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Narasaka and coworkers reported an early iteration of Cu‐catalyzed substitution‐type electrophilic amination of Grignard reagents utilizing O‐sulfonyloximes as aminating reagents. The reactions can also give products without copper catalysis, albeit with much lower yields. Because of the nature of the aminating reagents, subsequent acidic hydrolysis is needed to convert the imine products to the desired amines [5, 6]. A similar amination process of organozinc reagents was reported by the Erdik group around the same time. In this case, in addition to the O‐sulfonyloximes, the authors showed that the reaction can also proceed with methoxyamine when excess of the organometallic reagent was used (Scheme 1.3) [7, 8]. These early reactions have several drawbacks that affect their utilizations, including a very limited substrate scope, low conversion rate due to many side reactions, and, most importantly, the need to use a strong acid to hydrolyze the initial imine products. The use of strong acidic conditions in the hydrolysis makes these procedures unsuitable for substrates containing acid‐labile functionalities.

Scheme 1.3 Early examples of Cu‐catalyzed electrophilic amination.

Source: Erdik and Ay [2] and Tsutsui et al. [5].

Scheme 1.4 Cu‐catalyzed electrophilic amination of organozinc reagents.

In 2004, the Johnson group at UNC reported the Cu‐catalyzed electrophilic amination of diorganozinc reagents using acyl hydroxylamines as aminating reagents [9]. This is the first report of Cu‐catalyzed electrophilic amination reactions that give tertiary amines as products (Scheme 1.4). Compared to the O‐sulfonyloximes, O‐acyl hydroxylamines are more synthetically accessible and have better atom economy. A limitation, however, is that the nitrogen must be fully substituted (i.e. no acidic N—H bond is tolerated). In place of the diorganozinc substrate, this reaction can also use a Grignard reagent as the nucleophile, which is arguably more accessible and convenient to use [10].

Scheme 1.5 Cu‐catalyzed electrophilic amination via aryne intermediate.

After the initial disclosure of Johnson and coworkers, subsequent research showed that other organometallic reagents can also serve as the nucleophile.

A unique reaction was reported by Greaney and coworkers at the University of Manchester in the UK [11]. In this case, an aryne intermediate is first generated in situ via iodine–magnesium exchange, followed by elimination. A nucleophile subsequently attacks the aryne, and the resulting arylmetal undergoes Cu‐catalyzed electrophilic amination with the hydroxylamine‐derived electrophilic aminating reagent to furnish aryl amines as the final products (Scheme 1.5). This reaction gives access to unique aromatic products with a 1,2‐bis substitution pattern. The nucleophiles that can be used in this reaction include arylamines, thiophenols, and arylselenols. The overall transformation exhibits excellent regioselectivity; however, the isolated yield is lowered in those cases in which the reactants are sterically encumbered.

One important consideration in these types of reactions is that the nucleophile has to be able to coexist with the aminating reagent in order for the catalytic cycle to be established. Otherwise, the nucleophile may directly react (i.e. protonation and/or uncatalyzed nucleophilic attack) with the aminating reagent and may lead to the formation of undesired by‐products. This puts limitations on both the nucleophilicity and basicity of the organometallic nucleophiles. Organozinc compounds, Grignard reagents, and organoaluminum [12] reagents have been shown to be suitable nucleophiles for these types of reactions, while organolithium reagents are generally unsuitable because of their strong basicity and tendency to participate in side reactions that involve electron transfer pathways.

To address this issue and provide a solution for the direct electrophilic amination of organolithium reagents via copper catalysis, the group of A. B. Smith III (University of Pennsylvania, 2013) developed a protocol in which a siloxane transfer reagent is used to modulate the reactivity of the organolithium reagents (Scheme 1.6) [13]. The siloxane reagent acts as an “attenuator” for the more reactive organolithium reagents and lowers its reactivity by forming a less basic complex that can more readily participate in the catalytic cycle and, in the meantime, prevents the direct attack on the aminating reagent by the organolithium.

Scheme 1.6 Cu‐catalyzed electrophilic amination of organolithium reagents.

This type of C—N bond‐forming reaction can also take place directly between cuprates and electrophilic aminating reagents. One reason to justify the use of stoichiometric amounts of a copper salt (i.e. full transmetalation) is that the low basicity of the resulting cuprate can tolerate the presence of N–H protons in the aminating reagent, thereby enabling the synthesis of primary and secondary amine products without the use of excess organometallic reagent. The Kürti group has demonstrated this possibility with the use of sterically hindered N–H oxaziridines (Scheme 1.7) [14]. Compared to the tertiary amines, unprotected primary amines are more versatile building blocks for further functionalization.

These sterically hindered N–H oxaziridines can be readily synthesized on multigram scale from the corresponding N–H imines and meta‐chloroperbenzoic acid (mCPBA). The N–H oxaziridines are bench‐stable compounds and can also be readily purified via flash column chromatography and using regular silica gel as the stationary phase. The steric hindrance created by the bulky alkyl groups reduces the kinetic acidity of the oxaziridine N—H bond, thus allowing the cuprates to be aminated as opposed to suffering unproductive proton transfer.

Scheme 1.7 Electrophilic amination of arylcuprates using a NH‐oxaziridine.

Since the advent of direct C–H cupration of arenes, it is now also possible to utilize cuprate nucleophiles without first going through a separate transmetalation step. Uchiyama and coworkers (at RIKEN, Japan) showed that it was indeed possible to directly aminate aryl cuprates with O‐benzyl hydroxylamine. The directed C–H cupration of arenes was achieved using a strong base (TMP)₂Cu(CN)Li₂, which can selectively deprotonate at the ortho position of the amide directing group. The resulting aryl cuprates can be directly primary aminated with benzyl hydroxylamine (Scheme 1.8) [15]. The hygroscopic nature of O‐benzyl hydroxylamine necessitates its use as a stock solution in an organic solvent.

The instability of organometallic reagents used in the aforementioned reactions imposes limits on their widespread utilization, especially in an industrial setting. Efforts have been made to replace the air‐ and moisture‐sensitive organometallic reagents with more stable alternatives that can be conveniently stored and used. Miura and coworkers (Osaka University, Japan) have shown that both arylboronates (Scheme 1.9) [16] and arylsilanes (Scheme 1.10) [17] can serve as starting materials in Cu‐catalyzed electrophilic amination reactions. These reactions can proceed under ambient temperature and furnish the corresponding anilines in good to excellent isolated yields. The enhanced stability of arylboronates and arylsilanes reduces the complexity of the operation and, at the same time, the wide commercial availability of arylboronates also adds convenience to these types of reactions.

Scheme 1.8 Electrophilic amination via directed C–H cupration.

Scheme 1.9 Cu‐catalyzed electrophilic amination of arylboronates.

Hirano and Miura discovered that ambident nucleophiles such as silyl ketene acetals are also suitable nucleophiles for the Cu‐catalyzed electrophilic amination reactions. These reactions result in the formation of alpha‐amino esters as products. The first generation of this reaction uses chloramines as aminating reagents [18], while the second generation can proceed with the more stable and much safer O‐benzoyl hydroxylamines (Scheme 1.11) [19]. This method provides a potential route for the syntheses of unnatural as well as modified natural amino acids.

Scheme 1.10 Cu‐catalyzed electrophilic amination of aryl silanes.

Source: Modified from Miki et al. [17].

Weak nucleophiles such as styrenes and some electron‐deficient heterocycles can also participate in Cu‐catalyzed electrophilic amination reactions.

In the case of styrenes, the substrates can undergo hydroamination or aminoboration depending on the specific reaction conditions. Hirano, Miura, and coworkers have demonstrated that styrenes can be stereoselectively functionalized with benzoyl hydroxylamine and bis(pinacolato)diboron under Cu catalysis (Scheme 1.12) [20]. The resulting products can further participate in transition‐metal‐catalyzed cross‐coupling reactions.

When polymethylhydrosiloxane (PMHS) is used instead of bis(pinacolato)diboron, hydroamination products can be obtained under similar reaction conditions (Scheme 1.13). In these cases, it is proposed that the reaction proceeds with an initial CuH addition across the C—C bond of the olefins, followed by the electrophilic amination of the resulting cuprates [21].

With chiral ligands, the hydroamination reactions can give enantiomerically enriched products. Both the Miura (Scheme 1.14) and Buchwald (Scheme 1.15) groups have developed conditions using chiral phosphine ligands [21, 22].

Buchwald and coworkers have also reported the hydroamination of aryl acetylenes. The reaction is highly stereoselective, giving E‐enamines as the major products. The enamine products can be further reduced to give alkyl amines, which are important building blocks in organic synthesis (Scheme 1.16) [23].

Scheme 1.11 Cu‐catalyzed electrophilic amination of silyl enol ethers.

Source: Modified from Matsuda et al. [19].

Scheme 1.12 Cu‐catalyzed electrophilic catalyzed aminoboration of styrenes.

Source: Modified from Matsuda et al. [20].

Scheme 1.13 Cu‐catalyzed electrophilic hydroamination of styrenes.

Source: Modified from Miki et al. [21].

Scheme 1.14 Enantioselective Cu‐catalyzed electrophilic hydroamination of styrenes.

Source: Miki et al. [21].

Scheme 1.15 Enantioselective Cu‐catalyzed electrophilic hydroamination of styrenes.

Source: Modified from Zhu et al. [22].

Scheme 1.16 Cu‐catalyzed electrophilic amination of alkynes.

Source: Shi and Buchwald [23].

Scheme 1.17 Cu‐catalyzed annulative electrophilic amination.

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

ortho‐Alkynyl phenols and anilines can also undergo annulative amination with electrophilic aminating reagents under Cu catalysis. Miura and coworkers have developed conditions for the synthesis of aminated benzofurans and indoles (Scheme 1.17) [24]. The transformation is operationally simple and proceeds at room temperature. The mechanism was probed and the authors concluded that the most plausible pathway is a nonradical electrophilic amination of the heteroarylcuprate species in the C—N bond‐forming step.

Similar intramolecular reactions can also take place with substrates containing unactivated terminal alkenes. In 2015, the Wang group (Duke University) reported the copper‐catalyzed vicinal diamination of unactivated alkenes with hydroxylamines that is both regio‐ and stereoselective. The first iteration of this reaction takes place on unsaturated amides and gives 4‐amino‐2‐pyrrolidones as the products (Scheme 1.18) [25]. This transformation is considered to be the first metal‐catalyzed alkene 1,2‐diamination that enables the direct incorporation of an electron‐rich amino group.

In 2016, Wang and coworkers successfully expanded the substrate scope to include unsaturated carboxylic acids, which undergo amino‐lactonization under the reaction conditions (Scheme 1.19) [26]. The overall transformation allows the practitioner to access quickly and efficiently a wide range of amino‐substituted γ‐ and δ‐lactones as well as 1,2‐amino alcohol derivatives, which are of significant value in the synthesis of natural products and active pharmaceutical ingredients.

Scheme 1.18 Cu‐catalyzed electrophilic diamination.

Source: Modified from Shen and Wang [25].

An unusual case of ring‐opening amination of cyclopropanols has been reported by the Dai group [27]. In this reaction, a base‐initiated ring‐opening of cyclopropanol generates a carbanion nucleophile, which participates in the Cu‐catalyzed electrophilic amination and affords β‐aminoketones as products (Scheme 1.20). The catalytic cycle involves the oxidation of the Cu(I) complex to the corresponding Cu(III) species by the hydroxylamine reagent. Next, the Cu(III) intermediate promotes the ring‐opening of the cyclopropanol substrate and the resulting copper‐homoenolate undergoes reductive elimination to form the new C—N bond and to regenerate the catalytically active Cu(I) species. Overall, the transformation proceeds under mild reaction conditions and it is also compatible with a number of sensitive functionalities such as esters, epoxides, and unsaturated carbonyl compounds.

With electron‐deficient arenes, direct C–H amination is also possible. Miura and coworkers have reported the Cu‐catalyzed direct C–H amination using benzoyl hydroxylamines as aminating reagents (Scheme 1.21) [28]. Electron‐deficient aromatic substrates such as fluoroarenes, oxadiazoles, and thiazoles can be directly aminated to furnish the corresponding aryl and heteroaryl amines. The Yotphan group later expanded the substrate scope to include benzoxazoles [29], while the Li group applied the reaction to enable the C–H amination of quinoline N‐oxide [30].

Scheme 1.19 Cu‐catalyzed electrophilic amino‐lactonization.

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

Scheme 1.20 Cu‐catalyzed ring‐opening amination.

Source: Modified from Ye and Dai [27].

Scheme 1.21 Cu‐catalyzed C–H amination of heterocycles.

Source: Matsuda et al. [28].