N-alkylation Of Amines Research Articles

Catalytic Fe2+ Cation Pair Site for Base-free N-Alkylation of Aromatic Amines with Alcohols.

The development of heterogeneous Fe catalysts is very attractive due to the ubiquitous, abundant, and inexpensive nature of Fe as a resource. However, Fe oxides are commonly inert as catalysts and hence, the design and fabrication of active Fe sites are essential. Herein, the fabrication of an active Fe cation pair site by simple reduction treatment of SiO2-supported FeOx (FeOx/SiO2) is presented. The active Fe cation pair site was formed by the removal of the oxygen atom between Fe cations of the FeOx on SiO2, namely oxygen vacancy formation, which is induced by temperature-controlled reduction treatment. 773 K reduction maximized the Fe cation pair sites without the decomposition of FeOx species, which was an effective catalytic one for the N-alkylation of amines mainly proceeded through Meerwein-Ponndorf-Verley (MPV) type reduction, which is achieved by the stabilization of six-membered ring transition state derived from imines and alcohols over the open active site of the Fe cation pair site.

Catalytic N-Alkylation of (Hetero)Aromatic Amines and Tandem Annulation Reactions.

A general and practical approach for N-alkylation of heteroaromatic amines with heteroaromatic alcohols is always challenging and rarely reported. Here, we designed and synthesized phosphine-free, robust, and efficient N,N-bidentate-Co(II) complexes for a universal N-alkylation of amines strategy. This present catalytic methodology can be applied to a wide range of substrates by varying alcohols, including aryl, aliphatic, acyclic, and cyclic groups, with heteroaromatic amines such as aminopyridine, 2-aminopyrimidine, and aminoquinoline to provide diverse monoalkylated organonitrogen compounds in good to excellent yields (108 examples). In addition, the utility of the developed catalytic protocol was also extended successfully for the dehydrogenative synthesis of biologically important quinoline derivatives (11 examples). Particularly, 8-aminoquinoline reacted differently with tandem N-alkylated-transfer hydrogenative byproduct (N-benzyl-1,2,3,4-tetrahydroquinolin-8-amine) was obtained, revealing the catalytic activity of the complex I. The reaction proceeded under environmentally benign conditions, which liberates water as the sole byproduct. Notably, a concise synthesis of acetylcholinesterase inhibitors (AChEIs) scaffolds as potential cognition enhancers illustrated the utility of the present protocol. Interestingly, various control and deuterium-labeled experiments were performed, suggesting that the reaction proceeds via the borrowing hydrogen pathway.

N-alkylation of amines for the synthesis of potential antiviral agents: A structural modification approach

The threat of emerging viral outbreaks has increased the need for fast and effective development of therapeutics against emerging pathogens. One approach is to modify the structure of existing therapeutic agents to achieve the desired antiviral properties. Here, we attempted to synthesize a new antiviral compound by modifying the structure of chloroquine using the N-alkylation of the primary amine (N1,N1-diethylpentane-1,4-diamine) that is used in chloroquine synthesis. Chloroquine is commonly used to treat malaria. Like chloroquine, chloroquine is used for treating conditions such as rheumatoid arthritis, lupus, and malaria. For instance, in malaria treatment, it targets and inhibits the growth of the malaria parasite, aiding in its elimination from the body. The synthesized compounds MP1, C1, and TT1 were further tested in vitro against the B.1 lineage of SARS-CoV-2. One of the compounds, MP1, demonstrated minor effectiveness, with an IC50 of XX at only a high concentration (at a concentration of 60 μM) and decreased both the number of SARS-CoV-2 copies and the amount of infectious virus. Although the synthesized compounds failed to markedly inhibit SARS-CoV-2, this could be a pontial mechanism for manipulating the drug structure against other pathogens. MP1, TT1, C1, and chloroquine diphosphate were used as ligands for molecular docking to determine the principal interactions between these compounds and the active site of the protein downloaded from the Protein Data Bank (PDB ID: 6lzg). Finally, ADMET assays were performed on the synthesized compounds to determine their pharmacokinetics and bioavailability.

Brønsted Acid Triggers [6/7 + 1] Cascade Cyclization by N-Alkyl Amine C(sp3)-N Cleavage: Mild Synthesis of Benzo[1,4]oxazepane and Dihydrobenzo[1,5]oxazocine.

A catalyst-free mild synthesis was reported to produce medium-ring oxazepane and oxazocine derivatives from aminomaleimides and N-alkyl amines. The substrate and acidic additives were employed to cleave the C(sp3)-N bond as a one-carbon synthon for C-C and C-O coupling, thus facilitating the [n + 1] cascade cyclization reaction, which enabled the construction of seven- and eight-membered N,O-heterocycles at room temperature. The method exhibits abroad substrate scope and remarkable tolerance toward various functional groups (seven-membered 28 examples, eight-membered 8 examples, and activated N-alkyl amine 12 examples) and utilization of natural products (2 examples).

Enable biomass-derived alcohols mediated alkylation and transfer hydrogenation

A single-atom catalyst with generally regarded inert Zn–N4 motifs derived from ZIF-8 is unexpectedly efficient for the activation of alcohols, enabling alcohol-mediated alkylation and transfer hydrogenation. C-alkylation of nitriles, ketones, alcohols, N-heterocycles, amides, keto acids, and esters, and N-alkylation of amines and amides all go smoothly with the developed method. Taking the α-alkylation of nitriles with alcohols as an example, the α-alkylation starts from the (1) nitrogen-doped carbon support catalyzed dehydrogenation of alcohols into aldehydes, which further condensed with nitriles to give vinyl nitriles, followed by (2) transfer hydrogenation of C=C bonds in vinyl nitriles on Zn–N4 sites. The experimental results and DFT calculations reveal that the Lewis acidic Zn-N4 sites promote step (2) by activating the alcohols. This is the first example of highly efficient single-atom catalysts for various organic transformations with biomass-derived alcohols as the alkylating reagents and hydrogen donors.

Continuous-Flow N-Alkylation of Amines Using a Heterogeneous Polysilane-Palladium Catalyst

Continuous-Flow N-Alkylation of Amines Using a Heterogeneous Polysilane-Palladium Catalyst

Nickel complexes bearing quinoline derived NNS donor ligands as catalytic activators for N-alkylation of anilines with alcohols.

Herein, we have reported a new series of NNS-donor ligands coordinated Ni(II) complexes and utilized them as catalytic activator to synthesize N-alkylated aminesand 1,2-disubstituted benzimidazoles. Theseparate reaction of [C9H6N-NH-C(O)-CH2-S-Ar] [Ar = C6H5 (L1); C6H4Cl-4 (L2);C6H4Me-4 (L3) and C6H4-OMe-4 (L4)]with Ni(OAc)2 in methanol at 80°C for 3 hours resulted in octahedral nickel complexes [(L1-H)2Ni] (C1), [(L2-H)2Ni] (C2), [(L3-H)2Ni] (C3), and [(L4-H)2Ni] (C4), respectively. All compounds have been characterized by micro and spectroscopic analysis. The molecular structure of complexes C1-C3 has also been determined by single crystal X-ray diffraction data. The utility of complexes C1-C4 were evaluated for the N-alkylation of aniline with benzyl alcohols, and for 1,2-disubstituted benzimidazoles synthesis. The obtained results indicate that complex C1 showed better catalytic activity in both N-alkylation of amines with benzyl alcohols [catalyst loading: 2.0 mol%; Yield up to 92%], and for 1,2-disubstituted benzimidazoles derivatives [catalyst loading: 2.0 mol%; Yield up to 94%)]. The mechanistic studies suggested that the reaction works through hydrogen borrowing from benzyl alcohol and its subsequent utilization for in situ reduction of imine. The experimentally observed catalytic reactivity patterns of complexes C1-C4 have found in good agreement with the HOMO-LUMO energy gaps obtained by DFT analysis of corresponding complexes.

Atomic-Level Asymmetric Tuning of the Co1-N3P1 Catalyst for Highly Efficient N-Alkylation of Amines with Alcohols.

Despite the extensive development of non-noble metals for the N-alkylation of amines with alcohols, the exploitation of catalysts with high selectivity, activity, and stability still faces challenges. The controllable modification of single-atom sites through asymmetric coordination with a second heteroatom offers new opportunities for enhancing the intrinsic activity of transition metal single-atom catalysts. Here, we prepared the asymmetric N/P hybrid coordination of single-atom Co1-N3P1 by absorbing the Co-P complex on ZIF-8 using a concise impregnation-pyrolysis process. The catalyst exhibits ultrahigh activity and selectivity in the N-alkylation of aniline and benzyl alcohol, achieving a turnover number (TON) value of 3480 and a turnover frequency (TOF) value of 174-h. The TON value is 1 order of magnitude higher than the reported catalysts and even 37-fold higher than that of the homogeneous catalyst CoCl2(PPh3)2. Furthermore, the catalyst maintains its high activity and selectivity even after 6 cycles of usage. Controlling experiments and isotope labeling experiments confirm that in the asymmetric Co1-N3P1 system, the N-alkylation of aniline with benzyl alcohol proceeds via a transfer hydrogenation mechanism involving the monohydride route. Theoretical calculations prove that the superior activity of asymmetric Co1-N3P1 is attributed to the higher d-band energy level of Co sites, which leads to a more stable four-membered ring transition state and a lower reaction energy barrier compared to symmetrical Co1-N4.

N-Alkylation of Amines Utilizing Magnetic Nano Chitosan Functionalized with EDTA/Co(II)

This research work has explored the application of a magnetic catalyst composed of coreshell nanoparticles [Fe3O4@SiO2@CS@EDTA/Co(II)], known as NCM@EDTA/Co(II), in the conversion of various alcohols containing electron-donating or electron-withdrawing groups into their respective secondary or primary amine derivatives. The investigation has focused on optimizing reaction conditions by considering factors, such as the inclusion of a base, duration of reaction time, reaction temperature, catalyst quantity, and choice of transition metal, in order to determine the optimal parameters. The most favorable outcomes have been achieved by using 0.2 mmol of catalyst per 1 mmol of substrate under reflux conditions for a duration ranging from 3 to 24 hours. The reaction has demonstrated high efficiency, with the catalyst's easy separation via an external magnetic field, stability, and recyclability, highlighting its potential applications in chemistry and industrial environments.

In silico and in vitro inhibition abilities of novel benzene sulfonamides on carbonic anhydrase and choline esterases

Compounds that possess a benzene sulfonamide structure are utilized in a wide range of fields. It is reported in the literature that many compounds belonging to this class of compounds exhibit various pharmacological properties such as antibacterial, antifungal, antiviral, anticancer, inflammatory, antiglaucoma, and anticholinergic effects. Carbonic anhydrase (CA) enzymes play a critical role in pH regulation, long-term synaptic turnover and are therefore thought to be associated with such diseases as mental retardation, Alzheimer’s disease (AD) and Down syndrome. Studies have reported that there is an increase in the levels of hCA-I and hCA-II isoenzymes in AD. AD is a complex, multifactorial disorder, so therapy should probably address not only the cholinergic system but also additional systems. Based on these features, a series of novel substituted benzene sulfonamides were synthesized from 1,2,3-trimethoxy-5-methylbenzene. Sulfonyl chloride 9 was synthesized from the reaction of 1,2,3-trimethoxy-5-methylbenzene and excess chlorosulfonic acid. The reaction of the obtained sulfonyl chloride with NH3 and N-alkyl amines, aniline, and phenethylamine gave substituted benzene sulfonamide derivatives 10–16. The synthesized compounds were evaluated for their carbonic anhydrase (hCA I-II), acetyl cholinesterase (AChE) and butyryl cholinesterase (BChE) inhibitory properties. Some of the substituted benzene sulfonamide derivatives 10–16 showed inhibitory effect on hCA isoenzymes. The Ki values determined for the hCA I enzyme are in the range of 102.01–147.19 µM. Benzene sulfonamide derivatives 10–16 showed an inhibitory effect on AChE and BChE. The Ki values determined for AChE and BChE enzymes are in the range of 28.76–308.08 µM and 42.80–445.60 µM, respectively. It was determined that sulfonamides 15–16 were selective inhibitors for the hCA I and 10 showed 11-fold more selectivity on AChE than BChE. In addition, the in-silico SAR and ADME properties of the synthesized compounds were also investigated.

Palladium-Catalyzed Remote Hydrosulfonamidation of Alkenes: Access to Primary N-Alkyl Sulfamides by the SuFEx Reaction.

Herein, we establish a remote hydrosulfonamidation (HSA) of alkenes using palladium catalysis, where N-fluoro-N-(fluoro-sulfonyl)-carbamate with a sulfur(VI) fluoride moiety is demonstrated as a good amidation reagent. The anti-Markovnikov HSA reaction of terminal alkenes and the remote HSA of internal alkenes are achieved to efficiently yield primary N-alkyl-N-(fluorosulfonyl)-carbamates. In addition, this protocol enables the high-value utilization of alkane by combining the dehydrogenation process. The generated N-alkyl products exhibit a unique reactivity of sulfur(VI) fluorides, which can be directly transferred to N-alkyl sulfamides or amines via the sulfur(VI) fluoride exchange reaction, thereby streamlining their synthesis. Moreover, a (pyridyl) benzazole-type ligand proved to be vital for the excellent chemo- and regioselectivities.

Reductive N-Alkylation of Amines with Ketones Using Heterogeneous Polysilane-Palladium Catalysts under Continuous-Flow Conditions.

This work reports a continuous-flow reductive N-alkylation of amines with ketones using molecular hydrogen. The reaction, performed with highly active polysilane-modified heterogeneous palladium catalysts, enables the efficient synthesis of diversely substituted amines under mild flow conditions. The developed catalyst exhibits sustained activity for 5 days (turnover number of >2400). Moreover, the utility of the method is demonstrated by the synthesis of a key intermediate of the active pharmaceutical ingredient teneligliptin.

Novel half-sandwich ruthenium(II) nicotinic hydrazone complexes: An efficient class of catalyst for the N-alkylation of amines with benzyl alcohol via transfer hydrogen mechanism and effective antibacterial agents

A new series of half sandwich ruthenium(II) complexes supported by nicotinic acid hydrazone derivatives of general formula [Ru(ɳ6-p-cymene)(Cl)(L)], where L represents N’-benzylidenenicotinohydrazide (HL1), N’-(naphthalen-1-ylmethylene)nicotinohydrazide (HL2) or N’-(pyren-1-ylmethylene)nicotinohydrazide (HL3) were synthesized and fully characterized. The solid-state molecular structures of ligands and complexes were elucidated with single-crystal X-ray diffraction. The ligands HL1 and HL2 possess monoclinic crystal system with P21/c and C2/c space groups respectively, whereas all the three Ru(II) complexes C1–3 are typical three-legged piano-stool geometries with orthorhombic(Aba2) (C1) and triclinic(P-1) (C2–3) systems respectively. The catalytic activities of these ruthenium complexes in the synthesis of N-alkylated amines were explored. Under optimal reaction condition, the complex C3 was found to be the most efficient catalyst for the N-alkylation of primary to secondary amines using benzyl alcohol. A wide range of substrates have been studied that includes anilines bearing electron withdrawing/electron donating group, fused aromatic, heteroaromatic, alicyclic and aliphatic amines with good to excellent yield. In addition, the antibacterial activity of the complexes were tested against different human pathogenic bacteria, among them C2 complex with naphthyl moiety was found to be the most active one against both Gram-positive (S. aureus and E. faecalis) and Gram-negative (E. coli and K. pneumoniae) bacteria. These two different studies demonstrate the catalytic and biological importance of our newly prepared Ruthenium complex.

Light-Switchable N-Alkylation Using Amine-Functionalized MOF

Catalytic N-alkylation is a frequently employed method to synthesize secondary amines and imines, yet selectivity control remains as a challenge that normally requires specialized catalysts under harsh reaction conditions. Here we propose a light-switchable N-alkylation of amines with aromatic halides for selective synthesis of secondary amines and imines, using an amine-functionalized metal-organic framework (MIL-125-NH2) under mild conditions. The MIL-125-NH2 catalyst possesses Lewis acidic sites, which catalyze direct dehalogenative condensation of bromides with primary amines to produce secondary amines in the dark. Upon irradiation, the MIL-125-NH2 reduces molecular oxygen to create oxygen radicals, converting bromides into the corresponding aldehydes to yield imines via a dehydrative coupling with amines. With appropriate acidity, rapid oxygen reduction kinetics, and optimized adsorption of aromatic bromides and generated water, the system catalyzes the conversion of a wide range of substrates, thus featuring it a promising method for applications.

N-Alkylation of amines with primary/secondary alcohols using a novel cobalt(II) inverse triazolyl-pyridine complex.

Herein, we report a highly effective homogeneous methodology for the N-alkylation of amines with primary and secondary alcohols using a Co(II)-complex of an inverse triazolyl-pyridine ligand. The developed methodology tolerates various functional groups to produce the desired N-alkylated products in up to 98% yield. A number of control experiments establish that the developed methodology follows a hydrogen auto-transfer (HAT) pathway.

Graphene-supported organoiridium clusters catalyze N-alkylation of amines via hydrogen borrowing reaction.

Graphene-supported organic iridium clusters (GSOICs) have been designed, prepared, characterized, and used for N-alkylation of amines via hydrogen borrowing reactions. Structural analysis data (including IR, XPS, TEM and EDS) show that organoiridium clusters are uniformly formed on the surface of graphene, and the grain size of GSOIC is between 1 and 3 nm. After being activated by the auxiliary ligand TMPP (tris(4-methoxyphenyl)phosphine), GSOIC showed excellent catalytic performance for hydrogen borrowing reaction, with its turnover frequency (TOF) reaching 13.67 h-1. Multi-cycle catalysis shows that the GSOIC/TMPP catalytic system exhibits high stability and reliability, with the turnover number (TON) of each catalytic cycle reaching 328, and the cumulative TON of 10 consecutive catalytic cycles reaching 3280. These systems exhibit excellent N-alkylation for a variety of substrates under one-pot conditions without the need for bases, solvents, and other additives, representing a sustainable and environmentally friendly catalytic reaction strategy.

A sustainable strategic approach for N-alkylation of amines with activation of alcohols triggered via a hydrogen auto-transfer reaction using a Pd(II) complex: evidence for metal-ligand cooperativity.

This work describes a new well-defined, air-stable, phosphine free palladium(II) [Pd(L)Cl] (1) catalyst. This catalyst was utilized for N-alkylation of amines and indole synthesis where H2O was found to be the by-product. A broad range of aromatic amines were alkylated using this homogeneous catalyst with a catalyst loading of 0.1 mol%. Greener aromatic and aliphatic primary alcohols were utilized and a hydrogen auto-transfer strategy via a metal-ligand cooperative approach was investigated. The precursor of the antihistamine-containing drug molecule tripelennamine was synthesized on a gram scale for large-scale applicability of the current synthetic methodology. A number of control experiments were performed to investigate the possible reaction pathway and the outcomes of these experiments indicated the azo-chromophore as a hydrogen reservoir during the catalytic cycle.

Titanium-Catalyzed Selective N-Alkylation of Amines with Alcohols via Borrowing Hydrogen Methodology.

The N-alkylation of amines with alcohols using earth-abundant and nonprecious metal catalysts has gained considerable attention in the pharmaceutical industry. We described titanium-catalyzed synthetic protocol for N-alkylation of amines with alcohols via borrowing hydrogen or hydrogen autotransfer reactions. The methodology enables the selective monoalkylation of various substituted (hetero)aromatic amines in good to excellent yields (up to 97% yield). The importance of the protocol was further demonstrated by the applicability of earth-abundant metal catalysis and the synthesis of 32 N-alkylated amines. The work allows the utilization of titanium-based catalysts for various reactions to expand the nature blueprint in catalysis.

Activity enhancement of Ru/CeO2 for N-alkylation of amines with alcohols through tailoring metal-support interaction

Efficient and selective N-alkylation of amines with alcohols via transfer hydrogenation is of great significance but extremely challenging. Here, we report the production of N–benzylaniline (BZA) from benzyl alcohol and aniline over various fine-shaped Ru/CeO2 catalysts. The Ru/CeO2–R (rod) catalyst exhibits the highest catalytic activity among all catalysts, in which the yield of BZA reaches up to 88% with complete conversion, significantly higher than that of Ru/CeO2-C (cube, 52%) and Ru/CeO2-O (octahedron, 32%). Extensive experimental investigations disclose that Ru nanoparticles with a metallic state promote the dehydrogenation of the hydroxyl group and hydrogenation of imines, while the CeO2–R with rich oxygen vacancies facilitates the adsorption and activation of reactants. Furthermore, kinetic studies and time-resolved operando dual-beam Fourier transform infrared spectroscopy analysis confirms the transfer hydrogenation pathway, in which the benzyl alcohol is firstly dehydrogenated to benzaldehyde, followed by spontaneously reacting with aniline, and finally transforms into the N-benzylaniline rapidly.

Bio-based surfactants derived from pectin

Surfactants derived from renewable resources and synthesized using renewable feedstock and sustainable methods have become a major research focus over the past decade in the surfactant industry. This research presents an approach for rapidly converting readily available polysaccharides, like pectin derived from fruit waste, into safely biodegradable surface-active polymers. Commercially available pectin was modified with n-alkyl amines having different alkyl chain lengths using potassium carbonate as a catalyst. The effect of pectin molecular weight, alkyl chain length and degree of substitution (DS) on surface-active properties of the modified pectin derivatives was studied. Surface tension decreased slightly with lowering molecular weight, whereas interfacial tension decreased dramatically. Cytotoxicity evaluations using human dermal fibroblast, HepG2 and Jurkat cells demonstrated that these polysaccharide-based surfactants exhibit lower cytotoxicity compared to the conventional surfactants such as octyl phenol ethoxylates (i.e., Triton™ X-100), and therefore are more environmentally friendly. Biodegradation studies show that all modified pectins are “ultimately biodegradable” except for Pectin-amide C8 (1:10).