Microwave-assisted synthesis of 3,1,2- and 2,1,8-Re(I) and 99mTc(I)-metallocarborane complexes

Article abstract of DOI:10.1021/ic0605928

Microwave heating was used to prepare η⁵-rhenium carborane complexes in aqueous reaction media. For carboranes bearing sterically demanding substituents, isomerization of the cage from 3,1,2 to 2,1,8 derivatives occurred concomitantly with complexation. Microwave heating was equally effective at the tracer level using technetium-99m, affording access to a new class of synthons for designing novel molecular imaging agents.

Full text of DOI:10.1021/ic0605928

Inorg. Chem. 2006, 45, 5727−5729
Microwave-Assisted Synthesis of 3,1,2- and 2,1,8-Re(I) and
99mTc(I)
Metallocarborane Complexes
−
Andrew E. C. Green, Patrick W. Causey, Anika S. Louie, Andrea F. Armstrong,
Laura E. Harrington, and John F. Valliant*
Departments of Chemistry and Medical Physics & Applied Radiation Sciences,
McMaster UniVersity, 1280 Main Street West, Hamilton, Ontario, Canada L8S 4M1
Received April 7, 2006
Microwave heating was used to prepare
η
5-rhenium carborane
radiation as an alternate heat source was investigated with
some surprising and rather useful consequences.
complexes in aqueous reaction media. For carboranes bearing
sterically demanding substituents, isomerization of the cage from
3,1,2 to 2,1,8 derivatives occurred concomitantly with complexation.
Microwave heating was equally effective at the tracer level using
technetium-99m, affording access to a new class of synthons for
designing novel molecular imaging agents.
As an initial experiment, the carboxylic acid-functionalized
nido-ortho-carborane 12,4d (Scheme 1) was heated in a
microwave reactor with an excess of [Re(CO)3(H2O)3]Br3
in 0.1 M KF(aq) (Scheme 1) and the progress of the reaction
was monitored by HPLC. The desired metallocarborane
complex 3,1,2-[K][Re(CO)3(RHC2B9H9)] (R ) CH2CH2-
CO2H) (2) was present in >90% yield after 7 min at 180
°C: near-quantitative conversion can be achieved in only 5
min if the reaction is heated at 200 °C. We have observed
that 2 can also be formed when the corresponding closo-
carborane 3 is used in place of 1. Ultimately, we found that
the maximum isolated yields were obtained by heating the
carborane with an excess of [Re(CO)3(H2O)3]Br, followed
by a second heating in the presence of an additional amount
of the rhenium reagent. This approach ensures complete
consumption of the nido-carborane ligand, which often has
a similar Rf value to its metal complex, thereby facilitating
chromatographic purification.
As stated previously, when rhenacarboranes are prepared
in aqueous media using a conventional heat source, the
presence of fluoride is required to prevent premature
decomposition of the metal(I) starting material.2 Since these
same complexation reactions occur within mere minutes
using a microwave reactor, it was of interest to see whether
equally good conversion to the desired metallocarboranes
could be achieved without fluoride. Indeed, the nido-
carborane 1 formed the corresponding rhenium complex 2
in the absence of fluoride with no significant decrease in
yield. This is somewhat remarkable given the absence of an
obvious base, traditionally thought to be needed to afford
good yields of this class of metallocarboranes.4 Reactions
Because of their compact size, robustness, and versatile
synthetic chemistry, organometallic complexes of 99mTc(I)
and Re(I) are considered highly attractive cores from which
to prepare molecular radioimaging and radiotherapy agents.1
Regrettably, the preparation of organometallic imaging and
therapy agents has been hampered by the fact that traditional
organometallic ligands are generally incompatible with the
reaction conditions routinely used to prepare radiopharma-
ceuticals. This includes the need to complete labeling
reactions in less than one half-life, in aqueous reaction media,
while employing only very small amounts (i.e., 10-9-10-12
mol) of the radioisotope.
With these requirements in mind, we recently developed
a methodology that can be used to prepare η5-carborane
complexes of both 99mTc(I) and Re(I) in water.2 The approach
entails using fluoride ion to prevent the decomposition of
the technetium or rhenium starting materials over the
prolonged reaction times and elevated temperatures needed
to form the desired complexes. However, for certain func-
tionalized carboranes, particularly those with sterically
demanding substituents, only modest product yields could
be achieved even under optimized reaction conditions. To
overcome this limitation, the impact of using microwave
(3) Lazarova, N.; James, S.; Babich, J.; Zubieta, J. Inorg. Chem. Commun.
2004, 7, 1023-1026.
* To whom correspondence should be addressed. E-mail:
valliant@mcmaster.ca.
(1) Alberto, R. Top. Curr. Chem. 2005, 252, 1.
(2) (a) Sogbein, O. O.; Merdy, P.; Morel, P.; Valliant, J. F. Inorg. Chem.
2004, 43, 3032-3034. (b) Sogbein, O. O.; Green, A. E. C.; Schaffer,
P.: Chankalal, R.; Lee, E.; Healy, B. D.; Morel, P.; Valliant, J. F.
Inorg. Chem. 2005, 44, 9574-9584. (c) Sogbein, O. O.; Green, A. E.
C.; Valliant, J. F. Inorg. Chem. 2005, 44, 9585-9591.
(4) (a) Hawthorne, M. F.; Andrews, T. D. J. Am. Chem. Soc. 1965, 87,
2496-2496. (b) Hawthorne, M. F.; Young, D. C.; Andrews, T. D.
Howe, D. V.; Pilling, R. L.; Pitts, A. D.; Reintjes, M.; Warren, L. F.
Wegner, P. A. J. Am. Chem. Soc. 1968, 90, 879-896. (c) Ellis, D.
D.; Jelliss, P. A.; Stone, F. G. A. Organometallics 1999, 18, 4982-
4994. (d) Valliant, J. F.; Morel, P.; Schaffer, P.; Kaldis, J. H. Inorg.
Chem. 2002, 41, 628-630.
10.1021/ic0605928 CCC: $33.50
Published on Web 06/22/2006
© 2006 American Chemical Society
Inorganic Chemistry, Vol. 45, No. 15, 2006 5727

COMMUNICATION
Scheme 1. Microwave-Assisted Synthesis of 3,1,2 Metallocarboranes
Scheme 2. Microwave-Assisted Synthesis of 2,1,8 Metallocarboranes
Figure 1. Thermal ellipsoid plot of 5a (30% probability ellipsoids); Na
and H atoms omitted for clarity. Selected bond lengths (Å) and angles
(deg): Re2-C1 2.302(4), Re2-B3 2.277(5), C1-B3 1.699(6), B3-B7
1.783(6), B3-Re2-B7 45.3(2), B3-C1-B6 110.0(5).
carried out at 10 °C increments between 100 and 200 °C.
The 1H NMR spectra of the reaction mixtures indicated that
the first step of this process consists of the conversion of
the closo-carborane 4 to the corresponding nido-cage with
of other closo- and nido-carboranes with [Re(CO)3(H2O)3]-
Br conducted in the absence of fluoride gave varying yields,
depending on the substituents present on the ligand. Though
a more detailed study of these reactions is currently in
progress, to ensure maximum yields all subsequent reactions
described here were carried out in the presence of fluoride.
-
concomitant formation of BF4 , as indicated by 11B NMR
spectroscopy. This is followed by η5-coordination of the
carborane to the [Re(CO)3]+ core and simultaneous isomer-
ization to yield 5a: no evidence for either the isomerization
of the free nido-carborane ligand or for the initial formation
of the 3,1,2 isomer was found. At a reaction temperature of
200 °C, 95% of the product is associated with migration of
the C-aryl group (5a) while 5% involves migration of the
CH group (5b) out of the bonding face.
To determine if a similar isomerization process could take
place from a 3,1,2 isomer, 3,1,2-[Re(CO)3(RHC2B9H9)]- (R
) Ph) (7a, Scheme 1) was prepared from the corresponding
nido-carborane using a conventional approach involving
anhydrous reaction conditions and a strong base (nBuLi).4
The identity of the product was confirmed by X-ray
crystallography and multinuclear NMR spectroscopy. A
sample of 7a was then heated at 200 °C in aqueous ethanol
in the microwave reactor for 15 min; subsequent spectro-
scopic characterization revealed quantitative conversion to
the 2,1,8 complex 7b.
Proton nuclear Overhauser effect (nOe) experiments were
carried out on the closo-carborane 88 and both isomers 7a
and 7b, wherein the resonance due to the carborane CH unit
was irradiated: in the case of 8 and 7a, significant enhance-
ment of the resonances associated with the protons of the
phenyl ring was evident. No such enhancement was observed
for the 2,1,8 isomer 7b due to the greater distance between
the two cage carbon atoms. Similar experiments provide a
convenient means of assessing whether isomerization of a
given carborane ligand has occurred in systems where X-ray
quality crystals cannot be obtained.
To determine if this microwave methodology were equally
effective when using more sterically hindered carborane
ligands, the monohydroxyphenyl carborane 45 was combined
with [Re(CO)3(H2O)3]Br in aqueous ethanol and the mixture
heated at 200 °C for 15 min (Scheme 2). The product was
recrystallized from methanol and characterized by multi-
nuclear NMR spectroscopy and single-crystal X-ray diffrac-
tion. Curiously, the X-ray structure6 (Figure 1) revealed that
the complex obtained was not the expected 3,1,2 metallo-
carborane, but rather an isomer, 2,1,8-[Na][Re(CO)3-
(RHC2B9H9)] (R ) 4-PhOH) (5a), where the cage carbon
atom linked to the aryl group has migrated out of the bonding
face of the η5-carborane ligand. In simple terms, the observed
product can be viewed as a 120° rotation of one of the
triangular faces of the carborane. Isomerization of this nature
has been noted for other sterically hindered metal-carborane
complexes7 but not for η5-complexes of rhenium.
To gain some insight into how the microwave-heated
reaction of 4 with [Re(CO)3(H2O)3]Br proceeds, a 1H NMR
spectroscopy study of this reaction as a function of temper-
ature was conducted. Using the microwave’s autosampler
feature to full advantage, a series of 15 min reactions was
(5) Yamamoto, K.; Endo, Y. Bioorg. Med. Chem. Lett. 2001, 11, 2389-
2392.
(6) Crystal data for 5a: C12H17B9NaO8Re, Mr ) 595.74, monoclinic, space
group P2(1)/c, a ) 11.7890(5) Å, b ) 24.5236(9) Å, c ) 7.1903(3)
Å, â ) 94.935(2)°, V ) 2071.07(14) Å3, Z ) 4, Fcalcd ) 1.911 g
cm-3, µ ) 5.926 mm-1, R1 ) 0.0669, wR2 ) 0.0757.
(7) (a) Warren, L. F.; Hawthorne, M. F. J. Am. Chem. Soc. 1970, 92,
1157-1173. (b) Baghurst, D. R.; Copley, R. C. B.; Fleischer, H.;
Mingos, D. M. P.; Kyd, G. O.; Yellowlees, L. J.; Welch, A. J.;
Spalding, T. R.; O’Connell, D. J. Organomet. Chem. 1993, 447, C14-
C17. (c) Safronov, A. V.; Dolgushin, F. M.; Petrovskii, P. V.;
Chizhevsky, I. T. Organometallics 2005, 24, 2964-2970.
A major driving force behind the isomerization of these
carborane ligands is likely relief of the steric interactions
between the aromatic ring and the CO groups on the metal.7
(8) Brian, P. T.; Cowie, J.; Donohoe, D. J.; Hnyk, D.; Ranik, D. W. H.;
Reed, D.; Reid, B. D.; Robertson, H. E.; Welch, A. J. Inorg. Chem.
1996, 35, 1701-1708.
5728 Inorganic Chemistry, Vol. 45, No. 15, 2006

COMMUNICATION
This is supported by the fact that when the more sterically
encumbered bis-substituted carborane 99 was reacted with
[Re(CO)3(H2O)3]Br at 200 °C (Scheme 2), the observed
product was exclusively the 2,1,8 isomer 10. Conversely,
when a methylene spacer was incorporated as in the mono-
functionalized benzyl carborane 11 (Scheme 1), microwave
reactions with [Re(CO)3(H2O)3]Br yielded exclusively the
3,1,2-isomer 12, even after prolonged (35 min) heating at
200 °C. The unexpected complexity of the NMR spectra of
10 and related compounds were initially attributed to multiple
conformational states of the aryl rings;2b however, the
observed 1H, 13C, and 11B NMR spectra can now be readily
assigned to the isomerized product 10, which lacks the
symmetry possessed by the initially anticipated 3,1,2 isomer.
A more detailed study is in progress to examine both
electronic and steric substituent effects on the barrier to
isomerization. This information will be compared to data
reported for the isomerization of other metallocarborane
complexes which include both C2B9 derivatives and smaller
heteroboranes.10
The subsequent step in our in investigation was to
determine whether microwave heating could be used to
perform analogous metal-carborane complexation reactions
at the tracer level using 99mTc in place of rhenium. The
microwave reactor vials are similar to reaction vessels
typically employed in radiochemistry experiments. A further
convenience is that the commercial microwave system
employed is equipped with a pressure monitoring system and
rapid cooling capabilities. Thus, if proven successful, this
methodology should be readily adaptable to the preparation
of radiopharmaceuticals. For ease of comparison with our
previous radiolabeling work,2c the nido-carborane 1 was used
and combined with [99mTc(CO)3(H2O)3]+ prepared11 in the
presence of fluoride. The desired product 3,1,2-[Na][Tc-
(CO)3(RHC2B9H9)] (R ) CH2CH2CO2H) (13) was obtained
in 64% isolated yield. The only byproduct, TcO4 , was
-
readily separated from the product by a convenient and easily
automated solid-phase extraction procedure. This yield is
lower than that obtained using a conventional heat source;2c
however, the reaction was complete in 15 min and the
product obtained in high effective specific activity and >99%
radiochemical purity. Efforts to further optimize the reaction
yield, by means including minimizing the amount of dis-
solved oxygen present in the reaction mixture, are currently
in progress.
It is clear that microwave heating greatly increases the
rate and, in certain cases, the yield of the reactions used to
prepare Re(I) and Tc(I) carborane complexes compared to
conventional heating methods. Although microwave-assisted
synthesis has been used elsewhere in carborane chemistry,7b
this is the first report of such a reaction for preparing
metallocarboranes in water at the tracer level. In light of the
success of this work, we have begun exploring the general
utility of microwave-assisted synthesis for preparing orga-
nometallic complexes of other radiometals including the
therapeutic isotopes 186Re and 188Re, which undergo substitu-
tion reactions much more slowly than with 99mTc.
Acknowledgment. This work was supported by NSERC
of Canada and the ORDCF (The Ontario Consortium for
Small Animal Imaging Grant). We thank the Province of
Ontario for an OGSST scholarship for A.E.C.G. The as-
sistance of Prof. D. W. Hughes in running nOe experiments
is gratefully acknowledged, as is the generosity of Prof. J.
McNulty in providing access to the microwave reactor.
Supporting Information Available: Details of the syntheses
of compounds 2, 5a/b, 10, 12, and 13; characterization data. This
material is available free of charge via the Internet at http://
pubs.acs.org.
(9) Endo, Y.; Yoshimi, T.; Iijima, T.; Yamakoshi, Y. Bioorg. Med. Chem.
Lett. 1999, 9, 3387-3392.
(10) (a) Dunn, S.; Rosair, G. M.; Thomas, R. LI.; Weller, A. S.; Welch,
A. J. Angew Chem., Int. Ed. Engl. 1997, 36, 645-646. (b) Garrioch,
R. M.; Kuballa, P.; Low, K. S.; Rosair, G. M.; Welch, A. J. J.
Organomet. Chem. 1999, 575, 57-62. (c) Hawthorne, M. F.; Kalous-
tian, M. K.; Wiersemay, R. J. J. Am. Chem. Soc. 1971, 93, 4912-
4913. (d) Hosmane, N. S.; Maguire, J. A. Organometallics 2005, 24,
1356-1389.
IC0605928
(11) (a) Alberto, R.; Schibli, R.; Egli, A.; Schubiger, A. P.; Abram, U.;
Kaden, T. A. J. Am. Chem. Soc. 1998, 120, 7987-7988. (b) Alberto,
R.; Ortner, K.; Wheatley, N.; Schibli, R.; Schubiger, A. P. J. Am.
Chem. Soc. 2001, 123, 3135-3136.
Inorganic Chemistry, Vol. 45, No. 15, 2006 5729