Читать книгу Methodologies in Amine Synthesis - Группа авторов - Страница 35

Electrophilic addition of aminium radical cations to unsaturated C=C bonds represents another attractive approach for the C—N bond construction. Generally, in visible‐light‐induced reactions, direct SET oxidation of the N—H bonds by the excited photocatalysts affords the crucial aminium radical cation intermediates, which are further converted into α‐amino radicals after addition to unsaturated C=C bonds to allow the C—N bond formation. In this field, representative work has been demonstrated independently by the research groups of Zheng and Knowles.

In 2012, Zheng's group disclosed a visible‐light‐induced intramolecular C—N bond formation/cyclization reaction of styryl diarylamines 60 and 62 to prepare N‐arylindoles 61 and 63 under the irradiation of a white light‐emitting diode (LED) and ambient conditions (Scheme 3.10) [23]. Interestingly, a 1,2‐carbon shift process is observed in the reaction of substrates 62 with their C2 position fully occupied, affording R¹‐shifted indole products 63 in moderate yields, wherein aryl groups are preferentially transferred over alkyl groups (63a). A reasonable reaction scope is presented, covering various substrates with electron‐donating or electron‐withdrawing substituents on Ar₁, as well as a wide range of substituents on C2 and C3 (61a–61e). Moreover, the R¹‐migration process represents an elegant strategy for ring expansion (63b). Nevertheless, functional groups on Ar₂ are limited to para‐alkoxy ones to facilitate their effective oxidation.

Scheme 3.10 Photocatalytic C—N bond formation for the preparation of N‐arylindoles.

Source: Modified from Maity and Zheng [23].

A plausible mechanism for the above photocatalytic transformation is proposed in Scheme 3.11. The reaction occurs with the oxidation of substrate 60 by the excited state photocatalyst Ru^II* to generate the key aminium radical cation 64. The subsequent intramolecular electrophilic addition of 64 to its tethered C=C bonds affords intermediate 65, which then turns into benzylic radical 66 after a proton abstraction. The oxidation into the corresponding benzylic cation 67 and the further aromatization of 67 upon deprotonation finally result in the desired N‐arylindole 61. As for substrate 62, the reaction proceeds through the same pathway before reaching benzylic cation 68. Then, a 1,2‐carbon shift event follows, in which one of the substituents on C2 migrates onto C3, providing cationic intermediate 69, which is further deprotonated to deliver the final product 63.

Thereafter, the authors applied this intramolecular C—N bond formation strategy and the same privileged structure to another photoredox cyclization protocol, in which two aliphatic rings are formed in one step to furnish fused indolines 71 (Scheme 3.12) [24]. Herein, remote nucleophilic functional groups such as –OH and –NHBoc are installed at the C2 position of the 2‐styryl anilines 70 to attack the in situ generated benzylic carbocations, and the desired cyclization products 71 are successfully obtained under photocatalytic conditions similar to their previous work.

Scheme 3.11 Mechanistic proposal for the photocatalytic synthesis of N‐arylindoles.

Scheme 3.12 Visible‐light‐initiated tandem reaction for the synthesis of fused N‐arylindolines.

Source: Modified from Morris et al. [24].

In 2014, an intramolecular anti‐Markovnikov hydroamination protocol of aryl olefins was disclosed by Knowles' group, for the construction of structurally diverse N‐aryl heterocycles 73 in a simple reaction system under mild photocatalytic conditions (Scheme 3.13) [25]. The reaction is proposed to begin with the direct oxidation of aniline 72 by the photoexcited catalyst Ir^III* to generate the crucial aminium radical cation 74, as supported by both CV data and luminescence quenching experiments. The following sequence of the intramolecular addition to the tethered alkene of intermediate 74, the one‐electron reduction of benzylic radical 75 by Ir^II, and the proton transfer from alcoholic solvent to 76 delivers the final product 73. A wide range of substrates bearing various substituents on both aromatic groups (Ar¹ and Ar²) are proven compatible with this method, providing cyclization products in good to excellent yields, including five‐ or six‐membered, heterocylic, and bicyclic ones (73a–73h). However, application of this protocol to intermolecular couplings turned out to be unsuccessful, which is likely due to the fact that the bimolecular C—N bond formation fails to outcompete the favorable electron back‐transfer from the Ir^II complex to the aminium intermediate, as speculated by the authors.

Scheme 3.13 Photocatalytic intramolecular hydroamination of olefins with aminium radical cations.

Source: Modified from Musacchio et al. [25].

With their further exploration into photocatalytic amination of alkenes, Knowles and coworkers next developed an intermolecular anti‐Markovnikov hydroamination of unactivated alkenes 78 with secondary aliphatic amines 77, which is not accessible using their previous protocol (Scheme 3.14) [26]. Various structurally diverse alkenes, including terminal and di/tri/tetra‐substituted internal ones, smoothly undergo this redox‐neutral hydroamination with a wide range of secondary alkyl amines under facile conditions (79a–79i). Specifically, the aminium radical cation intermediate would preferentially add to the more electron‐rich olefin when two electronically differentiated C=C bonds exist in one substrate (79d, 79e). Notably, this direct hydroamination method can also be applied to the intramolecular C—N bond construction (79j). Nevertheless, aromatic amines, α‐amino acids, and tetramethylpiperidine have been proven as inert amine partners in this reaction.

Scheme 3.14 Photocatalytic intermolecular hydroamination of unactivated olefins with secondary alkyl amines.

Source: Modified from Musacchio et al. [26].

The mechanism proposed by the authors is depicted in Scheme 3.14b. As supported by Stern–Volmer experiments, piperidine 77a can effectively quench the photoexcited Ir^III* to produce the N‐centered radical cation species 80a, which then adds onto an alkene acceptor, e.g. 78a, to form a new C—N bond along with an adjacent C‐radical (81a). Differently from their previous amination protocol (Scheme 3.13), intermediate 81a then abstracts a hydrogen atom from the TRIP thiol cocatalyst to deliver a closed‐shell ammonium ion 82a and a transient thiyl radical (ArS^·). Subsequently, a SET process takes place between ArS^· and the reduced Ir^II species to provide ArS⁻ and the regenerated ground‐state photocatalyst Ir^III. The final hydroamination product 79a is furnished after the deprotonation of 82a by anion ArS⁻. According to the obtained redox potentials, the final products 79 could possibly be further oxidized by the excited Ir^III*, but high yields of 79 have still been obtained in these transformations without meaningful amounts of decomposition. The authors speculate that this outcome may result from the protective action of the thiol cocatalyst by reducing any α‐amino radical that could be engaged in further deleterious side reactions.

Again in 2019, an intermolecular anti‐Markovnikov hydroamination of unactivated olefins 84 was achieved by Knowles' group, using simple primary alkyl amines 83 under mild photoredox conditions (Scheme 3.15) [27]. An identical mechanism to the former one via an aminium radical cation intermediate 86 is proposed for this transformation employing a different iridium photocatalyst with divergent reactivity. Despite the presence of excess olefin, high selectivities, generally over 20 : 1, are observed for secondary over tertiary amine products.

In the typical visible‐light‐induced reactions described above, the photoredox catalysts harvest visible light to reach their excited states, which then undergo further single‐electron redox events with reactants. Recently, a new photoactivation paradigm has emerged, wherein the transition‐metal‐based photocatalysts also directly engage in the bond formation/cleavage processes. In this area, a growing number of photoinduced C—N bonds forming methodologies using Cu‐based unconventional photocatalysts have lately been developed by Fu, Hwang, Kobayashi, etc., and their progresses have been summarized by Gevorgyan in 2017 [28]. As an example, Hwang and coworkers reported a visible‐light‐induced, Cu‐catalyzed reaction for the preparation of α‐ketoamides from anilines 87 and alkynes 88 under ambient conditions (Scheme 3.16) [29]. Using oxygen as a green oxidant, this ligand‐ and base‐free method features high atom economy and is compatible with a wide range of aniline and alkyne substrates. Notably, bioactive epoxide hydrolase inhibitors 89i and 89j are smoothly prepared within a single step from commercial starting materials by means of this strategy.

A plausible pathway is proposed on the basis of a series of detailed mechanistic studies (Scheme 3.17). Via a weak Cu^I–aniline complex formed by catalyst CuCl and aniline 87, Cu^I–phenylacetylide 90 is generated upon the addition of alkyne 88, which then reaches its excited state 91 under blue light irradiation. The following SET oxidation of 91 by O₂ provides an electron‐deficient Cu^II–phenylacetylide 92 as well as a superoxide. The following nucleophilic addition of aniline 87 to complex 92 results in the Cu^III species 93, which next undergoes reductive elimination to furnish the highly reactive Cu^I‐coordinated ynamine 94. The intermediate 94 readily reacts with O₂ to generate the Cu^II peroxo‐complex 95, which then tautomerizes into the Cu^I species 96. Finally, complex 96 is attacked by Cl⁻ to regenerate the catalyst CuCl, and the subsequent ring cleavage of the resulting intermediate 97 furnishes the final α‐ketoamide product 89.

Scheme 3.15 Photocatalytic intermolecular anti‐Markovnikov hydroamination of unactivated olefins with primary alkyl amines.

Source: Miller et al. [27].

Scheme 3.16 Photoinduced, CuCl‐catalyzed oxidative C–N coupling of anilines with terminal alkynes.

Source: Modified from Sagadevan et al. [29].

Scheme 3.17 Proposed mechanism for the photoinduced, CuCl‐catalyzed C–N coupling of anilines with terminal alkynes.