Palladium(0)-mediated rapid methylation and fluoromethylation on carbon frameworks by reacting methyl and fluoromethyl iodide with aryl and alkenyl boronic acid esters: Useful for the synthesis of [11C]CH 3-C-and [18F]FCH2-C-containing PET tracers (PET = positron emission tomography)

Article abstract of DOI:10.1002/chem.200801974

The rapid methylation and fluoromethylation on aryl and alkenyl carbon frameworks by reacting methyl and fluoromethyl iodide with aryl and alkenyl boronates have been studied with the focus on the realization of the synthesis of [¹¹C]CH₃- and [¹⁸F]FCH₂-labeled positron emission tomography (PET) tracers. The coupling of methyl iodide and pinacol phenylboronate (40 equiv) is accomplished in > 91% yield within 5 min at 60 °C under the conditions of [Pd₂(dba)₃]/P(o- CH₃C₆H₄)₃/K₂CO ₃ (0.5:2:2; dba = di-benzylideneacetone) in DMF. The reaction shows a high generality and is applicable to various types of aryl and alkenyl boronates, giving the corresponding methylated derivatives in high yields (80-99). This reaction is also useful for the rapid incorporation of the fluoromethyl group. Thus, this boron protocol provides a firm chemical basis for the synthesis of ¹¹C- and ¹⁸F-incorporated PET tracers and can be used as a complementary method for [¹¹C]methylation together with our previous and ongoing processes using organotributylstannanes.

Full text of DOI:10.1002/chem.200801974

FULL PAPER
DOI: 10.1002/chem.200801974
Palladium(0)-Mediated Rapid Methylation and Fluoromethylation on
Carbon Frameworks by Reacting Methyl and Fluoromethyl Iodide with Aryl
11
À
and Alkenyl Boronic Acid Esters: Useful for the Synthesis of [ C]CH3 C-
18
À
and [ F]FCH2 C-Containing PET Tracers (PET=Positron Emission
Tomography)**
Hisashi Doi,[a] Ikuya Ban,[b] Akihito Nonoyama,[b] Kengo Sumi,[b] Chunxiang Kuang,[b]
Takamitsu Hosoya,[c] Hideo Tsukada,[d] and Masaaki Suzuki*[a, b]
Abstract: The rapid methylation and
fluoromethylation on aryl and alkenyl
carbon frameworks by reacting methyl
and fluoromethyl iodide with aryl and
alkenyl boronates have been studied
with the focus on the realization of the
synthesis of [11C]CH3- and [18F]FCH2-
labeled positron emission tomography
(PET) tracers. The coupling of methyl
iodide and pinacol phenylboronate
(40 equiv) is accomplished in >91%
yield within 5 min at 608C under the
conditions
of
[Pd
(dba)3]/P(o-
high yields (80–99%). This reaction is
also useful for the rapid incorporation
of the fluoromethyl group. Thus, this
boron protocol provides a firm chemi-
cal basis for the synthesis of 11C- and
18F-incorporated PET tracers and can
be used as a complementary method
for [11C]methylation together with our
previous and ongoing processes using
organotributylstannanes.
CH3C6H4)3/K2CO3 (0.5:2:2; dba=di-
benzylideneacetone) in DMF. The re-
action shows a high generality and is
applicable to various types of aryl and
alkenyl boronates, giving the corre-
sponding methylated derivatives in
À
Keywords: boron · C C coupling ·
isotopic labeling · palladium · PET
(positron emission tomography)
Introduction
Positron emission tomography (PET) is a powerful non-in-
vasive molecular imaging technique used for highly accurate
diagnoses and the investigation of the in vivo biochemistry
of bioactive compounds,[1] especially applicable for a human
microdosing study during early clinical drug development.[2]
Thus, the increasing need for the development of biological-
ly significant PET tracers has required an efficient synthetic
strategy for the molecular probe design and advances in ra-
diolabeling methodology.[3] Short-lived radionuclides, 11C
and 18F with a half-life of 20.4 min and 109.8 min, respective-
ly, among others, have often been used for radiolabeling.[1,3]
In this context, we have recently developed palladium(0)-
mediated rapid methylation onto organic frameworks such
as aryl-, alkynyl-, and alkenyl structures based on the cross-
coupling reaction of methyl iodide and the corresponding
[a] Dr. H. Doi, Prof. Dr. M. Suzuki
RIKEN Center for Molecular Imaging Science (CMIS)
6-7-3 Minatojima-minamimachi, Chuo-ku
Kobe 650-0047 (Japan)
Fax : (+81)78-304-7112
E-mail: suzuki.masaaki@riken.jp
[b] I. Ban, A. Nonoyama, Dr. K. Sumi, Dr. C. Kuang,
Prof. Dr. M. Suzuki
Division of Regeneration and Advanced Medical Science
Gifu University Graduate School of Medicine, 1–1 Yanagido
Gifu 501-1194 (Japan)
[c] Dr. T. Hosoya
Graduate School of Bioscience and Biotechnology
Tokyo Institute of Technology, 4259 Nagatsuta-cho
Midori-Ku, Yokohama 226-8501 (Japan)
stannyl compounds.[4] Actually, the rapid sp3–sp2
ACHTUNGTRENNUNG(phenyl)
[d] Dr. H. Tsukada
Central Research Laboratory
Hamamatsu Photonics K.K., Hirakuchi 5000, Hamakita-ku
Hamamatsu, Shizuoka 434-8601 (Japan)
coupling using [11C]methyl iodide has successfully been used
for the synthesis of the 11C-labeled 15R-TIC methyl ester, an
imaging probe for a novel prostacyclin receptor (IP2) in the
central nervous system,[5] to realize receptor imaging in the
[**] Rapid Methylation on Carbon Frameworks For PET Tracer Synthesis,
Part 8; for Parts 1–7, see references [4a–g].
Chem. Eur. J. 2009, 15, 4165 – 4171
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4165

monkey and human brains.[4a–d,f,h] To meet the further de-
mands of efficient labeling chemistry in PET, we have se-
lected an organoboron compound[6] as a complementary
substrate to the organostannane with the aim of realizing
another powerful methodology for not only the rapid
[11C]methylation, but also for rapid [18F]fluoromethylation.
Actually, the Merck group has already reported the synthe-
sis of [11C]toluene derivatives by using arylborons and
ACTHNGUTERNNUG
nuclear reaction of 14N(p,a)11C in a small cyclotron for re-
search and clinical use, the coupling reaction must be con-
ducted with a large excess amount of the substrate.[1,3,4] In
addition, the reaction with 11C, which has a short half life,
must be accomplished within several minutes (ꢀ5 min) in
order to leave enough time for its workup and chromato-
graphic purification.[1,3,4] Considering such conditions in
actual PET tracer synthesis, we set up the model reaction
using an excess amount of pinacol phenylboronate (1) to
methyl iodide (1/CH3I 40:1), and the reaction time was
fixed at 5 min, similar to our previous studies using organo-
stannanes.[4a,c,e,g] These results are summarized in Table 1.
Usually, the Suzuki–Miyaura reaction is conducted using the
[11C]methyl iodide in the presence of [Pd
ACHTNUTRGNE(NUG dppf)Cl2] (dppf=
1,1’-bis(diphenylphosphino)ferrocene) and K3PO4 in DMF
by microwave heating under PET conditions.[7] In contrast,
we have initially concentrated on establishing a general pro-
tocol for the palladium(0)-mediated rapid methylation and
fluoromethylation by a simple and convenient thermal heat-
ing methodology, and eventually succeeded in determining
the practical reaction conditions derived from many experi-
ments under usual organic
combination of [Pd
(dppf)] as a palladium catalyst and K2CO3 or K3PO4 as a
base at 50–1008C for 2–20 h in benzene or ethereal sol-
ACHTUTGNERN(NUG PPh3)4], [PdCl2ACHTUGNTNER(NUGN PPh3)2], or [PdCl2-
AHCTUNGTRENNUNG
chemical conditions without
Table 1. Rapid trapping of methyl iodide with pinacol phenylboronate.[a]
the fear of radiation expo-
sure.[4a,c,e,g] In this paper, we
describe simple and mild
ACHTUNGTRENNUNG
a
protocol of rapid methylation
and fluoromethylation based
on the sp3–sp2 type Suzuki–
Miyaura coupling, which is po-
tentially useful for the synthe-
Entry Pd0 complex
Ligand
Pd:L
[mol ratio]
Additive[b]
Solvent
Yield [%][c]
39
1
2
3
4
5
6
7
8
9
[Pd
[PdCl
[PdCl
[Pd2A(dba)3]
[Pd2A(dba)3]
[Pd2A(dba)3]
[Pd2A(dba)3]
[Pd2A(dba)3]
[Pd2A(dba)3]
G
–
–
–
–
–
–
K2CO3
K3PO4
K3PO4
K2CO3
K2CO3
Cs2CO3
K3PO4
1,4-dioxane
DME/H2O 9:1 24
DME/H2O 9:1 28
DMF
DMF/H2O 9:1
DMF
11
C
G
À
sis
of
[ C]CH3 C-
À
and
E
18
[ F]FCH2 C-containing PET
N
C
P(o-CH3C6H4)3 1:2
P(o-CH3C6H4)3 1:2
P(o-CH3C6H4)3 1:2
P(o-CH3C6H4)3 1:2
P(o-CH3C6H4)3 1:2
P(o-CH3C6H4)3 1:2
91
94
92
87
81
81
tracers.[8]
R
E
N
CHTUNGTRENNUNG
G
N
DMF
U
G
CuCl/K2CO3 DMF
KF DMF
Results and Discussion
A
CHTUNGTRENNUNG
[a] Reaction was carried out with pinacol phenylboronate (400 mmol), Pd (10 mmol), and methyl iodide
(10 mmol). [b] 20 mmol of the additive was used. [c] Yield was determined by GLC analysis based on CH3I.
DME: dimethoxyethane, DMF: N,N-dimethylformamide, dba: dibenzylideneacetone, dppf: 1,1’-bis(diphenyl-
phosphino)ferrocene.
The conditions for the synthe-
sis of PET tracers are different
from those for ordinary organ-
ic syntheses. In particular,
since the available amount of [11C]CH3I[9] is extremely low
(10À6–10À9 mol) after several reaction steps starting from the
vents.[10] Therefore, we first attempted the cross-coupling re-
action at 608C for 5 min using these Pd0 catalysts and bases,
but the application of these standard conditions for the
methylation did not produce any satisfactory results (24–
39% yields; entries 1–3 in Table 1). We then considered the
use of a Pd0 complex coordinated with a bulky phosphine in
a non-volatile solvent with a high polarity, which was used
successfully in our previous studies on rapid methylations
using organostannanes.[4a,c,e,g] As expected, the reaction was
dramatically promoted by the use of the tri-o-tolylphosphine
complex in DMF in the presence of K2CO3, K2CO3/H2O,
Cs2CO3, or K3PO4 to give the desired toluene in 87–94%
yields (entries 4–7 in Table 1).
Abstract in Japanese:
As shown in Scheme 1, the coupling reaction of methyl
iodide and 1 probably proceeds by a mechanism composed
of four elementary processes [Eqs. (1)–(4)] as exemplified
by the presence of K2CO3 or K2CO3/H2O:
1) The oxidative addition of methyl iodide to Pd0 species to
generate the methyl-PdII iodide 2 [Eq. (1)].
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Chem. Eur. J. 2009, 15, 4165 – 4171

Isotope Labeling
FULL PAPER
pling.[4a,c,g] Also, bases such as
K2CO3, Cs2CO3, and K3PO4,
may play a key role in produc-
ing their synergic effects,
namely, the activation of
a
boron complex and the neu-
tralization of the reaction
system after transmetalation.
DMF may stabilize the palladi-
um
intermediates
formed
during the reaction.[4a,c,e,g]
The utility of the conditions
is demonstrated by the rapid
methylation of various aryl and
alkenyl boronates as summar-
ized in Tables 2 and 3. Thus,
Scheme 1. A possible reaction mechanism.
2) The formation of a boron ate complex 3 with a higher
À
polarity of the B C bond by the coordination of a base
2À
such as CO3 or OHÀ in a mixed system of K2CO3/H2O
Table 3. Rapid trapping of methyl iodide with pinacol alkenylboronates.
[Eq. (2)].
Entry[a]
Organoboron
Yield [%] of
3) The transmetalation between 2 and 3 to afford the [PdII-
methylated product[b]
A
ACHTUNGTRENNUNG(phenyl)] complex 4 [Eq. (3)]; the unstable [B-
ACHTUNGTRENNUNG
1
2
95
92
converted to the more stable borate [B
and KI.
4) The final reductive elimination from 4 leading to the de-
(pin)(OZ)2]À (6)
ACHTUNGTRENNUNG
sired toluene [Eq. (4)].
The formation of the coordinatively unsaturated Pd0 and
PdII complexes with bulky tri-o-tolylphosphine (1948[11a] or
2188[11b] as a cone angle) during the course of the reaction
seems significant for effectively promoting the sp3–sp2 cou-
3
4
96
86
Table 2. Rapid trapping of methyl iodide with pinacol arylboronates.
Entry[a]
Organoboron
Yield [%] of
methylated product[b]
5
6
99
99
R
R-CH3
1
2
3
4
5
6
7
8
9
4-CH3OC6H4-
3-benzyloxyC6H4-
4-CH3C6H4-
4-PhC6H4-
4-FC6H4-
4-CH3OCOC6H4-
4-NO2C6H4-
thiophen-2-yl-
furan-2-yl-
98
95
99
91
[a] Reaction was carried out using methyl iodide (10 mmol), pinacol alke-
nylboronate (400 mmol), [Pd2A(dba)3] (5 mmol), P(o-tolyl)3 (20 mmol), and
K2CO3 (20 mmol). [b] Yield was determined by GLC analysis based on
G
ACHTUNGTRENNUNG
93
82, 96[c]
99
CH3I.
92
85
10
11
pyridin-4-yl-
isoquinolin-4-yl-
80
85
the reactions with arylborons with electron-donating and
electron-withdrawing groups on their aromatic rings were
carried out under the conditions of [Pd2ACTHUNTRGNE(UGN dba)3]/P(o-
CH3C6H4)3/K2CO3 (0.5:2:2; dba=dibenzylideneacetone) in
DMF (the conditions of entry 4 in Table 1), giving the corre-
sponding methylation products in 80–99% yields (entries 1–
13 in Table 2).[12] The use of the mixed solvent DMF/H2O
accelerated the reaction to some extent (96% yield; entry 6
in Table 2). Interestingly, the methylation of the thiophenyl
and furanyl borons proceeded smoothly at 608C for 5 min to
12
13
92[d]
92[d]
[a] Reaction was carried out using methyl iodide (10 mmol), pinacol aryl-
boronate (400 mmol), [Pd2A(dba)3] (5 mmol), P(o-tolyl)3 (20 mmol), and
K2CO3 (20 mmol). [b] Yield was determined by GLC analysis based on
CH3I. [c] Mixed solvent (DMF/H2O 9:1) was used. [d] Based on toluene
as the product.
C
ACHTUNGTRENNUNG
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4167

M. Suzuki et al.
give the methylated products in 92 and 85% yield, respec-
tively (entries 8 and 9), which were much higher yields when
compared to our previous method with the corresponding
stannyl compounds (73 and 40% yield, respectively).[4a] The
reactions with heteroaromatic borates, such as the pyridine
and isoquinoline moieties, gave the desired 4-picoline and 4-
methylisoquinoline in 80 and 85% yield, respectively (en-
tries 10 and 11). The six-membered cyclic borates are also
applicable for the reaction (entries 12 and 13). Based on the
radiolabeling conditions in PET, the reactions that make use
of higher excess (five to ten times) of Pd0–phosphine and
K2CO3 relative to methyl iodide were investigated. Thus, the
reactions with the ratio of 1:40:2.5:10:10 and 1:40:5:20:20 of
Scheme 2. Rapid trapping of fluoromethyl iodide with pinacol phenylbor-
onate.
found to be more effective for promoting the fluoromethyla-
tion, giving the desired benzyl fluoride up to 57% yield
(average, 47% yield); thus the conditions would be poten-
tially useful for the synthesis of a [18F]fluoromethyl-labeled
PET
tracer.
Recently,
the
synthetic
route
of
[18F]fluoromethyl iodide ([18F]FCH2I) has been explored as
a PET chemical process.[14] If the above rapid methylation
conditions could be applied to the [18F]fluoromethylation,
the 18F incorporation process can save much time in compar-
ison to ordinary methods following the SN2 reaction usually
conducted at 60–1508C for 5–40 min,[1,3] thus allowing a
PET study without a significant loss of the initial high 18F
specific activity.
CH3I/1/ACHTUNGTRENNUNG[Pd2ACHTUNGTRENNUNG(dba)3]/P(o-CH3C6H4)3/K2CO3 at 608C for 5 min
gave toluene in 92 and 94% yield, respectively. Thus, we
found that the use of a large excess of Pd0–phosphine did
not negatively influence the methylation, but rather im-
proved the yield, promising the high potential for the syn-
thesis of a PET tracer.
This newly devised procedure was also applied to the
methylation of various kinds of alkenyl compounds to pro-
duce the corresponding methylalkenes in 86–99% yields
(entries 1–6 in Table 3). The E and Z stereoisomers gave the
corresponding methylated products with the retention of
their stereochemistry, confirming that the reaction proceeds
under complete stereocontrol (entries 1 and 2 in Table 3).
For the ready purification of the desired tiny amount of
the [11C]methylation product, it is important that the
[11C]methylation product should have a shorter retention
time and a conclusive time difference compared to that of
the starting boron substrate during HPLC separation on re-
versed phase silica gel.[1,3,4] In this context, we compared the
HPLC behavior of boronic acid 7 with the lipophilic boronic
ester 1 and several other more lipophilic esters 8 and 9. As
expected, the retention times of the starting borons 7, 1, 8,
and 9 were 2.1, 10.0, 21.5, and 43.1 min, respectively. Thus,
the retention times increased with the increasing lipophilici-
ty of the boron species, making the tracer purification easier
if we choose the boronic ester with a higher lipophilicity. In-
terestingly, toluene (the retention time: 5.9 min) appeared
between the boronic acid 7 and boronic esters, suggesting
that the use of a boronic ester would be better than boronic
acid for the entire PET tracer synthetic process including
purification. In addition, the methylations using 7,[10j] 8, and
9 also proceeded smoothly to give toluene in 89, 79, and
87% yield, respectively.[13]
The actual [11C]methylation based on the conditions es-
tablished in the study (entry 4 in Table 1) was well demon-
strated in the synthesis of [11C]xylene (Scheme 3). Thus, the
Scheme 3. Synthesis of a 11C-labeled arene by rapid methylation.
reaction of pinacol tolylboronate (the substrate of entry 3 in
Table 2) with [11C]methyl iodide gave the [11C]xylene in
96% HPLC analytical yield (Figure 1). For this
[11C]methylation, the use of K2CO3 was more effective than
KF or CsF.
We are currently trying the applications of these methods
to the 11C- and 18F-labeling of biologically and pharmaceuti-
cally significant compounds. As an example, [11C]Celecoxib
([11C]-10),[15] a clinically important COX-2 inhibitor, was
The conditions of entry 4 in Table 1 were also applicable
for the synthesis of the fluoromethyl arene (Scheme 2).
Here, the use of the 1:3 ratio of Pd/P(o-CH3C6H4)3 was
Figure 1. HPLC profile of the [11C]methylation products by radiation de-
tector.
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Isotope Labeling
FULL PAPER
(60 mꢁ0.25 mm i.d., GL Science), TC-WAX (60 mꢁ0.25 mm i.d., GL
Science), and CP-volamine (60 mꢁ0.32 mm i.d., VARIAN); carrier
gases: N2 or He; injection temperature: 2608C or 2808C; detection tem-
perature: 2608C or 2808C. Organic chemical reactions, except the radio-
labeling reaction of Scheme 3, were performed under Ar with Schlenk
techniques. Solvents and solutions were transferred by syringe–septum
and cannula techniques. Dimethoxyethane (DME) and 1,4-dioxane were
used after distillation over sodium-benzophenone ketyl under Ar. N,N-
Dimethylformamide (DMF) was commercial grade. Methyl iodide was
distilled prior to use. Phenylboronic acid pinacol ester in Table 1, all aryl-
boronates in Table 2, and trans-2-phenylvinylboronic acid pinacol ester in
Table 3 were commercially available (from Aldrich and Wako). Tris(di-
benzylideneacetone)dipalladium(0) (Aldrich), tetrakis(triphenylphosphi-
ne)palladium(0) (Aldrich), dichlorobis(triphenylphosphine)palladium(II)
successfully synthesized by using the corresponding pinacol
arylborate under PET conditions in high yield.[16] These
methods will be applicable to the synthesis of ingenious
[11C]CH3- and [18F]FCH2-incorporated heteroaromatic PET
tracers, [11C]-11[6c,17b] and [18F]-12,[17] which exhibit extremely
high affinity for metabotropic glutamate receptor subtype 5,
starting from a common boronate precursor 13. The results
in these practical studies will be reported in due course.
(Strem), dichloroACTHNUGTRNEUNG[1,1’-bis(diphenylphosphino)ferrocene]palladium(II) di-
chloromethane adduct (Strem), copper(I) chloride, potassium carbonate,
tripotassium phosphate, cesium carbonate, potassium fluoride (all from
Wako) were commercial grade. Toluene, 4-methoxytoluene, 1-benzyloxy-
3-methylbenzene, p-xylene, 4-phenyltoluene, 4-fluorotoluene, methyl p-
methylbenzoate, 4-nitrotoluene, 2-methylthiophene, 2-methylfuran, 4-pi-
coline, 4-methylisoquinoline, trans-2-heptene, cis-2-heptene, trans-b-meth-
ylstyrene, 1-methyl-1-cyclohexene, ethyl 3,3-dimethylacrylate, 3-methyl-2-
buten-1-ol, and benzyl fluoride were used as authentic samples. Litera-
ture procedures were used to prepare 1-alkenylboronates[10d,20] of en-
tries 1, 2, 4, 5 in Table 3 and fluoromethyl iodide.[21] (Dialkoxyboryl)bu-
tene-1-ol of entry 6 in Table 3 was prepared by diisobutylaluminum hy-
dride reduction of (dialkoxyboryl)acrylate of entry 5 in Table 3. Cyclic ar-
ylboronates 8 and 9 were prepared by the condensation of phenylboronic
acid and 2,4-dimethyl-2,4-pentanediol or (1,1’-bicyclopentyl)-1,1’-diol in
diethyl ether. Benzyl fluoride as an authentic sample was prepared by
fluorination of benzyl bromide with potassium fluoride and [18]crown-6.
The [11C]methylation in Scheme 3 was conducted in a lead-shielded hot-
cell with remote control of all operations at PET center of Hamamatsu
Conclusion
We have developed the Suzuki–Miyaura type rapid methyla-
tion by trapping of methyl iodide with excess amounts of
aryl and alkenyl boron compounds in the presence of [Pd2-
ACHTUNGTRENNUNG(dba)3], P(o-CH3C6H4)3, and K2CO3 or K2CO3/H2O in high
yield.[8] The reaction conditions are also applicable for the
fluoromethylation.[8] Thus, a firm chemical basis was provid-
ed for the synthesis of the [11C]CH3- and [18F]FCH2-labeled
PET tracers. This novel methodology possesses several at-
tractive features for the synthesis of PET tracers. Since syn-
thetic methods for a variety of boron compounds have re-
cently been developed due to the increased importance of
these compounds in the synthesis of the carbon frameworks
of complex natural products and artificial drug candi-
dates,[10,18] we can use organoboron chemistry for the synthe-
sis of a PET tracer. In addition, the separation of a tiny
amount of the desired labeled compound from the remain-
ing large amount of a substrate can be realized on the basis
of structural manipulation of a boron substrate by regulating
the hydrophobicity of its bis-alkoxy moiety. Generally, orga-
noboron compounds are less toxic and more reactive in
combination with some bases when compared to organo-
stannanes.[19] However, it is also a fact that there exists some
limitations in the use of a boron compound for a PET study
due to its instability, which makes its preparation and recov-
ery after the reaction difficult. Therefore, this boron proto-
col could be used in complement for the [11C]methylation
together with our previous methods using organotributyl-
stannanes.[4]
ACTHNUTRGNEUNG
Photonics K.K. [11C]Carbon dioxide was produced by a 14N(p,a)11C reac-
tion by using a Sumitomo CYPRIS HM-18 cyclotron (Sumitomo Heavy
Industries), and then converted to [11C]methyl iodide by treatment with
lithium aluminum hydride followed by hydriodic acid using an automated
synthesis system (Cupid, Sumitomo Heavy Industries). The obtained
[11C]methyl iodide was used for palladium(0)-mediated rapid
[11C]methylation shown in Scheme 3. The analytical HPLC system for the
[11C]methylation products consisted of a CCPM pump (TOSOH), UV-
8010 UV-detector (TOSHO), and RLC-700 Radio analyzer (Aloka). The
synthesis of 11C-labeled Celecoxib was conducted by using a Sumitomo
CYPRIS HM-12S cyclotron (Sumitomo Heavy Industries) and an auto-
mated synthesis system for 11C-labeling in RIKEN CMIS.
Product analysis
Condition A: instrument: Shimadzu GC-2010, carrier gas: He, capillary
column: GL Science TC-1701, injection temperature: 2808C, detection
temperature: 2808C, initial column temperature: 808C, final: 2008C, tem-
perature ramp rate: 58CminÀ1 from 10 to 14 min, flow rate:
0.55 mLminÀ1
, retention time: toluene (13.0 min), 4-methoxytoluene
(10.7 min), p-xylene (17.3 min), 4-fluorotoluene (13.8 min), 2-methylthio-
phene (13.4 min), 2-methylfuran (9.3 min), 1-methyl-1-cyclohexene
(11.9 min).
Condition B: instrument: Shimadzu GC-2010, carrier gas: He, capillary
column: GL Science TC-1701, injection temperature: 2808C, detection
temperature: 2808C, initial column temperature: 1208C, final: 2008C,
temperature ramp rate: 58CminÀ1 from
3 to 19 min, flow rate:
0.46 mLminÀ1, retention time: methyl p-methylbenzoate (20.3 min), 4-ni-
trotoluene (22.6 min).
Condition C: instrument: Shimadzu GC-2010, carrier gas: He, capillary
column: GL Science TC-1701, injection temperature: 2808C, detection
temperature: 2808C, initial column temperature: 1608C, final: 2208C,
temperature ramp rate: 58CminÀ1 from
3 to 15 min, flow rate:
Experimental Section
0.39 mLminÀ1, retention time: 1-benzyloxy-3-methylbenzene (28.1 min),
4-phenyltoluene (21.7 min).
Gereral: GLC analysis was performed on Shimadzu GC-2010 and Shi-
madzu GC-17 A instruments equipped with a flame ionization detector;
capillary columns, TC-1 (60 mꢁ0.25 mm i.d., GL Science), TC-1701
Condition D: instrument: Shimadzu GC-2010, carrier gas: He, capillary
column: GL Science TC-1, injection temperature: 2808C, detection tem-
Chem. Eur. J. 2009, 15, 4165 – 4171
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www.chemeurj.org
4169

M. Suzuki et al.
perature: 2808C, initial column temperature: 708C, final: 2108C, temper-
ature ramp rate: 108CminÀ1 from 5 to 9 min and 208CminÀ1 from 17 to
(0.45 mL) at RT. After trapping of [11C]methyl iodide in the solution, the
resulting mixture was heated at 60–658C by hot air. A sampling solution
(5 mL) taken from the reaction mixture was analyzed by HPLC with a
UV-absorbance detector and a radiation detector. HPLC profile of the
reaction mixture by radiation detector was shown in Scheme 3. HPLC
analytical yield of [11C]xylene: 96%, calculated by peak area ratio of
[11C]product distributions. The isolated yield was not determined because
the isolation of volatile [11C]xylene is dangerous.
22 min, flow rate: 0.57 mLminÀ1
(13.9 min).
,
retention time: benzylfluoride
Condition E: instrument: Shimadzu GC-17 A, carrier gas: N2, capillary
column: VARIAN CP-volamine, injection temperature: 2608C, detection
temperature: 2608C, initial column temperature: 1008C, final: 2008C,
temperature ramp rate: 108CminÀ1 from 10 to 20 min, flow rate:
0.5 mLminÀ1, retention time: 4-picoline (15.3 min).
Condition F: instrument: Shimadzu GC-17 A, carrier gas: N2, capillary
column: VARIAN CP-volamine, injection temperature: 2608C, detection
temperature: 2608C, column temperature: 2308C, flow rate:
2.1 mLminÀ1, retention time: 4-methylisoquinoline (29.3 min).
Acknowledgements
This work was supported in part by a Grant-in-Aid for Creative Scientific
Research (No. 13NP0401) and 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
(MEXT) of Japan.
Condition G: instrument: Shimadzu GC-2010, carrier gas: He, capillary
column: GL Science TC-1701, injection temperature: 2808C, detection
temperature: 2808C, initial column temperature: 808C, final: 1008C, tem-
perature ramp rate: 58CminÀ1 from 10 to 14 min, flow rate:
0.4 mLminÀ1, retention time: trans-2-heptene (10.6 min), cis-2-heptene
(10.8 min), 1-methylcyclohexene (13.1 min).
Condition H: instrument: Shimadzu GC-2010, carrier gas: He, capillary
column: GL Science TC-1701, injection temperature: 2808C, detection
temperature: 2808C, initial column temperature: 808C, final: 2008C, tem-
perature ramp rate: 108CminÀ1 from 10 to 22 min, flow rate:
0.4 mLminÀ1, retention time: trans-b-methylstyrene (23.6 min), ethyl 3,3-
dimethylacrylate (19.1 min).
[1] a) M. E. Phelps, PET: Molecular Imaging and Its Biological Applica-
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Condition I: instrument: Shimadzu GC-2010, carrier gas: He, capillary
column: GL Science TC-WAX, injection temperature: 2808C, detection
temperature: 2808C, initial column temperature: 1508C, final: 2008C,
temperature ramp rate: 108CminÀ1 from 10 to 15 min, flow rate:
0.4 mLminÀ1, retention time: 3-methyl-2-butene-1-ol (9.6 min).
HPLC analysis of [11C]xylene: column: Inertsil ODS-3 (4.6ꢁ150 mm, GL
Science), eluent: CH3CN/H2O 3:2 (v/v), flow rate: 1.0 mLminÀ1, UV
wavelength: 266 nm, retention time: 11.4 min.
Rapid coupling of methyl iodide with pinacol phenylboronate (40 equiv)
to afford toluene (Table 1, entry 4): In a dry Schlenk tube (10 mL), [Pd2-
ACHTUNGTRENNUNG(dba)3] (4.6 mg, 5.0 mmol), P(o-CH3C6H4)3 (6.1 mg, 20 mmol), and K2CO3
(2.8 mg, 20 mmol) were placed under Ar. After addition of DMF
(0.5 mL), the mixture was stirred for 5 min at RT, followed by successive
addition of solutions of 1 (81.6 mg, 400 mmol) in DMF (0.5 mL) and
methyl iodide in DMF (0.4m, 25 mL, 10 mmol). The resulting mixture was
stirred under Ar at 608C for 5 min, rapidly cooled (ice bath), filtered
through a short column of SiO2 (0.5 g), and then eluted with diethyl
ether. The combined eluates were analyzed by GLC with nonane (0.1m,
50 mL, 5 mmol) as the internal standard. Yield of toluene: 91%. The con-
centration of methyl iodide used in this experiment was the minimum
concentration required for exact direct analysis of toluene produced in
the reaction. Methylation using arylboronates in entries 1–13 of Table 2
and alkenylboronates in entries 1–6 of Table 3 was conducted by the
same procedure.
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Rapid coupling of fluoromethyl iodide with pinacol phenylboronate
(40 equiv) to afford benzyl fluoride (Scheme 2): In a dry Schlenk tube
(10 mL), [Pd2ACHTUNGTRENNUNG(dba)3] (4.6 mg, 5.0 mmol), P(o-CH3C6H4)3 (9.1 mg,
30 mmol), and K2CO3 (2.8 mg, 20 mmol) were placed under Ar. After ad-
dition of DMF (0.5 mL), the mixture was stirred for 5 min at RT, fol-
lowed by successive addition of solutions of 1 (81.6 mg, 400 mmol) in
DMF (0.5 mL) and fluoromethyl iodide in DMF (0.2m, 50 mL, 10 mmol).
The resulting mixture was stirred under Ar at 608C for 5 min, rapidly
cooled (ice bath), filtered through a short column of SiO2 (0.5 g), and
then eluted with diethyl ether. The combined eluates were analyzed by
GLC with nonane (0.1m, 50 mL, 5 mmol) as the internal standard. Yield
of benzyl fluoride: up to 57%, average 47%.
Rapid coupling of [11C]methyl iodide with pinacol tolylboronate
(40 equiv) to afford [11C]xylene (Scheme 3): [11C]Methyl iodide (ca. 3–
5 GBq) formed from [11C]CO2 according to the established method[1,3]
was trapped in
a solution of [Pd2ACHTUNTGNRUEGN(dba)3] (2.9 mg, 3.2 mmol), P(o-
CH3C6H4)3 (3.9 mg, 12.8 mmol), K2CO3 (1.0 mg, 7.2 mmol), and 4-(4,4,5,5,-
tetramethyl-1,3,2-dioxaborolan-2-yl)toluene (1.8 mg, 8 mmol) in DMF
4170
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ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2009, 15, 4165 – 4171

Isotope Labeling
FULL PAPER
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[12] The reactions of methyl iodide (0.1 mmol) with an equimolar
amount of 3-benzyloxyphenyl pinacolboron (0.1 mmol; the substrate
of entry 2 in Table 2) using a catalytic amount of [Pd2ACTHUNTRGNE(UGN dba)3]/P(o-
CH3C6H4)3/K2CO3 (0.05:0.2:0.2 in molar ratio) in DMF (1 mL) at
Received: September 24, 2008
608C for 5 min and at 608C for 180 min afforded the corresponding
Published online: March 12, 2009
Chem. Eur. J. 2009, 15, 4165 – 4171
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
4171