Tetrabutylammonium fluoride-promoted α-[11C]methylation of α-arylesters: A simple and robust method for the preparation of 11C-labeled ibuprofen

Article abstract of DOI:10.1016/j.tetlet.2010.09.007

Tetrabutylammonium fluoride-promoted α-[¹¹C]methylation of α-arlylesters was developed. The method was amenable to the remote-controlled synthesis of ¹¹C-labeled ibuprofen.

Full text of DOI:10.1016/j.tetlet.2010.09.007

Tetrahedron Letters 51 (2010) 5908–5911
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Tetrabutylammonium fluoride-promoted
a a-arylesters: a
-[11C]methylation of
simple and robust method for the preparation of 11C-labeled ibuprofen
⇑
Koichi Kato , Tatsuya Kikuchi, Nobuki Nengaki, Takuya Arai, Ming-Rong Zhang
Department of Molecular Probes, National Institute of Radiological Sciences, 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
Article history:
Tetrabutylammonium fluoride-promoted
a a-arlylesters was developed. The
-[11C]methylation of
method was amenable to the remote-controlled synthesis of 11C-labeled ibuprofen.
Received 24 August 2010
Accepted 1 September 2010
Available online 9 September 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Carbon-11
Isotopic labeling
Ibuprofen
Tetrabutylammonium fluoride
Positron emission tomography
Positron emission tomography (PET) can be used for non-inva-
sive imaging of tracers and their metabolites labeled with posi-
tron-emitting radionuclides. PET images provide metabolic and
biochemical information that describes enzyme activities, receptor
interactions, and transporter regulations. This molecular informa-
tion is useful for clinical diagnosis and helps to promote the impor-
tance of PET as a tool for drug research and development.1,2 The
use of an adequate tracer is crucial for simplifying the interpreta-
tion of PET images. The development of labeling methodology as
well as the structure of the tracer itself is the key to the success
of PET.
2-Arylpropionates are integral structural components that are
found in nonsteroidal anti-inflammatory drugs (NSAIDs), including
ibuprofen, naproxen, and flurbiprofen among others. NSAIDs are
used in the treatment of cancer and Alzheimer’s disease, both of
which can be diagnosed using PET.5 The pharmacological effects
of NSAIDs are dependent on or independent of cyclooxygenases
(COX-1 or COX-2). Regulation of COX activities is related to the
progression of various diseases, therefore, in vivo imaging of COX
enzymes is an emerging topic in PET research.6 Assessment of
uridine diphosphate glucuronosyltransferase (UGT)-catalyzed glu-
curonide conjugation is a significant issue in pharmacological re-
search because these enzymes can act to elevate the withdrawal
of carboxylic acid containing drugs.7 The direct measurement of
the pharmacokinetics of 2-arylpropionates by in vivo PET will help
to advance this field of study. However, the use of 2-arylpropio-
nates as potential PET tracers requires the incorporation of car-
bon-11 into their common structure.
Since carbon is a ubiquitous element in organic molecules, car-
bon-11 (T1/2 = 20.3 min) is the most viable of the positron-emitting
isotopes for incorporating into a variety of molecules. Carbon-11 is
produced via the 14N(p,
[
a)
11C nuclear reaction by a cyclotron as
11C]O2 or [11C]H4. These are converted into more reactive 11C-
labeling agents, such as iodo[11C]methane (1), [11C]cyanide, and
11C]carbon monoxide.3 Among these agents 1 is used most
[
a a-arylesters using 1 yields a variety of
-[11C]Methylation of
frequently, and is a rational starting point for other 11C-labeling
agents that can be exploited to develop 11C-labeling methodology.
To date, this strategy has been utilized for [11C]methyl triflate,
nitro[11C]methane, and [11C]formaldehyde.4 Another approach is
to use 1 to design a new 11C-labeling methodology that affords a
common structural framework of biologically active compounds.
For this purpose, we incorporated the [11C]methyl group into acti-
vated methylenes of carbon acids to yield potential building blocks
for PET research.
11C-labeled esters of 2-arylpropionates, which are components of
11C-labeled NSAIDs (Scheme 1). Using organolithium bases such
as alkyl lithium or lithium diisopropylamide for the activation of
the
a
-CH is not adequate because of their moisture sensitivity.8
O
O
*
O
*
1
Ar
Ar
R1
Ar
R1
OR2
OR2
OH
R1
* = 11
C
⇑
Corresponding author.
E-mail address: katok@nirs.go.jp (K. Kato).
Scheme 1. Plan for the preparation of 11C-labeled
a-arylesters.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.09.007

K. Kato et al. / Tetrahedron Letters 51 (2010) 5908–5911
5909
As well, the requirement for strict stoichiometry of these reagents
is technically cumbersome for the radiolabeling synthesis. Phase-
transfer conditions rely on the strong basic activity of the metal
hydroxide; however, vigorous stirring reactions are difficult for
11C-labeling reactions.9 In addition, their latent saponification will
a
-[11C]methylation of 2a by the treatment of 1 and 2a with tetra-
butylammonium hydroxide. The reaction yielded 3a in 6.8 3.5%
radiochemical conversion while more than 50% of 1 remained
unreacted. This result indicates that fluoride is an active base for
the
a
-[11C]methylation of 2a even in a hydrated form. Moreover,
become an obstacle for the formation of
a
-anions. Recently,
the ester hydrolysis of 2a was a considerable side reaction, which
was promoted by hydroxide during the [11C]methylation reac-
tion.12b We also observed [11C]methyl phenylacetate (4), which
might be derived from the hydrolysis of 2a following [11C]methyl
ester formation (Eq. (2)). However, the radiochemical conversion
of 4 was negligibly low (<2%). In addition to the hydrolysis, a fur-
ther side reaction occurred involving nucleophilic substitution of
1 by hydroxide to form [11C]methanol. In this case, [11C]methanol
was also observed but the radiochemical conversion was only
around 1%.
a
-[11C]methylation of
a-arylesters using metal hydride and 1
was reported.10 However, metal hydrides are not well solubilized
in organic solvents. The method using the homogeneous condi-
tions is preferable to 11C-labeling synthesis because of its suitabil-
ity for remote-controlled synthesis. Therefore, we attempted to
identify another type of base that could activate the
homogeneous conditions.
a-CH under
We focused on the use of fluoride ion as a base.11,12 Fluoride-
mediated 11C-labeling reactions using 1 have been employed for
the [11C]methylation of hetero-atoms, such as oxygen and nitro-
gen.11b Fluoride-mediated 11C–C bond formation via the nitroaldol
reaction and the Michael addition reaction using nitro[11C]meth-
ane have also been reported.13 Nitromethane is more acidic than
[
11C]Methylation promoted by TBAF was extended to other
a-
arylesters and the results are summarized in Table 1. The influence
of fluoro and methoxy substitutions was investigated as represen-
tatives of electron-withdrawing and donating groups, respectively,
because these functional groups have been identified in biologi-
cally active 2-arylpropionates. The [11C]methylation of 4-fluoro
compound 2b gave a similar result to 2a (entry 1). In contrast to
2a and 2b, [11C]methylation of 2c (entry 2) was slower, although,
it had a slightly higher pKa and its corresponding anion had in-
creased nucleophilicity.16 Thus, unreacted 1 was observed from
the treatment of 1 and 4-methoxyphenyl compound 2c with TBAF
for 30 s with a corresponding decrease in radiochemical conver-
sion. An extended reaction time improved the radiochemical con-
version of 2c (entry 3). Increasing the amounts of both 2c and
TBAF yielded 3c more efficiently after 30 s of reaction time (entry
4). Therefore, the slower [11C]methylation of 2c may be attributed
to the low concentration of the corresponding anion of 2c, which is
the result of small differences between the pKa of 2c and the basi-
city of the fluoride. In addition, we consider that the formation of
hydrogen bifluoride from HF and TBAF might contribute to lower-
ing the concentration of active fluoride over the course of time
(Scheme 2).12c,d In this regard, the radiochemical conversion of
3c was decreased considerably (less than 30%) when we prepared
a mixture of 2c and TBAF approximately 30 min before the
a-arylesters and there are no reports of fluoride-mediated
11C-labeling into active methylenes using 1.14 In contrast to 11C-
labeling, Hammond and co-workers recently reported a C–C
bond-forming reaction using tetrabutylammonium fluoride (TBAF),
where an aldol reaction of a propargyl or allenyl ester and a variety
of aldehydes yielded the thermodynamic-favored product selec-
tively.11c,d The TBAF-promoted activation of carbon acids is suit-
able for 11C-labeling because it can be carried out under
homogeneous conditions. Therefore, we decided to explore the
TBAF-promoted
a
-[11C]methylation of
a-arylesters.
O
O
1
TBAF, THF
rt, 30 s
ð1Þ
OMe
OMe
2a
*
* = 11
C
3a
We first investigated the TBAF-promoted [11C]methylation of
methyl phenylacetate (2a) yielding methyl 2-phenyl-[3-11C]propi-
onate (3a). The reactions started with the addition of 37–555 MBq
(1–15 mCi) of 1 to a mixture of 20 lmol of 2a and 20 lmol of TBAF
(method A). Treatment of 1 and 2a with TBAF at room temperature
(rt) yielded 3a efficiently.15 The 11C-labeling agent 1 was consumed
within 30 s and the radiochemical conversion of 3a was more than
95% (Eq. (1)). Because the [11C]methylation at rt was very rapid and
efficient and the radiochemical conversion of 3a was not largely
different at other reaction temperatures (0 °C and 50 °C, data not
shown), we selected rt for further investigation. It was also expedi-
ent to use a commercial solution of TBAFꢀ3H2O in THF for the
[
11C]methylation of 2c was carried out.
Ibuprofen is a representative of 2-arylpropionate NSAIDs and its
4-isobutyl analog 2d can be used in the synthesis of 11C-labeled
ibuprofen. This analog was also incorporated by the [11C]methyl
Table 1
TBAF mediated
11C]methylation. Landini et al. reported that the basicities of the
a
-[11C]methylationa
[
quaternary ammonium fluorides were lowered by increasing the
number of solvated H2O molecules.12a They found that fluoride-
mediated Hofmann-like elimination of hexyl group of tetrahexy-
lammonium fluoride did not occur at hydration states higher than
six. In consideration of their results, we used dry solvent for the
O
O
*
1
Ar
Ar
OMe
OMe
TBAF
THF, rt
R
R
* = 11C
30 s or 3 min
3b-e
2b-e
TBAF-promoted
a
-[11C]methylation, but we did not use an inert
Entry
2
Ar
R
TBAF
mol)
Method 3 ARCb (%)
atmosphere for preparing the reaction solutions or conducting
(
lmol)
(l
the reactions.
1
2
3c
4
5
6
7
8
2b (20)
2c (20)
2c (20)
2c (40)
2d (20)
2e (20)
2e (20)
2e (40)
p-F–C6H4
p-MeO–C6H4
p-MeO–C6H4
p-MeO–C6H4
p-Bui–C6H4
C6H5
H
H
H
H
H
20
20
20
40
20
A
A
A
A
A
A
B
B
91.1 4.0
57.1 0.2
63.9 0.7
65.7 1.1
89.3 3.3
2.2 1.0
O
O
O
1
+
O-
O[11C]H3
NBu4
OMe
Me 20
Me 20
Me 40
2a
4
C6H5
C6H5
32.8 4.3
45.5 2.6
ð2Þ
a
Each reaction was carried out more than three times.
Average radiochemical conversion (ARC) was determined by radiochromato-
gram of analytical HPLC after decay correction.
Because of the use of TBAFꢀ3H2O, hydroxide might promote the
b
a
-[11C]methylation reaction instead of fluoride.12b To confirm the
c
Reactions were carried out for 3 min.
activity of fluoride, we investigated the hydroxide-promoted

5910
K. Kato et al. / Tetrahedron Letters 51 (2010) 5908–5911
Bu4NF
Bu4N+ + ArCH-CO2Me + HF
Bu4NHF2
Bu4NF + ArCH2CO2Me
1
ArCH([11C]H3)CO2Me
Scheme 2. Summarized reaction scheme forming HF2ꢂ
.
1
a) , TBAF, THF
O
O
rt, 30 s
b) NaOH aq.
MeOH-H2O
80 ºC, 3 min
OMe
OH
*
* = 11C
2d
5, 77.3 4.9% (2 steps)
Figure 1. Synthesis of 11C-labeled ibuprofen.
group with an 89.3 3.3% radiochemical conversion (entry 5).
11C]Methylation into methyl 2-phenylpropionate (2e) affording
dimethyl analog 3e was investigated because further incorporation
of a methyl group at the -position might provide a better sub-
of 3d was observed in the synthesis starting with >15 GBq of
[
11C]O2.10 In addition, they found that acid form 5 was stable
[
against radiolysis. The target of our PET studies was acid form 5,
and we obtained a sufficient amount of this via hydrolysis of 3d
starting with <15 GBq. Therefore, we did not encounter any serious
problems in our remote-controlled synthesis of 5.
a
strate for the glucuronidation catalyzed by UGT2B7, a major UGT
isoform for acylglucronidation.7b Moreover, routes for the prepara-
tion of
a
,a-dimethyl compounds are necessary to avoid future
We demonstrated a TBAF-mediated a a-
-[11C]methylation of
problems regarding the enantiomeric center at the 2-position of
arylesters and the synthesis of 11C-labeled ibuprofen as a repre-
sentative example of the success of the methodology. Compared
with the former report, our method can be performed under
homogeneous conditions throughout the entire process and is
advantageous for remote-controlled tracer synthesis.18 These
improvements will facilitate the development of PET tracers of
11C-labeled arylpropionate NSAIDs.
arylpropionates. Although, an isotopically substituted (3-11C)-di-
methyl analog still has an enantiomeric center at the
a-position,
the behavior of both enantiomers is not expected to largely influ-
ence the pharmacokinetic analyses under PET scan conditions.17
The
a-methyl group has increased nucleophilicity through an
inductive effect and decreased steric hindrance. Because of the po-
sitive and negative effects of an additional methyl group,
The procedure for the remote-controlled synthesis of 5.
[
11C]methylation of 2e was expected to give a similar result to that
The 11C-labeled precursor 1 was prepared and transferred in a
N2 gas stream (flow rate 30 mL/min) to the reaction vessel contain-
of 2a.16a However, there were other factors affecting the
[
11C]methylation of 2e and the reaction gave very different results
ing a solution of 2d (20 lmol) in THF (300 lL) and TBAF (20 lmol)
at rt. After 90 s, the radioactivity of the vessel reached a plateau
and then the gas stream was stopped. After 30 s, a 1:1 mixture of
aqueous 1 M NaOH and MeOH (400 lL) was added to the reaction
mixture. The resulting solution was heated to 80 °C and stored for
3 min while maintaining the temperature. After cooling by air flow,
from the [11C]methylation of 2-arylacetates. Thus, the order of
addition of the reactants was essential for yielding 3e, and a min-
imal amount of 3e was obtained by the addition of 1 to a mixture
of 2e and TBAF (entry 6). In this manner, the 11C-labeling agent 1
was converted primarily to an unidentified radioactive compound
whose retention time was similar to that of 2e. The desired
of 2e might be transient and a considerable amount of the
may be transferred to other species that reacted with 1. In contrast,
measurable [11C]methylation of 3e was observed by the addition of
TBAF to a mixture of 1 and 2e (method B, entry 7). In this case, we
a
a
-anion
-anion
a 9:1 mixture of eluent and AcOH (500
resulting mixture was injected into the semi-preparative HPLC
(Waters XBridge C18, 5
CH3CN/30 mM NH4OAc/AcOH; flow rate, 4 mL/min; and retention
time, 9 min).
lL) was added and then the
l
m, 7.5 ꢁ 250 mm I.D.; eluent, 60/40/0.2
believe that some of the desired a-anions of 2e immediately react
with 1 yielding 3e before other reactive species are generated. Fi-
nally, improved radiochemical conversion of 3e was obtained by
the treatment of increased amounts of both 2e and TBAF (entry 8).
We chose 2d to complete Scheme 1. Thus, the test synthesis of
2-(4-isobutyl)phenyl-[3-11C]propionic acid ([11C]ibuprofen, 5)
started with approximately 370 MBq (10 mCi) of 1, which was re-
acted via alkaline hydrolysis of 3d by the addition of a 1:1 mixture
of an aqueous solution of 1 M NaOH and MeOH at rt. The resulting
mixture was heated to 80 °C and stored at the same temperature
for 3 min. The ester hydrolysis of 3d was completed and the overall
radiochemical conversion of 5 was 77.3 4.9% in two steps (Fig. 1).
The synthetic preparation of 5 can be completed in a one-pot man-
ner for both the methylation and hydrolysis and does not require a
strictly inert atmosphere. The homogeneity of the reaction mixture
throughout the entire process results in a decreased failure rate. Fi-
nally, the method was amenable to the remote-controlled synthe-
sis of 5, which started from approximately 11.1 GBq (300 mCi,
calculated amount) of [11C]O2 and resulted in >1 GBq of 5 within
30 min from the end of bombardment. According to Takashima-
Hirano et al., methyl ester 3d was labile and significant radiolysis
Acknowledgments
This work was supported in part by a consignment grant for
the Molecular Imaging Program on Research Base for PET Diagno-
sis from the Ministry of Education, Culture, Sports, Science and
Technology of Japan. We thank the staff of the Cyclotron Opera-
tion and Radiochemistry sections for technical support using
radio isotopes.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2010.09.007.
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