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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.

gem-Difluoroalkenes and trifluoromethyl alkanes are prominent structures in biologically active compounds. Radical alkylation of α-trifluoromethyl alkenes represents a useful strategy to access these structures. However, reported methods have relied on the use of pre-functionalized radical precursors and examples involving the use of simple hydrocarbons as coupling partners are elusive. Here we report a chemodivergent methodology based on the direct activation of C(sp3)–H bonds enabled by HAT photoredox catalysis. This protocol provides an efficient platform for preparing both gem-difluoroalkenes and trifluoromethyl alkanes from ubiquitous hydrocarbon feedstocks, including gaseous alkanes. Importantly, chemoselectivity is easily achieved by simple modification of reaction conditions and/or additives. [ABSTRACT FROM AUTHOR]

Alkylation reactions and their products are considered crucial in various contexts. Synthetically, the alkylation of a nucleophile is usually promoted using hazardous alkyl halides. Here, we aim to highlight the potential of pnictogen (ammonium or phosphonium) and chalcogen salts (sulfonium, selenonium, and telluronium) to function as alkylating agents. These compounds can be considered as non‐volatile electrophilic alkyl reservoirs. We will center our discussion on the strategies developed in recent years to expand the synthetic utility of these salts in terms of transferable alkyl groups, substrate scope, and product selectivity. [ABSTRACT FROM AUTHOR]

Glaucoma is one of the major causes of irreversible blindness worldwide. Increased intraocular pressure (IOP) is a key factor in the onset and progression of this disease. The drugs used to treat glaucoma influence a variety of biological targets. Azolopyrimidine derivatives have attracted significant attention as potential agents for the treatment of glaucoma because they presumed to be analogs of adenosine receptor (AR) agonists and antagonists. In this study, a series of novel 3(4)‐alkyl‐[1,2,4]triazolo[1,5‐a]pyrimidin‐7‐amines were synthesized to develop promising ophthalmic hypotensive drugs. The synthesized compounds demonstrated significant hypotensive activity against IOP, which opens new possibilities for glaucoma therapy. [ABSTRACT FROM AUTHOR]

A relay catalytic system is developed for the asymmetric hydrogenative coupling of indoles with α,β-unsaturated ketones, affording enantioenriched chiral γ-indole alcohols with broad substrate scope and excellent enantioselectivities (32 examples, up to >99% ee). Mechanistic studies suggest that the relay catalytic system consists of copper-catalyzed alkylation and ruthenium-catalyzed asymmetric hydrogenation. [ABSTRACT FROM AUTHOR]

A Palladium catalyzed C4‐ alkylation of indoles using epoxide as an alkylating agent and pivaloyl as a weak chelating group has been demonstrated. A variety of substituted epoxides and indoles furnished the desired β‐indolylethyl alcohols in 38%–87% yields. Control experiments indicate that the C−H cleavage step is irreversible. The resultant hydroxyl group has been converted to various functional groups to demonstrate the synthetic utility of this protocol. [ABSTRACT FROM AUTHOR]

Here we reported the photo‐catalyzed C−H alkylation of pyridyl‐substituted N‐benzyl anilines through nitrogen‐centred radical 1,5‐hydrogen atom transfer. A broad range of methylpyridyl‐substituted aniline and hydroxylamine acid derivatives were successfully transformed into the corresponding products in moderate yields without adding any base and metal. This protocol features mild reaction conditions, a broad range of substrates, remarkable functional group tolerance and simple operation procedure. [ABSTRACT FROM AUTHOR]

We report here a selective C6‐nitration of benzothiazolones in the presence of iron nitrate as nitro source. A series of novel 6‐nitrobenzothiazolin‐2‐one derivatives were prepared with moderate to excellent yields at room temperature. The method shows good regioselectivity, broad substrate scope and excellent compatibility with functional groups. Further transformations were performed for the reduction of nitro groups, amination of carbonyl groups and alkylation of amine at the 3‐position in the product. [ABSTRACT FROM AUTHOR]

We are reporting a convenient method for the synthesis of bis(indolyl)methane derivatives from relatively cheap and commercially available chemicals such as indoles and aldehydes in a one‐pot procedure using Ga‐MCM‐41‐SO3H heterogeneous catalyst. Notably, the use of this catalyst has resulted in high yield of products (up to 98 %) under mild conditions, and the catalyst was found to be stable and reusable, retaining its highly catalytic activity even after five runs. Interestingly, two alkaloids Arsindoline A and Turbomycine B were successfully synthesized in the employment of this catalyst. These findings suggest that Ga‐MCM‐41‐SO3H could be a promising alternative to traditional acid homogeneous catalysts in the synthesis of bis(indolyl)methane derivatives, offering several advantages including ease of separation and reuse, high stability, and low toxicity. [ABSTRACT FROM AUTHOR]

The catalytic asymmetric electrophilic functionalization of the less reactive N-heteroaromatic compounds has been reported using the approach of the introduction of an exocyclic amino substituent. This strategy has allowed enantioselective Friedel–Crafts alkylation in pyrazoles, isoxazoles and isothiazoles, as well as in aminoindoles, aminobenzofurans and aminobenzothiophenes. Several stereoselective methods have been used for the 1,4-addition or 1,2-addition of these heteroaromatic compounds to different electrophiles employing organocatalysts or chiral metal complexes. The activating exocyclic amino substituent has also been used as a nucleophile in tandem reactions, including formal cycloadditions ([3+2] and [3+3]), for the synthesis of highly functionalized chiral nitrogen heterocycles. [ABSTRACT FROM AUTHOR]

The development of novel synthetic methods for quaternary ammonium salts is highly demanded since the current synthesis heavily relies on the conventional Menshutkin reaction. Herein, we report photoredox-catalyzed alkylation of α-brominated alkenylammonium salts. Mechanistically, the generation of a highly reactive α-ammoniovinyl radical is the key to our method. This reaction enables the synthesis of various unprecedented α-alkylated alkenylammonium salts. [ABSTRACT FROM AUTHOR]

A photochemical protocol for the alkylation of diazines (pyrimidines, pyrazines, and pyridazines) with N -(acyloxy)phthalimides has been developed. The process is facilitated by the presence of triethylamine under irradiation with 427–390 nm light; this enables rapid cross-coupling reactions to construct a wide range of alkylated diazines. [ABSTRACT FROM AUTHOR]

Six silica-supported phosphotungstic acid catalysts (PTA/SiO2) of different composition (20–70 wt% PTA content) have been synthesized and characterized by elemental analysis, BET, BJH, NH3-TPD methods, FT-IR spectroscopy of adsorbed pyridine and 1H MAS NMR techniques. The new composite catalysts were first applied in the Friedel–Crafts alkylation of toluene with 1-octene as a benchmark process under batch conditions in order to screen their activity and recyclability. The combined analytical techniques together with the catalytic studies enabled the identification of the main factors affecting the activity of the catalysts. Based on these preliminary experiments, the best performing catalyst system (50 wt% PTA/SiO2) was investigated in continuous flow mode using an in-house-made flow reactor. The thorough screening of the reaction conditions (temperature, toluene/1-octene molar ratio and flow rate) provided firm evidence that the 50 wt% PTA/SiO2 composite is highly active, selective and stable catalyst under mild reaction conditions even at elevated flow rate. Additionally, the catalyst used in the flow mode could successfully be regenerated and reused in the alkylation process. [ABSTRACT FROM AUTHOR]

Dabigatran is a direct thrombin inhibitor widely applied in atrial fibrillation anticoagulation therapy. The stable isotope-labeled dabigatran etexilate were required. [2H4] dabigatran etexilate was prepared from [2H5] bromobenzene through nitration, cyanation, Pinner reaction, esterfication, reduction and alkylation. [2H3] dabigatran etexilate was obtained after acylchlorination, acylamidation, alkylation, reduction, cyclization, alkylation. [2H4] O-n-hexylacarbamate derivative was condensed with [2H3] benzimidazole to afford [2H7] dabigatran etexilate. Three versions of deuterium labelled dabigatran etexilate with excellent deuterium enrichment could be applied in LC/MS analysis. [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]

This document provides information about the synthesis and characterization of various compounds, including indazoles and pyrazolopyridines. The compounds were synthesized using specific reactions and purification techniques, and their structures were confirmed using various spectroscopic techniques. The document includes data such as chemical shifts, yields, melting points, and spectroscopic data for each compound. The authors acknowledge the support of the Central Laboratory of Pharmacy at Ankara University and declare no conflicts of interest. [Extracted from the article]

Dehydrogenative coupling (DC) and borrowing hydrogen(ation) (BH) reactions are crucial in modern organic synthesis, offering efficient and sustainable ways to create valuable compounds. However, they often face a significant challenge: the alkoxide trap. This Concept explores the alkoxide trap in DC and BH reactions, starting with the basic mechanisms and the role of alkoxide intermediates. It then examines how the alkoxide trap leads to catalyst deactivation and reduced selectivity, influenced by thermodynamic and kinetic factors. To address this, we review recent advances in catalyst design, ligand engineering, and optimized reaction conditions, along with the use of in‐situ spectroscopy and computational modelling, to better understand the underlying processes and guide rational catalyst development. Furthermore, this Concept highlights the broad applicability of DC, and BH reactions across various substrates, underscoring the urgency of addressing the alkoxide trap issue to unlock their full synthetic potential. [ABSTRACT FROM AUTHOR]

Herein, we report an inexpensive first‐row transition metal Ni heterogeneous catalytic system for the Csp3‐mono alkylation of fluorene using alcohols as alkylating agents via borrowing hydrogen strategy. The catalytic protocol displayed versatility with high yields of the desired products using various types of primary alcohols, including aryl/hetero aryl methanols, and aliphatic alcohols as alkylating agents. The catalyst Ni NPs@N−C was synthesized via high‐temperature pyrolysis strategy, using ZIF‐8 as the sacrificial template. The Ni NPs@N−C catalyst was characterized by XPS, HR‐TEM, HAADF‐STEM, XRD and ICP‐MS. The catalyst is stable even in the air at room temperature, displayed excellent activity and could be recycled 5 times without appreciable loss of its activity. [ABSTRACT FROM AUTHOR]

Herein, we present a comprehensive total synthesis of cannabidiol integrating both batch and continuous flow conditions. Our approach is planned to streamline the synthesis of olivetolic acid derivatives and utilize an enantiomerically pure monoterpene moiety obtained from naturally occurring (R)‐(+)‐limonene by photocatalysis. Key reactions, including the synthesis of olivetolic ester and a Friedel‐Crafts alkylation, are successfully adapted to continuous flow, resulting in improved yields and selectivities. This study not only offers a scalable and efficient route for cannabidiol synthesis but also contributes to the synthetic approaches to access cannabinoids (diversity synthesis), with potential applications in medicinal and industrial contexts. [ABSTRACT FROM AUTHOR]

A straightforward method for the dehydrogenative alkylation of quinoxalin-2(1H)-ones with alkylbenzenes has been developed, facilitated by a photoexcited nitroarene. The reaction's success hinges on the dual role of the photoexcited nitroarene molecule, acting as both a hydrogen atom transfer (HAT) reagent and an oxidant. This technique is both atom-economical and cost-effective, due to the readily available nitroarene, which serves as the sole intermediary in the reaction process. [ABSTRACT FROM AUTHOR]

The use of (para)-formaldehyde for the methylation/alkylation of C(sp2)–H and N–H bonds, utilizing a combination of silane and hexafluoroisopropanol (HFIP) as activators, is reported. Overcoming the complexity of C(sp2)–H methylation on aryl and indole substrates, the process utilizes a Friedel–Crafts alkylation, followed by silane as a hydride donor, under a mild acidic medium. The method has been employed for the synthesis of the antifungal drug butenafine and a derivative of the non-steroidal anti-inflammatory drug (NSAID) flurbiprofen. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

A new strategy for the asymmetric allylic alkylation of azlactones with α-(trifluoromethyl)allyl acetates catalyzed by Pd(OAc)2 /(R)-BINAP is designed and developed, providing access to unsaturated α-quaternary α-amino acid derivatives bearing a trifluoromethyl group and contiguous quaternary and tertiary stereogenic centers. The products are obtained in good yields with exclusive regioselectivity and excellent stereoselective control under relatively mild reaction conditions. A scale-up experiment shows no loss of reactivity or stereoselectivity. The synthetic utility of the current strategy is demonstrated through transformations of a representative product to afford several potentially bioactive species. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

A palladium-catalyzed coupling reaction has been developed for the generation of tertiary alkylation products by reacting olefins with diversely functionalized 1,3-dicarbonyls. The reaction involves the tertiary C–H alkylation of 1,3-dicarbonyls with olefins to produce a tertiary alcohol, followed by C–C bond cleavage. [ABSTRACT FROM AUTHOR]

Acetic acid‐mediated three‐component double Friedel–Crafts alkylation reaction for the synthesis of α, α‐diaryl oxindole derivatives is demonstrated. The reaction is successful with various isatin, indole, and N, N‐disubstituted aniline derivatives. The efficiency of the reaction is further enhanced by a four‐component reaction of isatin, electrophiles and acetic anhydride for the synthesis of N‐acylated 3,3‐diaryl oxindole derivatives facilitated by dual activation of C3 and N1 acetylation in a single‐step. Various unsymmetrical and symmetrical 3,3‐diaryl oxindoles were prepared in single‐step MCR reaction under easy to operate reaction conditions. [ABSTRACT FROM AUTHOR]

Application of the [1,2]-Wittig rearrangement and cyclisation approach to 3-arylphthalides has been evaluated for the synthesis of three bioactive natural products. While this is successful in the case of crycolide, providing the second synthesis of this compound, the more sterically demanding targets isopestacin and cryphonectric acid prove not to be amenable to this approach, with the 2,6-disubstituted aryl groups causing the failure of the rearrangement and alkylation steps, respectively. Direct oxidation of the substituted benzhydrols resulting from [1,2]-Wittig rearrangement using MnO2 provides a new route to 3-aryl-3-hydroxyisoindolinones, and this method has been used in the synthesis of two 3-aryl-3-benzyloxyisoindolinone anticancer agents. [ABSTRACT FROM AUTHOR]

Anti-wear and anti-oxidation abilities are two key properties of lubricants that play a crucial role in ensuring long-term stable equipment operation. In this study, we aimed to develop a base oil with good anti-oxidation and anti-wear properties for use under extreme pressure. The as-prepared metallocene polyalphaolefin (mPAO) was chemically modified using the trifluoromethanesulfonic acid (TfOH) catalysis through an alkylating reaction with triphenyl phosphorothioate (TPPT). During the experiments, when the reaction temperature exceeded 70 °C or the concentration of TfOH exceeded 2.67%, the β -scission reaction in the alkylation process became significantly more pronounced. The physical and chemical properties of TPPT-modified mPAO (T-mPAO) were evaluated by nuclear magnetic resonance spectroscopy, Fourier trans-form infrared spectroscopy, gel–permeation chromatography, and ASTM standards. T-mPAO showed significantly improved antioxidant capacity, with the initial oxidation temperature increasing by 32 °C compared to the base oil, and it exhibited the slowest increase in acid number in the 96-h oven oxidation test. The tribological tests showed that T-mPAO had the lowest friction coefficient, wear track, and wear rate (72.7% lower than that of mPAO) as well as the highest PB (238 kg) and PD (250 kg) among all tested samples. Compared to mPAO, the average friction coefficient of TPPT-modified mPAO in the four-ball friction test was reduced by 30.5%, and by 16.4% in the TE77 reciprocating friction test. Based on the experimental results, T-mPAO had strong anti-oxidation ability and excellent lubricating performance.The successful synthesis of multifunctional mPAO has enabled lubricant base oil additization, making it possible to use it in more demanding work scenarios, greatly broadening its application scope and making lubricant formulation blending more flexible. [ABSTRACT FROM AUTHOR]

Among the natural tetramic acids with a decalinoyl part, signermycin B is unique because it contains a cis‐decalin. In this paper, we demonstrate that the cis‐decalin section of signermycin B can be accessed by an anionic oxy‐Cope rearrangement. The substrate, a tricyclic dienol was prepared by an intramolecular Diels‐Alder reaction of a masked ortho‐benzoquinone, generated by oxidation of an α‐methoxyphenol in presence of cis‐2‐hexenol. After a superfluous bromine on the cycloadduct was removed, reaction of the tricyclic ketone with isopropenylmagnesium bromide led to the tricyclic trienol that underwent the oxy‐Cope rearrangement to a cis‐decalinone. While we could show, that introduction of the 4‐ethyl substituent (signermycin B numbering) is possible by enolate alkylation, the 4‐epi‐isomer was formed. [ABSTRACT FROM AUTHOR]

The 2,2‐difluoroethyl group is an important lipophilic hydrogen bond donor in medicinal chemistry, but its incorporation into small molecules is often challenging. Herein, we demonstrate electrophilic 2,2‐difluoroethylation of thiol, amine and alcohol nucleophiles with a hypervalent iodine reagent, (2,2‐difluoro‐ethyl)(aryl)iodonium triflate, via a proposed ligand coupling mechanism. This transformation offers a complementary strategy to existing 2,2‐difluoroethylation methods and allows access to a wide range of 2,2‐difluoroethylated nucleophiles, including the drugs Captopril, Normorphine and Mefloquine. [ABSTRACT FROM AUTHOR]

α-Hydroxy-benzylphosphonates obtained by the Pudovik reaction of substituted benzaldehydes and dialkyl phosphites were added to the triple bond of dialkyl acetylenedicarboxylates. Optimum conditions involved a 24 hours stirring in the presence of 10% diazabicycloundecene in dichloromethane to afford the adducts as a mixture of predominant E - and a minor Z -isomers in 75–90% yields after flash chromatography. The structures of the geometrical isomers were confirmed by NOE- and ROE-measurements. Catalytic hydrogenation of the olefinic moiety of the adducts led to the diastereoisomers of corresponding saturated derivatives. [ABSTRACT FROM AUTHOR]

Comprehensive Summary: A novel visible‐light‐induced radical cascade 6‐endo cyclization of dienes (N‐(2‐vinylphenyl)acryl amides) is developed utilizing α‐carbonyl bromides as alkyl reagents. This approach affords an efficient way for synthesizing six‐membered benzo‐fused lactam derivatives with chemo‐ and regio‐selectivity and good functional group tolerance. Primary, secondary, and tertiary bromides are well‐compatible with this cascade cyclization reaction. [ABSTRACT FROM AUTHOR]

In recent years, Morita‐Baylis‐Hillman (MBH) carbonates have been extensively used in domino reactions for the synthesis of novel cyclic and acyclic compounds. This review highlights the progress made in the last decade in the synthesis of a series of compounds from an uncyclized reaction or annulation of MBH carbonates, which demonstrates that the excellent reactivity and high research value of MBH carbonates as representative substrates in organic synthesis. We hope the summary and understanding of the reactivity of MBH carbonates can inspire chemists to apply these substrates in the design of more efficient domino reactions, which will be beneficial for the organic synthesis and drug chemistry. [ABSTRACT FROM AUTHOR]

Enantioselective transition metal‐catalyzed C−H alkylation emerges as one of the most atom‐ and step‐economical routes to chiral quaternary carbons, while big challenges still remain with acyl C−H alkylations. Herein, we use a Ni−Al bimetallic catalyst to facilitate a highly regioselective and highly enantioselective C−H alkylation of formamides with alkenes, constructing various oxindoles bearing a chiral quaternary carbon in up to 94 % yield and up to 95 % ee. [ABSTRACT FROM AUTHOR]

Herein, we report Rh(III) catalyzed aldehydic or aryl C–H alkylation via C–C bond activation of cyclopropanols, facilitating the synthesis of β-functionalized ketones. The protocol employs cyclopropanol as the alkylating agent with 2-aminobenzaldehyde or aniline derivatives to access a variety of unsymmetrical 1,4-diketones or β-aryl ketones, respectively. The practicality of these transformations is showcased through the modification of natural products, gram-scale synthesis, broad substrate scope and postfunctionalizations. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Indole motifs are omnipresent in nature and can be found in many natural products as well as pharmaceuticals. It is for this reason synthetic transformations of indole have become a topic of interest for the organic and medicinal chemist community for decades. In this review, we have emphasized the functionalization of indoles via transition‐metal‐free approaches. This review touches on many aspects in different sub‐sections, which gives a proposition of the tactics employed for the functionalization of indoles and an overview of the road ahead. [ABSTRACT FROM AUTHOR]

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]

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]

Amino acids with unusual types of chirality and their derivatives have recently attracted attention as precursors in the synthesis of chiral catalysts and peptide analogues with unique properties. In this study, we have synthesized a new nido-carborane-based planar-chiral amino acid, in the molecule of which the amino group is directly bonded to the B(3) atom, and the carboxyl group is attached to the B(9) atom through the CH2S+(Me) fragment. 3-Amino-9-dimethylsulfonio-nido-carborane, prepared in three steps from 3-amino-closo-carborane in a high yield, was a key intermediate in the synthesis of the target planar-chiral amino acid. The carboxymethyl group at the sulfur atom was introduced by the demethylation reaction of the dimethylsulfonio derivative, followed by S-alkylation. The structure of new 3,9-disubstituted nido-carboranes was studied for the first time using NMR spectroscopy. The resonances of all boron atoms in the 11B NMR spectrum of 3-amino-9-dimethylsulfonio-nido-carborane were assigned based on the 2D NMR correlation experiments. The nido-carborane-based planar-chiral amino acid and related compounds are of interest as a basis for peptide-like compounds and chiral ligands. [ABSTRACT FROM AUTHOR]

It is not known why the number of proteinogenic amino acids is limited to 20. Since Miller's experiment, many studies have shown that amino acids could have been generated under prebiotic conditions. However, the amino acid compositions obtained from simulated experiments and exogenous origins are different from those of life. We hypothesized that some simple precursor compounds generated by high-energy reactions were selectively combined by organic reactions to afford a limited number of amino acids. To this direction, we propose two scenarios. One is the reaction of HCN with each side-chain precursor (the aminomalononitrile scenario), and the other is alkylation of the "complex glycine precursor", which is the main product of proton irradiation of the primordial atmosphere (the new polyglycine scenario). Here, selective formation of the 20 amino acids is described focusing on the latter scenario. The structural features of proteinogenic amino acids can be described systematically. The scenario consists of three stages: a high-energy reaction stage (Gly, Ala, Asn, and Asp were established); an alkylation stage (Gln, Glu, Ser, Thr, Val, Ile, Leu, and Pro were generated in considerable amounts); and a peptide formation stage (Phe, Tyr, Trp, His, Lys, Arg, Cys, and Met were selected due to their structural advantages). This scenario is a part of the evolution of Garakuta World, in which many prebiotic materials are contained. [ABSTRACT FROM AUTHOR]

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, [([(O2CCH2C6H4CO2)(μ‐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. [ABSTRACT FROM AUTHOR]

An enantioselective tandem sequence that comprises a cycloaromatization process followed by an intramolecular desymmetrizing Friedel‐Crafts alkylation of functionalized cyclohexadienones has been accomplished. The process takes place in good yields (65–95%), with excellent diastereoselectivity (>20:1) and enantiomeric ratios up to 90.5:9.5 in the presence of (R)‐BINOL‐derived N‐triflyl phosphoramides, and it gains access to a family of pyrrolo[2,1‐a]isoquinoline derivatives in a simple manner, with the simultaneous generation of two vicinal stereocenters, one of them a tetrasubstituted carbon stereocenter. [ABSTRACT FROM AUTHOR]

Enantioselective transformation of ubiquitous C(sp3)−H bonds into three‐dimensional chiral scaffolds is of longstanding interest to synthetic chemists. Herein, an asymmetric paired electrolysis enables a highly efficient and sustainable approach to the enantioselective alkylation of sulfonylimines via C(sp3)−H functionalization. In this protocol, anodic oxidation for benzylic radical formation and Lewis acid‐catalyzed sulfonylimine reduction on the cathode were seamlessly cross‐coupled (up to 88 % yield). Enantioenriched chiral amines containing a tetrasubstituted carbon stereocenter are accessed with high enantioselectivity (up to 96 % ee). Mechanistic studies suggest that the amine generated in situ could serve as a base to deprotonate phenols and decrease the oxidation potential of the reaction, allowing phenols with lower potentials to be preferentially oxidized. [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]

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]