Metal-free Conditions Research Articles

The Oxidation of Electron-Rich Arenes Using a H2O2-Proline System.

This study introduces a novel proline-catalyzed oxidation system employing hydrogen peroxide to synthesize quinones from a diverse range of substrates, including hydroquinones, phenols, resorcinols, aldehydes, and polycyclic aromatics. This approach is well-aligned with green chemistry principles, offering a more environmentally benign approach than earlier studies. Notably, this approach uses cost-effective reagents, proline as a readily available organocatalyst, reduced equivalents of H2O2, metal-free conditions, and notably short reaction times to achieve moderate-to-high yields. This promising approach encourages further exploration of the H2O2-proline system in oxidation reactions. This study's innovative approach and good results set a strong foundation for future research to expand the scope and efficiency of green oxidation processes.

Green Synthesis of Diphenyl-Substituted Alcohols Via Radical Coupling of Aromatic Alcohols Under Transition-Metal-Free Conditions.

Alcohols are common alkylating agents and starting materials alternative to harmful alkyl halides. In this study, a simple, benign and efficient pathway was developed to synthesize 1,3-diphenylpropan-1-ols via the β-alkylation of 1-phenylethanol with benzyl alcohols. Unlike conventional borrowing hydrogen processes in which alcohols were activated by transition-metal catalyzed dehydrogenation, in this work, t-BuONa was suggested to be a dual-role reagent, namely, both base and radical initiator, for the radical coupling of aromatic alcohols. The cross-coupling reaction readily proceeded under transition metal-free conditions and an inert atmosphere, affording 1,3-diphenylpropan-1-ol with an excellent yield. A good functional group tolerance in benzyl alcohols was observed, leading to the production of various phenyl-substituted propan-1-ol derivatives in moderate-to-good yields. The mechanistic studies proposed that the reaction could involve the formation of reactive radical anions by base-mediated deprotonation and single electron transfer.

Identification of O-arylated huperzinines as novel cholinergic anti-inflammatory pathway agonists against gout arthritis

Lycodine alkaloids are important natural products with diverse biological effects. In this manuscript, we set out the first structural optimization of the 2-pyridone moiety of Lycodine alkaloid via selective O-arylation under metal-free conditions and obtained a series of potent bioactive molecules against monosodium urate (MSU)-induced IL-1β production. Further investigations demonstrated that these natural product derivatives could activate the neuro-immunomodulatory cholinergic anti-inflammatory pathway (CAP) to block the initial phase of NLRP3 inflammasome activation. Compared with the clinical drugs hydrocortisone and indomethacin, as well as commercially available CAP agonists GTS-21 and pnu282987, 3k and 3q possessed greater potency against MSU-induced IL-1β production. Meanwhile, these molecules possessed less cytotoxicity against promonocytic THP-1 macrophages when compared with colchicine. This work reports a concise strategy for direct modification of 2-pyridone moiety from natural Lycodine alkaloids, and provides novel frameworks for discovering CAP activators and drugs for gout arthritis.

Regio- and Diastereoselective Synthesis of Polysubstituted Piperidines Enabled by Boronyl Radical-Catalyzed (4+2) Cycloaddition.

Piperidines are widely present in small molecule drugs and natural products. Despite many methods have been developed for their synthesis, new approaches to polysubstituted piperidines are highly desirable. This work presents a radical (4+2) cycloaddition reaction for synthesis of piperidines featuring dense substituents at 3,4,5-positions that are not readily accessible by known methods. Using commercially available diboron(4) compounds and 4-phenylpyridine as the catalyst precursors, the boronyl radical-catalyzed cycloaddition between 3-aroyl azetidines and various alkenes, including previously unreactive 1,2-di-, tri-, and tetrasubstituted alkenes, has delivered the polysubstituted piperidines in generally high yield and diastereoselectivity. The reaction also features high modularity, atom economy, broad substrate scope, metal-free conditions, simple catalysts and operation. The utilization of the products has been demonstrated by selective transformations. A plausible mechanism, with the ring-opening of azetidine as the rate-limiting step, has been proposed based on the experimental and computational results.

Hexafluoroisopropanol (HFIP)-Mediated Intramolecular Cyclization of Allenamides To Access C1-Vinyl Tetrahydro-β-carbolines.

The construction of biologically interesting N-heterocycles under metal-free conditions is a constant goal in industry and academia. Herein, we have developed an hexafluoroisopropanol (HFIP)-mediated intramolecular cyclization of allenamides, providing tetrahydro-β-carboline derivatives embedded with a C1-vinyl functionality. The metal-free protocol provided tetrahydro-β-carboline derivatives atom-efficiently under room temperature with a broad substrate scope in good to excellent yields. The potential impact of the protocol is further highlighted by synthesizing derivatives of biologically important molecules and diversified scaffolds via postsynthetic modifications.

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.

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 radical anions 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.

Product Selectivity Control in the Brønsted Acid-Mediated Reactions with 2-Alkynylanilines.

Brønsted acid-catalysed/mediated reactions of the 2-alkynylanilines are reported. While metal-catalysed reactions of these valuable building blocks have led to the establishment of robust protocols for the selective, diverse-oriented syntheses of significant heterocyclic derivatives, we here demonstrate the practical advantages of an alternative methodology under metal-free conditions. Our investigation into the key factors influencing the product selectivity in Brønsted acid-catalysed/mediated reactions of 2-alkynylanilines reveals that different reaction pathways can be directed towards the formation of diverse valuable products by simply choosing appropriate reaction conditions. The origins of chemo- and regioselectivity switching have been explored through Density Functional Theory (DFT) calculations.

Synthesis of sulfonated naphthols via metal-free oxidative coupling of beta-tetralones and sodium sulfinates

The efficient synthesis of sulfonated naphthols was realized by dehydroaromatization of β-tetralones with sodium sulfinates under metal-free conditions. Iodine-containing reagents played an important role in this oxidative coupling process. Sodium sulfinates served as a stable and readily available sulfur source, providing sulfones in good to excellent yields. A wide range of functional groups were well tolerated in this reaction.

Visible-Light Photoredox-Catalyzed Difunctionalization of Alkynes with Quinoxalin-2(1H)-Ones, P4S10, and Alcohols.

Visible-light photoredox-catalyzed method has been developed for the synthesis of quinoxalin-2(1H)-one-containing vinyl phosphorodithioates via direct difunctionalization of alkynes with quinoxalin-2(1H)-ones, P4S10 and alcohols. This four-component reaction could be carried out under metal-free and mild conditions, affording a number of quinoxalin-2(1H)-one-containing vinyl phosphorodithioates in moderate to good yields with Z-isomers as the major products. Photocatalytic radical mechanism is proposed based on the results of radical trapping and fluorescence quenching experiments.

Electrochemical Glycosylation via Halogen-Atom-Transfer for C-Glycoside Assembly.

Glycosyl donor activation emerged as an enabling technology for anomeric functionalization, but aimed primarily at O-glycosylation. In contrast, we herein disclose mechanistically distinct electrochemical glycosyl bromide donor activations via halogen-atom transfer and anomeric C-glycosylation. The anomeric radical addition to alkenes led to C-alkyl glycoside synthesis under precious metal-free reaction conditions from readily available glycosyl bromides. The robustness of our e-XAT strategy was further mirrored by C-aryl and C-acyl glycosides assembly through nickela-electrocatalysis. Our approach provides an orthogonal strategy for glycosyl donor activation with expedient scope, hence representing a general method for direct C-glycosides assembly.

One-Pot Tandem/Spirocyclization Reaction: Synthesis of Spiro[pyridine-thiazolidine] Ring Derivatives.

An efficient one-pot, three-component approach was devised to synthesize spiro[pyridine-thiazolidine] ring skeletons using thiazole salts, aldehydes, and enaminones. This method allows the assembly of structurally diverse spiroazepines through [3 + 1 + 2] tandem/spirocyclization reactions. This spirocyclization reaction offers several advantages, including transition metal-free conditions, high chemoselectivity, and the ability to construct structurally novel polycyclic compounds.

Synthesis of Spirocyclic-1,3-Indandione Containing-Cyclopentenones and -Benzotropones.

Synthesis of functionalized 1,3-indandiones containing-cyclopentenones and -benzotropones has been achieved by the reaction of 1,5-diphenylpenta-1,4-diyn-3-ones with 1,3-indandiones, bindone respectively. The developed method involves Michael-anti-Michael addition cascade reactions under transition-metal-free conditions. This is the first report to synthesise diverse benzotropone fused with 1,3-indandiones under transition metal-free conditions from bindone.

Green Late-Stage Functionalization of Tryptamines.

An efficient and rapid protocol for the oxidative halogenation of tryptamines with 10 % aqueous NaClO has been developed. This reaction is featured by its operational simplicity, metal-free conditions, no purification, and high yield. Notably, the resulting key intermediates are suitable for further functionalization with various nucleophiles, including amines, N-aromatic heterocycles, indoles and phenols. The overall transformation exhibits broad functional-group tolerance and is applicable to the late-stage functionalization of complex biorelevant molecules.

Highly efficient capture and conversion of CO2 into cyclic carbonates from actual flue gas under atmospheric pressure

Chemical conversion of CO2 to cyclic carbonates is one of the most attractive strategies for CO2 capture and storage utilization. Herein, a binary organocatalyst of 3-aminobenzylalcohol/n-Bu4NI was used to gently catalyze the insertion of CO2 into the terminal/internal epoxides to generate cyclic carbonates under metal-free and solvent-free conditions. Twelve representative terminal epoxides reacted with CO2 to achieve excellent cyclic carbonate yields of up to 98.3 % at 30 °C and 1 atm CO2 and six low activity internal di-substituted epoxides were converted to corresponding cyclic carbonates with yields of up to 96.2 %. Experiments on actual flue gas and water resistance revealed the potential industrial value of this binary organocatalyst. The yield of cyclic carbonate reached 99 % by using actual flue gas under very mild conditions of 60 °C and 1 atm. The results of 4-fold epoxide amplification experiment showed that the residual CO2 in the flue gas was only 793 ppm after reaction at 1 atm and 60 °C, indicating the good CO2 capture and conversion ability. Reaction kinetics and catalytic mechanism of the cycloaddition were investigated in detail. The synergistic effect among functional groups of catalysts on substrates is the essential factor for the high activity of the catalyst.

Photocatalytic Pyridine Synthesis with Enaminones and TMEDA under Metal-Free Conditions.

Reported herein is a new photocatalytic annulation for the synthesis of 2,3,4,6-tetrasubstituted pyridines with enaminones and N,N,N',N'-tetramethyl ethylenediamine (TMEDA). The photocatalytic reactions take place without requiring a transition metal reagent and provide products with broad scope. The methyl in TMEDA acts as the carbon source in pyridine ring construction, and BrCF2CO2Et plays the role of the terminal oxidant for free radical quenching.

A Type of Stable Amides Behaves as Acyl Transfer Reagents upon Visible-Light Irradiation through Self-Aromatization.

Organic molecules with light-modifiable reactivity are important in many fields because they can serve as the "switch" for light to trigger chemical processes. Herein, we disclose a new type of stable non-twisted amides, the reactivity of which can be turned on by light as acyl transfer reagents. Upon photo-activation, these amides react with various nucleophiles including amines, phenols, hydroxide, thiols, boronic acids, and alkynes either under metal-free or metal-catalysis conditions. This reactivity hinges on the design and synthesis of a photo-activatable reagent (7-nitro-5,6-dihydrophenanthridine), which undergoes self-aromatization enabled by an internal oxidant under light. This masked acyl donor group is anticipated to be useful in scenarios where light is preferred to trigger a chemical process.

Light-Driven Intramolecular Cyclopropanation of Alkene-Tethered N-Tosylhydrazones: Synthesis of Fused-Cyclopropane γ-Lactones.

Fused-cyclopropane ring-containing γ-lactone compounds are versatile building blocks in many fields, including the synthesis of biologically active compounds. Here, we report the light-driven intramolecular cyclopropanation of alkene-tethered N-tosylhydrazones in the presence of Cs2CO3 and visible light. We have synthesized various electronically and sterically substituted and heterocyclic-containing fused-(spiro)cyclopropane γ-lactone compounds in good yields under transition metal-free conditions using a radical-free approach. In addition, the one-pot synthesis of fused-cyclopropane γ-lactones from α-ketoesters and their synthetic utility are also presented.

Metal-Free Decarboxylative Allylation of Oxime Esters under Light Irradiation.

Allylation reactions, often used as a key step for constructing complex molecules and drug candidates, typically rely on transition-metal (TM) catalysts. Even though TM-free radical allylations have been developed using allyl-stannanes, -sulfides, -silanes or -sulfones, much less procedures have been reported using simple and commercially available allyl halides, that are used for the preparation of the before-mentioned allyl derivatives. Here, we present a straightforward photocatalytic protocol for the decarboxylative allylation of oxime esters using allyl bromide derivatives under metal-free and mild conditions. This methodology yields a diverse variety of functionalized molecules including several pharmaceutically relevant molecules.

Electrochemically Direct Fluorination Functionalization of Styrenes with Different Fluorine Source: Access to Fluoroalkyl Derivatives.

A mild protocol for electrochemically oxidative fluorodifunctionalization of styrenes has been demonstrated. The reaction proceeds under metal, external oxidant, and catalyst free conditions, allowing tunable access to a wide variety of synthetically useful fluoroalkyl derivatives, such as β-fluorosulfone/fluoromethyl, fluorothiocyanation, and vinylsulfonyl derivatives. Moreover, CsF was shown to be the proper fluorine source for this electrochemical fluorodifunctionalization transformation.