Palladium-mediated carboxylation of aryl halides (triflates) or benzyl halides using [13C]/[11C]carbon monoxide with tetrabutylammonium hydroxide or trimethylphenylammonium hydroxide

Article abstract of DOI:10.1039/b206420k

[Carbonyl-¹¹C]carboxylic acids were synthesised using palladium-mediated reaction of [¹¹C]carbon monoxide with aryl halides/triflates and benzyl halides in combination with either tetrabutylammonium hydroxide or trimethylphenylammoni

Full text of DOI:10.1039/b206420k

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Palladium-mediated carboxylation of aryl halides (triflates) or
benzyl halides using [13C]/[11C]carbon monoxide with tetrabutyl-
ammonium hydroxide or trimethylphenylammonium hydroxide
1
Farhad Karimi*a and Bengt Långströma,b
a Department of Organic Chemistry, Institute of Chemistry, Box 531, S-751 21 Uppsala,
Sweden
b Uppsala Research Imaging Solutions AB, S-751 85 Uppsala, Sweden
Received (in Cambridge, UK) 3rd July 2002, Accepted 13th August 2002
First published as an Advance Article on the web 5th September 2002
[Carbonyl-11C]carboxylic acids were synthesised using palladium-mediated reaction of [11C]carbon monoxide with
aryl halides/triflates and benzyl halides in combination with either tetrabutylammonium hydroxide or trimethylphenyl-
ammonium hydroxide. The radiochemical yields were in the range 20-85%. In a typical experiment starting with 2.1
GBq [11C]carbon monoxide, 0.6 GBq of HPLC-purified 1-[carbonyl-11C]naphthoic acid (13) was obtained within
25 min of the start of the carbonylation reaction (67% decay-corrected radiochemical yield). The specific radioactivity
of [carbonyl-11C]nicotinic acid (17) was in the order of 750 GBq µmolϪ1 using 10.0 µAh bombardment. [Carbonyl-
13C]nicotinic acid (17) was synthesised to verify the position of the labelling (δ 166.1) determined by 13C NMR.
dioxide to [11C]carbon monoxide and a micro-autoclave
(200 µl). The reaction mixture, containing tetrakis(triphenyl-
phosphine)palladium(), an aryl halide or triflate and tetra-
methylammonium hydroxide or trimethylphenylammonium
Introduction
Positron emission tomography (PET) is a powerful tool for
non-invasive investigation of biologically active compounds in
vivo. The increasing application of PET in nuclear medicine1
hydroxide (as hydroxide donor), was transferred by anhydrous
and drug development2 stimulates a need for further improve-
THF to a micro-autoclave at high pressure (35 Mpa). The
ment of rapid and efficient methods for incorporation of
micro-autoclave was then heated at 180 or 190 ЊC for 5 min
[11C]carbon in new tracers with high specific radioactivity.3
before releasing the crude reaction mixture into a flask at
Zerovalent palladium mediated carbonylation of organo-
reduced pressure. The target compounds and the correspond-
halides using [11C]carbon monoxide and appropriate nucleo-
ing halides or triflates are presented in Figs. 1 and 2. The
philes has been previously used for synthesis of 11C-amides,4
results show that in nearly all cases trimethylphenylammonium
11C-imides5 and 11C-hydrazides.6 However, the use of this
hydroxide seems to be a suitable hydroxide source (Table 1).
When an aqueous solution of sodium hydroxide (1 M) or
water was used as hydroxide source, almost no product was
method is limited to organohalides having no β-protons bound
to sp3 carbons due to the competing β-elimination.7
11C-Carboxylic acids have been synthesised previously using
obtained.
either a Grignard reaction of phenylmagnesium chloride and
In order to investigate the scope and limitations of aryl
[11C]carbon dioxide8,9 or via hydrolysis of the corresponding
bromide/iodide and triflate reactivity, the compounds 1, 2, 10
11C-nitrile.10
and 14 were synthesised using the corresponding halides or
triflates 20, 21, 29 and 33 under comparable conditions. The
results showed that the triflates are preferred to the correspond-
ing bromides but a higher reaction temperature is required.
Here we report a mild and rapid method for synthesis of
various [11C]carboxylic acids using the corresponding
organohalide or triflate with tetrakis(triphenylphosphine)-
palladium(), and [11C]carbon monoxide to form the appropri-
When 1-fluoro-4-(iodomethyl)benzene (29a) was used
ate Pd–acyl complex followed by using a nucleophile substrate
as a hydroxide source i.e. tetramethylammonium hydroxide or
trimethylphenylammonium hydroxide.
instead of 1-(bromomethyl)-4-fluorobenzene (29b), the radio-
chemical yield of 11C-carboxylic acid 10 was increased from
12% to 24% (using trimethylphenylammonium hydroxide, 25 µl,
37.5 mmol). Increasing the concentration of hydroxide source
resulted in a lower yield (10%).
In the case of 14, where the aryl bromide (33a) was used a
Results and discussion
Grignard reactions with [11C]carbon dioxide have been previ-
ously used for synthesis of [11C]carboxylic acids. This approach
is somewhat limited due to undesired side reactions and only a
few examples of [11C]carbon dioxide-derived 11C-labelled acids
have been reported.8,9 Another drawback with this approach
is isotopic dilution from atmospheric carbon dioxide (3.4 ×
104 ppm). Furthermore, using the corresponding 11C-nitrile
derivatives followed by hydrolysis (in two steps) might limit the
presence of some functional groups. Moreover longer reaction
time is another disadvantage of the latter method.
yield of only 7% was obtained. However, when the correspond-
ing triflate (33b) was employed the yield was increased to 39%.
2-Phenyl[carbonyl-11C]propionic acid (16) was synthesised
with a 14% yield using (1-bromoethyl)benzene, but to our
surprise (1-iodoethyl)benzene gave no product.
The determined specific radioactivity for 17 was in the range
750 30 GBq µmolϪ1 (n = 2) at 27 min after the end of bom-
bardment (using 10.0 µAh). The specific radioactivity obtained
indicates that there was no significant isotopic dilution during
the synthesis after the radionuclide production.
In this report, [11C]carboxylic acids were synthesised in a sys-
tem equipped with a device for local reduction of [11C]carbon
Identification of the labelled compounds was made with ana-
lytical LC after addition of appropriate reference substances.
2256
J. Chem. Soc., Perkin Trans. 1, 2002, 2256–2259
This journal is © The Royal Society of Chemistry 2002
DOI: 10.1039/b206420k

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Fig. 1 Target compounds.
Additional confirmation of the identity of compounds 3, 8, 11,
12, 15, 17–19 was made by LC-MS. The identity of [carbonyl-
11C]nicotinic acid was confirmed using 13C NMR analysis of
[carbonyl-13C]nicotinic acid, which was prepared using the
same procedure. The 13C signal at 166.1 ppm corresponded to
the 13C signal from the carbonyl carbon of authentic nicotinic
acid.
Fig. 2 Aryl halides/triflates.
Experimental
General
[11C]Carbon dioxide was produced with a cyclotron, and
reduced to [11C]carbon monoxide by passing though a zinc
furnace at 400 ЊC.12,13 This was concentrated and enclosed with
the reaction mixture in a micro-autoclave (200 µl).
In comparison to labelling reactions using [11C]carbon
dioxide or [11C]cyanide, the scope of the palladium-mediated
carbonylation with [11C]carbon monoxide is not limited to the
synthesis of various [11C]carboxylic acids. A further advantage
is that higher specific radioactivities may be obtained and the
synthesis can be easily automated. One disadvantage of using
this approach is a lower yield due to the competing β-hydride
elimination, when organohalides having β-hydrogen bound to
sp3 carbons are used.
Liquid chromatographic analysis (LC) was performed with a
Beckman 126 gradient pump and a Beckman 166 variable wave-
length UV-detector in series with a βϩ-flow detector. The fol-
lowing mobile phases were used: 0.05 M ammonium formate
pH 3.5 (A), acetonitrile–water (50 : 7) (B), acetonitrile (C) and
0.01 M formic acid (D). For analytical LC a Jones Chrom-
atography Genesis C18, 4 µm, 250 × 4.6 mm id column was used
at a flow rate of 1.5 ml minϪ1. For semi-preparative LC, a Jones
Chromatography Genesis C18, 4 µm, 250 × 10 mm (id), column
was used at a flow rate of 4 ml minϪ1. “Synthia”, an automated
synthesis system,14 was used for LC injection and fraction
collection. Data collection and LC control were performed with
the use of a Beckman System Gold chromatography software
package.
Radioactivity was measured using an ion chamber (Veenstra
Instrumenten bv, VDC-202). For measurements of radio-
activity during synthesis, a portable dose-rate meter was used.
In the analysis of the 11C-labelled compounds, unlabelled
reference substances were used for comparison in all the LC
runs. The identities of synthesised compounds were determined
Conclusions
The use of tetrakis(triphenylphosphine)palladium() with
[11C]carbon monoxide and the organohalide in combination
with tetramethylammonium hydroxide or trimethylphenyl-
ammonium hydroxide (as nucleophilic source) is an efficient
method for the synthesis of [carbonyl-11C]carboxylic acids
with high specific radioactivity. According to our observations
triflates11 might be suitable as precursors for the synthesis
of [11C]carboxylic acids. This is potentially valuable for
11C-labelling since carboxylic acids are important intermediates
which can be converted into other functional groups such as
esters, acid chlorides, amides and aldehydes.
J. Chem. Soc., Perkin Trans. 1, 2002, 2256–2259
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Table 1 Radiochemical yields and synthesis parameters for the 11C-labelled carboxylic acids shown in Fig. 1
LC-MS (ESIϩ)d
Compound
Methoda
Trapping efficiency (%)b
Radiochemical yield (%)c
m/z [M ϩ H]ϩ
1
eA (7)
f B (5)
g C (2)
A (1)
B (2)
C (2)
B (4)
A (1)
B (2)
A (2)
B (4)
A (1)
B (3)
A (2)
B (2)
A (2)
B (2)
B (2)
B (2)
A (1)
B (2)
B (3)
C (2)
A (2)
B (1)
B (3)
A (4)
B (2)
A (2)
B (3)
B (2)
91
88
79
98
76
81
91
68
71
55
94
79
85
93
79
92
86
60
89
96
93
80
72
95
67
19
96
77
88
82
57
4
2
1
59
78
85
35
77
75
76
46
74
40
21
31
70
26
73
33
24
50
42
23
66
7
4
2
1
—
—
2
1
1
1
1
1
1
3
4
153
—
2
4
2
2
8
4
5
—
6
7
8
—
—
165
3
2
1
2
1
1
1
2
5
2
3
1
2
1
9
10
11
12
13
—
—
252
262
—
2
4
1
3
1
2
1
1
14
15
—
39
10
25
227
16
17
2
3
1
1
1
1
14 3h
—
124
20
65
4
75
68
8
3
1
1
1
18
19
125
129
a Values in parentheses show number of runs. b Decay-corrected, the fraction of radioactivity left in the crude product after purging with nitrogen.
c Decay-corrected, calculated from the amount of radioactivity in the crude product before nitrogen purge, and the radioactivity of the LC-purified
product. d Using mobile phases C and D. e Me4NϩOHϪ was used as hydroxide source. f Me3PhNϩOHϪ was used as hydroxide source. g The appropri-
ate triflate was used instead of halide. h Analytical radiochemical yield determined by LC.
using 1H and 13C NMR and LC-MS. NMR spectra were
recorded on a Varian XL 300 (300 MHz) with chloroform-d1 as
internal standard. LC-MS was performed using a Micromass
VG Quattro with electrospray ionisation using mobile phases
C and D. A Beckman 126 pump, a CMA 240 autosampler and
an XTerra MS C18 3.5 µm, 4.6 × 100 mm column were used
for the LC-MS separation with mobile phases C and D.
THF was distilled under nitrogen from sodium–benzo-
phenone.
saturated Na2S2O3 (50 ml), and then brine (40 ml). The organic
phase was dried over MgSO4, and concentrated by evaporation
of the volatile fraction by vacuum. The crude product was
purified by flash silica gel column chromatography. Elution
with pentane yielded the title compound (4.84 g, 98%).
GC-MS: m/z = 236, 109.
1,5-Dichloro-3-iodo-2,4-dimethoxybenzene (30)
3,5-Dichloro-2,6-dimethoxybenzoic acid (0.50 g, 2.0 mmol),
iodine (0.81 g, 3.2 mmol) and mercury() oxide (0.22 g,
1.0 mmol) were dissolved in nitrobenzene (10 ml). The reaction
mixture was heated at 160–165 ЊC for 2 h under an argon
atmosphere and then left to cool to room temperature over-
night. The resulting mixture was washed with NaOH (1.5 M,
50 ml), dried over MgSO4 and the solvent evaporated under
reduced pressure. The crude product was purified by flash
chromatography (ether–pentane, 20 : 80) to obtain 0.50 g, 75%
of 30. δH (300 MHz, CDCl3): 7.43 (s, 1H), 3.86 (s, 6H). 13C
NMR (300 MHz, CDCl3): 155.5, 134.5, 130.8, 129.3, 123.4,
92.2, 60.5. GC-MS: m/z = 334, 332.
All chemicals were purchased from Aldrich or Chemtronica
(Sweden). Compounds 21b,15 29a,16 30 and 3117 were syn-
thesised according to the literature.
4-Chlorophenyl trifluoromethanesulfonate (21b)
To an ice-cooled solution of 4-chlorophenol (0.88 g, 6.86
mmol) in dry pyridine (10 ml) trifluoromethanesulfonic
anhydride (1.50 ml, 8.92 mmol) was slowly added under argon
atmosphere. The mixture was stirred at room temperature for
2.5 h and refluxed for an additional 1 h. The solvent was
removed under reduced pressure and the residue was par-
titioned between water and methylene chloride. The aqueous
layer was extracted with methylene chloride (3 × 70 ml). The
combined organic phases were dried over MgSO4, concentrated
and purified by flash chromatography using ethyl acetate–
pentane (1 : 1) to give the title compound (1.30 g, 71%).
GC-MS: m/z = 261, 129.
1-Bromo-3-iodo-2,4-dimethoxybenzene (31)
The synthesis was performed as described for 30 except that
3-bromo-2,6-dimethoxybenzoic acid was used. The purified
compound 31 was obtained (72%). δH (300 MHz, CDCl3): 7.45
(d, 1H), 6.49 (d, 1H), 3.80–3.85 (d, 6H). 13C NMR (300 MHz,
CDCl3): 159.0, 157.3, 133.1, 107.9, 107.4, 85.0, 60.4, 55.8.
GC-MS: m/z = 344, 342.
1-Fluoro-4-(iodomethyl)benzene (29a)
Hydriodic acid (57%, 10 ml) was added to (4-fluorophenyl)-
methanol (2.65 g, 21.0 mmol) at room temperature. The reac-
tion mixture was refluxed for 1 h then cooled to room tem-
perature, diluted with ether (30 ml) followed by washing with
Labelling experiments
General
procedure
A.
Tetrakis(triphenylphosphine)-
palladium() (≈ 3 µmol) and the appropriate halide (≈ 9 µmol)
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J. Chem. Soc., Perkin Trans. 1, 2002, 2256–2259

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were placed in a vial (1 ml). The vial was flushed with nitrogen
then dry THF (220 µl) was added. The resulting mixture was
heated (70 ЊC, 1 min) and kept at room temperature for 10–
15 min. An aqueous solution of tetramethylammonium hydrox-
ide (1.5 M, 25 µl, 37.5 µmol) was added and shaken just before
injection into the micro-autoclave (200 µl) at high pressure
(35 Mpa), pre-charged with [11C]carbon monoxide. The mixture
was heated at 180 ЊC for 5 min and the crude product trans-
ferred to a pre-evacuated vial (5 ml). The micro-autoclave was
washed with THF (250 µl), which was collected into the same
vial. The radioactivity of the vial was measured before and after
purging with nitrogen. The solvent was reduced to 0.1 ml by
heating at 80 ЊC and flushing with nitrogen. The crude mixture
was dissolved in acetonitrile–water before injection onto the
semi-preparative LC using solvent A and B or C. The identity
and radiochemical purity of the collected fraction were
analysed by analytical LC and LC-MS.
semi-preparative LC as described before, to obtain the desired
product (78%). 13C NMR (300 MHz, CDCl3): 166.1.
Acknowledgements
We thank Dr Robert Moulder for linguistic advice and The
Swedish Nature Research Council for its support by grant
K3464 (B. L.).
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autoclave, which was pre-charged with [11C]carbon monoxide.
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