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K-Ras is the most commonly mutated oncogene in human cancer. The recently approved non-small cell lung cancer drugs sotorasib and adagrasib covalently capture an acquired cysteine in K-Ras-G12C mutation and lock it in a signaling-incompetent state. However, covalent inhibition of G12D, the most frequent K-Ras mutation particularly prevalent in pancreatic ductal adenocarcinoma, has remained elusive due to the lack of aspartate-targeting chemistry. Here we present a set of malolactone-based electrophiles that exploit ring strain to crosslink K-Ras-G12D at the mutant aspartate to form stable covalent complexes. Structural insights from X-ray crystallography and exploitation of the stereoelectronic requirements for attack of the electrophile allowed development of a substituted malolactone that resisted attack by aqueous buffer but rapidly crosslinked with the aspartate-12 of K-Ras in both GDP and GTP state. The GTP-state targeting allowed effective suppression of downstream signaling, and selective inhibition of K-Ras-G12D-driven cancer cell proliferation in vitro and xenograft growth in mice.

Herein, we report concise total syntheses of diterpene natural products (-)-crinipellins A and B with a tetraquinane skeleton, three adjacent all-carbon quaternary centers, and multiple oxygenated and labile functional groups. Our synthesis features a convergent Kozikowski β-alkylation to unite two readily available building blocks with all the required carbon atoms, an intramolecular photochemical [2 + 2] cycloaddition to install three challenging and adjacent all-carbon quaternary centers and a 5-6-4-5 tetracyclic skeleton, and a controlled Cargill rearrangement to rearrange the 5-6-4-5 tetracyclic skeleton to the desired tetraquinane skeleton. These strategically enabling transformations allowed us to complete total syntheses of (-)-crinipellins A and B in 12 and 13 steps, respectively. The results of quantum chemical computations revealed that the Bronsted acid-catalyzed Cargill rearrangements likely involve stepwise paths to products and the AlR3-catalyzed Cargill rearrangements likely involve a concerted path with asynchronous alkyl shifting events to form the desired product.

Despite the limited success of copper-catalyzed alkylations, (NNS)CuCl proved to be an effective catalyst for the sp3 C–H alkylation of fluorene with alcohols. Various primary alcohols and challenging secondary alcohols were successfully used. The practical applicability of the method was effectively tested with several post-functionalization reactions. This copper-catalyzed alkylation of fluorene involved a borrowing hydrogen mechanism. [ABSTRACT FROM AUTHOR]

Comprehensive Summary The difunctionalization of bicyclo[1.1.0]butanes is an under‐explored transformation that accesses to moieties that are otherwise difficult to prepare. Herein, a new oxidative radical alkylarylation of N‐aryl bicyclobutyl amides with C(sp3)−H feedstocks is achieved in an atom‐economic and photocatalyst‐ and light‐free manner. This protocol follows a sequential C(sp3)–H/C(sp2)–H functionalization, providing an efficient route for diversity‐oriented synthesis of functionalized 3‐spirocyclobutyl oxindoles. In particular, a wide range of C(sp3)−H feedstocks, including ether, alcohol, amine, thioether, polychlorinated methane, silane, acetone, acetonitrile, toluene, and alkane are all suitable for the C(sp3)−H functionalization, demonstrating the broad applicability of this transformation. [ABSTRACT FROM AUTHOR]

We herein propose an approach to visualize the Menschutkin reaction at an interface between a self-assembled monolayer with nucleophilic properties and water containing alkyl halides. An organic field-effect transistor functionalized with a nucleophilic monolayer has detected in situ alkylation depending on differences in the leaving group ability and the bulkiness of electrophilic alkyls. [ABSTRACT FROM AUTHOR]

Various indoles undergo Friedel–Crafts alkylation at the 3-position when treated with secondary arylmethyl acetates in the presence of trimethylsilyl trifluoromethanesulfonate (TMSOTf) and 2,6-lutidine. Tertiary benzylic alcohols are also effective alkylating agents, undergoing TMSOTf-promoted activation to yield alkylated indoles that feature quaternary centers. A related study shows that benzofuran reacts under similar conditions to yield 2-alkylated benzofurans when treated with similar alkylating agents, and the reaction has been extended to include other representative heteroarenes. Yields for these Friedel–Crafts alkylation products range from 43%–99% over a wide range of substrate combinations. [ABSTRACT FROM AUTHOR]

Comprehensive Summary: Transition‐metal‐catalyzed asymmetric alkylation of aldehydes represents a straightforward strategy for the synthesis of chiral secondary alcohols. However, efficient methods using organoborons as coupling reagents are rare. Herein, we report a highly enantioselective nickel‐catalyzed alkylation reaction of aldehydes, using readily available alkylborons as nucleophiles. A wide variety of chiral secondary alcohols were prepared from commercially available aldehydes with high yields. The key to the excellent enantioselectivity and chemoselectivity was the employment of a bulky C2‐symmetric chiral NHC ligand. This protocol features excellent enantiocontrol, mild conditions, and good functional group compatibility. [ABSTRACT FROM AUTHOR]

Comprehensive Summary: Transition‐metal‐catalyzed asymmetric alkylation of aldehydes represents a straightforward strategy for the synthesis of chiral secondary alcohols. However, efficient methods using organoborons as coupling reagents are rare. Herein, we report a highly enantioselective nickel‐catalyzed alkylation reaction of aldehydes, using readily available alkylborons as nucleophiles. A wide variety of chiral secondary alcohols were prepared from commercially available aldehydes with high yields. The key to the excellent enantioselectivity and chemoselectivity was the employment of a bulky C2‐symmetric chiral NHC ligand. This protocol features excellent enantiocontrol, mild conditions, and good functional group compatibility. [ABSTRACT FROM AUTHOR]

Comprehensive Summary A visible‐light‐induced decarboxylative radical cascade cyclization reaction between N‐(2‐cyanoaryl)‐acrylamides and alkyl N‐(acyloxy)phthalimide (NHPI esters) for the construction of phenanthridine derivatives has been developed. This approach utilizes lithium iodide (LiI) and triphenylphosphine (PPh3) as the redox catalysts and the alkyl radical is produced through the photoactivation of the electron donor‐acceptor (EDA) complex. A series of primary, secondary, and tertiary alkyl‐substituted phenanthridines are prepared in up to 82% yield without transition‐metal catalysts, chemical oxidants, or metal‐/organic dye‐based photocatalysts. [ABSTRACT FROM AUTHOR]

The alkylation of 4-hydroxythiocoumarins (1a–f) was carried out with various allyl bromides as well as propargyl bromides using K2CO3 (2 equiv.) in anhydrous acetone at room temperature, and the corresponding regioselective S-alkylated products 4a–l and 5a–n were obtained in good yields. Then, the synthesis of a variety of new sulfur heterocycles is accomplished by employing thio-Claisen rearrangement from the corresponding S-allyl ethers (4a–l) and S-propargyl ethers (5a–n) to provide the cyclised products 7a–o and 8a–n in good yields. Interestingly, the S-propargyl ethers of the corresponding 4-hydroxythiocoumarins (1a–f) provided two different products depending on the solvent. Furthermore, various 4-hydroxythiocoumarins provided the cyclised products 10a–f directly upon reaction with 2-methylbut-3-yn-2-ol (9) in the presence of 10 mol% p-TSA as catalyst in nitromethane solvent at 80 °C. DFT calculations were performed to investigate the formation of different products, and the findings have been thoroughly discussed. The results demonstrate several notable attributes, including good to excellent yield, highly regioselective product formation, and high atom economy. [ABSTRACT FROM AUTHOR]

The photoinduced decarboxylative radical cascade alkylation/cyclization strategy of diverse benzimidazoles containing unactivated alkene moieties towards the synthesis of polycyclic benzimidazoles via ligand-to-metal-charge-transfer (LMCT) has been developed. Specifically, the reaction initiates the decarboxylation of alkyl carboxylic acids through light-induced charge transfer from the ligand to iron, resulting in the formation of alkyl radical centers. Moreover, the protocol has prominent features, such as a broad substrate scope, high regioselectivity, mild reaction conditions, operational simplicity and readily available air acting as the sole oxidant. [ABSTRACT FROM AUTHOR]

We disclose herein a metal-free cascade reductive Friedel–Crafts alkylation/cyclization of keto acids/esters for the synthesis of tetralones and indanones. Owing to the simple reaction conditions and setup, this protocol features broad substrate generality, facile scalability, and remarkable functional group tolerance, including the synthesis of bioactive molecule sertraline. [ABSTRACT FROM AUTHOR]

Although strategies of olefin hydroalkylation continue to emerge rapidly, the precise control of the regio- or chemoselectivity and the expansion of the reaction range are still challenges. Herein, a straightforward route for cobalt-catalyzed anti-Markovnikov hydroalkylation of unactivated olefins with alkyl iodides has been achieved. The developed reaction is compatible with oxa-, aza-, cyclo- and a series of other functional groups as well as the frameworks of some bioactive compounds. Mechanism studies confirm that an alkyl radical is involved and cobalt–alkyl insertion followed by protonation with water are possible pathways in this reaction. [ABSTRACT FROM AUTHOR]

Tris-(2-pyridylmethyl)amines (TPA or TPMA) are polipyrydine-based ligands extensively used in catalysis and supramolecular chemistry due their capability to form stable tetradentate complexes with a large variety of metals. The unsubstituted ligand, which is also commercially available, can be synthesised by consecutive alkylation of a picoline or by reductive amination of a pyridine aldehyde. In this article, we report a novel synthetic method which opens to the post-functionalisation of these ligands in the benzylic position. This novel derivatization strategy, beside providing synthetic access to novel structures and functions, has been used to prepare a series of metal complexes which have been tested in photochemical hydrogen evolution. [ABSTRACT FROM AUTHOR]

The introduction of allyl fluorides as alternative electrophiles in asymmetric allylic alkylation reactions has recently attracted significant interest. Despite the intrinsic thermodynamically demanding C–F bond-cleavage event, the fluorophilic nature of the silicon atom is key in assisting the activation and cleavage of the allylic C–F bond. Thus, the use of silylated compounds as unconventional nucleophiles, together with the Lewis basicity of fluorine when acting as a leaving group, enables the development of innovative chemical transformations within mild and selective catalytic schemes. This Synpacts article summarizes the diverse defluorinative asymmetric allylic alkylations with allyl fluorides reported to date under both chiral Lewis base and transition-metal catalysis. [ABSTRACT FROM AUTHOR]

Indoles are common motifs in functional agricultural and pharmaceutical molecules. Heteroatom alkylation is the most frequently used chemical reaction in the pharmaceutical field. Developing protocols for the nucleophilic substitution of (indol-2-yl)methyl electrophiles is important for functionalizing indoles. There are few studies on the nucleophilic substitution at the 2′-position of the electrophiles without an electron-withdrawing group at the 1-position or substituents at the 2′- and 3-positions, where the existing approaches require high temperatures and long reaction times. In this study, we demonstrated rapid (7–12 s) and mild (25 °C) microflow nucleophilic substitution at the 2′-position of indole derivatives without an electron-withdrawing group at the 1-position and substituents at the 2′- or 3-positions. Comparable batch conditions resulted in a lower yield. [ABSTRACT FROM AUTHOR]

A mild and efficient reaction for synthesizing esters from thioamide precursors has been established. This method is accomplished in one pot under mild conditions. The process involves the alkylation and activation of inert thioamides, which leads to the cleavage of stable C–N and C–S bonds, eventually resulting in valuable esters with a broad range of substrates. The transformation can be easily carried out at room temperature using thioamide substrates, reactants, and activating agents. This protocol has been demonstrated by synthesizing important esters with applications. [ABSTRACT FROM AUTHOR]

We report facile and versatile procedures for the synthesis of exo - and endo -isomeric spirocyclic hybrids of pharmacophoric (1 R ,5 S)-8-azabicyclo[3.2.1]octane (nortropane) and 1,3-oxazinan-2-one fragments. Our approach consists of the hydrocyanation of endo - and exo -isomeric N -Cbz-protected nortropane-3-spiroepoxides, the reduction of hydroxy nitriles into amino alcohols, the synthesis of N -alkylated amino alcohols via reductive amination, the spirocyclization of the amino alcohols, N -alkylation of the unsubstituted 1,3-oxazinan-2-one fragment in the spiro compounds, and removal of the Cbz protecting groups. [ABSTRACT FROM AUTHOR]

Owing to the low energy consumption and few by-products, toluene alkylation is regarded as a promising way to produce p-xylene. The zeolites with the characteristics of 10-MR were usually employed to catalyze the toluene alkylation after being modified. However, the catalyst activity is liable to sharp decrease by common modifying strategies. In this study, the alkylation of toluene with dimethyl carbonate was catalyzed by the MCM-22 zeolites with selective dealumination and silanization treatment. The Al sites on the MCM-22 external surface were first eliminated by oxalic acid, and then trimethylsilyl groups were grafted at the external surface of MCM-22 by bonding with Si–OH formed from dealumination. This modification strategy can not only reduce the Brønsted acid sites on the external surface and narrow the pore entrance size but also retain more internal active sites, leading to improving PX selectivity without a significant decrease in activity. Compared to parent MCM-22, the PX selectivity was doubled, and the toluene conversion only decreased from 39 to 34% over 200-DeMCM-22 catalyst at 400 °C. [ABSTRACT FROM AUTHOR]

Herein, we developed a photoinduced remote selective C(sp3)−H alkylation of protected amines in the presence of cesium formate. The protected amines were synthesized from commercially available inexpensive 2‐iodo benzoyl chloride. Under mild reaction conditions, the in situ generated aryl radical is converted to α‐amidoalkyl radical via [1,5]‐HAT process, which combines with different Michael acceptors and affords corresponding alkylation products in good yields. Preliminary mechanistic studies revealed that formate anion acts as a source of carbon dioxide radical anion (CO2⋅−) and hydrogen atom donor was directly confirmed by isotope‐labeling studies. [ABSTRACT FROM AUTHOR]

A method for the radical functionalization of 1,2,4‐oxadiazoles using alkyl halides as precursors of radicals is described. The reaction efficiency is determined by potassium tetrafluoropyridinyl thiolate additive, which plays dual role. First, the thiolate converts alkyl halides into more reactive fluorinated aryl sulfides, which undergo photoredox activation of the C−S bond. Second, the thiolate decreases the unproductive loss of alkyl radicals by converting them back to the sulfides. [ABSTRACT FROM AUTHOR]

In this study, a novel approach for the tertiary α‐alkylation of ketones using alkanes with electron‐deficient C─H bonds is presented, employing a synergistic catalytic system combining inexpensive copper salts with aminocatalysis. This methodology addresses the limitations of traditional alkylation methods, such as the need for strong metallic bases, regioselectivity issues, and the risk of over alkylation, by providing a high reactivity and chemoselectivity without the necessity for pre‐functionalized substrates. The dual catalytic strategy enables the direct functionalization of C(sp3)─H bonds, demonstrating remarkable selectivity in the presence of conventional C(sp3)─H bonds that are adjacent to heteroatoms or π systems, which are typically susceptible to single‐electron transfer processes. The findings contribute to the advancement of alkylation techniques, offering a practical and efficient route for the construction of C(sp3)─C(sp3) bonds, and paving the way for further developments in the synthesis of complex organic molecules. [ABSTRACT FROM AUTHOR]

Covalent polymerization of organic molecules into crystalline one‐dimensional (1D) polymers is effective for achieving desired thermal, optical, and electrical properties, yet it remains a persistent synthetic challenge for their inherent tendency to adopt amorphous or semicrystalline phases. Here we report a strategy to synthesize crystalline 1D covalent organic frameworks (COFs) composing quasi‐conjugated chains with benzoxazine linkages via the one‐pot Mannich reaction. Through [4+2] and [2+2] type Mannich condensation reactions, we fabricated stoichiometric and sub‐stoichiometric 1D covalent polymeric chains, respectively, using doubly and singly linked benzoxazine rings. The validity of their crystal structures has been directly visualized through state‐of‐the‐art cryogenic low‐dose electron microscopy techniques. Post‐synthetic functionalizations of them with a chiral MacMillan catalyst produce crystalline organic photocatalysts that demonstrated excellent catalytic and recyclable performance in light‐driven asymmetric alkylation of aldehydes, affording up to 94 % enantiomeric excess [ABSTRACT FROM AUTHOR]

A ruthenium‐catalyzed N‐benzyltriflamide assisted C−H alkylation with maleimide followed by hydrolysis of in situ generated imine has been developed for the first time. This synthetic method results in the efficient synthesis of o‐succinimide derivatives of benzaldehydes. This reaction involves less expensive and mild reaction conditions and shows excellent site selectivity and good functional group compatibility. [ABSTRACT FROM AUTHOR]

The electrophilic alkylation of dianions of fullerene derivatives generated by deprotonation of the corresponding dihydrides is described, using the example of the regioselective synthesis of a trifunctional derivative C70(CF3)8(CH3)H with a near-equatorial location of all addends. The structure of the first synthesized compound is established by means of mass spectrometry and one- and two-dimensional NMR correlation spectroscopy. The reasons for the high regioselectivity of the formation of the single isomer C70(CF3)8(CH3)H are explained using quantum chemical calculations at the level of density functional theory for isomers of anionic intermediates and the product. Electron absorption and fluorescence spectroscopy are used to demonstrate the fundamental effect of the near-equatorial location of addends in the C70(CF3)8(CH3)H compound on its optical and fluorescent properties. [ABSTRACT FROM AUTHOR]

Presented herein is a switchable synthesis of naphthalenone spiroindanediones or 4‐acyl‐1‐naphthols via condition‐controlled divergent cascade reactions of aryl enaminones with diazoindanediones. When the reaction was carried out in the presence of an oxidative additive, naphthalenone spiroindanedione was formed through C(sp2)−H alkylation followed by simultaneous spiroannulation and elimination of dimethylamine. When the reaction was carried out in the presence of an acid additive, on the other hand, 4‐acyl‐1‐naphthol was formed through ring opening of the spiroindanedione moiety attacked by the in situ released dimethylamine. In addition, the reactions are suitable for gram‐scale applications and compatible with a variety of substrates. Moreover, the naphthol products allow structural elaborations and hybridization with a drug, thus further enhancing the value of this developed method. [ABSTRACT FROM AUTHOR]

Aromatic nitro compounds are important intermediates in synthetic organic chemistry. In this work, catechol was used as raw materials, and nitro‐catechol derivatives with different alkylation substitutions were synthesized using two different synthetic routes. More than 15 new previously undescribed compounds were obtained. Each compound was meticulously characterized using a suite of physicochemical techniques, with selective compounds further analyzed via X‐Ray diffraction to ascertain their structure. These newly synthesized compounds hold significant promise as candidates for further chemical modification, which underlines their potential usefulness in the field of the fine synthesis of organic compounds. [ABSTRACT FROM AUTHOR]

We report an unprecedented iron‐catalyzed C−H annulation using readily available 2‐vinylbenzofurans as the reaction pattern. The redox‐neutral strategy, based on cheap, non‐toxic, and earth‐abundant iron catalysts, exploits triazole assistance to promote a cascade C−H alkylation, benzofuran ring‐opening and insertion into a Fe−N bond, to form highly functionalized isoquinolones. Detailed mechanistic studies supported by DFT calculations fully disclosed the manifold of the iron catalysis. [ABSTRACT FROM AUTHOR]

A tricyclic annulated 1,4,2-diazaborole is readily accessed via reaction of a bidentate pyridyl-carbene ligand with MesBBr2 followed by reduction. Dearomatization of the flanking rings is shown to increase reactivity of this heterocycle in the form of a B-centred alkylation with MeI. Its reaction with hydrido-, fluoro-, and chloro-boranes reveal an unprecedented ring expansion reaction to form a diverse family of B2C2N2 heterocycles, reduction of which allows facile access to the first examples of Cs symmetric 1,4,2,5-diazadiborinines. DFT calculations have shed light on the electronic structures of the reduced species and provide insight into mechanistic aspects of the observed ring-expansion. [ABSTRACT FROM AUTHOR]

In this study, we present the successful application of new and known stable 16‐electron ruthenium(II) pincer complexes POCOP, based on the naphthoresorcinate backbone, [Ru(X)(POCOP)(CO)] (X = H, Cl, Br, I, OCOCF3), in the catalytic alkylation of ketones and the coupling between amines and primary alcohols under mild conditions. These protocols demonstrated tolerance to a wide range of alcohols, ketones, and anilines, with reactions proceeding in high conversions and selectivity towards the hydrogenated ketones and the imines. The use of an excess of alcohol as the proton source facilitated the formation of the hydrogenated products. These results mark a significant advancement in the development of catalytic reactions with ruthenium POCOP pincer derivatives. [ABSTRACT FROM AUTHOR]

Objective In the sulfuric acid alkylation unit, the main causes and solutions to the deactivation of the hydrogenation catalyst were found by analyzing the running status of the selective hydrogenation reactor of 1,3-butadiene. Methods By analyzing the feedstock properties before and after catalyst deactivation, the effect of feedstock properties changes on the 1,3-butadiene removal rate was investigated. Results For the selective hydrogenation of the 1,3-butadiene catalyst, a high level of pH, caustic sodium and total sulfur contents in feedstock will inhibit the active centers of the catalyst. Conclusion The harmful impurities in feedstock were removed by optimizing operation. Additionally, the deactivated catalysts were re-activated by on-line treatment with pure hydrogen, the catalyst activity was significantly restored and maintained long-cycle running after re-starting up. [ABSTRACT FROM AUTHOR]

The human alkylation B (AlkB) homologs, ALKBH2 and ALKBH3, respond to methylation damage to maintain genomic integrity and cellular viability. Both ALKBH2 and ALKBH3 are direct reversal repair enzymes that remove 1-methyladenine (1meA) and 3-methylcytosine (3meC) lesions commonly generated by alkylating chemotherapeutic agents. Thus, the existence of deficiencies in ALKBH proteins can be exploited in synergy with chemotherapy. In this study, we investigated possible interactions between ALKBH2 and ALKBH3 with other proteins that could alter damage response and discovered an interaction with the mismatch repair (MMR) system. To test whether the lack of active MMR impacts ALKBH2 and/or ALKBH3 response to methylating agents, we generated cells deficient in ALKBH2, ALKBH3, or both in addition to Mlh homolog 1 (MLH1), another MMR protein. We found that MLH1koALKBH3ko cells showed enhanced resistance toward SN1- and SN2-type methylating agents, whereas MLH1koALKBH2ko cells were only resistant to SN1-type methylating agents. Concomitant loss of ALKBH2 and ALKBH3 (ALKBH2ko3ko) rendered cells sensitive to SN1- and SN2-agents, but the additional loss of MLH1 enhanced resistance to both types of damage. We also showed that ALKBH2ko3ko cells have an ATR-dependent arrest at the G2/M checkpoint, increased apoptotic signaling, and replication fork stress in response to methylation. However, these responses were not observed with the loss of functional MLH1 in MLH1koALKBH2ko3ko cells. Finally, in MLH1koALKBH2ko3ko cells, we observed elevated mutant frequency in untreated and temozolomide treated cells. These results suggest that obtaining a more accurate prognosis of chemotherapeutic outcome requires information on the functionality of ALKBH2, ALKBH3, and MLH1. [ABSTRACT FROM AUTHOR]

In the Neurospora circadian system, the White Collar Complex (WCC) formed by WC-1 and WC-2 drives expression of the frequency (frq) gene whose product FRQ feedbacks to inhibit transcriptional activity of WCC. Phosphorylation of WCC has been extensively studied, but the extent and significance of other post-translational modifications (PTM) have been poorly studied. To this end, we used mass-spectrometry to study alkylation sites on WCC, resulting in discovery of nine acetylation sites. Mutagenesis analysis showed most of the acetylation events individually do not play important roles in period determination. Moreover, mutating all the lysines falling in either half of WC-1 or all the lysine residues in WC-2 to arginines did not abolish circadian rhythms. In addition, we also found nine mono-methylation sites on WC-1, but like acetylation, individual ablation of most of the monomethylation events did not result in a significant period change. Taken together, the data here suggest that acetylation or mono-methylation on WCC is not a determinant of the pace of the circadian feedback loop. The finding is consistent with a model in which repression of WCC’s circadian activity is mainly controlled by phosphorylation. Interestingly, light induced expression of some light-responsive genes has been modulated in certain wc-1 acetylation mutants, suggesting that WC-1 acetylation events differentially regulate light responses. [ABSTRACT FROM AUTHOR]

Control of the regioselectivity of nucleophiles toward alkylating agents is a fundamental problem in heterocyclic chemistry. Substrate-controlled TfOH-catalyzed alkylation of 4-hydroxycoumarin with diazo compounds has been developed to provide rapid access to the C3- or O-alkylated 4-hydroxycoumarins with high efficiency. The regioselectivity can be determined by varying the electronic nature of the diazo substrates, especially those bearing a methylthio group. [ABSTRACT FROM AUTHOR]

A novel synthesis strategy to access 2-alkoxyquinoline derivatives via a palladium-driven cascade reaction is disclosed. Unlike classic methods based on the alkylation of 2-quinolones with alkyl halides, the present method benefits from the de novo assembly of the quinoline core starting from 1,3-butadiynamides. Palladium-catalyzed reaction cascades with N-(2-iodophenyl)-N-tosyl-1,3-butadiynamides and primary alcohols as external nucleophiles proceed under mild reaction conditions and selectively deliver a variety of differently functionalized 4-alkenyl 2-alkoxyquinolines in a single batch transformation. [ABSTRACT FROM AUTHOR]

As an important class of nitrogen-containing fused heterocyclic compounds, imidazo[1,2-a]pyridines often exhibit significant biological activities, such as analgesic, anticancer, antiosteoporosis, anxiolytic, etc. Using Y(OTf)3 as a Lewis acid catalyst, a simple and efficient method has been developed for the synthesis of C3-alkylated imidazo[1,2-a]pyridines through the three-component aza-Friedel–Crafts reaction of imidazo[1,2-a]pyridines, aldehydes, and amines in the normal air atmosphere without the protection of inert gas and special requirements for anhydrous and anaerobic conditions. A series of imidazo[1,2-a]pyridine derivatives were obtained with moderate to good yields, and their structures were confirmed by 1H NMR, 13C NMR, and HRMS. Furthermore, this conversion has the advantages of simple operation, excellent functional group tolerance, high atomic economy, broad substrate scope, and can achieve gram-level reactions. Notably, this methodology may be conveniently applied to the further design and rapid synthesis of potential biologically active imidazo[1,2-a]pyridines with multifunctional groups. [ABSTRACT FROM AUTHOR]

The catalytic performance of Hβ zeolite treated with different concentration of NaOH on the alkylation of tert-butanol with phenol was studied. The effect of NaOH concentration on the crystallinity, morphology, textural property and acidity of Hβ zeolite was studied by X-ray diffraction (XRD), scanning electron microscope characterization (SEM), N2 adsorption–desorption, Fourier transform infrared spectroscopy (FT-IR) and pyridine adsorption infrared spectra (Py-IR) techniques. A certain concentration of NaOH treatment can regulate the pore structure of Hβ zeolite and remove part of framework aluminum and framework silicon, thus achieving the purpose of regulating the pore structure and acidity of the catalyst. Though lower Bronsted to Lewis acid amount ratio when treated NaOH concentrations were 0.15 mol/L, leading to the increasing of selectivity to 4-TBP. The Hβ-0.2 M showed the high selectivity of 90.21% for synthesis of 4-tert-butyl-phenol (4-TBP), compared with the unmodified parent zeolite, the selectivity of 4-TBP improved 16.7%. [ABSTRACT FROM AUTHOR]

Oxidative α-C(sp3)–H alkylation of N -arylated glycine derivatives with 4-alkyldihydropyridine derivatives (alkyl-DHPs) as versatile alkyl radical precursors has been developed. Utilizing visible-light-driven photoredox catalysis and ammonium persulfate as an oxidizing agent, this methodology facilitates the site-selective alkylation of glycine derivatives, enabling the site-selective alkylation of peptides. The reaction exhibits broad substrate scope, including various alkyl radicals and acid-labile functional groups. This approach expands the synthetic toolbox in peptide chemistry, offering a mild and efficient method for the synthesis of modified peptides. [ABSTRACT FROM AUTHOR]

The cellular response to oxidants or xenobiotics comprises two key pathways, resulting in modulation of NRF2 and FOXO transcription factors, respectively. Both mount a cytoprotective response, and their activation relies on crucial protein thiol moieties. Using fumaric acid esters (FAEs), known thiol‐reactive compounds, we tested for activation of NRF2 and FOXO pathways in cultured human hepatoma cells by dimethyl/diethyl as well as monomethyl/monoethyl fumarate. Whereas only the diesters caused acute glutathione depletion and activation of the stress kinase p38MAPK, all four FAEs stimulated NRF2 stabilization and upregulation of NRF2 target genes. However, no significant FAE‐induced activation of FOXO‐dependent target gene expression was observed. Therefore, while both NRF2 and FOXO pathways are responsive to oxidants and xenobiotics, FAEs selectively activate NRF2 signaling. [ABSTRACT FROM AUTHOR]

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The multifunctional groups of 5-hydroxymethylfurfural (5-HMF) make it could extend carbon chain by different C–C coupling reactions and extensively applied in the bio-jet fuel synthesis. Herein, one-pot reaction of lignocellulose derived chemicals with 5-HMF was studied by experimental and density functional theory (DFT) methods. The kinetic models of products were established and the apparent activation energies of the products by C–C coupling reaction of phenol, anisole, guaiacol, cyclohexanone and acetone with 5-HMF on Hβ were 95.3 kJ/mol, 104.8 kJ/mol, 90.4 kJ/mol, 90.0 kJ/mol and 112.2 kJ/mol, indicating these reactions centering on 5-HMF competitive intensively. Then the effects of the catalysis were analyzed by applying commercial catalysis to the mixed coupling reaction of 5-HMF. It was found that Brønsted acid is more favorable to alkylation reaction, and Lewis acid is more beneficial to aldol condensation reaction. By Fukui function, due to the nucleophilic index of cyclohexanone (2.74 eV) is higher than that (2.48 eV) of acetone, and the Mulliken electronegativity (3.43 eV) is weaker than that (3.55 eV) of acetone, cyclohexanone is more conducive than acetone to the aldol condensation reaction. This work provides data reference for product regulation in the bio-jet fuel synthesis. [ABSTRACT FROM AUTHOR]

Comprehensive Summary The alkali tert‐butoxide (tBuOK or tBuONa) mediated generation of aryl free radical from aryl iodide remarks a milestone discovery in the free radical chemistry. However, the equivalent “alkyl halide to alkyl free radical” transformation has not yet been realized in applicable synthesis by similar catalytic tactic. In this paper, the first practical “alkyl halide to alkyl free radical” transformation mediated by tBuOK or TMSOK in the direct α‐C—H alkylation of benzoins is presented. As the parallelly significant issue as aryl free radical generation, the current work, while bringing a rather facile and useful new approach for the synthesis of diverse benzoins, represents also an important step in the alkyl free radical‐based synthesis by displaying the higher generality of simple alkali base mediated radical formation. [ABSTRACT FROM AUTHOR]

A direct C−H alkylation of naphthoquinones with acetone and 1,3‐dicarbonyl compounds was developed to construct C−C bonds of alkyl‐substituted naphthoquinone derivatives. It proceeded through an oxidative radical cross dehydrogenation coupling process under simple and mild conditions. This method provides a facile and efficient route for synthesis of functionalized naphthoquinones from readily available feedstocks. [ABSTRACT FROM AUTHOR]

The alkylation of arenes is one of the most fundamental transformations in synthetic chemistry and the transition‐metal‐catalyzed direct C−H alkylation represents a straightforward and attractive approach from both atom and step‐economy perspectives. Epoxides, the smallest three‐membered saturated O‐heterocycles that can be easily prepared in racemic or enantioenriched forms, are highly useful building blocks for the synthesis of complex organic molecules. Owing to their inherent high ring‐strain, epoxides readily undergo ring‐opening reactions and have been used as alkylating reagents for C−H alkylation catalyzed by transition metals. This review summarizes recent advances in utilizing epoxides as alkylating reagents in transition‐metal‐catalyzed C−H alkylation as well as their synthetic applications in organic synthesis. [ABSTRACT FROM AUTHOR]

We herein report that the highly hydrophobic ether 4‐MeTHP constitutes a promising resource for the development of sustainable synthetic methodologies grounded on the use of organometallic reagents. The beneficial effects of 4‐MeTHP as reaction medium are illustrated in the organolithium‐promoted anionic ortho‐Fries rearrangement of 1,1'‐bi‐2‐naphthol (BINOL)‐based carbamates under bench‐type conditions. The use of 4‐MeTHP induces a remarkable and unexpected stability of the organolithiums species, enabling the efficient preparation of chiral (bis)carboxamide catalysts. Furthermore, superior performances of 4‐MeTHP than other environmentally responsible solvents are observed using the synthesized BINOL catalysts in the asymmetric addition of organozinc reagents to aldehydes. Spectroscopic studies in solution suggest that 4‐MeTHP plays a key role in these reactions by inducing the preferential formation of a reactive monomeric dinuclear complex. This methodology allows for the asymmetric assembly of enantioenriched secondary alcohols in good yields and high stereoselectivity, working at 0 °C and under air. [ABSTRACT FROM AUTHOR]

Ferrocene-substituted carbenes have emerged as attractive, redox-active ligands. However, among the compounds studied to date, ferrocenylated 1,2,4-triazol-5-ylidenes, which are closely related to the archetypal imidazol-2-ylidenes, are still unknown. Here, we demonstrate that the triazolium salt [CHN(Me)NCHN(Fc)]I (2; Fc = ferrocenyl), obtained by alkylation of 4-ferrocenyl-4H-1,2,4-triazole (1) with MeI, reacts selectively with metal alkoxide/hydroxide precursors [(cod)Rh(OMe)]2 and [(IPr)Au(OH)] (cod = cycloocta-1,5-diene, IPr = 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene) to produce the ferrocene-substituted 1,2,4-triazol-5-ylidene complexes [(cod)RhI{CN(Me)NCHN(Fc)}] and [(IPr)Au{CN(Me)NCHN(Fc)}]I in good yields. The complexes were characterised by NMR and IR spectroscopy, mass spectrometry, cyclic voltammetry, and single-crystal X-ray diffraction analysis. Density function theory (DFT) calculations were used to rationalise the electrochemical behaviour of the carbene complexes and to elucidate the bonding situation in these compounds. An analysis using intrinsic bond orbitals (IBOs) revealed that the 1,2,4-triazol-5-ylidene ligand exerted a strong trans influence and showed a synergistic stabilisation by the negative inductive and positive π-donor effects of the nitrogen atoms adjacent to the carbene carbon atom; these effects were enhanced by conjugation with the CH＝N bond at the exterior, similar to that in imidazol-2-ylidenes. [ABSTRACT FROM AUTHOR]

A series of twenty alkyl derivatives (2–21) of 4-amino benzoic acid (1, PABA) have been prepared using potassium carbonate and opportune alkylating agents under simple and mild reaction conditions. Compounds (16–21) are reported for the first time. Electron impact mass spectrometry (EIMS), Fourier transform infrared (FTIR) and Proton nuclear magnetic resonance (1H-NMR) spectroscopic techniques were adopted for the characterization of these analogues. In the present study, the cytotoxic screening of sixteen compounds (3, 5–11, 13 and 15–21) was also achieved against lung (NCI-H460) and oral squamous carcinoma (CAL-27) cell lines. Compound 20 has shown magnificent inhibitory properties against NCI-H460 cell line (IC50 15.59 and 20.04 µM, respectively) at a lower dose than that of the control (cisplatin; IC50 21.00 µM). One-way analysis of variance (ANOVA), t-test and Pearson correlation coefficient (PCC) have been performed to determine the reliability of current data through statistical package for the social sciences (SPSS). [ABSTRACT FROM AUTHOR]

Dimethylallyl tryptophan synthases (DMATSs) are aromatic prenyltransferases that catalyze the transfer of a prenyl moiety from a donor to an aromatic acceptor during the biosynthesis of microbial secondary metabolites. Due to their broad substrate scope, DMATSs are anticipated as biotechnological tools for producing bioactive prenylated aromatic compounds. Our study explored the substrate scope and product profile of a recombinant RePT, a novel DMATS from the thermophilic fungus Rasamsonia emersonii. Among a variety of aromatic substrates, RePT showed the highest substrate conversion for l-tryptophan and l-tyrosine (> 90%), yielding two mono-prenylated products in both cases. Nine phenolics from diverse phenolic subclasses were notably converted (> 10%), of which the stilbenes oxyresveratrol, piceatannol, pinostilbene, and resveratrol were the best acceptors (37–55% conversion). The position of prenylation was determined using NMR spectroscopy or annotated using MS2 fragmentation patterns, demonstrating that RePT mainly catalyzed mono-O-prenylation on the hydroxylated aromatic substrates. On l-tryptophan, a non-hydroxylated substrate, it preferentially catalyzed C7 prenylation with reverse N1 prenylation as a secondary reaction. Moreover, RePT also possessed substrate-dependent organic solvent tolerance in the presence of 20% (v/v) methanol or DMSO, where a significant conversion (> 90%) was maintained. Our study demonstrates the potential of RePT as a biocatalyst for the production of bioactive prenylated aromatic amino acids, stilbenes, and various phenolic compounds. Key points: • RePT catalyzes prenylation of diverse aromatic substrates. • RePT enables O-prenylation of phenolics, especially stilbenes. • The novel RePT remains active in 20% methanol or DMSO. [ABSTRACT FROM AUTHOR]

This article discusses the use of advanced NMR techniques to differentiate between regioisomeric N-alkylation of indazoles and pyrazolopyridines. The study focuses on the synthesis of various regioisomers and the use of 2D NMR techniques to determine their structures. The results and discussion section provides detailed information on the experimental methods and findings. The study concludes that the regioselective N-alkylation of these molecules is important for the development of new active pharmaceutical ingredients. The text also provides technical information about the synthesis and characterization of various compounds, including methyl 1-(4-fluorobenzyl)-1H-indazole-5-carboxylate and 1-(4-Fluorobenzyl)-1H-pyrazolo[4,3-b]pyridine. The authors acknowledge the support of the Central Laboratory of Pharmacy at Ankara University. [Extracted from the article]

Producing sp3‐hybridized carbon‐enriched molecules is of particular interest due to their high success rate in clinical trials. The installation of aliphatic chains onto aromatic scaffolds was accomplished by nickel‐catalyzed C(sp2)−C(sp3) cross‐electrophile coupling with arylsulfonium salts. Thus, simple non‐prefunctionalized arenes could be alkylated through the formation of aryldibenzothiophenium salts. The reaction employs an electrochemical approach to avoid potentially hazardous chemical redox agents, and importantly, the one‐pot alkylation proved also viable, highlighting the robustness of our approach. [ABSTRACT FROM AUTHOR]