Aryl Difluoromethyl Research Articles

C−F bond activation enables synthesis of aryl difluoromethyl bicyclopentanes as benzophenone-type bioisosteres

Bioisosteric design has become an essential approach in the development of drug molecules. Recent advancements in synthetic methodologies have enabled the rapid adoption of this strategy into drug discovery programs. Consequently, conceptionally innovative practices would be appreciated by the medicinal chemistry community. Here we report an expeditous synthetic method for synthesizing aryl difluoromethyl bicyclopentane (ADB) as a bioisostere of the benzophenone core. This approach involves the merger of light-driven C−F bond activation and strain-release chemistry under the catalysis of a newly designed N-anionic-based organic photocatalyst. This defluorinative coupling methodology enables the direct conversion of a wide variety of commercially available trifluoromethylaromatic C−F bonds (more than 70 examples) into the corresponding difluoromethyl bicyclo[1.1.1]pentanes (BCP) arenes/difluoromethyl BCP boronates in a single step. The strategy can also be applied to [3.1.1]and [4.1.1]propellane systems, providing access to analogues with different geometries. Moreover, we have successfully used this protocol to rapidly prepare ADB-substituted analogues of the bioactive molecule Adiporon. Biological testing has shown that the ADB scaffold has the potential to enhance the pharmacological properties of benzophenone-type drug candidates.

Accessing structurally diverse aryl difluoromethyl ethers with bromo(difluoro)acetic acid.

We report a new streamlined approach for the difluoromethylation of ubiquitous phenols using inexpensive bromo(difluoro)acetic acid, yielding a wide array of structurally diverse OCF2H-based building blocks in a single step. This method displays broad functional group compatibility and is amenable for effective late-stage diversification and lignin-derived monomers.

Aryl Fluoroalkyl Sulfoxides: Optical Stability and pKa Measurement

AbstractThe enantiomeric separation of aryl trifluoromethyl and difluoromethyl sulfoxides was realized via chiral chromatography. The configurational stability of each set of enantiomers was then studied by thermal enantiomerization. The ΔG≠ values obtained cover a range of 38.2–41.0 kcal mol−1 at 214 °C, thus demonstrating their optical stability at room temperature. However, a shorter half‐life time has been observed for difluoromethyl sulfoxides. Furthermore, the acidities of six aryl difluoromethyl sulfoxides were determined in DMSO by an overlapping indicator method using UV‐visible spectrophotometric titrations. The pKa values fall in range of 20.3–22.5 and differ by about 10 log units compared to non‐fluorinated analogues.

(Arylsulfinyl)difluoromethylation of Alkyl Halides: Facile Access to Diverse Fluorinated Compounds

AbstractA facile and efficient (arylsulfinyl)difluoromethylation of alkyl halides with aryl difluoromethyl sulfoxide (ArSOCF2H) has been developed. The reaction tolerates a variety of functional groups and afford the (arylsulfinyl)difluoromethylated products in moderate to good yields. Reduction of the sulfoxide products can conveniently afford aromatic difluoroalkylsulfides in good yields and the transformation of phenylsulfinyl group to other useful moieties is also accomplished. It is noted that the difluoromethyl heteroaryl sulfoxides (2‐PySOCF2H and BTSOCF2H) give heteroaryl thioethers rather than difluoroalkyled sulfoxides by removal of carbonylfluoride (COF2).

(Het)aryl Difluoromethyl‐Substituted β‐Alkoxyenones: Synthesis and Heterocyclizations

An efficient approach to the preparation of β‐alkoxyenones bearing (het)aryl difluoromethyl substituents is described. The method included acylation of acyclic or cyclic vinyl ethers with (het)aryl difluoroacetyl chlorides. The method worked well for most substrates, except aryl‐substituted derivatives bearing electron‐donating groups in o‐ or p‐positions, and heteroaromatic compounds bearing sufficiently basic nitrogen atom. Synthetic utility of (het)aryl difluoromethyl‐substituted β‐alkoxyenones as CCC bis‐electrophiles was demonstrated by heterocyclizations with common 1,2‐ and 1,3‐bis‐nucleophiles leading to compounds with (het)aryl–CF2–(het)aryl motif, in particular (het)aryl difluoromethyl‐substituted pyrazoles, isoxazoles, and pyrimidines – promising chemotypes for drug discovery.

Difluoromethylation of Phenols and Thiophenols with the S-(Difluo-romethyl)sulfonium Salt: Reaction, Scope, and Mechanistic Study.

A facile and practical approach for the difluoromethylation of phenols and thiophenols was described. Making use of the recently developed bench-stable S-(difluoromethyl)sulfonium salt as the difluorocarbene precursor, a wide variety of diversely functionalized phenols and thiophenols were readily converted to their corresponding aryl difluoromethyl ethers in good to excellent yields in the presence of lithium hydroxide. Chemoselectivity of various O,S-nucleophiles toward difluorocarbene was systematically studied, suggesting the reactivity order ArS- > RS-, ArO- > ROH > RO-, ArSH, ArOH, RSH.

Deoxyfluorination of (Hetero)aryl Aldehydes Using Tetramethylammonium Fluoride and Perfluorobutanesulfonyl Fluoride or Trifluoromethanesulfonic Anhydride

AbstractThis Communication describes the conversion of (hetero)aryl aldehydes into the corresponding (hetero)aryl difluoromethyl products using anhydrous NMe4F in combination with perfluorobutanesulfonyl fluoride or trifluoromethanesulfonic anhydride.

Efficient asymmetric synthesis of aryl difluoromethyl sulfoxides and their use to access enantiopure α-difluoromethyl alcohols

The -CHF2 moiety has shown a growing interest in pharmaceutical and agrochemical applications over the last few years. Its introduction is therefore a current research topic for organic chemists. Several groups have reported the synthesis of difluoromethylated compounds. However, the more challenging enantioselective introduction of the difluoromethyl group has been scarcely described yet. We recently developed a new strategy, based on the use of an enantiopure difluoromethyl sulfoxide used as chiral and traceless auxiliary, for the synthesis of highly enantioenriched α-difluoromethyl alcohols. The first method developed in our laboratory aims to access highly stereoenriched α,α-difluoro-β-hydroxysulfoxides through the condensation of the enantiopure difluoromethyl sulfoxide on carbonyl derivatives. It is noteworthy that highly diastereo- and enantioenriched α,α-difluoro-β-hydroxysulfoxides can also be accessed after the diastereoselective reduction of highly enantioenriched α,α-difluoro-β-ketosulfoxides. Finally, the expected difluoromethyl-substituted alcohols can be obtained after removal of the chiral auxiliary with complete retention of stereoenrichment at carbon.

Copper‐Mediated Di‐ and Monofluoromethanesulfonylation of Arenediazonium Tetrafluoroborates: Probing the Fluorine Effect

A copper‐mediated di‐ and monofluoromethanesulfonylation of arenediazonium tetrafluoroborates using di‐ and monofluoromethanesulfinate reagents provides aryl difluoromethyl (or monofluoromethyl) sulfones in good yields. It was found that the relative reactivity of these sodium fluoroalkanesulfinates in the present reactions decreases in the following order: CH2FSO2Na > CF2HSO2Na > CF3SO2Na.

Strategies for improving the solubility and metabolic stability of griseofulvin analogues

We report two types of modifications to the natural product griseofulvin as strategies to improve solubility and metabolic stability: the conversion of aryl methyl ethers into aryl difluoromethyl ethers at metabolic hotspots and the conversion of the C-ring ketone into polar oximes. The syntheses of the analogues are described together with their solubility, metabolic half-life in vitro and antiproliferative effect in two cancer cell lines. We conclude that on balance, the formation of polar oximes is the most promising strategy for improving the properties of the analogues.

Decarboxylative Trifluoromethylating Reagent [Cu(O2 CCF3 )(phen)] and Difluorocarbene Precursor [Cu(phen)2 ][O2 CCF2 Cl

This article describes the new economic decarboxylative trifluoromethylating reagent [Cu(phen)(O2 CCF3 )] (1; phen=1,10-phenanthroline) and the efficient difluorocarbene precursor [Cu(phen)2 ][O2 CCF2 Cl] (2). Treatment of copper tert-butoxide with phen and subsequent addition of trifluoroacetic acid or chlorodifluoroacetic acid afforded air-stable complexes 1 and 2, respectively, which were characterized by X-ray crystallography. The copper(I) ion in 1 is coordinated by a bidentate phen ligand, a monodentate trifluoroacetate group, and a molecule of CH3 CN in a distorted tetrahedral coordination geometry. The molecular structure of 2 adopts an ionic form that consists of a [Cu(phen)2 ]+ cation and a chlorodifluoroacetate anion. Complex 1 reacted with a variety of aryl and heteroaryl halides to form trifluoromethyl (hetero)arenes in good yields. The corresponding Hammett plot exhibited a linear relationship and a reaction parameter (ρ)=+0.56±0.02, which indicated that the trifluoromethylation reaction proceeded via a nucleophilic reactive species. Complex 2 reacts with phenols to produce aryl difluoromethyl ethers in modest-to-excellent yields. Mechanistic investigations revealed that the difluoromethylation reaction proceeds by initial copper-mediated formation of difluorocarbene and subsequent concerted addition of difluorocarbene to the phenol to form a three-center transition state.

ChemInform Abstract: Synthesis of Aryl Tri‐ and Difluoromethyl Thioethers via a C—H‐Thiocyanation/Fluoroalkylation Cascade.

AbstractThe synthesis of aryl trifluoromethyl thioethers and aryl difluoromethyl thioethers proceed with remarkable regioselectivity for the most electron‐rich, sterically least hindered position of the arene.

Synthesis of aryl tri- and difluoromethyl thioethers via a C-H-thiocyanation/fluoroalkylation cascade.

An AlCl3 -catalyzed CH thiocyanation was discovered and combined with a Langlois-type trifluoromethylation to afford aryl trifluoromethyl thioethers directly from arenes, N-thiocyanatosuccinimide (NTS) and Ruppert-Prakash reagent. An analogous combination with a copper-mediated difluoromethylation gives access to aryl difluoromethyl thioethers. Both processes proceed with exceptional regioselectivity for the most electron-rich, sterically least hindered position of the arene. The sulfur and fluoroalkyl groups originate from different sources, so that the use of expensive, preformed fluoroalkylthiolation reagents is avoided.

Difluoromethylation of 2-hydroxychalcones using sodium 2-chloro-2,2-difluoroacetate as difluoromethylating agent

Difluoromethylation of 2-hydroxychalcones using sodium 2-chloro-2,2-difluoroacetate as the difluoromethylating agent was developed. Under facile conditions, a wide range of aryl difluoromethyl ethers were obtained in yields of 36%–80%. It is noteworthy that the new addition products, 2,2-difluoro-2H-benzofuran derivatives, were also synthesized in the reactions. The yield of 2,2-difluoro-2H-benzofuran derivative could be up to 35% when 3-methyl-2-hydroxychalcone was used as the reactant. A plausible reaction mechanism was proposed.

Synthesis of Difluoromethyl Ethers with Difluoromethyltriflate

Difluoromethyl ethers are found increasingly in pharmaceuticals, agrochemicals, and materials.[1] Aryl difluoromethyl ethers are found in medicinally important compounds that include enzyme inhibitors,[2] anti-HIV agents[3] and atimicrobial agents.[4] Pantoprazole (Protonix®), a proton-pump inhibitor, is among the top 100 pharmaceuticals and contains a difluoromethyl ether.[5]

ChemInform Abstract: N‐Heterocyclic Carbene‐Catalyzed Difluorocarbene Generation and Its Application to Aryl Difluoromethyl Ether Synthesis.

NHC-catalyzed generation of difluorocarbene from trimethylsilyl 2,2-difluoro-2-(fluorosulfonyl)acetate (TFDA) enables the synthesis of enol difluoromethyl ethers starting from cyclohexenones and te...

NHC-catalyzed generation of difluorocarbene and its application to difluoromethylation of oxygen nucleophiles

Controlled generation of difluorocarbene was effected by an NHC catalyst under mild conditions starting from trimethylsilyl 2,2-difluoro-2-fluorosulfonylacetate (TFDA). Cyclohexenones and tetralones were treated with TFDA in the presence of catalytic amounts of N,N′-dimesitylimidazolium chloride and sodium carbonate. The ketones were difluoromethylated with the generated difluorocarbene to afford enol difluoromethyl ethers without difluorocyclopropanation. The ethers thus obtained were dehydrogenated with DDQ to furnish aryl difluoromethyl ethers in high yield. Under similar conditions, secondary amides underwent difluoromethylation selectively on the oxygen atom to give difluoromethyl imidates, which allows the formation of 2-difluoromethoxypyridines.

N-Heterocyclic Carbene-catalyzed Difluorocarbene Generation and its Application to Aryl Difluoromethyl Ether Synthesis

Abstract NHC-catalyzed generation of difluorocarbene from trimethylsilyl 2,2-difluoro-2-(fluorosulfonyl)acetate (TFDA) enables the synthesis of enol difluoromethyl ethers starting from cyclohexenones and tetralones. The resultant enol difluoromethyl ethers were successively dehydrogenated with DDQ to furnish aryl difluoromethyl ethers in good to high yield.

Oxidation of Primary Aliphatic and Aromatic Aldehydes with Difluoro(aryl)-λ3-bromane

Oxidation of primary aliphatic aldehydes with p-trifluoromethylphenyl(difluoro)-λ(3)-bromane in dichloromethane at 0 °C afforded acid fluorides selectively in good yields, while that of aromatic aldehydes in chloroform at room temperature produced aryl difluoromethyl ethers. A larger migratory aptitude of aryl groups compared to primary alkyl groups during a 1,2-shift from carbon to an electron-deficient oxygen atom in bromane(III) Criegee-type intermediates will result in these differences in the reaction courses.

2-Chloro-2,2-difluoroacetophenone: A Non-ODS-Based Difluorocarbene Precursor and Its Use in the Difluoromethylation of Phenol Derivatives

A novel and non-ODS-based (ODS = ozone-depleting substance) preparation of 2-chloro-2,2-difluoroacetophenone (1) was achieved in high yield by using 2,2,2-trifluoroacetophenone as the starting material. Compound 1 was found to act as a good difluorocarbene reagent, which readily reacts with a variety of structurally diverse phenol derivatives 4 in the presence of potassium hydroxide or potassium carbonate to produce aryl difluoromethyl ethers 5 in good yields. This new and easy-to-handle synthetic methodology offers an environmentally friendly alternative to other Freon- or Halon-based difluoromethylating approaches.