Regioselective Fluorination Research Articles

Regioselective fluorination of allenes enabled by I(I)/I(III) catalysis

The prominence and versatility of propargylic fluorides in medicinal chemistry, coupled with the potency of F/H and F/OH bioisosterism, has created a powerful impetus to develop efficient methods to facilitate their construction. Motivated by the well-established conversion of propargylic alcohols to allenes, an operationally simple, organocatalysis-based strategy to process these abundant unsaturated precursors to propargylic fluorides would be highly enabling: this would consolidate the bioisosteric relationship that connects propargylic alcohols and fluorides. Herein, we describe a highly regioselective fluorination of unactivated allenes based on I(I)/I(III) catalysis in the presence of an inexpensive HF source that serves a dual role as both nucleophile and Brønsted acid activator. This strategy enables a variety of secondary and tertiary propargylic fluorides to be prepared: these motifs are prevalent across the bioactive small molecule spectrum. Facile product derivatisation, concise synthesis of multi-vicinal fluorinated products together with preliminary validation of enantioselective catalysis are disclosed. The expansive potential of this platform is also demonstrated through the highly regioselective organocatalytic oxidation, chlorination and arylation of allenes. It is envisaged that the transformation will find application in molecular design and accelerate the exploration of organofluorine chemical space.

Photoinduced Regioselective Fluorination and Vinylation of Remote C(sp3)-H Bonds Using Thianthrenium Salts.

Herein, a photoredox-driven practical protocol for fluorinated alkene synthesis using easily accessible and modular thianthrenium salts with electron-withdrawing alkynes or propargyl alcohols is reported. Vinyl radical intermediates, formed by the reaction between the alkyl or trifluoromethyl thianthrenium salts and electronically diverse alkynes, can mediate the key 1,5-HAT process of regioselective C(sp3)-H fluorination and vinylation. This protocol provides straightforward access to structurally diverse trifluoromethyl- or distally fluoro-functionalized alkene products in 21-79% yields with a broad substrate range under mild photocatalytic conditions.

Synthesis of fluorinated spiro-1,3-oxazines and thiazines via Selectfluor-mediated intramolecular cyclization.

A fluorination-induced intramolecular cyclization for the synthesis of fluoro-substituted spiro-1,3-oxazine and spiro-1,3-thiazine derivatives is described. N-(2-(Cyclohex-1-en-1-yl)ethyl)benzamide and benzothioamide are used as the substrates, and the cationic fluorinating agent Selectfluor works as the fluoride source. The reaction yields a single diastereomer. The scope of this regioselective fluorination reaction is established by preparing thirty different spirooxazine and spirothiazine derivatives.

Regioselective Fluorination of Amino Acid Derivatives

Key words regioselective fluorination - cesium fluoride - potassium fluoride

Regioselective Fluorination of Acenes: Tailoring of Molecular Electronic Levels and Solid-State Properties.

Optoelectronic properties of molecular solids are important for organic electronic devices and are largely determined by the adopted molecular packing motifs. In this study, we analyzed such structure‐property relationships for the partially regioselective fluorinated tetracenes 1,2,12‐trifluorotetracene, 1,2,10,12‐tetrafluorotetracene and 1,2,9,10,11‐pentafluorotetracene that were further compared with tetracene and perfluoro‐tetracene. Quantum chemical DFT calculations in combination with optical absorption spectroscopy data show that the frontier orbital energies are lowered with the degree of fluorination, while their optical gap is barely affected. However, the crystal structure changes from a herringbone packing motif of tetracene towards a planar stacking motif of the fluorinated tetracene derivatives, which is accompanied by the formation of excimers and leads to strongly red‐shifted photoluminescence with larger lifetimes.

Catalytic Access to Functionalized Allylic gem‐Difluorides via Fluorinative Meyer–Schuster‐Like Rearrangement

AbstractAn unprecedented approach for efficient synthesis of functionalized allylic gem‐difluorides via catalytic fluorinative Meyer–Schuster‐like rearrangement is disclosed. This transformation proceeded with readily accessible propargylic fluorides, and low‐cost B–F reagents and electrophilic reagents by sulfide catalysis. A series of iodinated, brominated, and trifluoromethylthiolated allylic gem‐difluorides that were difficult to access by other methods were facilely produced with a wide range of functional groups. Importantly, the obtained iodinated products could be incorporated into different drugs and natural products, and could be expediently converted into many other valuable gem‐difluoroalkyl molecules as well. Mechanistic studies revealed that this reaction went through a regioselective fluorination of alkynes followed by a formal 1,3‐fluorine migration under the assistance of the B–F reagents to give the desired products.

Catalytic Access to Functionalized Allylic gem-Difluorides via Fluorinative Meyer-Schuster-Like Rearrangement.

An unprecedented approach for efficient synthesis of functionalized allylic gem-difluorides via catalytic fluorinative Meyer-Schuster-like rearrangement is disclosed. This transformation proceeded with readily accessible propargylic fluorides, and low-cost B-F reagents and electrophilic reagents by sulfide catalysis. A series of iodinated, brominated, and trifluoromethylthiolated allylic gem-difluorides that were difficult to access by other methods were facilely produced with a wide range of functional groups. Importantly, the obtained iodinated products could be incorporated into different drugs and natural products, and could be expediently converted into many other valuable gem-difluoroalkyl molecules as well. Mechanistic studies revealed that this reaction went through a regioselective fluorination of alkynes followed by a formal 1,3-fluorine migration under the assistance of the B-F reagents to give the desired products.

Copper-Mediated Fluorination of Aryl Trisiloxanes with Nucleophilic Fluoride.

A method for the nucleophilic fluorination of heptamethyl aryl trisiloxanes to form fluoroarenes is reported. The reaction proceeds in the presence of Cu(OTf)2 and KHF2 as the fluoride source under mild conditions for a broad range of heptamethyltrisiloxyarenes with high functional group tolerance. The combination of this method with the silylation of aryl C-H bonds enables the regioselective fluorination of non-activated arenes controlled by steric effects following a two-step protocol.

Regioselective Fluorination of α‐Hydroxy‐β‐aminophosphonates by Using PyFluor

We report a simple protocol for the synthesis of α‐fluoro‐β‐aminophosphonates by the regioselective fluorination of α‐hydroxy‐β‐aminophosphonates under mild conditions. The fluorination reactions were mediated by the PyFluor reagent and occurred with the retention of configuration. The main products of this reaction were a series of α‐fluoro‐β‐aminophosphonates, which can be used as precursors in the preparation of medicinally important compounds (e.g., dipeptide analogues).

Copper-Catalyzed Direct C-5 Fluorination of 8-Aminoquinolines by Remote C–H Activation

A convenient method was developed for direct regioselective fluorination of 8-aminoquinolines at the C-5 position by copper-catalyzed remote C–H activation using Selectfluor as the electrophile fluorinating reagent. With this method, diverse fluorinated quinoline derivatives were facilely obtained under mild conditions with moderate yields.

Synthesis of a 3'-Fluoro-3'-deoxytetrose Adenine Phosphonate.

A new synthetic route to a 3'-fluoro-3'-deoxytetrose adenine phosphonate has been developed. The synthesis starts from l-xylose and key steps include the stereospecific introduction of the phosphonomethoxy group and adenine. In addition, a regioselective fluorination reaction allows access to the desired 3'-fluoro-3'-deoxytetrose moiety. This methodology allows the straightforward synthesis of a 3'-fluoro-3'-deoxytetrose adenine phosphonate and can be expanded toward the synthesis of other types of 3'-fluoro nucleoside phosphonates.

Silver-Catalyzed Regioselective Fluorination of Carbonyl Directed Alkynes: Synthesis of α-Fluoroketones.

A novel silver-catalyzed fluorination reaction of carbonyl directed alkynes in the presence of N-fluorobenzenesulfonimide and water with high regioselectivities has been developed. The established protocol provides an alternative method for rapid assembly of α-fluoroketone derivatives under simple and mild reaction conditions. The reaction pathway involves a ring closure and opening process for the construction of new C-O and C-F bonds. In addition, a fluorine-containing indanone was observed through further N-heterocyclic carbene catalyzed intramolecular crossed-benzoin reaction of α-fluoroketone.

ChemInform Abstract: Regioselective Electrophilic Fluorination of Rationally Designed Imidazole Derivatives.

AbstractLithium tetramethylpiperidide is found to efficiently promote the regioselective fluorination of N‐protected 2‐substituted imidazoles (I) and (IV) to give the products regioselectively.

A highly regio- and stereoselective synthesis of α-fluorinated imides via fluorination of chiral enamides.

A highly π-facial selective and regioselective fluorination of chiral enamides is described. The reaction involves an enantioselective fluorination exclusively at the electron-rich enamide olefin with N-F reagents such as Selectfluor and N-fluoro-benzenesulfonimide [NFSI] accompanied by trapping of the β-fluoro-iminium cationic intermediate with water. The resulting N,O-hemiacetal could be oxidized using Dess-Martin periodinane, leading to an asymmetric sequence for syntheses of chiral α-fluoro-imides and optically enriched α-fluoro-ketones.

Regioselective fluorination in synthesis of deoxyfluoro quercitols from d-(−)-quinic acid

A facile synthesis of six new deoxyfluoro querciotls from d-(−)-quinic acid is described. The key steps involve the regioselective fluorination as well as highly stereoselective dihydroxylation. These synthetic deoxyfluoro quercitols are considered as potential glycosidase inhibitors.

ChemInform Abstract: A Two‐Step Sequence to Ethyl α‐Fluorocyclopropanecarboxylates Through MIRC Reaction of Ethyl Dichloroacetate and Highly Regioselective Fluorination.

AbstractThe two‐step sequence yields monofluorinated cyclopropane derivatives which are of pharmaceutical interest due to their biological activities.

Mechanistic Investigations of Palladium-Catalyzed Allylic Fluorination

A computational and experimental approach was employed to study the mechanism of the palladium(0)-catalyzed fluorination of allylic chlorides with AgF as fluoride source. Our findings indicate that an allylpalladium fluoride is a key intermediate necessary for the generation of both the nucleophile and electrophile. Evidence was also obtained to support a homobimetallic mechanism in which C–F bond formation occurs by nucleophilic attack of a neutral allylpalladium fluoride on a cationic allylpalladium electrophile (with fluoride as counterion). The high branched selectivity and unusual ligand effects observed in the regioselective fluorination are assessed in light of this mechanism and calculated transition states. These results may have important implications for the mechanism of other transition-metal-catalyzed fluorinations.

A Two‐Step Sequence to Ethyl α‐Fluorocyclopropanecarboxylates Through MIRC Reaction of Ethyl Dichloroacetate and Highly Regioselective Fluorination

AbstractA two‐step sequence to ethyl α‐fluorocyclopropanecarboxylates has been developed. Ethyl α‐chlorocyclopropanecarboxylates were first obtained through a Michael‐initiated ring closure reaction of terminal electron‐deficient olefins with ethyl 2,2‐dichloroacetate under mild basic conditions. Subsequent smooth conversion into the corresponding monofluorinated analogues in good yields was through a halogen exchange reaction with potassium bifluoride. Further investigation clearly demonstrated that potassium bifluoride in this reaction system played a dual role of base and nucleophilic reagent. This is the first successful example reported hitherto for producing ethyl α‐fluorocyclopropanecarboxylate directly through fluorination of its chlorinated analogue with alkali bifluoride.

Copper‐Catalyzed Regioselective Fluorination of Allylic Halides

Group activity: A novel copper-catalyzed fluorination of internal allylic bromides and chlorides has been developed by using Et3N⋅3 HF as the fluorine source. A functional group (FG) within the substrate is required to achieve the allylic fluorination, and a variety of secondary allylic fluoride compounds can be accessed in good yield with excellent regioselectivity.

Copper‐Catalyzed Regioselective Fluorination of Allylic Halides

Gruppenaktivität: Eine neuartige kupferkatalysierte Fluorierung von internen Allylbromiden und -chloriden mit Et3N⋅3 HF als Fluorquelle wurde entwickelt. Im Substrat wird eine funktionelle Gruppe (FG) benötigt, um die allylische Fluorierung herbeizuführen, und eine Vielzahl an sekundären Allylfluoriden ist in guten Ausbeuten mit exzellenter Regioselektivität zugänglich.