Synthesis Of Acrylonitriles Research Articles

Biological activity and computational analysis of novel acrylonitrile derived benzazoles as potent antiproliferative agents for pancreatic adenocarcinoma with antioxidative properties

Continuing our research into the anticancer properties of acrylonitriles, we present a study involving the design, synthesis, computational analysis, and biological assessment of novel acrylonitriles derived from methoxy, hydroxy, and N-substituted benzazole. Our aim was to examine how varying the number of methoxy and hydroxy groups, as well as the N-substituents on the benzimidazole core, influences their biological activity. The newly synthesized acrylonitriles exhibited strong and selective antiproliferative effects against the Capan-1 pancreatic adenocarcinoma cell line, with IC50 values ranging from 1.2 to 5.3 μM. Consequently, these compounds were further evaluated in three other pancreatic adenocarcinoma cell lines, while their impact on normal PBMC cells was also investigated to determine selectivity. Among these compounds, the monohydroxy-substituted benzimidazole derivative 27 emerged with the most profound and broad-spectrum anticancer antiproliferative activity being emerged as a promising lead candidate. Moreover, a majority of the acrylonitriles in this series exhibited significant antioxidative activity, surpassing that of the reference molecule BHT, as demonstrated by the FRAP assay (ranging from 3200 to 5235 mmolFe2+/mmolC). Computational analysis highlighted the prevalence of electron ionization in conferring antioxidant properties, with computed ionization energies correlating well with observed activities.

Palladium-Catalyzed Alkyne Hydrocyanation toward Ligand-Controlled Stereodivergent Synthesis of (E)- and (Z)-Trisubstituted Acrylonitriles.

We herein describe a palladium-catalyzed hydrocyanation of propiolamides for the stereodivergent synthesis of trisubstituted acrylonitriles. This synthetic method tolerated various primary, secondary and tertiary propiolamides. The cautious selection of a suitable ligand is essential to the success of this stereodivergent process. Control experiments indicate the intermediacy of E-acrylonitriles, which lead to Z-acrylonitriles via isomerization. The density functional theory calculations suggests that the bidentate ligand L2 enables a feasible cyclometallation/isomerization pathway for the E to Z isomerization, while the monodentate ligand L1 inhibits the isomerization, leading to divergent stereoselectivity. The usefulness of this method can be demonstrated by the readily derivatization of products to give various E- and Z-trisubstituted alkenes. In addition, the E- and Z-acrylonitrile products have also been successfully employed in cycloaddition reactions.

Palladium‐Catalyzed Alkyne Hydrocyanation toward Ligand‐Controlled Stereodivergent Synthesis of (E)‐ and (Z)‐Trisubstituted Acrylonitriles

AbstractWe herein describe a palladium‐catalyzed hydrocyanation of propiolamides for the stereodivergent synthesis of trisubstituted acrylonitriles. This synthetic method tolerated various primary, secondary and tertiary propiolamides. The cautious selection of a suitable ligand is essential to the success of this stereodivergent process. Control experiments indicate the intermediacy of E‐acrylonitriles, which lead to Z‐acrylonitriles via isomerization. The density functional theory calculations suggests that the bidentate ligand L2 enables a feasible cyclometallation/isomerization pathway for the E to Z isomerization, while the monodentate ligand L1 inhibits the isomerization, leading to divergent stereoselectivity. The usefulness of this method can be demonstrated by the readily derivatization of products to give various E‐ and Z‐trisubstituted alkenes. In addition, the E‐ and Z‐acrylonitrile products have also been successfully employed in cycloaddition reactions.

Palladium-Catalyzed Alkyne Hydrocyanation toward Ligand-Controlled Stereodivergent Synthesis of Trisubstituted Acrylonitriles

Palladium-Catalyzed Alkyne Hydrocyanation toward Ligand-Controlled Stereodivergent Synthesis of Trisubstituted Acrylonitriles

Electroorganic Synthesis of Tertiary Cyanoformamide from Trichloroacetonitrile Catalyzed By B12 Complex

Cyanoformamide is the key motifs of pharmaceuticals, agricultural chemicals, and component of the natural products, and it is vital building block in the synthesis of lactams,acrylonitriles, tetrazoles, unsymmetrical ketones, symmetric & asymmetric substituted ureas, and other heterocyclic compounds.[1] Herein the one-pot procedure for synthesis of tertiary cyanoformamide has been developed with electrochemical method by B12 complex[2] as catalyst under mild conditions, at room temperature under air. Over thirty examples of cyanoformamide were synthesized in moderate to good yields. This user-friendly strategy is compatible with a broad range of biologically active cyanoformamide and easily scalable with the cheap and simple experimental set-up.

Synthesis of Acrylonitriles via Mild Base Promoted Tandem Nucleophilic Substitution‐Isomerization of α‐Cyanohydrin Methanesulfonates

AbstractMain observation and conclusionWe have developed an efficient synthesis of acrylonitriles via mild base promoted tandem nucleophilic substitution‐isomerization of α‐cyanohydrin methanesulfonates with alkenylboronic acids. This transition metal‐free protocol works under simple and mild conditions and offers good chemical yields for a wide range of substrates and demonstrates good functional group tolerance.image

Indole acrylonitriles as potential anti-hyperglycemic agents: Synthesis, α-glucosidase inhibitory activity and molecular docking studies

One of the most prevailing metabolic disorder diabetes mellitus has become the global health issue that has to be addressed and cured. Different marketed drugs have been made available for the treatment of diabetes but there is still a need of introducing new therapeutic agents that are economical and have lesser or no side effects. The current study deals with the synthesis of indole acrylonitriles (3–23) and the evaluation of these compounds for their potential for α-glucosidase inhibition. The structures of these synthetic molecules were deduced by using different spectroscopic techniques. Acarbose (IC50 = 2.91 ± 0.02 μM) was used as standard in this study and the synthetic molecules (3–23) have shown promising α-glucosidase inhibitory activity. Compounds 4, 8, 10, 11, 14, 18, and 21 displayed superior inhibition of α-glucosidase enzyme in the range of (IC50 = 0.53 ± 0.01–1.36 ± 0.04 μM) as compared to the standard acarbose. Compound 10 (IC50 = 0.53 ± 0.01 μM) was the most effective inhibitor of this library and displayed many folds enhanced activity in contrast to the standard. Molecular docking of synthetic compounds was performed to verify the binding interactions of ligand with the active site of enzyme. This study had identified a number of potential α-glucosidase inhibitors that can be used for further research to identify a potent therapeutic agent against diabetes.

Direct Access to Highly Enantioenriched α-Branched Acrylonitriles through a One-Pot Sequential Asymmetric Michael Addition/Retro-Dieckmann/Retro-Michael Fragmentation Cascade.

A highly enantioselective synthesis of α-branched acrylonitriles is reported featuring a one-pot sequential asymmetric Michael addition/retro-Dieckmann/retro-Michael fragmentation cascade. The method, which relies on a solid, bench-stable, and commercially available acrylonitrile surrogate, is practical, scalable, and highly versatile and provides a direct access to a wide range of enantioenriched nitrile-containing building blocks. Most importantly, the method offers a new tool to incorporate an acrylonitrile moiety in an asymmetric fashion.

Aggregation-Induced Emission and Organogels with Chiral and Racemic Pyrene-Substituted Cyanostyrenes.

The synthesis, photophysical investigations, and organogel formation of pyrene-phenyl acrylonitriles (1-6) bearing mono-, di-, and trichiral and racemic substitutions were studied. The molecules self-assemble in water and show remarkable emission wavelength and intensity changes associated with distinct color changes. Cryo-scanning electron microscopy (Cryo-SEM) images show the formation of uniform nanoaggregates for the monosubstituted derivatives and network-like structures for di- and trisubstituted derivatives. The favorable π-π stacking ability of the coplanar pyrene ring, steric restrictions due to the cyano group, and beneficial noncovalent interactions from the citronellol moiety allow the molecules to form excellent organogels with fibrous and twisted ribbon morphology for the racemic and chiral derivatives. The organogels based on small molecules could be of high relevance for potential investigations involving soft biological matter.

Sequential Palladium-Catalyzed Allylic Alkylation/retro-Dieckmann Fragmentation Strategy for the Synthesis of α-Substituted Acrylonitriles.

A straightforward synthesis of α-substituted acrylonitriles is described using 4-cyano-3-oxotetrahydro-thiophene (c-THT) as an acrylonitrile surrogate. This unprecedented two-step sequence featuring a palladium-catalyzed allylic alkylation (Pd-AA) and a retro-Dieckmann fragmentation provides a general entry into diversely substituted 1,4-dienes.

Sulfonic acid functionalized metal-organic framework (S-IRMOF-3): a novel catalyst for sustainable approach towards the synthesis of acrylonitriles.

A sulfonic acid functionalized metal–organic framework (S-IRMOF-3) has been synthesized by dropwise addition of chlorosulfonic acid (0.5 mL) in IRMOF-3 (1 g) containing 20 mL of CHCl3 at 0 °C under simple stirring. The catalyst was applied in Knoevenagel condensation of various aromatic and hetero-aromatic aldehydes forming acrylonitrile derivatives. The catalyst was characterized thoroughly by using FT-IR, XRD, 13C MAS NMR, SEM, EDX, elemental mapping, TEM, BET, NH3-TPD and TGA/DTA techniques. The presence of characteristic bands at 1694 cm−1, 1254–769 cm−1 and 1033 cm−1 in the FT-IR spectrum, 2θ ≃ 6.7° and 9.8° in the XRD pattern and δ = 31.79, 39.55, 129.61, 131.46 (4C, CH), 133.54, 140.07 (2C), 167.71, 171.47 ppm (2C, 2C Created by potrace 1.16, written by Peter Selinger 2001-2019 ]]> O) in the solid state 13C MAS NMR spectrum confirmed the successful formation of catalyst. This new eco-friendly approach resulted in a significant improvement in the synthetic efficiency (90–96% yield), high product purity, and minimizing the production of chemical wastes without using highly toxic reagents for the synthesis of acrylonitriles with selectivity for (Z)-isomer. Steric interactions seem to have an influence on the control of the Z-configurational isomers. By performing DFT calculations, it was found that the (Z)-isomer 3a is stabilized by 1.64 kcal mol−1 more than the (E)-isomer. The catalyst could be reused for five consecutive cycles without substantial loss in catalytic activity.

Stereoselective Synthesis of Fully-Substituted Acrylonitriles via Formal Acylcyanation of Electron-Rich Alkynes.

A Sc(OTf)3-catalyzed formal acylcyanation of electron-rich alkynes for the efficient synthesis of fully-substituted acrylonitriles is described. By means of alkyne carbonyl metathesis, the reaction features mild conditions, high regio- and stereoselectivity, and a broad scope. The strong preference of the nitrile group for inward rotation in the torquoselective ring opening of the oxetane intermediate determines the remarkable Z selectivity of this process.

Synthesis of β-Difluoroalkylated Acrylonitriles in the Presence of Copper Powder.

A highly regio- and stereoselective copper-mediated cyanodifluoroalkylation of alkynes with ethyl difluoroiodoacetate and trimethylsilyl cyanide (TMSCN) is described. The three-component coupling reaction provides straightforward access to a variety of useful difluoroalkyl-substituted acrylonitriles. The introduction of the nitrile unit is of great importance in drug discovery for the modification of this fragment. Preliminary mechanistic investigations indicate that a vinyl iodide intermediate and a difluoroalkyl radical might be involved in this transformation.

Design, synthesis, and biological evaluation of sulfonyl acrylonitriles as novel inhibitors of cancer metastasis and spread.

The spread of intra-abdominal cancers is a vexing clinical problem for which there is no widely effective treatment. We discovered previously that (2E)-3-[(4-tert-butylphenyl)sulfonyl]acrylonitrile (1) induced cancer cell apoptosis during adhesion to normal mesothelial cells which line the peritoneum. We recently demonstrated that the sulfonylacrylonitrile portion of 1 and hydrophobic aryl substitution were essential for pro-apoptotic activity in cancer cells. Here we synthesized a diverse series of analogues of 1 in order to improve the efficacy and pharmaceutical properties. Analogues and 1 were compared in their ability to cause cancer cell death during adhesion to normal mesothelial cell monolayers. Potent analogues identified in the in vitro assay were validated and found to exhibit improved inhibition of intra-abdominal cancer in two clinically relevant murine models of ovarian and pancreatic cancer spread and metastasis, highlighting their potential clinical use as an adjunct to surgical resection of cancers.

The copper-catalyzed synthesis of β-trifluoromethylated acrylonitriles and trifluoromethyl-substituted 2H-azirines.

The direct assembly of acrylonitriles and valuable 2H-azirines from readily available starting materials is described. This novel alkyne difunctionalization reaction proceeded under mild reaction conditions. Considering the versatile roles of 2H-azirines, this work paves the way for further modification into various heterocycles.

ChemInform Abstract: Alkylation/Elimination from Azetidinium Ylides: An Entry to Functionalized Acrylonitriles.

AbstractA one‐pot two‐step sequence for the synthesis of acrylonitriles involving alkylation of azetidinium ylides followed by regioselective Hofmann elimination is developed.

Synthesis and biological evaluation of sulfonyl acrylonitriles as novel inhibitors to peritoneal carcinomatosis

The vast majority of cancer patients die from metastasis, the process by which cancer cells spread to secondary tissues through body fluids. Peritoneal carcinomatosis is a type of metastasis in which cancer cells gain access to the intra-abdominal cavity and then implant in the peritoneum, the thin tissue that lines the abdominal wall and internal organs. Unfortunately, peritoneal carcinomatosis can occur following surgical resection of intra-abdominal malignancies. We previously reported proapoptotic activity of (2E)-3-[[4-(1,1-dimethylethyl)phenyl]sulfonyl]-2-propenenitrile (BAY 11-7085, 1) on colon and pancreatic cancer cells during adhesion and demonstrated that this compound could significantly inhibit peritoneal carcinomatosis in mice.1,2 In order to determine the chemical basis of the anti-metastatic properties of BAY 11-7085, a series of analogs were synthesized and evaluated for their ability to induce apoptosis in pancreatic and ovarian cancer cells during adhesion to mesothelial cells, which line the surface of the peritoneum. The co-culture assay results were validated using a murine peritoneal carcinomatosis model. These analogs may greatly benefit patients undergoing surgical resections of colorectal, pancreatic, and ovarian cancers depending on their tolerability.

A Facile, One-Pot Synthesis of β-Substituted (Z)-Acrylonitriles Utilizing an α-Diaminoboryl Carbanion

A simple three-step single-pot procedure for Z-stereoselective synthesis of beta-monosubstituted acrylonitriles has been established. The reaction involves olefination of aldehydes with an in situ generated alpha-diaminoboryl carbanion species. Various aromatic and aliphatic aldehydes were smoothly converted into the corresponding (Z)-olefin products (up to 96:4 ratio) in good yields (80-98%).

Heteroaromatization with Sulfonamido Phenyl Ethanone, Part II: Synthesis of Novel Thiazolyl Acetonitriles and Thiazolyl Acrylonitriles and Their Derivatives Containing Dimethylsulfonamide Moiety

Thiazolyl acetonitrile (2) was prepared and converted to pyrazolo[5,1-c][1,2,4]triazine (5), thiazoline-4-one derivatives (10,12), thiazolo[3,2-a]pyridine (13), coumarin (14), and benzo[f]coumarin (16) derivatives through reactions with a variety of organic electrophiles and nucleophiles. Thiazolyl acrylonitrile derivatives (17, 18, 21, 26–28, 31–33) were also prepared, and their activity with a variety of reagents was investigated. The structure of these compounds was elucidated on the basis of elemental analysis, IR, 1H-NMR, and mass spectra. The antimicrobial and antifungal activities of the prepared compounds are also reported.

A New Simple Synthesis of α-Substituted Acrylonitriles

Synthese de benzyl-2-, propargyl-2-, alkyl-2 et phenyl-3'propyl-2 acrylonitriles a partir d'(oxo-4 perhydro) thiophenecarbonitrile-3