Alkyl Radical Precursors Research Articles

(o-Phenylenediamino)borylstannanes: Efficient Reagents for Borylation of Various Alkyl Radical Precursors.

(o-Phenylenediamino)borylstannanes were newly synthesized to achieve radical boryl substitutions of a variety of alkyl radical precursors. Dehalogenative, deaminative, decharcogenative, and decarboxylative borylations proceeded in the presence of a radical initiator to give the corresponding organic boron compounds. Radical clock experiments and computational studies have provided insights into the mechanism of the homolytic substitution (SH 2) of the borylstannanes with alkyl radical intermediates. DFT calculation disclosed that the phenylenediamino structure lowered the LUMO level including the vacant p-orbital on the boron atom to enhance the reactivity to alkyl radicals in SH 2. Moreover, C(sp3 )-H borylation of THF was accomplished using the triplet state of xanthone.

Development of Organosilicon Peroxides as Practical Alkyl Radical Precursors and Their Applications to Transition Metal Catalysis

Abstract This account highlights the development of efficient methods for generation of alkyl radicals from organosilicon peroxides and their applications in selective alkylation reactions. Compared with commonly used organic peroxides, a more diverse range of organosilicon peroxides can be prepared as bench-stable alkyl radical precursors, and their use in combination with transition metal catalysts allows for generation of alkyl radicals under mild conditions. Consequently, these methods have opened up a new way for the formation of various carbon–carbon and carbon–heteroatom bonds, affording highly functionalized carbon skeletons in chemoselective or asymmetric manners.

BI-OAc-Accelerated C3-H Alkylation of Quinoxalin-2(1H)-ones under Visible-Light Irradiation.

An efficient, photoredox-catalyst-free radical alkylation of quinoxalin-2(1H)-ones has been described. This reaction utilizes 4-alkyl-1,4-dihydropyridines (R-DHPs) as alkyl radical precursors and acetoxybenziodoxole (BI-OAc) as an electron acceptor to undergo single-electron transfer with photoexcited R-DHPs. The benign conditions allow for good compatibility in the scope of both quinoxalin-2(1H)-ones and R-DHPs. The synthetic value of the protocol was also demonstrated by the successful functionalization of natural products and drug-based complex molecules.

Copper-Catalyzed Asymmetric Radical 1,2-Carboalkynylation of Alkenes with Alkyl Halides and Terminal Alkynes.

A copper-catalyzed intermolecular three-component asymmetric radical 1,2-carboalkynylation of alkenes has been developed, providing straightforward access to diverse chiral alkynes from readily available alkyl halides and terminal alkynes. The utilization of a cinchona alkaloid-derived multidentate N,N,P-ligand is crucial for the efficient radical generation from mildly oxidative precursors by copper and the effective inhibition of the undesired Glaser coupling side reaction. The substrate scope is broad, covering (hetero)aryl-, alkynyl-, and aminocarbonyl-substituted alkenes, (hetero)aryl and alkyl as well as silyl alkynes, and tertiary to primary alkyl radical precursors with excellent functional group compatibility. Facile transformations of the obtained chiral alkynes have also been demonstrated, highlighting the excellent complementarity of this protocol to direct 1,2-dicarbofunctionalization reactions with C(sp2/sp3)-based reagents.

Synthesis of Aliphatic Amides through a Photoredox Catalyzed Radical Carbonylation Involving Organosilicates as Alkyl Radical Precursors

AbstractAlkyl radicals, from primary to tertiary, formed by photocatalyzed oxidation of organosilicates, are involved efficiently in radical carbonylation with carbon monoxide (CO), in the presence of various amines and CCl4, leading to a variety of amides in moderate to good yields.magnified image

Copper-catalysed photoinduced decarboxylative alkynylation: a combined experimental and computational study.

Redox-active esters (RAEs) as alkyl radical precursors have demonstrated great advantages for C–C bond formation. A decarboxylative cross-coupling method is described to afford substituted alkynes from various carboxylic acids using copper catalysts CuCl and Cu(acac)2. The photoexcitation of copper acetylides with electron-rich NEt3 as a ligand provides a general strategy to generate a range of alkyl radicals from RAEs of carboxylic acids, which can be readily coupled with a variety of aromatic alkynes. The scope of this cross-coupling reaction can be further expanded to aliphatic alkynes and alkynyl silanes using a catalytic amount of preformed copper-phenylacetylide. In addition, DFT calculations revealed the favorable reaction pathway and that the bidentate acetylacetonate ligand of the copper intermediate plays an important role in inhibiting the homo-coupling of the alkyne.

Generation of (Z)-β-alkenyl alkylsulfones via a copper-catalyzed decarboxylative alkylsulfonylation

A copper-catalyzed three-component reaction of acrylamides, sulfur dioxide and phenyliodine(iii) dicarboxylates is developed. The conversion using phenyliodine dicarboxylates as alkyl radical precursors provides diverse (Z)-β-alkenyl alkylsulfones.

Terminal-oxidant-free photocatalytic C-H alkylations of heteroarenes with alkylsilicates as alkyl radical precursors.

We report the photocatalytic C-H alkylations of heteroarenes with alkylsilicates bearing C,O-bidentate ligands under acidic conditions. Irradiation of heteroaromatics in the presence of the silicates and trifluoroacetic acid produced the corresponding alkylated compounds. The present reaction system does not require any terminal oxidant although the reaction seems to be a formal oxidation reaction. This study demonstrates that alkylsilicates can be used in photocatalytic radical chemistry under acidic conditions.

Photoinduced deaminative strategies: Katritzky salts as alkyl radical precursors.

Primary amines are one of the most predominant functional groups found in organic molecules. These entities help form the chemical architecture of natural products, bioactive molecules, synthetic building blocks and catalysts. Due to their ubiquitous presence, the development of strategies for the construction of C-C or C-X bonds through deaminative processes is of high importance. Deaminative methods offer new possibilities on the retrosynthetic rationale, and enable late-stage-functionalization of complex structures. As a result of the recent development of photoinduced processes, a variety of photo-mediated deaminative protocols employing 2,4,6-triphenyl-pyridinium salts - Katritzky Salts - as activating agents have been recently realized. This review covers the most recent developments of deaminative strategies by using Katritzky Salts as alkyl radical reservoirs, with particular concern on photoinduced processes applied to organic synthesis.

Photoredox‐Catalyzed Cyclopropanation of 1,1‐Disubstituted Alkenes via Radical‐Polar Crossover Process

AbstractThe photoredox‐neutral catalyzed cyclopropanation of 1,1‐disubstituted alkenes via radical addition‐anionic cyclization cascade has been successfully developed. Another new protocol based on photocatalytic allylation and cyclopropanation cascade was also described between allylic halide and halomethyl radical. In addition to the successful use of bis‐catecholato silicates as the alkyl radical precursors, the acyl and alkyl radicals derived from 1,4‐dihydropyridines were also engaged in this radical‐polar crossover process. The competing experiments displayed that the 3‐exo‐tet mode of cyclization preferred over 4‐exo and 5‐exo cyclization modes, allowing for the selective 3‐exo‐tet cyclization. The superior nucleofuge character of bromide over chloride and tosylate has been demonstrated in the reaction of bromomethyl radical with homoallylic (pseudo)halides. This new protocol is characterized by its redox‐neutral process, broad substrate scope, mild conditions, and good functional‐group compatibility.magnified image

Photoinduced Sulfonylation Reactions through the Insertion of Sulfur Dioxide

Recent advances in the photoinduced sulfonylation reactions through the insertion of sulfur dioxide are summarized. Among the approaches developed in the sulfonylation reactions, the insertion of sulfur dioxide via radical process can be accomplished with the assistance of photoredox catalysis in the presence of visible light or under ultraviolet irradiation, depending the substrates used in the reactions. Under ultraviolet irradiation, the conversion can be completed under metal‐ and additive‐free conditions. It is noteworthy that alkyl halides possessing eliminable β‐hydrogen atom are effective as alkyl radical precursors with the insertion of sulfur dioxide. Two parts, according to the photoinduced reaction pathways, are introduced: (a) photo‐initiated formation of radical with the subsequent capture of sulfur dioxide; (b) photo‐assisted single electron transfer (SET) after insertion of sulfur dioxide. During the transformation, an oxidative or reductive single electron transfer would occur under visible light photoredox catalysis.

Potassium Alkylpentafluorosilicates, Primary Alkyl Radical Precursors in the C-1 Alkylation of Tetrahydroisoquinolines.

In this study, we demonstrate that potassium alkylpentafluorosilicates (RSiF5K2) are efficient primary alkyl radical precursors for selective C(sp3)-C(sp3) bond-forming reactions. RSiF5K2 reagents are white, free-flowing solids and are moisture and air stable. This class of reagents enables the direct C-1 alkylation of tetrahydroisoquinolines under mild conditions via single-electron transfer. The broad substrate scope of both alkylpentafluorosilicates and tetrahydroisoquinolines is tolerated in this transformation. Both radical scavenger and EPR capture experiments show that the primary radical is generated by the oxidation of RSiF5K2. A mechanism involving alkyl radical addition to an iminium salt followed by reduction by an amine is proposed.

Aliphatic Aldehydes: Novel Radical Alkylating Reagents

AbstractThe emergence of radical chemistry has driven chemists to develop general and efficient radical reactions as well as to discover safe and cost‐effective radical sources. Among the various transformations, the radical‐involved alkylation reaction continues to blossom since the alkyl unit is ubiquitous in biological and pharmaceutical compounds. The utilization of aliphatic aldehydes as alkyl radical precursors via peroxides or oxygen‐initiated decarbonylation reactions has attracted great attention over the past decade due to their ready availability and the simple operation. Although examples of radical acylation reactions starting from aldehydes have been reviewed before, reviews on decarbonylative radical reactions of aliphatic aldehydes are scarce. In this review, we summarize recent significant advances in this rapidly growing area, mainly focusing on reaction design and reaction mechanisms.magnified image

Photoredox- or Metal-Catalyzed in Situ SO2-Capture Reactions: Synthesis of β-Ketosulfones and Allylsulfones.

The first report of the in situ capture of the SO2 fragment of the trifluoromethylsulfonyl radical is described here. With cyclobutanone oximes as representative alkyl radical precursors, vinyl triflates and allyl trifluoromethylsulfones were employed as radical acceptors and SO2 sources to provide various β-ketosulfones and allylsulfones, known to be significant building blocks. Without the use of any additives including external SO2 gas, the reaction was performed under mild photoredox- or metal-catalytic conditions while tolerating various functional groups.

Photoredox-catalyzed synthesis of sulfones through deaminative insertion of sulfur dioxide.

Katritzky salts are used as the alkyl radical precursors with the insertion of sulfur dioxide under photoredox catalysis. This transformation first enables direct generation of various alkylsulfonyl radicals by photoinduced single electron reduction, leading to diverse dialkyl sulfones in good to excellent yields. A radical pathway is proposed under visible-light induced conditions with the insertion of sulfur dioxide.

Leaving Group Assisted Strategy for Photoinduced Fluoroalkylations Using N‐Hydroxybenzimidoyl Chloride Esters

AbstractRedox‐active esters (RAEs) as alkyl radical precursors have been extensively developed for C−C bond formations. However, the analogous transformations of fluoroalkyl radicals from the corresponding acid or ester precursors remain challenging because of the high oxidation potential of the fluoroalkyl carboxylate anions. The newly developed N‐hydroxybenzimidoylchloride (NHBC) ester provides a general leaving group assisted strategy to generate a portfolio of fluoroalkyl radicals, and can be successfully applied in photoinduced decarboxylative hydrofluoroalkylation and heteroarylation of unactivated olefins. In addition, DFT calculations revealed that the NHBC ester proceeds by the fluorocarbon radical pathway, whereas other well‐known RAEs proceed by the nitrogen radical pathway.

Leaving Group Assisted Strategy for Photoinduced Fluoroalkylations Using N-Hydroxybenzimidoyl Chloride Esters.

Redox-active esters (RAEs) as alkyl radical precursors have been extensively developed for C-C bond formations. However, the analogous transformations of fluoroalkyl radicals from the corresponding acid or ester precursors remain challenging because of the high oxidation potential of the fluoroalkyl carboxylate anions. The newly developed N-hydroxybenzimidoylchloride (NHBC) ester provides a general leaving group assisted strategy to generate a portfolio of fluoroalkyl radicals, and can be successfully applied in photoinduced decarboxylative hydrofluoroalkylation and heteroarylation of unactivated olefins. In addition, DFT calculations revealed that the NHBC ester proceeds by the fluorocarbon radical pathway, whereas other well-known RAEs proceed by the nitrogen radical pathway.

Quinone C–H Alkylations via Oxidative Radical Processes

A brief survey of radical additions to quinones is reported. Carboxylic acids, aldehydes, and unprotected amino acids are compared as alkyl radical precursors for the mono- or bis- C–H alkylation of several quinones. Two methods for radical initiation are discussed comparing inorganic persulfates and Selectfluor as stoichiometric oxidants. Kinetic analysis reveals dramatic differences in the rate of radical initiation depending on the identity of the radical precursor and oxidant. Synthetic strategies for efficiently producing alkyl-quinones are discussed in the context of selecting optimum radical precursors and initiators depending on quinone identity and functional groups present.

Cascade C(sp3)-S Bond Cleavage and Imidoyl C-S Formation: Radical Cyclization of 2-Isocyanoaryl Thioethers toward 2-Substituted Benzothiazoles.

A cascade radical cyclization of 2-isocyanoaryl thioethers with H-phosphorus oxides, organoboronic acids, or alkyl radical precursors has been efficiently developed, providing a novel and highly efficient methodology to structurally diverse C2-substituted benzothiazole derivatives with broad functional group tolerance and good yields. This cascade radical process achieves the first cycloaddition of an imidoyl radical from isocyanide to sulfur atom, rending C(sp2)-S bond formation.

Light-Sensitive Alkoxyamines as Versatile Spatially- and Temporally- Controlled Precursors of Alkyl Radicals and Nitroxides.

The use of UV/visible light irradiation as a means to initiate organic syntheses is increasingly attractive due to the high spatial and temporal control conferred by photochemical processes. The aim of this work is thus to demonstrate that alkoxyamines bearing a chromophore on the alkyl moiety can provide a photoprotecting group for the sensitive nitroxide functionality, that is known to degrade through redox processes. The dissociation of various photosensitive alkoxyamines was studied from 223 to 298 K under UV/visible irradiation, depending on the nature of the chromophore. In each case a rapid (typically in less than 1 h) and near-quantitative dissociation was observed. As an illustration of the interest of this approach, a pyrene-based alkoxyamine was employed for the spatially controlled coupling of polymer chains onto Si wafers to produce micropatterned surfaces.