Amination Strategy Research Articles

A Voltage-Controlled Strategy for Modular Shono-Type Amination.

Shono-type oxidation to generate functionalized heterocycles is a powerful method for late-stage diversification of relevant pharmacophores; however, development beyond oxygen-based nucleophiles remains underdeveloped. The limited scope can often be ascribed to constant current electrolysis resulting in potential drifts that oxidize a desired nucleophilic partner. Herein, we report a voltage-controlled strategy to selectively oxidize a broad scope of substrates, enabling modular C-N bond formation from protected amine nucleophiles. We implement an electroanalytically guided workflow using cyclic voltammetry (CV) and differential pulse voltammetry (DPV) to identify oxidation potentials across a range of heterocyclic substrates. Controlled potential electrolysis (CPE) selectively generates α-functionalized C-N products in moderate to good yields using carbamate-, sulfonamide-, and benzamide-derived nucleophiles. The importance of voltage control is further exemplified through a systematic study comparing our developed CPE method to constant current electrolysis (CCE) protocols. Voltage-guided CCE and traditionally optimized CCE reveal the importance of maintaining voltage control for high yields and selectivity over a broad scope; a case study with a morpholine-derived substrate illustrates the negative impact of potential drifting under CCE. Sulfonamide drugs, which have significant oxidation potential overlap with model substrates, are rendered competent nucleophiles under CPE. Lastly, sequential voltage-controlled C-N and C-O functionalization of a model substrate generates difunctionalized pyrrolidines further broadening the utility of this reaction.

Nickel-based perovskite-catalysed direct phenol-to-aniline liquid-phase transformations.

Liquid phase direct amination of phenols to primary anilines with hydrazine was achieved using commercial NiLa-perovskite catalysts as bifunctional Lewis acid/redox-active catalysts without adding any external hydride sources. The amination strategy took place efficiently in the absence of any amount of reducing gasses (H2/NH3) and noble metals under mild conditions.

Chemical synthesis of site-selective advanced glycation end products in α-synuclein and its fragments.

Advanced glycation end products (AGEs) arise from the Maillard reaction between dicarbonyls and proteins, nucleic acids, or specific lipids. Notably, AGEs are linked to aging and implicated in various disorders, spanning from cancer to neurodegenerative diseases. While dicarbonyls like methylglyoxal preferentially target arginine residues, lysine-derived AGEs, such as N(6)-(1-carboxymethyl)lysine (CML) and N(6)-(1-carboxyethyl)lysine (CEL), are also abundant. Predicting protein glycation in vivo proves challenging due to the intricate nature of glycation reactions. In vitro, glycation is difficult to control, especially in proteins that harbor multiple glycation-prone amino acids. α-Synuclein (aSyn), pivotal in Parkinson's disease and synucleinopathies, has 15 lysine residues and is known to become glycated at multiple lysine sites. To understand the influence of glycation in specific regions of aSyn on its behavior, a strategy for site-specific glycated protein production is imperative. To fulfill this demand, we devised a synthetic route integrating solid-phase peptide synthesis, orthogonal protection of amino acid side-chain functionalities, and reductive amination strategies. This methodology yielded two disease-related N-terminal peptide fragments, each featuring five and six CML and CEL modifications, alongside a full-length aSyn protein containing a site-selective E46CEL modification. Our synthetic approach facilitates the broad introduction of glycation motifs at specific sites, providing a foundation for generating glycated forms of synucleinopathy-related and other disease-relevant proteins.

Photoinduced amination of iodoalkanes enabled by bifunctional O-benzoyl oxime

A photo-induced amination strategy that facilitates the transformation of iodoalkanes and bifunctional O-benzoyl oxime into alkyl amines is herein reported.

Vapor-phase postsynthetic amination of hypercrosslinked polymers for efficient iodine capture

Hypercrosslinked polymers (HCPs) with large surface areas, high intrinsic porosities and low production costs may be available platforms for iodine capture. However, the lack of iodine-philicity binding sites limits their adsorption capacity. Here we use vapor-phase postsynthetic amination strategy to introduce electron-donating amino groups into the prefabricated HCPs for enhancing their iodine capture performance. Through simple vapor-phase exposure, the halogen-containing HCPs can be grafted by amines through nucleophilic substitution toward chloro groups. Combining with the abundant amino groups and high porosities, the amino-functionalized porous polymers show substantially increased iodine adsorption capacity, about 221% as that of original one, accompanied by excellent recyclability. Mechanism investigations reveal the key roles of the electron-donor amino groups and π-conjugated benzene rings along with structure characteristics of porous polymer frameworks in iodine capture. Moreover, this vapor-phase amination strategy shows good generality and can be extended to various amines, e.g., ethylenediamine, 1,3-diaminopropane and diethylenetriamine. Our work proves that this simple vapor-phase postsynthetic functionalization strategy may be applied in other porous polymers with wide application prospects in adsorption, separation and storage.

Facile surface amination strategy of PIM-1 based membranes for efficient CO2 capture

Carbon dioxide capture by membrane method is considered an important way to solve global warming, and it has become one of the most active research fields at present. Herein, a facile surface amination strategy by diazonium-induced anchoring process (DIAP) was introduced in the modification of polymers of intrinsic microporosity-1 (PIM-1) based membranes for efficient separation of CO2/N2. According to the detection of the chemical and surface properties, the polyaminophenylene (PAP) layer grafting on the surface could be regulated by simply changing the modification time. The modified membranes show significant increase in the CO2/N2 selectivity, which is attributed to the enhanced solubility-selectivity of the amino-rich surface. However, the attachment of the noncovalently grafted aniline groups increases the mass transfer resistance and surface non-uniformity, thereby significantly damaging the permeability of the membranes. Therefore, methanol is employed to clean the redundant PAP. As a result, the permeability of the membranes after methanol post-treatment increases evidently, while the membranes maintain good CO2/N2 selectivity. The selectivity of CO2/N2 and the permeability of CO2 are 34.1 and 11421.5 Barrer respectively at the optimal modification condition, which exceeds the upper bound established in 2019. This work will encourage the researchers to pay more attention to surface modification for CO2 capture, which might be relatively easy for industrial scale-up.

Efficient Metal-Free Oxidative C–H Amination for Accessing Dibenzoxazepinones via μ-Oxo Hypervalent Iodine Catalysis

Dibenzoxazepinones exhibit unique biological activities and serve as building blocks for synthesizing pharmaceutical compounds. Despite remarkable advancements in organic chemistry and recent developments in synthetic approaches to dibenzoxazepinone motifs, there is a strong demand for more streamlined synthesis methods. The application of the catalytic C–H amination strategy, which enables the direct transformation of inert aromatic C–H bonds into C–N bonds, offers a rapid route to access dibenzoxazepinone frameworks. Hypervalent-iodine-catalyzed oxidative C–H amination has the potential to become an effective approach for synthesizing dibenzoxazepinones. In this study, we present our method of employing μ-oxo hypervalent iodine catalysis for intramolecular oxidative C–H amination of O-aryl salicylamides, facilitating the synthesis of target dibenzoxazepinone derivatives bearing various functional groups in a highly efficient manner.

Late-Stage Diversification of Peptides via Pd-Catalyzed Site-Selective δ-C(sp2)-H Fluorination and Amination.

Site-selective C-H fluorination is an attractive strategy for directly transforming inert C-H bonds into C-F bonds, yet it remains a significant challenge. Herein, we have developed an efficient and versatile strategy for site-selective fluorination and amination of phenylalanine-containing peptides via late-stage Pd-catalyzed δ-C(sp2)-H activation, providing a valuable tool for the in situ synthesis of fluorinated indoline scaffolds within peptides.

A General Photocatalytic Strategy for Nucleophilic Amination of Primary and Secondary Benzylic C-H Bonds.

We report a visible-light photoredox-catalyzed method that enables nucleophilic amination of primary and secondary benzylic C(sp3)-H bonds. A novel amidyl radical precursor and organic photocatalyst operate in tandem to transform primary and secondary benzylic C(sp3)-H bonds into carbocations via sequential hydrogen atom transfer (HAT) and oxidative radical-polar crossover. The resulting carbocation can be intercepted by a variety of N-centered nucleophiles, including nitriles (Ritter reaction), amides, carbamates, sulfonamides, and azoles, for the construction of pharmaceutically relevant C(sp3)-N bonds under unified reaction conditions. Mechanistic studies indicate that HAT is amidyl radical-mediated and that the photocatalyst operates via a reductive quenching pathway. These findings establish a mild, metal-free, and modular protocol for the rapid diversification of C(sp3)-H bonds to a library of aminated products.

Nickel-Catalyzed Amination of Alkyl Electrophiles.

Bimolecular nucleophilic substitution SN2 is the earliest and most important means of amination of alkyl electrophiles; its practical utilization is largely limited to primary or activated substrates. Furthermore, a persistent challenge lies in establishing C(sp3)-N bonds from alkyl substrates in cross-coupling chemistry using palladium and nickel catalysts. Therefore, the methods of constructing C(sp3)-N bonds remain rare from alkyl electrophiles. The existing routes are limited to copper catalysis and photoredox catalysis. Here, we demonstrate an alternative amination strategy for rapid construction of C(sp3)-N bonds from accessible alkyl electrophiles, which were used as radical precursors under nickel catalysis by Ni (III) species reductive eliminations in high efficiency.

Ionic Liquid Hydrogen-bonding Promoted Alcohols Amination over Cobalt Catalyst via Dihydrogen Autotransfer Mechanism.

Higher amines are important high-valuable chemicals with wide applications, and amination of alcohols is a green route to them, which however generally suffers from harsh reaction conditions and use of equivalent base. Herein, we report an ionic liquid (IL) hydrogen-bonding promoted dihydrogen autotransfer strategy for amination of bio-alcohols to higher amines over cobalt catalyst under base-free conditions. Co(BF4)2·6H2O complexed with triphos and IL (e.g., tetrabutylphosphonium tetrafluoroborate, [P4444][BF4]) shows high performances for the reaction, and is tolerate to wide scopes of amines and bio-alcohols, affording higher amines in good to excellent yields. Mechanism investigation indicates that the [BF4]- anion activates alcohol via hydrogen bonding, promoting transfer of both hydroxyl H and a-H of alcohol to cobalt catalyst to form aldehyde intermediate and cobalt dihydride complex, which involve in subsequent reductive amination. This strategy provides a green and effective route for alcohol amination, which may have promising applications in alcohol-involved alkylation reactions.

Post‐synthesis amination of polymer of intrinsic microporosity membranes for CO2 separation

AbstractMembrane separation is an energy‐saving technology for carbon capture. However, it is subjected to permeability‐selectivity trade‐off limitation. Although chemical functionalization is proposed to boost separation efficiency, controlling sorption–diffusion process remains extremely challenging. In this study, a facile, controllable, and versatile chemical vapor amination strategy is reported to simultaneously tune gas sorption and diffusion in polymer of intrinsic microporosity (PIM)‐based membranes for improving carbon capture performance. Through simple exposure in amine vapors under mild conditions, nucleophilic substitution of amines toward ether and halogen groups induce grafting, ring‐opening, terminal replacement, chain‐scission, and crosslinking of PIM‐1, thereby underpinning CO2‐philicity and tailoring passageway. The prepared CO2‐philic membranes exhibit substantially improved CO2/N2 selectivity over 30.8, about 226% as that of original one, accompanied by high CO2 permeability of 2590 Barrer, which can surpass the trade‐off upper bound of polymer membranes. Our results reveal that post‐synthesis amination is an effective route to obtain high‐performance membranes.

Synthesis of α-Aminophosphonates by Umpolung-Enabled Cu-Catalyzed Regioselective Hydroamination

A copper-catalyzed regioselective hydroamination of α,β-unsaturated phosphonates has been developed to form corresponding α-aminophosphonates of interest in medicinal chemistry. The introduction of an umpolung, electrophilic amination strategy with the hydroxylamine derivative is the key to achieving the α-amination regioselectivity, which is otherwise difficult under the conventional nucleophilic hydroamination conditions with the parent amine. Asymmetric synthesis with a chiral bisphosphine ligand and application to a related silylamination reaction are also described.

Toward explicit anion transport nanochannels for osmotic power energy using positive charged MXene membrane via amination strategy

The reverse electrodialysis (RED) is a potential technique to harvest osmotic energy caused by different salinities. Owing to the negative surface-charged controlling effects of nanofluidic channel in 2D membrane, the power density has been achieved with high energy conversion efficiency for cations (Na+ with the counterpart of Cl−). However, anion-selective nanofluidic channel is rare but still required for promising application of RED due to its high higher diffusion rate resulting in desirable osmotic power energy. In this work, we constructed a two-dimensional layered MXene membrane with positive charge via amination strategy of 3-aminopropyltriethoxysilane (APTES) toward anion selectivity for efficient osmotic power harvesting. The power density of the resultant membrane can achieve a maximum of 10.98 W m−2 at a natural salinity gradient, higher than the commercial benchmark of 5 W m−2. Under regulating environmental conditions including operation temperatures, pH and the existence of pollutants (heavy metal ions and organic pollution) of the simulated electrolyte solution, a higher power density of 20.66 W m−2 can be reached through Cl− transmembrane transport. During 10-h testing, the attenuation of output power density was just 3%. The applicable stability still maintains under the contaminative environment of heavy metal ions or organic pollution. These results will bring an innovative design of anion-selective membrane for osmotic energy conversion and widen the practical application in ion selectivity.

Copper-Catalyzed Three-Component Aminofluorination of Alkenes and 1,3-Dienes: Direct Entry to Diverse β-Fluoroalkylamines.

Rapid and efficient access to structurally diverse β-fluoroalkylamines is in high demand, with their wide presence and great importance in medicinal chemistry and drug development. Direct 1,2-aminofluorination of alkenes offers an ideal strategy for one-step entry to β-fluorinated amines from readily available starting materials. Yet the synthesis of valuable β-fluorinated alkylamines remains an unsolved challenge, due to the inherent incompatibility between electrophilic fluoride sources and the electron-rich alkylamines. We report an unprecedented, catalytic, three-component aminofluorination of diverse alkenes and 1,3-dienes, which has been achieved by an innovative copper-catalyzed electrophilic amination strategy using O-benzoylhydroxylamines as alkylamine precursors. The use of Et3N·3HF is also critical, not only as a commercially available and inexpensive fluoride source to enable effective fluorination but also as an acid source for the formation of aminyl radical cations for electrophilic amination. Mechanistic experiments suggest the involvement of aminyl radical species and carbon-radical intermediates under reaction conditions. This method features high regioselectivity and good tolerance of diverse functional groups and provides a practical and direct entry to a broad range of β-fluorinated electron-rich alkylamines. Synthetic applications of this method have also been highlighted by its use for the rapid entry to β-fluoridated amine-containing pharmaceuticals, natural products, and bioactive compounds.

Combined radical and ionic approach for the enantioselective synthesis of β-functionalized amines from alcohols.

Chiral amines are among the most important organic compounds and have widespread applications. Enantioselective construction of chiral amines is a major aim in organic synthesis. Among synthetic methods, direct functionalization of omnipresent C-H bonds with common organic nitrogen compounds represents one of the most attractive strategies. However, C-H amination strategies are largely limited to constructing a specific type of N-heterocycles or amine derivatives. To maximize the synthetic potential of asymmetric C-H amination, we report here an approach that unites the complementary reactivities of radical and ionic chemistry for streamlined synthesis of functionalized chiral amines. This synthesis merges the development of an enantioselective radical process for 1,5-C(sp 3)-H amination of alkoxysulfonyl azides via Co(II)-based metalloradical catalysis with an enantiospecific ionic process for ring-opening of the resulting five-membered chiral sulfamidates by nucleophiles. Given that alkoxysulfonyl azides are derived from the corresponding alcohols, this approach offers a powerful synthetic tool for enantioselective β-C-H amination of common alcohols while converting the hydroxy group to other functionalities through formal nucleophilic substitution.

Nickel‐Catalysed Amination of Arenes and Heteroarenes

AbstractC(sp2)−N cross‐coupling is one of the most powerful transformations in organic synthesis to construct highly ubiquitous anilines and aniline derivatives. The dominance of Pd‐ and Cu‐based catalytic systems is evident in the field for a long time. However, Ni‐catalysed methodologies to achieve this reaction have grown gradually as sustainable alternatives in the last two decades. Recent reports of highly applicable photocatalytic and electrochemical amination strategies sufficiently enhanced the potential of Ni‐catalysed aminations. This review summarizes the advancement of this cross‐coupling reaction as a general and efficient method over the last 5 years.

Conformationally locked cis-1,2-diaminocyclohexane-based chiral ligands for asymmetric catalysis

An efficient synthesis for a new conformationally locked chiral cis-1,2-diaminocyclohexane scaffold has been developed. The conformational lock allows for convenient symmetrical derivatization of the amino groups through the reductive amination strategy. A series of optically pure chiral ligands based on the cis-DACH scaffold has been generated to demonstrate a proof-of-concept for these ligands as chiral catalysts in the asymmetric Henry reaction. Excellent yields with moderate enantioselectivity were demonstrated at room temperature, with an increase in enantioselectivity at lower temperatures, showing the potential of this new type of cis-DACH ligand.

N‐Ligand‐Enabled Aromatic Nucleophilic Amination of 1,2‐Diaryl‐o‐Carboranes with (R2N)2Mg for Selective Synthesis of 4‐R2N‐o‐Carboranes and 2‐R2N‐m‐Carboranes

AbstractThe nucleophilic aromatic BH substitution reaction of carboranes is uncommon, compared to the electrophilic one. This work reported a pyridine‐enabled transition‐metal‐free regioselective nucleophilic aromatic cage B(4)‐H amination of 1,2‐diaryl‐o‐carboranes with magnesium bisamides, giving a series of B(4)‐aminated o‐carboranes. DFT calculations showcased a stepwise B−N formation/B−H cleavage process, in which Mg−H formation/cage closure is the rate‐determining step. Unprecedentedly, in the presence of 4,4′‐di‐tert‐butyl‐2,2′‐dipyridyl (dtbpy), a tandem B(4)‐amination/cage isomerization reaction of o‐carboranes was discovered for the facile preparation of B(2)‐aminated m‐carboranes. Control experiments indicated that magnesium complex, bidentate ligand (dtbpy) and reaction temperature were crucial in the cage isomerization process. This direct nucleophilic aromatic cage B−H amination reaction offers an alternative strategy for selective amination of o‐ and m‐carboranes.

N-Ligand-Enabled Aromatic Nucleophilic Amination of 1,2-Diaryl-o-Carboranes with (R2 N)2 Mg for Selective Synthesis of 4-R2 N-o-Carboranes and 2-R2 N-m-Carboranes.

The nucleophilic aromatic BH substitution reaction of carboranes is uncommon, compared to the electrophilic one. This work reported a pyridine-enabled transition-metal-free regioselective nucleophilic aromatic cage B(4)-H amination of 1,2-diaryl-o-carboranes with magnesium bisamides, giving a series of B(4)-aminated o-carboranes. DFT calculations showcased a stepwise B-N formation/B-H cleavage process, in which Mg-H formation/cage closure is the rate-determining step. Unprecedentedly, in the presence of 4,4'-di-tert-butyl-2,2'-dipyridyl (dtbpy), a tandem B(4)-amination/cage isomerization reaction of o-carboranes was discovered for the facile preparation of B(2)-aminated m-carboranes. Control experiments indicated that magnesium complex, bidentate ligand (dtbpy) and reaction temperature were crucial in the cage isomerization process. This direct nucleophilic aromatic cage B-H amination reaction offers an alternative strategy for selective amination of o- and m-carboranes.