Lithium trimethylsilyl ynolate: A new [11C] precursor and its application in heterocyclic synthesis

Article abstract of DOI:10.1016/j.tetlet.2011.02.066

[¹¹C]Lithium trimethylsilyl ynolate was characterized to be a new precursor in carbon-11 chemistry. It was obtained from [¹¹C] carbon monoxide and lithiated silyldiazomethane. The new precursor might be of high potential for the incorporation of carbon 11 into heterocyclic ring systems for which labeling methods are not well developed. More examples will certainly follow if other researchers will apply this useful method.

Full text of DOI:10.1016/j.tetlet.2011.02.066

Tetrahedron Letters 52 (2011) 2309–2311
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Tetrahedron Letters
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[11C]Lithium trimethylsilyl ynolate: a new [11C] precursor and its application
in heterocyclic synthesis
Michael W. Nader a, , Franz Oberdorfer b
⇑
a ARGOS Zyklotron GmbH, Seilerstätte 4, A-4010 Linz, Austria
b ZAG Zyklotron AG, Hermann-von-Helmholtz-Platz 1, D-76344 Eggenstein-Leopoldshafen, Germany
a r t i c l e i n f o
a b s t r a c t
11C]Lithium trimethylsilyl ynolate was characterized to be a new precursor in carbon-11 chemistry. It
Article history:
[
was obtained from [11C]carbon monoxide and lithiated silyldiazomethane. The new precursor might be
of high potential for the incorporation of carbon 11 into heterocyclic ring systems for which labeling
methods are not well developed. More examples will certainly follow if other researchers will apply this
useful method.
Received 28 September 2010
Revised 13 February 2011
Accepted 15 February 2011
Available online 23 February 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
[
11C]Carbon monoxide
Ynolate
1,3-Dipolar cycloaddition
Heterocyclic synthesis
Pyrazolo[5.1-c]triazine-4-one
Carbon-11 (t = 20.4 min) labeled compounds have found
thermore, ynolates make the ketenylation reaction applicable to
labeling chemistry.
½
important applications in medical research using Positron Emis-
sion Tomography (PET). There is a growing demand for carbon-
11 labeled compounds, and thus a corresponding need for new
methods of synthesis of complicated benzoic and heteroaromatic
structures. Thus, it appears desirable for future PET applications
to have suitable methods of 11C-labeling in heteroaromatic rings.
An outstanding characteristic of the ring labeled tracers is their
metabolic stability.
The existence of the lithiumenolate should be proven by
[7+2]cycloaddition with 3-diazo-5-methyl-4-phenyl-1H-pyra-
zole.10 3-Diazo-5-methyl-4-phenyl-1H-pyrazole 6 readily adds to
olefins and acetylene derivatives to give 1,7-cycloadducts. Thus,
1,3-dipolar cycloaddition has been shown to be of great synthetic
potential for the preparation of five-ring heterocycles.11–13
For the in situ preparation of the silyl ynolate a solution of com-
mercially available trimethylsilyldiazomethane was lithiated with
an equivalent amount of butyllithium and exposed to an atmo-
spheric pressure of carbon monoxide at À78 °C. The lithiated silyl-
diazomethane reacts with carbon monoxide to give acyllithium,
and this is immediately rearranged to a ketene intermediate 4.
After an extrusion of dinitrogen the desired silyl ynolate is
obtained.
In order to perform the cycloaddition reaction a solution of
3-diazo-5-methyl-4-phenyl-1H-pyrazole 6 in dichloro-methane
was added dropwise to an ice-cold solution of lithium trimethyl-
silyl ynolate 5. After 24 h no diazopyrazole was detected by the at-
tempted coupling with 2-naphthol.12 After the hydrolysis with a
saturated aqueous solution of ammonium chloride, separation of
the phases and evaporation of the solvent, the crude product was
purified by column chromatography on silica gel with diethyl ether
as the eluent.
Recently, ynolates have been shown to be promising precursors
in organic chemistry.1,2 Ynolates are the triple bond analogues of
enolates. Whereas, the chemistry of enolates is well established,
only a few attempts have been made to use ynolates in organic
synthesis. The first ynolates were generated by extrusion of benzo-
nitriles from lithio-3.4-diphenylisoxazole.3,4 A different method
was used by Kowalski et al., who synthesized ynolates by rear-
rangement of
a
-keto dianions.5 Another approach to the synthesis
of lithium ynolates was based on the oxidation of acetylides.6,7
A new route to the lithium silylynolate involves in situ trapping
of carbon monoxide by lithiated silyldiazomethan (Fig. 1). This is
followed by the extrusion of dinitrogen from acyllithium and pro-
vides a lithium trimethylsilyl ynolate.8 This synthesis shows an
easy and feasible entry to lithium ynolates. It offers a method for
the synthesis of 11C-labeled ynolates, since a high yield production
of [11C]carbon monoxide has been demonstrated recently.9 Fur-
In fact, we obtained the suggested 7-methyl-8-phenyl-3-trim-
ethylsilylpyrazolo-[5.1-c][1,2,4]triazin-(1H)4-one 9 in a yield of
22%. The structure of the compound could be confirmed by
⇑
Corresponding author. Tel.: +43 732 785 125; fax: +43 732 785 125 14.
E-mail address: michael.nader@iason.eu (M.W. Nader).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.02.066

2310
M. W. Nader, F. Oberdorfer / Tetrahedron Letters 52 (2011) 2309–2311
O
11C
Li
H
Li
11CO
BuLi
Me3Si
Me3Si
Me3Si
3
- 78°C
THF
N2
N2
N2
2
1
O
O
OLi
11C
N
11C
-N2
Me3Si
4
Li
Me3Si
N
Li
Me3Si
5
Figure 1. [11C]carbon monoxide based preparation of [11C]lithium trimethylsilyl ynolate.
1H NMR, 13C NMR, IR as well as mass spectroscopy. Thus, the IR
spectrum showed characteristic absorptions at 1690 cmÀ1 (CO),
at 1620 cmÀ1 (C@N) and an absorption at 3162 cmÀ1 (N–H). Fur-
thermore, the intramolecular hydrazone structure was supported
by a 1H NMR-signal (exchangeable with D2O) at 14.2 ppm (N–H).
The ESI-promoted mass spectrum of 9 showed the expected molec-
ular ion at m/z = 298.9 (M+H+). All results were consistent with
spectroscopical data of related published pyrazolo[5.1-c][1,2,4]tri-
azine-(1H)4-one derivatives.14
The
prepared
7-methyl-8-phenyl-3-trimethylsilyl-pyrazo-
lo[5.1-c][1,2,4]triazine-(1H)4-one 9 can be considered as a struc-
tural analogue of naturally occurring purines which have attracted
interest due to their broad spectrum of biological properties. Fur-
thermore, the prepared purinone derivative could be easily applied
as an aglycone in the synthesis of nucleoside analogues with prom-
ising pharmacological applications.15
According to Padwa and Kumagai.16 the mechanism of the reac-
tion possibly involves an initial [3+2]cycloaddition to form unsta-
The above synthesis was applied to the one-pot synthesis of car-
ble spirobicycles, which rearrange spontaneously by
a
bonyl labeled
o[5.1-c][1,2,4]triazine-(1H)4-one starting from
[
11C]7-methyl-8-phenyl-3-trimethylsilyl-pyrazol-
[1,5]sigmatropic shift to the pyrazolotriazinone. On the other hand,
a [7+2]cycloaddition process was favored by Ege and Gilbert.17
Alternatively, based on the results of Shindo et al.18,19 and Ege
and Gilbert.20 we propose a two-step ionic mechanism involving
initial nucleophilic attack of the negatively charged ketene carbon
at the electrophilic diazo group of 3-diazo-5-methyl-4-phenyl-1H-
pyrazole 6 followed by a ring closure of ring nitrogen and the
carbonyl group of the ketene 7. In the final step, the resulting 7-
methyl-8-phenyl-3-trimethylsilylpyrazolo[5.1-c][1,2,4]triazine
was hydrolyzed to provide 7-methyl-8-phenyl-3-trimethylsilylpy-
razolo[5.1-c][1,2,4]triazine-(1H)-4-one 9.
In order to support the described synthetic pathway, we
performed the 1,3-dipolar cycloaddition of lithium trimethysilyl
[
11C]carbon
monoxide (Fig. 2). [Carbonyl-11C]7-methyl-8-phenyl-3-trimethyl-
silyl-pyrazolo[5.1-c][1,2,4]triazine-(1H)4-one 9 was obtained in a
decay corrected yield of 40 3% (n = 10; decay corrected to the start
of the 19 min synthesis based on the starting activity of [11C]carbon
monoxide) and this corresponds to a chemical yield of 22%. A typi-
cal synthesis starting with 37 GBq of [11C]carbon monoxide deliv-
ered 7.5 GBq of the respective labeled product at the end of
synthesis that compares well with the yield of other carbon-11 la-
beled products. The product could be separated in 99% radiochem-
ical purity with a specific activity of 5.6 GBq/mmol (150 mCi/mmol)
as determined by radio-HPLC.
8
Figure 2. 1,3-Dipolar cycloaddition of [11C]lithium trimethylsilylynolate and 3-diazo-5-methyl-4-phenyl-1H-pyrazole.

M. W. Nader, F. Oberdorfer / Tetrahedron Letters 52 (2011) 2309–2311
2311
Acknowledgment
This work was performed in part at the German Cancer
Research Center (DKFZ), Department of Radiochemistry, Heidel-
berg, Germany. The authors acknowledge the support of the DKFZ.
References and notes
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Figure 3. 1,3-Dipolar cycloaddition of lithium trimethysilyl ynolate with benzoni-
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