Metal-free Conditions Research Articles

Organocatalyzed Carbonylation of Alkyl Halides Driven by Visible Light.

Herein, we describe a new strategy for the carbonylation of alkyl halides with different nucleophiles to generate valuable carbonyl derivatives under visible light irradiation. This method is mild, robust, highly selective, and proceeds under metal-free conditions to prepare a range of structurally diverse esters and amides in good to excellent yields. In addition, we highlight the application of this activation strategy for 13C isotopic incorporation. We propose that the reaction proceeds by a photoinduced reduction to afford carbon-centered radicals from alkyl halides, which undergo subsequent single electron-oxidation to form a carbocationic intermediate. Carbon monoxide is trapped by the carbocation to generate an acylium cation, which can be attacked by a series of nucleophiles to give a range of carbonyl products.

Mechanochemical cyclization of push-pull enamines with propargyl alcohols

We developed an efficient mechanochemical method for the synthesis of 1,2-dihydropyridine derivatives from push-pull enamines and tert-propargyl alcohols under ball milling with p-TsOH/HFIP. The reaction proceeds smoothly under metal-free conditions with fast, efficient, and high-yielding synthesis of 1,2-dihydropyridines. The reaction shows excellent atom economy, with a broad substrate generality.

Microwave Promoted Tandem Reaction of Free Primary Arylamines with Diazo Compounds Under Metal-Free Condition in Water: Clean Synthesis of 2,2-Disubstituted 3-Oxindoles.

Herein, a microwave promoted tandem reaction of free primary arylamines with diazo compounds in water for clean synthesis of 2,2-disubstituted 3-oxindoles is present. Water plays important roles in the whole cascade process: O-H insertion to diazo, air oxidation, ortho C-H functionalization, cyclization and 1,2-ester migration. In particular, water plays a mediation role in the site selective ortho-C-H addition.

Metal-Free Diversification of Unprotected Amino Acid Drugs via Tandem Reaction of 2-(2-oxo-2-aryl/alkylethyl)benzonitrile in Aqueous Medium.

Herein, we report an efficient strategy towards the synthesis of amino acid substituted isoquinoline derivatives via reaction of unprotected amino acid/amino acid ester/amino acid based drugs with 2-(2-oxo-2-aryl/alkylethyl)benzonitrile under metal-free conditions. The developed protocol is highly simple and shows functional group tolerance to provide corresponding novel amino acid substituted isoquinolines in aqueous medium. The applicability of the reaction is an easier modification of well-known drugs and successfully extended to gram-scale synthesis.

Comprehensive Review on the Synthesis of [1,2,3]Triazolo[1,5-a]Quinolines.

This report outlines the evolution and recent progress about the different protocols to synthesize the N-heterocycles fused hybrids, specifically [1,2,3]triazolo[1,5-a]quinoline. This review encompasses a broad range of approaches, describing several reactions for obtaining this since, such as dehydrogenative cyclization, oxidative N-N coupling, Dieckmann condensation, intramolecular Heck, (3+2)-cycloaddition, Ullman-type coupling and direct intramolecular arylation reactions. We divided this review in three section based in the starting materials to synthesize the target [1,2,3]triazolo[1,5-a]quinolines. Starting materials containing quinoline or triazole units previously formed, as well as starting materials which both quinoline and triazole units are formed in situ. Different methods of obtaining are described, such as metal-free or catalyzed conditions, azide-free, using conventional heating or alternative energy sources, such as electrochemical and photochemical methods. Mechanistic insights underlying the reported reactions were also described in this comprehensive review.

Visible-light-mediated cyclopropanation reactions of 3-diazooxindoles with olefins

Visible-light-mediated metal-free cyclopropanation reaction of diazo compounds with different olefins or arenes have been fully developed in recent years. However, electron-deficient olefins still could not be well tolerated in these reactions. Here, by using 3-diazooxindole as the carbene precursor, the visible-light-mediated cyclopropanation reaction of diazo compounds with electron-deficient olefins was successfully developed. The electron-rich olefins were also well tolerated in the reactions. A series of spirocyclopropyloxindoles were synthesized in moderate to high yields under mild, metal-free conditions. Mechanism studies reveal that both singlet and triplet carbenes are probably involved in the reaction.

Synthesis of Diaryl Diselenides and Ditellurides via Bromide-Catalyzed C–Se/C–Te Bond Formation Using Se/Te Powder and Boronic Acid

AbstractDiaryl diselenides and diaryl ditellurides are commonly employed as selenyl or telluryl sources, and they have a wide range of applications in organic synthesis. Herein, various diaryl diselenides/ditellurides are furnished in moderate to excellent yields under metal-free conditions. This method features high efficiency, good functional group tolerance, straightforward operation, and easy scale-up (running in 4 mmol-scale for most cases). Mechanistic studies indicate that this reaction may proceed via a radical pathway. Significantly, the correct matching of Br– and dimethyl sulfoxide under an air atmosphere is critical to this transformation.

Electrochemical Giese Reaction of α-Trifluoromethylstyrenes with Disulfides: Efficient Access to β-Trifluoromethylated Thioethers.

An electrochemical Giese-type hydrothiolation of α-trifluoromethylstyrenes with disulfides is disclosed for the first time under metal-free and mild conditions. This approach provides a facile methodology for β-trifluoromethylated thioethers in moderate to good yields with high functional group tolerance starting from readily available substrates. Additionally, late-stage modification of drug molecules and gram-scale synthesis show practical advantages. The radical pathway of this reaction has been revealed by control experiments and cyclic voltammetry measurements.

DMSO-Catalyzed Double P-O Bond or Double P-S Bond Formations of Phosphinic Acids.

A DMSO-catalyzed double P-O bond or double P-S bond formation of phosphinic acid with an O- or S-containing nucleophile has been developed. Under metal-free and mild conditions, this simple procedure provides a compatible and rapid access to a variety of phosphonates and dithiophosphates. The DFT calculation of stabilization energy (SE) and the mechanism studies demonstrated that the "just right" Lewis base property and the relatively "soft" interaction strength with the phosphenium-dication ensure the unique catalytic activity of DMSO in this transformation.

Deoxygenation of benzylphenyl sulfones using 1,2-bis(diphenylphosphino)ethane (dppe)/NBS under metal-free conditions

An efficient route for the chemoselective deoxygenation of benzylphenyl sulfones to the corresponding sulfides has been developed using a mixture of 1,2-bis(diphenylphosphino)ethane(dppe) and NBS as an effective promoter. This is the first development on the deoxygenation of diverse benzylphenyl sulfones under metal-free conditions. The mild reaction conditions, formation of the water soluble by-product and tolerance of a wide range of functional groups promote its broad applications in organic synthesis.

Visible-Light-Induced Multi-Component Nitrooxylation Reactions of α-Diazoesters, Cyclic Ethers, and Tert-Butyl Nitrite Leading to Organic Nitrate Esters.

A simple and efficient strategy has been developed for the synthesis of organic nitrate esters via visible-light-induced multi-component nitrooxylation reactions of α-diazoesters, cyclic ethers, and tert-butyl nitrite under open air atmosphere. This transformation could be conducted under mild and metal-free conditions to provide a number of organic nitrate esters in moderate to good yields using air as the green oxidant.

Radical 6-Endo Addition Enables Pyridine Synthesis under Metal-Free Conditions.

Metal-free synthesis of heterocycles is highly sought after in the pharmaceutical industry and has garnered widespread attention due to eliminating the need to remove trace metal catalysts from the reaction. We report a radical 6-endo addition method for pyridine synthesis from cyclopropylamides and alkynes under metal-free conditions. Various terminal and substituted alkynes are inserted as C2 units into cyclopropylamides to synthesize versatile pyridines with 57 examples. Mechanistic investigations and computational studies indicate the unprecedented 6-endo-trig addition of vinyl radicals to the imine nitrogen atom rather than the conventional 5-exo-trig addition to the imine carbon atom, in which the hypervalent iodine(III) plays a critical role. This reaction easily scales up with excellent functional group compatibility and suits the late-stage pyridine installation on complex molecules.

Photocatalytic Decarboxylative Allylation of α-Amino Acids and Peptides under Metal-Free Conditions.

We developed an organophotoredox catalytic system to facilitate the decarboxylative allylation coupling process concerning α-amino acids and related C-terminal carboxylate peptides using Morita-Baylis-Hillman adducts as allylic precursors. This metal-free method operates under mild conditions and is compatible with various amino acids. The versatility of this protocol, particularly in chemical biology research, has been preliminarily demonstrated through the ligation of bioactive peptide chains.

Recent Progress in Synthetic Applications of Hypervalent Iodine(III) Reagents.

Hypervalent iodine(III) compounds have found wide application in modern organic chemistry as environmentally friendly reagents and catalysts. Hypervalent iodine reagents are commonly used in synthetically important halogenations, oxidations, aminations, heterocyclizations, and various oxidative functionalizations of organic substrates. Iodonium salts are important arylating reagents, while iodonium ylides and imides are excellent carbene and nitrene precursors. Various derivatives of benziodoxoles, such as azidobenziodoxoles, trifluoromethylbenziodoxoles, alkynylbenziodoxoles, and alkenylbenziodoxoles have found wide application as group transfer reagents in the presence of transition metal catalysts, under metal-free conditions, or using photocatalysts under photoirradiation conditions. Development of hypervalent iodine catalytic systems and discovery of highly enantioselective reactions using chiral hypervalent iodine compounds represent a particularly important recent achievement in the field of hypervalent iodine chemistry. Chemical transformations promoted by hypervalent iodine in many cases are unique and cannot be performed by using any other common, non-iodine-based reagent. This review covers literature published mainly in the last 7-8 years, between 2016 and 2024.

Organic Photoredox-Catalyzed Site-Selective Alkylation of Glycine Derivatives and Peptides via Infrequent 1,2-Hydrogen Atom Transfer of Amidyl Radicals.

Herein, we disclose a visible-light-driven photoredox-catalyzed protocol for site-selective alkylation of glycine derivatives via 1,2-hydrogen atom transfer, which is distinguished by metal free and mild conditions, high chemoselectivity, and good functional group compatibility. This protocol provides a unique approach for synthesizing valuable α,β-diamino acid derivatives. Furthermore, the potential synthetic merit of this transformation is proven by a scale-up reaction and late-stage functionalization of peptides.

Metal-free radical selenothiocyanation of terminal and internal alkynes.

We report herein a synthetic strategy for the generation of direct selenothiocyanation from both terminal and internal alkynes via a radical process. Alkynes derived from bioactive molecules, such as L(-)-borneol and L-menthol, are suitable for selenothiocyanation reaction. This method features metal-free conditions and readily available reagents.

Metal-free Borylation of α-Naphthamides and Phenylacetic Acid Drug.

Site-selective C-H borylation is an important strategy for constructing molecular diversity in arenes and heteroarenes. Although transition-metal-catalyzed borylation is well explored, developing metal-free strategies remains scarce. Herein, we developed a straightforward approach for BBr3-mediated selective C-H borylation of naphthamide and phenyl acetamide derivatives under metal-free conditions. This methodology appears to be economical and cost-effective. Successful borylation of drug molecules such as ibuprofen and indoprofen demonstrates the versatility and utility of this metal-free borylation. An exclusive monoselectivity was observed without a trace of diboration. Despite the possibility of forming a 5-membered boronated intermediate at the ortho-position, the selectively 6-membered intermediate paved the way for the formation of the peri-product, which was further supported by detailed computational investigation.

Electro-sustainable Synthesis: Rapid and Efficient Production of Benzothiazole Derivatives through Electrochemical Means for Sustainable Chemistry

Abstract: Electro-organic synthesis suggested a mild, environmentally benign, and atom-efficient pathway to interesting and useful organic compounds. Organic electrochemistry offers an excellent alternative to conventional methods of organic synthesis, avoiding harsh, oxidizing and reducing agents, etc. In our reported work, electro-organic synthesis was carried out in an undivided cell at room temperature in the presence of lithium perchlorate as a supporting electrolyte. Electricity is utilized here instead of a chemical substance with a simple graphite-iron electrode combination. The generation of 2-substituted benzothiazoles was achieved through the amalgamation of bis(2- aminophenyl)disulfides with aromatic aldehydes under the influence of the electrodes. This synthetic process yielded a diverse array of 2-substituted benzothiazoles with satisfactory to excellent yields (64-91%). This is a gentle, sustainable, and metal-free condition for the synthesis of 2-substituted benzothiazoles. In this procedure, subsequent procedural steps encompassed the introduction of distilled water followed by filtration and drying processes to ensure the refinement of the final products.

Metal-Free Synthesis of Polysubstituted Triazoloquinoxalines Using Alkynols as the Key Building Blocks.

o-Phenylenediamines, o-nitroanilines, and Boc-o-phenylenediamines were converted to N-Ts/Ns-o-phenylenediamines, followed by Mitsunobu alkylation with prop-2-yn-1-ols. After one-pot azidation, the resulting intermediates underwent Huisgen cycloaddition, which yielded Ts/Ns-dihydrotriazoloquinoxalines. Cleavage of the arylsulfonyl moiety provided (dihydro)triazoloquinoxalines with the possibility of modifying the N 5 position. The application of but-3-yn-1-ols and pent-4-yn-1-ols allowed the preparation of benzotriazolodiazepines and benzotriazolodiazocines. The developed protocols enable the preparation of diversely substituted products from readily available starting materials under mild and metal-free conditions.

Electrochemically Driven Denitrative Cyanation of Nitroarenes.

A practical denitrative cyanation of feedstock nitroarenes under mild and transition metal-free reaction conditions has been developed. The key to success lies in the use of electrochemically driven, inexpensive ionic liquid N-methylimidazolium p-toluenesulfonate-promoted selective cathode reduction of nitroarenes to anilines, followed by diazoation, cathode reduction to form the aryl radical, and the essential radical cyanation process in one pot. Our protocol shows broad functional group tolerance and can be applied for the modification of bioactive targets.