Reduction Of Nitriles Research Articles

Mechanistic Vistas of Trivalent Nitrogen Compound Reduction by Samarium Diiodide

AbstractIn trivalent nitrogen compounds, the nitrogen lone pair is highly amenable to bind to samarium iodide prior to electron transfer. As SmI2 is more azaphilic than oxophilic, its affinity to the nitrogen lone pair is more pronounced in aza substrates than in the analogous carbonyl compounds. The impact of this binding is very large in terms of reaction rate and at the same time gives rise to unique mechanistic phenomena, which include unusual kinetic rate orders, catalysis by quantum dots, and remote functionalization. Even reduction of nitriles was found to be affected by this coordination to SmI2. This review focuses on the reduction mechanisms of three groups of compounds: imines, azobenzene, and nitriles.

The synthesis and cholinesterase inhibitory activities of solasodine analogues with seven-membered F ring

Solasodine analogues containing a seven-membered F ring with a nitrogen atom placed at position 22a were prepared from diosgenin or tigogenin in a four-step synthesis comprising of the simultaneous opening of the F-ring and introduction of cyanide in position 22α, activation of the 26-hydroxyl group as mesylate, nitrile reduction, and N-cyclization. Solasodine, six obtained 22a(N)-homo analogues, as well as four 26a-homosolasodine derivatives and their open-chain precursors (13 in total) were tested as potential inhibitors of acetyl- and butyryl-cholinesterases and showed activity at micromolar concentrations. The structure-activity relationship study revealed that activities against studied esterases are affected by the structure of E/F rings and the substitution pattern of ring A. The most potent compound 8 acted as non-competitive inhibitors and exerted IC50 = 8.51 μM and 7.05 μM for eeAChE and eqBChE, respectively. Molecular docking studies revealed the hydrogen bond interaction of 8 with S293 of AChE; further rings are stabilized via hydrophobic interaction (ring A) or interaction with Y341 and W286 (rings B and C). Biological experiments showed no neurotoxicity of differentiated SH-SY5Y cells. More importantly, results from neuroprotective assay based on glutamate-induced cytotoxicity revealed that most derivatives had the ability to increase the viability of differentiated SH-SY5Y cells in comparison to galantamine and lipoic acid assayed as standards. The newly synthesized solasodine analogues are able to inhibit and to bind cholinesterases in noncompetitive mode of inhibition and exhibited neuroprotection potential of differentiated neuroblastoma cells after Glu-induced toxicity.

Benzimidazole fragment containing Mn-complex catalyzed hydrosilylation of ketones and nitriles

The synthesis of a new bidentate (NN)–Mn(I) complex is reported and its catalytic activity towards the reduction of ketones and nitriles is studied. On comparing the reactivity of various other Mn(I) complexes supported by benzimidazole ligand, it was observed that the Mn(I) complexes bearing 6-methylpyridine and benzimidazole fragments exhibited the highest catalytic activity towards monohydrosilylation of ketones and dihydrosilylation of nitriles. Using this protocol, a wide range of ketones were selectively reduced to the corresponding silyl ethers. In case of unsaturated ketones, the chemoselective reduction of carbonyl group over olefinic bonds was observed. Additionally, selective dihydrosilylation of several nitriles were also achieved using this complex. Mechanistic investigations with radical scavengers suggested the involvement of radical species during the catalytic reaction. Stoichiometric reaction of the Mn(I) complex with phenylsilane revealed the formation of a new Mn(I) complex.

Catalytic Nitrile Hydroboration: A Route to N,N-Diborylamines and Uses Thereof.

Catalytic reduction of nitriles is considered as an attractive and atom-economical route to a diversity of synthetically valuable primary amines. Compared to other methods, dihydroboration approach has been developed relatively recently but has already attracted the attention of many research groups due to reasonably mild reaction conditions, selectivity control and the access to N,N-diborylamines, which emerged as powerful reagents for C-N bond forming reactions. Early developments in catalytic dihydroboration of nitriles implied precious metal catalysts along with harsh conditions and prolonged reaction times, whereas recent advances mostly rely on base and main group metal catalytic systems with significantly improved profiles. This minireview aims to provide an overview of advances and challenges of dihydroboration of nitriles with d-, f- and main group metal catalysts. Mechanistic features of different catalytic systems, functional group tolerance and scope of the methods are also presented. The synthetic utility of N,N-diborylamies, beyond simple protodeborylation, is discussed in the aspect of N-arylation, imine and amide synthesis.

Discovery of potent thrombin inhibitors from a protease-focused DNA-encoded chemical library

DNA-encoded chemical libraries are collections of compounds individually coupled to unique DNA tags serving as amplifiable identification barcodes. By bridging split-and-pool combinatorial synthesis with the ligation of unique encoding DNA oligomers, million- to billion-member libraries can be synthesized for use in hundreds of healthcare target screens. Although structural diversity and desirable molecular property ranges generally guide DNA-encoded chemical library design, recent reports have highlighted the utility of focused DNA-encoded chemical libraries that are structurally biased for a class of protein targets. Herein, a protease-focused DNA-encoded chemical library was designed that utilizes chemotypes known to engage conserved catalytic protease residues. The three-cycle library features functional moieties such as guanidine, which interacts strongly with aspartate of the protease catalytic triad, as well as mild electrophiles such as sulfonamide, urea, and carbamate. We developed a DNA-compatible method for guanidinylation of amines and reduction of nitriles. Employing these optimized reactions, we constructed a 9.8-million-membered DNA-encoded chemical library. Affinity selection of the library with thrombin, a common protease, revealed a number of enriched features which ultimately led to the discovery of a 1 nM inhibitor of thrombin. Thus, structurally focused DNA-encoded chemical libraries have tremendous potential to find clinically useful high-affinity hits for the rapid discovery of drugs for targets (e.g., proteases) with essential functions in infectious diseases (e.g., severe acute respiratory syndrome coronavirus 2) and relevant healthcare conditions (e.g., male contraception).

Synthesis of spirocyclic β- and γ-sultams by one-pot reductive cyclization of cyanoalkylsulfonyl fluorides.

One-pot intramolecular cyclization of novel sp3-enriched cyanoalkylsulfonyl fluorides into spirocyclic β- or γ-sultams is disclosed. The method relies on nitrile group reduction followed by sulfonylation of amino group thus formed upon mild conditions (NaBH4, NiCl2·6H2O in MeOH). Cyclization proceeds smoothly with considerable efficiency (48-84%, 10 examples) on up to 30 g scale. The cyanoalkylsulfonyl fluoride intermediates can be obtained via S-nucleophilic substitution in β-functionalized alkanenitriles or double alkylation of α-alkylthioacetonitrile, followed by oxidative chlorination with Cl2 and further reaction with KHF2. The title mono- and bifunctional sultams are advanced sp3-enriched building blocks for drug discovery and organic synthesis providing novel substitution patterns and frameworks mimicking saturated nitrogen heterocycles such as pyrrolidine/pyrrolidone.

Silver Nanoparticle Catalyzed Selective Reduction of Nitro Compounds and Nitriles

Silver Nanoparticle Catalyzed Selective Reduction of Nitro Compounds and Nitriles

Unexpected NADPH Hydratase Activity in the Nitrile Reductase QueF from Escherichia coli.

The nitrile reductase QueF catalyzes NADPH‐dependent reduction of the nitrile group of preQ0 (7‐cyano‐7‐deazaguanine) into the primary amine of preQ1 (7‐aminomethyl‐7‐deazaguanine), a biologically unique reaction important in bacterial nucleoside biosynthesis. Here we have discovered that the QueF from Escherichia coli—its D197A and E89L variants in particular (apparent k cat≈10−2 min−1)—also catalyze the slow hydration of the C5=C6 double bond of the dihydronicotinamide moiety of NADPH. The enzymatically C6‐hydrated NADPH is a 3.5:1 mixture of R and S forms and rearranges spontaneously through anomeric epimerization (β→α) and cyclization at the tetrahydronicotinamide C6 and the ribosyl O2. NADH and 1‐methyl‐ or 1‐benzyl‐1,4‐dihydronicotinamide are not substrates of the enzymatic hydration. Mutagenesis results support a QueF hydratase mechanism, in which Cys190—the essential catalytic nucleophile for nitrile reduction—acts as the general acid for protonation at the dihydronicotinamide C5 of NADPH. Thus, the NADPH hydration in the presence of QueF bears mechanistic resemblance to the C=C double bond hydration in natural hydratases.

Controlled Reduction of Nitriles by Sodium Hydride and Zinc Chloride

A new protocol for the controlled reduction of nitriles to aldehydes was developed using a combination of sodium hydride and zinc chloride. The iminyl zinc intermediates derived from aromatic nitriles could be further functionalized with allylmetal nucleophiles to afford homoallylamines. As the method allows the reduction of various aliphatic and aromatic nitriles with a concise procedure under milder reaction conditions and exhibits wide functional group compatibility, it is well suited for use in various opportunities in chemical synthesis.

One-pot method for the synthesis of 1-aryl-2-aminoalkanol derivatives from the corresponding amides or nitriles.

We have identified a novel one-pot method for the synthesis of β-amino alcohols, which is based on C–H bond hydroxylation at the benzylic α-carbon atom with a subsequent nitrile or amide functional group reduction. This cascade process uses molecular oxygen as an oxidant and sodium bis(2-methoxyethoxy)aluminum hydride as a reductant. The substrate scope was examined on 30 entries and, although the respective products were provided in moderate yields only, the above simple protocol may serve as a direct and powerful entry to the sterically congested 1,2-amino alcohols that are difficult to prepare by other routes. The plausible mechanistic rationale for the observed results is given and the reaction was applied to a synthesis of a potentially bioactive target.

Catalytic Reduction of Nitriles by Polymethylhydrosiloxane Using a Phenalenyl-Based Iron(III) Complex.

The reduction of nitriles to primary amines using an inexpensive silane such as polymethylhydrosiloxane (PMHS) is an industrially important reaction. Herein we report the synthesis of an earth-abundant Fe(III) complex bearing a phenalenyl-based ligand that was characterized by mass spectroscopy, elemental analysis, cyclic voltammetry, and single-crystal X-ray diffraction. The complex showed excellent catalytic activity toward reduction of aromatic, heteroaromatic, aliphatic, and sterically crowded nitriles to produce primary amines using polymethylhydrosiloxane (PMHS).

Selective Synthesis of Secondary Amines from Nitriles by a User‐Friendly Cobalt Catalyst

AbstractSelective hydrogenation/reductive amination of nitriles to secondary amines catalyzed by an inexpensive and user‐friendly cobalt complex, (Xantphos)CoCl2, is reported. The use of (Xantphos)CoCl2 and ammonia borane (NH3−BH3) combination affords the selective reduction of nitriles to symmetrical secondary amines, whereas the employment of (Xantphos)CoCl2 and dimethylamine borane (Me2NH−BH3) along with external amines produce unsymmetrical secondary amines and tertiary amines. The general applicability of this methodology is demonstrated by the synthesis of 43 symmetrical and unsymmetrical secondary and tertiary amines bearing diverse functionalities.magnified image

A Facile and Convenient Synthesis of Boc-Protected 5-Carboxyspermine

Gene therapy is a powerful technology for treating incurable and hereditary disease in humans. In the recent years, a lot of studies have been done on the development of DNA carriers. Nonviral vectors, like liposomes, polymers, and micelles, has become common vehicles due to their safety. The key compound of DOGS, DOSPA and DOSPER is the 5-carboxyspermine which formed the poly amine head-group and carries four positive charges. In general, multivalent head-group shows more transfection efficiency than monovalent analogues. In this paper, the efficient and simple synthesis of Boc-protected 5-carboxyspermine is described. Boc-protected polyamines were synthesized from (S)- 2,5-diaminopentanoic acid monohydrochloride (L-ornithine) monohydrochloride through both cyanoethylation and direct catalytic reduction of nitriles with the combination of nickel (II) chloride, sodium borohydride and di-tert-butyl decarbonate (BOC2O) in a one-pot two-reaction.

Green and convenient protocols for the efficient reduction of nitriles and nitro compounds to corresponding amines with NaBH4 in water catalyzed by magnetically retrievable CuFe2O4 nanoparticles

In this study, firstly, CuFe2O4 nanoparticles were prepared by a simple operation. The structure of the mentioned nanoparticles was characterized by Fourier transform infrared spectroscopy, X-ray diffraction, scanning electron microscopy, transmission electron microscopy, energy-dispersive X-ray spectroscopy, inductively coupled plasma-optical emission spectrometry, vibrating sample magnetometer and also Brunauer–Emmett–Teller and Barrett–Joyner–Halenda analyses. The prepared magnetically copper ferrite nanocomposite was successfully applied as a simple, cost-effective, practicable, and recoverable catalyst on the green, highly efficient, fast, base-free, and ligand-free reduction of nitriles and also on the affordable and eco-friendly reduction of nitro compounds with the broad substrate scope to the corresponding amines with NaBH4 in water at reflux in high to excellent yields.

Cobalt pincer complexes for catalytic reduction of nitriles to primary amines

An efficient cobalt pincer type complex catalyzes the hydrogenation of nitriles to amines under mild conditions with high yields.

Facile synthesis of supported Ru-Triphos catalysts for continuous flow application in selective nitrile reduction.

The selective catalytic hydrogenation of nitriles represents an important but challenging transformation for many homogeneous and heterogeneous catalysts. Herein, we report the efficient and modular solid-phase synthesis of immobilized Triphos-type ligands in very high yields, involving only minimal work-up procedures. The corresponding supported ruthenium-Triphos catalysts are tested in the hydrogenation of various nitriles. Under mild conditions and without the requirement of additives, the tunable supported catalyst library provides selective access to both primary amines and secondary imines. Moreover, the first application of a Triphos-type catalyst in a continuous flow process is presented demonstrating high catalyst life-time over at least 195 hours without significant activity loss.

Cobalt-based molecular electrocatalysis of nitrile reduction: evolving sustainability beyond hydrogen.

Two new cobalt bis-iminopyridines, [Co(DDP)(H2O)2](NO3)2 (1, DDP = cis-[1,3-bis(2-pyridinylenamine)] cyclohexane) and [Co(cis-DDOP)(NO3)](NO3) (2, cis-DDOP = cis-3,5-bis[(2-Pyridinyleneamin]-trans-hydroxycyclohexane) electrocatalyse the 4-proton, 4-electron reduction of acetonitrile to ethylamine. For 1, this reduction occurs in preference to reduction of protons to H2. A coordinating hydroxyl proton relay in 2 reduces the yield of ethylamine and biases the catalytic system back towards H2.

Interplay of nucleophilic catalysis with proton transfer in the nitrile reductase QueF from Escherichia coli

Proton relay through an active-site network of hydrogen bonds promotes enzymatic nitrile reduction to amine via a covalent thioimidate enzyme intermediate.

Hydrosilane Reduction of Nitriles to Primary Amines by Cobalt-Isocyanide Catalysts.

Reduction of nitriles to silylated primary amines was achieved by combination of 1,1,3,3-tetramethyldisiloxane (TMDS) as the hydrosilane and a catalytic amount of Co(OPiv)2 (Piv = CO tBu) associated with isocyanide ligands. The resulting silylated amines were subjected to acid hydrolysis or treatment with acid chlorides to give the corresponding primary amines or imides in good yields. One-pot synthesis of primary amides to primary amines with hydrosilanes was also achieved by iron-cobalt dual catalyst systems.

A co-relation study of efficient photocatalytic reduction of aromatic nitriles and band energies of Cu loaded elongated TiO2 nanocatalysts

Abstract Photoreduction of nitroaromatics into amines with TiO2 (P25) via greener method has attracted a great deal of interest. Generally, this reaction is feasible as the reduction potential of nitro groups (-0.5 eV) lies below the conduction band (-0.85 eV vs. NHE) of TiO2. However, functional groups such as nitrile (-CN), azido (-N3), aceto (-CH3CO), etc. are generally not photoreduced by conventional P25 due to their unfavorable reduction potential relative to titania. This report demonstrates efficient photocatalytic reduction of aromatic nitriles by tuning the band energies of Cu-TiO2 nanostructures of different morphologies. The band energetics were determined by optical and electrochemical studies which revealed that Cu loaded titania nanotubes (Cu-TNT) possess more negative conduction band gap (-2.7 eV vs. vacuum) energy as compared to LUMO level of benzonitrile (-2.82 eV). This factor has probably facilitated better reduction efficiency of benzonitrile (> 90%) and its derivatives with Cu-TNT in comparison to almost no reactivity with Cu-P25 under similar conditions. In addition to suitable conduction band position of Cu-TNT, presence of anatase phase and higher surface area (204 m2/g) might have enhanced the reaction rate.