Pd(0)-mediated [11C]carbonylation of aryl and heteroaryl boronic acid pinacol esters with [11C]carbon monoxide under ambient conditions and a facile process for the conversion of [carbonyl-11C]esters to [carbonyl-11C]amides

Article abstract of DOI:10.1016/j.tet.2015.01.008

A new method has been developed for the Pd(0)-mediated [¹¹C]carbonylation of aryl/heteroaryl boronic acid pinacol esters with [¹¹C]carbon monoxide in the presence of p-benzoquinone and triphenylphosphine in a mixture of N,N-dimethylformamide (DMF) and methanol (MeOH) or just MeOH under ambient pressure at 65 °C. This method was used to convert a variety of different aryl/heteroaryl boronates to the corresponding [carbonyl-¹¹C]esters with decay-corrected radiochemical yields in the range of 6-80%. Furthermore, some of these [carbonyl-¹¹C]esters were treated with sodium hydroxide or aqueous ammonium to give the corresponding [carbonyl-¹¹C]carboxylic acids and amides, respectively. This new method was also used to achieve the direct syntheses of [¹¹C]aspirin using water or tetramethylammonium hydroxide as the nucleophile instead of MeOH in DMF.

Full text of DOI:10.1016/j.tet.2015.01.008

Tetrahedron 71 (2015) 1588e1596
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
11
Pd(0)-mediated [ C]carbonylation of aryl and heteroaryl boronic
11
acid pinacol esters with [ C]carbon monoxide under ambient
11
conditions and a facile process for the conversion of [carbonyl- C]
11
esters to [carbonyl- C]amides
*
Hideki Ishii , Katsuyuki Minegishi, Koutaro Nagatsu, Ming-Rong Zhang
Molecular Probe Program, Molecular Imaging Center, National Institute of Radiological Science (NIRS), 4-9-1 Anagawa, Inage-ku, Chiba 263-8555,
Japan
a r t i c l e i n f o
a b s t r a c t
A new method has been developed for the Pd(0)-mediated [11C]carbonylation of aryl/heteroaryl boronic
acid pinacol esters with [ C]carbon monoxide in the presence of p-benzoquinone and triphenylphos-
Article history:
Received 14 December 2014
Received in revised form 6 January 2015
Accepted 7 January 2015
11
phine in a mixture of N,N-dimethylformamide (DMF) and methanol (MeOH) or just MeOH under am-
ꢀ
bient pressure at 65 C. This method was used to convert a variety of different aryl/heteroaryl boronates
Available online 19 January 2015
to the corresponding [carbonyl-11C]esters with decay-corrected radiochemical yields in the range of
6
e80%. Furthermore, some of these [carbonyl-11C]esters were treated with sodium hydroxide or aqueous
Keywords:
Carbon monoxide
Palladium
11
ammonium to give the corresponding [carbonyl- C]carboxylic acids and amides, respectively. This new
method was also used to achieve the direct syntheses of [11C]aspirin using water or tetramethy-
lammonium hydroxide as the nucleophile instead of MeOH in DMF.
11-Carbon
Carbonylation
Aspirin
Ó 2015 Elsevier Ltd. All rights reserved.
1
. Introduction
and high pressure (if necessary) and high temperature (if neces-
sary) conditions, because CO is poorly soluble in most common
solvents and not very reactive. Several interesting pieces of
equipment and useful methods, however, have been developed to
overcome these issues and allow for the successful synthesis of
7,8
9
Synthetic methods for incorporating a carbonyl moiety into an
aryl or heteroaryl group are powerful processes for the construction
of valuable synthetic intermediates and interesting pharmacologi-
cal compounds. A wide variety of different metal-catalyzed car-
bonylation reactions have been reported in the literature to date,
including the reactions of aryl and heteroaryl halides, triflates and
boronates with carbon monoxide, which have been used exten-
1
1
10
[carbonyl- C]compounds including high-pressure vessels, recir-
11
12
11
culation systems, microfluidic reactor systems, chemical [ C]O-
13,14
15
fixation techniques,
microwave systems and Xe-gas carrier
1
6
11
systems. Several Pd-mediated rapid [ C]carbonylation reactions
have recently been reported that can be conducted without the
1
e4
sively.
The application of these reactions to the synthesis of
11
positron emission tomography (PET) probes has attracted consid-
erable attention from researchers because of their tolerance to-
wards a wide variety of functional groups, which has resulted in the
synthesis of several useful diagnostic probes.5,6 PET probes are
need for specialist equipment, except for the [ C]O generation
system. For example, Dahl et al. reported the palladium-mediated
C]carbonylation of aryl halide and triflates under atmospheric
conditions using xantphos as a supporting ligand to give [ C]am-
ides, [ C]esters, [ C]carboxylic acids, [ C]aldehydes and [ C]ke-
tones in good to excellent yields. Vilar et al. also succeeded in the
synthesis of [ C]amides from aryl halides under atmospheric
conditions using a combination of a palladium(II) dimer and
a hindered phosphine. In a separate study, Suzuki and co-workers
reported the palladium-mediated oxidative [ C]carbonylation of
aryl boronates under atmospheric conditions to produce [ C]esters
in low to moderate yields. As part of the same study, the authors
also reported the successful synthesis of
(Scheme 1).
17
11
[
11
11
18
11
11
11
11
generally synthesized using short-lived isotopes such as C and
F
14
(t
1/2¼20.4 and 119 min, respectively), and the synthetic processes
11
used to construct these probes are therefore required to progress
much more rapidly than conventional reactions, especially for 11C-
labeled PET probes. However, a typical carbonylation reaction using
CO generally requires excess amount of CO, and long reaction times,
18
11
11
11
[ C]tamibarotene
*
Corresponding author. Tel.: þ81 43 206 4039; fax: þ81 43 206 3261; e-mail
address: ishiihd@nirs.go.jp (H. Ishii).
http://dx.doi.org/10.1016/j.tet.2015.01.008
0
040-4020/Ó 2015 Elsevier Ltd. All rights reserved.

H. Ishii et al. / Tetrahedron 71 (2015) 1588e1596
1589
Scheme 1. [11C]Carbomethoxylation of aryl boronic acid neopentyl glycol esters.
Among these methods, the process reported by Suzuki appears
11
to be suitable for the synthesis of [carbonyl- C] containing PET
probes because it can be applied to boronate ester precursors,
which are much more stable and less toxic than the corresponding
aryl halides/triflates. Although Suzuki’s method was used to com-
1
1
plete the synthesis of [ C]tamibarotene, it has subsequently only
been applied to the synthesis of several p-substituted methyl
benzoate derivatives (Scheme 1). With this in mind, we decided to
Scheme 3. [11C]carbomethoxylation of boronic acid neopentyl ester (3).
11
study the scope and limitation of this [ C]carbonylation reaction
using a variety of aryl/heteroaryl boronates. We also investigated
the application of this process to the synthesis of [ C-carbonyl]
aspirin and [11C-carbonyl]salicylic acid, as well as several related
derivatives.
Aspirin is one of the oldest drugs, and is still used today to
provide pain relief and alleviate the symptoms of a fever. In-
terestingly, however, this drug has recently attracted considerable
attention for its role in preventing the risk of several types of
radioactivity of the vessel was measured. The vessel was then held
at ambient temperature for 5 min. As shown in Scheme 3, the re-
action proceeded smoothly to give the desired product 4a in 15%
decay-corrected radiochemical yield (RCY).
11
11
The [ C]carbomethoxylation reaction was also conducted using
phenyl boronic acid pinacol ester (3a), as shown in Scheme 4. The
same reaction was conducted using phenylboronic acid pinacol
ester (3a) because more boronic acid pinacol esters are commer-
cially available than the corresponding neopentyl esters. Un-
fortunately, however, this reaction only afforded a trace amount of
4a (Scheme 4). Furthermore, it was not possible to increase the yield
of this reaction by simply extending the reaction time (1%, after
19
20
21
cancer, Alzheimer’s disease (AD) and heart attacks. Sasaki
et al.22 reported the synthesis of [ C]salicylic acid (1) and [ C]as-
11
11
pirin (2) via the Grignard reaction of 2-bromomagnesiumanisole
with [11C]O
as part of their work towards investigating the role
2
of hydroxyl radicals in the brains of mice (Scheme 2). The bio-
distribution results of this particular study revealed that com-
pound 1 showed better uptake into the mouse brain than 2. Fur-
2
3
14
thermore, Brune et al. reported the accumulation of [ C]aspirin
in the inflamed tissues of rats. These results prompted us to in-
11
11
vestigate the synthesis of [ C]salicylic acid (1) and [ C]aspirin (2),
as well as their [11C]derivatives, to develop a simpler and more
efficient method for their production.
Scheme 4. [11C]carbomethoxylation of phenyl boronic acid pinacol ester (3a).
Scheme 2. Synthesis of [11C]salicylic acid (1) and [11C]aspirin (2).
2
2
. Results and discussion
10 min). Although it has been reported that boronic acid neopentyl
esters are much more reactive than the corresponding pinacol es-
ters, we did not expect such a disappointing result. To increase the
.1. Synthesis of methyl-[11C]esters
24
reactivity of 3a, it was therefore decided that the reaction would be
conducted at an elevated temperature of 65 C for 5 min.
This [11C]O generating system was initially applied to the syn-
ꢀ
11
thesis of methyl [ C]benzoate 4a using a previously published
Pleasingly, the heated reaction proceeded efficiently to give
18
11
11
method from the literature. Briefly, the freshly generated [ C]O
methyl [ C]benzoate (4a) in 46ꢁ4% RCY (Table 1, entry 1). Fur-
11
gas was bubbled into a reaction vessel containing a mixture of
thermore, the [ C]carbonylation of 3a proceeded much more ef-
ꢀ
palladium(II) acetate [Pd(OAc)
2
], triphenylphosphine (PPh
3
), p-
ficiently when it was conducted at the higher temperature of 65 C
benzoquinone (PBQ) and phenyl boronic acid neopentyl ester (3) in
a 1:1 (v/v) mixture of N,N-dimethylformamide (DMF) and metha-
nol (MeOH) at ambient temperature. After all of the freshly gen-
erated [11C]O gas had passed through the reaction vessel, the
using only MeOH as the solvent, with 3a being isolated in a RCY of
65ꢁ2%. The higher temperature conditions were therefore applied
to a variety of different aryl boronic acid pinacol esters using the
two different solvent conditions (i.e., a 1:1 mixture of MeOH and

1590
H. Ishii et al. / Tetrahedron 71 (2015) 1588e1596
DMF [1:1] or MeOH). As shown in Table 1, all of the pinacol esters
the phenyl ring of the substrate was also well tolerated, with the
corresponding methyl [ C]salicylate 4f being formed in good yield
11
11
tested successfully underwent the [ C]carbonylation reaction at
11
the higher temperature to give the corresponding [ C]esters. No-
tably, the presence of a p-hydroxyl group on the phenyl rings of
substrates 3b and 3h was well tolerated under these conditions,
with the corresponding [1 C]ester 4b and 4h being formed in good
yields in both solvent systems (Table 1, entries 2 and 9). The benzyl
protected substrate 3c gave a slightly lower yield than 3b (Table 1,
entry 3). The presence of a hydroxyl group at the ortho-position of
in MeOH (Table 1, entry 6). Interestingly, the corresponding O-
acetyl substrate 3g decomposed under these reaction conditions to
give the de-acetylated analog 4f as the major product in good RCY
in both solvent systems (Table 1, entry 7). The presence of a free
amino group on the phenyl ring of the substrate had an adverse
impact on the reaction, with the desired product being formed in
a very low yield (Table 1, entry 4). However, Boc-protection of the
1
Table 1
[
11C]Carbomethoxylation of aryl boronic acid pinacol esters
1
1
O
CO
PPh , PBQ
2,
3
O
Ar
B
Pd(OAc)
11C
Ar
O
MeOH - DMF (1:1) or MeOH
65 °C, 5 min
OCH3
3
4
Entry
1
Compound
Product
Solvent
Yield %a
O
B
O
O
11C
MeOHdDMF
MeOH
46ꢁ4
65ꢁ2
OCH3
3
a
4a
O
O
11C
HO
B
HO
MeOHdDMF
MeOH
68ꢁ19
80ꢁ13
2
O
OCH3
3
b
4b
O
O
11C
MeOHdDMF
53ꢁ6
46ꢁ6
BnO
BnO
B
3
4
O
OCH3
MeOH
3
c
4c
O
O
O
H N
B
H N
11C
MeOHdDMF
MeOH
12ꢁ2
6ꢁ2
2
2
OCH3
O
3
d
4d
Boc
HN
Boc
HN
O
11C
MeOHdDMF
MeOH
72ꢁ7
B
5
6
7
56ꢁ15
O
OCH3
3
e
4
e
OH
OH
O
O
MeOHdDMF
MeOH
19ꢁ5
64ꢁ4
11C
B
O
OCH3
3
f
4f
OAc
OAc
O
O
MeOHdDMF
MeOH
21ꢁ4 (4g), 60ꢁ5 (4f)
11C
B
20ꢁ14 (4g), 73ꢁ10 (4f)
O
OCH3
3
g
4g
MeO
HO
MeO
HO
O
O
B
11C
OCH3
MeOHdDMF
MeOH
53ꢁ15
80ꢁ10
8
O
4
h
3
h
O
B
O
11C
MeOHdDMF
MeOH
60ꢁ9
16ꢁ6
O
OCH3
N
9
H
N
H
4i
3
i
a
Average radiochemical yield (n¼3)ꢁstandard deviation was determined by radiochromatogram of analytical HPLC based on the starting radioactivity of the reaction vessel
after decay correction.

H. Ishii et al. / Tetrahedron 71 (2015) 1588e1596
1591
amino group led to a much higher yield of the [11C]ester (Table 1,
entry 5). The presence of a nitrogen atom was also well tolerated in
substrate 3i bearing an indole ring, where the corresponding [ C]
ester 4i was produced in good RCY using a mixture of MeOH and
DMF as the solvent (Table 1, entry 10).
results of this comparison revealed that there was no discernible
difference in the yields between the boronic acids and the corre-
sponding pinacol esters. These results therefore demonstrated that
11
11
these [ C]carbonylation conditions could also be applied to bo-
ronic acid derivatives.
This result prompted us to investigate the application of this
reaction to several alkenyl- and alkyl-based boronic acid pinacol
esters, including 2-phenylvinyl boronic acid pinacol ester (5a), vinyl
boronic acid pinacol ester (5b) and benzyl boronic acid pinacol
ester (5c). As shown in Table 2, alkenyl compounds 5a and 5b gave
the corresponding [11C]esters 6a and 6b in moderate RCYs using
a mixture of MeOH and DMF (Table 2, Entry 1). In contrast, benzyl
The alkoxy-[11C]carbonylation of heteroaryl boronic acid pinacol
esters was also investigated using a variety of different alcohols,
including benzyl alcohol, ethanol and tert-butyl alcohol (Table 5).
The results of these experiments revealedthat benzyloxyand ethoxy
11
groups could be efficiently introduced to the [ C]carbonyl group
using our newly developed conditions to give the corresponding
esters 11a and 11b in moderate RCYs. However, the attempted alk-
11
11
boronic acid pinacol ester (5c) only afforded a low yield of the [ C]
ester 6c.
oxy-[ C]carbonylation of 3-quinolineboronic acid pinacol ester (7b)
using tert-butyl alcohol was unsuccessful (Table 5, entry 3).
Table 2
[
11C]Carbomethoxylation of allyl and alkyl boronic acid pinacol esters
1
1
O
CO
PPh , PBQ
2,
3
O
R
B
Pd(OAc)
11C
OCH3
R
O
MeOH - DMF (1:1) or MeOH
65 °C, 5 min
5
6
Entry
1
Compound
Product
Solvent
Yield %a
O
O
11C
OCH3
B
MeOHdDMF
MeOH
29ꢁ15
10ꢁ9
O
5
a
6a
O
MeOHdDMF
34ꢁ16
O
B
11C
2
O
OCH3
6
b
MeOH
27ꢁ13
4ꢁ1
5
b
MeOHdDMF
MeOH
O
b
O
nd
B
11C
3
O
5
c
OCH
3
6
c
a
Average radiochemical yield (n¼3)ꢁstandard deviation was determined by radiochromatogram of analytical HPLC based on the starting radioactivity of the reaction vessel
after decay correction.
b
nd: Not detected.
In most cases, the reaction mixtures existed as brown suspen-
sions when before they were heated in MeOH, whereas the use of
a mixture of MeOH and DMF as the solvent afforded clear brown
solutions. However, black solutions were observed in both solvent
2.2. Synthesis of [11C]salicylic acid (1), [11C]nicotinic acid (12)
and [ C]aspirin (2)
11
According to the literature,18 [11C]esters can be readily
ꢀ
11
systems after the reaction mixtures had been heated at 65 C for
hydrolyzed to give the corresponding [ C]acids. As shown in
1
8
5
(
min. Given that Suzuki and co-workers reported a very low RCY
2%) for the [11C]carbonylation of 3 in MeOH at ambient tempera-
ture, it is highly likely that the solubility of the substrate could have
Table 6 esters 3f and 7e were successfully hydrolyzed with
11
aqueous sodium hydroxide to give the [ C]carboxylic acids 1 and
12, respectively, in good to excellent yields (Table 6, entries 1 and
11
a significant impact on the success of the [ C]carbonylation re-
action, although further studies would be needed to develop a de-
tailed understanding of the effects of the solvent system on the
reaction.
2). Unfortunately, however, this method could not be applied to
11
the synthesis of [ C]aspirin (2) because it contains a readily
hydrolyzable O-acetyl group. For this reason, we also investigated
11
the direct [ C]carboxylation of boronic ester 3g. Although
2
5
We also investigated the application of our newly developed
reaction conditions to a series of heteroaryl boronic acid pinacol
esters. As expected, all of the pyridine-, quinoline- and
isoquinoline-bearing pinacol boronic esters tested in the current
study reacted smoothly under the optimized conditions to give the
desired [11C]esters 8a, 8b and 8c in good to moderate RCYs (Table 3,
entries 1e3). Pinacol boronic acid esters bearing thiophene (7d)
and furan-(7e) ring systems also reacted to give the corresponding
L ꢀa ngstr o€ m et al. recommended the use of a 6 M aqueous so-
lution of tetramethylammonium hydroxide (TBAOH) as the hy-
droxyl source, the application of these conditions to the
11
palladium-mediated [ C]carboxylation of 3g failed to provide
11
a better yield than that obtained using only water, with [ C]as-
pirin (2) being formed in a low RCY of 15ꢁ2% (Scheme 5). No-
11
tably, this reaction did not lead to the formation of any [ C]
salicylic acid (1).
11
Compared with the other [11C]carbonylation reactions, the di-
[
C]esters 8d and 8e, although the RCYs were much lower (Table 3,
11
entries 4 and 5).
rect synthesis of [ C]aspirin (2) was inefficient, but this simple and
direct strategy for the synthesis of 2 could be useful for generating
Several boronic acid derivatives were also investigated to pro-
vide an effective comparison with the pinacol esters (Table 4). The
11
a [ C]aspirin PET probe.

1592
H. Ishii et al. / Tetrahedron 71 (2015) 1588e1596
Table 3
11C]Carbomethoxylation of heteroaryl boronic acid pinacol esters
[
11CO
Pd(OAc) , PPh ,PBQ
O
O
ArHet
B
2
3
ArHet 11C
O
7
MeOH - DMF (1:1) or MeOH
65 °C, 5 min
OCH3
8
Entry
1
Compound
Product
Solvent
Yield %a
O
O
B
11C
OCH3
MeOHdDMF
MeOH
52ꢁ2
O
64ꢁ26
N
N
a
7
8a
O
O
B
11C
2
MeOHdDMF
MeOH
22ꢁ11
46ꢁ8
O
OCH3
N
b
N
b
8
7
O
O
O
11C
OCH3
B
3
MeOHdDMF
MeOH
75ꢁ17
60ꢁ9
N
N
8
c
7
c
O
O
11C
B
OCH3
4
O
MeOHdDMF
MeOH
29ꢁ11
11ꢁ3
S
S
8
d
7
d
O
O
B
5
11C
MeOHdDMF
MeOH
17ꢁ6
10ꢁ4
O
OCH
3
O
e
O
7
8
e
a
Average radiochemical yield (n¼3)ꢁstandard deviation was determined by radiochromatogram of analytical HPLC based on the starting radioactivity of the reaction vessel
after decay correction.
11
2
.3. Amidation of methyl-[ C]esters
trimethylsilyl hydride (Et
3
SiH) and tributyltin hydride (Bu
3
SnH)
(
[
Scheme 6). Unfortunately, we could not detect any of the desired
We also investigated the amidation of several [11C]ester, in-
11
C]aldehyde 14. Therefore, here we provided the [ C]carbonyla-
11
11
cluding compounds 4b,f,g and 8aec, by treating them with aque-
ous ammonia. Thus, [11C]esters 4f and 8a were smoothly converted
tion method seemed undesirable for the synthesis of [ C]aldehyde
compounds.
11
11
to the corresponding amides [ C]salicylamide (13a) and [ C]nic-
otinamide (13b) in moderate RCYs by treatment with a 25% aque-
ous ammonia solution (Table 7, entries 3 and 4). Pleasingly, the
application of the amidation conditions to the 4-hydroxyphenyl
3
. Conclusion
The palladium-mediated [11C]carbonylation of aryl/heteroaryl,
11
derivative 4b afforded the corresponding [ C]amide 13c in good
RCY (Table 7, entry 1). Disappointingly, however, the benzyloxy
derivative 4c did not react with the ammonia solution, even when
the reaction time was extended considerably (Table 7, entry 4). In
11
alkenyl and alkyl boronic acid pinacol esters with [ C]O in the
presence of PBQ and PPh in DMF-MeOH or just MeOH has been
3
extensively studied. A number of substituents and/or the existence
of heteroaromatic systems have been found to tolerate the reaction
conditions to give the corresponding [carbonyl- C]esters with
11
contrast, the quinoline and isoquinoline [ C]esters 8b and 8c
reacted successfully with ammonia to afford the corresponding
amides 13e and 13f in moderate RCYs (Table 7, entries 5 and 6).
11
11
RCYs in the range of 6e80%. Several of these [carbonyl- C]esters
were converted to the corresponding [carbonyl- C]carboxylic acids
11
and amides following their treatment with aqueous sodium hy-
droxide and ammonium solutions, respectively. This new method
was also successfully used for the direct synthesis of [ C]aspirin
(2), with water or TBAOH being used as the nucleophile instead of
MeOH. It is noteworthy that aspirin has recently been reported to
2
.4. An attempt on the synthesis of [11C]aldehyde 14
11
Last, we also investigated the synthesis of the [11C]aldehyde 14
from 3h using a series of appropriate hydrogen sources such as

H. Ishii et al. / Tetrahedron 71 (2015) 1588e1596
1593
Table 4
[
synthesis of 2 could therefore help to analyze the mechanism of
action of these anti-inflammatory drugs.
11C]carbomethoxylation of aryl boronic acid
11CO
Pd(OAc) , PPh , PBQ
OH
O
2
3
B
11C
4. Experimental
4.1. General
Ar
OH
DMF - MeOH
Ar
OMe
65 °C, 5 min
10
4a, 8b, and 8e
Entry
Compound
OH
Product
Solvent
Yield %a
All commercially available reagents and solvents were used
without further purification. The radioactivity in all the experi-
ments were determined by a dose calibrator (IGC-3R Curiemeter;
Aloka, Tokyo, Japan). High-performance liquid chromatography
(HPLC) was conducted using a JASCO HPLC system with a NaI(Tl)
B
1
4a
8b
MeOHdDMF
MeOH
54ꢁ3
OH
19ꢁ12
1
0a
11
scintillation detector system. C-labeled products were identi-
OH
B
12
fied by the comparison of the retention time of those C-au-
thentic samples, which were purchased or synthesized by known
chemical procedures. Flush column chromatography was per-
formed using silica gel Wakogel C-200. Analytical thin-layer
chromatography (TLC) was performed on Merck silica gel 60 F-
OH
2
MeOHdDMF
MeOH
50ꢁ14
82ꢁ12
N
1
0b
OH
2
54 (0.25 mm layer thickness) plates and visualized with UV
3
8e
MeOHdDMF
MeOH
16ꢁ5
10ꢁ4
B
OH
light.
O
4.2. Preparation of [11C]O and the labeling reaction
1
0c
a
Average radiochemical yield (n¼3)ꢁstandard deviation was determined by ra-
2 2
C]O a gas target
[11 was produced by a 14N(p, )11C reaction in a N
diochromatogram of analytical HPLC based on the starting radioactivity of the re-
action vessel after decay correction.
on a CYPRIS HM-18 cyclotron (Sumitomo Heavy Industries, Co. Ltd.,
Table 5
Alkoxy-[11C]carbonylation of heteroaryl boronic acid pinacol esters
11CO
Pd(OAc) , PPh , PBQ
O
O
2
3
B
11C
ArHet
O
DMF - ROH
5 °C, 5 min
Ar
OR
6
11a-c
7a,b
Entry
1
Compound
Product
Alcohol ratio (DMF/ROH)
Yield %a
O
11C
11a
O
BnOH
(3/1)
52ꢁ11 (n¼3)
B
O
OBn
7
a
N
N
O
O
B
11C
2
EtOH
34
O
O
OEt
(1/1)
N
N
7
b
11b
O
O
B
3
11C
t-BuOH
(1/1)
ndb
Ot-Bu
N
N
7
b
11c
a
Decay-corrected radiochemical yield based on trapped [11C]carbon monoxide.
nd: Not detected.
b
directly activate the adenosine monophosphate-activated protein
Tokyo, Japan), and the resulting [11C]O
2
gas was concentrated by
2
6
ꢀ
kinase (AMPK) and reduce the risk of cancer. The development of
new methods for the synthesis of radiochemical probes such as 2 is
therefore of critical importance to develop a deeper understanding
of the relationship between AMPK activation and the novel effect of
salicylic acid compounds, such as reducing the risk of cancer, Alz-
heimer’s disease and heart attack. This new approach for the direct
solidification onto a stainless steel coil at ꢂ145 to ꢂ155 C. The
ꢀ
11
stainless steel coil was then heated to ꢂ70 C, and the [ C]O
2
gas
11
ꢀ
was reduced to [ C]O by passing it through a Mo column at 850 C.
11
2
Following the removal of any unreduced [ C]O from the gas
stream using an ascarite column, the resultant [ C]O/He stream
was concentrated on another stainless coil, which filled with
11

1594
H. Ishii et al. / Tetrahedron 71 (2015) 1588e1596
Table 6
Synthesis of [11C]salicylic acid (1) and [11C]nicotinic acid (12)
O
R
O
R
O
B
R
X
11CO
11C
11C
6
M NaOH aq.
O
OMe
OH
Pd(OAc) , PPh , PBQ
2
3
MeOH
5 °C, 5 min
X = CH, R = OH
X = N, R = H
X
X
65°C, 2 min
6
ester
1
or 12
3
f or 7a
Entry
1
Compound
Product
Solvent
MeOH
Yield %a
O
OH
OH
O
B
11C
OH
58ꢁ5
O
O
1
3
a
O
O
B
11C
2
MeOH
76ꢁ14
OH
N
N
7
a
12
a
Average radiochemical yield (n¼3)ꢁstandard deviation was determined by radiochromatogram of analytical HPLC based on the starting radioactivity of the reaction vessel
after decay correction.
Scheme 5. Direct synthesis of [11C]aspirin (2).
Table 7
Synthesis of aryl [carbonyl-11C]amide
11CO
O
O
Pd(OAc)
2
,
O
B
25%
NH aq.
3
PPh , PBQ
11C
11C
3
Ar/HetAr
OMe
Ar/HetAr
NH2
Ar/HetAr
O
DMF - MeOH
or MeOH
5 °C, 5 min
6
5 °C, 5 min
6
1
3a-c, and 13e,f
3b,c,g, and 7a-c
4b,f,g, and 8a-c
Entry
Compound
[11C]ester
Product
Yield %c
O
OH
O
B
OH
11C
1a
4f
NH2
46ꢁ7
O
O
1
3a
3
f
O
O
B
11C
2b
8a
4b
NH2
35ꢁ24
78ꢁ14
N
N
7
a
13b
O
O
B
11C
3a
O
NH2
HO
HO
1
3c
3
b

H. Ishii et al. / Tetrahedron 71 (2015) 1588e1596
1595
Table 7 (continued )
Entry
Compound
[11C]ester
Product
Yield %c
O
O
B
11C
4a
O
4c
NH2
nd.d
BnO
BnO
3
c
13d
O
O
B
11C
5a
8b
NH2
23ꢁ7
O
N
N 7
b
13e
O
6a
O
O
8c
11C NH2
18ꢁ3
B
N
N
13f
7c
a
In MeOH.
In DMFdMeOH (1:1).
b
c
Average radiochemical yield (n¼3)ꢁstandard deviation was determined by radiochromatogram of analytical HPLC based on the starting radioactivity of the reaction vessel
after decay correction.
d
nd: Not detected.
Scheme 6. Synthesis of the [11C]aldehyde 14.
molecular sieves at ꢂ70 to ꢂ80 C. The concentrated [11C]O gas was
then released by heating with He carrier gas (flow rate 2.0 mL/min),
and the resulting mixture was bubbled into a reaction vessel (5 mL
volume) containing the reaction mixture via a needle at ambient
temperature. After all of the radioactive gas had passed through the
ꢀ
vessel, the needles were removed. The radioactivity of the vessel
was then measured and the mixture was heated at 65 C for 5 min.
ꢀ
The progress of the reaction was monitored by HPLC analysis and
the radiochemical yield was calculated based on the amount of
11
trapped [ C]O in the vessel (Fig. 1).
Fig. 1. Schematic drawing of the [11C]carbonylation reaction system.

1596
H. Ishii et al. / Tetrahedron 71 (2015) 1588e1596
4
.3. Typical procedure for the synthesis of [11C]esters
References and notes
1
. Colquhoun, H. M.; Thompson, D. J.; Twigg, M. V. Carbonylation: Direct Synthesis
A mixture of 3g (5.0 mg, 19
PPh (10 mg, 38 mol), and p-benzoquinone (2.0 mg, 19
placed in 5.0 mL vial and dissolved in DMF (400
m
mol), Pd(OAc)
2
(4.2 mg, 19
mol) was
L)dMeOH
400 mL) or MeOH (800 mL). Then [ C]O gas was passed through the
mmol),
of Carbonyl Compounds; Plenum. Press: New York, NY, 1991.
. Maitlis, P.; Haynes, A. Metal-catalysis in Industrial Organic Processes; RSC:
Cambridge, UK, 2006.
3
m
m
2
m
11
3. Koll a^ ar, L. Modern Carbonylation Methods; Wiley-VCH: Weinheim, Germany, 2008.
(
4. Beller, M.; Wu, X.-F. Transition Metal Catalyzed Carbonylation Reactions: Car-
vial with a stream of helium (2 mL/min) and the mixture was
bonylative Activation of C-X Bonds; Springer: Heidelberg, 2013.
ꢀ
heated at 65 C for 5 min. Part of the resulting mixture was purified
5. L ꢀa ngstr o€ m, B.; Itsenko, O.; Rahman, O. J. Labelled Compd. Radiopharm. 2007, 50, 794.
. Kealey, S.; Gee, A.; Miller, P. J. Labelled Compd. Radiopharm. 2014, 57, 195.
. Fogg, P. G. T.; Gerrard, W. Solubility of Gases in Liquids: a Critical Evaluation of
6
7
by high-performance liquid chromatography (HPLC) and the RCY of
the fraction was determined by a NaI(Tl) well-type scintillation
detector system. Products were identified by comparison their re-
tention times with those of the authentic samples. The detail HPLC
conditions of each compound were provided in the supplemental
materials.
Gas/Liquid Systems in Theory and Practice; J. Wiley: Chichester, UK; New York,
NY, 1991.
8. Recently, Skrydstrup and coworkers have developed the simpler and safer in-
site CO-precursor ‘COgen’, which are now commercially available. By the use
of COgen is possible to do stoichiometric carbonylation: Hermange, P.; Lind-
hardt, A. T.; Taaning, R. H.; Bjerglund, K.; Lupp, D.; Skrydstrup, T. J. Am. Chem.
Soc. 2011, 133, 6061.
9. Tsuji, J. Transition Metal Reagents and Catalysts: Innovations in Organic Synthesis;
Jorn Wiley & Sons: Chichester, UK, 2000; pp 85e92.
Acknowledgements
ꢀ
€
1
1
1
0. Itsenko, O.; Kihlberg, T.; Langstrom, B. Nat. Protoc. 2006, 1, 798.
1. Lidstr o€ m, P.; Kihlberg, T.; L ꢀa ngstr o€ m, B. J. Chem. Soc., Perkin Trans. 1 1997, 2701.
2. Miller, P. W.; Long, N. J.; de Mello, A. J.; Vilar, R.; Audrain, H.; Bender, D.;
Passchier, J.; Gee, A. Angew. Chem., Int. Ed. 2007, 46, 2875.
3. Kealey, S.; Plisson, C.; Collier, T. L.; Long Nicholas, J.; Husbands Stephen, M.;
Martarello, L.; Gee Antony, D. Org. Biomol. Chem. 2011, 9, 3313.
4. Buscemi, G.; Miller, P. W.; Kealey, S.; Gee, A. D.; Long, N. J.; Passchierb, J.; Vilar,
R. Org. Biomol. Chem. 2011, 9, 3499.
5. Dahl, K.; Schou, M.; Rahman, O.; Halldin, C. Eur. J. Org. Chem. 2014, 307.
16. Eriksson, J.; Johan, H.; Windhorst, A. D. J. Labelled Compd. Radiopharm. 2012, 55, 223.
7. Dahl, K.; Schou, M.; Amini, N.; Halldin, C. Eur. J. Org. Chem. 2013, 1228.
8. Takashima-Hirano, M.; Ishii, H.; Suzuki, M. ACS Med. Chem. Lett. 2012, 3, 804.
9. Cuzick, J.; Thorat, M. A.; Bosetti, C.; Brown, P. H.; Burn, J.; Cook, N. R.; Ford, L. G.;
Jacobs, E. J.; Jankowski, J. A.; La Vecchia, C.; Law, M.; Meyskens, F.; Rothwell, P.
M.; Senn, H. J.; Umar, A. Ann. Oncol. 2014, 25, 2065.
We thank the staff of the Cyclotron Operation Section and the
Department of Molecular Probes of the National Institute of Ra-
diological Sciences (NIRS) for their support with the operation of
the cyclotron and the production of radioisotopes. This study was
supported in part by a consignment expense for the Molecular
Imaging Program on ‘Research Base for Exploring New Drugs’ from
the Ministry of Education, Culture, Sports, Science and Technology
1
1
1
1
1
1
(
2
MEXT) of Japan and in part by JSPS KAKENHI Grant Number (C)
4590156. In this context, we would like to thank Prof. Dr. M.
Suzuki (He was a team leader in the RIKEN project at that time and
now specially approved project researcher in National Center for
Geriatrics and Gerontology, Japan) for his kind suggestion and
valuable comments.
2
2
2
0. Pomponi, M. F. L.; Gambassi, G.; Pomponi, M.; Masullo, C. Aging Dis. 2010, 1, 37.
1. Fuster, V.; Dyken, M. L.; Vokonas, P. S.; Hennekens, C. Circulation 1993, 87, 659.
2. Sasaki, T.; Ogawa, K.; Ishii, S.; Senda, M. Appl. Radiat. Isot. 1999, 50, 905.
23. Brune, K.; Rainsford, K. D.; Schweitzer, A. Br. J. Clin. Pharmacol. 1980, 10, 279S.
2
4. Zhang, N.; Hoffman, D.; Gutsche, N.; Gupta, J.; Percec, V. J. Org. Chem. 2012, 77,
956.
5. Karimi, F.; L ꢀa ngstr o€ m, B. J. Chem. Soc., Perkin Trans. 1 2002, 2256.
5
2
Supplementary data
26. Hawley, S. A.; Fullerton, M. D.; Ross, F. A.; Schertzer, J. D.; Chevtzoff, C.; Walker,
K. J.; Peggie, M. W.; Zibrova, D.; Green, K. A.; Mustard, K. J.; Kemp, B. E.; Sa-
kamoto, K.; Steinberg, G. R.; Hardie, D. G. Science 2012, 336, 918.
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.tet.2015.01.008.