Propargylic Reactions Research Articles

Mechanistic Insights into Chloride‐Dependent Uncaging Reaction of Propargyl and Allene‐Protected Substrates by Pd‐Complexes

This study investigates the effect of chloride levels on the mode of action of palladium complexes for the activation of propargyl‐ and allene‐protected fluorophores and chemotherapeutic drugs through uncaging reactions. Four Pd(II) complexes were synthesized and characterized using spectroscopic techniques to confirm their structure and electronic properties. Kinetic studies and density functional theory calculations revealed that chloride ions in PBS significantly enhance catalytic efficiency, particularly for allenyl‐protected substrates compared to propargylic counterparts. This enhancement is attributed to the neutral charge nature of the Pd complex. The data suggest that neutral complexes are less prone to chloride exchange by water molecules. Additionally, chloride ligands counterbalance the unusually high stability of the key σ‐bound η1‐Pd intermediates in the aquo complexes in PB, leading to higher reactivity. These results highlight the impact of fine‐tuning the electronic properties of the metal center through both designed ligands and environmental factors. Bench evaluations and tests with living breast cancer cells demonstrated that a Pd catalyst complex with a bidentate ligand effectively activates the prodrugs propargyl‐5‐fluorouracil (Prop‐5FU) and allene‐5‐Fluorouracil (Alle‐5FU), the latter being a novel prodrug. The Pd catalyst successfully released the active drug, inducing cytotoxicity, especially with Alle‐5FU, which operates at lower catalyst concentrations than Pro‐5FU.

Synthesis of α-Quaternary Aldehydes via a Dual Ni/Rh-Catalyzed Tandem Isomerization–Propargylation Reaction

Synthesis of α-Quaternary Aldehydes via a Dual Ni/Rh-Catalyzed Tandem Isomerization–Propargylation Reaction

Synthesis of Selenium-Containing N-Quinazolinyl Acroleins via a 3,3-Radical Rearrangement Cascade Reaction.

An effective approach for the construction of 2-aryl-3-(3-oxo-1-aryl-2-(organoselanyl)prop-1-en-1-yl)quinazolin-4(3H)-ones was developed. Excellent to almost quantitative yields were obtained by the cascade reaction of propargyl quinazoline-4-yl ethers, diselenides, and 70% tert-butyl hydrogen peroxide aqueous solution under metal-free and mild conditions. The synthesized hybrids, with conglomeration of quinazolinone, organoselenium, aldehyde, and fully substituted alkene moieties in one molecule, will have the potential for applications in development of new drugs or drug candidates.

Highly selective synthesis of selenium-containing (E)-N-propenolquinazolinones via FeCl3-mediated cascade reaction of propargyl quinazoline-4-yl ethers with diselenides.

An effective approach for the highly selective synthesis of selenium-containing (E)-N-propenolquinazolinones via an FeCl3·6H2O mediated cascade reaction of propargyl quinazoline-4-yl ethers and diselenides has been developed. Mechanistic investigations revealed that the reaction of FeCl3 and (PhSe)2 generates, in situ, the electrophilic species PhSe[FeCl4]·6H2O, which triggers the cascade reaction.

Cationic indium catalysis as a powerful tool for generating α-alkyl propargyl cations for SN1 reactions

Dehydration is an abundant and promising process in chemical, biochemical, and industrial fields. Dehydration methods can contribute to building a modern and sustainable society with minimal environmental impact. Breakthrough advances in the dehydrative SN1 reaction can be achieved through the discovery of new cationic indium catalysts. Here we show that the breakthrough advances in the dehydrative SN1 reaction can be achieved using the cationic indium catalysts. The dehydrative carbon–carbon bond formation of α-alkyl propargyl alcohols afforded a wide variety of α-aryl- and heteroaryl-propargyl compounds. Mechanistic investigations into this process revealed that the InCl3/AgClO4/Bu4NPF6/1,1’-binaphthol catalytic system generated a powerful cationic indium catalyst that could promote the dehydration of alcohols. Labile α-alkyl propargyl cations were found to self-condense, and the catalyst system efficiently regenerated propargyl cations for reaction with nucleophiles. This propargylation reaction directly proceeded from the corresponding alcohols under mild and open-air conditions and tolerated a broad scope of functional groups. Furthermore, a wide variety of nucleophiles, including aromatic and heteroaromatic compounds, phenols, alcohols, and sulfonamides, reacted with the corresponding cations to afford the propargyl compounds in good to high yields. Finally, the synthetic utility of this reaction was demonstrated by the synthesis of colchicine and allocolchicine analogues. The dehydration process could help create new compounds that were previously impossible to synthesize and is more eco-friendly and efficient than conventional methods.

A VUV photoionization study on the gas-phase synthesis of the first five-membered carbon ring - C7H6 isomers

Utilizing synchrotron photoionization and molecular-beam mass spectrometry methodologies, this investigation deciphered the gas-phase reaction of propargyl with vinylacetylene by employing a high-temperature micro reactor within a time scale of tens to hundreds of microseconds, thereby precluding interference from secondary reactions. One of the typical C5-membered cyclic structures, fulvenallene, along with its isomers 1-ethynyl-1,3-cyclopentadiene and 5-ethynyl-1,3-cyclopentadiene, were synthesized. The latter two isomers were detected and identified for the first time within the confines of our experiments. The detailed formation mechanisms of these C7H6 isomers were meticulously examined with the incorporation of quantum computations on the potential energy surfaces and rate constants.

SYNTHESIS AND CHEMICAL MODIFICATION OF NEW HYDROXYBEZALDEHYDE DERIVATIVES

A high pharmacological ability of aromatic benzaldehydes makes them important intermediates for the synthesis of medicinal preparations, such as anticancer, bactericidal, antifungal, and herbicidal drugs. The purpose of this work is the synthesis of biologically active compounds, based on 4-hydroxybenzaldehyde and 4-hydroxy-3-methoxybenzaldehyde and the establishment of the structure of the synthesized compounds. Results and discussion. New carbonodithioates, based on O-aromatic systems have been synthesized by the interaction of 4-hydroxybenzaldehyde and 4-hydroxy-3-methoxybenzaldehyde with carbon disulfide in the presence of sodium hydroxide in ethanol at the room temperature. As a result of the reactions, sodium O-(4-formylphenyl)carbodithioate (86 %) and sodium O-(4-formyl-2-methoxyphenyl)carbodithioate (80%) have been isolated. The interaction of sodium xanthates with acid chlorides (4-methoxy-, 4-nitro-, 2,4-dinitrobenzoic) in chloroform has led to the formation of aromatic thioanhydrides of carbonodithioic acids in 55-80 % yields. The reactivity of hydroxybenzaldehydes and their dithiocarboxylic derivatives has been studied in the propargylation reaction. Propargylation of 4-hydroxybenzaldehyde and 4-hydroxy-3-methoxybenzaldehyde has been carried out with propargyl bromide in the presence of a 3-fold excess of K2CO3 in acetone at the temperature of 60°C. The propargylation reaction of sodium xanthate has been carried out with propargyl bromide in acetone at the room temperature. Conclusion. As a result of the reactions, carbonodithioates, thioanhydrides, acetylenic and thioacetylenic ethers have been synthesized based, on O-aromatic systems (4-hydroxybenzaldehyde and 4-hydroxy-3-methoxybenzaldehyde). The structure of the synthesized compounds has been established on the basis of elemental analysis data, IR spectra, 1Н and 13С NMR spectroscopy.

A convenient method for the construction of triazole-bonded chalcone derivatives from acetophenone: Synthesis and free radical scavenging investigation

The substituted 1,2,3-triazole core is prevalent in numerous commercially available drugs utilized for a wide range of clinical applications. Simultaneously, chalcone represents a privileged framework discovered in natural products exhibiting intriguing bioactivities. In this study, we synthesized triazole-bonded chalcone compounds (4ax-4by), starting from a simple aromatic ketone, acetophenone, which underwent aldol condensation to give hydroxychalcone intermediate. In the second step, the hydroxyl group of chalcone compound was adducted with propargyl moiety through propargylation reaction. Then, the propargylated products underwent smooth copper-mediated azide-alkyne cyclization to give the triazole-bonded chalcones as the final products. They were characterized by IR, NMR and HRMS, and evaluated their radical scavenging activity against 2,2-diphenyl-1-picrylhydrazyl (DPPH). Among the tested products, compound 4by was denoted as the most potent derivative which can inhibit DPPH radical in 91.62 ± 0.10% at 500 ppm.•Acetophenone as a simple ketone was modified to triazole-bonded chalcones.•Modification was performed through three steps reaction.•Final products exhibited free radical scavenging activity.

Synthesis of carbohydrate–BODIPY hybrids

Abstract Owing to the relevance of fluorescently labeled carbohydrates in the study of biological processes, we have investigated several routes for the preparation of saccharides covalently linked to borondipyrromethene (BODIPY) fluorophores. We have shown that BODIPY dyes can be used as aglycons through synthetic saccharide protocols. In particular, a per-alkylated 8-(2-hydroxy-methylphenyl)-4,4′-dicyano-BODIPY derivative, which withstands glycosylation and protection/deprotection reaction conditions without decomposition, has been used in the stepwise synthesis of two fluorescently labeled trisaccharides. These saccharides displayed high water solubility and a low tendency to (H-)aggregation, a phenomenon that causes loss of photophysical efficiency in BODIPYs. Two additional synthetic strategies toward glyco-BODIPYs have also been described. The first method relies on a Ferrier-type C-glycosylation of the BODIPY core, leading to linker-free carbohydrate–BODIPY hybrids. Secondly, the application of the Nicholas propargylation reaction to 1,3,5,7-tetramethyl BODIPYs provides access to 2,6-dipropargylated BODIPYs that readily undergo CuAAC reactions with azido-containing sugars. From a photophysical standpoint, the BODIPY-labeled saccharides could be used as stable and fluorescent water-soluble chromophores, thereby addressing one of the current challenges in molecular imaging.

Radical–Radical Reactions in Molecular Weight Growth: The Phenyl + Propargyl Reaction

The mechanism for hydrocarbon ring growth in sooting environments is still the subject of considerable debate. The reaction of phenyl radical (C6H5) with propargyl radical (H2CCCH) provides an important prototype for radical-radical ring-growth pathways. We studied this reaction experimentally over the temperature range of 300-1000 K and pressure range of 4-10 Torr using time-resolved multiplexed photoionization mass spectrometry. We detect both the C9H8 and C9H7 + H product channels and report experimental isomer-resolved product branching fractions for the C9H8 product. We compare these experiments to theoretical kinetics predictions from a recently published study augmented by new calculations. These ab initio transition state theory-based master equation calculations employ high-quality potential energy surfaces, conventional transition state theory for the tight transition states, and direct CASPT2-based variable reaction coordinate transition state theory (VRC-TST) for the barrierless channels. At 300 K only the direct adducts from radical-radical addition are observed, with good agreement between experimental and theoretical branching fractions, supporting the VRC-TST calculations of the barrierless entrance channel. As the temperature is increased to 1000 K we observe two additional isomers, including indene, a two-ring polycyclic aromatic hydrocarbon, and a small amount of bimolecular products C9H7 + H. Our calculated branching fractions for the phenyl + propargyl reaction predict significantly less indene than observed experimentally. We present further calculations and experimental evidence that the most likely cause of this discrepancy is the contribution of H atom reactions, both H + indenyl (C9H7) recombination to indene and H-assisted isomerization that converts less stable C9H8 isomers into indene. Especially at low pressures typical of laboratory investigations, H-atom-assisted isomerization needs to be considered. Regardless, the experimental observation of indene demonstrates that the title reaction leads, either directly or indirectly, to the formation of the second ring in polycyclic aromatic hydrocarbons.

Chiral aldehyde-nickel dual catalysis enables asymmetric α−propargylation of amino acids and stereodivergent synthesis of NP25302

The combined catalytic systems derived from organocatalysts and transition metals exhibit powerful activation and stereoselective-control abilities in asymmetric catalysis. This work describes a highly efficient chiral aldehyde-nickel dual catalytic system and its application for the direct asymmetric α−propargylation reaction of amino acid esters with propargylic alcohol derivatives. Various structural diversity α,α−disubstituted non-proteinogenic α−amino acid esters are produced in good-to-excellent yields and enantioselectivities. Furthermore, a stereodivergent synthesis of natural product NP25302 is achieved, and a reasonable reaction mechanism is proposed to illustrate the observed stereoselectivity based on the results of control experiments, nonlinear effect investigation, and HRMS detection.

The role of radical-radical chain-propagating pathways in the phenyl + propargyl reaction

Well-skipping radical-radical reactions can provide a chain-propagating pathway for formation of polycyclic radicals implicated in soot inception. Here we use controlled pyrolysis in a microreactor to isolate and examine the role of well-skipping channels in the phenyl (C6H5) + propargyl (C3H3) radical-radical reaction at temperatures of 800–1600 K and pressures near 25 Torr. The temperature and concentration dependence of the closed-shell (C9H8) and radical (C9H7) products are observed using electron-ionization mass spectrometry. The flow in the reactor is simulated using a boundary layer model employing a chemical mechanism based on recent rate coefficient calculations. Comparison between simulation and experiment shows reasonable agreement, within a factor of 3, while suggesting possible improvements to the model. In contrast, eliminating the well-skipping reactions from the chemistry mechanism causes a much larger discrepancy between simulation and experiment in the temperature dependence of the radical concentration, revealing that the well-skipping pathways, especially to form indenyl radical, are significant at temperatures of 1200 K and higher. While most C9H7 forms by well-skipping at 25 Torr, an additional simulation indicates that the well-skipping channels only contribute around 3% of the C9Hx yield at atmospheric pressure, thus indicating a negligible role of the well-skipping pathways at atmospheric and higher pressures.

Multichannel Radical-Radical Reaction Dynamics of NO + Propargyl Probed by Broadband Rotational Spectroscopy.

Chirped-pulse rotational spectroscopy in a quasi-uniform flow has been used to investigate the reaction dynamics of a multichannel radical-radical reaction of relevance to planetary atmospheres and combustion. In this work, the NO + propargyl (C3H3) reaction was found to yield six product channels containing eight detected species. These products and their branching fractions (%), are as follows: HCN (50), HCNO (18), CH2CN (12), CH3CN (7.4), HC3N (6.2), HNC (2.3), CH2CO (1.3), HCO (1.8). The results are discussed in light of previous unimolecular photodissociation studies of isoxazole and prior potential energy surface calculations of the NO + C3H3 system. The results also show that the product branching is strongly influenced by the excess energy of the reactant radicals. The implications of the title reaction to the planetary atmospheres, particularly to Titan, are discussed.

CHEMICAL MODIFICATION OF NAFTALINE-1-IL-BIS(SODIUM CARBAMODITHIOATE)

Interest in numerous naphthylamine derivatives is due to a wide range of their biological activity (growth-stimulating, antimicrobial, anticancer, antiviral, antihypertensive, antidiabetic, etc.). The aim of the workis the synthesis of biologically active N,S,O-containing substances in the series of acetylenic, alkoxy- and aroxyalkyl esters of naphthylamine. Study of acylation, propargylation and alkylation reactions of naphthalene-1-yl-bis(sodium carbamodiothioate). Methodology. New derivatives of naphthylbisdithiocarbamic acid were synthesized as a result of the modification of disubstituted α-naphthylaminedithiocarbamate. It was shown that the interaction of α-naphthylaminebisdithiocarbamate with benzoic acid chloride, propargyl bromide and alkyl halides (2-methoxyethyl, 2-ethoxyethyl, 2-phenoxyethyl, 3-phenoxypropyl) leads to the formation of the corresponding thioanhydride, dithioacetylenic, alkoxy- and aroxyalkyl esters of naphthylbisdithiocarbamic acid. Synthesis was carried out in acetone at room temperature for 1.5 – 3 h. Reaction coursewas monitored by TLC method. Results and discussion. It was established that propargylation, acylation and alkylation reactions of α-naphthylaminedithiocarbamine derivative proceed easily and with high yields (66 − 91%). The structure of the synthesized compounds was established based on the data of elemental analysis and 1H and 13C NMR spectroscopy. Thus, were synthesized new potentially biologically active naphthylbisdithiocarbamic acid derivatives, combining pharmacophore groups in their structure.

Study on synthesis of some substituted N-propargyl isatins by propargylation reaction of corresponding isatins using potassium carbonate as base under ultrasound- and microwave-assisted conditions

Study on synthesis of some substituted N-propargyl isatins by propargylation reaction of corresponding isatins using potassium carbonate as base under ultrasound- and microwave-assisted conditions

Total Synthesis of Ritterazine B.

The first total synthesis of the cytotoxic alkaloid ritterazine B is reported. The synthesis features a unified approach to both steroid subunits, employing a titanium-mediated propargylation reaction to achieve divergence from a common precursor. Other key steps include gold-catalyzed cycloisomerizations that install both spiroketals and late stage C-H oxidation to incorporate the C7' alcohol.

First aromatic ring formation by the radical-chain reaction of vinylacetylene and propargyl

Abstract Recent investigations illustrated that clustering of hydrocarbons by radical-chain reaction (CHRCR) mechanism provides key mechanistic steps for the rapid synthesis of polycyclic aromatic hydrocarbons (PAHs) and soot. Resonance-stabilized radicals (RSRs) play critical roles in this mechanism, and non-benzene first-ring species have attracted considerable attention as precursors of larger aromatic hydrocarbons. C7H7 RSRs, such as benzyl, tropyl, vinyl-cyclopentadienyl, are particularly stable and are thus quite important in the growth of PAHs. The addition of vinylacetylene to propargyl radical, a prototypical CHRCR reaction, provides a facile route to C7H7 RSRs. We have directly investigated the reaction of propargyl and vinylacetylene in isomer-resolved elementary experiments by synchrotron vacuum ultra-violet photoionization molecular beam mass spectrometry (SVUV-PI-MBMS). In good agreement with theoretical predictions, vinyl-cyclopentadienyl is found to be the major product of vinylacetylene and propargyl reaction while benzyl is minor. This work demonstrates a feasible CHRCR pathway, not proceeding through benzene, for PAH formation.

Effects of pressure on soot formation in laminar coflow methane/air diffusion flames doped with n-heptane and toluene between 2 and 8 atm

There is currently a lack of adequate understanding of soot formation in flames fueled with liquid hydrocarbons at elevated pressures. In this study, laminar coflow n-heptane and toluene doped CH4/air diffusion flames were numerically investigated under a constant carbon mass flow rate at pressures between 2 and 8 atm to understand how pressure affects the sooting propensity of these two main components of surrogate fuels mimicking gasoline. Numerical simulations were performed using a detailed reaction mechanism containing 175 species and 1175 reactions and a sectional soot model. Soot inception is modeled by collisions among pyrene, BAPYR and BGHIF. Soot surface growth and oxidation are modeled using the hydrogen abstraction acetylene addition (HACA) mechanism as well as PAH surface condensation. The predicted sensitivity of soot production to pressure is in better agreement with the measurements of Daca and Gülder (2017) when the soot aging effect is considered in HACA surface growth. The predicted soot concentrations are in overall good agreement with measurements. Propargyl recombination and propargyl reaction with propyne are important pathways for the formation of benzene. In methane+toluene flames, attack of toluene by H radical is an effective benzene formation pathway low in the flame, but the relative importance of benzene formation from toluene is reduced with increasing pressure. Although all the soot formation processes are enhanced with increasing pressure, PAH condensation is enhanced the most, followed by HACA and inception. At 6 and 8 atm, PAH condensation becomes comparable to HACA. The pressure dependence of the sooting propensity follows the order of methane+toluene < methane+n-heptane < methane, consistent with measurements. This result can be explained by the pressure dependence of benzene formation pathways, the kinetic effect of pressure, and the scrubbing effect of soot production on the gas-phase species involved in soot formation.

Stitching alkynes into bryostatin 3

Organic Chemistry The bryostatin family of marine natural products has been explored for a wide variety of pharmaceutical applications but remains challenging to source. The general structure comprises a macrocycle that contains three smaller, six-membered rings. Bryostatin 3 is distinguished by the added complexity of a fourth, fused lactone ring. Trost et al. report a convergent synthesis of this complex molecule, taking advantage of alkyne coupling reactions to stitch together three main fragments and asymmetric dihydroxylation and propargylation reactions to set stereochemistry. Science , this issue p. [1007][1] [1]: /lookup/doi/10.1126/science.abb7271

Stereoselective Synthesis of Dysoxylactam A.

The first report on the stereoselective synthesis of dysoxylactam A is disclosed. The five stereogenic centers of the fatty acid chain are created by utilizing Merck-Carreira and Marshall's propargylation reaction, Evans' alkylation methodology, and Noyori's transfer hydrogenation protocol.