Nucleophilic Reagents Research Articles

Base-Promoted Coupling of HFIP in Cu-Catalyzed Asymmetric Ring Opening of Cyclic Diaryliodoniums.

We report a Cu-catalyzed asymmetric ring-opening reaction of cyclic diaryliodoniums with 1,1,1,3,3,3-hexafluoroisopropanol (HFIP), enabling the construction of axially chiral biaryl compounds containing HFIP ether. HFIP is highly polar and exceptionally stable; thus, it is commonly used as a solvent due to its poor nucleophilicity. However, its use as a nucleophilic reagent has been rare. In this study, we successfully employed HFIP as a nucleophilic coupling partner in a Cu-catalyzed asymmetric ring-opening experiment of cyclic diaryliodoniums.

Photocatalyzed Aryl C‐H Fluorocarbonylation with CF2Br2

AbstractThe use of abundant and inexpensive fluorine feedstocks to synthesize fluorinated compounds is a promising strategy that has not been extensively investigated. Dibromodifluoromethane (CF2Br2) is an inexpensive fluorine source that has rarely been used for C−H fluoroalkylation. This study reveals an iridium‐catalyzed, tunable strategy for synthesizing acyl fluorides and difluorobromomethylated products using CF2Br2. To achieve the desired products, this process only requires the change of solvent (from DMSO to 1,4‐dioxane) under blue LED illumination. A variety of arenes and heteroarenes with electron‐donating substituents were successfully used, yielding the corresponding products in moderate to good yields. Mechanistic experiments revealed that DMSO served a dual role, functioning as both solvent and nucleophilic reagent in C−H fluorocarbonylation.

A Regioselective, One-Pot, Transition-Metal-Free α-Alkylation of Quinone Monoacetals for Various Organic Transformations.

Regioselective reactions of biologically significant quinones are challenging. An unprecedented advancement in quinone monoacetal (QMA) chemistry is proposed for constructing regioselective and less explored α-alkylated QMAs through the Morita-Baylis-Hillman (MBH) reaction. Electrophilic QMAs were transformed to nucleophilic umpolung reagents for aldol-type condensation with several electrophiles. Mechanistic studies reveal that solvent (TFE:water (1:1)) and in situ-generated potassium acetate accelerate the reaction. The ensuing MBH adducts were scalable and underwent several post-synthetic transformations and late-stage functionalization.

Biosynthesis of Nonribosomal Peptides Chitinimides Reveal a Special Type of Thioesterase Domains.

Non-ribosomal peptide synthetases (NRPSs) and their tailored enzymes have diverse biological functions. In this study, we investigated the biosynthesis and function of chitinimides, which belong to the non-ribosomal peptide (NRP) subfamily featuring a pyrrolidine-containing part (X part) connected to the polypeptide chain via an ester bond. A conserved gene cassette, chmHIJK, is responsible for oxyacylation of the pyrrolidine moiety in the X part. The thioesterase (TE) domain of ChmC (ChmC-TE) catalyzes transesterification reactions with a free X part or methanol as a nucleophilic reagent to form different chitinimides. The crucial amino acid residues in the ChmC-TE domains responsible for the specific recognition of the X part were identified, and they were conserved in all the biosynthetic pathways of this NRP subfamily to form a signature motif, YNHNR, suggesting a special type of TE domain in NRPSs. Chitinimides demonstrate the biological function of promoting the swarming ability of the native producer. This study provides deep insights into the biosynthesis of this special NRP subfamily, and shows that the special TE domain could be used to generate diverse NRPs by combinatorial biosynthesis.

Hydrogen Peroxide-Assisted Alkaline Defluorination of the Fumigant and Potent Greenhouse Gas, Sulfuryl Fluoride: Hydrogen Peroxide as a Nucleophilic Reagent.

Sulfuryl fluoride (SO2F2, SF) is an effective and increasingly popular fumigant for treating buildings and commodities in international trade but has come under scrutiny as a potent greenhouse gas. Passage of vent gases through an alkaline spray has been proposed for scrubbing SF, but base hydrolysis is insufficiently fast and generates equal yields of fluoride and fluorosulfate, the latter of unknown environmental hazard. We report here that alkaline hydrogen peroxide (H2O2) markedly accelerates SF removal and gives nearly quantitative yield of fluoride, with fluorosulfate produced in less than 3.5% yield. The other major products are sulfate, peroxymonosulfate, and oxygen. The oxidation state of S was unchanged. Hydroxyl and superoxide radical scavengers had no effect on the rate. The reaction proceeds by sequential nucleophilic displacement of fluoride by hydroperoxide ion (HO2-) to form a transient diperoxysulfate species that rapidly undergoes intramolecular redox rearrangement to give sulfate and singlet oxygen. Peroxymonosulfate, produced through side reactions, can fully defluorinate SF as well, although more slowly. Two new peaks were detected in the 19F-NMR spectrum corresponding to intermediates. Fluoride can be removed conventionally, and the other products are innocuous or short-lived. Thus, H2O2-assisted alkaline defluorination promises to be an effective method for scrubbing spent SF fumes and preventing SF from reaching the atmosphere. This study highlights the benefits of H2O2 and peroxymonosulfate as nucleophiles in remediation chemistry.

Natural Deep Eutectic Solvents as Absorbing Solution and Preparation Solvent of Perovskite Nanocrystals Simultaneously for CH3I Gas Visual Sensing.

Methyl iodide (CH3I) gas as a toxic gas causes great harm to organisms due to its high volatility and high reactivity with biological nucleophiles. Unfortunately, the sensing and detection of CH3I gas are challenging because of the diffusive nature of the gases and its low concentrations in the environment. Herein, we have developed a fast, green, and sensitive CH3I gas visual sensing method based on the capture technology of toxic gases by natural deep eutectic solvents (NADESs) coupled to the halide rapid exchange capability of perovskite nanocrystals (PNCs). In this strategy, NADESs are used as an absorption solution to adsorb gaseous CH3I, while simultaneously exposing I- through the action of the nucleophilic reagent; then, CsPbBr3 PNCs were synthesized in NADESs and used as sensing material to achieve I- exchange. Benefiting from the capture and enrichment of CH3I gas, the sensitivity of the gas sensor was highly improved. The sensor exhibited the lowest detection limit (limits of detection) of 164.15 μmol/m3, below the minimum safe level for human inhalation, which is 200 μmol/m3. This breakthrough offers greater possibilities for the quantitative detection of CH3I gas.

The Progress of Reductive Coupling Reaction by Iron Catalysis.

The transition metal catalyzed coupling reaction has revolutionized the strategies for forging the carbon-carbon bonds. In contrast to traditional cross-coupling methods using pre-prepared nucleophilic organometallic reagents, reductive coupling reactions for the C-C bonds formation provide some advantages. Because both coupling partners are reduced in the final products using a stoichiometric amount of a reductant, this approach not only avoids the need to use sensitive organometallic species, but also provides an orthogonal and complementary access to classical coupling reaction. Notably, the reductive coupling reactions feature readily available fragments, promote good step economy, exhibit high functional group tolerance and unique chemoselectivity, which have propelled their increasingly popular in the organic synthesis. In recent years, due to the low price, minimal toxicity, and environmentally benign character, iron-catalyzed carbon-carbon coupling reactions have garnered significant attention from the organic synthetic chemists and pharmacologists, especially the iron-catalyzed reductive coupling. This review aims to provide an insightful overview of recent advances in iron-catalyzed reductive coupling reactions, and to illustrate their possible reaction mechanisms.

Photocatalyzed Aryl C-H Fluorocarbonylation with CF2Br2.

The use of abundant and inexpensive fluorine feedstocks to synthesize fluorinated compounds is a promising strategy that has not been extensively investigated. Dibromodifluoromethane (CF2Br2) is an inexpensive fluorine source that has rarely been used for C-H fluoroalkylation. This study reveals an iridium-catalyzed, tunable strategy for synthesizing acyl fluorides and difluorobromomethylated products using CF2Br2. To achieve the desired products, this process only requires the change of solvent (from DMSO to 1,4-dioxane) under blue LED illumination. A variety of arenes and heteroarenes with electron-donating substituents were successfully used, yielding the corresponding products in moderate to good yields. Mechanistic experiments revealed that DMSO served a dual role, functioning as both solvent and nucleophilic reagent in C-H fluorocarbonylation.

Palladium-Catalyzed Suzuki-Miyaura Reactions with Triazenyl-Tethered Aryl Bromides: Exploiting the Orthogonal Coupling Sites under Different Conditions.

Transition-metal-catalyzed cross-coupling of arenes bearing two or more potential coupling sites is often challenging because of the chemoselectivity issue. If orthogonal cross-couplings were applicable, one can develop a synthetically useful approach for consecutive functionalization of the starting arenes compounds. We herein reported a Suzuki-Miyaura coupling of triazenyl-substituted aryl bromides catalyzed by PdCl2(PCy3)2/PPh3 under basic conditions. The resultant polyfunctionalized aryl triazenes could undergo Suzuki-Miyaura couplings under acidic conditions or be converted to many other functionalized arenes. This orthogonal coupling strategy allows for a sequential functionalization of arenes with same type of nucleophilic reagents toward the synthesis of diverse biaryls and teraryls.

Base-Mediated Chemodivergent [4 + 1] and [2 + 1] Cycloadditions of N-Alkylpyridiniums and Enones.

Divergent synthesis of structurally different products from the same kinds of starting materials is highly synthetically useful but very challenging. Herein, we reported a base-mediated chemodivergent [4 + 1] and [2 + 1] cycloaddition of N-alkylpyridinium and enone under mild conditions, leading to furan-fused bicycles with high diastereoselectivity and spirobicycles, respectively, from moderate to high yields. N-Alkylpyridinium salts were modular nucleophilic transfer reagents and C1 synthons, which underwent tandem Michael addition to the α,β-unsaturated ketones and cyclization under the base conditions. Late-stage derivatization of 4-propyldicyclohexylanone from an important industrial raw of liquid crystal display (LCD) screens was realized. In vitro, compound 3f exhibited good activities against human colon cancer cells (HCT116) with IC50 values in 9.82 ± 0.27 μM. Further biological evaluations investigated the mechanism of the effective inhibition of cell growth, including apoptosis ratio detection, cell cycle analysis, and migration capacity of HCT116 cells. In apoptosis effect studies, complex 3f increased the percentage of apoptotic HCT116 cells to 26.8% (15 μM).

Three-Component Reaction of Cyclopropanols, DABSO, and N-(Sulfonyl)acrylamides: Preparation of Sulfone-Bridged 1,7-Dicarbonyl Compounds.

A cascade reaction of cyclopropyl alcohols, DABSO (1,4-diazoniabicyclo[2.2.2]octane-1,4-disulfinate), and N-(sulfonyl)acrylamides has been developed. This tandem process went through a cyclopropanol ring opening and Michael addition sequence. The γ-keto sulfinate generated from the reaction between cyclopropanol and DABSO serves as the nucleophilic reagent, and N-(sulfonyl)acrylamide is used as the Michael addition acceptor. By utilizing this strategy, multitudinous sulfone-bridged 1,7-dicarbonyl compounds that contain both a β-sulfonyl amide unit and γ-keto sulfone skeleton were conveniently synthesized.

Synthesis, spectroscopic analysis, molecular docking and DFT study of some new heterocyclic compounds tethered 4‑hydroxy-1-methylquinoline-2(1H)one

A diversity of heterocyclic compounds (3, 6–8, 9, 11 and 12) linked 4‑hydroxy-1-methylquinoline-2(1H)one moiety have been synthesized from ring opening ring closure reaction (RORC) of 4‑hydroxy-6-methyl-3-nitro-2H-pyrano[3,2-c]quinoline-2,5(6H)‑dione (2) with various nucleophilic reagents namely hydrazine hydrate, phenylhydrazine, 3-hydrazino-5,6-diphenyl-1,2,4-triazine (4), 7‑chloro-4-hydrazino quinoline (5), 3-amino-1,2,4-triazole, 2-aminobenzimidazole and 3-amino-4,6-dimethyl-1H-pyrazolo[3,4-b]pyridine (10). The biological efficiency of the synthesized compounds against hepatocellular carcinoma cell lines (HepG-2) was analyzed both experimentally and theoretically (topoisomerase IIβ protein). Compound 12 (IC50=4.36 µM/L) has the highest anticancer activity against HepG-2 cell lines in comparison with the positive control (Cis-platin). The synthesized compounds were optimized by DFT/B3LYP functionality using the 6–311G++(d,p) basis set. Frontier molecular orbital analysis using global reactivity parameters indicated that compounds 1 and 12 have the largest) ∆E = 4.268 eV) and smallest) ∆E = 3.344 eV) energy gap, respectively. Thus, compound 1 (η= 2.134 eV) is harder than other compounds and has high stability. While compound 12 (S = 0.598eV-1) is softer than other compounds and more reactive. MEP surface and Fukui function were used to show charge distribution and show reactive zones within the molecules. For further validate of the NMR results, GIAO method was utilized to evaluation the 1HNMR and 13CNMR chemical shifts which were then correlate with the experimental spectra. Non-linear optical (NLO) behavior was further studied and compared to urea, which is a prototype substrate, and found to be greater than that of urea. Swiss-ADME (absorption, distribution, metabolism and excretion) analysis was performed to examine the drug-likeness properties of the current compounds. Finally, using the topoisomerase IIβ protein (PDB ID: 4G0U) receptor, molecular docking studies were used to examine the binding interactions of the synthesized compounds and correlated with anticancer activity.

Superior and efficient performance of cost-effective MIP-202 catalyst over UiO-66-(CO2H)2 in epoxide ring opening reactions

This study explored the catalytic performance of two robust zirconium-based metal–organic frameworks (MOFs), MIP-202(Zr) and UiO-66-(CO2H)2 in the ring-opening of epoxides using alcohols and amines as nucleophilic reagents. The MOFs were characterized by techniques such as FT-IR, PXRD, FE-SEM, and EDX. Through systematic optimization of key parameters (catalyst amount, time, temperature, solvent), MIP-202(Zr) achieved 99% styrene oxide conversion in 25 min with methanol at room temperature using 5 mg catalyst. In contrast, UiO-66-(CO2H)2 required drastically harsher conditions of 120 min, 60 °C, and four times the catalyst loading to reach 98% conversion. A similar trend was observed for ring-opening with aniline –MIP-202(Zr) gave 93% conversion in one hour at room temperature, while UiO-66-(CO2H)2 needed two hours at 60 °C for 95% conversion. The superior performance of MIP-202(Zr) likely stems from cooperative Brønsted/Lewis acid sites and higher proton conductivity enabling more efficient epoxide activation. Remarkably, MIP-202(Zr) maintained consistent activity over five recycles in the ring-opening of styrene oxide by methanol and over three recycles in the ring-opening of styrene oxide by aniline. Testing various epoxide substrates and nucleophiles revealed trends in reactivity governed by electronic and steric effects. The results provide useful insights into tuning Zr-MOF-based catalysts and highlight the promise of the cost-effective and sustainable MIP-202(Zr) for diverse epoxide ring-opening reactions on an industrial scale.

Efficient synthetic strategies for fused pyrimidine and pyridine derivatives: A review

AbstractPyrimidine and its derivatives play a paramount role in drug discovery as privileged pharmacophores with considerable chemical and biological significance and its presence in genes. This review aims to assemble a systematic evaluation of synthetic tactics of various fused pyrimidine derivatives containing nitrogen heterocycles such as pyridopyridines, pyridopyrimidines, and pyrimidopyrimidine from a pharmacological point of view and deliver an overview of methodologies presenting the chemistry of fused pyrimidine derivatives. The review details the importance of various catalysts and ring substitution using various electrophilic and nucleophilic reagents. These synthetic strategies were elaborated based on the different synthetic routes that lead to the specific type of pyrimidine and pyridine fused derivatives. The literature accumulates various developments in one‐pot condensation, the Knoevenagel–Michael addition mechanism, microwave and ultrasound irradiation, intramolecular cyclization, nano‐catalytic reactions, and so forth. Short reaction times, catalyst reusability, solvent‐free conditions, excellent yields, and stereo‐selectivity are some of the benefits of certain synthetic approaches.

Electrophilic Behavior of the "Nucleophilic" Pyramidane: Reactivity of Ge-Pyramidane towards Organolithium Reagents.

The particular reactivity of the recently discovered class of the main group element polyhedral clusters, pyramidanes, remains largely unexplored. In this communication, we report the reaction of the germapyramidane with tert-butyllithium leading to the rather unusual organogermanium compound [Li+(thf)2]⋅2-, as the product of the formal insertion of a Ge-apex into the C-Li bond. This reactivity mode exemplifies unusual electrophilic behaviour of a pyramidane, which is a priori considered as a nucleophilic reagent. Being highly reactive, [Li+(thf)2]⋅2- readily undergoes reactions with electrophiles (MeI, EtBr), initially forming intermediate germahousenes, which isomerize to the thermodynamically more favourable germoles.

A General Iron-Catalyzed Decarboxylative Oxygenation of Aliphatic Carboxylic Acids.

We report an iron-catalyzed decarboxylative C(sp3)-O bond-forming reaction under mild, base-free conditions with visible light irradiation. The transformation uses readily available and structurally diverse carboxylic acids, iron photocatalyst, and 2,2,6,6-tetramethylpiperidine 1-oxyl (TEMPO) derivatives as oxygenation reagents. The process exhibits a broad scope in acids possessing a wide range of stereoelectronic properties and functional groups. The developed reaction was applied to late-stage oxygenation of a series of bio-active molecules. The reaction leverages the ability of iron complexes to generate carbon-centered radicals directly from carboxylic acids by photoinduced carboxylate-to-iron charge transfer. Kinetic, electrochemical, EPR, UV/Vis, HRMS, and DFT studies revealed that TEMPO has a triple role in the reaction: as an oxygenation reagent, an oxidant to turn over the Fe-catalyst, and an internal base for the carboxylic acid deprotonation. The obtained TEMPO adducts represent versatile synthetic intermediates that were further engaged in C-C and C-heteroatom bond-forming reactions using commercial organo-photocatalysts and nucleophilic reagents.

A General Iron‐Catalyzed Decarboxylative Oxygenation of Aliphatic Carboxylic Acids

AbstractWe report an iron‐catalyzed decarboxylative C(sp3)−O bond‐forming reaction under mild, base‐free conditions with visible light irradiation. The transformation uses readily available and structurally diverse carboxylic acids, iron photocatalyst, and 2,2,6,6‐tetramethylpiperidine 1‐oxyl (TEMPO) derivatives as oxygenation reagents. The process exhibits a broad scope in acids possessing a wide range of stereoelectronic properties and functional groups. The developed reaction was applied to late‐stage oxygenation of a series of bio‐active molecules. The reaction leverages the ability of iron complexes to generate carbon‐centered radicals directly from carboxylic acids by photoinduced carboxylate‐to‐iron charge transfer. Kinetic, electrochemical, EPR, UV/Vis, HRMS, and DFT studies revealed that TEMPO has a triple role in the reaction: as an oxygenation reagent, an oxidant to turn over the Fe‐catalyst, and an internal base for the carboxylic acid deprotonation. The obtained TEMPO adducts represent versatile synthetic intermediates that were further engaged in C−C and C‐heteroatom bond‐forming reactions using commercial organo‐photocatalysts and nucleophilic reagents.

Recent Progress on Multi-Component Reactions Involving Nucleophile, Arynes and CO2.

Carbon dioxide (CO2) is a non-toxic, abundant and recoverable source of carbon monoxide. Despite its thermodynamically stable and kinetically inert nature, research on CO2 utilisation is ongoing. CO2-based aryne reactions, crucial for synthesising ortho-substituted benzoic acids and their cyclisation products, have garnered significant attention, and multi-component reactions (MCRs) involving CO2, aryne and nucleophilic reagents have been extensively studied. This review highlights recent advancements in CO2 capture reactions utilising phenylalkyne reactive intermediates. Mechanistic insights into these reactions are provided together with prospects for further development in this field.

Co3O4–TiO2 supported into N-doped magnetic 3D porous microspheres as the “one stone with two birds” strategy for highly efficient removal of organic dyes via synergistic adsorption-photocatalysis

Constructing heterojunctions with rich porosity and unique microstructures is the main way to obtain efficient adsorption and photocatalysis. A ternary composite of Co3O4–TiO2 supported in N-doped magnetic 3D porous microspheres (Co3O4–TiO2/N-MCMs) was successfully constructed with hierarchical pore structures, large specific surface areas, and abundant active sites. The Co3O4–TiO2/N-MCMs possessed excellent adsorption and solar degradation capabilities for representative azo dye (methyl orange, MO) and triphenylmethane dye (rhodamine B, RhB), and the total removal rate of the two dyes with different initial concentration reached up to 99.0% and 99.2% within 2 h, respectively. MO and RhB were rapidly adsorbed and enrichment into Co3O4–TiO2/N-MCMs via pore filling, and then degraded by the nucleophilic reagents (•O– 2 and •OH). Characterizations and theoretical calculations demonstrated that Co3O4–TiO2/N-MCMs contained a sufficient amount of p-n type heterojunctions between Co3O4 and TiO2, which could effectively promote spatial separation of photogenerated e--h+ pairs to improve degradation ability and reduce band gap to extend visible-light absorption. Moreover, N-doping could further transfer photogenerated electrons from heterojunctions to reaction areas to effectively prolong the lifetime of photogenerated electrons. The LC-MS results showed that MO and RhB can be mineralized into H2O and CO2 without generating any secondary pollution. Furthermore, Co3O4–TiO2/N-MCMs exhibited excellent magnetic separation capability and reusability. This study designed a novel photocatalyst for highly efficient removal of organic dyes via “One stone with two birds” strategy of synergistic adsorption-photocatalysis, which could simplify the treating process and exhibit a highly promising in practical applications.

Synthesis and utility of N-boryl and N-silyl enamines derived from the hydroboration and hydrosilylation of N-heteroarenes and N-conjugated compounds.

Catalytic hydroboration and hydrosilylation have emerged as promising strategies for the reduction of unsaturated hydrocarbons and carbonyl compounds, as well as for the dearomatization of N-heteroarenes. Various catalysts have been employed in these processes to achieve the formation of reduced products via distinct reaction pathways and intermediates. Among these intermediates, N-silyl enamines and N-boryl enamines, which are derived from hydrosilylation and hydroboration, are commonly underestimated in this reduction process. Because these versatile intermediates have recently been utilized in situ as nucleophilic reagents or dipolarophiles for the synthesis of diverse molecules, an expeditious review of the synthesis and utilization of N-silyl and N-boryl enamines is crucial. In this review, we comprehensively discuss a wide range of hydrosilylation and hydroboration catalysts used for the synthesis of N-silyl and N-boryl enamines. These catalysts include main-group metals (e.g., Mg and Zn), transition metals (e.g., Rh, Ru, and Ir), earth-abundant metals (e.g., Fe, Co, and Ni), and non-metal catalysts (including P, B, and organocatalysts). Furthermore, we highlight recent research efforts that have leveraged these versatile intermediates for the synthesis of intriguing molecules, offering insights into future directions for these invaluable building blocks.