A unified flow strategy for the preparation and use of trifluoromethyl-heteroatom anions.

The trifluoromethyl group (CF3) is a key functionality in pharmaceutical and agrochemical development, greatly enhancing the efficacy and properties of resulting compounds. However, attaching the CF3 group to heteroatoms such as sulfur, oxygen, and nitrogen poses challenges because of the lack of general synthetic methods and reliance on bespoke reagents. Here, we present a modular flow platform that streamlines the synthesis of heteroatom-CF3 motifs. Our method uses readily available organic precursors in combination with cesium fluoride as the primary fluorine source, facilitating the rapid generation of N-trifluoromethyl(R) [NCF3(R)], SCF3 (trifluoromethylthio), and OCF3 (trifluoromethoxy) anions on demand without reliance on perfluoroalkyl precursor reagents. This strategy offers a more environmentally friendly synthesis of trifluoromethyl(heteroatom)-containing molecules, with the potential for scalability in manufacturing processes facilitated by flow technology.

In-Flow Generation of Thionyl Fluoride (SOF2) Enables the Rapid and Efficient Synthesis of Acyl Fluorides from Carboxylic Acids.

Herein, we report an approach for generating thionyl fluoride (SOF2) from the commodity chemicals thionyl chloride (SOCl2) and potassium fluoride (KF). The methodology relies on a microfluidic device that can efficiently produce and dose this toxic gaseous reagent under extremely mild and safe conditions. Subsequently, the in situ-generated thionyl fluoride is reacted with an array of structurally and electronically differing carboxylic acids, leading to the direct and efficient synthesis of highly sought-after acyl fluorides. Importantly, our investigation also highlights the inherent modularity of this flow-based platform. We demonstrate the adaptability of this approach by not only synthesizing acyl fluorides but also directly converting carboxylic acids into a diverse array of valuable compounds such as esters, thioesters, amides, and ketones. This versatility showcases the potential of this approach for a wide range of synthetic applications, underscoring its significance in the realm of chemical synthesis.

C1-4 Alkylation of Aryl Bromides with Light Alkanes enabled by Metallaphotocatalysis in Flow.

The homologous series of gaseous C1-4 alkanes represents one of the most abundant sources of short alkyl fragments. However, their application in synthetic organic chemistry is exceedingly rare due to the challenging C-H bond cleavage, which typically demands high temperatures and pressures, thereby limiting their utility in the construction of complex organic molecules. In particular, the formation of C(sp2)-C(sp3) bonds is crucial for constructing biologically active molecules, including pharmaceuticals and agrochemicals. In this study, we present the previously elusive coupling between gaseous alkanes and (hetero)aryl bromides, achieved through a combination of Hydrogen Atom Transfer (HAT) photocatalysis and nickel-catalyzed cross coupling at room temperature. Utilizing flow technology allowed us to conduct this novel coupling reaction with reduced reaction times and in a scalable fashion, rendering it practical for widespread adoption in both academia and industry. Density Functional Theory (DFT) calculations unveiled that the oxidative addition constitutes the rate-determining step, with the activation energy barrier increasing with smaller alkyl radicals. Furthermore, radical isomerization observed in propane and butane analogues could be attributed to the electronic properties of the bromoarene coupling partner, highlighting the crucial role of oxidative addition in the observed selectivity of this transformation.

Electrochemical Asymmetric Radical Functionalization of Aldehydes Enabled by a Redox Shuttle.

Aminocatalysis is a well-established tool that enables the production of enantioenriched compounds under mild conditions. Its versatility is underscored by its seamless integration with various synthetic approaches. While the combination of aminocatalysis with metal catalysis, photochemistry, and stoichiometric oxidants has been extensively explored, its synergy with electrochemical activation remains largely unexplored. Herein, we present the successful merger of electrochemistry and aminocatalysis to perform SOMO-type transformations, expanding the toolkit for asymmetric electrochemical synthesis. The methodology harnesses electricity to drive the oxidation of catalytically generated enamines, which ultimately partake in enantioselective radical processes, leading to α-alkylated aldehydes. Crucially, mechanistic studies highlight how this electrochemical strategy is enabled by the use of a redox shuttle, 4,4'-dimethoxybiphenyl, to prevent catalyst degradation and furnishing the coveted compounds in good yield and high enantioselectivity.

Photocatalytic (3 + 2) dipolar cycloadditions of aziridines driven by visible-light.

Herein, we document the design and development of a novel (3 + 2) cycloaddition reaction aided by the activity of an organic photocatalyst and visible light. The process is extremely fast, taking place in a few minutes, with virtually complete atom economy. A large variety of structurally diverse aziridines were used as masked ylides in the presence of different types of dipolarophiles (28 examples with up to 94% yield and >95 : 5 dr). Mechanistic insights obtained from photophysical, electrochemical and experimental studies highlight that the chemistry is driven by the in situ generation of the reactive ylide through two consecutive electron-transfer processes. We also report an aerobic cascade process, where an additional oxidation step grants access to a vast array of pyrrole derivatives (19 examples with up to 95% yield). Interestingly, the extended aromatic core exhibits a distinctive absorption and emission profile, which can be easily used to tag the effectiveness of this covalent linkage.

Scale-Up of Photochemical Reactions: Transitioning from Lab Scale to Industrial Production.

In the past two decades, we have witnessed a rapid emergence of new and powerful photochemical and photocatalytic synthetic methods. Although these methods have been used mostly on a small scale, there is a growing need for efficient scale-up of photochemistry in the chemical industry. This review summarizes and contextualizes the advancements made in the past decade regarding the scale-up of photo-mediated synthetic transformations. Simple scale-up concepts and important fundamental photochemical laws have been provided along with a discussion concerning suitable reactor designs that should facilitate scale-up of this challenging class of organic reactions.

The Merger of Benzophenone HAT Photocatalysis and Silyl Radical-Induced XAT Enables Both Nickel-Catalyzed Cross-Electrophile Coupling and 1,2-Dicarbofunctionalization of Olefins.

A strategy for both cross-electrophile coupling and 1,2-dicarbofunctionalization of olefins has been developed. Carbon-centered radicals are generated from alkyl bromides by merging benzophenone hydrogen atom transfer (HAT) photocatalysis and silyl radical-induced halogen atom transfer (XAT) and are subsequently intercepted by a nickel catalyst to forge the targeted C(sp3)-C(sp2) and C(sp3)-C(sp3) bonds. The mild protocol is fast and scalable using flow technology, displays broad functional group tolerance, and is amenable to a wide variety of medicinally relevant moieties. Mechanistic investigations reveal that the ketone catalyst, upon photoexcitation, is responsible for the direct activation of the silicon-based XAT reagent (HAT-mediated XAT) that furnishes the targeted alkyl radical and is ultimately involved in the turnover of the nickel catalytic cycle.

Homogeneous catalytic C(sp3)-H functionalization of gaseous alkanes.

The conversion of light alkanes into bulk chemicals is becoming an important challenge as it effectively avoids the use of prefunctionalized alkylating reagents. The implementation of such processes is, however, hampered by their gaseous nature and low solubility, as well as the low reactivity of the C-H bonds. Efforts have been made to enable both polar and radical processes to activate these inert compounds. In addition, these methodologies also benefit significantly from the development of a suitable reactor technology that intensifies gas-liquid mass transfer. In this review, we critically highlight these developments, both from a conceptual and a practical point of view. The recent expansion of these mechanistically-different methods have enabled the use of various gaseous alkanes for the development of different bond-forming reactions, including C-C, C-B, C-N, C-Si and C-S bonds.

Rapid and Direct Photocatalytic C(sp3 )-H Acylation and Arylation in Flow.

Herein, we report a photocatalytic procedure that enables the acylation/arylation of unfunctionalized alkyl derivatives in flow. The method exploits the ability of the decatungstate anion to act as a hydrogen atom abstractor and produce nucleophilic carbon-centered radicals that are intercepted by a nickel catalyst to ultimately forge C(sp3 )-C(sp2 ) bonds. Owing to the intensified conditions in flow, the reaction time can be reduced from 12-48 hours to only 5-15 minutes. Finally, kinetic measurements highlight how the intensified conditions do not change the reaction mechanism but reliably speed up the overall process.

Catalytic asymmetric C-C cross-couplings enabled by photoexcitation.

Enantioselective catalytic processes are promoted by chiral catalysts that can execute a specific mode of catalytic reactivity, channeling the chemical reaction through a certain mechanistic pathway. Here, we show how by simply using visible light we can divert the established ionic reactivity of a chiral allyl-iridium(III) complex to switch on completely new catalytic functions, enabling mechanistically unrelated radical-based enantioselective pathways. Photoexcitation provides the chiral organometallic intermediate with the ability to activate substrates via an electron-transfer manifold. This redox event unlocks an otherwise inaccessible cross-coupling mechanism, since the resulting iridium(II) centre can intercept the generated radicals and undergo a reductive elimination to forge a stereogenic centre with high stereoselectivity. This photochemical strategy enables difficult-to-realize enantioselective alkyl-alkyl cross-coupling reactions between allylic alcohols and readily available radical precursors, which are not achievable under thermal activation.