Direct Amination Research Articles

Mechanistic Approach Toward the C4-Selective Amination of Pyridines via Nucleophilic Substitution of Hydrogen.

The development of site-selective functionalization of N-heteroarenes is highly desirable in streamlined synthesis. In this context, direct amination of pyridines stands as an important synthetic methodology, with particular emphasis on accessing 4-aminopyridines, a versatile pharmacophore in medicinal chemistry. Herein, we report a reaction manifold for the C4-selective amination of pyridines by employing nucleophilic substitution of hydrogen (SNH). Through 4-pyridyl pyridinium salt intermediates, 4-aminopyridine products are obtained in reaction with aqueous ammonia without intermediate isolation. The notable regioselectivity was achieved by the electronic tuning of the external pyridine reagents along with the maximization of polarizability in the proton elimination stage. Further mechanistic investigations provided a guiding principle for the selective C-H pyridination of additional N-heteroarenes, presenting a strategic avenue for installation of diverse functional groups.

Selective amination of furfuryl alcohol to furfurylamine over nickel catalysts promoted by alumina encapsulation

Direct amination of bio-based furfuryl alcohol over metal catalysts provides an alternative route to produce furfurylamine without consuming expensive reducing reagents. The harsh and reductive condition of furfuryl alcohol amination, however, requires high durability and excellent resistance to side furan-ring hydrogenation for efficient catalysts, which is still substantially challenging to non-noble metals. We show here that alumina-encapsulated Ni catalysts prepared via a sol–gel method exhibited an outstanding and stable performance in selective amination of furfuryl alcohol to furfurylamine under mild NH3 and H2 partial pressures. Structural characterization unveiled that the alumina framework with appropriate mesopores effectively restrained the agglomeration of Ni nanoparticles and the side furan-ring hydrogenation. A volcano-type dependance of the intrinsic activity of Ni nanoparticles on their sizes was established with the maximum attained at about 5 nm, which correlated well with the redox ability of surface Ni sites. Kinetic assessments further indicated the kinetic relevance of furfural formation from furfuryl alcohol dehydrogenation, evidenced by quasi-zero and negative reaction orders on NH3 and H2 pressures, respectively. Combined with infrared spectroscopy, furfuryl alcohol was identified as the predominant adsorbed species with a nearly saturated coverage under reaction condition, consistent with the high susceptibility of furan-ring hydrogenations to H2 pressure. As a consequence, a slight amount of inert Ag (0.05 wt%) was introduced onto the alumina-encapsulated Ni catalysts to weaken the adsorption of furfuryl alcohol and its derivatives, which suppressed the side over-hydrogenation reactions to an extremely low level without sacrificing catalytic activity significantly.

Engineering the substrate acceptance of l-amine dehydrogenase enables the collective biocatalytic synthesis of N-heterocyclic primary amines

Chiral N-heterocyclic primary amines are highly attractive synthons in the pharmaceutical industry. Amine dehydrogenases (AmDHs)-catalyzed direct asymmetric reductive amination of the readily available N-heterocyclic ketones represents a promising approach for synthesizing N-heterocyclic primary amines. However, the limited substrate acceptance of AmDHs restricts their application in biocatalytic synthesis. Here, we engineered the substrate acceptance of L-EsAmDH from Exiguobacterium sibiricum to access a panel of structurally diverse N-heterocyclic ketones. Through reverse substrate design and combining with substrate walking strategy, two active mutants with extended substrate specificity toward N-Boc-4-acetylpiperidine were identified, and two additional rounds of iterative site mutagenesis further increased the activity by 116.3-fold. The optimal mutant M4-2 (L49G/V303A/L307A/T143A) exhibited significantly expanded N-Boc, N-Bn, and N-Cbz-substituted heterocyclic ketones scope, and its practical biocatalytic synthesis performance was verified in the gram-scale synthesis of (R)-4-aminoethyl-1-Boc-piperidine, achieving 95 % conversion, >99 % ee, and an overall isolated yield of 86 % (9.8 g). Our study lays the foundation for the collective biocatalytic synthesis of structurally diverse N-heterocyclic primary amines and gives referable guidance for engineering AmDH family members into versatile biocatalysts.

Tf2O-Mediated P(O)-N Bond Formation of Either P(O)-OH or P(O)-H Reagents with Multitype Amines.

We have developed a Tf2O-mediated approach for the direct amination of either P(O)-OH or P(O)-H reagents with a variety of aliphatic or aromatic amines. Without the requirement of precious metals and toxic reagents, this protocol provides an alternative route to various phosphinamides and phosphoramides. The reaction proceeds under simple and mild conditions and can be effectively scaled up with similar efficiency.

Molybdenum-doped carbon nitride as an efficient heterogeneous catalyst for direct amination of nitroarenes with arylboronic acids

Heterogeneous metal-catalyzed chemical conversions with a recyclable catalyst are very ideal and challenging for sustainable organic synthesis. A new bipyridyl-Mo(IV)-carbon nitride (CN-K/Mo-Bpy) was prepared by supporting molybdenum complex on C3N4-K and characterized by FT-IR, XRD, SEM, XPS and ICP-OES. Heterogeneous CN–Mo-Bpy catalyst can be applied to the direct amination of nitroarenes and arylboronic acid, thus constructing various valuable diarylamines in high to excellent yields with a wide substrate scope and good functional group tolerance. It is worth noting that this heterogeneous catalyst has high chemical stability and can be recycled for at least five times without reducing its activity.

Silane and fluorine free facile hydrophobicization of water hyacinth biomass for oil-water separations

As the adverse effects of using plastics and perfluorinated alkyl substances become more apparent, there is a growing need for sustainable hydrophobic products. Cellulose and its derivatives are the most abundant and widely used polymers, and cellulose-based products have great potential in industries where plastics and other hydrophobic polymers are used, such as stain-resistant fabrics, food packaging, and oil-water separation applications. In this study, we extracted cellulose from water hyacinth (WH) biomass, known for its negative environmental impact, and converted it into hydrophobic cellulose. This addresses the issue of managing WH waste and creating an environmentally friendly hydrophobic material. Initially, aldehyde groups were introduced through oxidation with periodate, followed by direct octadecyl amine (ODA) grafting onto dialdehyde cellulose (DAC) via a Schiff base condensation. The resulting ODA modified cellulose (ODA-C) was dispersed in ethanol and used to coat various materials, including cotton fabric, cellulose filter paper, and packaging paper. The modified materials showed excellent hydrophobicity as measured by their water contact angles (WCAs), and the application of the coating was demonstrated for oil-water separation, stain-resistant hydrophobic fabric, and paper-based packaging materials. FTIR, XRD, and WCA analysis confirmed the successful modification of cellulose. A high separation efficiency of 99% was achieved for diesel/water separation using modified filter paper (MoFP), under gravity. On application of the coating, cotton fabric became hydrophobic and resisted staining from dye, and paper-based packaging materials became more robust by becoming water-resistant. Overall, the facile synthesis, low cost, high efficiency, and use of environmentally friendly sustainable materials make this a promising strategy for hydrophobically modifying surfaces for a wide range of applications while reducing the menace of water hyacinth.

Transition-Metal-Catalyzed Direct Arylation of Ammonia

AbstractIn the past few decades, transition-metal-catalyzed direct amination of aryl halides with ammonia has attracted significant attention from chemists because of its broad substrate scope, good functional group compatibility, and high reaction selectivity. Herein, recent examples of transition-metal-catalyzed syntheses of aniline derivatives starting from aryl halides are reviewed.1 Introduction2 Heat-Driven Transition-Metal-Catalyzed Amination of Aryl Electrophiles2.1 Palladium-Catalyzed Amination2.2 Copper-Catalyzed Amination2.3 Nickel-Catalyzed Amination3 Light-Driven Transition-Metal-Catalyzed Amination of Aryl Electrophiles4 Conclusion and Outlook

Naturally occurring phytic acid: an advanced Brønsted acid catalyst for direct amination reactions of allylic alcohols.

Phytic acid is abundant in various plant-based foods and is considered agricultural waste. Here, we demonstrate the effectiveness of this organophosphorus acid as a sustainable catalyst for the direct amination reactions of allylic alcohols. This approach is successfully performed in air using technical grade solvents, affording allylanilines in moderate to excellent yields. Challenging electron-rich anilines react effectively, and their corresponding Friedel-Crafts side products can be minimised under the optimised reaction conditions. A variety of asymmetrically substituted allylic alcohols are tolerated, while the scope is extended to amide, and C-, O- and S-nucleophiles.

Solid‐phase synthetic method for N‐alkyl‐7‐alkylamino‐2‐aryloxazolo[5,4‐d]pyrimidine‐5‐carboxamide derivatives

AbstractOxazolo[5,4‐d]pyrimidine derivatives have been reported to exhibit interesting biological activities. Herein, we described a solid‐phase synthetic method to produce N‐alkyl‐7‐alkylamino‐2‐aryloxazolo[5,4‐d]pyrimidine‐5‐carboxamide derivatives. The strategy consists of loading the template compounds (i.e., 2‐aryl‐6,7‐dihydrooxazolo[5,4‐d]pyrimidin‐7‐one‐5‐carboxylic acids) onto aminated acid‐sensitive methoxybenzaldehyde (AMEBA) resins, the subsequent benzotriazol‐1‐yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP)‐mediated direct amination with primary/secondary amines, and the final cleavage from the solid support to afford the target compounds. The template 2‐aryl‐6,7‐dihydrooxazolo[5,4‐d]pyrimidin‐7‐one‐5‐carboxylic acids were prepared using a five‐step solution‐phase synthetic route from ethyl 2‐cyano‐2‐(hydroxyimino)acetate. BOP‐mediated direct amination conditions were optimized by a solution‐phase model study. The solid‐phase synthetic method provided the 17 target compounds in 16%–92% five‐step overall isolated yields from the Merrified resin for selected template compounds and primary/secondary amines.

Photoredox-Catalyzed Alkene Amination: C(sp2)-H/N-H Radical-Radical Cross Dehydrogenative Coupling.

Direct alkene C-H/N-H cross dehydrogenative coupling is an infrequent, highly challenging transformation. Herein, a photoredox radical-radical cross-coupling reaction between ketene dithioacetal as a persistent alkene radical cation and azole nitrogen center radical (NCR) was developed. This direct alkene amination proceeded through a synergistic photoredox and cobalt catalysis, with only H2 evolution. The reaction showed excellent tolerance and highly regio- and stereospecific manner, expanding the scope of C(sp2)-N construction methods and radical cross-coupling modes.

Design and Application of New Pyridine-Derived Chiral Ligands in Asymmetric Catalysis.

ConspectusThe innovation of chiral ligands has been crucial for the asymmetric synthesis of functional molecules, as demonstrated by several types of widely applied "privileged" ligands. In this context, chiral pyridine-derived ligands, by far some of the oldest and most widely utilized ligands in catalysis, have attracted considerable research interest in the past half-century. However, the development of broadly applicable chiral pyridine units (CPUs) has been plagued by several intertwining challenges, thus delaying advancements in many asymmetric reactions.This Account aims to summarize the recent progress in new CPU-containing ligands, focusing on a rationally designed, modular, and tunable CPU developed in our laboratory. A significant problem thwarting conventional designs is the paradox between broad reactivity and stereoselectivity; that is, while enhanced stereoselectivity may be achieved by introducing chiral elements close to the N atom, the concomitant increase in local steric hindrance often limits catalytic activity and scope. Our newly developed CPU features a rigid [6-5-3] fused-ring framework and a tunable spirocyclic ketal side wall. The well-defined three-dimensional structure minimizes local (inner layer) steric hindrance and tunes the peripheral environment (outer layer) by remote substituents, thus securing reactivity and stereoselectivity. Different chelating ligands were readily assembled using this chiral structural module, with applications in mechanistically diverse transition-metal-catalyzed reactions. Thus, a series of chiral 2,2'-bipyridine ligands were successfully employed in the development of a general, efficient, and highly enantioselective nickel-catalyzed intermolecular reductive addition, Ullmann coupling of ortho-chlorinated aryl aldehydes, and carboxylation of benzylic (pseudo)halides with CO2. Notably, these chiral 2,2'-bipyridine ligands exhibited superior catalytic activity in the reactions compared to common N-based ligands. In addition, highly enantioselective iridium-catalyzed C-H borylation was developed using a CPU-containing N,B-bidentate ligand. Furthermore, mechanistically challenging, additive-free, and broad-scope transfer hydrogenative direct asymmetric reductive amination was achieved using a half-sandwich iridium catalyst supported by a chiral N,C-bidentate ligand. The new ligands demonstrated excellent performance in securing high catalytic activity and stereoselectivity, which, when combined with experimental and computational mechanistic investigations, supported the "double-layer control" design concept.Considering the broad applications of pyridine-derived ligands, the research progress described herein should inspire the creation of novel chiral catalysts and drive the development of many catalytic asymmetric reactions.

Copper-catalyzed direct oxidative amination of maleimides and quinones with formamides in the presence of an oxidant KIO3

A facile, efficient, and practical method for copper-catalyzed direct amination of maleimides and quinones with formamides in the presence of an oxidant KIO3 has been developed. It allows a facile access to a wide range of functionalized molecules with privileged scaffolds in drugs and natural products such as maleimides and quinones. A variety of substituted 3-amino-maleimides and 2-amino-quinones were synthesized with moderate to excellent yield.

Oxidative Nickel-Catalyzed ortho-C-H Amination of (Iso)quinolines with Alicyclic Amines Directed by a Sacrificial N-Oxide Group.

Transition metal (TM)-catalyzed direct amination of C-H bonds on free or fused pyridine (Py) rings with free amines still remains scarce because amines and the Py ring tend to adopt a nonproductive N-bound coordination with many TMs, leading to a significant decrease of catalytic reactivity. We herein disclose a nickel-catalyzed and a sacrificial N-oxide group directed oxidative coupling of (iso)quinolyl C-H bonds and alicyclic amines, which furnishes bioimportant amino(iso)quinolines efficiently and selectively in a single step. Noteworthy, this protocol avoids the use of aggressive reactants and very strong bases usually required when aminating on nonoxidized Py rings.

Atroposelective Synthesis of 2‐Arylindoles via Chiral Phosphoric Acid‐Catalyzed Direct Amination of Indoles†

Comprehensive SummaryIndole‐based atropisomers are a very important class of axially chiral compounds. However, the atroposelective synthesis of axially chiral 2‐arylindole remains largely unexplored. In this study, we report the successful synthesis of atropisomeric 2‐arylindoles using direct amination of indoles with p‐quinonediimines in the presence of chiral phosphoric acid as a catalyst. Quinonediimine acts as an aminating reagent through formal polarity inversion of imine. The malonate group on the 2‐aryl of 2‐indoles was found to be essential for high enantioselectivity of the products. This could be due to the additional interaction between the ester group and the catalyst, as well as the intramolecular hydrogen bonding. Our findings provide a new strategy for the asymmetric construction of 2‐arylindole atropisomers.

Ir/XuPhos-catalyzed direct asymmetric reductive amination of ketones with secondary amines

We herein report a novel iridium catalyst with XuPhos as a chiral monodentate phosphine ligand for the direct asymmetric reductive amination of ketones with secondary amines, providing a series of chiral tertiary amines efficiently.

Penta- versus hexa-coordinated iridium catalysts control the reactivity of the direct reductive amination between aliphatic amines and aliphatic ketones: a DFT-guided mechanism

The mechanism of the iridium-catalysed direct reductive amination between aliphatic partners was studied by DFT calculations leading to important changes in the rate-determining step depending on the nature of the ligand coordinating to iridium.

Direct synthesis of chiral β-arylamines via additive-free asymmetric reductive amination enabled by tunable bulky phosphoramidite ligands.

This report describes an additive-free iridium-catalyzed direct asymmetric reductive amination that enables the efficient synthesis of chiral β-arylamines, which are important pharmacophores present in a wide variety of pharmaceutical drugs. The reaction makes use of bulky and tunable phosphoramidite ligands for high levels of enantiomeric control, even for alkylamino coupling partners which lack secondary coordinating sites. The synthetic value of this succinct procedure is demonstrated by single-step synthesis of multiple drugs, analogs and key intermediates. Mechanistic investigations reveal an enamine-reduction pathway, in which H-bonding, steric repulsion, and CH-π and electrostatic interactions play important roles in defining the spatial environment for the "outer-sphere" hydride addition.

Observing C-N bond formation in plasma: a case study of benzene and dinitrogen coupling via an arylnitrenium ion intermediate.

Directly fixing dinitrogen into value-added organics is one of the core issues, and yet a long-standing challenge, in chemical synthesis. In earlier discrete studies, direct amination of benzene with N2 has been achieved via non-thermal plasma-liquid reaction. Nonetheless, the reaction mechanism thereof remains elusive and the amination product was non-selective primarily including aniline and diphenylamine. Herein, non-thermal plasma reaction in combination with on-line mass spectrometry was employed to probe the reaction pathway by on-line detection of the transient intermediate and the stable amination product. The long-lived atomic nitrogen ions N+(3P) as well as the arylnitrenium ions' intermediacy were shown to play a pivotal role in the amination process, and the product distribution was affected by an external hydrogen source and likely dependent on the competing hydrogen abstraction reaction and intersystem crossing of the initially generated triplet state arylnitrenium ions. The mechanistic investigation in this work has implications for plasma-based nitrogen conversion into organics, but also has broader relevance for understanding the C-N coupling by other means directly with N2.

Direct amination of poly(p-phenylene oxide) to substituted anilines over bimetallic Pd–Ru catalysts

We demonstrate a novel route for the upcycling of poly(phenylene oxide) (PPO) into dimethylanilines using a bimetallic Pd7Ru3/CNT catalyst. This represents the first successful transformation of PPO into nitrogen-containing compounds.

Organocatalytic aromatization-promoted umpolung reaction of imines.

The umpolung functionalization of imines bears vast synthetic potential, but polarity inversion is less efficient compared with the carbonyl counterparts. Strong nucleophiles are often required to react with the N-electrophiles without catalytic and stereochemical control. Here we show an effective strategy to realize umpolung of imines promoted by organocatalytic aromatization. The attachment of strongly electron-withdrawing groups to imines could enhance the umpolung reactivity by both electronegativity and aromatic character, enabling the direct amination of (hetero)arenes with good efficiencies and stereoselectivities. Additionally, the application of chiral Brønsted acid catalyst furnishes (hetero)aryl C-N atropisomers or enantioenriched aliphatic amines via dearomative amination from N-electrophilic aromatic precursors. Control experiments and density functional theory calculations suggest an ionic mechanism for the umpolung reaction of imines. This disconnection expands the options to forge C-N bonds stereoselectively on (hetero)arenes, which represents an important synthetic pursuit, especially in medicinal chemistry.