Metal-free Conditions Research Articles

Light-Driven Organocatalyzed Controlled Radical Copolymerization of (Perfluoroalkyl)ethylenes and Vinyl Esters/Amides.

Fluoropolymers of well-defined structures exhibit significant potential in a broad range of high-tech applications. However, the controlled synthesis of fluoropolymers from easily available monomers remains difficult. In this work, we report the development of an organocatalyzed controlled radical copolymerization of (perfluoroalkyl)ethylenes (PFAEs) and unconjugated vinyl monomers (UCMs) under light irradiation, which has enabled on-demand access toward side-chain fluorinated polymers under metal-free conditions. This method furnishes a large variety of polymers with diverse fluoroalkyl and ester/amide as pendent groups, tunable molar masses, and low dispersities (ca. Đ = 1.1-1.3), and adjustable fractions of PFAE and UCM units. Obtained fluoropolymers exhibit good chain-end fidelity and activity, allowing chain-extension polymerizations to prepare block copolymers of complicated compositions. Furthermore, the PFAE copolymers exhibit outstanding light transmission and low refractive index.

Highly Regioselective Dehydrogenative Hydrazination of Tropones.

Direct C(sp2)-H bond functionalization of the tropone skeleton constitutes an atom-economical strategy to access substituted tropones that exist in some bioactive compounds. Herein, we report a convenient method for the preparation of 2-hydrazinotropones via C(sp2)-H bond functionalization. A variety of tropones participated in the dehydrogenative hydrazination reaction with hydrazine, delivering structurally diverse 2-hydrazinotropones in moderate to good yields with extremely high regioselectivity. This method is featured by operational simplicity and metal-free reaction conditions, thereby tolerating various functional groups.

Organic Photoredox Catalytic Difluoroalkylation of Unactivated Olefins to Access Difluoro-Containing Tetrahydropyridazines.

Herein, we disclose a readily available phenothiazine derivative as an organocatalyst, which upon excitation with 371 nm light acquires a strongly reducing power and serves to induce the radical cascade difluoromethylation/cyclization reaction of N-homoallylacetohydrazides. A variety of CF2COR-tetrahydropyridazines have been obtained in moderate to excellent yields. This catalytic platform proceeds under metal-free conditions with a wide substrate scope and broad functional group compatibility, which unlocks the new reactivity of phenothiazine derivatives and adds significant synthetic value to N-heterocycles.

Recent advances in transition-metal-free arylation reactions involving hypervalent iodine salts

Diaryliodonium salts have become widely recognized as arylating agents in the last two decades. Both, symmetrical and unsymmetrical forms of these salts serve as effective electrophilic arylating reagents in various organic syntheses. The use of diaryliodoniums in C–C and carbon–heteroatom bond formations, particularly under metal-free conditions, has further enhanced the popularity of these reagents. In this review, we concentrate on various arylation reactions involving carbon and other heteroatoms, encompassing rearrangement reactions in the absence of any metal catalyst, and summarize advancements made in the last five years.

Brook-Oxidation Reaction of Acylsilanes: General Access to α-Ketoamides and α-Ketothioamides.

A novel chemoselective Brook-oxidation reaction of acylsilanes initiated by the carbamoyl anion has been successfully developed for the first time. This method enables the synthesis of diverse α-ketoamides and α-ketothioamides under transition metal-free and strong oxidant-free conditions with high yields and high chemoselectivity. It also demonstrates tolerance toward a wide range of functional groups. The synthetic utility of this process is underscored by its successful application in the synthesis of an orexin receptor antagonist from acylsilane, highlighting its potential for the development of novel therapeutic agents and further exploration in synthetic chemistry.

Organocatalytic Asymmetric Construction of 2,6-Diazabicyclo-[2.2.2]octanes by Harnessing the Potential of an 3-Oxindolium Ion Intermediate.

Due to its structural complexity and intrinsic sensitivity of bridged aminal junction, 2,6-diazabicyclo[2.2.2]octane (2,6-DABCO) has remained a highly desirable target in synthetic chemistry. However, the asymmetric access to this unit is still insufficient and hampered by the need for meticulously created functionalities for intricate double aza-cyclizations. Herein, we have developed a novel enantio- and diastereoselective protocol to access polycyclic chiral 2,6-DABCOs under metal-free conditions. This domino process involves the amine-catalyzed [4+2] annulation between glutaraldehyde and 2-arylindol-3-ones, followed by an acid-mediated Pictet-Spengler reaction/intramolecular aza-cyclization cascade sequence with tryptamine by trapping of in situ generated 3-oxindolium ion intermediate for the first time. Overall, 2,6-DABCOs fused with medicinally relevant scaffolds were isolated with good yield and excellent stereoselectivity by constructing five new bonds and four stereocenters in a one-pot operation.

Selective Access to 2‐Phenylquinazolin‐4(3H)‐Ones and 2,3‐Dihydroquinazolin‐4(1H)‐Ones from Same Precursors in Organic Salts Derived DES

AbstractA binary mixture of organic salts, also known as ionic liquids, [C12mim][Br]:[MPIM][HCOO] denoted as BmIL1 has been explored as bifunctional catalyst for the selective synthesis of 2‐phenylquinazolin‐4(3H)‐ones and 2,3‐dihydroquinazolin‐(1H)‐ones from same precursors under metal, ligand and additive free conditions. The methodology has been extended to the synthesis of 2‐phenylquinazolin‐4(3H)‐ones via another pathway from different precursors under the same catalytic system. Greener synthesis of existing drugs reestablished the multifunctionality of BmIL1. Gram scale synthesis of both the products, DFT calculations and sc‐XRD data add significance to the developed protocol. Moreover, high atom economy and eco score values justify the sustainability of the methodology.

Boron-Mediated Selective C-H Hydroxylation of 1-Phenyl-1H-Pyrazoles.

A novel strategy for boron-mediated C-H hydroxylation of 1-phenyl-1H-pyrazoles is presented. The protocol exhibits high efficiency and site exclusivity, offering the corresponding phenols in moderate to excellent yields with wide functional group tolerance under simple and metal-free conditions. Moreover, the hydroxylated products show good derivatization applications. This route provides a convenient and practical way to obtain functionalized 1-phenyl-1H-pyrazoles.

Divergent Regioselective Synthesis of Functionalized 1,2,3-1H-Triazoles from Nitriles and Arylazides Under Metal-Free and/or Solvent-Free Conditions.

Highly selective and divergent syntheses, which are crucial in both organic synthesis and medicinal chemistry, involve significant advancements in compound accessibility. By modifying α-cyano esters into α-cyano ketones, the synthesis pathway broadens to include a diverse range of 4-CN, 5-amino, and 5-arylamino derivatives of 1,2,3-triazoles, which are achieved notably through the Dimroth rearrangement. This versatility extends further with the potential for a triple cascade reaction, leading to the production of carboximidamide compounds, which are facilitated by the Cornforth rearrangement. Advancements in compound accessibility not only expand the repertoire of synthesized molecules but also open new avenues for potential pharmacological agents. Building on these findings, we have developed an innovative and efficient method for the divergent synthesis of functionalized 1,2,3-triazoles. This method strategically utilizes α-cyanocarbonyls and arylazides by harnessing their reactivity and compatibility to orchestrate a variety of molecular transformations. By optimizing these substrates, our goal is to simplify synthetic routes, improve product yields, and accelerate the discovery and development of new chemical entities with promising biological activities.

Iodine(III)-Mediated Keto-oximation of O-Alkynyl Hydroxylamines: ARoute to 3-Acyl Isoxazolines and 1,2-Oxazines.

An intramolecular iodine(III)-mediated keto-oximation of O-alkynyl hydroxylamines offers rapid and straightforward access to 3-acyl Δ2-isoxazolines and 1,2-oxazines. This approach features mild, metal-free, and aerobic reaction conditions with good functional group tolerance. Moreover, the synthetic utility of this method is demonstrated by the synthesis of unique structural motifs such as isoxazolidine, 3-vinyl isoxazoline, and 2,5-diphenylpyrazine derivatives by the conversion of 3-acyl Δ2-isoxazolines, thereby showcasing its efficiency and applicability in synthetic chemistry.

Transition-metal-free nucleophilic substitution of alkenyl boronic acids with propargylic mesylates sp3-carbon electrophiles

We developed a highly versatile transition metal-free Suzuki type cross-coupling protocol. Alkenyl/aryl boronic acids could couple smoothly with propargylic mesylates Csp3 electrophiles in the presence of mild bases. The counterion in the base plays a crucial role for the reactivity. Our metal-free condition is orthogonal towards the classic transition metal catalysed Suzuki reactions.

Alkyl Sulfonium Salts Enabled Radical Thiocyanohydroxylation of Alkenes.

Herein, we report a novel and practical strategy for alkyl sulfonium salts mediating radical thiocyanohydroxylation of alkenes. This reaction features metal-free and mild conditions, generation of noncarbon radicals from the readily available alkyl sulfonium salts, easy handling, and excellent functional group compatibility. A diverse range of activated and unactivated alkenes worked well to deliver various β-thiocyanato alcohols.

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.

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.

Base-Mediated Annulation of ortho-Iminophenols and ortho-Vinylphenols with MBH Carbonates of Isatins: Straightforward Access to Dihydrobenzofuran and Benzofuran Derivatives.

We have developed a convenient synthetic protocol for efficient construction of significant dihydrobenzofuran and benzofuran scaffolds by Lewis base-mediated annulation reaction ortho-iminophenols and ortho-vinylphenols with MBH carbonates of isatins under mild and metal-free conditions. The selective generation of different kinds of dihydrobenzofuran and benzofuran derivatives was successfully achieved by employing different substituted isatin-derived MBH carbonates with ortho-N-tosyliminophenols and ortho-vinylphenols. The features included broad substrate scopes, excellent functional group compatibility, high molecular diversity, and atomic economy.

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 N-heterocyclic amides from imidazoheterocycles through convergent paired electrolysis.

An efficient ring opening of imidazoheterocycles induced by a direct C-H azidation resulting in an unusual formation of N-heterocyclic amides has been successfully developed through convergent paired electrolysis. A broad scope of pyridylbenzamides could be obtained in moderate to excellent yields under exogenous-oxidant, electrolyte- and metal-free electrochemical conditions. The methodology was transferred to continuous flow conditions resulting in notable improvements particularly in terms of cost-efficiency over traditional batch versions.

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.