Aliphatic Alkynes Research Articles

Hydrosilylation of Alkynes Catalyzed by an Iron(II) PCP Pincer Alkyl Complex

Vinylsilanes are very useful building blocks in organic synthesis and have widespread applications in life sciences and materials chemistry. Here we describe the potential of complex cis‐[Fe(PCP‐iPr)(CH2CH2CH3)(CO)2] as an effective catalyst for the hydrosilylation of both terminal and internal alkynes with SiPhH3 to give vinylsilanes. The reactions were typically performed with a catalyst loading of 1 mol% for 24 h at 70oC. The catalytic reaction is initiated by migratory insertion of a CO ligand into the Fe‐alkyl bond to yield an acyl intermediate which reacts with silanes to form the 16e‐ Fe(II) silyl catalyst [Fe(PCP‐iPr)(SiPhH2)(CO)]. In the case of aliphatic terminal alkynes good regioselectivity (anti‐Markovnikov addition) towards the thermodynamically more stable β‐(E)‐vinylsilanes in ratios of up to 10:90 was achieved, while for aromatic alkynes the selectivities were poor with ratios of β‐(Z)‐ to β‐(E)‐vinylsilanes of about 40:60. With internal unsymmetrical alkynes, the two possible regioisomers of the syn‐addition of SiPhH3 were obtained in different ratios with no clear trend towards one regioisomer. Internal symmetrical alkynes yielded exclusively the respective syn‐products in high yields. Mechanistic investigations including deuterium labelling studies were undertaken to provide a reasonable reaction mechanism.

Copper‐Catalyzed Enantioselective Hydrophosphorylation of Unactivated Alkynes

P‐stereogenic phosphorus compounds are essential across various fields, yet their synthesis via enantioselective P‐C bond formation remains both challenging and underdeveloped. We report the first copper‐catalyzed enantioselective hydrophosphorylation of alkynes, facilitated by a newly designed chiral 1,2‐diamine ligand. Unlike previous methods that rely on kinetic resolution with less than 50% conversion, our approach employs a distinct dynamic kinetic asymmetric transformation mechanism, achieving complete conversion of racemic starting materials. This reaction is compatible with a broad range of aromatic and aliphatic terminal alkynes, producing products with high yields (up to 95%), exclusive cis selectivity, and exceptional regio‐ and enantioselectivity (> 20:1 r.r. and up to 96% ee). The resulting products were further transformed into a diverse array of enantioenriched P‐stereogenic scaffolds. Preliminary mechanistic studies were conducted to elucidate the reaction details.

Copper-Catalyzed Enantioselective Hydrophosphorylation of Unactivated Alkynes.

P-stereogenic phosphorus compounds are essential across various fields, yet their synthesis via enantioselective P-C bond formation remains both challenging and underdeveloped. We report the first copper-catalyzed enantioselective hydrophosphorylation of alkynes, facilitated by a newly designed chiral 1,2-diamine ligand. Unlike previous methods that rely on kinetic resolution with less than 50 % conversion, our approach employs a distinct dynamic kinetic asymmetric transformation mechanism, achieving complete conversion of racemic starting materials. This reaction is compatible with a broad range of aromatic and aliphatic terminal alkynes, producing products with high yields (up to 95 %), exclusive cis selectivity, and exceptional regio- and enantioselectivity (>20 : 1 r.r. and up to 96 % ee). The resulting products were further transformed into a diverse array of enantioenriched P-stereogenic scaffolds. Preliminary mechanistic studies were conducted to elucidate the reaction details.

Hydromethylthiolation of alkynes via nucleophilic addition of dimethyl disulfide in DMSO

A hydromethylthiolation method for various alkynes has been developed using dimethyl disulfide as a source of the nucleophilic methylthiolate anion in a DMSO/EtOH or DMSO/H2O solvent system, with KOH as the base. For terminal aromatic alkynes, the reactions predominantly yield (Z)-anti-Markovnikov hydromethylthiolation products. The ratio of anti-Markovnikov to Markovnikov products typically exceeds 10:1, while the ratio of (Z)- to (E)-anti-Markovnikov products usually surpasses 7:1. In contrast, terminal aliphatic alkynes primarily produce Markovnikov hydromethylthiolation products. Reactions of internal aromatic alkynes also successfully produce the corresponding hydromethylthiolation products, whereas internal aliphatic alkynes do not exhibit reactivity in this system. The proposed mechanism suggests that in a basic DMSO solvent system, each equivalent of dimethyl disulfide is converted into two equivalents of methylthiolate anion. This anion then undergoes nucleophilic addition to the alkyne substrates, yielding hydromethylthiolation products. The regioselectivity and stereoselectivity of the hydromethylthiolation are influenced by the stability of the vinyl carbanion intermediate. Additionally, this method is also applicable to the hydrothiolation of alkynes using other disulfides.

Photoinduced Nickel-Catalyzed Homolytic C(sp3)-N Bond Activation of Isonitriles for Selective Carbo- and Hydro-Cyanation of Alkynes.

The exploration of strong chemical bonds as synthetic handles offers new disconnection strategies for the synthesis of functionalized molecules via transition metal catalysis. However, the slow oxidative addition rate of these covalent bonds to a transition metal center hampers their synthetic utility. Here, we report a C(sp3)-N bond activation strategy that bypasses thermodynamically challenging 2e- or 1e- oxidative addition via a distinct pathway in nickel catalysis. This strategy leverages a previously unknown activation pathway of photoinduced inner-sphere charge transfer of low-valent nickel(isonitriles), triggering a C(sp3)-N bond cleavage distal to the metal-ligand interaction to deliver nickel(cyanide) and versatile alkyl radicals. Utilizing this catalytic strategy, the selective intermolecular 1,2-carbocyanation reaction of alkynes with alkyl isonitriles as both alkylating and cyanating agents can be achieved, delivering a wide array of trisubstituted alkenyl nitriles with excellent atom-economy, regio-, and stereoselectivity under mild conditions. Furthermore, Markovnikov-selective hydrocyanation of aliphatic alkynes can be accomplished through the synergistic action of a photocatalyst utilizing isonitriles as the cyanation agents. Mechanistic investigations support the photogeneration of low-valent Ni(isonitrile) complexes that undergo photochemical homolysis of the C(sp3)-N bond to engage catalytic cyanation with alkynes.

Ambient Semi‐Hydrogenation of Terminal Alkynes with NaBH4 Catalyzed by Palladium Nanowires

AbstractThe semi‐hydrogenation of terminal alkynes is achieved with sodium borohydride (NaBH4) as the reductant and palladium nanowires (PdNWs) as the catalysts under ambient conditions. The reaction proceeds smoothly in the presence of only 0.32 mol % of PdNWs, giving the hydrogenated products with up to 98 % overall yields, in which 97 % are semi‐hydrogenated products. Under the optimal reaction conditions, both aromatic and aliphatic terminal alkynes have been successfully converted to the corresponding olefins with high efficiency and good selectivity. This method promotes the hydrogenation of terminal alkynes under mild conditions and opens up a window for the application of metal nanowires in organic syntheses.

Merging Pd(0)-Catalyzed Selective Cacyl–O Bond Activation of Enol Esters with π-Acid Catalysis: Net Hydroxyacylation of Aliphatic Alkynes with Carboxylic Acids

Merging Pd(0)-Catalyzed Selective C_acyl–O Bond Activation of Enol Esters with π-Acid Catalysis: Net Hydroxyacylation of Aliphatic Alkynes with Carboxylic Acids

Hydroboration of Terminal Alkynes Catalyzed by a Mn(I) Alkyl PCP Pincer Complex Following Two Diverging Pathways.

A stereo- and regioselective Mn(I)-catalyzed hydroboration of terminal alkynes with pinacolborane (HBPin) is described. The hydroboration reaction is highly Z-selective in the case of aryl alkynes and E-selective in the case of aliphatic alkynes. The reaction requires no additives or solvents and proceeds with a catalyst loading of 1 mol % at 50-70 °C. The most active precatalyst is the bench-stable alkyl Mn(I) complex cis-[Mn(PCP-iPr)(CO)2(CH2CH2CH3)]. The catalytic process is initiated by the migratory insertion of a CO ligand into the Mn-alkyl bond to yield an acyl intermediate. This species undergoes C-H and B-H bond cleavage of the alkyne (aromatic alkynes) and HBPin (in the case of aliphatic alkynes) forming the active Mn(I) alkynyl and boryl catalysts [Mn(PCP-iPr)(CO)(C≡CR)] and [Mn(PCP-iPr)(CO)(BPin)], respectively. A broad variety of aromatic and aliphatic alkynes was efficiently and selectively borylated. Mechanistic insights are provided based on experimental data and DFT calculations. The functionalized alkenes can be used for further applications in cross-coupling reactions.

CuBr-Catalyzed Coupling of Propargyl Bromides with Terminal Alkynes: Syntheses of 1,4-Diynes and Alkynyl Shift Access to Unsymmetrical 1, n-Diynes.

A CuBr-catalyzed cross-coupling reaction of propargyl bromides with terminal alkynes for the synthesis of 1, n-diynes was investigated. In N,N-dimethylacetamide (DMAc), the cross-coupling reactions of 3-bromo-1-arylpropynes, 3-bromo-1-phenyl-butyne/pentyne with aromatic terminal alkynes in the presence of CuBr and K3PO4 under nitrogen at 40 °C occur to give 1, 5-diaryl-1, 4-diynes having 3-CH2/3-CHMe/3-CHEt/3-CHiPr moieties with high chemoselectivity. Under similar reaction conditions, either the reactions of 3-bromo-1-arylpropynes with aliphatic terminal alkynes or the reactions of 3-bromo-1-alkylpropynes with aromatic terminal alkynes afforded the unexpected unsymmetric 1, 4-disubstituted 1, 3-diynes through one of the alkynyl group shifts to the side conjugating with the aryl group; in these cases, 1, 5-disubstituted 1, 4-diynes could not be obtained at all. In addition, when 3-bromo-1-phenyl-butynes react with aliphatic terminal alkynes bearing a distal phenyl group, the formed 1, 4-diynes are expected not to undergo the alkynyl group shift due to the methyl group at 3-position to form 1, 3-diynes; however, 1, 4-diynes could not be obtained either, and the 1, 5-, 1, 6-, and 1, 7-diynes, by an unprecedented remote alkynyl shift to the side conjugating with the aryl group, were isolated from the reaction mixtures in good yields.

Cu@CuFe2O4 nanoparticles catalyzed oxidative functionalization of alkynes: Access to α,α‐dichloro ketones

In this study, novel Cu@CuFe2O4 nanoparticles were prepared by virtue of a simple method. By utilizing a compatible system involving N‐chlorosuccinimide (NCS) as the chlorine source and Cu@CuFe2O4 magnetic nanoparticles (NPs) as recyclable catalyst, we present a novel and practical method for directly obtaining aryl α,α‐dichloroketones in aqueous trifluoroethanol (TFE). The catalyst was recovered and reused up to five times with no significant decrease in activity. The current study provides a foundational raw material for the subsequent synthesis of chlorinated functional molecules, which is achieved through a mild transformation of arylalkynes using readily available commercial feedstocks and exhibiting good tolerance with various substituents on the aromatic ring, including the aliphatic alkyne. This novel heterogeneous catalyst may be used in numerous industrial applications because of its merits, such as considerable recyclability, low requirement for catalyst loading, cost‐effectiveness, and ease of handling.

Nickel-Catalyzed Mono- and Dihydrosilylation of Aliphatic Alkynes in Aqueous and Aerobic Conditions

Nickel-Catalyzed Mono- and Dihydrosilylation of Aliphatic Alkynes in Aqueous and Aerobic Conditions

Regio‐ and Stereo‐Selective Synthesis of (E)‐β‐Alkenyl Boronates by Phosphene‐Free CuI‐Catalyzed Hydroboration and Carboboration of Alkynes and Access to Allyl‐Vinyl Ethers

AbstractA convenient and operationally trivial protocol to access synthetically versatile vinylboronates through CuI catalyzed hydroboration and carboboration of alkynes utilizing bis(pinacolato)diboron (B2pin2) as the boron precursor in a 1, 10‐phenanthroline (phen) ligand environment is reported. This is a highly efficient and practical method for the synthesis of regio‐ and stereoselective (E)‐β‐vinylboronates from simple aromatic and aliphatic alkynes. These organoboron compounds have further been utilized for the synthesis of allyl‐vinyl ethers, which are potential starting materials for the Claisen rearrangement via an improved CuII mediated coupling of allyl alcohols and vinylboronates. The vinylboronates were also subjected to Suzuki‐Miyaura cross coupling reaction, allowing access to the corresponding tri‐ and tetra‐substituted alkenes with good isolated yields.

Reactions of aliphatic terminal alkynes with Ti(OiPr)4/BuLi: selectivity, kinetic aspects, and a new tetramerisation process

Reactions of aliphatic terminal alkynes with Ti(OiPr)4/BuLi: selectivity, kinetic aspects, and a new tetramerisation process

E-Selective Radical Difunctionalization of Unactivated Alkynes: Preparation of Functionalized Allyl Alcohols from Aliphatic Alkynes.

Radical difunctionalization of aliphatic alkynes provides direct access to valuable multi-substituted alkenes, but achieving a high level of chemo- and stereo-control remains a formidable challenge. Herein a novel photoredox neutral alkyne di-functionalization is reported through functional group migration followed by a radical-polar crossover and energy transfer-enabled stereoconvergent isomerization of alkenes. In this sequence, a hydroxyalkyl and an aryl group are incorporated concomitantly into an alkyne, leading to diversely functionalized E-allyl alcohols. The scope of alkynes is noteworthy, and the reaction tolerates aliphatic alkynes containing hydrogen donating C─H bonds that are prone to intramolecular hydrogen atom transfer. The protocol features broad functional group compatibility, high product diversity, and exclusive chemo- and stereoselectivity, thus providing a practical strategy for the elusive radical di-functionalization of unactivated alkynes.

Copper Dispersed Covalent Organic Framework for Azide-Alkyne Cycloaddition and Fast Synthesis of Rufinamide in Water.

A crystalline porous bipyridine-based Bpy-COF with a high BET surface area (1864m2g-1) and uniform mesopore (4.0nm) is successfully synthesized from 1,3,5-tris-(4'-formyl-biphenyl-4-yl)triazine and 5,5'-diamino-2,2'-bipyridine via a solvothermal method. After Cu(I)-loading, the resultant Cu(I)-Bpy-COF remained the ordered porous structure with evenly distributed Cu(I) ions at a single-atom level. Using Cu(I)-Bpy-COF as a heterogeneous catalyst, high conversions for cycloaddition reactions are achieved within a short time (40min) at 25°C in water medium. Moreover, Cu(I)-Bpy-COF proves to be applicable for aromatic and aliphatic azides and alkynes bearing various substituents such as ester, hydroxyl, amido, pyridyl, thienyl, bulky triphenylamine, fluorine, and trifluoromethyl groups. The high conversions remain almost constant after five cycles. Additionally, the antiepileptic drug (rufinamide) is successfully prepared by a simple one-step reaction using Cu(I)-Bpy-COF, proving its practical feasibility for pharmaceutical synthesis.

Additive-free oxychlorination of unsaturated C-C bonds with tert-butyl hypochlorite and water.

Herein we report an additive-free protocol for the facile synthesis of α,α-dichloroketones and α-chlorohydrins from various aryl terminal, diaryl internal, and aliphatic terminal alkynes and alkenes, respectively. The commercially available tert-butyl hypochlorite (tBuOCl) was employed as a suitable chlorinating reagent, being accompanied by the less harmful tBuOH as the by-product. In addition, the oxygen atoms in the products came from water rather than molecular oxygen, based on the 18O-labelling experiments. Meanwhile, the diastereoselectivity of the Z- and the corresponding E-alkenes has been compared and rationalized. Using a group of control experiments, the possible mechanisms have been proposed as the initial electrophilic chlorination of unsaturated C-C bonds in a Markovnikov-addition manner in general followed by a nucleophilic addition with water. This work simplified the oxychlorination method with a mild chlorine source and a green oxygen source under ambient conditions.

Catalytic HF Shuttling between Fluoroalkanes and Alkynes.

In this paper, we report BF3 ⋅ OEt2 as a catalyst to shuttle equivalents of HF from a fluoroalkane to an alkyne. Reactions of terminal and internal aliphatic alkynes led to formation of difluoroalkane products, while diarylalkynes can be selectively converted into fluoroalkenes. The method tolerates numerous sensitive functional groups including halogen, protected amine, ester and thiophene substituents. Mechanistic studies (DFT, probe experiments) suggest the catalyst is involved in both the defluorination and fluorination steps, with BF3 acting as a Lewis acid and OEt2 a weak Lewis base that mediates proton transfer. In certain cases, the interconversion of fluoroalkene and difluoroalkane products was found to be reversible. The new catalytic system was applied to demonstrate proof-of-concept recycling of poly(vinylidene difluoride).

Catalytic HF Shuttling between Fluoroalkanes and Alkynes**

AbstractIn this paper, we report BF3 ⋅ OEt2 as a catalyst to shuttle equivalents of HF from a fluoroalkane to an alkyne. Reactions of terminal and internal aliphatic alkynes led to formation of difluoroalkane products, while diarylalkynes can be selectively converted into fluoroalkenes. The method tolerates numerous sensitive functional groups including halogen, protected amine, ester and thiophene substituents. Mechanistic studies (DFT, probe experiments) suggest the catalyst is involved in both the defluorination and fluorination steps, with BF3 acting as a Lewis acid and OEt2 a weak Lewis base that mediates proton transfer. In certain cases, the interconversion of fluoroalkene and difluoroalkane products was found to be reversible. The new catalytic system was applied to demonstrate proof‐of‐concept recycling of poly(vinylidene difluoride).

Bioisosteric Replacement through 1,2,3-triazolyl Linkage Significantly Potentiate Biological Activity in Lidocaine and Etidocaine Analogs: Rational Design and Local Anesthetic Activity

Abstract: Cytochrome P450 3A4, the most abundant form of isoenzyme, in combination with several other isoforms, metabolizes lignocaine into mono-ethylglycine xylidide (MEGX) and glycylxylidide (GX), through N-dealkylation, ring hydroxylation, amide cleavage, and conjugation process which contribute the toxic effects. Inspiring by the rationality, functional approaches, and predictable facts lay by the emerging research groups, we were unquestionably fascinated by the rational development of novel lignocaine and etidocaine compounds, which are highly metabolically stable by applying non-classical bioisosteric principles. Distinctively, we have investigated the efficacy of 1,4- disubstituted-1,2,3-triazoles as metabolically stable trans-amide bond mimics. The 1,2,3- triazoles have been described in the literature as amide bond bioisosteres, which are analogous in stipulations of size, planarity, hydrogen bonding properties, and dipole moment. The systematic replacement of the single amide bonds by the 1,2,3-triazole heterocycle in the backbone of the peptide, often termed a “triazole scan,” provided several stabilized analogs with marked improved in-vivo local anesthetic properties. The analogs were synthesized using azide-alkyne cycloaddition. The 2a-b was coupled with aromatic and aliphatic alkynes using click chemistry in the presence of copper sulfate pentahydrate and L-sodium ascorbate in a Fritsch ball mill under solvent-free conditions at 300 rpm, furnishing the conjugates 4a-n in 80- 85% yields. The study perceptively opened new avenues of systematic replacement of the single amide bonds by the 1,2,3-triazole heterocycle in the backbone of the peptide, thereby providing several stabilized analogs with marked improved in-vivo local anesthetic properties. The best active candidates 4a, 4b and 4g produced analogous local anesthetic activity with that of the lignocaine.

Multicomponent Reaction: Pd/Cu-Catalyzed Borocarbonylation of Aryldiazonium Salts with Aliphatic Terminal Alkynes to gem-Bis(boryl) Ketones.

We report the development of Pd/Cu-catalyzed selective 2,1-borocarbonylation reactions of aliphatic terminal alkynes with aryldiazonium salts and B2 Pin2 to prepare gem-bis(boryl) ketones in one-pot. A series of corresponding products are obtained with good to excellent yields under a carbon monoxide atmosphere (10 bar). In addition, wide functional-group tolerance can be observed. Preliminary mechanistic studies reveal that ethyl acetate serves as a proton source in the reaction.