N-methylation Of Amines Research Articles

Poly(2,2'-Bibenzimidazole)-Supported Iridium Complex: A Recyclable Metal-Polymer Ligand Bifunctional Catalyst for the N-Methylation of Amines with Methanol.

The design and development of new types of catalysts is one of the most important topics for modern chemistry. Herein, a polymer-supported iridium complex Cp*Ir@Poly(2,2'-BiBzIm) was designed and synthesized by the coordinative immobilization of [Cp*IrCl2]2 on 2,2'-bibenzimidazoles. In the presence of the catalyst (0.5 mol % Ir) and Cs2CO3 (0.3 equiv), a variety of N-methylated amines were obtained in high yields with complete selectivity. More importantly, the catalyst could be recycled without an obvious loss of activity for six cycles. Apparently, the designed catalyst combines the advantages of both homogeneous and heterogeneous catalysis.

CO2-Driven N-Formylation/N-Methylation of Amines Using C-Scorpionate Metal Complexes.

C-scorpionate metal complexes, specifically, [NiCl2(tpm)]·3H2O, [CoCl2(tpm)]·3H2O and [PdCl2(tpm)] [tpm = hydrotris(1H-pyrazol-1-yl)methane], were effective in the N-formylation and N-methylation of amines using carbon dioxide, as carbon source, in the presence of sodium borohydride. Various parameters were studied, including reaction time, temperature, solvent volume, presence of additives, and catalyst amount. These parameters were found to have a significant impact on the selectivity of the product. [NiCl2(tpm)]·3H2O exhibited good conversion at 80 °C, but its selectivity towards formamide decreased with prolonged reaction time. Increasing the amount of [NiCl2(tpm)]·3H2O, the selectivity changed. [PdCl2(tpm)] showed different selectivity compared to [NiCl2(tpm)]·3H2O, while [CoCl2(tpm)]·3H2O presented poor results. Monitoring the reaction course by 1H NMR revealed the presence of an intermediate species that influenced product formation. These results highlight the versatility and catalytic potential of C-scorpionate metal complexes in the N-formylation/N-methylation of amines in the catalytic system (NaBH4/MeCN/CO2).

Tuneable reduction of CO2 – organocatalyzed selective formylation and methylation of amines

The selective N-formylation and N-methylation of amines with carbon dioxide (CO2) catalyzed by methyltriphenylphosphonium methylcarbonate and tuned by polymethylhydrosiloxane or trimethoxysilane as reducing agents is reported.

Bis(N-Heterocyclic Carbene) Manganese(I) Complexes in Catalytic N-Formylation/N-Methylation of Amines Using Carbon Dioxide and Phenylsilane.

A series of six Mn(I) complexes with general formula [MnBr(bisNHC)(CO)3 ], having a bidentate bis(N-heterocyclic carbene) ligand (bisNHC), has been developed by varying the bridging group between the NHC donors, the nitrogen wingtip substituents and the heterocyclic ring. The synthesis of the complexes has been accomplished by in situ transmetalation of the bisNHC from the corresponding silver(I) complexes. Removal of the bromide anion affords the corresponding solvento complexes [Mn(bisNHC)(CO)3 (CH3 CN)](BF4 ). The influence of the bisNHC structure on its electron donor ability has been evaluated by FTIR and 13 C NMR spectroscopy, both in the neutral and cationic complexes. Finally, the isolated Mn(I)-bisNHC complexes have been employed as homogeneous catalysts in the reductive N-formylation and N-methylation of amines with CO2 as C1 source and phenylsilane as reducing agent, showing a high selectivity for the N-methylated product. Preliminary mechanistic investigations suggest that, in the adopted reaction conditions, the formylated product can be formed via different reaction pathways, either metal-catalyzed or not, while the methylation reaction requires the use of the Mn(I) catalyst.

N-Alkylation of Amines by C1-C10 Aliphatic Alcohols Using A Well-Defined Ru(II)-Catalyst. A Metal-Ligand Cooperative Approach.

A Ru(II)-catalyzed efficient and selective N-alkylation of amines by C1-C10 aliphatic alcohols is reported. The catalyst [Ru(L1a)(PPh3)Cl2] (1a) bearing a tridentate redox-active azo-aromatic pincer, 2-((4-chlorophenyl)diazenyl)-1,10-phenanthroline (L1a) is air-stable, easy to prepare, and showed wide functional group tolerance requiring only 1.0 mol % (for N-methylation and N-ethylation) and 0.1 mol % of catalyst loading for N-alkylation with C3-C10 alcohols. A wide array of N-methylated, N-ethylated, and N-alkylated amines were prepared in moderate to good yields via direct coupling of amines and alcohols. 1a efficiently catalyzes the N-alkylation of diamines selectively. It is even suitable for synthesizing N-alkylated diamines using (aliphatic) diols producing the tumor-active drug molecule MSX-122 in moderate yield. 1a showed excellent chemo-selectivity during the N-alkylation using oleyl alcohol and monoterpenoid β-citronellol. Control experiments and mechanistic investigations revealed that the 1a-catalyzed N-alkylation reactions proceed via a borrowing hydrogen transfer pathway where the hydrogen removed from the alcohol during the dehydrogenation step is stored in the ligand backbone of 1a, which in the subsequent steps transferred to the in situ formed imine intermediate to produce the N-alkylated amines.

N-Alkylation and N-Methylation of Amines with Alcohols Catalyzed by Nitrile-Substituted NHC-Ir(III) and NHC-Ru(II) Complexes.

A series of nitrile-modified N-heterocyclic carbene (NHC) complexes of Ir(III) (2a-e) and Ru(II) (3a-d) have been prepared by transmetallation of [IrCp*Cl2]2 and [RuCl2(p-cymene)]2 forming an in situ NHC-Ag complex. The structures of all complexes were characterized by 1H NMR, 13C NMR, and Fourier transform infrared (FT-IR) spectroscopies. And the structures were clearly elucidated by performing X-ray diffraction studies on 2b, 3a, and 3c single crystals. The complexes of NHC-Ir(III) (2a-e) and NHC-Ru(II) (3a-d) were investigated in the N-alkylation reaction of aniline derivatives with benzyl alcohols to form N-benzyl amines and in the N-methylation reaction of aniline derivatives with methanol. Both reactions were performed in solvent-free media. The Ir(III) complexes (2a-e) were found to perform essentially better than similar Ru(II) complexes (3a-d) in the N-alkylation and N-methylation reactions. Among the Ir(III) complexes (2a-e), the best results were obtained with 2b. The catalytic mechanisms of both reactions were revealed by 1H NMR study. Formation of Ir-hydride species was observed for both reactions. This new report provides useful information to evaluate the activity of complexes and the differences in sensitivity between the NHCs.

Active Pd Catalyst for the Selective Synthesis of Methylated Amines with Methanol.

Selective N-methylation of amines with methanol is an important reaction in the synthesis of high-value-added fine chemicals, including dyes, surfactants, pharmaceuticals, agrochemicals, and materials. However, N-methylated amines possess higher reactivities and are prone to further transform into N,N-dimethylated amines. Therefore, it is still a challenge to controllably regulate the selectivity of N-methylation using heterogeneous catalysts without the use of base. Herein, we developed a series of Pd/Zn(Al)O catalysts with abundant basic sites, and the selectivity of N-methylation was controlled by a heterogeneous Pd/Zn(Al)O catalyst with a Zn/Al ratio of 10 and a Pd loading of 0.4 wt % in the pressure of H2. The experimental results showed that the appropriate basic properties of the catalyst were beneficial to form the desired N-methylated amine. The low loading of Pd in the catalyst was highly dispersed on the support, providing sufficient active sites. These were attributed to the Zn vacancies formed by Al-doped Zn, which were beneficial to form the highly active and stable Pd sites. Furthermore, a series of amines and nitrobenzenes with different functional groups were well tolerated for the selective synthesis of N-methylated amines in the absence of base.

Hydrogenation of C=N bonds on TiO2 surface: The effect of the Cu2O/TiO2 p-n heterojunction photocatalyst

As a widely used semiconductor photocatalyst, TiO2 has been explored in organic compounds hydrogenation. In this study, the hydrogenation of C=N bonds on the surface of TiO2 was accomplished for the first time utilizing Cu2O/TiO2 type-II (p-n) heterojunction. The probe reactions, hydrogenation of N-benzylphenylamine with benzyl alcohol, and N-methylation of amines with methanol exhibited that the hydrogenation of C=N bonds on TiO2 surface can be achieved through borrowing hydrogen reaction (BH, alcohols as hydrogen source). Additionally, the BH reaction rate could be improved by adding external H+ to the reaction system. The catalytic activity of Cu2O/TiO2 was discovered to remain at an efficient level even after six reaction cycles.

Continuous-flow reductive N-methylation with highly active heterogeneous Pd catalysts and sequential-flow synthesis of N-monomethyl amines

We describe continuous-flow N-methylation with formaldehyde and H2 using heterogeneous Pd catalysts as a green synthetic method to access N-methyl amines.

MnO2 nanostructures as sustainable catalysts for selectivity tuning and syntheses of amine coupling products with bio-derived glycerol

This work reports crystalline MnO2 nanomaterials as a sustainable catalyst, for economical synthesis of N-substituted formamides and N-methyl amine products in the presence of air:O2 mixture (9:1) using bio-derived glycerol. This process provides flexible selectivity tuning between N-formamides and N-methyl amines, based on MnO2 crystal structure and glycerol concentration. The as-prepared (α, β, γ & δ) MnO2 nanostructures have been characterized in detail. This process was tested further with γ-MnO2 nanorods, which delivers yields in the range of 43-90% for a diverse substrate library of 16 amine substrates for N-formamide products and β-MnO2 for synthesis of N-methyl amines from secondary amines. The varied crystalline MnO2 nanostructures and their surface Mn (III)/Mn (IV) species ratios have been shown to steer the selectivity of the reaction differently, where α- and γ-MnO2 forming N-formamide with higher selectivity, while β- and δ-MnO2 leans more towards formation of N-methyl amine and N-formamide equally. The reusability of MnO2 catalysts up to 7 runs has been shown. The gram scale synthesis of formamides also shows yields of up to 75% using γ-MnO2 at pre-determined parameters.

Ruthenium(II)-Catalyzed Hydrogenation and Tandem (De)Hydrogenation via Metal-Ligand Cooperation: Base- and Solvent-Assisted Switchable Selectivity.

A versatile, selective, solvent (methanol vs ethanol)- and base (potassium vs lithium carbonate)-assisted switchable synthesis of saturated ketone and α-methyl saturated ketone from α,β-unsaturated ketone is developed. Mechanistic aspects, evaluated from spectroscopic studies, in situ monitoring of the reaction progress, control studies, and labeling studies, further indicate the involvement of a tandem dehydrogenation-condensation-hydrogenation sequence in the reaction, in which the interconvertible coordination mode (imino N → Ru and amido N-Ru) of coordinated imidazole with Ru(II)-para-cymene is crucial, without which the efficiency and selectivity of the catalyst are completely lost. The catalyst demonstrates good efficiency, selectivity, and functional group tolerance and displays a broad scope (69 examples) for monomethylation and hydrogenation of unsaturated chalcones, double methylation of ketones, and N-methylation of amines.

Recyclable polymerized Lewis acid poly-BPh(C6F5)2 catalyzed selective N-formylation and N-methylation of amines with carbon dioxide and phenylsilanes

A new boron-centered polymer, which is named poly-BPh(C6F5)2 (polymerized-bis(perfluorophenyl)-(phenyl)borane) was designed and synthesized, which is found to be an efficient catalyst for selective N-formylation and N-methylation of amines using CO2 as C1 building block in the presence of hydrosilanes. Milder reaction conditions (even at room temperature and 1 bar of CO2), remarkable recyclability, tolerance against a variety of functional groups and excellent yields reveal the excellent stability and catalytic activity of poly-BPh(C6F5)2. The process herein represents a simple, ecologically friendly and efficient route for CO2 chemical fixation into value-added chemicals.

Platinum nanoparticles as recyclable heterogeneous catalyst for selective methylation of amines and imines with formic acid: Indirect utilization of CO2

N-methylation of amines and imines with formic acid as C1 source by easily prepared Pt NPs as heterogeneous catalyst is reported here. Primary, secondary amines and imines were successfully methylated in good to excellent yields under mild conditions. Both aromatic and aliphatic amines could be applied as substrates. Meanwhile, the heterogeneous Pt NPs were capable to be recylcled and reused for 7 times without significant decrease of reactivity. This protocol provided an indirect utilization pathway of CO2 by using formic acid as C1 source.

Tandem synthesis of N-methylated tertiary amines via three-component coupling of carbonyl compounds, amines, and methanol.

An Ir-catalyzed tandem synthesis of various N-methylated tertiary amines from three-component coupling of carbonyl compounds, amines, and methanol following reductive amination/N-methylation is reported for the first time. A wide array of substrates with tolerance of different functional groups was demonstrated. The protocol was extended to the synthesis of N-methyl containing pharmaceutically important drug molecules. A probable catalytic cycle was proposed based on various control experiments and different analytical techniques such as NMR, IR and ESI-MS.

Selective NMR detection of N-methylated amines using cavitand-decorated silica nanoparticles as receptors.

We report a strategy for the realization of NMR chemosensors based on the spontaneous self-assembly of lower rim pyridinium-functionalized tetraphopshonate cavitands on commercial silica nanoparticles. These nanohybrids enable the selective detection of physiologically relevant N-methylated amines, with a limit of detection of 31 μM, via STD-based NMR experiments, achieving for the first time fine structural selectivity in nanoparticle-assisted NMR chemosensing.

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.

Selective N-Alkylation of Amines with DMC over Biogenic Cu-Zr Bimetallic Nanoparticles.

Herein, we report the green synthesis of copper–zirconium bimetallic nanoparticles (Cu–Zr BNPs) from aqueous solutions using Azadirachta indica leaf extract as a reducing and stabilizing agent. The CuO, ZrO2 NP, and Cu–Zr BNP samples were characterized by X-ray diffraction and Fourier transform infrared (FTIR) spectroscopy, and the morphologies of the samples were analyzed by high-resolution transmission electron microscopy (HR-TEM) with selected area electron diffraction analysis (SAED). The synthesized Cu–Zr BNPs have been employed as efficient catalysts for the selective N-methylation of aromatic and aliphatic amines with dimethyl carbonate. The effect of process conditions on the percentage conversion of benzylamine with dimethyl carbonate as a model reaction has been investigated. The Cu–Zr bimetallic nanoparticle catalytic system in a 1:2 molar ratio was able to convert amines into the corresponding N-methylated amines with a selectivity up to 91% at 180 °C in 4 h. The analysis of catalytic reusability confirmed that the reported heterogeneous catalyst can be used for five consecutive cycles without much loss in activity. Thus, the current protocol can be considered as a simpler, reproducible, and environmentally benign approach for N-methylation of amines.

Continuous Flow Chiral Amine Racemization Applied to Continuously Recirculating Dynamic Diastereomeric Crystallizations.

A new, dynamic diastereomeric crystallization method has been developed, in which the mother liquors are continuously separated, racemized over a fixed-bed catalyst, and recirculated to the crystallizer in a resolution-racemization-recycle (R3) process. Separating the racemization from crystallization overcomes problems of using catalysts in situ, that suffer conflicting sets of conditions, inhibition, and separation. Continuous racemization has been achieved through the covalent attachment of [IrCp*I2]2 SCRAM catalyst to Wang resin solid support to give a fixed-bed catalyst. One tertiary and a variety of secondary optically enriched amines have been racemized efficiently, with residence times compatible with the crystallization (2.25-30 min). The catalyst demonstrates lower turnover (TOF) than the homogeneous analogue but with reuse shows a long lifetime (e.g., 40 recycles, 190 h) giving acceptable turnover number (TON) (up to 4907). The slow release of methylamine during racemization of N-methyl amines was found to inactivate the catalyst, which could be partially reactivated using hydroiodic acid. Dynamic crystallization is achieved in the R3 process through the continual removal of the more soluble diastereomer and supply of the less soluble one. The solubility of the diastereomers was determined, and the difference correlates to the rate of resolution but is also affected by the rates of racemization, crystal growth, and dissolution. A variety of cyclic and acyclic amine salts were resolved using mandelic acid (MA) and ditoluoyl tartaric acid (DTTA) with higher resolvability (S = yield × d.e.) than the simple diastereomeric crystallization alone. Comparing resolvabilities, resolutions were 1.6-44 times more effective with the R3 process than batch, though one case was worse. Further investigation of this revealed an unusual thermodynamic switching behavior: rac-N-methylphenethylamine was initially resolved as an (S,S)-bis-alkylammonium tartrate crystal but over time became the equivalent (R,S) salt. Thermal, mixing, concentration, stoichiometry, and seeding conditions were all found to affect the onset of the switching behavior which is only associated with difunctional resolving reagents.

A polymeric ionic liquid catalyst for the N-formylation and N-methylation of amines using CO2/PhSiH3

We describe a polymeric ionic liquid (PIL) derived from trimethyl(p-vinylbenzyl)ammonium chloride ([VBTAm]Cl) that efficiently catalyzes the N-formylation of amines employing CO2 and PhSiH3 at room temperature with low catalyst loadings in near-quantitative yield. Under more forcing conditions N-methylated products can be selectively obtained. The PIL catalyst can be easily recovered and reused repeatedly without a decrease in activity. The reaction mechanism was studied in situ using high-pressure NMR spectroscopy and a tentative mechanistic cycle has been proposed.

N-Methylation of Amines with Methanol in Aqueous Solution Catalyzed by a Water-Soluble Metal-Ligand Bifunctional Dinuclear Iridium Catalyst.

The N-methylation of amines with methanol in aqueous solution was proposed and accomplished by using a water-soluble metal-ligand bifunctional dinuclear iridium catalyst. In the presence of [(Cp*IrCl)2(thbpym)][Cl]2 (1 mol %), a range of desirable products were obtained in high yields under environmentally benign conditions. Notably, this research exhibited the potential of transition metal-catalyzed activation of methanol as a C1 source for the construction of the C-N bond in aqueous solution.