Α-aminoalkyl Radicals Research Articles

Silyl Radicals as Single-Electron Reductants: α-Aminoalkyl Radical Formation via a Photocatalytic Oxidatively Initiated Radical Chain Process.

The α-amino-radical constitutes a versatile reactive intermediate that has been used to great effect in the synthesis of complex amine-containing products. Here, we report the development of a multicomponent photocatalytic platform enabling access to all-alkyl α-amino-radicals, exploiting the oxidative formation of silyl-radicals from commercially available tris(trimethylsilyl)silane. A key design element of the new process involves the role of silyl-radicals in generating α-amino-radicals from iminium ions as part of an oxidatively initiated photocatalytic radical chain process. This distinct activation mode is showcased by engaging the ensuing radicals in cross-radical coupling with persistent arene radical anions, enabling the arylation of in situ-generated all-alkyl iminium ions to furnish alkyl-substituted benzylamines.

Subphthalocyanine metallo-organic cage as catalytic molecular photoreactor for the functionalization of fullerenes

ABSTRACT Subphthalocyanines (SubPcs) are aromatic chromophores with a bowlshaped structure and outstanding optoelectronic properties. The cavity formed by a C3-symmetry trispyridyl-SubPc, Pd(II)-metalloorganic capsule has proved an optimal, shape-complementary space for the complexation of C60. Taking advantage of the intense green light absorption of the SubPc components of the capsule, and their ability to transfer energy/electrons from the excited state, our group has recently described the unprecedented use of SubPc cages as molecular photoreactors to perform photoredox-triggered addition of diphenylamine radicals over encapsulated C60. Unfortunately, the reaction could only be performed using stoichiometric amounts of the cage due to inhibition of the SubPc cavity by the addition compound. Here, we describe the preparation of a more flexible SubPc cage built with a related C1-symmetry trispyridyl-SubPc (C1-SubPc-cage), which could facilitate the exchange between the complexed addition compound and pristine fullerene, thus allowing to use it in catalytic amounts. After assessing the ability of C1-SubPc-cage to host C60, the addition of α-aminoalkyl radicals in the presence of the cage under green light irradiation was tested. Curiously, optimisation of the reaction conditions (using catalytic amounts of C1-SubPc-cage in diluted solutions) rendered a different reaction outcome, that is, a cyclopropanated fullerene, in remarkably high yields.

Photoinduced Intermolecular Radical Hydroalkylation of Olefins via Ligated Boryl Radicals-Mediated Halogen Atom Transfer.

Light-mediated Halogen-Atom Transfer (XAT) has become a significant methodology in contemporary synthesis. Unlike α-aminoalkyl and silyl radicals, ligated boryl radicals (LBRs) have not been extensively explored as halogen atom abstractors. In this study, we introduce NHC-ligated boranes as optimal radical chain carriers for the intermolecular reductive radical hydroalkylation and hydroarylation of electron-deficient olefins by using direct UV-A light irradiation. DFT analysis allowed us to rationalize the critical role of the NHC ligand in facilitating efficient chain propagation.

Photocatalytic, α-Aminoalkyl Radical-Mediated, Methylene-Extrusive Ring-Closing Transformation of o-Alkynyl and o-Cyano Acrylamides.

Herein we report a visible-light-induced, α-aminoalkyl radical-mediated cascade reaction of 1,7-enynes that establishes a unique ring-closing enyne transformation pathway which occurs with concomitant loss of a methylene moiety. The α-aminoalkyl radical derived from N,N-dimethylaniline was demonstrated to be a traceless promoter of enyne reorganization leading to 4-alkylquinolinones. The reaction can also be extended to nitrile-substituted acrylamide systems, leading to carbostyrils. Experiments with deuterated N,N-dimethylaniline-d6 (PhN(CD3)2) established the involvement of 1,5-H atom transfer in the mechanism.

Transition State Analysis of Key Steps in Dual Photoredox-Cobalt-Catalyzed Elimination of Alkyl Bromides.

A combination of inter- and intramolecular 13C kinetic isotope effects and density functional theory analysis is used to evaluate the key mechanistic events of sequentially operating catalytic cycles in the dual photoredox-cobalt-catalyzed elimination of alkyl bromides. The results point to a mechanism proceeding via irreversible halogen-atom transfer (XAT) from the alkyl halide, resulting in an alkyl radical, which undergoes hydrogen-atom transfer (HAT) to a Co(II) intermediate to deliver the product olefin. Alternative pathways involving nucleophilic substitution by a Co(I) species and by β-hydride elimination are discounted based on the poor agreement of experimental and predicted 13C KIEs. This mechanistic understanding is used to evaluate the origins of regioselectivity in the elimination step for an unsymmetrical alkyl halide catalyzed by electronically and sterically distinct cobaloxime catalysts. This study represents the experimental validation of the key features of the transition state structure of XAT by α-aminoalkyl radicals, an important class of atom transfer reactions that generate carbon-centered radicals from alkyl and aryl halides. Furthermore, it illustrates the power of 13C KIEs in probing complex mechanisms in metallaphotoredox catalysis.

Visible-Light Photoredox-Catalyzed Intermolecular α-Aminomethyl/Carboxylative Dearomatization of Indoles with CO2 and α-Aminoalkyl Radical Precursors.

Disclosed here is a visible-light photoredox-catalyzed intermolecular sequential α-aminomethyl/carboxylative dearomatization of indoles with CO2 and α-aminoalkyl radical precursors, affording a series of functionalized indoline-3-carboxylic acids and lactams in good yields with high regioselectivity. This multicomponent reaction provides a green and facile method for the synthesis of diverse functionalized indolines by using CO2 as the carboxylic and carbonyl source.

Photoredox-Catalyzed C(sp3)–H Difluoroallylation of Amides

AbstractA photoredox-catalyzed, bromine-radical-mediated C(sp3)–H difluoroallylation of amides is disclosed. This modular approach exploits the hydrogen atom transfer (HAT) ability of photooxidatively generated bromine radicals to convert both cyclic and acyclic amides into the corresponding α-amino alkyl radicals that then are coupled with readily available trifluoromethyl alkenes. This method is distinguished by its mild conditions, broad substrate scope (30 examples), and the use of a simple HAT reagent, namely sodium bromide (NaBr). This strategy offers a promising paradigm for the incorporation of carbonyl isosteres into saturated aliphatic amines.

A radical 1,4-aryl migration enables nickel-catalysed remote cross-electrophile coupling of β-bromo amino acid esters with vinyl triflates.

A radical 1,4-aryl migration enabling a cross-electrophile coupling reaction toward remote transalkylation of N-benzyl alanine has been developed. In this strategy, with the occurrence of a radical-mediated Turce-Smiles rearrangement, key α-aminoalkyl radicals are generated. The as-formed α-aminoalkyl radical serves as a robust coupling partner for cross-electrophilic coupling with vinyl triflates, affording a series of olefin-tethered amino acid motifs.

Visible light-induced halogen-atom transfer by N-heterocyclic carbene-ligated boryl radicals for diastereoselective C(sp3)-C(sp2) bond formation.

Photoinduced halogen-atom transfer (XAT) has rapidly emerged as a programmable approach to generate carbon-centered radical intermediates, mainly relying on silyl and α-aminoalkyl radicals as halogen abstractors. More recently, ligated boryl radicals have also been proposed as effective halogen abstractors under visible-light irradiation. In this study, we describe the use of this approach to enable C(sp3)-C(sp2) bond formation via radical addition of carbon-centered radicals generated via XAT onto chloroalkynes. Our mechanistic investigation reveals a complex interplay of highly reactive radical intermediates which, under optimized conditions, delivered the targeted vinyl chlorides in excellent yields and Z : E ratios. Finally, we demonstrated the synthetic value of these products in transition metal-based cross-coupling reactions.

Aminomethylations of electron-deficient compounds-bringing iron photoredox catalysis into play.

The α-functionalisation of N-containing compounds is an area of broad interest in synthetic chemistry due to their presence in biologically active substances among others. Visible light-induced generation of nucleophilic α-aminoalkyl radicals as reactive intermediates that can be trapped by electron-deficient alkenes presents an attractive and mild approach to achieve said functionalisation. In this work, [Fe(iii)(phtmeimb)2]PF6 (phtmeimb = phenyl(tris(3-methylimidazol-2-ylidene))borate), an N-heterocyclic carbene (NHC) complex based on Earth-abundant iron, was used as photoredox catalyst to efficiently drive the formation of α-aminoalkyl radicals from a range of different α-trimethylsilylamines and their subsequent addition to a number of electron-deficient alkenes under green light irradiation. Mechanistic investigations elucidated the different reaction steps of the complete photocatalytic cycle. In terms of yields and substrate scope, we show that [Fe(iii)(phtmeimb)2]PF6 can compete with noble metal photoredox catalysts, for instance outcompeting archetypal [Ru(bpy)3]Cl2 under comparable reaction conditions, illustrating that iron photocatalysts can efficiently facilitate photoredox reactions of synthetic value.

Photocatalytic α-aminoalkyl radical addition of amines mediated by benzophenone under visible light

The photocatalytic α-aminoalkyl radical addition of amines faciliated by benzophenone is disclosed. This is an example of a photocatalytic alkylation method that uses low-toxicity solvents and mild reaction conditions.

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

In the present manuscript, we have developed a unique catalytic system by merging photoexcited ketone catalysis, halogen atom transfer (XAT), and nickel catalysis to forge C(sp3)-C(sp2) cross-electrophile coupling products from unactivated iodoalkanes and (hetero)aryl bromides. The synergistic catalytic system works under mild reaction conditions and tolerates a variety of functional groups; moreover, this strategy allows the late-stage modification of medicinally relevant molecules. Preliminary mechanistic studies reveal the role of the α-aminoalkyl radical, which further participates in the XAT process with alkyl iodides to generate the desired alkyl radical, which eventually intercepts with the nickel catalytic cycle to liberate the products in good to excellent yields.

Integrating Hybrid Perovskite Nanocrystals into Metal-Organic Framework as Efficient S-Scheme Heterojunction Photocatalyst for Synergistically Boosting Controlled Radical Photopolymerization under 980 nm NIR Light.

S-scheme heterojunction photocatalyst MAPbI3@PCN-222 with light absorption extending to the NIR region is constructed by embedding organic-inorganic hybrid perovskite (MAPbI3) into porphyrinic Zr-MOF (PCN-222). Both in situ X-ray photoelectron spectroscopy, ultraviolet photoelectron spectral characterization, and photocatalytic polymerization experiment prove the formation of S-scheme heterojunction. MAPbI3@PCN-222 with a low dosage (90 ppm) displays an impressive photocatalytic ability for 980 nm light-mediated photoinduced electron/energy-transfer-reversible addition-fragmentation chain-transfer (PET-RAFT) polymerization in air. The well-defined controllable-molecular weight polymers including block copolymers and ultrahigh-molecular weight polymers can be achieved with narrow distributions (Mw/Mn < 1.20) via rapid photopolymerization. The industrial application potential of the photocatalyst also has been proved by scale-up synthesis of polymers with low polydispersity under NIR light-induced photopolymerization in a large-volume reaction system (200 mL) with high monomer conversion up to 99%. The penetration photopolymerization through the 5 mm polytetrafluoroethylene plate and excellent photocontrollable behavior illustrate the existence of long-term photogenerated electron transfer of heterojunction and abundant free radicals in photopolymerization. The photocatalyst still retains high catalytic activity after 10 cycles of photopolymerization in air. It is revealed for the first time that the special PET-RAFT polymerization pathway is initiated by the aldehyde-bearing α-aminoalkyl radical derived from the oxidization of triethanolamine (TEOA) by the heterojunction photocatalyst. This research offers a new insight into understanding the NIR-light-activated PET-RAFT polymerization mechanism in the presence of TEOA.

Carbonylation of α-Aminoalkyl radicals to the direct synthesis of α-Amino acid derivatives

α-Amino acid derivatives are indispensable motifs in various areas. Herein, we developed an unprecedented and general α-aminoalkyl carbonylation protocol that activates a variety of inert C–H bonds as native functional handles toward the direct synthesis of various α-amino acid derivatives. The key to the success of this mode is the installation of an appropriate electron-withdrawing group which can modulate the nucleophilicity of the α-aminoalkyl radical and provides a matching polarity for the subsequent carbonylation process. This catalytic strategy features a remarkably broad substrate scope and excellent tolerance of sensitive functional groups, offering general and practical access to α-amino acid derivatives.

Electrochemical halogen-atom transfer alkylation via α-aminoalkyl radical activation of alkyl iodides

Alkyl halides, widely recognized as important building blocks and reagents in organic synthesis, can serve as versatile alkyl radical precursors in radical-based transformations. However, generating alkyl radicals directly from unactivated alkyl halides under mild conditions remains a challenge due to their extremely low reduction potentials. To address this issue, α-aminoalkyl radicals were employed as efficient halogen-atom transfer (XAT) reagents in the photoredox activation of unactivated alkyl halides. Here, we report an effective electrooxidation strategy for generating alkyl radicals from unactivated alkyl iodides via an electrochemical halogen-atom transfer (e-XAT) process under mild conditions. The α-aminoalkyl radicals generated by anodic oxidation are demonstrated to be efficient XAT reagents in these transformations. This facile electricity-driven strategy obviates the need for sacrificial anodes and external chemical oxidants. The method successfully applies to a wide variety of alkyl iodides, including primary, secondary, and tertiary, as well as structurally diverse olefins, exhibiting excellent functional group tolerance. Moreover, we further demonstrate the utility of this strategy by rapidly functionalizing complex molecules and biomolecules.

Photoinduced α-Aminoalkylation of Sulfonylarenes with Alkylamines.

α-Aminoalkylation of sulfonylarenes with alkylamines was found to be induced by photoirradiation. Here various types of alkylamines, such as trialkylamines, dialkylamines, N,N-dialkylanilines and N-alkylanilines as well as sulfonylarenes containing an azole, azine, heterole or benzene ring are available. The reaction proceeds through a homolytic aromatic substitution (HAS) process consisting of addition of an α-aminoalkyl radical to a sulfonylarene and elimination of the sulfonyl radical to give the α-arylalkylamine, where photoirradiation is considered to induce homolysis of sulfonylarenes leading to the generation of α-aminoalkyl radicals that make a radical chain operative.

Fe-Catalyzed C-H Alkenylation of Dialkyl Anilines with Disulfonylethenes.

The oxidative alkenylation reaction of α-aminoalkyl C(sp3)-H bonds has been investigated with (E)-1,2-bis(sulfonyl)ethenes. The catalytic process of iron-polypyridyl complexes drives the single-electron oxidation of dialkyl anilines, resulting in the formation of α-aminoalkyl radical species. Subsequent cascades of radical addition and elimination reactions ensue, ultimately leading to the generation of sulfonylated allylic amine products. The utility of these products extends further, enabling the synthesis of multisubstituted heterocycles like pyrroles, pyrazines, and triazoles.

Cross-Electrophile C-PIII Coupling of Chlorophosphines with Organic Halides: Photoinduced PIII and Aminoalkyl Radical Generation Enabled by Pnictogen Bonding.

Pnictogen bonding (PnB) has gained recognition as an appealing strategy for constructing novel architectures and unlocking new properties. Within the synthetic community, the development of a straightforward and much simpler protocol for cross-electrophile C-PIII coupling remains an ongoing challenge with organic halides. In this study, we present a simple strategy for photoinduced PnB-enabled cross-electrophile C-PIII couplings using readily available chlorophosphines and organic halides via merging single electron transfer (SET) and halogen atom transfer (XAT) processes. In this photomediated transformation, the PnB formed between chlorophosphines and alkyl amines facilitates the photogeneration of PIII radicals and α-aminoalkyl radicals through SET. Subsequently, the resulting α-aminoalkyl radicals activate C-X bonds via XAT, leading to the formation of carbon radicals. This methodology offers operational simplicity and compatibility with both aliphatic and aromatic chlorophosphines and organic halides.

Electrochemical Direct α-Arylation of Alkylamines with Sulfonylarenes.

The electrochemical α-arylation of alkylamines with sulfonylarenes has been developed. Here, diverse trialkylamines and aryl(dimethyl)amines are applicable to the α-arylation with sulfonylarenes having an azole, azine, and benzene nucleus. The α-arylation was scaled up using an electrolysis flow cell. Mechanistic studies show that anodic oxidation of an alkylamine with a sulfinate as a mediator followed by deprotonation gives an α-aminoalkyl radical, which undergoes homolytic aromatic substitution (HAS) on a sulfonylarene to give the corresponding α-arylalkylamine.

Photocatalytic, Intermolecular Olefin Alkylcarbofunctionalization Triggered by Haloalkyl Radicals Generated via Halogen Atom Transfer.

A visible-light-mediated, haloalkyl-radical-initiated, three-component olefin difunctionalization is reported. The application of haloalkyl radicals generated via halogen atom abstraction by α-aminoalkyl radicals has been demonstrated for accessing a new halogenated chemical space. Overall, the alkylcarbofunctionalization of styrenes was accomplished by employing them as (poly)haloalkyl radical acceptors and subsequent C-C bond formation with quinoxalinones.