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New bispyridinium dichlorides based on 2,2-bis(hydroxymethyl)propane-1,3-diyl spacer were synthesized from pentaerythritol, 4-aminopyridine, and carboxylic acids. The resulting biocides possess a high antibacterial effect. The minimal inhibitory concentration (MIC) of these compounds against pathogenic bacteria, namely, gram-positive Methicillin-resistant Staphylococcus aureus (strain ATCC 25923) and gram-negative Escherichia coli (ATCC 25922) and Pseudomonas aeruginosa (ATCC 27853), was established. The influence of the alkyl substituent length in salts on their microbiological activity was studied. [ABSTRACT FROM AUTHOR]

Functionalization of unactivated sp3 C—H bonds of cyclic and linear alkanes to high‐value‐added chemicals is one of the most important classes of chemical transformations and has high synthetic potential in synthetic chemistry. A metal‐free, green, and sustainable functionalization of unactivated alkyl sp3 C—H bonds is reported using iodine(III) as a feasible dehydrogenation agent under visible light or KBr, and alkyl chlorides, bromides, alcohols, and ketones could be constructed by addition of different coupling reagents. More details are discussed in the article by Zhai et al. on page 505—510. [ABSTRACT FROM AUTHOR]

Glutathione peroxidase 4 (GPX4) is the most promising target for inducing ferroptosis. GPX4-targeting strategies primarily focus on inhibiting its activity or adjusting its cellular level. However, small inhibitors have limitations due to the covalent reactive alkyl chloride moiety, which could lead to poor selectivity and suboptimal pharmacokinetic properties. Herein, we designed and synthesized a series of proteolysis targeting chimeras (PROTACs) by connecting RSL3, a small molecule inhibitor of GPX4, with six different ubiquitin ligase ligands. As a highly effective degrader, compound 18a is a potent degrader (DC 50, 48h = 1.68 μM, D max, 48h = 85 %). It also showed an obvious anti-proliferative effect with the IC 50 value of 2.37 ± 0.17 μM in HT1080. Mechanism research showed that compound 18a formed a ternary complex with GPX4 and cIAP and induced the degradation of GPX4 through the ubiquitin-proteasome system pathway. Furthermore, compound 18a also induced the accumulation of lipid peroxides and mitochondrial depolarization, subsequently triggering ferroptosis. Our work demonstrated the practicality and efficiency of the PROTAC strategy and offered a promising avenue for designing degraders to induce ferroptosis in cancer cells. [Display omitted] • For the two sites of RSL3, four series of GPX4 degraders were designed. • Compound 18a exhibit the degradation of GPX4 and cytotoxicity in HT1080 cells. • A novel GPX4 degrader compound 18a effectively induced cell ferroptosis. [ABSTRACT FROM AUTHOR]

Ferroptosis is a form of non-apoptotic cell death, regulated by phospholipid hydroperoxide glutathione peroxidase 4 (GPX4), a selenoprotein with a selenocysteine residue (sec) in the active site. GPX4 is a promising target for cancer cells in therapy-resistant conditions via ferroptosis, which can reduce the level of lipid reactive oxygen species (ROS). So far, all existing GPX4 inhibitors covalently bind to GPX4 via a reactive alkyl chloride moiety or masked nitrile-oxide electrophiles with poor selectivity and pharmacokinetic properties and most were obtained by cell phenotype-based screening. Lacking of effective high-throughput screening methods for GPX4 protein limits the discovery of GPX4 inhibitors. Here, we report a fluorescence polarization (FP)-based high throughput screening (HTS) assay for GPX4-U46C-C10A-C66A in vitro , and found Metamizole sodium from our in-house compound library inhibits GPX4-U46C-C10A-C66A enzyme activity. Structure-activity relationships (SAR) demonstrated the importance of sulfonyl group on interaction between Metamizole sodium and GPX4-U46C-C10A-C66A. Our FP assay could be an effective tool for discovery of GPX4 inhibitors and Metamizole sodium was a potential inhibitor for GPX4 in vitro. [Display omitted] • Using FITC modified peptide, a FP-based HTS assay for GPX4-U46C-C10A-C66A in vitro was established. • Metamizole sodium inhibited GPX4-U46C-C10A-C66A in an uncompetitive and non-covalent reversible manner. • Using rational drug design, a series of Metamizole sodium derivatives were synthesized and evaluated. • SAR demonstrated the importance of sulfonyl group on interaction between Metamizole sodium and GPX4-U46C-C10A-C66A. • Molecular docking results showed that Metamizole sodium competitively binds to the peptide-binding pocket. [ABSTRACT FROM AUTHOR]

[Display omitted] • Low-cost copper-catalyzed challenging alkylation reaction. • Use of unactivated alkyl chlorides containing β-hydrogens. • Regioselective alkylation of ubiquitous phenols. • Excellent substrate scope and reaction mechanism. The use of unactivated alkyl chlorides in regioselective C−H alkylation is a highly challenging process with diverse applications of alkylation strategy in drug discovery and agrochemistry. In this work, we report an efficient and cost-effective copper-catalyzed protocol for the coupling of unactivated alkyl chlorides with the C−H bond of phenol derivatives via 2-pyridinyl chelation assistance. The reaction shows a high level of regioselectivity, leading to an exclusive ortho alkylation and providing a broad scope with the endurance of numerous functionalities such as silyl, ether, thioether, pyrrolyl, indolyl, carbazolyl groups, including alkyl bearing fatty alcohol, nonylphenol, and vitamin E. Detailed mechanistic investigations suggest that the alkylation occurs through a two-electron oxidative addition of alkyl chloride to an active Cu(I) species. Deuterium labeling and kinetics experiments indicate a facile and reversible C−H bond activation process. Overall, the alkylation follows a Cu(I)/Cu(III) pathway involving chelation-assisted smooth C−H metalation and rate-limiting C−Cl oxidative addition of alkyl chloride. [ABSTRACT FROM AUTHOR]

The hydrochlorination of alkenes has been extensively studied in research and is commonly featured in organic chemistry textbooks as an exemplification of the Markovnikov rule. However, the application of this reaction is typically limited to specific alkenes, such as highly substituted ones, styrenes, or strained systems. Conversely, monosubstituted or 1,2-disubstituted alkenes do not readily react with HCl gas or solutions of HCl gas at practical rates. The challenges associated with hydrochlorination reactions for these "non-activated" alkenes have spurred considerable research efforts over the past 30 years, which constitute the primary focus of this review. The discussion begins with classical polar hydrochlorinations, followed by metal-promoted radical hydrochlorinations, and concludes with a brief overview of recent anti-Markovnikov hydrochlorinations., (Copyright © 2024, Müller.)

Cross-coupling reactions have developed into powerful approaches for carbon–carbon bond formation. In this work, a Ni-catalyzed migratory Suzuki–Miyaura cross-coupling featuring high benzylic or allylic selectivity has been developed. With this method, unactivated alkyl electrophiles and aryl or vinyl boronic acids can be efficiently transferred to diarylalkane or allylbenzene derivatives under mild conditions. Importantly, unactivated alkyl chlorides can also be successfully used as the coupling partners. To demonstrate the applicability of this method, we showcase that this strategy can serve as a platform for the synthesis of terminal, partially deuterium-labeled molecules from readily accessible starting materials. Experimental studies suggest that migratory cross-coupling products are generated from Ni(0/II) catalytic cycle. Theoretical calculations indicate that the chain-walking occurs at a neutral nickel complex rather than a cationic one. In addition, the original-site cross-coupling products can be obtained by alternating the ligand, wherein the formation of the products has been rationalized by a radical chain process. Migratory cross-coupling reactions are powerful tools to form bonds at predictable positions. Here the authors report a nickel-catalyzed migratory Suzuki–Miyaura cross-coupling of unactivated alkyl electrophiles with aryl and vinyl boron reagents and provide experimental and computational mechanistic evidence. [ABSTRACT FROM AUTHOR]

The unsymmetrical bidentate phosphine ligands (Me)2PCH2CH2CH2P(Et)2 (14), (Me)2PCH2CH2CH2P(iPr)2 (15), (Me)2PCH2CH2CH2P(Cy)2 (16), and (Me)2PCH2CH2CH2P(Ph)2 (17) were synthesized using air–stable phosphine oxide intermediates. In the first step, sodium phosphinites formed by deprotonation of (Me)2P(O)H, (Et)2P(O)H, and (iPr)2P(O)H were alkylated by 1-bromo-3-chloropropane. The different substitution rates of the chloride and bromide groups allowed the isolation of the intermediates (Me)2P(O)CH2CH2CH2Cl (2), (Et)2P(O)CH2CH2CH2Cl (3), and (iPr)2P(O)CH2CH2CH2Cl (4). Subsequent reaction of (Me)2P(O)CH2CH2CH2Cl (2) with the sodium phosphinites generated from (Et)2P(O)H, (iPr)2P(O)H, (tBu)2P(O)H, (Cy)2P(O)H, or (Ph)2P(O)H gave unsymmetrical bidentate phosphine oxides; reduction of these oxides yielded the unsymmetrical phosphines. The unsymmetrical bidentate phosphines react with metal salts to form complexes. X-ray crystal structures of cis-Pt((Me)2P(CH2CH2CH2)P(iPr)2)Cl2 (20) and racemic [CuI((Me)2P(CH2CH2CH2)P(Ph)2)]Cl (21) were obtained. The kinetics and scope of the synthetic route were also explored. Experiments showed that the rate of substitution of the alkyl chloride group in (R)2P(O)CH2CH2CH2Cl-type oxides increases relative to unsubstituted alkyl chlorides due to the presence of the phosphonyl group on one end of the molecule. The scope of the reaction involving 1,2-dihaloalkanes was also investigated, and it was found that the reaction mixture of sodium dimethylphosphinite and 1,2-dihaloalkanes formed tetramethylbis(phosphine) monoxide (22), which decomposes on work-up to give complex reaction mixtures. [ABSTRACT FROM AUTHOR]

• Kinetics of Cl removal by alkanes evince coupled irreversible steps for Cl deposition and removal. • Isotherm accurately predicts measured Cl coverages as a function of alkyl chloride and alkane pressures. • Ethene oxidation and Cl removal plausibly have distinct active site requirements. High partial oxidation selectivity in ethylene oxidation over Ag catalysts is achieved in part via the presence of adsorbed chlorine promoters. Chlorine coverage during ethylene oxidation is maintained by co-feeding organic chlorides in ppm levels and alkane moderators in concentrations of ~0.5 mol%. The relative efficacy of organic chlorides in Cl deposition and of alkanes in Cl removal is typically estimated using empirical correlations. Apparent kinetics of Cl removal were measured by feeding ethyl chloride and propane during ethylene oxidation catalysis over a highly-promoted Ag/α-Al 2 O 3 catalyst and quantifying the rate of chloropropane formation during steady state reaction. Propane oxychlorination forms 1- and 2-chloropropane in a ~1:2 ratio, as expected given the lower bond dissociation enthalpy of methylene than methyl C H bonds in propane, and at total rates on the order of 10-4 mol C 3 H 7 Cl (mol Ag surf)-1 s−1. Concurrent ethylene oxidation rates of order 10-1 mol (mol Ag surf)-1 s−1 provide evidence that Cl moderation occurs in a distinct catalytic cycle over promoted Ag catalysts. Cl removal has a supralinear dependence on propane pressure (P C3H8) and an inverse dependence on ethyl chloride pressure (P C2H5Cl) at high P C2H5Cl /P C3H8 , while Cl removal is positive order in pressures of both C 2 H 5 Cl and C 3 H 8 at low P C2H5Cl /P C3H8 , as expected for surfaces that are increasingly covered in Cl as P C2H5Cl /P C3H8 increases. Chloropropane formation rates were positive order in dioxygen pressure for all P C2H5Cl /P C3H8 ratios. Taken together, the kinetics of Cl removal require both rate determining deposition of Cl from an alkyl chloride and kinetically relevant removal of Cl by an alkane. We develop a kinetic model that describes these trends and allows for quantification of rate and equilibrium parameters, and provide evidence for the elementary steps enumerated by measuring a kinetic isotope effect and assessing the fate of alkyl fragments from chloroethane and chloropropane in gas-phase batch reactions. Rate and equilibrium constants regressed from this kinetic model are used to develop an isotherm for Cl coverage as a function of the ratio of organic chloride promoter to alkane moderator pressures. This isotherm quantitatively predicts Cl coverages measured in situ after steady state reactions with feedstreams containing both ethyl chloride-ethane and ethyl chloride-propane mixtures. Measured reaction orders for chloropropane formation with respect to ethylene and carbon dioxide pressure reflect surface ethylene and carbon dioxide coverages that are lower for sites that form chloropropane than for sites that form ethylene oxide, suggesting that site ensembles for Cl deposition and removal vary from those involved in selective oxidation of ethylene. [ABSTRACT FROM AUTHOR]

Transition‐metal‐catalyzed cross‐coupling chemistry can be regarded as one of the most powerful protocols to construct carbon–carbon bonds. While the field is still dominated by palladium catalysis, there is an increasing interest to develop protocols that utilize cheaper and more sustainable metal sources. Herein, we report a selective, practical, and fast iron‐based cross‐coupling reaction that enables the formation of Csp−Csp3 and Csp2−Csp3 bonds. In a telescoped flow process, the reaction can be combined with the Grignard reagent synthesis. Moreover, flow allows the use of a supporting ligand to be avoided without eroding the reaction selectivity. [ABSTRACT FROM AUTHOR]

Here, we demonstrate that a metallaphotoredox‐catalyzed cross‐electrophile coupling mechanism provides a unified method for the α‐arylation of diverse activated alkyl chlorides, including α‐chloroketones, α‐chloroesters, α‐chloroamides, α‐chlorocarboxylic acids, and benzylic chlorides. This strategy, which is effective for a wide variety of aryl bromide coupling partners, is predicated upon a halogen atom abstraction/nickel radical‐capture mechanism that is generically successful across an extensive range of carbonyl substrates. The construction and use of arylacetic acid products have further enabled two‐step protocols for the delivery of valuable building blocks for medicinal chemistry, such as aryldifluoromethyl and diarylmethane motifs. [ABSTRACT FROM AUTHOR]

In this study, CaCl2- and MgCl2–alcohol solvates of different stoichiometric quantities of ethyl alcohol (EtOH) and methyl alcohol (MeOH) were synthesized and characterized via coupled thermogravimetric–differential scanning calorimetry, thermogravimetric–mass spectrometric evolved gas analysis (TG-MS), spectroscopic analysis (Raman) methods as well as by X-ray diffraction. Correlations between the obtained calorimetric, thermodynamic, kinetic, and crystallographic data were carried out. The CaCl2–alcohol systems seem suitable for heat storage based on the feasible recovery of the salt. However, Raman spectroscopic results revealed that the MgCl2–EtOH solvates were instable compounds. Irreversible transformation of MgCl2–alcohol solvates related to the formation of alkyl chloride appeared upon heating, as proven by TG-MS and Raman spectroscopic measurements. Pure salt–alcohol solvates could not be prepared under technically applicable conditions. The samples contained at least traces of water. Appearance of side reactions resulting in magnesium oxychlorides, oxyhydroxides, and possible release of HCl with cycling may contribute to corrosion of reactor components. Based on these considerations, MgCl2–alcohol solvate systems are not recommended for heat storage. [ABSTRACT FROM AUTHOR]

• Heterolytic C Cl cleavage enthalpy governs Cl deposition by alkyl chlorides. • Homolytic C H cleavage enthalpy governs efficacy in Cl moderation by alkanes. • Ethylene oxide formation rate and selectivity are not a function of Cl source or Cl moderator identity. • Oxygen species participate in heterolytic C Cl cleavage, homolytic C H cleavage, and proton abstraction from gas-phase acids. The selectivity of Ag ethylene epoxidation catalysts correlates with surface coverage of the promoter chlorine. Cl coverage, in turn, is a function of co-fed organic chloride and alkane moderator pressures. Organic molecules can be classified based on their deprotonation enthalpy, as those that are inert, those capable of selective oxidation, or those that act as gas-phase acids. The influence of alkane moderator and alkyl chloride promoter identities on Cl coverage was assessed by titration of Cl by ethane in a recirculating gas-phase batch reactor immediately following steady-state reactions with various alkane and alkyl chlorides included in ethylene oxidation feedstreams. The faculty of organic molecules for Cl removal correlates with the weakest C H bond dissociation enthalpy, such that molecules with C H bonds susceptible to homolysis remove Cl more effectively than those with stronger C H bonds. Cl deposition likely occurs via heterolytic cleavage of C Cl bonds in alkyl chlorides, such that molecules with weak C Cl bonds deposit multiple monolayers of Cl. Cl coverage affects ethylene epoxidation rates identically regardless of the organic chloride or the aliphatic hydrocarbon employed, demonstrating that these molecules only impact catalysis by moderating Cl coverage. These findings implicate the concurrent prevalence of homolytic and heterolytic pathways during ethylene epoxidation on promoted Ag/α-Al 2 O 3 catalysts and provide context to examine additional roles of surface oxygen beyond involvement in oxidation pathways. [ABSTRACT FROM AUTHOR]

Nonactivated alkyl chlorides are readily available and bench-stable feedstocks; however, they exhibit an inherent chemical inertness, in part, due to their large negative reduction potentials, which have precluded their widespread use as radical precursors in visible-light photocatalysis. Herein, we highlight some recent strategies for activating challenging organic halides under light irradiation, with special emphasis in C(sp3)–halide bonds. In this line, a brief summary of the reactivity of Vitamin B12 , F430 cofactor and derivatives is required to comprehend the chemistry behind our developed Cu/M (M = Co, Ni) dual catalytic system. Catalyst design has been key for developing a mild and general photoredox methodology for the intramolecular reductive cyclization of nonactivated alkyl chlorides with tethered alkenes. The cleavage of strong C(sp3)–Cl bonds is mediated by a highly nucleophilic low-valent cobalt or nickel intermediate generated by visible-light photoredox reduction employing a copper photosensitizer. [ABSTRACT FROM AUTHOR]

The development of a nickel-catalyzed C–H alkylation of aromatic substrates with unactivated alkyl halides is described. This carbocyclization facilitates the synthesis of diverse fused ring systems from simple aromatic substrates and is an attractive alternative to traditional polar or radical-mediated ring formations. The present system uses unactivated primary and secondary alkyl bromides and chlorides, while avoiding the use of precious palladium catalysts and more reactive alkyl halides commonly used in related C–H alkylations. Image 1 [ABSTRACT FROM AUTHOR]

This study investigates the feasibility of using hydrophilic deep eutectic solvent (DES) as green and effective extractant for the extraction and preconcentration of alkyl gallates from vegetable oils. In a typical experiment, 120 µL of choline chloride:ethylene glycol DES was added to 1.0 g of oil sample which was previously diluted with 1 mL of n-hexane. The extraction was accelerated by vortex stirring of the two phases. At this stage, hydrogen bonding interactions between the phenyl hydroxyls of alkyl gallates and chloride anion of choline salt were likely the main forces driving the extraction. After extraction, the analytes in the DES phase were separated and determined by high-performance liquid chromatography with ultraviolet detection. The method detection limits for propyl gallate and octyl gallate were 2.1 and 4.6 µg kg-1, respectively. The precision of the method varied between 4.6-6.4% (intra-day) and 5.4-7.5% (inter-day). The recoveries (accuracies) obtained from spiked vegetable oil samples were in the range of 78-106%. [ABSTRACT FROM AUTHOR]

Summary of main observation and conclusion: We report herein an unprecedented protocol for radical carbotrifluoromethylation of unactivated alkenes. With Cu(OTf)2 as the catalyst, the reaction of unactivated alkenes, TMSCF3 and activated alkyl chlorides at room temperature provides the corresponding carbotrifluoromethylation products in satisfactory yields. Directed by trifluoromethylation of alkyl radicals, the method exhibits an excellent regioselectivity that is opposite to those driven by CF3 radical addition. [ABSTRACT FROM AUTHOR]

The chemical inertness of abundant and commercially available alkyl chlorides precludes their widespread use as reactants in chemical transformations. Presented in this work is a metallaphotoredox methodology to achieve the catalytic intramolecular reductive cyclization of unactivated alkyl chlorides with tethered alkenes. The cleavage of strong C(sp3)−Cl bonds is mediated by a highly nucleophilic low‐valent cobalt or nickel intermediate generated by visible‐light photoredox reduction employing a copper photosensitizer. The high basicity and multidentate nature of the ligands are key to obtaining efficient metal catalysts for the functionalization of unactivated alkyl chlorides. The chemical inertness of abundant and commercially available alkyl chlorides precludes their widespread use as reactants in chemical transformations. Presented here is a methodology to achieve the catalytic intramolecular reductive cyclization of unactivated alkyl chlorides with tethered alkenes. The cleavage of strong C(sp3)−Cl bonds is mediated by either a highly nucleophilic low‐valent cobalt or nickel intermediate, generated by employing a copper photosensitizer in a visible‐light photoredox reduction. [ABSTRACT FROM AUTHOR]

Abstract A new family of asymmetrical 1,2-squaraine dyes (1,2-SQs) were designed and synthesized in high yields. The photophysical analysis presented that these 1,2-SQs showed strong red fluorescence in crystal state but weak fluorescence in solution, suggesting their aggregation-induced emission enhancement (AIEE) properties. Single crystals X-ray diffraction revealed that the intense fluorescence in the crystal state can be attributed to the effects of long alkyl chains or large group substituents in the molecules, which efficiently prevented the tight intermolecular contact and reduced π–π interactions. The biocompatibility and cell imaging applications of SQ4 were further investigated. The results demonstrated that SMMC-7721 cell can be clearly imaged by SQ4, which inferred SQ4 had excellent biocompatibility and potential value for bioimaging. Graphical abstract Image 1 Highlights • Crystal red fluorescent 1,2-SQs were designed and easily prepared with high fluorescence quantum yield (up to 42.45%). • 1,2-SQs exhibited typical aggregation-induced emission enhancement (AIEE) properties. • SQ4 showed excellent biocompatibility and can be used for cell imaging. [ABSTRACT FROM AUTHOR]

• Unprecedented type of photoredox/nickel dual-catalysis strategy. • Energy transfer pathway is involved in the catalytic process. • Regioselective cyclization of readily available activated and unactivated alkenes with alkyl chlorides. • Construction of several kinds of useful nitrogen-containing heterocycles. A photoredox/nickel dual catalysis is presented for the construction of several kinds of useful nitrogen-containing heterocycles. This protocol is regioselective and features a broad substrate scope. It provides a direct access to nitrogen-containing heterocycles by reacting alkyl chlorides with readily available activated and unactivated alkenes. Moreover, this protocol can be easily scalable to a gram-scale, and it is feasible to use sunlight as the light source. Mechanistic studies suggest that the energy transfer pathway is involved in the catalytic process. A photoredox/nickel dual catalysis is employed for the construction of several kinds of useful nitrogen-containing heterocycles. [Display omitted] [ABSTRACT FROM AUTHOR]

A novel visible-light promoted radical cyclization reaction of 3-indolylallylamides with sulfonyl chlorides as coupling partners has been described, which provides a unique approach toward the synthesis of functionalized tetrahydrocarbolinones. This reaction involves the reduction of sulfonyl chlorides to sulfonyl radicals, addition of sulfonyl radicals to alkenyl moiety, and following cycloaddition to indolyl at the C2 position. This photocatalytic reaction tolerates a broad range of aryl and alkyl sulfonyl chlorides with diverse functional groups, which provides a direct and operationally simple protocol to construct functionalized tetrahydrocarbolinones. [Display omitted] [ABSTRACT FROM AUTHOR]

• Fluorinated benzenesulfonyl chlorides reacted with 2,4-dihydroxyacetophenone or 2-hydroxy-4-methoxyacetophenone. • The corresponding sulfonic ester derivatives were evaluated in vitro against biochemical targets linked to diabetes mellitus. • The substrates and the corresponding sulfonic ester derivatives exhibited strong nitric oxide scavenging activity. • Hydrophilic, hydrophobic and electrostatic interactions are predicted to stabilize ligand-receptor interactions. Small molecule multi-target drugs substituted with fluorine atom/s or fluorine-containing group/s continue to attract considerable interest in medicinal chemistry due to their advantages in the treatment of multifactorial diseases. In this study, fluorine-containing alkyl and benzenesulfonyl chloride building blocks were reacted with 2,4-dihydroxyacetophenone 1a or 2-hydroxy-4-methoxyacetophenone 1b to afford the corresponding sulfonic ester derivatives 2a – f and 2g – j , respectively. Detailed crystallographic characterization was performed on a representative compound from each series. The compounds were evaluated through enzymatic assays in vitro for potential to inhibit biochemical targets linked to type 2 diabetes mellitus. Compound 1a and its 4-(4-fluorophenyl)sulfonyl derivative 2d exhibited strong and significant inhibitory effect in vitro against α-glucosidase (IC 50 = 0.97 ± 0.02 μM and 0.81 ± 0.07 μM, respectively) and α-amylase (IC 50 = 6.89 ± 0.04 μM and 4.87 ± 0.02 μM, respectively) compared to acarbose (IC 50 = 8.60 ± 0.20 μM and 1.96 ± 0.03 μM, respectively). The presence of a 4-fluorophenylsulfonyl moiety resulted in moderate inhibitory activity for 2d (IC 50 = 27.05 ± 0.01 μM) against protein tyrosine phosphatase 1 beta (PTP1B) compared to the PTP1B inhibitor, suramin (IC 50 = 4.63 ± 0.003 μM). The test compounds exhibited strong to moderate nitric oxide radical scavenging activity in vitro against ascorbic acid (IC 50 = 5.53 ± 0.03 μM) with IC 50 values in the range 0.05–19.30 μM. Compounds 1a and 2d did not inhibit superoxide dismutase (SOD) activity. Molecular docking revealed the involvement of hydrophobic, hydrophilic and electrostatic interactions with amino acid residues in the active site of the test enzymes. [Display omitted] [ABSTRACT FROM AUTHOR]

Short gram‐scale asymmetric syntheses of asperazine, pestalazine A, and their unnatural congeners thereof, have been achieved in ≈10 steps by using readily accessible starting materials. The nickel‐catalyzed reductive coupling protocol was utilized as a key step for the direct construction of C3asp3−C7′sp2 bond furnishing the diaryl‐substituted quaternary carbon centers with remarkable steric hindrance. The streamlined access to this core structure of heterodimeric tryptophans under the mild reaction conditions, makes this strategy hold a great promise in the concise synthesis of other relevant oligomeric pyrroloindoline alkaloids with unique C3a−C7′ linkages. Highly efficient syntheses of bioactive alkaloids (+)‐asperazine and (+)‐pestalazine A were realized by means of Ni‐catalyzed reductive coupling between 7‐iodotryptophan and 3‐chlorocyclotryptophan derivatives. This key reaction secured the construction of C3a−C7′ bond and the associated sterically congested all‐carbon quaternary stereocenter in a single step. [ABSTRACT FROM AUTHOR]

An efficient method for the metal‐free deaminative borylation of alkylamines, using bis(catecholato)diboron as the boron source, to directly synthesize various alkyl potassium trifluoroborate salts is introduced. The key to this high reactivity is the utilization of pyridinium salt activated alkylamines, with a catalytic amount of a bipyridine‐type Lewis base as a promoter. This transformation shows good functional‐group compatibility (e.g. it is unimpeded by the presence of a ketone, indole, internal alkene, or unactivated alkyl chloride) and can serve as a powerful synthetic tool for borylation of amine groups in complex compounds. Mechanistic experiments and computations suggest a mechanism in which the Lewis base activated B2cat2 unit intercepts an alkyl radical generated by single‐electron transfer (SET) from a boron‐based reductant. N to B: A mild catalytic system was developed for the preparation of alkyl potassium trifluoroborate salts by C−N bond cleavage. This method has good functional‐group compatibility and can serve as a powerful synthetic tool for late‐stage borylative cleavage of C−N bonds in complex compounds. dtbpy=4,4′‐di‐tert‐butyl‐2,2′‐bipyridine. [ABSTRACT FROM AUTHOR]

NMP-mediated chlorination of aliphatic alcohols has been developed for the synthesis of alkyl chlorides. This facile, efficient and practical approach used simple and readily available aryl sulfonyl chlorides as the chlorination reagent for the construction of C-Cl bond in good to excellent yields with mild conditions and broad substrate scope. [ABSTRACT FROM AUTHOR]

Calorimetric measurements were conducted on aqueous solutions of n-alkylammonium chlorides (CnAC; H(CH2)nNH3Cl, n = 1 - 12) at 298.15 K. The solute partial molar enthalpy, Hs, was evaluated with reference to the infinitely diluted state. At low concentrations, the Hs increased with the molality, mt, until the critical micelle concentration (CMC) was reached. In the concentration range between the CMC and about three times the CMC, the Hs decreased linearly with increasing log mt. The Hs observed at the CMC was taken as the enthalpy of micelle formation, ΔHm, which was expressed as ΔHm/kJ mol-1 = 20.1 - 1.4n for CnAC with n from 7 to 12. The Gibbs energy of micelle formation, ΔGm, was estimated from the CMC values: Δ Gm/kJ mol-1 = 4.1 - 3.3 n with n from 5 to 12. The entropy of micelle formation, Δ Sm, was calculated as TΔ Sm / kJ mol-1 = 16.4 + 1.9 n with n from 7 to 12. The large positive entropy term was determined to be the driving force for micelle formation. It was inferred that the difference of the CMC of CnAC and sodium n-alkyl sulfate (SCnS;H(CH2)nOSO3Na, n = 5 - 13) homologs seemed to be caused by the difference in the number of possible hydrogen bonds to the head group of the micelle state. Based on an attempt to calculate the Hs for C12AC from the partial molar enthalpy and the concentrations of the constituent individual ions above the CMC, the increase in concentration of the micellar ions seemed to be the largest contribution to the concentration dependence of the Hs. [ABSTRACT FROM AUTHOR]

Abstract: A general formamide‐catalyzed protocol for the efficient transformation of alcohols into alkyl chlorides, which is promoted by substoichiometric amounts (down to 34 mol %) of inexpensive trichlorotriazine (TCT), is introduced. This is the first example of a TCT‐mediated dihydroxychlorination of an OH‐containing substrate (e.g., alcohols and carboxylic acids) in which all three chlorine atoms of TCT are transferred to the starting material. The consequently enhanced atom economy facilitates a significantly improved waste balance (E‐factors down to 4), cost efficiency, and scalability (>50 g). Furthermore, the current procedure is distinguished by high levels of functional‐group compatibility and stereoselectivity, as only weakly acidic cyanuric acid is released as exclusive byproduct. Finally, a one‐pot protocol for the preparation of amines, azides, ethers, and sulfides enabled the synthesis of the drug rivastigmine with twofold SN2 inversion, which demonstrates the high practical value of the presented method. [ABSTRACT FROM AUTHOR]

A practical method for the nucleophilic substitution (SN) of alcohols furnishing alkyl chlorides, bromides, and iodides under stereochemical inversion in high catalytic efficacy is introduced. The fusion of diethylcyclopropenone as a simple Lewis base organocatalyst and benzoyl chloride as a reagent allows notable turnover numbers up to 100. Moreover, the use of plain acetyl chloride as a stoichiometric promotor in an invertive SN-type transformation is demonstrated for the first time. The operationally straightforward protocol exhibits high levels of stereoselectivity and scalability and tolerates a variety of functional groups. [ABSTRACT FROM AUTHOR]

Abstract: Graphene quantum dot (GQD)–organic hybrid compounds (GQD‐2 b–e) were prepared by introducing 3,4,5‐tri(hexadecyloxy)benzyl groups (C16) and linear chains terminated with a 2‐ureido‐4‐[1H]‐pyrimidinone (UPy) moiety onto the periphery of GQD‐1. GQD‐2 b–e formed supramolecular assemblies through hydrogen bonding between the UPy units. GPC analysis showed that GQDs with high loadings of the UPy group formed larger assemblies, and this trend was confirmed by DOSY and viscosity measurements. AFM images showed the polymeric network structures of GQD‐2 e on mica with flat structures (ca. 1.1 nm in height), but no such structures were observed in GQD‐2 a, which only carries the C16 group. GQD‐2 c and GQD‐2 d formed organogels in n‐decanol, and the gelation properties can be altered by replacing the alkyl chains in the UPy group with ethylene glycol chains (GQD‐3). GQD can thus be used as a platform for supramolecular polymers and organogelators by suitable chemical functionalization. [ABSTRACT FROM AUTHOR]

Chitosan oligosaccharide (COS) is an important carbohydrate-based biomaterial for synthesizing candidate drugs and biological agents. This study synthesized COS derivatives by grafting acyl chlorides of different alkyl chain lengths (C8, C10, and C12) onto COS molecules and further investigated their physicochemical properties and antimicrobial activity. The COS acylated derivatives were characterized using Fourier transform infrared spectroscopy, 1H nuclear magnetic resonance spectroscopy, X-ray diffraction, and thermogravimetric analysis. COS acylated derivatives were successfully synthesized and possessed high solubility and thermal stability. As for the evaluation of antibacterial activity, COS acylated derivatives did not significantly inhibit Escherichia coli and Staphylococcus aureus , but they significantly inhibited Fusarium oxysporum , which was superior to that of COS. Transcriptomic analysis revealed that COS acylated derivatives exerted antifungal activity mainly by downregulating the expression of efflux pumps, disrupting cell wall integrity, and impeding normal cell metabolism. Our findings provided a fundamental theory for the development of environmentally friendly antifungal agents. [Display omitted] [ABSTRACT FROM AUTHOR]

Direct fluorination of tertiary alkyl bromides and iodides with Selectfluor is described. The halogen-exchange fluorination proceeds efficiently in acetonitrile at room temperature under metal-free conditions and exhibits a wide range of functional group compatibility. Furthermore, the reactions are highly selective in that alkyl chlorides and primary and secondary alkyl bromides remain intact. A radical mechanism is proposed for this selective fluorination. [ABSTRACT FROM AUTHOR]

We describe the first one-pot borylation/Suzuki–Miyaura sp2–sp3 cross-coupling between readily available aryl (pseudo)halides and activated alkyl chlorides. This method streamlines the synthesis of diaryl methanes, α-aryl carbonyls and allyl aryl compounds, substructures that are commonly found in life changing drug molecules. [ABSTRACT FROM AUTHOR]

The asymmetric synthesis of (−)-N-methylwelwitindolinone B isothiocyanate is reported. Critical challenges overcome through these studies include the stereoselective installation of the sterically congested C13 alkyl chloride and control of the wayward reactivity of the indole unit to standard oxidants. A Pt-catalyzed hydrosilylation helped stymie unwanted rearrangements facilitated by vinyl group participation during the chloride installation step, and a new FeII-catalyzed oxidation accomplished the problematic conversion of indole into 2-indolinone. [ABSTRACT FROM AUTHOR]

[Display omitted] A three-step sequence to construct pyrroles from three components including 2,2-dimethoxyethylamine, aryl/alkyl sulfonyl chlorides and alkynes bearing electron-withdrawing groups is presented. The pyrroles are proposed to arise via a 5- exo -trig cyclization proceeding through both oxocarbenium and N -sulfonyliminium ions. This modular route allows for the variability at the N -sulfonyl group, the C 2 and C3 substituents for rational vectoring of the pyrrole nucleus for downstream processes. [ABSTRACT FROM AUTHOR]

Efficient copper-catalyzed cross-coupling reactions of non-activated alkyl chlorides, including primary, secondary, and tertiary alkyl chlorides, with phenyl Grignard reagents were achieved. Preparation of phenylmagnesium bromide in 2-methyltetrahydrofuran is critical for the success of the reaction. This protocol expands the synthetic toolbox for the construction of C C bonds of non-activated primary, secondary, and tertiary alkyl chlorides via copper-catalyzed cross-coupling. [ABSTRACT FROM AUTHOR]

We previously reported a protein knockdown system for HaloTag-fused proteins using hybrid small molecules consisting of alkyl chloride, which binds covalently to HaloTag, linked to BE04 ( 2 ), a bestatin ( 3 ) derivative with an affinity for cellular inhibitor of apoptosis protein 1 (cIAP1, a kind of ubiquitin ligase). This system addressed several limitations of prior protein knockdown technology, and was applied to degrade two HaloTag-fused proteins. However, the degradation activity of these hybrid small molecules was not potent. Therefore, we set out to improve this system. We report here the design, synthesis and biological evaluation of novel hybrid compounds 4a and 4b consisting of alkyl chloride linked to IAP antagonist MV1 ( 5 ). Compounds 4a and 4b were confirmed to reduce the levels of HaloTag-fused tumor necrosis factor α (HaloTag-TNFα), HaloTag-fused cell division control protein 42 (HaloTag-Cdc42), and unfused HaloTag protein in living cells more potently than did BE04-linked compound 1b . Analysis of the mode of action revealed that the reduction of HaloTag-TNFα is proteasome-dependent, and is also dependent on the linker structure between MV1 ( 5 ) and alkyl chloride. These compounds appear to induce ubiquitination at the HaloTag moiety of HaloTag-fused proteins. Our results indicate that these newly synthesized MV1-type hybrid compounds, 4a and 4b , are efficient tools for protein knockdown for HaloTag-fused proteins. [ABSTRACT FROM AUTHOR]

The introduction of a chlorine atom to a carbon center in an enantioselective manner via conventional C–Cl bond formation is difficult. Here we report a new approach to this class of tertiary alkyl chlorides with high optical purities. Instead of forming a new C–Cl bond, our approach involves carbene-catalyzed desymmetrization of 2-chloro-1,3-diols as the key step to set up the chiral carbon center with excellent enantiomeric excess. [ABSTRACT FROM AUTHOR]

A catalytic carboxylation of unactivated primary, secondary, and tertiary alkyl chlorides with CO2, at atmospheric pressure is described. This protocol represents the first intermolecular cross-electrophile coupling of unactivated alkyl chlorides, thus leading to new knowledge in the cross-coupling arena. [ABSTRACT FROM AUTHOR]

An efficient, eco-friendly, and simple one-pot approach for the synthesis of 2-imino-1,3-dithiolanes via reaction of allyl chloride, primary amines, carbon disulfide, and I2 under solvent-free conditions is presented. The obtained 5-iodomethyl-2-imino-1,3- dithiolanes were converted into silyl-protected terminal alkynyl sulfides substituted 2-imino-1,3-dithiolanes by treatment with lithium 2,2,2-tris(trimethylsilyl)ethanedithioate, produced by the reaction of tris(trimethylsilyl)methyllithium (TsiLi) with CS2. [ABSTRACT FROM AUTHOR]

The use of low-cost manganese(II) bromide (MnBr2) and tetramethylethylenediamine (TMEDA) catalyzes the cross coupling of (bis)pinacolatodiboron with a wide range of alkyl halides, demonstrating the first manganese-catalyzed coupling with alkyl electrophiles. This method allows access to primary, secondary, and tertiary boronic esters from the parent chlorides, which were previously inaccessible as coupling partners. The reaction proceeds in high yield with as little as 1000 ppm catalyst loading, while 5 mol % can provide high yields in as little as 30 min. Finally, radical-clock experiments revealed that at 0 °C direct borylation outcompetes alternative radical processes, thereby providing synthetically useful, temperature-controlled reaction outcomes. [ABSTRACT FROM AUTHOR]

A direct nucleophilic trifluoromethylthiolation of alkyl chlorides, bromides and tosylates with AgSCF3 was described. It was found that the presence of nBu4NI or a combination of nBu4NI/ nBu4NBr significantly enhanced the reaction rates. The reaction conditions were mild, thus allowing the tolerance of a variety of functional groups. [ABSTRACT FROM AUTHOR]

Reduction of the neutral carbene tetrachlorosilane adduct (cAAC)SiCl4 (cAAC=cyclic alkyl(amino) carbene :C(CMe2)2(CH2)N(2,6-iPr2C6H3) with potassium graphite produces stable (cAAC)3Si3, a carbene-stabilized triatomic silicon(0) molecule. The Si−Si bond lengths in (cAAC)3Si3 are 2.399(8), 2.369(8) and 2.398(8) Å, which are in the range of Si−Si single bonds. Each trigonal pyramidal silicon atom of the triangular molecule (cAAC)3Si3 possesses a lone pair of electrons. Its bonding, stability, and electron density distributions were studied by quantum chemical calculations. [ABSTRACT FROM AUTHOR]

The Cu-catalyzed oxidative [2+2+1] annulation of 1,n-enynes (n = 6, 7) with α-carbonyl alkyl bromides through C–Br/C–H functionalization has been developed. Using Ag2CO3/tert-butyl hydroperoxide (TBHP) as co-oxidants, α-carbonyl alkyl bromides provide two bonds, the α-C(sp3)–Br bonds and the α-C(sp3)–H bonds, to cyclize with the 1,n-enynes and Cu(MeCN)4PF6, thus forming three new C–C bonds and two rings in a single reaction. [ABSTRACT FROM AUTHOR]

A method is presented for the direct transformation of a ketone to the corresponding reduced alkyl chloride or bromide. The process involves the reaction of a ketone trityl hydrazone with tBuOCl to give a diazene which readily collapses to the α-chlorocarbinyl radical, reduction of which by a hydrogen atom source gives the alkyl chloride product. The use of N-bromosuccinimide provides the corresponding alkyl bromide. This unique transformation provides a reductive halogenation that complements Barton's redox-neutral vinyl halide synthesis. [ABSTRACT FROM AUTHOR]

A novel and regioselective approach to carbonyl-containing alkyl chlorides via silver-catalyzed ring-opening chlorination of cycloalkanols is reported. Concurrent C(sp3)-C(sp3) bond cleavage and C(sp3)-Cl bond formation efficiently occur with good yields under mild conditions, and the chlorinated products are readily transformed into other useful synthetic intermediates and drugs. The reaction features complete regioselectivity, high efficiency, and excellent practicality. [ABSTRACT FROM AUTHOR]

The reductive lithiation of phenyl thioethers, or alkyl chlorides, by either preformed aromatic radical anions or by lithium metal and an aromatic electron-transfer catalyst, is commonly used to prepare organolithiums. Revealed herein is that these two methods are fundamentally different. Reductions with radical anions occur in solution, whereas the catalytic reaction occurs on the surface of lithium, which is constantly reactivated by the catalyst, an unconventional catalyst function. The order of relative reactivity is reversed in the two methods as the dominating factor switches from electronic to steric effects of the alkyl substituent. A catalytic amount of N,N-dimethylaniline (DMA) and Li ribbon can achieve reductive lithiation. DMA is significantly cheaper than alternative catalysts, and conveniently, the Li ribbon does not require the removal of the oxide coating when DMA is used as the catalyst. [ABSTRACT FROM AUTHOR]