1.2 Mechanisms of two main types of electrophilic amination.
1.2 Cu‐Catalyzed Reactions
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 (
