Dialkyl Acetylene Research Articles

Synthesis of 1,3-Enynes by Iron-Catalyzed Propargylic C-H Functionalization: An Alkyne Analogue for the Eschenmoser Methenylation.

A two-step protocol for the conversion of alkyl-substituted alkynes to 1,3-enynes is reported. In this α-methenylation process, an iron-catalyzed propargylic C-H functionalization delivers tetramethylpiperidine-derived homopropargylic amines which undergo facile Cope elimination upon N-oxidation to afford the enyne products. A range of aryl alkyl and dialkyl acetylenes were found to be suitable substrates for this process, which constitutes an alkyne analogue for the Eschenmoser methenylation of carbonyl derivatives. In addition, a new bench-stable precatalyst for iron-catalyzed propargylic C-H functionalization is reported.

Enantioselective and Regiodivergent Synthesis of Propargyl‐ and Allenylsilanes through Catalytic Propargylic C−H Deprotonation

AbstractWe report a highly enantioselective intermolecular C−H bond silylation catalyzed by a phosphoramidite‐ligated iridium catalyst. Under reagent‐controlled protocols, propargylsilanes resulting from C(sp3)−H functionalization, as well the regioisomeric and synthetically versatile allenylsilanes, could be obtained with excellent levels of enantioselectivity and good to excellent control of propargyl/allenyl selectivity. In the case of unsymmetrical dialkyl acetylenes, good to excellent selectivity for functionalization at the less‐hindered site was also observed. A variety of electrophilic silyl sources (R3SiOTf and R3SiNTf2), either commercial or in situ‐generated, were used as the silylation reagents, and a broad range of simple and functionalized alkynes, including aryl alkyl acetylenes, dialkyl acetylenes, 1,3‐enynes, and drug derivatives were successfully employed as substrates. Detailed mechanistic experiments and DFT calculations suggest that an η3‐propargyl/allenyl Ir intermediate is generated upon π‐complexation‐assisted deprotonation and undergoes outer‐sphere attack by the electrophilic silylating reagent to give propargylic silanes, with the latter step identified as the enantiodetermining step.

Enantioselective and Regiodivergent Synthesis of Propargyl- and Allenylsilanes through Catalytic Propargylic C-H Deprotonation.

We report a highly enantioselective intermolecular C-H bond silylation catalyzed by a phosphoramidite-ligated iridium catalyst. Under reagent-controlled protocols, propargylsilanes resulting from C(sp3)-H functionalization, as well the regioisomeric and synthetically versatile allenylsilanes, could be obtained with excellent levels of enantioselectivity and good to excellent control of propargyl/allenyl selectivity. In the case of unsymmetrical dialkyl acetylenes, good to excellent selectivity for functionalization at the less-hindered site was also observed. A variety of electrophilic silyl sources (R3SiOTf and R3SiNTf2), either commercial or in situ-generated, were used as the silylation reagents, and a broad range of simple and functionalized alkynes, including aryl alkyl acetylenes, dialkyl acetylenes, 1,3-enynes, and drug derivatives were successfully employed as substrates. Detailed mechanistic experiments and DFT calculations suggest that an η3-propargyl/allenyl Ir intermediate is generated upon π-complexation-assisted deprotonation and undergoes outer-sphere attack by the electrophilic silylating reagent to give propargylic silanes, with the latter step identified as the enantiodetermining step.

Iron‐Catalyzed Alkenylzincation of Internal Alkynes†

Comprehensive SummaryThe alkenylzincation of internal alkynes is an effective method for the synthesis of multi‐substituted conjugated dienes; however, the current catalytic systems for this reaction are limited in terms of substrate scope and selectivity control, which restricts its practical applications. Herein, we report the first iron‐catalyzed alkenylzincation of internal alkynes, which features mild conditions, simple operation, broad substrate scope (including aryl/alkyl, diaryl, and dialkyl acetylenes), excellent functional group tolerance (tolerating highly active functional groups such as ester, methylthio, amide, sulfonyl, cyano, etc.), and high activity (with a turnover number of up to 11500, the highest record for carbometallation reactions). Notably, the catalytic system described in this article also realized the highly selective vinylzincation of unfunctionalized internal alkynes as well as the alkenylzincation of unsymmetrical diarylacetylenes and dialkyl acetylenes, which have not been achieved with other catalytic systems reported in the literatures. The current study provides a highly selective access to synthetically important multi‐substituted conjugated dienes.

Design, synthesis and biological evaluation of spiroisoquinoline-pyrimidine derivatives as anticancer agents against MCF-7 cancer cell lines

Quinoline derived scaffolds have long been reported for their promising biological responses such as anti-Alzheimer, antituberculosis, antioxidants, anti-inflammatory etc. Pyrimidine, a versatile pharmacophore, has also been employed for developing a variety of bioactive molecules. Therefore, we envisioned to incorporate these two privileged moieties into a single one for improved biological applications. In this work, we developed an efficient catalyst free synthesis of spiroisoquinlino-pyrimidine conjugates via one-pot multicomponent reaction of various 1,3-dicarbonyls, isoquinoline and dialkyl acetylene dicarboxylates. We further evaluated antiproliferative activity of all the compounds against MCF-7 human breast cancer cells. Out of several compounds synthesized, three compounds IVc, IVg and IVi having substituent methyl and dioxyl ring in molecule have shown potent anticancer activity. The most potent cytotoxic compound against breast cancer cells in our study was found to be IVi with IC50 value of 98.8 μM.

Synthesis of new functionalized maleimides and phthalimides from maleimide, phthalimide, acetylenicesters, and phosphorus nucleophiles

An efficient and convenient three-component reaction of dialkyl acetylene dicarboxylates with trialkyl(aryl) phosphites in the presence of maleimide or phthalimide provides a straightforward approach to the synthesis of stable dialkyl(aryl) phosphoryl succinates in excellent yields. While the reactions were carried out in the presence of triphenylphosphine, stabilized phosphoranes, obtained from three component reaction, undergo a smooth intramolecular Wittig reaction in boiling toluene to produce functionalized 2H-pyrrol-2-ones in good yields.

The stannylvinyl cation that never was! New concentration- and temperature-dependent probe studies confirm an entirely free radical mechanism and O–Sn coordinative control of the hydrostannation of propargylically-oxygenated dialkyl acetylenes with stannanes and cat. Et3B

O-Directed free radical hydrostannation of the β-cyclopropyl propargyl alcohol 57 with stannanes and cat. Et3B in THF/H2O or PhMe/MeOH failed to deliver any of the expected products of α-stannylvinyl cation capture. Instead only α-stannyl-β-cyclopropylvinyl radical intermediates were detected, which underwent fast H-atom abstraction and/or cyclopropane ring-opening as a result of eliminative β-scission. A second alkynol probe 23 was also studied in this O-directed free radical hydrostannation process. It gave rise to an α:β stannyl radical addition regiochemistry that changed markedly in favor of the α-adduct (26) when the reaction was conducted at high stannane concentrations. This outcome confirmed that O–Sn coordinative control must be responsible for the strong α-regiochemical preference of hydrostannations run at higher stannane concentrations, since a non-coordinative, electronically-controlled, stannyl radical addition would always give rise to a fixed and identical ratio of α:β-regioisomers. The formation of 27 further confirmed the exclusively free radical nature of these reactions.

An Efficient Phosphotungstic Acid Catalysed Synthesis of 4,5‐Dioxopyrrolidines and Study of the Mechanistic Effect of the Solvent on the Reaction

AbstractAn efficient protocol for the synthesis of dioxopyrrolidine scaffolds has been established using phosphotungstic acid as an effective catalyst in a multicomponent reaction of aromatic primary amines, dialkyl acetylene dicarboxylates and formaldehyde at room temperature in alcohol as a green solvent. In this methodology, the reactant solvent has an important part and is involved in the reaction mechanism to increase the versatility of the product. This protocol involves environment friendly, cost effective methodology with a comparatively simple reaction mechanism.

ONE POT MULTICOMPONENT SYNTHESIS OF HIGHLY FUNCTIONALIZED PYRIDINES USING MORPHOLINE ORGANOBASE CATALYST

An atom efficient synthesis of polysubstituted dihydropyridine derivatives was accomplished by the one-pot four-component condensation of aldehydes, amines, dialkyl acetylene dicarboxylates and active methylene group-containing compounds such as malononitrile or ethyl cyanoacetate using morpholine as a catalyst at ambient temperature. Broad substrate scope, non-chromatographic purification, good yields of the products makes it be a useful and valuable methodology for employing the 1,4-dipolar intermediates in synthetic organic chemistry. Use of organobase as a single catalyst, room temperature conditions renders the method protocol as a significant addition to the existing methods for the synthesis of multifunctionalized dihydropyridines.

Fast ring-opening of an intermediary α-stannyl-β-cyclopropylvinyl radical does not support formation of an α-stannylvinyl cation in the O-directed free radical hydrostannation of dialkyl acetylenes.

O-directed hydrostannation of β-cyclopropyl propargyl alcohol 22 with stannanes and cat. Et3B in THF/H2O or PhMe/MeOH fails to deliver any detectable products of α-stannylvinyl cation capture. Instead only α-stannyl-β-cyclopropylvinyl radical intermediates can be detected, which undergo fast H-atom abstraction and/or cyclopropane ring-opening as a result of eliminative β-scission.

The O‐Directed Free Radical Hydrostannation of Propargyloxy Dialkyl Acetylenes with Ph3SnH/cat. Et3B. A Refutal of the Stannylvinyl Cation Mechanism

In this Personal Account, we will give an overview of the room temperature O-directed free radical hydrostannation reaction of propargylically-oxygenated dialkyl acetylenes with Ph3 SnH and catalytic Et3 B/O2 in PhMe. We will show how this excellent reaction evolved, and how it has since been used to stereoselectively construct the complex trisubstituted olefin regions of three synthetically challenging natural product targets: (+)-pumiliotoxin B, (-)-(3R)-inthomycin C, and (+)-acutiphycin. Throughout this Account, we will pay special attention to highlighting important facets of the I-SnPh3 exchange processes that have so far been used in the various different steric settings that we have addressed, and we will document the range of cross coupling protocols that have critically underpinned the first successful applications of this method in complex natural product total synthesis. Last, but not least, we will comment on various aspects of the O-directed free radical hydrostannation mechanism that have been published by ourselves, and others, and we will discuss all of the factors that can contribute to the observed stereo-and regio-chemical outcomes. We will also challenge and refute the recent non-directed stannylvinyl cation mechanism put forward by Organ, Oderinde and Froese for our reaction, and we will show how it cannot be operating in these exclusively free radical hydrostannations.

Synthesis of Novel Functionalized Triphenylphosphanylidene‐Spirobarbiturates through a Three‐Component Reaction

AbstractSynthesis of novel functionalized triphenylphosphanylidene‐7,9‐diazaspiro[4.5]dec‐1‐ene‐2‐carboxylates has been reported by one‐pot three component reactions of triphenyl phosphine, dialkyl acetylene dicarboxylates, and 5‐arylidene‐1,3‐dimethylpyrimidine‐2,4,6‐triones in THF at room temperature. The products are obtained in high yields and have been fully characterized. The structure has been further confirmed by X‐ray analysis of single crystal of one of the compounds.

A Phosphine-mediated Synthesis of 2,3,4,5-tetra-substituted N-hydroxypyrroles from α-oximino Ketones and Dialkyl Acetylenedicarboxylates Under Ionic Liquid Green-media.

The development of multicomponent reactions (MCRs) in the presence of task-specific ionic liquids (ILs), used not only as environmentally benign reaction media, but also as catalysts, is a new approach that meet with the requirements of sustainable chemistry. In recent years, the use of ionic liquids as a green media for organic synthesis has become a chief study area. This is due to their unique properties such as non-volatility, non-flammability, chemical and thermal stability, immiscibility with both organic compounds and water and recyclability. Ionic liquids are used as environmentally friendly solvents instead of hazardous organic solvents. We report the condensation reaction between α-oximinoketone and dialkyl acetylene dicarboxylate in the presence of triphenylphosphine to afford substituted pyrroles under ionic liquid conditions in good yields. Densely functionalized pyrroles was easily prepared from reaction of α-oximinoketones, dialkyl acetylene dicarboxylate in the presence of triphenylphosphine in a quantitative yield under ionic liquid conditions at room temperature. In conclusion, ionic liquids are indicated as a useful and novel reaction medium for the selective synthesis of functionalized pyrroles. This reaction medium can replace the use of hazardous organic solvents. Easy work-up, synthesis of polyfunctional compounds, decreased reaction time, having easily available-recyclable ionic liquids, and good to high yields are advantages of present method.

Alkyl Isocyanides Promoted Synthesis of Functionalized Azadienes from Dialkyl Acetylene Dicarboxylates and N-Hydroxysuccinimide

The reaction between N-Hydroxy succinimide with dialkyl acetylene dicarboxylates in the presence of isocyanides, leads to functionalized azadienes in good yields. The product were analized and the structures of reaction compounds were deduced from their IR, 1HNMR and 13CNMR spectra.

A convenient synthesis of alkyl-2-(2-imino-4-oxothiazolidin-5-ylidene)acetate derivatives involving an electrogenerated base of acetonitrile

ABSTRACTWe report a simple method for the synthesis of alkyl-2-(2-imino-4-oxothiazolidin-5-ylidene) acetate derivatives 3 in good yields under mild conditions. The electrogenerated cyanomethyl base (EGB), obtained from electroreduction of acetonitrile-0.1 M TBABF4, assists the reaction between thiourea derivatives 1 and dialkyl acetylene dicarboxylate 2. The expected products, 3/4, and the structure obtained from X-ray diffraction confirm that the main products are the five-membered heterocycles 3. Furthermore, a mechanism, to explain the reaction pathways, is proposed based on the thermodynamic and kinetic data obtained from quantum calculations.

A Highly Flexible Green Synthesis of 3,4,5-Substituted Furan-2(5H)-ones Using Nano-CdZr4(PO4)6 as Catalyst under Microwave Irradiation

ABSTRACTA concise and efficient method for the synthesis of 3,4,5-substituted furan-2 (5H)-ones was achieved through a three-component reaction of amines, dialkyl acetylene dicarboxylate, and aromatic aldehydes using nano-CdZr4(PO4)6 as catalyst under microwave irradiation. This method has several advantages such as, high efficiency, short reaction times, simple workup, and recyclability of the catalyst up to seven runs without considerable loss of activity.

Computational study on the mechanism of the three-component reaction of dimethylacetylene dicarboxylate and triphenylphosphine with 2-acetylbutyrolactone

The molecular mechanism of the three-component reaction of triphenylphosphine, dialkyl acetylene dicarboxylate, and 2-acetylbutyrolactone to synthesize the stabilized phosphorus ylide and 1,3-butadiene derivative via the intramolecular Wittig reaction has been investigated using the density functional theory method at the B3LYP/6-31G level of theory. Two possible reaction pathways have been characterized in detail to form the cyclobutene intermediate and in the next step; the cyclobutene intermediate undergoes the conrotatory ring-opening reaction to produce the 1,3-butadiene derivative along two possible pathways. The calculated results indicate that two pathways (pathways II and II-a) are the most energy favorable among all of the pathways, so they occur more than do the others. Moreover, the phosphorus ylide is more stable than the corresponding 1,3-butadiene, demonstrating that the intramolecular Wittig reaction could not easily occur at room temperature, which is in agreement with the experimental results.

ChemInform Abstract: DABCO‐Catalyzed Synthesis of 3‐Bromo‐/3‐iodo‐2H‐pyrans from Propargyl Alcohols, Dialkyl Acetylene Dicarboxylates, and N‐Bromo‐/N‐Iodosuccinimides.

The DABCO-catalyzed reaction of propargyl alcohols with dialkyl acetylene dicarboxylates and N-bromo-/N-iodosuccinimides under mild conditions has been developed. The reactions give 3-bromo-/3-iodo-2H-pyrans in up to 98% yield.

Synthesis of fused pyranocarbazolones with biological interest

Fused pyranocarbazolones were synthesized from the reactions of hydroxycarbazoles with ethyl propiolate in the presence of catalytic amount of I nCl 3. Carbalkoxypyranocarbazolones and methylenefurocarbazolones were obtained from the reactions of hydroxycarbazoles with dialkyl acetylene dicarboxylates in the presence of Ph 3P in refluxing toluene. Furanone 10a (IC 50 = 10 µM) followed by pyranocarbazolones 9a and 11b are interesting lipoxygenase inhibitors. Pyranocarbazolones 9b , 11a-b are potent anti-lipid peroxidation agents and this is correlated to the presence of the coumarin ring.

Synthesis of polysubstituted pyrroles in aqueous medium directly from nitro compounds

A novel approach for the synthesis of polysubstituted pyrroles has been followed through multicomponent reaction of nitro compounds, phenacyl bromide or its derivatives and dialkyl acetylene dicarboxylates using indium in dilute aqueous HCl at room temperature. The products are formed in high yields (75–87%) in 10–16 h.