Propargylic Alkylation Research Articles

Doubly Stereoconvergent Propargylic Alkylation of α-Cyanocarbonyls: Enantioselective Construction of Vicinal Stereocenters.

An asymmetric propargylic alkylation of α-cyanocarbonyls is developed for the first time under cooperative Cu(I) and organocatalysis. With ethynyl benzoxazinanones as the propargylic electrophile, this decarboxylative doubly stereoconvergent reaction evades alkyne hydroamination to furnish acyclic α-propargylic cyanocarbonyls, bearing vicinal tertiary and quaternary stereocenters, with high diastereo- and enantioselectivity (up to >20:1 dr and 99.5:0.5 er).

Ligand-Controlled Diastereodivergency in Propargylic Alkylation of Vinylogous Aza-Enamines: Construction of 1,3-Stereocenters.

The first diastereodivergent propargylic alkylation reaction is developed. This Cu(I)-catalyzed formal decarboxylative [4+2] cycloaddition between ethynyl benzoxazinanone and vinylogous aza-enamine delivers each diastereomer of tetrahydroquinoline derivatives, bearing 1,3-stereocenters, using either i-Pr-Pybox or BINAP as the ligand under otherwise identical reaction conditions. This is the first application of vinylogous aza-enamines in a transition metal-catalyzed transformation and the first example of the creation of 1,3-stereocenters in a propargylic substitution reaction.

Photocatalytic Aerobic Cyclization of N-Propargylamides Enabled by Selenium-π-Acid Catalysis.

A dual catalytic approach combining photocatalyst and selenium-π-acid synergy has been used to cyclized of N-propargylamides. This method offers readily access to oxazole aldehydes under chemical oxidant-free conditions with low catalyst loadings, where air acts as a terminal and gratuitous oxidant. The reaction is demonstrated with a range of substrates, including aryl and alkyl propargyl amides, and in the late-stage functionalization of several amide-containing drug molecules. Mechanistic studies suggest that the acridinium catalyst is able to oxidize diselenide and generate singlet oxygen (1 O2 ), which is responsible for this transformation.

Asymmetric Semipinacol Rearrangement Enabled by Copper-Catalyzed Propargylic Alkylation

Asymmetric Semipinacol Rearrangement Enabled by Copper-Catalyzed Propargylic Alkylation

Stereodivergent propargylic alkylation of enals via cooperative NHC and copper catalysis

Despite that asymmetric stereodivergent synthesis has experienced great success to provide unusual processes for the creation of chirality complexity, concepts appliable to asymmetric stereodivergent catalysis are still limited. The dependence on the unusual capacity of each catalyst to precisely control the reactive site planar in the region poses unparalleled constraints on this field. Here, we first demonstrate that the chiral Cu-allenylidene species can participate in the stereodivergent propargylic alkylation of enals, in concert with chiral N-heterocyclic carbenes (NHCs). Thus, all four stereoisomers were obtained with excellent enantioselectivity and diastereoselectivity (up to >99% e.e. and >95:5 d.r.) from the same starting materials by simply altering chiral Cu-Pybox complex and NHC combinations. The rich chemistry workable in the products enables the structurally diverse synthesis of chiral functional molecules and holds great potential in alkaloid synthesis, as showcased by the preparation of the key building block to access (-)-perophoramidine.

Decarboxylative Propargylic Alkylation: Synthesis of Tetrasubstituted α-Amino Acid Esters

Key words copper catalysis - amino acids esters - asymmetric synthesis - decarboxylation - propargylic alkylation

Copper-Catalyzed Decarboxylative Propargylic Alkylation of Enol Carbonates: Stereoselective Synthesis of Quaternary α-Amino Acids

A copper-catalyzed asymmetric decarboxylative propargylic alkylation of enol carbonates has been realized, allowing for the highly stereoselective formation of acyclic vicinal tri- and tetrasubstituted stereocenters. With this strategy, a series of optically active quaternary α-amino acid esters with an adjunct chiral tertiary propargylic moiety have been prepared from propargyl azlactone-enol carbonates in high yields and with good to excellent diastereo- and enantioselectivities. The success of this reaction exemplifies the high potential of the decarboxylative strategy to resolve unmet challenges present in traditional catalytic propargylic alkylation.

Collective synthesis of acetylenic pharmaceuticals via enantioselective Nickel/Lewis acid-catalyzed propargylic alkylation

Chiral acetylenic derivatives are found in many bioactive compounds and are versatile functional groups in organic chemistry. Here, we describe an enantioselective nickel/Lewis acid-catalyzed asymmetric propargylic substitution reaction from simple achiral materials under mild condition. The introduction of a Lewis acid cocatalyst is crucial to the efficiency of the transformation. Notably, we investigate this asymmetric propargylic substitution reaction for the development of a range of structurally diverse natural products. The power of this strategy is highlighted by the collective synthesis of seven biologically active compounds: (−)-Thiohexital, (+)-Thiopental, (+)-Pentobarbital, (−)-AMG 837, (+)-Phenoxanol, (+)-Citralis, and (−)-Citralis Nitrile.

Reaction of Lithiated Propargyl Ethers with Carbonyl Compounds – A Regioselective Route to Furan Derivatives

AbstractThe deprotonation of 3-aryl-substituted alkyl propargyl ethers with n-butyllithium provides an ambident anion that reacts with carbonyl compounds to provide mixtures of γ-substituted products with alkoxyallene substructure and of α-substituted propargyl ethers. The ratio of the two product types strongly depends on the solvent: in diethyl ether the γ-substituted products predominate whereas the more polar tetrahydrofuran favors the α-adducts. The primary addition products undergo 5-endo-trig or 5-endo-dig cyclizations under various reaction conditions to afford isomeric furan derivatives. The highest selectivity in favor of α-substituted products was achieved by employing a MOM-protected propargyl ether. During the protonation step no evidence for a proton shift leading to an isomeric allenyl anion was found. A brief mechanistic discussion tries to rationalize the observed regio­selectivities.

Cooperative Ni/Cu‐Catalyzed Asymmetric Propargylic Alkylation of Aldimine Esters

AbstractA novel Ni/Cu dual catalysis gives rise to fundamentally new cooperative reactivity and enables the regio‐ and enantioselective propargylic alkylation reaction. A diverse set of α‐quaternary propargylated amino ester derivatives were synthesized in good yields with excellent enantioselectivity (up to 99 % ee). This work highlights the power of cooperative catalysis, which can be expected to have broad implications in homogeneous catalysis beyond the highly valuable synthetic intermediates.

Cooperative Ni/Cu-Catalyzed Asymmetric Propargylic Alkylation of Aldimine Esters.

A novel Ni/Cu dual catalysis gives rise to fundamentally new cooperative reactivity and enables the regio- and enantioselective propargylic alkylation reaction. A diverse set of α-quaternary propargylated amino ester derivatives were synthesized in good yields with excellent enantioselectivity (up to 99 % ee). This work highlights the power of cooperative catalysis, which can be expected to have broad implications in homogeneous catalysis beyond the highly valuable synthetic intermediates.

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.

Construction of All-Carbon Quaternary Stereocenters by Palladium-Catalyzed Decarboxylative Propargylation.

A method for the construction of chiral quaternary stereocenters has been accomplished via decarboxylative palladium-catalyzed propargylic alkylation. Both pressurized sealed tubes and microwave irradiation have proven successful for this transformation, yet despite these forcing conditions a range of α-aryl,α-propargyl, and α-alkyl,α-propargyl containing all-carbon quaternary products have been synthesized in good yields and high enantioselectivities (up to 92:8 er). While palladium-catalyzed decarboxylative allylic alkylation has been well studied, this work represents the furthest advancement for the propargylic variant to date.

Nucleophilic Addition of Ketones To Acetylenes and Allenes: AQuantum-Chemical Insight.

A CBS-Q//B3 based study has been carried out to elucidate the mechanism of the KOH/DMSO superbase catalyzed ketones nucleophilic addition to alkyl propargyl and alkyl allenyl ethers yielding, along with (Z)-monoadducts, up to 26% of unexpected (E)-diadducts. The impact of different substrates (alkynes versus allenes) on the reaction mechanism has been discussed in detail. Along with the model reaction of acetone addition to propyne and allene, the addition of acetone and acetophenone to methyl propargyl and methyl allenyl ethers is considered. The limiting reaction stage of the starting ketone carbanion addition to propargyl and allenyl systems occurs with activation energies typical for vinylation of ketones. In contrast, the addition of intermediate α-carbanions to the terminal position of methyl allenyl ether is associated with unusually low activation barriers. The results obtained explain the composition of the reaction products and indicate the participation of mainly the allene form in the reaction.

Enantioconvergent Copper Catalysis: In Situ Generation of the Chiral Phosphorus Ylide and Its Wittig Reactions.

The Wittig reaction, which produces alkenes from phosphorus ylides (P-ylides) and carbonyls, is one of the most powerful tools in chemical synthesis. This Nobel Prize-winning reaction is widely used in natural product synthesis, fine chemical production (i.e., medicines and agricultural agents), and polymer functionalization. Despite these great achievements, the potential of the Wittig reaction, particularly regarding the access of chiral alkene building blocks, has not been fully exploited. The main area that requires additional exploration is the development of general and practical methods to efficiently prepare chiral P-ylides. Here, we show that highly functionalized chiral P-ylides can be easily synthesized through a copper-catalyzed asymmetric propargylic alkylation reaction from phosphonium salts and racemic propargylic esters. The subsequent Wittig reactions enable the synthesis of versatile alkene building blocks, chiral α-propargylic acrylates, and α-propargylic allenoates, with a wide substrate scope and satisfactory functional group compatibility. This transformation features inexpensive transition-metal catalysts, user-friendly conditions, easily available feedstock, and high-valued products.

Cu-Catalyzed asymmetric Friedel-Crafts propargylic alkylation of phenol derivatives.

A copper-catalyzed asymmetric Friedel-Crafts propargylic alkylation of electron-rich phenol derivatives with a variety of propargylic esters has been described. With Cu(OTf)2 decorated with a chiral tridentate ketimine P,N,N-ligand as the catalyst, asymmetric Friedel-Crafts propargylic alkylation of 3,5-dialkoxyphenol derivatives proceeded smoothly in high yields and with good to excellent enantioselectivities. The present study suggested that the presence of an electron-rich substituent on the meta-position of phenol is essential for the promotion of Friedel-Crafts propargylic alkylation, and the substrate bearing two electron-rich groups on both the 3,5-positions of phenol tends to give a satisfactory performance.

Development of a New Multifunctional Cationic Surfactant System with Corrosion Inhibiting Ability

Four alkyl propargyl bis(hydroxyethyl) ammonium surfactants with different lengths in hydrophobic tail (C8–C16) are prepared by direct alkylation of diethanolamine with alkyl bromides. The surfactants exhibit excellent surface properties. The critical micelle concentration (CMC) values of the surfactants 2c and 2d are found to be 7.63×10-4 and 1.23×10-4 mol/L, and the corresponding surface tension (γCMC) values are 31.83 and 31.69 mN/m, respectively. Furthermore, all of the synthesized propargyl quaternary ammonium salts are found to be very effective in inhibiting the corrosion of N80 steel (IE% = 92–98%). They can be used at a relatively high temperature (≥90°C) and a low concentration (0.039 wt.%). In addition, the apparent viscosity of surfactant 2d is studied at various temperatures, and it can be used as a viscoelastic surfactant up to 100°C. The synthesized surfactants possess multiple functions and have a very good compatibility with VES systems. They can be potentially used in various oil field applications such as enhanced oil recovery, fracturing, acid diversion, and well stimulation.

ChemInform Abstract: Highly Diastereo‐ and Enantioselective Copper‐Catalyzed Propargylic Alkylation of Acyclic Ketone Enamines for the Construction of Two Vicinal Stereocenters.

AbstractA highly diastereo‐/enantioselective construction of two vicinal chiral centers via the copper‐catalyzed propargylic alkylation of acyclic ketone enamines with propargylic esters by using a bulky and structurally rigid tridentate ketimine P,N,N‐ligand is developed.

ChemInform Abstract: Enantioselective Copper‐Catalyzed Decarboxylative Propargylic Alkylation of Propargylic Esters with β‐Keto Acids.

AbstractThe optimized mild reaction conditions including the chiral ligand allow the synthesis of β‐ethynyl ketones in high yields with excellent enantioselectivities.

Cooperative catalysis: enantioselective propargylic alkylation of propargylic alcohols with enecarbamates using ruthenium/phosphoramide hybrid catalysts.

The diastereo- and enantioselective propargylic alkylation of propargylic alcohols with E-enecarbamates in the presence of a catalytic amount of thiolate-bridged diruthenium complexes bearing an optically active phosphoramide moiety gives the corresponding propargylic alkylated products (up to 97 % ee).