have also applied the protocol to the modification of biomolecules [36].
Scheme 3.22 Anodic N—H bond cleavage for aromatic C—H bond amination.
Source: Modified from Zhao et al. [34].
Scheme 3.23 Electrochemical oxidative C–H amination of phenols.
Source: Modified from Tang et al. [35].
3.3 Amination via N‐atom Nucleophilic Addition
As introduced in Section 3.2, construction of C—N bonds via N‐radical addition pathway relies on N‐centered radical (or radical cation) species, generated by oxidation of N—H bonds, as key intermediates. On the contrary, aminations via N‐atom nucleophilic addition pathway proceed through the oxidation of the C–H partners, and the amines usually serve as nucleophiles to attack the generated C‐centered cationic intermediates during the C—N bonds forming processes.
3.3.1 Aromatic C(sp2)—H Bond Amination
As documented in the literature precedents, direct oxidation of (hetero)arenes is feasible under photo‐ or electrochemical conditions, and the resulting radical cation intermediates could then be attacked by nucleophiles such as –NHR, –OH, and –CN−. Yet, among the electrochemical amination reactions via arene radical cation intermediates, methods directly employing simple N–H nucleophiles are still not common. Nevertheless, notable progress has been advanced via photoredox catalysis, wherein strongly nucleophilic azoles usually serve as the amine partners.
In 2015, a photocatalytic site‐selective CDC amination of unfunctionalized arenes with azoles was described by Nicewicz's group using an organic catalyst system consisting of an acridinium photocatalyst and a nitroxyl radical (Scheme 3.24) [37]. Upon irradiation with visible light, the photoexcited acridinium photocatalyst Mes‐Acr+* is able to directly oxidize arene 130 into the corresponding radical cation 134, which is subsequently attacked by the amine nucleophile 131 to form cationic radical 135. Deprotonation of 135 affords radical intermediate 136, which further undergoes aromatization via a TEMPO‐mediated HAT process to furnish the final product 133. Alternatively, intermediate 136 can also be trapped by O2 to form 1,3‐cyclohexadienyl peroxyl radical 137, which then converts into product 133 after the internal elimination of the hydroperoxyl radical HOO·. The closure of two catalytic cycles is indicated by the regeneration of ground‐state photocatalyst Mes‐Acr+ from the SET oxidation of Mes‐Acr· by O2 or HOO·, and TEMPO from a HAT process between TEMPO‐H and O2 or O‐radical species such as O2·− and HOO·. In the scope exploration, a variety of aromatic compounds including complex drug‐like structures are firstly investigated, with the corresponding amination products obtained in moderate to good yields. A series of heterocyclic nucleophiles including pyrazoles, triazoles, tetrazoles, imidazoles, and benzimidazoles are proven as suitable coupling partners for the CDC amination with arenes. Particularly, reactions between a commercially available ammonium carbamate H4N+H2NCO2− (132) and various (hetero)arenes directly furnish primary aniline products.
Scheme 3.24 Site‐selective aromatic C–H amination via photoredox catalysis.
Source: Modified from Romero et al. [37].
The direct oxidative C–N cross‐coupling between arenes and azoles has also been realized with other photocatalytic systems. In 2017, Lei's group employed a dual catalytic system combining an acridinium photocatalyst with a Co‐based cocatalyst for the C—N bond formation to access N‐arylazoles (Scheme 3.25) [38]. This sustainable protocol does not require any sacrificial oxidant, and the released H2 gas is the only by‐product. Various aromatics including substituted benzenes, biphenyls, and anisole derivatives are smoothly aminated under the standard conditions. Based on the kinetic isotope effect (KIE) experiments and other mechanistic studies, the reaction begins with the oxidation of 138 by the photoexcited Mes‐Acr+*, which leads to the formation of Mes‐Acr· and radical cation 141. The ground‐state photocatalyst Mes‐Acr+ is then regenerated by single‐electron oxidation of Mes‐Acr· by CoIII catalyst. On the other hand, nucleophilic attack of amine 139 to radical cation 141 forms radical intermediate 142 after deprotonation, which subsequently undergoes a single‐electron oxidation by CoII to form cation 143. The final product 140 is delivered after deprotonation of 143.
In the same year, Pandey's group reported a regioselective method for the direct C(sp2)–H amination of anisoles with different azoles under visible light conditions using Selectfluor as an external oxidant (Scheme 3.26) [39]. As a strong oxidant, Selectfluor is capable of oxidizing the photoexcited RuII* to its higher valence state RuIII and meanwhile furnishing radical cation 147. The resulting RuIII then readily undergoes a SET reduction with the electron‐rich arene 144 to complete the photocatalytic cycle and simultaneously generates radical cation 148, which is further attacked by the amine nucleophile 145 to give radical intermediate 149. After deprotonation of 149 by 2,6‐lutidine and H‐atom abstraction of 150 by radical 147, the desired amination product 146 is finally obtained.
In 2019, an electrochemical alternative was disclosed by Wu and coworkers, wherein exclusive ortho‐selectivity of amination was achieved in the most cases, under metal‐ and oxidant‐free conditions (Scheme 3.27) [40]. During the optimization of the reaction conditions using anisole 151a and pyrazole 152a, the authors found that the addition of trifluoroacetic acid (TFA) could effectively enhance the ortho‐regioselectivity. Similarly, in the subsequent scope evaluation, it was also observed that reactions with TFA provided significantly higher o:p selectivity than the corresponding ones without it (153a, 153d, and 153e). The proposed mechanism is depicted in Scheme 3.27b. Anisole 151a is preferentially oxidized to provide the radical cation 154a at the anode, after which pyrazole 152a as a nucleophile attacks 154a to form the ortho‐aminated intermediate 156a via a putative intermediate 155a with TFA‐assisted hydrogen
