Generation Of Ylides Research Articles

Efficient generation of novel phosphorus ylides via chemoselective and chemospecific reactions utilizing 2-(arylamino)-2-thioxoacetamide and methyl benzoylglycinates as precursors with activated acetylenic compounds

A chemospecific and chemoselective procedure has been developed for the efficient synthesis of novel phosphorus compounds, achieving moderate to excellent yields. This method involves the reaction of 2-(arylamino)-2-thioxoacetamide and methyl benzoylglycinate precursors with PPh3 in the presence of activated acetylenic esters. Notably, the reaction exhibits superior selectivity toward the NH2 group in 2-(arylamino)-2-thioxoacetamide, rather than the NH group. Moreover, when methyl benzoylglycinates are employed as a precursor, the reaction yields two distinct families of ylides, each with its own unique percentage yield.

Dearomatization of Pyridines: Photochemical Skeletal Enlargement for the Synthesis of 1,2-Diazepines.

In this report, we developed a unified and standardized one-pot sequence that converts pyridine derivatives into 1,2-diazepines by inserting a nitrogen atom. This skeletal transformation capitalizes on the in situ generation of 1-aminopyridinium ylides, which rearrange under UV light irradiation. A thorough evaluation of the key parameters (wavelength, reaction conditions, activating agent) allowed us to elaborate on a simple, mild, and user-friendly protocol. The model reaction was extrapolated to more than 40 examples, including drug derivatives, affording unique 7-membered structures. Mechanistic evidence supports the transient presence of a diazanorcaradiene species. Finally, pertinent transformations of the products, including ring contraction reactions to form pyrazoles, were conducted and paved the way to a broad application of the developed protocol.

Photocatalytic (3 + 2) dipolar cycloadditions of aziridines driven by visible-light.

Herein, we document the design and development of a novel (3 + 2) cycloaddition reaction aided by the activity of an organic photocatalyst and visible light. The process is extremely fast, taking place in a few minutes, with virtually complete atom economy. A large variety of structurally diverse aziridines were used as masked ylides in the presence of different types of dipolarophiles (28 examples with up to 94% yield and >95 : 5 dr). Mechanistic insights obtained from photophysical, electrochemical and experimental studies highlight that the chemistry is driven by the in situ generation of the reactive ylide through two consecutive electron-transfer processes. We also report an aerobic cascade process, where an additional oxidation step grants access to a vast array of pyrrole derivatives (19 examples with up to 95% yield). Interestingly, the extended aromatic core exhibits a distinctive absorption and emission profile, which can be easily used to tag the effectiveness of this covalent linkage.

New routes towards azomethine ylide generation from prolines to synthesize diverse N-heterocycles: a DFT supported endo-selective mechanism.

Azomethine ylides are generated using either organocatalysts or metal catalysts via a ballet of decarboxylative C-N coupling choreographed by prolines. These strategies enable diastereoselective [3 + 2] cycloaddition, C-C coupling, and ring annulation, providing sustainable routes. The synthesized pyrrolizines and other heterocycles have potential applications in the development of crucial biomolecules and pharmaceuticals. The endoselectivity of the azomethine ylide is realized and supported through DFT calculations.

Blue LED induced three component reactions for the generation of 4, 6-dioxo-hexahydro-1H-furo[3, 4-c] pyrrole: Their evaluation as anticancer agents through PARP inhibition.

Herein we report a catalyst, metal and additive free generation of carbonyl ylides by blue LED irradiation of aryl diazoacetates in presence of aldehydes. The resulting ylides underwent [3+2] cycloaddition with substituted maleimides present in the reaction mixture to afford 4, 6-dioxo-hexahydro-1H-furo[3, 4-c] pyrrole in excellent yields. Fifty compounds were synthesized based on this scaffold. Molecular docking indicated them to be potential poly ADP ribose polymerase (PARP) inhibitor. Screening a representative member of the library against PARP enzyme revealed a few potential inhibitors with IC50 of 600-700 nM. The phenotypic screening against MCF7, A549 and HePG2 cells furthermore indicated that these compounds selectively inhibit the proliferation of A549, HeLa and HePG2 cells with IC50 of 1 - 2 mM. The mechanism of action of the most active compound at the cellular level was investigated.

Triethylamine-Promoted Oxidative Cyclodimerization of 2H-Azirine-2-carboxylates to Pyrimidine-4,6-dicarboxylates: Experimental and DFT Study.

An unprecedented oxidative cyclodimerization reaction of 2H-azirine-2-carboxylates to pyrimidine-4,6-dicarboxylates under heating with triethylamine in air is described. In this reaction, one azirine molecule undergoes formal cleavage across the C-C bond and another across the C=N bond. According to the experimental study and DFT calculations, the key steps of the reaction mechanism include nucleophilic addition of N,N-diethylhydroxylamine to an azirine to form an (aminooxy)aziridine, generation of an azomethine ylide, and its 1,3-dipolar cycloaddition to the second azirine molecule. The crucial condition for the synthesis of pyrimidines is generation of N,N-diethylhydroxylamine in the reaction mixture in a very low concentration, which is ensured by the slow oxidation of triethylamine with air oxygen. Addition of a radical initiator accelerated the reaction and resulted in higher yields of the pyrimidines. Under these conditions, the scope of the pyrimidine formation was elucidated, and a series of pyrimidines was synthesized.

Synthesis of Hexahydropyrrolo-isoquinolines by 1,3-Dipolar cycloaddition of tetrahydroisoquinolines and cinnamaldehydes

A new method is described for the synthesis of hexahydropyrrolo-isoquinolines through the 1,3-dipolar cycloaddition of cinnamaldehydes with azomethine ylides generated from cinnamaldehydes and tetrahydroisoquinolines. The carbonyl CO groups of cinnamaldehydes serve as the precursor for the generation of azomethine ylides and the CC double bonds of cinnamaldehyde act as the dipolarophiles in the cycloaddition. The key features are easily available substrates, good functional group tolerance and mild reaction conditions. The relative configurations of products are confirmed by X-ray single crystal structure analysis, and a possible mechanism is proposed. A gram-scale experiment and some chemical transformations were conducted to show the synthetic utility of this approach. Finally, a plausible mechanism was proposed to clarify the formation of products with different configurations.

1,3-Dipolar Cycloaddition of 3-Chromonyl-Substituted Glycine Imino Esters with Arylidenes and in situ Diastereodivergent via Retrocycloaddition.

1,3-Dipolar cycloaddition through in situ generation of azomethine ylide provides a straightforward and critically important sustainable approach for access to diverse pyrrolidine chemical space. Herein, we developed a metal-free AcOH-activated 1,3-dipolar cycloaddition protocol that permits the synthesis of uncommon pyrrolidine cycloadducts with excellent diastereoselectivity. The challenging substrates of 3-formylchromone, glycine ester.HCl and arylidene dipolarophile were reacted in the presence of AcONa, which played a dual role as a base and AcOH source, to deliver firstly endo-cycloadduct. Under prolonged reaction time at room temperature or heating; the endo-adduct underwent diastereodivergent via a sequence of retro-cycloaddition, stereomutation of the generated syn-dipole into anti-dipole and recycloaddition; to furnish the scarcely known exo'-cycloadduct with high diastereodivergency. The reaction worked well with a broad range of substrates and the stereochemistry of the obtained cycloadducts was determined without ambiguity using NMR- and X-ray analysis. Experimental and theoretical DFT calculation studies were performed to support the proposed reaction mechanism and elucidate the key role of AcOH in the process which seems more beneficial than other transition metal-catalyzed processes.

Copper‐Catalyzed Enantioselective Doyle–Kirmse Reaction of Azide‐Ynamides via α‐Imino Copper Carbenes

Abstract[2,3]‐Sigmatropic rearrangement reaction involving sulfonium ylide (Doyle–Kirmse reaction) generated from metal carbenes represents one of the powerful methods for the construction of C(sp3)−S and C−C bonds. Although significant advances have been achieved, the asymmetric versions via the generation of sulfonium ylides from metal carbenes have been rarely reported to date, and they have so far been limited to diazo compounds as metal carbene precursors. Here, we describe a copper‐catalyzed enantioselective Doyle–Kirmse reaction via azide‐ynamide cyclization, leading to the practical and divergent assembly of an array of chiral [1,4]thiazino[3,2‐b]indoles bearing a quaternary carbon stereocenter in generally moderate to excellent yields and excellent enantioselectivities. Importantly, this protocol represents a unique catalytic asymmetric Doyle–Kirmse reaction via a non‐diazo approach and an unprecedented asymmetric [2,3]‐sigmatropic rearrangement via α‐imino metal carbenes.

Copper-Catalyzed Enantioselective Doyle-Kirmse Reaction of Azide-Ynamides via α-Imino Copper Carbenes.

[2,3]-Sigmatropic rearrangement reaction involving sulfonium ylide (Doyle-Kirmse reaction) generated from metal carbenes represents one of the powerful methods for the construction of C(sp3 )-S and C-C bonds. Although significant advances have been achieved, the asymmetric versions via the generation of sulfonium ylides from metal carbenes have been rarely reported to date, and they have so far been limited to diazo compounds as metal carbene precursors. Here, we describe a copper-catalyzed enantioselective Doyle-Kirmse reaction via azide-ynamide cyclization, leading to the practical and divergent assembly of an array of chiral [1,4]thiazino[3,2-b]indoles bearing a quaternary carbon stereocenter in generally moderate to excellent yields and excellent enantioselectivities. Importantly, this protocol represents a unique catalytic asymmetric Doyle-Kirmse reaction via a non-diazo approach and an unprecedented asymmetric [2,3]-sigmatropic rearrangement via α-imino metal carbenes.

Recent Advances in the Generation of Onium Ylides for Sommelet–Hauser Rearrangements

AbstractThe Sommelet–Hauser rearrangement of X-benzylic onium ylides (X = heteroatom) is an interesting transformation in organic synthesis. This rearrangement proceeds via dearomative [2,3]-sigmatropic rearrangement, followed by aromatization to form a carbon(sp2)–carbon(sp3) bond. Few advances were made in studies performed around 2000 on this rearrangement because of several competitive side reactions and structural limitations. However, studies performed in the last 15 years on the rearrangement have remarkably expanded the substrate scope and synthetic applications. In this review, the utility of the Sommelet–Hauser rearrangement and recent advances for the generation of onium ylides are described.1 Introduction2 Base-Induced Rearrangement3 Transition-Metal-Catalyzed Rearrangement4 Light-Mediated Rearrangement5 Aryne-Induced Rearrangement6 Conclusions and Outlook

Visible light-driven conjunctive olefination

Carboxylic acids and aldehydes are ubiquitous in chemistry and are native functionalities in many bioactive molecules and natural products. As such, a general cross-coupling process that involves these partners would open new avenues to achieve molecular diversity. Here we report a visible-light-mediated and transition metal-free conjunctive olefination that uses an alkene 'linchpin' with a defined geometry to cross-couple complex molecular scaffolds that contain carboxylic acids and aldehydes. The chemistry merges two cornerstones of organic synthesis-namely, the Wittig reaction and photoredox catalysis-in a catalytic cycle that couples a radical addition process with the redox generation of a phosphonium ylide. The methodology allows the rapid structural diversification of bioactive molecules and natural products in a native form, with a high functional group tolerance, and also forges a new alkene functional group with a programmable E-Z stereochemistry.

Electrochemical Generation of a Nonstabilized Azomethine Ylide: Access to Substituted N-Heterocycles.

Azomethine ylides are fascinating 1,3-dipoles for [3 + 2] cycloaddition reactions toward the construction of N-heterocycles. Herein, an efficient and environmentally benign electrochemical approach for the generation of a nonstabilized azomethine ylide has been established under metal-free and external oxidant-free conditions. The resulting 1,3-dipole undergoes a [3 + 2] cycloaddition reaction with olefins. This electrosynthetic methodology indulges a straightforward and facile approach for the construction of substituted pyrrolidines.

Blue Light-Emitting Diode-Mediated In Situ Generation of Pyridinium and Isoquinolinium Ylides from Aryl Diazoesters: Their Application in the Synthesis of Diverse Dihydroindolizine.

Blue light-emitting diode-mediated environmentally sustainable three component reactions among pyridine/isoquinoline 1/2, aryl diazoesters 3, and acrylic ester/3-alkenyl oxindoles 5/6 provide various dihydroindolizines 7 to 9 in excellent yield. The principle of the strategy is photolytic generation of nitrogen ylides from N-heteroarenes and aryl diazoesters and their subsequent [3 + 2] cycloaddition reaction with dipolarophiles. Detailed mechanistic analysis of the transformation through control experiments establishes this strategy as the foundation for the photolytic multicomponent reaction.

Pyrrolidino[2,1–a]phthalazino[60]fullerenes: A New Family of Fullerene Derivatives for Photovoltaic Applications

A reaction of phthalaldehyde with tosylhydrazide and alcohols, used as solvents, is serendipitously discovered, resulting in the formation of the corresponding phthalazinium salts. The obtained salts represent convenient precursors for the generation of azomethine ylides and readily functionalize the fullerene C60 upon treatment with a base to produce a new family of fullerene derivatives bearing pyrrolidino[2,1–a]phthalazine moiety on the fullerene cage. The revealed reaction provides a convenient synthetic route for the preparation of a broad variety of fullerene derivatives incorporating the substituents stemming from readily accessible alcohols. The obtained fullerene derivatives are investigated as electron‐transport materials in p–i–n perovskite solar cells and delivered encouraging power conversion efficiencies of >14%. The ease of the preparation and tunability of optoelectronic properties of pyrrolidino[2,1–a]phthalazino[60]fullerenes make them highly promising materials for organic electronics and photovoltaics.

Palladium-catalyzed diastereoselective synthesis of 2,2,3-trisubstituted dihydrobenzofurans via intramolecular trapping of O-ylides with activated alkenes

An efficient palladium catalyzed diastereoselective synthesis of 2,2,3-trisubstituted dihydrobenzofurans has been accomplished in good yield as a single diastereomer. The transformation involves in-situ generation of oxonium ylide from 2-hydroxyphenyl substituted enone and diazo compound followed by intramolecular trapping via Michael addition. Successful integration of the developed method with intramolecular aldol condensation afforded potent dibenzofuran derivatives in good yield.

Generation of zwitterionic trifluoromethyl N-allylic ylides and their use in switchable divergent annulations.

The previously unreported zwitterionic N-allylic ylide species from the corresponding Morita-Baylis-Hillman carbonates of trifluoromethyl ketones and acrylonitrile are generated under the catalysis of cinchona-derived tertiary amines, and subsequently participate in switchable asymmetric [3+2] or [4+1] annulations with 1-azadienes in chemo-, regio-, and stereodivergent manners via catalyst or substrate control. A diverse range of frameworks, having a trifluoromethylated all-carbon quaternary stereogenic centre or a tetrasubstituted alkene moiety, are generally constructed in good yields with excellent enantioselectivity.

Design and synthesis of nature-inspired chromenopyrroles as potential modulators of mitochondrial metabolism

Chromenopyrrole derivatives with multiple stereocenters and variable ring fusion pattern are found in many natural products and biologically appealing molecules. By employing a build/couple/pair strategy, we have recently reported on the discovery of a serendipitous cascade to access a diverse collection of chromenopyrroles. This protocol features a one-pot cascade that includes the generation of azomethine ylide and intramolecular [3 + 2]-cycloaddition. Phenotypic screening of the developed pilot library enabled the identification of chemical probes that efficiently suppress mitochondrial membrane potential, elevate reactive oxygen species content, and deplete ATP content in a hepatoma cell line (Hepa1-6), without affecting the proliferation of T- or B-cells. This selective targeting represents a new approach for the treatment of cancer.

Efforts towards Rh(II)-catalyzed N-alkoxyazomethine ylide generation: Disparate reactivities of O-tethered α-diazo keto and -β-ketoester oximes

Abstract Azomethine ylide [3 + 2]-cycloaddition reactions are among the most powerful and well-studied chemical transformations to construct five-membered nitrogen-containing frameworks. However, cycloadditions of azomethine ylides bearing N-alkoxy substituents have largely been overlooked. This has been the case despite the potential for (1) accessing heterocycles with good regio- and diastereocontrol, (2) the presence of a cleavable tether which can be manipulated downstream via N–O bond cleavage, and (3) the promise of interesting structural diversity. Herein, we describe our efforts toward dirhodium-catalyzed intramolecular N-alkoxyazomethine ylide generation from α-diazoketo and -β-ketoester oximes and the disparate reactivities observed.

Synthesis of Epoxides from Alkyl Bromides and Alcohols with in Situ Generation of Dimethyl Sulfonium Ylide in DMSO Oxidations.

Direct conversion of the readily available alkyl bromides and alcohols to value-added epoxides using dimethyl sulfoxide (DMSO) under mild reaction conditions has been developed. Benzyl and allyl bromides, and activated and unactivated alcohols all proceeded smoothly to give epoxides in high to excellent yield. Dimethyl sulfide, generated by DMSO oxidations, was in situ elaborated to form the substituted dimethyl sulfonium ylide species that participates in the Corey-Chaykovsky epoxidation in a domino and one-pot fashion, respectively.