Direct Synthesis of α-Amino Nitriles from Sulfonamides via Base-Mediated C–H Cyanation

Abstract

Herein, we disclose a transition-metal-free reaction system that enables α-cyanation of sulfonamides through C–H bond cleavage for the preparation of α-amino nitriles, including difficult-to-access all-alkyl α-tertiary scaffolds. More than 50 substrate examples prove a wide functional group tolerance. Additionally, its synthetic practicality is highlighted by gram-scalability and the late-stage modification of natural compounds. Mechanistic experiments suggest that this process involves in situ formation of an imine intermediate via base-promoted elimination of HF.

Regioselective N–F and α C(sp3)–H Arylation of Aliphatic N-Fluorosulfonamides with Imidazopyridines

“…On the basis of the above mechanistic studies and a previous report, plausible mechanisms were proposed for N–F and α C­(sp 3 )–H arylation of N -fluorosulfonamides (Scheme ). Initially, a single electron transfer (SET) between Cu­(I) species and N -fluorosulfonamide 1a afforded a copper­(II)-coordinated amidyl radical A , which underwent a radical addition process to provide intermediate B .…”

“…Meanwhile, most of the above transformations required the addition of transition metals. To the best of our knowledge, C­(sp 3 )–H functionalization of N -fluoroamides at the α position to nitrogen atom is still limited, , which in some reports utilized substrates without the δ C­(sp 3 )–H bond. , Until now, only C­(sp 3 )–H cyanation of N -fluoroamides was achieved at the α-carbon position under basic conditions (Scheme b) . Moreover, the exploration of N -fluoroamides in other transformations remains to be developed.…”

Organocatalytic Synthesis of α-Aminonitriles: A Review

“…Recently base mediated C-H bond cyanation for the synthesis of α-aminonitriles from sulfonamides is reported by Shi and coworkers [51]. They developed an effective and metal-free synthetic protocol containing N-fluorotosylamides, TMSCN, Et 3 N in toluene is capable of α-C-H bonds dehydrocyanation of amides at 40 • C to achieve excellent yields up to 90%.…”

“…They developed an effective and metal-free synthetic protocol containing N-fluorotosylamides, TMSCN, Et 3 N in toluene is capable of α-C-H bonds dehydrocyanation of amides at 40 • C to achieve excellent yields up to 90%. Broad applicability of this reaction system was proved by taking various complex molecules to achieve high isolated yields [51].…”

Fluoroamide-Directed Regiodivergent C-Alkylation of Nitroalkanes

“…This reaction is hampered by the electron-deficient protecting group on the nitrogen atom, which has a much lower electron density than an amine. Very recently, the groups of Zhang and Loh independently reported base-promoted fluoroamide-directed α-C–H cyanations (Scheme B, left). These elegant reactions offer a modern orthogonal approach to well-known δ-C–H functionalization protocols involving 1,5-HAT.…”