Synthesis of 11C-amides using [11C]carbon monoxide and in situ activated amines by palladium-mediated carboxaminations

Article abstract of DOI:10.1039/b209553j

[¹¹C]Carbon monoxide at low concentrations, aryl halides and amines were used in the palladium-mediated synthesis of twenty ¹¹C-amides. In the study several approaches to improve the radiochemical yield were explored. Eight of the selected amides were prepared by in situ activation of the amines using lithium bis(trimethylsilyl)amide and the radiochemical yields of these reactions were improved compared to utilising a previous reported method. In the synthesis of 1-[carbonyl-¹¹C]benzoyl-3-methyl-1H-indole (11) from 3-methyl-1H-indole (25), the corresponding organotin-amine was prepared prior to the acylation reaction. In a typical experiment, N-(4-hydroxyphenyl)-[carbonyl-¹¹C]acetamide (5) was prepared in 15% radiochemical yield using 4-aminophenol (20) but the yield increased to 63% when the amine was activated by lithium bis(trimethylsilyl)amide.

Full text of DOI:10.1039/b209553j

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11
Synthesis of C-amides using [11C]carbon monoxide and in situ
activated amines by palladium-mediated carboxaminations
Farhad Karimia and Bengt Långström*a,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 1st October 2002, Accepted 11th November 2002
First published as an Advance Article on the web 23rd December 2002
[11C]Carbon monoxide at low concentrations, aryl halides and amines were used in the palladium-mediated synthesis
of twenty 11C-amides. In the study several approaches to improve the radiochemical yield were explored. Eight of the
selected amides were prepared by in situ activation of the amines using lithium bis(trimethylsilyl)amide and the
radiochemical yields of these reactions were improved compared to utilising a previous reported method. In the
synthesis of 1-[carbonyl-11C]benzoyl-3-methyl-1H-indole (11) from 3-methyl-1H-indole (25), the corresponding
organotin–amine was prepared prior to the acylation reaction. In a typical experiment, N-(4-hydroxyphenyl)-
[carbonyl-11C]acetamide (5) was prepared in 15% radiochemical yield using 4-aminophenol (20) but the yield
increased to 63% when the amine was activated by lithium bis(trimethylsilyl)amide.
Introduction
Short-lived positron-emitting radionuclides have been incorpor-
Scheme 1
ated into compounds for applications in non-invasive in vivo
studies using Positron Emission Tomography (PET).1 Special
amine were transferred to the micro-autoclave reactor vessel
synthetic strategies are required due to the short half-life of 11
C
pre-charged with [11C]carbon monoxide. The reaction was
standardised and performed by heating the autoclave to the
appropriate temperature for 5 min before releasing the crude
mixture into an evacuated receiving flask. The target com-
pounds and the corresponding halides and amines are
presented in Figs. 1–3. The results are summarised Tables 1–3.
The 11C-labelling of the target molecules 1a–1g, 3 and 4 was
performed according to the previous method (method A) using
the amines i.e. pyrrolidine and dimethylamine. The isolated
radiochemical yields of the compounds were in the range of
72–91% (Table 1).
(t = 20.3 min) and the use of sub-micromole quantities of
½
reactants. [11C]Carbon monoxide has been recognised as a
potential precursor for 11C-labelling, but so far it has found
limited use in labelling chemistry2 due to its low reactivity and
the difficulty of trapping it in the reaction medium.3 The trap-
ping problem was overcome by the development of a micro-
autoclave system.4 By use of this technique, a wide range of
compounds containing a carbonyl functionality5 have been
prepared in 11C-synthesis.
In this paper, the method of synthesising 11C-amides has
been improved by the activation of amine nucleophiles, e.g. in
situ activation of aniline, before reacting with the Pd–acyl
complex.
Further investigation showed that this method5a was not
effective in 11C-labelling when using less reactive amines, aniline
derivatives and indoles. Compounds 5–10 were therefore
selected to explore how the synthesis of the 11C-amides using
lithium bis(trimethylsilyl)amide could improve the radio-
chemical yields (method B) compared to method A. The
isolated radiochemical yields for compounds 5–10 were in the
range of 19–85% (Table 1) when method B was used.
The aniline derivatives showed low reactivities in the pal-
ladium-promoted carboxamination when compounds 5, 6a, 8,
9a and 10b were synthesized by method A. In these cases the
analytical radiochemical yields were 31, 27, <0.1, 20 and 10%
(Table 1). Using lithium bis(trimethylsilyl)amide (1 M in THF)
to activate the amine by method B, the isolated radiochemical
yields of 5, 6a, 8, 9a and 10b were increased to 63, 72, 25, 80 and
65%, respectively (Table 1).
The isolated radiochemical yield of 7-pyridin-2-yl-7-aza-
bicyclo[4.2.0]octa-1,3,5-trien-8-[carbonyl-11C]one (7) was 19%
when the synthesis was performed in the presence of lithium
bis(trimethylsilyl)amide (method B). However, the isolated
radiochemical yield of 7 was increased to 71% using method A.
The explanation is that the higher reactivity of N-(2-bromo-
phenyl)pyridin-2-amine (17) is favored by the ring closure
reaction (Table 1).
The impact of the lithium bis(trimethylsilyl)amide concen-
tration was investigated in the synthesis of 5-[carbonyl-11C]-
benzoyl-5H-dibenzo[b,f]azepine (8) and N-phenyl[carbonyl-
11C]benzamide (9a). For compound 8, amide concentrations of
Results and discussion
In the last few years palladium-mediated reactions using
[11C]carbon monoxide at low concentrations have been explored
as an approach to isotopic labelling with a view to preparing
compounds containing various functional groups.6
In order to further expand the use of the previously reported
method for synthesis of 11C-amides,5a a series of relatively
reactive amines such as pyrrolidine (19) and dimethylamine was
studied. When using less reactive amines, e.g. aniline, aniline
derivatives and indole (25), the previous method gave products
in low yields or even no product at all. One approach to
solving this problem may be to perform the reaction in two
steps. In the first step the corresponding organo-acyl-complex
(R11COPd(PPh3)2)X) is generated and then the second step
involves the reaction of the appropriate anion of the amine.7
The short half-life of 11C frequently restricts the experimental
procedure and so, if possible, it is advantageous to perform the
labelling synthesis by a one-pot procedure. In the case of in situ
amide synthesis, activation of the appropriate amines could be
an approach to overcome this limitation (Scheme 1).
All the 11C-amides were synthesised using a stainless steel
micro-autoclave. The reaction mixtures containing tetrakis(tri-
phenylphosphine)palladium(), aryl halide and the appropriate
T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 3
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 5 4 1 – 5 4 6
541

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Fig. 3 Amines.
0.1, 0.2 and 0.3 M gave analytical radiochemical yields of 33, 18
and 2%, respectively. In the case of 9a, the analytical radio-
chemical yields were 90 and 55% when the concentrations of
the reagent were 0.1 and 0.2 M (Table 2).
Further investigation showed that lithium bis(trimethylsilyl)-
amide gave higher radiochemical yields than potassium bis-
(trimethylsilyl)amide (0.5 M in toluene). For compound 9a
the radiochemical yield decreased from 90% to 8% when 0.1 M
of potassium bis(trimethylsilyl)amide was used instead of
0.1 M of lithium bis(trimethylsilyl)amide. Similarly the radio-
chemical yield of 10b decreased form 76% to 19% under similar
conditions (Table 2).
The labelling method was further studied in the synthesis of
1-benzoyl-3-methyl-1H-indole (11). When 3-methyl-1H-indole
(25) was used in method A or activated by lithium bis(tri-
methylsilyl)amide (method B), the analytical radiochemical
yield was in both cases less than 0.1%. However, the isolated
radiochemical yield was improved to 32% by in situ generation
of the corresponding organotin–amine by treating lithium
amide with trimethyltin chloride at room temperature (Scheme
2, Table 1). In the attempts to perform the synthesis of (11) in a
Fig. 1 Target compounds.
Scheme 2
one-pot procedure, around 90% of radioactivity remained in
the stainless steel micro-autoclave.
It is well-known that organohalides, e.g. (1-bromoethyl)-
benzene (13), having β-protons bound to sp3 carbons may give
low yields due to competing elimination when utilized in
palladium-catalysed reactions.5a,8 It was therefore assumed that
the competing reaction would limit its use in amide synthesis.
However when trying to synthesize 1-(2-phenyl[carbonyl-11C]-
propanoyl)pyrrolidine (2) using (1-iodoethyl)benzene, the trap-
ping efficiency was good (99%) although the radiochemical
yield as expected was low (<1%) when performed at 150 ЊC. In
another case compound 13 was used, and the trapping effi-
ciency was 94% with a 28% radiochemical yield of 2 at 150 ЊC.
When the synthesis was performed at 100 ЊC, the isolated radio-
chemical yield increased to 58%. The synthesis of 2 using
Fig. 2 Halides.
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 5 4 1 – 5 4 6
542

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Table 1 Trapping efficiencies and radiochemical yields for the 11C-labelled amides shown in Fig. 1
Comp.
Method
Trapping efficiency (%)a, b, c
Radiochemical yield (%)a, d, e
LC-MS (ESIϩ)f m/z[M ϩ H]ϩ
1a
1b
1c
1d
1e
1f
1g
2
A
A
A
A
A
A
A
Ag
Ah
Ah, i
A
A
A
B
A
B
B
A
B
A
B
A
B
B
B
A
B
A
B
C
99(3)
99(2)
99(2)
99(3)
99(2)
99(4)
97(2)
99(2)
94(2)
95(3)
99(3)
96(2)
84(2)
99(2)
85(7)
99(2)
99(2)
98(3)
89(2)
80(2)
87(2)
93(2)
96(3)
98(2)
99(2)
83
94(85%)
98(89%)
92(81%)
97(88%)
94(83%)
98(91%)
80(72%)
<0.1
177
176
210
206
221
208
248
204
28
77(58%)
96(87%)
88(79%)
31(15%)
71(63%)
27(17%)
82(72%)
85(74%)
79(71%)
28(19%)
<0.1
33(25%)
20
90(80%)
92(85%)
58(48%)
10
3
4
5
156
152
152
6a
328
6b
7
277
197
8
298
198
9a
9b
10a
10b
256
199
199
99(2)
93(5)
85(2)
97(3)
76(65%)
<0.1
<0.1
11
236
41(32%)
a All results are presented as mean values with a maximum range of 5%. b Decay-corrected mean values and the fraction of radioactivity left in the
crude product after purging with nitrogen. c Values in parentheses show the number of runs. d Analytical yield determined by HPLC. e Values in
parentheses show decay-corrected isolated radiochemical yields calculated from the amount of radioactivity in the crude product before nitrogen
purge, and the radioactivity of the LC purified product. f Using mobile phases C and D. g Using (1-iodoethyl)benzene. h Using (1-bromoethyl)-
benzene. i The reaction was performed at 100 ЊC.
Table 2 Trapping efficiencies and radiochemical yields for compounds 8, 9a and 10b varying the reagents
Trapping efficiency (%)c d, e
Radiochemical yield (%)b c, f
Comp.
R–Xa/M–RЈb
150 ЊC
190 ЊC
150 ЊC
190 ЊC
8
8
X = I/M = Li (0.1 M)
X = I/M = Li (0.2 M)
X = I/M = Li (0.3 M)
X = I
X = I/M = Li (0.1 M)
X = I/M = Li (0.2 M)
X = I/M = K (0.1 M)
X = I/M = K (0.05 M)
X = I/M = K (0.03 M)
X = OTf/M = Li (0.1 M)
X = OTf/M = Li (0.1 M)
X = I/M = Li (0.1 M)
X = I/M = K (0.1 M)
X = I/M = K (0.05 M)
99(2)
99
98
—
—
—
—
—
—
—
—
33(25%)
18
2
20
90(80%)
55
8
48
28
6
—
76(65%)
19
—
—
—
—
—
—
—
—
—
32
65(55%)
—
—
8
9ag
9a
9a
9a
9a
9a
9a
9ah
10b
10b
10b
93(2)
96(3)
99
99(2)
99(2)
99(2)
98(2)
—
—
96(2)
94(2)
—
—
—
99(2)
99
99
24
—
a R–X = the corresponding organoiodide or triflate. b M–RЈ = lithium or potassium bis(trimethylsilyl)amide c All results are presented as mean values
with a maximum range of 5%. d Decay-corrected mean values and the fraction of radioactivity left in the crude product after purging with nitrogen.
e Analytical yield determined by HPLC. Values in parentheses show number of runs. f Values in parentheses show decay-corrected isolated radio-
chemical yields calculated from the amount of radioactivity in the crude product before nitrogen purge, and the radioactivity of the LC purified
product. g The synthesis was performed as described in method B. h The synthesis was performed using tetrabutylammonium iodide.
(1-iodoethyl)benzene indicated that the possible competing
β-hydride elimination may be suppressed under some specific
conditions.
sulfonate and aniline (23a) was studied. Compound 9a was
produced in 32% yield after pre-treating the aniline with lithium
bis(trimethylsilyl)amide. We also investigated the impact of
using tetrabutylammonium iodide with triflates in the carb-
onylation reaction. The radiochemical yield of 9a increased
to 65% when performing the reaction at 190 ЊC using phenyl
trifluoromethanesulfonate treated with tetrabutylammonium
iodide combined with activation of the amine as described in
method B. As a comparison, the synthesis of 9a using iodo-
benzene gave 80% isolated radiochemical yield at 150 ЊC
In this report, the use of organoiodides is usually preferred
but sometimes they are not easy to prepare. Occasionally the
triflate may be an alternative.9
In our previous report5a it was suggested that the bromide
in R11COPd(PPh3)2Br may be exchanged with iodide under
certain conditions. In the 11C-labelling of N-phenyl[carbonyl-
11C]benzamide (9a), the use of phenyl trifluoromethane-
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 5 4 1 – 5 4 6
543

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Table 3 Experimental data for the synthesis of compounds 1a–1f, 2, 8, 11 and 17
Comp.
Yield (%)
GC-MS
δH
δC
1a
1b
1c
93
94
97
177, 175, 106
176, 174, 105
210, 208, 139
—
—
—
—
7.41 (2H, d), 7.30 (2H, d), 3.56 (2H, t),
3.35 (2H, t), 1.85 (4H, m)
168.3, 135.6, 135.3, 128.5, 128.3, 49.4,
46.1, 26.2, 24.2
1d
1e
1f
86
98
96
206, 204, 135
221, 178, 150
208, 207, 98
—
—
—
—
7.23 (2H, t), 6.98 (2H, t), 3.59 (2H, s), 3.43
(4H, m), 1.85 (4H, m)
169.2, 163.3, 160.1, 130.5, 130.4, 115.4,
115.1, 46.8, 45.9, 41.1, 26.1, 24.3
2
8a
94
98
94
—
204, 203, 98
298, 297, 192
236, 235, 105
250, 249, 169
—
—
—
—
—
—
—
11b
17
154.8, 148.0, 137.6, 132.6, 127.9, 122.8,
119.9, 115.8, 109.8
a To a solution of 5H-dibenzo[b,f]azepine (1.04g, 5.4 mmol) in THF (5 ml) butyllithium (2.5 M in hexane, 2.4 ml) was added at room temperature
under nitrogen atmosphere. The reaction mixture was stirred for 15 min. The solvent was evaporated under reduced pressure. The residue was
dissolved in methylene chloride (5 ml) and benzoyl chloride (0.70 ml, 6.0 mmol) was added. The resulting mixture was stirred overnight at room
temperature, treated with saturated NaHCO3 (50 ml) and extracted with methylene chloride (3 × 50 ml). The pooled extracts were dried (MgSO4) and
concentrated under reduced pressure. The crude product was purified to give 8 (1.57g). b A mixture of 3-methyl-1H-indole (25) (0.75 g, 5.72 mmol) in
dry methylene chloride (3.0 ml) was treated with lithium bis(trimethylsilyl)amide (1 M in THF, 5.9 ml, 5.9 mmol) under nitrogen atmosphere at room
temperature. To this was added benzoyl chloride (0.7 ml, 6.03 mmol) and the mixture stirred at room temperature for 24 h. The reaction mixture was
diluted with NaHCO3 (50 ml) and extracted with methylene chloride (3 × 50 ml). The combined organic phases were dried and concentrated under
reduced pressure. The crude product was purified to give 11 (1.26, 94%).
(Table 2). This suggests that organoiodides are preferred
compared to the corresponding triflate, which occasionally may
be used.
βϩ-flow detector.15 The following 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 Chromatography Genesis C18, 4 µm,
Since a closed system is used for all the syntheses, washing of
the system is an important factor to consider in order to secure
a reasonable reproducibility of the experiments. Could there be
a risk of contamination when performing a series of experi-
ments? This so called “carry over effect” between experiments
in the micro-autoclave was explored. When the micro-autoclave
was washed and conditioned as described in the Experimental
section, the reproducibility was better than 95%.
250 × 4.6 mm (id) column was used at a flow of 1.5 ml minϪ1
.
For semi-preparative LC, a Jones Chromatography Genesis
(UK) C18, 4 µm, 250 × 10 mm (id), column was used at a flow of
4 ml minϪ1. Synthia, an automated synthesis system,16 was used
for LC injection and fraction collection. Data collection and
LC control were performed using a Beckman System Gold
chromatography software package (USA).
Radioactivity measurements were performed using an ion
chamber (Veenstra Instrumenten bv, VDC-202, Holland). For
coarse estimations of radioactivity during synthesis, a portable
dose-rate meter was used (Långenäs eltekniska AB, Sweden).
In the analysis of the 11C-compounds, unlabelled reference
substances were used for comparison in all LC runs. The iden-
Conclusions
[11C]Carbon monoxide at low concentrations with tetrakis-
(triphenylphosphine) palladium() and the organohalide with
in situ activated amine (as nucleophile) may be an efficient
approach to the synthesis of 11C-amides, when using an amine
of low reactivity such as aniline. The method is rapid, mild
and in many cases the reaction can be conducted in a one-pot
procedure probably suitable for automation.
1
tity of the synthesised compounds was determined using H
and 13C NMR and LC-MS. NMR spectra were recorded on a
Varian XL 300 (300 MHz) and chloroform-d1 was used 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 a
XTerra MS C18 3.5 µm, 100 × 4.6 mm (id) column were used.
THF was distilled under nitrogen from sodium–benzo-
phenone.
Experimental
General
The synthesis of compounds 1a,17 1b,18 1c, 1d,19 1e,20 1f, 2,21
8,22 1123 and 1724 (Table 3) were performed according to the
literature. All chemicals were purchased from Aldrich, Fluka,
Chemtronica (Sweden) or Research Biochemical International.
[11C]Carbon was produced by the 14N(p,α)11C nuclear reac-
tion10 using the Scanditronix cyclotron at Uppsala University
PET Centre and a target containing a N2 gas target. The pro-
duced [11C]carbon dioxide was transferred from the target and
trapped on a Porapak Q column at Ϫ196 ЊC. The trapped
labelled gas was then released by heating in a slow stream of
helium (g) (10 ml minϪ1). The gas flow was passed through a
small tube containing zinc powder at 400 ЊC.11 The [11C]carbon
monoxide produced was trapped on a short silica column at
Ϫ196 ЊC12 and released by warming the silica column to 60 ЊC,
and finally transferred into the high-pressure stainless steel
micro-autoclave.13,14 At the beginning of each experimental
session, the micro-autoclave was washed and conditioned using
10 ml THF, then heated to 150 ЊC for 5 min, followed by repeat-
ing the washing with 10 ml THF. The reactor was washed with
2 ml THF between each experiment.
General procedure for synthesis of compounds 1a,17 1b,18 1c, 1d,19
1e,20 1f and 221 (presented in Table 3)
Thionyl chloride (2 ml, 27.4 mmol) was added dropwise to the
appropriate carboxylic acid (2.28 mmol) at room temperature
under nitrogen atmosphere. The resulting mixture was stirred
at 80 ЊC for 2 h. The volatile fraction was evaporated under
reduced pressure. The mixture was dissolved in CH2Cl2 (2 ml).
To this was added a solution of the corresponding amine
(2.34 mmol) and the mixture was stirred overnight at room
temperature. The reaction mixture was then poured into satur-
ated NaHCO3 (50 ml) and extracted with methylene chloride
(3 × 50 ml). The pooled extracts were dried (MgSO4) and con-
centrated under reduced pressure. The resulting crude product
was purified by flash chromatography.
Liquid chromatographic analysis (LC) was performed with
a Beckman 126 gradient pump and a Beckman 166 variable
wavelength UV-detector (Fullerton, CA, USA) in series with a
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 5 4 1 – 5 4 6
544

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Labelling experiments
[11C]carbon monoxide. The reactor was heated at the setting
temperature (190 ЊC) for 5 min. The crude product was treated
Method A (11C-compounds 1a–1g and 2–4). Tetrakis(triphenyl-
phosphine)palladium() (≈ 2.6 µmol) and halide (≈ 9.0 µmol)
were placed in a vial (1 ml). The vial was flushed with nitrogen
gas and dry THF (250 µl) was added. The resulting mixture was
heated at 70 ЊC for 1 min and kept at room temperature for
10–15 min. Amine (≈ 50 µmol) was added and the reaction
mixture was shaken just before injection into the micro-
autoclave pre-charged with [11C]carbon monoxide. The mixture
was heated at the selected temperature for 5 min. The crude
product was transferred to a pre-evacuated vial (3 ml). The
micro-autoclave was washed with THF (250 µl) and the wash
collected in the same vial. The radioactivity of the reaction
mixture 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 and injected onto a semi-preparative
LC. The identity of the collected fraction was determined by
analytical LC and LC-MS.
as described in method B.
Method C
1-[carbonyl-11C]Benzoyl-3-methyl-1H-indole (11). A capped
vial (1 ml) containing
a solution of tetrakis(triphenyl-
phosphine)palladium() (3.0 mg, 2.6 µmol) and iodobenzene
(12b) (1.0 µl, 8.9 µmol) in dry THF (125 µl) was flushed with
nitrogen and shaken for 10 min. The reaction mixture was
injected into the micro-autoclave pre-charged with [11C]carbon
monoxide. The micro-autoclave was heated at 100 ЊC for
4 minutes. The crude product was placed in a pre-evacuated
vial (3 ml), which was charged with 3-methyl-1H-indole (25)
(5.9 mg, 45 µmol) dissolved in THF (75 µl), treated with BuLi
(1.6 M in hexane, 15 µl) followed with trimethyltin chloride
(1 M in THF, 25 µl), heated at 70 ЊC for 1 min and kept at room
temperature for 15 min. The resulting mixture was heated at
80 ЊC for an additional 6 min, and the remaining procedure was
as described in method B.
7-Pyridin-2-yl-7-azabicyclo[4.2.0]octa-1,3,5-trien-8-[carb-
onyl-11C]one (7). N-(2-Bromophenyl)pyridin-2-amine (17) (4.4
mg, 18 µmol) and tetrakis(triphenylphosphine)palladium()
(3.0 mg, 2.6 µmol) were used as described in method A.
Acknowledgements
We thank Professor Wyn Brown for linguistic advice and the
Science Council for grant K3464 (B. L.).
Method B (11C-compounds 5–6 and 8–10b). A capped vial
(1 ml) containing a solution of tetrakis(triphenylphosphine)-
palladium() (≈ 2.6 µmol) and halide (≈ 9.0 µmol) in dry THF
(125 µl) was flushed with nitrogen. The reaction mixture was
heated at 70 ЊC for 1 min and kept at room temperature for
10–15 min. Another capped vial (1 ml) was flushed with nitro-
gen and charged with amine (≈ 25.0 µmol) in anhydrous
THF (100 µl) and lithium bis(trimethylsilyl)amide (1 M in
THF, 25 µl, 25 µmol), then shaken and kept at room temper-
ature for 10–15 min. The reaction mixture in the first vial was
transferred to the vial containing the amine just before injection
into the micro-autoclave pre-charged with [11C]carbon mon-
oxide. The micro-autoclave was heated at 150 ЊC for 5 minutes.
The crude product was transferred to a vial (3 ml) under
reduced pressure. The crude product was treated as described
for method A.
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7-Pyridin-2-yl-7-azabicyclo[4.2.0]octa-1,3,5-trien-8-[carb-
onyl-11C]one (7). A vial (1 ml) was charged with tetrakis-
(triphenylphosphine)palladium() (3.0 mg, 2.6 µmol), N-(2-
bromophenyl)pyridin-2-amine (17) (4.2 mg, 17 µmol) and THF
(225 µl). The solution was heated at 70 ЊC for 1 min and kept at
room temperature for 10–15 min. Lithium bis(trimethylsilyl)-
amide (1 M in THF, 25 µl, 25 µmol) was added just before
injection into the micro-autoclave. The resulting mixture was
treated as described for method B.
N-Phenyl[carbonyl-11C]benzamide (9a) using the correspond-
ing triflate. Tetrakis(triphenylphosphine)palladium() (3.0 mg,
2.6 µmol) and phenyl trifluoromethanesulfonate (1.4 µl, 8.9
µmol) were put into a vial (1 ml). The vial was flushed with
nitrogen gas and dry THF (100 µl) was added. The resulting
mixture was heated at 70 ЊC for 1 min and kept at room temper-
ature for 5 min. The resulting mixture was transferred into
another vial (1 ml) containing a solution of tetrabutyl-
ammonium iodide (18 mg, 49 µmol) in DMSO (25 µl). The
reaction mixture was flushed with nitrogen gas, heated at 70 ЊC
for 1 min and kept at room temperature for 15 min. Another
capped vial (1 ml) was flushed with nitrogen and charged with
amine in anhydrous THF (100 µl) and lithium bis(trimethyl-
silyl)amide (1 M in THF, 25 µl, 25 µmol), then shaken and kept
at room temperature for 10–15 min. The reaction mixture in the
first vial was transferred to the vial containing the amine just
before injection into the micro-autoclave pre-charged with
14 P. Lidström, T. Kihlberg and B. Långström, J. Chem. Soc.,
Perkin Trans. 1, 1997, 2701–2706.
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