Aryl Alkynes Research Articles

Elucidating the ruthenium-mediated conversion of aryl alkynes to alkoxy(benzyl)carbene and benzyl carbonyl complexes

Metal vinylidenes are key intermediates in the activation of terminal alkynes. Previous studies concerning ruthenium η6-arene complexes showed how the elusive vinylidenes are often transformed into more stable alkoxy(alkyl)carbene complexes upon reaction with alcohols, highlighting their electrophilicity. We reinvestigated the reactivity of terminal alkynes and alcohols with ruthenium(II) η6-arene precursors and we found out new aspects of the formation and the reactivity of the alkoxy(carbene)complexes. First, the reactivity of ruthenium complexes bearing different η6-arene, phosphane, halide co-ligands on the activation process of a series of arylalkynes have been examined. Under optimized conditions, a series of alkoxy(benzyl)carbene complexes of general formula [RuCl{C(OR’)CH2(4-C5H4R)}(PR’’3)(η6-arene)]+ were obtained. Five compounds were isolated in 82–96 % yield and they were characterized by spectroscopic techniques and X-ray diffraction in three cases. Notably, these carbene complexes are the predominant reaction products even in presence of a large molar excess of water in the mixture for short reaction times.In fact, DFT calculations on a model system showed that the vinylidene intermediate, resulting from the Ru/alkyne interaction, is preferentially attacked by MeOH instead of water. The subsequent formation of carbonyl complexes was assessed in various conditions by IR and NMR and four unprecedented and comparatively rare benzyl carbonyl complexes of general formula [Ru{CH2(4-C6H4R)}(CO)(PPh3)(η6-arene)]+ are reported, including the crystal structure of one example. Next, an unprecedented reactivity study on selected alkoxy(benzyl)carbene complexes was carried out. Joint experimental and computational results indicate that these benzyl carbonyl complexes may actually arise from the reaction of the carbene complexes with water, a reactivity pathway that has never been considered in previous studies on the Ru-mediated hydrolytic cleavage of alkynes.

Electrocatalytic regio- and stereoselective carboxylation of terminal alkynes with CO2

Carboxylation with CO2 is a practical and streamlined way to construct a variety of sophisticated carboxylic acids and their derivatives. However, a series of elegant methods focus mainly on C(sp3)– and C(sp2)– carboxylation and involve transition-metal catalysis, photocatalysis, and electrocatalysis. Direct electrocatalytic carboxylation of alkynes with CO2 remains elusive. Herein, we report an electroreductive catalytic system for carboxylation of the C(sp)–C(sp) bonds of alkynes with CO2. Reactions of readily available aryl alkynes regioselectively and stereoselectively provided (E)-cinnamic acids under metal- and additive-free conditions. Mechanistic studies indicated that the reactions involve two successive electroreductions.

Ligand-controlled regiodivergent arylation of aryl(alkyl)alkynes and asymmetric synthesis of axially chiral 9-alkylidene-9,10-dihydroanthracenes

Transition metal-catalyzed addition of organometallics to aryl(alkyl)alkynes has been well known to proceed with the regioselectivity in forming a carbon–carbon bond at the alkyl-substituted carbon (β-addition). Herein, the reverse regiochemistry with high selectivity in giving 1,1-diarylalkenes (α-addition) was realized in the reaction of arylboronic acids with aryl(alkyl)alkynes by use of a rhodium catalyst coordinated with a chiral diene ligand, whereas the arylation of the same alkynes proceeded with the usual regioselectivity (β-addition) in the presence of a rhodium/DM-BINAP catalyst. The regioselectivity can be switched by the choice of ligands on the rhodium catalysts. This reverse regioselectivity also enabled the catalytic asymmetric synthesis of phoenix-like axially chiral alkylidene dihydroanthracenes with high enantioselectivity through an α-addition/1,4-migration/cyclization sequence.

Photocatalytic C(sp3)-P and C(sp2)-P Bond Formation via a Phosphorus Radical Cation.

A straightforward method for the phosphorylation of electron-deficient alkenes and aryl alkynes has been developed, leading to C(sp3)-P and C(sp2)-P bond formation. This process involves the generation of phosphorus radical cation intermediates through the photocatalyzed oxidation of ethyl diarylphosphinites. The coupling with electron-deficient alkenes encompasses a variety of heteroaromatics, including pyridine, (benzo)thiazole, and benzoxazole, as well as α,β-unsaturated esters and amides. Impressively, the coupling of radical cations with aryl alkynes demonstrated remarkable regioselectivity, thereby facilitating the synthesis of rare α-aryl vinyl phosphine oxides.

DFT Investigation on Palladium-Catalyzed [2 + 2 + 1] Spiroannulation between Aryl Halides and Alkynes: Mechanism, Base Additive Role, and Solvent and Ligand Effects.

Transition metal-catalyzed spiroannulations are practical strategies for constructing spirocyclic skeletons of pharmaceutical and biological significance, yet the microscopic mechanism still lacks in-depth explorations. Here, the palladium-catalyzed [2 + 2 + 1] spiroannulation between aryl halides and alkynes was studied by employing the density functional theory (DFT) method. Based on comprehensive explorations on a couple of possible reaction pathways, it is found that the reaction probably experiences C-I oxidative addition, alkyne migration insertion, Cs2CO3-assisted aryl C-H activation, C-Br bond oxidative addition, C-C coupling, arene dearomatization and reductive elimination in sequence and leads to the formation of the spiro[4,5]decane pentacyclic product (P) ultimately. Among these, the C-Br bond oxidative addition step acts as the rate-determining step (RDS) of the whole reaction, featuring a practical free energy barrier of 32.4 kcal·mol-1 at 130 °C. Computationally predicted kinetics such as half-life transferred from the RDS step's barrier on the optimal reaction pathway (1.2 × 101 h) coincides well with corresponding experimental results (91% yield of the spiro[4,5]decane pentacyclic product P after reacting 10 h at 130 °C). In addition, theoretical predictions regarding the solvent/ligand effects and base additive role in the reaction, rationalized by distortion-interaction/natural population/noncovalent interaction analyses, are also in good agreement with experimental data and trend. This good agreement between experiment and theory makes sense for new designations and further experimental improvements of such Pd-catalyzed transformations.

Gold-Catalyzed Heteroannulation of Anthranilic Acids with Alkynes: Synthesis of 3,1-Benzoxazin-4-ones.

We demonstrated a rapid and facile approach for the synthesis of various 3,1-benzoxazin-4-ones via a gold-catalyzed heteroannulation of readily available nonprotected anthranilic acids and simple aryl alkynes. Our preliminary mechanistic investigation indicated that the double incorporation of alkynes into anthranilic acids occurs through the formation of bisenamine intermediates.

Mn(II)-Catalyzed Markovnikov Hydroiodination of Terminal Aryl Alkynes.

A Mn(II)-catalyzed Markovnikov hydroiodination of terminal aryl alkynes with TMSI as the iodination reagent has been developed. Cheap Mn(OAc)2·4H2O was employed as the catalyst. Twenty-five aryl alkynes (including two internal alkynes) were successfully transformed into their α-iodide styrene derivatives, including those natural product-based alkynes and poly alkynyl benzenes. The reaction has good chemoselectivity of alkynes over alkenes, which enabled the tolerance of olefin in the substrate. Gram-scale synthesis was also conducted.

Palladium-Catalyzed Hiyama-Type Coupling of Thianthrenium and Phenoxathiinium Salts.

Here, we demonstrate palladium-catalyzed Hiyama-type cross-coupling reactions of aryl thianthrenium or phenoxathiinium salts. By employing stable and inexpensive organosilanes, the arylation, alkenylation, and alkynylation were realized in high efficiency using commercially available Pd(tBu3P)2 as the catalyst, thus providing a reliable method for preparation of biaryls, styrenes, and aryl acetylenes with a broad functional group tolerance under mild conditions. Given the accessibility of aryl thianthrenium or phenoxathiinium salts from simple arenes in a remarkable regioselective fashion, this protocol also provides an attractive approach for the late-stage modification of complex bioactive scaffolds.

Regioselective Annulation of 3(5)‐Aminopyrazole with Aryl Ketones or Aryl Alkynes Using N,N‐Dimethylethanolamine as a Single/Triple Carbon Synthon

AbstractAn efficient and regioselective cyclization for construction of pyrazolo[3,4‐b]pyridines and methylene‐bridged bis(pyrazolo[1,5‐a]pyrimidines) has been established. It involves a [3+2+1] annulation of 3(5)‐aminopyrazole, N,N‐dimethylethanolamine (DMEA), with 1,2‐insertion of aryl methyl ketones or 2,1‐insertion of aryl alkynes. DMEA is oxidized through C(sp3)‐H activation to provide a single or triple carbon source.

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.

Base-Promoted Annulated Aromatization of Aryl Acetylenes with Dimethyl Sulfoxide to Access Symmetrical/Unsymmetric m-Terphenyl.

A protocol for selective and efficient synthesis of symmetrical and unsymmetrical m-terphenyls is presented among aryl acetylene and DMSO in the presence of KOH and methanol. In this reaction, two molecules of aryl acetylene contribute four carbons, and DMSO, as a dual carbon donor, provides two carbons to a new aromatic ring. This protocol can be tolerated for the electron-donating or disubstituted phenylacetylenes as well as the heterocyclic acetylene derivatives.

Constructing Pd and Cu Crowding Single Atoms by Protein Confinement to Promote Sonogashira Reaction.

For multicenter-catalyzed reactions, it is important to accurately construct heterogeneous catalysts containing multiple active centers with high activity and low cost, whichis more challenging compared to homogeneous catalysts because of the low activity and spatial confinement of active centers in the loaded state. Herein, a convenient protein confinement strategy is reported to locate Pd and Cu single atoms in crowding state on carbon coated alumina for promoting Sonogashira reaction, the most powerful method for constructing the acetylenic moiety in molecules. The single-atomic Pd and Cu centers take advantage in not only the maximized atomic utilization for low cost, but also the much-enhanced performance by facilitating the activation of aryl halides and alkynes. Their locally crowded dispersion brings them closer to each other, which facilitates the transmetallation process of acetylide intermediates between them. Thus, the Sonogashira reaction is drove smoothly by the obtained catalyst with a turnover frequency value of 313 h-1, much more efficiently than that by commercial Pd/C and CuI catalyst, conventional Pd and Cu nanocatalysts, and mixed Pd and Cu single-atom catalyst. The obtained catalyst also exhibits the outstanding durability in the recycling test.

Oxime Palladacycle Supported on Magnetic Meoporous Silica: An Efficient Catalyst for Copper‐Free Acyl Sonogashira Reaction

AbstractThe catalytic activity of the supported bis(oxime palladacycle) catalyst was evaluated in the acyl Sonogashira reaction. The reaction conditions, such as solvent, base, and palladium content, were screened to achieve the best catalytic performance. Tetrahydrofuran (THF) solvent, triethylamine (Et3N) base, and the reaction temperature of 110 °C were found to be ideal for achieving high yields of the desired products. Furthermore, a catalyst loading of only 0.22 mol% palladium was sufficient to achieve good conversion. Broad ranges of aryl acetylenes and benzoyl chlorides were successfully coupled to give the desired acetylenic ketones. The reaction appeared to proceed efficiently using a small amount of catalyst. The magnetic property of the catalyst allowed for easy separation using an external magnet. The catalyst was stable and reused for multiple reaction runs without a significant deactivation. After seven cycles, the catalyst maintained over 90 % of its initial catalytic activity.

Catalyst-Free Visible Light-Driven Hydrosulfonylation of Alkenes and Alkynes with Sulfonyl Chlorides in Water.

A convenient and sustainable method for synthesizing sulfonyl-containing compounds through a catalyst-free aqueous-phase hydrosulfonylation of alkenes and alkynes with sulfonyl chlorides under visible light irradiation is presented. Unactivated alkenes, electron-deficient alkenes, alkyl and aryl alkynes can be hydrosulfonylated with various sulfonyl chlorides at room temperature with excellent yields and geometric selectivities by using tris(trimethylsilyl)silane as a hydrogen atom donor and silyl radical precursor to activate sulfonyl chlorides. Mechanistic studies revealed that the photolysis of tris(trimethylsilyl)silane in aqueous solution to produce silyl radical is crucial for the success of this reaction.

Photocatalytic Reductive Functionalization of Aryl Alkynes via Alkyne Radical Anions

Photocatalytic Reductive Functionalization of Aryl Alkynes via Alkyne Radical Anions

Probing Isosteric Replacement for Immunoadjuvant Design: Bis-Aryl Triazole Trehalolipids are Mincle Agonists.

Herein, we report the modular synthesis and immunological activity of seven bis-aryl triazole trehalolipids (1a-1g) as Brartemicin analogs. The compounds comprised one or two octyloxy (C8) alkyl chains and were synthesized using the venerable CuAAc reaction between the respective aryl acetylenes and a trehalose diazide. A Mincle reporter cell assay revealed that all lipidated analogs activated Mincle. Two compounds, 1c and 1d, produced strong Mincle-dependent immune responses in vitro. The activity was dependent on the degree of alkylation and regiochemistry, with 1c and 1d showing significantly increased IL-1β production in vitro compared to monoalkylated compounds and dialkylated compounds lacking ortho substitution. Molecular docking of 1c positioned the triazole in proximity to Arg-183, which may offer additional interactions that could explain the binding affinity for this class of ligand. These findings demonstrate the capability of triazole-linked Brartemicin analogs as Mincle-mediated Th1/Th17 vaccine adjuvants.

Cross-Coupling Between Aryl Halides and Aryl Alkynes Catalyzed by an Odd Alternant Hydrocarbon.

Catalytic cross-coupling between aryl halides and alkynes is considered an extremely important organic transformation (popularly known as the Sonogashira coupling) and it requires a transition metal-based catalyst. Accomplishing such transformation without any transition metal-based catalyst in the absence of any external stimuli such as heat, photoexcitation or cathodic current is highly challenging. This work reports transition-metal-free cross-coupling between aryl halides and alkynes synthesizing a rich library of internal alkynes without any external stimuli. A chemically double-reduced phenalenyl (PLY)-based molecule with the super-reducing property was employed for single electron transfer to activate aryl halides generating reactive aryl radicals, which subsequently react with alkyne. This protocol covers not only various types of aryl, heteroaryl and polyaryl halides but also applies to a large variety of aromatic alkynes at room temperature. With a versatile substrate scope successfully tested on more than 75 entries, this radical-mediated pathway has been explained by several control experiments. All the key reactive intermediates have been characterized with spectroscopic evidence. Detailed DFT calculations have been instrumental in portraying the mechanistic pathway. Furthermore, we have successfully extended this transition-metal-free catalytic strategy for the first time towards solvent-free cross-coupling between solid aryl halide and alkyne substrates.

A copper- and amine-free sonogashira reaction catalyzed by a supported bis(oxime palladacycle) on magnetized SBA-15

The recently reported magnetic catalyst, Fe3O4@SBA-bis(oxime palladacycle), was incorporated in the Sonogashira reaction. The potential catalytic activity of the catalyst was evaluated by optimizing the reaction conditions. It was discovered that using dimethylsulfoxide (DMSO) as a solvent, a catalyst loading of 0.25 mol% palladium, Cs2CO3 as a base, and a reaction temperature of 120 °C resulted in the highest yields. The catalyst showed excellent activity with a wide range of aryl halides and aryl acetylenes in the Sonogashira reaction. The use of a low catalyst loading further highlighted its efficiency. Moreover, the catalyst demonstrated noteworthy reusability by consistently preserving its activity and stability through seven successive runs. The magnetic properties of the catalyst allowed for easy separation and recovery.

Fluorosulfonyl Arylation of Alkynes via Electron Donor-Acceptor Photoactivation.

A radical fluorosulfonyl arylation of alkynes with sulfuryl chlorofluoride as the FSO2 radical precursor via electron donor-acceptor photoactivation driven by daylight or a blue light-emitting diode is disclosed. A series of valuable benzo-fused carbocycles and heterocycles have been produced with simple operation under mild conditions in the absence of any external catalysts or additives. The synthetic potential of this protocol has further demonstrated excellent scalability, as well as diverse postderivatizations, including SuFEx reactions and other useful cascade reactions.

Transfer Hydrogenation of Vinyl Arenes and Aryl Acetylenes with Ammonia Borane Catalyzed by Schiff Base Cobalt(II) Complexes.

A series of bench-stable Co(II) complexes containing hydrazone Schiff base ligands were evaluated in terms of their activity and selectivity in carbon-carbon multiple bond transfer hydrogenation. These cobalt complexes, especially a Co(II) precatalyst bearing pyridine-2-yl-N(Me)N=C-(1-methyl)imidazole-2-yl ligand, activated by LiHBEt3, were successfully used in the transfer hydrogenation of substituted styrenes and phenylacetylenes with ammonia borane as a hydrogen source. Key advantages of the reported catalytic system include mild reaction conditions, high selectivity and tolerance to functional groups of substrates.