Copper-mediated <sup>11</sup>C-carboxylation of aryl- and heteroarylstannanes
Bibliographic record
Abstract
Carbon-11 (99.8% b+, t1/2 = 20.3 min) is a valuable radionuclide for molecular imaging with positron emission tomography (PET). For the majority of 11C-radiopharmaceuticals, [11C]CO2 is produced directly in target by the 14N(p,a)11C reaction in a medical cyclotron (10-30 MeV) and converted to [11C]CH3I or [11C]CH3OTf. The direct formation of 11C-labeled carbonyl groups using [11C]CO2-fixation, via organic bases, followed by covalent bond formation, is established for routine radiopharmaceutical production at our laboratories for the preparation of 11C-ureas and 11C-carbamates. However, the need exists for novel synthetic methodologies that incorporate [11C]CO2 into radiotracers of interest for the preparation of 11C-amides and 11C-carboxylic acids. Conversion of aryl boronic esters to [11C]carboxylic acids has been achieved by copper(I)-mediated [11C]CO2 fixation with limited success. We report herein a novel Cu(I)-mediated strategy for the carboxylation of aryl- and heteroarylstannanes. The method is transferable as both a radiosynthesis method for the preparation of carbon-11 labeled aromatic carboxylic acids using sub-stoichiometric quantities of [11C]CO2, as well as a mild (i.e. 1 atm) carboxylation method using non-radioactive CO2. The Cu(I) mediated carboxylation of arylstannanes using 1 atm. CO2 was achieved with isolated yields of 58% and 33% for the formation of benzoic acid and 4-(trifluoromethyl)benzoic acid, respectively. The preparation of [11C]benzoic acid was subsequently achieved with the following optimized reaction conditions: temperature: 100 C; time: 5 minutes; solvent: DMF (600 u00b5L); [PhSnBu3] = 0.1 M; [copper (I) thiophene-2-carboxylate] = 9.4 mM; and [N,N,Nu2032,Nu2032-tetramethylethylenediamine] = 1.3 M. [11C]Benzoic acid was prepared with a (decay-corrected) RCY of 45%, molar activity Am = 250 mCi/u03bcmol, and radiochemical purity >99%, with a synthesis and purification time of ca. 21 minutes. Evaluation of the substrate scope with several aryl- and heteroarylstannanes were next carried out: moderate RCYs (ca. 30u201370%) were obtained with para-substituted arylstannanes (pMe, pMeO and pCF3). Formation of 11C-carboxylic acids bearing 3-pyridyl, and 2-pyrazyl groups were successfully generated with RCYs between 32u201334%, while transfer of electron-rich heteroarenes 2-furyl and 2-thienyl were generally lower (<3%). We are currently applying this method towards the radiosynthesis of [11C]bexarotene, a retinoid X receptor (RXR) agonist.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.004 | 0.002 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".