Deoxyfluorination of Phenols

Tang, Pingping; Wang, Weike; Ritter, Tobias

doi:10.1021/ja2048072

Cited by 249 publications

(178 citation statements)

References 29 publications

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“…If dimethyl ether was used (with even greater solubilizing power) the rate of reaction appeared to increase (more rapid color changes), but not the isolated yield. Future efforts towards fluorinated metallocenes might benefit from recent developments in transition metal-catalyzed fluorinations (for example, from phenols, 22 aryl triflates, 23 stannanes, 24 boronic acids, 25 silanes 26 or iodides 27 ). 28 As with FcCl and fcCl 2 , aqueous FeCl 3 was used to remove FcH and FcH/FcF impurities from FcF and fcF 2 , respectively (Table 1).…”

mentioning

confidence: 99%

The Unusual Redox Properties of Fluoroferrocenes Revealed through a Comprehensive Study of the Haloferrocenes

Inkpen

Hildebrand

et al. 2015

Organometallics

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ABSTRACT:We report the synthesis and full characterization of the entire haloferrocene (FcX) and 1,1'-dihaloferrocene (fcX 2 ) series (X = I, Br, Cl, F; Fc = ferrocenyl, fc = ferrocene-1,1'-diyl). Finalization of this simple, yet intriguing set of compounds has been delayed by synthetic challenges associated with the incorporation of fluorine substituents. Successful preparation of fluoroferrocene (FcF) and 1,1'-difluoroferrocene (fcF 2 ) were ultimately achieved using reactions between the appropriate lithiated ferrocene species and N-fluorobenzenesulfonimide (NFSI). The crude reaction products, in addition to those resulting from analogous preparations of chloroferrocene (FcCl) and 1,1'-dichloroferrocene (fcCl 2 ), were utilized as model systems to probe the limits of a previously reported 'oxidative purification' methodology. From this investigation and careful solution voltammetry studies, we find that the fluorinated derivatives exhibit the lowest redox potentials of each of the FcX and fcX 2 series. This counter-intuitive result is discussed with reference to the spectroscopic, structural and first principles calculations of these and related materials.

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mentioning

confidence: 99%

The Unusual Redox Properties of Fluoroferrocenes Revealed through a Comprehensive Study of the Haloferrocenes

Inkpen

Hildebrand

et al. 2015

Organometallics

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“…Also, very importantly, DAST works best on aliphatic alcohols, especially benzylic alcohols like three of the four examples used in this paper, and it does not deoxyfluorinate phenols. Future efforts are aimed toward expanding the range of metabolites that can be converted to their fluoro substituted analogs, exploring other fluorination reagents for this purpose (Al-Maharik and O'Hagan, 2011;Tang, et al, 2011;Fujimoto and Ritter, 2015;Nielsen, et al, 2015), investigating the utility of other sources of P450 activity (e.g., liver microsomes) for the enzymatic portion of the procedure, and working toward generating multiply fluorinated analogs from secondary metabolites possessing more than one hydroxyl group. Furthermore, the methodology described in the paper has utility in diversification of lead molecules in order to impact other properties critical in drug discovery, such as potency, selectivity, DDI, and distribution properties.…”

Section: Discussionmentioning

confidence: 99%

Biosynthesis of Fluorinated Analogs of Drugs Using Human Cytochrome P450 Enzymes Followed by Deoxyfluorination and Quantitative Nuclear Magnetic Resonance Spectroscopy to Improve Metabolic Stability

Obach

Walker

Brodney

2016

Drug Metabolism and Disposition

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Replacement of hydrogen with fluorine is a useful drug design strategy when decreases in cytochrome P450 (P450) metabolic lability are needed. In this paper, a facile two-step method of inserting fluorine into metabolically labile sites of drug molecules is described that utilizes less than 1 mg of starting material and quantitative NMR spectroscopy to ascertain the structures and concentrations of products. In the first step, hydroxyl metabolites are biosynthesized using human P450 enzymes, and in the second step these metabolites are subjected to deoxyfluorination using diethylaminosulfur trifluoride (DAST). The method is demonstrated using midazolam, celecoxib, ramelteon, and risperidone as examples and CYP3A5, 2C9, 1A2, and 2D6 to catalyze the hydroxylations. The drugs and their fluoro analogs were tested for metabolic lability. 9-Fluororisperidone and 49-fluorocelecoxib were 16 and 4 times more metabolically stable than risperidone and celecoxib, respectively, and 2-fluororamelteon and ramelteon were metabolized at the same rate. 19-Fluoromidazolam was metabolized at the same rate as midazolam by CYP3A4 but was more stable in CYP3A5 incubations. The P450-catalyzed sites of metabolism of the fluorine-containing analogs were determined. Some of the metabolites arose via metabolism at the fluorine-substituted carbon, wherein the fluorine was lost to yield aldehydes. In summary, this method offers an approach whereby fluorine can be substituted in metabolically labile sites, and the products can be tested to determine whether an enhancement in metabolic stability was obtained.

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“…1 (s, 9 H). 13 C NMR (75 MHz, CDCl 3 ): δ = 141. 2, 138.7, 136.0, 133.8, 133.1, 130.6, 130.0, 128.8, 128.6, 126.9, 125.0, 121.0, 116.4, 112.9, 32.8, 30.6, 21.2, 17.4 …”

Section: (E)-8-(44-dimethylpent-2-en-2-yl)-5-(m-tolyl)imidazo[15-a]mentioning

confidence: 99%

Selective C(8)–H Activation of Imidazopyridines Mediated by Cooperative Nickel–Aluminum Catalysis

Liu

Chen

et al. 2016

Synthesis

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This work is dedicated to the victims of the recent Tainan earthquake. N N Ar N N R N N R N N Ar 5-substituted imidazopyridine 3-arylimidazopyridine IMes R 3 P ligands Ni-Al C-H activation at C828 examples 17-98% yield Ni(cod) 2 (5 mol%) ligand (5-20 mol%) 60-100 °C AlMe 3 (20-100 mol%) Abstract A catalytic paradigm is described featuring a synergistic interaction between nickel, aluminum and different ligands to impart a rather remote C-H alkenylation of imidazo[1,5-a]pyridines at the C-8 position without the necessity of installing a directing group. The scope of the direct C-H activation reactions of various 5-aryl-and 3-arylimidazopyridines is established using different sterically hindered alkynes.

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Deoxyfluorination of Phenols

Abstract: An operationally simple ipso-fluorination of phenols with a new deoxyfluorination reagent is presented.

Cited by 249 publications

References 29 publications

The Unusual Redox Properties of Fluoroferrocenes Revealed through a Comprehensive Study of the Haloferrocenes

The Unusual Redox Properties of Fluoroferrocenes Revealed through a Comprehensive Study of the Haloferrocenes

Biosynthesis of Fluorinated Analogs of Drugs Using Human Cytochrome P450 Enzymes Followed by Deoxyfluorination and Quantitative Nuclear Magnetic Resonance Spectroscopy to Improve Metabolic Stability

Selective C(8)–H Activation of Imidazopyridines Mediated by Cooperative Nickel–Aluminum Catalysis

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