Difluoromethylation Reagent Research Articles

A Difluoromethylation Reagent: Access to Difluoromethyl Arenes through Palladium Catalysis.

A new radical difluoromethylation was developed by using inexpensive and readily available difluoroacetic anhydride and N-phenyl-4-methylbenzenesulfonamide for the first time. The reaction of arylboronic acids with the new difluoromethylation reagent, N-phenyl-N-tosyldifluoroacetamide, proceeded smoothly in the presence of palladium catalyst to provide difluoromethylarenes in satisfactory to excellent yields. The electronic property (electron-donating or electron-withdrawing) of the substituent linked to the aromatic ring did not considerably influence the reactivity of arylboronic acid. Various groups, including the synthetically useful functional groups Cl, CN, and NO2, were tolerated well under the current reaction conditions.

Sulfone Electrophiles in Cross-Electrophile Coupling: Nickel-Catalyzed Difluoromethylation of Aryl Bromides.

Fluoroalkyl fragments have played a critical role in the design of pharmaceutical and agrochemical molecules in recent years due to the enhanced biological properties of fluorinated molecules compared to their non-fluorinated analogues. Despite the potential advantages conferred by incorporating a difluoromethyl group in organic compounds, industrial adoption of difluoromethylation methods lags behind fluorination and trifluoromethylation. This is due in part to challenges in applying common difluoromethyl sources towards industrial applications. We report here the nickel-catalyzed cross-electrophile coupling of (hetero)aryl bromides with difluoromethyl 2-pyridyl sulfone, a sustainably sourced, crystalline difluoromethylation reagent. The scope of this reaction is demonstrated with 24 examples (67 ± 16% average yield) including a diverse array of heteroaryl bromides and precursors to difluoromethyl-containing preclinical pharmaceuticals. This reaction can be applied to small-scale parallel synthesis and benchtop scale-up under mild conditions. As sulfone reagents are uncommon electrophiles in cross-electrophile coupling, the mechanism of this process was investigated. Studies confirmed the formation of •CF2H instead of difluorocarbene. A series of modified difluoromethyl sulfones revealed that sulfone reactivity does not correlate exclusively with reduction potential and that coordination of cations or nickel to the pyridyl group is essential to reactivity, setting out parameters for matching the reactivity of sulfones in cross-electrophile coupling.

Difluoromethyl phenoxathiinium salt: a new general and versatile difluoromethylating reagent

Difluoromethyl phenoxathiinium salt: a new general and versatile difluoromethylating reagent

Hydrodifluoromethylation of unactivated alkenes enabled by Visible‐Light Photocatalysis

AbstractIn the present manuscript, we have reported a general catalytic strategy that allows the synthesis of a variety of difluoro methylated alkanes from the corresponding unactivated alkenes using commercially available radical difluoromethylating reagent (CF2HSO2Na) under visible light photocatalysis. Further, this strategy allows the late‐stage modification of various alkenes derived from pharmaceutically relevant drugs.

Difluoromethyl phenoxathiinium salt: A new general and versatile difluoromethylating reagent with divergent ·CF2H, CF2H+, and:CF2 reactivities

Difluoromethyl phenoxathiinium salt: A new general and versatile difluoromethylating reagent with divergent ·CF2H, CF2H+, and:CF2 reactivities

Difluorocarbene in Cycloadditions and Annulations for the Synthesis of gem‐Difluorocarbocycles and gem‐Difluoroheterocycles

AbstractDifluorocarbene is a simple, readily prepared, and versatile difluorinated one‐carbon synthon. It can be applied as both the difluoromethylating reagent in the carbene insertion and the difluoromethylenating reagent in various cycloadditions and annulations. This concept article provides an account of applications of difluorocarbene in cycloadditions and annulations for synthesis of gem‐difluorocarbocycles and gem‐difluoroheterocycles. The synthesized gem‐difluorocarbocycles include 2,2‐difluorobicyclo[1.1.1]pentanes, 4,4‐/5,5‐difluoro‐cyclopentenes, 2,2‐difluorocyclopentanones, and 5,5‐difluorocyclopent‐2‐enones via tandem [2+1] cycloaddition and ring‐expansion or [4+1] annulations. The prepared gem‐difluoroheterocycles involve 2,2‐/3,3‐difluoro‐2,3‐dihydrofurans, 2,2‐difluoro‐2,3‐dihydrobenzofurans, 2,2‐difluoro‐2,3‐dihydrobenzothiophenes, 2,2‐difluorobenzofuran‐3(2H)‐ones, 2,2‐difluorobenzothiophen‐3(2H)‐ones, 2,2‐difluoro‐2,3‐dihydrothieno[2,3‐b]pyridines, 2,2‐difluorothieno[2,3‐b]pyridine‐3(2H)‐ones, 5,5‐difluorooxazolines and thiazolines, and spirocyclic 2,2‐difluorobenzo[d][1,3]aza/phosphaborol‐1‐ium‐3‐yliums via [4+1] annulations, 1,1‐difluoro‐1,4,5,9b‐tetrahydro‐2H‐[1,2]diazeto[4,1‐a]isoquinolines and 1,1‐difluoro‐1,4,5,9b‐tetrahydro‐2H‐[1,2]diazeto[1,4‐a]pyrrolo[2,1‐c]pyrazines via [3+1] annulation, 1,1‐difluoro‐1,9a‐dihydropyrido[2,1‐c][1,4]thiazines and 3,3‐difluorobenzo[e][1,4,2]oxaza/phosphaborinin‐4‐ium‐2‐uides via [5+1] annulations, 9,9‐difluoro‐8‐azabicyclo[5.2.0]nona‐2,4,6‐trienes via [8+1] annulation, 4,4‐difluorooxazolidines and 3,3‐difluoropyrrolidines via [2+2+1] annulations. Difluorocarbene generated from different readily available precursors proceeds these cycloadditions and annulations well. The substrate scopes, proposed mechanisms, selected product examples and their applications are discussed.

(SIPr)Ag(CF2 H)]: A Shelf-Stable, Versatile Difluoromethylation Reagent.

Due to its unique physical and electrophilic properties, the difluoromethyl group (-CF2 H) has been playing an irreplaceable role in the field of pharmaceutical and agrochemical industry. Methods that could efficiently incorporate the difluoromethyl group into the target molecules are increasing in the recent years. Developing a stable and efficient difluoromethylating reagent is thus highly attractive. In this review, we describe the development of a nucleophilic difluoromethylation reagent [(SIPr)Ag(CF2 H)], including its elemental reaction, difluoromethylation reaction with different types of electrophiles, and its application in the synthesis of a nucleophilic and an electrophilic difluoromethylthiolating reagent.

Indium mediated barbier-type allylation: Synthesis of highly functionalized homoallylic difluorohydrins

Indium-mediated Barbier-type allylation of halogenated difluoroacetophenone is reported for the first time. This method can directly and conveniently access homoallylic difluorohydrin alcohol blocks from halogenated difluoroacetophenones, and has good functional group compatibility. As a novel difluoromethylation reagent, the block has potential in the synthesis of fluorinated compounds.

Visible‐Light Photoredox‐Catalyzed Decarboxylative Double Difluoromethylation of β,γ‐Unsaturated Carboxylic Acids for the Synthesis of Difluoromethylated Allylic Compounds

AbstractThe regioselective synthesis of double difluoromethylated allylic products from easily accessible β,γ‐unsaturated carboxylic acids and difluoromethylation reagents under visible‐light photocatalysis is reported. This transformation tolerates various bromodifluoroacetates and fluorinated phosphonates, providing access to various difluoromethylated allylic products in 54–93% yield with 80:20 to 99:1 Z/E, which can not be readily synthesized using the currently known methods. Choosing fac‐[Ir(ppy)3] as the photocatalyst and 1,4‐diazabicyclo[2.2.2]octane (DABCO) as the additive is crucial for the success of this transformation.magnified image

Rapid 18 F- and 19 F-Difluoromethylation through Desulfurative Fluorination of Transient N-, O-, and C-Linked Dithioles.

The difluoromethyl group plays an important role in modern medicinal and agrochemistry. While several difluoromethylation reagents have been reported, these typically rely on difluoromethyl carbenes or anions, or target specific processes. Here, we describe a conceptually unique and general process for O-H, N-H and C-H difluoromethylation that involves the formation of a transient dithiole followed by facile desulfurative fluorination using silver(I) fluoride. We also introduce the 5,6-dimethoxy-1,3-benzodithiole (DMBDT) function, which undergoes sufficiently rapid desulfurative fluorination to additionally support 18 F-difluoromethylation. This new process is compatible with the wide range of functional groups typically encountered in medicinal chemistry campaigns, and the use of Ag18 F is demonstrated in the production of 18 F-labeled derivatives of testosterone, perphenazine, and melatonin, 58.0±2.2, 20.4±0.3 and 32.2±3.6 MBq μmol-1 , respectively. We expect that the DMBDT group and this 18 F/19 F-difluoromethylation process will inspire and support new efforts in medicinal chemistry, agrochemistry and radiotracer production.

Difluoromethylsulfonyl Imidazolium Salt for Difluoromethylation of Alkenes.

Herein, we describe the design and synthesis of a difluoromethylsulfonyl imidazolium salt, which can act as a radical difluoromethylation reagent to achieve the challenging amino- and oxy-difluoromethylation of alkenes. Notably, the three steps for the synthesis of the imidazolium salt do not require any tedious distillation or column chromatography purification process, and the amino- and oxy-difluoromethylation paths are simply determined by the selection of reaction solvents.

Ph4P]+[Cu(CF2H)2]−: A Powerful Difluoromethylating Reagent Inspired by Mechanistic Investigation

AbstractThe quest of the active species in copper‐mediated difluoromethylation of aryl halides led to the discovery of a powerful difluoromethylating reagent [Ph4P]+[Cu(CF2H)2]−2. Complex2was able to difluoromethylate a variety of electrophiles including electron‐deficient and electron‐rich aryl iodides, heteroaryl iodides, activated heteroaryl bromides, chloride and aryl bromides with a directing group, as well as other electrophiles such as alkenyl iodide, benzyl bromides, allyl bromides, alkyl iodide, allyl carbonates and acid chloride. In addition, in the presence of an oxidant, complex2reacted with various lithiumnbutyl arylboronic acid pinacol esters, alkyne and heteroarene. Moreover, complex2could transmetalate the difluoromethyl reagent to other metals such as [Ph4P]+[CuCl2]−and [(DPPF)PdCl2].

Ph4 P]+ [Cu(CF2 H)2 ]- : A Powerful Difluoromethylating Reagent Inspired by Mechanistic Investigation.

The quest of the active species in copper-mediated difluoromethylation of aryl halides led to the discovery of a powerful difluoromethylating reagent [Ph4 P]+ [Cu(CF2 H)2 ]- 2. Complex 2 was able to difluoromethylate a variety of electrophiles including electron-deficient and electron-rich aryl iodides, heteroaryl iodides, activated heteroaryl bromides, chloride and aryl bromides with a directing group, as well as other electrophiles such as alkenyl iodide, benzyl bromides, allyl bromides, alkyl iodide, allyl carbonates and acid chloride. In addition, in the presence of an oxidant, complex 2 reacted with various lithium nbutyl arylboronic acid pinacol esters, alkyne and heteroarene. Moreover, complex 2 could transmetalate the difluoromethyl reagent to other metals such as [Ph4 P]+ [CuCl2 ]- and [(DPPF)PdCl2 ].

Visible-Light-Mediated Tandem Difluoromethylation/Cyclization of Alkenyl Aldehydes toward CF2H-Substituted Chroman-4-one Derivatives.

An efficient and facile visible-light-mediated tandem difluoromethylation/cyclization of alkenyl aldehydes, with easily accessible and air-stable [Ph3PCF2H]+Br- as the difluoromethylation reagent, has been established. A range of CF2H-substituted chroman-4-one skeletons and their derivatives, such as 2,3-dihydroquinolin-4(1H)-ones, chroman, 3,4-dihydronaphthalen-1(2H)-one, 2,3-dihydrobenzofuran, and 2,3-dihydro-1H-inden-1-one, are efficiently produced in moderate to good yields with excellent chemoselectivity under mild reaction conditions.

A Fruitful Decade of Organofluorine Chemistry: New Reagents and Reactions

A Fruitful Decade of Organofluorine Chemistry: New Reagents and Reactions

Visible‐Light Induced Ipso‐Difluoromethylation of N‐Arylpropiolamides to Synthesize 3‐Difluoromethyl Spiro[4.5]trienones

AbstractA visible light‐induced radical ipso‐difluoromethylation of N‐arylpropiolamides to synthesize 3‐difluoromethyl spiro[4.5]trienones was developed for the first time. In this transformation PhI(O2CCHF2)2 was used as difluoromethylation reagent and PhI(OAc)2 was employed as oxidant. Due to the cheap and readily accessible reagents and oxidant as well as the mild reaction conditions, this method is as an efficient and practical strategy for the synthesis of difluoromethyl‐substituted spiro[4.5]trienones.

Difluoromethylthiolator: A Toolbox of Reagents for Difluoromethylthiolation.

Recently, the strategic installation of a fluorine atom or a fluoroalkyl group site-selectively at the specific position of the target molecule has become a routine approach and daily practice for medicinal chemists in their endeavor to fine tune the structure of the lead compound to improve its physicochemical properties such as the cell membrane permeability and metabolic stability. Among many fluoroalkyl groups, the difluoromethylthio group (-SCF2H) has attracted recent intense attention. Largely due to the weak acidity of the proton in the difluoromethylthio group, the difluoromethylthio group is generally considered to be a lipophilic hydrogen-bonding donor and a bioisostere of the hydroxy/thio group that might interact with the heteroatom of the enzyme via a hydrogen bond to improve the binding selectivity of the drug molecule. Besides, the difluoromethylthio group is less lipophilic, less electron-withdrawing, and less stable to the acidic or basic environment than its analogue trifluoromethylthio group (-SCF3), making it easier to regulate the metabolic stability of drug molecules. These beneficial effects render the difluoromethylthio group one of the most favorable functional groups in drug design; consequently, there is an urgent need to develop new strategies for the efficient introduction of the difluoromethylthio group into small molecules under mild conditions. Over the last few decades, several different approaches to the preparation of difluoromethylthiolated compounds have been developed, including the difluoromethylation of thiolated substrates with an electrophilic/nucleophilic difluoromethylating reagent or the insertion of a difluoromethyl carbene into the S-H bond of the thiols. In contrast, we adopt an alternative approach to the preparation of difluoromethylthiolated compounds by late-stage direct difluoromethylthiolation of the specific substrates with a difluoromethylthiolating reagent. With this aim in mind, in the last 6 years we have successfully developed a toolbox of reagents that are capable of the direct introduction of the difluoromethylthio group into the target molecules, including nucleophilic difluoromethylthiolating reagent [(SIPr)AgSCF2H] I, electrophilic difluoromethylthiolating reagent PhthSCF2H II, three optically pure difluoromethylthiolating reagents camphorsultam-SCF2H III, radical difluoromethylthiolating reagent PhSO2SCF2H IV, and reagent PhSO2SCFClH V that could be used for the preparation of 18F-labeled [18F]ArSCF2H. These reagents reacted with a broad range of substrates to get access to difluoromethylthiolated compounds efficiently, thus providing medicinal chemists a powerful weapon for the direct introduction of the difluoromethylthio group into promising molecules during the search for new drugs.

Visible-light induced direct C-H difluoromethylation of quinoxalin-2(1H)-ones by [bis(difluoroacetoxy)iodo]benzene under catalysis-free conditions

Visible light-induced direct C-H difluoromethylation of quinoxalin-2(1 H )-ones by employing [bis(difluoroacetoxy)iodo]benzene as a difluoromethylation reagent is reported for the first time. The inexpensive and readily accessible reagents and the catalysis-Free reaction conditions render this method an alternative and practical strategy for the synthesis of C3-difluoromethylated quinoxalin-2(1 H )-ones. Transition-metal-free trifluoromethylthiolation and difluoromethylthiolation of thiols with trifluoromethanesulfonyl chloride and difluoromethanesulfonyl chloride.

Visible-light induced radical aryldifluoromethylation of N-arylacrylamides by [bis(difluoroacetoxy)iodo]benzene

Visible light-induced radical aryldifluoromethylation of N-arylacrylamides using [bis(difluoroacetoxy)iodo]benzene as a difluoromethylation reagent is reported for the first time. The inexpensive and readily accessible reagents and the mild reaction conditions render this method an alternative and practical strategy for the synthesis of difluoromethyl substituted oxindoles.

Visible-light-initiated tandem synthesis of difluoromethylated oxindoles in 2-MeTHF under additive-, metal catalyst-, external photosensitizer-free and mild conditions

An efficient and eco-friendly protocol for synthesizing difluoromethylated oxindoles through a visible-light induced one-pot tandem reaction of N-arylacrylamides, difluoroacetic acid and PhI(OAc)2 was developed. This reaction proceeded in the absence of any additive, base, metal-catalyst and external photosensitizer, using cheap and easily available CHF2CO2H as the difluoromethylation reagent and bulk biomass-derived 2-MeTHF as the sole solvent. 26 Examples of N-arylacrylamide substrates were investigated, and all of them successfully underwent difluoromethylation to deliver the target products in good to excellent yields.