Pyridyl-cyclopentadiene Re(CO)2+ complexes as a compact core system for SPECT ligand development

Article abstract of DOI:10.1021/om100521s

An η¹,η⁵-rhenium complex has been prepared, starting from a CpRe(CO)₃ complex substituted with a pendant aromatic amine. This unique complex has potential application as a surrogate for a technetium-99m complex, a common radioisotope for biomedical imaging applications. Chelation occurred via photochemical decarbonylation of the rhenium, which opened a binding site for the aromatic amine.

Full text of DOI:10.1021/om100521s

Organometallics 2010, 29, 3669–3671 3669
DOI: 10.1021/om100521s
þ
Pyridyl-Cyclopentadiene Re(CO)2 Complexes as a Compact Core
System for SPECT Ligand Development
Nathan C. Ackroyd*,‡ and John A. Katzenellenbogen*,†
†Department of Chemistry, University of Illinois, 600 South Mathews Avenue, Urbana, Illinois, 61801, and
‡Department of Chemical and Biological Sciences, Mount Royal University, 4825 Mount Royal Gate SW,
Calgary, Alberta, Canada T3E 6K6
Received May 27, 2010
Summary: An η1,η5-rhenium complex has been prepared,
starting from a CpRe(CO)3 complex substituted with a pen-
dant aromatic amine. This unique complex has potential
application as a surrogate for a technetium-99m complex, a
common radioisotope for biomedical imaging applications.
Chelation occurred via photochemical decarbonylation of the
rhenium, which opened a binding site for the aromatic amine.
Figure 1. Photochemical cyclization.
Introduction
be prepared.10-12 The CpTc(CO)3 unit works well with high
molecular weight biomolecules, whose physical and chemical
Because of its long half-life (6 h) and widespread avail-
ability, 99 mTc is currently used for approximately 85% of all
properties dominate over the relatively small pendant com-
clinical radioisotopic imaging applications.1,2 Examples of
plex. With smaller biological molecules and small-molecule
the use of technetium in imaging include simple complexes
such as the myocardial imaging agent Sestamibi,3,4 as well as
carbonyl ligands have the potential to negatively affect
drugs, however, the polarity and steric size of the three
technetium-containing complexes appended to biological
molecules of interest,5 often macromolecules.6-8 A com-
pharmacokinetic properties. Burying the metal further with-
in the ligand would reduce its accessibility to solvent and
monly used pendent complex is the organometallic cyclo-
replace one of its CO groups, a change that is predicted to
reduce its surface polarity by approximately one log unit.13
pentadienyl tricarbonyl technetium unit, CpTc(CO)3,
because of its high stability9 and the ease with which it can
With this goal in mind, it was decided to synthesize a model
complex using rhenium in place of technetium, with a
*To whom correspondence should be addressed. E-mail: nackroyd@
mtroyal.ca; jkatezene@uiuc.edu.
pyridylmethyl substituent added to the Cp core. The nitro-
gen of the pyridine should allow it to displace a CO under
photochemical conditions and bind the metal with a second
binding site, as shown in Figure 1.14
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nostic Agents with Tc-99m. Semin. Nucl. Med. 2001, 31, 278–85.
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1661.
Results
To reduce exposure to radioactive isotopes, all synthetic
steps were performed using rhenium instead of technetium.15
Rhenium has been widely used as a surrogate for technetium
because rhenium analogues of technetium compounds
can generally be prepared under similar conditions and
their physical properties are similar. The synthesis of
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Media: A Single Sample Story!. Angew. Chem., Int. Ed. 2000, 39, 254–
256.
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r
2010 American Chemical Society
Published on Web 07/20/2010
pubs.acs.org/Organometallics

3670 Organometallics, Vol. 29, No. 16, 2010
Scheme 1. Synthesis of the Pyridyl-Cyclopentadienyl Core
Ackroyd and Katzenellenbogen
η1,η5-pyridylmethylcyclopentadienyl rhenium(I) dicarbonyl,
PyCp(CO)2, involves two key steps: the attachment of the
metal tricarbonyl to a cyclopentadienide, and the displace-
ment of one carbonyl ligand and the concomitant cycliza-
tion to produce an η1,η5 complex. Production of the pyridyl
cyclopentadiene 3 proceeds in two steps from commercially
available 2-pyridylmethanol (1), as shown in Scheme 1.
R-Hydroxypicoline (1) was activated as the tosylate 2,16
which was displaced using Cp anion to form the monosub-
stituted cyclopentadiene 3. Cyclopentadiene 3 was isolated
as a mixture of isomers, due to the propensity of cyclopenta-
dienes to undergo a 1,5-hydride shift, which in the case
of substituted rings results in double-bond regioisomers.
No Diels-Alder dimerization of 3 was observed under
standard isolation and characterization conditions at room
temperature. Deprotonation of the cyclopentadiene 3 iso-
mers formed one nucleophilic dienide, which coordinated
to a rhenium tricarbonyl complex to form the piano-stool
pyridylmethyl Cp complex 4.17 The essential pyridine to
rhenium cyclization occurs via photoirradiation under
inert atmosphere to provide the desired rhenium dicarbonyl
complex 5.14
Figure 2. Space-filling model of the η5-complex.
Figure 3. Space-filling model of the η1,η5-complex.
and are not uniformly bidentate.23 To our knowledge, this is
the first example of a pendant aromatic amine bound to
rhenium. Our interest in such complexes is twofold: rhenium
complexes serve as model systems for technetium in the
development of imaging agents;15 and there is a need to
modify the in vivo stability and pharmacokinetic properties
of certain metal complexes such that they make effective
small-molecule imaging agents.
Discussion
Several examples exist in the literature of transition metals,
including rhenium, with bidentate alkyl-amine-substituted
cyclopentadienide ligands.14,18-20 Examples of Cp ligands
with aromatic amine substituents are far less common21,22
Comparison of the energy minimization space-filling
models of the η5-complex (Figure 2) and the η1,η5-complex
(Figure 3) illustrates the change in topology that arises from
pyridine chelation. The original CpRe(CO)3 complex 4
(Figure 2) shows the classic “piano-stool” structure, with
the η5-tricarbonyl metal system extending normal to the
plane of the cyclopentadienyl ring on one side, with the
pyridine substituent angled to occupy space on the other side
of the Cp ring. By contrast, in the η1,η5-complex 5 (Figure 3),
the pyridyl ring, in replacing one of the CO ligands, has
rotated downward onto the other face of the Cp ring, where it
overall wraps itself much more around the metal center,
making a more compact structure. We were surprised, how-
ever, to find that chelation did not have the effect on surface
polarity predicted by calculations. Using an ethyl acetate/
hexanes mixture showed no separation of the two complexes
by thin-layer chromatography. Instead, purification of the
η1,η5-complex was accomplished by precipitation from a
mixture of both complexes. The addition of hexanes to a
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(19) Jutzi, P.; Siemeling, U. Cyclopentadienyl Compounds with
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dienyl, a Ligand with a Tailored Fit for Chelate Complexes. Chem. Ber.
1996, 129, 459–464.
(22) Krut’ko, D.; Borzov, M.; Liao, L.; Nie, W.; Churakov, A.;
Howard, J.; Lemenovskii, D. 1-Methylimidazol-2-yl-Functionalized
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Note
Organometallics, Vol. 29, No. 16, 2010 3671
methylene chloride solution resulted in the selective precipi-
tation of the η1,η5-complex, suggesting that the surface
polarity was increased, rather than decreased as expected.
It appears that the loss of a polar CO ligand was more than
compensated for by the introduction of formal charge on the
pyridyl nitrogen.
136.65, 144.82, 148.99, 163.22. EI-MS: m/z264.0 (Mþ). Anal. Calcd
for C13H13NO3S: 264.068748. Found: HREI-MS 264.069052.
2-Cyclopenta-1,4-dienylmethylpyridine (3). To a solution of
2.0 M sodium cyclopentadienide (150 mL, 300 mmol) was added
a solution of 2-pyridylmethyl toluene-4-sulfonate (2) (4.090 g,
15.53 mmol) at 0 °C in tetrahydrofuran (100 mL). Stirring was
continued for 90 min. The solution was then quenched with
5 mL of 6 N HCl, neutralized with NaHCO3, and filtered
through Celite. The solvent was removed, and the residue was
redissolved in ethyl acetate. The organic phase was washed with
saturated NaCl, filtered through Celite, and dried over Na2SO4.
Solvent was removed to provide a brown oil, which was was
purified to a mixture of isomers by column chromatography
over triethylamine-treated silica gel, eluted with 50% ethyl
acetate/hexanes (brown oil, 1.435 g, 59%). 1H NMR (CDCl3):
δ 8.52 (m, 0.99H), 7.56 (m, 1.07H), 7.14 (m, 1.07H), 7.09 (m,
1.08H), 6.41 (m, 1.75H), 6.24 (m, 1H), 6.07 (m, 0.63H), 3.90 (m,
2.2H), 2.97 (m, 1.31H), 2.89 (m, 1.18H). 13C NMR (100 MHz,
CDCl3): δ 38.98, 39.90, 41.28, 43.15, 121.07, 122.86, 122.90,
128.19, 128.57, 131.69, 132.25, 134.07, 134.27, 136.33, 136.39,
144.06, 146.31, 149.17, 149.21, 160.14, 160.60. EI-MS: m/z 157.1
(Mþ). Anal. Calcd for C11H11N: 156.081324. Found: HREI-MS
156.081071.
Conclusion
We present here the synthesis of an η1,η5-cyclopentadi-
enide rhenium complex with an aromatic amine side chain
chelated to the metal center. Polarity increased slightly due to
chelation by the aromatic amine, a change that may be
beneficial for some imaging applications. The selective
synthesis of monosubstituted Cp rings for use as tethered
imaging agents may be challenging; thus, the use of an
appropriately substituted alkylpyridyl methanol would
allow for introduction of a tether. Chelation could then be
used, or not, depending on the requirements to adjust the
polarity or steric contour of the system.
η5-Cyclopentadienylmethylpyridinylrhenium Tricarbonyl (4).
To a solution of cyclopentadienylmethylpyridine (3) (0.222 g,
1.41 mmol) at -78 °C in tetrahydrofuran (10 mL) was added
2.0 M n-BuLi (1.4 mL, 2.8 mmol). The solution was stirred for
5 min. A solution of [ReBr(THF)(CO)3]2 (0.603 g 0.71 mmol)
in tetrahydrofuran (10 mL) was cannulated into the solution
and stirring continued for 20 min, followed by quenching with
3 mL of methanol and 2 mL of 1 N HCl. The aqueous phase was
extracted with methylene chloride. The organic extracts were
washed with saturated NaCl and dried over Na2SO4. Solvent
was removed to provide a brown oil, which was purified by
column chromatography over triethylamine-treated silica gel,
eluted with 50% ethyl acetate/hexanes (brown oil, 0.171 g, 28%).
1H NMR (CDCl3): δ 8.53 (dd, 1H, J = 4.88, 0.90), 7.63 (ddd, 1H,
J = 7.81, 7.57, 1.79), 7.18 (d, 1H, J = 7.81), 7.15 (dd, 1H, J =
7.57, 0.98), 5.37 (t, 2H, J = 2.20), 5.21 (t, 2H, J = 2.20), 3.82 (s,
3H). 13C NMR (100 MHz, CDCl3): δ 36.77, 83.47, 84.73, 107.18,
121.90, 122.75, 136.85, 149.31, 158.97, 194.19. CI-MS: m/z 428.0
(Mþ þ 1). Anal. Calcd for C14H11NO3Re: 428.029658. Found:
HRCI-MS 428.02965.
Experimental Section
General Comments. Synthetic operations were carried out
under an atmosphere of nitrogen or argon, using standard
Schlenk techniques, and flame-dried glassware was used. All
reagents are commercially available from Aldrich, Strem, or
Fisher and were used without further purification, unless other-
wise stated. Solvents were purified using a solvent dispensing
system fabricated by J. C. Meyer, based on a design published by
Pangborn et al.24
Reaction progress was monitored using analytical thin-layer
chromatography (TLC) on silica gel 60 F254 plastic plates from
EM Science. Visualization was achieved by either using UV light
(254 nm) or phosphomolybdic acid indicator. Purification was
done either by recrystallization or by flash column chromato-
graphy using Woelm silica gel (0.040-0.063 mm).25
1H and 13C NMR spectra were recorded on a U400 or U500
Varian FT-NMR spectrometer. Chemical shifts (δ) are reported
in parts per million downfield from tetramethylsilane or by
reference to the proton resonance of incomplete deuteration of
NMR solvent. Both high- and low-resolution electron impact
(EI) and chemical ionization (CI) mass spectra were obtained on
a VG Instruments 70-VSE spectrometer.
η1,η5-Pyridylmethylcyclopentadienylrhenium Dicarbonyl
(PyCp(CO)2). A solution of cyclopentadienylrhenium (4) (0.171 g
0.40 mmol) in dry tetrahydrofuran (10 mL) in a quartz Schlenk
tube under a nitrogen atmosphere was irradiated in a Rayonet
apparatus under a nitrogen atmosphere with 300 nm low-
pressure Hg lamps for 90 min. Solvent was removed to provide
a red-brown solid, which was purified by precipitation from
methylene chloride using hexanes (red solid, 0.068 g, 42%). 1H
NMR (CDCl3): δ 8.94 (dd, 1H, J = 4.89, 1.52), 7.39 (ddd, 1H,
J = 7.81, 7.57, 1.54), 6.80 (dd, 1H, J = 5.13, 0.73), 6.78 (dd, 1H,
J = 4.88, 0.73), 5.47 (t, 2H, J = 2.08), 5.07 (t, 2H, J = 2.08), 3.75
(s, 3H). 13C NMR (100 MHz, CDCl3): δ 35.75, 77.19, 80.20,
122.89, 123.45, 134.78, 159.68, 176.23, 204.69. FAB-MS: m/z
399.1 (Mþ). Anal. Calcd for C13H10NO2Re: 397.02415. Found:
HRFAB-MS 397.0240.
2-Pyridylmethyl Toluene-4-sulfonate (2). To a stirred suspen-
sion of crushed KOH (4.702 g, 83.37 mmol) in dry tetrahydro-
furan (100 mL) were added 10 drops of deionized water and
2-pyridylcarbinol (1) (1.725, 15.81 mmol). Stirring was contin-
ued for 18 h at RT. The white solid was filtered and washed with
diethyl ether, and the mother liquor was dried over Na2SO4.
Solvent was removed to provide a red oil (4.128 g, 99%). The
1
product was taken on without need for further purification. H
NMR (CDCl3): δ 8.41 (ddd, 1H, J = 4.88, 4.39, 0.98), 7.73
(AA0XX0, 2H, J = 8.30), 7.58 (dd, 1H J = 7.81, 7.69), 7.29 (d,
1H, J = 7.81), 7.24 (AA0XX0, 2H, J = 8.55), 7.12 (ddd, 1H, J =
7.69, 4.80, 0.49), 5.05 (s, 2H), 2.32 (s, 3H). 13C NMR (100 MHz,
CDCl3): δ 21.28, 71.54, 121.69, 123.10, 127.67, 129.64, 132.33,
Acknowledgment. We thank the United States Army
Medical Research and Materiel Command Breast Cancer
Research Program DAMD-17-03-1-0681 and the Na-
tional Institutes of Health PHS 5R01 CA025836 for
funding.
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Timmers, F. J. Safe and Convenient Procedure for Solvent Purification.
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Technique for Preparative Separations with Moderate Resolution.
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