Unlocking full and fast conversion in photocatalytic carbon dioxide reduction for applications in radio-carbonylation.

Harvesting sunlight to drive carbon dioxide (CO2) valorisation represents an ideal concept to support a sustainable and carbon-neutral economy. While the photochemical reduction of CO2 to carbon monoxide (CO) has emerged as a hot research topic, the full CO2-to-CO conversion remains an often-overlooked criterion that prevents a productive and direct valorisation of CO into high-value-added chemicals. Herein, we report a photocatalytic process that unlocks full and fast CO2-to-CO conversion (<10 min) and its straightforward valorisation into human health related field of radiochemistry with carbon isotopes. Guided by reaction-model-based kinetic simulations to rationalize reaction optimisations, this manifold opens new opportunities for the direct access to 11C- and 14C-labeled pharmaceuticals from their primary isotopic sources [11C]CO2 and [14C]CO2.

Novel alpha6 preferring GABA-A receptor ligands based on loreclezole.

The family of GABA-A receptors contains nineteen mammalian subunits from which pentameric, GABA gated anion channels are assembled. The subunit encoded by the GABRA6 gene is highly expressed in the cerebellum and the receptors to which it contributes have recently been demonstrated to be a promising candidate as a novel drug target. Here we examined a series of loreclezole derivatives for potentially selective action at α6ß3γ2 receptors with the help of computational methods and functional testing with the two-electrode voltage clamp technique. The synthetic routes to some previously published ligands were improved, and a new derivative was synthesized based on computational docking results. This new loreclezole derivative, [3-(2-chloro-4-methylphenyl)-3-methylbutanenitrile (40)], was shown to display stronger modulatory action in concatenated α6ß3γ2 receptors compared to their α1ß3γ2 counterpart. The hypothetical bound state structure provides valuable guidance for future design of selective therapeutics.

Modular and Chemoselective Strategy for the Direct Access to α-Fluoroepoxides and Aziridines via the Addition of Fluoroiodomethyllithium to Carbonyl-Like Compounds.

An expeditious, high-yielding synthesis of rare α-fluoroepoxides and α-fluoroaziridines through the addition of the unkown fluoroiodomethyllithium (LiCHIF)-formed via deprotonation the commercially available fluoroiodomethane with a lithium amide base-to carbonyl-like compounds is documented. The ring-closure reactions, leading to α-fluorinated three-membered heterocycles, rely on the diversely reactive C-I and C-F bonds. Excellent chemoselectivity was observed in the presence of highly sensitive functionalities-aldehyde, ketone, nitrile, alkene-which remained untouched during the homologation sequence.

Sustainable Asymmetric Organolithium Chemistry: Enantio- and Chemoselective Acylations through Recycling of Solvent, Sparteine, and Weinreb "Amine".

The well-established Hoppe-Beak chemistry, which involves enantioselective generation of organolithium compounds in the presence of (-)-sparteine, was revisited and applied to unprecedented acylations with Weinreb amides to access highly enantioenriched α-oxyketones and cyclic α-aminoketones. Recycling of the sustainable solvent cyclopentyl methyl ether, sparteine, and the released Weinreb "amine" [HNMe(OMe)] was possible through a simple work-up procedure that enabled full recovery of these precious materials. The methodology features a robust scope and flexibility, thus allowing the enantioselective preparation of scaffolds amenable of further derivatization.

Design, Synthesis, and Pharmacological Evaluation of Novel ß2/3 Subunit-Selective γ-Aminobutyric Acid Type A (GABAA) Receptor Modulators.

Subunit-selective modulation of γ-aminobutyric acid type A receptors (GABAAR) is considered to exert fewer side effects compared to unselective clinically used drugs. Here, the ß2/3 subunit-selective GABAAR modulators valerenic acid (VA) and loreclezole (LOR) guided the synthesis of novel subunit-selective ligands with simplified structures. We studied their effects on GABAARs expressed in Xenopus laevis oocytes using two-microelectrode voltage clamp technique. Five compounds showed significantly more efficacious modulation of GABA-evoked currents than VA and LOR with retained potency and selectivity. Compound 18 [( E)-2-Cyano-3-(2,4-dichlorophenyl)but-2-enamide] induced the highest maximal modulation of GABA-induced chloride currents ( Emax: 3114 ± 242%), while 12 [( Z)-3-(2,4-dichlorophenyl)but-2-enenitrile] displayed the highest potency (EC50: 13 ± 2 µM). Furthermore, in hippocampal neurons 12 facilitated phasic and tonic GABAergic inhibition, and in vivo studies revealed significantly more potent protection against pentylenetetrazole (PTZ)-induced seizures compared to VA and LOR. Collectively, compound 12 constitutes a novel, simplified, and subunit-selective GABAAR modulator with low-dose anticonvulsant activity.

Cyclopentyl Methyl Ether: An Elective Ecofriendly Ethereal Solvent in Classical and Modern Organic Chemistry.

Solvents represent one of the major contributions to the environmental impact of fine-chemical synthesis. As a result, the use of environmentally friendly solvents in widely employed reactions is a challenge of vast real interest in contemporary organic chemistry. Within this Review, a great variety of examples showing how cyclopentyl methyl ether has been established as particularly useful for this purpose are reported. Indeed, its low toxicity, high boiling point, low melting point, hydrophobicity, chemical stability towards a wide range of conditions, exceptional stability towards the abstraction of hydrogen atoms, relatively low latent heat of vaporization, and the ease with which it can be recovered and recycled enable its successful employment as a solvent in a wide range of synthetic applications, including organometallic chemistry, catalysis, biphasic reactions, oxidations, and radical reactions.

A practical guide for using lithium halocarbenoids in homologation reactions.

ABSTRACT: Lithium halocarbenoids are versatile reagents for accomplishing homologation processes. The fast α-elimination they suffer has been considered an important limitation for their extensive use. Herein, we present a series of practical considerations for an effective employment in the homologation of selected carbon electrophiles.

Homologation chemistry with nucleophilic α-substituted organometallic reagents: chemocontrol, new concepts and (solved) challenges.

The transfer of a reactive nucleophilic CH2X unit into a preformed bond enables the introduction of a fragment featuring the exact and desired degree of functionalization through a single synthetic operation. The instability of metallated α-organometallic species often poses serious questions regarding the practicability of using this conceptually intuitive and simple approach for forming C-C or C-heteroatom bonds. A deep understanding of processes regulating the formation of these nucleophiles is a precious source of inspiration not only for successfully applying theoretically feasible transformations (i.e. determining how to employ a given reagent), but also for designing new reactions which ultimately lead to the introduction of molecular complexity via short experimental sequences.

Exploiting a "Beast" in Carbenoid Chemistry: Development of a Straightforward Direct Nucleophilic Fluoromethylation Strategy.

The first direct and straightforward nucleophilic fluoromethylation of organic compounds is reported. The tactic employs a "fleeting" lithium fluorocarbenoid (LiCH2F) generated from commercially available fluoroiodomethane. Precise reaction conditions were developed for the generation and synthetic exploitation of such a labile species. The versatility of the strategy is showcased in ca. 50 examples involving a plethora of electrophiles. Highly valuable chemicals such as fluoroalcohols, fluoroamines, and fluoromethylated oxygenated heterocycles could be prepared in very good yields through a single synthetic operation. The scalability of the reaction and its application to complex molecular architectures (e.g., steroids) are documented.

Recent advancements on the use of 2-methyltetrahydrofuran in organometallic chemistry.

ABSTRACT: Since the introduction of 2-methyltetrahydrofuran as an useful alternative to the classical tetrahydrofuran, there has been a continuous interest in the synthetic community operating at academic and industrial towards it. In particular, the much higher stability that basic organometallic reagents display in 2-methyltetrahydrofuran makes it suitable for processes involving such sensitive species including asymmetric transformations. The easy formation of an azeotropic mixture with water, the substantial immiscibility with water, and the fact it derives from natural sources (corncobs or bagasse), allow to consider it in agreement with the Anastas' Geen Chemistry principles. In this minireview, selected examples of its employment in organometallic transformations ranging from carbanions to radical and transition metal-catalyzed processes are provided.

Isocyanates and isothiocyanates as versatile platforms for accessing (thio)amide-type compounds.

The addition of carbon (Grignard and organolithium reagents) and hydride nucleophiles (Schwartz reagent) to isocyanates and isothiocyanates constitutes a versatile, direct and high yielding approach to the synthesis of functionalized (thio)amide derivatives including haloamides and formamides. The chemoselective delivery of a nucleophilic (eventually configurationally stable) organometallic species to a given iso(thio)cyanate is the crucial parameter for the success of the strategy. Thus, the influence of the factors governing classical methodologies (e.g. dehydrative condensation) such as steric hindrance and electronic properties of the reactants become practically negligible.

The Use of the Comins-Meyers Amide in Synthetic Chemistry: an Overview.

Formylation reactions are fundamental operations in synthetic chemistry allowing the incorporation into a given structure formyl groups amenable to further deiivatization. Conceptually, the introduction of such groups through the reaction between an electrophilic donor and a nucleophilic acceptor (i.e. organometallic reagent) constitutes a reliable technique with widespread applications. In this Highlight, we summarize the effectiveness of the so called Comnins-Meyers amide - [2-(N-methyl-N-formylamino]pyridine - in such a chemistry with vistas to the synthesis of natural products and biologically active substrates.

A Robust, Eco-Friendly Access to Secondary Thioamides through the Addition of Organolithium Reagents to Isothiocyanates in Cyclopentyl Methyl Ether (CPME).

The nucleophilic addition of widely available and variously functionalized organolithium reagents to isothiocyanates represents a straightforward, high-yielding, one-pot method to access secondary thioamides. The simple reaction conditions required and the broad scope (>50 cases examples) makes it a robust and reliable method to access both simple and complex thioamides, including enantiopure ones. Noxious and unpleasant-smelling sulfurating agents, usually employed in the literature established methods, are avoided during the whole synthetic procedure thus, rendering the protocol highly attractive, also for sustainability aspects.