Electron-deficient Alkynes Research Articles

Amino-yne reaction: An exquisite method for polymer-polymer conjugation and post-polymerization modification

The amino-yne reaction, which performs between an electron-deficient alkyne and an amine, has been shown to proceed with high efficiency under mild conditions and has recently gained much interest in many fields of polymer and material science. However, this reaction has not been tested as a polymer–polymer conjugation method and has also not been employed for post-polymerization modification (PPM) of amine-functional polymers. In this study, we aimed to extend the feasibility of amino-yne reactions using the aforementioned strategies. For this purpose, for the first time, amine end-functional polymers, namely polystyrene (PS-NH2) and poly(N-isopropylacrylamide) (PNIPAM-NH2), which were prepared experimentally or obtained commercially, were reacted with activated alkyne end-functional poly(ethylene glycol) (mPEG-alkyne) via amino-yne reaction to achieve the corresponding block copolymers, PNIPAM-b-PEG and PS-b-PEG. Both reactions proceeded at room temperature without the use of any additives or catalysts. Polymer-polymer conjugation reactions were found to be highly effective, as confirmed by GPC and 1H NMR analyses. The amino-yne reaction was then utilized for the modifications of two readily available amine-functional polymers: polyethylene imine (PEI) and aminoethylaminopropylmethylsiloxane-dimethylsiloxane copolymer (poly(AEAPMS-co-DMS)). These polymers were reacted with various mono- and difunctional propiolate esters at room temperature for just two minutes. Experimental results show that both polymers could be modified with quantitative or near-quantitative efficiency, particularly with difunctional propiolates. We believe that this work has once again demonstrated the power of the amino-yne reaction, and this chemistry will definitely continue to attract interest among synthetic polymer chemists due to its rapid character, readily available starting materials, and mild conditions.

Synthesis of polyfluoroalkylphosphorylated dihydroquinolines and dihydroisoquinolines decorated with N-acylethenyl substituents by the reaction of bis(polyfluoroalkyl)phosphonates with electron-deficient acetylenes and quinolines

Dihydroquinolines and dihydroisoquinolines decorated with 2- or 4-polyfluoroalkylphosphoryl groups and N-acylethenyl, cyanoethenylphenyl substituents were synthesized in up to 91% yield via straightforward strategy including simultaneous catalyst- and solvent-free mild (room temperature, 0.2–20 h) N-ethenylation/C-phosphorylation of quinolines and isoquinolines with electron-deficient acetylene / bis(polyfluoroalkyl)phosphonate pairs. The structural interplay between 2 and 4-regioisomers was studied. The reaction with terminal acylacetylenes afforded N-acylethenyl-2-phosphoryl-1,2-dihydroquinolines of the E-configuration relative to the double bond. On the contrary, with cyanophenylacetylene, under similar conditions, a mixture of 1,2- and 1,4-regioisomers was formed (the N-ethenyl substituents having both the E- and Z-configuration) along with double phosphorylated bisadducts, 2,4-bis(polyfluoroalkylphosphoryl)-1,2,3,4-tetrahydro(iso)quinolines. The 1,4-isomers prove to be the thermodynamic products since they can be exclusively obtained by heating (70–75 °С) a mixture of 2- and 4-regioisomers. The synthesized compounds represent a new family of possible drug precursors.

Tandem-Michael-cyclization cascade to make pyridines: Use of electron-deficient acetylenes for the synthesis of indolizines in aqueous media

A mild, greener approach via tandem-Michael-cyclization cascade reaction towards the construction of a group of di- and tri-differently substituted indolizine with a broad scope of the substrate is described. The synthetic route to indolizine having different substituents, benzoyl at C5, alkyl/aryl, at C6, and ester at C7 positions is established where different N-alkylated pyrrole-2-carbaldehydes and electron-deficient acetylenes are employed for the synthesis of pyridine moiety. This methodology features water-mediated reactions compatible with various functional groups affording indolizines in good yield without using any oxidant, additive, or catalyst as well. Successfully this methodology has been extended to prepare dicarboxylate and nitrile-substituted indolizines which can be proven important from a biological activity point of view in future.

Recent Advances in the Gold-Catalyzed Reactions of Propargyl Esters.

ConspectusLate-transition-metal-based complexes represent an indispensable catalytic tool in chemical synthesis due to their ability to increase molecular complexity rapidly and efficiently from readily accessible substrates in a single operation. Added to this is the exquisite control of product chemo-, diastereo-, enantio-, and site-selectivities achieved by catalytic systems of the transition-metal salts that have been developed to mediate a wide range of functional group transformations. Within this venerable synthetic toolbox, complexes and salts of Au(I) and Au(III) have emerged in recent years as an invaluable addition as a result of their potent σ- and π-Lewis acidities and ability to stabilize cationic reaction intermediates. The insights provided by mechanistic studies examining the various electronic, steric, and stereoelectronic factors at play in the organogold species that are expected to be formed in the catalytic chemistry of the transition-metal complex have also been pivotal in understanding and exploring their potential synthetic utility. Illustrative of this, for example, is the contribution made by the gold-catalyzed cycloisomerization chemistry of propargyl esters in synthetic strategies to a variety of bioactive natural products and compounds of current pharmaceutical and materials interest. This Account summarizes our efforts over the past decade toward realizing new single-step strategies for carbocyclic and heterocyclic synthesis that relied on the gold-catalyzed reactions of propargyl esters. It outlines synthetic methods developed by the group that exploited the unique reactivities of the gold-carbene species typically generated from the [2,3]-sigmatropic rearrangement of the compound class containing a terminal or electron-deficient alkyne moiety on exposure to the transition-metal salt. This Account also describes the realization of synthetic methods initiated by the gold-catalyzed 1,3-acyloxy migration of propargyl esters with an electronically unbiased disubstituted C≡C bond that delivers the corresponding allenyl ester that is primed for further reactivity on activation by the group 11 metal complex. The studies formed a part of an ongoing overarching program within our group that was focused on determining reactivities in gold catalysis that would enable their application as readily recognizable disconnections in retrosynthetic analysis. They were additionally a part of efforts aimed at evaluating the opportunities offered by the relativistic effects possessed by a Au(I) and Au(III) complex, the most pronounced among the d-block elements and thus the catalyst of choice in alkyne activation chemistry, to generate new chemical space. For instance, we demonstrated in several studies the cycloisomerization of 1,3- and 1,4-enyne esters to be a reliable strategy for the in situ formation of a wide range of 1,4-cyclopentadienyl derivatives. Their further reaction with an appropriately placed functional group or a second starting material was then shown to afford a variety of synthetic targets containing the five-membered ring structure. An example of this was the assembly of a new member of the 1H-isoindole compound family that was found to exhibit potent TNF-α (tumor necrosis factor-α) inhibitor activity.

Synthesis and spectroscopic properties of novel indolizines and azaindolizines

Novel indolizines and pyrrolo[1,2-c]pyrimidines bearing a 3-carbonylchromen-2-one moiety on the pyrrole rings were synthesized and spectroscopic properties of some of synthesized compounds were investigated. Synthetic procedures started from 4-substituted pyrimidines, 3-(2-bromoacetyl)-2H-chromen-2-one and electron-deficient alkynes via 3+2 dipolar cycloaddition of cycloimmonium-ylides, generated in situ from their corresponding quaternary salts, in the presence of an epoxide playing the role of acid scavenger and reaction solvent. The structures of novel compounds were confirmed by chemical analyses, IR and NMR spectroscopy. Spectroscopic properties of some of the synthesized compounds were investigated.

Synthesis, Properties, and Application of Small-Molecule Hole-Transporting Materials Based on Acetylene-Linked Thiophene Core.

Three small molecule organic compounds based on conjugated acetylene-linked methoxy triphenylamine terminal groups with different substituted thiophene cores were synthesized and firstly applied as hole-transporting materials (HTMs). The electron-deficient acetylene linkers can tune the energy levels of frontier molecular orbitals. The physical property measurements show that the HTMs (CJ-05, CJ-06, and CJ-07) possess good stability, hydrophobicity, and film-forming ability. Further, the HTMs were applied in the MAPbI3-based perovskite solar cells (PSCs), and the best power conversion efficiency (PCE) of 6.04%, 6.77%, and 6.48% was achieved, respectively, which implies that they exhibit great potential in photovoltaic applications.

Design, synthesis and in vitro antitubercular evaluation of novel 7-methoxy pyrrolo[1,2-a]quinoline analogues as CYP 121 inhibitors

A novel series of pyrrolo[1,2-a]quinoline analogues (4a-n) was designed via a heterocyclic fusion approach for their antitubercular evaluation. The targeted compounds were synthesized by reacting 6-methoxy quinoline with different substituted phenacyl bromides, to get quinolinium ylide intermediates (2a-i), which have further undergone [3+2] cycloaddition with electron-deficient acetylenes to furnish novel 7-methoxy pyrrolo[1,2-a]quinoline derivatives (4a-n). All these newly synthesized intermediate products and final compounds have been characterized by spectroscopic techniques such as 1H NMR, 13C NMR, HRMS, and FT-IR. The intermediate ylides and final pyrrolo[1,2-a]quinoline analogues were evaluated for their antitubercular potential against the Mtb H37Rv strain (ATCC 27294). All the tested compounds exhibited antitubercular activity with the MIC99 in the range of 25–50 µM (10.4–25.7 µg/mL), compared to the standard drug Isoniazid (0.195 µM=0.026 µg/mL). An in silico molecular docking study revealed the strong binding affinity of target compounds with the enzyme Mtb CYP 121. The pharmacokinetic properties and toxicity predictions indicate overall drug-likeness for synthesized compounds. In this study, the compounds 4i, 4j, and 4k displayed considerable anti-TB activity against Mtb H37Rv with MIC99 values of 25 µM (10.43, 10.54, and 11.65 µg/mL respectively). CC50 of the test compounds were determined by cell viability assay using THP-1 macrophages. The compounds having methoxy and halogen substitution at the para position of the benzoyl fragment of designed molecules exhibited the best activity among the series.

Design, synthesis, characterization, and anti-tubercular activity of novel ethyl-3-benzoyl-6, 8-difluoroindolizine-1-carboxylate analogues: Molecular target identification and molecular docking studies

A series of novel Ethyl-3-benzoyl-6,8-difluoroindolizine-1-carboxylate analogues (4a-r) were synthesized by reacting 3,5-difluoropyridine, with phenacyl bromide to get quaternary pyridinium N-ylide in the presence of acetone and potassium iodide as a catalyst, further these pyridinium N-ylide intermediate reacts with various electron-deficient acetylenes, to get Ethyl-3-benzoyl-6,8-difluoroindolizine-1-carboxylate analogues (4a-r). All newly synthesized compounds were characterized by spectroscopic techniques such as 1H NMR, 13C NMR, IR, and HRMS. All the synthesized intermediates and final compounds were evaluated for their anti-tubercular activities against M. tuberculosis H37Rv (ATCC 27294). All the compounds exhibited anti-tuberculosis activity in the range of 6.25–50 µM against H37Rv. In silico evaluation of pharmacokinetic properties indicated overall drug-likeness for these compounds. The molecular target identification for these compounds was also carried out using a computational method approach. Docking studies were performed to investigate the binding affinities as well as the interaction of these compounds with target proteins. In this study, 4h, 4b, and 4o emerged as the promising anti-TB agents against M. tuberculosis H37Rv, with MIC99 values of 2.61 µg/mL, 4.67 µg/mL, and 5.02 µg/mL respectively.

Photoinduced Remote C(sp3)-H Imination Enabled by Vinyl Radical-Mediated 1,5-Hydrogen Atom Transfer.

A vinyl radical-mediated 1,5-hydrogen atom transfer strategy for remote C(sp3)-H imination under visible-light-induced photochemical metal-free conditions afforded diverse γ-imino alkenes with excellent stereoselectivity. Oxime ester-based bifunctional reagents provided not only nucleophilic alkyl radicals for radical addition reactions with electron-deficient alkynes but also long-lived steady-state imine radicals for trapping alkyl radicals following the intramolecular 1,5-hydrogen migration of unstable olefin radicals.

Synthesis of Guaipyridine Alkaloids Rupestine M and L by Cycloaddition/Cycloreversion of an Intermediate 1,4-Oxazinone.

A new method to prepare 1,4-oxazinone intermediates was developed based on aza-conjugate addition of β-amino alcohols to electron-deficient alkyne precursors. A tandem intramolecular cycloaddition/cycloreversion reaction sequence was evaluated, leading to the synthesis of the guaipyridine alkaloid natural products rupestine M and L. Starting from (-)-citronellal and thus a known configuration of the C5 stereocenter, a revised absolute configuration of natural rupestine L is suggested based on optical rotation.

Aerobic oxyfunctionalization of alkynes by a bioinspired flavin–metal ion photocatalytic system

α-Keto ketals and benzannulated oxo-spiroketals have been regioselectively synthesized using a Sc3+-coordinated riboflavin tetraacetate photocatalyst with electron-deficient alkynes and alkynediols, respectively.

Iron-catalyzed divergent approach to naphthyridinones and quinolinones: leveraging Povarov and carbonyl-alkyne metathesis reactions of electron deficient alkynes

We have successfully developed a novel synthetic route for the synthesis of naphthyridinones.

Synthesis of 2-trifluoromethylated 3-pyrrolines/pyrrolidines via [3+2] cycloaddition of azomethine ylides with the participation of 3,3,3-trifluoroalanine

2-Trifluoromethylated 3-pyrrolines and pyrrolidines were synthesized via condensation of 3,3,3-trifluoroalanine with carbonyl compounds, decarboxylative formation of azomethine ylides, and the subsequent [3+2] cycloaddition with electron deficient alkynes and alkenes. The reaction proceeded under mild conditions to give the adducts in moderate to good yields. The product 3-pyrroline was successfully converted to the corresponding pyrrole upon treatment with o-iodoxybenzoic acid.

Activation of Alkynes by a Redox-Active Carboranyl Diphosphine and Formation of Boron-Containing Phosphacycles.

In this work, we report the reactivity of the carboranyl diphosphine, 1-PtBu2-2-PiPr2-C2B10H10, with terminal alkynes, resulting in the formation of boron-containing phosphacycles. The reported system combines the nucleophilic activation of electron-deficient terminal alkynes via electron-rich phosphine groups with the redox behavior of carborane clusters to promote a sequence of metal-free intramolecular B-H bond activation and cyclization, creating an alkenylphosphonium cycle fused with a reduced open nido-carborane cluster.

Ru-Catalyzed Benzannulation of Vinyl Sulfoxonium Ylide with Electron-Deficient Alkynes and Alkenes.

Herein, we report carbene-mediated benzannulation of vinyl sulfoxonium ylides with electron-deficient alkynes and alkenes to synthesize oxygenated arenes. This protocol features excellent regioselectivity, a broad substrate scope, and mild reaction conditions. Mechanistic studies revealed that the reaction proceeds through furan generation, cycloaddition, ring cleavage, and aromatization cascades. The synthesized arenes have been utilized in diverse product transformations and arene ring homologation.

Organosuperbase-Catalyzed 1,1-Diboration of Alkynes

1,1-Diboryl alkenes are versatile building blocks in organic synthesis and medicinal chemistry. However, there have been only a small number of established methods to prepare this class of compounds, and most of them used transition-metal catalysts, which are undesirable in the preparation of biologically relevant compounds. Herein, we report an unprecedented application of P1–tBu phosphazene as a superbasic organocatalyst to promote 1,1-diboration reactions of unactivated aromatic and electron-deficient terminal alkynes. The dual Brønsted and Lewis basicity of this phosphazene enables the activation of reaction substrates and allows for high regio- and stereoselectivity to be obtained. A combination of thorough experimental and computational studies suggests interesting mechanistic insights for these phosphazene-catalyzed diboration reactions, which are also discussed in detail.

SNHAr Reaction of Pyridines with Bis(polyfluoroalkyl)phosphonates Assisted by Electron-Deficient Acetylenes

SNHAr Reaction of Pyridines with Bis(polyfluoroalkyl)phosphonates Assisted by Electron-Deficient Acetylenes

Preparation of [18F]Alkenyl Fluorides Using No-Carrier-Added [18F]AgF via Silver-Mediated Direct Radiofluorination of Alkynes.

We have developed a versatile method for the radiosynthesis of [18F]alkenyl fluorides using no-carrier-added [18F]AgF via the silver-mediated direct radiofluorination of alkynes. A variety of electron-deficient internal alkynes were compatible with this strategy and gave the desired product in good regioselectivity and RCY. This method could also be applied to the late-stage radiofluorination and showed potential in nuclear medicine development.

Theoretical Study of Mechanism and Product Selectivity of Metal-Catalyzed Reactions of Alkynyl Thioethers with Isoxazoles/Anthranils

Density functional theory (DFT) calculations were performed to investigate the detailed mechanisms of metal-catalyzed reactions of alkynyl thioethers with isoxazoles/anthranils. The origins of the product selectivities were also explored. The results show that when [IPrAu(CH3CN)]+ was used as the catalyst, β-selective addition gave a sulfenylated pyrrole/indole as the primary product. However, the major product was a sulfur-substituted β-keto enamide, which was formed via α-addition, when [Zn(OTf)]+ was used. The product selectivity was determined by the first nucleophilic attack step. We found that the catalyst and substrate both played crucial roles in guiding the product selectivity. The electronic effects of ligands on the catalyst and substituents on the substrate were the dominant factor. For the anthranil substrate, the preference for C1–C6 bond coupling rather than C1–C4 bond coupling can be attributed to effective conjugation between the carbonyl group and the phenyl moiety during C1–C6 bond coupling. These insights into the mechanisms of metal-catalyzed reactions of alkynyl thioethers with isoxazoles/anthranils will facilitate the design of new catalytic reactions of isoxazoles with electron-deficient alkynes.

Consecutive Alkylation, "Click", and "Clip" Reactions for the Traceless Methionine-Based Conjugation and Release of Methionine-Containing Peptides.

"Click" reactions have revolutionized research in many areas of science. However, a disadvantage of the high stability of the Click product is that identifying simple treatments for cleanly dissociating the latter under the same guiding principles, i.e., a "Clip" reaction, remains a challenge. This study demonstrates that electron-deficient alkynes, conveniently installed on methionine residues, can participate in well-known Click (nucleophilic thiol-allene addition) and subsequent Clip reactions (radical thiol-ene addition). To illustrate this concept, a variety of bioconjugates (peptide-peptide; peptide-fluorophore; peptide-polymer; and peptide-protein) were prepared. Interestingly, the Clip reaction of these bioconjugates releases the original peptides concurrent with regeneration of their unmodified methionine residue, in minutes. Moreover, the conjugates demonstrate substantial stability toward endogenous levels of reactive species in bacteria, illustrating the potential for this chemistry in the biosciences. The reaction conditions employed in the Click and Clip steps are compatible with the preservation of the integrity of biomolecules/fluorophores and involve readily accessible reagents and the natural functional groups on peptides/proteins.