Primary Aliphatic Amines Research Articles

A Tandem Dehydrogenation‐Driven Cross‐Coupling between Cyclohexanones and Primary Amines for Construction of Benzoxazoles

AbstractHerein, we report a transition metal‐free, operationally simple, general method for straightforward syntheses of 2‐substituted benzoxazoles from readily available cyclohexanones and aliphatic primary amines by an imine α‐oxygenation‐initiated cascade reaction sequence. The key to achieving high selectivity and excellent functional‐group tolerance is the use of TEMPO as a mild oxidant that selectively oxidizes the reaction intermediates through its multiple reactivity modes, thus facilitating the individual steps to proceed in succession. More than 70 substrate combinations are disclosed, demonstrating the reliability of this protocol to synthesize structurally diverse products, including marketed drugs, drug candidate, and natural products that are unattainable by the existing methods.

A Tandem Dehydrogenation-Driven Cross-Coupling between Cyclohexanones and Primary Amines for Construction of Benzoxazoles.

Herein, we report a transition metal-free, operationally simple, general method for straightforward syntheses of 2-substituted benzoxazoles from readily available cyclohexanones and aliphatic primary amines by an imine α-oxygenation-initiated cascade reaction sequence. The key to achieving high selectivity and excellent functional-group tolerance is the use of TEMPO as a mild oxidant that selectively oxidizes the reaction intermediates through its multiple reactivity modes, thus facilitating the individual steps to proceed in succession. More than 70 substrate combinations are disclosed, demonstrating the reliability of this protocol to synthesize structurally diverse products, including marketed drugs, drug candidate, and natural products that are unattainable by the existing methods.

Cu(I)-Catalyzed and Base-Promoted [5 + 2 + 1] Cascade Cyclization of 2-Nitrochalcones with Aliphatic Primary Amines to 5H-Pyrimido[5,4-b]indole Frameworks.

An unprecedented [5 + 2 + 1] cascade cyclization to the preparation of 5H-pyrimido[5,4-b]indole derivatives has been disclosed. The novel protocol of 2-nitrochalcones reacted with aliphatic primary amines catalyzed by CuI and promoted by Cs2CO3, which underwent a critical intermediate 2,3-disubstituted indole, providing structurally diverse 5H-pyrimido[5,4-b]indoles in generally high yields (77-90%) and broad substrate scopes (34 examples).

N-Methylation of Amines with Methanol Catalyzed by Iridium(I) Complexes Bearing an N,O-Functionalized NHC Ligand

A set of neutral [IrBr(L2)(κC-tBuImCH2PyCH2OMe)] and cationic [Ir(L2)(κ2C,N-tBuImCH2PyCH2OMe)]PF6 (L2 = cod, (CO)2) Ir(I) compounds featuring a flexible lutidine-derived polydentate ligand having NHC and −OMe as donor functions have been evaluated as catalyst precursors for the N-methylation of aniline using methanol both as a reducing agent and a C1 source. The carbonyl complexes are somewhat more active than the related diene compounds with the neutral compound [IrBr(CO)2(κC-tBuImCH2PyCH2OMe)] being the more active. A range of aromatic primary amines, including heterocyclic amines, have been selectively transformed into the corresponding N-methylamino derivatives using this catalyst at a low catalyst loading (0.1 mol %) and substoichiometric amounts of Cs2CO3 (half equiv) as a base, in methanol at 423 K. For aliphatic primary amines, selective N,N-dimethylation was achieved under the same catalytic conditions. The unselective deprotonation of the methylene linkers in [IrBr(CO)2(κC-tBuImCH2PyCH2OMe)] affords two isomeric neutral complexes featuring a coordinated dearomatized pyridine core, which were converted into [Ir(OMe)(CO)2(κC-tBuImCH2PyCH2OMe)] upon addition of methanol. This compound undergoes thermal activation of a C–H bond of the tert-butyl group to give the cyclometalated iridium(I) complex [Ir(CO)2{κ2C,C-(-CH2Me2C-ImCH2PyCH2OMe)}] featuring a bidentate C,C-coordinated NHC ligand. Mechanistic investigations support a borrowing hydrogen mechanism proceeding through iridium(I) intermediates with the methoxo complex as the catalytic active species and the cyclometalated complex as the catalyst resting state. Deuterium labeling experiments have demonstrated that both species are in equilibrium under catalytic conditions, which is consistent with the exhibited catalytic activity of the cyclometalated complex.

Helical Amide Derivatives: Synthesis by Insertion of Aliphatic ­Primary Amines into Benzo-Fused 2,2′-Diphenoquinones and Dia­stereomeric Resolution

AbstractWe have developed a method for synthesizing novel helical amide derivatives. Nucleophilic primary amines were inserted into benzo-fused 2,2′-biphenoquinones to form helical amides containing seven-membered rings. When optically pure primary amines were used in this reaction, a mixture of two amide diastereoisomers was obtained and separated into diastereomerically pure products by high-performance liquid chromatography. In contrast, the reaction of enantiomerically pure benzo-fused 2,2′-biphenoquinones with achiral aliphatic primary amines afforded enantiomerically pure helical amides with stereospecificity and retention of configuration.

Covalent organic framework modified polyacrylamide electrospun nanofiber membrane as a “turn-on” fluorescent sensor for primary aliphatic amine gas

Covalent organic frameworks (COFs) for fluorescence sensing have been under intensive investigation recently because of their excellent molecule recognition and chemical sensing capabilities. However, the utilization of COFs-based sensors is limited by the arduousness in processing and forming. Herein, a composite material is designed based on the synergy effects, which use polyacrylamide (PAM) as a matrix and TFP-PPDA COF as reinforcement. PAM/TFP-PPDA composite nanofibrous membrane (NFM) is prepared combined with electrospinning technology. PAM/TFP-PPDA can effectively use fluorescence sensing of volatile organic compounds (VOCs) to achieve the specific detection of primary aliphatic amine on the fluorescence enhances (turn-on) effect. Significantly, a linear "turn-on" relationship is observed between PAM/TFP-PPDA and the amines over a wide range of concentrations. The donor-acceptor electron-transfer mechanism of "turn-on" responsive chemosensor is further investigated using molecular simulations and density functional theory (DFT) methods. This work expanded the use of new technologies in COFs composite molding and paved the way for developing fluorescence sensors for the gas response.

Study of surface modification strategies to create glassy carbon-supported, aptamer-based sensors for continuous molecular monitoring

Electrochemical, aptamer-based (E-AB) sensors uniquely enable reagentless, reversible, and continuous molecular monitoring in biological fluids. Because of this ability, E-AB sensors have been proposed for therapeutic drug monitoring. However, to achieve translation from the bench to the clinic, E-AB sensors should ideally operate reliably and continuously for periods of days. Instead, because these sensors are typically fabricated on gold surfaces via self-assembly of alkanethiols that are prone to desorption from electrode surfaces, they undergo significant signal losses in just hours. To overcome this problem, our group is attempting to migrate E-AB sensor interfaces away from thiol-on-gold assembly towards stronger covalent bonds. Here, we explore the modification of carbon electrodes as an alternative substrate for E-AB sensors. We investigated three strategies to functionalize carbon surfaces: (I) anodization to generate surface carboxylic groups, (II) electrografting of arenediazonium ions, and (III) electrografting of primary aliphatic amines. Our results indicate that electrografting of primary aliphatic amines is the only strategy achieving monolayer organization and packing densities closely comparable to those obtained by alkanethiols on gold. In addition, the resulting monolayers enable covalent tethering of DNA aptamers and support electrochemical sensing of small molecule targets or complimentary DNA strands. These monolayers also achieve superior stability under continuous voltammetric interrogation in biological fluids relative to benchmark thiol-on-gold monolayers when a positive voltage scan window is used. Based on these results, we postulate the electrografting of primary aliphatic amines as a path forward to develop carbon-supported E-AB sensors with increased operational stability.Graphical abstract

Sensitive 1,1-dicyanovinyl push-pull dye for primary amine sensing in solution by fluorescence

1,1-dicyanovinyl push-pull dye PTTCN undergoes rapid and reversible aza-Michael addition with volatile primary aliphatic amines in solution in DMSO, yielding highly fluorescent imine derivatives. This reaction is accompanied by a dramatic colour change as well as a strong increase in fluorescence (1200-fold increase) allowing sensitive turn-on detection of primary amine in solution. In the solid state, PTTCN is emissive and reaction with primary amine vapours results in a shift in fluorescence and a possible ratiometric detection of primary amines. The selectivity is excellent for primary amines over secondary, tertiary and aromatic amines as well as over thiols and fluorescence spectroscopy allows to discriminate between primary amines and other nitrogen nucleophiles such as hydrazine and ammonia. Finally, we show as proof-of-concept that the fluorescence turn-on reaction can be used in response to the vapours of volatile amines released during food spoilage.

One-pot solvent-free microwave-assisted aza-Michael addition reaction of acrylonitrile

A novel and highly effective one-pot microwave-assisted aza-Michael addition reaction of acrylonitrile, as Michael acceptor with various primary aliphatic and aromatic amines, as Michael donor has been reported. The reaction was catalyzed by a cost-effective, highly efficient and eco-friendly catalyst, molecular sieve of 4 A0 size, under solvent-free conditions. A detail investigation on reaction controlling parameters like reaction timing and amount of catalyst was studied. The plausible mechanistic pathway has been proposed for the formation of acrylonitrile adducts. The identity of the synthesized products was established by conventional spectroscopic techniques FT-IR, 1H and 13C{1H} NMR, ESI-MS and DLS measurements. DLS result shows hydrodynamic diameter of lower alkyl chain in the range of 200–300 nm and for higher alkyl chain around 1 μm. Sheldon's hot filtration test confirms the significance of the catalyst and their heterogeneity was also confirmed by recycling it for five consecutive cycles without any noticeable change in the yield.

Eco-friendly and regiospecific intramolecular cyclization reactions of cyano and carbonyl groups in N,N-disubstituted cyanamide.

Eco-friendly, low-cost and high-yielding synthetic route toward imidazoles and oxazoles has been developed. 1-(4,6-Dimethylpyrimidin-2-yl)-2-(alkylamino)-1,5-dihydro-4H-imidazol-4-one 3a-c have been synthesized via regiospecific reaction of ethyl 2-(N-(4,6-dimethylpyrimidin-2-yl)cyanamide)acetate 1 with primary aliphatic amines in water as green solvent. While, the reaction between 4,6-dimethylpyrimidin-2-yl(2-oxo-2-phenylethyl)cyanamide 2 and primary aliphatic amines using water and/or iso-propanol as green solvents afforded 3-(4,6-dimethylpyrimidin-2-yl)-5-phenyl-1,3-oxazole-2(3H)-imine 6 and 1-(4,6-dimethylpyrimidin-2-yl)-N-alkyl-4-phenyl-1H-imidazol-2-amine 7a-d, respectively.

Development of a simple validated spectrofluorometric method for the assay of midodrine in tablets dosage form; Application to content uniformity testing

A new sensitive spectrofluorimetric technique has been established for the estimation of midodrine hydrochloride. This method depends on the condensation reaction of ortho-phthalaldehyde with the primary aliphatic amine of midodrine in the presence of 2-mercapto-ethanol. The pH of the medium was adjusted to 9.0 using 0.1 M borate buffer. The fluorescence of the product was measured at wavelength of 451 nm after excitation at 334 nm. The method was rectilinear over a concentrations range of 0.1 to 1.5 µg mL−1. The lower detection and quantitation limits were 31 and 94 ng mL−1, respectively. The method was investigated following the guidelines of the International Council of Harmonization. Analysis of commercial tablet dosage form was carried out successfully by the current method with excellent recovery percentages and with no influence from coexisted pharmaceutical additives .This method was used to evaluate the uniformity of the contents of commercial tablets according to the United States Pharmacopoeia.

Assessment of larvicidal and genotoxic potentials of extracts of Hyptis suaveolens against Culex quinquefasciatus based on enzyme profile and RAPD-PCR assay

Vector control strategies have focused on the development of effective and ecofriendly alternatives. In the present study, investigation of larvicidal and genotoxic effects of leaves of Hyptis suaveolens from four different extraction solvents (aqueous, hexane, methanol and acetone) on fourth instar larvae of Culex quinquefasciatus was carried out. Extraction was done using soxhlet apparatus and the characteristics functional group of active constituents were identified using Fourier Transform Infrared spectrophotometer. Larvicidal activities were screened using three different concentrations (50, 150 and 250 mg/mL) following WHO standard protocol and mortality was recorded after 24, 48 and 72 hr. Hexane extract showed the highest mortality (27.92, 38.75, 90.42 %; LC50: 272.5, 191.3, 114.8 mg/mL), followed by aqueous extract (20.83, 34.58, 59.58 %; LC50: 496.6, 392.9, 208.1 mg/mL) and acetone extract (20.83, 32.08, 59.58 %; LC50: 1111.2, 393.6, 266.1 mg/mL) and methanol extract (17.92, 29.17, 52.92 %; LC50: 466.0, 400.1, 272.3 mg/mL). Enzyme profile such as superoxide dismutase (SOD), glutathione-S-transferase (GST), catalase (CAT), glutathione (GSH) and alkaline phosphatase (ALP) were significantly altered in the larvae exposed to the four extracts. Phytochemical screening of all solvents extract revealed the presence of saponins, flavonoids, terpenoids and alkaloids as common constituents. Random Amplified Polymorphic DNA-Polymerase Chain Reaction (RAPD-PCR) profile implied hexane and aqueous extracts altered the DNA of larvae. Furthermore, FTIR Spectroscopic analysis revealed phenols, alcohols, aliphatic primary amines and saponins as the major groups in the extracts. Conclusively, this study established the lethal potential of extracts of H. suaveolens as alternative plant-based and eco-friendly larvicide against Cx. quinquefasciatus.

Diarylation of N- and O-nucleophiles through a metal-free cascade reaction

Diarylation of N- and O-nucleophiles through a metal-free cascade reaction

BOPPY-based novel fluorescent dopamine D2 and D3 receptor ligands

Dopamine is one of the crucial neurotransmitters in the human brain. Its out-of-range concentration can lead to various neurological diseases with special interest for dopamine D2 and D3 receptor subtypes. Although BODIPY is a highly versatile structural moiety for fluorescence labeling, we have looked out for structurally related pyridine-based moieties. We used BOPPY labelling of well-described D2R/D3R pharmacophores to obtain ligands with moderate to low nanomolar binding affinities as well as low to excellent quantum yields for bright fluorescence ligands. To best of our knowledge, this is the first report on the application of BOPPY fluorophores to GPCR ligands. This approach offers a general applicable way for fluorescence labelling via primary aliphatic amine elements.

Catalyst-free direct ring-opening of cyclic aldimines with aliphatic primary amines to construct o-hydroxy schiff bases

We firstly describe a catalyst-free direct ring-opening of cyclic aldimines with abundant aliphatic primary amines to construct o-hydroxy schiff bases under mild reaction conditions. The corresponding products were generated in good to excellent yields (80–99%). In addition, a gram-scale reaction and further application of the reaction strategy were performed.

Ring opening and skeletal reconstruction of 3-vinyl benzofuranone-chromone synthons: catalyst-free access to skeletally-diverse 2-pyridone and optically active imidazoline derivatives.

Herein is reported the first example of ring opening and skeletal reconstruction of 3-vinyl benzofuranone-chromones 1 as versatile synthons, which can react with ammonia or primary aliphatic amines as binucleophiles, for the eco-friendly and atom-economical synthesis of diverse and functionalized 2-pyridones 3 with potential biological activity in good to excellent yields (77-93%). When using optically active 1,2-diphenylethylenediamine 2 as the binucleophile, the in situ generated 2-pyridone intermediates are successfully transformed to novel optically active functionalized imidazoline derivatives 4 with high efficiency (up to 87% yield). In particular, this is the first report on the catalyst-free intramolecular cyclization occurring between an amide and a primary aliphatic amine for the construction of imidazoline molecules.

Antimicrobial Properties of Ocimum Species: An In Vitro Study.

This study aimed to determine the antimicrobial activity of ethanol-extracts obtained from Ocimum gratissimum L. (clove or African basil, Lamiaceae) and O. santum L. (holy basil) against some microorganisms present in oral cavity related to either medical or dental disease. Antimicrobial properties of both ethanol-extracts of Ocimum species against Streptococcus mutans KPSK2, S. pyogenes ATCC 19615, Staphylococcus aureus ATCC 16794, and Candida albicans ATCC 10231 were primarily determined by agar disk diffusion method. The minimum inhibitory concentration (MIC) and minimum bactericidal or fungicidal concentration (MBC or MFC) of these herbal extracts were further determined by broth micro-dilution method. Ethanol-extracts of O. sanctum L. and O. gratissimum L. inhibited the growth of all tested microorganisms in various degrees ranging from the strongest antimicrobial activity of O. sanctum against S. pyogenes [MIC at 0.19% (w/v); MBC at 0.78% (w/v)] to the least inhibitory activity of O. gratissimum against C. albicans [MIC at 12.5% (w/v); undetectable MFC]. The ethanol-extract of O. sanctum showed stronger antimicrobial property against the tested bacteria and fungus than O. gratissimum. The ethanol-extracts of both Ocimum species showed stronger antibacterial than antifungal activity. However, the ethanol-extract of O. gratissimum even at a high concentration of 50% (w/v) was unable to eliminate the tested fungus. Ethanol-extracts of Ocimum species contain effective antibacterial and antifungal properties that may be beneficial for further development of antimicrobial agents in medical and dental fields.

Facile C-N bond cleavage of primary aliphatic amines by (salen)ruthenium(VI) nitrido complexes.

We report the first example of oxidative cleavage of the strong C-N bonds of primary amines by a ruthenium(VI) nitrido complex. The driving force for this very fast C-N cleavage reaction comes from the formation of stable NN after the initial coupling of the amine N and the nitrido ligand.

Synthesis and characterization of rare earth/lithium complexes stabilized by ethylenediamine-bridged bis(phenolate) ligands and their activity in catalyzing amidation reactions

Rare earth/lithium complexes stabilized by ethylenediamine-bridged bis(phenolate) ligands have been synthesized and characterized. In addition to five rare earth/lithium amides isolated as major complexes, two other rare earth/lithium complexes bearing two phenolate ligands were also isolated. The activities of rare earth/lithium amides in catalyzing the amidation of aldehydes and amines were studied, which revealed that the yttrium/lithium complex was highly active for a wide range of substrates, generating 58 examples of amides in 42-99% yields under mild conditions (i.e., room temperature, 3-hour reaction time, additive-free). More importantly, this is the first example of rare earth-based catalysts capable of catalyzing the amidation of primary aliphatic amines.

Nitriles as main products from the oxidation of primary amines by ferrate(VI): Kinetics, mechanisms and toxicological implications for nitrogenous disinfection byproduct control

Ferrate (Fe(VI)), a promising water treatment oxidant, can be used for micropollutant abatement or disinfection byproduct mitigation. However, knowledge gaps remain concerning the interaction between Fe(VI) and dissolved organic matter structures, notably primary amines. This study investigated degradation kinetics and products of several aliphatic primary amines by Fe(VI). Primary amines showed appreciable reactivity toward Fe(VI) (2.7–68 M−1s−1 at pH 7–9), ranking as follows: benzylamine > phenethylamine > phenylpropylamine > methylamine ≈ propylamine. Nitriles were the main oxidation products of the primary amines, with molar yields of 61–103%. Minor products included aldehydes, carboxylic acids, nitroalkanes, nitrite, nitrate, and ammonia. The buffering conditions were important. Compared to phosphate, borate enhanced the reactivity of the amines and shifted the products from nitriles to carbonyls. An evaluation of the effect potency of some cyano-compounds by an in vitro bioassay for oxidative stress response and cytotoxicity suggested that non-halogenated nitriles are unlikely to pose a significant threat because they were only toxic at high concentrations, acted as baseline toxicants and did not cause oxidative stress, unlike halonitroalkanes or halonitriles. The formation of non-halogenated nitriles is preferable to the formation of nitroalkanes arising from the ozonation of primary amines (other than amino acid N-terminals) because, during chlorination, nitriles remain unreactive while nitroalkanes lead to potent halonitroalkanes.