Nickel‐Catalyzed Mono‐Selective α‐Arylation of Acetone with Aryl Chlorides and Phenol Derivatives

Abstract

The challenging nickel‐catalyzed mono‐α‐arylation of acetone with aryl chlorides, pivalates, and carbamates has been achieved for the first time. A nickel/Josiphos‐based catalytic system is shown to feature unique catalytic behavior, allowing the highly selective formation of the desired mono‐α‐arylated acetone. The developed methodology was applied to a variety of (hetero)aryl chlorides including biologically relevant derivatives. The methodology has been extended to the unprecedented coupling of acetone with phenol derivatives. Mechanistic studies allowed the isolation and characterization of key Ni0 and NiII catalytic intermediates. The Josiphos ligand is shown to play a key role in the stabilization of NiII intermediates to allow a Ni0/NiII catalytic pathway. Mechanistic understanding was then leveraged to improve the protocol using an air‐stable NiII pre‐catalyst.

Ligand-controlled regioselective and chemodivergent defluorinative functionalization of gem-difluorocyclopropanes with simple ketones

“…In addition, it is well-known that mono-alkylation of simple and readily available acetone is challenging due to: (1) the much less acidic C–H bond compared with other carbonyl compounds; (2) increased susceptibility to undertake overalkylations; (3) the large excess loading and/or as solvent. 24 However, we were delighted to find that our developed Pd/NHC catalytic protocol could well address these challenges, affording the corresponding mono-alkylation product 3z in 75% yield, which showcased the great potential of this method in the selective functionalization of destabilized carbon nucleophiles.…”

On the application of 3d metals for C–H activation toward bioactive compounds: The key step for the synthesis of silver bullets

“…The same catalyst used in the previous example (nickel-cod) was also explored very recently by Amgoune and co-workers in an α-C(sp 3 )-H arylation of ketones in the presence of another chiral ferrocene ligand [264]. The desired arylated products were successfully obtained in moderate to good yields (Scheme 56A and B).…”

From Academia to the Market – Air-stable Ni(II)/Josiphos Catalysts

“…Also more complex aryl chloride starting materials could be converted to the desired product in moderate to excellent yield (products 4j & 4k, Scheme 5). [18] Next, we decided to investigate the use of air/moisture stable Ni(ii) catalysts for the α-arylation of acetone. The reactions were performed in the presence of 10 mol% of Ni(ii) precursor.…”