Rapid methylation on carbon frameworks useful for the synthesis of 11CH3-incorporated PET tracers: Pd(0)-mediated rapid coupling of methyl iodide with an alkenyltributylstannane leading to a 1-methylalkene

Article abstract of DOI:10.1039/b515215a

The Pd(0)-mediated rapid coupling of methyl iodide with an excess of alkenyltributylstannane was examined with the aim of incorporating a short-lived ¹¹C-labeled methyl group into a biologically significant organic compound with a 1-methylalkene unit for the synthesis of a PET tracer. Four sets of reaction conditions (A-D) were used, all performed in DMF at 60 °C for 5 min. Condition B, using CH₃I/stannane/Pd₂(dba) ₃/P(o-tolyl)₃/CuCl/K₂CO₃ (1: 40: 0.5: 4-6: 2: 5), works well in almost all cases. Condition D, using CH ₃I/stannane/Pd₂(dba)₃/P(o-tolyl) ₃/CuX (X = Br, Cl, or I)/CsF (1: 40: 0.5-5: 2-20: 2-20: 5-50), shows the best results with regard to general applicability to tin substrates, affording the corresponding methylated product in >90% yield based on consumption of methyl iodide. P(t-Bu)₂Me was less effective than P(o-tolyl)₃, particularly for α,β-unsaturated carbonyl substrates. No regio- or stereoisomerization occurred under these reaction conditions. The efficiency of the protocol was demonstrated by synthesis of an ¹¹C-methylated compound. The Royal Society of Chemistry 2006.

Full text of DOI:10.1039/b515215a

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Rapid methylation on carbon frameworks useful for the synthesis of
11CH3-incorporated PET tracers: Pd(0)-mediated rapid coupling of methyl
iodide with an alkenyltributylstannane leading to a 1-methylalkene†‡
Takamitsu Hosoya,a,b Kengo Sumi,a Hisashi Doi,a Masahiro Wakaoa and Masaaki Suzuki*a,b
Received 26th October 2005, Accepted 8th December 2005
First published as an Advance Article on the web 3rd January 2006
DOI: 10.1039/b515215a
The Pd(0)-mediated rapid coupling of methyl iodide with
an excess of alkenyltributylstannane was examined with
the aim of incorporating a short-lived 11C-labeled methyl
group into a biologically significant organic compound
with a 1-methylalkene unit for the synthesis of a PET
tracer. Four sets of reaction conditions (A–D) were used, all
performed in DMF at 60 ◦C for 5 min. Condition B, using
CH3I/stannane/Pd2(dba)3/P(o-tolyl)3/CuCl/K2CO3 (1 : 40 :
0.5 : 4–6 : 2 : 5), works well in almost all cases. Condition D,
using CH3I/stannane/Pd2(dba)3/P(o-tolyl)3/CuX (X = Br, Cl,
or I)/CsF (1 : 40 : 0.5–5 : 2–20 : 2–20 : 5–50), shows the best
results with regard to general applicability to tin substrates,
affording the corresponding methylated product in >90%
yield based on consumption of methyl iodide. P(t-Bu)2Me was
less effective than P(o-tolyl)3, particularly for a,b-unsaturated
carbonyl substrates. No regio- or stereoisomerization
occurred under these reaction conditions. The efficiency
of the protocol was demonstrated by synthesis of an 11C-
methylated compound.
Among the positron-emitting radionuclides currently available,
11C is one of the most practical in terms of radioactivity,4 (half-
life, t1/2 = 20.3 min), and, most importantly, it can potentially
replace carbon atoms in all organic compounds. In addition,
various synthetically well-established precursors, such as 11CH3I,
11CO, and 11CO2, are readily available.5 In contrast to these
advantages, there is a temporal restriction in the preparation of
PET tracers incorporating 11C,5c as the total time allowed for
synthesis of a PET tracer should generally be set within two
to three radionuclide half-lives. This means that the complete
preparation of a 11C-labeled tracer must be accomplished within
40 to 60 min. Considering the time for reaction, purification, and
injection, the time allowed for the reaction in tracer synthesis
is only about 5 to 10 min, and thus the development of a
rapid reaction is crucial. To meet this necessity, we have already
established the rapid Stille-type cross-coupling6 of methyl iodide
with excess amounts of aryl- or alkynyltributylstannanes.1a–f These
Pd(0)-mediated reactions, between sp3 and sp2 or sp-hybridized
carbons, respectively, at the reaction centers, proceed efficiently
within 5 min (60 ◦C in DMF) to give the corresponding methylated
compounds in high yields.1g–k The use of an organostannane7 as a
precursor is favorable because of (1) its high tolerance to various
chemical reaction and chromatographic purification conditions,
which enables the incorporation of a radioisotope in the final step,
and (2) its extremely low polarity, which enables easy separation
of the desired product from the large amount of unreacted
stannane. Indeed, the sp3–sp2(aryl) coupling reaction was applied
successfully to the synthesis of 15R-[11C]TIC methyl ester,1b,c,f ,8
an efficient prostaglandin probe, and we achieved imaging of
a novel prostacyclin receptor (IP2)8b,d expressed in the central
nervous system in living monkey and human brains by intravenous
injection.1b,f ,8e
Some notable benefits of PET tracer synthesis using such simple
11C-methylation on carbon frameworks are as follows: (1) the
methyl group, being nonpolar and the least bulky group, has
little effect on the biological activity of the parent compound;
(2) its half-life (20.3 min) is short, making many basic research
experiments or clinical trials possible per day without any special
precautions, including treatment of radiolabeled byproducts after
the synthesis reaction; and (3) the tolerance of C–CH3 derivatives
to metabolic processes is high compared with O–CH3 and N–
CH3 derivatives. Taking these advantages into consideration, we
focused on expanding the utility of the rapid methylation to a
wider range of substrates. Here, we have investigated the rapid sp3–
sp2(alkenyl) coupling for the synthesis of new PET tracers with a
1-methylalkene structure, which is observed frequently in various
biologically significant compounds, exemplified by the retinoids
Positron emission tomography (PET) is a non-invasive in vivo
imaging method that enables distribution analysis of a radiotracer
in living systems, such as the brain, heart, and other active tissues
and organs.2 PET tracers with a short-lived positron-emitting
radionuclide as a detectable indicator are utilized to monitor
the biochemical processes and localization of target molecules in-
volved in important biofunctions and related phenomena, and are
useful tools for the diagnosis of disease and drug development.2–4
Due to the high level of radioactivity and strong permeability
of c-ray photons produced through annihilation events of such
short-lived radionuclides, to be safe enough for PET in humans,
the dosage of the radiotracer must be extremely low (femto–
attomolar level), far below its critical concentration at which
pharmacological effects can arise – a concept referred to as
microdosing.3
aDivision of Regeneration and Advanced Medical Science, Gifu University
Graduate School of Medicine, Yanagido 1-1, Gifu, 501-1194, Japan. E-mail:
suzukims@biomol.gifu-u.ac.jp
bDepartment of Biomolecular Science, Faculty of Engineering, Gifu Univer-
sity, Yanagido 1-1, Gifu, 501-1193, Japan
† Electronic supplementary information (ESI) available: General experi-
mental remarks and synthetic methods, and characterization of alkenyl-
tributylstannanes and the corresponding 1-methylalkenes. See DOI:
10.1039/b515215a
‡ Rapid methylation on carbon frameworks for PET tracer synthesis: Part
7. For Parts 1–6, see ref. 1a–f .
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(1a–c), vitamin K2 (2), squalene (3), and other isoprenoids, and
have succeeded in developing a novel general protocol applicable
to a wide variety of alkenyltributylstannanes.
3–8) markedly, with the exception of 4l (entry 12). Therefore, the
nature and quantity of the sterically congested triaryl phosphine
are important for facilitating the cross-coupling reaction.
We reviewed the reaction conditions that have been used for
standard sp2–sp2 coupling, and our observations indicated that
combined use of a Cu(I)X salt, CsF, and phosphines works very
efficiently, as shown in Table 3. The Cu(I)/F− system was first
reported by Baldwin et al. to enhance the Stille cross-coupling
of the sp2–sp2 substrate combination.12 However, their original
conditions, (Pd(PPh3)4/CuI/CsF, or PdCl2/P(t-Bu)3/CuI/CsF,
were insufficient for our purposes – the methylation of 4e
using CH3I/stannane/Pd(PPh3)4/CuI/CsF (1 : 40 : 1 : 2 : 2)
and CH3I/stannane/PdCl2/P(t-Bu)3/CuI/CsF (1 : 40 : 1 : 2 :
2 : 2) in DMF for 5 min at 60 ◦C gave 5e in yields
of only 24 and 2%, respectively. Likewise, reaction using
CH3I/stannane/Pd2(dba)3/PPh3/CuI/CsF (1 : 40 : 0.5 : 4 :
2 : 5) and CH3I/stannane/Pd2(dba)3/P(◦t-Bu)3/CuI/CsF (1 : 40 :
0.5 : 2 : 2 : 5) in DMF for 5 min at 60 C also gave 5e in yields
of only 31 and 27%, respectively. However, during the course of
the study, we found that use of the bulky phosphines P(t-Bu)2Me
or P(o-tolyl)3, instead of P(t-Bu)3, strongly promoted the reaction.
The details are summarized in Table 3. The conditions consisting
of P(t-Bu)2Me, CuBr, and CsF in 2 equiv. each with respect to
methyl iodide (Table 3, entry 1, 5th column; condition C of Table 1)
seemed the best in terms of the minimum use of the phosphine and
fluoride ions, affording the desired product 5e in 99% yield, but
the reaction was very sensitive to the quantity of the phosphine;
using 2 to 4 equiv. gave the coupling product in only 36% yield. This
limitation was overcome by changing the copper(I) salt from CuBr
to CuCl or CuI in addition to increasing the quantity of fluoride
ions. Thus, the reaction using P(t-Bu)2Me/CuCl or CuI/CsF (2 or
4 : 2 : 5) gave the coupling product in 99% yield (Table 3, entries 1
and 2, 3rd and 9th columns; modified condition C of Table 1). The
use of P(o-tolyl)3 proved to be another good choice to promote
the coupling reaction efficiently. Thus, the process using P(o-tolyl)3
(2 equiv.), CuBr (2 equiv.), and CsF (5 equiv.) afforded 5e in 99%
yield (Table 3, entry 3, 6th column; condition D in Table 1).13
Further, the increase in the quantity of this bulky phosphine
(4 equiv.) promoted the reaction almost perfectly (Table 3, entry
4, 3rd, 6th and 9th columns; modified condition D in Table 1).
Considering these results in Table 3, conditions C and D
including their slight modifications, namely CH3I/stannane/
Pd2(dba)3/P(t-Bu)Me/CuX/CsF (1 : 40 : 0.5 : 2–4 : 2 : 2–5) and
CH3I/stannane/Pd2(dba)3/P(o-tolyl)3/CuX/CsF (1 : 40 : 0.5 : 2–
4 : 2 : 5), respectively, were applied to the other tin compounds,
4a–d,f–l (Table 1). Condition D and its modification based on
the quantity of P(o-tolyl)3 worked well for all entries, giving the
coupling products in >90% yields, but condition C was poorer
than D for entries 9 and 12. This difference is presumably due to
the higher nucleophilic character of trialkylphosphines compared
with triarylphosphines,14 which tends to undergo 1,4-conjugate
addition to a,b-unsaturated carbonyl groups.15 This unfavorable
side effect was enhanced with the increase in quantity of the
phosphine ligand (Table 1, modification of condition C, entries 9
and 12), the effects of which are in marked contrast to the reactions
using P(o-tolyl)3, which favor larger amounts of the phosphine
ligand (Table 1, modification of condition D, entries 9 and 12).
From a practical viewpoint, the use of P(o-tolyl)3 is also more
convenient than P(t-Bu)2Me, because the former is a crystalline
We chose 12 non-functional and functional 1-alkenyl-
tributylstannanes, 4a–l. With a practical PET tracer synthesis
in mind, we used a 1 : 40 ratio9 of methyl iodide to tin
substrate for rapid methylation (Table 1). First, we examined
the conditions reported previously by Fu and co-workers for
sp3–sp2(vinyl) coupling.10a,b However, the methylation of 4a and
4e based on CH3I/4a or 4e/[(p-allyl)PdCl]2/P(t-Bu)2Me/Me4NF
(molar ratio 1 : 40 : 0.5 : 3 : 1.9) system in the presence of
3 A molecular sieves in THF for 5 min at 60 ◦C gave the
˚
desired products 5a and 5e in yields of only 5 and 2% (GLC),
respectively, based on the consumption of CH3I. The reaction
using Pd2(dba)3/P(t-Bu)2Me as the Pd(0) source with CH3I/4a
or 4e/Pd2(dba)3/P(t-Bu)2Me/Me4NF (1 : 40 : 0.5 : 3 : 1.9) in
THF for 5 min at 60 ◦C also gave the desired products 5a and
5e, in only 23 and 7%, respectively. Changing the solvent to DMF
slightly improved the yields, but the extent of improvement was
unsatisfactory (51 and 12%, respectively). Therefore, we applied
our conditions established previously for sp3–sp2(aryl) coupling
to the vinyl system.1a Thus, the mixture CH3I/4a/Pd2(dba)3/P(o-
tolyl)3/CuCl/K2CO3 (1 : 40 : 0.5 : 2 : 2 : 2) in DMF was heated
at 60 ◦C for 5 min (Table 1, entry 1, condition A), giving the
methylated product (E)-2-heptene (5a) as a single product in
95% yield. Likewise, the reaction of Z-isomer 4b gave (Z)-2-
heptene (5b) in 96% yield (entry 2). Thus, methylation proceeded
with complete stereocontrol. Further, we checked the reactions
for 10 additional 1-alkenyltributylstannanes, 4c–l, to confirm the
generality of condition A. The reaction of the tin substrate with
a b-styryl structure or a substituent at the a-position tended to
lower the reaction yield to 70% (entries 3–6, 8, and 12). The use of
Cs2CO3 instead of K2CO3 in condition A was effective in improving
the yields of some of these substrates with conjugated alkenes, such
as 4h, 4k, and 4l, giving the products in yields of >95% (entries
8, 11, and 12). However, methylation of b-tributylstannylstyrenes
and a-substituted non-conjugated alkenylstannanes 4c–g was still
unsatisfactory, affording the products in yields of 71–82% (entries
3–7). In these cases, increasing the quantity of added P(o-tolyl)3
up to 4–6 equiv. under condition A markedly improved the yield
of the reaction product of 4e in the presence of CuCl or CuBr but
not CuI, giving 5e in a yield of 96–98% (Table 2).11 The results
using CH3I/stannane/Pd2(dba)3/P(o-tolyl)3/CuCl/K2CO3 (1 :
40 : 0.5 : 4–6 : 2 : 5) (condition B) are summarized in Table 1. These
conditions were found to improve the reactions of 4c–h (entries
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Table 1 Rapid trapping of methyl iodide with 1-alkenyltributylstannanes
Yield of 5 (%)b
Conditionsc
Entry
1
1-Alkenyltributylstannanea
Methylated product
A
B
C
D
95
98
99
99
98
2
96
99
99
3
70
89 (88e)
90
83 (87,g 88,h 91i)
4
5
77
71
89 (89e)
96
87(90f)
99
84 (90,g 89,h 95i)
99 (99,j 99k)
6
7
71
84
91
99
98
99
99
99
8
77 (95d)
88 (93e)
95
89 (91h)
9
10
11
96
99
95
90
83 (80f)
99
85 (96h)
86 (93h)
95
94
91 (96d)
86 (90f)
12
71 (98d)
71 (72e)
54 (41f)
84 (91h)
a Stereoisomerically pure (>99 : 1) as judged from 1H-NMR spectra. b The products were detected by GLC analysis (as single products) by comparison with
authentic samples. Yields were determined by GLC analysis based on CH3I consumption using n-nonane, n-heptane, or n-decane as an internal standard,
and are an average of 2 or 3 runs. c All reactions performed in DMF at 60 ◦C for 5 min. Reaction conditions (molar ratio): A: CH3I/stannane/Pd2(dba)3/P(o-
tolyl)3/CuCl/K2CO3 (1 : 40 : 0.5 : 2 : 2 : 2); B: CH3I/stannane/Pd2(dba)3/P(o-tolyl)3/CuCl/K2CO3 (1 : 40 : 0.5 : 4 : 2 : 5); C: CH3I/stannane/Pd2(dba)3/P(t-
Bu)2Me/CuBr/CsF (1 : 40 : 0.5 : 2 : 2 : 2); D: CH3I/stannane/Pd2(dba)3/P(o-tolyl)3/CuBr/CsF (1 : 40 : 0.5 : 2 : 2 : 5). d Cs2CO3 was used instead of
K2CO3. e CH3I/stannane/Pd2(dba)3/P(o-tolyl)3/CuCl/K2CO3 (1 : 40 : 0.5 : 6 : 2 : 5). f CH3I/stannane/Pd2(dba)3/P(t-Bu)2Me/CuCl/CsF (1 : 40 : 0.5 :
4 : 2 : 5). g CH3I/stannane/Pd2(dba)3/P(o-tolyl)3/CuCl/CsF (1 : 40 : 0.5 : 4 : 2 : 5). h CH3I/stannane/Pd2(dba)3/P(o-tolyl)3/CuBr/CsF (1 : 40 : 0.5 : 4 :
2 : 5). i CH3I/stannane/Pd2(dba)3/P(o-tolyl)3/CuI/CsF (1 : 40 : 0.5 : 4 : 2 : 5). j CH3I/stannane/Pd2(dba)3/P(o-tolyl)3/CuBr/CsF (1 : 40 : 2.5 : 10 : 10 :
25). k CH3I/stannane/Pd2(dba)3/P(o-tolyl)3/CuBr/CsF (1 : 40 : 5 : 20 : 20 : 50).
compound that is stable in air, while the latter is an air-sensitive
oily material, which necessitates handling in a glove-box under
an inert gas. Thus, considering the wide range of applicable tin
substrates and the ease of use of triarylphosphines, condition D
should be better than C for actual PET tracer synthesis.
phosphines (e.g., cone angle 194◦ (P(o-tolyl)3) vs. 145◦ (PPh3)),17
seems to be important to enhance the sp3–sp2(alkenyl) coupling
efficiency under any of the conditions, similar to the case of
sp3–sp2(phenyl) coupling.1a,c The trialkylphosphines P(t-Bu)2Me
and P(t-Bu)3 have markedly higher r-electron-donating ability
than aryl-substituted phosphines (e.g., pKa 11.4 (P(t-Bu)3) vs.
3.1 (P(o-tolyl)3, 2.7 (PPh3)).14 In these trialkylphosphines, the
The use of a coordinatively unsaturated Pd(0) complex, such
as Pd[P(o-tolyl)3]2,16 and therefore the use of sterically bulky
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a
Table 2 Rapid trapping of methyl iodide with tributyl(cyclohexen-1-yl)stannane (4e) to give 5e, using K2CO3
Additives (equiv.)
CuCl (2) + K2CO3 (y)
CuBr (2) + K2CO3 (y)
CuI (2) + K2CO3 (y)
Entry
Phosphine (x equiv.)
y = 0
y = 2
y = 5
y = 0
y = 2
y = 5
y = 0
y = 2
y = 5
1
2
3
P(o-tolyl)3 (x = 2)
P(o-tolyl)3 (x = 4)
P(o-tolyl)3 (x = 6)
—
—
—
71
76
79
84
96
98
—
—
—
56
59
61
82
96
98
—
—
—
21
23
27
51
50
63
a Yields (%) of 5e determined by GLC analysis based on CH3I consumption using n-nonane as an internal standard. Data are the averages of two runs.
Reaction conditions: CH3I/4e/Pd2(dba)3/PR3/CuX/K2CO3 (molar ratio, 1 : 40 : 0.5 : x : 2 : y) in DMF, 60 ◦C, 5 min.
Table 3 Rapid trapping of methyl iodide with tributyl(cyclohexen-1-yl)stannane (4e) to give 5e, using CsF a
Additives (equiv.)
CuCl (2) + CsF (y)
CuBr (2) + CsF (y)
CuI (2) + CsF (y)
Entry
Phosphine (x equiv.)
y = 0
y = 2
y = 5
y = 0
y = 2
y = 5
y = 0
y = 2
y = 5
1
2
3
4
P(t-Bu)2Me (x = 2)
P(t-Bu)2Me (x = 4)
P(o-tolyl)3 (x = 2)
P(o-tolyl)3 (x = 4)
—
—
—
47b
43b
—
99
99
96
99
40b
—
99
36
66b
—
99
33
99
99
—
—
—
18b
27b
—
99
99
38b
99
—
31b
—
—
86b
59b
a Yields (%) of 5e determined by GLC analysis based on CH3I consumption using n-nonane as an internal standard. Data are the averages of two runs
unless otherwise noted. Reaction conditions: CH3I/4e/Pd2(dba)3/PR3/CuX/CsF (molar ratio, 1 : 40 : 0.5 : x : 2 : y) in DMF, 60 ◦C, 5 min. b Data from a
single run.
property of an alkyl ligand on the phosphine atom influences
the coupling efficiency to a great extent, as indicated by the
large difference between the rapid methylation of alkynylstannanes
(sp3–sp coupling)1e and the rapid sp3–sp2(alkenyl) coupling in
this study. However, the role of an alkyl substituent for such
marked discrimination remains unclear. The high efficiency of the
combined use of Cu(I)X and CsF is considered to be due to the
synergic effect of the generation of a more reactive organocopper
species through Sn/Cu transmetallation18,19 and the removal of
(n-Bu)3SnX (X = Cl, Br, or I) by the formation of insoluble
(n-Bu)3SnF to shift the equilibrium to the alkenylcopper.12 In a
similar manner, the efficiency of the combination of Cu(I)X and
K2CO3, as employed in conditions A or B in Table 1, could be
explained by another synergic effect of Sn/Cu transmetallation
in Pd/Cu/F additives with respect to methyl iodide, promising
that the combined Pd/Cu/F system would be applicable to
actual PET studies.9 From our experience of PET studies, heating
the mixture of methyl iodide/stannane/Pd(0)/CuX/F− under
continuous operations with (1) prior mixing of [11C]methyl iodide
and Pd(0), and then (2) mixing the resulting solution with a
stannane, copper(I) salt, and fluoride salt, was expected to be
better in terms of high reproducibility.1c,f Using this method, the
reaction of 4e using CH3I/Pd2(dba)3/P(o-tolyl)3 (1 : 2.5 : 10) and
4e/CuBr/CsF (40 : 10 : 25), gave 5e in 99% yield. Accordingly, the
actual synthesis of the PET tracer was conducted under conditions
B and D with continuous stepwise mixing using [11C]CH3I and the
stannane 4l to give [11C]-5l in a high radiochemical yield of 85%
(HPLC analytical yield) for both conditions (Scheme 1).21
and formation of the stable bis(tributylstannyl)carbonate, [(n-
20
Bu)3SnO]2C O. Thus, the synergic effect concept12 and the
=
introduction of a bulky triarylphosphine allowed realization of
an efficient general protocol for rapid sp3–sp2(alkenyl) Stille
coupling reaction potentially useful for PET tracer synthesis. We
also investigated the reactions using excess Pd/Cu/F additives
for methyl iodide (5- and 10-fold), CH3I/4e/Pd2(dba)3/P(o-
tolyl)3/CuBr/CsF (1 : 40 : 2.5 : 10 : 10 : 25 and 1 : 40 : 5 : 20 : 20 :
50), giving 5e in the same 99% yield (Table 1, modified condition
D, entry 5). Thus, the reaction is not influenced by the increase
Scheme 1 Synthesis of [11C]-5l.
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In summary, we have developed an efficient protocol for
the rapid trapping of methyl iodide with an excess of an
alkenyltributylstannane, by rapid sp3–sp2(alkenyl) coupling.22 This
method provides a firm chemical basis for the synthesis of short-
lived 11CH3-labeled PET tracers with a 1-methylalkene unit.
Retinoids (1) and their artificial derivatives are involved in
important biological signal pathways as agonists targeting nuclear
RAR/RXR receptors23 and the prototypical G protein-coupled
receptor, rhodopsin.24 Squalene (3), a triterpenoid containing six
isoprene units, is a major metabolite derived from mevalonic acid
and is a key intermediate in the production of important bioactive
steroids. PET studies using the corresponding 11C-labeled tracers
would contribute to the possibility of in vivo biomolecular studies.
The synthesis of the above-mentioned PET tracers and their use
in molecular imaging will be reported in due course.
K. Na˚gren, A. Rimland and H. Sva¨rd, J. Nucl. Med., 1987, 28, 1037–
1040; (c) G. Antoni, T. Kihlberg and B. La˚ngstro¨m, in: Handbook of
Radiopharmaceuticals, ed. M. J. Welch and C. S. Redvanly, Wiley, West
Sussex, 2003, pp. 141–194.
6 (a) J. K. Stille, Angew. Chem., Int. Ed. Engl., 1986, 25, 508–524; (b) V.
Farina, V. Krishnamurthy and W. J. Scott, Org. React., 1997, 50, 1–657;
(c) P. Espinet and A. M. Echavarren, Angew. Chem., Int. Ed., 2004, 43,
4704–4734.
7 For reviews on organostannanes, see: A. G. Davies, Organotin Chem-
istry (2nd edn), Wiley-VCH, Weinheim, 2004.
8 (a) M. Suzuki, K. Kato, R. Noyori, Yu. Watanabe, H. Takechi, K.
Matsumura, B. La˚ngstro¨m and Y. Watanabe, Angew. Chem., Int. Ed.
Engl., 1996, 35, 334–336; (b) H. Takechi, K. Matsumura, Yu. Watanabe,
K. Kato, R. Noyori, M. Suzuki and Y. Watanabe, J. Biol. Chem., 1996,
271, 5901–5906; (c) M. Bjo¨rkman, Y. Andersson, H. Doi, K. Kato, M.
Suzuki, R. Noyori, Y. Watanabe and B. La˚ngstro¨m, Acta Chem. Scand.,
1998, 52, 635–640; (d) Yu. Watanabe, K. Matsumura, H. Takechi, K.
Kato, H. Morii, M. Bjo¨rkman, B. La˚ngstro¨m, R. Noyori, M. Suzuki
and Y. Watanabe, J. Neurochem., 1999, 72, 2583–2592; (e) R. Noyori,
Angew. Chem., Int. Ed., 2002, 41, 2008–2022.
9 The synthesis of PET tracers is rather different from standard organic
syntheses. The reaction involves the trapping of an extremely small
amount of 11CH3I (approximately 100 nmol level containing 12CH3I)
with a large amount (mg) of reacting substrate. Therefore, we set up
the reaction using an excess of alkenylstannane, with respect to methyl
iodide.
10 (a) K. Menzel and G. C. Fu, J. Am. Chem. Soc., 2003, 125, 3718–3719;
(b) H. Tang, K. Menzel and G. C. Fu, Angew. Chem., Int. Ed., 2003,
42, 5079–5082.
Acknowledgements
This work was supported in part by a Grant-in-Aid for Creative
Scientific Research (No. 13NP0401) of the Ministry of Education,
Culture, Sports, Science, and Technology (MEXT) of Japan. M.W.
thanks JSPS. Incorporation of 11C was performed in a PET
laboratory at Hamamatsu photonics K.K.
11 The increased amount of P(o-tolyl)3 was not effective when Cs2CO3
was used instead of K2CO3, as confirmed using 4e.
12 S. P. H. Mee, V. Lee and J. E. Baldwin, Angew. Chem., Int. Ed., 2004,
43, 1132–1136.
Notes and references
13 Typical procedure (Table 1, entry 5, condition D): In a dry Schlenk tube
(10 mL), Pd2(dba)3 (4.6 mg, 5.0 lmol), P(o-tolyl)3 (6.1 mg, 20 lmol),
CuBr (2.9 mg, 20 lmol), and CsF (7.6 mg, 50 lmol) were placed
under Ar. After addition of DMF (500 lL), the mixture was stirred
for 5 min at room temperature followed by successive additions of
solutions of stannane 4e (148 mg, 400 lmol) in DMF (500 lL) and
methyl iodide (12.5 lL, 0.80 M DMF solution, 10 lmol). After stirring
at 60 ◦C for 5 min, the mixture was cooled rapidly in an ice bath.
After addition of diethyl ether (1 mL), the mixture was loaded onto
a short column of silica gel (0.5 g) and then eluted with diethyl ether
(ca. 1 mL), followed by addition of n-nonane (50 lL, 0.10 M DMF
solution, 5.0 lmol) as an internal standard. The resulting solution
was analyzed by GLC (Shimadzu GC-2010 instrument equipped with
a flame ionization detector; capillary column: GL Science TC-1701,
60 m × 0.25 mm i.d., film thickness of stationary phase = df = 0.25 lm;
carrier gas: He; flow rate: 0.4 mL min−1; injector temperature: 280 ◦C;
dete◦ctor temperature: 280 ◦C; col◦umn temperature: initial 80 ◦C, final
100 C; temperature gradient: +5 C min−1, from 10 to 14 min); yield of
1-methylcyclohexene (5e): 99% based on starting CH3I; retention time:
12.2 min (cf. n-nonane: 16.1 min).
14 T. Allman and R. G. Goel, Can. J. Chem., 1982, 60, 716–722.
15 (a) D. A. White and M. M. Baizer, Tetrahedron Lett., 1973, 3597–3600;
(b) E. Go´mez-Bengoa, J. M. Cuerva, C. Mateo and A. M. Echavarren,
J. Am. Chem. Soc., 1996, 118, 8553–8565; (c) D. H. Valentine, Jr. and
J. H. Hillhouse, Synthesis, 2003, 317–334; (d) D. Basavaiah, A. J. Rao
and T. Satyanarayana, Chem. Rev., 2003, 103, 811–891.
16 (a) S. Enomoto, H. Wada, S. Nishida, Y. Mukaida, M. Yanaka, H.
Takita, Jpn. Kokai Tokkyo Koho, JP 53144552, 1978; (b) F. Paul, J. Patt
and J. F. Hartwig, J. Am. Chem. Soc., 1994, 116, 5969–5970; (c) F. Paul,
J. Patt and J. F. Hartwig, Organometallics, 1995, 14, 3030–3039.
17 C. A. Tolman, Chem. Rev., 1977, 77, 313–348.
1 (a) M. Suzuki, H. Doi, M. Bjo¨rkman, Y. Andersson, B. La˚ngstro¨m,
Y. Watanabe and R. Noyori, Chem.–Eur. J., 1997, 3, 2039–2042;
(b) M. Suzuki, R. Noyori, B. La˚ngstro¨m and Y. Watanabe, Bull.
Chem. Soc. Jpn., 2000, 73, 1053–1070; (c) M. Suzuki, H. Doi, K.
Kato, M. Bjo¨rkman, B. La˚ngstro¨m, Y. Watanabe and R. Noyori,
Tetrahedron, 2000, 56, 8263–8273; (d) M. Bjo¨rkman, H. Doi, B. Resul,
M. Suzuki, R. Noyori, Y. Watanabe and B. La˚ngstro¨m, J. Labelled
Compd. Radiopharm., 2000, 43, 1327–1334; (e) T. Hosoya, M. Wakao,
Y. Kondo, H. Doi and M. Suzuki, Org. Biomol. Chem., 2004, 2, 24–27;
(f) M. Suzuki, H. Doi, T. Hosoya, B. La˚ngstro¨m and Y. Watanabe,
Trends Anal. Chem., 2004, 23, 595–607. See also the applications by
other groups based on our method: [p-11C-methyl]MADAM: (g) J.
Tarkiainen, J. Vercouillie, P. Emond, J. Sandell, J. Hiltunen, Y. Frangin,
D. Guilloteau and C. Halldin, J. Labelled Compd. Radiopharm., 2001,
44, 1013–1023; [11C]toluene: (h) M. Gerasimov, J. Logan, R. A. Ferrieri,
R. D. Muller, D. Alexoff and S. L. Dewey, Nucl. Med. Biol., 2002,
29, 607–612, and references therein; 5-[11C]methyl-6-nitroquipazine:
(i) J. Sandell, M. Yu, P. Emond, L. Garreau, S. Chalon, K. Na˚gren,
D. Guilloteau and C. Halldin, Bioorg. Med. Chem. Lett., 2002, 12,
3611–3613, and references therein (j) J. Madsen, P. Merachtsaki, P.
Davoodpour, M. Bergstro¨m, B. La˚ngstro¨m, K. Andersen, C. Thomsen,
L. Martiny and G. M. Knudsen, Bioorg. Med. Chem., 2003, 11, 3447–
3456; 5-11C-methyl-A-85380: (k) Y. Iida, M. Ogawa, M. Ueda, A.
Tominaga, H. Kawashima, Y. Magata, S. Nishiyama, H. Tsukada,
T. Mukai and H. Saji, J. Nucl. Med., 2004, 45, 878–884; (3-ethyl-
2-[11C]methyl-6-quinolinyl)(cis-4-methoxycyclohexyl)methanone: (l) Y.
Huang, R. Narendran, F. Bischoff, N. Guo, Z. Zhu, S.-A. Bae, A. S.
Lesage and M. Laruelle, J. Med. Chem., 2005, 48, 5096–5099.
2 (a) J. S. Fowler, A. P. Wolf, J. R. Barrio, J. C. Mazziotta and M. E.
Phelps, in: Positron Emission Tomography and Autoradiography, ed.
M. E. Phelps, J. C. Mazziotta and H. R. Schelbert, Raven Press,
New York, 1986, ch. 9–11; (b) B. La˚ngstro¨m and R. F. Dannals, in:
Principles of Nuclear Medicine (2nd edn), ed. H. N. Wagner, Z. Szabo
and J. W. Buchanan, W. B. Saunders Publishing, Philadelphia, 1995,
sect. 1, ch. 11; (c) J. S. Fowler and A. P. Wolf, Acc. Chem. Res., 1997,
30, 181–188.
3 (a) M. Bergstro¨m, A. Grahne´n and B. La˚ngstro¨m, Eur. J. Clin.
Pharmacol., 2003, 59, 357–366; (b) G. Lappin and R. C. Garner, Nat.
Rev. Drug Discovery, 2003, 2, 233–240.
4 C. M. L. West, T. Jones and P. Price, Nat. Rev. Cancer, 2004, 4, 457–469.
5 (a) R. A. Ferrieri and A. P. Wolf, Radiochim. Acta, 1983, 34, 69–83;
(b) B. La˚ngstro¨m, G. Antoni, P. Gullberg, C. Halldin, P. Malmborg,
18 (a) V. Farina, S. Kapadia, B. Krishnan, C. Wang and L. S. Liebeskind,
J. Org. Chem., 1994, 59, 5905–5911; (b) X. Han, B. M. Stoltz and E. J.
Corey, J. Am. Chem. Soc., 1999, 121, 7600–7605; (c) A. L. Casado and
P. Espinet, Organometallics, 2003, 22, 1305–1309.
´
19 A. Garc´ıa Mart´ınez, J. Os´ıo Barcina, M. R. Colorado Heras and A. De
Frensno Cerezo, Organometallics, 2001, 20, 1020–1023.
20 (a) R. E. Maleczka, Jr., W. P. Gallagher and I. Terstiege, J. Am. Chem.
Soc., 2000, 122, 384–385; (b) W. P. Gallagher, I. Terstiege and R. E.
Maleczka, Jr., J. Am. Chem. Soc., 2001, 123, 3194–3204.
21 PET tracer synthesis (Table 1, entry 12, condition D): [11C]Methyl
iodide was prepared from [11C]CO2 by reduction with LiAlH4, followed
414 | Org. Biomol. Chem., 2006, 4, 410–415
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by HI treatment according to the established method. [11C]Methyl
iodide was trapped in a solution of Pd2(dba)3 (1.8 mg, 1.9 lmol) and
P(o-tolyl)3 (2.4 mg, 7.9 lmol) in DMF (270 lL) at room temperature.
The solution was transferred to a vial containing stannane 4l (2.1 mg,
4.5 lmol), CuBr (2.9 mg, 20 lmol), and CsF (7.6 mg, 50 lmol) in
DMF (60 lL), washed with DMF (40 lL), and the resulting mixture
was heated at 65 ◦C for 5 min. Salts and palladium residues in
the reaction mixture were removed by solid-phase extraction, and
washed with DMF–H2O (1 : 5, 0.3 mL). The combined eluates were
analyzed by HPLC. Radiochemical yield of [11C]-5l: 85%; retention
time: 9.9 min. (GL Science inertsil ODS3, 5 lm, 150 × 4.6 mm i.d.;
mobile phase: CH3CN–H2O 57 : 43; flow rate: 1.5 mL min−1; detection:
230 nm).
22 The reaction of CH3I with an equimolar amount of 4a (30 lmol each)
using a catalytic amount of Pd(0), Pd2(dba)3/P(o-tolyl)3/CuCl/CsF
(0.05 : 0.8 : 2 : 5), in DMF (3 mL) at 80 ◦C for 5 min afforded 5a in 72%
yield. Thus, methylation is also useful for introduction of 13CH3, CD3,
and long-lived 14CH3 into organic frameworks to synthesize molecular
probes for metabolic studies. In particular, the synthesis of a 14C-
enriched methylated probe has attracted a great deal of attention in
view of drug microdosing in humans and the subsequent long-term
analysis of metabolites by accelerator mass spectrometry (AMS) – see
ref. 3b.
23 H. Kagechika, Curr. Med. Chem., 2002, 9, 591–608.
24 Y. Fujimoto, N. Fishkin, G. Pescitelli, J. Decatur, N. Berova and K.
Nakanishi, J. Am. Chem. Soc., 2002, 124, 7294–7303.
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The Royal Society of Chemistry 2006
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