A convenient three-component synthesis of substituted cyclopentadienyl tricarbonyl rhenium complexes

Full text of DOI:10.1021/ja980433q

4514
J. Am. Chem. Soc. 1998, 120, 4514-4515
Communications to the Editor
A Convenient Three-Component Synthesis of
Substituted Cyclopentadienyl Tricarbonyl Rhenium
Complexes
Scheme 1
Filippo Minutolo and John A. Katzenellenbogen*
Department of Chemistry, UniVersity of Illinois
00 South Mathews AVe., Urbana, Illinois 61801
6
ReceiVed February 9, 1998
Scheme 2
Radiolabeling biologically interesting molecules with 99mTc and
186
188
Re/ Re is a subject of increasing interest because of the
1
99m
medical utility of these short-lived radionuclides.
Tc is the
2
most widely used radionuclide for imaging, while radiopharma-
186
188
ceuticals labeled with Re and Re have provided promising
results in tumor radiotherapy.3 There have been recent efforts
5
devoted to the preparation of η -cyclopentadienyl-tricarbonyl-
3 3
technetium CpTc(CO) and rhenium CpRe(CO)
complexes,4
,5
since they present favorable structural and chemical features (small
size, low polarity, high stability) and are very different from
inorganic complexes of these metals.6,7 However, up until now
the preparation of these organometallic species has been cumber-
some and has required rather harsh conditions.4 As far as physical
and chemical properties are concerned, technetium and rhenium
8
are very similar. Therefore, reactions involving the stable natural
isotopes 1 Re and Re can be reliably studied as models for
85
187
the radioisotopes 186Re/ Re as well as for Tc.
188
99m
Herein, we report a fast and versatile “one pot/three component
assembly” reaction for the efficient synthesis of halo-, carbonyl-
oxy-, and hydroxy-substituted CpRe(CO)
diazocyclopentadiene (CpN ) as the Cp precursor. Insertion
reactions of CpN with pentacarbonyl-rhenium halides [ReX-
CO) ] for the preparation of halogen-substituted CpRe(CO)
3
3
complexes, using
2
2
4 2
We have found that a different rhenium precursor, (Et N) -
(
5
9
[ReBr
pressure carbonylation/reduction of perrhenate, once dissolved
in acetonitrile, reacts much more readily with CpN , giving the
in good yield after only 45
3 3
(CO)
] (1),10 recently synthesized by a convenient low-
complexes have been reported. However, the use of the
11
pentacarbonyl precursor requires long reaction times (12-15 h
2
in refluxing benzene for bromo- and iodo-CpRe(CO)
are poorly suited for radiolabeling.
3
), which
9,12
3
bromo-substituted CpRe(CO) 2
min at 80 °C (Scheme 1). The increased reactivity of this
precursor is likely due to the known property of 1 to exchange
all its three bromide anions with three molecules of a coordinating
solvent like acetonitrile, to give the species 3.10 The dative solvent
molecules are then readily displaced during coordination by a
(1) See, for example: (a) Technetium and Rhenium in Chemistry and
Nuclear Medicine; Nicolini, M., Bandoli, G., Mazzi, U., Eds.; Raven Press:
New York, 1990. (b) Hom, R. K.; Katzenellenbogen, J. A. Nucl. Med. Biol.
1
997, 24, 485-498.
(
2) Schwochau, K. Angew. Chem., Int. Ed. Engl. 1994, 33, 2258-2267.
(3) (a) Lisic, E. C.; Mirzadeh, S.; Knapp, F. F., Jr. J. Labelled Compd.
5
η -cyclopentadienyl (Cp) ligand (Scheme 1).
Radiopharm. 1993, 33, 65-75. (b) John, E.; Thakur, M. L.; DeFulvio, J.;
McDevitt, M. R.; Damjanov, I. J. Nucl. Med. 1993, 34, 260-267.
Although this transformation constitutes an important improve-
9
(4) (a) Spradau, T. W.; Katzenellenbogen, J. A. Organometallics submitted
ment of this precedented insertion reaction, the substituent on
for publication. (b) Wenzel, M. J. Labelled Compd. Radiopharm. 1992, 31,
41-650.
5) Top, S.; El Hafa, H.; Vessi e` res, A.; Quivy, J.; Vaissermann, J.; Hughes,
the final complex so far was only a bromine, or potentially another
halogen if the precursor was a different rhenium trihalide
tricarbonyl species.9 Therefore, we envisaged the possibility of
replacing the bromide anion in the rhenium precursor 1 with a
noncoordinating, nonnucleophilic counterion, such as a triflate
6
(
D. W.; McGlinchey, M. J.; Mornon, J.-P.; Thoreau, E.; Jaouen, G. J. Am.
Chem. Soc. 1995, 117, 7, 8372-8380 and references therein.
(
6) (a) Hom, R. K.; Katzenellenbogen, J. A. J. Org. Chem. 1997, 62, 6290-
6
1
297. (b) Hom, R. K.; Chi, D. Y.; Katzenellenbogen, J. A. J. Org. Chem.
996, 61, 2624-2631. (c) Chi, D. Y.; O’Neil, J. P.; Anderson, C. J.; Welch,
-
(TfO ), by treatment of a solution of 1 in acetonitrile with silver
M. J.; Katzenellenbogen, J. A. J. Med. Chem. 1994, 37, 928-937.
triflate (AgOTf), to give the species 4 (Scheme 2). This allowed
us to study the introduction onto the Cp ring of “external”
nucleophiles (5a-f), not already present in the rhenium precursor,
(
7) The large size and significant dipole moment associated with most
inorganic Re and Tc complexes (generally tetradentate oxo-metal species)
can change the properties of the ligand to which they are attached (or are part
of) very significantly, thereby interfering with receptor binding affinity and
cell membrane permeability. Some of these complexes also have limited
stability under physiological conditions (see ref 6). These inconveniences may
be avoided with cyclopentadienyl tricarbonyl metal systems.
(10) Alberto, R.; Egli, A.; Abram, U.; Hegetschweiler, K.; Gramlich, V.;
Schubiger, P. A. J. Chem. Soc., Dalton Trans. 1994, 2815-2820.
(11) (a) Alberto, R.; Schibli, R.; Schubiger, P. A. Polyhedron 1996, 15,
1079-1089. (b) Alberto, R.; Schibli, R.; Egli, A.; Schubiger, P. A.; Herrmann,
W. A.; Artus, G.; Abram, U.; Kaden, T. A. J. Organomet. Chem. 1995, 492,
217-224.
(
8) See: Boog, N. M.; Kaesz, H. D. Technetium and Rhenium. In
ComprehensiVe Organometallic Chemistry; Wilkinson, G., Stone, G. F. A.,
Abel, E. W., Eds.; Pergamon Press: Oxford, U.K., 1982; Vol. 4, pp 161-
2
42.
(12) Nesmeyanov, A. N.; Kolobova, N. E.; Makarov, Yu. V.; Anisimov,
K. N. IzV. Akad. Nauk SSSR, Ser. Khim. 1969, 2, 1992-1996.
(9) Herrmann, W. A. Chem. Ber. 1978, 111, 2458-2460.
S0002-7863(98)00433-8 CCC: $15.00 © 1998 American Chemical Society
Published on Web 04/23/1998

Communications to the Editor
J. Am. Chem. Soc., Vol. 120, No. 18, 1998 4515
Table 1. Isolated Yield in the Reaction of 1 with CpN
equiv) and Several Nucleophiles (2.0 equiv)
2
(1.2
Scheme 3
1
3
entry
nucleophile
isolated yield (%)b
product
1
2
3
4
5
6
5a
5b
5c
53
62
69
59
72
60
6a
6b
6b
6c
6d
6e
a
as shown by the effective functionalization of the complex with
an N-Boc protected amino acid (L-phenylalanine, entry 6).
Preliminary experiments with thiols and acetylides, however, have
so far not given satisfactory yields of the desired product, although
further attempts are being made in order to extend this reaction
to a wider variety of nucleophiles. Finally, hydrolysis of 6b with
a solution of HCl in dioxane and dry methanol gives 6f in almost
quantitative yields (Scheme 3), expanding the scope of this
5d
a
5e
5f
a
a
b
Ratio carboxylic acid / Et
initial rhenium precursor 1 (Schemes 1 and 2).
3
N ) 1:2. Yields are referred to the
to give differently substituted CpRe(CO)
Scheme 2). The most significant results are reported in Table 1.
3
complexes (6a-e,
reaction to the preparation of hydroxy-substituted CpRe(CO)
complexes.
3
All yields are based on complexes isolated after purification by
flash chromatography.13
In summary, the reaction herein reported represents an efficient
new approach to simultaneously assemble three different units
It is worth noting that the yield range achieved (53-72%) is
quite satisfactory, considering that this reaction simultaneously
assembles three different components. Halide exchange of
bromide with iodide worked well (entry 1), producing the iodo-
(
(
nucleophile, Cp, and Re precursors) to produce substituted CpRe-
CO) complexes in short reaction times and under mild condi-
3
tions. To our knowledge, this method constitutes the first
synthesis of R-COO-CpRe(CO) and HO-CpRe(CO) com-
plexes, as well as an improved synthesis of halo-CpRe(CO)
9
,14,15a
3
3
substituted CpRe(CO)
3
6a,
which had previously been shown
3
to be an excellent substrate in the Stille coupling reaction with
organo-tin reagents.15 Even more interesting was the introduction
complexes. We think that the results herein reported give useful
indications of the possibility of attaching such complexes onto
biologically interesting organic molecules, and thereby to produce
new classes of rhenium- and technetium-labeled radiopharma-
ceuticals.16
of carboxylate substituents onto the Cp ring, because this
constitutes a good method for directly binding the CpRe(CO)
portion to organic molecules. To the best of our knowledge,
carbonyloxy-substituted CpRe(CO) complexes have never been
3
3
prepared before. As shown in Table 1, carboxylate salts proved
to be excellent nucleophiles for this reaction (entry 2 and 4).
Carboxylic acids could also be deprotonated in situ by triethy-
Acknowledgment. We are grateful for support of this research through
grants from the National Institutes of Health (5R01 CA25836) and the
Department of Energy (DE FG02 86ER60401). NMR spectra were
obtained in the Varian Oxford Instrument Center for Excellence in NMR
Laboratory. Funding for this instrumentation was provided in part from
the W. M. Keck Foundation, the National Institutes of Health (PHS 1
S10 RR104444-01), and the National Science Foundation (NSF CHE 96-
3
lamine (Et N), as shown in entries 3, 5, and 6, without affecting
the yields. Both aliphatic and aromatic carboxylic acids proved
to be effective nucleophiles. Moreover, the reaction tolerates the
presence of a free alcoholic (entry 4) or phenolic (entry 5)
hydroxyl group, which does not compete with the carboxylate
for nucleophilic substitution onto the Cp ring. Primary amine
groups inhibit the reaction, but amide NH bonds are well-tolerated,
10502). Mass spectra were obtained on instruments supported by grants
from the National Institute of General Medical Sciences (GM 27029),
the National Institutes of Heath (RR 01575), and the National Science
Foundation (PCM 8121494).
(
13) Typical experimental procedure: 39 mg (0.050 mmol) of 1 were
dissolved in anhydrous CH CN (1.5 mL) and treated with 40 mg (0.15 mmol)
of AgOTf. AgBr was removed by filtration, and the supernatant was added
to a solution containing CpN (0.060 mmol) and the nucleophile (0.10 mmol)
in CH CN (1 mL). If free carboxylic acids were used as the nucleophile, 0.20
mmol of triethylamine was also added. The mixture was heated at 80 °C for
Supporting Information Available: Purification conditions and
characterization data of compounds 6b-f (5 pages, print/PDF). See any
current masthead page for ordering information and Web access
instructions.
3
2
3
4
5 min, then concentrated under vacuum. The crude reaction product was
JA980433Q
purified by flash chromatography. Characterization data and purification
conditions of compounds 6b-f are given in the Supporting Information.
(16) We have successfully performed reactions to produce bromocyclo-
9
9g
(
14) Nesmeyanov, A. N.; Kolobova, N. E.; Anisimov, K. N.; Makarov,
pentadienyl tricarbonyl technetium from [ Tc]pertechnetate and chlorocy-
99m
Yu. V. IzV. Akad. Nauk SSSR, Ser. Khim. 1969, 2, 357-359.
clopentadienyl tricarbonyl technetium from [ Tc]pertechnetate; yields
comparable to those with perrhenate were obtained. This demonstrates that
this reaction works well with technetium at both the macroscopic and tracer
level.
(
15) (a) Lo Sterzo, C.; Miller, M. M.; Stille, J. K. Organometallics 1989,
8
6
, 2331-2337. (b) Lo Sterzo, C.; Stille, J. K. Organometallics 1990, 9, 687-
94.