Pyridinium Ylides Research Articles

Electron donor-acceptor complex enabled photocascade strategy for the synthesis of trans-dihydrofuro[3,2-c]chromen-4-one scaffolds via radical conjugate addition of pyridinium ylide.

A visible-light-induced photocascade strategy is disclosed for the synthesis of trans-dihydrofuro[3,2-c]chromen-4-one scaffolds. The photocascade consists of electron donor-acceptor (EDA) complex enabled formation of arylidene coumarinone, followed by 1,4-radical conjugate addition (1,4-RCA) of an in situ generated pyridinium ylide radical (PyYR) towards diastereoselective formation of the trans-dihydrofuro[3,2-c]chromen-4-one scaffold in good to excellent yield. Thorough mechanistic investigations comprising photophysical, spectroscopic, electrochemical and DFT studies provide further insights into the reaction mechanism.

Bifunctional Lewis Base-Catalyzed (3 + 2) Cycloadditions of Pyrazolone-Derived MBH Carbonates with Arynes.

The (3 + 2) cycloaddition of arynes with allylic ylides remains a formidable challenge because both intermediates are highly reactive and prone to spontaneous quenching. Here, we report a (3 + 2) cycloaddition of pyrazolone MBH carbonates with arynes, enabling the efficient synthesis of diverse indene-fused spiropyrazolones. The key is employing a new bifunctional Lewis base catalyst to facilitate the cycloaddition of in situ generated allylic pyridinium ylides with arynes.

Photolytic ortho-Selective Amino Pyridylation of Aryl Isocyanates with N-Amino Pyridinium Ylides for the Synthesis of N-Arylsulfonyl Ureas.

Herein, we report an expedient synthesis of aryl sulfonyl ureas 4 and 5 from N-amino pyridinium ylides and aryl isocyanates. N-Aminopyridinium ylides 3 are synthesized via blue light-emitting diode irradiation of pyridine/isoquinoline and appropriate iminoiodinanes. The strategy involved a hitherto unknown carboamination of imine moieties (of aryl isocyanates) via a three-component reaction of pyridine derivatives/isoquinoline 1, N-aryl sulfonyl iminoiodinanes 2, and numerous aryl isocyanates at room temperature in 2-methyl tetrahydrofuran to afford the target compounds in moderate to excellent yields. N-Arylpyridinium ylides 3 (as intermediates) undergo a [3+2] cycloaddition with the aryl isocyanates followed by the aromatization of the pyridine/isoquinoline moiety to afford compounds 4. On the basis of the substitution pattern among the reactants, in some cases pyridine extrusion occurs during the reaction to afford depyridinylated aryl sulfonyl ureas 5. In general, isocyanates are used as dipolarophiles in [3+2] cycloaddition reactions. However, regioselective amino pyridylation of these species is a first. Control experiments and density functional theory calculations elucidate the reaction mechanism. The batch process of the protocol could be seamlessly transferred to the photoflow synthesis.

Synthetic and theoretical study on novel N-ylidic complexes of mercury as new antibacterial agents

The novel structure of Hg(II) complexes including the pyridinium ylide C5H5NCHC(O)C6H4-m-Br (Y) were synthesized and reported in this study. In the first step, the pyridinium salt C5H5NCH2C(O)C6H4-m-Br (S) was produced by reacting 2,3′-dibromoactophenone and pyridine. then, treatment of S with K2CO3 gave the related pyridinium ylide Y. Finally, the reaction of Y with HgX2 and Hg(NO3)2·H2O leads to the formation of novel binuclear [HgY2][HgX4] (X=Cl (1); X=Br (2); X=I (3)) and polymeric [HgY(NO3)2]n (4) complexes. The structure of complex 2 was also determined by X-ray diffraction analysis. The obtained analyses proved the coordination through the ylidic carbon to metallic center. Additionally, Natural Bond Orbital (NBO), Energy Decomposition Analysis (EDA), and EDA-NOCV studies are also used to investigate the nature of metal–ligand bonding in the complexes. Finally, the antibacterial activity of 1–4 was also examined against Gram positive and negative represented significant levels of inhibitory potency respected to used standards.

Synthesis of Secondary Amines via Self-Limiting Alkylation.

N-centered nucleophilicity increases upon alkylation, and thus selective partial alkylation of ammonia and primary amines can be challenging: Poor selectivity and overalkylation are often observed. Here we introduce N-aminopyridinium salts as ammonia surrogates for the synthesis of secondary amines via self-limiting alkylation chemistry. Readily available N-aryl-N-aminopyridinium salts engage in N-alkylation and in situ depyridylation to afford secondary aryl-alkyl amines without any overalkylation products. The method overcomes classical challenges in selective amine alkylation by accomplishing alkylation via transient, highly nucleophilic pyridinium ylide intermediates and can be applied in the context of complex molecular scaffolds. These findings establish N-aminopyridinium salts as ammonia synthons in synthetic chemistry and a strategy to control the extent of amine alkylation.

Synthesis, characterization and theoretical studies of tris-cyclometalated rhodium(III) complexes: applications to asymmetric transfer hydrogenation of ketones

This paper presents the synthesis of {Rh[PyCH=C(O)Rn]3} complexes, where R1 = 4-cyanophenyl (L1), R2 = 3-nitrophenyl (L2), and R3 = 4-fluorophenyl (L3). These complexes were derived from the reactions of potassium hexachlororhodate(III) with related pyridinium ylides: PyCH=C(O)C6H4-p-CN (Y1), PyCH=C(O)C6H4-m-NO2 (Y2), and PyCH=C(O)C6H4-p-F (Y3). The reactions were carried out in methanol-water mixtures under mild conditions. The synthesized complexes were characterized using FT-IR, ESI-MS, multinuclear NMR (1H and 13C), and elemental analysis techniques (CHN). Furthermore, these Rh(III) compounds demonstrated excellent catalytic activity, high turnover number (TON), and turnover frequency (TOF) in the hydrogenation of various ketones, resulting in a series of alcohol products with outstanding yields and efficiencies. To investigate the structures of L1, L2, and L3, density function theory (DFT) calculations were performed at the BP86/def2-SVP level of theory. The study employed natural bond orbital analysis (NBO) and energy-decomposition analysis (EDA) to examine the strength and nature of the donor-acceptor bonds between the pyridinium ylide (Y) and Rh fragments in the complexes. Additionally, variations in natural orbitals for chemical valence (NOCV) were investigated.

Pyridinium Ylide-Mediated Diastereoselective Synthesis of Spirocyclopropanyl-pyrazolones via Cascade Michael/Substitution Reaction.

We have devised a highly diastereoselective formal [2 + 1] annulation reaction of arylidene/alkylidine-pyrazolones with in situ-generated supported as well as standard pyridinium ylides to construct spirocyclopropanyl-pyrazolones. The cascade approach exhibits a wide range of functional group tolerance, gram-scale capability, and substrate versatility. A diverse range of spirocyclic cyclopropanes was synthesized extensively with both mediators, and the supported pyridine was reused in subsequent cycles. Density functional theory calculations confirmed the formation of spirocyclopropane as the lower energy pathway.

Light-Induced Generation and Cycloaddition Reactions of Benzyne: Synthesis of Naphthoxindoles E and Annulated Indolizines.

By virtue of their high electrophilic nature, benzynes serve as reactive dienophiles in numerous cycloaddition reactions. However, in situ generation of benzyne involves either base-mediated thermal reactions, low-temperature conditions, or metal-catalyzed reactions of substituted arenes. This limits the applicability of benzynes as suitable dipolarophiles in cycloaddition reactions. Herein, we have reported a UVA (365 nM)-induced in situ generation of benzynes (from triazenyl benzoic acid) and subsequently their [4 + 2] Diels-Alder and [3 + 2] cycloaddition reactions with appropriate reaction partners such as N-protected alkylidene oxindole carboxylates and pyridinium ylides to afford naphthoxindoles E and pyrido[2,1-a]isoindole, respectively, in moderate to excellent yield. The reactions occurred at room temperature and under reagent-free reaction conditions. Each of these building blocks is pharmaceutically relevant; hence, this highlights an interesting strategy to access these classes of compounds.

Diastereoselective dearomative cycloaddition of bicyclobutanes with pyridinium ylides: a modular approach to multisubstituted azabicyclo[3.1.1]heptanes.

Diastereoselective (3+3) cycloaddition between bicyclobutanes and pyridinium ylides forms azabicyclo[3.1.1]heptanes via pyridine dearomatization. These reactions proceed under ambient conditions with no need for photochemistry or catalysis, and tolerate a wide range of functional gorups. The resulting multicyclic ring systems have diverse synthetic handles for further transformations, making them potentially valuable for the design of Csp3-rich drug candidates. These include semi-reduction of the dihydropyridine, and diastereoselective photochemical skeletal rearrangement to give a tetrasubstituted cyclobutane.

Highly diastereoselective synthesis of pyridinium-substituted piperidin-2-ones from pyridinium ylides, aldehydes, Michael acceptors, and ammonium acetate

Highly diastereoselective synthesis of pyridinium-substituted piperidin-2-ones from pyridinium ylides, aldehydes, Michael acceptors, and ammonium acetate

Catalyst‐free oxidative [3+2]‐annulation of (2‐nitroethene‐1,1‐diyl)bis(methylsulfane) and pyridinium ylides: Efficient synthesis of (methylsulfanyl)indolizines heterocycles

AbstractA facile and efficient protocol has been developed for the synthesis of (methylsulfanyl)indolizine derivatives via oxidative [3+2]‐annulation of bis(methylthio)‐2‐nitroethylen(BMTNE) and pyridinium ylides under K2CO3. The target products could be obtained in moderate to good yields.

Energy-transfer-induced [3+2] cycloadditions of N-N pyridinium ylides.

Photocycloaddition is a powerful reaction to enable the conversion of alkenes into high-value synthetic materials that are normally difficult to obtain under thermal conditions. Lactams and pyridines, both prominent in pharmaceutical applications, currently lack effective synthetic strategies to combine them within a single molecular structure. Here we describe an efficient approach to diastereoselective pyridyl lactamization via a photoinduced [3+2] cycloaddition, based on the unique triplet-state reactivity of N-N pyridinium ylides in the presence of a photosensitizer. The corresponding triplet diradical intermediates allow the stepwise radical [3+2] cycloaddition with a broad range of activated and unactivated alkenes under mild conditions. This method exhibits excellent efficiency, diastereoselectivity and functional group tolerance, providing a useful synthon for ortho-pyridyl γ- and δ-lactam scaffolds with syn-configuration in a single step. Combined experimental and computational studies reveal that the energy transfer process leads to a triplet-state diradical of N-N pyridinium ylides, which promotes the stepwise cycloaddition.

Copper‐Catalyzed [3+2] Annulation of Pyridinium Ylides with α‐CF3 Ketones: Synthesis of Functionalized 2‐Fluoroindolizines

AbstractA copper‐catalyzed [3+2] annulation of the in situ generated pyridinium ylides with α‐CF3 ketones was realized, in which α‐CF3 ketones first acted as the synthetic equivalents of unstable fluoroalkynones. With this protocol, a series of functionalized 2‐fluoroindolizines were afforded in moderate to good yields under ambient conditions with air as the oxidant.

A reusable polymer anchored pyridine mediated formal [4 + 1] annulation reaction for the diastereoselective synthesis of 2,3-dihydrobenzofurans.

We have developed a highly stereoselective formal [4 + 1] annulation reaction to construct trans-2,3-dihydrobenzofurans utilising in situ generated supported pyridinium ylide. This approach has excellent substrate versatility and gram-scale synthesis capability. Moreover, the polymer-anchored pyridine has been recovered and reused multiple times. The product has been transformed into valuable molecules.

Regio- and diastereoselective construction of conjugate oxindole derivatives enabled by delayed acyl transfer of pyridinium ylides

Herein, we design and develop a one-pot cascade strategy for the assembly of multi-substituted conjugate oxindole derivatives. This approach represents a new reaction mode for carbene gem-difunctionalization by delayed acyl transfer instead of delayed proton transfer.

Diastereoselective Synthesis of Dispiropyrrolidinyloxindoles via DBU‐Promoted [3+2]‐Cycloaddition of Cyclic Pyridinium Ylides and α,β‐Unsaturated Ketones

AbstractA novel [3+2]‐cycloaddition reaction of cyclic pyridinium ylides and α,β‐unsaturated ketones derived from indanones for the synthesis of dispiropyrrolidinyloxindoles is described herein. Various types of dispiropyrrolidinyloxindoles can be conveniently accessed with moderate to good yields and up to >99 : 1 dr from easily available pyridinium salts which bear an electron‐withdrawing group on the pyridine ring under mild conditions for short reaction time.

Synthesis of Multi-Substituted 4,5-Dihydrofurans: Microwave Assisted Reaction of β-Ketonitriles, Aldehydes and Pyridinium Phenacyl Salts via [1+1+3] Knoevenagel-Michael-Oxa-Michael Cyclization Triple Cascade Sequence

A microwave assisted protocol for the development of fully substituted dihydrofurans has been explained as a three component triple cascade reaction between pyridinium ylide, phenacyl nitriles and aldehydes. This [1+1+3] annulation protocol produced the dihydrofurans having two stereocentres. A total of 14 molecules have been synthesized with high chemical yields.

Diastereoselective Synthesis of Dihydrobenzofuran-Fused Spiroindolizidines via Double-Dearomative [3 + 2] Cycloadditions.

Spiroindolizidine oxindoles represent a kind of privileged scaffold in many biologically active natural alkaloids. 2,3-Dihydrobenzofuran derivatives exhibit significant bioactivities in a variety of pharmaceuticals. Herein, we assembled these two privileged fragments into a small molecule via double-dearomative [3 + 2] cycloadditions with pyridinium ylides and 2-nitrobenzofurans. This protocol features remarkable advantages including wide substrate scope, mild condition, high level of diastereoselectivities and yields. Thus, a collection of spiroindolizidine-fused dihydrobenzofurans/indolines were facilely produced efficiently.

Difluorocarbene-Triggered Acyl Rearrangement Reaction: A Strategy for the Direct Introduction of the gem-Difluoromethylene Group.

A novel metal- and catalyst-free dearomative reaction of 2-oxypyridines to construct gem-difluoromethylenated N-substituted 2-pyridones has been developed. The reaction involves an attractive acyl rearrangement from O to CF2 of difluorocarbene-derived pyridinium ylides, which provides a new strategy for the direct introduction of the gem-difluoromethylene group with high efficiency and selectivity as well as broad substrate scope. Gram-scale synthesis and synthetic transformations have also been demonstrated.

Synthesis of 2,3-bifunctional imidazo[1,2-a]pyridines through cycloadditions of pyridinium ylides with N-cyano-4-methyl-N-phenylbenzenesulfonamide

Imidazo[1,2-a]pyridine is recognized as a “drug prejudice” due to its wide applications in medicinal chemistry. In this work, we developed a [3 + 2] cycloadditions/oxidation reaction of pyridinium ylides with N-cyano-4-methyl-N-phenylbenzenesulfonamide for the synthesis of 2,3-bifunctional imidazo[1,2-a]pyridines. The N-cyano-4-methyl-N-phenylbenzenesulfonamide serves as an activated nitrile, exhibiting higher activity than common alkyl or aryl nitrile in the reaction. The strategy features high chemoselectivity, easily accessible materials, and broad substrate scope. The scale-up reaction demonstrated the practicability of this method, and the imidazo[1,2-a]pyridines products could be easily transformed into their derivatives.