Cyanomethyl Research Articles

Visible Light‐Induced Cyanomethyl Radical Triggered Cascade Cyclization of Phenyl‐Linked 1,6‐Enynes with a‐Halogenated Acetonitriles

Photo‐promoted cyanomethyl radical procedures for the preparation of 2,3‐dihydro‐1H‐indenes and 2,8‐dihydrocyclopenta[a]indenes from phenyl‐linked 1,6‐enynes with α‐halogenated acetonitriles are reported. The iodocyanomethylation/cyclization is performed via an atom‐transfer radical addition (ATRA) strategy under photocatalyst‐ and oxidant‐free conditions. In particular, the photoinduced cyanomethylative cascade bicyclization is carried out under the fac‐Ir(ppy)3/Na2CO3 catalystic symtem and visible light irradiation. These methods offer a one‐step and atom‐economical access to diverse cyano‐group containing five‐membered rings with broad substrate scope and high selectivity. A plausible reaction mechanism is also proposed.

Development of a chemical scaffold for inhibiting nonribosomal peptide synthetases in live bacterial cells.

The adenylation (A) domain is essential for non-ribosomal peptide synthetases (NRPSs), which synthesize various peptide-based natural products, including virulence factors, such as siderophores and genotoxins. Hence, the inhibition of A-domains could attenuate the virulence of pathogens. 5'-O-N-(Aminoacyl or arylacyl)sulfamoyladenosine (AA-AMS) is a bisubstrate small-molecule inhibitor of the A-domains of NRPSs. However, the bacterial cell permeability of AA-AMS is typically a problem owing to its high hydrophilicity. In this study, we investigated the influence of a modification of 2'-OH in the AMS scaffold with different functional groups on binding to target enzymes and bacterial cell penetration. The inhibitor 7 with a cyanomethyl group at 2'-OH showed desirable inhibitory activity against both recombinant and intracellular gramicidin S synthetase A (GrsA) in the gramicidin S-producer Aneurinibacillus migulanus ATCC 9999, providing an alternative scaffold to develop novel A-domain inhibitors.

A homochiral polar molecular piezoelectric material with phase transition and high piezoelectricity precisely designed by cyanomethyl group substitution

A chiral non-polar SHG inactive compound without phase transition is transformed into a chiral polar SHG active compound with phase transition by the introduction of cyanomethyl group, and the d22 value is raised significantly from 0 to 18 pC/N.

3-Fluoro-2H-azirine: Generation, Characterization, and Photochemistry.

The elusive 3-fluoro-2H-azirine, cyclic NCH2CF, has been generated through the stepwise decomposition of the acryloyl azide CH2CFC(O)N3 in an N2-matrix at 10 K. The characterization of cyclic NCH2CF with matrix-isolation IR spectroscopy is supported by 15N isotope labeling and the calculations with density functional theory (DFT) at the B3LYP/6-311++G(3df,3pd) level of theory. Upon irradiation at 193 nm, cyclic NCH2CF undergoes ring opening by forming the more stable nitrile isomer CH2FCN. In contrast to the photodecomposition reactions, the high-vacuum flash pyrolysis of CH2CFC(O)N3 in the gas phase at 500 °C yields the Curtius rearrangement product CH2CFNCO along with secondary fragmentation to the atmospherically relevant fluorocarbonyl radical (FCO) and cyanomethyl radical (CH2CN). Calculations on the potential energy profile for the decomposition reactions of CH2CFC(O)N3 demonstrate that the excessive energy, arising from the highly exothermic Curtius rearrangement of the azide, plays a key role in driving further dissociation reactions of CH2CFNCO by overcoming the formidable barriers (>50 kcal mol-1) under the pyrolysis conditions.

Detection and modelling of CH3NC in TMC-1

ABSTRACT Two closely related isomeric pairs of cyanides, CH3[CN/NC] and H2C[CN/NC], are studied in cold, dark interstellar cloud conditions. In contrast to the diverse detections of methyl cyanide (CH3CN) in space, methyl isocyanide (CH3NC) has previously only been observed in warm and hot star-forming regions. We report the detection of CH3NC in the cold pre-stellar core Taurus Molecular Cloud (TMC-1) using the Green Bank Telescope with a detection significance of 13.4σ. Hyperfine transitions in H2CCN and quadrupole interactions in CH3CN and CH3NC were matched to a spectral line survey from the Green Bank Telescope Observations of TMC-1: Hunting for Aromatic Molecules large project on the Green Bank Telescope, resulting in abundances with respect to hydrogen of $1.92^{+0.13}_{-0.07} \times 10^{-9}$ for the cyanomethyl radical (H2CCN), $5.02^{+3.08}_{-2.06} \times 10^{-10}$ for CH3CN, and $2.97^{+2.10}_{-1.37} \times 10^{-11}$ for CH3NC. Efforts to model these molecules with the three-phase gas-grain code nautilus in TMC-1 conditions overproduce both CH3CN and CH3NC, though the ratio of ∼5.9 per cent is consistent across observations and models of these species. This may point to missing destruction routes in the model. The models capture the larger abundance of H2CCN well. Dissociative recombination is found to be the primary production route for these molecules, and reactions with abundant ions are found to be the primary destruction routes. H + CH3NC is investigated with transition state theory as a potential destruction route, but found to be too slow in cold cloud conditions to account for the discrepancy in modelled and observed abundances of CH3NC.

Synthesis of 2-Cyanomethyl Indane Derivatives via Pd-Catalyzed Alkene Difunctionalization Reactions of Alkyl Nitriles.

The synthesis of indanes bearing substituted cyanomethyl groups at C2 is achieved through Pd-catalyzed coupling reactions between 2-allylphenyl triflate derivatives and alkyl nitriles. Related partially saturated analogues were generated from analogous transformations of alkenyl triflates. The use of a preformed BrettPhosPd(allyl)(Cl) complex as a precatalyst was essential for the success of these reactions.

Visible-Light-Promoted Direct C3-H Cyanomethylation of 2H-Indazoles.

The efficient visible-light-promoted cyanomethylation of 2H-indazoles in the presence of Ir(ppy)3 as the photocatalyst and bromoacetonitrile as the cyanomethyl radical source was achieved under mild conditions, providing a series of C3-cyanomethylated derivatives in good yields.

In Silico Evaluation of the Thr58-Associated Conserved Water with KRAS Switch-II Pocket Binders.

The KRAS switch-II pocket (SII-P) has proven to be one of the most successful tools for targeting KRAS with small molecules to date. This has been demonstrated with several KRAS(G12C)-targeting covalent inhibitors, already resulting in two FDA-approved drugs. Several earlier-stage compounds have also been reported to engage KRAS SII-P with other position 12 mutants, including G12D, G12S, and G12R. A highly conserved water molecule exists in the KRAS SII-P, linking Thr58 of switch-II and Gly10 of β1 sheet. This conserved water is also present in the cocrystal structures of most of the disclosed small-molecule inhibitors but is only displaced by a handful of SII-P binders. Here, we evaluated the conserved water molecule energetics by the WaterMap for the SII-P binders with publicly disclosed structures and studied the water behavior in the presence of selected inhibitors by microsecond timescale molecular dynamics (MD) simulations using two water models (total simulation time of 120 μs). Our data revealed the high-energy nature of this hydration site when coexisting with an SII-P binder and that there is a preference for a single isolated hydration site in this location within the most advanced compounds. Furthermore, water displacement was only achieved with a few disclosed compounds and was suboptimal, as for instance a cyanomethyl group as a water displacer appears to introduce repulsion with the native conformation of Thr58. These results suggested that this conserved water should be considered more central when designing new inhibitors, especially in the design of noncovalent inhibitors targeting the SII-P.

Visible-light-driven 1,2-hydro(cyanomethylation) of alkenes with chloroacetonitrile.

A regioselective 1,2-hydro(cyanomethylation) of unactivated aliphatic alkenes is reported. A cyanomethyl radical is generated from haloacetonitriles. This radical adds onto alkenes to form alkyl radicals, which undergo hydrogen atom transfer from thiol to produce one-carbon-extended nitriles. Furthermore, the alkyl radicals are applied to cascade cyclization.

Detection of L1014F knockdown resistance mutation in Culex tritaeniorhynchus populations

Culex tritaeniorhynchus is a major Japanese encephalitis virus vector distributed in Southeast Asia and surrounding countries. The aim of the present study is to investigate insecticide resistance status among 10 Cx. tritaeniorhynchus populations of the Mediterranean region of Turkey. Bioassay results indicated that all of the populations were resistant or at least possibly resistant to 1,1′-(2,2,2-Trichloroethane-1,1-diyl) bis (4-chlorobenzene) (DDT) (4%), [(dimethoxyphosphorothioyl) sulfanyl] butanedioate, Diethyl (malathion) (5%), and 2-[(Propan-2-yl) oxy] phenyl methylcarbamate (propoxur) (0,1%). Whereas, some of the populations were still susceptible to 3-Phenoxybenzyl (1RS)-cis, trans-3-(2,2-dichlorovinyl)-2,2-dimethyl cyclopropane carboxylate (permethrin) (0,75%) and (S)-Cyano (3-phenoxy phenyl) methyl (1R,3R)-3-(2,2-dibromoethen-1-yl)-2,2-dimethylcyclopropane-1-carboxylate (deltamethrin) (0,05%). Biochemical analysis results showed altered alpha esterase, beta esterase, para-nitrophenyl acetate (PNPA), and glutathione-s-transferase (GST) levels in some populations while all of the populations had increased oxidase levels except for the Yumurtalık population. Additionally, all of the populations had sensitive acetylcholinesterase (AChE) levels similar to the control group except for the Erzin population. Correlation analysis showed a significant correlation between mortality rates for deltamethrin and alpha esterase, beta esterase, PNPA, and GST levels while mortality rates for permethrin were significantly correlated with GST levels. An allele-specific polymerase chain reaction (AS-PCR) detected high L1014F allele frequency in the populations. Overall results indicate the urgent need for monitoring and mapping of insecticide resistance in Cx. tritaeniorhynchus populations of the study area for effective vector control management.

Advances in Research at Synthesis Process Optimization and Quality Standard Improvement of O-desmethylvenlafaxine Succinate.

We herein describe an optimal approach for the efficient synthesis of O-desmethylvenlafaxine succinate monohydrate (DVS) with high yield and high purity through 5-step reactions, including benzyl protection of the phenolic hydroxyl group, cyclohexanone condensation, deprotection, cyano reduction, dimethylation, and succinic acid salt formation from p-hydroxybenzene acetonitrile as a starting material. 4-Benzyloxyphenylacetonitrile (Intermediate I) was prepared by the hydroxyl protection of the bromide benzyl-p-hydroxyphenylacetonitrile catalyzed by potassium carbonate with 99.83% purity and 98.92% yields. The 1, 2-nucleophilic addition of intermediate I to cyclohexanone promoted by sodium hydroxide with the homogeneous catalyst (n-Bu)4N+Br− to the preparation of 1-[Cyano(4-benzyloxyphenyl)methyl]cyclohexanol (Intermediate II) was obtained by 99.13% purity and 99.71% yields. Cyclohexanone residues and benzyl bromide residues were trace, and tetrabutylammonium bromide residues were UNDER 0.7 ppm, which further improves the residual standards for genotoxic impurities (GIs). 1-[2-amino-1-(4-hydroxyphenyl)ethyl]cyclohexanol hydrochloride (Intermediate III) was prepared by 10% palladium-carbon under 2.0 MPa up to 98.32% purity and 94.20% yields. O-desmethylvenlafaxine (ODV) was synthesized by dimethylation of intermediate III with 37% formaldehyde solution and 85% formic acid solution. The highest purity was up to 99.20% and the yield was up to 84.77%. O-desmethylvenlafaxine succinate monohydrate (DVS) was formed from succinic acid and O-desmethylvenlafaxine (ODV) and crystallized in a mixed solvent of acetone and water (3:1) to obtain 99.92% purity and 90.27% yields. The 5-step total yields of desvenlafaxine succinate monohydrate is 71.09%, and its crystal form has characteristic peaks at 5, 10, 21, and 26 min by XRD powder diffraction, which is consistent with the crystalline form I. Compared with conventional synthesis strategy, we revealed a novel and green process with a high total yield, high atomic economy, low environmental pollution, high operational safety, and high residual standards for genotoxic impurities (GIs), which improves drug safety.

Cyanomethyl (CNMe) ether: an orthogonal protecting group for saccharides

Synthesis, orthogonal deprotection with common protecting groups and reagent tolerance of cyanomethyl (CNMe) ether protected sugars have been explored.

Metal‐free Radical Cyclization of Olefinic 1,3‐Dicarbonyls and Olefinic Amides with Nitrile C(sp3)−H Bonds in Aqueous Media

AbstractA radical cyclization of olefinic 1,3‐dicarbonyls and olefinic amides with nitrile C(sp3)−H bonds for the preparation of valuable 2,3‐dihydrofurans and benzoxazines have been developed. This protocol can be conducted at metal‐ and base‐free conditions in aqueous media with moderate to good yields. Moreover, the practicality of this strategy is further highlighted by gram‐scale reactions. The mechanistic investigation reveals that the transformation is initiated by in‐situ formed cyanomethyl radical.

Reactions of New N-(2,2-Dichloro-1-cyanoethenyl)amides with Aliphatic Amines

The reaction of the newly synthesized N-(2,2-dichloro-1-cyanoethenyl)prop-2-enamide and 4-chloro-N-(2,2-dichloro-1-cyanoethenyl)butanamide with methylamine or dimethylamine gave rise to previously unknown 5-amino-1,3-oxazole-4-carbonitriles. In the case of the reaction of N-(2,2-dichloro-1-cyanoethenyl)amides with ethylenediamine diacetate, new (Z)-2,3,5,6,7,8-hexahydro-7-oxo-1H-imidazo[1,2-a][1,4]diazepine-9-carbonitrile and 4-chloro-N-(cyano(imidazolidin-2-ylidene)methyl)butanamide were obtained.

Gas-Phase Formation and Isomerization Reactions of Cyanoacetaldehyde, a Prebiotic Molecule of Astrochemical Interest

Cyanoacetaldehyde (NC–CH2CH═O) is considered, together with guanidine and urea, as a precursor of the pyrimidine bases cytosine and uracil. Although it has not yet been detected in the interstellar medium (ISM), several hypotheses have been put forward about its synthesis in solution and in the gas phase. In this paper, we present a gas-phase model of the barrierless reaction between formyl (HCO) and cyanomethyl (CH2CN) radicals leading to cyanoacetaldehyde and focus on its evolution through isomerization and dissociation pathways. The potential-energy surface for all reactions has been explored by DFT calculations employing double-hybrid functionals and further refined through the “Cheap” composite scheme. Our results indicate that the direct association of the two reacting radicals (HCO and CH2CN) is strongly exothermic and thus thermodynamically favored under the harsh conditions of the ISM. Microcanonical rate constants computed with the help of the StarRate program for energies up to 6 kJ mol–1 above the dissociation limit show that the most abundant products are the two conformers of cyanoacetaldehyde (nitrile and carbonyl groups in a cis or trans configuration) which, despite having comparable stability, are obtained with a cis/trans ratio of 0.35:0.65. The formation of other products with relative abundances not exceeding 10% is also discussed.

Novel pyrano-triazolo-pyrimidine derivatives as anti- α-amylase agents: Synthesis, molecular docking investigations and computational analysis

A novel series of pyranotriazolopyrimidine derivatives 3a-j was synthesized and characterized by 1H NMR, 13C NMR, and HRMS experimental data. The synthesized compounds were assessed for their inhibitory potential on the α-amylase enzyme. Results showed that seven of the synthesized compounds displayed potent α-amylase inhibitory activity. Compound 3b (IC50 = 2.78 ± 0.14 μg/mL) bearing a cyanomethyl group at triazole ring, exhibited the highest activity followed by 2a, 2b and 3c with IC50 values ranging from 3.15 ± 0.25 to 4.15 ± 0.10 μg/mL, in comparison to the standard acarbose IC50 = 6.84 ± 1.22 μg/mL). A molecular docking study was performed to investigate the possible inhibitory mechanism at the binding site of the target enzyme which reinforced the observed activity of compounds 2a, 2b, 3b, and 3c. The analysis revealed the strength of intermolecular hydrogen bonding and hydrophobic interactions in the ligand-receptor complexes as significant descriptors to rationalize the inhibition results obtained. Several physicochemical properties related to the pharmacokinetics of the synthesized derivatives were predicted. These properties were found to lie within the desired limit and we have noticed that all compounds are likely to be orally active as they obeyed Lipinski's rule of five. HOMO-LUMO energy gap and some reactivity descriptor's parameters were evaluated using Density Functional Theory (DFT) employing B3LYP level with 6-311++G (d,p) basis set.

Laboratory microwave spectroscopy of the doubly deuterated cyanomethyl radical, D2CCN

The microwave spectrum of the doubly deuterated cyanomethyl radical (D2CCN) in its ground electronic state (2B1) has been observed for the lowest four rotational transitions (NKa,Kc = 10,1–00,0, 20,2–10,1, 21,2–10,1 and 21,1–11,0) using a Fourier transform microwave spectrometer in combination with a pulsed discharge nozzle. A total of 394 hyperfine components were measured and subjected to a least squares analysis which allowed determining twelve hyperfine constants for nitrogen and deuterium nuclei. With this new set of molecular constants we obtained accurate predictions for low N rotational transitions with hyperfine structure, and searched for this species in TMC–1.

Space and laboratory observation of the deuterated cyanomethyl radical HDCCN

Our observations of TMC-1 with the Yebes 40 m radio telescope in the 31.0–50.3 GHz range allowed us to detect a group of unidentified lines, showing a complex line pattern indicative of an open-shell species. The observed frequencies of these lines and the similarity of the spectral pattern with that of the 20, 2–10, 1 rotational transition of H2CCN indicate that the lines arise from the deuterated cyanomethyl radical, HDCCN. Using Fourier transform microwave spectroscopy experiments combined with electric discharges, we succeeded in producing the radical HDCCN in the laboratory and observed its 10, 1–00, 0 and 20, 2–10, 1 rotational transitions. From our observations and assuming a rotational temperature of 5 K, we derive an abundance ratio H2CCN/HDCCN = 20 ± 4. The high abundance of the deuterated form of H2CCN is well accounted for by a standard gas-phase model, in which deuteration is driven by deuteron transfer from the H2D+ molecular ion.

DFT Investigation of Hydrogen Atom Abstraction from NHC-Boranes by Methyl, Ethyl and Cyanomethyl Radicals-Composition and Correlation Analysis of Kinetic Barriers.

Understanding the hydrogen atom abstraction (HAA) reactions of N-heterocyclic carbene (NHC)-boranes is essential for extending the practical applications of boron chemistry. In this study, density functional theory (DFT) computations were performed for the HAA reactions of a series of NHC-boranes attacked by •CH2CN, Me• and Et• radicals. Using the computed data, we investigated the correlations of the activation and free energy barriers with their components, including the intrinsic barrier, the thermal contribution of the thermodynamic reaction energy to the kinetic barriers, the activation Gibbs free energy correction and the activation zero-point vibrational energy correction. Furthermore, to describe the dependence of the activation and free energy barriers on the thermodynamic reaction energy or reaction Gibbs free energy, we used a three-variable linear model, which was demonstrated to be more precise than the two-variable Evans–Polanyi linear free energy model and more succinct than the three-variable Marcus-theory-based nonlinear HAA model. The present work provides not only a more thorough understanding of the compositions of the barriers to the HAA reactions of NHC-boranes and the HAA reactivities of the substrates but also fresh insights into the suitability of various models for describing the relationships between the kinetic and thermodynamic physical quantities.

Cyanomethyl Ether as an Orthogonal Participating Group for Stereoselective Synthesis of 1,2-trans-β-O-Glycosides.

Stereoselective formation of glycosidic linkages has been the prime focus for contemporary carbohydrate chemistry. Herein, we report cyanomethyl (CNMe) ether as an efficient and effective participating orthogonal protecting group for the stereoselective synthesis of 1,2-trans-β-O-glycosides. The participating group facilitated good to high β-selective glycosylation with a broad range of electron-rich and electron-deficient glycosyl acceptors. Detailed experimental and theoretical studies reveal the involvement of CNMe ether in the formation of a six-membered imine-type cyclic intermediate for the observed stereoselectivity. Rapid incorporation and selective removal of the CNMe ether group in the presence of benzyl ether and isopropylidene acetal protection have also been reported here. The nitrile group provided an opportunity for the glycodiversification through further derivatizations.