Tetra- and monoorganotin reagents in palladium-mediated cross-coupling reactions for the labeling with carbon-11 of PET tracers

Article abstract of DOI:10.1055/s-2008-1032206

The palladium-catalyzed cross-coupling reactions between a (trimethylstannyi)arene and [¹¹C]methyl iodide (Stille reaction) or between an aryl halide and a [¹¹C]monomethyltin reagent issued from Lappert's stannylene, were developed for the synthesis of poly functional [ ¹¹C]methyl quinolines and quinolinimides as potential tracers for positron emission tomography (PET). Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1032206

978
PAPER
Tetra- and Monoorganotin Reagents in Palladium-Mediated Cross-Coupling
Reactions for the Labeling with Carbon-11 of PET Tracers
Labelingwith
C
h
arbon-11 of
o
PE
T
T
racersmas Bourdier,a Michael Huiban,a Aline Huet,b Franck Sobrio,a Eric Fouquet,b Cécile Perrio,*a Louisa Barré*a
a
Groupe de Développements Méthodologiques en Tomographie par Emission de Positons, UMR CEA 2E,
Université de Caen-Basse Normandie, Centre Cyceron, 15 Boulevard Henri Becquerel, 14070 Caen Cedex, France
b
Laboratoire de Chimie Organique et Organométallique, UMR CNRS 3802, Université Bordeaux I,
351 Cours de la Libération, 33405 Talence Cedex, France
Fax +33(2)31470275; E-mail: perrio@cyceron.fr; E-mail: barre@cyceron.fr
Received 28 November 2007; revised 10 December 2007
troducing a methyl group labeled with carbon-11 onto an
aryl moiety.9–20 It proceeds by a palladium-mediated
cross-coupling reaction between an aryltriorganostannane
precursor and [11C]methyl iodide as the electrophilic part-
Abstract: The palladium-catalyzed cross-coupling reactions be-
tween a (trimethylstannyl)arene and [11C]methyl iodide (Stille reac-
tion) or between an aryl halide and a [11C]monomethyltin reagent
issued from Lappert’s stannylene, were developed for the synthesis
of polyfunctional [11C]methyl quinolines and quinolinimides as po- ner leading to the formation of a Csp2–11Csp3 bond
tential tracers for positron emission tomography (PET).
(Scheme 1, route A). It is compatible with a broad range
of functional groups and can be run under neutral condi-
tions. However, several drawbacks can be pointed out
such as the recovery of tetraorganotin byproducts of high
toxicity in the crude final mixture and, in case of a func-
tionalized organostannane, the occurrence of the 11C-
methylation of nucleophilic groups as an unwanted side
reaction.15,18 Thus, difficulties for tracer purification may
be encountered and additional protection/deprotection
steps could be envisaged.
Key words: positron emission tomography, carbon-11, Stille,
monoorganotin, [11C]methyl iodide
Positron emission tomography (PET) is a powerful imag-
ing technique for clinical, medical, and biological investi-
gations in various areas such as oncology, cardiology, and
neuroscience, and also for drug development. This tech-
nique requires a specific radiotracer used as a probe to
monitor the biochemical processes and localization of a
target molecule involved in important biofunctions and
related phenomena. Due to the increasing need of this
technique in in vivo biochemistry and medicine, the devel-
opment of new PET tracers and radiolabeling strategies is
always demanding.1–3 PET uses short half-life radioiso-
topes, e.g. carbon-11 (t1/2 = 20.4 min) and fluorine-18
(t1/2 = 109.6 min). Thus, rapid synthetic processes includ-
ing organic transformations and purifications are re-
quired. Moreover, the radioisotopes are available in forms
of a limited number of labeled precursors in submicromo-
lar quantities (e.g., for carbon-11: 11CO2 and 11CH4 pro-
duced by the cyclotron then giving access to H11CN,
11CO, 11COCl2 or 11CH3I). Reactions are carried out using
a large excess of substrate and reagents compared to the
labeled reactant, and have to be efficient, selective, and
preferably without any intermediate purification. Finally,
the overall radiosyntheses have to be suitable for automa-
tion to avoid radiation exposure.
Recently, we described a new methodology based on the
transfer reaction of the [11C]methyl group from the 11C-
labeled hypervalent methylstannate [11C]1 onto an aryl
halide (Scheme 1, route B).21 The monoorganotin reagent
[11C]1 was obtained by oxidative addition of [11C]methyl
iodide to Lappert’s stannylene22,23 {Sn[N(TMS)2]2} fol-
lowed by in situ activation with tetrabutylammonium
fluoride as fluoride source. Both steps were immediate
and quantitative. The further palladium-mediated
[11C]methyl transfer between [11C]1 and various bromo-
quinolines and naphthalenes as model substrates, was
found very efficient for the synthesis of the corresponding
[11C]methylarenes. Although less straightforward com-
pared to the Stille reaction, this new approach holds sev-
eral advantages such as the ligand-free conditions, the
formation of a nontoxic and easily removable inorganic
tin byproduct, the ease for purification, as well as the
availability of the aryl halide as the substrate. Due to the
The majority of 11C-labeled PET tracer preparations in-
volve the synthetically well-established [11C]methyl
iodide4 either in nucleophilic alkylation reactions on ni-
trogen, oxygen, and sulfur or in carbon–carbon bond-
forming reactions where organometallic compounds are
widely applied.5–20 The Stille reaction remains the only re-
liable method for the radiosynthesis of PET tracers by in-
route A
ArSnR3, "Pd"
11CH3I
Ar11CH3
ArX, "Pd"
route B
F
–
1) Sn[N(TMS)2]2
2) TBAF
N(TMS)2
H311C Sn
N(TMS)2
F
[
11C]1
SYNTHESIS 2008, No. 6, pp 0978–0984
Advanced online publication: 28.02.2008
DOI: 10.1055/s-2008-1032206; Art ID: Z27507SS
© Georg Thieme Verlag Stuttgart · New York
x
x
.
x
x
.2
0
0
8
Scheme
1
Palladium-mediated coupling reactions using
[11C]methyl iodide and tetraorganotin (route A) or monoorganotin
(route B) reagents

PAPER
Labeling with Carbon-11 of PET Tracers
979
total conversion of [11C]methyl iodide into [11C]methyl- prepared mixture of potassium carbonate, copper(I) chlo-
stannate [11C]1, no 11C-methylation of nucleophilic group ride, and tin precursor in N,N-dimethylformamide was
bearing the starting aryl halide could be expected.
added. The reaction vial was heated at 90 °C for five min-
utes. Analysis of the crude products was assessed by
HPLC and radioTLC by comparison with authentic stable
samples as references. The [11C]methyl incorporation rate
was calculated by combining both radioTLC and HPLC.
RadioTLC displayed the ratio between the tracer [11C]2–
5 and radioactive polar species7 due to the complexation
of [11C]methyl iodide with palladium. HPLC was used to
calculate the ratio between the tracer [11C]2–5 and unre-
acted [11C]methyl iodide.
Our next interest was directed to the rapid introduction of
a [11C]methyl group onto a polyfunctional arene for the
synthesis of new PET tracers. In the course of our pro-
gram with the aim of developing radioligands for the non-
invasive study of the functions and diseases involving
cerebral neurokinin and opiate receptors, such as anxiety,
depression, psychosis, schizophrenia, and Parkinson’s
disease, we identified SB 222200 224–28 and analogues 3
and 429 (NK-3 receptor antagonists) and quinolinimide
530,31 (ligand of delta opioid receptors) as candidates for
radiolabeling (Figure 1). These compounds bear a methyl
group at different positions on the heterocyclic ring (quin-
oline or pyridine), we undertook to study their radiosyn-
thesis according to both methods A and B. We report
herein our comparative results in terms of efficiency,
mildness of conditions, reliability, and automation.
1) Pd2dba3, P(o-tolyl)3
DMF, 0 °C, 3 min
11CH3I
Ar11CH3
11C]
2–5
2) ArSnMe3 6–9
[
CuCl, K2CO3
DMF, 90 °C, 5 min
Scheme 2 Synthesis of radiotracers [11C]2–5 by Stille reaction
(route A)
Ph
Ph
Table 1 Radiochemical Yields in [11C]2–5 Obtained by Stille
O
NH
O
NH
Coupling (Route A)a
*CH3
Ph
*CH3
R
Entry ArSnMe3
Ar11CH3 Yieldb
(%)
N
N
Ph
Ph
2 (SB 222200)
3 R = Me
4 R = OMe
O
NH
1
2
3
6
7
8
[11C]2
[11C]3
[11C]4
53
30
60
5
3
4
n-Bu
SnMe3
N
S
N
Ph
Ph
O
O
N
O
O
O
NH
Me3Sn
Me
Ph
N
N
5
*CH3
Ph
Figure 1 Target molecules 2–5 for labeling with carbon-11
(*C = 12C or 11C)
O
NH
Me3Sn
n-Bu
OMe
Ph
The Stille reaction using [11C]methyl iodide has been pre-
viously carefully examined both on model compounds
and for tracer development.9–20 From these studies, the use
of tris(dibenzylideneacetone)dipalladium(0) and tri-2-
tolylphosphine in N,N-dimethylformamide in the pres-
ence of potassium carbonate and copper(I) chloride, has
been established as the optimized reaction conditions. We
applied those conditions to the radiosynthesis of tracers
[11C]2–5 from the corresponding aryltrimethylstannanes
6–9 (see experimental part for preparation). A five-minute
cross-coupling reaction time was chosen (Scheme 2).
Briefly, the procedure was as follows. [11C]Methyl iodide,
obtained by reduction of [11C]carbon dioxide followed by
reaction with hydroiodic acid, was trapped in N,N-dimeth-
ylformamide containing tris(dibenzylideneacetone)dipal-
ladium (0) and tri-2-tolylphosphine. Then, a freshly
N
N
S
O
O
4
9
[11C]5
65
6
N
O
O
N
SnMe3
a ArSnMe3 (3.75 mmol), Pd2dba3 (1.5 mmol), P(o-Tol)3 (6 mmol), CuCl
(6 mmol), K2CO3 (6 mmol).
b [11C]Methyl incorporation rate decay corrected and calculated from
trapped 11CH3I (n = 5–10).
Synthesis 2008, No. 6, 978–984 © Thieme Stuttgart · New York

980
T. Bourdier et al.
PAPER
[11C]Methyl incorporation rates for compounds [11C]2, [11C]3 was increased to 30% by elevating temperatures T1
[11C]4, and [11C]5 ranged from 50 to 70% (Table 1, entries and T2 to 150 °C (entry 5). This former reached 65% by
1, 3, 4). The percentages of recovered [11C]methyl iodide using two different temperatures, respectively 120 and
and labeled polar species were each ca. 15–20%. 150 °C for T1 and T2 (entry 4). Under the same conditions,
[11C]Methylquinoline [11C]3 was formed in radiochemi- the analogue [11C]4 was formed in similar radiochemical
cal yield that did not exceed 33% (entry 2). In this latter yield (entry 7). These results showed that more drastic
case, most of radioactivity was recovered as polar com- conditions were required to obtain 6-[11C]methylquinoli-
pounds. Due to the minor structural modifications be- necarboxamides compared to the unsubstituted 6-
tween (trimethylstannyl)quinolines 7 and 8, we have no [11C]methylquinoline21 and that degradation of [11C]meth-
explanation for this falling yield. No attempts to increase ylstannate [11C]1 probably occurred during tetrahydrofu-
the radiochemical yield by increasing the Stille reaction ran evaporation at 150 °C. None of the tested conditions
temperature were undertaken.
allowed the formation of 3-[11C]methylquinolinecarboxa-
mide [11C]2 and 2-[11C]methylquinolinimide [11C]5 (en-
tries 2, 9). Reactions being successful starting from
bromoquinolines as model substrates,18 the fact that the
electrophiles were bromo compounds instead of iodo de-
rivatives as for the radiosynthesis of quinolines [11C]3 and
[11C]4, did not seem to us relevant. We found that the bro-
moquinolinimide precursor 14 was not stable at tempera-
tures higher than 100 °C. However, this was not the case
for 3-bromoquinoline 11.
The radiosynthesis of tracers [11C]2 and [11C]5 was car-
ried out in production mode using an automated system
including HPLC purification. Both radiotracers [11C]2
and [11C]5 were isolated within 35 minutes total synthesis
time EOB (End Of Bombardment). Decay corrected ra-
diochemical yields calculated from the amount of trapped
[11C]methyl iodide were close to the [11C]methyl incorpo-
ration rates reported above. The radiochemical purity was
greater than 95% determined by analytical HPLC.
The automated radiosynthesis of tracers [11C]3 and [11C]4
via the stannate [11C]1 was achieved within 50 minutes
total synthesis time including HPLC purification. In all
assays, the radiochemical yields ranged from 18 to 56%
(n >10) and the radiochemical purity was greater than
99% determined by analytical HPLC.
We performed the radiosynthesis of radiotracers [11C]2–5
via the stannate [11C]1 according to Scheme 3. [11C]Meth-
yl iodide obtained from cyclotron produced [11C]CO2,
was trapped into tetrahydrofuran containing Lappert’s
stannylene leading immediately and quantitatively to
[11C]methyltin [11C]10. Tetrabutylammonium fluoride
was added at room temperature to obtain the stannate In order to investigate why the route B has failed for the
[11C]1, and tetrahydrofuran was removed by heating un- radiosynthesis of 3-[11C]methylquinolinecarboxamide
der nitrogen. After addition of the catalyst and the electro- [11C]2, we studied the cross-coupling reaction in nonra-
phile 11–14 in dioxane, the mixture was heated for five dioactive chemistry32 using stable stannate 1 prepared
minutes and the transfer reaction was quenched with wa- from methyl iodide (Scheme 3). The formation of 3-meth-
ter. Analysis of the crude products was assessed as above ylquinolinecarboxamide 2 was not observed. The starting
by HPLC and radioTLC. Only two radioactive products 3-bromoquinoline 11 was not recovered and the corre-
corresponding to the expected radiotracer [11C]2–5 and to sponding reduced quinolinecarboxamide 15 was isolated
polar tin byproduct derived from hydrolysis of unreacted as the only identified product (50% yield). It is notewor-
stannate [11C]1, were detected.
thy that quinoline 15 was also formed in Stille reaction
from 3-bromoquinoline 6 leading to SB 222200 2, but to
a lesser extent.28 We presumed that the oxidative addition
of 3-bromoquinoline 11 to palladium occurred and that an
intramolecular hydrogen transfer leading to quinoline 15
took place instead of the transmetalation step (Scheme 4).
Under the same conditions, 6-iodoquinolines 12 and 13
were converted into 6-methylquinolines 3 and 4 in 65 and
60% yields respectively.
Several parameters such as a Lappert’s stannylene/
tetrabutylammonium fluoride ratio of 1:3, the removal of
tetrahydrofuran after the formation of the [11C]methyl-
stannate [11C]1, the use of tris(dibenzylideneacetone)di-
palladium(0) under ligand-free conditions as the catalytic
system, and the need for dioxane as coupling solvent,
were previously identified as crucial for the radiosynthe-
sis.21 In a first set of experiments, the heating temperatures
for tetrahydrofuran elimination (T1) and [11C]methyl- In conclusion, we explored the use of the monoorganotin
transfer reaction (T2) were both fixed at 120 °C as de- derivative [11C]1 in the radiosynthesis of polyfunctional
scribed for the synthesis of model 11C-compounds.21 Un- and heteroaromatic tracers [11C]2–5 as an alternative
der these conditions, the radiochemical yields of [11C]2–5 route to the classical Stille reaction. Although not applica-
did not exceed 11% (Table 2, entries 1, 3, 6, 8). The ble in all cases, this novel approach was as or more effi-
[11C]methyl incorporation rate for 6-[11C]methylquinoline cient as the Stille method for the radiosynthesis of the
ArX 11–14
Pd2dba3
–
I
F
H3C11 Sn
F
11CH3I
1) TBAF, TA
N(TMS)2
N(TMS)2
N(TMS)2
N(TMS)2
Sn[N(TMS)2]2
Sn
Ar11CH3
11C]2–5
THF
TA, 5 min
H3C11
2) ∆ (T1), 3 min
dioxane
∆ (T2), 5 min
[
11C]1
[
[
11C]10
Scheme 3 Synthesis of radiotracers [11C]1–4 through [11C]monomethyltin reagent (route B)
Synthesis 2008, No. 6, 978–984 © Thieme Stuttgart · New York

PAPER
Labeling with Carbon-11 of PET Tracers
981
Table 2 Radiochemical Yields in Radiotracers [11C]2–5 (Route B)a
Entry
ArX
Ar11CH3
T1 (°C)
T2 (°C)
Yieldb (%)
Ph
O
NH
1
2
120
120
120
150
–
–
11
[11C]2
Br
N
O
Ph
Ph
3
4
5
120
120
150
120
150
150
8
59
37
4
6
3
NH
12
13
[11C]3
I
Me
Ph
N
Ph
O
NH
6
7
120
120
120
150
11
60
3
5
[11C]4
I
OMe
Ph
N
n-Bu
N
S
O
O
8
9
120
120
120
150
<3
10
14
[11C]5
3
N
O
O
N
Br
a ArX (15 mmol), Sn[N(TMS)2]2 (15 mmol), TBAF (45 mmol), Pd2dba3 (5 mmol).
b Radiochemical yield decay corrected and calculated from 11CH3I (n = 5–10).
1
MHz, respectively, with broadband H decoupling. MS analyses
and HRMS were recorded using a QTOF Micro spectrometer
(Waters). IR spectra were recorded on a Perkin-Elmer spectropho-
tometer 16 PC-FT-IR. The melting points were obtained from a
Electrothermal digital apparatus. TLC was performed on silica gel
60F254 plates and visualized by UV irradiation. Optical rotation are
given in 10–1 deg cm2 g–1. THF was dried and distilled from Na/ben-
zophenone ketyl under N2 prior to use. MeCN was dried over CaH2
and distilled. DMF was dried over CaH2 and distilled under vacuum
prior to use (0.02 bar). All the reagents commercially available were
used without further purification. Compounds 2,24,25 5,31 6,28 11,28
13,33 and 1431 were prepared according to previously described pro-
cedures.
1, Pd2dba3
dioxane
ArX
ArCH3
110 °C, 3 h
11–13
2–4
Ph
Ph
O
N
H
O
NH
Pd(II)-Br
11
N
Ph
N
Ph
15
Scheme 4 Nonradioactive methyl-transfer reaction from stannate 1
to quinolines 11–13
6-Iodo-3-methyl-2-phenyl-N-[(S)-1-phenylpropyl]quinoline-4-
carboxamide (12)
A mixture of 5-iodoisatin (1 equiv), propiophenone (1.2 equiv), and
KOH pellets (85%, 3 equiv) in EtOH (5–50 mL) was refluxed for
72 h. After concentration under vacuum, the residue was dissolved
in H2O and washed with Et2O (2 ×). The ice-cold aqueous layer was
acidified to pH 1 with 37% HCl. The precipitate formed was fil-
tered, washed with H2O, and dried at 65 °C in an oven to give the
crude 6-iodo-3-methyl-2-phenylquinoline-4-carboxylic acid hydro-
chloride (10 g, 85%) as a beige solid; mp 198 °C.
1H NMR (DMSO-d6): d = 8.12 (d, J = 1.8 Hz, 1 H), 8.02 (dd, J = 8.8
Hz, J = 1.8 Hz, 1 H), 7.82 (d, J = 8.8 Hz, 1 H), 7.65–7.57 (m, 2 H),
7.53–7.42 (m, 3 H), 2.38 (s, 3 H).
tracers [11C]3,4. It was also advantageous from purifica-
tion point of view as tracers [11C]3,4 were obtained with a
higher purity than that found with the Stille reaction. All
these results confirmed the potential of this method for the
radiosynthesis of PET tracers.
1H, 13C, and 119Sn NMR spectra were recorded on a Bruker DPX
250 MHz with CDCl3 as the solvent and TMS as the internal stan-
dard. 13C and 119Sn NMR spectra were recorded at 62.9 and 93.2
Synthesis 2008, No. 6, 978–984 © Thieme Stuttgart · New York

982
T. Bourdier et al.
PAPER
13C NMR (DMSO-d6): d = 168.3, 160.8, 144.4, 139.7, 139.4, 137.8,
13C NMR (CDCl3): d = 166.9, 158.2, 155.4, 147.2, 145.6, 141.7,
131.4, 130.3, 129.3, 129.2, 129.0, 128.9, 128.4, 127.8, 125.6, 123.5,
119.7, 57.2, 49.9, 28.1, 10.8, –9.6.
119Sn NMR (CDCl3): d = –23.29.
132.5, 131.1, 128.9, 128.5, 128.1, 125.2, 124.1, 94.0, 17.7.
EDCI (2 equiv) was added slowly at –5 °C to a mixture of Et3N (2
equiv), (S)-phenylpropylamine (1.1 equiv), HOBt (2 equiv), and 6-
iodo-3-methyl-2-phenylquinoline-4-carboxylic acid hydrochloride
(1 equiv) in THF–MeCN (7:3, 20–40 mL). The mixture was stirred
at –5 °C for 1 h, then at r.t. for 18 h. After filtration, the filtrate was
concentrated under reduced pressure. The residue was dissolved in
Et2O (80 mL), and the organic phase was washed with sat. NaCl,
dried (MgSO4), and filtered. Purification by column chromatogra-
phy (pentane–EtOAc, 85:15 containing 0.1% Et3N) afforded the ti-
tle quinoline 12 as a yellow solid; yield: 1.7 g (87%); mp 212–215
°C.
Anal. Calc for C29H32N2O2Sn: C, 62.28; H, 5.77; N, 5.72. Found: C,
62.31; H, 5.46; N, 5.37.
6-{2-[2-(4-Butylphenylsulfonyl)-1,2,3,4-tetrahydroisoquinolin-
1-yl]ethyl}-2-(trimethylstannyl)-5H-pyrrolo[3,4-b]pyridine-
5,7(6H)-dione (9)
Following the typical procedure for 7 using chloroquinolinimide
analogue precursor31 (0.718 g, 1.33 mmol), (Me3Sn)2 (0.662 g, 2
mmol), anhyd dioxane (11 mL), and Pd(PPh3)4 (0.078 g, 0.067
mmol); chromatography (silica gel, heptane–EtOAc, 8:2) gave 9 as
a white solid; yield: 0.544 g (61%); mp 86–88 °C.
[a]D –58.4 (c 0.5, MeOH).
IR (KBr): 3238, 1709, 1489, 1459, 1425, 1371, 1335, 1205, 1133,
887, 822, 759, 696 cm–1.
IR (KBr): 1779, 1728, 1336, 1162 cm–1.
1H NMR (CDCl3): d = 7.96–7.85 (m, 1 H), 7.79 (dd, J = 8.8 Hz,
J = 1.8 Hz, 1 H), 7.62 (d, J = 8.8 Hz, 1 H), 7.40–7.29 (m, 10 H),
6.91 (d, J = 8.5 Hz, 1 H), 5.15–5.02 (m, 1 H), 2.19 (s, 3 H), 1.87–
1.79 (m, 2 H), 0.96 (t, J = 7.3 Hz, 3 H).
13C NMR (CDCl3): d = 166.6, 161.1, 145.0, 141.7, 141.5, 139.9,
137.9, 133.2, 131.0, 129.0, 128.7, 128.4, 127.7, 126.7, 125.8, 125.3,
93.2, 55.7, 28.8, 17.5, 11.2.
1H NMR (CDCl3): d = 7.92 (d, J = 7.4 Hz, 1 H), 7.74 (d, J = 7.4 Hz,
1 H), 7.59 (d, J = 8.3 Hz, 2 H), 7.15–6.95 (m, 5 H), 6.81 (d, J = 7.3
Hz, 1 H), 5.10 (dd, J = 9.7 Hz, J = 5.1 Hz, 1 H), 4.05–3.85 (m, 3 H),
3.70–3.50 (m, 1 H), 2.60–2.45 (m, 4 H), 2.30–2.00 (m, 2 H), 1.48
(qt, J = 7.3 Hz, 2 H), 1.21 (sextet, J = 7.3 Hz, 2 H), 0.86 (t, J = 7.3
Hz, 3 H), 0.40 (s, 9 H).
13C NMR (CDCl3): d = 182.8, 167.1, 166.8, 151.4, 148.1, 137.4,
135.5, 134.4, 132.5, 128.9, 128.7, 127.4, 127.0, 126.8, 126.7, 126.2,
125.8, 54.6, 38.8, 35.8, 35.3, 33.0, 25.8, 22.9, 13.8, –9.0.
MS (EI+): m/z (%) = 506 (M+, 8), 380 (43), 246 (86), 91 (100).
3-Methyl-2-phenyl-N-[(S)-1-phenylpropyl]-6-(trimethylstan-
nyl)quinoline-4-carboxamide (7); Typical Procedure
119Sn NMR (CDCl3): d = –35.4.
Anal. Calcd for C31H37N3O4SSn: C, 55.87; H, 5.60; N, 6.31. Found:
C, 55.86; H, 6.04; N, 6.28.
To a mixture of 12 (0.9 g, 1.77 mmol) and (Me3Sn)2 (0.83 g, 2.5
mmol) in anhyd dioxane (10 mL) was added, under N2, Pd(PPh3)4
(0.150 g, 0.13 mmol). After stirring at reflux for 2 h, the mixture
was cooled to r.t. and filtered through Celite. The filtrate was con-
centrated under reduced pressure. The oily residue was purified by
chromatography (silica gel, heptane–EtOAc, 8:2) to give 7 as a
white solid; yield: 0.616 g (64%); mp 159–160 °C.
3,6-Dimethyl-2-phenyl-N-[(S)-1-phenylpropyl]quinoline-4-car-
boxamide (3); Typical Procedure
To a mixture of iodo-bis(N,N-bistrimethylsilylamino)methyltin
1032 (2.22 mmol) and 1 M TBAF in THF (6.65 mL, 6.65 mmol) in
dioxane (10 mL) was added, under N2, a mixture of 12 (0.69 g, 1.33
mmol) and Pd2(dba)3 (101 mg, 0.11 mmol) in dioxane (5 mL). After
stirring at 120 °C for 10 min, the mixture was cooled to r.t. and fil-
tered through Celite. The filtrate was concentrated under reduced
pressure. The oily residue was purified by chromatography (silica
gel, pentane–EtOAc, 85:15 containing 0.1% Et3N) to give 3 as a
white solid; yield: 0.35 g (65%); mp 100–101 °C.
[a]D –18.8 (c 0.5, MeOH).
IR (KBr): 3230, 1630, 1537, 1494, 1444, 1344, 823, 758, 696 cm–1.
1H NMR (CDCl3): d = 6.99–7.30 (m, 13 H), 6.07–6.16 (m, 1 H),
5.21–5.27 (m, 1 H), 2.26 (s, 3 H), 1.91–2.10 (m, 2 H), 1.02 (t,
J = 7.3 Hz, 3 H), 0.25 (s, 9 H).
13C NMR (CDCl3): d = 169.7, 156.8, 152.5, 147.5, 144.6, 141.8,
139.3, 134.4, 128.8, 128.2, 127.6, 126.1, 125.6, 123.5, 122.5, 121.8,
49.8, 28.1, 16.1, 11.2, –9.5.
119Sn NMR (CDCl3): d = –23.58.
[a]D –37.4 (c 0.5, MeOH).
IR (KBr): 3232, 1642, 1547, 1345, 1301, 762, 698 cm–1.
1H NMR (CDCl3): d = 8.27 (d, J = 8.8 Hz, 1 H), 7.83–7.72 (m, 11
H), 6.97 (d, J = 7.9 Hz, 1 H), 5.58–5.50 (m, 1 H), 2.74 (s, 3 H), 2.62
(s, 3 H), 2.31–2.25 (m, 2 H), 1.36 (t, J = 7.4 Hz, 3 H).
13C NMR (CDCl3): d = 167.4, 159.5, 144.7, 143.3, 141.8, 137.0,
131.2, 129.1, 128.9, 128.8, 128.7, 128.6, 128.2, 128.1, 127.5, 126.7,
126.6, 123.1, 55.4, 28.8, 21.6, 17.3, 11.0.
MS (EI+): m/z (%) = 394 (M+, 47), 260 (100), 217 (41).
HRMS (EI+): m/z [M+] calcd for C27H26N2O: 394.2047; found:
Anal. Calcd for C29H32N2OSn: C, 64.11; H, 5.94; N, 5.16. Found:
C, 64.19; H, 6.44; N, 5.25.
3-Methoxy-2-phenyl-N-[(S)-1-phenylpropyl]-6-(trimethylstan-
nyl)quinoline-4-carboxamide (8)
Following the typical procedure for 7 using 13 (1.11 g, 2.12 mmol),
(Me3Sn)2 (0.89 g, 2.7 mmol), anhyd dioxane (10 mL), and
Pd(PPh3)4 (0.150 g, 0.13 mmol); chromatography (silica gel, hep-
tane–EtOAc, 8:2) gave 8 as a white solid; yield: 1.0 g (84%); mp
148–150 °C.
394.2045.
3-Methoxy-6-methyl-2-phenyl-N-[(S)-1-phenylpropyl]quino-
line-4-carboxamide (4)
[a]D –19.4 (c 0.5, MeOH).
Following the typical procedure for 3 using 13 (0.70 g, 1.34 mmol)
and a heating time of 25 min; chromatography (silica gel, pentane–
EtOAc, 85:15 containing 0.1% Et3N) gave 4 as a white solid; yield:
0.33 g (60%); mp 94–95 °C.
IR (KBr): 3238, 1630, 1538, 1445, 1381, 1343, 1301, 1024, 825,
759, 694 cm–1.
1H NMR (CDCl3): d = 7.26–7.54 (m, 13 H), 6.26–6.34 (m, 1 H),
5.29–5.38 (q, 1 H), 3.53 (s, 3 H), 1.95–2.07 (m, 2 H), 1.09 (t, J = 7.4
Hz, 3 H), 0.31 (s, 9 H).
[a]D –42.6 (c 0.5, MeOH).
IR (KBr): 3230, 1645, 1544, 1347, 1305, 763, 697 cm–1.
Synthesis 2008, No. 6, 978–984 © Thieme Stuttgart · New York

PAPER
Labeling with Carbon-11 of PET Tracers
983
1H NMR (CDCl3): d = 8.02–7.91 (m, 1 H), 7.55–7.31 (m, 11 H),
6.89 (d, J = 8.6 Hz, 1 H), 5.22–5.13 (m, 1 H), 3.60 (s, 3 H), 2.38 (s,
3 H), 1.99–1.85 (m, 2 H), 0.99 (t, J = 7.3 Hz, 3 H).
3-Methoxy-6-[11C]methyl-2-phenyl-N-[(S)-1-phenylpro-
pyl]quinoline-4-carboxamide ([11C]4)
TLC: Rf = 0.28 (EtOAc–heptanes, 30:70).
13C NMR (CDCl3): d = 164.9, 153.2, 147.7, 143.5, 141.8, 137.4,
137.3, 133.4, 130.7, 129.1, 129.0, 128.8, 128.4, 128.3, 128.2, 128.1,
127.2, 126.7, 126.6, 125.1, 123.1, 61.7, 55.4, 28.8, 21.5, 10.7.
HPLC (Nucleosil 100-5 C18 column, 4 × 250 mm, 10 mm; MeOH–
H2O (75:25); flow rate: 1 mL/min; detection: l = 254 nm): tR = 10.4
min.
MS (EI+): m/z (%) = 410 (M+, 31), 276 (100).
HRMS (EI+): m/z [M+] calcd for C27H26N2O2: 410.1994; found:
6-{2-[2-(4-Butylphenylsulfonyl)-1,2,3,4-tetrahydroisoquinolin-
1-yl]ethyl}-2-[11C]methyl-5H-pyrrolo[3,4-b]pyridine-5,7(6H)-
dione ([11C]5)
410.1993.
TLC: Rf = 0.45 (EtOAc–heptanes, 50:50).
Radiosyntheses
HPLC (Zorbax RX-SIL column, 2.1 × 150 mm, 5 mm; EtOAc–hep-
tanes (30:70); flow rate: 0.5 mL/min; detection: l = 254 nm):
tR = 7.8 min.
[11C]CO2 production was performed using a Cyclone 18/9 IBA cy-
clotron at the Cyceron PET Centre. The nuclear reaction 14N (p, a)
11C was performed in a N2 target gas containing 0.5% O2 which was
bombarded with 18 MeV protons. 11CH3I was produced by reduc-
tion of [11C]CO2 with 0.1 M LiAlH4 in THF (200 mL) at r.t., and sub-
sequent reaction with 57% HI in H2O (1.5 mL) at 140 °C.4
Radioactive products [11C]2–5 were identified by comparison with
nonradioactive authentic samples 2–5. HPLC analyses were carried
out with a Merck L-6200 pump and a Merck L-4250 variable wave-
length UV-detector in series with a Novelec b+-flow detector.
RadioTLC analyses were performed on Merck 60F254 silica gel
plates using a Packard Instant Imager. The radiochemical yields
were determined from the radioTLC and HPLC chromatograms
representing the percentage of radioactivity area of cross-coupling
product [11C]2–5 related to the total radioactivity area.
Acknowledgment
The authors thank the Ministère de la Recherche et des Nouvelles
Technologies, CEA (Commissariat à l’Energie Atomique), CNRS
(Centre National de la Recherche Scientifique), the PUNCH-Orga
Network (Pôle Universitaire Normand de Chimie Organique), the
Région Basse-Normandie and the European Union (FEDER fun-
ding) for financial support.
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Synthesis 2008, No. 6, 978–984 © Thieme Stuttgart · New York

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T. Bourdier et al.
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Synthesis 2008, No. 6, 978–984 © Thieme Stuttgart · New York