- Tetramethylammonium Fluoride Alcohol Adducts for SNAr Fluorination
-
Nucleophilic aromatic fluorination (SNAr) is among the most common methods for the formation of C(sp2)-F bonds. Despite many recent advances, a long-standing limitation of these transformations is the requirement for rigorously dry, aprotic conditions to maintain the nucleophilicity of fluoride and suppress the generation of side products. This report addresses this challenge by leveraging tetramethylammonium fluoride alcohol adducts (Me4NF·ROH) as fluoride sources for SNAr fluorination. Through systematic tuning of the alcohol substituent (R), tetramethylammonium fluoride tert-amyl alcohol (Me4NF·t-AmylOH) was identified as an inexpensive, practical, and bench-stable reagent for SNAr fluorination under mild and convenient conditions (80 °C in DMSO, without the requirement for drying of reagents or solvent). A substrate scope of more than 50 (hetero) aryl halides and nitroarene electrophiles is demonstrated.
- Bland, Douglas C.,Lee, So Jeong,Morales-Colón, Mariá T.,Sanford, Melanie S.,Scott, Peter J. H.,See, Yi Yang
-
supporting information
p. 4493 - 4498
(2021/06/28)
-
- Nucleophilic Fluorination of Heteroaryl Chlorides and Aryl Triflates Enabled by Cooperative Catalysis
-
Aryl and heteroaryl fluorides are growing to be dominant motifs in pharmaceuticals and agrochemicals, yet they are rare in both nature and commodity chemicals. As a consequence, there is an increasingly urgent need to develop mild, cost-effective, and scalable methods for fluorination. The most straightforward route to synthesize aryl fluorides is through the halide exchange "halex"reaction, but conditions, cost, and atom economy preclude most available methods from large-scale manufacturing processes. We report a new approach that leverages the cooperative action of 18-crown-6 ether and tetramethylammonium chloride to catalytically access the reactivity of tetramethylammonium fluoride and achieve halex fluorinations under mild conditions with operational ease. The described methodology readily converts both heteroaryl chlorides and aryl triflates to their corresponding (hetero)aryl fluorides in high yields and purities.
- Hong, Cynthia M.,Whittaker, Aaron M.,Schultz, Danielle M.
-
p. 3999 - 4006
(2021/03/09)
-
- Radical Decarboxylative Carbometalation of Benzoic Acids: A Solution to Aromatic Decarboxylative Fluorination
-
Abundant aromatic carboxylic acids exist in great structural diversity from nature and synthesis. To date, the synthetically valuable decarboxylative functionalization of benzoic acids is realized mainly by transition-metal-catalyzed decarboxylative cross couplings. However, the high activation barrier for thermal decarboxylative carbometalation that often requires 140 °C reaction temperature limits both the substrate scope as well as the scope of suitable reactions that can sustain such conditions. Numerous reactions, for example, decarboxylative fluorination that is well developed for aliphatic carboxylic acids, are out of reach for the aromatic counterparts with current reaction chemistry. Here, we report a conceptually different approach through a low-barrier photoinduced ligand to metal charge transfer (LMCT)-enabled radical decarboxylative carbometalation strategy, which generates a putative high-valent arylcopper(III) complex, from which versatile facile reductive eliminations can occur. We demonstrate the suitability of our new approach to address previously unrealized general decarboxylative fluorination of benzoic acids.
- Xu, Peng,López-Rojas, Priscila,Ritter, Tobias
-
supporting information
p. 5349 - 5354
(2021/05/05)
-
- METHOD FOR AROMATIC FLUORINATION
-
Disclosed is a f fluorination method comprising providing a fluorinating reagent and a solvent to a reaction mixture; providing a compound having the formula Ar-X to the reaction mixture; wherein, A is a aryl, substituted aryl, heteroaryl or substituted heteroaryl, and X is CI, Br, I or NO2, providing tetramethylammonium 2,6-dimethylphenolate to the reaction mixture; and reacting under conditions sufficient to provide a species having the formula Ar-F.
- -
-
Paragraph 0039-0041; 0050
(2018/03/25)
-
- Diastereoselective Synthesis of Dialkylated Bis(phosphino)ferrocenes: Their Use in Promoting Silver-Mediated Nucleophilic Fluorination of Chloroquinolines
-
The diastereoselective synthesis of dialkylated ferrocenyl bis(phosphane)s bearing aryl, alkyl, and hetero- or polycyclic substituents on the phosphino groups is reported, together with their characterization in the solid state by X-ray structure analysis
- Roger, Julien,Royer, Sylviane,Cattey, Hélène,Savateev, Aleksandr,Smaliy, Radomyr V.,Kostyuk, Aleksandr N.,Hierso, Jean-Cyrille
-
p. 330 - 339
(2017/02/05)
-
- Multiple Approaches to the in Situ Generation of Anhydrous Tetraalkylammonium Fluoride Salts for SNAr Fluorination Reactions
-
This article focuses on the development of practical approaches to the in situ generation of anhydrous fluoride salts for applications in nucleophilic aromatic substitution (SNAr) reactions. We report herein that a variety of combinations of inexpensive nucleophiles (e.g., tetraalkylammonium cyanide and phenoxide salts) and fluorine-containing electrophiles (e.g., acid fluoride, fluoroformate, benzenesulfonyl fluoride, and aryl fluorosulfonate derivatives) are effective for this transformation. Ultimately, we demonstrate that the combination of tetramethylammonium 2,6-dimethylphenoxide and sulfuryl fluoride (SO2F2) serves as a particularly practical route to anhydrous tetramethylammonium fluoride. This procedure is applied to the SNAr fluorination of a range of electron-deficient aryl and heteroaryl chlorides as well as nitroarenes.
- Cismesia, Megan A.,Ryan, Sarah J.,Bland, Douglas C.,Sanford, Melanie S.
-
p. 5020 - 5026
(2017/05/24)
-
- PROCESS FOR FLUORINATING COMPOUNDS
-
Disclosed are mild temperature (e.g., from 0 to 80°C) SNAr fluorinations of a variety of halide and sulfonate substituted aryl and heteroaryl substrates using NMe4F.
- -
-
Page/Page column 20-21; 29; 31-32
(2017/02/28)
-
- C-H FLUORINATION OF HETEROCYCLES WITH SILVER (II) FLUORIDE
-
The present invention provides compositions and methods for the selective C-H fluorination of nitrogen-containing heteroarenes with AgF2, which has previously been considered too reactive for practical, selective C-H fluorination. Fluorinated heteroarenes are prevalent in numerous pharmaceuticals, agrochemicals and materials. However, the reactions used to introduce fluorine into these molecules require pre-functionalized substrates or the use of F2 gas. The present invention provides a mild and general method for the C-H fluorination of nitrogen-containing heteroarene compounds to 2-fluoro-heteroarenes with commercially available AgF2. In various embodiments, these reactions occur at ambient temperature within one hour and occur with exclusive selectivity for fluorination at the 2-position. Exemplary reaction conditions are effective for fluorinating diazine heteroarenes to form a single fluorinated isomer.
- -
-
Page/Page column 37
(2015/02/19)
-
- Acyl azolium fluorides for room temperature nucleophilic aromatic fluorination of chloro- and nitroarenes
-
The reaction of acid fluorides with N-heterocyclic carbenes (NHCs) produces anhydrous acyl azolium fluorides. With appropriate selection of acid fluoride and NHC, these salts can be used for the room temperature SNAr fluorination of a variety of aryl chlorides and nitroarenes.
- Ryan, Sarah J.,Schimler, Sydonie D.,Bland, Douglas C.,Sanford, Melanie S.
-
supporting information
p. 1866 - 1869
(2015/04/27)
-
- Anhydrous Tetramethylammonium Fluoride for Room-Temperature SNAr Fluorination
-
This paper describes the room-temperature SNAr fluorination of aryl halides and nitroarenes using anhydrous tetramethylammonium fluoride (NMe4F). This reagent effectively converts aryl-X (X = Cl, Br, I, NO2, OTf) to aryl-F under mild conditions (often room temperature). Substrates for this reaction include electron-deficient heteroaromatics (22 examples) and arenes (5 examples). The relative rates of the reactions vary with X as well as with the structure of the substrate. However, in general, substrates bearing X = NO2 or Br react fastest. In all cases examined, the yields of these reactions are comparable to or better than those obtained with CsF at elevated temperatures (i.e., more traditional halex fluorination conditions). The reactions also afford comparable yields on scales ranging from 100 mg to 10 g. A cost analysis is presented, which shows that fluorination with NMe4F is generally more cost-effective than fluorination with CsF.
- Schimler, Sydonie D.,Ryan, Sarah J.,Bland, Douglas C.,Anderson, John E.,Sanford, Melanie S.
-
p. 12137 - 12145
(2016/01/09)
-
- Mild fluorination of chloropyridines with in situ generated anhydrous tetrabutylammonium fluoride
-
This paper describes the fluorination of nitrogen heterocycles using anhydrous NBu4F. Quinoline derivatives as well as a number of 3- and 5-substituted pyridines undergo high-yielding fluorination at room temperature using this reagent. These results with anhydrous NBu4F compare favorably to traditional halex fluorinations using alkali metal fluorides, which generally require temperatures of ≥100 °C.
- Allen, Laura J.,Muhuhi, Joseck M.,Bland, Douglas C.,Merzel, Rachel,Sanford, Melanie S.
-
p. 5827 - 5833
(2014/07/08)
-
- THERAPEUTIC COMPOUNDS AND COMPOSITIONS
-
Compounds of general formula (I) and compositions comprising compounds of general formula I that modulate pyruvate kinase are described herein. Also described herein are methods of using the compounds that modulate pyruvate kinase in the treatment of diseases.
- -
-
Page/Page column 177
(2014/09/29)
-
- THERAPEUTIC COMPOUNDS AND COMPOSITIONS
-
Compounds of general formula I: and compositions comprising compounds of general formula I that modulate pyruvate kinase are described herein. Also described herein are methods of using the compounds that modulate pyruvate kinase in the treatment of diseases.
- -
-
Paragraph 0728; 0729
(2014/09/30)
-
- THERAPEUTIC COMPOUNDS AND COMPOSITIONS
-
Compounds of general formula (I) and compositions comprising compounds of general formula (I) that modulate pyruvate kinase are described herein. Also described herein are methods of using the compounds that modulate pyruvate kinase in the treatment of diseases.
- -
-
Page/Page column 190; 191
(2014/09/29)
-
- Selective C-H fluorination of pyridines and diazines inspired by a classic amination reaction
-
Fluorinated heterocycles are prevalent in pharmaceuticals, agrochemicals, and materials. However, reactions that incorporate fluorine into heteroarenes are limited in scope and can be hazardous. We present a broadly applicable and safe method for the site-selective fluorination of a single carbon-hydrogen bond in pyridines and diazines using commercially available silver(II) fluoride. The reactions occur at ambient temperature within 1 hour with exclusive selectivity for fluorination adjacent to nitrogen. The mild conditions allow access to fluorinated derivatives of medicinally important compounds, as well as a range of 2-substituted pyridines prepared by subsequent nucleophilic displacement of fluoride. Mechanistic studies demonstrate that the pathway of a classic pyridine amination can be adapted for selective fluorination of a broad range of nitrogen heterocycles.
- Fier, Patrick S.,Hartwig, John F.
-
p. 956 - 960
(2013/12/04)
-
- Elemental fluorine. Part 10.1 Selective fluorination of pyridine, quinoline and quinoxaline derivatives with fluorine-iodine mixtures
-
Selective fluorination of a range of pyridine and quinoline substrates to give corresponding 2-fluoro-derivatives can be readily achieved in high yield at room temperature using elemental fluorine-iodine mixtures. Reaction of fluorine with iodine forms, in situ, systems that function like sources of both iodonium and fluoride ions and fluorination of heterocyclic derivatives is suggested to proceed by fluoride ion attack on intermediate W-iodo-heterocyclic species. Quinoxaline derivatives react under similar conditions to give either the 2-fluoro- or 2,3-difluoro-quinoxaline derivatives depending on the ratio of fluorine passed through the solution. In related processes, pyridine can be alkoxylated upon reaction of an appropriate alcohol and fluorine.
- Chambers, Richard D.,Parsons, Mandy,Sandford, Graham,Skinner, Christopher J.,Atherton, Malcolm J.,Moilliet, John S.
-
p. 803 - 810
(2007/10/03)
-
- Process for the preparation of fluorinated heterocyclic compounds
-
A method of fluorinating a heterocyclic organic compound comprises the step of reacting a heterocyclic compound with elemental fluorine in the presence of another halogen. The reaction may be conducted in the presence of a base.
- -
-
-
- NUCLEOPHILIC FLUORINATION OF CHLORINATED N-HETEROCYCLES WITH TETRABUTYLPHOSPHONIUM HYDROGENDIFLUORIDE AND DIHYDROGENTRIFLUORIDE
-
Fluorination of various chlorinated N-heterocycles with tetrabutylphosphonium hydrogendifluoride (1) or dihydrogentrifluoride (2) readilly proceeded in high yields under mild conditions.
- Uchibori, Yukitaka,Umeno, Masayuki,Yoshioka, Hirosuke
-
p. 1507 - 1510
(2007/10/02)
-
- Directed ortho-Lithiation of Chloroquinolines. Application to Synthesis of 2,3-Disubstituted Quinolines
-
2-, 3- and 4-Chloroguinolines were selectively lithiated at low temperature by lithium diisopropylamide at the more acidic C-3, C-4 and C-3 positions respectively.Reaction of 2-chloro-3-lithioquinoline with electrophiles led to various 2,3-disubstituted quinolines.The versatility of this functionalization methodology is enhanced by the C-2 halogen reactivity towards oxygen or nitrogen nucleophiles.So, a great variety of 2,3-disubstituted quinolines were synthesized, such as 2-chloro, 2-alkoxy, 2-aminoquinolines or 2-quinolones bearing an hydroxy, carbonyl (aldehyde, ketone or carboxylic acid), iodo, trimethylsilyl or boronic acid moiety at the C-3.Some of the resulting 2,3-disubstituted synthons were annelated to tetracyclic polyaromatics, which possess the xanthone or indole structure.This could be achieved via further functionalization of the quinoline ring either by SNAr2 or heteroaromatic cross-coupling reactions, after the first directed-lithiation step.
- Marsais, F.,Godard, A.,Queguiner, G.
-
p. 1589 - 1594
(2007/10/02)
-