Studies on radical reactions for the syntheses of pharmaceutically relevant organic motifs
Bibliographic record
Abstract
Organic synthesis plays a significant role in the pharmaceutical industry, particularly in providing a large array of pharmaceutically active molecules for drug discovery. In spite of numerous methods developed, there are still many limitations in the existing synthetic methodologies for pharmarceutically important organic motifs. Two such motifs are organofluorine derivatives and nitrogen heterocycles. This thesis focuses on my research on the development of new and efficient methodologies for the syntheses of these two motifs. Chapter 2 describes the development of a new radical fluorodecarboxylation method using xenon difluoride. This method can efficiently convert 2-aryl-2-fluoroacetic acids with different substitutents to difluoromethyl aryl ethers in good to excellent yields (53-80%). Chapter 3 details studies on the mechanism of fluorine transfer in radical fluorinations by N-F reagents, including Selectfluor and N-fluorobenzenesulfonimide (NFSI). Two strategies, carbocation rearrangement and carbocation trapping, were applied to identify the possible carbocation intermediates during the fluorinations of alkyl radicals. The results of our studies are consistent with a fluorine atom transfer pathway between alkyl radicals and either Selectfluor or NFSI. Mechanistic studies into silver-catalyzed radical fluorination method indicated the formation of carbocations, presumably via a single electron transfer pathway between alkyl radicals and the silver catalyst. The carbocation formation was supported by the detection of the products from carbocation rearrangement as well as carbocation trapping by nucleophiles. Chapter 4 describes the development of a novel 6-endo-trig radical cyclization onto hydrazones for the regio-controlled and stereoselective syntheses of tetrahydrophthalazines. Two synthetic protocols using this radical cyclization were developed, including one-pot or stepwise processes, to access substituted tetrahydrophthalazines. These protocols showed good efficiency and robustness, and were able to afford high yields (50-98%) of the desired products with excellent functional group tolerance. This radical cyclization is also the first method to achieve excellent trans-diastereoselectivity in the syntheses of 1,4-disubstituted tetrahydrophthalazines. Chapter 5 describes the applications of the 6-endo-trig radical cyclization for the syntheses of other nitrogen-containing motifs, such as tetrahydroazaphthalazines, tetrahydropyradizines, dihydrophthalazines, aromatic phthalazines, and pyrazolo phthalazine diones. Additionally, we have developed a Pt-catalyzed hydrogenation for the cleavage of N-N bonds of the tetrahydrophthalazines, as a new route to 1,4-diamines.
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 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 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 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 itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, 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".