Boronic acids in the three-component synthesis of carbon-substituted cyclopentadienyl tricarbonyl rhenium complexes [9]

Full text of DOI:10.1021/ja982146s

13264
J. Am. Chem. Soc. 1998, 120, 13264-13265
Scheme 1
Boronic Acids in the Three-Component Synthesis of
Carbon-Substituted Cyclopentadienyl Tricarbonyl
Rhenium Complexes
Filippo Minutolo and John A. Katzenellenbogen*
Department of Chemistry, UniVersity of Illinois
600 South Mathews AVenue, Urbana, Illinois 61801
ReceiVed June 22, 1998
The use of η5-cyclopentadienyl-tricarbonyl rhenium and tech-
netium complexes in radiolabeling biologically interesting mol-
ecules is still rather underdeveloped, despite the excellent
structural and chemical properties of such complexes.1 The main
reason for this is that the synthesis of these kinds of complexes
is rather difficult and generally requires rather harsh conditions1a,b
or laborious procedures.1c We recently reported2 a new “three-
component” synthesis that provides a convenient way for prepar-
ing halo-, carbonyloxy-, and hydroxy-substituted CpRe(CO)3
complexes by a one-pot reaction of diazocyclopentadiene (C5H4N2),3
a rhenium(I) tricarbonyl species (2, Scheme 1)4 and a nucleophile
(halide or carboxylate anions) (Scheme 1, eq a). The rapidity and
simplicity of this reaction made it a promising method for labeling
biologically interesting compounds with Re-186, Re-188, and Tc-
99m radionuclides.5 However, so far the functionality linking the
organic portion and the metal complex has been limited to an
ester group (Scheme 1, eq a), which in some cases might undergo
a hydrolytic cleavage when used in ViVo. A carbon-carbon bond
would provide a more secure connection between the radioactive
metal portion and the organic molecule. To prepare such a
carbon-carbon linkage, a palladium-catalyzed cross-coupling
reaction might be utilized to connect a previously prepared halo-
CpRe(CO)3 complex2 with an organometallic species.6 This
approach, however, involves long reaction times and often requires
additional protection/deprotection steps of sensitive functional
groups present on the organic moiety and, thus, is not suitable
for short-lived radionuclides such as Tc-99m (6 h half-life).1c
Intrigued by the possibility of using a carbon nucleophile
instead of a halide or a carboxylate in the three-component
reaction,2 we started to investigate the use of several organome-
tallic reagents with the aim of directly obtaining a carbon-linked
CpRe(CO)3 complex in one-pot. We were particularly interested
in boronic acids, which have already been successfully employed
in Pd-catalyzed cross-coupling reactions.7 Moreover, in recent
years these organometallic species have attracted a great deal of
attention, since they are nonflammable, stable to water and air,
and easy to handle. We were pleased to find that, as shown in
Scheme 1 and Table 1, boronic acids proved to be ideal “masked-
carbanion” nucleophiles under our reaction conditions.
In general, the reaction of C5H4N2 and the rhenium(I) tricar-
bonyl species with the boronic acids 3a-e (Scheme 1, eq b, and
Table 1) turned out to be slower than with the carboxylates.2 In
fact, using the same amount of nucleophile (2 equiv), longer times
(14 h) were required to obtain acceptable yields (42-76%) of
the complex (conditions B, Table 1). However, we found that
with a 5-fold increase of the concentration of nucleophile
(conditions A), satisfactory yields could be obtained within short
reaction times (45 min), which are essential in radiolabeling. Both
aryl- and vinyl-substituted boronic acids showed a good reactiv-
ity,10 and the effect of a para-substituents on the aromatic ring
of several phenylboronic acids (3a-d) was also determined.
The influence of different substitution patterns on the reactivity
of boronic acids 3a-d can be qualitatively established looking
both at the yields obtained within short reaction times (conditions
A) and at the results obtained in a competition experiment reported
below. As shown in Table 1 (conditions A), the reactivity of the
phenylboronic acids is lowered by electron-withdrawing para-
substituents, such as an acetyl (3b, entry 2, Table 1) or a bromo
group (3c, entry 3), compared to the unsubstituted phenylboronic
acid (3a, entry 1), whereas it is significantly increased by an
electron-donating group, like a para-methoxy group (3d, entry
4). This order of reactivity (3d > 3a > 3c > 3b) was also
confirmed by a competition experiment in which equimolar
amounts of boronic acid 3a-d (10 equiv each) were allowed to
react with C5H4N2 (1.5 eq) and the rhenium precursor 2 (1.0 equiv)
at 80 °C for 15 min. NMR analysis of the crude reaction mixture
showed the following product ratios, normalized to 1.0 for the
unsubstituted phenylboronic acid 4a: 1.4 (4d), 1.0 (4a), 0.8 (4c),
0.3 (4b). The increased reactivity of electron-rich aryl boronic
acids in this reaction is just the opposite to what had previously
been observed in the Suzuki Pd-catalyzed cross-coupling reaction
with the same class of boronic acids.11 These observations indicate
(1) (a) Wenzel, M. J. Labelled Compd. Radiopharm. 1992, 31, 641-650.
(b) Spradau, T. W.; Katzenellenbogen, J. A. Organometallics 1998, 17, 2009-
2017. (c) Top, S.; El Hafa, H.; Vessie`res, A.; Quivy, J.; Vaissermann, J.;
Hughes, D. W.; McGlinchey, M. J.; Mornon, J.-P.; Thoreau, E.; Jaouen, G.
J. Am. Chem. Soc. 1995, 117, 8372-8380.
(2) Minutolo, F.; Katzenellenbogen, J. A. J. Am. Chem. Soc. 1998, 120,
4514-4515.
(3) (a) Herrmann, W. A. Chem. Ber. 1978, 111, 2458-2460. (b) Reimer,
J. K.; Shaver, A. J. Organomet. Chem. 1975, 93, 239-252.
(4) (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. (c) Alberto, R.; Egli, A.; Abram, U.; Hegetschweiler, K.; Gramlich,
V.; Schubiger, P. A. J. Chem. Soc., Dalton Trans. 1994, 2815-2820.
(5) Studies using “cold” (nonradioactive) rhenium isotopes can be consid-
ered as models for reactions with γ-emitter technetium-99m, due to a high
similarity in the chemical behavior of these two metals. 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 161-242.
(8) Typical experimental procedure: Compound 1 (39 mg, 0.050 mmol)
was dissolved in anhydrous CH3CN (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 C5H4N2 (0.060 mmol), the boronic acid (3a-
e, see Table 1), and triethylamine (see Table 1) in CH3CN (1 mL). The mixture
was heated at 80 °C for the time indicated in Table 1 and then concentrated
under vacuum. The crude reaction product was purified by flash chromatog-
raphy. Characterization data and purification conditions of compounds 4a-e
are given in the Supporting Information.
(9) (a) Matteson, D. S.; Jesthi, P. K. J. Organomet. Chem. 1976, 110, 25-
37. (b) In our experiments, compound 3e was synthesized according to a
general procedure reported in: Brown, H. C.; Gupta, S. K. J. Am. Chem.
Soc. 1975, 97, 5249-5255.
(6) (a) Lo Sterzo, C.; Miller, M. M.; Stille, J. K. Organometallics 1989, 8,
2331-2337. (b) Lo Sterzo, C.; Stille, J. K. Organometallics 1990, 9, 687-
694.
(10) Alkyl-boronic acids, such as n-butyl- and n-decyl-boronic acids,
showed poor reactivities under our reaction conditions (10 and 14% yields,
respectively).
(7) Miyaura, N.; Suzuki, A. Chem. ReV. 1995, 95, 2457-2483 and
references therein.
(11) Moriya, T.; Miyaura, N.; Suzuki, A. Synlett 1994, 149-151.
10.1021/ja982146s CCC: $15.00 © 1998 American Chemical Society
Published on Web 12/04/1998

Communications to the Editor
J. Am. Chem. Soc., Vol. 120, No. 50, 1998 13265
decided to try this reaction on compound 5 (Scheme 2),13 an
estradiol derivative containing a vinylboronic acid group in the
17R position.
Table 1. Isolated Yields Attained in the Three-Component
Reaction of Several Boronic Acids (3a-e, Scheme 1)8
isolated yield (%)a
The rhenium precursor 2, prepared as shown in Scheme 1,4
reacted in one pot with boronic acid 5 (5 equiv), Et3N (10 equiv)
and C5H4N2 (3 equiv) in refluxing acetonitrile/acetone 1:1 mixture.
After 45 min, complex 6 was obtained in 50% isolated yield
following flash chromatography. In this case, the cosolvent
(acetone) was needed because compound 5 was only partially
soluble in pure acetonitrile.14 A classical organometallic approach
to 6 would have required protection/deprotection steps of the two
OH groups. However, such additional steps turned out to be
unnecessary in the reaction herein reported. An important side
reaction, the protodeboronation of the excess of 5, did occur,
producing considerable amounts of 17R-vinylestradiol. Neverthe-
less, complex 6 could be efficiently purified by chromatography.14
In conclusion, the results presented in this report illustrate a
marked extension of the three-component reaction toward the
preparation of carbon-substituted CpRe(CO)3 complexes, using
a very accessible class of organometallic reagents, the boronic
acids. The method herein reported is unique since it produces in
one pot a carbon-carbon bond between a nucleophile and the
Cp ring, in addition to the Cp-rhenium bond formation, without
the need for any catalyst. Mild conditions, short times, and good
yields suggest that this reaction should have great potential in
the radiolabeling of biologically interesting molecules.
boronic
acid
conditions conditions
entry
R
product
Ab
Bc
1
2
3
4
5
3a
3b
3c
phenyl
4a
4b
4c
4d
4e
64
34
39
74
51
59
52
50
42
76
4-acetylphenyl
4-bromophenyl
4-methoxyphenyl
1-nonenyl
3d
3e9
a Yields are based on compound 1. b Conditions A: 10 equiv of
boronic acid (3a-e) and 20 equiv of Et3N, with respect to the rhenium
precursor 1 (Scheme 1), and 45 min reaction time. c Conditions B: 2
equiv of boronic acid, 4 equiv of Et3N, and 14 h reaction time.
Scheme 2
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 the
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
96-10502). Mass spectra were obtained on instruments supported by grants
from the National Institute of General Medical Sciences (GM 27029),
the National Institutes of Health (RR 01575), and the National Science
Foundation (PCM 8121494).
that a higher nucleophilicity of the organometallic precursor is
likely responsible for a faster reaction. Moreover, the use of a
palladium species such as Pd(PPh3)4, which is indispensable in
the Suzuki coupling of boronic acids,7 has no effect whatsoever
in our reaction. To our knowledge, this is the first example of an
uncatalyzed carbon-carbon bond formation reaction involving
boronic acids as precursors. We also found that a cyclic boronic
ester, namely, 2-phenyl-1,3,2-dioxaborinane, which reacts readily
under Suzuki conditions, is completely unreactive in our reaction,
showing that the presence of a free boronic acid is essential for
the three-component reaction to occur.12
Supporting Information Available: Purification conditions and
characterization data of compounds 4a-e and 6 (6 pages, print/PDF).
See any current masthead page for ordering information and Web access
instructions.
As already observed in our previously reported reaction of
carboxylates,2 several functional groups are tolerated. The keto
group in 3b (entry 2) is not affected, and more importantly, the
aryl-bromo functionality in 3c (entry 3), which would be reactive
in a Pd-catalyzed reaction, is completely inert. Alcohol and
phenolic hydroxyl groups are also tolerated, as shown by the
example reported below in Scheme 2.
JA982146S
(13) Nakatsuka, I.; Ferreira, N. L.; Eckelman, W. C.; Francis, B. E.;
Rzeszotarski, W. J.; Gibson, R. E.; Jagoda, E. M.; Reba, R. C. J. Med. Chem.
1984, 27, 1287-1291.
(14) When the reaction is run in pure acetonitrile under the same conditions,
the isolated yield of complex 6 is much lower (27%). Use of cosolvents other
than acetone either gave lower yield (36% yield with 2-butanone) or completely
inhibited the reaction (∼0% yield with methanol). Experimental procedure:
Compound 1 (39 mg, 0.050 mmol) was dissolved in anhydrous CH3CN (2
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 boronic acid
5 (0.25 mmol) and triethylamine (0.50 mmol) in acetone (2 mL). The resulting
mixture was treated with C5H4N2 (0.15 mmol), heated to reflux for 45 min,
and then concentrated under vacuum. The crude reaction product was purified
by flash chromatography (Hex/EtOAc/AcOH 75:25:0.2). See Supporting
Information for characterization data on compound 6.
Encouraged by these results, especially by the excellent
reactivity of the vinylboronic acid 3e9 (entry 5, Table 1), we
(12) Some preliminary investigations on the reaction mechanism indicate
that both carboxylic acids (ref 2) and boronic acids (present paper) react
through an initial association between the rhenium precursor 2 (Scheme 1)
and the nucleophile. More extensive studies aimed at clarifying the reaction
mechanism are currently under investigation in our laboratories.