Pd0-mediated rapid coupling between methyl iodide and heteroarylstannanes: an efficient and general method for the incorporation of a positron-emitting11C radionuclide into heteroaromatic frameworks

Article abstract of DOI:10.1002/chem.200901145

The Pd⁰-mediated rapid trapping of methyl iodide with an excess amount of a heteroaryl-substituted tributylstannane has been investigated with the aim of incorporating a shortlived ¹¹C-labelled methyl group into the heteroaromatic carbon frameworks of important organic compounds, such as drugs with various heteroaromatic structures, in order to execute a positron emission tomography (PET) study of vital systems. The reaction was first performed by using our previously developed CH₃I/stannane/[Pd ₂(dba)₃]/ P(o-CH₃C₆H ₄)₃/CuCl/K₂CO₃ (1:40:0.5:2:2:2) system in DMF at 60°C for 5 min (conditions A), however, the reaction gave low yields for various heteroaromatic compounds. Increasing the amount of phosphine ligand (condi tions B) led to a significant improvement in the yield, but the conditions were still not suitable for a range of basic heteroaromatic structures. Use of the CuBr/CsF system (conditions C) also provided a result similar to that obtained under conditions B with an increased amount of the phosphine. Thus, pyridine and related heteroaromatic compounds remained less reactive substrates. The problem was overcome by replacing the DMF solvent with N-methyl-2-pyrolidinone (NMP). The reaction in NMP at 60-100°C for 5 min using a CH₃I/stannane/[Pd₂-(dba)₃]/P(o-CH ₃C₆H₄)₃/CuBr/CsF (1:40:0.5:16:2:5) combination (conditions D) gave the methylated products in yields of more than 80% (based on the reaction of CH3I) for all of the heteroaromatic compounds listed in this study. Thus, the combined use of NMP and an increased amount of phosphine is important for promoting the reaction efficiently. The use of this general approach to rapid methylation has been well demonstrated by the synthesis of the PET tracers 2- and 3-[¹¹C]methylpyridines by using [Pd₂(dba)₃]/P(o-CH₃C₆H ₄)₃/CuBr/CsF (1:16:2:5) in NMP at 60°C for 5 min, which gives the desired products in HPLC analytical yields of 88 and 91%, respectively.

Full text of DOI:10.1002/chem.200901145

FULL PAPER
DOI: 10.1002/chem.200901145
Pd0-Mediated Rapid Coupling between Methyl Iodide and
Heteroarylstannanes: An Efficient and General Method for the Incorporation
11
of a Positron-Emitting C Radionuclide into Heteroaromatic Frameworks**
Masaaki Suzuki,*[a, b] Kengo Sumi,[b] Hiroko Koyama,[b] Siqin,[b] Takamitsu Hosoya,[b]
Misato Takashima-Hirano,[a] and Hisashi Doi[a]
Abstract: The Pd0-mediated rapid trap-
ping of methyl iodide with an excess
amount of a heteroaryl-substituted tri-
tions B) led to a significant improve-
ment in the yield, but the conditions
were still not suitable for a range of
basic heteroaromatic structures. Use of
the CuBr/CsF system (conditions C)
also provided a result similar to that
obtained under conditions B with an
increased amount of the phosphine.
Thus, pyridine and related heteroaro-
matic compounds remained less reac-
tive substrates. The problem was over-
come by replacing the DMF solvent
with N-methyl-2-pyrolidinone (NMP).
The reaction in NMP at 60–1008C for
ACHTUNGNERTN(NUG dba)3]/P(o-CH3C6H4)3/CuBr/CsF
(1:40:0.5:16:2:5) combination (condi-
tions D) gave the methylated products
in yields of more than 80% (based on
the reaction of CH3I) for all of the het-
eroaromatic compounds listed in this
study. Thus, the combined use of NMP
and an increased amount of phosphine
is important for promoting the reaction
efficiently. The use of this general ap-
proach to rapid methylation has been
well demonstrated by the synthesis of
ACHTUNGTRENNUNGbuACHTUNGTRENNUNGtylstannane has been investigated
with the aim of incorporating a short-
lived 11C-labelled methyl group into
the heteroaromatic carbon frameworks
of important organic compounds, such
as drugs with various heteroaromatic
structures, in order to execute a posi-
tron emission tomography (PET) study
of vital systems. The reaction was first
performed by using our previously de-
the
[11C]methylpyridines by using [Pd2-
(dba)3]/P(o-CH3C6H4)3/CuBr/CsF
PET
tracers
2-
and
3-
veloped
CH3I/stannane/ACTHNGUTREN[UNG Pd2ACHTUNGRTEN(NUNG dba)3]/
P(o-CH3C6H4)3/CuCl/K2CO3
5 min using
a
CH3I/stannane/
G
ACHTUNGTRENNUNG
(1:40:0.5:2:2:2) system in DMF at 608C
for 5 min (conditions A), however, the
reaction gave low yields for various
heteroaromatic compounds. Increasing
the amount of phosphine ligand (condi-
(1:16:2:5) in NMP at 608C for 5 min,
which gives the desired products in
HPLC analytical yields of 88 and 91%,
respectively.
À
Keywords: C C coupling · hetero-
cycles · isotopic labeling · palladi-
um · tin
Introduction
the dynamic behavior of a radiotracer in living systems, such
as the brain, the heart, and other active tissues and organs.[2]
In this regard, a PET tracer is utilized to visualize the locali-
zation of a target molecule involved in biofunctions and also
its biochemical processes (metabolic pathways), and there-
fore PET imaging is a useful tool for disease diagnosis.[2–4]
Because PET requires only an extremely low dose of a ra-
Positron emission tomography (PET) is a noninvasive, in
vivo molecular imaging method that enables the analysis of
[a] Prof. Dr. M. Suzuki, M. Takashima-Hirano, Dr. H. Doi
RIKEN Center for Molecular Imaging Science
6-7-3 Minatojima-minamimachi, Chuo-ku, Kobe 650-0047 (Japan)
Fax : (+81)78-304-7131
ACHUTNGRENdNUG ioACHUTNGTRENtNGUN racer, much lower than its pharmacological dose, the in-
troduction of a human microdose study using PET during
the early stage of drug development (phase 0) has been pro-
posed as an efficient means of avoiding the huge attrition
(>90%) of drug candidates during clinical trials, which
causes the high cost per approved new molecular entity
(NME).[3]
E-mail: suzuki.masaaki@riken.jp
[b] Prof. Dr. M. Suzuki, Dr. K. Sumi, Dr. H. Koyama, Siqin,
Dr. T. Hosoya
Division of Regeneration and Advanced Medical Science
Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu
501-1194 (Japan)
Among the available positron-emitting radionuclides, 11C
is one of the most expedient in terms of high radioactivity,[4]
[**] Rapid Methylation on Carbon Frameworks for PET Tracer Synthesis,
Part 9; for Parts 1–8, see refs. [1a–h].
Chem. Eur. J. 2009, 15, 12489 – 12495
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
12489

1
short radiation lifetime (t = =20.4 min), and, most of all, all
ping substrate that remains after the reaction.[6] To meet
such severe restrictions for the PET tracer synthesis, we
have been developing a procedure for the rapid cross-cou-
pling of methyl iodide with excess amounts of aryl-, alkenyl-,
or alkynyltributylstannanes[1a–g] in addition to a reaction in-
volving the use of boranes.[1h] These Pd0-mediated cross-cou-
pling reactions between sp3- and sp2-, and sp3- and sp-hy-
bridized carbon atoms at the reaction centers proceeded
within 5 min under mild conditions (608C in DMF) to give
the desired compounds in high yields.[1a–h] Among these
2
the carbon atoms present in organic compounds could po-
tentially be replaced by 11C. In addition, various synthetical-
ly well-established precursors, such as 11CH3I, 11CO, and
11CO2, are readily available.[4] In particular, the introduction
of a 11CH3 group into an organic framework by carbon
À
carbon bond formation has the following significant bene-
fits: 1) A flexible molecular design is possible because the
methyl group is the least bulky and nonpolar organic func-
tional group and thus produces only a slight change in the
biological activities of the parent compound, 2) the short
half-life of the 11C-incorporated tracer allows many preclini-
cal or clinical trials per day without any special care, such as
the treatment of radiolabeled byproducts produced after the
synthesis, thereby allowing fast and safe drug screening, and
3) a much higher tolerance of the C-CH3 derivatives against
metabolic processes in comparison with O-CH3 and N-CH3
derivatives, which ensures that the information obtained in a
PET study is highly reliable. However, there exists a tempo-
ral restriction on the preparation of 11C-incorporated PET
tracers.[5] Because, in general, the total synthesis time should
be set to within 2–3 half-lives of the radionuclide, the time
allowed for 11C incorporation is only about 5–10 min on the
basis of the total reaction time, purification, and injection.
In addition, an extremely small amount of the desired radio-
labeled product should be cleanly separated from the reac-
tion mixture, particularly from the large amount of the trap-
methods, the sp3–sp2
ACTHNUGRTENUNG(aryl) coupling reaction has successfully
been utilized for the synthesis of the (15R)-[11C]TIC methyl
ester ((15R)-TIC=(15R)-16-m-tolyl-17,18,19,20-tetranoriso-
carbacyclin),[1b,c,f,7] a novel 11C-incorporated prostaglandin
probe used in the molecular imaging of a novel prostacyclin
receptor (IP2, which is a target protein of prostacyclin
(PGI2))[7b,d] in living monkey and human brains administered
by intravenous injections.[1b,f,7e] Our rapid coupling reactions
are now increasingly being utilized in the 11C-labeling of bio-
logically significant molecules by other groups.[1i,k–n] Howev-
er, as indicated by us[1a–h] and others,[1i–s] the reaction condi-
tions for rapid C-methylation using stannanes seem not to
have been optimized, particularly in the case of heteroaro-
matic frameworks such as thiophene and furan as well as
pyridine-type structures with a basic nitrogen atom(s) in the
core structure.[1m,q] The strong demand for high-yielding
rapid methylation of such structures with a heteroaromatic
core, which often appear in major drugs and their promising
candidates, prompted us to conduct this study.
We disclose herein an efficient, general protocol for the
rapid C-methylation of heteroaromatic frameworks for the
synthesis of PET tracers in high yields.[1h]
Abstract in Japanese:
Results and Discussion
We chose nine basic and nonbasic heteroaromatic aryltribu-
tylstananes, 1a–i, for the rapid methylation reaction
(Table 1) and a 1:40 ratio[8] of methyl iodide and tin sub-
strate was set up for the PET tracer synthesis. To start with
we evaluated the conditions previously reported by Saji and
co-workers for the synthesis of 5-methyl-3-[2-(S)-azetidinyl-
methoxy]pyridine ([11C]5MA) in a radiochemical yield of
30%[1m] by using the tin substrate 1e (entry 5 in Table 1) as
a model compound. Thus, the reaction was conducted by
using
CH3I/1e/ACTHGUNERTUNN[G Pd2ACHTUNGTRENGNUN(dba)3]/P(o-CH3C6H4)3/CuCl/K2CO3
(1:40:0.5:2:2:2 molar ratio) in DMF at 808C for 3 min to
give the methylated product 2e in a yield of 53% (GLC)
based on the reaction of CH3I. Furthermore, the conditions
reported by Laruelle and co-workers for the synthesis of the
[11C]-incorporated
quinoline
derivative
(3-ethyl-2-
[11C]methyl-6-quinolinyl)(cis-4-methoxycyclohexyl)metha-
none (radiochemical yield 47%)[1q] were also evaluated in
the reaction of methyl iodide and 1d as a model reaction
(entry 4 in Table 1) using the combination CH3I/1d/
(dba)3]/P(o-CH3C6H4)3 (1:40:0.5:2) in DMF in a stepwise
procedure: [Pd2A(dba)3] and P(o-CH3C6H4)3 (1:4) were mixed
ACHTUNGTRENNUNG[Pd2-
AHCTUNGTRENNUNG
CTHUNGTRENNUNG
12490
www.chemeurj.org
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2009, 15, 12489 – 12495

Radionuclide Incorporation in Heteroaromatic Frameworks
FULL PAPER
Table 1. Rapid trapping of methyl iodide with heteroaryl-substituted tributylstannanes.
which gave yields of 35–67%
with 6–20 equiv of phosphine.
Thus, we found that the reac-
tion efficiency was typically in-
creased by increasing the quan-
tity of the added phosphine up
to 16 equiv for both the CuCl/
K2CO3 and CuBr/CsF synergic
systems. With such a phosphine
effect, we conducted the reac-
tion with the other stannanes
listed in Table 1 using CH3I/
Entry
Heteroarylstannane
Methylated product
Yield [%][a]
A[b]
28
B[b]
C[b]
D[b]
80
1
2
75
73
57
87
91
94
3
52
88
90
94
4
5
6
16 (14)[c]
25 (53)[d]
79
67
61
60
63
66
68
81
80
87
1d/ACTHNUGTRENNUG[Pd2ACHTUNGTRNEN(UNG dba)3]/P(o-CH3C6H4)3/
CuCl/K2CO3 (1:40:0.5:16:2:5)
at 608C for 5 min in DMF
(conditions B) and CH3I/
stannane/ACHTNUGTRENN[UG Pd2ACHTUNGTREN(NUGN dba)3]/P(o-
CH3C6H4)3/CuBr/CsF
7
8
3
50
72
48
70
62 (87)[e]
90
25
(1:40:0.5:16:2:5) at 608C for
5 min in DMF (conditions C),
which gave yields of 87, 88,
and 83% for 2b, 2c, and 2i, re-
spectively, under conditions B,
91 and 90% for 2b and 2c, re-
spectively, under conditions C,
and 48–75% for the other en-
tries under both conditions.
Thus, pyridine and related
basic heteroaromatic com-
pounds still remained less reac-
tive substrates even under
9
12
83
75
83
[a] The products were identified by GLC analysis by comparison with authentic samples. The yields were de-
termined by GLC based on CH3I consumption using n-nonane and n-heptane as internal standards and are
the average of 2 or 3 runs. [b] Reaction conditions (molar ratio): A: CH3I/stannane/
CuCl/K2CO3 (1:40:0.5:2:2:2) in DMF at 608C for 5 min; B: CH3I/stannane/[Pd2A(dba)3]/P
[Pd2A(dba)3]/P
[Pd2A(dba)3]/P
(o-tolyl)3 (1:40:0.5:2) in DMF at
[Pd2A(dba)3]/P(o-tolyl)3/CuCl/K2CO3
(1:40:0.5:2:2:2) in DMF at 808C for 3 min (see ref. [1n]). [e] The reaction was conducted at 1008C.
G
2ACHTUNGTRNENUG(dba)3]/PACHTUNGTRNEN(UGN o-tolyl)3/
R
U
ACHTUNGTRENNUNG
(1:40:0.5:16:2:5) in DMF at 608C for 5 min; C: CH3I/stannane/
(1:40:0.5:16:2:5) in DMF at 608C for 5 min; D: CH3I/stannane/
A
G
ACHTUNGTRENNUNG
R
ACHTUNGTRENNUNG
(1:40:0.5:16:2:5) in NMP at 608C for 5 min. [c] CH3I/stannane/
ACHTUGNTRNEU[NGN Pd2ACHTUNREGTG(NNUN dba)3]/PACTHUNGTRENNUNG
1208C for 5 min (stepwise procedure; see ref. [1m]). [d] CH3I/stannane/
R
ACHTUNGTRENNUNG
in DMF at room temperature and stirred for 1 min and then
the resulting Pd0 complex was transferred to a DMF solu-
tion of 1d and heated at 1208C for 5 min to give 2d in a
yield of only 14%. Based on these results, we concluded
that the reaction conditions previously used for the methyla-
tion of heteroaromatic compounds are still insufficient and
therefore a further basic study is needed to improve the
yields, which prompted us to systematically reinvestigate the
rapid methylation of the compounds listed in Table 1.
these conditions (entries 4–8). Therefore we continued to
search for reaction conditions that generally give high yields
for a wide range of substrates. The answer surprisingly in-
volved simply changing the solvent from DMF to N-methyl-
2-pyrrolidinone (NMP)! It is of interest that such a solvent
effect was not observed for the CH3I/1d/
CH3C6H4)3/CuCl/K2CO3 system, but was apparent for the
CH3I/1d/[Pd2A(dba)3]/P(o-CH3C6H4)3/CuBr/CsF reaction
ACHTUGTNRNENUG[Pd2ACHUTNGTREN(NGUN dba)3]/P(o-
A
CHTUNGTRENNUNG
system (entry 3 in Table 2), which gave 2d in a yield of
81%. The effects of other solvents are also summarized in
Table 2. HMPA, DMSO, 1,3-dimethylimidazolidin-2-one
(DMI), THF, and toluene were not effective (Table 2,
entry 3). Accordingly, NMP was the best of the amide-type
solvents used, including N,N-dimethylacetamide (DMA),
NMP gave the highest yield of 81%, whereas DMA gave a
yield of 69%. Note that the reaction with the CH3I/1d/
First, we conducted the reactions of stannanes 1a–i under
the conditions[1a] previously developed by us for sp3–sp2-
A
ACHTUNGRTEN[NUNG Pd2-
ACHTUNGTRENNUNG
for 5 min in DMF (see conditions A in Table 1), which gave
far-from-ideal yields (3–57%), except for the conversion of
1 f to 2 f (79%, entry 6). Again, we recognized the difficulty
of optimizing the conditions of these reactions. We then
chose the conversion of 1d to 2d as a model reaction for op-
timizing the reaction conditions (Table 2). Interestingly, in-
creasing the quantity of added phosphine for Pd0 from 2 to
20 equiv significantly improved the yield from 16 to 71%
(entry 4 in Table 1 and entry 4 in Table 2, respectively). Sim-
ilar phenomena were observed in our previous studies in-
[Pd{P
ACHTUNGTREN(UNNG tBu)3}2]/CsF (1:40:1:5) system in NMP, in which the
bulky triarylphosphine, P(o-CH3C6H4)3, is replaced by the
trialkylphosphine, PACTHNUTRGNEUNG(tBu)3, gave an unexpectedly poor yield
(21%, Table 2, entry 3).[9a,d] The addition of CuBr to this
system improved the yield only to a small extent (39%).
The addition of amines such as 2,6-lutidine, triethylamine,
and 1,4-diazabicycloACHTUNRGTNE[NUG 2.2.2]octane (DABCO) to the reaction
under conditions B or C prohibited the reaction to a signifi-
cant extent.
volving rapid sp3–sp2
K2CO3 synergic system.[1g] The reagents comprised the
CH3I/1d/[Pd2A(dba)3]/P(o-CH3C6H4)3/CuBr/CsF combination,
A
A
CHTUNGTRENNUNG
Chem. Eur. J. 2009, 15, 12489 – 12495
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
12491

M. Suzuki et al.
and CuI intermediates transiently formed in the reaction to
suppress metal deposition. We have found in this study that
the use of an excess amount of the triarylphosphine, P(o-
CH3C6H4)3, and NMP as the solvent for the combination
CH3I/stannane/Pd0/phosphine/CuI/CsF is the best choice for
the reaction. The basicity of the phosphine influences the re-
action to a significant extent,[1e] as is evident by the fact that
the use of P(o-CH3C6H4)3 gives results much superior to P-
Table 2. Rapid trapping of methyl iodide with tri-n-butyl(2-pyridyl)stan-
nane (1d) to give 2d and the effects of solvent and additives.[a]
Entry
P
(o-tolyl)3
Yield [%][b]
CuBr/CsF
(equiv of CH3I)
CuCl/K2CO3
AHCTUNTGRENGUN(N tBu3)3 in the rapid methylation reaction (81 vs. 21%, re-
synergic system
synergic system
spectively, see Table 2, entry 3).[9a] We considered that a het-
eroatom with a lone-pair electron or a basic nitrogen atom
included in the tin substrate structure could possibly coordi-
nate to the metal species to decrease the nucleophilicity of
1
2
3
6
8
16
43
55
35
49
67 (66)[c] (10)[d]
(34)[e] (46)[f]
(81)[c] (21)[g] (39)[h] 65
(69)[i] (18)[j,k] (20)[l]
(38)[m] (23)[d] (34)[e] (19)[f]
(20)[n] (7)[o]
À
the C Sn bond, prohibiting the substitution reaction be-
II
À
À
À
À
tween Aryl Sn (or Aryl Cu) and CH3 Pd I to a consider-
able extent. Here, excess phosphine[11] and the NMP solvent
serve to dissociate such a coordination to regenerate the nu-
cleophilic tin(IV) or copper(I) to promote the reaction. The
reason why the use of DMSO, HMPA, or a urea derivative
is not efficient for the reaction, but not polar aprotic sol-
vents like amide, remains unclear. The inhibitory effect of
an amine additive is presumably due to its strong coordina-
tion with the active site of the metal complexes.
4
20
71
67
[a] Reaction conditions (molar ratio): CH3I/1d/
G
N
ACHTUNGTRNEN(UNG o-tolyl)3/
CuCl/K2CO3 (1:40:0.5:6–20:2:2) or CH3I/1d/[Pd2A(dba)3]/PACHTGNUTRENNUNG
N
N
(o-tolyl)3/CuBr/
CsF (1:40:0.5:6–20:2:5) in DMF at 608C for 5 min. [b] Yields of 2d were
determined by GLC analyses based on CH3I consumption using n-hep-
tane as the internal standard. [c] Reaction performed in NMP as the sol-
vent. [d] Reaction performed in DMSO as the solvent. [e] Reaction per-
formed in HMPA as the solvent. [f] Reaction performed in DMF in the
presence of 2,6-lutidine (17 equiv). [g] Fuꢁs original conditions[9a,d] (molar
ratio): CH3I/1d/Pd[P
ACHTUNGTRENNUNG
The utility of conditions D was demonstrated by the syn-
thesis of 2-[11C]methylpyridine (2-[11C]picoline, [11C]2d) and
3-[11C]methylpyridine (3-[11C]picoline, [11C]2e). In our expe-
rience of PET studies, the continuous operations of
1) mixing [11C]methyl iodide and Pd0, and then 2) mixing the
resulting methylpalladium(II) with a stannane, copper(I)
salt, and fluoride anion gives a better result in terms of the
reproducibility of the reaction.[1c,f] Thus, the PET tracers
[11C]2d and [11C]2e were synthesized by such a protocol.
The successive mixing of the Pd0 complex with [11C]CH3I in
NMP and then with the stannanes 1d and 1e in the presence
ditions CuBr (molar ratio): CH3I/1d/Pd[PACTHUNGTRENNUNG
+
(1:40:1:2:5) in NMP. [i] Reaction performed in DMA as the solvent.
[j] Reaction performed in DMI as the solvent. [k] The yields of 2d were
determined by HPLC analysis based on CH3I consumption using isoqui-
noline as the internal standard. [l] Reaction performed in toluene as the
solvent. [m] Reaction performed in THF as the solvent. [n] Reaction per-
formed in DMF in the presence of triethylamine (14 equiv). [o] Reaction
performed in DMF in the presence of DABCO (18 equiv).
With the best solvent in hand, the reaction with CH3I/
stannane/ACHTUNGTRENNUNG[Pd2ACHTUNGTRENNUNG(dba)3]/P(o-CH3C6H4)3/CuBr/CsF
(1:40:0.5:16:2:5) in NMP at 608C for 5 min (conditions D)
was conducted for the other stannanes listed in Table 1 and
gave yields in excess of 80% for all compounds except for
the stannane 1g in entry 7 of Table 1.[10] The yield of 2g was
improved to 87% by conducting the reaction at 1008C (im-
proved conditions D). Thus, we established the conditions
for rapid methylation that are generally applicable to a wide
range of heteroaromatic frameworks including those with a
basic nitrogen atom(s) in the structure. As described in our
previous studies, the use of a coordinatively unsaturated Pd0
complex, such as [Pd{P(o-CH3C6H4)3}2][1a–d,f–h] and [Pd{P-
of CuBr and CsF in NMP under conditions D ([Pd2ACHTUNGTRENNUNG(dba)3]/
P(o-CH3C6H4)3/CuBr/CsF (1:16:2:5))[12] at 608C for 5 min
produced 2- and 3-[11C]methylpyridine in yields of 88 and
91%, respectively (by HPLC analysis; Scheme 1).[13]
ACHTUNGTRENNUNG
(tBu)3}2],[1e] is crucial for promoting rapid cross-coupling re-
Scheme 1. Synthesis of 2- and 3-[11C]methylpyridines ([11C]2d and
[11C]2e).
actions. The bulky triaryl- and trialkylphosphines serve to
generate the reactive coordinatively unsaturated Pd0 and
PdII complexes during the course of the reaction. An in-
crease in the quantity of the reactive trapping substrate
[1a]
transmetalated by a combination of CuI/K2CO3
or CuI/
These conditions are useful for methylation using an
excess amount of an organostannane as the substrate, but
also for the methylation with a nearly equal amount of the
substrate. Thus, the reaction of CH3I with 1.4 equiv of 1d
using [Pd2ACHTUNRGTNEGN(U dba)3]/P(o-CH3C6H4)3/CuBr/CsF (0.5:16:2:5) in
NMP (1 mL) at 608C for 60 min afforded 2d in a yield of
CsF[1g] through synergic effects is also important for promot-
ing the reaction.[1g] Because the yields did not change by
using a combination of CuI and CsF instead of CuI and
K2CO3 (see Table 1, conditions B and C), the formation of a
hypervalent tin intermediate is not important in the reac-
tion.[1t,u,v] DMF weakly coordinates to the unstable Pd0, PdII,
84%. Accordingly, this methylation reaction can be used to
12492
www.chemeurj.org
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2009, 15, 12489 – 12495

Radionuclide Incorporation in Heteroaromatic Frameworks
FULL PAPER
introduce 13CH3, CD3, and the long-lived 14CH3 into hetero-
aromatic frameworks to synthesize molecular probes for
metabolic studies. In particular, the synthesis of a 14C-en-
riched methylated probe is attracting considerable attention
for drug microdosing in humans as is the long-term analyti-
cal tool of metabolites by accelerator mass spectrometry
(AMS).[2b,14]
(Tokyo Kasei), tri-n-butyl(2-pyridyl)stannane (Tokyo Kasei), and tri-n-
butyl(3-pyridyl)stannane (Frontier) are commercially available. 2-Methyl-
furan, 2-methylthiophene, 3-methyl-1-phenylpyrazole, 2-methylpyridine,
3-methylpyridine, 4-methylpyridine, 5-methylpyrimidine, 4-methylpyrida-
zine, and 4-methylisoquinoline were used as authentic samples. n-Nonane
and n-heptane used as the internal standard for GC analyses were of
commercial grade. 1-Phenyl-3-(tributylstannyl)pyrazole[16] and tri-n-
butyl(4-pyridazinyl)stannane[17] were prepared according to literature
procedures. Tri-n-butyl(4-pyridyl)stannane was prepared by the reaction
of 4-pyridnyllithium with tributylstannyl chloride in diethyl ether. Tri-n-
butyl(4-isoquinolyl)stannane was prepared by the same procedure. Tri-n-
butyl(5-pyrimidinyl)stannane was prepared by the reaction between the
corresponding bromide compounds and hexabutylditin in the presence of
tetrakis(tiphenylphosphine)palladium(0). The [11C]methylation reaction
in Scheme 1 was conducted in a lead-shielded hot cell with remote con-
Conclusion
We have developed an efficient protocol for Pd0-mediated
rapid C-methylation by the reaction of methyl iodide with
an excess amount of a heteroaryl-substituted tributylstan-
nane using NMP as the solvent in the presence of excess
phosphine with the aim of synthesizing a short-lived 11C-in-
corporated PET tracer. The rapid C-methylation strategy is
quite general and applicable to a wide variety of basic and
nonbasic heteroaromatic compounds. The method is well
demonstrated by the reactions of [11C]CH3I with the tin pre-
cursors 1d and 1e, which give 2-[11C]methylpyridine
([11C]2d) and 3-[11C]methylpyridine ([11C]2e), respectively,
both in high radiochemical yields. Two kinds of rapid C-
methylation reactions are now available, the reaction of
methyl iodide with a heteroaromatic stannane and also with
a borane[1h] precursor. These methods could be used comple-
mentarily depending on the ease of synthesis of the tin or
borane precursor and the efficiency of their reactions with
methyl iodide. The combination of PET and AMS technolo-
gies allows the dynamic behavior of organic molecules
(drugs and their candidates) in the human body to be ana-
lyzed by using the microdosing concept[3,15] at an early stage
of drug development to significantly improve the attrition of
drug candidates during clinical trials. The application of
these methods to the synthesis of PET tracers of biological
significance and their use in molecular imaging will be dem-
onstrated in due course.
trol of all operations. [11C]Carbon dioxide was produced by a 14N
ACHTUNGTRENNUNG
(p,a)11C
reaction using Sumitomo CYPRIS HM-12S cyclotron (Sumitomo
a
Heavy Industries) and then converted into [11C]methyl iodide by treat-
ment with lithium aluminum hydride followed by hydriodic acid using an
original automated synthesis system for 11C-labeling in RIKEN Center
for Molecular Imaging Science. The [11C]methyl iodide obtained was
used for the palladium(0)-mediated rapid [11C]methylation reaction
shown in Scheme 1. The analytical HPLC system used for the
[11C]methylation products consisted of an Aloka radioanalyzer (RLC-
700) and a Shimadzu HPLC system with a system controller (CBM-20A),
an online degasser (DGU-20A3), a solvent delivery unit (LC-20AB), a
column oven (CTO-20AC), a photodiode array detector (SPD-M20A),
and software (LC solution).
Product analysis
Conditions 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 tempera-
ture: 1008C; temperature ramp rate ; 58CminÀ1 from 10 to 14 min; flow
rate: 0.50 mLminÀ1; retention time: 2-methylfuran (2a) 9.2 min, 2-meth-
ylthiophene (2b) 13.4 min.
Conditions B: Instrument: Shimadzu GC-17A; carrier gas: N2; capillary
column: GL Science CP-Volamine; injection temperature: 2608C; detec-
tion temperature: 2608C; column temperature: 2308C; flow rate:
2.1 mLminÀ1; retention time: 3-methyl-1-phenylpyrazole (2c) 26.6 min, 4-
methylpyridine (2e) 15.1 min, 4-methylisoquinoline (2i) 29.6 min.
Conditions C: Instrument: Shimadzu GC-17A; carrier gas: N2; capillary
column: GL Science CP-Volamine; injection temperature: 2608C; detec-
tion temperature: 2608C; initial column temperature: 1008C; final tem-
perature: 2008C; temperature ramp rate; 108CminÀ1 from 10 to 20 min;
flow rate: 0.50 mLminÀ1; retention time: 2-methylpyridine (2d) 19.6 min.
Conditions D: Instrument: Shimadzu GC-17A; carrier gas: N2; capillary
column: GL Science CP-Volamine; injection temperature: 2608C; detec-
tion temperature: 2608C; initial column temperature: 1508C; final tem-
perature: 2008C; temperature ramp rate; 108CminÀ1 from 10 to 15 min;
flow rate: 0.40 mLminÀ1; retention time: 3-methylpyridine (2e) 15.1 min,
5-methylpyrimidine (2g) 15.1 min, 4-methylpyridazine (2h) 22.3 min.
HPLC analysis of 2-[11C]methylpyridine: Column: COSMOSIL, C18-MS-
II (4.6ꢂ150 mm, Nacalai); eluent: CH3CN/H2O=20:80 (v/v); flow rate:
1.0 mLminÀ1; column temperature: 308C; UV wavelength: 254 nm; re-
tention time: 4.9–5.0 min.
HPLC analysis of 3-[11C]methylpyridine: Column: COSMOSIL, C18-MS-
II (4.6ꢂ150 mm, Nacalai); eluent: CH3CN/H2O=25:75 (v/v); flow rate:
1.0 mLminÀ1; column temperature: 308C; UV wavelength: 254 nm; re-
tention time: 4.6–4.8 min.
Experimental Section
General: GLC analysis was performed on Shimadzu GC-2010 and GC-
17A instruments equipped with a flame ionization detector; capillary col-
umns: TC-1701 (60 mꢂ0.25 mm i.d., df=0.25 mm, GL Science) and CP-
Volamine (60 mꢂ0.32 mm i.d., GL Science); carrier gases: N2 or He. The
organic chemical reactions, except for the radiolabeling reaction shown
in Scheme 1, were performed by using Schlenk techniques under argon.
Solvents and solutions were transferred by syringe-septum and cannula
techniques. Dehydrated N,N-dimethylformamide (DMF; Kanto Kagaku),
dehydrated N-methyl-2-pyrrolidinone (NMP; Kanto), dehydrated tetra-
hydrofuran (THF; Wako), and dehydrated toluene (Wako) were of com-
mercial grade. Methyl iodide was distilled prior to use. Tris(dibenzyl
ACHTUNGERTNiNUNG -
Rapid coupling of methyl iodide with tri-n-butyl(4-isoquinolyl)stannane
(1i) to afford 4-methylisoquinoline (2i; Table 1, entry 9, conditions B): In
G
ACHTUNGTRENNUNG
copper(I) chloride (Wako), copper(I) bromide (Wako), potassium car-
bonate (Wako), cesium fluoride (Aldrich), 1,3-dimethylimidazolidine-2-
one (DMI; Nacalai Tesque, Inc.), N,N-dimethylacetamide (DMA;
Kanto), dimethyl sulfoxide (Kanto), hexamethylphosphoramide (HMPA;
Tokyo Kasei), 2,6-lutidine (Nacalai), triethylamine (Nacalai), and 1,4-
a
dry Schlenk tube (10 mL), [Pd2ACTHUNGRETNNU(G dba)3] (4.6 mg, 5.0 mmol), P(o-
CH3C6H4)3 (49 mg, 160 mmol), CuCl (2.0 mg, 20 mmol), and K2CO3
(6.9 mg, 50 mmol) were placed under argon. After the addition of DMF
(500 mL), the mixture was stirred for 5 min at RT and then solutions of
stannane 1i (167 mg, 400 mmol, 40 equiv) in DMF (500 mL) and methyl
iodide (12.5 mL, 0.800m in DMF, 10.0 mmol) were successively added.
diazabicyclo
ACHTUNGTRENNUNG[2.2.2]octane (DABCO; Kanto) were of commercial grade.
Tri-n-butyl(2-furyl)stannane (Aldrich), tri-n-butyl(2-thienyl)stannane
ACHTUNGTRENNUNG
Chem. Eur. J. 2009, 15, 12489 – 12495
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
12493

M. Suzuki et al.
After stirring at 608C for 5 min, the mixture was rapidly cooled in an ice
bath and diethyl ether (1 mL) was added. The resulting mixture was
loaded onto a short column of silica gel (0.5 g) and eluted with diethyl
ether (ca. 1 mL) followed by the addition of n-nonane (50 mL, 0.10m
DMF solution, 5.0 mmol) as the internal standard. The resulting solution
was analyzed under conditions B; yield of 2i: 83% based on starting
CH3I. The methylation reactions reported in entries 1–8 of Table 1 and
entries 1–4 of Table 2 using the synergic system of CuCl/K2CO3 were con-
ducted by following the same procedure.
Technology (MEXT) of Japan. We thank Mr. Jeongwan Son for his tech-
nical assistance in part of the study.
[1] Parts 1–8: a) M. Suzuki, H. Doi, M. Bjçrkman, Y. Andersson, B.
Lꢃngstrçm, Y. Watanabe, R. Noyori, Chem. Eur. J. 1997, 3, 2039–
2042; b) M. Suzuki, R. Noyori, B. Lꢃngstrçm, Y. Watanabe, Bull.
Chem. Soc. Jpn. 2000, 73, 1053–1070; c) M. Suzuki, H. Doi, K.
Kato, M. Bjçrkman, B. Lꢃngstrçm, Y. Watanabe, R. Noyori, Tetrahe-
dron 2000, 56, 8263–8273; d) M. Bjçrkman, H. Doi, B. Resul, M.
Suzuki, R. Noyori, Y. Watanabe, B. Lꢃngstrçm, J. Labelled Compd.
Radiopharm. 2000, 43, 1327–1334; e) T. Hosoya, M. Wakao, Y.
Kondo, H. Doi, M. Suzuki, Org. Biomol. Chem. 2004, 2, 24–27;
f) M. Suzuki, H. Doi, T. Hosoya, B. Lꢃngstrçm, Y. Watanabe, TrAC
Trends Anal. Chem. 2004, 23, 595–607; g) T. Hosoya, K. Sumi, H.
Doi, M. Wakao, M. Suzuki, Org. Biomol. Chem. 2006, 4, 410–415;
Patent: M. Suzuki, T. Hosoya, JP 2005-306670, 2005; M. Suzuki, T.
Hosoya, PCT/JP2006/320104, 2006; M. Suzuki, T. Hosoya, WO/2007/
046258; h) rapid C-methylation using a boronic acid ester as the
trapping agent: M. Suzuki, H. Doi, H. Tsukada, JP 2006-229169,
2006; M. Suzuki, H. Doi, H. Tsukada, PCT/JP2007/066411, 2007; M.
Suzuki, H. Doi, H. Tsukada, WO/2008/023780, 2008; H. Doi, I. Ban,
A. Nonoyama, K. Sumi, C. Kuang, T. Hosoya, H. Tsukada, M.
Suzuki, Chem. Eur. J. 2009, 15, 4165–4171; see also the application
by other groups based on our method: i) 11C-labelled PGF2a ana-
logue of [p-11C-methyl]MADAM: J. Tarkiainen, J. Vercouillie, P.
Emond, J. Sandell, J. Hiltunen, Y. Frangin, D. Guilloteau, C. Hall-
din, J. Labelled Compd. Radiopharm. 2001, 44, 1013–1023;
Rapid coupling of methyl iodide with tri-n-butyl(2-thienyl)stannane (1b)
to afford 2-methylthiophene (2b; Table 1, entry 2, conditions C): In a dry
Schlenk tube (10 mL), [Pd2ACHTUNGTRNEN(UG dba)3] (4.6 mg, 5.0 mmol), P(o-CH3C6H4)3
(49 mg, 160 mmol), CuBr (2.9 mg, 20 mmol), and CsF (7.6 mg, 50 mmol)
were placed under argon. After the addition of DMF (500 mL), the mix-
ture was stirred for 5 min at RT and then solutions of stannane 1b
(149 mg, 400 mmol, 40.0 equiv) in DMF (500 mL) and methyl iodide
(12.5 mL, 0.800m in DMF, 10.0 mmol) were successively added. After stir-
ring at 608C for 5 min, the mixture was rapidly cooled in an ice bath and
diethyl ether (1 mL) was added. The resulting mixture was loaded onto a
short column of silica gel (0.5 g) and eluted with diethyl ether (ca. 1 mL),
followed by the addition of n-nonane (50 mL, 0.10m DMF solution,
5.0 mmol) as the internal standard. The resulting solution was analyzed
under conditions A; yield of 2b: 91% based on starting CH3I. The meth-
ylation reactions reported in entries 1 and 3–9 of Table 1 and entries 1–4
of Table 2 using the synergic system of CuBr/CsF were conducted by fol-
lowing the same procedure.
Rapid coupling of methyl iodide with tri-n-butyl(2-pyridyl)stannane (1d)
to afford 2-methylpyridine (2d; Table 1, entry 4, conditions D): In a dry
Schlenk tube (10 mL), [Pd2ACHTUNGTRNEN(UG dba)3] (4.6 mg, 5.0 mmol), P(o-CH3C6H4)3
j) ACTHNUTRGNEUNG
[11C]toluene: M. Gerasimov, J. Logan, R. A. Ferrieri, R. D.
(49 mg, 160 mmol), CuBr (2.9 mg, 20 mmol) and CsF (7.6 mg, 50 mmol)
were placed under argon. After the addition of NMP (500 mL), the mix-
ture was stirred for 5 min at RT and then solutions of stannane 1d
(147 mg, 400 mmol, 40.0 equiv) in NMP (500 mL) and methyl iodide
(12.5 mL, 0.800m in NMP, 10.0 mmol) were successively added. After stir-
ring at 608C for 5 min, the mixture was rapidly cooled in an ice bath and
diethyl ether (1 mL) was added. The resulting mixture was loaded onto a
short column of silica gel (0.5 g) and eluted with diethyl ether (ca. 1 mL),
followed by the addition of n-heptane (50 mL, 0.10m DMF solution,
5.0 mmol) as the internal standard. The resulting solution was analyzed by
GLC under conditions C; yield of 2d: 81% based on starting CH3I. The
methylation reactions reported in entries 1–3 and 5–9 of Table 1 were
conducted by following the same procedure.
Muller, D. Alexoff, S. L. Dewey, Nucl. Med. Biol. 2002, 29, 607–612,
and references therein; k) 5-[11C]methyl-6-nitroquipazine: J. Sandell,
M. Yu, P. Emond, L. Garreau, S. Chalon, K. Nꢃgren, D. Guilloteau,
C. Halldin, Bioorg. Med. Chem. Lett. 2002, 12, 3611–3613, and ref-
erences therein; l) 11C-labelled citalopram analogue: J. Madsen, P.
Merachtsaki, P. Davoodpour, M. Bergstrçm, B. Lꢃngstrçm, K. An-
dersen, C. Thomsen, L. Martiny, G. M. Knudsen, Bioorg. Med.
Chem. 2003, 11, 3447–3456; m) ACHTNUGRTNEUNG
[11C]5MA for imaging of brain nico-
tinic acetylcholine receptors: Y. Iida, M. Ogawa, M. Ueda, A. Tomi-
naga, H. Kawashima, Y. Magata, S. Nishiyama, H. Tsukada, T.
Mukai, H. Saji, J. Nucl. Med. 2004, 45, 878–884; n) ACTHNUTRGNEUNG
[11C]celecoxib
for imaging COX-2 expression: J. Prabhakaran, V. J. Majo, N. R.
Simpson, R. L. V. Heertum, J. J. Mann, J. S. D. Kumar, J. Labelled
Compd. Radiopharm. 2005, 48, 887–895; for the use of the trime-
thylstannane derivative for [11C]methylation, see: o) O. Langer, T.
Forngren, J. Sandell, F. Dolle, B. Lꢃngstrçm, K. Nꢃgren, C. Halldin,
J. Labelled Compd. Radiopharm. 2003, 46, 55–65; p) L. Samuelsson,
B. Lꢃngstrçm, J. Labelled Compd. Radiopharm. 2003, 46, 263–272;
q) (3-ethyl-2-[11C]methyl-6-quinolinyl)(cis-4-methoxycyclohexyl)me-
thanone for imaging of the metabotropic glutamate 1 receptor: Y.
Huang, R. Narendran, F. Bischoff, N. Guo, Z. Zhu, S.-A Bae, A. S.
Lesage, M. Laruelle, J. Med. Chem. 2005, 48, 5096–5099; r) J. Toyo-
hara, K. Kumata, K. Fukushi, T. Irie, K. Suzuki, J. Nucl. Med. 2006,
47, 1717–1722; s) I. Bennacef, C. Perrio, M.-C. Lasne, L. Barrꢄ, J.
Org. Chem. 2007, 72, 2161–2165; for the use of functional organo-
stannanes, see: t) T. Bourdier, M. Huiban, A. Huet, F. Sobrio, E.
Fouquet, C. Perrio, L. Barrꢄ, Synthesis 2008, 978–984; u) M.
Huiban, A. Huet, L. Barrꢄ, F. Sobrio, E. Fouquet, C. Perrio, Chem.
Commun. 2006, 97–99; v) T. Forngren, L. Samuelsson, B. Lꢃng-
strçm, J. Labelled Compd. Radiopharm. 2004, 47, 71–78.
Rapid coupling of [11C]methyl iodide with tri-n-butyl(2-pyridyl)stannane
(1d) to afford 2-[11C]methylpyridine ([11C]2d; Scheme 1): [11C]Methyl
iodide (ca. 5–10 GBq) formed from [11C]CO2 according to the established
method[2] was trapped in a solution of [Pd
CHTUNGTERN(NUNG dba)3] (2.5 mg, 2.7 mmol) and
2A
P(o-CH3C6H4)3 (13 mg, 44 mmol) in NMP (0.27 mL) at RT. The mixture
was added to solution of stannane 1d (3.0 mg, 8.1 mmol), CuBr
a
(0.78 mg, 5.4 mmol), and CsF (2.1 mg, 14 mmol) in NMP (0.06 mL). The
resulting mixture was placed at RT for 1 min and then heated at 608C for
5 min. The reaction mixture was diluted with CH3CN (2 mL) and filtered.
A sample solution (5 mL) taken from the filtrate was analyzed by HPLC
with a UV absorbance detector and a radiation detector. HPLC analyti-
cal yield of [11C]2d: 88%, calculated by peak area ratio of the
[11C]product distributions. The isolated yield was not determined because
the isolation of volatile 2-[11C]methylpyridine was dangerous. Rapid cou-
pling using tri-n-butyl(3-pyridyl)stannane (1e) to afford 3-
[11C]methylpyridine ([11C]2e) was conducted by the same procedure. The
HPLC analytical yield of [11C]2e was 91%.
[2] a) J. S. Fowler, A. P. Wolf, J. R. Barrio, J. C. Mazziotta, M. E. Phelps
in Positron Emission Tomography and Autoradiography (Eds.: M. E.
Phelps, J. C. Mazziotta, H. R. Schelbert), Raven Press, New York,
1986, Chapter 9–11; b) B. Lꢃngstrçm, R. F. Dannals in Principle of
Nuclear Medicine, 2nd ed. (Eds.: H. N. Wagner, Z. Szabo, J. W. Bu-
chanan, W. B. Saunders), Publishing, Philadelphia, 1995, Section 1,
Chapter 11; c) J. S. Fowler, A. P. Wolf, Acc. Chem. Res. 1997, 30,
181–188.
Acknowledgements
This work was supported in part by a Grant-in-Aid for Creative Scientific
Research (No. 13NP0401) and Research & Development of Life Science
Fields responding to the needs of society, Molecular Imaging Research
Program, of the Ministry of Education, Culture, Sports, Science and
[3] a) G. Lappin, R. C. Garner, Nat. Rev. Drug Discovery 2003, 2, 233–
240; b) M. Bergstrçm, A. Grahnꢄn, B. Lꢃngstrçm, Eur. J. Clin. Phar-
12494
www.chemeurj.org
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2009, 15, 12489 – 12495

Radionuclide Incorporation in Heteroaromatic Frameworks
FULL PAPER
macol. 2003, 59, 357–366; c) The European Medicines Agency,
Evaluation of Medicines for Human Use (EMEA), Position paper
on non-clinical safety studies to support clinical trials with a single
microdose, CPMP/SWP/2599/02/Rev1, 23 June 2004; d) U. S. De-
partment of Health and Human Services, Food and Drug Adminis-
tration, Center for Drug Evaluation and Research, Guidance for In-
dustry, Investigators, and Reviewers, Exploratory IND Studies, Janu-
ary 2006; e) Japanꢁs response to microdosing study, Notification No.
0603001, 3 June 2008, Guidance for the Conduct of Microdoing
Clinical Trials, Evaluation and Licensing Division, Pharmaceutical
and Food Safety Bureau, Ministry of Health, Labour and Welfare,
Japan.
Am. Chem. Soc. 2002, 124, 6343–6348; see also the iron-catalyzed
alkenylation of organomagnesium compounds: b) G. Cahiez, H.
Avedissian, Synthesis 1998, 1199–1205; and the palladium-catalyzed
arylation with aryl chlorides: c) H. A. Chiong, O. Daugulis, Org.
Lett. 2007, 9, 1449–1451; d) G. C. Fu, Acc. Chem. Res. 2008, 41,
1555–1564. The combination of [Pd{PACHTNUTRGNEUNG(tBu)3}2]/CsF in DMF is effec-
tive for the rapid methylation of 1-alkynylstannane with methyl
iodide, which gives 1-methylalkyne.[1e]
[10] Pyridine formed by destannylation was not observed by GC analy-
sis.
[11] F. Paul, J. Patt, J. F. Hartwig, Organometallics 1995, 14, 3030–3039.
[12] Phosphine was limited to 16 equiv in the small-scale synthesis of the
PET tracers due to its limited solubility. Thus, the conditions defined
by the use of NMP as solvent and an increased ratio of the phos-
phine ligand are highly tolerant and could be applied to some im-
proved conditions in actual PET tracer synthesis, as long as such re-
quired two factors are not changed.
[4] C. M. L. West, T. Jones, P. Price, Nat. Rev. Cancer 2004, 4, 457–469.
[5] a) R. A. Ferrieri, A. P. Wolf, Radiochim. Acta 1983, 34, 69–83; b) B.
Lꢃngstrçm, G. Antoni, P. Gullberg, C. Halldin, P. Malmborg, K.
Nꢃgren, A. Rimland, H. Svꢅrd, J. Nucl. Med. 1987, 28, 1037–1040;
c) G. Antoni, T. Kihlberg, B. Lꢃngstrçm in Handbook of Radiophar-
maceuticals (Eds.: M. J. Welch, C. S. Redvanl), Wiley, New York,
2003, pp. 141–194.
[13] Trimethylstannane derivatives have sometimes been used as trap-
ping substrates because of their high reactivity.[1o–s] However, their
[6] The palladium-catalyzed cross-coupling reaction of 11C-labelled hy-
pervalent methylstannane and a heteroaromatic halide has been re-
ported. However, it would be difficult to separate the
[11C]methylated product from the large amount of remaining un-
reactive halide substrate, see ref. [1t–v].
use has serious disadvantages from a practical point of view:
1) Tin(IV) compounds of the trimethylstannyl group are extremely
toxic; 2) their reactions suffer from scrambling due to the undesired
cross-coupling reactions between 11CH3I and (CH3)3SnR, which pro-
duce highly volatile 11CH3CH3 which is quite dangerous for radio-
tracer synthesis. Such a side-reaction inevitably decreases the yield
and specific radioactivity of the desired labeled compound to a sig-
nificant extent. Based on this information, we emphasize again[1a]
the fact that tributylstannane[1a–g,i–n] or bisalkoxyborane deriva-
tives[1h] are much better precursors for PET tracer synthesis.
[14] a) R. C. Garner, Current Drug Metab. 2000, 1, 205–213; b) G.
Lappin, R. C. Garner, Anal. Bioanal. Chem. 2004, 378, 356–364.
[15] a) M. Bergstrçm, A. Grahnꢄn, B. Lꢃngstrçm, Eur. J. Clin. Pharma-
col. 2003, 59, 357–366; b) R. D. Combes, T. Berridge, J. Connelly,
M. D. Eve, R. C. Garner, S. Toon, P. Wilcox, Eur. J. Pharm. Sci.
2003, 19, 1–11; c) I. R. Wilding, J. A. Bell, Drug Discovery Today
2005, 10, 890–894.
[7] a) M. Suzuki, K. Kato, R. Noyori, Yu. Watanabe, H. Takechi, K.
Matsumura, B. Lꢃngstrçm, Y. Watanabe, Angew. Chem. 1996, 108,
366–369; Angew. Chem. Int. Ed. Engl. 1996, 35, 334–336; b) H.
Takechi, K. Matsumura, Yu. Watanabe, K. Kato, R. Noyori, M.
Suzuki, Y. Watanabe, J. Biol. Chem. 1996, 271, 5901–5906; c) M.
Bjçrkman, Y. Andersson, H. Doi, K. Kato, M. Suzuki, R. Noyori, Y.
Watanabe, B. Lꢃngstrçm, Acta Chem. Scand. 1998, 52, 635–640;
d) Yu. Watanabe, K. Matsumura, H. Takechi, K. Kato, H. Morii, M.
Bjçrkman, B. Lꢃngstrçm, R. Noyori, M. Suzuki, Y. Watanabe, J.
Neurochem. 1999, 72, 2583–2592; e) R. Noyori, Angew. Chem. 2002,
114, 2108–2123; Angew. Chem. Int. Ed. 2002, 41, 2008–2022.
[8] The synthesis of PET tracers is rather different by usual organic syn-
thetic methods. The reaction involves the trapping of an extremely
small amount of 11CH3I (approximately 100 nmol of 12CH3I) with a
large amount (mg) of a reacting substrate. Therefore, we performed
the reaction by using an excess amount of an alkenylstannane with
the methyl iodide.
[16] T. Sakamoto, F. Shiga, D. Uchiyama, Y. Kondo, H. Yamanaka, Het-
erocycles 1992, 33, 813–818.
[17] J. Sauer, D. K. Heldmann, J. Hetzenegger, J. Krauthan, H. Sichert, J.
Schuster, Eur. J. Org. Chem. 1998, 2885–2896.
[9] For the effect of NMP on the [Pd{P
G
Received: April 30, 2009
in the presence of CsF, see: a) A. F. Littke, L. Schwarz, G. C. Fu, J.
Published online: October 9, 2009
Chem. Eur. J. 2009, 15, 12489 – 12495
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
12495