One-pot formation of substituted cyclopentadienyl and indenyltricarbonyl rhenium complexes through in situ generation of cyclopentadienyl- and indenyltributylstannanes

Full text of DOI:10.1021/ja005585b

J. Am. Chem. Soc. 2001, 123, 4093-4094
4093
Scheme 1. Comparison of Reactivity of Rhenium Sources
One-Pot Formation of Substituted Cyclopentadienyl
and Indenyltricarbonyl Rhenium Complexes through
in Situ Generation of Cyclopentadienyl- and
Indenyltributylstannanes
a solution of 1 in MeCN was treated with a THF solution of
CpTBT at room temperature, formation of CpRe(CO)3 was
complete within 5 min, and this material could be obtained in 80%
yield, after isolation and chromatography (Scheme 1). The
corresponding reaction with BrRe(CO)5 required 6 h at reflux in
THF to achieve a similar yield. It should be noted that under
analogous conditions, neither of the other Cp donors, nickelocene
nor trimethylsilyl-cyclopentadiene, produced any significant
amount of CpRe(CO)3.
With this promising result in hand, we attempted to prepare a
variety of substituted cyclopentadienyl- and indenyltributyltin
compounds. Unfortunately, we were unable to isolate most of
these compounds, because of the facility with which they under-
went protonolysis (destannylation). To circumvent this hydrolysis
problem, we chose not to isolate the tributyltin species, but rather
to generate them in situ, and use them directly in the reaction
with the addition of the metal precursor 1.
Recently, tin-amines have been used in palladium-catalyzed
amination reactions of aryl halides.8 However, the tin-amines have
long been known for their ability to react with protic solvents,
such as alcohols, thiols, and other amines, to form the corre-
sponding tin-alkoxides, sulfides, or amines under mild conditions.9
They also are known to react with the relatively acidic protons
of cyclopentadiene and indene to form the corresponding enyl-
tin species.6b,10
Our initial attempt to utilize the tin-amines was in the prepa-
ration of unsubstituted CpRe(CO)3. When we treated a THF
solution of freshly cracked cyclopentadiene with diethylamino-
tributyltin at room temperature for 2 h, added this mixture to a
solution of 1 in a minimal amount of MeCN, and refluxed the
resulting solution, we indeed saw formation of CpRe(CO)3 by
TLC analysis. After 1 h, CpRe(CO)3 was isolated, as above, in
81% yield.
Richard R. Cesati III and John A. Katzenellenbogen*
Department of Chemistry
UniVersity of Illinois at Urbana-Champaign
Urbana, Illinois 61801
ReceiVed September 6, 2000
The extensive use of metallic radionuclides in nuclear medicine
is dominated by technetium-99m (γ, t1/2 ) 6 h), and radiophar-
maceuticals labeled with this isotope are used in approximately
80% of all diagnostic imaging procedures.1 For tumor radiothera-
peutic purposes, rhenium-186 (â, t1/2 ) 91 h) and rhenium-188
(â, t1/2 ) 17 h) have shown great promise.2 Recently, a large
number of publications have appeared describing the synthesis
of low-valent technetium and rhenium (i.e., M(CO)3+) and their
use for the preparation of new radiopharmaceuticals.3 Our own
interest has been focused on the development of novel methods
for the generation of stable substituted η5-cyclopentadienyltri-
carbonyl rhenium and technetium (CpRe(CO)3 and CpTc(CO)3)
complexes for radiolabeling biologically interesting molecules,
especially small molecule ligands for receptors.4 However, until
recently, the preparation of these organometallic species has
required harsh conditions and multistep procedures.5 Herein we
describe the utility of trialkyltin-substituted cyclopentadienes in
the efficient synthesis of substituted CpRe(CO)3 complexes.
Reactions of trialkylstannylcyclopentadienes with Group VII
pentacarbonyl halides [MX(CO)5] for the preparation of unsub-
stituted CpRe(CO)3 complexes have been reported.6 Most reac-
tions utilized the trimethyltin derivative and were complete within
3-7 h, with manganese, as expected, exhibiting a higher rate of
reaction than rhenium. However, for this chemistry to be useful
for radiolabeling receptor ligands, we needed to be able to include
additional functionality in the cyclopentadienyl ring.
To extend this reaction to other ring systems, we attempted to
carry out the analogous reaction using indene rather than
cyclopentadiene. In this experiment, a THF solution of indene
was treated with diethylamino-tributyltin at reflux for 1 h. TLC
showed complete consumption of the indene starting material and
formation of a new, higher Rf, compound. However, upon addition
of the MeCN solution of 1 at room temperature, TLC analysis
showed the rapid reappearance of free indene, with no detectable
formation of the desired indenyltricarbonyl rhenium (InTR)
complex. It is unlikely that adventitious water can account for
this complete protonolysis. Rather, because the pKa values of
indene and the solvent MeCN are comparable, it is more likely
that the indene anion is being protonated by this solvent, although
it is not clear why this same protonation would not happen with
the more basic Cp-tin species. In any case, we developed as an
alternative a strictly aprotic system in THF solvent.
Our initial studies focused on the reaction of tributylstannyl-
cyclopentadiene (CpTBT) with (Et4N)2[ReBr3(CO)3] (1)3a as the
source of Re(CO)3+, an approach analogous to that which we
used in a related three-component condensation.7 Because the
metal precursor 1 is insoluble in THF, it was dissolved in
acetonitrile (MeCN). CpTBT, being insoluble in MeCN, was
dissolved in THF, which was used as reaction cosolvent. When
(1) Schwochau, K. Angew. Chem., Int. Ed. Engl. 1994, 33, 2258.
(2) (a) John, E.; Thakur, M. L.; DeFulvio, J.; McDevitt, M. R.; Damjanov,
I. J. Nucl. Med. 1993, 34, 260. (b) Lisic, E. C.; Mirzadeh, S.; Knapp, F. F.,
Jr. J. Labelled Compd. Radiopharm. 1993, 33, 65.
(3) (a) Alberto, R.; Egli, A.; Abram, U.; Hegetschweiler, K.; Gramlich J.
Chem. Soc., Dalton Trans. 1994, 2815. (b) Alberto, R.; Schibli, R.; Egli, A.;
Schubiger, A. P.; Abram, U. J. Am. Chem. Soc. 1998, 120, 7987. (c) 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. (d) Le Bideau, F.;
Kaloum, E. B.; Haquette, P.; Kernbach, U.; Marrot, J.; Stephan, E. Chem.
Commun. 2000, 211. (e) Salmain, M.; Gunn, M.; Gorfti, A.; Top, S.; Jaouen,
G. Bioconj. Chem. 1993, 4, 425. (f) Top, S.; Lehn, J. S.; Morel, P.; Jaouen,
G. J. Organomet. Chem. 1999, 583, 63.
(4) Preliminary accounts of related work: Cesati, R. R., III; Tamagnan,
G.; Baldwin, R. M.; Zoghbi, S. S.; Innis, R. B.; Katzenellenbogen, J. A. J.
Labelled Compd. Radiopharm. 1999, 42, S1, 150-152
(5) Spradau, T. S.; Katzenellenbogen, J. A. Organometallics, 1998, 17,
2009.
(6) The following citations contain several examples of reactions involving
silyl-substituted compounds as well as one example of a methyl-substituted
compound. (a) Abel, E. W.; Moorhouse, S. J. Organomet. Chem. 1971, 28,
211. (b) Abel, E. W.; Moorhouse, S. J. Chem. Soc., Dalton Trans. 1973, 1706.
(7) (a) Minutolo, F.; Katzenellenbogen, J. A. J. Am. Chem. Soc. 1998, 120,
4514. (b) Minutolo, F.; Katzenellenbogen, J. A. J. Am. Chem. Soc. 1998, 120,
13264. (c) Minutolo, F.; Katzenellenbogen, J. A. Organometallics 1998, 18,
13, 2519.
(8) (a) Buchwald, S. L.; Guram, A., Process and catalysts for the preparation
of arylamines. U.S. Patent 5576460, 19961119, 1996. (b) Guram, A. S.;
Buchwald, S. L. J. Am. Chem. Soc. 1994, 116, 7901. (c) Hartwig, J. F.;
Richards, S.; Baranano, D.; Paul, F. J. Am. Chem. Soc. 1996, 118, 3626. (d)
Louie, J.; Hartwig, J. F. J. Am. Chem. Soc. 1995, 117, 11598. (e) Louie, J.;
Paul, F.; Hartwig, J. F. Organometallics 1996, 15, 2794. (f) Paul, F.; Patt, J.;
Hartwig, J. F. J. Am. Chem. Soc. 1994, 116, 5969. (g) Yamamoto, T.;
Nishiyama, S.; Koie, Y., Preparation of N-arylamines. Japanese Patent
11100355, 19990413, 1999.
(9) (a) Anderson, J. W.; Barker, G. K.; Drake, J. E.; Rodger, M. In J. Chem.
Soc., Dalton Trans. 1973, 1716. (b) George, T. A.; Lappert, M. F. J. Chem.
Soc. A 1969, 992. (c) Haenssgen, D.; Roelle, W. J. Organomet. Chem. 1974,
71, 231. (d) Matsuda, I.; Itoh, K.; Ishii, Y. J. Organomet. Chem. 1974, 69,
353. (e) Roubineau, A.; Pommier, J. C. J. Organomet. Chem. 1976, 107, 63.
(10) Abel, E. W.; Moorhouse, S. J. Organomet. Chem. 1971, 29, 227.
10.1021/ja005585b CCC: $20.00 © 2001 American Chemical Society
Published on Web 04/04/2001

4094 J. Am. Chem. Soc., Vol. 123, No. 17, 2001
Communications to the Editor
Table 1. Structures and Isolated Yields in the Reaction of 3 with
Various Cyclopentadienes and Indenes
Scheme 2. Studies on in Situ Generation of Enyl-Stannanes
A simple form of the metal precursor that is soluble in THF is
[(THF)BrRe(CO)3]2 (3), which is a halide-bridged dimer in the
solid state that becomes a monomer [(THF)2BrRe(CO)3] in THF
solution.11 It should be noted that the related technetium complex,
[
[
99mTc](THF)2ClTc(CO)3, can be produced by the reduction of
99mTc]NH4TcO4 by BH3‚THF in the presence of a chloride source,
according to the methods developed by Alberto.3b Our hope was
that precursor 3 would offer similar reactivity in THF as did
precursor 1 in MeCN.
For this study, we attempted to generate the CpTBT in the
+
presence of the Re(CO)3 source, as this would simplify the in
During this transmetalation, attack of halide at tin can occur in
an inter- or intramolecular fashion, but the exact nature of this
transition state is unknown. Based on literature precedent,6b it is
likely that the reaction occurs through initial olefin coordination
to form an η2-intermediate, then directly to a η3-intermediate, and
finally to the η5-product.
situ, two-step procedure used above. We were pleased to find
that treatment of a solution of the metal precursor 3 and
cyclopentadiene in THF with diethylamino-tributyltin at reflux
for 2 h afforded CpRe(CO)3 in 28% yield. More importantly, when
we performed the analogous procedure with indene, we success-
fully isolated InTR, although in a relatively modest 30% yield
(Scheme 2). To our knowledge, this result represents the first
one-pot synthesis of CpRe(CO)3 and InTR, using an in situ
generated enyl-stannane.
Several aspects of this reaction deserve comment. First and
foremost is that CpRe(CO)3 was not formed under the reaction
conditions in the absence of the tin reagent. It is also of note that
the yields of both reactions improved somewhat with extended
reaction times, although the yields were lower than expected when
compared to the results obtained from metal precursor 1 in MeCN.
We believe that the different reaction temperatures used in the
two cases are not as important as the greater polarity and ionizing
potential of MeCN compared to THF. These factors may become
more apparent in future mechanistic studies.
To demonstrate the utility of this reaction, we wished to extend
it to more complex substrates. Our results are summarized in Table
1. When the substituted cyclopentadiene 4a is subjected to the
reaction conditions described above, the corresponding p-meth-
oxyphenyl-substituted CpRe(CO)3 (4b)4b was formed in 65%
yield: In three separate trials, the yields of this compound
consistently averaged 65%. Similarly, the phenyl-tropane 5a gave
the highly functionalized alkyl-substituted CpRe(CO)3 5b in 26%
yield. Although the reaction worked with these substrates, it did
not work with several others (e.g., other diarylindenes). Efforts
to make more complex rhenium tricarbonyl complexes, specifi-
cally those with estrogenic cores, are currently underway in our
laboratories.12
In summary, the reaction herein reported has proved to be
a mild and efficient method for the preparation of substituted
CpRe(CO)3 complexes.13 The reaction is quite complementary
to other protocols developed in our laboratories. It is not limited
by the need for an electron-withdrawing substituent as in the
double ligand transfer reaction, and it does not require the isolation
of a reactive cyclopentadienyl source as in the three-component
condensation. The reaction can be extended to the use of indenyl
ring systems and shows tolerance of a variety of functional groups.
The main limitation of the reaction is the yield, which is modest,
when the reaction times need to be kept short to achieve efficient
radiochemical synthesis with a short-lived radionuclide (e.g., the
Tc-99m half-life is 6 h). The solvent MeCN gives the best yields
of CpRe(CO)3, although this solvent proved to be incompatible
with the indenyl ring system. In THF, the reaction can be carried
out in a single pot, and in this solvent it can be extended to more
complex systems. We feel that the reaction should provide a
powerful extension of the recent work by Jaouen, who has shown
that substituted cyclopentadienes can be produced cleanly by
irradiation of cyclopentadienyltricarbonyl manganese complexes.14
Acknowledgment. Supported through grants from the U.S. Army
(DAMD17-97-1-7292), NIH (PHS 5 T32 CA09067), and DOE (DE FG02
86ER60401 and 98ER82653). We are grateful to Dr. Gilles Tamagnan
for advice and the preparation of tropane precursors.
Supporting Information Available: Complete experimental proce-
dures and spectral data for compounds 4a, 4b, 5a, and 5b (PDF). This
material is available free of charge via the Internet at http://pubs.acs.org.
The mechanism of this reaction is not known; however, the
transmetalation to rhenium appears to be the rate-limiting step.
JA005585B
(11) Vitali, D.; Calderazzo, F. Gazz. Chim. Ital. 1972, 102, 587.
(12) (a) Anstead, G. M.; Altenbach, R. J.; Wilson, S. R.; Katzenellenbogen,
J. A. J. Med. Chem. 1988, 31, 1316. (b) Anstead, G. M.; Wilson, S. R.;
Katzenellenbogen, J. A. J. Med. Chem. 1989, 32, 2163. (c) Fink, B. E.;
Mortensen, D. S.; Stauffer, S. R.; Aron, Z. D.; Katzenellenbogen, J. A. Chem.
Biol. 1999, 6, 205.
(13) Polymer-supported tin reagents are currently utilized in radio-
chemical preparations; cf.: Hunter, D. H.; et al. Organometallics 1999, 18,
5577. Hunter, D. H.; et al. J. Labelled Compd. Radiopharm. 1999, 42, 653.
(14) Top, S.; Kaloun, E. B.; Jaouen, G. J. Am. Chem. Soc. 2000, 122, 736.