Functionalisation of11C-labelled olefins via a Heck coupling reaction

Article abstract of DOI:10.1039/b003960h

A method for incorporation of ¹¹C (β⁺, t_1/2 = 20.3 min) in internal alkenes has been developed. [β-¹¹C]Styrene and [1-¹¹C]pent-l-ene were synthesized from benzaldehyde and butyraldehyde respectively, using [¹¹C]methylenetri-o-tolylphosphorane in a Wittig reaction. The radiochemical yield based on analytical liquid chromatography was 85-90%. The ¹¹C-labelled olefins were further coupled with several aromatic halides in a palladium mediated cross-coupling reaction forming the compounds (E)-[β-¹¹C]stilbene) (4′-amino[β-¹¹C]stilbene, (E)-[β-¹¹C]stilbene-2′-methanol, (E)-3′-ethoxycarbonyl[β-¹¹C]stilbene, (E)-4′-methyl[β-¹¹C]stilbene, (E)-1-phenyl[1-¹¹C]pent-1-ene and (E)-1-(4-aminophenyl)[1-¹¹C]pent-l-ene. The reaction sequence was performed without purification of the intermediate ¹¹C-labelled olefin. Radiochemical yields of the coupling products were 47-55% according to analytical liquid chromatography. The decay-corrected isolated radiochemical yield of (E)-[β-¹¹C]stilbene was approximately 38% and the total synthesis time was 40 min, counted from the end of radionuclide production to the isolated product. In a typical experiment starting from 4.7 GBq [¹¹C]methyl iodide, 450 MBq of (E)[β-¹¹C]stilbene was obtained in a radiochemical purity higher than 95%. This method was also used for the synthesis of (E)-(β-¹³C)stilbene, which was used to verify the labelling position by ¹³C NMR. The Royal Society of Chemistry 2000.

Full text of DOI:10.1039/b003960h

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11
Functionalisation of C-labelled olefins via a Heck coupling
reaction
Margareta Björkman and Bengt Långström*
1
Uppsala University PET Centre, SE-751 85 Uppsala, Sweden.
E-mail: bengt.langstrom@pet.uu.se
Received (in Cambridge, UK) 17th May 2000, Accepted 6th July 2000
Published on the Web 18th August 2000
ϩ
11
A method for incorporation of 11C (β , t = 20.3 min) in internal alkenes has been developed. [β- C]Styrene and
₁
₂

[1-11C]pent-1-ene were synthesized from benzaldehyde and butyraldehyde respectively, using [11C]methylenetri-o-
tolylphosphorane in a Wittig reaction. The radiochemical yield based on analytical liquid chromatography was
85–90%. The 11C-labelled olefins were further coupled with several aromatic halides in a palladium mediated cross-
coupling reaction forming the compounds (E)-[β-11C]stilbene, (E)-4Ј-amino[β-11C]stilbene, (E)-[β-11C]stilbene-2Ј-
methanol, (E)-3Ј-ethoxycarbonyl[β-11C]stilbene, (E)-4Ј-methyl[β-11C]stilbene, (E)-1-phenyl[1-11C]pent-1-ene and
(E)-1-(4-aminophenyl)[1-11C]pent-1-ene. The reaction sequence was performed without purification of the inter-
mediate 11C-labelled olefin. Radiochemical yields of the coupling products were 47–55% according to analytical
liquid chromatography. The decay-corrected isolated radiochemical yield of (E)-[β-11C]stilbene was approximately
38% and the total synthesis time was 40 min, counted from the end of radionuclide production to the isolated
product. In a typical experiment starting from 4.7 GBq [11C]methyl iodide, 450 MBq of (E)-[β-11C]stilbene
was obtained in a radiochemical purity higher than 95%. This method was also used for the synthesis of
(E)-(β-13C)stilbene, which was used to verify the labelling position by 13C NMR.
This reaction is established as an efficient and versatile method
Introduction
for forming carbon–carbon bonds and the tolerance of many
different functional groups on the substrates makes it a suitable
reaction for preparation of functionalised olefins.
Positron emission tomography (PET) has become an important
tool for non-invasive investigations of the fate of biologically
interesting compounds in vivo.1 As well as the interest in PET
within the field of nuclear medicine, the technology has
attracted attention in the development of new drugs.2 The
In the present paper a method is described where a 11C-label
was incorporated in aromatic and aliphatic alkene structures
using the Wittig reaction. The 11C-labelled olefins were then
coupled with different haloarenes, mediated by a palladium
catalyst, resulting in 11C-labelled internal alkenes (Schemes 1
and 2).
radionuclides most frequently combined with PET are 11C, 15
O
and 18F with half-lives of 20.3, 2.07 and 110 min, respectively.
The demand for new labelled compounds is ever increasing and
new routes often have to be developed to synthesise the target
compounds. In order to increase the scope of synthetic possi-
bilities new methods need to be investigated. Since the number
of 11C-labelled precursors will always be limited, it is important
to explore the development of methods for multi-step synthesis.
Synthesis time has to be kept within the time frame set by the
half-life of the nuclide, which means that the reactions have
to be efficient and preferably without purification in between
reaction steps.
One of the most frequently used 11C-labelled precursors in
the production of PET tracers is [11C]methyl iodide.1 Among
its applications has been the formation of [11C]methylene-
triphenylphosphoranes,3 from which 11C-labelled olefins have
been synthesised.4 Olefination reactions with [11C]methylene-
triphenylphosphoranes are general and effective reactions with
few limitations regarding the aldehyde reagents.
Palladium-mediated reactions have come to play an import-
ant role in the development of carbon–[11C]carbon bond form-
ation.5 Due to the small amount of the 11C-labelled compound†
the reactions are performed with an excess amount of pal-
ladium species compared to labelled compound, rather than
with the catalytic amounts used under conventional reaction
conditions with stable compounds. A common method for
functionalising olefins is the palladium-mediated Heck reaction
where a haloarene or a haloalkene is coupled with an alkene.6
Scheme 1
Results and discussion
[β-11C]Styrene and [1-11C]pent-1-ene were synthesised from
[11C]methyl iodide, benzaldehyde and butyraldehyde respec-
tively using tri-o-tolylphosphine in o-dichlorobenzene with
† The total amount of methyl iodide is typically in the range of 10–100
nmol.
DOI: 10.1039/b003960h
J. Chem. Soc., Perkin Trans. 1, 2000, 3031–3034
This journal is © The Royal Society of Chemistry 2000
3031

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Table 1 Radiochemical yield determined by analytical LC as the percentage of the total amount of activity in samples withdrawn from the reaction
mixture, n > 5
Radiochemical
yield (%)
Unreacted
Entry
Halide
[β-11C]styrene (%)
Product
1
2
55 (38)a
2
0
53 (40)a
3
4
43
49
3
5
5
47 (34)a
1
a Decay-corrected isolated radiochemical yield.
palladium solution was pre-prepared and flushed with
nitrogen gas. To promote the reaction the final reaction mix-
ture was heated for five minutes. [1-11C]Pent-1-ene was coupled
with two aromatic halides, iodobenzene and 4-iodoaniline.
Radiochemical yields‡ of the resulting products, (E)-1-phenyl-
[1-11C]pent-1-ene (6) and (E)-1-(4-aminophenyl)[1-11C]pent-1-
ene (7) were 54 and 47%, respectively. [β-11C]Styrene was
coupled with five aromatic halides resulting in the 11C-labelled
stilbene analogues presented in Table 1. Radiochemical purity
of the isolated product was more than 95% and the total syn-
thesis time from the end of radionuclide production to the
isolated product was 40 min.
Aryl exchange between palladium and phosphine
In the beginning of the investigation, triphenylphosphine was
used to form the phosphonium ylide in the Wittig reaction. It
was then revealed that the triphenylphosphine was also acting
as a ligand to palladium and causing an aryl exchange between
palladium and the phosphine to take place in the Heck reac-
tion. This was evident since the same product, (E)-[11C]stilbene,
was formed in the Heck reaction with [11C]styrene, regardless of
which aromatic halide was added to the reaction mixture. The
aryl exchange has been reported to take place between phos-
phorus bound aryl and palladium bound aryl8,9 or alkyl10
groups within a palladium complex, (Fig. 1).
A suggested mechanism for this process involves the
formation of a phosphonium salt from the oxidatively added
moiety together with one of the phosphine ligands, via a
reductive elimination. If the salt is oxidatively added to the
palladium again a different carbon–phosphorus bond may be
broken.9,11
Scheme 2
epichlorohydrin as base precursor. The application of epi-
chlorohydrin as a base precursor has been described earlier.7
The reaction conditions were analogous to those reported pre-
viously.3 Radiochemical yields‡ were 85–90% in both cases and
the remaining radioactivity was mainly unreacted [11C]methyl
iodide and [11C]methyltri-o-tolylphosphonium salt.
The Heck reaction was performed in a one pot procedure
by adding the unpurified 11C-labelled olefin to a solution of
palladium mediator and halide in o-dichlorobenzene. The
‡ The radiochemical yield of the products was determined by analytical
liquid chromatography (LC) as the percentage of the total amount of
activity in samples withdrawn from the reaction mixture.
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Characterisation
After each LC-analysis a GM-tube was used to establish that
there was no residual radioactivity on the LC-column, in the
form of uneluted 11C-labelled by-products.
The identities of 1, 2, 3, 4, 5 and 6 were verified using two
different analytical LC-systems and co-elution of the authentic
reference compounds and the 11C-labelled products.
The identity of 7 was verified by LC-MS analysis, where the
positively charged protonated molecular ion was detected, m/z
162. For further verification, 2 was also analysed by LC-MS and
here a peak at m/z 196, which represents [M ϩ H]ϩ, was present
during the analysis of both the reference compound and the
labelled product. Simultaneous labelling of 1 with 11C and 13C
was employed in order to record a 13C NMR spectrum. The
product gave a signal at 127.5 ppm which corresponds to a vinyl
carbon in the (E)-stilbene reference. A labelled side product
eluting approximately one minute after the main product on
analytical LC was detected in each Heck reaction. Com-
mercially available (Z)-stilbene was used to verify this product
in the analysis of the reaction mixture after synthesis of 1. The
radiochemical yields of the by-products assumed to be the
cis-compounds were in the order of 5–10%.
Fig. 1
It was confusing to see the aryl exchange in this reaction
since tri-o-tolylphosphine was used as a ligand to palladium
and the aryl exchange has been reported to be suppressed by
this palladium complex.9 The complex has also been reported
to give good results in Heck reactions12 and the formation of
tetraarylphosphonium salts, which has been reported to be a
problem in Heck reactions with electron rich aryl halides, can
also be suppressed by this ligand.13 However, the products
formed after the aryl exchange did not originate from a
palladium complex with tri-o-tolylphosphine but from a
complex with triphenylphosphine as the ligand. This indicated
that there was triphenylphosphine remaining from the Wittig
reaction that was acting as ligand to palladium and causing
the exchange to take place. To avoid the exchange, triphenyl-
phosphine had to be excluded from the reaction mixture
before the Heck reaction was performed. In order to simplify
automation and minimise the loss of radioactivity due to
transfers, a one pot system is preferred in most labelling syn-
theses with short-lived radionuclides. The automation of
labelling synthesis is important in order to ensure radiation
protection for the chemists and also to ensure the pharma-
ceutical integrity of the labelled compound. Instead of
purifying the intermediate olefin, the triphenylphosphine in
the Wittig reaction was exchanged for tri-o-tolylphosphine. Tri-
o-tolylphosphine worked equally well as a Wittig reagent
and no other modifications to the method reported earlier3
were needed. A method using polymer-bound triphenyl-
phosphine for the synthesis of [11C]methylenetriphenyl-
phosphoranes has been developed14 and this approach was
also investigated. In this method the polymer was removed
from the reaction solution by filtration using a syringe filter
unit. The major drawback using the polymer-bound tri-
phenylphosphine was that one third of the radioactivity was lost
after filtering of the polymer matrix from the reaction solution.
Washing of the filter and the polymer did not improve this
result.
Conclusion
11C-Labelled internal alkenes have been synthesised from the
readily available precursor [11C]methyl iodide via a general
method. The synthesis sequence could be performed in one pot
when tri-o-tolylphosphine was used in the Wittig reaction. The
cross-coupling reaction was compatible with many different
functional groups on the halides and no protective groups were
necessary in the cases presented herein. An advantage of this
method is the availability of labelling positions in carbon–
carbon bonds that are not bonded to heteroatoms. This should
be a rather stable position regarding biological processes, which
makes the method an interesting option when alternative label-
ling positions are necessary. Furthermore, the method could be
used for the incorporation of other carbon isotopes e.g. the
synthesis of 13C-labelled stilbene, which in this case was used to
verify the position of the label by 13C NMR.
Experimental
General
[11C]Carbon dioxide was prepared by the 14N(p, α)11C nuclear
reaction using a nitrogen (AGA Nitrogen 6.0) gas target (con-
taining 0.05% oxygen, AGA Oxygen 4.8) and 17 MeV protons
produced by the Scanditronix MC-17 cyclotron at the Uppsala
University PET Centre. [11C]Carbon dioxide was converted to
[11C]methyl iodide by reaction with lithium aluminium hydride
and subsequent reaction with hydriodic acid,17 using a semi-
automated synthesis system, Synthia.18
o-Dichlorobenzene is a medium polar solvent suitable for the
Wittig reaction. o-Dibromobenzene has also been reported
as a good solvent for Wittig reactions with [11C]methyl
iodide,14 but this solvent could be implemented in the Heck
reaction. For the Heck reaction a more polar solvent than
o-dichlorobenzene is usually preferred,15 but since a polar
solvent also enhances the ligand interchange,9 o-dichloro-
benzene seemed to be a good compromise. Microwave heating
of the reaction mixture was investigated since high temper-
atures are required for the coupling reaction to take place,
and improved results have been reported using this method.16
In this case however, conventional heating was equally efficient
and offered a more convenient way of handling the radioactive
reaction mixture. As more than one equivalent of the palladium
catalyst was used compared to the 11C-labelled olefin, formed in
the Wittig reaction, no base was used to regenerate the active
palladium species.
Chromatography
LC was performed using a Beckman 126 pump and a Beckman
166 UV detector in series with a βϩ-flow detector. Data collec-
tion was performed using the Beckman System Gold chrom-
atography software package for semi-preparative LC and the
Beckman System Nouveau Chromatography Software Package
for analytical LC. The analytical LC column used was a
Beckman Ultrasphere 5 µm Octyl, (250 × 4.6 mm) and the
semi-preparative LC column was a Jones Chromatography
Genesis C-18 (250 × 10 mm). Mobile phases were 0.05 M
ammonium formate pH 3.5 (A), 0.025 M potassium dihydro-
genphosphate pH 4.7 (B) and acetonitrile–water (50:7) (C).
The LC was performed at room temperature and the UV-
detection at 254 nm. LC-MS equipment consisted of a
Beckman 126 pump, a CMA 240 autosampler (CMA Micro-
J. Chem. Soc., Perkin Trans. 1, 2000, 3031–3034
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dialysis, Stockholm, Sweden) and
a
VG Quattro mass
150 ЊC. Epichlorohydrin (80 µL, 1.0 mmol) and benzaldehyde
spectrometer (Micromass, Manchester, UK) equipped with
pneumatically assisted electrospray. The column in the LC-MS
system was a Beckman Ultrasphere 5 µm Octyl, (250 × 4.6
mm). A post column split was used, with 1% of the total flow of
1 ml minϪ1 delivered to the electrospray probe and 99%
delivered to a Beckman 166 UV detector in series with a
Bioscan Flow-count βϩ-detector. Mobile phases were 100 mM
TFA in water (D) and methanol (E). Isocratic elution 0–6 min
with D:E (75:25) and a linear gradient to D:E (95:5) after
6 min was employed to elute the analytes.
(20 µL, 0.2 mmol) were added to the solution and the mixture
was heated for an additional 5 min. To the mixture a solution of
Pd2(dba)3 (2 mg, 2.2 µmol), P(o-Tol)3 (2.2 mg, 7.2 µmol) and
iodobenzene (10 µL, 90 µmol) in 200 µL DMF was added. The
resulting mixture was heated for 7 min at 150 ЊC whereafter a
sample was withdrawn from the reaction mixture for analysis.
The mixture was diluted to a total volume of 3 mL with
acetonitrile–water and injected onto a semi-preparative LC-
column. The column was eluted with an isocratic elution at a
flow of 5 mL minϪ1 with solvents A:C (75:25) followed by a
linear gradient 6–12 min (5:95). The product was collected
after approximately 9 min and the collected fraction was diluted
with water and concentrated on a C-18 solid phase extraction
column. After washing with water the product was eluted with
ethanol. The identity and radiochemical purity of the collected
fraction was verified using analytical LC with the authentic
reference added to the solution. The ethanol was evaporated
and the residue was dissolved in CDCl3. 13C NMR δ 127.5.
Chemicals
Iodobenzene, 4-bromoaniline, 4-iodoaniline, 2-iodobenzyl
alcohol, 4-iodotoluene, styrene, Z)-stilbene, (E)-stilbene, benz-
aldehyde, butyraldehyde, (E)-1-phenylpent-1-ene, pent-1-ene,
N,N-dimethylformamide (DMF), tri-o-tolylphosphine (P(o-
Tol)3), and tris(dibenzylideneacetone)dipalladium(0) (Pd2-
(dba)3) were purchased from Aldrich and used without further
purification. 1,2-Dichlorobenzene (o-DCB) and epichloro-
hydrin were used freshly distilled. 3-Iodoethyl benzoate was
synthesised from 3-iodobenzoic acid in an esterification
reaction. Reference compounds for the labelled products,
(E)-stilbene, (E)-4-aminostilbene, (E)-stilbene-2-methanol,
(E)-3-ethoxycarbonylstilbene and (E)-4-methylstilbene, were
synthesised from styrene with iodobenzene, 4-bromoaniline,
2-iodobenzyl alcohol, 3-iodoethyl benzoate and 4-iodotoluene,
respectively, using an established method.16 The reference com-
Acknowledgements
Financial support was provided by the Swedish Natural Science
Research Council (K-KU 3463). Grants from C. F. Liljewalchs
foundation and from Göransson-Sandvikens foundation are
gratefully acknowledged.
References
1
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[11C]Methyl iodide was distilled through a Sicapent drying
tower and was trapped in a solution of P(o-Tol)3 (5 mg, 16
µmol) in 200 µL o-DCB. After trapping of [11C]methyl iodide
the solution was heated for 3 min at 150 ЊC. Epichlorohydrin
(80 µL, 1.0 mmol) and benzaldehyde (20 µL, 0.2 mmol) or
butyraldehyde (18 µL, 0.2 mmol) were added to the solution and
the mixture was heated for an additional 2 min. To this solution
Pd2(dba)3 (2 mg, 2.2 µmol), P(o-Tol)3 (2.2 mg, 7.2 µmol) and
halide (90 µmol) in 200 µL DMF were added. The resulting
mixture was heated for 5 min at 150 ЊC whereafter a sample was
withdrawn from the reaction mixture for analysis. The identity
and radiochemical yield were determined by analytical LC
with isocratic elution 1.5 mL minϪ1 (B:C) (70:30, v:v). When
semi-preparative LC was performed the reaction mixture was
diluted to a total volume of 3 mL with acetonitrile–water and
injected onto a semi-preparative LC-column. The column was
eluted isocratically at a flow of 5 mL minϪ1 with solvents A:C
(75:25, v:v) followed by a linear gradient 6–12 min (5:95). The
radiochemical purity and identity of the collected fraction was
determined by analytically LC as described above.
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[ꢀ-11C]- and [ꢀ-13C]Stilbene
[11C]Methyl iodide was distilled through a Sicapent drying
tower and was trapped in a solution of P(o-Tol)3 (5 mg, 16
µmol) in 200 µL o-DCB. After trapping of [11C]methyl iodide,
15 µmol (13C)CH3I (99% 13C) in 10 µL DMF was added to the
solution and the resulting mixture was heated for 5 min at
3034
J. Chem. Soc., Perkin Trans. 1, 2000, 3031–3034