Читать книгу Methodologies in Amine Synthesis - Группа авторов - Страница 38

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 Co^III 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 Co^II 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 Ru^II* to its higher valence state Ru^III and meanwhile furnishing radical cation 147. The resulting Ru^III 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 bond interaction. Final product 153a is formed after deprotonation and rearomatization of 156a.

Scheme 3.25 Photoinduced oxidant‐free C–H amination of arenes with azoles.

Source: Modified from Niu et al. [38].

Scheme 3.26 Selective C–H amination of electron‐rich arenes via photoredox catalysis.

Source: Modified from Pandey et al. [39].

Scheme 3.27 Electrochemical ortho‐amination of aromatic C—H bonds with azoles.

Source: Modified from Wang et al. [40].

Electron‐rich pyrroles and thiophenes can easily be oxidized into their corresponding radical cations to undergo further C—N bond formation processes via N‐atom nucleophilic addition pathway. In 2016, König and coworkers realized a photocatalytic C(sp²)–H sulfonamidation of pyrroles to reach a range of N‐(2‐pyrrole)sulfonamides 159 (Scheme 3.28) [41]. In this transformation, N‐substituted pyrrole 157 is first oxidized by the photoexcited organic dye Mes‐Acr⁺ into its corresponding radical cation 160, which is attacked by strong anionic nucleophile 161, resulting from deprotonation of sulfonamide 158 to generate radical intermediate 162. The final amination product 159 is afforded via a HAT process with O₂^·− or alternatively through further oxidation and deprotonation sequence of 162.

Scheme 3.28 Direct C2‐sulfonamidation of pyrroles via visible‐light photoredox catalysis.

Source: Modified from Meyer et al. [41].

Scheme 3.29 DDQ‐mediated C2‐amination of thiophenes via visible‐light photoredox catalysis.

Source: Modified from Song et al. [42].

In the following year, Lei and coworkers disclosed a photocatalytic C(sp²)–H amination of thiophenes with azoles, employing 2,3‐dicyano‐5,6‐dichlorobenzoquinone (DDQ) as an organic photocatalyst, tert‐butyl nitrite (TBN) as an electron transfer mediator, and aerobic oxygen as the oxidant (Scheme 3.29) [42]. The photoexcited catalyst DDQ* upon visible light irradiation possesses a high oxidation potential (E_red = 3.18 V vs. saturated calomel electrode [SCE]) and thus can easily oxidize thiophene 163 into radical cation 166. Nucleophilic addition by azole 164 and the following proton donation to DDQ^·− convert radical cation 166 into radical intermediate 167, which undergoes further HAT process with the formed DDQH^· to yield the desired products 165 and DDQH₂. To complete the photocatalytic cycle, DDQH₂ then participates in another cycle involving TBN to regenerate the original photocatalyst DDQ.

Scheme 3.30 Photocatalytic benzene C–H amination and hydroxylation with hydrogen evolution.

Source: Modified from Zheng et al. [43].

Apart from the most widely used N–H nucleophile azoles, ammonia as an abundantly available and cheap reagent has also attracted attention of researchers, and has been exploited in nucleophilic CDC amination. In 2016, Wu and Tung and coworkers developed a dual catalytic cross‐coupling between aromatic C—H bonds and ammonia or water under visible‐light conditions to furnish anilines or phenols with the evolution of hydrogen gas (Scheme 3.30) [43]. N‐Methylquinolinum salts QuCN⁺ClO₄⁻ and QuH⁺ClO₄⁻ are employed as the photocatalysts (QuR⁺), whose the excited states possess enough oxidizing power (E_red* = 2.72 and 2.46 V vs. SCE, respectively) to accept an electron from benzene (E_ox = 2.48 V vs. SCE) to furnish the reduced photocatalyst QuR^· along with the crucial radical cation 171. Subsequently, the former is oxidized by Co^III catalyst to regenerate the ground‐state photocatalyst QuR⁺; meanwhile, the latter is captured by a nucleophile to form radical 172, which further donates an electron to Co^II to produce cationic species 173. The final product 170 is formed after further deprotonation of 173. On the basis of CV studies, the redox potential values demonstrate that product 170 is also capable of quenching the excited photocatalyst QuR⁺*, which may result in its further functionalization. However, mono‐functionalized benzene is obtained as the only product, and no multiaminated or hydroxylated products can be detected even after prolonged reaction time. A hypothesis for this result, advanced by the authors, is that the rapid back‐electron transfer from the reduced QuR^· to the formed radical cation of 170 protects product 170 from overoxidation.