Synthesis of Heterocycle Substituted 1-Aryl-4-piperidones
Bibliographic record
Abstract
A series of heterocycle substituted 1-aryl-4-pipeidones were prepared via Knoevenagel condensations between nitrogen-containing 5-membered heterocycles and benzaldehyde (1) followed by reduction or amination.The oxadiazolidinedione ring was formed by reacting the N-hydroxyurea (10) with methyl chloroformate and sodium hydride.As part of a research program directed at the development of human β 3 agonists, a series of 1-aryl-4piperidones with various heterocyclic acid equivalents were required in the hope of obtaining potent and selective β 3 agonists with good pharmacokinetic properities. 1, 2Herein, we report the synthesis of 1-aryl-4-piperidones with nitrogen-containing 5-membered heterocycles as surrogates for the carboxylic acid functionality. 3The heterocycles reported here are thiazolidinedione, pseudothiohydantoin, hydantoin, rhodanine, oxadiazolidinedione, and thiazolidinone.The thiazolidineone, pseudothiohydantoin, hydantoin or rhodanine substituted 1-aryl-4-piperidones (4a-d and 6a-d) were prepared according to Scheme 1. Knoevenagel condensations between benzaldehyde (1) 4 and 2,4-thiazolidinedione, hydantoin, pseudothiohydantoin, or rhodanine (2a-d) followed by acidic hydrolysis provided the olefinic piperidones (4a-d).The condensations were usually effected in refluxing ethanol in the presence of piperidine.It was found more satisfactory to condense benzaldehyde (1) with 2d (rhodanine) in the presence of β-alanine in refluxing acetic acid.The reduced alkylpiperidone (6a) was obtained by a hydrogen transfer reaction 5 (5% Na-Hg in wet THF) followed by an acidic ketal hydrolysis.A much slower reaction was observed on reduction of thiazolidinedione (3a) under catalytic hydrogenation due to the presence of sulfur in the molecule.Similarly, the reduced pseudothiohydantoin (6b) and hydantoin (6c) analogues were obtained by 5% Na-Hg reduction and acidic hydrolysis.However, treatment of rhodanine (3d) with 5% Na-Hg resulted in the formation of a partially hydrolyzed dimeric compound (5). 6The reduced rhodanine (6d) was successfully prepared by reduction of 3d with lithium borohydride in pyridine/THF 7 followed by acidic hydrolysis.
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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) | 0.003 | 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".