1583-83-1

Usage

Uses

Used in Pharmaceutical Industry:
4-(Difluoromethoxy)toluene is used as a key intermediate in the synthesis of various pharmaceutical compounds, contributing to the development of new drugs and medications.
Used in Agrochemical Industry:
4-(DIFLUOROMETHOXY)TOLUENE is utilized as an intermediate in the production of agrochemicals, playing a crucial role in the creation of pesticides and other agricultural chemicals to protect crops and enhance yield.
Used in Chemical Synthesis:
4-(Difluoromethoxy)toluene is employed as an intermediate in the synthesis of a wide range of chemicals, expanding its applications across various industries.
Used as a Solvent:
Due to its solvent properties, 4-(Difluoromethoxy)toluene is used in various chemical processes, facilitating reactions and improving the efficiency of production methods.
Used in Consumer Products:
4-(DIFLUOROMETHOXY)TOLUENE is found in some consumer products, where it may contribute to the product's performance, longevity, or other desired attributes.

InChI:InChI=1/C8H8F2O/c1-6-2-4-7(5-3-6)11-8(9)10/h2-5,8H,1H3

Upstream product

• 75-61-6 dibromodifluoromethane 
• 1192-96-7 potassium p-cresolate 
• 106-44-5 p-cresol 
• 75-46-7 trifluoromethan 
• 65094-22-6 diethyl (bromodifluoromethyl)phosphonate 
• 108-88-3 toluene 
• 33104-40-4 dichloromethyl 4-methylphenyl ether 
• 1864-97-7 p-tolyl formate 
• 104-87-0 4-methyl-benzaldehyde 
• 353-59-3 halon-1211 
• 1717-59-5 2,2-difluoro-2-(fluorosulfonyl)acetic acid 
• 75-45-6 Chlorodifluoromethane 

Downstream Products

• 3447-53-8 4-(difluoromethoxy)benzyl bromide 
• 126300-85-4 2-(4-Difluoromethoxy-benzyl)-2-formylamino-malonic acid diethyl ester 
• 126300-89-8 2-Amino-3-(4-difluoromethoxy-phenyl)-propionic acid 

Relevant academic research and scientific papers

Redox-Neutral TEMPO Catalysis: Direct Radical (Hetero)Aryl C?H Di- and Trifluoromethoxylation

Applications of TEMPO. catalysis for the development of redox-neutral transformations are rare. Reported here is the first TEMPO.-catalyzed, redox-neutral C?H di- and trifluoromethoxylation of (hetero)arenes. The reaction exhibits a broad substrate scope, has high functional-group tolerance, and can be employed for the late-stage functionalization of complex druglike molecules. Kinetic measurements, isolation and resubjection of catalytic intermediates, UV/Vis studies, and DFT calculations support the proposed oxidative TEMPO./TEMPO+ redox catalytic cycle. Mechanistic studies also suggest that Li2CO3 plays an important role in preventing catalyst deactivation. These findings will provide new insights into the design and development of novel reactions through redox-neutral TEMPO. catalysis.

Catalytic radical difluoromethoxylation of arenes and heteroarenes

Intermolecular C-H difluoromethoxylation of (hetero)arenes remains a long-standing and unsolved problem in organic synthesis. Herein, we report the first catalytic protocol employing a redox-active difluoromethoxylating reagent 1a and photoredox catalysts for the direct C-H difluoromethoxylation of (hetero)arenes. Our approach is operationally simple, proceeds at room temperature, and uses bench-stable reagents. Its synthetic utility is highlighted by mild reaction conditions that tolerate a wide variety of functional groups and biorelevant molecules. Experimental and computational studies suggest single electron transfer (SET) from excited photoredox catalysts to 1a forming a neutral radical intermediate that liberates the OCF2H radical exclusively. Addition of this radical to (hetero)arenes gives difluoromethoxylated cyclohexadienyl radicals that are oxidized and deprotonated to afford the products of difluoromethoxylation.

DIFLUOROMETHOXYLATION AND TRIFLUOROMETHOXYLATION COMPOSITIONS AND METHODS FOR SYNTHESIZING SAME

The present invention provides a compound having the structure (I), a processing of making the compound; and a process of using the compound as a reagent for the difluoromethoxylation and trifluoromethoxylation of arenes or heteroarenes.

Difluoromethyl bioisostere: Examining the lipophilic hydrogen bond donor concept

There is a growing interest in organic compounds containing the difluoromethyl group, as it is considered a lipophilic hydrogen bond donor that may act as a bioisostere of hydroxyl, thiol, or amine groups. A series of difluoromethyl anisoles and thioanisoles was prepared and their druglike properties, hydrogen bonding, and lipophilicity were studied. The hydrogen bond acidity parameters A (0.085-0.126) were determined using Abraham's solute 1H NMR analysis. It was found that the difluoromethyl group acts as a hydrogen bond donor on a scale similar to that of thiophenol, aniline, and amine groups but not as that of hydroxyl. Although difluoromethyl is considered a lipophilicity enhancing group, the range of the experimental Δlog P(water-octanol) values (log P(XCF2H) - log P(XCH3)) spanned from -0.1 to +0.4. For both parameters, a linear correlation was found between the measured values and Hammett σ constants. These results may aid in the rational design of drugs containing the difluoromethyl moiety.

Three step procedure for the preparation of aromatic and aliphatic difluoromethyl ethers from phenols and alcohols using a chlorine/fluorine exchange methodology

Difluoromethyl ethers are prepared from phenols in three steps via their respective formate ester derivatives. The formates are first converted to dichloromethyl ethers by treatment with PCl5. These ethers are then induced to undergo chlorine/fluorine exchange to form the respective difluoromethyl ethers. The chlorine/fluorine exchange is carried out by either a room temperature, solvolytic process using THF-5HF or Et3N-3HF as exchange medium, where HF is the ultimate source of fluorine, or by a direct displacement process in sulfolane at 125 C, where KF is the source of fluorine. By one or another of these processes, virtually all phenols, electron-rich and electron-poor, can be converted to their respective difluoromethyl ethers in good yields. Aliphatic alcohols are also able to be converted to their difluoromethyl ether derivatives using the Et3N-3HF exchange medium.

Use of fluoroform as a source of difluorocarbene in the synthesis of difluoromethoxy- and difluorothiomethoxyarenes

Fluoroform, CHF3, a non-ozone-depleting, nontoxic, and inexpensive gas can be used as a difluorocarbene source in a process for the conversion of phenols and thiophenols to their difluoromethoxy and difluorothiomethoxy derivatives. The reactions are carried out at moderate temperatures and atmospheric pressure, using potassium hydroxide as base in a two-phase (water/dioxane or water/acetonitrile) process to provide moderate to good yields of the respective products.

Oxidation of primary aliphatic and aromatic aldehydes with difluoro(aryl)-λ3-bromane

Oxidation of primary aliphatic aldehydes with p- trifluoromethylphenyl(difluoro)-λ3-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.

Utility of silicon tetrafluoride as a catalyst of reactions with xenon difluoride: Fluorinations of phenyl alkenes and benzaldehydes

Application of silicon tetrafluoride to fluorinations with xenon difluoride as a catalyst is investigated. It was found that vic-difluorination of phenyl alkenes and transformation of benzaldehydes to difluoromethoxybenzenes using xenon difluoride are enhanced by silicon tetrafluoride.

A SIMPLE CONVENIENT METHOD FOR PREPARATION OF DIFLUOROMETHYL ETHERS USING FLUOROSULFONYLDIFLUOROACETIC ACID AS A DIFLUOROCARBENE PRECURSOR

In the presence of catalytic amounts of sodium sulfate or cuprous iodide, a variety of alkyl and aryl difluoromethyl ethers were synthesized in moderate yields by the reaction of the corresponding alcohols and phenols with fluorosulfonyldifluoroacetic acid (1) in acetonitrile under mild conditions.Fluorosulfonyldifluoroacetate anion (5) is believed to readily eliminate SO2, CO2 and F(1-), thus liberating CF2:; insertion of difluorocarbene into O-H bonds and its capture by fluorode ion then result in the formation of ethers and by-product CF3H, respectively.

IMPROVEMENT OF THE SYNTHESIS OF ARYL DIFLUOROMETHYL ETHERS AND THIOEHTERS BY USING A SOLID-LIQUID PHASE-TRANSFER TECHNIQUE

A new solid-liquid phase-transfer technique has been used to synthesize aryl difluoromethyl ehters and thioethers.Phenols (or thiophenols) and chlorodifuoromethane, dissolved in a cheap aprotic solvent of low polarity, are contacted with solid sodium hydroxide in the presence of a catalytic amount of tris-(3,6-dioxaheptyl)amine.The work-up of the reaction mixtures is very simple.Although yields are similar in both homogeneous and heterogeneous procedures using phenols, improved yields are obtained for thiophenols when using phase-transfer conditions.