Electron-deficient Alkynes Research Articles

1,3-Dipolar cycloaddition for selective synthesis of functionalized spiro[indoline-3,3′-pyrrolizines

The 1,3-dipolar cycloaddition reaction of dimethyl hex-2-en-4-ynedioate with azomethine ylides derived from reaction of l-proline with various isatins in methanol selectively resulted in the formation of functionalized spiro[indoline-3,3′-pyrrolizine]acrylates as main products and spiro[indoline-3,3′-pyrrolizine]propiolates as minor products. This result indicated that the electron-deficient alkyne has higher reactivity than that of electron-deficient alkene in 1,3-dipolar cycloaddition reaction.

Microwave induced synthesis, and pharmacological properties of novel 1-benzoyl-4-bromopyrrolo[1,2-a]quinoline-3-carboxylate analogues

Abstract Eco-friendly methods of heterocyclic synthesis are highly important in view of pharmacology. This synthetic chemistry deals with the application of environmental friendly chemical compounds synthesis using microwave methods. Greener method of synthesis of benzo-fused indolizines like ethyl 4-Bromo-1-(substituted-benzoyl)pyrrolo[1,2-a]quinoline-3-carboxylate analoguos 1a-n using the one-pot method with 3‑bromo quinolone, phenacyl bromide and electron-deficient alkynes in the presence of triethylamine base with acetonitrile as a solvent. The structures of all the newly synthesized pyrrolo[1,2-a]quinoline have been confirmed by spectroscopic techniques. All the synthesized test compounds were screened for their antibacterial activity using six different types of gram-positive and gram-negative bacterial strains. The compounds 1a, 1k, and 1l exhibited a significant zone of inhibition against all six bacterial strains, and the test compound 1i showed potent free radical scavenging activity with the highest percentage inhibition of 49.27 at 100 µg/mL.

Solvent‐free synthesis and 1,3‐dipolar cycloaddition reactions of N‐methyl‐C‐(2‐furyl) nitrone in a ball mill and anticancer activities of the new cycloadducts

AbstractAn efficient method of mechanochemistry for the synthesis of N‐methyl‐C‐(2‐furyl) nitrone and intermolecular 1,3‐dipolar cycloaddition reactions with activated alkenes and electron deficient alkynes has been studied by employing ball milling technique. This method is found to accelerate significantly the reaction rate and improved yields of isoxazolidine and isoxazoline derivatives. A comparative study with the corresponding solvent‐free microwave‐induced reaction showed the superiority of the ball milling method. Significant anticancer activity of the new molecules have made this protocol more attractive. All the new isoxazolidine and isoxazoline derivatives have been screened for anticancer activities and were found to be active.

Copper-Catalyzed Cascade Cyclization Reaction of Enamines and Electron-Deficient Terminal Alkynes: Synthesis of Polysubstituted Pyrido[1,2-a]indoles.

A novel copper-catalyzed cascade cyclization reaction between enamines and electron-deficient terminal alkynes has been developed. The reaction provides a new and efficient strategy for the construction of polysubstituted pyrido[1,2-a]indoles by the formation of two rings, three C-C bonds, and one C-N bond in a single step from readily available acyclic starting materials.

Metal-Free Synthesis of 3-(Iso)quinolinyl 4-Chromenones and 3-(Iso)quinolinyl 4-Quinolones from (Iso)quinoline N-Oxides and Ynones.

A general approach for the synthesis of 3-(iso)quinolinyl 4-chromenones and 3-(iso)quinolinyl 4-quinolones from (iso)quinoline N-oxides and ynones under metal-free conditions was developed. The reaction of (iso)quinoline N-oxide with the electron-deficient alkyne first generated an (iso)quinolinyl β-diketone intermediate, which then underwent an intramolecular dehydration, affording 3-(iso)quinolinyl 4-chromenones and 3-(iso)quinolinyl 4-quinolones.

Molecular diversity of triphenylphosphine promoted reaction of electron-deficient alkynes and arylidene Meldrum acid (N,N'-dimethylbarbituric acid)

The three-component reaction of triphenylphosphine, dimethyl hex-2-en-4-ynedioate and arylidene N,N'-dimethylbarbituric acids in dry methylene dichloride at room temperature afforded trans-1,3-disubstituted 7,9-diazaspiro[4.5]dec-1-enes in good yields and with high diastereoselectivity. However, the similar three-component reaction with arylidene Meldrum acids resulted in a mixtures of cis/trans-1,2-disubstituted 7,9-dioxaspiro[4.5]dec-1-enes. Additionally, the three-component reaction of triphenylphosphine, dimethyl but-2-ynedioate and arylidene Meldrum acids gave polysubstituted 5-(triphenyl-λ5-phosphanylidene)cyclopenta-1,3-dienes. A plausible reaction mechanism was proposed for the formation of various products with different regioselectivity and diastereoselectivity.

Microwave - Assisted Synthesis of a Library of Pyrrolo[1,2-c]quinazolines

A library of new pyrrolo[1,2-c]quinazoline derivatives was obtained by the one-pot, three-component microwave-assisted synthesis, starting from quinazolines, 2-bromoacetyl derivatives and electron-deficient alkynes in 1,2-epoxybutane via 1,3-dipolar cycloaddition of quinazolinium N-ylides. This synthetic pathway offers a simple and rapid access to a large range of pyrrolo[1,2-c]quinazoline derivatives.

Efficient Straightforward Synthesis of Amidopiperazinophanes as Versatile Novel Supramolecular Scaffolds

A simple one-pot synthesis of amidopiperazinophanes with a combination of electron-deficient amide groups and electron-rich alkyne and piperazine functionalities has been achieved by using multicomponent reaction (MCR) methodology with the Mannich reaction. Herein, we demonstrate the synthesis of macrocyclic amide structures in good yields. These macrocycles, with electron donor/acceptor sites, are versatile molecules for host–guest and binding.

Mechanochemical synthesis and cycloaddition reactions of fluoro nitrone under solvent‐free conditions and potential antimicrobial activities of the cycloadducts

AbstractSynthesis and cycloaddition reactions of fluoro nitrone under solvent‐free conditions using ball‐milling technique have been reported. Significant change in rate and yields of the cycloadducts have been noticed compared with solvent‐free microwave‐induced reactions of fluoro nitrones. The present study reports synthesis of N‐benzyl fluoro nitrone and its cycloaddition reactions with maleimides and few electron deficient alkynes under solvent‐free conditions. The synthesized fluoro cycloadducts were found to exhibit potential antimicrobial activities.

Organocatalytic Asymmetric Michael/Dieckmann Cyclization Reaction of Alkynones To Construct Spirocyclopentene Oxindoles.

A highly enantioselective conjugate addition/Dieckmann cyclization of 3-carboxymethyl substituted oxindoles with electron-deficient internal alkynes was achieved under the catalysis of a chiral guanidine catalyst and NaH. This protocol provides access to a wide range of synthetically useful optically active spirocyclopentenone oxindoles and their derivatives under mild reaction conditions.

Synthesis of Nanographenes, Starphenes, and Sterically Congested Polyarenes by Aryne Cyclotrimerization.

In recent years, synthetic transformations based on aryne chemistry have become particularly popular, mostly due to the spread of methods to generate these highly reactive intermediates in a controlled manner under mild reaction conditions. In fact, aryne cycloadditions such as the Diels-Alder reaction are nowadays widely used for the efficient preparation of polycyclic aromatic compounds. In 1998, our group discovered that arynes can undergo transition metal-catalyzed reactions, a finding that opened new perspectives in aryne chemistry. In particular, Pd-catalyzed [2 + 2 + 2] cycloaddition of arynes allowed the straightforward synthesis of triphenylene derivatives such as starphenes or cloverphenes. We found that this reaction is compatible with different substituents and sterically demanding arynes as starting materials. This transformation is especially useful to increase the molecular complexity in one single step, transforming molecules formed by n cycles in structures with 3n + 1 cycles. In fact, we took advantage of this protocol to prepare a large variety of sterically congested polycyclic aromatic hydrocarbons such as helicenes or twisted polyarenes. Soon after the discovery of the reaction, the co-cyclotrimerization of arynes with other reaction partners, such as electron deficient alkynes, significantly expanded the potential of this transformation. Also the use of catalysts based on alternative metals besides Pd (e.g., Ni, Cu, Au) or the use of other strained intermediates such as cycloalkynes or cycloallenes added value to this reaction. In addition, we realized that the Pd-catalyzed aryne cyclotrimerization reaction is particularly useful for the bottom-up preparation of well-defined nanographenes by chemical methods. Although the extreme insolubility of these planar nanographenes hampered their manipulation and characterization by conventional methods, recent advances in single molecule on-surface characterization by atomic force microscopy (AFM) and scanning tunneling microscopy (STM) with functionalized tips under ultrahigh vacuum (UHV) conditions, permitted the impressive visualization of these nanographenes with submolecular resolution, together with the examination of the corresponding molecular orbital densities. Moreover, arynes have been shown to possess a rich on-surface chemistry. In particular, arynes have been generated and studied on-surface, showing that the reactivity is preserved even at cryogenic temperatures. On-surface aryne cyclotrimerization was also demonstrated to obtain large starphene derivatives. Therefore, it is expected that the combination of aryne cycloadditions and on-surface synthesis will provide notable findings in the near future, including the "à la carte" preparation of graphene materials or the synthesis of elusive molecules with unique properties.

Electron-Deficient Alkynes as Dipolarophile in Pd-Catalyzed Enantioselective (3 + 2) Cycloaddition Reaction with Vinyl Cyclopropanes.

The activated alkynes have been used successfully for the first time as the dipolarophile in the palladium-catalyzed asymmetric (3 + 2) cycloaddition, affording highly functionalized cyclopentenes in good to high yields with high chemoselectivities and good to high enantioselectivities. The introduction of an additional carbonyl group at the α-position of the alkynyl esters is the key to activating the carbon-carbon triple bond. The reaction process was investigated, and an inverse process of Pd-catalyzed (3 + 2) cycloaddition was observed.

Thio- and Seleno-Michael addition: An efficient tool for the delivery of sulfur and selenium functionalities

1,2-Mercapto alcohols and 1,2-mercapto amines proved to be useful reagents towards Michael acceptors, such as α,β-ethylenic ketones, esters and nitriles leading to variously polyfunctionalized unsymmetric sulfides. Reaction of 1,2-mercapto alcohols with electron-deficient alkynes allowed to obtain β-hydroxy vinyl sulfides as valuable precursors of 1,3-oxathiolane derivatives. Extension to β-hydroxy selenols resulted in the isolation of unsymmetric selenides, formed through a Se-alkylation.

Oxidative Annulation of Acetanilides with Alkynes Catalyzed by Cyclopentadienyl Rhodium(III) Complexes with Pendant Amides

AbstractIt has been established that a cationic cyclopentadienyl (Cp) rhodium(III) complex with a pendant N‐phenylcarbamoyl moiety (CpA1RhIII) showed high catalytic activity towards the oxidative [3+2] annulation of acetanilides with internal alkynes to produce substituted indoles. Catalytic activity of the CpA1RhIII complex in the reactions of symmetric internal alkynes (diphenylacetylene and 6‐dodecyne) was higher than that of the Cp*‐rhodium(III) complex and comparable to that of a Cp‐rhodium(III) complex with two ethoxycarbonyl groups (CpERhIII). On the other hand, the CpA1RhIII complex showed significantly higher catalytic activity than the CpERhIII complex in the reactions of unsymmetric internal alkynes (1‐phenyl‐1‐propyne and 1‐phenyl‐1‐hexyne). Additionally, the catalytic activity of the CpA1RhIII complex in the oxidative tandem [2+2+2] annulation‐lactamization of acetanilides with two unsymmetric electron‐deficient internal alkynes (ethtyl 2‐butynoate) was also comparable to that of the CpERhIII complex.

Phosphine-catalyzed bishydrophosphorylation of electron-deficient alkynes

Tertiary phosphines (n-Bu3P, Ph3P) efficiently catalyze the vicinal bis-addition of dialkyl phosphites and diaryl phosphine oxides to alkynoates though the tandem α-umpolung/β-Michael addition. This reaction offers a simple metal-free method for gram-scale preparation of practically useful bisphosphonates and bisphosphine oxides under mild conditions with high atom economy and selectivity.

Синтез и антимикробная активность новых фосфорсодержащих производных пиридина

The directed synthesis of new pharmacophoric molecules is one of the urgent tasks of organic chemistry. A special place in this area is occupied by vital nitrogen-containing heterocycles and their derivatives, on the basis of which new promising precursors of drugs are created. For example, pyridinium salts are part of such well-known drugs as pyridoxine, mexidol and metadoxine. Phosphorus-containing pyridine derivatives, among which compounds with cytotoxic and antimicrobial properties have been identified, are also being actively studied now. Thus, the development of convenient approaches for obtaining new functional phosphorus-containing pyridine derivatives is an important and timely task. Special attention is paid to synthetic methods that correspond to the PASE (pot, atom and step economy) paradigm. Using this approach, we have synthesized hydrochlorides and tosylates of 4-bis(2-phenylethyl)chalcogenophosphoryl-pyridine, not described previously, by practically quantitative interaction of the available 4-bis(2-phenylethyl)chalcogenophosphorylpyridines with hydrochloric or 4-methylbenzenesulfonic acids at room temperature or slight heating (40-45 °C). The reaction proceeds regioselectively on the nitrogen atom of the base pyridine. The second reaction center in the 4-bis(2-phenylethyl)chalcogenophosphorylpyridine molecule, chalcogenophosphoryl group, does not participate in the studied process, even when using an excess of hydrochloric acid. The starting 4-bis(2-phenylethyl)chalcogenophosphorylpyridines are easily obtained on the basis of the original reaction of pyridine with secondary phosphine chalcogenides with the assistance of electron-deficient acetylenes. Using the example of microorganisms of different taxonomic groups: Bacillus subtilis B-406, Enterococcus durans B-603, Penicillium citreo-viride F-1777, Escherichia coli B-1238, we have found that the target hydrochlorides and tosylates of 4-bis(2-phenylethyl)chalcogenophosphorylpyridine exhibit pronounced antimicrobial activity against non-spore gram-positive microorganisms.

Sequential Nucleophilic "Click" Reactions for Functional Amphiphilic Homopolymers.

Amphiphilic homopolymers with high densities of functional groups are synthetically challenging. Thiol-yne nucleophilic click reactions have been investigated to introduce multiple functional groups in polymers with high density. An electron deficient alkyne group bearing methacrylate monomer was polymerized using reversible addition-fragmentation chain-transfer (RAFT) polymerization. Subsequently, the electron deficient alkyne group on polymer side chain was readily reacted with a thiol reagent using triethylamine (TEA) as the organocatalyst. This reaction was found to be very efficient under mild conditions. The resultant homopolymer bearing thiol vinyl ether functional groups could perform a second thiol addition with a stronger base, such as triazabicyclodecene (TBD), to prepare multifunctional homopolymers. This stepwise addition process was monitored by 1H NMR as well as gel permeation chromatography. The fidelity of this method was demonstrated by attaching four different functionalities, including both hydrophobic and hydrophilic moieties. Furthermore, these dual functionalized polymers bearing dithio-acetal groups are sensitive to reactive oxygen species (ROS), which compromises the host-guest properties of the assembly in response to this stimulus. The ROS responsive polymers reported here may have potential use in therapeutic delivery.

Reactions of Diaziridines with Benzynes Give N-Arylhydrazones.

Reactions of thermally generated benzynes with diaziridines are reported. These trapping reactions follow the same pathway as reported earlier by Heine and co-workers with electron-deficient alkynes. The resulting N-arylhydrazones were obtained efficiently in a single step. The preference for the mode of addition of the nucleophilic diaziridine nitrogen atom to the more electrophilic benzyne carbon was consistent with what is predicted on the basis of distortion analysis. The feasibility of converting the hydrazone into a Fisher-indole adduct was demonstrated.

Total Synthesis of Callyspongiolide, Part 2: The Ynoate Metathesis/cis-Reduction Strategy.

The macrocyclic core of the cytotoxic marine natural product callyspongiolide (1) was forged by ring-closing alkyne metathesis (RCAM) of an ynoate precursor using a molybdenum alkylidyne complex endowed with triarylsilanolate ligands as the catalyst. This result is remarkable in view of the failed attempts documented in the literature at converting electron deficient alkynes with the aid of more classical catalysts. The subsequent Z-selective semi-reduction of the resulting cycloalkyne by hydrogenation over nickel boride required careful optimization in order to minimize overreduction and competing dehalogenation of the compound's alkenyl iodide terminus as needed for final attachment of the side chain of 1 by Sonogashira coupling. The required cyclization precursor itself was prepared via Kocienski olefination.

Catalyst-Free Phosphorylation of Acridine with Secondary Phosphine Chalcogenides: Nucleophilic Addition vs SNHAr Reaction.

Acridine adds secondary phosphine chalcogenides HP(X)R2 (X = O, S, Se; R = Ar, ArAlk) under catalyst-free conditions at 70-75 °C (both in the presence and absence of the electron-deficient acetylenes) to give 9-chalcogenophosphoryl-9,10-dihydroacridines in 61-94% yields. This contrasts with pyridines, which under similar conditions undergo an SNHAr reaction, wherein electron-deficient acetylenes play the role of oxidants. For acridine, the SNHAr step has been accomplished by the oxidation of the intermediate 9-phosphoryl-9,10-dihydroacridines (X = O) with chloranil.