New Prospects toward the Synthesis of Difluoromethylated Phosphate Mimics

Ivanova, Maria V.; Bayle, Alexandre; Besset, Tatiana; Pannecoucke, Xavier; Poisson, Thomas

doi:10.1002/chem.201601310

Cited by 66 publications

(25 citation statements)

References 90 publications

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“…Fluorinated phosphonates relative to their non‐fluorinated analogues are characterized by reduced p K a values. Because of the presence of one or more fluorine atoms, these derivatives have CX 2 –P systems with large dihedral angles and opportunities for the formation of hydrogen bonds (C–F ··· H–X) . On the biological level, however, small changes in such properties can often lead to significant changes in the activity of the modified molecule, which can arise from completely different interactions between the substrate and receptor.…”

Section: Introductionmentioning

confidence: 99%

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

2018

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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).

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Section: Introductionmentioning

confidence: 99%

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

2018

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“…图 1 亲电氟烷硫基试剂 Figure 1 Electrophilic fluoroalkylthiolating reagents 二氟甲基膦酸酯通常被认为是磷酸酯的生物电子等排体 [9] , 主要是因为(1) 从空间构型上来看, 二氟亚甲基与氧很相似, 该基团被认为与酯基氧的 apicophilicity 是类似的;…”

Section: 通过此类试剂可以方便快捷地向目标分子中引入三氟unclassified

N-[(Diethoxyphosphoryl)difluoromethylthio]phthalimide: A New Electrophilic Fluoroalkylthiolating Reagent

Shen¹,

Lü²,

Shen³

2020

Acta Chim. Sinica

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A shelf-stable reagent for the preparation of fluoroalkylthiolated compounds, [(diethylphosphonate)difluoromethylthio]phthalimide 1, was successfully developed, which reacted with a variety of nucleophiles such as electron-rich heteroarenes, β-ketoesters, oxindoles, benzofuranones in high yield, thus providing a new and efficient approach for the introduction of fluoroalkylthiolated phosphonate moiety. General procedure for the preparation of [(diethylphosphonate)difluoromethylthio]phthalimide 1: to a suspension of silver fluoride (7.6 g, 60 mmol) in anhydrous acetonitrile (100 mL) was added diethyl (difluoro(trimethylsilyl)methyl)phosphonate (13.0 g, 50.0 mmol) at-40 ℃. The mixture was allowed to stir at 0 ℃ until a dark brown solution was formed (approximately 15 min). N-(Chlorosulfenyl)phalimide (16.0 g, 75.0 mmol) was then added at-40 ℃, and the resulting mixture was stirred at-40 ℃ for 2 h. The mixture was filtered, and the solvent was evaporated in vacuo. The residue was recrystallized using the mixed solvent (petroleum ether/dichloromethane) three times to give [(diethylphosphonate)difluoromethylthio]phthalimide 1 as a white solid (5.5 g, 30%). General procedure for reaction of indoles with 1: to a 25 mL Schlenk tube charged with indole (35.1 mg, 0.3 mmol) and reagent 1 (132 mg, 0.36 mmol) and magnesium bromide (82 mg, 0.45 mmol) was added 1,2-dichloroethane (2.0 mL). The mixture was stirred at room temperature for 15 min. The mixture was filtered and the solvent was evaporated in vacuo. The residue was purified by flash chromatography on silica gel to give diethyl (((1H-indol-3-yl)thio)difluoromethyl)phosphonate 3a (93 mg, 93%) as a brown oil. General procedure for reaction of soft carbon nucleophile with reagent 1: to a 25 mL Schlenk tube charged with carbon nucleophiles (153 mg, 0.750 mmol), K 2 CO 3 (103 mg, 0.75 mmol) and reagent 1 (182 mg, 0.50 mmol) was added dichloromethane (3.0 mL). The mixture was stirred at room temperature for 12 h. The reaction mixture was filtered and the solvent was evaporated in vacuo. The residue was purified by flash chromatography on silica gel to give ethyl-2-(((diethoxyphosphoryl)difluoromethyl)thio)-1-oxo-2,3-dihydro-1H-indene-2-carboxylate 5b (160 mg, 76%) as a yellow oil.

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“…A series of phosphonium difluoroalkyl sources such as Ph 3 P + CF 2 CO 2 − , (Me 2 N) 3 P + CF 2 CO 2 ‐ , have recently been shown to introduce a CF 2 Y moiety into alkenes, alkynes, phenols, thiols, carboxylic acids, and heterocyclic amines . These recently reviewed methods are not included in this review article.…”

Section: Introductionmentioning

confidence: 99%

Difluoromethylation Reactions of Organic Compounds

Yerien

Barata‐Vallejo

Postigo

2017

Chemistry A European J

404

153

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The relevance of the -CF H moiety has attracted considerable attention from organic synthetic and medicinal chemistry communities, because this group can act as a more lipophilic isostere of the carbinol, thiol, hydroxamic acid, or amide groups. Being weakly acidic, the CF H moiety can establish hydrogen-bonding interactions to improve the binding selectivity of biologically active compounds. Therefore, the hydroxyl, amino, and thio substituents of lead structures are routinely replaced by a CF H motif in drug discovery, with great benefits in the pharmacological activity of drugs and drug candidates and agrochemicals. Consequently, the late-stage introduction of CF H is a sought-after strategy in designing bioactive compounds. Secondly, but nonetheless relevant and meaningful, is the study of synthetic pathways to introduce a CF -Y moiety (Y≠H, F) into organic substrates because compounds that contain a CF -Y functionality have also found vast applications in medicinal chemistry and in other areas, such as that of fungicides, insecticides, etc., and thus, this functionality deserves special attention. Although emphasis is made on difluoromethylation strategies to functionalize different families of organic compounds, three main methodological protocols will be presented in this review article for the late-stage introduction of a CF H or CF Y moieties into organic substrates: i) a metal-photoredox catalysis; ii) through transition metal-catalyzed thermal protocols; and iii) from transition-metal-free strategies.

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New Prospects toward the Synthesis of Difluoromethylated Phosphate Mimics

Cited by 66 publications

References 90 publications

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

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

N-[(Diethoxyphosphoryl)difluoromethylthio]phthalimide: A New Electrophilic Fluoroalkylthiolating Reagent

Difluoromethylation Reactions of Organic Compounds

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