Improved yields for the palladium-mediated 11C-carbonylation reaction using microwave technology

Article abstract of DOI:10.1002/ejoc.201300989

Microwave heating technology was applied for the palladium-mediated ¹¹C-carbonylation of aryl halides and triflates at ambient pressure using xantphos as supporting ligand. Improved yields were observed for the ¹¹C-aminocarbonylation of electron-deficient aryl halides in comparison to thermal heating and the approach even allowed the use of an aryl chloride as substrate. The scope of this reaction was further extended to ¹¹C-labeled aryl acid and two ¹¹C-labeled aryl esters. Microwave heating was applied for the palladium-mediated ¹¹C- carbonylation of aryl halides and triflates using xantphos as supporting ligand. Improved yields were observed for the ¹¹C-aminocarbonylation of electron-deficient aryl halides in comparison to thermal heating and even allowed the use of an aryl chloride as substrate. A ¹¹C-labeled aryl acid and two ¹¹C-labeled aryl esters were also obtained. Copyright

Full text of DOI:10.1002/ejoc.201300989

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201300989
11
Improved Yields for the Palladium-Mediated C-Carbonylation Reaction
Using Microwave Technology
Kenneth Dahl,*[a] Magnus Schou,[b] Obaidur Rahman,[a] and Christer Halldin[a]
Keywords: Medicinal chemistry / Radiopharmaceuticals / Microwave chemistry / Radiochemistry / Isotopic labeling /
Carbonylation
Microwave heating technology was applied for the palla-
dium-mediated 11C-carbonylation of aryl halides and triflates
at ambient pressure using xantphos as supporting ligand. Im-
proved yields were observed for the 11C-aminocarbonylation
of electron-deficient aryl halides in comparison to thermal
heating and the approach even allowed the use of an aryl
chloride as substrate. The scope of this reaction was further
extended to 11C-labeled aryl acid and two 11C-labeled aryl
esters.
the synthesis of radiopharmaceuticals for PET[6] and, today,
numerous examples exist in which radiosynthesis times have
been reduced as a consequence of microwave heating.[7]
In an effort to widen the scope of our newly developed
methodology we were thus led to examine the potential use
of microwave-assisted heating as a possible means to reduce
reaction time and improve selectivity for the 11C-carb-
onylation reaction (Scheme 1). However, the application of
microwave-enhanced carbonylation using gaseous carbon
monoxide has been very little explore, and only a few pa-
pers have been published describing this approach.[8]
Introduction
Positron emission tomography (PET) is a powerful non-
invasive imaging tool that uses radiolabeled compounds as
molecular probes to investigate biological processes in
vivo.[1] The synthesis of these biological probes presents a
particular challenge, since the employed radionuclei in PET
are short-lived, only present in minute chemical amounts
and emit gamma radiation.[2]
[11C]Carbon monoxide (11CO), derived from the positron
emitting isotope 11C (t1/2 = 20.4 min), has been increasingly
recognized as an important 11C-labeling reagent because it
can provide access to a wide range of carbonyl-containing
compounds through transition-metal-mediated 11C-carb-
onylation.[3] Despite its versatility, the widespread use of
11CO has long been hampered by the lack of a simple
method for its efficient introduction. In our long-term ob-
jective to improve general access to this synthon, we re-
cently reported a novel 11C-carbonylation protocol in which
11CO is trapped and incorporated as a part of the 11CO-
insertion procedure.[4] The method is general, simple, and
has the potential to bring wide access to the attractive syn-
thon [11C]carbon monoxide.
Scheme 1. Microwave-enhanced Pd-mediated [11C]carbonylation
route to form the [11C]carbonyl-containing product.
The application of microwaves as an efficient heating
source for organic synthesis was recognized in the mid-
1980s.[5] Shortly thereafter microwaves were also applied in
Results and Discussion
Our initial efforts focused on establishing optimal micro-
wave conditions for the 11C-aminocarbonylation reaction.
[a] Karolinska Institutet, Department of Clinical Neuroscience, We selected [11C]-3-nitro-benzyl benzamide ([11C]6) as a tar-
get molecule, which was prepared by 11C-aminocarb-
Centre for Psychiatric Research, Karolinska Hospital,
17176 Stockholm, Sweden
onylation of 3-nitro-iodobenzene (4) with benzylamine (5),
using the Pd2(π-cinnamyl)Cl2–xantphos catalytic system in
0.7 mL of anhydrous tetrahydrofuran (THF; Scheme 2). In
E-mail: kenneth.dahl@ki.se
www.ki.se
[b] AstraZeneca Translational Sciences Centre, PET centre of
Excellence, Department of Clinical Neuroscience, Karolinska
Institutet, Karolinska Hospital,
our previous studies using thermal heating conditions,[4]
a
five minute reaction gave [11C]6 in 73% 11C-trapping effi-
ciency (TE) and 46% radiochemical yield (RCY) (Figure 1,
diagram A, entry 1), indicating significant room for im-
17176 Stockholm, Sweden
www.astrazeneca.com
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201300989.
Eur. J. Org. Chem. 2014, 307–310
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K. Dahl, M. Schou, O. Rahman, C. Halldin
SHORT COMMUNICATION
provement with regards to both TE and RCY. TE corre-
sponds to the total amount of 11CO that is converted into
nonvolatile product at the end of reaction. In a typical ex-
periment, the coupling reagents were prepared in a standard
disposable glass vial commonly used for HPLC purposes
(4 mL), and installed in the synthesis module approximately
5 min prior to the start of the synthesis. 11CO was concen-
trated and introduced in a controlled stream of helium
(20 mL/min) into a closed reaction vessel, and the sealed
reaction vessel was manually transferred to the microwave
cavity. In this work a single-mode microwave reactor
equipped with temperature control was used.
Scheme 2. The model palladium-mediated [11C]carbonylation reac-
tion for the formation of 3-nitrobenzyl-[carbonyl-11C]benzamide.
A series of experiments was thus conducted in which the
TE and RCY of [11C]6 was investigated as a function of
time and temperature. The microwave maximum power was
kept fixed at 250 W to minimize the time required to reach
the set temperature. The results are summarized in Figure 1.
Under identical conditions (100 °C for 5 min), a relative
35% increase in RCY was observed with microwave heating
compared with thermal heating (Figure 1, diagram A, en-
tries 1 and 2). Heating at 120 °C for 5 min using active cool-
ing (AC) resulted in quantitative TE with an improvement
in RCY to 81% (Figure 1, diagram A, entry 4), which is a
78% increase in overall RCY compared with conventional
heating.
The use of higher temperatures (140–160 °C) were tested
with the aim of completing the reaction in shorter time,
however, RCYs were decreased due to the formation of an
unknown radioactive byproduct. For example, at 140 °C the
RCY was decreased by 12% (Figure 1, diagram A, entry 5)
and a similar result was observed when the reaction was
conducted at 160 °C for 2 min (Figure 1, diagram A, en-
try 8). Attempts to run the reaction at 120 °C with a re-
duced reaction time resulted in decreased TE and thereby
lower RCY. Therefore, 120 °C and a 5 min reaction time
with active cooling was established as the preferred settings
for the microwave-enhanced Pd-catalyzed [11C]aminocarb-
onylation.
Figure 1. (A) Trapping efficiency (TE) and radiochemical yield
(RCY) examined as a function of time and temperature. Reaction
conditions: substrate (20 μmol), benzylamine (100 μL), xantphos
(14 μmol), Pd2[π-cinnamyl]Cl2 (14 μmol). Thermal heating:
[1] 100 °C/5 min.[4] MW heating: [2] 100 °C /5 min, [3] 100 °C/
5 min/AC, [4] 120 °C/5 min/AC, [5] 140 °C/5 min/AC, [6] 120 °C/
3 min/AC, [7] 140 °C/3 min/AC, [8] 160 °C/2 min/AC. (B) TE and
RCY examined by using different solvents.
We continued our study by performing the reaction in
different solvents. A series of commonly used solvents with
different microwave properties was screened. The results are would be produced as the main product. On the other hand,
summarized in Figure 1 (diagram B). Quantitative TE was a significant amount (85.5%) of an unidentified byproduct,
observed in eight of the ten examined solvents, with 1,4- likely to be the corresponding ethyl [11C]benzoate, was pro-
dioxane and dimethyl sulfoxide (DMSO) being exceptions. duced when EtOH was used as solvent. Although MeOH
Although we did notice a large variation in product distri- showed promise as a reaction media, THF was selected as
bution between the examined solvents (6–83%), it was note- the solvent of choice for the continued study.
worthy that the highly protic solvent MeOH exhibited a
The optimal conditions were then applied to the 11C-
similar or better RCY of [11C]6 compared with the investi- aminocarbonylation of a range of functionalized aryl iod-
gated aprotic solvents under microwave conditions. One ides, an aryl triflate and an aryl chloride by using 5 as a
would expect that the corresponding methyl [11C]benzoate model amine nucleophile. The selected substrates were first
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Palladium-Mediated 11C-Carbonylation
investigated by using conventional heating to facilitate rapid the conditions used for the aminocarbonylation, the hy-
comparison between the two conditions. The results are droxy and alkoxy nucleophiles (water, methanol and eth-
summarized in Table 1. The RCYs of substrates containing anol) were also used as reaction media. When 11C-hydroxy-
electron-withdrawing groups in the meta-position were gen- carbonylation was conducted in an equimolar mixture of
erally increased under microwave-enhanced conditions aqueous sodium hydroxide and THF, the corresponding
(Table 1, entries 3–5), whereas the RCY for the disubsti- carboxylic acid [11C]11a was produced in 97% RCY
tuted substrate, 3,5-nitro-iodobenzene, was not improved (Table 2, entry 1). Following the same protocol but using a
(Table 1, entry 6). Surprisingly, appreciable RCYs were ob- 1:1 mixture of THF and alcohol, the corresponding alkyl
tained when chlorobenzene was used as substrate under [11C]benzoates were produced with excellent and reproduc-
both heating technologies, although a relative 21% increase ible RCYs (Table 2, entries 2–3). Replacing ethanol with
in RCY was obtained with microwave heating compared a solution of its lithium salt in anhydrous THF provided
with thermal heating (Table 1, entry 1). This is, to the best [11C]11c in 73% RCY (Table 2, entry 4), with [11C]-
of our knowledge, the first example of a successful 11C- benzoic acid as the main byproduct. These encouraging re-
carbonylation of an aryl chloride. In addition, a 16% im- sults imply that the use of microwave-enhanced 11C-carb-
provement in product distribution was observed for sub- onylation provides a facile route to 11C-esters labeled in the
strate 7c compared with reported results obtained with carbonyl position. Traditionally, 11C-labeled compounds
thermal heating, whereas the RCY was not improved when with carbonyl functionality have been synthesized through
the nonhalide substrate 7b was used as substrate. Thus, the multi-step protocols, typically using the direct application
increased yield observed for 11C-aminocarbonylation of of [11C]carbon dioxide in the carboxylation of Grignard
four of the six aryl substrates examined herein supports the reagent.[9] However, unlike the method describe in this pa-
view that microwave irradiation increases the efficiency of per, such methodologies are highly sensitive to trace
11C-amide formation for electron-deficient aryl halides.
amounts of moisture and oxygen, and therefore a high ra-
diochemical yield is generally very difficult to maintain.
Table 1. Difference in 11CO trapping efficiency (TE) and radio-
chemical yield (RCY) was examined for six different aminocarb-
onylation reactions between microwave and thermal heating.[a]
Table 2. Results for the Pd-mediated 11C-carbonylation using O-
centered nucleophiles.[a]
Entry
Nu
R
TE [%]
RCY [%][d]
1
2
3
4
H2O[b]
MeOH
EtOH
H
Ͼ 99
Ͼ 99
Ͼ 99
Ͼ 99
97Ϯ1
93Ϯ1
82Ϯ1
73Ϯ6
Me
Et
Et
LiOEt[c]
[a] Reaction conditions: substrate (20 μmol), nucleophile (400 μL),
xantphos (14 μmol), Pd2[π-cinnamyl]Cl2 (14 μmol), THF (400 μL),
120 °C, 5 min. [b] NaOH (70 μmol) was used as base. [c] Reaction
was performed with LiOEt (100 μmol) in pure THF. [d] Average of
two runs.
Conclusions
[a] Reaction conditions: substrate (20 μmol), benzylamine (100 μL),
xantphos (14 μmol), Pd2[π-cinnamyl]Cl2 (14 μmol), THF (0.7 mL),
microwave (120 °C, 5 min, AC) or thermal (120 °C, 5 min) heating.
[b] Average of two runs.
We herein described the first application of microwave
heating to facilitate Pd-mediated 11C-carbonylation of aryl
substrates. By using microwave irradiation at ambient pres-
sure in a disposable glass vial, we observed improved yields
To further examine the scope of this methodology, we in the 11C-aminocarbonylation of electron-deficient aryl
turned our attention to functional groups other than halides, and the approach even allowed the use of an aryl
amides. Beside amides, carboxylic acids and esters are two chloride as substrate. The scope of this reaction was further
of the most abundant functional groups in biologically im- extended to the synthesis of 11C-labeled aryl acid and two
portant compounds and drug-like molecules. To this end, 11C-labeled aryl esters. These results further demonstrate
two esters and a carboxylic acid were produced by using the utility and potential of 11CO as a labeling precursor for
iodobenzene as substrate (Table 2). However, in contrast to application in PET.
Eur. J. Org. Chem. 2014, 307–310
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K. Dahl, M. Schou, O. Rahman, C. Halldin
SHORT COMMUNICATION
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Experimental Section
General Procedure for the Microwave-Enhanced [11C]Carbonylation
Reaction: 11CO2 was reduced online to 11CO by using a pre-heated
quartz column (850 °C) charged with Mo-powder. Unreacted
11CO2 was subsequently removed by an ascarite trap and the 11CO
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ide, Pd-source, ligand and amine dissolved in appropriate solvent)
equipped with a rubber septum. The sealed reaction vessel was
manually transferred to the microwave cavity and heated at the
desired temperature for 2–5 min, after which the vial was cooled to
room temp. The radioactivity was measured before and after the
vial was purged with nitrogen. Radiochemical purity (RCP) of the
crude reaction mixture was established with radio-HPLC. For a
more detailed description of the reaction procedure, see the Sup-
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Supporting Information (see footnote on the first page of this arti-
cle): General methods, experimental procedures, and radio-HPLC
chromatograms.
Acknowledgments
This research was supported by GEMS PET Systems AB (GE
Healthcare). The authors thank all members of the PET group at
Karolinska Institutet for their support.
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Received: October 22, 2013
Published Online: November 22, 2013
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