Generation Of Alkyl Radicals Research Articles

Cobalt(II)-Catalyzed C–H Alkylation of N-Heterocycles with 1,4-Dihydropyridines

The rapid incorporation of alkyl and acyl groups into C–H bonds of N-heterocycles is in demand for the development of lead candidates in drug discovery. Herein, we report the cobalt(II)-catalyzed C–H alkylation and acylation of N-heterocycles with 1,4-dihydropyridines (DHPs) as alkylating and acylating agents. Notably, a combination of KBrO3 and a Co(II) catalyst was successfully employed for the generation of alkyl and acyl radicals from DHPs. A series of heterocycles, including azauracils, quinoxalinones, pyrazinones, pyridones, quinolones, quinazolinones, xanthines, chromones, and azine N-oxides, were compatible under the developed conditions. The applicability of the developed protocol in challenging contexts is highlighted by the selective modification of drug candidates as well as the gram-scale synthesis of bioactive molecules. Combined mechanistic investigations aided the elucidation of a plausible reaction mechanism.

Oxygen-independent alkyl radical nanogenerator enhances breast cancer therapy

The hypoxic microenvironment of breast cancer substantially reduces oxygen-dependent free radical generation. Overexpression of glutathione (GSH) in tumor cells mitigates the impact of free radical generation. In this study, we designed and developed an oxygen-independent alkyl radical nanogenerator (copper monosulfide/2,2′-azabis(2-imidazoline) dihydrochloride@bovine serum albumin; CuS/AIPH@BSA) with spatiotemporally controlled properties and GSH consumption to enhance breast cancer therapy. We encapsulated the alkyl radical initiator, AIPH, in hollow mesoporous CuS nanoparticles with photothermal conversion effect and enveloped them in BSA. AIPH was released and decomposed to generate alkyl radicals in hypoxic breast cancer with the photothermal conversion effect of CuS under near-infrared laser irradiation. CuS consumed high GSH levels in tumor cells because it could form complex with GSH and thereby enhanced free radical treatment. In vivo and in vitro assays demonstrated the anti-tumor efficacy of the rationally designed free-radical nanogenerator in hypoxic microenvironment of breast cancer without showing systemic toxicity.

Enantioselective Radical Addition to Ketones through Lewis Acid-Enabled Photoredox Catalysis.

Photocatalysis opens up a new window for carbonyl chemistry. Despite a multitude of photochemical reactions of carbonyl compounds, visible light-induced catalytic asymmetric transformations remain elusive and pose a formidable challenge. Accordingly, the development of simple, efficient, and economic catalytic systems is the ideal pursuit for chemists. Herein, we report an enantioselective radical photoaddition to ketones through a Lewis acid-enabled photoredox catalysis wherein the in situ formed chiral N,N'-dioxide/Sc(III)-ketone complex serves as a temporary photocatalyst to trigger single-electron transfer oxidation of silanes for the generation of nucleophilic radical species, including primary, secondary, and tertiary alkyl radicals, giving various enantioenriched aza-heterocycle-based tertiary alcohols in good to excellent yields and enantioselectivities. The results of electron paramagnetic resonance (EPR) and high-resolution mass spectrum (HRMS) measurements provided favorable evidence for the stereocontrolled radical addition process involved in this reaction.

Organophotocatalytic Generation of Alkyl Radicals by C–C Bond Cleavage and Radical Conjugate Addition

Organophotocatalytic Generation of Alkyl Radicals by C–C Bond Cleavage and Radical Conjugate Addition

Dual-Role Halogen-Bonding-Assisted EDA-SET/HAT Photoreaction System with Phenol Catalyst and Aryl Iodide: Visible-Light-Driven Carbon-Carbon Bond Formation.

Electron donor-acceptor (EDA) complex-mediated single-electron transfer (SET) is a crucial method for generating carbon radicals. Hydrogen atom transfer (HAT) enables the direct generation of alkyl radicals. We report a dual-role EDA-SET/HAT photoreaction system for carbon-carbon bond formation using a phenol catalyst and aryl iodide. This system facilitates addition of alkyl radicals generated from ethers, amide, sulfide, and cycloalkane to arenes. Mechanistic studies revealed that EDA complex formation is mediated by halogen bonding between phenoxide and aryl iodide. Irradiation of the EDA complex with visible light generates an aryl radical, which abstracts a hydrogen atom from an sp3 carbon to form an alkyl radical.

Visible Light-Induced Deoxygenation and Allylation/Vinylation of Pyridyl Ethers.

The generation of alkyl radicals by deoxygenation of unactivated ethers under visible light catalysis is a hitherto unmet challenge. Herein, we report a visible light-induced deoxygenation of pyridyl ethers via formation of their pyridinium salts. The generated benzylic radicals further react with allyl/alkenyl sulfones to provide a series of coupling products in good to moderate yields. This process is proposed to undergo a reductive quenching cycle, which was elucidated by chemical, optical, and electrical experiments.

Alkyl Radical Generation via C-C Bond Cleavage in 2-Substituted Oxazolidines.

There is an urgent need to develop uncharged radical precursors to be activated under mild photocatalyzed conditions. 2-Substituted-1,3-oxazolidines (Eox < 1.3 V vs SCE, smoothly prepared from the corresponding aldehydes) have been herein employed for the successful release of tertiary, α-oxy, and α-amido radicals under photo-organo redox catalysis. The reaction relies on the unprecedented C–C cleavage occurring from the radical cation of these heterocyclic derivatives. Such a protocol is applied to the visible-light-driven conjugate radical addition onto Michael acceptors and vinyl (hetero)arenes under mild metal-free conditions.

Photocatalytic Regioselective Difunctionalization of Alkenes with Diazo Compounds and tert-Butyl Nitrite: Access to γ-Oximino Esters.

A visible-light photocatalytic regioselective difunctionalization of alkenes with diazo compounds and tert-butyl nitrite has been developed. The protocol provides an efficient approach to γ-oximino esters under mild conditions. Significantly, this transformation not only shows the good compatibility of nucleophilic diazo compounds and electrophilic tert-butyl nitrite but also displays diazo compounds generating alkyl radicals that preferred addition to alkenes over nitroso radicals.

Ni/Photoredox-Catalyzed C(sp2)–C(sp3) Cross-Coupling of Alkyl Pinacolboronates and (Hetero)Aryl Bromides

Utilizing quinoline as a mild, catalytic additive, broadly applicable conditions for the Ni/photoredox-catalyzed C(sp2)-C(sp3) cross-coupling of (hetero)aryl bromides and alkyl pinacolboronate esters were developed, which can be applied to both batch and flow reactions. In addition to primary benzylic nucleophiles, both stabilized and nonstabilized secondary alkyl boronic esters are effective coupling partners. Density functional theory calculations suggest that alkyl radical generation occurs from an alkyl-B(pin)-quinoline complex, which may proceed via an energy transfer process.

Recent Progress in Fragmentation of Katritzky Salts Enabling Formation of C-C, C-B, and C-S Bonds.

Since their discovery in 1970s, Katritzky salts have emerged as one of the most important classes of building blocks for use in organic synthesis and drug discovery. These bulky pyridinium salts derived from alkylamine can readily generate alkyl radical and undergo a variety of organic transformation reactions such as alkylation, arylation, alkenylation, alkynylation, carbonylation, sulfonylation, and borylation. Through these transformations, complexed molecules bearing new C-C, C-B, or C-S bonds can be constructed in easy ways and in simple steps. This review aims to summarize recent advances in these versatile building blocks in well-classified categories. Representative examples and their reaction mechanisms are discussed. The hope is to provide the scientific community with convenient access to collective information and accelerate further research.

Alkylation/Ipso-cyclization of Active Alkynes Leading to 3-Alkylated Aza- and Oxa-spiro[4,5]-trienones.

A method for the preparation of 3-alkylated spiro[4.5]trienones via alkylation/ipso-cyclization of activated alkynes with 4-alkyl-DHPs under transition-metal-free conditions is proposed. This alkylation successively undergoes the generation of alkyl radicals, addition of alkyl radicals to the alkynes, and intramolecular ipso-cyclization. The mechanism studies suggest that the alkylation/ipso-cyclization involves a radical process. This ipso-cyclization procedure shows a series of advantages, such as accessibility, mild conditions, high efficiency, greater safety, and an environmentally friendly method.

Boryl Radical Activation of Benzylic C-OH Bond: Cross-Electrophile Coupling of Free Alcohols and CO2 via Photoredox Catalysis.

A new strategy for the direct cleavage of the C(sp3)-OH bond has been developed via activation of free alcohols with neutral diphenyl boryl radical generated from sodium tetraphenylborate under mild visible light photoredox conditions. This strategy has been verified by cross-electrophile coupling of free alcohols and carbon dioxide for the synthesis of carboxylic acids. Direct transformation of a range of primary, secondary, and tertiary benzyl alcohols to acids has been achieved. Control experiments and computational studies indicate that activation of alcohols with neutral boryl radical undergoes homolysis of the C(sp3)-OH bond, generating alkyl radicals. After reducing the alkyl radical into carbon anion under photoredox conditions, the following carboxylation with CO2 affords the coupling product.

Photo-induced trifunctionalization of bromostyrenes via remote radical migration reactions of tetracoordinate boron species

Tetracoordinate boron species have emerged as radical precursors via deboronation by photo-induced single electron transfer (SET) pathway. These reactions usually produce an alkyl radical and boron-bound species, and the valuable boron species are always discarded as a by-product. Given the importance of boron species, it will be very attractive if the two parts could be incorporated into the eventual products. Herein we report a photo-catalyzed strategy in which in situ generated tetracoordinated boron species decomposed into both alkyl radicals and boron species under visible light irradiation, due to the pre-installation of a vinyl group on the aromatic ring, the newly generated alkyl radical attacks the vinyl group while leaving the boron species on ipso-position, then both radical part and boron moiety are safely incorporated into the final product. Tertiary borons, secondary borons, gem-diborons as well as 1,2-diborons, and versatile electrophiles are all well tolerated under this transformation, of note, ortho-, meta- and para-bromostyrenes all demonstrated good capabilities. The reaction portraits high atom economy, broad substrate scope, and diversified valuable products with tertiary or quaternary carbon center generated, with diborons as substrates, Csp2-B and Csp3-B are established simultaneously, which are precious synthetic building blocks in chemical synthesis.

Decarboxylative alkylarylation of alkenes with PhI(O2CR)2 to access benzimidazo[2,1-a]isoquinolin-6(5H)-ones catalyzed by a low-valent divanadium complex

Herein, we report a divanadium-catalyzed decarboxylative alkylarylation of alkenes with hypervalent iodine(III) reagents (HIRs) for the rapid construction of tetracyclic benzimidazo[2,1-a]isoquinolin-6(5H)-ones. This transformation proceeds regioselectively with viarously substituted N-methacryloyl-2-arylbenzoimidazoles and diverse aliphatic acid-derived HIRs under mild conditions. Furthermore, mechanistic investigations revealed that the in situ generated alkyl radical triggered this regioselective 6-exo cyclization.

Copper-Catalyzed Bromo-cyanomethylative Cyclization of Enynes.

A copper-catalyzed bromo-cyanomethylative cyclization of 1,6-enynes is demonstrated. The treatment of 2-bromoacetonitrile with CuI enables the alkyl radical generation and triggers the radical addition/cyclization/bromination sequence, giving various vinyl C-Br bonds containing functionalized heterocycles in good yields.

Efficient Photocatalytic Carbonyl Alkylative Amination Enabled by Titanium-Dioxide-Mediated Decarboxylation.

Herein, a heterogeneous carbonyl alkylative amination reaction that proceeds by photoredox catalysis has been developed. The use of nano titanium dioxide (TiO2 , 25 nm) as photocatalyst allows efficient synthesis of diverse amines in good to excellent yields. Mechanistic studies reveal a single-electron-transfer mechanism involving the photoexcitation of TiO2 to generate alkyl radicals from carboxylic acids decarboxylation. This protocol highlights the utility of using heterogeneous semiconductor photocatalysts to promote a practical and general synthesis of complex amines from readily available feedstocks.

Alkyl-GeMe3 : Neutral Metalloid Radical Precursors upon Visible-Light Photocatalysis.

Single-electron transfer (SET) oxidation of ionic hypervalent complexes, in particular alkyltrifluoroborates (Alkyl-BF3 - ) and alkylbis(catecholato)silicates (Alkyl-Si(cat)2 - ), have contributed substantially to alkyl radical generation compared to alkali or alkaline earth organometallics because of their excellent activity-stability balance. Herein, another proposal is reported by using neutral metalloid compounds, Alkyl-GeMe3 , as radical precursors. Alkyl-GeMe3 shows comparable activity to that of Alkyl-BF3 - and Alkyl-Si(cat)2 - in radical addition reactions. Moreover, Alkyl-GeMe3 is the first successful group 14 tetraalkyl nucleophile in nickel-catalyzed cross-coupling. Meanwhile, the neutral nature of these organogermanes offset the limitation of ionic precursors in purification and derivatization. A preliminary mechanism study suggests that an alkyl radical is generated from a tetraalkylgermane radical cation with the assistance of a nucleophile, which may also result in the development of more non-ionic alkyl radical precursors with a metalloid center.

Alkyl‐GeMe3: Neutral Metalloid Radical Precursors upon Visible‐Light Photocatalysis

AbstractSingle‐electron transfer (SET) oxidation of ionic hypervalent complexes, in particular alkyltrifluoroborates (Alkyl‐BF3−) and alkylbis(catecholato)silicates (Alkyl‐Si(cat)2−), have contributed substantially to alkyl radical generation compared to alkali or alkaline earth organometallics because of their excellent activity–stability balance. Herein, another proposal is reported by using neutral metalloid compounds, Alkyl‐GeMe3, as radical precursors. Alkyl‐GeMe3 shows comparable activity to that of Alkyl‐BF3− and Alkyl‐Si(cat)2− in radical addition reactions. Moreover, Alkyl‐GeMe3 is the first successful group 14 tetraalkyl nucleophile in nickel‐catalyzed cross‐coupling. Meanwhile, the neutral nature of these organogermanes offset the limitation of ionic precursors in purification and derivatization. A preliminary mechanism study suggests that an alkyl radical is generated from a tetraalkylgermane radical cation with the assistance of a nucleophile, which may also result in the development of more non‐ionic alkyl radical precursors with a metalloid center.

Direct photolysis of 4-tert-alkyl-1,4-dihydropyridines under blue-light irradiation for the generation of tertiary alkyl radicals

4-tert-Alkyl-dihydropyridines can serve as tertiary radical precursors under visible-light irradiation in the absence of exogeneous photocatalysts or oxidants.

Boron, silicon, nitrogen and sulfur-based contemporary precursors for the generation of alkyl radicals by single electron transfer and their synthetic utilization.

Recent developments in the use of boron, silicon, nitrogen and sulfur derivatives in single-electron transfer reactions for the generation of alkyl radicals are described. Photoredox catalyzed, electrochemistry promoted or thermally-induced oxidative and reductive processes are discussed highlighting their synthetic scope and discussing their mechanistic pathways.