Preparation of 11C-amides by rhodium-catalyzed addition of organozinc iodides to 11C-isocyanates
Bibliographic record
Abstract
64 Objectives: Amides are a prodigious functional group in medicinal chemistry, however many powerful and versatile synthetic strategies for their bond formation using stable isotopes prove ineffective or impractical for carbon-11. We have explored alternative methods for the generation of 11C-amides in suitable yields for radiotracer development. Methods: Initially, organozinc iodides were prepared through zinc insertions into aryl and alkyl iodides1 before undergoing rhodium-mediated reactions with substituted isocyanates to produce amide products in moderate yields (10-87%). This technique was carried out with the subsequent use of in situ prepared 11C-isocyanates2 using a Synthra MeIplus Research module for the preparation of various 11C-amides in sufficient radiochemical yields (18-99%). Results: A diverse substrate scope was prepared using aryl and alkyl organozinc iodides with a variety of substituted isocyanates, generating products with yields ranging from 10-87%. Aryl zinc iodides produced a range of products with yields from 21-87%; alkyl zinc iodides were less effective but still derived anilides in yields from 10-64%. The use of electron-withdrawing groups on the isocyanate provided superior yields (alkyl: 41-60%, aryl: 79-87%) compared to those with electron-donating groups (alkyl: 10-32%, aryl: 30-62%). Sterically hindered isocyanates could be tolerated (alkyl: 10-32%, aryl: 39-62%), as well as aliphatic isocyanates coupled with aryl zinc iodides (alkyl: 0%-Trace, aryl: 25-63%). These results informed development of the radiochemical method by harnessing derivatization with the organozinc iodide nucleophile of in situ 11C-isocyanates. Optimization was directed towards the synthesis of [11C]acetanilide, providing decay-corrected radiochemical yields of 80.9 ± 2.1%. Additional work was completed for the preparation of more complex products in sufficient yields for radiotracer development (18-99%), including [11C]propanil, and other biologically-relevant compounds. Conclusions: We have developed a radiosynthetic procedure for the preparation of 11C-amides using rhodium-catalyzed reactions between organozinc iodides and in situ prepared 11C-isocyanates. This technique provides suitable yields for continued radiotracer development. Support: NSERC RGPIN-2017-06167 References: [1] Krasovskiy, A. et al. Angew. Chem. Int. Ed. 2006, 45 (36), 6040-6044. [2] Dheere, A. K. H. et al. Chem. Commun. 2013, 49 (74), 8193-8195.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
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 | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 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 | 0.001 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 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".