Methodologies in Amine Synthesis. Группа авторов

Therefore, 246a and 247a are simultaneously oxidized at the anode to afford radical cation 249a and radical 251a after deprotonation. The subsequent radical/radical cross‐coupling produces cationic species 252a, which turns into the final product 248a after further deprotonation. Shortly after the publication of this work, Song and Li and coworkers also disclosed their independent research, which is very close to Lei's work [56].

      3.4.1.2 Aryl C(sp²)—N Bond Formation Using Azoles

In 2017, Adimurthy's group developed a regioselective C–H amination of heteroarenes with azoles using acridinium salt Mes‐Acr⁺ClO₄⁻ as the photocatalyst under visible light irradiation (Scheme 3.43) [57]. Quinoline amides 253 and imidazopyridines 254 serve as eligible substrates, which undergo regioselective amination at C5 and C3 position, respectively, with various azoles 255. Taking the amination of 253 as an example, it is proposed that the transformation proceeds through cross‐coupling of N‐radical cation 258 and C‐radical species 260 on the basis of a series of mechanistic investigations.

Scheme 3.43 Selective C–H amination of heteroarenes with azoles via an organic photoredox system.

      Source: Modified from Samanta et al. [57].

More recently, Lei and coworkers disclosed an electrochemical C‐3 amination of imidazo[1,2‐a]pyridines 262 with amines 263 via an oxidative C–H/N–H cross‐coupling (Scheme 3.44) [58]. The reaction is supposed to proceed via a cross‐coupling process of electrochemically generated C‐ and N‐radicals (Scheme 3.44b). Additionally, an intramolecular C–N coupling through a Cp₂Fe‐mediated sequence of N‐radical formation and addition to the adjacent unsaturated moiety was also reported in the same article for the synthesis of 10H‐benzo[4,5]imidazo[1,2‐a]indole derivatives 266 from 265.

One more electrochemical C–H azolation was next developed by Feng and Chen and coworkers in 2019, wherein phenol and aniline derivatives are regioselectively aminated with azoles via a radical–radical cross‐coupling pathway (Scheme 3.45) [59]. During the investigation of the substrate scope, high ortho‐selectivity to the –XH group of this azolation is observed, and the sterically less‐hindered ortho‐position is preferred when asymmetrical phenols are applied (273b). In light of the mechanistic studies and reported work, the reaction mechanism is believed to involve a radical/radical cross‐coupling of 275 and 276, which are generated from anodic oxidation of substrates 271 and 272.

Scheme 3.44 Electrochemical oxidative C–H/N–H cross‐couplings for C—N bond formation with hydrogen evolution.

      Source: Modified from Yu et al. [58].

      3.4.2 Other C—N Bond Formation via Radical Cross‐coupling

The conjugate amination of α,β‐unsaturated carbonyl compounds represents a fundamental strategy to construct highly valuable β‐aminocarbonyl moieties. However, the direct addition of N‐centered radicals to electron‐deficient C=C bonds is unfavorable, at least as an intermolecular processes. To address this challenge, Meggers and coworkers realized a visible‐light‐induced enantioselective β‐amination of α,β‐unsaturated 2‐acyl imidazoles 278 with N‐aryl carbamates 279 using an iridium‐based photocatalyst in combination with a chiral‐at‐rhodium Lewis acid (Δ‐RhO), through a PCET‐enabled N–H activation with the aid of a weak phosphate base, followed by a C–N radical cross‐coupling (Scheme 3.46) [60]. The reaction mechanism is proposed in Scheme 3.46b, which begins with a PCET process between the photoexcited Ir^III* and substrate 279 with the aid of the Brønsted base, affording the carbamoyl radical 281 and the reduced Ir^II species. On the other hand, chiral catalyst Δ‐RhO binds the α,β‐unsaturated compound 278 to form the Rh‐bonded intermediate 282,which then undergoes single‐electron reduction with Ir^II to provide the Rh‐enolate radical intermediate 283 and meanwhile regenerate photocatalyst Ir^III. Subsequently, the cross‐coupling of radical intermediates 281 and 283 furnishes the C—N bond of 284. Alternative pathways via the addition of carbamate radical 281 or the corresponding anion to the C=C bonds of Rh‐coordinated intermediate 282 have been discussed and excluded on the basis of the experimental observations.

Scheme 3.45 Electro‐oxidative C–H azolation of phenol and aniline derivatives.

      Source: Modified from Feng et al. [59].

Direct amination of C(sp³)—H bonds via C/N‐radical cross‐coupling pathway often employs a HAT strategy (mainly 1,5‐HAT) and occurs intramolecularly. This topic has been discussed in detail within another chapter. As a distinct example, in 2017, Lei's group reported a metal‐ and oxidant‐free electrochemical protocol for the direct intermolecular C(sp³)—N bond construction via a radical cross‐coupling pathway (Scheme 3.47) [61]. The activated C(sp³)—H bonds on benzylic or allylic sites, as well as those on the α‐positions to O, S, and N atoms (286), can be aminated with various azoles 287 using this method (288a–288f). A tentative mechanism is proposed by the authors on the basis of the mechanistic studies and literature reports, as shown in Scheme 3.47b, in which N‐radical 289 serves as both a HAT reagent to produce C‐radical 290 and as a coupling partner to react with 290 to afford C–N cross‐coupling product 288.

Scheme 3.46 Enantioselective amination via PCET followed by stereo‐controlled radical cross‐coupling.

      Source: Modified from Zhou et al. [60].

3.5 Summary and Conclusions

This chapter focuses on the recent progress in direct