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The activated C(sp³)–H adjacent to a nitrogen atom is also prone to photo/electrochemical oxidation and to subsequent nucleophilic amination. In 2019, Zeng and coworkers reported an electrochemical dehydrogenative imidation of N‐methyl benzylamines 208 with phthalimides 209 to obtain various phthalimide‐protected gem‐diamines 210 (Scheme 3.36) [50]. Notably, the amination occurs regioselectively at the methyl group rather than at the benzylic position of each N‐methyl benzylamine. Apart from multiple phthalimides with different substituents (210a–210e), certain triazoles are also viable amine sources (210f). Based on CV studies, revealing that benzylamine 208a is easier to be oxidized than phthalimide 209a, a plausible mechanism is proposed as shown in Scheme 3.36b. The reaction is initiated by anodic oxidation of 208a to give the radical cation 211a, which undergoes deprotonation and further oxidation to generate the iminium intermediate 212a. Meanwhile, MeOH is reduced at the cathode to give MeO⁻ and H₂. Simultaneously, 209a is deprotonated by MeO⁻ to give the anionic intermediate 213a, which then undergoes a Mannich‐type addition to 212a generating product 210a.

Scheme 3.36 Electrochemical dehydrogenative imidation of N‐methyl‐substituted benzylamines.

Source: Modified from Lian et al. [50].

Almost simultaneously, Lei's group also reported an electrochemical direct imidation of N‐methyl anilines with hydrogen evolution under acidic conditions (Scheme 3.37) [51]. Acetic acid plays a key role in this reaction, other acids such as HCOOH, H₂SO₄, and TsOH could not enable the reaction to proceed, while nPrCOOH led to reduced efficiency. Cyclic amides, heteroatom‐containing amides, and succinimides are well tolerated in this transformation and afford products in moderate to good yields (216a–216e). The proposed reaction mechanism is nearly identical to the previous one.

Recently, an elegant visible‐light‐driven intramolecular C–N cross‐coupling reaction was disclosed by Zheng's research group under mild and metal‐free conditions (Scheme 3.38) [52]. Various polycyclic quinazolinone derivatives (221a–221f and 223a–221d), including natural products tryptanthrin, rutaecarpine, and their analogs (223b–221d), could be smoothly furnished via this protocol. Further demonstration of gram‐scale synthesis and solar‐driven transformation proves the potential of this strategy for practical applications.

Scheme 3.37 Electrochemical dehydrogenative imidation of N‐methyl substituted anilines.

Source: Modified from Wang et al. [51].

The mechanistic proposal, on the basis of control experiments, DFT calculations, UV–vis spectroscopy, and electron paramagnetic resonance (EPR) studies, as well as X‐ray characterization of the key intermediate, is outlined in Scheme 3.39 with 221a taken as the example. The reaction is initiated by a photoisomerization of 220a upon irradiation with visible light to produce the photoisomer 222a, which displays absorbance around 395 nm and has a short lifetime. The long‐lived photoisomer complex 223a is then generated by the coordination of (R)-(-)-1,1'-binaphthyl-2,2'-diyl hydrogenphosphate [(R)‐BPA] through hydrogen bonding, which can induce the SET process under irradiation with visible light to generate the radical pair 224a. The resulting superoxide radical anion abstracts a hydrogen atom from 224a to produce amino radical 225a, which undergoes intramolecular 1,6‐HAT process to generate radical 226a. Then, the radical recombination of 226a and HOO^· forms the key intermediate hydroperoxide 227a, which is easily converted into iminium ion 228a under acidic conditions provided by the Brønsted acid (R)‐BPA. Finally, the polycyclic quinazolinone product 221a is formed through intramolecular nucleophilic addition with release of H₂O₂. As an alternative pathway, the oxidation by‐product 229a, formed from the hydroperoxide 227a, can be efficiently converted into 221a under the standard reaction conditions, as proven by a control experiment.

Scheme 3.38 Light‐driven direct intramolecular C–N cross‐coupling.

Source: Modified from Jing et al. [52].