Photoredox-Nickel Dual-Catalyzed C-Alkylation of Secondary Nitroalkanes: Access to Sterically Hindered α-Tertiary Amines

Abstract

The preparation of tertiary nitroalkanes via the nickel-catalyzed alkylation of secondary nitroalkanes using aliphatic iodides is reported. Previously, catalytic access to this important class of nitroalkanes via alkylation has not been possible due to the inability of catalysts to overcome the steric demands of the products. However, we have now found that the use of a nickel catalyst in combination with a photoredox catalyst and light leads to much more active alkylation catalysts. These can now access tertiary nitroalkanes. The conditions are scalable as well as air and moisture tolerant. Importantly, reduction of the tertiary nitroalkane products allows rapid access to α-tertiary amines.

Synthetic Approaches to the Challenging Direct C‐Alkylation and C‐Allylation of Unactivated Nitroalkanes

“…The efficiency of this process can be notably increased allowing a photoredox reactivation of the catalyst 113 using tris(2‐phenylpyridine)iridium(III) [Ir(ppy) 3 ] under blue LED irradiation (Scheme 37). [72] This improved protocol avoids the utilization of diethylzinc as activator and enables the utilization of a wide arrays of functionalized nitro derivatives ranging from nitromethane to secondary nitroalkanes. Reduction of the Ni(II) nitronate 116 is provided by the excited state of the photocatalyst Ir(ppy) 3 obtained by blue LED irradiation.…”

Remote Radical 1,3-, 1,4-, 1,5-, 1,6- and 1,7-Difunctionalization Reactions

“…In addition to traditional homolytic bond cleavage-based radical reactions induced by radical initiators or photolysis [ 15 , 16 , 17 ], other methods such as single electron transfer reagents [ 18 , 19 , 20 , 21 , 22 ], catalytic photoredox [ 23 , 24 , 25 , 26 , 27 , 28 ], and electrochemical reactions [ 29 , 30 , 31 , 32 , 33 , 34 , 35 ] have been developed and are gaining increasing popularity. For the remote 1,3-, 1,4-, 1,5-, 1,6- and 1,7-difunctionalization reactions presented in this paper, the initial addition of the radical X is followed by radical rearrangement through resonance, hydrogen atom transfer (HAT), group transfer, or opening of strained-rings to relocate the position of the radical.…”

α-Tertiary Primary Amine Synthesis via Photocatalytic C(sp3)–H Aminoalkylation

“…7 Recently, the Rovis group reported a net-reductive radical coupling approach for the synthesis of sterically hindered primary amines by electrochemical coupling or photocatalytic coupling of N-unprotected ketimine hydro-chloride salts with 4-cyanopyridines (Scheme 1b). 8 Other methods that give access to α-tertiary primary amines include the alkylation of secondary nitroalkanes followed by reduction, 9 and the photoredox-catalyzed hydroamination of alkenes with ammonium salts. 10 Native C(sp 3 )−H substrates are ubiquitous and readily available feedstocks, which, as the most ideal alkyl radical precursors, have been widely used in photocatalytic bond formation events, recently.…”

“…Of particular note, acid-sensitive silylprotected benzylic ethers were compatible (7−10). A wide range of heteroaromatic ethers including thiophene (9), furan (10), and pyridine (11) moieties were proceeded smoothly as well. Cyclic ethers including phthalane (12), isochromane (13), 1,3-dioxolane (14,15), THF (16), and acyclic ethers (17,18) could be employed as potent C(sp 3 )−H substrates and afforded the desired corresponding products in good to excellent yields.…”