Late-Stage N-Me Selective Arylation of Trialkylamines Enabled by Ni/Photoredox Dual Catalysis

Abstract

The diversity and wide availability of trialkylamines render them ideal sources for rapid construction of complex amine architectures. Herein, we report that a nickel/photoredox dual catalysis strategy affects site-selective α-arylation of various trialkylamines. Our catalytic system shows exclusive N-Me selectivity with a wide range of trialkylamines under mild conditions, even in the context of late-stage arylation of pharmaceutical compounds bearing this common structural motif. Mechanistic studies indicate the unconventional behavior of Ni catalyst upon intercepting the α-amino radicals, in which only the primary α-amino radical undergoes a successful cross-coupling process.

Remote and Proximal Hydroaminoalkylation of Alkenes Enabled by Photoredox/Nickel Dual Catalysis

“…of (2,2,6,6-tetramethylpiperidin-1-yl)­oxyl (TEMPO), indicating a possible radical pathway. Moreover, a diamine product was detected by high-resolution mass spectrometry (HRMS), which was probably formed by the radical addition of an α-amino radical to an iminium ion intermediate . Furthermore, silyl ketene acetal 68 was synthesized and subjected into the standard conditions (Scheme e).…”

α‐Amino Radical Halogen Atom Transfer Agents for Metallaphotoredox‐Catalyzed Cross‐Electrophile Couplings of Distinct Organic Halides

“…The reaction also proceeded with other electron donors; while N , N ‐diisopropylethylamine (DIPEA) afforded a clean transformation (entry 11), pentamethylpiperidine (PMP) gave a low yield of the desired product (entry 12). No aryl‐amino alkyl coupling product was formed despite the commonly observed reactivity of α‐amino radicals in dual Ni/photoredox catalysis, [15] implying that the XAT process predominates over other pathways like interception of such radicals by Ni II/I [15b,c] . Recent studies have shown that the radical anions of 4‐CzIPN and its derivatives can be photoexcited to afford potent reductants that can reduce substrates with redox potentials more negative than −2.0 V [16] .…”

The Nickel Age in Synthetic Dual Photocatalysis: A Bright Trip Toward Materials Science

“…[33] In 2021, Shen and Rovis published a late-stage functionalization protocol for the N-methyl arylation of trialkylamines enabled by dual Ni/organophotoredox catalysis (Figure 9). [65] The authors envisaged the use of 4-CzIPN (17) as organic dye together with a Ni II metal complex 5 e to achieve the selective production of pharmaceutically relevant derivatives under blue light irradiation. A variety of aryl bromides 2 b were effectively coupled with different amines 6 to generate the corresponding benzylamines 24 under mild reaction conditions (up to 91 % yield).…”