Electron-deficient Alkynes Research Articles

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.

Triplet Energy Transfer (EnT)-Promoted 1,3-Dipolar Cycloaddition Reactions of N-(Trimethylsilyl)methylphthalimide with Electron-Deficient Alkynes and Alkenes.

Triplet energy transfer (EnT)-promoted photochemical pathways, arisen by visible light and its photosensitizers, have gained significant attention as a complementary strategy for initiating organic transformations in photochemical reactions that are unlikely to occur through a single electron transfer (SET) process. In the present study, we investigated the triplet EnT-promoted 1,3-dipolar cycloaddition reactions of N-(trimethylsilyl)methylphthalimide with electron-deficient alkynyl and alkenyl dipolarophiles. The triplet excited state of N-(trimethylsilyl)methylphthalimide, promoted by the triplet EnT from thioxanthone (TXA) photosensitizer, underwent sequential intramolecular SET and carbon-to-oxygen migration of the silyl group to form azomethine ylide. This generated ylide cycloadded to alkynes or alkenes to regioselectively and stereospecifically produce a nitrogen-containing benzopyrrolizidine scaffold with multiple stereogenic centers. Crucially, the stereoselectivity of these cycloaddition reactions (i.e., endo versus exo addition) was influenced by the nature of the dipolarophiles.

Synthesis and structural elucidation of novel quaternary pyridinium salt and indolizine derivatives as an anti-tubercular agent: In Silico and In Vitro screening

The in vitro anti-mycobacterial activity of a novel series of diversely substituted quaternary pyridinium salts (3a-m) and indolizines (5a-h) were assessed against H37Rv strain of Mycobacterium tuberculosis (M.tb). The series of intermediate 1-(2-oxo-2-phenylethyl)-4-(piperidin-1-yl)pyridin-1-ium bromide, which contains a heterocyclic ring molecule, has been prepared by reacting with 4-(piperidin-1-yl)pyridine and phenacyl bromide at room temperature. The final ethyl 3-benzoyl-7-(piperidin-1-yl)indolizine-1-carboxylate analogues were prepared by using pyridin-1-ium bromide with electron-deficient acetylene, undergoing 1, 3-dipolar cycloaddition at the ambient temperature using anhydrous potassium carbonate and N, N-dimethylformamide as a solvent. All the newly synthesized compounds were characterized by spectroscopic techniques such as 1H and 13C NMR, and HRMS. All the synthesized intermediates and final compounds were evaluated for their anti-tubercular activities against H37Rv (ATCC 27294) strain. All the compounds exhibited anti-tubercular activities in the range of 12.5–50 µM. In vitro screening of all derivatives concluded that among all the screened candidates 3k emerged as an active hit with MIC 12.5 µM, 3l and 3m with MIC 25 µM.

BioLindlar Catalyst: Ene-Reductase-Promoted Selective Bioreduction of Cyanoalkynes to Give (Z)-Cyanoalkenes.

The direct synthesis of alkenes from alkynes usually requires the use of transition-metal catalysts. Unfortunately, efficient biocatalytic alternatives for this transformation have yet to be discovered. Herein, the selective bioreduction of electron-deficient alkynes to alkenes catalysed by ene-reductases (EREDs) is described. Alkynes bearing ketone, aldehyde, ester, and nitrile moieties have been effectively reduced with excellent conversions and stereoselectivities, observing clear trends for the E/Z ratios depending on the nature of the electron-withdrawing group. In the case of cyanoalkynes, (Z)-alkenes were obtained as the major product, and the reaction scope was expanded to a wide variety of aromatic substrates (up to >99 % conversion, and Z/E stereoselectivities of up to >99/1). Other alkynes containing aldehyde, ketone, or ester functionalities also proved to be excellent substrates, and interestingly gave the corresponding (E)-alkenes. Preparative biotransformations were performed on a 0.4 mmol scale, producing the desired (Z)-cyanoalkenes with good to excellent isolated yields (63-97 %). This novel reactivity has been rationalised through molecular docking by predicting the binding poses of key molecules in the ERED-pu-0006 active site.

Revealing the mechanism, Regio- and stereo selectivity and solvent effects of [3 + 2] cycloaddition reactions involving N-benzyl fluoro nitrone and electron-deficient alkynes

The [3 + 2] cycloaddition reactions (32CA) between N-benzyl fluoro nitrone and electron-deficient dipolarophiles alkynes have been studied using molecular electron density theory at the B3LYP-D3/6-31G(d) level. The findings indicate that, in these 32CA reactions, a one-step mechanism is in play with asynchronous transition states. The topological analyses of these transition states are consistent with the presence of non-covalent interactions at the bonding regions between atoms. The analysis of the energy profile in gas phase and in the presence of solvents indicates a preference for a specific site addition over the others. Parr functions were thus used to justify such regioselectivity. In addition, we show that solvents do not modify the regioselectivity achieved, but it increases the activation energies and reduces the exothermic nature of this 32CA reaction. The present findings are in agreement with the experimental results.

Red-Light-Promoted Radical Cascade Reaction to Access Tetralins and Dialins Enabled by Zinc(II)porphyrin, A Light-Flexible Catalyst.

[5,15-Bis(pentafluorophenyl)-10,20-diphenylporphinato]zinc(II) (1), a metalloporphyrin derivative that was recently reported as an efficient photocatalyst driven by blue LEDs by our group, was found to catalyze a red-light-promoted (630 nm LEDs) radical cascade reaction of N-3-arylpropionyloxyphthalimides with radicophiles including electron-deficient alkenes and alkynes, providing access to a range of functionalized tetralin and dialin derivatives. The radical cascade reaction catalyzed by 1 took place via an oxidative quenching cycle in DMSO, where no sacrificial electron donor was required, uncovering a unique solvent effect capable of promoting the porphyrin catalysis.

Leveraging Pyrazolium Ylide Reactivity to Access Indolizine and 1,2-Dihydropyrimidine Derivatives.

N-Heterocyclic ylides are important synthetic precursors to rapidly build molecular complexity. Pyrazolium ylides have largely been unexplored, and we demonstrate their diverse utility in this report. We show that these readily accessible building blocks can be used to construct different heterocyclic skeletons by varying the coupling partner. Indolizines can be formed via an N-deletion type mechanism when reacting pyrazolium salts with electron deficient alkynes. 1,2-Dihydropyrimidines can be formed via a rearrangement mechanism when reacting pyrazolium ylides with isocyanates. These reactions enable access to valuable heteroarenes without the need for transition metal catalysis, high temperatures, or strong bases.

Design, synthesis and characterization of ethyl 3-benzoyl-7-morpholinoindolizine-1-carboxylate as anti-tubercular agents: In silico screening for possible target identification.

A thorough search for the development of innovative drugs to treat tuberculosis, especially considering the urgent need to address developing drug resistance, we report here a synthetic series of ethyl 3-benzoyl-7-morpholinoindolizine-1-carboxylate analogues (5a-o) as potent anti-tubercular agents. These morpholino-indolizines were synthesized by reacting 4-morpholino pyridinium salts, with various electron-deficient acetylenes to afford the ethyl 3-benzoyl-7-morpholinoindolizine-1-carboxylate analogues (5a-o). All synthesized intermediate and final compounds are characterized by spectroscopic methods such as 1H NMR, 13C NMR and HRMS and further examined for their anti-tubercular activity against the M. tuberculosis H37Rv strain (ATCC 27294-American type cell culture). All the compounds screened for anti-tubercular activity in the range of 6.25-50 μM against the H37Rv strain of Mycobacterium tuberculosis. Compound 5g showed prominent activity with MIC99 2.55 μg/mL whereas compounds 5d and 5j showed activity with MIC99 18.91 μg/mL and 25.07 μg/mL, respectively. In silico analysis of these compounds revealed drug-likeness. Additionally, the molecular target identification for Malate synthase (PDB 5CBB) is attained by computational approach. The compound 5g with a MIC99 value of 2.55 μg/mL against M. tuberculosis H37Rv emerged as the most promising anti-TB drug and in silico investigations suggest Malate synthase (5CBB) might be the compound's possible target.

Cyclization Reactions of In Situ-Generated Acyl Ketene with Ynones to Form Oxacycles.

Acyl ketenes react with polar unsaturated functional groups to give unique heterocyclic rings, yet reactions with unpolarized unsaturated functional groups have not been reported. Herein, we describe two effective ring-forming reactions between acetyl ketene and electron-deficient alkynes. The first reaction involves in situ tethering between acetyl ketene and nucleophile-containing 1,3-diynones, which promotes sequential intramolecular 1,6/1,4-additions to generate 2-methylene-2H-pyrans in various yields (24-91%). The other involves a zwitterionic intermediate generated from acetyl ketene and DABCO, which undergoes a Michael addition with terminal alkynyl ketones to generate 3-acyl-4-pyrones (11-79%).

Rapid polythioether synthesis and thioether network formation using thiol-yne chemistry of electron-deficient alkynes

The preparation of polythioethers has gained importance again after the development of click chemistry reactions. The thiol-X reactions, i.e., thiol-ene reactions based on free radical mechanism facilitated by light or heat, and thiol-Michael and thiol-epoxy reactions, which are the main synthetic pathways for the synthesis of polymers (linear, hyperbranched (HB), and network) with thioether linkages and meet most of the features of click reactions strategy, have currently been revisited. For a while, our group has focused on synthesizing linear, HB, and network polythioethers based on electron-deficient alkyne-containing precursors. We have shown that electron-deficient alkyne-containing monomers and polymers offer a suitable platform for thiol-Michael (i.e., thiol-yne) click reactions to yield linear, HB, and network structures rapidly under ambient conditions. The central structure in these polythioether syntheses is electron-deficient alkyne bonds of acetylenedicarboxylates, which are then reacted with dithiols in chloroform through an organobase 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD) at ambient temperatures. Moreover, acetylenedicarboxylates are functionalized using copper-free azide-alkyne cycloaddition reaction followed by reacting with multifunctional allyl and SH derivatives through thiol-ene photopolymerization resulting in polymeric networks with thioether linkages. This feature article highlights our contribution to the synthesis of linear, HB, and network polythioether based on various electron-deficient alkyne precursors.

Coinage (Au, Ag, Cu) metal-catalyzed (3 + 2) annulation of α-aminoketones and electron-deficient alkynes as a route to 3-EWG-substituted pyrroles

Coinage (Au, Ag, Cu) metal-catalyzed (3 + 2) annulation of α-aminoketones and electron-deficient alkynes provides a modular one-step route to a variety of 3-EWG-substituted pyrroles.

Cascade hydroarylation/Diels-Alder cycloaddition of alkynylindoles with electron-deficient alkynes and alkenes.

Herein, a novel cascade gold(I)-catalyzed hydroarylation of alkynylindoles and subsequent Diels-Alder cycloaddition with electron-deficient alkynes and alkenes is described. A variety of azepino-fused hydrocarbazoles and carbazoles were obtained in moderate to excellent yields. Key features of this methodology are low catalyst loadings, high regioselectivity, broad functional group tolerances, access to important heterocycles, and 100% atom economy.

Stereodivergent sila-germylenation vs. sila-stannylenation of an internal alkyne.

We report on the insertion of electron deficient alkyne, dimethyl acetylene dicarboxylate (DMAD), into the E-Si bond of hypersilyl tetrylenes, PhC(NtBu)2ESi(SiMe3)3 (E = Ge and Sn), at room temperature. Uniquely, the germylene leads to cis alkenes, while the stannylene gives access to trans alkenes, and the insight into divergent stereoselectivity has been obtained by DFT studies.

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.

Catalyst- and solvent-free regiospecific SNHAr phosphinylation of pyridines with H-phosphinates mediated by benzoylphenylacetylene.

Pyridines undergo a facile SNHAr phosphinylation with H-phosphinates under catalyst- and solvent-free conditions (50-55 °C) in the presence of benzoylphenylacetylene to afford 4-phosphinylpyridines in up to 68% yield. In this reaction, benzoylphenylacetylene activates the pyridine ring by the formation of a 1,3(4)-dipolar complex, deprotonates H-phosphinates to generate P-centered anions and finally acts as an oxidizer, being eliminated from an intermediate ion pair. Terminal electron-deficient acetylenes (methyl propiolate and benzoylacetylene) are inefficient as mediators in the above SNHAr process.

Nucleophilic substitution of hydrogen in pyridine and its derivatives by organophosphorus nucleophiles in the presence of electron-deficient acetylenes

The review considers publications on a new easy functionalization of pyridinoids (pyridines, quinolines, isoquinolines, acridine, phenanthridine) by the electron-deficient acetylene (esters of acetylenecarboxylic acids, acylacetylenes, cyanoacetylenes)/P-nucleophile (phosphine chalcogenides, H -phosphonates) system. Particular attention is paid to the SN H reaction of regioselective cross-coupling of pyridines with secondary phosphine chalcogenides, initiated by acylacetylenes and leading to the formation of 4-chalcogenophosphorylpyridines. In these processes, acetylenes act as trimodal adjuvants by (1) activating the pyridine ring towards P-nucleophiles, (2) deprotonating the P-H bond, and (3) facilitating the nucleophilic addition of the P-centered anion to the heterocyclic fragment, followed by the release of selectively reduced (to E -alkenes) acetylenes.

Synthesis of pyrenocycloalkenes by using [2 + 2] photocycloaddition to pyrene and Diels–Alder reaction

Photoreaction of pyrene 1 with methyl cinnamate 15a gave a photocycloadduct 16a at 4,5-position of pyrene stereoselectively. Oxidation of 16a using DDQ yielded a pyrenocyclobutene derivative 18a. Functional group conversion of the ester moiety of 18a resulted in the synthesis of carboxylic acid 19, alcohols 20 and 21, sulfonate 23, and methylenecyclobutene 24. Diels–Alder reactions of 18a with electron-deficient alkenes or alkynes 25a–f afforded cycloadducts, pyrenocyclohexenes 26a–c and pyrenocyclohexadienes 26e, f stereoselectively in good yields. Thermal reactions of pyrenocyclobutene-linked electron-deficient alkenes 22a, b produced 4-benzyl-5-alkenylpyrenes 29a, b via ring cleavage followed by 1,5-hydrogen transfer.

Non-Friedländer Route to Diversely 3-Substituted Quinolines through Au(III)-Catalyzed Annulation Involving Electron-Deficient Alkynes.

Gold(III)-catalyzed annulation of electron-deficient alkynes and 2-amino-arylcarbonyls provides general modular one-step access to a broad scope of quinoline products. This highly selective reaction is a useful alternative to the classic Friedländer synthesis, which requires harsh reaction conditions. In contrast, the developed method works under relatively mild PicAuCl2-catalyzed conditions and exhibits a high functional group tolerance (40 examples; yields of ≤96%). Another feature of the developed approach is a versatility toward other electron-deficient alkynes. Alkynylsulfones, alkynylcarbonyls, alkynylphosphonates, propiolonitriles, and trifluoromethylated alkynes can be used as the starting materials for the preparation of quinolines diversely substituted at position 3. On the basis of experimental data, we proposed a reaction mechanism in which gold(III) functions as a strong electrophilic activator of the C≡C bond and the carbonyl group. The synthetic potential of the presented method is additionally illustrated by practical postmodifications of the obtained compounds, including a two-step synthesis of interpirdine, a potent drug candidate.

Iterative Dual-Metal and Energy Transfer Catalysis Enables Stereodivergence in Alkyne Difunctionalization: Carboboration as Case Study.

Stereochemically defined tetrasubstituted olefins are widespread structural elements of organic molecules and key intermediates in organic synthesis. However, flexible methods enabling stereodivergent access to E and Z isomers of fully substituted alkenes from a common precursor represent a significant challenge and are actively sought after in catalysis, especially those amenable to complex multifunctional molecules. Herein, we demonstrate that iterative dual-metal and energy transfer catalysis constitutes a unique platform for achieving stereodivergence in the difunctionalization of internal alkynes. The utility of this approach is showcased by the stereodivergent synthesis of both stereoisomers of tetrasubstituted β-boryl acrylates from internal alkynoates with excellent stereocontrol via sequential carboboration and photoisomerization. The reluctance of electron-deficient internal alkynes to undergo catalytic carboboration has been overcome through cooperative Cu/Pd-catalysis, whereas an Ir complex was identified as a versatile sensitizer that is able to photoisomerize the resulting sterically crowded alkenes. Mechanistic studies by means of quantum-chemical calculations, quenching experiments, and transient absorption spectroscopy have been applied to unveil the mechanism of both steps.

Synthesis and Applications of π-Conjugation-Extended Vinyl Sulfoxonium Ylides.

Herein, we report the synthesis of π-conjugation-extended vinyl sulfoxonium ylides from vinyl sulfoxonium ylide and electron-deficient alkynes. The new dienoate ylides are used in various transformations, such as X-H (X = S, O) insertion, halogenation, carbene-mediated transformation, and radical-mediated reductions to obtain a variety of conjugated dienoates.