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

Abstract

The amination of aryl halides has become one of the most commonly practiced C−N bond-forming reactions in pharmaceutical and laboratory syntheses. 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 Et 3 N as a weak, soluble base, which allows a broad substrate scope that includes bromoand 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 H 2 O 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 Et 3 N. The use of a simple, commercially available ligand, PAd 3 , 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 crosscoupling reactions with sensitive substrates and functionality.

Palladium-catalyzed denitrative N-arylation of nitroarenes with pyrroles, indoles, and carbazoles

“…Therefore, considerable efforts have been devoted to the development of new methods for the synthesis of this key skeleton. 5 Among the many methods for the synthesis of these highly valuable compounds, the Pd-catalyzed Buchwald–Hartwig amination 6 and the Cu-mediated Ullmann-type coupling 7 remain attractive, wherein aryl halides are generally used as electrophiles to couple with N–H heteroarenes. Alternatively, the Cu-promoted oxidative Chan–Lam cross-coupling reaction 8 of aryl borons with N–H heteroarenes can also access N -arylated heterocycles (Scheme 1a).…”

Synthesis and catalytic activity of palladium complexes bearing N-heterocyclic carbenes (NHCs) and 1,4,7-triaza-9-phosphatricyclo[5.3.2.1]tridecane (CAP) ligands

“…Firstly, we selected an alternative base as it is an important variable operating significant influence on the outcome of the Buchwald-Hartwig amination (Table 2). 18 Even though we obtained satisfactory yield with NaO t Bu as a base and the yield can be further improved by performing the reaction for longer reaction times (Table 2, entry 1), the best results were obtained when using KO t Bu (Table 2, entry 4). The often-used potassium hydroxide and the milder Cs 2 CO 3 did not improve the outcome of the reaction (Table 2, entries 2 and 3).…”

Capturing the Most Active State of a Palladium(0) Cross-Coupling Catalyst

“…In this study, we report definitive solution spectroscopic and crystallographic characterization of catalytically relevant Pd(0) complexes coordinated by a single monodentate ancillary ligand PAd3 (Ad = 1-adamantyl) (Fig 1C). The use of PAd3, recently reported by our group, was key to accelerating B-to-Pd TM at a sufficiently low temperature to stabilize coordinatively unsaturated Pd(0) [30][31][32][33][34] .…”