Terminal Alkynes Research Articles

Photo-induced microfluidic production of ultrasmall platinum nanoparticles.

We describe here the synthesis of ultrasmall Pt nanoparticles (NPs) obtained by a robust and reliable protocol using UV-Vis photoreduction of a platinum salt precursor, under continuous flow conditions. These ligand-free Pt NPs were rapidly dispersed onto a solid support or stabilized towards aggregation as a colloidal solution by the addition of an appropriate ligand in the reaction mixture. The proposed protocol exploits a microfluidic platform where the Pt4+ precursor is photo-reduced to small Pt0 NPs (1.3 nm) at room temperature in the presence of ethanol, without any additional reducing agent. We apply the protocol to prepare Pt NPs highly dispersed on carbon support (Pt/C) proven to be a very efficient heterogeneous catalyst for both the hydrosilylation of terminal alkynes and hydrogenation of nitroaromatic compounds, selected as model reactions. Furthermore, we exploit the versatility of this microfluidic approach to produce stabilized aqueous/ethanol colloidal solutions of Pt NPs, employing a ligand of choice (e.g., PVP or a thiol-ligand). These colloids offer long-term storage and further ligand modification. We showcase the synthesis of biocompatible glycol-stabilized Pt nanoparticles as an exemplary application.

Regio- and chemoselective hydroboration of terminal alkynes with pinacolborane catalyzed by organo rare earth metal complexes

We herein report the regio- and chemoselective hydroboration of terminal alkynes with pinacolborane by a series of constrained-geometry catalyst-type or CGC-type rare earth metal monoalkyl complexes.

Utilizing perhalopyridine-based alkynes as suitable precursors for the synthesis of novel poly(1,2,3-triazolyl)-substituted perhalopyridines.

A novel series of poly(1,2,3-triazolyl)-substituted perhalopyridines 5a-f were successfully synthesized from the click reaction of the terminal alkynes (drived from the nucleophilic substitution reactions of PFP 1a and PCP 1b with excess amounts of propargyl alcohol) with aryl azides 4a-c under ultrasonic irradiation. Likewise, the sonication of reaction mixtures containing pyridyl cores 3, alkyl bromides 6a,b, and NaN3 under one-pot conditions afforded their respective aliphatic 1,2,3-triazoles 7a-d in yields ranging from 71% to 83%. We next developed an effective method for the regioselective preparation of 2,3,4,5-tetrachloro-6-(prop-2-yn-1-yloxy)pyridine 3c through SNAr reaction of PCP with propargyl alcohol without the utilization of any catalyst. It was then used to fabricate several ((1,2,3-triazol-4-yl)methoxy)-3,4,5,6-tetrachloropyridines 8a-c under the reaction conditions. Finally, the Pd(PPh3)4-catalyzed SMC reaction of tris-triazoles 5b,e with arylboronic acids 9a-c offered a practical method for the synthesis of biaryl-embedded poly(1,2,3-triazoles) 10a-f in good yields.

Transfer semi-hydrogenation of terminal alkynes with a well-defined iron complex.

The synthesis and characterization of a bis-iron(II) complex was accomplished upon treatment of a phosphine free NNN-pincer ligand (L) with FeCl2·4H2O under ambient conditions. The deep greenish colored iron(II) complex (Fe-1) was characterized by a single-crystal X-ray diffraction study along with IR spectroscopy, UV-Vis spectroscopy, mass spectrometry, and elemental analysis. The Fe-1 complex was tested for the transfer semi-hydrogenation of terminal alkynes to the corresponding alkenes through the dehydrogenation of dimethyl amine-borane. This procedure enables the conversion of various structurally different terminal alkynes to alkenes under mild conditions. Control experiments were performed to shed light on the possible intermediates generated during the present protocol.

Design, synthesis and modelling of photoreactive chemical probes for investigating target engagement of plasmepsin IX and X in Plasmodium falciparum.

The emergence of Plasmodium parasite resistance to current front-line antimalarial treatments poses a serious threat to global malaria control and highlights the necessity for the development of therapeutics with novel targets and mechanisms of action. Plasmepsins IX and X (PMIX/PMX) have been recognised as highly promising targets in Plasmodium due to their contribution to parasite's pathogenicity. Recent research has demonstrated that dual PMIX/PMX inhibition results in the impairment of multiple parasite's life cycle stages, which is an important feature in drug resistance prevention. Herein we report novel hydroxyethylamine photoaffinity labelling (PAL) probes, designed for PMIX/PMX target engagement and proteomics experiments in Plasmodium parasites. The prepared probes have both a photoreactive group (diazirine or benzophenone) for covalent attachment to target proteins, and a terminal alkyne handle allowing their use in bioorthogonal ligation. One of the synthesised benzophenone probes was shown to be highly promising as demonstrated by its outstanding antimalarial potency (IC50 = 15 nM versus D10 P. falciparum) and its inhibitory effect against PfPMX in an enzymatic assay. Molecular docking and molecular dynamics studies show that the inclusion of the benzophenone and alkyne handle does not alter the binding mode compared to the parent compound. The photoaffinity probe can be used in future chemical proteomics studies to allow hydroxyethylamine drug scaffold target identification and validation in Plasmodium. We expect our findings to act as a tool for future investigations on PMIX/PMX inhibition in antimalarial drug discovery.

Lewis acid catalyzed Markovnikov hydrobromination and hydrochlorination of alkynes using TMSX (X = Br, Cl).

Markovnikov hydrobromination and hydrochlorination of alkynes were achieved using TMSX (X = Br, Cl) instead of corrosive HX (X = Br, Cl) as the bromination and chlorination reagents. Mn(OAc)2·4H2O was used as the hydrobromination catalyst for electron-neutral/rich alkynes. For the hydrobromination of electron-deficient alkynes and hydrochlorination of alkynes, Zn(OAc)2·2H2O was employed as the catalyst. Mechanistic studies suggested that the in situ formed TMS-substituted alkyne might be a reactive intermediate and the proton of the terminal alkyne should be a hydrogen source for the hydrohalogenation reaction.

Efficient and selective external activator-free cobalt catalyst for hydroboration of terminal alkynes enabled by BiPyPhos.

Herein, a robust catalyst system, composed of a bipyridine-based diphosphine ligand (BiPyPhos) and a cobalt precursor Co(acac)2, is successfully developed and applied in the hydroboration of terminal alkynes, exclusively affording various versatile β-E-vinylboronates in high yields at room temperature.

Synthesis and biological evaluation of moiramide B derivatives.

Moiramide B is a peptide-polyketide hybrid with a bacterial origin and interesting antibiotic activity. Besides its structurally conserved peptide part, it contains a highly variable fatty acid side chain. We modified this part of the molecule by introducing a terminal alkyne, and we then subjected it to click reactions and Sonogashira couplings. This provided a library of moiramide B derivatives with high and selective in vivo activities against S. aureus.

Rhodium-catalysed homo-coupling of terminal alkynes: divergent synthesis of bioactive 1,3-diynes and conjugated enediynes

C(sp)–C(sp) cross-coupling of terminal alkynes represents a robust tool for building biologically active 1,3-diynes although confronted with huge challenges regarding selectivity control.

Electrochemical trifluoromethylation of alkynes: the unique role of DMSO as a masking auxiliary

An electrochemical trifluoromethylation method for terminal alkynes has been developed, facilitating the synthesis of CF3-alkynes with DMSO as a masking auxiliary.

Palladium(ii) complexes bearing mesoionic carbene ligands: catalytic application in domino Sonogashira coupling/cyclization reactions for one-pot synthesis of benzofuran and indole derivatives.

Bioactive heterocycles such as benzofuran and indole derivatives were synthesized from commercially available 2-iodoarenes and alkynes via domino Sonogashira coupling followed by cyclization reaction using well-defined palladium PEPPSI (Pyridine Enhanced Precatalyst Preparation Stabilization and Initiation) complexes (2a and 2b). These reactions tolerate a variety of 2-iodoarenes and diversely substituted terminal alkynes, resulting in the corresponding product in moderate to good yields in an open-air atmosphere. In particular, two palladium(ii) PEPPSI complexes 2a and 2b were synthesized in good yields from the reaction of corresponding 1,2,3-triazol-5-ylidene (MIC: mesoionic carbene), PdCl2, KI, and K2CO3 in pyridine at 110 °C and structurally characterized by various spectroscopic techniques including NMR spectroscopy, IR spectroscopy, HRMS and elemental analysis studies. Complex 2b is also characterized by X-ray crystallography.

Synergistic catalysis by Brønsted acid and Pd species on a mesoporous ZSM-5 zeolite for the oxidative homocoupling of terminal alkynes

The Brønsted acid and Pd species on Pd@MZSM-5 synergetically catalyzed the oxidative homocoupling of terminal alkynes, where the Brønsted acid promote the alkyne chemisorption and benefit the formation of the alkynyl-palladium(ii) complex.

Photoinduced selective perfluoroalkylation of terminal alkynes via electron donor-acceptor complexes.

Herein, we report a photoinduced selective perfluoroalkylation of terminal alkynes driven by the noncovalent interaction between a thymol anion and fluoroalkyl iodides. By precisely tuning the reaction solvent, a wide range of 37 structurally diverse perfluoroalkylated alkynes and alkenes, including ibuprofen, empagliflozin, galactose, isoxepac and indomethacin, were obtained in up to 92% yields. Mechanistic studies reveal the formation of EDA complexes between the thymol anion and fluoroalkyl iodides. This strategy may provide an important complement to traditional approaches to prepare useful perfluoroalkylated alkynes and alkenes.

Metal-catalyzed Markovnikov-type selective hydrofunctionalization of terminal alkynes.

Metal-catalyzed highly Markovnikov-type selective hydrofunctionalization of terminal alkynes provides a straightforward and atom-economical route to access 1,1-disubstituted alkenes, which have a wide range of applications in organic synthesis. However, the highly Markovnikov-type selective transformations are challenging due to the electronic and steric effects during the addition process. With the development of metal-catalyzed organic synthesis, different metal catalysts have been developed to solve this challenge, especially for platinum group metal catalysts. In this perspective, we review homogeneous metal-catalyzed Markovnikov-type selective hydrofunctionalization of terminal alkynes according to the classified element types as well as reaction mechanisms. Future avenues for investigation are also presented to help expand this exciting field.

The synthesis of alk-2-ynl Weinreb amides via Pd/Cu-catalysed oxidative carbonylation of terminal alkynes.

Synthesis of alk-2-ynl-Weinreb amides via Pd-catalyzed oxidative carbonylation of terminal alkynes and N,O-dimethylhydroxylamine hydrochloride at room temperature under low CO/O2 pressure is reported for the first time. This protocol offers tolerance of various functional groups under mild reaction conditions. The protocol incorporates aromatic- and aliphatic-substituted alkynes through a one-step oxidative carbonylative route toward desired alkynyl Weinreb amides, which are of considerable importance as valuable synthetic building blocks.

Electroreductive deuteration of N-propynylamides to enamides

A migratory reductive deuteration of terminal alkynes to access enamides with more than 3 deuteriums incorporated per molecule was realized.

Synthesis, Crystal structure, Anticancer evaluation and Hirshfeld surface analysis of novel antipyrine gathered bis-triazoles as breast adenocarcinoma inhibitors

A series of novel substituted antipyrine attached bis-triazoles 7(a-h) were synthesized via coupling followed by click chemistry reaction. Their structure was established by means of physico-chemical spectral studies and a single-crystal X-ray diffraction analysis (7c and 7f). X-ray diffraction results exhibited that 7c and 7f were crystallized in triclinic space group P¯1 where a=9.352 (3), b=11.002 (3), c=14.616 (4) Å and also revealed that the bis-triazole ring formed by two terminal alkyne groups joined with substituted azides (6a-h). The Hirshfeld surface analysis of the crystal surface shows that the most contributions for H…H/H…H, C… H/H …C, N…H / H…N, O…H/H…O, and C …C interactions. Breast adenocarcinoma cell line used test the compounds anticancer effects by MTT assay. Compound 7f was found to be most promising scaffold, exhibiting a anticancer effect near to standard imatinib (IC50 at 25.03±0.01 mg). The results exhibited that these analogues could be lead compounds in search for new effective anticancer agents.

Electrocatalytic Semihydrogenation of Terminal Alkynes Using Ligand-Based Transfer of Protons and Electrons.

Alkyne semihydrogenation is a broadly important transformation in chemical synthesis. Here, we introduce an electrochemical method for the selective semihydrogenation of terminal alkynes using a dihydrazonopyrrole Ni complex capable of storing an H2 equivalent (2H+ + 2e-) on the ligand backbone. This method is chemoselective for the semihydrogenation of terminal alkynes over internal alkynes or alkenes. Mechanistic studies reveal that the transformation is concerted and Z-selective. Calculations support a ligand-based hydrogen-atom transfer pathway instead of a hydride mechanism, which is commonly invoked for transition metal hydrogenation catalysts. The synthesis of the proposed intermediates demonstrates that the catalytic mechanism proceeds through a reduced formal Ni(I) species. The high yields for terminal alkene products without over-reduction or oligomerization are among the best reported for any homogeneous catalyst. Furthermore, the metal-ligand cooperative hydrogen transfer enabled with this system directs the efficient flow of H atom equivalents toward alkyne reduction rather than hydrogen evolution, providing a blueprint for applying similar strategies toward a wide range of electroreductive transformations.

Copper-catalysed electrophilic carboamination of terminal alkynes with benzyne looked at through the computational lens.

A detailed computational mechanistic study of the copper-catalysed three-component-type electrophilic carboamination of terminal alkynes with benzyne and an archetypal O-benzoylhydroxylamine electrophile is presented. Probing various plausible pathways for relevant elementary steps and scrutinising performance degradation pathways, with the aid of a reliable computational protocol applied to a realistic catalyst model combined with kinetic analysis, identified the pathways preferably traversed in productive catalysis. It entails rapid alkynylcupration of in situ generated benzyne to deliver the arylcopper nucleophile that undergoes amination with the O-benzoylhydroxylamine electrophile to afford copper benzoate. Umpolung-enabled electrophilic amination favours a multistep SN2-type oxidative addition/N-C bond-forming reductive elimination sequence involving a short-lived formal {P^P}CuIII carboxylate amido aryl intermediate. SN2-type displacement of the benzoate leaving group at the arylcopper nucleophile, which represents the catalyst resting state, is predicted to be the turnover limiting step. Alkynolysis transforms copper benzoate back to catalytically competent alkynylcopper. The computational probe of a wider range of substrates reveals that only severely ring-strained C6-arynes, C6-cycloalkynes and electron-deficient cyclopropenes featuring a highly reactive C≡C linkage could replace benzyne. Moreover, strict control of stationary benzyne concentration is indispensable for electrophilic carboamination to ever become achievable.

Pd/C-catalyzed regiodivergent hydrocarboxylation and esterification of alkynes.

An unprecedented and highly reactive Pd/C catalytic system has been introduced for the regiodivergent hydrocarboxylation of terminal alkynes to selectively afford various acrylic and cinnamic acids employing oxalic acid as a CO source as well as a promoter for the formation of the active Pd-H complex. Herein, the formation of cinnamic acid is proposed to follow a unique anti-Markovnikov hydroiodination mechanism and the formation of acrylic acid might follow the traditional hydrocarboxylation pathway. Additionally, internal alkynes undergo hydrocarboxylation and carbonylative esterification with aliphatic alcohols to yield different α,β-unsaturated acids and esters respectively. The designed strategies were successfully leveraged for a diverse class of α,β-unsaturated acids and esters with excellent selectivity and yields under mild reaction conditions. Furthermore, the acid functionalization of complicated naturally derived alkynes, utilizing economical and bench-stable oxalic acid and a commercially accessible reusable catalyst with gram-scale applicability are the additional benefits of the established protocol.