Читать книгу Methodologies in Amine Synthesis - Группа авторов - Страница 36

In the early years, the direct oxidative aminations of unfunctionalized arenes were achieved using iodine‐based reagents by the research groups of DeBoef, Chang, and Antonchick, wherein the employed amine partners were mainly sulfonamides and phthalimides. With the development of photoredox and electrochemical methodologies, more and more sustainable synthetic alternatives have emerged for the direct C(sp²)—N bond formation of simple arenes via N‐radical species addition pathways.

In 2016, Yu and Zhang and coworkers reported a visible‐light‐induced CDC amination of heteroarenes 98 with sulfonamides 99 using bleach (aqueous NaClO solution) as the oxidant (Scheme 3.18) [30]. Multiple heteroarenes such as indoles, pyrroles, and benzofurans can undergo this transformation with N‐methyl‐para‐toluene sulfonamide to afford their corresponding C2‐amide products (100a–d). The scope of sulfonamides is also explored using 1,3‐dimethyl‐1H‐indole as the heteroarene partner, with R¹ and R² being aromatic or aliphatic moieties (100e–100h). Furthermore, attempts to apply this protocol to intramolecular C2‐amination/cyclization of indoles succeeded in building fused indole derivatives (100i, 100j). The proposed mechanism is depicted in Scheme 3.18b. After excitation of the photocatalyst Ir^III under visible light irradiation, the excited Ir^III* is then oxidized by NaClO to its higher valence state Ir^IV, as demonstrated by fluorescence quenching experiments. The resulting Ir^IV is capable of directly oxidizing sulfonamide 99 into N‐centered radical 101, meanwhile regenerating Ir^III to complete the photocatalytic cycle. The subsequent addition of N‐radical 101 onto the C2 position of heteroarene 98 forms benzylic radical 102, which undergoes further oxidation/deprotonation sequence to deliver the desired product 100 via cationic intermediate 103.

Scheme 3.18 Visible‐light‐induced direct C–H amination of heteroarenes with sulfonamides.

Source: Modified from Tong et al. [30].

In the following year, another CDC amination of heteroarenes 104 using phthalimide 105 as the N–H source was then disclosed by Itoh's group, employing 2‐tert‐butylanthraquinone (2‐t‐Bu‐AQN) as the photocatalyst and aerobic oxygen as the external oxidant (Scheme 3.19) [31]. Multiple heteroarenes are smoothly aminated under the metal‐free conditions, including diverse N‐protected indoles and pyrroles as well as benzo[b]thiophene (106a–106d). Based on several control experiments, the authors postulate that, after the deprotonation by K₂CO₃ and the single‐electron oxidation by the photoexcited AQN*, phthalimide 105 is converted into the key N‐centered radical 107, and the resulting AQN^·− is then oxidized back to the original AQN by aerobic oxygen to complete the photocatalytic cycle. Subsequently, the desired amination product 106 is furnished from intermediate 107 after a radical addition/SET oxidation/aromatization sequence.

Scheme 3.19 Visible‐light‐mediated C–H amination of heteroarenes.

Source: Modified from Yamaguchi et al. [31].

In the same year, Itami and coworkers disclosed a CDC amination of aromatic C(sp²)–H enabled by visible light photoredox catalysis, using sulfonimides 110 as the N–H sources and a widely used Ru‐complex as the photocatalyst (Scheme 3.20) [32]. The substrate scopes of both coupling partners are reasonable, covering a variety of arylsulfonimides bearing various substituents and different arenes and heterocycles (111a–111f). The mechanism proposed by the authors is presented in Scheme 3.20b. First, the hypervalent iodine oxidant 1‐butoxy‐1λ³‐benzo[d][1,2]iodaoxol‐3(1H)‐one (IBB) undergoes a SET reduction by the photoexcited catalyst Ru^II* to generate a radical intermediate 112 along with a Ru^III species. The subsequent single‐electron oxidation of sulfonimide 110 by Ru^III yields the key imidyl radical 113, which then adds onto arene 109 to afford radical intermediate 114. Next, cationic intermediate 116 formed via a SET process between 112 and 114, further aromatizes to afford the desired amination product 111.

Scheme 3.20 Photocatalytic dehydrogenative C–H imidation of arenes with sulfonimides.

Source: Modified from Ito et al. [32].

Remarkably, aliphatic amines have also been successfully applied as aminating reagents for the CDC amination of arenes. In 2017, Nicewicz's group reported a challenging intermolecular C—N bond formation between simple arenes 117 and primary aliphatic amines 118 by means of photoredox catalysis (Scheme 3.21) [33]. This transformation, which employs a mixed solvent of 1,2‐dichloroethane (1,2‐DCE) and phosphate buffer (pH = 8), accommodates a wide range of electron‐rich aromatic and heteroaromatic compounds and diverse primary aliphatic amines including amino acids. According to fluorescence quenching experiments, both the arenes and amines are able to quench the excited photocatalyst; thus, both of their radical cations are potential reaction intermediates. However, even the less electron‐rich arenes such as benzene and toluene, which are unlikely to be oxidized by the excited photocatalyst, can undergo smooth amination to afford the corresponding aniline products (119d, 119e). Consequently, an arene radical cation pathway can be excluded in such cases. Based on all mechanistic studies, a plausible mechanism is presented by the authors as shown in Scheme 3.21b. For the reactions of electron‐poor/neutral arenes, radical cation 120 produced from SET oxidation of amine 118 by the photoexcited Mes‐Acr⁺* is the only possible intermediate, which subsequently adds onto arene 117 to form a cyclohexadienyl radical 121. Upon oxidation by O₂ and deprotonation, 121 aromatizes to form the desired amination product 119. As for the reactions of electron‐rich arenes, both amine radical cation and arene radical cation can serve as potential intermediates, and the mechanism via the latter will be discussed in Section 3.3.

Scheme 3.21 Photocatalytic aryl C–H amination using primary aliphatic amines.

Source: Modified from Margrey et al. [33].

Organic electrochemistry has also been applied to generate N‐radicals directly from N—H bonds for addition to aromatic moieties. In 2017, Xu and coworkers described an electrochemical approach to access amidinyl radical 123 via the anodic N—H bond cleavage of substrate 122 (Scheme 3.22) [34]. Through the intramolecular cyclization of N‐radicals 123 onto their arene and heteroarene moieties, various tetracyclic benzimidazoles or pyridoimidazoles 124 are furnished with high efficiency. The reaction can also easily be scaled‐up by simply switching up the constant current (124a–124d). Additionally, substrate 122e with two potential cyclization sites is selected as an example to investigate the cyclization tendency of amidinyl radical 123e. Based on both experimental and theoretical results, 6‐endo‐trig cyclization (path a) to form a six‐membered ring takes precedence over the alternative five‐membered ring formation (path b).

In 2018, Lei's group developed a metal‐ and oxidant‐free electrochemical protocol for the oxidative C–H amination of unprotected phenols (Scheme 3.23) [35]. Various phenothiazine derivatives 126 generally couple at the ortho‐position of electron‐rich phenols 125, affording N‐aryl phenothiazines 127 in good to excellent yields. Low yields of 127 are achieved using phenols with an electron‐withdrawing group (127b) or electron‐neutral diaryl amines (127g, 127h). When both ortho‐positions of the phenol are occupied, the amination occurs at the para‐position instead (127f). The reaction is believed to proceed via an N‐radical cation addition to the aromatic ring of the phenol (Scheme 3.23b). Taking 127a as an example, phenothiazine 126a is first oxidized at the anode to generate a radical cation intermediate 128a, which then undergoes electrophilic addition to 125a, affording the hydroxyl carbon radical 129a. Subsequent anodic oxidation and deprotonation of 129a gives the final C(sp²)—N bond formation product 127a. Simultaneously, the reduction of protons at the cathode releases hydrogen gas during the process. In the following year, these authors 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].