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A highly selective palladium-catalyzed carbonylative arylation of weakly acidic benzylic C(sp 3 )–H bonds of azaarylmethylamines with aryl bromides under 1 atm of CO gas has been achieved. This work represents the first examples of use of such weakly acidic pronucleophiles in this class of transformations. In the presence of a NIXANTPHOS-based palladium catalyst, this one-pot cascade process allows a range of azaarylmethylamines containing pyridyl, quinolinyl and pyrimidyl moieties and acyclic and cyclic amines to undergo efficient reactions with aryl bromides and CO to provide α-amino aryl-azaarylmethyl ketones in moderate to high yields with a broad substrate scope and good tolerance of functional groups. This reaction proceeds via in situ reversible deprotonation of the benzylic C–H bonds to give the active carbanions, thereby avoiding prefunctionalized organometallic reagents and generation of additional waste. Importantly, the operational simplicity, scalability and diversity of the products highlight the potential applicability of this protocol.
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Palladium‐Catalyzed Benzylic C(sp 3 )−H Carbonylative Arylation with Aryl Bromides
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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- PAR ID:
- 10415602
- Publisher / Repository:
- Wiley Blackwell (John Wiley & Sons)
- Date Published:
- Journal Name:
- Angewandte Chemie International Edition
- Volume:
- 62
- Issue:
- 23
- ISSN:
- 1433-7851
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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