Alkylidene Malononitriles Research Articles

Base-Mediated Regioselective [3 + 3] Annulation of Alkylidene Malononitriles with Trifluoromethyl Alkenes via Dual C-F Bond Cleavage.

A base-mediated regioselective [3 + 3] annulation of alkylidene malononitriles with trifluoromethyl alkenes was described. The reaction proceeds through sequential intermolecular SN2' and intramolecular SNV-type cyclization by cleaving dual C-F bonds in a trifluoromethyl group, which discriminate multiple carbon-nucleophilic sites using a single base. Various bicycles bearing a monofluorocyclohexene motif were assembled from readily available starting materials under mild conditions via a one-pot cascade approach.

Synthesis, structural, spectroscopic and theoretical insights into a new malononitrile derivative: A candidate for nonlinear optical applications

Functionalized alkylidene malononitriles play a crucial role as donor-acceptor molecules, exhibiting notable nonlinear optical (NLO) properties. Allylidene malononitriles, an analogue of alkylidene malononitriles, have not been explored before for their optical properties. The present work deals with the synthesis of (Z)-2-(3-(4-bromophenyl)-3-chloroallylidene) malononitrile using Knoevenagel condensation reaction of Z-3-(4-bromophenyl)-3-chloroacrylaldehyde and malononitrile. Structure of the compound was elucidated by single-crystal X-ray crystallography and related spectroscopic studies like FT-IR, NMR (1H, 13C), and UV–Vis spectroscopy, which were further supported with computational studies using Density Functional Theory (DFT) approach. The photoluminescence spectra showed that the compound exhibited an emission peak at 425 nm with an excitation wavelength of 352 nm. The single crystal study reveals that the compound belongs to a monoclinic system with space group P21/c. The thermal characteristics of the compound was analysed using TGA-DTA/DSC. Investigation of the third-order nonlinear susceptibility was done by femtosecond Z-scan technique and demonstrated the potential of phenyl-substituted allylidene malononitriles for its nonlinear optical applications. The observed positive lensing and strong reverse saturable absorption (RSA) at both visible (532 nm) and Near IR (800 nm) regions make this compound a promising candidate for optoelectronic applications.

Organocatalyzed diastereoselective cyclization of β-alkyl nitroolefins with alkylidene malononitriles: new approach to azetidine nitrones and isoxazoles

An organocatalytic domino reaction of β-alkyl nitroolefins with alkylidene malononitriles to give azetidine nitrones with good diastereoselectivities is reported. The in situ-generated nitrones were transmuted into isoxazoles catalyzed by acid.

Organocatalyzed Modular Synthesis of Polycyclic Dihydropyridines and Pyridines through Sulfamate Linchpin.

The cascade annulation between alkylidene malononitriles and cyclic sulfamidate imines has been controlled by leveraging the sulfamate functionality under organocatalysis, which allows selective access to polycyclic and densely functionalized dihydropyridines and pyridines in high yields. The protocol is scalable and shows broad substrate scope. The products were also engaged in the preparation of tetracyclic pyridopyrimidines, showcasing the synthetic versatility.

Diastereoselective Indole-Dearomative Cope Rearrangements by Compounding Minor Driving Forces.

Reported herein is the discovery of a diastereoselective indole-dearomative Cope rearrangement. A suite of minor driving forces promote dearomatization: (i) steric congestion in the starting material, (ii) alkylidene malononitrile and stilbene conjugation events in the product, and (iii) an unexpected intramolecular π-π* stack on the product side of the equilibrium. The key substrates are rapidly assembled from simple starting materials, resulting in many successful examples. The products are structurally complex and bear vicinal stereocenters generated by the dearomative Cope rearrangement. They also contain a variety of functional groups for interconversion to complex architectures.

Efficient Synthesis of 7,8-Dihydro-6H-benzo[c]chromen-6-one Derivatives by Base-Mediated Chemoselective Annulation of Alkylidene Malononitriles with α,β-Unsaturated Coumarins

AbstractAn efficient and chemoselective synthesis of biologically valuable 7,8-dihydro-6H-benzo[c]chromen-6-ones is described. In this method, neither a metal catalyst nor expensive starting materials are needed, and the products can be purified by simple filtration and washing with EtOH. Readily available starting materials, green and mild conditions, synthetically useful yields, and operational simplicity are some highlighted advantages of this unprecedented transformation.

Synthetic Dihydropyridines as Novel Antiacanthamoebic Agents.

Acanthamoeba is an opportunistic pathogen widely spread in the environment. Acanthamoeba causes excruciating keratitis which can lead to blindness. The lack of effective drugs and its ability to form highly resistant cyst are one of the foremost limitations against successful prognosis. Current treatment involves mixture of drugs at high doses but still recurrence of infection can occur due to ineffectiveness of drugs against the cyst form. Pyridine and its natural and synthetic derivatives are potential chemotherapeutic agents due to their diverse biological activities. To study the antiamoebic effects of four novel synthetic dihydropyridine (DHP) compounds against Acanthamoeba castellanii belonging to the T4 genotype. Furthermore, to evaluate their activity against amoeba-mediated host cells cytopathogenicity as well as their cytotoxicity against human cells. Dihydropyridines were synthesized by cyclic dimerization of alkylidene malononitrile derivatives. Four analogues of functionally diverse DHPs were tested against Acanthamoeba castellanii by using amoebicidal, encystation and excystation assays. Moreover, Lactate dehydrogenase assays were carried out to study cytopathogenicity and cytotoxicity against human cells. These compounds showed significant amoebicidal and cysticidal effects at 50 μM concentration, whereas, two of the DHP derivatives also significantly reduced Acanthamoebamediated host cell cytotoxicity. Moreover, these DHPs were found to have low cytotoxicity against human cells suggesting a good safety profile. The results suggest that DHPs have potential against Acanthamoeba especially against the more resistant cyst stage and can be assessed further for drug development.

Synthesis of Dibenzofurans Derivatives via Benzannulation of 2‐Nitrobenzofurans and Alkylidene Malononitriles

AbstractAlthough various methods for the preparation of dibenzofurans are available, an efficient, general synthesis of dibenzofurans from benzofurans remains an unsolved problem. Herein, we provide the first benzannulation of readily prepared 2‐nitrobenzofurans with alkylidene malononitriles. This methodology enables facile assembly of a wide variety of highly functionalized dibenzofurans in moderate to excellent yields under metal‐free conditions. Gram‐scale synthesis and further elaborations of the product were succesfully performed, demonstrating synthetic utility of this method.

Vinylogous Annulation Cascade Toward Stereoselective Synthesis of Highly Functionalized Indanone Derivatives

AbstractA base promoted vinylogous annulation cascade of alkylidene malononitriles with cyclopentene‐1,3‐diones with a subsequent reduction sequence has been devised to furnish densely functionalized 3‐hydroxyindanone scaffolds in high yields with excellent diastereoselectivity. Unlike preceding approaches that account for the formation of the pentanoid ring, this strategy features construction of the aromatic ring. The protocol is scalable, displays very broad substrates scope including late‐stage functionalization of bioactive estrone, applicable to activated coumarin system, and is suitable to access an indenoquinoline derivative.magnified image

Double Thiol-Chiral Brønsted Base Catalysis: Asymmetric Cross Rauhut-Currier Reaction and Sequential [4 + 2] Annulation for Assembly of Different Activated Olefins.

A double catalytic system combining 2-mercaptobenzoic acid and a chiral phase transfer substance was disclosed for the intermolecular cross Rauhut-Currier reaction of 2-cyclopentenone and isatin-based alkylidene malononitriles. The resulting chiral adducts were sequentially assembled with diverse electron-deficient olefins to furnish highly enantioenriched cyclohexane derivatives (up to 96:4 er, >19:1 dr). A similar catalytic system of 2-mercaptobenzoic acid and quinine was further developed for the reaction of 2-cyclopentenone and α-cyano chalcones (up to 96.5:3.5 er).

Asymmetric Organocatalytic Michael Addition–Cyclisation Cascade of Cyclopentane-1,2-dione with Alkylidene Malononitriles

An asymmetric organocatalytic cascade reaction between cyclopentane-1,2-diones and alkylidene malononitriles affords highly substituted 4H-pyrans in moderate to high enantiomeric excess. The selective reduction of a bridged double bond leads to the formation of cis-substituted cyclopentanone with three contiguous stereogenic centres.

4 + 2] Annulation of 3-Nitroindoles with Alkylidene Malononitriles: Entry to Substituted Carbazol-4-amine Derivatives.

A general and transition-metal-free method for the construction of the carbazol-4-amine motif via a vinylogous Michael addition/cyclization/isomerization/elimination reaction of 3-nitroindoles with alkylidene malononitriles has been developed. This novel methodology allows the facile synthesis of a series of di- and trisubstituted carbazol-4-amine derivatives in moderate to good yields. A gram-scale experiment was successfully performed, highlighting the practicability of this method. Moreover, this strategy is also applicable to 3-nitrobenzothiophene, affording the corresponding dibenzo[ b, d]thiophen-1-amine derivatives in moderate yields.

Exploring the Remote Reactivity of π-Extended Carbonyl Compounds: The Vinylogous Alkylidene Malononitrile Activation Strategy

The installation of malononitrile into π-extended carbonyl compounds gives rise to vinylogous alkylidene malononitriles (also known as π-extended dicyanovinylidenes), the direct functionalization of which at remote C(sp3) pronucleophilic sites becomes possible and viable. Starting from easily accessible representative polyunsaturated malononitriles, mild conditions were found to directly couple them to complementary enal acceptors. In all cases, the malononitrile handle proved an indispensable (and optionally traceless) activating ingredient for the vinylogous reactions to proceed efficiently and selectively. Merging the vinylogy concept with the malononitrile HOMO-raising activation strategy and complementary organocatalytic activation modalities (i.e. LUMO-lowering iminium ion activation) turned out to be a successful option, as demonstrated by the number of diverse carbocyclic and heterocyclic chiral products that were (stereo)selectively accessed through this chemistry.1 Introduction2 Reactions of Cyclohexenylidene Malononitriles with Enals3 Reactions of Allylidene Malononitriles with Enals4 Reactions of Indolylmethylene Malononitriles with Enals5 Conclusion

Novel thiophene-containing push-pull chromophores that include carbazole and triphenylamine moieties: study of optical and electrochemical properties

Novel carbazole- and triphenylamine-containing alkylidene malononitriles that include thiophene and bithienyl fragments as π-spacers were synthesized. Quantum-chemical calculations of the frontier molecular orbital energies were performed using the B3LYP/6-31G(d) method with regard to solvent. Electronic absorption spectra and fluorescence spectra were recorded for all the obtained compounds; their electrochemical properties were also studied. The experimental energy values of HOMO and LUMO levels were derived from resulting data. Thin films were obtained by the spin coating technique, and their surface morphology was studied using a NTEGRA Prima scanning tunneling microscope.

Organocatalyzed Enantioselective Synthesis of 2‐Amino‐4H‐chromene Derivatives

Optically active 2‐amino‐5‐oxo‐5,6,7,8‐tetrahydro‐4H‐chromene‐3‐carboxylates, 2‐amino‐5‐oxo‐5,6,7,8‐tetrahydro‐4H‐chromene‐3‐carbonitriles, and 2‐amino‐8‐oxo‐5,6,7,8‐tetrahydro‐4H‐chromene‐3‐carbonitriles were synthesized. Using cinchona alkaloid‐derived bifunctional catalysts, the corresponding 2‐amino‐4H‐chromene derivatives were obtained in high yields and moderate to high ee values (up to 82% ee) from the tandem Michael addition–cyclization reaction between 1,3‐cyclohexanediones or 1,2‐cyclohexanediones and (E)‐3‐aryl‐2‐cyanoacrylate or alkylidene malononitrile derivatives.

Synthesis and bioactivity of novel amino-pyrazolopyridines

Here we describe the synthesis and biological activity of novel amino-pyrazolopyridines with anti-NF-κB and pro-apoptotic potential. α-Methylene ketones were used as a starting point for synthesis of amino-pyrazolopyridine 3. The alkylidene malononitriles 1 were obtained by the Knoevenagel reaction of ketones with malononitriles. Vilsmeier–Haack reaction allowed direct access to 2-chloro-3-cyanopyridines 2. Those products, by refluxing with hydrazine hydrate, allowed cyclization to amino-pyrazolopyridines 3a–g, which were not previously described in the literature.Bioactivity results indicated that amino-pyrazolopyridines 3a, 3b and 3g induced apoptotic cell death in K562 cancer cells with an IC50 of 36.5 ± 3.9 μM, 27.6 ± 4.5 μM and 35.0 ± 2.3 μM, respectively, after 72 h. In addition, compounds 3a, 3b and 3g exerted NF-κB inhibition activity with an IC50 of 4.7 ± 1.6 μM, 6.9 ± 1.9 μM and 39.8 ± 3.9 μM, respectively, after 8 h in K562 cells activated with TNFα. Compounds 3b and 3g showed interesting differential toxicity as viability of peripheral blood mononuclear cells (PBMCs) from healthy donors remained largely unaffected by this treatment.

ChemInform Abstract: Improved Synthesis of Mono‐ and Disubstituted 2‐Halonicotinonitriles from Alkylidene Malononitriles.

Pyridines with 2,3,4 and/or 5 substitution remain challenging to prepare. Existing strategies to form multisubstituted 2-halonicotinonitriles via enamines suffer from dimerization of the starting a...

High‐Pressure‐Mediated Extension of the Privileged Steroid Scaffold

AbstractThe commercially available steroid dehydroepiandrosterone 3‐acetate (DHEA) was converted into new, highly functionalized spiro derivatives by modification of the D‐ring. The transformation proceeded through conversion of the C‐17 carbonyl group into an electron‐deficient alkene, followed by either [2+2] or [4+2] cycloaddition. The cycloaddition reactions were successful for alkylidene malononitriles and 2‐cyano acrylates. Application of high pressure (15 kbar) was essential for good conversions due to the high steric hindrance on position C‐17. The cycloadducts formed from the reaction of 2‐cyano acrylates and Danishefsky's diene have high potential for further functionalization.

Improved Synthesis of Mono- and Disubstituted 2-Halonicotinonitriles from Alkylidene Malononitriles

Pyridines with 2,3,4 and/or 5 substitution remain challenging to prepare. Existing strategies to form multisubstituted 2-halonicotinonitriles via enamines suffer from dimerization of the starting alkylidene malononitriles resulting in low yields. Through alteration of reaction conditions, a new high yielding method into enamines was realized by condensing DMF-DMA and alkylidene malononitriles in the presence of substoichiometric acetic anhydride. Cyclization of the resulting enamines under Pinner conditions provided 2-halonicotinonitriles in high overall yields.

ChemInform Abstract: Conjugate Allylation Reactions of Alkylidene Malononitriles Mediated by NHC‐Ligated Palladium Catalysts.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.