Synthesis and Chemical Reactivity of a 6-Me-3,2-Hydroxypyridinone Dithiazolide with Primary Amines: A route to New Hexadentate Chelators for Hard Metal(III) Ions

Article abstract of DOI:10.1002/jhet.2372

A hydroxypyridinone building block, bifunctionalized with thiazoline, has been prepared from orthogonally protected 2-(3-(benzyloxy)-4-(ethoxycarbonyl)-6-methyl-2-oxopyridin-1(2H)-yl) acetic acid. The reactivity of the dithiazolide has been explored with

Full text of DOI:10.1002/jhet.2372

Month 2015
Synthesis and Chemical Reactivity of a 6-Me-3,2-Hydroxypyridinone
Dithiazolide with Primary Amines: A route to New Hexadentate
Chelators for Hard Metal(III) Ions
Sylvie L. Pailloux, Sean Nguyen, Stephanie Zhou, Marisa E. Hom, Michelle N. Keyser,
*
Danil Smiles, and Kenneth N. Raymond
Department of Chemistry, University of California, Berkeley, California 94720-1460, USA
*
E-mail: raymond@socrates.berkeley.edu
Additional Supporting Information may be found in the online version of this article.
Received June 26, 2014
DOI 10.1002/jhet.2372
Published online 00 Month 2015 in Wiley Online Library (wileyonlinelibrary.com).
A hydroxypyridinone building block, bifunctionalized with thiazoline, has been prepared from orthogo-
nally protected 2-(3-(benzyloxy)-4-(ethoxycarbonyl)-6-methyl-2-oxopyridin-1(2H)-yl) acetic acid. The reac-
tivity of the dithiazolide has been explored with two primary amines, leading to the synthesis and
characterization of four new hexadentate ligands. Their complexes with selected hard trivalent ions pertinent
to potential molecular imaging applications have been surveyed.
J. Heterocyclic Chem., 00, 00 (2015).
INTRODUCTION
We have developed powerful MRI contrast agents involv-
ing 1,2-HOPO and 1-Me-3,2-HOPO, which have been con-
nected with a tripodal primary amine (TREN, TACN,
Mesyl) to form hexadentate ligands that strongly complex
Gd(III) [7–9]. These complexes have two or three sites avail-
able for water coordination (q), improving the relaxivity of
the complex by a factor of 2 or 3 in comparison to all other
contrast agents currently on the market, which have a q=1.
To allow the incorporation of solubilizing moieties
(dendrimers) or the conjugation to nano-supports (MS2, ester
amine (EA) dendrimer), one HOPO moiety has been re-
placed by a terephthalamide (TAM) that has two amides built
into the motif [10–12]. However, the thermodynamic stabil-
ity of the Gd complexes is lowered when more than one
HOPO unit is substituted by a TAM moiety [13,14].
Hydroxypyridinones (HOPOs) have been developed for
the last 20years as chelators for hard metal ions [1]. The
HOPO 6 membered ring has three major isomers [1]: 3,4-
HOPO, 3,2-HOPO, and 1,2-HOPO, as depicted in Figure 1.
Some HOPOs have been used in pharmaceutical applica-
tions, because their affinity for iron makes them good candi-
dates for treating metal overload, protozoic and bacterial
infections, and neurodegeneration [2]. HOPOs also have
been employed as MMP inhibitors, as well as for antidiabetic
and anticancer treatments when coordinated to d-block ele-
ments such as Zn, Mo, V, Ru, and Os [3]. Additionally,
HOPOs with Gd and Ga have been utilized as imaging
probes and as decorporation agents of actinides [4]. Lastly,
several studies of luminescence performance of 1,2-HOPO
complexes with europium have been published, and they dis-
play good quantum yields [5,6].
To mitigate the thermodynamic stability problem, a new
HOPO (6-Me-3,2-HOPO) has been developed and is de-
scribed herein. This scaffold enables functionalization of
© 2015 HeteroCorporation

S. L. Pailloux, S. Nguyen, S. Zhou, M. E. Hom, M. N. Keyser, D. Smiles, and K. N. Raymond
Vol 000
as well as a simpler purification. H and 13C NMR spectra
for 4 were consistent with previously described spectra [13].
Specifically, the 13C NMR spectrum contains a diagnostic
methylene carbon δ (ppm) 74.04. The molecular structure
of 4 was unequivocally confirmed by single crystal X-ray dif-
fraction structure determination (see Supporting Information:
CCDC 1010120). Compound 5 results from N-alkylation of
the enolate of an amide (Scheme 1). We first envisaged the
synthesis of the diester 5 using potassium on alumina [13].
In this case, the tert-butyl ester 5 was obtained with moderate
yield. Alternatively, by using potassium carbonate in
dimethylformamide (DMF), the O-alkylated 5a was also ob-
tained (Scheme 2).
1
Figure 1. Examples of the hydroxypyridinone family.
the 1-N position, allowing for structural adjustment and the
formation of neutral complexes with M(III) metal ions. This
chemistry also supports the formation of a cage environment,
which increases the kinetic stability of the complex [1,4].
With the exception of work by Gopalan [15], Rapoport
[16], and Van der Eycken [17], very little work has been re-
ported on 3,2-HOPOs that enables reactivity at the 1-N posi-
tion or leads to the development of new HOPO systems. We
describe herein a scalable synthesis for a new HOPO deriva-
tive bi-functionalized at positions 1 and 4 with thiazolide
rings. Facile reaction of this reagent with primary amines en-
ables for the synthesis of tripodal and bi-macrocyclic cage li-
gands that are capable of hexadentate coordination with hard
metal ions such as Gd(III) and Ga(III).
In comparison with 5, 5a is considered to be more ther-
modynamically stable because of its higher aromaticity.
1
The H NMR spectra of thermodynamic 5a and kinetic 5
compounds are presented in Figure 2. The methylene reso-
nance for the O-alkylated compound 5a shows a more aro-
matic shift (δ= 6.96ppm) than the N-alkylated compound 5
(δ =6.19 ppm). In addition, the molecular structure of 5
was confirmed by single X-ray crystallography diffraction
methods (see Supporting Information: CCDC 1010119).
Functional similarity between HOPO and quinolinone
systems suggested the development of a one-step selective
N-alkylation over O-alkylation of compound 4 through the
use of magnesium tert-butoxide [21]. In the present sys-
tem, it is expected that the Mg(II) ion coordinates with
the carbonyl O atom of the cyclic amide to form a five-
membered ring intermediate (Scheme 3) that favors N-
alkylation, producing compound 6 with 80% yield [21].
It is noted that the acid 6 was first obtained by acid hydro-
lysis of the tert-butyl ester 5 with high yield (Scheme 1).
The amide bond formation was first attempted by gener-
ating the N-hydroxysuccinimide (NHS) active ester inter-
RESULTS AND DISCUSSION
The formation of the HOPO ring 3 (Scheme 1) followed
a procedure described by Feist [18]. However, yields ob-
1
tained were typically lower by 20–30%. The H NMR
spectrum was consistent with previously described results
[13,18], and the 13C NMR spectrum showed a characteris-
tic peak at δ (ppm) 102.18 for the only carbon in the ring
carrying a proton [13]. A single X-ray diffraction determi-
nation of 3 has been previously described [13].
The reaction of HOPO 3 with tert-butyl iodoacetate pre-
sents a possible competition between N-alkylation and
O-alkylation. This was previously addressed by us through
the use of cetylpyridinium for phase transfer that favors the
O-alkylation [13]. In a second approach, we studied the use
of strong bases such as 1,8-diazabicyclo[5.4.0]undec-7-ene,
which favors O- over N-alkylation in a homogeneous mixture
[19,20]. By using this approach, we succeeded in synthesizing
6-Me-3,2-HOPO(Bn) 4 with better yield and reproducibility
Scheme 2. O-Alkylation of the enolate form of 6-Me-3,2-HOPO 4.
Scheme 1. Synthesis of bifunctionalized 6-methyl-3,2-HOPOs, 5 and 6.
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Synthesis and Chemical Reactivity of a 6-Me-3,2-Hydroxypyridinone Dithiazolide
with Primary Amines
Figure 2. 1H NMR comparison between resulting products of competitive N-5 (bottom) versus O-alkylation 5a (top).
Scheme 3. Possible mechanism of N-alkylation of 6-Me-3,2-HOPO 4.
Scheme 4. Reactivity of functionalized 6-Me-3,2-HOPO.
mediate, 6a (Scheme 4). Compound 10c was obtained with
moderate yield. Saponification of the ester function of 10c
was obtained, but the activation of position 4 in active ester
NHS or thiazolide failed. Benzyl group of compound 10c
was removed in acidic condition and permitted the synthe-
sis of the Gd complex 12c in the following step.
To access a cage structure or more soluble structures, the
dithiazolide intermediate 8 was developed (Scheme 4).
Following saponification of 6, the di-acid 7 was combined
with O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium
tetrafluoroborate (TBTU) and 2-mercaptothiazolide to give
8 with a good overall yield. Compound 8 displays four
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S. L. Pailloux, S. Nguyen, S. Zhou, M. E. Hom, M. N. Keyser, D. Smiles, and K. N. Raymond
Vol 000
characteristic triplets in its 1H NMR spectrum at 4.62,
4.31, 3.42, and 2.88ppm. These peaks correspond to the
four methylene groups present in the two thiazolide
fragments.
presence of pyridine. The resulting Gd complex 12–12c
was characterized by microanalysis and by mass spectrom-
etry, and the latter showed the expected isotopic distribu-
tions and mass/charge values. In general, the coordination
of the deprotected ligand 11–11c to the M(III) ions results
in broadening of the peaks in the IR spectra compared with
the free ligands. In the cases of the Gd complexes with the
tripodal ligand (11, 11a, 11c), a shift (δνCO~30 cm) of the
band assigned to the carbonyl of the ring toward lower
frequency upon coordination was observed from 1660–
1650 cmꢀ1 for the ligand to 1630–1620 cmꢀ1 for the com-
plexes 12, 12a, and 12c. The bi-macrocycle cage 11b was
also complexed to Ga(NO3)3 and GdCl3·6H2O. In these
complexes, the shift for the carbonyl of the ring stretching
frequencies in the IR spectra were not as significant as ob-
served with complex Gd(III) 12b and complex Ga(III) 12d.
However, the mass spectra and microanalyses confirmed
the formation of these complexes. The Gd(III) complexes
12, 12a, and 12c appear to be monomeric with the respec-
tive ligands 11–11a and 11c bonded in hexadentate coordi-
nation modes. This is in contrast to the Gd(III) complex
12b where it is thought that only two HOPO units coordi-
nate the Gd(III) ion and that the third HOPO moiety
assisted with the formation of polymers by coordinating
to a second Gd(III) ion. The Ga(III) ion in complex 12d
is assumed to be inside the cage of 11b. This conclusion
was reached based upon the size of a similar cage (e.g.,
Primary amines tert-butyl-(2-aminoethyl)carbamate and
TREN regioselectively reacted with the thiazolide (on the
N side) of 8 with formation of 9 and 9a, respectively
1
(Scheme 5). The H NMR spectra of 9 and 9a show two
methylene signals δ (ppm) 4.32 and 2.89 (9) and 4.30
and 2.98 (9a) corresponding to the resonance of the
thiazolide left in position 4 of the ring. The monothiazolide
of 9 and 9a reacts further with the primary aliphatic amines
of TREN and tert-butyl (2-aminoethyl)carbamate, respec-
tively, to form 10 and 10a. The methylene protons of
TREN were observed at δ (ppm) 3.01 and 2.24 for 10
1
and δ (ppm) 3.19 and 2.53 for 10a in their respective H
NMR spectra. The macrocyclic cage 10b was obtained
by reaction of one equivalent of TREN with one equivalent
of 9a using high dilution conditions. In all cases, the
deprotections of BOC and benzyl groups were achieved
by treatment with acid.
The coordination chemistry of the new hexadentate
ligand was surveyed with hard, trivalent cations. In partic-
ular, one equivalent of each of the deprotected ligands
11–11b (Scheme 5) and 11c (Scheme 4) was combined
with one equivalent of gadolinium chloride hexahydrate
(GdCl3·6H2O) at reflux in methanol (MeOH) and in the
Scheme 5. Synthesis of hexadentate HOPO-based ligands 11–11b.
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Synthesis and Chemical Reactivity of a 6-Me-3,2-Hydroxypyridinone Dithiazolide
with Primary Amines
solid (9.43 g, 56%). IR (KBr, ν cmꢀ1): 1712 (C¼O, ester), 1646
(C¼O, ring). 1H NMR (300 MHz, CDCl3 + TMS): (δ, ppm):
12.31 (s, 1H), 7.31–7.53 (m, 5H), 6.17 (s, 1H), 5.27 (s, 2H),
4.29 (q, J = 7.1 Hz, 2H), 2.33 (s, 3H), 1.29 (t, J = 7.1 Hz, 3H);
13C{1H} NMR (400 MHz, CDCl3): (δ, ppm): 165.32, 162.20,
144.54, 139.59, 137.26, 133.24, 128.55, 128.27, 128.03, 104.35,
74.01, 61.69, 18.54, 14.11.[M + H]+ calcd for C16H18NO4
288.1236, Found 288.1232 m/z.
BC-TREN-TAM) that has been shown to be more appro-
priate for the incorporation of Ga(III) ion (radius = 76pm
for 6 coordinate) than Gd(III) ion (radius = 119pm for 8
coordinate) [22,23].
In conclusion, an optimal synthesis for a key intermedi-
ate dithiazolide HOPO 8 has been developed, which sup-
ports formation of four new ligands, and their formation
of Gd(III) and Ga(III) complexes is described. This work
is intended to support MRI and PET molecular imaging.
Ethyl 3-(benzyloxy)-1-(2-(tert-butoxy)-2-oxoethyl)-6-methyl-2-
oxo-1,2-dihydropyridine-4-carboxylate (5).
Dimethoxyethane
(5 mL) was added under inert conditions to a sample of 4 (0.3 g,
1.04 mmol, 1 eq.) and KF alumina (182 mg, 3.13 mmol, 3 eq.)
previously purged with N2. tert-Butyl iodoacetate (182 mg,
3.13 mmol, 3 eq.) was added dropwise under N2. The reaction
mixture was heated (2 h, 45°C) then left to stir (12 h, 23°C). The
alumina was removed by filtration, and the filtrate was concentrated
to dryness. The residue was purified by flash chromatography using
a gradient of MeOH in DCM. The compound (recovered at 5% of
MeOH) with the shortest retention time in HPLC C18 was
characterized as 5 (146 mg, 35%), and the last eluted was found to
be the starting material 4. IR (KBr, ν cmꢀ1):1740 (C¼O, ester),
1661 (C¼O, ring). 1H NMR (500 MHz, CDCl3): (δ, ppm): 7.49 (d,
J= 5.0 Hz, 2H), 7.35 (dd, J= 5.0 Hz, 2H), 7.30 (d, J= 5.0 Hz, 1H),
6.19 (s, 1H), 5.24 (s, 2H), 4.73 (s, 2H), 4.27 (q, J= 7.0 Hz, 2H),
2.38 (s, 3H), 1.48 (s, 9H), 1.27 (t, J= 7.0 Hz, 3H,). 13C{1H} NMR
(500 MHz, CDCl3) (δ, ppm): 166.5, 165.2, 160.2, 144.9, 139.7,
137.1, 130.3, 128.5, 128.2, 127.9, 104.0, 82.8, 73.8, 61.5, 46.5,
27.9, 20.0, 14.0. [M + H]+ calcd for C22H28NO6: 402.1838, Found
402.1916 m/z. Anal. Calcd (found) for C22H27NO6: C, 65.82
(65.18); H, 6.78 (6.63); N, 3.49 (3.02).
EXPERIMENTAL
General information.
Unless otherwise noted, starting
materials were obtained from commercial suppliers and used
without further purification. All organic extracts were dried over
anhydrous MgSO4 and solvents removed in vacuo. Infrared
spectra were recorded with the Nicolet (Thermo Scientific, San
1
Jose, CA) 580 spectrophotometer using KBr tablets. H spectra
were recorded on a Bruker (Bellica, MA) AVB 300 at
300 MHz, a Bruker AVB 400 at 400 MHz, or a Bruker AVB
600 at 600 MHz. 13C spectra were collected using a Bruker
AVB 400 at 100 MHz or a Bruker AVB 600 at 150 MHz. The
residual solvent peak or TMS was used as an internal reference.
Elemental analysis, mass spectrometry (high resolution;
electrospray ionization mass spectrometry), and X-ray
diffraction data were obtained at the analytical facilities at the
University of California, Berkeley.
Ethyl 3-hydroxy-6-methyl-2-oxo-1,2-dihydropyridine-4-carboxylate
2-(3-(Benzyloxy)-4-(ethoxycarbonyl)-6-methyl-2-oxopyridin-1
(2H)-yl) acetic acid (6). Sample of 4 (4.10 g, 14.3 mmol, 1 eq.),
magnesium di-tert-butoxide (Mg(OtBu)2, 5.28g, 31.0mmol,
2.2 eq.), and potassium tert-butoxide (KOtBu, 1.79g, 16.0mmol,
1.1 eq.) were combined in a round bottom flask, purged three
times with nitrogen and then THF (200 ml) was added. A solution
of bromoacetic acid (5.29 g, 38.0 mmol, 2.7 eq.) in dry THF
(20 mL) was added dropwise, and the reaction mixture was stirred
(12 h, 23°C). The solvent was evaporated, and the dark brown oil
was dissolved in DCM (30 mL). The mixture was quenched with
aqueous 3M HCl solution (2×30mL) and washed with Millipore
water (2×30mL). The organic layers were collected and dried
with Na2SO4, and the solvent was evaporated. Diisopropyl ether
was added, and the mixture was stirred (12 h, 23°C) to cause
precipitation. The brown solid 6 was collected by filtration and
dried to give compound 6 as a beige solid (3.9 g, 80%). IR (KBr,
ν cmꢀ1): 1733 (C¼O, acid), 1716 (C¼O, ester), 1645 (C¼O,
ring). 1H NMR (300MHz, CDCl3 + TMS): (δ, ppm): 7.28–7.46
(m, 5H), 6.27 (s, 1H), 5.19 (s, 2H), 4.82 (s, 2H), 4.26 (q,
J = 7.1 Hz, 2H), 2.26 (s, 3H), 1.28 (t, J = 7.1 Hz, 3H); 13C{1H}
NMR (400 MHz, CDCl3 + TMS): (δ, ppm): 170.09, 164.85,
160.94, 144.89, 140.18, 136.92, 131.42, 128.60, 128.27, 128.04,
105.43, 74.24, 61.80, 46.54, 20.15, 14.07. [M ꢀ H]ꢀ calcd for
C18H18NO6 344.1134, Found 344.1147 m/z. Anal. Calcd (found)
for C18H19NO6: C, 62.60 (61.45); H, 5.55 (5.69); N, 4.06 (4.16).
Ethyl 3-(benzyloxy)-1-(2-((2,5-dioxopyrrolidin-1-yl)oxy)-2-
(3).
In a round bottom flask, diethyl oxalacetate (100.0g,
0.476mol, 1 eq.) was dissolved in dry tetrahydrofuran (THF;
600 mL). Chloroacetone (47.0g, 0.50 mol, 1.05eq.) was added to
the reaction mixture, and then ammonia gas was bubbled through
the mixture (40min), resulting in a red mixture. A catalytic
quantity of aluminum chloride (AlCl3, 6.44 g, 0.05 mol, 0.09 eq.)
was added slowly, and the mixture was stirred (4days, 23°C). The
yellow heterogeneous mixture was centrifuged (6000 rpm,
30min), and the resulting yellow solid was quenched using
aqueous 6M HCl solution. The solid was collected by filtration and
dried in a desiccator to give 3 as a beige solid (18.1 g, 19%). IR
1
(KBr, ν cmꢀ1): 1678 (C¼O, ester), 1644 (C¼O, ring). H NMR
(300MHz, CDCl3 + MS): δ (ppm): 12.77 (s, 1H), 10.77 (s, 1H),
6.53 (s, 1H), 4.42 (q, J = 7.1 Hz, 2H), 2.34 (s, 3H), 1.42 (t,
J = 7.1 Hz, 3H); 13C{1H} NMR (400 MHz, CDCl3 + TMS): (δ,
ppm): 169.21, 160.18, 150.74, 133.27, 115.40, 102.20, 62.28,
18.63, 14.09. [M+ H]+ calcd for C9H12NO4 198.0766, Found
198.0762 m/z.
Ethyl 3-(benzyloxy)-6-methyl-2-oxo-1,2-dihydropyridine-4-
carboxylate (4).
1,8-Diazabicyclo[5.4.0]undec-7-ene (13.6 g,
89.0 mmol, 1.5 eq.) was added to a solution containing 3 (11.5 g,
58.6 mmol, 1 eq.) in isopropanol (200 mL). The reaction mixture
was refluxed at 83°C under N2 before adding benzyl bromide
(15.2 g, 88.9 mmol, 1.5 eq.) dropwise. Refluxing was maintained
for 4 h, and then the solvent was evaporated. The resulting dark
brown oil was dissolved in dichloromethane (DCM, 30 mL),
washed with aqueous 3M HCl solution (2×30 mL) and then with
Millipore water (3×30 mL). The organic layers were combined
and dried with Na2SO4, and the solvent was evaporated.
Diisopropyl ether (250 mL) was added to the oily residue, which
precipitated after a day, and 4 was recovered as a light brown
oxoethyl)-6-methyl-2-oxo-1,2
dihydropyridine-4-carboxylate
(6a). A solution of NHS (0.66 g, 5.79 mmol, 2 eq.) and N,N′-
dicyclohexylcarbodiimide (0.89 g, 4.35 mmol, 1.5 eq.) in DMF
(3 mL) was added dropwise to a solution containing 6 (1 g,
2.89 mmol, 1 eq.) in DMF (10 mL), and the mixture was stirred
(24 h, 23°C). The volatile components were removed under
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S. L. Pailloux, S. Nguyen, S. Zhou, M. E. Hom, M. N. Keyser, D. Smiles, and K. N. Raymond
Vol 000
vacuum, and the residue was dissolved in DCM (20 mL) and
water (10 mL). The organic phase was collected and dried over
MgSO4 and concentrated until dryness. The residue was
crystallized from isopropyl alcohol (10 mL) to give 6a as a
white solid (0.78 g, 71%). IR (KBr, ν cmꢀ1): 1707 (C¼O,
ester), 1648 (C¼O, ring). 1H NMR (300 MHz, CDCl3): (δ,
ppm): 7.31–7.44 (m, 5H), 6.21 (s, 1H), 5.26 (s, 2H,), 5.18 (s,
2H), 4.26 (q, J = 7.1 Hz, 2H), 2.86 (s, 4H), 2.34 (s, 3H), 1.24 (t,
J = 7.1 Hz, 3H). Anal. Calcd (found) for C22H22N2O8: C, 59.73
(57.53); H, 5.01 (6.03); N, 6.33 (6.78).
in DCM (100mL). The reaction mixture was stirred for 4 h after
the end of the addition before being concentrated and purified
using CombiFlash (gradient of MeOH in DCM). The fractions
were collected (10% MeOH) and evaporated to dryness to give 9
as a light yellow solid (1.87 g, 86%). IR (KBr, ν cmꢀ1): 1697
(C¼O, ester), 1685 (C¼O, amides), 1654 (C¼O, ring), 1598
(C¼S, thiaz). 1H NMR (300MHz, CDCl3 + TMS): (δ, ppm):
7.32–7.43 (m, 5H), 6.90 (s, 1H), 6.03 (s, 1H), 5.27 (s, 2H), 4.91
(s, 1H), 4.70 (J = 7.3 Hz, 2H), 2.43 (s, 3H), 1.43 (s, 9H); 13C{1H}
NMR (400 MHz, CDCl3 + TMS): (δ, ppm): 200.98, 167.49,
165.76, 159.88, 141.38, 141.28, 137.45, 133.40, 128.44, 128.37,
128.22, 104.75, 79.55, 74.09, 55.07, 50.78, 48.81, 40.30, 29.14,
28.39, 20.52. [M+ H]+ calcd for C26H33N4O6S2 561.1842, Found
561.1835 m/z. Anal. Calcd (found) for C26H32N4O6S2: C, 55.70
(55.32); H, 5.75 (4.99); N, 9.99 (9.50).
3-(Benzyloxy)-1-(carboxymethyl)-6-methyl-2-oxo-1,2-dihydrop
yridine-4-carboxylic acid (7).
A solution of NaOH (1.33 g,
33.3mmol, 2.9 eq.) in water (40 mL) was added to a solution
containing 6 (3.98 g, 11.5 mmol, 1 eq.) in ethanol (140 mL). The
reaction mixture was stirred (1.5h, 23°C), and reaction progress
was monitored via TLC (DCM:MeOH 9:1). The solvent was
evaporated, the resulting dark oil was suspended in ethyl acetate,
and the solution was concentrated twice to ensure that all the
ethanol was removed. The oil was dissolved in water (20ml), and
the flask was placed in an ice bath. Compound 7 was recovered
by acidification of the aqueous solution with aqueous 3M HCl
solution (50 mL). A light brown precipitate was recovered after
stirring (12h, 23°C) then dried to give 7 as a white solid (3.4 g,
98%). IR (KBr, ν cmꢀ1): 1720 (C¼O, acid), 1647 (C¼O, ring).
1H NMR (300 MHz, DMSO-d6): (δ, ppm): 7.35–7.49 (m, 5H),
6.25 (s, 1H), 5.09 (s, 2H), 4.79 (s, 2H), 2.31 (s, 3H); 13C{1H}
NMR (600 MHz, DMSO-d6): (δ, ppm): 170.30, 167.45, 160.47,
143.48, 142.79, 138.21, 133.18, 129.23, 129.20, 128.95, 103.80,
73.96, 47.10, 20.51. [M + H]+ calcd for C16H16NO6 318.0978,
Found 318.0977 m/z, [M+ Na]+ calcd for C16H15NO6Na
340.0797, Found 340.0804m/z [M ꢀ H]ꢀ calcd for C16H14NO6
316.0821, Found 316.0835m/z. Anal. Calcd (found) for
C16H21NO9 (L+ 3H2O): C, 51.75 (56.46); H, 5.70 (4.90); N, 3.77
(4.12).
N,N′,N″-(Nitrilotris(ethane-2,1-diyl))tris(2-(3-hydroxy-6-methyl-2-
oxo-4-(2-thioxothiazolidine-3-carbonyl)pyridin-1(2H)-yl)acetamide)
(9a).
A solution containing TREN (43 mg, 0.29 mmol,
0.53 eq.) and DIPEA (78 mg, 0.60 mmol, 1.1 eq.) in DCM
(37 mL) was added at a rate of 1.5 mL/h using an automated
syringe to a solution containing 8 (290 mg, 0.56 mmol, 1 eq.)
in DCM (50 mL). The reaction mixture was stirred (12 h,
23°C), the solvent was evaporated, and the mixture purified
through CombiFlash (gradient of MeOH in DCM). The
fractions of the column were collected (10% MeOH) and
evaporated. The yellow residue was solubilized in a minimum
of DCM, followed by a slow precipitation with addition of
diethyl ether to give 9a as a yellow solid (143 mg, 57%). IR
(KBr, ν cmꢀ1): 1700 (C¼O, amides), 1655 (C¼O, ring), 1600
(C¼S, thiaz). 1H NMR (300MHz, CDCl3 + TMS): (δ, ppm):
8.09 (t, J = 6.2 Hz, 3H), 7.29–7.31 (m, 15H), 5.94 (s, 3H), 5.13
(s, 6H), 4.65 (s, 6H), 4.30 (t, J = 7.3 Hz, 6H), 3.19 (s, 6H), 2.98 (t,
J = 7.3 Hz, 6H), 2.53 (s, 6H), 2.17 (s, 9H); 13C{1H} NMR
(400 MHz, CDCl3 + TMS): (δ, ppm): δ (ppm): 200.92, 167.01,
175.75, 159.67, 142.12, 141.37, 137.43, 133.46, 128.52, 128.18,
127.79, 104.25, 75.65, 55.24, 50.83, 48.47, 38.54, 29.22, 20.43. [M
+H]+ calcd for C63H67N10O12S6 1347.3264, Found 1347.3253 m/z.
Anal. Calcd (found) for C63H66N10O12S6: C, 56.15 (55.9); H, 4.94
(5.02); N, 10.39 (10.50).
3-(Benzyloxy)-6-methyl-1-(2-oxo-2-(2-thioxothiazolidin-3-yl)ethyl)-
4-(2-thioxothiazolidine-3-carbonyl)pyridin-2(1H)-one (8).
N,N-
Diisopropylethylamine (DIPEA, 5.00 g, 38.7 mmol, 4.6 eq.) was
added dropwise to a suspension of 7 (2.68 g, 8.44 mmol, 1 eq.),
TBTU (6.26 g, 19.5 mmol, 2.3 eq.), 4-(dimethylamino)pyridine
(0.11 g, 0.925 mmol, 0.11 eq.), and 2-mercaptothiazoline (2.26 g,
19.0 mmol, 2.2 eq.) in DCM (80 mL). After addition, the reaction
mixture turned dark brown, and it was stirred (40 min, 23°C). The
solvent was evaporated and immediately purified using
CombiFlash (gradient of EtOAc in DCM). The fractions were
collected at 40% EtOAc, concentrated, and washed with diethyl
ether to give 8 as a yellow solid (2.9 g, 66%). IR (KBr, ν cmꢀ1):
1699 (C¼O amide), 1653 (C¼O, ring), 1597 (C¼S, thiaz). 1H
NMR (300 MHz, CDCl3 +TMS): (δ, ppm): 7.31–7.43 (m, 5H),
6.02 (s, 1H), 5.63 (s, 2H), 5.26 (s, 2H), 4.62 (t, J= 7.5 Hz, 2H),
4.31 (t, J= 7.3 Hz, 2H), 3.42 (t, J= 7.5 Hz, 2H), 2.88 (t, J=7.3Hz,
2H), 1.58 (s, 3H). 13C{1H} NMR (400 MHz, CDCl3 +TMS): (δ,
ppm): 202.06, 200.79, 168.13, 165.95, 159.22, 141.39, 140.49,
137.57, 132.96, 128.39, 128.33, 128.10, 104.17, 73.87, 55.84,
55.07, 51.29, 29.33, 29.14, 20.47. [M + H]+ calcd for
C22H22N3O4S4: 520.0493, Found: 520.0484 m/z. Anal. Calcd
(found) for C22H21N3O4S4: C, 50.85 (50.40); H, 4.07 (4.10); N,
8.09 (8.32).
Tri-tert-butyl (((2,2′,2″-((((nitrilotris(ethane-2,1-diyl))tris(azanediyl))
tris(carbonyl))tris(3-(benzyloxy)-6-methyl-2-oxopyridine-4,1(2H)-diyl))
tris(acetyl))tris(azanediyl))tris(ethane-2,1-diyl))tricarbamate (10).
A
solution of TREN (0.506 g, 3.45 mmol, 0.36 eq.) and DIPEA (1.52 g,
11.2 mmol, 1.2 eq.) in DCM (50 mL) was added at a rate of 1.5 mL/h
via automated syringe to a solution of 9 (5.31 g, 9.47 mmol, 1 eq.) in
DCM (120 mL). After complete addition, the mixture was stirred (4 h,
23°C) before being evaporated and purified using CombiFlash
(gradient of MeOH in DCM). The fractions were collected (5%
MeOH) and evaporated to give 10 as a white solid (2.28 g, 49%). IR
(KBr, ν cmꢀ1): 1691 (C¼O, amide), 1677 (C¼O, ester), 1658 (C¼O,
1
ring). H NMR (300 MHz, CDCl3 +TMS): (δ, ppm): 7.77 (s, 3H),
7.43 (s, 3H), 7.28 (s, 15H), 6.60 (s, 3H), 5.13 (s, 6H), 4.72 (s, 6H),
3.38 (s, 6H), 3.27 (s, 6H), 3.01 (s, 3H), 2.39 (s, 9H), 2.24 (s, 6H), 1.41
(s, 27H); 13C{1H} NMR (400 MHz, CDCl3 +TMS): (δ, ppm): 167.44,
163.23, 160.28, 156.65, 143.81, 140.44, 136.25, 130.81, 128.79,
128.73, 128.63, 105.39, 79.53, 74.70, 51.86, 48.40, 40.37, 40.22,
37.24, 28.38, 20.33. [M + Na]+ calcd for C75H99N13O18Na 1492.7129,
Found 1492.7120 m/z, [M+H]+ calcd for C75H100N13O18 1470.7311,
Found 1470.7312 m/z. Anal. Calcd (found) for C75H99N13O18 +3H2O:
C, 59.08 (58.92); H, 6.94 (6.72); N, 11.94 (11.98).
tert-Butyl (2-(2-(3-(benzyloxy)-6-methyl-2-oxo-4-(2-thioxothia
zolidine-3-carbonyl)pyridin-1(2H)-yl)acetamido)ethyl)carbamate
(9). A solution of tert-butyl (2-aminoethyl)carbamate (703 mg,
4.39 mmol, 1.1 eq.) in DCM (40 mL) was added at 1.2 mL/h using
an automated syringe to a solution of 8 (2.00 g, 3.84 mmol, 1 eq.)
Tri-tert-butyl (((1,1′,1″-(((nitrilotris(ethane-2,1-diyl))tris(azanediyl))
tris(2-oxoethane-2,1-diyl))tris(3-hydroxy-6-methyl-2-oxo-1,2-dihydrop
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2015
Synthesis and Chemical Reactivity of a 6-Me-3,2-Hydroxypyridinone Dithiazolide
with Primary Amines
yridine-1,4-diyl-4-carbonyl))tris(azanediyl))tris(ethane-2,1-diyl))tricarb
amate (10a). A solution containing 9a (0.143 g, 0.106 mmol, 1 eq.)
in DCM (50 mL) was added dropwise at a rate of 1.5 mL/h via
automated syringe to a solution of DIPEA (69 mg, 0.53 mmol,
5eq.) and tert-butyl (2-aminoethyl)carbamate (51 mg, 0.32 mmol,
3eq.) in DCM (20 mL). The solvent was evaporated, and the
mixture was purified via CombiFlash (gradient of MeOH in
DCM). The fractions were collected (5% MeOH) and evaporated.
The recovered clear oil was re-dissolved in a minimal amount of
DCM and precipitated by slow addition of diethyl ether to give
10a as a white solid (63 mg, 41%). IR (KBr, ν cmꢀ1): 1710
N,N′,N″-(Nitrilotris(ethane-2,1-diyl))tris(1-(2-((2-aminoethyl)
amino)-2-oxoethyl)-3-hydroxy-6-methyl-2-oxo-1,2-dihydropyridine-
4-carboxamide) (11).
A solution containing 10 (231 mg,
0.16 mmol, 1 eq.) in glacial acetic acid (5 mL) and concentrated HCl
(5 mL) was added to a DTPA-washed round-bottom flask. The
resulting yellow mixture was stirred (12 h, 23°C) then the solvent
was evaporated. The yellow solid was dissolved in a minimal
amount of Millipore water and transferred to a centrifuge tube
containing diethyl ether. MeOH was added to the biphasic mixture
until a white precipitate appeared. The precipitate was centrifuged
(6000 rpm, 30 min), and the process was repeated three times to
give 11 as a light yellow crystalline solid (169 mg, 98%). IR (KBr, ν
cmꢀ1):1717 (C¼O, amide), 1658 (C¼O, ring).1H NMR (300 MHz,
CD3OD): δ (ppm): 6.44 (s, 2H), 4.83 (br s, 6H), 3.92 (br s, 6H),
3.57 (t, J= 5.7 Hz, 6H), 3.14 (t, J= 5.7 Hz, 6H), 2.27 (s, 9H). 13C
{1H} NMR (400 MHz, CDCl3 +TMS): δ (ppm): 167.71, 166.66,
159.17, 145.46, 135.15, 117.24, 102.76, 52.14, 47.54, 38.58, 36.82,
34.52, 19.91. [M + H]+ calcd for C39H58N13O12 900.4328, Found
900.4330 m/z. Anal Calcd for (found) C39H61N13O12Cl4: C, 44.79
(44.32); H, 5.88 (6.51); N, 17.41 (17.02).
1
(C¼O, amides), 1690 (C¼O, ester), 1650 (C¼O, ring), H NMR
(300 MHz, CDCl3 +TMS): (δ, ppm): 8.16 (s, 3H), 7.93 (s, 3H),
7.35 (s, 15H), 6.59 (s, 3H), 5.17 (s, 6H), 5.06 (s, 3H), 4.80 (s,
6H), 3.28 (s, 12H), 3.14 (s, 6H), 2.64 (s, 6H), 2.27 (s, 9H), 1.41
(s, 27H); 13C{1H} NMR (400 MHz, CDCl3 +TMS) (δ, ppm):
166.91, 163.79, 160.30, 156.07, 143.27, 141.01, 136.01, 130.2,
128.94, 128.85, 128.44, 105.59, 79.30, 74.39, 53.77, 48.38, 40.37,
39.82, 38.79, 28.41, 20.35. [M + H]+ calcd for C75H100N13O18
1470.7311, Found 1470.7306 m/z. Anal. Calcd (found) for
C75H99N13O18: C, 61.25 (60.62); H, 6.79 (6.81); N, 12.38 (12.04).
1,1′,1″-(((Nitrilotris(ethane-2,1-diyl))tris(azanediyl))tris
(2-oxoethane-2,1-diyl))tris(N-(2-aminoethyl)-3-hydroxy-6-
Macrocycle BC-TREN-tris-6-Me-3,2-HOPO(Bn) (10b).
A
first solution containing 9a (0.34 g, 0.23mmol, 1 eq.) in DCM
(25 mL) was prepared. A second solution of TREN (0.03 g,
0.23 mmol, 1 eq.) and DIPEA (0.12 g, 0.93 mmol, 4 eq.) in DCM
(25 mL) was also prepared. Both solutions were simultaneously
added to DCM (110 mL) at a rate of 1 mL/h using automated
syringes. The reaction was stirred for 1 day after the end of the
addition. TLC showed the formation of a single major spot. The
reaction mixture was evaporated and purified using CombiFlash
(gradient of MeOH 0.1% N(Et)3 in DCM). The fractions were
collected (5% MeOH) and evaporated to give compound 10b as a
light beige solid (142 mg, 53%). IR (KBr, ν cmꢀ1): 1720 (C¼O,
amide), 1654 (C¼O, ring). 1H NMR (300MHz, CD3OD): (δ,
ppm): 7.21 (br s, 15H), 6.27 (br s, 3H), 5.20 (br s, 6H), 4.80 (br s,
6H), 3.45 (br s, 6H), 3.05 (br s, 6H), 2.21 (br s, 21H). 13C{1H}
NMR (600 MHz, CDCl3 with a drop of MeOH 600 MHz): (δ,
ppm): 169.0, 163.53, 159.76, 143.23, 140.71, 135.93, 131.10,
128.09 104.0, 74.17, 50.41, 48.22, 38.43, 36.93, 19.74. [M + H]+
calcd for C60H70N11O12 1136.5205, Found 1136.5227 m/z. Anal.
Calcd (found) for C60H69N11O12: C, 59.6 (53.25); H, 5.92 (6.75);
N, 12.74 (13.20).
methyl-2-oxo-1,2-dihydropyridine-4-carboxamide) (11a).
A
solution containing 10a (148 mg, 0.10 mmol) in glacial acetic
acid (2 mL) and concentrated HCl (2 mL) was added to a 25-mL
DTPA-washed round bottom flask. The resulting yellow mixture
was stirred (12 h, 23°C), and then the solvent was evaporated.
The yellow solid was dissolved in a minimal amount of
Millipore water and transferred to a centrifuge tube containing
diethyl ether. MeOH was added to the biphasic mixture until a
white precipitate appeared. The precipitate was centrifuged
(6000 rpm, 30 min), and the process was repeated three times, to
give 11a as a light yellow crystalline solid (51 mg, 56%). IR
(KBr, ν cmꢀ1): 1691 (C¼O, amides), 1658 (C¼O, ring). 1H
NMR (300 MHz, DMSO-d6): (δ, ppm): 8.67 (s, 6H), 8.04 (s,
9H), 6.44 (s, 3H), 4.65 (s, 6H), 3.66, (s, 6H), 3.47 (s, 6H), 3.28
(s, 6H), 2.91 (s, 6H), 2.12 (s, 9H). 13C{1H} NMR (400 MHz,
CDCl3 + TMS): (δ, ppm): 170.24, 167.51, 159.72, 144.29,
136.03, 116.0, 104.58, 54.30, 48.03, 39.12, 37.13, 34.82, 19.07.
[M ꢀ H]ꢀ calcd for C39H56N13O12 898.4171, Found
898.4158 m/z. Anal. Calcd (found) for C39H73Cl4N13O18
(L·4HCl, 6H2O): C, 40.59 (39.05); H, 6.38 (7.10); N, 15.78
(9.60), (very hydroscopic).
Diethyl 1,1′-(((((2-(2-(3-(benzyloxy)-4-(ethoxycarbonyl)-6-methyl-2-
oxopyridin-1(2H)-yl)-N-methylacetamido)ethyl)azanediyl)bis(ethane-
2,1-diyl))bis(azanediyl))bis(2-oxoethane-2,1-diyl))bis(3-(benzyloxy)-6-
methyl-2-oxo-1,2-dihydropyridine-4-carboxylate) (10c). A solution
containing DIPEA (90 mg, 0.69 mmol, 5 eq.) and tris(2-aminoethyl)
amine (TREN, 20 mg, 0.14 mmol, 1 eq.) in DCM (5 mL) was added
to a solution of 6a (0.2 g, 0.45 mmol, 3.3 eq.) in dry DCM (5 mL).
The reaction mixture was stirred (12 h, 23°C) then the organic phase
was washed with water (2×5 mL). The organic phase was dried using
MgSO4 and concentrated to dryness to give compound 10c as a light
beige solid (85 mg, 50%). IR (KBr, ν cmꢀ1): 1731 (C¼O, ester),
1690 (C¼O, amide), 1655 (C¼O, ring). 1H NMR (300 MHz,
CDCl3): (δ, ppm): 7.36–7.38 (m, 2H), 7.23–7.29 (m, 3H), 5.04 (s,
2H), 4.67 (br s, 2H), 4.24 (q, J= 7.2 Hz, 2H), 3.21 (br s, 2H), 2.55
(br s, 2H), 2.04 (s, 3H), 1.25 (t, J= 7.2 Hz, 3H,). 13C{1H} NMR
(CDCl3, 600 MHz): (δ, ppm): 166.89, 164.82, 160.65, 144.70,
141.73, 137.23, 131.20, 128.38, 127.98, 127.73, 104.73, 73.80,
61.66, 52.87, 38.38, 33.96, 20.22, 14.09. [M + H]+ calcd for
C60H70N7O15 1128.493, Found: 1128.4914 m/z. Anal. Calcd (found)
for C60C69N7O15: C, 63.87 (64.20); H, 6.16 (5.09); N, 8.69 (8.53).
Macrocycle BC-TREN-tris-6-Me3,2-HOPO (11b).
A
solution containing 10b (142 mg, 0.12 mmol) in concentrated
HCl (2 mL) and glacial acetic acid (2 mL) was added to a
DTPA-washed round bottom flask. The reaction was stirred
(48 h, 23°C). The solvent was removed, and the residue was
precipitated using a mixture of water, MeOH, and diethyl ether
to give compound 11b as a light beige solid (86 mg, 80%). IR
(KBr, ν cmꢀ1):1680 (C¼O, amides), 1658 (C¼O, ring). 1H
NMR (300 MHz, DMSO-d6): (δ, ppm): 8.65 (OH, br s), 8.45
(NH, br s), 7.87 (NH, br s), 6.35 (3H, s), 4.72 (6H, s), 3.34
(6H,m), 3.10 (6H, m), 2.47 (12H, m), 2.09 (9H,s). 13C{1H}
NMR (600 MHz, DMSO-d6): (δ, ppm): 185.0, 169.7, 159.2,
145.0, 135.6, 117.5, 103.1, 56.5, 46.5, 46.4, 34.8, 34.5, 18.8;
[M+ H+] calcd for C39H52N11O12 866.3797, Found 866.3792 m/z.
Anal. Calcd (found) for C39H53N11O12Cl2: C, 49.89 (50.40); H,
5.69 (6.43); N, 16.41 (16.21).
Triethyl-1,1′,1″-(((nitrilotris(ethane-2,1-diyl))tris(azanediyl))
tris(2-oxoethane-2,1-diyl))tris(3-hydroxy-6-methyl-2-oxo-1,2-
dihydropyridine-4-carboxylate) (11c). A solution containing
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

S. L. Pailloux, S. Nguyen, S. Zhou, M. E. Hom, M. N. Keyser, D. Smiles, and K. N. Raymond
Vol 000
10c (140 mg, 0.12 mmol) in glacial acetic acid (1.5 mL) and
concentrated HCl (1.5 mL) was added to a DTPA-washed
round bottom flask. The mixture was stirred (12 h, 23°C). The
solvent was removed, then the residue was solubilized in a
minimum of MeOH, and a solid was precipitated with diethyl
ether. The solid was recovered after centrifugation of the
suspension (6000 rpm, 30min) to give compound 11c as a light
beige solid (100 mg, 95%). IR (KBr, ν cmꢀ1): 1700 (C¼O, ester),
1685 (C¼O amide), 1655 (C¼O, ring). 1H NMR (300 MHz,
CDCl3): (δ, ppm): 10.41 (s, 1H), 8.23 (s, 1H), 6.33 (s, 1H), 4.91
(s, 2H), 4.36 (q, 2H), 3.25 (s, 2H), 2.57 (s, 2H), 2.33 (s, 3H), 1.37
(t, 7.2 Hz, 3H ). 13C{1H} NMR (600 MHz, CDCl3): (δ, ppm):
167.45, 166.03, 159.38, 147.03, 134.67, 114.25, 102.37, 64.84,
61.00, 48.69, 19.71, 14.03, please note that one methylene is
under the MeOH peak. [M+ H]+ calcd for C39H52H7O15:
858.3521, Found: 858.3528m/z. Anal Calcd (found) for
C39H52N7O15Cl: C, 52.37 (53.01); H, 5.86 (6.06); N, 10.97 (11.62).
Gd(III)-N,N′,N″-(nitrilotris(ethane-2,1-diyl))tris(1-(2-((2-
(Lꢀ3Gd+3Cl·H2O) 1073.2519, Found 1073.2487 m/z. Anal.
Calcd (found) for C40H66N10O20GdCl5 (Lꢀ2Gdꢀ32Cl·2H2O
+ GdCl3·6H2O): C, 32.05 (31.85); H, 4.44 (5.27); N, 9.35 (8.74).
Gd-triethyl-1,1′,1″-(((nitrilotris(ethane-2,1-diyl))tris(azanediyl))
tris(2-oxoethane-2,1-diyl))tris(3-hydroxy-6-methyl-2-oxo-1,2-dihy
dropyridine-4-carboxylate) (12c).
A solution of GdCl3·6H2O
(40 mg, 0.011 mmol, 1 eq.) in MeOH (5 mL) was added to a
solution containing 11c (94 mg, 0.11 mmol, 1 eq.) in MeOH (1 mL),
followed by the addition of pyridine (40 mg, 0.326 mmol, 3 eq.).
The reaction mixture was stirred (24 h, 95°C). After cooling, the
complex was recovered in a minimum of MeOH by slow addition
of diethyl ether. The precipitate was washed three times with
diethyl ether and recovered after centrifugation (6000 rpm, 30 min)
to give complex 12c as a white solid (85 mg, 60%). IR (KBr, ν
cmꢀ1): 1700 (C¼O, ester), 1650 (C¼O, amide), 1567 (C¼O, ring).
[M + H]+ calcd for C39H51Gd2N7O16Cl3 1294.0928, Found
1294.0776 m/z, Anal. Calcd (found) for C39H50Gd2N7O16Cl3: C,
36.20 (32.78); H, 3.90 (5.01); N, 7.72 (7.67).
aminoethyl)amino)-2-oxoethyl)-3-hydroxy-6-methyl-2-oxo-1,2-
Ga-BC-TREN-tris-6-Me3,2-HOPO (12d). A solution of Ga
(acetyl acetate) (Ga-Acac 8.48 mg, 0.02 mmol, 1 eq.) in MeOH
(2 mL) was added to a solution of 11b (20 mg, 0.02 mmol, 1 eq.)
in MeOH (5 mL) and water (2 mL) followed by the addition of
pyridine (131 mg, 1.66 mmol, 72 eq.). The reaction mixture was
stirred (24 h, 95°C). The solvent was removed, and the residue
was precipitated using a minimum of MeOH and slow addition
of diethyl ether. The solid was recovered after centrifugation
(6000 rpm, 30 min) to a give 12d as a white powder (8 mg,
36%). IR (KBr, ν cmꢀ1): 1654 (C¼O, amide), 1648 (C¼O,
ring). [M + H]+ calcd for C39H49N11O12Ga 932.2812, Found
932.2822 m/z, [M + H + H2O]+ calcd for C39H50N11O13Ga
950.2924, Found 950.2931 m/z, [M + H + 2H2O]+ calcd for
C39H52N11O14Ga 968.3029, Found 968.3042 m/z. Anal. Calcd
(found) for C39H64GaN11O26. [LGa + Ga(OH)4·2H2O]: C, 33.90
(33.08); H, 4.67 (5.14); N, 11.15 (10.11).
dihydropyridine-4-carboxamide) (12).
A
solution of
gadolinium (III) chloride hexahydrate (GdCl3.6 H2O, 72 mg,
0.19 mmol, 1.5 eq.) in water (2 mL) was added to a solution
containing 11 (139 mg, 0.13 mmol, 1 eq.) in Millipore water
(5 mL) and placed in a 25 mL DTPA-washed round-bottom
flask. Pyridine (497 mg, 6.28 mmol, 47 eq.) was added to the
reaction mixture and was refluxed (12 h, 95°C). The solvent was
evaporated. The solid was dissolved in a minimal amount of
MeOH and added to a centrifuge tube containing diethyl ether.
The precipitate was recovered after centrifugation (6000 rpm,
30 min), and the process was repeated three times, to give
complex 12 as a light gray solid (160 mg, 98%). IR (KBr, ν
cmꢀ1):1680 (C¼O, amides), 1624 (C¼O, ring). [M + H]+ calcd
for C39H55N13O12Gd 1055.3344, Found 1055.3348 m/z. Anal.
Calcd
(found)
for
C39H70Gd2N13O20Cl3
(GdL(H2O)2
+ Gd·Cl3·6H2O): C, 32.04 (31.19); H, 4.83 (5.63); N, 12.46 (10.54).
Gd-1,1′,1″-(((nitrilotris(ethane-2,1-diyl))tris(azanediyl))tris
(2-oxoethane-2,1-diyl))tris(N-(2-aminoethyl)-3-hydroxy-6-methyl-
2-oxo-1,2-dihydropyridine-4-carboxamide) (12a). A solution of
GdCl3.6 H2O (2.31 mg, 6.22mmol, 1eq.) in Millipore water (1 mL)
was added to 11a (6.51 mg, 6.22 mmol, 1eq.) in MeOH (5 ml).
Pyridine (20 μL) was then added, and the reaction mixture was
stirred (24 h, 95°C). After cooling, the complex was recovered
by precipitation using a minimum of MeOH and addition of
diethyl ether until a white precipitate appeared. The precipitate
was washed three times with diethyl ether and recovered after
centrifugation (6000 rpm, 30 min), to give complex 12a as a light
gray solid (6 mg 91%). IR (KBr, ν cmꢀ1): 1690 (C¼O, amide),
1624 (C¼O, ring). [M + H]+ calcd for C39H55N13O12Gd 1055.3256,
Found 1055.3338 m/z. Anal. Calcd (found) for C39H58N13O17Gd3
(LGd(H2O) + Gd2O3): C, 32.24 (32.04); H, 4.02 (5.33); N, 12.53
(11.06).
Acknowledgments. This work was supported by NIH (HL069832).
The authors wish to thank the mass spectrometry facility (Dr Andersen
Ulla and Dr Nichiporuck Rita) and the X-ray facility (Dr Antonio
DiPasquale) for their help in collecting the respective data and for
interpretation of the X-ray diffraction data. The authors thank
Professor Richmond Sarpong for the use of the IR spectrometer and
Dr Jide Xu for scientific discussions.
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Raymond, K. N. Inorg Chem 2010, 49, 9928.
Gd-BC-TREN-tris-6-Me3,2-HOPO (12b).
A solution of
GdCl3·6H2O (4.29 mg, 0.01 mmol, 1 eq.) in MeOH (2 mL) was
added to a solution containing 11b (10 mg, 0.01 mmol, 1 eq.) in
MeOH (5 mL), followed by the addition of pyridine (4.25 mg,
0.03 mmol, 3 eq.). The reaction was stirred (24 h, 95°C), then
the solvent was removed, and the residue was precipitated in a
minimum of MeOH with a slow addition of diethyl ether to
give complex 12b as a white gray solid (6mg, 48%). IR (KBr, ν
cmꢀ1): 1682 (C¼O, amides), 1650 (C¼O, ring). [M ꢀ H]ꢀ calcd
for C39H48ClN11O12Gd (Lꢀ3Gd+3Cl) 1055.2413, Found
1055.2395 m/z; [Mꢀ H]ꢀ calcd for C39H50ClN11O13Gd
[6] Moore, E. G.; Samuel, A. P. S.; Raymond, K. N. Acc Chem
Res 2009, 42, 542.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2015
Synthesis and Chemical Reactivity of a 6-Me-3,2-Hydroxypyridinone Dithiazolide
with Primary Amines
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[12] (a) Floyd, W. C., III; Klemm, P. J.; Smiles, D. E.; Kohlgruber, A. C.;
Pierre, V. C.; Mynar, J. L.; Frechet, J. M.; Raymond, K. N. J Am Chem
Soc 2011, 133, 2390; (b) Praveena, G. D.; Datta, A.; Dante, R. W.;
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N. G.; Raymond, K. N.; Xu, J.; D’Aleo, A. PCT Int Appl 2011, WO
2011025790 A1 20110303; (c) Sanderson, P. E.; Lyle, T. A.; Dorsey, B. D.;
Stanton, M. G.; Staas, D.; Coburn, C.; Naylor-Olsen, A. M.; Morrissette,
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet