Propargylic Carbonates Research Articles

Nickel-Catalyzed Photoredox Allenylation of Alkyl Halides.

We report a dual Ni/photoredox-catalyzed cross-coupling method for propargyl carbonates and nonactivated alkyl bromides, facilitating the synthesis of a variety of substituted allenes under mild and practical conditions. Mechanistically, the reaction integrates Ni-catalyzed activation of the propargyl electrophile via SN2' oxidative addition at Ni(I) with silyl radical-induced activation of the alkyl halide through halogen-atom transfer. This methodology provides a gentle approach for introducing allenyl groups into complex halogenated aliphatic molecules, offering further opportunities for derivatization.

Nickel-Catalyzed Asymmetric (3 + 2) Annulations of Propargylic Carbonates and Vinylogous Donors via an Alkenylation Pathway.

The transition-metal-catalyzed alkenylation strategy of propargylic alcohol derivatives provides an efficient protocol to access multifunctional products in a double-nucleophilic attack pattern. While limited relevant asymmetric examples have been reported via palladium catalysis, here we first demonstrate that a nonprecious Ni(0)-based chiral complex can efficiently promote the tandem substitution process between propargylic carbonates and N-trifluoroethyl ketimines via consecutive aza-vinylogous activations, finally accomplishing a (3 + 2) annulation reaction to afford products embedding a 4-methylene-3,4-dihydro-2H-pyrrole framework with high regio-, diastereo-, and enantiocontrol. Their assemblies with a few all-carbon-based vinylogous precursors are also successful, and enantioenriched adducts containing a 3-methylenecyclopentene scaffold are furnished effectively. The substitution patterns for both types of substrates are substantial, and an array of synthetic elaborations is conducted to deliver more versatile architectures with high application potential. In addition, density functional theory calculations and control experiments have been conducted to rationalize the catalytic pathways and regio- and enantioselectivity control.

Synthesis of Chiral Endocyclic Allenes and Alkynes via Pd-Catalyzed Asymmetric Higher-Order Dipolar Cycloaddition.

A Pd-catalyzed asymmetric higher-order dipolar cycloaddition between allenyl carbonates and azadienes is achieved by exploiting novel alkylidene-π-allyl-Pd dipoles. This research provides a modular platform for the synthesis of challenging chiral endocyclic allenes bearing a medium-sized heterocyclic motif and a centrally chiral stereocenter in good yields with high enantio- and diastereoselectivities (29 examples, up to 97% yield, 97:3 er and >19:1 dr). Experimental and computational studies elucidate the possible reaction mechanism and the observed stereochemical results. Based on the mechanistic understanding, a new π-propargyl-Pd dipole was designed to further extend the success of the higher order dipolar cycloaddition strategy to the synthesis of 10-membered endocyclic alkynes from propargyl carbonates and azadienes (13 examples, up to 98% yield and 94.5:5.5 er).

Recent Advances in Electrochemical Carboxylation with CO2.

ConspectusCarbon dioxide (CO2) is recognized as a greenhouse gas and a common waste product. Simultaneously, it serves as an advantageous and commercially available C1 building block to generate valuable chemicals. Particularly, carboxylation with CO2 is considered a significant method for the direct and sustainable production of important carboxylic acids. However, the utilization of CO2 is challenging owing to its thermodynamic stability and kinetic inertness. Recently, organic electrosynthesis has emerged as a promising approach that utilizes electrons or holes as environmentally friendly redox reagents to produce reactive intermediates in a controlled and selective manner. This technique holds great potential for the CO2 utilization.Since 2015, our group has been dedicated to exploring the utilization of CO2 in organic synthesis with a particular focus on electrochemical carboxylation. Despite the significant advancements made in this area, there are still many challenges, including the activation of inert substrates, regulation of selectivity, diversity in electrolysis modes, and activation strategies. Over the past 7 years, our team, with many great experts, has presented findings on electrochemical carboxylation with CO2 under mild conditions. In this context, we primarily highlight our contributions to selective electrocarboxylations, encompassing new reaction systems, selectivity control methods, and activation approaches.We commenced our research by establishing a Ni-catalyzed electrochemical carboxylation of unactivated aryl halides and alkyl bromides in conjunction with a useful paired anodic reaction. This approach eliminates the need for sacrificial anodes, rendering the carboxylation process sustainable. To further utilize the widely existing yet cost-effective alkyl chlorides, we have developed a deep electroreductive system to achieve carboxylation of unactivated alkyl chlorides and poly(vinyl chloride), allowing the direct modification and upgrading of waste polymers.Through precise adjustment of the electroreductive conditions, we successfully demonstrated the dicarboxylation of both strained carbocycles and acyclic polyarylethanes with CO2 via C-C bond cleavage. Furthermore, we have realized the dicarboxylative cyclization of unactivated skipped dienes to produce the valuable ring-tethered adipic acids through single-electron reduction of CO2 to the CO2 radical anion (CO2•-). In terms of the asymmetric carboxylation, Guo's and our groups have recently achieved the nickel-catalyzed enantioselective electroreductive carboxylation reaction using racemic propargylic carbonates and CO2, paving the way for the synthesis of enantioenriched propargylic carboxylic acids.In addition to the aforementioned advancements, Lin's and our groups have also developed new electrolysis modes to achieve regiodivergent C-H carboxylation of N-heteroarenes dictated by electrochemical reactors. The choice of reactors plays a crucial role in determining whether the hydrogen atom transfer (HAT) reagents are formed anodically, consequently influencing the carboxylation pathways of N-heteroarene radical anions in the distinct electrolyzed environments.

Palladium-Catalyzed Heteroannulation of Salicylamides with Propargyl Carbonates: Synthesis of 1,4-Benzoxazepin-5-ones.

Herein, we report a palladium-catalyzed method to synthesize 1,4-benzoxazepin-5-ones using salicylamides and propargyl carbonates. The heteroannulation provides a wide range of products in good to excellent yields with broad functional group tolerance. In addition, H2O is used as a low-cost, abundant, and safe solvent, which is important in terms of sustainability.

Switchable Regioselective C-H Activation/Annulation of Acrylamides with Alkynes for the Synthesis of 2-Pyridones.

A catalyst-based switchable regioselective C-H activation/annulation of acrylamides with propargyl carbonates has been developed, delivering C5 or C6 alkenyl substituted 2-pyridones. This robust protocol proceeds with a broad substrate scope and good functional group tolerance under redox-neutral reaction conditions. More significantly, this reaction is highly effective with previously challenging unsymmetrical alkynes, including unbiased alkyl-alkyl substituted alkynes, with perfect and switchable regioselectivity. Additionally, mechanistic studies and DFT calculations were performed to shed light on the switchable regioselectivity.

Copper-Catalyzed Difunctionalization of Propargylic Carbonates through Tandem Nucleophilic Substitution/Boroprotonation.

Highly functionalized organic molecules are in high demand, but their preparation is challenging. Copper-catalyzed transformation of alkynyl- and allenyl-containing substrates has emerged as a powerful tool to achieve this objective. Herein, an efficient copper-catalyzed difunctionalization of propargylic carbonates through tandem nucleophilic substitution/boroprotonation has been developed, affording the formation of thiol-, selenium-, and boron-functionalized alkenes with high yield and stereoselectivity. Two distinct catalytic mechanisms involving a single reaction without any requirement of catalyst change were successfully demonstrated.

Enantioselective Nickel-Electrocatalyzed Reductive Propargylic Carboxylation with CO2.

The exploitation of carbon dioxide (CO2) as a sustainable, plentiful, and harmless C1 source for the catalytic synthesis of enantioenriched carboxylic acids has long been acknowledged as a pivotal task in synthetic chemistry. Herein, we present a current-driven nickel-catalyzed reductive carboxylation reaction with CO2 fixation, facilitating the formation of C(sp3)-C(sp2) bonds by circumventing the handling of moisture-sensitive organometallic reagents. This electroreductive protocol serves as a practical platform, paving the way for the synthesis of enantioenriched propargylic carboxylic acids (up to 98% enantiomeric excess) from racemic propargylic carbonates and CO2. The efficacy of this transformation is exemplified by its successful utilization in the asymmetric total synthesis of (S)-arundic acid, (R)-PIA, (S)-chizhine D, (S)-cochlearin G, and (S,S)-alexidine, thereby underscoring the potential of asymmetric electrosynthesis to achieve complex molecular architectures sustainably.

Enantioselective propargylic amination and related tandem sequences to α-tertiary ethynylamines and azacycles.

Chiral α-tertiary amines and related azacycles are sought-after compounds for drug development. Despite progress in the catalytic asymmetric construction of aza-quaternary stereocentres, enantioselective synthesis of multifunctional α-tertiary amines remains underdeveloped. Enantioenriched α-disubstituted α-ethynylamines are attractive synthons for constructing chiral α-tertiary amines and azacycles, but methods for their catalytic enantioselective synthesis need to be expanded. Here we describe an enantioselective asymmetric Cu(I)-catalysed propargylic amination (ACPA) of simple ketone-derived propargylic carbonates to give both α-dialkylated and α-alkyl-α-aryl α-tertiary ethynylamines. Sterically confined pyridinebisoxazoline (PYBOX) ligands, with a C4 shielding group and relaying groups, play a key role in achieving excellent enantioselectivity. The syntheses of quaternary 2,5-dihydropyrroles, dihydroquinines, dihydrobenzoquinolines and dihydroquinolino[1,2-α]quinolines are reported, and the synthetic value is further demonstrated by the enantioselective catalytic total synthesis of a selective multi-target β-secretase inhibitor. Enantioselective Cu-catalysed propargylic substitutions with O- and C-centred nucleophiles are also realized, further demonstrating the potential of the PYBOX ligand.

Isolation of Cationic η3-Allenylnickel(II) Key Intermediate Complexes: Origins of Enantioselectivity and Regioselectivity in Nickel(0)-Catalyzed Asymmetric Propargylic Substitutions.

Herein, we report the synthesis and isolation of cationic η3-allenylnickel(II) complexes that bear rac-BINAP as a bidentate ligand for the first time via Me3SiOTf-promoted C-O bond cleavage of propargylic tert-butyl carbonate. In contrast, in the presence of the monodentate phosphine ligand PEt3, treatment of propargylic tert-butyl carbonate with Ni(cod)2 resulted in a gradual C-O bond cleavage leading to η1-allenylnickel(II) complexes, i.e., trans-(PEt3)2Ni(η1-CPh═C═CHR)(OBoc). X-ray diffraction and NMR spectroscopy studies of [(η3-RCH-CCPh)Ni(rac-BINAP)](OTf) revealed that the complex adopts an η3-allenyl coordination mode both in the crystal lattice and in solution. A thorough structural comparison between [(η3-RCH-CCPh)Ni(rac-BINAP)](OTf) and palladium and platinum analogues revealed that the η3-allenyl moiety in the nickel complex is similar to that observed in palladium and platinum complexes, albeit that each Ni-C bond is shorter than the corresponding Pd-C and Pt-C bonds due to the smaller ionic radius of nickel to that of Pd or Pt. The reactions of either N-methylaniline or sodium N-methylanilide with [(η3-RCH-CCPh)Ni((R)-BINAP)](OTf) furnished (R)-PhC≡CCH(NMePh)Me as an asymmetric propargylic substitution (APS) product with excellent enantioselectivity. Furthermore, when the nickel-catalyzed APS reaction of propargylic tert-butyl carbonate with N-methylaniline was conducted in DMSO at 60 °C in the presence of 5 mol % of [(η3-RCH-CCPh)Ni((R)-BINAP)](OTf) and 7.5 mol % of sodium N-methylanilide as a catalytic precursor and an additive, respectively, (R)-PhC≡CCH(NMePh)Me was obtained in 79% yield with 90% ee. The experimental results and computational calculations strongly suggest that the nickel-catalyzed APS reaction might proceed via a cationic η3-allenylnickel(II) species as the key reaction intermediate.

Visible light promoted synthesis of allenes

This review article summarizes the visible light mediated synthesis of allenes from substrates like 1,3-enynes, propargylic carbonates, homopropargylic alcohols, propargylic oxalates, alkynyl diazo compounds, and terminal alkynyl aziridines.

Investigating chemical diversity: o-propargylphenols as key compounds in the divergent synthesis of 2-substituted benzofurans and chromenes.

In this study, we explored and optimized a MW-enhanced divergent approach for the synthesis of 2-substituted benzofurans and chromenes, starting from seventeen substituted o-propargylphenols characterized by a monoaryl substitution on the propargylic sp3 carbon. Firstly, we developed a robust platform for the preparation of a library of o-propargylphenols. Under basic conditions, o-propargylphenols reacted regioselectively to yield benzofurans in yields ranging from 43% to 100%. Conversely, under cationic gold catalysis, we were able to obtain the corresponding 4H-chromenes, albeit in more variable yields (from 25% to 93%) and slightly lower regioselectively. We also proposed plausible mechanisms to explain the divergent outcomes observed. Our findings underscore the potential of diversity-oriented synthesis in the investigation of molecular complexity. Our neglected o-propargylphenols have proven to be versatile and strategic starting materials for accessing oxygen-containing heterocyclic scaffolds through intramolecular cyclization reactions.

Palladium-Catalyzed Alkylation and Dienylation of Propargylic Carbonates with Hydrazones through Carbonyl Umpolung

Palladium-Catalyzed Alkylation and Dienylation of Propargylic Carbonates with Hydrazones through Carbonyl Umpolung

Copper-Catalyzed Umpolung Reactivity of Propargylic Carbonates in the Presence of Diboronates: One Stone Four Birds.

Allylation and propargylation are two powerful synthetic strategies for making new substances that have been of significant importance in chemistry, medicine, and material fields. Conventional tactics employ various preformed allylation and propargylation reagents. In this study, a conceptually novel copper-catalyzed and B2pin2-mediated Umpolung reactivity of propargylic carbonates has been achieved for the first time, realizing both allylation and propargylation of aldehydes and ketones without additional reductants. Three types of allylation products and one type of propargylation product are generated efficiently, and all allylation products are formed with syn-configurations predominantly. The choice of ligands plays a vital role in modulating the Umpolung modes. The synthetic applications have been demonstrated in a myriad of further transformations including natural product synthesis, and systematic mechanistic studies have been conducted to reveal detailed insights into the Umpolung processes.

Enantiospecific Synthesis of 1,3‐Disubstituted Allenes from Propargylic Carbonates through a Borylation‐1,2‐Elimination Process

AbstractAn array of enantioenriched vinyl boronates bearing an allylic carbonate moiety have been prepared through selective hydroboration of propargyl carbonates. Treatment of these vinyl boronates with TBAF in THF affords enantioenriched 1,3‐disubstituted allenes through a novel 1,2‐anti elimination in good yields and high enantiospecificities.

Rh(II)/Pd(0) Dual-Catalyzed Regio-Divergent Three-Component Propargylic Substitution.

Regio-divergent propargylic substitution to generate functionally diverse products from identical starting materials remains a formidable challenge, probably due to the unpredictable regiochemical complexity. In practically, the synthesis of α-quaternary propargylic-substituted products is still much less developed, and preprepared nucleophiles are generally applied in this type of reaction with propargylic substrates, which limits the reaction efficiency and diversity of the obtained products. Herein, we disclose unprecedented three-component propargylic substitution of α-diazo esters with amines and propargylic carbonates under dirhodium/palladium dual catalysis. The key to the success of this multicomponent propargylic substitution is to avoid two-component side reactions through a tandem process of dirhodium(II)-catalyzed carbene insertion and palladium-catalyzed regiodivergent propargylic substitution. The judicious selection of a diphosphine (dppf) or monophosphine (tBuBrettphos) as the ligand is crucial for the reaction to generate different products in a switchable way, α-quaternary 1,3-dienyl or propargylated products, with high regio- and chemoselectivities.

Photoredox cobalt-catalyzed regio-, diastereo- and enantioselective propargylation of aldehydes via propargyl radicals

Catalytic enantioselective introduction of a propargyl group constitutes one of the most important carbon–carbon forming reactions, as it is versatile to be transformed into diverse functional groups and frequently used in the synthesis of natural products and biologically active molecules. Stereoconvergent transformations of racemic propargyl precursors to a single enantiomer of products via propargyl radicals represent a powerful strategy and provide new reactivity. However, only few Cu- or Ni-catalyzed protocols have been developed with limited reaction modes. Herein, a photoredox/cobalt-catalyzed regio-, diastereo- and enantioselective propargyl addition to aldehydes via propargyl radicals is presented, enabling construction of a broad scope of homopropargyl alcohols that are otherwise difficult to access in high efficiency and stereoselectivity from racemic propargyl carbonates. Mechanistic studies and DFT calculations provided evidence for the involvement of propargyl radicals, the origin of the stereoconvergent process and the stereochemical models.

Cu(II)-mediated annulation of 4-hydroxycoumarins with propargyl carbonates: Facile access to furo[3,2-c]coumarin scaffold

An efficient and facile approach to furo[3,2-c]coumarin was developed from 4-hydroxycoumarins and propargyl carbonates. This protocol underwent [3 + 2] annulation process smoothly under mild reaction conditions to afford the desired products in moderate to excellent yields. A plausible mechanism was proposed. The products obtained could be readily converted into potentially bioactive furocoumarin derivatives.

Copper-Catalyzed Asymmetric Propargylic Substitution of 2,2,2-Trifluoroethyl-isoxazoles with Propargylic Alcohol Derivatives.

The trifluoromethyl group is one of the most functional and widely used fluoroalkyl groups in medicinal chemistry and drug discovery. However, few methodologies have been reported for the asymmetric introduction of the trifluoromethyl group into organic molecules. In this study, a diastereo- and enantioselective propargylic substitution reaction was performed between propargylic carbonates and 2,2,2-trifluoroethyl-substituted nitroisoxazoles catalyzed by a Cu-pybox complex. This method enables the preparation of a series of propargylation products with two contiguous stereogenic centers, one of which is a chiral trifluoromethyl-bearing carbon. In most cases, the desired products were produced in high yields with good to excellent diastereo- and enantioselectivities.

Deoxygenative Silylation of C(sp3)–O Bonds with Hydrosilane by Cooperative Catalysis of Gold Nanoparticles and Solid Acids

Efficient deoxygenative silylation of C(sp3)–O bonds with hydrosilanes by supported Au catalysts is described. Gold nanoparticles supported on TiO2 enabled various hydrosilanes to be used as sources of silyl groups in C–Si cross-coupling reactions. A variety of alkyl acetates and propargyl carbonates participated in the Au-catalyzed reactions to furnish the corresponding alkyl and allenylsilanes in high yields. In addition, Au/TiO2 was also effective for ring-opening silylation of cyclic ethers. A detailed mechanistic investigation corroborated that the title reaction involves the formation of silyl and alkyl radical intermediates, and the cooperation of Au nanoparticles as single-electron transfer catalysts and Lewis acid sites at the surface of metal oxides was responsible for the unusual reactivity of hydrosilanes for specific C(sp3)–Si bond formation.