7.4
9.0
SCP4
13.4
11.1
11.3
11.5
11.7
11.4
11.2
<9
19.7
17.0
16.6
16.8
17.5
16.5
16.3
16.6
25.5
19.4
18.7
18.6
19.6
18.5
17.8
18.9
CYCAMS: 5d (78%) m-BENZCAMS 5e (72%) p-BENZCAMS: 5f (57%)
5-LICAMS (5a)
2-MeCAMS (5b)
3-MeCAMS (5c)
CYCAMS (5d)
m-BENZCAMS (5e)
p-BENZCAMS (5f)
LysCAMS (5h)
CO2H
LYSCAMSa: 5h (88%)
MENTCAMS: 5g (0%)
Figure 3. Sulfonation of CAM analogues (aH2SO4, 60 ꢀC).

A. Leydier et al. / Tetrahedron 64 (2008) 6662–6669
6665
O
NH
NH
O
H
N
H
N
O
O
H1
OH
OH
HO
HO
H1
OH
OH
HO
HO
HO3S
SO3H
HO3S
SO3H
H2
+ UO2(NO3)2
H2
+ UO2(NO3)2
b5
a5
7.9 7.8 7.7 7.6 7.5 7.4 7.3 7.2 7.1 7.0 6.9 6.8 6.7 6.6 6.5 6.4 6.3 6.2 6.1
(ppm)
7.90 7.80 7.70 7.60 7.50 7.40 7.30 7.20 7.10 7.00 6.90 6.80 6.70 6.60
(ppm)
a4
b4
7.90 7.80 7.70 7.60 7.50 7.40 7.30 7.20 7.10 7.00 6.90 6.80 6.70 6.60
(ppm)
7.9 7.8 7.7 7.6 7.5 7.4 7.3 7.2 7.1 7.0 6.9 6.8 6.7 6.6 6.5 6.4 6.3 6.2 6.1
(ppm)
b3
a3
7.90 7.80 7.70 7.60 7.50 7.40 7.30 7.20 7.10 7.00 6.90 6.80 6.70 6.60
(ppm)
7.9 7.8 7.7 7.6 7.5 7.4 7.3 7.2 7.1 7.0 6.9 6.8 6.7 6.6 6.5 6.4 6.3 6.2 6.1
(ppm)
b2
a2
7.9 7.8 7.7 7.6 7.5 7.4 7.3 7.2 7.1 7.0 6.9 6.8 6.7 6.6 6.5 6.4 6.3 6.2 6.1
(ppm)
7.90 7.80 7.70 7.60 7.50 7.40 7.30 7.20 7.10 7.00 6.90 6.80 6.70 6.60
(ppm)
a1
b1
7.90 7.80 7.70 7.60 7.50 7.40 7.30 7.20 7.10 7.00 6.90 6.80 6.70 6.60
7.5
7.4 7.3 7.2 7.1 7.0 6.9 6.8 6.7 6.6 6.5 6.4 6.3 6.2 6.1
7.9 7.8 7.7 7.6
(ppm)
(ppm)
a
b
7.5
7.90 7.80 7.70 7.60 7.50 7.40 7.30 7.20 7.10 7.00 6.90 6.80 6.70 6.60
7.9 7.8 7.7 7.6
7.4 7.3 7.2 7.1 7.0 6.9 6.8 6.7 6.6 6.5 6.4 6.3 6.2 6.1
(ppm)
(ppm)
Figure 4. 1H NMR spectra of 5a (a: in D2O, a1: in D2O/NaOD/NaNO3 (0.05 mol Lꢁ1)) and 5d (b: in D2O, b1: in D2O/NaOD/NaNO3 (0.05 mol Lꢁ1)) in the presence of various amounts of
UO2(NO3)2$6H2O at pH 12 (a2, b2: 0.25 equiv; a3, b3: 0.5 equiv; a4, b4: 0.75 equiv; a5, b5: 1 equiv) at 238 K.
4. Experimental section
Table 2
Changes in the 1H NMR aromatic shifts of 5a–d and 5h upon addition of
4.1. General
UO2(NO3)2$6H2O (1 equiv) in D2O/NaOD
L
H2
H1
L–UO2
H2
H1
All the organic reagents used were pure commercial products
from Aldrich, Acros, Fluka, Avocado and Lancaster & Maybridge ex-
cept 1c. This diamine was obtained by a Mitsunobu-like azidation
of the commercial corresponding diol22 followed by reduction.
(2,3)-Dibenzyloxybenzoic acid,23,24 N,N0-bis(2,3-dihydroxy-5-sul-
fonylbenzoyl)-1,5-diamino pentane (5a),18,25 N,N0-[1,3-phenyl-
enebis(methylene)]-bis-(2,3-dihydroxy benzamide) (4e)26 and
N,N0-(1,4-[3-(sulfophenylene)bis(methylene)]-bis-(2,3-dihydroxy-
5-sulfonylbenzoyl)) (5f)27 weresynthesised as previouslydescribed.
The solvents were purchased from Carlo Erba, Acros, Pro-Labo, Fluka
and Aldrich. Anhydrous solvents were obtained from Acros; anhy-
drous THF and dry CH2Cl2 were distilled in the laboratory. Flash
5a
6.85
6.83 (6.83)
6.90
6.88 (6.88)
6.86 (6.87)
7.49
7.46 (7.46)
7.53
7.51 (7.51)
7.48 (7.49)
5a–U
5b–U
5c–U
5d–U
5h–U
7.09
7.06 (7.07)
7.10
7.10 (7.10)
7.10 (7.12)
7.68
7.67 (7.68)
7.72
7.64 (7.70)
7.69 (7.70)
5ba
5c
5db
5ha
a
Chemical shift of H1 and H2 in dissymmetric structures.
Chemical shift of the minor stereoisomer.
b
Finally, whatever the ligands 5a–d and 5h be, the 1:1 stoichi-
ometry of the uranyl complexes was confirmed by the total dis-
appearance of the two resonance signals of H1 and H2 protons of
the free ligands without appearance of new resonance signals
(Fig. 4a5 and b5).
chromatography was carried out on Merck Silica Si60 (40–63 mm).
1H and 13C NMR spectra were recorded on a Bruker AC-200
(200.13 MHz for 1H, 50.32 MHz for 13C) or AC-300 FT (300.13 MHz
3. Conclusion
for 1H, 75.46769 MHz for 13C) spectrometer;
d values are given in
parts per million and J in hertz. Elemental analysis (C, H, N, S, O, F)
was carried out by the Service Central d’Analyse of the CNRS (Sol-
aize). High resolution mass spectra: HR LSIMS (Liquid Secondary
Ionisation Mass Spectrometry: thioglycerol), HR CIMS (isobutan)
and HR EIMS were carried out on a Finnegan MAT 95xL by the UCBL
Centre de Spectroscopie de Masse.
The newly synthesised dipodal bis-catecholamide uranophiles
5a–f,h were obtained by an efficient synthetic route from different
diamines. Their binding abilities for uranyl cation were determined
by UV spectrophotometry in aqueous media under acidic, neutral
as well as basic pH conditions. These experiments showed that the
efficiency of these hydrosoluble chelating agents depends on the
nature of the spacers. The best uranophile ligand was found to be
CYCAMS 5d obtained as a mixture of cis/trans isomers, which dis-
plays association constants log K up to 17 under physiological
conditions. These binding properties were found significantly su-
perior than those observed with 5-LICAMS, a well known ligand
that displays in vivo uranyl removal capabilities. Separation of
CYCAMS isomers and evaluation of their in vivo efficiency are
planned in the near future.
4.2. 3-Methyl-(1,5)-diazopentane
DBU (6 mL, 42.5 mmol) was added dropwise to 2.03 g of 3-
methyl-1,5-pentanediol (17.1 mmol) and 8.5 mL of diphenylphos-
phoryl azide (39.4 mmol) in 40 mL of dry DMF under argon at 0 ꢀC.
The mixture was allowed to rise to room temperature and heated at
65 ꢀC for 16 h. The mixture was evaporated, the residue was

6666
A. Leydier et al. / Tetrahedron 64 (2008) 6662–6669
dissolved in 100 mL of dichloromethane and extracted sub-
sequently with 2ꢃ50 mL of 1 M HCl, 2ꢃ50 mL of water, 100 mL of
brine, dried over MgSO4, filtered, evaporated and purified by silica
gel column chromatography (cyclohexane/EtOAc 95:5) to give pure
3-methyl-(1,5)-diazopentane (2.21 g, 76%) as clear oil. 1H NMR
4.4.3. N,N0-Bis(2,3-dimethoxybenzoyl)-3-methyl-(1,5)
diaminopentane (3c)
Compound 3c was obtained from oxalyl chloride (1.6 mL,
18.6 mmol), 2,3-dimethoxybenzoic acid (2.19 g, 12 mmol) in CH2Cl2
(20 mL), 3-methylpent-(1,5)-diamine 1c (0.64 g, 5.5 mmol) and
3.4 mL of triethylamine (24.2 mmol) in 30 mL of dry CH2Cl2. Puri-
fication on silica gel (EtOAc) afforded 3c (1.79 g, 73%) as yellow oil.
(CDCl3, 300 MHz, 25 ꢀC):
d
¼3.31 (m, 4H), 1.62 (m, 4H), 1.46 (m, 1H),
13
0.94 (d, J¼6.6 Hz, 3H); C NMR (CDCl3, 75 MHz, 25 ꢀC):
¼49.6,
d
35.9, 28.3, 19.3.
Rf 0.50. 1H NMR (CDCl3, 300 MHz, 25 ꢀC):
d
¼7.90 (br s, 2H), 7.53 (dd,
J¼7.9, 1.7 Hz, 2H), 6.89–7.02 (m, 4H), 3.76 (s, 12H), 3.38–3.44 (m,
4.3. 3-Methyl-(1,5)-diaminopentane (1c)
4H), 1.39–1.61 (m, 4H), 1.13 (m, 1H, 1.77), 0.93 (d, J¼5 Hz, 3H). 13
C
NMR (CDCl3, 75 MHz, 25 ꢀC):
d
¼165.5, 152.8, 147.6, 127.2, 124.6,
LiAlH4 (0.6 g, 15.8 mmol) was carefully added to a solution of
0.94 g of 3-methyl-1,5-diazopentane (5.6 mmol) in 40 mL of freshly
distilled THF under argon at 0 ꢀC. The mixture was allowed to raise
to room temperature and stirred for 16 h. The reaction mixture was
cooled to 0 ꢀC, 2 mL of water and then 4 mL NaOH were added
slowly. The resulting precipitate was filtrated over Celite, washed
with THF (100 mL) and solvents were removed under vacuum to
give 1c (0.6 g, 92%) as translucent oil. 1H NMR (CDCl3, 300 MHz,
122.8,115.5, 61.5, 56.3, 37.9, 36.8, 29.0,19.6. HR ESIMS calculated for
C
C
24H32N2O6$Naþ¼467.2158; found¼453.2158. Anal. Calcd (%) for
24H32N2O6: C, 64.85; H, 7.26; N, 6.30; O, 21.60. Found: C, 64.95; H,
7.41; N, 6.05.
4.4.4. N,N0-Bis(2,3-dimethoxybenzamido)-cyclohexane-(1,3)-
bismethylamine (3d)
Compound 3d was obtained from oxalyl chloride (1.1 mL,
12.6 mmol), 2,3-dimethoxybenzoic acid (1.57 g, 8.6 mmol) in
CH2Cl2 (15 mL), (1,3)-cyclohexane-bis-(methylamine) 1d (0.6 g,
4.2 mmol) and 1.4 mL of triethylamine (10 mmol) in 30 mL of dry
CH2Cl2. Purification on silica gel (EtOAc) afforded 3d (1.91 g, 97%) as
an 80:20 mixture of cis (3d1) and trans (3d2) diastereoisomers.
Rf 0.63. HR ESIMS calculated for C26H35N2Oþ6 ¼471.2495;
found¼471.2494. Anal. Calcd (%) for C26H34N2O6: C, 66.36; H, 7.28;
N, 5.95; O, 20.40. Found: C, 66.26; H, 7.67; N, 5.67. NMR data for the
25 ꢀC):
d
¼2.66 (m, 4H),1.26–1.38 (m, 5H), 0.88 (d, J¼6.6 Hz, 3H); 13
C
NMR (CDCl3, 75 MHz, 25 ꢀC):
d
¼41.6, 40.4, 28.6, 20.0.
4.4. General procedure for the synthesis of compounds 3a–h
Oxalyl chloride (1.5 equiv) was added dropwise to a solution of
2,3-dimethoxybenzoic acid (1 equiv) or 2,3-dibenzyloxybenzoic
acid (1 equiv) in the required volume of dry CH2Cl2. After adding
a drop of dry DMF, the mixture was stirred until the end of HCl
release. After evaporation of solvents and residual oxalyl chloride,
the residue was dissolved in dry CH2Cl2 and added dropwise to
a solution of 1a–h (0.5 equiv) and triethylamine (1.1 equiv) in the
required volume of dry CH2Cl2. After 18 h under stirring, the mix-
ture was washed with water (2ꢃ50 mL), brine (50 mL), then dried
over MgSO4 and evaporated to dryness. The residue was purified by
flash chromatography (SiO2) to give 3a–h (73–98%).
major stereoisomer 3d1. 1H NMR (CDCl3, 300 MHz, 25 ꢀC):
d
¼7.99 (br
t, 2H), 7.55 (dd, J¼7.9, 1.7 Hz, 2H), 7.01 (t, J¼7.9 Hz, 4H), 6.91 (dd,
J¼7.9, 1.7 Hz, 2H), 3.74 (s, 12H), 3.21 (br t, 4H), 1.68–1.73 (m, 3H),
1.53–1.55 (m, 3H), 1.11–1.29 (m, 2H), 0.82–0.89 (m, 2H). 13C NMR
(CDCl3, 75 MHz, 25 ꢀC):
d
¼165.5, 152.8, 147.6, 127.2, 124.7, 122.9,
115.6, 61.6, 56.4, 46.2, 38.1, 35.5, 31.1, 25.7. NMR data for the minor
1
stereoisomer 3d2. H NMR (CDCl3, 300 MHz, 25 ꢀC):
d
¼7.91 (br t,
2H), 7.52 (dd, J¼7.9, 1.7 Hz, 2H), 6.99 (t, J¼7.9 Hz, 4H), 6.91 (dd,
J¼7.9, 1.7 Hz, 2H), 3.72 (s, 12H), 3.30 (br t, 4H), 1.68–1.73 (m, 3H),
1.42–1.44 (m, 3H), 1.11–1.29 (m, 2H), 0.64–0.70 (m, 2H). 13C NMR
4.4.1. N,N0-(1,5-Pentane)bis(2,3-dimethoxybenzamide) (3a)
Compound 3a was obtained from oxalyl chloride (4.8 mL,
55.8 mmol), 2,3-dimethoxybenzoic acid (5.79 g, 31.78 mmol) in
CH2Cl2 (20 mL), 1,5-diaminopentane 1a (1.62 g, 15.88 mmol) and
4.9 mL of triethylamine (35.2 mmol) in 20 mL of dry CH2Cl2. Puri-
fication on silica gel (EtOAc/cyclohexane 1:2) afforded 3a (6.7 g,
(CDCl3, 75 MHz, 25 ꢀC):
115.6, 61.64, 56.4, 44.0, 33.3, 33.1, 29.7, 20.6.
d
¼165.5, 152.8, 147.6, 127.1, 124.7, 122.9,
4.4.5. N,N0-[1,3-Phenylenebis(methylene)]bis-(2,3-dimethoxy
benzamide) (3e)
Compound 3e was obtained from oxalyl chloride (1 mL,
11.6 mmol), 2,3-dimethoxybenzoic acid (1.5 g, 8.2 mmol) in CH2Cl2
(15 mL), m-xylenediamine 1e (0.537 g, 3.9 mmol) and 1.2 mL of
triethylamine (8.5 mmol) in 30 mL of dry CH2Cl2. Purification on
silica gel (EtOAc) afforded 3e (1.77 g, 97%) as yellow oil.27 Rf 0.71. 1H
1
98%) as yellow oil.25,18 Rf 0.16. H NMR (CDCl3, 300 MHz, 25 ꢀC):
d
¼8.02 (br s, 2H), 7.66 (dd, J¼6.2, 2.2 Hz, 2H), 7.13 (m, 2H), 7.03 (dd,
J¼5.9, 2.2 Hz, 2H), 3.81 (s, 12H), 3.42–3.51 (m, 4H), 1.64–1.69
(m, 4H, 1.77), 1.50–1.53 (m, 2H). 13C NMR (CDCl3, 75 MHz, 25 ꢀC):
d
¼165.5, 152.9, 147.7, 127.3, 124.8, 123.1, 115.6, 61.6, 56.4, 39.9, 29.7,
24.9. HR ESIMS calculated for
C
23H30N2O6$Hþ¼453.2002;
NMR (CDCl3, 300 MHz, 25 ꢀC):
d
¼8.37 (br s, 2H), 7.73 (dd, J¼7.9,
found¼453.20006. Anal. Calcd (%) for C23H30N2O6: C, 64.17; H, 7.02;
1.7 Hz, 2H), 7.32 (m, 4H), 7.16 (t, J¼8.1 Hz, 2H), 6.98 (dd, J¼8.3,
N, 6.51; O, 22.30. Found: C, 64.21; H, 7.09; N, 6.40.
1.7 Hz, 2H), 4.68 (d, J¼5.6 Hz, 4H), 3.89 (s, 6H), 3.84 (s, 6H). 13C NMR
(CDCl3, 75 MHz, 25 ꢀC):
d
¼165.6, 152.9, 147.9, 139.5, 129.4, 127.2,
4.4.2. N,N0-[1,5-(2-Methylpentane)]-bis-(2,3-dimethoxy
benzamide) (3b)
Compound 3b was obtained from oxalyl chloride (1.1 mL,
12.8 mmol), 2,3-dimethoxybenzoic acid (1.55 g, 8.5 mmol) in
CH2Cl2 (15 mL), DITEK A 1b (0.468 g, 4 mmol) and 1.2 mL of trie-
thylamine (8.5 mmol) in 30 mL of dry CH2Cl2. Purification on silica
gel (EtOAc) afforded 3b (1.7 g, 95%) as yellow oil. Rf 0.63. 1H NMR
127.0, 126.9, 124.8, 123.1, 115.8, 61.6, 56.4, 44.0. HR ESIMS calculated
for C26H29N2Oþ6 ¼465.2026; found¼465.2026. Anal. Calcd (%) for
C24H32N2O6: C, 67.23; H, 6.08; N, 6.03; O, 20.67. Found: C, 67.21; H,
6.19; N, 5.93.
4.4.6. N,N0-[1,4-Phenylenebis(methylene)]bis(2,3-dimethoxy
benzamide) (3f)
(CDCl3, 300 MHz, 25 ꢀC):
d
¼8.03 (br s, 2H), 7.62 (dd, J¼6, 1.9 Hz,
Compound 3f was obtained from oxalyl chloride (1.8 mL,
13 mmol), 2,3-dimethoxybenzoic acid (3.24 g, 17.8 mmol) in CH2Cl2
(30 mL), p-xylenediamine 1f (1.21 g, 8.9 mmol) and 5.2 mL of tri-
ethylamine (37.4 mmol) in 30 mL of dry CH2Cl2. Purification on silica
gel (EtOAc/cyclohexane 1:2) afforded 3f (1.77 g, 97%) as white
2H), 6.88–7.09 (m, 4H), 3.85 (s, 12H), 3.26–3.43 (m, 4H), 2.11 (m,
1H), 1.27–1.79 (m, J¼1.77 Hz, 4H), 0.97 (d, J¼6.4 Hz, 3H). 13C NMR
(CDCl3, 75 MHz, 25 ꢀC):
d
¼165.6, 152.8, 147.6, 127.2, 124.7, 122.9,
115.5, 61.6, 56.4, 45.7, 40.1, 33.5, 32.1, 27.4, 18.1. HR ESIMS calculated
for C24H32N2O6$Naþ¼467.2158; found¼453.2159. Anal. Calcd (%)
for C24H32N2O6: C, 64.85; H, 7.26; N, 6.30; O, 21.60. Found: C, 64.93;
H, 7.30; N, 6.17.
solid.28 Rf 0.35.1H NMR (CDCl3, 300 MHz, 25 ꢀC):
2H), 7.53 (dd, J¼7.9, 1.7 Hz, 2H), 7.21 (s, 4H), 6.97 (t, J¼8.1 Hz, 2H),
6.87 (dd, J¼8.3, 1.7 Hz, 2H), 4.51 (d, J¼5.6 Hz), 3.70 (s, 6H), 3.68 (s,
d
¼8.37 (t, J¼5.4 Hz,

A. Leydier et al. / Tetrahedron 64 (2008) 6662–6669
6667
13
6H). C NMR (CDCl3, 75 MHz, 25 ꢀC):
d¼165.5, 152.9, 147.7, 138.1,
evaporated to dryness. Distilled water (50 mL) was added and the
pH was adjusted to 1 with 3 N HCl. The mixture was extracted with
3ꢃ50 mL of CH2Cl2. The combined organic phases were combined,
extracted with 2ꢃ100 mL of distilled water, 100 mL brine, dried
over MgSO4, filtered and evaporated to dryness to give 3i0 as a white
128.2, 127.1, 124.7, 122.9, 115.7, 61.6, 56.3, 43.7. HR ESIMS calculated
for C26H29N2Oþ6 ¼465.2026; found¼465.2028. Anal. Calcd (%) for
C
24H32N2O6: C, 67.23; H, 6.08; N, 6.03; O, 20.67. Found: C, 67.35; H,
6.11; N, 5.88.
powder (4.46 g, 92%).28 1H NMR (CDCl3, 300 MHz, 25 ꢀC):
d¼10.7
4.4.7. N,N0-Bis(2,3-dimethoxybenzoyl)-(1,8)-diamido-p-
menthane (3g)
(br s, 1H), 8.47 (d, J¼7.4 Hz, 1H), 7.85 (m, 1H), 7.54–7.64 (m, 2H),
6.99–7.30 (m, 24H), 4.89–5.10 (m, 8H), 4.50–4.54 (m, 1H), 2.99–3.04
(m, 2H), 1.32–1.61 (m, 2H), 1.10–1.28 (m, 4H). 13C NMR (CDCl3,
Compound 3g was obtained from oxalyl chloride (1.7 mL,
19.8 mmol), 2,3-dimethoxybenzoic acid (3.22 g, 17.7 mmol) in CH2Cl2
(30 mL), 1,8-diamino-p-menthane 1g (70% pure, 2.1 g, 8.8 mmol) and
2.7 mL of triethylamine (19.4 mmol) in 30 mL of dry CH2Cl2. Purifica-
tion on silica gel (EtOAc/cyclohexane 1:2) afforded 3g (4.08 g, 93%) as
a mixture of cis/trans diastereoisomers. Rf 0.83. 1H NMR (CDCl3,
75 MHz, 25 ꢀC):
d
¼175.6, 166.0, 165.8, 152.2, 152.1, 147.9, 147.5,
136.8, 136.7, 136.6, 136.4, 129.7, 129.5, 129.4, 129.3, 129.2, 129.0,
128.9, 128.8, 128.7, 128.6, 128.2, 128.1, 127.5, 126.9, 125.3, 124.9,
124.6, 123.7, 119.4, 117.5, 117.2, 76.9, 76.7, 71.8, 71.7, 53.1, 40.0, 31.7,
29.2, 23.4. HR ESIMS calculated for C48H46N2O8Naþ¼801.3152;
found¼801.3153. Anal. Calcd (%) for C48H46N2O8: C, 74.02; H, 5.95;
N, 3.60; O, 16.43. Found: C, 74.13; H, 6.11; N, 3.33.
300 MHz, 25 ꢀC):
d¼7.80 (br s, 1H), 7.74 (br s, 1H), 7.52 (m, 2H), 7.00–
7.05 (m, 2H), 6.89–6.94 (m, 2H), 3.75–3.83 (m,12H), 2.05–2.30 (m, 3H),
1.59–1.63 (m, 2H),1.20–1.37 (m,13H).13C NMR (CDCl3, 75 MHz, 25 ꢀC):
d
¼165.5,164.1,152.9,152.8,147.5,147.4,128.2,128.1,124.8,124.7,122.8,
4.4.11. (N,N0)-2,6-Bis(2,3-dimethoxybenzamido)hexanoic acid (3i)
A mixture of 3h (2.28 g, 4.54 mmol) and lithium hydroxide
(0.95 mg, 22.6 mmol) in THF/water (3:1) (40 mL) was stirred for
18 h and evaporated to dryness. Distilled water (50 mL) was added
and the pH was adjusted to 1 with 3 N HCl. The mixture was
extracted with 3ꢃ50 mL of CH2Cl2. The combined organic phases
were combined, extracted with 2ꢃ50 mL of distilled water, 50 mL
brine, dried over MgSO4, filtered and evaporated to dryness to give
3i as a white powder (1.73 g, 80%). 1H NMR (CDCl3, 300 MHz,
122.7, 115.4, 115.3, 61.7, 61.6, 56.5, 56.5, 56.4, 53.3, 44.7, 37.4, 27.8, 24.7,
23.2. HR ESIMS calculated for
C
28H38N2O6Naþ¼521.2628;
found¼521.2629. Anal. Calcd (%) for C28H38N2O6: C, 67.45; H, 7.68; N,
5.62; O, 19.25. Found: C, 67.55; H, 7.78; N, 5.42.
4.4.8. Ethyl-(N,N0)-2,6-bis(2,3-dimethoxybenzamido)
hexanoate (3h)
Compound 3h was obtained from oxalyl chloride (2.3 mL,
26.7 mmol), 2,3-dimethoxybenzoic acid (3.3 g, 18.1 mmol) in
CH2Cl2 (25 mL), ethyl-2,6-diaminohexanoate dihydrochloride 1h
(2.12 g, 9 mmol) and 6.3 mL of triethylamine (45.3 mmol) in 50 mL
of dry CH2Cl2. Purification on silica gel (EtOAc/cyclohexane 1:2)
afforded 3h (3.46 g, 76%) as yellow oil. Rf 0.43. 1H NMR (CDCl3,
25 ꢀC):
d
¼9.79 (br s, 1H), 8.81 (d, J¼7.5 Hz, 1H), 8.07 (m, 1H), 7.59–
7.67 (m, 2H), 6.97–7.08 (m, 4H), 4.80–4.86 (m, 1H), 3.80–3.89 (m,
12H), 3.40–3.42 (q, J¼6.2 Hz, 4H), 1.86–2.04 (m, 2H), 1.59–1.63 (m,
13
2H), 1.47–1.52 (m, 2H). C NMR (CDCl3, 75 MHz, 25 ꢀC):
d
¼175.0,
166.0, 165.5, 153.0, 152.9, 148.3, 147.8, 126.9, 126.2, 124.8, 124.7,
123.1, 123.0, 116.1, 115.8, 62.0, 61.7, 56.5, 56.4, 52.9, 40.0, 32.5, 29.6,
23.1. HR ESIMS calculated for
300 MHz, 25 ꢀC):
d
¼8.62 (d, J¼7.7 Hz, 1H), 7.92 (m, 1H), 7.52–7.57
(m, 2H), 6.90–7.02 (m, 4H), 4.74 (m, 1H), 4.08–4.15 (q, J¼7.1 Hz),
3.73–3.85 (m, 12H), 3.31–3.38 (q, J¼6.2 Hz, 4H), 1.74–1.88 (m, 2H),
1.56–1.61 (m, 2H), 1.32–1.41 (m, 2H), 1.12–1.29 (m, 3H). 13C NMR
(CDCl3, 75 MHz, 25 ꢀC):
147.7, 127.1, 126.3, 124.6, 123.7, 122.9, 122.8, 117.3, 116.0, 115.6, 61.8,
61.7, 61.5, 56.5, 56.4, 52.7, 39.7, 32.6, 29.5, 23.1, 14.5. HR ESIMS
calculated for C26H35N2Oþ8 ¼525.2213; found¼525.2212. Anal. Calcd
(%) for C26H34N2O8: C, 62.14; H, 6.82; N, 5.57; O, 25.47. Found: C,
62.38; H, 6.75; N, 5.40.
C
24H30N2O8Naþ¼497.1900;
found¼497.1904. Anal. Calcd (%) for C24H30N2O8$CH2Cl2: C, 53.67;
H, 5.40; N, 5.01; O, 22.88. Found: C, 53.71; H, 5.70; N, 4.68.
d¼172.6, 165.5, 165.0, 153.0, 152.9, 148.1,
4.5. General procedure for the synthesis of compounds 4a–g
To a solution of 3a–g (1 equiv) in dry CH2Cl2 was added drop-
wise a solution of BBr3 (6–7 equiv) in dry CH2Cl2 under deep stir-
ring at 0 ꢀC. The resulting white solution was stirred overnight and
the mixture was then carefully poured into crushed ice under heavy
stirring until complete hydrolysis. The resulting precipitate was
collected by filtration, washed with cold water (3ꢃ50 mL) and
CH2Cl2 and dissolved in methanol. Precipitation with water and
filtration afforded pure 4a–g, which were dried under vacuum.
4.4.9. Ethyl-(N,N0)-2,6-bis(2,3-bis(benzyloxy)benzamido)
hexanoate (3h0)
Compound 3h0 was obtained from oxalyl chloride (4 mL,
46 mmol), 2,3-dibenzyloxybenzoic acid 7 (8.3 g, 24.8 mmol) in
CH2Cl2 (50 mL), ethyl-2,6-diaminohexanoate dihydrochloride 1h
(3 g, 12.1 mmol) and 8 mL of triethylamine (57.1 mmol) in 50 mL of
dry CH2Cl2 and 50 mL of dry MeCN. Purification on silica gel (EtOAc/
cyclohexane 1:2) afforded 3h0 (5.37 g, 55%) as yellow oil. Rf 0.38. 1H
4.5.1. N,N0-Bis(2,3-dihydroxybenzoyl)-1,5-diaminopentane (4a)
Compound 4a was obtained from 3a (6.67 g, 15.56 mmol) in
CH2Cl2 (200 mL) and BBr3 (25 mL, 99 mmol) in CH2Cl2 (100 mL).
NMR (CDCl3, 300 MHz, 25 ꢀC):
d
¼8.38 (d, J¼7.5 Hz, 1H), 7.78 (m,
Compound 4a was obtained as a white powder (4.49 g, 77%).18 1
H
1H), 7.60–7.64 (m, 2H), 7.16–7.35 (m, 20H), 7.01–7.07 (m, 4H), 4.95–
5.17 (m, 8H), 4.48 (m,1H), 4.04–4.10 (q, J¼6.6 Hz, 2H), 3.00–3.06 (m,
2H), 1.30–1.56 (m, 2H), 1.10–1.28 (m, 7H). 13C NMR (CDCl3, 75 MHz,
25 ꢀC):
136.7, 136.4, 129.7, 129.6, 129.4, 129.3, 129.2, 129.1, 128.9, 128.8,
128.7, 128.6, 128.3, 128.2, 127.1, 126.5, 125.4, 124.8, 124.7, 123.7,
119.3, 117.6, 117.3, 76.8, 76.5, 71.9, 71.7, 61.6, 53.1, 39.8, 32.1, 29.2,
NMR (DMSO-d6, 300 MHz, 25 ꢀC):
d
¼12.9 (s, 2H), 9.13 (s, 2H), 8.78
(br s, 2H), 7.29 (dd, J¼8.1,1 Hz, 2H), 6.90 (dd, J¼8.1,1 Hz, 2H), 6.70 (t,
J¼8.1 Hz, 2H), 3.29–3.27 (br q, 4H), 1.60–1.56 (m, 4H), 1.37–1.33 (m,
13
d
¼172.6, 165.7, 165.4, 152.2, 152.1, 147.4, 147.2, 136.9, 136.8,
2H). C NMR (CDCl3, 75 MHz, 25 ꢀC):
d¼170.1, 150.1, 146.6, 119.1,
118.2, 117.4, 115.2, 39.2, 28.9, 24.2. HR ESIMS calculated for
C
C
19H22N2O6$Naþ¼397.1376; found¼397.13762. Anal. Calcd (%) for
19H22N2O6: C, 60.95; H, 5.92; N, 7.48; O, 25.64. Found: C, 60.92; H,
23.5, 14.7. HR ESIMS calculated for
C
50H51N2Oþ8 ¼807.3645;
6.28; N, 7.16.
found¼807.3647. Anal. Calcd (%) for C50H50N2O8: C, 74.42; H, 6.25;
N, 3.47; O, 15.86. Found: C, 74.56; H, 6.27; N, 3.31.
4.5.2. N,N0-Bis(2,3-dihydroxybenzoyl)-2-methyl-1,5-diamino
pentane (4b)
4.4.10. (N,N0)-2,6-Bis(2,3-bis(benzyloxy)benzamido)
hexanoic acid (3i0)
A mixture of 3h0 (5.01 g, 6.2 mmol) and lithium hydroxide (1 g,
23.8 mmol) in THF/water (3:1) (120 mL) was stirred for 18 h and
Compound 4b was obtained from 3b (3.8 g, 8.56 mmol) in
CH2Cl2 (120 mL) and BBr3 (5.5 mL, 58 mmol) in CH2Cl2 (60 mL).
Compound 4b was obtained as a white powder (2.82 g, 85%). 1H
NMR (CD3OD, 300 MHz, 25 ꢀC):
d¼8.43 (br s, 2H), 7.23 (d, J¼7.5 Hz,

6668
A. Leydier et al. / Tetrahedron 64 (2008) 6662–6669
1H), 7.21 (d, J¼7.5 Hz, 1H), 6.94 (d, J¼7.5 Hz, 2H), 6.69 (t, J¼7.5 Hz,
4.5.7. N,N0-Bis(2,3-dihydroxybenzoyl)-(1,8)-diamido-p-
menthane (4g)
2H), 3.19–3.41 (m, 4H), 1.12–1.85 (m, 5H), 0.98 (d, J¼8.8 Hz, 3H). 13
C
NMR (CDCl3, 75 MHz, 25 ꢀC):
d
¼171.9,151.0,147.6,119.7, 119.5,117.4,
Compound 4a was obtained from 3g (1.7 g, 3.66 mmol) in
CH2Cl2 (40 mL) and BBr3 (2.1 mL, 22.2 mmol) in CH2Cl2 (40 mL).
Compound 4g was obtained as a brown powder, which was dried
115.9, 46.9, 41.2, 34.7, 33.1, 28.2, 18.5. HR ESIMS calculated for
C
C
20H24N2O6$Naþ¼411.1533; found¼411.1533. Anal. Calcd (%) for
1
20H24N2O6: C, 61.85; H, 6.23; N, 7.21; O, 24.71. Found: C, 61.95; H,
under vacuum (1.36 g, 90%). H NMR (CD3OD, 300 MHz, 25 ꢀC):
6.31; N, 7.03.
d
¼7.17–7.26 (m, 2H), 6.85–6.90 (m, 2H), 6.63–6.70 (m, 2H), 2.09–
2.42 (m, 3H), 1.55–1.70 (m, 2H), 1.24–1.45 (m, 13H). 13C NMR
(CD3OD, 75 MHz, 25 ꢀC):
4.5.3. N,N0-Bis-(2,3-dihydroxybenzoyl)-3-methyl-1,5-diamino
pentane (4c)
Compound 4a was obtained from 3c (1.75 g, 3.94 mmol) in
CH2Cl2 (100 mL) and BBr3 (2.4 mL, 25.4 mmol) in CH2Cl2 (80 mL).
Compound 4c was obtained as a white powder (1.19 g, 78%). 1H
NMR (CD3OD, 300 MHz, 25 ꢀC):
d
¼170.4, 170.1, 164.2, 164.1, 149.2, 148.7,
147.5, 147.4, 120.6, 120.4, 120.2, 119.8, 119.6, 119.3, 58.7, 55.1,
45.6, 38.0, 28.2, 25.1, 24.2. HR ESIMS calculated for
C
C
24H30N2O6Naþ¼465.2002; found¼465.2006. Anal. Calcd (%) for
24H30N2O6: C, 65.14; H, 6.83; N, 6.33; O, 21.69. Found: C, 65.33; H,
d
¼7.20 (d, J¼7.9 Hz, 2H), 6.92 (m,
7.00; N, 5.97.
J¼7.9 Hz, 2H), 6.70 (t, J¼7.9 Hz, 2H), 3.30–3.46 (m, 5H), 1.49–1.74
(m, 4H), 1.04 (d, J¼5.7 Hz, 3H, CH–CH3). 13C NMR (CD3OD, 75 MHz,
4.5.8. (N,N0)-2,6-Bis(2,3-dihydroxybenzamido)hexanoic acid (4h)
A mixture of 3i0 (4.3 g, 5.5 mmol) and Pd/C (10%) (430 mg) in
THF (150 mL) was stirred under H2 atmosphere for 96 h. The
resulting mixture was filtered over Celite, evaporated to dryness
25 ꢀC):
d
¼171.9, 150.6, 147.7, 120.0, 119.9, 119.1, 117.2, 38.9, 37.7, 30.1,
20.2. HR ESIMS calculated for
C
20H24N2O6$Naþ¼411.1533;
found¼411.1532. Anal. Calcd (%) for C20H24N2O6: C, 61.85; H, 6.23;
N, 7.21; O, 24.71. Found: C, 62.14; H, 6.18; N, 6.97.
and dried under vacuum to give 4h as a white powder (2.09 g,
99%).28 H NMR (DMSO-d6, 300 MHz, 25 ꢀC):
d
¼12.09 (br s, 1H),
1
4.5.4. N,N0-Bis(2,3-dihydroxybenzamido)-cyclohexane-(1,3)-
bismethylamine (4d)
9.13 (br s), 8.88 (d, J¼7.4 Hz, 1H), 8.77 (m, 1H), 7.45 (d, J¼7.8 Hz, 2H),
7.29 (d, J¼7.9 Hz, 2H), 6.92–6.99 (m, 2H), 6.67–6.72 (m, 2H), 4.44–
Compound 4a was obtained from 3d (1.65 g, 3.94 mmol) in
CH2Cl2 (40 mL) and BBr3 (2.2 mL, 23.2 mmol) in CH2Cl2 (40 mL).
Compound 4d was obtained as an 80:20 mixture of cis (4d1) and
trans (4d2) diastereoisomers (1.36 g, 90%). HR ESIMS calculated for
4.48 (m, 1H), 3.30–3.34 (m, 2H), 1.67–1.72 (m, 2H), 1.35–1.58 (m,
13
4H). C NMR (DMSO-d6, 75 MHz, 25 ꢀC):
d
¼173.7, 170.1, 169.9,
150.0, 149.5, 146.5, 129.2, 128.5, 119.1, 118.5, 118.2, 117.4, 115.5,
115.3, 52.7, 39.1, 30.6, 28.7, 23.6. HR ESIMS calculated for
C
C
C
C
22H26N2O6Naþ¼437.1689; found¼437.1691. Anal. Calcd (%) for
20H23N2Oþ8 ¼419.1454; found¼419.1460. Anal. Calcd (%) for
22H26N2O6: C, 63.76; H, 6.32; N, 6.76; O, 23.16. Found: C, 63.87; H,
20H22N2O8$THF: C, 58.89; H, 5.97; N, 5.72; O, 29.42. Found: C,
6.39; N, 6.58. NMR data for the major stereoisomer 4d1. 1H NMR
59.05; H, 6.22; N, 5.38.
(CD3OD, 300 MHz, 25 ꢀC):
d
¼7.22 (dd, J¼7.9, 1.1 Hz, 2H), 6.94 (dd,
J¼7.9, 1.1 Hz, 2H), 6.71 (t, J¼7.9 Hz, 2H), 3.22 (d, J¼8.4 Hz, 4H), 1.41–
1.78 (m, 6H),1.10–1.29 (m, 2H), 0.86–0.92 (m, 2H). 13C NMR (CD3OD,
4.6. General procedure for the synthesis of compounds 5a–f
and 5h
75 MHz, 25 ꢀC):
d
¼171.9, 164.1, 150.3, 147.7, 120.2, 120.1, 119.3, 117.3,
47.3, 39.3, 36.7, 32.2, 26.9. NMR data for the minor stereoisomer 4d2.
1H NMR (CD3OD, 300 MHz, 25 ꢀC):
Compounds 4a–f or 4h were added portionwise to a solution of
oleum (H2SO4/SO3 20%) at 0 ꢀC or H2SO4 96% at 50 ꢀC under stirring.
The resulting white solution was allowed to warm to room tem-
perature and stirred overnight. The mixture was then poured into
Et2O (200 mL). The resulting precipitate was filtered off under ar-
gon and dried under vacuum to give 5a–f.
d
¼7.19 (dd, J¼7.9, 1.1 Hz, 2H),
6.93 (dd, J¼7.9, 1.1 Hz, 2H), 6.9 (t, J¼7.9 Hz, 2H), 3.32 (d, J¼8.4 Hz,
4H), 1.41–1.78 (m, 6H), 1.10–1.29 (m, 2H), 0.64–0.72 (m, 2H). 13C
NMR (CD3OD, 75 MHz, 25 ꢀC):
d
¼171.9, 164.1, 150.3, 147.7, 120.2,
120.1, 119.3, 117.3, 45.0, 34.5, 33.6, 30.9, 22.4.
4.5.5. N,N0-[1,3-Phenylenebis(methylene)]-bis-(2,3-dihydroxy
benzamide) (4e)
4.6.1. N,N0-Bis(2,3-dihydroxy-5-sulfonylbenzoyl)-1,5-diamino
pentane (5a)12
Compound 4a was obtained from 3e (1.7 g, 3.66 mmol) in
CH2Cl2 (40 mL) and BBr3 (2.1 mL, 22.2 mmol) in CH2Cl2 (40 mL).
Compound 5a was obtained from 4a (1.99 g, 5.3 mmol) in oleum
Compound 4e was obtained as a brown powder (1.36 g, 90%).27 1
H
(20 mL) to give 5a as a hygroscopic grey powder (2.4 g, 79%). 1H
NMR (CD3OD, 300 MHz, 25 ꢀC):
d
¼7.22–7.37 (m, 6H), 6.92–6.96 (dd,
NMR (D2O, 300 MHz, 25 ꢀC):
d
¼7.62 (s, 2H), 7.32 (s, 2H), 3.37–3.33
J¼7.9, 1.5 Hz, 2H), 6.69–6.74 (t, J¼8 Hz, 2H), 4.59 (m, 4H). 13C NMR
(t, J¼6.6 Hz, 4H), 1.66–1.62 (m, 4H), 1.46–1.42 (m, 2H). 13C NMR
(CD3OD, 75 MHz, 25 ꢀC):
d
¼171.9, 150.7, 147.6, 140.5, 130.4, 127.9,
(CDCl3, 75 MHz, 25 ꢀC):
d
¼169.1, 149.8, 145.1, 133.6, 116.7,
120.4, 120.3, 119.4, 117.1, 44.5. HR ESIMS calculated for
115.6, 115.2, 39.5, 28.0, 23.4. HR ESIMS calculated for
C
C
22H20N2O6$Naþ¼431.1219; found¼431.1222. Anal. Calcd (%) for
C
C
19H21N2O12Sꢁ2 ¼533.0536; found¼533.05365. Anal. Calcd (%) for
22H20N2O6: C, 64.70; H, 4.94; N, 6.86; O, 23.51. Found: C, 64.77; H,
19H21N2O12S2$3H2O: C, 38.84; H, 4.63; N, 4.76; O, 40.84; S, 10.91.
5.04; N, 6.68.
Found: C, 39.21; H, 4.87; N, 4.35.
4.5.6. N,N0-[1,4-Phenylenebis(methylene)]-bis-(2,3-dihydroxy
benzamide) (4f)
4.6.2. N,N0-Bis(2,3-dihydroxy-5-sulfonylbenzoyl)-2-methyl-1,5-
diaminopentane (5b)
Compound 5b was obtained from 4b (691 mg, 1.77 mmol) in
oleum (20 mL) to give 5b as a hygroscopic grey powder (752 mg,
Compound 4a was obtained from 3f (2.3 g, 4.95 mmol) in CH2Cl2
(150 mL) and BBr3 (2.8 mL, 29.6 mmol) in CH2Cl2 (100 mL). Com-
pound 4f was obtained as a brown powder, which was dried under
vacuum (1.7 g, 84%).27 1H NMR (DMSO-d6, 300 MHz, 25 ꢀC):
d¼9.28
77%). 1H NMR (D2O, 200 MHz, 25 ꢀC):
d
¼7.59 (br d, 1H), 7.58 (br d,
(t, J¼5.6 Hz, 2H), 7.30 (dd, J¼8, 1.4 Hz, 2H), 7.25 (s, 4H), 6.87 (m, 2H),
1H), 7.28 (s, 2H), 3.13–3.28 (m, 4H), 1.22–1.69 (m, 5H), 0.93 (d,
6.65 (t, J¼7.9 Hz, 2H), 4.44 (d, J¼5.8 Hz). 13C NMR (CDCl3, 75 MHz,
J¼6.2 Hz, 3H). C NMR (CDCl3, 50 MHz, 25 ꢀC):
¼169.2, 149.9,
d
13
25 ꢀC):
d
¼170.0, 150.0, 146.6, 138.0, 127.7, 119.3, 118.4, 117.6, 115.3,
145.2, 133.4, 116.9, 116.5, 115.7, 39.5, 28.0, 23.4. HR ESIMS calculated
42.5. HR ESIMS calculated for
C
22H20N2O6$Naþ¼431.1219;
for C20H24N2O12Sꢁ2 ¼547.0692; found¼547.0688. Anal. Calcd (%) for
found¼431.1220. Anal. Calcd (%) for C22H20N2O6: C, 64.70; H, 4.94;
C20H24N2O12S2$6H2O: C, 36.58; H, 5.53; N, 4.27; O, 43.86, S, 9.77.
N, 6.86; O, 23.51. Found: C, 64.81; H, 5.07; N, 6.62.
Found: C, 36.76; H, 5.74; N, 3.87.

A. Leydier et al. / Tetrahedron 64 (2008) 6662–6669
6669
4.6.3. N,N0-Bis(2,3-dihydroxy-5-sulfonylbenzoyl)-3-methyl-1,5-
diaminopentane (5c)
4.6.7. N,N0-[2,6-Bis(2,3-dihydroxy-5-sulfonyl-benzamido)]
hexanoic acid (5h)
Compound 5c was obtained from 4c (595 mg, 1.5 mmol) in
oleum (12 mL) to give 5c as a hygroscopic white powder (650 mg,
Compound 5h was obtained from 4h (448 mg, 1.07 mmol) in
H2SO4 (2 mL) to give 5h as a hygroscopic grey powder (0.55 g, 90%).
79%). 1H NMR (D2O, 200 MHz, 25 ꢀC):
d
¼7.57 (s, 2H), 7.27 (s, 2H),
1H NMR (D2O, 300 MHz, 25 ꢀC):
d
¼7.64 (d, J¼2.1 Hz, 1H), 7.54 (d,
3.25–3.73 (m, 4H), 1.09–1.50 (m, 5H). 13C NMR (CDCl3, 50 MHz,
J¼2.1 Hz, 1H), 7.27 (d, J¼2.1 Hz, 1H), 7.24 (d, J¼2.1 Hz, 1H), 4.51–4.56
25 ꢀC):
d
¼169.0, 150.0, 145.2, 133.8, 116.9, 116.3, 115.9, 37.9, 35.3,
(m, 1H), 3.27–3.33 (m, 2H), 1.80–1.95 (m, 2H), 1.56–1.59 (m, 2H),
27.8, 19.0. HR ESIMS calculated for C20H24N2O12Sꢁ2 ¼547.0692;
found¼547.0691. Anal. Calcd (%) for C20H24N2O12S2$2H2O: C, 41.09;
H, 4.83; N, 4.79; O, 38.32, S, 10.90. Found: C, 41.07; H, 5.08; N, 4.56.
1.44–1.50 (m, 4H). C NMR (DMSO-d6, 75 MHz, 25 ꢀC):
d
¼176.0,
13
169.11, 168.8, 149.9, 149.4, 145.1, 145.0, 133.8, 133.6, 117.4, 116.7,
116.3, 116.1, 115.9, 115.6, 52.9, 39.3, 30.7, 27.7, 23.3. HR ESIMS cal-
culated for C20H21N2O14Sꢁ2 ¼577.0440; found¼577.0439. Anal. Calcd
(%) for C20H22N2O8$2H2O: C, 39.09; H, 4.26; N, 4.56; O, 41.65; S,
10.44. Found: C, 39.15; H, 4.12; N, 4.28.
4.6.4. N,N0-Bis(2,3-dihydroxy-5-sulfonylbenzoyl) cyclohexane-
(1,3)-bismethylamine (5d)
Compound 5d was obtained from 4d (585 mg, 1.4 mmol) in
oleum (12 mL) to give 5d as a hygroscopic grey powder corre-
sponding to a mixture of cis/trans diastereoisomers of 80:20 ratio
(632 mg, 78%). HR ESIMS calculated for C22H25N2O12Sꢁ2 ¼573.0849;
found¼573.0846. Anal. Calcd (%) for C22H26N2O12S2$2H2O: C, 43.27;
H, 4.95; N, 4.59; O, 36.68; S, 10.50. Found: C, 43.36; H, 5.08; N, 4.37.
NMR data for the major stereoisomer 5d1. 1H NMR (D2O, 300 MHz,
Acknowledgements
We thank Dr. Bouchu, Genevieve Herault and Marie-Christine
Duclos for analytical assistance. This work was supported by
a program of interdisciplinary research called ‘Nuclear and Envi-
`
ronmental Toxicology, Tox-Nuc-E’ funded by the Commissariat a
25 ꢀC):
J¼6.8 Hz, 4H), 1.26–1.62 (m, 6H), 0.98–1.09 (m, 2H), 0.86–0.92 (m,
2H). 13C NMR (CDCl3, 75 MHz, 25 ꢀC):
¼169.3, 149.9, 145.3, 133.9,
116.9, 115.8, 46.1, 37.4, 34.61, 30.3, 25.2. NMR data for the minor
stereoisomer 5d2. 1H NMR (D2O, 300 MHz, 25 ꢀC):
d
¼7.64 (d, J¼2 Hz, 2H), 7.36 (d, J¼2 Hz, 2H), 3.23 (d,
´
l’Energie Atomique (CEA) and Comite National pour la Recherche
Scientifique (CNRS).
d
References and notes
d
¼7.62 (d, J¼2 Hz,
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2. Bulman, R. A. Coord. Chem. Rev. 1980, 31, 221–250.
3. Galle, P. Toxiques Nucleaires; Masson: Paris, 1997, pp 185–205.
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2319.
7. Xu, G.; Yang, C.; Liu, B.; Wu, X.; Xie, Y. Heteroat. Chem. 2004, 15, 251–257.
8. Martinez, A. B.; Cabrini, R. L.; Ubios, A. M. Health Phys. 2000, 78, 668–671.
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10. Ubios, A. M.; Braun, E. M.; Cabrini, R. L. Health Phys. 1994, 66, 540–544.
11. Fukuda, S.; Iida, H.; Ikeda, M.; Yan, X.; Xie, Y. Health Phys. 2005, 89, 81–88.
12. Durbin, P.; Kullgren, B.; Ebbe, S. N.; Xu, J.; Raymond, K. N. Health Phys. 2000, 78,
511–521.
13. Sylwester, E. R.; Allen, P. G.; Dharmawardana, U. R.; Sutton, M. Inorg. Chem.
2001, 40, 2835–2841.
14. Domingo, J. L.; Llobet, J. M.; Corbella, J. J. Fundam. Appl. Toxicol. 1990, 14, 88–95.
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2H), 7.32 (d, J¼2 Hz, 2H), 3.23 (d, J¼6.8 Hz, 4H), 1.26–1.62 (m, 6H),
0.98–1.09 (m, 2H), 0.66–0.74 (m, 2H). 13C NMR (CDCl3, 75 MHz,
´
25 ꢀC):
20.6.
d¼168.9, 149.7, 145.2, 133.7, 116.5, 115.7, 43.6, 32.6, 31.8, 29.1,
4.6.5. 2,4-Bis[(2,3-dihydroxy-5-sulfobenzoyl)aminomethyl]-
benzenesulfonic acid (5e)
Compound 5e was obtained from 4e26 (1.13 g, 2.7 mmol) in
oleum (12 mL) to give 5e as a hygroscopic grey powder (1.3 g, 72%).
1H NMR (D2O, 200 MHz, 25 ꢀC):
d
¼7.83 (d, J¼8.5 Hz, 1H), 7.64 (d,
J¼2.06 Hz, 1H), 7.63 (br s, 1H), 7.58 (d, J¼2.06 Hz, 1H), 7.29–7.31
(m, 1H), 7.27 (d, J¼2.06 Hz, 1H), 4.91 (s, 2H), 4.57 (s, 2H). 13C NMR
(D2O, 50 MHz, 25 ꢀC):
d
¼169.5, 169.3, 150.0, 150.0, 145.2,
143.4, 142.0, 139.8, 139.0, 135.6, 133.8, 127.9, 126.0, 125.4,
123.2, 117.0, 116.0, 115.6, 42.7, 41.0. HR ESIMS calculated for
C
C
22H19N2O12Sꢁ2 ¼646.9948; found¼646.9950. Anal. Calcd (%) for
16. Bosque, M. A.; Domingo, J. L.; Llobet, J. M.; Corbella, J. Toxicology 1993, 79, 149–
156.
17. Ramounet-Le Gall, B.; Grillon, G.; Rateau, G.; Burgada, R.; Bailly, T.; fritsch, P.
Radiat. Prot. Dosim. 2003, 105, 535–538.
22H20N2O12S2$5H2O: C, 35.77; H, 4.09; N, 3.79; O, 43.32; S, 13.02.
Found: C, 36.03; H, 4.30; N, 3.62.
18. Gorden, A. E. V.; Xu, J.; Raymond, K. N.; Durbin, P. Chem. Rev. 2003, 103, 4207–
4282.
19. Xu, J.; Raymond, K. N. Inorg. Chem. 1999, 38, 308–315.
20. Vickery, E. H.; Pahler, L. F.; Eisenbraun, E. J. J. Org. Chem. 1979, 44, 4444–4446.
21. Thomas, F.; Beguin, C.; Pierre, J.-L.; Serratrice, G. Inorg. Chim. Acta 1999, 291,
148–157.
22. Thompson, A. S.; Humphrey, G. R.; DeMarco, A. M.; Mathre, D. J.; Grabowski,
E. J. J. J. Org. Chem. 1993, 58, 5886–5888.
23. Gardner, R. A.; Kinkade, R.; Wang, C.; Phanstiel, O. I. V. J. Org. Chem. 2004, 69,
3530–3537.
24. Laursen, B.; Denieul, M.-P.; Skrydstrup, T. Tetrahedron 2002, 58, 2231–2238.
25. Duhme, A.-K.; Dauter, Z.; Hider, R. C.; Pohl, S. Inorg. Chem. 1996, 35, 3059–3061.
26. Duhme, A.-K. J. Chem. Soc., Dalton Trans. 1997, 773–778.
27. Weitl, F. L.; Harris, W. R.; Raymond, K. N. J. Med. Chem. 1979, 22, 1281–1283.
28. Schnabelrauch, M.; Wittmann, S.; Rahn, K.; Mollmann, U.; Reissbrodt, R.;
Heinisch, L. BioMetals 2000, 13, 333–348.
4.6.6. 2,5-Bis[(2,3-dihydroxy-5-sulfonylbenzoyl)-aminomethyl]-
benzenesulfonic acid (5f)
Compound 5f was obtained from 4f (470 mg, 1.15 mmol) in
oleum (12 mL) to give 5f as a hygroscopic grey powder (430 mg,
1
57%).27 H NMR (D2O, 200 MHz, 25 ꢀC):
d
¼7.74 (s, 1H), 7.59 (d,
J¼1.7 Hz, 1H), 7.55 (d, J¼1.7 Hz, 1H), 7.31–7.33 (m, 2H), 7.23 (d,
J¼1.7 Hz, 2H), 4.82 (s, 2H), 4.42 (s, 2H). 13C NMR (D2O, 50 MHz,
25 ꢀC):
d
¼169.7, 169.2, 150.2, 145.4, 141.0, 138.0, 134.4, 134.1, 130.7,
129.7, 126.4, 117.2, 116.8, 116.1, 43.0, 41.0. HR ESIMS calculated for
C
C
22H19N2O12Sꢁ2 ¼646.9948; found¼646.9946. Anal. Calcd (%) for
22H20N2O12S2$4H2O: C, 36.67; H, 3.92; N, 3.89; O, 42.18; S, 13.35.
Found: C, 36.58; H, 4.05; N, 3.84.