Divergent Late‐Stage (Hetero)aryl C−H Amination by the Pyridinium Radical Cation

Abstract

(Hetero)arylamines constitute some of the most prevalent functional molecules, especially as pharmaceuticals. However, structurally complex aromatics currently cannot be converted into arylamines, so instead, each product isomer must be assembled through a multistep synthesis from simpler building blocks. Herein, we describe a late‐stage aryl C−H amination reaction for the synthesis of complex primary arylamines that other reactions cannot access directly. We show and rationalize through a mechanistic analysis the reasons for the wide substrate scope and the constitutional diversity of the reaction, which gives access to molecules that would not have been readily available otherwise.

Pyridinium Salts as Redox‐Active Functional Group Transfer Reagents

“…[88] Independently and concurrently,Ritter and co-workers as well as acollaboration of the Carreira and Togni groups have reported the selective light-mediated generation of ap yridyl radical cation for the direct C(sp 2 ) À Hamination of arenes and heteroarenes (43). [97,98] Togni, Carreira, and co-workers identified as imple N-trifloxypyridinium salt 58 as well as the commonly available N-fluoropyridinium salt as suitable precursors to generate pyridyl radical cations selectively over the high energy radicals which would result from the commonly observed homolysis pathway,n amely trifloxy or fluorine radicals,r espectively.T he best yields were obtained with the N-trifloxypyridinium 58,which was shown to provide awide range of pyridinylated products 59 (Scheme 26). Such aryl pyridinium compounds constitute aw ell-known class of organic molecules that can be readily transformed into adiverse range of valuable piperidine derivatives.Conversely, if the pyridination reaction is terminated with an ucleophilic amine,t he aryl pyridinium products undergo in situ Zincke hydrolysis to yield aryl amines 60.Importantly,the existence of the pyridyl radical cation was corroborated by EPR studies conducted under irradiation with visible light.…”

“…Reviews strated until very recently. [88,97,98] Akey finding in the study by Togni, Carreira, and co-workers is that the commonly used Nfluoropyridinium reagent fragments directly to an N-centered radical cation and fluoride anion under single-electron reducing conditions.T his selectivity is proposed to be driven by the thermodynamic preference for the generation of ar eactive but more stable pyridyl radical cation over the direct expulsion of af luorine radical (FC). Theg eneration of af luorine radical would be unexpected and represents the reverse reaction of the synthesis of N-fluoropyridinium, typically prepared by direct fluorination of pyridine by fluorine gas.T he formation of the pyridyl radical cation is further supported by both synthetic evidence by virtue of CÀ Hp yridination over fluorination of arenes as well as spectroscopic evidence of the pyridyl radical cation by EPR spectroscopy (see Section 2.4).…”

A Retrosynthetic Approach for Photocatalysis

“…Ritter and co-workers reported the visible-light-mediated amination of arenes by photoredox catalysis (Scheme 34). [138] The method employed commercially available Ru(bpy) 3 (PF 6 ) 2 as the photocatalyst and either butylamine propylamine or piperidine as the base in the second reaction step. The reaction mixture was irradiated with blue LEDs for 15-90 min or with a CFL for 24 h giving the corresponding products in generally good yields (60-80 %).…”

Photochemical Strategies for Carbon–Heteroatom Bond Formation

“…[1e] The formation of N-centered radicals that react with unactivated (hetero)aromatic compounds is an appealing alternative. Amidyl and sulfonamidyl radicals (25) were accessed by reductive cleavage of suitable precursors (26) such as N-sulfonyloxysulfonamides (27), [24] N-acyloxyphthalimides (28), [25] and N-aryloxyamides (29) [26] using a sufficiently strong reducing PC (Scheme 5). The electrophilic radical species (25) was proposed to react with (hetero)aromatic compounds (21), to form a radical intermediate (30), that is subsequently oxidized by the photocatalyst, closing the catalytic cycle and affording the desired products (32) after deprotonation.…”