Methodologies in Amine Synthesis. Группа авторов

was found to be a suitable alternative nitrogen source. In addition to Cu, Mn and Fe are also capable of catalyzing the formation of metallanitrenes. These “tamed” nitrenes are more stable and have longer lifetimes, making them uniquely suitable for synthetic studies. However, the N‐sulfonyl groups are hard to remove, limiting the usefulness of the resulting products.

Scheme 1.27 Fe‐catalyzed electrophilic amination of styrenes.

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

      Recently, studies have shown that hydroxylamines can also serve as the nitrogen sources for metallanitrenes. Using hydroxylamines, it is now possible to generate N–H and N–alkyl amine products without sulfonyl groups. This section focuses on reactions that involve hydroxylamine‐derived metallanitrenes.

Metallanitrenes are generated from O‐activated hydroxylamines, in which the nitrogen atom bears a strong leaving group and a transition metal catalyst. In 2014, Kürti, Falck, and coworkers developed an N–H aziridination procedure for unactivated olefins using O‐(2,4‐dinitrophenyl)hydroxylamine (DPH) as the nitrogen source and a dirhodium carboxylate catalyst. Computational studies conducted by the Ess group support the intermediacy of a Rh–nitrene pathway (Scheme 1.28) [43].

Scheme 1.28 Rh‐catalyzed formation of metallanitrenes.

As the smallest nitrogen‐containing heterocycles, aziridines are important synthetic building blocks for the synthesis of amines. Recently, it has been shown that natural product analogs containing aziridine functionalities can possess improved biological activities than their natural counterparts [44]. Despite their importance, the majority of literature has focused on the synthesis of aziridines bearing electron‐withdrawing sulfonyl groups on the nitrogen atom (i.e. N‐tosylaziridines). The stability of the sulfonyl group renders the deprotection and functionalization of these aziridines difficult. In comparison, unprotected N–H aziridines can be further functionalized with relative ease.

      The transformation is operationally simple as neither the aminating reagent nor the catalyst is air‐ or moisture‐sensitive. The functional group tolerance is excellent as hydroxyl groups, epoxides, and esters in the substrates are unaffected. The NH‐aziridination is stereospecific and no scrambling of the olefin stereochemistry is observed even in sensitive styrene‐type substrates. When more than one C—C double bond is present in the substrate, the more electron‐rich one undergoes aziridination preferentially. The aziridination of terminal double bonds requires a slightly higher catalyst loading. The triple bond of alkynes and electron‐deficient double bonds (i.e. α,β‐unsaturated carbonyl compounds) remain unchanged under the reaction conditions. The choice of solvent is important because the presence of trifluoroethanol is required for aziridination.

The first iteration of this reaction uses the nitro group‐containing DPH as the aminating reagent (Scheme 1.29). Because of its thermal instability, there were some concerns about its safety in industrial‐scale settings. To address this issue, the Kürti group developed an improved version of this reaction in 2017 [45]. Instead of the nitro‐containing DPH, the new version can proceed with the stable and inexpensive hydroxylamine‐O‐sulfonic acid (HOSA) (Scheme 1.30). Because HOSA is a zwitterionic compound, its solubility in common organic solvents is very low. However, through the addition of an equivalent of a mild base (i.e. pyridine), HOSA can be solubilized. Hexafluoroisopropanol (HFIP) was identified as the optimal solvent, and under these modified conditions, the olefin aziridination reaction can proceed at room temperature and with generally higher rates compared to the original DPH process. The scope of substrates is further expanded and now includes nitrogen heterocycles with basic nitrogen atoms. A further advantage is that the inorganic sulfate by‐product is water‐soluble and nontoxic, which greatly simplifies the purification.

Scheme 1.29 Rh‐catalyzed NH‐aziridination of unactivated olefins using DPH.

Because N‐alkyl HOSA derivatives can be readily prepared on multigram scale [46], it was demonstrated that N‐Me as well as N‐isopropyl units could be stereospecifically transferred to olefins, leading to the corresponding N‐alkylaziridines.

Further studies on this catalytic system by the three groups showed that the Rh–nitrene intermediate can also facilitate the C–H amination of electron‐rich aromatic rings (Scheme 1.31) [47]. In 2016, the Falck, Kürti, and Ess groups published the direct C–H amination of arenes. By using a more reactive aminating reagent and modifying the acidity of the reaction, Rh–nitrene intermediate can be directly inserted into the aromatic π‐system of electron‐rich arenes. Using this protocol, both inter‐ and intramolecular arene C–H amination can be achieved.

Scheme 1.30 Rh‐catalyzed NH‐aziridination of unactivated olefins using HOSA.

1.5 Transition‐Metal‐Free Electrophilic Amination Reactions

Although the mechanism of uncatalyzed electrophilic amination reactions seems straightforward, in practice, these uncatalyzed reactions often suffer from poor efficiency and low yields. A common issue with uncatalyzed electrophilic amination is the side reaction between the nucleophile and the highly reactive aminating reagent. It is especially difficult to directly synthesize primary or secondary amines under uncatalyzed conditions because the unmasked NH protons will usually quench the strongly basic nucleophiles used in the reactions (Scheme 1.32).

      In recent years, several approaches have been developed to address these issues and finally achieve practical TM‐free electrophilic aminations.

One approach is to use a mild nucleophile to avoid quenching and/or side reactions. In 2012, the Kürti group reported a TM‐free primary amination of arylboronic acids (Scheme 1.33) [48].

This strategy exploits the fact that hydroxylamines can act as both electrophiles and nucleophiles. The nitrogen atom in the DPH aminating reagent first acts as a nucleophile to attack the boronic acid, and subsequently, it acts as an electrophile to accept an intramolecular nucleophilic attack to furnish the aniline products. Before this method, the direct conversion of arylboronic acids to the corresponding primary arylamines under mild conditions was not possible. Now, even halogenated primary arylamines may be readily prepared under transition‐metal‐free conditions.