Bicyclo[1.1.1]pentane Ketones via Friedel-Crafts Acylation
Bibliographic record
Abstract
Bicyclo[1.1.1]pentane (BCP) is a rigid aliphatic hydrocarbon with a three-dimensional (3D), propeller-like shape and a molecular size which makes it a targeted bioisosteric replacement for phenylene and acetylene groups in medicinal chemistry. For the pharmaceutical application of BCP, simple, efficient, and cost-effective synthetic tools are required to enable the exploration of BCP’s potential as a bioisostere across a broad chemical space. With numerous sophisticated protocols for C(sp3) functionalization of rigid aliphatic hydrocarbons reported in literature, the synthesis of BCP mono- and diketones remains a challenging task, limited by both substrate scope and expensive photocatalysts. Here we present a protocol for Friedel-Crafts acylation of (hetero)aromatic hydrocarbons with BCP acyl chlorides; in particular, the first method to access diaromatic BCP 1,3-diketones. Reaction optimization, substrate scope, and reactivity of the products are discussed. 35 mono- and diketones are reported accompanied by 7 examples of post-synthetic modifications. The synthesis of a BCP analogue of fenofibrate is reported. Non-covalent interactions of the compounds in the solid state are discussed, including a Hirshfeld analysis.
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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 | 0.001 |
| 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".