New synthetic approach for the incorporation of 3-hydroxypyridin-2(1 H)-one (3,2-HOPO) ligands: Synthesis of structurally diverse poly 3,2-HOPO chelators

Article abstract of DOI:10.1055/s-0030-1258337

The 3,2-HOPO sulfonamide reagent 3 was prepared from commercial 2,3-dihydroxypyridine in four steps in good yields. Sulfonamide 3 readily underwent selective alkylation with dibromides in the presence of base or could be coupled to alcohols using Mitsunob

Full text of DOI:10.1055/s-0030-1258337

PAPER
57
New Synthetic Approach for the Incorporation of 3-Hydroxypyridin-2(1H)-
one (3,2-HOPO) Ligands: Synthesis of Structurally Diverse Poly 3,2-HOPO
Chelators
S
tructurall
a
yDiverse
P
y
oly3,2-H
O
P
a
O
C
helato
n
r
s
thi Arumugam, Hayley A. Brown, Hollie K. Jacobs,* Aravamudan S. Gopalan*
Department of Chemistry and Biochemistry, New Mexico State University, Las Cruces, NM 88003-8001, USA
Fax +1(575)6462649; E-mail: hjacobs@nmsu.edu; E-mail: agopalan@nmsu.edu
Received 22 September 2010; revised 18 October 2010
tors with reduced organic and aqueous solubility that can
limit their efficacy in the desired applications.
Abstract: The 3,2-HOPO sulfonamide reagent 3 was prepared
from commercial 2,3-dihydroxypyridine in four steps in good
yields. Sulfonamide 3 readily underwent selective alkylation with
dibromides in the presence of base or could be coupled to alcohols
using Mitsunobu conditions. The utility of this nucleophilic 3-hy-
droxypyridin-2(1H)-one (3,2-HOPO) reagent was demonstrated by
the synthesis of some tris- and tetrakis-3,2-HOPO chelators. This
approach for tethering 3,2-HOPO ligands is unique and flexible as
shown by the preparation of 3,2-HOPO/iminocarboxylic acid che-
lator 17.
A while ago, we disclosed a method for introduction of
3,2-HOPO moieties onto a variety of nucleophilic plat-
forms including polyamines8 and polyphenols9 that uses
novel bicyclic 3,2-HOPO imidate electrophiles III. While
IIIa and IIIb reacted readily with secondary amines, their
reaction with aliphatic primary amines generally gave
amidine products, limiting the use of this methodology for
the introduction of 3,2-HOPO ligands onto amine plat-
forms.
Key words: 3-hydroxypyridin-2(1H)-one, synthesis, polydentate
chelators, mixed ligand chelators, sulfonamide
OR1
X
OR1
O
OR1
There has been much recent interest in the synthesis of
chelators containing the 3-hydroxypyridin-2(1H)-one
(3,2-HOPO) ligand arising from their ability to form
strong complexes with hard metal ions.1 3,2-HOPO chela-
tors have been examined for a variety of medical applica-
tions including the treatment of iron overload diseases,2
cancer treatment,3 and as contrast agents in magnetic res-
OR1
MsO–
O
N
O
N+
N
X
O
N
n
R2
Nu
O
I
II
IIIa n = 1
IIIb n = 2
IV
onance imaging (MRI).4 Hydroxypyridinone chelators Figure 1
also form strong complexes with actinide(IV) ions leading
to possible applications in environmental remediation and
A synthon, such as IV, that allows the 3,2-HOPO ligand
to serve as a nucleophile rather than as an electrophile
would permit access to a diverse array of 3,2-HOPO
ligands including mixed ligand systems and would com-
plement existing methodology. In this paper, we report the
preparation and applications of a nucleophilic 3,2-HOPO
sulfonamide reagent 3 that can be effectively tethered
onto suitable platforms by alkylation reactions. This re-
agent allows access to new classes of 3,2-HOPO chelators
including mixed ligand systems.
biological detoxification.5 Recently, the syntheses of
HOPO chelators which also carry other ligand groups,
such as hydroxamates, have been reported due to their po-
tential biomedical applications.6
The direct alkylation of 2,3-dihydroxypyridine can be ac-
complished, but requires harsh conditions and, hence, is
not a convenient method for the preparation of polyden-
tate chelators.7 The preferred approach that has been used
to introduce the 3,2-HOPO ligand involved the reaction of
an amine in the spacer moiety with an activated carboxy-
lic acid linker attached to the pyridinone ring system fol-
lowed by removal of protecting groups to expose the free
ligand. 3,2-HOPO has been linked to the amine spacer
either through an activated ester on the ring nitrogen as
depicted in I (Figure 1), or through an activated carboxylic
acid group on the pyridinone ring, see II. While the result-
ing amide linkages may be advantageous in the metal ion
complexation process, they can lead to polydentate chela-
The first challenge was to establish a convenient method
for the preparation of 3,2-HOPO amine 2 (Scheme 1). In
contrast to alkylation reactions, which require harsh con-
ditions, 2,3-dihydroxypyridine undergoes Michael addi-
tions more readily. Reaction of 2,3-dihydroxypyridine
with acrylonitrile in the presence of cesium fluoride cata-
lyst in acetonitrile at 60 °C gave the corresponding nitrile
adduct in good yield and sufficient purity for direct use in
the next step. Treatment of the crude nitrile with benzyl
bromide and potassium carbonate in refluxing acetonitrile
gave benzyl-protected 3,2-HOPO nitrile 1, which was
conveniently purified by washing with diethyl ether. Se-
lective reduction of the nitrile in the presence of the pyri-
SYNTHESIS 2011, No. 1, pp 0057–0064
x
x
.
x
x
.2
0
1
0
Advanced online publication: 26.11.2010
DOI: 10.1055/s-0030-1258337; Art ID: M06510SS
© Georg Thieme Verlag Stuttgart · New York

58
J. Arumugam et al.
PAPER
dinone ring was a major concern.10 However, selective group using DBU and thioglycerol in N,N-dimethylform-
reduction of the nitrile to the corresponding 3,2-HOPO amide gave complex mixtures that were difficult to purify.
amine 2 could be achieved using borane–tetrahydrofuran However, the nosyl group could be easily cleaved with
complex. It was found that the best method for the isola- thioacetic acid and lithium hydroxide in N,N-dimethyl-
tion of the free 3,2-HOPO amine 2 involved quenching formamide at room temperature to furnish the bis-3,2-
the reaction mixture with methanol followed by stirring HOPO amine 6 in 75% yield after purification.13,14 Alkyl-
with concentrated hydrochloric acid for 24 hours. After ation of the secondary amine 6 with 3,2-HOPO imidate
adjusting the pH of the mixture to 8 with sodium hydrox- salt IIIb in the presence of excess of triethylamine in ace-
ide, the 3,2-HOPO amine 2 could be extracted into dichlo- tonitrile at 60 °C gave 7 in good yield after purification.8a
romethane and isolated in 93% yield with satisfactory Removal of the benzyl groups using hydrobromic acid–
purity.11 The desired 3,2-HOPO amine could be readily acetic acid (1:1) gave the target tris-3,2-HOPO chelator 8
prepared on a large scale without the need for chromato- as its hydrobromide salt in 81% yield.
graphic purification.
Ns
The amine 2 is a useful 3,2-HOPO synthon, as it can be
coupled using standard procedures to various activated
N
3, Ph3P (3.5 equiv)
DIAD (2.0 equiv)
acid derivatives like I and II. However, we were interest-
ed in its alkylation reactions that could lead to new chela-
tors without the geometric constraints imposed by amide
linkages. In order to achieve selective monoalkylations, it
was thought best to use the corresponding 4-nitrobenzene-
sulfonyl (nosyl) derivative of 2. Treatment of 3,2-HOPO
amine 2 with 4-nitrobenzenesulfonyl chloride in the pres-
ence of N-methylmorpholine (1.2 equiv) in dichlo-
romethane gave the desired 3,2-HOPO sulfonamide
reagent 3 as a light-yellow solid in 73% yield after chro-
matographic purification.
OBn
O
50 °C, 1 d, 64%
N
O
N
N
O
OBn
BnO
CH2OH
5
4
HSCH2CO2H (2 equiv)
LiOH⋅H2O (4 equiv)
DMF, r.t., 5.5 h, 75%
H
N
O
IIIb, Et3N (2.0 equiv)
OR
1. acrylonitrile (5 equiv)
CsF (cat.), MeCN
60 °C, 22 h, 72%
N
N
OBn
O
OH
OH
60 °C, 72%
N
N
O
O
3
2. BnBr (1.1 equiv)
K2CO3, MeCN
80 °C, 95%
N
N
BnO
OBn
HBr–AcOH
(1:1 ), r.t.
7 R = Bn
8 R = H, 81%
6
CN
1
Scheme 2 Synthesis of tris-3,2-HOPO chelator 8
BH3⋅THF
0 °C to r.t., 93%
p-nitrobenzenesulfonyl
chloride (1 equiv)
The availability of structurally diverse diamines has made
them a well-exploited spacer group for the introduction of
ligand moieties. Hence, the tris-3,2-HOPO 12 and tet-
rakis-3,2-HOPO 14 assembled on a propane-1,3-diamine
platform were attractive targets to demonstrate the useful-
ness of our methodology. To our satisfaction, the
monoalkylation of 3 could be achieved in high yields us-
ing excess 1,3-dibromopropane in the presence of potassi-
um carbonate in refluxing acetonitrile to give 9 in
excellent yield (Scheme 3). Further alkylation of 9 with
bis-3,2-HOPO amine 6 followed by removal of the nosyl
group gave 11. Debenzylation using standard reaction
conditions gave the tris-3,2-HOPO chelator 12 as the hy-
drobromide salt. It is important to point out that the di-
amine platform of 12 can be easily modified by the use of
other dibromides in the initial alkylation of 3.
N-methylmorpholine (1.2 equiv)
CH2Cl2, 0 °C to r.t., 73%
OBn
O
OBn
O
N
N
NH
Ns
NH2
2
Ns =
O2S
NO2
3
Scheme 1 Synthesis of 3,2-HOPO sulfonamide 3
With the nosyl reagent 3 in hand, it was decided that the
best way to demonstrate its synthetic utility was by the
synthesis of polydentate chelators such as the tripodal
TREN-based tris-3,2-HOPO chelator 8 shown in
Scheme 2. TREN-based 3,2-HOPO and hydroxamate
chelators have been of much interest for the binding of
hard metal ions.12 Reaction of the sulfonamide reagent 3
using triphenylphosphine and diisopropyl azodicarboxyl-
ate in tetrahydrofuran at 50 °C with 3,2-HOPO alcohol 48a
gave the nosyl-bis-3,2-HOPO amine 5 in 64% yield after
silica gel chromatography. Attempts to remove the nosyl
The above synthetic scheme was readily modified to pre-
pare tetrakis-3,2-HOPO chelators, a class of compounds
which have been of interest for their actinide ion binding
(Scheme 4).5 The alkylation of 1,3-dibromopropane (1
equiv) with two equivalents of bis-3,2-HOPO amine 6 us-
ing potassium carbonate in refluxing acetonitrile gave the
Synthesis 2011, No. 1, 57–64 © Thieme Stuttgart · New York

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Structurally Diverse Poly 3,2-HOPO Chelators
59
Ns
N
N
Br
Br(CH2)3Br (11 equiv)
K2CO3, MeCN, reflux
21 h, 93%
3
O
OBn
9
K2CO3, 6
MeCN, reflux
2 d, 72%
HN
N
N
Ns
N
N
N
HSCH2CO2H (2 equiv)
O
O
LiOH⋅H2O (4 equiv)
DMF, r.t., 3 h, 77%
N
N
OR
OBn
O
O
N
N
O
O
OR
OBn
OBn
OR
10
11 R = Bn
12 R = H, 90%
HBr–AcOH
(1:1 ), r.t.
Scheme 3 Synthesis of tris-3,2-HOPO chelator 12
corresponding tetrabenzyl-protected 3,2-HOPO 13 in in the presence of potassium carbonate gave 16 in 59%
good yield after purification. Removal of the benzyl pro- yield for two steps after purification. The concurrent re-
tecting groups gave the tetrakis-3,2-HOPO chelator 14 as moval of both benzyl and tert-butyl protecting groups in
the hydrobromide salt.
the last step using hydrobromic acid/acetic acid (1:1) is a
matter of convenience and gave the desired mixed ligand
chelator 17 as a light-brown solid (Scheme 5). The chela-
tor 17 is water soluble as might be expected.
N
N
N
O
O
In conclusion, the development of strategies and synthetic
methodologies for the incorporation of the 3,2-HOPO
moiety into a diverse array of platforms is of great impor-
tance due to the potential environmental and biomedical
applications of these metal ion chelators. The chemistry
presented in this paper is applicable to the synthesis of a
broad array of polydentate 3,2-HOPO targets and related
analogues. The amine 2 can be prepared from commer-
cially available material in three steps and is a useful re-
agent for direct coupling with carboxylic acids to tether
the 3,2-HOPO moiety. It can be converted into its nosyl
derivative 3 in good yields. The sulfonamide 3 can under-
go selective alkylation reactions with dibromides or can
participate in Mitsunobu reactions with alcohols under
mild conditions. The usefulness of this synthetic approach
has been demonstrated by the synthesis of some novel
tris- and tetrakis-3,2-HOPO chelators. The synthesis of
mixed 3,2-HOPO-iminoacetic acid chelator 17, highlights
the use of this method to access desired mixed ligand tar-
gets. Also, the approach is amenable to the preparation of
hexadentate chelators such as tris-3,2-HOPO 11 which
have a functional handle for the introduction of a fluores-
cent reporter group15 or attachment to other
biomolecules16 of interest.
N
Br(CH2)3Br
RO
N
OR
K2CO3
MeCN
O
O
N
reflux, 67%
RO
6
OR
(2 equiv)
13 R = Bn
14 R = H, 74%
HBr–AcOH
(1:1 ), r.t.
Scheme 4 Synthesis of tetrakis-3,2-HOPO chelator 14
Finally, it was felt relevant to demonstrate the use of this
methodology to make a mixed 3,2-HOPO ligand system.
The ability to access mixed 3,2-HOPO ligand chelators,
carrying other metal-binding ligands such as iminocar-
boxylic acids and hydroxamic acids would provide new
classes of molecules with interesting coordination chem-
istry and biological activity.6 The iminoacetic acid/3,2-
HOPO chelator 17 was chosen as a target for this synthetic
study. Dialkylation of 1,3-dibromopropane with two
equivalents of sulfonamide 3,2-HOPO 3 gave the desired
bis-3,2-HOPO 15 in 74% yield along with 6% of the
monoalkylated product 9. The nosyl groups of 15 were re-
moved using standard conditions and the resulting di-
amine was used without purification. Dialkylation of the
crude diamine with tert-butyl bromoacetate in acetonitrile
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60
J. Arumugam et al.
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O
O
Br(CH2)3Br
K2CO3, MeCN
reflux, 20 h, 74%
3
Ns
N
N
N Ns
N
N
N
t-BuO
Ot-Bu
OBn
1. HSCH2CO2H
LiOH⋅H2O, DMF, r.t.
+ 9 (6%)
O
2. BrCH2CO2t-Bu (2.0 equiv)
K2CO3, MeCN, r.t.
(2.0 equiv)
O
O
O
N
N
59% (2 steps)
BnO
OBn
BnO
15
16
HBr–AcOH (1:1 )
5 d, r.t., 81%
O
O
N
N
N
HO
HO
OH
O
O
N
OH
17
Scheme 5 Synthesis of mixed 3,2-HOPO/iminoacetic acid chelator 17
1H (200 MHz) and 13C NMR (50 MHz) spectra were recorded on a
mmol) and the mixture was heated at reflux for 19 h. The solvent
and excess BnBr were removed in vacuo. The residue was dissolved
in CH2Cl2 (100 mL) and washed with sat. NaHCO3 (2 × 60 mL).
The aqueous layer was extracted once more with CH2Cl2 (40 mL).
The combined organic layers were then washed with sat. NaCl (2 ×
100 mL), dried (MgSO4), and filtered. The solid product was
washed with Et2O (2 × 50 mL) and collected via vacuum filtration.
The white crystalline product was dried under reduced pressure to
give nitrile 1 (10.3 g, 95%); mp 138–140 °C.
1
Varian XL 200. H (300 MHz) and 13C NMR (75 MHz) spectra
1
were recorded on a 300 MHz Varian NMR. H NMR (400 MHz)
spectra were recorded on a Varian Unity 400 spectrometer. NMR
spectral samples were prepared in CDCl3 relative to TMS or D2O as
noted. For 1H NMR spectra obtained in D2O, the HOD peak at d =
4.72 ppm was used as internal reference. For 13C NMR spectra ob-
tained in D2O, 1,4-dioxane (d = 66.5) was used as an internal refer-
ence. Analytical and preparative TLC was performed on silica 60/
F254 plastic plates (EM Science). Column chromatography was
performed on silica gel (Merck 60–200 mesh) or basic alumina
(Aldrich 150 mesh). Chromatography solvents were reagent grade
and were obtained from either Fisher Scientific or VWR Scientific.
Reagents were obtained from Aldrich or Lancaster chemical com-
panies and were used as received. Anhyd THF was collected from
a GlassContour™ solvent purification system. Other dry solvents
(MeCN, CH2Cl2, etc) were obtained from Acros. Desert Analytics
(Tucson, Arizona) performed elemental analyses.
IR (KBr): 2946, 2246, 1652, 1611, 1457 cm–1.
1H NMR (200 MHz, CDCl3): d = 2.94 (t, J = 6.6 Hz, 2 H), 4.19 (t,
J = 6.6 Hz, 2 H), 5.12 (s, 2 H), 6.11 (t, J = 7.0 Hz, 1 H), 6.70 (dd,
J = 1.5, 7.7 Hz, 1 H), 6.98 (dd, J = 1.5, 7.0 Hz, 1 H), 7.30–7.46 (m,
5 H).
13C NMR (50 MHz, CDCl3): d = 16.9, 46.2, 70.7, 105.2, 115.9,
117.1, 127.2, 128.0, 128.4, 128.8, 135.9, 148.8, 157.7.
Anal. Calcd for C15H14N2O2: C, 70.85; H, 5.55; N, 11.02. Found: C,
70.46; H, 5.25; N, 10.89.
3-(3-Hydroxy-2-oxopyridin-1(2H)-yl)propanenitrile and 3-[3-
(Benzyloxy)-2-oxopyridin-1(2H)-yl]propanenitrile (1)
3-(3-Hydroxy-2-oxopyridin-1(2H)-yl)propanenitrile
3-[3-(Benzyloxy)-2-oxopyridin-1(2H)-yl]propanamine (2)
To a soln of nitrile 1 (2.00 g, 7.87 mmol) in anhyd THF (40 mL) at
0 °C was added BH3·THF (11.6 mL, 11.7 mmol) and the soln stirred
at r.t. for 39 h. The mixture was cooled to 0 °C, quenched with
MeOH and the solvent removed in vacuo. The crude product was
dissolved in MeOH (40 mL), cooled to 0 °C, and the pH adjusted to
2 with concd HCl. After stirring at r.t. for 24 h, the solvent was re-
moved in vacuo and the resulting thick oil was washed with EtOAc
(3 × 5 mL). The remaining residue was dissolved in H2O (15 mL)
and cooled to 0 °C. The pH was adjusted to 8 with 20% aq NaOH
and the product extracted into CH2Cl2 (3 × 100 mL), dried
(Na2SO4), and filtered and the solvent was removed in vacuo. The
crude amine 2 (1.88 g, 93%) was dried under reduced pressure and
used without purification.11
To a soln of 2,3-dihydroxypyridine (10.0 g, 90 mmol) in MeCN
(110 mL) was added CsF (1.37 g, 9 mmol) and acrylonitrile (29 mL,
450 mmol) and the soln was heated at reflux for 3 d. The solvent and
excess acrylonitrile were removed in vacuo. The product was dis-
solved in hot MeCN (2 × 100 mL) and the solids were filtered off.
The solvent was removed under reduced pressure and the resulting
solid washed with cold H2O (50 mL) at 0 °C for 1 h. The product
was collected by vacuum filtration and then dried under reduced
pressure to give the crude nitrile as a solid (10.7 g, 72%), which was
used without purification.
IR (neat): 3217, 2247, 1656, 1605 cm–1.
1H NMR (200 MHz, CDCl3): d = 2.93 (t, J = 6.2 Hz, 2 H), 4.23 (t,
J = 6.2 Hz, 2 H), 6.24 (t, J = 7.3 Hz, 1 H), 6.76–6.94 (m, 3 H).
IR (neat): 3367, 2944, 1652, 1601 cm–1.
13C NMR (50 MHz, CDCl3): d = 17.3, 46.4, 107.5, 114.7, 116.8,
1H NMR (400 MHz, CDCl3): d = 1.86–1.93 (m, 2 H), 2.71 (t,
J = 6.6 Hz, 2 H), 4.09 (t, J = 6.8 Hz, 2 H), 5.12 (s, 2 H), 6.03 (t,
J = 7.0 Hz, 1 H), 6.64 (dd, J = 1.7, 7.2 Hz, 1 H), 6.92 (dd, J = 1.8,
6.8 Hz, 1 H), 7.30–7.45 (m, 5 H).
126.9, 146.7, 158.4.
3-[3-(Benzyloxy)-2-oxopyridin-1(2H)-yl]propanenitrile (1)
To a soln of the crude nitrile (7.0 g, 42.6 mmol) in MeCN (70 mL)
was added K2CO3 (6.48 g, 46.9 mmol) and BnBr (5.6 mL, 46.9
Synthesis 2011, No. 1, 57–64 © Thieme Stuttgart · New York

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Structurally Diverse Poly 3,2-HOPO Chelators
61
N-{3-[3-(Benzyloxy)-2-oxopyridin-1(2H)-yl]propyl}-4-nitro-
benzenesulfonamide (3)
13C NMR (50 MHz, CDCl3): d = 29.4, 46.0, 47.3, 70.8, 104.5,
115.7, 127.3, 127.9, 128.5, 129.3, 136.4, 148.8, 158.2.
A soln of 4-nitrobenzenesulfonyl chloride (0.96 g, 4.33 mmol) in
CH2Cl2 (10 mL) was added to a soln of amine 2 (1.12 g, 4.34 mmol)
and N-methylmorpholine (0.57 mL, 5.19 mmol) in CH2Cl2 at 0 °C.
After stirring at r.t. for 4 h, the solvent was removed in vacuo and
the residue dissolved in 15% CH2Cl2–EtOAc (80 mL). The organic
layer was washed with H2O (2 × 50 mL) and dried (Na2SO4) and the
solvent was removed in vacuo. The crude product was purified by
chromatography (silica gel, 30% EtOAc–hexane to 2% MeOH–
CHCl3) to give sulfonamide 3,2-HOPO 3 (1.41 g, 73%) as a pale-
yellow solid; mp 165–167 °C.
Anal. Calcd for C30H33N3O4·0.12CHCl3: C, 70.39; H, 6.50; N, 8.18.
Found: C, 70.08; H, 6.44; N, 8.37.
Tris{3-[3-(benzyloxy)-2-oxopyridin-1(2H)-yl]propyl}amine (7)
A soln of Et3N (0.17 mL, 1.22 mmol) in anhyd MeCN (1 mL) was
added to a soln of benzyl-protected 3,2-HOPO amine 6 (0.30 g, 0.6
mmol) in anhyd MeCN (2 mL). A soln of 3,2-HOPO iminium salt
IIIb11 (0.30 g, 0.90 mmol) in MeCN (6 mL) was added and the mix-
ture was heated at 60 °C for 22 h. The volatiles were removed under
reduced pressure and the residue purified on basic alumina (0–2%
MeOH–EtOAc). The benzyl-protected tris-3,2-HOPO 7 (0.32 g,
72%) was obtained as a viscous brown oil.
IR (KBr): 3103, 1652, 1599, 1521 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.92–1.98 (m, 2 H), 2.85–2.89 (m,
2 H), 4.12 (t, J = 6.3 Hz, 2 H), 5.09 (s, 2 H), 6.12 (t, J = 7.0 Hz, 1
H), 6.67 (dd, J = 1.4, 7.4 Hz, 1 H), 6.84 (dd, J = 1.6, 6.8 Hz, 1 H),
6.92 (unres t, 1 H), 7.33–7.43 (m, 5 H), 8.08 (d, J = 8.8 Hz, 2 H),
8.26 (d, J = 9.0 Hz, 2 H).
13C NMR (50 MHz, CDCl3 with a few drops of CD3OD): d = 29.6,
39.4, 46.2, 70.8, 106.3, 115.9, 124.1, 127.3, 128.2, 128.4, 128.6,
135.7, 146.2, 148.6, 149.8, 158.6.
IR (neat): 1651, 1603, 1555 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.87–1.95 (m, 6 H), 2.52 (t,
J = 6.6 Hz, 6 H), 4.06 (t, J = 7.6 Hz, 6 H), 5.09 (s, 6 H), 6.00 (t,
J = 7.0 Hz, 3 H), 6.62 (dd, J = 1.4, 7.4 Hz, 3 H), 6.99 (dd, J = 1.2,
7.0 Hz, 3 H), 7.27–7.44 (m, 15 H).
13C NMR (50 MHz, CDCl3): d = 26.4, 48.4, 50.4, 70.6, 104.5,
115.3, 127.2, 127.9, 128.5, 129.4, 136.3, 148.7, 158.0.
Anal. Calcd for C21H21N3O6S: C, 56.87; H, 4.77; N, 9.48. Found: C,
56.57; H, 4.94; N, 9.18.
Anal. Calcd for C45H48N4O6: C, 72.95; H, 6.53; N, 7.56. Found: C,
73.17; H, 6.66; N, 7.42.
N,N-Bis{3-[3-(benzyloxy)-2-oxopyridin-1(2H)-yl]propyl}-4-ni-
trobenzenesulfonamide (5)
Tris{3-[3-hydroxy-2-oxopyridin-1(2H)-yl]propyl}amine Tetra-
hydrobromide (8·4HBr)
A soln of 3,2-HOPO alcohol 4 (0.591 g, 2.28 mmol) in anhyd THF
(10 mL) was added to a suspension of sulfonamide 3,2-HOPO 3
(1.01 g, 2.28 mmol) and Ph3P (2.09 g, 7.97 mmol) in THF (15 mL)
and the mixture stirred at r.t. for 5 min. DIAD (0.88 mL, 4.54 mmol)
was slowly added and the mixture heated at 50 °C for 24 h. The sol-
vent was removed under reduced pressure and the residue purified
by chromatography (silica gel, 60–90% EtOAc–hexane) to give sul-
fonamide 5 (0.99 g, 64%) as a light-red solid; mp 45–46 °C.
Benzyl-protected tris-3,2-HOPO amine 7 (0.30 g, 0.412 mmol) was
dissolved in concd HBr–AcOH (1:1, 20 mL) and stirred at r.t. for 67
h. The volatiles were removed under reduced pressure. The residue
was washed with EtOAc and Et2O and dried under high vacuum for
24 h. The product was lyophilized to yield tris-3,2-HOPO chelator
8 (0.264 g, 81%) as a light brown tetrahydrobromide salt.
IR (KBr): 3408, 1645, 1543 cm–1.
1H NMR (D2O, 300 MHz): d = 1.96–2.06 (m, 6 H), 3.09–3.14 (m, 6
H), 3.98 (t, J = 7.0 Hz, 6 H), 6.30 (t, J = 7.0 Hz, 3 H), 6.89 (dd,
J = 1.8, 7.6 Hz, 3 H), 7.07 (dd, J = 1.8, 7.0 Hz, 3 H).
13C NMR (75 MHz, D2O): d = 23.2, 46.7, 49.7, 109.0, 118.8, 128.8,
145.4, 158.3.
IR (KBr): 1654, 1603, 1528 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.02–2.12 (m, 4 H), 3.25 (t,
J = 7.6 Hz, 4 H), 4.01 (t, J = 7.3 Hz, 4 H), 5.10 (s, 4 H), 6.04 (t,
J = 7.3 Hz, 2 H), 6.65 (dd, J = 1.8, 7.3 Hz, 2 H), 6.95 (dd, J = 1.7,
7.0 Hz, 2 H), 7.32–7.44 (m, 10 H), 7.92 (d, J = 9.1 Hz, 2 H), 8.33
(d, J = 8.8 Hz, 2 H).
13C NMR (50 MHz, CDCl3): d = 28.4, 46.4, 47.3, 70.8, 105.0,
115.5, 124.5, 127.3, 128.0, 128.3, 128.5, 128.9, 136.2, 144.6, 148.8,
150.0, 158.1.
Anal. Calcd for C24H30N4O6·4HBr: C, 36.30; H, 4.32; N, 7.05.
Found: C, 36.05; H, 4.22; N, 6.89.
N-{3-[3-(Benzyloxy)-2-oxopyridin-1(2H)-yl]propyl}-N-(3-bro-
mopropyl)-4-nitrobenzenesulfonamide (9)
Anal. Calcd for C36H36N4O8S·0.5H2O: C, 62.32; H, 5.38; N, 8.08.
Found: C, 62.03; H, 5.18; N, 8.19.
Sulfonamide 3,2-HOPO 3 (0.60 g, 1.35 mmol) and 1,3-dibromopro-
pane (1.5 mL, 14.8 mmol) were dissolved in anhyd MeCN (12 mL)
followed by the addition of K2CO3 (0.37 g, 2.70 mmol) and the mix-
ture was heated at reflux for 21 h. The solvent was removed under
reduced pressure. The residue was diluted with EtOAc (60 mL),
washed with H2O (2 × 20 mL), and dried (Na2SO4) and the solvent
was removed in vacuo. The crude product was purified by chroma-
tography (silica gel, 50–60% EtOAc–hexane) to give 9 (0.712 g,
93%) as a viscous yellow oil.
N,N-Bis{3-[3-(benzyloxy)-2-oxopyridin-1(2H)-yl]propyl}amine
(6)
Mercaptoacetic acid (0.24 mL, 3.45 mmol) and LiOH·H2O (0.303
g, 7.22 mmol) were added to a soln of sulfonamide 3,2-HOPO 5
(1.17 g, 1.71 mmol) in DMF (5 mL) and the mixture stirred at r.t.
for 5.5 h. The solvent was removed under reduced pressure. The res-
idue was dissolved in CH2Cl2 (80 mL) and washed with sat.
NaHCO3 (3 × 60 mL), dried (Na2SO4), and the solvent removed un-
der reduced pressure. The crude product was purified by column
chromatography (basic alumina, 0–10% MeOH–EtOAc) to give
amine 6 (0.64 g, 75%) as a viscous red oil.
IR (neat): 1652, 1603, 1531 cm–1.
1H NMR (400 MHz, CDCl3): d = 2.08–2.16 (m, 4 H), 3.25–3.33 (m,
4 H), 3.40 (t, J = 6.5 Hz, 2 H), 4.02 (t, J = 7.0 Hz, 2 H), 5.11 (s, 2
H), 6.08 (t, J = 6.8 Hz, 1 H), 6.67 (d, J = 7.0 Hz, 1 H), 6.94 (d,
J = 6.6 Hz, 1 H), 7.31–7.44 (m, 5 H), 7.98 (d, J = 8.0 Hz, 2 H), 8.37
(d, J = 8.8 Hz, 2 H).
13C NMR (50 MHz, CDCl3): d = 30.5, 31.9, 33.9, 48.9, 49.4, 49.5,
72.8, 107.1, 117.5, 126.5, 129.4, 130.1, 130.4, 130.6, 130.8, 138.2,
146.8, 151.0, 152.2, 160.2.
IR (neat): 3302, 1652, 1602 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.90–1.97 (m, 4 H), 2.59 (t,
J = 6.6 Hz, 4 H), 4.08 (t, J = 6.8 Hz, 4 H), 5.11 (s, 4 H), 6.00 (t,
J = 7.2 Hz, 2 H), 6.62 (dd, J = 1.8, 7.4 Hz, 2 H), 6.96 (dd, J = 1.6,
6.8 Hz, 2 H), 7.29–7.44 (m, 10 H).
Synthesis 2011, No. 1, 57–64 © Thieme Stuttgart · New York

62
J. Arumugam et al.
PAPER
Anal. Calcd for C24H26BrN3O6S·0.8CHCl3: C, 45.13; H, 4.09; N,
6.37. Found: C, 45.40; H, 4.44; N, 6.67.
1H NMR (400 MHz, D2O): d = 2.03–2.16 (m, 8 H), 3.01 (t, J = 7.4
Hz, 2 H), 3.08 (t, J = 7.6 Hz, 2 H), 3.17–3.27 (m, 6 H), 4.04–4.11
(m, 6 H), 6.35–6.40 (m, 3 H), 6.95–6.99 (m, 3 H), 7.12–7.16 (m, 3
H).
13C NMR (50 MHz, D2O): d = 20.5, 23.2, 25.5, 44.2, 44.6, 46.6,
46.7, 49.9, 109.0, 118.9, 119.0, 129.0, 145.2, 145.3, 158.4, 158.6.
N-{3-[3-(Benzyloxy)-2-oxopyridin-1(2H)-yl]propyl}-N-[3-
(bis{3-[3-(benzyloxy)-2-oxopyridin-1(2H)-yl]propyl}ami-
no)propyl]-4-nitrobenzenesulfonamide (10)
A soln of bromide 9 (0.64 g, 1.14 mmol) in anhyd MeCN (15 mL)
was added to a suspension of benzyl-protected 3,2-HOPO amine 6
(0.53 g, 1.06 mmol) and K2CO3 (0.59 g, 4.2 mmol) in anhyd MeCN
(15 mL) and the mixture heated at reflux for 48 h. The solvent was
removed under reduced pressure and the residue was diluted with
CHCl3 (60 mL) and washed with sat. NaHCO3 (1 × 40 mL). The
aqueous layer was again extracted with CHCl3 (1 × 40 mL) and the
combined organic layers were dried (Na2SO4), and the solvent was
removed in vacuo. The crude product was purified on basic alumina
(60–70% EtOAc–hexane to 2% MeOH–EtOAc) to give 10 (0.749
g, 72%) as a yellow solid; mp 42–43 °C.
Anal. Calcd for C27H37N5O6·4HBr·H2O: C, 37.31; H, 4.99; N, 8.06.
Found: C, 37.53; H, 4.69; N, 8.38.
N,N,N¢,N¢-Tetrakis{3-[3-(benzyloxy)-2-oxopyridin-1(2H)-
yl]propyl}propane-1,3-diamine (13)
1,3-Dibromopropane (30.6 mL, 0.30 mmol) was added to a suspen-
sion of benzyl-protected bis-3,2-HOPO 6 (0.30 g, 0.60 mmol) and
K2CO3 (0.21 g, 1.5 mmol) in anhyd MeCN (6 mL) and the mixture
was heated at reflux for 2 d. The solvent was removed under re-
duced pressure. The residue was diluted with CHCl3 (50 mL) and
washed with NaHCO3 (30 mL). The aqueous layer was again ex-
tracted with CHCl3 (30 mL). The combined organic layers were
dried (Na2SO4) and the solvent removed under reduced pressure.
The crude product was purified on basic alumina (2% MeOH–
EtOAc) to provide benzyl-protected 3,2-HOPO 13 (0.21 g, 67%) as
a viscous oil.
IR (neat): 1652, 1603, 1528 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.71–1.80 (m, 2 H), 1.83–1.92 (m,
4 H), 2.00–2.10 (m, 2 H), 2.40–2.49 (m, 6 H), 3.22 (t, J = 7.3 Hz, 2
H), 3.33 (t, J = 9.1 Hz, 2 H), 3.97–4.03 (m, 6 H), 5.08 (s, 2 H), 5.09
(s, 4 H), 5.97–6.03 (m, 3 H), 6.63 (dd, J = 1.5, 7.6 Hz, 3 H), 6.97 (d,
J = 6.7 Hz, 3 H), 7.26–7.43 (m, 15 H), 8.01 (d, J = 8.8 Hz, 2 H),
8.32 (d, J = 8.8 Hz, 2 H).
13C NMR (50 MHz, CDCl3): d = 26.4, 26.9, 28.4, 46.4, 47.3, 47.6,
48.3, 50.6, 50.8, 70.6, 104.4, 104.7, 115.2, 115.4, 124.4, 127.2,
127.8, 128.3, 129.1, 129.2, 136.1, 136.2, 144.8, 148.7, 149.8, 157.8,
157.9.
IR (neat): 2949, 2811, 1651, 1602, 1555 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.46–1.60 (m, 2 H), 1.84–1.93 (m,
8 H), 2.42–2.49 (m, 12 H), 3.99 (t, J = 7.6 Hz, 8 H), 5.07 (s, 8 H),
5.97 (t, J = 7.0 Hz, 4 H), 6.60 (dd, J = 1.7, 7.3 Hz, 4 H), 6.98 (dd,
J = 1.7, 6.7 Hz, 4 H), 7.27–7.43 (m, 20 H).
13C NMR (75 MHz, CDCl3): d = 23.7, 26.3, 48.2, 50.6, 51.5, 70.5,
104.4, 115.3, 127.2, 127.8, 128.4, 129.4, 136.2, 148.6, 157.9.
Anal. Calcd for C54H58N6O10S·0.4CHCl3: C, 63.38; H, 5.71; N,
8.15. Found: C, 63.47; H, 5.64; N, 8.41.
Anal. Calcd for C63H70N6O8·0.5CHCl3: C, 69.40; H, 6.47; N, 7.65.
Found: C, 69.33; H, 6.54; N, 7.68.
N,N,N¢-Tris{3-[3-(benzyloxy)-2-oxopyridin-1(2H)-yl]pro-
pyl}propane-1,3-diamine (11)
N,N,N¢,N¢-Tetrakis{3-[3-hydroxy-2-oxopyridin-1(2H)-yl]pro-
pyl}propane-1,3-diamine Hydrobromide Salt (14·HBr)
Benzyl-protected 3,2-HOPO 13 (0.13 g, 0.13 mmol) was dissolved
in concd HBr–glacial AcOH (1:1, 10 mL) and stirred at r.t. for 4 d.
The volatiles were removed under reduced pressure. The residue
was washed with EtOAc and Et2O and dried under high vacuum for
24 h. The product was lyophilized from H2O–MeCN to yield tet-
rakis-3,2-HOPO chelator 14 (0.11 g, 74%) as a reddish hydrobro-
mide salt.
Mercaptoacetic acid (0.132 mL, 1.9 mmol) and LiOH·H2O (0.16 g,
3.8 mmol) were added to a soln of sulfonamide 10 (0.94 g, 0.95
mmol) in DMF (6 mL) and the soln stirred at r.t. for 3 h. The solvent
was removed under reduced pressure. The residue was diluted with
CHCl3 (80 mL) and washed with sat. NaHCO3 (40 mL). The aque-
ous layer was again extracted with CHCl3 (50 mL). The combined
organic layers were washed with sat. NaHCO3 (60 mL) and dried
(Na2SO4) and the solvent was removed under reduced pressure. The
crude product was purified on basic alumina (2–10% MeOH–
EtOAc) to give amine 11 (0.590 g, 78%) as a red oil.
IR (KBr): 2963, 1640, 1600, 1544 cm–1.
IR (neat): 3302, 1652, 1602 cm–1.
1H NMR (D2O, 300 MHz): d = 2.07–2.16 (m, 10 H), 3.17–3.26 (m,
12 H), 4.04 (t, J = 6.7 Hz, 8 H), 6.35 (t, J = 7.3 Hz, 4 H), 6.96 (dd,
J = 1.7, 7.6 Hz, 4 H), 7.15 (dd, J = 1.7, 6.7 Hz, 4 H).
13C NMR (50 MHz, D2O): d = 18.6, 23.3, 46.7, 49.8, 50.0, 109.0,
118.8, 128.9, 145.4, 158.4.
1H NMR (300 MHz, CDCl3): d = 1.56–1.65 (m, 2 H), 1.85–1.97 (m,
6 H), 2.47 (t, J = 6.7 Hz, 6 H), 2.58–2.64 (m, 4 H), 3.97–4.06 (m, 6
H), 5.09 (s, 6 H), 5.95–6.02 (m, 3 H), 6.62 (dd, J = 1.5, 7.3 Hz, 3 H),
6.92–6.96 (m, 3 H), 7.28–7.44 (m, 15 H).
13C NMR (75 MHz, CDCl3): d = 26.4, 27.0, 29.3, 46.3, 47.3, 48.0,
48.3, 50.7, 51.5, 70.6, 104.4, 115.4, 127.2, 127.8, 128.4, 129.3,
136.3, 148.8, 158.0.
Anal. Calcd for C35H46N6O8·5.7HBr: C, 36.88; H, 4.57; N, 7.37;
Found: C, 36.54; H, 4.77; N, 7.76.
N,N¢-Bis{3-[3-(benzyloxy)-2-oxopyridin-1(2H)-yl]propyl}-
N,N¢-propane-1,3-diyldi-4-nitrobenzenesulfonamide (15)
K2CO3 (0.60 g, 4.4 mmol) was added to a soln of sulfonamide 3,2-
HOPO 3 (0.78 g, 1.75 mmol) and 1,3-dibromopropane (0.18 g, 0.87
mmol) in anhyd MeCN (20 mL) and the mixture was heated at re-
flux for 20 h. The solvent was removed under reduced pressure and
the residue was diluted with CH2Cl2 (40 mL), washed with H2O (3
× 20 mL), and dried (Na2SO4) and the solvent was removed in
vacuo. The crude product was purified by chromatography (silica
gel, 50–80% EtOAc–hexane) to give dialkylated compound 15 as a
yellow solid (0.60 g, 74%) and monoalkylated compound 9 (0.064
g, 6%); mp 76–78 °C.
Anal. Calcd for C48H55N5O6·0.7CHCl3: C, 66.35; H, 6.37; N, 7.94.
Found: C, 66.73; H, 6.45; N, 8.31.
N,N,N¢-Tris{3-[3-(hydroxy)-2-oxopyridin-1(2H)-yl]propyl}pro-
pane-1,3-diamine Tetrahydrobromide (12·4HBr)
Benzyl-protected 3,2-HOPO 11 (0.60 g, 0.745 mmol) was dissolved
in concd HBr–AcOH (1:1, 28 mL) and the soln stirred at r.t. for 66
h. The volatiles were removed under reduced pressure. The residue
was washed with EtOAc and Et2O and dried under high vacuum for
24 h. The product was lyophilized to yield tris-3,2-HOPO chelator
12 (0.63 g, 90%) as the tetrahydrobromide salt.
IR (KBr): 3400, 2960, 1640, 1547 cm–1.
IR (KBr): 1654, 1604, 1528 cm–1.
Synthesis 2011, No. 1, 57–64 © Thieme Stuttgart · New York

PAPER
Structurally Diverse Poly 3,2-HOPO Chelators
63
1H NMR (400 MHz, CDCl3): d = 2.01–2.07 (m, 6 H), 3.22–3.26 (m,
8 H), 3.98 (t, J = 7.2 Hz, 4 H), 5.07 (s, 4 H), 6.04 (t, J = 7.2 Hz, 2
H), 6.66 (dd, J = 1.6, 7.6 Hz, 2 H), 6.94 (dd, J = 1.6, 6.8 Hz, 2 H),
7.30–7.41 (m, 10 H), 7.97 (d, J = 9.0 Hz, 4 H), 8.36 (d, J = 9.0 Hz,
4 H).
13C NMR (50 MHz, CDCl3): d = 28.2, 28.7, 46.8, 47.6, 70.8, 105.0,
115.3, 124.5, 127.4, 128.1, 128.5, 129.0, 136.0, 144.5, 148.9, 150.1,
158.0.
mixed ligand chelator 16 (0.23 g, 81%) as a light-brown hydrobro-
mide salt.
IR (KBr): 3413, 2961, 1741, 1641, 1597, 1547 cm–1.
1H NMR (300 MHz, D2O): d = 2.12–2.25 (m, 6 H), 3.27–3.36 (m, 8
H), 4.05–4.10 (m, 8 H), 6.37 (t, J = 7.02 Hz, 2 H), 6.96 (dd, J = 1.5,
7.6 Hz, 2 H), 7.16 (dd, J = 1.5, 6.7 Hz, 2 H).
13C NMR (50 MHz, D2O): d = 19.1, 23.6, 46.5, 52.0, 52.1, 53.7,
109.0, 119.0, 129.0, 145.3, 158.6, 168.2.
Anal. Calcd for C45H46N6O12S2: C, 58.30; H, 5.00; N, 9.07. Found:
C, 58.46; H, 5.03; N, 9.28.
Anal. Calcd for C23H32N4O8·5HBr·2H2O: C, 29.60; H, 4.43; N,
6.00: Found C, 29.47; H, 4.38; N, 5.88.
N,N¢-Bis{3-[3-(benzyloxy)-2-oxopyridin-1(2H)-yl]propyl}pro-
pane-1,3-diamine and Di-tert-butyl N,N¢-Bis{3-[3-(benzyloxy)-
2-oxopyridin-1(2H)-yl]propyl}-2,2¢-(propane-1,3-diyldiimi-
no)diacetate (16)
N,N¢-Bis{3-[3-(benzyloxy)-2-oxopyridin-1(2H)-yl]propyl}pro-
pane-1,3-diamine
Thioacetic acid (0.06 mL, 0.86 mmol) and LiOH·H2O (76 mg, 1.81
mmol) were added to a soln of disulfonamide 15 (0.20 g, 0.22
mmol) in DMF (3 mL) and the mixture stirred at r.t. for 1.5 h. The
mixture was then diluted with CH2Cl2 (40 mL) and washed with sat.
NaHCO3 (15 mL). The aqueous layer was again extracted with
CH2Cl2 (30 mL). The combined organic layers were washed with
sat. NaHCO3 (20 mL), dried (Na2SO4) and the solvent was removed
under reduced pressure. The crude diamine was used without puri-
fication.
Acknowledgment
This research was supported by grants from the National Institutes
of Health under PHS Grant No. S06GM08136 and
1SC3GM084809-01 and by a Howard Hughes Medical Institute
Undergraduate Science Education grant (award 52005881, fel-
lowship to H.A.B.). We also thank Drs. Vincent J. Huber and
Rajesh Pandey for their contributions to the synthesis of amine 2.
References
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IR (CHCl3): 3300, 1652, 1602 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.61–1.70 (m, 2 H), 1.88–1.98 (m,
4 H), 2.59–2.68 (m, 8 H), 4.05 (t, J = 7.0 Hz, 4 H), 5.11 (s, 4 H),
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IR (neat): 2931, 1731, 1653, 1605, 1554 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.44 (s, 18 H), 1.57–1.65 (m, 2 H),
1.87–1.96 (m, 4 H), 2.58–2.62 (m, 8 H), 3.21 (s, 4 H), 4.03 (t,
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10 H).
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Chem. 2008, 13, 229. (d) Jurchen, K. M. C.; Raymond, K.
M. Inorg. Chem. 2006, 45, 1078. (e) Abergel, R. J.;
13C NMR (75 MHz, CDCl3): d = 25.4, 26.7, 28.1, 48.0, 51.2, 52.2,
55.5, 70.7, 80.8, 104.3, 115.5, 127.3, 127.8, 128.4, 129.7, 136.4,
148.8, 158.1, 170.7.
Anal. Calcd for C45H60N4O8·0.25CHCl3: C, 66.91; H, 7.47; N, 6.90:
Found: C, 67.11; H, 7.28; N, 6.74.
N,N¢-Bis{3-[3-(hydroxy)-2-oxopyridin-1(2H)-yl]propyl}-2,2¢-
(propane-1,3-diyldiimino)diacetic Acid (17)
Compound 16 (0.28 g, 0.35 mmol) was dissolved in concd HBr–
glacial AcOH (1:1, 30 mL) and stirred at r.t. for 5 d. The volatiles
were removed under reduced pressure. The residue was washed
with EtOAc and Et2O and dried under high vacuum for 24 h to yield
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64
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Synthesis 2011, No. 1, 57–64 © Thieme Stuttgart · New York