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Abstract A novel, selective and high‐yielding palladium‐catalyzed carbonylative arylation of a variety of weakly acidic (pKa25–35 in DMSO) benzylic and heterobenzylic C(sp3)−H bonds with aryl bromides has been achieved. This system is applicable to a range of pro‐nucleophiles for access to sterically and electronically diverse α‐aryl or α,α‐diaryl ketones, which are ubiquitous substructures in biologically active compounds. The Josiphos SL‐J001‐1‐based palladium catalyst was identified as the most efficient and selective, enabling carbonylative arylation with aryl bromides under 1 atm CO to provide the ketone products without the formation of direct coupling byproducts. Additionally, (Josiphos)Pd(CO)2was identified as the catalyst resting state. A kinetic study suggests that the oxidative addition of aryl bromides is the turnover‐limiting step. Key catalytic intermediates were also isolated.
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H-bonded reusable template assisted para-selective ketonisation using soft electrophilic vinyl ethers
Abstract In nature, enzymatic pathways generate Caryl−C(O) bonds in a site-selective fashion. Synthetically, Caryl−C(O) bonds are synthesised in organometallic reactions using prefunctionalized substrate materials. Electrophilic routes are largely limited to electron-rich systems, non-polar medium, and multiple product formations with a limited scope of general application. Herein we disclose a directedpara-selective ketonisation technique of arenes, overriding electronic bias and structural congestion, in the presence of a polar protic solvent. The concept of hard–soft interaction along with in situ activation techniques is utilised to suppress the competitive routes. Mechanistic pathways are investigated both experimentally and computationally to establish the hypothesis. Synthetic utility of the protocol is highlighted in formal synthesis of drugs, drug cores, and bioactive molecules.
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- Award ID(s):
- 1654122
- PAR ID:
- 10153713
- Publisher / Repository:
- Nature Publishing Group
- Date Published:
- Journal Name:
- Nature Communications
- Volume:
- 9
- Issue:
- 1
- ISSN:
- 2041-1723
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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