Imides Research Articles

Bridging Frontiers in Macromolecular and Supramolecular Sciences with Living Cationic Ring‐Opening Polymerization of Self‐Organizable Dendronized Cyclic‐Imino Ethers Generating Soft Frank–Kasper and Quasicrystal Arrays

AbstractLiving cationic ring‐opening polymerization accompanied by isomerization of cyclic imino ethers is performed at high temperatures that provide access to the synthesis of self‐organizable systems in their isotropic melt or solution state. This Perspective discusses fundamental mechanistic principles of this polymerization and bridges with the polymerization of dendronized cyclic iminoethers forming polymers that self‐organize soft Frank–Kasper and quasicrystal periodic and quasiperiodic arrays. These two fields represent frontiers in macromolecular and supramolecular science. A brief discussion of the impact of this polymerization on biomaterials and how it impacted contemporary mechanistic investigations is also made. Expected impacts via future synthetic developments and mechanistic investigations are discussed.

Diastereoselective Stereo-Divergent Synthesis of Spiroindolines via Ligand-Controlled Silver(I)-Catalyzed Asymmetric [3 + 2] cycloadditions

A series of spirocyclic pyrrolidine derivatives with quaternary stereocenters was constructed via asymmetric [3 + 2] cycloaddition reactions between imino esters and 2-oxindole. By ingenious use of ligands on the silver catalyst allows stereoselectivity to either endo-isomers (ee up to 98 %, yields up to 96 %) with (R, Rp)-Ph-Phosferrox or exo-isomers (ee up to 99 %, yields up to 87 %) with (R)-BINAP. This work is notable for its high yields, broad substrate adaptability and excellent enantioselectivity.

Evaluating the Ability of External Electric Fields to Accelerate Reactions in Solution.

This study investigates the catalytic effects of external electric fields (EEFs) on two reactions in solution: the Menshutkin reaction and the Chapman rearrangement. Utilizing a scanning tunneling microscope-based break-junction (STM-BJ) setup and monitoring reaction rates through high-performance liquid chromatography connected to a UV detector (HPLC-UV) and ultraperformance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UPLC-q-ToF-MS), we observed no rate enhancement for either reaction under ambient conditions. Density functional theory (DFT) calculations indicate that electric field-induced changes in reactant orientation and the minimization of activation energy are crucial factors in determining the efficacy of EEF-driven catalysis. Our findings suggest that the current experimental setups and field strengths are insufficient to catalyze these reactions, underscoring the importance of these criteria in assessing the reaction candidates.

Pd/Cu-Cocatalyzed Enantio- and Diastereodivergent Wacker-Type Dicarbofunctionalization of Unactivated Alkenes.

The Wacker and Wacker-type reactions are some of the most fundamental and powerful transformations in organic chemistry for their ability to efficiently produce valuable chemicals. Remarkable progress has been achieved in asymmetric oxy/aza-Wacker-type reactions; however, asymmetric Wacker-type dicarbofunctionalization remains underdeveloped, especially for the concurrent construction of two stereocenters. Herein, we report a Pd/Cu-cocatalyzed enantio- and diastereodivergent Wacker-type dicarbofunctionalization of alkene-tethered aryl triflates with imino esters. A series of 2-indanyl motifs bearing adjacent carbon stereocenters could be easily synthesized in moderate to excellent yields and with good to excellent diastereo- and enantioselectivities (up to >20:1 dr and >99% ee). Density functional theory calculations revealed that the origin of diastereoselectivity in this Pd/Cu synergistic catalytic system is jointly determined by both the intermolecular anti-carbopalladation of alkenes and the reductive elimination processes, in accordance with the Curtin-Hammett principle.

Catalytic asymmetric synthesis of 1,2-diamines.

The asymmetric catalytic synthesis of 1,2-diamines has received considerable interest, especially in the last ten years, due to their presence in biologically active compounds and their applications for the development of synthetic building blocks, chiral ligands and organocatalysts. Synthetic strategies based on C-N bond-forming reactions involve mainly (a) ring opening of aziridines and azabenzonorbornadienes, (b) hydroamination of allylic amines, (c) hydroamination of enamines and (d) diamination of olefins. In the case of C-C bond-forming reactions are included (a) the aza-Mannich reaction of imino esters, imino nitriles, azlactones, isocyano acetates, and isothiocyanates with imines, (b) the aza-Henry reaction of nitroalkanes with imines, (c) imine-imine coupling reactions, and (d) reductive coupling of enamines with imines, and (e) [3+2] cycloaddition with imines. C-H bond forming reactions include hydrogenation of CN bonds and C-H amination reactions. Other catalytic methods include desymmetrization reactions of meso-diamines.

L-PTMI-co-L-PEI copolymers obtained through copolymerization of cyclic imino ethers and their chain modification: Antibacterial properties and cytotoxicity

Polymeric antimicrobial agents are intensively investigated as potential novel antibiotics. In this work we use copolymerization of 2-propyl-2-oxazine (PrOzi) and 2-methyl-2-oxazoline (MeOx) combined with hydrolysis of the polymer side chains as a tool to obtain various linear polymeric derivatives of polytrimethylenimines (L-PTMI) and polyethylenimine (L-PEI). To obtain well-defined polymers, initially we determined copolymerization rates, and subsequently, we investigated the hydrolytic rates of various repeating units, namely PrOzi, MeOx, and 2-methyl-2-oxazine (MeOzi) in both homo- and copolymers. We observed that the structure of the polymeric main chain significantly influences the rate of acidic hydrolysis. In particular, the protonated L–PEI repeating unit (r.u.) accelerates the hydrolytic cleavage of the amide bond more than the protonated L-PTMI r.u., due to the shorter distance between amine centers.The biological activity of the polymers was assessed against three model microorganisms, namely Escherichia coli, Staphylococcus aureus and Candida albicans, and benchmarked in toxicity test against human lung fibroblast cell line. The antibacterial activity of L-PTMI-co-L–PEI increases monotonically with the increasing content of PTMI r.u., indicating an additive effect of covalently bonded L-PTMI and L-PEI. The antimicrobial activity of the copolymers is almost identical to that of the tested polymer blends in the corresponding ratios.The introduction of up to 40 % of PrOzi r.u. into the polyamine structure of PTMI (PPrOzi–co-L-PTMI copolymer) does not decrease the antimicrobial activity, compared to L–PTMI. The molecule remains active, particularly against Staphylococcus aureus (MIC = 4 μg/mL). At the same time, the presence of amide r.u. reduces toxicity. The highest observable selectivity index can reach values as high as 20 (PPrOzi40%–co-L-PTMI60%).

Asymmetric Cyanation of α-Ketimino Ester Derivatives with Chiral Ru-Li Combined Catalysts.

Asymmetric cyanation of α-ketimino esters catalyzed by combined systems of amino acid/BINAP derivative/Ru(II) complexes and lithium compounds was examined. The use of an appropriate combination of amino acid and BINAP ligands achieved high enantioselectivity for a variety of α-alkynyl (Val/XylBINAP/Ru), α-alkenyl (Val/TolBINAP/Ru), and α-aryl imino esters (Val/XylBINAP/Ru) as well as an isatin-derived cyclic imino amide (t-Leu/BINAP/Ru) to afford the α-cyano-α-amino esters and the amide with an α-nitrogen-substituted quaternary chiral center with up to 98% ee.

Synthesis, Reactivity and Application of Vinyl Sulfoximines and Vinyl Aminosulfoxonium Salts

AbstractThe combination of a sulfonimidoyl and aminosulfoxonium group with a double bond renders vinyl sulfoximines and vinyl aminosulfoxonium salts particularly versatile classes of compounds in organic synthesis. The discussion of vinyl sulfoximines includes in addition to the synthesis, the Michael reaction and its application in asymmetric synthesis, the synthesis, structure and application of α‐lithiovinyl sulfoximines, the nickel‐catalyzed and copper‐mediated anionic cross‐coupling reaction of α‐metallovinyl sulfoximines, the synthesis of acyclic and cyclic dienyl vinyl sulfoximines and the ring‐closing metathesis, the hydroalumination and reductive Pauson‐Khand reaction, the nickel‐catalyzed cross‐coupling reaction, the vinyl‐allyl isomerization, the cycloaddition, and the cyclization. The discussion of vinyl aminosulfoxonium salts includes in addition to the synthesis, the Michael reaction, the ethylenation of protic nucleophiles, the synthesis of allyl aminosulfoxonium salts and the nucleophilic substitution, the synthesis of allyl aminosulfoxonium ylides and the imino ester aziridination, the synthesis of vinyl aminosulfoxonium ylides, the synthesis of alkynes and dihydrofurans, the nickel‐catalyzed cross‐coupling reaction, and the intramolecular substitution of the amino group.

Phosphine Catalyzed Michael-Type Additions: The Synthesis of Glutamic Acid Derivatives from Arylidene-α-amino Esters.

The reaction of arylidene-α-amino esters with electrophilic alkenes to yield Michael-type addition compounds is optimized using several phosphines as organocatalysts. The transformation is very complicated due to the generation of several final compounds, including those derived from the 1,3-dipolar cycloadditions. For this reason, the selection of the reaction conditions is a very complex task and the slow addition of the acrylic system is very important to complete the process. The study of the variation in the structural components of the starting imino ester is performed as well as the expansion of other electron-poor alkenes. The crude products have a purity higher than 90% in most cases without any purification. A plausible mechanism is detailed based on the bibliography and the experimental results. The synthesis of pyroglutamate entities, after the reduction of the imino group and cyclization, is performed in high yields. In addition, the hydrolysis of the imino group, under acidic media, represents a direct access to glutamate surrogates.

Synthesis of Spirocyclic Pyrrolidine Compounds via Silver-Catalyzed Asymmetric [3 + 2] Cycloaddition Reaction of Imino Esters with α-Alkylidene Succinimides.

In this study, the AgOAc/ThioClickFerrophos (TCF) complex was used to successfully catalyze asymmetric [3 + 2] cycloaddition between glycine imino esters and CO2Me-appended α-alkylidene succinimides to afford spiropyrrolidines in good yields with high diastereo- and enantioselectivities (up to 95% ee). The silver/TCF afforded endo-(2,5-cis) cycloadducts in contrast to the previous exo'-(2,5-trans) selective reaction with ylidene-2,3-dioxopyrrolidine. A wide variety of imino esters bearing electron-donating and electron-withdrawing groups on the phenyl groups and heteroaryl substrates were utilized in this reaction. The scope of α-alkylidene succinimides was investigated, which revealed that substituents on α-benzylidene derivatives had negligible effect on the product yield and stereoselectivity, and α-alkylidene derivatives could be efficiently used as dipolarophiles.

Preparation of a ruthenium complex covalently bonded to multilayer graphene and its evaluation as a photocatalyst.

Multilayer graphene (MLG), obtained by mild sonication of graphite in NMP, was functionalised via 1,3-dipolar cycloaddition with azomethine ylides generated by thermal 1,2-prototropy from various imino esters. The microwave-assisted functionalisation took place in five hours at 100 °C. The resulting MLG, containing substituted proline-based amine functional groups, was characterized using XPS and showed a nitrogen loading three times that obtained for the same transformation performed for five days using convection-assisted heating. The preparation of the imino ester containing a bipyridine unit at the arylidene position allowed for the preparation of the corresponding functionalised MLG, which incorporated the ruthenium atom to achieve a heterogeneous MLG-Ru complex. This supported complex was tested, as a proof of concept, as a photocatalyst of the aerobic oxidative hydroxylation of 4-methoxyphenylboronic acid.

Comparison of the hydrophilicity of water-soluble poly(2-alkyl-2-oxazoline)s, poly(2-alkyl-2-oxazine)s and poly(2,4-dialkyl-2-oxazoline)s

The hydrophilicity of a series of water-soluble poly(cyclic imino ether)s (PCIE) was systemically ranked to enable informed decision-making about the choice of PCIE for specific applications in the future.

H2O/D2O as the only H/D source for photocatalytic phosphine-mediated radical transfer hydrogenation/deuteration of α-aryl imino esters

A method for the transfer hydrogenation of α-aryl imino esters using photocatalytic water as the sole hydrogen source has been developed. The substrate is wildely applicable and the yield is up to 99%.

Influence of polymer amphiphilicity on the cyclization efficiency of poly(2-oxazoline)s

The steadily increasing interest in cyclic polymers has led to a plethora of proposed applications, particularly as biomaterials. However, the large-scale synthesis of cyclic polymers remains one of the greatest challenges in the field. One reason for this is the poorly understood role of the polymer structure on the cyclization efficiency, leading to synthesis protocols that must be optimized on a case-by-case basis without consideration for the chemical nature of the polymer. Recently, we found through a combination of laboratory experiments and molecular dynamics simulations that the polymer backbone flexibility has a major influence on the cyclization efficiency of poly(cyclic imino ether)s. Concurrently, we identified that a more flexible polymer backbone was also better solvated in the given organic solvent. To deconvolute the importance of the polymer backbone flexibility and solvation, in this study a variety of α-alkyne, ω-azide terminated (co)polymers of 2-ethyl-2-oxazoline and 2–n-butyl-2-oxazoline with different amphiphilicities, but the same polymer backbone, have been synthesized and subjected to copper-catalysed azide-alkyne cycloaddition (CuAAC) reactions in water. In agreement with our previous studies, it was observed that an increase in polymer chain hydrophobicity, and hence a decrease in solvation, leads to a significant decrease in cyclization efficiency. To further understand the effect of different CuAAC reaction conditions on the reaction outcome, different polymer concentrations and reaction temperatures were screened. This study highlights the importance of polymer amphiphilicity, and more generally solvation, in CuAAC protocols aimed towards the synthesis of cyclic polymers.

Microwave-Assisted Functionalization of Single-Walled Carbon Nanotubes as a Platform for a Supported Iridium Catalyst

AbstractSingle-walled carbon nanotubes (SWCNTs) were functionalized by treatment with imino esters through 1,3-dipolar cycloaddition activated by thermal 1,2-prototropy. The reaction was optimized and analyzed by using various heating methods. The functionalization afforded pyrrolidino-functionalized nanotubes that were characterized by using several techniques. The ester group was then transformed into the corresponding SWCNT–iridium carboxylate and, as a proof of concept, the product was tested as a catalyst in the hydrogen-transfer reaction of acetophenone to yield 1-phenylethanol.

Enantio- and Diastereoselective Copper-Catalyzed Synthesis of Chiral Aziridines with Vicinal Tetrasubstituted Stereocenters.

A Cu-catalyzed coupling of cyclic imino esters with 2H-azirines has been developed to synthesize novel optically active aziridines in high yields with excellent levels of diastereo- and enantioselectivities under mild conditions. This novel protocol features a broad substrate scope and good functional group compatibility, and it enriches the existing reaction type of rapid synthesis of optically active aziridines bearing vicinal tetrasubstituted stereogenic carbon centers.

Syntheses of diaza[1.1.1] and [1.1.1.1] paracyclophanes by smiles rearrangement

Highly strained diaza[1.1.1] and [1.1.1.1]paracyclophanes were synthesized using Smiles rearrangement (paracyclophane is hereafter abbreviated as PCP). Smiles rearrangement allowed the synthesis of compounds with bridging groups, which could not be obtained using the previously reported Chapman rearrangement method. The two synthetic methods are complementary to each other and therefore useful for the synthesis of diaza[1n]PCP. However, in Chapman rearrangement, the diaza[1.1.1]PCP precursor is a rigid molecule and the precursor could not be synthesized. In contrast, the Smiles rearrangement uses a PCP-precursor rearrangement with low distortion; thus, [1.1.1]PCP can be obtained. Furthermore, the syntheses of 1a and 2 can be performed on a gram scale. However, due to their low solubility, the molecular structure could not be confirmed by crystallographic analysis; therefore, these structures were optimized by DFT calculations and discussed.

Copper-catalyzed enantioselective fluoroalkenylation of cyclic imino esters

A copper-catalyzed enantioselective fluoroalkenylation of cyclic imino esters was developed. Using this protocol, tetrasubstituted monofluoroalkenes bearing a quaternary center were afforded in good yields with high E/Z-selectivities and excellent enantioselectivities.

Organocatalytic synthesis of axially chiral tetrasubstituted allenes.

Asymmetric organocatalysis is a growing method for the synthesis of axially chiral tetrasubstituted allenes, the most challenging one among allene syntheses. In this method, chiral organocatalysts such as phase-transfer catalysts, peptides, disulfonimides, and binaphthyl/bispiro phosphoric acids have displayed remote control of regio- and stereoselectivity. Highly functionalized enantiopure allenes including those with an adjacent tertiary or quaternary stereocenter have been efficiently prepared with high levels of regio-, diastereo-, and enantioselectivity using this method. Several mechanistic pathways, including electrophilic addition to cumulenolate or zwitterionic enolate intermediates, alkynylogous Mukaiyama aldol reaction, nucleophilic addition to quinone methides, and dearomative addition to imino esters, were proposed. The method is necessary for providing access to axially chiral tetrasubstituted allenes, which can be utilized for the preparation of novel ligands, natural products, and organic materials, particularly those having complex structures. This review covers the enantioselective organocatalytic synthesis of these tetrasubstituted allenes and the mechanistic insights into the formation of the chiral axis up to July 2022.

Probing the Biocompatibility and Immune Cell Association of Chiral, Water-Soluble, Bottlebrush Poly(2-oxazoline)s.

Poly(2-oxazoline)s (POx) have received substantial attention as poly(ethylene glycol) (PEG) alternatives in the biomedical field due to their biocompatibility, high functionality, and ease of synthesis. While POx have demonstrated strong potential as biomaterial constituents, the larger family of poly(cyclic imino ether)s (PCIE) to which POx belongs remains widely underexplored. One highly interesting sub-class of PCIE is poly(2,4-disubstituted-2-oxazoline)s (PdOx), which bear an additional substituent on the backbone of the polymers' repeating units. This allows fine-tuning of the hydrophilic/hydrophobic balance and renders the PdOx chiral when enantiopure 2-oxazoline monomers are used. Herein, we synthesize new water-soluble (R-/S-/RS-) poly(oligo(2-ethyl-4-methyl-2-oxazoline) methacrylate) (P(OEtMeOxMA)) bottlebrushes and compare them to well-established PEtOx- and PEG-based bottlebrush controls in terms of their physical properties, hydrophilicity, and biological behavior. We reveal that the P(OEtMeOxMA) bottlebrushes show a lower critical solution temperature behavior at a physiologically relevant temperature (∼44 °C) and that the enantiopure (R-/S-) variants display a chiral secondary structure. Importantly, we demonstrate the biocompatibility of the chiral P(OEtMeOxMA) bottlebrushes through cellular association and mouse biodistribution studies and show that these systems display higher immune cell association and organ accumulation than the two control polymers. These novel materials possess properties that hold promise for applications in the field of nanomedicine and may be beneficial carriers for therapeutics that require enhanced cellular association and immune cell interaction.