Rapid methylation of terminal acetylenes by the Stille coupling of methyl iodide with alkynyltributylstannanes: A general protocol potentially useful for the synthesis of short-lived 11CH3-labeled PET tracers with a 1-propynyl group

Article abstract of DOI:10.1039/b311532a

The Pd(0)-mediated rapid coupling (trapping) reaction of methyl iodide with an excess amount of alkynyltributyl-stannane has been developed with the aim to incorporate a short-lived ¹¹C-labeled methyl group into biologically active organic compounds with a 1-propynyl structural unit.

Full text of DOI:10.1039/b311532a

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Rapid methylation of terminal acetylenes by the Stille coupling of
methyl iodide with alkynyltributylstannanes: a general protocol
11
potentially useful for the synthesis of short-lived CH3-labeled
PET tracers with a 1-propynyl group†
Takamitsu Hosoya,a,b Masahiro Wakao,a Yurie Kondo,b Hisashi Doia and Masaaki Suzuki*a,b
a Division of Regeneration and Advanced Medical Science,
Gifu University Graduate School of Medicine, Yanagido 1-1, Gifu 501-1193, Japan.
E-mail: suzukims@biomol.gifu-u.ac.jp
b Department of Biomolecular Science, Faculty of Engineering, Gifu University, Yanagido 1-1,
Gifu 501-1193, Japan
Received 22nd September 2003, Accepted 30th October 2003
First published as an Advance Article on the web 11th November 2003
The Pd(0)-mediated rapid coupling (trapping) reaction of
methyl iodide with an excess amount of alkynyltributyl-
stannane has been developed with the aim to incorporate
a short-lived 11C-labeled methyl group into biologically
active organic compounds with a 1-propynyl structural
unit.
of the coupling reaction,15,16 and (3) the extremely low polarity
of tributyl-substituted alkynylstannanes makes for easy
chromatographic isolation of the desired 11C-incorporated
coupling product from the remaining excess amount of tin
substrate after the reaction.13,16 Although innumerable reports
have described,14,17 the reports of Stille reactions between sp3/sp
carbons are quite limited,18,19 and, to our surprise, Stille reac-
tions including methyl iodide remain unexplored. Described
herein is a general protocol which provides a firm chemical
basis for the synthesis of a 11CH3-incorporated PET tracer with
a 1-propynyl moiety in the structure.
Positron emission tomography (PET) is a particularly powerful,
noninvasive method for the molecular imaging of living systems
such as the brain, heart, and other active organs.1 In the PET
study, a specific organic PET tracer is efficiently used as a
molecular probe to monitor the biochemical processes and
localization of a target molecule involved in important bio-
functions and related phenomena. The need for the develop-
ment of new PET tracers has grown with the increase in the
use of this technique in in vivo biochemistry and medicine.1
In light of this need, we have recently developed the rapid
Stille cross-coupling (5 min, 60 ЊC in DMF) of methyl iodide
with aryltributylstannanes possessing sp3 and sp2 carbons,
respectively, at the reaction centers2 and applied it successfully
to the synthesis of a short-lived, 11C-incorporated PET tracer
(t1/2 = 20.3 min), 15R-[11C]TIC methyl ester,3 an efficient prosta-
glandin probe, using 11CH3I,4 a synthetically established
precursor, to image a novel prostacyclin (PGI2) receptor (IP2)
present in the central nervous system in living monkey and
human brains.3,5
Non-functional tributyl-1-hexynylstannane (2) was used as a
trapping agent to establish the standard reaction conditions.
The reaction conditions were fixed at 60 ЊC in DMF2a for 5 min
with the use of a large excess (40-fold) of the stannyl substrate,
keeping the actual PET tracer synthesis in mind.13 Initially,
some Pd(0)-complexes often utilized in the Stille reaction14
(Table 1, entries 1–4), and our conditions previously established
in the rapid methylation of aryl substrates2 (entry 6) were
investigated, resulting in the desired 2-heptyne (3) in yields
between 11 and 61%. In the course of further studies, we noted
that the steric and electronic properties of phosphine ligands
influenced the yield of the coupling product. Among the
ligands examined, tri-tert-butylphosphine (PtBu3)20 facilitated
the reaction the most, resulting in a 72% yield (entry 9). The
reaction was further improved to give an 81% yield (entry 10)
by the direct use of bis(tri-tert-butylphosphine)palladium(0)
(Pd(PtBu3)2), a commercially available complex,21 instead of
generating it in situ by mixing Pd2(dba)3 and PtBu3. Further, the
addition of CsF or KF facilitated an even higher reaction yield
(entries 14 and 15, respectively), while the addition of LiCl or
TBAF retarded the reaction (entries 12 and 13, respectively).22
Thus, as can be seen in Table 1, the highest yield (95%) was
generated by the reaction in the presence of KF (entry 15).‡
Our next interest has been directed at the rapid introduction
of a 11CH3 group to an alkyne terminal to develop new PET
tracers of biologically significant molecules with a 1-propynyl
structure. Examples of molecules with this structure include
iloprost (1) (a stable PGI2 analogue specific for the PGI2 recep-
tor, IP1,3 in peripheral systems used as potential therapeutic
agent),6,7 beraprost (a PGI2 analogue possessing the same ω
side-chain as 1),8 2-(1-propnyl)estradiol (a tubulin polymeriz-
ation inhibitor),9 RU 28362 (a glucocorticoid receptor agon-
ist),10 E3620 (a 5-HT3 receptor antagonist/5-HT4 receptor
agonist),11 2Ј-deoxy-5-(1-propynyl)uridine (an antiviral
agent),12 and several others. Among the numerous methylation
methods available,13 the Stille coupling14 using an alkynyltri-
butylstannane as a trapping substrate of methyl iodide is ideal
because: (1) the usual reaction conditions are compatible with a
broad range of functional groups,13 (2) alkynylstannanes are
tolerant enough of various reaction, workup, and chromato-
graphic conditions to be transformed intact to the actual stage
† Electronic supplementary information (ESI) available: general
experimental remarks and synthetic methods and characterization
of tributylalkynylstannanes and the corresponding methylacetylenes.
See http://www.rsc.org/suppdata/ob/b3/b311532a/
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 2 4 – 2 7
T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 4
24

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Table 1 Rapid coupling of methyl iodide with tributyl-1-hexynylstannane (2)
Entry
Pd catalyst (µmol)
Additive(s) (µmol)
Yield of 3a (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
Pd(PPh3)4 (10)
Pd2(dba)3 (5)
Pd2(dba)3 (5)
Pd2(dba)3 (5)
Pd2(dba)3 (5)
Pd2(dba)3 (5)
Pd2(dba)3 (5)
Pd2(dba)3 (5)
Pd2(dba)3 (5)
Pd(PtBu3)2 (10)
Pd(PtBu3)2 (10)
Pd(PtBu3)2 (10)
Pd(PtBu3)2 (10)
Pd(PtBu3)2 (10)
Pd(PtBu3)2 (10)
Pd2(dba)3 (5)
—
PPh3 (20)
27
11
30
61
20
43
49
67
72
81
45
27
15
92
95
10
P(2-furyl)3 (20)
AsPh3 (20)
P(o-tolyl)3 (20)
P(o-tolyl)3 (20), K2CO3 (20), CuCl (20)
P(cyclohexyl)3 (20)
PMe(tBu)2 (20)
PtBu3 (20)
—
K2CO3 (20), CuCl (20)
LiCl (20)
TBAF (20)
CsF (20)
KF (20)
PMe(tBu)2 (20), CsF (20)
a Determined by GLC analysis based on CH3I consumption.
Interestingly, the addition of CsF to the Pd2(dba)3/PMe(tBu)2
system19,20 led to an unexpectedly poor result (entry 16).
The reaction of methyl iodide and a stoichiometric amount
of 2 at 60 ЊC for 5 min also proceeded under catalytic condi-
tions (CH3I/2/Pd(PtBu3)2/KF = 1/1/0.1/1 and 1/1/0.02/1) to give
96 and 91% of 3, respectively, strengthening the utility of the
coupling reaction from the synthetic point of view.23
(3)
(4)
The reaction most likely proceeds by the mechanism pro-
posed in eqns. (1)–(4), where M = Bu3Sn or Bu3SnFϪ. First,
methyl iodide undergoes oxidative addition with Pd(PtBu3)2 to
generate methyl–Pd() iodide 4 or 4Ј (eqn. (1)).24,25 These Pd()
complexes may then react directly with alkynylstannane 5 or
more favorably with the hypervalent stannate 6, formed in situ
by the addition of a fluoride ion source (eqn. (2)), to afford the
(alkynyl)(methyl)Pd() complex 7 (eqn. (3)). Finally, the desired
methylalkyne 8 is formed by reductive elimination of the Pd()
complex 7 (eqn. (4)).13f Here, we assume that the bulkiness
(cone angle 182Њ)26 and the strong σ-electron-donating ability
(pKa = 11.4)27 of PtBu3 would contribute to the generation of
highly reactive, coordinatively unsaturated Pd(0) and Pd()
intermediates, and also to the stabilization of the palladium
complexes to avoid metal precipitation at high temperatures
throughout the reaction cycle. We further assume that the
extraordinarily high basicity of PtBu3 would also serve not only
to increase the nucleophilicity for the oxidative addition step
(eqn. (1)), but also to facilitate the dissociation of iodide to
stabilize the transition state structure for the substitution
step (eqn. (3)). In addition, the effect of fluoride ion can be
explained by its facilitation of the formation of the hypervalent
stannyl complex 6, whose nucleophilic C–Sn bond is more polar
than that in 5 (eqn. (2)).20,28 The choice of a proper counter
cation in the formation of the stannate complex 6 is also
important to promote the reaction effectively, although the role
of the cationic species remains unclear.
The best protocol (entry 15 in Table 1)‡ allows for the con-
trolled methylation of a variety of alkynyltributylstannanes con-
sisting of oxygen-based functional groups such as ethers, hydroxy
groups, and ester groups. Compounds 9–14 are examples in our
studies that were generated in 80, 89, 91, 88, 96 and 82% yields,
respectively.29 The reaction was also applicable to the stannyl
precursors 15 and 16, which are the substrates with steroid and
deoxyribonucleoside frameworks, giving methylated compounds
17 and 1812 in 87 and 74%29 yields, respectively.
Finally, we demonstrated the trapping protocol of methyl
iodide with a five-fold amount of stannyl precursor 19 leading
to iloprost methyl ester (20) in 81% yield (based on the con-
sumption of CH3I) (Scheme 1).§ This ester 20 undergoes rapid
enzymatic hydrolysis in the vital system to generate the free acid
1 as the bioactive form,3 and, therefore, the corresponding
[11C]iloprost methyl ester can be used as a PET tracer.30
Thus, we have succeeded in elaborating the rapid methylation
of terminal acetylenes under mild conditions, which is poten-
tially useful for the synthesis of short-lived 11CH3-labeled PET
tracers to promote in vivo molecular science for medical
purposes. The synthesis of actual PET tracers and their use for
molecular imaging will be reported in due course.
(1)
(2)
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. and H. D. are thankful for JSPS fellowships.
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 2 4 – 2 7
25

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Notes and references
‡ Trapping reaction of methyl iodide with an excess amount of tributyl-1-
hexynylstannane (2) leading to 2-heptyne (3): In a dry Schlenk tube
(10 mL), bis(tri-tert-butylphosphine)palladium(0) (5.1 mg, 10 µmol)
and potassium fluoride (1.2 mg, 20 µmol) were placed under Ar. After
the addition of DMF (950 µL), the mixture was stirred for 5 min at
room temperature followed by successive additions of a methyl iodide
solution (50 µL, 0.20 M, 10 µmol) in DMF and a stannane 2 (148 mg,
400 µmol). After stirring at 60 ЊC for 5 min, the mixture was rapidly
cooled in an ice bath, followed by the addition of n-nonane (50 µL, 0.10
M diethyl ether solution, 5.0 µmol) as an internal standard, and diethyl
ether (1 mL). The mixture was loaded onto a short column of silica-gel
(1.0 g) and then eluted with diethyl ether (ca. 1 mL). The combined
eluates were analyzed by GLC (Shimadzu GC-14B instrument
equipped with a flame ionization detector; capillary column: GL
Science TC-5, 60 m × 0.25 mm i.d., df = 0.25 µm; carrier gas: He; flow
rate: 0.5 mL minϪ1; injector temperature: 280 ЊC; detector temperature:
280 ЊC; column temperature: initial 70 ЊC, final 100 ЊC; temperature
rising rate: 5 ЊC minϪ1, from 10 to 16 min): yield of 2-heptyne (3): 95%
based on starting CH3I; retention time: 12.6 min (cf. n-nonane: 17.9
min).
§ Application to the synthesis of iloprost methyl ester (20): In a
dry Schlenk tube (10 mL), bis(tri-tert-butylphosphine)palladium(0)
(0.8 mg, 1.6 µmol) and potassium fluoride (0.2 mg, 3.2 µmol) were
placed under Ar. After the addition of DMF (400 µL), the mixture was
stirred for 5 min at room temperature followed by successive additions
of a methyl iodide solution (32 µL, 50 mM, 1.6 µmol) in DMF and a
solution of stannane 19 (5.1 mg, 8.0 µmol) in DMF (400 µL). After
stirring at 60 ЊC for 5 min, the mixture was rapidly cooled in an ice bath,
followed by the removal of insoluble materials by filtration through a
plug of cotton. The filtrate was azeotropically concentrated with tolu-
ene under reduced pressure, and the residual material was filtered
through a short column of silica-gel (1.0 g, eluted with n-hexane–
ethyl acetate = 1 : 1). Anisole (10 µL, 0.20 M CH3CN solution,
2.0 µmol) was added to the combined eluates as an internal standard,
and the mixture was then analyzed by reversed-phase HPLC (Mightysil
RP-18 GP column: Kanto Chemical, 150 × 4.6 mm i.d.; eluted by
CH3CN/H2O = 45/55; flow rate 1.0 mL minϪ1; column oven temperature
40 ЊC; detected by UV at 203 nm); yield of iloprost methyl ester (20):
81% based on starting CH3I; retention time: 21.1 and 22.6 min
(16R- and 16S-epimers, respectively) (cf. anisole: 7.4 min).
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O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 2 4 – 2 7
26

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13 The reaction is usually conducted using >10Ϫ6 g of 11CH3I and 10Ϫ3
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29 In these cases, the stepwise procedure, which consists of the addition
of an alkynylstannane after mixing the palladium complex and
methyl iodide in DMF for 1 min at 60 ЊC, was employed. The total
synthetic time was fixed to 5 min. See also ref. 2b. Yields were deter-
mined by GLC or HPLC analysis based on CH3I consumption. In
the actual PET tracer synthesis, the reaction mixture is subjected
directly to reversed-phase HPLC purification (CH3CN–H2O solvent
system) to afford the desired radiolabeled compound in nanomole
scale, which is used immediately.
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15 It was found that alkynylboronic acids or alkynylboronates used
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30 Successful synthesis of [11C]iloprost methyl ester will be reported
independently.
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 2 4 – 2 7
27