Nucleophilic Addition Research Articles

Conformational Landscape of α-Halopropiophenones Determined by nJC-H NMR Reveals Unexpected Patterns and Geometric Constraints.

The conformational features of α-halopropiophenones were investigated to understand the influence of α-halogens on conformation through hyperconjugative interactions, electrostatics, and steric factors. Using NMR, C-H scalar coupling constants were measured in different solvents, revealing a pattern in the conformational equilibria, which we validated by computational means. This behavior arises largely from hyperconjugative effects with the exception of the fluoro-derivatives, which are also influenced by steric and electrostatic interactions. In all cases, the contribution to hyperconjugation of the α-halo ketones is driven by the oxygen lone pair (rather than the C-X bond), which donates electron density to the adjacent C-C bonds. Additionally, C-Cα bond rotation generates distortions in the side chain, responsible for destabilization, thus affecting system conjugation. These structural features identified for the α-halo ketones are also reflected in their reactivity, which is distinct from that expected for nucleophilic addition.

Nucleophiles realizing the reduction of ZnO content for vulcanization accompanied by the improvement in thermo‐oxidative resistance for vulcanized isoprene rubbers

AbstractAt present, vulcanization is an indispensable process in rubber industries and ZnO is an important ingredient in vulcanization reactions. However, ZnO is toxic to aquatic organisms and the use of ZnO is unfavorable to the sustainable development of rubber industry. The decrease of ZnO content without the reduction in properties of rubbers has been an open question in rubber industries. In this work, our group designs nucleophiles with an ability to open the ring of sulfur. With the decrease of ZnO content, the addition of nucleophiles maintains the ring‐opening capacity of sulfur. As a result, changes in several properties of rubbers such as tensile strength, tear strength, and crosslinking density are negligible with the reduction of ZnO content. Also, the thermo‐oxidative resistance of rubbers improves dramatically with the decrease of ZnO content and addition of nucleophiles. Through designing nucleophiles to reduce the content of ZnO, this work provides a strategy to develop sustainable rubber industries.

Electrochemical Lactonization Enabled by Unusual Shono-Type Oxidation from Functionalized Benzoic Acids.

A novel method for electrochemical lactonization via C(sp3)-H functionalization was developed. This metal- and oxidant-free strategy enabled the efficient synthesis of various lactones. Gram-scale reaction and derivatization of the lactone product demonstrated the synthetic utility of this methodology. Mechanistic studies using control experiments and CV curves elucidated the proposed intramolecular HAT and the oxidative cyclization pathway. An unusual Shono-type oxidation was realized through this electrochemical approach, proceeding without a traditional nucleophilic addition process.

Stereochemical Aspects of the C-Glycosylation of Pyranosides and Furanosides

AbstractThe stereoselective synthesis of α- and β-C-glycosides is one of the most challenging areas of research in the field of glycoside chemistry. In this review, we summarize the various methods available for stereocontrolled glycosylation and also discuss the predictive models available to explain the stereochemical outcome of six- and five-membered-ring oxocarbenium ions with allyltrimethylsilane nucleophile under Lewis acid conditions.1 Introduction2 Stereochemical Aspects during Glycoside Bond Formation in Pyranosides2.1 Lewis Acid Mediated Nucleophilic Addition to Six-Membered-Ring Oxocarbenium Ions2.2 Arylalane Addition to Anhydroglucose2.3 Glucal Epoxide Method2.4 Glycosyl Leaving Group Substitution Method2.5 Glycosylation via Transition-Metal-Mediated Cross-Coupling3 Stereochemical Aspects during Glycoside Bond Formation in Furanosides­3.1 Lewis Acid Mediated Nucleophilic Addition to Five-Membered-Ring Oxocarbenium Ions4 Summary and Conclusion

Understanding selectivity of nucleophilic addition to β-formyl-α-haloenoates: A synthetic and theoretical investigation

The reactions of β-formyl-α-haloenoates with nitrogen-centered nucleophiles are described. DFT calculations have been used to better understand what factors influence and determine the chemo- and regioselectivity of the nucleophilic addition of amines to such systems. The easy synthetic approaches to the functionally substituted enoate derivatives including tertiary dehydroamino acid esters and furan-2(5H)-ones provides highlight of this work.

Facile Synthesis of Quinoline-Substituted 3-Hydroxy-2-oxindoles and 3-Amino-2-oxindoles via a Palladium-Catalyzed Cascade Intramolecular Cyclization/Intermolecular Nucleophilic Addition Reaction.

An efficient cascade intramolecular cyclization/intermolecular nucleophilic addition reaction of allenyl benzoxazinone with isatin or isatin-derived ketimine has been established by using Pd0-π-Lewis base catalysis. A series of 3-hydroxy-2-oxindoles and 3-amino-2-oxindoles with quaternary carbon atoms at the C3 position were synthesized in good yields under mild conditions through this protocol.

Eu(OTf)3‐Catalyzed Formal Dipolar [4π+2σ] Cycloaddition of Bicyclo‐[1.1.0]butanes with Nitrones: Access to Polysubstituted 2‐Oxa‐3‐azabicyclo[3.1.1]heptanes

AbstractHerein, we have synthesized multifunctionalized 2‐oxa‐3‐azabicyclo[3.1.1]heptanes, which are considered potential bioisosteres for meta‐substituted arenes, through Eu(OTf)3‐catalyzed formal dipolar [4π+2σ] cycloaddition of bicyclo[1.1.0]butanes with nitrones. This methodology represents the initial instance of fabricating bicyclo[3.1.1]heptanes adorned with multiple heteroatoms. The protocol exhibits both mild reaction conditions and a good tolerance for various functional groups. Computational density functional theory calculations support that the reaction mechanism likely involves a nucleophilic addition of nitrones to bicyclo[1.1.0]butanes, succeeded by an intramolecular cyclization. The synthetic utility of this novel protocol has been demonstrated in the concise synthesis of the analogue of Rupatadine.

Aggregation-induced emission activity of sensor TBM-C1 hybrid of methoxy-triphenylamine (OMe-TPA) and dicyanovinyl for cyanide detection in aqueous THF: Mechanistic insights and potential applications

A series fluorescent probes (TBM-Cx (x = 1, 4, 8)) were designed based on embedding various alkoxy chains on the electron donor of triphenylamine (TPA)-based dicyanovinyl (MT) compound with an electron-deficient benzothiadiazole (BTD) for sensitive, selective, and visualizing detection of cyanide in aqueous solution. Due to the nucleophilic addition of CN−, the intramolecular charge transfer (ICT) of these probes was inhibited by the destroyed conjugated structure, exhibiting excellent “turn-on” fluorescence response toward cyanide anion (CN−) in tetrahydrofuran (THF). However, the alkoxy chains with different lengths embedded in TPA not only enhance the sensitivity and solubility, but also regulate the emission behavior from ICT to aggregation-induced emission (AIE) characteristics. The binding mechanism and AIE sensing performances between the probes and CN− have been investigated and compared in THF/water mixture by spectral tools and theoretical calculations. The results showed that the ICT-based TBM-C1 probe with methoxy chain showed significantly turn-on fluorescence response to CN− as low as 0.077 μM in THF/water solution at high water fraction (90 %). Due to the AIE sensing process, TBM-C1 was successfully employed to determine CN− in food and water samples, image CN− in living cells and BALB/c mice, and prepare test kits for visualizing cyanide.

Eu(OTf)3 -Catalyzed Formal Dipolar [4π+2σ] Cycloaddition of Bicyclo-[1.1.0]butanes with Nitrones: Access to Polysubstituted 2-Oxa-3-azabicyclo[3.1.1]heptanes.

Herein, we have synthesized multifunctionalized 2-oxa-3-azabicyclo[3.1.1]heptanes, which are considered potential bioisosteres for meta-substituted arenes, through Eu(OTf)3 -catalyzed formal dipolar [4π+2σ] cycloaddition of bicyclo[1.1.0]butanes with nitrones. This methodology represents the initial instance of fabricating bicyclo[3.1.1]heptanes adorned with multiple heteroatoms. The protocol exhibits both mild reaction conditions and a good tolerance for various functional groups. Computational density functional theory calculations support that the reaction mechanism likely involves a nucleophilic addition of nitrones to bicyclo[1.1.0]butanes, succeeded by an intramolecular cyclization. The synthetic utility of this novel protocol has been demonstrated in the concise synthesis of the analogue of Rupatadine.

Microwave-Mediated, Catalyst-Free Synthesis of 1,2,4-Triazolo[1,5-a]pyridines from Enaminonitriles.

A catalyst-free, additive-free, and eco-friendly method for synthesizing 1,2,4-triazolo[1,5-a]pyridines under microwave conditions has been established. This tandem reaction involves the use of enaminonitriles and benzohydrazides, a transamidation mechanism followed by nucleophilic addition with nitrile, and subsequent condensation to yield the target compound in a short reaction time. The methodology demonstrates a broad substrate scope and good functional group tolerance, resulting in the formation of products in good-to-excellent yields. Furthermore, the scale-up reaction and late-stage functionalization of triazolo pyridine further demonstrate its synthetic utility. A plausible reaction pathway, based on our findings, has been proposed.

Exploring alkyl-diamine chain length effects on electrochemical behavior of AuNPs fabricated electrodes: Influence of linkers on the sensitive detection of hydrazine

In this electrochemical exploration, we scrutinized the influence of alkyl-diamine (AD) chain length as crucial linkers between glassy carbon electrodes (GCE) and citrate-capped gold nanoparticles (Cit-AuNPs), focusing on their conductive behavior and sensing proficiency, particularly in hydrazine detection. Meticulous examination of self-assembled monolayers (SAMs) formed by three distinct ADs, namely 1,6-hexanediamine (HDA), 1,8-octanediamine (ODA) and 1,10-decanediamine (DDA) unfolded over GC surfaces revealed a precise adherence to Langmuir adsorption kinetics during the SAM formation process. Utilizing cyclic voltammetry (CV) and electrochemical impedance spectroscopy (EIS), the electrochemical activity of the [Ru(NH₃)₆]³⁺/²⁺ redox pair at electrodes modified with ADs was investigated. The proposed mechanism involves a Michael-like nucleophilic addition process at the GC surface/diamine solution interface during the SAM formation. Analysis across various techniques underscored the compact nature of the DDA-formed SAM in comparison to HDA and ODA. Exploiting the free amine functional groups on the SAMs, the as-synthesized Cit-AuNPs were attached on the electrode surface and investigated comprehensively through CV, EIS, attenuated total reflection Fourier-transform infrared spectroscopy, X-ray photoelectron spectroscopy, and scanning electron microscopy. Remarkably, Cit-AuNPs attached DDA-SAM/GC electrode offered superior electro active surface area, establishing an advanced electrochemical platform for carcinogenic hydrazine determination. The DDA/Cit-AuNPs electrode demonstrated a linear determination range of 0.003–1 mM, limits of detection at 11 nM, and sensitivity of 1080 µA mM−1 cm−2. This study gives a complete picture of how AD chain lengths, SAM formation, Cit-AuNPs attachment, and electrocatalytic performance work together to make an advanced electrochemical sensing scaffold for environmental pollutants determination.

Tungsten-anisole complex provides 3,6-substituted cyclohexenes for highly diversified chemical libraries.

Medicinal chemists use vast combinatorial molecular libraries to develop leads for new pharmaceuticals. The syntheses of these compounds typically rely on coupling molecular fragments through atoms with planar (sp2) geometry. These so-called flat molecules often lack the protein binding site specificity needed to be an effective drug. Here, we demonstrate a coupling strategy in which a cyclohexene is used as a linker to connect two diverse molecular fragments while forming two new tetrahedral (sp3) stereocenters. These connections are made with the aid of a tungsten complex that activates anisole toward an unusual double protonation, followed by sequential nucleophilic additions. As a result, either cis- or trans-disubstituted cyclohexenes can be prepared with a range of chemical diversity unparalleled by other dearomatization methods.

Synthesis of Benzo[c]cinnolinium Salts from 2-Azobiaryls by Copper(II) or Electrochemical Oxidation.

Synthesis of benzo[c]cinnolinium salts by copper(II)-promoted or electrochemical oxidation of 2-azobiaryls is described. A variety of diversely functionalized benzo[c]cinnolinium salts were easily constructed by this strategy with excellent functional group tolerance and high efficiency. An interesting fluorescence centered at 571 nm is revealed by a benzo[c]cinnolinium salt with electron push-pull substitutions. The mechanism is proposed to go through single-electron transfer driven by oxidant and intramolecular cyclization via nucleophilic addition, followed by an anion exchange.

Synthesis of Functionalized Tetrasubstituted Allenes by the Addition of Bis(trimethylsilyl)ketene Acetals to Ynones Catalyzed by Gold(I).

We have developed a straightforward and rapid methodology for the synthesis of tetrasubstituted allenes bearing carboxylic acids in the 1,3-position through the gold(I)-catalyzed nucleophilic addition of bis(trimethylsilyl)ketene acetals to ynones. The reaction was evaluated with several substrates, and 21 allenes were obtained in moderate to good yields. Using DFT calculations, we studied the mechanism of the reaction, which suggested a nucleophilic 1,4-addition pathway. The potential of allenes to act as a source of highly functionalized lactones was also explored.

Total Synthesis of Racemic Benzomalvin E, a Quinazolinone Isolated from Pencilium sp. FN070315 and Exploration to the Direct Synthesis of (E)-Benzomalvin B.

We present the first total synthesis of (±) benzomalvin E, featuring a quinazolino moiety with a 6-6-6-7-fused tetracyclic skeleton containing three nitrogen atoms. The key transformation involves Cu-catalyzed intramolecular C-N arylation of quinazolinone, leading to a sclerotigenin analogue that undergoes nucleophilic addition with benzaldehyde, enabling the synthesis of (±) benzomalvin E in six linear steps with a 33% overall yield. The (±) benzomalvin E's structure was validated by 2-D NMR and single crystal XRD analysis and was further transformed into (E)-benzomalvin B.

Copper-Catalyzed Direct Asymmetric Vinylogous Mannich Reaction between β,γ-Alkynyl-α-ketimino Esters and β,γ-Unsaturated N-Acylpyrazoles.

We report a Cu(I)-Ph-BPE-catalyzed asymmetric vinylogous Mannich reaction of β,γ-alkynyl-α-ketimino esters with β,γ-unsaturated N-acylpyrazoles. In this process, the Cu(I)-Ph-BPE catalyst activates the β,γ-alkynyl-α-ketimino ester through N,O-coordination, enabling the subsequent nucleophilic addition of a dienolate generated from the β,γ-unsaturated N-acylpyrazole via α-position deprotonation with a catalytic amount of tertiary amine. The reactions gave useful products with very high enantioselectivities. A broad range of substrates with various substituents are tolerated in this reaction. The versatility of this method was demonstrated by a gram-scale reaction, and subsequent elaboration of the Mannich adducts was also provided.

Dihydro-10H-indeno[1,2-b]benzofurans and Tetrahydroindeno[1,2-c]isochromenes via Stereoselective Intramolecular Carbocation Cascade Cyclization.

Nazarov cyclization of the (E)-(2-stilbenyl)methanols under the catalysis of p-TsOH immobilized on silica (PTS-Si) proceeded to give the corresponding indanyl cation with the exclusive trans relationship at the two newly formed adjacent stereogenic centers. The ensuing intramolecular nucleophilic addition by the MOM-protected phenol (m = 0) or benzyl alcohol (m = 1) furnished the Indane-fused benzofuran [5/5] or isochroman [5/6] system, respectively, with the exclusive cis stereocontrol at the two-carbon ring junction. Thus, in a single step, from nonchiral starting materials, the intramolecular cascade carbocation cyclization (CCC) furnished the [5/5] or [5/6] oxygen-containing Indane fused-ring systems in moderate to good yields with excellent stereoselectivity on all three contiguous stereogenic centers.

Iodine‐Catalyzed Cascade Reaction of 2‐Styrylbenzaldehydes with Indoles in the Synthesis of 1H‐Indenes via 4π‐Electrocyclization

AbstractA cascade reaction between 2‐styrylbenzaldehydes and indoles has been developed for the synthesis of 1H‐indenes. An iodine‐catalyzed nucleophilic addition of indoles to an aldehyde group of 2‐styrylbenzaldehydes leads to the formation of carbocation intermediates that undergo 4π‐electrocyclization to give indenes with a trisubstituted double bond. These indenes are transformed into thermodynamically more stable products with a fully substituted double bond under the reaction conditions. Minor quantities of indolylbenzo[b]carbazoles are also produced as by‐products.

The synthesis of biphenyl ether/vanillin‐based flame retardants for enhancing both the flame retardant properties and mechanical performance of epoxy resin

AbstractImparting good flame retardancy and mechanical properties to epoxy resin (EP), while pursuing the sustainable and safe application of EP, we synthesized a novel reactive phosphorus/nitrogen flame retardant for biomass through nucleophilic addition reaction, which contains flexible ether bonds and rigid aromatic ring structure (DVD). Owing to the cooperative effect of aryl ether diamine, phosphorus phenanthrene, and biomass vanillin, the DVD exhibited excellent flame retardancy. EP/DVD‐1 (0.4 wt% phosphorus content) achieved UL‐94 V‐0 rating, with an improvement in limiting oxygen index value from 26.5% (pure EP) to 32.5%. In the CCT, the modified DVD EP showed a 44.5% reduction in peak peak of heat release rate (PHRR) and a 38.0% reduction in total heat release compared to pure EPs. And flame retardant epoxy resin (FREP) still had good transparency after the addition of DVD, which indicated the nice compatibility between DVD andEP. What was noteworthiness was that at high levels of addition, the mechanical properties of modified EP for DVD was still improved compared to pure EP. These results demonstrate that DVD is an excellent and multifunctional bio‐based flame retardant with broad application prospects in the field of EP material modification.

Deep Eutectic Solvents as Catalysts in the Synthesis of Active Pharmaceutical Ingredients and Precursors

Deep Eutectic Solvents (DESs) have appeared in recent years as an appealing alternative to classical organic solvents, due to their valuable environmental properties. In addition, these compounds, formed by the combination of one hydrogen bond donor with a hydrogen bond acceptor at a defined stoichiometric ratio, present other valuable activities not only as a reaction medium. DESs can also be employed as catalysts through hydrogen-bond interactions in different chemical transformations, thus substituting hazardous reagents and solvents. The search for novel and more environmentally friendly catalysts is an area of interest of pharmaceutical chemists, and therefore, the efforts made in the application of DESs as catalysts in the synthesis of APIs or its precursors are described, focusing mainly on condensations, nucleophilic additions to carbonyl moieties, and multicomponent reactions.