Synthesis of 3-Hydroxy-2-pyridinone Derivatives of 4-tert-Butylcalix[4]arenes: A New Class of Selective Extractants of Actinide(IV) Ions

Full text of DOI:10.1021/jo990387s

J . Org. Chem. 1999, 64, 6097-6101
6097
ligands developed for the selective extraction of actinide-
(IV) ions, as well as uranyl ion, have been disclosed.10,11
In general, these hydroxamate systems extract both iron-
(III) and actinide(IV) ions efficiently under mildly acidic
conditions, but exhibit little selectivity for the actinide
ion.
Syn th esis of 3-Hyd r oxy-2-p yr id in on e
Der iva tives of 4-ter t-Bu tylca lix[4]a r en es:
A New Cla ss of Selective Extr a cta n ts of
Actin id e(IV) Ion s
Timothy N. Lambert, Lakkaraju Dasaradhi,
Vincent J . Huber, and Aravamudan S. Gopalan*
The dibasic 3-hydroxy-2-pyridinone (3,2-HOPO) ligand,
as well as its positional isomers (1,2-HOPO and 3,4-
HOPO), are well-known for their strong affinity for hard
trivalent and tetravalent cations.12 The syntheses of
chelators carrying this ligand moiety (mono-, di-, and
trihydroxypyridinones) have been of interest due to their
strong iron binding properties and potential applications
in the treatment of patients suffering from iron overload
diseases (Cooley’s Anemia).13-15 Also, the synthesis of a
trihydroxypyridinone derivative for the complexation of
gadolinium to generate useful contrast agents for MRI
has been reported.16 Desferrioxamine derivatives carry-
ing an additional hydroxypyridininone group have been
synthesized for enhanced actinide binding.17 The syn-
thesis of a number of other tetrahydroxypyridinones and
their usefulness for in vivo clearance of plutonium have
been reported.18-20 Incorporation of the hydroxypyridi-
none ligands onto calixarene platforms yields a new class
Department of Chemistry and Biochemistry, New Mexico
State University, Las Cruces, New Mexico 88003-8001
Received March 4, 1999
Organic extractants capable of selective and efficient
removal of actinides, such as plutonium and americium,
from aqueous process waste streams containing high
concentrations of other metal ions and anions are poten-
tially useful in radioactive waste remediation.1 Calix[4]-
arenes2-4 that are immobilized in the cone conformation
present an ideal platform for preorganization of the
ligand groups on the same face of the molecule and hence
for the construction of selective extractants for actinides.
Recently, some reports have appeared on the synthesis
of calix[4]arene extractants for actinides having four
CMPO (octyl(phenyl)N,N-diisobutylcarbamoyl meth-
ylphosphine oxide)-like groups appended to the upper
rim.5-7 The authors found that these calixarene deriva-
tives were better extractants for actinides, such as Np,
Pu, and Am, than CMPO itself.5 The synthesis of a lower
rim functionalized CMPO derivative as well as a tet-
raiminocarboxylate calix[4]arene derivative with some
preliminary actinide extraction studies has been recently
published.8 High nitrate concentration (4 M NaNO3 in 1
M HNO3) was required for efficient extraction of actinide
ions into the organic layer by both the upper rim and
lower rim calix CMPO derivatives. In contrast, the
iminocarboxylate was an efficient extractant for thorium-
(IV) at pH 2 from a 0.10 M sodium nitrate solution into
chloroform.8 Another class of calixarene derivatives with
phosphine oxide groups attached to the lower rim has
been synthesized and shown to have high efficiency for
the extraction of Th(IV) and Pu(IV) from simulated
nuclear waste.9 The syntheses and complexation proper-
ties of a number of calixarene-based tetrahydroxamate
(9) Malone, J . F.; Marrs, D. J .; McKervey, M. A.; O’Hagan, P.;
Thompson, N.; Walker, A.; Arnaud-Neu, F.; Mauprivez, O.; Schwing-
Weill, M.-J .; Dozol, J .-F.; Rouquette, H.; Simon, N. J . Chem. Soc.,
Chem. Commun. 1995, 2151.
(10) Dasaradhi, L.; Stark, P. C.; Huber, V. J .; Smith, P. H.; J arvinen,
G. D.; Gopalan, A. S. J . Chem. Soc., Perkin Trans. 2 1997, 1187.
(11) Araki, K.; Hashimoto, N.; Otsuka, H.; Nagasaki, T.; Shinkai,
S. Chem. Lett. 1993, 829. (a) Shinkai, S.; Koreishi, H.; Ueda, K.;
Arimura, T.; Manabe, O. J . Am. Chem. Soc. 1987, 109, 6371. (b)
Shinkai, S.; Shiramama, Y.; Satoh, H.; Manabe, O.; Arimura, T.;
Fujimoto, K.; Matsuda, T. J . Chem. Soc., Perkin Trans. 2 1989, 1167.
(c) Nagasaki, T.; Shinkai, S. J . Chem. Soc., Perkin Trans. 2 1991, 1063.
(12) Tilbrook, G. S.; Hider, R. C. Metal Ions Biol. Syst. 1998, 35,
691.
(13) Rai, B. L.; Dekhordi, L. S.; Khodr, H.; Liu, Z.; Hider, R. C. J .
Med. Chem. 1998, 41, 3347.
(14) Sun, Y.; Motekaitis, R. J .; Martell, A. E. Inorg. Chim. Acta 1998,
281, 60.
(15) Meyer, M.; Telford, J . R.; Cohen, S. M.; White, D. J .; Xu, J ide;
Raymond, K. N. J . Am. Chem. Soc. 1997, 119, 10093.
(16) Xu, J .; Franklin, S. J .; Whisenhunt, D. W.; Raymond, K. N. J .
Am. Chem. Soc. 1995, 117, 7245.
(17) Whisenhunt, D. W.; Neu, M. P.; Hou, Z.; Xu, J .; Hoffman, D.
C.; Raymond, K. N. Inorg. Chem. 1996, 35, 4128.
(1) Metal-Ion Separation and Preconcentration; Bond, A. H., Dietz,
M. L., Rogers, R. D., Eds.; ACS Symposium Series 716; American
Chemical Society: Washington, DC, 1999.
(2) Schwing-Weill, M.-J .; Arnaud-Neu, F. Gazz. Chim. Ital. 1997,
127, 687.
(18) Stradling, G. N. Radiat. Prot. Dosim. 1994, 53, 297.
(19) Xu, J .; Kullgren, B.; Durbin, P. W.; Raymond, K. N. J . Med.
Chem. 1995, 38, 2606.
(20) Bailly, T.; Burgada, R. C. R. Acad. Sci. Paris. 1998, t.1 Serie
II, 241.
(3) Casnati, A. Gazz. Chim. Ital. 1997, 127, 637.
(21) a) Raymond, K. N.; Garrett, T. M. Pure Appl. Chem. 1988, 60,
1807. (b) Raymond, K. N.; Smith, W. L. Struct. Bond. (Berlin) 1981,
43, 159.
(22) Boyle, N. C.; Nicholson, G. P.; Piper, T. J .; Taylor, D. M.;
Williams, D. R.; Williams, D. R. Appl. Radiat. Isot. 1997, 48, 183.
(23) McKervey, M. A.; Millership, J . S.; Russell, J . A.; Nieuwen-
huyzen, M.; Pitarch, M. Supramolec. Chem. 1998, 9, 115.
(4) For some recent reviews on calixarenes, see: (a) Gutsche, C. D.
Calixarenes; Royal Society of Chemistry: Cambridge, 1989. (b) Calix-
arenes: A Versatile Class of Molecules; Vicens, J ., Bo¨hmer, V., Eds.;
Kluwer: Dordrecht, 1991. (c) Gutsche, C. D. Aldrichimica Acta 1995,
28, 3. (d) Bo¨hmer, V. Angew. Chem., Int. Ed. Engl. 1995, 34, 713. (e)
Shinkai, S. Tetrahedron 1993, 49, 8933. (f) Takeshita, M.; Shinkai, S.
Bull. Chem. Soc. J pn. 1995, 68, 1088. (g) Ikeda, A.; Shinkai, S. Chem.
Rev. 1997, 97, 1713. (h) Roundhill, D. M. Prog. Inorg. Chem. 1995, 43,
533.
(5) Arnaud-Neu, F.; Bo¨hmer, V.; Dozol, J .-F.; Gru¨ttner, C.; J akobi,
R. A.; Kraft, D.; Mauprivez, O.; Rouquette, H.; Schwing-Weill, M.-J .;
Simon, N.; Vogt, W. J . Chem. Soc., Perkin Trans. 2 1996, 1175.
(6) Delmau, L. H.; Simon, N.; Schwing-Weill, M.-J .; Arnaud-Neu,
F.; Dozol, J .-F.; Eymard, S.; Tournois, B.; Bo¨hmer, V.; Gru¨ttner, C.;
Musigmann, C.; Tunayar, A. J . Chem. Soc., Chem. Commun. 1998,
1627.
(24) In the molecular modeling of
1 using CAChe Mechanics
program, the distances between the amide proton of one ligand chain
and the carbonyl oxygen of the proximal amide were found to be
between 2.01 and 2.22 Å and are consistent with strong hydrogen-
bonding interactions. Additionally,
a similar type of interstrand
hydrogen-bonding network was indicated between the hydroxypyridi-
none groups on adjacent chains. The molecular modeling dynamics
simulations of calixarene 2 indicated that there were a large number
of structures with potential energies comparable to that of the lowest
energy structure identified. This suggests that the ligand arms of 2
show little preorganization in absence of an alkali metal ion. The MM2
force field used by the CAChe Mechanics program utilizes augmented
parameters to accommodate atoms and interactions not explicitly
defined by MM2. This “augmented” MM2 parameter set was used
without modification.
(7) For resorcin[4]arene-based CMPO cavitands, see: Boerrigter, H.;
Verboom, W.; de J ong, F.; Reinhoudt, D. N. Radiochim. Acta 1998,
81, 39.
(8) Lambert, T. N.; J arvinen, G. D.; Gopalan, A. S. Tetrahedron Lett.
1999, 40, 1613.
10.1021/jo990387s CCC: $18.00 © 1999 American Chemical Society
Published on Web 07/16/1999

6098 J . Org. Chem., Vol. 64, No. 16, 1999
Notes
Sch em e 1
F igu r e 1. Potential preorganization of ligand arms through
(a) hydrogen bonding in calix[4]arene extractant 1 and (b)
alkali metal coordination in extractant 2. L ) 3,2-HOPO
ligand.
of extractants whose synthesis and complexation behav-
ior has so far not been examined. In this paper, we report
the preparation of two calixarene tetrahydroxypyridinone
extractants, designed for the specific extraction of ac-
tinides, and some of their metal ion extraction properties.
sequence that begins from commercially available tert-
butylcalix[4]arene (Scheme 1). The distally disubstituted
calixarene 3 was first prepared by alkylation of tert-
butylcalix[4]arene with N-4-iodobutylphthalimide in the
presence of K2CO3 in DMF at 60 °C. Further reaction of
3 with the same alkylating reagent at room temperature
in DMF gave the cone tetraphthalimide 4 in 48% yield
after careful purification by column chromatography. In
our hands, this two-step procedure, rather than a one-
step exhaustive alkylation in DMF, was preferable for
easy isolation of the desired cone isomer 4. The phthal-
imido protecting groups were then readily removed by
refluxing with an excess of aqueous methylamine to give
the tetraamine 5.27 The tetraamine 5 was then coupled
to the known N-hydroxysuccinimide ester 6,28 prepared
from commercially available 2,3-dihydroxypyridine in
four steps, to give the protected tetrahydroxypyridinone
7. The desired tetrahydroxypyridinone extractant 1 was
obtained in excellent yield after cleavage of the O-benzyl
ethers by hydrogenolysis.
It is generally accepted that selective binding of
chelators to tetravalent actinide ions can be achieved by
taking advantage of their higher coordination number (8
or more) and more flexible coordination geometry relative
to the smaller transition metals.21,22 While the hydroxy-
pyridinone ligand is a strong complexant of actinide ions,
the preorganization of the ligand arms on a calix[4]arene
platform should also help to overcome unfavorable en-
tropic factors in actinide complexation. We hypothesized
that interstrand hydrogen bonds between an amide
proton in one ligand arm with the amide carbonyl group
on a proximal chain in chelator 1 would help in the
preorganization of the ligand arms so as to favor actinide
complexation (Figure 1a). Such examples of hydrogen
bonding are well documented in supramolecular chem-
istry.23 In the potentially ditopic chelator 2 (Figure 1b),
it was of interest to determine if the coordination of an
alkali metal cation by the four diethyleneoxy ligand
chains would lead to a conformation favorable for binding
(25) For some recent examples, see: (a) Ohto, K.; Ishibashi, H.;
Inoue, K. Chem. Lett. 1998, 631. (b) Ohto, K.; Shitarsuchi, K.; Inoue,
K. Goto, M.; Nakashio, F.; Shinkai, S.; Nagasaki, T. Solvent Extr. Ion
Exch. 1996, 14, 459. (c) Koh, K. N.; Imada, T.; Nagasaki, T.; Shinkai,
S. Tetrahedron Lett. 1994, 24, 4157.
(26) For some recent examples, see: (a) Pelizzi, N.; Casnati, A.;
Friggeri, A.; Ungaro, R. J . Chem. Soc., Perkin Trans. 2 1998, 1307. (b)
Scheerder, J .; van Duynhoven, J . P. M.; Engbersen, J . F. J .; Reinhoudt,
D. N. Angew. Chem., Int. Ed. Engl. 1996, 35, 1090.
(27) Motawia, M. S.; Wengel, J .; Abdel-Megid, A. E.-S.; Pedersen,
E. B. Synthesis 1989, 384.
(28) Streater, M.; Taylor, P. D.; Hider, R. C.; Porter, J . J . Med. Chem.
1990, 33, 1749.
An4+ 24
If true, extractants of this class may be particu-
.
larly useful for situations where the actinide waste
stream contains moderately high concentrations of cat-
ions, such as Na+ or K+. A few calixarene-derived ditopic
ligands have been examined for the simultaneous com-
plexation of two cations25 or the complexation of an anion
and a cation.26
The tetrahydroxypyridinone 1 was prepared in a
relatively straightforward manner using a short synthetic

Notes
J . Org. Chem., Vol. 64, No. 16, 1999 6099
Ta ble 1. %Mn + Extr a cted by Ca lixa r en e Liga n d s
1 a n d 2a
Sch em e 2
Th4+
Fe3+
Eu3+
Cu2+
initial
pH
1
2
1
2
1
2
1
2
0b
1c
2d
88
>99
>99
>98
>99
>99
29
32
79
26
65
99
2
7
2
1
11
11
12
8
a
Into CHCl3 from 0.10 M NaNO3, [1] ) 1.0 mM, [2] ) 1.0 mM.
[Th4+] ) 0.19 mM, [Fe3+] ) 0.19 mM, where pH 0 is ∼8.2 M
b
HNO3 (0.10 M NaNO3). c [Th4+] ) 0.19 mM, [Fe3+] ) 0.24 mM,
[Eu3+] ) 0.23 mM, [Cu2+] ) 0.25 mM. [Th4+] ) 0.19 mM, [Fe3+
]
d
) 0.24 mM, [Eu3+] ) 0.24 mM, [Cu2+] ) 0.25 mM.
droxypyridinone cone isomer 15 in 86% yield. Hydro-
genolysis of the O-benzyl ether groups gave tetrahydroxy-
pyridinone 2 in excellent yield.
The ability of hydroxypyridinone chelators 1 and 2 to
extract Th(IV), Fe(III), Eu(III), and Cu(II) from acidic
solutions (0.10 M NaNO3) into chloroform was examined,
and initial results are quite promising. Thorium(IV) and
Eu(III) were chosen for these studies, as they are
surrogates for Pu(IV) and Am(III) present in radioactive
waste streams. Both calixarenes 1 and 2 are highly
efficient in extracting Th(IV) into chloroform from aque-
ous solutions at pH values of 0, 1, and 2 (Table 1). Under
comparable conditions, the extraction of Fe(III) by these
ligands is less efficient and shows a significant pH
dependence. It appears that the chelator 2 is more
efficient than 1 for the extraction of Fe(III) in the pH
range examined. Both chelators 1 and 2 are poor extrac-
tants for Eu(III) and Cu(II) into chloroform under similiar
conditions. The relative efficiencies of extraction in these
experiments are consistent with the relative hardness of
the cations utilized in this study.
Sch em e 3
The actinide selectivity of extractants 1 and 2 was also
investigated in a competitive study involving approxi-
mately equimolar quantitites of the desired ligand (0.25
mM), Fe(III) (0.24 mM), and Th(IV) (0.23 mM) at pH 1.
Under these conditions, calixarene 1 removed 63% of the
Th(IV) present and less than 9% of the Fe(III), displaying
considerable selectivity for the larger cation. Calixarene
2, although less efficient, was also selective for the
extraction of Th(IV) (52%) over Fe(III) (15%). Further
studies are needed to understand the complexation/
extraction properties of these ligands and to establish the
nature of the observed actinide selectivity. The influence
of alkali metal ions on the extraction of actinides by the
potentially ditopic extractant 2 also needs to be investi-
gated.
In conclusion, efficient synthetic routes for two hy-
droxypyridinone calixarene derivatives, a new class of
extractants for actinides, have been developed. Results
from metal ion extraction studies indicate that both these
ligands are efficient extractants for Th(IV) and Fe(III)
in comparison to Eu(III) and Cu(II) in the pH range of
1-2. Morever, both 1 and 2 extract Th(IV) selectively in
the presence of Fe(III) under competitive conditions at
pH 1. These results clearly warrant the further develop-
ment of this new class of actinide extractants for their
potential application in radioactive waste remediation.
Our sythetic route to the chelator 2 was more conver-
gent, but required the preparation of a suitable alkylating
agent with a protected hydroxypyridinone moiety. This
was accomplished in five steps that began from the
known carboxylic acid 8 (Scheme 2).28 The pyridinone
carboxylic acid 8 was easily reduced with borane in THF
to provide the alcohol 9 in good yield. Alkylation of the
alcohol with 2-(2-bromoethoxy)tetrahydro-2H-pyran was
slow, but proceeded effectively to give 10. The THP
protecting group was then removed using catalytic p-
TsOH in MeOH to obtain the alcohol 11. Conversion of
alcohol 11 into the iodide 13 was readily accomplished
in two steps (86% yield) via its mesylate 12. In general,
in this synthetic sequence, column chromatographic
purification was required in only one step (in the alkyla-
tion to give 10) and the crude products were of sufficient
purity to be used directly in the next step.
With iodide 13 in hand, the tetrahydroxypyridinone 2
was prepared readily from 4-tert-butylcalix[4]arene in
two steps (Scheme 3). The alkylation of 4-tert-butylcalix-
[4]arene with 13 using K2CO3 in refluxing MeCN gave
the distally disubstituted calixarene 14 in excellent yield.
Further reaction of 14 with alkylating agent 13 and NaH
at room temperature in DMF gave the protected hy-
Exp er im en ta l Section
1
Gen er a l Meth od s. H NMR (200 MHz) and 13C NMR (50 or
100 MHz) spectra were recorded in CDCl3 with signals recorded
downfield from an internal tetramethylsilane reference unless
otherwise noted. Elemental analyses were performed by Desert
Analytics, Tucson, AZ. Analytical and preparative thin-layer

6100 J . Org. Chem., Vol. 64, No. 16, 1999
Notes
chromatography was performed on silica 60/F254 plastic- or glass-
backed plates (EM Science). Column chromatography was done
on silica gel (Merck 230-400 mesh). Radial chromatography was
performed on a Chromatotron (Harrison Scientific) using silica
gel 60 plates. THF was freshly distilled from sodium/benzophe-
none. Dry DMF was obtained from Aldrich Chemical Co. in a
SureSeal container.
(s, 36 H), 1.59-1.70 (m, 8 H), 1.92-2.07 (m, 8 H), 3.09 (d, J )
12.6 Hz, 4 H), 3.18-3.30 (unresolved q, 8 H), 3.84 (t, J ) 7 Hz,
8 H), 4.32 (d, J ) 12.6 Hz, 4 H), 4.49 (s, 8 H), 4.96 (s, 8 H), 5.99
(t, J ) 7.2 Hz, 4 H), 6.64 (d, J ) 6.8 Hz, 4 H), 6.85 (d, J ) 6.8
Hz, 4 H), 6.74 (s, 8 H), 7.26-7.36 (m, 20 H), 8.38 (unresolved t,
4 H); 13C NMR (100 MHz, CDCl3) δ 26.2, 28.2, 31.0, 31.4, 33.8,
40.4, 51.6, 70.7, 75.0, 104.6, 115.5, 124.8, 125.0, 125.1, 127.7,
128.2, 128.6, 130.6, 133.7, 136.1, 144.3, 148.6, 153.8, 158.2, 167.5.
Anal. Calcd for C116H136N8O16: C, 73.39; H, 7.22; N, 5.9. Found:
C, 73.45; H, 7.37; N, 5.73.
25,26,27,28-T e t r a k is (4-p h t h a lim id o b u t o x y )-p -t er t -
bu tylca lix[4]a r en e (4). A mixture of 4-tert-butylcalix[4]arene
(2.00 g, 3.00 mmol), N-(4-iodobutyl)phthalimide (4.06 g, 12.0
mmol) and K2CO3 (0.950 g, 6.08 mmol) in DMF (30 mL) was
heated at 60 °C for 24 h. The DMF was removed in vacuo, the
residue was diluted with water, and the product extracted into
CHCl3. The combined organic extracts were dried (Na2SO4) and
filtered, and the solvent was removed in vacuo. The residue was
dissolved in a minimum amount of CHCl3, and the crude product
was precipitated by the addition of methanol. The precipitated
solid was isolated by vacuum filtration and dried under vacuum.
The dialkylated product 3 (2.20 g, 69%) was used in the next
step without further purification: IR (KBr) 3307, 1768, 1711
25,26,27,28-Tetr a k is{4-[2-(3-h yd r oxy-2-oxo-1,2-d ih yd r o-
1-p yr id yl)a ceta m id o]bu toxy}-p-ter t-bu tylca lix[4]a r en e (1).
Palladium on carbon (10%, 0.087 g) was added to a solution of
7 (0.210 g, 0.093 mmol) in 33% acetic acid/ethanol (6 mL), and
the mixture was stirred under H2 at room temperature. After
36 h, the reaction mixture was filtered through Celite, and the
Celite was washed with small amounts of CHCl3. The solvent
was removed in vacuo, and the residue was washed with diethyl
ether to give 1 (0.145 g, 100%) as a rose-colored solid: mp 238
°C (dec); IR (KBr) 1599, 1655, 2954, 3300 cm-1 1H NMR (200
;
cm-1
;
1H NMR (200 MHz, CDCl3) δ 0.97 (s, 18 H), 1.25 (s, 18
MHz, CDCl3) δ 1.06 (s, 36 H), 1.58-1.75 (m, 8 H), 1.93-2.08
(m, 8 H), 3.09 (d, J ) 12.2 Hz, 4 H), 3.31 (unresolved t, 8 H),
3.80 (unresolved t, 8 H), 4.29 (d, J ) 12.2 Hz, 4 H), 4.60 (br s, 8
H), 6.13 (unresolved t, 4 H), 6.7-6.8 (m, 12 H), 6.91 (d, J ) 5
Hz, 4 H), 7.67-7.78 (m 4 H); 13C NMR (100 MHz, CDCl3) δ 26.2,
28.1, 31.0, 31.4, 33.8, 40.4, 52.3, 74.9, 107.3, 115.8, 125.0, 128.5,
133.7, 144.6, 146.6, 153.5, 158.8, 167.2. Anal. Calcd for
C88H112N8O16‚H2O: C, 67.93; H, 7.39; N, 7.20. Found: C, 67.91;
H, 7.37; N, 7.01.
H), 2.02-2.18 (m, 8 H), 3.28 (d, J ) 13.0 Hz, 4 H), 3.82-3.94
(m, 4 H), 3.97-4.08 (m, 4 H), 4.10 (d, J ) 13.0 Hz, 4 H), 6.8 (s,
4 H), 7.1 (s, 4 H), 7.5 (s, 2 H), 7.6 (m, 4 H), 7.8 (m, 4 H).
To a solution of the dialkylated compound 3 (3.8 g, 3.6 mmol)
in dry DMF (40 mL) under N2 at 0 °C was added NaH (60% in
oil, 433 mg, 10.8 mmol), and the reaction mixture was stirred
at 0 °C until gas evolution ceased. To this mixture at 0 °C was
added a solution of N-(4-iodobutyl)phthalimide (4.7 g, 14.4 mmol)
in DMF (20 mL) via an addition funnel over a period of 20 min.
The reaction was allowed to warm to room temperature, stirred
for 24 h, and finally heated at 60 °C for 1 h. The reaction was
then allowed to cool to room temperature and quenched with
water. The DMF was removed in vacuo, the residue was diluted
with water, and the product extracted into CHCl3. The combined
organic extracts were dried (Na2SO4) and filtered, and the
solvent was removed in vacuo. The crude product was purified
using column chromatography (66% ethyl acetate/hexanes) to
give the tetraamide 4 (2.40 g, 48%): mp 75 °C; IR (KBr) 1615,
1713, 1772, 3466 cm-1; 1H NMR (200 MHz, CDCl3) δ 1.06 (s, 36
H), 1.70-1.85 (m, 8 H), 2.01-2.18 (m, 8 H) 3.10 (d, J ) 12.5 Hz,
4 H), 3.77 (t, J ) 7.0 Hz, 8 H), 3.92 (t, J ) 7.1 Hz, 8 H), 4.37 (d,
J ) 12.5 Hz, 4 H), 6.75 (s, 8 H), 7.57-7.77 (m, 16 H); 13C NMR
(100 MHz, CDCl3) δ 25.4, 27.6, 31.2, 31.4, 33.8, 38.0, 74.6, 123.0,
125.0, 132.3, 133.6, 133.8, 144.3, 153.5, 168.2. Anal. Calcd for
C92H100N4O12: C, 76.01; H, 6.93; N, 3.85. Found: C, 75.74; H,
6.73; N, 3.97.
3-(Ben zyloxy)-1-(2-h yd r oxyeth yl)-2(1H)-p yr id in on e (9).
To a solution of acid 828 (5.77 g, 22.3 mmol) in freshly distilled
THF (20 mL) under N2 was added BH3‚THF (1 M, 44.5 mmol),
and the reaction mixture was stirred at room temperature for 5
h. The reaction mixture was poured over crushed ice, extracted
with dichloromethane, dried (MgSO4), and filtered, and the
solvents were removed in vacuo to give 9 (4.59 g, 84%) as a white
solid which was used in the next step without purification: mp
75-76 °C; IR (KBr) 1594, 3369 cm-1; 1H NMR (200 MHz, CDCl3)
δ 3.94 (t, J ) 4.8 Hz, 2 H), 4.13 (t, J ) 4.4 Hz, 2 H), 5.09 (s, 2
H), 6.05 (t, J ) 7.2 Hz, 1 H), 6.68 (d, J ) 6.6 Hz, 1 H), 6.98 (d,
J ) 6.8 Hz, 1 H) 7.31-7.44 (m, 5 H); 13C NMR (50 MHz, CDCl3)
δ 53.46, 61.61, 71.08, 105.31, 116.37, 127.72, 128.46, 128.98,
130.65, 136.08, 148.98, 159.09. Anal. Calcd for C14H15O3N: C,
68.57; H, 6.12; N, 5.71. Found: C, 68.36; H, 6.26; N, 5.66.
3-(Be n zyloxy)-1-{2-[2-t e t r a h yd r o-2H -2-p yr a n yloxy]-
eth oxy}eth yl-2(1H)-p yr id in on e (10). To a solution of alcohol
9 (3.0 g, 12.2 mmol) in freshly distilled THF (40 mL) at 0 °C
under N2 was added NaH (60% in oil, 1.49 g, 37.3 mmol), and
the suspension was stirred for 5 min at 0 °C and then stirred at
room temperature for 20 min. The suspension was then cooled
to 0 °C and 2-(2-bromoethoxy)tetrahydro-2H-pyran (7.67 g, 36.9
mmol) was slowly added. The reaction was then heated at reflux
until disappearance of starting material was indicated by TLC
analysis (2.5-3 d). The reaction mixture was then cooled to room
temperature, and the reaction was carefully quenched by the
addition of water. The solvents were removed in vacuo, and the
oily residue was dissolved in ethyl acetate, washed with water,
and saturated NaCl. The organic layer was dried (Na2SO4) and
filtered, and the solvents were removed in vacuo to yield a light
brown oil (6.21 g). The crude product was purified by column
chromatography with ethyl acetate/hexanes gradient elution
followed by methanol/ethyl acetate gradient elution to yield 10
25,26,27,28-Tetr a k is(4-a m in obu toxy)-p-ter t-bu tylca lix[4]-
a r en e (5). A solution of 4 (2.4 g, 1.6 mmol) in THF (10 mL) was
added to 40% aqueous methylamine (150 mL) at room temper-
ature, and the solution was heated at 60 °C for 24 h. The reaction
mixture was cooled, and the solid amine was separated by
vacuum filtration on a sintered glass funnel and washed with
water. The crystals were dissolved in CHCl3, dried (Na2SO4),
and filtered, and the solvent was removed in vacuo to give the
tetraamine 5 (1.48 g, 76%) as a white solid. The tetraamine was
dried at 80 °C for 24 h under vacuum before its use in the next
step: mp 192 °C; IR (KBr) 1580, 3490 cm-1; 1H NMR (200 MHz,
CDCl3) δ 1.07 (s, 36 H), 1.45-1.69 (m, 8 H), 1.93-2.10 (m, 8 H),
2.76 (t, J ) 7 Hz, 8 H), 3.12 (d, J ) 12.5 Hz, 4 H), 3.87 (t, J )
7 Hz, 8 H), 4.38 (d, J ) 12.5 Hz, 4 H), 6.77 (s, 8 H); 13C NMR
(100 MHz, CDCl3) δ 27.8, 30.4, 31.1, 31.2, 31.4, 33.8, 42.4, 75.0,
125.0, 133.7, 144.4, 153.5. Anal. Calcd for C60H92N4O4‚2H2O: C,
74.34; H, 9.98; N 5.78. Found: C, 73.96; H, 9.58; N, 5.75.
25,26,27,28-Tetr a k is{4-[2-(3-(ben zyloxy)-2-oxo-1,2-d ih y-
d r o-1-p yr id yl)a ce t a m id o]b u t oxy}-p -t er t -b u t ylca lix[4]-
a r en e (7). The NHS ester 628 (3.12 g, 8.73 mmol) was added to
a solution of the tetraamine 5 (1.30 g, 1.09 mmol) in DMF (30
mL) under N2, and the reaction mixture was heated at 60 °C
for 16 h. The mixture was then cooled, and the DMF was
removed in vacuo. The residue was dissolved in CHCl3 and
washed with saturated NaHCO3 and water. The organic layer
was dried (Na2SO4), filtered, and the solvent was removed in
vacuo. The residue was washed with acetonitrile to remove
unreacted NHS ester and then recrystallized from 95% ethanol
to give 7 (2.16 g, 92% yield): mp 238 °C; IR (KBr) 1597, 1653,
1715, 2362, 3065, 3311 cm-1; 1H NMR (200 MHz, CDCl3) δ 1.06
1
as a light yellow oil (3.89, 85%): IR (neat) 1604, 1654 cm-1; H
NMR (200 MHz, CDCl3) δ 1.32-1.97 (br m, 6 H), 3.40-3.54 (m,
2 H), 3.55-3.65 (m, 3 H), 3.75-3.90 (m, 3 H), 4.17 (t, J ) 5.1
Hz, 2 H), 4.58 (t, J ) 3.3 Hz, 1 H), 5.11 (s, 2 H), 5.97 (t, J ) 7.1
Hz, 1 H), 6.65 (dd, J ) 7.4 and 1.7 Hz, 1 H), 7.05 (dd, J ) 6.9
and 1.7 Hz, 1 H), 7.23-7.49 (m, 5 H); 13C NMR (50 MHz, CDCl3)
δ 19.4, 25.5, 30.6, 49.7, 62.2, 66.6, 69.0, 70.8, 98.9, 103.8, 116.1,
127.4, 128.0, 128.6, 130.8, 136.6, 148.8, 158.3. Anal. Calcd for
C21H27O5N: C, 67.53; H, 7.29; N, 3.75. Found: C, 67.80; H, 7.26;
N, 3.77.
3-(Ben zyloxy)-1-[2-(2-h yd r oxyeth oxy)eth yl]-2(1H)-p yr i-
d in on e (11). To a solution of the THP ether 10 (2.90 g, 7.71
mmol) in methanol (10 mL) was added p-TsOH (0.146 g, 0.77
mmol), and the solution was stirred at room temperature for 8
h. The methanol was removed in vacuo, and the resulting residue

Notes
J . Org. Chem., Vol. 64, No. 16, 1999 6101
was dissolved in dichloromethane and washed with saturated
NaHCO3 and water. The organic layer was then dried (Na2SO4)
and filtered, and the solvents were removed in vacuo to yield
the crude alcohol 11 (2.33 g, 100%) as a viscous oil which was
used in the next step without purification. An analytical sample
was prepared by radial chromatography (ethyl acetate/hexanes
gradient elution followed by methanol/ethyl acetate gradient
70.8, 75.3, 104.1, 116.0, 125.1, 125.5, 127.4, 128.0, 128.6, 130.2,
131.2, 132.7, 136.6, 141.4, 147.0, 148.5, 149.8, 150.6. Anal. Calcd
for C76H90O10N2‚H2O: C, 75.45; H, 7.67; N, 2.32. Found: C,
75.53; H, 7.39; N, 2.49.
25,26,27,28-Tetr a k is-2-[2-(3-ben zyloxy-2-oxo-1,2-d ih yd r o-
1-p yr id yl)eth oxy]eth oxy-p-ter t-bu tylca lix[4]a r en e (15). So-
dium hydride (60% in oil, 0.06 g, 1.45 mmol) was added to a
solution of 14 (0.64 g, 0.54 mmol) in dry DMF (10 mL) at 0 °C
under N2, and the mixture was stirred at 0 °C for 5 min and
then at room temperature for 25 min. The reaction was cooled
to 0 °C, and iodide 13 (0.86 g, 2.15 mmol) was added. The
reaction was allowed to stir under N2 at 0 °C for 1 h and then
at room temperature for 6 d. The reaction was quenched by the
addition of water and diluted further with water, and the product
was extracted into dichloromethane. The organic layer was then
dried (Na2SO4) and filtered, and the solvents were removed in
vacuo. Purification of the crude product by column chromatog-
raphy (ethyl acetate/hexanes gradient elution) gave the unre-
acted iodide 7 (0.39 g) and the all-cone product 15 (0.802 g,
1
elution): IR (neat) 1599, 1651, 3404 cm-1; H NMR (200 MHz,
CDCl3) δ 2.68 (br s, 1 H), 3.51 (t, J ) 4.0 Hz, 2 H), 3.58-3.71
(m, 2 H), 3.78 (t, J ) 5.0 Hz, 2 H), 4.15 (t, J ) 5.0 Hz, 2 H), 5.08
(s, 2 H), 6.00 (t, J ) 7.2 Hz, 1 H), 6.67 (d, J ) 7.3 Hz, 1 H), 6.99
(d, J ) 6.3 Hz, 1 H), 7.22-7.47 (m, 5 H); 13C NMR (50 MHz,
CDCl3) δ 49.7, 61.6, 68.9, 70.8, 72.5, 104.4, 115.9, 127.4, 128.0,
128.6, 130.3, 136.4, 148.8, 158.3. Anal. Calcd for C16O4H19N: C,
66.41; H, 6.62; N, 4.84. Found: C, 66.28; H, 6.55; N, 4.72.
3-(Ben zyloxy)-1-[2-(2-m eth a n esu lfon yloxyeth oxy)eth yl]-
2(1H)-p yr id in on e (12). Methanesulfonyl chloride (1.18 g, 10.4
mmol) was added dropwise to a solution of 11 (2.0 g, 6.92 mmol)
in dichloromethane (25 mL) and Et3N (1.40 g, 13.8 mmol) at 0
°C under an atmosphere of N2. The reaction was stirred at 0 °C
for 1 h and then at room temperature for 1.5 h. The reaction
mixture was then diluted with dichloromethane and washed
with 2 M HCl, saturated NaHCO3, and saturated NaCl. The
organic layer was dried (MgSO4) and filtered, and the solvents
were removed in vacuo to yield the crude mesylate 12 (2.38 g,
94%) which was used in the next step without purification. An
analytical sample was obtained by radial chromatography (ethyl
1
86%): mp 58-60 °C; IR (KBr) 1605, 1656 cm-1; H NMR (200
MHz, CDCl3) δ 1.06 (s, 36 H), 3.07 (d, J ) 12.5 Hz, 4 H), 3.76 (t,
J ) 4.7 Hz, 8 H), 3.84 (unresolved t, 8 H), 3.99 (unresolved t, 8
H), 4.10 (t, J ) 4.8 Hz, 8 H), 4.33 (d, J ) 12.5 Hz, 4 H), 5.05 (s,
8 H), 5.89 (t, J ) 7.2 Hz, 4 H), 6.59 (dd, J ) 7.4 and 1.6 Hz, 4
H), 6.74 (s, 8 H), 6.92 (dd, J ) 6.9 and 1.6 Hz, 4 H), 7.20-7.43
(m, 20 H); 13C NMR (50 MHz, CDCl3) δ 31.0, 31.3, 33.8, 49.8,
68.6, 70.6, 72.8, 104.0, 115.6, 125.0, 127.3, 127.9, 128.4, 130.7,
133.6, 136.3, 144.8, 148.5, 153.2, 158.0. Anal. Calcd for
C108H124O16N4‚1.5 H2O: C, 73.64; H, 7.27; N, 3.19. Found: C,
73.67; H, 7.03; N, 3.23.
acetate/hexanes gradient elution): IR (neat) 1606, 1652 cm-1
;
1H NMR (200 MHz, CDCl3) δ 2.96 (s, 3 H), 3.67-3.71 (m, 2 H),
3.84 (t, J ) 5.0 Hz, 2 H), 4.18 (t, J ) 5.0 Hz, 2 H), 4.28-4.33 (m,
2 H), 5.12 (s, 2 H), 6.02 (t, J ) 7.1 Hz, 1 H), 6.66 (dd, J ) 7.4
and 1.7 Hz, 1 H), 6.98 (dd, J ) 6.8 and 1.7 Hz, 1 H), 7.30-7.47
(m, 5 H); 13C NMR (50 MHz, CDCl3) δ 37.6, 49.5, 68.8, 70.8,
104.3, 115.9, 127.4, 128.0, 128.6, 130.5, 136.4, 148.7, 158.1. Anal.
Calcd for C17H21O6NS: C, 55.57; H, 5.77; N, 3.81. Found: C,
55.46; H, 5.91; N, 3.65.
25,26,27,28-Tetr a k is-2-[2-(3-h yd r oxy-2-oxo-1,2-d ih yd r o-
1-p yr id yl)eth oxy]eth oxy-p-ter t-bu tylca lix[4]a r en e (2). Pal-
ladium on carbon (5%, 0.26 g) was added to a solution of 15 (0.60
g, 0.35 mmol) in ethanol (25 mL), and the reaction was stirred
under H2 at room temperature for 22 h. The reaction mixture
was then diluted with CHCl3, and the catalyst was filtered off.
The solvents were removed in vacuo to provide 2 as a pale rose
solid (0.46 g, 96%): mp 218 °C (dec); IR (KBr) 1599, 1651, 3237
3-(Ben zyloxy)-1-[2-(2-iod oeth oxy)eth yl]-2(1H)-p yr id in o-
n e (13). Sodium iodide (1.40 g, 9.34 mmol) was added to a
solution of mesylate 12 (2.27 g, 6.18 mmol) in acetone (20 mL),
and the resulting mixture was heated at reflux for 26 h. The
solvent was then removed in vacuo, and the oily residue was
dissolved in dichloromethane, washed with water, and a Na2-
SO3 solution (10% by weight). The dichloromethane layer was
dried (Na2SO4) and filtered, and the solvents were removed in
vacuo to give 13 (2.71 g, 92%) as a light yellow solid which was
used in the next step without purification. An analytical sample
was obtained by radial chromatography (ethyl acetate/hexanes
1
cm-1; H NMR (200 MHz, CDCl3) δ 1.06 (s, 36 H), 3.03 (d, J )
12.8 Hz, 4 H), 3.78 (unresolved t, 8 H), 3.84 (t, J ) 4.7 Hz, 8 H),
3.97 (unresolved t, 8 H), 4.15 (t, J ) 4.7 Hz, 8 H), 4.29 (d, J )
12.8 Hz, 4 H), 6.03 (t, J ) 7.1 Hz, 4 H), 6.74 (s, 8 H), 6.76 (d, J
) 7.0 Hz, 4 H), 6.81 (d, J ) 7 Hz, 4 H); 13C NMR (50 MHz, CDCl3)
δ 31.4, 33.9, 50.2, 68.7, 70.8, 72.8, 106.2, 114.4, 125.1, 128. 7,
133.7, 144.9, 146.6, 153.4, 158.6. Anal. Calcd for C80H100O16N4:
C, 69.93; H, 7.34; N, 4.08. Found: C, 69.54; H, 7.54; N, 3.84.
Solven t Extr a ction Stu d ies. The protocol for metal ion
extraction experiments followed procedures described earlier.10
A solution of 0.10 M NaNO3/1% HNO3 was adjusted to pH 1 or
2 with concentrated aqueous NaOH. To a known volume of the
aqueous solution, at the desired pH, was then added the
appropriate quantity (80-90 µL) of the metal ion stock solution
(∼0.25 M). Equal volumes (4 mL:4 mL) of the aqueous solution
at the specified pH, containing the desired concentration of the
metal ion of interest, and chloroform containing a 4-5-fold molar
excess of the ligand (1.0 mM) were contacted for 2 h at ambient
temperature with gentle shaking. The layers were separated
carefully by centrifugation, and the concentrations of the metal
ions in the aqueous layers were determined by ICP analysis
against NIST traceable standards. The percent metal ion
extracted by the ligands could then be determined. All reported
extraction values are the average of two or more individual
extractions, and the necessary control experiments were also
performed to ensure that metal precipitation was not relevant
to metal ion removal.
1
gradient elution): mp 86-88 °C; IR (KBr) 1604, 1646 cm-1; H
NMR (200 MHz, CDCl3) δ 3.19 (t, J ) 6.4 Hz, 2 H), 3.67 (t, J )
6.4 Hz, 2 H), 3.82 (t, J ) 5.0 Hz, 2 H), 4.18 (t, J ) 5.0 Hz, 2 H),
5.12 (s, 2 H), 6.01 (t, J ) 7.14 Hz, 1 H), 6.67 (dd, J ) 7.4 and 1.7
Hz, 1 H), 7.04 (dd, J ) 6.9 and 1.7 Hz, 1 H), 7.22-7.47 (m, 5 H);
13C NMR (50 MHz, CDCl3) δ 42.7, 49.7, 68.29, 70.6, 71.0, 104.0,
115.9, 127.3, 127.8, 128.4, 130.6, 136.3, 148.7, 158.2. Anal. Calcd
for C16H18O3NI: C, 48.12; H, 4.55; N, 3.51. Found: C, 48.48; H,
4.65; N, 3.32.
25,27-Bis-2-[2-(3-(ben zyloxy)-2-oxo-1,2-dih ydr o-1-pyr idyl)-
eth oxy]eth oxy-26,28-d ih yd r oxy-p-ter t-bu tylca lix[4]a r en e
(14). The iodide 13 (2.36 g, 5.9 mmol) was added to a suspension
of 4-tert-butylcalix[4]arene (0.96 g, 1.48 mmol) and K2CO3 (0.43
g, 3.11 mmol) in acetonitrile (30 mL), and the reaction mixture
was heated at reflux for 26 h. The solvents were then removed
in vacuo, and the residue was extracted with dichloromethane.
The dichloromethane solution was then washed with water, Na2-
SO3 (10% by weight), dried (Na2SO4), and filtered, and the
solvents were removed in vacuo. The crude product was purified
by column chromatography. The iodide 13 (0.79 g) was recovered
by elution with ethyl acetate. Elution with 5% methanol/ethyl
acetate gave the desired dialkylated product 14 (1.68 g, 96%)
as a crystalline white solid: mp 68-70 °C; IR (KBr) 1606, 1656,
3422 cm-1; 1H NMR (200 MHz, CDCl3) δ 0.94 (3, 18 H), 1.30 (s,
18 H), 3.24 (d, J ) 13.2 Hz, 4 H), 3.77-3.89 (m, 4 H), 3.94 (t, J
) 4.5 Hz, 4 H), 4.05-4.60 (m, 4 H), 4.24 (t, J ) 4.5 Hz, 4 H),
4.30 (d, J ) 13.2 Hz, 4 H), 5.07 (s, 4 H), 5.79 (t, J ) 7.1 Hz, 2
H), 6.53 (dd, J ) 7.5 and 1.6 Hz, 2 H), 6.75 (s, 4 H), 7.03 (s, 4
Ack n ow led gm en t. This work was supported by the
Waste-Management Education and Research Consor-
tium of New Mexico. Drs. Gordon J arvinen (LANL),
Paul Smith (DOE), and Hollie J acobs (NMSU) are
thanked for helpful discussions. Dr. Nirmal Koshti
(NMSU) is thanked for his assistance in the preparation
of hydroxypyridinone precursor 9. Dr. Gary Rayson
(NMSU) and Mr. Patrick Williams (NMSU) are thanked
for their assistance in ICP analyses.
H), 7.06 (dd, J ) 7.5 and 1.6 Hz, 2 H), 7.23-7.46 (m, 10 H); 13
NMR (50 MHz, CDCl3) δ 31.0, 31.4, 31.8, 33.9, 50.4, 69.3, 70.0,
C
J O990387S