Palladium-Catalyzed Amidation and Amination of (Hetero)aryl Chlorides under Homogeneous Conditions Enabled by a Soluble DBU/NaTFA Dual-Base System

Abstract

The palladium-catalyzed coupling of aryl and heteroaryl chlorides with primary amides under mild homogeneous reaction conditions is reported. Successful C−N coupling is enabled by the use of a unique "dual-base" system consisting of DBU and NaTFA, which serve as proton acceptor and halide scavenger, respectively, using low catalyst loadings (0.5 mol %) with readily available, air-stable palladium precatalysts. The DBU/NaTFA system also enables the room-temperature coupling of primary aryl amines with aryl chlorides and is tolerant of a variety of base-sensitive functional groups.

Organic Superbases in Recent Synthetic Methodology Research

“… [76] Concurrent with these studies, scientists led by Simmons at Bristol‐Myers Squibb employed a DBU/NaTFA dual base system with a readily available t BuBrettPhos Pd precatalyst to couple aryl chloride substrates with amides and primary aryl amines (Figure 15 c). [77] These conditions are especially suited for large scale applications as NaTFA additive helps sequester the chloride anion from DBU⋅HCl to prevent its coordination to catalytic Pd intermediates. Very recently, Newman used high‐throughput experimentation to identify amination conditions employing inexpensive Pd catalysts and DBU that are amenable to batch and flow processes (Figure 15 d).…”

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

“…which have been shown to coordinate to catalytic intermediates, thereby inhibiting catalysis. 12 Newman and coworkers recently employed DBU in high-throughput screenings of Pd-catalyzed amination chemistry, thereby demonstrating the utility of mild organic amine bases in cross-coupling reactions in batch and flow processes. 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.…”

“…The advantage of the DBU/NaTFA dual-base system, besides being readily available and inexpensive, is that the NaTFA additive helps sequester any soluble halide anions from DBU•HX, which have been shown to coordinate to catalytic intermediates, thus inhibiting catalysis. 12 Newman and co-workers have recently employed DBU in high-throughput screenings of Pdcatalyzed amination chemistry, thereby demonstrating the utility of using mild organic amine bases for cross-coupling reactions in batch and flow processes. 13 Figure 1 Palladium-catalyzed C-N cross-coupling of amides employing an organic amine 'dual-base' system (DBU/NaTFA), and the nickel-catalyzed transformations reported herein.…”

“…While generally effective, the poor solubility of such inorganic bases in organic reaction media gives rise to a number of complications, including clogging/stirring issues and unpredictable reaction kinetics associated with the batch-specific morphology of the base (e.g., particle size). An elegant solution to this problem was reported by Simmons and co-workers in 2019, 12 whereby a combination of a weak-amine Brønsted base (1,8-diazabicyclo[5.4.0]undec-7-ene; DBU) and sodium trifluoroacetate (NaTFA) was employed successfully in Pd-catalyzed C(sp 2 )-N cross-couplings of (hetero)aryl chlorides with primary amides or anilines (Scheme 1). The advantage of the DBU/NaTFA dual-base system, besides being readily available and inexpensive, is that the NaTFA additive helps sequester any soluble halide anions from DBU•HX, Scheme 1 Palladium-catalyzed C-N cross-coupling of amides employing an organic amine 'dual-base' system (DBU/NaTFA), and the nickelcatalyzed transformations reported herein.…”

Nickel‐Catalyzed N‐Arylation of Fluoroalkylamines

“…While Buchwald and co‐workers recently disclosed the first Ni‐catalyzed C‐N cross‐couplings that make use of such a base (NEt 3 ) without recourse to microwave, photoredox, or electrochemical protocols and/or use of exogenous reductants, the reported transformations are restricted to reactions of (hetero)aryl triflates and anilines [25] . Given our interest in cross‐couplings of aryl chlorides (as well as less reactive phenol‐derived electrophiles), we selected the “dual‐base” DBU/NaOTf system [24a] (DBU=1,8‐diazabicyclo(5.4.0)undec‐7‐ene) to test in C‐N cross‐couplings of 2,2‐difluoroethylamine using ( PAd2‐DalPhos )Ni( o ‐tol)Cl as a pre‐catalyst (Figure 4 A). We were pleased to find that at elevated temperature (100 °C) this protocol allowed for such cross‐couplings to be achieved with otherwise base‐sensitive aryl chloride or phenol‐derived electrophiles bearing aldehyde, ketone, or ester functionality, leading to the desired N ‐(β‐fluoroalkyl)anilines ( 1 d , 3 a – 3 e ) [26] .…”