Ethyl Propiolate Research Articles

Reevaluating ortho-Carborane Synthesis: Success with Mono-Substituted Acetylenes in the Presence of Silver Salts

The study shows that traditional methods for synthesizing ortho-carboranes from nido-B10H14 and its complexes (B10H12L2) using donor- and acceptor-disubstituted acetylenes yielding low efficiencies (yields 0 - 12%). Attempts to improve yields with ionic liquids and silver salts as catalysts were unsuccessful with disubstituted acetylenes. However, it has been found that the use of mono-substituted acetylenes (phenylacetylene, ethyl propiolate) in the presence of silver salts in the reaction with B10H12L2 substrates produces ortho-carboranes in high yields (~90%). This suggests that the key step is the formation and subsequent addition of silver acetylenides, and not the donor-acceptor π-complexes previously assumed. This finding allows us to better understand the mechanisms of the ortho-carboranes formation and offers an efficient pathway for their synthesis.

Synthesis, characterization and larvicidal studies of ethyl 3-benzoyl-7-(piperidin-1-yl)indolizine-1-carboxylate analogues against Anopheles arabiensis and cheminformatics approaches

According to WHO, in 2021, there was an estimation of 247 million malaria cases from 84 malaria-endemic countries. Globally an estimated count of 2 billion malaria cases and 11.7 million deaths due to malaria were recorded in the past two decades. Further, the emergence of drug-resistant mosquitos threatens mankind. Therefore, the development of newer larvicidal agents is the need of the hour. This research identifies a new series of variably substituted indolizines for their effectiveness in controlling Anopheles arabiensis larvae through larvicidal activity. The series of Ethyl 3-benzoyl-7-(piperidin-1-yl)indolizine-1-carboxylate analogues (4a-j) were synthesized by reacting 4-(piperidin-1-yl)pyridine, phenacyl bromides with ethyl propiolate via 1, 3-dipolar cycloaddition and the green metrics of the process are reported. All the newly synthesized compounds were characterized by spectroscopic techniques such as 1H NMR,13C NMR, FT-IR, and HRMS. The larvicidal effectiveness of the newly synthesized compounds was assessed against Anopheles arabiensis. Among the compounds studied, namely 4c, 4d, 4e, and 4f, displayed the most notable larval mortality rates within the series, reaching 73%, 81%, 76%, and 71% respectively, in contrast with the negative control acetone. In comparison, the standard Temephos exhibited a mortality rate of 99% at the same concentration. Furthermore, computational approaches including molecular docking and molecular dynamics simulations identified the potential targets of the series compounds as the larval Acetylcholinesterase (AChE) enzyme and the Sterol Carrier Protein-2 (SCP-2) protein. However, it is essential for these computational predictions to undergo experimental validation. Communicated by Ramaswamy H. Sarma

Reactivities of tertiary phosphines towards allenic, acetylenic, and vinylic Michael acceptors.

The addition of phosphines (PR3) to Michael acceptors is a key step in many Lewis-base catalysed reactions. The kinetics of the reactions of ten phosphines with ethyl acrylate, ethyl allenoate, ethyl propiolate, ethenesulfonyl fluoride, and ethyl 2-butynoate in dichloromethane at 20 °C was followed by photometric and NMR spectroscopic methods. The experimentally determined second-order rate constants k 2 show that electronic effects in sterically unencumbered phosphines affect their nucleophilicity towards different classes of Michael acceptors in the same ordering. Michael acceptors with sp-hybridised electrophilic centres, however, are less susceptible to changes in the PR3 nucleophilicity than those with sp2-hybridised reactive sites. Linear correlations of lg k 2 from this work with published rate constants for SN2 and SN1 reactions as well as with Brønsted basicities and fugalities for PR3 demonstrate the generality of the detected reactivity trends. Computed reaction barriers (ΔG ‡ calc) as well as reaction energies (ΔG add) for Michael adduct formations show excellent correlations with experimentally obtained reaction barriers (ΔG ‡ exp) corroborating the interpretation of the kinetic data and revealing the philicity/fugality features of the reactants in phospha-Michael additions.

On the Question of Zwitterionic Intermediates in the [3+2] Cycloaddition Reactions between Aryl Azides and Ethyl Propiolate.

The molecular mechanism of the [3+2] cycloaddition reactions between aryl azides and ethyl propiolate was evaluated in the framework of the Molecular Electron Density Theory. It was found that independently of the nature of the substituent within the azide molecule, the cycloaddition process is realized via a polar but single-step mechanism. All attempts of localization as postulated earlier by Abu-Orabi and coworkers' zwitterionic intermediates were not successful. At the same time, the formation of zwitterions with an "extended" conformation is possible on parallel reaction paths. The ELF analysis shows that the studied cycloaddition reaction leading to the 1,4-triazole proceeds by a two-stage one-step mechanism. It also revealed that both zwitterions are created by the donation of the nitrogen atom's nonbonding electron densities to carbon atoms of ethyl propiolate.

Preparation and Carbocupration–Silylation of Allyl Propiolates: Vicinal Functionalization To Form Polysubstituted (E)-Vinylic Silanes

AbstractThe preparation and TMSOTf-mediated catalytic carbocupration–silylation of allylic propiolates has been investigated, expanding on previous syntheses of a variety of β-alkyl- and β-aryl-substituted vinylsilanes from an ethyl propiolate precursor. With few exceptions, the series of synthesized O-allyl (E)-vinylsilanes has been isolated in high yields (61–89%) with exceptional diastereoselectivities (E/Z >20:1). Additionally, we demonstrated a novel LDA-initiated, TMSCl-mediated Ireland–Claisen rearrangement of a representative allylic ester.

On the Copper(I)-Catalyzed Cross-Coupling of 1-Bromoalkynes with N-Heterocyclic Organozinc Reagents: Substrate Scope and Catalyst Evaluation

AbstractNitrogen-containing heterocycles are ubiquitous in FDA-approved small molecule pharmaceuticals. Herein, we expand on a novel synthetic method for the production of saturated N-heterocyclic pharmacophore motifs with an internal alkyne for elaboration. The treatment of N,N-dimethylhydrazinoalkenes with diethylzinc followed by a Cu(I)-catalyzed cross-coupling with 1-bromoalkynes affords piperidines and pyrrolidines in respectable yields. Functional group tolerance is demonstrated by the inclusion of heteroatom-bearing alkynes. Unexpectedly, the use of ethyl propiolate as the trapping electrophile led to selective N-functionalization with the formation of vinylogous urethanes. Alternative Cu(I) complexes were also evaluated as prospective catalysts. This synthetic protocol can readily be achieved on a preparative scale.

Exploring Pyrrolo-Fused Heterocycles as Promising Anticancer Agents: An Integrated Synthetic, Biological, and Computational Approach.

Five new series of pyrrolo-fused heterocycles were designed through a scaffold hybridization strategy as analogs of the well-known microtubule inhibitor phenstatin. Compounds were synthesized using the 1,3-dipolar cycloaddition of cycloimmonium N-ylides to ethyl propiolate as a key step. Selected compounds were then evaluated for anticancer activity and ability to inhibit tubulin polymerization in vitro. Notably, pyrrolo[1,2-a]quinoline 10a was active on most tested cell lines, performing better than control phenstatin in several cases, most notably on renal cancer cell line A498 (GI50 27 nM), while inhibiting tubulin polymerization in vitro. In addition, this compound was predicted to have a promising ADMET profile. The molecular details of the interaction between compound 10a and tubulin were investigated through in silico docking experiments, followed by molecular dynamics simulations and configurational entropy calculations. Of note, we found that some of the initially predicted interactions from docking experiments were not stable during molecular dynamics simulations, but that configurational entropy loss was similar in all three cases. Our results suggest that for compound 10a, docking experiments alone are not sufficient for the adequate description of interaction details in terms of target binding, which makes subsequent scaffold optimization more difficult and ultimately hinders drug design. Taken together, these results could help shape novel potent antiproliferative compounds with pyrrolo-fused heterocyclic cores, especially from an in silico methodological perspective.

One-pot Synthesis of 2-Aminoindole through SET Oxidative Cyclization: Concise Synthesis of Tryptanthrin and Phaitanthrin E.

An efficient domino approach for the synthesis of biologically important 2-aminoindole derivatives has been developed using CuBr2 -mediated SET oxidative cyclization as a key step. This one-pot multicomponent strategy utilizes readily available ethyl propiolate, tosyl azide, and substituted aryl amines as starting materials. The generality and scope of this mild method are demonstrated with a wide variety of substrates to furnish functionalized 2-aminoindoles in good yields. The synthetic power of this strategy is further exemplified in the concise synthesis of biologically important alkaloids, Phaitanthrin E and Tryptanthrin.

Pulsed-post column derivatization coupled to green liquid chromatography for the determination of glutathione and cysteine based on thioacrylates formation

In the present work, we developed a method for the determination of thiols (cysteine and glutathione) in yeast samples under the new concept of Pulsed-post column derivatization (Pulsed-PCD). For the chromatographic separation of the analytes, 100% aqueous mobile phase was used and the eluted compounds reacted on-line with the injected pulses (100 μL) of the derivatizing reagent (ethyl propiolate + Britton-Robinson buffer). Spectrophotometric detection of the derivatives was carried out at 285 nm. The Pulsed-PCD configuration, the selection of the analytical column and the pulsed-PCD reaction conditions were investigated. The method was validated for the determination of endogenous content of the analytes in dry and fresh yeasts, with LODs of 3.0 μmol L−1. The percent recovery ranged between 85.2 and 114.4% in all cases and the results were compared with a corroborative method based on classical PCD. The analytical greenness of the proposed method was evaluated using two tools; Analytical Eco-Scale and Green Analytical Procedure Index (GAPI). The greenness score of the HPLC-Pulsed-PCD method (score = 77) was compared with that of the corroborative HILIC-PCD method (score = 71) and was found to be greener in terms of the amount of chemicals used and the produced wastes.

Synthesis of aryl‐functionalized, 1,5‐disubstituted 1,2,3‐triazoles and derivatives by arylation of zwitterionic ruthenium triazolato complexes

AbstractThe synthesis of a series of ruthenium 1,5‐disubstituted 1,2,3‐triazolato complexes, 1,5‐disubstituted 1,2,3‐triazoles, and a triazolium salt is reported. Treatment of the ruthenium azido complex [Ru]‐N3 (1, [Ru] = (η5‐C5H5)(dppe)Ru, dppe = Ph2PCH2CH2PPh2) with an excess of ethyl propiolate results in the formation of a mixture of the Z‐ and E‐forms of zwitterionic N(1)‐bound N(3)‐ethyl acryl‐4‐carboxylate triazolato complexes [Ru]N3(CH=CHCO2Et)C2H(CO2) (Z‐2) and (E‐2). The arylation of 2 with aromatic bromides gives a series of cationic N(1)‐bound N(3)‐ethyl acryl‐4‐alkoxycarbonyl triazolato complexes {[Ru]N3(CH=CHCO2Et)C2H(CO2CH2R)}[Br] (3a, R = Ph; 3b, R = C6F5; 3c, R = 4‐C6H4CN, 3d, R = 2,6‐C6H3F2) and the subsequent cleavage of the Ru‐N bond of 3a–d gives 1,5‐disubstituted 1,2,3‐triazoles N3(CH=CHCO2Et)C2H(CO2CH2R) (4a, R = Ph; 4b, R = C6F5; 4c, R = 4‐C6H4CN; 4d, R = 2,6‐C6H3F2) and [Ru]‐Br. A 1,2,3‐triazolium salt [N3(CH=CHCO2Et)(CH2C6F5)C2H2][Br] (5) was formed by transformation of 4b in BrCH2C6F5/chloroform mixture. The structures of Z‐3a and Z‐5 were confirmed by single‐crystal x‐ray diffraction analysis and both complexes participate in non‐covalent aromatic interactions in the solid‐state structures which can be favorable in the binding of DNA/biomolecular targets and have shown great potential in the application of biologically active anticancer drugs.

Photochromism of 2H-naphtho[1,2-b]pyran-4-carboxylates

New 2H-naphthopyrans substituted at C-4 by a carboxylate group were synthesized through the one-pot acid-catalyzed reaction of naphthols with ethyl 4,4-diaryl-4-hydroxybut-2-ynoate which was easily obtained from ethyl propiolate. These colorless compounds show photochromic properties under UV irradiation. The carboxylate group exerts a strong effect on the thermal fading speed of the colored species leading to a fast switch between the colored and colorless states, which, however, can be appropriately counterbalanced leading to a noticeable color change at room temperature. The mechanism of this reversible transformation was studied by NMR.

Solid-state silica gel-catalyzed synthesis of fluorescent polysubstituted 1,4- and 1,2-dihydropyridines.

We present the green, highly atom-economical, solid-state silica gel-catalyzed synthesis of polysubstituted 1,4- and 1,2-dihydropyridines (DHPs) from commercially available materials, amines and ethyl propiolate. The DHP skeleton was assembled by heating the reactants and silica gel in a closed vessel. Aliphatic amines provided 1,4-isomers as the main or only DHP products, but the reactions of aromatic amines yielded a mixture of 1,4- and 1,2-isomers. To the best of our knowledge, this is the first example of the formation of a 1,2-DHP structure by the reaction of an amine with propiolic ester. Addition of 1 mass percent of H2SO4 to silica gel shifted the product distribution to 1,4-DHP as the main or the only isomer obtained. Experimental and theoretical analyses led to the identification of two key intermediates en route to DHPs and the explanation of the observed regioisomeric ratios. 1,2-DHPs show blue-cyan fluorescence in MeOH with the quantum yield Φ = 0.10-0.22 relative to quinine sulfate Φ = 0.58 and 1,4-DHPs show blue-violet fluorescence with Φ = 0.09-0.81.

Synthesis of ethyl 2-((4-phenyl-1H-1,2,3-triazol-1-yl)methyl)-4H/2H-chromene-3-carboxylates by cycloaddition of ethyl 2-(azidomethyl)-4H-chromene-3-carboxylates with alkynes

The cycloaddition reaction has been carried out between ethyl 2-(azidomethyl)-4H-chromene-3-carboxylates and phenylacetylenes/ activated alkynes. Phenylacetylene, 4-fluorophenylacetylene were provided mixture of 2H- and 4H-triazolylchromene-3-carboxylates, whereas methyl, methoxyphenylacetylene and acetylenedicarboxylates were provided exclusively 2H-triazolylchromene-3-carboxylates. Interestingly, prop-2-yn-1-ol and ethyl propiolate were provided exclusively 4H-triazolylchromene-3-carboxylates.

Reactivity of pyrimidinylphosphazenes with acetylenic esters: Competitive [4 + 2] and [2 + 2] tandem cycloaddition or retro‐cycloaddition approaches

AbstractIn the search for new intermediates for heterocyclic synthesis, the reactivity of 6‐iminophosphoranepyrimidines against dimethyl acetylenedicarboxylate (DMAD) and ethyl propiolate as dienophiles, was studied in this work. The presence of a viable 2‐azadienic moiety in pyrimidin‐4‐one rings (oxo derivatives) favored reaction of DMAD by [4 + 2]/retro‐[4 + 2] sequence, in addition to the expected [2 + 2] cycloaddition/retrocycloaddition involving phosphazene moiety. In contrast, pyrimidine derivatives lacking a viable 2‐azadienic residue reacted only through phosphazene group by the aforementioned [2 + 2]/retro‐[2 + 2] tandem process. Ethyl propiolate (non‐symmetric dienophile) proved less reactive in the study, giving rise to undesired side reactions.

Diastereoselective synthesis and spectral characterization of trans-4,4a-dihydro-3H-benzo[4,5]oxazolo[3,2-a]pyridines

An efficient one-pot multi-component reaction for the diastereoselective synthesis of novel trans-4,4a-dihydro-3H-benzo[4,5]oxazolo[3,2-a]pyridines starting from readily available cinnamaldehydes, o-aminophenol and 1,3-dicarbonyl compounds/ ethyl propiolate catalysed by AcOH is described. The products could be obtained in 3 h under refluxing conditions with perfect diastereoselectivity. Single crystal X-ray analysis confirmed the trans-derivative as the only isomer. All the compounds were unequivocally confirmed by NMR, HRMS and XRD analysis. To discuss the special pattern of methylene protons (H8a: td and H8b: dt) on the NMR of the compound 4a, NMR spectra analysis (1D-NMR and 2D-NMR) was conducted in details by the chemical shifts, couplings and correlations. XRD analysis of 4a and 6a further aids to disclose the spatial effect of methyl group on the geometry of the tetrahydropyridine rings of the compounds.

Studies on chemoselective synthesis of 1,4- and 1,2-dihydropyridine derivatives by a Hantzsch-like reaction: a combined experimental and DFT study.

In the experimental process of preparing diethyl 3,5-dicarboxylate-1,4-dihydropyridine (1,4-DHP) by a Hantzsch-like reaction, it was found that a by-product named diethyl 3,5-dicarboxylate-1,2-dihydropyridine (1,2-DHP) was produced in the reaction. To discuss this phenomenon, the effects of the reaction conditions on the yield ratio of 1,4-DHP and 1,2-DHP were studied by using aromatic amines, aromatic aldehydes and ethyl propiolate as raw materials. The mechanisms for the formation of 1,4-DHP and 1,2-DHP were proposed based on the isolated intermediate named diethyl 4-((phenylamino)methylene)pent-2-enedioate generated by the Michael addition of aniline and ethyl propiolate. The transition state structures were optimized and the reaction energy barriers of intermediates in the speculated mechanisms were calculated by DFT calculations at the M062X/def2TZVP//B3LYP-D3/def-SVP level. It was found that the reaction energy barriers and dominant configurations of intermediates IM2 and IM3' are the determinants for the chemoselectivity. Together, these results demonstrate a high chemoselectivity in the synthesis of 1,4-DHPs and 1,2-DHPs by a Hantzsch-like reaction and that 1,4-DHPs and 1,2-DHPs can be easily obtained under different conditions.

Synthesis, Characterization and Crystal Structures of Zwitterionic Triazolato Complexes by Reaction of a Ruthenium Azido Complex with Excess Ethyl Propiolate

The synthesis and structures of two novel zwitterionic ruthenium triazolato complexes are reported. The treatment of the ruthenium azido complex [Ru]-N3 (1, [Ru] = (η5-C5H5)(dppe)Ru, dppe = Ph2PCH2CH2PPh2) with an excess of ethyl propiolate in CHCl3 or CH2Cl2 under ambient conditions for 15 days results in the formation of a mixture of the Z- and E-forms of N(1)-bound ruthenium 3-ethylacryl-4-carboxylate-3H-1,2,3-triazolato complexes [Ru]N3(CH=CHCO2Et)C2H(CO2) (Z-3) and (E-3) in a ratio of ca. 5:2. The structures of E-3 and Z-3 were confirmed by single-crystal X-ray diffraction analysis and fully characterized by 1H, 31P, 13C NMR and IR spectroscopy, mass spectrometry, and elemental analysis. The negatively charged carboxylate moieties of the zwitterionic ruthenium triazolato complexes Z-3 and Z-3 are highly nucleophilic and reactive toward a variety of electrophiles, making Z-3 and Z-3 potential starting materials for the development of biologically active 1,2,3-triazole derivatives.

Gold(I) complexes with multifunctional phosphane ligands: Synthesis and catalysis

Two novel gold(I) complexes with a phosphoguanidine ligand and with a novel cationic phosphane ligand have been prepared and structurally characterized. The phosphoguanidine ligand supports oxidative addition of biphenylene to the gold(I) centre, though the yield of the reaction is low. The phopshoguanidine gold(I) complexes is also able to efficiently catalyze the hydroamination of phenylacetylene with mesitylamine, whereas the gold(I) complex with the cationic phosphane ligand, due to its more electron-poor character, promotes the hydroarylation of ethyl propiolate with mesitylene.

Revealing the Origin of Π‐facial and Regioselectivity in the Diels‐Alder Reaction of Unsymmetrical, Cage‐annulated 1,3‐Cyclohexadiene with Ethyl Propiolate Dienophile: a DFT Study

AbstractDFT [M06‐2X/6‐31+G(d,p) and MPWB1 K/6‐311G(d)] calculations have elucidated the origins of π‐facial and regioselectivity in the Diels‐Alder reactions of hexacyclo [7.5.1.01,6.06,13.08,12.010,14] pentadeca‐2,4‐diene‐7,15‐dione (HPDD) and hexacyclo [7.5.2.01,6.06,13.08,12.010,14] hexadeca‐2,4‐diene‐7,16‐dione (HHDD) dienes with ethyl propiolate (EP) as the dienophile. The origin of π‐facial stereoselectivity of these Diels‐Alder reactions has been rationalized with molecular electrostatic potential (MESP), potential energy surface (PES), and Non‐Covalent Interaction (NCI). The role of the steric effect on the π‐facial stereoselectivity of these Diels‐Alder reactions has also been observed. The origin of distal/proximal regioselectivity of HHDD with EP was explained by attractive Non‐Covalent Interaction (NCI) and electrostatic repulsion. This is one of the rare examples in Diels‐Alder reaction with both the π‐facial stereoselectivity and the regioselectivity with single diene and dienophile.

Activated Isobutylene-Isoprene Rubber—Synthesis, Peroxide Cure, and Mechanical Properties

EIIR, a derivative of isobutylene-isoprene rubber (IIR) with geminal vinylidene-acrylate motifs, has been synthesized by grafting ethyl propiolate to IIR via EtAlCl2-catalyzed Alder-ene reaction. M...