C3-Alkylation of Imidazo[1,2-a]pyridines via Three-Component Aza-Friedel-Crafts Reaction Catalyzed by Y(OTf)3.

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.

Production of Jet Fuel Range Aromatics by Alkylation of Benzene with Olefins over Bifunctional Ga/ZSM-5 Catalyst.

Aromatic components of C8-C15 are playing indispensable roles in multi-functional properties of jet fuel. Here, we reported the controllable alkylation of benzene with mixed olefins of ethylene and propylene toward C8-C15 aromatic hydrocarbons for jet fuels over the bifunctional Ga/ZSM-5 catalyst. The resultant 2Ga/ZSM-5 exhibited a superior selectivity of 86.4% (yield of 55.5%) to C8-C15 range aromatics, at benzene conversion of 40.3%, ethylene and propylene conversion of 99.5% and 99.2%, respectively. The incorporation of Ga species could effectively weaken the strong acid sites of ZSM-5 and endow 2Ga/ZSM-5 catalyst with appropriate acidity, therefore facilitating the benzene alkylation process and suppressing the undesired hydrogen transfer or aromatization side reactions as well, thus improving the yield of desired C8-C15aromatics for jet fuels. This work provided insight into the development of promising bifunctional catalyst for the oriented transformation of biomass-derived chemicals to aviation fuels.

Inhibition of human DNA alkylation damage repair enzyme ALKBH2 by HIV protease inhibitor ritonavir.

The human DNA repair enzyme AlkB homologue-2 (ALKBH2) repairs methyl adducts from genomic DNA and is overexpressed in several cancers. However, there are no known inhibitors available for this crucial DNA repair enzyme. The aim of this study was to examine whether the first-generation HIV protease inhibitors having strong anti-cancer activity can be repurposed as inhibitors of ALKBH2. We selected four such inhibitors and performed in vitro binding analysis against ALKBH2 based on alterations of its intrinsic tryptophan fluorescence and differential scanning fluorimetry. The effect of these HIV protease inhibitors on the DNA repair activity of ALKBH2 was also evaluated. Interestingly, we observed that one of the inhibitors, ritonavir, could inhibit ALKBH2-mediated DNA repair significantly via competitive inhibition and sensitized cancer cells to alkylating agent methylmethane sulfonate (MMS). This work may provide new insights into the possibilities of utilizing HIV protease inhibitor ritonavir as a DNA repair antagonist.

HFIP-Mediated Dual C(Ar)-Alkylation Process towards the Regioselective Synthesis of Triarylmethanes (TRAMs).

The distinct roles of different chemical species are essential for the discovery of novel chemical transformations in organic synthesis. Here, we have designed a potential strategy for the synthesis of triarylmethanes (TRAMs) using the dual C(aryl)-alkylation process. This protocol was influenced by 1,1,1,3,3,3-hexafluoro isopropanol (HFIP) as a pivotal reagent and proceeds through the selective para C-H functionalization method. The described approach has been proven to be highly efficient in terms of substrate scope with excellent functional group tolerance and gram scale synthesis of the desired product with 90% yield. The recyclability and reusability of HFIP has enhanced the feasibility of this protocol towards the sustainable synthesis of TRAMs.

Nickel complexes bearing quinoline derived NNS donor ligands as catalytic activators for N-alkylation of anilines with alcohols.

Herein, we have reported a new series of NNS-donor ligands coordinated Ni(II) complexes and utilized them as catalytic activator to synthesize N-alkylated aminesand 1,2-disubstituted benzimidazoles. The separate reaction of  [C9H6N-NH-C(O)-CH2-S-Ar] [Ar = C6H5 (L1); C6H4Cl-4 (L2);C6H4Me-4 (L3) and C6H4-OMe-4 (L4)] with Ni(OAc)2 in methanol at 80°C for 3 hours resulted in octahedral nickel complexes [(L1-H)2Ni] (C1), [(L2-H)2Ni] (C2), [(L3-H)2Ni] (C3), and [(L4-H)2Ni] (C4), respectively. All compounds have been characterized by micro and spectroscopic analysis. The molecular structure of complexes C1-C3 has also been determined by single crystal X-ray diffraction data. The utility of complexes C1-C4 were evaluated for the N-alkylation of aniline with benzyl alcohols, and for 1,2-disubstituted benzimidazoles synthesis. The obtained results indicate that complex C1 showed better catalytic activity in both N-alkylation of amines with benzyl alcohols [catalyst loading: 2.0 mol%; Yield up to 92%], and for 1,2-disubstituted benzimidazoles derivatives [catalyst loading: 2.0 mol%; Yield up to 94%)]. The mechanistic studies suggested that the reaction works through hydrogen borrowing from benzyl alcohol and its subsequent utilization for in situ reduction of imine. The experimentally observed catalytic reactivity patterns of complexes C1-C4 have found in good agreement with the HOMO-LUMO energy gaps obtained by DFT analysis of corresponding complexes.

A New Structural Motif in Aggregation of Methylalumoxanes: Non-hydrolytic Route by the Alkylation of Dicarboxylic Acids.

Alumoxanes are typically produced via controlled hydrolysis of short-chain alkyl aluminium compounds which leads to oligomeric species that are usually difficult to obtain in crystalline form. Simultaneously, various alternative non-hydrolytic approaches to alumoxanes have also been used. In this work, we report on a new methylalumoxane scaffold derived from the alkylation of a series of dicarboxylic acids: itaconic acid (HO2CCH2C(=CH2)CO2H), succinic acid (HO2CCH2CH2CO2H) and homophthalic acid (HO2CCH2C6H4CO2H). The reactions of AlMe3 with a selected dicarboxylic acid in the molar ratio 4:1 conducted at elevated temperature occur with double methylation of each carboxylic group and provide to the formation of a new methylalumoxane aggregate, Me10Al6O4, flanked by methylaluminium diolate units. We also aimed to obtain dialkylaluminium derivatives of dicarboxylic acids by the controlled reaction of the appropriate acid with AlMe3 in the 1:2 stoichiometry. While the synthesis of organoaluminium derivatives of flexible aliphatic dicarboxylic acids (itaconic and succinic acids) is challenging due to their insolubility, the related homophtalate compound readily forms a molecular tetranuclear cluster, [(homophtalate)(AlMe2)2]2. The molecular and crystal structures of the resulting compounds were determined via NMR spectroscopic analysis and single crystal X-ray diffraction crystallography.

Recent Progress in the Conversion of Methylfuran into Value-Added Chemicals and Fuels.

2-methylfuran is a significant organic chemical raw material which can be produced by hydrolysis, dehydration, and selective hydrogenation of biomass hemicellulose. 2-methylfuran can be converted into value-added chemicals and liquid fuels. This article reviews the latest progress in the synthesis of liquid fuel precursors through hydroxyalkylation/alkylation reactions of 2-methylfuran and biomass-derived carbonyl compounds in recent years. 2-methylfuran reacts with olefins through Diels-Alder reactions to produce chemicals, and 2-methylfuran reacts with anhydrides (or carboxylic acids) to produce acylated products. In the future application of 2-methylfuran, developing high value-added chemicals and high-density liquid fuels are two good research directions.

Symmetric Aromatic Amidoalkylations of Triphenylenes.

Triphenylene derivatives are highly investigated for their electronic, supramolecular and photophysical properties, but the direct modification of the central aromatic core is particularly challenging especially in the internal positions 1, 4, 5, 8, 9, and 12. Herein we present an efficient alkylation method of 2,3,6,7,10,11-hexasubstituted triphenylene derivatives leading to tris-alkylated C3-symmetric derivatives in good yields using N-(hydroxymethyl)carboxamide or N-(alkoxylmethyl)carboxamide alkylating agents.

α-Halocarbonyls as a Valuable Functionalized Tertiary Alkyl Source.

This review introduces the synthetic organic chemical value of α-bromocarbonyl compounds with tertiary carbons. This α-bromocarbonyl compound with a tertiary carbon has been used primarily only as a radical initiator in atom transfer radical polymerization (ATRP) reactions. However, with the recent development of photo-radical reactions (around 2010), research on the use of α-bromocarbonyl compounds as tertiary alkyl radical precursors became popular (around 2012). As more examples were reported, α-bromocarbonyl compounds were studied not only as radicals but also for their applications in organometallic and ionic reactions. That is, α-bromocarbonyl compounds act as nucleophiles as well as electrophiles. The carbonyl group of α-bromocarbonyl compounds is also attractive because it allows the skeleton to be converted after the reaction, and it is being applied to total synthesis. In our survey until 2022, α-bromocarbonyl compounds can be used to perform a full range of reactions necessary for organic synthesis, including multi-component reactions, cross-coupling, substitution, cyclization, rearrangement, stereospecific reactions, asymmetric reactions. α-Bromocarbonyl compounds have created a new trend in tertiary alkylation, which until then had limited reaction patterns in organic synthesis. This review focuses on how α-bromocarbonyl compounds can be used in synthetic organic chemistry.

Fluorinated Dialkyl Chloronium Salts: Synthesis and Reactivity for Fluoroalkylation and Hydride Abstraction.

A new concept for the synthesis of dialkyl chloronium cations [R‒Cl‒R]+ is described (R = CH3, CH2CF3), that allows the formation of fluorinated derivatives. By utilizing the xenonium salt [XeOTeF5][M(OTeF5)n] (M = Sb, n = 6; M = Al, n = 4) chlorine atoms of chloroalkanes or the deactivated chlorofluoroalkane CH2ClCF3 are oxidized and removed as ClOTeF5 leading to the isolation of the corresponding chloronium salt. Since the resulting highly electrophilic cation [Cl(CH2CF3)2]+ is able to alkylate weak nucleophiles, this compound can be utilized for the introduction of a fluorinated alkyl group to those. In addition, the fluorinated alkyl chloronium cation displays a high hydride ion affinity, enabling the activation of linear hydrocarbons by hydride abstraction even at low temperatures ultimately leading to the formation of branched carbocations.

A Modified Arbuzov-Michalis Reaction for Selective Alkylation of Nucleophiles.

The alkylation of nucleophiles is among the most fundamental and well-developed transformations in chemistry. However, to achieve selective alkylation of complex substrates remains a nontrivial task. We report herein a general and selective alkylation method without using strong acids, bases, or metals. In this method, the readily available phosphinites/phosphites, in combination with ethyl acrylate, function as effective alkylating agents. Various nucleophilic groups, including alcohols, phenols, carboxylic acids, imides, and thiols can be alkylated. This method can be applied in the late-stage alkylation of natural products and pharmaceutical agents, achieving chemo- and site-selective modification of complex substrates. Experimental studies indicate the relative reactivity of a nucleophile depends on its acidity and its steric environment. Mechanistic studies suggest the reaction pathway resembles that of the Arbuzov-Michalis reaction.

Enantioselective S-Alkylation of Sulfenamides by Phase-Transfer Catalysis.

A general phase-transfer catalyst (PTC) mediated enantioselective alkylation of N-acylsulfenamides is reported. Essential to achieving high selectivity was the use of the triethylacetyl sulfenamide protecting group along with aqueous KOH as the base under biphasic aqueous conditions to enable the reaction to be performed at -40 °C. With these key parameters, enantiomeric ratios up to 97.5:2.5 at the newly generated chiral sulfur center were achieved with an inexpensive cinchona alkaloid derived PTC. Broad scope and excellent functional group compatibility was observed for a variety of S-(hetero)aryl and branched and unbranched S-alkyl sulfenamides. Moreover, to achieve high selectivity for the opposite enantiomer, a pseudoenantiomeric catalyst was designed and synthesized from inexpensive cinchonidine. Given that sulfoximines are a bioactive pharmacophore of ever-increasing interest, selected product sulfilimines were oxidized to the corresponding sulfoximines with subsequent reductive cleavage affording the free-NH sulfoximines in high yields. The utility of the disclosed method was further demonstrated by the efficient asymmetric synthesis of atuveciclib, a phase I clinical candidate for which only chiral HPLC separation had previously been reported for isolation of the desired (R)-sulfoximine stereoisomer.

Covalent binding of withanolides to cysteines of protein targets.

Withanolides represent an important category of natural products with a steroidal lactone core. Many of them contain an α,ß-unsaturated carbonyl moiety with a high reactivity toward sulfhydryl groups, including protein cysteine thiols. Different withanolides endowed with marked antitumor and anti-inflammatory have been shown to form stable covalent complexes with exposed cysteines present in the active site of oncogenic kinases (BTK, IKKß, Zap70), metabolism enzymes (Prdx-1/6, Pin1, PHGDH), transcription factors (Nrf2, NFκB, C/EBPß) and other structural and signaling molecules (GFAP, ß-tubulin, p97, Hsp90, vimentin, Mpro, IPO5, NEMO, …). The present review analyzed the covalent complexes formed through Michael addition alkylation reactions between six major withanolides (withaferin A, physalin A, withangulatin A, 4ß-hydroxywithanolide E, withanone and tubocapsanolide A) and key cysteine residues of about 20 proteins and the resulting biological effects. The covalent conjugation of the α,ß-unsaturated carbonyl system of withanolides with reactive protein thiols can occur with a large set of soluble and membrane proteins. It points to a general mechanism, well described with the leading natural product withaferin A, but likely valid for most withanolides harboring a reactive (electrophilic) enone moiety susceptible to react covalently with cysteinyl residues of proteins. The multiplicity of reactive proteins should be taken into account when studying the mechanism of action of new withanolides. Proteomic and network analyses shall be implemented to capture and compare the cysteine covalent-binding map for the major withanolides, so as to identify the protein targets at the origin of their activity and/or unwanted effects. Screening of the cysteinome will help understanding the mechanism of action and designing cysteine-reactive electrophilic drug candidates.

Prenylation of aromatic amino acids and plant phenolics by an aromatic prenyltransferase from Rasamsonia emersonii.

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.

Structures and Protein Engineering of the α-Keto Acid C-Methyltransferases SgvM and MrsA for Rational Substrate Transfer.

S-adenosyl-l-methionine-dependent methyltransferases (MTs) are involved in the C-methylation of a variety of natural products. The MTs SgvM from Streptomyces griseoviridis and MrsA from Pseudomonas syringae pv. syringae catalyze the methylation of the ß-carbon atom of α-keto acids in the biosynthesis of the antibiotic natural products viridogrisein and 3-methylarginine, respectively. MrsA shows high substrate selectivity for 5-guanidino-2-oxovalerate, while other α-keto acids, such as the SgvM substrates 4-methyl-2-oxovalerate, 2-oxovalerate, and phenylpyruvate, are not accepted. Here we report the crystal structures of SgvM and MrsA in the apo form and bound with substrate or S-adenosyl-l-methionine. By investigating key residues for substrate recognition in the active sites of both enzymes and engineering MrsA by site-directed mutagenesis, the substrate range of MrsA was extended to accept α-keto acid substrates of SgvM with uncharged and lipophilic ß-residues. Our results showcase the transfer of the substrate scope of α-keto acid MTs from different biosynthetic pathways by rational design.

Michael addition-activated alkylation of G-quadruplex DNA with methylamine-protected vinyl-quinazolinone derivatives.

The role of G-quadruplex (G4) in cellular processes can be investigated by the covalent modification of G4-DNA using alkylating reagents. Controllable alkylating reagents activated by external stimuli can react elegantly and selectively. Herein, we report a chemical activation system that can significantly boost the reaction rate of methylamine-protected vinyl-quinazolinone (VQ) derivative for the alkylation of G4-DNA. The two screened activators can transform low-reactive VQ-NHR' to highly reactive intermediates following the Michael addition mechanism. This approach expands the toolbox of activable G4 alkylating reagents.

Diastereoselective Synthesis of Sulfoxide-Functionalized N-Heterocyclic Carbene Ruthenium Complexes: An Experimental and Computational Study.

The synthesis of sulfoxide-functionalized NHC ligand precursors were carried out by direct and mild oxidation from corresponding thioether precursors with high selectivity. Using these salts, a series of cationic [Ru(II)(η6-p-cymene)(NHC-SO)Cl]+ complexes were obtained in excellent yields by the classical Ag2O transmetallation route. NMR analyses suggested a chelate structure for the metal complexes, and X-ray diffractometry studies of complexes 4 b, 4 c, 4dBArF and 4 e unambiguously confirmed the preference for the bidentate (κ2-C,S) coordination mode of the NHC-SO ligands. Interestingly, only one diastereomer, in the form of an enantiomeric pair, was observed both in 1H NMR and in the solid state for the complexes. DFT calculations showed a possible intrinsic energy difference between the two pairs of diastereomer. The calculated energy barriers suggested that inversion of the sulfoxide is only plausible from the higher energy diastereomer together with bulky substituents. Inverting the configuration at the Ru center instead shows a lower and accessible activation barrier to provide the most stable diastereomer through thermodynamic control, consistent with the observation of a single species by 1H NMR as a pair of enantiomers. All these complexes catalyse the ß-alkylation of secondary alcohols. Complex 4dPF6 bearing an NHC-functionalised S-Ad group has been further studied with different primary and secondary alcohols as substrates, showing high reactivity and high to moderate ß-ol-selectivities.

Preparation of Dearomatized p-Coumaric Acid Derivatives as DNA Damage Response Inhibitors with Potent In Vitro Antitumor Effect.

Our research group previously identified graviquinone (1) as a promising antitumor metabolite that is formed in situ when the antioxidant methyl caffeate scavenges free radicals. Furthermore, it exerted a DNA damaging effect on cancer cells and a DNA protective effect on normal keratinocytes. To expand and explore chemical space around qraviquinone, in the current work we synthesized 9 new alkyl-substituted derivatives and tested their in vitro antitumor potential. All new compounds bypassed ABCB1-mediated multidrug resistance and showed highly different cell line specificity compared with 1. All compounds were more potent in MDA-MB-231 than on MCF-7 cells. The n-butyl-substituted derivatives 2 and 8 modulated the cell cycle and inhibited the ATR-mediated phosphorylation of checkpoint kinase-1 in MCF-7 cells. As a significant expansion of our previous findings, our results highlight the potential antitumor value of alkyl-substituted graviquinone derivatives.

Synergistic Copper-Aminocatalysis for Direct Tertiary α-Alkylation of Ketones with Electron-Deficient Alkanes.

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.

Cs2CO3-Promoted Alkylation of 3-Cyano-2(1H)-Pyridones: Anticancer Evaluation and Molecular Docking.

Herein, a Cs2CO3-promoted N-alkylation of 3-cyano-2(1H)-pyridones containing alkyl groups with diverse alkyl halides to synthesize N-alkyl-2-pyridones over O-alkylpyridines is reported. The use of alkyl dihalides resulted in complex mixtures of N- and O-alkylated products. The primary factor influencing regioselectivity in these reactions is the electronic effects of substituents on the 2(1H)-pyridone ring, as evidenced by the preferential formation of O-alkylpyridines upon the introduction of aryl groups. Remarkably, we efficiently employed CuAAC and Ti(Oi-Pr)4-catalyzed amidation reactions to functionalize N-alkyl-2-pyridones containing propargyl and ester groups, leading to the synthesis of 1,2,3-triazoles and amides, respectively. Moreover, O-alkylpyridines 10 b and 10 d displayed remarkable selectivity toward the A-498 renal cancer cell line with growth inhibition percentages (%GI) of 54.75 and 67.64, respectively. The binding modes of compounds 10 b and 10 d to the PIM-1 kinase enzyme were determined through molecular docking studies.