Nucleophilic Ring Opening Research Articles

Accessing Azetidines through Magnesium‐Mediated Nitrogen Group Transfer from Iminoiodinane to Donor‐Acceptor Cyclopropanes

Herein, we report a Lewis acid‐mediated ring expansion of donor‐acceptor cyclopropanes (DACs) to substituted azetidines via nucleophilic nitrogen group transfer from readily accessible iminoiodinane. This protocol operates under mild, transition‐metal‐free conditions, and showcases excellent chemoselectivity, along with broad functional group tolerance. We report for the first time that challenging alkyl donor‐acceptor cyclopropanes can undergo ring expansion leading to aliphatic azetidines without relying on external oxidants or precious transition‐metal catalysts. Mechanistically, the coordination of a magnesium (Mg)‐Lewis acid to the DAC promotes nucleophilic ring opening with a putative Mg‐amide species generated from the iminoiodinane under the reaction conditions to furnish the azetidine products.

Accessing Azetidines through Magnesium-Mediated Nitrogen GroupTransfer from Iminoiodinane to Donor-Acceptor Cyclopropanes.

Herein, we report a Lewis acid-mediated ring expansion of donor-acceptor cyclopropanes (DACs) to substituted azetidines via nucleophilic nitrogen grouptransfer from readily accessible iminoiodinane. This protocol operates under mild, transition-metal-free conditions, and showcases excellent chemoselectivity, along with broad functional group tolerance. We report for the first time that challenging alkyl donor-acceptor cyclopropanes can undergo ring expansion leading to aliphatic azetidines without relying on external oxidants or precious transition-metal catalysts. Mechanistically, the coordination of a magnesium (Mg)-Lewis acid to the DAC promotes nucleophilic ring opening with a putative Mg-amide species generated from the iminoiodinane under the reaction conditions to furnish the azetidine products.

1,4‐Dioxane as Precursor of −CH2CH2−: A Simple and Convenient Strategy to Synthesize 1,2‐Disulfide Substituted Ethanes Initiated by Iodine

AbstractAn unprecedented I2‐initiated nucleophilic ring opening reaction of 1,4‐dioxane with thiols for the construction of various 1,2‐disulfide substituted ethanes has been developed. Previously, dihalogenated ethane, acetylene or ethylene are often used as the pre‐cursor of −CH2CH2−. Through the cleavage of two C−O bonds, 1,4‐dioxane as precursor of −CH2CH2− has been achieved for the first time. In the presence of HI, thiols could be replaced by disulfides as nucleophile. This protocol is very convenient and practical by its simple and mild conditions.

Efforts toward the Total Synthesis of Thuggacin A.

Thuggacin A (1) is a 17-membered-ring-polyketide antibiotic compound with excellent antituberculosis activity. The total synthesis of thuggacin A has not yet been reported so far. Herein, we disclose our efforts toward the convergent total synthesis of thuggacin A. The key synthetic features include our own one-pot cascade thiazole formation, Evans syn-aldol, Mukaiyama asymmetric aldol reaction, organosilicon-promoted selective alkyne reduction, Shiina macrolactonization, and a nucleophilic ring-opening of epoxide with alkyne to assemble the main framework of thuggacin A. The enantioselective synthesis of trimethylsilyl ethoxymethyl (SEM) derived thuggacin A analogue 2 was achieved in 18 longest linear steps with 2.0% overall yield, and the bioassay of 2 exhibited moderate antituberculosis activity with minimum inhibitory concentration (MIC) of 320 μg/mL.

Reversible Nucleophilic Ring-Opening of Tetraoxapentacene Derivatives: Accessing New Materials for Thermally Activated Delayed Fluorescence.

We report the unexpected nucleophilic ring-opening reaction of electron deficient dioxins in the presence of carbazole under basic conditions. This nucleophilic ring-opening reaction is reversible under basic conditions in the absence of nucleophiles. Further, we demonstrate that this unexpected reactivity can be used to prepare novel donor-acceptor compounds that are emissive in solution and as thin films and exhibit thermally activated delayed fluorescence (TADF).

Photocatalytic Regioselective Redox-Neutral 1,3-Oxypyridylation of Aryl Cyclopropanes.

Pyridines and cyclopropanes are important structural units in chemistry. Herein, we introduce a photoredox-catalyzed approach for the ring opening and 1,3-oxypyridylation of aryl cyclopropanes using 4-cyanopyridines and carboxylic acids. This sequential process involves single-electron oxidation of the aryl cyclopropane, leading to nucleophilic ring opening and radical pyridylation at the benzylic position. The redox-neutral reaction exhibits high regioselectivity under mild reaction conditions, offering a broad substrate scope and wide applicability.

Controlling the position of the nucleophilic ring-opening of 2-EWG-substituted azetidinium salts with fluoride by the N-1-(1-naphthyl)ethyl substituent and BINAM-derived bis-urea organocatalyst

BINAM (1,1′-binaphthyl-2,2′-diamine)-derived bis-urea-catalyzed nucleophilic ring-opening of optically active and diastereomerically pure 2-EWG (electron-withdrawing group)-substituted N-(1-(1-naphthyl)ethyl)azetidinium salts with cesium fluoride in dichloromethane at room temperature proceeds at the less sterically hindered 4-position over the electronically deficient 2-position. Selective ring-opening at the 4-position is achieved by the combination of chiral stereocenters, as in N-(1-(1-naphthyl)ethyl)azetidinium salt, and steric bulk of the chiral bis-urea catalysts. The reaction affords the corresponding γ-fluoro-α-aminobutyric acid derivatives in diastereomerically pure. This protocol is applicable to the synthesis of enantiomerically enriched (98 % ee) γ-fluoro-α-amino acid derivatives starting from the commercially available chiral 1-(1-naphthyl)ethylamine.

Magic Blue-Initiated SN2-Type Ring Opening of Activated Aziridines: Friedel-Crafts-Type Alkylation of Electron-Rich Arenes/Heteroarenes.

A transition metal-free, atom-economical, and highly stereospecific synthetic approach to Friedel-Crafts-type alkylation of arenes/heteroarenes has been developed. The protocol involves the catalytic aminium radical-cation salt (Magic Blue)-initiated SN2-type nucleophilic ring opening of activated aziridines with arenes/heteroarenes to give the corresponding 2,2-diarylethylamines up to 99% yield and 85% ee (for nonracemic aziridines) in a very short reaction time. Moreover, on reaction with 1,3-dimethylindole and benzofuran, aziridines undergo domino-ring-opening cyclization (DROC) to give the various biologically significant heterocyclic scaffolds in moderate to good yields.

Rapidly Diverse Synthesis of N‐Aryl‐5‐Substituted‐2‐Oxazolidinones via Nucleophilic Epoxide Ring Opening and Intramolecular Acyl Substitution of Epoxy Carbamates

AbstractThe method for converting epoxy carbamates to oxazolidinones is outlined in this study. This innovative approach combines intermolecular nucleophilic epoxide ring opening with intramolecular acyl substitution in a single step, thereby facilitating rapid conversion. Significantly, this method effectively addresses challenges associated with the use of expensive reagents, harsh reaction conditions, and prolonged reaction times, presenting a more efficient alternative. Demonstrating favorable reactivity across a diverse range of aryl groups, as well as benzyl or tert‐butyl carbamates, the method consistently yields satisfactory results, with oxazolidinone formation ranging from 55 % to 99 % in over 24 examples. The synthesized oxazolidinones, including 5 v–5 x, hold substantial promise as intermediates for the synthesis of crucial synthetic molecules. Furthermore, the versatility of this method is underscored by its successful application in the formation of the 6‐membered ring 1,3‐oxazinan‐2‐one. These findings not only contribute to the advancement of synthetic methodologies but also pave the way for a streamlined synthesis of important pharmaceutical compounds.

One-Pot Synthesis of Functionalized Benzotropones via a Phthalide Ring-Opening/Intramolecular Aldol Condensation Cascade.

A one-pot protocol was developed for the synthesis of functionalized benzotropone derivatives via a nucleophilic phthalide ring opening by a 5-lithiated dioxinone derivative, followed by an intramolecular aldol condensation. The method demonstrates exceptional versatility with diverse substrates, yielding a variety of functionalized benzotropones. Subsequent transformations of the obtained benzotropone derivatives were explored for their potential applications.

B2(OH)4-Mediated Reductive Ring-Opening of N-Tosyl Aziridines by Nitroarenes: A Green and Regioselective Access to Vicinal Diamines.

The nucleophilic ring-opening of aziridine derivatives provides an important synthetic tool for the preparation of various β-functionalized amines. Amines as nucleophiles are employed to prepare synthetically useful 1,2-diamines in the presence of various catalysts or activators. Herein, the B2(OH)4-mediated reductive ring-opening transformation of N-tosyl aziridines by nitroarenes was developed. This aqueous protocol employed nitroarenes as cheap and readily available amino sources and proceeds under external catalyst-free conditions. Control experiments and DFT calculations pointed to the in situ reduction of nitroarenes to aryl amines via N-aryl boramidic acid (E) and an SN1-type ring-opening of N-tosylaziridines by the resultant aryl amines with high regioselectivity.

Dual cross‐linking of XNBR latex with epoxy‐functional calcium silicate particles for the production of accelerator‐free medical gloves

AbstractIn this work, an innovative dual cross‐linking strategy for carboxylated nitrile butadiene rubber (XNBR) latex using epoxy‐modified calcium silicate particles is presented. In their role as dual cross‐linker, the particles are able to form covalent bonds (nucleophilic ring opening of epoxy moieties) as well as ionic cross‐links (calcium ions of the inorganic core) across the carboxylic acid groups of the rubber. To characterize the curing efficiency, thin elastomer films are prepared by using a conventional coagulant dipping process and their cross‐link densities, curing kinetics, and tensile properties are investigated as a function of the concentration of the cross‐linker and curing time. The results show that latex films containing 5 phr of epoxy‐functional particles give the highest tensile strength, which is further improved by pre‐vulcanizing the liquid latex compound at 60°C for 30 min. The latex formulations are stable over 3 days and the pre‐cured films exhibit a high resistance against gamma sterilization and subsequent accelerated aging. Moreover, sterile films do not cause any skin irritation or skin sensitization reactions, showing the high potential of epoxy‐functional particles in the production of accelerator‐free hypoallergenic gloves.

Synthesis of Chiral Vicinal Amino Alcohol Derivatives via Lewis Acid‐Catalyzed Asymmetric Ring Opening of Aziridines with Alcohols and Carboxylic Acids

AbstractUnder the catalysis of a Cu(I) or Ag(I) salt with a chiral diphosphine ligand, the enantioselective nucleophilic ring opening of racemic 2‐styrenylaziridines via kinetic resolution or dynamic kinetic asymmetric transformation (DyKAT) and of meso aziridines via desymmetrization with alcohols was realized. The reaction provided a range of chiral vicinal amino ether derivatives in 47%‐98% yields and with 50%–98% ee. The reaction could be extended to aliphatic carboxylic acids as nucleophiles. The synthetic utility was demonstrated in a four‐step formal synthesis of a diastereomer of the antirythmetic agent vernakalant.

Catalytic Aminium Radical-Cation Salt (Magic Blue)-Initiated SN2-Type Nucleophilic Ring-Opening Transformations of Aziridines.

A simple and atom economic protocol for the construction of C-X/C-C bonds via catalytic aminium radical-cation salt (Magic Blue)-initiated SN2-type nucleophilic ring-opening transformations of racemic and nonracemic aziridines with different hetero and carbon nucleophiles to afford various amino ethers, thioethers, and amines in up to 99% yield, and with perfect enantiospecificity for some substrates but reduced ee with others (for nonracemic aziridines), is developed. This aminium radical-cation salt-initiated, SN2-type nucleophilic ring-opening strategy, along with various cyclization protocols, is employed to synthesize various biologically significant compounds.

Substrate Directed Regio‐ and Enantioselective Ring‐Opening of Epoxides and Aziridines

AbstractThe oxirane and aziridine rings are valuable building blocks in modern synthetic chemistry and catalytic asymmetric ring opening reactions of these three membered ring systems have emerged as a powerful chemical tool for the synthesis of natural products and biologically active compounds. In this context, the regioselective ring‐opening of structurally or electronically unbiased epoxides and aziridines is challenging. Recently, metal‐catalyzed substrate directed strategies have successfully applied in the regio‐ and enantioselective ring opening of functionalized epoxy alcohols by the Yamamoto group. Subsequently, our group realized the ring opening reactions of functionalized 2,3‐aziridinyl alcohols with the dinuclear zinc complex. These enantioselective nucleophilic ring opening reactions of functionalized epoxy alcohols and aziridinyl alcohols allow for the facile synthesis of amino alcohol derivatives and the introduction of new concepts in catalysis.

A highly efficient and sustainable catalyst system for terminal epoxy-carboxylic acid ring opening reactions.

The nucleophilic ring opening of epoxides by carboxylic acids is an indispensable transformation for materials science and coating technologies. Due to this industrial significance, improvements in operational energy consumption and catalyst sustainability are highly desirable for this transformation. Herein, an efficient, environmentally benign and non-toxic halide free cooperative catalyst system based on an iron(iii) benzoate complex and guanidinium carbonate is reported. The novel catalyst system shows improved activity over onium halide catalysts under neat conditions and in several solvents, including anisole and nBuOAc. Detailed mechanistic studies using FeCl3/DMAP as a catalyst revealed the importance of a carboxylate bridged cationic trinuclear μ3-oxo iron cluster and guanidinium carbonate or DMAP as a carboxylate reservoir due to its superior activity.

Visible photons for the regioselective nucleophilic ring opening of epoxides

Herein, we introduce a visible-light promoted green, metal-free method for the regioselective nucleophilic ring opening of epoxides by exploiting arylazo sulfones as PhotoAcid Generators (PAGs).

Towards an asymmetric β-selective addition of azlactones to allenoates.

We herein report the asymmetric organocatalytic addition of azlactones to allenoates. Upon using chiral quaternary ammonium salt catalysts, i.e., Maruoka's binaphthyl-based spirocyclic ammonium salts, the addition of various azlactones to allenoates proceeds in a β-selective manner with moderate levels of enantioselectivities (up to 83:17 er). Furthermore, the obtained products can be successfully engaged in nucleophilic ring opening reactions, thus giving highly functionalized α-amino acid derivatives.

Synthesis of alkynyl sulfides via base-promoted nucleophilic ring-opening of α-bromostyrene sulfonium salt.

An efficient method for the synthesis of alkynyl sulfides via a C(sp3)-S bond cleavage of α-bromostyrene sulfonium salts has been developed. This base-promoted nucleophilic ring-opening pathway allows the preparation of diverse alkynyl sulfide compounds using tetramethylene sulfoxide as the sulfur source. The reaction proceeds with good functional group tolerance and could be applied to the late-stage functionalization of bioactive molecules and drugs. Furthermore, the synthetic utility of this method was demonstrated by a one-pot synthesis, scale-up reaction and further modification of various alkynyl sulfide products.

Branched-Selective Cross-Electrophile Coupling of 2-Alkyl Aziridines and (Hetero)aryl Iodides Using Ti/Ni Catalysis.

The arylation of 2-alkyl aziridines by nucleophilic ring-opening or transition-metal-catalyzed cross-coupling enables facile access to biologically relevant β-phenethylamine derivatives. However, both approaches largely favor C-C bond formation at the less-substituted carbon of the aziridine, thus enabling access to only linear products. Consequently, despite the attractive bond disconnection that it poses, the synthesis of branched arylated products from 2-alkyl aziridines has remained inaccessible. Herein, we address this long-standing challenge and report the first branched-selective cross-coupling of 2-alkyl aziridines with aryl iodides. This unique selectivity is enabled by a Ti/Ni dual-catalytic system. We demonstrate the robustness of the method by a twofold approach: an additive screening campaign to probe functional group tolerance and a feature-driven substrate scope to study the effect of the local steric and electronic profile of each coupling partner on reactivity. Furthermore, the diversity of this feature-driven substrate scope enabled the generation of predictive reactivity models that guided mechanistic understanding. Mechanistic studies demonstrated that the branched selectivity arises from a TiIII-induced radical ring-opening of the aziridine.