Redox-neutral Radical Research Articles

Threonine Aldolase-Catalyzed Enantioselective α-Alkylation of Amino Acids through Unconventional Photoinduced Radical Initiation.

Visible light-driven pyridoxal radical biocatalysis has emerged as a promising strategy for the stereoselective synthesis of valuable noncanonical amino acids (ncAAs). Previously, the use of well-tailored photoredox catalysts represented the key to enable efficient pyridoxal phosphate (PLP) enzyme-catalyzed radical reactions. Here, we report a PLP-dependent threonine aldolase-catalyzed asymmetric α-C-H alkylation of abundant amino acids using Katritzky pyridinium salts as alkylating agents. The use of engineered threonine aldolases allowed for this redox-neutral radical alkylation to proceed efficiently, giving rise to challenging α-trisubstituted and -tetrasubstituted ncAA products in a protecting-group-free fashion with excellent enantiocontrol. Mechanistically, this enantioselective α-alkylation capitalizes on the unique reactivity of the persistent enzymatic quinonoid intermediate derived from the PLP cofactor and the amino acid substrate to allow for novel radical C-C coupling. Surprisingly, this photobiocatalytic process does not require the use of well-established photoredox catalysts and operates through an unconventional photoinduced radical generation involving a PLP-derived aldimine. The ability to develop photobiocatalytic reactions without relying on classic photocatalysts or photoenzymes opens up new avenues for advancing stereoselective intermolecular radical reactions that are not known in either organic chemistry or enzymology.

Photoenzymatic Redox-Neutral Radical Hydrosulfonylation Initiated by FMN

Photoenzymatic Redox-Neutral Radical Hydrosulfonylation Initiated by FMN

Redox-Neutral Radical Cascade Cyclization of N-Arylacrylamides with Unactivated Alkyl and Aryl Chlorides.

Herein, we report the first metal-free, redox-neutral strategy for radical cascade alkylative radical addition, cyclization of N-arylacrylamides with unactivated alkyl chlorides to give corresponding 3,3-disubstituted oxindoles in moderate to good yields. This transformation's salient features are the utilization of an organo photocatalyst, mild reaction conditions, and broad substrate scope. Moreover, this methodology is suitable for hetero cycle derived acrylamides and further allowed to utilize aryl chlorides for radical cyclization reaction. Finally, DFT studies allow us to shed light on the reaction mechanism.

Photoredox radical/polar crossover enables C-H gem-difunctionalization of 1,3-benzodioxoles for the synthesis of monofluorocyclohexenes.

A photocatalytic C-H gem-difunctionalization of 1,3-benzodioxoles with two different alkenes for the synthesis of highly functionalized monofluorocyclohexenes is described. Using 4CzIPN as the photocatalyst, the direct single electron oxidation of 1,3-benzodioxoles allows their defluorinative coupling with α-trifluoromethyl alkenes to produce gem-difluoroalkenes in a redox-neutral radical polar crossover manifold. The C-H bond of the resultant γ,γ-difluoroallylated 1,3-benzodioxoles was further functionalized via radical addition to electron-deficient alkenes using a more oxidizing iridium photocatalyst. The capture of in situ generated carbanions by an electrophilic gem-difluoromethylene carbon and consecutive β-fluoride elimination afford monofluorocyclohexenes. The synergistic combination of multiple termination pathways of carbanions enables rapid incorporation of molecular complexity via stitching simple and readily accessible starting materials together.

Azido-alkynylation of alkenes through radical-polar crossover.

We report an azido-alkynylation of alkenes allowing a straightforward access to homopropargylic azides by combining hypervalent iodine reagents and alkynyl-trifluoroborate salts. The design of a photocatalytic redox-neutral radical polar crossover process was key to develop this transformation. A variety of homopropargylic azides possessing electron-rich and -poor aryls, heterocycles or ether substituents could be accessed in 34-84% yield. The products are synthetically useful building blocks that could be easily transformed into pyrroles or bioactive amines.

Frontispiece: Trifluoromethoxylation Reactions of (Hetero) arenes, Olefinic Systems and Aliphatic Saturated Substrates

Direct fluoroalkoxylation reactions of (hetero)arenes, carbon-carbon multiple bonds, and substitution reactions at Csp3 carbon centers by CF3O, CHF2O, and (CF3)2CFO groups are discussed in the Review (DOI: 10.1002/chem.202201776) by Postigo, Bonesi, and Barata-Vallejo with an emphasis on thermal radical, electron transfer, photocatalytic, electrochemical and redox-neutral radical methods.

Trifluoromethoxylation Reactions of (Hetero) arenes, Olefinic Systems and Aliphatic Saturated Substrates.

Direct fluoroalkoxylation reactions of (hetero)arenes, carbon-carbon multiple bonds, and substitution reactions at Csp3 carbon centers by CF3 O, CHF2 O, and (CF3 )2 CFO groups are discussed. Emphasis on thermal radical, electron transfer, photocatalytic, electrochemical and redox-neutral radical methods are placed to accomplish fluoroalkoxylation reactions. All these methods employ either radical fluoroalkoxylating reagents or some nucleophilic trifluoromethoxylating sources of CF3 O. A summary of all these methods is provided in Table 2.

A concise method for cyclic gem-difluoroacyl scaffolds via visible-light-mediated redox-neutral cascade radical cyclization of alkenes

A series of diverse alkenes were engaged in redox-neutral radical tandem cyclization initiated by a CF2 radical precursor via visible-light-induced photocatalysis, affording various cyclic gem-difluoroacyl arenes in good to excellent yields.

An organophotoredox-catalyzed redox-neutral cascade involving N-(acyloxy)phthalimides and allenamides: synthesis of indoles

An efficient visible organophotoredox-catalyzed redox-neutral radical cascade involving allenamides and alkyl N-(acyloxy)phthalimides allowing the synthesis of biologically important indole scaffolds is achieved.

Iron-Catalyzed Redox-Neutral Radical Cascade Reaction of [60]Fullerene with γ,δ-Unsaturated Oxime Esters: Preparation of Free (N-H) Pyrrolidino[2',3':1,2]fullerenes.

Herein an unprecedented iron(II)-catalyzed redox-neutral radical cascade reaction of [60]fullerene with γ,δ-unsaturated oxime esters is reported for the preparation of novel free (N-H) pyrrolidino[2',3':1,2]fullerenes. The transformation undergoes an intramolecular cyclization/intermolecular cyclization/oxidation/hydrolysis cascade, and features simple operation, broad substrate scope/high functional group compatibility as well as suitable for scale-up synthesis, providing a facile and practical access to a range of free pyrrolidino[2',3':1,2]fullerenes.

Photoexcited Flavoenzymes in an Asymmetric Redox-Neutral Radical Cyclization

Photoexcited Flavoenzymes in an Asymmetric Redox-Neutral Radical Cyclization

Asymmetric redox-neutral radical cyclization catalysed by flavin-dependent 'ene'-reductases.

Flavin-dependent ‘ene’-reductases (EREDs) are exquisite catalysts for effecting stereoselective reductions. While these reactions typically proceed through a hydride transfer mechanism, we recently found that EREDs can also catalyze reductive dehalogenations and cyclizations via single electron transfer mechanisms. Here we demonstrate that these enzymes can catalyze redox-neutral radical cyclizations to produce enantioenriched oxindoles from α-haloamides. This transformation is a C–C bond forming reaction currently unknown in nature and one for which there are no catalytic asymmetric examples. Mechanistic studies indicate the reaction proceeds via the flavin semiquinone/quinone redox couple, where ground state flavin semiquinone provides the electron for substrate reduction and flavin quinone oxidizes the vinylogous α-amido radical formed after cyclization. This mechanistic manifold was previously unknown for this enzyme family, highlighting the versatility of EREDs in asymmetric synthesis.

Catalytic enantioselective radical coupling of activated ketones with N-aryl glycines.

Asymmetric H-bonding catalysis as a viable strategy for enantioselective radical coupling of ketones is demonstrated. With a visible-light-mediated dual catalytic system involving a dicyanopyrazine-derived chromophore (DPZ) photosensitizer and a chiral phosphoric acid (CPA), N-aryl glycines with a variety of 1,2-diketones and isatins underwent a redox-neutral radical coupling process and furnished two series of valuable chiral 1,2-amino tertiary alcohols in high yields with good to excellent enantioselectivities (up to 97% ee). In this catalysis platform, the formation of neutral radical intermediates between ketyl and H-bonding catalyst CPA is responsible for presenting stereocontrolling factors. Its success in this work should provide inspiration for expansion to other readily accessible ketones to react with various radical species, thus leading to a productive approach to access chiral tertiary alcohol derivatives.

Direct C–H Functionalization of Heteroarenes via Redox-Neutral Radical Process: A Facile Route to C–C Bonds Formation

Aromatic heterocycles are an important class of compounds found in a wide range of natural products, pharmaceutically active molecules and organic materials. Recently, the direct radical functionalization of heteroaromatic C–H bonds has become an efficient and attractive method to access substituted heteroarenes. Especially, redox-neutral radical reactions have attracted much attention of chemists due to their potential advantages such as mild conditions, free of external oxidants, and good functional group tolerance. So far, a series of redox-neutral radical reactions have been developed. In this review, we mainly focus on the recent advance in direct redox-neutral radical C–H functionalization of heteroarenes. Herein, the direct C–H arylation, C–H alkylation, and C–H fluoroalkylation of heteroarenes are represented respectively, providing practical routes to C–C bond formation.1 Introduction2 C–H Arylation of Heteroarenes with Aryl Radicals3 C–H Alkylation of Heteroarenes with Alkyl Radicals4 C–H Fluoroalkylation of Heteroarenes with Fluorine-Containing Carbon Radicals5 Concluding Remarks

The recent achievements of redox-neutral radical C-C cross-coupling enabled by visible-light.

Visible-light photoredox catalysis has been esteemed as one sustainable and attractive synthetic tool. In the past four years, a new yet challenging trend, visible-light-driven redox-neutral radical C-C cross-coupling involving putative radical intermediates, has been booming rapidly. Its advent brings a powerful platform to achieve non-classical C-C connections, and should lead to fundamental changes in retrosynthetic analysis. In this tutorial review, we highlight the recent achievements of visible-light-mediated redox-neutral radical C(sp3)-C(sp2), C(sp3)-C(sp), and C(sp3)-C(sp3) bond formation, opening a new window for C-C cross-coupling through the photoredox electron shuttling cycle between two coupling partners. While radical-radical coupling steered by the persistent radical effect was proposed as a rational explanation for the redox-neutral photoredox events, alternative kinetically driven chain propagation and radical addition pathways cannot be ruled out. This tutorial review aims to highlight the recent achievements of photoredox-neutral radical C-C coupling in synthetic chemistry.

Copper-catalyzed redox-neutral C–H amination with amidoximes

CuI-catalyzed reactions of N-alkylamidoximes afforded dihydroimidazoles via sp(3) C-H amination. On the other hand, the reactions of N-benzoylamidoximes resulted in sp(2) C-H amination to form quinazolinones. The reaction mechanisms could be characterized as a redox-neutral radical pathway including a Cu(I)-Cu(II) redox catalytic cycle.

Properties and Reactivity of the Adenosine Radical Generated by Radiation-Induced Oxidation in Aqueous Solution

The formation of oxidation products of DNA bases induced by hole injection into DNA duplexes is closely related to the characteristics of the radical species generated, especially those from purine bases possessing lower oxidation potentials than pyrimidines. To investigate the reactivities of adenosine base radicals generated from the radical cations of adenosine (Ado), we have conducted extensive pulse radiolysis and steady-state X-radiolysis investigations of Ado under the conditions generating oxidizing radical species such as the sulfate radical anion (SO(4)(-*)). Kinetic analysis of the transient absorption spectra demonstrated that the redox-neutral radical of adenosine [Ado(-H)(*)] decays via a homogeneous bimolecular reaction, recombines with an alkyl alcohol radical, or abstracts hydrogen from the phosphate ion, with rate constants of 2k = 4.2 x 10(8) M(-1) s(-1) and k = 6.4-8.5 x 10(8) and 10(3)-10(4) M(-1) s(-1), respectively. High-dose pulsed electron beam irradiation, which generates high concentrations of Ado(-H)(*) during the radiolysis, yielded 8-oxo-7,8-dihydroadenosine (8-oxo-Ado) with a G value of 0.018 x 10(-7) mol J(-1). It is thus proposed that the disproportionation of Ado(-H)(*) might lead to the formation of 8-oxo-Ado as a minor process, which is in addition to the widely accepted mechanism in which the addition of hydroxyl radical to Ado initiates its formation.