Tertiary Alkylamines Research Articles

Metallaphotocatalytic triple couplings for modular synthesis of elaborate N-trifluoroalkyl anilines.

The integration of trifluoromethyl groups and three-dimensional quaternary carbon moieties into organic molecules has emerged as a prominent strategy in medicinal chemistry to augment drug efficacy. Although trifluoromethyl (hetero)aromatic amines and derivatives are prevalent frameworks in pharmaceuticals, the development of trifluoromethyl-embedded, intricately structured alkyl amine scaffolds for medicinal research remains a significant challenge. Herein, we present a metallaphotoredox multicomponent amination strategy employing 3,3,3-trifluoropropene, nitroarenes, tertiary alkylamines, and carboxylic acids. This synthetic pathway offers notable advantages, including the accessibility and cost-effectiveness of starting materials, high levels of chemo- and regioselectivity, and modularity. Furthermore, this approach enables the synthesis of a broad spectrum of aniline compounds featuring both trifluoromethyl group and distal quaternary carbon motifs along the aliphatic chains. The accelerated access to such elaborate N-trifluoroalkyl anilines likely involves three sequential radical-mediated coupling events, providing insightful implications for the retrosynthesis of potential compounds in organic synthesis and drug discovery.

Dual C2 Synthon Strategy for the Synthesis of Pyrimidines: Copper‐Catalyzed Aerobic α,β‐C(sp3)−H Bond Difunctionalization of Tertiary Alkylamines

AbstractHerein, we describe a two‐component methodology developed for the synthesis of pyrimidine derivatives using tertiary alkylamines and amidines. Tertiary alkylamines serve as dual C2 synthons through copper‐catalyzed aerobic difunctionalization of the α,β−C(sp3)−H bonds. The process operates under mild conditions and uses atmospheric oxygen as the oxidant. Notably, by this methodology yields up to 85% yields are obtained and a broad substrate scope is shown. Mechanistic studies indicate that the annulation proceeds via a radical‐mediated oxidation and C−N bond coupling process. This approach provides a pathway for synthesizing various heterocycles by employing tertiary alkylamines as dual C2 synthons.

Multicomponent Construction of Tertiary Alkylamines by Photoredox/Nickel-Catalyzed Aminoalkylation of Organohalides.

Tertiary alkylamines are privileged structural motifs widely present in natural products, pharmaceutical agents, and bioactive molecules, and their efficient synthesis has been a longstanding goal in organic chemistry. The functionalization of α-amino radicals derived from abundant precursors represents an emerging approach to accessing alkylamines, but application of this strategy to obtain tertiary alkylamines remains challenging. Here, we show that dual photoredox/nickel catalysis enables aminoalkylation of organohalides (sp2- and sp3-hybridized) in combination with secondary alkylamines and aldehydes. The multicomponent process proceeds through selective generation of α-amino radicals from the reduction of in situ-generated iminium ions by photoredox catalysis, followed by nickel-catalyzed cross-coupling to build a wide array of functionally diverse tertiary alkylamines. This strategy could also be extended to unprecedented four-component reactions and their asymmetric variants to deliver enantioenriched α-aryl-substituted γ-amino acid derivatives. Taken together, this work offers a streamlined synthetic route to aliphatic tertiary amines.

Structure-Activity Relationship of Benzophenazine Derivatives for Homogeneous and Heterogenized Photooxygenation Catalysis.

Singlet oxygen is a powerful oxidant used in various applications, such as organic synthesis, medicine, and environmental remediation. Organic and inorganic photosensitizers are commonly used to generate this reactive species through energy transfer with the triplet ground state of oxygen. We describe here a series of novel benzophenazine derivatives as a promising class of photosensitizers for singlet oxygen photosensitization. In this study, we investigated the structure-activity relationship of these benzophenazine derivatives. Akin to a molecular compass, the southern fragment was first functionalized with either aromatic tertiary amines, alkyl tertiary amines, aromatic sulfur groups, alkyl sulfur groups, or cyclic ethers. Enhanced photophysical properties (in terms of triplet excited-state lifetime, absorption wavelength, triplet state energy, and O2 quenching capabilities) were obtained with cyclic ether and sulfur groups. Conversely, the presence of an amine moiety was detrimental to the photocatalysts. The western and northern fragments were also investigated and slightly undesirable to negligible changes in photophysical properties were observed. The most promising candidate was then immobilized on silica nanoparticles and its photoactivity was evaluated in the citronellol photooxidation reaction. A high NMR yield of 97 % in desired product was obtained, with only a slight decrease over several recycling runs (85 % in the fourth run). These results provide insights into the design of efficient photosensitizers for singlet oxygen generation and the development of heterogeneous systems.

Electrochemical deoxygenative amination of stabilized alkyl radicals from activated alcohols

Alkylamine structures represent one of the most functional and widely used in organic synthesis and drug design. However, the general methods for the functionalization of the shielded and deshielded alkyl radicals remain elusive. Here, we report a general deoxygenative amination protocol using alcohol-derived carbazates and nitrobenzene under electrochemical conditions. A range of primary, secondary, and tertiary alkylamines are obtained. This practical procedure can be scaled up through electrochemical continuous flow technique.

Comparative analysis of commercial cleaning and disinfection formulations and protocols for effective eradication of biofilms formed by a Pseudomonas fluorescens strain isolated from a poultry meat plant

Pseudomonas spp. is the main genus of spoilage bacteria for meat stored under aerobic chilling conditions. Given their ability to adapt to various environmental conditions and to form biofilms, they are common among residential microbiota in the food industry. Biofilms are complex, structured microbial communities encased in a self-produced exopolysaccharide matrix. Resident biofilm bacteria show increased resistance against disinfectants and dynamic or hostile environments, and are therefore a persistent source of food contamination. Hence, there is a need to design and implement control strategies that are effective against biofilms in the food industry. In this study, we tested a series of commercial cleaning and disinfection agents applied by immersion or aerosolization against robust biofilms of a Pseudomonas fluorescens strain isolated from a poultry meat plant by comparing the sessile cell counts before and after the procedure. The single application of a) an alkaline or an enzymatic detergent, b) a disinfectant based on peracetic acid and hydrogen peroxide, or c) a detergent-disinfectant based on tertiary alkylamines or sodium hypochlorite, failed to completely eradicate the biofilm. However, two-step cleaning and disinfection procedures involving the application of a detergent (either alkaline or enzymatic at 50 °C) followed by the application of the disinfectant based on peracetic acid and hydrogen peroxide at the manufacturer's recommended concentrations did result in the complete eradication (p ≤ 0.05) of the robust biofilm. In addition, cleaning and disinfection procedures applied by aerosolization showed a notable efficacy (p ≤ 0.05) against surface-dried cells and sessile cells of P. fluorescens. Therefore, this approach could be regarded as a potentially viable alternative to commonly applied immersion techniques.

Thermodynamic property estimations for aqueous primary, secondary, and tertiary alkylamines, benzylamines, and their corresponding aminiums across temperature and pressure are validated by measurements from experiments

On Earth and beyond, organic chemistry often occurs in the presence of water within environments that deviate drastically from ambient conditions (25 °C and 1 bar). Accurately predicting aqueous organic reaction pathways is crucial toward understanding planetary scale processes such as the cycling of elements crucial for life (e.g., carbon and nitrogen). Advanced thermodynamic modeling can be utilized to determine the favorability of various organic reactions based on geologically relevant ranges of temperature and pressure, as well as compositional variables (e.g., pH). However, data that would otherwise allow for a diversity of organic compounds and environmental conditions to be modeled are sparse and rarely tested with experiments, particularly with regard to organic-nitrogen compounds. In this work, we develop a framework to estimate thermodynamic properties at ambient conditions that can then be extrapolated across ranges of temperature and pressure for aqueous primary, secondary, and tertiary amines and aminiums (protonated amines), specifically those structures containing linear alkyl chains and benzyl functional groups. We also performed hydrothermal experiments (250 °C, ∼40 bar) involving reactions of methylamines to test our resulting thermodynamic models, and we compare our models for other alkylamines and benzylamines to previous empirical measurements from the literature. Specifically, we use existing thermodynamic data along with our estimates at ambient conditions in combination with a variety of existing extrapolation methods related to the revised Helgeson-Kirkham-Flowers (HKF) equations of state to generate temperature- and pressure-dependent predictions of acid dissociation constants (i.e., pKa values) that strongly agree with previous empirical measurements. We use similar methods to predict product distributions for reactions involving primary, secondary, and tertiary amines/aminiums, as well as ammonia/ammonium and corresponding alcohols whose collective distributions depend on reversible substitution reactions. Our predictions are in good agreement with our experimental results involving the methylamine reaction system as well as previous experiments involving the benzylamine reaction system, for which we also produced thermodynamic estimates involving benzyl alcohol. The agreement between independent theoretical predictions and experimental measurements suggests that our estimated properties can be applied to modeling amine chemistry in other experimental and natural aqueous systems that range in temperature and pressure, providing new tools for planetary exploration.

Chemiluminescence and electrochemiluminescence of water-soluble iridium(III) complexes containing a tetraethylene-glycol functionalised triazolylpyridine ligand

BackgroundIridium(III) complexes, exhibiting high luminescence quantum yields and a wide range of emission colours, are promising alternatives to tris(2,2ʹ-bipyridine)ruthenium(II) for chemiluminescence (CL) and electrochemiluminescence (ECL) detection. This emerging class of reagent, however, is limited by the poor solubility of many iridium(III) complexes in aqueous solution, and lack of understanding of their remarkably variable selectivities towards different analytes. ResultsSeven [Ir(C^N)2(pt-TEG)]+ complexes, exhibiting a wide range of reduction potentials and emission energies, were examined with six model analytes. For CL, cerium(IV) was used as the oxidant. The alkylamine analytes generally produced greater CL and ECL with the more readily oxidised Ir(III) complexes (C^N = piq, bt, ppy), predominantly through the ‘direct’ pathway requiring oxidation of both metal complex and analyte. Aniline derivatives that did not also contain secondary or tertiary alkylamines elicited CL from the less readily oxidised complexes (C^N = df-ppy-CF3, df-ppy) via energy transfer. The most difficult to oxidise complexes (C^N = df(CF3)-ppy-Me, df(CN)-ppy) gave poor responses due to the limited potential window of the solvent and inefficiency of energy transfer to their high energy excited states. Greater CL and/or ECL intensities were generally obtained for each analyte with at least one Ir(III) complex than with [Ru(bpy)3]2+; superior limits of detection for two analytes were demonstrated. SignificanceThis exploration of CL/ECL in which the properties of luminophore, analyte and oxidant are all varied provides a new understanding of the influence of the metal-complex potentials and excited state energy on the light-producing and quenching pathways, and consequently, their distinct selectivity towards different analytes. These findings will guide the development of water-soluble Ir(III) complexes as CL and ECL reagents.

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.

Visible-light-induced alkyl-arylation of olefins via a halogen-atom transfer process.

Visible-light-induced three-component 1,2-alkyl-arylation of alkenes and alkyl radical addition/cyclization of acrylamides have been realized via a photocatalytic halogen-atom transfer (XAT) process. This metal-free protocol utilizes readily available tertiary alkylamine as both an electron donor and an XAT reagent for the activation of alkyl halides using naphthalimide (NI)-based organic photocatalysts. This process features broad substrate scope and good functional group tolerance under mild conditions, and could be effectively applied to a variety of medicinally relevant substrates.

Visible Light‐Induced EDA‐Complex Triggered Annulative Difunctionalization via Olefin‐Olefin Coupling and Radical Truce‐Smiles Rearrangement

AbstractAn EDA complex comprising N‐allyl bromodifluoroacetamides and tertiary alkyl amine was exploited to facilitate annulative difunctionalization reaction under visible‐light irradiation. This external photocatalyst‐free methodology garners olefin‐olefin coupling featuring a radical Truce‐Smiles rearrangement and produced long‐chain functionalized gem‐difluoropyrrolidones from N‐substituted methacryloyl sulfonamides, while simple N‐aryl methacrylamides furnished pyrrolidinone‐oxindole hybrid lactams in high yields. Mechanistic investigations substantiate a combined reaction mechanism, involving charge‐transfer EDA complex‐based radical cascade, alongside an α‐aminoalkyl radical‐triggered XAT process, exhibiting a quantum yield value of 1.48.

General Synthesis of Alkyl Amines via Borrowing Hydrogen and Reductive Amination

AbstractAmines are a very important class of compounds and the selective synthesis of differently substituted primary, secondary and tertiary alkyl amines is challenging. Here we present the synthesis of primary, secondary, and tertiary alkyl amines from ammonia and alcohols, aldehydes, ketones and hydrogen by combining borrowing hydrogen or hydrogen autotransfer and reductive amination with hydrogen. The key is a nanostructured, bimetallic Co/Sc catalyst able to mediate both reactions or concepts efficiently. We observe a broad product scope, a very good functional group tolerance, upscaling is easily accomplished and our catalyst is reusable.

Visible‐Light‐Mediated Cycloaddition of Azobenzenes and Nonstabilized Azomethine Ylides to Access 1,2,4‐Triazolidines

AbstractA visible‐light‐mediated cycloaddition of azobenzenes and nonstabilized azomethine ylides has been developed to access 1,2,4‐triazolidines. With readily available organic dye rose bengal as a photocatalyst and alkyl tertiary amines as precursors for azomethine ylides, the reaction proceeded smoothly under visible light irradiation at room temperature, affording various 4‐alkyl‐1,2‐diaryl‐1,2,4‐triazolidines with yields of up to 96%. Preliminarily mechanistic studies suggest that the nonstabilized azomethine ylides are formed in situ through photoredox catalysis.

Late-Stage Chloride Displacements Enable Access to Peptoids with cis-Inducing Alkylammonium Side Chains.

The synthesis of peptoids possessing multiple cis-inducing monomers with alkylammonium side chains is reported, where chloropropyl side chains are diversified on a solid support by late-stage SN2 displacements with amines. The conditions were optimized for a wide variety of primary, secondary, and tertiary alkyl amine nucleophiles. We also demonstrated that multiple chloride displacements could be achieved on sequences possessing trans-inducing N-aryl- and N-imino glycine monomers.

Dicyanovinyl-capped thiazologermoles with moderate donor-acceptor interaction as visible photoluminescence turn-on sensors for primary amines

Dicyanovinyl-capped thiazologermoles (DTzG-DCV and GIDTz-DCV) were synthesized, and their optical and electrochemical properties were investigated. Both DTzG-DCV and GIDTz-DCV showed solvatochromism, exhibiting red shifts of the photoluminescence (PL) bands with increasing solvent polarity from toluene to DMF, likely due to intramolecular donor–acceptor interaction. Moreover, they served as selective PL sensors, with spectral changes in the presence of amines and fluoride and iodide ions, but not other halogen ions, in solution. DTzG-DCV and GIDTz-DCV underwent a quick and high-yield reaction with n-butylamine to give imine derivatives, accompanied by PL color changes. Similar color changes were observed even in the solid state with n-butylamine and n-hexylamine. In contrast, reactions with secondary and tertiary alkylamines caused no obvious changes in PL color. The color changes are visible to the naked eye under irradiation with a portable UV lamp at 365 nm, and thus DTzG-DCV and GIDTz-DCV can be used for the quick and selective sensing of primary amines.

Visible-light-driven three-component reductive 1,2-diarylation of alkenes

The intermolecular alkene 1,2-diarylation provides straightforward access to polyarylalkanes but suffers from substrate limitation, requiring directing auxiliaries or prefunctionalized aryl components. Herein, we report the development of a photocatalytic strategy that enables a three-component 1,2-diarylation of alkenes under mild reductive conditions using simple tertiary alkylamine as the terminal reductant. Readily accessible aryl iodides and cyanides serve as the C(sp2) electrophiles to simultaneously install two different aryl moieties across the olefins with high regioselectivity. This protocol exhibits a broad substrate scope for all of aryl, heteroatom-substituted, and even unactivated alkenes and can be easily scaled up to the gram-scale. Mechanistic studies reveal a halogen-atom transfer (XAT) of aryl iodides to transient aryl radicals while a single-electron transfer (SET) of aryl cyanides to persistent aryl radical anions, both allowing for a regiocontrollable radical relay sequence.

Highly Diastereoselective Preparation of Tertiary Alkyl Isonitriles by Stereoinvertive Nucleophilic Substitution at a Nonclassical Carbocation.

A highly efficient SnCl4-catalyzed nucleophilic isocyanation of cyclopropyl ethers has been developed. The reaction proceeds at the quaternary carbon stereocenter of the cyclopropane with a complete inversion of configuration, providing a new avenue for the construction of synthetically challenging tertiary alkyl isonitriles with high diastereopurity. The diversity of the incorporated isocyanide group has been demonstrated by the transformation of tertiary alkyl isonitriles into the corresponding tertiary alkyl amines, amides, and cyclic ketoimines.

Synthesis and Properties of Poly(4-methyl-2-pentyne) Containing Quaternary Ammonium Salts with Methyl and Ethyl Substituents

In this work, functionalization of poly(4-methyl-2-pentyne) (PMP) with quaternary ammonium salts was carried out in order to increase CO2 selectivity in its membrane recovery. The introduction of functional groups was carried out by a two-stage method – bromination of the initial polymer and addition of tertiary alkylamines trimethylamine (TMA) and trimethylamine (TEA). It has been established that the optimal amount of introduced functional groups, while maintaining the mechanical properties of the polymer, is up to 5 mol. %. The results of organoelemental analysis and IR spectroscopy confirm the functionalization reaction of the PMP. X-ray diffraction patterns of the samples indicate an increase in the interchain distance in the series initial PMP–brominated PMP–functionalized PMP. TGA data confirm high thermal and thermal-oxidative stability. The coefficients of permeability, solubility and diffusion of PMP samples containing TMA and TEA salts were determined for individual gases. An increased ideal selectivity for the separation of gas pairs CO2/N2 by 2–3 times and CO2/CH4 by 1.5–2 times has been achieved while maintaining the permeability at a high level.

Regio-, Site-, and Stereoselective Three-Component Aminofluorination of 1,3-Dienes via Cooperative Silver Salt and Copper Catalysis

The intermolecular fluorodifunctionalization of 1,3-dienes offers straightforward access to highly functionalized allylic fluorides but suffers from low selectivities and limited substrate scope. Herein, we report the development of a cooperative silver salt and copper catalysis platform that enables an intermolecular three-component 1,2-aminofluorination of 1,3-dienes with N-bromodialkylamines and AgF. This protocol exhibits a broad substrate scope for both alkyl- and aryl-1,3-dienes with diverse functionalities, furnishing the allylic fluorides bearing homoallylic tertiary alkylamine moieties with high regio-, site-, and stereoselectivities. Moreover, the reactions of E/Z-mixed 1,3-dienes are allowed for the preparation of single E-products. Further mechanistic studies reveal a reaction sequence involving aminium radical cation (ARC) generation, aziridinium formation, and nucleophilic fluorination and highlight the pivotal role of the cooperative silver and copper complexes that enable the proceeding of aminofluorination reactions with good efficiencies and high selectivities.

N-Nitrosamine Formation in Pharmaceutical Solid Drug Products: Experimental Observations

The potential presence of N-nitrosamines in medicinal products has become a matter of concern for health authorities and pharmaceutical companies. However, very little information is available in published literature on N-nitrosamine formation within pharmaceutical drug products. In response, experiments were undertaken to test if secondary and tertiary amines present in solid drug products could undergo nitrosation due to the presence of nitrite in the excipients used in the manufacture of the drug product. This work focused on solid dosage forms exploring several model amines of varying chemical structure, solubility and pKa which were formulated using common excipients with and without added nitrite. Monitoring the formation of the N-nitrosamines after processing and upon stressed stability conditions showed that N-nitrosamine formation can occur in solid drug product formulations. The results show that the rate and extent of N-nitrosamine formation depend upon the solubility of the amine, level of nitrite, expected local acidity in water layers within the drug product and mode of processing. Our findings agree with the rank order of dosage form risk from the published EFPIA workflows for quality risk management of N-nitrosamine risks in medicines (EFPIA, 2022): amorphous > wet granulation > direct compression > dry blends. In all cases the level of N-nitrosamine formation in solid dosage forms plateaued at a level that was significantly lower than the maximum theoretical yield based on the level of nitrite present. Trace secondary amine impurities were shown to be a significantly lower risk relative to cases containing a secondary amine present at drug substance levels. A comparison of secondary and simple tertiary alkylamine reactivity showed the tertiary amine to be significantly less reactive with nitrite.