Nickel‐Catalyzed N‐Arylation of Fluoroalkylamines

Abstract

The Ni‐catalyzed N‐arylation of β‐fluoroalkylamines with broad scope is reported for the first time. Use of the air‐stable pre‐catalyst (PAd2‐DalPhos)Ni(o‐tol)Cl allows for reactions to be conducted at room temperature (25 °C, NaOtBu), or by use of a commercially available dual‐base system (100 °C, DBU/NaOTf), to circumvent decomposition of the N‐(β‐fluoroalkyl)aniline product. The mild protocols disclosed herein feature broad (hetero)aryl (pseudo)halide scope (X=Cl, Br, I, and for the first time phenol‐derived electrophiles), encompassing base‐sensitive substrates and enantioretentive transformations, in a manner that is unmatched by any previously reported catalyst system.

Mapping Dual‐Base‐Enabled Nickel‐Catalyzed Aryl Amidations: Application in the Synthesis of 4‐Quinolones

“…[13] Conversely, the more conventional approach of deploying judiciously selected soft ancillary ligands, including most commonly N-heterocyclic carbenes [14] or bisphosphines (P 2 ) [15] under thermal catalytic conditions, has given rise to Ni catalysts that are generally superior in terms of substrate scope relative to those based on photoredox/electrochemical/reductant protocols, [4][5][6]8] as well as established Cu-and Pd-based CÀ N cross-coupling catalyst systems. The use of P 2 -ligands has proven particularly effective in promoting the cross-coupling of a broad spectrum of nucleophiles (e.g., ammonia and linear alkylamines, [16] branched alkylamines, [17] fluoroalkylamines, [18] (hetero)anilines, [16e, 19] indoles, [16e] sulfonamides [20] ) in combination with a diversity of (hetero)aryl-X electrophiles (X = Cl, Br, I, and phenol derivatives), albeit in combination with inorganic bases. The first use of organic amine bases in thermal Ni-catalyzed CÀ N cross-couplings involved aryl triflate and aryl amine reaction partners and was disclosed in 2020 by Buchwald and coworkers; [21] shortly thereafter our group [18] successfully applied a "dual-base" [22] (DBU with NaTFA or NaOTf) strategy in developing the first Ni-catalyzed cross-coupling of fluoroalkylamines with (hetero)aryl-X electrophiles (X = Cl, Br, I, sulfonate, and sulfamate).…”

“…The use of P 2 -ligands has proven particularly effective in promoting the cross-coupling of a broad spectrum of nucleophiles (e.g., ammonia and linear alkylamines, [16] branched alkylamines, [17] fluoroalkylamines, [18] (hetero)anilines, [16e, 19] indoles, [16e] sulfonamides [20] ) in combination with a diversity of (hetero)aryl-X electrophiles (X = Cl, Br, I, and phenol derivatives), albeit in combination with inorganic bases. The first use of organic amine bases in thermal Ni-catalyzed CÀ N cross-couplings involved aryl triflate and aryl amine reaction partners and was disclosed in 2020 by Buchwald and coworkers; [21] shortly thereafter our group [18] successfully applied a "dual-base" [22] (DBU with NaTFA or NaOTf) strategy in developing the first Ni-catalyzed cross-coupling of fluoroalkylamines with (hetero)aryl-X electrophiles (X = Cl, Br, I, sulfonate, and sulfamate). We subsequently established that the use of DBU/NaTFA with Ni(COD) 2 / CyPAd-DalPhos (COD = 1,5-cyclooctadiene) catalyst mixtures enables the CÀ N cross-coupling of (hetero)aryl chlorides or phenol electrophiles with primary amides.…”

Nickel-Catalyzed N-Arylation of Amides with (Hetero)aryl Electrophiles by Using a DBU/NaTFA Dual-Base System

“…13 As part of our ongoing research program focused on developing new and synthetically useful Ni-catalyzed crosscoupling chemistry, we recently reported a successful application of the Simmons 12 dual-base strategy in the N-arylation of fluoroalkylamines with (hetero)aryl electrophiles by using (PAd2-DalPhos)Ni(o-tolyl)Cl (PAd2-DalPhos = L2; see Scheme 2 below) as a precatalyst. 14 The success of these C(sp 2 )-N cross-couplings involving generally poor fluoroalkylamine nucleophiles akin to amides, 15 when paired with the dearth of reports documenting Ni-catalyzed amide cross-couplings of this type generally, 16 led us to explore the utility of DalPhos and other prominent ligands in the development of the first Ni-catalyzed amide cross-couplings of (hetero)aryl (pseudo)halides in the presence of a weak organic amine base. The results of these investigations are disclosed below.…”

Mapping Dual‐Base‐Enabled Nickel‐Catalyzed Aryl Amidations: Application in the Synthesis of 4‐Quinolones

“…Conversely, the more conventional approach of deploying judiciously selected soft ancillary ligands, including most commonly N‐heterocyclic carbenes [14] or bisphosphines (P 2 ) [15] under thermal catalytic conditions, has given rise to Ni catalysts that are generally superior in terms of substrate scope relative to those based on photoredox/electrochemical/reductant protocols, [4–6, 8] as well as established Cu‐ and Pd‐based C−N cross‐coupling catalyst systems. The use of P 2 ‐ligands has proven particularly effective in promoting the cross‐coupling of a broad spectrum of nucleophiles (e.g., ammonia and linear alkylamines, [16] branched alkylamines, [17] fluoroalkylamines, [18] (hetero)anilines, [16e, 19] indoles, [16e] sulfonamides [20] ) in combination with a diversity of (hetero)aryl‐X electrophiles (X=Cl, Br, I, and phenol derivatives), albeit in combination with inorganic bases. The first use of organic amine bases in thermal Ni‐catalyzed C−N cross‐couplings involved aryl triflate and aryl amine reaction partners and was disclosed in 2020 by Buchwald and co‐workers; [21] shortly thereafter our group [18] successfully applied a “dual‐base” [22] (DBU with NaTFA or NaOTf) strategy in developing the first Ni‐catalyzed cross‐coupling of fluoroalkylamines with (hetero)aryl‐X electrophiles (X=Cl, Br, I, sulfonate, and sulfamate).…”

“…The use of P 2 ‐ligands has proven particularly effective in promoting the cross‐coupling of a broad spectrum of nucleophiles (e.g., ammonia and linear alkylamines, [16] branched alkylamines, [17] fluoroalkylamines, [18] (hetero)anilines, [16e, 19] indoles, [16e] sulfonamides [20] ) in combination with a diversity of (hetero)aryl‐X electrophiles (X=Cl, Br, I, and phenol derivatives), albeit in combination with inorganic bases. The first use of organic amine bases in thermal Ni‐catalyzed C−N cross‐couplings involved aryl triflate and aryl amine reaction partners and was disclosed in 2020 by Buchwald and co‐workers; [21] shortly thereafter our group [18] successfully applied a “dual‐base” [22] (DBU with NaTFA or NaOTf) strategy in developing the first Ni‐catalyzed cross‐coupling of fluoroalkylamines with (hetero)aryl‐X electrophiles (X=Cl, Br, I, sulfonate, and sulfamate). We subsequently established that the use of DBU/NaTFA with Ni(COD) 2 /CyPAd‐DalPhos (COD=1,5‐cyclooctadiene) catalyst mixtures enables the C−N cross‐coupling of (hetero)aryl chlorides or phenol electrophiles with primary amides [23]…”