Propargylic Acetates Research Articles

Highly Diastereo‐ and Enantioselective Copper‐Catalyzed Dipropargylic Amination to Access Bispropargylic Diamines

AbstractHerein we described the diastereo‐ and enantioselective copper‐catalyzed dipropargylic amination between propargylic acetates and diamines. The reaction features readily available substrates and broad functional group compatibility, as well as mild reaction conditions. Various synthetically valuable chiral bispropargylic diamines can be furnished in high yields with good to excellent diastereo‐ and enantioselectivities (up to 98% yield, >95 : 5 dr, >99% ee). The products further can be transformed into chiral bispropargylic diamines containing two internal alkyne groups and novel potential C2‐symmetric chiral tetraaza ligands without any loss of diastereo‐ and enantioselectivity.

Dual Palladium/Copper-Catalyzed anti-Selective Intermolecular Allenylsilylation of Terminal Alkynes: Entry to (E)-Silyl Enallenes.

A palladium-/copper-cocatalyzed three-component trans-allenylsilylation of terminal alkynes with propargyl acetates and PhMe2SiBpin is described, which is driven by the regioselective allenylation of the alkyne with propargyl acetates and then silylation. This method allows the simultaneous incorporation of an allene and silicon across the C≡C bond and provides a highly chemo-, regio-, and stereoselective alkyne difunctionalization route to the synthesis of valuable (E)-silyl enallenes. The utility of this method is highlighted by late-stage derivatization of bioactive compounds.

Toward Continuous-Flow Hyperpolarisation of Metabolites via Heterogenous Catalysis, Side-Arm-Hydrogenation, and Membrane Dissolution of Parahydrogen.

Side-arm hydrogenation (SAH) by homogeneous catalysis has extended the reach of the parahydrogen enhanced NMR technique to key metabolites such as pyruvate. However, homogeneous hydrogenation requires rapid separation of the dissolved catalyst and purification of the hyperpolarised species with a purity sufficient for safe in-vivo use. An alternate approach is to employ heterogeneous hydrogenation in a continuous-flow reactor, where separation from the solid catalysts is straightforward. Using a TiO2 -nanorod supported Rh catalyst, we demonstrate continuous-flow parahydrogen enhanced NMR by heterogeneous hydrogenation of a model SAH precursor, propargyl acetate, at a flow rate of 1.5 mL/min. Parahydrogen gas was introduced into the flowing solution phase using a novel tube-in-tube membrane dissolution device. Without much optimization, proton NMR signal enhancements of up to 297 (relative to the thermal equilibrium signals) at 9.4 Tesla were shown to be feasible on allyl-acetate at a continuous total yield of 33 %. The results are compared to those obtained with the standard batch-mode technique of parahydrogen bubbling through a suspension of the same catalyst.

Enantioselective Three-Component Coupling of Heteroarenes, Cycloalkenes and Propargylic Acetates.

Asymmetric coupling proceeds efficiently between propargylic acetates, cycloalkenes and electron-rich heteroarenes including indoles, pyrroles, activated furans and thiophenes. 2,3-Disubstituted tetrahydrofurans and pyrrolidines are produced in trans configuration and excellent enantiomeric ratios. The reaction proceeds via Wacker-type attack of nucleophilic heteroarenes on alkenes activated by allenyl PdII species.

Enantioselective Three‐Component Coupling of Heteroarenes, Cycloalkenes and Propargylic Acetates

AbstractAsymmetric coupling proceeds efficiently between propargylic acetates, cycloalkenes and electron‐rich heteroarenes including indoles, pyrroles, activated furans and thiophenes. 2,3‐Disubstituted tetrahydrofurans and pyrrolidines are produced in trans configuration and excellent enantiomeric ratios. The reaction proceeds via Wacker‐type attack of nucleophilic heteroarenes on alkenes activated by allenyl PdII species.

Selectivity for Alkynyl or Allenyl Imidamides and Imidates in Copper-Catalyzed Reactions of Terminal 1,3-Diynes and Azides.

Copper-catalyzed reactions of terminal 1,3-diynes with electron-deficient azides to generate either 3-alkynyl or 2,3-dienyl imidamides and imidates are described. The selectivity depends on the diyne substituents and the nucleophile that reacts with the ketenimide intermediate generated from the corresponding triazole precursor. Reactions of 1,3-diynes containing a propargylic acetate afford [3]cumulenyl imidamides, while reactions using methanol as the trapping agent selectively generate 2,3-dienyl imidates. Five-membered heterocycles were obtained from 1,3-diynes containing a homopropargylic hydroxyl or amine substituent.

A Rh(iii)-catalyzed C–H activation/regiospecific annulation cascade of benzoic acids with propargyl acetates to unusual 3-alkylidene-isochromanones

We developed a new approach to synthesize isochromanones with benzoic acids and propargyl acetates, which introducing an unusual exocyclic C–C double bond at the 3-position with high regioselectivity and moderate to excellent yields.

Pentannulation of N-heterocycles by a tandem gold-catalyzed [3,3]-rearrangement/Nazarov reaction of propargyl ester derivatives: a computational study on the crucial role of the nitrogen atom.

The tandem gold(I)-catalyzed rearrangement/Nazarov reaction of enynyl acetates in which the double bond is embedded in a piperidine ring was computationally and experimentally studied. The theoretical calculations predict that the position of the propargylic acetate substituent has a great impact on the reactivity. In contrast to our previous successful cyclization of the 2-substituted substrates, where the nitrogen favors the formation of the cyclized final product, the substitution at position 3 was computed to have a deleterious effect on the electronic properties of the molecules, increasing the activation barriers of the Nazarov reaction. The sluggish reactivity of 3-substituted piperidines predicted by the calculations was further confirmed by the results obtained with some designed substrates.

Au(I)-catalyzed cycloaddition pathways of non-terminal propargyl substrates

Novel chiral menthol-based pyridyl nitrone ligands were synthesized and Au(I) coordination of the ligands gave chiral Au(I)–nitrone complexes. 1H NMR studies of the gold(I) coordination experiments with nitrone ligands afforded a convenient method for monitoring complex formation. The catalytic effect of Au(I)–nitrone complexes, shown to tune catalytic systems to produce uncommon products, was evaluated in [2 + 2 + 2] cyclotrimerization and [2 + 4] cyclodimerization reactions of non-terminal propargyl acetals. Alternative gold(I)-catalyzed [2 + 2], [2 + 4] and [3 + 4] cycloaddition reaction pathways of non-terminal propargyl acetals with imine substrates gave a diverse range of N-heterocyclic products. The present screening study demonstrates the potential and the versatility of non-terminal propargyl acetals in gold(I)-catalyzed cycloaddition reactions.

Rhodium(III)-Catalyzed [4+3] Annulation of N-Aryl-pyrazolidinones and Propargylic Acetates: Access to Benzo[c][1,2]diazepines.

The generation of 2,3-dihydro-benzo[c][1,2]diazepine derivatives via rhodium(III)-catalyzed [4+3] annulation of pyrazolidinones and propargylic acetates is disclosed. The reaction proceeds smoothly under relatively mild conditions from propargylic acetates as novel C3 synthons. A range of dinitrogen-fused heterocyclic compounds are readily accessed by this approach.

Synthesis, in vitro antimicrobial assessment, and computational investigation of pharmacokinetic and bioactivity properties of novel trifluoromethylated compounds using in silico ADME and toxicity prediction tools

1,3-Dipolar cycloaddition reactions of a sugar-based trifluoromethylated nitrone-to-maleimide and allyl bromide afforded a series of cycloadducts in good yield. The same nitrone reacts with propargyl acetate lead, after rearrangement of 4-isoxazoline, to aziridine with good yield. The obtained compounds were evaluated for their in vitro antimicrobial potency. Additionally, we are interested in predicting their physicochemical parameters such as lipophilicity and bioactivity score as well as their pharmacokinetic properties such as absorption, distribution, metabolism, and excretion (ADME) such as plasma protein binding (PPB) penetration of the blood–brain barrier (BBB), human intestinal absorption (HIA), cellular permeability (PCaco-2), cell permeability of Madin–Darby canine kidney (PMDCK), P-glycoprotein (P-gp) efflux, CYP inducers, substrates and inhibitors’ skin and permeability (PS), and their toxicological behavior [mutagenicity, carcinogenicity, acute, environmental, cardiotoxicity (hERG inhibition)] using in silico computational methods. Also, we aimed to validate QSAR models for the elucidation of their antitarget using 32 sets of end-points (IC50, Ki and Kact). The obtained result provides good information about the pharmacotherapy potential and toxicity of the examined molecules with good compliance between in vitro antimicrobial and the predicted properties. Findings indicated and encouraged the use of these compounds and their derivatives for further in vivo evaluations in the design and the elucidation of the intrinsic mechanisms as well as the efficacy of the selected powerful drug.

A heterogeneous gold(I)-catalyzed regioselective hydration of propargyl acetates toward α-acyloxy methyl ketones

A heterogeneous gold(I)-catalyzed regioselective hydration of propargyl acetates has been developed that proceeds smoothly in 1,4-dioxane at room temperature in the presence of 1 mol% diphenylphosphine-modified MCM-41-anchored gold(I) complex [Ph2P-MCM-41-AuSbF6] as catalyst and provides an efficient and practical approach for the synthesis of a variety of α-acyloxy methyl ketones with high atom economy, good to excellent yield, and high functional group tolerance. This new immobilized gold(I) catalyst can readily be obtained by a simple preparative procedure from commercially available reagents, and recovered via a filtration process and reused at least seven times without apparent loss of activity.

Copper-Catalyzed Asymmetric Propargylic Alkylation with Oxindoles: Diastereo- and Enantioselective Construction of Vicinal Tertiary and All-Carbon Quaternary Stereocenters

A copper-catalyzed asymmetric propargylic alkylation of propargylic acetates with 3-substituted oxindoles for the stereoselective construction of vicinal tertiary and all-carbon quaternary stereocenters in a 3,3-disubstituted oxindole skeleton has been realized. The reaction proceeded smoothly under the catalysis of Cu(MeCN)4PF6 combined with a chiral tridentate ferrocenyl P,N,N ligand, leading to a broad range of optically active 3,3-disubstituted oxindoles in high yields and with excellent diastereo- and enantioselectivities.

Correction: Pd-Catalyzed oxidative isomerization of propargylic acetates: highly efficient access to α-acetoxyenones via alkenyl Csp2–O bond-forming reductive elimination from PdIV

Correction for 'Pd-Catalyzed oxidative isomerization of propargylic acetates: highly efficient access to α-acetoxyenones via alkenyl Csp2-O bond-forming reductive elimination from PdIV' by Jun Li et al., Chem. Commun., 2016, 52, 10644-10647, DOI: 10.1039/C6CC04463H.

Total Synthesis of (-)-Graminin A Based on Asymmetric Cyclization Carbonylation of Propargyl Acetate.

The first total synthesis of (-)-graminin A is described. Key features of our synthetic approach involve a palladium-catalyzed asymmetric cyclization carbonylation of prochiral propargylic acetate, conversion of the orthoester product into methyl 4-oxo-3-furancarboxylate, and copper complex-mediated aldol condensation of (+)-gregatin B bearing a diene moiety. A new synthesis of (+)-gregatin B and the first synthesis of (-)-graminin A were achieved.

Trialkylborane-Mediated Propargylation of Aldehydes Using γ-Stannylated Propargyl Acetates.

A transition-metal-free three-component process that combines aldehydes, 3-(tributylstannyl)propargyl acetates formed in situ from readily available propargyl acetates, and trialkylboranes provides access to a range of 1,2,4-trisubstituted homopropargylic alcohols. The addition of diisopropylamine plays a crucial role in the selective formation of homopropargylic alcohols. Importantly, this methodology can be extended to a single-flask reaction sequence starting from propargyl acetates.

Copper-catalyzed formal propargylic [3 + 2] cycloaddition for stereoselective construction of (E)-β-pyrazolylacrylates

A copper-catalyzed formal propargylic [3 + 2] cycloaddition between propargylic acetates and 3-(2-tosylhydrazono)propanoates for the synthesis of (E)-β-substituted-β-pyrazolylacrylates has been realized. The reaction showed broad substrate scope and excellent stereoselectivities, thus leading to a variety of (E)-β-substituted-β-pyrazolylacrylates in moderate to good yields. The employment of a tridentate diPh-pybox ligand proved to be crucial for the success of the reaction.

Copper-catalyzed asymmetric propargylic etherification of oximes promoted by chiral tridentate P,N,N-ligand

A copper-catalyzed asymmetric etherification of propargylic acetates with oximes as O-nucleophiles has been developed. The employment of a chiral tridentate P,N,N-ligand proved to be crucial for the success of the reaction. The reaction features a broad scope on either reaction partners and led to a variety of etherification products in good yields and enantioselectivities.

Iron-Catalyzed C-H Activation with Propargyl Acetates: Mechanistic Insights into Iron(II) by Experiment, Kinetics, Mössbauer Spectroscopy, and Computation.

An iron‐catalyzed C−H/N−H alkyne annulation was realized by using a customizable clickable triazole amide under exceedingly mild reaction conditions. A unifying mechanistic approach combining experiment, spectroscopy, kinetics, and computation provided strong support for facile C−H activation by a ligand‐to‐ligand hydrogen transfer (LLHT) mechanism. Combined Mössbauer spectroscopic analysis and DFT calculations were indicative of high‐spin iron(II) species as the key intermediates in the C−H activation manifold.

Front Cover: Formal Halo‐Meyer–Schuster Rearrangement of Propargylic Acetates through a Novel Intermediate and an Unexampled Mechanistic Pathway (Chem. Eur. J. 42/2019)

Front Cover: Formal Halo‐Meyer–Schuster Rearrangement of Propargylic Acetates through a Novel Intermediate and an Unexampled Mechanistic Pathway (Chem. Eur. J. 42/2019)