Copper-Mediated Fluorination of Aryl Iodides

Fier, Patrick S.; Hartwig, John F.

doi:10.1021/ja304410x

Cited by 219 publications

(128 citation statements)

References 32 publications

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“…By switching the solvent from acetonitrile to benzonitrile,t he yield was increased to 67 %( entry 2), whereas other solvents provided only trace amounts of 3aa with unexpected 1,4-diphenylbuta-1,3-diyne as the major product by the homocoupling of 1a (entries 3-6). An extensive screening of nitrogen sources (entries 7-11), ligands (entries 12-16), [18] temperature (entries 17 and 18), copper loading (entry 19), additives (entries 20 and 21), and the atmosphere (entries 22 and 23) revealed that the use of two equivalents of Cu(NO 3 ) 2 ·3 H 2 Oinbenzonitrile at 60 8 8Cunder nitrogen atmosphere using tert-butylnitrile (2.0 equiv) as an additive provides the most suitable conditions and afforded 3aa in 83 %yield.…”

Section: Methodsmentioning

confidence: 99%

Copper Nitrate Mediated Regioselective [2+2+1] Cyclization of Alkynes with Alkenes: A Cascade Approach to Δ²‐Isoxazolines

Gao

Gan

et al. 2015

Angew Chem Int Ed

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An efficient method for the regioselective synthesis of pharmacologically relevant polysubstituted Δ(2)-isoxazolines is based on the copper-mediated direct transformation of simple terminal alkynes and alkenes. The overall process involves the formation of four chemical bonds with inexpensive and readily available copper nitrate trihydrate as a novel precursor of nitrile oxides. The reaction can be easily handled and proceeds under mild conditions.

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Section: Methodsmentioning

confidence: 99%

Copper Nitrate Mediated Regioselective [2+2+1] Cyclization of Alkynes with Alkenes: A Cascade Approach to Δ²‐Isoxazolines

Gao

Gan

et al. 2015

Angew Chem Int Ed

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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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“…Pyridines substituted with chlorine-or methyl groups also afford good product yields (43 and 44). Quinolines, and pyrazine derivatives also render good yields of ortho-fluorine substituted products (46)(47)(48)(49), as is the case for pyrimidine and pyridazine substrates (50-54).…”

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confidence: 97%

Fluorination methods in drug discovery

2016

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Fluorination reactions of medicinal and biologically-active compounds will be discussed. Late stage fluorination strategies of medicinal targets have recently attracted considerable attention on account of the influence that the fluorine atom can impart to targets of medicinal importance, such as a modulation of lipophilicity, electronegativity, basicity and bioavailability, this latter as a consequence of membrane permeability. Therefore, the recourse to late-stage fluorine substitution on compounds with already known and relevant biological activity can provide the pharmaceutical industry with new leads with improved medicinal properties. The fluorination strategies will take into account different fluorinating reagents, nucleophilic, electrophilic and of radical nature. Diverse families of organic compounds such as (hetero)aromatic rings, and aliphatic substrates (sp 3 , sp 2 , and sp carbon atoms) will be studied in late-stage fluorination reaction strategies. The omniphobicity/lipophilicity and electrostatic interactions can be considered among the most prominent effects. Thus, introducing fluorine into an organic compound can significantly alter its biological properties.One other subtle but important effect of introducing fluorine into the backbone of a medicinal target is the inflection of acidity and basicity of the parent compound 4 , which can change, inter alia, the binding affinity, and bioavailability. Highly basic groups can have a detrimental effect on the bioavailability of a drug. Thus introducing a fluorine atom next to a basic group can reduce its basicity, enhancing its membrane permeability, and increasing bioavailability. Although the replacement of hydrogen for fluorine does not have a profound steric influence, electrostatic interactions with other groups can change conformations significantly. The replacement of hydrogen for fluorine on aromatic rings is a well-known strategy to decelerate oxidative metabolic processes by Cytochrome P450 monooxygenases. In this respect, the electron-withdrawing properties of fluorine on aromatic rings, which can slow down hydrolytic metabolism, alter reaction rates and stability of intermediates. Fluorine substitution on aromatic rings is also known to increase binding affinity, as a result of enhancing electrostatic interactions.However, it is difficult to predict the influence of fluorine substitution on the overall profile in a given situation.As numerous reports attest 1 , the number of marketed drugs that contain a fluorine atom has increased rapidly. As of 2009, the FDA-had approved >140 fluorine-containing drugs. This review article is intended to present new synthetic methodologies 9 for accomplishing fluorination reactions on molecules (drugs/prodrugs) with pharmacological activity. It is not our aim (Figure 3). would be beneficial to the syntheses. 3a.-Conversion of C Ar -H into C Ar -F BondsXu and co-workers 38 have developed an ortho C-H bond fluorination of 2-phenoxyl pyridine derivatives through a palladium-catalyzed reaction v...

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Copper-Mediated Fluorination of Aryl Iodides

Cited by 219 publications

References 32 publications

Copper Nitrate Mediated Regioselective [2+2+1] Cyclization of Alkynes with Alkenes: A Cascade Approach to Δ²‐Isoxazolines

Copper Nitrate Mediated Regioselective [2+2+1] Cyclization of Alkynes with Alkenes: A Cascade Approach to Δ²‐Isoxazolines

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

Fluorination methods in drug discovery

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Copper-Mediated Fluorination of Aryl Iodides

Cited by 219 publications

References 32 publications

Copper Nitrate Mediated Regioselective [2+2+1] Cyclization of Alkynes with Alkenes: A Cascade Approach to Δ2‐Isoxazolines

Copper Nitrate Mediated Regioselective [2+2+1] Cyclization of Alkynes with Alkenes: A Cascade Approach to Δ2‐Isoxazolines

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

Fluorination methods in drug discovery

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Copper Nitrate Mediated Regioselective [2+2+1] Cyclization of Alkynes with Alkenes: A Cascade Approach to Δ²‐Isoxazolines

Copper Nitrate Mediated Regioselective [2+2+1] Cyclization of Alkynes with Alkenes: A Cascade Approach to Δ²‐Isoxazolines