Copper-Assisted Direct Nitration of Cyclic Ketones with Ceric Ammonium Nitrate for the Synthesis of Tertiary α-Nitro-α-substituted Scaffolds

Abstract

An efficient and direct Cu-assisted nitrating approach to create synthetically valuable and challenging tertiary α-nitro-α-substituted moieties has been developed using ceric ammonium nitrate as a nitrating reagent, oxidant, and Lewis acid. Notably, the commonly used clinical drug ketamine was smoothly synthesized in four steps.

The DARK Side of Total Synthesis: Strategies and Tactics in Psychoactive Drug Production

“…103 Direct α -nitration mediated by ceric ammonium nitrate (CAN) and Cu(OAc) 2 provided α -nitro ketone (±)- 199 . Nitro reduction and subsequent reductive amination with aqueous formaldehyde yielded (±)-ketamine ( 165 ).…”

Synthesis of carbon‐14 labeled ketamine and norketamine

“…They have also been used as deuterated drugs for the optimization of metabolic and safety profiles of ketamine, leveraging the kinetic isotope effect of deuterium. Despite the existence of a number of cold synthetic approaches to ketamine and norketamine, [8][9][10][11][12][13][14][15][16] there appear to be no examples in the literature of radiolabeling at any metabolically stable positions, namely, the cyclohexyl or phenyl positions. 6,7 Ketamine itself undergoes N-demethylation in vivo as part of its biotransformation, making carbon-14 labeling at the N-methyl position unsuitable for longer duration studies.…”

Metal‐Free Nitration of the C(sp3)−H Bonds of 2‐Oxindoles through Radical Coupling Reaction at Room Temperature

“…[5] One example was reported by Liu and co-workers, who documented a Ag(I)-mediated direct nitration of the quinoxaline tertiary CÀH bond at 110 8C in the presence of K 2 S 2 O 8 using AgNO 2 as a nitro source. [7] To the best of our knowledge, there is only one reported example concerning the nitration of C(sp 3 )ÀH bonds through radical reaction using nonmetallic nitrating reagent. [7] To the best of our knowledge, there is only one reported example concerning the nitration of C(sp 3 )ÀH bonds through radical reaction using nonmetallic nitrating reagent.…”

“…[7,[12][13][14] Initially, NO radical and t-BuO radical were directly generated from t-BuO-NO. [7,[12][13][14] Initially, NO radical and t-BuO radical were directly generated from t-BuO-NO.…”

“…[7,[12][13][14] Initially, NO radical and t-BuO radical were directly generated from t-BuO-NO. [7,13] Subsequently, the t-BuO radical rapidly reacted with 2-oxindole 1 to generate alkyl radical A. [7,13] Subsequently, the t-BuO radical rapidly reacted with 2-oxindole 1 to generate alkyl radical A.…”