An Overview of α‐Aminoalkyl Radical Mediated Halogen‐Atom Transfer

Abstract

The merging of photocatalysis with halogen‐atom transfer (XAT) processes has proven to be a versatile tool for the generation of carbon‐centered radicals in organic synthesis. XAT processes are unique in that they generate radicals without requiring the use of strong reductants necessary for the traditional single electron transfer (SET) activation of halides. Pathways to achieve XAT in synthetic applications can be categorized into three major sections: i) heteroatom‐based activators, ii) metal‐based activators, and iii) carbon‐based activators among which α‐aminoalkyl radicals have taken the center stage. Access to these α‐aminoalkyl radicals as XAT reagents has gained significant attention in the past few years due to the robustness of the reactions, the simplicity of the reagents required, and the broadness of their applications. Generation of these α‐aminoalkyl radicals is simply achieved through the single electron oxidation of tertiary amines, which after deprotonation at the α‐position generates the α‐aminoalkyl radicals. Due to the wide scope of tertiary amines available and the tunable nucleophilicity of α‐aminoalkyl radical formed, this strategy has become an attractive alternative to heteroatom/metal‐based radicals for XAT. In this minireview, we focus our attention on recent (2020‐2023) developments and uses of this robust technology to mediate XAT processes.

Red Light–Blue Light Chromoselective C(sp2)–X Bond Activation by Organic Helicenium-Based Photocatalysis

“…31,33−36 Contemporary works from Leonori and colleagues have demonstrated tertiary amine-based XAT initiated by 4CzIPN under blue light irradiation 37,38 is a powerful alternative method, albeit mostly for C(sp 3 )−X bonds. 32,38,39 Metal-based red-light-mediated aryl halide activation has also been recently reported. 40,41 Within this frame of reference, we have investigated a photoredox approach for the α-arylation of ketones catalyzed by electron-rich acridiniums under green light irradiation (Figure 1b left).…”

“…4,29,30 In the context of organic photocatalyzed C−X bond activation, consecutive photoelectron transfer (conPET) 31 and halogen atom transfer (XAT) mechanisms are often the main pathways involved. 32 Perylene diimide (PDI), acridine, and carbazolebased photocatalysts are some prominent examples to undergo a two-photon excitation mechanism resulting in highly photoreducing behavior able to activate strong C(sp 2 )−X bonds. 31,33−36 Contemporary works from Leonori and colleagues have demonstrated tertiary amine-based XAT initiated by 4CzIPN under blue light irradiation 37,38 is a powerful alternative method, albeit mostly for C(sp 3 )−X bonds.…”

“…Aryl halides, which are a prevalent resource in the realm of organic chemistry for a wide range of arylation reactions, offer an ideal platform to investigate chromoselective photoredox catalysis thanks to the wide range of reduction potential and bond dissociation energy (BDE) spanning across this class of molecules. Generally, aryl halide functionalization has benefited from the establishment of robust transition-metal-based catalytic techniques to attain the desired arylation outcomes. , Recent times have also witnessed the introduction of novel methodologies, including photoredox, − electrochemical, ,, and enzymatic catalysis. ,, In the context of organic photocatalyzed C–X bond activation, consecutive photoelectron transfer (conPET) and halogen atom transfer (XAT) mechanisms are often the main pathways involved . Perylene diimide (PDI), acridine, and carbazole-based photocatalysts are some prominent examples to undergo a two-photon excitation mechanism resulting in highly photoreducing behavior able to activate strong C­(sp 2 )–X bonds. ,− Contemporary works from Leonori and colleagues have demonstrated tertiary amine-based XAT initiated by 4CzIPN under blue light irradiation , is a powerful alternative method, albeit mostly for C­(sp 3 )–X bonds. ,, Metal-based red-light-mediated aryl halide activation has also been recently reported. , Within this frame of reference, we have investigated a photoredox approach for the α-arylation of ketones catalyzed by electron-rich acridiniums under green light irradiation (Figure b left) .…”

“…Generally, aryl halide functionalization has benefited from the establishment of robust transition-metal-based catalytic techniques to attain the desired arylation outcomes. , Recent times have also witnessed the introduction of novel methodologies, including photoredox, − electrochemical, ,, and enzymatic catalysis. ,, In the context of organic photocatalyzed C–X bond activation, consecutive photoelectron transfer (conPET) and halogen atom transfer (XAT) mechanisms are often the main pathways involved . Perylene diimide (PDI), acridine, and carbazole-based photocatalysts are some prominent examples to undergo a two-photon excitation mechanism resulting in highly photoreducing behavior able to activate strong C­(sp 2 )–X bonds. ,− Contemporary works from Leonori and colleagues have demonstrated tertiary amine-based XAT initiated by 4CzIPN under blue light irradiation , is a powerful alternative method, albeit mostly for C­(sp 3 )–X bonds. ,, Metal-based red-light-mediated aryl halide activation has also been recently reported. , Within this frame of reference, we have investigated a photoredox approach for the α-arylation of ketones catalyzed by electron-rich acridiniums under green light irradiation (Figure b left) . The resulting α-arylated cyclic ketone scaffolds hold significant medicinal relevance and serve as pivotal synthons for an array of pharmaceutical agents and bioactive natural products, thereby making metal-free strategies very appealing. − Yet, this methodology was limited to aryl iodides, and relatively difficult substrates, such as aryl bromides, were not efficiently activated.…”

Synergistic Merger of Ketone, Halogen Atom Transfer (XAT), and Nickel-Mediated C(sp3)–C(sp2) Cross-Electrophile Coupling Enabled by Light

“…18−22 Recently, the concept of halogen atom transfer (XAT) under visible-light photocatalysis gained significant momentum. 23,24 This strategy allows the radical dehalogenative functionalization of haloalkanes and haloarenes. 25−30 Furthermore, this concept was successfully merged with metal catalysis, which eventually led to a variety of cross-coupling products.…”