Carbon-11 carboxylation of trialkoxysilane and trimethylsilane derivatives using [11C]CO2† †Electronic supplementary information (ESI) available. See DOI: 10.1039/d0cc00449a

A simple and rapid carbon-11 carboxylation radiosynthesis method.

Scheme 1 Current methods for the preparation of aromatic [ 11 C]carboxylic acids from [ 11 C]CO2 using: (a) Grignard reagents, (b) boronic esters and (c) trialkoxysilane and trimethylsilane derivatives -the latter used in this work.
Based on a search of the traditional synthetic chemistry literature, improved methods for the 11 Ccarboxylation of aryl and heteroaryl groups might be achieved by the use of trialkoxysilyl and trimethylsilyl derivatives via a so-called copper-catalysed desilylative carboxylation reaction. 5 Arylsilanes reacted readily with a fluoride anion source, such as cesium fluoride (CsF), potassium fluoride (KF), tetramethylammonium fluoride (Me 4 NF) to form a pentavalent silicate. 5-6 The pentavalent silicate was then converted in the presence of a copper catalyst to an arylcopper intermediate which reacted with non-radioactive CO 2 in moderate to excellent yields (27-99%). [5][6] Varying the substitution patterns of the aromatic ring with electron-withdrawing or electron donating groups did not alter the efficiency of substrate carboxylation. 5a-c Excellent results were also reported for the carboxylation of heteroaromatic compounds, such as thiophenyl, pyridyl and furanyl silane derivatives and their derivatization to ester products (89%-93%). 5b, c Compared to the traditional 11 C-carboxylation methodologies, the use of silyl derivatives would provide greater air and moisture stability and therefore easier handling and storage. Moreover, trimethylsilyl and trialkoxysilyl precursors are readily obtained via a plethora of synthetic reagents: Grignard or organolitium reagents 7 or functionalization of arylamides, 8 arylacyl fluorides, 9 aryl esters, 10 aryl cyanides Copper,Ruthenium).
With the aim developing more robust and versatile 11 C-carboxylation methodologies, we herein present the development of a novel 11 C-carboxylation protocol involving the use of arylsilyl derivatives. The [ 11 C]carboxylic acids were obtained in short synthesis times, with high molar activities and with broad applicability to range of trimethylsilane and trialkoxysilane derivatives. Scheme 2 Radiosynthetic approach to radiolabelled [ 11 C]carboxylic acids from cyclotron-produced [ 11 C]CO 2 .
This might be due to the poor reactivity of the pentavalent silicate intermediate and/or the absence of any [ 11 C]CO 2 trapping agent. The transmetallation of hypervalent silicates with copper catalysts (10%) however have been shown to form arylcopper intermediates that readily react with non-radioactive CO 2 . 5a Despite this finding, in our hands, the addition of 10% CuI to the reaction mixture did not promote the formation [ 11 C]1 (entry 2, Table 1). Moreover, the addition of a [ 11 C]CO 2 trapping agent (1,8-diazabicyclo[5.4.0]undec-7-ene, DBU, 0.6 equiv.) did not favour the formation of [ 11 C]1 either, although the TE increased from 6% to 77% (entry 1 versus 3).
We subsequently focused on selecting alternative fluoride sources, as CsF is highly hygroscopic and poorly soluble in organic solvents -even in the presence of 18-crown-6, which might have hampered the formation of [ 11 C]1. KF was investigated as a fluoride source as it has previously been used for the carboxylation of aryltrimethylsilanes, however, due its low reactivity KF in organic solvents the corresponding carboxylic acid derivative was only obtained with a low to moderate yield (17-74%). 5c, 13 To increase the reactivity of KF in organic solvents, we opted to explore the use of the polyether kryptofix (K2.2.2), to form a K + -cryptand complex.
In order to further increase the RCY of [ 11 C]1, an optimization process was subsequently performed by modifying: i) the amount of fluoride source, ii) the reaction temperature, iii) the amount of trapping reagent, iv) the amount of copper catalyst and v) the solvent.
The effect of the equivalents of fluoride source was initially investigated.
The use of a different solvent was investigated. Using tetrahydrofuran (THF) instead of DMF, had a negative effect on reactivity, with the RCY of [ 11 C]1 dropping to 1% (entry 12).
Encouraged by these results, BEMP was used as trapping agent for the following experiments which initially focused on the effect of a shorter reaction times. Halving the reaction time from 5 to 2.5 minutes resulted in halving the RCY of [ 11 C]1 (44% at 2.5 min. versus 82% at 5 min., entries 2-3, The effect of the solvent was also investigated during the optimisation of reaction conditions. The use of THF and acetonitrile (MeCN) gave low or zero yields of [ 11 C]1 (2% in THF and 0% in MeCN, entries 9-10, Table 2). The results presented in Table 1 and Reaction conditions were subsequently kept constant whilst studying the substrate scope of additional trialkoxysilyl and trimethylsilyl compounds.
Further studies focused on non-aromatic silane precursors such as fluorene and alkyne derivatives (entries 7-10). The radiolabelling of a fluorene moiety (5a)   In summary, we have developed a novel carbon-11 reaction using cyclotron-produced [ 11 C]CO 2 and aryltrimethylsilane and aryltrialkoxysilanes to obtain 11 C-carboxylic acid derivatives.
Aryltrimethylsilanes and aryltrialkoxysilanes are activated by a fluoride source (KF-K2.2.2) and copper catalyst which readily react with cyclotron-produced [ 11 C]CO 2 . We have also expanded the use of activated aryltrimethylsilanes as nucleophilic compounds for aromatic 11 C-methylation using [ 11 C]CH 3 I. The application of silane-mediated 11 C-carboxylation and 11 C-methylation reactions using to relevant radiopharmaceuticals will be reported in due course.
B. Yu, P. Yang, X. Gao, Z. Z. Yang, Y. F. Zhao, H. Y. Zhang and Z. M. Liu, New J. Chem., 2017, 41, 9250-9255. 13 F. Effenberger and W. Spiegler, Chem. Ber., 1985, 118, 3900-3914. 14 , Radiochemical yield was calculated by multiplying TE and RCP. Radiochemical purity (RCP) of the crude product has been determined by analytical radio-HPLC. The trapping efficiency (TE) has been calculated as a ratio of the decay corrected radioactivity in the vial and the total radioactivity produced by the cyclotron.

Preparation of the Vial
An oven-dried vial (KX Microwave Vials, 5 mL) and a crimp cap (Fisherbrand, centre hole with 3.0 mm PTFE seal aluminium silver 20 mm, part # 10132712) were used. The vials were prepared in a glovebox (Plas-Labs, Inc. 815 PGB Series) under nitrogen atmosphere and controlled CO 2 levels (lower than 30 ppm).

[ 11 C]CO 2 Production
[ 11 C]CO 2 was produced using a Siemens RD112 cyclotron by the 11 MeV proton bombardment of nitrogen (+0.5% O 2 ) gas via the 14 N(p,α) 11 C reaction. The cyclotron-produced [ 11 C]CO 2 was bubbled in a stream of helium gas with a flow rate of 60 mL/min post target depressurisation directly into a reaction v-vial (time from end of bombardment (EOB) to end of delivery (EOD) = 1 minute and 50 seconds).

Description of the system
The set up was implemented on an Eckert & Ziegler system (Modular-Lab Standard) and included two switching valves and a heating block. All gas transfer lines were fabricated from PTFE tubing (length: 10-

Description of the carbon-11 carboxylation
A cyclotron beam current of 5 µA was maintained for a bombardment time of 1 minute for all reaction optimization experiments producing ~ 300 MBq of carbon-11 at EOD.
[ 11 C]CO 2 (carried by helium gas) was bubbled directly from the target into a reaction vial containing aryltrimethylsilane or aryltrialkoxysilanes and reagents described in Tables 1-3  The amount of radioactivity in the Ascarite ® and vial were measured (to determine the trapping efficiency, TE), and an aliquot of the crude mixture analysed by radio-HPLC to determine the radiochemical purity, RCP.

Molar Activity calculation of [ 11 C]1
Eleven samples of 1 at different concentrations (1.15-0.011 μmol/mL) were analysed by HPLC to obtain a calibration curve of the peak area (mAU*s) versus μmol/mL. The peak areas of 1 were averaged and plotted in function of the corresponding μmol/mL ( Figure S2).
[ 11 C]1 was produced following the procedure of entry 2 ( The radioactivity in 1.00 mL of solution containing the purified [ 11 C]1 was determined. An aliquot of purified [ 11 C]1 (20 μL) was analysed by analytical radio-HPLC ( Figure S3) and the UV peak corresponding to 1 was integrated. The area of the UV peak was used to determine the μmol/mL of the associated 12 C-carrier content for [ 11 C]1 from the equation of the calibration curve. The molar activity (A m ) of [ 11 C]1 was calculated to be 3.1 ± 0.4 GBq/μmol (n = 3).

Description of the carbon-11 methylation to obtain [ 11 C]7
The [

Quality control of compounds [ 11 C]1-[ 11 C]7
HPLC analysis was performed on an Agilent 1200 system equipped with a UV detector (λ=254 nm) and a β+-flow detector coupled in series. A reverse-phase column (Phenomenex Luna-C18, 4.6 x 150 mm, 5 μm) was used with a flow rate of 1 mL/min.
t R = 7 minutes and 30 seconds.
t R = 5 minutes and 46 seconds.
t R = 5 minutes and 30 seconds.

Semipreparative HPLC method for the purification of [ 11 C]1.
HPLC analysis was performed on an Agilent 1200 system equipped with a UV detector (λ=254 nm) and a β+-flow detector coupled in series. A reverse-phase column (Phenomenex Luna-C18, 10 x 250 mm, 5 μm) was used with a flow rate of 4 mL/min.

Fig. S3 A)
Radio-HPLC chromatogram of HPLC-purified [ 11 C]1. B and C) UV chromatograms of HPLCpurified [ 11 C]1 at 250 and 254 nm, respectively. The difference between UV peaks (retention time (tR) = 5 minutes and 15 seconds) and radioactivity peaks (tR = 5 minutes and 28 seconds) is 13 seconds consistent with the expected delay time between detectors (13 seconds).