Nickel-Catalyzed Cross-Coupling Methylation of Aryl and Heteroaryl Electrophiles via Hydrazone Umpolung
Bibliographic record
Abstract
Methyl groups play a vital role in pharmaceutical substrates, where their installation onto aryl and heteroaryl moieties can often lead to enhanced drug-target interactions. This phenomenon has been termed the “magic methyl effect”, and it has become an important tool for the improvement of therapeutic potency during lead optimization stages in drug development. Herein, we report a new methodology for the methylation of various phenols as tosylates as well as aryl halides via a hydrazone-mediated Ni-catalyzed cross-coupling by introducing a new bench-stable methylating reagent in the form of formaldehyde hydrazone. The reaction produces moderate to good yields on a structurally diverse set of aryl and heteroaryl electrophiles. Experimental and computational investigations were carried out to support the proposed mechanism for this reaction.
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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) | 0.002 | 0.001 |
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".