Palladium-mediated [11C]carbonylation at atmospheric pressure: A general method using xantphos as supporting ligand

Article abstract of DOI:10.1002/ejoc.201201708

The palladium-catalyzed [¹¹C]carbonylation of aryl halides and triflates was achieved at atmospheric pressure by employing xantphos as the supporting ligand. Aryl halides were converted into their corresponding [ ¹¹C]amides in good t

Full text of DOI:10.1002/ejoc.201201708

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201201708
Palladium-Mediated [11C]Carbonylation at Atmospheric Pressure: A General
Method Using Xantphos as Supporting Ligand
Kenneth Dahl,*[a] Magnus Schou,*[a,b] Nahid Amini,[a] and Christer Halldin[a]
Keywords: Isotopic labeling / Radiolabeling / Radiochemistry / Carbonylation / Positron emission tomography
The palladium-catalyzed [11C]carbonylation of aryl halides
and triflates was achieved at atmospheric pressure by em-
ploying xantphos as the supporting ligand. Aryl halides were
converted into their corresponding [11C]amides in good to
excellent yields. The conditions were also successfully em-
ployed in the radiolabeling of an [11C]ester, a [11C]carboxylic
acid, an [11C]aldehyde, and a [11C]ketone.
Introduction
amounts. This means that reactions may not be driven by
access of the radiolabeled precursor.[1]
Of the available radionuclides for use in positron emis-
sion tomography (PET), the most interesting is arguably
11C (t1/2 = 20.4 min), as carbon is the main constituent in
nearly all biologically active compounds.[1] Herein we de-
scribe a novel methodology for the incorporation of 11C
through transition-metal-mediated [11C]carbonylation that
is general, simple, and robust (Scheme 1). The method has
the potential to bring wide access to the highly attractive
but elusive synthon [11C]carbon monoxide.
[11C]Carbon monoxide (11CO) has many attractive fea-
tures as a synthon in PET chemistry, including its facile
production and high versatility in transition-metal-medi-
ated [11C]carbonylation.[2] Despite the great potential of
11CO, its widespread use has since long been hampered by
the lack of a simple method for its introduction. It is be-
lieved that efficient radiolabeling with 11CO is impossible
without the use of high-pressure devices[3] (e.g., microauto-
claves) or chemical 11CO fixation reagents[4] (e.g., boron
[11C]carbonyl, CuTp11CO, etc.) as a result of the low solu-
bility of 11CO in organic solvents.[5] However, recently two
approaches were reported in which [11C]carbonylation was
achieved at near atmospheric pressure. Eriksson et al. ele-
gantly demonstrated that 11CO can be transferred to a
sealed reaction vial without noticeable pressure increase by
use of xenon gas.[6] However, only a few substrates were
radiolabeled in that study. Concomitant with this work be-
ing finalized, Suzuki et al. reported on an oxidant-assisted
methoxy[11C]carbonylation of aryl boronates under
atmospheric pressure.[7] This method produced a number of
[11C]esters in low to moderated yields but appears to be
limited to the syntheses of [11C]carboxylic acids and their
methyl esters, as the reaction solvent mixture of methanol/
dimethylformamide was essential for the reaction to pro-
ceed.
Scheme 1. Three-component Pd-mediated carbonylation to form
an [11C]carbonyl containing product.
Although many of the methods developed for synthetic
organic chemistry can also be applied to the radiochemistry
of 11C, its properties impose several challenges. First of all,
its short half-life precludes lengthy reactions and its high-
energy radioactive emission requires that syntheses be car-
ried out in lead-shielded fume hoods (hot cells). Further-
more, 11C is initially delivered from the cyclotron in simple
chemical forms, such as 11CO2 or 11CH4, and in minute
In an effort to develop a simple and versatile low-pres-
[a] Karolinska Institutet, Department of Clinical Neuroscience, sure method for the radiolabeling of molecules with 11CO,
Centre for Psychiatric Research, Karolinska Hospital,
we initiated a study focused on establishing a palladium–
17176 Stockholm, Sweden
ligand complex in which the 11CO is trapped as a part of
E-mail: kenneth.dahl@ki.se
the 11CO insertion procedure. Recently, Buchwald et al.
Homepage: www.ki.se
[b] AstraZeneca Translational Sciences Centre, PET Centre of
showed that lower CO pressures (1 bar) can be used in
Excellence, Department of Clinical Neuroscience, Centre for
aminocarbonylation reactions when using the wider bite
angle bidentate phosphane ligand xantphos as a supporting
ligand.[8] Although the partial pressure of 11CO in the reac-
tor is expected to be much lower than 1 bar, we hoped the
Psychiatric Research, Karolinska Hospital,
17176 Stockholm, Sweden
Homepage: www.astrazeneca.com
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201201708.
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Eur. J. Org. Chem. 2013, 1228–1231

Pd-Mediated [11C]Carbonylation at Atmospheric Pressure
wider bite angle would enhance the reactivity enough to lyst and produced N-benzyl-[carbonyl-11C]benzamide in
allow the [11C]carbonylation to occur.[9] We were thus led 54Ϯ1%, with an almost quantitative TE (Table 1, entry 7).
to investigate a series of ligands in the amino[11C]- This result is notable, as DPEphos and dppf have neutral
carbonylation of iodobenzene.
bite angles that are similar to that of xantphos, but these
ligands generated catalysts with quite disparate activity. The
flexible backbone structure of xantphos (bite angle: 97–
133°) may partly account for this phenomenon, as it is be-
lieved to induce a dynamic coordination environment that
may be of importance for catalyst activity in transition-
metal-catalyzed processes.[13] Further investigations using
tBu-xantphos and EA-xantphos (Table 1, entries 11 and 12)
did not improve the catalytic system.
We continued our study by exploring whether Pd(OAc)2
was the preferred palladium catalyst source for this reac-
tion. A series of palladium(0) and palladium(II) catalysts
was tested (Table 2). PdCl2, Pd2(dba)3, and Pd(PPh3)4 all
formed active Pd–ligand complexes, with RCYs in the range
of 78–92%. Remarkably, when using the palladium(II) cata-
lyst, Pd2(π-cinnamyl)Cl2, an almost quantitative conversion
to N-benzyl-[carbonyl-11C]benzamide was obtained. Pd2(π-
cinnamyl)Cl2 was therefore established as the preferred Pd
source for the Pd-catalyzed [11C]carbonylation.
Results and Discussion
The initial target was to discover a palladium complex
that allowed the efficient trapping of 11CO in solution.
Thus, a series of bidentate phosphane ligands with ranging
neutral bite angles from 78 to 110° (Table 1, entries 1–8)
was tested by using N-benzyl-[carbonyl-11C]benzamide
([11C]6) as a model compound for the reaction. The mono-
phosphane ligand PPh3 and the biaryl monophosphane li-
gand Sphos were also included, as these ligands are fre-
quently employed in carbonylation chemistry.[10] Despite
the success of biaryl monophosphanes in Pd-catalyzed C–
N bond-formation reactions,[11] Sphos was shown to be in-
efficient (Table 1, entry 9). Furthermore, the standard li-
gand for Pd-catalyzed [11C]carbonylation reactions,[2] PPh3,
showed poor trapping efficiency (21%) and gave a low ra-
diochemical yield (RCY) of the desired [11C]benzamide
(7.4%), which is in accord with earlier studies conducted Table 2. Effect of the Pd source on the 11CO trapping efficiency
and the analytical RCY of N-benzyl-[carbonyl-11C]benzamide.[a]
with a similar design.[12]
Entry Pd source
Trapped
RCP
[%]
RCY
[%]
Table 1. Effect of the ligand on the 11CO trapping efficiency and
the analytical radiochemical yield of N-benzyl-[carbonyl-11C]-
benzamide.[a]
11CO [%]
1
2
3
4
5
6
Pd(OAc)2
PdCl2
Pd2(dba)3
Pd(PPh3)4
Pd2[π-cinnamyl]Cl2
Pd2[π-cinnamyl]Cl2
Ͼ99
82
Ͼ99
96
54
96
93
54
79
92
82
98
–
85
Ͼ99
99Ϯ1[c]
61[b]
–
[a] Conditions: iodobenzene (20 μmol), benzylamine (100 μL),
xantphos (14 μmol), Pd source (14 μmol), THF (0.7 mL), 100 °C,
5 min. [b] Test was conducted in a solution mixture of the Pd cata-
lyst and xantphos without the aryl halide or benzylamine present.
[c] Average of three runs.
Entry Ligand[b]
Bite
Trapped
RCP[e]
[%]
RCY[f]
[%]
angle[c] 11CO[d] [%]
1
2
3
dppe
(S)-BINAP
dppp
78
92
95
31
18
63
40
85
55
Ͼ99
11
21
9
67
17
49
24
35
34
21
3
31
10
30
19
54
0
7
4
2
12
To investigate the utility of this methodology with regard
to solvent compatibility, some commonly used solvents
were tested. To our delight, low-pressure [11C]carbonylation
proceeded in good yields in all examined solvents with
RCYs above 76% (Table 3, entries 1 and 6–10). In addition,
4
5
dppb
dppf
99
106
108
110
–
145
217
140
–
6
7
8
DPEphos
xantphos
dcpp
54Ϯ1[g]
0
9
PPh3
Sphos
tBu-xantphos
EA-xantphos
35
42
18
35
10
11
12
12
34
Table 3. Effect of the solvent and reaction temperature on the ana-
lytical RCY of N-benzyl-[carbonyl-11C]benzamide.[a]
[a] Conditions: Iodobenzene (20 μmol), benzylamine (100 μL), li-
gand (14–48 μmol), Pd source (14 μmol), THF (0.7 mL), 100 °C,
5 min. [b] Ligand abbreviations are given in the Supporting Infor-
mation. [c] See ref.[8,13] [d] Decay corrected; the fraction of radio-
activity left in the crude product after purging with nitrogen. [e] Ra-
diochemical purity determined by radioanalytical HPLC. [f] Radio-
chemical yield based on the total radioactivity delivered to the reac-
tion vial. [g] Average of three runs.
Entry Solvent
Temp.
[°C]
Trapped
RCP
[%]
RCY
[%]
11CO [%]
1
2
3
4
5
6
7
8
9
10
THF
THF
THF
THF
100
80
60
Ͼ99
98
Ͼ99
Ͼ99
98
Ͼ99
Ͼ99
Ͼ99
Ͼ99
Ͼ99
99.6
98.3
96.4
92.5
88.6
99.4
96.1
96.3
85.6
77.6
99
97
95
92
87
98
95
95
85
77
40
THF
r.t.
100
100
100
100
100
1,4-dioxane
toluene
CH3CN
DMF
A number of bidentate ligands with previously demon-
strated utility in Pd-catalyzed processes gave low to moder-
ate yields (Table 1, entries 1, 2, 4 and 8), although dppp
and dppf showed some promise, with fairly high trapping
efficiency (TE) and RCYs near 30% (Table 1, entries 3 and
DMSO
[a] Conditions: iodobenzene (20 μmol), benzylamine (100 μL),
xantphos (14 μmol), Pd2[π-cinnamyl]Cl2 (14 μmol), solvent
5). To our delight, xantphos provided a highly active cata- (0.7 mL), r.t. to 100 °C, 5 min.
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K. Dahl, M. Schou, N. Amini, C. Halldin
SHORT COMMUNICATION
we also investigated the reaction at lower temperatures by Table 4. Effect of the nature of the substrate on the 11CO trapping
efficiency and the analytical RCY of the corresponding benzyl-
using THF as the solvent (Table 3, entries 1–5). Notably,
no obvious difference in TE was observed in the examined
[carbonyl-11C]benzamide.[a]
temperature range, but we did see a difference in product
distribution with a 10% decrease in product formation at
room temperature relative to that obtained at 100 °C. The
RCY at 100 °C (99%; Table 3, entry 1) is, to the best of our
knowledge, the best reported for N-benzyl-[carbonyl-11C]-
benzylamide. Although other solvents may be useful for
carbonylation cross-coupling reactions other than amino-
carbonylations,[10] THF was chosen for our continued study
on the aminocarbonylation of some functionalized arenes.
With the optimized reaction conditions in hand (Table 2,
entry 5), a series of aryl halides was successfully converted
into their corresponding benzylamides (Table 4). Excellent
RCYs (Ͼ96%) were obtained when using iodo- and bromo-
benzene (Table 4, entries 1 and 2) under the optimized con-
ditions. Chlorobenzene, in contrast (Table 4, entry 3), was
shown to be ineffective as a substrate under these condi-
tions. Phenyl triflate was also included in the investigation
(Table 4, entry 4) and produced N-benzyl-[carbonyl-11C]-
benzamide in good RCY. As expected, aryl iodides with
electron-donating substituents gave excellent RCYs
(Table 4, entries 9 and 10), whereas electron-withdrawing
groups in the ortho position were more or less well tolerated
(Table 4, entries 5–8). For example, the less deactivated sub-
strate o-chloroiodobenzene gave an RCY of 82% (Table 4,
entry 5), whereas o-dinitroiodobenzene only generated the
desired product in 13% yield (Table 4, entry 8). Product yields
were good to excellent when substrates containing electron-
withdrawing groups were situated in the para position
(Table 4, entries 11 and 12). As anticipated, the RCYs are
strongly dependent on the nature of the substrate and its ten-
dency to engage in oxidative addition with the Pd0 complex.
To further test the scope of this methodology, we decided
to apply this method to functional groups other than
amides. Thus, an ester, a carboxylic acid, a ketone, and an
aldehyde were prepared by using the conditions for the
[a] Conditions: substrate (20 μmol), benzylamine (100 μL),
xantphos (14 μmol), Pd2[π-cinnamyl]Cl2 (14 μmol), THF (0.7 mL),
100 °C, 5 min. [b] Average of three runs.
aminocarbonylation reaction with only minor modifica-
tions (Scheme 2). All investigated reactions showed high
TEs and the products were formed in moderate to good
yields. Although this shows that the scope extends beyond
aminocarbonylation, there may be room for substantial im-
provements in the RCY of these compounds if conditions
were optimized accordingly. In addition, microwave heat-
ing, with its well-known advantages over conventional heat-
ing could be an ideal improvement for this novel method.[14]
Further investigations on the application of palladium-me-
diated [11C]carbonylation are currently ongoing.
As a final testament to the utility of this method, a can-
didate radioligand for the histamine type-3 receptor,
[11C]15, was prepared by using the optimized conditions
(Scheme 3). Compound [11C]15 was obtained with a RCY
Scheme 2. Structures, TEs and RCYs of prepared [11C]ketone,
[11C]carboxylic acid, [11C]aldehyde, and [11C]ester.
of 95% with a TE over 99%. In a preparative run,
4170 MBq (112.8 mCi) isolated product ([11C]15) was ob-
tained in a 88% decay-corrected RCY calculated from 11CO (3280 Cimmol–1). The product identity was confirmed by
delivered to reaction vessel. The RCP was greater than 97% co-elution on HPLC with UV and radioactive detection
and the specific radioactivity was 121 GBqμmol–1 and LC–MS/MS.
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Eur. J. Org. Chem. 2013, 1228–1231

Pd-Mediated [11C]Carbonylation at Atmospheric Pressure
formed during this study, as all radioactive products were produced
in insufficient quantities.
Acknowledgments
This research was supported by GEMS PET Systems AB (GE
Healthcare). We thank Dr. Chad Elmore (AstraZeneca) for re-
viewing the language. We also thank all members of the PET group
at Karolinska Institutet for all their support.
Scheme 3. Radiosynthesis of the histamine type-3 receptor radioli-
gand [11C]15.
[1] P. W. Miller, N. J. Long, R. Vilar, A. D. Gee, Angew. Chem.
2008, 120, 9136–9172; Angew. Chem. Int. Ed. 2008, 47, 8998–
9033.
[2] B. Långström, O. Itsenko, O. Rahman, J. Labelled Compd. Ra-
diopharm. 2007, 50, 794–810.
[3] a) T. Kihlberg, B. Långström, J. Org. Chem. 1999, 64, 9201–
9205; b) T. Kihlberg, B. Långström, PCT int. Appl. 2002, WO
2002102711 A1.
[4] a) S. Kealey, P. W. Miller, N. J. Long, C. Plisson, L. Martarello,
A. D. Gee, Chem. Commun. 2009, 3696–3698; b) H. Audrain,
L. Martarello, A. Gee, D. Bender, Chem. Commun. 2004, 558–
559.
Conclusions
In summary, we herein described the development of a
Pd-mediated [11C]carbonylation protocol employing
xantphos as the supporting ligand. The reaction proceeds at
close to atmospheric pressure and at moderate temperatures
with aryl halides or aryl triflates as substrates. In addition
to the labeling of [11C]amides, the protocol also demon-
strated its utility in the radiosynthesis of an [11C]ester, a
[11C]carboxylic acid, an [11C]aldehyde, and a [11C]ketone.
Given the simplicity and efficiency of this method, it has
great potential to allow [11C]carbonylation reactions to be
performed in a routine fashion with similar ease as [11C]-
[5] a) Y. Andersson, B. Långström, J. Chem. Soc. Perkin Trans. 1
1995, 287–289; b) M. H. Al-Qahtani, V. W. Pike, J. Chem. Soc.
Perkin Trans. 1 2000, 1033–1036.
[6] J. Eriksson, J. van den Hoek, A. D. Windhorst, J. Labelled
Compd. Radiopharm. 2012, 55, 223–228.
methylations,[15] and we expect this novel method to be [7] M. Takashima-Hirano, H. Ishii, M. Suzuki, ACS Med. Chem.
Lett. 2012, 3, 804–807.
widely adapted in PET radiopharmaceutical research and
development.
[8] a) J. R. Martinelli, D. M. M. Freckmann, S. L. Buchwald, Org.
Lett. 2006, 8, 4843–4846; b) J. R. Martinelli, D. A. Watson,
D. M. M. Freckmann, T. E. Barder, S. L. Buchwald, J. Org.
Chem. 2008, 73, 7102–7107; c) A. Deagostino, P. Larini, E. G.
Occhiato, L. Pizzuto, C. Prandi, P. Venturello, J. Org. Chem.
2008, 73, 1941–1945.
Experimental Section
General Procedure for the Low-Pressure [11C]Carbonylation Reac-
tion: 11CO2 was reduced online to 11CO by using a preheated quartz
column (850 °C) charged with Mo powder. Unreacted 11CO2 was
subsequently removed by an ascarite trap, and the 11CO was con-
centrated on a silica gel trap immersed in liquid nitrogen. After
complete entrapment, the trap was heated to release the 11CO into
a vial (4 mL) containing the coupling reagents (aryl halide, Pd
source, ligand, and amine dissolved in anhydrous THF) equipped
with a rubber septum. The vial was heated at the desired tempera-
ture for 5 min, after which the vial was cooled to room temperature.
The radioactivity was measured before and after the vial was
purged with nitrogen. RCP of the crude reaction mixture was estab-
lished with radio-HPLC. For a more detailed description of the
reaction procedure see the Supporting Information.
[9] M. N. Birkholz, Z. Freixa, P. W. N. M. van Leeuwen, Chem.
Soc. Rev. 2009, 38, 1099–1118.
[10] A. Brennführer, H. Neumann, M. Beller, Angew. Chem. 2009,
121, 4176–4196; Angew. Chem. Int. Ed. 2009, 48, 4114–4133.
[11] D. S. Surry, S. L. Buchwald, Angew. Chem. 2008, 120, 6438–
6461; Angew. Chem. Int. Ed. 2008, 47, 6338–6361.
[12] P. Lidström, T. Kihlberg, B. Långström, J. Chem. Soc. Perkin
Trans. 1 1997, 2701–2706.
[13] a) P. W. N. M. van Leeuwen, P. C. J. Kamer, J. N. H. Reek, P.
Dierkes, Chem. Rev. 2000, 100, 2741–2769; b) L. A.
van der Veen, P. H. Keeven, G. C. Schoemaker, J. N. H. Reek,
P. C. J. Kamer, P. W. N. M. van Leeuwen, M. Lutz, A. L. Spek,
Organometallics 2000, 19, 872–883.
[14] V. P. Mehtaa, E. V. Van der Eycken, Chem. Soc. Rev. 2011, 40,
4925–4936.
[15] P. H. Elsinga, Methods 2002, 27, 208–217.
Received: December 18, 2012
Published Online: January 28, 2013
Minor changes have been made after publication in Early View.
Supporting Information (see footnote on the first page of this arti-
cle): General methods, experimental procedures, spectroscopic data
for new compounds. No NMR spectroscopic analysis was per-
Eur. J. Org. Chem. 2013, 1228–1231
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