Development of S_NAr Nucleophilic Fluorination: A Fruitful Academia-Industry Collaboration

Accounts of Chemical Research, Journal Year: 2020, Volume and Issue: 53(10), P. 2372 - 2383

Published: Sept. 24, 2020

ConspectusThe identification of reliable, general, and high yielding methods for the formation C(sp2)–fluorine bonds remains a major challenge synthetic organic chemists. A very common approach involves nucleophilic aromatic fluorination (SNAr fluorination) reactions aryl chlorides or nitroarenes. Despite being known more than century, traditional SNAr suffer from significant limitations, particularly on process scale. These include cost reagents [e.g., cesium fluoride (CsF)], requirement elevated temperatures long reaction times, poor functional group tolerance, need rigorous exclusion water. This Account summarizes our collaboration with Corteva Agriscience (previously Dow Agrosciences) to address many these challenges. has provided platform fundamental scientific advances involving development new methods, reagents, substrates mild reactions.Our early studies established that combination potassium (KF) superstoichiometric tetrabutylammonium chloride (Bu4NCl) serves as cost-effective alternative CsF chloropicolinate substrates. However, still require (>130 °C) afford moderate yields due competing decomposition substrate product. The temperature is largely slow rates resulting low concentration active fluorinating reagent [anhydrous (Bu4NF)] under conditions. To this issue, we developed several strategies generating solutions anhydrous tetraalkylammonium in situ by combining fluorine-containing electrophiles (e.g., hexafluorobenzene, acyl fluorides, sulfonyl fluorides) nucleophiles (R4NCN R4NOR). systems enable unusually conditions, affording nearly quantitative yield at room temperature. generation large quantities byproducts R4NF-forming step render unsuitable scale applications. As an alternative, next explored tetramethylammonium (Me4NF) transformations. highly reactive source can be synthesized directly inexpensive KF Me4NCl then dried heating vacuum. Unlike Bu4NF, it not susceptible Hofmann elimination. such, Me4NF stable isolable, well effective chloropicolinates other electron deficient substrates.The R4NF drew attention another associated reactions: their limitation bearing resonance electron-withdrawing groups. We hypothesized could addressed circumventing Meisenheimer intermediate, canonical mechanistic feature fluorination. By designing involve concerted delivery ipso C(sp2) center, deoxyfluorination arylfluorosulfonates using Me4NF. exhibits broad scope respect electrophile, both (CN, ester, CF3, Cl) moderately donating (phenyl, alkyl) substituents participating deoxyfluorination. conditions were also expanded nonaromatic substrates, including aldehydes benzylic/aliphatic alcohols.This concludes delineating ongoing challenges opportunities fast-moving field. For instance, one important future direction will moisture sensitivity In addition, application synthesis pharmaceuticals, agrochemicals, PET imaging agents continue test versatility compatibility methods.

Language: Английский

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Photocatalytic C−F Bond Activation of Fluoroarenes, gem‐Difluoroalkenes and Trifluoromethylarenes

Asian Journal of Organic Chemistry, Journal Year: 2021, Volume and Issue: 10(10), P. 2454 - 2472

Published: Aug. 18, 2021

Abstract Fluorine‐containing compounds have been widely applied on pharmaceuticals, agrochemicals, and materials. The synthetic methodology for the introduction of fluorine into organic motifs has witnessed dramatically development recently. Selective C−F bond activation functionalization easily accessible fluorinated provided an efficient way to synthesize novel products degradate extremely stable pollutants. As photocatalytic transformations, light induced direct under mild conditions leading production various functionalities become one most advanced methodologies available. This minireview summarizes recent activations compounds, including fluoroarenes, gem ‐difluoroalkenes trifluoromethylarenes, intends illustrate readers a comprehensive this research topic via demonstrating representative examples detailed mechanism according reaction types transformations.

Language: Английский

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Decarbonylative Fluoroalkylation at Palladium(II): From Fundamental Organometallic Studies to Catalysis

Journal of the American Chemical Society, Journal Year: 2021, Volume and Issue: 143(44), P. 18617 - 18625

Published: Oct. 28, 2021

This Article describes the development of a decarbonylative Pd-catalyzed aryl–fluoroalkyl bond-forming reaction that couples fluoroalkylcarboxylic acid-derived electrophiles [RFC(O)X] with aryl organometallics (Ar–M′). was optimized by interrogating individual steps catalytic cycle (oxidative addition, carbonyl de-insertion, transmetalation, and reductive elimination) to identify compatible pair coupling partners an appropriate Pd catalyst. These stoichiometric organometallic studies revealed several critical elements for design. First, uncatalyzed background reactions between RFC(O)X Ar–M′ can be avoided using M′ = boronate ester. Second, de-insertion Ar–RF elimination are two slowest when RF CF3. Both dramatically accelerated upon changing CHF2. Computational reveal favorable F2C–H---X interaction contributes accelerating in this system. Finally, transmetalation is slow X difluoroacetate but fast F. Ultimately, these enabled (SPhos)Pd-catalyzed difluoromethylation neopentylglycol esters difluoroacetyl fluoride.

Language: Английский

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Controllable Single and Double Difluoromethylene Insertions into C–Cu Bonds: Copper-Mediated Tetrafluoroethylation and Hexafluoropropylation of Aryl Iodides with TMSCF₂H and TMSCF₂Br

Journal of the American Chemical Society, Journal Year: 2022, Volume and Issue: 144(27), P. 12202 - 12211

Published: July 5, 2022

The selective difluoromethylene insertion into a C–Cu bond is challenging task and currently limited to either single CF2 CuCF3 or double insertions CuC6F5 (or (Z)-CF3CF = CFCu). Achieving both the same even more difficult. Herein, highly controllable CuCF2H species with TMSCF2Br reagent have been described, affording two previously unknown fluoroalkylcopper "Cu(CF2)nCF2H" (n 1 2) independently under different reaction conditions. This work represents first example of in manner. synthetic value obtained demonstrated by their reactions aryl iodides, halogenation agents, cinnamyl chloride, which enables direct transfer HCF2CF2 HCF2CF2CF2 moieties organic molecules. key fluorocarbon chain elongation from C1 C2 C3 presumably attributed reactivities 0, 1, 2 3) loading reagent.

Language: Английский

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Recent advances in transition-metal catalyzed directed C–H functionalization with fluorinated building blocks

Organic Chemistry Frontiers, Journal Year: 2022, Volume and Issue: 9(6), P. 1742 - 1775

Published: Jan. 1, 2022

This review focuses on the advances in transition-metal catalyzed reactions with fluorinated building blocks via directed C–H bond activation for construction of diverse organic molecules an insight into probable mechanistic pathway.

Language: Английский

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