Aryl Amination with Soluble Weak Base Enabled by a Water-Assisted Mechanism

Amination of aryl halides has become one of the most commonly practiced C–N bond-forming reactions in pharmaceutical and laboratory synthesis. The widespread use of strong or poorly soluble inorganic bases for amine activation nevertheless complicates the compatibility of this important reaction class with sensitive substrates as well as applications in flow and automated synthesis, to name a few. We report a palladium-catalyzed C–N coupling using Et₃N as a weak, soluble base, which allows a broad substrate scope that includes bromo- and chloro(hetero)arenes, primary anilines, secondary amines, and amide type nucleophiles together with tolerance for a range of base-sensitive functional groups. Mechanistic data have established a unique pathway for these reactions in which water serves multiple beneficial roles. In particular, ionization of a neutral catalytic intermediate via halide displacement by H₂O generates, after proton loss, a coordinatively-unsaturated Pd–OH species that can bind amine substrate triggering intramolecular N–H heterolysis. This water-assisted pathway operates efficiently with even weak terminal bases, such as Et₃N. The use of a simple, commercially available ligand, PAd₃, is key to this water-assisted mechanism by promoting coordinative unsaturation in catalytic intermediates responsible for the heterolytic activation of strong element-hydrogen bonds, which enables broad compatibility of carbon-heteroatom cross-coupling reactions with sensitive substrates and functionality.

Aryl Amination with Soluble Weak Base Enabled by a Water-Assisted Mechanism

Amination of aryl halides has become one of the most commonly practiced C–N bond-forming reactions in pharmaceutical and laboratory synthesis. The widespread use of strong or poorly soluble inorganic bases for amine activation nevertheless complicates the compatibility of this important reaction class with sensitive substrates as well as applications in flow and automated synthesis, to name a few. We report a palladium-catalyzed C–N coupling using Et₃N as a weak, soluble base, which allows a broad substrate scope that includes bromo- and chloro(hetero)arenes, primary anilines, secondary amines, and amide type nucleophiles together with tolerance for a range of base-sensitive functional groups. Mechanistic data have established a unique pathway for these reactions in which water serves multiple beneficial roles. In particular, ionization of a neutral catalytic intermediate via halide displacement by H₂O generates, after proton loss, a coordinatively-unsaturated Pd–OH species that can bind amine substrate triggering intramolecular N–H heterolysis. This water-assisted pathway operates efficiently with even weak terminal bases, such as Et₃N. The use of a simple, commercially available ligand, PAd₃, is key to this water-assisted mechanism by promoting coordinative unsaturation in catalytic intermediates responsible for the heterolytic activation of strong element-hydrogen bonds, which enables broad compatibility of carbon-heteroatom cross-coupling reactions with sensitive substrates and functionality.

Ni-Catalyzed Reductive Difunctionalization of Alkenes

Alkene difunctionalization represents one of the most efficient methods to synthesize highly functionalized molecules from simple and readily available starting materials. In contrast to the well-established redox-neutral alkene difunctionalization reactions, reductive alkene difunctionalization, which simultaneously introduces two electrophiles on both sides of the double bond, has been much less developed, especially in enantioselective manner. This review summarizes recent advances in the nickel-catalyzed reductive difunctionalization of alkenes and highlights the enantioselective transformations.1 Introduction2 Nickel-Catalyzed Racemic Reductive Difunctionalization of Alkenes3 Nickel-Catalyzed Enantioselective Reductive Difunctionalization of Alkenes3.1 Diarylation of Alkenes3.2 Aryl-alkenylation of Alkenes3.3 Aryl-monofluoroalkenylation of Alkenes3.4 Reductive Cyclization/Coupling with Alkynyl Bromides or Asymmetric Internal Alkynes3.5 Aryl-alkylation of Alkenes3.6 Aryl-amination of Alkenes4 Summary and Outlook