Methodologies in Amine Synthesis. Группа авторов

Ir^III* species and a proton abstraction by the base provides the key amidyl radical 2, which then cyclizes onto the attached C=C bonds to form a new C—N bond with an adjacent C‐centered radical (3). Subsequently, the nucleophilic radical 3 can further add onto an electrophilic olefin acceptor to deliver the carboamination product 4 after a tandem electron/proton transfer process. On the other hand, in the presence of catalytic thiophenol, radical 3 can also undergo a HAT process with the hydrogen donor to furnish the hydroamination product 5, while the resulting PhS^· is then engaged in a SET process with the Ir^II species to afford PhS⁻ and regenerate ground‐state photocatalyst Ir^III. The following protonation of PhS⁻ by the conjugate acid of the phosphate base indicates the closure of both catalytic cycles.

Later in 2016, Knowles' group employed the same strategy in the selective alkylation of remote C(sp³)—H bonds, which engages a 1,5‐HAT process with the aid of the amidyl radicals produced via PCET [10]. Simultaneously, a similar work was reported by Rovis' group [11]. Therefore, PCET activation has been proven as a powerful reaction mode for direct N‐radical formation from strong N—H bonds. Furthermore, it is also a promising platform to broadly explore this strategy in the construction of diversified C—N bonds.

Scheme 3.2 PCET‐mediated intramolecular carbo/hyrdroamination of alkenes.

      Source: Modified from Gentry and Knowles [9].

More recently, Knowles and coworkers reported a sulfonamidyl‐based hydroamination strategy, again via PCET activation (Scheme 3.3) [12]. Hydroamination products 7 and 10 could be smoothly furnished from intramolecular cyclization of 6 and intermolecular reaction between 8 and 9, respectively, employing 2,4,6‐triisopropyl‐thiophenol (TRIP thiol) as the HAT catalyst via the same pathway as depicted in Scheme 3.2. Apart from the broad substrate scope demonstrated, a series of tandem amination/C–H alkylation sequences were performed to highlight the synthetic versatility (Scheme 3.3b). The terminal alkene 11 was first subjected to the intermolecular anti‐Markovnikov hydroamination with p‐methoxyphenyl (PMP) sulfonamide 12 to afford the alkylated sulfonamide 13, and the newly installed secondary sulfonamide was then activated in a second oxidative PCET event using the same Ir/phosphate pair, leading to the site‐selective abstraction of the δ‐C—H bond to afford a carbon‐centered radical that can be further trapped by an electron‐deficient olefin 14 to afford the final product 15.

The reviving synthetic organic electrochemistry has been providing environmentally benign alternatives to the traditional synthetic methods because of its generally high atom economy and good functional group compatibility. In the electrochemical C—N bond formation from unfunctionalized N–H/C–H precursors, a series of advances have been achieved by Xu's group in the recent years. In 2016, Xu's group disclosed an electrocatalytic hydroamination of alkenes, in which an inexpensive organometallic reagent ferrocene was employed as a redox catalyst to enable the direct generation of amidyl radicals from N‐aryl amides 16 (Scheme 3.4) [13]. Based on the optimization of the reaction conditions, a mixed solvent tetrahydrofuran (THF)/MeOH in 5 : 1 ratio is demonstrated as the optimal choice, while no reaction takes place in the single solvent MeOH, which is also supported by the cyclic voltammetry (CV) observations.

Scheme 3.3 PCET‐mediated intra/intermolecular amination of alkenes. (a) Hydroamination of alkenes with primary or secondary sulfonamides. (b) Tandem amination/C–H alkylation.

      Source: Modified from Zhu et al. [12].

Scheme 3.4 Electrocatalytic intramolecular hydroamination of alkenes.

      Source: Modified from Zhu et al. [13].

As depicted in their mechanistic proposal (Scheme 3.4a), this reaction is supposed to begin with the anodic oxidation of ferrocene ([Cp₂Fe]) and the simultaneous cathodic reduction of cosolvent methanol. Subsequently, the electrochemically generated base MeO⁻ deprotonates the amide group of substrate 16 to afford anionic intermediate 18, which can be easily oxidized by [Cp₂Fe]⁺ to provide the key amidyl radical 19, along with the regenerated mediator [Cp₂Fe]. Radical 19 then cyclizes onto its tethered alkene to furnish intermediate 20, which further acquires a hydrogen atom from the H‐atom donor 1,4‐cyclohexadiene (1,4‐CHD) to yield the desired product 17. The scope exploration reveals that various carbamates, ureas, and amides can serve as viable substrates, providing the corresponding products in good to high yields under the standard conditions (Scheme 3.4b, 17a–17d). Notably, in the reactions of diene substrates 16a and 16b, tandem cyclization processes occurred to furnish polycyclic products 17e and 17f with high efficiency. Moreover, under standard conditions but in the absence of 1,4‐CHD, substrate 16c finally turns into indoline 21a after an oxidative termination step.

Again, Xu and coworkers employed the same electrochemical N‐radical formation strategy in the synthesis of highly functionalized (aza)indoles 23 through intramolecular N‐radical species addition of 22 to their remotely attached alkynyl moieties (Scheme 3.5) [14]. In this transformation, ferrocene is also selected as the redox mediator upon anodic oxidation, and the simultaneous cathodic reduction converts the cosolvent methanol into MeO⁻ base and H₂ gas. Subsequently, a SET process between the oxidized [Cp₂Fe]⁺ and anion 24 from deprotonation of 22 produces an electron‐deficient, N‐centered radical 25 and meanwhile regenerates [Cp₂Fe]. Radical 25 would then preferentially undergo a 6‐exo‐dig cyclization to vinyl radical 26, followed by a second cyclization to give the delocalized radical 27, as also supported by the density functional theory (DFT) calculations. Finally, rearomatization of 27 after an oxidation/deprotonation sequence delivers the final product 23. A broad substrate scope is demonstrated under the standard conditions, exhibiting high functional group tolerance (Scheme 3.5b). Notably, the late‐stage modification of ethinyl estradiol proceeds smoothly to deliver the indole‐functionalized estradiol 23a. The acid/base‐sensitive chiral amino esters (23b, 23c) as well as a free alcohol (23d) are also well tolerated under the electrolysis.