A Guide for Mono-Selective N-Methylation, N-Ethylation, and N-n-Propylation of Primary Amines, Amides, and Sulfonamides and Their Applicability in Late-Stage Modification.

This review provides a comprehensive overview of mono-alkylation methodologies targeting crucial nitrogen moieties - amines, amides, and sulfonamides - found in organic building blocks and pharmaceuticals. Emphasizing the intersection of chemical precision with drug discovery, the central challenge addressed is achieving one-pot mono-selective short-chain N-alkylations (methylations, ethylations, and n-propylations), preventing undesired overalkylation. Additionally, sustainable, safe, and benign alternatives to traditional alkylating agents, including alcohols, carbon dioxide, carboxylic acids, nitriles, alkyl phosphates, quaternary ammonium salts, and alkyl carbonates, are explored. This review, categorized by the nature of the alkylating agent, aids researchers in selecting suitable methods for mono-selective N-alkylation.

Strategies for Using Quaternary Ammonium Salts as Alternative Reagents in Alkylations.

Alkylation reactions are pivotal in organic chemistry, with wide-ranging utilization across various fields of applied synthetic chemistry. However, conventional reagents employed in alkylations often pose substantial health and exposure risks. Quaternary ammonium salts (QAS) present a promising alternative for these transformations offering significantly reduced hazards as they are non-cancerogenic, non-mutagenic, non-flammable, and non-corrosive. Despite their potential, their use in direct organic transformations remains relatively unexplored. This review outlines strategies for utilizing QAS as alternative reagents in alkylation reactions, providing researchers with safer approaches to chemical synthesis.

Tetraethylammonium Salts as Solid, Easy to Handle Ethylene Precursors and Their Application in Mizoroki-Heck Coupling.

In this study, we introduce a convenient Heck vinylation protocol that eliminates the requirement for ethylene gas as a coupling partner. In contrast to traditional methodologies, quaternary ammonium salts can serve as solid olefin precursors under ambient atmosphere conditions. The practicality of this method, distinguished by its convenience and safety in a one-pot reaction, renders it appealing for applications in research and discovery context.

Indium-Mediated Acyloxyallylation-Based Synthesis of Galacto-Configured Higher-Carbon Sugar Alcohols as Potential Phase Change Materials.

Sugar alcohols fulfilling specific structural requirements are a substance class with great potential as organic phase change materials (PCMs). Within this work, we demonstrate the indium-mediated acyloxyallylation (IMA) as a useful strategy for the synthesis of higher-carbon sugar alcohols of the galacto-family featuring all hydroxyl groups in a 1,3-anti-relationship with three major synthetic achievements: first, the dihydroxylation of the IMA-derived allylic sugar derivates was systematically studied in terms of diastereoselectivity, revealing a high degree of substrate control toward anti-addition. Second, we demonstrated the use of a "double Mitsunobu" reaction, inverting the stereochemistry of terminal diols. Third, the IMA toolbox was expanded to accomplish the synthesis of derivatives with up to 10 carbon atoms from particularly unreactive aldoses. Thermal investigations of all synthesized sugar alcohols, including examples with exclusive 1,3-anti- and suboptimal 1,3-syn-relationships as well as even and odd numbers of carbon atoms, were performed. We observed clear trends in melting points and thermal storage densities and discovered limitations of organic substances in this class with melting points above 240 °C as PCMs in terms of thermal stability. With our study, we provide insights into the dependence of thermal properties on structural features, thus contributing to further understanding of organic PCMs for thermal energy storage applications.

Allylation of C-, N-, and O-Nucleophiles via a Mechanochemically-Driven Tsuji-Trost Reaction Suitable for Late-Stage Modification of Bioactive Molecules.

We present the first solvent-free, mechanochemical protocol for a palladium-catalyzed Tsuji-Trost allylation. This approach features exceptionally low catalyst loadings (0.5 mol %), short reaction times (<90 min), and a simple setup, eliminating the need for air or moisture precautions, making the process highly efficient and environmentally benign. We introduce solid, nontoxic, and easy-to-handle allyl trimethylammonium salts as valuable alternative to volatile or hazardous reagents. Our approach enables the allylation of various O-, N-, and C-nucleophiles in yields up to 99 % even for structurally complex bioactive compounds, owing to its mild conditions and exceptional functional group tolerance.

Extraction techniques for bioactive compounds of cannabis.

Historically, cannabis has always constituted a component of the civilized world; archaeological discoveries indicate that it is one of the oldest crops, while, up until the 19th century, cannabis fibers were extensively used in a variety of applications, and its seeds comprised a part of human and livestock nutrition. Additional evidence supports its exploitation for medicinal purposes in the ancient world. The cultivation of cannabis gradually declined as hemp fibers gave way to synthetic fibers, while the intoxicating ability of THC eventually overshadowed the extensive potential of cannabis. Nevertheless, the proven value of certain non-intoxicating cannabinoids, such as CBD and CBN, has recently given rise to an entire market which promotes cannabis-based products. An increase in the research for recovery and exploitation of beneficial cannabinoids has also been observed, with more than 10 000 peer-reviewed research articles published annually. In the present review, a brief overview of the history of cannabis is given. A look into the classification approaches of cannabis plants/species as well as the associated nomenclature is provided, followed by a description of their chemical characteristics and their medically valuable components. The application areas could not be absent from the present review. Still, the main focus of the review is the discussion of work conducted in the field of extraction of valuable bioactive compounds from cannabis. We conclude with a summary of the current status and outlook on the topics that future research should address.

A Fujiwara-Moritani-Type Alkenylation Using a Traceless Directing Group Strategy: A Rare Example of C-C Bond Formation towards the C2-Carbon of Terminal Alkenes.

Herein we report, a rhodium-catalyzed Fujiwara-Moritani-type reaction of unactivated terminal alkenes and benzoic acid derivatives bearing electron donating residues under mild conditions. The acid functionality acts as a traceless directing group delivering products alkenylated in meta-position to the electron donating substituent in contrast to the usually obtained ortho- and para-substitution in Friedel-Crafts-type reactions. Remarkably, the new C-C bond is formed to the C2 of the terminal olefin, in contrast to similar reported transformations. Initially formed mixtures of exo- and endo-double bond isomers can be efficiently isomerized to the more stable endo-products.

Selective α-Methylation of Aryl Ketones Using Quaternary Ammonium Salts as Solid Methylating Agents.

We describe the use of phenyl trimethylammonium iodide (PhMe3NI) as an alternative methylating agent for introducing a CH3 group in α-position to a carbonyl group. Compared to conventional methylating agents, quaternary ammonium salts have the advantages of being nonvolatile, noncancerogenic, and easy-to-handle solids. This regioselective method is characterized by ease of operational setup, use of anisole as green solvent, and yields up to 85%.

Photocatalytic Hydroalkylation of Aryl-Alkenes.

Here, we present a visible light-catalyzed hydroalkylation of aryl-alkenes affording C-C bonds using aryl-alkenes and alkyl iodides. We demonstrate the formation of various hydroalkylation products in excellent yields, with primary, secondary, and tertiary alkyl iodides being tolerated in the reaction. Mechanistic experiments reveal a pathway consisting of halogen atom transfer followed by a radical-polar crossover mechanism delivering the desired hydroalkylation products.

Photocatalyst-free hydroacylations of electron-poor alkenes and enones under visible-light irradiation.

Herein we present a photocatalyst- and additive-free radical hydroacylation of electron-poor double bonds under mild reaction conditions. Using 4-acyl-Hantzsch ester radical reservoirs, various Michael acceptors, enones and para-quinone methide substrates could be used. The protocol enabled further derivatizations and it could also be extended to a few unactivated alkenes. Moreover, the nature of the radical process was also investigated.

Sterically Demanding Flexible Phosphoric Acids for Constructing Efficient and Multi-Purpose Asymmetric Organocatalysts.

Herein, we present a novel approach for various asymmetric transformations of cyclic enones. The combination of readily accessible chiral diamines and sterically demanding flexible phosphoric acids resulted in a simple and highly tunable catalyst framework. The careful optimization of the catalyst components led to the identification of a particularly powerful and multi-purpose organocatalyst, which was successfully applied for asymmetric epoxidations, aziridinations, aza-Michael-initiated cyclizations, as well as for a novel Robinson-like Michael-initiated ring closure/aldol cyclization. High catalytic activities and excellent stereocontrol was observed for all four reaction types, indicating the excellent versatility of our catalytic system. Furthermore, a simple change in the diamine's configuration provided easy access to both product antipodes in all cases.

Counterion-Enhanced Pd/Enamine Catalysis: Direct Asymmetric α-Allylation of Aldehydes with Allylic Alcohols by Chiral Amines and Achiral or Racemic Phosphoric Acids.

We report a straightforward and efficient Pd/enamine catalytic procedure for the direct asymmetric α-allylation of branched aldehydes. The use of simple chiral amines and easily prepared achiral or racemic phosphoric acids, together with a suitable Pd-source resulted in a highly active and enantioselective catalyst system for the allylation of various α-branched aldehydes with different allylic alcohols. The reported procedure could provide an easy access to both product antipodes. Furthermore, two possible orthogonal derivatizations of the enantioenriched aldehydes were performed without any decrease in enantioselectivity.

Chiral Phosphoric Acids as Versatile Tools for Organocatalytic Asymmetric Transfer Hydrogenations.

Herein, recent developments in the field of organocatalytic asymmetric transfer hydrogenation (ATH) of C=N, C=O and C=C double bonds using chiral phosphoric acid catalysis are reviewed. This still rapidly growing area of asymmetric catalysis relies on metal-free catalysts in combination with biomimetic hydrogen sources. Chiral phosphoric acids have proven to be extremely versatile tools in this area, providing highly active and enantioselective alternatives for the asymmetric reduction of α,ß-unsaturated carbonyl compounds, imines and various heterocycles. Eventually, such transformations are more and more often used in multicomponent/cascade reactions, which undoubtedly shows their great synthetic potential and the bright future of organocatalytic asymmetric transfer hydrogenations.

A Combined Deep Eutectic Solvent-Ionic Liquid Process for the Extraction and Separation of Platinum Group Metals (Pt, Pd, Rh).

Recovery of platinum group metals from spent materials is becoming increasingly relevant due to the high value of these metals and their progressive depletion. In recent years, there is an increased interest in developing alternative and more environmentally benign processes for the recovery of platinum group metals, in line with the increased focus on a sustainable future. To this end, ionic liquids are increasingly investigated as promising candidates that can replace state-of-the-art approaches. Specifically, phosphonium-based ionic liquids have been extensively investigated for the extraction and separation of platinum group metals. In this paper, we present the extraction capacity of several phosphonium-based ionic liquids for platinum group metals from model deep eutectic solvent-based acidic solutions. The most promising candidates, P66614Cl and P66614B2EHP, which exhibited the ability to extract Pt, Pd, and Rh quantitively from a mixed model solution, were additionally evaluated for their capacity to recover these metals from a spent car catalyst previously leached into a choline-based deep eutectic solvent. Specifically, P66614Cl afforded extraction of the three target precious metals from the leachate, while their partial separation from the interfering Al was also achieved since a significant amount (approx. 80%) remained in the leachate.

Characterization of a Structural Leoligin Analog as Farnesoid X Receptor Agonist and Modulator of Cholesterol Transport.

The ligand-activated farnesoid X receptor is an emerging therapeutic target for the development of drugs against metabolic syndrome-related diseases. In this context, selective bile acid receptor modulators represent a novel concept for drug development. Selective bile acid receptor modulators act in a target gene- or tissue-specific way and are therefore considered less likely to elicit unwanted side effects. Based on leoligin, a lignan-type secondary plant metabolite from the alpine plant Leontopodium nivale ssp. alpinum, 168 synthesized structural analogs were screened in a farnesoid X receptor in silico pharmacophore-model. Fifty-six virtual hits were generated. These hits were tested in a cell-based farnesoid X receptor transactivation assay and yielded 7 farnesoid X receptor-activating compounds. The most active one being LT-141A, with an EC50 of 6 µM and an Emax of 4.1-fold. This analog did not activate the G protein-coupled bile acid receptor, TGR5, and the metabolic nuclear receptors retinoid X receptor α, liver X receptors α/ß, and peroxisome proliferator-activated receptors ß/γ. Investigation of different farnesoid X receptor target genes characterized LT-141A as selective bile acid receptor modulators. Functional studies revealed that LT-141A increased cholesterol efflux from THP-1-derived macrophages via enhanced ATP-binding cassette transporter 1 expression. Moreover, cholesterol uptake in differentiated Caco-2 cells was significantly decreased upon LT-141A treatment. In conclusion, the leoligin analog LT-141A selectively activates the nuclear receptor farnesoid X receptor and has an influence on cholesterol transport in 2 model systems.

GABAA Receptor Ligands Often Interact with Binding Sites in the Transmembrane Domain and in the Extracellular Domain-Can the Promiscuity Code Be Cracked?

Many allosteric binding sites that modulate gamma aminobutyric acid (GABA) effects have been described in heteropentameric GABA type A (GABAA) receptors, among them sites for benzodiazepines, pyrazoloquinolinones and etomidate. Diazepam not only binds at the high affinity extracellular "canonical" site, but also at sites in the transmembrane domain. Many ligands of the benzodiazepine binding site interact also with homologous sites in the extracellular domain, among them the pyrazoloquinolinones that exert modulation at extracellular α+/ß- sites. Additional interaction of this chemotype with the sites for etomidate has also been described. We have recently described a new indole-based scaffold with pharmacophore features highly similar to pyrazoloquinolinones as a novel class of GABAA receptor modulators. Contrary to what the pharmacophore overlap suggests, the ligand presented here behaves very differently from the identically substituted pyrazoloquinolinone. Structural evidence demonstrates that small changes in pharmacophore features can induce radical changes in ligand binding properties. Analysis of published data reveals that many chemotypes display a strong tendency to interact promiscuously with binding sites in the transmembrane domain and others in the extracellular domain of the same receptor. Further structural investigations of this phenomenon should enable a more targeted path to less promiscuous ligands, potentially reducing side effect liabilities.

Allosteric GABAA Receptor Modulators-A Review on the Most Recent Heterocyclic Chemotypes and Their Synthetic Accessibility.

GABAA receptor modulators are structurally almost as diverse as their target protein. A plethora of heterocyclic scaffolds has been described as modulating this extremely important receptor family. Some made it into clinical trials and, even on the market, some were dismissed. This review focuses on the synthetic accessibility and potential for library synthesis of GABAA receptor modulators containing at least one heterocyclic scaffold, which were disclosed within the last 10 years.

Design and Synthesis of a Compound Library Exploiting 5-Methoxyleoligin as Potential Cholesterol Efflux Promoter.

5-Methoxyleoligin and leoligin are natural occurring lignans derived from Edelweiss (Leontopodium nivale ssp. alpinum), displaying potent pro-angiogenic and pro-arteriogenic activity. Cholesterol efflux from macrophages is associated with reverse cholesterol transport which inhibits the development of cardiovascular disease. Within this study, we developed a modular and stereoselective total synthesis of 5-methoxyleoligin which can be readily used to prepare a novel compound library of related analogs. The target 5-methoxyleoligin was synthesized exploiting a recently disclosed modular route, which allows also rapid synthesis of analogous compounds. All obtained products were tested towards macrophage cholesterol efflux enhancement and the performance was compared to the parent compound leoligin. It was found that variation on the aryl moiety in 2-position of the furan ring allows optimization of the activity profile, whereas the ester-functionality does not tolerate significant alterations.

Photocatalytic deaminative benzylation and alkylation of tetrahydroisoquinolines with N-alkylpyrydinium salts.

A ruthenium-catalyzed photoredox coupling of substituted N-aryltetrahydroisoquinolines (THIQs) and different bench-stable pyridinium salts was successfully developed to give fast access to 1-benzyl-THIQs. Furthermore, secondary alkyl and allyl groups were also successfully introduced via the same method. Additionally, the typically applied N-phenyl group in the THIQ substrate could be replaced by the cleavable p-methoxyphenyl (PMP) group and successful N-deprotection was demonstrated.

Investigations of the generality of quaternary ammonium salts as alkylating agents in direct C-H alkylation reactions: solid alternatives for gaseous olefins.

C-H alkylation reactions using short chain olefins as alkylating agents could be operationally simplified on the lab scale by using quaternary ammonium salts as precursors for these gaseous reagents: Hofmann elimination delivers in situ the desired alkenes with the advantage that the alkene concentration in the liquid phase is high. In case a catalytic system did not tolerate the conditions for Hofmann elimination, a very simple spatial separation of both reactions, Hofmann elimination and direct alkylation, was achieved to circumvent possible side reactions or catalyst deactivation. Additionally, the truly catalytically active species of a rhodium(i) mediated alkylation reaction could be identified by using this approach.