Cyanation Reaction Research Articles

Chalcogen Bond-Driven Alkylations: Selenoxide-Pillar[5]arene As A Recyclable Catalyst For Displacement Reactions In Water.

A novel strategy to catalyze alkylation reactions through chalcogen bond interaction using a supramolecular structure is presented herein. Utilizing just 1.0 mol% of selenoxide-pillar[5]arene (P[5]SeO) as the catalyst we achieved efficient catalysis in the cyanation of benzyl bromide in water. Our approach demonstrated high efficiency and effectiveness, with the results supported by designed control experiments and theoretical models, highlighting the catalytic effect of the pillar[5]arene through noncovalent interactions. Quantum-chemical calculations (ωB97X-D/def2-TZVP@SMD) pointed out that the catalyzed cyanation reaction followed an SN2-like mechanism, with energy barriers (ΔH‡) ranging from 16.7 to 18.2 kcal mol-1, exhibiting dissociative character depending on the para-substituent. 1H NMR analysis revealed that P[5]SeO acted as a catalyst through inclusion complex formation, facilitating the transfer of the electrophilic substrate to the aqueous solution for nucleophilic displacement. Our reaction protocol proved applicable to various substrates, including aromatic and alpha-carbonyl derivatives. The use of sodium azide as the nucleophile was also feasible. Importantly, our method allowed scalability, and the catalyst P[5]SeO could be recovered and reused effectively for multiple reaction cycles, showcasing sustainability.

BF3 ⋅ OEt2 as a Versatile Reagent: Applications in Organic Synthesis

AbstractBoron trifluoride diethyl etherate, commonly referred to as BF3 ⋅ OEt2, plays a crucial role as a potent reagent in various organic transformations, particularly in the synthesis of heterocyclic systems through the establishment of carbon‐carbon & carbon‐heteroatom bonds. Its Lewis acid properties, reactivity, and stability at room temperature make it essential for a wide range of chemical reactions. BF3 ⋅ OEt2 demonstrates remarkable efficacy in processes such as hydroxylation of double bonds, epoxide cleavage, acid esterification, cyanation, coupling, and diverse cyclization reactions, surpassing other Lewis acids in performance. Its significant impact on organic synthesis extends to the formation of natural products, highlighting its profound significance in the realm of chemistry. The unique properties and versatility of boron trifluoride diethyl etherate make it a fundamental tool for a diverse array of chemical transformations. The numerous applications of this reagent in organic synthesis have prompted the development of a comprehensive review, focusing on its various roles and contributions in this field.

Stereodivergent Hydrohalogenation of SCF3 Alkynes and Cross- Coupling Reactions.

SCF3-substituted internal alkynes undergo regio- and stereoselective hydrohalogenation to provide the corresponding β-halo-α-SCF3-alkenes. The regioselectivity is ensured by the strong polarization of the C≡C triple bond in SCF3-alkynes, while the stereoselectivity is governed by the strength of the proton donor and/or by the solvent polarity. The potential of β-iodo-α-SCF3-alkenes was illustrated in several cross-coupling, protodeiodination, and cyanation reactions.

ZnCo2O4@g-C3N4@Cu as a new and highly efficient heterogeneous photocatalyst for visible light-induced cyanation and Mizoroki-Heck cross-coupling reactions.

Conducting C-C cross-coupling reactions under convenient and mild conditions remains extremely challenging in traditional organic synthesis. In this study, ZnCo2O4@g-C3N4@Cu exhibited extraordinary photocatalytic performance as a new visible light harvesting heterogeneous copper-based photocatalyst in cyanation and Mizoroki-Heck visible-light-driven cross-coupling reactions at room temperature and in air. Surprisingly, by this method, the cyanation and Mizoroki-Heck cross-coupling reactions of various iodo-, bromo- and also the challenging chloroarenes with respectively K4[Fe(CN)6]·3H2O and olefins produced promising results in a sustainable and mild media. The significant photocatalytic performance of ZnCo2O4@g-C3N4@Cu arises from the synergistic optical properties of ZnCo2O4, g-C3N4, and Cu. These components can enhance the charge carrier generation and considerably reduce the recombination rate of photogenerated electron-hole pairs. No need to use heat or additives, applying an economical and benign light source, utilizing an environmentally compatible solvent, facile and low-cost photocatalytic approach, aerial conditions, high stability and convenient recyclability of the photocatalyst are the remarkable highlights of this methodology. Moreover, this platform exhibited the ability to be performed on a large scale, which is considered an important issue in industrial and pharmaceutical use. It is worth noting that this is the first time that a heterogeneous copper-based photocatalyst has been employed in visible light-promoted cyanation reactions of aryl halides.

Formation of a diiron-(μ-η1:η1-CN) complex from acetonitrile solution.

The activation of C-C bonds by transition-metal complexes is of continuing interest and acetonitrile (MeCN) has attracted attention as a cyanide source with comparatively low toxicity for organic cyanation reactions. A diiron end-on μ-η1:η1-CN-bridged complex was obtained from a crystallization experiment of an open-chain iron-NHC complex, namely, μ-cyanido-κ2C:N-bis{[(acetonitrile-κN)[3,3'-bis(pyridin-2-yl)-1,1'-(methylidene)bis(benzimidazol-2-ylidene)]iron(II)} tris(hexafluorophosphate), [Fe2(CN)(C2H3N)2(C25H18N6)2](PF6)3. The cyanide appears to originate from the MeCN solvent by C-C bond cleavage or through carbon-hydrogen oxidation.

Investigation of Enantioselectivity Using TADDOL Derivatives as Chiral Ligands in Asymmetric Cyanation Reactions.

This study investigates the enantioselectivity challenges of asymmetric cyanation reactions using TADDOL derivatives as chiral ligands, specifically focusing on the cyanosilylation of aldehydes and the cyanation of imines. Despite extensive optimization efforts, the highest achieved ee was only modest, peaking at 71% for the cyanosilylation reaction, while the cyanation of imines consistently resulted in racemic mixtures. Our comprehensive analysis, supported by experimental data and computational modeling, reveals significant barriers to enhancing the enantioselectivity. The results highlight a complex interplay between ligand structure and reaction conditions, demonstrating that even promising ligands such as TADDOL derivatives face substantial challenges in these reaction types. This study underscores the importance of understanding the mechanistic details through computational insights to guide future improvements in asymmetric catalysis.

Thioxanthrone-based ionic liquid as efficient and recyclable photocatalyst for α-cyanidation reaction of aromatic tertiary amines

A stabile and recyclable photocatalyst IL-TX was designed and synthesized by introducing the dye photocatalyst thioxanthenone into ionic liquids and its excellent photocatalytic performance was demonstrated by photophysical and electronic performance tests. The IL-TX was applied as a recyclable photocatalyst for α-cyanidation reaction of aromatic tertiary amines in MeOH at room temperature under blue light irradiation, and a range of cyanide products were obtained in good to excellent yields. Furthermore, the practicality of this protocol was further demonstrated through the optimization of the synthesis of the drug praziquantel and the natural product 8-oxopseudopalmatine. This study provides a greener and sustainable solution for photocatalytic cyanation reaction.

Nickel‐Catalyzed Reductive Coupling of Vinyl Triflates and 1,4‐Dicyanobenzene to Access Alkenyl Nitriles

AbstractWe report a vinyl cyanation reaction of vinyl triflates and readily available 1,4‐dicyanobenzene through a nickel‐catalyzed reductive coupling process. The reaction is operated under mild conditions with remarkable functional‐group compatibility. Cyclic vinyl triflates with various ring sizes and substituents at different positions all reacted smoothly. The synthetic utility is demonstrated by the derivatization of pharmaceutical and natural compounds, a scale‐up synthesis, and various functional group transformations. Preliminary mechanistic studies demonstrate that vinyl triflates are more reactive than 1,4‐dicyanobenzene towards the oxidative addition to nickel catalyst.

Synthesis of [11C]BIIB104, an α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic-Acid-Positive Allosteric Modulator, and Evaluation of the Bio-Distribution in Non-Human Primate Brains Using Positron Emission Tomography.

The aim of this study was to measure the brain penetrance and kinetics of BIIB104, a first-in-class AMPA receptor potentiator developed for cognitive impairment associated with schizophrenia. It was recently halted in phase 2 clinical development, and there are a lack of tools to directly measure AMPA receptor engagement. To achieve this, the drug candidate was radiolabeled with carbon-11, and its brain penetrance and kinetics were measured in non-human primates via dynamic PET scans. Radiolabeling was achieved through a three-step nucleophilic [11C]cyanation reaction in one pot, resulting in the high radioactivity and radiochemical purity (>99%) of [11C]BIIB104. The study found that [11C]BIIB104 entered the non-human primate brains at 4-5% ID at peak, with a homogeneous distribution. However, a mild regional heterogeneity was observed in the thalamus. The lack of conclusive evidence for a change in regional values after BIIB104 dosing suggests that any specific binding component of BIIB104 is negligible compared to the free and non-specific components in the living brain. Overall, the study demonstrated high brain uptake with minor variability in [11C]BIIB104 distribution across various brain regions, its kinetics were consistent with those of passive diffusion, and the dominating components were the free concentration and non-specific binding. This information is valuable for understanding the potential effects and mechanisms of BIIB104 in the brain.

Synthesis of cyanated Naphthalene diimide−Hydroazaacenes: Amphoteric-redox, low-lying LUMO, bright-red emission, aggregation and aromaticity evaluation

Herein we explored the synthesis and functionalization of NDI-hydroazaacenes, via two routes, at both the peripheries along the long-axis of the molecules. For the first time, we successfully performed cyanation reactions at the hydroazaacenes without the use of Pd-catalyst, enabling straightforward access to symmetric and asymmetrically substituted molecules. We also accessed NDI-hydroazaacenes with shorter substituents at the axial-positions allowing us to realize the single crystal data, which interestingly revealed π-stacked dimers with slipped orientation with the axial groups self-sorted in a syn-syn and anti-anti fashion. The tetracyano-substituted NDI-hydroazaacene showed a DFT predicted LUMO of −4.34 eV, which makes it the most electron-deficient hydroazaacene reported till date. In addition, we explored the amphoteric-redox properties of the NDI-hydroazaacene by generating radical anion/dianion and radical cation states. The molecules showed interesting J-type aggregation with concomitant color change from pink to blue in solution. Further, the molecules exhibited bright-red emission with quantum yields of 29–72 %. Computational studies showed the aromaticity/antiaromaticity can be subtly modulated by the substituents (H/Br/CN) on the rings.

Accessing Borazine Substitution Patterns through Late‐Stage Iodination

AbstractWe have defined a procedure for the late‐stage functionalization of aryl borazines to facilitate the synthesis of a diverse array of borazine derivatives with varying substitution patterns, paving the way for further exploration of the field. More in detail, we have studied and disclosed a simple iodination procedure that could be applied to several differently substituted substrates (1 a–i) with mostly good to excellent yields (47–96%). The representative iodinated compounds 2 b and 2 e, were utilized to test their use in further representative functionalization steps such as cyanation, Heck, and Sonogashira reactions. All products 3 a–e were obtained in satisfactory good to very good yields considering the multiple (three or six times) concomitant reactions.

A safe and efficient synthesis of N-Boc-β3-amino acid methyl esters from α-amino acids: applications in the formal synthesis of sedum alkaloids.

β3-Amino acids are essential components in the synthesis of biologically active compounds. However, obtaining them in enantiomerically pure forms remains challenging. This study investigates a safe and efficient method for synthesizing enantiopure N-Boc-β3-amino acid methyl esters, incorporating both natural and unnatural side chains. The procedure avoids the use of expensive and toxic reagents, providing a safer alternative to the hazardous Arndt-Eistert homologation and cyanation reactions, which typically begin with enantiopure α-amino acids. The practical value of this transformation was demonstrated in the formal synthesis of sedum alkaloids.

Cyanation of aryl halides using potassium hexacyanoferrate(ii) via direct mechanocatalysis

A solvent- and ligand-free cyanation reaction using a catalytically active Pd milling ball and K4[Fe(CN)6] as a safer cyanide source achieved up to 90% yield in 4 hours at room temp. Mechanistic steps were observed via XPS and PXRD.

Synthesis and characterization of a green and recyclable arginine-based palladium/CoFe2O4 nanomagnetic catalyst for efficient cyanation of aryl halides.

The utilization of magnetic nanoparticles in the fields of science and technology has gained considerable popularity. Among their various applications, magnetic nanoparticles have been predominantly employed in catalytic processes due to their easy accessibility, recoverability, effective surface properties, thermal stability, and low cost. In this particular study, cyanuric chloride and arginine were utilized to synthesize an arginine-based oligomeric compound (ACT), which was supported on cobalt ferrite, resulting in a green catalyst with high activity and convenient recyclability for the cyanation reaction of aryl halides. The Pd/CoFe2O4@ACT nanomagnetic catalyst demonstrated excellent performance in the cyanation of various aryl iodides and bromides, yielding favorable reaction outcomes at a temperature of 90 °C within a duration of 3 hours. The synthesized nanoparticles were successfully characterized using various techniques, including FTIR, FE-SEM, EDX/MAP, XRD, TEM, TGA, BET, and ICP-OES. Moreover, the Pd/CoFe2O4@ACT catalyst exhibited remarkable catalytic activity, maintaining an 88% performance even after five consecutive runs. Analysis of the reused catalyst through SEM and TEM imaging confirmed that there were no significant changes in the morphology or dispersion of the particles. Ultimately, it was demonstrated that the Pd/CoFe2O4@ACT nanomagnetic catalyst outperformed numerous catalysts previously reported in the literature for the cyanation of aryl halides.

Metallaphotoredox‐Catalyzed Three‐Component Couplings for Practical Synthesis of Ureas and Carbamates†

Comprehensive SummaryUreas are widely used in drugs, materials and catalysts because of their diamide structure, which can form strong hydrogen bonds. Therefore, it is of great scientific significance to develop efficient and green methods for the synthesis of urea compounds, especially unsymmetrical ureas. Here, we have disclosed novel and highly efficient three‐component coupling reactions of organic halides, sodium cyanate and amines enabled by nickel/photoredox dual catalysis for the preparation of unsymmetrical ureas. The reaction features simple and safe operations, broad substrate scopes, and product diversities. It allows the facile synthesis of N‐aryl/vinyl ureas from readily available, user‐friendly feedstocks under mild conditions (27 examples, 36%—98% yields). In addition, this method is further derived to alcohols as nucleophiles to synthesize a series of carbamates (15 examples, 40%—95% yields). The mechanism experiment shows that the isocyanate produced by the coupling of halide and sodium cyanate may be the key intermediate in this reaction.

Vaccination with post-translational modified, homocitrullinated peptides induces CD8 T-cell responses that mediate antitumor immunity

BackgroundPost-translational modification of proteins has the potential to alter the ability of T cells to recognize major histocompatibility complex (MHC) class -I and class-II restricted antigens, thereby resulting in altered...

Biocatalytic Synthesis of Metaxalone and Its Analogues.

A biocatalytic approach for the synthesis of metaxalone and its analogues was developed based on the reaction of epoxides and cyanate catalyzed by halohydrin dehalogenase. Gram-scale synthesis of chiral and racemic metaxalone was achieved with 44% (98% ee) and 81% yields, respectively, by protein engineering of the halohydrin dehalogenase HHDHamb from Acidimicrobiia bacterium. Additionally, various metaxalone analogues were synthesized at 28-40% yields (90-99% ee) for chiral forms and 77-92% yields for racemic forms.

Chiral Discrimination of Nitrile Compounds Using a 19F-Labeled Palladium Probe.

This study presents a 19F-labeled cyclopalladium probe for the rapid discrimination of chiral nitriles in pharmaceuticals, natural products, and agrochemicals. The probe binds reversibly to chiral nitriles, generating distinct 19F nuclear magnetic resonance signals for each enantiomer and enabling quick determination of enantiocomposition. The method allows for simultaneous detection of seven pairs of enantiomeric nitriles and application in assessing the enantiomeric excess of an asymmetric C-H cyanation reaction.

Copper-Catalyzed Enantioselective Decarboxylative Cyanation of Benzylic Acids Promoted by Hypervalent Iodine(III) Reagents.

Copper-catalyzed asymmetric radical cyanation reactions have emerged as a powerful strategy for rapid construction of α-chiral nitriles. However, the directly decarboxylative cyanation reactions of common alkyl carboxylic acids remain largely elusive. Herein, we report a protocol for copper-catalyzed direct and enantioselective decarboxylative cyanation of benzylic acids. The in situ activation of acid substrates by a commercially inexpensive hypervalent iodine(III) reagent promoted the yield of the alkyl radicals under mild reaction conditions without prefunctionalization. The structurally diverse chiral alkyl nitriles were produced in good yields with high enantioselectivities. In addition, the chiral products can be readily converted to other useful chiral compounds via further transformations.

Imparting Stability to Organic Photovoltaic Components through Molecular Engineering: Mitigating Reactions with Singlet Oxygen.

One key challenge in the development of viable organic photovoltaic devices is to design component molecules that do not degrade during combined exposure to oxygen and light. They should thus remain comparatively unreactive towards singlet molecular oxygen and not act as photosensitizers for the generation of this undesirable species. Here we present novel redox-active chromophores that combine these two properties. By functionalizing indenofluorene-extended tetrathiafulvalenes (IF-TTFs) with cyano groups at the indenofluorene core using Pd-catalyzed cyanation reactions, we find that the reactivity of the exocyclic fulvene carbon-carbon double bonds towards singlet oxygen is considerably reduced. The new cyano-functionalized IF-TTFs were tested in non-fullerene acceptor based organic photovoltaic "proof-of-principle" devices, revealing enhanced device stability.