Copper(i) scorpionate complexes and their application in palladium-mediated [11C]carbonylation reactions

Article abstract of DOI:10.1039/b906166e

Solutions of copper(i) tris(pyrazolyl)borate complexes have been used to greatly improve the solubility of [¹¹C]carbon monoxide, enabling it to be used in low-pressure, 'one-pot' palladium-mediated carbonylation reactions to form ¹¹C

Full text of DOI:10.1039/b906166e

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Copper(I) scorpionate complexes and their application
in palladium-mediated [ C]carbonylation reactions
1
1
a
a
a
b
Steven Kealey, Philip W. Miller, Nicholas J. Long,* Christophe Plisson,
b
ab
Laurent Martarello and Antony D. Gee*
Received (in Cambridge, UK) 30th March 2009, Accepted 23rd April 2009
First published as an Advance Article on the web 7th May 2009
DOI: 10.1039/b906166e
Solutions of copper(I) tris(pyrazolyl)borate complexes have been
1
lowering the pressure or purging the solution with an inert
8
1
11
gas. Such systems would not be suitable for trapping CO at
high dilution in an inert carrier gas stream as it might be prone
used to greatly improve the solubility of [ C]carbon monoxide,
enabling it to be used in low-pressure, ‘one-pot’ palladium-
1
1
11
to undesired CO loss. In order to achieve a high trapping
mediated carbonylation reactions to form C-radiolabelled
amides and ureas for use in positron emission tomography.
efficiency without the need for time consuming recirculation of
the gases, our studies focussed on complexes that could
1
1
Positron emission tomography (PET) is a powerful imaging
technique that uses radiolabelled compounds as molecular
probes to study biological processes in vivo. In addition to
bind CO relatively strongly, such that subsequent
decarbonylation could only be triggered by a chemical means,
for example, the introduction of a competing ligand.
9,10
1
its well-established role in disease diagnostics, PET can
Tris(pyrazolyl)borate (Tp) ligands
were deemed an ideal
benefit the drug development process by providing valuable
biodistribution and receptor occupancy data using sub-
partner for copper(I) in our studies due to their electron-
releasing properties which serve to strengthen the copper–
carbonyl bond through backbonding. Indeed, the Tp ligand
2
pharmacological doses of radiolabelled drug candidates.
Despite the great wealth of information that PET tracers can
1
1
was used to form the first stable and crystallographically
12
characterised
3
11
provide, their preparation is not trivial. C, for example, is
an important positron-emitting radionuclide due to the
ubiquity of carbon in biologically-active compounds.
However, its use is hindered by its short radioactive half-life
copper(I) carbonyl complex, Cu[Tp]CO.
Commercially-available potassium tris(3,5-dimethylpyrazolyl)-
borate (K[Tp*]) was employed in our studies due to its
increased organic solubility over its non-methylated analogue.
Importantly, the negative charge of the Tp* ligand results
in a neutral copper(I) complex thus eliminating the need for
non-coordinating counter ions which may interfere with
reactivity and reduce organic solubility.
(20 minutes), compounded by the handling restrictions
imposed when working with ionising radiation.
1
1
11
[
C]carbon monoxide is an appealing C labelling reagent
as it can be incorporated into a range of biologically-relevant
1
molecules, usually through metal-catalysed [ C]carbonylation
4
reactions. However, the widespread use of this gas has been
1
While it has been reported that Cu[Tp*]CO could be formed
by prolonged bubbling of unlabelled CO through an acetone
1
solution of K[Tp*] and CuCl, this would not be acceptable
3
restricted by poor reactivity as a consequence of low solubility
in organic solvents and its high dilution in inert carrier gases.
1
1
for use with CO due to the very small quantities of the gas
produced (picomoles) and the short radioactive half-life of
1
1
The last decade has seen CO emerge as a viable labelling
reagent through the use of microautoclave reactors which
enhance the reactivity of the gas using high pressures
1
1
11
C. Such small quantities of CO might benefit the trapping
process as there will be a large excess of the copper complex in
solution. In our experiments,w 11 mmol of K[Tp*] and CuCl in
1 ml THF was used as the CO trap, providing approximately
5
,6
11
(
ation reactions we have been exploring low-pressure techni-
4350 bar). In order to broaden the scope of [ C]carbonyl-
1
1
1
ques which could enhance the reactivity of CO by increasing
1
5
11
a 10 fold excess of trapping reagents (Scheme 1) over CO.
Control reactions were performed initially, to observe the
7
its solubility through a process of chemical complexation.
1
1
11
extent of CO trapping in solvent alone, or with only one
Here we present a simple one-pot procedure for efficient CO
trapping using a copper(I) tris(pyrazolyl)borate solution, and
component (CuCl or K[Tp*]) in solution. As expected, the
11
1
its applications in palladium-mediated [ C]carbonylation
1
solubility of CO in THF was extremely poor, with o1% of
the CO remaining in the vial after a single sweep of the
1
reactions to form [ C-carbonyl]amides as well as a new path-
1
11
1
1
way to [ C-carbonyl]ureas.
Solutions of copper(I) halides have a history of reversible
CO absorption, and typically rely on a weakly-bound carbonyl
ligand which allows dissociation to be achieved through
a
Department of Chemistry, Imperial College, London, UK SW7 2AZ.
E-mail: n.long@imperial.ac.uk
GlaxoSmithKline, Clinical Imaging Centre, Imperial College,
Hammersmith Hospital, London, UK W12 0NN.
E-mail: antony.d.gee@gsk.com
b
11
11
Scheme 1 (i) Trapping of CO via the formation of Cu[Tp*] CO.
11
(ii) CO release by addition of triphenylphosphine.
3
696 | Chem. Commun., 2009, 3696–3698
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1
1
11
Table 1
CO trapping and release reactions
Table
2
Palladium-mediated
[
Cu[Tp*] CO solutions: formation of [ C]N-benzylbenzamide and
C]carbonylation reactions using
11
11
b
b
11
[ C]dibenzylurea
Trapping
reagents
CO trapping
(%)
CO release
(%)
a
Entry
ac
RCP (%)
bc
RCY (%)
c
1
2
3
4
THF only
CuCl
K[Tp*]
o1
o1
o1
—
—
—
c
c
Entry Catalyst species
Temp./1C Amide Urea Amide Urea
d
c
1
2
3
4
Pd (dba) + dppp 100
3
84 Æ 6 2 Æ 1 67 Æ 2 2 Æ 1
20 Æ 3 70 Æ 9 13 Æ 2 45 Æ 6
CuCl + K[Tp*]
96 Æ 6
99 Æ 1
2
Pd(dppp)Cl
Pd(dppp)Cl2
—
2
100
100
100
a
b
1
1 mmol of reagents in 1.0 ml THF. Calculated as a fraction of the
radioactivity of the vial at the end of the reaction compared to the
c
untrapped waste gases. Average of 3 runs. Average of 14 runs.
0
0
92 Æ 7
0
0
47 Æ 6
0
0
d
a
b
Radiochemical purity determined by radio-analytic HPLC. Radio-
chemical yield based on total radioactivity delivered to the vial and
c
corrected for decay to end of bombardment. Average of 3 runs.
1
1
CO–He gas stream (Table 1, entry 1). Using CuCl produced
a suspension which displayed similarly poor trapping (entry 2).
In the last of the control experiments, a K[Tp*] solution was
1
1
used, again showing minimal trapping of CO (entry 3).
Solutions of CuCl and K[Tp*] produced an average trapping
efficiency of 96% (entry 4)—a vast improvement over the
control reactions, thus showing suitability of this system for
Scheme
3
Urea formation via palladium(II)-catalysed oxidative
1
1
efficient CO trapping.
Since displacement of the carbonyl ligand in Cu[Tp*]CO is
known to occur by addition of a competing phosphine donor
carbonylation of amines. [O] = co-oxidant.
1
1,14
(
which favourably binds to copper(I)),
we proceeded to
formed from hydrolysis of small amounts of Pd(II) acyl
intermediate present at the end of the reaction. Using the
examine this reaction in our setup by addition of triphenyl-
phosphine (two equivalents with respect to CuCl) to the
2
palladium(II) species, Pd(dppp)Cl , however, resulted in the
1
1
11
solution of Cu[Tp*] CO whilst passing a stream of argon
through the solution. This resulted in almost complete (99%)
displacement of the radioactivity from the vial to waste in one
formation of significant amounts (70%) of a C-labelled side
product which dramatically reduced the amide yield as
evidenced by radio-HPLC (entry 2). Given the limited number
of possible radiolabelled products which could form, it was
1
1
minute, indicating that CO release occurs rapidly, without
the need to heat the solution.
Having successfully used the CuCl–K[Tp*] system for
1
1
proposed that this species might be [ C]dibenzylurea, formed
via the oxidative carbonylation of two benzylamine molecules.
The identity of this product was confirmed by its co-elution
1
1
efficient CO capture and release, we sought to use the
1
1
11
CO for in situ [ C]carbonylation reactions, rather than
15
with an unlabelled reference sample of dibenzylurea. While
oxidative carbonylation of amines has been reported as an
displacing it from the vial. Our studies focused on palladium-
catalysed carbonylation reactions between aryl halides and
effective means of synthesising ureas using unlabelled CO
16–25
(Scheme 3),
reported for use in C radiolabelling experiments.
1
amines to produce [ C-carbonyl]amides—a functional group
1
to our knowledge, this pathway has not been
1
1
found in many important drug targets and natural products.
1
We selected the synthesis of [ C]N-benzylbenzamide from
1
Since the urea functionality features in many pharma-
ceuticals, versatile radiolabelling approaches to these
iodobenzene and benzylamine as a model reaction to test the
1
1
11
compounds are highly sought after. Most commonly, C-
Cu[Tp*] CO system. These reactions were performed by
addition of the carbonylation reagents (iodobenzene,
benzylamine, palladium catalyst and triphenylphosphine) to
1
labelling of ureas has been achieved using [ C]phosgene,
1
26–28
a method which is hindered by synthetic difficulties and poor
reproducibility. In order to explore the viability of this new
radiolabelling method, attempts were made to improve the
1
1
a solution of Cu[Tp*] CO, followed by heating the sealed vial
for 10 minutes (Scheme 2).w Following this, the reaction was
quenched by addition of water, and the crude product analysed
by high performance liquid chromatography (HPLC).
1
1
purity of [ C]dibenzylurea in our setup. In these experiments,
iodobenzene was removed from the reagent mixture thus
excluding amide–acid formation. This led to the formation
Use of an in situ catalytic species generated from Pd
2 3
(dba)
1
1
and 1,3-bis(diphenylphosphino)propane (dppp) obtained the
of [ C]dibenzylurea in high radiochemical purity (92%) and
moderate radiochemical yield (Table 2, entry 3) in the crude
reaction mixture. Since previous studies into Pd(II)-mediated
1
1
best results, producing [ C]N-benzylbenzamide in 84%
radiochemical purity and decay-corrected radiochemical yield
of 67% (Table 2, entry 1). In these reactions, the
radiochemical purity was reduced due to the formation of
1
1
7,29
[ C]carbonylation reactions
had not reported urea forma-
tion, we explored the possibility of a copper-mediated process
occurring in our experiments. In order to test this hypothesis,
control reactions were performed in the absence of any
palladium species and in otherwise identical conditions
1
1
small amounts (o15%) of [ C]benzoic acid, presumably
(
entry 4). These reactions resulted in no formation of radio-
1
1
labelled products, suggesting that [ C]dibenzylurea formation
is palladium-mediated, although a tandem palladium/copper-
mediated process cannot be ruled out. Further investigations
are currently underway to elucidate the precise nature of the
1
1
Scheme 2
[ C]carbonylation reaction between iodobenzene and
11
11
benzylamine, using a solution of Cu[Tp*] CO as the source of CO.
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Chem. Commun., 2009, 3696–3698 | 3697

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co-oxidant species, and to examine the scope of this reaction
towards a range of amine substrates including the formation
of unsymmetrical ureas.
1 D. H. S. Silverman, G. W. Small and M. E. Phelps, Clin. Positron
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2
V. J. Cunningham, C. A. Parker, E. A. Rabiner, A. D. Gee and
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Int. Ed., 2008, 47, 8998.
In summary, we have used a copper(I) tris(pyrazolyl)borate
3
1
complex to significantly improve the solubility of CO at
1
1
room temperature and pressure. These CO solutions open up
1
4 B. Langstrom, O. Itsenko and O. Rahman, J. Labelled Compd.
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1
1
a new means of performing [ C]carbonylation reactions for
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5
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1
6
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palladium-mediated [ C]carbonylation reactions has led to
an efficient and versatile method of synthesising either
1
1
C-labelled amides or ureas, depending on the choice of
8
M. I. Bruce, J. Organomet. Chem., 1972, 44, 209.
1
1
palladium catalyst used. This new approach to C-labelled
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radiopharmaceuticals. We are currently examining the use of
9 S. Trofimenko, Scorpionates: The Coordination Chemistry of
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0 J. A. McCleverty and T. J. Meyer, Comprehensive Coordination
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1
1
1
11
CO solutions for rapid [ C]carbonylation reactions
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1
2 M. R. Churchill, B. G. DeBoer, F. J. Rotella, O. M. Abu Salah and
1
Notes and references
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11
w Experimental procedure: [ C]carbon dioxide was produced using a
Siemens Eclipse HP cyclotron by 11 MeV proton bombardment of a
target containing nitrogen and 1% oxygen. CO was produced using
11
11
2
an Eckert and Ziegler reduction module by passing CO over a
molybdenum reductant at 850 1C. In a typical experiment, the
trapping solution was prepared by addition of CuCl (1.1 mg, 11 mmol)
and K[Tp*] (3.7 mg, 11 mmol) to a 5 mL V-bottomed glass vial,
flushing with nitrogen for 15 min followed by addition of anhydrous
THF (1.0 mL). The carbonylation reagents were prepared by addition
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2 3
of Pd(dppp)Cl (1.3 mg, 2 mmol), PPh (5.8 mg, 22 mmol) and
iodobenzene (2.3 mg, 11 mmol) to a second vial, flushing with nitrogen
for 15 min, followed by addition of benzylamine (0.1 ml) and
anhydrous dimethylformamide (0.4 ml). The aqueous quench, a pH
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4
ammonium formate buffer solution (0.5 ml), was added to the third
11
vial. [ C]Carbon monoxide was delivered to the trapping solution in a
helium carrier gas stream where it was bubbled through the solution at
a flow rate of 20 mL min . All waste gases were collected in a bag and
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À1
their radioactivity monitored in dose calibrator. Following delivery of
11
the CO to the vial, the carbonylation reagents were added and the
vial sealed and heated at 100 1C in a heating block. After 10 min at this
temperature the vial was allowed to cool for one minute at which point
the quench was added under a stream of argon, causing any unreacted
CO to be pushed from the vial into the waste bag. The vial was then
removed from the hot cell, its radioactivity measured and a 20 mL
aliquot was removed for analytical HPLC analysis (solvent: 60 : 40
À1
H
2
O–acetonitrile, flow: 1.5 mL min , column: Agilent XDB C18
{
5 mm, 4.6 Â 150 mm}).
3
698 | Chem. Commun., 2009, 3696–3698
This journal is ꢀc The Royal Society of Chemistry 2009