Palladium(II)-mediated 11C-carbonylative coupling of diaryliodonium salts with organostannanes-a new, mild and rapid synthesis of aryl [11C]ketones

Article abstract of DOI:10.1039/a907803g

Palladium(II)-mediated [¹¹C]carbonylative coupling of diaryliodonium salts with aryltributylstannanes for 1 min in DME-water (4:1 v/v) at RT gives a new mild and rapid route to aryl [¹¹C]ketones. Substituted aryltributylstannanes cou

Full text of DOI:10.1039/a907803g

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11
Palladium(II)-mediated C-carbonylative coupling of diaryl-
iodonium salts with organostannanes—a new, mild and rapid
synthesis of aryl [11C]ketones
1
Mohammed H. Al-Qahtania,b and Victor W. Pike*a
a Chemistry and Engineering Group, MRC Cyclotron Unit, Imperial College School of
Medicine, Hammersmith Hospital, Ducane Road, London, UK W12 ONN. E-mail:
victor.pike@csc.mrc.ac.uk
b Department of Chemistry, School of Physics and Chemistry, University of Surrey, Guildford,
UK GU2 5XH
Received (in Cambridge, UK) 28th September 1999, Accepted 28th January 2000
Published on the Web 22nd February 2000
Palladium()-mediated [11C]carbonylative coupling of diaryliodonium salts with aryltributylstannanes for 1 min in
DME–water (4:1 v/v) at RT gives a new mild and rapid route to aryl [11C]ketones. Substituted aryltributylstannanes
couple with diphenyliodonium bromide to give substituted [11C]benzophenones in generally very high radiochemical
yield (>98%, decay-corrected), while diphenyliodonium tosylates, bearing one or two substituents in one ring,
couple with phenyltributylstannane to give a mixture of substituted (30–43%) and unsubstituted [11C]benzophenone
(47–66%). These reactions are highly attractive for introducing cyclotron-produced carbon-11 (t1/2 = 20.4 min) into
prospective radiotracers for application in medical imaging with positron emission tomography.
cyclotron-produced no-carrier-added [11C]carbon dioxide over
Introduction
charcoal at 900 ЊC.3 On average about 6.0% (4.5–7.5%; n = 56)
Carbon-11 (t1/2 = 20.4 min; βϩ = 100%) is especially useful for
of the radioactivity was trapped by a single pass of the
labelling compounds as radiopharmaceuticals for medical
nitrogen–[11C]carbon monoxide through the small volume
imaging with positron emission tomography (PET).1 The
(~0.4 ml) of solvent (DME–water; 4:1 v/v)7 in the presence of
increasingly widespread application and development of PET
stimulates a need for rapid and efficient methods for the site-
specific incorporation of carbon-11 into prospective radio-
reactants. No effect of solvent on trapping efficiency was
studied here. However, polar solvents, such as DMSO, trap
[11C]carbon monoxide more efficiently than THF.5,6 By switch-
pharmaceuticals. Carbon monoxide has a rich chemistry for
ing to another more polar solvent, some advantage might
the introduction of carbonyl groups into organic compounds.2
have been gained for [11C]carbon monoxide solubilisation, but
Although [11C]carbon monoxide is readily prepared from
perhaps at the expense of reactivity.10
cyclotron-produced no-carrier-added [11C]carbon dioxide,3,4 it
Palladium()-mediated 11C-carbonylative coupling of
has not yet found widespread use for labelling organic com-
diphenyliodonium iodide (1a) with phenyltributylstannane (2a)
pounds. One of the reasons is the low solubility of [11C]carbon
at room temperature for 1 min gave a high radiochemical yield‡
monoxide in organic solvents, which limits the efficiency with
of [11C]benzophenone (3a) (55–75%, average 65% for n = 5,
which it can be trapped by a single pass into a reagent solution.
decay-corrected). On increasing the reaction time to 5, 10 and
However, there are now methods to overcome this problem,
20 min, the decay-corrected radiochemical yield increased
marginally to 75, 80 and 80%, respectively. Hence, a 1 min
reaction time gave the highest practical (non-decay-corrected)
including rapid recirculation of untrapped [11C]carbon mon-
oxide through the reagent solution5 or confinement of the
[11C]carbon monoxide with reactants in a high pressure micro-
radiochemical yield. The main radioactive byproduct in all
autoclave.6 Renewed interest in the potential to apply [11C]-
these reactions was [11C]benzoic acid. This product was also
carbon monoxide to the solution of labelling problems is there-
obtained in a control reaction from which phenyltributyl-
fore warranted.
stannane was omitted. [11C]Benzaldehyde was observed as
It has recently been reported that diaryliodonium salts
another minor byproduct in the reactions conducted for 1 min
(Ar1IϩAr 2XϪ)† couple carbonylatively with organostannanes in
(5–11%). This product was also obtained in a control reaction
the presence of a palladium() catalyst to give ketones.7b Since
(1 min) from which palladium() was omitted.
we have a ready access to several new diaryliodonium salts8,9
In reactions performed at room temperature for 20 min, the
and to [11C]carbon monoxide, we were interested to see if this
radiochemical yield of [11C]benzophenone increased with the
reaction could be applied generally to the rapid preparation of
molar ratio of phenyltributylstannane to diphenyliodonium
[11C]ketones (Scheme 1). Here we report our findings on the
iodide and was highest for a ratio of 2 (Fig. 1). By analogy with
preparation of substituted [11C]benzophenones from various
the reaction course generally accepted for other palladium()-
diaryliodonium salts and aryltributylstannanes.
mediated carbonylation reactions,11 it is assumed that the
[11C]carbonylative coupling of iodonium salts with aryltributyl-
stannanes proceeds through a catalytic cycle, involving oxid-
ative addition of palladium(0)§ to the iodonium salt to form a
Results and discussion
[11C]Carbon monoxide was readily produced by reducing
† Although the structure of the iodonium salts is shown formally as
Ar1IϩAr2XϪ, there is substantial evidence that these can exist as bridged
dimers where XϪ is halide.7a
‡ All radiochemical yields are decay-corrected and are based on the
radioactivity initially trapped in the solvent.
§ The added palladium() chloride is readily reduced to palladium(0).2
DOI: 10.1039/a907803g
J. Chem. Soc., Perkin Trans. 1, 2000, 1033–1036
This journal is © The Royal Society of Chemistry 2000
1033

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Ϫ
Scheme 1 Palladium()-mediated [11C]carbonylative coupling of diaryliodonium salts with aryltributylstannanes. In 1a, XϪ = IϪ, BrϪ, NO3 or
OTsϪ and in 1b–1f, XϪ = OTsϪ.
Table 1 Decay-corrected radiochemical yields of aryl [11C]ketones
(Ph11COAr2) from the reactions of diphenyliodonium bromide with dif-
ferent aryltributylstannanes (Ar2SnBu3) in the presence of palladium()
chloride at RT for 1 min
Organostannane
precursor
Radiochemical yield
of Ph11COAr2 (%)a
Ar2
2a
2b
2c
2d
2e
2f
Ph
96 (3a)
44b (3b)
>98 (3c)
>98 (3d)
>98 (3e)
>98 (3f)
>98 (3g)
2-Me-C6H4
3-Me-C6H4
2-OMe-C6H4
4-CF3-C6H4
3,5-di-F-C6H3
4-F-C6H4
2g
a Radiochemical yield (decay-corrected) from trapped [11C]carbon
monoxide. b The radioactive byproducts were [11C]benzoic acid,
[11C]benzaldehyde and an unknown compound (aggregate radio-
chemical yield 56%).
Fig. 1 Dependence of the radiochemical yield (decay-corrected) of
[11C]benzophenone (᭺) and [11C]benzoic acid (᭹) on the ratio of
phenyltributylstannane to diphenyliodonium bromide in palladium()-
mediated 11C-carbonylative coupling at RT for 20 min.
Table 2 Decay-corrected radiochemical yields of aryl [11C]ketones
from the reaction of different diaryliodonium tosylates (PhIϩAr1 OTsϪ)
with phenyltributylstannane (2a) in the presence of palladium()
chloride at RT for 1 min
σ-arylpalladium() complex, [11C]carbon monoxide insertion,
transmetallation with the aryltributylstannane, and finally
reductive elimination of palladium(0) to give the [11C]ketone
(Scheme 2). Hence, the transmetallation step seems to be pre-
ferred to the formation of the byproducts, [11C]benzaldehyde or
[11C]benzoic acid, which presumably arise by abstraction of a
free proton or hydroxy group, respectively, from the reaction
medium. This preference is promoted by a high ratio of the
phenyltributylstannane.
With respect to variation of the anion in the diphenylio-
donium salt, [11C]benzophenone was obtained in 75, 90, 92 and
96% radiochemical yields from the iodide, tosylate (toluene-p-
sulfonate), nitrate and bromide, respectively. Since the bromide
gave the highest radiochemical yield of [11C]benzophenone with
low byproduct formation, all further coupling experiments
with diphenyliodonium were run with bromide as counter-
anion. However, there is no clear indication for the role that
the anion plays in the reaction.
Two approaches were adopted for the general extension of
the conditions of the reaction [RT, 1 min, 1 mol% Pd()] to the
preparation of substituted [11C]benzophenones, namely i) the
use of different substituted aryltributylstannanes (2a–2g) with
diphenyliodonium bromide as partner and ii) the use of differ-
ent diaryliodonium tosylates bearing one or more substituents
in one aryl ring (1b–1f) with phenyltributylstannane as partner.
By the use of variously substituted phenyltributylstannanes
with diphenyliodonium bromide, exceptionally high radio-
Iodonium
salt
precursor
Radiochemical yield (%)a
Ar1
Ph11COAr2
Ph11COPh
Othersb
1b
1c
1d
1e
1f
2-Me-C6H4
3-Me-C6H4
2-OMe-C6H4
4-CF3-C6H4
4-F,3-Me-C6H3
42 (3b)
43 (3c)
37 (3d)
30 (3e)
37 (3h)
48
47
62
66
51
10
10
<1
4
12
a Radiochemical yield (decay-corrected) from trapped [11C]carbon
monoxide. b [11C]Benzoic acid plus [11C]benzaldehyde.
chemical yields (~98%) of several substituted [11C]benzo-
phenones (3c–3g) were obtained (Table 1). Only the 3-methyl-
benzophenone (3b) was obtained in a substantially lower, but
still useful, radiochemical yield (44%). In this case, [11C]benz-
aldehyde and [11C]benzoic acid were substantial radioactive
byproducts.
When different mono-substituted diaryliodonium tosylates
were used to partner phenyltributylstannane, the radiochemical
yields of the expected substituted [11C]benzophenones (3b–3h)
were substantially lower (30–43%) than from the already
described alternative approach employing a substituted aryl-
tributylstannane (Table 2). In each of these reactions the major
radioactive product was [11C]benzophenone (47–51%). Clearly,
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this product was expected since either aryl group in the iodonium
salt, phenyl or substituted phenyl, can in principle be incorpor-
ated into [11C]ketone (Scheme 2). The total radiochemical yield
ketones, benzoic acid and benzaldehyde were purchased from
Lancaster Synthesis. Diaryliodonium tosylates were prepared,
as reported.8,9 Aryltributylstannanes were purchased from
Maybridge Chemical Co., except phenyltributylstannane which
was purchased from Aldrich Chemical Co. Palladium()
chloride and all other reagents were purchased from Aldrich
Chemical Co. They were of greater than 99.5% purity and
used without further purification.
General analytical methods
Radio-GC was performed using a Shimadzu, GC 14A instru-
ment, fitted with a Poraplot 007 column (25 m, 25 ЊC) con-
nected to a capillary column injector (25 ЊC) supplied with
helium as carrier gas (1.5 bar; flow rate 5 ml minϪ1). The output
was connected to a micro-TCD detector connected in series to
a custom built radioactivity detector. Radio-HPLC was per-
formed using a µ-Bondapak C18 column (300 × 7.8 mm od)
eluted with acetonitrile–water–triethylamine (60:40:0.025 by
volume) at 3 ml minϪ1. Radioactive peaks were identified by
coinjection of reference compounds that were detected by their
absorbance at 254 nm.
Scheme 2 Probable reaction cycle for the palladium()-mediated
[11C]carbonylative coupling of diaryliodonium salts with aryltributyl-
stannanes to produce aryl [11C]ketones.
Preparation of [11C]carbon monoxide
[11C]Carbon dioxide was produced from the 14N(p,α)11C nuclear
reaction by irradiation of a target of nitrogen–0.1% oxygen (15
bar) with 19 MeV protons. The [11C]carbon dioxide was trans-
ferred in nitrogen from the target to a lead-shielded ‘hot-cell’
through stainless steel tubing at 500 ml minϪ1 and then through
a heated quartz tube containing charcoal at 900 ЊC.3 The gener-
ated [11C]carbon monoxide was passed over a sodalime trap to
eliminate any traces of unconverted [11C]carbon dioxide and
collected in a nitrogen-flushed 50 ml syringe as a mixture with
nitrogen gas. The radiochemical purity of the [11C]carbon
monoxide was >99% by radio-GC analysis.
of aryl [11C]ketones ranged from 88 to 99% (Table 2), showing
again the overall efficiency of the palladium(0)-mediated process.
In the iodonium salts, aryl rings bearing strongly electron-with-
drawing substituents (F or CF3) in the para position or a bulky
ortho substituent (OMe) were markedly less likely to be incor-
porated into the aryl [11C]ketone product than a phenyl ring.
This may reflect the existence of a trigonal bipyramidal trans-
ition state for the initial oxidative addition of palladium(0),
centred on the iodine() atom, in which one aryl group is pref-
erentially in an equatorial position and the other in an axial
position, with the preference determined by the pattern of sub-
stitution, especially the presence of a bulky ortho substituent.12
[11C]Benzaldehyde and [11C]benzoic acid were seen as low level
byproducts in all the reactions. The use of an iodonium salt
having identical substituents in each aryl ring would clearly be
expected to give a single aryl [11C]ketone product. Such salts
can be prepared by several general procedures.13–17
General procedure for synthesis of [11C]ketones
Either diphenyliodonium bromide (2.80 µmol) plus aryltri-
butylstannane (5.6 µmol) or diaryliodonium tosylate (2.80
µmol) plus phenyltributylstannane (5.6 µmol), were dissolved in
DME–H2O (4:1 v/v, 0.4 ml) within a septum-sealed reaction vial
(Pierce, volume, 2.0 ml). Palladium() chloride (0.028 µmol) in
(DME–H2O, 4:1 v/v; 22 µl) was added before a known quantity
of [11C]carbon monoxide (111–222 MBq; 3–6 mCi) in nitrogen
was passed from a 50 ml glass syringe through a needle (21
gauge) into the vented solution over ~30 s. The sealed reaction
mixture was left to stir at room temperature for 1 min. The
radioactivity trapped in the reaction vial was measured. The
reaction mixture was promptly analysed by radio-HPLC.
The radiochemical yields of [11C]ketones obtained here com-
pare favourably with those reported from the [11C]carbonylative
coupling of aryl iodides with aryltrialkylstannanes5,6,10 and are
achieved under significantly milder conditions (shorter reaction
time and lower temperature). They reaffirm the efficiency that
can be achieved in Pd()-mediated [11C]carbonylation reactions
for the synthesis of aryl [11C]ketones. This method is further
attractive for application in PET radiopharmaceutical produc-
tion because the reagents are stable, required in very small
amounts and used in a single pot. High specific radioactivities
can be expected, since the isotopic dilution of the [11C]carbon
monoxide with stable carbon monoxide from the atmosphere is
small; indeed carrier aryl ketones were not detected by UV
absorbance in the HPLC analyses of reaction mixtures. The
present approach is versatile with respect to functionality in
either the diaryliodonium salt or the partner aryltributyl-
stannane. Hence, the method should be extendable to the prep-
aration of [11C]benzophenones bearing different substituents in
each ring. Clearly, the opportunity that this method presents to
prepare substituted [11C]benzophenones in high radiochemical
yield from a 1 min reaction at room temperature is highly
attractive for 11C-chemistry and future PET radiopharm-
aceutical development.
Acknowledgements
The authors thank the King Faisal Specialist Hospital-
Research Centre, Saudi Arabia for the scholarship to MA-Q.
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