Aryl Nitriles Research Articles

Radiolabel Uncovers Nonintuitive Metabolites of BIIB104: Novel Release of [14C]Cyanide from 2-Cyanothiophene and Subsequent Formation of [14C]Thiocyanate.

BIIB104 (formerly PF-04958242), N-((3S,4S)-4-(4-(5-cyanothiophen-2-yl)phenoxy)tetrahydrofuran-3-yl)propane-2-sulfonamide, is an α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor potentiator investigated for the treatment of cognitive impairment associated with schizophrenia. Preliminary in vitro metabolism studies with non-radiolabeled BIIB104 in rat, dog, and human liver microsomes (RLM, DLM, and HLM) showed O-dealkylation in all three species, tetrahydrofuran hydroxylation dominating in DLM and HLM, and thiophene hydroxylation prevalent in RLM. However, a subsequent rat mass balance study with [nitrile-14C]BIIB104 showed incomplete recovery of administered radioactivity (∼80%) from urine and feces over 7 days following an oral dose, and an exceptionally long plasma total radioactivity half-life. Radiochromatographic metabolite profiling and identification, including chemical derivation, revealed that [14C]cyanide was a major metabolite of [nitrile-14C]BIIB104 in RLM, but a minor and trace metabolite in DLM and HLM, respectively. Correspondingly in bile duct-cannulated rats, [14C]thiocyanate accounted for ∼53% of total radioactivity excreted over 48 hours postdose and it, as an endogenous substance, explained the exceptionally long plasma radioactivity half-life. The release of [14C]cyanide from the 2-cyanothiophene moiety is postulated to follow an epoxidation-initiated thiophene-opening based on the detection of non-radiolabeled counterpart metabolites in RLM. This unusual biotransformation serves as a lesson regarding placement of the radioactive label on an aryl nitrile when material will be used for evaluating the metabolism of a new drug candidate. Additionally, the potential cyanide metabolite of nitrile-containing drug molecules may be detected in liver microsomes with liquid chromatography-mass spectrometry following a chemical derivatization. SIGNIFICANCE STATEMENT: Using [nitrile-14C]BIIB104, non-intuitive metabolites of BIIB104 were discovered involving a novel cyanide release from the 2-cyanothiophene motif via a postulated epoxidation-initiated thiophene-opening. This unusual biotransformation serves as a lesson regarding placement of the radioactive label on an aryl nitrile when material will be used for evaluating the metabolism of a new drug candidate.

Light-Triggered, Ni-Catalyzed Cyanation of Aryl Triflates with 1,4-Dicyanobenzene as the CN Source.

A light-triggered, Ni-catalyzed cyanation of aryl triflates was herein reported, which provides a benign photochemical synthesis of aryl nitriles using 1,4-dicyanobenzene as the CN source instead of HCN or a metallic CN source. This mild method uses a readily available bisphosphine ligand and a soluble organosilicon reagent as the reductant and is carried out under purple light without an external photocatalyst. This cyanation was effective for aryl triflates derived from phenols and bisphenols as well as lignin-derived phenolic compounds, demonstrating its potential utility for the synthesis of aryl nitriles from biomass.

Design, synthesis, anti-mycobacterial activity, molecular docking and ADME analysis of spiroquinoxaline-1,2,4-oxadiazoles via [3 + 2] cycloaddition reaction under ultrasound irradiation.

The development of anti-tuberculosis (anti-TB) drugs has become a challenging task in medicinal chemistry. This is because Mycobacterium tuberculosis (TB), the pathogen that causes tuberculosis, has an increasing number of drug-resistant strains, and existing medication therapies are not very effective. This resistance significantly demands new anti-TB drug profiles. Here, we present the design and synthesis of a number of hybrid compounds with previously known anti-mycobacterial moieties attached to quinoxaline, quinoline, tetrazole, and 1,2,4-oxadiazole scaffolds. A convenient ultrasound methodology was employed to attain spiroquinoxaline-1,2,4-oxadiazoles via [3 + 2] cycloaddition of quinoxaline Schiff bases and aryl nitrile oxides at room temperature. This approach avoids standard heating and column chromatography while producing high yields and shorter reaction times. The target compounds 3a-p were well-characterized, and their in vitro anti-mycobacterial activity (anti-TB) was evaluated. Among the screened compounds, 3i displayed promising activity against the Mycobacterium tuberculosis cell line H37Rv, with an MIC99 value of 0.78µg/mL. However, three compounds (3f, 3h, and 3o) exhibited potent activity with MIC99 values of 6.25µg/mL. To further understand the binding interactions, the synthesized compounds were docked against the tuberculosis protein 5OEQ using in silico molecular docking. Moreover, the most active compounds were additionally tested for their cytotoxicity against the RAW 264.7 cell line, and the cytotoxicity of compounds 3f, 3h, 3i, and 3o was 27.3, 28.9, 26.4, and 30.2µg/mL, respectively. These results revealed that the compounds 3f, 3h, 3i, and 3o were less harmful to humans. Furthermore, the synthesized compounds were tested for ADME qualities, and the results suggest that this series is useful for producing innovative and potent anti-tubercular medicines in the future.

Visible-Light-Induced Three-Component 1,2-Alkylpyridylation of Alkenes via a Halogen-Atom Transfer Process.

Visible-light-induced three-component 1,2-alkylpyridylation of alkenes with unactivated alkyl iodides and aryl cyanides is reported via a photocatalytic halogen-atom transfer (XAT) strategy. This metal-free protocol utilizes readily available tertiary alkylamine as the terminal reductant to smoothly convert alkyl iodides into the corresponding carbon radical species. The reaction features a broad substrate scope, excellent functional group tolerance, high efficiency, and mild reaction conditions. The practicability of this methodology is further demonstrated in the late-stage difunctionalization of bioactive molecules.

Recent investigations into deborylative (thio-/seleno-) cyanation of aryl boronic acids.

In this review, we intend to summarize the most important discoveries in the deborylative (thio-/seleno-) cyanation of aryl boronic acids from 2006 to the end of 2023. Thus, the review is divided into three parts. The first section focuses exclusively on cyanation of aryl boronic acids into aryl nitriles. The second section covers the available literature on the synthesis of aryl thiocyanates through thiocyanation of respective aryl boronic acids. The third will discuss selenocyanation of aryl boronic acids into aryl selenocyanates.

Arylgermylation of alkenes by cooperative photoactivation and hydrogen atom transfer strategy

We present an efficient photoredox/HAT dual catalyzed arylgermylation of alkenes by using readily available alkene, germyl hydrides and (hetero)aryl nitriles under mild conditions, providing a variety of high functionality germanium-containing...

Visible light catalyzed arylsilylation of alkenes to construct silicon-containing 1,1-diaryl moieties

We have developed an efficient photocatalyzed arylsilylation of alkenes, utilizing silylboranes and (hetero)aryl nitriles in the presence of base and photocatalyst.

Harnessing alcohols as sustainable reagents for late-stage functionalisation: synthesis of drugs and bio-inspired compounds.

Alcohol is ubiquitous with unparalleled structural diversity and thus has wide applications as a native functional group in organic synthesis. It is highly prevalent among biomolecules and offers promising opportunities for the development of chemical libraries. Over the last decade, alcohol has been extensively used as an environmentally friendly chemical for numerous organic transformations. In this review, we collectively discuss the utilisation of alcohol from 2015 to 2023 in various organic transformations and their application toward intermediates of drugs, drug derivatives and natural product-like molecules. Notable features discussed are as follows: (i) sustainable approaches for C-X alkylation (X = C, N, or O) including O-phosphorylation of alcohols, (ii) newer strategies using methanol as a methylating reagent, (iii) allylation of alkenes and alkynes including allylic trifluoromethylations, (iv) alkenylation of N-heterocycles, ketones, sulfones, and ylides towards the synthesis of drug-like molecules, (v) cyclisation and annulation to pharmaceutically active molecules, and (vi) coupling of alcohols with aryl halides or triflates, aryl cyanide and olefins to access drug-like molecules. We summarise the synthesis of over 100 drugs via several approaches, where alcohol was used as one of the potential coupling partners. Additionally, a library of molecules consisting over 60 fatty acids or steroid motifs is documented for late-stage functionalisation including the challenges and opportunities for harnessing alcohols as renewable resources.

Au nanoparticle-catalyzed double hydrosilylation of nitriles by diethylsilane.

We present the first example of Au-catalyzed reduction of nitriles into primary amines. In contrast to monohydrosilanes which are completely unreactive, diethylsilane (a dihydrosilane) is capable of reducing aryl or alkyl nitriles into primary amines under catalysis by Au nanoparticles supported on TiO2, via a smooth double hydrosilylation pathway. The produced labile N-disilylamines are readily deprotected by HCl in Et2O to form the hydrochloric salts of the corresponding amines in very good to excellent yields. The catalyst is recyclable and reusable at least in 5 consecutive runs.

Synthesis of a novel nanomagnetic N4 bis schiff base complex of copper(ii) as an efficient catalyst for click synthesis of tetrazoles.

In this study, we have prepared a novel bis-Schiff-base copper(ii) complex by modifying Fe3O4 with acetylacetone functionalities and subsequently forming a Schiff base with 2-picolylamine and CuCl2 through a template method. Immobilization of 2,4-pentanedione and its reaction with 2-picolylamine enabled the synthesis of 1,3-diketimines (HNacNac) as an anionic ligand. This unique design resulted in a tetradentate N4 coordination sphere for copper(ii) ion complexation. The resulting heterogeneous catalyst, [Fe3O4@Sil-Schiff-base-Cu(ii)], efficiently catalyzed the click condensation of diverse aryl nitriles with sodium azide to produce 5-substituted 1H-tetrazoles in high yields and selectivity. The catalyst demonstrated remarkable stability and recyclability without appreciable loss of catalytic activity, as confirmed by hot filtration and reusability studies.

Experimental thermochemical study of aryl nitriles: A structural energetic approach

The present work comprised a study of the thermochemical properties of three aryl nitriles: Methyl p-cyanobenzoate, p-Acetylbenzonitrile, and p-Methoxybenzonitrile. This study was carried out using calorimetric and thermal analysis techniques. Through differential scanning calorimetry, we obtained the temperatures and enthalpies of fusion, as well as the heat capacities in the crystal phase. Specific combustion energies were determined through static bomb combustion calorimetry, from which, the enthalpies of formation in the condensed phase were derived. Additionally, isothermal thermogravimetry was used to measure the mass loss rate as a function of temperature. Using the Langmuir equation in conjunction with benzoic acid as a calibration material, vapor pressures were determined as a function of temperature. With the obtained vapor pressures and the Clausius-Clapeyron equation, enthalpies of sublimation were calculated. Moreover, entropies and Gibbs sublimation energies were determined at T = 298.15 K. Finally, using these properties, enthalpies of formation in the gaseous phase at T = 298.15 K were calculated for the three mentioned compounds. With these data, an analysis of the energetic effect of different substituents in benzonitrile is presented.

A novel iodo bridged 1D CuI coordination polymer containing N,N-bidentate Schiff base ligand: Synthesis, structure, theoretical studies, electrochemical properties, and catalytic activity in the synthesis of tetrahydropyrimidines

In this study, a new 1D polymeric Cu(I) complex [Cu(L2Cl)I]n, where L = N,N′-bis(2-chlorobenzylidene)ethane-1,2-diamine, was synthesized and characterized using different analytical approaches, comprising 1H NMR, FT-IR, and CHN analysis. The geometrical features of the complex were determined through the single crystal X-ray diffraction (SC-XRD) method, which revealed that the copper atom is coordinated to the N atoms of the Schiff base. The bond angles surrounding Cu(I) ion indicated a somewhat distorted trigonal planar geometry of the complex. Hirshfeld surface analysis (HSA) was used to investigate the non-covalent intermolecular interactions, while theoretical studies were conducted utilizing DFT with B3P86/Def2-TZVP level of theory. The consistency between theoretical findings and experimental bond lengths of the [Cu(L2Cl)I]n confirmed the reliability of the theoretical conclusions. To better understand the intermolecular charge transfer features of the [Cu(L2Cl)I]n, the natural bond orbital as well as Atoms in Molecules analyses were also performed. The electrochemical behavior of the Cu(I) complex was explored at 25 °C using cyclic voltammetry in a pH 7.0 buffered solution. It is established that the quasi-reversible mechanism is consistent with the Cu(II)/Cu(I) redox system. Additionally, the catalytic action of this complex as a new catalyst was evaluated in the synthesis of derivatives of tetrahydropyrimidine by reacting 1,3-propylenediamine with various aryl nitriles under conventional thermal conditions.

Heteroditopic NHC Ligand Supported Manganese(I) Complexes: Synthesis, Characterization, and Activity as Non-bifunctional Phosphine-Free Catalyst for the α-Alkylation of Nitriles.

In the present work, several manganese(I) complexes of chelating heteroditopic ligands Mn1-3, featuring ImNHC (imidazol-2-ylidene) connected to a 1,2,3-triazole-N or tzNHC (1,2,3-triazol-5-ylidene) donors via a methylene spacer, with possible modifications at the triazole backbone have been synthesized and completely characterized. Notably, the CO stretching frequencies, electrochemical analysis, and frontier orbital analysis certainly suggest that the chelating ImNHC-tzNHC ligands have stronger donation capabilities than the related ImNHC-Ntz ligand in the synthesized complexes. Moreover, these well-defined phosphine-free Mn(I)-NHC complexes have been found to be effective non-bifunctional catalysts for the α-alkylation of nitriles using alcohols and importantly, the catalyst Mn1 containing ImNHC connected to a weaker triazole-N donor displayed higher activity compared to Mn2/Mn3 containing an unsymmetrical bis-carbene donors (ImNHC and tzNHC). A wide range of aryl nitriles were coupled with diverse (hetero)aromatic as well as aliphatic alcohols to get the corresponding products in good to excellent yields (32 examples, up to 95 % yield). The detailed mechanistic studies including deuterium labelling experiments reveal that the reaction follows a Borrowing Hydrogen pathway.

Fabrication of Fe3O4@AMNA-CuBr Nanocomposite as a Highly Efficient and Reusable Heterogenous Catalyst for Synthesis of Highly Substituted Oxazoles

Research on synthetic methods for the preparation of oxazoles is an important issue among synthetic chemists because oxazole derivatives are structural subunits of various natural active products and are valuable synthetic and pharmaceutical precursors. In this research work, we constructed CuBr supported on surface of magnetic Fe3O4 nanoparticles modified with 6-(aminomethyl)nicotinic acid [Fe3O4@AMNA-CuBr nanocomposite] and evaluated its catalytic activity for the preparation of highly substituted oxazoles through one-pot three-component reactions of diphenylacetylene derivatives with aryl nitriles and water in PEG as the solvent. The results shown that the Fe3O4@AMNA-CuBr catalyst was used 8 times without significant decrease in catalytic activity. XRD and TEM analysis confirmed that the structure and morphology that the Fe3O4@AMNA-CuBr catalyst did not change after 8 runs.

Transition-Metal-Catalyzed C-C Bond Formation from C-C Activation.

ConspectusC-C single bonds are ubiquitous in organic compounds. The activation and subsequent functionalization of C-C single bonds provide a unique opportunity to synthesize conventionally inaccessible molecules through the rearrangement of carbon skeletons, often with a favorable atom and step economy. However, the C-C bonds are thermodynamically and kinetically inert. Consequently, the activation of C-C bonds is particularly attractive yet challenging in the field of organic chemistry. In the past decade, we sought to develop efficient strategies to carry out transition-metal-catalyzed diverse C-C cleavage/C-C forming reactions and to obtain some insights into the intrinsic reactivities of different C-C bonds. With our efforts, readily available alcohols, carboxylic acids, and ketones served as suitable substrates for the catalytic C-C coupling reactions, which are reviewed in this Account. In 2009, we observed a Ni-catalyzed cross coupling of aryl nitriles with arylboronic esters through C-CN cleavage. Encouraged by these results, we are interested in transition-metal-catalyzed C-C bond activation. Due to their broad availability, we then turned our attention to C-C cleavage of carboxylic acids. Rhodium-catalyzed decarbonylative coupling of carboxylic acids with (hetero)arenes was then achieved through oxidative addition of in situ formed, more reactive mixed anhydrides to Rh(I) without the need for oxidants that are commonly required for the decarboxylative coupling of carboxylic acids. Subsequently, the decarbonylation of more challenging unstrained aryl ketones was realized under Rh catalysis assisted by N-containing directing groups. Following this work, a group exchange of aryl ketones with carboxylic acids was achieved through 2-fold C-C bond cleavage. By employing the chelation strategy, Rh-catalyzed C-C bond activation of secondary benzyl alcohols was also accomplished through β-carbon elimination of the rhodium alcoholate intermediates. The competing oxidation of secondary alcohols to ketones via β-hydrogen elimination of the same intermediates was suppressed as thermodynamically favorable five-membered rhodacycles are formed after β-carbon elimination. Different types of transformations of alcohols, including the Heck-type reaction with alkenes, cross coupling with arylsilanes, and Grignard-type addition with aldehydes or imines, have been achieved, showing the great potential of secondary alcohols in the formation of C-C bonds. These C-C bond-forming reactions are complementary to traditional cross couplings of aryl halides with organometallic reagents. However, these transformations produce small molecules as byproducts. To improve the atom economy, we then investigated C-C bond transformations of strained-ring cyclic compounds. Ni-catalyzed intermolecular cyclization of benzocyclobutenones with alkynes was recently achieved via the uncommon cleavage of the C1-C8 bond by employing a removable blocking strategy. Rh-catalyzed intramolecular annulation of benzocyclobutenols with alkynes was also achieved. In summary, our developments demonstrate the great potential of transition-metal-catalyzed C-C bond activation for the formation of new C-C bonds. To further expand the synthetic utility of C-C bond activation, more efforts are required to expand the substrate scope and to achieve earth-abundant metal-catalyzed transformations.

Research on catalytic application of Fe3O4@AAPA-AP-CuCl2 nanocomposite: First nanomagnetic copper catalyst for preparation of aryl nitriles from aldehydes

Nitrile derivatives play an important role in the synthesis of drugs and medicinal compounds; and use to treat diseases such as major depression, generalized anxiety, HIV and mild dementia-related anxiety in non-psychotic patients. In this paper, we found that CuCl2 supported on magnetic nanoparticles modified with 3-amino-2-(aminomethyl)propanoic acid and acylpyrrole [Fe3O4@AAPA-AP-CuCl2] is an ecofriendly and highly efficient catalyst for the preparation of nitriles from aldehydes under mild conditions. Based on our research, it is the first report on the utilization of magnetic copper nanocatalysts for the preparation of aryl nitriles from aldehydes (through radical-type cleavage of coordinated cyanide anion process). The structure of Fe3O4@AAPA-AP-CuCl2 nanocomposite was fully confirmed by many spectroscopic techniques. The Fe3O4@AAPA-AP-CuCl2 catalyst showed high activity and could be recovered and reused 7 times without significant loss in catalytic activity and selectivity. The advantages of this system can be mentioned: performing the reaction in environmentally friendly solvent, easy separation of the catalyst, high reusability, synthesis of products with high yields, providing NMR for all products.

Introducing of novel class of pyrano[2,3-c]pyrazole-5-carbonitrile analogs with potent antimicrobial activity, DNA gyrase inhibition, and prominent pharmacokinetic and CNS toxicity profiles supported by molecular dynamic simulation

Microbiological DNA gyrase is recognized as an exceptional microbial target for the innovative development of low-resistant and more effective antimicrobial drugs. Hence, we introduced a one-pot facile synthesis of a novel pyranopyrazole scaffold bearing different functionalities; substituted aryl ring, nitrile, and hydroxyl groups. All new analogs were characterized with full spectroscopic data. The antimicrobial screening for all analogs was assessed against standard strains of Gm + ve and Gm-ve through in vitro considers. The screened compounds displayed very promising MIC/MBC values against some of the bacterial strains with broad or selective antibacterial effects. Of these, 4j biphenyl analog showed 0.5-2/2-8 µg/mL MIC/MBC for suppression and killing of Gm + ve and Gm-ve strains. Moreover, the antimicrobial screening was assessed for the most potent analogs against certain highly resistant microbial strains. Consequently, DNA gyrase supercoiling assay was done for all analogs using ciprofloxacin as reference positive control. Obviously, the results showed a different activity profile with potent analog 4j with IC50 value 6.29 µg/mL better than reference drug 10.2 µg/mL. Additionally, CNS toxicity testing was done using the HiB5 cell line for attenuation of GABA/NMDA expression to both 4j and ciprofloxacin compounds that revealed better neurotransmitter modulation by novel scaffold. Importantly, docking and dynamic simulations were performed for the most active 4j analog to investigate its interaction with DNA binding sites, which supported the in vitro observations and compound stability with binding pocket. Finally, a novel scaffold pyranopyrazole was introduced as a DNA gyrase inhibitor with prominent antibacterial efficacy and low CNS side effect toxicity better than quinolones. Communicated by Ramaswamy H. Sarma

Catalyst free, one-pot green synthesis of 2-aryl-2-oxazoline derivatives from aryl nitrile using ionic liquid

A catalyst free methodology for the synthesis of 2-aryl-2-oxazoline derivatives under conventional heating using ionic liquid 1-butyl-3-methylimidazolium bromide ([bmim]Br) as neutral reaction media is described. Various aryl nitriles condensed with 2-aminoethanol was studied to afford corresponding products in good to excellent yields in short reaction time. This method is operationally simple, green, and easy workup procedure.

Easy and efficient direct conversion of aryl nitrile into aryl amide

Easy and efficient direct conversion of aryl nitrile into aryl amide

Palladium-Catalyzed Cyanation of Aryl Sulfonium Salts.

A palladium-catalyzed cyanation of aryl dimethylsulfonium salts using cheap, nontoxic, and bench-stable K4[Fe(CN)6]·3H2O as the cyanating reagent has been developed. The reactions proceeded well under base-free conditions with various sulfonium salts and provided aryl nitrile with yields of up to 92%. Aryl sulfides can be transformed to aryl nitriles directly via a one-pot process, and the protocol is scalable. Density functional theory calculations were performed to investigate the reaction mechanism that involved a catalytic cycle involving oxidative addition, ligand exchange, reductive elimination, and regeneration to yield the product.