Visible Light-Mediated (Hetero)aryl Amination Using Ni(II) Salts and Photoredox Catalysis in Flow: A Synthesis of Tetracaine

Abstract

We report a visible light-mediated flow process for C–N cross-coupling of (hetero)­aryl halides with a variety of amine coupling partners through the use of a photoredox/nickel dual catalyst system. Compared to the method in batch, this flow process enables a broader substrate scope, including less-activated (hetero)­aryl bromides and electron-deficient (hetero)­aryl chlorides, and significantly reduced reaction times (10 to 100 min). Furthermore, scale up of the reaction, demonstrated through the synthesis of tetracaine, is easily achieved, delivering the C–N cross-coupled products in consistently high yield of 84% on up to a 10 mmol scale.

An oscillatory plug flow photoreactor facilitates semi-heterogeneous dual nickel/carbon nitride photocatalytic C–N couplings

“…This corresponds to an exceptionally high productivity of 2.67 g h −1 (15 mmol h −1 ), a value to our knowledge only surpassed by some homogeneous Ir-or Ru-based photoredox catalyzed C-N couplings. 6,26 It is noteworthy that the larger version of the HANU™ reactor (150 mL volume, 10× scale up) maintains all of its process characteristics (e.g. channel dimensions, mass-, heat-, and light transfer capacities, RTD), thus allows for straightforward scale-up of such procedures.…”

“…2 Nonetheless, interest has been renewed through the possibility to overcome the typical limitations of those procedures in terms of sustainability, cost (of both metal and ligand) and harsh conditions. 3 Nickel is an appealing alternative to palladium due to its abundancy, 4 yet must be merged with electro-or photocatalysis, [5][6][7] due to the inability of NiIJII) to undergo reductive elimination, unless strong bases and complex ligands are used. 8 As recently demonstrated, dual nickel/photo catalytic cross-coupling methods represent a promising alternative to palladium catalyzed methods.…”

Spin-Forbidden Excitation Enables Infrared Photoredox Catalysis

“…Os(phen)3(PF6)2 (Os5) enables Ni-catalyzed Buchwald-Hartwig cross coupling of aryl bromides and amines 41 under DR irradiation. In light of recent work addressing poor batch scale performance of Ru(bpy)3(PF6)2 under blue light conditions, this is a particularly exciting area of potential impact 42 . Although we recognize that Os1-5 may not offer as much redox power as visible-light absorbing organic, Ru(II), or Ir(III) catalysts due to a lower T1 energy, we are fascinated that mild DR light is capable of both electron and energy transfer with Ni for C-N cross coupling and will continue to improve this ability through catalyst development.…”

C4-Alkylamination of C4-Halo-1H-1-tritylpyrazoles Using Pd(dba)2 or CuI

“…In their subsequent study on the amination of unprotected five-membered bromoheterocycles, Pd-catalyzed coupling reactions of 4-bromopyrazole with eleven aromatic amines, as well as one benzylic amine, were disclosed (Equation (3)) [ 21 ]. Recently, Buchwald et al described visible-light-mediated amination of aryl halides in the presence of nickel and photoredox catalysts, for which one example of the reaction between 1-benzyl-4-bromopyrazole and pyrrolidine was included (Equation (4)) [ 22 ].…”