Palladium-mediated conversion of para-aminoarylboronic esters into para-aminoaryl-11C-methanes

Article abstract of DOI:10.1016/j.tetlet.2012.11.001

Cross-couplings are an alternative to conventional ¹¹C- methylations which are generally employed in PET tracer synthesis. Therefore, we set out to develop a general procedure for the synthesis of para- ¹¹CH₃ labeled aromatic amines from the corresponding para-aminoarylboronic esters in the presence of free amines. Aryl boronic esters containing primary, secondary, and tertiary amines were successfully converted into corresponding labeled methyl derivatives in sufficient radiochemical yield to apply this method for tracer development. This procedure was applied to the labeling of CIMBI-712, a promising candidate for the in vivo imaging of the 5-HT₇ receptor in the CNS.

Full text of DOI:10.1016/j.tetlet.2012.11.001

Tetrahedron Letters 54 (2013) 213–216
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Palladium-mediated conversion of para-aminoarylboronic esters into
para-aminoaryl-11C-methanes
Valdemar L. Andersen a,b,c,d, , Matthias M. Herth a,b,c,d, , Szabolcs Lehel b, Gitte M. Knudsen c,d
,
Jesper L. Kristensen a,d,
⇑
a Department of Drug Design and Pharmacology, School of Pharmaceutical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken
2, Copenhagen 2100, Denmark
b PET and Cyclotron Unit, Copenhagen University Hospital, Blegdamsvej 9, Copenhagen 2100, Denmark
c Neurobiological Research Unit, Copenhagen University Hospital, Juliane Maries Vej 24, Copenhagen 2100, Denmark
d Center for Integrated Molecular Brain Imaging (CIMBI), Juliane Maries Vej 24, Copenhagen 2100, Denmark
a r t i c l e i n f o
a b s t r a c t
Cross-couplings are an alternative to conventional 11C-methylations which are generally employed in PET
tracer synthesis. Therefore, we set out to develop a general procedure for the synthesis of para-11CH3
labeled aromatic amines from the corresponding para-aminoarylboronic esters in the presence of free
amines. Aryl boronic esters containing primary, secondary, and tertiary amines were successfully con-
verted into corresponding labeled methyl derivatives in sufficient radiochemical yield to apply this
method for tracer development. This procedure was applied to the labeling of CIMBI-712, a promising
candidate for the in vivo imaging of the 5-HT7 receptor in the CNS.
Article history:
Received 9 July 2012
Revised 17 October 2012
Accepted 1 November 2012
Available online 10 November 2012
Keywords:
Cross-couplings
PET
Ó 2012 Elsevier Ltd. All rights reserved.
Carbon-11
Methyl iodide
Palladium
Positron emission tomography (PET) is widely used as a tool to
image biological processes in the body. For example, it allows the
imaging of neuroreceptors and transporters in vivo. Since its dis-
covery in 1976, 11C-methylation of amines and hydroxy-groups
via [11C]CH3I has been the most commonly used strategy for
obtaining 11C-labeled PET tracers.1 The disadvantage of this ap-
proach is twofold. Firstly, the presence of an N-methyl- or meth-
oxy- group in the ligand is necessary for the synthesis of a viable
precursor. Secondly, its applicability to various functional groups
often makes time consuming protection/deprotection a necessity.
Therefore, different 11C-labeling strategies have been developed.1
For example, cross-couplings via [11C]CH3I have been carried out
to broaden scope, and in recent years, mainly the Stille reaction
was applied in PET chemistry, even though examples where the
Suzuki reaction has been used for 11C-radiolabeling have appeared
in the literature.2,3
reactions can be considered pseudo-first-order.4 Therefore, the
higher reactivity in a Stille reaction does not play a key role. Thus,
a direct comparison of reactivities in preparative synthetic organic
chemistry and radiochemistry can be misleading.
The Stille reaction is not dependent on the presence of a base.
This is an advantage when working with compounds that are
unstable under basic conditions. On the other hand, the Suzuki
reaction uses less toxic reagents compared to the tin species ap-
plied in the Stille reaction. When a radiolabeled compound is to
be used in vivo, non-toxic reagents and precursors are preferable.
Therefore, we believe that the Suzuki reaction is the superior alter-
native for PET tracer production.
The use of the Suzuki reaction in PET chemistry has received
limited attention. A review in 2011 described the various endeav-
ors using the Suzuki reaction as a tool to insert 11C-labeled
Both the Stille and the Suzuki reactions have advantages and
disadvantages. In general, the reactivity in a Stille reaction is higher
and therefore gives faster reaction rates. However, in PET chemis-
try the very large excess of the precursor causes the concentration
of this to remain constant during the labeling step, and the
CH3
N
N
O
1
N
H
⇑
Corresponding author.
E-mail address: jekr@farma.ku.dk (J.L. Kristensen).
Equally contributed.
Figure 1. Structure of CIMBI-712.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.11.001

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V. L. Andersen et al. / Tetrahedron Letters 54 (2013) 213–216
OR
L
Pd
L
L
Ar Pd
L
PdL2
ArB(OR)2
11C]CH3I, K2CO3
Ar 11CH3
B
11CH3
[
11C]CH3I
11CH3
11CH3
[
I
OR
Pd2(dba)3, P(o-tolyl)3
N
N
Heat
DMF:H2O 9:1
Figure 2. Oxidative addition of
reductive elimination upon addition of the boronic substrate.
[
11C]MeI followed by transmetallalation and
11
2b
4b
3b
C]
and
[
[
11C]CH3I
O
B
11CH3
Pd-catalyst
Base
O
R
R
[
11C]3a-e
2a-e
N
N
N
H2N
R =
H
N
H
N
a
b
c
d
e
Figure 3. Model compounds portraying different amines encountered in PET
tracers.
Figure 4. Impact of the reaction temperature on the RCY.
Table 1
Effect of different Pd-systems on the RCYa
O
B
[
11C]CH3I, Pd2(dba)3
P(o-tolyl)3, base
11CH3
O
11C]CH3I
O
B
[
11CH3
Pd catalyst
K2CO3
O
60 °C
DMF:H2O 9:1
R
R
11
2b,e
3b,e
C]
[
N
N
60 °C
N
N
11
DMF:H2O 9:1
3e
C]
[
2e
Entry
Pd-catalyst
RCY (%)
1
2
3
4
Pd(PPh3)4
Pd(PPh3)2Cl2
Pd(dppf)Cl2
Pd2(dba)3 + P(o-tolyl)3
9
0
0
49
a
Reaction was carried out with 40 equiv of boronic ester, 1 equiv of Pd-catalyst,
2 equiv of ligand, and 2 equiv of base.
Table 2
Impact of the ester species on the RCYa
OR2
11C]CH3I, K2CO3
Figure 5. Impact of base on the RCY.
[
B
11CH3
OR2
Pd2(dba)3, P(o-tolyl)3
R1
R1
100 °C
unknown and competing alkylation of the nitrogen could, in prin-
ciple, be detrimental, as [11C]CH3I is known to react readily with
amines. The possibility of applying the Suzuki reaction to these
compounds is of great interest as many biologically active com-
pounds contain amines.
An example is the (phenylpiperazinyl-butyl)oxindoles devel-
oped by Volk et al. as selective 5-HT7 antagonists.8 Recently, we
developed a promising compound within this chemical class, CIM-
BI-712, see Figure 1.9 Its selectivity profile makes it a prime candi-
date for PET applications, ideally setup to be labeled via the Suzuki
reaction of the corresponding aryl boronic derivative.
11
DMF:H2O 9:1
3a-b
C]
[
2a-b (R2= pinacol)
4a-b
2
(R = neopentyl glycol)
Entry
R1
R2
(RCY) (%)
1
2
3
4
H
H
pinacol
neopentyl glycol
pinacol
71
72
59
58
N(CH3)2
N(CH3)2
neopentyl glycol
a
See Table 1 for the reaction conditions.
As Hostetler et al.6 and Doi et al.7 reported, the reaction be-
tween an aryl boronic derivative and [11C]CH3I is a stepwise pro-
cess, see Figure 2: first the oxidative addition, then the
transmetallation, and finally reductive elimination. Thus, the palla-
dium-carbon-11-complex can be formed quantitatively before the
aryl boronic precursor is added. Thus, 11C-Suzuki reactions can be
thought of as palladium-mediated rather than catalyzed as the Pd-
catalyst is used in large excess compared to [11C]CH3I. This led us
to hypothesize that N-11C-methylation of amines should only be
carbonyl groups or methyl groups.5 Additionally, it remarks that
the insertion of [11C]methyl groups has received no further atten-
tion, and a literature search only revealed two separate investiga-
tions on this subject. The Suzuki reaction has been investigated by
Hostetler et al.6 and Doi et al.7 using either microwave or conven-
tional heating. Previously the Suzuki reaction has been used to
label
applicability toward amine-containing compounds is still
[x- [
11C]palmitic acid2 and 11C]dehydropravastatin.3 The

V. L. Andersen et al. / Tetrahedron Letters 54 (2013) 213–216
215
Table 3
Comparison of the impact of conventional heating and microwave irradiation on the
RCY
O
B
[
11C]CH3I, Pd2(dba)3
P(o-tolyl)3, K2CO3
11CH3
O
60 °C
DMF:H2O 9:1
R
R
11
2b-e
3b-e
C]
[
Entry Product
RCY (%) conventional
heating
RCY (%) MW
heating
11CH3
1
77
82
54
5
N
3b
Figure 6. HPLC chromatograms of [11C]CIMBI-712 and CIMBI-712.
11CH3
H2N
2
3
3c
Primary, secondary, and tertiary amines are commonly ob-
served moieties in various PET tracers. Therefore, the possibility
to label model compounds bearing such motifs was investigated,
see Figure 3. Reference compounds and precursors were either
purchased or synthesized using standard procedures, see Supple-
mentary data.
11CH3
N
64
49
77
86
HN
3d
11CH3
In general, the choice of the palladium-catalyst (Pd-ligand) af-
fects the chemical yields quite dramatically.10 Therefore, the im-
pact on radiochemical yields (RCY) of four different Pd-ligand
systems, was tested (Table 1). In accordance with the findings of
Doi et al.,7 Pd2(dba)3 combined with P(o-tolyl)3 was found to be
the most efficient Pd-ligand system (Table 1).
N
4
N
3e
The reactivity of the organoboron species of the precursors also
influences the transmetallation in Suzuki couplings. Therefore, two
different ester moieties were tested. The neopentyl and corre-
sponding pinacol ester precursors displayed no impact on the
RCY (Table 2).
OR
a)
R = H (5)
R = Ms (6)
O
b)
O
N
H
N
H
Optimization of the reaction temperature was carried out using
4-(dimethylamino)phenylboronic esters. A range of temperatures
was set from 40–120 °C for the neopentyl glycol based ester and
50–120 °C for the pinacol based ester (conditions shown in Table
1). The labeling of both compounds was highly affected by the
reaction temperature. The RCY increased until 60 °C and decreased
afterward for both compounds (Fig. 4). This is possibly due to the
R
c)
N
R = Br (7)
N
d)
O
O
8
( )
R =
B
N
O
H
11
decomposition of PdIL2 CH3.
Scheme 1. Reagents and conditions: (a) 1,4-butanediol, Raney-Nickel, 200 °C, 12 h,
70%; (b) MeSO2Cl, Et3N, THF, À78 °C to rt, 2 h; (c) 1-(4-bromophenyl)piperazine,
Na2CO3, 130 °C, 55%; (d) bis(pinacolato)diboron, Pd(dppf)Cl2, KOAc, 1,4-dioxane,
100 °C, 12 h, 54%.
Furthermore, the Suzuki reaction is dependent on a base and
therefore, the effect of the utilized base was investigated. Bu4NOH,
NaOH, K2CO3, Cs2CO3, and the absence of a base were all tested
(conditions shown in Table 1). The RCYs varied from 17–77%.
Strong bases showed the lowest yields. Surprisingly, the radiosyn-
thesis without an additional base resulted in rather high RCYs of
64% and 81%, respectively. This demonstrates that amine-contain-
ing compounds can provide suitably basic conditions for 11C-Suzu-
ki reactions. However, Cs2CO3 and K2CO3 provided the highest
yields in our set-up and are thus preferable (Fig. 5).
O
B
11CH3
O
N
N
N
N
To summarize, the standard conditions for 11C-Suzuki cross-
couplings are as follows: Pd2(dba)3 and P(o-tolyl)3 (1:2) in DMF
is added to the trapped [11C]MeI and stirred at 60 °C for 2 minutes.
The aryl boronic ester and base are then added and the mixture is
heated at 60 °C for 5 minutes (see supporting information for full
details). Using these conditions p-[11C]tolylmethanamine
([11C]3c), 1-(p-[11C]tolyl)piperazine ([11C]3d), and 1-methyl-4-(p-
a)
RCY = 30%
120 GBq/µmol
O
O
[
11C]1
N
H
N
H
8
Scheme 2. Radiosynthesis of
11C]CH3I, K2CO3, Pd2(dba)3, P(o-tolyl)3, 60 °C, DMF:H2O (v:v 9:1).
[
11C]CIMBI-712. Reagents and conditions: (a)
[
[
11C]tolyl)piperazine ([11C]3e) were labeled starting from their
observed to a minor degree. Therefore, the aim of this study was to
develop a procedure in which compounds containing unprotected
amines could be labeled via the Suzuki reaction, and eventually ap-
ply this procedure to the labeling of CIMBI-712.
respective precursors 2c–e with RCYs ranging from 49–82%.
Hostetler et al. demonstrated the use of microwave (MW) irra-
diation as a way of increasing the RCYs in 11C-Suzuki reactions.6

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V. L. Andersen et al. / Tetrahedron Letters 54 (2013) 213–216
Therefore, we applied MW conditions for labeling compounds 3b–
e. Instead of 5 minute conventional heating, 3 minutes of MW
heating were applied. Changes in the RCY were variable. [11C]3d
and [11C]3e showed moderately increased RCYs, whereas reduced
RCYs for [11C]3c and [11C]3b were observed (Table 3).
CuI has previously been used to increase yields of Suzuki reac-
tions.11 As such [11C]3c and [11C]3e were obtained using CuI in 1:1
ratio with the respective boronic ester, but without improved
RCYs.
and tertiary amines without competing alkylation at these amino
groups. Finally, these conditions were used to label [11C]CIMBI-
712, a potential new 5-HT7 PET tracer.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.11.
001.
We then utilized the protocol to prepare CIMBI-712, a potential
5-HT7 PET tracer, see Figure 1.
References and notes
The precursor was prepared via a four-step synthesis starting
from oxindole (Scheme 1). 3-(4-Hydroxybutyl)-indolin-2-one (5)
was formed by a Raney-Nickel catalyzed reaction between oxin-
dole and 1,4-butanediol.8 The resulting alcohol was then converted
into the corresponding mesylate 68 and reacted with 1-(4-bromo-
phenyl)piperazine to give 3-{4-[4-(4-bromophenyl)piperazin-1-
yl]butyl}indolin-2-one (7). Finally, the boronic ester 8 was formed
via Miyaura borylation.
Labeling of 8 via the devised standard method (Scheme 2) fol-
lowed by preparative HPLC purification (Fig. 6) yielded the labeled
compound [11C]1 with a radiochemical purity P98% in 30% RCY at
the end of synthesis, with a typical specific activity of 120 GBq/
1. Allard, M.; Fouquet, E.; James, D.; Szlosek-Pinaud, M. Curr. Med. Chem. 2008, 15,
235–277.
2. Hostetler, E. D.; Fallis, S.; McCarthy, T. J.; Welch, M. J.; Katzenellenbogen, J. A. J.
Org. Chem. 1998, 63, 1348–1351.
3. Ijuin, R.; Takashima, T.; Watanabe, Y.; Sugiyama, Y.; Suzuki, M. Bioorg. Med.
Chem. 2012, 20, 3703–3709.
4. Chang, R. Physical Chemistry for the Chemical and Biological Sciences;
University Science Books, 2000.
5. Pretze, M.; Grosse-Gehling, P.; Mamat, C. Molecules 2011, 16, 1129–1165.
6. Hostetler, E. D.; Terry, G. E.; Burns, H. D. J. Labelled Compd. Radiopharm. 2005,
48, 629–634.
7. Doi, H.; Ban, I.; Nonoyama, A.; Sumi, K.; Kuang, C.; Hosoya, T.; Tsukada, H.;
Suzuki, M. Chemistry 2009, 15, 4165–4171.
8. Volk, B.; Barkoczy, J.; Hegedus, E.; Udvari, S.; Gacsalyi, I.; Mezei, T.; Pallagi, K.;
Kompagne, H.; Levay, G.; Egyed, A.; Harsing, L. G.; Spedding, M.; Simig, G. J.
Med. Chem. 2008, 51, 2522–2532.
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L. ACS Chem. Neurosci. 2012. http://dx.doi.org/10.1021/cn3001137.
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lmol. Labeling using Cs2CO3 was also attempted but was unsuc-
cessful. We are currently evaluating CIMBI-712 as a PET tracer,
and the results will be reported elsewhere.
In conclusion, a set of standard conditions for 11C-labeling via
the Suzuki reaction has been identified. Using these conditions it
was possible to label compounds containing primary, secondary,
11. Deng, J. Z.; Paone, D. V.; Ginnetti, A. T.; Kurihara, H.; Dreher, S. D.; Weissman, S.
A.; Stauffer, S. R.; Burgey, C. S. Org. Lett. 2009, 11, 345–347.