Methyl transfer reaction from monomethyltin reagent under palladium(0) catalysis: A versatile method for labelling with carbon-11

Article abstract of DOI:10.1039/b510286c

The ¹¹C-monomethylstannate prepared from [¹¹C]-methyl iodide and Lappert's stannylene, was subject to a palladium-mediated cross-coupling reaction with an aryl halide under ligand-free conditions, to afford easily purified ¹¹C-methyl(hetero)arenes in high radiochemical yields. The Royal Society of Chemistry 2006.

Full text of DOI:10.1039/b510286c

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Methyl transfer reaction from monomethyltin reagent under
palladium(0) catalysis: a versatile method for labelling with carbon-11{
a
Micka e¨ l Huiban, Aline Huet, Louisa Barr e´ , Franck Sobrio,* Eric Fouquet* and C e´ cile Perrio*
b
a
a
b
ac
Received (in Cambridge, UK) 22nd July 2005, Accepted 4th October 2005
First published as an Advance Article on the web 11th November 2005
DOI: 10.1039/b510286c
1
1
11
C-monomethylstannate prepared from [ C]-methyl
11
The
transferring the C-methyl group onto an aromatic or heteroaro-
matic structure by reaction with an electrophile 2 (Scheme 1).
We first evaluated the feasibility of the cross-coupling reaction
iodide and Lappert’s stannylene, was subject to a palladium-
mediated cross-coupling reaction with an aryl halide under
4
11
under rapid conditions using unlabelled methyl iodide. Formation
ligand-free conditions, to afford easily purified C-methyl-
hetero)arenes in high radiochemical yields.
of monoorganotin 1 from iodomethane and stannylene in THF
9
according to the previously described procedure, was quantitative
(
In recent years, the palladium mediated Stille reaction has proved
to be an important route for the synthesis of radiotracers for
and immediate. After in situ activation with TBAF (tetrabutyl-
ammonium fluoride, 3 equiv.), the resulting hypervalent stannate
reagent was engaged in a palladium-catalyzed cross-coupling
reaction with an aryl halide 2 (0.6 equiv.) in refluxing dioxane. In
order to minimize reaction times and optimize the reaction, the
nature and the amount of the catalytic system were varied
1–3
Positron Emission Tomography. It usually involves the reaction
1
1
of an aryltriorganostannane with easily synthesized [ C]-methy-
1
1
liodide as the electrophilic partner, leading to a C-carbon–carbon
coupled product. However, preparation of organostannane
precursors is not always straightforward, and in the case of
functionalized organostannanes, nucleophilic groups have to be
(Table 1). Results for reactions starting from 2-bromonaphthalene
2a were found to be representative.
2,4
Initially, bis(triphenylphosphine)palladium(II) chloride (1 mol%),
protected in order to prevent methylation as a side-reaction.
which was found to accelerate the transfer of n-alkyl groups more
9
than tetrakis(triphenylphosphine)palladium, was used as preca-
Moreover, the use of trimethylstannyl derivatives as substrates
would result in low specific activities, due to the competitive
3
transfer of an unlabelled methyl group. Finally, difficulties might
talyst (entry 1). The anticipated 2-methylnaphthalene 3a was
obtained in 91% yield after 30 min. Only traces of substrate–
substrate homocoupling product 4a were detected as side-
products. The catalyst was also generated in situ from Pd dba
be encountered in separating the tracer from triorganotin residues.
1
1
For these reasons, the use of an original [ C]-methyl labelled
2
3
version of Vedejs’ 1-aza-5-stannabicyclo[3,3,3]undecane was
5
6
(tris(dibenzilideneacetone)dipalladium, 1 mol%), used in conjunc-
tion with a ligand (4 mol%, 2 equiv. for each Pd atom). We
observed that the steric and electronic properties of the ligand
significantly influenced the course of the reaction. Using
triphenylphosphine, the formation of the cross-coupling product
3a was greatly reduced, whereas that of dinaphthalene 4a was
significantly enhanced (entry 2). Less donating trialkylphosphites,
and especially less sterically hindered trimethylphosphite, facili-
tated the cross-coupling reaction, resulting in the recovery of
product 3a in high yields after a short time (entries 3 and 4).
Finally, the reaction was performed under ligand-free conditions
attempted, and the Suzuki reaction was also proposed as an
alternative approach. However, no real improvement in terms
of efficiency or in the scope of the reaction has been demonstrated
so far.
Monoorganotins, activated by a fluoride source, have been
7
shown to be very reactive in the Stille coupling reaction, allowing
the transfer of vinyl, allyl, alkynyl, aryl, benzyl and even alkyl
8,9
10
groups onto aryl or vinyl halides or triflates in good to
excellent yields. They are far less toxic than di-, tri- and tetra-
1
1
alkylstannanes
and inorganic tin by-products are easily
12
removed. Since such reagents are readily prepared from
(
entries 5–7). The cross-coupling reaction took place, and was
strongly accelerated by increasing the amount of catalyst up to
mol%. Under the latter conditions, the yield of 3a reached 90%
13
Lappert’s stannylene (Sn[N(TMS)
2
]
2
) and an alkyl or aryl
8,9
halide,
we anticipated the possibility of synthesising the
11
C-monomethyltin reagent [ C]-1 from [ C]-iodomethane, and
5
11
11
after 5 min reaction time. The methyl transfer was found to be
efficient either starting from 3-bromoquinoline 2b (entry 10),
a
Groupe de D e´ veloppements M e´ thodologiques en Tomographie par
Emission de Positons, DRM-DSV, UMR CEA 2 FRE CNRS 2698,
Universit e´ de Caen-Basse Normandie, Centre Cyceron, 15 Boulevard
Becquerel, BP 5229, F-14074, Caen Cedex, France.
E-mail: sobrio@cyceron.fr; e.fouquet@lcoo.u-bordeaux1.fr;
perrio@cyceron.fr
b
Laboratoire de Chimie Organique et Organom e´ tallique, UMR CNRS
3802, Universit e´ Bordeaux I, 351 Cours de la Lib e´ ration, F-33405,
Talence Cedex, France
Laboratoire de Chimie Mol e´ culaire et Thioorganique, UMR CNRS
c
6
507, ENSICAEN, Universit e´ de Caen-Basse Normandie, 6 Boulevard
Mar e´ chal Juin, 14050, Caen Cedex, France
Electronic supplementary information (ESI) available: experimental
{
procedures and characterization data. See DOI: 10.1039/b510286c
Scheme 1 Methyl transfer reaction from stannane 1.
Chem. Commun., 2006, 97–99 | 97
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a
Table 1 Palladium-mediated methyl transfer reaction between 1 and aryl halides 2
b
Yield (%) Ar–Ar
c
Yield (%)
Entry Ar–X
Precatalyst/mol% Ligand/mol% Time/min Ar–CH
3
1
2
3
4
5
6
7
Pd(PPh
3
)
2
Cl
2
(1)
—
PPh (4)
3
P(OMe)
P(OiPr)
—
30
240
30
20
120
90
91
60
91
54
70
60
90
2
25
2
Pd
2
Pd
2
Pd
2
Pd
2
Pd
2
Pd
2
dba
dba
dba
dba
dba
dba
3
(1)
(1)
(1)
(1)
(2)
(5)
3
3
3
3
3
3
(4)
(4)
3
1
—
30
,1
—
—
5
8
9
0
Pd(PPh
3
)
(1)
(5)
2
Cl
2
(1)
—
P(OiPr)
—
15
5
2
82
85
90
,1
11
,1
Pd
Pd
2
dba
dba
3
3
(4)
1
2
3
11
12
13
Pd
2
Pd
2
Pd
2
dba
dba
dba
3
3
3
(1)
(2)
(5)
—
—
—
120
60
2
60
60
100
—
—
—
1
4
Pd
2
dba
3
(1)
(1)
—
—
30
5
95
86
—
—
15
Pd
2
dba
3
a
b
(1 mmol), 2 (0.6 mmol), TBAF (3 mmol). Isolated yield. Estimated by GC.
c
1
11
1-iodonaphthalene 2c (entry 11–13), 4-bromonitrobenzene 2d
[ C]-3b was not changed (entries 1–3). As anticipated, the amount
(
entry 14) or 4-iodotoluene 2e (entry 13).
of TBAF additive was shown to be crucial for an optimum
11
Having in hand conditions allowing a few minutes’ reaction
4
time compatible with the half-life of carbon-11, studies using
1
[
C-methyl transfer. The incorporation rate of carbon-11 increased
from 4 to 75% by using 1 to 3 equiv. of TBAF compared to the
stannylene (entries 5, 9–10). The need for 3 equiv. of TBAF was
explained as resulting from the side-reaction occurring between the
stannylene and the substrate 2b, leading to the corresponding
1
11
I were undertaken. To do so [ C]-CH
C]-CH
3
3
I obtained from
11
cyclotron produced [ C]-CO , was distilled into THF containing
2
11
the stannylene for the formation of [ C]-1. TBAF was added at
room temperature, and THF was removed by heating at 120 uC
under nitrogen. After addition of the catalyst and the electrophile
9
11
pentavalent tin species. The radiochemical yield of [ C]-3b was
not altered by decreasing the quantity of substrate 2b from 110 to
37 mmol, since it was always used in excess with respect to the
stannylene (entry 2 versus entry 4, and entry 5 versus entry 11). On
the other hand, the catalyst amount could not be lowered below
2
a,b,f–i in dioxane, the mixture was heated at 120 uC for 5 min,
then quenched with water. Analyses of the crude products were
performed by radio TLC and HPLC, by comparison with
11
11
authentic stable samples. Due to the small amount of [ C]-
4
3 mmol, otherwise formation of [ C]-3b was significantly reduced
11
3
CH I, and consequently of [ C]-1, it has to be kept in mind that
the coupling reactions were performed with an excess of palladium
catalyst. Furthermore, the presence of remaining stannylene
associated with the large excess of the electrophile might favour
the non-radioactive homocoupling reaction over the radioactive
methyl transfer. Thus, the development of the cross-coupling
reaction in radioactive chemistry required some adjustments and
the influence of the amount of each reagent was carefully
examined. The reaction using 3-bromoquinoline 2b as substrate
was taken as model (Table 2). In all cases, formation of the
11 11
[ C]-Methyl transfer from [ C]-1 onto 3-bromoquinoline 2b
Table 2
1
1
Sn[N(TMS)
Entry mmol
2
]
2
/ TBAF/
mmol
Pd
2b/mmol mmol
2 3
dba / Time/ [ C]-3b
a
min
(%)
1
2
3
20
15
7
60
40
21
45
45
45
45
45
30
15
45
110
110
110
75
75
75
75
75
75
75
5
5
5
5
3
3
3
1.5
3
5
5
5
5
5
10
15
5
5
5
74 ¡ 5
77 ¡ 7
70 ¡ 8
78 ¡ 2
75 ¡ 4
74 ¡ 6
72 ¡ 3
52 ¡ 23
38 ¡ 2
4 ¡ 2
4
5
6
7
8
9
10
15
15
15
15
15
15
15
15
11
expected radioactive 3-methylquinoline [ C]-3b was detected.
Homocoupling product 4b was obtained as a non-radioactive
1
1
side-product which was easily separated from [ C]-3b by
3
3
1
1
37
5
75 ¡ 1
preparative HPLC. Whatever the amount of stannylene used
a
11
3
Radiochemical yield decay corrected, based on [ C]-CH I (n = 2
1
1
11
7–20 mmol), the trapping of [ C]-CH I leading to [ C]-1,
(
3
or 3).
was quantitative and immediate, and the radiochemical yield in
9
8 | Chem. Commun., 2006, 97–99
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1
1
Table 3 Scope of the C-methyl transfer
use of easily available electrophiles as substrates, and the ease of
purification, make this methodology highly suitable for radio-
synthesis of PET tracers. We are currently further investigating the
scope of this methodology for the radiosynthesis of complex
biologically active compounds.
11
a
Entry Ar–X
1
mmol Ar– CH
3
RCY (%)
50
65 ¡ 12
The authors thank Professor M.-C. Lasne (ENSICAEN),
O. Tirel and M. Ibazizene (Centre Cyceron). The present work
was supported by the ‘‘Minist e` re de la Recherche et des Nouvelles
Technologies’’ (ACI program), CEA (Commissariat a` l’Energie
Atomique), CNRS (Centre National de la Recherche Scientifique),
the «PUNCH-Orga» Network (P oˆ le Universitaire Normand de
Chimie Organique), the ‘‘R e´ gion Basse-Normandie’’ and the
European Union (FEDER funding).
2
75
78 ¡ 2
3
4
50
50
41 ¡ 3
78 ¡ 5
Notes and references
1
L. Samuelsson and B. L a˚ ngstr o¨ m, J. Labelled Compd. Radiopharm.,
003, 46, 263; F. Karimi and B. L a˚ ngstr o¨ m, J. Labelled Compd.
2
Radiopharm., 2002, 45, 423; J. Tarkiainen, J. Vercouillie, P. Emond,
J. Sandell, J. Hiltunen, Y. Frangin, D. Guilloteau and C. Halldin,
J. Labelled Compd. Radiopharm., 2001, 44, 1013; M. Bj o¨ rkman, H. Doi,
B. Resul, M. Suzuki, R. Noyori, Y. Watanabe and B. L a˚ ngstr o¨ m,
J. Labelled Compd. Radiopharm., 2000, 43, 1327; M. Suzuki, H. Doi,
M. Bj o¨ rkman, Y. Andersson, B. L a˚ ngstr o¨ m, Y. Watanabe and
R. Noyori, Chem.-Eur. J., 1997, 3, 2039; Y. Andersson, A. Cheng
and B. L a˚ ngstr o¨ m, Act. Chem. Scand., 1995, 49, 683.
O. Langer, T. Forngren, J. Sandell, F. Doll e´ , B. L a˚ ngstr o¨ m, K. N a˚ gren
and C. Halldin, J. Labelled Compd. Radiopharm., 2003, 46, 55; J. Sandell,
M. Yu, P. Emond, L. Garreau, S. Chalon, K. N a˚ gren, D. Guilloteau
and C. Halldin, Bioorg. Med. Chem. Lett., 2002, 12, 3611.
5
6
75
75
63 ¡ 14
2
69 ¡ 2
3
4
J. Madsen, P. Merachtsaki, P. Davoodpour, M. Bergstr o¨ m,
B. L a˚ ngstr o¨ m, K. Andersen, C. Thomsen, L. Martiny and
G. M. Knudsen, Bioorg. Med. Chem., 2003, 11, 3447.
Chemistry using carbon-11 is linked to the short half-life of the
radioisotope (t1/2 = 20.4 min) and to the use of submicromolar
quantities of labelled reactant. Radiosyntheses have to be carried out
within a minimum of steps, and reactions have to be rapid, efficient,
selective and preferably without purification in between reaction steps,
while leading to high chemical and radiochemical purities, and high
specific radioactivities. Radiosynthesis strategies avoiding deprotection
steps are welcome. R. A. Ferrieri, G. Antoni, T. Khilberg and
B. L a˚ ngstr o¨ m, in Handbook of Radiopharmaceuticals. Radiochemistry
and Applications, ed. M. J. Welch and C. S. Redvanly, Wiley,
Chichester, 2003, pp. 229–282.
a
11
3
Radiochemical yield decay corrected, based on [ C]-CH I (n = 3).
(entries 4–5, 8). Taking into account all results we identified as
optimum conditions, the use of 15 mmol of stannylene, 45 mmol of
TBAF, 50–70 mmol of 3-bromoquinoline 2b, and 5 mmol of
1
1
Pd dba . Under these conditions, a radiochemical yield of [ C]-3b
3
2
up to 78% was obtained. We noted that the cross-coupling
reaction did not continue beyond 5 min (entries 5–7). In the course
of further studies aiming to simplify the procedure, dioxane was
found to be necessary for the coupling reaction. We observed that
5
T. Forngren, L. Samuelsson and B. L a˚ ngstr o¨ m, J. Labelled Compd.
Radiopharm., 2004, 47, 71; E. Vedejs, A. R. Haight and W. O. Moss,
J. Am. Chem. Soc., 1992, 114, 6556.
6 E. D. Hostetler and H. D. Burns, J. Labelled Compd. Radiopharm.,
003, 46, S1–S403.
For a recent review see: A. M. Echavarren, Angew. Chem., Int. Ed.,
005, 44, 3962.
11
2
the yield of [ C]-3b decreased significantly if evaporation of THF
was not complete (data not presented).
7
8
9
2
The radiosynthesis was extended to 2-bromonaphthalene 2a and
quinolines 2f–i bearing a bromine atom at different positions
E. Fouquet, M. Pereyre and A. L. Rodriguez, J. Org. Chem., 1997, 62,
5242.
A. Herve, A. L. Rodriguez and E. Fouquet, J. Org. Chem., 2005, 70,
1
1
(
Table 3). Radiochemical yields of corresponding [ C]-3 were
1
953.
0 E. Fouquet and A. L. Rodriguez, Synlett, 1998, 1323.
1 P. J. Smith, Health and safety aspect of tin chemicals, in Chemistry of
Tin, ed. P. J. Smith, 1998, ch. 11.
reproducible, in the range of 63–78% except for 2-methylquinoline
1
1
1
1
[
C]-3f (around 40%, entry 3).
In summary, we have developed the palladium-catalyzed methyl
1
1
12 E. Fouquet, M. Pereyre, A. L. Rodriguez and T. Roulet, Bull. Soc.
Chim. Fr., 1997, 134, 959.
transfer reaction from monomethylstannane 1 or [ C]-1 to various
1
1
aryl halide 2. The quantitative and immediate conversion of [ C]-
1
3 D. H. Harris and M. F. J. Lappert, J. Chem. Soc., Chem. Commun.,
974, 895; C. D. Schaeffer and J. J. Zuckerman, J. Am. Chem. Soc.,
1974, 96, 7160.
1
1
methyl iodide into methyltin reagent [ C]-1, the efficiency of the
1
rapid coupling reaction under ligand-free and rapid conditions, the
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Chem. Commun., 2006, 97–99 | 99