Discovery of a Distinctive Reagent for Divergent Arene Trifluoromethylsulfinylation
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Bibliographic record
Abstract
High Resolution Image Download MS PowerPoint Slide Simple and direct arene trifluoromethylsulfinylation is highly desirable in drug design but remains a major challenge. Herein, we report a modular, mild, innate C–H trifluoromethylsulfinylation of a wide variety of arenes via a distinctive trifluoromethylsulfinylating reagent N -hydroxyphthalimide- O -trifluoromethanesulfinate following divergent efficient pathways. This trifluoromethylsulfinylation can be conducted in a redox-neutral manner at room temperature with light-, metal-, and photocatalyst-free mild conditions. Mechanistic studies and density functional theory (DFT) calculations revealed that the success of this approach hinges upon the design of an activated trifluoromethanesulfite ester that proceeds via homolytic cleavage with a very low bond dissociation energy to generate a dummy aminoxyl radical (PINO) and active CF 3 S(O) radical, which could accidentally be transformed into a trifluoromethanesulfonic anhydride, CF 3 S(O)OS(O)CF 3, for the transfer of the S(O)CF 3 group into an exemplary set of strong EDG-substituted arenes. DFT computation corroborates that this novel reagent can be activated by TfOH via heterolytic cleavage to produce highly active CF 3 S(O)OTf, which is responsible for electrophilic trifluoromethylsulfinylation of the challenging weak EDG-substituted arene substrates through an electrophilic addition–elimination mechanism. Such C–H functionalization using N -hydroxyphthalimide- O -trifluoromethanesulfinate affords an innovative strategy and marked improvement over functionalization with previously developed reagents. Notably, simple and mild conditions, broad reactivities, good functional group compatibility, divergent reaction modes (homolysis and heterolysis), as well as late-stage trifluoromethylsulfinylation (LST) of complex biologically active molecules in these reactions underline the great potential of N -hydroxyphthalimide- O -trifluoromethanesulfinate for the preparation of functionalized drug-like molecules.
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Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.001 |
| 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) | 0.000 | 0.000 |
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 it