Synthesis Of Tertiary Amines Research Articles

Magnetically Induced Amination of Alcohols Using MNi@Cu (M=Fe, Co) Nanoparticles as Catalysts.

The synthesis of tertiary amines from alcohols (i.e. heptanol, dodecanol, cyclohexanol, benzylalcohol) and secondary amines (Me2NH (DMA), nPr2NH, nBu2NH) has been achieved in one step using trimetallic nanoparticles (NPs) displaying a magnetic core (Co4Ni6 and Fe3Ni7) and a Cu shell as both catalysts and heating agent in the presence of an alternating magnetic field. This methodology limits the redistribution reactions occurring on amines at high temperature leading to both much higher conversion and selectivity in the absence of solvent than usually observed using conventional heating. Moreover, Co4Ni6@Cu NPs were found moisture resistant, thereby allowing for performing the reaction with commercial DMA in water (40 % wt) with again high conversion and selectivity.

Magnetically Induced Amination of Alcohols Using MNi@Cu (M=Fe, Co) Nanoparticles as Catalysts

AbstractThe synthesis of tertiary amines from alcohols (i.e. heptanol, dodecanol, cyclohexanol, benzylalcohol) and secondary amines (Me2NH (DMA), nPr2NH, nBu2NH) has been achieved in one step using trimetallic nanoparticles (NPs) displaying a magnetic core (Co4Ni6 and Fe3Ni7) and a Cu shell as both catalysts and heating agent in the presence of an alternating magnetic field. This methodology limits the redistribution reactions occurring on amines at high temperature leading to both much higher conversion and selectivity in the absence of solvent than usually observed using conventional heating. Moreover, Co4Ni6@Cu NPs were found moisture resistant, thereby allowing for performing the reaction with commercial DMA in water (40 % wt) with again high conversion and selectivity.

Molybdenum oxides catalyzed the N,N‐dimethylamination of alcohols with N,N‐dimethylformamide for direct synthesis of tertiary amines

Molybdenum oxides (MoO3 − x, x = 1, 2, and 3) with three types of morphologies were prepared and applied to the reaction of benzyl alcohol with dimethylformamide (DMF) for synthesis of tertiary amines. The MoO3 − 1 catalyst prepared by direct calcination exhibited high activity and tertiary amines selectivity in the N,N-dimethylamination of benzyl alcohol under the reaction conditions at 150°C for 12 h using DMF as a methylating agent and solvent, as compared to MoO3 − 2 and MoO3 − 3 catalysts. This feature was ascribed to the high proportion of surface chemisorbed oxygen for MoO3 − 1 sample, which can promote the adsorbed benzyl alcohol transformation into benzaldehyde. The MoO3 − 1 catalyst was also found to be reusable in five consecutive runs without a significant decrease in catalytic activity. In addition, control experiments showed two parallel reaction routes in this catalytic system. One route is the reaction of benzaldehyde intermediate and DMF to form tertiary amines (Route I); the other route is that benzyl formate intermediate reacted with DMF (Route II), which has not been reported before and specifically involves the esterification of benzyl alcohol with formic acid from DMF decomposition to form benzyl formate.

Microwave-Assisted Synthesis of Tertiary Amines from Carbamates

Key words amines - carbamates - microwave heating - extrusive alkylation - tertiary amines

Synthesis of Tertiary Amines through Extrusive Alkylation of Carbamates.

Basic amines are key elements of many biologically active natural products and pharmaceuticals. Given their inherent reactivity, it is often necessary to protect basic amines during target-directed synthesis, which results in wasteful protection/deprotection sequences. We report a step-economical approach enabling the protection of secondary amines as carbamates prior to their conversion to tertiary amines via the formal extrusion of CO2. This method is applied to the synthesis of iboga alkaloids (±)-conodusine A and (±)-conodusine B.

A simplified, green synthesis of tertiary amines using the Leuckart-Wallach reaction in subcritical water

This research seeks to combine the reducing ability of N,N-disubstituted formamides with the ability of subcritical water to facilitate organic reactions to synthesize tertiary amines. A one-pot, direct reductive amination of aldehydes to form long-chain, tertiary amines was investigated at various temperatures, reaction times, and reagent equivalencies. The formamides act as both the nitrogen source and reducing agent when combined with subcritical water to provide a green route to tertiary amines without additional metal or Lewis acid catalysts.

Synthesis of tertiary amine functionalized Multi-Stimuli-Responsive latex nanoparticles by semicontinuous emulsion Polymerization: Investigation of responsivities and antimicrobial activity

Stimuli-responsive core–shell nanoparticles (CSNPs) are an important class of smart polymers, which their physical and chemical properties could be changed in response to induced external stimuli. In this study, the amphiphilic CSNPs were synthesized via semi-continuous seeded emulsion polymerization using dimethylamino ethyl methacrylate (DMAEMA) as a hydrophilic monomer, and styrene as a hydrophobic monomer. Developed CSNPs were obtained in two series, poly(N, N-dimethylamino ethyl methacrylate) (PDMAEMA)-polystyrene (PS) core–shell particles and PS-PDMAEMA core–shell particles. The PDMAEMA chains exhibited different responsivities towards temperature rising, pH change, and CO2-gas, which their smart behaviors were investigated by dynamic light scattering (DLS) analysis. The temperature-responsivity of CSNPs was confirmed by observed particle size variation in the case of PDMAEMA-PS (increase) and PS-PDMAEMA (decrease) core–shell latex particles, when temperature increased to 70 °C, above the lower critical solution temperature (LCST) of PDMAEMA. Protonation of tertiary amine functional groups in the presence of CO2 bubbling led to an increase in the size of CSNPs as a result of water swelling of PDMAEMA chains. On the other hand, the size of CSNPs was changed in acidic (pH = 4) and basic (pH = 10) media by swelling and deswelling of PDMAEMA located in the core or shell. Obtained results indicated that maximum antimicrobial activity was observed for PS-PDMAEMA CSNPs compared to PDMAEMA-PS, which is probably due to presence of the PDMAEMA on the surface and increase of positive charge related to amine groups in this sample. The developed antimicrobial latexes have potential applications for using as antibacterial additives in water-based coatings and adhesives.

Microwave-assisted N-alkylation of amines with alcohols catalyzed by MnCl2 : Anticancer, docking, and DFT studies.

A new protocol for the N-alkylation of amines with alcohols for the synthesis of tertiary amines in the presence of MnCl2 as a catalyst, under microwave conditions, is described. The advantages of this protocol include stable reaction profiles, a wide substrate variety, excellent yields, low cost, high yields, and easy workup conditions. The anticancer efficacy of all the synthesized compounds was tested in vitro against various cancer cell lines, such as MCF-7, MDA-MB-231 (human breast), HT-29, HCT 116 (colon cancer), A549 (human lung carcinoma), and Vero cells. Among the screened compounds, 3e, 3h, and 3i demonstrated potent anticancer activity, with compound 3h surpassing the reference drug cisplatin against A549, MCF7, MDA-MB-231, and HCT116 cancer cells. The introduction of an electron-withdrawing group on the phenyl ring resulted in increased anticancer activity. The most potent compounds, 3e, 3h, and 3i, were tested against VEGFR-2, HER2, and EGFR in multikinase inhibition assays, with compounds 3h and 3i showing improved potency against the HER2 kinase. The compounds formed two H-bonds with amino acids, indicating that they had a high affinity for the target HER2 kinase (PDB ID: 3RCD), according to the docking analysis. The absorption, distribution, metabolism, excretion, and toxicity properties of the optimized analogs were also assessed in vitro, enabling the discovery of promising anticancer agents. Finally, the B3LYP level was used to measure density functional theory geometry optimization and the related quantum parameters for the active compounds.

Tandem synthesis of tertiary amines using graphene encapsulated Ni nanocatalyst via nitro compounds hydrogenation and primary amine methylation

Development of the economic, environmentally friendly synthesis of amines from nitro compounds remains important and challenging. In this work, the graphene shell encapsulated none noble Ni-based catalysts were successfully designed and synthesized via an environmentally friendly method using H2O or EtOH as solvent. These fresh and recycling catalysts were characterized by X-ray diffraction and X-ray photoelectron spectroscopy. For the nitro compounds hydrogenation, Ni@C-600-H2O exhibits the best catalytic activity to achieve 100 mol/mol conversions of nitrobenzene and 99% selectivity of aniline under mild reaction conditions of 1.0 MPa H2 and 60 °C. Many halogen-substituted, olefin substituted nitro compounds and aliphatic nitro compounds were investigated and desired products were obtained in excellent selectivity. What is more, the catalyst had excellent stability and could be recycled 13 times without any significant loss in selectivity and activity. Furthermore, we also reported the methodology for tertiary amines synthesis using Ni-based catalyst via one-pot, cost-effective tandem combination reaction with nitrobenzene hydrogenation and amines N-methylation.

N-Dimethylation and N-Functionalization of Amines Using Ru Nanoparticle Catalysts and Formaldehyde or Functional Aldehydes as the Carbon Source.

N-methylated amines are essential bioactive compounds and have been widely used in the fine and bulk chemical industries, as well as in pharmaceuticals, agrochemicals, and dyes. Developing green, efficient, and low-cost catalysts for methylation of amines by using efficient and easily accessible methylating reagents is highly desired yet remains a significant challenge. Herein, we report the selective N-dimethylation of different functional amines with different functional aldehydes under easy-to-handle and industrially applicable conditions using carbon-supported Ru nanoparticles (Ru/C) as a heterogeneous catalyst. A broad spectrum of amines could be efficiently converted to their corresponding N,N-dimethyl amines with good compatibility of various functional groups. This method is widely applicable to N-dimethylation of primary amines including aromatic, aliphatic amines with formaldehyde, and synthesis of tertiary amines from primary, secondary amines with different functional aldehydes. The advantage of this newly described method includes operational simplicity, high turnover number, the ready availability of the catalyst, and good functional group compatibility. This Ru/C catalyzed N-dimethylation reaction possibly proceeds through a two-step N-methylation reaction process.

Rhodium‐Catalysed Reductive Amination for the Synthesis of Tertiary Amines

AbstractA procedure for the synthesis of tertiary amines via reductive amination of aldehydes with molecular hydrogen as a reducing agent using homogeneous rhodium catalysis is presented. Using an amine to aldehyde ratio of 4/1 enabled the synthesis of tertiary amines from nine different aldehydes and nine different secondary amines with selectivities up to 99% and turnover frequencies (TOF) up to 7200 h−1. The reaction showed a high tolerance against alcohol and ester functions allowing the formation of multifunctional molecules. In addition, secondary amines can also be produced by this synthesis. For all compounds, activities were determined by hydrogen gas‐uptake. In order to increase the sustainability and efficiency of the procedure, a dosing strategy has been successfully developed. Using the determined reaction indicators enabled the stoichiometric use of aldehydes and amines without significant loss of selectivity.magnified image

Synthesis of a tertiary amine by direct reductive amination of a carbonyl compound to form a scorpionate ligand; formation of Mn (II), Zn (II) and Cd (II) complexes, DFT calculations and, molecular docking studies

A hexadentate, asymmetric tripodal scorpionate type ligand, [[N1-Pyridin-2-ylmethyl-N1-[2-(4-pyridine-2-ylmethyl-piperazine-1-yl)-ethyl]-ethane-1,2-diamine]] (L) has been prepared. To form this ligand, the direct reductive amination of a carbonyl compound by NaBH4 was used for the synthesis of tertiary amine. The complexes [MnL])ClO4(2, [CdL])ClO4(2, [ZnL])ClO4(2 have also been prepared. The synthesized compounds were characterized by elemental analyses, FT-IR, ESI-MS and, NMR spectroscopy. An X-ray crystal structure of [MnL] (ClO4)2, shows that the coordination environment around the manganese is a distorted trigonal prism. The nature of metal–ligand bonding in the complexes was investigated by Natural Bond Orbital analysis, Energy Decomposition Analysis and Energy Decomposition Analysis using Natural Orbitals for Chemical Valence variation. Molecular docking has been used for the biological evaluation of the anticancer and antioxidant activities of the synthesized compounds. The docking results indicated that the Cd, Mn, and Zn-complexes had the highest binding affinity (MolDock Score) for the binding sites of cytochrome P450, myeloperoxidase, and cytochrome P450, respectively.

Hydrazone complexes of ruthenium(II): Synthesis, crystal structures and catalytic applications in N-alkylation reactions

A series of new Ru(II) complexes of 8-hydroxy quinoline-2-carboxyaldehyde hydrazone of the general formula [RuH(CO)(EPh3)2L] (1–6) (E = P or As, L = N’-((8-hydroxyquinolin-2-yl)methylene)thiophene-2-carbohydrazide (HQ-THy), N’-((8-hydroxyquinolin-2-yl)methylene)isonicotinohydrazide (HQ-IHy), N’-((8-hydroxyquinolin-2-yl)methylene) benzohydrazide (HQ-BHy)) have been synthesized. They have been characterized by elemental analysis, IR, NMR (1H, 13C &31P) and ESI-MS spectral methods. Further, structures of two of the complexes have been determined by single crystal X-ray diffraction technique which revealed a pseudo octahedral geometry with the coordination of the quinoline nitrogen and quinoline oxygen atoms of the ligand. All the new complexes have been employed as efficient catalysts in N-alkylation reactions for the synthesis of tertiary amines by the coupling of secondary amines with aromatic primary alcohols at low catalyst loading with maximum yields. In addition, the effects of substituents on the ligands, different solvents as well as bases and amounts of catalyst loading on the catalytic activity of the complexes have been thoroughly investigated. Complex 1 was found to be efficient catalyst towards N-alkylation of alcohols with the amine. Further, a variety of secondary amines and aromatic (hetero) primary alcohols with various functional groups have also been successfully used in the N-alkylation reactions and it has been found that only one equivalent of the alcohol was consumed in the process.

Tertiary Amine Synthesis by Radical Carbonyl Alkylative Amination

Highly efficient access to structurally diverse branched tertiary amines is a long-standing challenge in synthetic chemistry. In a recent paper published in Nature, Gaunt and co-workers disclose a practical strategy for the construction of synthetically intractable tertiary amines through visible-light-mediated radical carbonyl alkylative amination of aldehydes, amines, and alkyl halides.

A general carbonyl alkylative amination for tertiary amine synthesis.

The ubiquity of tertiary alkylamines in pharmaceutical and agrochemical agents, natural products and smallmolecule biological probes1,2 continues to stimulate enormous efforts towards their streamlined synthesis3–9. Arguably, the most robust method for tertiary alkylamine synthesis is carbonyl reductive amination3: comprising two elementary steps, condensation of a secondary alkylamine with an aliphatic aldehyde forms an all alkyl-iminium ion, which is reduced by a hydride reagent. Chemists have sought to develop direct strategies for a ‘higher order’ variant of this reaction via the union of an alkyl fragment with an in-situ generated all alkyl-iminium ion10–14. However, despite more than 70 years of research, the successful realization of a ‘carbonyl alkylative amination’ has remained elusive. Herein, we report that a practical and general solution can be accomplished by the addition of alkyl-radicals to all alkyl-iminium ions. The process is facilitated by visible-light and a silane reducing agent, which, together with the other reaction components, trigger a distinct radical initiation step to establish a chain process. An attractive feature of this operationally straightforward, metal-free and modular transformation is the unbiased nature of tertiary amines that arise from the traceless union of aldehydes and secondary amines with alkyl-halides. As such, the structural and functional diversity within these classes of abundant feedstocks provides a versatile and flexible strategy for the streamlined synthesis of complex tertiary amines.

Synthesis of tertiary amines by direct Brønsted acid catalyzed reductive amination.

Tertiary amines are ubiquitous and valuable compounds in synthetic chemistry, with a wide range of applications in organocatalysis, organometallic complexes, biological processes and pharmaceutical chemistry. One of the most frequently used pathways to synthesize tertiary amines is the reductive amination reaction of carbonyl compounds. Despite developments of numerous new reductive amination methods in the past few decades, this reaction generally requires non-atom-economic processes with harsh conditions and toxic transition-metal catalysts. Herein, we report simple yet practical protocols using triflic acid as a catalyst to efficiently promote the direct reductive amination reactions of carbonyl compounds on a broad range of substrates. Applications of this new method to generate valuable heterocyclic frameworks and polyamines are also included.

Iridium-Catalyzed Alkylation of Amine and Nitrobenzene with Alcohol to Tertiary Amine under Base- and Solvent-Free Conditions

Herein, an efficient and green method for the selective synthesis of tertiary amines has been developed that involves iridium-catalyzed alkylation of various primary amines with aromatic or aliphatic alcohols. Notably, the catalytic protocol enables this transformation in the absence of additional base and solvent. Furthermore, the alkylation of nitrobenzene with primary alcohol to tertiary amine has also been achieved by the same catalytic system. Deuterium-labeling experiments and a series of control experiments were conducted, and the results suggested that an intermolecular borrowing hydrogen pathway might exist in the alkylation process.

Scope and Limitations of Leuckart‐Wallach‐Type Reductive Amination: Chemoselective Synthesis of Tertiary Amines from Aldehydes under Neat Conditions

AbstractWe have developed a convenient method to synthesize tertiary amines selectively with a variety of aldehydes and primary amines using commercially available formic acid as reducing agent. In our methodology we have shown that we can prepare a variety of tertiary amines by changing both the amines as well as aldehydes. Clean reaction, operational simplicity, easily accessible reactants, metal and solvent‐free and environmentally friendly reaction conditions are the notable advantages of this procedure.

Terpene‐Derived Highly Branched C30‐Amines via Palladium‐Catalysed Telomerisation of β‐Farnesene

AbstractThe synthesis of highly branched long chain amines in one step is still a challenge. The palladium catalysed telomerisation of the renewable sesquiterpene β‐farnesene with secondary amines yields such tertiary amines and thus, was investigated within this work. Preliminary, a suitable palladium catalyst system was developed by a high‐throughput screening. It efficiently allows for the synthesis of tertiary amines with a highly branched C30‐carbon chain with yields up to 94% of the corresponding desired allylic C30‐amines. The generality of the protocol was proven for thirteen amines with linear and branched alkyl and aryl groups. A clear correlation between the scaffold of the amine, basicity and the activity as nucleophile in the telomerisation was uncovered. Based on the different polarities of the nonpolar in‐situ formed C30‐substituted tertiary amines and the polar solvent, a proof of concept for catalyst recovery by simple decantation was shown.magnified image

2-Aminoquinazolin-4(3H)-one as an Organocatalyst for the Synthesis of Tertiary Amines

The potential of 2-aminoquinazolin-4(3H)-one as an organocatalyst for the activation of aldehydes via noncovalent interaction for the synthesis of tertiary amines using formic acid as a reducing agent is reported for the first time. The developed protocol demonstrated a dilated substrate scope for aromatic and aliphatic amines with aromatic and aliphatic aldehydes. Furthermore, the current method was also fruitful for the derivatization of ciprofloxacin and its derivative in good to excellent yields.