Nickel‐Catalyzed Cross‐Coupling of Functionalized Difluoromethyl Bromides and Chlorides with Aryl Boronic Acids: A General Method for Difluoroalkylated Arenes

Abstract

Transition-metal-catalyzed difluoroalkylation of aromatics remains challenging despite the importance of difluoroalkylated arenes in medicinal chemistry. Herein, the first successful example of nickel-catalyzed difluoroalkylation of aryl boronic acids is described. The reaction allows access to a variety of functionalized difluoromethyl bromides and chlorides, and paves the way to highly cost-efficient synthesis of a wide range of difluoroalkylated arenes. The notable features of this protocol are its high generality, excellent functional-group compatibility, low-cost nickel-catalyst, and practicality for gram-scale production, thus providing a facile method for applications in drug discovery and development.

A Ligand‐Enabled Palladium‐Catalyzed Highly para‐Selective Difluoromethylation of Aromatic Ketones

“…When equal amounts of bromodifluoroacetate, acetophenone,a nd [Pd I P(tBu) 3 Br] 2 were employed in the reaction, the product 3a was obtained in 25 %y ield, along with the recovery of unreacted acetophenone (Scheme 3b). [15,22] Based on the above results and previous reports, [15,22] ap lausible catalytic cycle is proposed in Scheme 4. However,a na nalogous result was obtained when two equivalents of bromodifluoroacetate were used.…”

“…[14] Inspired by the aluminum Lewis-acid-enabled highly para-selective functionalization of arenes,w ee nvisaged that the site-selective difluoromethylation of aromatic ketones could be achieved by the coordination of asuitable Lewis acid with the carbonyl group of the ketone.Initially,acetophenone (1a)was treated with bromodifluoroacetate (2) [8,15] -a cheap and commercially available difluoromethylation reagent-in the presence of transition metals [16] and various Lewis acids.Unfortunately, amixture of the para-and meta-difluoromethylated products (3a and 4a,r espectively; para/meta (p/m) % 6/1 to 10/1) was obtained in less than 20 %y ield (Supporting Information). [14] Inspired by the aluminum Lewis-acid-enabled highly para-selective functionalization of arenes,w ee nvisaged that the site-selective difluoromethylation of aromatic ketones could be achieved by the coordination of asuitable Lewis acid with the carbonyl group of the ketone.Initially,acetophenone (1a)was treated with bromodifluoroacetate (2) [8,15] -a cheap and commercially available difluoromethylation reagent-in the presence of transition metals [16] and various Lewis acids.Unfortunately, amixture of the para-and meta-difluoromethylated products (3a and 4a,r espectively; para/meta (p/m) % 6/1 to 10/1) was obtained in less than 20 %y ield (Supporting Information).…”

The Fascinating Chemistry of α‐Haloamides

“…Meanwhile, the same research group disclosed that bromo and chlorodifluoroalkyl derivatives, including amides A , could cross‐couple to phenylboronic acid B with the intermediacy of the low costing nickel‐catalyst [Ni(NO 3 ) 2 ] in the presence of the ligand 2,2’‐bipyridine (bpy) (Scheme ). The new protocol paved the way to highly cost‐efficient synthesis of a wide range of difluoroalkylated arenes C .…”

Recent Progress toward the Introduction of Functionalized Difluoromethylated Building Blocks onto C(sp2) and C(sp) Centers

“…Subsequently, the same group reported the first nickel‐catalyzed ethoxycarbonyldifluoromethylation of arylboronic acids using BrCF 2 CO 2 Et (Scheme ) 17. The reaction was carried out in the presence of the inexpensive and readily available Ni(NO 3 ) 2 ⋅6 H 2 O precatalyst and 2,2‐bipyridine as a ligand to afford the difluoromethylated products 18 a – j in moderate to high yields.…”